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WO2010123006A1 - Pyrrolidine compound - Google Patents

Pyrrolidine compound Download PDF

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Publication number
WO2010123006A1
WO2010123006A1 PCT/JP2010/057017 JP2010057017W WO2010123006A1 WO 2010123006 A1 WO2010123006 A1 WO 2010123006A1 JP 2010057017 W JP2010057017 W JP 2010057017W WO 2010123006 A1 WO2010123006 A1 WO 2010123006A1
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Prior art keywords
alkyl
atom
optionally substituted
compound
alkoxy
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PCT/JP2010/057017
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French (fr)
Japanese (ja)
Inventor
真人 吉川
琢 亀井
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Definitions

  • the present invention relates to a pyrrolidine compound having excellent monoamine reuptake inhibitory activity and useful as a therapeutic / preventive agent for depression, anxiety, attention deficit / hyperactivity disorder, stress urinary incontinence and the like.
  • the monoamine neurotransmitters serotonin (5-HT), norepinephrine (NE), and dopamine (DA) are widely present in the brain and have various functions such as neurotransmission via their receptors. .
  • serotonin transporter: SERT, norepinephrine transporter: NET and dopamine transporter: DAT neurotransmission Ends.
  • Compounds showing inhibitory activity on monoamine reuptake are known to be effective in various diseases including neuropsychiatric diseases such as depression, and are widely used as therapeutic agents.
  • Triple Reuptake Inhibitor A compound that inhibits three types of reuptake, serotonin, norepinephrine, and dopamine, is called Triple Reuptake Inhibitor, and is expected to be used as a therapeutic agent for neuropsychiatric disorders and the like.
  • Depressive drugs include tricyclic antidepressants (TCA) typified by imipramine, selective serotonin reuptake inhibitors (SSRI) typified by fluoxetine, and selective serotonin norepinephrine typified by venlafaxine.
  • TCA tricyclic antidepressants
  • SSRI selective serotonin reuptake inhibitors
  • SNRI norepinephrine / dopamine reuptake inhibitors such as bupropion, monoamine oxidase inhibitors, etc. are used. From a point etc., it cannot necessarily be said that satisfaction is high (refer nonpatent literatures 1 and 2).
  • TCA, SSRI and SNRI are not only for depression, but also for neuropsychiatric disorders such as anxiety, attention deficit / hyperactivity disorder, neurodegenerative diseases such as Alzheimer's disease, diabetic pain, myofibrosis, etc. There are also reports that it is useful as a treatment for pain in the stomach or as a treatment for gastrointestinal diseases such as irritable bowel syndrome.
  • cycloalkylamine derivatives see Patent Documents 1 and 2
  • pyrrolidine derivatives see Patent Documents 3 and 4
  • bicycloamine derivatives Patent Documents 5 and 6
  • indole derivatives see Patent Document 7
  • bicyclo derivatives Patent Documents 8-10 and the like are known.
  • Patent Document 11 discloses a compound useful as a therapeutic agent for central nervous disease such as depression and anxiety caused by monoamine reuptake inhibitory action.
  • Ar represents a disubstituted phenyl group
  • R 1 and R 2 independently represent hydrogen, C 1-10 alkyl, and the like
  • R 3 represents hydrogen, C 1-6 alkyl, and the like.
  • Patent Document 12 includes, for example, formulas as therapeutic agents for diabetes, obesity, and metabolic diseases by 11- ⁇ -hydroxysteroid dehydrogenase (11 ⁇ HSD) inhibitory action.
  • 11 ⁇ HSD 11- ⁇ -hydroxysteroid dehydrogenase
  • Patent Document 13 describes, as an anti-obesity drug based on melanocortin receptor agonist activity, for example, a formula
  • Patent Document 14 discloses an intermediate of a compound useful as a therapeutic agent for diabetic complications due to laminin / nidogen interaction inhibitory activity.
  • Patent Document 15 discloses a compound useful as a therapeutic agent for central nervous system diseases caused by increased brain levels of catecholamine, dopamine, and norepinephrine.
  • Patent Document 16 discloses a compound useful as a therapeutic agent for central nervous system diseases due to an increase in brain levels of catecholamine, dopamine, and norepinephrine.
  • Ar represents phenyl, thiophenyl, furanyl, etc.
  • R 1 and R 2 independently represent fluorine or chlorine
  • R 3 represents hydrogen, methyl, etc.
  • X represents fluorine or hydroxy.
  • Monoamine serotonin, norepinephrine, dopamine, etc.
  • reuptake inhibitory activity useful as a preventive or therapeutic agent for depression, anxiety, attention deficit / hyperactivity disorder, stress urinary incontinence, etc.
  • Development of a compound having excellent properties in terms of action time, specificity, low toxicity and the like is desired.
  • the present invention is a compound having a chemical structure different from known compounds including the above-mentioned compounds, having a monoamine reuptake inhibitory activity and the like, and novel such as depression, anxiety, attention deficit / hyperactivity disorder, stress urinary incontinence
  • the purpose is to provide preventive and therapeutic drugs.
  • X is optionally substituted lower alkylene, —CO—, —CH 2 CO— or an optionally substituted 5-membered heterocyclic ring
  • R 1 is hydroxy, cyano, optionally substituted amino, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted phenyl, optionally substituted mercapto, Substituted sulfonyl or optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group
  • R 2 represents a hydrogen atom, a halogen atom, an optionally substituted lower alkyl, or an optionally substituted alkoxycarbonyl
  • R 3 is a hydrogen atom or lower alkyl
  • R 4 to R 13 are the same or different and each represents a hydrogen atom, a halogen atom or lower alkyl, In this case, At least one group of R 9 to R 13 represents a halogen atom or lower alkyl, or R 4 to R 9, R 12 and R 13 are the same
  • R 2 is a hydrogen atom and X—R 1 is —COOH
  • R 2 is a hydrogen atom, X is —CO—
  • R 1 is optionally substituted lower alkoxy
  • trans-N-2-adamantyl -3- (4-chlorophenyl) -prolinamide and
  • (3R) -3- (2-naphthalenyl) -L-prolyl-L-asparaginyl-L-alanyl-L-valineamide) ].
  • R 10 and R 11 are the same or different and are a hydrogen atom or a halogen atom (provided that at least one of R 10 and R 11 is a halogen atom), R 9 , R 12 and R 13 are all hydrogen atoms, the compound according to the above [1] or a salt thereof, [3] The compound or a salt thereof according to the above [1], wherein R 10 and R 11 are chlorine atoms, and R 9 , R 12 and R 13 are all hydrogen atoms, [4] X represents C 1-6 alkylene optionally substituted with 1 to 4 C 1-6 alkyl, —CO—, —CH 2 CO—, or a nitrogen atom, a sulfur atom and A 5-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from oxygen atoms, R 1 is (1) hydroxy, (2) cyano, (3) mono- or di-C 1-6 alkylamino, (4) C 3-6 cycl
  • R 1 is (1) a nitrogen atom other than a carbon atom and one nitrogen atom, which may be substituted with 1 to 3 substituents selected from C 1-6 alkyl, oxo, hydroxy and hydroxy C 1-6 alkyl; A 5- or 6-membered saturated nitrogen-containing heterocyclic group which may contain one heteroatom selected from oxygen atoms, or (2) C 1-6 alkyl, amino, C 3-6 cycloalkyl, C 1 -6 alkoxy C 1-6 alkyl, halogen atom, C 1-6 alkoxy-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylsulfonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, carbamoyl and C 1 Represents an amino optionally substituted with 1 or 2 substituents selected from -6 alkoxycarbamoyl; R 2 to R 9 represent a hydrogen atom, R 10 represents a halogen atom, R 11 represents a hydrogen
  • R 1 is (1) pyrrolidinyl optionally substituted with one substituent selected from hydroxy and hydroxy C 1-6 alkyl, or (2) C 1-6 alkyl, C 1-6 alkyl-carbonyl, C 1- It represents alkyl kill, aminosulfonyl, an amino substituted with 1 or 2 substituents selected from carbamoyl and mono- -C 1-6 alkoxy carbamoyl, R 2 to R 9 represent a hydrogen atom, R 10 and R 11 represent a halogen atom, R 12 and R 13 represent a hydrogen atom, The compound or a salt thereof according to the above [1], [7] ( ⁇ )-2,3-cis-3- (3,4-dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide or a salt thereof, [8] [(2R, 3R) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] [(3S) -3-hydroxypyrroli
  • the compound of the present invention or a prodrug thereof has excellent monoamine (serotonin, norepinephrine, dopamine, etc.) reuptake inhibitory activity, for example, depression, anxiety, attention deficit / hyperactivity disorder, stress urinary incontinence, etc. It is useful as a preventive and therapeutic drug for
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • lower alkyl includes linear or branched alkyl, for example, C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl). , Tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl, hexyl, 2-methylpentyl, 3-methylpentyl, 1,2-dimethylbutyl, 1,2, 2-trimethylpropyl etc.), preferably C 1-4 alkyl.
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl.
  • Tert-butyl 1-methylpropyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1,2-
  • lower alkoxy includes linear or branched alkoxy, for example, C 1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- Butoxy, tert-butoxy, 1-methylpropoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1,2-dimethylpropoxy, hexyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 1 , 2-dimethylbutoxy, 1,2,2-trimethylpropoxy, etc.), preferably C 1-4 alkoxy.
  • C 1-6 alkoxy eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- Butoxy, tert-butoxy, 1-methylpropoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1,2-dimethylprop
  • alkoxycarbonyl includes linear or branched alkoxycarbonyl, for example, C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl) , Butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), preferably C 1-4 alkoxy-carbonyl.
  • lower alkylene includes linear alkylene, for example, C 1-6 alkylene (eg, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene), preferably C 1-4 alkylene is mentioned.
  • C 1-6 alkylene eg, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene
  • examples of the “cyclic amino” of “optionally substituted cyclic amino” include 1-azetidinyl, 1-pyrrolidinyl, piperidino, thiomorpholino, morpholino, 1-piperazinyl, 1-pyrrolyl, 1- Examples thereof include 3- to 8-membered (preferably 5- or 6-membered) cyclic amino such as imidazolyl.
  • the “5-membered heterocycle” of the “optionally substituted 5-membered heterocycle” includes 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom ( 5- to 5-membered heterocyclic ring is preferable.
  • Aromatic heterocycles eg, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, imidazolidine, pyrazolidine, oxadiazolidine (eg, 1,2,4-oxadiazolidine, 1,3,4) -Oxadiazolidine), thiadiazolidine (eg, 1,2,4-thiadiazolidine, 1,3,4-thiadiazolidine), pyrroline, oxazoline, isoxazoline, thiazoline, isothiazoline, imidazoline, pyrazoline, oxadiazo Phosphorus (e
  • the “4- to 10-membered nitrogen-containing heterocyclic group” of the “optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group” includes a nitrogen atom in addition to the carbon atom and one nitrogen atom, Examples thereof include a 4- to 10-membered nitrogen-containing heterocyclic group which may contain 1 to 3 (preferably 1 or 2, more preferably 1) heteroatoms selected from a sulfur atom and an oxygen atom.
  • the “4- to 10-membered nitrogen-containing heterocyclic group” of the “optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group” may contain 1 to 3 (preferably 1 or 2, more preferably 1) heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom 4- to 10-membered (preferably 5- or 6-membered) saturated or unsaturated (preferably saturated) nitrogen-containing heterocyclic group (preferably non-aromatic nitrogen-containing heterocyclic group) (for example, azetidinyl, pyrrolidinyl, piperidinyl) , Morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl (eg, 1,4-diazepanyl), oxazepanyl (eg, 1,4-oxazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl
  • the “fused heteroaromatic ring” of the “optionally substituted fused heteroaromatic ring” formed by R 10 and R 11 together with the adjacent benzene ring includes a nitrogen atom, sulfur other than the carbon atom 9- to 14-membered (preferably 9- or 10-membered) condensed heteroaromatic ring containing 1 or 2 heteroatoms selected from atoms and oxygen atoms (for example, benzofuran, isobenzofuran, benzo [b] thiophene, benzo [c] Thiophene, indole, isoindole, benzimidazole, indazole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, cinnoline, phenanthridine, acridine, phenazine and the like.
  • the “lower alkyl” of the “optionally substituted lower alkyl” may have, (1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), (2) cyano, (3) hydroxy, (4) Nitro, (5) Formyl, (6) amino, (7) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, Ethylmethylamino), (8) C 1-6 alkyl-carbonylamino (preferably C 1-4 alkyl-carbonylamino) (eg, acetylamino, ethylcarbonylamino, etc.), (9) C 1-6 alkoxy-carbonylamino (preferably C 1-4 alkoxy-carbonylamino) (eg,
  • the “lower alkyl” of the “optionally substituted lower alkyl” may have The thing similar to a good substituent is mentioned.
  • the number of substituents is 1 to 4, preferably 1 to 3.
  • the “alkoxycarbonyl” of the “optionally substituted alkoxycarbonyl” may have, the “lower alkyl” of the “optionally substituted lower alkyl” may have The thing similar to a good substituent is mentioned.
  • the number of substituents is 1 to 4, preferably 1 to 3.
  • the “lower alkylene” of the “lower alkylene which may be substituted” may have, (1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), (2) cyano, (3) hydroxy, (4) Nitro, (5) optionally substituted lower alkyl (preferably C 1-6 alkyl, more preferably C 1-4 alkyl) Substituents selected from the above and the like. The number of substituents is 1 to 4, preferably 1 to 3.
  • the “mercapto” of the “optionally substituted mercapto” may have, (1) C 1-6 alkyl (preferably C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, tert -Pentyl, 1,2-dimethylpropyl, hexyl, 2-methylpentyl, 3-methylpentyl, 1,2-dimethylbutyl, 1,2,2-trimethylpropyl), (2) C 2-6 alkenyl (eg, ethenyl, 1-propenyl, 2-propenyl), (3) C 2-6 alkynyl (eg, ethynyl, 1-propynyl, 2-propynyl), (4) C 6-14 aryl (eg, phenyl, 1-na
  • Examples of the substituent that the “sulfonyl” of the “substituted sulfonyl” may have include the same substituents as the substituent that the “mercapto” of the “optionally substituted mercapto” may have. It is done.
  • phenyl of “optionally substituted phenyl” may have, (A) the substituent which the “lower alkyl” of the “optionally substituted lower alkyl” may have, and (b) (1) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom) , iodine), hydroxy and C 1-6 alkoxy (preferably C 1-4 alkoxy) (e.g., methoxy, ethoxy, to 1 selected from propoxy) optionally substituted with 1-3 substituents C 1 -6 alkyl (preferably C 1-4 alkyl) (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl, hexyl,
  • the substituent that the “cyclic amino” of the “optionally substituted cyclic amino” may have the oxo and the “phenyl” of the “optionally substituted phenyl” may have The thing similar to a good substituent is mentioned.
  • the number of substituents is 1 to 4, preferably 1 to 3.
  • the “phenyl” of the above-mentioned “optionally substituted phenyl” has.
  • the thing similar to the substituent which may be mentioned is mentioned.
  • the number of substituents is 1 to 4, preferably 1 to 3, and more preferably 1 or 2.
  • Examples of the substituent that the “4- to 10-membered nitrogen-containing heterocyclic group” in the “optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group” may have include oxo and the above-mentioned “substituted” Examples thereof include the same substituents that the “phenyl” of “may be phenyl” may have.
  • the number of substituents is 1 to 4, preferably 1 to 3.
  • the substituent that the “naphthalene ring” of the “optionally substituted naphthalene ring” or the “fused heteroaromatic ring” of the “optionally substituted condensed heteroaromatic ring” may have, the above-mentioned “ The thing similar to the substituent which "phenyl” of "the phenyl which may be substituted” may have is mentioned.
  • the number of substituents is 1 to 4, preferably 1 to 3.
  • Saturated non-aromatic nitrogen-containing heterocyclic group eg, thiomorpholinyl, piperazinyl, morpholinyl
  • a sulfonylamino substituted with one substituent selected from (14) (a) (i) amino optionally mono- or di-substituted with C 1-6 alkyl (preferably amino optionally mono- or di-substituted with C 1-4 alkyl, For example, amino, ethylamino, ethylmethylamino), (Ii) oxo, (Iii) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) (Preferably 1 or 2, more preferably 1) 4 to 10 membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group such as morpholinyl, Piperazin
  • C 1-6 alkoxycarbamoyl means mono- or di-C 1-6 alkoxycarbamoyl.
  • the “optionally substituted lower alkylene” represented by X is 1 to 4 selected from lower alkyl (preferably C 1-6 alkyl, more preferably C 1-4 alkyl), halogen atom and hydroxy And C 1-6 alkylene (preferably C 1-4 alkylene) which may be substituted with these substituents.
  • Another preferred embodiment of the “optionally substituted lower alkylene” represented by X is C 1-6 alkylene.
  • the “optionally substituted 5-membered heterocyclic ring” represented by X may further have a substituent at a substitutable position in addition to R 1 .
  • the “5-membered heterocycle” of the “optionally substituted 5-membered heterocycle” represented by X includes 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to the carbon atom ( A 5-membered aromatic heterocycle containing 1 to 3 is preferred.
  • Examples include azole, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole and the like.
  • oxadiazole eg, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane
  • thiadiazole eg, 1,2 , 3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, and more preferably oxadiazole (eg, 1,2,4-oxadiazole, 1,3,4-).
  • the “5-membered heterocycle” of the “optionally substituted 5-membered heterocycle” represented by X may have, (1) a halogen atom, (2) hydroxy, and (3) hydroxy, and C 1-6 alkoxy (preferably C 1-4 alkoxy) 1 to 3 substituents optionally substituted by C 1-6 alkyl selected from (preferably C 1-4 alkyl) 1 to 3 (preferably 1 or 2) substituents selected from
  • the “optionally substituted 5-membered heterocycle” represented by X is a 5-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. Is preferred.
  • the X, 1 to the four C 1-6 alkyl optionally substituted by C 1-6 alkylene (preferably, optionally substituted with one to four C 1-4 alkyl C 1- 4- alkylene), —CO—, —CH 2 CO— or a 5-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms (eg, 1, 2 , 4-oxadiazole, 1,3,4-oxadiazole).
  • Another preferred example of X is C 1-6 alkylene (preferably C 1-4 alkylene), —CO—, —CH 2 CO—, and among them, C 1-6 alkylene (preferably, C 1-4 alkylene), —CO—.
  • R 1 As the “optionally substituted amino” represented by R 1 , (1) amino, (2) Mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, di-) Propylamino, ethylmethylamino, etc.), (3) C 3-6 cycloalkylamino (eg, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino), (4) Hydrazino, (5) mono- or di- (C 1-6 alkylsulfonyl) amino (preferably mono- or di- (C 1-4 alkylsulfonyl) amino, eg methylsulfonylamino), (6) mono- or di- (C 1-6 alkyl-carbonyl
  • Saturated non-aromatic nitrogen-containing heterocyclic group eg, thiomorpholinyl, piperazinyl, morpholinyl
  • a sulfonylamino substituted with one substituent selected from (12) (a) (i) amino optionally mono- or di-substituted with C 1-6 alkyl (preferably amino optionally mono- or di-substituted with C 1-4 alkyl, For example, amino, ethylamino, ethylmethylamino), (Ii) oxo, (Iii) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) (Preferably 1 or 2, more preferably 1) 4 to 10 membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group such as morpholinyl, Piperazin
  • R 1 As another preferred embodiment of the “optionally substituted amino” represented by R 1 , (1) mono- or di-C 1-6 alkylamino, (2) C 3-6 cycloalkylamino, (3) Hydrazino, (4) C 1-6 alkoxy C 1-6 alkyl, Halogen atoms, C 1-6 alkoxy-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylsulfonyl, Aminosulfonyl, C 1-6 alkylaminosulfonyl, Examples include carbamoyl and amino optionally substituted with one or two substituents selected from C 1-6 alkoxycarbamoyl.
  • R 1 As still another preferred embodiment of the “optionally substituted amino” represented by R 1 , C 1-6 alkyl, amino, C 3-6 cycloalkyl, C 1-6 alkoxy C 1-6 alkyl, Halogen atoms, C 1-6 alkoxy-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylsulfonyl, Aminosulfonyl, C 1-6 alkylaminosulfonyl, And amino optionally substituted with one or two substituents selected from carbamoyl and C 1-6 alkoxycarbamoyl.
  • R 1 As the “optionally substituted amino” represented by R 1 , (1) amino, (2) Mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, di-) Propylamino, ethylmethylamino, etc.), (3) Hydrazino, (4) mono- or di- (C 1-6 alkylsulfonyl) amino (preferably mono- or di- (C 1-4 alkylsulfonyl) amino, eg methylsulfonylamino), (5) mono- or di- (C 1-6 alkyl-carbonyl) amino (preferably mono- or di- (C 1-4 alkyl-carbonyl) amino, eg methylcarbonylamino), (6) mono- or di- (C 1-6 alkoxy-carbonyl) amino
  • Saturated) non-aromatic nitrogen-containing heterocyclic group (eg, thiomorpholinyl, piperazinyl, morpholinyl) Sulfonylamino substituted with one substituent selected from: and (11) (a) (i) amino optionally mono- or di-substituted with C 1-6 alkyl (preferably C 1 Amino optionally mono- or di-substituted with -4 alkyl, such as amino, ethylamino, ethylmethylamino), (Ii) oxo, (Iii) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) (Preferably 1 or 2, more preferably 1) 4 to 10 membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group such as morpholinyl, Pipe
  • the “optionally substituted lower alkyl” represented by R 1 is C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy (preferably C 1 -4 alkyl, such as methyl, ethyl, isopropyl).
  • the “optionally substituted lower alkoxy” represented by R 1 is C 1-6 alkoxy optionally substituted with 1 to 3 substituents selected from the following (a) to (f): (Preferably C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.) (A) a halogen atom, (B) hydroxy, (C) oxo, (D) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino, such as ethylamino), (E) a 4- to 10-membered saturated heterocyclic group (eg, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl), and (f) 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom)
  • phenyl represented by R 1 , (1) a halogen atom, (2) cyano, (3) hydroxy, (4) Nitro, (5) Formyl, (6) amino, (7) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino), (8) C 1-6 alkyl-carbonylamino (preferably C 1-4 alkyl-carbonylamino), (9) C 1-6 alkoxy-carbonylamino (preferably C 1-4 alkoxy-carbonylamino), (10) C 1-6 alkoxy (preferably C 1-4 alkoxy) optionally substituted by 1 to 3 halogen atoms, (11) C 1-6 alkyl-carbonyloxy (preferably C 1-4 alkyl-carbonyloxy), (12) Carboxy, (13) C 1-6 alkoxy - carbonyl (preferably C 1-4 alkoxy - carbonyl), and (14) 1 to 3 halogen atoms optionally substituted by a C 1-6 alky
  • the “4- to 10-membered nitrogen-containing heterocyclic group” of the “optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group” represented by R 1 is a nitrogen atom in addition to a carbon atom and one nitrogen atom.
  • a 4- to 10-membered saturated non-aromatic nitrogen-containing heterocycle which may contain 1 to 3 (preferably 1 or 2, more preferably 1) heteroatoms selected from sulfur atom and oxygen atom Groups as well as phthalimide are preferred.
  • Examples of the 4- to 10-membered saturated non-aromatic nitrogen-containing heterocyclic group include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl (eg, 1,4-diazepanyl), oxazepanyl (eg, 1, 4-oxazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, pyrazolidinyl, oxadiazolidinyl (eg, 1,2,4-oxadiazolidinyl, 1,3,4-oxadiazinyl) Lysinyl), thiadiazolidinyl (eg, 1,2,4-thiadiazolidinyl, 1,3,4-thiadiazolidinyl), 1,3,8-triazaspir
  • the saturated non-aromatic nitrogen-containing heterocyclic group may contain one heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to the carbon atom and one nitrogen atom.
  • 4- to 10-membered saturated non-aromatic nitrogen-containing heterocyclic group more preferably 1,3,8-triazaspiro [4.5] decanyl, azetidinyl, thiazolidinyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl .
  • the 4- to 10-membered saturated non-aromatic nitrogen-containing heterocyclic group and phthalimide are preferably bonded to X through a nitrogen atom.
  • the “4- to 10-membered nitrogen-containing heterocyclic group” of the “optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group” represented by R 1 may have, (1) a halogen atom (eg, fluorine atom), (2) hydroxy, (3) hydroxy, and C 1-6 alkoxy (preferably C 1-4 alkoxy) 1 to 3 substituents optionally substituted by C 1-6 alkyl selected from (preferably C 1-4 alkyl, Eg methyl), (4) optionally substituted C 1-6 alkoxy (preferably C 1-4 alkoxy, such as methoxy), (5) an optionally substituted carbamoyl (preferably mono or di-C 1-6 alkyl-carbamoyl, more preferably mono or di-C 1-4 alkyl-carbamoyl, eg dimethylcarbamoyl), and (6) oxo 1 to 3 substituents selected from
  • Examples of the “optionally substituted mercapto” represented by R 1 include a mercapto optionally substituted with C 1-6 alkyl (preferably C 1-4 alkyl, such as methyl). , Ethylthio, propylthio, isopropylthio, butylthio.
  • “Substituted sulfonyl” represented by R 1 includes sulfonyl substituted with C 1-6 alkyl (preferably C 1-4 alkyl, such as methyl), and examples thereof include methylsulfonyl, ethylsulfonyl, propylsulfonyl, Examples include isopropylsulfonyl and butylsulfonyl.
  • R 1 (1) hydroxy, (2) cyano, (3) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, di-) Propylamino, ethylmethylamino, etc.), (4) C 3-6 cycloalkylamino (eg, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino), (5) Hydrazino, (6) C 1-6 alkyl (preferably C 1-4 alkyl such as methyl, ethyl, isopropyl) optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy, (7) C 1-6 alkoxy optionally substituted with 1 to 3 substituents selected from the following (a)
  • Saturated non-aromatic nitrogen-containing heterocyclic group eg, thiomorpholinyl, piperazinyl, morpholinyl
  • R 1 As another preferred embodiment of R 1 , (1) hydroxy, (2) cyano, (3) mono- or di-C 1-6 alkylamino, (4) C 3-6 cycloalkylamino, (5) Hydrazino, (6) C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy, (7) C 1-6 alkoxy optionally substituted by 1 to 3 substituents selected from a halogen atom and hydroxy, (8) phenyl, (9)
  • substituents selected from the following (a) to (e), selected from nitrogen atom, sulfur atom and oxygen atom A 4- to 10-membered saturated nitrogen-containing heterocyclic group which may contain one heteroatom, (A) a halogen atom, (B) hydroxy, (C) hydroxy, and C 1-6 1 to 3 substituents optionally substituted by C 1-6 alkyl selected from alkoxy, (D) C 1-6 alk
  • R 1 (1) C 1-6 alkyl, Oxo, One heteroatom selected from a nitrogen atom and an oxygen atom, in addition to a carbon atom and one nitrogen atom, optionally substituted by 1 to 3 substituents selected from hydroxy and hydroxy C 1-6 alkyl A 5- or 6-membered saturated nitrogen-containing heterocyclic group which may be contained, and (2) C 1-6 alkyl, amino, C 3-6 cycloalkyl, C 1-6 alkoxy C 1-6 alkyl, Halogen atoms, C 1-6 alkoxy-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylsulfonyl, Aminosulfonyl, C 1-6 alkylaminosulfonyl, And amino optionally substituted with one or two substituents selected from carbamoyl and C 1-6 alkoxycarbamoyl.
  • Halogen atom represented by R 2 include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom.
  • the “optionally substituted lower alkyl” represented by R 2 is 1 selected from a halogen atom (for example, a chlorine atom), hydroxy and C 1-6 alkoxy (preferably C 1-4 alkoxy, for example, methoxy). C 1-6 alkyl (preferably C 1-4 alkyl such as methyl) which may be substituted with 3 substituents.
  • a halogen atom for example, a chlorine atom
  • C 1-6 alkoxy preferably C 1-4 alkoxy, for example, methoxy
  • C 1-6 alkyl preferably C 1-4 alkyl such as methyl
  • the “optionally substituted alkoxycarbonyl” represented by R 2 is substituted with 1 to 3 substituents selected from hydroxy and C 1-6 alkoxy (preferably C 1-4 alkoxy). And C 1-6 alkoxy-carbonyl (preferably C 1-4 alkoxy-carbonyl). Of these, C 1-6 alkoxy-carbonyl is preferable.
  • alkoxycarbonyl represented by R 2
  • C 1-6 alkoxy-carbonyl is preferable, and C 1-4 alkoxy-carbonyl is more preferable.
  • R 2 (1) a hydrogen atom, (2) C 1 -C 1 which may be substituted with 1 to 3 substituents selected from halogen atom (eg chlorine atom), hydroxy and C 1-6 alkoxy (preferably C 1-4 alkoxy, eg methoxy) 6 alkyl (preferably C 1-4 alkyl, such as methyl) or (3) C 1-6 alkoxy-carbonyl (preferably C 1-4 alkoxy-carbonyl) is preferred, Substituted with 1 to 3 substituents selected from (1) a hydrogen atom, or (2) a halogen atom (eg chlorine atom), hydroxy and C 1-6 alkoxy (preferably C 1-4 alkoxy, eg methoxy) More preferably C 1-6 alkyl (preferably C 1-4 alkyl, eg methyl), More preferred is a hydrogen atom.
  • halogen atom eg chlorine atom
  • hydroxy and C 1-6 alkoxy preferably C 1-4 alkoxy, eg methoxy
  • 6 alkyl
  • R 3 represents a hydrogen atom or lower alkyl.
  • C 1-6 alkyl is preferable, and C 1-4 alkyl is more preferable.
  • R 3 is preferably a hydrogen atom or C 1-6 alkyl (preferably methyl, ethyl). R 3 is more preferably a hydrogen atom.
  • R 4 to R 8 are the same or different and each represents a hydrogen atom, a halogen atom or lower alkyl.
  • the “halogen atom” represented by R 4 to R 8 include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the “lower alkyl” represented by R 4 to R 8 is preferably C 1-6 alkyl, more preferably C 1-4 alkyl.
  • R 4 to R 8 are the same or different and are preferably a hydrogen atom, a halogen atom or C 1-6 alkyl (preferably C 1-4 alkyl), more preferably a hydrogen atom.
  • R 9 to R 13 are the same or different and each represents a hydrogen atom, a halogen atom or lower alkyl, and in this case, at least one group of R 9 to R 13 represents a halogen atom or a lower alkyl group, or R 9, R 12 and R 13 are the same or different and each represents a hydrogen atom, a halogen atom or lower alkyl, and each of R 10 and R 11 may be substituted together with the adjacent benzene ring. It forms a naphthalene ring or an optionally substituted fused heteroaromatic ring. Particularly preferably, R 9 to R 13 are the same or different and each represents a hydrogen atom, a halogen atom or C 1-6 alkyl.
  • At least one group of R 9 to R 13 is a halogen atom or C 1 1-6 alkyl, or, R 9, R 12 and R 13 are the same or different, a hydrogen atom, a halogen atom or C 1-6 alkyl, R 10 and R 11 are, benzene, each of which adjacent Together with the ring, it forms a naphthalene ring.
  • halogen atom represented by R 9 to R 13
  • examples of the “halogen atom” represented by R 9 to R 13 include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Preferably they are a fluorine atom or a chlorine atom, More preferably, it is a chlorine atom.
  • the “lower alkyl” represented by R 9 to R 13 is preferably C 1-6 alkyl, more preferably C 1-4 alkyl.
  • the optionally substituted naphthalene ring formed by R 10 and R 11 together with the adjacent benzene ring is 1 to 3 substituents selected from halogen atoms (for example, fluorine atoms). An optionally substituted naphthalene ring is exemplified.
  • the optionally substituted condensed heteroaromatic ring formed by R 10 and R 11 together with the adjacent benzene ring is 1 to 3 substituents selected from halogen atoms (for example, chlorine atoms) 9- to 14-membered (preferably 9- or 10-membered) condensed heteroaromatic ring containing 1 or 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom, optionally substituted by a group ( Preferably, indazole is used.
  • R 10 and R 11 are the same or different and are a hydrogen atom or a halogen atom (provided that at least one of R 10 and R 11 is a halogen atom), and R 9 , R 12 and R 13 are all hydrogen An atom is preferred.
  • R 10 and R 11 are chlorine atoms
  • R 9 , R 12 and R 13 are all hydrogen atoms.
  • Examples of the optionally substituted naphthalene ring or the optionally substituted condensed heteroaromatic ring formed by R 10 and R 11 together with the adjacent benzene ring include (1) a halogen atom, (2) hydroxy, (3) C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms (preferably C 1-4 alkyl), and (4) optionally substituted with 1 to 3 halogen atoms C 1-6 alkoxy (preferably C 1-4 alkoxy)
  • the condensed heteroaromatic ring is preferably a 9- to 14-membered (preferably 9- or 10-membered) condensed heteroaromatic ring containing 1 or 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom.
  • Examples include benzofuran, isobenzofuran, benzo [b] thiophene, benzo [c] thiophene, indole, isoindole, indazole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, cinnoline and the like.
  • R 4 to R 9, R 12 and R 13 are the same or different and each represents a hydrogen atom, a halogen atom or C 1-6 alkyl (preferably C 1-4 alkyl), and R 10 and R 11 are each It is preferable to form a naphthalene ring or a condensed heteroaromatic ring together with an adjacent benzene ring.
  • R 4 to R 9, R 12 and R 13 all represent a hydrogen atom, and R 10 and R 11 together with an adjacent benzene ring form a naphthalene ring or a condensed heteroaromatic ring. Is more preferable.
  • Preferred examples of compound (I) include X is 1 to 4 amino C 1-6 alkyl optionally substituted by C 1-6 alkylene (preferably, one to four C 1-4 optionally C 1-4 optionally substituted by alkyl Alkylene), —CO—, —CH 2 CO—, or a 5-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms (eg, 1, 2, 4-oxadiazole, 1,3,4-oxadiazole)
  • R 1 is (1) hydroxy, (2) cyano, (3) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, di-) Propylamino, ethylmethylamino, etc.), (4) C 3-6 cycloalkyla
  • Saturated non-aromatic nitrogen-containing heterocyclic group eg, thiomorpholinyl, piperazinyl, morpholinyl
  • compound (I) examples include X is 1 to 4 amino C 1-6 alkyl optionally substituted by C 1-6 alkylene (preferably, one to four C 1-4 optionally C 1-4 optionally substituted by alkyl Alkylene), —CO—, —CH 2 CO—, or a 5-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms (eg, 1, 2, 4-oxadiazole, 1,3,4-oxadiazole)
  • R 1 is (1) hydroxy, (2) cyano, (3) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino), (4) C 3-6 cycloalkylamino, (5) Hydrazino, (6) C 1-6 alkyl (preferably C 1-4 alkyl) optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy, (7) C 1-6 alkoxy (preferably C 1-4 alkoxy) optionally
  • X and R 1 include the following embodiments.
  • X is 1 to 4 amino C 1-6 alkyl optionally substituted by C 1-6 alkylene (preferably, one to four C 1-4 optionally C 1-4 optionally substituted by alkyl Alkylene)
  • R 1 is (1) hydroxy, (2) cyano, (3) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, di-) Propylamino, ethylmethylamino, etc.),
  • C 1-6 alkyl preferably C 1-4 alkyl such as methyl, ethyl, isopropyl
  • C 1-6 alkoxy optionally substituted with 1 to 3 substituents selected from the
  • methylsulfonylamino (8) mono- or di- (C 1-6 alkyl-carbonyl) amino (preferably mono- or di- (C 1-4 alkyl-carbonyl) amino, eg methylcarbonylamino), (9) mono- or di- (C 1-6 alkoxy-carbonyl) amino (preferably mono- or di- (C 1-4 alkoxy-carbonyl) amino, such as methoxycarbonylamino, ethoxycarbonylamino), (10) amino, (11) cyclic amino, (12) phthalimide, (13) (a) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably a heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) Or 4 to 10-membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group which may be contained (preferably 1 or 2, more preferably 1)), (B) aminocarbonylimino
  • Saturated non-aromatic nitrogen-containing heterocyclic group (eg, thiomorpholinyl, piperazinyl, morpholinyl)
  • a sulfonylamino substituted with one substituent selected from (16) (a) (i) amino optionally mono- or di-substituted with C 1-6 alkyl (preferably amino optionally mono- or di-substituted with C 1-4 alkyl, More preferably, amino, ethylamino, ethylmethylamino), (Ii) oxo, (Iii) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) (Preferably 1 or 2, more preferably 1) 4 to 10 membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group such as morpholinyl, Pipe
  • X is —CO— or —CH 2 CO—;
  • R 1 is (1) Mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, di-) Propylamino, ethylmethylamino, etc.), (2) C 3-6 cycloalkylamino (eg, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino), (3) Hydrazino, (4) C 1-6 alkyl (preferably C 1-4 alkyl such as methyl, ethyl, isopropyl) optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy, (5) C 1-6 alkoxy optionally substituted with 1 to 3 substituents selected from
  • X is a 5-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom (eg, 1,2,4-oxadiazole, 1,3,3 4-oxadiazole),
  • R 1 is (1) Compound (I) which is C 1-6 alkyl (preferably C 1-4 alkyl) optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy, or (2) phenyl .
  • suitable examples of compound (I) include the following compounds (I-1), (I-2), (I-3), (I-4) and (I-5) ).
  • Compound (I-1) The compound (I), X is C 1-6 alkylene optionally substituted with 1 to 4 C 1-6 alkyl, —CO—, —CH 2 CO—, or a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom.
  • R 1 is (1) hydroxy, (2) cyano, (3) mono- or di-C 1-6 alkylamino, (4) C 3-6 cycloalkylamino, (5) Hydrazino, (6) C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy, (7) C 1-6 alkoxy optionally substituted by 1 to 3 substituents selected from a halogen atom and hydroxy, (8) phenyl, (9)
  • substituents selected from the following (a) to (e), selected from nitrogen atom, sulfur atom and oxygen atom
  • a 4- to 10-membered saturated nitrogen-containing heterocyclic group which may contain one heteroatom, (A) a halogen atom, (B) hydroxy, (C) hydroxy, and C 1-6 1 to 3 substituents optionally substituted by C 1-6
  • R 1 is (1) cyano, (2) mono- or di-C 1-6 alkylamino, (3) C 3-6 cycloalkylamino, (4) Hydrazino, (5) C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy, (6) phenyl, (7)
  • substituents selected from the following (a) to (e), selected from nitrogen atom, sulfur atom and oxygen atom A 4- to 10-membered saturated nitrogen-containing heterocyclic group which may contain one heteroatom, (A) a halogen atom, (B) hydroxy, (C) hydroxy, and C 1-6 1 to 3 substituents optionally substituted by C 1-6 alkyl selected from alkoxy, (D) C 1-6 alkoxy, and (e) oxo, or (8) Amino, C 1-6 alkoxy C 1-6 alkyl, halogen
  • the “5-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom” in the definition of X of the compound (I-1) is preferably 1, 2,4-oxadiazole and 1,3,4-oxadiazole, and in the definition of R 1 , a hetero atom selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom
  • the “4- to 10-membered saturated nitrogen-containing heterocyclic group which may contain one atom” is preferably pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl.
  • R 1 is (1) a nitrogen atom other than a carbon atom and one nitrogen atom, which may be substituted with 1 to 3 substituents selected from C 1-6 alkyl, oxo, hydroxy and hydroxy C 1-6 alkyl; A 5- or 6-membered saturated non-aromatic nitrogen-containing heterocyclic group which may contain one heteroatom selected from oxygen atoms, or (2) C 1-6 alkyl, amino, C 3-6 cycloalkyl C 1-6 alkoxy C 1-6 alkyl, halogen atom, C 1-6 alkoxy-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylsulfonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, carbamoyl And an amino optionally substituted with 1 or 2 substituents selected from C 1-6 alkoxycarbam
  • a hetero atom selected from a nitrogen atom and an oxygen atom may be contained in addition to the carbon atom and one nitrogen atom.
  • the “aromatic nitrogen-containing heterocyclic group” is preferably pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl.
  • R 1 is (1) pyrrolidinyl optionally substituted with one substituent selected from hydroxy and hydroxy C 1-6 alkyl, or (2) C 1-6 alkyl, C 1-6 alkyl-carbonyl, C 1-6 Represents an amino substituted with one or two substituents selected from alkylkylsulfonyl, aminosulfonyl, carbamoyl and mono-C 1-6 alkoxycarbamoyl;
  • R 2 to R 9 represent a hydrogen atom
  • R 10 and R 11 represent a halogen atom
  • R 12 and R 13 represent a hydrogen atom, Compound.
  • R 1 is (1) pyrrolidinyl optionally substituted with one substituent selected from hydroxy and hydroxy C 1-6 alkyl, or (2) C 1-6 alkyl-carbonyl, C 1-6 alkylkylsulfonyl, aminosulfonyl And a compound representing amino substituted with one substituent selected from carbamoyl and mono-C 1-6 alkoxycarbamoyl.
  • the compounds described in Examples 1 to 232 and the like are preferable.
  • the compound (I) the following compounds or salts thereof are particularly preferable.
  • examples of such a salt include a salt with an inorganic base, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, basic or acidic Examples include salts with amino acids.
  • the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • salt with an organic base examples include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like.
  • salt with inorganic acid examples include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- And salts with toluenesulfonic acid.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like.
  • salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • pharmaceutically acceptable salts include, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, phthalic acid, etc., when the compound has a basic functional group.
  • salts with organic acids such as acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.) and alkaline earth metal salts (eg, calcium salts, magnesium salts, barium salts, etc.) And ammonium salts.
  • Compound (I) includes within its scope solvates (eg hydrates) and non-solvates.
  • compound (I) may be labeled with an isotope (eg, 3 H, 14 C, 35 S, 125 I, etc.).
  • Compound (I) may be a deuterium converter. Further, a deuterium converter obtained by converting 1 H into 2 H (D) is also encompassed in compound (I).
  • isomers such as enantiomers or diastereomers may exist. All such isomers and mixtures thereof are included within the scope of the present invention. In addition, isomers due to conformation or tautomerism may be produced, and such isomers or mixtures thereof are also included in the compound (I) of the present invention.
  • a compound represented by the following formula (I) or a salt thereof and a raw material compound thereof can be produced by a method known per se, for example, by a method shown in the following scheme.
  • room temperature usually indicates 0 to 30 ° C.
  • each symbol in the chemical structural formula described in the scheme has the same meaning as described above unless otherwise specified.
  • the compound in a formula also includes the case where it forms the salt, As such a salt, the thing similar to the salt of compound (I) etc. are mentioned, for example.
  • the compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method. At that time, it can be purified by separation means such as recrystallization, distillation, chromatography and the like.
  • the protecting group PRG refers to a protecting group for the nitrogen atom of an amine or amide.
  • Green's Protective Groups in Organic Synthesis 4th Edition 4 th Edition it can be used protecting groups described in 2006. Moreover, when introduction
  • preferred PRG includes tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, acetyl and the like.
  • LG includes, for example, a halogen atom (eg, chlorine atom, bromine atom, iodine atom), C 1-6 alkylsulfonyloxy (eg, methane) optionally substituted with a halogen atom.
  • a halogen atom eg, chlorine atom, bromine atom, iodine atom
  • C 1-6 alkylsulfonyloxy eg, methane
  • C 6-10 arylsulfonyloxy eg, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.
  • reaction when performing alkylation reaction, hydrolysis reaction, amination reaction, esterification reaction, amidation reaction, etherification reaction, oxidation reaction, reduction reaction, reductive amination reaction, etc.
  • the reaction is carried out according to a method known per se.
  • a method for example, Organic Functional Group Preparations (ORGANIC FUNCTIONAL GROUP PREPARATIONS), 2nd edition, Academic Press, Inc., published in 1989; Comprehensive Organic Transformation (Comprehensive Organics) Transformations), VCH Publishers Inc. And the method described in 1989.
  • solvent examples include hydrocarbon solvents, alcohol solvents, ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, sulfoxide solvents, ketone solvents, esters. It refers to a system solvent, a carboxylic acid solvent, water, etc., and these may be used in a mixture of two or more at an appropriate ratio.
  • Compound (Ia) can be produced by deprotection of compound (II).
  • Deprotection for example Greens Protective Groups in Organic Synthesis, 4th edition (Greene's Protective Groups in Organic Synthesis 4 th Edition), can be carried out according to the method described in 2006. Specifically, it can be carried out by acid treatment, alkali hydrolysis, catalytic hydrogenation reaction or the like.
  • the protecting group PRG a general amine protecting group can be used, and preferred examples include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, acetyl, methyl and the like.
  • the protecting group PRG is tert-butoxycarbonyl or acetyl
  • deprotection using an acid is preferred.
  • Step 1 is generally performed in a solvent used for organic synthesis, and a solvent that does not inhibit the reaction is appropriately selected.
  • solvents include alcohol solvents (eg, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc.), ether solvents (eg, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, Diisopropyl ether, ethylene glycol-dimethyl ether, etc.), ester solvents (eg, ethyl formate, ethyl acetate, n-butyl acetate, etc.), carboxylic acid solvents (eg, formic acid, acetic acid, propionic acid, etc.), halogenated hydrocarbons Solvent (eg, dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, 1,2-d
  • the “solvent” is preferably an ester solvent (for example, ethyl acetate), an alcohol solvent (for example, ethanol) or the like, and the protecting group PRG is an acetyl group.
  • the “solvent” is preferably an alcohol solvent (eg, ethanol).
  • Preferred examples of the “acid” include hydrochloric acid, hydrobromic acid, trifluoroacetic acid and the like.
  • the amount of the “acid” to be used is generally 1 to 100 molar equivalents, preferably 1 to 50 molar equivalents, per 1 mol of compound (II).
  • the reaction temperature is usually about 0 ° C.
  • the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.1 hour to about 24 hours. It's time.
  • deprotection can also be performed by a catalytic hydrogenation reaction or the like.
  • the “catalytic hydrogenation reaction” can be performed in a hydrogen atmosphere in the presence of a catalyst.
  • the “catalyst” include palladium (eg, palladium carbon, palladium hydroxide, palladium oxide, etc.), nickel (eg, developed nickel catalyst, etc.), platinum (eg, platinum oxide, platinum carbon, etc.), rhodium.
  • the amount of the “catalyst” to be used is generally 0.001 to 1 molar equivalent, preferably 0.01 to 0.2 molar equivalent, per 1 mol of compound (II).
  • the “solvent” is preferably an alcohol solvent (eg, methanol, ethanol, propanol, butanol, etc.), an ether solvent (eg, diethyl ether, dioxane, tetrahydrofuran, etc.), an ester solvent (eg, ethyl acetate, etc.), An acid solvent (for example, acetic acid etc.), water, or mixtures thereof are mentioned.
  • the hydrogen pressure at which the reaction is carried out is usually about 1 to about 50 atmospheres, preferably about 1 to about 10 atmospheres.
  • the reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 100 ° C.
  • the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 hours to about 40 ° C. It's time.
  • Compound (I) can be produced by reductive alkylation of compound (Ia).
  • the reaction is described, for example, in Organic Reactions, vol. 59, 1-714 (2002), and can be carried out by subjecting compound (Ia) and an imine intermediate produced from the corresponding aldehyde or ketone to a reduction reaction.
  • the amount of aldehyde or ketone to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (Ia).
  • Examples of the reducing agent used include aluminum reagents (eg, lithium aluminum hydride (LiAlH 4 ), diisobutylaluminum hydride (DIBAL-H), sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al), and alane. (AlH 3 )), boron reagents (eg, borane (BH 3 ), 9-borabicyclo [3.3.1] nonane (9-BBN), sodium borohydride (NaBH 4 ), sodium cyanoborohydride ( NaBH 3 CN), sodium triacetoxyborohydride (NaBH (OAc) 3 ) and the like).
  • aluminum reagents eg, lithium aluminum hydride (LiAlH 4 ), diisobutylaluminum hydride (DIBAL-H), sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al), and alane. (AlH 3 )
  • the amount of the “reducing agent” to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (Ia).
  • an acid may be added to promote the reaction.
  • Preferred examples of the “acid” include acetic acid.
  • the amount of the “acid” to be used is generally 0.1 to 10 molar equivalents, preferably 0.1 to 1 molar equivalents, per 1 mol of compound (Ia).
  • reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C.
  • reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
  • Compound (II) can be produced by the following [Production Method A] to [Production Method G].
  • [Production Method A] is Compound (IIa)
  • [Production Method B] is Compound (IIb) and (IIc)
  • [Production Method C] is Compound (IId)
  • [Production Method D] is Compound (IIe), (IIf) ) And (IIg)
  • [Production E] is compound (IIh) (IIi) and (IIj)
  • [Production F] is compound (IIk) and (IIl)
  • [Production G] is compound (IIm). A manufacturing method is shown.
  • R 14 and R 15 are the same or different and each represents a hydrogen atom or an optionally substituted lower alkyl, or R 14 and R 15 are substituted together with the nitrogen atom to which they are bonded. It may also form a 3- to 8-membered cyclic amino. ]
  • Step 3 Compound (IIa) can be produced by amidation of compound (III).
  • Step 3 can be performed, for example, by the method described in Journal of Organic Chemistry (J. Org. Chem.), 55, 270, (1990), and the corresponding amine or a hydrochloride thereof and a condensing agent (for example, Carbodiimides (eg, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, etc.), phosphoric acid derivatives (diethyl cyanophosphate, diphenylphosphoryl azide, etc.), 4- (4,6 -Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (DMT-MM: Kunishima et al., Tetrahedron, 55, 13159, (1999)) is used.
  • DMT-MM Kunishima et al
  • a condensing agent carbodiimide or a salt thereof
  • an appropriate condensation accelerator eg, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxy is used as necessary.
  • the amount of “amine or its hydrochloride” to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, per 1 mol of compound (III).
  • the amount of the “agent” is usually 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, preferably 1 to 2 molar equivalents relative to 1 mol of the compound (III).
  • Alkali metal or alkaline earth metal hydrides eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.
  • alkali metal or alkaline earth metal amides eg, lithium amide, sodium
  • Amides lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide
  • alkali metal or alkaline earth metal lower alkoxides eg, sodium methoxide, Strong bases such as sodium ethoxide, potassium tert-butoxide and the like
  • Alkali metal or alkaline earth metal hydroxides eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.
  • alkali metal or alkaline earth metal carbonates eg, sodium carbonate, Inorganic bases such as potassium carbonate, cesium carbonate,
  • the base to be added to the amidation for example, triethylamine or the like is preferable.
  • the amount of the “base” to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, per 1 mol of compound (III).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 100 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
  • R 16 represents an optionally substituted lower alkyl.
  • Compound (IIb) can be produced by reduction of the carboxy group of compound (III). Moreover, this process can also be performed without using a protecting group (PRG).
  • the reducing agent is used in an amount of 0.1 molar equivalent to a large excess (preferably 0.3 to 10 molar equivalents) per mole of compound (III).
  • the “reducing agent” the same as the “reducing agent” described in the above (Step 2) can be used, and among them, lithium aluminum hydride, borane complex (such as borane-THF complex) and the like are preferable.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, and ether solvents such as tetrahydrofuran are particularly preferable.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C.
  • the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.
  • Step 5 Compound (IIc) can be produced by O-alkylation of compound (IIb).
  • Step 5 can be performed by using an alkylating agent in the presence of a base, as described in, for example, Journal of Organic Chemistry (J. Org. Chem.), 52, 4665, (1987).
  • a base those similar to the “base” described in (Step 3) can be used.
  • alkali metal such as sodium hydride or alkaline earth metal hydride, alkali metal such as sodium amide, etc.
  • alkaline earth metal amides or alkali metal or alkaline earth metal lower alkoxides such as potassium tert-butoxide are preferred.
  • the “alkylating agent” is selected depending on R 16 to be introduced, and is a lower alkyl chloride such as methyl chloride, ethyl chloride, propyl chloride, butyl chloride, the corresponding lower alkyl bromide, the corresponding lower alkyl iodide, the corresponding methane And a lower alkyl sulfonate and a corresponding lower alkyl p-toluenesulfonate.
  • lower alkyl halides such as methyl iodide and ethyl bromide
  • the amount of the base to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (IIb).
  • the amount of the “alkylating agent” to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (IIb).
  • As the solvent those similar to the “solvent” described in the above (Step 1) can be used, but ether solvents such as tetrahydrofuran and amide solvents such as N, N-dimethylformamide are particularly preferable.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.
  • R 17 represents lower alkyl
  • Step 6 Compound (IId) can be produced by stereoselective reduction of compound (IV).
  • the reducing agent is used in an amount of 0.1 to 100 molar equivalents (preferably 0.3 to 10 molar equivalents) per 1 mol of compound (IV).
  • the “reducing agent” the same “reducing agent” as described in the above (Step 2) can be used, and among them, sodium borohydride and the like are preferable.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as ethanol are particularly preferable.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about 0 ° C. to about 100 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 hour. ⁇ About 24 hours.
  • R 16 represents an optionally substituted lower alkyl
  • R 17 represents a lower alkyl
  • R 18 represents an optionally substituted lower alkyl or an optionally substituted aromatic ring group. (Eg, phenyl, aromatic nitrogen-containing heterocyclic group). ]
  • Step 7 Compound (IIe) can be produced by reacting compound (IIr) with a carbon nucleophile. Depending on conditions, compound (IIf) may be obtained. Moreover, this process can also be performed without using a protecting group (PRG).
  • PRG protecting group
  • carbon nucleophile examples include organolithium reagents such as alkyllithium and aryllithium, organomagnesium reagents such as alkylmagnesium halide and arylmagnesium bromide (for example, methylmagnesium bromide, ethylmagnesium bromide, propylmagnesium bromide, etc.), nitromethane And enol ether compounds such as alkyl enol ethers and alkyl silyl enol ethers, and active methylene compounds such as alkyl or aryl sulfones, malonic acid esters, acetoacetic acid esters, and 1,3-dithiane.
  • organolithium reagents such as alkyllithium and aryllithium
  • organomagnesium reagents such as alkylmagnesium halide and arylmagnesium bromide (for example, methylmagnesium bromide, eth
  • organic magnesium reagents such as alkyl magnesium bromide or aryl magnesium bromide (for example, methyl magnesium bromide, ethyl magnesium bromide, propyl magnesium bromide, etc.) are preferable.
  • the amount of the “carbon nucleophile” to be used is generally 0.1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, relative to compound (IIr).
  • (Step 7) is performed in the presence of a base as necessary.
  • the “base” those similar to the “base” described in (Step 3) can be used.
  • alkali metal such as sodium hydride or alkaline earth metal hydride, alkali metal such as sodium amide, etc.
  • alkaline earth metal amides or alkali metal or alkaline earth metal lower alkoxides such as potassium tert-butoxide are preferred.
  • the amount of the “base” to be used is generally 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, per 1 mol of compound (IIr).
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, and ether solvents such as tetrahydrofuran are particularly preferable.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C.
  • the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.
  • Step 8 Compound (IIg) can be produced by O-alkylation of compound (IIe) according to (Step 5).
  • the base those similar to the “base” described in (Step 3) can be used, and among them, alkali metal or alkaline earth metal hydride such as sodium hydride, alkali metal or alkali such as sodium amide, etc.
  • An earth metal amide or an alkali metal or alkaline earth metal lower alkoxide such as potassium tert-butoxide is preferred.
  • alkylating agent those similar to the “alkylating agent” described in (Step 5) can be used, and among them, lower alkyl halides (methyl iodide, ethyl bromide, etc.) are preferable.
  • the amount of the “base” to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (IIe).
  • the amount of the “alkylating agent” to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (IIe).
  • reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C.
  • reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.
  • R 14 and R 15 are the same or different and each represents a hydrogen atom or an optionally substituted lower alkyl, or R 14 and R 15 are substituted together with the nitrogen atom to which they are bonded. It may also form a 3- to 8-membered cyclic amino. ]
  • Step 9 The hydroxy group of compound (IIb) is converted to a leaving group LG to produce compound (V).
  • a method for converting a hydroxy group into a leaving group LG for example, Organic Functional Group PREPARATIONS, 2nd edition, Academic Press, Inc., published in 1989; Comprehensive Organic Transformation (Comprehensive Organic Transformations), VCH Publishers Inc. 1989, etc., and the like.
  • the leaving group LG preferably, methanesulfonyloxy, a halogen atom (for example, a chlorine atom, a bromine atom, an iodine atom, etc.) and the like can be mentioned.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, but ether solvents such as tetrahydrofuran and hydrocarbon solvents such as toluene are particularly preferable.
  • the reaction temperature is usually about ⁇ 50 ° C. to about 150 ° C., preferably about 0 ° C. to about 100 ° C.
  • the reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.
  • this process can also be performed without using a protecting group (PRG).
  • PRG protecting group
  • the leaving group LG of compound (V) is substituted with a cyano group to produce compound (IIh).
  • Examples of the method for substituting the leaving group LG with a cyano group include the methods described in ADVANCED ORGANIC CHEMISTRY, 4th edition, Wiley-InterScience, 1992, and the like.
  • Preferred examples of the cyanating agent include sodium cyanide and potassium cyanide.
  • As the solvent those similar to the “solvent” described in the above (Step 1) can be used. Among them, an amide solvent such as N, N-dimethylformamide, an ether solvent such as tetrahydrofuran and the like are preferable.
  • the reaction temperature is generally about ⁇ 50 ° C. to about 200 ° C., preferably about 0 ° C. to about 150 ° C.
  • the reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.
  • Step 11 Compound (IIi) can be produced by hydrolysis of compound (IIh).
  • the hydrolysis can be performed by selecting from alkaline conditions and acidic conditions. Hydrolysis under alkaline conditions is performed in the presence of a base in a solvent that does not affect the reaction.
  • Examples of the “base” include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium ethoxide, potassium tert-butoxide and the like.
  • the amount of the “base” to be used is preferably about 1 to about 5 molar equivalents relative to 1 mol of compound (IIh).
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used.
  • reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C.
  • reaction time is usually about 0.1 hour to about 48 hours.
  • Hydrolysis under acidic conditions is performed in the presence of an acid in a solvent that does not affect the reaction.
  • an acid hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid and the like are preferable.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, and among them, a carboxylic acid solvent such as acetic acid or water is preferable.
  • the reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C., and the reaction time is usually about 0.1 to about 48 hours.
  • the hydrolysis reaction does not proceed under such conditions, for example, the method using sodium peroxide described in Journal of Organic Chemistry (J. Org. Chem.), 40, 1187, (1975), for example, Journal of the American A method using sodium nitrite in an acidic solvent such as sulfuric acid described in Chemical Society (J. Am. Chem. Soc.), 78, 5416, (1956) may be used.
  • an amino protecting group (PRG) is cut
  • Step 12 Compound (IIj) can be produced by amidation of compound (IIi) according to (Step 3), for example, in Journal of Organic Chemistry (J. Org. Chem.), 55, 270, (1990). It can be performed by the method described.
  • the condensing agent the same “condensing agent” as described in (Step 3) can be used, and among them, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide or 4- (4, 6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride is preferred.
  • the condensation accelerator 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole and the like are preferable.
  • the amount of amine or its hydrochloride to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, per 1 mol of compound (IIi).
  • the amount of the “condensing agent” to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, per 1 mol of compound (IIi).
  • the amount of the “condensation accelerator” to be used is generally 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, per 1 mol of compound (IIi).
  • reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C.
  • reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
  • R 17 represents lower alkyl
  • R 18 represents optionally substituted lower alkyl or an optionally substituted aromatic ring group (eg, phenyl, aromatic nitrogen-containing heterocyclic group).
  • Step 13 Compound (IIk) can be produced by esterification of compound (IIi).
  • Examples of the esterification method include the method described in New Experimental Chemistry Course 14 (Edited by Chemical Society of Japan), pages 1002 to 1027, and the like.
  • the ester methyl ester or ethyl ester is preferable.
  • the acid catalyst used preferably includes hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and the like.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as methanol and ethanol are particularly preferable.
  • the reaction temperature is generally about ⁇ 50 ° C.
  • reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.
  • compound (IIk) can also be produced via an acid halide.
  • a reagent to be used thionyl chloride, oxalyl chloride and the like are preferable.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as methanol and ethanol are particularly preferable.
  • the reaction temperature is generally about ⁇ 50 ° C. to about 200 ° C., preferably about 0 ° C. to about 150 ° C.
  • the reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.
  • methyl ester can be produced using diazomethane.
  • diazomethane trimethylsilyldiazomethane may be used.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as methanol and ethanol, ether solvents such as diethyl ether and the like are preferable.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 200 ° C., preferably about ⁇ 20 ° C. to about 50 ° C.
  • the reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.
  • Step 14 Compound (IIl) can be produced from compound (IIk) according to (Step 7).
  • the carbon nucleophile methylmagnesium bromide and the like are particularly preferable, and as the solvent, the same solvents as the “solvent” described in the above (Step 1) can be used, and among them, ether solvents such as tetrahydrofuran are preferable. .
  • the amount of the “carbon nucleophile” to be used is generally 0.1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, per 1 mol of compound (IIk).
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.
  • LG represents a halogen atom (for example, a chlorine atom, a bromine atom, an iodine atom, etc.).
  • Step 15 Compound (IIm) can be produced by dehalogenation of compound (V). This reaction is also carried out by the reduction reaction using the “reducing agent” described in (Step 2) for compound (V) or the “catalytic hydrogenation reaction” described in (Step 1). A reduction reaction is particularly preferred.
  • the hydride agent is used in an amount of 0.1 molar equivalent to large excess (preferably 0.3 to 10 molar equivalents) per mole of compound (V). Further, the radical initiator is used in an amount of 0.001 to 10 molar equivalents (preferably 0.01 to 1 molar equivalents) relative to 1 mol of Compound (V). At this time, as the “hydride agent”, tri-n-butyltin hydride and the like are preferable.
  • the “radical initiator” 2,2 ′-(E) -diazene-1,2-diylbis (2-methylpropanenitrile) and the like are preferable.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, and hydrocarbon solvents such as toluene are particularly preferable.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about 0 ° C. to about 110 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 hour. ⁇ About 24 hours.
  • Compound (IIn) and Compound (IIo) can be produced by [Production Method H] or [Production Method I] shown below.
  • R 2 represents a hydrogen atom or optionally substituted lower alkyl
  • R 8 represents a hydrogen atom or lower alkyl
  • R 17 represents lower alkyl.
  • Compound (cis-IIn) represents a cis form of compound (IIn)
  • compound (trans-IIn) represents a trans form of compound (IIn)
  • Compound (trans-IIo) represents a trans form of compound (IIo).
  • Step 16 Compound (VIII) can be produced by subjecting compound (VI) and compound (VII) to a cycloaddition reaction in the presence of a base.
  • Step 16 is performed in accordance with, for example, the description of Journal of Organic Chemistry (J. Org. Chem.), 55, 270, (1990), Chem. Letters, 7, 943, (1998). be able to.
  • the base those similar to the “base” described in (Step 3) can be used, and among them, alkali metal or alkaline earth metal hydride such as sodium hydride, alkali metal or alkali such as sodium amide, etc.
  • An earth metal amide or an alkali metal or alkaline earth metal lower alkoxide such as potassium tert-butoxide is preferred.
  • the amount of the “base” to be used is generally 0.1 to 10 molar equivalents, preferably 0.1 to 1 molar equivalents, per 1 mol of compound (VI).
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as ethanol are particularly preferable.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.
  • Step 17 Compound (IIn) can be produced by reduction of compound (VIII).
  • the reducing agent is preferably triethylsilane, and the amount used is usually 0.1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound (VIII).
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used. Among them, halogenated hydrocarbon solvents such as dichloromethane and chloroform or nitrile solvents such as acetonitrile are preferable.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C.
  • the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.
  • Step 18 Compound (cis-IIn) and compound (trans-IIo) can be produced by hydrolysis of compound (IIn).
  • Step 18 is, for example, a method described in Journal of Organic Chemistry (J. Org. Chem.), 55, 270, (1990), Chemistry Letters (Chem. Lett.), 7, 943, (1998) It can be carried out according to step 11).
  • Hydrolysis under alkaline conditions is particularly preferred. Hydrolysis under alkaline conditions is performed in the presence of a base in a solvent that does not affect the reaction. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium ethoxide, potassium tert-butoxide and the like.
  • the amount of the “base” to be used is preferably about 1 to about 5 molar equivalents relative to 1 mol of compound (IIn).
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used. Among them, alcohol solvents such as ethanol, ethers such as tetrahydrofuran, water, and the like are preferable.
  • the reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C., and the reaction time is usually about 0.1 hour to about 48 hours.
  • the ester at the trans position is preferentially hydrolyzed to obtain the compound (trans-IIo).
  • the amino protecting group (PRG) is cleaved during hydrolysis, the amino protecting group (PRG) can be introduced again.
  • R 8 represents a hydrogen atom or lower alkyl
  • R 17 represents lower alkyl
  • Step 19 Compound (cis-IIo) can be produced by hydrolysis of compound (cis-IIn).
  • Step 19 is, for example, a method described in Journal of Organic Chemistry (J. Org. Chem.), 55, 270, (1990), Chemistry Letters (Chem. Lett.), 7, 943, (1998) It can be carried out according to step 11).
  • the hydrolysis can be carried out by selecting from alkaline conditions and acidic conditions, but hydrolysis under acidic conditions is particularly preferred. Hydrolysis under acidic conditions is performed in the presence of an acid in a solvent that does not affect the reaction. As such an acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid and the like are preferable.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, and among them, a carboxylic acid solvent such as acetic acid or water is preferable.
  • the reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C., and the reaction time is usually about 0.1 hour to about 48 hours.
  • an amino protecting group (PRG) is cut
  • R 8 represents a hydrogen atom or lower alkyl
  • R 17 represents lower alkyl.
  • Compound (cis-IIp) represents a cis form of compound (IIp).
  • Compound (trans-IIq) represents a trans form of compound (IIq), and compound (cis-IIq) represents a cis form of compound (IIq).
  • Compound (cis-IIp) represents a cis form of compound (IIp).
  • trans-IIq represents a trans form of compound (IIq)
  • compound (cis-IIq) represents a cis form of compound (IIq).
  • Step 20 Compound (X) can be produced by subjecting compound (VI) and compound (IX) to a cycloaddition reaction in the presence of a base according to (Step 16).
  • a base those similar to the “base” described in (Step 3) can be used, and among them, alkali metal or alkaline earth metal hydride such as sodium hydride, alkali metal or alkali such as sodium amide, etc.
  • An earth metal amide or an alkali metal or alkaline earth metal lower alkoxide such as potassium tert-butoxide is preferred.
  • the amount of the “base” to be used is generally 0.1 to 10 molar equivalents, preferably 0.1 to 1 molar equivalents, per 1 mol of compound (VI).
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C.
  • the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.
  • Step 21 Compound (XI) can be produced by reduction of compound (X) according to (Step 17).
  • the reducing agent is preferably triethylsilane, and the amount used is usually 0.1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound (X).
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used. Among them, halogenated hydrocarbon solvents such as dichloromethane and chloroform or nitrile solvents such as acetonitrile are preferable.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.
  • Step 22 Compound (IIq) can be produced by hydrolyzing compound (XI) under acidic conditions according to (Step 11).
  • the hydrolysis proceeds with decarboxylation.
  • Hydrolysis under acidic conditions is performed in the presence of an acid in a solvent that does not affect the reaction.
  • an acid hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid and the like are preferable.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, and among them, a carboxylic acid solvent such as acetic acid or water is preferable.
  • the reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about 0 ° C.
  • an amino protecting group (PRG) when cut
  • PRG tert-butoxycarbonyl, benzyloxycarbonyl and the like are preferable as the protecting group PRG.
  • Step 23 Compound (IIp) can be produced by esterification of compound (IIq) according to (Step 13).
  • the ester methyl ester, ethyl ester and the like are particularly preferable.
  • the acid catalyst used preferably includes hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and the like.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as methanol and ethanol are particularly preferable.
  • the reaction temperature is generally about ⁇ 50 ° C. to about 200 ° C., preferably about 0 ° C. to about 150 ° C.
  • the reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.
  • An ester can also be produced via an acid halide.
  • a reagent to be used thionyl chloride, oxalyl chloride and the like are preferable.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as methanol and ethanol are particularly preferable.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 200 ° C., preferably about ⁇ 20 ° C. to about 50 ° C.
  • the reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.
  • methyl ester can be produced using diazomethane.
  • trimethylsilyldiazomethane may be used.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used. Among them, alcohol solvents such as methanol and ethanol, or ether solvents such as diethyl ether are preferable.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 200 ° C., preferably about ⁇ 20 ° C. to about 50 ° C.
  • the reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.
  • the amino protecting group (PRG) is cleaved during esterification, the amino protecting group (PRG) can be introduced again by the method described above. Of these, tert-butoxycarbonyl, benzyloxycarbonyl and the like are preferable as the protecting group PRG.
  • Step 24 Compound (cis-IIp), compound (trans-IIq) and compound (cis-IIq) can be produced by hydrolysis of compound (IIp) according to (Step 11).
  • (Step 24) is particularly preferably hydrolysis under alkaline conditions. Hydrolysis under alkaline conditions is performed in the presence of a base in a solvent that does not affect the reaction.
  • a base include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium ethoxide, potassium tert-butoxide and the like.
  • the amount of the “base” to be used is preferably about 1 to about 5 molar equivalents relative to 1 mol of compound (IIp).
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used. Among them, an alcohol solvent such as ethanol, an ether solvent such as tetrahydrofuran, or water is preferable.
  • the reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 hour. ⁇ About 24 hours. Note that the ester at the trans position is preferentially hydrolyzed due to steric hindrance between the amino protecting group (PRG) and the benzene ring at the 3-position of pyrrolidine.
  • PRG amino protecting group
  • an amino protecting group (PRG) when cut
  • PRG amino protecting group
  • tert-butoxycarbonyl, benzyloxycarbonyl and the like are preferable as the protecting group PRG.
  • compound (I-1) a compound in which R 4 and R 5 are hydrogen atoms (referred to as compound (I-1)) can also be produced by [Production Method K] shown below.
  • R 17 represents lower alkyl
  • Step 25 Compound (XIV) can be produced by addition reaction of compound (XIII) to compound (XII).
  • Step 25 is, for example, Angewante Chemie International Edition (Angew. Chem. Int. Ed.), 46, 2124, (2007), Australian Journal of Chemistry (Aust. J. Chem.), 47, 1441, (1994).
  • base those similar to the “base” described in (Step 3) can be used, and among them, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5 Amidines such as diazabicyclo [4.3.0] non-5-ene (DBN) are preferred.
  • DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
  • DBN 1,5 Amidines such as diazabicyclo [4.3.0] non-5-ene
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, and among them, a nitrile solvent such as acetonitrile and an ether solvent such as tetrahydrofuran are preferable.
  • the reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C.
  • the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 hour. ⁇ About 24 hours.
  • Compound (XV) can be produced by a reduction reaction of the nitro group of compound (XIV) followed by a cyclization reaction.
  • Examples of the method for reducing the nitro group include the methods described in New Experimental Chemistry Course 14 (Edited by The Chemical Society of Japan), pages 1333 to 1335, and the like.
  • zinc, iron, tin, tin (II) chloride, and the like are often used, and zinc is particularly preferable.
  • the reaction can be carried out even under neutral or alkaline conditions.
  • the amount of zinc used is usually 0.1 to a large excess, preferably 1 to 100 molar equivalents, relative to 1 mole of compound (XIV).
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, and among them, a carboxylic acid solvent (for example, acetic acid and the like) is preferable.
  • the reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 100 ° C., and the reaction time is usually about 5 minutes to about 150 hours, preferably about 0.5 hours to about 72 hours. It's time.
  • the catalytic hydrogenation reaction can be performed in a hydrogen atmosphere in the presence of a catalyst.
  • Catalyst examples include palladium (eg, palladium carbon, palladium hydroxide, palladium oxide, etc.), nickel (eg, developed nickel catalyst), platinum (eg, platinum oxide, platinum carbon, etc.), Rhodiums (for example, rhodium carbon) and the like can be mentioned.
  • the amount of the “catalyst” to be used is generally 0.001 to 1 molar equivalent, preferably 0.01 to 0.1 molar equivalent, per 1 mol of compound (XIV).
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used.
  • the hydrogen pressure at which the reaction is carried out is usually about 1 to about 50 atmospheres, preferably about 1 to about 10 atmospheres.
  • the reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 100 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 hours to about 40 ° C. It's time.
  • Step 27 Compound (I-1a) can be produced by reduction of compound (XV).
  • the reducing agent the same “reducing agent” as described in the above (Step 2) can be used, and among them, lithium aluminum hydride, borane complex (borane-THF complex and the like) and the like are preferable.
  • the “reducing agent” is generally used in 1 molar equivalent to large excess, preferably 1 to 10 molar equivalents, relative to compound (XV).
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, and ether solvents such as tetrahydrofuran are particularly preferable.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C.
  • the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.
  • Step 28 Compound (I-1b) can be produced by reductive alkylation of compound (I-1a).
  • the reaction is described, for example, in Organic Reactions, vol. 59, 1-714 (2002), or according to (Step 2).
  • the compound (I-1a) and an imine intermediate produced from the corresponding aldehyde or ketone are subjected to a reduction reaction. Is done.
  • the amount of aldehyde or ketone to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (I-1a).
  • As the reducing agent those similar to the “reducing agent” described in the above (Step 2) can be used.
  • the amount of the “reducing agent” to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (I-1a).
  • an acid may be added to promote the reaction.
  • Preferred examples of the “acid” include acetic acid.
  • the amount of the “acid” to be used is generally 0.1 to 10 molar equivalents, preferably 0.1 to 1 molar equivalents, per 1 mol of compound (I-1a).
  • reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C.
  • reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
  • Compound (II) may be prepared by a method other than the above by using Tetrahedron Letters, 44, 6779, (2003); Il Pharmaco, 54, 461, (1999); Tetrahedron Letters. (Tetrahedron Lett.), 48, 8695, (2007), and the like.
  • Compound (II) can also be produced by [Production Method L] shown below.
  • R 19 represents C 1-6 alkoxy-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylsulfonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, carbamoyl or C 1-6 alkoxycarbamoyl. Represents. ]
  • Step 29 Compound (IIs) can be produced by aminating the hydroxyl group of compound (IIb).
  • the “amination” is, for example, a method by azidation and subsequent reduction described in Journal of the American Chemical Society (J. Am. Chem. Soc.), 123, 9465, (2001), or tetrahedron. 50, 12713, (1994), followed by substitution with phthalimide and subsequent deprotection.
  • Compound (IIt) can be produced by acylating, carbamoylating, sulfonylating, or sulfamoylating the amino group of compound (IIs).
  • Acylation can be carried out, for example, by condensation of acid chloride, carbamoylation, for example, isocyanate, and sulfonylation, for example, by condensation of sulfonyl chloride with amine (IIs).
  • the sulfamoylation can be carried out, for example, by using the reagent described in Organic Letters, 14, 2241 (2001) and deprotecting the resulting intermediate.
  • compound (I) When compound (I) is obtained as a free compound, it can be converted to the target salt by a method known per se or a method analogous thereto, and conversely when it is obtained as a salt, it is known per se. It can be converted into a free form or other desired salt by the method or a method analogous thereto.
  • the compound (I) produced by such a method can be isolated and purified by ordinary separation means such as recrystallization, distillation, chromatography and the like.
  • compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and synthetic methods and separation methods known per se (for example, , Concentration, solvent extraction, column chromatography, recrystallization, etc.), each can be obtained as a single product.
  • compound (I) has an optical isomer
  • the optical isomer resolved from the compound is also encompassed in compound (I).
  • the optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemate according to a conventional method.
  • a method known per se for example, fractional recrystallization method, chiral column method, diastereomer method and the like are used.
  • Racemate and optically active compound for example, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.
  • Racemate and optically active compound for example, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.
  • Chiral column method A method in which a racemate or a salt thereof is separated by applying to a column for optical isomer separation (chiral column).
  • a column for optical isomer separation chiral column
  • a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series (manufactured by Daicel Chemical Industries), and water, various buffers (eg, phosphoric acid)
  • the optical isomers are separated by developing the solution as a single or mixed solution of a buffer solution or the like and an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.).
  • an organic solvent eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.
  • the separation is performed using a
  • Diastereomer method A mixture of racemates is converted into a mixture of diastereomers by chemical reaction with an optically active reagent, and this is converted into a single substance through ordinary separation means (for example, fractional recrystallization, chromatography method, etc.). Then, the optical isomer is obtained by separating the optically active reagent site by chemical treatment such as hydrolysis reaction.
  • the compound (I) when the compound (I) has a hydroxy or a primary or secondary amino in the molecule, the compound and an optically active organic acid (for example, MTPA [ ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid], ( -)-Menthoxyacetic acid etc.) are subjected to a condensation reaction to obtain ester or amide diastereomers, respectively.
  • an amide or ester diastereomer is obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. The separated diastereomer is converted into the optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.
  • Compound (I) may be a crystal.
  • Compound (I) may have a single crystal form or a mixture of a plurality of crystal forms. Further, the compound (I) may be a co-crystal.
  • Crystals of compound (I) can be produced by crystallization by applying a crystallization method known per se to compound (I).
  • the crystallization method include a crystallization method from a solution, a crystallization method from a vapor, a crystallization method from a melt, and the like.
  • the “crystallization from solution” includes a state in which the compound is not saturated by changing factors related to the solubility of the compound (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of the solvent.
  • a method of shifting from a supersaturated state to a supersaturated state is exemplified, and specific examples include a concentration method, a slow cooling method, a reaction method (diffusion method, electrolysis method), a hydrothermal growth method, and a flux method.
  • solvent used examples include aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), saturated hydrocarbons (eg, hexane, heptane, cyclohexane).
  • aromatic hydrocarbons eg, benzene, toluene, xylene, etc.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, etc.
  • saturated hydrocarbons eg, hexane, heptane, cyclohexane.
  • Etc. ethers
  • ethers eg, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.
  • nitriles eg, acetonitrile, etc.
  • ketones eg, acetone, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • acid amides Eg, N, N-dimethylformamide, etc.
  • esters eg, ethyl acetate, etc.
  • alcohols eg, methanol, ethanol, isopropyl alcohol, etc.
  • Examples of the “crystallization method from vapor” include a vaporization method (sealed tube method, air flow method), a gas phase reaction method, a chemical transport method, and the like.
  • crystallization from melt examples include normal freezing method (pulling method, temperature gradient method, Bridgman method), zone melting method (zone leveling method, float zone method), special growth method (VLS method, Liquid phase epitaxy method) and the like.
  • compound (I) is dissolved in an appropriate solvent (eg, alcohol such as methanol, ethanol, etc.) at a temperature of 20 to 120 ° C., and the resulting solution is dissolved.
  • an appropriate solvent eg, alcohol such as methanol, ethanol, etc.
  • Examples thereof include a method of cooling to a temperature below (for example, 0 to 50 ° C., preferably 0 to 20 ° C.).
  • the crystals of the present invention thus obtained can be isolated by, for example, filtration.
  • a method for analyzing the obtained crystal a crystal analysis method by powder X-ray diffraction is generally used. Further, examples of the method for determining the crystal orientation include a mechanical method and an optical method.
  • Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • crystal of the present invention has high purity, high quality, low hygroscopicity, and is stored for a long time under normal conditions. Is very stable. In addition, it has excellent biological properties (eg, pharmacokinetics (absorbability, distribution, metabolism, excretion), expression of drug efficacy, etc.) and is extremely useful as a medicine.
  • the specific rotation ([ ⁇ ] D ) is measured by using, for example, a polarimeter (JASCO, P-1030 polarimeter (No. AP-2)) and the like. Means degrees.
  • the melting point means a melting point measured using, for example, a trace melting point measuring device (Yanako, MP-500D type) or a DSC (differential scanning calorimetry) apparatus (SEIKO, EXSTAR6000).
  • a prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc.
  • Compound (I) prodrugs include compounds in which the amino group of compound (I) is acylated, alkylated, and phosphorylated [eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated.
  • prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, Molecular Design, pages 163 to 198. It may be.
  • the compound (I) or a salt thereof or a prodrug thereof (hereinafter abbreviated as compound (I ′)) of the present invention has an excellent monoamine (such as serotonin, norepinephrine, dopamine) reuptake inhibitory activity. Moreover, the compound (I ′) of the present invention has low toxicity and is safe. In particular, it is useful in that it does not exhibit phototoxicity.
  • the compound (I ′) of the present invention can be used for a monoamine in the brain (serotonin, norepinephrine) against mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.). Inhibiting the reuptake of monoamines in the brain as a substance having reuptake inhibitory activity, and improving symptoms of neuropsychiatric disorders such as depression and anxiety.
  • the compound (I ′) of the present invention is a monoamine (serotonin, norepinephrine, dopamine) for mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.). Etc.) As a substance having reuptake inhibitory activity, it inhibits reuptake of monoamines and improves lower urinary tract symptoms such as stress urinary incontinence.
  • Psychiatric and neurological diseases eg, depression (eg, major depression, cerebrovascular disorder depression, seasonal depression, drug-induced depression, HIV depression, etc.), anxiety (eg, general) sexual anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder), attention deficit / hyperactivity disorder (ADHD), bipolar disorder, mania, recurrent depression, persistent mood emotion disorder ( Eg, mood circulatory disorder, dysthymia, etc.), depressive neurosis, sleep disorder, diurnal rhythm disorder, eating disorder, drug dependence, premenstrual tension, autism, mood disorders due to menopause, senile dementia Mild cognitive dysfunction, hypersomnia, psychosomatic disorder, manic depression, posttraumatic stress disorder (PTSD), schizophrenia, anxiety, obsessive-
  • Pelvic organ prolapse anterior vaginal prolapse, retrovaginal prolapse, uterine prolapse, vaginal prolapse, rectal prolapse (rectal aneurysm), small intestinal aneurysm, cystocele, urethral aneurysm, etc.
  • Other diseases eg, diabetes, obesity, irritable bowel syndrome (IBS), Musm's leg syndrome (RLS), chronic fatigue syndrome, premenstrual syndrome (PMS), functional gastroenteropathy (FD), fecal incontinence, (Digestive system diseases, smoking cessation, various addictions)
  • the compound (I ′) of the present invention is useful as a monoamine reuptake inhibitor, and particularly useful as a prophylactic / therapeutic agent for depression, anxiety, attention deficit / hyperactivity disorder or stress urinary incontinence.
  • the compound (I ′) of the present invention has a reuptake inhibitory activity for serotonin, norepinephrine and dopamine, and thus is useful as a Triple® Reuptake® Inhibitor.
  • the compound (I ′) of the present invention since the compound (I ′) of the present invention has a norepinephrine reuptake inhibitory activity, it is useful as a norepinephrine reuptake inhibitor.
  • the “monoamine reuptake inhibitor” means a reuptake inhibitor of at least one monoamine selected from serotonin, norepinephrine and dopamine which are neurotransmitters.
  • Monoamine reuptake inhibitors include serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dopamine reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, serotonin-dopamine reuptake inhibitors Drugs, serotonin-norepinephrine-dopamine reuptake inhibitors.
  • the medicament containing the compound (I ′) can be obtained by using the compound of the present invention alone or a pharmacologically acceptable carrier according to a method known per se (eg, a method described in the Japanese Pharmacopoeia) as a method for producing a pharmaceutical preparation.
  • a method known per se eg, a method described in the Japanese Pharmacopoeia
  • tablets including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.
  • pills powders, granules, capsules (including soft capsules and microcapsules)
  • Lozenges syrups, solutions, emulsions, suspensions, controlled-release preparations (eg, immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, films (eg, oral disintegration) Film, oral mucosa adhesive film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), drip, transdermal preparation, ointment, lotion, patch Suppositories (eg, anal suppositories, Vaginal suppositories), pellets, nasal agents, pulmonary agents (inhalants), eye drops and the like.
  • controlled-release preparations eg, immediate-release preparations, sustained-release preparations, sustained-release microcapsules
  • aerosols films (e
  • the preparation of sustained-release preparation can be applied in accordance with the method described in JP-A-9-263545.
  • the medicament containing compound (I ′) can be used orally or parenterally (eg, intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, ophthalmic, intracerebral, rectal, intravaginal, Administration to the abdominal cavity, inside the tumor, proximal to the tumor, etc. and direct administration to the lesion).
  • the content of compound (I ′) varies depending on the form of the preparation, but is usually 0.01 to 100% by weight, preferably 0.1 to 100% by weight as compound (I) relative to the whole preparation. It is about 50% by weight, more preferably about 0.5 to 20% by weight.
  • pharmacologically acceptable carrier examples include excipients (eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose).
  • excipients eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.
  • binders eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose.
  • Crystalline cellulose alginic acid, gelatin, polyvinylpyrrolidone, etc.
  • lubricant eg, stearic acid, magnesium stearate, calcium stearate, talc, etc.
  • disintegrant eg, carboxymethylcellulose calcium, talc, etc.
  • diluent eg, Water for injection, physiological saline, etc.
  • additives for example, stabilizers, preservatives, coloring agents, fragrances, solubilizers, emulsifiers, buffers, isotonic agents, etc.
  • compound (I ′) is used as a dispersant (eg, surfactants such as Tween 80, HCO-60, polysaccharides such as carboxymethylcellulose, sodium alginate, hyaluronic acid, polysorbate, etc.), storage Agents (eg, methylparaben, propylparaben, etc.), isotonic agents (eg, sodium chloride, mannitol, sorbitol, glucose, etc.), buffers (eg, calcium carbonate, etc.), pH adjusters (eg, sodium phosphate, phosphorus, etc.)
  • a dispersant eg, surfactants such as Tween 80, HCO-60, polysaccharides such as carboxymethylcellulose, sodium alginate, hyaluronic acid, polysorbate, etc.
  • storage Agents eg, methylparaben, propylparaben, etc.
  • isotonic agents eg, sodium chloride, mannitol, sorbito
  • Injectables that can be used as oily suspensions by dispersing with vegetable oils such as sesame oil and corn oil or phospholipids such as lecithin mixed with them, or medium chain fatty acid triglycerides (eg, miglycol 812). To do.
  • vegetable oils such as sesame oil and corn oil or phospholipids such as lecithin mixed with them, or medium chain fatty acid triglycerides (eg, miglycol 812).
  • the prophylactic / therapeutic agent of the present invention can be used together with other drugs.
  • examples of the drug that can be blended or used in combination with compound (I ′) include the following.
  • Other central nervous disease prophylactic / therapeutic drugs Depressive drugs, anxiety drugs (eg, chlordiazepoxide, diazepam, potassium chlorazepate, lorazepam, clonazepam, alprazolam and other benzodiazepines), mood stabilizers (eg, carbonic acid carbonate) Lithium), 5-HT2 antagonists (eg, nefazodone, etc.), 5-HT1A agonists (eg, tandospirone, buspirone, Gepiron, etc.), CRF antagonists (eg, Pecacerfont, etc.), ⁇ 3 agonists (eg, Amibegron, etc.) ), Melatonin agonists (eg, ramelteon, ago
  • ⁇ -amyloid vaccine eg., ⁇ -amyloid degrading enzyme, etc.
  • brain function activator eg, aniracetam, nicergoline
  • Parkinson's disease drug eg, dopamine receptor agonist (eg, L-dopa, bromocryptene, pergolide] , Talipexol, Prasipexole, Cabergoline, Adamantazine, etc.), COMT inhibitors (eg, Entacapone, etc.)], Attention deficit / hyperactivity disorder (eg, modafinil, etc.), Amyotrophic lateral sclerosis (eg, , Riluzole, neurotrophic factor, etc.), insomnia drug (eg, etizolam, zopiclone, triazolam, zolpidem, indiplon), hypersomnia drug (eg, modafinil, etc.), anti-cytokine drug (TNF inhibitor,
  • dopamine receptor agonist eg,
  • Adrenaline ⁇ 1 receptor agonist eg, ephedrine hydrochloride, mitodrine hydrochloride, etc.
  • Adrenaline ⁇ 2 receptor agonist eg, Clenbuterol, etc.
  • Norepinephrine uptake inhibitor eg, Norepinephrine and serotonin uptake inhibitors (eg, duloxetine, etc.)
  • tricyclic antidepressants eg, imipramine hydrochloride, etc.
  • anticholinergic drugs or smooth muscle stimulants eg, oxybutynin hydrochloride, propiverine hydrochloride, selimevelin hydrochloride, etc.
  • female Hormonal drugs eg, conjugated estrogens (premarin), estriol, etc.
  • Diabetes therapeutic agent Insulin preparations [eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin zinc; protamine insulin zinc; insulin fragments Or derivatives (eg, INS-1 etc.)], insulin sensitivity enhancers (eg, pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, JTT-501, MCC-555, YM-440, GI-262570, KRP) -297, FK-614, CS-011, etc.), ⁇ -glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, phenformin, metformin, buformin, etc.), sulfonylurea agents (eg, Tolbutamide Glibenclamide, gliclazide, chlorpropamide
  • Aldose reductase inhibitors eg, tolrestat, epalrestat, zenarestat, zopolrestat, fidarestat (SNK-860), minarerestat (ARI-509), CT-112 etc.
  • nerve Nutritional factors eg, NGF, NT-3, etc.
  • AGE inhibitors eg, ALT-945, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (ALT-766), EXO-226, etc.
  • active oxygen elimination Drugs eg, thioctic acid, etc.
  • cerebral vasodilators eg, thioprid, etc.
  • Statin compounds that are cholesterol synthesis inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin or salts thereof (eg, sodium salt), etc.), squalene synthase Fibrate compounds having an inhibitor or triglyceride lowering effect (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.) and the like.
  • cholesterol synthesis inhibitors eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin or salts thereof (eg, sodium salt), etc.
  • squalene synthase Fibrate compounds having an inhibitor or triglyceride lowering effect eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.
  • Antihypertensive agent Angiotensin converting enzyme inhibitor (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonist (eg, losartan, candesartan cilexetil, etc.), calcium antagonist (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine) Etc.), clonidine and the like.
  • Angiotensin converting enzyme inhibitor eg, captopril, enalapril, delapril, etc.
  • angiotensin II antagonist eg, losartan, candesartan cilexetil, etc.
  • calcium antagonist eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine
  • Anti-obesity agents Central anti-obesity drugs (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, amphetopramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzolex, etc.), pancreatic lipase inhibitor (Eg, orlistat, etc.), ⁇ 3 agonist (eg, CL-316243, SR-58611-A, UL-TG-307, AJ-9679, AZ40140, etc.), peptidic appetite suppressant (eg, leptin, CNTF (hair-like) Somatic neurotrophic factor)), cholecystokinin agonists (eg, Lynchtripto, FPL-15849, etc.) and the like.
  • ⁇ 3 agonist eg, CL-316243, SR-58611-A, UL-TG-307, AJ-9679, AZ40140, etc.
  • Diuretics Xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, pentfurizide, polythiazide, methiclo Thiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), azosemide, isosorbide, etacrine Acid, piretanide, bumetanide, furosemide, etc.
  • Chemotherapeutic agents Alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), anticancer antibiotics (eg, mitomycin, adriamycin, etc.), plants Derived anticancer agents (eg, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etoposide, etc., among others, 5-fluorouracil derivatives such as furtulon or neoflutulon.
  • alkylating agents eg, cyclophosphamide, ifosfamide, etc.
  • antimetabolites eg, methotrexate, 5-fluorouracil, etc.
  • anticancer antibiotics eg, mitomycin, adriamycin, etc.
  • plants Derived anticancer agents eg, vincristine, vindesine
  • Immunotherapeutic agents Microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil, etc.), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), cytokines obtained by genetic engineering techniques (eg, , Interferon, interleukin (IL), etc.), colony stimulating factors (eg, granulocyte colony stimulating factor, erythropoietin, etc.), among them IL-1, IL-2, IL-12, etc.
  • cytokines obtained by genetic engineering techniques
  • IL Interferon, interleukin (IL), etc.
  • colony stimulating factors eg, granulocyte colony stimulating factor, erythropoietin, etc.
  • Anti-inflammatory agents Steroids (eg, dexamethasone, etc.), sodium hyaluronate, cyclooxygenase inhibitors (eg, indomethacin, ketoprofen, loxoprofen, meloxicam, ampiroxicam, celecoxib, rofecoxib, etc.) and the like.
  • cyclooxygenase inhibitors eg, indomethacin, ketoprofen, loxoprofen, meloxicam, ampiroxicam, celecoxib, rofecoxib, etc.
  • Glycation inhibitors eg, ALT-711, etc.
  • nerve regeneration promoters eg, Y-128, VX853, prostide, etc.
  • central nervous system agonists eg, desipramine, amitriptyline, imipramine, floxetine, paroxetine
  • Antidepressants such as doxepin
  • antiepileptic drugs eg, lamotrigine, carbamazepine
  • antiarrhythmic drugs eg, mexiletine
  • acetylcholine receptor ligands eg, ABT-594
  • endothelin receptor antagonists eg, ABT) -627
  • monoamine uptake inhibitors eg, tramadol
  • indoleamine uptake inhibitors eg, floxetine, paroxetine
  • narcotic analgesics eg, morphine
  • GABA receptor agonists eg, gabapentin
  • anticholinergic agent examples include atropine, scopolamine, homatropine, tropicamide, cyclopentrate, butylscopolamine bromide, propantheline bromide, methylbenactidium bromide, mepenzolate bromide, flavoxate, pirenzepine, ipratopium bromide, trihepium Xyphenidyl, oxybutynin, propiverine, darifenacin, tolterodine, temiverine, trospium chloride or its salts (eg, atropine sulfate, scopolamine hydrobromide, homatropine hydrobromide, cyclopentrate hydrochloride, flavoxate hydrochloride, pirenzepine hydrochloride, trihepine Xyphenidyl, oxybutynin hydrochloride, tolterodine tartrate, etc.) are used.
  • oxybutynin, propiverine, darifenacin, tolterodine, temiverine, Supiumu or a salt thereof are preferred.
  • oxybutynin hydrochloride, etc. tolterodine tartrate are preferred.
  • acetylcholinesterase inhibitors eg, distigmine and the like
  • distigmine and the like can also be used.
  • NK-2 receptor antagonists include GR159897, GR1499861, SR48968 (saredutant), SR144190, YM35375, YM38336, ZD7944, L-743986, MDL105212A, ZD6021, MDL105172A, SCH205528, pelysin RIS62373, R132 Perhydroisoindole derivatives such as RPR-106145, quinoline derivatives such as SB-414240, pyrrolopyrimidine derivatives such as ZM-253270, MEN11420 (nepadutant), SCH217048, L-659877, PD-147714 (CAM-2291), MEN10376, Pseudopeptide derivatives such as S16474 Other, GR100679, DNK333, GR94800, UK-224671, MEN10376, MEN10627, or the like salts thereof.
  • the administration time of the compound (I ′) and the concomitant drug is not limited, and the compound (I ′) or a pharmaceutical composition thereof and the concomitant drug or the pharmaceutical composition thereof are administered simultaneously to the administration subject.
  • administration may be performed with a time difference.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration form of the combination is not particularly limited as long as compound (I ′) and the concomitant drug are combined at the time of administration.
  • dosage forms include: (1) Administration of a single preparation obtained by simultaneously compounding compound (I ′) or a pharmaceutical composition thereof and a concomitant drug, (2) Simultaneous administration by the same route of administration of two types of preparations obtained by separately formulating Compound (I ′) or a pharmaceutical composition thereof and a concomitant drug or a pharmaceutical composition thereof, (3) Administration of two types of preparations obtained by separately formulating compound (I ′) or a pharmaceutical composition thereof and a concomitant drug or a pharmaceutical composition thereof at the same administration route with a time difference; (4) Simultaneous administration by different administration routes of two types of preparations obtained by separately formulating Compound (I ′) or a pharmaceutical composition thereof and a concomitant drug or a pharmaceutical composition thereof, (5) Administration of two types of preparations obtained by separately formulating Compound (I ′) or a pharmaceutical composition
  • the compounding ratio of the compound (I ′) and the concomitant drug in the combination agent of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of compound (I ′) in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight based on the whole preparation. %, More preferably about 0.5 to 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about the whole preparation About 0.5 to 20% by weight.
  • the content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. .
  • the same content may be used when compound (I ′) and the concomitant drug are formulated separately.
  • the dose varies depending on the type of compound (I ′), administration route, symptoms, patient age, etc., but for example, for adult patients with depression, anxiety, attention deficit / hyperactivity disorder or stress urinary incontinence
  • about 0.005 to 50 mg, preferably about 0.05 to 10 mg, more preferably about 0.2 to 4 mg as compound (I) per kg body weight per day is divided into 1 to 3 times. Can be administered.
  • the dosage is the type and content of compound (I ′), dosage form, duration of drug release, animal to be administered (eg, human, rat, mouse, Mammals such as cats, dogs, rabbits, cows, pigs, etc.), which vary depending on the purpose of administration. For example, when applied by parenteral administration, about 0.1 to about 100 mg of compound (I ′) is administered per week. It may be released from the dosage form.
  • the amount of the concomitant drug can be set as long as side effects do not become a problem.
  • the daily dose as a concomitant drug varies depending on the degree of symptoms, age of the subject, sex, body weight, sensitivity difference, timing of administration, interval, nature of the pharmaceutical preparation, formulation, type, type of active ingredient, etc.
  • the amount of the drug is usually about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg per kg body weight of the mammal by oral administration. Is usually administered in 1 to 4 divided doses per day.
  • the concomitant drug of the present invention When administering the concomitant drug of the present invention, it may be administered at the same time, but after administering the concomitant drug first, compound (I ′) may be administered, or compound (I ′) may be administered first.
  • the concomitant drug may be administered thereafter.
  • the time difference varies depending on the active ingredient, dosage form, and administration method to be administered.
  • the method includes administering Compound (I ′) within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour.
  • the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after administration of compound (I ′).
  • the method of administration is mentioned.
  • the pharmaceutical composition of the present invention has low toxicity and can be used safely.
  • the Example compounds shown below are excellent in absorbability when administered orally and can be advantageously used for oral preparations. It is also excellent in that it does not show phototoxicity.
  • NMR nuclear magnetic resonance spectrum s: singlet d: doublet ddd: double double doublet (double double doublet) dt: Double triplet (double triplet) dq: double quartet t: triplet q: quartet quint: quintet dd: double doublet (double doublet) m: multiplet br: broad brs: broad singlet J: Coupling constant THF: Tetrahydrofuran MeOH: Methanol DMF: N, N-Dimethylformamide DMSO: Dimethyl sulfoxide LC / MS: Liquid chromatography-mass spectrometry spectrum ESI: Electrospray ionization method [M + H] + : Molecular ion peak (LC in this specification) / MS measurements show [M + H] + unless otherwise specified) Me: methyl Et: ethyl Ac: acetyl Boc: tert-butoxycarbonyl TFA: trifluoroace
  • the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (1-15% ethyl acetate / hexane) to give the title compound as a colorless oil (0.65 g, 29%).
  • 3,4-Dichlorobenzaldehyde (10 g, 57 mmol) was dissolved in acetaldehyde (23 mL, 400 mmol). To this was added dropwise a solution of potassium hydroxide (0.42 g, 6.3 mmol) in methanol (5 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1 hr, acetic anhydride (28 mL) was added, and the mixture was heated under reflux for 1 hr. The mixture was allowed to cool to room temperature, 1N aqueous hydrochloric acid solution (95 mL) was added, and the mixture was heated under reflux for 1 hr.
  • Acetic acid 23 mL
  • 6 N aqueous hydrochloric acid 100 ⁇ mL
  • diethyl 1-acetyl-3- (3,4-dichlorophenyl) pyrrolidine-2,2-dicarboxylate 50 g, 130 ⁇ mmol
  • the solvent was distilled off under reduced pressure, and the residue was dried under reduced pressure.
  • the obtained residue was dissolved in methanol (200 mL), thionyl chloride (12 mL, 160 mmol) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 4 hr. The solvent was distilled off under reduced pressure. The obtained residue was dissolved in methanol and toluene, and the solvent was distilled off again. The obtained residue was dissolved in methanol (200 mL), sodium hydrogen carbonate (49 g, 590 mmol) and di-tert-butyl dicarbonate (35 mL, 150 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure.
  • the extract is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to give 1-tert-butyl 2-methyl (2R * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidine-1,2 -Dicarboxylate was obtained as a colorless oil (17 g, 47%). Further, citric acid was added to the aqueous layer to make it acidic, sodium chloride was added until saturation, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was dissolved in acetic acid (38 mL), 6N aqueous hydrochloric acid solution (150 mL) was added, and the mixture was heated to reflux overnight.
  • the reaction mixture was cooled to room temperature and concentrated under reduced pressure until the volume became about 1/4.
  • An 8 N aqueous sodium hydroxide solution was added to the resulting suspension to adjust the pH to about 7, and the precipitated solid was collected by filtration.
  • the obtained solid was placed in an eggplant flask, azeotroped with toluene, and dried to give the title compound as a white solid (13 g, 50%).
  • 3-Chloro-4-fluorobenzaldehyde 50 g, 320 mmol was dissolved in acetaldehyde (100 mL, 180 mmol).
  • the reaction mixture was stirred at 0 ° C. for 2 hr, acetic anhydride (30 mL, 320 mmol) was added, and the mixture was heated at 60 ° C. for 1 hr.
  • To the reaction mixture was added 3N aqueous hydrochloric acid (200 mL), and the mixture was heated at 100 ° C. for 1 hr.
  • the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was dissolved in acetonitrile (170 mL), triethylsilane (76 mL, 470 mmol) and trifluoroacetic acid (170 mL, 2.2 mol) were added, and the mixture was stirred at room temperature for 3 hr.
  • the solvent was distilled off under reduced pressure and diluted with ethyl acetate.
  • the obtained residue was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the aqueous layer was adjusted to pH about 3 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. After drying the organic layer over magnesium sulfate, the solvent was distilled off under reduced pressure to give 2,3-trans-1- (tert-butoxycarbonyl) -3- (3-chloro-4-fluorophenyl) pyrrolidine-2-carboxylic acid. The acid was obtained as a pale yellow oil (1.5 g, 22%).
  • Triethylsilane (12 mL, 75 mmol) and TFA (27 mL, 350 mmol) were added to a solution of the obtained residue in acetonitrile (27 mL), and the mixture was stirred at room temperature for 3.5 hours. After evaporating the solvent under reduced pressure, the resulting residue was diluted with ethyl acetate and washed with an aqueous potassium carbonate solution and an aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Triethylamine (2.4 mL, 17 mmol) and di-tert-butyl dicarbonate (3.9 mL, 17 mmol) were added to a solution of the obtained solid in methanol (60 mL), and the mixture was stirred at room temperature for 5 hours. After the reaction solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (25% ethyl acetate / hexane) to give the title compound as a white solid (0.49 g, 91%).
  • the obtained extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (5-25% ethyl acetate / hexane) to give the title compound as white crystals (0.23 g, 43%).
  • the obtained extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (25% ethyl acetate / hexane) to give the title compound as a white solid (0.39 g, 72%).
  • the obtained residue was purified by preparative HPLC, and the fraction collected was concentrated. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a white solid (46 mg, 19%).
  • the obtained extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (5-25% ethyl acetate / hexane) to give the title compound as a purple oil (0.48 g, 87%).
  • the obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.50 g, 90%).
  • the obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.47 g, 79%).
  • the obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.28 g, 72%).
  • the obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.35 g, 86%).
  • the extract was washed with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (3-30% ethyl acetate / hexane) to give the title compound as a colorless oil (4.4 g, 95%).
  • the obtained residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (3-30% ethyl acetate / hexane) to give the title compound as a colorless oil (0.14 g, 56%).
  • 1,3-borane-THF complex THF solution in 2,3-trans-1- (tert-butoxycarbonyl) -3- (3-chlorophenyl) pyrrolidine-2-carboxylic acid (0.5 g, 1.53 mmol) in THF (12.5 mL) (3.1 mL, 3.1 mmol) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour and then at room temperature overnight.
  • Methanol was added to the reaction mixture at 0 ° C., and the solvent was evaporated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate.
  • the extract was washed with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (3-30% ethyl acetate / hexane) to give the title compound as a colorless oil (0.44 g, 92%).
  • the fraction solution containing the optically active substance having the smaller retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give 2,3-cis-2- [3- (3,4-dichlorophenyl) pyrrolidine-2 -Il] propan-2-ol (short retention time) (0.26 g, 98.3% ee) was obtained.
  • LC / MS 274 Further, the fraction containing the optically active substance having the longer retention time was concentrated to give 2,3-cis-2- [3- (3,4-dichlorophenyl) pyrrolidin-2-yl] propane-2- All (long holding time) (0.25 g, 96.5% ee) was obtained.
  • the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (0-10% ethyl acetate / hexane) to give the title compound as a colorless oil (0.50 g, 93%).
  • the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by preparative HPLC, and the obtained fractions containing the two peaks were each concentrated and extracted with ethyl acetate.
  • the obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by basic silica gel column chromatography (ethyl acetate) to give a colorless oil.
  • the resulting oil was dissolved in pyridine (3 mL). 4-methylbenzenesulfonyl chloride (0.39 g, 2.0 mmol) was added thereto, and the mixture was stirred at 100 ° C. overnight under a nitrogen atmosphere.
  • the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtered over basic silica gel. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (3-40% ethyl acetate / hexane) to give the title compound as a colorless oil (0.090 g, 34%).
  • the obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained oil was crystallized from diisopropyl ether / ethyl acetate to give a white solid.
  • the obtained solid was dissolved in pyridine (6 mL). 4-methylbenzenesulfonyl chloride (0.76 g, 4.0 mmol) was added thereto, and the mixture was stirred at 100 ° C. overnight under a nitrogen atmosphere.
  • the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtered over basic silica gel. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (3-40% ethyl acetate / hexane) to give the title compound as a colorless oil (0.36 g, 68%).
  • the obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (20-100% ethyl acetate / hexane) to give a colorless oil (0.58 g).
  • the obtained oil (0.19 g) was dissolved in toluene (5 mL) and heated to reflux overnight. The solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow oil (0.17 g, 94%).
  • the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a colorless oil.
  • the obtained oil was dissolved in DMF (30 mL), sodium cyanide (0.37 g, 7.6 mmol) was added, and the mixture was stirred at 100 ° C. overnight.
  • the reaction solution was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.090 g, 56%).
  • the fraction containing the optically active substance having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give 1-tert-butyl 2-methyl-2,3-cis-3- (3,4- 26.2 g (99.9% ee) of dichlorophenyl) pyrrolidine-1,2-dicarboxylate (low retention time) were obtained. Further, the fraction containing the optically active substance having the longer retention time was concentrated to give 1-tert-butyl 2-methyl 2,3-cis-3- (3,4-dichlorophenyl) pyrrolidine-1,2 -26.8 g (99.9% ee) of dicarboxylate (long retention time) was obtained.
  • the obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.51 g).
  • the obtained extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained crystals were washed with diisopropyl ether to give the title compound as white crystals (0.30 g, 84%).
  • Acetic acid (3 mL) and 6N aqueous hydrochloric acid (15 mL) were added to diethyl 1-acetyl-3- (3,4-difluorophenyl) pyrrolidine-2,2-dicarboxylate (6.4 g), and heated under reflux overnight. did.
  • the solvent was distilled off under reduced pressure, and the residue was dried under reduced pressure.
  • the obtained residue was dissolved in methanol (30 mL), thionyl chloride (1.6 mL) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 4 hr.
  • the solvent was distilled off under reduced pressure.
  • the obtained residue was dissolved in methanol and toluene, and the solvent was distilled off again.
  • the obtained residue was dissolved in methanol (30 mL), sodium hydrogen carbonate (6.5 g) and di-tert-butyl dicarbonate (4.64 mL) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue and washed with water. The obtained extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.37 g).
  • Triethylamine (5.47 mL) and di-tert-butyl dicarbonate (3.36 mL) were added to a THF (40 mL) solution of the obtained (2S, 3S) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid monohydrochloride. ) was added and stirred at room temperature for 14 hours.
  • the reaction mixture was diluted with water and extracted with ethyl acetate.
  • the obtained extract was washed with 10% aqueous citric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the reaction mixture was diluted with water and extracted with ethyl acetate.
  • the obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.23 g).
  • the obtained extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (32.2 g).

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Abstract

A compound having a monoamine reuptake-blocking activity, which is represented by formula (I) [wherein X represents an optionally substituted lower alkylene group, -CO-, -CH2CO-, or an optionally substituted 5-membered heterocyclic ring; R1 represents a hydroxy group, a cyano group, or an optionally substituted amino, lower alkyl, lower alkoxy, phenyl, mercapto, sulfonyl or 4- to 10-membered nitrogenated heterocyclic ring group; R2 represents a hydrogen atom, a halogen atom, or an optionally substituted lower alkyl or alkoxycarbonyl group; R3 represents a hydrogen atom, or a lower alkyl group; and R4 to R13 independently represent a hydrogen atom, a halogen atom, or a lower alkyl group, wherein at least one of R9 to R13 represents a halogen atom or a lower alkyl group, or each of R10 and R11 and a benzene ring adjacent thereto together form an optionally substituted naphthalene ring or fused heteroaromatic ring], or a salt of the compound.

Description

ピロリジン化合物Pyrrolidine compound

　本発明は、優れたモノアミン再取り込み阻害活性を有し、うつ病、不安症、注意欠陥・多動性障害、腹圧性尿失禁等の治療・予防薬等として有用なピロリジン化合物に関する。 The present invention relates to a pyrrolidine compound having excellent monoamine reuptake inhibitory activity and useful as a therapeutic / preventive agent for depression, anxiety, attention deficit / hyperactivity disorder, stress urinary incontinence and the like.

（発明の背景）
　モノアミン神経伝達物質であるセロトニン（5-HT）、ノルエピネフリン（NE）およびドーパミン（DA）は、脳内に広範囲に存在し、それらの受容体を介する神経伝達など、様々な機能を有している。これらのモノアミンが神経終末から放出された後に、それぞれのトランスポーター（セロトニントランスポーター：SERT、ノルエピネフリントランスポーター：NETおよびドーパミントランスポーター：DAT）により、神経間隙から速やかに再取り込みされると、神経伝達が終結する。モノアミンの再取り込みの阻害活性を示す化合物は、うつ病などの精神神経疾患を始めとする様々な疾患で有効性が知られており、治療薬として広く用いられている。セロトニン、ノルエピネフリンおよびドーパミンの３種類の再取り込みを阻害する化合物は、Triple Reuptake Inhibitorとよばれ、精神神経疾患等の治療薬としての用途が期待されている。 (Background of the Invention)
The monoamine neurotransmitters serotonin (5-HT), norepinephrine (NE), and dopamine (DA) are widely present in the brain and have various functions such as neurotransmission via their receptors. . When these monoamines are released from the nerve endings and are rapidly re-incorporated from the nerve gap by the respective transporters (serotonin transporter: SERT, norepinephrine transporter: NET and dopamine transporter: DAT), neurotransmission Ends. Compounds showing inhibitory activity on monoamine reuptake are known to be effective in various diseases including neuropsychiatric diseases such as depression, and are widely used as therapeutic agents. A compound that inhibits three types of reuptake, serotonin, norepinephrine, and dopamine, is called Triple Reuptake Inhibitor, and is expected to be used as a therapeutic agent for neuropsychiatric disorders and the like.

　うつ病治療薬としては、イミプラミンに代表される三環性抗うつ薬（TCA）、フルオキセチンに代表される選択的セロトニン再取り込み阻害薬（SSRI）、ベンラファキシンに代表される選択的セロトニン・ノルエピネフリン再取り込み阻害薬（SNRI）やブプロピオンなどのノルエピネフリン・ドーパミン再取り込み阻害薬あるいはモノアミンオキシダーゼ阻害薬などが用いられているが、いずれも効果発現に数週間を要する点、有効性や改善率あるいは副作用の点などから、必ずしも充足度が高いとは言えない（非特許文献１、２参照）。 Depressive drugs include tricyclic antidepressants (TCA) typified by imipramine, selective serotonin reuptake inhibitors (SSRI) typified by fluoxetine, and selective serotonin norepinephrine typified by venlafaxine. Reuptake inhibitors (SNRI), norepinephrine / dopamine reuptake inhibitors such as bupropion, monoamine oxidase inhibitors, etc. are used. From a point etc., it cannot necessarily be said that satisfaction is high (refer nonpatent literatures 1 and 2).

　また、TCA、SSRIおよびSNRIは、うつ病のみならず不安症や注意欠陥・多動性障害などの精神神経疾患や、アルツハイマー病などの神経変性疾患における症状改善、糖尿病性疼痛や筋線維症などの疼痛治療、あるいは過敏性腸症候群などの消化器疾患の治療薬としても有用であるとの報告もある。 TCA, SSRI and SNRI are not only for depression, but also for neuropsychiatric disorders such as anxiety, attention deficit / hyperactivity disorder, neurodegenerative diseases such as Alzheimer's disease, diabetic pain, myofibrosis, etc. There are also reports that it is useful as a treatment for pain in the stomach or as a treatment for gastrointestinal diseases such as irritable bowel syndrome.

　また、モノアミン再取り込み阻害薬は、過活動膀胱や腹圧性尿失禁などの下部尿路疾患、とりわけ腹圧性尿失禁の治療薬としても有効であるとの報告がある。腹圧性尿失禁とは、咳やくしゃみ、軽い運動などによっておこる一過的な腹圧の上昇に伴った膀胱内圧の上昇により、尿が漏れる症状を特徴とする疾患である。この疾患は、女性に多く、出産や加齢などにより骨盤底筋群が弱体し、尿道抵抗が低下するためにおこるとされている（非特許文献３参照）。一方、腹圧の一過的な上昇に伴い膀胱内圧が上昇する際に、一連の神経反射を介して骨盤底筋及び尿道括約筋が能動的に収縮し、尿禁性が維持される尿禁性反射機構が存在することが明らかとなっている（非特許文献４－７参照）。近年、この尿禁性反射にモノアミン神経伝達物質であるセロトニンとノルエピネフリンが関与することが示された（非特許文献６－８参照）。さらに、セロトニン及びノルエピネフリン再取り込み阻害薬であるデュロキセチン（Ｄｕｌｏｘｅｔｉｎｅ）やノルエピネフリン再取り込み阻害薬であるエスレボキセチン（Ｅｓｒｅｂｏｘｅｔｉｎｅ）などを用いて、それぞれ、或いは両トランスポーターを阻害し神経伝達を増強することによって、腹圧性尿失禁の予防・治療効果があることが明らかとされた（非特許文献９－１１参照）。 In addition, it has been reported that monoamine reuptake inhibitors are effective as therapeutic agents for lower urinary tract diseases such as overactive bladder and stress urinary incontinence, particularly stress urinary incontinence. Stress urinary incontinence is a disease characterized by symptoms of urine leaking due to an increase in intravesical pressure accompanying a transient increase in abdominal pressure caused by coughing, sneezing, light exercise, and the like. This disease is common in women and is caused by weakening of the pelvic floor muscle group due to childbirth, aging, and the like, resulting in a decrease in urethral resistance (see Non-Patent Document 3). On the other hand, when intravesical pressure rises due to a transient increase in abdominal pressure, the pelvic floor muscles and urethral sphincters actively contract through a series of nerve reflexes, and urinary incontinence is maintained It is clear that a reflection mechanism exists (see Non-Patent Documents 4-7). In recent years, it has been shown that serotonin and norepinephrine, which are monoamine neurotransmitters, are involved in this urinary reflex (see Non-Patent Documents 6-8). Furthermore, by using serotonin and norepinephrine reuptake inhibitor duloxetine (Duloxetine) and norepinephrine reuptake inhibitor esreboxetine (Esreboxetine), respectively, or by inhibiting both transporters and enhancing neurotransmission, It has been clarified that there is a preventive / therapeutic effect on pressure urinary incontinence (see Non-Patent Document 9-11).

　モノアミン再取り込み阻害薬としては、市販薬以外にもこれまで数多く報告されており、例えばシクロアルキルアミン誘導体（特許文献１および２参照）、ピロリジン誘導体（特許文献３および４参照）、ビシクロアミン誘導体（特許文献５および６参照）、インドール誘導体（特許文献７参照）、ビシクロ誘導体（特許文献８－１０）などが知られている。 Many other monoamine reuptake inhibitors have been reported so far in addition to commercially available drugs. For example, cycloalkylamine derivatives (see Patent Documents 1 and 2), pyrrolidine derivatives (see Patent Documents 3 and 4), bicycloamine derivatives ( Patent Documents 5 and 6), indole derivatives (see Patent Document 7), bicyclo derivatives (Patent Documents 8-10) and the like are known.

　一方、特許文献１１には、モノアミン再取り込み阻害作用によるうつ病、不安症などの中枢神経疾患治療剤として有用な化合物として、式 On the other hand, Patent Document 11 discloses a compound useful as a therapeutic agent for central nervous disease such as depression and anxiety caused by monoamine reuptake inhibitory action.

Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002

〔式中、Ａｒは二置換フェニル基、Ｒ１およびＲ２は独立して水素、Ｃ１－１０アルキル等、Ｒ３は水素、Ｃ１－６アルキル等を示す。〕
で表される化合物が記載されている。 [In the formula, Ar represents a disubstituted phenyl group, R 1 and R 2 independently represent hydrogen, C 1-10 alkyl, and the like, and R 3 represents hydrogen, C 1-6 alkyl, and the like. ]
The compound represented by these is described.

　特許文献１２には、11-β-ヒドロキシステロイド脱水素酵素（11βHSD）阻害作用による糖尿病、肥満、代謝性疾患の治療剤として、例えば、式 Patent Document 12 includes, for example, formulas as therapeutic agents for diabetes, obesity, and metabolic diseases by 11-β-hydroxysteroid dehydrogenase (11βHSD) inhibitory action.

Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003

で表される化合物が記載されている。 The compound represented by these is described.

　特許文献１３には、メラノコルチン受容体作動活性による抗肥満薬として、例えば、式 Patent Document 13 describes, as an anti-obesity drug based on melanocortin receptor agonist activity, for example, a formula

Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004

で表される化合物が記載されている。 The compound represented by these is described.

　特許文献１４には、ラミニン／ニドゲン相互作用阻害活性による糖尿病合併症治療薬として有用な化合物の中間体として、式 Patent Document 14 discloses an intermediate of a compound useful as a therapeutic agent for diabetic complications due to laminin / nidogen interaction inhibitory activity.

Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005

で表される化合物が記載されている。 The compound represented by these is described.

　特許文献１５には、カテコールアミン、ドーパミン、ノルエピネフリンの脳内レベルの増加による中枢神経系疾患治療薬として有用な化合物として、式 Patent Document 15 discloses a compound useful as a therapeutic agent for central nervous system diseases caused by increased brain levels of catecholamine, dopamine, and norepinephrine.

Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006

〔式中、Ａｒはフェニル、チオフェニル、フラニル等、Ｒ１およびＲ２は独立してフッ素または塩素、Ｒ３は水素またはメチルを示す。〕
で表される化合物が記載されている。 [Wherein Ar represents phenyl, thiophenyl, furanyl, etc., R 1 and R 2 independently represent fluorine or chlorine, and R 3 represents hydrogen or methyl. ]
The compound represented by these is described.

　特許文献１６には、カテコールアミン、ドーパミン、ノルエピネフリンの脳内レベルの増加による中枢神経系疾患治療薬として有用な化合物として、式 Patent Document 16 discloses a compound useful as a therapeutic agent for central nervous system diseases due to an increase in brain levels of catecholamine, dopamine, and norepinephrine.

Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007

〔式中、Ａｒはフェニル、チオフェニル、フラニル等、Ｒ１およびＲ２は独立してフッ素または塩素、Ｒ３は水素、メチル等、Ｘはフッ素またはヒドロキシを示す。〕
で表される化合物が記載されている。 [Wherein, Ar represents phenyl, thiophenyl, furanyl, etc., R 1 and R 2 independently represent fluorine or chlorine, R 3 represents hydrogen, methyl, etc., and X represents fluorine or hydroxy. ]
The compound represented by these is described.

国際公開第２００７／０８１８５７号パンフレットInternational Publication No. 2007/081857 Pamphlet 国際公開第２００８／１５１１５６号パンフレットInternational Publication No. 2008/151156 国際公開第２００６／１２１２１８号パンフレットInternational Publication No. 2006/121218 Pamphlet 国際公開第２００８／０７４７０３号パンフレットInternational Publication No. 2008/074703 Pamphlet 国際公開第２００７／０９０８８６号パンフレットInternational Publication No. 2007/090886 Pamphlet 国際公開第２００８／０５７５７５号パンフレットInternational Publication No. 2008/057575 Pamphlet 国際公開第２００７／０６２９９６号パンフレットInternational Publication No. 2007/062996 Pamphlet 国際公開第２００８／０３１７７１号パンフレットInternational Publication No. 2008/031771 Pamphlet 国際公開第２００８／０３１７７２号パンフレットInternational Publication No. 2008/031772 Pamphlet 国際公開第２００８／０７４７１６号パンフレットInternational Publication No. 2008/0747416 Pamphlet 国際公開第２００７／０１６１５５号パンフレットInternational Publication No. 2007/016155 Pamphlet 国際公開第２００５／１０８３５９号パンフレットInternational Publication No. 2005/108359 Pamphlet 国際公開第２００５／０４０１０９号パンフレットInternational Publication No. 2005/040109 Pamphlet 国際公開第２０００／５２０５１号パンフレットInternational Publication No. 2000/52051 Pamphlet 国際公開第２００８／１４８７９９号パンフレットInternational Publication No. 2008/148799 Pamphlet 国際公開第２００８／１４８８０１号パンフレットInternational Publication No. 2008/148801 Pamphlet

Ａｎｎｕａｌ　Ｒｅｐｏｒｔｓ　ｉｎ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ，２００７年，第４２巻，ｐ．１３－２６Annual Reports in Medicinal Chemistry, 2007, Vol. 42, p. 13-26 Ｔｈｅ　Ａｎｎａｌｓ　ｏｆ　Ｐｈａｒｍａｃｏｔｈｅｒａｐｙ，２００２年，第３６巻，１０号，ｐ．１５７７－１５８９The Anals of Pharmacotherapy, 2002, Vol. 36, No. 10, p. 1577-1589 Ｔｈｅ　Ｊｏｕｒｎａｌ　ｏｆ　Ｆａｍｉｌｙ　Ｐｒａｃｔｉｃｅ，１９８２年，第１４巻，ｐ．９３５－９３６The Journal of Family Practice, 1982, Volume 14, p. 935-936 Ａｍｅｒｉｃａｎ　Ｊｏｕｒｎａｌ　ｏｆ　Ｐｈｙｓｉｏｌｏｇｙ－Ｒｅｇｕｌａｔｏｒｙ，Ｉｎｔｅｇｒａｔｉｖｅ　ａｎｄ　Ｃｏｍｐａｒａｔｉｖｅ　Ｐｈｙｓｉｏｌｏｇｙ，２００３年，第２８５巻，ｐ．Ｒ３５６－Ｒ３６５American Journal of Physiology-Regulatory, Integrative and Comparable Physiology, 2003, Vol. 285, p. R356-R365 Ａｍｅｒｉｃａｎ　Ｊｏｕｒｎａｌ　ｏｆ　Ｐｈｙｓｉｏｌｏｇｙ－Ｒｅｎａｌ　Ｐｈｙｓｉｏｌｏｇｙ，２００４年，第２８７巻，ｐ．Ｆ４３４－Ｆ４４１American Journal of Physiology-Renal Physiology, 2004, Vol. 287, p. F434-F441 Ａｍｅｒｉｃａｎ　Ｊｏｕｒｎａｌ　ｏｆ　Ｐｈｙｓｉｏｌｏｇｙ－Ｒｅｎａｌ　Ｐｈｙｓｉｏｌｏｇｙ，２００７年，第２９３巻，ｐ．Ｆ９２０－Ｆ９２６American Journal of Physiology-Renal Physiology, 2007, Vol. 293, p. F920-F926 Ｉｎｔｅｒｎａｔｉｏｎａｌ　Ｊｏｕｒｎａｌ　ｏｆ　Ｇｙｎａｃｏｌｏｇｙ　ａｎｄ　Ｏｂｓｔｅｒｉｃｓ，２００４年，第８６巻，ｐ．Ｓ３８－Ｓ５２International Journal of Gynecology and Obstetrics, 2004, Vol. 86, p. S38-S52 Ａｍｅｒｉｃａｎ　Ｊｏｕｒｎａｌ　ｏｆ　Ｐｈｙｓｉｏｌｏｇｙ－Ｒｅｎａｌ　Ｐｈｙｓｉｏｌｏｇｙ，２００７年，第２９２巻，ｐ．Ｆ６３９－Ｆ６４６American Journal of Physiology-Renal Physiology, 2007, Vol. 292, p. F639-F646 ＢＪＵ　Ｉｎｔｅｒｎａｔｉｏｎａｌ，２００４年，第９３巻，ｐ．３１１－３１８BJU International, 2004, Vol. 93, p. 311-318 ＢＪＵ　Ｉｎｔｅｒｎａｔｉｏｎａｌ，２００８年，第１０２巻，ｐ．２１４－２１８BJU International, 2008, Vol. 102, p. 214-218 Ａｎｎｕａｌ　ｍｅｅｔｉｎｇ　ｏｆ　Ａｍｅｒｉｃａｎ　Ｕｒｏｌｏｇｉｃａｌ　Ａｓｓｏｃｉａｔｉｏｎ，２００８年，演題番号１６６７Annual meeting of American Urological Association, 2008, Title # 1667

　モノアミン（セロトニン、ノルエピネフリン、ドーパミン等）再取り込み阻害活性を有し、うつ病、不安症、注意欠陥・多動性障害、腹圧性尿失禁等の予防・治療薬等として有用であり、かつ、薬効、作用時間、特異性、低毒性等の点で優れた性質を有する化合物の開発が望まれている。 Monoamine (serotonin, norepinephrine, dopamine, etc.) reuptake inhibitory activity, useful as a preventive or therapeutic agent for depression, anxiety, attention deficit / hyperactivity disorder, stress urinary incontinence, etc. Development of a compound having excellent properties in terms of action time, specificity, low toxicity and the like is desired.

　本発明は、前記の化合物を含む公知化合物とは化学構造が異なる、モノアミン再取り込み阻害活性等を有する化合物、およびうつ病、不安症、注意欠陥・多動性障害、腹圧性尿失禁等の新規な予防・治療薬を提供することを目的とする。 The present invention is a compound having a chemical structure different from known compounds including the above-mentioned compounds, having a monoamine reuptake inhibitory activity and the like, and novel such as depression, anxiety, attention deficit / hyperactivity disorder, stress urinary incontinence The purpose is to provide preventive and therapeutic drugs.

　本発明者らは、上記課題を解決するために鋭意研究した結果、下記式（Ｉ）で表される化合物が、優れたモノアミン（セロトニン、ノルエピネフリン、ドーパミン等）再取り込み阻害活性を有することを見出し、本発明を完成するに至った。 As a result of intensive studies to solve the above problems, the present inventors have found that a compound represented by the following formula (I) has an excellent monoamine (serotonin, norepinephrine, dopamine, etc.) reuptake inhibitory activity. The present invention has been completed.

　即ち、本発明は、
［１］式（Ｉ）： That is, the present invention
[1] Formula (I):

Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008

〔式中：
Ｘは、置換されていてもよい低級アルキレン、－ＣＯ－、－ＣＨ２ＣＯ－または置換されていてもよい５員複素環、
Ｒ１は、ヒドロキシ、シアノ、置換されていてもよいアミノ、置換されていてもよい低級アルキル、置換されていてもよい低級アルコキシ、置換されていてもよいフェニル、置換されていてもよいメルカプト、置換スルホニルまたは置換されていてもよい４～１０員含窒素複素環基、
Ｒ２は、水素原子、ハロゲン原子、置換されていてもよい低級アルキル、または置換されていてもよいアルコキシカルボニル、
Ｒ３は、水素原子または低級アルキル、
Ｒ４～Ｒ１３は、同一または異なって、水素原子、ハロゲン原子または低級アルキルを表し、
この場合において、
Ｒ９～Ｒ１３の少なくとも１つの基はハロゲン原子または低級アルキルを表し、あるいは、
Ｒ４～Ｒ９、Ｒ１２およびＲ１３は、同一または異なって、水素原子、ハロゲン原子または低級アルキルを表し、Ｒ１０およびＲ１１は、それぞれが隣接するベンゼン環と共に一体となって、置換されていてもよいナフタレン環または置換されていてもよい縮合複素芳香環を形成する。
（ただし、（ｉ）Ｒ２が水素原子かつＸ－Ｒ１が－ＣＯＯＨである化合物、（ｉｉ）Ｒ２が水素原子、Ｘが－ＣＯ－、およびＲ１が置換されていてもよい低級アルコキシである化合物、（ｉｉｉ）Ｒ２が水素原子かつＲ１がフェニル基上に置換基を有していてもよい４－フェニル－１－ピペラジニルである化合物、（ｉｖ）トランス－Ｎ－２－アダマンチル－３－（４－クロロフェニル）－プロリンアミドおよび（ｖ）（３Ｒ）－３－（２－ナフタレニル）－Ｌ－プロリル－Ｌ－アスパラギニル－Ｌ－アラニル－Ｌ－バリンアミドを除く。）〕で表される化合物またはその塩（以下、化合物（Ｉ）と称する）、
［２］Ｒ１０およびＲ１１は、同一または異なって、水素原子またはハロゲン原子（ただし、Ｒ１０およびＲ１１の少なくとも一方はハロゲン原子である）であり、
Ｒ９、Ｒ１２およびＲ１３は、いずれも水素原子である、上記［１］記載の化合物またはその塩、
［３］Ｒ１０およびＲ１１は塩素原子であり、Ｒ９、Ｒ１２およびＲ１３は、いずれも水素原子である、上記［１］記載の化合物またはその塩、
［４］Ｘは、１ないし４個のＣ１－６アルキルで置換されていてもよいＣ１－６アルキレン、－ＣＯ－、－ＣＨ２ＣＯ－、または炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個含有する５員芳香族複素環を表し、
Ｒ１は、
（１）ヒドロキシ、
（２）シアノ、
（３）モノ－またはジ－Ｃ１－６アルキルアミノ、
（４）Ｃ３－６シクロアルキルアミノ、
（５）ヒドラジノ、
（６）ハロゲン原子およびヒドロキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル、
（７）ハロゲン原子およびヒドロキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルコキシ、
（８）フェニル、
（９）以下の（ａ）～（ｅ）から選ばれる１ないし３個の置換基で置換されていてもよい、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子１個を含有していてもよい、４～１０員の飽和含窒素複素環基、
　（ａ）ハロゲン原子、
　（ｂ）ヒドロキシ、
　（ｃ）ヒドロキシおよびＣ１－６アルコキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル、
　（ｄ）Ｃ１－６アルコキシ、および
　（ｅ）オキソ、または、
（１０）Ｃ１－６アルコキシＣ１－６アルキル、ハロゲン原子、Ｃ１－６アルコキシ－カルボニル、Ｃ１－６アルキル－カルボニル、Ｃ１－６アルキルスルホニル、アミノスルホニル、Ｃ１－６アルキルアミノスルホニル、カルバモイルおよびＣ１－６アルコキシカルバモイルから選ばれる１または２個の置換基で置換されていてもよいアミノを表し、
Ｒ２は、
（１）水素原子、
（２）ヒドロキシおよびＣ１－６アルコキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル、または
（３）Ｃ１－６アルコキシ－カルボニルを表し、
Ｒ３は、水素原子またはＣ１－６アルキルを表し、
Ｒ４～Ｒ１３は、同一または異なって、水素原子、ハロゲン原子またはＣ１－６アルキルを表し、
この場合において、
Ｒ９～Ｒ１３の少なくとも１つの基はハロゲン原子またはＣ１－６アルキルを表し、あるいは、
Ｒ４～Ｒ９、Ｒ１２およびＲ１３は、同一または異なって、水素原子、ハロゲン原子またはＣ１－６アルキルを表し、
Ｒ１０およびＲ１１は、それぞれが隣接するベンゼン環と共に一体となって、ナフタレン環を形成する、上記［１］記載の化合物またはその塩、
［５］Ｘは、Ｃ１－６アルキレン、－ＣＯ－、または－ＣＨ２ＣＯ－を表し、
Ｒ１は、
（１）Ｃ１－６アルキル、オキソ、ヒドロキシおよびヒドロキシＣ１－６アルキルから選ばれる１ないし３個の置換基で置換されていてもよい、炭素原子および１個の窒素原子以外に窒素原子および酸素原子から選ばれるヘテロ原子１個を含有していてもよい、５または６員の飽和含窒素複素環基、または
（２）Ｃ１－６アルキル、アミノ、Ｃ３－６シクロアルキル、Ｃ１－６アルコキシＣ１－６アルキル、ハロゲン原子、Ｃ１－６アルコキシ－カルボニル、Ｃ１－６アルキル－カルボニル、Ｃ１－６アルキルスルホニル、アミノスルホニル、Ｃ１－６アルキルアミノスルホニル、カルバモイルおよびＣ１－６アルコキシカルバモイルから選ばれる１または２個の置換基で置換されていてもよいアミノを表し、
Ｒ２～Ｒ９は、水素原子を表し、
Ｒ１０はハロゲン原子を表し、
Ｒ１１は、水素原子またはハロゲン原子を表し、
Ｒ１２およびＲ１３は水素原子を表す、
上記［１］記載の化合物またはその塩、
［６］Ｘは、Ｃ１－６アルキレンまたは－ＣＯ－を表し、
Ｒ１は、
（１）ヒドロキシおよびヒドロキシＣ１－６アルキルから選択される１個の置換基で置換されていてもよいピロリジニル、または
（２）Ｃ１－６アルキル、Ｃ１－６アルキル－カルボニル、Ｃ１－６アルキルキルスルホニル、アミノスルホニル、カルバモイルおよびモノ－Ｃ１－６アルコキシカルバモイルから選ばれる１または２個の置換基で置換されたアミノを表し、
Ｒ２～Ｒ９は水素原子を表し、
Ｒ１０およびＲ１１はハロゲン原子を表し、
Ｒ１２およびＲ１３は水素原子を表す、
上記［１］記載の化合物またはその塩、
［７］（－）－２，３－ｃｉｓ－３－（３，４－ジクロロフェニル）－Ｎ，Ｎ－ジメチルピロリジン－２－カルボキサミドまたはその塩、
［８］［（２Ｒ，３Ｒ）－３－（３，４－ジクロロフェニル）ピロリジン－２－イル］［（３Ｓ）－３－ヒドロキシピロリジン－１－イル］メタノンまたはその塩、
［９］［（２Ｒ＊，３Ｓ＊）－３－（３，４－ジフルオロフェニル）ピロリジン－２－イル］（ピロリジン－１－イル）メタノンまたはその塩、
［１０］１－｛［（２Ｒ＊，３Ｓ＊）－３－（３，４－ジクロロフェニル）ピロリジン－２－イル］メチル｝－３－メトキシ尿素またはその塩、
［１１］Ｎ－｛［（２Ｒ，３Ｒ）－３－（３，４－ジクロロフェニル）ピロリジン－２－イル］メチル｝メタンスルホンアミドまたはその塩、
［１２］上記［１］記載の化合物またはその塩のプロドラッグ、
［１３］上記［１］記載の化合物またはその塩、またはそのプロドラッグを含有する医薬、
［１４］セロトニン再取り込み阻害薬、ノルエピネフリン再取り込み阻害薬、ドーパミン再取り込み阻害薬、セロトニン－ノルエピネフリン再取り込み阻害薬、ノルエピネフリン－ドーパミン再取り込み阻害薬、セロトニン－ドーパミン再取り込み阻害薬、またはセロトニン－ノルエピネフリン－ドーパミン再取り込み阻害薬である上記［１３］記載の医薬、
［１５］ノルエピネフリン再取り込み阻害薬である上記［１３］記載の医薬、
［１６］うつ病、不安症、注意欠陥・多動性障害または腹圧性尿失禁の予防・治療薬である上記［１３］記載の医薬、
［１７］哺乳動物に対して、上記［１］記載の化合物またはその塩、またはそのプロドラッグの有効量を投与することを特徴とする当該哺乳動物におけるうつ病、不安症、注意欠陥・多動性障害または腹圧性尿失禁の予防・治療方法、
［１８］うつ病、不安症、注意欠陥・多動性障害または腹圧性尿失禁の予防・治療薬を製造するための、上記［１］記載の化合物またはその塩、またはそのプロドラッグの使用、
［１９］うつ病、不安症、注意欠陥・多動性障害または腹圧性尿失禁の予防・治療に使用するための、上記［１］記載の化合物またはその塩、またはそのプロドラッグ
などに関する。 [In the formula:
X is optionally substituted lower alkylene, —CO—, —CH 2 CO— or an optionally substituted 5-membered heterocyclic ring,
R 1 is hydroxy, cyano, optionally substituted amino, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted phenyl, optionally substituted mercapto, Substituted sulfonyl or optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group,
R 2 represents a hydrogen atom, a halogen atom, an optionally substituted lower alkyl, or an optionally substituted alkoxycarbonyl,
R 3 is a hydrogen atom or lower alkyl,
R 4 to R 13 are the same or different and each represents a hydrogen atom, a halogen atom or lower alkyl,
In this case,
At least one group of R 9 to R 13 represents a halogen atom or lower alkyl, or
R 4 to R 9, R 12 and R 13 are the same or different and each represents a hydrogen atom, a halogen atom or lower alkyl, and R 10 and R 11 are each substituted together with the adjacent benzene ring. An optionally substituted naphthalene ring or an optionally substituted fused heteroaromatic ring is formed.
(However, (i) R 2 is a hydrogen atom and X—R 1 is —COOH, (ii) R 2 is a hydrogen atom, X is —CO—, and R 1 is optionally substituted lower alkoxy (Iii) a compound in which R 2 is a hydrogen atom and R 1 is 4-phenyl-1-piperazinyl which may have a substituent on the phenyl group, (iv) trans-N-2-adamantyl -3- (4-chlorophenyl) -prolinamide and (v) (3R) -3- (2-naphthalenyl) -L-prolyl-L-asparaginyl-L-alanyl-L-valineamide)]. Or a salt thereof (hereinafter referred to as compound (I)),
[2] R 10 and R 11 are the same or different and are a hydrogen atom or a halogen atom (provided that at least one of R 10 and R 11 is a halogen atom),
R 9 , R 12 and R 13 are all hydrogen atoms, the compound according to the above [1] or a salt thereof,
[3] The compound or a salt thereof according to the above [1], wherein R 10 and R 11 are chlorine atoms, and R 9 , R 12 and R 13 are all hydrogen atoms,
[4] X represents C 1-6 alkylene optionally substituted with 1 to 4 C 1-6 alkyl, —CO—, —CH 2 CO—, or a nitrogen atom, a sulfur atom and A 5-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from oxygen atoms,
R 1 is
(1) hydroxy,
(2) cyano,
(3) mono- or di-C 1-6 alkylamino,
(4) C 3-6 cycloalkylamino,
(5) Hydrazino,
(6) C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy,
(7) C 1-6 alkoxy optionally substituted by 1 to 3 substituents selected from a halogen atom and hydroxy,
(8) phenyl,
(9) In addition to carbon atom and one nitrogen atom, which may be substituted with 1 to 3 substituents selected from the following (a) to (e), selected from nitrogen atom, sulfur atom and oxygen atom A 4- to 10-membered saturated nitrogen-containing heterocyclic group which may contain one hetero atom,
(A) a halogen atom,
(B) hydroxy,
(C) hydroxy, and C 1-6 1 to 3 substituents optionally substituted by C 1-6 alkyl selected from alkoxy,
(D) C 1-6 alkoxy, and (e) oxo, or
(10) C 1-6 alkoxy C 1-6 alkyl, halogen atom, C 1-6 alkoxy-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylsulfonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl , An amino optionally substituted with one or two substituents selected from carbamoyl and C 1-6 alkoxycarbamoyl;
R 2 is
(1) a hydrogen atom,
(2) hydroxy and C 1-6 1 to 3 is optionally C 1-6 alkyl substituted with a substituent selected from alkoxy or (3), C 1-6 alkoxy - represents carbonyl,
R 3 represents a hydrogen atom or C 1-6 alkyl,
R 4 to R 13 are the same or different and each represents a hydrogen atom, a halogen atom or C 1-6 alkyl;
In this case,
At least one group of R 9 to R 13 represents a halogen atom or C 1-6 alkyl, or
R 4 to R 9 , R 12 and R 13 are the same or different and each represents a hydrogen atom, a halogen atom or C 1-6 alkyl;
R 10 and R 11 are each combined with an adjacent benzene ring to form a naphthalene ring, or a compound or a salt thereof according to the above [1],
[5] X represents C 1-6 alkylene, —CO—, or —CH 2 CO—.
R 1 is
(1) a nitrogen atom other than a carbon atom and one nitrogen atom, which may be substituted with 1 to 3 substituents selected from C 1-6 alkyl, oxo, hydroxy and hydroxy C 1-6 alkyl; A 5- or 6-membered saturated nitrogen-containing heterocyclic group which may contain one heteroatom selected from oxygen atoms, or (2) C 1-6 alkyl, amino, C 3-6 cycloalkyl, C 1 -6 alkoxy C 1-6 alkyl, halogen atom, C 1-6 alkoxy-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylsulfonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, carbamoyl and C 1 Represents an amino optionally substituted with 1 or 2 substituents selected from -6 alkoxycarbamoyl;
R 2 to R 9 represent a hydrogen atom,
R 10 represents a halogen atom,
R 11 represents a hydrogen atom or a halogen atom,
R 12 and R 13 represent a hydrogen atom,
The compound or a salt thereof according to the above [1],
[6] X represents C 1-6 alkylene or —CO—.
R 1 is
(1) pyrrolidinyl optionally substituted with one substituent selected from hydroxy and hydroxy C 1-6 alkyl, or (2) C 1-6 alkyl, C 1-6 alkyl-carbonyl, C 1- It represents alkyl kill, aminosulfonyl, an amino substituted with 1 or 2 substituents selected from carbamoyl and mono- -C 1-6 alkoxy carbamoyl,
R 2 to R 9 represent a hydrogen atom,
R 10 and R 11 represent a halogen atom,
R 12 and R 13 represent a hydrogen atom,
The compound or a salt thereof according to the above [1],
[7] (−)-2,3-cis-3- (3,4-dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide or a salt thereof,
[8] [(2R, 3R) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] [(3S) -3-hydroxypyrrolidin-1-yl] methanone or a salt thereof,
[9] [(2R * , 3S * )-3- (3,4-difluorophenyl) pyrrolidin-2-yl] (pyrrolidin-1-yl) methanone or a salt thereof,
[10] 1-{[(2R * , 3S * )-3- (3,4-dichlorophenyl) pyrrolidin-2-yl] methyl} -3-methoxyurea or a salt thereof,
[11] N-{[(2R, 3R) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] methyl} methanesulfonamide or a salt thereof,
[12] A prodrug of the compound according to [1] above or a salt thereof,
[13] A pharmaceutical comprising the compound according to [1] above or a salt thereof, or a prodrug thereof,
[14] Serotonin reuptake inhibitor, norepinephrine reuptake inhibitor, dopamine reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor, norepinephrine-dopamine reuptake inhibitor, serotonin-dopamine reuptake inhibitor, or serotonin-norepinephrine- The medicament according to [13] above, which is a dopamine reuptake inhibitor,
[15] The medicament according to the above [13], which is a norepinephrine reuptake inhibitor,
[16] The medicament according to [13] above, which is a prophylactic / therapeutic agent for depression, anxiety, attention deficit / hyperactivity disorder or stress urinary incontinence,
[17] Depression, anxiety, attention deficit / hyperactivity in the mammal, characterized by administering an effective amount of the compound or salt thereof, or prodrug thereof according to [1] above to the mammal Prevention and treatment of sexual disorders or stress urinary incontinence,
[18] Use of the compound of the above-mentioned [1] or a salt thereof, or a prodrug thereof for the manufacture of a prophylactic / therapeutic agent for depression, anxiety, attention deficit / hyperactivity disorder or stress urinary incontinence,
[19] The present invention relates to the compound of the above-mentioned [1], a salt thereof, or a prodrug thereof for use in the prevention / treatment of depression, anxiety, attention deficit / hyperactivity disorder or stress urinary incontinence.

　本発明の化合物またはそのプロドラッグは、優れたモノアミン（セロトニン、ノルエピネフリン、ドーパミン等）再取り込み阻害活性を有するため、例えば、うつ病、不安症、注意欠陥・多動性障害、腹圧性尿失禁等の予防・治療薬として有用である。 Since the compound of the present invention or a prodrug thereof has excellent monoamine (serotonin, norepinephrine, dopamine, etc.) reuptake inhibitory activity, for example, depression, anxiety, attention deficit / hyperactivity disorder, stress urinary incontinence, etc. It is useful as a preventive and therapeutic drug for

（発明の詳細な説明）
　以下に本発明について詳細に説明する。 (Detailed description of the invention)
The present invention is described in detail below.

　本明細書中、「ハロゲン原子」としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。 In the present specification, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

　本明細書中、「低級アルキル」としては、直鎖状もしくは分岐鎖状のアルキルが挙げられ、例えば、Ｃ１－６アルキル（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、１－メチルプロピル、ペンチル、イソペンチル、ネオペンチル、ｔｅｒｔ－ペンチル、１，２－ジメチルプロピル、ヘキシル、２－メチルペンチル、３－メチルペンチル、１，２－ジメチルブチル、１，２，２－トリメチルプロピル等）、好ましくはＣ１－４アルキルが挙げられる。 In this specification, “lower alkyl” includes linear or branched alkyl, for example, C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl). , Tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl, hexyl, 2-methylpentyl, 3-methylpentyl, 1,2-dimethylbutyl, 1,2, 2-trimethylpropyl etc.), preferably C 1-4 alkyl.

　本明細書中、「低級アルコキシ」としては、直鎖状もしくは分岐鎖状のアルコキシが挙げられ、例えば、Ｃ１－６アルコキシ（例、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ、１－メチルプロポキシ、ペンチルオキシ、イソペンチルオキシ、ネオペンチルオキシ、ｔｅｒｔ－ペンチルオキシ、１，２－ジメチルプロポキシ、ヘキシルオキシ、２－メチルペンチルオキシ、３－メチルペンチルオキシ、１，２－ジメチルブトキシ、１，２，２－トリメチルプロポキシ等）、好ましくはＣ１－４アルコキシが挙げられる。 In the present specification, “lower alkoxy” includes linear or branched alkoxy, for example, C 1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- Butoxy, tert-butoxy, 1-methylpropoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1,2-dimethylpropoxy, hexyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 1 , 2-dimethylbutoxy, 1,2,2-trimethylpropoxy, etc.), preferably C 1-4 alkoxy.

　本明細書中、「アルコキシカルボニル」としては、直鎖状もしくは分岐鎖状のアルコキシカルボニルが挙げられ、例えば、Ｃ１－６アルコキシ－カルボニル（例、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニル、イソブトキシカルボニル、ｓｅｃ－ブトキシカルボニル、ｔｅｒｔ－ブトキシカルボニル、ペンチルオキシカルボニル、ヘキシルオキシカルボニル等）、好ましくはＣ１－４アルコキシ－カルボニルが挙げられる。 In the present specification, “alkoxycarbonyl” includes linear or branched alkoxycarbonyl, for example, C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl) , Butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), preferably C 1-4 alkoxy-carbonyl.

　本明細書中、「低級アルキレン」としては、直鎖状のアルキレンが挙げられ、例えば、Ｃ１－６アルキレン（例、メチレン、エチレン、トリメチレン、テトラメチレン、ペンタメチレン、ヘキサメチレン）、好ましくはＣ１－４アルキレンが挙げられる。 In the present specification, “lower alkylene” includes linear alkylene, for example, C 1-6 alkylene (eg, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene), preferably C 1-4 alkylene is mentioned.

　本明細書中、「置換されていてもよい環状アミノ」の「環状アミノ」としては、例えば、１－アゼチジニル、１－ピロリジニル、ピペリジノ、チオモルホリノ、モルホリノ、１－ピペラジニル、１－ピロリル、１－イミダゾリル等の３ないし８員（好ましくは５または６員）の環状アミノが挙げられる。 In the present specification, examples of the “cyclic amino” of “optionally substituted cyclic amino” include 1-azetidinyl, 1-pyrrolidinyl, piperidino, thiomorpholino, morpholino, 1-piperazinyl, 1-pyrrolyl, 1- Examples thereof include 3- to 8-membered (preferably 5- or 6-membered) cyclic amino such as imidazolyl.

　本明細書中、「置換されていてもよい５員複素環」の「５員複素環」としては、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし４個（好ましくは１ないし３個）含有する５員複素環が挙げられる。 In the present specification, the “5-membered heterocycle” of the “optionally substituted 5-membered heterocycle” includes 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom ( 5- to 5-membered heterocyclic ring is preferable.

　「置換されていてもよい５員複素環」の「５員複素環」としては、
（１）炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし４個（好ましくは１ないし３個）含有する、５員の飽和または不飽和（好ましくは飽和）の非芳香族複素環（例えば、ピロリジン、テトラヒドロフラン、テトラヒドロチオフェン、オキサゾリジン、イソオキサゾリジン、チアゾリジン、イソチアゾリジン、イミダゾリジン、ピラゾリジン、オキサジアゾリジン（例、１，２，４－オキサジアゾリジン、１，３，４－オキサジアゾリジン）、チアジアゾリジン（例、１，２，４－チアジアゾリジン、１，３，４－チアジアゾリジン）、ピロリン、オキサゾリン、イソオキサゾリン、チアゾリン、イソチアゾリン、イミダゾリン、ピラゾリン、オキサジアゾリン（例、１，２，４－オキサジアゾリン、１，３，４－オキサジアゾリン）、チアジアゾリン（例、１，２，４－チアジアゾリン、１，３，４－チアジアゾリン）等）、
（２）炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし４個（好ましくは１ないし３個）含有する５員芳香族複素環（例えば、フラン、チオフェン、ピロール、オキサゾール、イソオキサゾール、チアゾール、イソチアゾール、イミダゾール、ピラゾール、１，２，３－オキサジアゾール、１，２，４－オキサジアゾール、１，３，４－オキサジアゾール、フラザン、１，２，３－チアジアゾール、１，２，４－チアジアゾール、１，３，４－チアジアゾール、１，２，３－トリアゾール、１，２，４－トリアゾール、テトラゾール等）が挙げられる。 As the “5-membered heterocycle” of the “optionally substituted 5-membered heterocycle”,
(1) A 5-membered saturated or unsaturated (preferably saturated) non-carbon containing 1 to 4 (preferably 1 to 3) heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms Aromatic heterocycles (eg, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, imidazolidine, pyrazolidine, oxadiazolidine (eg, 1,2,4-oxadiazolidine, 1,3,4) -Oxadiazolidine), thiadiazolidine (eg, 1,2,4-thiadiazolidine, 1,3,4-thiadiazolidine), pyrroline, oxazoline, isoxazoline, thiazoline, isothiazoline, imidazoline, pyrazoline, oxadiazo Phosphorus (eg, 1,2,4-oxadiazoline, , 3,4 oxadiazoline), thiadiazoline (e.g., 1,2,4-thiadiazoline, 1,3,4 thiadiazoline), etc.),
(2) A 5-membered aromatic heterocyclic ring containing 1 to 4 (preferably 1 to 3) heteroatoms selected from a nitrogen atom, sulfur atom and oxygen atom in addition to carbon atoms (for example, furan, thiophene, pyrrole, Oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane, 1,2, 3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole and the like.

　本明細書中、「置換されていてもよい４～１０員含窒素複素環基」の「４～１０員含窒素複素環基」としては、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは１または２個、より好ましくは１個）含有していてもよい４～１０員含窒素複素環基が挙げられる。 In the present specification, the “4- to 10-membered nitrogen-containing heterocyclic group” of the “optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group” includes a nitrogen atom in addition to the carbon atom and one nitrogen atom, Examples thereof include a 4- to 10-membered nitrogen-containing heterocyclic group which may contain 1 to 3 (preferably 1 or 2, more preferably 1) heteroatoms selected from a sulfur atom and an oxygen atom.

　「置換されていてもよい４～１０員含窒素複素環基」の「４～１０員含窒素複素環基」としては、
（１）炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは１または２個、より好ましくは１個）含有していてもよい、４～１０員（好ましくは５または６員）の飽和または不飽和（好ましくは飽和）の含窒素複素環基（好ましくは非芳香族含窒素複素環基）（例えば、アゼチジニル、ピロリジニル、ピペリジニル、モルホリニル、チオモルホリニル、ピペラジニル、アゼパニル、ジアゼパニル（例、１，４－ジアゼパニル）、オキサゼパニル（例、１，４－オキサゼパニル）、オキサゾリジニル、イソオキサゾリジニル、チアゾリジニル、イソチアゾリジニル、イミダゾリジニル、ピラゾリジニル、オキサジアゾリジニル（例、１，２，４－オキサジアゾリジニル、１，３，４－オキサジアゾリジニル）、チアジアゾリジニル（例、１，２，４－チアジアゾリジニル、１，３，４－チアジアゾリジニル）、ピロリニル、オキサゾリニル、イソオキサゾリニル、チアゾリニル、イソチアゾリニル、イミダゾリニル、ピラゾリニル、オキサジアゾリニル（例、１，２，４－オキサジアゾリニル、１，３，４－オキサジアゾリニル）、チアジアゾリニル（例、１，２，４－チアジアゾリニル、１，３，４－チアジアゾリニル）、１，３，８－トリアザスピロ［４．５]デカニル等）、
（２）炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは１または２個、より好ましくは１個）含有していてもよい５または６員芳香族含窒素複素環基（例えば、ピロリル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、イミダゾリル、ピラゾリル、１，２，３－オキサジアゾリル、１，２，４－オキサジアゾリル、１，３，４－オキサジアゾリル、フラザニル、１，２，３－チアジアゾリル、１，２，４－チアジアゾリル、１，３，４－チアジアゾリル、１，２，３－トリアゾリル、１，２，４－トリアゾリル、テトラゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、トリアジニル等）、および
（３）フタルイミド
が挙げられる。 As the “4- to 10-membered nitrogen-containing heterocyclic group” of the “optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group”,
(1) In addition to carbon atom and one nitrogen atom, it may contain 1 to 3 (preferably 1 or 2, more preferably 1) heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom 4- to 10-membered (preferably 5- or 6-membered) saturated or unsaturated (preferably saturated) nitrogen-containing heterocyclic group (preferably non-aromatic nitrogen-containing heterocyclic group) (for example, azetidinyl, pyrrolidinyl, piperidinyl) , Morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl (eg, 1,4-diazepanyl), oxazepanyl (eg, 1,4-oxazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, pyrazolidinyl, Oxadiazolidinyl (eg, 1,2,4-oxadiazolidinyl, , 3,4-oxadiazolidinyl), thiadiazolidinyl (eg, 1,2,4-thiadiazolidinyl, 1,3,4-thiadiazolidinyl), pyrrolinyl, oxazolinyl, isoxazolinyl, Thiazolinyl, isothiazolinyl, imidazolinyl, pyrazolinyl, oxadiazolinyl (eg, 1,2,4-oxadiazolinyl, 1,3,4-oxadiazolinyl), thiadiazolinyl (eg, 1,2,4-thiadiazolinyl, 1,3,4-thiadiazolinyl), 1,3,8-triazaspiro [4.5] decanyl, etc.),
(2) In addition to carbon atom and one nitrogen atom, it may contain 1 to 3 (preferably 1 or 2, more preferably 1) heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom Good 5- or 6-membered aromatic nitrogen-containing heterocyclic group (for example, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4 -Oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl , Pyrimidinyl, pyrazinyl, triazinyl, etc.), and (3) phthalimide

　Ｒ１０およびＲ１１が、それぞれが隣接するベンゼン環と共に一体となって形成する「置換されていてもよい縮合複素芳香環」の「縮合複素芳香環」としては、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１または２個含有する９ないし１４員（好ましくは９または１０員）縮合複素芳香環（例えば、ベンゾフラン、イソベンゾフラン、ベンゾ［ｂ］チオフェン、ベンゾ［ｃ］チオフェン、インドール、イソインドール、ベンゾイミダゾール、インダゾール、キノリン、イソキノリン、フタラジン、キノキサリン、キナゾリン、シンノリン、フェナントリジン、アクリジン、フェナジン等）が挙げられる。 The “fused heteroaromatic ring” of the “optionally substituted fused heteroaromatic ring” formed by R 10 and R 11 together with the adjacent benzene ring includes a nitrogen atom, sulfur other than the carbon atom 9- to 14-membered (preferably 9- or 10-membered) condensed heteroaromatic ring containing 1 or 2 heteroatoms selected from atoms and oxygen atoms (for example, benzofuran, isobenzofuran, benzo [b] thiophene, benzo [c] Thiophene, indole, isoindole, benzimidazole, indazole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, cinnoline, phenanthridine, acridine, phenazine and the like.

　「置換されていてもよい低級アルキル」の「低級アルキル」が有していてもよい置換基としては、
（１）ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、
（２）シアノ、
（３）ヒドロキシ、
（４）ニトロ、
（５）ホルミル、
（６）アミノ、
（７）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノ）（例、メチルアミノ、エチルアミノ、プロピルアミノ、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、エチルメチルアミノ等）、
（８）Ｃ１－６アルキル－カルボニルアミノ（好ましくはＣ１－４アルキル－カルボニルアミノ）（例、アセチルアミノ、エチルカルボニルアミノ等）、
（９）Ｃ１－６アルコキシ－カルボニルアミノ（好ましくはＣ１－４アルコキシ－カルボニルアミノ）（例、メトキシカルボニルアミノ、エトキシカルボニルアミノ、プロポキシカルボニルアミノ、ｔｅｒｔ－ブトキシカルボニルアミノ等）、
（１０）１ないし３個のハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）で置換されていてもよいＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ）（例、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ等）、
（１１）Ｃ７－１２アラルキルオキシ（例、ベンジルオキシ等）、
（１２）Ｃ６－１２アリールオキシ（例、フェノキシ等）、
（１３）Ｃ１－６アルキル－カルボニルオキシ（好ましくはＣ１－４アルキル－カルボニルオキシ）（例、アセチルオキシ等）、
（１４）カルボキシ、
（１５）Ｃ１－６アルコキシ－カルボニル（好ましくはＣ１－４アルコキシ－カルボニル）（例、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ｔｅｒｔ－ブトキシカルボニル等）、
（１６）Ｃ７－１２アラルキルオキシ－カルボニル（例、ベンジルオキシカルボニル等）、
（１７）Ｃ６－１２アリールオキシ－カルボニル（例、フェニルオキシカルボニル等）、
（１８）Ｃ１－６アルキル－カルボニル（好ましくはＣ１－４アルキル－カルボニル）（例、アセチル、エチルカルボニル、プロピルカルボニル、イソプロピルカルボニル、２，２－ジメチルプロピルカルボニル等）、
（１９）Ｃ３－６シクロアルキル－カルボニル（例、シクロプロピルカルボニル、シクロブチルカルボニル、シクロペンチルカルボニル、シクロヘキシルカルボニル）、
（２０）Ｃ７－１２アラルキル－カルボニル（例、ベンジルカルボニル等）、
（２１）Ｃ６－１２アリール－カルボニル（例、ベンゾイル等）、
（２２）カルバモイル、
（２３）チオカルバモイル、
（２４）モノ－またはジ－Ｃ１－６アルキル－カルバモイル（好ましくはモノ－またはジ－Ｃ１－４アルキル－カルバモイル）（例、メチルカルバモイル、エチルカルバモイル、プロピルカルバモイル、イソプロピルカルバモイル、ジメチルカルバモイル、ジエチルカルバモイル、ジプロピルカルバモイル等）、
（２５）モノ－またはジ－Ｃ７－１２アラルキル－カルバモイル（例、ベンジルカルバモイル、ジベンジルカルバモイル等）、
（２６）チオール、
（２７）Ｃ１－６アルキルチオ（好ましくはＣ１－４アルキルチオ）（例、メチルチオ、エチルチオ、プロピルチオ等）、
（２８）Ｃ７－１２アラルキルチオ（例、ベンジルチオ等）、
（２９）Ｃ１－６アルキルスルホニル（好ましくはＣ１－４アルキルスルホニル）（例、メチルスルホニル、エチルスルホニル、プロピルスルホニル、イソプロピルスルホニル等）、
（３０）Ｃ３－６シクロアルキルスルホニル（例、シクロプロピルスルホニル、シクロブチルスルホニル、シクロペンチルスルホニル等）、
（３１）Ｃ６－１２アリールスルホニル（例、フェニルスルホニル、１－ナフチルスルホニル、２－ナフチルスルホニル等）、
（３２）Ｃ７－１２アラルキルスルホニル（例、ベンジルスルホニル等）、
（３３）ウレイド、
（３４）Ｃ１－６アルキルウレイド（好ましくはＣ１－４アルキルウレイド）（例、メチルウレイド、エチルウレイド、プロピルウレイド等）、
（３５）Ｃ６－１２アリールウレイド（例、フェニルウレイド、１－ナフチルウレイド、２－ナフチルウレイド等）、
（３６）スルファモイル、
（３７）Ｃ６－１２アリール（例、フェニル、１－ナフチル、２－ナフチル等）、
（３８）置換されていてもよい環状アミノ（例、ピペリジノ等の３ないし８員環状アミノ）、
（３９）Ｃ３－１０シクロアルキル（例、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル等）、
（４０）４ないし１０員芳香族複素環基（例、ピロリル、ピラゾリル、ピリジニル、インダゾリル等）、
（４１）４ないし１０員飽和複素環基（例、アゼチジニル、ピロリジニル、ピペリジニル、ピペラジニル等）、
（４２）４ないし１０員の不飽和の非芳香族複素環基（例、テトラヒドロピリジニル等）、
（４３）モノ－またはジ－Ｃ１－６アルキルアミノカルボニルオキシ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノカルボニルオキシ）（例、メチルアミノカルボニルオキシ等）、
（４４）Ｃ１－６アルキルスルホニルアミノ（好ましくはＣ１－４アルキルスルホニルアミノ）、
（４５）Ｃ７－１２アラルキル（例、ベンジル、２－フェニルエチル、１－フェニルエチル、３－フェニルプロピル、４－フェニルブチル等）、
（４６）オキソ
等から選ばれる置換基が挙げられる。置換基の数は１ないし４個、好ましくは１ないし３個である。 As the substituent that the “lower alkyl” of the “optionally substituted lower alkyl” may have,
(1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom),
(2) cyano,
(3) hydroxy,
(4) Nitro,
(5) Formyl,
(6) amino,
(7) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, Ethylmethylamino),
(8) C 1-6 alkyl-carbonylamino (preferably C 1-4 alkyl-carbonylamino) (eg, acetylamino, ethylcarbonylamino, etc.),
(9) C 1-6 alkoxy-carbonylamino (preferably C 1-4 alkoxy-carbonylamino) (eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, tert-butoxycarbonylamino, etc.),
(10) C 1-6 alkoxy (preferably C 1-4 alkoxy) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) (eg, methoxy Ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.),
(11) C 7-12 aralkyloxy (eg, benzyloxy etc.),
(12) C 6-12 aryloxy (eg, phenoxy etc.),
(13) C 1-6 alkyl-carbonyloxy (preferably C 1-4 alkyl-carbonyloxy) (eg, acetyloxy etc.),
(14) carboxy,
(15) C 1-6 alkoxy-carbonyl (preferably C 1-4 alkoxy-carbonyl) (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, etc.),
(16) C 7-12 aralkyloxy-carbonyl (eg, benzyloxycarbonyl etc.),
(17) C 6-12 aryloxy-carbonyl (eg, phenyloxycarbonyl etc.),
(18) C 1-6 alkyl-carbonyl (preferably C 1-4 alkyl-carbonyl) (eg, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, 2,2-dimethylpropylcarbonyl, etc.),
(19) C 3-6 cycloalkyl-carbonyl (eg, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl),
(20) C 7-12 aralkyl-carbonyl (eg, benzylcarbonyl, etc.),
(21) C 6-12 aryl-carbonyl (eg, benzoyl, etc.),
(22) Carbamoyl,
(23) thiocarbamoyl,
(24) Mono- or di-C 1-6 alkyl-carbamoyl (preferably mono- or di-C 1-4 alkyl-carbamoyl) (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, dimethylcarbamoyl, diethyl) Carbamoyl, dipropylcarbamoyl, etc.),
(25) mono- or di-C 7-12 aralkyl-carbamoyl (eg, benzylcarbamoyl, dibenzylcarbamoyl, etc.),
(26) thiol,
(27) C 1-6 alkylthio (preferably C 1-4 alkylthio) (eg, methylthio, ethylthio, propylthio, etc.),
(28) C 7-12 aralkylthio (eg, benzylthio, etc.),
(29) C 1-6 alkylsulfonyl (preferably C 1-4 alkylsulfonyl) (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, etc.),
(30) C 3-6 cycloalkylsulfonyl (eg, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, etc.),
(31) C 6-12 arylsulfonyl (eg, phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.),
(32) C 7-12 aralkylsulfonyl (eg, benzylsulfonyl, etc.),
(33) Ureido,
(34) C 1-6 alkylureido (preferably C 1-4 alkylureido) (eg, methylureido, ethylureido, propylureido, etc.),
(35) C 6-12 arylureido (eg, phenylureido, 1-naphthylureido, 2-naphthylureido, etc.),
(36) Sulfamoyl,
(37) C 6-12 aryl (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.),
(38) an optionally substituted cyclic amino (eg, 3- to 8-membered cyclic amino such as piperidino),
(39) C 3-10 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.),
(40) 4- to 10-membered aromatic heterocyclic group (eg, pyrrolyl, pyrazolyl, pyridinyl, indazolyl, etc.),
(41) 4- to 10-membered saturated heterocyclic group (eg, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl etc.),
(42) a 4- to 10-membered unsaturated non-aromatic heterocyclic group (eg, tetrahydropyridinyl, etc.),
(43) mono- or di-C 1-6 alkylaminocarbonyloxy (preferably mono- or di-C 1-4 alkylaminocarbonyloxy) (eg, methylaminocarbonyloxy etc.),
(44) C 1-6 alkylsulfonylamino (preferably C 1-4 alkylsulfonylamino),
(45) C 7-12 aralkyl (eg, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, etc.),
(46) Substituents selected from oxo and the like. The number of substituents is 1 to 4, preferably 1 to 3.

　「置換されていてもよい低級アルコキシ」の「低級アルコキシ」が有していてもよい置換基としては、前記の「置換されていてもよい低級アルキル」の「低級アルキル」が有していてもよい置換基と同様のものが挙げられる。置換基の数は１ないし４個、好ましくは１ないし３個である。 As the substituent that the “lower alkoxy” of the “optionally substituted lower alkoxy” may have, the “lower alkyl” of the “optionally substituted lower alkyl” may have The thing similar to a good substituent is mentioned. The number of substituents is 1 to 4, preferably 1 to 3.

　「置換されていてもよいアルコキシカルボニル」の「アルコキシカルボニル」が有していてもよい置換基としては、前記の「置換されていてもよい低級アルキル」の「低級アルキル」が有していてもよい置換基と同様のものが挙げられる。置換基の数は１ないし４個、好ましくは１ないし３個である。 As the substituent that the “alkoxycarbonyl” of the “optionally substituted alkoxycarbonyl” may have, the “lower alkyl” of the “optionally substituted lower alkyl” may have The thing similar to a good substituent is mentioned. The number of substituents is 1 to 4, preferably 1 to 3.

　「置換されていてもよい低級アルキレン」の「低級アルキレン」が有していてもよい置換基としては、
（１）ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、
（２）シアノ、
（３）ヒドロキシ、
（４）ニトロ、
（５）置換されていてもよい低級アルキル（好ましくはＣ１－６アルキル、より好ましくはＣ１－４アルキル）
等から選ばれる置換基が挙げられる。置換基の数は１ないし４個、好ましくは１ないし３個である。 As the substituent that the “lower alkylene” of the “lower alkylene which may be substituted” may have,
(1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom),
(2) cyano,
(3) hydroxy,
(4) Nitro,
(5) optionally substituted lower alkyl (preferably C 1-6 alkyl, more preferably C 1-4 alkyl)
Substituents selected from the above and the like. The number of substituents is 1 to 4, preferably 1 to 3.

　「置換されていてもよいメルカプト」の「メルカプト」が有していてもよい置換基としては、
（１）Ｃ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、１－メチルプロピル、ペンチル、イソペンチル、ネオペンチル、ｔｅｒｔ－ペンチル、１，２－ジメチルプロピル、ヘキシル、２－メチルペンチル、３－メチルペンチル、１，２－ジメチルブチル、１，２，２－トリメチルプロピル）、
（２）Ｃ２－６アルケニル（例、エテニル、１－プロペニル、２－プロペニル）、
（３）Ｃ２－６アルキニル（例、エチニル、１－プロピニル、２－プロピニル）、
（４）Ｃ６－１４アリール（例、フェニル、１－ナフチル、２－ナフチル）、
（５）Ｃ７－１６アラルキル（例、ベンジル、フェネチル）
等から選ばれる置換基が挙げられる。 As the substituent that the “mercapto” of the “optionally substituted mercapto” may have,
(1) C 1-6 alkyl (preferably C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, tert -Pentyl, 1,2-dimethylpropyl, hexyl, 2-methylpentyl, 3-methylpentyl, 1,2-dimethylbutyl, 1,2,2-trimethylpropyl),
(2) C 2-6 alkenyl (eg, ethenyl, 1-propenyl, 2-propenyl),
(3) C 2-6 alkynyl (eg, ethynyl, 1-propynyl, 2-propynyl),
(4) C 6-14 aryl (eg, phenyl, 1-naphthyl, 2-naphthyl),
(5) C 7-16 aralkyl (eg, benzyl, phenethyl)
Substituents selected from the above and the like.

　「置換スルホニル」の「スルホニル」が有していてもよい置換基としては、前記の「置換されていてもよいメルカプト」の「メルカプト」が有していてもよい置換基と同様のものが挙げられる。 Examples of the substituent that the “sulfonyl” of the “substituted sulfonyl” may have include the same substituents as the substituent that the “mercapto” of the “optionally substituted mercapto” may have. It is done.

　「置換されていてもよいフェニル」の「フェニル」が有していてもよい置換基としては、
（ａ）前記の「置換されていてもよい低級アルキル」の「低級アルキル」が有していてもよい置換基、および
（ｂ）（１）ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、ヒドロキシおよびＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ）（例、メトキシ、エトキシ、プロポキシ等）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル）（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、１－メチルプロピル、ペンチル、イソペンチル、ネオペンチル、ｔｅｒｔ－ペンチル、１，２－ジメチルプロピル、ヘキシル、２－メチルペンチル、３－メチルペンチル、１，２－ジメチルブチル、１，２，２－トリメチルプロピル等）、
　　　（２）Ｃ７－１２アラルキル（例、ベンジル、２－フェニルエチル、１－フェニルエチル、３－フェニルプロピル、４－フェニルブチル等）、
　　　（３）Ｃ３－１０シクロアルキル（例、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル等）、
　　　（４）ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、ヒドロキシ、Ｃ１－６アルキル（好ましくはＣ１－４アルキル）（例、メチル、エチル、プロピル等）およびＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ）（例、メトキシ、エトキシ、プロポキシ等）から選ばれる１ないし３個の置換基で置換されていてもよいＣ６－１２アリール（例、フェニル、１－ナフチル、２－ナフチル等）
等から選ばれる置換基が挙げられる。置換基の数は１ないし４個、好ましくは１ないし３個である。 As the substituent that “phenyl” of “optionally substituted phenyl” may have,
(A) the substituent which the “lower alkyl” of the “optionally substituted lower alkyl” may have, and (b) (1) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom) , iodine), hydroxy and C 1-6 alkoxy (preferably C 1-4 alkoxy) (e.g., methoxy, ethoxy, to 1 selected from propoxy) optionally substituted with 1-3 substituents C 1 -6 alkyl (preferably C 1-4 alkyl) (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl, hexyl, 2-methylpentyl, 3-methylpentyl, 1,2-dimethylbutyl, 1,2, , 2-trimethylpropyl, etc.)
(2) C 7-12 aralkyl (eg, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, etc.),
(3) C 3-10 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.),
(4) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), hydroxy, C 1-6 alkyl (preferably C 1-4 alkyl) (eg, methyl, ethyl, propyl etc.) and C 1 C- 6-12 aryl optionally substituted with 1 to 3 substituents selected from -6 alkoxy (preferably C 1-4 alkoxy) (eg, methoxy, ethoxy, propoxy, etc.) (eg, phenyl, 1 -Naphthyl, 2-naphthyl, etc.)
Substituents selected from the above and the like. The number of substituents is 1 to 4, preferably 1 to 3.

　「置換されていてもよい環状アミノ」の「環状アミノ」が有していてもよい置換基としては、オキソおよび前記の「置換されていてもよいフェニル」の「フェニル」が有していてもよい置換基と同様のものが挙げられる。置換基の数は１ないし４個、好ましくは１ないし３個である。 As the substituent that the “cyclic amino” of the “optionally substituted cyclic amino” may have, the oxo and the “phenyl” of the “optionally substituted phenyl” may have The thing similar to a good substituent is mentioned. The number of substituents is 1 to 4, preferably 1 to 3.

　「置換されていてもよい５員複素環」の「５員複素環」が有していてもよい置換基としては、前記の「置換されていてもよいフェニル」の「フェニル」が有していてもよい置換基と同様のものが挙げられる。置換基の数は１ないし４個、好ましくは１ないし３個、より好ましくは１または２個である。 As the substituent that the “5-membered heterocyclic ring” of the “optionally substituted 5-membered heterocyclic ring” may have, the “phenyl” of the above-mentioned “optionally substituted phenyl” has. The thing similar to the substituent which may be mentioned is mentioned. The number of substituents is 1 to 4, preferably 1 to 3, and more preferably 1 or 2.

　「置換されていてもよい４～１０員含窒素複素環基」の「４～１０員含窒素複素環基」が有していてもよい置換基としては、オキソおよび前記の「置換されていてもよいフェニル」の「フェニル」が有していてもよい置換基と同様のものが挙げられる。置換基の数は１ないし４個、好ましくは１ないし３個である。 Examples of the substituent that the “4- to 10-membered nitrogen-containing heterocyclic group” in the “optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group” may have include oxo and the above-mentioned “substituted” Examples thereof include the same substituents that the “phenyl” of “may be phenyl” may have. The number of substituents is 1 to 4, preferably 1 to 3.

　「置換されていてもよいナフタレン環」の「ナフタレン環」または「置換されていてもよい縮合複素芳香環」の「縮合複素芳香環」が有していてもよい置換基としては、前記の「置換されていてもよいフェニル」の「フェニル」が有していてもよい置換基と同様のものが挙げられる。置換基の数は１ないし４個、好ましくは１ないし３個である。 As the substituent that the “naphthalene ring” of the “optionally substituted naphthalene ring” or the “fused heteroaromatic ring” of the “optionally substituted condensed heteroaromatic ring” may have, the above-mentioned “ The thing similar to the substituent which "phenyl" of "the phenyl which may be substituted" may have is mentioned. The number of substituents is 1 to 4, preferably 1 to 3.

　「置換されていてもよいアミノ」としては、
（１）アミノ、
（２）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノ）（例、メチルアミノ、エチルアミノ、プロピルアミノ、イソプロピルアミノ、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、エチルメチルアミノ等）、
（３）Ｃ３－６シクロアルキルアミノ（例、シクロプロピルアミノ、シクロブチルアミノ、シクロペンチルアミノ、シクロヘキシルアミノ）、
（４）Ｃ６－１２アリールアミノ（例、フェニルアミノ、１－ナフチルアミノ、２－ナフチルアミノ等）、
（５）Ｃ７－１２アラルキルアミノ（例、ベンジルアミノ、２－フェニルエチルアミノ、１－フェニルエチルアミノ等）、
（６）ヒドラジノ、
（７）モノ－またはジ－（Ｃ１－６アルキルスルホニル）アミノ（好ましくはモノ－またはジ－（Ｃ１－４アルキルスルホニル）アミノ、例えばメチルスルホニルアミノ）、
（８）モノ－またはジ－（Ｃ１－６アルキル－カルボニル）アミノ（好ましくはモノ－またはジ－（Ｃ１－４アルキル－カルボニル）アミノ、例えばメチルカルボニルアミノ）、
（９）モノ－またはジ－（Ｃ１－６アルコキシ－カルボニル）アミノ（好ましくはモノ－またはジ－（Ｃ１－４アルコキシ－カルボニル）アミノ、例えばメトキシカルボニルアミノ、エトキシカルボニルアミノ）、
（１０）置換されていてもよい環状アミノ、
（１１）（ａ）置換されていてもよい４～１０員含窒素複素環基（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは１または２個、より好ましくは１個）含有していてもよい、４～１０員の飽和または不飽和（好ましくは飽和）の非芳香族含窒素複素環基）、
　　　　（ｂ）アミノカルボニルイミノ、
　　　　（ｃ）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノ、例えばメチルアミノ）、
　　　　（ｄ）ヒドロキシカルボニル、および
　　　　（ｅ）Ｃ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えばメトキシ）で置換されていてもよい、フェニル（例、メトキシフェニル）
から選ばれる１ないし３個の置換基で置換されていてもよい、モノ－またはジ－Ｃ１－６アルキル（好ましくはＣ１－４アルキル）アミノ（例、モルホリニルエチルアミノ、［（アミノカルボニルイミノ）（メチルアミノ）メチル］アミノ、（ヒドロキシカルボニルメチル）アミノ、（メトキシフェニルメチル）アミノ）、
（１２）（ａ）ヒドロキシで置換されていてもよいＣ１－６アルキルで、モノ－またはジ－置換されていてもよいアミノ（好ましくは、ヒドロキシで置換されていてもよいＣ１－４アルキルで、モノ－またはジ－置換されていてもよいアミノ、例えば、アミノ、メチルアミノ、エチルアミノ、プロピルアミノ、ジメチルアミノ、（ヒドロキシエチル）アミノ）、
　　　　（ｂ）Ｃ３－６シクロアルキルアミノ（例、シクロプロピルアミノ）、
　　　　（ｃ）置換されていてもよい４～１０員含窒素複素環－アミノ（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは、１または２個、より好ましくは１個）含有していてもよい、５または６員芳香族含窒素複素環－アミノ、より好ましくは、ピリジルアミノ）、および
　　　　（ｄ）Ｃ１－６アルコキシアミノ（好ましくはＣ１－４アルコキシアミノ、例えばメトキシアミノ）
から選ばれる１個の置換基で置換された、カルボニルアミノ、
（１３）（ａ）Ｃ１－６アルキルでモノ－またはジ－置換されていてもよいアミノ（好ましくは、Ｃ１－４アルキルでモノ－またはジ－置換されていてもよいアミノ、例えば、アミノ、メチルアミノ、エチルアミノ、ジメチルアミノ）、
　　　　（ｂ）ヒドロキシで置換されていてもよいフェノキシ（例、ヒドロキシフェノキシ）、および
　　　　（ｃ）（ｉ）オキソ、および
　　　　　　　（ｉｉ）Ｃ１－６アルキル－カルボニル（例、メチルカルボニル）
　　　　　　　から選ばれる１ないし３個（好ましくは１または２個）の置換基で置換されていてもよい、４～１０員含窒素複素環基（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは１または２個、より好ましくは１個）含有していてもよい、４～１０員の飽和または不飽和（好ましくは飽和）の非芳香族含窒素複素環基）（例、チオモルホリニル、ピペラジニル、モルホリニル）
から選ばれる１個の置換基で置換された、スルホニルアミノ、
（１４）（ａ）（ｉ）Ｃ１－６アルキルでモノ－またはジ－置換されていてもよいアミノ（好ましくは、Ｃ１－４アルキルでモノ－またはジ－置換されていてもよいアミノ、例えば、アミノ、エチルアミノ、エチルメチルアミノ）、
　　　　　　　（ｉｉ）オキソ、
　　　　　　　（ｉｉｉ）置換されていてもよい４～１０員含窒素複素環基（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは、１または２個、より好ましくは１個）含有していてもよい、４～１０員の飽和または不飽和（好ましくは飽和）の非芳香族含窒素複素環基、例えば、モルホリニル、ピペラジニル、ピペリジニル）、および
　　　　　　　（ｉｖ）ヒドロキシ
　　　　から選ばれる１ないし３個の置換基で置換されていてもよい、Ｃ４－６シクロアルケニル（例、シクロブテニル、シクロペンテニル、シクロヘキセニル）、
　　　　（ｂ）Ｃ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）
から選ばれる１または２個の置換基で置換されたアミノ、
（１５）１または２個のハロゲン原子で置換されたアミノ
等が挙げられる。 As “optionally substituted amino”,
(1) amino,
(2) Mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, di-) Propylamino, ethylmethylamino, etc.),
(3) C 3-6 cycloalkylamino (eg, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino),
(4) C 6-12 arylamino (eg, phenylamino, 1-naphthylamino, 2-naphthylamino, etc.),
(5) C 7-12 aralkylamino (eg, benzylamino, 2-phenylethylamino, 1-phenylethylamino, etc.),
(6) Hydrazino,
(7) mono- or di- (C 1-6 alkylsulfonyl) amino (preferably mono- or di- (C 1-4 alkylsulfonyl) amino, such as methylsulfonylamino),
(8) mono- or di- (C 1-6 alkyl-carbonyl) amino (preferably mono- or di- (C 1-4 alkyl-carbonyl) amino, eg methylcarbonylamino),
(9) mono- or di- (C 1-6 alkoxy-carbonyl) amino (preferably mono- or di- (C 1-4 alkoxy-carbonyl) amino, such as methoxycarbonylamino, ethoxycarbonylamino),
(10) an optionally substituted cyclic amino;
(11) (a) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably a hetero atom selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) Or 4 to 10-membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group which may be contained (preferably 1 or 2, more preferably 1)),
(B) aminocarbonylimino,
(C) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino, such as methylamino),
(D) hydroxycarbonyl, and (e) phenyl (eg methoxyphenyl) optionally substituted with C 1-6 alkoxy (preferably C 1-4 alkoxy, eg methoxy)
Mono- or di-C 1-6 alkyl (preferably C 1-4 alkyl) amino (eg, morpholinylethylamino, [(amino), optionally substituted with 1 to 3 substituents selected from Carbonylimino) (methylamino) methyl] amino, (hydroxycarbonylmethyl) amino, (methoxyphenylmethyl) amino),
(12) (a) C 1-6 alkyl optionally substituted with hydroxy, optionally mono- or di-substituted amino (preferably C 1-4 alkyl optionally substituted with hydroxy) And optionally mono- or di-substituted amino, such as amino, methylamino, ethylamino, propylamino, dimethylamino, (hydroxyethyl) amino),
(B) C 3-6 cycloalkylamino (eg, cyclopropylamino),
(C) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic-amino (preferably 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) (Preferably 1 or 2, more preferably 1), 5 or 6-membered aromatic nitrogen-containing heterocyclic-amino, more preferably pyridylamino), and (d) C 1- 6 alkoxyamino (preferably C 1-4 alkoxyamino, eg methoxyamino)
A carbonylamino substituted with one substituent selected from
(13) (a) Amino optionally mono- or di-substituted with C 1-6 alkyl (preferably amino optionally mono- or di-substituted with C 1-4 alkyl, eg amino Methylamino, ethylamino, dimethylamino),
(B) phenoxy optionally substituted with hydroxy (eg, hydroxyphenoxy), and (c) (i) oxo, and (ii) C 1-6 alkyl-carbonyl (eg, methylcarbonyl)
A 4- to 10-membered nitrogen-containing heterocyclic group (preferably a nitrogen atom other than a carbon atom and one nitrogen atom) which may be substituted with 1 to 3 (preferably 1 or 2) substituents selected from 4- to 10-membered saturated or unsaturated (preferably 1 to 3 (preferably 1 or 2, more preferably 1) heteroatoms selected from atoms, sulfur atoms and oxygen atoms may be contained. Saturated) non-aromatic nitrogen-containing heterocyclic group) (eg, thiomorpholinyl, piperazinyl, morpholinyl)
A sulfonylamino substituted with one substituent selected from
(14) (a) (i) amino optionally mono- or di-substituted with C 1-6 alkyl (preferably amino optionally mono- or di-substituted with C 1-4 alkyl, For example, amino, ethylamino, ethylmethylamino),
(Ii) oxo,
(Iii) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) (Preferably 1 or 2, more preferably 1) 4 to 10 membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group such as morpholinyl, Piperazinyl, piperidinyl), and (iv) C 4-6 cycloalkenyl (eg, cyclobutenyl, cyclopentenyl, cyclohexenyl) optionally substituted with 1 to 3 substituents selected from hydroxy,
(B) C 1-6 alkyl (preferably C 1-4 alkyl, such as methyl)
Amino substituted with one or two substituents selected from
(15) Amino and the like substituted with 1 or 2 halogen atoms.

　本明細書中、「Ｃ１－６アルコキシカルバモイル」とは、モノまたはジ－Ｃ１－６アルコキシカルバモイルを意味する。 In the present specification, “C 1-6 alkoxycarbamoyl” means mono- or di-C 1-6 alkoxycarbamoyl.

　Ｘで表される「置換されていてもよい低級アルキレン」としては、低級アルキル（好ましくはＣ１－６アルキル、より好ましくはＣ１－４アルキル）、ハロゲン原子およびヒドロキシから選ばれる１ないし４個の置換基で置換されていてもよいＣ１－６アルキレン（好ましくはＣ１－４アルキレン）が挙げられる。好ましくは１ないし４個のＣ１－６アルキルで置換されていてもよいＣ１－６アルキレンであり、より好ましくは１ないし４個のＣ１－４アルキルで置換されていてもよいＣ１－４アルキレン（例、－ＣＨ２－、－Ｃ（ＣＨ３）２－、－ＣＨ２－Ｃ（ＣＨ３）２－）である。
　Ｘで表される「置換されていてもよい低級アルキレン」の別の好ましい態様としては、Ｃ１－６アルキレンである。 The “optionally substituted lower alkylene” represented by X is 1 to 4 selected from lower alkyl (preferably C 1-6 alkyl, more preferably C 1-4 alkyl), halogen atom and hydroxy And C 1-6 alkylene (preferably C 1-4 alkylene) which may be substituted with these substituents. Preferably one to four C 1-6 a C 1-6 alkylene optionally substituted with alkyl, more preferably optionally substituted by one to four C 1-4 alkyl C 1- 4 alkylene (eg, —CH 2 —, —C (CH 3 ) 2 —, —CH 2 —C (CH 3 ) 2 —).
Another preferred embodiment of the “optionally substituted lower alkylene” represented by X is C 1-6 alkylene.

　Ｘで表される「置換されていてもよい５員複素環」は、Ｒ１以外に、置換可能な位置にさらに置換基を有していてもよい。 The “optionally substituted 5-membered heterocyclic ring” represented by X may further have a substituent at a substitutable position in addition to R 1 .

　Ｘで表される「置換されていてもよい５員複素環」の「５員複素環」としては、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし４個（好ましくは１ないし３個）含有する５員芳香族複素環が好ましい。例えば、フラン、チオフェン、ピロール、オキサゾール、イソオキサゾール、チアゾール、イソチアゾール、イミダゾール、ピラゾール、１，２，３－オキサジアゾール、１，２，４－オキサジアゾール、１，３，４－オキサジアゾール、フラザン、１，２，３－チアジアゾール、１，２，４－チアジアゾール、１，３，４－チアジアゾール、１，２，３－トリアゾール、１，２，４－トリアゾール、テトラゾール等が挙げられる。より好ましくは、オキサジアゾール（例、１，２，３－オキサジアゾール、１，２，４－オキサジアゾール、１，３，４－オキサジアゾール、フラザン）またはチアジアゾール（例、１，２，３－チアジアゾール、１，２，４－チアジアゾール、１，３，４－チアジアゾール）であり、さらに好ましくは、オキサジアゾール（例、１，２，４－オキサジアゾール、１，３，４－オキサジアゾール）である。 The “5-membered heterocycle” of the “optionally substituted 5-membered heterocycle” represented by X includes 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to the carbon atom ( A 5-membered aromatic heterocycle containing 1 to 3 is preferred. For example, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadi Examples include azole, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole and the like. More preferably, oxadiazole (eg, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane) or thiadiazole (eg, 1,2 , 3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, and more preferably oxadiazole (eg, 1,2,4-oxadiazole, 1,3,4-). Oxadiazole).

　Ｘで表される「置換されていてもよい５員複素環」の「５員複素環」が有していてもよい置換基としては、
（１）ハロゲン原子、
（２）ヒドロキシ、および
（３）ヒドロキシおよびＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル）
から選ばれる１ないし３個（好ましくは１または２個）の置換基が挙げられる。 As the substituent that the “5-membered heterocycle” of the “optionally substituted 5-membered heterocycle” represented by X may have,
(1) a halogen atom,
(2) hydroxy, and (3) hydroxy, and C 1-6 alkoxy (preferably C 1-4 alkoxy) 1 to 3 substituents optionally substituted by C 1-6 alkyl selected from (preferably C 1-4 alkyl)
1 to 3 (preferably 1 or 2) substituents selected from

　Ｘで表される「置換されていてもよい５員複素環」としては、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個含有する５員芳香族複素環が好ましい。 The “optionally substituted 5-membered heterocycle” represented by X is a 5-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. Is preferred.

　Ｘとしては、１ないし４個のＣ１－６アルキルで置換されていてもよいＣ１－６アルキレン（好ましくは、１ないし４個のＣ１－４アルキルで置換されていてもよいＣ１－４アルキレン）、－ＣＯ－、－ＣＨ２ＣＯ－または炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個含有する５員芳香族複素環（例、１，２，４－オキサジアゾール、１，３，４－オキサジアゾール）が好ましい。
　Ｘの別の好ましい例としては、Ｃ１－６アルキレン（好ましくは、Ｃ１－４アルキレン）、－ＣＯ－、－ＣＨ２ＣＯ－であり、なかでも好ましくはＣ１－６アルキレン（好ましくは、Ｃ１－４アルキレン）、－ＣＯ－である。 The X, 1 to the four C 1-6 alkyl optionally substituted by C 1-6 alkylene (preferably, optionally substituted with one to four C 1-4 alkyl C 1- 4- alkylene), —CO—, —CH 2 CO— or a 5-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms (eg, 1, 2 , 4-oxadiazole, 1,3,4-oxadiazole).
Another preferred example of X is C 1-6 alkylene (preferably C 1-4 alkylene), —CO—, —CH 2 CO—, and among them, C 1-6 alkylene (preferably, C 1-4 alkylene), —CO—.

　Ｒ１で表される「置換されていてもよいアミノ」としては、
（１）アミノ、
（２）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノ）（例、メチルアミノ、エチルアミノ、プロピルアミノ、イソプロピルアミノ、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、エチルメチルアミノ等）、
（３）Ｃ３－６シクロアルキルアミノ（例、シクロプロピルアミノ、シクロブチルアミノ、シクロペンチルアミノ、シクロヘキシルアミノ）、
（４）ヒドラジノ、
（５）モノ－またはジ－（Ｃ１－６アルキルスルホニル）アミノ（好ましくはモノ－またはジ－（Ｃ１－４アルキルスルホニル）アミノ、例えばメチルスルホニルアミノ）、
（６）モノ－またはジ－（Ｃ１－６アルキル－カルボニル）アミノ（好ましくはモノ－またはジ－（Ｃ１－４アルキル－カルボニル）アミノ、例えばメチルカルボニルアミノ）、
（７）モノ－またはジ－（Ｃ１－６アルコキシ－カルボニル）アミノ（好ましくはモノ－またはジ－（Ｃ１－４アルコキシ－カルボニル）アミノ、例えばメトキシカルボニルアミノ、エトキシカルボニルアミノ）、
（８）置換されていてもよい環状アミノ
（９）（ａ）置換されていてもよい４～１０員含窒素複素環基（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは１または２個、より好ましくは１個）含有していてもよい、４～１０員の飽和または不飽和（好ましくは飽和）の非芳香族含窒素複素環基）、
　　　（ｂ）アミノカルボニルイミノ、
　　　（ｃ）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノ、例えばメチルアミノ）、
　　　（ｄ）ヒドロキシカルボニル、および
　　　（ｅ）Ｃ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えばメトキシ）で置換されていてもよい、フェニル（例、メトキシフェニル）
から選ばれる１ないし３個の置換基で置換されていてもよい、モノ－またはジ－Ｃ１－６アルキル（好ましくはＣ１－４アルキル）アミノ（例、モルホリニルエチルアミノ、［（アミノカルボニルイミノ）（メチルアミノ）メチル］アミノ、（ヒドロキシカルボニルメチル）アミノ、（メトキシフェニルメチル）アミノ）、
（１０）（ａ）ヒドロキシで置換されていてもよいＣ１－６アルキルで、モノ－またはジ－置換されていてもよいアミノ（好ましくは、ヒドロキシで置換されていてもよいＣ１－４アルキルで、モノ－またはジ－置換されていてもよいアミノ、例えば、アミノ、メチルアミノ、エチルアミノ、プロピルアミノ、ジメチルアミノ、（ヒドロキシエチル）アミノ）、
　　　　（ｂ）Ｃ３－６シクロアルキルアミノ（例、シクロプロピルアミノ）、
　　　　（ｃ）置換されていてもよい４～１０員含窒素複素環－アミノ（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは、１または２個、より好ましくは１個）含有していてもよい、５または６員芳香族含窒素複素環－アミノ、より好ましくは、ピリジルアミノ）、および
　　　　（ｄ）Ｃ１－６アルコキシアミノ（好ましくはＣ１－４アルコキシアミノ、例えばメトキシアミノ）
から選ばれる１個の置換基で置換された、カルボニルアミノ、
（１１）（ａ）Ｃ１－６アルキルでモノ－またはジ－置換されていてもよいアミノ（好ましくは、Ｃ１－４アルキルでモノ－またはジ－置換されていてもよいアミノ、例えば、アミノ、メチルアミノ、エチルアミノ、ジメチルアミノ）、
　　　　（ｂ）ヒドロキシで置換されていてもよいフェノキシ（例、ヒドロキシフェノキシ）、および
　　　　（ｃ）（ｉ）オキソ、および
　　　　　　　（ｉｉ）Ｃ１－６アルキル－カルボニル（例、メチルカルボニル）
　　　　　　　から選ばれる１ないし３個（好ましくは１または２個）の置換基で置換されていてもよい、４～１０員含窒素複素環基（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは１または２個、より好ましくは１個）含有していてもよい、４～１０員の飽和または不飽和（好ましくは飽和）の非芳香族含窒素複素環基）（例、チオモルホリニル、ピペラジニル、モルホリニル）
から選ばれる１個の置換基で置換された、スルホニルアミノ、
（１２）（ａ）（ｉ）Ｃ１－６アルキルでモノ－またはジ－置換されていてもよいアミノ（好ましくは、Ｃ１－４アルキルでモノ－またはジ－置換されていてもよいアミノ、例えば、アミノ、エチルアミノ、エチルメチルアミノ）、
　　　　　　　（ｉｉ）オキソ、
　　　　　　　（ｉｉｉ）置換されていてもよい４～１０員含窒素複素環基（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは、１または２個、より好ましくは１個）含有していてもよい、４～１０員の飽和または不飽和（好ましくは飽和）の非芳香族含窒素複素環基、例えば、モルホリニル、ピペラジニル、ピペリジニル）、および
　　　　　　　（ｉｖ）ヒドロキシ
　　　　から選ばれる１ないし３個の置換基で置換されていてもよい、Ｃ４－６シクロアルケニル（例、シクロブテニル、シクロペンテニル、シクロヘキセニル）、および
　　　　（ｂ）Ｃ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）
から選ばれる１または２個の置換基で置換されたアミノ、
（１３）１または２個のハロゲン原子で置換されたアミノ
等が挙げられる。 As the “optionally substituted amino” represented by R 1 ,
(1) amino,
(2) Mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, di-) Propylamino, ethylmethylamino, etc.),
(3) C 3-6 cycloalkylamino (eg, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino),
(4) Hydrazino,
(5) mono- or di- (C 1-6 alkylsulfonyl) amino (preferably mono- or di- (C 1-4 alkylsulfonyl) amino, eg methylsulfonylamino),
(6) mono- or di- (C 1-6 alkyl-carbonyl) amino (preferably mono- or di- (C 1-4 alkyl-carbonyl) amino, eg methylcarbonylamino),
(7) mono- or di- (C 1-6 alkoxy-carbonyl) amino (preferably mono- or di- (C 1-4 alkoxy-carbonyl) amino, eg methoxycarbonylamino, ethoxycarbonylamino),
(8) An optionally substituted cyclic amino (9) (a) An optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably a nitrogen atom, sulfur other than a carbon atom and one nitrogen atom) 4 to 10-membered saturated or unsaturated (preferably saturated) which may contain 1 to 3 (preferably 1 or 2, more preferably 1) heteroatoms selected from atoms and oxygen atoms Non-aromatic nitrogen-containing heterocyclic group),
(B) aminocarbonylimino,
(C) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino, such as methylamino),
(D) hydroxycarbonyl, and (e) phenyl (eg methoxyphenyl) optionally substituted with C 1-6 alkoxy (preferably C 1-4 alkoxy, eg methoxy)
Mono- or di-C 1-6 alkyl (preferably C 1-4 alkyl) amino (eg, morpholinylethylamino, [(amino), optionally substituted with 1 to 3 substituents selected from Carbonylimino) (methylamino) methyl] amino, (hydroxycarbonylmethyl) amino, (methoxyphenylmethyl) amino),
(10) (a) C 1-6 alkyl optionally substituted with hydroxy and optionally mono- or di-substituted amino (preferably C 1-4 alkyl optionally substituted with hydroxy) And optionally mono- or di-substituted amino, such as amino, methylamino, ethylamino, propylamino, dimethylamino, (hydroxyethyl) amino),
(B) C 3-6 cycloalkylamino (eg, cyclopropylamino),
(C) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic-amino (preferably 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) (Preferably 1 or 2, more preferably 1), 5 or 6-membered aromatic nitrogen-containing heterocyclic-amino, more preferably pyridylamino), and (d) C 1- 6 alkoxyamino (preferably C 1-4 alkoxyamino, eg methoxyamino)
A carbonylamino substituted with one substituent selected from
(11) (a) Amino optionally mono- or di-substituted with C 1-6 alkyl (preferably amino optionally mono- or di-substituted with C 1-4 alkyl, eg amino Methylamino, ethylamino, dimethylamino),
(B) phenoxy optionally substituted with hydroxy (eg, hydroxyphenoxy), and (c) (i) oxo, and (ii) C 1-6 alkyl-carbonyl (eg, methylcarbonyl)
A 4- to 10-membered nitrogen-containing heterocyclic group (preferably a nitrogen atom other than a carbon atom and one nitrogen atom) which may be substituted with 1 to 3 (preferably 1 or 2) substituents selected from 4- to 10-membered saturated or unsaturated (preferably 1 to 3 (preferably 1 or 2, more preferably 1) heteroatoms selected from atoms, sulfur atoms and oxygen atoms may be contained. Saturated) non-aromatic nitrogen-containing heterocyclic group) (eg, thiomorpholinyl, piperazinyl, morpholinyl)
A sulfonylamino substituted with one substituent selected from
(12) (a) (i) amino optionally mono- or di-substituted with C 1-6 alkyl (preferably amino optionally mono- or di-substituted with C 1-4 alkyl, For example, amino, ethylamino, ethylmethylamino),
(Ii) oxo,
(Iii) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) (Preferably 1 or 2, more preferably 1) 4 to 10 membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group such as morpholinyl, Piperazinyl, piperidinyl), and (iv) C 4-6 cycloalkenyl (eg, cyclobutenyl, cyclopentenyl, cyclohexenyl) optionally substituted with 1 to 3 substituents selected from hydroxy, and (b) C 1-6 alkyl (preferably C 1-4 alkyl, eg methyl)
Amino substituted with one or two substituents selected from
(13) Amino substituted with 1 or 2 halogen atoms.

　Ｒ１で表される「置換されていてもよいアミノ」の別の好ましい態様としては、
（１）モノ－またはジ－Ｃ１－６アルキルアミノ、
（２）Ｃ３－６シクロアルキルアミノ、
（３）ヒドラジノ、
（４）Ｃ１－６アルコキシＣ１－６アルキル、
　　　ハロゲン原子、
　　　Ｃ１－６アルコキシ－カルボニル、
　　　Ｃ１－６アルキル－カルボニル、
　　　Ｃ１－６アルキルスルホニル、
　　　アミノスルホニル、
　　　Ｃ１－６アルキルアミノスルホニル、
　　　カルバモイル、および
　　　Ｃ１－６アルコキシカルバモイル
から選択される１または２個の置換基で置換されていてもよいアミノ
等が挙げられる。 As another preferred embodiment of the “optionally substituted amino” represented by R 1 ,
(1) mono- or di-C 1-6 alkylamino,
(2) C 3-6 cycloalkylamino,
(3) Hydrazino,
(4) C 1-6 alkoxy C 1-6 alkyl,
Halogen atoms,
C 1-6 alkoxy-carbonyl,
C 1-6 alkyl-carbonyl,
C 1-6 alkylsulfonyl,
Aminosulfonyl,
C 1-6 alkylaminosulfonyl,
Examples include carbamoyl and amino optionally substituted with one or two substituents selected from C 1-6 alkoxycarbamoyl.

　Ｒ１で表される「置換されていてもよいアミノ」の更に別の好ましい態様としては、
　　　Ｃ１－６アルキル、
　　　アミノ、
　　　Ｃ３－６シクロアルキル、
　　　Ｃ１－６アルコキシＣ１－６アルキル、
　　　ハロゲン原子、
　　　Ｃ１－６アルコキシ－カルボニル、
　　　Ｃ１－６アルキル－カルボニル、
　　　Ｃ１－６アルキルスルホニル、
　　　アミノスルホニル、
　　　Ｃ１－６アルキルアミノスルホニル、
　　　カルバモイルおよび
　　　Ｃ１－６アルコキシカルバモイル
から選択される１または２個の置換基で置換されていてもよいアミノ
等が挙げられる。なかでもより好ましくは、
　　　Ｃ１－６アルキル、
　　　Ｃ１－６アルキル－カルボニル、
　　　Ｃ１－６アルキルキルスルホニル、
　　　アミノスルホニル、
　　　カルバモイルおよび
　　　モノ－Ｃ１－６アルコキシカルバモイル
から選択される１または２個の置換基で置換されたアミノ
である。 As still another preferred embodiment of the “optionally substituted amino” represented by R 1 ,
C 1-6 alkyl,
amino,
C 3-6 cycloalkyl,
C 1-6 alkoxy C 1-6 alkyl,
Halogen atoms,
C 1-6 alkoxy-carbonyl,
C 1-6 alkyl-carbonyl,
C 1-6 alkylsulfonyl,
Aminosulfonyl,
C 1-6 alkylaminosulfonyl,
And amino optionally substituted with one or two substituents selected from carbamoyl and C 1-6 alkoxycarbamoyl. More preferably,
C 1-6 alkyl,
C 1-6 alkyl-carbonyl,
C 1-6 alkylkylsulfonyl,
Aminosulfonyl,
Amino substituted with one or two substituents selected from carbamoyl and mono-C 1-6 alkoxycarbamoyl.

　Ｒ１で表される「置換されていてもよいアミノ」としては、
（１）アミノ、
（２）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノ）（例、メチルアミノ、エチルアミノ、プロピルアミノ、イソプロピルアミノ、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、エチルメチルアミノ等）、
（３）ヒドラジノ、
（４）モノ－またはジ－（Ｃ１－６アルキルスルホニル）アミノ（好ましくはモノ－またはジ－（Ｃ１－４アルキルスルホニル）アミノ、例えばメチルスルホニルアミノ）、
（５）モノ－またはジ－（Ｃ１－６アルキル－カルボニル）アミノ（好ましくはモノ－またはジ－（Ｃ１－４アルキル－カルボニル）アミノ、例えばメチルカルボニルアミノ）、
（６）モノ－またはジ－（Ｃ１－６アルコキシ－カルボニル）アミノ（好ましくはモノ－またはジ－（Ｃ１－４アルコキシ－カルボニル）アミノ、例えばメトキシカルボニルアミノ、エトキシカルボニルアミノ）、
（７）置換されていてもよい環状アミノ、
（８）（ａ）置換されていてもよい４～１０員含窒素複素環基（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは１または２個、より好ましくは１個）含有していてもよい、４～１０員の飽和または不飽和（好ましくは飽和）の非芳香族含窒素複素環基）、
　　　（ｂ）アミノカルボニルイミノ、
　　　（ｃ）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノ、例えばメチルアミノ）、
　　　（ｄ）ヒドロキシカルボニル、および
　　　（ｅ）Ｃ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えばメトキシ）で置換されていてもよい、フェニル（例、メトキシフェニル）
から選ばれる１ないし３個の置換基で置換されていてもよい、モノ－またはジ－Ｃ１－６アルキル（好ましくはＣ１－４アルキル）アミノ（例、モルホリニルエチルアミノ、［（アミノカルボニルイミノ）（メチルアミノ）メチル］アミノ、（ヒドロキシカルボニルメチル）アミノ、（メトキシフェニルメチル）アミノ）、
（９）（ａ）ヒドロキシで置換されていてもよいＣ１－６アルキルで、モノ－またはジ－置換されていてもよいアミノ（好ましくは、ヒドロキシで置換されていてもよいＣ１－４アルキルで、モノ－またはジ－置換されていてもよいアミノ、例えば、アミノ、メチルアミノ、エチルアミノ、プロピルアミノ、ジメチルアミノ、（ヒドロキシエチル）アミノ）、
　　　　（ｂ）Ｃ３－６シクロアルキルアミノ（例、シクロプロピルアミノ）、
　　　　（ｃ）置換されていてもよい４～１０員含窒素複素環－アミノ（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは、１または２個、より好ましくは１個）含有していてもよい、５または６員芳香族含窒素複素環－アミノ、より好ましくは、ピリジルアミノ）、および
　　　　（ｄ）Ｃ１－６アルコキシアミノ（好ましくはＣ１－４アルコキシアミノ、例えばメトキシアミノ）
から選ばれる１個の置換基で置換された、カルボニルアミノ、および
（１０）（ａ）Ｃ１－６アルキルでモノ－またはジ－置換されていてもよいアミノ（好ましくは、Ｃ１－４アルキルでモノ－またはジ－置換されていてもよいアミノ、例えば、アミノ、メチルアミノ、エチルアミノ、ジメチルアミノ）、
　　　　（ｂ）ヒドロキシで置換されていてもよいフェノキシ（例、ヒドロキシフェノキシ）、および
　　　　（ｃ）（ｉ）オキソ、および
　　　　　　　（ｉｉ）Ｃ１－６アルキル－カルボニル（例、メチルカルボニル）
　　　　　　　から選ばれる１ないし３個（好ましくは１または２個）の置換基で置換されていてもよい、４～１０員含窒素複素環基（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは１または２個、より好ましくは１個）含有していてもよい、４～１０員の飽和または不飽和（好ましくは飽和）の非芳香族含窒素複素環基）（例、チオモルホリニル、ピペラジニル、モルホリニル）
から選ばれる１個の置換基で置換された、スルホニルアミノ、および
（１１）（ａ）（ｉ）Ｃ１－６アルキルでモノ－またはジ－置換されていてもよいアミノ（好ましくは、Ｃ１－４アルキルでモノ－またはジ－置換されていてもよいアミノ、例えば、アミノ、エチルアミノ、エチルメチルアミノ）、
　　　　　　　（ｉｉ）オキソ、
　　　　　　　（ｉｉｉ）置換されていてもよい４～１０員含窒素複素環基（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは、１または２個、より好ましくは１個）含有していてもよい、４～１０員の飽和または不飽和（好ましくは飽和）の非芳香族含窒素複素環基、例えば、モルホリニル、ピペラジニル、ピペリジニル）、および
　　　　　　　（ｉｖ）ヒドロキシ
　　　　から選ばれる１ないし３個の置換基で置換されていてもよい、Ｃ４－６シクロアルケニル（例、シクロブテニル、シクロペンテニル、シクロヘキセニル）、および
　　　　（ｂ）Ｃ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）
から選ばれる１または２個の置換基で置換されたアミノ
が好ましい。 As the “optionally substituted amino” represented by R 1 ,
(1) amino,
(2) Mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, di-) Propylamino, ethylmethylamino, etc.),
(3) Hydrazino,
(4) mono- or di- (C 1-6 alkylsulfonyl) amino (preferably mono- or di- (C 1-4 alkylsulfonyl) amino, eg methylsulfonylamino),
(5) mono- or di- (C 1-6 alkyl-carbonyl) amino (preferably mono- or di- (C 1-4 alkyl-carbonyl) amino, eg methylcarbonylamino),
(6) mono- or di- (C 1-6 alkoxy-carbonyl) amino (preferably mono- or di- (C 1-4 alkoxy-carbonyl) amino, eg methoxycarbonylamino, ethoxycarbonylamino),
(7) an optionally substituted cyclic amino;
(8) (a) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably a hetero atom selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) Or 4 to 10-membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group which may be contained (preferably 1 or 2, more preferably 1)),
(B) aminocarbonylimino,
(C) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino, such as methylamino),
(D) hydroxycarbonyl, and (e) phenyl (eg methoxyphenyl) optionally substituted with C 1-6 alkoxy (preferably C 1-4 alkoxy, eg methoxy)
Mono- or di-C 1-6 alkyl (preferably C 1-4 alkyl) amino (eg, morpholinylethylamino, [(amino), optionally substituted with 1 to 3 substituents selected from Carbonylimino) (methylamino) methyl] amino, (hydroxycarbonylmethyl) amino, (methoxyphenylmethyl) amino),
(9) (a) C 1-6 alkyl optionally substituted with hydroxy, optionally mono- or di-substituted amino (preferably C 1-4 alkyl optionally substituted with hydroxy) And optionally mono- or di-substituted amino, such as amino, methylamino, ethylamino, propylamino, dimethylamino, (hydroxyethyl) amino),
(B) C 3-6 cycloalkylamino (eg, cyclopropylamino),
(C) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic-amino (preferably 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) (Preferably 1 or 2, more preferably 1), 5 or 6-membered aromatic nitrogen-containing heterocyclic-amino, more preferably pyridylamino), and (d) C 1- 6 alkoxyamino (preferably C 1-4 alkoxyamino, eg methoxyamino)
(10) (a) amino optionally substituted mono- or di-substituted with C 1-6 alkyl (preferably C 1-4 alkyl), substituted with one substituent selected from Optionally mono- or di-substituted amino such as amino, methylamino, ethylamino, dimethylamino),
(B) phenoxy optionally substituted with hydroxy (eg, hydroxyphenoxy), and (c) (i) oxo, and (ii) C 1-6 alkyl-carbonyl (eg, methylcarbonyl)
A 4- to 10-membered nitrogen-containing heterocyclic group (preferably a nitrogen atom other than a carbon atom and one nitrogen atom) which may be substituted with 1 to 3 (preferably 1 or 2) substituents selected from 4- to 10-membered saturated or unsaturated (preferably 1 to 3 (preferably 1 or 2, more preferably 1) heteroatoms selected from atoms, sulfur atoms and oxygen atoms may be contained. Saturated) non-aromatic nitrogen-containing heterocyclic group) (eg, thiomorpholinyl, piperazinyl, morpholinyl)
Sulfonylamino substituted with one substituent selected from: and (11) (a) (i) amino optionally mono- or di-substituted with C 1-6 alkyl (preferably C 1 Amino optionally mono- or di-substituted with -4 alkyl, such as amino, ethylamino, ethylmethylamino),
(Ii) oxo,
(Iii) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) (Preferably 1 or 2, more preferably 1) 4 to 10 membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group such as morpholinyl, Piperazinyl, piperidinyl), and (iv) C 4-6 cycloalkenyl (eg, cyclobutenyl, cyclopentenyl, cyclohexenyl) optionally substituted with 1 to 3 substituents selected from hydroxy, and (b) C 1-6 alkyl (preferably C 1-4 alkyl, eg methyl)
Preferred is amino substituted with 1 or 2 substituents selected from:

　Ｒ１で表される「置換されていてもよい低級アルキル」としては、ハロゲン原子およびヒドロキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル、例えば、メチル、エチル、イソプロピル）が挙げられる。 The “optionally substituted lower alkyl” represented by R 1 is C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy (preferably C 1 -4 alkyl, such as methyl, ethyl, isopropyl).

　Ｒ１で表される「置換されていてもよい低級アルコキシ」としては、以下の（ａ）～（ｆ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ等）が挙げられる：
　　　（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ、
　　　（ｃ）オキソ、
　　　（ｄ）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノ、例えばエチルアミノ）、
　　　（ｅ）４ないし１０員飽和複素環基（例、アゼチジニル、ピロリジニル、ピペリジニル、ピペラジニル）、および
　　　（ｆ）１ないし３個のハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）で置換されていてもよいＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ等）。 The “optionally substituted lower alkoxy” represented by R 1 is C 1-6 alkoxy optionally substituted with 1 to 3 substituents selected from the following (a) to (f): (Preferably C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.)
(A) a halogen atom,
(B) hydroxy,
(C) oxo,
(D) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino, such as ethylamino),
(E) a 4- to 10-membered saturated heterocyclic group (eg, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl), and (f) 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) Optionally substituted C 1-6 alkoxy (preferably C 1-4 alkoxy, eg methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.).

　Ｒ１で表される「置換されていてもよいフェニル」としては、
（１）ハロゲン原子、
（２）シアノ、
（３）ヒドロキシ、
（４）ニトロ、
（５）ホルミル、
（６）アミノ、
（７）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノ）、
（８）Ｃ１－６アルキル－カルボニルアミノ（好ましくはＣ１－４アルキル－カルボニルアミノ）、
（９）Ｃ１－６アルコキシ－カルボニルアミノ（好ましくはＣ１－４アルコキシ－カルボニルアミノ）、
（１０）１ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ）、
（１１）Ｃ１－６アルキル－カルボニルオキシ（好ましくはＣ１－４アルキル－カルボニルオキシ）、
（１２）カルボキシ、
（１３）Ｃ１－６アルコキシ－カルボニル（好ましくはＣ１－４アルコキシ－カルボニル）、および
（１４）１ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル）
から選ばれる１ないし３個の置換基で置換されていてもよいフェニルが挙げられる。Ｒ１で表される「置換されていてもよいフェニル」としては、フェニルが好ましい。 As the “optionally substituted phenyl” represented by R 1 ,
(1) a halogen atom,
(2) cyano,
(3) hydroxy,
(4) Nitro,
(5) Formyl,
(6) amino,
(7) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino),
(8) C 1-6 alkyl-carbonylamino (preferably C 1-4 alkyl-carbonylamino),
(9) C 1-6 alkoxy-carbonylamino (preferably C 1-4 alkoxy-carbonylamino),
(10) C 1-6 alkoxy (preferably C 1-4 alkoxy) optionally substituted by 1 to 3 halogen atoms,
(11) C 1-6 alkyl-carbonyloxy (preferably C 1-4 alkyl-carbonyloxy),
(12) Carboxy,
(13) C 1-6 alkoxy - carbonyl (preferably C 1-4 alkoxy - carbonyl), and (14) 1 to 3 halogen atoms optionally substituted by a C 1-6 alkyl (preferably C 1 -4 alkyl)
And phenyl optionally substituted by 1 to 3 substituents selected from: The “optionally substituted phenyl” represented by R 1 is preferably phenyl.

　Ｒ１で表される「置換されていてもよい４～１０員含窒素複素環基」の「４～１０員含窒素複素環基」としては、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは１または２個、より好ましくは１個）含有していてもよい、４～１０員の飽和非芳香族含窒素複素環基、ならびにフタルイミドが好ましい。４～１０員の飽和非芳香族含窒素複素環基としては、例えば、アゼチジニル、ピロリジニル、ピペリジニル、モルホリニル、チオモルホリニル、ピペラジニル、アゼパニル、ジアゼパニル（例、１，４－ジアゼパニル）、オキサゼパニル（例、１，４－オキサゼパニル）、オキサゾリジニル、イソオキサゾリジニル、チアゾリジニル、イソチアゾリジニル、イミダゾリジニル、ピラゾリジニル、オキサジアゾリジニル（例、１，２，４－オキサジアゾリジニル、１，３，４－オキサジアゾリジニル）、チアジアゾリジニル（例、１，２，４－チアジアゾリジニル、１，３，４－チアジアゾリジニル）、１，３，８－トリアザスピロ［４．５]デカニル等が挙げられる。該飽和非芳香族含窒素複素環基のなかでもより好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子１個を含有していてもよい、４～１０員の飽和非芳香族含窒素複素環基であり、さらに好ましくは、１，３，８－トリアザスピロ［４．５]デカニル、アゼチジニル、チアゾリジニル、イミダゾリジニル、ピロリジニル、ピペリジニル、ピペラジニルまたはモルホリニルである。該４～１０員の飽和非芳香族含窒素複素環基およびフタルイミドは、窒素原子を介してＸに結合するものが好ましい。 The “4- to 10-membered nitrogen-containing heterocyclic group” of the “optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group” represented by R 1 is a nitrogen atom in addition to a carbon atom and one nitrogen atom. A 4- to 10-membered saturated non-aromatic nitrogen-containing heterocycle which may contain 1 to 3 (preferably 1 or 2, more preferably 1) heteroatoms selected from sulfur atom and oxygen atom Groups as well as phthalimide are preferred. Examples of the 4- to 10-membered saturated non-aromatic nitrogen-containing heterocyclic group include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl (eg, 1,4-diazepanyl), oxazepanyl (eg, 1, 4-oxazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, pyrazolidinyl, oxadiazolidinyl (eg, 1,2,4-oxadiazolidinyl, 1,3,4-oxadiazinyl) Lysinyl), thiadiazolidinyl (eg, 1,2,4-thiadiazolidinyl, 1,3,4-thiadiazolidinyl), 1,3,8-triazaspiro [4.5] decanyl and the like It is done. More preferably, the saturated non-aromatic nitrogen-containing heterocyclic group may contain one heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to the carbon atom and one nitrogen atom. 4- to 10-membered saturated non-aromatic nitrogen-containing heterocyclic group, more preferably 1,3,8-triazaspiro [4.5] decanyl, azetidinyl, thiazolidinyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl . The 4- to 10-membered saturated non-aromatic nitrogen-containing heterocyclic group and phthalimide are preferably bonded to X through a nitrogen atom.

　Ｒ１で表される「置換されていてもよい４～１０員含窒素複素環基」の「４～１０員含窒素複素環基」が有していてもよい置換基としては、
（１）ハロゲン原子（例、フッ素原子）、
（２）ヒドロキシ、
（３）ヒドロキシおよびＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）、
（４）置換されていてもよいＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えばメトキシ）、
（５）置換されていてもよいカルバモイル（好ましくはモノまたはジ－Ｃ１－６アルキル－カルバモイル、より好ましくはモノまたはジ－Ｃ１－４アルキル－カルバモイル、例えばジメチルカルバモイル）、および
（６）オキソ
から選ばれる１ないし３個の置換基が挙げられる。 As the substituent that the “4- to 10-membered nitrogen-containing heterocyclic group” of the “optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group” represented by R 1 may have,
(1) a halogen atom (eg, fluorine atom),
(2) hydroxy,
(3) hydroxy, and C 1-6 alkoxy (preferably C 1-4 alkoxy) 1 to 3 substituents optionally substituted by C 1-6 alkyl selected from (preferably C 1-4 alkyl, Eg methyl),
(4) optionally substituted C 1-6 alkoxy (preferably C 1-4 alkoxy, such as methoxy),
(5) an optionally substituted carbamoyl (preferably mono or di-C 1-6 alkyl-carbamoyl, more preferably mono or di-C 1-4 alkyl-carbamoyl, eg dimethylcarbamoyl), and (6) oxo 1 to 3 substituents selected from

　Ｒ１で表される「置換されていてもよいメルカプト」としては、Ｃ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）で置換されていてもよいメルカプトが挙げられ、例えば、メチルチオ、エチルチオ、プロピルチオ、イソプロピルチオ、ブチルチオが挙げられる。 Examples of the “optionally substituted mercapto” represented by R 1 include a mercapto optionally substituted with C 1-6 alkyl (preferably C 1-4 alkyl, such as methyl). , Ethylthio, propylthio, isopropylthio, butylthio.

　Ｒ１で表される「置換スルホニル」としては、Ｃ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）で置換されたスルホニルが挙げられ、例えば、メチルスルホニル、エチルスルホニル、プロピルスルホニル、イソプロピルスルホニル、ブチルスルホニルが挙げられる。 “Substituted sulfonyl” represented by R 1 includes sulfonyl substituted with C 1-6 alkyl (preferably C 1-4 alkyl, such as methyl), and examples thereof include methylsulfonyl, ethylsulfonyl, propylsulfonyl, Examples include isopropylsulfonyl and butylsulfonyl.

　Ｒ１としては、
（１）ヒドロキシ、
（２）シアノ、
（３）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノ）（例、メチルアミノ、エチルアミノ、プロピルアミノ、イソプロピルアミノ、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、エチルメチルアミノ等）、
（４）Ｃ３－６シクロアルキルアミノ（例、シクロプロピルアミノ、シクロブチルアミノ、シクロペンチルアミノ、シクロヘキシルアミノ）、
（５）ヒドラジノ、
（６）ハロゲン原子およびヒドロキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル、エチル、イソプロピル）、
（７）以下の（ａ）～（ｆ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ等）
　　　（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ、
　　　（ｃ）オキソ、
　　　（ｄ）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノ、例えばエチルアミノ）、
　　　（ｅ）４ないし１０員飽和複素環基（例、アゼチジニル、ピロリジニル、ピペリジニル、ピペラジニル等）、および
　　　（ｆ）１ないし３個のハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）で置換されていてもよいＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ等）、
（８）フェニル、
（９）以下の（ａ）～（ｆ）から選ばれる１ないし３個の置換基で置換されていてもよい、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子１個を含有していてもよい、４～１０員の飽和非芳香族含窒素複素環基（例、１，３，８－トリアザスピロ［４．５]デカニル、アゼチジニル、チアゾリジニル、イミダゾリジニル、ピロリジニル、ピペリジニル、ピペラジニル、モルホリニル）
　　　（ａ）ハロゲン原子（例、フッ素原子）、
　　　（ｂ）ヒドロキシ、
　　　（ｃ）ヒドロキシおよびＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えばメトキシ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）、
　　　（ｄ）Ｃ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えばメトキシ）、
　　　（ｅ）モノ－またはジ－Ｃ１－６アルキルカルバモイル（好ましくはモノ－またはジ－Ｃ１－４アルキルカルバモイル、例えば、ジメチルカルバモイル）、および
　　　（ｆ）オキソ、
（１０）モノ－またはジ－（Ｃ１－６アルキルスルホニル）アミノ（好ましくはモノ－またはジ－（Ｃ１－４アルキルスルホニル）アミノ、例えばメチルスルホニルアミノ）、
（１１）モノ－またはジ－（Ｃ１－６アルキル－カルボニル）アミノ（好ましくはモノ－またはジ－（Ｃ１－４アルキル－カルボニル）アミノ、例えばメチルカルボニルアミノ）、
（１２）モノ－またはジ－（Ｃ１－６アルコキシ－カルボニル）アミノ（好ましくはモノ－またはジ－（Ｃ１－４アルコキシ－カルボニル）アミノ、例えばメトキシカルボニルアミノ、エトキシカルボニルアミノ）、
（１３）アミノ、
（１４）フタルイミド、
（１５）（ａ）置換されていてもよい４～１０員含窒素複素環基（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは１または２個、より好ましくは１個）含有していてもよい、４～１０員の飽和または不飽和（好ましくは飽和）の非芳香族含窒素複素環基）、
　　　（ｂ）アミノカルボニルイミノ、
　　　（ｃ）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノ、例えばメチルアミノ）、
　　　（ｄ）ヒドロキシカルボニル、および
　　　（ｅ）Ｃ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えばメトキシ）で置換されていてもよい、フェニル（例、メトキシフェニル）
から選ばれる１ないし３個の置換基で置換されていてもよい、モノ－またはジ－Ｃ１－６アルキル（好ましくはＣ１－４アルキル）アミノ（例、モルホリニルエチルアミノ、［（アミノカルボニルイミノ）（メチルアミノ）メチル］アミノ、（ヒドロキシカルボニルメチル）アミノ、（メトキシフェニルメチル）アミノ）、
（１６）（ａ）ヒドロキシで置換されていてもよいＣ１－６アルキルで、モノ－またはジ－置換されていてもよいアミノ（好ましくは、ヒドロキシで置換されていてもよいＣ１－４アルキルで、モノ－またはジ－置換されていてもよいアミノ、例えば、アミノ、メチルアミノ、エチルアミノ、プロピルアミノ、ジメチルアミノ、（ヒドロキシエチル）アミノ）、
　　　　（ｂ）Ｃ３－６シクロアルキルアミノ（例、シクロプロピルアミノ）、
　　　　（ｃ）置換されていてもよい４～１０員含窒素複素環－アミノ（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは、１または２個、より好ましくは１個）含有していてもよい、５または６員芳香族含窒素複素環－アミノ、より好ましくは、ピリジルアミノ）、および
　　　　（ｄ）Ｃ１－６アルコキシアミノ（好ましくはＣ１－４アルコキシアミノ、例えばメトキシアミノ）
から選ばれる１個の置換基で置換された、カルボニルアミノ、および
（１７）（ａ）Ｃ１－６アルキルでモノ－またはジ－置換されていてもよいアミノ（好ましくは、Ｃ１－４アルキルでモノ－またはジ－置換されていてもよいアミノ、例えば、アミノ、メチルアミノ、エチルアミノ、ジメチルアミノ）、
　　　　（ｂ）ヒドロキシで置換されていてもよいフェノキシ（例、ヒドロキシフェノキシ）、および
　　　　（ｃ）（ｉ）オキソ、および
　　　　　　　（ｉｉ）Ｃ１－６アルキル－カルボニル（例、メチルカルボニル）
　　　　　　　から選ばれる１ないし３個（好ましくは１または２個）の置換基で置換されていてもよい、４～１０員含窒素複素環基（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは１または２個、より好ましくは１個）含有していてもよい、４～１０員の飽和または不飽和（好ましくは飽和）の非芳香族含窒素複素環基）（例、チオモルホリニル、ピペラジニル、モルホリニル）
から選ばれる１個の置換基で置換された、スルホニルアミノ、
（１８）（ａ）（ｉ）Ｃ１－６アルキルでモノ－またはジ－置換されていてもよいアミノ（好ましくは、Ｃ１－４アルキルでモノ－またはジ－置換されていてもよいアミノ、より好ましくは、アミノ、エチルアミノ、エチルメチルアミノ）、
　　　　　　　（ｉｉ）オキソ、
　　　　　　　（ｉｉｉ）置換されていてもよい４～１０員含窒素複素環基（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは、１または２個、より好ましくは１個）含有していてもよい、４～１０員の飽和または不飽和（好ましくは飽和）の非芳香族含窒素複素環基、例えば、モルホリニル、ピペラジニル、ピペリジニル）、および
　　　　　　　（ｉｖ）ヒドロキシ
　　　　から選ばれる１ないし３個の置換基で置換されていてもよい、Ｃ４－６シクロアルケニル（例、シクロブテニル、シクロペンテニル、シクロヘキセニル）、および
　　　　（ｂ）Ｃ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）
から選ばれる１または２個の置換基で置換されたアミノ、
（１９）Ｃ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）で置換されていてもよいメルカプト、および
（２０）Ｃ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）で置換されたスルホニル
が好ましい。 As R 1 ,
(1) hydroxy,
(2) cyano,
(3) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, di-) Propylamino, ethylmethylamino, etc.),
(4) C 3-6 cycloalkylamino (eg, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino),
(5) Hydrazino,
(6) C 1-6 alkyl (preferably C 1-4 alkyl such as methyl, ethyl, isopropyl) optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy,
(7) C 1-6 alkoxy optionally substituted with 1 to 3 substituents selected from the following (a) to (f) (preferably C 1-4 alkoxy such as methoxy, ethoxy, propoxy , Isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.)
(A) a halogen atom,
(B) hydroxy,
(C) oxo,
(D) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino, such as ethylamino),
(E) a 4- to 10-membered saturated heterocyclic group (eg, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, etc.), and (f) 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) C 1-6 alkoxy optionally substituted by (preferably C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.),
(8) phenyl,
(9) In addition to carbon atom and one nitrogen atom, which may be substituted with 1 to 3 substituents selected from the following (a) to (f), selected from nitrogen atom, sulfur atom and oxygen atom A 4- to 10-membered saturated non-aromatic nitrogen-containing heterocyclic group (eg, 1,3,8-triazaspiro [4.5] decanyl, azetidinyl, thiazolidinyl, imidazolidinyl, Pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl)
(A) a halogen atom (eg, fluorine atom),
(B) hydroxy,
(C) hydroxy, and C 1-6 alkoxy (preferably C 1-4 alkoxy such as methoxy) 1 to 3 substituents optionally substituted by C 1-6 alkyl selected from (preferably C 1- 4 alkyl, such as methyl),
(D) C 1-6 alkoxy (preferably C 1-4 alkoxy, such as methoxy),
(E) mono- or di-C 1-6 alkylcarbamoyl (preferably mono- or di-C 1-4 alkylcarbamoyl, such as dimethylcarbamoyl), and (f) oxo,
(10) mono- or di- (C 1-6 alkylsulfonyl) amino (preferably mono- or di- (C 1-4 alkylsulfonyl) amino, such as methylsulfonylamino),
(11) mono- or di- (C 1-6 alkyl-carbonyl) amino (preferably mono- or di- (C 1-4 alkyl-carbonyl) amino, eg methylcarbonylamino),
(12) Mono- or di- (C 1-6 alkoxy-carbonyl) amino (preferably mono- or di- (C 1-4 alkoxy-carbonyl) amino, such as methoxycarbonylamino, ethoxycarbonylamino),
(13) amino,
(14) phthalimide,
(15) (a) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably a hetero atom selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) Or 4 to 10-membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group which may be contained (preferably 1 or 2, more preferably 1)),
(B) aminocarbonylimino,
(C) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino, such as methylamino),
(D) hydroxycarbonyl, and (e) phenyl (eg methoxyphenyl) optionally substituted with C 1-6 alkoxy (preferably C 1-4 alkoxy, eg methoxy)
Mono- or di-C 1-6 alkyl (preferably C 1-4 alkyl) amino (eg, morpholinylethylamino, [(amino), optionally substituted with 1 to 3 substituents selected from Carbonylimino) (methylamino) methyl] amino, (hydroxycarbonylmethyl) amino, (methoxyphenylmethyl) amino),
(16) (a) C 1-6 alkyl optionally substituted with hydroxy and optionally mono- or di-substituted amino (preferably C 1-4 alkyl optionally substituted with hydroxy) Optionally mono- or di-substituted amino such as amino, methylamino, ethylamino, propylamino, dimethylamino, (hydroxyethyl) amino),
(B) C 3-6 cycloalkylamino (eg, cyclopropylamino),
(C) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic-amino (preferably 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) (Preferably 1 or 2, more preferably 1), 5 or 6-membered aromatic nitrogen-containing heterocyclic-amino, more preferably pyridylamino), and (d) C 1- 6 alkoxyamino (preferably C 1-4 alkoxyamino, eg methoxyamino)
Carbonylamino substituted with one substituent selected from: (17) (a) amino optionally mono- or di-substituted with C 1-6 alkyl (preferably C 1-4 alkyl Optionally mono- or di-substituted amino such as amino, methylamino, ethylamino, dimethylamino),
(B) phenoxy optionally substituted with hydroxy (eg, hydroxyphenoxy), and (c) (i) oxo, and (ii) C 1-6 alkyl-carbonyl (eg, methylcarbonyl)
A 4- to 10-membered nitrogen-containing heterocyclic group (preferably a nitrogen atom other than a carbon atom and one nitrogen atom) which may be substituted with 1 to 3 (preferably 1 or 2) substituents selected from 4- to 10-membered saturated or unsaturated (preferably 1 to 3 (preferably 1 or 2, more preferably 1) heteroatoms selected from atoms, sulfur atoms and oxygen atoms may be contained. Saturated) non-aromatic nitrogen-containing heterocyclic group) (eg, thiomorpholinyl, piperazinyl, morpholinyl)
A sulfonylamino substituted with one substituent selected from
(18) (a) (i) amino optionally mono- or di-substituted with C 1-6 alkyl (preferably amino optionally mono- or di-substituted with C 1-4 alkyl, More preferably, amino, ethylamino, ethylmethylamino),
(Ii) oxo,
(Iii) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) (Preferably 1 or 2, more preferably 1) 4 to 10 membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group such as morpholinyl, Piperazinyl, piperidinyl), and (iv) C 4-6 cycloalkenyl (eg, cyclobutenyl, cyclopentenyl, cyclohexenyl) optionally substituted with 1 to 3 substituents selected from hydroxy, and (b) C 1-6 alkyl (preferably C 1-4 alkyl, eg methyl)
Amino substituted with one or two substituents selected from
(19) mercapto optionally substituted with C 1-6 alkyl (preferably C 1-4 alkyl, eg methyl), and (20) C 1-6 alkyl (preferably C 1-4 alkyl, eg methyl) A sulfonyl substituted with is preferred.

　Ｒ１の別の好ましい態様としては、
（１）ヒドロキシ、
（２）シアノ、
（３）モノ－またはジ－Ｃ１－６アルキルアミノ、
（４）Ｃ３－６シクロアルキルアミノ、
（５）ヒドラジノ、
（６）ハロゲン原子およびヒドロキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル、
（７）ハロゲン原子およびヒドロキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルコキシ、
（８）フェニル、
（９）以下の（ａ）～（ｅ）から選ばれる１ないし３個の置換基で置換されていてもよい、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子１個を含有していてもよい、４～１０員の飽和含窒素複素環基、
　（ａ）ハロゲン原子、
　（ｂ）ヒドロキシ、
　（ｃ）ヒドロキシおよびＣ１－６アルコキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル、
　（ｄ）Ｃ１－６アルコキシ、および
　（ｅ）オキソ、および
（１０）Ｃ１－６アルコキシＣ１－６アルキル、
　　　　ハロゲン原子、
　　　　Ｃ１－６アルコキシ－カルボニル、
　　　　Ｃ１－６アルキル－カルボニル、
　　　　Ｃ１－６アルキルスルホニル、
　　　　アミノスルホニル、
　　　　Ｃ１－６アルキルアミノスルホニル、
　　　　カルバモイルおよび
　　　　Ｃ１－６アルコキシカルバモイル
から選択される１または２個の置換基で置換されていてもよいアミノ
が挙げられる。 As another preferred embodiment of R 1 ,
(1) hydroxy,
(2) cyano,
(3) mono- or di-C 1-6 alkylamino,
(4) C 3-6 cycloalkylamino,
(5) Hydrazino,
(6) C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy,
(7) C 1-6 alkoxy optionally substituted by 1 to 3 substituents selected from a halogen atom and hydroxy,
(8) phenyl,
(9) In addition to carbon atom and one nitrogen atom, which may be substituted with 1 to 3 substituents selected from the following (a) to (e), selected from nitrogen atom, sulfur atom and oxygen atom A 4- to 10-membered saturated nitrogen-containing heterocyclic group which may contain one heteroatom,
(A) a halogen atom,
(B) hydroxy,
(C) hydroxy, and C 1-6 1 to 3 substituents optionally substituted by C 1-6 alkyl selected from alkoxy,
(D) C 1-6 alkoxy, and (e) oxo, and (10) C 1-6 alkoxy C 1-6 alkyl,
Halogen atoms,
C 1-6 alkoxy-carbonyl,
C 1-6 alkyl-carbonyl,
C 1-6 alkylsulfonyl,
Aminosulfonyl,
C 1-6 alkylaminosulfonyl,
And amino optionally substituted with one or two substituents selected from carbamoyl and C 1-6 alkoxycarbamoyl.

　Ｒ１の更に別の好ましい態様としては、
（１）Ｃ１－６アルキル、
　　　オキソ、
　　　ヒドロキシおよび
　　　ヒドロキシＣ１－６アルキル
から選択される１ないし３個の置換基で置換されていてもよい、炭素原子および１個の窒素原子以外に窒素原子および酸素原子から選ばれるヘテロ原子１個を含有していてもよい、５または６員の飽和含窒素複素環基、および
（２）Ｃ１－６アルキル、
　　　アミノ、
　　　Ｃ３－６シクロアルキル、
　　　Ｃ１－６アルコキシＣ１－６アルキル、
　　　ハロゲン原子、
　　　Ｃ１－６アルコキシ－カルボニル、
　　　Ｃ１－６アルキル－カルボニル、
　　　Ｃ１－６アルキルスルホニル、
　　　アミノスルホニル、
　　　Ｃ１－６アルキルアミノスルホニル、
　　　カルバモイルおよび
　　　Ｃ１－６アルコキシカルバモイル
から選択される１または２個の置換基で置換されていてもよいアミノ
が挙げられる。なかでもより好ましくは、
（１）ヒドロキシおよびヒドロキシＣ１－６アルキルから選択される１個の置換基で置換されていてもよいピロリジニル、および
（２）Ｃ１－６アルキル、
　　　Ｃ１－６アルキル－カルボニル、
　　　Ｃ１－６アルキルキルスルホニル、
　　　アミノスルホニル、
　　　カルバモイルおよび
　　　モノ－Ｃ１－６アルコキシカルバモイル
から選択される１または２個の置換基で置換されたアミノ
である。 As still another preferred embodiment of R 1 ,
(1) C 1-6 alkyl,
Oxo,
One heteroatom selected from a nitrogen atom and an oxygen atom, in addition to a carbon atom and one nitrogen atom, optionally substituted by 1 to 3 substituents selected from hydroxy and hydroxy C 1-6 alkyl A 5- or 6-membered saturated nitrogen-containing heterocyclic group which may be contained, and (2) C 1-6 alkyl,
amino,
C 3-6 cycloalkyl,
C 1-6 alkoxy C 1-6 alkyl,
Halogen atoms,
C 1-6 alkoxy-carbonyl,
C 1-6 alkyl-carbonyl,
C 1-6 alkylsulfonyl,
Aminosulfonyl,
C 1-6 alkylaminosulfonyl,
And amino optionally substituted with one or two substituents selected from carbamoyl and C 1-6 alkoxycarbamoyl. More preferably,
(1) pyrrolidinyl optionally substituted with one substituent selected from hydroxy and hydroxy C 1-6 alkyl, and (2) C 1-6 alkyl,
C 1-6 alkyl-carbonyl,
C 1-6 alkylkylsulfonyl,
Aminosulfonyl,
Amino substituted with one or two substituents selected from carbamoyl and mono-C 1-6 alkoxycarbamoyl.

　Ｒ２で表される「ハロゲン原子」としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。 "Halogen atom" represented by R 2 include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom.

　Ｒ２で表される「置換されていてもよい低級アルキル」としては、ハロゲン原子（例えば塩素原子）、ヒドロキシおよびＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えばメトキシ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）が挙げられる。 The “optionally substituted lower alkyl” represented by R 2 is 1 selected from a halogen atom (for example, a chlorine atom), hydroxy and C 1-6 alkoxy (preferably C 1-4 alkoxy, for example, methoxy). C 1-6 alkyl (preferably C 1-4 alkyl such as methyl) which may be substituted with 3 substituents.

　Ｒ２で表される「置換されていてもよいアルコキシカルボニル」としては、ヒドロキシおよびＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルコキシ－カルボニル（好ましくはＣ１－４アルコキシ－カルボニル）が挙げられる。なかでも好ましくは、Ｃ１－６アルコキシ－カルボニルである。 The “optionally substituted alkoxycarbonyl” represented by R 2 is substituted with 1 to 3 substituents selected from hydroxy and C 1-6 alkoxy (preferably C 1-4 alkoxy). And C 1-6 alkoxy-carbonyl (preferably C 1-4 alkoxy-carbonyl). Of these, C 1-6 alkoxy-carbonyl is preferable.

　Ｒ２で表される「置換されていてもよいアルコキシカルボニル」としては、Ｃ１－６アルコキシ－カルボニルが好ましく、Ｃ１－４アルコキシ－カルボニルがより好ましい。 As the “optionally substituted alkoxycarbonyl” represented by R 2 , C 1-6 alkoxy-carbonyl is preferable, and C 1-4 alkoxy-carbonyl is more preferable.

　Ｒ２としては、
（１）水素原子、
（２）ハロゲン原子（例えば塩素原子）、ヒドロキシおよびＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えばメトキシ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）、または
（３）Ｃ１－６アルコキシ－カルボニル（好ましくはＣ１－４アルコキシ－カルボニル）が好ましく、
（１）水素原子、または
（２）ハロゲン原子（例えば塩素原子）、ヒドロキシおよびＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えばメトキシ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）がより好ましく、
水素原子がさらに好ましい。 As R 2 ,
(1) a hydrogen atom,
(2) C 1 -C 1 which may be substituted with 1 to 3 substituents selected from halogen atom (eg chlorine atom), hydroxy and C 1-6 alkoxy (preferably C 1-4 alkoxy, eg methoxy) 6 alkyl (preferably C 1-4 alkyl, such as methyl) or (3) C 1-6 alkoxy-carbonyl (preferably C 1-4 alkoxy-carbonyl) is preferred,
Substituted with 1 to 3 substituents selected from (1) a hydrogen atom, or (2) a halogen atom (eg chlorine atom), hydroxy and C 1-6 alkoxy (preferably C 1-4 alkoxy, eg methoxy) More preferably C 1-6 alkyl (preferably C 1-4 alkyl, eg methyl),
More preferred is a hydrogen atom.

　Ｒ３は、水素原子または低級アルキルを表す。
　Ｒ３で表される「低級アルキル」としては、Ｃ１－６アルキルが好ましく、Ｃ１－４アルキルがより好ましい。
　Ｒ３は、好ましくは水素原子、Ｃ１－６アルキル（好ましくは、メチル、エチル）である。
　Ｒ３は、より好ましくは水素原子である。 R 3 represents a hydrogen atom or lower alkyl.
As the “lower alkyl” represented by R 3 , C 1-6 alkyl is preferable, and C 1-4 alkyl is more preferable.
R 3 is preferably a hydrogen atom or C 1-6 alkyl (preferably methyl, ethyl).
R 3 is more preferably a hydrogen atom.

　Ｒ４～Ｒ８は、同一または異なって、水素原子、ハロゲン原子または低級アルキルを表す。
　Ｒ４～Ｒ８で表される「ハロゲン原子」としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。
　Ｒ４～Ｒ８で表される「低級アルキル」としては、Ｃ１－６アルキルが好ましく、Ｃ１－４アルキルがより好ましい。
　Ｒ４～Ｒ８としては、同一または異なって、水素原子、ハロゲン原子またはＣ１－６アルキル（好ましくはＣ１－４アルキル）が好ましく、水素原子がより好ましい。 R 4 to R 8 are the same or different and each represents a hydrogen atom, a halogen atom or lower alkyl.
Examples of the “halogen atom” represented by R 4 to R 8 include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
The “lower alkyl” represented by R 4 to R 8 is preferably C 1-6 alkyl, more preferably C 1-4 alkyl.
R 4 to R 8 are the same or different and are preferably a hydrogen atom, a halogen atom or C 1-6 alkyl (preferably C 1-4 alkyl), more preferably a hydrogen atom.

　Ｒ９～Ｒ１３は、同一または異なって、水素原子、ハロゲン原子または低級アルキルを表し、この場合において、Ｒ９～Ｒ１３の少なくとも１つの基はハロゲン原子または低級アルキル基を表し、あるいは、Ｒ９、Ｒ１２およびＲ１３は、同一または異なって、水素原子、ハロゲン原子または低級アルキルを表し、Ｒ１０およびＲ１１は、それぞれが隣接するベンゼン環と共に一体となって、置換されていてもよいナフタレン環または置換されていてもよい縮合複素芳香環を形成する。
　なかでも好ましくは、Ｒ９～Ｒ１３は、同一または異なって、水素原子、ハロゲン原子またはＣ１－６アルキルを表し、この場合において、Ｒ９～Ｒ１３の少なくとも１つの基はハロゲン原子またはＣ１－６アルキルを表し、あるいは、Ｒ９、Ｒ１２およびＲ１３は、同一または異なって、水素原子、ハロゲン原子またはＣ１－６アルキルを表し、Ｒ１０およびＲ１１は、それぞれが隣接するベンゼン環と共に一体となって、ナフタレン環を形成する。 R 9 to R 13 are the same or different and each represents a hydrogen atom, a halogen atom or lower alkyl, and in this case, at least one group of R 9 to R 13 represents a halogen atom or a lower alkyl group, or R 9, R 12 and R 13 are the same or different and each represents a hydrogen atom, a halogen atom or lower alkyl, and each of R 10 and R 11 may be substituted together with the adjacent benzene ring. It forms a naphthalene ring or an optionally substituted fused heteroaromatic ring.
Particularly preferably, R 9 to R 13 are the same or different and each represents a hydrogen atom, a halogen atom or C 1-6 alkyl. In this case, at least one group of R 9 to R 13 is a halogen atom or C 1 1-6 alkyl, or, R 9, R 12 and R 13 are the same or different, a hydrogen atom, a halogen atom or C 1-6 alkyl, R 10 and R 11 are, benzene, each of which adjacent Together with the ring, it forms a naphthalene ring.

　Ｒ９～Ｒ１３で表される「ハロゲン原子」としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。好ましくはフッ素原子または塩素原子であり、より好ましくは塩素原子である。
　Ｒ９～Ｒ１３で表される「低級アルキル」としては、Ｃ１－６アルキルが好ましく、Ｃ１－４アルキルがより好ましい。
　Ｒ１０およびＲ１１が、それぞれが隣接するベンゼン環と共に一体となって形成する、置換されていてもよいナフタレン環としては、ハロゲン原子（例えばフッ素原子）から選ばれる１ないし３個の置換基で置換されていてもよい、ナフタレン環が挙げられる。
　Ｒ１０およびＲ１１が、それぞれが隣接するベンゼン環と共に一体となって形成する、置換されていてもよい縮合複素芳香環としては、ハロゲン原子（例えば塩素原子）から選ばれる１ないし３個の置換基で置換されていてもよい、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１または２個含有する９ないし１４員（好ましくは９または１０員）縮合複素芳香環（好ましくはインダゾール）が挙げられる。 Examples of the “halogen atom” represented by R 9 to R 13 include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Preferably they are a fluorine atom or a chlorine atom, More preferably, it is a chlorine atom.
The “lower alkyl” represented by R 9 to R 13 is preferably C 1-6 alkyl, more preferably C 1-4 alkyl.
The optionally substituted naphthalene ring formed by R 10 and R 11 together with the adjacent benzene ring is 1 to 3 substituents selected from halogen atoms (for example, fluorine atoms). An optionally substituted naphthalene ring is exemplified.
The optionally substituted condensed heteroaromatic ring formed by R 10 and R 11 together with the adjacent benzene ring is 1 to 3 substituents selected from halogen atoms (for example, chlorine atoms) 9- to 14-membered (preferably 9- or 10-membered) condensed heteroaromatic ring containing 1 or 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom, optionally substituted by a group ( Preferably, indazole is used.

　Ｒ１０およびＲ１１が、同一または異なって、水素原子またはハロゲン原子（ただし、Ｒ１０およびＲ１１の少なくとも一方はハロゲン原子である）であり、Ｒ９、Ｒ１２およびＲ１３が、いずれも水素原子である場合が好ましい。 R 10 and R 11 are the same or different and are a hydrogen atom or a halogen atom (provided that at least one of R 10 and R 11 is a halogen atom), and R 9 , R 12 and R 13 are all hydrogen An atom is preferred.

　Ｒ１０およびＲ１１が塩素原子であり、Ｒ９、Ｒ１２およびＲ１３がいずれも水素原子である場合がより好ましい。 More preferably, R 10 and R 11 are chlorine atoms, and R 9 , R 12 and R 13 are all hydrogen atoms.

　Ｒ１０およびＲ１１が、それぞれが隣接するベンゼン環と共に一体となって形成する、置換されていてもよいナフタレン環または置換されていてもよい縮合複素芳香環としては、
（１）ハロゲン原子、
（２）ヒドロキシ、
（３）１ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル）、および
（４）１ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ）
から選ばれる１ないし４個の置換基でそれぞれ置換されていてもよい、ナフタレン環または縮合複素芳香環が挙げられる。該縮合複素芳香環としては、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１または２個含有する９ないし１４員（好ましくは９または１０員）縮合複素芳香環が好ましい。例えば、ベンゾフラン、イソベンゾフラン、ベンゾ［ｂ］チオフェン、ベンゾ［ｃ］チオフェン、インドール、イソインドール、インダゾール、キノリン、イソキノリン、フタラジン、キノキサリン、キナゾリン、シンノリン等が挙げられる。 Examples of the optionally substituted naphthalene ring or the optionally substituted condensed heteroaromatic ring formed by R 10 and R 11 together with the adjacent benzene ring include
(1) a halogen atom,
(2) hydroxy,
(3) C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms (preferably C 1-4 alkyl), and (4) optionally substituted with 1 to 3 halogen atoms C 1-6 alkoxy (preferably C 1-4 alkoxy)
A naphthalene ring or a condensed heteroaromatic ring, each of which may be substituted with 1 to 4 substituents selected from The condensed heteroaromatic ring is preferably a 9- to 14-membered (preferably 9- or 10-membered) condensed heteroaromatic ring containing 1 or 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. . Examples include benzofuran, isobenzofuran, benzo [b] thiophene, benzo [c] thiophene, indole, isoindole, indazole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, cinnoline and the like.

　Ｒ4～Ｒ９、Ｒ１２およびＲ１３が、同一または異なって、水素原子、ハロゲン原子またはＣ１－６アルキル（好ましくはＣ１－４アルキル）を表し、Ｒ１０およびＲ１１が、それぞれが隣接するベンゼン環と共に一体となって、ナフタレン環または縮合複素芳香環を形成する場合が好ましい。 R 4 to R 9, R 12 and R 13 are the same or different and each represents a hydrogen atom, a halogen atom or C 1-6 alkyl (preferably C 1-4 alkyl), and R 10 and R 11 are each It is preferable to form a naphthalene ring or a condensed heteroaromatic ring together with an adjacent benzene ring.

　Ｒ4～Ｒ９、Ｒ１２およびＲ１３が、いずれも水素原子を表し、Ｒ１０およびＲ１１が、それぞれが隣接するベンゼン環と共に一体となって、ナフタレン環または縮合複素芳香環を形成する場合がより好ましい。 R 4 to R 9, R 12 and R 13 all represent a hydrogen atom, and R 10 and R 11 together with an adjacent benzene ring form a naphthalene ring or a condensed heteroaromatic ring. Is more preferable.

　化合物（Ｉ）の好適な例としては、
Ｘが、１ないし４個のＣ１－６アルキルで置換されていてもよいＣ１－６アルキレン（好ましくは、１ないし４個のＣ１－４アルキルで置換されていてもよいＣ１－４アルキレン）、－ＣＯ－、－ＣＨ２ＣＯ－または炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個含有する５員芳香族複素環（例、１，２，４－オキサジアゾール、１，３，４－オキサジアゾール）を表し、
Ｒ１が、
（１）ヒドロキシ、
（２）シアノ、
（３）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノ）（例、メチルアミノ、エチルアミノ、プロピルアミノ、イソプロピルアミノ、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、エチルメチルアミノ等）、
（４）Ｃ３－６シクロアルキルアミノ（例、シクロプロピルアミノ、シクロブチルアミノ、シクロペンチルアミノ、シクロヘキシルアミノ）、
（５）ヒドラジノ、
（６）ハロゲン原子およびヒドロキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル、エチル、イソプロピル）、
（７）以下の（ａ）～（ｆ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ等）
　　　（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ、
　　　（ｃ）オキソ、
　　　（ｄ）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノ、例えばエチルアミノ）、
　　　（ｅ）４ないし１０員飽和複素環基（例、アゼチジニル、ピロリジニル、ピペリジニル、ピペラジニル等）、および
　　　（ｆ）１ないし３個のハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）で置換されていてもよいＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ等）、
（８）フェニル、
（９）以下の（ａ）～（ｆ）から選ばれる１ないし３個の置換基で置換されていてもよい、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子１個を含有していてもよい、４～１０員の飽和非芳香族含窒素複素環基（例、１，３，８－トリアザスピロ［４．５]デカニル、アゼチジニル、チアゾリジニル、イミダゾリジニル、ピロリジニル、ピペリジニル、ピペラジニル、モルホリニル）
　　　（ａ）ハロゲン原子（例、フッ素原子）、
　　　（ｂ）ヒドロキシ、
　　　（ｃ）ヒドロキシおよびＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えばメトキシ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）、
　　　（ｄ）Ｃ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えばメトキシ）、
　　　（ｅ）モノ－またはジ－Ｃ１－６アルキルカルバモイル（好ましくはモノ－またはジ－Ｃ１－４アルキルカルバモイル、例えば、ジメチルカルバモイル）、および
　　　（ｆ）オキソ、
（１０）モノ－またはジ－（Ｃ１－６アルキルスルホニル）アミノ（好ましくはモノ－またはジ－（Ｃ１－４アルキルスルホニル）アミノ、例えばメチルスルホニルアミノ）、
（１１）モノ－またはジ－（Ｃ１－６アルキル－カルボニル）アミノ（好ましくはモノ－またはジ－（Ｃ１－４アルキル－カルボニル）アミノ、例えばメチルカルボニルアミノ）、
（１２）モノ－またはジ－（Ｃ１－６アルコキシ－カルボニル）アミノ（好ましくはモノ－またはジ－（Ｃ１－４アルコキシ－カルボニル）アミノ、例えばメトキシカルボニルアミノ、エトキシカルボニルアミノ）、
（１３）アミノ、
（１４）フタルイミド、
（１５）（ａ）置換されていてもよい４～１０員含窒素複素環基（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは１または２個、より好ましくは１個）含有していてもよい、４～１０員の飽和または不飽和（好ましくは飽和）の非芳香族含窒素複素環基）、
　　　（ｂ）アミノカルボニルイミノ、
　　　（ｃ）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノ、例えばメチルアミノ）、
　　　（ｄ）ヒドロキシカルボニル、および
　　　（ｅ）Ｃ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えばメトキシ）で置換されていてもよい、フェニル（例、メトキシフェニル）
から選ばれる１ないし３個の置換基で置換されていてもよい、モノ－またはジ－Ｃ１－６アルキル（好ましくはＣ１－４アルキル）アミノ（例、モルホリニルエチルアミノ、［（アミノカルボニルイミノ）（メチルアミノ）メチル］アミノ、（ヒドロキシカルボニルメチル）アミノ、（メトキシフェニルメチル）アミノ）、
（１６）（ａ）ヒドロキシで置換されていてもよいＣ１－６アルキルで、モノ－またはジ－置換されていてもよいアミノ（好ましくは、ヒドロキシで置換されていてもよいＣ１－４アルキルで、モノ－またはジ－置換されていてもよいアミノ、例えば、アミノ、メチルアミノ、エチルアミノ、プロピルアミノ、ジメチルアミノ、（ヒドロキシエチル）アミノ）、
　　　　（ｂ）Ｃ３－６シクロアルキルアミノ（例、シクロプロピルアミノ）、
　　　　（ｃ）置換されていてもよい４～１０員含窒素複素環－アミノ（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは、１または２個、より好ましくは１個）含有していてもよい、５または６員芳香族含窒素複素環－アミノ、より好ましくは、ピリジルアミノ）、および
　　　　（ｄ）Ｃ１－６アルコキシアミノ（好ましくはＣ１－４アルコキシアミノ、例えばメトキシアミノ）、
から選ばれる１個の置換基で置換された、カルボニルアミノ、および
（１７）（ａ）Ｃ１－６アルキルでモノ－またはジ－置換されていてもよいアミノ（好ましくは、Ｃ１－４アルキルでモノ－またはジ－置換されていてもよいアミノ、例えば、アミノ、メチルアミノ、エチルアミノ、ジメチルアミノ）、
　　　　（ｂ）ヒドロキシで置換されていてもよいフェノキシ（例、ヒドロキシフェノキシ）、および
　　　　（ｃ）（ｉ）オキソ、
　　　　　　　（ｉｉ）Ｃ１－６アルキル－カルボニル（例、メチルカルボニル）
　　　　　　　から選ばれる１ないし３個（好ましくは１または２個）の置換基で置換されていてもよい、４～１０員含窒素複素環基（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは１または２個、より好ましくは１個）含有していてもよい、４～１０員の飽和または不飽和（好ましくは飽和）の非芳香族含窒素複素環基）（例、チオモルホリニル、ピペラジニル、モルホリニル）
から選ばれる１個の置換基で置換された、スルホニルアミノ、
（１８）（ａ）（ｉ）Ｃ１－６アルキルでモノ－またはジ－置換されていてもよいアミノ（好ましくは、Ｃ１－４アルキルでモノ－またはジ－置換されていてもよいアミノ、より好ましくは、アミノ、エチルアミノ、エチルメチルアミノ）、
　　　　　　　（ｉｉ）オキソ、
　　　　　　　（ｉｉｉ）置換されていてもよい４～１０員含窒素複素環基（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは、１または２個、より好ましくは１個）含有していてもよい、４～１０員の飽和または不飽和（好ましくは飽和）の非芳香族含窒素複素環基、例えば、モルホリニル、ピペラジニル、ピペリジニル）、および
　　　　　　　（ｉｖ）ヒドロキシ
　　　　から選ばれる１ないし３個の置換基で置換されていてもよい、Ｃ４－６シクロアルケニル（例、シクロブテニル、シクロペンテニル、シクロヘキセニル）、および
　　　　（ｂ）Ｃ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）
から選ばれる１または２個の置換基で置換されたアミノ、
（１９）Ｃ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）で置換されていてもよいメルカプト、または
（２０）Ｃ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）で置換されたスルホニルを表し、
Ｒ２が、
（１）水素原子、
（２）ハロゲン原子（例えば塩素原子）、ヒドロキシおよびＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えばメトキシ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）、または
（３）Ｃ１－６アルコキシ－カルボニル（好ましくはＣ１－４アルコキシ－カルボニル）を表し、
Ｒ３が、水素原子またはＣ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル、エチル）を表し、
Ｒ4～Ｒ１３が、同一または異なって、水素原子、ハロゲン原子またはＣ１－６アルキル（好ましくはＣ１－４アルキル）を表し、
この場合において、
Ｒ９～Ｒ１３の少なくとも１つの基がハロゲン原子またはＣ１－６アルキル（好ましくはＣ１－４アルキル）を表し、あるいは、
Ｒ4～Ｒ９、Ｒ１２およびＲ１３が、同一または異なって、水素原子、ハロゲン原子またはＣ１－６アルキル（好ましくはＣ１－４アルキル）を表し、Ｒ１０およびＲ１１が、それぞれが隣接するベンゼン環と共に一体となって、
（ａ）ハロゲン原子（好ましくはフッ素原子）から選ばれる１ないし３個の置換基で置換されていてもよい、ナフタレン環、または
（ｂ）ハロゲン原子（好ましくは塩素原子）から選ばれる１ないし３個の置換基で置換されていてもよい、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１または２個含有する９ないし１４員（好ましくは９または１０員）縮合複素芳香環（好ましくはインダゾール）
を形成する、式（Ｉ）の化合物またはその塩が挙げられる。 Preferred examples of compound (I) include
X is 1 to 4 amino C 1-6 alkyl optionally substituted by C 1-6 alkylene (preferably, one to four C 1-4 optionally C 1-4 optionally substituted by alkyl Alkylene), —CO—, —CH 2 CO—, or a 5-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms (eg, 1, 2, 4-oxadiazole, 1,3,4-oxadiazole)
R 1 is
(1) hydroxy,
(2) cyano,
(3) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, di-) Propylamino, ethylmethylamino, etc.),
(4) C 3-6 cycloalkylamino (eg, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino),
(5) Hydrazino,
(6) C 1-6 alkyl (preferably C 1-4 alkyl such as methyl, ethyl, isopropyl) optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy,
(7) C 1-6 alkoxy optionally substituted with 1 to 3 substituents selected from the following (a) to (f) (preferably C 1-4 alkoxy such as methoxy, ethoxy, propoxy , Isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.)
(A) a halogen atom,
(B) hydroxy,
(C) oxo,
(D) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino, such as ethylamino),
(E) a 4- to 10-membered saturated heterocyclic group (eg, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, etc.), and (f) 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) C 1-6 alkoxy optionally substituted by (preferably C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.),
(8) phenyl,
(9) In addition to carbon atom and one nitrogen atom, which may be substituted with 1 to 3 substituents selected from the following (a) to (f), selected from nitrogen atom, sulfur atom and oxygen atom A 4- to 10-membered saturated non-aromatic nitrogen-containing heterocyclic group (eg, 1,3,8-triazaspiro [4.5] decanyl, azetidinyl, thiazolidinyl, imidazolidinyl, Pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl)
(A) a halogen atom (eg, fluorine atom),
(B) hydroxy,
(C) hydroxy, and C 1-6 alkoxy (preferably C 1-4 alkoxy such as methoxy) 1 to 3 substituents optionally substituted by C 1-6 alkyl selected from (preferably C 1- 4 alkyl, such as methyl),
(D) C 1-6 alkoxy (preferably C 1-4 alkoxy, such as methoxy),
(E) mono- or di-C 1-6 alkylcarbamoyl (preferably mono- or di-C 1-4 alkylcarbamoyl, such as dimethylcarbamoyl), and (f) oxo,
(10) mono- or di- (C 1-6 alkylsulfonyl) amino (preferably mono- or di- (C 1-4 alkylsulfonyl) amino, such as methylsulfonylamino),
(11) mono- or di- (C 1-6 alkyl-carbonyl) amino (preferably mono- or di- (C 1-4 alkyl-carbonyl) amino, eg methylcarbonylamino),
(12) Mono- or di- (C 1-6 alkoxy-carbonyl) amino (preferably mono- or di- (C 1-4 alkoxy-carbonyl) amino, such as methoxycarbonylamino, ethoxycarbonylamino),
(13) amino,
(14) phthalimide,
(15) (a) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably a hetero atom selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) Or 4 to 10-membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group which may be contained (preferably 1 or 2, more preferably 1)),
(B) aminocarbonylimino,
(C) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino, such as methylamino),
(D) hydroxycarbonyl, and (e) phenyl (eg methoxyphenyl) optionally substituted with C 1-6 alkoxy (preferably C 1-4 alkoxy, eg methoxy)
Mono- or di-C 1-6 alkyl (preferably C 1-4 alkyl) amino (eg, morpholinylethylamino, [(amino), optionally substituted with 1 to 3 substituents selected from Carbonylimino) (methylamino) methyl] amino, (hydroxycarbonylmethyl) amino, (methoxyphenylmethyl) amino),
(16) (a) C 1-6 alkyl optionally substituted with hydroxy and optionally mono- or di-substituted amino (preferably C 1-4 alkyl optionally substituted with hydroxy) Optionally mono- or di-substituted amino such as amino, methylamino, ethylamino, propylamino, dimethylamino, (hydroxyethyl) amino),
(B) C 3-6 cycloalkylamino (eg, cyclopropylamino),
(C) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic-amino (preferably 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) (Preferably 1 or 2, more preferably 1), 5 or 6-membered aromatic nitrogen-containing heterocyclic-amino, more preferably pyridylamino), and (d) C 1- 6 alkoxyamino (preferably C 1-4 alkoxyamino, eg methoxyamino),
Carbonylamino substituted with one substituent selected from: (17) (a) amino optionally mono- or di-substituted with C 1-6 alkyl (preferably C 1-4 alkyl Optionally mono- or di-substituted amino such as amino, methylamino, ethylamino, dimethylamino),
(B) phenoxy optionally substituted with hydroxy (eg, hydroxyphenoxy), and (c) (i) oxo,
(Ii) C 1-6 alkyl-carbonyl (eg, methylcarbonyl)
A 4- to 10-membered nitrogen-containing heterocyclic group (preferably a nitrogen atom other than a carbon atom and one nitrogen atom) which may be substituted with 1 to 3 (preferably 1 or 2) substituents selected from 4- to 10-membered saturated or unsaturated (preferably 1 to 3 (preferably 1 or 2, more preferably 1) heteroatoms selected from atoms, sulfur atoms and oxygen atoms may be contained. Saturated) non-aromatic nitrogen-containing heterocyclic group) (eg, thiomorpholinyl, piperazinyl, morpholinyl)
A sulfonylamino substituted with one substituent selected from
(18) (a) (i) amino optionally mono- or di-substituted with C 1-6 alkyl (preferably amino optionally mono- or di-substituted with C 1-4 alkyl, More preferably, amino, ethylamino, ethylmethylamino),
(Ii) oxo,
(Iii) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) (Preferably 1 or 2, more preferably 1) 4 to 10 membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group such as morpholinyl, Piperazinyl, piperidinyl), and (iv) C 4-6 cycloalkenyl (eg, cyclobutenyl, cyclopentenyl, cyclohexenyl) optionally substituted with 1 to 3 substituents selected from hydroxy, and (b) C 1-6 alkyl (preferably C 1-4 alkyl, eg methyl)
Amino substituted with one or two substituents selected from
(19) Mercapto optionally substituted with C 1-6 alkyl (preferably C 1-4 alkyl, eg methyl), or (20) C 1-6 alkyl (preferably C 1-4 alkyl, eg methyl) Represents a sulfonyl substituted with
R 2 is
(1) a hydrogen atom,
(2) C 1 -C 1 which may be substituted with 1 to 3 substituents selected from halogen atom (eg chlorine atom), hydroxy and C 1-6 alkoxy (preferably C 1-4 alkoxy, eg methoxy) 6 alkyl (preferably C 1-4 alkyl, such as methyl), or (3) C 1-6 alkoxy-carbonyl (preferably C 1-4 alkoxy-carbonyl),
R 3 represents a hydrogen atom or C 1-6 alkyl (preferably C 1-4 alkyl, such as methyl, ethyl),
R 4 to R 13 are the same or different and each represents a hydrogen atom, a halogen atom or C 1-6 alkyl (preferably C 1-4 alkyl);
In this case,
At least one group of R 9 to R 13 represents a halogen atom or C 1-6 alkyl (preferably C 1-4 alkyl), or
R 4 to R 9, R 12 and R 13 are the same or different and each represents a hydrogen atom, a halogen atom or C 1-6 alkyl (preferably C 1-4 alkyl), and R 10 and R 11 are each Together with the adjacent benzene ring,
(A) a naphthalene ring optionally substituted by 1 to 3 substituents selected from halogen atoms (preferably fluorine atoms), or (b) 1 to 3 selected from halogen atoms (preferably chlorine atoms) 9- to 14-membered (preferably 9- or 10-membered) condensed complex containing 1 or 2 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms, which may be substituted with one substituent Aromatic ring (preferably indazole)
A compound of formula (I) or a salt thereof that forms

　化合物（Ｉ）の好適な別の例としては、
Ｘが、１ないし４個のＣ１－６アルキルで置換されていてもよいＣ１－６アルキレン（好ましくは、１ないし４個のＣ１－４アルキルで置換されていてもよいＣ１－４アルキレン）、－ＣＯ－、－ＣＨ２ＣＯ－または炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個含有する５員芳香族複素環（例、１，２，４－オキサジアゾール、１，３，４－オキサジアゾール）を表し、
Ｒ１が、
（１）ヒドロキシ、
（２）シアノ、
（３）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノ）、
（４）Ｃ３－６シクロアルキルアミノ、
（５）ヒドラジノ、
（６）ハロゲン原子およびヒドロキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル）、
（７）ハロゲン原子およびヒドロキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ）、
（８）フェニル、または
（９）以下の（ａ）～（ｄ）から選ばれる１ないし３個の置換基で置換されていてもよい、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子１個を含有していてもよい、４～１０員の飽和非芳香族含窒素複素環基（例、ピロリジニル、ピペリジニル、ピペラジニル、モルホリニル）を表し、
　（ａ）ハロゲン原子、
　（ｂ）ヒドロキシ、
　（ｃ）ヒドロキシおよびＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル）、および
　（ｄ）Ｃ１－６アルコキシ（好ましくはＣ１－４アルコキシ）、
Ｒ２が、
（１）水素原子、
（２）ヒドロキシおよびＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル）、または
（３）Ｃ１－６アルコキシ－カルボニル（好ましくはＣ１－４アルコキシ－カルボニル）を表し、
Ｒ３が、水素原子またはＣ１－６アルキル（好ましくはＣ１－４アルキル）を表し、
Ｒ4～Ｒ１３が、同一または異なって、水素原子、ハロゲン原子またはＣ１－６アルキル（好ましくはＣ１－４アルキル）を表し、
この場合において、
Ｒ９～Ｒ１３の少なくとも１つの基がハロゲン原子またはＣ１－６アルキル（好ましくはＣ１－４アルキル）を表し、あるいは、
Ｒ4～Ｒ９、Ｒ１２およびＲ１３が、同一または異なって、水素原子、ハロゲン原子またはＣ１－６アルキル（好ましくはＣ１－４アルキル）を表し、Ｒ１０およびＲ１１が、それぞれが隣接するベンゼン環と共に一体となって、ナフタレン環を形成する、式（Ｉ）の化合物またはその塩が挙げられる。 Other suitable examples of compound (I) include
X is 1 to 4 amino C 1-6 alkyl optionally substituted by C 1-6 alkylene (preferably, one to four C 1-4 optionally C 1-4 optionally substituted by alkyl Alkylene), —CO—, —CH 2 CO—, or a 5-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms (eg, 1, 2, 4-oxadiazole, 1,3,4-oxadiazole)
R 1 is
(1) hydroxy,
(2) cyano,
(3) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino),
(4) C 3-6 cycloalkylamino,
(5) Hydrazino,
(6) C 1-6 alkyl (preferably C 1-4 alkyl) optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy,
(7) C 1-6 alkoxy (preferably C 1-4 alkoxy) optionally substituted by 1 to 3 substituents selected from a halogen atom and hydroxy,
(8) phenyl, or (9) a nitrogen atom, sulfur other than carbon atom and one nitrogen atom, which may be substituted with 1 to 3 substituents selected from the following (a) to (d) Represents a 4- to 10-membered saturated non-aromatic nitrogen-containing heterocyclic group (eg, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl) optionally containing one heteroatom selected from an atom and an oxygen atom;
(A) a halogen atom,
(B) hydroxy,
(C) hydroxy, and C 1-6 alkoxy (preferably C 1-4 alkoxy) one to three substituted with a substituent which may be the C 1-6 alkyl selected from (preferably C 1-4 alkyl) And (d) C 1-6 alkoxy (preferably C 1-4 alkoxy),
R 2 is
(1) a hydrogen atom,
(2) hydroxy and C 1-6 alkoxy (preferably C 1-4 alkoxy) one to three substituted with a substituent which may be the C 1-6 alkyl selected from (preferably C 1-4 alkyl) Or (3) C 1-6 alkoxy-carbonyl (preferably C 1-4 alkoxy-carbonyl)
R 3 represents a hydrogen atom or C 1-6 alkyl (preferably C 1-4 alkyl);
R 4 to R 13 are the same or different and each represents a hydrogen atom, a halogen atom or C 1-6 alkyl (preferably C 1-4 alkyl);
In this case,
At least one group of R 9 to R 13 represents a halogen atom or C 1-6 alkyl (preferably C 1-4 alkyl), or
R 4 to R 9, R 12 and R 13 are the same or different and each represents a hydrogen atom, a halogen atom or C 1-6 alkyl (preferably C 1-4 alkyl), and R 10 and R 11 are each Examples thereof include a compound of the formula (I) or a salt thereof which forms a naphthalene ring together with an adjacent benzene ring.

　ＸおよびＲ１の好適な態様としては、以下の態様が挙げられる。
　Ｘが、１ないし４個のＣ１－６アルキルで置換されていてもよいＣ１－６アルキレン（好ましくは、１ないし４個のＣ１－４アルキルで置換されていてもよいＣ１－４アルキレン）であり、
Ｒ１が、
（１）ヒドロキシ、
（２）シアノ、
（３）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノ）（例、メチルアミノ、エチルアミノ、プロピルアミノ、イソプロピルアミノ、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、エチルメチルアミノ等）、
（４）ハロゲン原子およびヒドロキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル、例えば、メチル、エチル、イソプロピル）、
（５）以下の（ａ）～（ｆ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えばメトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ等）
　　　（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ、
　　　（ｃ）オキソ、
　　　（ｄ）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノ、例えばエチルアミノ）、
　　　（ｅ）４ないし１０員飽和複素環基（例、アゼチジニル、ピロリジニル、ピペリジニル、ピペラジニル等）、および
　　　（ｆ）１ないし３個のハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）で置換されていてもよいＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ等）、
（６）以下の（ａ）～（ｆ）から選ばれる１ないし３個の置換基で置換されていてもよい、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子１個を含有していてもよい、４～１０員の飽和非芳香族含窒素複素環基（例、１，３，８－トリアザスピロ［４．５]デカニル、アゼチジニル、チアゾリジニル、イミダゾリジニル、ピロリジニル、ピペリジニル、ピペラジニル、モルホリニル）
　　　（ａ）ハロゲン原子（例、フッ素原子）、
　　　（ｂ）ヒドロキシ、
　　　（ｃ）ヒドロキシおよびＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）、
　　　（ｄ）Ｃ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えばメトキシ）、
　　　（ｅ）モノ－またはジ－Ｃ１－６アルキルカルバモイル（好ましくはモノ－またはジ－Ｃ１－４アルキルカルバモイル、例えばジメチルカルバモイル）、および
　　　（ｆ）オキソ
（７）モノ－またはジ－（Ｃ１－６アルキルスルホニル）アミノ（好ましくはモノ－またはジ－（Ｃ１－４アルキルスルホニル）アミノ、例えばメチルスルホニルアミノ）、
（８）モノ－またはジ－（Ｃ１－６アルキル－カルボニル）アミノ（好ましくはモノ－またはジ－（Ｃ１－４アルキル－カルボニル）アミノ、例えばメチルカルボニルアミノ）、
（９）モノ－またはジ－（Ｃ１－６アルコキシ－カルボニル）アミノ（好ましくはモノ－またはジ－（Ｃ１－４アルコキシ－カルボニル）アミノ、例えばメトキシカルボニルアミノ、エトキシカルボニルアミノ）、
（１０）アミノ、
（１１）環状アミノ、
（１２）フタルイミド、
（１３）（ａ）置換されていてもよい４～１０員含窒素複素環基（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは１または２個、より好ましくは１個）含有していてもよい、４～１０員の飽和または不飽和（好ましくは飽和）の非芳香族含窒素複素環基）、
　　　（ｂ）アミノカルボニルイミノ、
　　　（ｃ）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノ、例えばメチルアミノ）、
　　　（ｄ）ヒドロキシカルボニル、および
　　　（ｅ）Ｃ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えばメトキシ）で置換されていてもよい、フェニル（例、メトキシフェニル）
から選ばれる１ないし３個の置換基で置換されていてもよい、モノ－またはジ－Ｃ１－６アルキル（好ましくはＣ１－４アルキル）アミノ（例、モルホリニルエチルアミノ、［（アミノカルボニルイミノ）（メチルアミノ）メチル］アミノ、（ヒドロキシカルボニルメチル）アミノ、（メトキシフェニルメチル）アミノ）、
（１４）（ａ）ヒドロキシで置換されていてもよいＣ１－６アルキルで、モノ－またはジ－置換されていてもよいアミノ（好ましくは、ヒドロキシで置換されていてもよいＣ１－４アルキルで、モノ－またはジ－置換されていてもよいアミノ、例えば、アミノ、メチルアミノ、エチルアミノ、プロピルアミノ、ジメチルアミノ、（ヒドロキシエチル）アミノ）、
　　　　（ｂ）Ｃ３－６シクロアルキルアミノ（例、シクロプロピルアミノ）、
　　　　（ｃ）置換されていてもよい４～１０員含窒素複素環－アミノ（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは、１または２個、より好ましくは１個）含有していてもよい、５または６員芳香族含窒素複素環－アミノ、より好ましくは、ピリジルアミノ）、および
　　　　（ｄ）Ｃ１－６アルコキシアミノ（好ましくはＣ１－４アルコキシアミノ、より好ましくはメトキシアミノ）
から選ばれる１個の置換基で置換された、カルボニルアミノ、および
（１５）（ａ）Ｃ１－６アルキルでモノ－またはジ－置換されていてもよいアミノ（好ましくは、Ｃ１－４アルキルでモノ－またはジ－置換されていてもよいアミノ、例えば、アミノ、メチルアミノ、エチルアミノ、ジメチルアミノ）、
　　　　（ｂ）ヒドロキシで置換されていてもよいフェノキシ（例、ヒドロキシフェノキシ、および
　　　　（ｃ）（ｉ）オキソ、および
　　　　　　　（ｉｉ）Ｃ１－６アルキル－カルボニル（例、メチルカルボニル）
　　　　　　　から選ばれる１ないし３個（好ましくは１または２個）の置換基で置換されていてもよい、４～１０員含窒素複素環基（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは１または２個、より好ましくは１個）含有していてもよい、４～１０員の飽和または不飽和（好ましくは飽和）の非芳香族含窒素複素環基）（例、チオモルホリニル、ピペラジニル、モルホリニル）
から選ばれる１個の置換基で置換された、スルホニルアミノ、
（１６）（ａ）（ｉ）Ｃ１－６アルキルでモノ－またはジ－置換されていてもよいアミノ（好ましくは、Ｃ１－４アルキルでモノ－またはジ－置換されていてもよいアミノ、より好ましくは、アミノ、エチルアミノ、エチルメチルアミノ）、
　　　　　　　（ｉｉ）オキソ、
　　　　　　　（ｉｉｉ）置換されていてもよい４～１０員含窒素複素環基（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは、１または２個、より好ましくは１個）含有していてもよい、４～１０員の飽和または不飽和（好ましくは飽和）の非芳香族含窒素複素環基、例えば、モルホリニル、ピペラジニル、ピペリジニル）、および
　　　　　　　（ｉｖ）ヒドロキシ
　　　　から選ばれる１ないし３個の置換基で置換されていてもよい、Ｃ４－６シクロアルケニル（例、シクロブテニル、シクロペンテニル、シクロヘキセニル）、および
　　　　（ｂ）Ｃ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）
から選ばれる１または２個の置換基で置換されたアミノ、
（１７）Ｃ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）で置換されていてもよいメルカプト、または
（１８）Ｃ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）で置換されたスルホニル
である化合物（Ｉ）。 Preferable embodiments of X and R 1 include the following embodiments.
X is 1 to 4 amino C 1-6 alkyl optionally substituted by C 1-6 alkylene (preferably, one to four C 1-4 optionally C 1-4 optionally substituted by alkyl Alkylene),
R 1 is
(1) hydroxy,
(2) cyano,
(3) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, di-) Propylamino, ethylmethylamino, etc.),
(4) C 1-6 alkyl (preferably C 1-4 alkyl such as methyl, ethyl, isopropyl) optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy,
(5) C 1-6 alkoxy optionally substituted with 1 to 3 substituents selected from the following (a) to (f) (preferably C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, Isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.)
(A) a halogen atom,
(B) hydroxy,
(C) oxo,
(D) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino, such as ethylamino),
(E) a 4- to 10-membered saturated heterocyclic group (eg, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, etc.), and (f) 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) C 1-6 alkoxy optionally substituted by (preferably C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.),
(6) In addition to carbon atom and one nitrogen atom, which may be substituted with 1 to 3 substituents selected from the following (a) to (f), selected from nitrogen atom, sulfur atom and oxygen atom A 4- to 10-membered saturated non-aromatic nitrogen-containing heterocyclic group (eg, 1,3,8-triazaspiro [4.5] decanyl, azetidinyl, thiazolidinyl, imidazolidinyl, Pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl)
(A) a halogen atom (eg, fluorine atom),
(B) hydroxy,
(C) hydroxy, and C 1-6 alkoxy (preferably C 1-4 alkoxy) 1 to 3 substituents optionally substituted by C 1-6 alkyl selected from (preferably C 1-4 alkyl, Eg methyl),
(D) C 1-6 alkoxy (preferably C 1-4 alkoxy, such as methoxy),
(E) mono- or di-C 1-6 alkylcarbamoyl (preferably mono- or di-C 1-4 alkylcarbamoyl such as dimethylcarbamoyl), and (f) oxo (7) mono- or di- (C 1 -6 alkylsulfonyl) amino (preferably mono- - or di - (C 1-4 alkylsulfonyl) amino, e.g. methylsulfonylamino)
(8) mono- or di- (C 1-6 alkyl-carbonyl) amino (preferably mono- or di- (C 1-4 alkyl-carbonyl) amino, eg methylcarbonylamino),
(9) mono- or di- (C 1-6 alkoxy-carbonyl) amino (preferably mono- or di- (C 1-4 alkoxy-carbonyl) amino, such as methoxycarbonylamino, ethoxycarbonylamino),
(10) amino,
(11) cyclic amino,
(12) phthalimide,
(13) (a) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably a heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) Or 4 to 10-membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group which may be contained (preferably 1 or 2, more preferably 1)),
(B) aminocarbonylimino,
(C) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino, such as methylamino),
(D) hydroxycarbonyl, and (e) phenyl (eg methoxyphenyl) optionally substituted with C 1-6 alkoxy (preferably C 1-4 alkoxy, eg methoxy)
Mono- or di-C 1-6 alkyl (preferably C 1-4 alkyl) amino (eg, morpholinylethylamino, [(amino), optionally substituted with 1 to 3 substituents selected from Carbonylimino) (methylamino) methyl] amino, (hydroxycarbonylmethyl) amino, (methoxyphenylmethyl) amino),
(14) (a) C 1-6 alkyl optionally substituted with hydroxy, optionally mono- or di-substituted amino (preferably C 1-4 alkyl optionally substituted with hydroxy) Optionally mono- or di-substituted amino such as amino, methylamino, ethylamino, propylamino, dimethylamino, (hydroxyethyl) amino),
(B) C 3-6 cycloalkylamino (eg, cyclopropylamino),
(C) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic-amino (preferably 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) (Preferably 1 or 2, more preferably 1), 5 or 6-membered aromatic nitrogen-containing heterocyclic-amino, more preferably pyridylamino), and (d) C 1- 6 alkoxyamino (preferably C 1-4 alkoxyamino, more preferably methoxyamino)
Carbonylamino substituted with one substituent selected from: (15) (a) amino optionally mono- or di-substituted with C 1-6 alkyl (preferably C 1-4 alkyl Optionally mono- or di-substituted amino such as amino, methylamino, ethylamino, dimethylamino),
(B) phenoxy optionally substituted with hydroxy (eg, hydroxyphenoxy, and (c) (i) oxo, and (ii) C 1-6 alkyl-carbonyl (eg, methylcarbonyl)
A 4- to 10-membered nitrogen-containing heterocyclic group (preferably a nitrogen atom other than a carbon atom and one nitrogen atom) which may be substituted with 1 to 3 (preferably 1 or 2) substituents selected from 4- to 10-membered saturated or unsaturated (preferably 1 to 3 (preferably 1 or 2, more preferably 1) heteroatoms selected from atoms, sulfur atoms and oxygen atoms may be contained. Saturated) non-aromatic nitrogen-containing heterocyclic group) (eg, thiomorpholinyl, piperazinyl, morpholinyl)
A sulfonylamino substituted with one substituent selected from
(16) (a) (i) amino optionally mono- or di-substituted with C 1-6 alkyl (preferably amino optionally mono- or di-substituted with C 1-4 alkyl, More preferably, amino, ethylamino, ethylmethylamino),
(Ii) oxo,
(Iii) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) (Preferably 1 or 2, more preferably 1) 4 to 10 membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group such as morpholinyl, Piperazinyl, piperidinyl), and (iv) C 4-6 cycloalkenyl (eg, cyclobutenyl, cyclopentenyl, cyclohexenyl) optionally substituted with 1 to 3 substituents selected from hydroxy, and (b) C 1-6 alkyl (preferably C 1-4 alkyl, eg methyl)
Amino substituted with one or two substituents selected from
(17) C 1-6 alkyl (preferably C 1-4 alkyl, e.g. methyl) optionally substituted by mercapto or (18), C 1-6 alkyl (preferably C 1-4 alkyl, for example methyl) Compound (I), which is a sulfonyl substituted with

　Ｘが、－ＣＯ－または－ＣＨ２ＣＯ－であり、
Ｒ１が、
（１）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノ）（例、メチルアミノ、エチルアミノ、プロピルアミノ、イソプロピルアミノ、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、エチルメチルアミノ等）、
（２）Ｃ３－６シクロアルキルアミノ（例、シクロプロピルアミノ、シクロブチルアミノ、シクロペンチルアミノ、シクロヘキシルアミノ）、
（３）ヒドラジノ、
（４）ハロゲン原子およびヒドロキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル、例えば、メチル、エチル、イソプロピル）、
（５）以下の（ａ）～（ｆ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ等）
　　　（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ、
　　　（ｃ）オキソ、
　　　（ｄ）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくはモノ－またはジ－Ｃ１－４アルキルアミノ、ジメチルカルバモイル）、
　　　（ｅ）４ないし１０員飽和複素環基（例、アゼチジニル、ピロリジニル、ピペリジニル、ピペラジニル等）、および
　　　（ｆ）１ないし３個のハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）で置換されていてもよいＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ等）、
（６）以下の（ａ）～（ｆ）から選ばれる１ないし３個の置換基で置換されていてもよい、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子１個を含有していてもよい、４～１０員の飽和非芳香族含窒素複素環基（例、１，３，８－トリアザスピロ［４．５]デカニル、アゼチジニル、チアゾリジニル、イミダゾリジニル、ピロリジニル、ピペリジニル、ピペラジニル、モルホリニル）
　　　（ａ）ハロゲン原子（例、フッ素原子）、
　　　（ｂ）ヒドロキシ、
　　　（ｃ）ヒドロキシおよびＣ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えばメトキシ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル、例えばメチル）、
　　　（ｄ）Ｃ１－６アルコキシ（好ましくはＣ１－４アルコキシ）、
　　　（ｅ）置換されていてもよいカルバモイル（好ましくはモノ－またはジ－Ｃ１－６アルキルカルバモイル、より好ましくはモノ－またはジ－Ｃ１－４アルキルカルバモイル、例えばジメチルルバモイル）、および
　　　（ｆ）オキソ、
（７）Ｃ１－６アルコキシ－カルボニルアミノ（好ましくはＣ１－４アルコキシ－カルボニルアミノ、例えばメトキシカルボニルアミノ、エトキシカルボニルアミノ）、または
（８）（ａ）置換されていてもよい４～１０員含窒素複素環基（好ましくは、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個（好ましくは１または２個、より好ましくは１個）含有していてもよい、４～１０員の飽和または不飽和（好ましくは飽和）の非芳香族含窒素複素環基）、
　　　（ｂ）アミノカルボニルイミノ、
　　　（ｃ）モノ－またはジ－Ｃ１－６アルキルアミノ（好ましくは、モノ－またはジ－Ｃ１－４アルキルアミノ、例えば、メチルアミノ）、
　　　（ｄ）ヒドロキシカルボニル、および
　　　（ｅ）Ｃ１－６アルコキシ（好ましくはＣ１－４アルコキシ、例えばメトキシ）で置換されていてもよい、フェニル（例、メトキシフェニル）
から選ばれる１ないし３個の置換基で置換されていてもよい、モノ－またはジ－Ｃ１－６アルキル（好ましくはＣ１－４アルキル）アミノ（例、モルホリニルエチルアミノ、［（アミノカルボニルイミノ）（メチルアミノ）メチル］アミノ、（ヒドロキシカルボニルメチル）アミノ、（メトキシフェニルメチル）アミノ）
である化合物（Ｉ）。 X is —CO— or —CH 2 CO—;
R 1 is
(1) Mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, di-) Propylamino, ethylmethylamino, etc.),
(2) C 3-6 cycloalkylamino (eg, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino),
(3) Hydrazino,
(4) C 1-6 alkyl (preferably C 1-4 alkyl such as methyl, ethyl, isopropyl) optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy,
(5) C 1-6 alkoxy optionally substituted with 1 to 3 substituents selected from the following (a) to (f) (preferably C 1-4 alkoxy such as methoxy, ethoxy, propoxy , Isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.)
(A) a halogen atom,
(B) hydroxy,
(C) oxo,
(D) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino, dimethylcarbamoyl),
(E) a 4- to 10-membered saturated heterocyclic group (eg, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, etc.), and (f) 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) C 1-6 alkoxy optionally substituted by (preferably C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.),
(6) In addition to carbon atom and one nitrogen atom, which may be substituted with 1 to 3 substituents selected from the following (a) to (f), selected from nitrogen atom, sulfur atom and oxygen atom A 4- to 10-membered saturated non-aromatic nitrogen-containing heterocyclic group (eg, 1,3,8-triazaspiro [4.5] decanyl, azetidinyl, thiazolidinyl, imidazolidinyl, Pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl)
(A) a halogen atom (eg, fluorine atom),
(B) hydroxy,
(C) hydroxy, and C 1-6 alkoxy (preferably C 1-4 alkoxy such as methoxy) 1 to 3 substituents optionally substituted by C 1-6 alkyl selected from (preferably C 1- 4 alkyl, such as methyl),
(D) C 1-6 alkoxy (preferably C 1-4 alkoxy),
(E) an optionally substituted carbamoyl (preferably mono- or di-C 1-6 alkylcarbamoyl, more preferably mono- or di-C 1-4 alkylcarbamoyl such as dimethylrubamoyl), and (f) Oxo,
(7) C 1-6 alkoxy-carbonylamino (preferably C 1-4 alkoxy-carbonylamino, eg methoxycarbonylamino, ethoxycarbonylamino), or (8) (a) optionally substituted 4-10 members Nitrogen-containing heterocyclic group (preferably 1 to 3 hetero atoms (preferably 1 or 2 and more preferably 1 atom) selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom and 1 nitrogen atom) A 4 to 10-membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group which may be contained),
(B) aminocarbonylimino,
(C) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino, eg methylamino),
(D) hydroxycarbonyl, and (e) phenyl (eg methoxyphenyl) optionally substituted with C 1-6 alkoxy (preferably C 1-4 alkoxy, eg methoxy)
Mono- or di-C 1-6 alkyl (preferably C 1-4 alkyl) amino (eg, morpholinylethylamino, [(amino), optionally substituted by 1 to 3 substituents selected from Carbonylimino) (methylamino) methyl] amino, (hydroxycarbonylmethyl) amino, (methoxyphenylmethyl) amino)
Compound (I).

　Ｘが、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個含有する５員芳香族複素環（例、１，２，４－オキサジアゾール、１，３，４－オキサジアゾール）であり、
Ｒ１が、
（１）ハロゲン原子およびヒドロキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル（好ましくはＣ１－４アルキル）、または
（２）フェニル
である化合物（Ｉ）。 X is a 5-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom (eg, 1,2,4-oxadiazole, 1,3,3 4-oxadiazole),
R 1 is
(1) Compound (I) which is C 1-6 alkyl (preferably C 1-4 alkyl) optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy, or (2) phenyl .

　本発明の別の態様においては、化合物（Ｉ）の好適な例は、以下の化合物（Ｉ－１）、（Ｉ－２）、（Ｉ－３）、（Ｉ－４）および（Ｉ－５）である。 In another embodiment of the present invention, suitable examples of compound (I) include the following compounds (I-1), (I-2), (I-3), (I-4) and (I-5) ).

〔化合物（Ｉ－１）〕
　前記化合物（Ｉ）であって、
Ｘは、１ないし４個のＣ１－６アルキルで置換されていてもよいＣ１－６アルキレン、－ＣＯ－、－ＣＨ２ＣＯ－、または炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個含有する５員芳香族複素環を表し、
Ｒ１は、
（１）ヒドロキシ、
（２）シアノ、
（３）モノ－またはジ－Ｃ１－６アルキルアミノ、
（４）Ｃ３－６シクロアルキルアミノ、
（５）ヒドラジノ、
（６）ハロゲン原子およびヒドロキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル、
（７）ハロゲン原子およびヒドロキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルコキシ、
（８）フェニル、
（９）以下の（ａ）～（ｅ）から選ばれる１ないし３個の置換基で置換されていてもよい、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子１個を含有していてもよい、４～１０員の飽和含窒素複素環基、
　　　（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ、
　　　（ｃ）ヒドロキシおよびＣ１－６アルコキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル、
　　　（ｄ）Ｃ１－６アルコキシ、および
　　　（ｅ）オキソ、または
（１０）アミノ、Ｃ１－６アルコキシＣ１－６アルキル、ハロゲン原子、Ｃ１－６アルコキシ－カルボニル、Ｃ１－６アルキル－カルボニル、Ｃ１－６アルキルスルホニル、アミノスルホニル、Ｃ１－６アルキルアミノスルホニル、カルバモイルおよびＣ１－６アルコキシカルバモイルから選ばれる１または２個の置換基で置換されていてもよいアミノを表し、
Ｒ２は、
（１）水素原子、
（２）ヒドロキシおよびＣ１－６アルコキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル、または
（３）Ｃ１－６アルコキシ－カルボニルを表し、
Ｒ３は、水素原子またはＣ１－６アルキルを表し、
Ｒ４～Ｒ１３は、同一または異なって、水素原子、ハロゲン原子またはＣ１－６アルキルを表し、
この場合において、
Ｒ９～Ｒ１３の少なくとも１つの基はハロゲン原子またはＣ１－６アルキルを表し、あるいは、
Ｒ４～Ｒ９、Ｒ１２およびＲ１３は、同一または異なって、水素原子、ハロゲン原子またはＣ１－６アルキルを表し、
Ｒ１０およびＲ１１は、それぞれが隣接するベンゼン環と共に一体となって、ナフタレン環を形成する、
化合物。
　化合物（Ｉ－１）のなかでも、
Ｒ１が、
（１）シアノ、
（２）モノ－またはジ－Ｃ１－６アルキルアミノ、
（３）Ｃ３－６シクロアルキルアミノ、
（４）ヒドラジノ、
（５）ハロゲン原子およびヒドロキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル、
（６）フェニル、
（７）以下の（ａ）～（ｅ）から選ばれる１ないし３個の置換基で置換されていてもよい、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子１個を含有していてもよい、４～１０員の飽和含窒素複素環基、
　　　（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ、
　　　（ｃ）ヒドロキシおよびＣ１－６アルコキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル、
　　　（ｄ）Ｃ１－６アルコキシ、および
　　　（ｅ）オキソ、または、
（８）アミノ、Ｃ１－６アルコキシＣ１－６アルキル、ハロゲン原子、Ｃ１－６アルコキシ－カルボニル、Ｃ１－６アルキル－カルボニル、Ｃ１－６アルキルスルホニル、アミノスルホニル、Ｃ１－６アルキルアミノスルホニル、カルバモイルおよびＣ１－６アルコキシカルバモイルから選ばれる１または２個の置換基で置換されていてもよいアミノを表し、
Ｒ２～Ｒ９は、水素原子を表し、
Ｒ１０はハロゲン原子を表し、
Ｒ１１は、水素原子またはハロゲン原子を表し、
Ｒ１２およびＲ１３は水素原子を表す化合物が好ましい。
　化合物（Ｉ－１）のＸの定義における「炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個含有する５員芳香族複素環」とは、好ましくは１，２，４－オキサジアゾール、１，３，４－オキサジアゾールであり、また、Ｒ１の定義における「炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子１個を含有していてもよい、４～１０員の飽和含窒素複素環基」とは、好ましくはピロリジニル、ピペリジニル、ピペラジニル、モルホリニルである。 [Compound (I-1)]
The compound (I),
X is C 1-6 alkylene optionally substituted with 1 to 4 C 1-6 alkyl, —CO—, —CH 2 CO—, or a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. Represents a 5-membered aromatic heterocycle containing 1 to 3 heteroatoms of choice,
R 1 is
(1) hydroxy,
(2) cyano,
(3) mono- or di-C 1-6 alkylamino,
(4) C 3-6 cycloalkylamino,
(5) Hydrazino,
(6) C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy,
(7) C 1-6 alkoxy optionally substituted by 1 to 3 substituents selected from a halogen atom and hydroxy,
(8) phenyl,
(9) In addition to carbon atom and one nitrogen atom, which may be substituted with 1 to 3 substituents selected from the following (a) to (e), selected from nitrogen atom, sulfur atom and oxygen atom A 4- to 10-membered saturated nitrogen-containing heterocyclic group which may contain one heteroatom,
(A) a halogen atom,
(B) hydroxy,
(C) hydroxy, and C 1-6 1 to 3 substituents optionally substituted by C 1-6 alkyl selected from alkoxy,
(D) C 1-6 alkoxy, and (e) oxo, or (10) amino, C 1-6 alkoxy C 1-6 alkyl, halogen atom, C 1-6 alkoxy-carbonyl, C 1-6 alkyl-carbonyl Represents an amino optionally substituted by 1 or 2 substituents selected from C 1-6 alkylsulfonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, carbamoyl and C 1-6 alkoxycarbamoyl;
R 2 is
(1) a hydrogen atom,
(2) hydroxy and C 1-6 1 to 3 is optionally C 1-6 alkyl substituted with a substituent selected from alkoxy or (3), C 1-6 alkoxy - represents carbonyl,
R 3 represents a hydrogen atom or C 1-6 alkyl,
R 4 to R 13 are the same or different and each represents a hydrogen atom, a halogen atom or C 1-6 alkyl;
In this case,
At least one group of R 9 to R 13 represents a halogen atom or C 1-6 alkyl, or
R 4 to R 9 , R 12 and R 13 are the same or different and each represents a hydrogen atom, a halogen atom or C 1-6 alkyl;
R 10 and R 11 together with the adjacent benzene ring form a naphthalene ring,
Compound.
Among the compounds (I-1),
R 1 is
(1) cyano,
(2) mono- or di-C 1-6 alkylamino,
(3) C 3-6 cycloalkylamino,
(4) Hydrazino,
(5) C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy,
(6) phenyl,
(7) In addition to carbon atom and one nitrogen atom, which may be substituted with 1 to 3 substituents selected from the following (a) to (e), selected from nitrogen atom, sulfur atom and oxygen atom A 4- to 10-membered saturated nitrogen-containing heterocyclic group which may contain one heteroatom,
(A) a halogen atom,
(B) hydroxy,
(C) hydroxy, and C 1-6 1 to 3 substituents optionally substituted by C 1-6 alkyl selected from alkoxy,
(D) C 1-6 alkoxy, and (e) oxo, or
(8) Amino, C 1-6 alkoxy C 1-6 alkyl, halogen atom, C 1-6 alkoxy-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylsulfonyl, aminosulfonyl, C 1-6 alkyl Represents an amino optionally substituted with one or two substituents selected from aminosulfonyl, carbamoyl and C 1-6 alkoxycarbamoyl;
R 2 to R 9 represent a hydrogen atom,
R 10 represents a halogen atom,
R 11 represents a hydrogen atom or a halogen atom,
R 12 and R 13 are preferably a compound representing a hydrogen atom.
The “5-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom” in the definition of X of the compound (I-1) is preferably 1, 2,4-oxadiazole and 1,3,4-oxadiazole, and in the definition of R 1 , a hetero atom selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom The “4- to 10-membered saturated nitrogen-containing heterocyclic group which may contain one atom” is preferably pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl.

〔化合物（Ｉ－２）〕
　前記化合物（Ｉ）であって、
Ｘは、Ｃ１－６アルキレン、－ＣＯ－、または－ＣＨ２ＣＯ－を表し、
Ｒ１は、
（１）Ｃ１－６アルキル、オキソ、ヒドロキシおよびヒドロキシＣ１－６アルキルから選ばれる１ないし３個の置換基で置換されていてもよい、炭素原子および１個の窒素原子以外に窒素原子および酸素原子から選ばれるヘテロ原子１個を含有していてもよい、５または６員の飽和非芳香族含窒素複素環基、または
（２）Ｃ１－６アルキル、アミノ、Ｃ３－６シクロアルキル、Ｃ１－６アルコキシＣ１－６アルキル、ハロゲン原子、Ｃ１－６アルコキシ－カルボニル、Ｃ１－６アルキル－カルボニル、Ｃ１－６アルキルスルホニル、アミノスルホニル、Ｃ１－６アルキルアミノスルホニル、カルバモイルおよびＣ１－６アルコキシカルバモイルから選ばれる１または２個の置換基で置換されていてもよいアミノを表し、
Ｒ２～Ｒ９は、水素原子を表し、
Ｒ１０はハロゲン原子を表し、
Ｒ１１は、水素原子またはハロゲン原子を表し、
Ｒ１２およびＲ１３は水素原子を表す、
化合物。
　化合物（Ｉ－２）のＲ１の定義における「炭素原子および１個の窒素原子以外に窒素原子および酸素原子から選ばれるヘテロ原子１個を含有していてもよい、５または６員の飽和非芳香族含窒素複素環基」とは、好ましくはピロリジニル、ピペリジニル、ピペラジニル、モルホリニルである。 [Compound (I-2)]
The compound (I),
X represents C 1-6 alkylene, —CO—, or —CH 2 CO—.
R 1 is
(1) a nitrogen atom other than a carbon atom and one nitrogen atom, which may be substituted with 1 to 3 substituents selected from C 1-6 alkyl, oxo, hydroxy and hydroxy C 1-6 alkyl; A 5- or 6-membered saturated non-aromatic nitrogen-containing heterocyclic group which may contain one heteroatom selected from oxygen atoms, or (2) C 1-6 alkyl, amino, C 3-6 cycloalkyl C 1-6 alkoxy C 1-6 alkyl, halogen atom, C 1-6 alkoxy-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylsulfonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, carbamoyl And an amino optionally substituted with 1 or 2 substituents selected from C 1-6 alkoxycarbamoyl,
R 2 to R 9 represent a hydrogen atom,
R 10 represents a halogen atom,
R 11 represents a hydrogen atom or a halogen atom,
R 12 and R 13 represent a hydrogen atom,
Compound.
In the definition of R 1 of the compound (I-2), “a hetero atom selected from a nitrogen atom and an oxygen atom may be contained in addition to the carbon atom and one nitrogen atom. The “aromatic nitrogen-containing heterocyclic group” is preferably pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl.

〔化合物（Ｉ－３）〕
　前記化合物（Ｉ）であって、
Ｘは、Ｃ１－６アルキレンまたは－ＣＯ－を表し、
Ｒ１は、
（１）ヒドロキシおよびヒドロキシＣ１－６アルキルから選ばれる１個の置換基で置換されていてもよいピロリジニル、または
（２）Ｃ１－６アルキル、Ｃ１－６アルキル－カルボニル、Ｃ１－６アルキルキルスルホニル、アミノスルホニル、カルバモイルおよびモノ－Ｃ１－６アルコキシカルバモイルから選ばれる１または２個の置換基で置換されたアミノを表し、
Ｒ２～Ｒ９は水素原子を表し、
Ｒ１０およびＲ１１はハロゲン原子を表し、
Ｒ１２およびＲ１３は水素原子を表す、
化合物。
　化合物（Ｉ－３）としては、
Ｒ１は、
（１）ヒドロキシおよびヒドロキシＣ１－６アルキルから選ばれる１個の置換基で置換されていてもよいピロリジニル、または
（２）Ｃ１－６アルキル－カルボニル、Ｃ１－６アルキルキルスルホニル、アミノスルホニル、カルバモイルおよびモノ－Ｃ１－６アルコキシカルバモイルから選ばれる１個の置換基で置換されたアミノを表す化合物が好ましい。 [Compound (I-3)]
The compound (I),
X represents C 1-6 alkylene or —CO—.
R 1 is
(1) pyrrolidinyl optionally substituted with one substituent selected from hydroxy and hydroxy C 1-6 alkyl, or (2) C 1-6 alkyl, C 1-6 alkyl-carbonyl, C 1-6 Represents an amino substituted with one or two substituents selected from alkylkylsulfonyl, aminosulfonyl, carbamoyl and mono-C 1-6 alkoxycarbamoyl;
R 2 to R 9 represent a hydrogen atom,
R 10 and R 11 represent a halogen atom,
R 12 and R 13 represent a hydrogen atom,
Compound.
As compound (I-3),
R 1 is
(1) pyrrolidinyl optionally substituted with one substituent selected from hydroxy and hydroxy C 1-6 alkyl, or (2) C 1-6 alkyl-carbonyl, C 1-6 alkylkylsulfonyl, aminosulfonyl And a compound representing amino substituted with one substituent selected from carbamoyl and mono-C 1-6 alkoxycarbamoyl.

〔化合物（Ｉ－４）〕
　前記化合物（Ｉ）であって、
Ｒ１０およびＲ１１は、同一または異なって、水素原子またはハロゲン原子（ただし、Ｒ１０およびＲ１１の少なくとも一方はハロゲン原子である）を表し、
Ｒ９、Ｒ１２およびＲ１３は、いずれも水素原子を表す、
化合物。 [Compound (I-4)]
The compound (I),
R 10 and R 11 are the same or different and each represents a hydrogen atom or a halogen atom (provided that at least one of R 10 and R 11 is a halogen atom);
R 9 , R 12 and R 13 all represent a hydrogen atom,
Compound.

〔化合物（Ｉ－５）〕
　前記化合物（Ｉ）であって、
Ｒ１０およびＲ１１は、塩素原子を表し、
Ｒ９、Ｒ１２およびＲ１３は、いずれも水素原子を表す、
化合物。 [Compound (I-5)]
The compound (I),
R 10 and R 11 represent a chlorine atom,
R 9 , R 12 and R 13 all represent a hydrogen atom,
Compound.

　化合物（Ｉ）としては、実施例１～２３２に記載の化合物等が好ましい。
　化合物（Ｉ）としては、下記の化合物またはその塩が特に好ましい。
　（－）－２，３－ｃｉｓ－３－（３，４－ジクロロフェニル）－Ｎ，Ｎ－ジメチルピロリジン－２－カルボキサミドまたはその塩。
　［（２Ｒ，３Ｒ）－３－（３，４－ジクロロフェニル）ピロリジン－２－イル］［（３Ｓ）－３－ヒドロキシピロリジン－１－イル］メタノンまたはその塩。
　［（２Ｒ＊，３Ｓ＊）－３－（３，４－ジフルオロフェニル）ピロリジン－２－イル］（ピロリジン－１－イル）メタノンまたはその塩。
　１－｛［（２Ｒ＊，３Ｓ＊）－３－（３，４－ジクロロフェニル）ピロリジン－２－イル］メチル｝－３－メトキシ尿素またはその塩。
　Ｎ－｛［（２Ｒ，３Ｒ）－３－（３，４－ジクロロフェニル）ピロリジン－２－イル］メチル｝メタンスルホンアミドまたはその塩。 As the compound (I), the compounds described in Examples 1 to 232 and the like are preferable.
As the compound (I), the following compounds or salts thereof are particularly preferable.
(−)-2,3-cis-3- (3,4-Dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide or a salt thereof.
[(2R, 3R) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] [(3S) -3-hydroxypyrrolidin-1-yl] methanone or a salt thereof.
[(2R * , 3S * )-3- (3,4-difluorophenyl) pyrrolidin-2-yl] (pyrrolidin-1-yl) methanone or a salt thereof.
1-{[(2R * , 3S * )-3- (3,4-dichlorophenyl) pyrrolidin-2-yl] methyl} -3-methoxyurea or a salt thereof.
N-{[(2R, 3R) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] methyl} methanesulfonamide or a salt thereof.

　化合物（Ｉ）が塩である場合、このような塩としては、例えば、無機塩基との塩、アンモニウム塩、有機塩基との塩、無機酸との塩、有機酸との塩、塩基性または酸性アミノ酸との塩などが挙げられる。 When the compound (I) is a salt, examples of such a salt include a salt with an inorganic base, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, basic or acidic Examples include salts with amino acids.

　無機塩基との塩の好適な例としては、ナトリウム塩、カリウム塩などのアルカリ金属塩；カルシウム塩、マグネシウム塩、バリウム塩などのアルカリ土類金属塩；アルミニウム塩などが挙げられる。 Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.

　有機塩基との塩の好適な例としては、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、ジシクロヘキシルアミン、Ｎ，Ｎ’－ジベンジルエチレンジアミンなどとの塩が挙げられる。 Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like.

　無機酸との塩の好適な例としては、塩酸、臭化水素酸、硝酸、硫酸、リン酸などとの塩が挙げられる。 Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

　有機酸との塩の好適な例としては、ギ酸、酢酸、トリフルオロ酢酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸などとの塩が挙げられる。 Preferable examples of the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- And salts with toluenesulfonic acid.

　塩基性アミノ酸との塩の好適な例としては、アルギニン、リジン、オルニチンなどとの塩が挙げられる。 Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like.

　酸性アミノ酸との塩の好適な例としては、アスパラギン酸、グルタミン酸などとの塩が挙げられる。 Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.

　これらの塩のなかでも、薬学的に許容し得る塩が好ましい。薬学的に許容しうる好ましい塩としては、化合物内に塩基性官能基を有する場合には、例えば塩酸、臭化水素酸、硝酸、硫酸、リン酸等の無機酸との塩、または酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、メタンスルホン酸、ｐ－トルエンスルホン酸等の有機酸との塩が挙げられる。また、化合物内に酸性官能基を有する場合には、アルカリ金属塩（例、ナトリウム塩、カリウム塩等）、アルカリ土類金属塩（例、カルシウム塩、マグネシウム塩、バリウム塩等）等の無機塩、アンモニウム塩等が挙げられる。 Among these salts, pharmaceutically acceptable salts are preferable. Preferred pharmaceutically acceptable salts include, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, phthalic acid, etc., when the compound has a basic functional group. And salts with organic acids such as acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid. In addition, when the compound has an acidic functional group, inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.) and alkaline earth metal salts (eg, calcium salts, magnesium salts, barium salts, etc.) And ammonium salts.

　化合物（Ｉ）は溶媒和物（例えば、水和物）および無溶媒和物をその範囲内に包含する。また、化合物（Ｉ）は、同位元素（例、３Ｈ、１４Ｃ、３５Ｓ、１２５Ｉなど）などで標識されていてもよい。化合物（Ｉ）は、重水素変換体であってもよい。さらに、１Ｈを２Ｈ（Ｄ）に変換した重水素変換体も、化合物（Ｉ）に包含される。 Compound (I) includes within its scope solvates (eg hydrates) and non-solvates. In addition, compound (I) may be labeled with an isotope (eg, 3 H, 14 C, 35 S, 125 I, etc.). Compound (I) may be a deuterium converter. Further, a deuterium converter obtained by converting 1 H into 2 H (D) is also encompassed in compound (I).

　本発明による化合物（Ｉ）が不斉中心を有する場合、エナンチオマーあるいはジアステレオマーなどの異性体が存在しうる。このような異性体およびそれらの混合物はすべて本発明の範囲内に包含される。また、コンホメーションあるいは互変異性による異性体が生成する場合があるが、このような異性体あるいはその混合物も本発明の化合物（Ｉ）に含まれる。 When the compound (I) according to the present invention has an asymmetric center, isomers such as enantiomers or diastereomers may exist. All such isomers and mixtures thereof are included within the scope of the present invention. In addition, isomers due to conformation or tautomerism may be produced, and such isomers or mixtures thereof are also included in the compound (I) of the present invention.

　以下に、本発明の化合物の製造法を説明する。
（製造方法）
　下記式（Ｉ）で表される化合物またはその塩およびその原料化合物は、自体公知の手段を用いて、例えば以下のスキームで示される方法などによって製造することができる。 Below, the manufacturing method of the compound of this invention is demonstrated.
(Production method)
A compound represented by the following formula (I) or a salt thereof and a raw material compound thereof can be produced by a method known per se, for example, by a method shown in the following scheme.

Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009

　以下、「室温」は通常０ないし３０℃を示し、スキーム中に記載されている化学構造式中の各記号は、特記しない限り前記と同意義を示す。なお、式中の化合物は、塩を形成している場合も含み、このような塩としては、例えば化合物（Ｉ）の塩と同様のものなどが挙げられる。 Hereinafter, “room temperature” usually indicates 0 to 30 ° C., and each symbol in the chemical structural formula described in the scheme has the same meaning as described above unless otherwise specified. In addition, the compound in a formula also includes the case where it forms the salt, As such a salt, the thing similar to the salt of compound (I) etc. are mentioned, for example.

　また、各工程で得られた化合物は、反応液のままか粗製物として次の反応に用いることもできるが、常法に従って反応混合物から単離することもできる。その際、再結晶、蒸留、クロマトグラフィーなどの分離手段により精製することができる。 Further, the compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method. At that time, it can be purified by separation means such as recrystallization, distillation, chromatography and the like.

　以下にその反応式の略図を示すが、式中の化合物が市販されている場合には市販品をそのまま用いることもできる。また、化合物が置換基を有している場合、対応する前駆体においても同様の置換基を有しているものとする。 The schematic diagram of the reaction formula is shown below, but when the compound in the formula is commercially available, a commercially available product can be used as it is. Further, when the compound has a substituent, the corresponding precursor also has the same substituent.

　以下に記載の製造法において、保護基ＰＲＧとはアミンやアミドの窒素原子の保護基を指し、例えばグリーンズ・プロテクティブ・グループス・イン・オーガニック・シンセシス第４版（Ｇｒｅｅｎｅ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ　４ｔｈ　Ｅｄｉｔｉｏｎ）、２００６年に記載の保護基が使用できる。また、これら保護基の導入が必要な場合は、本書に記載の方法に準じて行うことができる。中でも好ましいＰＲＧとして、ｔｅｒｔ－ブトキシカルボニル、ベンジルオキシカルボニル、ベンジル、アセチルなどが挙げられる。 In the production method described below, the protecting group PRG refers to a protecting group for the nitrogen atom of an amine or amide. For example, Green's Protective Groups in Organic Synthesis 4th Edition 4 th Edition), it can be used protecting groups described in 2006. Moreover, when introduction | transduction of these protecting groups is required, it can carry out according to the method as described in this book. Among them, preferred PRG includes tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, acetyl and the like.

　脱離基はＬＧで示し、ＬＧとしては、例えば、ハロゲン原子（例えば、塩素原子、臭素原子、ヨウ素原子など）、ハロゲン原子で置換されていてもよいＣ１－６アルキルスルホニルオキシ（例えば、メタンスルホニルオキシ、エタンスルホニルオキシ、トリフルオロメタンスルホニルオキシなど）、Ｃ６－１０アリールスルホニルオキシ（例えば、ベンゼンスルホニルオキシ、ｐ－トルエンスルホニルオキシなど）などが用いられる。 The leaving group is represented by LG, and LG includes, for example, a halogen atom (eg, chlorine atom, bromine atom, iodine atom), C 1-6 alkylsulfonyloxy (eg, methane) optionally substituted with a halogen atom. Sulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), C 6-10 arylsulfonyloxy (eg, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.) are used.

　以下に記載の製造法において、アルキル化反応、加水分解反応、アミノ化反応、エステル化反応、アミド化反応、エーテル化反応、酸化反応、還元反応，還元的アミノ化反応などを行う場合、これらの反応は、自体公知の方法にしたがって行われる。このような方法としては、例えばオーガニック　ファンクショナル　グループ　プレパレーションズ（ＯＲＧＡＮＩＣ　ＦＵＮＣＴＩＯＮＡＬ　ＧＲＯＵＰ　ＰＲＥＰＡＲＡＴＩＯＮＳ）、第２版、アカデミックプレス社（ＡＣＡＤＥＭＩＣ　ＰＲＥＳＳ，　ＩＮＣ．）、１９８９年刊；コンプリヘンシブ・オーガニック・トランスフォーメーション（Ｃｏｍｐｒｅｈｅｎｓｉｖｅ　Ｏｒｇａｎｉｃ　Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ）、ＶＣＨ　Ｐｕｂｌｉｓｈｅｒｓ　Ｉｎｃ．、１９８９年刊等に記載の方法などが挙げられる。 In the production method described below, when performing alkylation reaction, hydrolysis reaction, amination reaction, esterification reaction, amidation reaction, etherification reaction, oxidation reaction, reduction reaction, reductive amination reaction, etc. The reaction is carried out according to a method known per se. As such a method, for example, Organic Functional Group Preparations (ORGANIC FUNCTIONAL GROUP PREPARATIONS), 2nd edition, Academic Press, Inc., published in 1989; Comprehensive Organic Transformation (Comprehensive Organics) Transformations), VCH Publishers Inc. And the method described in 1989.

　以下に述べる各工程は、無溶媒、あるいは化合物を適当な溶媒に溶解または懸濁して行うことができる。「溶媒」とは、例えば、炭化水素系溶媒、アルコール系溶媒、エーテル系溶媒、ハロゲン化炭化水素系溶媒、芳香族系溶媒、ニトリル系溶媒、アミド系溶媒、スルホキシド系溶媒、ケトン系溶媒、エステル系溶媒、カルボン酸系溶媒、水等を指し、これらは、二種以上を適宜の割合で混合して用いてもよい。 Each step described below can be performed without solvent or by dissolving or suspending the compound in an appropriate solvent. Examples of the “solvent” include hydrocarbon solvents, alcohol solvents, ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, sulfoxide solvents, ketone solvents, esters. It refers to a system solvent, a carboxylic acid solvent, water, etc., and these may be used in a mixture of two or more at an appropriate ratio.

化合物（Ｉ）の製造 Production of Compound (I)

Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010

（工程１）
　化合物（Ｉａ）は、化合物（ＩＩ）の脱保護により製造することができる。脱保護は、例えばグリーンズ・プロテクティブ・グループス・イン・オーガニック・シンセシス第４版（Ｇｒｅｅｎｅ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ　４ｔｈ　Ｅｄｉｔｉｏｎ）、２００６年に記載の方法等に準じて行うことができる。具体的には、酸処理、アルカリ加水分解、接触水素添加反応等によって実施できる。保護基ＰＲＧとしては、一般的なアミンの保護基を用いることができるが、好ましくは、ｔｅｒｔ－ブトキシカルボニル、ベンジルオキシカルボニル、ベンジル、アセチル、メチル等が挙げられる。 (Process 1)
Compound (Ia) can be produced by deprotection of compound (II). Deprotection, for example Greens Protective Groups in Organic Synthesis, 4th edition (Greene's Protective Groups in Organic Synthesis 4 th Edition), can be carried out according to the method described in 2006. Specifically, it can be carried out by acid treatment, alkali hydrolysis, catalytic hydrogenation reaction or the like. As the protecting group PRG, a general amine protecting group can be used, and preferred examples include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, acetyl, methyl and the like.

　例えば、保護基ＰＲＧがｔｅｒｔ－ブトキシカルボニルまたはアセチルの場合、酸を用いた脱保護が好ましい。 For example, when the protecting group PRG is tert-butoxycarbonyl or acetyl, deprotection using an acid is preferred.

　（工程１）は一般に有機合成に用いられる溶媒中で行われ、反応を阻害しない溶媒が適宜選択される。このような「溶媒」としては、アルコール系溶媒（例、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、ｔｅｒｔ－ブタノール等）、エーテル系溶媒（例、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル、エチレングリコール－ジメチルエーテル等）、エステル系溶媒（例、ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル等）、カルボン酸系溶媒（例、ギ酸、酢酸、プロピオン酸等）、ハロゲン化炭化水素系溶媒（例、ジクロロメタン、クロロホルム、四塩化炭素、トリクロロエチレン、１，２－ジクロロエタン、クロロベンゼン等）、炭化水素系溶媒（例、ｎ－ヘキサン等）、芳香族系溶媒（例、ベンゼン、トルエン等）、アミド系溶媒（例、ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド等）、ケトン系溶媒（例、アセトン、メチルエチルケトン、メチルイソブチルケトン等）、ニトリル系溶媒（例、アセトニトリル、プロピオニトリル等）、スルホキシド系溶媒（例、ジメチルスルホキシド等）等のほか、スルホラン、ヘキサメチルホスホルアミド、水等が単独または混合溶媒として用いられる。保護基ＰＲＧがｔｅｒｔ－ブトキシカルボニルの場合、「溶媒」として、好ましくは、エステル系溶媒（例えば、酢酸エチル等）、アルコール系溶媒（例えば、エタノール等）などが挙げられ、保護基ＰＲＧがアセチルの場合、「溶媒」として、好ましくは、アルコール系溶媒（例えば、エタノール等）などが挙げられる。「酸」として、好ましくは、塩酸、臭化水素酸、トリフルオロ酢酸などが挙げられる。「酸」の使用量は、化合物（ＩＩ）１モルに対し、通常、１ないし１００モル当量、好ましくは１ないし５０モル当量である。反応温度は、通常、約０℃～約１５０℃、好ましくは約２０℃～約８０℃であり、反応時間は、通常、約５分間～約７２時間、好ましくは約０．１時間～約２４時間である。保護基ＰＲＧがベンジルオキシカルボニルの場合、接触水素添加反応等によっても脱保護を行うことができる。「接触水素添加反応」は、水素雰囲気中、触媒の存在下で行うことができる。「触媒」としては、例えば、パラジウム類（例えば、パラジウム炭素、水酸化パラジウム、酸化パラジウム等）、ニッケル類（例えば、展開ニッケル触媒等）、白金類（例えば、酸化白金、白金炭素等）、ロジウム類（例えば、ロジウム炭素等）等が挙げられる。「触媒」の使用量は、化合物（ＩＩ）１モルに対し、通常、０．００１ないし１モル当量、好ましくは０．０１ないし０．２モル当量である。「溶媒」として好ましくは、アルコール系溶媒（例えば、メタノール、エタノール、プロパノール、ブタノールなど）、エーテル系溶媒（例えば、ジエチルエーテル、ジオキサン、テトラヒドロフランなど）、エステル系溶媒（例えば、酢酸エチルなど）、カルボン酸系溶媒（例えば、酢酸など）、水またはそれらの混合物が挙げられる。反応が行われる水素圧は、通常、約１～約５０気圧であり、好ましくは約１～約１０気圧である。反応温度は、通常、約０℃～約１５０℃、好ましくは約２０℃～約１００℃であり、反応時間は、通常、約５分間～約７２時間、好ましくは約０．５時間～約４０時間である。 (Step 1) is generally performed in a solvent used for organic synthesis, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such “solvents” include alcohol solvents (eg, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc.), ether solvents (eg, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, Diisopropyl ether, ethylene glycol-dimethyl ether, etc.), ester solvents (eg, ethyl formate, ethyl acetate, n-butyl acetate, etc.), carboxylic acid solvents (eg, formic acid, acetic acid, propionic acid, etc.), halogenated hydrocarbons Solvent (eg, dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, 1,2-dichloroethane, chlorobenzene, etc.), hydrocarbon solvent (eg, n-hexane, etc.), aromatic solvent (eg, benzene, toluene, etc.), Amide solvents (eg Amide, N, N-dimethylformamide, N, N-dimethylacetamide, etc.), ketone solvent (eg, acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), nitrile solvent (eg, acetonitrile, propionitrile, etc.), sulfoxide type In addition to a solvent (eg, dimethyl sulfoxide, etc.), sulfolane, hexamethylphosphoramide, water and the like are used alone or as a mixed solvent. When the protecting group PRG is tert-butoxycarbonyl, the “solvent” is preferably an ester solvent (for example, ethyl acetate), an alcohol solvent (for example, ethanol) or the like, and the protecting group PRG is an acetyl group. In this case, the “solvent” is preferably an alcohol solvent (eg, ethanol). Preferred examples of the “acid” include hydrochloric acid, hydrobromic acid, trifluoroacetic acid and the like. The amount of the “acid” to be used is generally 1 to 100 molar equivalents, preferably 1 to 50 molar equivalents, per 1 mol of compound (II). The reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.1 hour to about 24 hours. It's time. When the protecting group PRG is benzyloxycarbonyl, deprotection can also be performed by a catalytic hydrogenation reaction or the like. The “catalytic hydrogenation reaction” can be performed in a hydrogen atmosphere in the presence of a catalyst. Examples of the “catalyst” include palladium (eg, palladium carbon, palladium hydroxide, palladium oxide, etc.), nickel (eg, developed nickel catalyst, etc.), platinum (eg, platinum oxide, platinum carbon, etc.), rhodium. (For example, rhodium carbon and the like). The amount of the “catalyst” to be used is generally 0.001 to 1 molar equivalent, preferably 0.01 to 0.2 molar equivalent, per 1 mol of compound (II). The “solvent” is preferably an alcohol solvent (eg, methanol, ethanol, propanol, butanol, etc.), an ether solvent (eg, diethyl ether, dioxane, tetrahydrofuran, etc.), an ester solvent (eg, ethyl acetate, etc.), An acid solvent (for example, acetic acid etc.), water, or mixtures thereof are mentioned. The hydrogen pressure at which the reaction is carried out is usually about 1 to about 50 atmospheres, preferably about 1 to about 10 atmospheres. The reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 100 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 hours to about 40 ° C. It's time.

（工程２）
　化合物（Ｉ）は、化合物（Ｉａ）の還元的アルキル化によって製造することができる。該反応は、例えば、オーガニック　リアクションズ（Ｏｒｇａｎｉｃ　Ｒｅａｃｔｉｏｎｓ），　ｖｏｌ．５９，　１－７１４（２００２年）に記載の方法を用いることができ、化合物（Ｉａ）と、対応するアルデヒドやケトンより生成したイミン中間体を還元反応に付すことにより行われる。アルデヒドやケトンの使用量は、化合物（Ｉａ）１モルに対し、通常、１ないし１０モル当量、好ましくは１ないし３モル当量である。用いる還元剤としては、例えば、アルミニウム試薬（例、水素化アルミニウムリチウム（ＬｉＡｌＨ４）、水素化ジイソブチルアルミニウム（ＤＩＢＡＬ－Ｈ）、水素化ビス（２－メトキシエトキシ）アルミニウムナトリウム（Ｒｅｄ－Ａｌ）、アラン（ＡｌＨ３）等）、ホウ素試薬（例、ボラン（ＢＨ３）、９－ボラビシクロ［３．３．１］ノナン（９－ＢＢＮ）、水素化ホウ素ナトリウム（ＮａＢＨ４）、シアノ水素化ホウ素ナトリウム（ＮａＢＨ３ＣＮ）、トリアセトキシ水素化ホウ素ナトリウム（ＮａＢＨ（ＯＡｃ）３）等）等が挙げられる。好ましくは、ボラン、トリアセトキシ水素化ホウ素ナトリウム、シアノ水素化ホウ素ナトリウム等である。「還元剤」の使用量は、化合物（Ｉａ）１モルに対し、通常、１ないし２０モル当量、好ましくは１ないし５モル当量である。「ホウ素試薬」を用いる場合、反応を促進させるために酸を添加しても良い。「酸」として好ましくは酢酸等が挙げられる。「酸」の使用量は、化合物（Ｉａ）１モルに対し、通常、０．１ないし１０モル当量、好ましくは０．１ないし１モル当量である。溶媒としては、（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもエーテル系溶媒（例えば、テトラヒドロフランなど）等が好ましい。反応温度は、通常、約－１００℃～約１５０℃、好ましくは約０℃～約８０℃であり、反応時間は、通常、約５分間～約７２時間、好ましくは約１時間～約２４時間である。 (Process 2)
Compound (I) can be produced by reductive alkylation of compound (Ia). The reaction is described, for example, in Organic Reactions, vol. 59, 1-714 (2002), and can be carried out by subjecting compound (Ia) and an imine intermediate produced from the corresponding aldehyde or ketone to a reduction reaction. The amount of aldehyde or ketone to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (Ia). Examples of the reducing agent used include aluminum reagents (eg, lithium aluminum hydride (LiAlH 4 ), diisobutylaluminum hydride (DIBAL-H), sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al), and alane. (AlH 3 )), boron reagents (eg, borane (BH 3 ), 9-borabicyclo [3.3.1] nonane (9-BBN), sodium borohydride (NaBH 4 ), sodium cyanoborohydride ( NaBH 3 CN), sodium triacetoxyborohydride (NaBH (OAc) 3 ) and the like). Borane, sodium triacetoxyborohydride, sodium cyanoborohydride and the like are preferable. The amount of the “reducing agent” to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (Ia). When “boron reagent” is used, an acid may be added to promote the reaction. Preferred examples of the “acid” include acetic acid. The amount of the “acid” to be used is generally 0.1 to 10 molar equivalents, preferably 0.1 to 1 molar equivalents, per 1 mol of compound (Ia). As the solvent, those similar to the “solvent” described in (Step 1) can be used, and among them, ether solvents (for example, tetrahydrofuran and the like) are preferable. The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.

　化合物（ＩＩ）は、以下に示す［製造法Ａ］～［製造法Ｇ］によって製造することができる。［製造法Ａ］は化合物（ＩＩａ）、［製造法Ｂ］は化合物（ＩＩｂ）および（ＩＩｃ）、［製造法Ｃ］は化合物（ＩＩｄ）、［製造法Ｄ］は化合物（ＩＩｅ）、（ＩＩｆ）および（ＩＩｇ）、［製造法Ｅ］は化合物（ＩＩｈ）（ＩＩｉ）および（ＩＩｊ）、［製造法Ｆ］は化合物（ＩＩｋ）および（ＩＩｌ）、［製造法Ｇ］は化合物（ＩＩｍ）の製造法を示す。 Compound (II) can be produced by the following [Production Method A] to [Production Method G]. [Production Method A] is Compound (IIa), [Production Method B] is Compound (IIb) and (IIc), [Production Method C] is Compound (IId), [Production Method D] is Compound (IIe), (IIf) ) And (IIg), [Production E] is compound (IIh) (IIi) and (IIj), [Production F] is compound (IIk) and (IIl), and [Production G] is compound (IIm). A manufacturing method is shown.

Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011

［製造法Ａ］
化合物（ＩＩａ）の製造 [Production method A]
Production of Compound (IIa)

Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012

［式中、Ｒ１４およびＲ１５は、同一または異なって、水素原子または置換されていてもよい低級アルキルを表すか、あるいはＲ１４とＲ１５は、それらが結合する窒素原子と共に置換されていてもよい３ないし８員環状アミノを形成していてもよい。］ [Wherein R 14 and R 15 are the same or different and each represents a hydrogen atom or an optionally substituted lower alkyl, or R 14 and R 15 are substituted together with the nitrogen atom to which they are bonded. It may also form a 3- to 8-membered cyclic amino. ]

（工程３）
　化合物（ＩＩａ）は、化合物（ＩＩＩ）のアミド化により製造することができる。（工程３）は、例えばジャーナル　オブ　オーガニック　ケミストリー（Ｊ．Ｏｒｇ．Ｃｈｅｍ．），　５５，　２７０，　（１９９０）に記載の方法で行うことができ、対応するアミンまたはその塩酸塩と縮合剤（例えば、カルボジイミド類（例、ジシクロヘキシルカルボジイミド、ジイソプロピルカルボジイミド、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド等）、りん酸誘導体（シアノりん酸ジエチル、アジ化ジフェニルホスホリル等）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド（ＤＭＴ－ＭＭ：クニシマら、テトラヘドロン（Ｔｅｔｒａｈｅｄｒｏｎ），　５５，　１３１５９，　（１９９９）等）を用いる。「縮合剤」として、カルボジイミドまたはその塩酸塩などのカルボジイミド系縮合試薬を用いる場合、必要に応じて適当な縮合促進剤（例、１－ヒドロキシ－７－アザベンゾトリアゾール、１－ヒドロキシベンゾトリアゾール、Ｎ－ヒドロキシこはく酸イミド、Ｎ－ヒドロキシフタルイミドなど）を用いてもよい。「アミンまたはその塩酸塩」の使用量は、化合物（ＩＩＩ）１モルに対し、通常、１ないし１０モル当量、好ましくは１ないし２モル当量である。「縮合剤」の使用量は、化合物（ＩＩＩ）１モルに対し、通常、１ないし１０モル当量、好ましくは１ないし２モル当量である。また、上記した「縮合促進剤」の使用量は、化合物（ＩＩＩ）１モルに対して、通常、０．１ないし１０モル当量、好ましくは０．３ないし３モル当量である。溶媒としては、（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもＮ，Ｎ－ジメチルホルムアミド等のアミド系溶媒等が好ましい。また、本反応は適当な塩基を添加して行ってもよい。 (Process 3)
Compound (IIa) can be produced by amidation of compound (III). (Step 3) can be performed, for example, by the method described in Journal of Organic Chemistry (J. Org. Chem.), 55, 270, (1990), and the corresponding amine or a hydrochloride thereof and a condensing agent (for example, Carbodiimides (eg, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, etc.), phosphoric acid derivatives (diethyl cyanophosphate, diphenylphosphoryl azide, etc.), 4- (4,6 -Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (DMT-MM: Kunishima et al., Tetrahedron, 55, 13159, (1999)) is used. As a condensing agent, carbodiimide or a salt thereof When a carbodiimide-based condensation reagent such as an acid salt is used, an appropriate condensation accelerator (eg, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxy is used as necessary. The amount of “amine or its hydrochloride” to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, per 1 mol of compound (III). The amount of the “agent” is usually 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, preferably 1 to 2 molar equivalents relative to 1 mol of the compound (III). III) It is usually 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents relative to 1 mol. As the solvent, the “solution” described in (Step 1) is used. It may be the same as the "inter alia N, amide solvents such as N- dimethylformamide is preferred. Further, this reaction may be carried out by addition of a suitable base.

　「塩基」としては、
　１）アルカリ金属またはアルカリ土類金属の水素化物（例えば、水素化リチウム、水素化ナトリウム、水素化カリウム、水素化カルシウムなど）、アルカリ金属またはアルカリ土類金属のアミド類（例えば、リチウムアミド、ナトリウムアミド、リチウムジイソプロピルアミド、リチウムジシクロヘキシルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジドなど）、アルカリ金属またはアルカリ土類金属の低級アルコキシド（例えば、ナトリウムメトキシド、ナトリウムエトキシド、カリウム　ｔｅｒｔ－ブトキシドなど）などの強塩基；
　２）アルカリ金属またはアルカリ土類金属の水酸化物（例えば、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、水酸化バリウムなど）、アルカリ金属またはアルカリ土類金属の炭酸塩（例えば、炭酸ナトリウム、炭酸カリウム、炭酸セシウムなど）、アルカリ金属またはアルカリ土類金属の炭酸水素塩（例えば、炭酸水素ナトリウム、炭酸水素カリウムなど）などの無機塩基；および
　３）例えば、トリエチルアミン、エチルジイソプロピルアミン、Ｎ－メチルモルホリンなどのアミン類；例えば、１，８－ジアザビシクロ〔５．４．０〕ウンデカ－７－エン（ＤＢＵ）、１，５－ジアザビシクロ〔４．３．０〕ノナ－５－エン（ＤＢＮ）などのアミジン類；例えば、ピリジン、ジメチルアミノピリジン、イミダゾール、２，６－ルチジンなどの塩基性複素環化合物などの有機塩基などが挙げられる。 As "base"
1) Alkali metal or alkaline earth metal hydrides (eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), alkali metal or alkaline earth metal amides (eg, lithium amide, sodium) Amides, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide), alkali metal or alkaline earth metal lower alkoxides (eg, sodium methoxide, Strong bases such as sodium ethoxide, potassium tert-butoxide and the like;
2) Alkali metal or alkaline earth metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.), alkali metal or alkaline earth metal carbonates (eg, sodium carbonate, Inorganic bases such as potassium carbonate, cesium carbonate, etc.), alkali metal or alkaline earth metal hydrogen carbonates (eg, sodium bicarbonate, potassium bicarbonate, etc.); and 3) eg, triethylamine, ethyldiisopropylamine, N-methyl Amines such as morpholine; for example, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), etc. Amidines such as pyridine, dimethylaminopyridine, imidazole, 2,6-luti And organic bases such as basic heterocyclic compounds such as gin.

　該アミド化に添加する塩基としては、例えば、トリエチルアミン等が好ましい。「塩基」の使用量は、化合物（ＩＩＩ）１モルに対し、通常、１ないし１０モル当量、好ましくは１ないし２モル当量である。反応温度は、通常、約－１００℃～約１５０℃、好ましくは約０℃～約１００℃であり、反応時間は、通常、約５分間～約７２時間、好ましくは約１時間～約２４時間である。 As the base to be added to the amidation, for example, triethylamine or the like is preferable. The amount of the “base” to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, per 1 mol of compound (III). The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about 0 ° C. to about 100 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.

［製造法Ｂ］
化合物（ＩＩｂ）および（ＩＩｃ）の製造 [Production method B]
Production of compounds (IIb) and (IIc)

Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013

［式中、Ｒ１６は、置換されていてもよい低級アルキルを表す。］ [Wherein, R 16 represents an optionally substituted lower alkyl. ]

（工程４）
　化合物（ＩＩｂ）は、化合物（ＩＩＩ）のカルボキシ基の還元によって製造することができる。また、本工程は保護基（ＰＲＧ）を用いずに行うこともできる。化合物（ＩＩＩ）１モルに対して還元剤を０．１モル当量ないし大過剰（好ましくは０．３～１０モル当量）使用する。「還元剤」としては、前記（工程２）で述べた「還元剤」と同様のものを用いることができるが、中でも水素化アルミニウムリチウムやボラン錯体（ボラン－ＴＨＦ錯体など）などが好ましい。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもテトラヒドロフラン等のエーテル系溶媒が好ましい。反応温度は、通常、約－８０℃～約１５０℃、好ましくは約－３０℃～約１００℃であり、反応時間は、通常、約０．１時間～約７２時間、好ましくは約０．３時間～約２４時間である。 (Process 4)
Compound (IIb) can be produced by reduction of the carboxy group of compound (III). Moreover, this process can also be performed without using a protecting group (PRG). The reducing agent is used in an amount of 0.1 molar equivalent to a large excess (preferably 0.3 to 10 molar equivalents) per mole of compound (III). As the “reducing agent”, the same as the “reducing agent” described in the above (Step 2) can be used, and among them, lithium aluminum hydride, borane complex (such as borane-THF complex) and the like are preferable. As the solvent, those similar to the “solvent” described in the above (Step 1) can be used, and ether solvents such as tetrahydrofuran are particularly preferable. The reaction temperature is usually about −80 ° C. to about 150 ° C., preferably about −30 ° C. to about 100 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.

（工程５）
　化合物（ＩＩｃ）は、化合物（ＩＩｂ）のＯ－アルキル化によって製造することができる。（工程５）は、例えばジャーナル　オブ　オーガニック　ケミストリー（Ｊ．Ｏｒｇ．Ｃｈｅｍ．），　５２，　４６６５，　（１９８７）に記載のように、塩基の存在下、アルキル化剤を用いることによって行うことができる。「塩基」としては、（工程３）で述べた「塩基」と同様のものを用いることができるが、中でも水素化ナトリウムなどのアルカリ金属またはアルカリ土類金属の水素化物、ナトリウムアミドなどのアルカリ金属またはアルカリ土類金属のアミド類、あるいはカリウム　ｔｅｒｔ－ブトキシドなどのアルカリ金属またはアルカリ土類金属の低級アルコキシドが好ましい。「アルキル化剤」は、導入するＲ１６によって選択されるが、塩化メチル、塩化エチル、塩化プロピル、塩化ブチル等の低級アルキルクロライド、対応する低級アルキルブロマイド、対応する低級アルキルヨージド、対応するメタンスルホン酸低級アルキル、対応するｐ－トルエンスルホン酸低級アルキルなどが挙げられる。中でも低級アルキルハライド（ヨウ化メチル、臭化エチルなど）が好ましい。塩基の使用量は、化合物（ＩＩｂ）１モルに対して、通常、０．１ないし１０モル当量、好ましくは１ないし３モル当量である。「アルキル化剤」の使用量は、化合物（ＩＩｂ）１モルに対して、通常、０．１ないし１０モル当量、好ましくは１ないし３モル当量である。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもテトラヒドロフランなどのエーテル系溶媒、Ｎ，Ｎ－ジメチルホルムアミドなどのアミド系溶媒が好ましい。反応温度は、通常、約－８０℃～約１５０℃、好ましくは約－３０℃～約１００℃であり、反応時間は、通常、約０．１時間～約７２時間、好ましくは約０．３時間～約２４時間である。 (Process 5)
Compound (IIc) can be produced by O-alkylation of compound (IIb). (Step 5) can be performed by using an alkylating agent in the presence of a base, as described in, for example, Journal of Organic Chemistry (J. Org. Chem.), 52, 4665, (1987). As the “base”, those similar to the “base” described in (Step 3) can be used. Among them, alkali metal such as sodium hydride or alkaline earth metal hydride, alkali metal such as sodium amide, etc. Alternatively, alkaline earth metal amides or alkali metal or alkaline earth metal lower alkoxides such as potassium tert-butoxide are preferred. The “alkylating agent” is selected depending on R 16 to be introduced, and is a lower alkyl chloride such as methyl chloride, ethyl chloride, propyl chloride, butyl chloride, the corresponding lower alkyl bromide, the corresponding lower alkyl iodide, the corresponding methane And a lower alkyl sulfonate and a corresponding lower alkyl p-toluenesulfonate. Of these, lower alkyl halides (such as methyl iodide and ethyl bromide) are preferred. The amount of the base to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (IIb). The amount of the “alkylating agent” to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (IIb). As the solvent, those similar to the “solvent” described in the above (Step 1) can be used, but ether solvents such as tetrahydrofuran and amide solvents such as N, N-dimethylformamide are particularly preferable. The reaction temperature is usually about −80 ° C. to about 150 ° C., preferably about −30 ° C. to about 100 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.

［製造法Ｃ］
化合物（ＩＩｄ）の製造 [Production Method C]
Production of Compound (IId)

Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014

［式中、Ｒ１７は、低級アルキルを表す。］ [Wherein R 17 represents lower alkyl. ]

（工程６）
　化合物（ＩＩｄ）は、化合物（ＩＶ）の立体選択的還元によって製造することができる。化合物（ＩＶ）１モルに対して還元剤を０．１ないし１００モル当量（好ましくは０．３～１０モル当量）使用する。「還元剤」としては、前記（工程２）で述べた「還元剤」と同様のものを用いることができるが、中でも水素化ホウ素ナトリウムなどが好ましい。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもエタノール等のアルコール系溶媒が好ましい。反応温度は、通常、約－８０℃～約１５０℃、好ましくは約０℃～約１００℃であり、反応時間は、通常、約０．１時間～約７２時間、好ましくは約０．３時間～約２４時間である。 (Step 6)
Compound (IId) can be produced by stereoselective reduction of compound (IV). The reducing agent is used in an amount of 0.1 to 100 molar equivalents (preferably 0.3 to 10 molar equivalents) per 1 mol of compound (IV). As the “reducing agent”, the same “reducing agent” as described in the above (Step 2) can be used, and among them, sodium borohydride and the like are preferable. As the solvent, those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as ethanol are particularly preferable. The reaction temperature is usually about −80 ° C. to about 150 ° C., preferably about 0 ° C. to about 100 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 hour. ~ About 24 hours.

［製造法Ｄ］
化合物（ＩＩｅ）、（ＩＩｆ）および（ＩＩｇ）の製造 [Production Method D]
Preparation of compounds (IIe), (IIf) and (IIg)

Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015

［式中、Ｒ１６は、置換されていてもよい低級アルキルを表し、Ｒ１７は、低級アルキルを表し、Ｒ１８は、置換されていてもよい低級アルキルまたは置換されていてもよい芳香環基（例、フェニル、芳香族含窒素複素環基）を表す。］ [Wherein R 16 represents an optionally substituted lower alkyl, R 17 represents a lower alkyl, and R 18 represents an optionally substituted lower alkyl or an optionally substituted aromatic ring group. (Eg, phenyl, aromatic nitrogen-containing heterocyclic group). ]

（工程７）
　化合物（ＩＩｅ）は、化合物（ＩＩｒ）を炭素求核剤と反応させることにより製造することができる。条件により化合物（ＩＩｆ）が得られる場合もある。また、本工程は保護基（ＰＲＧ）を用いずに行うこともできる。「炭素求核剤」としては、アルキルリチウムあるいはアリールリチウムなどの有機リチウム試薬、アルキルマグネシウムハライドあるいはアリールマグネシウムブロミドなどの有機マグネシウム試薬（例えば、メチルマグネシウムブロミド、エチルマグネシウムブロミド、プロピルマグネシウムブロミドなど）、ニトロメタンなどのアルキルニトロ化合物、アルキルエノールエーテル、アルキルシリルエノールエーテルなどのエノールエーテル化合物、アルキルあるいはアリールスルホン、マロン酸エステル、アセト酢酸エステル、１，３－ジチアンなどの活性メチレン化合物などが挙げられる。中でも、アルキルマグネシウムブロミドあるいはアリールマグネシウムブロミドなどの有機マグネシウム試薬（例えば、メチルマグネシウムブロミド、エチルマグネシウムブロミド、プロピルマグネシウムブロミドなど）が好ましい。「炭素求核剤」の使用量は、化合物（ＩＩｒ）に対して、通常、０．１ないし２０モル当量、好ましくは１ないし１０モル当量である。（工程７）は必要に応じて塩基の存在下で行われる。「塩基」としては、（工程３）で述べた「塩基」と同様のものを用いることができるが、中でも水素化ナトリウムなどのアルカリ金属またはアルカリ土類金属の水素化物、ナトリウムアミドなどのアルカリ金属またはアルカリ土類金属のアミド類、あるいはカリウム　ｔｅｒｔ－ブトキシドなどのアルカリ金属またはアルカリ土類金属の低級アルコキシドが好ましい。「塩基」の使用量は、化合物（ＩＩｒ）１モルに対して、通常、０．１ないし１０モル当量、好ましくは０．３ないし３モル当量である。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもテトラヒドロフランなどのエーテル系溶媒が好ましい。反応温度は、通常、約－８０℃～約１５０℃、好ましくは約－３０℃～約１００℃であり、反応時間は、通常、約０．１時間～約７２時間、好ましくは約０．３時間～約２４時間である。 (Step 7)
Compound (IIe) can be produced by reacting compound (IIr) with a carbon nucleophile. Depending on conditions, compound (IIf) may be obtained. Moreover, this process can also be performed without using a protecting group (PRG). Examples of the “carbon nucleophile” include organolithium reagents such as alkyllithium and aryllithium, organomagnesium reagents such as alkylmagnesium halide and arylmagnesium bromide (for example, methylmagnesium bromide, ethylmagnesium bromide, propylmagnesium bromide, etc.), nitromethane And enol ether compounds such as alkyl enol ethers and alkyl silyl enol ethers, and active methylene compounds such as alkyl or aryl sulfones, malonic acid esters, acetoacetic acid esters, and 1,3-dithiane. Among these, organic magnesium reagents such as alkyl magnesium bromide or aryl magnesium bromide (for example, methyl magnesium bromide, ethyl magnesium bromide, propyl magnesium bromide, etc.) are preferable. The amount of the “carbon nucleophile” to be used is generally 0.1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, relative to compound (IIr). (Step 7) is performed in the presence of a base as necessary. As the “base”, those similar to the “base” described in (Step 3) can be used. Among them, alkali metal such as sodium hydride or alkaline earth metal hydride, alkali metal such as sodium amide, etc. Alternatively, alkaline earth metal amides or alkali metal or alkaline earth metal lower alkoxides such as potassium tert-butoxide are preferred. The amount of the “base” to be used is generally 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, per 1 mol of compound (IIr). As the solvent, those similar to the “solvent” described in the above (Step 1) can be used, and ether solvents such as tetrahydrofuran are particularly preferable. The reaction temperature is usually about −80 ° C. to about 150 ° C., preferably about −30 ° C. to about 100 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.

（工程８）
　化合物（ＩＩｇ）は、（工程５）に準じて、化合物（ＩＩｅ）のＯ－アルキル化によって製造することができる。塩基としては、（工程３）で述べた「塩基」と同様のものを用いることができるが、中でも水素化ナトリウムなどのアルカリ金属またはアルカリ土類金属の水素化物、ナトリウムアミドなどのアルカリ金属またはアルカリ土類金属のアミド類、あるいはカリウム　ｔｅｒｔ－ブトキシドなどのアルカリ金属またはアルカリ土類金属の低級アルコキシドが好ましい。アルキル化剤としては、（工程５）で述べた「アルキル化剤」と同様のものを用いることができるが、中でも低級アルキルハライド（ヨウ化メチル、臭化エチルなど）が好ましい。「塩基」の使用量は、化合物（ＩＩｅ）１モルに対して、通常、０．１ないし１０モル当量、好ましくは１ないし３モル当量である。「アルキル化剤」の使用量は、化合物（ＩＩｅ）１モルに対して、通常、０．１ないし１０モル当量、好ましくは１ないし３モル当量である。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもテトラヒドロフランなどのエーテル系溶媒、Ｎ，Ｎ－ジメチルホルムアミドなどのアミド系溶媒が好ましい。反応温度は、通常、約－８０℃～約１５０℃、好ましくは約－３０℃～約１００℃であり、反応時間は、通常、約０．１時間～約７２時間、好ましくは約０．３時間～約２４時間である。 (Step 8)
Compound (IIg) can be produced by O-alkylation of compound (IIe) according to (Step 5). As the base, those similar to the “base” described in (Step 3) can be used, and among them, alkali metal or alkaline earth metal hydride such as sodium hydride, alkali metal or alkali such as sodium amide, etc. An earth metal amide or an alkali metal or alkaline earth metal lower alkoxide such as potassium tert-butoxide is preferred. As the alkylating agent, those similar to the “alkylating agent” described in (Step 5) can be used, and among them, lower alkyl halides (methyl iodide, ethyl bromide, etc.) are preferable. The amount of the “base” to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (IIe). The amount of the “alkylating agent” to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (IIe). As the solvent, those similar to the “solvent” described in the above (Step 1) can be used, but ether solvents such as tetrahydrofuran and amide solvents such as N, N-dimethylformamide are particularly preferable. The reaction temperature is usually about −80 ° C. to about 150 ° C., preferably about −30 ° C. to about 100 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.

［製造法Ｅ］
化合物（ＩＩｈ）および（ＩＩｊ）の製造 [Production Method E]
Preparation of compounds (IIh) and (IIj)

Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016

［式中、Ｒ１４およびＲ１５は、同一または異なって、水素原子または置換されていてもよい低級アルキルを表すか、あるいはＲ１４とＲ１５は、それらが結合する窒素原子と共に置換されていてもよい３ないし８員環状アミノを形成していてもよい。］ [Wherein R 14 and R 15 are the same or different and each represents a hydrogen atom or an optionally substituted lower alkyl, or R 14 and R 15 are substituted together with the nitrogen atom to which they are bonded. It may also form a 3- to 8-membered cyclic amino. ]

（工程９）
　化合物（ＩＩｂ）のヒドロキシ基を脱離基ＬＧに変換し、化合物（Ｖ）を製造する。ヒドロキシ基を脱離基ＬＧにする方法として、例えばオーガニック　ファンクショナル　グループ　プレパレーションズ（ＯＲＧＡＮＩＣ　ＦＵＮＣＴＩＯＮＡＬ　ＧＲＯＵＰ　ＰＲＥＰＡＲＡＴＩＯＮＳ）、第２版、アカデミックプレス社（ＡＣＡＤＥＭＩＣ　ＰＲＥＳＳ，　ＩＮＣ．）、１９８９年刊；コンプリヘンシブ・オーガニック・トランスフォーメーション（Ｃｏｍｐｒｅｈｅｎｓｉｖｅ　Ｏｒｇａｎｉｃ　Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ）、ＶＣＨ　Ｐｕｂｌｉｓｈｅｒｓ　Ｉｎｃ．、１９８９年刊等に記載の方法などが挙げられる。脱離基ＬＧとして、好ましくは、メタンスルホニルオキシ、ハロゲン原子（例えば、塩素原子、臭素原子、ヨウ素原子など）等が挙げられる。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもテトラヒドロフラン等のエーテル系溶媒等や、トルエン等の炭化水素系溶媒が好ましい。反応温度は、通常、約－５０℃～約１５０℃、好ましくは約０℃～約１００℃である。反応時間は、通常、約１分間～約１０日間であり、好ましくは約０．５時間～約２４時間である。また、本工程は保護基（ＰＲＧ）を用いずに行うこともできる。 (Step 9)
The hydroxy group of compound (IIb) is converted to a leaving group LG to produce compound (V). As a method for converting a hydroxy group into a leaving group LG, for example, Organic Functional Group PREPARATIONS, 2nd edition, Academic Press, Inc., published in 1989; Comprehensive Organic Transformation (Comprehensive Organic Transformations), VCH Publishers Inc. 1989, etc., and the like. As the leaving group LG, preferably, methanesulfonyloxy, a halogen atom (for example, a chlorine atom, a bromine atom, an iodine atom, etc.) and the like can be mentioned. As the solvent, those similar to the “solvent” described in the above (Step 1) can be used, but ether solvents such as tetrahydrofuran and hydrocarbon solvents such as toluene are particularly preferable. The reaction temperature is usually about −50 ° C. to about 150 ° C., preferably about 0 ° C. to about 100 ° C. The reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours. Moreover, this process can also be performed without using a protecting group (PRG).

（工程１０）
　化合物（Ｖ）の脱離基ＬＧをシアノ基で置換し、化合物（ＩＩｈ）を製造する。脱離基ＬＧをシアノ基で置換する方法として、例えば、アドバンスト　オーガニック　ケミストリー（ＡＤＶＡＮＣＥＤ　ＯＲＧＡＮＩＣ　ＣＨＥＭＩＳＴＲＹ）、第４版、Ｗｉｌｅｙ－ＩｎｔｅｒＳｃｉｅｎｃｅ、１９９２年刊等に記載の方法などが挙げられる。シアノ化剤として、好ましくはシアン化ナトリウム、シアン化カリウム等が挙げられる。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもＮ，Ｎ－ジメチルホルムアミド等のアミド系溶媒やテトラヒドロフラン等のエーテル系溶媒等が好ましい。反応温度は、通常、約－５０℃～約２００℃、好ましくは約０℃～約１５０℃である。反応時間は、通常、約１分間～約１０日間、好ましくは約０．５時間～約２４時間である。 (Process 10)
The leaving group LG of compound (V) is substituted with a cyano group to produce compound (IIh). Examples of the method for substituting the leaving group LG with a cyano group include the methods described in ADVANCED ORGANIC CHEMISTRY, 4th edition, Wiley-InterScience, 1992, and the like. Preferred examples of the cyanating agent include sodium cyanide and potassium cyanide. As the solvent, those similar to the “solvent” described in the above (Step 1) can be used. Among them, an amide solvent such as N, N-dimethylformamide, an ether solvent such as tetrahydrofuran and the like are preferable. The reaction temperature is generally about −50 ° C. to about 200 ° C., preferably about 0 ° C. to about 150 ° C. The reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.

（工程１１）
　化合物（ＩＩｉ）は、化合物（ＩＩｈ）の加水分解によって製造することができる。該加水分解は、アルカリ性条件と酸性条件から選択して行うことができる。アルカリ性条件での加水分解は、塩基の存在下、反応に影響を及ぼさない溶媒中で行われる。「塩基」としては、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸カリウム、炭酸ナトリウム、ナトリム　エトキシド、カリウム　ｔｅｒｔ－ブトキシドなどが挙げられる。「塩基」の使用量は、化合物（ＩＩｈ）１モルに対して、好ましくは、約１ないし約５モル当量である。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもエタノールなどのアルコール系溶媒、テトラヒドロフランなどのエーテル類あるいは水などが好ましい。反応温度は、通常、約－１００℃～約２５０℃、好ましくは約０℃～約１５０℃であり、反応時間は、通常、約０．１時間～約４８時間である。酸性条件での加水分解は、酸の存在下、反応に影響を及ぼさない溶媒中で行われる。そのような酸としては、塩酸、臭化水素酸、硫酸、リン酸、過塩素酸等が好ましい。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でも酢酸などのカルボン酸系溶媒あるいは水が好ましい。反応温度は、通常、約－１００℃～約２５０℃、好ましくは約０℃～約１５０℃であり、反応時間は、通常、約０．１～約４８時間である。このような条件で加水分解反応が進行しない場合、例えばジャーナル　オブ　オーガニック　ケミストリー（Ｊ．Ｏｒｇ．Ｃｈｅｍ．），　４０，　１１８７，　（１９７５）に記載の過酸化ナトリウムを用いる方法や、例えばジャーナル　オブ　ジ　アメリカン　ケミカル　ソサイエティー（Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．），　７８，　５４１６，　（１９５６）に記載の硫酸等の酸性溶媒中、亜硝酸ナトリウムを用いる方法等を用いてもよい。なお、加水分解中にアミノ保護基（ＰＲＧ）が切断された場合、再度アミノ保護基（ＰＲＧ）を導入することもできる。 (Step 11)
Compound (IIi) can be produced by hydrolysis of compound (IIh). The hydrolysis can be performed by selecting from alkaline conditions and acidic conditions. Hydrolysis under alkaline conditions is performed in the presence of a base in a solvent that does not affect the reaction. Examples of the “base” include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium ethoxide, potassium tert-butoxide and the like. The amount of the “base” to be used is preferably about 1 to about 5 molar equivalents relative to 1 mol of compound (IIh). As the solvent, those similar to the “solvent” described in the above (Step 1) can be used. Among them, alcohol solvents such as ethanol, ethers such as tetrahydrofuran, water, and the like are preferable. The reaction temperature is usually about −100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C., and the reaction time is usually about 0.1 hour to about 48 hours. Hydrolysis under acidic conditions is performed in the presence of an acid in a solvent that does not affect the reaction. As such an acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid and the like are preferable. As the solvent, those similar to the “solvent” described in the above (Step 1) can be used, and among them, a carboxylic acid solvent such as acetic acid or water is preferable. The reaction temperature is usually about −100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C., and the reaction time is usually about 0.1 to about 48 hours. When the hydrolysis reaction does not proceed under such conditions, for example, the method using sodium peroxide described in Journal of Organic Chemistry (J. Org. Chem.), 40, 1187, (1975), for example, Journal of the American A method using sodium nitrite in an acidic solvent such as sulfuric acid described in Chemical Society (J. Am. Chem. Soc.), 78, 5416, (1956) may be used. In addition, when an amino protecting group (PRG) is cut | disconnected during a hydrolysis, an amino protecting group (PRG) can also be introduce | transduced again.

（工程１２）
　化合物（ＩＩｊ）は、（工程３）に準じて、化合物（ＩＩｉ）のアミド化により製造することができ、例えばジャーナル　オブ　オーガニック　ケミストリー（Ｊ．Ｏｒｇ．Ｃｈｅｍ．），　５５，　２７０，　（１９９０）に記載の方法で行うことができる。このとき縮合剤としては、（工程３）で述べた「縮合剤」と同様のものを用いることができるが、中でも１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミドや４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリドが好ましい。縮合促進剤としては、１－ヒドロキシ－７－アザベンゾトリアゾールや１－ヒドロキシベンゾトリアゾール等が好ましい。アミンまたはその塩酸塩の使用量は、化合物（ＩＩｉ）１モルに対し、通常、１ないし１０モル当量、好ましくは１ないし２モル当量である。「縮合剤」の使用量は、化合物（ＩＩｉ）１モルに対し、通常、１ないし１０モル当量、好ましくは１ないし２モル当量である。また、「縮合促進剤」の使用量は、化合物（ＩＩｉ）１モルに対して、通常、０．１ないし１０モル当量、好ましくは０．３ないし３モル当量である。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもテトラヒドロフランなどのエーテル系溶媒、Ｎ，Ｎ－ジメチルホルムアミドなどのアミド系溶媒が好ましい。反応温度は、通常、約－１００℃～約１５０℃、好ましくは約０℃～約８０℃であり、反応時間は、通常、約５分間～約７２時間、好ましくは約１時間～約２４時間である。 (Step 12)
Compound (IIj) can be produced by amidation of compound (IIi) according to (Step 3), for example, in Journal of Organic Chemistry (J. Org. Chem.), 55, 270, (1990). It can be performed by the method described. At this time, as the condensing agent, the same “condensing agent” as described in (Step 3) can be used, and among them, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide or 4- (4, 6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride is preferred. As the condensation accelerator, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole and the like are preferable. The amount of amine or its hydrochloride to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, per 1 mol of compound (IIi). The amount of the “condensing agent” to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, per 1 mol of compound (IIi). In addition, the amount of the “condensation accelerator” to be used is generally 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, per 1 mol of compound (IIi). As the solvent, those similar to the “solvent” described in the above (Step 1) can be used, but ether solvents such as tetrahydrofuran and amide solvents such as N, N-dimethylformamide are particularly preferable. The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.

［製造法Ｆ］
化合物（ＩＩｋ）および（ＩＩｌ）の製造 [Production Method F]
Preparation of compounds (IIk) and (IIl)

Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017

［式中、Ｒ１７は、低級アルキルを表し、Ｒ１８は置換されていてもよい低級アルキルまたは置換されていてもよい芳香環基（例、フェニル、芳香族含窒素複素環基）を表す。］ [Wherein, R 17 represents lower alkyl, and R 18 represents optionally substituted lower alkyl or an optionally substituted aromatic ring group (eg, phenyl, aromatic nitrogen-containing heterocyclic group). ]

（工程１３）
　化合物（ＩＩｋ）は、化合物（ＩＩｉ）のエステル化により製造することができる。エステル化の方法として、例えば、新実験化学講座１４（日本化学会編）、第１００２～１０２７頁等に記載の方法などが挙げられる。特に、エステルとしては、メチルエステルやエチルエステル等が好ましい。酸性条件下でエステル化を行う場合、用いる酸触媒として、好ましくは塩酸、硫酸、ｐ－トルエンスルホン酸等が挙げられる。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもメタノールやエタノール等のアルコール系溶媒等が好ましい。反応温度は、通常、約－５０℃～約２００℃、好ましくは約０℃～約１５０℃である。反応時間は、通常、約１分間～約１０日間、好ましくは約０．５時間～約２４時間である。また、酸ハロゲン化物を経由して、化合物（ＩＩｋ）を製造することもできる。用いる試薬として、塩化チオニルや塩化オキサリル等が好ましい。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもメタノールやエタノール等のアルコール系溶媒等が好ましい。反応温度は、通常、約－５０℃～約２００℃、好ましくは約０℃～約１５０℃である。反応時間は、通常、約１分間～約１０日間、好ましくは約０．５時間～約２４時間である。また、ジアゾメタンを用いてメチルエステルを製造することもできる。「ジアゾメタン」の代用として、トリメチルシリルジアゾメタンを用いてもよい。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもメタノールやエタノール等のアルコール系溶媒、もしくはジエチルエーテルなどのエーテル系溶媒等が好ましい。反応温度は、通常、約－８０℃～約２００℃、好ましくは約－２０℃～約５０℃である。反応時間は、通常、約１分間～約１０日間、好ましくは約０．５時間～約２４時間である。なお、エステル化を行う際にアミノ保護基（ＰＲＧ）が切断された場合、再度アミノ保護基（ＰＲＧ）を導入することもできる。 (Step 13)
Compound (IIk) can be produced by esterification of compound (IIi). Examples of the esterification method include the method described in New Experimental Chemistry Course 14 (Edited by Chemical Society of Japan), pages 1002 to 1027, and the like. In particular, as the ester, methyl ester or ethyl ester is preferable. When esterification is carried out under acidic conditions, the acid catalyst used preferably includes hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and the like. As the solvent, those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as methanol and ethanol are particularly preferable. The reaction temperature is generally about −50 ° C. to about 200 ° C., preferably about 0 ° C. to about 150 ° C. The reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours. In addition, compound (IIk) can also be produced via an acid halide. As a reagent to be used, thionyl chloride, oxalyl chloride and the like are preferable. As the solvent, those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as methanol and ethanol are particularly preferable. The reaction temperature is generally about −50 ° C. to about 200 ° C., preferably about 0 ° C. to about 150 ° C. The reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours. Also, methyl ester can be produced using diazomethane. As an alternative to “diazomethane”, trimethylsilyldiazomethane may be used. As the solvent, those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as methanol and ethanol, ether solvents such as diethyl ether and the like are preferable. The reaction temperature is usually about −80 ° C. to about 200 ° C., preferably about −20 ° C. to about 50 ° C. The reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours. When the amino protecting group (PRG) is cleaved during esterification, the amino protecting group (PRG) can be introduced again.

（工程１４）
　化合物（ＩＩｌ）は、（工程７）に準じて、化合物（ＩＩｋ）より製造することができる。炭素求核剤としては、特にメチルマグネシウムブロミド等が好ましく、溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもテトラヒドロフランなどのエーテル系溶媒が好ましい。「炭素求核剤」の使用量は、化合物（ＩＩｋ）１モルに対して、通常、０．１ないし２０モル当量、好ましくは１ないし１０モル当量である。反応温度は、通常、約－８０℃～約１５０℃、好ましくは約－３０℃～約１００℃であり、反応時間は、通常、約０．１時間～約７２時間、好ましくは約０．３時間～約２４時間である。 (Step 14)
Compound (IIl) can be produced from compound (IIk) according to (Step 7). As the carbon nucleophile, methylmagnesium bromide and the like are particularly preferable, and as the solvent, the same solvents as the “solvent” described in the above (Step 1) can be used, and among them, ether solvents such as tetrahydrofuran are preferable. . The amount of the “carbon nucleophile” to be used is generally 0.1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, per 1 mol of compound (IIk). The reaction temperature is usually about −80 ° C. to about 150 ° C., preferably about −30 ° C. to about 100 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.

［製造法Ｇ］
化合物（ＩＩｍ）の製造 [Production method G]
Production of compound (IIm)

Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018

［式中、ＬＧはハロゲン原子（例えば、塩素原子、臭素原子、ヨウ素原子など）を表す。］ [Wherein, LG represents a halogen atom (for example, a chlorine atom, a bromine atom, an iodine atom, etc.). ]

（工程１５）
　化合物（ＩＩｍ）は、化合物（Ｖ）の脱ハロゲン化によって製造することができる。本反応は、化合物（Ｖ）に対して（工程２）で述べた「還元剤」を用いた還元反応、あるいは、（工程１）で述べた「接触水素化反応」によっても行われるが、ラジカル還元反応が特に好ましい。化合物（Ｖ）１モルに対してヒドリド剤を０．１モル当量ないし大過剰（好ましくは０．３ないし１０モル当量）使用する。また、化合物（Ｖ）１モルに対してラジカル開始剤を０．００１ないし１０モル当量（好ましくは０．０１ないし１モル当量）使用する。この時、「ヒドリド剤」として、トリ－ｎ－ブチルスズヒドリド等が好ましい。また、「ラジカル開始剤」として２，２’－（Ｅ）－ジアゼン－１，２－ジイルビス（２－メチルプロパンニトリル）等が好ましい。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもトルエン等の炭化水素系溶媒が好ましい。反応温度は、通常、約－８０℃～約１５０℃、好ましくは約０℃～約１１０℃であり、反応時間は、通常、約０．１時間～約７２時間、好ましくは約０．３時間～約２４時間である。 (Step 15)
Compound (IIm) can be produced by dehalogenation of compound (V). This reaction is also carried out by the reduction reaction using the “reducing agent” described in (Step 2) for compound (V) or the “catalytic hydrogenation reaction” described in (Step 1). A reduction reaction is particularly preferred. The hydride agent is used in an amount of 0.1 molar equivalent to large excess (preferably 0.3 to 10 molar equivalents) per mole of compound (V). Further, the radical initiator is used in an amount of 0.001 to 10 molar equivalents (preferably 0.01 to 1 molar equivalents) relative to 1 mol of Compound (V). At this time, as the “hydride agent”, tri-n-butyltin hydride and the like are preferable. As the “radical initiator”, 2,2 ′-(E) -diazene-1,2-diylbis (2-methylpropanenitrile) and the like are preferable. As the solvent, those similar to the “solvent” described in the above (Step 1) can be used, and hydrocarbon solvents such as toluene are particularly preferable. The reaction temperature is usually about −80 ° C. to about 150 ° C., preferably about 0 ° C. to about 110 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 hour. ~ About 24 hours.

　化合物（ＩＩｎ）および化合物（ＩＩｏ）は、以下に示す［製造法Ｈ］または［製造法Ｉ］によって製造することができる。 Compound (IIn) and Compound (IIo) can be produced by [Production Method H] or [Production Method I] shown below.

Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019

［製造法Ｈ］
化合物（ｃｉｓ－ＩＩｎ）および化合物（ｔｒａｎｓ－ＩＩｏ）の製造 [Production Method H]
Production of Compound (cis-IIn) and Compound (trans-IIo)

Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020

［式中、Ｒ２は、水素原子または置換されていてもよい低級アルキルを表し、Ｒ８は、水素原子または低級アルキルを表し、Ｒ１７は、低級アルキルを表す。化合物（ｃｉｓ－ＩＩｎ）は化合物（ＩＩｎ）のｃｉｓ体を表し、化合物（ｔｒａｎｓ－ＩＩｎ）は化合物（ＩＩｎ）のｔｒａｎｓ体を表す。化合物（ｔｒａｎｓ－ＩＩｏ）は化合物（ＩＩｏ）のｔｒａｎｓ体を表す。］ [Wherein, R 2 represents a hydrogen atom or optionally substituted lower alkyl, R 8 represents a hydrogen atom or lower alkyl, and R 17 represents lower alkyl. Compound (cis-IIn) represents a cis form of compound (IIn), and compound (trans-IIn) represents a trans form of compound (IIn). Compound (trans-IIo) represents a trans form of compound (IIo). ]

（工程１６）
　化合物（ＶＩＩＩ）は、化合物（ＶＩ）と化合物（ＶＩＩ）を塩基の存在下、環化付加反応させることで製造することができる。（工程１６）は、例えばジャーナル　オブ　オーガニック　ケミストリー（Ｊ．Ｏｒｇ．Ｃｈｅｍ．），　５５，　２７０，　（１９９０）、ケミストリー　レターズ（Ｃｈｅｍ．Ｌｅｔｔ．），　７，　９４３，　（１９９８）に記載に準じて行うことができる。塩基としては、（工程３）で述べた「塩基」と同様のものを用いることができるが、中でも水素化ナトリウムなどのアルカリ金属またはアルカリ土類金属の水素化物、ナトリウムアミドなどのアルカリ金属またはアルカリ土類金属のアミド類、あるいはカリウム　ｔｅｒｔ－ブトキシドなどのアルカリ金属またはアルカリ土類金属の低級アルコキシドが好ましい。「塩基」の使用量は、化合物（ＶＩ）１モルに対して、通常、０．１ないし１０モル当量、好ましくは０．１ないし１モル当量である。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもエタノールなどのアルコール系溶媒が好ましい。反応温度は、通常、約－８０℃～約１５０℃、好ましくは約－３０℃～約１００℃であり、反応時間は、通常、約０．１時間～約７２時間、好ましくは約０．３時間～約２４時間である。 (Step 16)
Compound (VIII) can be produced by subjecting compound (VI) and compound (VII) to a cycloaddition reaction in the presence of a base. (Step 16) is performed in accordance with, for example, the description of Journal of Organic Chemistry (J. Org. Chem.), 55, 270, (1990), Chem. Letters, 7, 943, (1998). be able to. As the base, those similar to the “base” described in (Step 3) can be used, and among them, alkali metal or alkaline earth metal hydride such as sodium hydride, alkali metal or alkali such as sodium amide, etc. An earth metal amide or an alkali metal or alkaline earth metal lower alkoxide such as potassium tert-butoxide is preferred. The amount of the “base” to be used is generally 0.1 to 10 molar equivalents, preferably 0.1 to 1 molar equivalents, per 1 mol of compound (VI). As the solvent, those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as ethanol are particularly preferable. The reaction temperature is usually about −80 ° C. to about 150 ° C., preferably about −30 ° C. to about 100 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.

（工程１７）
　化合物（ＩＩｎ）は、化合物（ＶＩＩＩ）の還元によって製造することができる。（工程１７）は、例えばジャーナル　オブ　オーガニック　ケミストリー（Ｊ．Ｏｒｇ．Ｃｈｅｍ．），　５５，　２７０，　（１９９０）、ケミストリー　レターズ（Ｃｈｅｍ．Ｌｅｔｔ．），　７，　９４３，　（１９９８）に記載の方法で行うことができる。還元剤としては、トリエチルシランが好ましく、用いる量は化合物（ＶＩＩＩ）に対して、通常、０．１ないし１０当量、好ましくは１ないし３当量である。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもジクロロメタン、クロロホルムなどのハロゲン化炭化水素系溶媒またはアセトニトリルなどのニトリル系溶媒が好ましい。反応温度は、通常、約－８０℃～約１５０℃、好ましくは約－３０℃～約１００℃であり、反応時間は、通常、約０．１時間～約７２時間、好ましくは約０．３時間～約２４時間である。 (Step 17)
Compound (IIn) can be produced by reduction of compound (VIII). (Step 17) is performed by the method described in, for example, Journal of Organic Chemistry (J. Org. Chem.), 55, 270, (1990), Chem. Letters, 7, 943, (1998). be able to. The reducing agent is preferably triethylsilane, and the amount used is usually 0.1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound (VIII). As the solvent, those similar to the “solvent” described in the above (Step 1) can be used. Among them, halogenated hydrocarbon solvents such as dichloromethane and chloroform or nitrile solvents such as acetonitrile are preferable. The reaction temperature is usually about −80 ° C. to about 150 ° C., preferably about −30 ° C. to about 100 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.

（工程１８）
　化合物（ｃｉｓ－ＩＩｎ）および化合物（ｔｒａｎｓ－ＩＩｏ）は、化合物（ＩＩｎ）の加水分解によって製造することができる。（工程１８）は、例えばジャーナル　オブ　オーガニック　ケミストリー（Ｊ．Ｏｒｇ．Ｃｈｅｍ．），　５５，　２７０，　（１９９０）、ケミストリー　レターズ（Ｃｈｅｍ．Ｌｅｔｔ．），　７，　９４３，　（１９９８）に記載の方法や（工程１１）に準じて行うことができる。アルカリ性条件での加水分解が特に好ましい。アルカリ性条件での加水分解は、塩基の存在下、反応に影響を及ぼさない溶媒中で行われる。塩基としては、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸カリウム、炭酸ナトリウム、ナトリム　エトキシド、カリウム　ｔｅｒｔ－ブトキシドなどが挙げられる。「塩基」の使用量は、化合物（ＩＩｎ）１モルに対して、好ましくは約１ないし約５モル当量である。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもエタノールなどのアルコール系溶媒、テトラヒドロフランなどのエーテル類あるいは水などが好ましい。反応温度は、通常、約－１００℃～約２５０℃、好ましくは約０℃～約１５０℃であり、反応時間は、通常、約０．１時間～約４８時間である。なお、アミノ保護基（ＰＲＧ）とピロリジン３位のベンゼン環との立体障害により、トランス位のエステルが優先的に加水分解され、化合物（ｔｒａｎｓ－ＩＩｏ）が得られる。加水分解中にアミノ保護基（ＰＲＧ）が切断された場合、再度アミノ保護基（ＰＲＧ）を導入することもできる。 (Step 18)
Compound (cis-IIn) and compound (trans-IIo) can be produced by hydrolysis of compound (IIn). (Step 18) is, for example, a method described in Journal of Organic Chemistry (J. Org. Chem.), 55, 270, (1990), Chemistry Letters (Chem. Lett.), 7, 943, (1998) It can be carried out according to step 11). Hydrolysis under alkaline conditions is particularly preferred. Hydrolysis under alkaline conditions is performed in the presence of a base in a solvent that does not affect the reaction. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium ethoxide, potassium tert-butoxide and the like. The amount of the “base” to be used is preferably about 1 to about 5 molar equivalents relative to 1 mol of compound (IIn). As the solvent, those similar to the “solvent” described in the above (Step 1) can be used. Among them, alcohol solvents such as ethanol, ethers such as tetrahydrofuran, water, and the like are preferable. The reaction temperature is usually about −100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C., and the reaction time is usually about 0.1 hour to about 48 hours. Incidentally, due to the steric hindrance between the amino protecting group (PRG) and the benzene ring at the 3-position of pyrrolidine, the ester at the trans position is preferentially hydrolyzed to obtain the compound (trans-IIo). When the amino protecting group (PRG) is cleaved during hydrolysis, the amino protecting group (PRG) can be introduced again.

［製造法Ｉ］
化合物（ｃｉｓ－ＩＩｏ）の製造 [Production Method I]
Production of compound (cis-IIo)

Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021

［式中、Ｒ８は、水素原子または低級アルキルを表し、Ｒ１７は、低級アルキルを表す。］ [Wherein, R 8 represents a hydrogen atom or lower alkyl, and R 17 represents lower alkyl. ]

（工程１９）
　化合物（ｃｉｓ－ＩＩｏ）は、化合物（ｃｉｓ－ＩＩｎ）の加水分解によって製造することができる。（工程１９）は、例えばジャーナル　オブ　オーガニック　ケミストリー（Ｊ．Ｏｒｇ．Ｃｈｅｍ．），　５５，　２７０，　（１９９０）、ケミストリー　レターズ（Ｃｈｅｍ．Ｌｅｔｔ．），　７，　９４３，　（１９９８）に記載の方法や（工程１１）に準じて行うことができる。該加水分解は、アルカリ性条件と酸性条件から選択して行うことができるが、酸性条件での加水分解が特に好ましい。酸性条件での加水分解は、酸の存在下、反応に影響を及ぼさない溶媒中で行われる。そのような酸としては、塩酸、臭化水素酸、硫酸、リン酸、過塩素酸等が好ましい。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でも酢酸などのカルボン酸系溶媒あるいは水が好ましい。反応温度は、通常、約－１００℃～約２５０℃、好ましくは約０℃～約１５０℃であり、反応時間は、通常、約０．１時間～約４８時間である。なお、加水分解中にアミノ保護基（ＰＲＧ）が切断された場合、再度アミノ保護基（ＰＲＧ）を導入することもできる。 (Step 19)
Compound (cis-IIo) can be produced by hydrolysis of compound (cis-IIn). (Step 19) is, for example, a method described in Journal of Organic Chemistry (J. Org. Chem.), 55, 270, (1990), Chemistry Letters (Chem. Lett.), 7, 943, (1998) It can be carried out according to step 11). The hydrolysis can be carried out by selecting from alkaline conditions and acidic conditions, but hydrolysis under acidic conditions is particularly preferred. Hydrolysis under acidic conditions is performed in the presence of an acid in a solvent that does not affect the reaction. As such an acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid and the like are preferable. As the solvent, those similar to the “solvent” described in the above (Step 1) can be used, and among them, a carboxylic acid solvent such as acetic acid or water is preferable. The reaction temperature is usually about −100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C., and the reaction time is usually about 0.1 hour to about 48 hours. In addition, when an amino protecting group (PRG) is cut | disconnected during a hydrolysis, an amino protecting group (PRG) can also be introduce | transduced again.

　化合物（ＩＩｎ）、（ＩＩｏ）のうち、特に、Ｒ２が水素原子（それぞれ化合物（ＩＩｐ）、（ＩＩｑ））の場合、以下に示す［製造法Ｊ］によっても製造することができる。 Among compounds (IIn) and (IIo), in particular, when R 2 is a hydrogen atom (compounds (IIp) and (IIq), respectively), they can also be produced by [Production Method J] shown below.

Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022

［製造法Ｊ］
化合物（ｃｉｓ－ＩＩｐ）、化合物（ｔｒａｎｓ－ＩＩｑ）および化合物（ｃｉｓ－ＩＩｑ）の製造 [Production Method J]
Production of Compound (cis-IIp), Compound (trans-IIq) and Compound (cis-IIq)

Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023

［式中、Ｒ８は、水素原子または低級アルキルを表し、Ｒ１７は、低級アルキルを表す。化合物（ｃｉｓ－ＩＩｐ）は化合物（ＩＩｐ）のｃｉｓ体を表す。化合物（ｔｒａｎｓ－ＩＩｑ）は化合物（ＩＩｑ）のｔｒａｎｓ体、化合物（ｃｉｓ－ＩＩｑ）は化合物（ＩＩｑ）のｃｉｓ体を表す。］ [Wherein, R 8 represents a hydrogen atom or lower alkyl, and R 17 represents lower alkyl. Compound (cis-IIp) represents a cis form of compound (IIp). Compound (trans-IIq) represents a trans form of compound (IIq), and compound (cis-IIq) represents a cis form of compound (IIq). ]

（工程２０）
　化合物（Ｘ）は、（工程１６）に準じて、化合物（ＶＩ）と化合物（ＩＸ）を塩基の存在下、環化付加反応させることで製造することができる。塩基としては、（工程３）で述べた「塩基」と同様のものを用いることができるが、中でも水素化ナトリウムなどのアルカリ金属またはアルカリ土類金属の水素化物、ナトリウムアミドなどのアルカリ金属またはアルカリ土類金属のアミド類、あるいはカリウム　ｔｅｒｔ－ブトキシドなどのアルカリ金属またはアルカリ土類金属の低級アルコキシドが好ましい。「塩基」の使用量は、化合物（ＶＩ）１モルに対して、通常、０．１ないし１０モル当量、好ましくは０．１ないし１モル当量である。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもエタノールなどのアルコール系溶媒が好ましい。反応温度は、通常、約－８０℃～約１５０℃、好ましくは約－３０℃～約１００℃であり、反応時間は、通常、約０．１時間～約７２時間、好ましくは約０．３時間～約２４時間である。 (Step 20)
Compound (X) can be produced by subjecting compound (VI) and compound (IX) to a cycloaddition reaction in the presence of a base according to (Step 16). As the base, those similar to the “base” described in (Step 3) can be used, and among them, alkali metal or alkaline earth metal hydride such as sodium hydride, alkali metal or alkali such as sodium amide, etc. An earth metal amide or an alkali metal or alkaline earth metal lower alkoxide such as potassium tert-butoxide is preferred. The amount of the “base” to be used is generally 0.1 to 10 molar equivalents, preferably 0.1 to 1 molar equivalents, per 1 mol of compound (VI). As the solvent, those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as ethanol are particularly preferable. The reaction temperature is usually about −80 ° C. to about 150 ° C., preferably about −30 ° C. to about 100 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.

（工程２１）
　化合物（ＸＩ）は、（工程１７）に準じて、化合物（Ｘ）の還元によって製造することができる。還元剤としては、トリエチルシランが好ましく、用いる量は化合物（Ｘ）に対して、通常、０．１ないし１０当量、好ましくは１ないし３当量である。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもジクロロメタン、クロロホルムなどのハロゲン化炭化水素系溶媒またはアセトニトリルなどのニトリル系溶媒が好ましい。反応温度は、通常、約－８０℃～約１５０℃、好ましくは約－３０℃～約１００℃であり、反応時間は、通常、約０．１時間～約７２時間、好ましくは約０．３時間～約２４時間である。 (Step 21)
Compound (XI) can be produced by reduction of compound (X) according to (Step 17). The reducing agent is preferably triethylsilane, and the amount used is usually 0.1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound (X). As the solvent, those similar to the “solvent” described in the above (Step 1) can be used. Among them, halogenated hydrocarbon solvents such as dichloromethane and chloroform or nitrile solvents such as acetonitrile are preferable. The reaction temperature is usually about −80 ° C. to about 150 ° C., preferably about −30 ° C. to about 100 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.

（工程２２）
　化合物（ＩＩｑ）は、（工程１１）に準じて、化合物（ＸＩ）を酸性条件下で加水分解することで製造することができる。なお、該加水分解は脱炭酸を伴い進行する。酸性条件での加水分解は、酸の存在下、反応に影響を及ぼさない溶媒中で行われる。そのような酸としては、塩酸、臭化水素酸、硫酸、リン酸、過塩素酸等が好ましい。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でも酢酸などのカルボン酸系溶媒あるいは水が好ましい。反応温度は、通常、約－１００℃～約２５０℃、好ましくは約０℃～約１５０℃であり、反応時間は、通常、約０．１時間～約４８時間、好ましくは約１時間～約２４時間である。なお、加水分解中にアミノ保護基（ＰＲＧ）が切断された場合、前述した方法によって再度アミノ保護基（ＰＲＧ）を導入することもできる。保護基ＰＲＧとして、中でも、ｔｅｒｔ－ブトキシカルボニル、ベンジルオキシカルボニル等が好ましい。 (Step 22)
Compound (IIq) can be produced by hydrolyzing compound (XI) under acidic conditions according to (Step 11). The hydrolysis proceeds with decarboxylation. Hydrolysis under acidic conditions is performed in the presence of an acid in a solvent that does not affect the reaction. As such an acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid and the like are preferable. As the solvent, those similar to the “solvent” described in the above (Step 1) can be used, and among them, a carboxylic acid solvent such as acetic acid or water is preferable. The reaction temperature is usually about −100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C., and the reaction time is usually about 0.1 hour to about 48 hours, preferably about 1 hour to about 150 ° C. 24 hours. In addition, when an amino protecting group (PRG) is cut | disconnected during a hydrolysis, an amino protecting group (PRG) can also be introduce | transduced again by the method mentioned above. Of these, tert-butoxycarbonyl, benzyloxycarbonyl and the like are preferable as the protecting group PRG.

（工程２３）
　化合物（ＩＩｐ）は、（工程１３）に準じて、化合物（ＩＩｑ）のエステル化により製造することができる。エステルとしては、特にメチルエステルやエチルエステル等が好ましい。酸性条件下でエステル化を行う場合、用いる酸触媒として、好ましくは塩酸、硫酸、ｐ－トルエンスルホン酸等が挙げられる。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもメタノールやエタノール等のアルコール系溶媒等が好ましい。反応温度は、通常、約－５０℃～約２００℃、好ましくは約０℃～約１５０℃である。反応時間は、通常、約１分間～約１０日間、好ましくは約０．５時間～約２４時間である。また、酸ハロゲン化物を経由して、エステルを製造することもできる。用いる試薬として、塩化チオニルや塩化オキサリル等が好ましい。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもメタノールやエタノール等のアルコール系溶媒等が好ましい。反応温度は、通常、約－８０℃～約２００℃、好ましくは約－２０℃～約５０℃である。反応時間は、通常、約１分間～約１０日間、好ましくは約０．５時間～約２４時間である。また、ジアゾメタンを用いてメチルエステルを製造することもできる。「ジアゾメタン」の代用として、トリメチルシリルジアゾメタンを用いてもよい。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもメタノールやエタノール等のアルコール系溶媒、あるいはジエチルエーテル等のエーテル系溶媒が好ましい。反応温度は、通常、約－８０℃～約２００℃、好ましくは約－２０℃～約５０℃である。反応時間は、通常、約１分間～約１０日間、好ましくは約０．５時間～約２４時間である。なお、エステル化を行う際にアミノ保護基（ＰＲＧ）が切断された場合、前述した方法によって再度アミノ保護基（ＰＲＧ）を導入することもできる。保護基ＰＲＧとして、中でも、ｔｅｒｔ－ブトキシカルボニル、ベンジルオキシカルボニル等が好ましい。 (Step 23)
Compound (IIp) can be produced by esterification of compound (IIq) according to (Step 13). As the ester, methyl ester, ethyl ester and the like are particularly preferable. When esterification is carried out under acidic conditions, the acid catalyst used preferably includes hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and the like. As the solvent, those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as methanol and ethanol are particularly preferable. The reaction temperature is generally about −50 ° C. to about 200 ° C., preferably about 0 ° C. to about 150 ° C. The reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours. An ester can also be produced via an acid halide. As a reagent to be used, thionyl chloride, oxalyl chloride and the like are preferable. As the solvent, those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as methanol and ethanol are particularly preferable. The reaction temperature is usually about −80 ° C. to about 200 ° C., preferably about −20 ° C. to about 50 ° C. The reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours. Also, methyl ester can be produced using diazomethane. As an alternative to “diazomethane”, trimethylsilyldiazomethane may be used. As the solvent, those similar to the “solvent” described in the above (Step 1) can be used. Among them, alcohol solvents such as methanol and ethanol, or ether solvents such as diethyl ether are preferable. The reaction temperature is usually about −80 ° C. to about 200 ° C., preferably about −20 ° C. to about 50 ° C. The reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours. When the amino protecting group (PRG) is cleaved during esterification, the amino protecting group (PRG) can be introduced again by the method described above. Of these, tert-butoxycarbonyl, benzyloxycarbonyl and the like are preferable as the protecting group PRG.

（工程２４）
　化合物（ｃｉｓ－ＩＩｐ）、化合物（ｔｒａｎｓ－ＩＩｑ）および化合物（ｃｉｓ－ＩＩｑ）は、（工程１１）に準じて、化合物（ＩＩｐ）の加水分解によって製造することができる。（工程２４）は、アルカリ性条件での加水分解が特に好ましい。アルカリ性条件での加水分解は、塩基の存在下、反応に影響を及ぼさない溶媒中で行われる。「塩基」としては、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸カリウム、炭酸ナトリウム、ナトリム　エトキシド、カリウム　ｔｅｒｔ－ブトキシドなどが挙げられる。「塩基」の使用量は、化合物（ＩＩｐ）１モルに対して、好ましくは約１ないし約５モル当量である。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもエタノールなどのアルコール系溶媒、テトラヒドロフランなどのエーテル系溶媒あるいは水などが好ましい。反応温度は、通常、約－１００℃～約２５０℃、好ましくは約０℃～約１５０℃であり、反応時間は、通常、約０．１時間～約７２時間、好ましくは約０．３時間～約２４時間である。なお、アミノ保護基（ＰＲＧ）とピロリジン３位のベンゼン環との立体障害により、トランス位のエステルが優先的に加水分解される。なお、加水分解中にアミノ保護基（ＰＲＧ）が切断された場合、前述した方法によって再度アミノ保護基（ＰＲＧ）を導入することもできる。保護基ＰＲＧとして、中でも、ｔｅｒｔ－ブトキシカルボニル、ベンジルオキシカルボニル等が好ましい。 (Step 24)
Compound (cis-IIp), compound (trans-IIq) and compound (cis-IIq) can be produced by hydrolysis of compound (IIp) according to (Step 11). (Step 24) is particularly preferably hydrolysis under alkaline conditions. Hydrolysis under alkaline conditions is performed in the presence of a base in a solvent that does not affect the reaction. Examples of the “base” include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium ethoxide, potassium tert-butoxide and the like. The amount of the “base” to be used is preferably about 1 to about 5 molar equivalents relative to 1 mol of compound (IIp). As the solvent, those similar to the “solvent” described in the above (Step 1) can be used. Among them, an alcohol solvent such as ethanol, an ether solvent such as tetrahydrofuran, or water is preferable. The reaction temperature is usually about −100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 hour. ~ About 24 hours. Note that the ester at the trans position is preferentially hydrolyzed due to steric hindrance between the amino protecting group (PRG) and the benzene ring at the 3-position of pyrrolidine. In addition, when an amino protecting group (PRG) is cut | disconnected during a hydrolysis, an amino protecting group (PRG) can also be introduce | transduced again by the method mentioned above. Of these, tert-butoxycarbonyl, benzyloxycarbonyl and the like are preferable as the protecting group PRG.

　化合物（Ｉ）のうち、Ｒ４およびＲ５が水素原子である化合物（化合物（Ｉ－１）と称する）は、以下に示す［製造法Ｋ］によっても製造することができる。 Among compounds (I), a compound in which R 4 and R 5 are hydrogen atoms (referred to as compound (I-1)) can also be produced by [Production Method K] shown below.

Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024

［製造法Ｋ］
化合物（Ｉ－１ａ）および化合物（Ｉ－１ｂ）の製造 [Production method K]
Production of Compound (I-1a) and Compound (I-1b)

Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025

［式中、Ｒ１７は、低級アルキルを表す。］ [Wherein R 17 represents lower alkyl. ]

（工程２５）
　化合物（ＸＩＶ）は、化合物（ＸＩＩ）への化合物（ＸＩＩＩ）の付加反応により製造することができる。（工程２５）は、例えばアンゲバンテ　ケミー　インターナショナル　エディション（Ａｎｇｅｗ．Ｃｈｅｍ．Ｉｎｔ．Ｅｄ．），　４６，　２１２４，　（２００７）やオーストラリアン　ジャーナル　オブ　ケミストリー（Ａｕｓｔ．Ｊ．Ｃｈｅｍ．），　４７，　１４４１，　（１９９４）に記載の方法に準じて行うことができる。塩基としては、（工程３）で述べた「塩基」と同様のものを用いることができるが、中でも１，８－ジアザビシクロ〔５．４．０〕ウンデカ－７－エン（ＤＢＵ）、１，５－ジアザビシクロ〔４．３．０〕ノナ－５－エン（ＤＢＮ）などのアミジン類が好ましい。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもアセトニトリルなどのニトリル系溶媒やテトラヒドロフランなどのエーテル系溶媒などが好ましい。反応温度は、通常、約－１００℃～約２５０℃、好ましくは約０℃～約１５０℃であり、反応時間は、通常、約０．１時間～約７２時間、好ましくは約０．３時間～約２４時間である。 (Step 25)
Compound (XIV) can be produced by addition reaction of compound (XIII) to compound (XII). (Step 25) is, for example, Angewante Chemie International Edition (Angew. Chem. Int. Ed.), 46, 2124, (2007), Australian Journal of Chemistry (Aust. J. Chem.), 47, 1441, (1994). ). As the base, those similar to the “base” described in (Step 3) can be used, and among them, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5 Amidines such as diazabicyclo [4.3.0] non-5-ene (DBN) are preferred. As the solvent, those similar to the “solvent” described in the above (Step 1) can be used, and among them, a nitrile solvent such as acetonitrile and an ether solvent such as tetrahydrofuran are preferable. The reaction temperature is usually about −100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 hour. ~ About 24 hours.

（工程２６）
　化合物（ＸＶ）は、化合物（ＸＩＶ）のニトロ基の還元反応およびそれに続く環化反応により製造することができる。ニトロ基の還元方法として、例えば、新実験化学講座１４（日本化学会編）、第１３３３～１３３５頁等に記載の方法などが挙げられる。酸性条件下での還元には、亜鉛、鉄、スズおよび塩化スズ（ＩＩ）などがよく用いられるが、中でも亜鉛が好ましい。また亜鉛を用いた場合、中性もしくはアルカリ性条件下でも反応を行うことができる。用いる亜鉛の量は、化合物（ＸＩＶ）１モルに対し、通常、０．１ないし大過剰、好ましくは１ないし１００モル当量。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもカルボン酸系溶媒（例えば、酢酸など）が好ましい。反応温度は、通常、約０℃～約１５０℃、好ましくは約２０℃～約１００℃であり、反応時間は、通常、約５分間～約１５０時間、好ましくは約０．５時間～約７２時間である。また接触水素添加反応は、水素雰囲気中、触媒の存在下で行うことができる。「触媒」としては、例えば、パラジウム類（例えば、パラジウム炭素、水酸化パラジウム、酸化パラジウム等など）、ニッケル類（例えば、展開ニッケル触媒など）、白金類（例えば、酸化白金、白金炭素など）、ロジウム類（例えば、ロジウム炭素など）などが挙げられる。「触媒」の使用量は、化合物（ＸＩＶ）１モルに対し、通常、０．００１ないし１モル当量、好ましくは０．０１ないし０．１モル当量である。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもアルコール系溶媒（例えば、メタノール、エタノール、プロパノール、ブタノールなど）、エーテル系溶媒（例えば、ジエチルエーテル、ジオキサン、テトラヒドロフランなど）、エステル系溶媒（例えば、酢酸エチルなど）、カルボン酸系溶媒（例えば、酢酸など）、水またはそれらの混合物が好ましい。反応が行われる水素圧は、通常、約１～約５０気圧であり、好ましくは約１～約１０気圧である。反応温度は、通常、約０℃～約１５０℃、好ましくは約２０℃～約１００℃であり、反応時間は、通常、約５分間～約７２時間、好ましくは約０．５時間～約４０時間である。 (Step 26)
Compound (XV) can be produced by a reduction reaction of the nitro group of compound (XIV) followed by a cyclization reaction. Examples of the method for reducing the nitro group include the methods described in New Experimental Chemistry Course 14 (Edited by The Chemical Society of Japan), pages 1333 to 1335, and the like. For reduction under acidic conditions, zinc, iron, tin, tin (II) chloride, and the like are often used, and zinc is particularly preferable. In addition, when zinc is used, the reaction can be carried out even under neutral or alkaline conditions. The amount of zinc used is usually 0.1 to a large excess, preferably 1 to 100 molar equivalents, relative to 1 mole of compound (XIV). As the solvent, those similar to the “solvent” described in the above (Step 1) can be used, and among them, a carboxylic acid solvent (for example, acetic acid and the like) is preferable. The reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 100 ° C., and the reaction time is usually about 5 minutes to about 150 hours, preferably about 0.5 hours to about 72 hours. It's time. The catalytic hydrogenation reaction can be performed in a hydrogen atmosphere in the presence of a catalyst. Examples of the “catalyst” include palladium (eg, palladium carbon, palladium hydroxide, palladium oxide, etc.), nickel (eg, developed nickel catalyst), platinum (eg, platinum oxide, platinum carbon, etc.), Rhodiums (for example, rhodium carbon) and the like can be mentioned. The amount of the “catalyst” to be used is generally 0.001 to 1 molar equivalent, preferably 0.01 to 0.1 molar equivalent, per 1 mol of compound (XIV). As the solvent, those similar to the “solvent” described in the above (Step 1) can be used. Among them, alcohol solvents (for example, methanol, ethanol, propanol, butanol and the like), ether solvents (for example, diethyl) Ether, dioxane, tetrahydrofuran, etc.), ester solvents (such as ethyl acetate), carboxylic acid solvents (such as acetic acid), water or mixtures thereof are preferred. The hydrogen pressure at which the reaction is carried out is usually about 1 to about 50 atmospheres, preferably about 1 to about 10 atmospheres. The reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 100 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 hours to about 40 ° C. It's time.

（工程２７）
　化合物（Ｉ－１ａ）は、化合物（ＸＶ）の還元により製造することができる。還元剤としては、前記（工程２）で述べた「還元剤」と同様のものを用いることができるが、中でも水素化アルミニウムリチウムやボラン錯体（ボラン－ＴＨＦ錯体など）などが好ましい。化合物（ＸＶ）に対して「還元剤」を、通常、１モル当量ないし大過剰、好ましくは１ないし１０モル当量使用する。溶媒としては、前記（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもテトラヒドロフラン等のエーテル系溶媒が好ましい。反応温度は、通常、約－８０℃～約１５０℃、好ましくは約－３０℃～約１００℃であり、反応時間は、通常、約０．１時間～約７２時間、好ましくは約０．３時間～約２４時間である。 (Step 27)
Compound (I-1a) can be produced by reduction of compound (XV). As the reducing agent, the same “reducing agent” as described in the above (Step 2) can be used, and among them, lithium aluminum hydride, borane complex (borane-THF complex and the like) and the like are preferable. The “reducing agent” is generally used in 1 molar equivalent to large excess, preferably 1 to 10 molar equivalents, relative to compound (XV). As the solvent, those similar to the “solvent” described in the above (Step 1) can be used, and ether solvents such as tetrahydrofuran are particularly preferable. The reaction temperature is usually about −80 ° C. to about 150 ° C., preferably about −30 ° C. to about 100 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.

（工程２８）
　化合物（Ｉ－１ｂ）は、化合物（Ｉ－１ａ）の還元的アルキル化によって製造することができる。該反応は、例えば、オーガニック　リアクションズ（Ｏｒｇａｎｉｃ　Ｒｅａｃｔｉｏｎｓ），　ｖｏｌ．５９，　１－７１４（２００２年）に記載の方法や（工程２）に準じて行うことができ、化合物（Ｉ－１ａ）と、対応するアルデヒドやケトンより生成したイミン中間体を還元反応に付すことにより行われる。アルデヒドやケトンの使用量は、化合物（Ｉ－１ａ）１モルに対し、通常、１ないし１０モル当量、好ましくは１ないし３モル当量である。還元剤としては、前記（工程２）で述べた「還元剤」と同様のものを用いることができるが、中でもボラン、トリアセトキシ水素化ホウ素ナトリウム等が好ましい。「還元剤」の使用量は、化合物（Ｉ－１ａ）１モルに対し、通常、１ないし２０モル当量、好ましくは１ないし５モル当量である。「還元剤」として、ホウ素試薬を用いる場合、反応を促進させるために酸を添加してもよい。「酸」として好ましくは酢酸等が挙げられる。「酸」の使用量は、化合物（Ｉ－１ａ）１モルに対し、通常、０．１ないし１０モル当量、好ましくは０．１ないし１モル当量である。溶媒としては、（工程１）で述べた「溶媒」と同様のものを用いることができるが、中でもエーテル系溶媒（例えば、テトラヒドロフラン等）等が好ましい。反応温度は、通常、約－１００℃～約１５０℃、好ましくは約０℃～約８０℃であり、反応時間は、通常、約５分間～約７２時間、好ましくは約１時間～約２４時間である。 (Step 28)
Compound (I-1b) can be produced by reductive alkylation of compound (I-1a). The reaction is described, for example, in Organic Reactions, vol. 59, 1-714 (2002), or according to (Step 2). The compound (I-1a) and an imine intermediate produced from the corresponding aldehyde or ketone are subjected to a reduction reaction. Is done. The amount of aldehyde or ketone to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (I-1a). As the reducing agent, those similar to the “reducing agent” described in the above (Step 2) can be used. Among them, borane, sodium triacetoxyborohydride and the like are preferable. The amount of the “reducing agent” to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (I-1a). When a boron reagent is used as the “reducing agent”, an acid may be added to promote the reaction. Preferred examples of the “acid” include acetic acid. The amount of the “acid” to be used is generally 0.1 to 10 molar equivalents, preferably 0.1 to 1 molar equivalents, per 1 mol of compound (I-1a). As the solvent, those similar to the “solvent” described in (Step 1) can be used, and ether solvents (for example, tetrahydrofuran and the like) and the like are particularly preferable. The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.

　また、化合物（ＩＩ）は、上記以外の方法としてテトラへドロン　レターズ（Ｔｅｔｒａｈｅｄｒｏｎ　Ｌｅｔｔ．），　４４，　６７７９，　（２００３）；イル　ファーマコ（Ｉｌ　Ｆａｒｍａｃｏ），　５４，　４６１，　（１９９９）；テトラへドロン　レターズ（Ｔｅｔｒａｈｅｄｒｏｎ　Ｌｅｔｔ．），　４８，　８６９５，　（２００７）等に記載の方法を用いても製造することができる。 Compound (II) may be prepared by a method other than the above by using Tetrahedron Letters, 44, 6779, (2003); Il Pharmaco, 54, 461, (1999); Tetrahedron Letters. (Tetrahedron Lett.), 48, 8695, (2007), and the like.

Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026

　化合物（ＩＩ）は、以下に示す［製造法L］によっても製造することができる。 Compound (II) can also be produced by [Production Method L] shown below.

［製造法L］
化合物（ＩＩｔ）の製造 [Production method L]
Production of compound (IIt)

Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027

［式中、Ｒ１９は、Ｃ１－６アルコキシ－カルボニル、Ｃ１－６アルキル－カルボニル、Ｃ１－６アルキルスルホニル、アミノスルホニル、Ｃ１－６アルキルアミノスルホニル、カルバモイルまたはＣ１－６アルコキシカルバモイルを表す。］ [Wherein R 19 represents C 1-6 alkoxy-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylsulfonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, carbamoyl or C 1-6 alkoxycarbamoyl. Represents. ]

（工程２９）
　化合物（ＩＩs）は化合物（ＩＩb）の水酸基をアミノ化することによって製造することができる。該「アミノ化」は、例えばジャーナル　オブ　ジ　アメリカン　ケミカル　ソサイエティー（Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．），　１２３，　９４６５，　（２００１）に記載のアジド化と続く還元による方法や、テトラへドロン（Ｔｅｔｒａｈｅｄｒｏｎ），　５０,　１２７１３,　（１９９４）に記載のフタルイミドによる置換と続く脱保護による方法が挙げられる。 (Step 29)
Compound (IIs) can be produced by aminating the hydroxyl group of compound (IIb). The “amination” is, for example, a method by azidation and subsequent reduction described in Journal of the American Chemical Society (J. Am. Chem. Soc.), 123, 9465, (2001), or tetrahedron. 50, 12713, (1994), followed by substitution with phthalimide and subsequent deprotection.

（工程３０）
　化合物（ＩＩｔ）は化合物（ＩＩｓ）のアミノ基をアシル化、カルバモイル化、スルホニル化、またはスルファモイル化することにより製造することができる。
　アシル化は例えば酸クロリド、カルバモイル化は例えばイソシアネート、スルホニル化は例えばスルホニルクロリドをそれぞれアミン（ＩＩｓ）に対して縮合することによって実施することができる。スルファモイル化は例えばオーガニック　レターズ（Ｏｒｇａｎｉｃ　Ｌｅｔｔｅｒｓ），　１４，　２２４１，　（２００１）に記載の試薬を用い、得られた中間体を脱保護することによって実施することができる。 (Process 30)
Compound (IIt) can be produced by acylating, carbamoylating, sulfonylating, or sulfamoylating the amino group of compound (IIs).
Acylation can be carried out, for example, by condensation of acid chloride, carbamoylation, for example, isocyanate, and sulfonylation, for example, by condensation of sulfonyl chloride with amine (IIs). The sulfamoylation can be carried out, for example, by using the reagent described in Organic Letters, 14, 2241 (2001) and deprotecting the resulting intermediate.

　化合物（Ｉ）が遊離化合物として得られた場合には、自体公知の方法あるいはそれに準ずる方法によって、目的とする塩に変換することができ、逆に塩で得られた場合には、自体公知の方法あるいはそれに準ずる方法により、遊離体または目的とする他の塩に変換することができる。 When compound (I) is obtained as a free compound, it can be converted to the target salt by a method known per se or a method analogous thereto, and conversely when it is obtained as a salt, it is known per se. It can be converted into a free form or other desired salt by the method or a method analogous thereto.

　このような方法により生成した化合物（Ｉ）は、例えば、再結晶、蒸留、クロマトグラフィー等の通常の分離手段により単離、精製することができる。
　化合物（Ｉ）が、光学異性体、立体異性体、位置異性体、回転異性体を含有する場合には、これらも化合物（Ｉ）として含有されるとともに、自体公知の合成手法、分離手法（例えば、濃縮、溶媒抽出、カラムクロマトグラフィー、再結晶等）によりそれぞれを単品として得ることができる。例えば、化合物（Ｉ）に光学異性体が存在する場合には、該化合物から分割された光学異性体も化合物（Ｉ）に包含される。 The compound (I) produced by such a method can be isolated and purified by ordinary separation means such as recrystallization, distillation, chromatography and the like.
When compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and synthetic methods and separation methods known per se (for example, , Concentration, solvent extraction, column chromatography, recrystallization, etc.), each can be obtained as a single product. For example, when compound (I) has an optical isomer, the optical isomer resolved from the compound is also encompassed in compound (I).

　光学異性体は自体公知の方法により製造することができる。具体的には、光学活性な合成中間体を用いる、または、最終物のラセミ体を常法に従って光学分割することにより光学異性体を得る。
　光学分割法としては、自体公知の方法、例えば、分別再結晶法、キラルカラム法、ジアステレオマー法等が用いられる。 The optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemate according to a conventional method.
As the optical resolution method, a method known per se, for example, fractional recrystallization method, chiral column method, diastereomer method and the like are used.

　１）分別再結晶法
　ラセミ体と光学活性な化合物（例えば、（＋）－マンデル酸、（－）－マンデル酸、（＋）－酒石酸、（－）－酒石酸、（＋）－１－フェネチルアミン、（－）－１－フェネチルアミン、シンコニン、（－）－シンコニジン、ブルシン等）と塩を形成させ、これを分別再結晶法によって分離し、所望により、中和工程を経てフリーの光学異性体を得る方法。 1) Fractional recrystallization method Racemate and optically active compound (for example, (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.) to form a salt, which is separated by fractional recrystallization, and if desired, a free optical isomer is obtained through a neutralization step. Method.

　２）キラルカラム法
　ラセミ体またはその塩を光学異性体分離用カラム（キラルカラム）にかけて分離する方法。例えば液体クロマトグラフィーの場合、ＥＮＡＮＴＩＯ－ＯＶＭ（東ソー社製）あるいは、ＣＨＩＲＡＬシリーズ（ダイセル化学工業社製）等のキラルカラムに光学異性体の混合物を添加し、水、種々の緩衝液（例、リン酸緩衝液等）、有機溶媒（例、エタノール、メタノール、イソプロパノール、アセトニトリル、トリフルオロ酢酸、ジエチルアミン等）を単独あるいは混合した溶液として展開させることにより、光学異性体を分離する。また、例えばガスクロマトグラフィーの場合、ＣＰ－Ｃｈｉｒａｓｉｌ－ＤｅＸ　ＣＢ（ジーエルサイエンス社製）等のキラルカラムを使用して分離する。 2) Chiral column method A method in which a racemate or a salt thereof is separated by applying to a column for optical isomer separation (chiral column). For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series (manufactured by Daicel Chemical Industries), and water, various buffers (eg, phosphoric acid) The optical isomers are separated by developing the solution as a single or mixed solution of a buffer solution or the like and an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.). Further, for example, in the case of gas chromatography, the separation is performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Science).

　３）ジアステレオマー法
　ラセミ体の混合物を光学活性な試薬と化学反応によってジアステレオマーの混合物とし、これを通常の分離手段（例えば、分別再結晶、クロマトグラフィー法等）等を経て単一物質とした後、加水分解反応等の化学的な処理により光学活性な試薬部位を切り離すことにより光学異性体を得る方法。例えば、化合物（Ｉ）が分子内にヒドロキシまたは１，２級アミノを有する場合、該化合物と光学活性な有機酸（例えば、ＭＴＰＡ〔α－メトキシ－α－（トリフルオロメチル）フェニル酢酸〕、（－）－メントキシ酢酸等）等とを縮合反応に付すことにより、それぞれエステル体またはアミド体のジアステレオマーが得られる。一方、化合物（Ｉ）がカルボン酸基を有する場合、該化合物と光学活性アミンまたはアルコール試薬とを縮合反応に付すことにより、それぞれアミド体またはエステル体のジアステレオマーが得られる。分離されたジアステレオマーは、酸加水分解あるいは塩基性加水分解反応に付すことにより、元の化合物の光学異性体に変換される。 3) Diastereomer method A mixture of racemates is converted into a mixture of diastereomers by chemical reaction with an optically active reagent, and this is converted into a single substance through ordinary separation means (for example, fractional recrystallization, chromatography method, etc.). Then, the optical isomer is obtained by separating the optically active reagent site by chemical treatment such as hydrolysis reaction. For example, when the compound (I) has a hydroxy or a primary or secondary amino in the molecule, the compound and an optically active organic acid (for example, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid], ( -)-Menthoxyacetic acid etc.) are subjected to a condensation reaction to obtain ester or amide diastereomers, respectively. On the other hand, when the compound (I) has a carboxylic acid group, an amide or ester diastereomer is obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. The separated diastereomer is converted into the optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.

　化合物（Ｉ）は、結晶であってもよい。化合物（Ｉ）は単一の結晶形を有していてもよく、また複数の結晶形の混合物であってもよい。さらに、化合物（Ｉ）は、共結晶であってもよい。
　化合物（Ｉ）の結晶は、化合物（Ｉ）に自体公知の結晶化法を適用して、結晶化することによって製造することができる。
　ここで、結晶化法としては、例えば、溶液からの結晶化法、蒸気からの結晶化法、溶融体からの結晶化法等が挙げられる。 Compound (I) may be a crystal. Compound (I) may have a single crystal form or a mixture of a plurality of crystal forms. Further, the compound (I) may be a co-crystal.
Crystals of compound (I) can be produced by crystallization by applying a crystallization method known per se to compound (I).
Here, examples of the crystallization method include a crystallization method from a solution, a crystallization method from a vapor, a crystallization method from a melt, and the like.

　該「溶液からの結晶化法」としては、化合物の溶解度に関係する因子（溶媒組成、ｐＨ、温度、イオン強度、酸化還元状態等）または溶媒の量を変化させることによって、飽和していない状態から過飽和状態に移行させる方法が一般的であり、具体的には、例えば濃縮法、徐冷法、反応法（拡散法、電解法）、水熱育成法、融剤法等が挙げられる。用いられる溶媒としては、例えば、芳香族炭化水素類（例、ベンゼン、トルエン、キシレン等）、ハロゲン化炭化水素類（例、ジクロロメタン、クロロホルム等）、飽和炭化水素類（例、ヘキサン、ヘプタン、シクロヘキサン等）、エーテル類（例、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン等）、ニトリル類（例、アセトニトリル等）、ケトン類（例、アセトン等）、スルホキシド類（例、ジメチルスルホキシド等）、酸アミド類（例、Ｎ，Ｎ－ジメチルホルムアミド等）、エステル類（例、酢酸エチル等）、アルコール類（例、メタノール、エタノール、イソプロピルアルコール等）、水等が挙げられる。これらの溶媒は単独あるいは二種以上を適当な割合（例、１：１ないし１：１００（容積比））で混合して用いられる。必要に応じて種晶を使用することもできる。 The “crystallization from solution” includes a state in which the compound is not saturated by changing factors related to the solubility of the compound (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of the solvent. In general, a method of shifting from a supersaturated state to a supersaturated state is exemplified, and specific examples include a concentration method, a slow cooling method, a reaction method (diffusion method, electrolysis method), a hydrothermal growth method, and a flux method. Examples of the solvent used include aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), saturated hydrocarbons (eg, hexane, heptane, cyclohexane). Etc.), ethers (eg, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitriles (eg, acetonitrile, etc.), ketones (eg, acetone, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.), acid amides (Eg, N, N-dimethylformamide, etc.), esters (eg, ethyl acetate, etc.), alcohols (eg, methanol, ethanol, isopropyl alcohol, etc.), water and the like. These solvents may be used alone or in admixture of two or more at an appropriate ratio (eg, 1: 1 to 1: 100 (volume ratio)). A seed crystal can also be used as needed.

　該「蒸気からの結晶化法」としては、例えば気化法（封管法、気流法）、気相反応法、化学輸送法等が挙げられる。 Examples of the “crystallization method from vapor” include a vaporization method (sealed tube method, air flow method), a gas phase reaction method, a chemical transport method, and the like.

　該「溶融体からの結晶化法」としては、例えばノルマルフリージング法（引上げ法、温度傾斜法、ブリッジマン法）、帯溶融法（ゾーンレベリング法、フロートゾーン法）、特殊成長法（ＶＬＳ法、液相エピタキシー法）等が挙げられる。 Examples of the “crystallization from melt” include normal freezing method (pulling method, temperature gradient method, Bridgman method), zone melting method (zone leveling method, float zone method), special growth method (VLS method, Liquid phase epitaxy method) and the like.

　結晶化法の好適な例としては、化合物（Ｉ）を２０～１２０℃の温度下に、適当な溶媒（例、メタノール、エタノール等のアルコール類等）に溶解し、得られる溶液を溶解時の温度以下（例えば０～５０℃、好ましくは０～２０℃）に冷却する方法等が挙げられる。
　このようにして得られる本発明の結晶は、例えばろ過等によって単離することができる。
　得られた結晶の解析方法としては、粉末Ｘ線回折による結晶解析の方法が一般的である。さらに、結晶の方位を決定する方法としては、機械的な方法または光学的な方法等も挙げられる。
　化合物（Ｉ）は、薬学的に許容され得る共結晶または共結晶塩であってもよい。ここで、共結晶または共結晶塩とは、各々が異なる物理的特性（例えば、構造、融点、融解熱、吸湿性、溶解性および安定性等）を持つ、室温で二種またはそれ以上の独特な固体から構成される結晶性物質を意味する。共結晶または共結晶塩は、自体公知の共結晶化法に従い製造することができる。 As a preferred example of the crystallization method, compound (I) is dissolved in an appropriate solvent (eg, alcohol such as methanol, ethanol, etc.) at a temperature of 20 to 120 ° C., and the resulting solution is dissolved. Examples thereof include a method of cooling to a temperature below (for example, 0 to 50 ° C., preferably 0 to 20 ° C.).
The crystals of the present invention thus obtained can be isolated by, for example, filtration.
As a method for analyzing the obtained crystal, a crystal analysis method by powder X-ray diffraction is generally used. Further, examples of the method for determining the crystal orientation include a mechanical method and an optical method.
Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid. The cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.

　上記の製造法で得られる化合物（Ｉ）の結晶（以下、「本発明の結晶」と略記する）は、高純度、高品質であり、吸湿性が低く、通常条件下で長期間保存しても変質せず、安定性に極めて優れている。また、生物学的性質（例、体内動態（吸収性、分布、代謝、排泄）、薬効発現等）にも優れ、医薬として極めて有用である。 The crystal of compound (I) obtained by the above production method (hereinafter abbreviated as “crystal of the present invention”) has high purity, high quality, low hygroscopicity, and is stored for a long time under normal conditions. Is very stable. In addition, it has excellent biological properties (eg, pharmacokinetics (absorbability, distribution, metabolism, excretion), expression of drug efficacy, etc.) and is extremely useful as a medicine.

　本明細書中、比旋光度（［α］Ｄ）は、例えば旋光度計（日本分光（ＪＡＳＣＯ）、Ｐ－１０３０型旋光計（Ｎｏ．ＡＰ－２））等を用いて測定される比旋光度を意味する。
　本明細書中、融点は、例えば微量融点測定器（ヤナコ、ＭＰ－５００Ｄ型）またはＤＳＣ（示差走査熱量分析）装置（ＳＥＩＫＯ，ＥＸＳＴＡＲ６０００）等を用いて測定される融点を意味する。 In this specification, the specific rotation ([α] D ) is measured by using, for example, a polarimeter (JASCO, P-1030 polarimeter (No. AP-2)) and the like. Means degrees.
In the present specification, the melting point means a melting point measured using, for example, a trace melting point measuring device (Yanako, MP-500D type) or a DSC (differential scanning calorimetry) apparatus (SEIKO, EXSTAR6000).

　化合物（Ｉ）のプロドラッグは、生体内における生理条件下で酵素や胃酸等による反応により化合物（Ｉ）に変換する化合物、すなわち酵素的に酸化、還元、加水分解等を起こして化合物（Ｉ）に変化する化合物、胃酸等により加水分解などを起こして化合物（Ｉ）に変化する化合物をいう。化合物（Ｉ）のプロドラッグとしては、化合物（Ｉ）のアミノ基がアシル化、アルキル化、りん酸化された化合物［例、化合物（Ｉ）のアミノ基がエイコサノイル化、アラニル化、ペンチルアミノカルボニル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メトキシカルボニル化、テトラヒドロフラニル化、ピロリジルメチル化、ピバロイルオキシメチル化、ｔｅｒｔ－ブチル化された化合物など］；化合物（Ｉ）の水酸基がアシル化、アルキル化、りん酸化、ほう酸化された化合物（例、化合物（Ｉ）の水酸基がアセチル化、パルミトイル化、プロパノイル化、ピバロイル化、サクシニル化、フマリル化、アラニル化、ジメチルアミノメチルカルボニル化された化合物など）；化合物（Ｉ）のカルボキシ基がエステル化、アミド化された化合物［例、化合物（Ｉ）のカルボキシ基がエチルエステル化、フェニルエステル化、カルボキシメチルエステル化、ジメチルアミノメチルエステル化、ピバロイルオキシメチルエステル化、エトキシカルボニルオキシエチルエステル化、フタリジルエステル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メチルエステル化、シクロヘキシルオキシカルボニルエチルエステル化、メチルアミド化された化合物など］などが挙げられる。これらの化合物は自体公知の方法によって化合物（Ｉ）から製造することができる。
　また、化合物（Ｉ）のプロドラッグは、広川書店１９９０年刊「医薬品の開発」第７巻分子設計１６３頁から１９８頁に記載されているような、生理的条件で化合物（Ｉ）に変化するものであってもよい。 A prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc. A compound that changes to compound (I) upon hydrolysis by gastric acid or the like. Compound (I) prodrugs include compounds in which the amino group of compound (I) is acylated, alkylated, and phosphorylated [eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated. , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds and the like]; Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, or borated (eg, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanyl Dimethylaminomethylcarbonylated compounds, etc.); the carboxy group of compound (I) is esterified Compound amidated [eg, carboxy group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, Phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds, etc.]. These compounds can be produced from compound (I) by a method known per se.
In addition, the prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, Molecular Design, pages 163 to 198. It may be.

　本発明の化合物（Ｉ）もしくはその塩またはそのプロドラッグ（以下化合物（Ｉ’）と略記する）は優れたモノアミン（セロトニン、ノルエピネフリン、ドーパミン等）再取り込み阻害活性を有する。
　また、本発明の化合物（Ｉ’）は、毒性が低く、安全である。特に、光毒性を示さない点で有用である。 The compound (I) or a salt thereof or a prodrug thereof (hereinafter abbreviated as compound (I ′)) of the present invention has an excellent monoamine (such as serotonin, norepinephrine, dopamine) reuptake inhibitory activity.
Moreover, the compound (I ′) of the present invention has low toxicity and is safe. In particular, it is useful in that it does not exhibit phototoxicity.

　従って、本発明の化合物（Ｉ’）は、哺乳動物（例えば、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ヒツジ、サル、ヒトなど）に対して、脳内モノアミン類（セロトニン、ノルエピネフリン、ドーパミン等）再取り込み阻害活性を有する物質として、脳内モノアミン類が再取り込みされるのを阻害し、うつ病・不安症等の精神神経疾患の症状を改善する。
　また、本発明の化合物（Ｉ’）は、哺乳動物（例えば、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ヒツジ、サル、ヒトなど）に対して、モノアミン類（セロトニン、ノルエピネフリン、ドーパミン等）再取り込み阻害活性を有する物質として、モノアミン類が再取り込みされるのを阻害し、腹圧性尿失禁等の下部尿路症状を改善する。 Accordingly, the compound (I ′) of the present invention can be used for a monoamine in the brain (serotonin, norepinephrine) against mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.). Inhibiting the reuptake of monoamines in the brain as a substance having reuptake inhibitory activity, and improving symptoms of neuropsychiatric disorders such as depression and anxiety.
The compound (I ′) of the present invention is a monoamine (serotonin, norepinephrine, dopamine) for mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.). Etc.) As a substance having reuptake inhibitory activity, it inhibits reuptake of monoamines and improves lower urinary tract symptoms such as stress urinary incontinence.

　本発明の化合物（Ｉ’）は毒性が低く、かつ副作用も少ない等の医薬品として優れた性質も有するので、例えば、以下の疾患の予防・治療のために有用である。
（１）中枢神経疾患
（ａ）精神神経疾患〔例、うつ病（例、大うつ病、脳血管障害性うつ、季節性うつ、薬剤起因うつ、HIV性うつ等）、不安症（例、全般性不安障害、社会不安障害、強迫性障害、パニック障害、外傷後ストレス障害等）、注意欠陥・多動性障害（ADHD）、双極性障害、躁病、反復性うつ病、持続性気分感情障害（例、気分循環症、気分変調症等）、抑うつ神経症、睡眠障害、日周リズム障害、摂食障害、薬剤依存症、月経前緊張症、自閉症、更年期による気分障害、老人性認知症、軽度認知機能障害、過眠症、心身症、躁うつ病、心的外傷後ストレス障害（Posttraumatic stress disorder: PTSD）、統合失調症、不安神経症、強迫性神経症、脳卒中や脳血管障害に伴う気分障害や運動障害等〕
（ｂ）神経変性疾患（例、筋線維症、アルツハイマー病、パーキンソン病、神経変性疾患に伴う気分障害等）
（２）各種疼痛（例、神経因性疼痛、炎症性疼痛、繊維筋痛症等）
（３）下部尿路症状（例、過活動膀胱、腹圧性尿失禁、混合型尿失禁、骨盤内臓痛、間質性膀胱炎に伴う下部尿路症状等の排尿異常、男性下部尿路症状等）
（４）骨盤臓器脱（膣前壁脱、膣後壁脱、子宮脱、膣尖端の脱、直腸脱（直腸瘤）、小腸瘤、膀胱瘤、尿道瘤等）
（５）その他の疾患〔例えば、糖尿病、肥満、過敏性腸症候群（IBS）、ムズムズ脚症候群（RLS）、慢性疲労症候群、月経前症候群（PMS）、機能性胃腸症（FD）、便失禁、消化器系疾患、禁煙、各種依存症〕 Since the compound (I ′) of the present invention has excellent properties as a pharmaceutical such as low toxicity and few side effects, it is useful, for example, for the prevention and treatment of the following diseases.
(1) Central nervous system disease (a) Psychiatric and neurological diseases [eg, depression (eg, major depression, cerebrovascular disorder depression, seasonal depression, drug-induced depression, HIV depression, etc.), anxiety (eg, general) Sexual anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder), attention deficit / hyperactivity disorder (ADHD), bipolar disorder, mania, recurrent depression, persistent mood emotion disorder ( Eg, mood circulatory disorder, dysthymia, etc.), depressive neurosis, sleep disorder, diurnal rhythm disorder, eating disorder, drug dependence, premenstrual tension, autism, mood disorders due to menopause, senile dementia Mild cognitive dysfunction, hypersomnia, psychosomatic disorder, manic depression, posttraumatic stress disorder (PTSD), schizophrenia, anxiety, obsessive-compulsive disorder, stroke and cerebrovascular disorder (Such as mood disorders and movement disorders)
(B) Neurodegenerative diseases (eg, myofibrosis, Alzheimer's disease, Parkinson's disease, mood disorders associated with neurodegenerative diseases, etc.)
(2) Various pains (eg, neuropathic pain, inflammatory pain, fibromyalgia, etc.)
(3) Lower urinary tract symptoms (eg, overactive bladder, stress urinary incontinence, mixed urinary incontinence, pelvic visceral pain, urination abnormalities such as lower urinary tract symptoms associated with interstitial cystitis, male lower urinary tract symptoms, etc. )
(4) Pelvic organ prolapse (anterior vaginal prolapse, retrovaginal prolapse, uterine prolapse, vaginal prolapse, rectal prolapse (rectal aneurysm), small intestinal aneurysm, cystocele, urethral aneurysm, etc.)
(5) Other diseases [eg, diabetes, obesity, irritable bowel syndrome (IBS), Musm's leg syndrome (RLS), chronic fatigue syndrome, premenstrual syndrome (PMS), functional gastroenteropathy (FD), fecal incontinence, (Digestive system diseases, smoking cessation, various addictions)

　本発明の化合物（Ｉ’）は、モノアミン再取り込み阻害薬として有用であり、特に、うつ病、不安症、注意欠陥・多動性障害または腹圧性尿失禁の予防・治療薬として有用である。また、本発明の化合物（Ｉ’）は、セロトニン、ノルエピネフリンおよびドーパミンの再取り込み阻害活性を有することから、Triple Reuptake Inhibitorとして有用である。また、本発明の化合物（Ｉ’）は、ノルエピネフリンの再取り込み阻害活性を有することから、ノルエピネフリン再取り込み阻害薬として有用である。 The compound (I ′) of the present invention is useful as a monoamine reuptake inhibitor, and particularly useful as a prophylactic / therapeutic agent for depression, anxiety, attention deficit / hyperactivity disorder or stress urinary incontinence. In addition, the compound (I ′) of the present invention has a reuptake inhibitory activity for serotonin, norepinephrine and dopamine, and thus is useful as a Triple® Reuptake® Inhibitor. In addition, since the compound (I ′) of the present invention has a norepinephrine reuptake inhibitory activity, it is useful as a norepinephrine reuptake inhibitor.

　本発明において、「モノアミン再取り込み阻害薬」とは、神経伝達物質であるセロトニン、ノルエピネフリンおよびドーパミンから選ばれる少なくとも１つのモノアミンの再取り込み阻害薬を意味する。「モノアミン再取り込み阻害薬」としては、セロトニン再取り込み阻害薬、ノルエピネフリン再取り込み阻害薬、ドーパミン再取り込み阻害薬、セロトニン－ノルエピネフリン再取り込み阻害薬、ノルエピネフリン－ドーパミン再取り込み阻害薬、セロトニン－ドーパミン再取り込み阻害薬、セロトニン－ノルエピネフリン－ドーパミン再取り込み阻害薬が挙げられる。 In the present invention, the “monoamine reuptake inhibitor” means a reuptake inhibitor of at least one monoamine selected from serotonin, norepinephrine and dopamine which are neurotransmitters. Monoamine reuptake inhibitors include serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dopamine reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, serotonin-dopamine reuptake inhibitors Drugs, serotonin-norepinephrine-dopamine reuptake inhibitors.

　化合物（Ｉ’）を含有する医薬は、医薬製剤の製造法として自体公知の方法（例、日本薬局方記載の方法等）に従って、本発明化合物を単独で、または薬理学的に許容される担体と混合して、例えば錠剤（糖衣錠、フィルムコーティング錠、舌下錠、口腔内崩壊錠、バッカル錠等を含む）、丸剤、散剤、顆粒剤、カプセル剤（ソフトカプセル剤、マイクロカプセル剤を含む）、トローチ剤、シロップ剤、液剤、乳剤、懸濁剤、放出制御製剤（例、速放性製剤、徐放性製剤、徐放性マイクロカプセル剤）、エアゾール剤、フィルム剤（例、口腔内崩壊フィルム、口腔粘膜貼付フィルム）、注射剤（例、皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤）、点滴剤、経皮吸収型製剤、軟膏剤、ローション剤、貼付剤、坐剤（例、肛門坐剤、膣坐剤）、ペレット、経鼻剤、経肺剤（吸入剤）、点眼剤等とすることができる。徐放性製剤の調製は、特開平９－２６３５４５号公報に記載の方法に準ずることができる。
　また、化合物（Ｉ’）を含有する医薬は、経口的または非経口的（例、静脈内、筋肉内、皮下、臓器内、鼻腔内、皮内、点眼、脳内、直腸内、膣内、腹腔内、腫瘍内部、腫瘍の近位等への投与および直接的な病巣への投与）に安全に投与することができる。 The medicament containing the compound (I ′) can be obtained by using the compound of the present invention alone or a pharmacologically acceptable carrier according to a method known per se (eg, a method described in the Japanese Pharmacopoeia) as a method for producing a pharmaceutical preparation. For example, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules and microcapsules) , Lozenges, syrups, solutions, emulsions, suspensions, controlled-release preparations (eg, immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, films (eg, oral disintegration) Film, oral mucosa adhesive film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), drip, transdermal preparation, ointment, lotion, patch Suppositories (eg, anal suppositories, Vaginal suppositories), pellets, nasal agents, pulmonary agents (inhalants), eye drops and the like. The preparation of sustained-release preparation can be applied in accordance with the method described in JP-A-9-263545.
In addition, the medicament containing compound (I ′) can be used orally or parenterally (eg, intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, ophthalmic, intracerebral, rectal, intravaginal, Administration to the abdominal cavity, inside the tumor, proximal to the tumor, etc. and direct administration to the lesion).

　本発明の製剤において、化合物（Ｉ’）の含有量は、製剤の形態によって相違するが、通常、製剤全体に対する化合物（Ｉ）の量として０．０１～１００重量％、好ましくは０．１～５０重量％、さらに好ましくは０．５～２０重量％程度である。 In the preparation of the present invention, the content of compound (I ′) varies depending on the form of the preparation, but is usually 0.01 to 100% by weight, preferably 0.1 to 100% by weight as compound (I) relative to the whole preparation. It is about 50% by weight, more preferably about 0.5 to 20% by weight.

　前記の薬理学的に許容され得る担体としては、例えば、賦形剤（例えば、デンプン、乳糖、白糖、炭酸カルシウム、リン酸カルシウムなど）、結合剤（例えば、デンプン、アラビアゴム、カルボキシメチルセルロース、ヒドロキシプロピルセルロース、結晶セルロース、アルギン酸、ゼラチン、ポリビニルピロリドンなど）、滑沢剤（例えば、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルクなど）、崩壊剤（例えば、カルボキシメチルセルロースカルシウム、タルクなど）、希釈剤（例えば、注射用水、生理食塩水など）、添加剤（例えば、安定剤、保存剤、着色剤、香料、溶解助剤、乳化剤、緩衝剤、等張化剤など）などが挙げられる。 Examples of the pharmacologically acceptable carrier include excipients (eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose). , Crystalline cellulose, alginic acid, gelatin, polyvinylpyrrolidone, etc.), lubricant (eg, stearic acid, magnesium stearate, calcium stearate, talc, etc.), disintegrant (eg, carboxymethylcellulose calcium, talc, etc.), diluent (eg, Water for injection, physiological saline, etc.), additives (for example, stabilizers, preservatives, coloring agents, fragrances, solubilizers, emulsifiers, buffers, isotonic agents, etc.) and the like.

　例えば、注射剤とするには、化合物（Ｉ’）を分散剤（例、Ｔｗｅｅｎ　８０、ＨＣＯ－６０等の界面活性剤、カルボキシメチルセルロース、アルギン酸ナトリウム、ヒアルロン酸等の多糖類、ポリソルベート等）、保存剤（例、メチルパラベン、プロピルパラベン等）、等張化剤（例、塩化ナトリウム、マンニトール、ソルビトール、ブドウ糖等）、緩衝剤（例、炭酸カルシウム等）、ｐＨ調整剤（例、リン酸ナトリウム、リン酸カリウム等）等と共に水性懸濁剤とすることにより実用的な注射用製剤が得られる。また、ゴマ油、コーン油などの植物油あるいはこれにレシチンなどのリン脂質を混合したもの、あるいは中鎖脂肪酸トリグリセリド（例、ミグリオール８１２等）と共に分散して油性懸濁剤として実際に使用できる注射剤とする。 For example, for injection, compound (I ′) is used as a dispersant (eg, surfactants such as Tween 80, HCO-60, polysaccharides such as carboxymethylcellulose, sodium alginate, hyaluronic acid, polysorbate, etc.), storage Agents (eg, methylparaben, propylparaben, etc.), isotonic agents (eg, sodium chloride, mannitol, sorbitol, glucose, etc.), buffers (eg, calcium carbonate, etc.), pH adjusters (eg, sodium phosphate, phosphorus, etc.) A practical injectable preparation can be obtained by using an aqueous suspension together with potassium acid and the like. Injectables that can be used as oily suspensions by dispersing with vegetable oils such as sesame oil and corn oil or phospholipids such as lecithin mixed with them, or medium chain fatty acid triglycerides (eg, miglycol 812). To do.

　本発明の予防・治療薬においては、他の薬剤と共に用いることもできる。
　化合物（Ｉ’）と配合又は併用し得る薬物（以下、併用薬物と略記する）としては、例えば、以下のようなものが用いられる。
（１）他の中枢神経疾患の予防・治療薬
　うつ病治療薬、不安症治療薬（例、クロルジアゼポキシド、ジアゼパム、クロラゼプ酸カリウム、ロラゼパム、クロナゼパム、アルプラゾラム等のベンゾジアゼピン）、気分安定薬（例、炭酸リチウム等）、5-HT2拮抗薬（例、ネファゾドン等）、5-HT1A作動薬（例、タンドスピロン、ブスピロン、Gepiron等）、CRF拮抗薬（例、Pexacerfont等）、β３作動薬（例、Amibegron等）、メラトニン作動薬（例、ラメルテオン、agomelatine等）、α２拮抗薬（例、ミルタザピン、セチプチリン等）、NK2拮抗薬（例、Saredutant等）、GR拮抗薬（例、Mifepristone等）、NK-1拮抗薬（例、Casopitant、Orvepitant等）、統合失調症治療薬（例、クロルプロマジン、ハロペリドール、スルピリド、クロザピン、アリピプラゾール、クエチアピン、オランザピン、リスペリドン等）、アセチルコリンエステラーゼ阻害剤（例、ドネペジル、リバスチグミン、ガランタミン、ザナペジル等）、NMDA拮抗薬（例、メマンチン等）、βアミロイド蛋白産生、分泌、蓄積、凝集および/または沈着抑制剤[βセクレターゼ阻害剤、γセクレターゼ阻害作用剤、βアミロイド蛋白凝集阻害作用剤（例、ＰＴＩ－００７０３、ＡＬＺＨＥＭＥＤ（ＮＣ－５３１）、ＰＰＩ－３６８（特表平11－514333）、ＰＰＩ－５５８（特表平2001－500852）、ＳＫＦ－７４６５２（Biochem.J.（1999），340（1），283－289））、βアミロイドワクチン、βアミロイド分解酵素等]、脳機能賦活薬（例、アニラセタム、ニセルゴリン等）、パーキンソン病治療薬[例、ドーパミン受容体作動薬（例、Ｌ－ドーパ、ブロモクリプテン、パーゴライド、タリペキソール、プラシペキソール、カベルゴリン、アダマンタジン等）、COMT阻害剤（例、エンタカポン等）]、注意欠陥・多動性障害治療薬（例、モダフィニル等）、筋萎縮性側索硬化症治療薬（例、リルゾール、神経栄養因子等）、不眠症治療薬（例、エチゾラム、ゾピクロン、トリアゾラム、ゾルピデム、インディプロン等）、過眠症治療薬（例、モダフィニル等）、抗サイトカイン薬（ＴＮＦ阻害薬、ＭＡＰキナーゼ阻害薬等）、ステロイド薬（例、デキサメサゾン、ヘキセストロール、酢酸コルチゾン等）等が挙げられる。 The prophylactic / therapeutic agent of the present invention can be used together with other drugs.
Examples of the drug that can be blended or used in combination with compound (I ′) (hereinafter abbreviated as a concomitant drug) include the following.
(1) Other central nervous disease prophylactic / therapeutic drugs Depressive drugs, anxiety drugs (eg, chlordiazepoxide, diazepam, potassium chlorazepate, lorazepam, clonazepam, alprazolam and other benzodiazepines), mood stabilizers (eg, carbonic acid carbonate) Lithium), 5-HT2 antagonists (eg, nefazodone, etc.), 5-HT1A agonists (eg, tandospirone, buspirone, Gepiron, etc.), CRF antagonists (eg, Pecacerfont, etc.), β3 agonists (eg, Amibegron, etc.) ), Melatonin agonists (eg, ramelteon, agomelatine, etc.), α2 antagonists (eg, mirtazapine, setiptiline, etc.), NK2 antagonists (eg, Saredutant, etc.), GR antagonists (eg, Mifepristone, etc.), NK-1 antagonists Drugs (eg, Casopitant, Orvepitant, etc.), schizophrenia drugs (eg, chlorpromazine, haloperidol, sulpiride, clozapine, aripiprazole, quetiapine, o Nzapine, risperidone, etc.), acetylcholinesterase inhibitors (eg, donepezil, rivastigmine, galantamine, zanapezil, etc.), NMDA antagonists (eg, memantine, etc.), β amyloid protein production, secretion, accumulation, aggregation and / or deposition inhibitors [ β-secretase inhibitor, γ-secretase inhibitor, β-amyloid protein aggregation inhibitor (eg, PTI-00703, ALZHEMED (NC-531), PPI-368 (Special Tables Hei 11-514333), PPI-558 (Special Tables) 2001-500852), SKF-74652 (Biochem. J. (1999), 340 (1), 283-289)), β-amyloid vaccine, β-amyloid degrading enzyme, etc.], brain function activator (eg, aniracetam, nicergoline) Etc.), Parkinson's disease drug [eg, dopamine receptor agonist (eg, L-dopa, bromocryptene, pergolide] , Talipexol, Prasipexole, Cabergoline, Adamantazine, etc.), COMT inhibitors (eg, Entacapone, etc.)], Attention deficit / hyperactivity disorder (eg, modafinil, etc.), Amyotrophic lateral sclerosis (eg, , Riluzole, neurotrophic factor, etc.), insomnia drug (eg, etizolam, zopiclone, triazolam, zolpidem, indiplon), hypersomnia drug (eg, modafinil, etc.), anti-cytokine drug (TNF inhibitor, MAP) Kinase inhibitors, etc.), steroid drugs (eg, dexamethasone, hexestrol, cortisone acetate, etc.) and the like.

（２）他の腹圧性尿失禁の予防・治療薬
　アドレナリンα１受容体アゴニスト（例、塩酸エフェドリン、塩酸ミトドリン等）、アドレナリンβ２受容体アゴニスト（例、クレンブテロール（Ｃｌｅｎｂｕｔｅｒｏｌ）等）、ノルエピネフリン取り込み阻害物質、ノルエピネフリンおよびセロトニン取り込み阻害物質（例、デュロキセチン等）、３環性抗うつ薬（例、塩酸イミプラミン等）、抗コリン薬又は平滑筋刺激薬（例、塩酸オキシブチニン、塩酸プロピベリン、塩酸セリメベリン等）、女性ホルモン薬（例、結合型エストロゲン（プレマリン）、エストリオール等）等。 (2) Other prophylactic / therapeutic agents for stress urinary incontinence Adrenaline α1 receptor agonist (eg, ephedrine hydrochloride, mitodrine hydrochloride, etc.), Adrenaline β2 receptor agonist (eg, Clenbuterol, etc.), Norepinephrine uptake inhibitor, Norepinephrine and serotonin uptake inhibitors (eg, duloxetine, etc.), tricyclic antidepressants (eg, imipramine hydrochloride, etc.), anticholinergic drugs or smooth muscle stimulants (eg, oxybutynin hydrochloride, propiverine hydrochloride, selimevelin hydrochloride, etc.), female Hormonal drugs (eg, conjugated estrogens (premarin), estriol, etc.), etc.

（３）糖尿病治療剤
　インスリン製剤〔例、ウシ、ブタの膵臓から抽出された動物インスリン製剤；大腸菌、イーストを用い、遺伝子工学的に合成したヒトインスリン製剤；インスリン亜鉛；プロタミンインスリン亜鉛；インスリンのフラグメント又は誘導体（例、ＩＮＳ－１等）など〕、インスリン感受性増強剤（例、塩酸ピオグリタゾン、トログリタゾン、ロシグリタゾン又はそのマレイン酸塩、ＪＴＴ－５０１、ＭＣＣ－５５５、ＹＭ－４４０、ＧＩ－２６２５７０、ＫＲＰ－２９７、ＦＫ－６１４、ＣＳ－０１１等）、α－グルコシダーゼ阻害剤（例、ボグリボース、アカルボース、ミグリトール、エミグリテート等）、ビグアナイド剤（例、フェンホルミン、メトホルミン、ブホルミン等）、スルホニルウレア剤（例、トルブタミド、グリベンクラミド、グリクラジド、クロルプロパミド、トラザミド、アセトヘキサミド、グリクロピラミド、グリメピリド等）やその他のインスリン分泌促進剤（例、レパグリニド、セナグリニド、ミチグリニド又はそのカルシウム塩水和物、ＧＬＰ－１、ナテグリニド等）、ジペプチジルペプチダーゼＩＶ阻害剤（例、ビルダグリプチン、シタグリプチン、サクサグリプチン、アログリプチン、ＮＶＰ－ＤＰＰ－７２８、ＰＴ－１００、Ｐ３２／９８等）、β３アゴニスト（例、ＣＬ－３１６２４３、ＳＲ－５８６１１－Ａ、ＵＬ－ＴＧ－３０７、ＡＪ－９６７７、ＡＺ４０１４０等）、アミリンアゴニスト（例、プラムリンチド等）、ホスホチロシンホスファターゼ阻害剤（例、バナジン酸等）、糖新生阻害剤（例、グリコーゲンホスホリラーゼ阻害剤、グルコース－６－ホスファターゼ阻害剤、グルカゴン拮抗剤等）、ＳＧＬＴ（ｓｏｄｉｕｍ－ｇｌｕｃｏｓｅ　ｃｏｔｒａｎｓｐｏｒｔｅｒ）阻害剤（例、Ｔ－１０９５等）等。 (3) Diabetes therapeutic agent Insulin preparations [eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin zinc; protamine insulin zinc; insulin fragments Or derivatives (eg, INS-1 etc.)], insulin sensitivity enhancers (eg, pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, JTT-501, MCC-555, YM-440, GI-262570, KRP) -297, FK-614, CS-011, etc.), α-glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, phenformin, metformin, buformin, etc.), sulfonylurea agents (eg, Tolbutamide Glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, etc.) and other insulin secretagogues (eg, repaglinide, senaglinide, mitiglinide or its calcium salt hydrate, GLP-1, nateglinide, etc.) Dipeptidyl peptidase IV inhibitors (eg, vildagliptin, sitagliptin, saxagliptin, alogliptin, NVP-DPP-728, PT-100, P32 / 98, etc.), β3 agonists (eg, CL-316243, SR-58611-A, UL) -TG-307, AJ-9777, AZ40140, etc.), amylin agonist (eg, pramlintide, etc.), phosphotyrosine phosphatase inhibitor (eg, vanadic acid, etc.), gluconeogenesis inhibitor (eg, glycogen phospho) Reylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, etc.), SGLT (sodium-glucose transporter) inhibitors (eg, T-1095 etc.) and the like.

（４）糖尿病性合併症治療剤
　アルドース還元酵素阻害剤（例、トルレスタット、エパルレスタット、ゼナレスタット、ゾポルレスタット、フィダレスタット（ＳＮＫ－８６０）、ミナルレスタット（ＡＲＩ－５０９）、ＣＴ－１１２等）、神経栄養因子（例、ＮＧＦ、ＮＴ－３等）、ＡＧＥ阻害剤（例、ＡＬＴ－９４５、ピマゲジン、ピラトキサチン、Ｎ－フェナシルチアゾリウムブロミド（ＡＬＴ－７６６）、ＥＸＯ－２２６等）、活性酸素消去薬（例、チオクト酸等）、脳血管拡張剤（例、チアプリド等）等。 (4) Treatment for diabetic complications Aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolrestat, fidarestat (SNK-860), minarerestat (ARI-509), CT-112 etc.), nerve Nutritional factors (eg, NGF, NT-3, etc.), AGE inhibitors (eg, ALT-945, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (ALT-766), EXO-226, etc.), active oxygen elimination Drugs (eg, thioctic acid, etc.), cerebral vasodilators (eg, thioprid, etc.), etc.

（５）抗高脂血症剤
　コレステロール合成阻害剤であるスタチン系化合物（例、プラバスタチン、シンバスタチン、ロバスタチン、アトルバスタチン、フルバスタチン、セリバスタチン又はそれらの塩（例、ナトリウム塩等）等）、スクアレン合成酵素阻害剤あるいはトリグリセリド低下作用を有するフィブラート系化合物（例、ベザフィブラート、クロフィブラート、シムフィブラート、クリノフィブラート等）等。 (5) Antihyperlipidemic agents Statin compounds that are cholesterol synthesis inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin or salts thereof (eg, sodium salt), etc.), squalene synthase Fibrate compounds having an inhibitor or triglyceride lowering effect (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.) and the like.

（６）降圧剤
　アンジオテンシン変換酵素阻害剤（例、カプトプリル、エナラプリル、デラプリル等）、アンジオテンシンＩＩ拮抗剤（例、ロサルタン、カンデサルタン　シレキセチル等）、カルシウム拮抗剤（例、マニジピン、ニフェジピン、アムロジピン、エホニジピン、ニカルジピン等）、クロニジン等。 (6) Antihypertensive agent Angiotensin converting enzyme inhibitor (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonist (eg, losartan, candesartan cilexetil, etc.), calcium antagonist (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine) Etc.), clonidine and the like.

（７）抗肥満剤
　中枢性抗肥満薬（例、デキスフェンフルラミン、フェンフルラミン、フェンテルミン、シブトラミン、アンフェプラモン、デキサンフェタミン、マジンドール、フェニルプロパノールアミン、クロベンゾレックス等）、膵リパーゼ阻害薬（例、オルリスタット等）、β３アゴニスト（例、ＣＬ－３１６２４３、ＳＲ－５８６１１－Ａ、ＵＬ－ＴＧ－３０７、ＡＪ－９６７７、ＡＺ４０１４０等）、ペプチド性食欲抑制薬（例、レプチン、ＣＮＴＦ（毛様体神経栄養因子）等）、コレシストキニンアゴニスト（例、リンチトリプト、ＦＰＬ－１５８４９等）等。 (7) Anti-obesity agents Central anti-obesity drugs (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, amphetopramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzolex, etc.), pancreatic lipase inhibitor (Eg, orlistat, etc.), β3 agonist (eg, CL-316243, SR-58611-A, UL-TG-307, AJ-9679, AZ40140, etc.), peptidic appetite suppressant (eg, leptin, CNTF (hair-like) Somatic neurotrophic factor)), cholecystokinin agonists (eg, Lynchtripto, FPL-15849, etc.) and the like.

（８）利尿剤
　キサンチン誘導体（例、サリチル酸ナトリウムテオブロミン、サリチル酸カルシウムテオブロミン等）、チアジド系製剤（例、エチアジド、シクロペンチアジド、トリクロルメチアジド、ヒドロクロロチアジド、ヒドロフルメチアジド、ベンジルヒドロクロロチアジド、ペンフルチジド、ポリチアジド、メチクロチアジド等）、抗アルドステロン製剤（例、スピロノラクトン、トリアムテレン等）、炭酸脱水酵素阻害剤（例、アセタゾラミド等）、クロルベンゼンスルホンアミド系製剤（例、クロルタリドン、メフルシド、インダパミド等）、アゾセミド、イソソルビド、エタクリン酸、ピレタニド、ブメタニド、フロセミド等。 (8) Diuretics Xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, pentfurizide, polythiazide, methiclo Thiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), azosemide, isosorbide, etacrine Acid, piretanide, bumetanide, furosemide, etc.

（９）化学療法剤
　アルキル化剤（例、サイクロフォスファミド、イフォスファミド等）、代謝拮抗剤（例、メソトレキセート、５－フルオロウラシル等）、抗癌性抗生物質（例、マイトマイシン、アドリアマイシン等）、植物由来抗癌剤（例、ビンクリスチン、ビンデシン、タキソール等）、シスプラチン、カルボプラチン、エトポシド等、なかでも５－フルオロウラシル誘導体であるフルツロンあるいはネオフルツロン等。 (9) Chemotherapeutic agents Alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), anticancer antibiotics (eg, mitomycin, adriamycin, etc.), plants Derived anticancer agents (eg, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etoposide, etc., among others, 5-fluorouracil derivatives such as furtulon or neoflutulon.

（１０）免疫療法剤
　微生物又は細菌成分（例、ムラミルジペプチド誘導体、ピシバニール等）、免疫増強活性のある多糖類（例、レンチナン、シゾフィラン、クレスチン等）、遺伝子工学的手法で得られるサイトカイン（例、インターフェロン、インターロイキン（ＩＬ）等）、コロニー刺激因子（例、顆粒球コロニー刺激因子、エリスロポエチン等）等、なかでもＩＬ－１、ＩＬ－２、ＩＬ－１２等。 (10) Immunotherapeutic agents Microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil, etc.), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), cytokines obtained by genetic engineering techniques (eg, , Interferon, interleukin (IL), etc.), colony stimulating factors (eg, granulocyte colony stimulating factor, erythropoietin, etc.), among them IL-1, IL-2, IL-12, etc.

（１１）動物モデルや臨床で悪液質改善作用が認められている薬剤
　プロゲステロン誘導体（例、メゲステロールアセテート）〔ジャーナル・オブ・クリニカル・オンコロジー（Ｊｏｕｒｎａｌ　ｏｆ　Ｃｌｉｎｉｃａｌ　Ｏｎｃｏｌｏｇｙ）、第１２巻、２１３～２２５頁、１９９４年〕、メトクロプラミド系薬剤、テトラヒドロカンナビノール系薬剤（文献はいずれも上記と同様）、脂肪代謝改善剤（例、エイコサペンタエン酸等）〔ブリティシュ・ジャーナル・オブ・キャンサー（Ｂｒｉｔｉｓｈ　Ｊｏｕｒｎａｌ　ｏｆ　Ｃａｎｃｅｒ）、第６８巻、３１４～３１８頁、１９９３年〕、成長ホルモン、ＩＧＦ－１、あるいは悪液質を誘導する因子であるＴＮＦ－α、ＬＩＦ、ＩＬ－６、オンコスタチンＭに対する抗体等。 (11) Drugs that have been shown to improve cachexia in animal models and clinically Progesterone derivatives (eg, megesterol acetate) [Journal of Clinical Oncology, Vol. 12, 213-225 P., 1994], metoclopramide drugs, tetrahydrocannabinol drugs (the literature is the same as above), fat metabolism improving agents (eg, eicosapentaenoic acid, etc.) [British Journal of Cancer (British Journal of Cancer) , 68, 314-318, 1993], growth hormone, IGF-1, or antibodies to TNF-α, LIF, IL-6, oncostatin M, which are factors that induce cachexia, and the like.

（１２）消炎剤
　ステロイド剤（例、デキサメサゾン等）、ヒアルロン酸ナトリウム、シクロオキシゲナーゼ阻害剤（例、インドメタシン、ケトプロフェン、ロキソプロフェン、メロキシカム、アムピロキシカム、セレコキシブ、ロフェコキシブ等）等。 (12) Anti-inflammatory agents Steroids (eg, dexamethasone, etc.), sodium hyaluronate, cyclooxygenase inhibitors (eg, indomethacin, ketoprofen, loxoprofen, meloxicam, ampiroxicam, celecoxib, rofecoxib, etc.) and the like.

（１３）その他
　糖化阻害剤（例、ＡＬＴ－７１１等）、神経再生促進薬（例、Ｙ－１２８、ＶＸ８５３、ｐｒｏｓａｐｔｉｄｅ等）、中枢神経系作用薬（例、デシプラミン、アミトリプチリン、イミプラミン、フロキセチン、パロキセチン、ドキセピンなどの抗うつ薬）、抗てんかん薬（例、ラモトリジン、カルバマゼピン）、抗不整脈薬（例、メキシレチン）、アセチルコリン受容体リガンド（例、ＡＢＴ－５９４）、エンドセリン受容体拮抗薬（例、ＡＢＴ－６２７）、モノアミン取り込み阻害薬（例、トラマドル）、インドールアミン取り込み阻害薬（例、フロキセチン、パロキセチン）、麻薬性鎮痛薬（例、モルヒネ）、ＧＡＢＡ受容体作動薬（例、ギャバペンチン）、ＧＡＢＡ取り込み阻害薬（例、チアガビン）、α２受容体作動薬（例、クロニジン）、局所鎮痛薬（例、カプサイシン）、プロテインキナーゼＣ阻害剤（例、ＬＹ－３３３５３１）、抗不安薬（例、ベンゾジアゼピン類）、ホスホジエステラーゼ阻害薬（例、シルデナフィル）、ドーパミン受容体作動薬（例、アポモルフィン）、ドーパミン受容体拮抗薬（例、ハロペリドール）、セロトニン受容体作動薬（例、クエン酸タンドスピロン、スマトリプタン）、セロトニン受容体拮抗薬（例、塩酸シプロヘプタジン、オンダンセトロン）、セロトニン取り込み阻害薬（例、マレイン酸フルボキサミン、フロキセチン、パロキセチン）、睡眠導入剤（例、トリアゾラム、ゾルピデム）、抗コリン剤、α１受容体遮断薬（例、タムスロシン、シロドシン、ナフトピジル）、筋弛緩薬（例、バクロフェン）、カリウムチャンネル開口薬（例、ニコランジル）、カルシウムチャンネル遮断薬（例、ニフェジピン）、アルツハイマー病予防・治療薬（例、ドネペジル、リバスチグミン、ガランタミン）、パーキンソン病治療薬（例、Ｌ－ドーパ）、多発性硬化症予防・治療薬（例、インターフェロンβ－１ａ）、ヒスタミンＨ１受容体阻害薬（例、塩酸プロメタジン）、プロトンポンプ阻害薬（例、ランソプラゾール、オメプラゾール）、抗血栓薬（例、アスピリン、シロスタゾール）、ＮＫ－２受容体アンタゴニスト、ＨＩＶ感染症治療薬（サキナビル、ジドブジン、ラミブジン、ネビラピン）、慢性閉塞性肺疾患治療薬（サルメテロール、チオトロピウムブロミド、シロミラスト）等。 (13) Others Glycation inhibitors (eg, ALT-711, etc.), nerve regeneration promoters (eg, Y-128, VX853, prostide, etc.), central nervous system agonists (eg, desipramine, amitriptyline, imipramine, floxetine, paroxetine) , Antidepressants such as doxepin), antiepileptic drugs (eg, lamotrigine, carbamazepine), antiarrhythmic drugs (eg, mexiletine), acetylcholine receptor ligands (eg, ABT-594), endothelin receptor antagonists (eg, ABT) -627), monoamine uptake inhibitors (eg, tramadol), indoleamine uptake inhibitors (eg, floxetine, paroxetine), narcotic analgesics (eg, morphine), GABA receptor agonists (eg, gabapentin), GABA uptake Inhibitors (eg, tiagabin), alpha 2 receptor activation Drugs (eg, clonidine), local analgesics (eg, capsaicin), protein kinase C inhibitors (eg, LY-333531), anxiolytics (eg, benzodiazepines), phosphodiesterase inhibitors (eg, sildenafil), dopamine receptors Body agonists (eg, apomorphine), dopamine receptor antagonists (eg, haloperidol), serotonin receptor agonists (eg, tandospirone citrate, sumatriptan), serotonin receptor antagonists (eg, cyproheptadine hydrochloride, ondansetron) ), Serotonin uptake inhibitors (eg, fluvoxamine maleate, floxetine, paroxetine), sleep inducers (eg, triazolam, zolpidem), anticholinergic agents, α 1 receptor blockers (eg, tamsulosin, silodosin, naphthopidil), muscle Relaxants (eg, baclofen), potash Muchannel openers (eg, nicorandil), calcium channel blockers (eg, nifedipine), Alzheimer's disease prevention and treatment (eg, donepezil, rivastigmine, galantamine), Parkinson's disease (eg, L-dopa), multiple Drugs for preventing or treating sclerosis (eg, interferon β-1a), histamine H 1 receptor inhibitors (eg, promethazine hydrochloride), proton pump inhibitors (eg, lansoprazole, omeprazole), antithrombotic agents (eg, aspirin, cilostazol) ), NK-2 receptor antagonists, HIV infection therapeutic agents (saquinavir, zidovudine, lamivudine, nevirapine), chronic obstructive pulmonary disease therapeutic agents (salmeterol, tiotropium bromide, silomilast) and the like.

　抗コリン剤としては、例えば、アトロピン、スコポラミン、ホマトロピン、トロピカミド、シクロペントラート、臭化ブチルスコポラミン、臭化プロパンテリン、臭化メチルベナクチジウム、臭化メペンゾラート、フラボキサート、ピレンゼピン、臭化イプラトピウム、トリヘキシフェニジル、オキシブチニン、プロピベリン、ダリフェナシン、トルテロジン、テミベリン、塩化トロスピウム又はその塩（例、硫酸アトロピン、臭化水素酸スコポラミン、臭化水素酸ホマトロピン、塩酸シクロペントラート、塩酸フラボキサート、塩酸ピレンゼピン、塩酸トリヘキシフェニジル、塩酸オキシブチニン、酒石酸トルテロジン等）等が用いられ、なかでも、オキシブチニン、プロピベリン、ダリフェナシン、トルテロジン、テミベリン、塩化トロスピウム又はその塩（例、塩酸オキシブチニン、酒石酸トルテロジン等）が好適である。また、アセチルコリンエステラーゼ阻害薬（例、ジスチグミン等）なども使用することができる。 Examples of the anticholinergic agent include atropine, scopolamine, homatropine, tropicamide, cyclopentrate, butylscopolamine bromide, propantheline bromide, methylbenactidium bromide, mepenzolate bromide, flavoxate, pirenzepine, ipratopium bromide, trihepium Xyphenidyl, oxybutynin, propiverine, darifenacin, tolterodine, temiverine, trospium chloride or its salts (eg, atropine sulfate, scopolamine hydrobromide, homatropine hydrobromide, cyclopentrate hydrochloride, flavoxate hydrochloride, pirenzepine hydrochloride, trihepine Xyphenidyl, oxybutynin hydrochloride, tolterodine tartrate, etc.) are used. Among them, oxybutynin, propiverine, darifenacin, tolterodine, temiverine, Supiumu or a salt thereof (e.g., oxybutynin hydrochloride, etc. tolterodine tartrate) are preferred. In addition, acetylcholinesterase inhibitors (eg, distigmine and the like) can also be used.

　ＮＫ－２受容体アンタゴニストとしては、例えば、ＧＲ１５９８９７、ＧＲ１４９８６１、ＳＲ４８９６８（ｓａｒｅｄｕｔａｎｔ）、ＳＲ１４４１９０、ＹＭ３５３７５、ＹＭ３８３３６、ＺＤ７９４４、Ｌ－７４３９８６、ＭＤＬ１０５２１２Ａ、ＺＤ６０２１、ＭＤＬ１０５１７２Ａ、ＳＣＨ２０５５２８、ＳＣＨ６２３７３、Ｒ－１１３２８１などのピペリジン誘導体、ＲＰＲ－１０６１４５などのペルヒドロイソインドール誘導体、ＳＢ－４１４２４０などのキノリン誘導体、ＺＭ－２５３２７０などのピロロピリミジン誘導体、ＭＥＮ１１４２０（ｎｅｐａｄｕｔａｎｔ）、ＳＣＨ２１７０４８、Ｌ－６５９８７７、ＰＤ－１４７７１４（ＣＡＭ－２２９１）、ＭＥＮ１０３７６、Ｓ１６４７４などのプソイドペプチド誘導体、その他、ＧＲ１００６７９、ＤＮＫ３３３、ＧＲ９４８００、ＵＫ－２２４６７１、ＭＥＮ１０３７６、ＭＥＮ１０６２７、又はそれらの塩などが挙げられる。 Examples of NK-2 receptor antagonists include GR159897, GR1499861, SR48968 (saredutant), SR144190, YM35375, YM38336, ZD7944, L-743986, MDL105212A, ZD6021, MDL105172A, SCH205528, pelysin RIS62373, R132 Perhydroisoindole derivatives such as RPR-106145, quinoline derivatives such as SB-414240, pyrrolopyrimidine derivatives such as ZM-253270, MEN11420 (nepadutant), SCH217048, L-659877, PD-147714 (CAM-2291), MEN10376, Pseudopeptide derivatives such as S16474 Other, GR100679, DNK333, GR94800, UK-224671, MEN10376, MEN10627, or the like salts thereof.

　併用に際しては、化合物（Ｉ’）と併用薬物の投与時期は限定されず、化合物（Ｉ’）またはその医薬組成物と併用薬物またはその医薬組成物とを、投与対象に対し、同時に投与してもよいし、時間差をおいて投与してもよい。併用薬物の投与量は、臨床上用いられている投与量に準ずればよく、投与対象、投与ルート、疾患、組み合わせ等により適宜選択することができる。 In the combined use, the administration time of the compound (I ′) and the concomitant drug is not limited, and the compound (I ′) or a pharmaceutical composition thereof and the concomitant drug or the pharmaceutical composition thereof are administered simultaneously to the administration subject. Alternatively, administration may be performed with a time difference. The dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.

　併用の投与形態は、特に限定されず、投与時に、化合物（Ｉ’）と併用薬物とが組み合わされていればよい。このような投与形態としては、例えば、
（１）化合物（Ｉ’）またはその医薬組成物と併用薬物とを同時に製剤化して得られる単一の製剤の投与、
（２）化合物（Ｉ’）またはその医薬組成物と併用薬物またはその医薬組成物とを別々に製剤化して得られる２種の製剤の同一投与経路での同時投与、
（３）化合物（Ｉ’）またはその医薬組成物と併用薬物またはその医薬組成物とを別々に製剤化して得られる２種の製剤の同一投与経路での時間差をおいての投与、
（４）化合物（Ｉ’）またはその医薬組成物と併用薬物またはその医薬組成物とを別々に製剤化して得られる２種の製剤の異なる投与経路での同時投与、
（５）化合物（Ｉ’）またはその医薬組成物と併用薬物またはその医薬組成物とを別々に製剤化して得られる２種の製剤の異なる投与経路での時間差をおいての投与（例えば、化合物（Ｉ’）またはその医薬組成物；併用薬物またはその医薬組成物の順序での投与、あるいは逆の順序での投与）などが挙げられる。 The administration form of the combination is not particularly limited as long as compound (I ′) and the concomitant drug are combined at the time of administration. Examples of such dosage forms include:
(1) Administration of a single preparation obtained by simultaneously compounding compound (I ′) or a pharmaceutical composition thereof and a concomitant drug,
(2) Simultaneous administration by the same route of administration of two types of preparations obtained by separately formulating Compound (I ′) or a pharmaceutical composition thereof and a concomitant drug or a pharmaceutical composition thereof,
(3) Administration of two types of preparations obtained by separately formulating compound (I ′) or a pharmaceutical composition thereof and a concomitant drug or a pharmaceutical composition thereof at the same administration route with a time difference;
(4) Simultaneous administration by different administration routes of two types of preparations obtained by separately formulating Compound (I ′) or a pharmaceutical composition thereof and a concomitant drug or a pharmaceutical composition thereof,
(5) Administration of two types of preparations obtained by separately formulating Compound (I ′) or a pharmaceutical composition thereof and a concomitant drug or a pharmaceutical composition thereof at different administration routes (for example, Compound (I ′) or a pharmaceutical composition thereof; administration of a concomitant drug or a pharmaceutical composition thereof in the order, or administration in the reverse order).

　本発明の併用剤における化合物（Ｉ’）と併用薬物との配合比は、投与対象、投与ルート、疾患等により適宜選択することができる。
　例えば、本発明の併用剤における化合物（Ｉ’）の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約０．０１ないし１００重量％、好ましくは約０．１ないし５０重量％、さらに好ましくは約０．５ないし２０重量％程度である。 The compounding ratio of the compound (I ′) and the concomitant drug in the combination agent of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
For example, the content of compound (I ′) in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight based on the whole preparation. %, More preferably about 0.5 to 20% by weight.

　本発明の併用剤における併用薬物の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約０．０１ないし１００重量％、好ましくは約０．１ないし５０重量％、さらに好ましくは約０．５ないし２０重量％程度である。
　本発明の併用剤における担体等の添加剤の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約１ないし９９．９９重量％、好ましくは約１０ないし９０重量％程度である。
　また、化合物（Ｉ’）および併用薬物をそれぞれ別々に製剤化する場合も同様の含有量でよい。 The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about the whole preparation About 0.5 to 20% by weight.
The content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. .
The same content may be used when compound (I ′) and the concomitant drug are formulated separately.

　投与量は化合物（Ｉ’）の種類、投与ルート、症状、患者の年令などによっても異なるが、例えば、うつ病、不安症、注意欠陥・多動性障害または腹圧性尿失禁の成人患者に経口的に投与する場合、１日当たり体重１ｋｇあたり化合物（Ｉ）として約０．００５～５０ｍｇ、好ましくは約０．０５～１０ｍｇ、さらに好ましくは約０．２～４ｍｇを１～３回程度に分割投与できる。 The dose varies depending on the type of compound (I ′), administration route, symptoms, patient age, etc., but for example, for adult patients with depression, anxiety, attention deficit / hyperactivity disorder or stress urinary incontinence When orally administered, about 0.005 to 50 mg, preferably about 0.05 to 10 mg, more preferably about 0.2 to 4 mg as compound (I) per kg body weight per day is divided into 1 to 3 times. Can be administered.

　本発明の医薬組成物が徐放性製剤である場合の投与量は、化合物（Ｉ’）の種類と含量、剤形、薬物放出の持続時間、投与対象動物（例、ヒト、ラット、マウス、ネコ、イヌ、ウサギ、ウシ、ブタ等の哺乳動物）、投与目的により種々異なるが、例えば非経口投与により適用する場合には、１週間に約０．１～約１００ｍｇの化合物（Ｉ’）が投与製剤から放出されるようにすればよい。
　併用薬物は、副作用が問題とならない範囲でどのような量を設定することも可能である。併用薬物としての一日投与量は、症状の程度、投与対象の年齢、性別、体重、感受性差、投与の時期、間隔、医薬製剤の性質、調剤、種類、有効成分の種類などによって異なり、特に限定されないが、薬物の量として通常、たとえば経口投与で哺乳動物１ｋｇ体重あたり約０．００１～２０００ｍｇ、好ましくは約０．０１～５００ｍｇ、さらに好ましくは、約０．１～１００ｍｇ程度であり、これを通常１日１～４回に分けて投与する。 When the pharmaceutical composition of the present invention is a sustained-release preparation, the dosage is the type and content of compound (I ′), dosage form, duration of drug release, animal to be administered (eg, human, rat, mouse, Mammals such as cats, dogs, rabbits, cows, pigs, etc.), which vary depending on the purpose of administration. For example, when applied by parenteral administration, about 0.1 to about 100 mg of compound (I ′) is administered per week. It may be released from the dosage form.
The amount of the concomitant drug can be set as long as side effects do not become a problem. The daily dose as a concomitant drug varies depending on the degree of symptoms, age of the subject, sex, body weight, sensitivity difference, timing of administration, interval, nature of the pharmaceutical preparation, formulation, type, type of active ingredient, etc. Although not limited, the amount of the drug is usually about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg per kg body weight of the mammal by oral administration. Is usually administered in 1 to 4 divided doses per day.

　本発明の併用剤を投与するに際しては、同時期に投与してもよいが、併用薬物を先に投与した後、化合物（Ｉ’）を投与してもよいし、化合物（Ｉ’）を先に投与し、その後で併用薬物を投与してもよい。時間差をおいて投与する場合、時間差は投与する有効成分、剤形、投与方法により異なるが、例えば、併用薬物を先に投与する場合、併用薬物を投与した後１分～３日以内、好ましくは１０分～１日以内、より好ましくは１５分～１時間以内に化合物（Ｉ’）を投与する方法が挙げられる。化合物（Ｉ’）を先に投与する場合、化合物（Ｉ’）を投与した後、１分～１日以内、好ましくは１０分～６時間以内、より好ましくは１５分から１時間以内に併用薬物を投与する方法が挙げられる。 When administering the concomitant drug of the present invention, it may be administered at the same time, but after administering the concomitant drug first, compound (I ′) may be administered, or compound (I ′) may be administered first. The concomitant drug may be administered thereafter. When administered at a time difference, the time difference varies depending on the active ingredient, dosage form, and administration method to be administered. For example, when administering the concomitant drug first, within 1 minute to 3 days after administering the concomitant drug, preferably The method includes administering Compound (I ′) within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When compound (I ′) is administered first, the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after administration of compound (I ′). The method of administration is mentioned.

　本発明の医薬組成物は低毒性で安全に使用することができる。特に以下に示す実施例化合物は、経口投与されたときの吸収性において優れており、経口用製剤のために有利に使用できる。また光毒性を示さない点においても優れている。 The pharmaceutical composition of the present invention has low toxicity and can be used safely. In particular, the Example compounds shown below are excellent in absorbability when administered orally and can be advantageously used for oral preparations. It is also excellent in that it does not show phototoxicity.

　以下に、参考例、実施例、製剤例および試験例に基づいて本発明をより詳細に説明するが、本発明は実施例により限定されるものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。なお、実施例中、ラセミ体の立体化学は、ＩＵＰＡＣ命名法のＲ＊－Ｓ＊表記で示した。 Hereinafter, the present invention will be described in more detail based on Reference Examples, Examples, Formulation Examples, and Test Examples, but the present invention is not limited to the Examples and is within a range not departing from the scope of the present invention. It may be changed. In the examples, the stereochemistry of the racemate is indicated by the R * -S * notation in the IUPAC nomenclature.

　実施例、参考例中の記号は次のような意味である。
　ＮＭＲ　　　：核磁気共鳴スペクトル
　ｓ　　　　　：シングレット（ｓｉｎｇｌｅｔ）
　ｄ　　　　　：ダブレット（ｄｏｕｂｌｅｔ）
　ｄｄｄ　　　：ダブルダブルダブレット（ｄｏｕｂｌｅ　ｄｏｕｂｌｅ　ｄｏｕｂｌｅｔ）
　ｄｔ　　　　：ダブルトリプレット（ｄｏｕｂｌｅ　ｔｒｉｐｌｅｔ）
　ｄq　　　 　：ダブルクワルテット（ｄｏｕｂｌｅ　ｑｕａｒｔｅｔ）
　ｔ　　　　　：トリプレット（ｔｒｉｐｌｅｔ）
　ｑ　　　　　：クワルテット（ｑｕａｒｔｅｔ）
　ｑｕｉｎ　　：クインテット（ｑｕｉｎｔｅｔ）
　ｄｄ　　　　：ダブル　ダブレット（ｄｏｕｂｌｅ　ｄｏｕｂｌｅｔ）
　ｍ　　　　　：マルチプレット（ｍｕｌｔｉｐｌｅｔ）
　ｂｒ　　　　：ブロード（ｂｒｏａｄ）
　ｂｒｓ　　　：ブロード　シングレット（ｂｒｏａｄ　ｓｉｎｇｌｅｔ）
　Ｊ　　　　　：カップリング定数（ｃｏｕｐｌｉｎｇ　ｃｏｎｓｔａｎｔ）
　ＴＨＦ　　　：テトラヒドロフラン
　ＭｅＯＨ　　：メタノール
　ＤＭＦ　　　：Ｎ，Ｎ－ジメチルホルムアミド
　ＤＭＳＯ　　：ジメチルスルホキシド
　ＬＣ／ＭＳ　：液体クロマトグラフィー－質量分析スペクトル
　ＥＳＩ　　　：エレクトロスプレーイオン化法
　［Ｍ＋Ｈ］＋：分子イオンピーク（本明細書中のＬＣ／ＭＳ測定値は、特記なき限り、［Ｍ＋Ｈ］＋を示す）
　Ｍｅ　　　　：メチル
　Ｅｔ　　　　：エチル
　Ａｃ　　　　：アセチル
　Ｂｏｃ　　　：ｔｅｒｔ－ブトキシカルボニル
　ＴＦＡ　　　：トリフルオロ酢酸
　ＬＡＨ　　　：水素化アルミニウムリチウム
　ＨＯＢｔ　　：１－ヒドロキシベンゾトリアゾール
　ＷＳＣ　　　：１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド　塩酸塩
　ＤＭＴ－ＭＭ：４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウム　クロリド
　Ｍ　　　　　：モル濃度
　Ｎ　　　　　：規定濃度
　ＨＰＬＣ　　：高速液体クロマトグラフィー
　ＵＶ　　　　：紫外線
　ｍｐ　　　　：融点 Symbols in Examples and Reference Examples have the following meanings.
NMR: nuclear magnetic resonance spectrum s: singlet
d: doublet
ddd: double double doublet (double double doublet)
dt: Double triplet (double triplet)
dq: double quartet
t: triplet
q: quartet
quint: quintet
dd: double doublet (double doublet)
m: multiplet
br: broad
brs: broad singlet
J: Coupling constant
THF: Tetrahydrofuran MeOH: Methanol DMF: N, N-Dimethylformamide DMSO: Dimethyl sulfoxide LC / MS: Liquid chromatography-mass spectrometry spectrum ESI: Electrospray ionization method [M + H] + : Molecular ion peak (LC in this specification) / MS measurements show [M + H] + unless otherwise specified)
Me: methyl Et: ethyl Ac: acetyl Boc: tert-butoxycarbonyl TFA: trifluoroacetic acid LAH: lithium aluminum hydride HOBt: 1-hydroxybenzotriazole WSC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloric acid Salt DMT-MM: 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride M: Molar concentration N: Normal concentration HPLC: High performance liquid chromatography UV: UV mp: melting point

参考例１
メチル (3R*,4S*)-3-(3,4-ジクロロフェニル)-4-ニトロヘキサノアート Reference example 1
Methyl (3R * , 4S * )-3- (3,4-dichlorophenyl) -4-nitrohexanoate

Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028

1-a) メチル (2E)-3-(3,4-ジクロロフェニル)プロパ-2-エノアート 1-a) Methyl (2E) -3- (3,4-dichlorophenyl) prop-2-enoate

Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029

　(2E)-3-(3,4-ジクロロフェニル)プロパ-2-エン酸(15.0 g, 69 mmol)のメタノール(150 mL)溶液に、塩化チオニル(5.6 mL, 76 mmol)を0℃で滴下した後、反応混合物を室温で終夜攪拌した。減圧下溶媒を留去し、残渣を酢酸エチル(500 mL)に溶解させ、飽和炭酸水素ナトリウム水溶液で洗浄した。水層を再度酢酸エチル(300 mL)で抽出した。得られた抽出液を合わせた後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去し、表題化合物を無色結晶(15.7 g, 98%)として得た。
NMR (CDCl3) δ: 3.81 (3H, s), 6.41 (1H, d, J = 16.2 Hz), 7.33 (1H, dd, J = 8.5, 1.6 Hz), 7.45 (1H, d, J = 8.5 Hz), 7.54-7.60 (2H, m). To a solution of (2E) -3- (3,4-dichlorophenyl) prop-2-enoic acid (15.0 g, 69 mmol) in methanol (150 mL), thionyl chloride (5.6 mL, 76 mmol) was added dropwise at 0 ° C. After that, the reaction mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate (500 mL) and washed with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted again with ethyl acetate (300 mL). The obtained extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as colorless crystals (15.7 g, 98%).
NMR (CDCl 3 ) δ: 3.81 (3H, s), 6.41 (1H, d, J = 16.2 Hz), 7.33 (1H, dd, J = 8.5, 1.6 Hz), 7.45 (1H, d, J = 8.5 Hz) ), 7.54-7.60 (2H, m).

1-b) メチル (3R*,4S*)-3-(3,4-ジクロロフェニル)-4-ニトロヘキサノアート 1-b) Methyl (3R * , 4S * )-3- (3,4-dichlorophenyl) -4-nitrohexanoate

Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030

メチル (3R*,4R*)-3-(3,4-ジクロロフェニル)-4-ニトロヘキサノアート Methyl (3R * , 4R * )-3- (3,4-dichlorophenyl) -4-nitrohexanoate

Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031

　メチル(2E)-3-(3,4-ジクロロフェニル)プロパ-2-エノアート(1.0 g, 4.3 mmol)のアセトニトリル(15 mL)溶液に1-ニトロプロパン(1.2 mL, 13 mmol)と1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン(0.71 mL, 4.8 mmol)を加え、室温で3時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和塩化アンモニウム水溶液で洗浄した。得られた有機層を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（3-20% 酢酸エチル／ヘキサン）で精製することによりメチル (3R*,4S*)-3-(3,4-ジクロロフェニル)-4-ニトロヘキサノアート(0.55 g, 40%, Rf = 0.15)を白色固体として、メチル (3R*,4R*)-3-(3,4-ジクロロフェニル)-4-ニトロヘキサノアート(0.61 g, 44%, Rf = 0.30)を無色油状物として得た。
メチル (3R*,4S*)-3-(3,4-ジクロロフェニル)-4-ニトロヘキサノアート 
NMR (CDCl3) δ: 0.99 (3H, t, J = 7.3Hz), 1.78-2.05 (2H, m), 2.68 (1H, dd, J = 16.4, 9.0Hz), 2.84 (1H, dd, J = 16.4, 5.7Hz), 3.62 (3H, s), 3.63-3.69 (1H, m), 4.65-4.75 (1H, m), 7.02 (1H, dd, J = 8.3, 2.1Hz), 7.28 (1H, d, J = 2.1Hz), 7.38 (1H, d, J = 8.3Hz).
メチル (3R*,4R*)-3-(3,4-ジクロロフェニル)-4-ニトロヘキサノアート
NMR (CDCl3) δ: 0.88 (3H, t, J = 7.3 Hz), 1.42-1.56 (1H, m), 1.75-1.91 (1H, m), 2.59-2.78 (2H, m), 3.56 (3H, s), 3.62 (1H, td, J = 10.4, 4.5 Hz), 4.56 (1H, td, J = 10.4, 3.1 Hz), 7.06 (1H, dd, J = 8.3, 2.1 Hz), 7.31 (1H, d, J = 2.1 Hz), 7.43 (1H, d, J = 8.3 Hz). To a solution of methyl (2E) -3- (3,4-dichlorophenyl) prop-2-enoate (1.0 g, 4.3 mmol) in acetonitrile (15 mL) and 1-nitropropane (1.2 mL, 13 mmol) and 1,8- Diazabicyclo [5.4.0] undec-7-ene (0.71 mL, 4.8 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (3-20% ethyl acetate / hexane) to give methyl (3R * , 4S * )-3- (3,4-dichlorophenyl) -4-nitrohexanoate ( 0.55 g, 40%, Rf = 0.15) as a white solid, methyl (3R * , 4R * )-3- (3,4-dichlorophenyl) -4-nitrohexanoate (0.61 g, 44%, Rf = 0.30) ) Was obtained as a colorless oil.
Methyl (3R * , 4S * )-3- (3,4-dichlorophenyl) -4-nitrohexanoate
NMR (CDCl 3 ) δ: 0.99 (3H, t, J = 7.3Hz), 1.78-2.05 (2H, m), 2.68 (1H, dd, J = 16.4, 9.0Hz), 2.84 (1H, dd, J = 16.4, 5.7Hz), 3.62 (3H, s), 3.63-3.69 (1H, m), 4.65-4.75 (1H, m), 7.02 (1H, dd, J = 8.3, 2.1Hz), 7.28 (1H, d , J = 2.1Hz), 7.38 (1H, d, J = 8.3Hz).
Methyl (3R * , 4R * )-3- (3,4-dichlorophenyl) -4-nitrohexanoate
NMR (CDCl 3 ) δ: 0.88 (3H, t, J = 7.3 Hz), 1.42-1.56 (1H, m), 1.75-1.91 (1H, m), 2.59-2.78 (2H, m), 3.56 (3H, s), 3.62 (1H, td, J = 10.4, 4.5 Hz), 4.56 (1H, td, J = 10.4, 3.1 Hz), 7.06 (1H, dd, J = 8.3, 2.1 Hz), 7.31 (1H, d , J = 2.1 Hz), 7.43 (1H, d, J = 8.3 Hz).

参考例２
tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-エチルピロリジン-1-カルボキシラート Reference example 2
tert-butyl (2R * , 3R * ) -3- (3,4-dichlorophenyl) -2-ethylpyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032

　メチル (3R*,4R*)-3-(3,4-ジクロロフェニル)-4-ニトロヘキサノアート(2.1 g, 6.4 mmol)の酢酸(25 mL)溶液に、亜鉛粉末(2.1 g, 32 mmol)を加え、還流下5時間加熱した。反応混合物を酢酸エチルで希釈し、これをセライト濾過し、濾液を減圧濃縮した。残渣をトルエンで希釈し、再度減圧下濃縮した。
　得られた残渣をTHF(30 mL)に溶解させ、1 MボランTHF錯体THF溶液(16 mL)を加え、加熱還流下5時間攪拌した。反応混合物に6 N塩酸(16 mL)を加え、１時間加熱還流した後、8 N水酸化ナトリウム水溶液を用いて塩基性にした。水層が飽和になるまで塩化ナトリムを加えた後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。
　得られた残渣をTHF(30 mL)に溶解させ、ジ-tert-ブチル ジカルボナート(1.5 mL, 6.4 mmol)を加え、室温で終夜攪拌した。反応混合物を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（1-15% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.65 g, 29%)として得た。
NMR (CDCl3) δ: 0.88 (3H, t, J = 7.4 Hz), 1.48 (9H, s), 1.58-1.70 (2H, m), 1.77-1.90 (1H, m), 2.18-2.31 (1H, m), 3.02-3.10 (1H, m), 3.30-3.40 (1H, m), 3.56-3.84 (2H, m), 7.01 (1H, dd, J = 8.3, 2.1 Hz), 7.27 (1H, d, J = 2.1 Hz), 7.37 (1H, d, J = 8.3 Hz). To a solution of methyl (3R * , 4R * )-3- (3,4-dichlorophenyl) -4-nitrohexanoate (2.1 g, 6.4 mmol) in acetic acid (25 mL), zinc powder (2.1 g, 32 mmol) And heated under reflux for 5 hours. The reaction mixture was diluted with ethyl acetate, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was diluted with toluene and concentrated again under reduced pressure.
The obtained residue was dissolved in THF (30 mL), 1 M borane THF complex THF solution (16 mL) was added, and the mixture was stirred with heating under reflux for 5 hr. 6 N hydrochloric acid (16 mL) was added to the reaction mixture, and the mixture was heated to reflux for 1 hour, and then made basic with an 8 N aqueous sodium hydroxide solution. Sodium chloride was added until the aqueous layer became saturated, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was dissolved in THF (30 mL), di-tert-butyl dicarbonate (1.5 mL, 6.4 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (1-15% ethyl acetate / hexane) to give the title compound as a colorless oil (0.65 g, 29%).
NMR (CDCl 3 ) δ: 0.88 (3H, t, J = 7.4 Hz), 1.48 (9H, s), 1.58-1.70 (2H, m), 1.77-1.90 (1H, m), 2.18-2.31 (1H, m), 3.02-3.10 (1H, m), 3.30-3.40 (1H, m), 3.56-3.84 (2H, m), 7.01 (1H, dd, J = 8.3, 2.1 Hz), 7.27 (1H, d, J = 2.1 Hz), 7.37 (1H, d, J = 8.3 Hz).

参考例３
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-メチルプロピル)ピロリジン-1-カルボキシラート Reference example 3
tert-Butyl (2S * , 3R * )-3- (3,4-Dichlorophenyl) -2- (2-methylpropyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033

3-a) メチル (3R*,4S*)-3-(3,4-ジクロロフェニル)-6-メチル-4-ニトロヘプタノアート 3-a) Methyl (3R * , 4S * )-3- (3,4-dichlorophenyl) -6-methyl-4-nitroheptanoate

Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034

メチル (3R*,4R*)-3-(3,4-ジクロロフェニル)-6-メチル-4-ニトロヘプタノアート Methyl (3R * , 4R * )-3- (3,4-dichlorophenyl) -6-methyl-4-nitroheptanoate

Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035

　メチル(2E)-3-(3,4-ジクロロフェニル)プロパ-2-エノアート(1.5 g, 6.5 mmol)のアセトニトリル(20 mL)溶液に3-メチル-1-ニトロブタン(1.9 mL, 16 mmol, J. Am. Chem. Soc., 1956, 78, 1497)と1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン(1.1 mL, 1.1 mmol)を加え、室温で終夜攪拌した。反応混合物を減圧下濃縮し、酢酸エチルで希釈し、飽和塩化アンモニウム水溶液で洗浄した。得られた有機層を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。
　得られた残渣をシリカゲルカラムクロマトグラフィー（1-10% 酢酸エチル／ヘキサン）で精製することによりメチル (3R*,4S*)-3-(3,4-ジクロロフェニル)-6-メチル-4-ニトロヘプタノアート(0.94 g, 42%, Rf = 0.25)を白色固体として、メチル (3R*,4R*)-3-(3,4-ジクロロフェニル)-6-メチル-4-ニトロヘプタノアート(1.2 g, 51%, Rf = 0.35)を無色油状物として得た。
メチル (3R*,4S*)-3-(3,4-ジクロロフェニル)-6-メチル-4-ニトロヘプタノアート
NMR (CDCl3) δ: 0.92-0.98 (6H, m), 1.42-1.54 (2H, m), 1.94-2.04 (1H, m), 2.68 (1H, dd, J = 16.4, 8.9 Hz), 2.84 (1H, dd, J = 16.4, 5.7 Hz), 3.55-3.64 (4H, m), 4.82-4.90 (1H, m), 7.02 (1H, dd, J = 8.3, 2.1 Hz), 7.27 (1H, d, J = 2.1 Hz), 7.38 (1H, d, J = 8.3 Hz).
メチル (3R*,4R*)-3-(3,4-ジクロロフェニル)-6-メチル-4-ニトロヘプタノアート
NMR (CDCl3) δ: 0.84 (6H, d, J = 6.6 Hz), 1.04-1.14 (1H, m), 1.39-1.53 (1H, m), 1.86-1.97 (1H, m), 2.58-2.77 (2H, m), 3.54-3.66 (4H, m), 4.70-4.79 (1H, m), 7.05 (1H, dd, J = 8.3, 2.3 Hz), 7.30 (1H, d, J = 2.3 Hz), 7.43 (1H, d, J = 8.3 Hz). To a solution of methyl (2E) -3- (3,4-dichlorophenyl) prop-2-enoate (1.5 g, 6.5 mmol) in acetonitrile (20 mL) was added 3-methyl-1-nitrobutane (1.9 mL, 16 mmol, J. Am. Chem. Soc., 1956, 78, 1497) and 1,8-diazabicyclo [5.4.0] undec-7-ene (1.1 mL, 1.1 mmol) were added and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed with saturated aqueous ammonium chloride. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel column chromatography (1-10% ethyl acetate / hexane) to give methyl (3R * , 4S * )-3- (3,4-dichlorophenyl) -6-methyl-4-nitro Heptanoate (0.94 g, 42%, Rf = 0.25) as a white solid, methyl (3R * , 4R * )-3- (3,4-dichlorophenyl) -6-methyl-4-nitroheptanoate (1.2 g, 51%, Rf = 0.35) was obtained as a colorless oil.
Methyl (3R * , 4S * )-3- (3,4-dichlorophenyl) -6-methyl-4-nitroheptanoate
NMR (CDCl 3 ) δ: 0.92-0.98 (6H, m), 1.42-1.54 (2H, m), 1.94-2.04 (1H, m), 2.68 (1H, dd, J = 16.4, 8.9 Hz), 2.84 ( 1H, dd, J = 16.4, 5.7 Hz), 3.55-3.64 (4H, m), 4.82-4.90 (1H, m), 7.02 (1H, dd, J = 8.3, 2.1 Hz), 7.27 (1H, d, J = 2.1 Hz), 7.38 (1H, d, J = 8.3 Hz).
Methyl (3R * , 4R * )-3- (3,4-dichlorophenyl) -6-methyl-4-nitroheptanoate
NMR (CDCl 3 ) δ: 0.84 (6H, d, J = 6.6 Hz), 1.04-1.14 (1H, m), 1.39-1.53 (1H, m), 1.86-1.97 (1H, m), 2.58-2.77 ( 2H, m), 3.54-3.66 (4H, m), 4.70-4.79 (1H, m), 7.05 (1H, dd, J = 8.3, 2.3 Hz), 7.30 (1H, d, J = 2.3 Hz), 7.43 (1H, d, J = 8.3 Hz).

3-b) tert-ブチル(2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-メチルプロピル)ピロリジン-1-カルボキシラート 3-b) tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (2-methylpropyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036

　メチル (3R*,4S*)-3-(3,4-ジクロロフェニル)-6-メチル-4-ニトロヘプタノアート(0.94 g, 2.7 mmol)の酢酸(15 mL)溶液に、亜鉛粉末(0.88 g, 14 mmol)を加え、還流下5時間加熱した。反応混合物に亜鉛粉末(3.1 g, 47 mmol)を追加し、還流下終夜攪拌した。反応混合物を酢酸エチルで希釈し、これをセライト濾過し、濾液を減圧濃縮した。残渣をトルエンで希釈し、再度減圧下濃縮した。
　得られた残渣をTHF(15 mL)に溶解させ、1 MボランTHF錯体THF溶液(6.8 mL)を加え、加熱還流下5時間攪拌した。反応混合物に6 N塩酸(7 mL)を加え、１時間加熱還流した後、8 N水酸化ナトリウム水溶液を用いて塩基性にした。水層が飽和になるまで塩化ナトリムを加えた後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。
　得られた残渣をTHF(20 mL)に溶解させ、ジ-tert-ブチル ジカルボナート(0.62 mL, 2.7 mmol)を加え、室温で終夜攪拌した。反応混合物を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（1-10% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.48 g, 48%)として得た。
NMR (CDCl3) δ: 0.72-0.94 (8H, m), 1.04-1.15 (1H, m), 1.49 (9H, s), 2.06-2.33 (2H, m), 3.33-3.54 (3H, m), 4.07-4.27 (1H, m), 7.06 (1H, d, J = 8.3 Hz), 7.30 (1H, s), 7.39 (1H, d, J = 8.3 Hz). To a solution of methyl (3R * , 4S * )-3- (3,4-dichlorophenyl) -6-methyl-4-nitroheptanoate (0.94 g, 2.7 mmol) in acetic acid (15 mL), add zinc powder (0.88 g 14 mmol) and heated under reflux for 5 hours. Zinc powder (3.1 g, 47 mmol) was added to the reaction mixture, and the mixture was stirred overnight under reflux. The reaction mixture was diluted with ethyl acetate, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was diluted with toluene and concentrated again under reduced pressure.
The obtained residue was dissolved in THF (15 mL), 1 M borane THF complex THF solution (6.8 mL) was added, and the mixture was stirred with heating under reflux for 5 hr. 6N Hydrochloric acid (7 mL) was added to the reaction mixture, and the mixture was heated under reflux for 1 hr, and basified with 8N aqueous sodium hydroxide solution. Sodium chloride was added until the aqueous layer became saturated, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was dissolved in THF (20 mL), di-tert-butyl dicarbonate (0.62 mL, 2.7 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (1-10% ethyl acetate / hexane) to give the title compound as a colorless oil (0.48 g, 48%).
NMR (CDCl 3 ) δ: 0.72-0.94 (8H, m), 1.04-1.15 (1H, m), 1.49 (9H, s), 2.06-2.33 (2H, m), 3.33-3.54 (3H, m), 4.07-4.27 (1H, m), 7.06 (1H, d, J = 8.3 Hz), 7.30 (1H, s), 7.39 (1H, d, J = 8.3 Hz).

参考例４
tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-メチルプロピル)ピロリジン-1-カルボキシラート Reference example 4
tert-Butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (2-methylpropyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037

　メチル (3R*,4R*)-3-(3,4-ジクロロフェニル)-6-メチル-4-ニトロヘプタノアート(1.2 g, 3.3 mmol)の酢酸(15 mL)溶液に、亜鉛粉末(1.1 g, 17 mmol)を加え、還流下5時間加熱した。反応混合物に亜鉛粉末(3.5 g, 53 mmol)を追加し、還流下終夜攪拌した。反応混合物を酢酸エチルで希釈し、これをセライト濾過し、濾液を減圧濃縮した。残渣をトルエンで希釈し、再度減圧下濃縮した。
　得られた残渣をTHF(15 mL)に溶解させ、1 MボランTHF錯体THF溶液(8.3 mL)を加え、加熱還流下5時間攪拌した。反応混合物に6 N塩酸(8 mL)を加え、１時間加熱還流した後、8 N水酸化ナトリウム水溶液を用いて塩基性にした。水層が飽和になるまで塩化ナトリムを加えた後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。
　得られた残渣をTHF(20 mL)に溶解させ、ジ-tert-ブチル ジカルボナート(0.77 mL, 3.3 mmol)を加え、室温で終夜攪拌した。反応混合物を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（1-10% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.48 g, 39%)として得た。
NMR (CDCl3) δ: 0.85 (3H, d, J = 6.4 Hz), 0.92 (3H, d, J = 6.4 Hz), 1.34 (1H, t, J = 8.7 Hz), 1.49 (9H, s), 1.51-1.62 (2H, m), 1.76-1.87 (1H, m), 2.24-2.38 (1H, m), 3.01-3.08 (1H, m), 3.37-3.58 (2H, m), 3.84-4.02 (1H, m), 6.98 (1H, d, J = 8.3 Hz), 7.24 (1H, d, J = 1.5 Hz), 7.36 (1H, d, J = 8.3 Hz). To a solution of methyl (3R * , 4R * )-3- (3,4-dichlorophenyl) -6-methyl-4-nitroheptanoate (1.2 g, 3.3 mmol) in acetic acid (15 mL) was added zinc powder (1.1 g , 17 mmol) and heated under reflux for 5 hours. Zinc powder (3.5 g, 53 mmol) was added to the reaction mixture, and the mixture was stirred overnight under reflux. The reaction mixture was diluted with ethyl acetate, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was diluted with toluene and concentrated again under reduced pressure.
The obtained residue was dissolved in THF (15 mL), 1 M borane THF complex THF solution (8.3 mL) was added, and the mixture was stirred with heating under reflux for 5 hr. 6N Hydrochloric acid (8 mL) was added to the reaction mixture, and the mixture was heated to reflux for 1 hour and basified with 8N aqueous sodium hydroxide solution. Sodium chloride was added until the aqueous layer became saturated, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was dissolved in THF (20 mL), di-tert-butyl dicarbonate (0.77 mL, 3.3 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (1-10% ethyl acetate / hexane) to give the title compound as a colorless oil (0.48 g, 39%).
NMR (CDCl 3 ) δ: 0.85 (3H, d, J = 6.4 Hz), 0.92 (3H, d, J = 6.4 Hz), 1.34 (1H, t, J = 8.7 Hz), 1.49 (9H, s), 1.51-1.62 (2H, m), 1.76-1.87 (1H, m), 2.24-2.38 (1H, m), 3.01-3.08 (1H, m), 3.37-3.58 (2H, m), 3.84-4.02 (1H , m), 6.98 (1H, d, J = 8.3 Hz), 7.24 (1H, d, J = 1.5 Hz), 7.36 (1H, d, J = 8.3 Hz).

参考例５
1-tert-ブチル 2-メチル (2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート Reference Example 5
1-tert-butyl 2-methyl (2R * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038

5-a) (2E)-3-(3,4-ジクロロフェニル)プロパ-2-エナール 5-a) (2E) -3- (3,4-dichlorophenyl) prop-2-enal

Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039

　3,4-ジクロロベンズアルデヒド(10 g, 57 mmol)をアセトアルデヒド(23 mL, 400 mmol)に溶解させた。これに水酸化カリウム(0.42 g, 6.3 mmol)のメタノール(5 mL)溶液を0℃で滴下した。反応混合物を0℃で1時間攪拌した後、無水酢酸(28 mL)を加え、還流下1時間加熱した。一度室温まで放冷した後、1 N塩酸水溶液(95 mL)を加え、還流下1時間加熱した。室温にて終夜放置し、生じた固体を濾取し、水で洗浄した。この固体を酢酸エチルに溶解させ、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルにて洗浄し、表題化合物をベージュ色の固体(8.3 g, 73%)として得た。
NMR (CDCl3) δ: 6.69 (1H, dd, J = 16.0, 7.5 Hz), 7.34-7.42 (2H, m), 7.52 (1H, d, J = 8.3 Hz), 7.65 (1H, d, J = 2.1 Hz), 9.71 (1H, d, J = 7.5 Hz). 3,4-Dichlorobenzaldehyde (10 g, 57 mmol) was dissolved in acetaldehyde (23 mL, 400 mmol). To this was added dropwise a solution of potassium hydroxide (0.42 g, 6.3 mmol) in methanol (5 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1 hr, acetic anhydride (28 mL) was added, and the mixture was heated under reflux for 1 hr. The mixture was allowed to cool to room temperature, 1N aqueous hydrochloric acid solution (95 mL) was added, and the mixture was heated under reflux for 1 hr. The mixture was left overnight at room temperature, and the resulting solid was collected by filtration and washed with water. This solid was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound as a beige solid (8.3 g, 73%).
NMR (CDCl 3 ) δ: 6.69 (1H, dd, J = 16.0, 7.5 Hz), 7.34-7.42 (2H, m), 7.52 (1H, d, J = 8.3 Hz), 7.65 (1H, d, J = 2.1 Hz), 9.71 (1H, d, J = 7.5 Hz).

5-b) ジエチル 1-アセチル-3-(3,4-ジクロロフェニル)-5-ヒドロキシピロリジン-2,2-ジカルボキシラート 5-b) Diethyl 1-acetyl-3- (3,4-dichlorophenyl) -5-hydroxypyrrolidine-2,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040

　ジエチル (アセチルアミノ)プロパンジオアート(22 g, 99 mmol)をエタノール(300 mL)に溶解させ、これにナトリウム エタノラート(1.6 g, 20 mmol)を加え、室温で5分間攪拌した。反応混合物に(2E)-3-(3,4-ジクロロフェニル)プロパ-2-エナール(20 g, 99 mmol)を加え、室温で終夜攪拌した。反応混合物に酢酸を加え、pHを4にした後、減圧下溶媒を留去した。得られた残渣をジエチルエーテルと水で洗浄した後、減圧下乾燥させることにより、表題化合物を白色結晶(39 g, 95%)として得た。
NMR (DMSO-d6) δ: 0.89 (3H, t, J = 7.1 Hz), 1.22 (3H, t, J = 7.1 Hz), 2.02 (1H, dd, J = 12.4, 6.3 Hz), 2.15 (3H, s), 2.52-2.61 (1H, m), 3.74 (2H, q, J = 7.1 Hz), 4.07-4.25 (3H, m), 5.71 (1H, t, J = 4.9 Hz), 6.27 (1H, d, J = 4.7 Hz), 7.26 (1H, dd, J = 8.3, 1.9 Hz), 7.53 (1H, d, J = 1.9 Hz), 7.58 (1H, d, J = 8.2 Hz). Diethyl (acetylamino) propanedioate (22 g, 99 mmol) was dissolved in ethanol (300 mL), sodium ethanolate (1.6 g, 20 mmol) was added thereto, and the mixture was stirred at room temperature for 5 minutes. (2E) -3- (3,4-dichlorophenyl) prop-2-enal (20 g, 99 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. Acetic acid was added to the reaction mixture to adjust the pH to 4, and then the solvent was distilled off under reduced pressure. The obtained residue was washed with diethyl ether and water, and dried under reduced pressure to give the title compound as white crystals (39 g, 95%).
NMR (DMSO-d 6 ) δ: 0.89 (3H, t, J = 7.1 Hz), 1.22 (3H, t, J = 7.1 Hz), 2.02 (1H, dd, J = 12.4, 6.3 Hz), 2.15 (3H , s), 2.52-2.61 (1H, m), 3.74 (2H, q, J = 7.1 Hz), 4.07-4.25 (3H, m), 5.71 (1H, t, J = 4.9 Hz), 6.27 (1H, d, J = 4.7 Hz), 7.26 (1H, dd, J = 8.3, 1.9 Hz), 7.53 (1H, d, J = 1.9 Hz), 7.58 (1H, d, J = 8.2 Hz).

5-c) ジエチル 1-アセチル-3-(3,4-ジクロロフェニル)ピロリジン-2,2-ジカルボキシラート 5-c) Diethyl 1-acetyl-3- (3,4-dichlorophenyl) pyrrolidine-2,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041

　ジエチル 1-アセチル-3-(3,4-ジクロロフェニル)-5-ヒドロキシピロリジン-2,2-ジカルボキシラート(31 g, 73 mmol)とトリエチルシラン(18 mL, 110 mmol)をアセトニトリル(150 mL)に溶解させ、これにトリフルオロ酢酸(57 mL, 730 mmol)を加え、室温で2時間攪拌した。反応終了後、減圧下溶媒を留去し、酢酸エチルで希釈した。得られた溶液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（50-100% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を白色固体(24 g, 82%)として得た。
NMR (DMSO-d6) δ: 0.89 (3H, t, J = 7.1 Hz), 1.21 (3H, t, J = 7.1 Hz), 2.03 (3H, s), 2.14-2.27 (1H, m), 2.35-2.47 (1H, m), 3.56-3.67 (1H, m), 3.71-3.98 (4H, m), 4.09-4.25 (2H, m), 7.20 (1H, dd, J = 8.3, 2.1 Hz), 7.45 (1H, d, J = 2.1 Hz), 7.59 (1H, d, J = 8.3 Hz). Diethyl 1-acetyl-3- (3,4-dichlorophenyl) -5-hydroxypyrrolidine-2,2-dicarboxylate (31 g, 73 mmol) and triethylsilane (18 mL, 110 mmol) in acetonitrile (150 mL) To this was added trifluoroacetic acid (57 mL, 730 mmol), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and diluted with ethyl acetate. The obtained solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (50-100% ethyl acetate / hexane) to give the title compound as a white solid (24 g, 82%).
NMR (DMSO-d 6 ) δ: 0.89 (3H, t, J = 7.1 Hz), 1.21 (3H, t, J = 7.1 Hz), 2.03 (3H, s), 2.14-2.27 (1H, m), 2.35 -2.47 (1H, m), 3.56-3.67 (1H, m), 3.71-3.98 (4H, m), 4.09-4.25 (2H, m), 7.20 (1H, dd, J = 8.3, 2.1 Hz), 7.45 (1H, d, J = 2.1 Hz), 7.59 (1H, d, J = 8.3 Hz).

5-d) 1-tert-ブチル2-メチル (2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート 5-d) 1-tert-butyl 2-methyl (2R * , 3R * ) -3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸
　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸 2,3-cis-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid 2,3-trans-1- (tert-butoxycarbonyl) -3- (3, 4-dichlorophenyl) pyrrolidine-2-carboxylic acid

Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043

　ジエチル 1-アセチル-3-(3,4-ジクロロフェニル)ピロリジン-2,2-ジカルボキシラート(50 g, 130 mmol)に酢酸(23 mL)と6 N塩酸水溶液(100 mL)を加え、還流下終夜加熱した。減圧下、溶媒を留去し、残渣を減圧下乾燥させた。 Acetic acid (23 mL) and 6 N aqueous hydrochloric acid (100 に mL) were added to diethyl 1-acetyl-3- (3,4-dichlorophenyl) pyrrolidine-2,2-dicarboxylate (50 g, 130 、 mmol) and refluxed. Heated overnight. The solvent was distilled off under reduced pressure, and the residue was dried under reduced pressure.

　得られた残渣をメタノール(200 mL)に溶解させ、塩化チオニル(12 mL, 160 mmol)を0℃で滴下した後、室温で4時間攪拌した。減圧下、溶媒を留去した。得られた残渣をメタノールとトルエンに溶解させ、再度溶媒を留去した。
　得られた残渣をメタノール(200 mL)に溶解させ、炭酸水素ナトリウム(49 g, 590 mmol)とジ-tert-ブチル ジカルボナート(35 mL, 150 mmol)を加え、室温で終夜攪拌した。反応終了後、不溶物を濾別し、濾液を減圧下濃縮した。残渣に酢酸エチルを加え、水で洗浄した。得られた抽出液を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（5-40% 酢酸エチル／ヘキサン）で精製することにより、淡黄色の油状物を得た。
　得られた油状物をメタノール(300 mL)に溶解させ、1 N水酸化ナトリウム水溶液(95 mL)を加えた後、室温で20時間攪拌した。反応終了後、減圧下濃縮し、水を加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去することにより、1-tert-ブチル 2-メチル (2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラートを無色油状物(17 g, 47%)として得た。また、水層にクエン酸を加えて酸性にした後、飽和になるまで塩化ナトリウムを加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（30% 酢酸エチル／ヘキサン）で精製することにより、2,3-cis-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(3.4 g, 10%, Rf = 0.23)と2,3-trans-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(6.4 g, 19%, Rf = 0.23)をそれぞれ白色固体として得た。
1-tert-ブチル 2-メチル (2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート
NMR (CDCl3) δ: 1.40 (9H x 2/3, s), 1.47 (9H x 1/3, s), 2.07-2.17 (1H, m), 2.38-2.55 (1H, m), 3.35 (3H x 1/3, s), 3.37 (3H x 2/3, s), 3.39-3.51 (1H, m), 3.52-3.68 (1H, m), 3.78-3.95 (1H, m), 4.42-4.56 (1H, m), 7.03-7.11 (1H, m), 7.29-7.34 (1H, m), 7.38 (1H, d, J = 8.3 Hz). The obtained residue was dissolved in methanol (200 mL), thionyl chloride (12 mL, 160 mmol) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 4 hr. The solvent was distilled off under reduced pressure. The obtained residue was dissolved in methanol and toluene, and the solvent was distilled off again.
The obtained residue was dissolved in methanol (200 mL), sodium hydrogen carbonate (49 g, 590 mmol) and di-tert-butyl dicarbonate (35 mL, 150 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue and washed with water. The obtained extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (5-40% ethyl acetate / hexane) to give a pale yellow oil.
The obtained oil was dissolved in methanol (300 mL), 1N aqueous sodium hydroxide solution (95 mL) was added, and the mixture was stirred at room temperature for 20 hr. After completion of the reaction, the mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to give 1-tert-butyl 2-methyl (2R * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidine-1,2 -Dicarboxylate was obtained as a colorless oil (17 g, 47%). Further, citric acid was added to the aqueous layer to make it acidic, sodium chloride was added until saturation, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (30% ethyl acetate / hexane) to give 2,3-cis-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2. -Carboxylic acid (3.4 g, 10%, Rf = 0.23) and 2,3-trans-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (6.4 g, 19 %, Rf = 0.23) were obtained as white solids, respectively.
1-tert-butyl 2-methyl (2R * , 3R * ) -3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate
NMR (CDCl 3 ) δ: 1.40 (9H x 2/3, s), 1.47 (9H x 1/3, s), 2.07-2.17 (1H, m), 2.38-2.55 (1H, m), 3.35 (3H x 1/3, s), 3.37 (3H x 2/3, s), 3.39-3.51 (1H, m), 3.52-3.68 (1H, m), 3.78-3.95 (1H, m), 4.42-4.56 ( 1H, m), 7.03-7.11 (1H, m), 7.29-7.34 (1H, m), 7.38 (1H, d, J = 8.3 Hz).

5-e) 3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸 5-e) 3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid

Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044

　ジエチル 1-アセチル-3-(3,4-ジクロロフェニル)-5-ヒドロキシピロリジン-2,2-ジカルボキシラート(37 g, 89 mmol)をアセトニトリル(180 mL)に溶解し、トリエチルシラン(21 mL, 130 mmol)およびトリフルオロ酢酸(69 mL, 890 mol)を加え、室温で1.5時間攪拌した。減圧下溶媒を留去して、得られた残渣を酢酸エチルで希釈し、炭酸カリウム水溶液および飽和食塩水で順次洗浄した。有機層を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣を酢酸(38 mL)に溶解させ、6 N塩酸水溶液(150 mL)を加え、終夜加熱還流した。反応混合物を室温まで冷却後、体積が約1/4になるまで、減圧下濃縮した。得られた懸濁液に8 N水酸化ナトリウム水溶液を加え、pHを約7に調節して、析出した固体を濾取した。得られた固体をナスフラスコに入れ、トルエンを加え共沸して乾燥することにより、表題化合物を白色固体(13 g, 50%)として得た。
LC/MS 260.0
NMR (DMSO-d6) δ: 1.76-2.04 (1H, m), 2.17-2.34 (1H, m), 2.97-3.16 (1H, m), 3.37-3.48 (2H, m), 3.53-3.95 (2H, m), 7.17-7.42 (1H, m), 7.45-7.74 (2H, m), 8.70 (1H, brs). Diethyl 1-acetyl-3- (3,4-dichlorophenyl) -5-hydroxypyrrolidine-2,2-dicarboxylate (37 g, 89 mmol) was dissolved in acetonitrile (180 mL) and triethylsilane (21 mL, 130 mmol) and trifluoroacetic acid (69 mL, 890 mol) were added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, and the resulting residue was diluted with ethyl acetate and washed successively with aqueous potassium carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in acetic acid (38 mL), 6N aqueous hydrochloric acid solution (150 mL) was added, and the mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure until the volume became about 1/4. An 8 N aqueous sodium hydroxide solution was added to the resulting suspension to adjust the pH to about 7, and the precipitated solid was collected by filtration. The obtained solid was placed in an eggplant flask, azeotroped with toluene, and dried to give the title compound as a white solid (13 g, 50%).
LC / MS 260.0
NMR (DMSO-d 6 ) δ: 1.76-2.04 (1H, m), 2.17-2.34 (1H, m), 2.97-3.16 (1H, m), 3.37-3.48 (2H, m), 3.53-3.95 (2H , m), 7.17-7.42 (1H, m), 7.45-7.74 (2H, m), 8.70 (1H, brs).

5-f) 2,3-cis-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸
2,3-trans-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸 5-f) 2,3-cis-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid
2,3-trans-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid

Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045

　3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(13 g, 45 mmol)のメタノール(220 mL)溶液にトリエチルアミン(6.8 mL, 49 mmol)およびジ-tert-ブチル ジカルボナート(11 mL, 49 mmol)を加え、室温で終夜攪拌した。減圧下溶媒を留去し、得られた残留物を酢酸エチルで希釈して、1 N塩酸水溶液および飽和食塩水で順次洗浄した。有機層を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィーで3回(1回目；ヘキサン/酢酸エチル=1/1～酢酸エチルのみ、2回目；ヘキサンのみ～ヘキサン/酢酸エチル=1/1～酢酸エチルのみ、3回目；ヘキサンのみ～ヘキサン/酢酸エチル=1/1)精製し、合計で、2,3-cis-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸を白色固体(6.2 g, 39%)として、2,3-trans-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸を白色固体(0.73 g, 5%)としてそれぞれ得た。
2,3-cis-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸
LC/MS 260.0 [M+]-Boc
NMR (DMSO-d6) δ: 1.26-1.48 (9H, m), 1.99-2.17 (1H, m), 2.19-2.45 (1H, m), 3.21-3.47 (1H, m), 3.53-3.89 (2H, m), 4.22-4.53 (1H, m), 7.10-7.40 (1H, m), 7.42-7.74 (2H, m), 12.25 (1H, brs). To a solution of 3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (13 g, 45 mmol) in methanol (220 mL), triethylamine (6.8 mL, 49 mmol) and di-tert-butyl dicarbonate (11 mL, 49 mmol) was added and stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the resulting residue was diluted with ethyl acetate and washed successively with 1N aqueous hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography three times (first time; hexane / ethyl acetate = 1/1 to ethyl acetate only, second time; hexane only to hexane / ethyl acetate = 1/1 to ethyl acetate only, 3 Second time: hexane only to hexane / ethyl acetate = 1/1) purified to a total of 2,3-cis-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid As a white solid (6.2 g, 39%) and 2,3-trans-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid as a white solid (0.73 g, 5% %) Respectively.
2,3-cis-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid
LC / MS 260.0 [M + ] -Boc
NMR (DMSO-d 6 ) δ: 1.26-1.48 (9H, m), 1.99-2.17 (1H, m), 2.19-2.45 (1H, m), 3.21-3.47 (1H, m), 3.53-3.89 (2H , m), 4.22-4.53 (1H, m), 7.10-7.40 (1H, m), 7.42-7.74 (2H, m), 12.25 (1H, brs).

参考例６
1-tert-ブチル 2-メチル (2R*,3R*)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-1,2-ジカルボキシラート Reference Example 6
1-tert-butyl 2-methyl (2R * , 3R * ) -3- (3-chloro-4-fluorophenyl) pyrrolidine-1,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046

6-a) (2E)-3-(3-クロロ-4-フルオロフェニル)プロパ-2-エナール 6-a) (2E) -3- (3-chloro-4-fluorophenyl) prop-2-enal

Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047

　3-クロロ-4-フルオロベンズアルデヒド(50 g, 320 mmol)をアセトアルデヒド(100 mL, 180 mmol)に溶解させた。これに水酸化カリウム(2.0 g, 36 mmol)のメタノール(25 mL)溶液を0℃で滴下した。反応混合物を0℃で2時間攪拌した後、無水酢酸(30 mL, 320 mmol)を加え、60℃にて1時間加熱した。反応混合物に3 N塩酸水溶液(200 mL)を加え、100℃にて1時間加熱した。反応混合物を室温まで放冷後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下溶媒を留去して、表題化合物を茶色油状物(75 g, 100%)として得た。
LC/MS 185.1
NMR (DMSO-d6) δ: 6.65(1H, dd, J = 16.3, 7.6 Hz), 7.15-7.69 (4H, m), 9.69 (1H, d, J = 7.6 Hz). 3-Chloro-4-fluorobenzaldehyde (50 g, 320 mmol) was dissolved in acetaldehyde (100 mL, 180 mmol). A solution of potassium hydroxide (2.0 g, 36 mmol) in methanol (25 mL) was added dropwise thereto at 0 ° C. The reaction mixture was stirred at 0 ° C. for 2 hr, acetic anhydride (30 mL, 320 mmol) was added, and the mixture was heated at 60 ° C. for 1 hr. To the reaction mixture was added 3N aqueous hydrochloric acid (200 mL), and the mixture was heated at 100 ° C. for 1 hr. The reaction mixture was allowed to cool to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a brown oil (75 g, 100%).
LC / MS 185.1
NMR (DMSO-d 6 ) δ: 6.65 (1H, dd, J = 16.3, 7.6 Hz), 7.15-7.69 (4H, m), 9.69 (1H, d, J = 7.6 Hz).

6-b) ジエチル 1-アセチル-3-(3-クロロ-4-フルオロフェニル)ピロリジン-2,2-ジカルボキシラート 6-b) Diethyl 1-acetyl-3- (3-chloro-4-fluorophenyl) pyrrolidine-2,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048

　ジエチル (アセチルアミノ)プロパンジオアート(68 g, 320 mmol)をエタノール(500 mL)に溶解させ、これにナトリウム エタノラート(4.29 g, 63 mmol)、次いで、(2E)-3-(3-クロロ-4-フルオロフェニル)プロパ-2-エナール(58 g, 320 mmol)を加え、室温にて1時間、次いで、60℃にて1時間攪拌した。反応混合物を室温まで放冷後、酢酸を加え、pHを4～5に調整した後、減圧下溶媒を留去した。得られた残渣を酢酸エチルで希釈し、水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をアセトニトリル(170 mL)に溶解し、トリエチルシラン(76 mL, 470 mmol)およびトリフルオロ酢酸(170 mL, 2.2 mol)を加え、室温で3時間攪拌した。減圧下溶媒を留去し、酢酸エチルで希釈した。得られた残渣を飽和炭酸水素ナトリウム水溶液および飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～ヘキサン/酢酸エチル=1/1～酢酸エチルのみ～酢酸エチル/エタノール=3/1)で精製し、表題化合物を茶色油状物(61 g, 50%)として得た。
LC/MS 386.0
NMR (DMSO-d6) δ: 0.89 (3H, t, J = 7.1 Hz), 1.21 (3H, t, J = 7.1 Hz), 2.03 (3H, s), 2.14-2.26 (1H. m), 2.35-2.48 (1H, m), 3.48-4.24 (7H, m), 7.22 (1H, ddd, J = 8.7, 4.8, 2.2 Hz), 7.32-7.43 (2H, m). Diethyl (acetylamino) propanedioate (68 g, 320 mmol) was dissolved in ethanol (500 mL), sodium ethanolate (4.29 g, 63 mmol), then (2E) -3- (3-chloro- 4-Fluorophenyl) prop-2-enal (58 g, 320 mmol) was added, and the mixture was stirred at room temperature for 1 hour and then at 60 ° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, acetic acid was added to adjust the pH to 4-5, and the solvent was evaporated under reduced pressure. The resulting residue was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in acetonitrile (170 mL), triethylsilane (76 mL, 470 mmol) and trifluoroacetic acid (170 mL, 2.2 mol) were added, and the mixture was stirred at room temperature for 3 hr. The solvent was distilled off under reduced pressure and diluted with ethyl acetate. The obtained residue was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only-hexane / ethyl acetate = 1 / 1-ethyl acetate only-ethyl acetate / ethanol = 3/1) to give the title compound as a brown oil (61 g, 50 %).
LC / MS 386.0
NMR (DMSO-d 6 ) δ: 0.89 (3H, t, J = 7.1 Hz), 1.21 (3H, t, J = 7.1 Hz), 2.03 (3H, s), 2.14-2.26 (1H.m), 2.35 -2.48 (1H, m), 3.48-4.24 (7H, m), 7.22 (1H, ddd, J = 8.7, 4.8, 2.2 Hz), 7.32-7.43 (2H, m).

6-c) 2,3-cis-1-(tert-ブトキシカルボニル)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-2-カルボン酸 6-c) 2,3-cis-1- (tert-butoxycarbonyl) -3- (3-chloro-4-fluorophenyl) pyrrolidine-2-carboxylic acid

Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049

　ジエチル 1-アセチル-3-(3-クロロ-4-フルオロフェニル)ピロリジン-2,2-ジカルボキシラート(35 g, 91 mmol)の酢酸(52 mL)溶液に6 N塩酸水溶液(500 mL)を加え、100℃にて終夜攪拌した。反応溶媒を減圧留去した後、得られた固体を酢酸エチルで洗浄し、メタノール(270 mL)に溶解した。調製したメタノール溶液にトリエチルアミン(25 mL, 181 mmol)およびジ-tert-ブチル ジカルボナート(23 mL, 100 mmol)を加え、室温にて終夜攪拌した。反応溶媒を減圧留去した後、残留物を酢酸エチルで希釈し、1 N塩酸水溶液および飽和食塩水で洗浄した。有機層を硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～ヘキサン/酢酸エチル=3/1)で精製し、表題化合物を白色固体(3.2 g, 10%)として得た。また、1-(tert-ブトキシカルボニル)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-2-カルボン酸のcis体およびtrans体の混合物を白色固体(8.2 g, 26%)として得た。
2,3-cis-1-(tert-ブトキシカルボニル)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-2-カルボン酸
LC/MS 344.0
NMR (DMSO-d6) δ: 1.30-1.44 (9H, m), 1.99-2.12 (1H, m), 2.23-2.43 (1H, m), 3.23-3.40 (1H, m), 3.55-3.82 (2H, m), 4.32-4.39 (1H, m), 7.21-7.40 (2H, m), 7.43-7.52 (1H, m), 12.26 (1H, brs). To a solution of diethyl 1-acetyl-3- (3-chloro-4-fluorophenyl) pyrrolidine-2,2-dicarboxylate (35 g, 91 mmol) in acetic acid (52 mL) was added 6 N aqueous hydrochloric acid (500 mL). In addition, the mixture was stirred overnight at 100 ° C. After the reaction solvent was distilled off under reduced pressure, the obtained solid was washed with ethyl acetate and dissolved in methanol (270 mL). Triethylamine (25 mL, 181 mmol) and di-tert-butyl dicarbonate (23 mL, 100 mmol) were added to the prepared methanol solution, and the mixture was stirred overnight at room temperature. After the reaction solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate and washed with 1N aqueous hydrochloric acid and saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only-hexane / ethyl acetate = 3/1) to give the title compound as a white solid (3.2 g, 10%). Also, a mixture of cis and trans forms of 1- (tert-butoxycarbonyl) -3- (3-chloro-4-fluorophenyl) pyrrolidine-2-carboxylic acid was obtained as a white solid (8.2 g, 26%). .
2,3-cis-1- (tert-butoxycarbonyl) -3- (3-chloro-4-fluorophenyl) pyrrolidine-2-carboxylic acid
LC / MS 344.0
NMR (DMSO-d 6 ) δ: 1.30-1.44 (9H, m), 1.99-2.12 (1H, m), 2.23-2.43 (1H, m), 3.23-3.40 (1H, m), 3.55-3.82 (2H , m), 4.32-4.39 (1H, m), 7.21-7.40 (2H, m), 7.43-7.52 (1H, m), 12.26 (1H, brs).

6-d) 1-tert-ブチル2-メチル (2R*,3R*)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-1,2-ジカルボキシラート 6-d) 1-tert-butyl 2-methyl (2R * , 3R * ) -3- (3-chloro-4-fluorophenyl) pyrrolidine-1,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-2-カルボン酸 2,3-trans-1- (tert-butoxycarbonyl) -3- (3-chloro-4-fluorophenyl) pyrrolidine-2-carboxylic acid

Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051

　1-(tert-ブトキシカルボニル)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-2-カルボン酸のcis体およびtrans体の混合物(8.2 g, 24 mmol)のメタノール溶液に(トリメチルシリル)ジアゾメタンのジエチルエーテル溶液(2 M, 35 mL, 70 mmol)を0℃で滴下し、気体の発生が終了するまで攪拌した後、酢酸を気体の発生が終了するまで加えた。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～ヘキサン/酢酸エチル=1/1)で精製した。得られたエステル体のメタノール(58 mL)溶液に、1 N水酸化ナトリウム水溶液(9.7 mL)を加え、室温にて終夜攪拌した。反応混合物に、1 N水酸化ナトリウム水溶液(9.7 mL)を追加し、室温にて3時間、次いで60℃にて1時間攪拌した。室温まで放冷後、溶媒を減圧下留去した。残留物に水および酢酸エチルを加え、有機層を分取した。分取した有機層を硫酸マグネシウムで乾燥後、溶媒を減圧下留去して、1-tert-ブチル 2-メチル (2R*,3R*)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-1,2-ジカルボキシラートを茶色油状物(5.0 g, 56%)として得た。
LC/MS 358.0
NMR (DMSO-d6) δ: 1.18-1.63 (9H, m), 1.80-2.43 (2H, m), 2.94-4.76 (7H, m), 6.80-7.91 (3H, m). 1- (tert-Butoxycarbonyl) -3- (3-chloro-4-fluorophenyl) pyrrolidine-2-carboxylic acid in a mixture of cis and trans forms (8.2 g, 24 mmol) in (trimethylsilyl) diazomethane Of diethyl ether (2 M, 35 mL, 70 mmol) was added dropwise at 0 ° C. and stirred until gas evolution ceased, and then acetic acid was added until gas evolution ceased. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane only to hexane / ethyl acetate = 1/1). To a solution of the obtained ester in methanol (58 mL) was added 1 N aqueous sodium hydroxide solution (9.7 mL), and the mixture was stirred overnight at room temperature. A 1 N aqueous sodium hydroxide solution (9.7 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours and then at 60 ° C. for 1 hour. After cooling to room temperature, the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the residue, and the organic layer was separated. The separated organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1-tert-butyl 2-methyl (2R * , 3R * )-3- (3-chloro-4-fluorophenyl) pyrrolidine. -1,2-Dicarboxylate was obtained as a brown oil (5.0 g, 56%).
LC / MS 358.0
NMR (DMSO-d 6 ) δ: 1.18-1.63 (9H, m), 1.80-2.43 (2H, m), 2.94-4.76 (7H, m), 6.80-7.91 (3H, m).

　また、水層を1 N塩酸水溶液でpH 約3に調節し、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥後、溶媒を減圧下留去して、2,3-trans-1-(tert-ブトキシカルボニル)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-2-カルボン酸を淡黄色油状物(1.5 g, 22%)として得た。
LC/MS 244.0
NMR (DMSO-d6) δ: 1.25-1.48 (9H, m), 1.78-2.34 (3H, m), 3.06-3.80 (3H, m), 6.32-7.79 (3H, m), 11.91-12.52 (1H, m). The aqueous layer was adjusted to pH about 3 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. After drying the organic layer over magnesium sulfate, the solvent was distilled off under reduced pressure to give 2,3-trans-1- (tert-butoxycarbonyl) -3- (3-chloro-4-fluorophenyl) pyrrolidine-2-carboxylic acid. The acid was obtained as a pale yellow oil (1.5 g, 22%).
LC / MS 244.0
NMR (DMSO-d 6 ) δ: 1.25-1.48 (9H, m), 1.78-2.34 (3H, m), 3.06-3.80 (3H, m), 6.32-7.79 (3H, m), 11.91-12.52 (1H , m).

参考例７
1-tert-ブチル 2-メチル (2R*,3R*)-3-(3-クロロフェニル)ピロリジン-1,2-ジカルボキシラート Reference Example 7
1-tert-butyl 2-methyl (2R * , 3R * ) -3- (3-chlorophenyl) pyrrolidine-1,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052

7-a) (2E)-3-(3-クロロフェニル)プロパ-2-エナール 7-a) (2E) -3- (3-chlorophenyl) prop-2-enal

Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053

　3-クロロベンズアルデヒド(50 g, 0.36 mol)をアセトアルデヒド(140 mL, 2.49 mol)に溶解させた。これに水酸化カリウム(2.24 g, 40 mmol)のメタノール(26 mL)溶液を0℃で滴下した。反応混合物を0℃で1時間攪拌した後、無水酢酸(34 mL)を加え、還流下1時間加熱した。一度室温まで放冷した後、1 N塩酸水溶液(500 mL)を加え、還流下1時間加熱した。室温にて終夜放置し、酢酸エチルで希釈し抽出した。得られた抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（5-50% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を黄色の油状物(58 g, 98%)として得た。
NMR (CDCl3) δ: 6.70 (1H, dd, J = 16.0, 7.5 Hz), 7.34-7.49 (4H, m), 7.54 (1H, s), 9.71 (1H, d, J = 7.7 Hz). 3-Chlorobenzaldehyde (50 g, 0.36 mol) was dissolved in acetaldehyde (140 mL, 2.49 mol). A solution of potassium hydroxide (2.24 g, 40 mmol) in methanol (26 mL) was added dropwise thereto at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1 hr, acetic anhydride (34 mL) was added, and the mixture was heated under reflux for 1 hr. The mixture was allowed to cool to room temperature, 1N aqueous hydrochloric acid solution (500 mL) was added, and the mixture was heated under reflux for 1 hr. The mixture was left overnight at room temperature, diluted with ethyl acetate and extracted. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (5-50% ethyl acetate / hexane) to give the title compound as a yellow oil (58 g, 98%).
NMR (CDCl 3 ) δ: 6.70 (1H, dd, J = 16.0, 7.5 Hz), 7.34-7.49 (4H, m), 7.54 (1H, s), 9.71 (1H, d, J = 7.7 Hz).

7-b) ジエチル 1-アセチル-3-(3-クロロフェニル)-5-ヒドロキシピロリジン-2,2-ジカルボキシラート 7-b) Diethyl 1-acetyl-3- (3-chlorophenyl) -5-hydroxypyrrolidine-2,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054

　ジエチル (アセチルアミノ)プロパンジオアート(76 g, 0.35 mol)をエタノール(1 L)に溶解させ、これにナトリウム エタノラート(4.8 g, 70 mmol)を加え、室温で5分間攪拌した。反応混合物に(2E)-3-(3-クロロフェニル)プロパ-2-エナール(58 g, 0.35 mol)を加え、室温で終夜攪拌した。反応混合物に酢酸を加え、pHを4にした後、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテル、ヘキサンと水で洗浄した後、減圧下乾燥させることにより、表題化合物を白色結晶(86 g, 64%)として得た。
NMR (DMSO-d6) δ: 0.87 (3H, t, J = 7.1 Hz), 1.21 (3H, t, J = 7.1 Hz), 2.02 (1H, dd, J = 12.4, 6.2 Hz), 2.15 (3H, s), 2.50 (1H, dt, J = 3.7, 1.7 Hz), 3.72 (2H, qd, J = 7.1, 1.4 Hz), 4.07-4.25 (3H, m), 5.70 (1H, brs), 6.26 (1H, brs), 7.23 (1H, dd, J = 5.6, 1.8 Hz), 7.30-7.38 (3H, m). Diethyl (acetylamino) propanedioate (76 g, 0.35 mol) was dissolved in ethanol (1 L), sodium ethanolate (4.8 g, 70 mmol) was added thereto, and the mixture was stirred at room temperature for 5 minutes. (2E) -3- (3-Chlorophenyl) prop-2-enal (58 g, 0.35 mol) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. Acetic acid was added to the reaction mixture to adjust the pH to 4, and then the solvent was distilled off under reduced pressure. The obtained residue was washed with diisopropyl ether, hexane and water, and dried under reduced pressure to give the title compound as white crystals (86 g, 64%).
NMR (DMSO-d 6 ) δ: 0.87 (3H, t, J = 7.1 Hz), 1.21 (3H, t, J = 7.1 Hz), 2.02 (1H, dd, J = 12.4, 6.2 Hz), 2.15 (3H , s), 2.50 (1H, dt, J = 3.7, 1.7 Hz), 3.72 (2H, qd, J = 7.1, 1.4 Hz), 4.07-4.25 (3H, m), 5.70 (1H, brs), 6.26 ( 1H, brs), 7.23 (1H, dd, J = 5.6, 1.8 Hz), 7.30-7.38 (3H, m).

7-c) ジエチル 1-アセチル-3-(3-クロロフェニル)ピロリジン-2,2-ジカルボキシラート 7-c) Diethyl 1-acetyl-3- (3-chlorophenyl) pyrrolidine-2,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055

　ジエチル 1-アセチル-3-(3-クロロフェニル)-5-ヒドロキシピロリジン-2,2-ジカルボキシラート(86 g, 0.22 mol)とトリエチルシラン(54 mL, 0.34 mol)をアセトニトリル(430 mL)に溶解させ、これにトリフルオロ酢酸(173 mL, 2.24 mol)を加え、室温で2時間攪拌した。反応終了後、減圧下溶媒を留去し、酢酸エチルで希釈した。得られた溶液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（50-100% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を黄色の油状物(82 g, 100%)として得た。
NMR (DMSO-d6) δ: 0.88 (3H, t, J = 7.2 Hz), 1.22 (3H, t, J = 7.2 Hz), 2.04 (3H, s), 2.16-2.29 (1H, m), 2.37-2.54 (2H, m), 3.58-3.89 (3H, m), 3.95 (1H, t, J = 8.7 Hz), 4.17 (2H, quin, J = 7.2 Hz), 7.18 (1H, dd, J = 6.3, 2.4 Hz), 7.25 (1H, s), 7.31-7.38 (2H, m). Diethyl 1-acetyl-3- (3-chlorophenyl) -5-hydroxypyrrolidine-2,2-dicarboxylate (86 g, 0.22 mol) and triethylsilane (54 mL, 0.34 mol) dissolved in acetonitrile (430 mL) To this was added trifluoroacetic acid (173 mL, 2.24 mol), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and diluted with ethyl acetate. The obtained solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (50-100% ethyl acetate / hexane) to give the title compound as a yellow oil (82 g, 100%).
NMR (DMSO-d 6 ) δ: 0.88 (3H, t, J = 7.2 Hz), 1.22 (3H, t, J = 7.2 Hz), 2.04 (3H, s), 2.16-2.29 (1H, m), 2.37 -2.54 (2H, m), 3.58-3.89 (3H, m), 3.95 (1H, t, J = 8.7 Hz), 4.17 (2H, quin, J = 7.2 Hz), 7.18 (1H, dd, J = 6.3 , 2.4 Hz), 7.25 (1H, s), 7.31-7.38 (2H, m).

7-d) 3-(3-クロロフェニル)ピロリジン-2-カルボン酸　1塩酸塩 7-d) 3- (3-Chlorophenyl) pyrrolidine-2-carboxylic acid monohydrochloride

Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056

　ジエチル 1-アセチル-3-(3-クロロフェニル)ピロリジン-2,2-ジカルボキシラート(66 g, 0.18 mol)に酢酸(23 mL)と6 N塩酸水溶液(122 mL)を加え、還流下、終夜加熱攪拌した。減圧下溶媒を留去し、残渣を減圧下乾燥後、表題化合物を淡黄色結晶 (27 g, 58%)として得た。 Acetic acid (23 mL) and 6 N hydrochloric acid aqueous solution (122 mL) were added to diethyl 1-acetyl-3- (3-chlorophenyl) pyrrolidine-2,2-dicarboxylate (66 g, 0.18 mol) and refluxed overnight. Stir with heating. The solvent was distilled off under reduced pressure, and the residue was dried under reduced pressure to give the title compound as pale yellow crystalline candy (27 g, 58%).

7-e) 2,3-trans-1-(tert-ブトキシカルボニル)-3-(3-クロロフェニル)ピロリジン-2-カルボン酸および
2,3-cis-1-(tert-ブトキシカルボニル)-3-(3-クロロフェニル)ピロリジン-2-カルボン酸 7-e) 2,3-trans-1- (tert-butoxycarbonyl) -3- (3-chlorophenyl) pyrrolidine-2-carboxylic acid and
2,3-cis-1- (tert-butoxycarbonyl) -3- (3-chlorophenyl) pyrrolidine-2-carboxylic acid

Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057

　7-d)で得られた3-(3-クロロフェニル)ピロリジン-2-カルボン酸　1塩酸塩(21 g, 79.3 mmol)をメタノール(313 mL)に溶解させ、トリエチルアミン(33 mL, 0.24 mol)とジ-tert-ブチル ジカルボナート(26 mL, 0.11 mol)を加え、室温で終夜攪拌した。反応終了後、減圧下溶媒を留去し、残渣に酢酸エチルを加え、１ N塩酸水溶液および飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（5-40% 酢酸エチル／ヘキサン）で精製することにより、表題化合物の2,3-trans-1-(tert-ブトキシカルボニル)-3-(3-クロロフェニル)ピロリジン-2-カルボン酸（11 g, 44%）および2,3-cis-1-(tert-ブトキシカルボニル)-3-(3-クロロフェニル)ピロリジン-2-カルボン酸（1.8 g, 7%）をそれぞれ白色結晶として得た。
2,3-trans-1-(tert-ブトキシカルボニル)-3-(3-クロロフェニル)ピロリジン-2-カルボン酸
NMR (DMSO-d6) δ: 1.30-1.45 (9H, m), 1.99-2.12 (1H, m), 2.26-2.45 (1H, m), 3.23-3.43 (1H, m), 3.57-3.83 (2H, m), 4.32-4.39 (1H, m), 7.21-7.28 (1H, m), 7.28-7.38 (3H, m), 12.22 (1H, brs).
2,3-cis-1-(tert-ブトキシカルボニル)-3-(3-クロロフェニル)ピロリジン-2-カルボン酸
NMR (DMSO-d6) δ: 1.30-1.48 (9H, m), 1.92-2.08 (1H, m), 2.12-2.26 (1H, m), 3.28-3.47 (2H, m), 3.50-3.63 (1H, m), 3.98-4.11 (1H, m), 7.21-7.49 (4H, m), 12.62 (1H, brs). 7-d) 3- (3-chlorophenyl) pyrrolidine-2-carboxylic acid monohydrochloride (21 g, 79.3 mmol) obtained in methanol (313 mL) was dissolved in triethylamine (33 mL, 0.24 mol). Di-tert-butyl dicarbonate (26 mL, 0.11 mol) was added, and the mixture was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with 1N hydrochloric acid aqueous solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (5-40% ethyl acetate / hexane) to give 2,3-trans-1 -(tert-Butoxycarbonyl) -3- (3-chlorophenyl) pyrrolidine-2-carboxylic acid (11 g, 44%) and 2,3-cis-1- (tert-butoxycarbonyl) -3- (3-chlorophenyl ) Pyrrolidine-2-carboxylic acid (1.8 g, 7%) was obtained as white crystals.
2,3-trans-1- (tert-butoxycarbonyl) -3- (3-chlorophenyl) pyrrolidine-2-carboxylic acid
NMR (DMSO-d 6 ) δ: 1.30-1.45 (9H, m), 1.99-2.12 (1H, m), 2.26-2.45 (1H, m), 3.23-3.43 (1H, m), 3.57-3.83 (2H , m), 4.32-4.39 (1H, m), 7.21-7.28 (1H, m), 7.28-7.38 (3H, m), 12.22 (1H, brs).
2,3-cis-1- (tert-butoxycarbonyl) -3- (3-chlorophenyl) pyrrolidine-2-carboxylic acid
NMR (DMSO-d 6 ) δ: 1.30-1.48 (9H, m), 1.92-2.08 (1H, m), 2.12-2.26 (1H, m), 3.28-3.47 (2H, m), 3.50-3.63 (1H , m), 3.98-4.11 (1H, m), 7.21-7.49 (4H, m), 12.62 (1H, brs).

7-f) 1-tert-ブチル2-メチル (2R*,3R*)-3-(3-クロロフェニル)ピロリジン-1,2-ジカルボキシラート 7-f) 1-tert-butyl 2-methyl (2R * , 3R * )-3- (3-chlorophenyl) pyrrolidine-1,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(3-クロロフェニル)ピロリジン-2-カルボン酸(0.34 g, 1.04 mmol)のメタノール(9 mL)溶液に(トリメチルシリル)ジアゾメタンのジエチルエーテル溶液(2 M, 0.6 mL, 1.25 mmol)を0℃で滴下し、0℃で10分間、室温で１時間攪拌後、酢酸を0℃で滴下し、反応を停止した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（5-25% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.34 g, 96%)として得た。
NMR (DMSO-d6) δ: 1.28-1.44 (9H, m), 2.01-2.14 (1H, m), 2.25-2.45 (1H, m), 3.16-3.25 (3H, m), 3.27-3.44 (1H, m), 3.58-3.88 (2H, m), 4.41-4.49 (1H, m), 7.15-7.23 (1H, m), 7.26-7.39 (3H, m). 2,3-cis-1- (tert-butoxycarbonyl) -3- (3-chlorophenyl) pyrrolidine-2-carboxylic acid (0.34 g, 1.04 mmol) in methanol (9 mL) in (trimethylsilyl) diazomethane diethyl ether A solution (2 M, 0.6 mL, 1.25 mmol) was added dropwise at 0 ° C., and the mixture was stirred at 0 ° C. for 10 minutes and at room temperature for 1 hour, and then acetic acid was added dropwise at 0 ° C. to stop the reaction. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (5-25% ethyl acetate / hexane) to give the title compound as a colorless oil (0.34 g, 96%).
NMR (DMSO-d 6 ) δ: 1.28-1.44 (9H, m), 2.01-2.14 (1H, m), 2.25-2.45 (1H, m), 3.16-3.25 (3H, m), 3.27-3.44 (1H , m), 3.58-3.88 (2H, m), 4.41-4.49 (1H, m), 7.15-7.23 (1H, m), 7.26-7.39 (3H, m).

参考例８
1-tert-ブチル 2-メチル (2R*,3R*)-3-(4-クロロフェニル)ピロリジン-1,2-ジカルボキシラート Reference Example 8
1-tert-butyl 2-methyl (2R * , 3R * )-3- (4-chlorophenyl) pyrrolidine-1,2-dicarboxylate

8-a) (2E)-3-(4-クロロフェニル)プロパ-2-エナール 8-a) (2E) -3- (4-chlorophenyl) prop-2-enal

Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060

　4-クロロベンズアルデヒド(50 g, 0.36 mol)をアセトアルデヒド(140 mL, 2.49 mol)に溶解させた。これに水酸化カリウム(2.24 g, 40 mmol)のメタノール(26 mL)溶液を0℃で滴下した。反応混合物を0℃で1時間攪拌した後、無水酢酸(34 mL)を加え、還流下1時間加熱した。一度室温まで放冷した後、1 N塩酸水溶液(500 mL)を加え、還流下1時間加熱した。室温にて終夜放置し、酢酸エチルで希釈し抽出した。得られた抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（5-50% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を黄色の固体(47 g, 79%)として得た。
NMR (CDCl3) δ: 6.69 (1H, dd, J = 15.9, 7.6 Hz), 7.36-7.61 (5H, m), 9.71 (1H, d, J = 7.6 Hz). 4-Chlorobenzaldehyde (50 g, 0.36 mol) was dissolved in acetaldehyde (140 mL, 2.49 mol). To this was added dropwise a solution of potassium hydroxide (2.24 g, 40 mmol) in methanol (26 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1 hr, acetic anhydride (34 mL) was added, and the mixture was heated under reflux for 1 hr. The mixture was allowed to cool to room temperature, 1N aqueous hydrochloric acid solution (500 mL) was added, and the mixture was heated under reflux for 1 hr. The mixture was left overnight at room temperature, diluted with ethyl acetate and extracted. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (5-50% ethyl acetate / hexane) to give the title compound as a yellow solid (47 g, 79%).
NMR (CDCl 3 ) δ: 6.69 (1H, dd, J = 15.9, 7.6 Hz), 7.36-7.61 (5H, m), 9.71 (1H, d, J = 7.6 Hz).

8-b) ジエチル 1-アセチル-3-(4-クロロフェニル)ピロリジン-2,2-ジカルボキシラート 8-b) Diethyl 1-acetyl-3- (4-chlorophenyl) pyrrolidine-2,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061

　ジエチル (アセチルアミノ)プロパンジオアート(61 g, 0.28 mol)をエタノール(600 mL)に溶解させ、これにナトリウム エトキシド(3.8 g, 56 mmol)を加え、室温で5分間攪拌した。反応混合物に(2E)-3-(4-クロロフェニル)プロパ-2-エナール(47 g, 0.28 mol)を加え、室温で終夜攪拌した。反応混合物に酢酸を加え、pHを4にした後、減圧下溶媒を留去した。得られた残渣のアセトニトリル(27 mL)溶液にトリエチルシラン(12 mL, 75 mmol)およびＴＦＡ(27 mL, 350 mmol)を加え、室温にて3.5時間攪拌した。減圧下、溶媒を留去した後、得られた残渣を酢酸エチルで希釈し、炭酸カリウム水溶液および炭酸水素ナトリウム水溶液で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチルのみ)で精製し、表題化合物を淡黄色油状物(10 g, 54%)として得た。
LC/MS 367.9
NMR (DMSO-d6) δ: 0.86 (3H, t, J = 7.2 Hz), 1.12-1.32 (4H, m), 2.02 (3H, s), 2.13-2.47 (2H, m), 3.56-3.98 (4H, m), 4.09-4.23 (2H, m), 7.15-7.29 (2H, m), 7.34-7.42 (2H, m). Diethyl (acetylamino) propanedioate (61 g, 0.28 mol) was dissolved in ethanol (600 mL), sodium ethoxide (3.8 g, 56 mmol) was added thereto, and the mixture was stirred at room temperature for 5 minutes. (2E) -3- (4-Chlorophenyl) prop-2-enal (47 g, 0.28 mol) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. Acetic acid was added to the reaction mixture to adjust the pH to 4, and then the solvent was distilled off under reduced pressure. Triethylsilane (12 mL, 75 mmol) and TFA (27 mL, 350 mmol) were added to a solution of the obtained residue in acetonitrile (27 mL), and the mixture was stirred at room temperature for 3.5 hours. After evaporating the solvent under reduced pressure, the resulting residue was diluted with ethyl acetate and washed with an aqueous potassium carbonate solution and an aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate only) to give the title compound as a pale yellow oil (10 g, 54%).
LC / MS 367.9
NMR (DMSO-d 6 ) δ: 0.86 (3H, t, J = 7.2 Hz), 1.12-1.32 (4H, m), 2.02 (3H, s), 2.13-2.47 (2H, m), 3.56-3.98 ( 4H, m), 4.09-4.23 (2H, m), 7.15-7.29 (2H, m), 7.34-7.42 (2H, m).

8-c) 2,3-cis-1-(tert-ブトキシカルボニル)-3-(4-クロロフェニル)ピロリジン-2-カルボン酸 8-c) 2,3-cis-1- (tert-butoxycarbonyl) -3- (4-chlorophenyl) pyrrolidine-2-carboxylic acid

Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062

　ジエチル 1-アセチル-3-(4-クロロフェニル)ピロリジン-2,2-ジカルボキシラート(9.4 g, 26 mmol)の酢酸(11 mL)溶液に6 N塩酸水溶液(43 mL)を加え、110℃にて終夜攪拌した。室温まで放冷し、反応溶媒を減圧留去した。得られた水溶液を水で希釈し、酢酸エチルで洗浄した後、8 N水酸化ナトリウム水溶液を加え、pH約7に調節した。析出した固体を濾取し、水で洗浄した後、減圧下乾燥した。得られた固体のメタノール(60 mL)溶液にトリエチルアミン(2.4 mL, 17 mmol)およびジ-tert-ブチル ジカルボナート(3.9 mL, 17 mmol)を加え、室温にて5時間攪拌した。反応溶媒を減圧留去した後、残留物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～ヘキサン/酢酸エチル=1/1)で精製し、表題化合物を無色非定形固体(1.7 g, 20%)として得た。
LC/MS 326.1
NMR (DMSO-d6) δ: 1.30-1.45 (9H, m), 2.00-2.11 (1H, m), 2.27-2.44 (1H, m), 3.23-3.45 (1H, m), 3.55-3.80 (2H, m), 4.27-4.39 (1H, m), 7.26-7.32 (2H, m), 7.33-7.42 (2H, m), 12.18 (1H, brs). To a solution of diethyl 1-acetyl-3- (4-chlorophenyl) pyrrolidine-2,2-dicarboxylate (9.4 g, 26 mmol) in acetic acid (11 mL) was added 6 N aqueous hydrochloric acid (43 mL), and the mixture was heated to 110 ° C. And stirred overnight. The reaction solvent was distilled off under reduced pressure. The resulting aqueous solution was diluted with water and washed with ethyl acetate, and then an 8N aqueous sodium hydroxide solution was added to adjust the pH to about 7. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure. Triethylamine (2.4 mL, 17 mmol) and di-tert-butyl dicarbonate (3.9 mL, 17 mmol) were added to a solution of the obtained solid in methanol (60 mL), and the mixture was stirred at room temperature for 5 hours. After the reaction solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only-hexane / ethyl acetate = 1/1) to give the title compound as a colorless amorphous solid (1.7 g, 20%).
LC / MS 326.1
NMR (DMSO-d 6 ) δ: 1.30-1.45 (9H, m), 2.00-2.11 (1H, m), 2.27-2.44 (1H, m), 3.23-3.45 (1H, m), 3.55-3.80 (2H , m), 4.27-4.39 (1H, m), 7.26-7.32 (2H, m), 7.33-7.42 (2H, m), 12.18 (1H, brs).

8-d) 1-tert-ブチル2-メチル (2R*,3R*)-3-(4-クロロフェニル)ピロリジン-1,2-ジカルボキシラート 8-d) 1-tert-butyl 2-methyl (2R * , 3R * ) -3- (4-chlorophenyl) pyrrolidine-1,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(4-クロロフェニル)ピロリジン-2-カルボン酸(0.60 g, 1.8 mmol)のメタノール(5.0 mL)溶液に(トリメチルシリル)ジアゾメタンのジエチルエーテル溶液(2 M, 3.5 mL, 7 mmol)を0℃で滴下し、気体の発生が終了するまで攪拌した後、酢酸を気体の発生が終了するまで加えた。減圧下溶媒を留去し、得られた残渣を塩基性シリカゲルカラムクロマトグラフィー(ヘキサンのみ～ヘキサン/酢酸エチル=1/1)で精製して、表題化合物を無色油状物(0.56 g, 89%)として得た。
LC/MS 240.1 [M+]-Boc
NMR (DMSO-d6) δ: 1.24-1.46 (9H, m), 2.00-2.13 (1H, m), 2.22-2.42 (1H, m), 3.16-3.25 (3H, m), 3.27-3.44 (1H, m), 3.58-3.87 (2H, m), 4.39-4.51 (1H, m), 7.21-7.28 (2H, m), 7.32-7.42 (2H, m). 2,3-cis-1- (tert-butoxycarbonyl) -3- (4-chlorophenyl) pyrrolidine-2-carboxylic acid (0.60 g, 1.8 mmol) in methanol (5.0 mL) in (trimethylsilyl) diazomethane in diethyl ether A solution (2 M, 3.5 mL, 7 mmol) was added dropwise at 0 ° C. and stirred until gas evolution ceased, and then acetic acid was added until gas evolution ceased. The solvent was distilled off under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (hexane only to hexane / ethyl acetate = 1/1) to give the title compound as a colorless oil (0.56 g, 89%) Got as.
LC / MS 240.1 [M + ] -Boc
NMR (DMSO-d 6 ) δ: 1.24-1.46 (9H, m), 2.00-2.13 (1H, m), 2.22-2.42 (1H, m), 3.16-3.25 (3H, m), 3.27-3.44 (1H , m), 3.58-3.87 (2H, m), 4.39-4.51 (1H, m), 7.21-7.28 (2H, m), 7.32-7.42 (2H, m).

参考例９
1-tert-ブチル 2-メチル (2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート Reference Example 9
1-tert-butyl 2-methyl (2S * , 3R * ) -3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.20 g, 0.56 mmol)のメタノール(10 mL)溶液に(トリメチルシリル)ジアゾメタンのジエチルエーテル溶液(2 M, 0.31 mL, 0.61 mmol)を0℃で滴下し、0℃で2時間、室温で終夜攪拌した。その後、(トリメチルシリル)ジアゾメタンのジエチルエーテル溶液(2 M, ca.3 mL, 6 mmol)を0℃で加え、室温で1時間攪拌した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（5-25% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.21 g, 100%)として得た。
NMR (CDCl3) δ: 1.42 (9H x 2/3, s), 1.49 (9H x 1/3, s), 1.92-2.03 (1H, m), 2.24-2.38 (1H, m), 3.35-3.44 (1H, m), 3.55-3.80 (2H, m), 3.71-3.73 (3H, m), 4.19 (1H x 2/3, d, J = 6.8 Hz), 4.33 (1H x 1/3, d, J = 6.0 Hz), 7.07 (1H, dd, J = 8.3, 2.2 Hz), 7.33 (1H, d, J = 2.2 Hz), 7.41 (1H, d, J = 8.3 Hz). 2,3-trans-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.20 g, 0.56 mmol) in methanol (10 mL) in a solution of (trimethylsilyl) diazomethane A diethyl ether solution (2 M, 0.31 mL, 0.61 mmol) was added dropwise at 0 ° C., and the mixture was stirred at 0 ° C. for 2 hours and at room temperature overnight. Thereafter, (trimethylsilyl) diazomethane in diethyl ether (2 M, ca. 3 mL, 6 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (5-25% ethyl acetate / hexane) to give the title compound as a colorless oil (0.21 g, 100%).
NMR (CDCl 3 ) δ: 1.42 (9H x 2/3, s), 1.49 (9H x 1/3, s), 1.92-2.03 (1H, m), 2.24-2.38 (1H, m), 3.35-3.44 (1H, m), 3.55-3.80 (2H, m), 3.71-3.73 (3H, m), 4.19 (1H x 2/3, d, J = 6.8 Hz), 4.33 (1H x 1/3, d, J = 6.0 Hz), 7.07 (1H, dd, J = 8.3, 2.2 Hz), 7.33 (1H, d, J = 2.2 Hz), 7.41 (1H, d, J = 8.3 Hz).

参考例１０
1-tert-ブチル 2-メチル (2S*,3R*)-3-(3-クロロフェニル)ピロリジン-1,2-ジカルボキシラート Reference Example 10
1-tert-butyl 2-methyl (2S * , 3R * ) -3- (3-chlorophenyl) pyrrolidine-1,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3-クロロフェニル)ピロリジン-2-カルボン酸(0.40 g, 1.23 mmol)のメタノール(9 mL)溶液に(トリメチルシリル)ジアゾメタンのジエチルエーテル溶液(2 M, 0.62 mL, 1.23 mmol)を0℃で滴下し、0℃で1時間、室温で１時間攪拌後、酢酸を0℃で滴下し、反応を停止した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（5-25% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.42 g, 100%)として得た。
NMR (DMSO-d6) δ: 1.29-1.45 (9H, m), 2.00-2.12 (1H, m), 2.13-2.24 (1H, m), 3.33-3.47 (2H, m), 3.53-3.67 (4H, m), 4.10-4.19 (1H, m), 7.24-7.47 (4H, m). 2,3-trans-1- (tert-butoxycarbonyl) -3- (3-chlorophenyl) pyrrolidine-2-carboxylic acid (0.40 g, 1.23 mmol) in methanol (9 mL) in (trimethylsilyl) diazomethane in diethyl ether A solution (2 M, 0.62 mL, 1.23 mmol) was added dropwise at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 1 hour, and then acetic acid was added dropwise at 0 ° C. to stop the reaction. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (5-25% ethyl acetate / hexane) to give the title compound as a colorless oil (0.42 g, 100%).
NMR (DMSO-d 6 ) δ: 1.29-1.45 (9H, m), 2.00-2.12 (1H, m), 2.13-2.24 (1H, m), 3.33-3.47 (2H, m), 3.53-3.67 (4H , m), 4.10-4.19 (1H, m), 7.24-7.47 (4H, m).

参考例１１
tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(ジメチルカルバモイル)ピロリジン-1-カルボキシラート Reference Example 11
tert-Butyl (2R * , 3R * )-3- (3,4-Dichlorophenyl) -2- (dimethylcarbamoyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(1.1 g, 3.1 mmol)のDMF(10 mL)溶液にHOBt(0.72 g, 4.7 mmol)とWSC(0.90 g, 4.7 mmol)を加えた。これにジメチルアミンのTHF溶液(2 M, 7.8 mL, 16 mmol)を加え、室温で終夜攪拌した。続いて、50℃で30分間攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去することにより、表題化合物を白色固体(0.67 g, 55%)として得た。
NMR (CDCl3) δ: 1.38-1.48 (9H, m), 2.00-2.13 (1H, m), 2.47-2.51 (3H, m), 2.55-2.67 (1H, m), 2.68-2.71 (3H, m), 3.39-3.57 (2H, m), 3.78-3.96 (1H, m), 4.78-4.96 (1H, m), 7.08-7.14 (1H, m), 7.33-7.39 (2H, m). To a solution of 2,3-cis-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (1.1 g, 3.1 mmol) in DMF (10 mL) was added HOBt (0.72 g, 4.7 mmol) and WSC (0.90 g, 4.7 mmol) were added. To this was added a THF solution of dimethylamine (2 M, 7.8 mL, 16 mmol), and the mixture was stirred overnight at room temperature. Subsequently, the mixture was stirred at 50 ° C. for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a white solid (0.67 g, 55%). It was.
NMR (CDCl 3 ) δ: 1.38-1.48 (9H, m), 2.00-2.13 (1H, m), 2.47-2.51 (3H, m), 2.55-2.67 (1H, m), 2.68-2.71 (3H, m ), 3.39-3.57 (2H, m), 3.78-3.96 (1H, m), 4.78-4.96 (1H, m), 7.08-7.14 (1H, m), 7.33-7.39 (2H, m).

参考例１２
2,3-cis-3-(3,4-ジクロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド（保持時間小）
2,3-cis-3-(3,4-ジクロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド（保持時間大） Reference Example 12
2,3-cis-3- (3,4-dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide (low retention time)
2,3-cis-3- (3,4-dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide (large retention time)

Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067

　2,3-cis-3-(3,4-ジクロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド(0.62 g)を高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ　ＡＳ（５０ｍｍＩＤ×５００ｍｍＬ　ダイセル化学工業製）、移動相：Ａ）ヘキサン１００％、Ｂ）エタノール１００％、Ｃ）ジエチルアミン１００％、混合比：Ａ／Ｂ／Ｃ＝９００／１００／１、流速：８０ｍＬ／ｍｉｎ、カラム温度：２５℃）を用いて分画した。上記の高速液体クロマトグラフィー条件にて保持時間の小さい方の光学活性体を含有する分画液を濃縮して、2,3-cis-3-(3,4-ジクロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド（保持時間小：15.5min）（０．３０ｇ、＞９９％ｅｅ）を得た。
LC/MS 286.9
　また、保持時間の大きい方の光学活性体を含有する分画液を濃縮して、2,3-cis-3-(3,4-ジクロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド（保持時間大：40.0min）（０．３０ｇ、＞９９％ｅｅ）を得た。
LC/MS 286.9
　鏡像体過剰率（ｅｅ）は高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ　ＡＳ（４．６ｍｍＩＤ×２５０ｍｍＬ　ダイセル化学工業製）、移動相：Ａ）ヘキサン１００％、Ｂ）エタノール＝１００％、Ｃ）ジエチルアミン＝１００％、混合比：Ａ／Ｂ／Ｃ＝９００／１００／１、流速：１．０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて測定した（保持時間小：6.0min、保持時間大：13.0min）。 2,3-cis-3- (3,4-dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide (0.62 g) was subjected to high performance liquid chromatography (column: CHIRALPAK AS (50 mm ID × 500 mm L manufactured by Daicel Chemical Industries), Mobile phase: A) 100% hexane, B) 100% ethanol, C) 100% diethylamine, mixing ratio: A / B / C = 900/100/1, flow rate: 80 mL / min, column temperature: 25 ° C.) And fractionated. Concentrate the fraction containing the optically active substance with the shorter retention time under the above-mentioned high performance liquid chromatography conditions to obtain 2,3-cis-3- (3,4-dichlorophenyl) -N, N-dimethyl Pyrrolidine-2-carboxamide (low retention time: 15.5 min) (0.30 g,> 99% ee) was obtained.
LC / MS 286.9
In addition, the fraction containing the optically active substance having the longer retention time was concentrated to give 2,3-cis-3- (3,4-dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide (retention) Large time: 40.0 min) (0.30 g,> 99% ee).
LC / MS 286.9
The enantiomeric excess (ee) was determined by high performance liquid chromatography (column: CHIRALPAK AS (4.6 mm ID × 250 mmL, manufactured by Daicel Chemical Industries), mobile phase: A) hexane 100%, B) ethanol = 100%, C) diethylamine = 100 %, Mixing ratio: A / B / C = 900/100/1, flow rate: 1.0 mL / min, column temperature: 30 ° C. (retention time small: 6.0 min, retention time large: 13.0 min) ).

参考例１３
tert-ブチル (2R*,3R*)-2-(ジメチルカルバモイル)-3-(ナフタレン-2-イル)ピロリジン-1-カルボキシラート Reference Example 13
tert-Butyl (2R * , 3R * )-2- (Dimethylcarbamoyl) -3- (naphthalen-2-yl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068

13-a) (2E)-3-(ナフタレン-2-イル)プロパ-2-エナール 13-a) (2E) -3- (Naphthalen-2-yl) prop-2-enal

Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069

　2-ナフトアルデヒド(25 g, 160 mmol)をアセトアルデヒド(63 mL, 1.12 mol)に溶解させた。これに水酸化カリウム(1 g, 18 mmol)のメタノール(15 mL)溶液を0℃で滴下した。反応混合物を0℃で1時間攪拌した後、無水酢酸(15 mL)を加え、還流下1時間加熱した。一度室温まで放冷した後、1 N塩酸水溶液(250 mL)を加え、還流下1時間加熱した。室温にて終夜放置し、生じた固体を濾取し、水で洗浄した。この固体を酢酸エチルに溶解させ、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルにて洗浄し、表題化合物を黄色の固体(10 g, 35%)として得た。
NMR (CDCl3) δ: 6.84 (1H, dd, J = 15.9, 7.6 Hz), 7.49-8.05 (8H, m), 9.77 (1H, d, J = 7.7 Hz). 2-Naphtoaldehyde (25 g, 160 mmol) was dissolved in acetaldehyde (63 mL, 1.12 mol). A solution of potassium hydroxide (1 g, 18 mmol) in methanol (15 mL) was added dropwise thereto at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1 hr, acetic anhydride (15 mL) was added, and the mixture was heated under reflux for 1 hr. The mixture was allowed to cool to room temperature, 1N aqueous hydrochloric acid solution (250 mL) was added, and the mixture was heated under reflux for 1 hr. The mixture was left overnight at room temperature, and the resulting solid was collected by filtration and washed with water. This solid was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound as a yellow solid (10 g, 35%).
NMR (CDCl 3 ) δ: 6.84 (1H, dd, J = 15.9, 7.6 Hz), 7.49-8.05 (8H, m), 9.77 (1H, d, J = 7.7 Hz).

13-b) ジエチル 1-アセチル-5-ヒドロキシ-3-(ナフタレン-2-イル)ピロリジン-2,2-ジカルボキシラート 13-b) Diethyl 1-acetyl-5-hydroxy-3- (naphthalen-2-yl) pyrrolidine-2,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070

　ジエチル (アセチルアミノ)プロパンジオアート(12 g, 55 mmol)をエタノール(150 mL)に溶解させ、これにナトリウム エタノラート(0.75 g, 11 mmol)を加え、室温で5分間攪拌した。反応混合物に(2E)-3-(ナフタレン-2-イル)プロパ-2-エナール(10 g, 55 mmol)を加え、室温で終夜攪拌した。反応混合物に酢酸を加え、pHを4にした後、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルと水で洗浄した後、減圧下乾燥させることにより、表題化合物を黄色結晶(19 g, 87%)として得た。
NMR (DMSO-d6) δ: 0.73 (3H, t, J = 7.0 Hz), 1.23 (3H, t, J = 7.0 Hz), 2.05-2.17 (1H, m), 2.18 (3H, s), 2.76 (1H, td, J = 13.2, 5.1 Hz), 3.32-3.79 (3H, m), 4.07-4.28 (2H, m), 4.36 (1H, dd, J = 13.8, 5.9 Hz), 5.75 (1H, d, J = 4.9 Hz), 7.40 (1H, d, J = 8.3 Hz), 7.50 (2H, dd, J = 6.1, 3.4 Hz), 7.72-7.95 (4H, m). Diethyl (acetylamino) propanedioate (12 g, 55 mmol) was dissolved in ethanol (150 mL), sodium ethanolate (0.75 g, 11 mmol) was added thereto, and the mixture was stirred at room temperature for 5 minutes. (2E) -3- (Naphthalen-2-yl) prop-2-enal (10 g, 55 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. Acetic acid was added to the reaction mixture to adjust the pH to 4, and then the solvent was distilled off under reduced pressure. The obtained residue was washed with diisopropyl ether and water, and dried under reduced pressure to give the title compound as yellow crystals (19 g, 87%).
NMR (DMSO-d 6 ) δ: 0.73 (3H, t, J = 7.0 Hz), 1.23 (3H, t, J = 7.0 Hz), 2.05-2.17 (1H, m), 2.18 (3H, s), 2.76 (1H, td, J = 13.2, 5.1 Hz), 3.32-3.79 (3H, m), 4.07-4.28 (2H, m), 4.36 (1H, dd, J = 13.8, 5.9 Hz), 5.75 (1H, d , J = 4.9 Hz), 7.40 (1H, d, J = 8.3 Hz), 7.50 (2H, dd, J = 6.1, 3.4 Hz), 7.72-7.95 (4H, m).

13-c) 2,3-cis-1-(tert-ブトキシカルボニル)-3-(ナフタレン-2-イル)ピロリジン-2-カルボン酸および
2,3-trans-1-(tert-ブトキシカルボニル)-3-(ナフタレン-2-イル)ピロリジン-2-カルボン酸 13-c) 2,3-cis-1- (tert-butoxycarbonyl) -3- (naphthalen-2-yl) pyrrolidine-2-carboxylic acid and
2,3-trans-1- (tert-butoxycarbonyl) -3- (naphthalen-2-yl) pyrrolidine-2-carboxylic acid

Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071

Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072

　ジエチル 1-アセチル-5-ヒドロキシ-3-(ナフタレン-2-イル)ピロリジン-2,2-ジカルボキシラート(19 g, 48 mmol)とトリエチルシラン(11 mL, 71 mmol)をアセトニトリル(95 mL)に溶解させ、これにトリフルオロ酢酸(37 mL, 0.48 mol)を加え、室温で終夜攪拌した。反応終了後、減圧下溶媒を留去し、酢酸エチルで希釈した。得られた溶液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。
　得られた残渣に酢酸(25 mL)と6 N塩酸水溶液(100 mL)を加え、還流下終夜加熱した。減圧下溶媒を留去し、残渣を減圧下乾燥させて、表題化合物を白色固体(24 g, 82%)として得た。
　得られた白色固体をメタノール(220 mL)に溶解させ、トリエチルアミン(20 mL, 0.14 mol)とジ-tert-ブチル ジカルボナート(14 mL, 0.06 mol)を加え、室温で終夜攪拌した。反応終了後、減圧下溶媒を留去し、残渣に酢酸エチルを加え、１ N塩酸水溶液および飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（5-40% 酢酸エチル／ヘキサン）で精製することにより、表題化合物の2,3-cis-1-(tert-ブトキシカルボニル)-3-(ナフタレン-2-イル)ピロリジン-2-カルボン酸（12 g, 75%）および2,3-trans-1-(tert-ブトキシカルボニル)-3-(ナフタレン-2-イル)ピロリジン-2-カルボン酸（4 g, 25%）をそれぞれ白色結晶として得た。
2,3-cis-1-(tert-ブトキシカルボニル)-3-(ナフタレン-2-イル)ピロリジン-2-カルボン酸
NMR (DMSO-d6) δ: 1.31-1.47 (9H, m), 2.06-2.23 (1H, m), 2.44-2.68 (1H, m), 3.23-3.51 (1H, m), 3.70 (1H, q, J = 9.1 Hz), 3.82-3.99 (1H, m), 4.41-4.50 (1H, m), 7.48 (3H, d, J = 8.0 Hz), 7.72-7.92 (4H, m), 12.04 (1H, brs).
2,3-trans-1-(tert-ブトキシカルボニル)-3-(ナフタレン-2-イル)ピロリジン-2-カルボン酸
NMR (DMSO-d6) δ: 1.27-1.52 (9H, m), 2.05-2.19 (1H, m), 2.20-2.35 (1H, m), 3.23-3.73 (3H, m), 4.10-4.24 (1H, m), 7.40-7.58 (3H, m), 7.75-7.96 (4H, m), 12.55 (1H, brs). Diethyl 1-acetyl-5-hydroxy-3- (naphthalen-2-yl) pyrrolidine-2,2-dicarboxylate (19 g, 48 mmol) and triethylsilane (11 mL, 71 mmol) in acetonitrile (95 mL) To this was added trifluoroacetic acid (37 mL, 0.48 mol), and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure and diluted with ethyl acetate. The obtained solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
Acetic acid (25 mL) and 6N aqueous hydrochloric acid (100 mL) were added to the resulting residue, and the mixture was heated under reflux overnight. The solvent was evaporated under reduced pressure, and the residue was dried under reduced pressure to give the title compound as a white solid (24 g, 82%).
The obtained white solid was dissolved in methanol (220 mL), triethylamine (20 mL, 0.14 mol) and di-tert-butyl dicarbonate (14 mL, 0.06 mol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with 1N hydrochloric acid aqueous solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (5-40% ethyl acetate / hexane) to give 2,3-cis-1 of the title compound. -(tert-Butoxycarbonyl) -3- (naphthalen-2-yl) pyrrolidine-2-carboxylic acid (12 g, 75%) and 2,3-trans-1- (tert-butoxycarbonyl) -3- (naphthalene -2-yl) pyrrolidine-2-carboxylic acid (4 g, 25%) was obtained as white crystals.
2,3-cis-1- (tert-butoxycarbonyl) -3- (naphthalen-2-yl) pyrrolidine-2-carboxylic acid
NMR (DMSO-d 6 ) δ: 1.31-1.47 (9H, m), 2.06-2.23 (1H, m), 2.44-2.68 (1H, m), 3.23-3.51 (1H, m), 3.70 (1H, q , J = 9.1 Hz), 3.82-3.99 (1H, m), 4.41-4.50 (1H, m), 7.48 (3H, d, J = 8.0 Hz), 7.72-7.92 (4H, m), 12.04 (1H, brs).
2,3-trans-1- (tert-butoxycarbonyl) -3- (naphthalen-2-yl) pyrrolidine-2-carboxylic acid
NMR (DMSO-d 6 ) δ: 1.27-1.52 (9H, m), 2.05-2.19 (1H, m), 2.20-2.35 (1H, m), 3.23-3.73 (3H, m), 4.10-4.24 (1H , m), 7.40-7.58 (3H, m), 7.75-7.96 (4H, m), 12.55 (1H, brs).

13-d) tert-ブチル(2R*,3R*)-2-(ジメチルカルバモイル)-3-(ナフタレン-2-イル)ピロリジン-1-カルボキシラート 13-d) tert-butyl (2R * , 3R * )-2- (dimethylcarbamoyl) -3- (naphthalen-2-yl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000073

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(ナフタレン-2-イル)ピロリジン-2-カルボン酸(0.5 g, 1.46 mmol)のDMF(5 mL)溶液にHOBt(0.34 g, 2.2 mmol)とWSC(0.42 g, 2.2 mmol)を加えた。これにジメチルアミンのTHF溶液(2 M, 3.7 mL, 7.3 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウムと飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（25% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を白色固体(0.49 g, 91%)として得た。
NMR (DMSO-d6) δ: 1.27-1.47 (9H, m), 1.99-2.14 (1H, m), 2.20-2.32 (3H, m), 2.36-2.46 (3H, m), 2.52-2.68 (1H, m), 3.26-3.50 (1H, m), 3.60-3.92 (2H, m), 4.93-5.09 (1H, m), 7.36-7.54 (3H, m), 7.72-7.96 (4H, m). To a solution of 2,3-cis-1- (tert-butoxycarbonyl) -3- (naphthalen-2-yl) pyrrolidine-2-carboxylic acid (0.5 g, 1.46 mmol) in DMF (5 mL) was added HOBt (0.34 g, 2.2 mmol) and WSC (0.42 g, 2.2 mmol) were added. To this was added a THF solution of dimethylamine (2 M, 3.7 mL, 7.3 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (25% ethyl acetate / hexane) to give the title compound as a white solid (0.49 g, 91%).
NMR (DMSO-d 6 ) δ: 1.27-1.47 (9H, m), 1.99-2.14 (1H, m), 2.20-2.32 (3H, m), 2.36-2.46 (3H, m), 2.52-2.68 (1H , m), 3.26-3.50 (1H, m), 3.60-3.92 (2H, m), 4.93-5.09 (1H, m), 7.36-7.54 (3H, m), 7.72-7.96 (4H, m).

参考例１４
tert-ブチル (2R*,3R*)-3-(3-クロロ-4-フルオロフェニル)-2-(ジメチルカルバモイル)ピロリジン-1-カルボキシラート Reference Example 14
tert-Butyl (2R * , 3R * )-3- (3-Chloro-4-fluorophenyl) -2- (dimethylcarbamoyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-2-カルボン酸(0.52 g, 1.5 mmol)のエタノール(5.0 mL)溶液に、2 MジメチルアミンTHF溶液(0.83 mL, 1.7 mmol)およびDMT-MM(0.46 g, 1.7 mmol)を加え、室温にて終夜攪拌した。減圧下溶媒を留去した後、残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～ヘキサン/酢酸エチル=1/1)で精製して、表題化合物を無色非定形固体(0.16 g, 29%)として得た。
LC/MS 371.1
NMR (DMSO-d6) δ: 1.24-1.47 (9H, m), 1.88-2.10 (1H, m), 2.23-2.59 (7H, m), 3.21-3.44 (1H, m), 3.54-3.79 (2H, m), 4.83-5.02 (1H, m), 6.97-7.80 (3H, m). To a solution of 2,3-cis-1- (tert-butoxycarbonyl) -3- (3-chloro-4-fluorophenyl) pyrrolidine-2-carboxylic acid (0.52 g, 1.5 mmol) in ethanol (5.0 mL), add 2 M dimethylamine THF solution (0.83 mL, 1.7 mmol) and DMT-MM (0.46 g, 1.7 mmol) were added, and the mixture was stirred at room temperature overnight. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane only to hexane / ethyl acetate = 1/1) to give the title compound as a colorless amorphous solid (0.16 g, 29%). It was.
LC / MS 371.1
NMR (DMSO-d 6 ) δ: 1.24-1.47 (9H, m), 1.88-2.10 (1H, m), 2.23-2.59 (7H, m), 3.21-3.44 (1H, m), 3.54-3.79 (2H m), 4.83-5.02 (1H, m), 6.97-7.80 (3H, m).

参考例１５
tert-ブチル (2R*,3R*)-3-(3-クロロフェニル)-2-(ジメチルカルバモイル)ピロリジン-1-カルボキシラート Reference Example 15
tert-Butyl (2R * , 3R * )-3- (3-Chlorophenyl) -2- (dimethylcarbamoyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000075

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(3-クロロフェニル)ピロリジン-2-カルボン酸(0.5 g, 1.53 mmol)のDMF(4.5 mL)溶液にHOBt(0.35 g, 2.3 mmol)とWSC(0.44 g, 2.3 mmol)を加えた。これにジメチルアミンのTHF溶液(2 M, 3.8 mL, 7.65 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウムと飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（5-25% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を白色結晶(0.23 g, 43%)として得た。
NMR (DMSO-d6) δ: 1.27-1.43 (9H, m), 1.91-2.08 (2H, m), 2.34-2.54 (6H, m), 3.23-3.41 (1H, m), 3.56-3.76 (2H, m), 4.89-5.00 (1H, m), 7.20-7.26 (1H, m), 7.28-7.36 (3H, m). 2,3-cis-1- (tert-butoxycarbonyl) -3- (3-chlorophenyl) pyrrolidine-2-carboxylic acid (0.5 g, 1.53 mmol) in DMF (4.5 mL) solution with HOBt (0.35 g, 2.3 mmol ) And WSC (0.44 g, 2.3 mmol) were added. To this was added a THF solution of dimethylamine (2 M, 3.8 mL, 7.65 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (5-25% ethyl acetate / hexane) to give the title compound as white crystals (0.23 g, 43%).
NMR (DMSO-d 6 ) δ: 1.27-1.43 (9H, m), 1.91-2.08 (2H, m), 2.34-2.54 (6H, m), 3.23-3.41 (1H, m), 3.56-3.76 (2H , m), 4.89-5.00 (1H, m), 7.20-7.26 (1H, m), 7.28-7.36 (3H, m).

参考例１６
2,3-trans-3-(3,4-ジクロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド（保持時間小）
2,3-trans-3-(3,4-ジクロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド（保持時間大） Reference Example 16
2,3-trans-3- (3,4-dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide (low retention time)
2,3-trans-3- (3,4-dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide (large retention time)

Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076

　2,3-trans-3-(3,4-ジクロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド(1.2 g)を高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ　ＡＤ（５０ｍｍＩＤ×５００ｍｍＬ　ダイセル化学工業製）、移動相：Ａ）ヘキサン１００％、Ｂ）エタノール＝１００％、Ｃ）ジエチルアミン＝１００％、混合比：Ａ／Ｂ／Ｃ＝７００／３００／１（４５分からＡ）ヘキサン１００％、Ｂ）エタノール＝１００％、Ｃ）ジエチルアミン＝１００％、混合比：Ａ／Ｂ／Ｃ＝５００／５００／１．６に変更）、流速：８０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて分画した。上記の高速液体クロマトグラフィー条件にて保持時間の小さい方の光学活性体を含有する分画液を濃縮して、2,3-trans-3-(3,4-ジクロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド（保持時間小）（０．６０ｇ、＞９９％ｅｅ）を得た。
LC/MS 286.9
　また、保持時間の大きい方の光学活性体を含有する分画液を濃縮して、2,3-trans-3-(3,4-ジクロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド（保持時間大）（０．５９ｇ、＞９９％ｅｅ）を得た。
LC/MS 286.8
　鏡像体過剰率（ｅｅ）は高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ　ＡＤ（４．６ｍｍＩＤ×２５０ｍｍＬ　ダイセル化学工業製）、移動相：Ａ）ヘキサン１００％、Ｂ）エタノール＝１００％、Ｃ）ジエチルアミン＝１００％、混合比：Ａ／Ｂ／Ｃ＝９００／１００／１、流速：１．０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて測定した。 2,3-trans-3- (3,4-dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide (1.2 g) was subjected to high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID × 500 mm L manufactured by Daicel Chemical Industries), Mobile phase: A) Hexane 100%, B) Ethanol = 100%, C) Diethylamine = 100%, Mixing ratio: A / B / C = 700/300/1 (from 45 minutes A) Hexane 100%, B) Ethanol = 100%, C) diethylamine = 100%, mixing ratio: changed to A / B / C = 500/500 / 1.6), flow rate: 80 mL / min, column temperature: 30 ° C.). Concentrate the fraction containing the optically active substance with the shorter retention time under the above-mentioned high performance liquid chromatography conditions to obtain 2,3-trans-3- (3,4-dichlorophenyl) -N, N-dimethyl Pyrrolidine-2-carboxamide (short retention time) (0.60 g,> 99% ee) was obtained.
LC / MS 286.9
In addition, the fraction containing the optically active substance having the longer retention time was concentrated to give 2,3-trans-3- (3,4-dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide (retention) Large time) (0.59 g,> 99% ee).
LC / MS 286.8
The enantiomeric excess (ee) was determined by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mm ID × 250 mm L, manufactured by Daicel Chemical Industries), mobile phase: A) hexane 100%, B) ethanol = 100%, C) diethylamine = 100 %, Mixing ratio: A / B / C = 900/100/1, flow rate: 1.0 mL / min, column temperature: 30 ° C.).

参考例１７
tert-ブチル (2S*,3R*)-2-(ジメチルカルバモイル)-3-(ナフタレン-2-イル)ピロリジン-1-カルボキシラート Reference Example 17
tert-Butyl (2S * , 3R * )-2- (Dimethylcarbamoyl) -3- (naphthalen-2-yl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000077

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(ナフタレン-2-イル)ピロリジン-2-カルボン酸(0.5 g, 1.46 mmol)のDMF(5 mL)溶液にHOBt(0.34 g, 2.2 mmol)とWSC(0.42 g, 2.2 mmol)を加えた。これにジメチルアミンのTHF溶液(2 M, 3.7 mL, 7.3 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウムと飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（25% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を白色固体(0.39 g, 72%)として得た。
NMR (DMSO-d6) δ: 1.26-1.48 (9H, m), 2.02-2.34 (2H, m), 2.63-2.95 (6H, m), 3.41-3.55 (2H, m), 3.57-3.71 (1H, m), 4.63-4.76 (1H, m), 7.44-7.58 (3H, m), 7.76-7.98 (4H, m). 2,3-trans-1- (tert-butoxycarbonyl) -3- (naphthalen-2-yl) pyrrolidine-2-carboxylic acid (0.5 g, 1.46 mmol) in DMF (5 mL) was added to HOBt (0.34 g, 2.2 mmol) and WSC (0.42 g, 2.2 mmol) were added. To this was added a THF solution of dimethylamine (2 M, 3.7 mL, 7.3 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (25% ethyl acetate / hexane) to give the title compound as a white solid (0.39 g, 72%).
NMR (DMSO-d 6 ) δ: 1.26-1.48 (9H, m), 2.02-2.34 (2H, m), 2.63-2.95 (6H, m), 3.41-3.55 (2H, m), 3.57-3.71 (1H , m), 4.63-4.76 (1H, m), 7.44-7.58 (3H, m), 7.76-7.98 (4H, m).

参考例１８
tert-ブチル (2S*,3R*)-3-(3-クロロ-4-フルオロフェニル)-2-(ジメチルカルバモイル)ピロリジン-1-カルボキシラート Reference Example 18
tert-Butyl (2S * , 3R * )-3- (3-Chloro-4-fluorophenyl) -2- (dimethylcarbamoyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000078

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-2-カルボン酸(0.22 g, 0.6 mmol)のエタノール(10 mL)溶液に、2 MジメチルアミンTHF溶液(0.35 mL, 0.7 mmol)およびDMT-MM(0.19 g, 0.7 mmol)を加え、室温にて終夜攪拌した。減圧下溶媒を留去した後、残留物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物を分取HPLCにて精製して、分取したフラクションを濃縮した。残留物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去して、表題化合物を白色固体(46 mg, 19%)として得た。
LC/MS 371.2
NMR (DMSO-d6) δ: 1.27-1.47 (9H, m), 1.90-2.07 (1H, m), 2.09-2.32 (1H, m), 2.57-2.74 (3H, m), 2.80 (3H, s), 3.32-3.47 (2H, m), 3.50-3.66 (1H, m), 4.50-4.67 (1H, m), 7.23-7.43 (2H, m), 7.48-7.67 (1H, m). To a solution of 2,3-trans-1- (tert-butoxycarbonyl) -3- (3-chloro-4-fluorophenyl) pyrrolidine-2-carboxylic acid (0.22 g, 0.6 mmol) in ethanol (10 mL), add 2 M dimethylamine THF solution (0.35 mL, 0.7 mmol) and DMT-MM (0.19 g, 0.7 mmol) were added, and the mixture was stirred at room temperature overnight. After evaporating the solvent under reduced pressure, the residue was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative HPLC, and the fraction collected was concentrated. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a white solid (46 mg, 19%).
LC / MS 371.2
NMR (DMSO-d 6 ) δ: 1.27-1.47 (9H, m), 1.90-2.07 (1H, m), 2.09-2.32 (1H, m), 2.57-2.74 (3H, m), 2.80 (3H, s ), 3.32-3.47 (2H, m), 3.50-3.66 (1H, m), 4.50-4.67 (1H, m), 7.23-7.43 (2H, m), 7.48-7.67 (1H, m).

参考例１９
tert-ブチル (2S*,3R*)-3-(3-クロロフェニル)-2-(ジメチルカルバモイル)ピロリジン-1-カルボキシラート Reference Example 19
tert-Butyl (2S * , 3R * )-3- (3-Chlorophenyl) -2- (dimethylcarbamoyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000079

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3-クロロフェニル)ピロリジン-2-カルボン酸(0.51 g, 1.57 mmol)のDMF(4.5 mL)溶液にHOBt(0.36 g, 2.35 mmol)とWSC(0.45 g, 2.35 mmol)を加えた。これにエチルアミンのTHF溶液(2 M, 3.9 mL, 7.8 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウムと飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（5-25% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を紫色油状物(0.48 g, 87%)として得た。
NMR (DMSO-d6) δ: 1.26-1.48 (9H, m), 1.90-2.08 (1H, m), 2.11-2.26 (1H, m), 2.57-2.76 (3H, m), 2.80 (3H, s), 3.26-3.47 (2H, m), 3.50-3.62 (1H, m), 4.51-4.66 (1H, m), 7.21-7.47 (4H, m). 2,3-trans-1- (tert-butoxycarbonyl) -3- (3-chlorophenyl) pyrrolidine-2-carboxylic acid (0.51 g, 1.57 mmol) in DMF (4.5 mL) solution with HOBt (0.36 g, 2.35 mmol) ) And WSC (0.45 g, 2.35 mmol) were added. To this was added a THF solution of ethylamine (2 M, 3.9 mL, 7.8 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (5-25% ethyl acetate / hexane) to give the title compound as a purple oil (0.48 g, 87%).
NMR (DMSO-d 6 ) δ: 1.26-1.48 (9H, m), 1.90-2.08 (1H, m), 2.11-2.26 (1H, m), 2.57-2.76 (3H, m), 2.80 (3H, s ), 3.26-3.47 (2H, m), 3.50-3.62 (1H, m), 4.51-4.66 (1H, m), 7.21-7.47 (4H, m).

参考例２０
tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(エチルカルバモイル)ピロリジン-1-カルボキシラート Reference Example 20
tert-Butyl (2R * , 3R * )-3- (3,4-Dichlorophenyl) -2- (ethylcarbamoyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000080

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.89 g, 2.5 mmol)のDMF(10 mL)溶液にHOBt(0.57 g, 3.7 mmol)とWSC(0.71 g, 3.7 mmol)を加えた。これにエチルアミンのTHF溶液(2 M, 6.2 mL, 12 mmol)を加え、室温で2日間攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去することにより、表題化合物を白色結晶(0.74 g, 77%)として得た。
NMR (CDCl3) δ: 0.83 (3H, brs), 1.44 (9H, s), 2.06-2.19 (1H, m), 2.68 (1H, brs), 2.92-3.14 (2H, m), 3.39-3.57 (2H, m), 3.82 (1H, brs), 4.26 (1H, brs), 5.32-5.87 (1H, m), 7.11 (1H, dd, J = 8.3, 2.3 Hz), 7.34 (1H, d, J = 2.3 Hz), 7.36 (1H, d, J = 8.3 Hz). To a solution of 2,3-cis-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.89 g, 2.5 mmol) in DMF (10 mL) was added HOBt (0.57 g, 3.7 mmol) and WSC (0.71 g, 3.7 mmol) were added. To this was added a THF solution of ethylamine (2 M, 6.2 mL, 12 mmol), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as white crystals (0.74 g, 77%). It was.
NMR (CDCl 3 ) δ: 0.83 (3H, brs), 1.44 (9H, s), 2.06-2.19 (1H, m), 2.68 (1H, brs), 2.92-3.14 (2H, m), 3.39-3.57 ( 2H, m), 3.82 (1H, brs), 4.26 (1H, brs), 5.32-5.87 (1H, m), 7.11 (1H, dd, J = 8.3, 2.3 Hz), 7.34 (1H, d, J = 2.3 Hz), 7.36 (1H, d, J = 8.3 Hz).

参考例２１
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(エチルカルバモイル)ピロリジン-1-カルボキシラート Reference Example 21
tert-Butyl (2S * , 3R * )-3- (3,4-Dichlorophenyl) -2- (ethylcarbamoyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000081
Figure JPOXMLDOC01-appb-C000081

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(1.0 g, 2.8 mmol)のDMF(10 mL)溶液にHOBt(0.64 g, 4.2 mmol)とWSC(0.80 g, 4.2 mmol)を加えた。これにエチルアミンのTHF溶液(2 M, 6.9 mL, 14 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルで洗浄することにより、表題化合物を白色結晶(0.87 g, 81%)として得た。
NMR (CDCl3) δ: 1.12 (3H, t, J = 7.3 Hz), 1.48 (9H, brs), 1.95 (1H, brs), 2.30 (1H, brs), 3.19-3.89 (5H, m), 4.07-4.26 (1H, m), 5.84 (1H x 1/2, brs), 6.76 (1H x 1/2, brs), 7.05 (1H, dd, J = 8.3, 2.1 Hz), 7.29 (1H, d, J = 2.1 Hz), 7.38 (1H, d, J = 8.3 Hz). To a solution of 2,3-trans-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (1.0 g, 2.8 mmol) in DMF (10 mL) was added HOBt (0.64 g, 4.2 mmol) and WSC (0.80 g, 4.2 mmol) were added. To this was added a THF solution of ethylamine (2 M, 6.9 mL, 14 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.87 g, 81%).
NMR (CDCl 3 ) δ: 1.12 (3H, t, J = 7.3 Hz), 1.48 (9H, brs), 1.95 (1H, brs), 2.30 (1H, brs), 3.19-3.89 (5H, m), 4.07 -4.26 (1H, m), 5.84 (1H x 1/2, brs), 6.76 (1H x 1/2, brs), 7.05 (1H, dd, J = 8.3, 2.1 Hz), 7.29 (1H, d, J = 2.1 Hz), 7.38 (1H, d, J = 8.3 Hz).

参考例２２
tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(イソプロピルカルバモイル)ピロリジン-1-カルボキシラート Reference Example 22
tert-Butyl (2R * , 3R * )-3- (3,4-Dichlorophenyl) -2- (isopropylcarbamoyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000082

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.50 g, 1.4 mmol)のDMF(10 mL)溶液にHOBt(0.32 g, 2.1 mmol)とWSC(0.40 g, 2.1 mmol)を加えた。これにイソプロピルアミン(0.59 mL, 6.9 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルで洗浄することにより、表題化合物を白色結晶(0.50 g, 90%)として得た。
NMR (CDCl3) δ: 0.76 (3H, d, J = 6.6 Hz), 1.02 (3H, d, J = 6.6 Hz), 1.44 (9H, s), 2.06-2.18 (1H, m), 2.55 (1H, brs), 3.37-3.58 (2H, m), 3.70-3.86 (2H, m), 4.20 (1H, brs), 5.08-5.42 (1H, m), 7.10 (1H, dd, J = 8.5, 2.2 Hz), 7.33 (1H, d, J = 2.2 Hz), 7.36 (1H, d, J = 8.5 Hz). To a solution of 2,3-cis-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.50 g, 1.4 mmol) in DMF (10 mL) was added HOBt (0.32 g, 2.1 mmol) and WSC (0.40 g, 2.1 mmol) were added. To this was added isopropylamine (0.59 mL, 6.9 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.50 g, 90%).
NMR (CDCl 3 ) δ: 0.76 (3H, d, J = 6.6 Hz), 1.02 (3H, d, J = 6.6 Hz), 1.44 (9H, s), 2.06-2.18 (1H, m), 2.55 (1H , brs), 3.37-3.58 (2H, m), 3.70-3.86 (2H, m), 4.20 (1H, brs), 5.08-5.42 (1H, m), 7.10 (1H, dd, J = 8.5, 2.2 Hz ), 7.33 (1H, d, J = 2.2 Hz), 7.36 (1H, d, J = 8.5 Hz).

参考例２３
tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(ジエチルカルバモイル)ピロリジン-1-カルボキシラート Reference Example 23
tert-Butyl (2R * , 3R * )-3- (3,4-Dichlorophenyl) -2- (diethylcarbamoyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000083
Figure JPOXMLDOC01-appb-C000083

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.50 g, 1.4 mmol)のDMF(10 mL)溶液にHOBt(0.32 g, 2.1 mmol)とWSC(0.40 g, 2.1 mmol)を加えた。これにジエチルアミン(0.72 mL, 6.9 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルで洗浄することにより、表題化合物を白色結晶(0.17 g, 29%)として得た。
NMR (CDCl3) δ: 0.78-1.06 (6H, m), 1.36-1.52 (9H, m), 2.10 (1H, brs), 2.47-3.54 (7H, m), 3.75-3.97 (1H, m), 4.64-4.87 (1H, m), 7.09-7.17 (1H, m), 7.30-7.42 (2H, m). To a solution of 2,3-cis-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.50 g, 1.4 mmol) in DMF (10 mL) was added HOBt (0.32 g, 2.1 mmol) and WSC (0.40 g, 2.1 mmol) were added. Diethylamine (0.72 mL, 6.9 mmol) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.17 g, 29%).
NMR (CDCl 3 ) δ: 0.78-1.06 (6H, m), 1.36-1.52 (9H, m), 2.10 (1H, brs), 2.47-3.54 (7H, m), 3.75-3.97 (1H, m), 4.64-4.87 (1H, m), 7.09-7.17 (1H, m), 7.30-7.42 (2H, m).

参考例２４
tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-[エチル(メチル)カルバモイル]ピロリジン-1-カルボキシラート Reference Example 24
tert-butyl (2R * , 3R * ) -3- (3,4-dichlorophenyl) -2- [ethyl (methyl) carbamoyl] pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000084
Figure JPOXMLDOC01-appb-C000084

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.50 g, 1.4 mmol)のDMF(10 mL)溶液にHOBt(0.32 g, 2.1 mmol)とWSC(0.40 g, 2.1 mmol)を加えた。これにエチルメチルアミン(0.60 mL, 6.9 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルで洗浄することにより、表題化合物を白色結晶(0.27 g, 48%)として得た。
NMR (CDCl3) δ: 0.77-0.96 (3H, m), 1.39-1.48 (9H, m), 2.00-2.18 (1H, m), 2.41-3.03 (6H, m), 3.38-3.58 (2H, m), 3.78-3.96 (1H, m), 4.72-4.94 (1H, m), 7.07-7.17 (1H, m), 7.31-7.40 (2H, m). To a solution of 2,3-cis-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.50 g, 1.4 mmol) in DMF (10 mL) was added HOBt (0.32 g, 2.1 mmol) and WSC (0.40 g, 2.1 mmol) were added. Ethylmethylamine (0.60 mL, 6.9 mmol) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.27 g, 48%).
NMR (CDCl 3 ) δ: 0.77-0.96 (3H, m), 1.39-1.48 (9H, m), 2.00-2.18 (1H, m), 2.41-3.03 (6H, m), 3.38-3.58 (2H, m ), 3.78-3.96 (1H, m), 4.72-4.94 (1H, m), 7.07-7.17 (1H, m), 7.31-7.40 (2H, m).

参考例２５
tert-ブチル (2R*,3R*)-2-(シクロプロピルカルバモイル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート Reference Example 25
tert-Butyl (2R * , 3R * )-2- (Cyclopropylcarbamoyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000085
Figure JPOXMLDOC01-appb-C000085

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.50 g, 1.4 mmol)のDMF(10 mL)溶液にHOBt(0.32 g, 2.1 mmol)とWSC(0.40 g, 2.1 mmol)を加えた。これにシクロプロピルアミン(0.48 mL, 6.9 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルで洗浄することにより、表題化合物を白色結晶(0.45 g, 81%)として得た。
NMR (CDCl3) δ: 0.13-0.62 (4H, m), 1.44 (9H, s), 2.01-2.20 (1H, m), 2.35-2.76 (2H, m), 3.34-3.55 (2H, m), 3.81 (1H, brs), 4.21 (1H, brs), 5.39-5.98 (1H, m), 7.10 (1H, dd, J = 8.2, 1.9 Hz), 7.31 (1H, d, J = 1.9 Hz), 7.36 (1H, d, J = 8.2 Hz). To a solution of 2,3-cis-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.50 g, 1.4 mmol) in DMF (10 mL) was added HOBt (0.32 g, 2.1 mmol) and WSC (0.40 g, 2.1 mmol) were added. To this was added cyclopropylamine (0.48 mL, 6.9 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.45 g, 81%).
NMR (CDCl 3 ) δ: 0.13-0.62 (4H, m), 1.44 (9H, s), 2.01-2.20 (1H, m), 2.35-2.76 (2H, m), 3.34-3.55 (2H, m), 3.81 (1H, brs), 4.21 (1H, brs), 5.39-5.98 (1H, m), 7.10 (1H, dd, J = 8.2, 1.9 Hz), 7.31 (1H, d, J = 1.9 Hz), 7.36 (1H, d, J = 8.2 Hz).

参考例２６
tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(モルホリン-4-イルカルボニル)ピロリジン-1-カルボキシラート Reference Example 26
tert-butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (morpholin-4-ylcarbonyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000086

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.50 g, 1.4 mmol)のDMF(10 mL)溶液にHOBt(0.32 g, 2.1 mmol)とWSC(0.40 g, 2.1 mmol)を加えた。これにモルホリン(0.61 mL, 6.9 mmol)を加え、室温で1日攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルで洗浄することにより、表題化合物を白色結晶(0.43 g, 73%)として得た。
NMR (CDCl3) δ: 1.41 (9H x 1/2, s), 1.47 (9H x 1/2, s), 2.02-2.18 (1H, m), 2.49-2.86 (3H, m), 3.08-3.65 (8H, m), 3.84 (1H x 1/2, t, J = 9.3 Hz), 3.94 (1H x 1/2, t, J = 9.3 Hz), 4.77 (1H x 1/2, d, J = 8.1 Hz), 4.91 (1H x 1/2, d, J = 8.3 Hz), 7.12 (1H, dt, J = 8.3, 2.4 Hz), 7.37-7.43 (2H, m). To a solution of 2,3-cis-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.50 g, 1.4 mmol) in DMF (10 mL) was added HOBt (0.32 g, 2.1 mmol) and WSC (0.40 g, 2.1 mmol) were added. To this was added morpholine (0.61 mL, 6.9 mmol), and the mixture was stirred at room temperature for 1 day. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.43 g, 73%).
NMR (CDCl 3 ) δ: 1.41 (9H x 1/2, s), 1.47 (9H x 1/2, s), 2.02-2.18 (1H, m), 2.49-2.86 (3H, m), 3.08-3.65 (8H, m), 3.84 (1H x 1/2, t, J = 9.3 Hz), 3.94 (1H x 1/2, t, J = 9.3 Hz), 4.77 (1H x 1/2, d, J = 8.1 Hz), 4.91 (1H x 1/2, d, J = 8.3 Hz), 7.12 (1H, dt, J = 8.3, 2.4 Hz), 7.37-7.43 (2H, m).

参考例２７
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(モルホリン-4-イルカルボニル)ピロリジン-1-カルボキシラート Reference Example 27
tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (morpholin-4-ylcarbonyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000087
Figure JPOXMLDOC01-appb-C000087

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.50 g, 1.4 mmol)のDMF(10 mL)溶液にHOBt(0.32 g, 2.1 mmol)とWSC(0.40 g, 2.1 mmol)を加えた。これにモルホリン(0.37 mL, 4.2 mmol)を加え、室温で1日攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルで洗浄することにより、表題化合物を白色結晶(0.47 g, 79%)として得た。
NMR (CDCl3) δ: 1.42 (9H x 1/2, s), 1.48 (9H x 1/2, s), 1.89-2.06 (1H, m), 2.25-2.46 (1H, m), 2.96-3.90 (11H, m), 4.45 (1H x 1/2, d, J = 6.4 Hz), 4.61 (1H x 1/2, d, J = 5.3 Hz), 7.04-7.15 (1H, m), 7.31-7.37 (1H, m), 7.39-7.46 (1H, m). 2,3-trans-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.50 g, 1.4 mmol) in DMF (10 mL) was added to HOBt (0.32 g, 2.1 mmol) and WSC (0.40 g, 2.1 mmol) were added. To this was added morpholine (0.37 mL, 4.2 mmol), and the mixture was stirred at room temperature for 1 day. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.47 g, 79%).
NMR (CDCl 3 ) δ: 1.42 (9H x 1/2, s), 1.48 (9H x 1/2, s), 1.89-2.06 (1H, m), 2.25-2.46 (1H, m), 2.96-3.90 (11H, m), 4.45 (1H x 1/2, d, J = 6.4 Hz), 4.61 (1H x 1/2, d, J = 5.3 Hz), 7.04-7.15 (1H, m), 7.31-7.37 (1H, m), 7.39-7.46 (1H, m).

参考例２８
tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(ピペリジン-1-イルカルボニル)ピロリジン-1-カルボキシラート Reference Example 28
tert-Butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (piperidin-1-ylcarbonyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000088
Figure JPOXMLDOC01-appb-C000088

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.33 g, 0.92 mmol)のDMF(4 mL)溶液にHOBt(0.21 g, 1.4 mmol)とWSC(0.26 g, 1.4 mmol)を加えた。これにピペリジン(0.27 mL, 2.8 mmol)を加え、室温で1日攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルで洗浄することにより、表題化合物を白色結晶(0.28 g, 72%)として得た。
NMR (CDCl3) δ: 0.53-0.67 (1H, m), 1.15-1.48 (14H, m), 2.02-2.14 (1H, m), 2.48-2.87 (2H, m), 2.97-3.55 (5H, m), 3.79-3.96 (1H, m), 4.80-5.00 (1H, m), 7.13 (1H, dd, J = 8.3, 2.1 Hz), 7.36-7.40 (2H, m). 2,3-cis-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.33 g, 0.92 mmol) in DMF (4 mL) solution to HOBt (0.21 g, 1.4 mmol) and WSC (0.26 g, 1.4 mmol) were added. Piperidine (0.27 mL, 2.8 mmol) was added thereto, and the mixture was stirred at room temperature for 1 day. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.28 g, 72%).
NMR (CDCl 3 ) δ: 0.53-0.67 (1H, m), 1.15-1.48 (14H, m), 2.02-2.14 (1H, m), 2.48-2.87 (2H, m), 2.97-3.55 (5H, m ), 3.79-3.96 (1H, m), 4.80-5.00 (1H, m), 7.13 (1H, dd, J = 8.3, 2.1 Hz), 7.36-7.40 (2H, m).

参考例２９
tert-ブチル 4-{[(2R*,3R*)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]カルボニル}ピペラジン-1-カルボキシラート Reference Example 29
tert-butyl 4-{[(2R * , 3R * )-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] carbonyl} piperazine-1-carboxylate

Figure JPOXMLDOC01-appb-C000089
Figure JPOXMLDOC01-appb-C000089

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.33 g, 0.92 mmol)のDMF(4 mL)溶液にHOBt(0.21 g, 1.4 mmol)とWSC(0.26 g, 1.4 mmol)を加えた。これにtert-ブチル ピペラジン-1-カルボキシラート(0.51 g, 2.8 mmol)を加え、室温で1日攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルで洗浄することにより、表題化合物を白色結晶(0.36 g, 73%)として得た。
NMR (CDCl3) δ: 1.39-1.47 (18H, m), 2.03-2.16 (1H, m), 2.48-2.83 (3H, m), 2.93-3.58 (8H, m), 3.79-3.97 (1H, m), 4.78-4.95 (1H, m), 7.08-7.14 (1H, m), 7.36-7.41 (2H, m). 2,3-cis-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.33 g, 0.92 mmol) in DMF (4 mL) solution to HOBt (0.21 g, 1.4 mmol) and WSC (0.26 g, 1.4 mmol) were added. To this was added tert-butyl piperazine-1-carboxylate (0.51 g, 2.8 mmol), and the mixture was stirred at room temperature for 1 day. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.36 g, 73%).
NMR (CDCl 3 ) δ: 1.39-1.47 (18H, m), 2.03-2.16 (1H, m), 2.48-2.83 (3H, m), 2.93-3.58 (8H, m), 3.79-3.97 (1H, m ), 4.78-4.95 (1H, m), 7.08-7.14 (1H, m), 7.36-7.41 (2H, m).

参考例３０
tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-[(4-メチルピペラジン-1-イル)カルボニル]ピロリジン-1-カルボキシラート Reference Example 30
tert-butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2-[(4-methylpiperazin-1-yl) carbonyl] pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000090
Figure JPOXMLDOC01-appb-C000090

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.33 g, 0.92 mmol)のDMF(4 mL)溶液にHOBt(0.21 g, 1.4 mmol)とWSC(0.26 g, 1.4 mmol)を加えた。これに1-メチルピペラジン(0.31 mL, 2.8 mmol)を加え、室温で1日攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルで洗浄することにより、表題化合物を白色結晶(0.35 g, 86%)として得た。
NMR (CDCl3) δ: 1.09-1.19 (1H, m), 1.37-1.48 (9H, m), 1.77-1.87 (1H, m), 2.03-2.14 (4H, m), 2.16-2.29 (1H, m), 2.30-2.39 (1H, m), 2.51-2.97 (2H, m), 3.08-3.32 (2H, m), 3.41-3.71 (3H, m), 3.79-3.97 (1H, m), 4.77-4.97 (1H, m), 7.10-7.15 (1H, m), 7.37-7.41 (2H, m). 2,3-cis-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.33 g, 0.92 mmol) in DMF (4 mL) solution to HOBt (0.21 g, 1.4 mmol) and WSC (0.26 g, 1.4 mmol) were added. To this, 1-methylpiperazine (0.31 mL, 2.8 mmol) was added and stirred at room temperature for 1 day. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.35 g, 86%).
NMR (CDCl 3 ) δ: 1.09-1.19 (1H, m), 1.37-1.48 (9H, m), 1.77-1.87 (1H, m), 2.03-2.14 (4H, m), 2.16-2.29 (1H, m ), 2.30-2.39 (1H, m), 2.51-2.97 (2H, m), 3.08-3.32 (2H, m), 3.41-3.71 (3H, m), 3.79-3.97 (1H, m), 4.77-4.97 (1H, m), 7.10-7.15 (1H, m), 7.37-7.41 (2H, m).

参考例３１
tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(ピロリジン-1-イルカルボニル)ピロリジン-1-カルボキシラート Reference Example 31
tert-butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (pyrrolidin-1-ylcarbonyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000091
Figure JPOXMLDOC01-appb-C000091

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.50 g, 1.4 mmol)のDMF(10 mL)溶液にHOBt(0.32 g, 2.1 mmol)とWSC(0.40 g, 2.1 mmol)を加えた。これにピロリジン(0.57 mL, 6.9 mmol)を加え、室温で1日攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルで洗浄することにより、表題化合物を白色結晶(0.43 g, 74%)として得た。
NMR (CDCl3) δ: 1.25-1.50 (2H, m), 1.39 (9H x 1/2, s), 1.47 (9H x 1/2, s), 1.63-1.76 (2H, m), 2.00-2.13 (1H, m), 2.48-2.77 (2H, m), 3.02-3.15 (1H, m), 3.20-3.56 (4H, m), 3.83 (1H x 1/2, t, J = 9.3 Hz), 3.93 (1H x 1/2, t, J = 9.4 Hz), 4.56 (1H x 1/2, d, J = 8.1 Hz), 4.71 (1H x 1/2, d, J = 7.9 Hz), 7.16 (1H, dt, J = 8.3, 2.3 Hz), 7.36 (1H, d, J = 8.3 Hz), 7.42 (1H, dd, J = 4.3, 2.1 Hz). To a solution of 2,3-cis-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.50 g, 1.4 mmol) in DMF (10 mL) was added HOBt (0.32 g, 2.1 mmol) and WSC (0.40 g, 2.1 mmol) were added. To this was added pyrrolidine (0.57 mL, 6.9 mmol), and the mixture was stirred at room temperature for 1 day. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.43 g, 74%).
NMR (CDCl 3 ) δ: 1.25-1.50 (2H, m), 1.39 (9H x 1/2, s), 1.47 (9H x 1/2, s), 1.63-1.76 (2H, m), 2.00-2.13 (1H, m), 2.48-2.77 (2H, m), 3.02-3.15 (1H, m), 3.20-3.56 (4H, m), 3.83 (1H x 1/2, t, J = 9.3 Hz), 3.93 (1H x 1/2, t, J = 9.4 Hz), 4.56 (1H x 1/2, d, J = 8.1 Hz), 4.71 (1H x 1/2, d, J = 7.9 Hz), 7.16 (1H , dt, J = 8.3, 2.3 Hz), 7.36 (1H, d, J = 8.3 Hz), 7.42 (1H, dd, J = 4.3, 2.1 Hz).

参考例３２
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(ピロリジン-1-イルカルボニル)ピロリジン-1-カルボキシラート Reference Example 32
tert-Butyl (2S * , 3R * )-3- (3,4-Dichlorophenyl) -2- (pyrrolidin-1-ylcarbonyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000092
Figure JPOXMLDOC01-appb-C000092

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.50 g, 1.4 mmol)のDMF(4 mL)溶液にHOBt(0.32 g, 2.1 mmol)とWSC(0.40 g, 2.1 mmol)を加えた。これにピロリジン(0.34 mL, 4.2 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルで洗浄することにより、表題化合物を白色結晶(0.46 g, 80%)として得た。
NMR (CDCl3) δ: 1.40 (9H x 5/9, s), 1.48 (9H x 4/9, s), 1.71-2.08 (5H, m), 2.25-2.47 (1H, m), 2.58-2.67 (1H x 5/9, m), 2.79-2.89 (1H x 4/9, m), 3.29-3.84 (6H, m), 4.25 (1H x 5/9, d, J = 7.2 Hz), 4.43 (1H x 4/9, d, J = 5.3 Hz), 7.05-7.13 (1H, m), 7.32-7.36 (1H, m), 7.37-7.42 (1H, m). 2,3-trans-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.50 g, 1.4 mmol) in DMF (4 mL) was added to HOBt (0.32 g, 2.1 mmol) and WSC (0.40 g, 2.1 mmol) were added. To this was added pyrrolidine (0.34 mL, 4.2 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.46 g, 80%).
NMR (CDCl 3 ) δ: 1.40 (9H x 5/9, s), 1.48 (9H x 4/9, s), 1.71-2.08 (5H, m), 2.25-2.47 (1H, m), 2.58-2.67 (1H x 5/9, m), 2.79-2.89 (1H x 4/9, m), 3.29-3.84 (6H, m), 4.25 (1H x 5/9, d, J = 7.2 Hz), 4.43 ( 1H x 4/9, d, J = 5.3 Hz), 7.05-7.13 (1H, m), 7.32-7.36 (1H, m), 7.37-7.42 (1H, m).

参考例３３
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-{[(3R)-3-ヒドロキシピロリジン-1-イル]カルボニル}ピロリジン-1-カルボキシラート Reference Example 33
tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2-{[(3R) -3-hydroxypyrrolidin-1-yl] carbonyl} pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000093
Figure JPOXMLDOC01-appb-C000093

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.15 g, 0.4 mmol)のエタノール(2 mL)溶液に、(3R)-ピロリジン-3-オール (0.037 mL, 0.5 mmol)およびDMT-MM(0.13 g, 0.5 mmol)を加え、室温にて3時間攪拌した。減圧下溶媒を留去した後、残留物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチルのみ)で精製して、表題化合物を無色油状物(0.14 g, 78%)として得た。
LC/MS 429.2
NMR (DMSO-d6) δ: 1.26-1.46 (9H, m), 1.58-2.32 (4H, m), 3.34-3.63 (5H, m), 3.79-3.89 (2H, m), 3.98-4.40 (2H, m), 4.75-5.03 (1H, m), 7.22-7.38 (1H, m), 7.51-7.68 (2H, m). To a solution of 2,3-trans-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.15 g, 0.4 mmol) in ethanol (2 mL), (3R)- Pyrrolidin-3-ol (0.037 mL, 0.5 mmol) and DMT-MM (0.13 g, 0.5 mmol) were added, and the mixture was stirred at room temperature for 3 hours. After evaporating the solvent under reduced pressure, the residue was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate only) to give the title compound as a colorless oil (0.14 g, 78%).
LC / MS 429.2
NMR (DMSO-d 6 ) δ: 1.26-1.46 (9H, m), 1.58-2.32 (4H, m), 3.34-3.63 (5H, m), 3.79-3.89 (2H, m), 3.98-4.40 (2H , m), 4.75-5.03 (1H, m), 7.22-7.38 (1H, m), 7.51-7.68 (2H, m).

参考例３４
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-{[(3S)-3-ヒドロキシピロリジン-1-イル]カルボニル}ピロリジン-1-カルボキシラート Reference Example 34
tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2-{[(3S) -3-hydroxypyrrolidin-1-yl] carbonyl} pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000094
Figure JPOXMLDOC01-appb-C000094

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.15 g, 0.4 mmol)のエタノール(2 mL)溶液に、(3S)-ピロリジン-3-オール(0.037 mL, 0.5 mmol)およびDMT-MM(0.13 g, 0.5 mmol)を加え、室温にて3時間攪拌した。減圧下溶媒を留去した後、残留物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチルのみ)で精製して、表題化合物を無色油状物(0.16 g, 86%)として得た。
LC/MS 429.3
NMR (DMSO-d6) δ: 1.22-1.49 (9H, m), 1.53-2.36 (4H, m), 3.35-3.69 (5H, m), 3.77-3.93 (2H, m), 4.08-4.50 (2H, m), 4.69-5.07 (1H, m), 7.20-7.39 (1H, m), 7.48-7.70 (2H, m). To a solution of 2,3-trans-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.15 g, 0.4 mmol) in ethanol (2 mL), add (3S)- Pyrrolidin-3-ol (0.037 mL, 0.5 mmol) and DMT-MM (0.13 g, 0.5 mmol) were added, and the mixture was stirred at room temperature for 3 hours. After evaporating the solvent under reduced pressure, the residue was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate only) to give the title compound as a colorless oil (0.16 g, 86%).
LC / MS 429.3
NMR (DMSO-d 6 ) δ: 1.22-1.49 (9H, m), 1.53-2.36 (4H, m), 3.35-3.69 (5H, m), 3.77-3.93 (2H, m), 4.08-4.50 (2H , m), 4.69-5.07 (1H, m), 7.20-7.39 (1H, m), 7.48-7.70 (2H, m).

参考例３５
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-{[(2S)-2-(ヒドロキシメチル)ピロリジン-1-イル]カルボニル}ピロリジン-1-カルボキシラート Reference Example 35
tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2-{[(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] carbonyl} pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000095
Figure JPOXMLDOC01-appb-C000095

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.15 g, 0.4 mmol)のエタノール(2 mL)溶液に、(2S)-ピロリジン-2-イルメタノール(0.045 mL, 0.5 mmol)およびDMT-MM(0.13 g, 0.5 mmol)を加え、室温にて3時間攪拌した。減圧下溶媒を留去した後、残留物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチルのみ)で精製して、表題化合物を無色油状物(0.13 g, 72%)として得た。
LC/MS 443.3
NMR (DMSO-d6) δ: 1.25-1.47 (9H, m), 1.50-2.35 (7H, m), 3.00-3.28 (2H, m), 3.35-3.71 (4H, m), 3.85-4.06 (1H, m), 4.17-4.47 (1H, m), 4.58-4.94 (1H, m), 7.10-7.30 (3H, m). To a solution of 2,3-trans-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.15 g, 0.4 mmol) in ethanol (2 mL), (2S)- Pyrrolidin-2-ylmethanol (0.045 mL, 0.5 mmol) and DMT-MM (0.13 g, 0.5 mmol) were added, and the mixture was stirred at room temperature for 3 hours. After evaporating the solvent under reduced pressure, the residue was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate only) to give the title compound as a colorless oil (0.13 g, 72%).
LC / MS 443.3
NMR (DMSO-d 6 ) δ: 1.25-1.47 (9H, m), 1.50-2.35 (7H, m), 3.00-3.28 (2H, m), 3.35-3.71 (4H, m), 3.85-4.06 (1H , m), 4.17-4.47 (1H, m), 4.58-4.94 (1H, m), 7.10-7.30 (3H, m).

参考例３６
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-{[(2R)-2-(ヒドロキシメチル)ピロリジン-1-イル]カルボニル}ピロリジン-1-カルボキシラート Reference Example 36
tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2-{[(2R) -2- (hydroxymethyl) pyrrolidin-1-yl] carbonyl} pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000096
Figure JPOXMLDOC01-appb-C000096

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.15 g, 0.4 mmol)のエタノール(2 mL)溶液に、(2R)-ピロリジン-2-イルメタノール(0.045 mL, 0.5 mmol)およびDMT-MM(0.13 g, 0.5 mmol)を加え、室温にて3時間攪拌した。減圧下溶媒を留去した後、残留物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチルのみ)で精製して、表題化合物を無色油状物(0.15 g, 81%)として得た。
LC/MS 443.2
NMR (DMSO-d6) δ: 1.15-1.52 (9H, m), 1.54-2.26 (5H, m), 2.94-5.10 (11H, m), 6.84-7.93 (3H, m). To a solution of 2,3-trans-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.15 g, 0.4 mmol) in ethanol (2 mL), (2R)- Pyrrolidin-2-ylmethanol (0.045 mL, 0.5 mmol) and DMT-MM (0.13 g, 0.5 mmol) were added, and the mixture was stirred at room temperature for 3 hours. After evaporating the solvent under reduced pressure, the residue was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only to ethyl acetate only) to give the title compound as a colorless oil (0.15 g, 81%).
LC / MS 443.2
NMR (DMSO-d 6 ) δ: 1.15-1.52 (9H, m), 1.54-2.26 (5H, m), 2.94-5.10 (11H, m), 6.84-7.93 (3H, m).

参考例３７
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-{[(2S)-2-(メトキシメチル)ピロリジン-1-イル]カルボニル}ピロリジン-1-カルボキシラート Reference Example 37
tert-Butyl (2S * , 3R * )-3- (3,4-Dichlorophenyl) -2-{[(2S) -2- (methoxymethyl) pyrrolidin-1-yl] carbonyl} pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000097
Figure JPOXMLDOC01-appb-C000097

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.15 g, 0.42 mmol)のDMF(3 mL)溶液にHOBt(0.096 g, 0.63 mmol)とWSC(0.12 g, 0.63 mmol)を加えた。これに(2S)-2-(メトキシメチル)ピロリジン(0.10 mL, 0.83 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルで洗浄することにより、表題化合物を白色結晶(0.19 g, 100%)として得た。
LC/MS 357.2 [M+]-Boc 2,3-trans-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.15 g, 0.42 mmol) in DMF (3 mL) was added to HOBt (0.096 g, 0.63 mmol) and WSC (0.12 g, 0.63 mmol) were added. To this was added (2S) -2- (methoxymethyl) pyrrolidine (0.10 mL, 0.83 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.19 g, 100%).
LC / MS 357.2 [M + ] -Boc

参考例３８
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-{[(2R)-2-(メトキシメチル)ピロリジン-1-イル]カルボニル}ピロリジン-1-カルボキシラート Reference Example 38
tert-butyl (2S * , 3R * ) -3- (3,4-dichlorophenyl) -2-{[(2R) -2- (methoxymethyl) pyrrolidin-1-yl] carbonyl} pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000098
Figure JPOXMLDOC01-appb-C000098

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.15 g, 0.42 mmol)のDMF(3 mL)溶液にHOBt(0.096 g, 0.63 mmol)とWSC(0.12 g, 0.63 mmol)を加えた。これに(2R)-2-(メトキシメチル)ピロリジン(0.10 mL, 0.83 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルで洗浄することにより、表題化合物を白色結晶(0.19 g, 100%)として得た。
LC/MS 357.2 [M+]-Boc 2,3-trans-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.15 g, 0.42 mmol) in DMF (3 mL) was added to HOBt (0.096 g, 0.63 mmol) and WSC (0.12 g, 0.63 mmol) were added. (2R) -2- (methoxymethyl) pyrrolidine (0.10 mL, 0.83 mmol) was added thereto, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.19 g, 100%).
LC / MS 357.2 [M + ] -Boc

参考例３９
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-[(3,3-ジフルオロピロリジン-1-イル)カルボニル]ピロリジン-1-カルボキシラート Reference Example 39
tert-Butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2-[(3,3-difluoropyrrolidin-1-yl) carbonyl] pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000099
Figure JPOXMLDOC01-appb-C000099

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.15 g, 0.42 mmol)のDMF(3 mL)溶液にHOBt(0.096 g, 0.63 mmol)とWSC(0.12 g, 0.63 mmol)を加えた。これに3,3-ジフルオロピロリジン　1塩酸塩(0.12 g, 0.83 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルで洗浄することにより、表題化合物を白色結晶(0.18 g, 96%)として得た。
LC/MS 349.1 [M+]-Boc 2,3-trans-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.15 g, 0.42 mmol) in DMF (3 mL) was added to HOBt (0.096 g, 0.63 mmol) and WSC (0.12 g, 0.63 mmol) were added. To this was added 3,3-difluoropyrrolidine monohydrochloride (0.12 g, 0.83 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.18 g, 96%).
LC / MS 349.1 [M + ] -Boc

参考例４０
tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート Reference Example 40
tert-Butyl (2R * , 3R * )-3- (3,4-Dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000100
Figure JPOXMLDOC01-appb-C000100

　1-tert-ブチル 2-メチル (2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート(0.42 g, 1.1 mmol)のTHF(10 mL)溶液にテトラヒドロほう酸リチウム(0.055 g, 2.5 mmol)を0℃で加え、室温で2日間攪拌した。反応混合物に水を加えた後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（3-30% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.26 g, 67%)として得た。
NMR (CDCl3) δ: 1.49 (9H, s), 2.07-2.18 (1H, m), 2.21-2.38 (1H, m), 3.22-3.54 (4H, m), 3.63 (2H, t, J = 8.9 Hz), 4.20-4.30 (1H, m), 7.07 (1H, d, J = 8.3 Hz), 7.31 (1H, brs), 7.39 (1H, d, J = 8.2 Hz). 1-tert-butyl 2-methyl (2R * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate (0.42 g, 1.1 mmol) in THF (10 mL) Lithium borate (0.055 g, 2.5 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (3-30% ethyl acetate / hexane) to give the title compound as a colorless oil (0.26 g, 67%).
NMR (CDCl 3 ) δ: 1.49 (9H, s), 2.07-2.18 (1H, m), 2.21-2.38 (1H, m), 3.22-3.54 (4H, m), 3.63 (2H, t, J = 8.9 Hz), 4.20-4.30 (1H, m), 7.07 (1H, d, J = 8.3 Hz), 7.31 (1H, brs), 7.39 (1H, d, J = 8.2 Hz).

参考例４１
tert-ブチル (2R*,3R*)-3-(3-クロロ-4-フルオロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート Reference Example 41
tert-Butyl (2R * , 3R * )-3- (3-Chloro-4-fluorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000101
Figure JPOXMLDOC01-appb-C000101

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-2-カルボン酸(0.50 g, 1.5 mmol)のTHF(10 mL)溶液に、1.1 MボランTHF錯体THF溶液(5.3 mL, 5.8 mmol)を加え、室温にて終夜攪拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～ヘキサン/酢酸エチル=1/1)で精製して、表題化合物を無色油状物(0.42 g, 87%)として得た。
LC/MS 230.1 [M+]-Boc
NMR (DMSO-d6) δ: 1.41 (9H, brs), 1.90-2.03 (1H, m), 2.37-2.48 (1H, m), 2.88-3.05 (1H, m), 3.25-3.37 (1H, m), 3.40-3.58 (3H, m), 3.79-3.94 (1H, m), 4.42 (1H, brs), 7.26-7.43 (2H, m), 7.52-7.62 (1H, m). To a solution of 2,3-cis-1- (tert-butoxycarbonyl) -3- (3-chloro-4-fluorophenyl) pyrrolidine-2-carboxylic acid (0.50 g, 1.5 mmol) in THF (10 mL) was added 1.1. M borane THF complex THF solution (5.3 mL, 5.8 mmol) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only-hexane / ethyl acetate = 1/1) to give the title compound as a colorless oil (0.42 g, 87%).
LC / MS 230.1 [M + ] -Boc
NMR (DMSO-d 6 ) δ: 1.41 (9H, brs), 1.90-2.03 (1H, m), 2.37-2.48 (1H, m), 2.88-3.05 (1H, m), 3.25-3.37 (1H, m ), 3.40-3.58 (3H, m), 3.79-3.94 (1H, m), 4.42 (1H, brs), 7.26-7.43 (2H, m), 7.52-7.62 (1H, m).

参考例４２
tert-ブチル (2R*,3R*)-3-(3-クロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート Reference Example 42
tert-Butyl (2R * , 3R * )-3- (3-Chlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000102
Figure JPOXMLDOC01-appb-C000102

　1-tert-ブチル 2-メチル (2R*,3R*)-3-(3-クロロフェニル)ピロリジン-1,2-ジカルボキシラート(5 g, 15 mmol)のTHF(125 mL)溶液に1 MボランTHF錯体THF溶液(31 mL, 31 mmol)を0℃で加え、0℃で2時間攪拌後、室温で終夜攪拌した。反応混合物にメタノールを0℃で加えた後、減圧下溶媒を留去した。得られた残渣に水を加え、酢酸エチルで抽出した。抽出液を飽和炭酸ナトリウム水溶液および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（3-30% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(4.4 g, 95%)として得た。
NMR (DMSO-d6) δ: 1.42 (9H, s), 1.90-2.04 (2H, m), 2.92-3.04 (1H, m), 3.25-3.37 (1H, m), 3.40-3.58 (3H, m), 3.88 (1H, brs), 4.40 (1H, brs), 7.24-7.36 (3H, m), 7.42 (1H, s). 1-tert-butyl 2-methyl (2R * , 3R * )-3- (3-chlorophenyl) pyrrolidine-1,2-dicarboxylate (5 g, 15 mmol) in THF (125 mL) in 1 M borane A THF complex THF solution (31 mL, 31 mmol) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 2 hours and then at room temperature overnight. Methanol was added to the reaction mixture at 0 ° C., and the solvent was evaporated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (3-30% ethyl acetate / hexane) to give the title compound as a colorless oil (4.4 g, 95%).
NMR (DMSO-d 6 ) δ: 1.42 (9H, s), 1.90-2.04 (2H, m), 2.92-3.04 (1H, m), 3.25-3.37 (1H, m), 3.40-3.58 (3H, m ), 3.88 (1H, brs), 4.40 (1H, brs), 7.24-7.36 (3H, m), 7.42 (1H, s).

参考例４３
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート Reference Example 43
tert-Butyl (2S * , 3R * )-3- (3,4-Dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000103
Figure JPOXMLDOC01-appb-C000103

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.26 g, 0.72 mmol)のTHF(5 mL)溶液に1 MボランTHF錯体THF溶液(3.1 mL)を加え、室温で6時間攪拌した後、50℃で1時間加熱した。反応混合物にメタノール／酢酸混合液(9:1, 10 mL)を加えた後、減圧下溶媒を留去した。得られた残渣を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（3-30% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.14 g, 56%)として得た。
NMR (CDCl3) δ: 1.50 (9H, s), 1.83-1.99 (1H, m), 2.11-2.22 (1H, m), 2.84-2.94 (1H, m), 3.29-3.41 (1H, m), 3.57-3.66 (1H, m), 3.69-3.92 (3H, m), 4.81 (1H, d, J = 7.4 Hz), 7.07 (1H, dd, J = 8.3, 1.9 Hz), 7.33 (1H, d, J = 1.9 Hz), 7.39 (1H, d, J = 8.2 Hz). 1,3-borane-THF complex in a solution of 2,3-trans-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.26 g, 0.72 mmol) in THF (5 mL) A THF solution (3.1 mL) was added, and the mixture was stirred at room temperature for 6 hours, and then heated at 50 ° C. for 1 hour. A methanol / acetic acid mixture (9: 1, 10 mL) was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (3-30% ethyl acetate / hexane) to give the title compound as a colorless oil (0.14 g, 56%).
NMR (CDCl 3 ) δ: 1.50 (9H, s), 1.83-1.99 (1H, m), 2.11-2.22 (1H, m), 2.84-2.94 (1H, m), 3.29-3.41 (1H, m), 3.57-3.66 (1H, m), 3.69-3.92 (3H, m), 4.81 (1H, d, J = 7.4 Hz), 7.07 (1H, dd, J = 8.3, 1.9 Hz), 7.33 (1H, d, J = 1.9 Hz), 7.39 (1H, d, J = 8.2 Hz).

参考例４４
tert-ブチル (2S*,3R*)-3-(3-クロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート Reference Example 44
tert-Butyl (2S * , 3R * )-3- (3-Chlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000104
Figure JPOXMLDOC01-appb-C000104

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3-クロロフェニル)ピロリジン-2-カルボン酸(0.5 g, 1.53 mmol)のTHF(12.5 mL)溶液に1 MボランTHF錯体THF溶液(3.1 mL, 3.1 mmol)を0℃で加え、0℃で1時間攪拌後、室温で終夜攪拌した。反応混合物にメタノールを0℃で加えた後、減圧下溶媒を留去した。得られた残渣に水を加え、酢酸エチルで抽出した。抽出液を飽和炭酸ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（3-30% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.44 g, 92%)として得た。
NMR (DMSO-d6) δ: 1.41 (9H, s), 1.78-1.94 (1H, m), 2.15-2.31 (1H, m), 3.20-3.34 (1H, m), 3.38-3.55 (4H, m), 3.58-3.74 (1H, m), 4.86 (1H, t, J = 5.7 Hz), 7.18 (1H, d, J = 7.6 Hz), 7.23-7.40 (3H, m). 1,3-borane-THF complex THF solution in 2,3-trans-1- (tert-butoxycarbonyl) -3- (3-chlorophenyl) pyrrolidine-2-carboxylic acid (0.5 g, 1.53 mmol) in THF (12.5 mL) (3.1 mL, 3.1 mmol) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour and then at room temperature overnight. Methanol was added to the reaction mixture at 0 ° C., and the solvent was evaporated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (3-30% ethyl acetate / hexane) to give the title compound as a colorless oil (0.44 g, 92%).
NMR (DMSO-d 6 ) δ: 1.41 (9H, s), 1.78-1.94 (1H, m), 2.15-2.31 (1H, m), 3.20-3.34 (1H, m), 3.38-3.55 (4H, m ), 3.58-3.74 (1H, m), 4.86 (1H, t, J = 5.7 Hz), 7.18 (1H, d, J = 7.6 Hz), 7.23-7.40 (3H, m).

参考例４５
tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-ヒドロキシプロパン-2-イル)ピロリジン-1-カルボキシラート Reference Example 45
tert-Butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000105
Figure JPOXMLDOC01-appb-C000105

　1-tert-ブチル 2-メチル (2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート(0.58 g, 1.6 mmol)のTHF(15 mL)溶液に1 Mメチルマグネシウムブロミド THF溶液(4.7 mL)を0℃で加え、室温で4時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、塩基性シリカゲル上で濾過し、濾液を減圧下濃縮した。得られた残渣をTHF(15 mL)に再度溶解させ、1 Mメチルマグネシウムブロミド THF溶液(4.7 mL)を加え、室温で終夜攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、塩基性シリカゲル上で濾過し、濾液を減圧下濃縮することにより、表題化合物を淡黄色油状物(0.52 g, 90%)として得た。
NMR (CDCl3) δ: 0.77-0.94 (6H, m), 1.50 (9H, s), 2.03-2.15 (1H, m), 2.54-2.66 (1H, m), 3.45-3.69 (4H, m), 4.20 (1H, brs), 7.19 (1H, d, J = 7.3 Hz), 7.36-7.47 (2H, m). 1-tert-butyl 2-methyl (2R * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate (0.58 g, 1.6 mmol) in THF (15 mL) M methylmagnesium bromide THF solution (4.7 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered on basic silica gel, and the filtrate was concentrated under reduced pressure. The obtained residue was redissolved in THF (15 mL), 1 M methylmagnesium bromide THF solution (4.7 mL) was added, and the mixture was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered over basic silica gel, and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow oil (0.52 g, 90%).
NMR (CDCl 3 ) δ: 0.77-0.94 (6H, m), 1.50 (9H, s), 2.03-2.15 (1H, m), 2.54-2.66 (1H, m), 3.45-3.69 (4H, m), 4.20 (1H, brs), 7.19 (1H, d, J = 7.3 Hz), 7.36-7.47 (2H, m).

参考例４６
2,3-cis-2-[3-(3,4-ジクロロフェニル)ピロリジン-2-イル]プロパン-2-オール（保持時間小）
2,3-cis-2-[3-(3,4-ジクロロフェニル)ピロリジン-2-イル]プロパン-2-オール（保持時間大） Reference Example 46
2,3-cis-2- [3- (3,4-dichlorophenyl) pyrrolidin-2-yl] propan-2-ol (low retention time)
2,3-cis-2- [3- (3,4-dichlorophenyl) pyrrolidin-2-yl] propan-2-ol (large retention time)

Figure JPOXMLDOC01-appb-C000106
Figure JPOXMLDOC01-appb-C000106

　2-[(2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]プロパン-2-オール(0.67 g)を高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ　ＡＤ（５０ｍｍＩＤ×５００ｍｍＬ　ダイセル化学工業製）、移動相：Ａ）ヘキサン１００％、Ｂ）エタノール１００％、Ｃ）ジエチルアミン１００％、混合比：Ａ／Ｂ／Ｃ＝９５０／５０／１、流速：８０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて分画した。上記の高速液体クロマトグラフィー条件にて保持時間の小さい方の光学活性体を含有する分画液を濃縮して、2,3-cis-2-[3-(3,4-ジクロロフェニル)ピロリジン-2-イル]プロパン-2-オール（保持時間小）（０．２６ｇ、９８．３％ｅｅ）を得た。
LC/MS 274
　また、保持時間の大きい方の光学活性体を含有する分画液を濃縮して、2,3-cis-2-[3-(3,4-ジクロロフェニル)ピロリジン-2-イル]プロパン-2-オール（保持時間大）（０．２５ｇ、９６．５％ｅｅ）を得た。
LC/MS 274
　鏡像体過剰率（ｅｅ）は高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ　ＡＤ（４．６ｍｍＩＤ×２５０ｍｍＬ　ダイセル化学工業製）、移動相：Ａ）ヘキサン１００％、Ｂ）エタノール１００％、Ｃ）ジエチルアミン１００％、混合比：Ａ／Ｂ／Ｃ＝９５０／５０／１、流速：１．０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて測定した。 2-[(2R * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidin-2-yl] propan-2-ol (0.67 g) was subjected to high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID × 500 mm L Daicel). Chemical Industries), mobile phase: A) hexane 100%, B) ethanol 100%, C) diethylamine 100%, mixing ratio: A / B / C = 950/50/1, flow rate: 80 mL / min, column temperature: (30 ° C.). The fraction solution containing the optically active substance having the smaller retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give 2,3-cis-2- [3- (3,4-dichlorophenyl) pyrrolidine-2 -Il] propan-2-ol (short retention time) (0.26 g, 98.3% ee) was obtained.
LC / MS 274
Further, the fraction containing the optically active substance having the longer retention time was concentrated to give 2,3-cis-2- [3- (3,4-dichlorophenyl) pyrrolidin-2-yl] propane-2- All (long holding time) (0.25 g, 96.5% ee) was obtained.
LC / MS 274
The enantiomeric excess (ee) was determined by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mm ID × 250 mmL manufactured by Daicel Chemical Industries), mobile phase: A) hexane 100%, B) ethanol 100%, C) diethylamine 100%, Mixing ratio: A / B / C = 950/50/1, flow rate: 1.0 mL / min, column temperature: 30 ° C.).

参考例４７
tert-ブチル (2R*,3R*)-2-(2-ヒドロキシプロパン-2-イル)-3-(ナフタレン-2-イル)ピロリジン-1-カルボキシラート Reference Example 47
tert-butyl (2R * , 3R * )-2- (2-hydroxypropan-2-yl) -3- (naphthalen-2-yl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000107
Figure JPOXMLDOC01-appb-C000107

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(ナフタレン-2-イル)ピロリジン-2-カルボン酸(0.50 g, 1.47 mmol)のメタノール(15 mL)溶液に(トリメチルシリル)ジアゾメタンのジエチルエーテル溶液(2 M, 2.2 mL, 4.39 mmol)を0℃で滴下し、0℃で10分間、室温で１時間攪拌後、酢酸を0℃で滴下し、反応を停止した。減圧下溶媒を留去し、得られた残渣のTHF(15 mL)溶液に1 Mメチルマグネシウムブロミド THF溶液(4.39 mL, 4.39 mmol)を0℃で加え、室温で4時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（3-20% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.37 g, 71%)として得た。
NMR (CDCl3) δ: 0.66 (3H, brs), 0.99 (3H, brs), 1.52 (9H, s), 2.14-2.28 (1H, m), 2.71-2.89 (1H, m), 3.61-3.98 (4H, m), 4.35 (1H, brs), 7.43-7.52 (3H, m), 7.72-7.84 (4H, m). 2,3-cis-1- (tert-butoxycarbonyl) -3- (naphthalen-2-yl) pyrrolidine-2-carboxylic acid (0.50 g, 1.47 mmol) in methanol (15 mL) solution of (trimethylsilyl) diazomethane Diethyl ether solution (2 M, 2.2 mL, 4.39 mmol) was added dropwise at 0 ° C., and the mixture was stirred at 0 ° C. for 10 minutes and at room temperature for 1 hour, and then acetic acid was added dropwise at 0 ° C. to stop the reaction. The solvent was distilled off under reduced pressure, 1 M methylmagnesium bromide THF solution (4.39 mL, 4.39 mmol) was added to a THF (15 mL) solution of the obtained residue at 0 ° C., and the mixture was stirred at room temperature for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (3-20% ethyl acetate / hexane) to give the title compound as a colorless oil (0.37 g, 71%).
NMR (CDCl 3 ) δ: 0.66 (3H, brs), 0.99 (3H, brs), 1.52 (9H, s), 2.14-2.28 (1H, m), 2.71-2.89 (1H, m), 3.61-3.98 ( 4H, m), 4.35 (1H, brs), 7.43-7.52 (3H, m), 7.72-7.84 (4H, m).

参考例４８
tert-ブチル (2R*,3R*)-3-(3-クロロ-4-フルオロフェニル)-2-(2-ヒドロキシプロパン-2-イル)ピロリジン-1-カルボキシラート Reference Example 48
tert-Butyl (2R * , 3R * )-3- (3-Chloro-4-fluorophenyl) -2- (2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000108
Figure JPOXMLDOC01-appb-C000108

　1-tert-ブチル 2-メチル (2R*,3R*)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-1,2-ジカルボキシラート(0.37 g, 1.0 mmol)のTHF(5.0 mL)溶液に3 Mメチルマグネシウムブロミド ジエチルエーテル溶液(4.2 mL, 13 mmol)を室温にて加え、終夜攪拌した。反応混合物に、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去して、表題化合物を淡黄色油状物(0.35 g, 95%)として得た。
LC/MS 302.2 [M+]-tBu
NMR (DMSO-d6) δ: 0.54 (3H, s), 0.96 (3H, brs), 1.42 (9H, s), 1.88-2.00 (1H, m), 2.63-2.84 (1H, m), 3.35-3.54 (3H, m), 3.96 (1H, brs), 4.21 (1H, brs), 7.30 (1H, t, J = 8.9 Hz), 7.40-7.50 (1H, m), 7.63 (1H, dd, J = 7.2, 1.9 Hz). 1-tert-butyl 2-methyl (2R * , 3R * )-3- (3-chloro-4-fluorophenyl) pyrrolidine-1,2-dicarboxylate (0.37 g, 1.0 mmol) in THF (5.0 mL) To the solution was added 3 M methylmagnesium bromide diethyl ether solution (4.2 mL, 13 mmol) at room temperature, and the mixture was stirred overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow oil (0.35 g, 95%).
LC / MS 302.2 [M +] -tBu
NMR (DMSO-d 6 ) δ: 0.54 (3H, s), 0.96 (3H, brs), 1.42 (9H, s), 1.88-2.00 (1H, m), 2.63-2.84 (1H, m), 3.35- 3.54 (3H, m), 3.96 (1H, brs), 4.21 (1H, brs), 7.30 (1H, t, J = 8.9 Hz), 7.40-7.50 (1H, m), 7.63 (1H, dd, J = 7.2, 1.9 Hz).

参考例４９
tert-ブチル (2R*,3R*)-3-(3-クロロフェニル)-2-(2-ヒドロキシプロパン-2-イル)ピロリジン-1-カルボキシラート Reference Example 49
tert-Butyl (2R * , 3R * )-3- (3-Chlorophenyl) -2- (2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000109
Figure JPOXMLDOC01-appb-C000109

　1-tert-ブチル 2-エチル (2R*,3R*)-3-(3-クロロフェニル)ピロリジン-1,2-ジカルボキシラート(0.5 g, 1.41 mmol)のTHF(5 mL)溶液に1 Mメチルマグネシウムブロミド THF溶液(4.2 mL)を0℃で加え、室温で終夜攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（25-50% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.4 g, 84%)として得た。
NMR (DMSO-d6) δ: 0.53 (3H, s), 0.89-1.06 (3H, m), 1.42 (9H, s), 1.87-2.03 (1H, m), 2.68-2.88 (1H, m), 3.35-3.53 (3H, m), 3.88-4.03 (1H, m), 4.09-4.25 (1H, m), 7.22-7.36 (2H, m), 7.38-7.44 (1H, m), 7.49 (1H, brs). 1-tert-butyl 2-ethyl (2R * , 3R * )-3- (3-chlorophenyl) pyrrolidine-1,2-dicarboxylate (0.5 g, 1.41 mmol) in THF (5 mL) in 1 M methyl Magnesium bromide THF solution (4.2 mL) was added at 0 ° C., and the mixture was stirred overnight at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (25-50% ethyl acetate / hexane) to give the title compound as a colorless oil (0.4 g, 84%).
NMR (DMSO-d 6 ) δ: 0.53 (3H, s), 0.89-1.06 (3H, m), 1.42 (9H, s), 1.87-2.03 (1H, m), 2.68-2.88 (1H, m), 3.35-3.53 (3H, m), 3.88-4.03 (1H, m), 4.09-4.25 (1H, m), 7.22-7.36 (2H, m), 7.38-7.44 (1H, m), 7.49 (1H, brs ).

参考例５０
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-ヒドロキシプロパン-2-イル)ピロリジン-1-カルボキシラート Reference Example 50
tert-Butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000110
Figure JPOXMLDOC01-appb-C000110

　1-tert-ブチル 2-メチル (2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート(1.33 g, 3.6 mmol)のTHF(20 mL)溶液に1 Mメチルマグネシウムブロミド THF溶液(11 mL)を0℃で加え、0℃で1時間、室温で2日間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（3-25% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.74 g, 56%)として得た。
NMR (CDCl3) δ: 1.09-1.19 (6H, m), 1.51 (9H, s), 1.69-1.82 (1H, m), 2.27 (1H, brs), 3.14 (1H, brs), 3.26-3.36 (1H, m), 3.87 (1H, brs), 4.06 (1H, brs), 5.07 (1H, brs), 7.02 (1H, d, J = 8.2 Hz), 7.26 (1H, brs), 7.36 (1H, d, J = 8.2 Hz). 1-tert-butyl 2-methyl (2S * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate (1.33 g, 3.6 mmol) in THF (20 mL) M methylmagnesium bromide THF solution (11 mL) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 2 days. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (3-25% ethyl acetate / hexane) to give the title compound as a colorless oil (0.74 g, 56%).
NMR (CDCl 3 ) δ: 1.09-1.19 (6H, m), 1.51 (9H, s), 1.69-1.82 (1H, m), 2.27 (1H, brs), 3.14 (1H, brs), 3.26-3.36 ( 1H, m), 3.87 (1H, brs), 4.06 (1H, brs), 5.07 (1H, brs), 7.02 (1H, d, J = 8.2 Hz), 7.26 (1H, brs), 7.36 (1H, d , J = 8.2 Hz).

参考例５１
tert-ブチル 2,3-trans-3-(3,4-ジクロロフェニル)-2-(2-ヒドロキシプロパン-2-イル)ピロリジン-1-カルボキシラート（保持時間小）
tert-ブチル 2,3-trans-3-(3,4-ジクロロフェニル)-2-(2-ヒドロキシプロパン-2-イル)ピロリジン-1-カルボキシラート（保持時間大） Reference Example 51
tert-butyl 2,3-trans-3- (3,4-dichlorophenyl) -2- (2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate (low retention time)
tert-butyl 2,3-trans-3- (3,4-dichlorophenyl) -2- (2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate (large retention time)

Figure JPOXMLDOC01-appb-C000111
Figure JPOXMLDOC01-appb-C000111

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-ヒドロキシプロパン-2-イル)ピロリジン-1-カルボキシラート(1.3 g)を高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ　ＡＤ（５０ｍｍＩＤ×５００ｍｍＬ　ダイセル化学工業製）、移動相：Ａ）ヘキサン１００％、Ｂ）イソプロピルアルコール１００％、混合比：Ａ／Ｂ＝９５０／５０、流速：８０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて分画した。上記の高速液体クロマトグラフィー条件にて保持時間の小さい方の光学活性体を含有する分画液を濃縮して、tert-ブチル 2,3-trans-3-(3,4-ジクロロフェニル)-2-(2-ヒドロキシプロパン-2-イル)ピロリジン-1-カルボキシラート（保持時間小：18.0min）（０．６２ｇ、＞９９％ｅｅ）を得た。
LC/MS 300.0 [M+]-OtBu
　また、保持時間の大きい方の光学活性体を含有する分画液を濃縮して、tert-ブチル 2,3-trans-3-(3,4-ジクロロフェニル)-2-(2-ヒドロキシプロパン-2-イル)ピロリジン-1-カルボキシラート（保持時間大：30.1min）（０．６２ｇ、＞９９％ｅｅ）を得た。
LC/MS 300.0 [M+]-OtBu
　鏡像体過剰率（ｅｅ）は高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ　ＡＤ（４．６ｍｍＩＤ×２５０ｍｍＬ　ダイセル化学工業製）、移動相：Ａ）ヘキサン１００％、Ｂ）エタノール＝１００％、Ｃ）ジエチルアミン＝１００％、混合比：Ａ／Ｂ／Ｃ＝９５０／５０／１、流速：１．０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて測定した。（保持時間小：7.1min、保持時間大：12.4min） tert-Butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate (1.3 g) was subjected to high performance liquid chromatography (column : CHIRALPAK AD (50 mm ID × 500 mmL manufactured by Daicel Chemical Industries), mobile phase: A) 100% hexane, B) 100% isopropyl alcohol, mixing ratio: A / B = 950/50, flow rate: 80 mL / min, column temperature: 30 Fractionation was performed using (° C). The fraction solution containing the optically active substance having the smaller retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give tert-butyl 2,3-trans-3- (3,4-dichlorophenyl) -2- (2-Hydroxypropan-2-yl) pyrrolidine-1-carboxylate (low retention time: 18.0 min) (0.62 g,> 99% ee) was obtained.
LC / MS 300.0 [M + ] -O t Bu
In addition, the fraction containing the optically active substance having the longer retention time is concentrated to obtain tert-butyl 2,3-trans-3- (3,4-dichlorophenyl) -2- (2-hydroxypropane-2 -Yl) pyrrolidine-1-carboxylate (long retention time: 30.1 min) (0.62 g,> 99% ee) was obtained.
LC / MS 300.0 [M + ] -O t Bu
The enantiomeric excess (ee) was determined by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mm ID × 250 mm L, manufactured by Daicel Chemical Industries), mobile phase: A) hexane 100%, B) ethanol = 100%, C) diethylamine = 100 %, Mixing ratio: A / B / C = 950/50/1, flow rate: 1.0 mL / min, column temperature: 30 ° C.). (Retention time low: 7.1min, retention time high: 12.4min)

参考例５２
tert-ブチル (2S*,3R*)-2-(2-ヒドロキシプロパン-2-イル)-3-(ナフタレン-2-イル)ピロリジン-1-カルボキシラート Reference Example 52
tert-Butyl (2S * , 3R * )-2- (2-hydroxypropan-2-yl) -3- (naphthalen-2-yl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000112
Figure JPOXMLDOC01-appb-C000112

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(ナフタレン-2-イル)ピロリジン-2-カルボン酸(0.58 g, 1.70 mmol)のメタノール(10 mL)溶液に(トリメチルシリル)ジアゾメタンのジエチルエーテル溶液(2 M, 0.85 mL, 1.70 mmol)を0℃で滴下し、0℃で10分間、室温で１時間攪拌後、酢酸を0℃で滴下し、反応を停止した。減圧下溶媒を留去した。得られた残渣のTHF(10 mL)溶液に1 Mメチルマグネシウムブロミド THF溶液(5.1 mL)を0℃で加え、0℃で1時間、室温で終夜攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（25-50% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.47 g, 78%)として得た。
NMR (DMSO-d6) δ: 1.04-1.22 (6H, m), 1.32-1.51 (9H, m), 1.83 (1H, brs), 2.38-2.57 (1H, m), 3.62-3.95 (4H, m), 4.46-4.71 (1H, m), 7.28 (1H, brs), 7.41-7.54 (2H, m), 7.59 (1H, brs), 7.75-7.92 (3H, m). 2,3-trans-1- (tert-butoxycarbonyl) -3- (naphthalen-2-yl) pyrrolidine-2-carboxylic acid (0.58 g, 1.70 mmol) in methanol (10 mL) solution of (trimethylsilyl) diazomethane Diethyl ether solution (2 M, 0.85 mL, 1.70 mmol) was added dropwise at 0 ° C., and the mixture was stirred at 0 ° C. for 10 minutes and at room temperature for 1 hour, and acetic acid was added dropwise at 0 ° C. to stop the reaction. The solvent was distilled off under reduced pressure. To a solution of the obtained residue in THF (10 mL) was added 1 M methylmagnesium bromide THF solution (5.1 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour and at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (25-50% ethyl acetate / hexane) to give the title compound as a colorless oil (0.47 g, 78%).
NMR (DMSO-d 6 ) δ: 1.04-1.22 (6H, m), 1.32-1.51 (9H, m), 1.83 (1H, brs), 2.38-2.57 (1H, m), 3.62-3.95 (4H, m ), 4.46-4.71 (1H, m), 7.28 (1H, brs), 7.41-7.54 (2H, m), 7.59 (1H, brs), 7.75-7.92 (3H, m).

参考例５３
tert-ブチル (2S*,3R*)-3-(3-クロロ-4-フルオロフェニル)-2-(2-ヒドロキシプロパン-2-イル)ピロリジン-1-カルボキシラート Reference Example 53
tert-Butyl (2S * , 3R * )-3- (3-Chloro-4-fluorophenyl) -2- (2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000113
Figure JPOXMLDOC01-appb-C000113

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-2-カルボン酸(0.59 g, 1.7 mmol)のメタノール(5 mL)溶液に(トリメチルシリル)ジアゾメタンのジエチルエーテル溶液(2 M, 3.5 mL, 7 mmol)を0℃で滴下し、気体の発生が終了するまで攪拌した後、酢酸を気体の発生が終了するまで加えた。減圧下溶媒を留去し、得られた残渣を塩基性シリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチルのみ)で精製し、1-tert-ブチル 2-メチル (2S*,3R*)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-1,2-ジカルボキシラートの粗精製物を無色油状物(0.43 g, 71%)として得た。
LC/MS 258.0 [M+]-tBu
　得られた1-tert-ブチル 2-メチル (2S*,3R*)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-1,2-ジカルボキシラート(0.43 g, 1.2 mmol)のTHF(10 mL)溶液に3 Mメチルマグネシウムブロミド ジエチルエーテル溶液(1.2 mL, 3.7 mmol)を0℃にて加え、室温にて終夜攪拌した。反応混合物に、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～ヘキサン/酢酸エチル=1/1)で精製して、表題化合物を無色油状物(0.14 g, 33%)として得た。
LC/MS 258.2 [M+]-tBu
NMR (DMSO-d6) δ: 1.02-1.14 (6H, m), 1.40 (9H, brs), 1.60-1.80 (1H, m), 2.28-2.47 (1H, m), 3.24-3.39 (1H, m), 3.48-3.82 (3H, m), 4.59 (1H, brs), 7.06-7.27 (2H, m), 7.35 (1H, t, J = 9.0 Hz). To a solution of 2,3-trans-1- (tert-butoxycarbonyl) -3- (3-chloro-4-fluorophenyl) pyrrolidine-2-carboxylic acid (0.59 g, 1.7 mmol) in methanol (5 mL), add (trimethylsilyl ) A solution of diazomethane in diethyl ether (2 M, 3.5 mL, 7 mmol) was added dropwise at 0 ° C. and stirred until gas evolution ceased, and then acetic acid was added until gas evolution ceased. The solvent was distilled off under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (hexane only to ethyl acetate only), and 1-tert-butyl 2-methyl (2S * , 3R * )-3- ( A crude product of 3-chloro-4-fluorophenyl) pyrrolidine-1,2-dicarboxylate was obtained as a colorless oil (0.43 g, 71%).
LC / MS 258.0 [M + ] -tBu
1-tert-butyl 2-methyl (2S * , 3R * )-3- (3-chloro-4-fluorophenyl) pyrrolidine-1,2-dicarboxylate (0.43 g, 1.2 mmol) in THF ( 10 mL) solution was added 3 M methylmagnesium bromide diethyl ether solution (1.2 mL, 3.7 mmol) at 0 ° C. and stirred overnight at room temperature. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only-hexane / ethyl acetate = 1/1) to give the title compound as a colorless oil (0.14 g, 33%).
LC / MS 258.2 [M + ] -tBu
NMR (DMSO-d 6 ) δ: 1.02-1.14 (6H, m), 1.40 (9H, brs), 1.60-1.80 (1H, m), 2.28-2.47 (1H, m), 3.24-3.39 (1H, m ), 3.48-3.82 (3H, m), 4.59 (1H, brs), 7.06-7.27 (2H, m), 7.35 (1H, t, J = 9.0 Hz).

参考例５４
tert-ブチル (2S*,3R*)-3-(3-クロロフェニル)-2-(2-ヒドロキシプロパン-2-イル)ピロリジン-1-カルボキシラート Reference Example 54
tert-Butyl (2S * , 3R * )-3- (3-Chlorophenyl) -2- (2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000114
Figure JPOXMLDOC01-appb-C000114

　1-tert-ブチル 2-メチル (2S*,3R*)-3-(3-クロロフェニル)ピロリジン-1,2-ジカルボキシラート(0.42 g, 1.23 mmol)のTHF(10 mL)溶液に1 Mメチルマグネシウムブロミド THF溶液(3.7 mL)を0℃で加え、0℃で1時間、室温で終夜攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（25-50% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.14 g, 33%)として得た。
NMR (DMSO-d6) δ: 1.08 (3H, brs), 1.11 (3H, brs), 1.41 (9H, brs), 1.61-1.80 (1H, m), 2.31-2.49 (1H, m), 3.24-3.39 (1H, m), 3.55 (1H, brs), 3.73 (2H, brs), 4.57 (1H, brs), 7.03-7.15 (2H, m), 7.21-7.38 (2H, m). 1-tert-butyl 2-methyl (2S * , 3R * )-3- (3-chlorophenyl) pyrrolidine-1,2-dicarboxylate (0.42 g, 1.23 mmol) in THF (10 mL) in 1 M methyl Magnesium bromide THF solution (3.7 mL) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour and at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (25-50% ethyl acetate / hexane) to give the title compound as a colorless oil (0.14 g, 33%).
NMR (DMSO-d 6 ) δ: 1.08 (3H, brs), 1.11 (3H, brs), 1.41 (9H, brs), 1.61-1.80 (1H, m), 2.31-2.49 (1H, m), 3.24- 3.39 (1H, m), 3.55 (1H, brs), 3.73 (2H, brs), 4.57 (1H, brs), 7.03-7.15 (2H, m), 7.21-7.38 (2H, m).

参考例５５
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-1-カルボキシラート Reference Example 55
tert-Butyl (2S * , 3R * )-3- (3,4-Dichlorophenyl) -2- (methoxymethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000115
Figure JPOXMLDOC01-appb-C000115

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート(1.2 g, 3.4 mmol)とヨードメタン(2.1 mL, 34 mmol)のDMF(15 mL)溶液に水素化ナトリウム(0.18 g, 4.4 mmol)を0℃で加え、0℃で3時間、室温で終夜攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、水で希釈した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（3-15% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.95 g, 79%)として得た。
NMR (CDCl3) δ: 1.49 (9H, s), 1.79-1.92 (1H, m), 2.20-2.34 (1H, m), 3.35 (3H, s), 3.37-3.63 (5H, m), 3.82-3.94 (1H, m), 7.03 (1H, dd, J = 8.3, 2.1 Hz), 7.29 (1H, d, J = 2.1 Hz), 7.37 (1H, d, J = 8.3 Hz). of tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (1.2 g, 3.4 mmol) and iodomethane (2.1 mL, 34 mmol) Sodium hydride (0.18 g, 4.4 mmol) was added to the DMF (15 mL) solution at 0 ° C., and the mixture was stirred at 0 ° C. for 3 hours and at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (3-15% ethyl acetate / hexane) to give the title compound as a colorless oil (0.95 g, 79%).
NMR (CDCl 3 ) δ: 1.49 (9H, s), 1.79-1.92 (1H, m), 2.20-2.34 (1H, m), 3.35 (3H, s), 3.37-3.63 (5H, m), 3.82- 3.94 (1H, m), 7.03 (1H, dd, J = 8.3, 2.1 Hz), 7.29 (1H, d, J = 2.1 Hz), 7.37 (1H, d, J = 8.3 Hz).

参考例５６
2,3-trans-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン（保持時間小）
2,3-trans-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン（保持時間大） Reference Example 56
2,3-trans-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine (low retention time)
2,3-trans-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine (large retention time)

Figure JPOXMLDOC01-appb-C000116
Figure JPOXMLDOC01-appb-C000116

　(2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン(0.51 g)を高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ　ＩＣ（５０ｍｍＩＤ×５００ｍｍＬ　ダイセル化学工業製）、移動相：Ａ）ヘキサン１００％、Ｂ）エタノール１００％、Ｃ）ジエチルアミン１００％、混合比：Ａ／Ｂ／Ｃ＝９５０／５０／１、流速：８０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて分画した。上記の高速液体クロマトグラフィー条件にて保持時間の小さい方の光学活性体を含有する分画液を濃縮して、2,3-trans-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン（保持時間小）（０．２３ｇ、９８．３％ｅｅ）を得た。
LC/MS 259.9
　また、保持時間の大きい方の光学活性体を含有する分画液を濃縮して、2,3-trans-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン（保持時間大）（０．２４ｇ、９５．６％ｅｅ）を得た。
LC/MS 259.9
　鏡像体過剰率（ｅｅ）は高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ　ＩＣ（４．６ｍｍＩＤ×２５０ｍｍＬ　ダイセル化学工業製）、移動相：Ａ）ヘキサン１００％、Ｂ）エタノール１００％、混合比：Ａ／Ｂ＝９５０／５０、流速：１．０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて測定した。 (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine (0.51 g) was subjected to high performance liquid chromatography (column: CHIRALPAK IC (50 mm ID × 500 mm L manufactured by Daicel Chemical Industries), transfer Phase: A) 100% hexane, B) 100% ethanol, C) 100% diethylamine, mixing ratio: A / B / C = 950/50/1, flow rate: 80 mL / min, column temperature: 30 ° C.) Fractionated. The fraction solution containing the optically active substance having the smaller retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give 2,3-trans-3- (3,4-dichlorophenyl) -2- (methoxymethyl ) Pyrrolidine (short retention time) (0.23 g, 98.3% ee) was obtained.
LC / MS 259.9
Further, the fraction containing the optically active substance having the longer retention time is concentrated to give 2,3-trans-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine (large retention time). (0.24 g, 95.6% ee) was obtained.
LC / MS 259.9
The enantiomeric excess (ee) was determined by high performance liquid chromatography (column: CHIRALPAK IC (4.6 mm ID × 250 mmL, manufactured by Daicel Chemical Industries), mobile phase: A) hexane 100%, B) ethanol 100%, mixing ratio: A / B = 950/50, flow rate: 1.0 mL / min, column temperature: 30 ° C.).

参考例５７
tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-1-カルボキシラート Reference Example 57
tert-Butyl (2R * , 3R * )-3- (3,4-Dichlorophenyl) -2- (methoxymethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000117
Figure JPOXMLDOC01-appb-C000117

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート(0.30 g, 0.87 mmol)とヨードメタン(0.54 mL, 8.7 mmol)のDMF(3 mL)溶液に水素化ナトリウム(0.050 g, 1.3 mmol)を0℃で加え、0℃で3時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、水で希釈した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（0-10% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.28 g, 90%)として得た。
NMR (CDCl3) δ: 1.48 (9H, s), 1.96-2.10 (1H, m), 2.42-2.59 (1H, m), 2.84-2.98 (1H, m), 3.08 (3H, s), 3.32-3.67 (4H, m), 3.88-4.07 (1H, m), 7.14 (1H, dd, J = 8.3, 2.1 Hz), 7.39 (1H, d, J = 8.3 Hz), 7.41 (1H, d, J = 2.1 Hz). of tert-butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (0.30 g, 0.87 mmol) and iodomethane (0.54 mL, 8.7 mmol) Sodium hydride (0.050 g, 1.3 mmol) was added to the DMF (3 mL) solution at 0 ° C., and the mixture was stirred at 0 ° C. for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0-10% ethyl acetate / hexane) to give the title compound as a colorless oil (0.28 g, 90%).
NMR (CDCl 3 ) δ: 1.48 (9H, s), 1.96-2.10 (1H, m), 2.42-2.59 (1H, m), 2.84-2.98 (1H, m), 3.08 (3H, s), 3.32- 3.67 (4H, m), 3.88-4.07 (1H, m), 7.14 (1H, dd, J = 8.3, 2.1 Hz), 7.39 (1H, d, J = 8.3 Hz), 7.41 (1H, d, J = 2.1 Hz).

参考例５８
tert-ブチル 2,3-cis-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-1-カルボキシラート（保持時間小）
tert-ブチル 2,3-cis-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-1-カルボキシラート（保持時間大） Reference Example 58
tert-butyl 2,3-cis-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine-1-carboxylate (low retention time)
tert-butyl 2,3-cis-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine-1-carboxylate (large retention time)

Figure JPOXMLDOC01-appb-C000118
Figure JPOXMLDOC01-appb-C000118

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-1-カルボキシラート(1.8 g)を高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ　ＡＤ（５０ｍｍＩＤ×５００ｍｍＬ　ダイセル化学工業製）、移動相：Ａ）ヘキサン１００％、Ｂ）イソプロピルアルコール１００％、混合比：Ａ／Ｂ＝９５０／５０、流速：８０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて分画した。上記の高速液体クロマトグラフィー条件にて保持時間の小さい方の光学活性体を含有する分画液を濃縮して、tert-ブチル 2,3-cis-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-1-カルボキシラート（保持時間小：13.0min）（０．８５ｇ、＞９９％ｅｅ）を得た。
LC/MS 259.9 [M+]-Boc
　また、保持時間の大きい方の光学活性体を含有する分画液を濃縮して、tert-ブチル 2,3-cis-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-1-カルボキシラート（保持時間大：24.5min）（０．８３g、＞９９％ｅｅ）を得た。
LC/MS 259.9 [M+]-Boc
　鏡像体過剰率（ｅｅ）は高速液体クロマトグラフィー（カラム：ＣＨＩＲＡＬＰＡＫ　ＡＤ（４．６ｍｍＩＤ×２５０ｍｍＬ　ダイセル化学工業製）、移動相：Ａ）ヘキサン１００％、Ｂ）イソプロピルアルコール１００％、混合比：Ａ／Ｂ＝９５０／５０、流速：１．０ｍＬ／ｍｉｎ、カラム温度：３０℃）を用いて測定した（保持時間小：4.9min、保持時間大：7.7min）。 tert-Butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine-1-carboxylate (1.8 g) was subjected to high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID × 500 mmL manufactured by Daicel Chemical Industries, Ltd.), mobile phase: A) 100% hexane, B) 100% isopropyl alcohol, mixing ratio: A / B = 950/50, flow rate: 80 mL / min, column temperature: 30 ° C.) Drew. The fraction solution containing the optically active substance having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give tert-butyl 2,3-cis-3- (3,4-dichlorophenyl) -2- (Methoxymethyl) pyrrolidine-1-carboxylate (low retention time: 13.0 min) (0.85 g,> 99% ee) was obtained.
LC / MS 259.9 [M + ] -Boc
Further, the fraction containing the optically active substance having the longer retention time was concentrated to give tert-butyl 2,3-cis-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine-1 -Carboxylate (large retention time: 24.5 min) (0.83 g,> 99% ee) was obtained.
LC / MS 259.9 [M + ] -Boc
The enantiomeric excess (ee) was determined by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mm ID × 250 mmL manufactured by Daicel Chemical Industries), mobile phase: A) hexane 100%, B) isopropyl alcohol 100%, mixing ratio: A / B = 950/50, flow rate: 1.0 mL / min, column temperature: 30 ° C.) (low retention time: 4.9 min, high retention time: 7.7 min).

参考例５９
tert-ブチル (2R*,3R*)-3-(3-クロロ-4-フルオロフェニル)-2-(メトキシメチル)ピロリジン-1-カルボキシラート Reference Example 59
tert-Butyl (2R * , 3R * )-3- (3-Chloro-4-fluorophenyl) -2- (methoxymethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000119
Figure JPOXMLDOC01-appb-C000119

　tert-ブチル (2R*,3R*)-3-(3-クロロ-4-フルオロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート(0.64 g, 1.9 mmol)のDMF(10 mL)溶液にヨードメタン(1.2 mL, 19 mmol)および水素化ナトリウム(60%油性)(0.10 g, 2.5 mmol)を0℃にて加え、徐々に室温に昇温して4時間攪拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～ヘキサン/酢酸エチル=1/1)で精製して、表題化合物を無色油状物(0.54 g, 81%)として得た。
LC/MS 336.1 [M+]+Na
NMR (DMSO-d6) δ: 1.42 (9H, s), 1.84-2.06 (1H, m), 2.38 (1H, brs), 2.81-2.90 (1H, m), 2.95 (3H, brs), 3.21-3.62 (4H, m), 3.98 (1H, brs), 7.29-7.42 (2H, m), 7.53 (1H, d, J = 7.6 Hz). tert-Butyl (2R * , 3R * )-3- (3-Chloro-4-fluorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (0.64 g, 1.9 mmol) in DMF (10 mL) To the solution, iodomethane (1.2 mL, 19 mmol) and sodium hydride (60% oily) (0.10 g, 2.5 mmol) were added at 0 ° C., and the mixture was gradually warmed to room temperature and stirred for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only-hexane / ethyl acetate = 1/1) to give the title compound as a colorless oil (0.54 g, 81%).
LC / MS 336.1 [M + ] + Na
NMR (DMSO-d 6 ) δ: 1.42 (9H, s), 1.84-2.06 (1H, m), 2.38 (1H, brs), 2.81-2.90 (1H, m), 2.95 (3H, brs), 3.21- 3.62 (4H, m), 3.98 (1H, brs), 7.29-7.42 (2H, m), 7.53 (1H, d, J = 7.6 Hz).

参考例６０
tert-ブチル (2R*,3R*)-3-(3-クロロフェニル)-2-(メトキシメチル)ピロリジン-1-カルボキシラート Reference Example 60
tert-Butyl (2R * , 3R * )-3- (3-Chlorophenyl) -2- (methoxymethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000120
Figure JPOXMLDOC01-appb-C000120

　tert-ブチル (2R*,3R*)-3-(3-クロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート(0.25 g, 0.80 mmol)とヨードメタン(0.5 mL, 8.0 mmol)のDMF(3 mL)溶液に水素化ナトリウム(0.042 g, 1.0 mmol)を0℃で加え、室温で3時間攪拌した。反応混合物を水で希釈した後、酢酸エチルで抽出した。抽出液を水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（10-50% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.26 g, 99%)として得た。
NMR (DMSO-d6) δ: 1.42 (9H, s), 1.91-2.03 (1H, m), 2.34-2.47 (1H, m), 2.85 (1H, d, J = 10.2 Hz), 2.95 (2H, brs), 3.32 (3H, s), 3.35-3.44 (1H, m), 3.44-3.54 (1H, m), 3.99 (1H, brs), 7.26-7.40 (4H, m). DMF of tert-butyl (2R * , 3R * )-3- (3-chlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (0.25 g, 0.80 mmol) and iodomethane (0.5 mL, 8.0 mmol) 3 mL) solution was added sodium hydride (0.042 g, 1.0 mmol) at 0 ° C. and stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (10-50% ethyl acetate / hexane) to give the title compound as a colorless oil (0.26 g, 99%).
NMR (DMSO-d 6 ) δ: 1.42 (9H, s), 1.91-2.03 (1H, m), 2.34-2.47 (1H, m), 2.85 (1H, d, J = 10.2 Hz), 2.95 (2H, brs), 3.32 (3H, s), 3.35-3.44 (1H, m), 3.44-3.54 (1H, m), 3.99 (1H, brs), 7.26-7.40 (4H, m).

参考例６１
tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(エトキシメチル)ピロリジン-1-カルボキシラート Reference Example 61
tert-Butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (ethoxymethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000121
Figure JPOXMLDOC01-appb-C000121

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート(0.50 g, 1.4 mmol)とヨードエタン(1.2 mL, 14 mmol)のDMF(5 mL)溶液に水素化ナトリウム(0.075 g, 1.9 mmol)を0℃で加え、0℃で3時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、水で希釈した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（0-10% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.50 g, 93%)として得た。
NMR (CDCl3) δ: 1.05 (3H, t, J = 7.0 Hz), 1.48 (9H, s), 1.96-2.09 (1H, m), 2.46-2.63 (1H, m), 2.98 (1H, d, J = 10.2 Hz), 3.07-3.23 (2H, m), 3.35-3.67 (4H, m), 3.92-4.07 (1H, m), 7.11-7.17 (1H, m), 7.38 (1H, d, J = 8.3 Hz), 7.44 (1H, d, J = 1.9 Hz). of tert-butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (0.50 g, 1.4 mmol) and iodoethane (1.2 mL, 14 mmol) Sodium hydride (0.075 g, 1.9 mmol) was added to the DMF (5 mL) solution at 0 ° C., and the mixture was stirred at 0 ° C. for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0-10% ethyl acetate / hexane) to give the title compound as a colorless oil (0.50 g, 93%).
NMR (CDCl 3 ) δ: 1.05 (3H, t, J = 7.0 Hz), 1.48 (9H, s), 1.96-2.09 (1H, m), 2.46-2.63 (1H, m), 2.98 (1H, d, J = 10.2 Hz), 3.07-3.23 (2H, m), 3.35-3.67 (4H, m), 3.92-4.07 (1H, m), 7.11-7.17 (1H, m), 7.38 (1H, d, J = 8.3 Hz), 7.44 (1H, d, J = 1.9 Hz).

参考例６２
tert-ブチル 2,3-cis-3-(3,4-ジクロロフェニル)-2-(1-メトキシ-1-メチルエチル)ピロリジン-1-カルボキシラート Reference Example 62
tert-butyl 2,3-cis-3- (3,4-dichlorophenyl) -2- (1-methoxy-1-methylethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000122
Figure JPOXMLDOC01-appb-C000122

62-a) tert-ブチル2,3-cis-3-(3,4-ジクロロフェニル)-2-(1-ヒドロキシ-1-メチルエチル)ピロリジン-1-カルボキシラート 62-a) tert-butyl 2,3-cis-3- (3,4-dichlorophenyl) -2- (1-hydroxy-1-methylethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000123
Figure JPOXMLDOC01-appb-C000123

　参考例７９で得た1-tert-ブチル 2-メチル2,3-cis-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート（保持時間小）(4.0 g, 32.1 mmol)のTHF(100 mL)溶液に1 Mメチルマグネシウムブロミド THF溶液(32 mL)を0℃で加え、0℃で1時間、室温で終夜攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（3-30% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を白色固体(3.8 g, 94%)として得た。
NMR (CDCl3) δ: 0.77-0.94 (6H, m), 1.50 (9H, s), 2.03-2.15 (1H, m), 2.54-2.66 (1H, m), 3.45-3.69 (4H, m), 4.20 (1H, brs), 7.19 (1H, d, J = 7.3 Hz), 7.36-7.47 (1H, m). 1-tert-butyl 2-methyl-2,3-cis-3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate obtained in Reference Example 79 (short retention time) (4.0 g, 32.1 mmol) To a THF (100 mL) solution was added 1 M methylmagnesium bromide THF solution (32 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour and at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (3-30% ethyl acetate / hexane) to give the title compound as a white solid (3.8 g, 94%).
NMR (CDCl 3 ) δ: 0.77-0.94 (6H, m), 1.50 (9H, s), 2.03-2.15 (1H, m), 2.54-2.66 (1H, m), 3.45-3.69 (4H, m), 4.20 (1H, brs), 7.19 (1H, d, J = 7.3 Hz), 7.36-7.47 (1H, m).

62-b) tert-ブチル2,3-cis-3-(3,4-ジクロロフェニル)-2-(1-メトキシ-1-メチルエチル)ピロリジン-1-カルボキシラート 62-b) tert-butyl 2,3-cis-3- (3,4-dichlorophenyl) -2- (1-methoxy-1-methylethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000124
Figure JPOXMLDOC01-appb-C000124

　tert-ブチル 2,3-cis-3-(3,4-ジクロロフェニル)-2-(1-ヒドロキシ-1-メチルエチル)ピロリジン-1-カルボキシラート(0.20 g, 0.53 mmol)とヨードメタン(0.33 mL, 5.3 mmol)のDMF(3 mL)溶液に水素化ナトリウム(0.028 g, 0.70 mmol)を加え、室温で6日間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、水で希釈した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（3-15% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.085 g, 41%)として得た。
LC/MS 288.2 [M+]-Boc tert-Butyl 2,3-cis-3- (3,4-dichlorophenyl) -2- (1-hydroxy-1-methylethyl) pyrrolidine-1-carboxylate (0.20 g, 0.53 mmol) and iodomethane (0.33 mL, Sodium hydride (0.028 g, 0.70 mmol) was added to a solution of 5.3 mmol) in DMF (3 mL), and the mixture was stirred at room temperature for 6 days. A saturated aqueous ammonium chloride solution was added to the reaction mixture, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (3-15% ethyl acetate / hexane) to give the title compound as a colorless oil (0.085 g, 41%).
LC / MS 288.2 [M + ] -Boc

参考例６３
エチル (2S*,3R*)-1-アセチル-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-2-カルボキシラート Reference Example 63
Ethyl (2S * , 3R * )-1-acetyl-3- (3,4-dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-2-carboxylate

Figure JPOXMLDOC01-appb-C000125
Figure JPOXMLDOC01-appb-C000125

　ジエチル 1-アセチル-3-(3,4-ジクロロフェニル)ピロリジン-2,2-ジカルボキシラート(0.80 g, 2 mmol)のエタノール(4 mL)溶液に水素化ホウ素ナトリウム(0.17 g, 4 mmol)を加え、室温で3.5時間、次いで60℃で4時間攪拌した。反応混合物を室温まで冷却後、水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチルのみ～メタノール/酢酸エチル=1/10)で精製して、表題化合物を白色固体(0.48 g, 67%)として得た。
LC/MS 360.0
NMR (DMSO-d6) δ: 0.88 (3H, t, J = 7.1 Hz), 1.99 (3H, s), 2.01-2.12 (1H, m), 2.31-2.47 (1H, m), 3.37-3.58 (2H, m), 3.63-3.76 (2H, m), 3.79-3.93 (2H, m), 4.19 (1H, dd, J = 11.6, 5.0 Hz), 5.02 (1H, dd, J = 7.4, 5.2 Hz), 7.20 (1H, dd, J = 8.5, 2.1 Hz), 7.42 (1H, d, J = 2.1 Hz), 7.60 (1H, d, J = 8.3 Hz). Sodium borohydride (0.17 g, 4 mmol) was added to a solution of diethyl 1-acetyl-3- (3,4-dichlorophenyl) pyrrolidine-2,2-dicarboxylate (0.80 g, 2 mmol) in ethanol (4 mL). The mixture was further stirred at room temperature for 3.5 hours and then at 60 ° C. for 4 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only-ethyl acetate only-methanol / ethyl acetate = 1/10) to give the title compound as a white solid (0.48 g, 67%).
LC / MS 360.0
NMR (DMSO-d 6 ) δ: 0.88 (3H, t, J = 7.1 Hz), 1.99 (3H, s), 2.01-2.12 (1H, m), 2.31-2.47 (1H, m), 3.37-3.58 ( 2H, m), 3.63-3.76 (2H, m), 3.79-3.93 (2H, m), 4.19 (1H, dd, J = 11.6, 5.0 Hz), 5.02 (1H, dd, J = 7.4, 5.2 Hz) , 7.20 (1H, dd, J = 8.5, 2.1 Hz), 7.42 (1H, d, J = 2.1 Hz), 7.60 (1H, d, J = 8.3 Hz).

参考例６４
エチル (2S*,3R*)-1-アセチル-3-(3-クロロ-4-フルオロフェニル)-2-(ヒドロキシメチル)ピロリジン-2-カルボキシラート Reference Example 64
Ethyl (2S * , 3R * )-1-acetyl-3- (3-chloro-4-fluorophenyl) -2- (hydroxymethyl) pyrrolidine-2-carboxylate

Figure JPOXMLDOC01-appb-C000126
Figure JPOXMLDOC01-appb-C000126

　ジエチル 1-アセチル-3-(3-クロロ-4-フルオロフェニル)ピロリジン-2,2-ジカルボキシラート(1.80 g, 5 mmol)のエタノール(10 mL)溶液に水素化ホウ素ナトリウム(0.42 g, 10 mmol)を加え、60℃で2時間攪拌した。反応混合物を室温まで冷却後、水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチルのみ～メタノール/酢酸エチル=1/10)で精製して、表題化合物を無色油状物(0.77 g, 45%)として得た。
LC/MS 344.0
NMR (DMSO-d6) δ: 0.88 (3H, t, J = 7.0 Hz), 1.96-2.11 (4H, m), 2.32-2.47 (1H, m), 3.36-3.58 (2H, m), 3.63-3.75 (2H, m), 3.79-3.93 (2H, m), 4.19 (1H, dd, J = 11.7, 4.9 Hz), 5.00 (1H, dd, J = 7.4, 5.1 Hz), 7.18-7.26 (1H, m), 7.33-7.43 (2H, m). Diethyl 1-acetyl-3- (3-chloro-4-fluorophenyl) pyrrolidine-2,2-dicarboxylate (1.80 g, 5 mmol) in ethanol (10 mL) was added to sodium borohydride (0.42 g, 10 mmol) was added, and the mixture was stirred at 60 ° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only-ethyl acetate only-methanol / ethyl acetate = 1/10) to give the title compound as a colorless oil (0.77 g, 45%).
LC / MS 344.0
NMR (DMSO-d 6 ) δ: 0.88 (3H, t, J = 7.0 Hz), 1.96-2.11 (4H, m), 2.32-2.47 (1H, m), 3.36-3.58 (2H, m), 3.63- 3.75 (2H, m), 3.79-3.93 (2H, m), 4.19 (1H, dd, J = 11.7, 4.9 Hz), 5.00 (1H, dd, J = 7.4, 5.1 Hz), 7.18-7.26 (1H, m), 7.33-7.43 (2H, m).

参考例６５
エチル (2S*,3R*)-1-アセチル-3-(4-クロロフェニル)-2-(ヒドロキシメチル)ピロリジン-2-カルボキシラート Reference Example 65
Ethyl (2S * , 3R * )-1-acetyl-3- (4-chlorophenyl) -2- (hydroxymethyl) pyrrolidine-2-carboxylate

Figure JPOXMLDOC01-appb-C000127
Figure JPOXMLDOC01-appb-C000127

　ジエチル 1-アセチル-3-(4-クロロフェニル)ピロリジン-2,2-ジカルボキシラート(0.60 g, 1.6 mmol)のエタノール(10 mL)溶液に水素化ホウ素ナトリウム(0.14 g, 3.3 mmol)を加え、60℃で6時間攪拌した。反応混合物を室温まで冷却後、水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチルのみ～メタノール/酢酸エチル=1/5)で精製して、表題化合物を無色油状物(0.23 g, 43%)として得た。
LC/MS 326.0
NMR (DMSO-d6) δ: 0.86 (3H, t, J = 7.2 Hz), 1.94-2.14 (4H, m), 2.35-2.47 (1H, m), 3.37-3.58 (2H, m), 3.61-3.72 (2H, m), 3.79-3.93 (2H, m), 4.20 (1H, dd, J = 11.4, 4.9 Hz), 4.95 (1H, dd, J = 7.6, 4.9 Hz), 7.17-7.26 (2H, m), 7.33-7.42 (2H, m). Sodium borohydride (0.14 g, 3.3 mmol) was added to a solution of diethyl 1-acetyl-3- (4-chlorophenyl) pyrrolidine-2,2-dicarboxylate (0.60 g, 1.6 mmol) in ethanol (10 mL), The mixture was stirred at 60 ° C. for 6 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only-ethyl acetate only-methanol / ethyl acetate = 1/5) to give the title compound as a colorless oil (0.23 g, 43%).
LC / MS 326.0
NMR (DMSO-d 6 ) δ: 0.86 (3H, t, J = 7.2 Hz), 1.94-2.14 (4H, m), 2.35-2.47 (1H, m), 3.37-3.58 (2H, m), 3.61- 3.72 (2H, m), 3.79-3.93 (2H, m), 4.20 (1H, dd, J = 11.4, 4.9 Hz), 4.95 (1H, dd, J = 7.6, 4.9 Hz), 7.17-7.26 (2H, m), 7.33-7.42 (2H, m).

参考例６６
tert-ブチル (2S*,3R*)-2-アセチル-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-1-カルボキシラート
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-ヒドロキシプロパン-2-イル)-2-(メトキシメチル)ピロリジン-1-カルボキシラート Reference Example 66
tert-Butyl (2S * , 3R * )-2-acetyl-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine-1-carboxylate
tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (2-hydroxypropan-2-yl) -2- (methoxymethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000128
Figure JPOXMLDOC01-appb-C000128

　1-tert-ブチル 2-エチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-1,2-ジカルボキシラート(0.43 g, 1 mmol)のTHF(10 mL)溶液に3 Mメチルマグネシウムブロミド ジエチルエーテル溶液(3.3 mL, 10 mmol)を加え、0℃にて3時間、次いで60℃にて2時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物を分取HPLCにて精製し、得られた2つのピークを含むフラクションをそれぞれ濃縮し、酢酸エチルで抽出した。それぞれの有機層を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去して、tert-ブチル (2S*,3R*)-2-アセチル-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-1-カルボキシラートを無色油状物(0.14 g, 35%)として、tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-ヒドロキシプロパン-2-イル)-2-(メトキシメチル)ピロリジン-1-カルボキシラートを無色油状物(0.038 g, 9%)として得た。
tert-ブチル (2S*,3R*)-2-アセチル-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-1-カルボキシラート
LC/MS 302.1 [M+]-Boc
NMR (DMSO-d6) δ: 1.29-1.47 (9H, m), 1.81 (3H, s), 2.00-2.15 (1H, m), 3.22-3.43 (5H, m), 3.66-3.93 (4H, m), 7.21 (1H, ddd, J = 8.4, 4.4, 2.1 Hz), 7.44 (1H, dd, J = 7.9, 2.1 Hz), 7.57 (1H, dd, J = 8.5, 1.7 Hz).
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-ヒドロキシプロパン-2-イル)-2-(メトキシメチル)ピロリジン-1-カルボキシラート
LC/MS 418.0
NMR (DMSO-d6) δ: 0.30-0.61 (3H, m), 0.84-1.13 (3H, m), 1.42 (9H, s), 1.69-1.88 (1H, m), 2.56-2.90 (1H, m), 3.22-3.65 (6H, m), 3.71-4.22 (1H, m), 4.43-4.91 (1H, m), 7.31 (1H, dd, J = 8.4, 1.8 Hz), 7.49-7.65 (3H, m). 1-tert-butyl 2-ethyl (2S * , 3R * ) -3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine-1,2-dicarboxylate (0.43 g, 1 mmol) in THF To the (10 mL) solution was added 3 M methylmagnesium bromide diethyl ether solution (3.3 mL, 10 mmol), and the mixture was stirred at 0 ° C. for 3 hours and then at 60 ° C. for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative HPLC, and the obtained fractions containing the two peaks were each concentrated and extracted with ethyl acetate. Each organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and tert-butyl (2S * , 3R * )-2-acetyl-3- (3,4-dichlorophenyl) -2- (methoxy Methyl) pyrrolidine-1-carboxylate as a colorless oil (0.14 g, 35%) as tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (2-hydroxypropane- 2-yl) -2- (methoxymethyl) pyrrolidine-1-carboxylate was obtained as a colorless oil (0.038 g, 9%).
tert-Butyl (2S * , 3R * )-2-acetyl-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine-1-carboxylate
LC / MS 302.1 [M + ] -Boc
NMR (DMSO-d 6) δ : 1.29-1.47 (9H, m), 1.81 (3H, s), 2.00-2.15 (1H, m), 3.22-3.43 (5H, m), 3.66-3.93 (4H, m ), 7.21 (1H, ddd, J = 8.4, 4.4, 2.1 Hz), 7.44 (1H, dd, J = 7.9, 2.1 Hz), 7.57 (1H, dd, J = 8.5, 1.7 Hz).
tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (2-hydroxypropan-2-yl) -2- (methoxymethyl) pyrrolidine-1-carboxylate
LC / MS 418.0
NMR (DMSO-d 6 ) δ: 0.30-0.61 (3H, m), 0.84-1.13 (3H, m), 1.42 (9H, s), 1.69-1.88 (1H, m), 2.56-2.90 (1H, m ), 3.22-3.65 (6H, m), 3.71-4.22 (1H, m), 4.43-4.91 (1H, m), 7.31 (1H, dd, J = 8.4, 1.8 Hz), 7.49-7.65 (3H, m ).

参考例６７
1-tert-ブチル 2-エチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-1,2-ジカルボキシラート Reference Example 67
1-tert-butyl 2-ethyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine-1,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000129
Figure JPOXMLDOC01-appb-C000129

67-a) 1-tert-ブチル2-エチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1,2-ジカルボキシラート 67-a) 1-tert-butyl 2-ethyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-1,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000130
Figure JPOXMLDOC01-appb-C000130

　エチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-2-カルボキシラート　1塩酸塩(3.63 g, 10 mmol)のエタノール(30 mL)溶液にトリエチルアミン(4.2 mL, 31 mmol)およびジ-tert-ブチル ジカルボナート(3.6 mL, 15 mmol)を加え、室温にて終夜攪拌した。減圧下溶媒を留去し、得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～ヘキサン/酢酸エチル=1/1)で精製して、表題化合物を無色非定形固体(4.2 g, 98%)として得た。
LC/MS 319.9 [M+]-Boc
NMR (DMSO-d6) δ: 0.88-1.03 (3H, m), 1.27-1.44 (9H, m), 1.90-2.06 (1H, m), 2.21-2.44 (1H, m), 3.23 (1H, m, J = 10.7, 10.7, 5.7, 5.4 Hz), 3.50-3.65 (1H, m), 3.69-4.13 (5H, m), 5.02-5.25 (1H, m), 7.21 (1H, d, J = 8.7 Hz), 7.44 (1H, s), 7.54-7.64 (1H, m). Ethyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-2-carboxylate monohydrochloride (3.63 g, 10 mmol) in ethanol (30 mL) in triethylamine (4.2 mL, 31 mmol) and di-tert-butyl dicarbonate (3.6 mL, 15 mmol) were added, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane only to hexane / ethyl acetate = 1/1) to give the title compound as a colorless amorphous solid (4.2 g, 98%) Got as.
LC / MS 319.9 [M + ] -Boc
NMR (DMSO-d 6 ) δ: 0.88-1.03 (3H, m), 1.27-1.44 (9H, m), 1.90-2.06 (1H, m), 2.21-2.44 (1H, m), 3.23 (1H, m , J = 10.7, 10.7, 5.7, 5.4 Hz), 3.50-3.65 (1H, m), 3.69-4.13 (5H, m), 5.02-5.25 (1H, m), 7.21 (1H, d, J = 8.7 Hz ), 7.44 (1H, s), 7.54-7.64 (1H, m).

67-b) 1-tert-ブチル2-エチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-1,2-ジカルボキシラート 67-b) 1-tert-butyl 2-ethyl (2S * , 3R * ) -3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine-1,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000131
Figure JPOXMLDOC01-appb-C000131

　1-tert-ブチル 2-エチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1,2-ジカルボキシラート(2.1 g, 5 mmol)のDMF(25 mL)溶液にヨードメタン(3.1 mL, 50 mmol)および水素化ナトリウム(60%油性)(0.26 g, 6.5 mmol)を加え、0℃で2時間攪拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去して、表題化合物を淡黄色油状物(2.2 g, 100%)として得た。
LC/MS 332.1 [M+]-Boc
NMR (DMSO-d6) δ: 0.85-1.03 (3H, m), 1.28-1.46 (9H, m), 1.90-2.05 (1H, m), 2.25-2.44 (1H, m), 3.09-3.29 (1H, m), 3.35-3.43 (3H, m), 3.54-4.04 (6H, m), 7.13-7.22 (1H, m), 7.38 (1H, dd, J = 7.5, 2.1 Hz), 7.55-7.66 (1H, m). DMF of 1-tert-butyl 2-ethyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-1,2-dicarboxylate (2.1 g, 5 mmol) To the (25 mL) solution was added iodomethane (3.1 mL, 50 mmol) and sodium hydride (60% oily) (0.26 g, 6.5 mmol), and the mixture was stirred at 0 ° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a pale yellow oil (2.2 g, 100%).
LC / MS 332.1 [M +] -Boc
NMR (DMSO-d 6 ) δ: 0.85-1.03 (3H, m), 1.28-1.46 (9H, m), 1.90-2.05 (1H, m), 2.25-2.44 (1H, m), 3.09-3.29 (1H , m), 3.35-3.43 (3H, m), 3.54-4.04 (6H, m), 7.13-7.22 (1H, m), 7.38 (1H, dd, J = 7.5, 2.1 Hz), 7.55-7.66 (1H , m).

参考例６８
1-tert-ブチル 2-エチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-メチルピロリジン-1,2-ジカルボキシラート Reference Example 68
1-tert-butyl 2-ethyl (2R * , 3R * ) -3- (3,4-dichlorophenyl) -2-methylpyrrolidine-1,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000132
Figure JPOXMLDOC01-appb-C000132

68-a) エチル (2R*,3R*)-2-(クロロメチル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボキシラート　1塩酸塩 68-a) Ethyl (2R * , 3R * )-2- (chloromethyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylate monohydrochloride

Figure JPOXMLDOC01-appb-C000133
Figure JPOXMLDOC01-appb-C000133

　エチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-2-カルボキシラート　1塩酸塩(0.050 g, 0.14 mmol)のトルエン(3 mL)懸濁液に塩化チオニル(0.015 mL, 0.21 mmol)を加え、90℃にて6時間攪拌した。反応混合物を室温まで冷却した後、析出物を濾取し、酢酸エチルで洗浄して、表題化合物を淡茶色固体(0.035 g, 67%)として得た。
LC/MS 338.1
NMR (DMSO-d6) δ: 0.89 (3H, t, J = 7.2 Hz), 2.35-2.47 (2H, m), 3.38-4.07 (5H, m), 4.08-4.53 (2H, m), 7.31 (1H, dd, J = 8.5, 2.5 Hz), 7.56-7.72 (2H, m), 9.52-11.08 (2H, m). Suspension of ethyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-2-carboxylate monohydrochloride (0.050 g, 0.14 mmol) in toluene (3 mL) Was added with thionyl chloride (0.015 mL, 0.21 mmol) and stirred at 90 ° C. for 6 hours. After the reaction mixture was cooled to room temperature, the precipitate was collected by filtration and washed with ethyl acetate to give the title compound as a light brown solid (0.035 g, 67%).
LC / MS 338.1
NMR (DMSO-d 6 ) δ: 0.89 (3H, t, J = 7.2 Hz), 2.35-2.47 (2H, m), 3.38-4.07 (5H, m), 4.08-4.53 (2H, m), 7.31 ( 1H, dd, J = 8.5, 2.5 Hz), 7.56-7.72 (2H, m), 9.52-11.08 (2H, m).

68-b) 1-tert-ブチル2-エチル (2R*,3R*)-2-(クロロメチル)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート 68-b) 1-tert-butyl 2-ethyl (2R * , 3R * )-2- (chloromethyl) -3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000134
Figure JPOXMLDOC01-appb-C000134

　エチル (2R*,3R*)-2-(クロロメチル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボキシラート　1塩酸塩(1.49 g, 4 mmol)のTHF(40 mL)懸濁液にトリエチルアミン(0.61 mL, 4.4 mmol)およびジ-tert-ブチル ジカルボナート(1.0 mL, 4.4 mmol)を加え、室温にて終夜攪拌した。減圧下溶媒を留去し、得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～ヘキサン/酢酸エチル=1/1)で精製して、表題化合物を無色油状物(1.2 g, 69%)として得た。
LC/MS 338.1 [M+]-Boc
NMR (DMSO-d6) δ: 0.85-1.07 (3H, m), 1.26-1.44 (9H, m), 1.82-2.23 (1H, m), 2.28-2.48 (1H, m), 3.22-3.41 (1H, m), 3.66-4.10 (5H, m), 4.16-4.55 (1H, m), 7.11-7.32 (1H, m), 7.43 (1H, dd, J = 7.0, 2.1 Hz), 7.62 (1H, d, J = 8.3 Hz). Suspension of ethyl (2R * , 3R * )-2- (chloromethyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylate monohydrochloride (1.49 g, 4 mmol) in THF (40 mL) Were added triethylamine (0.61 mL, 4.4 mmol) and di-tert-butyl dicarbonate (1.0 mL, 4.4 mmol), and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane only to hexane / ethyl acetate = 1/1) to give the title compound as a colorless oil (1.2 g, 69%). Obtained.
LC / MS 338.1 [M + ] -Boc
NMR (DMSO-d 6 ) δ: 0.85-1.07 (3H, m), 1.26-1.44 (9H, m), 1.82-2.23 (1H, m), 2.28-2.48 (1H, m), 3.22-3.41 (1H , m), 3.66-4.10 (5H, m), 4.16-4.55 (1H, m), 7.11-7.32 (1H, m), 7.43 (1H, dd, J = 7.0, 2.1 Hz), 7.62 (1H, d , J = 8.3 Hz).

68-c) 1-tert-ブチル2-エチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-メチルピロリジン-1,2-ジカルボキシラート 68-c) 1-tert-butyl 2-ethyl (2R * , 3R * ) -3- (3,4-dichlorophenyl) -2-methylpyrrolidine-1,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000135
Figure JPOXMLDOC01-appb-C000135

　1-tert-ブチル 2-エチル (2R*,3R*)-2-(クロロメチル)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート(0.49 g, 1.1 mmol)のトルエン(10 mL)溶液に、2,2'-(E)-ジアゼン-1,2-ジイルビス(2-メチルプロパンニトリル)(0.018 g, 0.1 mmol)およびトリブチルスタンナン(0.45 mL, 1.7 mmol)を加え、窒素雰囲気下、100℃にて2時間攪拌した。室温まで冷却後、反応混合物にフッ化カリウム水溶液および酢酸エチルを加え、5分間攪拌した。反応混合物をセライト濾過し、濾液を酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサンのみ～ヘキサン/酢酸エチル=1/2)で精製して、表題化合物を無色油状物(0.18 g, 41%)として得た。
LC/MS 302.1 [M+]-Boc
NMR (DMSO-d6) δ: 0.92-1.04 (3H, m), 1.27-1.43 (9H, m), 1.49-1.58 (3H, m), 1.88-1.98 (2H, m), 2.23-2.46 (1H, m), 3.32-3.52 (1H, m), 3.69-3.91 (3H, m), 7.16-7.25 (1H, m), 7.40-7.47 (1H, m), 7.53-7.67 (1H, m). 1-tert-butyl 2-ethyl (2R * , 3R * )-2- (chloromethyl) -3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate (0.49 g, 1.1 mmol) in toluene To the (10 mL) solution, add 2,2 '-(E) -diazene-1,2-diylbis (2-methylpropanenitrile) (0.018 g, 0.1 mmol) and tributylstannane (0.45 mL, 1.7 mmol). The mixture was stirred at 100 ° C. for 2 hours in a nitrogen atmosphere. After cooling to room temperature, an aqueous potassium fluoride solution and ethyl acetate were added to the reaction mixture, and the mixture was stirred for 5 minutes. The reaction mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane only-hexane / ethyl acetate = 1/2) to give the title compound as a colorless oil (0.18 g, 41%).
LC / MS 302.1 [M + ] -Boc
NMR (DMSO-d 6 ) δ: 0.92-1.04 (3H, m), 1.27-1.43 (9H, m), 1.49-1.58 (3H, m), 1.88-1.98 (2H, m), 2.23-2.46 (1H , m), 3.32-3.52 (1H, m), 3.69-3.91 (3H, m), 7.16-7.25 (1H, m), 7.40-7.47 (1H, m), 7.53-7.67 (1H, m).

参考例６９
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピロリジン-1-カルボキシラート Reference Example 69
tert-Butyl (2S * , 3R * )-3- (3,4-Dichlorophenyl) -2- (5-methyl-1,3,4-oxadiazol-2-yl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000136
Figure JPOXMLDOC01-appb-C000136

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.51 g, 1.4 mmol) のDMF(4 mL)溶液にHOBt(0.33 g, 2.1 mmol)とWSC(0.41 g, 2.1 mmol)を加えた。これにアセトヒドラジド(0.32 g, 4.3 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、無色油状物を得た。
　得られた油状物をピリジン(3 mL)に溶解させた。これに4-メチルベンゼンスルホニル クロリド(0.39 g, 2.0 mmol)を加え、窒素雰囲気下、100℃で終夜攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、塩基性シリカゲル上で濾過した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（3-40% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.090 g, 34%)として得た。
NMR (CDCl3) δ: 1.32 (9H x 5/9, brs), 1.47 (9H x 4/9, brs), 2.06-2.16 (1H, m), 2.46 (1H, brs), 2.53 (3H, s), 3.58-3.88 (3H, m), 4.88-5.08 (1H, m), 7.05 (1H, dd, J = 8.3, 2.3 Hz), 7.31 (1H, d, J = 1.9 Hz), 7.40 (1H, d, J = 8.3 Hz). To a solution of 2,3-trans-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.51 g, 1.4 mmol) in DMF (4 mL), add HOBt (0.33 g, 2.1 mmol) and WSC (0.41 g, 2.1 mmol) were added. Acetohydrazide (0.32 g, 4.3 mmol) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate) to give a colorless oil.
The resulting oil was dissolved in pyridine (3 mL). 4-methylbenzenesulfonyl chloride (0.39 g, 2.0 mmol) was added thereto, and the mixture was stirred at 100 ° C. overnight under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtered over basic silica gel. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (3-40% ethyl acetate / hexane) to give the title compound as a colorless oil (0.090 g, 34%).
NMR (CDCl 3 ) δ: 1.32 (9H x 5/9, brs), 1.47 (9H x 4/9, brs), 2.06-2.16 (1H, m), 2.46 (1H, brs), 2.53 (3H, s ), 3.58-3.88 (3H, m), 4.88-5.08 (1H, m), 7.05 (1H, dd, J = 8.3, 2.3 Hz), 7.31 (1H, d, J = 1.9 Hz), 7.40 (1H, d, J = 8.3 Hz).

参考例７０
tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピロリジン-1-カルボキシラート Reference Example 70
tert-butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (5-methyl-1,3,4-oxadiazol-2-yl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000137
Figure JPOXMLDOC01-appb-C000137

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.50 g, 1.4 mmol) のDMF(4 mL)溶液にHOBt(0.33 g, 2.1 mmol)とWSC(0.41 g, 2.1 mmol)を加えた。これにアセトヒドラジド(0.31 g, 4.2 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた油状物をジイソプロピルエーテル／酢酸エチルで結晶化することにより、白色固体を得た。
　得られた固体をピリジン(6 mL)に溶解させた。これに4-メチルベンゼンスルホニル クロリド(0.76 g, 4.0 mmol)を加え、窒素雰囲気下、100℃で終夜攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、塩基性シリカゲル上で濾過した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（3-40% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.36 g, 68%)として得た。
NMR (CDCl3) δ: 1.32 (9H x 5/9, brs), 1.47 (9H x 4/9, brs), 2.06-2.16 (1H, m), 2.46 (1H, brs), 2.53 (3H, s), 3.58-3.88 (3H, m), 4.88-5.08 (1H, m), 7.05 (1H, dd, J = 8.3, 2.3 Hz), 7.31 (1H, d, J = 1.9 Hz), 7.40 (1H, d, J = 8.3 Hz). To a solution of 2,3-cis-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.50 g, 1.4 mmol) in DMF (4 mL) was added HOBt (0.33 g, 2.1 mmol) and WSC (0.41 g, 2.1 mmol) were added. Acetohydrazide (0.31 g, 4.2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained oil was crystallized from diisopropyl ether / ethyl acetate to give a white solid.
The obtained solid was dissolved in pyridine (6 mL). 4-methylbenzenesulfonyl chloride (0.76 g, 4.0 mmol) was added thereto, and the mixture was stirred at 100 ° C. overnight under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtered over basic silica gel. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (3-40% ethyl acetate / hexane) to give the title compound as a colorless oil (0.36 g, 68%).
NMR (CDCl 3 ) δ: 1.32 (9H x 5/9, brs), 1.47 (9H x 4/9, brs), 2.06-2.16 (1H, m), 2.46 (1H, brs), 2.53 (3H, s ), 3.58-3.88 (3H, m), 4.88-5.08 (1H, m), 7.05 (1H, dd, J = 8.3, 2.3 Hz), 7.31 (1H, d, J = 1.9 Hz), 7.40 (1H, d, J = 8.3 Hz).

参考例７１
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピロリジン-1-カルボキシラート Reference Example 71
tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (3-methyl-1,2,4-oxadiazol-5-yl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000138
Figure JPOXMLDOC01-appb-C000138

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.50 g, 1.4 mmol) のDMF(4 mL)溶液にHOBt(0.33 g, 2.1 mmol)とWSC(0.41 g, 2.1 mmol)を加えた。これにN-ヒドロキシエタンイミドアミド(0.31 g, 4.2 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（20-100% 酢酸エチル／ヘキサン）で精製することにより、無色油状物(0.58 g)を得た。
　得られた油状物(0.19 g)をトルエン(5 mL)に溶解させ、終夜加熱還流した。減圧下溶媒を留去することにより、表題化合物を淡黄色油状物(0.17 g, 94%)として得た。
NMR (CDCl3) δ: 1.29 (9H x 2/3, s), 1.47 (9H x 1/3, brs), 2.03-2.18 (1H, m), 2.39 (3H, s), 2.41-2.49 (1H, m), 3.48-3.60 (1H, m), 3.65-3.92 (2H, m), 4.90 (1H x 2/3, d, J = 6.9 Hz), 5.09 (1H x 1/3, d, J = 5.5 Hz), 7.02 (1H, dd), 7.29 (1H, d, J = 2.2 Hz), 7.40 (1H, d, J = 8.2 Hz). To a solution of 2,3-trans-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.50 g, 1.4 mmol) in DMF (4 mL) was added HOBt (0.33 g, 2.1 mmol) and WSC (0.41 g, 2.1 mmol) were added. N-hydroxyethaneimidoamide (0.31 g, 4.2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (20-100% ethyl acetate / hexane) to give a colorless oil (0.58 g).
The obtained oil (0.19 g) was dissolved in toluene (5 mL) and heated to reflux overnight. The solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow oil (0.17 g, 94%).
NMR (CDCl 3 ) δ: 1.29 (9H x 2/3, s), 1.47 (9H x 1/3, brs), 2.03-2.18 (1H, m), 2.39 (3H, s), 2.41-2.49 (1H , m), 3.48-3.60 (1H, m), 3.65-3.92 (2H, m), 4.90 (1H x 2/3, d, J = 6.9 Hz), 5.09 (1H x 1/3, d, J = 5.5 Hz), 7.02 (1H, dd), 7.29 (1H, d, J = 2.2 Hz), 7.40 (1H, d, J = 8.2 Hz).

参考例７２
tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピロリジン-1-カルボキシラート Reference Example 72
tert-Butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (3-methyl-1,2,4-oxadiazol-5-yl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000139
Figure JPOXMLDOC01-appb-C000139

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.50 g, 1.4 mmol) のDMF(4 mL)溶液にHOBt(0.33 g, 2.1 mmol)とWSC(0.41 g, 2.1 mmol)を加えた。これにN-ヒドロキシエタンイミドアミド(0.31 g, 4.2 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（20-100% 酢酸エチル／ヘキサン）で精製することにより、無色油状物を得た。
　得られた油状物をトルエン(12 mL)に溶解させ、終夜加熱還流した。減圧下溶媒を留去することにより、表題化合物を淡黄色油状物(0.51 g, 99%)として得た。
LC/MS 398 To a solution of 2,3-cis-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.50 g, 1.4 mmol) in DMF (4 mL) was added HOBt (0.33 g, 2.1 mmol) and WSC (0.41 g, 2.1 mmol) were added. N-hydroxyethaneimidoamide (0.31 g, 4.2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (20-100% ethyl acetate / hexane) to give a colorless oil.
The resulting oil was dissolved in toluene (12 mL) and heated to reflux overnight. The solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow oil (0.51 g, 99%).
LC / MS 398

参考例７３
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(3-フェニル-1,2,4-オキサジアゾール-5-イル)ピロリジン-1-カルボキシラート Reference Example 73
tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (3-phenyl-1,2,4-oxadiazol-5-yl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000140
Figure JPOXMLDOC01-appb-C000140

　2,3-trans-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.30 g, 0.83 mmol) のDMF(4 mL)溶液にHOBt(0.19 g, 1.2 mmol)とWSC(0.24 g, 1.2 mmol)を加えた。これにN-ヒドロキシベンゼンカルボキシミドアミド(0.14 g, 1.0 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去することにより、無色油状物(0.58 g)を得た。
　得られた油状物(0.19 g)をトルエン(10 mL)に溶解させ、5時間加熱還流した後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（3-20% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.33 g, 86%)として得た。
LC/MS 360.2 [M+]-Boc To a solution of 2,3-trans-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.30 g, 0.83 mmol) in DMF (4 mL) was added HOBt (0.19 g, 1.2 mmol) and WSC (0.24 g, 1.2 mmol) were added. To this was added N-hydroxybenzenecarboximidamide (0.14 g, 1.0 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a colorless oil (0.58 g).
The obtained oil (0.19 g) was dissolved in toluene (10 mL), heated to reflux for 5 hours, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (3-20% ethyl acetate / hexane) to give the title compound as a colorless oil (0.33 g, 86%).
LC / MS 360.2 [M + ] -Boc

参考例７４
tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(3-フェニル-1,2,4-オキサジアゾール-5-イル)ピロリジン-1-カルボキシラート Reference Example 74
tert-Butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (3-phenyl-1,2,4-oxadiazol-5-yl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000141
Figure JPOXMLDOC01-appb-C000141

　2,3-cis-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.30 g, 0.83 mmol) のDMF(4 mL)溶液にHOBt(0.19 g, 1.2 mmol)とWSC(0.24 g, 1.2 mmol)を加えた。これにN-ヒドロキシベンゼンカルボキシミドアミド(0.14 g, 1.0 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去することにより、無色油状物(0.58 g)を得た。
　得られた油状物(0.19 g)をトルエン(10 mL)に溶解させ、5時間加熱還流した後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（3-20% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.21 g, 55%)として得た。
LC/MS 360.2 [M+]-Boc To a solution of 2,3-cis-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.30 g, 0.83 mmol) in DMF (4 mL) was added HOBt (0.19 g, 1.2 mmol) and WSC (0.24 g, 1.2 mmol) were added. To this was added N-hydroxybenzenecarboximidamide (0.14 g, 1.0 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a colorless oil (0.58 g).
The obtained oil (0.19 g) was dissolved in toluene (10 mL), heated to reflux for 5 hours, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (3-20% ethyl acetate / hexane) to give the title compound as a colorless oil (0.21 g, 55%).
LC / MS 360.2 [M + ] -Boc

参考例７５
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-[2-(ジメチルアミノ)-2-オキソエチル]ピロリジン-1-カルボキシラート Reference Example 75
tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- [2- (dimethylamino) -2-oxoethyl] pyrrolidine-1-carboxylate

75-a) tert-ブチル(2S*,3R*)-2-(シアノメチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート 75-a) tert-butyl (2S * , 3R * )-2- (cyanomethyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000143
Figure JPOXMLDOC01-appb-C000143

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート(2.4 g, 6.9 mmol)とトリエチルアミン(2.9 mL, 21 mmol)をTHF(25 mL)に溶解させ、塩化メタンスルホニル(0.59 mL, 7.6 mmol)を0℃で加えた後、0℃で2時間攪拌した。反応混合物に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去することにより、無色油状物を得た。
　得られた油状物をDMF(30 mL)に溶解させ、シアン化ナトリウム(0.37 g, 7.6 mmol)を加え、100℃で終夜攪拌した。反応溶液を酢酸エチルで希釈した後、水と飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（3-15% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(1.0 g, 42%)として得た。
LC/MS 255.5 [M+]-Boc tert-Butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (2.4 g, 6.9 mmol) and triethylamine (2.9 mL, 21 mmol) After dissolving in THF (25 mL) and adding methanesulfonyl chloride (0.59 mL, 7.6 mmol) at 0 ° C., the mixture was stirred at 0 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a colorless oil.
The obtained oil was dissolved in DMF (30 mL), sodium cyanide (0.37 g, 7.6 mmol) was added, and the mixture was stirred at 100 ° C. overnight. The reaction solution was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (3-15% ethyl acetate / hexane) to give the title compound as a colorless oil (1.0 g, 42%).
LC / MS 255.5 [M +]-Boc

75-b) [(2S*,3R*)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]酢酸 75-b) [(2S * , 3R * )-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] acetic acid

Figure JPOXMLDOC01-appb-C000144
Figure JPOXMLDOC01-appb-C000144

　tert-ブチル (2S*,3R*)-2-(シアノメチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート(1.0 g, 2.9 mmol)に48%臭化水素酸水溶液(30 mL)を加え、終夜加熱還流した。反応終了後、減圧下溶媒を留去することで白色固体を得た。
　得られた固体をメタノール(30 mL)に溶解させ、トリエチルアミン(1.2 mL, 0.87 mmol)とジ-tert-ブチル ジカルボナート(1.5 mL, 6.3 mmol)を加え、室温で4時間攪拌した。減圧下溶媒を留去し、残渣に1 N水酸化ナトリウム水溶液(10 mL)を加え、水で希釈した後、酢酸エチルで洗浄した。得られた水層をクエン酸を用いて酸性にした後、飽和になるまで塩化ナトリウムを加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去することにより、表題化合物を白色結晶(0.90 g, 84%)として得た。
NMR (DMSO-d6) δ: 1.40 (9H, s), 1.94-2.04 (1H, m), 2.08-2.33 (3H, m), 3.20-3.29 (1H, m), 3.36-3.44 (1H, m), 3.53-3.61 (1H, m), 4.37-4.45 (1H, m), 7.31 (1H, dd, J = 8.3, 1.9 Hz), 7.53 (1H, d, J = 8.3 Hz), 7.57 (1H, s), 11.72 (1H, brs). tert-Butyl (2S * , 3R * )-2- (Cyanomethyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate (1.0 g, 2.9 mmol) in 48% aqueous hydrobromic acid solution (30 mL ) Was added and heated to reflux overnight. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain a white solid.
The obtained solid was dissolved in methanol (30 mL), triethylamine (1.2 mL, 0.87 mmol) and di-tert-butyl dicarbonate (1.5 mL, 6.3 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure, 1N aqueous sodium hydroxide solution (10 mL) was added to the residue, and the mixture was diluted with water and washed with ethyl acetate. The obtained aqueous layer was acidified with citric acid, sodium chloride was added until saturation, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as white crystals (0.90 g, 84%).
NMR (DMSO-d 6 ) δ: 1.40 (9H, s), 1.94-2.04 (1H, m), 2.08-2.33 (3H, m), 3.20-3.29 (1H, m), 3.36-3.44 (1H, m ), 3.53-3.61 (1H, m), 4.37-4.45 (1H, m), 7.31 (1H, dd, J = 8.3, 1.9 Hz), 7.53 (1H, d, J = 8.3 Hz), 7.57 (1H, s), 11.72 (1H, brs).

75-c) tert-ブチル(2S*,3R*)-3-(3,4-ジクロロフェニル)-2-[2-(ジメチルアミノ)-2-オキソエチル]ピロリジン-1-カルボキシラート 75-c) tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- [2- (dimethylamino) -2-oxoethyl] pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000145
Figure JPOXMLDOC01-appb-C000145

　[(2S*,3R*)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]酢酸(0.15 g, 0.40 mmol)のDMF(3 mL)溶液にHOBt(0.061 g, 0.40 mmol)とWSC(0.077 g, 0.40 mmol)を加えた。これに2 MジメチルアミンTHF溶液(0.60 mL)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルで洗浄することにより、表題化合物を白色結晶(0.090 g, 56%)として得た。
NMR (CDCl3) δ: 1.47 (9H, s), 2.08-2.24 (3H, m), 2.35 (1H, brs), 2.66 (3H, s), 2.74 (3H, brs), 3.37-3.67 (3H, m), 4.76 (1H, brs), 7.10 (1H, dd, J = 8.3, 1.9 Hz), 7.32 (1H, d, J = 1.9 Hz), 7.36 (1H, d, J = 8.3 Hz). [(2S * , 3R * )-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] acetic acid (0.15 g, 0.40 mmol) in DMF (3 mL) solution to HOBt (0.061 g, 0.40 mmol) and WSC (0.077 g, 0.40 mmol) were added. To this was added 2 M dimethylamine THF solution (0.60 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.090 g, 56%).
NMR (CDCl 3 ) δ: 1.47 (9H, s), 2.08-2.24 (3H, m), 2.35 (1H, brs), 2.66 (3H, s), 2.74 (3H, brs), 3.37-3.67 (3H, m), 4.76 (1H, brs), 7.10 (1H, dd, J = 8.3, 1.9 Hz), 7.32 (1H, d, J = 1.9 Hz), 7.36 (1H, d, J = 8.3 Hz).

参考例７６
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-ヒドロキシ-2-メチルプロピル)ピロリジン-1-カルボキシラート Reference Example 76
tert-Butyl (2S * , 3R * )-3- (3,4-Dichlorophenyl) -2- (2-hydroxy-2-methylpropyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000146
Figure JPOXMLDOC01-appb-C000146

76-a) tert-ブチル(2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-メトキシ-2-オキソエチル)ピロリジン-1-カルボキシラート 76-a) tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (2-methoxy-2-oxoethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000147
Figure JPOXMLDOC01-appb-C000147

　[(2S*,3R*)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]酢酸(0.15 g, 0.40 mmol)をメタノール(5 mL)に溶解させ、2 Mトリメチルシリルジアゾメタン・ジエチルエーテル溶液(1.2 mL)を0℃で滴下し、0℃で1時間攪拌した。反応終了後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（3-20% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.15 g, 96%)として得た。
NMR (CDCl3) δ: 1.47 (9H, s), 2.07-2.28 (3H, m), 2.36-2.44 (1H, m), 3.38 (3H, brs), 3.43-3.63 (3H, m), 4.59 (1H, brs), 7.08 (1H, d, J = 8.3 Hz), 7.31 (1H, brs), 7.38 (1H, d, J = 8.3 Hz). [(2S * , 3R * )-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] acetic acid (0.15 g, 0.40 mmol) was dissolved in methanol (5 mL). 2 M trimethylsilyldiazomethane / diethyl ether solution (1.2 mL) was added dropwise at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (3-20% ethyl acetate / hexane) to give the title compound as a colorless oil (0.15 g, 96%).
NMR (CDCl 3 ) δ: 1.47 (9H, s), 2.07-2.28 (3H, m), 2.36-2.44 (1H, m), 3.38 (3H, brs), 3.43-3.63 (3H, m), 4.59 ( 1H, brs), 7.08 (1H, d, J = 8.3 Hz), 7.31 (1H, brs), 7.38 (1H, d, J = 8.3 Hz).

76-b) tert-ブチル(2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-ヒドロキシ-2-メチルプロピル)ピロリジン-1-カルボキシラート 76-b) tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (2-hydroxy-2-methylpropyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000148
Figure JPOXMLDOC01-appb-C000148

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-メトキシ-2-オキソエチル)ピロリジン-1-カルボキシラート(0.15 g, 0.39 mmol)をTHF(5 mL)に溶解させ、1 Mメチルマグネシウムブロミド THF溶液(1.2 mL)を0℃で滴下した。0℃で1時間攪拌した後、室温で終夜攪拌した。さらに1 Mメチルマグネシウムブロミド THF溶液(1.2 mL)を追加し、室温で3時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去することにより、表題化合物を無色油状物(0.14 g, 93%)として得た。
NMR (CDCl3) δ: 1.09 (6H, s), 1.28-1.39 (1H, m), 1.49 (9H, s), 1.59-1.72 (1H, m), 2.13-2.30 (2H, m), 3.36-3.57 (3H, m), 4.37-4.47 (1H, m), 4.76 (1H, brs), 7.02 (1H, dd, J = 8.3, 1.7 Hz), 7.26 (1H, s), 7.40 (1H, d, J = 8.3 Hz). tert-Butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (2-methoxy-2-oxoethyl) pyrrolidine-1-carboxylate (0.15 g, 0.39 mmol) in THF (5 mL 1 M methylmagnesium bromide THF solution (1.2 mL) was added dropwise at 0 ° C. After stirring at 0 ° C. for 1 hour, the mixture was stirred at room temperature overnight. Further, 1 M methylmagnesium bromide THF solution (1.2 mL) was added, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (0.14 g, 93%).
NMR (CDCl 3 ) δ: 1.09 (6H, s), 1.28-1.39 (1H, m), 1.49 (9H, s), 1.59-1.72 (1H, m), 2.13-2.30 (2H, m), 3.36- 3.57 (3H, m), 4.37-4.47 (1H, m), 4.76 (1H, brs), 7.02 (1H, dd, J = 8.3, 1.7 Hz), 7.26 (1H, s), 7.40 (1H, d, J = 8.3 Hz).

参考例７７
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-オキソ-2-ピロリジン-1-イルエチル)ピロリジン-1-カルボキシラート Reference Example 77
tert-Butyl (2S * , 3R * )-3- (3,4-Dichlorophenyl) -2- (2-oxo-2-pyrrolidin-1-ylethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000149
Figure JPOXMLDOC01-appb-C000149

　[(2S*,3R*)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]酢酸(0.10 g, 0.27 mmol)のDMF(3 mL)溶液にHOBt(0.061 g, 0.40 mmol)とWSC(0.077 g, 0.40 mmol)を加えた。これにピロリジン(0.067 mL, 0.80 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルで洗浄することにより、表題化合物を白色固体(0.11 g, 100%)として得た。
NMR (CDCl3) δ: 1.47 (9H, s), 1.63-1.84 (4H, m), 2.00-2.38 (4H, m), 2.84-3.26 (4H, m), 3.37-3.65 (3H, m), 4.82 (1H, brs), 7.12 (1H, dd, J = 8.1, 1.7 Hz), 7.32-7.37 (2H, m). [(2S * , 3R * )-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] acetic acid (0.10 g, 0.27 mmol) in DMF (3 mL) solution to HOBt (0.061 g, 0.40 mmol) and WSC (0.077 g, 0.40 mmol) were added. To this was added pyrrolidine (0.067 mL, 0.80 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound as a white solid (0.11 g, 100%).
NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.63-1.84 (4H, m), 2.00-2.38 (4H, m), 2.84-3.26 (4H, m), 3.37-3.65 (3H, m), 4.82 (1H, brs), 7.12 (1H, dd, J = 8.1, 1.7 Hz), 7.32-7.37 (2H, m).

参考例７８
tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-モルホリン-4-イル-2-オキソエチル)ピロリジン-1-カルボキシラート Reference Example 78
tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (2-morpholin-4-yl-2-oxoethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000150
Figure JPOXMLDOC01-appb-C000150

　[(2S*,3R*)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]酢酸(0.10 g, 0.27 mmol)のDMF(3 mL)溶液にHOBt(0.061 g, 0.40 mmol)とWSC(0.077 g, 0.40 mmol)を加えた。これにモルホリン(0.070 mL, 0.80 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルで洗浄することにより、表題化合物を白色固体(0.11 g, 89%)として得た。
NMR (CDCl3) δ: 1.47 (9H, s), 1.63-1.84 (4H, m), 2.00-2.38 (4H, m), 2.84-3.26 (4H, m), 3.37-3.65 (3H, m), 4.82 (1H, brs), 7.12 (1H, dd, J = 8.1, 1.7 Hz), 7.32-7.37 (2H, m). [(2S * , 3R * )-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] acetic acid (0.10 g, 0.27 mmol) in DMF (3 mL) solution to HOBt (0.061 g, 0.40 mmol) and WSC (0.077 g, 0.40 mmol) were added. To this was added morpholine (0.070 mL, 0.80 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound as a white solid (0.11 g, 89%).
NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.63-1.84 (4H, m), 2.00-2.38 (4H, m), 2.84-3.26 (4H, m), 3.37-3.65 (3H, m), 4.82 (1H, brs), 7.12 (1H, dd, J = 8.1, 1.7 Hz), 7.32-7.37 (2H, m).

参考例７９
1-tert-ブチル 2-メチル 2,3-cis-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート（保持時間小）
1-tert-ブチル 2-メチル 2,3-cis-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート（保持時間大） Reference Example 79
1-tert-butyl 2-methyl 2,3-cis-3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate (low retention time)
1-tert-butyl 2-methyl 2,3-cis-3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate (large retention time)

Figure JPOXMLDOC01-appb-C000151
Figure JPOXMLDOC01-appb-C000151

　1-tert-ブチル 2-メチル (2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート(54.0 g)を高速液体クロマトグラフィー（カラム：CHIRALPAK AD (50 mm i.d.×500 mmL、ダイセル化学工業製)、移動相：ヘキサン/2-プロパノール＝50/50、流速：60 mL/min、カラム温度：30℃）を用いて分画した。上記の高速液体クロマトグラフィー条件にて保持時間の小さい方の光学活性体を含有する分画液を濃縮して、1-tert-ブチル 2-メチル2,3-cis-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート（保持時間小）26.2 g (99.9% ee)を得た。
　また、保持時間の大きい方の光学活性体を含有する分画液を濃縮して、1-tert-ブチル 2-メチル2,3-cis-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート（保持時間大）26.8 g (99.9% ee)を得た。
　なお、鏡像体過剰率（ee）は高速液体クロマトグラフィー（カラム：CHIRALPAK AD (4.6 mm i.d.×500 mmL、ダイセル化学工業製）、移動相：ヘキサン/2-プロパノール＝50/50、流速：0.5 mL/min、カラム温度：30℃）を用いて測定した（保持時間小：7.6 min、保持時間大：17.6 min）。 1-tert-butyl 2-methyl (2R * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate (54.0 g) was subjected to high performance liquid chromatography (column: CHIRALPAK AD (50 (mm id × 500 mmL, manufactured by Daicel Chemical Industries), mobile phase: hexane / 2-propanol = 50/50, flow rate: 60 mL / min, column temperature: 30 ° C.). The fraction containing the optically active substance having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give 1-tert-butyl 2-methyl-2,3-cis-3- (3,4- 26.2 g (99.9% ee) of dichlorophenyl) pyrrolidine-1,2-dicarboxylate (low retention time) were obtained.
Further, the fraction containing the optically active substance having the longer retention time was concentrated to give 1-tert-butyl 2-methyl 2,3-cis-3- (3,4-dichlorophenyl) pyrrolidine-1,2 -26.8 g (99.9% ee) of dicarboxylate (long retention time) was obtained.
The enantiomeric excess (ee) is high performance liquid chromatography (column: CHIRALPAK AD (4.6 mm id × 500 mmL, manufactured by Daicel Chemical Industries), mobile phase: hexane / 2-propanol = 50/50, flow rate: 0.5 mL. / min, column temperature: 30 ° C.) (low retention time: 7.6 min, high retention time: 17.6 min).

参考例８０
1-tert-ブチル 2-メチル (2R,3R)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート（保持時間小） Reference Example 80
1-tert-butyl 2-methyl (2R, 3R) -3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate (low retention time)

Figure JPOXMLDOC01-appb-C000152
Figure JPOXMLDOC01-appb-C000152

1-tert-ブチル 2-メチル (2S,3S)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート（保持時間大） 1-tert-butyl 2-methyl (2S, 3S) -3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate (large retention time)

Figure JPOXMLDOC01-appb-C000153
Figure JPOXMLDOC01-appb-C000153

　1-tert-ブチル 2-メチル (2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート(54.0 g)を高速液体クロマトグラフィー（カラム：CHIRALPAK AD (50 mm i.d.×500 mmL、ダイセル化学工業製)、移動相：ヘキサン/2-プロパノール＝50/50、流速：60 mL/min、カラム温度：30℃）を用いて分画した。上記の高速液体クロマトグラフィー条件にて保持時間の小さい方の光学活性体を含有する分画液を濃縮して、1-tert-ブチル 2-メチル (2R,3R)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート(26.2 g, 99.9% ee, LC/MS 274.0)を白色固体として得た。
　また、保持時間の大きい方の光学活性体を含有する分画液を濃縮して、1-tert-ブチル 2-メチル (2S,3S)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート(26.2 g, 99.9% ee, LC/MS 274.0)を白色固体として得た。
　なお、鏡像体過剰率（ee）は高速液体クロマトグラフィー（カラム：CHIRALPAK AD (4.6 mm i.d.×500 mmL、ダイセル化学工業製）、移動相：ヘキサン/2-プロパノール＝50/50、流速：0.5 mL/min、カラム温度：30℃）を用いて測定した（保持時間小：7.6 min、保持時間大：17.6 min）。 1-tert-butyl 2-methyl (2R * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate (54.0 g) was subjected to high performance liquid chromatography (column: CHIRALPAK AD (50 (mm id × 500 mmL, manufactured by Daicel Chemical Industries), mobile phase: hexane / 2-propanol = 50/50, flow rate: 60 mL / min, column temperature: 30 ° C.). The fraction containing the optically active form having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give 1-tert-butyl 2-methyl (2R, 3R) -3- (3,4- Dichlorophenyl) pyrrolidine-1,2-dicarboxylate (26.2 g, 99.9% ee, LC / MS 274.0) was obtained as a white solid.
Further, the fraction containing the optically active substance having the longer retention time is concentrated to give 1-tert-butyl 2-methyl (2S, 3S) -3- (3,4-dichlorophenyl) pyrrolidine-1,2 -Dicarboxylate (26.2 g, 99.9% ee, LC / MS 274.0) was obtained as a white solid.
The enantiomeric excess (ee) is high performance liquid chromatography (column: CHIRALPAK AD (4.6 mm id × 500 mmL, manufactured by Daicel Chemical Industries), mobile phase: hexane / 2-propanol = 50/50, flow rate: 0.5 mL. / min, column temperature: 30 ° C.) (low retention time: 7.6 min, high retention time: 17.6 min).

参考例８１
(2R,3R)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸 1塩酸塩 Reference Example 81
(2R, 3R) -3- (3,4-Dichlorophenyl) pyrrolidine-2-carboxylic acid monohydrochloride

Figure JPOXMLDOC01-appb-C000154
Figure JPOXMLDOC01-appb-C000154

　1-tert-ブチル 2-メチル (2R,3R)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート(6.2 g, 17 mmol)に酢酸(9 mL)と6規定塩酸水溶液(36 mL)を加え、還流下終夜加熱した。反応液を0℃に冷却し、生じた結晶を濾取することにより、表題化合物を白色結晶(4.7 g, 95%)として得た。
1H NMR (300 MHz, DMSO-d6) δ 2.07-2.21 (1H, m), 2.40-2.48 (1H, m), 3.22-3.32 (1H, m), 3.50-3.59 (1H, m), 3.94 (1H, dd, J = 17.0, 8.3 Hz), 4.58 (1H, d, J = 9.1 Hz), 7.31 (1H, dd, J = 8.3, 2.3 Hz), 7.59-7.63 (2H, m), 9.17 (1H, br s), 10.48 (1H, br s), 13.69 (1H, br s). 1-tert-butyl 2-methyl (2R, 3R) -3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate (6.2 g, 17 mmol) in acetic acid (9 mL) and 6N aqueous hydrochloric acid (36 mL) was added and heated under reflux overnight. The reaction mixture was cooled to 0 ° C., and the resulting crystals were collected by filtration to give the title compound as white crystals (4.7 g, 95%).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.07-2.21 (1H, m), 2.40-2.48 (1H, m), 3.22-3.32 (1H, m), 3.50-3.59 (1H, m), 3.94 (1H, dd, J = 17.0, 8.3 Hz), 4.58 (1H, d, J = 9.1 Hz), 7.31 (1H, dd, J = 8.3, 2.3 Hz), 7.59-7.63 (2H, m), 9.17 ( 1H, br s), 10.48 (1H, br s), 13.69 (1H, br s).

参考例８２
(2R,3R)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸 Reference Example 82
(2R, 3R) -1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid

Figure JPOXMLDOC01-appb-C000155
Figure JPOXMLDOC01-appb-C000155

　(2R,3R)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸 1塩酸塩(4.7 g, 16 mmol)をTHF(50 mL)に懸濁させ、トリエチルアミン(6.6 mL, 47 mmol)とジ-tert-ブチル ジカルボナート(4.4 mL, 19 mmol)を加え、室温で終夜攪拌した。反応終了後、酢酸エチルを加え、水と飽和食塩水で洗浄した。得られた抽出液を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた結晶を酢酸エチル／ジイソプロピルエーテルで洗浄することにより、表題化合物を無色結晶(5.5 g, 97%)として得た。
1H NMR (300 MHz, DMSO-d6) δ 1.34 (9 H x 2/3, s), 1.41 (9 H x 1/3, s), 2.00-2.12 (1H, m), 2.24-2.45 (1H, m), 3.26-3.41 (1H, m), 3.59-3.83 (2H, m), 4.35-4.40 (1H, m), 7.28 (1H, dd, J = 8.3, 1.9 Hz), 7.52-7.59 (2H, m), 12.28 (1H, br s). (2R, 3R) -3- (3,4-Dichlorophenyl) pyrrolidine-2-carboxylic acid monohydrochloride (4.7 g, 16 mmol) was suspended in THF (50 mL) and triethylamine (6.6 mL, 47 mmol) And di-tert-butyl dicarbonate (4.4 mL, 19 mmol) were added and stirred at room temperature overnight. After completion of the reaction, ethyl acetate was added and washed with water and saturated brine. The obtained extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with ethyl acetate / diisopropyl ether to give the title compound as colorless crystals (5.5 g, 97%).
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.34 (9 H x 2/3, s), 1.41 (9 H x 1/3, s), 2.00-2.12 (1H, m), 2.24-2.45 ( 1H, m), 3.26-3.41 (1H, m), 3.59-3.83 (2H, m), 4.35-4.40 (1H, m), 7.28 (1H, dd, J = 8.3, 1.9 Hz), 7.52-7.59 ( 2H, m), 12.28 (1H, br s).

参考例８３
tert-ブチル (2R,3R)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート Reference Example 83
tert-butyl (2R, 3R) -3- (3,4-dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000156
Figure JPOXMLDOC01-appb-C000156

　(2R,3R)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(17 g)のTHF(340 mL)溶液に0.9ＭボランTHF錯体THF溶液(124 mL)を0℃で滴下し、徐々に室温に昇温して1時間攪拌した。45℃で2時間攪拌した。反応混合物を濃縮し、残渣に10％クエン酸水(20 mL)を0℃で加え、水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル/ヘキサン) で精製して標題化合物 (13.7 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.49 (9H, s), 2.12 (1H, dt, J = 12.1, 6.0 Hz), 2.20-2.51 (1H, m), 3.20-3.73 (6H, m), 3.98-4.34 (1H, m), 7.03-7.21 (1H, m), 7.28-7.46 (2H, m). (2R, 3R) -1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (17 g) in THF (340 mL) solution in 0.9 M borane THF complex THF solution ( 124 mL) was added dropwise at 0 ° C., and the mixture was gradually warmed to room temperature and stirred for 1 hour. The mixture was stirred at 45 ° C. for 2 hours. The reaction mixture was concentrated, 10% aqueous citric acid (20 mL) was added to the residue at 0 ° C., diluted with water, and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (13.7 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.49 (9H, s), 2.12 (1H, dt, J = 12.1, 6.0 Hz), 2.20-2.51 (1H, m), 3.20-3.73 (6H, m), 3.98-4.34 (1H, m), 7.03-7.21 (1H, m), 7.28-7.46 (2H, m).

参考例８４
tert-ブチル (2R,3R)-3-(3,4-ジクロロフェニル)-2-[(1,3-ジオキソ-1,3-ジヒドロ-2H-イソインドール-2-イル)メチル]ピロリジン-1-カルボキシラート Reference Example 84
tert-butyl (2R, 3R) -3- (3,4-dichlorophenyl) -2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] pyrrolidine-1- Carboxylate

Figure JPOXMLDOC01-appb-C000157
Figure JPOXMLDOC01-appb-C000157

　tert-ブチル (2R,3R)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート（8.63g）とフタルイミド(4.03g)とトリフェニルフォスフィン(19.6g)のTHF(172 mL)溶液に40％アゾジカルボン酸ジエチルのトルエン溶液（34 mL）を0℃で加え、徐々に室温に昇温して14時間攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル/ヘキサン) で精製して標題化合物 (1.96 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.06-1.21 (9H, m), 2.17-2.34 (1H, m), 2.39-2.65 (1H, m), 3.13-3.34 (1H, m), 3.34-3.68 (4H, m), 4.54-4.80 (1H, m), 7.12-7.24 (1H, m), 7.30-7.48 (2H, m), 7.67 (2H, ddd, J = 15.5, 5.1, 3.2 Hz), 7.74-7.88 (2H, m). tert-Butyl (2R, 3R) -3- (3,4-Dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (8.63 g), phthalimide (4.03 g) and triphenylphosphine (19.6 g) To a THF (172 mL) solution of 40% diethyl azodicarboxylate in toluene (34 mL) was added at 0 ° C., and the mixture was gradually warmed to room temperature and stirred for 14 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.96 g).
1 H NMR (300 MHz, CDCl 3) δ 1.06-1.21 (9H, m), 2.17-2.34 (1H, m), 2.39-2.65 (1H, m), 3.13-3.34 (1H, m), 3.34-3.68 (4H, m), 4.54-4.80 (1H, m), 7.12-7.24 (1H, m), 7.30-7.48 (2H, m), 7.67 (2H, ddd, J = 15.5, 5.1, 3.2 Hz), 7.74 -7.88 (2H, m).

参考例８５
tert-ブチル (2R,3R)-2-(アミノメチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキラート Reference Example 85
tert-Butyl (2R, 3R) -2- (Aminomethyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000158
Figure JPOXMLDOC01-appb-C000158

　tert-ブチル (2R,3R)-3-(3,4-ジクロロフェニル)-2-[(1,3-ジオキソ-1,3-ジヒドロ-2H-イソインドール-2-イル)メチル]ピロリジン-1-カルボキシラート(9.93 g)のエタノール(100 mL)とTHF(100 mL)溶液に、ヒドラジン 一水和物（20 mL）を加え、室温で14時間攪拌した。反応混合物をろ過し、濾液を減圧下留去した。得られた残渣に水を加え、酢酸エチルで抽出を行った。得られた抽出液を水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、標題化合物 (7.0 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.44-1.52 (9H, m), 2.09-2.18 (1H, m), 2.29-2.47 (2H, m), 2.58 (1H, brs), 3.37-3.66 (3H, m), 3.93-4.16 (1H, m), 7.14 (1H, brs), 7.41 (2H, d, J = 8.3 Hz). tert-butyl (2R, 3R) -3- (3,4-dichlorophenyl) -2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] pyrrolidine-1- Hydrazine monohydrate (20 mL) was added to a solution of carboxylate (9.93 g) in ethanol (100 mL) and THF (100 mL), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was filtered and the filtrate was distilled off under reduced pressure. Water was added to the obtained residue, and extraction was performed with ethyl acetate. The obtained extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (7.0 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.44-1.52 (9H, m), 2.09-2.18 (1H, m), 2.29-2.47 (2H, m), 2.58 (1H, brs), 3.37-3.66 (3H , m), 3.93-4.16 (1H, m), 7.14 (1H, brs), 7.41 (2H, d, J = 8.3 Hz).

参考例８６
tert-ブチル (2R,3R)-2-({[(tert-ブトキシカルボニル)スルファモイル]アミノ}メチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート Reference Example 86
tert-butyl (2R, 3R) -2-({[(tert-butoxycarbonyl) sulfamoyl] amino} methyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000159
Figure JPOXMLDOC01-appb-C000159

　tert-ブチル (2R,3R)-2-(アミノメチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート(0.50g)のTHF(2.5 mL)とアセトニトリル(2.5 mL)混合溶液にN-(tert-ブトキシカルボニル)-N-[4- (ジメチルアザニウミリデン)-1,4- ジヒドロピリジン-1-イルスルホニル]アザニド(0.52 g)を加え、室温で14時間攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル/ヘキサン) で精製して標題化合物 (0.51 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.42-1.60 (18H, m), 2.10-2.43 (2H, m), 2.72-2.99 (2H, m), 3.33-3.66 (3H, m), 4.35 (1H, brs), 5.45 (1H, brs), 6.49 (1H, brs), 7.08 (1H, d, J = 8.0 Hz), 7.31 (1H, brs), 7.43 (1H, d, J = 8.3 Hz). To a mixed solution of tert-butyl (2R, 3R) -2- (aminomethyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate (0.50 g) in THF (2.5 mL) and acetonitrile (2.5 mL) N- (tert-butoxycarbonyl) -N- [4- (dimethylazaniumylidene) -1,4-dihydropyridin-1-ylsulfonyl] azanide (0.52 g) was added and stirred at room temperature for 14 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.51 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.42-1.60 (18H, m), 2.10-2.43 (2H, m), 2.72-2.99 (2H, m), 3.33-3.66 (3H, m), 4.35 (1H , brs), 5.45 (1H, brs), 6.49 (1H, brs), 7.08 (1H, d, J = 8.0 Hz), 7.31 (1H, brs), 7.43 (1H, d, J = 8.3 Hz).

参考例８７
tert-ブチル (2R,3R)-2-[(カルバモイルアミノ)メチル]-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート Reference Example 87
tert-butyl (2R, 3R) -2-[(carbamoylamino) methyl] -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000160
Figure JPOXMLDOC01-appb-C000160

　tert-ブチル (2R,3R)-2-(アミノメチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキラート(0.2g)のTHF(3 mL)溶液に トリエチルアミン(0.12 mL)とイソシアン酸トリメチルシリル(0.115 mL)を加え、室温で14時間攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル/ヘキサン) で精製して標題化合物 (0.12 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.49 (9H, s), 2.10-2.20 (1H, m), 2.23-2.40 (1H, m), 2.75 (1H, d, J = 13.2 Hz), 2.93-3.11 (1H, m), 3.31-3.61 (3H, m), 4.15-4.33 (1H, m), 7.09 (1H, d, J = 7.9 Hz), 7.31 (1H, d, J = 1.5 Hz), 7.42 (1H, d, J = 8.3 Hz).
LC/MS 288.2 tert-Butyl (2R, 3R) -2- (aminomethyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate (0.2 g) in THF (3 mL) in triethylamine (0.12 mL) and isocyan Trimethylsilyl acid (0.115 mL) was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.12 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.49 (9H, s), 2.10-2.20 (1H, m), 2.23-2.40 (1H, m), 2.75 (1H, d, J = 13.2 Hz), 2.93- 3.11 (1H, m), 3.31-3.61 (3H, m), 4.15-4.33 (1H, m), 7.09 (1H, d, J = 7.9 Hz), 7.31 (1H, d, J = 1.5 Hz), 7.42 (1H, d, J = 8.3 Hz).
LC / MS 288.2

参考例８８
tert-ブチル (2R,3R)-3-(3,4-ジクロロフェニル)-2-{[(メチルスルホニル)アミノ]メチル}ピロリジン-1-カルボキシラート Reference Example 88
tert-butyl (2R, 3R) -3- (3,4-dichlorophenyl) -2-{[(methylsulfonyl) amino] methyl} pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000161
Figure JPOXMLDOC01-appb-C000161

　tert-ブチル (2R,3R)-2-(アミノメチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキラート(0.2g)のTHF(3 mL)溶液に トリエチルアミン(0.12 mL)とイソシアン酸トリメチルシリル(0.067 mL)を加え、室温で14時間攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル/ヘキサン) で精製して標題化合物 (0.24 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.41-1.59 (9H, m), 2.12-2.42 (2H, m), 2.70-2.94 (5H, m), 3.41-3.66 (3H, m), 4.34 (1H, brs), 5.91 (1H, brs), 7.08 (1H, brs), 7.29-7.33 (1H, m), 7.44 (1H, d, J = 8.3 Hz).
LC/MS 323.2, 325.3 tert-Butyl (2R, 3R) -2- (aminomethyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate (0.2 g) in THF (3 mL) in triethylamine (0.12 mL) and isocyan Trimethylsilyl acid (0.067 mL) was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.24 g).
1 H NMR (300 MHz, CDCl 3) δ 1.41-1.59 (9H, m), 2.12-2.42 (2H, m), 2.70-2.94 (5H, m), 3.41-3.66 (3H, m), 4.34 (1H , brs), 5.91 (1H, brs), 7.08 (1H, brs), 7.29-7.33 (1H, m), 7.44 (1H, d, J = 8.3 Hz).
LC / MS 323.2, 325.3

参考例８９
tert-ブチル (2R,3R)-3-(3,4-ジクロロフェニル)-2-{[(3S)-3-ヒドロキシピロリジン-1-イル]カルボニル}ピロリジン-1-カルボキシラート Reference Example 89
tert-butyl (2R, 3R) -3- (3,4-dichlorophenyl) -2-{[(3S) -3-hydroxypyrrolidin-1-yl] carbonyl} pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000162
Figure JPOXMLDOC01-appb-C000162

　(2R,3R)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.30 g, 0.83 mmol)のDMF(5 mL)溶液にHOBt(0.19 g, 1.2 mmol)とWSC(0.24 g, 1.2 mmol)を加えた。これに(3S)-ピロリジン-3-オール(0.14 mL, 1.7 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウムと飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた結晶をジイソプロピルエーテルで洗浄することにより、表題化合物を白色結晶(0.30 g, 84%)として得た。
1H NMR (300 MHz, CDCl3) δ 1.18-1.69 (10H, m), 1.74-1.92 (1H, m), 2.01-2.15 (1H, m), 2.56-2.87 (2H, m), 3.08-3.68 (5H, m), 3.77-4.01 (1H, m), 4.03-4.33 (1H, m), 4.48-4.80 (1H, m), 7.13-7.18 (1H, m), 7.33-7.44 (2H, m). (2R, 3R) -1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.30 g, 0.83 mmol) in DMF (5 mL) was added to HOBt (0.19 g, 1.2 mmol) and WSC (0.24 g, 1.2 mmol) were added. To this was added (3S) -pyrrolidin-3-ol (0.14 mL, 1.7 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crystals were washed with diisopropyl ether to give the title compound as white crystals (0.30 g, 84%).
1 H NMR (300 MHz, CDCl 3 ) δ 1.18-1.69 (10H, m), 1.74-1.92 (1H, m), 2.01-2.15 (1H, m), 2.56-2.87 (2H, m), 3.08-3.68 (5H, m), 3.77-4.01 (1H, m), 4.03-4.33 (1H, m), 4.48-4.80 (1H, m), 7.13-7.18 (1H, m), 7.33-7.44 (2H, m) .

参考例９０
tert-ブチル (2R,3R)-3-(3,4-ジクロロフェニル)-2-{[(3R)-3-ヒドロキシピロリジン-1-イル]カルボニル}ピロリジン-1-カルボキシラート Reference Example 90
tert-butyl (2R, 3R) -3- (3,4-dichlorophenyl) -2-{[(3R) -3-hydroxypyrrolidin-1-yl] carbonyl} pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000163
Figure JPOXMLDOC01-appb-C000163

　(2R,3R)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.30 g, 0.83 mmol)、(3R)-ピロリジン-3-オール(87 mg, 1.0 mmol)、DMT-MM(0.35 g, 1.2 mmol)のエタノール(10 mL)溶液を室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（10-70% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.20 g, 56%)として得た。
1H NMR (300 MHz, CDCl3) δ 1.37-1.48 (9H, m), 1.55-1.89 (3H, m), 2.05-2.14 (1H, m), 2.49-2.79 (2H, m), 3.08-3.25 (1H, m), 3.38-3.68 (4H, m), 3.79-3.97 (1H, m), 4.13-4.26 (1H, m), 4.65 (1H, br s), 7.12-7.19 (1H, m), 7.34-7.44 (2H, m). (2R, 3R) -1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.30 g, 0.83 mmol), (3R) -pyrrolidin-3-ol (87 mg , 1.0 mmol), a solution of DMT-MM (0.35 g, 1.2 mmol) in ethanol (10 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (10-70% ethyl acetate / hexane) to give the title compound as a colorless oil (0.20 g, 56%).
1 H NMR (300 MHz, CDCl 3 ) δ 1.37-1.48 (9H, m), 1.55-1.89 (3H, m), 2.05-2.14 (1H, m), 2.49-2.79 (2H, m), 3.08-3.25 (1H, m), 3.38-3.68 (4H, m), 3.79-3.97 (1H, m), 4.13-4.26 (1H, m), 4.65 (1H, br s), 7.12-7.19 (1H, m), 7.34-7.44 (2H, m).

参考例９１
3-(3,4-ジフルオロフェニル)プロパ-2-エナール Reference Example 91
3- (3,4-Difluorophenyl) prop-2-enal

Figure JPOXMLDOC01-appb-C000164
Figure JPOXMLDOC01-appb-C000164

　3,4-ジフルオロベンズアルデヒド (8.1g)をアセトアルデヒド(23 mL)に溶解させた。これに水酸化カリウム(0.42 g)のメタノール(5 mL)溶液を0℃で滴下した。反応混合物を0℃で1時間攪拌した後、無水酢酸(15 mL)を加え、還流下1時間加熱した。一度室温まで放冷した後、1規定塩酸水溶液(250 mL)を加え、還流下1時間加熱した。室温にて終夜放置し、反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することにより、標題化合物 (4.18 g)を得た。
1H NMR (300 MHz, DMSO-d6) δ 6.91 (1H, dd, J = 16.0, 7.7 Hz), 7.48-7.67 (2H, m), 7.71 (1H, d, J = 15.8 Hz), 7.96 (1H, ddd, J = 11.9, 8.1, 1.9 Hz), 9.67 (1H, d, J = 7.5 Hz). 3,4-Difluorobenzaldehyde (8.1 g) was dissolved in acetaldehyde (23 mL). A solution of potassium hydroxide (0.42 g) in methanol (5 mL) was added dropwise thereto at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1 hr, acetic anhydride (15 mL) was added, and the mixture was heated under reflux for 1 hr. The mixture was allowed to cool to room temperature, 1N aqueous hydrochloric acid solution (250 mL) was added, and the mixture was heated under reflux for 1 hr. The reaction mixture was left standing at room temperature overnight, diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (4.18 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ 6.91 (1H, dd, J = 16.0, 7.7 Hz), 7.48-7.67 (2H, m), 7.71 (1H, d, J = 15.8 Hz), 7.96 ( 1H, ddd, J = 11.9, 8.1, 1.9 Hz), 9.67 (1H, d, J = 7.5 Hz).

参考例９２
ジエチル 1-アセチル-3-(3,4-ジフルオロフェニル)-5-ヒドロキシピロリジン-2,2-ジカルボキシラート Reference Example 92
Diethyl 1-acetyl-3- (3,4-difluorophenyl) -5-hydroxypyrrolidine-2,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000165
Figure JPOXMLDOC01-appb-C000165

　ジエチル (アセチルアミノ)プロパンジオアート(5.1 g)をエタノール(70 mL)に溶解させ、これにナトリウム エタノラート(0.32 g)を加え、室温で10分間攪拌した。反応混合物に3-(3,4-ジフルオロフェニル)プロパ-2-エナール (4 g)を加え、室温で終夜攪拌した。反応混合物に酢酸を加え、pHを4にした後、減圧下溶媒を留去した。得られた残渣をジイソプロピルエーテルと水で洗浄した後、減圧下乾燥させることにより、表題化合物(9 g)を得た。
1H NMR (300 MHz, CDCl3) δ 0.81-1.10 (3H, m), 1.18-1.38 (3H, m), 1.93-2.12 (2H, m), 2.19-2.36 (3H, m), 2.65 (1H, dt, J = 13.2, 4.7 Hz), 3.73-4.01 (2H, m), 4.22-4.62 (2H, m), 5.76 (1H, d, J = 4.9 Hz), 6.83-7.20 (3H, m). Diethyl (acetylamino) propanedioate (5.1 g) was dissolved in ethanol (70 mL), sodium ethanolate (0.32 g) was added thereto, and the mixture was stirred at room temperature for 10 min. 3- (3,4-Difluorophenyl) prop-2-enal (4 g) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. Acetic acid was added to the reaction mixture to adjust the pH to 4, and then the solvent was distilled off under reduced pressure. The obtained residue was washed with diisopropyl ether and water, and dried under reduced pressure to give the title compound (9 g).
1 H NMR (300 MHz, CDCl 3) δ 0.81-1.10 (3H, m), 1.18-1.38 (3H, m), 1.93-2.12 (2H, m), 2.19-2.36 (3H, m), 2.65 (1H , dt, J = 13.2, 4.7 Hz), 3.73-4.01 (2H, m), 4.22-4.62 (2H, m), 5.76 (1H, d, J = 4.9 Hz), 6.83-7.20 (3H, m).

参考例９３
ジエチル 1-アセチル-3-(3,4-ジフルオロフェニル)ピロリジン-2,2-ジカルボキシラート Reference Example 93
Diethyl 1-acetyl-3- (3,4-difluorophenyl) pyrrolidine-2,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000166
Figure JPOXMLDOC01-appb-C000166

　ジエチル 1-アセチル-3-(3,4-ジフルオロフェニル)-5-ヒドロキシピロリジン-2,2-ジカルボキシラート (9 g, 48 mmol)とトリエチルシラン(5.9 mL, 71 mmol)をアセトニトリル(50 mL)に溶解させ、これにトリフルオロ酢酸(18.5 mL)を加え、室温で終夜攪拌した。反応終了後、減圧下溶媒を留去し、酢酸エチルで希釈した。得られた溶液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することにより、標題化合物(6.4 g)を得た。
1H NMR (300 MHz, CDCl3) δ 0.98 (3H, t, J = 7.2 Hz), 1.24-1.38 (3H, m), 2.14 (3H, s), 2.20-2.33 (1H, m), 2.42-2.61 (1H, m), 3.63-4.04 (5H, m), 4.30 (2H, q, J = 7.2 Hz), 6.89-7.01 (1H, m), 7.01-7.15 (2H, m). Diethyl 1-acetyl-3- (3,4-difluorophenyl) -5-hydroxypyrrolidine-2,2-dicarboxylate (9 g, 48 mmol) and triethylsilane (5.9 mL, 71 mmol) in acetonitrile (50 mL) ), Trifluoroacetic acid (18.5 mL) was added thereto, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure and diluted with ethyl acetate. The obtained solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (6.4 g).
1 H NMR (300 MHz, CDCl 3 ) δ 0.98 (3H, t, J = 7.2 Hz), 1.24-1.38 (3H, m), 2.14 (3H, s), 2.20-2.33 (1H, m), 2.42- 2.61 (1H, m), 3.63-4.04 (5H, m), 4.30 (2H, q, J = 7.2 Hz), 6.89-7.01 (1H, m), 7.01-7.15 (2H, m).

参考例９４
1-tert-ブチル 2-メチル 3-(3,4-ジフルオロフェニル)ピロリジン-1,2-ジカルボキシラート Reference Example 94
1-tert-butyl 2-methyl 3- (3,4-difluorophenyl) pyrrolidine-1,2-dicarboxylate

Figure JPOXMLDOC01-appb-C000167
Figure JPOXMLDOC01-appb-C000167

　ジエチル 1-アセチル-3-(3,4-ジフルオロフェニル)ピロリジン-2,2-ジカルボキシラート(6.4g)に酢酸(3 mL)と6規定塩酸水溶液(15 mL)を加え、還流下終夜加熱した。減圧下、溶媒を留去し、残渣を減圧下乾燥させた。得られた残渣をメタノール(30 mL)に溶解させ、塩化チオニル(1.6 mL)を0℃で滴下した後、室温で4時間攪拌した。減圧下、溶媒を留去した。得られた残渣をメタノールとトルエンに溶解させ、再度溶媒を留去した。得られた残渣をメタノール(30 mL)に溶解させ、炭酸水素ナトリウム(6.5 g)とジ-tert-ブチル ジカルボナート(4.64 mL)を加え、室温で終夜攪拌した。反応終了後、不溶物を濾別し、濾液を減圧下濃縮した。残渣に酢酸エチルを加え、水で洗浄した。得られた抽出液を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することにより、標題化合物(2.37 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.36-1.54 (9H, m), 1.89-2.18 (1H, m), 2.22-2.60 (1H, m), 3.28-3.98 (6H, m), 4.06-4.58 (1H, m), 6.91-6.99 (1H, m), 7.00-7.17 (2H, m). Acetic acid (3 mL) and 6N aqueous hydrochloric acid (15 mL) were added to diethyl 1-acetyl-3- (3,4-difluorophenyl) pyrrolidine-2,2-dicarboxylate (6.4 g), and heated under reflux overnight. did. The solvent was distilled off under reduced pressure, and the residue was dried under reduced pressure. The obtained residue was dissolved in methanol (30 mL), thionyl chloride (1.6 mL) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 4 hr. The solvent was distilled off under reduced pressure. The obtained residue was dissolved in methanol and toluene, and the solvent was distilled off again. The obtained residue was dissolved in methanol (30 mL), sodium hydrogen carbonate (6.5 g) and di-tert-butyl dicarbonate (4.64 mL) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue and washed with water. The obtained extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.37 g).
1 H NMR (300 MHz, CDCl 3) δ 1.36-1.54 (9H, m), 1.89-2.18 (1H, m), 2.22-2.60 (1H, m), 3.28-3.98 (6H, m), 4.06-4.58 (1H, m), 6.91-6.99 (1H, m), 7.00-7.17 (2H, m).

参考例９５
(2R*,3S*)-1-(tert-ブトキシカルボニル)-3-(3,4-ジフルオロフェニル)ピロリジン-2-カルボン酸 Reference Example 95
(2R * , 3S * )-1- (tert-butoxycarbonyl) -3- (3,4-difluorophenyl) pyrrolidine-2-carboxylic acid

Figure JPOXMLDOC01-appb-C000168
Figure JPOXMLDOC01-appb-C000168

　1-tert-ブチル 2-メチル3-(3,4-ジフルオロフェニル)ピロリジン-1,2-ジカルボキシラート (2.37 g)をメタノール(40 mL)に溶解させ、1N NaOH(14 mL)を加え、室温で14時間攪拌した。反応終了後、減圧下、溶媒を留去した。残渣に酢酸エチルと水を加え、分液した。水層に10%クエン酸水溶液を加え、酢酸エチルで抽出した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することにより、標題化合物(0.451 g）を得た。
1H NMR (300 MHz, CDCl3) δ 1.32-1.58 (9H, m), 1.87-2.11 (1H, m), 2.22-2.47 (1H, m), 3.32-3.86 (3H, m), 4.08-4.46 (1H, m), 6.89-7.22 (3H, m). 1-tert-butyl 2-methyl 3- (3,4-difluorophenyl) pyrrolidine-1,2-dicarboxylate (2.37 g) is dissolved in methanol (40 mL), 1N NaOH (14 mL) is added, Stir at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the residue for liquid separation. A 10% aqueous citric acid solution was added to the aqueous layer, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.451 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.32-1.58 (9H, m), 1.87-2.11 (1H, m), 2.22-2.47 (1H, m), 3.32-3.86 (3H, m), 4.08-4.46 (1H, m), 6.89-7.22 (3H, m).

参考例９６
tert-ブチル (2R*,3S*)-3-(3,4-ジフルオロフェニル)-2-(ピロリジン-1-イルカルボニル)ピロリジン-1-カルボキシラート Reference Example 96
tert- butyl (2R *, 3S *) -3- (3,4- difluorophenyl) -2- (pyrrolidin-1-ylcarbonyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000169
Figure JPOXMLDOC01-appb-C000169

　(2R*,3S*)-1-(tert-ブトキシカルボニル)-3-(3,4-ジフルオロフェニル)ピロリジン-2-カルボン酸 (0.3 g)のアセトニトリル(5 mL)溶液にHOBt(0.185 g)とWSC(0.263 g)を加えた。これにピロリジン (0.09 mL)を加え、室温で14時間攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウムと飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することにより、標題化合物 (0.21 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.28-1.52 (9H, m), 1.65-2.12 (5H, m), 2.17-2.50 (1H, m), 2.50-2.95 (1H, m), 3.28-3.94 (6H, m), 4.19-4.52 (1H, m), 6.81-7.21 (3H, m). (2R * , 3S * )-1- (tert-butoxycarbonyl) -3- (3,4-difluorophenyl) pyrrolidine-2-carboxylic acid (0.3 g) in acetonitrile (5 mL) in HOBt (0.185 g) And WSC (0.263 g) were added. To this was added pyrrolidine (0.09 mL), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.21 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.28-1.52 (9H, m), 1.65-2.12 (5H, m), 2.17-2.50 (1H, m), 2.50-2.95 (1H, m), 3.28-3.94 (6H, m), 4.19-4.52 (1H, m), 6.81-7.21 (3H, m).

参考例９７
(2S,3S)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸 Reference Example 97
(2S, 3S) -1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid

Figure JPOXMLDOC01-appb-C000170
Figure JPOXMLDOC01-appb-C000170

　1-tert-ブチル 2-メチル(2S,3S)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート(5.0 ｇ)の酢酸(7.2 mL)溶液に６Ｎ塩酸水溶液(29 mL)を加え、加熱還流下14時間攪拌した。反応混合物を0℃で0.5時間攪拌し、析出した固体を濾取、減圧乾燥し(2S,3S)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸　1塩酸塩を白色固体として得た。得られた(2S,3S)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸　1塩酸塩のＴＨＦ(40 mL)溶液にトリエチルアミン（5.47 mL）とジ-tert-ブチル ジカルボナート(3.36 mL)を加え、室温で14時間攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を10％クエン酸水と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル/ヘキサン) で精製して標題化合物 (1.2 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.31-1.49 (9H, m), 2.05-2.23 (1H, m), 2.29-2.55 (1H, m), 3.32-3.52 (1H, m), 3.52-3.72 (1H, m), 3.72-3.87 (1H, m), 4.42-4.55 (1H, m), 7.04-7.10 (1H, m), 7.33 (1H, s), 7.34-7.39 (1H, m). 1-tert-butyl 2-methyl (2S, 3S) -3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate (5.0 g) in acetic acid (7.2 mL) and 6N aqueous hydrochloric acid (29 mL) ) Was added, and the mixture was stirred for 14 hours with heating under reflux. The reaction mixture was stirred at 0 ° C. for 0.5 hour, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain (2S, 3S) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid monohydrochloride as a white solid. It was. Triethylamine (5.47 mL) and di-tert-butyl dicarbonate (3.36 mL) were added to a THF (40 mL) solution of the obtained (2S, 3S) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid monohydrochloride. ) Was added and stirred at room temperature for 14 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with 10% aqueous citric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.2 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.31-1.49 (9H, m), 2.05-2.23 (1H, m), 2.29-2.55 (1H, m), 3.32-3.52 (1H, m), 3.52-3.72 (1H, m), 3.72-3.87 (1H, m), 4.42-4.55 (1H, m), 7.04-7.10 (1H, m), 7.33 (1H, s), 7.34-7.39 (1H, m).

参考例９８
tert-ブチル (2S,3S)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート Reference Example 98
tert-butyl (2S, 3S) -3- (3,4-dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000171
Figure JPOXMLDOC01-appb-C000171

　(2S,3S)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸 (1.2 g)のTHF(24 mL)溶液に1.0Ｍ ボランTHF錯体THF溶液(8 mL)を0℃で滴下し、徐々に室温に昇温して1時間攪拌した。40℃で2時間攪拌した。反応混合物を濃縮し、残渣に10％クエン酸水を0℃で加え、水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和重曹水と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル/ヘキサン) で精製して標題化合物 (0.37 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.42-1.57 (9H, m), 2.08-2.18 (1H, m), 2.23-2.49 (1H, m), 3.20-4.42 (7H, m), 7.09 (1H, brs), 7.30-7.55 (2H, m). (2S, 3S) -1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (1.2 g) in THF (24 mL) solution in 1.0 M borane THF complex THF solution ( 8 mL) was added dropwise at 0 ° C., and the mixture was gradually warmed to room temperature and stirred for 1 hour. The mixture was stirred at 40 ° C. for 2 hours. The reaction mixture was concentrated, 10% aqueous citric acid was added to the residue at 0 ° C., diluted with water, and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.37 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.42-1.57 (9H, m), 2.08-2.18 (1H, m), 2.23-2.49 (1H, m), 3.20-4.42 (7H, m), 7.09 (1H , brs), 7.30-7.55 (2H, m).

参考例９９
tert-ブチル (2S,3S)-3-(3,4-ジクロロフェニル)-2-[(1,3-ジオキソ-1,3-ジヒドロ-2H-イソインドール-2-イル)メチル]ピロリジン-1-カルボキシラート Reference Example 99
tert-butyl (2S, 3S) -3- (3,4-dichlorophenyl) -2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] pyrrolidine-1- Carboxylate

Figure JPOXMLDOC01-appb-C000172
Figure JPOXMLDOC01-appb-C000172

　tert-ブチル (2S,3S)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート（0.37 g）とフタルイミド (0.17 g)とトリフェニルフォスフィン(0.857 g)のTHF(6 mL)溶液に40％アゾジカルボン酸ジエチルのトルエン溶液（1.5 mL）を 0℃で加え、徐々に室温に昇温して14時間攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル/ヘキサン) で精製して標題化合物 (0.42 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.14 (9H, s), 2.36 (1H, s), 2.52 (1H, brs), 3.17-3.78 (5H, m), 4.67 (1H, brs), 7.14-7.24 (1H, m), 7.28-7.48 (2H, m), 7.61-7.74 (2H, m), 7.74-7.84 (2H, m). tert-Butyl (2S, 3S) -3- (3,4-Dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (0.37 g), phthalimide (0.17 g) and triphenylphosphine (0.857 g) To a THF (6 mL) solution was added 40% diethyl azodicarboxylate in toluene (1.5 mL) at 0 ° C., and the mixture was gradually warmed to room temperature and stirred for 14 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.42 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.14 (9H, s), 2.36 (1H, s), 2.52 (1H, brs), 3.17-3.78 (5H, m), 4.67 (1H, brs), 7.14- 7.24 (1H, m), 7.28-7.48 (2H, m), 7.61-7.74 (2H, m), 7.74-7.84 (2H, m).

参考例１００
tert-ブチル (2S,3S)-2-(アミノメチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキラート Reference Example 100
tert-Butyl (2S, 3S) -2- (Aminomethyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000173
Figure JPOXMLDOC01-appb-C000173

　tert-ブチル (2S,3S)-3-(3,4-ジクロロフェニル)-2-[(1,3-ジオキソ-1,3-ジヒドロ-2H-イソインドール-2-イル)メチル]ピロリジン-1-カルボキシラート(0.42 g)のエタノール(10 mL)溶液に、ヒドラジン一水和物（2 mL）を加え、室温で14時間攪拌した。反応混合物をろ過し、濾液を減圧下留去した。得られた残渣に水を加え、酢酸エチルで抽出を行った。得られた抽出液を水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、標題化合物 (0.23 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.40-1.72 (9H, m), 2.04-2.24 (1H, m), 2.31-2.51 (2H, m), 2.58 (1H, brs), 3.34-3.77 (3H, m), 3.91-4.23 (1H, m), 7.03-7.76 (3H, m). tert-butyl (2S, 3S) -3- (3,4-dichlorophenyl) -2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] pyrrolidine-1- Hydrazine monohydrate (2 mL) was added to a solution of carboxylate (0.42 g) in ethanol (10 mL), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was filtered and the filtrate was distilled off under reduced pressure. Water was added to the obtained residue, and extraction was performed with ethyl acetate. The obtained extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.23 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.40-1.72 (9H, m), 2.04-2.24 (1H, m), 2.31-2.51 (2H, m), 2.58 (1H, brs), 3.34-3.77 (3H , m), 3.91-4.23 (1H, m), 7.03-7.76 (3H, m).

参考例１０１
tert-ブチル (2S,3S)-2-({[(tert-ブトキシカルボニル)スルファモイル]アミノ}メチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート Reference Example 101
tert-butyl (2S, 3S) -2-({[(tert-butoxycarbonyl) sulfamoyl] amino} methyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000174
Figure JPOXMLDOC01-appb-C000174

　tert-ブチル (2S,3S)-2-(アミノメチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート(0.23 g)のTHF(1 mL)とアセトニトリル(1 mL)混合溶液にトリエチルアミン(0.138 mL)とN-(tert-ブトキシカルボニル)-N-[4-(ジメチルアザニウミリデン)-1,4-ジヒドロピリジン-1-イルスルホニル]アザニド(0.3 g)を加え、室温で14時間攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル/ヘキサン) で精製して標題化合物 (0.23 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.41-1.60 (18H, m), 2.12-2.44 (2H, m), 2.84 (2H, brs), 3.31-3.68 (2H, m), 4.19-4.44 (1H, m), 6.50 (1H, brs), 7.08 (1H, d, J = 7.9 Hz), 7.31 (1H, brs), 7.42 (1H, s). To a mixed solution of tert-butyl (2S, 3S) -2- (aminomethyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate (0.23 g) in THF (1 mL) and acetonitrile (1 mL) Triethylamine (0.138 mL) and N- (tert-butoxycarbonyl) -N- [4- (dimethylazaaniumylidene) -1,4-dihydropyridin-1-ylsulfonyl] azanide (0.3 g) were added, and the mixture was stirred at room temperature. Stir for hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.23 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.41-1.60 (18H, m), 2.12-2.44 (2H, m), 2.84 (2H, brs), 3.31-3.68 (2H, m), 4.19-4.44 (1H , m), 6.50 (1H, brs), 7.08 (1H, d, J = 7.9 Hz), 7.31 (1H, brs), 7.42 (1H, s).

参考例１０２
tert-ブチル (2R*,3S*)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート Reference Example 102
tert-Butyl (2R * , 3S * )-3- (3,4-Dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000175
Figure JPOXMLDOC01-appb-C000175

　1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸 （cis / trans 混合物）(45 g)のTHF(900 mL)溶液に1.0ＭボランTHF錯体THF溶液(300 mL)を0℃で滴下し、徐々に室温に昇温して1時間攪拌した。40℃で2時間攪拌した。反応混合物を濃縮し、残渣に10％クエン酸水を0℃で加え、水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和重曹水と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル/ヘキサン) で精製して標題化合物 (32.2 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.50 (9H, s), 1.83-1.99 (1H, m), 2.11-2.22 (1H, m), 2.84-2.94 (1H, m), 3.29-3.41 (1H, m), 3.57-3.66 (1H, m), 3.69-3.92 (3H, m), 4.81 (1H, d, J = 7.4 Hz), 7.07 (1H, dd, J = 8.3, 1.9 Hz), 7.33 (1H, d, J = 1.9 Hz), 7.39 (1H, d, J = 8.2 Hz). 1- (tert-Butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (cis / trans mixture) (45 g) in THF (900 mL) solution in 1.0 M borane THF complex THF solution ( 300 mL) was added dropwise at 0 ° C., and the mixture was gradually warmed to room temperature and stirred for 1 hour. The mixture was stirred at 40 ° C. for 2 hours. The reaction mixture was concentrated, 10% aqueous citric acid was added to the residue at 0 ° C., diluted with water, and extracted with ethyl acetate. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (32.2 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.50 (9H, s), 1.83-1.99 (1H, m), 2.11-2.22 (1H, m), 2.84-2.94 (1H, m), 3.29-3.41 (1H , m), 3.57-3.66 (1H, m), 3.69-3.92 (3H, m), 4.81 (1H, d, J = 7.4 Hz), 7.07 (1H, dd, J = 8.3, 1.9 Hz), 7.33 ( 1H, d, J = 1.9 Hz), 7.39 (1H, d, J = 8.2 Hz).

参考例１０３
tert-ブチル (2R*,3S*)-3-(3,4-ジクロロフェニル)-2-[(1,3-ジオキソ-1,3-ジヒドロ-2H-イソインドール-2-イル)メチル]ピロリジン-1-カルボキシラート Reference Example 103
tert-Butyl (2R * , 3S * )-3- (3,4-Dichlorophenyl) -2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] pyrrolidine- 1-carboxylate

Figure JPOXMLDOC01-appb-C000176
Figure JPOXMLDOC01-appb-C000176

　tert-ブチル (2R*,3S*)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート （30 g）、フタルイミド（14 g)およびトリフェニルフォスフィン(67.6 g)のTHF(600 mL)溶液に40％アゾジカルボン酸ジエチルのトルエン溶液（118 mL）を0℃で加え、徐々に室温に昇温して5時間攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル/ヘキサン) で精製して標題化合物 (34.2 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.28-1.55 (9H, m), 1.85 (1H, dq, J = 13.4, 6.9 Hz), 2.23-2.41 (1H, m), 3.19 (1H, brs), 3.40 (1H, dt, J = 10.8, 7.1 Hz), 3.53-3.95 (2H, m), 3.95-4.14 (1H, m), 4.18-4.51 (1H, m), 6.95 (1H, brs), 7.10-7.30 (2H, m), 7.69 (2H, brs), 7.73-7.83 (2H, m). tert-butyl (2R * , 3S * )-3- (3,4-dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (30 g), phthalimide (14 g) and triphenylphosphine (67.6 To a solution of g) in THF (600 mL) was added 40% diethyl azodicarboxylate in toluene (118 mL) at 0 ° C, and the mixture was gradually warmed to room temperature and stirred for 5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (34.2 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.28-1.55 (9H, m), 1.85 (1H, dq, J = 13.4, 6.9 Hz), 2.23-2.41 (1H, m), 3.19 (1H, brs), 3.40 (1H, dt, J = 10.8, 7.1 Hz), 3.53-3.95 (2H, m), 3.95-4.14 (1H, m), 4.18-4.51 (1H, m), 6.95 (1H, brs), 7.10- 7.30 (2H, m), 7.69 (2H, brs), 7.73-7.83 (2H, m).

参考例１０４
tert-ブチル (2R*,3S*)-2-(アミノメチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート Reference Example 104
tert-Butyl (2R * , 3S * )-2- (Aminomethyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000177
Figure JPOXMLDOC01-appb-C000177

　tert-ブチル (2R*,3S*)-3-(3,4-ジクロロフェニル)-2-[(1,3-ジオキソ-1,3-ジヒドロ-2H-イソインドール-2-イル)メチル]ピロリジン-1-カルボキシラート (5 g)のエタノール(50 mL)とTHF(50 mL)混合溶液に、ヒドラジン一水和物（10 mL）を加え、室温で14時間攪拌した。反応混合物をろ過し、濾液を減圧下留去した。得られた残渣に水を加え、酢酸エチルで抽出を行った。得られた抽出液を水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、標題化合物 (4.32 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.34-1.58 (11H, m), 1.80-1.96 (1H, m), 2.14-2.36 (1H, m), 2.81 (1H, brs), 2.99 (1H, dd, J = 12.8, 5.7 Hz), 3.36 (2H, dt, J = 11.2, 7.2 Hz), 3.73 (2H, brs), 6.99-7.09 (1H, m), 7.30 (1H, d, J = 2.3 Hz), 7.38 (1H, d, J = 8.3 Hz). tert-Butyl (2R * , 3S * )-3- (3,4-Dichlorophenyl) -2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] pyrrolidine- Hydrazine monohydrate (10 mL) was added to a mixed solution of 1-carboxylate (5 g) in ethanol (50 mL) and THF (50 mL), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was filtered and the filtrate was distilled off under reduced pressure. Water was added to the obtained residue, and extraction was performed with ethyl acetate. The obtained extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (4.32 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.34-1.58 (11H, m), 1.80-1.96 (1H, m), 2.14-2.36 (1H, m), 2.81 (1H, brs), 2.99 (1H, dd , J = 12.8, 5.7 Hz), 3.36 (2H, dt, J = 11.2, 7.2 Hz), 3.73 (2H, brs), 6.99-7.09 (1H, m), 7.30 (1H, d, J = 2.3 Hz) , 7.38 (1H, d, J = 8.3 Hz).

参考例１０５
tert-ブチル (2R*,3S*)-3-(3,4-ジクロロフェニル)-2-({[(4-ニトロフェノキシ)カルボニル]アミノ}メチル)ピロリジン-1-カルボキシラート Reference Example 105
tert-butyl (2R * , 3S * )-3- (3,4-dichlorophenyl) -2-({[(4-nitrophenoxy) carbonyl] amino} methyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000178
Figure JPOXMLDOC01-appb-C000178

　tert-ブチル (2R*,3S*)-2-(アミノメチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート (1 g)のアセトニトリル(10 mL)溶液にトリエチルアミン（0.767 mL)とクロロギ酸4-ニトロフェニル(0.7 g)を加え、室温で14時間攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウムと飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することにより、標題化合物 (1.54 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.46-1.70 (9H, m), 1.86-2.01 (1H, m), 2.15-2.33 (1H, m), 3.10 (1H, brs), 3.31-3.67 (3H, m), 3.71-4.06 (2H, m), 6.73 (1H, brs), 7.09 (1H, dd, J = 8.3, 1.9 Hz), 7.22-7.47 (4H, m), 8.24 (2H, d, J = 8.7 Hz). tert-Butyl (2R * , 3S * )-2- (Aminomethyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate (1 g) in acetonitrile (10 mL) in triethylamine (0.767 mL) And 4-nitrophenyl chloroformate (0.7 g) were added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.54 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.46-1.70 (9H, m), 1.86-2.01 (1H, m), 2.15-2.33 (1H, m), 3.10 (1H, brs), 3.31-3.67 (3H , m), 3.71-4.06 (2H, m), 6.73 (1H, brs), 7.09 (1H, dd, J = 8.3, 1.9 Hz), 7.22-7.47 (4H, m), 8.24 (2H, d, J = 8.7 Hz).

参考例１０６
tert-ブチル (2R*,3S*)-3-(3,4-ジクロロフェニル)-2-{[(メトキシカルバモイル)アミノ]メチル}ピロリジン-1-カルボキシラート Reference Example 106
tert- butyl (2R *, 3S *) -3- (3,4- dichlorophenyl) -2 - {[(methoxycarbamoyl) amino] methyl} pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000179
Figure JPOXMLDOC01-appb-C000179

　tert-ブチル (2R*,3S*)-3-(3,4-ジクロロフェニル)-2-({[(4-ニトロフェノキシ)カルボニル]アミノ}メチル)ピロリジン-1-カルボキシラート（0.5 g）をアセトニトリル（5 mL） に溶解させ、炭酸カリウム(0.269 mg)とトリエチルアミン(0.27 mL)とo-メチルヒドロキシルアミン　塩酸塩（0.162 ｇ）を加えた。反応混合物を80℃で14時間加熱攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製することにより、標題化合物 (0.36 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.50 (9H, s), 1.76-1.98 (1H, m), 2.14-2.35 (1H, m), 3.03-4.06 (9H, m), 6.81-7.01 (1H, m), 7.08 (1H, d, J = 7.9 Hz), 7.33 (1H, s), 7.35-7.43 (1H, m). tert-Butyl (2R * , 3S * )-3- (3,4-dichlorophenyl) -2-({[(4-nitrophenoxy) carbonyl] amino} methyl) pyrrolidine-1-carboxylate (0.5 g) in acetonitrile (5 mL), potassium carbonate (0.269 mg), triethylamine (0.27 mL) and o-methylhydroxylamine hydrochloride (0.162 g) were added. The reaction mixture was heated and stirred at 80 ° C. for 14 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.36 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.50 (9H, s), 1.76-1.98 (1H, m), 2.14-2.35 (1H, m), 3.03-4.06 (9H, m), 6.81-7.01 (1H , m), 7.08 (1H, d, J = 7.9 Hz), 7.33 (1H, s), 7.35-7.43 (1H, m).

参考例１０７
1-tert-ブチル 2-メチル (2R,3S)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート（保持時間小） Reference Example 107
1-tert-butyl 2-methyl (2R, 3S) -3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate (low retention time)

Figure JPOXMLDOC01-appb-C000180
Figure JPOXMLDOC01-appb-C000180

1-tert-ブチル 2-メチル (2S,3R)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート（保持時間大） 1-tert-butyl 2-methyl (2S, 3R) -3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate (large retention time)

Figure JPOXMLDOC01-appb-C000181
Figure JPOXMLDOC01-appb-C000181

　1-tert-ブチル 2-メチル (2R*,3S*)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート(14.4 g)を高速液体クロマトグラフィー（カラム：CHIRALPAK IC (50 mm i.d.×500 mmL、ダイセル化学工業製)、移動相：ヘキサン/2-プロパノール＝50/50、流速：60 mL/min、カラム温度：30℃）を用いて分画した。上記の高速液体クロマトグラフィー条件にて保持時間の小さい方の光学活性体を含有する分画液を濃縮して、1-tert-ブチル 2-メチル (2R,3S)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート(14.4 g, 99.9% ee, LC/MS 274.0)を淡黄色油状物として得た。
　また、保持時間の大きい方の光学活性体を含有する分画液を濃縮して、1-tert-ブチル 2-メチル (2S,3R)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート(26.2 g, 99.9% ee, LC/MS 274.0)を淡黄色油状物として得た。
　なお、鏡像体過剰率（ee）は高速液体クロマトグラフィー（カラム：CHIRALPAK AD (4.6 mm i.d.×250 mmL、ダイセル化学工業製）、移動相：ヘキサン/2-プロパノール＝50/50、流速：0.5 mL/min、カラム温度：30℃）を用いて測定した（保持時間小：11.0 min、保持時間大：15.7 min）。 1-tert-butyl 2-methyl (2R * , 3S * )-3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate (14.4 g) was subjected to high performance liquid chromatography (column: CHIRALPAK IC (50 (mm id × 500 mmL, manufactured by Daicel Chemical Industries), mobile phase: hexane / 2-propanol = 50/50, flow rate: 60 mL / min, column temperature: 30 ° C.). The fraction containing the optically active form having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give 1-tert-butyl 2-methyl (2R, 3S) -3- (3,4- Dichlorophenyl) pyrrolidine-1,2-dicarboxylate (14.4 g, 99.9% ee, LC / MS 274.0) was obtained as a pale yellow oil.
Further, the fraction containing the optically active substance having the longer retention time is concentrated to give 1-tert-butyl 2-methyl (2S, 3R) -3- (3,4-dichlorophenyl) pyrrolidine-1,2 -Dicarboxylate (26.2 g, 99.9% ee, LC / MS 274.0) was obtained as a pale yellow oil.
The enantiomeric excess (ee) is high performance liquid chromatography (column: CHIRALPAK AD (4.6 mm id × 250 mmL, manufactured by Daicel Chemical Industries), mobile phase: hexane / 2-propanol = 50/50, flow rate: 0.5 mL. / min, column temperature: 30 ° C.) (low retention time: 11.0 min, high retention time: 15.7 min).

参考例１０８
(2R,3S)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸 Reference Example 108
(2R, 3S) -1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid

Figure JPOXMLDOC01-appb-C000182
Figure JPOXMLDOC01-appb-C000182

　1-tert-ブチル 2-メチル (2R,3S)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート(5.0 g, 13.0 mmol)をMeOH(40 mL)と1 N 水酸化ナトリウム水溶液(6.7 mL)に溶解させ、室温で終夜攪拌した。反応液を減圧下溶媒留去し、得られた残渣に水を加え、1規定塩酸で酸性にした後、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去することにより、表題化合物を白色結晶(4.1 g, 88%)として得た。
LC/MS 304.0 [M+H-Boc] 1-tert-butyl 2-methyl (2R, 3S) -3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate (5.0 g, 13.0 mmol) and 1 N hydroxylated with MeOH (40 mL) It was dissolved in an aqueous sodium solution (6.7 mL) and stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure, water was added to the resulting residue, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as white crystals (4.1 g, 88%).
LC / MS 304.0 [M + H-Boc]

参考例１０９
tert-ブチル (2R,3S)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート Reference Example 109
tert-butyl (2R, 3S) -3- (3,4-dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000183
Figure JPOXMLDOC01-appb-C000183

　(2R,3S)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸 (0.70 g, 1.94 mmol)のTHF(3 mL)溶液に0.9M ボランTHF溶液(2.6 mL, 2.34 mmol) を氷冷下加えた。室温で20分攪拌後、氷冷下にて再度0.9M ボランTHF溶液(2.6 mL, 2.34 mmol)を加え、室温で20時間攪拌した。水(10 mL) および10%クエン酸水溶液(5 mL) を加え室温で20分攪拌し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（10-50% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.52 g, 78%)として得た。
1H NMR (300 MHz, CDCl3) δ 1.49 (9H, s), 1.80-2.30 (2H, m), 2.80-3.00 (1H, m), 3.30-3.40 (1H, m), 3.55-3.95 (4H, m), 4.80-4.90 (1H, m), 7.07 (1H, dd, J = 8.1, 1.5 Hz), 7.33 (1H, d, J = 1.5 Hz), 7.38 (1H, d, J= 8.1 Hz).
LC/MS 246.0 [M+]-t-Bu (2R, 3S) -1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.70 g, 1.94 mmol) in THF (3 mL) in 0.9 M borane THF solution (2.6 mL, 2.34 mmol) was added under ice cooling. After stirring at room temperature for 20 minutes, 0.9M borane THF solution (2.6 mL, 2.34 mmol) was added again under ice cooling, and the mixture was stirred at room temperature for 20 hours. Water (10 mL) and 10% aqueous citric acid solution (5 mL) were added, and the mixture was stirred at room temperature for 20 min and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (10-50% ethyl acetate / hexane) to give the title compound as a colorless oil (0.52 g, 78%).
1 H NMR (300 MHz, CDCl 3 ) δ 1.49 (9H, s), 1.80-2.30 (2H, m), 2.80-3.00 (1H, m), 3.30-3.40 (1H, m), 3.55-3.95 (4H , m), 4.80-4.90 (1H, m), 7.07 (1H, dd, J = 8.1, 1.5 Hz), 7.33 (1H, d, J = 1.5 Hz), 7.38 (1H, d, J = 8.1 Hz) .
LC / MS 246.0 [M + ] -t-Bu

参考例１１０
tert-ブチル (2R,3S)-3-(3,4-ジクロロフェニル)-2-[(1,3-ジオキソ-1,3-ジヒドロ-2H-イソインドール-2-イル)メチル]ピロリジン-1-カルボキシラート Reference Example 110
tert-butyl (2R, 3S) -3- (3,4-dichlorophenyl) -2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] pyrrolidine-1- Carboxylate

Figure JPOXMLDOC01-appb-C000184
Figure JPOXMLDOC01-appb-C000184

　tert-ブチル (2R,3S)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート(520 mg, 1.50 mmol)のTHF(10 mL)溶液にフタルイミド(243 mg. 1.65 mmol)、40% ジエチルアゾジカルボキシレート(DEAD)トルエン溶液 (2.05 mL, 4.51 mmmol) およびトリフェニルホスフィン(1.18 g, 4.50 mmmol) を加え、室温で20時間攪拌した。水を加えて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（10-50% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色粉末(957 mg, 92%)として得た。
1H NMR (300 MHz, CDCl3) δ 1.25-1.50 (9H, m), 1.80-1.90 (1H, m), 2.25-2.40 (1H, m), 3.10-4.50 (6H, m), 6.90-7.00 (1H, m), 7.10-7.30 (2H, m), 7.60-7.80 (4H, m).
LC/MS 418.9 [M+]-t-Bu tert-Butyl (2R, 3S) -3- (3,4-Dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (520 mg, 1.50 mmol) in THF (10 mL) in phthalimide (243 mg 1.65 mmol), 40% diethyl azodicarboxylate (DEAD) toluene solution (2.05 mL, 4.51 mmmol) and triphenylphosphine (1.18 g, 4.50 mmmol) were added, and the mixture was stirred at room temperature for 20 hours. Water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (10-50% ethyl acetate / hexane) to give the title compound as a colorless powder (957 mg, 92%).
1 H NMR (300 MHz, CDCl 3 ) δ 1.25-1.50 (9H, m), 1.80-1.90 (1H, m), 2.25-2.40 (1H, m), 3.10-4.50 (6H, m), 6.90-7.00 (1H, m), 7.10-7.30 (2H, m), 7.60-7.80 (4H, m).
LC / MS 418.9 [M + ] -t-Bu

参考例１１１
tert-ブチル (2R,3S)-2-(アミノメチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート Reference Example 111
tert-butyl (2R, 3S) -2- (aminomethyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000185
Figure JPOXMLDOC01-appb-C000185

　tert-ブチル (2R,3S)-3-(3,4-ジクロロフェニル)-2-[(1,3-ジオキソ-1,3-ジヒドロ-2H-イソインドール-2-イル)メチル]ピロリジン-1-カルボキシラート(650 mg, 1.37 mmol)のTHF(5 mL)溶液にヒドラジン1水和物(1.0 mL)およびエタノール(5 mL) を加え、室温で1時間攪拌した。生成した固形物をろ去し、ろ液を濃縮後、シリカゲルカラムクロマトグラフィー（塩基性シリカゲル、0-50% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(354 mg, 75%)として得た。
1H NMR (300 MHz, CDCl3) δ 1.49 (9H, s), 1.80-1.95 (1H, m), 2.25-2.30 (1H, m), 2.70-2.90 (1H, m), 2.99 (1H, dd, J =13.1, 5.7 Hz), 3.20-3.40 (2H, m), 3.55-3.90 (2H, m), 4.00-4.25 (2H, m), 7.05 (1H, dd, J = 8.1, 2.0 Hz), 7.30 (1H, d, J = 2.0 Hz), 7.37 (1H, d, J= 8.1 Hz).
LC/MS 289.0 [M+]-t-Bu tert-butyl (2R, 3S) -3- (3,4-dichlorophenyl) -2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] pyrrolidine-1- Hydrazine monohydrate (1.0 mL) and ethanol (5 mL) were added to a solution of carboxylate (650 mg, 1.37 mmol) in THF (5 mL), and the mixture was stirred at room temperature for 1 hour. The resulting solid was removed by filtration, and the filtrate was concentrated and purified by silica gel column chromatography (basic silica gel, 0-50% ethyl acetate / hexane) to give the title compound as a colorless oil (354 mg, 75 %).
1 H NMR (300 MHz, CDCl 3 ) δ 1.49 (9H, s), 1.80-1.95 (1H, m), 2.25-2.30 (1H, m), 2.70-2.90 (1H, m), 2.99 (1H, dd , J = 13.1, 5.7 Hz), 3.20-3.40 (2H, m), 3.55-3.90 (2H, m), 4.00-4.25 (2H, m), 7.05 (1H, dd, J = 8.1, 2.0 Hz), 7.30 (1H, d, J = 2.0 Hz), 7.37 (1H, d, J = 8.1 Hz).
LC / MS 289.0 [M + ] -t-Bu

参考例１１２
tert-ブチル (2R,3S)-3-(3,4-ジクロロフェニル)-2-{[(メチルスルホニル)アミノ]メチル}ピロリジン-1-カルボキシラート Reference Example 112
tert-butyl (2R, 3S) -3- (3,4-dichlorophenyl) -2-{[(methylsulfonyl) amino] methyl} pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000186
Figure JPOXMLDOC01-appb-C000186

　tert-ブチル (2R,3S)-2-(アミノメチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート (350 mg, 1.01 mmol)およびトリエチルアミン(0.172 mL, 1.23 mmmol) のTHF(10 mL)溶液にメタンスルホニルクロリド (0.095 mL, 1.23 mmol)を氷冷下加え、室温で3時間攪拌した。水を加え酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（0-50% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.185 g, 43%)として得た。
1H NMR (300 MHz, CDCl3) δ 1.49 (9H, s), 1.80-2.00 (1H, m), 2.15-2.30 (1H, m), 2.09 (3H, s), 3.20-3.60 (4H, m), 3.65-3.90 (2H, m), 5.55-5.65 (1H, m), 7.11 (1H, dd, J = 8.1, 2.1 Hz), 7.35 (1H, d, J = 2.1 Hz), 7.39 (1H, d, J= 8.1 Hz).
LC/MS 366.9 [M+]-t-Bu tert-butyl (2R, 3S) -2- (aminomethyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate (350 mg, 1.01 mmol) and triethylamine (0.172 mL, 1.23 mmmol) in THF ( 10 mL) To the solution was added methanesulfonyl chloride (0.095 mL, 1.23 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (0-50% ethyl acetate / hexane) to give the title compound as a colorless oil (0.185 g, 43%).
1 H NMR (300 MHz, CDCl 3 ) δ 1.49 (9H, s), 1.80-2.00 (1H, m), 2.15-2.30 (1H, m), 2.09 (3H, s), 3.20-3.60 (4H, m ), 3.65-3.90 (2H, m), 5.55-5.65 (1H, m), 7.11 (1H, dd, J = 8.1, 2.1 Hz), 7.35 (1H, d, J = 2.1 Hz), 7.39 (1H, d, J = 8.1 Hz).
LC / MS 366.9 [M + ] -t-Bu

参考例１１３
tert-ブチル (2R,3S)-2-[(アセチルアミノ)メチル]-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート Reference Example 113
tert-butyl (2R, 3S) -2-[(acetylamino) methyl] -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000187
Figure JPOXMLDOC01-appb-C000187

　tert-ブチル (2R,3S)-2-(アミノメチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート (120 mg, 0.348 mmol)およびトリエチルアミン(0.074 mL, 0.53 mmol) のTHF(10 mL)溶液に無水酢酸 (0.050 mL, 0.53 mmol)を室温で加え、室温で20時間攪拌した。水を加え酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（0-50% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.039 g, 29%)として得た。
1H NMR (300 MHz, CDCl3) δ 1.50 (9H, s), 1.80-2.10 (4H, m), 2.15-2.30 (1H, m), 3.00-4.00 (6H, m), 7.00-7.20 (2H, m), 7.25-7.40 (2H, m).
LC/MS 287.1 [M+]-Boc tert-butyl (2R, 3S) -2- (aminomethyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate (120 mg, 0.348 mmol) and triethylamine (0.074 mL, 0.53 mmol) in THF ( 10 mL) solution was added acetic anhydride (0.050 mL, 0.53 mmol) at room temperature and stirred at room temperature for 20 hours. Water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (0-50% ethyl acetate / hexane) to give the title compound as a colorless oil (0.039 g, 29%).
1 H NMR (300 MHz, CDCl 3) δ 1.50 (9H, s), 1.80-2.10 (4H, m), 2.15-2.30 (1H, m), 3.00-4.00 (6H, m), 7.00-7.20 (2H , m), 7.25-7.40 (2H, m).
LC / MS 287.1 [M + ] -Boc

参考例１１４
tert-ブチル (2R,3S)-2-({[(tert-ブトキシカルボニル)スルファモイル]アミノ}メチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート Reference Example 114
tert-butyl (2R, 3S) -2-({[(tert-butoxycarbonyl) sulfamoyl] amino} methyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000188
Figure JPOXMLDOC01-appb-C000188

　tert-ブチル (2R,3S)-2-(アミノメチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート (120 mg, 0.348 mmol)のアセトニトリル(10 mL)溶液にN-(tert-ブトキシカルボニル)-N-[4- (ジメチルアザニウミリデン)-1,4- ジヒドロピリジン-1-イルスルホニル]アザニド(136 mg, 0.45 mmol)を室温で加え、室温で20時間攪拌した。水を加え酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（0-50% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.139 g, 76%)として得た。
1H NMR (300 MHz, CDCl3) δ 1.47 (9H, s), 1.49 (9H, s), 1.40-2.00 (2H, m), 2.15-2.30 (1H, m), 3.10-4.00 (6H, m), 6.10-6.25 (1H, m), 7.09 (1H, dd, J = 8.2, 2.1 Hz), 7.34 (1H, d, J = 2.1 Hz), 7.39 (1H, d, J = 8.2 Hz).
LC/MS 412.2 [M+]-t-Bu-t-Bu To a solution of tert-butyl (2R, 3S) -2- (aminomethyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate (120 mg, 0.348 mmol) in acetonitrile (10 mL) was added N- (tert -Butoxycarbonyl) -N- [4- (dimethylazaniumylidene) -1,4-dihydropyridin-1-ylsulfonyl] azanide (136 mg, 0.45 mmol) was added at room temperature, and the mixture was stirred at room temperature for 20 hours. Water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (0-50% ethyl acetate / hexane) to give the title compound as a colorless oil (0.139 g, 76%).
1 H NMR (300 MHz, CDCl 3 ) δ 1.47 (9H, s), 1.49 (9H, s), 1.40-2.00 (2H, m), 2.15-2.30 (1H, m), 3.10-4.00 (6H, m ), 6.10-6.25 (1H, m), 7.09 (1H, dd, J = 8.2, 2.1 Hz), 7.34 (1H, d, J = 2.1 Hz), 7.39 (1H, d, J = 8.2 Hz).
LC / MS 412.2 [M + ] -t-Bu-t-Bu

参考例１１５
(2S,3R)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸 Reference Example 115
(2S, 3R) -1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid

Figure JPOXMLDOC01-appb-C000189
Figure JPOXMLDOC01-appb-C000189

　1-tert-ブチル 2-メチル (2S,3R)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート(5.0 g, 13.0 mmol)をMeOH(40 mL)と1N 水酸化ナトリウム水溶液(6.7 mL)に溶解させ、室温で終夜攪拌した。反応液を減圧下溶媒留去し、得られた残渣に水を加え、1規定塩酸で酸性にした後、酢酸エチルで抽出した。得られた抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去することにより、表題化合物を白色結晶(4.3 g, 92%)として得た。
LC/MS 304.0 (M+H-Boc) 1-tert-butyl 2-methyl (2S, 3R) -3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate (5.0 g, 13.0 mmol) in MeOH (40 mL) and 1N sodium hydroxide Dissolve in aqueous solution (6.7 mL) and stir at room temperature overnight. The reaction mixture was evaporated under reduced pressure, water was added to the resulting residue, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as white crystals (4.3 g, 92%).
LC / MS 304.0 (M + H-Boc)

参考例１１６
tert-ブチル (2S,3R)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート Reference Example 116
tert-butyl (2S, 3R) -3- (3,4-dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000190
Figure JPOXMLDOC01-appb-C000190

　(2S,3R)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸 (5.50 g, 15.3 mmol)のTHF(50 mL)溶液に1M ボランTHF溶液(40 mL, 40 mmol) を加え、室温で20時間攪拌した。水(10 mL) および10%クエン酸水溶液(5 mL) を加え室温で20分攪拌し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（10-50% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(5.34 g, quant.)として得た。
1H NMR (300 MHz, CDCl3) δ 1.50 (9H, s), 1.80-2.30 (2H, m), 2.80-3.00 (1H, m), 3.30-3.40 (1H, m), 3.55-3.95 (4H, m), 4.80-4.90 (1H, m), 7.07 (1H, dd, J = 8.2, 2.1 Hz), 7.33 (1H, d, J = 2.1Hz), 7.39 (1H, d, J= 8.2 Hz).
LC/MS 246.0 [M+]-t-Bu (2S, 3R) -1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (5.50 g, 15.3 mmol) in THF (50 mL) solution in 1M borane THF solution ( 40 mL, 40 mmol) was added, and the mixture was stirred at room temperature for 20 hours. Water (10 mL) and 10% aqueous citric acid solution (5 mL) were added, and the mixture was stirred at room temperature for 20 min and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (10-50% ethyl acetate / hexane) to give the title compound as a colorless oil (5.34 g, quant.).
1 H NMR (300 MHz, CDCl 3 ) δ 1.50 (9H, s), 1.80-2.30 (2H, m), 2.80-3.00 (1H, m), 3.30-3.40 (1H, m), 3.55-3.95 (4H , m), 4.80-4.90 (1H, m), 7.07 (1H, dd, J = 8.2, 2.1 Hz), 7.33 (1H, d, J = 2.1 Hz), 7.39 (1H, d, J = 8.2 Hz) .
LC / MS 246.0 [M + ] -t-Bu

参考例１１７
tert-ブチル (2S,3R)-3-(3,4-ジクロロフェニル)-2-[(1,3-ジオキソ-1,3-ジヒドロ-2H-イソインドール-2-イル)メチル]ピロリジン-1-カルボキシラート Reference Example 117
tert-butyl (2S, 3R) -3- (3,4-dichlorophenyl) -2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] pyrrolidine-1- Carboxylate

Figure JPOXMLDOC01-appb-C000191
Figure JPOXMLDOC01-appb-C000191

　tert-ブチル (2S,3R)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート(3.07 g, 8.87 mmol)のTHF(50 mL)溶液にフタルイミド(1.57 g. 10.7 mmol)、40% ジエチルアゾジカルボキシレート(DEAD)トルエン溶液 (12.1 mL, 26.6 mmmol) およびトリフェニルホスフィン(6.98 g, 26.6 mmmol) を加え、室温で20時間攪拌した。水を加えて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（10-50% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色粉末(3.30 g, 78%)として得た。
1H NMR (300 MHz, CDCl3) δ 1.25-1.50 (9H, m), 1.80-1.90 (1H, m), 2.25-2.40 (1H, m), 3.10-4.50 (6H, m), 6.90-7.00 (1H, m), 7.10-7.30 (2H, m), 7.60-7.80 (4H, m).
LC/MS 418.9 [M+]-t-Bu tert-butyl (2S, 3R) -3- (3,4-dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (3.07 g, 8.87 mmol) in THF (50 mL) in phthalimide (1.57 g 10.7 mmol), 40% diethyl azodicarboxylate (DEAD) toluene solution (12.1 mL, 26.6 mmmol) and triphenylphosphine (6.98 g, 26.6 mmmol) were added, and the mixture was stirred at room temperature for 20 hours. Water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (10-50% ethyl acetate / hexane) to give the title compound as a colorless powder (3.30 g, 78%).
1 H NMR (300 MHz, CDCl 3 ) δ 1.25-1.50 (9H, m), 1.80-1.90 (1H, m), 2.25-2.40 (1H, m), 3.10-4.50 (6H, m), 6.90-7.00 (1H, m), 7.10-7.30 (2H, m), 7.60-7.80 (4H, m).
LC / MS 418.9 [M + ] -t-Bu

参考例１１８
tert-ブチル (2S,3R)-2-(アミノメチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート Reference Example 118
tert-butyl (2S, 3R) -2- (aminomethyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000192
Figure JPOXMLDOC01-appb-C000192

　tert-ブチル (2S,3R)-3-(3,4-ジクロロフェニル)-2-[(1,3-ジオキソ-1,3-ジヒドロ-2H-イソインドール-2-イル)メチル]ピロリジン-1-カルボキシラート(3.20 g, 6.73 mmol)のTHF(50 mL)溶液にヒドラジン1水和物(5.0 mL)およびエタノール(50 mL) を加え、室温で4時間攪拌した。生成した固形物をろ去し、ろ液を濃縮後、シリカゲルカラムクロマトグラフィー（塩基性シリカゲル、0-50% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(1.90 g, 82%)として得た。
1H NMR (300 MHz, CDCl3) δ 1.49 (9H, s), 1.80-1.95 (1H, m), 2.25-2.30 (1H, m), 2.70-2.90 (1H, m), 2.99 (1H, dd, J =13.2, 5.7 Hz), 3.20-3.40 (2H, m), 3.55-3.90 (2H, m), 4.00-4.25 (2H, m), 7.05 (1H, dd, J = 8.1, 2.1 Hz), 7.30 (1H, d, J = 2.1 Hz), 7.37 (1H, d, J= 8.1 Hz).
LC/MS 289.2 [M+]-t-Bu tert-butyl (2S, 3R) -3- (3,4-dichlorophenyl) -2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] pyrrolidine-1- Hydrazine monohydrate (5.0 mL) and ethanol (50 mL) were added to a solution of carboxylate (3.20 g, 6.73 mmol) in THF (50 mL), and the mixture was stirred at room temperature for 4 hours. The formed solid was removed by filtration, and the filtrate was concentrated and purified by silica gel column chromatography (basic silica gel, 0-50% ethyl acetate / hexane) to give the title compound as a colorless oil (1.90 g, 82 %).
1 H NMR (300 MHz, CDCl 3 ) δ 1.49 (9H, s), 1.80-1.95 (1H, m), 2.25-2.30 (1H, m), 2.70-2.90 (1H, m), 2.99 (1H, dd , J = 13.2, 5.7 Hz), 3.20-3.40 (2H, m), 3.55-3.90 (2H, m), 4.00-4.25 (2H, m), 7.05 (1H, dd, J = 8.1, 2.1 Hz), 7.30 (1H, d, J = 2.1 Hz), 7.37 (1H, d, J = 8.1 Hz).
LC / MS 289.2 [M + ] -t-Bu

参考例１１９
tert-ブチル (2S,3R)-3-(3,4-ジクロロフェニル)-2-{[(メチルスルホニル)アミノ]メチル}ピロリジン-1-カルボキシラート Reference Example 119
tert-butyl (2S, 3R) -3- (3,4-dichlorophenyl) -2-{[(methylsulfonyl) amino] methyl} pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000193
Figure JPOXMLDOC01-appb-C000193

　tert-ブチル (2S,3R)-2-(アミノメチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート (300 mg, 0.87 mmol)およびトリエチルアミン(0.160 mL, 1.15 mmmol) のTHF(10 mL)溶液にメタンスルホニルクロリド (0.088 mL, 1.14 mmol)を氷冷下加え、室温で20時間攪拌した。水を加え酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（0-50% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.295 g, 70%)として得た。
1H NMR (300 MHz, CDCl3) δ 1.50 (9H, s), 1.80-2.00 (1H, m), 2.15-2.30 (1H, m), 2.09 (3H, s), 3.20-3.60 (4H, m), 3.65-3.90 (2H, m), 5.55-5.65 (1H, m), 7.11 (1H, dd, J = 8.2, 2.1 Hz), 7.35 (1H, d, J = 2.1 Hz), 7.40 (1H, d, J= 8.2 Hz).
LC/MS 367.1 [M+]-t-Bu tert-Butyl (2S, 3R) -2- (aminomethyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate (300 mg, 0.87 mmol) and triethylamine (0.160 mL, 1.15 mmmol) in THF ( 10 mL) To the solution was added methanesulfonyl chloride (0.088 mL, 1.14 mmol) under ice cooling, and the mixture was stirred at room temperature for 20 hours. Water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (0-50% ethyl acetate / hexane) to give the title compound as a colorless oil (0.295 g, 70%).
1 H NMR (300 MHz, CDCl 3 ) δ 1.50 (9H, s), 1.80-2.00 (1H, m), 2.15-2.30 (1H, m), 2.09 (3H, s), 3.20-3.60 (4H, m ), 3.65-3.90 (2H, m), 5.55-5.65 (1H, m), 7.11 (1H, dd, J = 8.2, 2.1 Hz), 7.35 (1H, d, J = 2.1 Hz), 7.40 (1H, d, J = 8.2 Hz).
LC / MS 367.1 [M + ] -t-Bu

参考例１２０
tert-ブチル (2S,3R)-2-[(アセチルアミノ)メチル]-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート Reference Example 120
tert-butyl (2S, 3R) -2-[(acetylamino) methyl] -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000194
Figure JPOXMLDOC01-appb-C000194

　tert-ブチル (2S,3R)-2-(アミノメチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート (300 mg, 0.87 mmol)およびトリエチルアミン(0.160 mL, 1.15 mmol) のTHF(10 mL)溶液に塩化アセチル (0.081 mL, 1.14 mmol)を室温で加え、室温で20時間攪拌した。水を加え酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（0-50% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.271 g, 80%)として得た。
1H NMR (300 MHz, CDCl3) δ 1.50 (9H, s), 1.80-2.10 (4H, m), 2.15-2.30 (1H, m), 3.00-4.00 (6H, m), 7.00-7.20 (2H, m), 7.25-7.35 (1H, m), 7.38 (1H, d, J= 8.4 Hz).
LC/MS 287.1 [M+]-Boc tert-butyl (2S, 3R) -2- (aminomethyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate (300 mg, 0.87 mmol) and triethylamine (0.160 mL, 1.15 mmol) in THF ( 10 mL) To the solution was added acetyl chloride (0.081 mL, 1.14 mmol) at room temperature, and the mixture was stirred at room temperature for 20 hours. Water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (0-50% ethyl acetate / hexane) to give the title compound as a colorless oil (0.271 g, 80%).
1 H NMR (300 MHz, CDCl 3 ) δ 1.50 (9H, s), 1.80-2.10 (4H, m), 2.15-2.30 (1H, m), 3.00-4.00 (6H, m), 7.00-7.20 (2H , m), 7.25-7.35 (1H, m), 7.38 (1H, d, J = 8.4 Hz).
LC / MS 287.1 [M + ] -Boc

参考例１２１
tert-ブチル (2S,3R)-2-({[(tert-ブトキシカルボニル)スルファモイル]アミノ}メチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート Reference Example 121
tert-butyl (2S, 3R) -2-({[(tert-butoxycarbonyl) sulfamoyl] amino} methyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000195
Figure JPOXMLDOC01-appb-C000195

　tert-ブチル (2S,3R)-2-(アミノメチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート (300 mg, 0.87 mmol)のアセトニトリル(10 mL)溶液にN-(tert-ブトキシカルボニル)-N-[4- (ジメチルアザニウミリデン)-1,4- ジヒドロピリジン-1-イルスルホニル]アザニド(344 mg, 1.14 mmol)を室温で加え、室温で20時間攪拌した。水を加え酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（0-50% 酢酸エチル／ヘキサン）で精製することにより、表題化合物を無色油状物(0.263 g, 58%)として得た。
1H NMR (300 MHz, CDCl3) δ 1.47 (9H, s), 1.49 (9H, s), 1.40-2.00 (2H, m), 2.15-2.30 (1H, m), 3.10-4.00 (6H, m), 6.10-6.25 (1H, m), 7.09 (1H, dd, J = 8.2, 2.1 Hz), 7.33 (1H, d, J = 2.1 Hz), 7.38 (1H, d, J = 8.2 Hz).
LC/MS 412.1 [M+]-t-Bu-t-Bu To a solution of tert-butyl (2S, 3R) -2- (aminomethyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate (300 mg, 0.87 mmol) in acetonitrile (10 mL) was added N- (tert -Butoxycarbonyl) -N- [4- (dimethylazaniumylidene) -1,4-dihydropyridin-1-ylsulfonyl] azanide (344 mg, 1.14 mmol) was added at room temperature, and the mixture was stirred at room temperature for 20 hours. Water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (0-50% ethyl acetate / hexane) to give the title compound as a colorless oil (0.263 g, 58%).
1 H NMR (300 MHz, CDCl 3 ) δ 1.47 (9H, s), 1.49 (9H, s), 1.40-2.00 (2H, m), 2.15-2.30 (1H, m), 3.10-4.00 (6H, m ), 6.10-6.25 (1H, m), 7.09 (1H, dd, J = 8.2, 2.1 Hz), 7.33 (1H, d, J = 2.1 Hz), 7.38 (1H, d, J = 8.2 Hz).
LC / MS 412.1 [M + ] -t-Bu-t-Bu

実施例１
(2S*,3R*)-3-(3,4-ジクロロフェニル)-2-エチルピロリジン　1塩酸塩 Example 1
(2S * , 3R * ) -3- (3,4-Dichlorophenyl) -2-ethylpyrrolidine monohydrochloride

Figure JPOXMLDOC01-appb-C000196
Figure JPOXMLDOC01-appb-C000196

　メチル (3R*,4S*)-3-(3,4-ジクロロフェニル)-4-ニトロヘキサノアート(1.6 g, 5.0 mmol)の酢酸(20 mL)溶液に、亜鉛粉末(1.6 g, 25 mmol)を加え、還流下5時間加熱した。反応混合物を酢酸エチルで希釈し、これをセライト濾過し、濾液を減圧濃縮した。残渣をトルエンで希釈し、再度、減圧下濃縮した。
　得られた残渣をTHF(25 mL)に溶解させ、1 MボランTHF錯体THF溶液(13 mL)を加え、加熱還流下、5時間攪拌した。反応混合物に6 N塩酸(12 mL)を加え、１時間加熱還流した後、8 N水酸化ナトリウム水溶液を用いて塩基性にした。水層が飽和になるまで塩化ナトリムを加えた後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。
　得られた残渣をTHF(25 mL)に溶解させ、ジ-tert-ブチル ジカルボナート(1.1 mL, 5.0 mmol)を加え、室温で3時間攪拌した。反応混合物を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（1-15% 酢酸エチル／ヘキサン）で精製することにより無色油状物を得た。
　得られた油状物をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(20 mL)を加えた。反応混合物を3時間加熱還流し、減圧下濃縮した。得られた残渣を酢酸エチルを用いて再結晶した後、HPLCにて精製した。得られた溶液を減圧下濃縮し、飽和炭酸水素ナトリウム水溶液で中和し、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。
　得られた残渣をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(0.3 mL)を加え、室温で15分間攪拌した。反応混合物を減圧下濃縮し、得られた固体を酢酸エチルより再結晶して、表題化合物を無色結晶(0.22 g, 17%)として得た。
NMR (DMSO-d6) δ: 0.80 (3H, d, J = 14.6 Hz), 1.03-1.31 (2H, m), 2.06-2.21 (1H, m), 2.29-2.45 (1H, m), 3.13-3.24 (1H, m), 3.41-3.50 (1H, m), 3.58-3.71 (2H, m), 7.31 (1H, dd, J = 8.2, 2.2 Hz), 7.51-7.69 (2H, m), 9.24 (2H, brs).
LC/MS 244.0
mp 154-155℃
Anal. Calcd. for C12H15NCl2・HCl: C, 51.36; H, 5.75; N, 4.99; Cl, 37.90. Found: C, 51.28; H, 5.69; N, 4.97; Cl, 38.08. To a solution of methyl (3R * , 4S * )-3- (3,4-dichlorophenyl) -4-nitrohexanoate (1.6 g, 5.0 mmol) in acetic acid (20 mL), zinc powder (1.6 g, 25 mmol) And heated under reflux for 5 hours. The reaction mixture was diluted with ethyl acetate, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was diluted with toluene and concentrated again under reduced pressure.
The obtained residue was dissolved in THF (25 mL), 1 M borane THF complex THF solution (13 mL) was added, and the mixture was stirred with heating under reflux for 5 hr. 6N Hydrochloric acid (12 mL) was added to the reaction mixture, and the mixture was heated to reflux for 1 hour and basified with 8N aqueous sodium hydroxide solution. Sodium chloride was added until the aqueous layer became saturated, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was dissolved in THF (25 mL), di-tert-butyl dicarbonate (1.1 mL, 5.0 mmol) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (1-15% ethyl acetate / hexane) to give a colorless oil.
The obtained oil was dissolved in methanol (10 mL), and 4 N hydrochloric acid-ethyl acetate solution (20 mL) was added. The reaction mixture was heated to reflux for 3 hours and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and purified by HPLC. The resulting solution was concentrated under reduced pressure, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was dissolved in methanol (10 mL), 4N hydrochloric acid-ethyl acetate solution (0.3 mL) was added, and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the obtained solid was recrystallized from ethyl acetate to give the title compound as colorless crystals (0.22 g, 17%).
NMR (DMSO-d 6) δ : 0.80 (3H, d, J = 14.6 Hz), 1.03-1.31 (2H, m), 2.06-2.21 (1H, m), 2.29-2.45 (1H, m), 3.13- 3.24 (1H, m), 3.41-3.50 (1H, m), 3.58-3.71 (2H, m), 7.31 (1H, dd, J = 8.2, 2.2 Hz), 7.51-7.69 (2H, m), 9.24 ( 2H, brs).
LC / MS 244.0
mp 154-155 ℃
Anal.Calcd.for C 12 H 15 NCl 2 HCl: C, 51.36; H, 5.75; N, 4.99; Cl, 37.90. Found: C, 51.28; H, 5.69; N, 4.97; Cl, 38.08.

実施例２
(2R*,3R*)-3-(3,4-ジクロロフェニル)-2-エチルピロリジン　1塩酸塩 Example 2
(2R * , 3R * ) -3- (3,4-Dichlorophenyl) -2-ethylpyrrolidine monohydrochloride

Figure JPOXMLDOC01-appb-C000197
Figure JPOXMLDOC01-appb-C000197

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-エチルピロリジン-1-カルボキシラート(0.65 g, 1.9 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(20 mL)を加えた。反応混合物を1時間加熱還流し、減圧下濃縮した。得られた固体をジエチルエーテルで洗浄した後、メタノール／酢酸エチルより再結晶して、表題化合物を無色結晶(0.38 g, 72%)として得た。
NMR (DMSO-d6) δ: 0.88 (3H, t, J = 7.4 Hz), 1.45-1.63 (1H, m), 1.64-1.82 (1H, m), 1.94-2.13 (1H, m), 2.25-2.42 (1H, m), 3.03-3.16 (1H, m), 3.19-3.31 (1H, m), 3.33-3.47 (2H, m), 7.41 (1H, dd, J = 8.3, 2.1 Hz), 7.62 (1H, d, J = 8.3 Hz), 7.74 (1H, d, J = 2.1 Hz), 9.65 (2H, brs).
LC/MS 244.0
mp 200-201℃
Anal. Calcd. for C12H15NCl2・HCl: C, 51.36; H, 5.75; N, 4.99; Cl, 37.90. Found: C, 51.32; H, 5.70; N, 4.97; Cl, 37.93. Dissolve tert-butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2-ethylpyrrolidine-1-carboxylate (0.65 g, 1.9 mmol) in methanol (10 mL) and add 4 N hydrochloric acid -An ethyl acetate solution (20 mL) was added. The reaction mixture was heated to reflux for 1 hour and concentrated under reduced pressure. The obtained solid was washed with diethyl ether and recrystallized from methanol / ethyl acetate to give the title compound as colorless crystals (0.38 g, 72%).
NMR (DMSO-d 6 ) δ: 0.88 (3H, t, J = 7.4 Hz), 1.45-1.63 (1H, m), 1.64-1.82 (1H, m), 1.94-2.13 (1H, m), 2.25- 2.42 (1H, m), 3.03-3.16 (1H, m), 3.19-3.31 (1H, m), 3.33-3.47 (2H, m), 7.41 (1H, dd, J = 8.3, 2.1 Hz), 7.62 ( 1H, d, J = 8.3 Hz), 7.74 (1H, d, J = 2.1 Hz), 9.65 (2H, brs).
LC / MS 244.0
mp 200-201 ℃
Anal.Calcd.for C 12 H 15 NCl 2・ HCl: C, 51.36; H, 5.75; N, 4.99; Cl, 37.90.Found: C, 51.32; H, 5.70; N, 4.97; Cl, 37.93.

実施例３
(2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-メチルプロピル)ピロリジン　1塩酸塩 Example 3
(2S * , 3R * )-3- (3,4-Dichlorophenyl) -2- (2-methylpropyl) pyrrolidine monohydrochloride

Figure JPOXMLDOC01-appb-C000198
Figure JPOXMLDOC01-appb-C000198

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-メチルプロピル)ピロリジン-1-カルボキシラート(0.48 g, 1.3 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(20 mL)を加えた。反応混合物を1時間加熱還流し、減圧下濃縮した。得られた固体をジエチルエーテルで洗浄した後、メタノール／酢酸エチルより再結晶して、表題化合物を無色結晶(0.23 g, 58%)として得た。
NMR (DMSO-d6) δ: 0.74-0.90 (7H, m), 1.20-1.31 (1H, m), 1.45-1.56 (1H, m), 2.06-2.21 (1H, m), 2.32-2.44 (1H, m), 3.15-3.26 (1H, m), 3.42-3.52 (1H, m), 3.66 (1H, q, J = 7.9 Hz), 3.78-3.88 (1H, m), 7.33 (1H, dd, J = 8.4, 2.2 Hz), 7.58-7.64 (2H, m), 9.43 (2H, brs).
LC/MS 272.0
mp 211-212℃
Anal. Calcd. for C14H19NCl2・HCl: C, 54.47; H, 6.53; N, 4.54; Cl, 34.46. Found: C, 54.47; H, 6.56; N, 4.46; Cl, 34.46. tert-Butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (2-methylpropyl) pyrrolidine-1-carboxylate (0.48 g, 1.3 mmol) dissolved in methanol (10 mL) 4N hydrochloric acid-ethyl acetate solution (20 mL) was added. The reaction mixture was heated to reflux for 1 hour and concentrated under reduced pressure. The obtained solid was washed with diethyl ether and recrystallized from methanol / ethyl acetate to give the title compound as colorless crystals (0.23 g, 58%).
NMR (DMSO-d 6 ) δ: 0.74-0.90 (7H, m), 1.20-1.31 (1H, m), 1.45-1.56 (1H, m), 2.06-2.21 (1H, m), 2.32-2.44 (1H , m), 3.15-3.26 (1H, m), 3.42-3.52 (1H, m), 3.66 (1H, q, J = 7.9 Hz), 3.78-3.88 (1H, m), 7.33 (1H, dd, J = 8.4, 2.2 Hz), 7.58-7.64 (2H, m), 9.43 (2H, brs).
LC / MS 272.0
mp 211-212 ℃
Anal.Calcd.for C 14 H 19 NCl 2・ HCl: C, 54.47; H, 6.53; N, 4.54; Cl, 34.46.Found: C, 54.47; H, 6.56; N, 4.46; Cl, 34.46.

実施例４
(2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-メチルプロピル)ピロリジン　1塩酸塩 Example 4
(2R * , 3R * )-3- (3,4-Dichlorophenyl) -2- (2-methylpropyl) pyrrolidine monohydrochloride

Figure JPOXMLDOC01-appb-C000199
Figure JPOXMLDOC01-appb-C000199

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-メチルプロピル)ピロリジン-1-カルボキシラート(0.48 g, 1.3 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(20 mL)を加えた。反応混合物を1時間加熱還流し、減圧下濃縮した。得られた固体をジエチルエーテルで洗浄した後、メタノール／酢酸エチルより再結晶して、表題化合物を無色結晶(0.25 g, 63%)として得た。
NMR (DMSO-d6) δ: 0.77 (3H, d, J = 1.7 Hz), 0.79 (3H, d, J = 1.7 Hz), 1.15-1.25 (1H, m), 1.55-1.77 (2H, m), 1.96-2.11 (1H, m), 2.27-2.38 (1H, m), 3.00-3.12 (1H, m), 3.20-3.44 (2H, m), 3.55 (1H, td, J = 10.0, 4.2 Hz), 7.41 (1H, dd, J = 8.3, 2.1 Hz), 7.63 (1H, d, J = 8.3 Hz), 7.74 (1H, d, J = 2.1 Hz), 9.55 (2H, brs).
LC/MS 272.1
mp 240-241℃
Anal. Calcd. for C14H19NCl2・HCl: C, 54.47; H, 6.53; N, 4.54; Cl, 34.46. Found: C, 54.49; H, 6.56; N, 4.46; Cl, 34.22. dissolving tert- butyl (2R *, 3R *) -3- (3,4- dichlorophenyl) -2- (2-methylpropyl) pyrrolidine-1-carboxylate (0.48 g, 1.3 mmol) in methanol (10 mL) 4N hydrochloric acid-ethyl acetate solution (20 mL) was added. The reaction mixture was heated to reflux for 1 hour and concentrated under reduced pressure. The obtained solid was washed with diethyl ether and recrystallized from methanol / ethyl acetate to give the title compound as colorless crystals (0.25 g, 63%).
NMR (DMSO-d 6 ) δ: 0.77 (3H, d, J = 1.7 Hz), 0.79 (3H, d, J = 1.7 Hz), 1.15-1.25 (1H, m), 1.55-1.77 (2H, m) , 1.96-2.11 (1H, m), 2.27-2.38 (1H, m), 3.00-3.12 (1H, m), 3.20-3.44 (2H, m), 3.55 (1H, td, J = 10.0, 4.2 Hz) , 7.41 (1H, dd, J = 8.3, 2.1 Hz), 7.63 (1H, d, J = 8.3 Hz), 7.74 (1H, d, J = 2.1 Hz), 9.55 (2H, brs).
LC / MS 272.1
mp 240-241 ℃
Anal.Calcd.for C 14 H 19 NCl 2・ HCl: C, 54.47; H, 6.53; N, 4.54; Cl, 34.46.Found: C, 54.49; H, 6.56; N, 4.46; Cl, 34.22.

実施例５
メチル (2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボキシラート　1塩酸塩 Example 5
Methyl (2R * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylate monohydrochloride

Figure JPOXMLDOC01-appb-C000200
Figure JPOXMLDOC01-appb-C000200

　1-tert-ブチル 2-メチル (2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート(0.17 g, 0.45 mmol)をメタノール(3 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(6 mL)を加えた。反応混合物を2時間加熱還流し、減圧下濃縮した。得られた固体を酢酸エチル／ヘキサンより再結晶して、表題化合物を無色結晶(70 mg, 50%)として得た。
NMR (DMSO-d6) δ: 2.10-2.25 (1H, m), 2.37-2.48 (1H, m), 3.23-3.31 (1H, m), 3.35 (3H, s), 3.52-3.62 (1H, m), 3.93 (1H, q, J = 8.7 Hz), 4.69 (1H, d, J = 9.1 Hz), 7.26 (1H, dd, J = 8.3, 2.3 Hz), 7.57 (1H, d, J = 2.3 Hz), 7.62 (1H, d, J = 8.3 Hz), 9.85 (2H, brs).
LC/MS 274.0
mp 162-163℃
Anal. Calcd. for C12H13NO2Cl2・HCl: C, 46.40; H, 4.54; N, 4.51; Cl, 34.24. Found: C, 46.18; H, 4.57; N, 4.47; Cl, 33.95. 1-tert-butyl 2-methyl (2R * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate (0.17 g, 0.45 mmol) was dissolved in methanol (3 mL). 4N hydrochloric acid-ethyl acetate solution (6 mL) was added. The reaction mixture was heated to reflux for 2 hours and concentrated under reduced pressure. The obtained solid was recrystallized from ethyl acetate / hexane to give the title compound as colorless crystals (70 mg, 50%).
NMR (DMSO-d 6) δ : 2.10-2.25 (1H, m), 2.37-2.48 (1H, m), 3.23-3.31 (1H, m), 3.35 (3H, s), 3.52-3.62 (1H, m ), 3.93 (1H, q, J = 8.7 Hz), 4.69 (1H, d, J = 9.1 Hz), 7.26 (1H, dd, J = 8.3, 2.3 Hz), 7.57 (1H, d, J = 2.3 Hz) ), 7.62 (1H, d, J = 8.3 Hz), 9.85 (2H, brs).
LC / MS 274.0
mp 162-163 ℃
Anal.Calcd.for C 12 H 13 NO 2 Cl 2 HCl: C, 46.40; H, 4.54; N, 4.51; Cl, 34.24.Found: C, 46.18; H, 4.57; N, 4.47; Cl, 33.95.

実施例６
メチル (2R*,3R*)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-2-カルボキシラート　1塩酸塩 Example 6
Methyl (2R * , 3R * )-3- (3-chloro-4-fluorophenyl) pyrrolidine-2-carboxylate monohydrochloride

Figure JPOXMLDOC01-appb-C000201
Figure JPOXMLDOC01-appb-C000201

　1-tert-ブチル 2-メチル (2R*,3R*)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-1,2-ジカルボキシラート(0.20 g)の酢酸エチル(3.0 mL)溶液に4 N塩酸－酢酸エチル溶液(3.0 mL)を加え、室温で終夜攪拌した。溶媒を減圧留去し、減圧下乾燥して、表題化合物を白色固体(0.10 g, 62%)として得た。
LC/MS 258.2
NMR (DMSO-d6) δ: 2.10-2.29 (1H, m), 2.36-2.48 (1H, m), 3.22-3.40 (4H, m), 3.52-3.64 (1H, m), 3.94 (1H, q, J = 8.9 Hz), 4.69 (1H, d, J = 9.2 Hz), 7.22-7.34 (1H, m), 7.40 (1H, t, J = 8.9 Hz), 7.53 (1H, dd, J = 7.0, 2.3 Hz), 10.01 (2H, brs).
mp 153-154℃ To a solution of 1-tert-butyl 2-methyl (2R * , 3R * )-3- (3-chloro-4-fluorophenyl) pyrrolidine-1,2-dicarboxylate (0.20 g) in ethyl acetate (3.0 mL) 4N Hydrochloric acid-ethyl acetate solution (3.0 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure and dried under reduced pressure to obtain the title compound as a white solid (0.10 g, 62%).
LC / MS 258.2
NMR (DMSO-d 6 ) δ: 2.10-2.29 (1H, m), 2.36-2.48 (1H, m), 3.22-3.40 (4H, m), 3.52-3.64 (1H, m), 3.94 (1H, q , J = 8.9 Hz), 4.69 (1H, d, J = 9.2 Hz), 7.22-7.34 (1H, m), 7.40 (1H, t, J = 8.9 Hz), 7.53 (1H, dd, J = 7.0, 2.3 Hz), 10.01 (2H, brs).
mp 153-154 ℃

実施例７
メチル (2R*,3R*)-3-(3-クロロフェニル)ピロリジン-2-カルボキシラート　1塩酸塩 Example 7
Methyl (2R * , 3R * )-3- (3-chlorophenyl) pyrrolidine-2-carboxylate monohydrochloride

Figure JPOXMLDOC01-appb-C000202
Figure JPOXMLDOC01-appb-C000202

　1-tert-ブチル 2-メチル (2R*,3R*)-3-(3-クロロフェニル)ピロリジン-1,2-ジカルボキシラート(0.3 g, 0.88 mmol)を酢酸エチル(5 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(5 mL)を加えた。反応混合物を終夜攪拌し、減圧下溶媒を留去した。得られた固体をジエチルエーテル／メタノールで洗浄した後、表題化合物を白色結晶(0.22 g, 92%)として得た。
NMR (DMSO-d6) δ: 2.12-2.30 (1H, m), 2.37-2.48 (1H, m), 3.22-3.39 (1H, m), 3.32 (3H, s), 3.53-3.65 (1H, m), 3.87-4.00 (1H, m), 4.69 (1H, d, J = 9.5 Hz), 7.19-7.25 (1H, m), 7.34-7.39 (3H, m), 9.63-10.27 (2H, m).
LC/MS 240.1
mp 154-155℃
Anal. Calcd. for C12H14NO2Cl・HCl: C, 52.19; H, 5.47; N, 5.07; O, 11.59; Cl, 25.68. Found: C, 52.01; H, 5.44; N, 4.96. 1-tert-butyl 2-methyl (2R * , 3R * )-3- (3-chlorophenyl) pyrrolidine-1,2-dicarboxylate (0.3 g, 0.88 mmol) was dissolved in ethyl acetate (5 mL), A 4 N hydrochloric acid-ethyl acetate solution (5 mL) was added. The reaction mixture was stirred overnight and the solvent was removed under reduced pressure. The obtained solid was washed with diethyl ether / methanol, and the title compound was obtained as white crystals (0.22 g, 92%).
NMR (DMSO-d 6 ) δ: 2.12-2.30 (1H, m), 2.37-2.48 (1H, m), 3.22-3.39 (1H, m), 3.32 (3H, s), 3.53-3.65 (1H, m ), 3.87-4.00 (1H, m), 4.69 (1H, d, J = 9.5 Hz), 7.19-7.25 (1H, m), 7.34-7.39 (3H, m), 9.63-10.27 (2H, m).
LC / MS 240.1
mp 154-155 ℃
Anal.Calcd.for C 12 H 14 NO 2 Cl.HCl: C, 52.19; H, 5.47; N, 5.07; O, 11.59; Cl, 25.68.Found: C, 52.01; H, 5.44; N, 4.96.

実施例８
メチル (2R*,3R*)-3-(4-クロロフェニル)ピロリジン-2-カルボキシラート　1塩酸塩 Example 8
Methyl (2R * , 3R * )-3- (4-chlorophenyl) pyrrolidine-2-carboxylate monohydrochloride

Figure JPOXMLDOC01-appb-C000203
Figure JPOXMLDOC01-appb-C000203

　1-tert-ブチル 2-メチル (2R*,3R*)-3-(4-クロロフェニル)ピロリジン-1,2-ジカルボキシラート(0.16 g)の酢酸エチル(2.0 mL)溶液に4 N塩酸－酢酸エチル溶液(2.0 mL)を加え、室温で終夜攪拌した。溶媒を減圧留去し、減圧下乾燥して、表題化合物を白色非定形固体(0.09 g, 73%)として得た。
LC/MS 240.2
NMR (DMSO-d6) δ: 2.10-2.26 (1H, m), 2.35-2.48 (1H, m), 3.23-3.42 (4H, m), 3.51-3.65 (1H, m), 3.84-4.01 (1H, m), 4.66 (1H, d, J = 9.1 Hz), 7.20-7.33 (2H, m), 7.35-7.51 (2H, m), 9.98 (2H, brs). 1-tert-butyl 2-methyl (2R * , 3R * )-3- (4-chlorophenyl) pyrrolidine-1,2-dicarboxylate (0.16 g) in ethyl acetate (2.0 mL) in 4 N hydrochloric acid-acetic acid Ethyl solution (2.0 mL) was added, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure and dried under reduced pressure to obtain the title compound as a white amorphous solid (0.09 g, 73%).
LC / MS 240.2
NMR (DMSO-d 6) δ : 2.10-2.26 (1H, m), 2.35-2.48 (1H, m), 3.23-3.42 (4H, m), 3.51-3.65 (1H, m), 3.84-4.01 (1H , m), 4.66 (1H, d, J = 9.1 Hz), 7.20-7.33 (2H, m), 7.35-7.51 (2H, m), 9.98 (2H, brs).

実施例９
メチル (2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボキシラート　1塩酸塩 Example 9
Methyl (2S * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylate monohydrochloride

Figure JPOXMLDOC01-appb-C000204
Figure JPOXMLDOC01-appb-C000204

　1-tert-ブチル 2-メチル (2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-1,2-ジカルボキシラート(0.17 g, 0.45 mmol)をメタノール(5 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(10 mL)を加えた。反応混合物を1時間加熱還流し、減圧下濃縮した。得られた固体をエタノール／ヘキサンより再結晶して、表題化合物を無色結晶(85 mg, 58%)として得た。
NMR (DMSO-d6) δ: 2.10-2.25 (1H, m), 2.37-2.48 (1H, m), 3.23-3.31 (1H, m), 3.35 (3H, s), 3.52-3.62 (1H, m), 3.93 (1H, q, J = 8.7 Hz), 4.69 (1H, d, J = 9.1 Hz), 7.26 (1H, dd, J = 8.3, 2.3 Hz), 7.57 (1H, d, J = 2.3 Hz), 7.62 (1H, d, J = 8.3 Hz), 9.85 (2H, brs).
LC/MS 274.0 1-tert-butyl 2-methyl (2S * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidine-1,2-dicarboxylate (0.17 g, 0.45 mmol) was dissolved in methanol (5 mL). 4N hydrochloric acid-ethyl acetate solution (10 mL) was added. The reaction mixture was heated to reflux for 1 hour and concentrated under reduced pressure. The obtained solid was recrystallized from ethanol / hexane to give the title compound as colorless crystals (85 mg, 58%).
NMR (DMSO-d 6 ) δ: 2.10-2.25 (1H, m), 2.37-2.48 (1H, m), 3.23-3.31 (1H, m), 3.35 (3H, s), 3.52-3.62 (1H, m ), 3.93 (1H, q, J = 8.7 Hz), 4.69 (1H, d, J = 9.1 Hz), 7.26 (1H, dd, J = 8.3, 2.3 Hz), 7.57 (1H, d, J = 2.3 Hz) ), 7.62 (1H, d, J = 8.3 Hz), 9.85 (2H, brs).
LC / MS 274.0

実施例１０
エチル (2S*,3R*)-3-(3-クロロフェニル)ピロリジン-2-カルボキシラート　1塩酸塩 Example 10
Ethyl (2S * , 3R * )-3- (3-chlorophenyl) pyrrolidine-2-carboxylate monohydrochloride

Figure JPOXMLDOC01-appb-C000205
Figure JPOXMLDOC01-appb-C000205

　1-tert-ブチル 2-エチル (2S*,3R)-3-(3-クロロフェニル)ピロリジン-1,2-ジカルボキシラート(0.23 g, 0.68 mmol)を酢酸エチル(3 mL)に溶解させ、11 N塩酸－エタノール溶液(2.5 mL)を加えた。反応混合物を終夜攪拌し、減圧下溶媒を留去した。得られた固体をジエチルエーテル／メタノールで洗浄した後、表題化合物を褐色結晶(0.13 g, 64%)として得た。
NMR (DMSO-d6) δ: 1.11 (3H, t, J = 7.1 Hz), 2.00-2.20 (1H, m), 2.34-2.49 (1H, m), 3.22-3.33 (1H, m), 3.43-3.66 (2H, m), 4.01-4.29 (2H, m), 4.38 (1H, d, J = 9.6 Hz), 7.33-7.44 (3H, m), 7.55 (1H, s), 9.82 (2H, brs).
LC/MS 254.2
mp 200-201℃
Anal. Calcd. for C13H16NO2Cl・HCl: C, 53.81; H, 5.90; N, 4.83; O, 11.03; Cl, 24.43. Found: C, 53.44; H, 6.21; N, 4.79. 1-tert-butyl 2-ethyl (2S * , 3R) -3- (3-chlorophenyl) pyrrolidine-1,2-dicarboxylate (0.23 g, 0.68 mmol) was dissolved in ethyl acetate (3 mL) and 11 N hydrochloric acid-ethanol solution (2.5 mL) was added. The reaction mixture was stirred overnight and the solvent was removed under reduced pressure. The obtained solid was washed with diethyl ether / methanol, and the title compound was obtained as brown crystals (0.13 g, 64%).
NMR (DMSO-d 6 ) δ: 1.11 (3H, t, J = 7.1 Hz), 2.00-2.20 (1H, m), 2.34-2.49 (1H, m), 3.22-3.33 (1H, m), 3.43- 3.66 (2H, m), 4.01-4.29 (2H, m), 4.38 (1H, d, J = 9.6 Hz), 7.33-7.44 (3H, m), 7.55 (1H, s), 9.82 (2H, brs) .
LC / MS 254.2
mp 200-201 ℃
.. Anal Calcd for C 13 H 16 NO 2 Cl · HCl:. C, 53.81; H, 5.90; N, 4.83; O, 11.03; Cl, 24.43 Found: C, 53.44; H, 6.21; N, 4.79.

実施例１１
(2R*,3R*)-3-(3,4-ジクロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド　1塩酸塩 Example 11
(2R * , 3R * )-3- (3,4-Dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide monohydrochloride

Figure JPOXMLDOC01-appb-C000206
Figure JPOXMLDOC01-appb-C000206

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(ジメチルカルバモイル)ピロリジン-1-カルボキシラート(0.70 g, 1.8 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(20 mL)を加えた。反応混合物を1時間加熱還流し、減圧下濃縮した。得られた固体をメタノール／酢酸エチルより再結晶して、表題化合物を無色結晶(0.36 g, 61%)として得た。
NMR (DMSO-d6) δ: 1.98-2.13 (1H, m), 2.40-2.49 (1H, m), 2.55 (3H, s), 2.67 (3H, s), 3.13-3.25 (1H, m), 3.51-3.62 (1H, m), 3.99 (1H, q, J = 8.7 Hz), 4.94 (1H, d, J = 9.4 Hz), 7.24 (1H, dd, J = 8.3, 2.1 Hz), 7.53 (1H, d, J = 2.1 Hz), 7.59 (1H, d, J = 8.3 Hz), 9.63 (2H, brs).
LC/MS 286.9
mp 248-249℃
Anal. Calcd. for C13H16N2OCl・HCl: C, 48.24; H, 5.29; N, 8.66. Found: C, 47.95; H, 5.29; N, 8.67. tert-butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (dimethylcarbamoyl) pyrrolidine-1-carboxylate (0.70 g, 1.8 mmol) was dissolved in methanol (10 mL), A 4N hydrochloric acid-ethyl acetate solution (20 mL) was added. The reaction mixture was heated to reflux for 1 hour and concentrated under reduced pressure. The obtained solid was recrystallized from methanol / ethyl acetate to give the title compound as colorless crystals (0.36 g, 61%).
NMR (DMSO-d 6 ) δ: 1.98-2.13 (1H, m), 2.40-2.49 (1H, m), 2.55 (3H, s), 2.67 (3H, s), 3.13-3.25 (1H, m), 3.51-3.62 (1H, m), 3.99 (1H, q, J = 8.7 Hz), 4.94 (1H, d, J = 9.4 Hz), 7.24 (1H, dd, J = 8.3, 2.1 Hz), 7.53 (1H , d, J = 2.1 Hz), 7.59 (1H, d, J = 8.3 Hz), 9.63 (2H, brs).
LC / MS 286.9
mp 248-249 ℃
Anal.Calcd.for C 13 H 16 N 2 OCl.HCl: C, 48.24; H, 5.29; N, 8.66. Found: C, 47.95; H, 5.29; N, 8.67.

実施例１２
(+)-2,3-cis-3-(3,4-ジクロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド　1塩酸塩 Example 12
(+)-2,3-cis-3- (3,4-Dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide monohydrochloride

Figure JPOXMLDOC01-appb-C000207
Figure JPOXMLDOC01-appb-C000207

　参考例１２で得た2,3-cis-3-(3,4-ジクロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド（保持時間小）(0.30 g, 1.0 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(0.3 mL)を加えた。反応混合物を室温で10分間攪拌した後、減圧下濃縮した。得られた固体をエタノール／ジエチルエーテルより再結晶して、表題化合物を無色結晶(0.28 g, 84%)として得た。
比旋光度（25℃, c=0.4460, メタノール）:+37.6度
NMR (DMSO-d6) δ: 1.98-2.13 (1H, m), 2.39-2.49 (1H, m), 2.55 (3H, s), 2.67 (3H, s), 3.13-3.24 (1H, m), 3.52-3.62 (1H, m), 3.99 (1H, dd, J = 17.8, 8.7 Hz), 4.94 (1H, d, J = 9.5 Hz), 7.24 (1H, dd, J = 8.3, 2.3 Hz), 7.53 (1H, d, J = 2.3 Hz), 7.59 (1H, d, J = 8.3), 9.69 (2H, brs).
LC/MS 287.3
mp 239-240℃
Anal. Calcd. for C13H16N2OCl2・HCl: C, 48.24; H, 5.29; N, 8.66. Found: C, 47.94; H, 5.39; N, 8.49. 2,3-cis-3- (3,4-dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide (low retention time) (0.30 g, 1.0 mmol) obtained in Reference Example 12 was added to methanol (10 mL). 4N hydrochloric acid-ethyl acetate solution (0.3 mL) was added. The reaction mixture was stirred at room temperature for 10 minutes and then concentrated under reduced pressure. The obtained solid was recrystallized from ethanol / diethyl ether to give the title compound as colorless crystals (0.28 g, 84%).
Specific rotation (25 ℃, c = 0.4460, methanol): +37.6 degrees
NMR (DMSO-d 6 ) δ: 1.98-2.13 (1H, m), 2.39-2.49 (1H, m), 2.55 (3H, s), 2.67 (3H, s), 3.13-3.24 (1H, m), 3.52-3.62 (1H, m), 3.99 (1H, dd, J = 17.8, 8.7 Hz), 4.94 (1H, d, J = 9.5 Hz), 7.24 (1H, dd, J = 8.3, 2.3 Hz), 7.53 (1H, d, J = 2.3 Hz), 7.59 (1H, d, J = 8.3), 9.69 (2H, brs).
LC / MS 287.3
mp 239-240 ℃
Anal.Calcd.for C 13 H 16 N 2 OCl 2 HCl: C, 48.24; H, 5.29; N, 8.66. Found: C, 47.94; H, 5.39; N, 8.49.

実施例１３
(-)-2,3-cis-3-(3,4-ジクロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド　1塩酸塩 Example 13
(-)-2,3-cis-3- (3,4-Dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide monohydrochloride

Figure JPOXMLDOC01-appb-C000208
Figure JPOXMLDOC01-appb-C000208

　参考例１２で得た2,3-cis-3-(3,4-ジクロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド（保持時間大）(0.30 g, 1.0 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(0.3 mL)を加えた。反応混合物を室温で10分間攪拌した後、減圧下濃縮した。得られた固体をエタノール／ジエチルエーテルより再結晶して、表題化合物を無色結晶(0.27 g, 82%)として得た。
比旋光度（25℃, c=0.4640, メタノール）:-36.5度
NMR (DMSO-d6) δ: 1.97-2.13 (1H, m), 2.40-2.47 (1H, m), 2.55 (3H, s), 2.66 (3H, s), 3.18 (1H, td, J = 10.6, 8.0 Hz), 3.53-3.61 (1H, m), 3.98 (1H, dd, J = 17.8, 8.7 Hz), 4.93 (1H, d, J = 9.5 Hz), 7.24 (1H, dd, J = 8.3, 1.9 Hz), 7.53 (1H, d, J = 1.9 Hz), 7.59 (1H, d, J = 8.3 Hz), 9.58 (2H, brs).
LC/MS 287.3
mp 239-240℃
Anal. Calcd. for C13H16N2OCl2・HCl: C, 48.24; H, 5.29; N, 8.66. Found: C, 48.04; H, 5.40; N, 8.54. 2,3-cis-3- (3,4-dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide (long retention time) (0.30 g, 1.0 mmol) obtained in Reference Example 12 was added to methanol (10 mL). 4N hydrochloric acid-ethyl acetate solution (0.3 mL) was added. The reaction mixture was stirred at room temperature for 10 minutes and then concentrated under reduced pressure. The obtained solid was recrystallized from ethanol / diethyl ether to give the title compound as colorless crystals (0.27 g, 82%).
Specific rotation (25 ℃, c = 0.4640, methanol): -36.5 degrees
NMR (DMSO-d 6 ) δ: 1.97-2.13 (1H, m), 2.40-2.47 (1H, m), 2.55 (3H, s), 2.66 (3H, s), 3.18 (1H, td, J = 10.6 , 8.0 Hz), 3.53-3.61 (1H, m), 3.98 (1H, dd, J = 17.8, 8.7 Hz), 4.93 (1H, d, J = 9.5 Hz), 7.24 (1H, dd, J = 8.3, 1.9 Hz), 7.53 (1H, d, J = 1.9 Hz), 7.59 (1H, d, J = 8.3 Hz), 9.58 (2H, brs).
LC / MS 287.3
mp 239-240 ℃
Anal.Calcd.for C 13 H 16 N 2 OCl 2・ HCl: C, 48.24; H, 5.29; N, 8.66. Found: C, 48.04; H, 5.40; N, 8.54.

実施例１４
(2R*,3R*)-N,N-ジメチル-3-(ナフタレン-2-イル)ピロリジン-2-カルボキサミド　1塩酸塩 Example 14
(2R * , 3R * )-N, N-dimethyl-3- (naphthalen-2-yl) pyrrolidine-2-carboxamide monohydrochloride

Figure JPOXMLDOC01-appb-C000209
Figure JPOXMLDOC01-appb-C000209

　tert-ブチル (2R*,3R*)-2-(ジメチルカルバモイル)-3-(ナフタレン-2-イル)ピロリジン-1-カルボキシラート(0.49 g, 1.3 mmol)を酢酸エチル(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(3 mL)を加えた。反応混合物を終夜攪拌し、減圧下溶媒を留去した。得られた固体をエタノールより再結晶して、表題化合物を白色結晶(0.28 g, 68%)として得た。
NMR (DMSO-d6) δ: 2.15-2.33 (1H, m), 2.43 (3H, s), 2.44-2.57 (4H, m), 3.18-3.39 (1H, m), 3.66 (1H, ddd, J = 11.2, 8.0, 3.2 Hz), 4.09 (1H, q, J = 9.1 Hz), 4.99 (1H, d, J = 9.5 Hz), 7.34 (1H, dd, J = 8.5, 1.7 Hz), 7.46-7.56 (2H, m), 7.80 (1H, s), 7.84-7.94 (3H, m), 9.41 (2H, brs).
LC/MS 269.3
mp 250-251℃
Anal. Calcd. for C17H20N2O・HCl: C, 66.99; H, 6.94; N, 9.19. Found: C, 66.94; H, 6.79; N, 9.21. Dissolve tert-butyl (2R * , 3R * )-2- (dimethylcarbamoyl) -3- (naphthalen-2-yl) pyrrolidine-1-carboxylate (0.49 g, 1.3 mmol) in ethyl acetate (10 mL). 4N hydrochloric acid-ethyl acetate solution (3 mL) was added. The reaction mixture was stirred overnight and the solvent was removed under reduced pressure. The obtained solid was recrystallized from ethanol to give the title compound as white crystals (0.28 g, 68%).
NMR (DMSO-d 6 ) δ: 2.15-2.33 (1H, m), 2.43 (3H, s), 2.44-2.57 (4H, m), 3.18-3.39 (1H, m), 3.66 (1H, ddd, J = 11.2, 8.0, 3.2 Hz), 4.09 (1H, q, J = 9.1 Hz), 4.99 (1H, d, J = 9.5 Hz), 7.34 (1H, dd, J = 8.5, 1.7 Hz), 7.46-7.56 (2H, m), 7.80 (1H, s), 7.84-7.94 (3H, m), 9.41 (2H, brs).
LC / MS 269.3
mp 250-251 ℃
Anal.Calcd.for C 17 H 20 N 2 O.HCl: C, 66.99; H, 6.94; N, 9.19.Found: C, 66.94; H, 6.79; N, 9.21.

実施例１５
(2R*,3R*)-3-(3-クロロ-4-フルオロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド　1塩酸塩 Example 15
(2R * , 3R * )-3- (3-Chloro-4-fluorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide monohydrochloride

Figure JPOXMLDOC01-appb-C000210
Figure JPOXMLDOC01-appb-C000210

　tert-ブチル (2R*,3R*)-3-(3-クロロ-4-フルオロフェニル)-2-(ジメチルカルバモイル)ピロリジン-1-カルボキシラート(0.16 g)の酢酸エチル(2.0 mL)溶液に4 N塩酸－酢酸エチル溶液(2.0 mL)を加え、室温で終夜攪拌した。溶媒を減圧留去し、残留物を酢酸エチル／ジエチルエーテルより再結晶して、表題化合物を白色固体(0.12 g, 90%)として得た。
LC/MS 271.3
NMR (DMSO-d6) δ: 1.95-2.21 (1H, m), 2.35-2.48 (1H, m), 2.54 (3H, s), 2.64 (3H, s), 3.10-3.26 (1H, m), 3.48-3.64 (1H, m), 3.84-4.11 (1H, m), 4.92 (1H, d, J = 9.8 Hz), 7.12-7.62 (3H, m), 8.84 (1H, brs), 10.19 (1H, brs).
mp 233-234℃ To a solution of tert-butyl (2R * , 3R * )-3- (3-chloro-4-fluorophenyl) -2- (dimethylcarbamoyl) pyrrolidine-1-carboxylate (0.16 g) in ethyl acetate (2.0 mL) N hydrochloric acid-ethyl acetate solution (2.0 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate / diethyl ether to obtain the title compound as a white solid (0.12 g, 90%).
LC / MS 271.3
NMR (DMSO-d 6 ) δ: 1.95-2.21 (1H, m), 2.35-2.48 (1H, m), 2.54 (3H, s), 2.64 (3H, s), 3.10-3.26 (1H, m), 3.48-3.64 (1H, m), 3.84-4.11 (1H, m), 4.92 (1H, d, J = 9.8 Hz), 7.12-7.62 (3H, m), 8.84 (1H, brs), 10.19 (1H, brs).
mp 233-234 ℃

実施例１６
(2R*,3R*)-3-(3-クロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド　1塩酸塩 Example 16
(2R *, 3R *) -3- (3- chlorophenyl) -N, N-dimethyl-pyrrolidine-2-carboxamide monohydrochloride

Figure JPOXMLDOC01-appb-C000211
Figure JPOXMLDOC01-appb-C000211

　tert-ブチル (2R*,3R*)-3-(3-クロロフェニル)-2-(ジメチルカルバモイル)ピロリジン-1-カルボキシラート(0.23 g, 0.65 mmol)を酢酸エチル(3 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(2.5 mL)を加えた。反応混合物を終夜攪拌し、減圧下溶媒を留去した。得られた固体をジイソプロピルエーテルで洗浄した後、表題化合物を無色結晶(0.17 g, 92%)として得た。
NMR (DMSO-d6) δ: 1.98-2.16 (1H, m), 2.37-2.50 (1H, m), 2.52 (3H, s), 2.59 (3H, s), 3.19 (1H, td, J = 10.7, 7.4 Hz), 3.58 (1H, ddd, J = 11.1, 8.0, 2.8 Hz), 3.87-4.01 (1H, m), 4.92 (1H, d, J = 9.5 Hz), 7.17-7.24 (1H, m), 7.29-7.40 (3H, m), 9.35 (2H, brs).
LC/MS 253.3
mp 218-219℃
Anal. Calcd. for C13H17N2OCl・HCl: C, 53.99; H, 6.27; N, 9.69; O, 5.53; Cl, 24.52. Found: C, 53.84; H, 6.28; N, 9.64. tert-Butyl (2R * , 3R * )-3- (3-chlorophenyl) -2- (dimethylcarbamoyl) pyrrolidine-1-carboxylate (0.23 g, 0.65 mmol) was dissolved in ethyl acetate (3 mL) and 4 N hydrochloric acid-ethyl acetate solution (2.5 mL) was added. The reaction mixture was stirred overnight and the solvent was removed under reduced pressure. The obtained solid was washed with diisopropyl ether to give the title compound as colorless crystals (0.17 g, 92%).
NMR (DMSO-d 6 ) δ: 1.98-2.16 (1H, m), 2.37-2.50 (1H, m), 2.52 (3H, s), 2.59 (3H, s), 3.19 (1H, td, J = 10.7 , 7.4 Hz), 3.58 (1H, ddd, J = 11.1, 8.0, 2.8 Hz), 3.87-4.01 (1H, m), 4.92 (1H, d, J = 9.5 Hz), 7.17-7.24 (1H, m) , 7.29-7.40 (3H, m), 9.35 (2H, brs).
LC / MS 253.3
mp 218-219 ℃
Anal.Calcd.for C 13 H 17 N 2 OCl.HCl: C, 53.99; H, 6.27; N, 9.69; O, 5.53; Cl, 24.52.Found: C, 53.84; H, 6.28; N, 9.64.

実施例１７
(2S*,3R*)-3-(3,4-ジクロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド　1塩酸塩 Example 17
(2S * , 3R * )-3- (3,4-Dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide monohydrochloride

Figure JPOXMLDOC01-appb-C000212
Figure JPOXMLDOC01-appb-C000212

　(2S*,3R*)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸 (0.40 g, 1.1 mmol)のEtOH(10 mL)溶液にDMT-MM(0.46 g, 1.7 mmol)を加え、これにジメチルアミンのTHF溶液(2 M, 2.0 mL, 4.0 mmol)を加え、室温で終夜攪拌した。反応混合物を減圧下濃縮し、酢酸エチルで希釈した後、水と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去することにより、tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(ジメチルカルバモイル)ピロリジン-1-カルボキシラートを淡黄色の油状物として得た。
　得られたtert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(ジメチルカルバモイル)ピロリジン-1-カルボキシラート(0.43 g, 1.1 mmol)をメタノール(5 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(10 mL)を加えた。反応混合物を4時間加熱還流し、減圧下濃縮した。得られた固体を酢酸エチルで洗浄した後、HPLCにて精製した。得られた溶液を減圧下濃縮し、飽和炭酸水素ナトリウム水溶液で中和し、塩化ナトリウムを飽和になるまで溶解させた後、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。
　得られた残渣を酢酸エチル(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(0.3 mL)を加え、室温で10分間攪拌した。反応混合物を減圧下濃縮し、得られた固体を酢酸エチルより再結晶して、表題化合物を白色結晶(0.13 g, 35%)として得た。
NMR (DMSO-d6) δ: 1.97-2.12 (1H, m), 2.33-2.46 (1H, m), 2.55 (3H, s), 2.86 (3H, s), 3.25-3.37 (1H, m), 3.43-3.58 (2H, m), 4.76 (1H, d, J = 7.9 Hz), 7.48 (1H, dd, J = 8.3, 2.1 Hz), 7.66 (1H, d, J = 8.3 Hz), 7.83 (1H, d, J = 2.1 Hz), 9.50 (2H, brs).
LC/MS 287.0
mp 212-213℃
Anal. Calcd. for C13H16N2OCl2・HCl: C, 48.24; H, 5.29; N, 8.66; Cl, 32.86. Found: C, 48.03; H, 5.28; N, 8.52; Cl, 33.02. (2S * , 3R * )-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.40 g, 1.1 mmol) in EtOH (10 mL) in DMT-MM (0.46 g, 1.7 mmol) was added, a THF solution of dimethylamine (2 M, 2.0 mL, 4.0 mmol) was added thereto, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give tert-butyl (2S * , 3R * ) -3- (3,4-Dichlorophenyl) -2- (dimethylcarbamoyl) pyrrolidine-1-carboxylate was obtained as a pale yellow oil.
Obtained tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (dimethylcarbamoyl) pyrrolidine-1-carboxylate (0.43 g, 1.1 mmol) in methanol (5 mL) After dissolution, 4 N hydrochloric acid-ethyl acetate solution (10 mL) was added. The reaction mixture was heated to reflux for 4 hours and concentrated under reduced pressure. The obtained solid was washed with ethyl acetate and purified by HPLC. The obtained solution was concentrated under reduced pressure, neutralized with a saturated aqueous sodium hydrogen carbonate solution, sodium chloride was dissolved until saturation, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was dissolved in ethyl acetate (10 mL), 4N hydrochloric acid-ethyl acetate solution (0.3 mL) was added, and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure, and the obtained solid was recrystallized from ethyl acetate to give the title compound as white crystals (0.13 g, 35%).
NMR (DMSO-d 6 ) δ: 1.97-2.12 (1H, m), 2.33-2.46 (1H, m), 2.55 (3H, s), 2.86 (3H, s), 3.25-3.37 (1H, m), 3.43-3.58 (2H, m), 4.76 (1H, d, J = 7.9 Hz), 7.48 (1H, dd, J = 8.3, 2.1 Hz), 7.66 (1H, d, J = 8.3 Hz), 7.83 (1H , d, J = 2.1 Hz), 9.50 (2H, brs).
LC / MS 287.0
mp 212-213 ℃
Anal.Calcd.for C 13 H 16 N 2 OCl 2 HCl: C, 48.24; H, 5.29; N, 8.66; Cl, 32.86.Found: C, 48.03; H, 5.28; N, 8.52; Cl, 33.02.

実施例１８
(-)-2,3-trans-3-(3,4-ジクロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド　1塩酸塩 Example 18
(-)-2,3-trans-3- (3,4-Dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide monohydrochloride

Figure JPOXMLDOC01-appb-C000213
Figure JPOXMLDOC01-appb-C000213

　参考例１６で得た2,3-trans-3-(3,4-ジクロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド（保持時間小）(0.60 g, 2.1 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(0.8 mL)を加えた。反応混合物を室温で10分間攪拌した後、減圧下濃縮した。得られた固体をメタノール／酢酸エチルより再結晶して、表題化合物を白色結晶(0.47 g, 69%)として得た。
比旋光度（25℃, c=0.4715, メタノール）:-79.2度
NMR (DMSO-d6)δ: 1.97-2.14 (1H, m), 2.31-2.46 (1H, m), 2.56 (3H, s), 2.86 (3H, s), 3.25-3.37 (1H, m), 3.41-3.60 (2H, m), 4.76 (1H, d, J = 7.9 Hz), 7.50 (1H, dd, J = 8.3, 2.1 Hz), 7.66 (1H, d, J = 8.3 Hz), 7.84 (1H, d, J = 2.1 Hz), 9.59 (2H, brs).
LC/MS 287.1
Anal. Calcd. for C13H16N2OCl2・HCl: C, 48.24; H, 5.29; N, 8.66. Found: C, 48.18; H, 5.17; N, 8.48. 2,3-trans-3- (3,4-dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide (short retention time) (0.60 g, 2.1 mmol) obtained in Reference Example 16 was added to methanol (10 mL). 4N hydrochloric acid-ethyl acetate solution (0.8 mL) was added. The reaction mixture was stirred at room temperature for 10 minutes and then concentrated under reduced pressure. The obtained solid was recrystallized from methanol / ethyl acetate to give the title compound as white crystals (0.47 g, 69%).
Specific rotation (25 ℃, c = 0.4715, methanol): -79.2 degrees
NMR (DMSO-d 6 ) δ: 1.97-2.14 (1H, m), 2.31-2.46 (1H, m), 2.56 (3H, s), 2.86 (3H, s), 3.25-3.37 (1H, m), 3.41-3.60 (2H, m), 4.76 (1H, d, J = 7.9 Hz), 7.50 (1H, dd, J = 8.3, 2.1 Hz), 7.66 (1H, d, J = 8.3 Hz), 7.84 (1H , d, J = 2.1 Hz), 9.59 (2H, brs).
LC / MS 287.1
Anal.Calcd.for C 13 H 16 N 2 OCl 2 HCl: C, 48.24; H, 5.29; N, 8.66. Found: C, 48.18; H, 5.17; N, 8.48.

実施例１９
(+)-2,3-trans-3-(3,4-ジクロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド　1塩酸塩 Example 19
(+)-2,3-trans-3- (3,4-Dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide monohydrochloride

Figure JPOXMLDOC01-appb-C000214
Figure JPOXMLDOC01-appb-C000214

　参考例１６で得た2,3-trans-3-(3,4-ジクロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド（保持時間大）(0.59 g, 2.1 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(0.8 mL)を加えた。反応混合物を室温で10分間攪拌した後、減圧下濃縮した。得られた固体をメタノール／酢酸エチルより再結晶して、表題化合物を白色結晶(0.44 g, 66%)として得た。
比旋光度（25℃, c=0.4815, メタノール）:+80.1度
NMR (DMSO-d6) δ: 1.96-2.14 (1H, m), 2.32-2.47 (1H, m), 2.56 (3H, s), 2.86 (3H, s), 3.23-3.38 (1H, m), 3.42-3.59 (2H, m), 4.75 (1H, d, J = 7.9 Hz), 7.48 (1H, dd, J = 8.3, 2.2 Hz), 7.66 (1H, d, J = 8.3 Hz), 7.83 (1H, d, J = 2.2 Hz), 9.50 (2H, brs).
LC/MS 287.1
Anal. Calcd. for C13H16N2OCl2・HCl: C, 48.24; H, 5.29; N, 8.66. Found: C, 48.19; H, 5.20; N, 8.51. 2,3-trans-3- (3,4-dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide (long retention time) (0.59 g, 2.1 mmol) obtained in Reference Example 16 was added to methanol (10 mL). 4N hydrochloric acid-ethyl acetate solution (0.8 mL) was added. The reaction mixture was stirred at room temperature for 10 minutes and then concentrated under reduced pressure. The obtained solid was recrystallized from methanol / ethyl acetate to give the title compound as white crystals (0.44 g, 66%).
Specific rotation (25 ℃, c = 0.4815, methanol): +80.1 degrees
NMR (DMSO-d 6 ) δ: 1.96-2.14 (1H, m), 2.32-2.47 (1H, m), 2.56 (3H, s), 2.86 (3H, s), 3.23-3.38 (1H, m), 3.42-3.59 (2H, m), 4.75 (1H, d, J = 7.9 Hz), 7.48 (1H, dd, J = 8.3, 2.2 Hz), 7.66 (1H, d, J = 8.3 Hz), 7.83 (1H , d, J = 2.2 Hz), 9.50 (2H, brs).
LC / MS 287.1
Anal.Calcd.for C 13 H 16 N 2 OCl 2 HCl: C, 48.24; H, 5.29; N, 8.66. Found: C, 48.19; H, 5.20; N, 8.51.

実施例２０
(2S*,3R*)-N,N-ジメチル-3-(ナフタレン-2-イル)ピロリジン-2-カルボキサミド　1塩酸塩　　　 Example 20
(2S * , 3R * ) -N, N-Dimethyl-3- (naphthalen-2-yl) pyrrolidine-2-carboxamide monohydrochloride

Figure JPOXMLDOC01-appb-C000215
Figure JPOXMLDOC01-appb-C000215

　tert-ブチル (2S*,3R*)-2-(ジメチルカルバモイル)-3-(ナフタレン-2-イル)ピロリジン-1-カルボキシラート(0.39 g, 1.1 mmol)を酢酸エチル(3 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(3 mL)を加えた。反応混合物を終夜攪拌し、減圧下溶媒を留去した。得られた固体をジイソプロピルエーテルで洗浄した後、エタノールより再結晶して、表題化合物を無色結晶(0.22 g, 68%)として得た。
NMR (DMSO-d6) δ: 2.12-2.30 (1H, m), 2.38-2.55 (4H, m), 2.84 (3H, s), 3.29-3.47 (1H, m), 3.47-3.68 (2H, m), 4.82 (1H, d, J = 8.3 Hz), 7.48-7.59 (2H, m), 7.63 (1H, dd, J = 8.5, 1.7 Hz), 7.85-8.01 (4H, m), 9.39 (2H, brs).
LC/MS 269.1
mp 227-228℃
Anal. Calcd. for C17H20N2O・HCl: C, 66.99; H, 6.94; N, 9.19; O, 5.25; Cl, 11.62. Found: C, 66.72; H, 7.00; N, 8.84. tert-Butyl (2S * , 3R * )-2- (dimethylcarbamoyl) -3- (naphthalen-2-yl) pyrrolidine-1-carboxylate (0.39 g, 1.1 mmol) was dissolved in ethyl acetate (3 mL). 4N hydrochloric acid-ethyl acetate solution (3 mL) was added. The reaction mixture was stirred overnight and the solvent was removed under reduced pressure. The obtained solid was washed with diisopropyl ether and recrystallized from ethanol to give the title compound as colorless crystals (0.22 g, 68%).
NMR (DMSO-d 6 ) δ: 2.12-2.30 (1H, m), 2.38-2.55 (4H, m), 2.84 (3H, s), 3.29-3.47 (1H, m), 3.47-3.68 (2H, m ), 4.82 (1H, d, J = 8.3 Hz), 7.48-7.59 (2H, m), 7.63 (1H, dd, J = 8.5, 1.7 Hz), 7.85-8.01 (4H, m), 9.39 (2H, brs).
LC / MS 269.1
mp 227-228 ℃
Anal.Calcd.for C 17 H 20 N 2 O.HCl: C, 66.99; H, 6.94; N, 9.19; O, 5.25; Cl, 11.62. Found: C, 66.72; H, 7.00; N, 8.84.

実施例２１
(2S*,3R*)-3-(3-クロロ-4-フルオロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド　1塩酸塩 Example 21
(2S *, 3R *) -3- (3- chloro-4-fluorophenyl) -N, N-dimethyl-pyrrolidine-2-carboxamide monohydrochloride

Figure JPOXMLDOC01-appb-C000216
Figure JPOXMLDOC01-appb-C000216

　tert-ブチル (2S*,3R*)-3-(3-クロロ-4-フルオロフェニル)-2-(ジメチルカルバモイル)ピロリジン-1-カルボキシラート(46 mg)の酢酸エチル(1.0 mL)溶液に4 N塩酸－酢酸エチル溶液(1.0 mL)を加え、室温で終夜攪拌した。溶媒を減圧留去し、減圧下乾燥して、表題化合物を無色油状物(38 mg, 100%)として得た。
LC/MS 271.3
NMR (DMSO-d6) δ: 2.02-2.14 (1H, m), 2.32-2.45 (1H, m), 2.53 (3H, s), 2.86 (3H, s), 3.27-3.56 (3H, m), 4.67-4.83 (1H, m), 7.37-7.55 (2H, m), 7.79 (1H, dd, J = 7.2, 2.1 Hz), 8.82 (1H, brs), 10.21 (1H, brs). tert-Butyl (2S * , 3R * )-3- (3-chloro-4-fluorophenyl) -2- (dimethylcarbamoyl) pyrrolidine-1-carboxylate (46 mg) in ethyl acetate (1.0 mL) N hydrochloric acid-ethyl acetate solution (1.0 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and dried under reduced pressure to give the title compound as a colorless oil (38 mg, 100%).
LC / MS 271.3
NMR (DMSO-d 6 ) δ: 2.02-2.14 (1H, m), 2.32-2.45 (1H, m), 2.53 (3H, s), 2.86 (3H, s), 3.27-3.56 (3H, m), 4.67-4.83 (1H, m), 7.37-7.55 (2H, m), 7.79 (1H, dd, J = 7.2, 2.1 Hz), 8.82 (1H, brs), 10.21 (1H, brs).

実施例２２
(2S*,3R*)-3-(3-クロロフェニル)-N,N-ジメチルピロリジン-2-カルボキサミド　1塩酸塩  Example 22
(2S * , 3R * )-3- (3-Chlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide monohydrochloride

Figure JPOXMLDOC01-appb-C000217
Figure JPOXMLDOC01-appb-C000217

　tert-ブチル (2S*,3R*)-3-(3-クロロフェニル)-2-(ジメチルカルバモイル)ピロリジン-1-カルボキシラート(0.48 g, 1.36 mmol)を酢酸エチル(3 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(3 mL)を加えた。反応混合物を終夜攪拌し、減圧下溶媒を留去した。得られた固体をジエチルエーテル／メタノールで洗浄して、表題化合物を褐色結晶(0.36 g, 91%)として得た。
NMR (DMSO-d6) δ: 1.98-2.16 (1H, m), 2.40 (1H, m), 2.51 (3H, s), 2.86 (3H, s), 3.27-3.39 (1H, m), 3.42-3.56 (2H, m), 4.74 (1H, d, J = 8.0 Hz), 7.35-7.45 (3H, m), 7.59 (1H, brs), 8.82 (1H, brs), 9.99 (1H, brs).
LC/MS 253.3
mp 197-198℃
Anal. Calcd. for C13H17N2OCl・HCl: C, 53.99; H, 6.27; N, 9.69; O, 5.53; Cl, 24.52. Found: C, 53.35; H, 6.29; N, 9.58. tert- butyl (2S *, 3R *) -3- (3- chlorophenyl) -2- (dimethylcarbamoyl) pyrrolidine-1-carboxylate (0.48 g, 1.36 mmol) was dissolved in ethyl acetate (3 mL), 4 N hydrochloric acid-ethyl acetate solution (3 mL) was added. The reaction mixture was stirred overnight and the solvent was removed under reduced pressure. The obtained solid was washed with diethyl ether / methanol to give the title compound as brown crystals (0.36 g, 91%).
NMR (DMSO-d 6 ) δ: 1.98-2.16 (1H, m), 2.40 (1H, m), 2.51 (3H, s), 2.86 (3H, s), 3.27-3.39 (1H, m), 3.42- 3.56 (2H, m), 4.74 (1H, d, J = 8.0 Hz), 7.35-7.45 (3H, m), 7.59 (1H, brs), 8.82 (1H, brs), 9.99 (1H, brs).
LC / MS 253.3
mp 197-198 ℃
Anal.Calcd.for C 13 H 17 N 2 OCl.HCl: C, 53.99; H, 6.27; N, 9.69; O, 5.53; Cl, 24.52. Found: C, 53.35; H, 6.29; N, 9.58.

実施例２３
(2R*,3R*)-3-(3,4-ジクロロフェニル)-N-エチルピロリジン-2-カルボキサミド　1塩酸塩 Example 23
(2R * , 3R * )-3- (3,4-Dichlorophenyl) -N-ethylpyrrolidine-2-carboxamide monohydrochloride

Figure JPOXMLDOC01-appb-C000218
Figure JPOXMLDOC01-appb-C000218

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(エチルカルバモイル)ピロリジン-1-カルボキシラート(0.74 g, 1.9 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(20 mL)を加えた。反応混合物を2時間加熱還流し、減圧下濃縮した。得られた固体をメタノール／酢酸エチルより再結晶して、表題化合物を無色結晶(0.48 g, 78%)として得た。
NMR (DMSO-d6) δ: 0.58 (3H, t, J = 7.3 Hz), 2.13-2.29 (1H, m), 2.30-2.44 (1H, m), 2.65-2.80 (1H, m), 2.82-2.98 (1H, m), 3.20-3.32 (1H, m), 3.50-3.60 (1H, m), 3.80-3.93 (1H, m), 4.41 (1H, d, J = 9.2 Hz), 7.25 (1H, dd, J = 8.3, 2.1 Hz), 7.51 (1H, d, J = 2.1 Hz), 7.58 (1H, d, J = 8.3 Hz), 8.43 (1H, t, J = 5.5 Hz), 9.67 (2H, brs).
LC/MS 287.0
mp 181-182℃
Anal. Calcd. for C13H16N2OCl2・HCl: C, 48.24; H, 5.29; N, 8.66. Found: C, 47.96; H, 5.28; N, 8.57. tert-butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (ethylcarbamoyl) pyrrolidine-1-carboxylate (0.74 g, 1.9 mmol) was dissolved in methanol (10 mL), A 4N hydrochloric acid-ethyl acetate solution (20 mL) was added. The reaction mixture was heated to reflux for 2 hours and concentrated under reduced pressure. The obtained solid was recrystallized from methanol / ethyl acetate to give the title compound as colorless crystals (0.48 g, 78%).
NMR (DMSO-d 6 ) δ: 0.58 (3H, t, J = 7.3 Hz), 2.13-2.29 (1H, m), 2.30-2.44 (1H, m), 2.65-2.80 (1H, m), 2.82- 2.98 (1H, m), 3.20-3.32 (1H, m), 3.50-3.60 (1H, m), 3.80-3.93 (1H, m), 4.41 (1H, d, J = 9.2 Hz), 7.25 (1H, dd, J = 8.3, 2.1 Hz), 7.51 (1H, d, J = 2.1 Hz), 7.58 (1H, d, J = 8.3 Hz), 8.43 (1H, t, J = 5.5 Hz), 9.67 (2H, brs).
LC / MS 287.0
mp 181-182 ℃
Anal.Calcd.for C 13 H 16 N 2 OCl 2・ HCl: C, 48.24; H, 5.29; N, 8.66. Found: C, 47.96; H, 5.28; N, 8.57.

実施例２４
(2S*,3R*)-3-(3,4-ジクロロフェニル)-N-エチルピロリジン-2-カルボキサミド　1塩酸塩 Example 24
(2S *, 3R *) -3- (3,4- dichlorophenyl) -N- ethyl-pyrrolidine-2-carboxamide monohydrochloride

Figure JPOXMLDOC01-appb-C000219
Figure JPOXMLDOC01-appb-C000219

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(エチルカルバモイル)ピロリジン-1-カルボキシラート(0.87 g, 2.2 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(20 mL)を加えた。反応混合物を2時間加熱還流し、減圧下濃縮した。得られた固体をメタノール／酢酸エチルより再結晶して、表題化合物を無色結晶(0.55 g, 76%)として得た。
NMR (DMSO-d6) δ: 0.96 (3H, t, J = 7.2 Hz), 2.02-2.20 (1H, m), 2.30-2.45 (1H, m), 2.95-3.21 (2H, m), 3.24-3.37 (1H, m), 3.38-3.55 (2H, m), 4.01 (1H, d, J = 9.1 Hz), 7.37 (1H, dd, J = 8.3, 2.3 Hz), 7.63 (1H, d, J = 8.3 Hz), 7.70 (1H, d, J = 2.3 Hz), 8.36 (1H, t, J = 5.5 Hz), 9.63 (2H, brs).
LC/MS 287.0
mp 184-186℃
Anal. Calcd. for C13H16N2OCl2・HCl: C, 48.24; H, 5.29; N, 8.66. Found: C, 48.39; H, 5.31; N, 8.65. tert- butyl (2S *, 3R *) -3- (3,4- dichlorophenyl) -2- (ethylcarbamoyl) pyrrolidine-1-carboxylate (0.87 g, 2.2 mmol) was dissolved in methanol (10 mL), A 4N hydrochloric acid-ethyl acetate solution (20 mL) was added. The reaction mixture was heated to reflux for 2 hours and concentrated under reduced pressure. The obtained solid was recrystallized from methanol / ethyl acetate to give the title compound as colorless crystals (0.55 g, 76%).
NMR (DMSO-d 6 ) δ: 0.96 (3H, t, J = 7.2 Hz), 2.02-2.20 (1H, m), 2.30-2.45 (1H, m), 2.95-3.21 (2H, m), 3.24- 3.37 (1H, m), 3.38-3.55 (2H, m), 4.01 (1H, d, J = 9.1 Hz), 7.37 (1H, dd, J = 8.3, 2.3 Hz), 7.63 (1H, d, J = 8.3 Hz), 7.70 (1H, d, J = 2.3 Hz), 8.36 (1H, t, J = 5.5 Hz), 9.63 (2H, brs).
LC / MS 287.0
mp 184-186 ° C
Anal.Calcd.for C 13 H 16 N 2 OCl 2 HCl: C, 48.24; H, 5.29; N, 8.66. Found: C, 48.39; H, 5.31; N, 8.65.

実施例２５
(2R*,3R*)-3-(3,4-ジクロロフェニル)-N-イソプロピルピロリジン-2-カルボキサミド　1塩酸塩 Example 25
(2R * , 3R * )-3- (3,4-Dichlorophenyl) -N-isopropylpyrrolidine-2-carboxamide monohydrochloride

Figure JPOXMLDOC01-appb-C000220
Figure JPOXMLDOC01-appb-C000220

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(イソプロピルカルバモイル)ピロリジン-1-カルボキシラート(0.50 g, 1.2 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(20 mL)を加えた。反応混合物を1時間加熱還流し、減圧下濃縮した。得られた固体をメタノール／酢酸エチルより再結晶して、表題化合物を無色結晶(0.36 g, 86%)として得た。
NMR (DMSO-d6) δ: 0.46 (3H, d, J = 6.3), 0.94 (3H, d, J = 6.6), 2.12-2.28 (1H, m), 2.30-2.43 (1H, m), 3.18-3.31 (1H, m), 3.42-3.60 (2H, m), 3.79-3.91 (1H, m), 4.37 (1H, d, J = 9.3), 7.24 (1H, dd, J = 8.3, 2.2), 7.50 (1H, d, J = 2.2), 7.58 (1H, d, J = 8.2), 8.22 (1H, d, J = 7.7). (2H観測できず)
LC/MS 301.1
mp 253-254℃
Anal. Calcd. for C14H18N2OCl2・HCl: C, 49.80; H, 5.67; N, 8.30. Found: C, 49.74; H, 5.56; N, 8.11. tert-butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (isopropylcarbamoyl) pyrrolidine-1-carboxylate (0.50 g, 1.2 mmol) was dissolved in methanol (10 mL), A 4N hydrochloric acid-ethyl acetate solution (20 mL) was added. The reaction mixture was heated to reflux for 1 hour and concentrated under reduced pressure. The obtained solid was recrystallized from methanol / ethyl acetate to give the title compound as colorless crystals (0.36 g, 86%).
NMR (DMSO-d 6 ) δ: 0.46 (3H, d, J = 6.3), 0.94 (3H, d, J = 6.6), 2.12-2.28 (1H, m), 2.30-2.43 (1H, m), 3.18 -3.31 (1H, m), 3.42-3.60 (2H, m), 3.79-3.91 (1H, m), 4.37 (1H, d, J = 9.3), 7.24 (1H, dd, J = 8.3, 2.2), 7.50 (1H, d, J = 2.2), 7.58 (1H, d, J = 8.2), 8.22 (1H, d, J = 7.7).
LC / MS 301.1
mp 253-254 ℃
Anal.Calcd.for C 14 H 18 N 2 OCl 2・ HCl: C, 49.80; H, 5.67; N, 8.30. Found: C, 49.74; H, 5.56; N, 8.11.

実施例２６
(2R*,3R*)-3-(3,4-ジクロロフェニル)-N,N-ジエチルピロリジン-2-カルボキサミド　1塩酸塩 Example 26
(2R * , 3R * )-3- (3,4-Dichlorophenyl) -N, N-diethylpyrrolidine-2-carboxamide monohydrochloride

Figure JPOXMLDOC01-appb-C000221
Figure JPOXMLDOC01-appb-C000221

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(ジエチルカルバモイル)ピロリジン-1-カルボキシラート(0.17 g, 0.40 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(20 mL)を加えた。反応混合物を1時間加熱還流し、減圧下濃縮した。得られた固体を酢酸エチル／ヘキサンより再結晶して、表題化合物を無色結晶(0.13 g, 92%)として得た。
NMR (DMSO-d6) δ: 0.41 (3H, t, J = 7.1 Hz), 1.01 (3H, t, J = 7.0 Hz), 1.95-2.14 (1H, m), 2.43-2.76 (3H, m), 3.08-3.20 (1H, m), 3.25-3.47 (2H, m), 3.50-3.59 (1H, m), 3.98-4.09 (1H, m), 4.75 (1H, d, J = 9.9 Hz), 7.27 (1H, dd, J = 8.2, 1.9 Hz), 7.51 (1H, d, J = 1.9 Hz), 7.55 (1H, d, J = 8.2 Hz). (2H観測できず)
LC/MS 315.1
mp 266-267℃
Anal. Calcd. for C15H20N2OCl2・HCl: C, 51.23; H, 6.02; N, 7.97. Found: C, 50.97; H, 6.01; N, 7.74. tert-butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (diethylcarbamoyl) pyrrolidine-1-carboxylate (0.17 g, 0.40 mmol) was dissolved in methanol (10 mL), A 4N hydrochloric acid-ethyl acetate solution (20 mL) was added. The reaction mixture was heated to reflux for 1 hour and concentrated under reduced pressure. The obtained solid was recrystallized from ethyl acetate / hexane to give the title compound as colorless crystals (0.13 g, 92%).
NMR (DMSO-d 6 ) δ: 0.41 (3H, t, J = 7.1 Hz), 1.01 (3H, t, J = 7.0 Hz), 1.95-2.14 (1H, m), 2.43-2.76 (3H, m) , 3.08-3.20 (1H, m), 3.25-3.47 (2H, m), 3.50-3.59 (1H, m), 3.98-4.09 (1H, m), 4.75 (1H, d, J = 9.9 Hz), 7.27 (1H, dd, J = 8.2, 1.9 Hz), 7.51 (1H, d, J = 1.9 Hz), 7.55 (1H, d, J = 8.2 Hz).
LC / MS 315.1
mp 266-267 ℃
Anal.Calcd.for C 15 H 20 N 2 OCl 2・ HCl: C, 51.23; H, 6.02; N, 7.97. Found: C, 50.97; H, 6.01; N, 7.74.

実施例２７
(2R*,3R*)-3-(3,4-ジクロロフェニル)-N-エチル-N-メチルピロリジン-2-カルボキサミド　1塩酸塩  Example 27
(2R * , 3R * )-3- (3,4-Dichlorophenyl) -N-ethyl-N-methylpyrrolidine-2-carboxamide monohydrochloride

Figure JPOXMLDOC01-appb-C000222
Figure JPOXMLDOC01-appb-C000222

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-[エチル(メチル)カルバモイル]ピロリジン-1-カルボキシラート(0.27 g, 0.66 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(20 mL)を加えた。反応混合物を1時間加熱還流し、減圧下濃縮した。得られた固体をエタノール／酢酸エチルより再結晶して、表題化合物を白色結晶(0.11 g, 48%)として得た。
NMR (DMSO-d6) δ: 0.49 (3H x 2/3, t, J = 7.0 Hz), 0.96 (3H x 1/3, t, J = 7.0 Hz), 2.03 (1H, m), 2.43-2.75 (5H, m), 3.11-3.23 (1H, m), 3.35-3.43 (1H, m), 3.51-3.61 (1H, m), 3.94-4.05 (1H, m), 4.84 (1H x 1/3, d, J = 9.6 Hz), 4.88 (1H x 2/3, d, J = 9.9 Hz), 7.21 (1H x 1/3, dd, J = 8.4, 2.3 Hz), 7.29 (1H x 2/3, dd, J = 8.2, 2.2 Hz), 7.51 (1H x 1/3, d, J = 2.2 Hz), 7.55 (1H x 2/3, d, J = 1.9 Hz), 7.58 (1H, d, J = 8.2 Hz). (2H観測できず)
LC/MS 301.1
mp 239-240℃
Anal. Calcd. for C14H18N2OCl2・HCl: C, 49.80; H, 5.67; N, 8.30. Found: C, 49.54; H, 5.49; N, 8.11. tert- butyl (2R *, 3R *) -3- (3,4- dichlorophenyl) -2- [ethyl (methyl) carbamoyl] pyrrolidine-1-carboxylate (0.27 g, 0.66 mmol) in methanol (10 mL) After dissolution, 4N hydrochloric acid-ethyl acetate solution (20 mL) was added. The reaction mixture was heated to reflux for 1 hour and concentrated under reduced pressure. The obtained solid was recrystallized from ethanol / ethyl acetate to give the title compound as white crystals (0.11 g, 48%).
NMR (DMSO-d 6 ) δ: 0.49 (3H x 2/3, t, J = 7.0 Hz), 0.96 (3H x 1/3, t, J = 7.0 Hz), 2.03 (1H, m), 2.43- 2.75 (5H, m), 3.11-3.23 (1H, m), 3.35-3.43 (1H, m), 3.51-3.61 (1H, m), 3.94-4.05 (1H, m), 4.84 (1H x 1/3 , d, J = 9.6 Hz), 4.88 (1H x 2/3, d, J = 9.9 Hz), 7.21 (1H x 1/3, dd, J = 8.4, 2.3 Hz), 7.29 (1H x 2/3 , dd, J = 8.2, 2.2 Hz), 7.51 (1H x 1/3, d, J = 2.2 Hz), 7.55 (1H x 2/3, d, J = 1.9 Hz), 7.58 (1H, d, J = 8.2 Hz). (Cannot observe 2H)
LC / MS 301.1
mp 239-240 ℃
Anal.Calcd.for C 14 H 18 N 2 OCl 2・ HCl: C, 49.80; H, 5.67; N, 8.30. Found: C, 49.54; H, 5.49; N, 8.11.

実施例２８
(2R*,3R*)-N-シクロプロピル-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボキサミド　1塩酸塩 Example 28
(2R * , 3R * )-N-cyclopropyl-3- (3,4-dichlorophenyl) pyrrolidine-2-carboxamide monohydrochloride

Figure JPOXMLDOC01-appb-C000223
Figure JPOXMLDOC01-appb-C000223

　tert-ブチル (2R*,3R*)-2-(シクロプロピルカルバモイル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート(0.45 g, 1.1 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(20 mL)を加えた。反応混合物を1時間加熱還流し、減圧下濃縮した。得られた固体を酢酸エチルより再結晶して、表題化合物を無色結晶(0.38 g, 100%)として得た。
NMR (DMSO-d6) δ: -0.50 - -0.39 (1H, m), 0.07-0.18 (1H, m), 0.32-0.43 (1H, m), 0.44-0.56 (1H, m), 2.09-2.44 (3H, m), 3.19-3.31 (1H, m), 3.50-3.61 (1H, m), 3.79-3.91 (1H, m), 4.38 (1H, d, J = 9.4 Hz), 7.23 (1H, dd, J = 8.5, 2.1 Hz), 7.49 (1H, d, J = 2.1 Hz), 7.59 (1H, d, J = 8.5 Hz), 8.55 (1H, d, J = 3.4 Hz), 8.98 (1H, brs), 10.38 (1H, brs).
LC/MS 299.1
mp 233-234℃
Anal. Calcd. for C14H17N2OCl2・HCl+0.5H2O: C, 49.80; H, 5.67; N, 8.30. Found: C, 49.54; H, 5.49; N, 8.11. tert-Butyl (2R * , 3R * )-2- (cyclopropylcarbamoyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate (0.45 g, 1.1 mmol) was dissolved in methanol (10 mL). 4N hydrochloric acid-ethyl acetate solution (20 mL) was added. The reaction mixture was heated to reflux for 1 hour and concentrated under reduced pressure. The obtained solid was recrystallized from ethyl acetate to give the title compound as colorless crystals (0.38 g, 100%).
NMR (DMSO-d 6 ) δ: -0.50--0.39 (1H, m), 0.07-0.18 (1H, m), 0.32-0.43 (1H, m), 0.44-0.56 (1H, m), 2.09-2.44 (3H, m), 3.19-3.31 (1H, m), 3.50-3.61 (1H, m), 3.79-3.91 (1H, m), 4.38 (1H, d, J = 9.4 Hz), 7.23 (1H, dd , J = 8.5, 2.1 Hz), 7.49 (1H, d, J = 2.1 Hz), 7.59 (1H, d, J = 8.5 Hz), 8.55 (1H, d, J = 3.4 Hz), 8.98 (1H, brs ), 10.38 (1H, brs).
LC / MS 299.1
mp 233-234 ℃
Anal.Calcd.for C 14 H 17 N 2 OCl 2・ HCl + 0.5H 2 O: C, 49.80; H, 5.67; N, 8.30. Found: C, 49.54; H, 5.49; N, 8.11.

実施例２９
[(2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル](モルホリン-4-イル)メタノン　1塩酸塩 Example 29
[(2R * , 3R * )-3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] (morpholin-4-yl) methanone monohydrochloride

Figure JPOXMLDOC01-appb-C000224
Figure JPOXMLDOC01-appb-C000224

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(モルホリン-4-イルカルボニル)ピロリジン-1-カルボキシラート(0.43 g, 1.0 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(20 mL)を加えた。反応混合物を2時間加熱還流し、減圧下濃縮した。得られた固体を酢酸エチルより再結晶して、表題化合物を無色結晶(0.30 g, 82%)として得た。
NMR (DMSO-d6) δ: 1.99-2.16 (1H, m), 2.38-2.47 (1H, m), 2.80-2.89 (1H, m), 2.94-3.07 (2H, m), 3.08-3.28 (3H, m), 3.35-3.41 (1H, m), 3.43-3.53 (2H, m), 3.54-3.62 (1H, m), 3.95 (1H, q, J = 8.7 Hz), 4.95 (1H, d, J = 9.8 Hz), 7.26 (1H, dd, J = 8.3, 1.9 Hz), 7.55 (1H, d, J = 1.9 Hz), 7.64 (1H, d, J = 8.3 Hz), 9.59 (2H, brs).
LC/MS 329.0
mp 286-287℃
Anal. Calcd. for C15H18N2O2Cl2・HCl: C, 49.27; H, 5.24; N, 7.66. Found: C, 49.36; H, 5.30; N, 7.66. tert-Butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (morpholin-4-ylcarbonyl) pyrrolidine-1-carboxylate (0.43 g, 1.0 mmol) in methanol (10 mL) 4N hydrochloric acid-ethyl acetate solution (20 mL) was added. The reaction mixture was heated to reflux for 2 hours and concentrated under reduced pressure. The obtained solid was recrystallized from ethyl acetate to give the title compound as colorless crystals (0.30 g, 82%).
NMR (DMSO-d 6 ) δ: 1.99-2.16 (1H, m), 2.38-2.47 (1H, m), 2.80-2.89 (1H, m), 2.94-3.07 (2H, m), 3.08-3.28 (3H , m), 3.35-3.41 (1H, m), 3.43-3.53 (2H, m), 3.54-3.62 (1H, m), 3.95 (1H, q, J = 8.7 Hz), 4.95 (1H, d, J = 9.8 Hz), 7.26 (1H, dd, J = 8.3, 1.9 Hz), 7.55 (1H, d, J = 1.9 Hz), 7.64 (1H, d, J = 8.3 Hz), 9.59 (2H, brs).
LC / MS 329.0
mp 286-287 ℃
Anal.Calcd.for C 15 H 18 N 2 O 2 Cl 2・ HCl: C, 49.27; H, 5.24; N, 7.66. Found: C, 49.36; H, 5.30; N, 7.66.

実施例３０
[(2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル](モルホリン-4-イル)メタノン　1塩酸塩 Example 30
[(2S * , 3R * )-3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] (morpholin-4-yl) methanone monohydrochloride

Figure JPOXMLDOC01-appb-C000225
Figure JPOXMLDOC01-appb-C000225

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(モルホリン-4-イルカルボニル)ピロリジン-1-カルボキシラート(0.47 g, 1.1 mmol)をメタノール(5 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(10 mL)を加えた。反応混合物を室温で1時間攪拌した後、減圧下濃縮した。得られた固体をエタノールより再結晶して、表題化合物を無色結晶(0.33 g, 82%)として得た。
NMR (DMSO-d6) δ: 1.98-2.18 (1H, m), 2.33-2.47 (1H, m), 2.81-2.93 (1H, m), 2.95-3.07 (1H, m), 3.10-3.21 (1H, m), 3.24-3.62 (8H, m), 4.80 (1H, d, J = 8.1 Hz), 7.54 (1H, dd, J = 8.3, 2.1 Hz), 7.66 (1H, d, J = 8.3 Hz), 7.89 (1H, d, J = 2.1 Hz), 9.79 (2H, brs).
LC/MS 329.2
mp 246-247℃
Anal. Calcd. for C15H18N2O2Cl2・HCl: C, 49.27; H, 5.24; N, 7.66. Found: C, 49.21; H, 5.22; N, 7.67. tert-Butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (morpholin-4-ylcarbonyl) pyrrolidine-1-carboxylate (0.47 g, 1.1 mmol) in methanol (5 mL) 4N hydrochloric acid-ethyl acetate solution (10 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The obtained solid was recrystallized from ethanol to give the title compound as colorless crystals (0.33 g, 82%).
NMR (DMSO-d 6 ) δ: 1.98-2.18 (1H, m), 2.33-2.47 (1H, m), 2.81-2.93 (1H, m), 2.95-3.07 (1H, m), 3.10-3.21 (1H , m), 3.24-3.62 (8H, m), 4.80 (1H, d, J = 8.1 Hz), 7.54 (1H, dd, J = 8.3, 2.1 Hz), 7.66 (1H, d, J = 8.3 Hz) , 7.89 (1H, d, J = 2.1 Hz), 9.79 (2H, brs).
LC / MS 329.2
mp 246-247 ℃
Anal.Calcd.for C 15 H 18 N 2 O 2 Cl 2・ HCl: C, 49.27; H, 5.24; N, 7.66. Found: C, 49.21; H, 5.22; N, 7.67.

実施例３１
[(2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル](ピペリジン-1-イル)メタノン　1塩酸塩 Example 31
[(2R * , 3R * )-3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] (piperidin-1-yl) methanone monohydrochloride

Figure JPOXMLDOC01-appb-C000226
Figure JPOXMLDOC01-appb-C000226

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(ピペリジン-1-イルカルボニル)ピロリジン-1-カルボキシラート(0.28 g, 0.66 mmol)をメタノール(5 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(10 mL)を加えた。反応混合物を室温で3時間攪拌した後、減圧下濃縮した。得られた固体を酢酸エチルより再結晶して、表題化合物を無色結晶(0.19 g, 78%)として得た。
NMR (DMSO-d6) δ: 0.91-1.11 (2H, m), 1.31-1.50 (4H, m), 1.96-2.12 (1H, m), 2.37-2.48 (1H, m), 2.84-2.92 (1H, m), 2.97-3.06 (1H, m), 3.17 (1H, td, J = 10.7, 7.4 Hz), 3.26-3.32 (2H, m), 3.52-3.61 (1H, m), 3.96 (1H, q, J = 9.1 Hz), 4.93 (1H, d, J = 9.8 Hz), 7.24 (1H, dd, J = 8.3, 2.3 Hz), 7.52 (1H, d, J = 2.3 Hz), 7.61 (1H, d, J = 8.3 Hz), 9.50 (2H, brs).
LC/MS 327.2
mp 262-263℃
Anal. Calcd. for C16H20N2OCl2・HCl: C, 52.84; H, 5.82; N, 7.70. Found: C, 52.79; H, 6.07; N, 7.52. tert-Butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (piperidin-1-ylcarbonyl) pyrrolidine-1-carboxylate (0.28 g, 0.66 mmol) in methanol (5 mL) 4N hydrochloric acid-ethyl acetate solution (10 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The obtained solid was recrystallized from ethyl acetate to give the title compound as colorless crystals (0.19 g, 78%).
NMR (DMSO-d 6 ) δ: 0.91-1.11 (2H, m), 1.31-1.50 (4H, m), 1.96-2.12 (1H, m), 2.37-2.48 (1H, m), 2.84-2.92 (1H , m), 2.97-3.06 (1H, m), 3.17 (1H, td, J = 10.7, 7.4 Hz), 3.26-3.32 (2H, m), 3.52-3.61 (1H, m), 3.96 (1H, q , J = 9.1 Hz), 4.93 (1H, d, J = 9.8 Hz), 7.24 (1H, dd, J = 8.3, 2.3 Hz), 7.52 (1H, d, J = 2.3 Hz), 7.61 (1H, d , J = 8.3 Hz), 9.50 (2H, brs).
LC / MS 327.2
mp 262-263 ℃
Anal.Calcd.for C 16 H 20 N 2 OCl 2・ HCl: C, 52.84; H, 5.82; N, 7.70. Found: C, 52.79; H, 6.07; N, 7.52.

実施例３２
[(2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル](ピペラジン-1-イル)メタノン　2塩酸塩 Example 32
[(2R * , 3R * )-3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] (piperazin-1-yl) methanone dihydrochloride

Figure JPOXMLDOC01-appb-C000227
Figure JPOXMLDOC01-appb-C000227

　tert-ブチル 4-{[(2R*,3R*)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]カルボニル}ピペラジン-1-カルボキシラート(0.36 g, 0.67 mmol)をメタノール(5 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(10 mL)を加えた。反応混合物を室温で3時間攪拌した後、減圧下濃縮した。得られた固体をエタノールより再結晶して、表題化合物を無色結晶(0.19 g, 78%)として得た。
NMR (DMSO-d6) δ: 1.99-2.15 (1H, m), 2.37-2.47 (1H, m), 2.57-2.66 (1H, m), 2.70-2.78 (1H, m), 2.85-3.07 (4H, m), 3.20 (1H, td, J = 10.7, 7.4 Hz), 3.53-3.63 (1H, m), 3.70-3.84 (2H, m), 3.96 (1H, dd, J = 17.4, 9.1 Hz), 5.05 (1H, d, J = 9.5 Hz), 7.25 (1H, dd, J = 8.3, 1.9 Hz), 7.54 (1H, d, J = 1.9 Hz), 7.62 (1H, d, J = 8.3 Hz), 9.54 (4H, brs).
mp 266-268℃
Anal. Calcd. for C15H19N3OCl2・HCl+H2O: C, 42.98; H, 5.53; N, 10.02. Found: C, 43.09; H, 5.65; N, 9.97. tert-butyl 4-{[(2R * , 3R * )-1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] carbonyl} piperazine-1-carboxylate (0.36 g , 0.67 mmol) was dissolved in methanol (5 mL), and 4 N hydrochloric acid-ethyl acetate solution (10 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The obtained solid was recrystallized from ethanol to give the title compound as colorless crystals (0.19 g, 78%).
NMR (DMSO-d 6 ) δ: 1.99-2.15 (1H, m), 2.37-2.47 (1H, m), 2.57-2.66 (1H, m), 2.70-2.78 (1H, m), 2.85-3.07 (4H , m), 3.20 (1H, td, J = 10.7, 7.4 Hz), 3.53-3.63 (1H, m), 3.70-3.84 (2H, m), 3.96 (1H, dd, J = 17.4, 9.1 Hz), 5.05 (1H, d, J = 9.5 Hz), 7.25 (1H, dd, J = 8.3, 1.9 Hz), 7.54 (1H, d, J = 1.9 Hz), 7.62 (1H, d, J = 8.3 Hz), 9.54 (4H, brs).
mp 266-268 ℃
Anal.Calcd.for C 15 H 19 N 3 OCl 2・ HCl + H 2 O: C, 42.98; H, 5.53; N, 10.02. Found: C, 43.09; H, 5.65; N, 9.97.

実施例３３
[(2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル](4-メチルピペラジン-1-イル)メタノン　2塩酸塩 Example 33
[(2R * , 3R * )-3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] (4-methylpiperazin-1-yl) methanone dihydrochloride

Figure JPOXMLDOC01-appb-C000228
Figure JPOXMLDOC01-appb-C000228

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-[(4-メチルピペラジン-1-イル)カルボニル]ピロリジン-1-カルボキシラート(0.35 g, 0.78 mmol)をメタノール(5 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(10 mL)を加えた。反応混合物を室温で3時間攪拌した後、減圧下濃縮した。得られた固体をエタノールより再結晶して、表題化合物を無色結晶(0.12 g, 38%)として得た。
NMR (DMSO-d6) δ: 1.69-2.46 (3H, m), 2.58-3.31 (9H, m), 3.58 (1H, brs), 3.91-4.30 (3H, m), 4.93-5.16 (1H, m), 7.17-7.27 (1H, m), 7.47-7.66 (2H, m), 8.96 (1H, brs), 10.36-11.86 (2H, m).
LC/MS 342.0
mp 249-252℃ tert-Butyl (2R * , 3R * )-3- (3,4-Dichlorophenyl) -2-[(4-methylpiperazin-1-yl) carbonyl] pyrrolidine-1-carboxylate (0.35 g, 0.78 mmol) Dissolved in methanol (5 mL), 4N hydrochloric acid-ethyl acetate solution (10 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The obtained solid was recrystallized from ethanol to give the title compound as colorless crystals (0.12 g, 38%).
NMR (DMSO-d 6 ) δ: 1.69-2.46 (3H, m), 2.58-3.31 (9H, m), 3.58 (1H, brs), 3.91-4.30 (3H, m), 4.93-5.16 (1H, m ), 7.17-7.27 (1H, m), 7.47-7.66 (2H, m), 8.96 (1H, brs), 10.36-11.86 (2H, m).
LC / MS 342.0
mp 249-252 ℃

実施例３４
[(2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル](ピロリジン-1-イル)メタノン　1塩酸塩 Example 34
[(2R * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidin-2-yl] (pyrrolidin-1-yl) methanone monohydrochloride

Figure JPOXMLDOC01-appb-C000229
Figure JPOXMLDOC01-appb-C000229

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(ピロリジン-1-イルカルボニル)ピロリジン-1-カルボキシラート(0.43 g, 1.0 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(20 mL)を加えた。反応混合物を1時間加熱還流した後、減圧下濃縮した。得られた固体をエタノール／ヘキサンより再結晶して、表題化合物を無色結晶(0.30 g, 84%)として得た。
NMR (DMSO-d6) δ: 1.22-1.46 (2H, m), 1.57-1.80 (2H, m), 2.00-2.21 (1H, m), 2.33-2.47 (1H, m), 2.69-2.82 (1H, m), 2.82-2.94 (1H, m), 3.14-3.30 (3H, m), 3.57 (1H, t, J = 9.5 Hz), 3.98 (1H, q, J = 8.5 Hz), 4.70 (1H, d, J = 9.5 Hz), 7.27 (1H, d, J = 8.3 Hz), 7.55 (1H, s), 7.60 (1H, dd, J = 8.3, 1.5 Hz), 9.65 (2H, brs).
LC/MS 313.0
mp 227-228℃
Anal. Calcd. for C15H17N2OCl2・HCl: C, 51.52; H, 5.48; N, 8.01. Found: C, 51.24; H, 5.44; N, 7.90. tert-Butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (pyrrolidin-1-ylcarbonyl) pyrrolidine-1-carboxylate (0.43 g, 1.0 mmol) in methanol (10 mL) 4N hydrochloric acid-ethyl acetate solution (20 mL) was added. The reaction mixture was heated to reflux for 1 hour and then concentrated under reduced pressure. The obtained solid was recrystallized from ethanol / hexane to give the title compound as colorless crystals (0.30 g, 84%).
NMR (DMSO-d 6 ) δ: 1.22-1.46 (2H, m), 1.57-1.80 (2H, m), 2.00-2.21 (1H, m), 2.33-2.47 (1H, m), 2.69-2.82 (1H , m), 2.82-2.94 (1H, m), 3.14-3.30 (3H, m), 3.57 (1H, t, J = 9.5 Hz), 3.98 (1H, q, J = 8.5 Hz), 4.70 (1H, d, J = 9.5 Hz), 7.27 (1H, d, J = 8.3 Hz), 7.55 (1H, s), 7.60 (1H, dd, J = 8.3, 1.5 Hz), 9.65 (2H, brs).
LC / MS 313.0
mp 227-228 ℃
Anal.Calcd.for C 15 H 17 N 2 OCl 2・ HCl: C, 51.52; H, 5.48; N, 8.01.Found: C, 51.24; H, 5.44; N, 7.90.

実施例３５
[(2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル](ピロリジン-1-イル)メタノン　1塩酸塩 Example 35
[(2S * , 3R * )-3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] (pyrrolidin-1-yl) methanone monohydrochloride

Figure JPOXMLDOC01-appb-C000230
Figure JPOXMLDOC01-appb-C000230

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(ピロリジン-1-イルカルボニル)ピロリジン-1-カルボキシラート(0.46 g, 1.1 mmol)をメタノール(5 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(10 mL)を加えた。反応混合物を室温で1時間攪拌した後、減圧下濃縮した。得られた固体をエタノールより再結晶して、表題化合物を無色結晶(0.30 g, 77%)として得た。
NMR (DMSO-d6) δ: 1.61-1.79 (4H, m), 2.02-2.17 (1H, m), 2.34-2.45 (1H, m), 2.54-2.63 (1H, m), 3.25-3.40 (4H, m), 3.43-3.53 (1H, m), 3.54-3.65 (1H, m), 4.53 (1H, d, J = 8.1 Hz), 7.51 (1H, dd, J = 8.3, 2.3 Hz), 7.65 (1H, d, J = 8.3 Hz), 7.84 (1H, d, J = 2.3 Hz), 9.83 (2H, brs).
LC/MS 313.3
mp 188-189℃
Anal. Calcd. for C15H18N2OCl2・HCl: C, 51.52; H, 5.48; N, 8.01. Found: C, 51.39; H, 5.45; N, 8.03. tert-Butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (pyrrolidin-1-ylcarbonyl) pyrrolidine-1-carboxylate (0.46 g, 1.1 mmol) in methanol (5 mL) 4N hydrochloric acid-ethyl acetate solution (10 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The obtained solid was recrystallized from ethanol to give the title compound as colorless crystals (0.30 g, 77%).
NMR (DMSO-d 6 ) δ: 1.61-1.79 (4H, m), 2.02-2.17 (1H, m), 2.34-2.45 (1H, m), 2.54-2.63 (1H, m), 3.25-3.40 (4H , m), 3.43-3.53 (1H, m), 3.54-3.65 (1H, m), 4.53 (1H, d, J = 8.1 Hz), 7.51 (1H, dd, J = 8.3, 2.3 Hz), 7.65 ( 1H, d, J = 8.3 Hz), 7.84 (1H, d, J = 2.3 Hz), 9.83 (2H, brs).
LC / MS 313.3
mp 188-189 ° C
Anal.Calcd.for C 15 H 18 N 2 OCl 2・ HCl: C, 51.52; H, 5.48; N, 8.01. Found: C, 51.39; H, 5.45; N, 8.03.

実施例３６
[(2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル][(3R)-3-ヒドロキシピロリジン-1-イル]メタノン　1塩酸塩 Example 36
[(2S * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidin-2-yl] [(3R) -3-hydroxypyrrolidin-1-yl] methanone monohydrochloride

Figure JPOXMLDOC01-appb-C000231
Figure JPOXMLDOC01-appb-C000231

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-{[(3R)-3-ヒドロキシピロリジン-1-イル]カルボニル}ピロリジン-1-カルボキシラート(0.14 g)のメタノール(2.0 mL)溶液に10%塩酸－メタノール溶液(2.0 mL)を加え、室温で3時間攪拌した。溶媒を減圧留去し、減圧下乾燥して、表題化合物を無色非定形固体(56 mg, 47%)として得た。
LC/MS 329.2
NMR (DMSO-d6) δ: 1.53-2.19 (3H, m), 2.30-2.47 (1H, m), 2.57-2.76 (1H, m), 3.12-3.67 (6H, m), 3.91-4.68 (3H, m), 7.40-7.51 (1H, m), 7.61-7.69 (1H, m), 7.75-7.86 (1H, m), 8.90 (1H, brs), 9.98-10.45 (1H, m). tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2-{[(3R) -3-hydroxypyrrolidin-1-yl] carbonyl} pyrrolidine-1-carboxylate (0.14 g) To a methanol (2.0 mL) solution was added 10% hydrochloric acid-methanol solution (2.0 mL), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure and dried under reduced pressure to obtain the title compound as a colorless amorphous solid (56 mg, 47%).
LC / MS 329.2
NMR (DMSO-d 6 ) δ: 1.53-2.19 (3H, m), 2.30-2.47 (1H, m), 2.57-2.76 (1H, m), 3.12-3.67 (6H, m), 3.91-4.68 (3H , m), 7.40-7.51 (1H, m), 7.61-7.69 (1H, m), 7.75-7.86 (1H, m), 8.90 (1H, brs), 9.98-10.45 (1H, m).

実施例３７
[(2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル][(3S)-3-ヒドロキシピロリジン-1-イル]メタノン　1塩酸塩 Example 37
[(2S * , 3R * )-3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] [(3S) -3-hydroxypyrrolidin-1-yl] methanone monohydrochloride

Figure JPOXMLDOC01-appb-C000232
Figure JPOXMLDOC01-appb-C000232

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-{[(3S)-3-ヒドロキシピロリジン-1-イル]カルボニル}ピロリジン-1-カルボキシラート(0.16 g)のメタノール(2.0 mL)溶液に10%塩酸－メタノール溶液(2.0 mL)を加え、室温で3時間攪拌した。溶媒を減圧留去し、減圧下乾燥して、表題化合物を無色非定形固体(30 mg, 23%)として得た。
LC/MS 329.2
NMR (DMSO-d6) δ: 1.52-2.22 (4H, m), 2.30-2.46 (1H, m), 2.58-2.86 (1H, m), 3.15-3.73 (5H, m), 3.87-4.76 (3H, m), 7.41-7.53 (1H, m), 7.65 (1H, dd, J = 8.3, 2.7 Hz), 7.74-7.85 (1H, m), 8.90 (1H, brs), 9.91-10.71 (1H, m). tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2-{[(3S) -3-hydroxypyrrolidin-1-yl] carbonyl} pyrrolidine-1-carboxylate (0.16 g) To a methanol (2.0 mL) solution was added 10% hydrochloric acid-methanol solution (2.0 mL), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure and dried under reduced pressure to obtain the title compound as a colorless amorphous solid (30 mg, 23%).
LC / MS 329.2
NMR (DMSO-d 6 ) δ: 1.52-2.22 (4H, m), 2.30-2.46 (1H, m), 2.58-2.86 (1H, m), 3.15-3.73 (5H, m), 3.87-4.76 (3H , m), 7.41-7.53 (1H, m), 7.65 (1H, dd, J = 8.3, 2.7 Hz), 7.74-7.85 (1H, m), 8.90 (1H, brs), 9.91-10.71 (1H, m ).

実施例３８
[(2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル][(2S)-2-(ヒドロキシメチル)ピロリジン-1-イル]メタノン　1塩酸塩 Example 38
[(2S * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidin-2-yl] [(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] methanone monohydrochloride

Figure JPOXMLDOC01-appb-C000233
Figure JPOXMLDOC01-appb-C000233

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-{[(2S)-2-(ヒドロキシメチル)ピロリジン-1-イル]カルボニル}ピロリジン-1-カルボキシラート(0.13 g)のメタノール(2.0 mL)溶液に10%塩酸－メタノール溶液(2.0 mL)を加え、室温で3時間攪拌した。溶媒を減圧留去し、減圧下乾燥して、表題化合物を無色非定形固体(0.10 g, 88%)として得た。
LC/MS 343.3
NMR (DMSO-d6) δ: 1.14-2.46 (7H, m), 2.56-4.90 (9H, m), 7.27-7.98 (3H, m), 8.50-9.39 (1H, m), 9.87-10.39 (1H, m). tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2-{[(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] carbonyl} pyrrolidine-1-carboxylate ( To a solution of 0.13 g) in methanol (2.0 mL) was added 10% hydrochloric acid-methanol solution (2.0 mL), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure and dried under reduced pressure to obtain the title compound as a colorless amorphous solid (0.10 g, 88%).
LC / MS 343.3
NMR (DMSO-d 6 ) δ: 1.14-2.46 (7H, m), 2.56-4.90 (9H, m), 7.27-7.98 (3H, m), 8.50-9.39 (1H, m), 9.87-10.39 (1H , m).

実施例３９
[(2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル][(2R)-2-(ヒドロキシメチル)ピロリジン-1-イル]メタノン　1塩酸塩 Example 39
[(2S * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidin-2-yl] [(2R) -2- (hydroxymethyl) pyrrolidin-1-yl] methanone monohydrochloride

Figure JPOXMLDOC01-appb-C000234
Figure JPOXMLDOC01-appb-C000234

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-{[(2R)-2-(ヒドロキシメチル)ピロリジン-1-イル]カルボニル}ピロリジン-1-カルボキシラート(0.15 g)のメタノール(2.0 mL)溶液に10%塩酸－メタノール溶液(2.0 mL)を加え、室温で3時間攪拌した。溶媒を減圧留去し、減圧下乾燥して、表題化合物を無色非定形固体(62 mg, 48%)として得た。
LC/MS 343.3
NMR (DMSO-d6) δ: 1.23-2.45 (7H, m), 2.56-4.83 (9H, m), 7.29-7.93 (3H, m), 8.61-9.45 (1H, m), 9.95-10.66 (1H, m). tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2-{[(2R) -2- (hydroxymethyl) pyrrolidin-1-yl] carbonyl} pyrrolidine-1-carboxylate ( To a solution of 0.15 g) in methanol (2.0 mL) was added 10% hydrochloric acid-methanol solution (2.0 mL), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure and dried under reduced pressure to obtain the title compound as a colorless amorphous solid (62 mg, 48%).
LC / MS 343.3
NMR (DMSO-d 6 ) δ: 1.23-2.45 (7H, m), 2.56-4.83 (9H, m), 7.29-7.93 (3H, m), 8.61-9.45 (1H, m), 9.95-10.66 (1H , m).

実施例４０
[(2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル][(2S)-2-(メトキシメチル)ピロリジン-1-イル]メタノン　1塩酸塩 Example 40
[(2S * , 3R * )-3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] [(2S) -2- (methoxymethyl) pyrrolidin-1-yl] methanone monohydrochloride

Figure JPOXMLDOC01-appb-C000235
Figure JPOXMLDOC01-appb-C000235

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-{[(2S)-2-(メトキシメチル)ピロリジン-1-イル]カルボニル}ピロリジン-1-カルボキシラート(0.19 g, 0.42 mmol)をメタノール(3 mL)に溶解させ、10%塩酸－メタノール溶液(10 mL)を加えた。反応混合物を室温で1時間攪拌した後、減圧下濃縮した。得られた残渣をメタノールに溶解させ、活性炭で処理した後、濾過した。濾液を減圧下濃縮することにより、表題化合物を淡黄色油状物(0.15 g, 92%)として得た。
NMR (DMSO-d6) δ: 1.50-1.88 (4H, m), 1.99-2.45 (2H, m), 3.17-3.82 (10H, m), 4.01-4.40 (1H, m), 4.44-4.58 (1H, m), 7.36-7.53 (1H, m), 7.63-7.70 (1H, m), 7.73-7.84 (1H, m), 9.88 (2H, brs).
LC/MS 357.2 tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2-{[(2S) -2- (methoxymethyl) pyrrolidin-1-yl] carbonyl} pyrrolidine-1-carboxylate ( 0.19 g, 0.42 mmol) was dissolved in methanol (3 mL), and 10% hydrochloric acid-methanol solution (10 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The obtained residue was dissolved in methanol, treated with activated carbon, and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a pale yellow oil (0.15 g, 92%).
NMR (DMSO-d 6 ) δ: 1.50-1.88 (4H, m), 1.99-2.45 (2H, m), 3.17-3.82 (10H, m), 4.01-4.40 (1H, m), 4.44-4.58 (1H , m), 7.36-7.53 (1H, m), 7.63-7.70 (1H, m), 7.73-7.84 (1H, m), 9.88 (2H, brs).
LC / MS 357.2

実施例４１
[(2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル][(2R)-2-(メトキシメチル)ピロリジン-1-イル]メタノン　1塩酸塩 Example 41
[(2S * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidin-2-yl] [(2R) -2- (methoxymethyl) pyrrolidin-1-yl] methanone monohydrochloride

Figure JPOXMLDOC01-appb-C000236
Figure JPOXMLDOC01-appb-C000236

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-{[(2R)-2-(メトキシメチル)ピロリジン-1-イル]カルボニル}ピロリジン-1-カルボキシラート(0.19 g, 0.42 mmol)をメタノール(3 mL)に溶解させ、10%塩酸－メタノール溶液(10 mL)を加えた。反応混合物を室温で1時間攪拌した後、減圧下濃縮した。得られた残渣をメタノールに溶解させ、活性炭で処理した後、濾過した。濾液を減圧下濃縮することにより、表題化合物を淡黄色油状物(0.13 g, 79%)として得た。
NMR (DMSO-d6) δ: 1.51-1.93 (4H, m), 2.06-2.46 (2H, m), 3.17 (3H, s), 3.24-3.50 (7H, m), 3.99-4.38 (1H, m), 4.53 (1H, brs), 7.34-7.85 (3H, m), 8.77-9.39 (1H, m), 10.40-10.87 (1H, m).
LC/MS 357.2 tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2-{[(2R) -2- (methoxymethyl) pyrrolidin-1-yl] carbonyl} pyrrolidine-1-carboxylate ( 0.19 g, 0.42 mmol) was dissolved in methanol (3 mL), and 10% hydrochloric acid-methanol solution (10 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The obtained residue was dissolved in methanol, treated with activated carbon, and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a pale yellow oil (0.13 g, 79%).
NMR (DMSO-d 6 ) δ: 1.51-1.93 (4H, m), 2.06-2.46 (2H, m), 3.17 (3H, s), 3.24-3.50 (7H, m), 3.99-4.38 (1H, m ), 4.53 (1H, brs), 7.34-7.85 (3H, m), 8.77-9.39 (1H, m), 10.40-10.87 (1H, m).
LC / MS 357.2

実施例４２
[(2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル](3,3-ジフルオロピロリジン-1-イル)メタノン　1塩酸塩 Example 42
[(2S *, 3R *) -3- (3,4- dichlorophenyl) pyrrolidin-2-yl] (3,3-difluoro-1-yl) methanone monohydrochloride

Figure JPOXMLDOC01-appb-C000237
Figure JPOXMLDOC01-appb-C000237

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-[(3,3-ジフルオロピロリジン-1-イル)カルボニル]ピロリジン-1-カルボキシラート(0.18 g, 0.40 mmol)をメタノール(3 mL)に溶解させ、10%塩酸－メタノール溶液(5 mL)を加えた。反応混合物を室温で1時間攪拌した後、減圧下濃縮した。得られた残渣をHPLCにて精製した。得られた溶液を減圧下濃縮し、1 N水酸化ナトリウム水溶液で中和し、飽和になるまで塩化ナトリウムを加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣を酢酸エチルに溶解させ、4 N塩酸－酢酸エチル溶液(0.2 mL)を加え、室温で10分間攪拌した。反応混合物を減圧下濃縮することにより、表題化合物を無色油状物(0.066 g, 43%)として得た。
NMR (DMSO-d6) δ: 2.00-2.47 (4H, m), 2.83-3.13 (1H, m), 3.28-4.00 (6H, m), 4.38-4.65 (1H, m), 7.43-7.53 (1H, m), 7.62-7.68 (1H, m), 7.77-7.85 (1H, m), 9.05 (1H, brs), 10.61 (1H, brs).
LC/MS 349.3 tert-butyl (2S * , 3R * ) -3- (3,4-dichlorophenyl) -2-[(3,3-difluoropyrrolidin-1-yl) carbonyl] pyrrolidine-1-carboxylate (0.18 g, 0.40 mmol ) Was dissolved in methanol (3 mL), and 10% hydrochloric acid-methanol solution (5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The obtained residue was purified by HPLC. The resulting solution was concentrated under reduced pressure, neutralized with 1N aqueous sodium hydroxide solution, sodium chloride was added until saturation, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in ethyl acetate, 4N hydrochloric acid-ethyl acetate solution (0.2 mL) was added, and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure to give the title compound as a colorless oil (0.066 g, 43%).
NMR (DMSO-d 6 ) δ: 2.00-2.47 (4H, m), 2.83-3.13 (1H, m), 3.28-4.00 (6H, m), 4.38-4.65 (1H, m), 7.43-7.53 (1H , m), 7.62-7.68 (1H, m), 7.77-7.85 (1H, m), 9.05 (1H, brs), 10.61 (1H, brs).
LC / MS 349.3

実施例４３
[(2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]メタノール　1塩酸塩 Example 43
[(2R * , 3R * )-3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] methanol monohydrochloride

Figure JPOXMLDOC01-appb-C000238
Figure JPOXMLDOC01-appb-C000238

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート(0.26 g, 0.75 mmol)をメタノール(5 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(10 mL)を加えた。反応混合物を終夜加熱還流し、減圧下濃縮した。得られた固体をメタノール／酢酸エチルより再結晶して、表題化合物を白色結晶(0.15 g, 71%)として得た。
NMR (DMSO-d6) δ: 2.22-2.35 (2H, m), 3.15-3.28 (3H, m), 3.42-3.53 (1H, m), 3.64 (1H, q, J = 8.7 Hz), 3.84-3.95 (1H, m), 5.25 (1H, brs), 7.35 (1H, dd, J = 8.3, 2.1 Hz), 7.61 (1H, d, J = 8.3 Hz), 7.64 (1H, d, J = 2.1 Hz), 9.29 (2H, brs).
LC/MS 246.0
mp 167-168℃
Anal. Calcd. for C11H13NOCl2・HCl: C, 46.75; H, 4.99; N, 4.96; Cl, 37.64. Found: C, 46.79; H, 4.94; N, 4.92; Cl, 37.51. tert-butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (0.26 g, 0.75 mmol) was dissolved in methanol (5 mL), A 4N hydrochloric acid-ethyl acetate solution (10 mL) was added. The reaction mixture was heated to reflux overnight and concentrated under reduced pressure. The obtained solid was recrystallized from methanol / ethyl acetate to give the title compound as white crystals (0.15 g, 71%).
NMR (DMSO-d 6 ) δ: 2.22-2.35 (2H, m), 3.15-3.28 (3H, m), 3.42-3.53 (1H, m), 3.64 (1H, q, J = 8.7 Hz), 3.84- 3.95 (1H, m), 5.25 (1H, brs), 7.35 (1H, dd, J = 8.3, 2.1 Hz), 7.61 (1H, d, J = 8.3 Hz), 7.64 (1H, d, J = 2.1 Hz ), 9.29 (2H, brs).
LC / MS 246.0
mp 167-168 ℃
Anal.Calcd.for C 11 H 13 NOCl 2 HCl: C, 46.75; H, 4.99; N, 4.96; Cl, 37.64.Found: C, 46.79; H, 4.94; N, 4.92; Cl, 37.51.

実施例４４
[(2R*,3R*)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-2-イル]メタノール　1塩酸塩 Example 44
[(2R * , 3R * )-3- (3-Chloro-4-fluorophenyl) pyrrolidin-2-yl] methanol monohydrochloride

Figure JPOXMLDOC01-appb-C000239
Figure JPOXMLDOC01-appb-C000239

　tert-ブチル (2R*,3R*)-3-(3-クロロ-4-フルオロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート(0.42 g)のエタノール(2.0 mL)溶液に11.4 M塩酸－エタノール溶液(2.0 mL)を加え、室温で1.5時間攪拌した。溶媒を減圧留去し、減圧下乾燥して、表題化合物を白色固体(0.29 g, 100%)として得た。
LC/MS 230.2
NMR (DMSO-d6) δ: 2.21-2.35 (2H, m), 3.11-3.28 (3H, m), 3.41-3.53 (1H, m), 3.56-3.70 (1H, m), 3.80-3.96 (1H, m), 5.25 (1H, t, J = 4.5 Hz), 7.30-7.45 (2H, m), 7.54-7.64 (1H, m), 8.96 (1H, brs), 9.72 (1H, brs).
mp 150-151℃ 11.4 M in ethanol (2.0 mL) solution of tert-butyl (2R * , 3R * )-3- (3-chloro-4-fluorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (0.42 g) Hydrochloric acid-ethanol solution (2.0 mL) was added, and the mixture was stirred at room temperature for 1.5 hr. The solvent was distilled off under reduced pressure and dried under reduced pressure to obtain the title compound as a white solid (0.29 g, 100%).
LC / MS 230.2
NMR (DMSO-d 6 ) δ: 2.21-2.35 (2H, m), 3.11-3.28 (3H, m), 3.41-3.53 (1H, m), 3.56-3.70 (1H, m), 3.80-3.96 (1H , m), 5.25 (1H, t, J = 4.5 Hz), 7.30-7.45 (2H, m), 7.54-7.64 (1H, m), 8.96 (1H, brs), 9.72 (1H, brs).
mp 150-151 ℃

実施例４５
[(2R*,3R*)-3-(3-クロロフェニル)ピロリジン-2-イル]メタノール　1トリフルオロ酢酸塩 Example 45
[(2R * , 3R * )-3- (3-Chlorophenyl) pyrrolidin-2-yl] methanol 1 trifluoroacetate

Figure JPOXMLDOC01-appb-C000240
Figure JPOXMLDOC01-appb-C000240

　tert-ブチル (2R*,3R*)-3-(3-クロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート(0.20 g, 0.64 mmol)をメタノール(0.5 mL)および酢酸エチル(2 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(2.5 mL)を加えた。反応混合物を終夜攪拌し、減圧下溶媒を留去した。得られた残渣をHPLCにて精製し、表題化合物を無色の油状物 (0.10 g, 48%)として得た。
NMR (DMSO-d6) δ: 2.23-2.36 (2H, m), 3.12-3.30 (2H, m), 3.41-3.56 (1H, m), 3.64 (1H, q, J = 9.0 Hz), 3.83-3.96 (1H, m), 5.25 (1H, brs), 7.27-7.32 (1H, m), 7.32-7.44 (3H, m), 8.82 (1H, brs), 9.59 (1H, brs). (1H観測できず)
LC/MS 212.3 tert-butyl (2R * , 3R * )-3- (3-chlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (0.20 g, 0.64 mmol) in methanol (0.5 mL) and ethyl acetate (2 mL 4N hydrochloric acid-ethyl acetate solution (2.5 mL) was added. The reaction mixture was stirred overnight and the solvent was removed under reduced pressure. The obtained residue was purified by HPLC to give the title compound as a colorless oil (0.10 g, 48%).
NMR (DMSO-d 6 ) δ: 2.23-2.36 (2H, m), 3.12-3.30 (2H, m), 3.41-3.56 (1H, m), 3.64 (1H, q, J = 9.0 Hz), 3.83- 3.96 (1H, m), 5.25 (1H, brs), 7.27-7.32 (1H, m), 7.32-7.44 (3H, m), 8.82 (1H, brs), 9.59 (1H, brs). )
LC / MS 212.3

実施例４６
[(2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]メタノール　1塩酸塩 Example 46
[(2S * , 3R * )-3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] methanol monohydrochloride

Figure JPOXMLDOC01-appb-C000241
Figure JPOXMLDOC01-appb-C000241

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート(0.14 g, 0.40 mmol)をメタノール(3 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(6 mL)を加えた。反応混合物を終夜加熱還流し、減圧下濃縮した。得られた固体をメタノール／酢酸エチル／ジエチルエーテルより再結晶して、表題化合物を無色結晶(0.094 g, 82%)として得た。
NMR (DMSO-d6) δ: 1.98-2.13 (1H, m), 2.29-2.41 (1H, m), 3.16-3.31 (2H, m), 3.37-3.46 (1H, m), 3.48-3.62 (3H, m), 5.43 (1H, t, J = 5.1 Hz), 7.40 (1H, dd, J = 8.3, 2.3 Hz), 7.64 (1H, d, J = 8.3 Hz), 7.72 (1H, d, J = 2.3 Hz), 9.00 (1H, brs), 9.66 (1H, brs).
LC/MS 246.0
mp 140-141℃
Anal. Calcd. for C11H13NOCl2・HCl: C, 46.75; H, 4.99; N, 4.96; Cl, 37.64. Found: C, 46.84; H, 4.96; N, 4.96; Cl, 37.85. tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (0.14 g, 0.40 mmol) was dissolved in methanol (3 mL), A 4N hydrochloric acid-ethyl acetate solution (6 mL) was added. The reaction mixture was heated to reflux overnight and concentrated under reduced pressure. The obtained solid was recrystallized from methanol / ethyl acetate / diethyl ether to give the title compound as colorless crystals (0.094 g, 82%).
NMR (DMSO-d 6) δ : 1.98-2.13 (1H, m), 2.29-2.41 (1H, m), 3.16-3.31 (2H, m), 3.37-3.46 (1H, m), 3.48-3.62 (3H , m), 5.43 (1H, t, J = 5.1 Hz), 7.40 (1H, dd, J = 8.3, 2.3 Hz), 7.64 (1H, d, J = 8.3 Hz), 7.72 (1H, d, J = 2.3 Hz), 9.00 (1H, brs), 9.66 (1H, brs).
LC / MS 246.0
mp 140-141 ℃
Anal.Calcd.for C 11 H 13 NOCl 2 HCl: C, 46.75; H, 4.99; N, 4.96; Cl, 37.64.Found: C, 46.84; H, 4.96; N, 4.96; Cl, 37.85.

実施例４７
[(2S*,3R*)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-2-イル]メタノール　1塩酸塩 Example 47
[(2S * , 3R * )-3- (3-Chloro-4-fluorophenyl) pyrrolidin-2-yl] methanol monohydrochloride

Figure JPOXMLDOC01-appb-C000242
Figure JPOXMLDOC01-appb-C000242

　(2S*,3R*)-1-(tert-ブトキシカルボニル)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-2-カルボン酸(0.25 g)のTHF(5.0 mL)溶液に1.1 Mボラン-THF錯体THF溶液（1.3 mL）を加え、室温にて終夜攪拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物を酢酸エチル(2.0 mL)に溶解し、4 N塩酸－酢酸エチル溶液(2.0 mL)を加え、室温にて終夜攪拌した。溶媒を減圧留去し、得られた残留物を分取HPLCにて精製して、分取したフラクションを濃縮した。残留物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物をエタノール(1.0 mL)に溶解し、11.4 M塩酸－エタノール溶液(1.0 mL)を加えた。溶媒を減圧留去し、減圧下乾燥して、表題化合物を淡茶色固体(14 mg, 7%)として得た。
NMR (DMSO-d6) δ: 1.95-2.16 (1H, m), 2.24-2.42 (1H, m), 3.18-3.66 (6H, m), 5.42 (1H, brs), 7.37-7.46 (2H, m), 7.67 (1H, d, J = 7.6 Hz), 8.92 (1H, brs), 9.70 (1H, brs).
LC/MS 230.2 (2S * , 3R * )-1- (tert-butoxycarbonyl) -3- (3-chloro-4-fluorophenyl) pyrrolidine-2-carboxylic acid (0.25 g) in THF (5.0 mL) in 1.1 M borane -THF complex THF solution (1.3 mL) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate (2.0 mL), 4N hydrochloric acid-ethyl acetate solution (2.0 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, the resulting residue was purified by preparative HPLC, and the fraction collected was concentrated. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethanol (1.0 mL), and 11.4 M hydrochloric acid-ethanol solution (1.0 mL) was added. The solvent was distilled off under reduced pressure and dried under reduced pressure to obtain the title compound as a light brown solid (14 mg, 7%).
NMR (DMSO-d 6 ) δ: 1.95-2.16 (1H, m), 2.24-2.42 (1H, m), 3.18-3.66 (6H, m), 5.42 (1H, brs), 7.37-7.46 (2H, m ), 7.67 (1H, d, J = 7.6 Hz), 8.92 (1H, brs), 9.70 (1H, brs).
LC / MS 230.2

実施例４８
[(2S*,3R*)-3-(3-クロロフェニル)ピロリジン-2-イル]メタノール　1トリフルオロ酢酸塩 Example 48
[(2S * , 3R * )-3- (3-Chlorophenyl) pyrrolidin-2-yl] methanol 1 trifluoroacetate

Figure JPOXMLDOC01-appb-C000243
Figure JPOXMLDOC01-appb-C000243

　tert-ブチル (2S*,3R*)-3-(3-クロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート(0.44 g, 1.41 mmol)を酢酸エチル(3 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(2.5 mL)を加えた。反応混合物を終夜攪拌し、減圧下溶媒を留去した。得られた残渣をHPLCにて精製し、表題化合物を無色の油状物 (0.11 g, 17%)として得た。
NMR (DMSO-d6) δ: 1.97-2.16 (1H, m), 2.35 (1H, td, J = 8.2, 4.0 Hz), 3.15-3.29 (2H, m), 3.42 (1H, ddd, J = 11.5, 8.5, 3.4 Hz), 3.48-3.64 (3H, m), 5.42 (1H, t, J = 4.9 Hz), 7.31-7.44 (3H, m), 7.50 (1H, brs), 9.30 (2H, brs).
LC/MS 212.2 tert- butyl (2S *, 3R *) -3- (3- chlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (0.44 g, 1.41 mmol) was dissolved in ethyl acetate (3 mL), 4 N hydrochloric acid-ethyl acetate solution (2.5 mL) was added. The reaction mixture was stirred overnight and the solvent was removed under reduced pressure. The obtained residue was purified by HPLC to give the title compound as a colorless oil (0.11 g, 17%).
NMR (DMSO-d 6 ) δ: 1.97-2.16 (1H, m), 2.35 (1H, td, J = 8.2, 4.0 Hz), 3.15-3.29 (2H, m), 3.42 (1H, ddd, J = 11.5 , 8.5, 3.4 Hz), 3.48-3.64 (3H, m), 5.42 (1H, t, J = 4.9 Hz), 7.31-7.44 (3H, m), 7.50 (1H, brs), 9.30 (2H, brs) .
LC / MS 212.2

実施例４９
2-[(2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]プロパン-2-オール　1塩酸塩 Example 49
2-[(2R * , 3R * )-3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] propan-2-ol monohydrochloride

Figure JPOXMLDOC01-appb-C000244
Figure JPOXMLDOC01-appb-C000244

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-ヒドロキシプロパン-2-イル)ピロリジン-1-カルボキシラート(0.52 g, 1.4 mmol)をメタノール(5 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(10 mL)を加えた。反応混合物を4時間加熱還流し、減圧下濃縮した。得られた固体をメタノール／酢酸エチルより再結晶して、表題化合物を無色結晶(0.18 g, 42%)として得た。
NMR (DMSO-d6) δ: 0.93 (3H, s), 1.08 (3H, s), 1.99-2.13 (1H, m), 2.28-2.44 (1H, m), 3.25-3.33 (1H, m), 3.48-3.59 (1H, m), 3.63-3.72 (2H, m), 5.05 (1H, s), 7.37 (1H, dd, J = 8.3, 1.9 Hz), 7.54 (1H, d, J = 8.3 Hz), 7.66 (1H, d, J = 1.9 Hz), 8.70 (1H, brs), 10.13 (1H, brs).
LC/MS 274.0
mp 220-221℃
Anal. Calcd. for C13H17NOCl2・HCl: C, 50.26; H, 5.84; N, 4.51; Cl, 34.24. Found: C, 50.30; H, 5.85; N, 4.44; Cl, 34.22. tert-Butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate (0.52 g, 1.4 mmol) in methanol (5 4N hydrochloric acid-ethyl acetate solution (10 mL) was added. The reaction mixture was heated to reflux for 4 hours and concentrated under reduced pressure. The obtained solid was recrystallized from methanol / ethyl acetate to give the title compound as colorless crystals (0.18 g, 42%).
NMR (DMSO-d 6 ) δ: 0.93 (3H, s), 1.08 (3H, s), 1.99-2.13 (1H, m), 2.28-2.44 (1H, m), 3.25-3.33 (1H, m), 3.48-3.59 (1H, m), 3.63-3.72 (2H, m), 5.05 (1H, s), 7.37 (1H, dd, J = 8.3, 1.9 Hz), 7.54 (1H, d, J = 8.3 Hz) , 7.66 (1H, d, J = 1.9 Hz), 8.70 (1H, brs), 10.13 (1H, brs).
LC / MS 274.0
mp 220-221 ℃
Anal.Calcd.for C 13 H 17 NOCl 2・ HCl: C, 50.26; H, 5.84; N, 4.51; Cl, 34.24.Found: C, 50.30; H, 5.85; N, 4.44; Cl, 34.22.

実施例５０
(+)-2,3-cis-2-[3-(3,4-ジクロロフェニル)ピロリジン-2-イル]プロパン-2-オール　1塩酸塩 Example 50
(+)-2,3-cis-2- [3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] propan-2-ol monohydrochloride

Figure JPOXMLDOC01-appb-C000245
Figure JPOXMLDOC01-appb-C000245

　参考例４６で得た2,3-cis-2-[3-(3,4-ジクロロフェニル)ピロリジン-2-イル]プロパン-2-オール（保持時間小）(0.26 g, 0.94 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(0.25 mL)を加えた。反応混合物を室温で10分間攪拌した後、減圧下濃縮した。得られた固体をエタノール／ヘキサンより再結晶して、表題化合物を無色結晶(0.24 g, 83%)として得た。
比旋光度（25℃, c=0.4665, メタノール）:+7.7度
NMR (DMSO-d6) δ: 0.93 (3H, s), 1.08 (3H, s), 1.99-2.13 (1H, m), 2.28-2.44 (1H, m), 3.25-3.33 (1H, m), 3.48-3.59 (1H, m), 3.63-3.72 (2H, m), 5.05 (1H, s), 7.37 (1H, dd, J = 8.3, 1.9 Hz), 7.54 (1H, d, J = 8.3 Hz), 7.66 (1H, d, J = 1.9 Hz), 8.70 (1H, brs), 10.13 (1H, brs).
LC/MS 274.3
mp 250-251℃
Anal. Calcd. for C13H17NOCl2・HCl: C, 50.26; H, 5.84; N, 4.51. Found: C, 50.36; H, 5.86; N, 4.30. 2,3-cis-2- [3- (3,4-dichlorophenyl) pyrrolidin-2-yl] propan-2-ol (retention time short) (0.26 g, 0.94 mmol) obtained in Reference Example 46 was added to methanol ( 10 N), and 4N hydrochloric acid-ethyl acetate solution (0.25 mL) was added. The reaction mixture was stirred at room temperature for 10 minutes and then concentrated under reduced pressure. The obtained solid was recrystallized from ethanol / hexane to give the title compound as colorless crystals (0.24 g, 83%).
Specific rotation (25 ℃, c = 0.4665, methanol): +7.7 degrees
NMR (DMSO-d 6 ) δ: 0.93 (3H, s), 1.08 (3H, s), 1.99-2.13 (1H, m), 2.28-2.44 (1H, m), 3.25-3.33 (1H, m), 3.48-3.59 (1H, m), 3.63-3.72 (2H, m), 5.05 (1H, s), 7.37 (1H, dd, J = 8.3, 1.9 Hz), 7.54 (1H, d, J = 8.3 Hz) , 7.66 (1H, d, J = 1.9 Hz), 8.70 (1H, brs), 10.13 (1H, brs).
LC / MS 274.3
mp 250-251 ℃
Anal.Calcd.for C 13 H 17 NOCl 2・ HCl: C, 50.26; H, 5.84; N, 4.51. Found: C, 50.36; H, 5.86; N, 4.30.

実施例５１
(-)-2,3-cis-2-[3-(3,4-ジクロロフェニル)ピロリジン-2-イル]プロパン-2-オール　1塩酸塩 Example 51
(-)-2,3-cis-2- [3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] propan-2-ol monohydrochloride

Figure JPOXMLDOC01-appb-C000246
Figure JPOXMLDOC01-appb-C000246

　参考例４６で得た2,3-cis-2-[3-(3,4-ジクロロフェニル)ピロリジン-2-イル]プロパン-2-オール（保持時間大）(0.25 g, 0.90 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(0.25 mL)を加えた。反応混合物を室温で10分間攪拌した後、減圧下濃縮した。得られた固体をエタノール／ヘキサンより再結晶して、表題化合物を無色結晶(0.23 g, 81%)として得た。
比旋光度（25℃, c=0.4695, メタノール）:-6.2度
NMR (DMSO-d6) δ: 0.93 (3H, s), 1.08 (3H, s), 1.99-2.13 (1H, m), 2.28-2.44 (1H, m), 3.25-3.33 (1H, m), 3.48-3.59 (1H, m), 3.63-3.72 (2H, m), 5.05 (1H, s), 7.37 (1H, dd, J = 8.3, 1.9 Hz), 7.54 (1H, d, J = 8.3 Hz), 7.66 (1H, d, J = 1.9 Hz), 8.70 (1H, brs), 10.13 (1H, brs).
mp 250-251℃
LC/MS 274.3
Anal. Calcd. for C13H17NOCl2・HCl: C, 50.26; H, 5.84; N, 4.51. Found: C, 49.99; H, 5.87; N, 4.40. 2,3-cis-2- [3- (3,4-dichlorophenyl) pyrrolidin-2-yl] propan-2-ol (long retention time) (0.25 g, 0.90 mmol) obtained in Reference Example 46 was dissolved in methanol ( 10 N), and 4N hydrochloric acid-ethyl acetate solution (0.25 mL) was added. The reaction mixture was stirred at room temperature for 10 minutes and then concentrated under reduced pressure. The obtained solid was recrystallized from ethanol / hexane to give the title compound as colorless crystals (0.23 g, 81%).
Specific rotation (25 ℃, c = 0.4695, methanol): -6.2 degrees
NMR (DMSO-d 6 ) δ: 0.93 (3H, s), 1.08 (3H, s), 1.99-2.13 (1H, m), 2.28-2.44 (1H, m), 3.25-3.33 (1H, m), 3.48-3.59 (1H, m), 3.63-3.72 (2H, m), 5.05 (1H, s), 7.37 (1H, dd, J = 8.3, 1.9 Hz), 7.54 (1H, d, J = 8.3 Hz) , 7.66 (1H, d, J = 1.9 Hz), 8.70 (1H, brs), 10.13 (1H, brs).
mp 250-251 ℃
LC / MS 274.3
.. Anal Calcd for C 13 H 17 NOCl 2 · HCl:. C, 50.26; H, 5.84; N, 4.51 Found: C, 49.99; H, 5.87; N, 4.40.

実施例５２
2-[(2R*,3R*)-3-(ナフタレン-2-イル)ピロリジン-2-イル]プロパン-2-オール　1塩酸塩 Example 52
2 - [(2R *, 3R *) -3- ( naphthalen-2-yl) pyrrolidin-2-yl] propan-2-ol monohydrochloride

Figure JPOXMLDOC01-appb-C000247
Figure JPOXMLDOC01-appb-C000247

　tert-ブチル (2R*,3R*)-2-(2-ヒドロキシプロパン-2-イル)-3-(ナフタレン-2-イル)ピロリジン-1-カルボキシラート(0.37 g, 1.04 mmol)をエタノール(5 mL)に溶解させ、11 N塩酸－エタノール溶液(2 mL)を加えた。反応混合物を終夜攪拌し、減圧下溶媒を留去した。得られた固体をジイソプロピルエーテルで洗浄した後、エタノールより再結晶して、表題化合物を白色結晶(0.2 g, 64%)として得た。
NMR (DMSO-d6) δ: 0.85 (3H, s), 0.96 (3H, s), 2.21-2.36 (1H, m), 2.37-2.57 (1H, m), 3.25-3.51 (1H, m), 3.58-3.71 (1H, m), 3.71-3.88 (2H, m), 5.05 (1H, s), 7.43-7.58 (3H, m), 7.78-7.95 (4H, m), 8.62 (1H, brs), 9.82 (1H, brs).
LC/MS 256.3
mp 203-204℃
Anal. Calcd. for C17H21NO・HCl: C, 69.97; H, 7.60; N, 4.80; O, 5.48; Cl, 12.15. Found: C, 69.81; H, 7.46; N, 4.74. tert-Butyl (2R * , 3R * )-2- (2-hydroxypropan-2-yl) -3- (naphthalen-2-yl) pyrrolidine-1-carboxylate (0.37 g, 1.04 mmol) in ethanol (5 11N hydrochloric acid-ethanol solution (2 mL) was added. The reaction mixture was stirred overnight and the solvent was removed under reduced pressure. The obtained solid was washed with diisopropyl ether and recrystallized from ethanol to give the title compound as white crystals (0.2 g, 64%).
NMR (DMSO-d 6 ) δ: 0.85 (3H, s), 0.96 (3H, s), 2.21-2.36 (1H, m), 2.37-2.57 (1H, m), 3.25-3.51 (1H, m), 3.58-3.71 (1H, m), 3.71-3.88 (2H, m), 5.05 (1H, s), 7.43-7.58 (3H, m), 7.78-7.95 (4H, m), 8.62 (1H, brs), 9.82 (1H, brs).
LC / MS 256.3
mp 203-204 ℃
Anal.Calcd.for C 17 H 21 NO.HCl: C, 69.97; H, 7.60; N, 4.80; O, 5.48; Cl, 12.15. Found: C, 69.81; H, 7.46; N, 4.74.

実施例５３
2-[(2R*,3R*)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-2-イル]プロパン-2-オール　1塩酸塩 Example 53
2-[(2R * , 3R * )-3- (3-Chloro-4-fluorophenyl) pyrrolidin-2-yl] propan-2-ol monohydrochloride

Figure JPOXMLDOC01-appb-C000248
Figure JPOXMLDOC01-appb-C000248

　tert-ブチル (2R*,3R*)-3-(3-クロロ-4-フルオロフェニル)-2-(2-ヒドロキシプロパン-2-イル)ピロリジン-1-カルボキシラート(0.35 g)のエタノール(2.0 mL)溶液に11.4 M塩酸－エタノール溶液(2.0 mL)を加え、室温で1.5時間攪拌した。溶媒を減圧留去し、得られた残留物を酢酸エチルより再結晶して、表題化合物を白色粉末(0.23 g, 80%)として得た。
LC/MS 258.4
NMR (DMSO-d6) δ: 0.91 (3H, s), 1.06 (3H, s), 1.97-2.19 (1H, m), 2.24-2.44 (1H, m), 3.21-3.76 (4H, m), 5.05 (1H, brs), 7.25-7.44 (2H, m), 7.61 (1H, dd, J = 7.0, 2.1 Hz), 8.63 (1H, brs), 10.01 (1H, brs).
mp 204-205℃ tert-butyl (2R * , 3R * )-3- (3-chloro-4-fluorophenyl) -2- (2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate (0.35 g) in ethanol (2.0 11.4 M hydrochloric acid-ethanol solution (2.0 mL) was added to the solution, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethyl acetate to obtain the title compound as a white powder (0.23 g, 80%).
LC / MS 258.4
NMR (DMSO-d 6 ) δ: 0.91 (3H, s), 1.06 (3H, s), 1.97-2.19 (1H, m), 2.24-2.44 (1H, m), 3.21-3.76 (4H, m), 5.05 (1H, brs), 7.25-7.44 (2H, m), 7.61 (1H, dd, J = 7.0, 2.1 Hz), 8.63 (1H, brs), 10.01 (1H, brs).
mp 204-205 ℃

実施例５４
2-[(2R*,3R*)-3-(3-クロロフェニル)ピロリジン-2-イル]プロパン-2-オール　1塩酸塩 Example 54
2-[(2R * , 3R * )-3- (3-Chlorophenyl) pyrrolidin-2-yl] propan-2-ol monohydrochloride

Figure JPOXMLDOC01-appb-C000249
Figure JPOXMLDOC01-appb-C000249

　tert-ブチル (2R*,3R*)-3-(3-クロロフェニル)-2-(2-ヒドロキシプロパン-2-イル)ピロリジン-1-カルボキシラート(0.40 g, 1.18 mmol)をエタノール(4 mL)に溶解させ、4 N塩酸－エタノール溶液(3 mL)を加えた。反応混合物を終夜攪拌し、減圧下溶媒を留去した。得られた固体をジイソプロピルエーテルで洗浄した後、エタノールより再結晶して、表題化合物を無色結晶(0.11 g, 34%)として得た。
NMR (DMSO-d6) δ: 0.87 (3H, s), 1.03 (3H, s), 2.05-2.19 (1H, m), 2.29-2.43 (1H, m), 3.23-3.36 (1H, m), 3.48-3.60 (1H, m), 3.61-3.70 (2H, m), 5.07 (1H, s), 7.32 (3H, s), 7.45 (1H, s), 8.53 (1H, brs), 9.85 (1H, brs).
LC/MS 240.2
mp 212-213℃
Anal. Calcd. for C13H18NOCl・HCl: C, 56.53; H, 6.93; N, 5.07; O, 5.79; Cl, 25.67. Found: C, 56.44; H, 6.79; N, 4.95. tert-Butyl (2R * , 3R * )-3- (3-Chlorophenyl) -2- (2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate (0.40 g, 1.18 mmol) in ethanol (4 mL) 4N hydrochloric acid-ethanol solution (3 mL) was added. The reaction mixture was stirred overnight and the solvent was removed under reduced pressure. The obtained solid was washed with diisopropyl ether and recrystallized from ethanol to give the title compound as colorless crystals (0.11 g, 34%).
NMR (DMSO-d 6 ) δ: 0.87 (3H, s), 1.03 (3H, s), 2.05-2.19 (1H, m), 2.29-2.43 (1H, m), 3.23-3.36 (1H, m), 3.48-3.60 (1H, m), 3.61-3.70 (2H, m), 5.07 (1H, s), 7.32 (3H, s), 7.45 (1H, s), 8.53 (1H, brs), 9.85 (1H, brs).
LC / MS 240.2
mp 212-213 ℃
Anal.Calcd.for C 13 H 18 NOCl.HCl: C, 56.53; H, 6.93; N, 5.07; O, 5.79; Cl, 25.67. Found: C, 56.44; H, 6.79; N, 4.95.

実施例５５
2-[(2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]プロパン-2-オール　1塩酸塩 Example 55
2-[(2S * , 3R * )-3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] propan-2-ol monohydrochloride

Figure JPOXMLDOC01-appb-C000250
Figure JPOXMLDOC01-appb-C000250

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-ヒドロキシプロパン-2-イル)ピロリジン-1-カルボキシラート(0.20 g, 53 mmol)をメタノール(3 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(6 mL)を加えた。反応混合物を1時間加熱還流し、減圧下濃縮した。得られた固体をエタノール／ジエチルエーテルより再結晶して、表題化合物を無色結晶(0.13 g, 78%)として得た。
NMR (DMSO-d6) δ: 1.00 (3H, s), 1.14 (3H, s), 1.82-1.98 (1H, m), 2.29-2.44 (1H, m), 3.05-3.16 (1H, m), 3.34-3.43 (1H, m), 3.45-3.55 (1H, m), 3.65 (1H, d, J = 9.1), 5.35 (1H, s), 7.44 (1H, dd, J = 8.5, 1.9), 7.61 (1H, d, J = 8.5), 7.75 (1H, d, J = 1.9), 8.48 (1H, brs), 10.14 (1H, brs).
LC/MS 274.3
mp 265-266℃
Anal. Calcd. for C13H17NOCl2・HCl: C, 50.26; H, 5.84; N, 4.51. Found: C, 50.21; H, 5.62; N, 4.43. tert-Butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate (0.20 g, 53 mmol) in methanol (3 4N hydrochloric acid-ethyl acetate solution (6 mL) was added. The reaction mixture was heated to reflux for 1 hour and concentrated under reduced pressure. The obtained solid was recrystallized from ethanol / diethyl ether to give the title compound as colorless crystals (0.13 g, 78%).
NMR (DMSO-d 6 ) δ: 1.00 (3H, s), 1.14 (3H, s), 1.82-1.98 (1H, m), 2.29-2.44 (1H, m), 3.05-3.16 (1H, m), 3.34-3.43 (1H, m), 3.45-3.55 (1H, m), 3.65 (1H, d, J = 9.1), 5.35 (1H, s), 7.44 (1H, dd, J = 8.5, 1.9), 7.61 (1H, d, J = 8.5), 7.75 (1H, d, J = 1.9), 8.48 (1H, brs), 10.14 (1H, brs).
LC / MS 274.3
mp 265-266 ℃
.. Anal Calcd for C 13 H 17 NOCl 2 · HCl:. C, 50.26; H, 5.84; N, 4.51 Found: C, 50.21; H, 5.62; N, 4.43.

実施例５６
(-)-2,3-trans-2-[3-(3,4-ジクロロフェニル)ピロリジン-2-イル]プロパン-2-オール　1塩酸塩 Example 56
(-)-2,3-trans-2- [3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] propan-2-ol monohydrochloride

Figure JPOXMLDOC01-appb-C000251
Figure JPOXMLDOC01-appb-C000251

　参考例５１で得たtert-ブチル 2,3-trans-3-(3,4-ジクロロフェニル)-2-(2-ヒドロキシプロパン-2-イル)ピロリジン-1-カルボキシラート（保持時間小）(0.62 g, 1.7 mmol)をメタノール(5 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(10 mL)を加えた。反応混合物を室温で1時間攪拌し、減圧下濃縮した。得られた固体をエタノール／ジエチルエーテルより再結晶して、表題化合物を無色結晶(0.38 g, 74%)として得た。
比旋光度（25℃, c=0.4750, メタノール）:-25.1度
NMR (DMSO-d6) δ: 1.00 (3H, s), 1.14 (3H, s), 1.82-1.98 (1H, m), 2.29-2.44 (1H, m), 3.05-3.16 (1H, m), 3.34-3.43 (1H, m), 3.45-3.55 (1H, m), 3.65 (1H, d, J = 9.1 Hz), 5.35 (1H, s), 7.44 (1H, dd, J = 8.5, 1.9 Hz), 7.61 (1H, d, J = 8.5 Hz), 7.75 (1H, d, J = 1.9 Hz), 8.48 (1H, brs), 10.14 (1H, brs).
LC/MS 274.3
mp 271-272℃
Anal. Calcd. for C13H17NOCl2・HCl: C, 50.26; H, 5.84; N, 4.51. Found: C, 50.32; H, 5.75; N, 4.52. Tert-butyl 2,3-trans-3- (3,4-dichlorophenyl) -2- (2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate obtained in Reference Example 51 (short retention time) (0.62 g, 1.7 mmol) was dissolved in methanol (5 mL), and 4 N hydrochloric acid-ethyl acetate solution (10 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The obtained solid was recrystallized from ethanol / diethyl ether to give the title compound as colorless crystals (0.38 g, 74%).
Specific rotation (25 ℃, c = 0.4750, methanol): -25.1 degrees
NMR (DMSO-d 6 ) δ: 1.00 (3H, s), 1.14 (3H, s), 1.82-1.98 (1H, m), 2.29-2.44 (1H, m), 3.05-3.16 (1H, m), 3.34-3.43 (1H, m), 3.45-3.55 (1H, m), 3.65 (1H, d, J = 9.1 Hz), 5.35 (1H, s), 7.44 (1H, dd, J = 8.5, 1.9 Hz) , 7.61 (1H, d, J = 8.5 Hz), 7.75 (1H, d, J = 1.9 Hz), 8.48 (1H, brs), 10.14 (1H, brs).
LC / MS 274.3
mp 271-272 ° C
Anal.Calcd.for C 13 H 17 NOCl 2・ HCl: C, 50.26; H, 5.84; N, 4.51. Found: C, 50.32; H, 5.75; N, 4.52.

実施例５７
(+)-2,3-trans-2-[3-(3,4-ジクロロフェニル)ピロリジン-2-イル]プロパン-2-オール　1塩酸塩 Example 57
(+)-2,3-trans-2- [3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] propan-2-ol monohydrochloride

Figure JPOXMLDOC01-appb-C000252
Figure JPOXMLDOC01-appb-C000252

　参考例５１で得たtert-ブチル 2,3-trans-3-(3,4-ジクロロフェニル)-2-(2-ヒドロキシプロパン-2-イル)ピロリジン-1-カルボキシラート（保持時間大）(0.62 g, 1.6 mmol)をメタノール(5 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(10 mL)を加えた。反応混合物を室温で1時間攪拌し、減圧下濃縮した。得られた固体をエタノール／ジエチルエーテルより再結晶して、表題化合物を無色結晶(0.39 g, 77%)として得た。
比旋光度（25℃, c=0.4665, メタノール）:+26.3度
NMR (DMSO-d6) δ: 1.00 (3H, s), 1.14 (3H, s), 1.82-1.98 (1H, m), 2.29-2.41 (1H, m), 3.06-3.16 (1H, m), 3.34-3.43 (1H, m), 3.45-3.55 (1H, m), 3.65 (1H, d, J = 9.2 Hz), 5.35 (1H, s), 7.44 (1H, dd, J = 8.3, 2.1 Hz), 7.62 (1H, d, J = 8.3 Hz), 7.76 (1H, d, J = 2.1 Hz), 8.81 (2H, brs).
LC/MS 274.3
mp 271-272℃
Anal. Calcd. for C13H17NOCl2・HCl: C, 50.26; H, 5.84; N, 4.51. Found: C, 50.31; H, 5.81; N, 4.45. Tert-Butyl 2,3-trans-3- (3,4-dichlorophenyl) -2- (2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate obtained in Reference Example 51 (large retention time) (0.62 g, 1.6 mmol) was dissolved in methanol (5 mL), and 4 N hydrochloric acid-ethyl acetate solution (10 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The obtained solid was recrystallized from ethanol / diethyl ether to give the title compound as colorless crystals (0.39 g, 77%).
Specific rotation (25 ℃, c = 0.4665, methanol): +26.3 degrees
NMR (DMSO-d 6 ) δ: 1.00 (3H, s), 1.14 (3H, s), 1.82-1.98 (1H, m), 2.29-2.41 (1H, m), 3.06-3.16 (1H, m), 3.34-3.43 (1H, m), 3.45-3.55 (1H, m), 3.65 (1H, d, J = 9.2 Hz), 5.35 (1H, s), 7.44 (1H, dd, J = 8.3, 2.1 Hz) , 7.62 (1H, d, J = 8.3 Hz), 7.76 (1H, d, J = 2.1 Hz), 8.81 (2H, brs).
LC / MS 274.3
mp 271-272 ° C
Anal.Calcd.for C 13 H 17 NOCl 2・ HCl: C, 50.26; H, 5.84; N, 4.51.Found: C, 50.31; H, 5.81; N, 4.45.

実施例５８
2-[(2S*,3R*)-3-(ナフタレン-2-イル)ピロリジン-2-イル]プロパン-2-オール　1塩酸塩 Example 58
2-[(2S * , 3R * )-3- (Naphthalen-2-yl) pyrrolidin-2-yl] propan-2-ol monohydrochloride

Figure JPOXMLDOC01-appb-C000253
Figure JPOXMLDOC01-appb-C000253

　tert-ブチル (2S*,3R*)-2-(2-ヒドロキシプロパン-2-イル)-3-(ナフタレン-2-イル)ピロリジン-1-カルボキシラート(0.47 g, 1.3 mmol)をエタノール(5 mL)に溶解させ、11.4 N塩酸－エタノール溶液(3 mL)を加えた。反応混合物を終夜攪拌し、減圧下溶媒を留去した。得られた固体をジイソプロピルエーテルで洗浄した後、エタノールより再結晶して、表題化合物を無色結晶(0.17 g, 60%)として得た。
NMR (DMSO-d6) δ: 1.02 (3H, s), 1.12 (3H, s), 1.92-2.09 (1H, m), 2.34-2.48 (1H, m), 3.13-3.27 (1H, m), 3.38-3.51 (1H, m), 3.55-3.68 (1H, m), 3.70-3.80 (1H, m), 5.38 (1H, s), 7.44-7.61 (3H, m), 7.80-7.99 (4H, m), 8.50 (1H, brs), 9.44 (1H, brs).
LC/MS 256.2
mp 230-231℃
Anal. Calcd. for C17H21NO・HCl: C, 69.97; H, 7.60; N, 4.80; O, 5.48; Cl, 12.15. Found: C, 69.69; H, 7.68; N, 4.73. tert-butyl (2S * , 3R * )-2- (2-hydroxypropan-2-yl) -3- (naphthalen-2-yl) pyrrolidine-1-carboxylate (0.47 g, 1.3 mmol) in ethanol (5 11.4 N hydrochloric acid-ethanol solution (3 mL) was added. The reaction mixture was stirred overnight and the solvent was removed under reduced pressure. The obtained solid was washed with diisopropyl ether and recrystallized from ethanol to give the title compound as colorless crystals (0.17 g, 60%).
NMR (DMSO-d 6 ) δ: 1.02 (3H, s), 1.12 (3H, s), 1.92-2.09 (1H, m), 2.34-2.48 (1H, m), 3.13-3.27 (1H, m), 3.38-3.51 (1H, m), 3.55-3.68 (1H, m), 3.70-3.80 (1H, m), 5.38 (1H, s), 7.44-7.61 (3H, m), 7.80-7.99 (4H, m ), 8.50 (1H, brs), 9.44 (1H, brs).
LC / MS 256.2
mp 230-231 ℃
Anal.Calcd.for C 17 H 21 NO.HCl: C, 69.97; H, 7.60; N, 4.80; O, 5.48; Cl, 12.15. Found: C, 69.69; H, 7.68; N, 4.73.

実施例５９
2-[(2S*,3R*)-3-(3-クロロ-4-フルオロフェニル)ピロリジン-2-イル]プロパン-2-オール　1塩酸塩 Example 59
2-[(2S * , 3R * )-3- (3-Chloro-4-fluorophenyl) pyrrolidin-2-yl] propan-2-ol monohydrochloride

Figure JPOXMLDOC01-appb-C000254
Figure JPOXMLDOC01-appb-C000254

　tert-ブチル (2S*,3R*)-3-(3-クロロ-4-フルオロフェニル)-2-(2-ヒドロキシプロパン-2-イル)ピロリジン-1-カルボキシラート(0.14 g)の酢酸エチル(2.0 mL)溶液に4 N塩酸－酢酸エチル溶液(2.0 mL)を加え、室温で終夜攪拌した。溶媒を減圧留去し、得られた残留物を酢酸エチル／ジエチルエーテルより再結晶して、表題化合物を白色粉末(96 mg, 81%)として得た。
LC/MS 258.2
NMR (DMSO-d6) δ: 1.00 (3H, s), 1.14 (3H, s), 1.82-2.02 (1H, m), 2.25-2.41 (1H, m), 3.28-3.85 (4H, m), 5.34 (1H, s), 7.39 (1H, t, J = 8.9 Hz), 7.43-7.52 (1H, m), 7.72 (1H, dd, J = 7.2, 2.3 Hz), 8.50 (1H, brs), 10.29 (1H, brs).
mp 214-216℃ tert-butyl (2S * , 3R * )-3- (3-chloro-4-fluorophenyl) -2- (2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate (0.14 g) in ethyl acetate ( 2.0 mL) solution was added 4N hydrochloric acid-ethyl acetate solution (2.0 mL) and stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate / diethyl ether to give the title compound as a white powder (96 mg, 81%).
LC / MS 258.2
NMR (DMSO-d 6 ) δ: 1.00 (3H, s), 1.14 (3H, s), 1.82-2.02 (1H, m), 2.25-2.41 (1H, m), 3.28-3.85 (4H, m), 5.34 (1H, s), 7.39 (1H, t, J = 8.9 Hz), 7.43-7.52 (1H, m), 7.72 (1H, dd, J = 7.2, 2.3 Hz), 8.50 (1H, brs), 10.29 (1H, brs).
mp 214-216 ℃

実施例６０
2-[(2S*,3R*)-3-(3-クロロフェニル)ピロリジン-2-イル]プロパン-2-オール　1塩酸塩 Example 60
2-[(2S * , 3R * )-3- (3-Chlorophenyl) pyrrolidin-2-yl] propan-2-ol monohydrochloride

Figure JPOXMLDOC01-appb-C000255
Figure JPOXMLDOC01-appb-C000255

　tert-ブチル (2S*,3R*)-3-(3-クロロフェニル)-2-(2-ヒドロキシプロパン-2-イル)ピロリジン-1-カルボキシラート(0.14 g, 0.41 mmol)をエタノール(2 mL)に溶解させ、4 N塩酸－エタノール溶液(1.5 mL)を加えた。反応混合物を終夜攪拌し、減圧下溶媒を留去した。得られた固体をジイソプロピルエーテルで洗浄した後、表題化合物を褐色結晶(0.09 g, 79%)として得た。
NMR (DMSO-d6) δ: 1.00 (3H, s), 1.13 (3H, s), 1.82-2.00 (1H, m), 2.29-2.43 (1H, m), 3.12 (1H, td, J = 10.5, 6.6 Hz), 3.38 (1H, dt, J = 11.0, 4.0 Hz), 3.44-3.54 (1H, m), 3.65 (1H, d, J = 9.1 Hz), 5.34 (1H, s), 7.28-7.36 (1H, m), 7.36-7.44 (2H, m), 7.53 (1H, brs), 8.46 (1H, brs), 10.02 (1H, brs).
LC/MS 240.2
mp 193-194℃
Anal. Calcd. for C13H18NOCl・HCl: C, 56.53; H, 6.93; N, 5.07; O, 5.79; Cl, 25.67. Found: C, 56.24; H, 6.81; N, 4.89. tert-Butyl (2S * , 3R * )-3- (3-Chlorophenyl) -2- (2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate (0.14 g, 0.41 mmol) in ethanol (2 mL) 4N hydrochloric acid-ethanol solution (1.5 mL) was added. The reaction mixture was stirred overnight and the solvent was removed under reduced pressure. The obtained solid was washed with diisopropyl ether to give the title compound as brown crystals (0.09 g, 79%).
NMR (DMSO-d 6 ) δ: 1.00 (3H, s), 1.13 (3H, s), 1.82-2.00 (1H, m), 2.29-2.43 (1H, m), 3.12 (1H, td, J = 10.5 , 6.6 Hz), 3.38 (1H, dt, J = 11.0, 4.0 Hz), 3.44-3.54 (1H, m), 3.65 (1H, d, J = 9.1 Hz), 5.34 (1H, s), 7.28-7.36 (1H, m), 7.36-7.44 (2H, m), 7.53 (1H, brs), 8.46 (1H, brs), 10.02 (1H, brs).
LC / MS 240.2
mp 193-194 ℃
Anal.Calcd.for C 13 H 18 NOCl.HCl: C, 56.53; H, 6.93; N, 5.07; O, 5.79; Cl, 25.67. Found: C, 56.24; H, 6.81; N, 4.89.

実施例６１
2-[(2R*,3R*)-3-(3,4-ジクロロフェニル)-1-メチルピロリジン-2-イル]プロパン-2-オール　1塩酸塩 Example 61
2-[(2R * , 3R * )-3- (3,4-dichlorophenyl) -1-methylpyrrolidin-2-yl] propan-2-ol monohydrochloride

Figure JPOXMLDOC01-appb-C000256
Figure JPOXMLDOC01-appb-C000256

　2-[(2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]プロパン-2-オール　1塩酸塩(0.080 g, 0.26 mmol)のメタノール(10 mL)溶液に37%ホルムアルデヒド(0.096 mL, 1.3 mmol)水溶液、トリアセトキシほう酸ナトリウム(0.27 g, 1.3 mmol)および酢酸(0.015 mL, 0.26 mmol)を加え、室温で2日間攪拌した。減圧下溶媒を留去し、水で希釈し、飽和炭酸水素ナトリウム水溶液で中和し、これを酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥させ、減圧下溶媒を留去した。得られた残渣をメタノール(5 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(0.25 mL)を加えた。反応混合物を室温で10分間攪拌した後、減圧下濃縮した。得られた固体をメタノール／酢酸エチルより再結晶して、表題化合物を無色結晶(0.054 g, 65%)として得た。
NMR (DMSO-d6) δ: 0.76 (3H, s), 0.93 (3H, s), 2.13-2.28 (1H, m), 2.35-2.46 (1H, m), 2.98 (3H, d, J = 4.9 Hz), 3.04-3.19 (1H, m), 3.75-3.89 (2H, m), 3.97-4.10 (1H, m), 5.48 (1H, s), 7.43 (1H, d, J = 8.3 Hz), 7.63 (1H, d, J = 8.3 Hz), 7.74 (1H, s), 9.31 (1H, brs).
LC/MS 288.0
mp 224-225℃
Anal. Calcd. for C14H19NOCl2・HCl: C, 51.79; H, 6.21; N, 4.31; Cl, 32.76. Found: C, 51.39; H, 6.29; N, 4.26; Cl, 32.46. To a solution of 2-[(2R * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidin-2-yl] propan-2-ol monohydrochloride (0.080 g, 0.26 mmol) in methanol (10 mL), 37 % Aqueous formaldehyde (0.096 mL, 1.3 mmol), sodium triacetoxyborate (0.27 g, 1.3 mmol) and acetic acid (0.015 mL, 0.26 mmol) were added, and the mixture was stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure, diluted with water, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (5 mL), and 4 N hydrochloric acid-ethyl acetate solution (0.25 mL) was added. The reaction mixture was stirred at room temperature for 10 minutes and then concentrated under reduced pressure. The obtained solid was recrystallized from methanol / ethyl acetate to give the title compound as colorless crystals (0.054 g, 65%).
NMR (DMSO-d 6 ) δ: 0.76 (3H, s), 0.93 (3H, s), 2.13-2.28 (1H, m), 2.35-2.46 (1H, m), 2.98 (3H, d, J = 4.9 Hz), 3.04-3.19 (1H, m), 3.75-3.89 (2H, m), 3.97-4.10 (1H, m), 5.48 (1H, s), 7.43 (1H, d, J = 8.3 Hz), 7.63 (1H, d, J = 8.3 Hz), 7.74 (1H, s), 9.31 (1H, brs).
LC / MS 288.0
mp 224-225 ℃
Anal.Calcd.for C 14 H 19 NOCl 2・ HCl: C, 51.79; H, 6.21; N, 4.31; Cl, 32.76.Found: C, 51.39; H, 6.29; N, 4.26; Cl, 32.46.

実施例６２
(2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン　1塩酸塩 Example 62
(2S * , 3R * )-3- (3,4-Dichlorophenyl) -2- (methoxymethyl) pyrrolidine monohydrochloride

Figure JPOXMLDOC01-appb-C000257
Figure JPOXMLDOC01-appb-C000257

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-1-カルボキシラート(0.17 g, 47 mmol)をメタノール(5 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(10 mL)を加えた。反応混合物を3時間加熱還流し、減圧下濃縮した。得られた固体を酢酸エチル／ジエチルエーテルより再結晶して、表題化合物を白色結晶(0.13 g, 96%)として得た。
NMR (DMSO-d6) δ: 1.97-2.13 (1H, m), 2.29-2.42 (1H, m), 3.16-3.25 (2H, m), 3.28 (3H, s), 3.36-3.47 (2H, m), 3.50-3.59 (1H, m), 3.67-3.76 (1H, m), 7.40 (1H, dd, J = 8.3, 2.1 Hz), 7.64 (1H, d, J = 8.3 Hz), 7.73 (1H, d, J = 2.1 Hz), 9.45 (2H, brs).
LC/MS 260.0
mp 161-162℃
Anal. Calcd. for C12H15NOCl2・HCl: C, 48.59; H, 5.44; N, 4.72; Cl, 35.86. Found: C, 48.61; H, 5.42; N, 4.69; Cl, 35.99. tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine-1-carboxylate (0.17 g, 47 mmol) was dissolved in methanol (5 mL), A 4N hydrochloric acid-ethyl acetate solution (10 mL) was added. The reaction mixture was heated to reflux for 3 hours and concentrated under reduced pressure. The obtained solid was recrystallized from ethyl acetate / diethyl ether to give the title compound as white crystals (0.13 g, 96%).
NMR (DMSO-d 6) δ : 1.97-2.13 (1H, m), 2.29-2.42 (1H, m), 3.16-3.25 (2H, m), 3.28 (3H, s), 3.36-3.47 (2H, m ), 3.50-3.59 (1H, m), 3.67-3.76 (1H, m), 7.40 (1H, dd, J = 8.3, 2.1 Hz), 7.64 (1H, d, J = 8.3 Hz), 7.73 (1H, d, J = 2.1 Hz), 9.45 (2H, brs).
LC / MS 260.0
mp 161-162 ℃
Anal.Calcd.for C 12 H 15 NOCl 2・ HCl: C, 48.59; H, 5.44; N, 4.72; Cl, 35.86.Found: C, 48.61; H, 5.42; N, 4.69; Cl, 35.99.

実施例６３
2,3-trans-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン　1塩酸塩（保持時間小） Example 63
2,3-trans-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine monohydrochloride (low retention time)

Figure JPOXMLDOC01-appb-C000258
Figure JPOXMLDOC01-appb-C000258

　参考例５６で得た2,3-trans-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン（保持時間小）(0.23 g, 0.87 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(0.25 mL)を加えた。反応混合物を室温で10分間攪拌した後、減圧下濃縮した。得られた固体をエタノール／ヘキサンより再結晶して、表題化合物を無色結晶(0.18 g, 69%)として得た。
NMR (DMSO-d6) δ: 1.97-2.13 (1H, m), 2.29-2.41 (1H, m), 3.14-3.25 (2H, m), 3.28 (3H, s), 3.35-3.47 (2H, m), 3.55-3.64 (1H, m), 3.67-3.77 (1H, m), 7.41 (1H, dd, J = 8.5, 2.1 Hz), 7.63 (1H, d, J = 8.5 Hz), 7.74 (1H, d, J = 2.1 Hz), 9.69 (2H, brs).
LC/MS 260.2
mp 169-170℃ 2,3-trans-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine (low retention time) (0.23 g, 0.87 mmol) obtained in Reference Example 56 was dissolved in methanol (10 mL). 4N hydrochloric acid-ethyl acetate solution (0.25 mL) was added. The reaction mixture was stirred at room temperature for 10 minutes and then concentrated under reduced pressure. The obtained solid was recrystallized from ethanol / hexane to give the title compound as colorless crystals (0.18 g, 69%).
NMR (DMSO-d 6 ) δ: 1.97-2.13 (1H, m), 2.29-2.41 (1H, m), 3.14-3.25 (2H, m), 3.28 (3H, s), 3.35-3.47 (2H, m ), 3.55-3.64 (1H, m), 3.67-3.77 (1H, m), 7.41 (1H, dd, J = 8.5, 2.1 Hz), 7.63 (1H, d, J = 8.5 Hz), 7.74 (1H, d, J = 2.1 Hz), 9.69 (2H, brs).
LC / MS 260.2
mp 169-170 ℃

実施例６４
2,3-trans-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン　1塩酸塩（保持時間大） Example 64
2,3-trans-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine monohydrochloride (long retention time)

Figure JPOXMLDOC01-appb-C000259
Figure JPOXMLDOC01-appb-C000259

　参考例５６で得た2,3-trans-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン（保持時間大）(0.24 g, 0.91 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(0.25 mL)を加えた。反応混合物を室温で10分間攪拌した後、減圧下濃縮した。得られた固体をエタノール／ヘキサンより再結晶して、表題化合物を無色結晶(0.22 g, 82%)として得た。
NMR (DMSO-d6) δ: 1.97-2.13 (1H, m), 2.29-2.41 (1H, m), 3.14-3.25 (2H, m), 3.28 (3H, s), 3.35-3.47 (2H, m), 3.55-3.64 (1H, m), 3.67-3.77 (1H, m), 7.41 (1H, dd, J = 8.5, 2.1 Hz), 7.63 (1H, d, J = 8.5 Hz), 7.74 (1H, d, J = 2.1 Hz), 9.69 (2H, brs).
LC/MS 260.2
mp 165-166℃ 2,3-trans-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine (long retention time) (0.24 g, 0.91 mmol) obtained in Reference Example 56 was dissolved in methanol (10 mL). 4N hydrochloric acid-ethyl acetate solution (0.25 mL) was added. The reaction mixture was stirred at room temperature for 10 minutes and then concentrated under reduced pressure. The obtained solid was recrystallized from ethanol / hexane to give the title compound as colorless crystals (0.22 g, 82%).
NMR (DMSO-d 6 ) δ: 1.97-2.13 (1H, m), 2.29-2.41 (1H, m), 3.14-3.25 (2H, m), 3.28 (3H, s), 3.35-3.47 (2H, m ), 3.55-3.64 (1H, m), 3.67-3.77 (1H, m), 7.41 (1H, dd, J = 8.5, 2.1 Hz), 7.63 (1H, d, J = 8.5 Hz), 7.74 (1H, d, J = 2.1 Hz), 9.69 (2H, brs).
LC / MS 260.2
mp 165-166 ℃

実施例６５
(2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(エトキシメチル)ピロリジン　1塩酸塩 Example 65
(2S * , 3R * )-3- (3,4-Dichlorophenyl) -2- (ethoxymethyl) pyrrolidine monohydrochloride

Figure JPOXMLDOC01-appb-C000260
Figure JPOXMLDOC01-appb-C000260

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシラート(0.17 g, 0.49 mmol)のDMF(5 mL)溶液に水素化ナトリウム(0.022 g, 0.54 mmol)を0℃で加え、0℃で10分間攪拌した。反応混合物にヨードエタン(0.12 mL, 1.5 mmol)のTHF(5 mL)溶液を0℃で滴下し、室温で3日間攪拌した後、50℃で1日間攪拌した。飽和塩化アンモニウム水溶液を加え、水で希釈した後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（0-20% 酢酸エチル／ヘキサン）で精製することにより、無色油状物を得た。
　得られた油状物をメタノール(3 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(6 mL)を加えた。反応混合物を終夜加熱還流し、減圧下濃縮した。得られた固体をジエチルエーテルで洗浄することにより、表題化合物を白色結晶(0.023 g, 92%)として得た。
NMR (DMSO-d6) δ: 1.11 (3H, t, J = 7.0 Hz), 1.97-2.13 (1H, m), 2.29-2.41 (1H, m), 3.16-3.29 (2H, m), 3.37-3.52 (4H, m), 3.54-3.62 (1H, m), 3.67-3.75 (1H, m), 7.40 (1H, dd, J = 8.3, 2.3 Hz), 7.63 (1H, d, J = 8.3 Hz), 7.73 (1H, d, J = 2.3 Hz), 9.45 (2H, brs).
LC/MS 274.0 Hydrogenate tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (0.17 g, 0.49 mmol) in DMF (5 mL) Sodium (0.022 g, 0.54 mmol) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 10 minutes. A solution of iodoethane (0.12 mL, 1.5 mmol) in THF (5 mL) was added dropwise to the reaction mixture at 0 ° C., and the mixture was stirred at room temperature for 3 days, and then stirred at 50 ° C. for 1 day. Saturated aqueous ammonium chloride solution was added, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0-20% ethyl acetate / hexane) to give a colorless oil.
The obtained oil was dissolved in methanol (3 mL), and 4 N hydrochloric acid-ethyl acetate solution (6 mL) was added. The reaction mixture was heated to reflux overnight and concentrated under reduced pressure. The obtained solid was washed with diethyl ether to give the title compound as white crystals (0.023 g, 92%).
NMR (DMSO-d 6 ) δ: 1.11 (3H, t, J = 7.0 Hz), 1.97-2.13 (1H, m), 2.29-2.41 (1H, m), 3.16-3.29 (2H, m), 3.37- 3.52 (4H, m), 3.54-3.62 (1H, m), 3.67-3.75 (1H, m), 7.40 (1H, dd, J = 8.3, 2.3 Hz), 7.63 (1H, d, J = 8.3 Hz) , 7.73 (1H, d, J = 2.3 Hz), 9.45 (2H, brs).
LC / MS 274.0

実施例６６
(2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン　1塩酸塩 Example 66
(2R * , 3R * )-3- (3,4-Dichlorophenyl) -2- (methoxymethyl) pyrrolidine monohydrochloride

Figure JPOXMLDOC01-appb-C000261
Figure JPOXMLDOC01-appb-C000261

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-1-カルボキシラート(0.76 g, 2.1 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(20 mL)を加えた。反応混合物を1時間加熱還流し、減圧下濃縮した。得られた固体を酢酸エチルより再結晶して、表題化合物を無色結晶(0.53 g, 85%)として得た。
NMR (DMSO-d6) δ: 2.21-2.34 (2H, m), 3.04-3.25 (3H, m), 3.15 (3H, s), 3.42-3.51 (1H, m), 3.67 (1H, q, J = 8.8 Hz), 3.97-4.07 (1H, m), 7.36 (1H, dd, J = 8.3, 1.9 Hz), 7.62 (1H, d, J = 8.3 Hz), 7.65 (1H, d, J = 1.9 Hz), 9.56 (2H, brs).
LC/MS 260.0
mp 162-163℃
Anal. Calcd. for C12H15NOCl2・HCl: C, 48.59; H, 5.44; N, 4.72. Found: C, 48.54; H, 5.44; N, 4.70. tert-butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine-1-carboxylate (0.76 g, 2.1 mmol) was dissolved in methanol (10 mL), A 4N hydrochloric acid-ethyl acetate solution (20 mL) was added. The reaction mixture was heated to reflux for 1 hour and concentrated under reduced pressure. The obtained solid was recrystallized from ethyl acetate to give the title compound as colorless crystals (0.53 g, 85%).
NMR (DMSO-d 6 ) δ: 2.21-2.34 (2H, m), 3.04-3.25 (3H, m), 3.15 (3H, s), 3.42-3.51 (1H, m), 3.67 (1H, q, J = 8.8 Hz), 3.97-4.07 (1H, m), 7.36 (1H, dd, J = 8.3, 1.9 Hz), 7.62 (1H, d, J = 8.3 Hz), 7.65 (1H, d, J = 1.9 Hz ), 9.56 (2H, brs).
LC / MS 260.0
mp 162-163 ℃
Anal.Calcd.for C 12 H 15 NOCl 2 HCl: C, 48.59; H, 5.44; N, 4.72. Found: C, 48.54; H, 5.44; N, 4.70.

実施例６７
(-)-2,3-cis-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン　1塩酸塩 Example 67
(-)-2,3-cis-3- (3,4-Dichlorophenyl) -2- (methoxymethyl) pyrrolidine monohydrochloride

Figure JPOXMLDOC01-appb-C000262
Figure JPOXMLDOC01-appb-C000262

　参考例５８で得たtert-ブチル 2,3-cis-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-1-カルボキシラート（保持時間小）(0.85 g, 2.4 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(20 mL)を加えた。反応混合物を室温で3時間攪拌し、減圧下濃縮した。得られた固体をエタノール／ジエチルエーテルより再結晶して、表題化合物を白色結晶(0.54 g, 78%)として得た。
比旋光度（25℃, c=0.4895, メタノール）:-70.8度
NMR (DMSO-d6) δ: 2.22-2.33 (2H, m), 3.09 (1H, dd, J = 10.6, 4.2 Hz), 3.13-3.24 (2H, m), 3.15 (3H, s), 3.41-3.51 (1H, m), 3.68 (1H, q, J = 8.8 Hz), 4.02 (1H, td, J = 8.5, 4.2 Hz), 7.37 (1H, dd, J = 8.3, 2.3 Hz), 7.62 (1H, d, J = 8.3 Hz), 7.65 (1H, d, J = 2.3 Hz), 9.69 (2H, brs).
LC/MS 260.2
mp 187-188℃
Anal. Calcd. for C12H15NOCl2・HCl: C, 48.59; H, 5.44; N, 4.72. Found: C, 48.56; H, 5.29; N, 4.66. The tert-butyl 2,3-cis-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine-1-carboxylate (retention time short) (0.85 g, 2.4 mmol) obtained in Reference Example 58 was used. Dissolved in methanol (10 mL), 4N hydrochloric acid-ethyl acetate solution (20 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The obtained solid was recrystallized from ethanol / diethyl ether to give the title compound as white crystals (0.54 g, 78%).
Specific rotation (25 ℃, c = 0.4895, methanol): -70.8 degrees
NMR (DMSO-d 6 ) δ: 2.22-2.33 (2H, m), 3.09 (1H, dd, J = 10.6, 4.2 Hz), 3.13-3.24 (2H, m), 3.15 (3H, s), 3.41- 3.51 (1H, m), 3.68 (1H, q, J = 8.8 Hz), 4.02 (1H, td, J = 8.5, 4.2 Hz), 7.37 (1H, dd, J = 8.3, 2.3 Hz), 7.62 (1H , d, J = 8.3 Hz), 7.65 (1H, d, J = 2.3 Hz), 9.69 (2H, brs).
LC / MS 260.2
mp 187-188 ℃
Anal.Calcd.for C 12 H 15 NOCl 2 HCl: C, 48.59; H, 5.44; N, 4.72. Found: C, 48.56; H, 5.29; N, 4.66.

実施例６８
(+)-2,3-cis-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン　1塩酸塩 Example 68
(+)-2,3-cis-3- (3,4-Dichlorophenyl) -2- (methoxymethyl) pyrrolidine monohydrochloride

Figure JPOXMLDOC01-appb-C000263
Figure JPOXMLDOC01-appb-C000263

　参考例５８で得たtert-ブチル 2,3-cis-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-1-カルボキシラート（保持時間大）(0.83 g, 2.3 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(20 mL)を加えた。反応混合物を室温で3時間攪拌し、減圧下濃縮した。得られた固体をエタノール／ジエチルエーテルより再結晶して、表題化合物を白色結晶(0.62 g, 91%)として得た。
比旋光度（25℃, c=0.4700, メタノール）:+72.4度
NMR (DMSO-d6) δ: 2.22-2.33 (2H, m), 3.09 (1H, dd, J = 10.6, 4.2 Hz), 3.13-3.24 (2H, m), 3.15 (3H, s), 3.41-3.51 (1H, m), 3.68 (1H, q, J = 8.8 Hz), 4.02 (1H, td, J = 8.5, 4.2 Hz), 7.37 (1H, dd, J = 8.3, 2.3 Hz), 7.62 (1H, d, J = 8.3 Hz), 7.65 (1H, d, J = 2.3 Hz), 9.69 (2H, brs).
LC/MS 260.3
mp 187-188℃
Anal. Calcd. for C12H15NOCl2・HCl: C, 48.59; H, 5.44; N, 4.72. Found: C, 48.55; H, 5.33; N, 4.69. The tert-butyl 2,3-cis-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine-1-carboxylate obtained in Reference Example 58 (large retention time) (0.83 g, 2.3 mmol) was used. Dissolved in methanol (10 mL), 4N hydrochloric acid-ethyl acetate solution (20 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The obtained solid was recrystallized from ethanol / diethyl ether to give the title compound as white crystals (0.62 g, 91%).
Specific rotation (25 ℃, c = 0.4700, methanol): +72.4 degrees
NMR (DMSO-d 6 ) δ: 2.22-2.33 (2H, m), 3.09 (1H, dd, J = 10.6, 4.2 Hz), 3.13-3.24 (2H, m), 3.15 (3H, s), 3.41- 3.51 (1H, m), 3.68 (1H, q, J = 8.8 Hz), 4.02 (1H, td, J = 8.5, 4.2 Hz), 7.37 (1H, dd, J = 8.3, 2.3 Hz), 7.62 (1H , d, J = 8.3 Hz), 7.65 (1H, d, J = 2.3 Hz), 9.69 (2H, brs).
LC / MS 260.3
mp 187-188 ℃
.. Anal Calcd for C 12 H 15 NOCl 2 · HCl:. C, 48.59; H, 5.44; N, 4.72 Found: C, 48.55; H, 5.33; N, 4.69.

実施例６９
(2R*,3R*)-3-(3-クロロ-4-フルオロフェニル)-2-(メトキシメチル)ピロリジン　1塩酸塩 Example 69
(2R * , 3R * )-3- (3-Chloro-4-fluorophenyl) -2- (methoxymethyl) pyrrolidine monohydrochloride

Figure JPOXMLDOC01-appb-C000264
Figure JPOXMLDOC01-appb-C000264

　tert-ブチル (2R*,3R*)-3-(3-クロロ-4-フルオロフェニル)-2-(メトキシメチル)ピロリジン-1-カルボキシラート(0.54 g)の酢酸エチル(5.0 mL)溶液に4 N塩酸－酢酸エチル溶液(5.0 mL)を加え、室温で終夜攪拌した。溶媒を減圧留去し、得られた残留物を酢酸エチル／ジエチルエーテルより再結晶して、表題化合物を白色粉末(0.42 g, 96%)として得た。
LC/MS 244.3
NMR (DMSO-d6) δ: 2.18-2.36 (2H, m), 3.02-3.12 (2H, m), 3.15 (3H, s), 3.16-3.27 (1H, m), 3.40-3.51 (1H, m), 3.59-3.75 (1H, m), 3.94-4.06 (1H, m), 7.31-7.47 (2H, m), 7.53-7.66 (1H, m), 9.58 (2H, brs).
mp 216-224℃ tert-Butyl (2R * , 3R * )-3- (3-Chloro-4-fluorophenyl) -2- (methoxymethyl) pyrrolidine-1-carboxylate (0.54 g) in ethyl acetate (5.0 mL) N hydrochloric acid-ethyl acetate solution (5.0 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate / diethyl ether to give the title compound as a white powder (0.42 g, 96%).
LC / MS 244.3
NMR (DMSO-d 6 ) δ: 2.18-2.36 (2H, m), 3.02-3.12 (2H, m), 3.15 (3H, s), 3.16-3.27 (1H, m), 3.40-3.51 (1H, m ), 3.59-3.75 (1H, m), 3.94-4.06 (1H, m), 7.31-7.47 (2H, m), 7.53-7.66 (1H, m), 9.58 (2H, brs).
mp 216-224 ℃

実施例７０
(2R*,3R*)-3-(3-クロロフェニル)-2-(メトキシメチル)ピロリジン　1塩酸塩 Example 70
(2R * , 3R * )-3- (3-Chlorophenyl) -2- (methoxymethyl) pyrrolidine monohydrochloride

Figure JPOXMLDOC01-appb-C000265
Figure JPOXMLDOC01-appb-C000265

　tert-ブチル (2R*,3R*)-3-(3-クロロフェニル)-2-(メトキシメチル)ピロリジン-1-カルボキシラート(0.26 g, 0.80 mmol)を酢酸エチル(2.5 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(2.5 mL)を加えた。反応混合物を終夜攪拌し、減圧下溶媒を留去した。表題化合物を淡黄色の油状物(0.16 g, 78%)として得た。
NMR (DMSO-d6) δ: 2.30 (2H, t, J = 8.1 Hz), 3.03-3.11 (1H, m), 3.15 (3H, s), 3.38-3.52 (2H, m), 3.67 (2H, dd, J = 17.8, 8.7 Hz), 3.96-4.09 (1H, m), 7.28-7.52 (4H, m), 9.05 (1H, brs), 9.80 (1H, brs).
LC/MS 226.1 tert-Butyl (2R * , 3R * )-3- (3-chlorophenyl) -2- (methoxymethyl) pyrrolidine-1-carboxylate (0.26 g, 0.80 mmol) was dissolved in ethyl acetate (2.5 mL) and 4 N hydrochloric acid-ethyl acetate solution (2.5 mL) was added. The reaction mixture was stirred overnight and the solvent was removed under reduced pressure. The title compound was obtained as a pale yellow oil (0.16 g, 78%).
NMR (DMSO-d 6 ) δ: 2.30 (2H, t, J = 8.1 Hz), 3.03-3.11 (1H, m), 3.15 (3H, s), 3.38-3.52 (2H, m), 3.67 (2H, dd, J = 17.8, 8.7 Hz), 3.96-4.09 (1H, m), 7.28-7.52 (4H, m), 9.05 (1H, brs), 9.80 (1H, brs).
LC / MS 226.1

実施例７１
(2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(エトキシメチル)ピロリジン　1塩酸塩 Example 71
(2R * , 3R * )-3- (3,4-Dichlorophenyl) -2- (ethoxymethyl) pyrrolidine monohydrochloride

Figure JPOXMLDOC01-appb-C000266
Figure JPOXMLDOC01-appb-C000266

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(エトキシメチル)ピロリジン-1-カルボキシラート(0.50 g, 1.3 mmol)をメタノール(10 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(20 mL)を加えた。反応混合物を1時間加熱還流し、減圧下濃縮した。得られた固体を酢酸エチル／ヘキサンで再結晶することにより、表題化合物を白色結晶(0.36 g, 87%)として得た。
NMR (DMSO-d6) δ: 1.04 (3H, t, J = 7.0 Hz), 2.21-2.34 (2H, m), 3.09-3.32 (5H, m), 3.42-3.52 (1H, m), 3.67 (1H, q, J = 8.8 Hz), 3.95-4.05 (1H, m), 7.37 (1H, dd, J = 8.3, 2.3 Hz), 7.62 (1H, d, J = 8.3 Hz), 7.65 (1H, d, J = 2.3 Hz), 9.55 (2H, brs).
LC/MS 274.3
mp 135-136℃
Anal. Calcd. for C13H18NOCl2・HCl: C, 50.26; H, 5.84; N, 4.51. Found: C, 49.98; H, 5.84; N, 4.36. tert-butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (ethoxymethyl) pyrrolidine-1-carboxylate (0.50 g, 1.3 mmol) was dissolved in methanol (10 mL), A 4N hydrochloric acid-ethyl acetate solution (20 mL) was added. The reaction mixture was heated to reflux for 1 hour and concentrated under reduced pressure. The obtained solid was recrystallized from ethyl acetate / hexane to give the title compound as white crystals (0.36 g, 87%).
NMR (DMSO-d 6 ) δ: 1.04 (3H, t, J = 7.0 Hz), 2.21-2.34 (2H, m), 3.09-3.32 (5H, m), 3.42-3.52 (1H, m), 3.67 ( 1H, q, J = 8.8 Hz), 3.95-4.05 (1H, m), 7.37 (1H, dd, J = 8.3, 2.3 Hz), 7.62 (1H, d, J = 8.3 Hz), 7.65 (1H, d , J = 2.3 Hz), 9.55 (2H, brs).
LC / MS 274.3
mp 135-136 ℃
Anal.Calcd.for C 13 H 18 NOCl 2・ HCl: C, 50.26; H, 5.84; N, 4.51. Found: C, 49.98; H, 5.84; N, 4.36.

実施例７２
2,3-cis-3-(3,4-ジクロロフェニル)-2-(1-メトキシ-1-メチルエチル)ピロリジン　1塩酸塩 Example 72
2,3-cis-3- (3,4-dichlorophenyl) -2- (1-methoxy-1-methylethyl) pyrrolidine monohydrochloride

Figure JPOXMLDOC01-appb-C000267
Figure JPOXMLDOC01-appb-C000267

　参考例６２で得たtert-ブチル 2,3-cis-3-(3,4-ジクロロフェニル)-2-(1-メトキシ-1-メチルエチル)ピロリジン-1-カルボキシラート(0.085 g, 0.22 mmol)をメタノール(3 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(6 mL)を加えた。反応混合物を室温で1時間攪拌し、減圧下濃縮した。得られた固体をエタノール／ジエチルエーテルより再結晶して、表題化合物を白色結晶(0.061 g, 86%)として得た。
NMR (DMSO-d6) δ: 0.90 (3H, s), 1.07 (3H, s), 2.00-2.14 (1H, m), 2.30-2.44 (1H, m), 2.91 (3H, s), 3.22-3.30 (1H, m), 3.47-3.58 (1H, m), 3.64-3.74 (1H, m), 3.80 (1H, d, J = 7.3 Hz), 7.34 (1H, dd, J = 8.5, 2.1 Hz), 7.55 (1H, d, J = 8.5 Hz), 7.64 (1H, d, J = 2.1 Hz), 8.51 (1H, brs), 10.16 (1H, brs).
LC/MS 288.2
Anal. Calcd. for C14H19NOCl2・HCl: C, 51.79; H, 6.21; N, 4.31. Found: C, 51.66; H, 6.15; N, 4.25. Tert-butyl 2,3-cis-3- (3,4-dichlorophenyl) -2- (1-methoxy-1-methylethyl) pyrrolidine-1-carboxylate obtained in Reference Example 62 (0.085 g, 0.22 mmol) Was dissolved in methanol (3 mL), and 4 N hydrochloric acid-ethyl acetate solution (6 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The obtained solid was recrystallized from ethanol / diethyl ether to give the title compound as white crystals (0.061 g, 86%).
NMR (DMSO-d 6 ) δ: 0.90 (3H, s), 1.07 (3H, s), 2.00-2.14 (1H, m), 2.30-2.44 (1H, m), 2.91 (3H, s), 3.22- 3.30 (1H, m), 3.47-3.58 (1H, m), 3.64-3.74 (1H, m), 3.80 (1H, d, J = 7.3 Hz), 7.34 (1H, dd, J = 8.5, 2.1 Hz) , 7.55 (1H, d, J = 8.5 Hz), 7.64 (1H, d, J = 2.1 Hz), 8.51 (1H, brs), 10.16 (1H, brs).
LC / MS 288.2
Anal.Calcd.for C 14 H 19 NOCl 2・ HCl: C, 51.79; H, 6.21; N, 4.31.Found: C, 51.66; H, 6.15; N, 4.25.

実施例７３
エチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-2-カルボキシラート　1塩酸塩 Example 73
Ethyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-2-carboxylate monohydrochloride

Figure JPOXMLDOC01-appb-C000268
Figure JPOXMLDOC01-appb-C000268

　エチル (2S*,3R*)-1-アセチル-3-(3,4-ジクロロフェニル)-2-(ヒドロキシメチル)ピロリジン-2-カルボキシラート(0.16 g)のエタノール(2.5 mL)溶液に11.4 N塩酸－エタノール溶液(5.0 mL)を加え、室温で1時間、次いで60℃で1時間攪拌した。溶媒を減圧留去し、得られた残留物を酢酸エチル／ジイソプロピルエーテルより再結晶して、表題化合物を白色粉末(0.11 g, 68%)として得た。
LC/MS 318.0
NMR (DMSO-d6) δ: 0.80 (3H, t, J = 7.2 Hz), 2.18-2.47 (2H, m), 3.34-3.43 (1H, m), 3.52-3.62 (2H, m), 3.69-4.01 (4H, m), 5.98 (1H, t, J = 5.1 Hz), 7.27 (1H, dd, J = 8.3, 2.3 Hz), 7.58 (1H, d, J = 1.9 Hz), 7.63 (1H, d, J = 8.3 Hz), 9.70 (2H, brs).
mp 171-172℃ 11.4 N hydrochloric acid in ethanol (2.5 mL) solution of ethyl (2S * , 3R * )-1-acetyl-3- (3,4-dichlorophenyl) -2- (hydroxymethyl) pyrrolidine-2-carboxylate (0.16 g) -An ethanol solution (5.0 mL) was added, and the mixture was stirred at room temperature for 1 hour and then at 60 ° C for 1 hour. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate / diisopropyl ether to give the title compound as a white powder (0.11 g, 68%).
LC / MS 318.0
NMR (DMSO-d 6 ) δ: 0.80 (3H, t, J = 7.2 Hz), 2.18-2.47 (2H, m), 3.34-3.43 (1H, m), 3.52-3.62 (2H, m), 3.69- 4.01 (4H, m), 5.98 (1H, t, J = 5.1 Hz), 7.27 (1H, dd, J = 8.3, 2.3 Hz), 7.58 (1H, d, J = 1.9 Hz), 7.63 (1H, d , J = 8.3 Hz), 9.70 (2H, brs).
mp 171-172 ° C

実施例７４
エチル (2S*,3R*)-3-(3-クロロ-4-フルオロフェニル)-2-(ヒドロキシメチル)ピロリジン-2-カルボキシラート　1塩酸塩 Example 74
Ethyl (2S * , 3R * )-3- (3-chloro-4-fluorophenyl) -2- (hydroxymethyl) pyrrolidine-2-carboxylate monohydrochloride

Figure JPOXMLDOC01-appb-C000269
Figure JPOXMLDOC01-appb-C000269

　エチル (2S*,3R*)-1-アセチル-3-(3-クロロ-4-フルオロフェニル)-2-(ヒドロキシメチル)ピロリジン-2-カルボキシラート(0.77 g)のエタノール(2.0 mL)溶液に11.4 N塩酸－エタノール溶液(2.0 mL)を加え、60℃で2時間攪拌した。溶媒を減圧留去し、得られた残留物を酢酸エチル／ジイソプロピルエーテルより再結晶して、表題化合物を白色結晶(0.52 g, 70%)として得た。
LC/MS 302.1
NMR (DMSO-d6) δ: 0.81 (3H, t, J = 7.2 Hz), 2.17-2.32 (1H, m), 2.36-2.47 (1H, m), 3.34-3.43 (1H, m), 3.51-3.63 (2H, m), 3.68-4.00 (4H, m), 5.97 (1H, t, J = 5.1 Hz), 7.25-7.33 (1H, m), 7.42 (1H, t, J = 8.9 Hz), 7.53 (1H, dd, J = 7.0, 2.1 Hz), 9.71 (2H, brs).
mp 178-180℃ To a solution of ethyl (2S * , 3R * )-1-acetyl-3- (3-chloro-4-fluorophenyl) -2- (hydroxymethyl) pyrrolidine-2-carboxylate (0.77 g) in ethanol (2.0 mL) 11.4 N hydrochloric acid-ethanol solution (2.0 mL) was added, and the mixture was stirred at 60 ° C. for 2 hr. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate / diisopropyl ether to give the title compound as white crystals (0.52 g, 70%).
LC / MS 302.1
NMR (DMSO-d 6 ) δ: 0.81 (3H, t, J = 7.2 Hz), 2.17-2.32 (1H, m), 2.36-2.47 (1H, m), 3.34-3.43 (1H, m), 3.51- 3.63 (2H, m), 3.68-4.00 (4H, m), 5.97 (1H, t, J = 5.1 Hz), 7.25-7.33 (1H, m), 7.42 (1H, t, J = 8.9 Hz), 7.53 (1H, dd, J = 7.0, 2.1 Hz), 9.71 (2H, brs).
mp 178-180 ℃

実施例７５
エチル (2S*,3R*)-3-(4-クロロフェニル)-2-(ヒドロキシメチル)ピロリジン-2-カルボキシラート　1塩酸塩 Example 75
Ethyl (2S * , 3R * )-3- (4-chlorophenyl) -2- (hydroxymethyl) pyrrolidine-2-carboxylate monohydrochloride

Figure JPOXMLDOC01-appb-C000270
Figure JPOXMLDOC01-appb-C000270

　エチル (2S*,3R*)-1-アセチル-3-(4-クロロフェニル)-2-(ヒドロキシメチル)ピロリジン-2-カルボキシラート(0.23 g)のエタノール(2.5 mL)溶液に11.4 N塩酸－エタノール溶液(5.0 mL)を加え、60℃で1.5時間攪拌した。溶媒を減圧留去し、得られた残留物をエタノール／酢酸エチルより再結晶して、表題化合物を白色粉末(0.15 g, 65%)として得た。
LC/MS 284.2
NMR (DMSO-d6) δ: 0.78 (3H, t, J = 7.2 Hz), 2.15-2.31 (1H, m), 2.35-2.47 (1H, m), 3.34-3.45 (1H, m), 3.51-3.62 (2H, m), 3.64-3.76 (1H, m), 3.78-4.02 (3H, m), 5.94 (1H, t, J = 5.1 Hz), 7.20-7.31 (2H, m), 7.37-7.49 (2H, m), 9.68 (2H, brs).
mp 210-211℃ Add 11.4 N hydrochloric acid-ethanol to a solution of ethyl (2S * , 3R * )-1-acetyl-3- (4-chlorophenyl) -2- (hydroxymethyl) pyrrolidine-2-carboxylate (0.23 g) in ethanol (2.5 mL). The solution (5.0 mL) was added and stirred at 60 ° C. for 1.5 hours. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethanol / ethyl acetate to obtain the title compound as a white powder (0.15 g, 65%).
LC / MS 284.2
NMR (DMSO-d 6 ) δ: 0.78 (3H, t, J = 7.2 Hz), 2.15-2.31 (1H, m), 2.35-2.47 (1H, m), 3.34-3.45 (1H, m), 3.51- 3.62 (2H, m), 3.64-3.76 (1H, m), 3.78-4.02 (3H, m), 5.94 (1H, t, J = 5.1 Hz), 7.20-7.31 (2H, m), 7.37-7.49 ( 2H, m), 9.68 (2H, brs).
mp 210-211 ℃

実施例７６
[3-(3,4-ジクロロフェニル)-1-エチルピロリジン-2,2-ジイル]ジメタノール　1塩酸塩 Example 76
[3- (3,4-Dichlorophenyl) -1-ethylpyrrolidine-2,2-diyl] dimethanol monohydrochloride

Figure JPOXMLDOC01-appb-C000271
Figure JPOXMLDOC01-appb-C000271

　水素化リチウムアルミニウム(0.25 g)のTHF(20 mL)懸濁液にジエチル 1-アセチル-3-(3,4-ジクロロフェニル)ピロリジン-2,2-ジカルボキシラート(1.2 g)のTHF(10 mL)溶液を加え、室温にて30分間攪拌した。反応混合物に水(3.0 mL)を加え、セライトろ過した。濾液を減圧下濃縮し、得られた残留物を塩基性シリカゲルカラムクロマトグラフィー(ヘキサンのみ～酢酸エチル/ヘキサン＝1/1)で精製し、[3-(3,4-ジクロロフェニル)-1-エチルピロリジン-2,2-ジイル]ジメタノールを淡黄色油状物(0.38 g, 42%)として得た。
LC/MS 304.1
NMR (DMSO-d6) δ: 1.04 (3H, t, J = 7.2 Hz), 2.00-2.14 (2H, m), 2.61-2.88 (4H, m), 2.96-3.14 (2H, m), 3.22-3.42 (3H, m), 3.95-4.09 (1H, m), 4.41 (1H, t, J = 4.1 Hz), 7.32 (1H, dd, J = 8.4, 2.0 Hz), 7.52 (1H, d, J = 8.3 Hz), 7.57 (1H, d, J = 1.9 Hz). To a suspension of lithium aluminum hydride (0.25 g) in THF (20 mL), diethyl 1-acetyl-3- (3,4-dichlorophenyl) pyrrolidine-2,2-dicarboxylate (1.2 g) in THF (10 mL) ) Solution was added and stirred at room temperature for 30 minutes. Water (3.0 mL) was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (hexane only to ethyl acetate / hexane = 1/1) to obtain [3- (3,4-dichlorophenyl) -1-ethyl. Pyrrolidine-2,2-diyl] dimethanol was obtained as a pale yellow oil (0.38 g, 42%).
LC / MS 304.1
NMR (DMSO-d 6 ) δ: 1.04 (3H, t, J = 7.2 Hz), 2.00-2.14 (2H, m), 2.61-2.88 (4H, m), 2.96-3.14 (2H, m), 3.22- 3.42 (3H, m), 3.95-4.09 (1H, m), 4.41 (1H, t, J = 4.1 Hz), 7.32 (1H, dd, J = 8.4, 2.0 Hz), 7.52 (1H, d, J = 8.3 Hz), 7.57 (1H, d, J = 1.9 Hz).

　[3-(3,4-ジクロロフェニル)-1-エチルピロリジン-2,2-ジイル]ジメタノール(0.38 g)の酢酸エチル(4.0 mL)溶液に4 N塩酸－酢酸エチル溶液(3.0 mL)を加え、室温で5分間攪拌した。溶媒を減圧留去し、得られた残留物をエタノール／酢酸エチルより再結晶して、表題化合物を淡茶色粉末(0.34 g, 80%)として得た。
LC/MS 304.1
NMR (DMSO-d6) δ: 1.27-1.44 (3H, m), 2.07-2.65 (2H, m), 2.76-4.06 (9H, m), 5.30-5.69 (1H, m), 5.78-6.09 (1H, m), 7.29-7.88 (3H, m), 9.28-9.98 (1H, m).
mp 208-209℃ To a solution of [3- (3,4-dichlorophenyl) -1-ethylpyrrolidine-2,2-diyl] dimethanol (0.38 g) in ethyl acetate (4.0 mL) was added 4 N hydrochloric acid-ethyl acetate solution (3.0 mL). And stirred for 5 minutes at room temperature. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethanol / ethyl acetate to obtain the title compound as a light brown powder (0.34 g, 80%).
LC / MS 304.1
NMR (DMSO-d 6 ) δ: 1.27-1.44 (3H, m), 2.07-2.65 (2H, m), 2.76-4.06 (9H, m), 5.30-5.69 (1H, m), 5.78-6.09 (1H , m), 7.29-7.88 (3H, m), 9.28-9.98 (1H, m).
mp 208-209 ℃

実施例７７
1-[(2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-2-イル]エタノン　1塩酸塩 Example 77
1-[(2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidin-2-yl] ethanone monohydrochloride

Figure JPOXMLDOC01-appb-C000272
Figure JPOXMLDOC01-appb-C000272

　tert-ブチル (2S*,3R*)-2-アセチル-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-1-カルボキシラート(0.20 g)の酢酸エチル(4.0 mL)溶液に4 N塩酸－酢酸エチル溶液(4.0 mL)を加え、室温で1時間攪拌した。溶媒を減圧留去し、得られた残留物をエタノール／酢酸エチルより再結晶して、表題化合物を白色粉末(0.14 g, 85%)として得た。
LC/MS 302.2
NMR (DMSO-d6) δ: 1.61 (3H, s), 2.03-2.20 (1H, m), 2.33-2.48 (1H, m), 3.35 (3H, s), 3.37-3.43 (1H, m), 3.46-3.57 (1H, m), 3.65 (1H, dd, J = 9.3, 8.0 Hz), 3.95 (1H, d, J = 11.1 Hz), 4.18 (1H, d, J = 11.1 Hz), 7.29 (1H, dd, J = 8.4, 2.2 Hz), 7.63 (1H, d, J = 2.1 Hz), 7.66 (1H, d, J = 8.5 Hz), 9.47 (2H, brs).
mp 237-238℃ tert- butyl (2S *, 3R *) -2-acetyl-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine-1-ethyl acetate (4.0 mL) carboxylate (0.20 g) solution 4N Hydrochloric acid-ethyl acetate solution (4.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethanol / ethyl acetate to give the title compound as a white powder (0.14 g, 85%).
LC / MS 302.2
NMR (DMSO-d 6 ) δ: 1.61 (3H, s), 2.03-2.20 (1H, m), 2.33-2.48 (1H, m), 3.35 (3H, s), 3.37-3.43 (1H, m), 3.46-3.57 (1H, m), 3.65 (1H, dd, J = 9.3, 8.0 Hz), 3.95 (1H, d, J = 11.1 Hz), 4.18 (1H, d, J = 11.1 Hz), 7.29 (1H , dd, J = 8.4, 2.2 Hz), 7.63 (1H, d, J = 2.1 Hz), 7.66 (1H, d, J = 8.5 Hz), 9.47 (2H, brs).
mp 237-238 ℃

実施例７８
エチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-2-カルボキシラート　1塩酸塩 Example 78
Ethyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine-2-carboxylate monohydrochloride

Figure JPOXMLDOC01-appb-C000273
Figure JPOXMLDOC01-appb-C000273

　1-tert-ブチル 2-エチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-1,2-ジカルボキシラート(0.86 g)の酢酸エチル(5.0 mL)溶液に4 N塩酸－酢酸エチル溶液(5.0 mL)を加え、室温で終夜攪拌した。溶媒を減圧留去し、得られた残留物を酢酸エチル／ジイソプロピルエーテルより再結晶して、表題化合物を白色粉末(0.60 g, 82%)として得た。
LC/MS 332.3
NMR (DMSO-d6) δ: 0.84 (3H, t, J = 7.2 Hz), 2.19-2.47 (2H, m), 3.33 (3H, s), 3.38-3.49 (1H, m), 3.52-3.66 (2H, m), 3.70-4.00 (4H, m), 7.27 (1H, dd, J = 8.4, 2.2 Hz), 7.58 (1H, d, J = 2.3 Hz), 7.64 (1H, d, J = 8.3 Hz), 9.90 (2H, brs).
mp 172-173℃ 1-tert-butyl 2-ethyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidine-1,2-dicarboxylate (0.86 g) in ethyl acetate (5.0 4N Hydrochloric acid-ethyl acetate solution (5.0 mL) was added to the solution, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate / diisopropyl ether to give the title compound as a white powder (0.60 g, 82%).
LC / MS 332.3
NMR (DMSO-d 6 ) δ: 0.84 (3H, t, J = 7.2 Hz), 2.19-2.47 (2H, m), 3.33 (3H, s), 3.38-3.49 (1H, m), 3.52-3.66 ( 2H, m), 3.70-4.00 (4H, m), 7.27 (1H, dd, J = 8.4, 2.2 Hz), 7.58 (1H, d, J = 2.3 Hz), 7.64 (1H, d, J = 8.3 Hz) ), 9.90 (2H, brs).
mp 172-173 ° C

実施例７９
2-[(2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-2-イル]プロパン-2-オール　1塩酸塩 Example 79
2-[(2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidin-2-yl] propan-2-ol monohydrochloride

Figure JPOXMLDOC01-appb-C000274
Figure JPOXMLDOC01-appb-C000274

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-ヒドロキシプロパン-2-イル)-2-(メトキシメチル)ピロリジン-1-カルボキシラート(28 mg)の酢酸エチル(1.0 mL)溶液に4 N塩酸－酢酸エチル溶液(1.0 mL)を加え、室温で終夜攪拌した。溶媒を減圧留去し、得られた残留物を酢酸エチル／ジイソプロピルエーテルより再結晶して、表題化合物を白色粉末(13 mg, 54%)として得た。
LC/MS 318.2
NMR (DMSO-d6) δ: 0.71 (3H, s), 1.01 (3H, s), 2.06-2.24 (1H, m), 2.34-2.47 (1H, m), 3.05 (1H, brs), 3.39-3.51 (4H, m), 3.59-3.84 (3H, m), 5.36 (1H, s), 7.41 (1H, dd, J = 8.3, 1.9 Hz), 7.58 (1H, d, J = 8.3 Hz), 7.67 (1H, d, J = 1.9 Hz), 8.41 (1H, brs), 9.20 (1H, brs).
mp 229-231℃ tert-Butyl (2S * , 3R * )-3- (3,4-Dichlorophenyl) -2- (2-hydroxypropan-2-yl) -2- (methoxymethyl) pyrrolidine-1-carboxylate (28 mg) 4N Hydrochloric acid-ethyl acetate solution (1.0 mL) was added to an ethyl acetate (1.0 mL) solution, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate / diisopropyl ether to give the title compound as a white powder (13 mg, 54%).
LC / MS 318.2
NMR (DMSO-d 6) δ : 0.71 (3H, s), 1.01 (3H, s), 2.06-2.24 (1H, m), 2.34-2.47 (1H, m), 3.05 (1H, brs), 3.39- 3.51 (4H, m), 3.59-3.84 (3H, m), 5.36 (1H, s), 7.41 (1H, dd, J = 8.3, 1.9 Hz), 7.58 (1H, d, J = 8.3 Hz), 7.67 (1H, d, J = 1.9 Hz), 8.41 (1H, brs), 9.20 (1H, brs).
mp 229-231 ℃

実施例８０
[(2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-2-イル]メタノール　1塩酸塩 Example 80
[(2R *, 3R *) -3- (3,4- dichlorophenyl) -2- (methoxymethyl) pyrrolidin-2-yl] methanol monohydrochloride

Figure JPOXMLDOC01-appb-C000275
Figure JPOXMLDOC01-appb-C000275

80a) [(2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-2-イル]メタノール
　エチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-2-カルボキシラート　1塩酸塩(290 mg)のTHF(5.0 mL)懸濁液に水素化リチウムアルミニウム(60 mg)を加え、室温にて30分間攪拌した。反応混合物に水(0.5 mL)、1 N水酸化ナトリウム水溶液(0.5 mL)および水(0.5 mL)を順次加え、セライトろ過した。濾液を減圧下濃縮し、得られた残留物を塩基性シリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン＝1/1～酢酸エチルのみ)で精製し、表題化合物を無色非定形固体（0.13 g, 57%）として得た。
LC/MS 290.0
NMR (DMSO-d6) δ: 1.97-2.15 (2H, m), 2.77-3.27 (8H, m), 3.30 (3H, s), 4.18 (1H, brs), 7.24 (1H, dd, J = 8.3, 2.3 Hz), 7.47 (1H, d, J = 1.9 Hz), 7.50 (1H, d, J = 8.3 Hz). 80a) [(2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidin-2-yl] methanol ethyl (2S * , 3R * )-3- (3,4- Lithium aluminum hydride (60 mg) was added to a suspension of dichlorophenyl) -2- (methoxymethyl) pyrrolidine-2-carboxylate monohydrochloride (290 mg) in THF (5.0 mL), and the mixture was stirred at room temperature for 30 minutes. . Water (0.5 mL), 1N aqueous sodium hydroxide solution (0.5 mL) and water (0.5 mL) were sequentially added to the reaction mixture, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (ethyl acetate / hexane = 1/1 to ethyl acetate only) to give the title compound as a colorless amorphous solid (0.13 g, 57% ).
LC / MS 290.0
NMR (DMSO-d 6 ) δ: 1.97-2.15 (2H, m), 2.77-3.27 (8H, m), 3.30 (3H, s), 4.18 (1H, brs), 7.24 (1H, dd, J = 8.3 , 2.3 Hz), 7.47 (1H, d, J = 1.9 Hz), 7.50 (1H, d, J = 8.3 Hz).

80b) [(2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-2-イル]メタノール　1塩酸塩
　[(2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(メトキシメチル)ピロリジン-2-イル]メタノール(0.13 g)の酢酸エチル(2.0 mL)溶液に4 N塩酸－酢酸エチル溶液(2.0 mL)を加え、室温で30分間攪拌した。溶媒を減圧留去し、得られた残留物を酢酸エチルより再結晶して、表題化合物を白色粉末(0.13 g, 92%)として得た。
LC/MS 290.2
NMR (DMSO-d6) δ: 2.19-2.31 (1H, m), 2.40-2.48 (1H, m), 3.10-3.50 (7H, m), 3.51-3.56 (3H, m), 5.45 (1H, brs), 7.34 (1H, dd, J = 8.3, 2.3 Hz), 7.58-7.67 (2H, m), 9.20 (2H, brs).
mp 193-194℃ 80b) [(2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (methoxymethyl) pyrrolidin-2-yl] methanol monohydrochloride [(2R * , 3R * )-3- (3 , 4-Dichlorophenyl) -2- (methoxymethyl) pyrrolidin-2-yl] methanol (0.13 g) in ethyl acetate (2.0 mL) was added 4 N hydrochloric acid-ethyl acetate solution (2.0 mL) for 30 minutes at room temperature. Stir. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethyl acetate to obtain the title compound as a white powder (0.13 g, 92%).
LC / MS 290.2
NMR (DMSO-d 6 ) δ: 2.19-2.31 (1H, m), 2.40-2.48 (1H, m), 3.10-3.50 (7H, m), 3.51-3.56 (3H, m), 5.45 (1H, brs ), 7.34 (1H, dd, J = 8.3, 2.3 Hz), 7.58-7.67 (2H, m), 9.20 (2H, brs).
mp 193-194 ℃

実施例８１
エチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-メチルピロリジン-2-カルボキシラート　1塩酸塩 Example 81
Ethyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2-methylpyrrolidine-2-carboxylate monohydrochloride

Figure JPOXMLDOC01-appb-C000276
Figure JPOXMLDOC01-appb-C000276

　1-tert-ブチル 2-エチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-メチルピロリジン-1,2-ジカルボキシラート(0.16 g)の酢酸エチル(4.0 mL)溶液に4 N塩酸－酢酸エチル溶液(4.0 mL)を加え、室温で終夜攪拌した。溶媒を減圧留去し、得られた残留物を減圧下乾燥して、表題化合物を淡黄色非定形固体(0.14 g, 100%)として得た。
LC/MS 302.0
NMR (DMSO-d6) δ: 0.90 (3H, t, J = 7.1 Hz), 1.65 (3H, s), 2.25-2.48 (2H, m), 3.37-3.68 (3H, m), 3.72-4.02 (2H, m), 7.25-7.30 (1H, m), 7.52-7.58 (1H, m), 7.58-7.67 (1H, m), 9.94 (2H, brs). 1-tert-butyl 2-ethyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2-methylpyrrolidine-1,2-dicarboxylate (0.16 g) in ethyl acetate (4.0 mL) 4N Hydrochloric acid-ethyl acetate solution (4.0 mL) was added to the mixture, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the resulting residue was dried under reduced pressure to give the title compound as a pale yellow amorphous solid (0.14 g, 100%).
LC / MS 302.0
NMR (DMSO-d 6 ) δ: 0.90 (3H, t, J = 7.1 Hz), 1.65 (3H, s), 2.25-2.48 (2H, m), 3.37-3.68 (3H, m), 3.72-4.02 ( 2H, m), 7.25-7.30 (1H, m), 7.52-7.58 (1H, m), 7.58-7.67 (1H, m), 9.94 (2H, brs).

実施例８２
2-[(2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]-5-メチル-1,3,4-オキサジアゾール　1トリフルオロ酢酸塩 Example 82
2-[(2S * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidin-2-yl] -5-methyl-1,3,4-oxadiazole 1 trifluoroacetate

Figure JPOXMLDOC01-appb-C000277
Figure JPOXMLDOC01-appb-C000277

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピロリジン-1-カルボキシラート(90 mg, 0.23 mmol)のトルエン(1 mL)溶液にトリフルオロ酢酸(1 mL)を加え、室温で1時間攪拌した。減圧下溶媒を留去し、飽和炭酸水素ナトリウム水溶液で中和した後、飽和になるまで塩化ナトリウムを加えた。反応混合物を酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をHPLCで精製することにより、表題化合物を白色固体(84 mg, 90%)として得た。
NMR (DMSO-d6) δ 2.13-2.30 (1H, m), 2.50 (3H, s), 2.52-2.61 (1H, m), 3.40-3.50 (1H, m), 3.57-3.66 (1H, m), 3.84-3.97 (1H, m), 5.16 (1H, d, J = 10.6 Hz), 7.44 (1H, dd, J = 8.3, 1.9 Hz), 7.64 (1H, d, J = 8.3 Hz), 7.79 (1H, d, J = 1.9 Hz), 10.18 (2H, brs).
LC/MS 298.1 tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (5-methyl-1,3,4-oxadiazol-2-yl) pyrrolidine-1-carboxylate (90 To a toluene (1 mL) solution of mg, 0.23 mmol) was added trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure and neutralizing with a saturated aqueous sodium hydrogen carbonate solution, sodium chloride was added until saturation. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by HPLC to give the title compound as a white solid (84 mg, 90%).
NMR (DMSO-d 6 ) δ 2.13-2.30 (1H, m), 2.50 (3H, s), 2.52-2.61 (1H, m), 3.40-3.50 (1H, m), 3.57-3.66 (1H, m) , 3.84-3.97 (1H, m), 5.16 (1H, d, J = 10.6 Hz), 7.44 (1H, dd, J = 8.3, 1.9 Hz), 7.64 (1H, d, J = 8.3 Hz), 7.79 ( 1H, d, J = 1.9 Hz), 10.18 (2H, brs).
LC / MS 298.1

実施例８３
2-[(2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]-5-メチル-1,3,4-オキサジアゾール　1トリフルオロ酢酸塩 Example 83
2-[(2R * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidin-2-yl] -5-methyl-1,3,4-oxadiazole 1 trifluoroacetate

Figure JPOXMLDOC01-appb-C000278
Figure JPOXMLDOC01-appb-C000278

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピロリジン-1-カルボキシラート(0.36 g, 0.90 mmol)のトルエン(3 mL)溶液にトリフルオロ酢酸(3 mL)を加え、室温で1時間攪拌した。減圧下溶媒を留去し、飽和炭酸水素ナトリウム水溶液で中和した後、飽和になるまで塩化ナトリウムを加えた。反応混合物を酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をHPLCで精製することにより、表題化合物を無色油状物(0.26 g, 70%)として得た。
NMR (DMSO-d6) δ 2.37 (3H, s), 2.46-2.56 (2H, m), 3.45-3.56 (1H, m), 3.67-3.77 (1H, m), 4.01 (1H, dd, J = 17.8, 9.1 Hz), 5.59 (1H, d, J = 8.3 Hz), 7.16 (1H, dd, J = 8.3, 1.9 Hz), 7.50 (1H, d, J = 1.9 Hz), 7.53 (1H, d, J = 8.3 Hz), 10.27 (2H, brs).
LC/MS 298.3 tert-butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (5-methyl-1,3,4-oxadiazol-2-yl) pyrrolidine-1-carboxylate (0.36 g, 0.90 mmol) in toluene (3 mL) was added trifluoroacetic acid (3 mL), and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure and neutralizing with a saturated aqueous sodium hydrogen carbonate solution, sodium chloride was added until saturation. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by HPLC to give the title compound as a colorless oil (0.26 g, 70%).
NMR (DMSO-d 6 ) δ 2.37 (3H, s), 2.46-2.56 (2H, m), 3.45-3.56 (1H, m), 3.67-3.77 (1H, m), 4.01 (1H, dd, J = 17.8, 9.1 Hz), 5.59 (1H, d, J = 8.3 Hz), 7.16 (1H, dd, J = 8.3, 1.9 Hz), 7.50 (1H, d, J = 1.9 Hz), 7.53 (1H, d, J = 8.3 Hz), 10.27 (2H, brs).
LC / MS 298.3

実施例８４
5-[(2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]-3-メチル-1,2,4-オキサジアゾール　1塩酸塩 Example 84
5 - [(2S *, 3R *) -3- (3,4- dichlorophenyl) pyrrolidin-2-yl] -3-methyl-1,2,4-oxadiazole monohydrochloride

Figure JPOXMLDOC01-appb-C000279
Figure JPOXMLDOC01-appb-C000279

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピロリジン-1-カルボキシラート(0.17 g, 0.43 mmol)をメタノール(3 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(6 mL)を加えた。反応混合物を室温で1時間攪拌し、減圧下濃縮した。得られた結晶を酢酸エチル／ジエチルエーテルで洗浄することにより、表題化合物を白色結晶(0.13 g, 91%)として得た。
NMR (DMSO-d6) δ 2.12-2.27 (1H, m), 2.37 (3H, s), 2.53-2.62 (1H, m), 3.38-3.50 (1H, m), 3.54-3.66 (1H, m), 3.76-3.90 (1H, m), 5.24 (1H, d, J = 10.2 Hz), 7.48 (1H, dd, J = 8.3, 1.9 Hz), 7.65 (1H, d, J = 8.3 Hz), 7.83 (1H, d, J = 1.9 Hz), 10.55 (2H, brs).
LC/MS 298.3
mp 234-235℃
Anal. Calcd. for C13H13N3OCl2・HCl: C, 46.66; H, 4.22; N, 12.56. Found: C, 46.70; H, 4.22; N, 12.57. tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (3-methyl-1,2,4-oxadiazol-5-yl) pyrrolidine-1-carboxylate (0.17 g, 0.43 mmol) was dissolved in methanol (3 mL), and 4 N hydrochloric acid-ethyl acetate solution (6 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate / diethyl ether to give the title compound as white crystals (0.13 g, 91%).
NMR (DMSO-d 6 ) δ 2.12-2.27 (1H, m), 2.37 (3H, s), 2.53-2.62 (1H, m), 3.38-3.50 (1H, m), 3.54-3.66 (1H, m) , 3.76-3.90 (1H, m), 5.24 (1H, d, J = 10.2 Hz), 7.48 (1H, dd, J = 8.3, 1.9 Hz), 7.65 (1H, d, J = 8.3 Hz), 7.83 ( 1H, d, J = 1.9 Hz), 10.55 (2H, brs).
LC / MS 298.3
mp 234-235 ℃
Anal.Calcd.for C 13 H 13 N 3 OCl 2 HCl: C, 46.66; H, 4.22; N, 12.56. Found: C, 46.70; H, 4.22; N, 12.57.

実施例８５
5-[(2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]-3-メチル-1,2,4-オキサジアゾール　1塩酸塩 Example 85
5-[(2R * , 3R * )-3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] -3-methyl-1,2,4-oxadiazole monohydrochloride

Figure JPOXMLDOC01-appb-C000280
Figure JPOXMLDOC01-appb-C000280

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピロリジン-1-カルボキシラート(0.51 g, 1.3 mmol)をメタノール(5 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(10 mL)を加えた。反応混合物を室温で1時間攪拌し、減圧下濃縮した。得られた結晶をエタノール／ジエチルエーテルより再結晶して、表題化合物を白色結晶(0.25 g, 58%)として得た。
NMR (DMSO-d6) δ 2.29 (3H, s), 2.36-2.56 (2H, m), 3.44-3.55 (1H, m), 3.66-3.76 (1H, m), 4.00-4.10 (1H, m), 5.62 (1H, d, J = 8.3 Hz), 7.16 (1H, dd, J = 8.3, 1.9 Hz), 7.49-7.54 (2H, m), 10.67 (2H, brs).
LC/MS 298.1
mp 275-276℃
Anal. Calcd. for C13H13N3OCl2・HCl: C, 46.66; H, 4.22; N, 12.56. Found: C, 46.54; H, 4.24; N, 12.36. tert-butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (3-methyl-1,2,4-oxadiazol-5-yl) pyrrolidine-1-carboxylate (0.51 g, 1.3 mmol) was dissolved in methanol (5 mL), and 4 N hydrochloric acid-ethyl acetate solution (10 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The obtained crystals were recrystallized from ethanol / diethyl ether to give the title compound as white crystals (0.25 g, 58%).
NMR (DMSO-d 6 ) δ 2.29 (3H, s), 2.36-2.56 (2H, m), 3.44-3.55 (1H, m), 3.66-3.76 (1H, m), 4.00-4.10 (1H, m) , 5.62 (1H, d, J = 8.3 Hz), 7.16 (1H, dd, J = 8.3, 1.9 Hz), 7.49-7.54 (2H, m), 10.67 (2H, brs).
LC / MS 298.1
mp 275-276 ℃
Anal.Calcd.for C 13 H 13 N 3 OCl 2 HCl: C, 46.66; H, 4.22; N, 12.56. Found: C, 46.54; H, 4.24; N, 12.36.

実施例８６
5-[(2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]-3-フェニル-1,2,4-オキサジアゾール　1塩酸塩 Example 86
5-[(2S * , 3R * )-3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] -3-phenyl-1,2,4-oxadiazole monohydrochloride

Figure JPOXMLDOC01-appb-C000281
Figure JPOXMLDOC01-appb-C000281

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(3-フェニル-1,2,4-オキサジアゾール-5-イル)ピロリジン-1-カルボキシラート(0.33 g, 0.72 mmol)をメタノール(5 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(10 mL)を加えた。反応混合物を室温で1時間攪拌し、減圧下濃縮した。得られた結晶をエタノールより再結晶して、表題化合物を白色結晶(0.22 g, 77%)として得た。
NMR (DMSO-d6) δ: 2.18-2.34 (1H, m), 2.54-2.65 (1H, m), 3.45-3.56 (1H, m), 3.60-3.70 (1H, m), 3.92-4.04 (1H, m), 5.32 (1H, d, J = 10.2 Hz), 7.51-7.70 (5H, m), 7.90 (1H, d, J = 2.3 Hz), 8.01 (2H, dd, J = 7.8, 1.7 Hz), 10.72 (2H, brs).
LC/MS 360.1
mp 202-203℃
Anal. Calcd. for C18H15N3OCl2・HCl: C, 54.50; H, 4.07; N, 10.59. Found: C, 54.44; H, 4.07; N, 10.62. tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (3-phenyl-1,2,4-oxadiazol-5-yl) pyrrolidine-1-carboxylate (0.33 g, 0.72 mmol) was dissolved in methanol (5 mL), and 4N hydrochloric acid-ethyl acetate solution (10 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The obtained crystals were recrystallized from ethanol to give the title compound as white crystals (0.22 g, 77%).
NMR (DMSO-d 6 ) δ: 2.18-2.34 (1H, m), 2.54-2.65 (1H, m), 3.45-3.56 (1H, m), 3.60-3.70 (1H, m), 3.92-4.04 (1H , m), 5.32 (1H, d, J = 10.2 Hz), 7.51-7.70 (5H, m), 7.90 (1H, d, J = 2.3 Hz), 8.01 (2H, dd, J = 7.8, 1.7 Hz) , 10.72 (2H, brs).
LC / MS 360.1
mp 202-203 ℃
Anal.Calcd.for C 18 H 15 N 3 OCl 2 HCl: C, 54.50; H, 4.07; N, 10.59. Found: C, 54.44; H, 4.07; N, 10.62.

実施例８７
5-[(2R*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]-3-フェニル-1,2,4-オキサジアゾール　1塩酸塩 Example 87
5-[(2R * , 3R * )-3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] -3-phenyl-1,2,4-oxadiazole monohydrochloride

Figure JPOXMLDOC01-appb-C000282
Figure JPOXMLDOC01-appb-C000282

　tert-ブチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-(3-フェニル-1,2,4-オキサジアゾール-5-イル)ピロリジン-1-カルボキシラート(0.51 g, 1.1 mmol)をメタノール(5 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(10 mL)を加えた。反応混合物を室温で1時間攪拌し、減圧下濃縮した。得られた結晶をエタノールより再結晶して、表題化合物を白色結晶(0.32 g, 73%)として得た。
NMR (DMSO-d6) δ: 2.53-2.63 (2H, m), 3.48-3.61 (1H, m), 3.76-3.87 (1H, m), 4.06-4.16 (1H, m), 5.75 (1H, d, J = 8.3 Hz), 7.22 (1H, dd, J = 8.3, 1.9 Hz), 7.47-7.66 (5H, m), 7.92-7.98 (2H, m), 10.64 (2H, brs).
LC/MS 360.2
mp 206-207℃
Anal. Calcd. for C18H15N3OCl2・HCl: C, 54.50; H, 4.07; N, 10.59. Found: C, 54.48; H, 4.07; N, 10.59. tert-butyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2- (3-phenyl-1,2,4-oxadiazol-5-yl) pyrrolidine-1-carboxylate (0.51 g, 1.1 mmol) was dissolved in methanol (5 mL), and 4 N hydrochloric acid-ethyl acetate solution (10 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The obtained crystals were recrystallized from ethanol to give the title compound as white crystals (0.32 g, 73%).
NMR (DMSO-d 6 ) δ: 2.53-2.63 (2H, m), 3.48-3.61 (1H, m), 3.76-3.87 (1H, m), 4.06-4.16 (1H, m), 5.75 (1H, d , J = 8.3 Hz), 7.22 (1H, dd, J = 8.3, 1.9 Hz), 7.47-7.66 (5H, m), 7.92-7.98 (2H, m), 10.64 (2H, brs).
LC / MS 360.2
mp 206-207 ℃
Anal.Calcd.for C 18 H 15 N 3 OCl 2 HCl: C, 54.50; H, 4.07; N, 10.59. Found: C, 54.48; H, 4.07; N, 10.59.

実施例８８
(2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボヒドラジド　2塩酸塩 Example 88
(2S * , 3R * ) -3- (3,4-Dichlorophenyl) pyrrolidine-2-carbohydrazide dihydrochloride

Figure JPOXMLDOC01-appb-C000283
Figure JPOXMLDOC01-appb-C000283

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピロリジン-1-カルボキシラート(0.14 g, 0.35 mmol)をメタノール(3 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(6 mL)を加えた。反応混合物を室温で1時間攪拌し、減圧下濃縮した。得られた結晶をメタノール／酢酸エチルより再結晶して、表題化合物を白色結晶(0.10 g, 92%)として得た。
NMR (DMSO-d6) δ: 2.12 (1H, m), 2.36-2.47 (1H, m), 3.26-3.41 (1H, m), 3.43-3.59 (2H, m), 4.26 (1H, d, J = 8.9 Hz), 7.42 (1H, dd, J = 8.3, 2.1 Hz), 7.64 (1H, d, J = 8.3 Hz), 7.75 (1H, d, J = 2.1 Hz), 9.26 (1H, brs), 10.85 (1H, brs), 11.41 (1H, brs). (2H観測できず)
LC/MS 274.1 tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (5-methyl-1,3,4-oxadiazol-2-yl) pyrrolidine-1-carboxylate (0.14 g, 0.35 mmol) was dissolved in methanol (3 mL), and 4 N hydrochloric acid-ethyl acetate solution (6 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The obtained crystals were recrystallized from methanol / ethyl acetate to give the title compound as white crystals (0.10 g, 92%).
NMR (DMSO-d 6 ) δ: 2.12 (1H, m), 2.36-2.47 (1H, m), 3.26-3.41 (1H, m), 3.43-3.59 (2H, m), 4.26 (1H, d, J = 8.9 Hz), 7.42 (1H, dd, J = 8.3, 2.1 Hz), 7.64 (1H, d, J = 8.3 Hz), 7.75 (1H, d, J = 2.1 Hz), 9.26 (1H, brs), 10.85 (1H, brs), 11.41 (1H, brs). (Cannot observe 2H)
LC / MS 274.1

実施例８９
2-[(2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]-N,N-ジメチルアセトアミド　1塩酸塩 Example 89
2-[(2S * , 3R * )-3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] -N, N-dimethylacetamide monohydrochloride

Figure JPOXMLDOC01-appb-C000284
Figure JPOXMLDOC01-appb-C000284

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-[2-(ジメチルアミノ)-2-オキソエチル]ピロリジン-1-カルボキシラート(0.090 g, 0.22 mmol)を10%塩酸－メタノール(10 mL)に溶解させ、室温で2時間攪拌した。減圧下溶媒を留去することにより、表題化合物を淡黄色油状物(0.063 g, 93%)として得た。
NMR (DMSO-d6) δ: 2.15-2.34 (3H, m), 2.51-2.59 (1H, m), 2.70 (3H, s), 2.72 (3H, s), 3.39-3.48 (1H, m), 3.62-3.72 (1H, m), 4.11 (1H, q, J = 5.2 Hz), 4.17-4.26 (1H, m), 7.33 (1H, dd, J = 8.3, 2.1 Hz), 7.60 (1H, d, J = 8.3 Hz), 7.60 (1H, d, J = 2.1 Hz), 9.40 (2H, brs).
LC/MS 301.2 tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- [2- (dimethylamino) -2-oxoethyl] pyrrolidine-1-carboxylate (0.090 g, 0.22 mmol) It was dissolved in% hydrochloric acid-methanol (10 mL) and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow oil (0.063 g, 93%).
NMR (DMSO-d 6 ) δ: 2.15-2.34 (3H, m), 2.51-2.59 (1H, m), 2.70 (3H, s), 2.72 (3H, s), 3.39-3.48 (1H, m), 3.62-3.72 (1H, m), 4.11 (1H, q, J = 5.2 Hz), 4.17-4.26 (1H, m), 7.33 (1H, dd, J = 8.3, 2.1 Hz), 7.60 (1H, d, J = 8.3 Hz), 7.60 (1H, d, J = 2.1 Hz), 9.40 (2H, brs).
LC / MS 301.2

実施例９０
1-[(2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]-2-メチルプロパン-2-オール　1塩酸塩 Example 90
1-[(2S * , 3R * )-3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] -2-methylpropan-2-ol monohydrochloride

Figure JPOXMLDOC01-appb-C000285
Figure JPOXMLDOC01-appb-C000285

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-ヒドロキシ-2-メチルプロピル)ピロリジン-1-カルボキシラート(0.14 g, 0.36 mmol)を10%塩酸－メタノール(10 mL)に溶解させ、室温で2時間攪拌した後、減圧下溶媒を留去した。得られた結晶をエタノール／ジエチルエーテルから再結晶して、表題化合物を白色結晶(0.050 g, 43%)として得た。
NMR (DMSO-d6) δ: 1.02-1.08 (1H, m), 1.09 (3H, s), 1.11 (3H, s), 1.46 (1H, dd, J = 14.7, 11.1 Hz), 2.07-2.24 (1H, m), 2.25-2.40 (1H, m), 3.14-3.29 (1H, m), 3.43-3.55 (1H, m), 3.65 (1H, q, J = 8.0 Hz), 3.99-4.10 (1H, m), 5.11 (1H, brs), 7.32 (1H, dd, J = 8.5, 2.1 Hz), 7.57-7.65 (2H, m), 9.14 (2H, brs).
LC/MS 288.2
mp 211-213℃
Anal. Calcd. for C14H19NOCl2・HCl: C, 51.79; H, 6.21; N, 4.31. Found: C, 51.63; H, 6.18; N, 4.20. tert-Butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (2-hydroxy-2-methylpropyl) pyrrolidine-1-carboxylate (0.14 g, 0.36 mmol) in 10% hydrochloric acid -After dissolving in methanol (10 mL) and stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure. The obtained crystals were recrystallized from ethanol / diethyl ether to give the title compound as white crystals (0.050 g, 43%).
NMR (DMSO-d 6 ) δ: 1.02-1.08 (1H, m), 1.09 (3H, s), 1.11 (3H, s), 1.46 (1H, dd, J = 14.7, 11.1 Hz), 2.07-2.24 ( 1H, m), 2.25-2.40 (1H, m), 3.14-3.29 (1H, m), 3.43-3.55 (1H, m), 3.65 (1H, q, J = 8.0 Hz), 3.99-4.10 (1H, m), 5.11 (1H, brs), 7.32 (1H, dd, J = 8.5, 2.1 Hz), 7.57-7.65 (2H, m), 9.14 (2H, brs).
LC / MS 288.2
mp 211-213 ℃
Anal.Calcd.for C 14 H 19 NOCl 2・ HCl: C, 51.79; H, 6.21; N, 4.31.Found: C, 51.63; H, 6.18; N, 4.20.

実施例９１
[(2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]アセトニトリル　1塩酸塩 Example 91
[(2S * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidin-2-yl] acetonitrile monohydrochloride

Figure JPOXMLDOC01-appb-C000286
Figure JPOXMLDOC01-appb-C000286

　tert-ブチル (2S*,3R*)-2-(シアノメチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート(0.17 g, 0.48 mmol)をメタノール(5 mL)に溶解させ、4 N塩酸－酢酸エチル溶液(10 mL)を加えた。反応混合物を室温で1時間攪拌し、減圧下濃縮した。得られた結晶をエタノールより再結晶して、表題化合物を白色結晶(0.070 g, 50%)として得た。
NMR (DMSO-d6) δ: 2.25-2.36 (2H, m), 2.58 (1H, dd, J = 17.3, 6.6 Hz), 2.77 (1H, dd, J = 17.3, 7.7 Hz), 3.15-3.29 (1H, m), 3.41-3.52 (1H, m), 3.73 (1H, q, J = 8.6 Hz), 4.22 (1H, q, J = 7.7 Hz), 7.37 (1H, dd, J = 8.5, 2.2 Hz), 7.62 (1H, d, J = 8.5 Hz), 7.66 (1H, d, J = 2.2 Hz), 9.99 (2H, brs).
LC/MS 255.0 tert-Butyl (2S * , 3R * )-2- (cyanomethyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate (0.17 g, 0.48 mmol) was dissolved in methanol (5 mL) and 4 N hydrochloric acid-ethyl acetate solution (10 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The obtained crystals were recrystallized from ethanol to give the title compound as white crystals (0.070 g, 50%).
NMR (DMSO-d 6 ) δ: 2.25-2.36 (2H, m), 2.58 (1H, dd, J = 17.3, 6.6 Hz), 2.77 (1H, dd, J = 17.3, 7.7 Hz), 3.15-3.29 ( 1H, m), 3.41-3.52 (1H, m), 3.73 (1H, q, J = 8.6 Hz), 4.22 (1H, q, J = 7.7 Hz), 7.37 (1H, dd, J = 8.5, 2.2 Hz ), 7.62 (1H, d, J = 8.5 Hz), 7.66 (1H, d, J = 2.2 Hz), 9.99 (2H, brs).
LC / MS 255.0

実施例９２
2-[(2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]-1-(ピロリジン-1-イル)エタノン　1塩酸塩 Example 92
2-[(2S * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidin-2-yl] -1- (pyrrolidin-1-yl) ethanone monohydrochloride

Figure JPOXMLDOC01-appb-C000287
Figure JPOXMLDOC01-appb-C000287

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-オキソ-2-ピロリジン-1-イルエチル)ピロリジン-1-カルボキシラート(0.11 g, 0.27 mmol)を10%塩酸－メタノール(10 mL)に溶解させ、室温で5時間攪拌し、減圧下濃縮した。得られた結晶をエタノール／ヘキサンより再結晶して、表題化合物を白色結晶(0.059 g, 61%)として得た。
NMR (DMSO-d6) δ: 1.57-1.81 (4H, m), 2.12-2.37 (3H, m), 2.40-2.46 (1H, m), 2.87-2.96 (1H, m), 3.07-3.25 (4H, m), 3.40-3.50 (1H, m), 3.68 (1H, dd, J = 17.4, 8.3 Hz), 4.20-4.28 (1H, m), 7.32 (1H, dd, J = 8.3, 2.3 Hz), 7.58-7.62 (2H, m), 9.27 (2H, brs).
LC/MS 327.1
mp 201-202℃
Anal. Calcd. for C16H20N2OCl2・HCl: C, 52.84; H, 5.82; N, 7.70. Found: C, 52.95; H, 5.82; N, 7.44. tert-butyl (2S * , 3R * )-3- (3,4-dichlorophenyl) -2- (2-oxo-2-pyrrolidin-1-ylethyl) pyrrolidine-1-carboxylate (0.11 g, 0.27 mmol) The mixture was dissolved in 10% hydrochloric acid-methanol (10 mL), stirred at room temperature for 5 hours, and concentrated under reduced pressure. The obtained crystals were recrystallized from ethanol / hexane to give the title compound as white crystals (0.059 g, 61%).
NMR (DMSO-d 6 ) δ: 1.57-1.81 (4H, m), 2.12-2.37 (3H, m), 2.40-2.46 (1H, m), 2.87-2.96 (1H, m), 3.07-3.25 (4H , m), 3.40-3.50 (1H, m), 3.68 (1H, dd, J = 17.4, 8.3 Hz), 4.20-4.28 (1H, m), 7.32 (1H, dd, J = 8.3, 2.3 Hz), 7.58-7.62 (2H, m), 9.27 (2H, brs).
LC / MS 327.1
mp 201-202 ℃
Anal.Calcd.for C 16 H 20 N 2 OCl 2・ HCl: C, 52.84; H, 5.82; N, 7.70. Found: C, 52.95; H, 5.82; N, 7.44.

実施例９３
2-[(2S*,3R*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]-1-(モルホリン-4-イル)エタノン　1塩酸塩 Example 93
2-[(2S * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidin-2-yl] -1- (morpholin-4-yl) ethanone monohydrochloride

Figure JPOXMLDOC01-appb-C000288
Figure JPOXMLDOC01-appb-C000288

　tert-ブチル (2S*,3R*)-3-(3,4-ジクロロフェニル)-2-(2-モルホリン-4-イル-2-オキソエチル)ピロリジン-1-カルボキシラート(0.11 g, 0.24 mmol)を10%塩酸－メタノール(10 mL)に溶解させ、室温で5時間攪拌した後、減圧下溶媒を留去することにより、表題化合物を無色油状物(0.091 g, 100%)として得た。
NMR (DMSO-d6) δ: 2.19-2.37 (3H, m), 2.51-2.60 (1H, m), 3.04-3.27 (5H, m), 3.36-3.59 (5H, m), 3.62-3.74 (1H, m), 4.21-4.31 (1H, m), 7.32 (1H, dd, J = 8.3, 2.3 Hz), 7.57-7.63 (2H, m), 9.04 (1H, brs), 9.55 (1H, brs).
LC/MS 343.1 tert-Butyl (2S * , 3R * )-3- (3,4-Dichlorophenyl) -2- (2-morpholin-4-yl-2-oxoethyl) pyrrolidine-1-carboxylate (0.11 g, 0.24 mmol) After dissolving in 10% hydrochloric acid-methanol (10 mL) and stirring at room temperature for 5 hours, the solvent was distilled off under reduced pressure to obtain the title compound as a colorless oil (0.091 g, 100%).
NMR (DMSO-d 6 ) δ: 2.19-2.37 (3H, m), 2.51-2.60 (1H, m), 3.04-3.27 (5H, m), 3.36-3.59 (5H, m), 3.62-3.74 (1H , m), 4.21-4.31 (1H, m), 7.32 (1H, dd, J = 8.3, 2.3 Hz), 7.57-7.63 (2H, m), 9.04 (1H, brs), 9.55 (1H, brs).
LC / MS 343.1

実施例９４－１
[(2R*,3R*)-3-(3,4-ジクロロフェニル)-2-メチルピロリジン-2-イル]メタノール Example 94-1
[(2R * , 3R * )-3- (3,4-dichlorophenyl) -2-methylpyrrolidin-2-yl] methanol

Figure JPOXMLDOC01-appb-C000289
Figure JPOXMLDOC01-appb-C000289

　LAH(0.29 g, 7.5 mmol)のTHF(19 mL)懸濁液に、エチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-メチルピロリジン-2-カルボキシラート　1塩酸塩(1.3 g, 3.8 mmol)を加え、室温にて15分間攪拌した。反応混合物に、水(1.0 mL)、1 N 水酸化ナトリウム水溶液(1.0 mL)および水(1.0 mL)を順次加え、セライト濾過した。濾液を減圧下濃縮し、得られた残留物を塩基性シリカゲルカラムクロマトグラフィー(酢酸エチルのみ～酢酸エチル/メタノール＝4/1)で精製し、表題化合物を無色油状物(0.33 g, 34%)として得た。
LC/MS 260.1
NMR (DMSO-d6) δ: 1.06 (3H, s), 1.92-2.25 (2H, m), 2.56-2.75 (1H, m), 2.77-3.18 (5H, m), 4.06 (1H, brs), 7.26 (1H, dd, J = 8.3, 2.3 Hz), 7.37-7.65 (2H, m).
mp 223℃ To a suspension of LAH (0.29 g, 7.5 mmol) in THF (19 mL), ethyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2-methylpyrrolidine-2-carboxylate monohydrochloride (1.3 g, 3.8 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. Water (1.0 mL), 1 N aqueous sodium hydroxide solution (1.0 mL) and water (1.0 mL) were sequentially added to the reaction mixture, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (ethyl acetate only to ethyl acetate / methanol = 4/1) to give the title compound as a colorless oil (0.33 g, 34%). Got as.
LC / MS 260.1
NMR (DMSO-d 6 ) δ: 1.06 (3H, s), 1.92-2.25 (2H, m), 2.56-2.75 (1H, m), 2.77-3.18 (5H, m), 4.06 (1H, brs), 7.26 (1H, dd, J = 8.3, 2.3 Hz), 7.37-7.65 (2H, m).
mp 223 ℃

実施例９４－２
[(2R*,3R*)-3-(3,4-ジクロロフェニル)-2-メチルピロリジン-2-イル]メタノール　1塩酸塩 Example 94-2
[(2R * , 3R * )-3- (3,4-dichlorophenyl) -2-methylpyrrolidin-2-yl] methanol monohydrochloride

Figure JPOXMLDOC01-appb-C000290
Figure JPOXMLDOC01-appb-C000290

　[(2R*,3R*)-3-(3,4-ジクロロフェニル)-2-メチルピロリジン-2-イル]メタノール(0.33 g, 1.3 mmol)のメタノール(3.0 mL)溶液に塩酸－メタノール溶液(3.0 mL)を加え、室温で5時間攪拌した。溶媒を減圧留去し、得られた残留物をメタノール／酢酸エチルより再結晶して、表題化合物を白色粉末(0.32 g, 85%)として得た。
LC/MS 260.2
NMR (DMSO-d6) δ: 1.35 (3H, s), 2.26 (1H, m), 2.52-2.62 (1H, m), 2.76-3.11 (1H, m), 3.16-3.48 (4H, m), 5.49 (1H, brs), 7.38 (1H, dd, J = 8.3, 2.3 Hz), 7.51-7.87 (2H, m), 8.60-9.74 (2H, m). [(2R * , 3R * )-3- (3,4-dichlorophenyl) -2-methylpyrrolidin-2-yl] methanol (0.33 g, 1.3 mmol) in methanol (3.0 mL) was added to a hydrochloric acid-methanol solution (3.0 mL) was added and stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from methanol / ethyl acetate to give the title compound as a white powder (0.32 g, 85%).
LC / MS 260.2
NMR (DMSO-d 6 ) δ: 1.35 (3H, s), 2.26 (1H, m), 2.52-2.62 (1H, m), 2.76-3.11 (1H, m), 3.16-3.48 (4H, m), 5.49 (1H, brs), 7.38 (1H, dd, J = 8.3, 2.3 Hz), 7.51-7.87 (2H, m), 8.60-9.74 (2H, m).

実施例９５－１
2-[(2R*,3R*)-3-(3,4-ジクロロフェニル)-2-メチルピロリジン-2-イル]プロパン-2-オール Example 95-1
2-[(2R * , 3R * )-3- (3,4-dichlorophenyl) -2-methylpyrrolidin-2-yl] propan-2-ol

Figure JPOXMLDOC01-appb-C000291
Figure JPOXMLDOC01-appb-C000291

　エチル (2R*,3R*)-3-(3,4-ジクロロフェニル)-2-メチルピロリジン-2-カルボキシラート　1塩酸塩(0.27 g, 0.8 mmol)のTHF(8.0 mL)溶液に、1 Mメチルマグネシウムブロミド THF溶液(8.0 mL)を加え、室温で1時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、セライト濾過した。濾液を減圧下濃縮して、表題化合物を淡黄色油状物(0.21 g, 91%)として得た。
LC/MS 288.1
NMR (DMSO-d6) δ: 0.61-1.55 (14H, m), 2.16-2.40 (2H, m), 7.30-7.68 (3H, m). To a solution of ethyl (2R * , 3R * )-3- (3,4-dichlorophenyl) -2-methylpyrrolidine-2-carboxylate monohydrochloride (0.27 g, 0.8 mmol) in THF (8.0 mL) was added 1 M methyl. Magnesium bromide THF solution (8.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give the title compound as a pale yellow oil (0.21 g, 91%).
LC / MS 288.1
NMR (DMSO-d 6 ) δ: 0.61-1.55 (14H, m), 2.16-2.40 (2H, m), 7.30-7.68 (3H, m).

実施例９５－２
2-[(2R*,3R*)-3-(3,4-ジクロロフェニル)-2-メチルピロリジン-2-イル]プロパン-2-オール　1塩酸塩 Example 95-2
2-[(2R * , 3R * )-3- (3,4-dichlorophenyl) -2-methylpyrrolidin-2-yl] propan-2-ol monohydrochloride

Figure JPOXMLDOC01-appb-C000292
Figure JPOXMLDOC01-appb-C000292

　2-[(2R*,3R*)-3-(3,4-ジクロロフェニル)-2-メチルピロリジン-2-イル]プロパン-2-オール(0.093 g, 0.32 mmol)のメタノール(1.0 mL)溶液に塩酸－メタノール溶液(1.0 mL)を加え、室温で5時間攪拌した。溶媒を減圧留去し、得られた残留物をメタノール／ジエチルエーテルより再結晶して、表題化合物を白色粉末(0.067 g, 64%)として得た。
LC/MS 288.2
NMR (DMSO-d6) δ: 0.82 (3H, s), 1.05 (3H, s), 1.46 (3H, s), 2.20-2.43 (2H, m), 3.36-3.61 (3H, m), 5.23 (1H, s), 7.37 (1H, dd, J = 8.3, 2.3 Hz), 7.56 (1H, d, J = 8.3 Hz), 7.65 (1H, d, J = 2.3 Hz), 8.32 (1H, brs), 9.20 (1H, brs).
mp 210℃ To a solution of 2-[(2R * , 3R * )-3- (3,4-dichlorophenyl) -2-methylpyrrolidin-2-yl] propan-2-ol (0.093 g, 0.32 mmol) in methanol (1.0 mL) Hydrochloric acid-methanol solution (1.0 mL) was added, and the mixture was stirred at room temperature for 5 hr. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from methanol / diethyl ether to obtain the title compound as a white powder (0.067 g, 64%).
LC / MS 288.2
NMR (DMSO-d 6 ) δ: 0.82 (3H, s), 1.05 (3H, s), 1.46 (3H, s), 2.20-2.43 (2H, m), 3.36-3.61 (3H, m), 5.23 ( 1H, s), 7.37 (1H, dd, J = 8.3, 2.3 Hz), 7.56 (1H, d, J = 8.3 Hz), 7.65 (1H, d, J = 2.3 Hz), 8.32 (1H, brs), 9.20 (1H, brs).
mp 210 ℃

実施例９６
　上記と同様の方法により、以下の表に示す実施例９６の化合物を合成した。 Example 96
The compound of Example 96 shown in the following table was synthesized by the same method as described above.

実施例９７
[(2R,3R)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル][(3S)-3-ヒドロキシピロリジン-1-イル]メタノン １塩酸塩 Example 97
[(2R, 3R) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] [(3S) -3-hydroxypyrrolidin-1-yl] methanone monohydrochloride

Figure JPOXMLDOC01-appb-C000293
Figure JPOXMLDOC01-appb-C000293

　tert-ブチル (2R,3R)-3-(3,4-ジクロロフェニル)-2-{[(3S)-3-ヒドロキシピロリジン-1-イル]カルボニル}ピロリジン-1-カルボキシラート(0.30 g, 0.70 mmol)を10%塩酸メタノール溶液(10 mL)に溶解させ、室温で終夜攪拌した。溶媒を減圧留去し、得られた結晶をエタノール／酢酸エチルより再結晶して、表題化合物を淡黄色結晶(0.18 g, 70%, 融点 243-244℃)として得た。
1H NMR (300 MHz, DMSO-d6) δ 1.25-1.39 (0.6H, m), 1.46-1.68 (1H, m), 1.76-1.89 (0.4H, m), 2.03-2.19 (1H, m), 2.36-2.47 (1H, m), 2.69 (0.4H, d, J = 13.3 Hz), 2.85-3.08 (1.6H, m), 3.16-3.30 (2.6H, m), 3.44-3.62 (1.4H, m), 3.88-4.02 (1.6H, m), 4.11-4.15 (0.4H, m), 4.69-4.78 (1.4H, m), 5.13 (0.6H, d, J = 3.4 Hz), 7.20-7.29 (1H, m), 7.50-7.61 (2H, m), 9.46 (2H, br s).
Anal. Calcd. for C15H18N2O2Cl2・HCl: C, 49.27; H, 5.24; N, 7.66. Found: C, 49.01; H, 5.29; N, 7.48.
LC/MS 329.1 tert-butyl (2R, 3R) -3- (3,4-dichlorophenyl) -2-{[(3S) -3-hydroxypyrrolidin-1-yl] carbonyl} pyrrolidine-1-carboxylate (0.30 g, 0.70 mmol ) Was dissolved in 10% hydrochloric acid in methanol (10 mL) and stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethanol / ethyl acetate to give the title compound as pale yellow crystals (0.18 g, 70%, melting point 243-244 ° C.).
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.25-1.39 (0.6H, m), 1.46-1.68 (1H, m), 1.76-1.89 (0.4H, m), 2.03-2.19 (1H, m) , 2.36-2.47 (1H, m), 2.69 (0.4H, d, J = 13.3 Hz), 2.85-3.08 (1.6H, m), 3.16-3.30 (2.6H, m), 3.44-3.62 (1.4H, m), 3.88-4.02 (1.6H, m), 4.11-4.15 (0.4H, m), 4.69-4.78 (1.4H, m), 5.13 (0.6H, d, J = 3.4 Hz), 7.20-7.29 ( 1H, m), 7.50-7.61 (2H, m), 9.46 (2H, br s).
Anal.Calcd.for C 15 H 18 N 2 O 2 Cl 2・ HCl: C, 49.27; H, 5.24; N, 7.66. Found: C, 49.01; H, 5.29; N, 7.48.
LC / MS 329.1

実施例９８および９９
　上記と同様の方法により、以下の表に示す実施例９８および９９の化合物を合成した。 Examples 98 and 99
The compounds of Examples 98 and 99 shown in the following table were synthesized by the same method as described above.

実施例１００
[(2R,3R)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル][(3R)-3-ヒドロキシピロリジン-1-イル]メタノン １塩酸塩 Example 100
[(2R, 3R) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] [(3R) -3-hydroxypyrrolidin-1-yl] methanone monohydrochloride

Figure JPOXMLDOC01-appb-C000294
Figure JPOXMLDOC01-appb-C000294

　tert-ブチル (2R,3R)-3-(3,4-ジクロロフェニル)-2-{[(3R)-3-ヒドロキシピロリジン-1-イル]カルボニル}ピロリジン-1-カルボキシラート(0.20 g, 0.47 mmol)を10%塩酸メタノール溶液(10 mL)に溶解させ、室温で終夜攪拌した。溶媒を減圧留去し、得られた残渣を分取HPLCにより精製した。得られた溶液を減圧下濃縮し、1 N水酸化ナトリウム水溶液を加えた後、飽和状態になるまで塩化ナトリウムを加え、酢酸エチルで抽出した。得られた抽出液を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。
　得られた残渣のメタノール(10 mL)溶液に10%塩酸メタノール溶液(0.20 mL)を加え、室温で10分間攪拌した。溶媒を減圧下留去し、得られた結晶をエタノール／酢酸エチルより再結晶して、表題化合物を白色結晶(0.10 g, 59%, 融点 207-209℃)として得た。
1H NMR (300 MHz, DMSO-d6) δ1.21 (0.6H, d), 1.43-1.54 (0.4H, m), 1.67-1.81 (1H, m), 2.03-2.21 (1H, m), 2.36-2.47 (1H, m), 2.72-3.09 (2H, m), 3.13-3.28 (2H, m), 3.35-3.64 (2H, m), 3.90-4.04 (1.6H, m), 4.19-4.26 (0.4H, m), 4.65 (0.4H, d, J = 8.7 Hz), 4.71 (0.6H, d, J = 9.5 Hz), 4.92 (0.4H, d, J = 3.0 Hz), 5.00 (0.6H, d, J = 3.0 Hz), 7.22-7.28 (1H, m), 7.50-7.61 (2H, m), 9.42 (2H, br s).
Anal. Calcd. for C15H18N2O2Cl2・HCl+0.3H2O: C, 48.55; H, 5.32; N, 7.55. Found: C, 48.46; H, 5.32; N, 7.49.
LC/MS 329.0 tert-butyl (2R, 3R) -3- (3,4-dichlorophenyl) -2-{[(3R) -3-hydroxypyrrolidin-1-yl] carbonyl} pyrrolidine-1-carboxylate (0.20 g, 0.47 mmol ) Was dissolved in 10% hydrochloric acid in methanol (10 mL) and stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative HPLC. The obtained solution was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution was added, sodium chloride was added until saturated, and the mixture was extracted with ethyl acetate. The obtained extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
To a solution of the obtained residue in methanol (10 mL) was added 10% hydrochloric acid methanol solution (0.20 mL), and the mixture was stirred at room temperature for 10 min. The solvent was evaporated under reduced pressure, and the obtained crystals were recrystallized from ethanol / ethyl acetate to give the title compound as white crystals (0.10 g, 59%, melting point 207-209 ° C).
1 H NMR (300 MHz, DMSO-d 6 ) δ1.21 (0.6H, d), 1.43-1.54 (0.4H, m), 1.67-1.81 (1H, m), 2.03-2.21 (1H, m), 2.36-2.47 (1H, m), 2.72-3.09 (2H, m), 3.13-3.28 (2H, m), 3.35-3.64 (2H, m), 3.90-4.04 (1.6H, m), 4.19-4.26 ( 0.4H, m), 4.65 (0.4H, d, J = 8.7 Hz), 4.71 (0.6H, d, J = 9.5 Hz), 4.92 (0.4H, d, J = 3.0 Hz), 5.00 (0.6H, d, J = 3.0 Hz), 7.22-7.28 (1H, m), 7.50-7.61 (2H, m), 9.42 (2H, br s).
Anal.Calcd.for C 15 H 18 N 2 O 2 Cl 2・ HCl + 0.3H 2 O: C, 48.55; H, 5.32; N, 7.55. Found: C, 48.46; H, 5.32; N, 7.49.
LC / MS 329.0

実施例１０１
[(2R,3R)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル][(2R)-2-（ヒドロキシメチル）ピロリジン-1-イル]メタノン １塩酸塩 Example 101
[(2R, 3R) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] [(2R) -2- (hydroxymethyl) pyrrolidin-1-yl] methanone monohydrochloride

Figure JPOXMLDOC01-appb-C000295
Figure JPOXMLDOC01-appb-C000295

　(2R,3R)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)ピロリジン-2-カルボン酸(0.30 g, 0.83 mmol)のDMF(5 mL)溶液にHOBt(0.19 g, 1.2 mmol)とWSC(0.24 g, 1.2 mmol)を加えた。これに(2R)-ピロリジン-2-イルメタノール(0.17 mL, 1.7 mmol)を加え、室温で終夜攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出を行った。得られた抽出液を飽和炭酸水素ナトリウムと飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去することにより、無色油状物を得た。これを10%塩酸メタノール溶液(10 mL)に溶解させ、室温で終夜攪拌した。溶媒を減圧留去し、得られた結晶をエタノール／酢酸エチルより再結晶して、表題化合物を淡黄色結晶(0.19 g, 66%)として得た。
1H NMR (300 MHz, DMSO-d6) δ 0.81-0.96 (0.6H, m), 1.28-1.38 (0.6H, m), 1.51-1.77 (2.8H, m), 2.03-2.44 (2H, m), 2.77-2.95 (1H, m), 3.11-3.29 (4H, m), 3.51-3.63 (1.6H, m), 3.78 (0.4H, br s), 3.95-4.05 (1H, m), 4.63 (0.4H, t), 4.69 (0.4H, d, J = 9.5 Hz), 5.02 (0.6H, d, J = 9.8 Hz), 5.15 (0.6H, t, J = 5.1 Hz), 7.24-7.33 (1H, m), 7.54-7.65 (2H, m), 9.32 (2H, br s).
LC/MS 343.0 (2R, 3R) -1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid (0.30 g, 0.83 mmol) in DMF (5 mL) was added to HOBt (0.19 g, 1.2 mmol) and WSC (0.24 g, 1.2 mmol) were added. To this was added (2R) -pyrrolidin-2-ylmethanol (0.17 mL, 1.7 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The obtained extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a colorless oil. This was dissolved in 10% hydrochloric acid methanol solution (10 mL) and stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethanol / ethyl acetate to give the title compound as pale yellow crystals (0.19 g, 66%).
1 H NMR (300 MHz, DMSO-d 6 ) δ 0.81-0.96 (0.6H, m), 1.28-1.38 (0.6H, m), 1.51-1.77 (2.8H, m), 2.03-2.44 (2H, m ), 2.77-2.95 (1H, m), 3.11-3.29 (4H, m), 3.51-3.63 (1.6H, m), 3.78 (0.4H, br s), 3.95-4.05 (1H, m), 4.63 ( 0.4H, t), 4.69 (0.4H, d, J = 9.5 Hz), 5.02 (0.6H, d, J = 9.8 Hz), 5.15 (0.6H, t, J = 5.1 Hz), 7.24-7.33 (1H , m), 7.54-7.65 (2H, m), 9.32 (2H, br s).
LC / MS 343.0

実施例１０２～１８１
　上記と同様の方法により、以下の表に示す実施例１０２～１８１の化合物を合成した。 Examples 102-181
The compounds of Examples 102 to 181 shown in the following table were synthesized by the same method as described above.

実施例１８２
[(2R*,3S*)-3-(3,4-ジフルオロフェニル)ピロリジン-2-イル](ピロリジン-1-イル)メタノン １塩酸塩 Example 182
[(2R * , 3S * )-3- (3,4-Difluorophenyl) pyrrolidin-2-yl] (pyrrolidin-1-yl) methanone monohydrochloride

Figure JPOXMLDOC01-appb-C000296
Figure JPOXMLDOC01-appb-C000296

　tert-ブチル (2R*,3S*)-3-(3,4-ジフルオロフェニル)-2-(ピロリジン-1-イルカルボニル)ピロリジン-1-カルボキシラート（0.1 ｇ）に４規定塩酸－酢酸エチル溶液(4 mL)を加えた。反応混合物を室温で1時間攪拌し、溶媒を減圧下留去した。得られた残渣をジイソプロピルエーテル－酢酸エチルより結晶化して、標題化合物を無色結晶(0.06 g)として得た。
1H NMR (300 MHz, CDCl3) δ 1.63-1.98 (4H, m), 2.20-2.68 (3H, m), 3.22-3.74 (5H, m), 3.87 (1H, ddd, J = 10.9, 7.7, 3.2 Hz), 4.67 (1H, d, J = 8.7 Hz), 6.94-7.57 (3H, m), 9.69-10.26 (2H, m).
LC/MS 281.5 tert-Butyl (2R * , 3S * )-3- (3,4-difluorophenyl) -2- (pyrrolidin-1-ylcarbonyl) pyrrolidine-1-carboxylate (0.1 g) in 4N hydrochloric acid-ethyl acetate solution (4 mL) was added. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-ethyl acetate to give the title compound as colorless crystals (0.06 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.63-1.98 (4H, m), 2.20-2.68 (3H, m), 3.22-3.74 (5H, m), 3.87 (1H, ddd, J = 10.9, 7.7, 3.2 Hz), 4.67 (1H, d, J = 8.7 Hz), 6.94-7.57 (3H, m), 9.69-10.26 (2H, m).
LC / MS 281.5

実施例１８３～２１９
　上記と同様の方法により、以下の表に示す実施例１８３～２１９の化合物を合成した。 Examples 183 to 219
The compounds of Examples 183 to 219 shown in the following table were synthesized by the same method as described above.

実施例２２０
N-{[(2R,3R)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]メチル}スルファミド 1塩酸塩 Example 220
N-{[(2R, 3R) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] methyl} sulfamide monohydrochloride

Figure JPOXMLDOC01-appb-C000297
Figure JPOXMLDOC01-appb-C000297

　tert-ブチル (2R,3R)-2-({[(tert-ブトキシカルボニル)スルファモイル]アミノ}メチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート (0.51 g)をエタノール(4 mL)に溶解させ、4規定塩酸－酢酸エチル溶液(8 mL)を加えた。反応混合物を室温で1.5時間攪拌し、溶媒を減圧下留去した。得られた残渣をエタノール－酢酸エチルより結晶化して、標題化合物を無色結晶(0.31g, 融点 174-175℃)として得た。
1H NMR (300 MHz, DMSO-d6) δ 2.14-2.44 (2H, m), 2.61 (1H, dt, J = 14.7, 4.3 Hz), 2.84 (1H, ddd, J = 14.0, 11.0, 6.8 Hz), 3.15-3.29 (1H, m), 3.45-3.56 (1H, m), 3.71 (1H, q, J = 8.4 Hz), 4.01 (1H, d, J = 6.8 Hz), 6.71 (2H, s), 6.81 (1H, t, J = 6.0 Hz), 7.29-7.49 (1H, m), 7.56-7.75 (2H, m), 9.09 (1H, brs), 9.89 (1H, brs).
LC/MS 324.2 tert-Butyl (2R, 3R) -2-({[(tert-butoxycarbonyl) sulfamoyl] amino} methyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate (0.51 g) in ethanol (4 4N hydrochloric acid-ethyl acetate solution (8 mL) was added. The reaction mixture was stirred at room temperature for 1.5 hours, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethanol-ethyl acetate to give the title compound as colorless crystals (0.31 g, melting point 174-175 ° C).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.14-2.44 (2H, m), 2.61 (1H, dt, J = 14.7, 4.3 Hz), 2.84 (1H, ddd, J = 14.0, 11.0, 6.8 Hz ), 3.15-3.29 (1H, m), 3.45-3.56 (1H, m), 3.71 (1H, q, J = 8.4 Hz), 4.01 (1H, d, J = 6.8 Hz), 6.71 (2H, s) , 6.81 (1H, t, J = 6.0 Hz), 7.29-7.49 (1H, m), 7.56-7.75 (2H, m), 9.09 (1H, brs), 9.89 (1H, brs).
LC / MS 324.2

実施例２２１
　上記と同様の方法により、以下の表に示す実施例２２１の化合物を合成した。 Example 221
The compound of Example 221 shown in the following table was synthesized by the same method as above.

実施例２２２
N-{[(2S,3S)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]メチル}スルファミド 1塩酸塩 Example 222
N-{[(2S, 3S) -3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] methyl} sulfamide monohydrochloride

Figure JPOXMLDOC01-appb-C000298
Figure JPOXMLDOC01-appb-C000298

　tert-ブチル (2S,3S)-2-({[(tert-ブトキシカルボニル)スルファモイル]アミノ}メチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート (0.23 g)をエタノール(2 mL)に溶解させ、4規定塩酸－酢酸エチル溶液(4 mL)を加えた。反応混合物を室温で1時間攪拌し、溶媒を減圧下留去した。得られた残渣をエタノール－酢酸エチルより結晶化して、標題化合物を無色結晶(0.132 g, 融点 174-176℃)として得た。
1H NMR (300 MHz, DMSO-d6) δ 2.15-2.41 (2H, m), 2.61 (1H, dt, J = 14.4, 4.4 Hz), 2.82 (1H, ddd, J = 13.9, 11.1, 7.2 Hz), 3.12-3.28 (1H, m), 3.46 (1H, dd, J = 14.6, 7.8 Hz), 3.71 (1H, q, J = 8.3 Hz), 4.00 (1H, d, J = 8.0 Hz), 6.71 (2H, s), 6.80 (1H, t, J = 6.1 Hz), 7.36 (1H, dd, J = 8.5, 2.1 Hz), 7.58-7.74 (2H, m), 9.03 (1H, brs), 9.83 (1H, brs).
LC/MS 324.2 tert-Butyl (2S, 3S) -2-({[(tert-Butoxycarbonyl) sulfamoyl] amino} methyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate (0.23 g) in ethanol (2 4N hydrochloric acid-ethyl acetate solution (4 mL) was added. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethanol-ethyl acetate to give the title compound as colorless crystals (0.132 g, melting point: 174-176 ° C).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.15-2.41 (2H, m), 2.61 (1H, dt, J = 14.4, 4.4 Hz), 2.82 (1H, ddd, J = 13.9, 11.1, 7.2 Hz ), 3.12-3.28 (1H, m), 3.46 (1H, dd, J = 14.6, 7.8 Hz), 3.71 (1H, q, J = 8.3 Hz), 4.00 (1H, d, J = 8.0 Hz), 6.71 (2H, s), 6.80 (1H, t, J = 6.1 Hz), 7.36 (1H, dd, J = 8.5, 2.1 Hz), 7.58-7.74 (2H, m), 9.03 (1H, brs), 9.83 ( 1H, brs).
LC / MS 324.2

実施例２２３
1-{[(2R*,3S*)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]メチル}-3-メトキシ尿素 １塩酸塩 Example 223
1-{[(2R * , 3S * )-3- (3,4-dichlorophenyl) pyrrolidin-2-yl] methyl} -3-methoxyurea monohydrochloride

Figure JPOXMLDOC01-appb-C000299
Figure JPOXMLDOC01-appb-C000299

　tert-ブチル (2R*,3S*)-3-(3,4-ジクロロフェニル)-2-{[(メトキシカルバモイル)アミノ]メチル}ピロリジン-1-カルボキシラート (0.36 ｇ)をエタノール（2 mL）に溶解させ、4規定塩酸－酢酸エチル溶液(4 mL)を加えた。反応混合物を室温で1時間攪拌し、溶媒を減圧下留去し、標題化合物を無色固体(0.25 g)として得た。
1H NMR (300 MHz, DMSO-d6) δ 1.94-2.11 (1H, m), 2.25-2.43 (1H, m), 3.11-3.30 (2H, m), 3.36-3.54 (6H, m), 3.59-3.69 (1H, m), 7.30 (1H, t), 7.41 (1H, dd, J = 8.5, 2.1 Hz), 7.63 (1H, d, J = 8.3 Hz), 7.73 (1H, d, J = 1.9 Hz), 9.14-9.72 (3H, m).
LC/MS 318.2 tert-Butyl (2R * , 3S * )-3- (3,4-dichlorophenyl) -2-{[(methoxycarbamoyl) amino] methyl} pyrrolidine-1-carboxylate (0.36 g) in ethanol (2 mL) After dissolution, 4N hydrochloric acid-ethyl acetate solution (4 mL) was added. The reaction mixture was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (0.25 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.94-2.11 (1H, m), 2.25-2.43 (1H, m), 3.11-3.30 (2H, m), 3.36-3.54 (6H, m), 3.59 -3.69 (1H, m), 7.30 (1H, t), 7.41 (1H, dd, J = 8.5, 2.1 Hz), 7.63 (1H, d, J = 8.3 Hz), 7.73 (1H, d, J = 1.9 Hz), 9.14-9.72 (3H, m).
LC / MS 318.2

実施例２２４
　上記と同様の方法により、以下の表に示す実施例２２４の化合物を合成した。 Example 224
The compound of Example 224 shown in the following table was synthesized by the same method as described above.

実施例２２５
1-{[(2R,3R)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]メチル}尿素 1塩酸塩 Example 225
1-{[(2R, 3R) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] methyl} urea monohydrochloride

Figure JPOXMLDOC01-appb-C000300
Figure JPOXMLDOC01-appb-C000300

　tert-ブチル (2R,3R)-2-[(カルバモイルアミノ)メチル]-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート(0.12 g)をエタノール(2 mL)に溶解させ、4規定塩酸－酢酸エチル溶液(4 mL)を加えた。反応混合物を室温で1時間攪拌し、溶媒を減圧下留去した。得られた残渣をエタノール－酢酸エチルより結晶化して、標題化合物を無色結晶(0.093 g, 融点 209-210℃)として得た。
1H NMR (300 MHz, DMSO-d6) δ 2.18-2.38 (2H, m), 2.68 (1H, d, J = 14.4 Hz), 2.83-3.03 (1H, m), 3.08-3.31 (1H, m), 3.41-3.57 (1H, m), 3.57-3.72 (1H, m), 3.89 (1H, brs), 6.24 (1H, brs), 7.36 (1H, dd, J = 8.3, 2.3 Hz), 7.50-7.71 (2H, m), 9.39 (1H, brs), 9.57 (1H, brs).
LC/MS 288.2 Dissolve tert-butyl (2R, 3R) -2-[(carbamoylamino) methyl] -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate (0.12 g) in ethanol (2 mL) and add 4N Hydrochloric acid-ethyl acetate solution (4 mL) was added. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethanol-ethyl acetate to give the title compound as colorless crystals (0.093 g, melting point 209-210 ° C).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.18-2.38 (2H, m), 2.68 (1H, d, J = 14.4 Hz), 2.83-3.03 (1H, m), 3.08-3.31 (1H, m ), 3.41-3.57 (1H, m), 3.57-3.72 (1H, m), 3.89 (1H, brs), 6.24 (1H, brs), 7.36 (1H, dd, J = 8.3, 2.3 Hz), 7.50- 7.71 (2H, m), 9.39 (1H, brs), 9.57 (1H, brs).
LC / MS 288.2

実施例２２６
N-{[(2R,3R)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]メチル}メタンスルホンアミド 1塩酸塩 Example 226
N-{[(2R, 3R) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] methyl} methanesulfonamide monohydrochloride

Figure JPOXMLDOC01-appb-C000301
Figure JPOXMLDOC01-appb-C000301

　tert-ブチル (2R,3R)-3-(3,4-ジクロロフェニル)-2-{[(メチルスルホニル)アミノ]メチル}ピロリジン-1-カルボキシラート(0.24 g)をエタノール(2 mL)に溶解させ、4規定塩酸－酢酸エチル溶液(4 mL)を加えた。反応混合物を室温で1時間攪拌し、溶媒を減圧下留去した。得られた残渣をエタノール－ジイソプロピルエーテルより結晶化して、標題化合物を無色結晶(0.177 g, 融点 137-138℃)として得た。
1H NMR (300 MHz, DMSO-d6) δ 2.19-2.30 (1H, m), 2.30-2.43 (1H, m), 2.73 (1H, dt, J = 14.0, 4.7 Hz), 2.85-3.00 (4H, m), 3.17-3.30 (1H, m), 3.51 (1H, ddd, J = 11.6, 8.4, 3.8 Hz), 3.72 (1H, q, J = 8.7 Hz), 3.89-4.03 (1H, m), 7.28-7.42 (2H, m), 7.59-7.72 (2H, m), 9.37-9.74 (2H, m).
Anal. Calcd for C12H16Cl2N2O3S・HCl: C, 40.07; H, 4.76; N, 7.79. Found: C, 40.22;H, 4.71; N, 7.86.
LC/MS 323.2, 325.3 tert-Butyl (2R, 3R) -3- (3,4-dichlorophenyl) -2-{[(methylsulfonyl) amino] methyl} pyrrolidine-1-carboxylate (0.24 g) was dissolved in ethanol (2 mL). 4N hydrochloric acid-ethyl acetate solution (4 mL) was added. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethanol-diisopropyl ether to give the title compound as colorless crystals (0.177 g, melting point 137-138 ° C).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.19-2.30 (1H, m), 2.30-2.43 (1H, m), 2.73 (1H, dt, J = 14.0, 4.7 Hz), 2.85-3.00 (4H , m), 3.17-3.30 (1H, m), 3.51 (1H, ddd, J = 11.6, 8.4, 3.8 Hz), 3.72 (1H, q, J = 8.7 Hz), 3.89-4.03 (1H, m), 7.28-7.42 (2H, m), 7.59-7.72 (2H, m), 9.37-9.74 (2H, m).
Anal.Calcd for C 12 H 16 Cl 2 N 2 O 3 S.HCl: C, 40.07; H, 4.76; N, 7.79. Found: C, 40.22; H, 4.71; N, 7.86.
LC / MS 323.2, 325.3

実施例２２７
N-{[(2R,3S)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]メチル}メタンスルホンアミド 1塩酸塩 Example 227
N-{[(2R, 3S) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] methyl} methanesulfonamide monohydrochloride

Figure JPOXMLDOC01-appb-C000302
Figure JPOXMLDOC01-appb-C000302

　tert-ブチル (2R,3S)-3-(3,4-ジクロロフェニル)-2-{[(メチルスルホニル)アミノ]メチル}ピロリジン-1-カルボキシラート(185 mg, 0.437 mmmol) のエタノール (5 mL) 溶液に２規定塩化水素－エタノール溶液 (10 mL) を加え、室温で1時間攪拌した。減圧下、溶媒を留去し、エタノール－酢酸エチルから結晶化させることにより、表題化合物を無色結晶(154 mg, 98%, 融点203-205℃)として得た。
1H NMR (300 MHz, DMSO-d6) δ 1.95-2.10 (1H, m), 2.30-2.45 (1H, m), 2.93 (3H, s), 3.10-3.50 (5H, m), 3.60-3.75 (1H, m), 7.35-7.45 (2H, m), 7.64 (1H, d, J= 8.7 Hz), 7.72 (1H, d, J = 2.1 Hz), 8.80-10.20 (2H, br).
LC/MS 323.2 [M+]
Anal. Calcd. for C12H16Cl2N2O2S・HCl・0.2H2O: C, 39.67; H, 4.83; N, 7.71. Found: C, 39.52; H, 4.75; N, 7.72. tert-Butyl (2R, 3S) -3- (3,4-dichlorophenyl) -2-{[(methylsulfonyl) amino] methyl} pyrrolidine-1-carboxylate (185 mg, 0.437 mmmol) in ethanol (5 mL) To the solution was added 2N hydrogen chloride-ethanol solution (10 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was crystallized from ethanol-ethyl acetate to give the title compound as colorless crystals (154 mg, 98%, melting point 203-205 ° C.).
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.95-2.10 (1H, m), 2.30-2.45 (1H, m), 2.93 (3H, s), 3.10-3.50 (5H, m), 3.60-3.75 (1H, m), 7.35-7.45 (2H, m), 7.64 (1H, d, J = 8.7 Hz), 7.72 (1H, d, J = 2.1 Hz), 8.80-10.20 (2H, br).
LC / MS 323.2 [M + ]
Anal.Calcd.for C 12 H 16 Cl 2 N 2 O 2 S.HCl.0.2H 2 O: C, 39.67; H, 4.83; N, 7.71. Found: C, 39.52; H, 4.75; N, 7.72.

実施例２２８
N-{[(2R,3S)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]メチル}アセトアミド　１塩酸塩 Example 228
N-{[(2R, 3S) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] methyl} acetamide monohydrochloride

Figure JPOXMLDOC01-appb-C000303
Figure JPOXMLDOC01-appb-C000303

　tert-ブチル (2R,3S)-2-[(アセチルアミノ)メチル]-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート(39 mg, 0.10 mmmol) のエタノール (2 mL) 溶液に２規定塩化水素－エタノール溶液 (5 mL) を加え、室温で1時間攪拌した。減圧下、溶媒を留去し、エタノール－酢酸エチルから結晶化させることにより、表題化合物を無色結晶(29 mg, 90%, 融点174-176℃)として得た。
1H NMR (300 MHz, DMSO-d6) δ 1.77 (3H, s), 1.95-2.10 (1H, m), 2.25-2.45 (1H, m), 3.10-3.70 (6H, m), 7.40 (1H, dd, J = 8.2, 2.1 Hz), 7.63 (1H, d, J = 8.2 Hz), 7.72 (1H, d, J = 2.1 Hz), 8.20-8.35 (1H, m), 8.90-9.20 (1H, br), 9.60-9.95 (1H, br).
LC/MS 287.0 [M+]
Anal. Calcd. for C13H16Cl2N2O・HCl・0.2H2O: C, 47.71 H, 5.36; N, 8.56. Found: C, 47.69; H, 5.26; N, 8.65 2 in a solution of tert-butyl (2R, 3S) -2-[(acetylamino) methyl] -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate (39 mg, 0.10 mmmol) in ethanol (2 mL) Normal hydrogen chloride-ethanol solution (5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol-ethyl acetate to give the title compound as colorless crystals (29 mg, 90%, melting point: 174-176 ° C).
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.77 (3H, s), 1.95-2.10 (1H, m), 2.25-2.45 (1H, m), 3.10-3.70 (6H, m), 7.40 (1H , dd, J = 8.2, 2.1 Hz), 7.63 (1H, d, J = 8.2 Hz), 7.72 (1H, d, J = 2.1 Hz), 8.20-8.35 (1H, m), 8.90-9.20 (1H, br), 9.60-9.95 (1H, br).
LC / MS 287.0 [M + ]
Anal.Calcd.for C 13 H 16 Cl 2 N 2 O · HCl · 0.2H 2 O: C, 47.71 H, 5.36; N, 8.56. Found: C, 47.69; H, 5.26; N, 8.65

実施例２２９
N-{[(2R,3S)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]メチル}硫酸 ジアミド　１塩酸塩 Example 229
N-{[(2R, 3S) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] methyl} sulfuric acid diamide monohydrochloride

Figure JPOXMLDOC01-appb-C000304
Figure JPOXMLDOC01-appb-C000304

　tert-ブチル (2R,3S)-2-({[(tert-ブトキシカルボニル)スルファモイル]アミノ}メチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート (135 mg, 0.257 mmmol) のエタノール (5 mL) 溶液に２規定塩化水素－エタノール溶液 (10 mL) を加え、室温で1時間攪拌した。減圧下、溶媒を留去し、エタノールから結晶化させることにより、表題化合物を無色結晶(75 mg, 81%, 融点202-203℃)として得た。
1H NMR (300 MHz, DMSO-d6) δ 1.95-2.10 (1H, m), 2.25-2.45 (1H, m), 3.00-3.55 (5H, m), 3.60-3.75 (1H, m), 6.74 (2H, s), 6.80-7.00 (1H, m), 7.41 (1H, dd, J= 8.7, 1.8 Hz), 7.64 (1H, d, J= 8.7 Hz), 7.72 (1H, d, J = 1.8 Hz), 8.90-9.20 (1H, br), 9.60-9.90 (1H, br).
LC/MS 323.9 [M+]
Anal. Calcd. for C11H15Cl2N3O2S・HCl: C, 36.63; H, 4.47; N, 11.65. Found: C, 36.56; H, 4.43; N, 11.55. of tert-butyl (2R, 3S) -2-({[(tert-butoxycarbonyl) sulfamoyl] amino} methyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate (135 mg, 0.257 mmmol) To the ethanol (5 mL) solution was added 2N hydrogen chloride-ethanol solution (10 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was distilled off under reduced pressure, and crystallization from ethanol gave the title compound as colorless crystals (75 mg, 81%, melting point 202-203 ° C.).
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.95-2.10 (1H, m), 2.25-2.45 (1H, m), 3.00-3.55 (5H, m), 3.60-3.75 (1H, m), 6.74 (2H, s), 6.80-7.00 (1H, m), 7.41 (1H, dd, J = 8.7, 1.8 Hz), 7.64 (1H, d, J = 8.7 Hz), 7.72 (1H, d, J = 1.8 Hz), 8.90-9.20 (1H, br), 9.60-9.90 (1H, br).
LC / MS 323.9 [M + ]
Anal.Calcd.for C 11 H 15 Cl 2 N 3 O 2 S.HCl: C, 36.63; H, 4.47; N, 11.65.Found: C, 36.56; H, 4.43; N, 11.55.

実施例２３０
N-{[(2S,3R)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]メチル}メタンスルホンアミド　1塩酸塩 Example 230
N-{[(2S, 3R) -3- (3,4-Dichlorophenyl) pyrrolidin-2-yl] methyl} methanesulfonamide monohydrochloride

Figure JPOXMLDOC01-appb-C000305
Figure JPOXMLDOC01-appb-C000305

　tert-ブチル (2S,3R)-3-(3,4-ジクロロフェニル)-2-{[(メチルスルホニル)アミノ]メチル}ピロリジン-1-カルボキシラート(295 mg, 0.699 mmmol) のエタノール (5 mL) 溶液に7規定塩化水素－エタノール溶液 (5 mL) を加え、室温で20分攪拌した。減圧下、溶媒を留去し、エタノールから結晶化させることにより、表題化合物を無色結晶(233 mg, 93%, 融点204-205℃)として得た。
1H NMR (300 MHz, DMSO-d6) δ 1.95-2.10 (1H, m), 2.30-2.45 (1H, m), 2.92 (3H, s), 3.10-3.50 (5H, m), 3.60-3.75 (1H, m), 7.35-7.45 (2H, m), 7.62 (1H, d, J= 8.4 Hz), 7.71 (1H, d, J = 2.1 Hz), 9.10-9.30 (1H, br), 9.75-9.95 (1H, br).
LC/MS 323.2 [M+]
Anal. Calcd. for C12H16Cl2N2O2S・HCl: C, 40.07; H, 4.76; N, 7.79. Found: C, 40.05; H, 4.87; N, 7.71. tert-Butyl (2S, 3R) -3- (3,4-dichlorophenyl) -2-{[(methylsulfonyl) amino] methyl} pyrrolidine-1-carboxylate (295 mg, 0.699 mmmol) in ethanol (5 mL) To the solution was added 7N hydrogen chloride-ethanol solution (5 mL), and the mixture was stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure, and the residue was crystallized from ethanol to give the title compound as colorless crystals (233 mg, 93%, melting point 204-205 ° C.).
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.95-2.10 (1H, m), 2.30-2.45 (1H, m), 2.92 (3H, s), 3.10-3.50 (5H, m), 3.60-3.75 (1H, m), 7.35-7.45 (2H, m), 7.62 (1H, d, J = 8.4 Hz), 7.71 (1H, d, J = 2.1 Hz), 9.10-9.30 (1H, br), 9.75- 9.95 (1H, br).
LC / MS 323.2 [M + ]
Anal.Calcd.for C 12 H 16 Cl 2 N 2 O 2 S.HCl: C, 40.07; H, 4.76; N, 7.79. Found: C, 40.05; H, 4.87; N, 7.71.

実施例２３１
N-{[(2S,3R)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]メチル}アセトアミド　１塩酸塩 Example 231
N-{[(2S, 3R) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] methyl} acetamide monohydrochloride

Figure JPOXMLDOC01-appb-C000306
Figure JPOXMLDOC01-appb-C000306

　tert-ブチル (2S,3R)-2-[(アセチルアミノ)メチル]-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート(270 mg, 0.697 mmmol) のエタノール (5 mL) 溶液に7規定塩化水素－エタノール溶液 (5 mL) を加え、室温で20分攪拌した。減圧下、溶媒を留去することにより、表題化合物を無色結晶(189 mg, 84%, 融点174-175℃)として得た。
1H NMR (300 MHz, DMSO-d6) δ 1.77 (3H, s), 1.95-2.10 (1H, m), 2.25-2.45 (1H, m), 3.10-3.70 (6H, m), 7.40 (1H, dd, J = 8.1, 1.8 Hz), 7.62 (1H, d, J = 8.1 Hz), 7.72 (1H, d, J = 1.8 Hz), 8.20-8.35 (1H, m), 9.05-9.30 (1H, br), 9.75-9.95 (1H, br).
LC/MS 287.2 [M+]
Anal. Calcd. for C13H16Cl2N2O・HCl: C, 48.24 H, 5.29; N, 8.66. Found: C, 48.23; H, 5.38; N, 8.63 7 in a solution of tert-butyl (2S, 3R) -2-[(acetylamino) methyl] -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate (270 mg, 0.697 mmmol) in ethanol (5 mL) Normal hydrogen chloride-ethanol solution (5 mL) was added, and the mixture was stirred at room temperature for 20 min. The solvent was distilled off under reduced pressure to obtain the title compound as colorless crystals (189 mg, 84%, melting point: 174-175 ° C.).
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.77 (3H, s), 1.95-2.10 (1H, m), 2.25-2.45 (1H, m), 3.10-3.70 (6H, m), 7.40 (1H , dd, J = 8.1, 1.8 Hz), 7.62 (1H, d, J = 8.1 Hz), 7.72 (1H, d, J = 1.8 Hz), 8.20-8.35 (1H, m), 9.05-9.30 (1H, br), 9.75-9.95 (1H, br).
LC / MS 287.2 [M + ]
Anal.Calcd.for C 13 H 16 Cl 2 N 2 O · HCl: C, 48.24 H, 5.29; N, 8.66. Found: C, 48.23; H, 5.38; N, 8.63

実施例２３２
N-{[(2S,3R)-3-(3,4-ジクロロフェニル)ピロリジン-2-イル]メチル}硫酸 ジアミド　１塩酸塩 Example 232
N-{[(2S, 3R) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] methyl} sulfuric acid diamide monohydrochloride

Figure JPOXMLDOC01-appb-C000307
Figure JPOXMLDOC01-appb-C000307

　tert-ブチル (2S,3R)-2-({[(tert-ブトキシカルボニル)スルファモイル]アミノ}メチル)-3-(3,4-ジクロロフェニル)ピロリジン-1-カルボキシラート (260 mg, 0.257 mmmol) のエタノール (5 mL) 溶液に２規定塩化水素－エタノール溶液 (10 mL) を加え、室温で1時間攪拌した。減圧下、溶媒を留去し、エタノールから結晶化させることにより、表題化合物を無色結晶(75 mg, 81%, 融点202-204℃)として得た。
1H NMR (300 MHz, DMSO-d6) δ 1.95-2.10 (1H, m), 2.25-2.45 (1H, m), 3.00-3.55 (5H, m), 3.60-3.75 (1H, m), 6.75 (2H, s), 6.80-7.00 (1H, m), 7.41 (1H, dd, J = 8.7, 2.4 Hz), 7.63 (1H, d, J = 8.7 Hz), 7.73 (1H, d, J= 2.4Hz), 9.05-9.30 (1H, br), 9.75-10.00 (1H, br).
LC/MS 324.2 [M+]
Anal. Calcd. for C11H15Cl2N3O2S・HCl: C, 36.63; H, 4.47; N, 11.65. Found: C, 36.83; H, 4.57; N, 11.68. of tert-butyl (2S, 3R) -2-({[(tert-butoxycarbonyl) sulfamoyl] amino} methyl) -3- (3,4-dichlorophenyl) pyrrolidine-1-carboxylate (260 mg, 0.257 mmmol) To the ethanol (5 mL) solution was added 2N hydrogen chloride-ethanol solution (10 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was distilled off under reduced pressure, and the residue was crystallized from ethanol to give the title compound as colorless crystals (75 mg, 81%, melting point 202-204 ° C.).
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.95-2.10 (1H, m), 2.25-2.45 (1H, m), 3.00-3.55 (5H, m), 3.60-3.75 (1H, m), 6.75 (2H, s), 6.80-7.00 (1H, m), 7.41 (1H, dd, J = 8.7, 2.4 Hz), 7.63 (1H, d, J = 8.7 Hz), 7.73 (1H, d, J = 2.4 Hz), 9.05-9.30 (1H, br), 9.75-10.00 (1H, br).
LC / MS 324.2 [M + ]
Anal.Calcd.for C 11 H 15 Cl 2 N 3 O 2 S.HCl: C, 36.63; H, 4.47; N, 11.65.Found: C, 36.83; H, 4.57; N, 11.68.

　上記と同様の方法により合成した実施例９６、９８、９９、１０２～１８１、１８３～２１９、２２１および２２４の化合物を、以下の表１～１２に示す。なお、表中のＭＳは実測値を示す。また、ＭＳのデータを記載していない化合物については、ＮＭＲのデータを記載した。
　表１～１２に記載した化合物の構造式において、「－ＮＨ－」は「－Ｎ－」と略記されている。 The compounds of Examples 96, 98, 99, 102 to 181, 183 to 219, 221 and 224 synthesized by the same method as described above are shown in Tables 1 to 12 below. In the table, MS indicates an actual measurement value. In addition, NMR data were described for compounds for which MS data was not described.
In the structural formulas of the compounds described in Tables 1 to 12, “—NH—” is abbreviated as “—N—”.

Figure JPOXMLDOC01-appb-T000308
Figure JPOXMLDOC01-appb-T000308

Figure JPOXMLDOC01-appb-T000309
Figure JPOXMLDOC01-appb-T000309

Figure JPOXMLDOC01-appb-T000310
Figure JPOXMLDOC01-appb-T000310

Figure JPOXMLDOC01-appb-T000311
Figure JPOXMLDOC01-appb-T000311

Figure JPOXMLDOC01-appb-T000312
Figure JPOXMLDOC01-appb-T000312

Figure JPOXMLDOC01-appb-T000313
Figure JPOXMLDOC01-appb-T000313

Figure JPOXMLDOC01-appb-T000314
Figure JPOXMLDOC01-appb-T000314

Figure JPOXMLDOC01-appb-T000315
Figure JPOXMLDOC01-appb-T000315

Figure JPOXMLDOC01-appb-T000316
Figure JPOXMLDOC01-appb-T000316

Figure JPOXMLDOC01-appb-T000317
Figure JPOXMLDOC01-appb-T000317

Figure JPOXMLDOC01-appb-T000318
Figure JPOXMLDOC01-appb-T000318

Figure JPOXMLDOC01-appb-T000319
Figure JPOXMLDOC01-appb-T000319

試験例１
（１）ヒトドーパミントランスポーター発現プラスミドの構築
　特開平5-076385記載のpTB1411に含まれるSRαプロモーターは、制限酵素HindIII(タカラバイオ社製)で切断し、平滑末端化後、さらに制限酵素EcoRI(タカラバイオ社製)で切断し、断片化した。一方、pCIベクターは、制限酵素BglII(タカラバイオ社製)で切断し、T4DNAポリメラーゼで平滑末端化後、さらに制限酵素EcoRI(タカラバイオ社製)で切断した。このサイトにSRαプロモーター断片を挿入して、pCI-SRaを作製した。次いで、pCI-SRaを制限酵素ClaI(タカラバイオ社製)で切断後、平滑末端化したサイトに、pGFP-C1(東洋紡社製)を制限酵素Bsu36I(第一化学薬品社製)で切断後、平滑末端化した1.63Kbの断片を挿入し、pMSRα neoを作製した。ヒトドーパミントランスポーターcDNAは、ヒト黒質cDNAライブラリーよりPCRにより増幅し、pCRIIベクター（Invitrogen社製）に挿入した。塩基配列を確認・修正後、pMSRα neoにサブクローニングし、ヒトドーパミントランスポーター発現プラスミドを構築した。 Test example 1
(1) Construction of human dopamine transporter expression plasmid The SRα promoter contained in pTB1411 described in JP-A-5-076385 is cleaved with restriction enzyme HindIII (manufactured by Takara Bio Inc.), blunt-ended, and further subjected to restriction enzyme EcoRI (Takara). (Manufactured by Bio Inc.) and fragmented. On the other hand, the pCI vector was cleaved with the restriction enzyme BglII (Takara Bio), blunt-ended with T4 DNA polymerase, and further cleaved with the restriction enzyme EcoRI (Takara Bio). An SRα promoter fragment was inserted into this site to prepare pCI-SRa. Next, after cleaving pCI-SRa with restriction enzyme ClaI (Takara Bio), blunt-ended sites, pGFP-C1 (Toyobo) after cleavage with restriction enzyme Bsu36I (Daiichi Chemical) A blunt-ended 1.63 Kb fragment was inserted to prepare pMSRα neo. Human dopamine transporter cDNA was amplified by PCR from a human substantia nigra cDNA library and inserted into a pCRII vector (Invitrogen). After confirming and correcting the nucleotide sequence, it was subcloned into pMSRα neo to construct a human dopamine transporter expression plasmid.

（２）ヒトモノアミン発現細胞の作製
　ヒトセロトニントランスポーターcDNAは、ヒト脳cDNAライブラリーよりPCRにより増幅し、pCRII-TOPOベクター（Invitrogen社製）に挿入した。塩基配列を確認・修正後、pcDNA３．１ベクター（Invitrogen社製）にサブクローニングし、ヒトセロトニントランスポーター発現プラスミドを構築した。ヒトノルエピネフリントランスポーターcDNAは、Invitrogen社より購入し、塩基配列を確認・修正後、pcDNA３．１ベクターにサブクローニングし、ヒトノルエピネフリントランスポーター発現プラスミドを構築した。
　これら作製したモノアミントランスポーター発現プラスミドを、FuGENE6（Roche Diagnostics社製）を用い、添付のプロトコールに従いCHO-K1細胞に導入し、それぞれの発現細胞を樹立した。 (2) Preparation of human monoamine-expressing cells Human serotonin transporter cDNA was amplified by PCR from a human brain cDNA library and inserted into a pCRII-TOPO vector (Invitrogen). After confirming and correcting the base sequence, it was subcloned into pcDNA3.1 vector (manufactured by Invitrogen) to construct a human serotonin transporter expression plasmid. Human norepinephrine transporter cDNA was purchased from Invitrogen, and after confirming and correcting the nucleotide sequence, it was subcloned into pcDNA3.1 vector to construct a human norepinephrine transporter expression plasmid.
These prepared monoamine transporter expression plasmids were introduced into CHO-K1 cells using FuGENE6 (Roche Diagnostics) according to the attached protocol to establish each expression cell.

（３）ヒトセロトニントランスポーターに対する阻害作用
　ヒトセロトニントランスポーター阻害活性の測定にはヒトセロトニントランスポーターを安定発現したCHO細胞を用いた。特に記載が無い限り、これらのCHO細胞は、10%牛胎児血清(MOREGATE)を含むHam/F12培地(Invitrogen)を用いて培養した。
　ほぼコンフルエントになるまで培養した細胞を、PBS (Invitrogen)を用いてリンスした後、Trypsin/EDTA (Invitrogen)を用いて剥がし、遠心操作にて回収した。得られた細胞の数を測定し、培地1 mLあたり3×105個の細胞が含まれるように希釈し、96 well white plate (Corning)に1穴あたり100 μLずつ分注後、CO2培養器にて一晩培養した。
　次に、アッセイバッファー（126 mM NaCl, 4.95 mM KCl, 1.26 mM KH2PO4, 1.26 mM MgSO4, 10 mM HEPES, 2.32 mM CaCl2, 5.52 mM Glucose, 0.5% BSA）を調製し、細胞プレートの培地を除去した後、80 μLずつアッセイバッファーを添加した。また試験化合物をアッセイバッファーにて終濃度の10倍濃度となるように希釈し、ポリプロピレン製96 well plateに分注した。その希釈した試験化合物を10 μLずつ細胞プレートに分注した。[3H]-5-ヒドロキシトリプタミン（GE Healthcare）をアッセイバッファーにて200 nMとなるように希釈し、それを細胞プレートに10 μLずつ分注した。[3H]-5-ヒドロキシトリプタミンを添加してから20分経過したところで、アッセイバッファーを吸引除去し、PBS (Invitrogen)で1穴あたり150 μL、2回洗浄した。Microscinti20（PerkinElmer）を1穴あたり100 μLずつ分注し、30分前後攪拌した。放射活性はTopCount（PerkinElmer）で測定した。
　各化合物の10 μMの阻害活性を、10 μMのParoxetine（セロトニントランスポーター阻害剤）の阻害活性を100%とする相対活性値として算出した。その結果を表１３および１４に示す。 (3) Inhibitory effect on human serotonin transporter For the measurement of human serotonin transporter inhibitory activity, CHO cells stably expressing human serotonin transporter were used. Unless otherwise stated, these CHO cells were cultured using Ham / F12 medium (Invitrogen) containing 10% fetal calf serum (MOREGATE).
Cells cultured until almost confluent were rinsed with PBS (Invitrogen), then detached with Trypsin / EDTA (Invitrogen), and collected by centrifugation. Count the number of cells obtained, dilute to contain 3 × 10 5 cells per mL of medium, dispense 100 μL per well into a 96 well white plate (Corning), and culture with CO 2 Incubated overnight in a vessel.
Next, prepare assay buffer (126 mM NaCl, 4.95 mM KCl, 1.26 mM KH 2 PO 4 , 1.26 mM MgSO 4 , 10 mM HEPES, 2.32 mM CaCl 2 , 5.52 mM Glucose, 0.5% BSA) After removing the medium, 80 μL of assay buffer was added. Further, the test compound was diluted with an assay buffer so as to have a concentration 10 times the final concentration, and dispensed into a 96-well plate made of polypropylene. 10 μL of the diluted test compound was dispensed into the cell plate. [3H] -5-hydroxytryptamine (GE Healthcare) was diluted to 200 nM with an assay buffer, and 10 μL was dispensed onto the cell plate. After 20 minutes from the addition of [3H] -5-hydroxytryptamine, the assay buffer was removed by aspiration and washed twice with PBS (Invitrogen) at 150 μL per well. Microscinti20 (PerkinElmer) was dispensed at 100 μL per well and stirred for about 30 minutes. Radioactivity was measured with TopCount (PerkinElmer).
The 10 μM inhibitory activity of each compound was calculated as a relative activity value where the inhibitory activity of 10 μM Paroxetine (a serotonin transporter inhibitor) was taken as 100%. The results are shown in Tables 13 and 14.

Figure JPOXMLDOC01-appb-T000320
Figure JPOXMLDOC01-appb-T000320

Figure JPOXMLDOC01-appb-T000321
Figure JPOXMLDOC01-appb-T000321

試験例２　ヒトノルエピネフリントランスポーターに対する阻害作用
　ヒトノルエピネフリントランスポーター阻害活性の測定にはヒトノルエピネフリントランスポーターを安定発現したCHO細胞を用いた。特に記載が無い限り、これらのCHO細胞は10%牛胎児血清(MOREGATE)を含むHam/F12培地(Invitrogen)を用いて培養した。
　ほぼコンフルエントになるまで培養した細胞を、PBS (Invitrogen)を用いてリンスした後、Trypsin/EDTA (Invitrogen)を用いて剥がし、遠心操作にて回収した。得られた細胞の数を測定し、培地1 mLあたり3×105個の細胞が含まれるように希釈し、96 well white plate (Corning)に1穴あたり100 μLずつ分注後、CO2培養器にて一晩培養した。
　次にアッセイバッファー（126 mM NaCl, 4.95 mM KCl, 1.26 mM KH2PO4, 1.26 mM MgSO4, 10 mM HEPES, 2.32 mM CaCl2, 5.52 mM Glucose, 0.5% BSA）を調製し、細胞プレートの培地を除去した後、80 μLずつアッセイバッファーを添加した。また試験化合物をアッセイバッファーにて終濃度の10倍濃度となるように希釈し、ポリプロピレン製96 well plateに分注した。その希釈した試験化合物を10 μLずつ細胞プレートに分注した。[3H]-ノルエピネフリン（GE Healthcare）をアッセイバッファーにて200 nMとなるように希釈し、それを細胞プレートに10 μLずつ分注した。[3H]-ノルエピネフリンを添加してから45分経過したところで、アッセイバッファーを吸引除去し、PBS (Invitrogen)で1穴あたり150 μL、2回洗浄した。Microscinti20（PerkinElmer）を1穴あたり100 μLずつ分注し、30分前後攪拌した。放射活性はTopCount（PerkinElmer）で測定した。
　各化合物の10 μMの阻害活性を、10 μMのDMI（ノルエピネフリントランスポーター阻害剤）の阻害活性を100%とする相対活性値として算出した。その結果を表１５および１６に示す。 Test Example 2 Inhibitory Action on Human Norepinephrine Transporter For measurement of human norepinephrine transporter inhibitory activity, CHO cells stably expressing human norepinephrine transporter were used. Unless otherwise stated, these CHO cells were cultured using Ham / F12 medium (Invitrogen) containing 10% fetal calf serum (MOREGATE).
Cells cultured until almost confluent were rinsed with PBS (Invitrogen), then detached with Trypsin / EDTA (Invitrogen), and collected by centrifugation. Count the number of cells obtained, dilute to contain 3 × 10 5 cells per mL of medium, dispense 100 μL per well into a 96 well white plate (Corning), and culture with CO 2 Incubated overnight in a vessel.
Next, prepare the assay buffer (126 mM NaCl, 4.95 mM KCl, 1.26 mM KH 2 PO 4 , 1.26 mM MgSO 4 , 10 mM HEPES, 2.32 mM CaCl 2 , 5.52 mM Glucose, 0.5% BSA). Then, 80 μL of assay buffer was added. Further, the test compound was diluted with an assay buffer so as to have a concentration 10 times the final concentration, and dispensed into a 96-well plate made of polypropylene. 10 μL of the diluted test compound was dispensed into the cell plate. [3H] -norepinephrine (GE Healthcare) was diluted to 200 nM with an assay buffer, and 10 μL was dispensed onto the cell plate. 45 minutes after the addition of [3 H] -norepinephrine, the assay buffer was removed by aspiration and washed twice with PBS (Invitrogen) at 150 μL per well. Microscinti20 (PerkinElmer) was dispensed at 100 μL per well and stirred for about 30 minutes. Radioactivity was measured with TopCount (PerkinElmer).
The 10 μM inhibitory activity of each compound was calculated as a relative activity value with the inhibitory activity of 10 μM DMI (norepinephrine transporter inhibitor) as 100%. The results are shown in Tables 15 and 16.

Figure JPOXMLDOC01-appb-T000322
Figure JPOXMLDOC01-appb-T000322

Figure JPOXMLDOC01-appb-T000323
Figure JPOXMLDOC01-appb-T000323

試験例３　ヒトドーパミントランスポーターに対する阻害作用
　ヒトドーパミントランスポーター阻害活性の測定にはヒトドーパミントランスポーターを安定発現したCHO細胞を用いた。特に記載が無い限り、これらのCHO細胞は10%牛胎児血清(MOREGATE)を含むHam/F12培地(Invitrogen)を用いて培養した。
　アッセイ前日に、ほぼコンフルエントになるまで培養した細胞を、PBS (Invitrogen)を用いてリンスした後、Trypsin/EDTA (Invitrogen)を用いて剥がし、遠心操作にて回収した。得られた細胞の数を測定し、培地1 mLあたり3×105個の細胞が含まれるように希釈し、96 well white plate (Corning)に1穴あたり100 μLずつ分注後、CO2培養器にて一晩培養した。
　試験当日にアッセイバッファー（126 mM NaCl, 4.95 mM KCl, 1.26 mM KH2PO4, 1.26 mM MgSO4, 10 mM HEPES, 2.32 mM CaCl2, 5.52 mM Glucose, 0.5% BSA）を調製し、細胞プレートの培地を除去した後、80 μLずつアッセイバッファーを添加した。また試験化合物をアッセイバッファーにて終濃度の10倍濃度となるように希釈し、ポリプロピレン製96 well plateに分注した。その希釈した試験化合物を10 μLずつ細胞プレートに分注した。アッセイバッファーで[3H]-ドーパミン（GE Healthcare）を200 nMとなるように希釈し、またコールドのドーパミンを10 μMとなるように希釈した。それを細胞プレートに10 μLずつ分注した。[3H]-ドーパミンを添加してから60分経過したところで、アッセイバッファーを吸引除去し、PBS (Invitrogen)で1穴あたり150 μL、2回洗浄した。Microscinti20（PerkinElmer）を1穴あたり100 μLずつ分注し、30分前後攪拌した。放射活性はTopCount（PerkinElmer）で測定した。
　各化合物の10 μMの阻害活性を、100 μMのNomifensine（ドーパミントランスポーター阻害剤）の阻害活性を100%とする相対活性値として算出した。その結果を表１７および１８に示す。 Test Example 3 Inhibitory action on human dopamine transporter For the measurement of human dopamine transporter inhibitory activity, CHO cells stably expressing human dopamine transporter were used. Unless otherwise stated, these CHO cells were cultured using Ham / F12 medium (Invitrogen) containing 10% fetal calf serum (MOREGATE).
On the day before the assay, the cells cultured until they were almost confluent were rinsed with PBS (Invitrogen), detached with Trypsin / EDTA (Invitrogen), and collected by centrifugation. Count the number of cells obtained, dilute to contain 3 × 10 5 cells per mL of medium, dispense 100 μL per well into a 96 well white plate (Corning), and culture with CO 2 Incubated overnight in a vessel.
Prepare the assay buffer (126 mM NaCl, 4.95 mM KCl, 1.26 mM KH 2 PO 4 , 1.26 mM MgSO 4 , 10 mM HEPES, 2.32 mM CaCl 2 , 5.52 mM Glucose, 0.5% BSA) on the day of the test. After removing the medium, 80 μL of assay buffer was added. Further, the test compound was diluted with an assay buffer so as to have a concentration 10 times the final concentration, and dispensed into a 96-well plate made of polypropylene. 10 μL of the diluted test compound was dispensed into the cell plate. [3H] -Dopamine (GE Healthcare) was diluted to 200 nM with assay buffer, and cold dopamine was diluted to 10 μM. 10 μL was dispensed onto the cell plate. When 60 minutes had elapsed since the addition of [3 H] -dopamine, the assay buffer was removed by aspiration and washed twice with PBS (Invitrogen) at 150 μL per well. Microscinti20 (PerkinElmer) was dispensed at 100 μL per well and stirred for about 30 minutes. Radioactivity was measured with TopCount (PerkinElmer).
The 10 μM inhibitory activity of each compound was calculated as a relative activity value with the inhibitory activity of 100 μM Nomifensine (dopamine transporter inhibitor) as 100%. The results are shown in Tables 17 and 18.

Figure JPOXMLDOC01-appb-T000324
Figure JPOXMLDOC01-appb-T000324

Figure JPOXMLDOC01-appb-T000325
Figure JPOXMLDOC01-appb-T000325

試験例４　尿道抵抗上昇作用の測定
　尿道抵抗上昇作用の測定は、松本ら（ＰＣＴ／ＪＰ２００８／７０８０９）の方法に習い、修正して、次のようにして行った。すなわち、ＳＤ雌性ラットをウレタン（０．７　ｇ／ｋｇ，腹腔内投与; ＷＡＫＯ）で麻酔し、更に、ハロセン（１．０％；Ｔａｋｅｄａ）麻酔を追加して、排尿反射を消失させるために脊髄をＴｈ８－９で切断した。開腹後、膀胱内圧測定用および生理食塩水注入用のカテーテル（ＰＥ－１００；Ｃｌａｙ　Ａｄａｍｓ）を膀胱に挿入した。膀胱内圧測定用カテーテルは圧トランスデユーサー（ＲＥＦ６８５６４０；Ｎｉｈｏｎ　Ｋｏｄｅｎ）、アンプ（ＲＰＭ-６００８Ｍ；Ｎｉｈｏｎ　Ｋｏｄｅｎ）、多チャンネルデーター解析装置（ＭＰ１５０；Ｂｉｏｐａｃｋ）を介してコンピューターに接続し、膀胱内圧の変化を１００　ｓａｍｐｌｅｓ／秒の頻度でハードディスクに記録した。生理食塩水は、インフュージョンポンプ（Ｋｄｓ１００；ＫＤＳｃｉｅｎｔｉｆｉｃ）を用いて０．１　ｍＬ／秒の速度で膀胱内へ注入し、尿道口から生理食塩水の漏出が観察されたときに注入を停止し、膀胱内の生理食塩水を排出させた。生理食塩水を膀胱内へ注入し漏出するまでの最大圧をＬＰＰ（Ｌｅａｋ　ｐｏｉｎｔ　ｐｒｅｓｓｕｒｅ）値とした。ＬＰＰ値が安定するまで測定を繰り返し、最後の３回のＬＰＰ値を平均し結果とした。また、静脈内投与による溶媒効果を小さくするために、溶媒を膀胱内圧測定の１０分前に投与した。薬物の作用については、ＬＰＰ値（Ｐｒｅ値）を測定した後に薬物を静脈内投与し、１０分後に、再びＬＰＰ値（Ｐｏｓｔ値）を測定し、薬物による尿道抵抗上昇作用は、ＬＰＰ値（Ｐｏｓｔ値）とＬＰＰ値（Ｐｒｅ値）の差で表した。また、薬物は、５０％　Ｎ，Ｎ－ｄｉｍｅｔｈｙｌａｃｅｔａｍｉｄｅ（Ｗａｋｏ）と５０％　Ｐｏｌｙｅｔｈｙｌｅｎｅ　ｇｌｙｃｏｌ４００（Ｗａｋｏ）の混合液を溶媒として用いて、３ｍｇ／ｋｇにて溶解し、０．５ｍＬ／ｋｇの割合で静脈内投与した。
　実施例９７の化合物、実施例１８２の化合物、または、溶媒をラットへ投与し、上述した方法において、尿道抵抗上昇作用を測定した。表１９に示すように、実施例９７または実施例１８２の化合物の化合物を投与したラットにおいて、溶媒を投与したラットに比べて、有意な尿道抵抗上昇が確認された。上記により、実施例９７および実施例１８２の化合物が有意な尿道抵抗上昇作用を有することが示された。 Test Example 4 Measurement of urethral resistance increasing action The measurement of the urethral resistance increasing action was carried out as follows according to the method of Matsumoto et al. (PCT / JP2008 / 70809). That is, SD female rats were anesthetized with urethane (0.7 g / kg, intraperitoneal administration; WAKO), and further added with halothane (1.0%; Takeda) anesthesia to eliminate the micturition reflex. Was cleaved with Th8-9. After laparotomy, a catheter (PE-100; Clay Adams) for measuring intravesical pressure and injecting physiological saline was inserted into the bladder. The intravesical pressure measurement catheter is connected to a computer via a pressure transducer (REF 695640; Nihon Koden), an amplifier (RPM-6008M; Nihon Koden), and a multi-channel data analyzer (MP150; Biopack) to measure changes in the intravesical pressure. Recording was performed on the hard disk at a frequency of 100 samples / second. Saline was infused into the bladder at a rate of 0.1 mL / sec using an infusion pump (Kds100; KDScientific) and stopped when saline leakage was observed from the urethral orifice, Saline in the bladder was drained. The maximum pressure until physiological saline was injected into the bladder and leaked was defined as an LPP (Leak point pressure) value. The measurement was repeated until the LPP value became stable, and the last three LPP values were averaged to obtain a result. In order to reduce the solvent effect due to intravenous administration, the solvent was administered 10 minutes before the measurement of intravesical pressure. As for the action of the drug, the LPP value (Pre value) was measured and then the drug was intravenously administered. Ten minutes later, the LPP value (Post value) was measured again. Value) and LPP value (Pre value). The drug is dissolved at 3 mg / kg intravenously at a rate of 0.5 mL / kg using a mixture of 50% N, N-dimethylacetamide (Wako) and 50% Polyethylene glycol 400 (Wako) as a solvent. Administered.
The compound of Example 97, the compound of Example 182 or the solvent was administered to rats, and the effect of increasing urethral resistance was measured by the method described above. As shown in Table 19, a significant increase in urethral resistance was confirmed in rats administered with the compound of Example 97 or Example 182 compared to rats administered with the solvent. From the above, it was shown that the compounds of Example 97 and Example 182 have a significant urethral resistance increasing action.

Figure JPOXMLDOC01-appb-T000326
Figure JPOXMLDOC01-appb-T000326

製剤例１
　化合物（Ｉ’）を含有する医薬は、例えば、以下の処方によって製造することができる。
１．カプセル剤
（１）実施例１で得られた化合物 　４０ｍｇ
（２）ラクトース 　　　　　　　　７０ｍｇ
（３）微結晶セルロース 　　　　　　９ｍｇ
（４）ステアリン酸マグネシウム 　　１ｍｇ
１カプセル 　　　　　　　　　　１２０ｍｇ
　（１）、（２）、（３）および（４）の１／２を混和した後、顆粒化する。これに残りの（４）を加えて全体をゼラチンカプセルに封入する。 Formulation Example 1
The pharmaceutical containing compound (I ') can be manufactured by the following prescription, for example.
1. Capsule (1) 40 mg of the compound obtained in Example 1
(2) Lactose 70mg
(3) Microcrystalline cellulose 9mg
(4) Magnesium stearate 1mg
1 capsule 120mg
After mixing 1/2 of (1), (2), (3) and (4), granulate. The remaining (4) is added to this and the whole is enclosed in a gelatin capsule.

２．錠剤
（１）実施例１で得られた化合物 　４０ｍｇ
（２）ラクトース 　　　　　　　　５８ｍｇ
（３）コーンスターチ 　　　　　　１８ｍｇ
（４）微結晶セルロース 　　　　３．５ｍｇ
（５）ステアリン酸マグネシウム ０．５ｍｇ
１錠 　　　　　　　　　　　　　１２０ｍｇ
　（１）、（２）、（３）、（４）の２／３および（５）の１／２を混和した後、顆粒化する。残りの（４）および（５）をこの顆粒に加えて錠剤に加圧成型する。 2. Tablet (1) Compound obtained in Example 1 40 mg
(2) Lactose 58mg
(3) Corn starch 18mg
(4) Microcrystalline cellulose 3.5mg
(5) Magnesium stearate 0.5mg
1 tablet 120mg
After mixing 2/3 of (1), (2), (3), (4) and 1/2 of (5), granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.

製剤例２
　日局注射用蒸留水５０ｍＬに実施例１で得られた化合物５０ｍｇを溶解した後、日局注射用蒸留水を加えて１００ｍＬとする。この溶液を滅菌条件下でろ過し、次にこの溶液１ｍＬずつを取り、滅菌条件下、注射用バイアルに充填し、凍結乾燥して密閉する。 Formulation Example 2
After dissolving 50 mg of the compound obtained in Example 1 in 50 mL of JP injection distilled water, JP JP distilled water is added to make 100 mL. The solution is filtered under sterile conditions, then 1 mL of this solution is taken and filled into injection vials under sterile conditions, lyophilized and sealed.

　本発明の化合物またはそのプロドラッグは、優れたモノアミン（セロトニン、ノルエピネフリン、ドーパミン等）再取り込み阻害活性を有するため、例えば、うつ病、不安症、注意欠陥・多動性障害、腹圧性尿失禁等の安全な予防・治療薬として有用である。 Since the compound of the present invention or a prodrug thereof has excellent monoamine (serotonin, norepinephrine, dopamine, etc.) reuptake inhibitory activity, for example, depression, anxiety, attention deficit / hyperactivity disorder, stress urinary incontinence, etc. It is useful as a safe preventive / therapeutic drug.

　本出願は、日本で出願された特願２００９－１０３４６０を基礎としており、その内容は本明細書にすべて包含されるものである。 This application is based on Japanese Patent Application No. 2009-103460 filed in Japan, the contents of which are incorporated in full herein.

Claims (19)

　式（Ｉ）：
Figure JPOXMLDOC01-appb-C000001
〔式中：
Ｘは、置換されていてもよい低級アルキレン、－ＣＯ－、－ＣＨ２ＣＯ－または置換されていてもよい５員複素環、
Ｒ１は、ヒドロキシ、シアノ、置換されていてもよいアミノ、置換されていてもよい低級アルキル、置換されていてもよい低級アルコキシ、置換されていてもよいフェニル、置換されていてもよいメルカプト、置換スルホニルまたは置換されていてもよい４～１０員含窒素複素環基、
Ｒ２は、水素原子、ハロゲン原子、置換されていてもよい低級アルキル、または置換されていてもよいアルコキシカルボニル、
Ｒ３は、水素原子または低級アルキル、
Ｒ４～Ｒ１３は、同一または異なって、水素原子、ハロゲン原子または低級アルキルを表し、
この場合において、
Ｒ９～Ｒ１３の少なくとも１つの基はハロゲン原子または低級アルキルを表し、あるいは、
Ｒ４～Ｒ９、Ｒ１２およびＲ１３は、同一または異なって、水素原子、ハロゲン原子または低級アルキルを表し、Ｒ１０およびＲ１１は、それぞれが隣接するベンゼン環と共に一体となって、置換されていてもよいナフタレン環または置換されていてもよい縮合複素芳香環を形成する。
（ただし、（ｉ）Ｒ２が水素原子かつＸ－Ｒ１が－ＣＯＯＨである化合物、（ｉｉ）Ｒ２が水素原子、Ｘが－ＣＯ－、およびＲ１が置換されていてもよい低級アルコキシである化合物、（ｉｉｉ）Ｒ２が水素原子かつＲ１がフェニル基上に置換基を有していてもよい４－フェニル－１－ピペラジニルである化合物、（ｉｖ）トランス－Ｎ－２－アダマンチル－３－（４－クロロフェニル）－プロリンアミドおよび（ｖ）（３Ｒ）－３－（２－ナフタレニル）－Ｌ－プロリル－Ｌ－アスパラギニル－Ｌ－アラニル－Ｌ－バリンアミドを除く。）〕で表される化合物またはその塩。 Formula (I):
Figure JPOXMLDOC01-appb-C000001
[In the formula:
X is optionally substituted lower alkylene, —CO—, —CH 2 CO— or an optionally substituted 5-membered heterocyclic ring,
R 1 is hydroxy, cyano, optionally substituted amino, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted phenyl, optionally substituted mercapto, Substituted sulfonyl or optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group,
R 2 represents a hydrogen atom, a halogen atom, an optionally substituted lower alkyl, or an optionally substituted alkoxycarbonyl,
R 3 is a hydrogen atom or lower alkyl,
R 4 to R 13 are the same or different and each represents a hydrogen atom, a halogen atom or lower alkyl,
In this case,
At least one group of R 9 to R 13 represents a halogen atom or lower alkyl, or
R 4 to R 9, R 12 and R 13 are the same or different and each represents a hydrogen atom, a halogen atom or lower alkyl, and R 10 and R 11 are each substituted together with the adjacent benzene ring. An optionally substituted naphthalene ring or an optionally substituted fused heteroaromatic ring is formed.
(However, (i) R 2 is a hydrogen atom and X—R 1 is —COOH, (ii) R 2 is a hydrogen atom, X is —CO—, and R 1 is optionally substituted lower alkoxy (Iii) a compound wherein ( 2 ) R 2 is a hydrogen atom and R 1 is 4-phenyl-1-piperazinyl optionally having a substituent on the phenyl group, (iv) trans-N-2-adamantyl -3- (4-chlorophenyl) -prolinamide and (v) (3R) -3- (2-naphthalenyl) -L-prolyl-L-asparaginyl-L-alanyl-L-valineamide)]. Or a salt thereof. 　Ｒ１０およびＲ１１は、同一または異なって、水素原子またはハロゲン原子（ただし、Ｒ１０およびＲ１１の少なくとも一方はハロゲン原子である）であり、
Ｒ９、Ｒ１２およびＲ１３は、いずれも水素原子である、請求項１記載の化合物またはその塩。 R 10 and R 11 are the same or different and are a hydrogen atom or a halogen atom (provided that at least one of R 10 and R 11 is a halogen atom);
The compound or a salt thereof according to claim 1, wherein R 9 , R 12 and R 13 are all hydrogen atoms. 　Ｒ１０およびＲ１１は塩素原子であり、Ｒ９、Ｒ１２およびＲ１３は、いずれも水素原子である、請求項１記載の化合物またはその塩。 The compound or a salt thereof according to claim 1, wherein R 10 and R 11 are chlorine atoms, and R 9 , R 12 and R 13 are all hydrogen atoms. 　Ｘは、１ないし４個のＣ１－６アルキルで置換されていてもよいＣ１－６アルキレン、－ＣＯ－、－ＣＨ２ＣＯ－、または炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子を１ないし３個含有する５員芳香族複素環を表し、
Ｒ１は、
（１）ヒドロキシ、
（２）シアノ、
（３）モノ－またはジ－Ｃ１－６アルキルアミノ、
（４）Ｃ３－６シクロアルキルアミノ、
（５）ヒドラジノ、
（６）ハロゲン原子およびヒドロキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル、
（７）ハロゲン原子およびヒドロキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルコキシ、
（８）フェニル、
（９）以下の（ａ）～（ｅ）から選ばれる１ないし３個の置換基で置換されていてもよい、炭素原子および１個の窒素原子以外に窒素原子、硫黄原子および酸素原子から選ばれるヘテロ原子１個を含有していてもよい、４～１０員の飽和含窒素複素環基、
　（ａ）ハロゲン原子、
　（ｂ）ヒドロキシ、
　（ｃ）ヒドロキシおよびＣ１－６アルコキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル、
　（ｄ）Ｃ１－６アルコキシ、および
　（ｅ）オキソ、または、
（１０）Ｃ１－６アルコキシＣ１－６アルキル、ハロゲン原子、Ｃ１－６アルコキシ－カルボニル、Ｃ１－６アルキル－カルボニル、Ｃ１－６アルキルスルホニル、アミノスルホニル、Ｃ１－６アルキルアミノスルホニル、カルバモイルおよびＣ１－６アルコキシカルバモイルから選ばれる１または２個の置換基で置換されていてもよいアミノを表し、
Ｒ２は、
（１）水素原子、
（２）ヒドロキシおよびＣ１－６アルコキシから選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル、または
（３）Ｃ１－６アルコキシ－カルボニルを表し、
Ｒ３は、水素原子またはＣ１－６アルキルを表し、
Ｒ４～Ｒ１３は、同一または異なって、水素原子、ハロゲン原子またはＣ１－６アルキルを表し、
この場合において、
Ｒ９～Ｒ１３の少なくとも１つの基はハロゲン原子またはＣ１－６アルキルを表し、あるいは、
Ｒ４～Ｒ９、Ｒ１２およびＲ１３は、同一または異なって、水素原子、ハロゲン原子またはＣ１－６アルキルを表し、
Ｒ１０およびＲ１１は、それぞれが隣接するベンゼン環と共に一体となって、ナフタレン環を形成する、請求項１記載の化合物またはその塩。 X is C 1-6 alkylene optionally substituted with 1 to 4 C 1-6 alkyl, —CO—, —CH 2 CO—, or a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. Represents a 5-membered aromatic heterocycle containing 1 to 3 heteroatoms of choice,
R 1 is
(1) hydroxy,
(2) cyano,
(3) mono- or di-C 1-6 alkylamino,
(4) C 3-6 cycloalkylamino,
(5) Hydrazino,
(6) C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy,
(7) C 1-6 alkoxy optionally substituted by 1 to 3 substituents selected from a halogen atom and hydroxy,
(8) phenyl,
(9) In addition to carbon atom and one nitrogen atom, which may be substituted with 1 to 3 substituents selected from the following (a) to (e), selected from nitrogen atom, sulfur atom and oxygen atom A 4- to 10-membered saturated nitrogen-containing heterocyclic group which may contain one heteroatom,
(A) a halogen atom,
(B) hydroxy,
(C) hydroxy, and C 1-6 1 to 3 substituents optionally substituted by C 1-6 alkyl selected from alkoxy,
(D) C 1-6 alkoxy, and (e) oxo, or
(10) C 1-6 alkoxy C 1-6 alkyl, halogen atom, C 1-6 alkoxy-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylsulfonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl , An amino optionally substituted with one or two substituents selected from carbamoyl and C 1-6 alkoxycarbamoyl;
R 2 is
(1) a hydrogen atom,
(2) hydroxy and C 1-6 1 to 3 is optionally C 1-6 alkyl substituted with a substituent selected from alkoxy or (3), C 1-6 alkoxy - represents carbonyl,
R 3 represents a hydrogen atom or C 1-6 alkyl,
R 4 to R 13 are the same or different and each represents a hydrogen atom, a halogen atom or C 1-6 alkyl;
In this case,
At least one group of R 9 to R 13 represents a halogen atom or C 1-6 alkyl, or
R 4 to R 9 , R 12 and R 13 are the same or different and each represents a hydrogen atom, a halogen atom or C 1-6 alkyl;
The compound or a salt thereof according to claim 1, wherein R 10 and R 11 together with the adjacent benzene ring form a naphthalene ring. 　Ｘは、Ｃ１－６アルキレン、－ＣＯ－、または－ＣＨ２ＣＯ－を表し、
Ｒ１は、
（１）Ｃ１－６アルキル、オキソ、ヒドロキシおよびヒドロキシＣ１－６アルキルから選ばれる１ないし３個の置換基で置換されていてもよい、炭素原子および１個の窒素原子以外に窒素原子および酸素原子から選ばれるヘテロ原子１個を含有していてもよい、５または６員の飽和含窒素複素環基、または
（２）Ｃ１－６アルキル、アミノ、Ｃ３－６シクロアルキル、Ｃ１－６アルコキシＣ１－６アルキル、ハロゲン原子、Ｃ１－６アルコキシ－カルボニル、Ｃ１－６アルキル－カルボニル、Ｃ１－６アルキルスルホニル、アミノスルホニル、Ｃ１－６アルキルアミノスルホニル、カルバモイルおよびＣ１－６アルコキシカルバモイルから選ばれる１または２個の置換基で置換されていてもよいアミノを表し、
Ｒ２～Ｒ９は、水素原子を表し、
Ｒ１０はハロゲン原子を表し、
Ｒ１１は、水素原子またはハロゲン原子を表し、
Ｒ１２およびＲ１３は水素原子を表す、
請求項１記載の化合物またはその塩。 X represents C 1-6 alkylene, —CO—, or —CH 2 CO—.
R 1 is
(1) a nitrogen atom other than a carbon atom and one nitrogen atom, which may be substituted with 1 to 3 substituents selected from C 1-6 alkyl, oxo, hydroxy and hydroxy C 1-6 alkyl; A 5- or 6-membered saturated nitrogen-containing heterocyclic group which may contain one heteroatom selected from oxygen atoms, or (2) C 1-6 alkyl, amino, C 3-6 cycloalkyl, C 1 -6 alkoxy C 1-6 alkyl, halogen atom, C 1-6 alkoxy-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylsulfonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, carbamoyl and C 1 Represents an amino optionally substituted with 1 or 2 substituents selected from -6 alkoxycarbamoyl;
R 2 to R 9 represent a hydrogen atom,
R 10 represents a halogen atom,
R 11 represents a hydrogen atom or a halogen atom,
R 12 and R 13 represent a hydrogen atom,
The compound according to claim 1 or a salt thereof. 　Ｘは、Ｃ１－６アルキレンまたは－ＣＯ－を表し、
Ｒ１は、
（１）ヒドロキシおよびヒドロキシＣ１－６アルキルから選択される１個の置換基で置換されていてもよいピロリジニル、または
（２）Ｃ１－６アルキル、Ｃ１－６アルキル－カルボニル、Ｃ１－６アルキルキルスルホニル、アミノスルホニル、カルバモイルおよびモノ－Ｃ１－６アルコキシカルバモイルから選ばれる１または２個の置換基で置換されたアミノを表し、
Ｒ２～Ｒ９は水素原子を表し、
Ｒ１０およびＲ１１はハロゲン原子を表し、
Ｒ１２およびＲ１３は水素原子を表す、
請求項１記載の化合物またはその塩。 X represents C 1-6 alkylene or —CO—.
R 1 is
(1) pyrrolidinyl optionally substituted with one substituent selected from hydroxy and hydroxy C 1-6 alkyl, or (2) C 1-6 alkyl, C 1-6 alkyl-carbonyl, C 1- It represents alkyl kill, aminosulfonyl, an amino substituted with 1 or 2 substituents selected from carbamoyl and mono- -C 1-6 alkoxy carbamoyl,
R 2 to R 9 represent a hydrogen atom,
R 10 and R 11 represent a halogen atom,
R 12 and R 13 represent a hydrogen atom,
The compound according to claim 1 or a salt thereof. 　（－）－２，３－ｃｉｓ－３－（３，４－ジクロロフェニル）－Ｎ，Ｎ－ジメチルピロリジン－２－カルボキサミドまたはその塩。 (-)-2,3-cis-3- (3,4-dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide or a salt thereof. 　［（２Ｒ，３Ｒ）－３－（３，４－ジクロロフェニル）ピロリジン－２－イル］［（３Ｓ）－３－ヒドロキシピロリジン－１－イル］メタノンまたはその塩。 [(2R, 3R) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] [(3S) -3-hydroxypyrrolidin-1-yl] methanone or a salt thereof. 　［（２Ｒ＊，３Ｓ＊）－３－（３，４－ジフルオロフェニル）ピロリジン－２－イル］（ピロリジン－１－イル）メタノンまたはその塩。 [(2R * , 3S * )-3- (3,4-difluorophenyl) pyrrolidin-2-yl] (pyrrolidin-1-yl) methanone or a salt thereof. 　１－｛［（２Ｒ＊，３Ｓ＊）－３－（３，４－ジクロロフェニル）ピロリジン－２－イル］メチル｝－３－メトキシ尿素またはその塩。 1-{[(2R * , 3S * )-3- (3,4-dichlorophenyl) pyrrolidin-2-yl] methyl} -3-methoxyurea or a salt thereof. 　Ｎ－｛［（２Ｒ，３Ｒ）－３－（３，４－ジクロロフェニル）ピロリジン－２－イル］メチル｝メタンスルホンアミドまたはその塩。 N-{[(2R, 3R) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] methyl} methanesulfonamide or a salt thereof. 　請求項１記載の化合物またはその塩のプロドラッグ。 A prodrug of the compound according to claim 1 or a salt thereof. 　請求項１記載の化合物またはその塩、またはそのプロドラッグを含有する医薬。 A pharmaceutical comprising the compound according to claim 1 or a salt thereof, or a prodrug thereof. 　セロトニン再取り込み阻害薬、ノルエピネフリン再取り込み阻害薬、ドーパミン再取り込み阻害薬、セロトニン－ノルエピネフリン再取り込み阻害薬、ノルエピネフリン－ドーパミン再取り込み阻害薬、セロトニン－ドーパミン再取り込み阻害薬、またはセロトニン－ノルエピネフリン－ドーパミン再取り込み阻害薬である請求項１３記載の医薬。 Serotonin reuptake inhibitor, norepinephrine reuptake inhibitor, dopamine reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor, norepinephrine-dopamine reuptake inhibitor, serotonin-dopamine reuptake inhibitor, or serotonin-norepinephrine-dopamine reuptake The medicament according to claim 13, which is an inhibitor. 　ノルエピネフリン再取り込み阻害薬である請求項１３記載の医薬。 The medicament according to claim 13, which is a norepinephrine reuptake inhibitor. 　うつ病、不安症、注意欠陥・多動性障害または腹圧性尿失禁の予防・治療薬である請求項１３記載の医薬。 14. The medicament according to claim 13, which is a prophylactic / therapeutic agent for depression, anxiety, attention deficit / hyperactivity disorder or stress urinary incontinence. 　哺乳動物に対して、請求項１記載の化合物またはその塩、またはそのプロドラッグの有効量を投与することを特徴とする当該哺乳動物におけるうつ病、不安症、注意欠陥・多動性障害または腹圧性尿失禁の予防・治療方法。 A depression, anxiety, attention deficit / hyperactivity disorder or abdomen in the mammal, characterized by administering an effective amount of the compound according to claim 1 or a salt thereof, or a prodrug thereof to the mammal. Prevention and treatment of pressure urinary incontinence. 　うつ病、不安症、注意欠陥・多動性障害または腹圧性尿失禁の予防・治療薬を製造するための、請求項１記載の化合物またはその塩、またはそのプロドラッグの使用。 Use of the compound according to claim 1 or a salt thereof or a prodrug thereof for the manufacture of a prophylactic / therapeutic agent for depression, anxiety, attention deficit / hyperactivity disorder or stress urinary incontinence. 　うつ病、不安症、注意欠陥・多動性障害または腹圧性尿失禁の予防・治療に使用するための、請求項１記載の化合物またはその塩、またはそのプロドラッグ。
  The compound according to claim 1 or a salt thereof, or a prodrug thereof, for use in the prevention or treatment of depression, anxiety, attention deficit / hyperactivity disorder or stress urinary incontinence.
PCT/JP2010/057017 2009-04-21 2010-04-20 Pyrrolidine compound Ceased WO2010123006A1 (en)

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