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HK1026700B - 1,4-substituted cyclic amine derivatives or dihydroindole derivatives and medicament thereof - Google Patents

1,4-substituted cyclic amine derivatives or dihydroindole derivatives and medicament thereof Download PDF

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Publication number
HK1026700B
HK1026700B HK00105871.3A HK00105871A HK1026700B HK 1026700 B HK1026700 B HK 1026700B HK 00105871 A HK00105871 A HK 00105871A HK 1026700 B HK1026700 B HK 1026700B
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HK
Hong Kong
Prior art keywords
piperidin
group
indoline
fluorophenethyl
added
Prior art date
Application number
HK00105871.3A
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Chinese (zh)
Other versions
HK1026700A1 (en
Inventor
北泽则孝
上野贡嗣
高桥惠子
木村祯治
佐佐木淳
川野弘毅
冈部忠志
小松诚
松永学
洼田笃彦
Original Assignee
卫材R&D管理有限公司
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Publication date
Application filed by 卫材R&D管理有限公司 filed Critical 卫材R&D管理有限公司
Priority claimed from PCT/JP1998/001481 external-priority patent/WO1998043956A1/en
Publication of HK1026700A1 publication Critical patent/HK1026700A1/en
Publication of HK1026700B publication Critical patent/HK1026700B/en

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Description

1, 4-substituted cyclic amine derivative or indoline derivative and drug thereof
Technical Field
The present invention relates to a drug having a 5-hydroxytryptamine antagonistic action and having high clinical utility, and particularly to a therapeutic, ameliorating or prophylactic agent for spastic paralysis or a central muscle relaxant for improving muscular rigidity.
Background of the invention and Prior Art
Muscular tension, which causes neck, shoulder and wrist syndromes with rigidity or pain of skeletal muscles of neck, shoulder, wrist and back due to abnormal posture, fatigue, aging change of back and the like; scapulohumeral periarthritis in which tissues constituting shoulder joints are inflamed due to changes of shoulder joints under stimulation such as trauma; or spastic paralysis, which is caused by hypertonia of hand and foot muscles and hinders voluntary movements, due to central nervous system disorders such as cerebrovascular disorders, etc., may be caused by one or more of these causes, and have serious effects on daily life.
In particular, spastic paralysis is a disease which is accompanied by symptoms such as spasm of hands and feet, stiffness, difficulty in walking, etc., and which seriously hinders daily life.
The treatment of the above-mentioned diseases is generally mainly drug therapy, and at present, a central muscle relaxant or a peripheral muscle relaxant is generally administered.
Examples of the central muscle relaxant include tolperisone hydrochloride, chloroaminobutyric acid, tizanidine hydrochloride, chlorzoxazone, and chlordiazepoxide.
Specific examples of the peripheral muscle relaxant include succinylcholine chloride, pancuronium bromide, and tolteroline sodium.
Central muscle relaxants act by selectively acting on the central nervous system. Therefore, although it is expected that the more the central nervous system acts, the stronger muscle relaxing action is exerted, there is a problem that extrapyramidal symptoms or nervous symptoms such as drowsiness, dull feeling, weakness and the like are also exhibited, and there is no drug which can balance the effects and side effects.
Diazepam is originally an agent for calming nerves, and is effective for mental symptoms accompanied by anxiety, tension, depression, etc., but it has a too strong action for improving the state of muscle tension alone, and although spastic paralysis is alleviated, vertigo occurs in the opposite direction.
On the other hand, only injections of succinylcholine chloride or pancuronium bromide, which are peripheral muscle relaxants, are available on the market, and thus, long-term use is difficult.
In addition, dantrolene sodium is an injection and also an oral preparation, has stronger muscle relaxation effect, but has narrow safety range, easily causes lack of muscle tension, and is difficult to take except for professional doctors.
In summary, no therapeutic or ameliorating agent having high clinical efficacy and excellent safety has been found in the prior art for ameliorating myotonic symptoms such as spastic paralysis.
Disclosure of the invention
Therefore, the present inventors have focused attention on a compound having a 5-hydroxytryptamine antagonistic action in order to develop a therapeutic, ameliorating, prophylactic and central muscle relaxant agent for spastic paralysis which has a potent myotonic symptom-ameliorating effect and is highly safe, and have conducted extensive studies. As a result, the present inventors have found that a novel 1, 4-substituted cyclic amine derivative having the following general formula or a pharmacologically acceptable salt thereof has an excellent central muscle relaxant effect and is excellent in safety, and have solved the above-mentioned problems, thereby completing the present invention.
Accordingly, an object of the present invention is to provide a novel drug having high clinical utility, which can improve the disadvantages of the conventional central muscle relaxants, i.e., which can be expected to exert a strong muscle relaxing action on the upper central nervous system, but has a problem of showing extrapyramidal symptoms or neurological symptoms such as drowsiness, dullness, and weakness, thereby balancing the effects and side effects.
Further, the 1, 4-substituted cyclic amine derivative (I) of the present invention is expected to have utility as a compound having an anti-5-hydroxytryptamine in the prevention, treatment, and improvement of depression, affective disorder, schizophrenia, sleep disorder, anxiety, spinal cord injury, thrombosis, hypertension, cerebral circulatory disorder, peripheral circulatory disorder, drug dependence, and the like.
The 1, 4-substituted cyclic amine derivative (I) of the present invention is represented by the following general formula:
wherein A, B, C, D may be the same or different and each represents a methine group or a nitrogen atom, and at least 2 of them are methine groups.
The bond represented by the following general formula has the meaning of a single bond or a double bond:
t has the meaning of methine and nitrogen atom.
Y, Z each independently represents a methine group, a nitrogen atom, a group represented by the formula
Or a group represented by the formula,
at least one of which is a nitrogen atom.
R1、R2May be the same or different and represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkylsulfonamidoalkyl group, a lower haloalkylsulfonamidoalkyl group, a 2-pyrrolidone-1-yl group, a 1-hydroxy-1- (methoxypyridyl) methyl group, a methoxypyridylcarbonyl group, a 1, 3-propanesultamido-2-yl group, a lower hydroxypiperidinylcarbonylalkyl group, a lower hydroxyalkylaminoalkyl group, a lower haloalkylaminoalkyl group, a lower dihaloalkylamidoalkyl group, a lower heteroarylamidoalkyl group, a lower hydroxyalkylaminoalkyl group, an optionally substituted amino group, a nitro group, a lower alkyl group, a lower alkoxy group, a lower acyl group, a lower alkoxyalkoxy group, a cyano group, a lower alkylsulfonyl group, a sulfonamido group, a hydroxy lower alkyl group, a hydroxy lower alkoxy group, a lower alkoxy, Lower alkylsulfonamido, N-lower alkylsulfonamido, lower acylamino, optionally substituted aminoalkyl, lower acylaminoalkyl optionally substituted at the nitrogen atom, optionally substituted aryl, optionally substituted arylsulfonamido, lower alkylsulfonyloxy, oximinomethyl, (2-pyrrolidin-1-yl) methyl, (2-piperidone-1-yl) methyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, cycloalkylcarbonylaminoalkyl, optionally substituted ureido lower alkyl, succinimidyl, (succinimid-1-yl) lower alkyl, amido, optionally substituted carbamoyl lower alkyl, optionally substituted thiocarbamoyl lower alkyl, substituted thiocarbamoyl lower alkyl, Formyl, aromatic acyl, heteroarylcarbonyl, halo-lower alkyl, (2-imidazolidinone-1-yl) methyl, (2, 4-imidazolidinedion-3-yl) methyl, (2-oxazolidin-3-yl) methyl, (glutarimide-1-yl) methyl, optionally substituted heteroaryl hydroxyalkyl, cyano-lower alkyl, 1-hydroxy-lower cycloalkyl, (2, 4-thiazolidinedione-3-yl) methyl, optionally substituted 4-piperidinemethyl, heteroarylacyl, pyrrolidinylcarbonyl-lower alkyl, optionally substituted aminosulfonylalkyl, carboxy-lower alkyl or lower alkylamido alkyl. In addition, R 1And R2Optionally substituted alicyclic rings, optionally substituted heterocyclic ringsOr alkylenedioxy, and these rings may also be substituted.
R3Represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl lower alkyl group, a lower alkoxy group, a formyl group, an optionally substituted aralkyloxy group, a hydroxyl lower alkoxy group, an optionally substituted sulfamoyl group or a sulfamoyl lower alkyl group in which a nitrogen atom is optionally substituted.
R4Represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxyalkyl group, an aryloxyalkyl group in which the aryl group is optionally substituted, or an aralkyloxyalkyl group in which the aryl group is optionally substituted.
R5Represents lower alkyl, lower acyl, lower alkoxycarbonyl, aromatic acyl or the formula
-Q1-(CH2)s-Q2-R6
The group shown.
[ in the formula, Q1、Q2May each represent a single bond, or one of them represents a single bond, the other represents an oxygen atom, a carbonyl group, a group represented by the formula-NHCO-, a group represented by the formula-NHSO2A group represented by-or of the formula > CH-R7A group represented by (wherein R is7Represents a hydroxyl group, a lower alkyl group or a halogen atom);
s represents 0 or an integer of 1 to 6;
R6represents a group selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted benzoheteroaryl, 1, 4-benzodioxanyl, 1, 3-benzodioxolyl, benzothiazolyl or cyano. ]
n represents 0 or an integer of 1 to 3.
m represents 0 or an integer of 1 to 6.
p represents an integer of 1 to 3.
Specific examples of the halogen atom in the above definition include a chlorine atom, a fluorine atom, a bromine atom and an iodine atom.
The optionally substituted amino group specifically represents an amino group and a group in which the amino group is substituted with, for example, a lower alkyl group or an optionally substituted aryl group.
Specific examples of the lower alkyl group include alkyl groups having 1 to 6 carbon atoms such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, and a hexyl group; as the lower alkoxy group, there may be mentioned, specifically, for example, a group in which the above-mentioned lower alkyl group is bonded to an oxygen atom such as methoxy, ethoxy, propoxy, etc.; specific examples of the lower acyl group include a group having a carbonyl group bonded to a lower alkoxy group such as an acetyl group, a propionyl group, and a butyryl group; examples of the lower alkoxyalkoxy group include, for example, methoxy, methoxyethoxy, methoxypropoxy and the like wherein the alkoxy group is further substituted with an alkoxy group; specific examples of the alkylsulfonyl group include the aforementioned lower alkyl groups and sulfonyl groups (-SO) such as methylsulfonyl group and ethylsulfonyl group 2-) the resulting group is bound; the sulfonamide group is of the formula (-SO)2NH2) A group represented by (a); specific examples of the hydroxy lower alkyl group include groups in which the lower alkyl group is substituted with 1 or more hydroxy groups such as hydroxymethyl, hydroxyethyl and hydroxypropyl; specific examples of the lower alkylsulfonamide group include the lower alkyl groups and sulfonylamino (-SO) groups such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, butylsulfonylamino and N-methylmethanesulfonylamino2N <) is bonded; specific examples of the lower acylamino group include an amino group bonded to a lower fatty acid having 2 to 6 carbon atoms, such as an acetylamino group, a propionylamino group, and a butyrylamino group.
Examples of the lower acylaminoalkyl group optionally substituted as the nitrogen atom include a group in which the lower acyl group is bonded to an amino lower alkyl group such as acetamidomethyl, propionamidomethyl and butyramidomethyl, and the nitrogen atom may be further substituted with a lower alkyl group.
As optionally substituted arylsulfonamido groupSpecifically, for example, there are an aryl group such as a benzenesulfonamide group or a toluenesulfonamide group and a sulfonamide group (-SO)2NH-) bonded radicals, aryl groups optionally also being further substituted; as the lower alkylsulfonyloxy group, specifically mentioned are the above-mentioned lower alkyl group and sulfonyloxy group (-SO) 3-) a bound group; as the optionally substituted aminoalkyl group, specifically, there may be mentioned, for example, a group in which an amino group is bonded to the lower alkyl group, and the nitrogen atom may be further substituted with a lower alkyl group, a lower alkylsulfonyl group or the like.
As the optionally substituted aryl group, there may be mentioned, for example, phenyl, naphthyl and the like or a group further substituted by these. Among them, preferred substituents are a halogen atom, a lower alkoxy group, more preferably a fluorine atom, a chlorine atom and a methoxy group. The above-mentioned substituents may be the same or different. As the optionally substituted heteroaryl group, there are specifically mentioned, for example, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a quinolyl group, an isoquinolyl group, a furyl group, a thienyl group, a thiazolyl group and the like, or a group further substituted thereof; as the optionally substituted aralkyl group, there are specifically mentioned, for example, benzyl, phenethyl, phenylpropyl and the like or a further substituted group thereof; as the optionally substituted heteroaralkyl group, there may be mentioned, specifically, for example, a picolyl group, a pyridylethyl group, a pyrazinylmethyl group, a pyridonemethyl group, a pyrrolidone methyl group, a pyrrolylmethyl group, an imidazolyl methyl group, a triazolylmethyl group, a thiazolyl methyl group and the like, or a group further substituted therewith; examples of the cycloalkylcarbonylaminoalkyl group include carbonylaminoalkyl groups bonded to a cycloalkyl group having 3 to 8 carbon atoms.
As optionally substituted carbamoyl lower alkyl, there may be mentioned, specifically, for example, carbamoylmethyl (H)2NCOCH2-) or a group wherein the nitrogen atom thereof is substituted with 1 or 2 such as lower alkyl, cycloalkyl, lower hydroxyalkyl, lower dihydroxyalkyl, lower carbamoylalkylcarbamoylalkyl, lower dialkylaminoalkyl, lower cyanoalkyl, lower alkoxyalkyl, lower haloalkyl, etc.; as optionally substituted thiocarbamoyl lower alkyl, there may be mentioned, specifically, for example, thiocarbamoylmethyl (H)2NCSCH2-) or their nitrogen atoms are substituted by lowerAlkyl groups, and the like.
Specific examples of the heteroarylcarbonyl group include a pyridylcarbonyl group, a pyrrolylcarbonyl group, a thiazolylcarbonyl group and the like; examples of the halogenated lower alkyl group include lower alkyl groups substituted with a halogen atom such as chloromethyl, fluoromethyl, and fluoroethyl.
Further, as the optionally substituted heteroarylhydroxyalkyl group, there are specifically mentioned, for example, pyridylhydroxymethyl, thiazolylhydroxymethyl, pyrimidylhydroxymethyl, pyrrolylhydroxymethyl and the like.
Specific examples of the 1, 4-substituted cyclic amine derivative (I) according to the present invention include the following compounds, but the present invention is not limited thereto.
(1)1- [1- (4-fluorophenyl) piperidin-4-yl ] indoline
(2)1- [1- (4-fluorobenzyl) piperidin-4-yl ] indoline
(3)1- (1-phenethylpiperidin-4-yl) indolines
(4)1- [1- (4-bromophenylethyl) piperidin-4-yl ] indoline
(5)1- [1- (3-Chloroethyl) piperidin-4-yl ] indoline
(6)1- [1- (4-Chloroethyl) piperidin-4-yl ] indoline
(7)1- [1- (2-fluorophenethyl) piperidin-4-yl ] indoline
(8)1- [1- (3-fluorophenethyl) piperidin-4-yl ] indoline
(9)1- [1- (4-fluorophenethyl) piperidin-4-yl ] indoline
(10)1- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] indoline
(11)1- [1- (3, 4-difluorophenethyl) piperidin-4-yl ] indoline
(12)1- [1- (3, 5-difluorophenethyl) piperidin-4-yl ] indoline
(13)1- [1- (4-fluorophenylpropyl) piperidin-4-yl ] indoline
(14)1- {1- [2- (4-fluorophenyl) propyl ] piperidin-4-yl } indoline
(15)1- [1- (4-fluorobenzenebutyl) piperidin-4-yl ] indoline
(16)1- [1- (4-fluorophenethyl) piperidin-4-yl ] methylindoline
(17)1- {2- [1- (4-fluorophenethyl) piperidin-4-yl ] ethyl } indoline
(18)1- [1- (4-methoxyphenethyl) piperidin-4-yl ] indoline
(19)1- [1- (3-methoxyphenethyl) piperidin-4-yl ] indoline
(20)1- [1- (4-Hydroxyphenylethyl) piperidin-4-yl ] indoline
(21)1- [1- (4-cyanophenethyl) piperidin-4-yl ] indoline
(22)1- [1- (3-hydroxymethylphenethyl) piperidin-4-yl ] indoline
(23)1- [1- (4-hydroxymethylphenethyl) piperidin-4-yl ] indoline
(24)1- {1- [4- (2-hydroxyethyl) phenethyl ] piperidin-4-yl } indoline
(25)1- {1- [4- (1-hydroxyethyl) phenethyl ] piperidin-4-yl } indoline
(26)1- {1- [4- (2-hydroxyethoxy) phenethyl ] piperidin-4-yl } indoline
(27)1- [1- (4-trifluoromethylphenethyl) piperidin-4-yl ] indoline
(28)1- [1- (4-Methanesulfonylphenethyl) piperidin-4-yl ] indoline
(29)1- [1- (4-Nitrophenylethyl) piperidin-4-yl ] indoline
(30)1- [1- (4-Aminophenethyl) piperidin-4-yl ] indoline
(31)1- [1- (4-methanesulfonylaminophenylethyl) piperidin-4-yl ] indoline and
1- {1- [ 4-bis (methylsulfonyl) aminophenylethyl ] piperidin-4-yl } indoline
(32)1- [1- (4-Acetylaminophenylethyl) piperidin-4-yl ] indoline
(33)1- [1- (4-Ethylaminophenylethyl) piperidin-4-yl ] indoline
(34)1- [1- (4-Oximethylphenethyl) piperidin-4-yl ] indoline
(35)1- [1- (4-Aminomethylphenylethyl) piperidin-4-yl ] indoline
(36)1- [1- (4-Acetylaminomethyl-phenethyl) piperidin-4-yl ] indoline
(37)1- [1- (4-chloroacetamidomethylphenylethyl) piperidin-4-yl ] indoline
(38)1- [1- (4-Methanesulphonylaminomethylphenethyl) piperidin-4-yl ] indoline
(39)1- [1- (4-propionylaminomethylphenethyl) piperidin-4-yl ] -3-methylindoline
(40)1- [1- (4-carbamoylphenethyl) piperidin-4-yl ] indoline
(41)1- [1- (4-N-Isopropylcarbamoylmethylphenethyl) piperidin-4-yl ] indoline
(42)1- [1- (4-sulfamoylmethylphenethyl) piperidin-4-yl ] indoline
(43)1- {1- [3- (2-hydroxyethoxy) phenethyl ] piperidin-4-yl } indoline
(44)1- {1- [4- (2-dimethylaminoethoxy) phenethyl ] piperidin-4-yl } indoline
(45)1- {1- [3, 4-bis (hydroxymethyl) phenethyl ] piperidin-4-yl } indoline
(46)1- {1- [3, 4- (methylenedioxy) phenethyl ] piperidin-4-yl } indoline
(47)1- {1- [2- (4-Chlorophenylsulfonamido) ethyl ] piperidin-4-yl } indoline
(48)1- {1- [2- (4-Methoxyphenylsulphonamido) ethyl ] piperidin-4-yl } indoline
(49)1- {1- [2- (4-pyridinyl) ethyl ] piperidin-4-yl } indoline
(50)1- {1- [2- (2-pyridinyl) ethyl ] piperidin-4-yl } indoline
(51)1- {1- [2- (3-pyridinyl) ethyl ] piperidin-4-yl } indoline
(52)1- {1- [2- (2-methoxy-5-pyridyl) ethyl ] piperidin-4-yl } indoline
(53)1- {1- [2- (3-methoxypyridin-5-yl) ethyl ] piperidin-4-yl } indoline
(54)1- {1- [2- (2-cyanopyridin-5-yl) ethyl ] piperidin-4-yl } indoline
(55)1- {1- [2- (2-hydroxymethylpyridin-5-yl) ethyl ] piperidin-4-yl } indoline
(56)1- {1- [2- (3-hydroxymethylpyridin-5-yl) ethyl ] piperidin-4-yl } indoline
(57)1- [1- (2, 6-difluoro-3-pyridylethyl) piperidin-4-yl ] indoline
(58)1- {1- [2- (2-thienyl) ethyl ] piperidin-4-yl } indoline
(59)1- {1- [2- (3-thienyl) ethyl ] piperidin-4-yl } indoline
(60)1- [1- (2-Thiazolylethyl) piperidin-4-yl ] indoline
(61)1- [1- (4-methyl-5-thiazolylethyl) piperidin-4-yl ] indoline
(62)1- {1- [ (indol-3-yl) ethyl ] piperidin-4-yl } indoline
(63)1- {1- [2- (6-benzothiazolyl) ethyl ] piperidin-4-yl } indoline
(64)1- [1- (5-methoxy-2-thienyl) ethylpiperidin-4-yl ] indoline
(65)1- [1- (2-methoxy-5-thiazolyl) ethylpiperidin-4-yl ] indoline
(66)1- [1- (2-cyano-5-thiazolyl) ethylpiperidin-4-yl ] indoline
(67)1- (1-pyrazinylethylpiperidin-4-yl) indoline
(68)1- {1- [2- (4-bromopyrazol-1-yl) ethyl ] piperidin-4-yl } indoline
(69)1- {1- [3- (4-fluorophenoxy) propyl ] piperidin-4-yl } indoline
(70)1- {1- [3- (4-hydroxymethylphenoxy) propyl ] piperidin-4-yl } indoline
(71)1- {1- [3- (4-Hydroxyethylphenoxy) propyl ] piperidin-4-yl } indoline
(72)1- {1- [4- (4-fluorophenyl) -4-oxybutyl ] piperidin-4-yl } indoline
(73)1- {1- [4- (4-fluorophenyl) -4-hydroxybutyl ] piperidin-4-yl } indoline
(74)1- [1- (phthalimid-1-yl) ethylpiperidin-4-yl ] indoline
(75)1- [1- (4-fluorobenzamido) ethylpiperidin-4-yl ] indoline
(76)1- {1- [1- (3, 4-dimethoxyphenyl) propan-2-yl ] piperidin-4-yl } indoline
(77)1- {1- [ (1, 4-benzodioxan-2-yl) methyl ] piperidin-4-yl } indoline
(78)1- {1- [3- (3, 4-methylenedioxyphenoxy) propyl ] piperidin-4-yl } indoline
(79)1- [1- (4-fluorophenethyl) -3-methylpiperidin-4-yl ] indoline
(80)1- (1-benzyl-3-hydroxymethylpiperidin-4-yl) indoline
(81)1- [1- (4-fluorophenethyl) -3-hydroxymethylpiperidin-4-yl ] indoline
(82)1- [1- (4-fluorophenethyl) -3-hydroxymethylpiperidin-4-yl ] indoline
(83)1- [2- (4-Acetylaminomethyl-phenyl) -ethyl ] -4- (indan-1-yl) piperidine-1-oxide
(84)1- [ 1-ethyl-3- (4-fluorophenoxymethyl) piperidin-4-yl ] indoline
(85)1- [ 1-ethyl-3- (4-fluorobenzyloxymethyl) piperidin-4-yl ] indoline
(86)1- [ 1-ethyl-3- (4-fluorobenzyloxymethyl) piperidin-4-yl ] indoline
(87)1- (1-acetylpiperidin-4-yl) indoline-7-carbaldehyde
(88)1- [1- (tert-Butoxycarbonyl) piperidin-4-yl ] -6-bromoindoline
(89)1- [1- (tert-Butoxycarbonyl) piperidin-4-yl ] -6-hydroxymethylindoline
(90)1- [1- (tert-Butoxycarbonyl) piperidin-4-yl ] -6-aminomethylindoline
(91)1- (1-benzylpiperidin-4-yl) -6-bromoindoline
(92)1- (1-benzylpiperidin-4-yl) -6-fluoroindoline
(93)1- (1-benzylpiperidin-4-yl) -6-formylindoline
(94)1- (1-benzylpiperidin-4-yl) -6-oxime methylindoline
(95)1- (1-benzylpiperidin-4-yl) -6-aminomethylindoline
(96)1- (1-benzylpiperidin-4-yl) -6-acetamidomethylindoline
(97)1- [1- (4-methoxyphenylethyl) piperidin-4-yl ] -6-acetamidomethylindoline
(98)1- [1- (4-Chloroethyl) piperidin-4-yl ] -6-acetamidomethylindoline
(99)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -5-methoxyindoline
(100)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline
(101)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline
(102)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-chloroindoline
(103)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-fluoroindoline
(104)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-hydroxyindoline
(105)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -4-methoxyindoline
(106)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methoxyindoline
(107)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -7-methoxyindoline
(108)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6, 7-dimethoxyindoline
(109)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-nitroindoline
(110)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminoindoline
(111)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methylaminoindoline
(112)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-ethylaminoindoline
(113)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-isopropylaminoindoline
(114)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-dimethylaminoindoline
(115)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidoindoline
(116)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methanesulfonamidoindoline
(117)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-ethanesulfonylaminoindoline
(118)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-propanesulfonylaminoindoline
(119)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (4-fluorophenylsulfonylamino) indoline
(120)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (N-methylmethanesulfonamido) indoline
(121)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-hydroxyethoxyindoline
(122)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methanesulfonyloxyindoline
(123)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -7-hydroxyethoxyindoline
(124)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-cyanoindoline
(125)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carbamoylindoline
(126)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-pyrrolylcarbonyl) indoline
(127)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetylindoline
(128)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methanesulfonylindoline
(129)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-thiocarbamoylmethylindole
(130)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindoline
(131)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-oxime methylindoline
(132)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindoline
(133)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindoline
(134)1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindoline
(135)1- [1- (3-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindoline
(136)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-hydroxymethylindoline
(137)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-hydroxyethyl) indoline
(138)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-hydroxypropyl) indoline
(139)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-hydroxy-1-methylethyl) indoline
(140)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-hydroxycyclobutyl) indoline
(141)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-hydroxycyclopentyl) indoline
(142)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-chloromethylindoline
(143)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-fluoromethyl indoline
(144)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-fluoroethyl) indoline
(145)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-cyanomethylindoline
(146)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline
(147)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carbamoylmethylindoline
(148)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (methylcarbamoylmethyl) indoline
(149)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (ethylcarbamoylmethyl) indoline
(150)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (n-propylcarbamoylmethyl) indoline
(151)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (isopropylcarbamoylmethyl) indoline
(152)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (isobutylcarbamoylmethyl) indoline
(153)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (tert-butylcarbamoylmethyl) indoline
(154)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (cyclopropylcarbamoylmethyl) indoline
(155)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (tetramethylenecarbamoylmethyl) indoline
(156)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-propionylaminomethylindoline
(157)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-n-butyrylaminomethylindoline
(158)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-isobutyrylaminomethylindoline
(159)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-cyclopropanecarboxamidomethylindoline
(160)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methylsulfonylaminomethylindoline
(161)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-ureidomethylindoline
(162)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-N-methylaminomethylindoline
(163)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-N-methylacetamidomethyl indoline
(164)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (N-methylsulfamoylmethyl) indoline
(165)1- [1- (4-fluorophenylethyl) piperidin-4-yl ] -6- (1-acetamidomethyl) indoline
(166)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidoethylindoline
(167)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ (piperidin-4-yl) methyl ] indoline
(168)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ (1-acetylpiperidin-4-yl) methyl ] indoline
(169)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ (1-ethylpiperidin-4-yl) methyl ] indoline
(170)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ (1-methylpiperidin-4-yl) methyl ] indoline
(171)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-pyridinyl) indoline
(172)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-thiazolyl) indoline
(173)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-methylpyrrol-2-yl) indoline
(174)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-pyridyl) methyl ] indoline
(175)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [1- (2-pyridyl) methyl ] indoline
(176)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (3-pyridinyl) methyl ] indoline
(177)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [1- (3-pyridyl) methyl ] indoline
(178)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-hydroxy-4-pyridylmethyl) indoline
(179)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (4-pyridylmethyl) indoline
(180)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-pyridylcarbonyl) indoline
(181)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-pyridyl) ethyl ] indoline
(182)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [1- (2-pyridyl) ethyl ] indoline
(183)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (3-pyridylcarbonyl) indoline
(184)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-methoxypyridin-3-yl) methyl ] indoline
(185)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [1- (2-methoxypyridin-3-yl) methyl ] indoline
(186)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-methoxypyridin-6-yl) methyl ] indoline
(187)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [1- (2-methoxypyridin-6-yl) methyl ] indoline
(188)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-methoxypyridin-5-yl) methyl ] indoline
(189)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [1- (2-methoxypyridin-5-yl) methyl ] indoline
(190)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-pyridon-5-yl) methyl ] indoline
(191)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-dimethylaminopyridin-5-yl) methyl ] indoline
(192)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-chloropyridin-5-yl) methyl ] indoline
(193)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [1- (2-thiazolyl-5-yl) -1-hydroxymethyl ] indoline
(194)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-thiazolylcarbonyl) indoline
(195)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [1- (4-thiazolyl) -1-hydroxymethyl ] indoline
(196)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [1- (5-thiazolyl) -1-hydroxymethyl ] indoline
(197)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (pyrimidin-2-yl) methyl ] indoline
(198)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (pyrimidin-5-yl) methyl ] indoline
(199)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-pyrrolyl) methyl ] indoline
(200)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-N, N-dimethylaminomethylindoline
(201)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (4-fluorophenyl) indoline
(202)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-pyrrolidinone-1-yl) methylindoline
(203)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-piperidon-1-yl) methylindoline
(204)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (succinimidin-1-yl) methylindoline
(205)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (glutarimide-1-yl) methylindoline
(206)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-imidazolidinonyl) methylindoline
(207)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2, 4-imidazolidinedione-3-yl) methylindoline
(208)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-oxazolidin-3-yl) methylindoline
(209)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2, 4-thiazolidinedione-3-yl) methylindoline
(210)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (pyrrol-1-yl) methylindoline
(211)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (imidazol-1-yl) methylindoline
(212)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1, 2, 3-triazol-1-yl) methylindoline and 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1, 2, 3-triazol-2-yl) methylindoline
(213)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1, 2, 4-triazol-2-yl) methylindoline
(214)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-thiazolyl) methylindoline
(215)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -3- (4-methoxybenzyl) indoline
(216)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -3-methylindoline
(217)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -5-chloro-6-aminoindoline
(218)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -5-chloro-6-methanesulfonylaminoindoline
(219)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -5-chloro-6-methoxyindoline
(220)1- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-aminoindoline
(221)1- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-methanesulfonylaminoindoline
(222)1- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-acetamidoindoline
(223)1- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-bromoindoline
(224)1- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindoline
(225)1- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-carbamoylmethylindoline
(226)1- {1- [3- (4-fluorophenyl) propyl ] piperidin-4-yl } -6-acetamidomethylindoline
(227)1- {1- [4- (4-fluorophenyl) butyl ] piperidin-4-yl } -6-acetamidomethylindoline
(228)1- [1- (4-methoxyphenylethyl) piperidin-4-yl ] -6-methoxyindoline
(229)1- [1- (4-methoxyphenethyl) piperidin-4-yl ] -6-fluoroindoline
(230)1- [1- (4-sulfamoylphenethyl) piperidin-4-yl ] -6-methoxyindoline
(231)1- [1- (4-fluorophenoxypropyl) piperidin-4-yl ] -6-bromoindoline
(232)1- [1- (4-fluorophenoxypropyl) piperidin-4-yl ] -6-acetamidomethylindoline
(233)1- {1- [2- (6-benzothiazolyl) ethyl ] piperidin-4-yl } -6-methoxyindoline
(234)1- [1- (4-fluorophenethyl) piperidin-4-yl ] thiazolo [5, 4-f ] indoline
(235)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminothiazolo [5, 4-f ] indoline
(236)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -7-hydroxy- (4a, 7a) -cyclohexanoindole and 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -4-hydroxy- (3b, 6a) -cyclohexanoindole
(237)1- (1-methylpiperidin-4-yl) -6- (fluorobenzenesulfonylamino) indoline
(238)1- (1-ethylpiperidin-4-yl) -6- (fluorobenzenesulfonylamino) indoline
(239)1- (1-ethylpiperidinyl) -4- (4-fluorophenyl) indoline
(240)1- (1-ethylpiperidin-4-yl) -3- (4-fluorophenyl) indoline
(241)1- (1-ethylpiperidin-4-yl) -3- (4-methoxyphenyl) indoline
(242)1- (1-ethylpiperidin-4-yl) -3- (4-methoxybenzyl) indoline
(243)1- [ (1-ethylpiperidin-4-yl) methyl ] -3- (4-methoxybenzyl) indoline
(244)1- (1-ethylpiperidin-4-yl) -3- (4-fluorobenzyl) indoline
(245)1- (1-ethylpiperidin-4-yl) -3- (3-pyridylmethyl) indoline
(246)1- (1-ethylpiperidin-4-yl) -3- (3-methoxyphenylethyl) indoline
(247)1- (1-ethylpiperidin-4-yl) -3- (3-fluorophenethyl) indoline
(248)1- [1- (4-fluorophenethyl) piperidin-4-yl ] indane
(249)1- [1- (4-methoxyphenethyl) piperidin-4-yl ] indane
(250)1- {4- [2- (4-fluorophenyl) ethyl ] piperazin-1-yl } -6-methoxyindane
(251)1- (4-ethylpiperazin-1-yl) -6-methoxyindane
(252)1- (4-ethylpiperazin-1-yl) -2-ethoxycarboxyaminoindane
(253)1- (4-ethylpiperazin-1-yl) -2-methylaminoindane
(254)1- (4-ethylpiperazin-1-yl) -2- [ methyl- (4-trifluorobenzyl) amino ] indan
(255)7- [ 4-hydroxy-1- (4-fluorophenethyl) piperidin-4-yl ] -5, 6-dihydro-7H-azaindene
(256)7- [1- (4-fluorophenethyl) piperidin-4-ylidene ] -5, 6-dihydroazaindene
(257)7- [1- (4-fluorophenethyl) piperidin-4-yl ] -5, 6-dihydro-7H-azaindene
(258)7- [4- (4-fluorophenethyl) piperazin-1-yl ] -5, 6-dihydro-7H-azaindene
(259)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-chloro-7-azaindoline
(260)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -7-azaindoline
(261)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-fluoro-7-azaindoline
(262)1- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-chloro-7-azaindoline
(263)1- [1- (4-methoxyphenethyl) piperidin-4-yl ] -6-chloro-7-azaindoline
(264)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-azaindoline
(265)5- [1- (4-fluorophenethyl) piperidin-4-ylidene ] -7-methyl-5, 6-dihydrocyclopentapyrazine
(266)5- [1- (4-fluorophenethyl) piperidin-4-yl ] -7-methyl-5, 6-dihydro-5H-cyclopentapyrazine
(267)1- {1- [2- (4-methoxyphenyl) ethyl ] piperidin-4-yl } -7-methoxy-1, 2, 3, 4-tetrahydroquinoline
(268)1- {1- [2- (4-fluorophenyl) ethyl ] piperidin-4-yl } -7-methoxy-1, 2, 3, 4-tetrahydroquinoline
(269)1- [1- (4-cyanopropyl) piperidin-4-yl ] -7-methoxy-1, 2, 3, 4-tetrahydroquinoline
(270)1- {1- [2- (2-thienyl) ethyl ] piperidin-4-yl } -7-methoxy-1, 2, 3, 4-tetrahydroquinoline
(271)1- {1- [2- (4-fluorophenyl) ethyl ] piperidin-4-yl } -7, 8-dimethoxy-1, 2, 3, 4-tetrahydroquinoline
(272)1- {1- [2- (4-fluorophenyl) ethyl ] piperidin-4-yl } -7, 8-methylenedioxy-1, 2, 3, 4-tetrahydroquinoline
(273)1- {1- [2- (4-fluorophenyl) ethyl ] piperidin-4-yl } -7-methoxy-8-methyl-1, 2, 3, 4-tetrahydroquinoline
(274)1- {1- [2- (4-fluorophenyl) -2-oxyethyl ] piperidin-4-yl } -7-methoxy-1, 2, 3, 4-tetrahydroquinoline
(275)1- {1- [2- (4-fluorophenyl) -2-hydroxyethyl ] piperidin-4-yl } -7-methoxy-1, 2, 3, 4-tetrahydroquinoline
(276)1- {1- [2- (4-fluorophenyl) -2-fluoroethyl ] piperidin-4-yl } -7-methoxy-1, 2, 3, 4-tetrahydroquinoline
(277)1- [2- (4-fluorophenyl) ethyl ] -4- (6-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) piperidine
(278)1- [2- (4-fluorophenyl) ethyl ] -4- [6- (2-hydroxy) ethoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) piperidine
(279) Trans-1- (4-ethylpiperazin-1-yl) -7-methoxy-2- (4-trifluoromethylphenoxy) -1, 2, 3, 4-tetrahydronaphthalene
(280)1- {4- [2- (4-fluorophenyl) ethyl ] piperazin-1-yl } -7-methoxy-1, 2, 3, 4-tetrahydronaphthalene
(281)1- {4- [2- (4-fluorophenyl) -2-oxyethyl ] piperazin-1-yl } -7-methoxy-1, 2, 3, 4-tetrahydronaphthalene
(282)1- (4-fluorophenethyl) -4- (2-methoxybenzcycloheptan-9-yl) piperazine
(283)5- {4- [2- (4-fluorophenyl) ethyl ] piperazin-1-yl ] } -5, 6, 7, 8-tetrahydroisoquinoline
(284)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -5, 6-methylenedioxyindoline
(285)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethyl indole
(286)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (N-isopropylcarbamoylmethyl) indole
(287)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-methylpyrrol-2-yl) indole
(288)1- [1- (4-Acetylamidomethylphenethyl) piperidin-4-yl ] indole
(289)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-cyanoindole
(290)1- [1- (4-fluorophenethyl) -3-methylpiperidin-4-yl ] indole
(291)1- [1- (4-fluorophenethyl) homopiperidin-4-yl ] -6-methoxyindoline
(292)1- [1- (4-fluorophenethyl) pyrrolidin-3-yl ] -6-methoxyindoline
(293)3, 3-dimethyl-1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline
(294)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (ethylcarbamoylmethyl) indole
(295)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ N- (cyclopropylcarbamoyl) methyl ] indole
(296)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ N- (isobutylcarbamoyl) methyl ] indole
(297)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (n-propylcarbamoylmethyl) indole
(298)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (tetramethylenecarbamoylmethyl) indole
(299)1- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-carbamoylmethylindole
(300)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-hydroxyethyl) carbamoylmethylindole
(301)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-dimethylcarbamoylmethylindole
(302)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (4-hydroxypiperidin-1-yl) carbonylmethylindole
(303)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ bis (2-hydroxyethyl) carbamoylmethyl ] indole
(304)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1, 3-dihydroxypropan-2-yl) carbamoylmethylindole
(305)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carbamoylmethylindole
(306)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (carbamoylmethyl) carbamoylmethylindole
(307)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-dimethylaminoethyl) carbamoylmethylindole
(308)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-cyanomethyl carbamoylmethylindole
(309)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-methoxyethyl) carbamoylmethylindole
(310)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-fluoroethyl) carbamoylmethylindole
(311)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [2- (ethylcarbamoyl) ethyl ] indole
(312)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [2- (pyrrolidin-1-yl) ethyl ] carbamoylmethylindole
(313)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [2- (morpholin-4-yl) ethyl ] carbamoylmethylindole
(314)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (pyridin-4-yl) methylcarbamoylmethylindole
(315)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [2- (pyridin-2-yl) ethyl ] carbamoylmethylindole
(316)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methylcarbamoylmethylindole
(317)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-methoxypyridin-5-yl) carbonylindole
(318)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ (2-methoxypyridin-5-yl) hydroxymethyl ] indole
(319)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-hydroxypropyl) indole
(320)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-hydroxy-1-methylethyl) indoline
(321)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (3-hydroxypropyl) indole
(322)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methanesulfonamidomethylindole
(323)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-isopropylsulfonylaminomethylindole
(324)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-n-propylsulfonylaminomethylindole
(325)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (3-chloropropyl) sulfonylaminomethylindole
(326)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1, 3-propanesul-tam-2-yl) methylindole
(327)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-propionylaminomethylindole
(328) 3-chloro-1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindole
(329)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (4-hydroxybutyramidomethyl) indole
(330)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-hydroxyethoxyindole
(331)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methanesulfonylindole
(332)1- [1- (2, 6-difluoro-3-pyridylethyl) piperidin-4-yl ] indole
(333)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-fluoroindole
(334)1- [1- (4-fluorophenethyl) piperidin-4-yl ] thiazolo [5, 4-f ] indole
(335)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (N-methylmethanesulfonamido) indole
(336)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methanesulfonyloxyindole
(337)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carbamoylindole
(338)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (N-methylsulfamoylmethyl) indole
(339)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidoindole
(340)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1, 2-dihydroxypropan-3-yl) carbamoylmethylindole
(341)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (pyridin-2-yl) methylcarbamoylmethylindole
(342)1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-methylcarbamoylmethylindole
(343)1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6- (1-acetylpiperidin-4-yl) methylcarbamoylmethylindole
(344)1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-ethylcarbamoylmethylindole
(345)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-ethylpiperidin-4-yl) methylcarbamoylmethylindole
(346)1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6- (2-hydroxyethyl) carbamoylmethylindole
(347)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1, 3-dioxolan-2-yl) methylcarbamoylmethylindole
(348)1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindole
(349)1- [1- (4-Chloroethyl) piperidin-4-yl ] -6-acetamidomethylindole
(350)1- [1- (3-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethyl indole
(351)1- [1- (4-methoxyphenylethyl) piperidin-4-yl ] -6-acetamidomethyl indole
(352)1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethyl indole
(353)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2, 4-imidazolidinedione-3-yl) methylindole
(354)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-isobutyramidomethylindole
(355)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-imidazolidinonyl) methylindole
(356)1- {1- [4- (4-fluorophenyl) butyl ] piperidin-4-yl } -6-acetamidomethylindole
(357)1- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-acetamidomethyl indole
(358)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-pyrrolidinone-1-yl) methylindole
(359)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-N-methylacetamidomethylindole
(360)1- [1- [3- (4-fluorophenyl) propyl ] piperidin-4-yl ] -6-acetamidomethylindole
(361)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-N-methylaminomethylindole
(362)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (n-butyryl) aminomethylindole
(363)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-cyclopropanecarboxamidomethylindole
(364)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-hydroxyacetamidomethylindole
(365)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-difluoroacetamidomethyl indole
(366)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-fluoroacetamidomethylindole
(367)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (3-chloropropylamido) methylindole
(368)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-imidazolecarbonylaminomethylindole
(369)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (3-hydroxypropionylamino) methylindole
(370)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -3-formyl-6-acetamidomethylindole
(371)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -3-hydroxyimino-6-acetamidomethylindole
(372)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -3-hydroxymethyl-6-acetamidomethylindole
(373)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-chloroacetamidomethylindole
(374)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoacetamidomethyl indole
(375)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (N, N-dimethylaminoacetamido) methylindole
(376)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ (piperidin-1-yl) acetamido ] methylindole
(377)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (3-bromopropionamido) methylindole
(378)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (3-N, N-dimethylaminopropionyl) aminomethylindole
(379)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [3- (piperidin-1-yl) propionamido ] methylindole
(380)1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-propionamidomethylindole
(381)1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-fluoroacetamidomethylindole
(382)1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6- (3-hydroxypropionylamino) methylindole
(383)1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-hydroxyacetamidomethylindole
(384)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methoxycarbonylaminomethylindole
(385)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-N, N-dimethylaminocarbonylaminomethylindole
(386)1- {1- [2- (3-pyridinyl) ethyl ] piperidin-4-yl } -6-acetamidomethylindole
(387) 3-cyano-1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethyl indole
(388)1- {4- [ (1-hydroxyethyl) phenethyl ] piperidin-4-yl } -6-acetamidomethylindole
(389)1- [1- (4-bromophenylethyl) piperidin-4-yl ] -6-acetamidomethyl indole
(390)1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-formylindole
(391)1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-hydroxymethylindole
(392)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-hydroxyethyl) indole
(393)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-ureidomethylindole
(394)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (3-methylureido) methylindole
(395)3, 3-dimethyl-1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidoindoline
(396)2, 2-dimethyl-1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methoxyindoline
(397)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (3-methylureido) methylindole
The 1, 4-substituted cyclic amine derivative (I) of the present invention may also have optical isomers or geometric isomers, and the present invention is not limited thereto, and any one of the optical isomers may be used, or a mixture thereof may be used. In addition, the geometric isomers are also not limited, and may be any one or a mixture thereof. In addition, the polymorphism is also not limited, and can be any single crystal form or a mixture, and besides anhydrous, the polymorphism can also be a hydrate.
The pharmacologically acceptable salt of the present invention is not limited as long as it can form the 1, 4-substituted cyclic amine derivative (I) of the present invention. Specific examples thereof include inorganic acid addition salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, perchlorate and phosphate, organic acid addition salts such as oxalate, maleate, fumarate and succinate, sulfonic acid addition salts such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and camphorsulfonate, and amino acid addition salts. Among them, hydrochloride and oxalate are preferred.
The 1, 4-substituted cyclic amine derivative (II) of the present invention is represented by the following general formula:
Wherein, the substituent represented by R is selected from 1 of the following groups:
(wherein, the bond represented by the following general formula:
and R1、R2、R3Have the same meanings as described above. )
R4、R5Y, Z, m and p have the same meanings as described above.
Specific examples of the 1, 4-substituted cyclic amine derivative (II) include, but are not limited to, compounds similar to the above-mentioned 1, 4-substituted cyclic amine derivative (I).
In addition, the 1, 4-substituted cyclic amine derivative (III) of the present invention is represented by the following general formula:
wherein the bond is represented by the following general formula:
and R1、R2、R3、R4、R5Have the same meanings as described above.
Further, the 1, 4-substituted cyclic amine derivative (IV) of the present invention is represented by the following general formula:
wherein the bond is represented by the following general formula:
and R1、R2、R3、R4、R6、Q1、Q2And s have the same meanings as described above.
Further, the 1, 4-substituted cyclic amine derivative (V) of the present invention is represented by the following general formula:
in the formula R1、R2、R3、R4、R6And s have the same meanings as described above.
Further, the 1, 4-substituted cyclic amine derivative (VI) of the present invention is represented by the following general formula:
in the formula R1、R2、R3、R4、R6And s have the same meanings as described above.
Among the 1, 4-substituted cyclic amine derivatives (I) to (VI) of the present invention, particularly preferred compounds are, from the viewpoint of pharmacological effects and safety, as follows:
(1)1- [1- (4-Acetylaminomethyl-phenethyl) piperidin-4-yl ] indoline
(2)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carbamoylindoline
(3)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methylsulfonyldihydroindole
(4)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindoline
(5)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-hydroxyethyl) indoline
(6)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (n-propylcarbamoylmethyl) indoline
(7)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (isopropylcarbamoylmethyl) indoline
(8)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-ureidomethylindoline
(9)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-N-methylacetamidomethyl indoline
(10)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [1- (4-thiazolyl) -1-hydroxymethyl ] indoline
(11)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethyl indole
LD of Compounds of the present invention50The value is particularly high and the safety is particularly high.
Further, WO96/23784, Japanese patent application laid-open No. Hei 8-512, 299(WO95/01976), WO97/06155 and the like disclose compounds having indoline skeleton or indane skeleton, but are completely different from the 1, 4-substituted cyclic amine derivatives (I) to (VI) of the present invention in structure.
The present invention provides a method for treating a disease which can be treated by antagonism of 5-hydroxytryptamine, by administering an effective amount of the above compound or a pharmacologically acceptable salt thereof to a human; the use of the above compounds or their pharmacologically acceptable salts for the treatment of diseases which can be effectively treated by the antagonism of 5-hydroxytryptamine.
The invention comprises the following scheme:
(1)
a 1, 4-substituted cyclic amine derivative represented by the general formula (XXI) or a pharmacologically acceptable salt thereof.
(2) m is 0, and a 1, 4-substituted cyclic amine derivative represented by the general formula (XXII) or a pharmacologically acceptable salt thereof.
(3) 1, 4-substituted cyclic amine derivatives represented by general formula (I) wherein m is 1 to 6, or pharmacologically acceptable salts thereof.
Which comprises the following steps:
(16)1- [1- (4-fluorophenethyl) piperidin-4-yl ] methylindoline
(17)1- [2- [1- (4-fluorophenethyl) piperidin-4-yl ] ethyl ] indoline
(243)1- [ (1-ethylpiperidin-4-yl) methyl ] -3- (4-methoxybenzyl) indoline
(4) A1, 4-substituted cyclic amine derivative represented by the following general formula (XXIII) or a pharmacologically acceptable salt thereof.
Which comprises the following steps:
(256)7- [1- (4-fluorophenethyl) piperidin-4-ylidene ] -5, 6-dihydroazaindene
(265)5- [1- (4-fluorophenethyl) piperidin-4-ylidene ] -7-methyl-5, 6-dihydrocyclopentapyrazine
(5)
A 1, 4-substituted cyclic amine derivative represented by the general formula (XXIV) or a pharmacologically acceptable salt thereof.
The method for producing the 1, 4-substituted cyclic amine derivative (I) of the present invention is not particularly limited, and for example, it can be produced as follows.
(1) T ═ nitrogen atom, m ═ 0, Y ═ methine, and Z ═ nitrogen atom
In this case, the 1, 4-substituted cyclic amine derivative (IX) can be produced by reacting the condensed cyclic amine (VII) with the cyclic ketone (VIII) in the presence of a reducing agent according to a conventional method for reductive amination, for example, the method described in "New Experimental chemistry lecture" 14-III, 1380 issued by Wan, and the protecting group can be removed if necessary, followed by introduction of the substituent R5And synthesizing. Expressed by a chemical reaction formula, the reaction is as follows:
[ wherein the chemical bond represented by the following general formula represents a single bond or a double bond.
A、B、C、D、R1、R2、R3、R4、R5N and p have the same meanings as described above. G represents a hydrogen atom or a protecting group, and L means a leaving group such as a hydroxyl group, a halogen atom, or a methanesulfonyloxy group.]
Substituent R1、R2、R3、R4Can be further chemically modified, thereby also synthesizing the 1, 4-moietyA peripheral compound of a substituted cyclic amine derivative.
The reducing agent is not particularly limited as long as it is generally used for reductive N-alkylation, and sodium triacetoxyborohydride, sodium cyanoborohydride, lithium aluminum hydride, and the like are preferred.
(2) T ═ nitrogen atom, n ═ 0, m ═ 0, Y ═ methine, Z ═ nitrogen atom
In particular, when n is 0 in the 1, 4-substituted cyclic amine derivative (I) other than (1), the amine (XI) is treated with oxalyl chloride and then with aluminum chloride to give a diketone (XII), which is then reduced to give an indole derivative (XII), and the protecting group is removed if necessary, and the substituent R is introduced5To give indole derivative (XIV). Reducing the obtained product to synthesize an indoline derivative (XV). Expressed by a chemical reaction formula, the reaction is as follows:
[ wherein the chemical bond represented by the following general formula, and
A、B、C、D、R1、R2、R4、R5p, Pr. G, L have the same meanings as described above.]
(3) Indole derivatives having a nitrogen atom as T ═ 0, m ═ 0, Y ═ methine, and Z ═ nitrogen atom
In addition to the indole derivative (XIV) in the above (2), the indoline derivative (XV) is oxidized by a conventional method to obtain the indole derivative (XIV). The reagents and catalysts used therein are not limited, and active manganese dioxide is more preferable.
(4) T ═ methine, n ═ 0, m ═ 0, Y ═ methine, and Z ═ nitrogen atom
By introducing substituent R into 1- (piperidin-4-yl) indoline derivative (XVI)5And synthesizing. Expressed by a chemical reaction formula, the reaction is as follows:
[ wherein the chemical bond represented by the following formula,
And A, B, C, D, R1、R2、R4、R5P, L have the same meanings as above.]
(5) T ═ nitrogen atom, n ═ 1, m ═ 0, Y ═ methine, Z ═ nitrogen atom
Introduction of substituent R into 1- (4-piperidinyl) -1, 2, 3, 4-tetrahydroquinoline derivative (XVIII)5And synthesizing. Expressed by a chemical reaction formula, the reaction is as follows:
[ wherein the chemical bond represented by the following formula,
And A, B, C, D, R1、R2、R3、R4、R5P, L have the same meanings as above.]
The compounds having structures other than the above-mentioned structures (1) to (5) among the 1, 4-substituted cyclic amine derivatives (I) of the present application can be prepared in the same manner as in the examples described below.
In the present invention, the 4-substituted cyclic amine derivative (XX) represented by the following general formula used in the preparation of the 1, 4-substituted cyclic amine derivative (I) is a novel compound useful for the preparation of 1, 4-substituted cyclic amine derivatives (I) to (VI) which are drugs having 5-hydroxytryptamine antagonistic action and having high clinical utility, and particularly useful as a therapeutic, ameliorating, prophylactic or central muscle relaxant for the amelioration of myotonia.
Wherein the chemical bond represented by the following general formula,
And A, B, C, D, R1、R2、R3、R4N and p have the same meanings as above, but R 1、R2、R3、R4Except for the case where all represent hydrogen atoms.
Specific examples of the 4-substituted cyclic amine derivative (XX) include the following compounds, but are not limited thereto.
(1)1- (piperidin-4-yl) -6-fluoroindoline
(2)1- (piperidin-4-yl) -6-bromoindoline
(3)1- (piperidin-4-yl) -6-nitroindoline
(4)1- (piperidin-4-yl) -6-methoxyindoline
(5)1- (piperidin-4-yl) -6-acetamidomethylindoline
(6)1- (piperidin-4-yl) -6-fluoroindoles
(7)1- (piperidin-4-yl) -6-bromoindole
(8)1- (piperidin-4-yl) -6-nitroindoles
(9)1- (piperidin-4-yl) -6-methoxyindole
(10)1- (piperidin-4-yl) -6-acetamidomethylindole
Examples of administration forms of the compound of the present invention include oral preparations such as powders, fine granules, tablets, coated tablets and capsules, external preparations such as ointments, patches and suppositories, and injection preparations. The preparation can be prepared by conventional method using conventional preparation carrier.
That is, in the case of preparing an oral preparation, a powder, a fine granule, a tablet, a coated tablet, a capsule and the like are prepared from a 1, 4-substituted cyclic amine derivative or a pharmacologically acceptable salt thereof and an excipient, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a taste corrigent and the like, according to a conventional method.
Examples of the excipient include lactose, corn starch, white sugar, glucose, mannitol, sorbitol, crystalline cellulose, and silica; examples of the binder include polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polypropylene glycol-polyethylene oxide block copolymer, and meglumine; as the disintegrating agent, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin, carboxymethylcellulose calcium, and the like; as the lubricant, for example, magnesium stearate, talc, polyethylene glycol, silicon dioxide, hardened vegetable oil, and the like; the colorant may be added to a pharmaceutical; examples of the taste corrigent include cocoa powder, menthol, aromatic powder, peppermint oil, borneol, and cinnamon powder. The tablets and granules may of course be sugar-coated or otherwise coated as desired.
In the case of producing an injection preparation, a pH adjuster, a dissolving agent, an isotonic agent, etc. may be added to the 1, 4-substituted cyclic amine derivative or a pharmacologically acceptable salt thereof, and a dissolution aid, a stabilizer, etc. may be added as necessary to prepare the preparation according to a conventional method.
The method for producing the external preparation is not limited, and the preparation can be produced by a conventional method, that is, various materials commonly used in medicines, quasi drugs, and cosmetics can be used as a base material for the preparation.
Specifically, the base material used is, for example, animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyols, water-soluble polymers, clay minerals, purified water, and the like, and if necessary, pH adjusters, antioxidants, chelating agents, preservatives, antifungal agents, colorants, perfumes, and the like may be added. In addition, other components having differentiation inducing effect, blood flow promoter, bactericide, antiinflammatory agent, cell activator, vitamins, amino acids, humectant, keratolytic agent, etc. can also be added. The amount of the base material to be added may be the concentration specified in the conventional production of an external preparation.
In the present invention, the clinical dose of the 1, 4-substituted cyclic amine derivative or the pharmacologically acceptable salt thereof varies depending on the symptoms, severity, age, complications, and the like, and is not limited. Further, the amount of the salt varies depending on the kind of the salt and the administration route, and is usually 0.01mg to 1000mg, preferably 0.1mg to 500mg, more preferably 0.5mg to 100mg per day for an adult, and it can be administered orally, intravenously, by suppository or transdermally.
Hereinafter, the effect of the present invention is confirmed by a binding test of the compound of the present invention to each receptor of 5-hydroxytryptamine 1A and 5-hydroxytryptamine 2, and the safety effect is confirmed by an α 1 adrenergic receptor binding test.
Compounds having 5-hydroxytryptamine antagonistic activity are useful as therapeutic, ameliorating, prophylactic or central muscle relaxant for spastic paralysis, for example, as described in the following publications:
(1) the "latest medical classics" release, 1 st edition, 3 rd print, page 809, "セロトニン" (5-hydroxytryptamine) strip
(2) Williams & Wilkins, Stedman's medical dictionary, 24 th edition, page 1277, "serotonin" strip
(3) Neural advancement, 37(3), 459-467, 1993
(4) Journal of medicine (medicine ジヤ - ナル)30(8), 2030-2068, 1994
(5)DN&P，5(8)，453-460，1992
(6) A compound having a low ability to bind to alpha 1 adrenergic receptors, which is less likely to cause orthostatic hypotension or the like due to its influence on blood pressure and is highly safe, is described in annual neurological examination (Annals of Neurology), 30 (4); 533-541, 1991.
ADVANTAGEOUS EFFECTS OF INVENTION
(1) 5-hydroxytryptamine 1A, 5-hydroxytryptamine 2, alpha 1 adrenoceptor binding assay methods:
(reagent)
The following reagents were used in this experiment:
1) 5-Hydroxytryptamine hydrogen oxalate (5-HT binoxalate, Sigma Co.)
2) Dimethylergometrine maleate (RBI) radiolabelled compounds the following reagents (NEN) were used.
3)[3H]8-hydroxy-dipropylaminonaphthalene (8-OH-DPAT)
4)[3H]Ketanserin hydrochloride (Ketanserin hydrochloride)
5)[3H]Prazosin (Prazosin)
The above reagent and the water-insoluble compound in the test compound were dissolved in ethanol and then diluted with distilled water to an ethanol concentration of 10%. The maleic acid dimethyl ergometrine alkali is dissolved by distilled water for use. (animals)
6-8 weeks SD rats
(preparation of acceptor Source)
The rats were sacrificed by decapitation, the brains were enucleated, and the hippocampus and cortex were separated. Hippocampus and cortex were used for binding assays for each receptor of 5-hydroxytryptamine 1A, 5-hydroxytryptamine 2, respectively.
Hippocampus was homogenized with 50-fold wet weight of 0.32M sucrose solution and cortex with 10-fold wet weight of 0.32M sucrose solution using a Teflon glass homogenizer. Then centrifuged at 1000 Xg for 10 min. The resulting supernatant was centrifuged at 20000 Xg for 20 minutes. The hippocampal-derived pellet was further suspended in 50-fold amount of 50mM Tris-hydrochloric acid (pH7.4) relative to the initial wet weight, and the cortical-derived pellet was further suspended in 10-fold amount of 50mM Tris-hydrochloric acid (pH7.4), incubated at room temperature for 30 minutes, and centrifuged at 20000 Xg for 20 minutes. The resulting pellet was subjected to 2 more identical suspension-centrifugation cycles. The hippocampal pellet was suspended in 100 times the initial wet weight of 50mM Tris-HCl (pH7.4), and the cortical pellet was suspended in 20 times the amount of 50mM Tris-HCl (pH7.4) as the receptor fraction. The acceptor fraction was stored at-80 ℃ until use.
([3H]8-hydroxy-dipropylamino-tetrahydronaphthalene binding test)
Mixing the subject compound with 0.5nM in the receptor part of the hippocampus3H]8-hydroxy-dipropylaminonaphthalene, incubated at room temperature for 30 minutes. Then, the cell was filtered through a glass filter using a cell collector. The glass filter was washed with 50mM Tris-hydrochloric acid (pH7.4), and then the radioactivity bound to the receptor was measured with a liquid scintillation counter. The binding detected in the presence of 10. mu.M 5-hydroxytryptamine hydrogen oxalate was taken as non-specific binding.
([3H]Ketanserin hydrochloride binding test)
Mixing the subject compound with 0.3nM in the receptor portion of the cerebral cortex3H]Ketanserin hydrochloride, 37 degrees C temperature in 15 minutes. Then using cell collector with glass filterAnd (4) filtering by using a filter. The glass filter was washed with 50mM Tris-hydrochloric acid (pH7.4) and the radioactivity bound to the receptor was measured with a liquid scintillation counter. The binding detected in the presence of 1. mu.M dimethylallocerine was taken as non-specific binding.
Calculating IC by probabilistic method50The Ki value was determined by the following equation.
Ki＝IC50/(1+c/Kd)
Wherein c is the radioligand concentration and Kd is the dissociation constant of the radioligand for the receptor determined by Scatchard analysis.
([3H]Prazosin binding assay
Mixing the compound of interest and about 0.2nM in the receptor portion of the cerebral cortex 3H]Prazosin, incubated for 60 minutes at room temperature. Then, the cell was filtered through a glass filter using a cell collector. The glass filter was washed with 50mM Tris-hydrochloric acid (pH7.4), and then the radioactivity bound to the receptor was measured by a liquid scintillation counter. The binding detected in the presence of 10. mu.M phentolamine was taken as non-specific binding.
Evaluation of the binding ability of each receptor of 5-hydroxytryptamine 1A and 5-hydroxytryptamine 2 is performed by the above method for representative examples of the compound of the present invention, and is shown in the following table (No. of the compound in the table corresponds to the number of the example). Meanwhile, a positive control compound cyproheptadine hydrochloride (CAS registry No.969-33-51) and cyclobenzaprine hydrochloride (CAS registry No.6202-23-91) having an anti-5-hydroxytryptamine effect were used for comparison.
TABLE 1
Examples 5HT1a(nM) 5HT2(nM) Examples 5HT1a(nM) 5HT2(nM)
134567891011121315161718192021222324252627 623.9428.706.0010.104.5034.3013.503.008.105.708.5024.2028.60109.3219.010.138.8015.201.9024.007.4026.508.302.90＞200 ＞20017.4024.908.1017.4012.8026.9011.606.0027.9016.30＞20028.6013.8516.360.127.000.2242.7012.2014.60174.2013.1019.5028.80 28293031323334353637383940414243444546474849505253 46.90-21.9020.8030.205.701.9016.604.504.6015.001.6043.6619.8135.804.204.0015.201.10206.2015.3054.5031.202.5021.50 8.1036.5015.704.1030.2024.309.1037.6014.9014.8021.808.90＞2005.035.7037.9043.706.404.2092.3035.0029.9052.205.602.10
TABLE 2
Examples 5HT1a(nM) 5HT2(nM) Examples 5H1a(nM) 5HT2(nM)
54555657585960616263646566676869707172737576777879 7.1041.9020.7014.6026.2012.0060.805.006.203.2014.808.8050.90262.5047.209.7041.9025.4025.9034.903.6043.2044.502.40115.40 10.3017.801.701.1034.8028.90＞20012.507.401.2014.204.8085.0027.1039.5029.9027.6028.2021.107.2030.30＞20013.7029.6026.50 8182848599102103104105106107108110111112113114116117118119120121122123 44.3071.20＞200169.60-2.703.902.40＞2000.707.70172.3023.305.503.2013.705.800.500.600.700.201.000.500.20251.10 119.005.30133.7056.208.7028.4015.806.0017.406.401.702.2016.0074.20165.20＞20023.2014.3010.7010.4045.5011.2022.8015.202.70
TABLE 3
Examples 5HT1a(nM) 5HT2(nM) Examples 5HT1a(nM) 5HT2(nM)
124125126127128129130131132133136137138139140141143144145146147148149150151 1.100.101.230.210.340.950.490.172.083.703.400.651.982.316.233.031.861.498.07163.971.319.587.4413.008.84 45.804.76129.305.084.700.659.1215.2114.270.056.206.685.938.8035.07342.743.363.3848.77＞2000.770.250.500.160.57 152153154155156157158159160161162163164165166167168169170171172173174175176 16.4015.486.5214.837.804.118.185.583.863.230.982.410.545.500.796.493.8416.3947.450.390.120.060.241.491.67 0.274.240.00061.332.600.180.160.768.000.4327.087.7534.061.2217.0718.434.0613.7816.26178.0052.4370.071.850.350.05
TABLE 4
Examples 5HT1a(nM) 5HT2(nM) Examples 5HT1a(nM) 5HT2(nM)
177178179181182183184185186187189190191192193194195196197198199200201202203 0.2510.170.171029.004.281.1815.1314.5814.5565.037.720.4929.061.026.924.595.731.6710.4013.701.984.847.052.570.55 0.922.530.419.622.913.863.064.733.325.012.020.330.322.902.88＞2001.151.171.272.211.19233.98＞2005.134.61 204205206207208209210211212213214215216218219221222224225228229230232233234 1.062.761.490.812.336.982.500.530.821.033.50126.404.704.5019.601.900.043.095.740.342.5013.3037.650.601.10 4.490.122.172.691.054.724.931.210.360.180.901.0042.9011.7030.902.4018.105.117.61＞200＞200＞20048.19＞2003.30
TABLE 5
Examples 5HT1a(nM) 5HT2(nM) Examples 5HT1a(nM) 5HT2(nM)
235236237238240241242243244245246247248249250251254255256257258259260261 0.2029.2030.4086.60＞200360.00＞200＞200＞200＞200＞200＞2002.902.101.6058.50＞200＞2000.402.8035.200.601.301.50 14.6010.60＞200＞20027.601658.302.3053.002.5011.2060.0052.906.8020.2018.80＞200176.8015.7012.100.614.805.9012.905.30 262263264265266277278279281282283284285286287288291292 1.500.4611.3025.2031.6022.80＞2000.2235.1958.7039.504.500.443.740.100.26.992.0 2.10＞200138.9034.2022.603.603.9090.4011.20150.0040.904.701.393.12＞2000.1100.658.8
ABC 2529.572.5 291.680.4
A; cyclobenazaprine b; CyproheptadineC; compound 5 in WO96/23774
TABLE 5 (continuation)
Examples 5HT1a(nM) 5HT2(nM) Fruit of Chinese wolfberryExamples of the embodiments 5HT1a(nM) 5HT2(nM)
294295296297298299300301302303304305306307308309310311312313314315316317 1.050.850.320.981.860.111.730.82.923.68.370.062.827.020.733.851.341.088.2713.070.726.741.820.76 2.863.642.734.1721.32.543.5521.9360.4835.856.263.293.870.833.841.022.2946.390.561.581.11.181.26＞20 318319320321322323324325326327328329330331332333334335336337338339 1.490.560.550.140.080.140.10.650.41.042.062.060.110.112.241.080.040.22＜0.2＜0.20.07＜0.2 8.324.544＞2030.36＞20＞2010.86＞202.64＞202.41＞208.2816.17＞20＞20＞20＞20＞20＞20＞20
Table 5 (continuation 2)
Examples 5HT1a(nM) 5HT2(nM) Examples 5HT1a(nM) 5HT2(nM)
340341342343344345346347349350351352353354355356357358359360361362363364365366367368369 3.022.080.651.541.784.8213.462.240.221.920.271.580.781.220.351.520.380.730.7126.60.270.461.51.730.420.481.631.632.02 2.840.6738.151.641.640.291.490.658.1211.44＞200.7512.574.796.87＞201.314.027.39＞20＞203.543.394.233.112.051.760.562.88 370372373375376378379380381382383384385386387388389390391392393394397 ＞20＞200.241.560.9114.29.652.871.377.595.340.132.415.3863.52.260.530.991.720.650.851.181.28 ＞20＞201.773.372.11.541.251.562.023.311.810.250.97＞20＞20＞2015.4611.566.8338.152.540.962.27
Thereafter, the binding ability of the compounds of the present invention to α 1 adrenoceptor was evaluated according to the above test methods, and the results are shown in the following table (No. of the compounds in the table corresponds to No. of the examples).
Further, compound 5(Co. No.5) disclosed in Table 2 of WO96/23784 having the following chemical structure, which is a typical example of a known compound having an anti-5-hydroxytryptamine activity, is also used. This compound was prepared according to the method described in WO96/23784 (see reference example 1 below).
TABLE 6
Examples α1(nM) Examples α1(nM)
9111319222636384265687577103106121125133137147149151162164166 76.514718855.511351.139244.223055.7223.488.6248.777.771.358.246.37261.65125.59156.84304.15292.16222.63638.02193.71 168182184187189197204206216235236248250277280283285291292 72.5670.07188.42＞200442.2468.59183.23104.7581.5977.872.275.3263354.4122219726.8171.5178.3
Compound 5 of CyclobenzaprinCyproheptadineWO 96/23784 -190016.8
Table 6 (continue)
Examples α1(nM) Examples α1(nM)
294295296297298300301302303304305306307308309310311312313314316317318319320 80.7195.3238.5226.327.9224.666.9142.9306.914135.9147.551.559.4122.984.48553.314451.363.740046.642.526.1 321322323324325326327328329330331332333334335336338339 20341.386.960.94716799140149338.77765.9247.1212.228.453.721.331.7
Table 6 (continuation 2)
Examples α1(nM) Examples α1(nM)
340341342343344345346347349350351352353354355358359360361362363364365366 339.847.62538.174.9103.2115.544.388.5123.417596.7144.190.539.541.875.969077.414410628961.674.6 367368369370372375376378379380381382383385386387388389390391392393397 45.837.6121.4255.5206.461.446.743.730.3116100.7163.1120.121.626.226.2365.84534.3116.22537.827.1
From tables 1 to 6, it is shown that the 1, 4-substituted cyclic amine derivatives of the present invention have 5-hydroxytryptamine antagonistic action, are drugs having clinical utility and high safety, and are particularly useful as a therapeutic, ameliorating, prophylactic or central muscle relaxant for spastic paralysis or for ameliorating myotonic symptoms.
In addition, it is found that the compound of the present invention has a low ability to bind to α 1 adrenergic receptors, hardly affects blood pressure, and is a highly safe drug, as compared with compound 5 disclosed in WO96/23784, which is a representative example of known compounds.
(2) Mouse Morphine Induced cauda lifting reaction (Morphine Induced Straub Tail Phonomenon)
According to Drug development research Drug dev. res, 11: 53-57, 1987 methods evaluate the tonic-alleviating effect of the compounds of the invention.
The test was carried out using 4-5 week-old ddY male mice (SLC, Jinggang) and 8 mice per group. Positive control compounds used were cyproheptadine hydrochloride, cyclobenzaprine hydrochloride, and tiotropine hydrochloride [ CAS accession No.: 51322-75-9] and chloroaminobutyric acid (Baclofen [ CAS registry No.: 1134-47-0 ]). The test compound and the positive control compound were dissolved with a 5% glucose injection or suspended with 0.5% methylcellulose. Morphine hydrochloride was dissolved in physiological saline for injection.
The test compounds were administered to mice either orally (p.o.) or intraperitoneally (i.p.) at the test concentrations, and vehicle was administered to the control group. The subject compounds were administered 15 minutes later with 12.5mg/kg morphine hydrochloride subcutaneously. The tail muscle tone was observed after morphine hydrochloride administration for 15, 30 and 45 minutes, and the tail lifting reaction was judged to be positive when the tone was observed.
And comparing and identifying the tail lifting rate difference of the test group and the control group at each observation time by using X-two multiplication to calculate the minimum effective dosage with statistical significance (p is less than 0.05).
The following table shows the evaluation results.
TABLE 7
Examples i.p.(mg/Kg) p.o.(mg/Kg) Examples i.p.(mg/Kg) p.o.(mg/Kg)
92234364265103106121125133137147149151162166 10-≤101≤10-≤1010-10.3-≤0.31-13 -＞1030≤31030＞30＞30103≤0.31≤3≤33＞103 168182184186189197204206235248250277285 ------3--≤1010＜11 10103101010310＞103030301
CyclobenzaprineCyproheptadineTizanidineBaclofen 10313 --110
It can be seen from table 7 that the compounds of the present invention have excellent tonic-alleviating effects in vivo.
Examples
The present invention will be specifically described below with reference to production examples and examples, but the present invention is not intended to be limited to these examples. Hereinafter, Hydrochloride means Hydrochloride, Free means Free base, Oxalate means Oxalate.
PREPARATION EXAMPLE 14 Synthesis of Fluorophenethyl bromide
Triphenylphosphine (222g) and N-bromosuccinimide (151g) were added to a dichloromethane (1l) solution of 4-fluorophenethanol (100g) under ice cooling, and stirred for 1 hour. After concentration under reduced pressure, the precipitated crystals were filtered off, and the filtrate was concentrated to give the title compound (133g) as a colorless oil.
(yield 92%)
1H-NMR(400MHz，CDCl3)；δ(ppm)3.14(2H，t，J＝8Hz)、3.54(2H，t，J＝8Hz)、6.98-7.03(2H，m)、7.15-7.18(2H，m).
PREPARATION EXAMPLE 21 Synthesis of bromo-3- (4-fluorophenyl) propane
Thionyl chloride (6.8ml) was added dropwise to ethanol (20ml) under ice cooling, and the mixture was stirred for 15 minutes. Then, 3- (4-fluorophenyl) propionic acid (2.853g) was added thereto, and the mixture was stirred at room temperature for 11 hours and concentrated under reduced pressure. After dilution with ethyl acetate (500ml), a saturated aqueous sodium hydrogencarbonate solution and a saturated brine were washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a colorless oil (3.456 g). This was dissolved in tetrahydrofuran (90ml), and lithium aluminum hydride (0.863g) was added thereto under ice cooling, followed by stirring for 1 hour. Water (0.9ml), a 5N aqueous solution (0.9ml) of sodium hydroxide and water (2.7ml) were added to the reaction solution, and the precipitated solid was filtered off and concentrated under reduced pressure to give a pale yellow oil (2.557 g). This was treated by the method of example 1 to give the title compound (2.354g) as a yellow oil. (yield: 63.6%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.14(2H，tt，J＝6.6，7.0Hz)、2.76(2H，t，J＝7.0Hz)、3.38(2H，t，J＝6.6Hz)、6.98(2H，t，J＝8.8Hz)、7.16(2H，m).
PREPARATION EXAMPLE 31 Synthesis of bromo-4- (4-fluorophenyl) butane
(3-1)3- (4-fluorophenyl) propane-1, 1-dicarboxylic acid
Sodium (0.7g) was dissolved in ethanol (17.5ml), and diethyl malonate (9.1ml) and 4-fluorophenethyl bromide (4.1g) were added to the solution, followed by heating and refluxing for 2.5 hours. After cooling, the mixture was diluted with ethyl acetate (500ml), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solution was dissolved in ethanol (10ml), added with potassium hydroxide (10.2g) and dissolved in water (10ml), and the mixture was stirred at 80 ℃ for 3 hours. After cooling, the mixture was acidified with hydrochloric acid, diethyl ether was added to separate organic layers, which were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (6.938g) as a pale yellow oil.
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.25(2H，dt，J＝7.6Hz)、2.70(2H，t，J＝7.6Hz)、3.42(1H，t，J＝7.6Hz)、6.97(2H，t，J＝8.8Hz)、7.12(2H，m).
(3-2)4- (4-fluorophenyl) butanoic acid
The above 3- (4-fluorophenyl) propane-1, 1-dicarboxylic acid (6.938g) was directly heated and stirred at 180 ℃ for 40 minutes to give the title compound (4.877g) as a brown oil.
1H-NMR(400MHz。CDCl3)；δ(ppm)
1.94(2H，m)、2.37(2H，t，J＝7.6Hz)、2.65(2H，t，J＝7.6Hz)、6.97(2H。t，J＝8.8Hz)、7.15(2H，m).
(3-3)4- (4-fluorophenyl) butanoic acid ethyl ester
Under ice cooling, a solution obtained by dissolving thionyl chloride (6.8ml) dropwise in ethanol (20ml) was added thereto, stirred at room temperature for 11 hours, and concentrated under reduced pressure. After dilution with ethyl acetate (500ml), washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the title compound (7.178g) was obtained as a brown oil.
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.34(3H，dt，J＝2.0，7.0Hz)、1.93(2H，m)、2.31(2H，dt，J＝0，7.2Hz)、2.63(2H，t，J＝7.2Hz)、4.12(2H，dq，J＝2.0，7.0Hz)、6.97(2H，t，J＝8.8Hz)、7.13(2H，m).
(3-4)4- (4-fluorophenyl) butan-1-ol
Ethyl 4- (4-fluorophenyl) butyrate (7.178g) was dissolved in tetrahydrofuran (120ml), and lithium aluminum hydride (1.55g) was added thereto under ice cooling, followed by stirring for 1 hour. Water (1.5ml), 5N aqueous sodium hydroxide solution (1.55ml) and water (4.5ml) were added to the residue, and the precipitated solid was filtered off and concentrated under reduced pressure to give the title compound (3.890g) as a brown oil.
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.58-1.71(4H，m)、2.61(2H，t，J＝7.0Hz)、3.66(2H，dt，J＝2.8，6.4Hz)、6.96(2H，t，J＝8.8Hz)，7.13(2H，m).
(3-5) 1-bromo-4- (4-fluorophenyl) butane
The title compound (4.250g) was obtained as a yellow oil by the method of production example 1 using the above 4- (4-fluorophenyl) butan-1-ol (7.178g) (yield 91.9%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.75(2H，m)、1.88(2H，m)、2.62(2H，t，J＝7.6Hz)、3.42(2H，t，J＝7.0Hz)、6.97(2H，t，J＝8.8Hz)、7.13(2H，m).
PREPARATION EXAMPLE 44 Synthesis of bromophenethyl bromide
The title compound (2.345g) was obtained as a pale yellow oil by the method of production example 1 using 4-bromobenzeneethanol (1.3 ml). (yield 88.8%)
1H-NMR(400MHz，CDl3)；δ(ppm)
3.12(2H，t，J＝7.4Hz)、3.54(2H，t，J＝7.4Hz)、7.09(2H，d，J＝8.4Hz)、7.45(2H，d，J＝8.4Hz).
PREPARATION EXAMPLE 53 Synthesis of Chlorophenylethyl bromide
The title compound (1.417g) was obtained as a pale yellow oil by the method of production example 1 using 3-chlorophenethanol (1.0 ml). (yield 64.6%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.14(2H，t，J＝8.6Hz)、3.56(2H，t，J＝8.6Hz)、7.11(1H，m)、7.21(1H，s)、7.45(2H，m).
PREPARATION EXAMPLE 64-Chlorophylethyl bromide Synthesis
The title compound (2.639ml) was obtained as a pale yellow oil by the method of production example 1 using 4-chlorophenethanol (5 ml). (yield 32.6%)
(No NMR)
PREPARATION EXAMPLE 74 Synthesis of methoxyethyl bromide
The title compound (0.838g) was obtained as a pale yellow oil by the method of production example 1 using 4-methoxyphenylethanol (0.61 g). (yield 97.4%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.10(2H，t，J＝7.6Hz)，3.53(2H，t，J＝7.6Hz)、3.80(3H，s)、6.86(2H，d，J＝8.2Hz)、7.13(2H，d，J＝8.2Hz).
PREPARATION EXAMPLE 84 Synthesis of- (2-bromoethyl) benzyl alcohol
(2-bromoethyl) benzaldehyde (1.178g) was dissolved in ethanol (20ml), and lithium aluminum hydride (0.189g) was added thereto, followed by stirring at room temperature for 1 hour. It was diluted with ethyl acetate (200ml), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.439g) as a pale yellow oil. (yield 40.1%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.02(1H，br-s)、3.16(2H，t，J＝7.6Hz)、3.56(2 H，t，J＝7.6Hz)、7.20(2H，d，J＝8.4Hz)、7.31(2H，d，J＝8.4Hz).
PREPARATION EXAMPLE 94 Synthesis of- (2-bromoethyl) benzaldehyde
(2-bromoethyl) benzene (2.72ml) was dissolved in methylene chloride (20ml), and a 1.0M titanium tetrachloride/methylene chloride solution (40ml) and then dichloromethyl ether (2.72ml) were added dropwise while maintaining the internal temperature at-10 ℃. After stirring at room temperature for 6 hours, the reaction mixture was poured onto ice, extracted with ethyl acetate, washed with saturated brine and saturated aqueous sodium bicarbonate solution, and then washed with saturated brine. Dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The title compound (5.408g) was obtained as a tan oil.
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.26(2H，t，J＝7.2Hz)、3.61(2H，t，J＝7.2Hz)，7.40(2H，d，J＝8.4Hz)、7.86(2H，d，J＝8.4Hz)、10.01(1H，s).
PREPARATION EXAMPLE 104 Synthesis of (2-bromoethyl) benzaldoxime
The above 4- (2-bromoethyl) benzaldehyde (2.72g) was dissolved in ethanol (80ml), and water (20ml), hydroxylamine hydrochloride (1.53g) and sodium acetate trihydrate (2.99g) were added to the solution, followed by heating and refluxing for 30 minutes. After cooling, water and ethyl acetate (500ml) were added to the reaction solution, and the organic layer was separated, washed with saturated brine and dried over anhydrous sodium sulfate. Concentrating under reduced pressure. The title compound (5.408g) was obtained as a tan oil.
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.18(2H，t，J＝7.4Hz)、3.57(2H，t，J＝7.4Hz)、7.24(2H，d，J＝8.0Hz)、7.52(2H，d，J＝8.0Hz)、8.13(1H，s).
PREPARATION EXAMPLE 114 Synthesis of cyanophenylethyl bromide
Using 4- (2-bromoethyl) benzaldoxime (1.0g), the procedure of example 20 was followed to give the title compound (0.977) as a brown oil.
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.23(2H，t，J＝7.2Hz)、3.59(2H，t，J＝7.2Hz)、7.34(2H，d，J＝7.4Hz)，7.63(2H，d，J＝7.4Hz).
PREPARATION EXAMPLE 124 Synthesis of carbamoyl phenethyl bromide
4-Cyanophenethyl bromide (0.997g) was dissolved in sulfuric acid (20ml), and the mixture was stirred at room temperature for 15 hours. Pour into ice. Diethyl ether was added and the organic layer was separated. Washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as colorless crystals (0.619 g). (yield 62.0%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.23(2H，t，J＝7.3Hz)、3.59(2H，t，J＝7.3Hz)、7.31(2H，d，J＝8.4Hz)、7.78(2H，d，J＝8.4Hz).
PREPARATION EXAMPLE 13 Synthesis of N-isopropyl-4- (2-bromoethyl) phenylacetamide
(13-1) N-isopropyl-4-bromophenylacetamide
4-Bromobenzoic acid (10g) was dissolved in tetrahydrofuran (200ml), and N, N-carbonyldiimidazole (7.54g) was added thereto and the mixture was stirred at room temperature for 15 minutes. Isopropylamine (3.96ml) was added and stirred at room temperature for 24 hours. After concentration under reduced pressure, ethyl acetate (500ml) and a saturated aqueous solution of sodium hydrogencarbonate were added to separate organic layers, which were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound as colorless crystals (11.3 g). (yield 94.8%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.08(6H，d，J＝6.8Hz)、3.47(2H，s)、4.06(1H，m)、5.17(1H，br-s)、7.13(2H，d，J＝8.8Hz)、7.47(2H，d，J＝8.8Hz).
(13-2) N-isopropyl-4-vinylphenylacetamide
N-isopropyl-4-bromophenylacetamide (1.0g) and vinyltributyltin (1.4ml) were dissolved in toluene (12ml), and tetrakis (triphenylphosphine) palladium (0.5g) was added to the solution, followed by refluxing under heating for 4 hours. After cooling, the mixture was diluted with ethyl acetate, the solid was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as colorless crystals (0.578g) (. high yield 72.8%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.08(6H，d，J＝6.4Hz)、3.55(2H，s)、4.07(1H，m)、5.21(1H，br-s)、5.28(1H，dd，J＝0.8.10.8Hz)、5.76(1H，dd，J＝0.8，17.6Hz)、6.718(1H，dd，J＝10.8，17.6Hz)、7.21(2H，J＝8.0Hz)、7.40(2H，d，J＝8.8Hz).
(13-3) N-isopropyl-4- (2-hydroxyethyl) phenylacetamide
N-isopropyl-4-vinylphenylacetamide (0.378g) was dissolved in tetrahydrofuran (4.4ml), and a 1..0M (borane-tetrahydrofuran complex)/tetrahydrofuran solution (5.6ml) was added dropwise under ice cooling, followed by stirring for 2 hours. A5N aqueous sodium hydroxide solution (3ml) and a 30% aqueous hydrogen peroxide solution (3ml) were added thereto, and the mixture was stirred for 10 hours. Ethyl acetate and water were added to the residue, and the organic layer was partitioned, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate-methanol) to give the title compound as colorless crystals (0.134 g). (yield 32.6%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.08(6H，dd，J＝1.6，6.8Hz)、2.87(2H，t，J＝6.6Hz)、3.51(2H，s)、3.87(2H，t，J＝6.6Hz)、4.07(1H，m)、5.26(1H，br-s)、7.19(2H，J＝8.6Hz)、7.22(2H，d，J＝8.6Hz).
(13-4) N-isopropyl-4- (2-bromoethyl) phenylacetamide
Using N-isopropyl-4- (2-hydroxyethyl) phenylacetamide (0.134g), the title compound was obtained as colorless crystals (0.029g) (yield 16.9%) according to production example 1
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.08(6H，d，J＝6.4Hz)、3.16(2H，t，J＝7.4Hz)、3.15(2H，s)、3.57(2H，t，J＝7.4Hz)、4，06(1H，m)、5.20(1H，br-s)、7.21(4H，s).
PREPARATION EXAMPLE 143- [2- (tert-butyl) dimethylsilyloxyethoxy ] phenethyl bromide
[ wherein TBDMS represents a (tert-butyl) dimethylsilyl group ]
The procedure of example 35 was repeated using 3-hydroxyphenylethanol (1.5g) and 1-bromo-2- (tert-butyl) dimethylsiloxyethane (3.4g) to give a pale yellow oil, which was used in the procedure of preparation example 1 to give the title compound (1.996g) as a pale yellow oil. (yield 55.4%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
0.11(6H，s)、0.92(9H，s)、3.13(2H，t，J＝7.6Hz)、3.56(H，t，J＝7.6Hz)、3.97(2H，m)、4.04(2H，m)、6.78(3H，m)、7.21(1H，m).
PREPARATION EXAMPLE 151, 2-DIHYDROXYMETHYL-4-BROMOBENE
(15-1) 4-Bromophthalic acid dimethyl ester
Methanol (500ml) was added to 4-bromophthalic anhydride (50.25 g). Chlorosulfonic acid (1ml) was added thereto, the mixture was refluxed overnight under heating, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). The title compound (39.98g) was obtained as a colorless oil. (yield 66.1%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.90(3H，s)、3.92(3H，s)、7.63(1H，d，J＝8.4Hz)、7.68(1H，dd，J＝2.0，8.4Hz)、7.84(1H，d，J＝2.0Hz).
(15-2)1, 2-dihydroxymethyl-4-bromobenzene
Lithium aluminum hydride (8.77g) was suspended in tetrahydrofuran (400ml), and the suspension was stirred under ice-cooling. Dimethyl 4-bromophthalate (39.98g) was dissolved in tetrahydrofuran (100ml), and added dropwise thereto. After stirring for another 30 minutes, water (8.8ml), a 5N aqueous solution of sodium hydroxide (8.8ml) and water (26.4ml) were added in this order. The mixture was diluted with ethyl acetate, and insoluble matter was filtered off, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (13.7g) as a colorless powder. (yield 43.1%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.18(1H，br-t)、3.27(1H，br-t)、4.63-4.65(2H，m)、7.20(1H，d，J＝8.0Hz)、7.43(1H，dd，J＝2.0，8.0Hz)、7.49(1H，d，J＝2.0Hz).
Preparation example 163, 4-bis [ (tert-butyl) dimethylsiloxymethyl ] phenethyl Bromide Synthesis (16-1)3, 4-bis [ (tert-butyl) dimethylsiloxymethyl ] phenethyl alcohol
1, 2-Dimethylol-4-bromobenzene (3.110g) was used in accordance with J.Am.chem.Soc., 6190(1972), to give a colorless oil (6.000 g). Dissolved in tetrahydrofuran (56ml), and an n-butyllithium/n-hexane solution (4.2ml) was added under a nitrogen atmosphere at-78 ℃ followed by ethylene oxide (1.36ml), and the mixture was stirred for 3 hours. Water and diethyl ether were added to the reaction solution, and the organic layer was partitioned, washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.214g) as a colorless oil. (yield 37.6%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
0.11(6H，s)、0.95(9H，s)、2.87(2H，t，J＝6.4Hz)、3.85(2H，q，J＝6.4Hz)、4.72(2H，s)、4.74(2H，s)、7.11(1H，dd，J＝1.6，7.6Hz)、7.29(1H，d，J＝1.6Hz)、7.36(1H，d，J＝7.6Hz).
(16-2)3, 4-bis [ (tert-butyl) dimethylsiloxymethyl ] phenethyl bromide
Using 3, 4-dimethylolphenethyl alcohol (0.41g), pyridine (0.16ml) was added to the solution, and the title compound (0.421g) was obtained as a colorless oil by the same method as in production example 1. (yield 88.9%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
0.11(6H，s)、0.95(9H，s)、3.16(2H，t，J＝7.8Hz)，3.56(2H，t，J＝7.8Hz)、4.71(2H，s)、4.74(2H，s)、7.10(1H，dd，J＝1.6，7.6Hz)、7.27(1H，d，J＝1.6Hz)、7.36(1H，d，J＝7.6Hz).
PREPARATION 173 SYNTHESIS OF (TERT-BUTYL) DIMETHYLSILOXYMETHYLPHENYL BROMIDE
(17-1)3- (tert-butyl) dimethylsiloxymethylbenzyl alcohol
1, 3-Benzenedimethanol (10g) was dissolved in tetrahydrofuran (210ml), and sodium hydride (1.16g) was added under ice cooling, followed by dropwise addition of a solution of (tert-butyl) dimethylchlorosilane (4.36g) in tetrahydrofuran (40ml), and stirring was carried out at room temperature for 3 hours. Adding water, and concentrating under reduced pressure. Ethyl acetate (200ml) was added to the residue, and the organic layer was partitioned, washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrating under reduced pressure. Purification by silica gel column chromatography (hexane/ethyl acetate) gave the title compound (2.108g) as a colorless oil. (yield 29.1%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
0.10(6H，s)、0.95(9H，s)、1.57(1H，br-s)、4.70(2H，s)、4.75(2H，s)、7.23-7.35(4H，m).
(17-2)3- (tert-butyl) dimethylsilyloxymethylbenzaldehyde
Dimethyl sulfoxide (1.43ml) was dissolved in dichloromethane (31ml), and oxalyl chloride (0.88ml) was added dropwise under a nitrogen atmosphere at-78 ℃ and stirred for 30 minutes. A solution of 3- (tert-butyl) dimethylsiloxymethylbenzyl alcohol (2.108g) dissolved in methylene chloride (10ml) was added dropwise thereto, followed by addition of diisopropylethylamine (4.4ml) and stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. Purification by silica gel column chromatography (hexane/ethyl acetate) gave the title compound (2.132g) as a light-colored oil. (yield 100%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
0.12(6H，s)、0.95(9H，s)、4.81(2H，s)、7.50(1H，t，J＝7.6Hz)、7.61(1H，d，J＝7.6Hz)、7.77(1H，d，J＝7.6Hz)、7.83(1H，s)、10.02(1H，s).
(17-3)3- (tert-butyl) dimethylsiloxymethylstyrene
Methyltriphenylphosphonium bromide (3.16g) was suspended in tetrahydrofuran (30ml), and potassium tert-butoxide (0.99g) was added thereto under ice-cooling, followed by stirring at room temperature for 10 minutes, followed by ice-cooling again, dropwise addition of a solution of 3- (tert-butyl) dimethylsilyloxymethylbenzaldehyde (2.132g) in tetrahydrofuran (0.88ml), and stirring at room temperature for 5 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned, washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrating under reduced pressure. Purification by silica gel column chromatography (hexane/ethyl acetate) gave the title compound (1.930g) as a yellow oil. (yield 93.0%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
0.10(6H，s)、0.95(9H，s)、4.74(2H，s)、5.24(1H，dd，J＝1.2，11.2Hz)、5.75(1H，dd，J＝1.2，17.6Hz)、6.72(1H，dd，J＝11.2，17.6Hz)、7.21(1H，m)、7.29(2H，m)、7.38(1H，s).
(17-4)3- (tert-butyl) dimethylsiloxymethylphenylethanol
3- (tert-butyl) dimethylsiloxymethylstyrene (0.5g) was added to a solution of 0.5M (9-borabicyclo [3.3.1] nonane) in tetrahydrofuran, and the title compound (0.494g) was obtained as a colorless oil by the method of J.Am.chem.Soc., 7765 (1974). (yield 92.2%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
0.110(6H，s)、0.95(9H，s)、2.88(2H，t，J＝6.4Hz)、3.87(2H，q，J＝6.4Hz)、4.73(2H，s)、7.09-7.34(4H，m).
(17-5)3- (tert-butyl) dimethylsilyloxyphenethyl bromide
The title compound (0.390g) was obtained as a colorless oil by the procedure of production example 1 using 3- (tert-butyl) dimethylsiloxymethylphenethyl alcohol (0.494 g). (yield 63.7%)
PREPARATION EXAMPLE 184- [2- (tert-butyl) dimethylsilyloxyethyl ] phenethyl bromide
(18-1) dimethyl 1, 4-benzenediacetate
Under ice cooling, thionyl chloride (6.6ml) was dropped into methanol (26ml), stirred for 15 minutes, and then 1, 4-benzenediacetic acid (5.0g) was added thereto. Stirred at room temperature for 35 hours and concentrated under reduced pressure. Ethyl acetate (500ml) was diluted, which was washed with a saturated aqueous solution of sodium hydrogencarbonate, with saturated brine and dried over anhydrous sodium sulfate. Concentrating under reduced pressure. The title compound was obtained as colorless crystals.
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.61(4H，s)、3.69(6H，s)、7.25(4H，d，J＝6.4Hz).
(18-2)1, 4-Benzenediethanol
Dimethyl 1, 4-benzenediacetate (all) synthesized in production example (18-1) was dissolved in tetrahydrofuran (100ml), and lithium aluminum hydride (2.44g) was added thereto under ice cooling, followed by stirring at room temperature for 3 hours. Water (2.5ml), a 5N aqueous solution (2.5ml) of sodium hydroxide and water (7.5ml) were added thereto under ice cooling, and the precipitated solid was filtered off and concentrated under reduced pressure. The title compound was obtained as colorless crystals (4.555 g).
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.40(2H，t，J＝6.0Hz)、2.85(4H，t，J＝6.4Hz)、3.86(4H，q，J＝6.4Hz)、7.19(4H，s)，
(18-3)4- [2- (tert-butyl) dimethylsilyloxyethyl ] phenethyl alcohol
The title compound (0.869g) was obtained as a colorless oil by the method of production example (17-1) using 1, 4-benzenediethanol (4.555 g). (yield 30.1%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
-0.01(6H，s)，0.91(9H，s)、2.80(2H，t，J＝7.2Hz)、2.84(2H，t，J＝6.4Hz)、3.79(2H，t，J＝7.2Hz)、3.84(2H，q，J＝6.4Hz)、7.15(4H，s).
(18-4)4- [2- (tert-butyl) dimethylsilyloxyethyl ] phenethyl bromide
4- [2- (tert-butyl) dimethylsilyloxyethyl ] phenethyl alcohol (0.869g) the procedure of preparation 1 was repeated to give the title compound (0.700g) as a colorless oil. (yield 65.8%)
PREPARATION EXAMPLE 194 Synthesis of (1-hydroxyethyl) phenethyl bromide
4- (2-bromoethyl) benzaldehyde (3.245g) was dissolved in tetrahydrofuran (60ml), and a 3M methylmagnesium bromide/diethyl ether solution (4.9ml) was added dropwise under ice cooling, followed by stirring for 1.5 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.745g) as a brown oil. (yield 83.8%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.49(3H，d，J＝6.4Hz)、1.81(1H，br-s)，3.16(2H，t，J＝7.6Hz)、3.57(2H，t，J＝7.6Hz)、4.89(1H，q，J＝6.4Hz)、7.20(2H，d)、7.33(2H，d).
PREPARATION 204 Synthesis of methanesulfonylphenethyl bromide
(20-1)4- (2-tert-butyldimethylsilyloxyethyl) -1-bromobenzene
A solution of 4-bromobenzyl ethanol (10g), imidazole (4.0g) and (tert-butyl) dimethylsilyl chloride (9.0g) in dimethylformamide (50ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added to the concentrate, and the organic layer was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane/ethyl acetate). The title compound (13.9g) was obtained as a colorless oil. (yield 88%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
-0.02(6H，s)、0.89(9H，s)、2.79(2H，t，J＝7Hz)、3.80(2H，t，J＝7Hz)、7.10(2H，d，J＝8Hz)、7.42(2H，d，J＝8Hz).
(20-2) 4-Methylsulfonylphenylethanol
To a solution of 4- [2- (tert-butyl) dimethylsilyloxyethyl ] -1-bromobenzene (5.0g) in tetrahydrofuran (50ml) was added dropwise a 2.5M n-butyllithium/hexane solution (7.6ml) at-78 ℃ over 10 minutes. After 10 minutes, a saturated sulfur dioxide/tetrahydrofuran (200ml) solution was added and the temperature was raised to room temperature. The reaction mixture was concentrated under reduced pressure, and dimethylformamide (100ml) and methyl iodide (2.7g) were added to the residue, followed by stirring at 50 ℃ for 6 hours. After concentration under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution and ethyl acetate were added to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was added with tetrahydrofuran and tetrabutylammonium fluoride. Stirred at 0 ℃ for 2 hours. Water and ethyl acetate were added to the reaction mixture to separate an organic layer. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (dichloromethane/ethanol) to give the title compound (1.9g) as a colorless oil. (yield 60%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.45(1H，t，J＝7Hz)，2.85(2H，t，J＝7Hz)、3.04(3H，s)、3.92(2H，q，J＝7Hz)、7.44(2H，d，J＝8Hz)、7.89(2H，d，J＝8Hz).
(20-3) 4-Methylsulfonylphenylethyl bromide
The title compound (1.9g) was obtained as a colorless oil by the method of production example 1 using 4-methanesulfonylphenethyl alcohol (1.9 g). (yield 76%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.05(3H，s)、3.27(2H，t，J＝7Hz)、3.61(2H，t，J＝7Hz)、7.43(2H，d，J＝8Hz)、7.90(2H，d，J＝8Hz).
PREPARATION 214 Synthesis of sulfamoylphenethyl bromide
Phenethyl bromide (5.0g) was added dropwise to chlorosulfonic acid (15ml) under ice cooling, and the mixture was stirred for 1 hour. The reaction mixture was diluted with ice water and ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine, and then with ammonia (10ml) and stirred for 1 hour. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. Concentrated under reduced pressure, and the precipitated crystals were washed with isopropyl ether and air-dried to give the title compound as white crystals (1.4 g). (yield 22%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
3.20(2H，t，J＝7Hz)、3.31(2H，br-s)、3.77(2H，t，J＝7Hz)、7.48(2H，d，J＝8Hz)、7.74(2H，d，J＝8Hz).
PREPARATION 221 SYNTHESIS OF BROMO-3- (4-FLUOROPHENYL) PROPANE
A mixture of 4-fluorophenol (11g), 1, 3-dibromopropane (61g), sodium hydroxide (8.0g), tetra-n-butylammonium bromide (6.0g), dichloromethane (200ml) and water (200ml) was vigorously stirred at room temperature overnight. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane/isopropyl ether). The title compound (16.5g) was obtained as a colorless oil. (yield 71%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.24-2.36(2H，m)、3.60(2H，t，J＝7Hz)、4.08(2H，t，J＝7Hz)、6.80-6.89(2H，m)，6.93-7.00(2H，m).
PREPARATION EXAMPLE 233 Synthesis of bromopropoxy-1, 2-methylenedioxybenzene
3, 4-methylenedioxyphenol (4.144g) was dissolved in N, N-dimethylformamide (40ml), and 60% sodium hydride (1.2g) was added under ice cooling, followed by stirring for 1 hour, and then 1, 3-dibromopropane (9.1ml) was added thereto and the mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water and dried (MgSO) 4) Concentrating under reduced pressure, and purifying by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compoundSolid 1.341 g. (yield 17%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.25-2.32(2H，m)、3.59(2H，t，J＝6.4Hz)、4.03(2H，t，J＝5.8Hz)、5.92(2H，s)、6.33(1H，dd，J＝8.8Hz，2.4Hz)、6.49(1H，d，J＝2.4Hz)、6.71(1H，d，J＝8.8Hz).
PREPARATION EXAMPLE 244 Synthesis of (3-Bromopropoxy) phenethyl alcohol
4-Hydroxyphenylethanol (4.145g), 1, 3-dibromopropane (9.1ml) and tetrabutylammonium bromide (967mg) were added to a solution of dichloromethane (100ml) and sodium hydroxide (2.4 g)/water (100ml), and stirred vigorously at room temperature overnight. The dichloromethane layer was washed with water and dried (MgSO4) Concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound as a colorless solid (1.005 g). (yield 13%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.31(2H，qui，J＝6Hz)、2.81(2H，t，J＝6.4Hz)、3.60(2H，t，J＝6.4Hz)、3.83(2H，t，J＝6.4Hz)、4.09(2H，t，J＝6Hz)、6.86(2H，d，J＝8.6Hz)、7.08(2H，d，J＝8.6Hz)，
PREPARATION EXAMPLE 254- (3-Bromopropoxy) benzyl alcohol Synthesis
From 4-hydroxybenzyl alcohol (3.724g) by the method of production example 24, the title compound was obtained as 314mg of a pale yellow solid. (yield 4%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.31(2H，qui，J＝6.3Hz)、3.30(2H，t，J＝6.3Hz)、4.10(2H，t，J＝6.3Hz)、4.60(2H，d，J＝5.8Hz)、6.90(2H，d，J＝8.9Hz)、7.30(2H，d，J＝8.9Hz).
Preparation example 263 Synthesis of (2-bromoethyl) pyridine
(26-1) 3-Pyridylethanol
Ethyl 3-pyridylacetate (2.0ml) was dissolved in tetrahydrofuran (66ml), and lithium aluminum hydride (0.5g) was added thereto under ice cooling, followed by stirring for 30 minutes, water (0.5ml), a 5N aqueous solution of sodium hydroxide (0.5ml) and water (1.5ml) were added, and the resulting precipitate was filtered off, washed with ethyl acetate, and concentrated under reduced pressure to give the title compound (1.636g) as a pale yellow oil. (yield; quantitative)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.84(2H，t，J＝6.4Hz)，3.85(2H，t，J＝6.4Hz)、7.20(1H，m)、7.57(1H，m)、8.36(2H，m).
(26-2)3- (2-bromoethyl) pyridine
The reaction mixture was back-extracted with 3-pyridylethanol (0.4g) by the method of production example 1, and the reaction mixture was made alkaline with aqueous sodium hydroxide solution, extracted with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.481g) as a brown oil. (yield 79.5%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.18(2H，t，J＝7.2Hz)、3.58(2H，t，J＝7.2Hz)、7.47(1H，m)、7.55(1H，dt，J＝1.6，7.2Hz)、7.67(1H，ddd，J＝1.6，7.2，10.8Hz)、8.51(1H、m).
PREPARATION EXAMPLE 271 Synthesis of bromo-2- (2-methoxypyridin-5-yl) ethane
(27-1)2- (2-methoxypyridin-5-yl) ethanol
5-bromo-2-methoxypyridine (2.628g) synthesized in Tetrahedron, 1373, (1985) was dissolved in diethyl ether (40ml) to give the title compound (1.324g) as a pale yellow oil in the same manner as in production example 16-1. (yield 62.7%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.79(2H，t，J＝6.4Hz)，3.82(2H，br-t)、3.91(3H，s)、6.71(1H，d，J＝8.4Hz)、7.46(1H，dd，J＝2.4，8.4Hz)、8.01(1H，d，J＝2.4Hz).
(27-2) 1-bromo-2- (2-methoxypyridin-5-yl) ethane
Using 2- (2-methoxypyridin-5-yl) ethanol (1.342g), the reaction was carried out as in production example 1, followed by back-extraction to give the title compound (1.221g) as a brown oil. (yield 64.5%)
1H-NMR(400MHz、CDCl3)；δ(ppm)
3.09(2H，t，J＝7.4Hz)、3.52(2H，t，J＝7.4Hz)、3.93(3H，s)、6.71(1H，d，J＝8.4Hz)、7.44(1H，dd，J＝2.4，8.4Hz)、8.02(1H，d，J＝2.4Hz).
PREPARATION EXAMPLE 281-bromo-2- (2-cyanopyridin-5-yl) ethane Synthesis
(28-1)2- (3-pyridyl) ethanol
3-Pyridylacetic acid hydrochloride (25g) according to production example 3-3 and then production example 3-4, the title compound (16.938g) was obtained as a yellow oil. (yield 95.5%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.86(2H，t，J＝6.8Hz)、3.88(2H，t，J＝6.8Hz)、7.22(1H，dd，J＝4.8，7.6Hz)、7.527(1H，d，J＝7.6Hz)、8.42(1H，dd，J＝2.0，4.8Hz)、8.44(1H，d，J＝2.0Hz).
(28-2)2- (3-pyridyl) -1-triphenylmethyloxyethane
Using 2- (3-pyridyl) ethanol (5.0g), the title compound (10.096g) was obtained as a yellow oil according to Tetrahedron Lett.579 (1986). (yield 68.0%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.86(2H，t，J＝6.4Hz)、3.32(2H，t，J＝6.4Hz)、7.08-7.38(16H，m)、7.53(1H，d，J＝8.0Hz)、8.46(2H，m).
(28-3)3- (2-Triphenylmethoxyethyl) pyridine-N-oxide
Using 2- (3-pyridyl) -1-triphenylmethyloxyethane (10.096g), the title compound (11.201g) was obtained as a yellow oil according to Tetrahedron Lett.1475 (1986). (yield: quantitative)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.86(2H，t，J＝6.4Hz)、3.32(2H，t，J＝6.4Hz)、7.08-7.38(16H，m)、7.53(1H，d，J＝8.0Hz)，8.46(2H，m).
(28-4)2- (2-cyanopyridin-5-yl) -1-triphenylmethyloxyethane
2-cyano-5- (2-triphenylmethoxyethyl) pyridine-N-oxide (8.0g), trimethylsilyl cyanide (11.2ml), according to Synthesis, 314(1983), gave the title compound (2.831g) as a pale yellow color. (yield, 30.0%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.91(2H，t，J＝6.0Hz)、3.38(2H，t，J＝6.0Hz)、7.20-7.35(16H，m)、7.60(2H，m)、8.55(1H，s).
(28-5)2- (2-cyanopyridin-5-yl) ethanol
2- (2-Cyanopyridin-5-yl) -1-triphenylmethyloxyethane (2.631g) in a Tetrahedron letter (38.0ml) using formic acid. 579(1986) to give the title compound as colorless crystals (0.445 g). (yield 45.7%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.95(2H，t，J＝5.8Hz)、3.94(2H，t，J＝5.8Hz)、7.64(1H，d，J＝8.0Hz)、7.75(1H，dd，J＝2.0，8.0Hz)、8.61(1H，d，J＝2.0Hz).
(28-6) 1-bromo-2- (2-cyanopyridin-5-yl) ethane
The title compound was obtained as colorless crystals (0.406g) by the method of production example 1 using 2- (2-cyanopyridin-5-yl) ethanol (0.423 g). (yield 67.3%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.30(2H，t，J＝6.8Hz)、3.94(2H，t，J＝6.8Hz)、7.71(1H，d，J＝8.0Hz)、7.78(1H，dd，J＝2.4，8.0Hz)、8.62(1H，d，J＝2.4Hz).
Preparation example 295 Synthesis of- (2-bromoethyl) -3- (tert-butyl) dimethylsiloxymethylpyridine
(29-1) 5-Bromonicotinic acid methyl ester
The title compound was obtained as colorless crystals (10.052g) by the method of production example 3-3 using 5-bromonicotinic acid (10g) and methanol. (yield 94.0%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.97(3H，s)、8.44(1H，dd，J＝1.6，2.4Hz)、8、85(1H，d，J＝2.4Hz)、9.13(1H，d，J＝1.6Hz).
(29-2) 5-bromo-3-hydroxymethylpyridine
The title compound (3.410g) was obtained as a yellow oil by the same procedures as in production example 3-4 using methyl 5-bromonicotinate (5.0g) and methanol. (yield 78.4%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.50(1H，m)、3.97(2H，s)、7.90(1H，s)、8.48(1H，s)、8.58(1H，s).
(29-3) 5-bromo-3- (tert-butyldimethylsilyloxymethyl) pyridine
Using 5-bromo-3-hydroxymethylpyridine (3.41g), imidazole (13.33g), tert-butyldimethylsilyl chloride (13.57g), N, N-dimethylformamide (63ml), the title compound (5.605g) was obtained as a yellow oil (yield: quantitative) in accordance with J.Am.chem.Soc.6190(1972) of the national society for chemistry
1H-NMR(400MHz，CDCl3)；δ(ppm)
0.12(6H，s)、0.95(9H，s)、4.74(2H，s)、7.81(1H，s)、8.47(1，s)、8.56(1H，s).
(29-4)5- (2-hydroxyethyl) -3- (tert-butyl) dimethylsiloxymethylpyridine
The procedure of preparation example 16-1 was repeated using 5-bromo-3- (tert-butyl) dimethylsiloxymethylpyridine (3.41g) and diethyl ether as solvents to give the title compound (0.827g) as a brown oil. (yield 26.0%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
0.12(6H，s)、0.95(9H，s)、1.61(1H，m)、2.88(2H，t，J＝6，4Hz)、3.89(2H，q，J＝6.4Hz)、4.75(2H，s)、7.54(1H，s)、8.38(1H，s)、8.43(1H，s).
(29-5)5- (2-bromoethyl) -3- (tert-butyl) dimethylsiloxymethylpyridine
The procedure of preparation example 1 was repeated using 5- (2-hydroxyethyl) -3- (tert-butyl) dimethylsiloxymethylpyridine (0.4g) to give the title compound (0.248g) as a yellow pigment. (yield 50.0%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
0.12(6H，s)、0.95(9H，s)、3.18(2H，t，J＝7.2Hz)、3.57(2H，t，J＝7.2Hz)、4.76(2H，s)、7.53(1H，s)、8.38(1H，d，J＝2.0Hz)、8.46(1H，d，J＝2.0Hz).
PREPARATION EXAMPLE 305- (2-BROMOETHYL) -3-METHOXYPYRIDINE SYNTHESIS
Methoxymethyltriphenylphosphonium chloride (3.0g) was suspended in tetrahydrofuran (10ml), and potassium tert-butoxide (0.98g) was added thereto under ice cooling, followed by stirring for 15 minutes. To this was added a solution of 5-methoxy-3-pyridinecarboxaldehyde (0.4g) synthesized according to heterocycle, 2159(1987) dissolved in tetrahydrofuran (5ml), and the mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the residue, and the organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give a yellow oil (0.364 g). Dissolved in 1N hydrochloric acid (44ml) and stirred at 60 ℃ for 3 hours. The mixture was cooled, made alkaline with an aqueous sodium hydroxide solution, extracted with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a yellow oil (0.220 g). After dissolving the resulting mixture in ethanol, sodium borohydride (0.054g) was added thereto under ice cooling, the mixture was stirred at room temperature for 30 minutes, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a pale yellow oil (0.188 g). Thus, the title compound (0.181g) was obtained as a brown oil in the same manner as in production example 1. (yield 28.4%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.16(2H，t，J＝6.4Hz)、3.57(2H，t，J＝6.4Hz)，3.88(3H，s)、7.08(1H，s)、8.10(1H，s)、8.21(1H，s).
PREPARATION EXAMPLE 312 Synthesis of- (2-bromoethyl) thiophene
Using 2-thienylethanol (0.44ml), the title compound (0.490g) was obtained as a colorless oil in accordance with production example 1. (yield 64.0%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.38(2H，t，J＝7.6Hz)、3.58(2H，t，J＝7.6Hz)、6.89(1H，d，J＝1.2Hz)、6.96(1H，d，J＝4.2Hz)、7.19(1H，dd，J＝1.2，4.2Hz).
PREPARATION EXAMPLE 323 Synthesis of (2-bromoethyl) thiophene
The procedure of preparation example 1 was repeated using 3-thienylethanol (0.45ml) to give the title compound (0.389g) as a pale yellow oil. (yield 59.9%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.21(2H，t，J＝7.6Hz)、3.57(2H，t，J＝7.6Hz)、6.98(1H，d，J＝4.8Hz)、7.09(1H，s)、7.29 1H，d，J＝4.8Hz).
PREPARATION EXAMPLE 332 Synthesis of- (2-bromoethyl) thiazole
(33-1)2- (2-hydroxyethyl) thiazole
Thiazole (5.0g) was dissolved in diethyl ether (150ml), and the title compound (1.173g) was obtained as a brown oil by the method of production example 16-1. Yield (15.5%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.24(2H，t，J＝6.0Hz)、4.02(2H，m)、7.23(1H，d，J＝3.4Hz)、7.69(1H，d，J＝3.4Hz)，
(33-2)2- (2-bromoethyl) thiazole
2- (2-hydroxyethyl) thiazole (1.173g), the title compound (0.362g) was obtained as a pale yellow oil by the method of production example 1. (yield 24.9%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.57(2H，t，J＝7.2Hz)、3.75(2H，t，J＝7.2Hz)、7.26(1H，d，J＝3.4Hz)、7.74(1H，d，J＝3.4Hz).
PREPARATION 346- (2-BROMOETHYL) BENZOTHIAZOLE SYNTHESIS
(34-1) 2-amino-6-ethoxycarbonylmethylbenzothiazole
Ethyl 4-aminophenylacetate (18g) was dissolved in acetic acid (120ml), and ethyl thiocyanate (29.3g) was added thereto, and liquid bromine (6.2ml) was added dropwise over 45 minutes while keeping the internal temperature at about 10 ℃ under ice cooling. After that, the mixture was stirred at room temperature for 1.5 hours, and then stirred at 80 ℃ for about 2 hours. Pouring the reaction solution into ice water, adjusting the alkalinity with 8N sodium hydroxide aqueous solution, extracting with chloroform, washing with water, drying with anhydrous magnesium sulfate, and concentrating under reduced pressure. The title compound was obtained as orange crystals (22.23 g). (yield 93.66%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.26(3H，t，J＝7.2Hz)、3.65(2H，s)、4.16(2H，q，J＝7.2Hz)、5.31(2H，br-s)，7.22(1H，dd，J＝2.0，8.4Hz)、7.48(1H，d，J＝8.4Hz)、7.53(1H，d，J＝2.0Hz).
(34-2) (6-benzothiazolyl) acetic acid ethyl ester
2-amino-6-ethoxycarbonylmethylbenzothiazole (20g) was dissolved in N, N-dimethylformamide (17ml), and isoamyl nitrite (2.3ml) was added dropwise at 65 ℃ and then stirred for 15 minutes. The reaction mixture was cooled, poured into ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.341g) as an orange oil. (yield 71.6%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.26(3H，t，J＝7.2Hz)、3.77(2H，s)、4.18(2H，q，J＝7.2Hz)、7.45(1H，d，J＝8.4Hz)、7.90(1H，s)、8.09(1H，d，J＝8.4Hz)、8.97(1H，s).
(34-3)6- (2-hydroxyethyl) benzothiazole
Using ethyl (6-benzothiazolyl) acetate (0.22g), the title compound (0.130g) was obtained as a brown oil by the method of production example 18-2. (yield 72.5%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.14(1H，m)、3.01(2H，t，J＝6.4Hz)、3.93(2H，t，J＝6.4Hz)、7.36(1H，dd，J＝1.6，8.4Hz)、7.81(1H，d，J＝1.6Hz)、8.02(1H，d，J＝8.4Hz)、8.97(1H，s).
(34-4)6- (2-bromoethyl) benzothiazole
The reaction mixture was purified by direct silica gel column chromatography (hexane/ethyl acetate) using 6- (2-hydroxyethyl) benzothiazole (0.130g) according to preparation example 1 to give the title compound (0.080g) as a yellow oil. (yield 45.5%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.32(2H，t，J＝7.6Hz)、3.64(2H，t，J＝7.6Hz)、7.37(1H，dd，J＝1.6，8.4Hz)、7.82(1H，d，J＝1.6Hz)、8.09(1H，d，J＝8.4Hz)、8.97(1H，s).
PREPARATION EXAMPLE 35 Synthesis of (5-methoxy-2-thienyl) ethyl bromide
2.5M n-butyllithium/hexane solution (23ml) was added dropwise to an ether solution (50ml) of 2-methoxythiophene (5.0g) at-78 ℃ and stirred to warm to room temperature. After 10 minutes, ethylene oxide (2.5ml) was added dropwise at-78 ℃ and the mixture was warmed to room temperature and stirred for 1 hour. Saturated aqueous ammonium chloride and ethyl acetate were added to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and purified by silica gel column chromatography (hexane/ethyl acetate). After diluting with dichloromethane (50ml), triphenylphosphine (4.0g) and N-bromosuccinimide (2.7g) were added thereto under ice cooling, and the mixture was stirred overnight. After concentration under reduced pressure, the precipitated crystals were filtered off, and the filtrate was concentrated to give the title compound (1.7g) as a brown oil. (yield 18%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.19(2H，t，J＝7Hz)、3.51(2H，t，J＝7Hz)、3.85(3H，s)，6.01(1H，d，J＝4Hz)、6.47(1H，d，J＝4Hz).
PREPARATION EXAMPLE 36 Synthesis of (2-methoxy-5-thiazolyl) ethyl bromide
The same procedures used in preparation example 35 were repeated except for using 2-methoxythiazole (3.9g) to give the title compound (1.4g) as a brown oil. (yield 19%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.20(2H，t，J＝7Hz)、3.51(2H，t，J＝7Hz)、4.03(3H，s)、6.89(1H，s).
PREPARATION EXAMPLE 37 Synthesis of (2-cyano-5-thiazolyl) ethyl bromide
(37-1) (2-formyl-5-thiazolyl) ethyl bromide
A solution of 2-formylthiazole (5.0g), 1, 3-propanediol (6.7g) and p-toluenesulfonic acid (0.5g) in toluene (100ml) was heated under reflux overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was diluted with diethyl ether (200ml), and a 2.5M n-butyllithium/hexane solution (23ml) was added dropwise thereto at-78 ℃ while stirring, and the temperature was raised to room temperature. After 10 minutes, ethylene oxide (2.5g) was added dropwise at-78 ℃ and the mixture was warmed to room temperature and stirred for 1 hour. Saturated aqueous ammonium chloride and ethyl acetate were added to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and purified by silica gel column chromatography (hexane/ethyl acetate). After diluting with dichloromethane (50ml), triphenylphosphine (3.9g) and N-bromosuccinimide (2.7g) were added thereto under ice cooling, and the mixture was stirred overnight. Concentrating under reduced pressure, filtering out precipitated crystal, and concentrating the filtrate. The residue was diluted with tetrahydrofuran (20ml), and 2N hydrochloric acid (30ml) was added to the diluted solution, followed by refluxing under heating for 1 day. The reaction solution was made alkaline by adding an aqueous sodium hydroxide solution, and ethyl acetate was added to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.5g) as a brown oil. (yield 26%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.40(2H，t，J＝7Hz)、3.78(2H，t，J＝7Hz)、7.94(1H，s)、9.93(1H，s).
(37-2) (2-cyano-5-thiazolyl) ethyl bromide
As described above, a suspension of (2-formyl-5-thiazolyl) ethyl bromide (2.5g), hydroxylamine hydrochloride (0.79g) and anhydrous sodium acetate (1.87g) in ethanol (50ml) was stirred at room temperature for 1 day. The reaction mixture was diluted with ethyl acetate and water, and the resulting mixture was made alkaline with 8N aqueous sodium hydroxide solution to separate an organic layer, which was then washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was diluted with dichloromethane (50ml), triethylamine (2.3g) was added, trifluoromethanesulfonic anhydride (3.2g) was added dropwise at-78 ℃ and the temperature was raised to room temperature. Saturated aqueous sodium bicarbonate and chloroform were added and the organic layer was partitioned. The residue was dried over anhydrous magnesium sulfate and purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.2g) as a brown oil. (yield 8.1%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.40(2H，t，J＝7Hz)、3.76(2H，t，J＝7Hz)、7.87(1H，s).
PREPARATION 381- (2-BROMOETHYL) -4-BROMOPYRAZOLE SYNTHESIS
(38-1)1- (2-hydroxyethyl) -4-bromopyrazole
1- (2-Benzyloxyethyl) -4-bromopyrazole (1.078g) was dissolved in ethanol (20ml), and concentrated hydrochloric acid (15ml) was added thereto and the mixture was stirred at 80 ℃ for 10 hours. Cooling, and concentrating under reduced pressure. Adding saturated aqueous sodium bicarbonate solution, extracting with ethyl acetate, washing the organic layer with water, and drying (MgSO)4). Concentration under reduced pressure gave 525mg of the title compound as a colorless oil. (yield: 71%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.30(1H，br-s)、3.90(2H，t，J＝5Hz)、4.15(2H，t，J＝5Hz)、7.40(1H，s)、7.45(1H，s).
(38-2)1- (2-bromoethyl) -4-bromopyrazole
The same procedures used in preparation example 1 were repeated except for using 1- (2-hydroxyethyl) -4-bromopyrazole (525mg) to give 200mg of the title compound as a colorless oil. (yield 30%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.61(2H，t，J＝6.2Hz)、4.62(2H，t，J＝6.2Hz)、7.50(1H，s)、7.51(1H，s).
Preparation example 39L Synthesis of- (2-benzyloxyethyl) -4-bromopyrazole
4-bromopyrazole (2.205g) was dissolved in tetrahydrofuran (20ml), and 60% sodium hydride (625mg) was added thereto under ice cooling and stirred, and after 30 minutes, benzyl-2-bromoethyl ether (3.872g) prepared from 2-benzyloxyethanol by the same method as in production example 1 was added and stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound 2.287g as a colorless oil. (yield 53%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.79(2H，t，J＝5.4Hz)、4.29(2H，t，J＝5.4Hz)、4.48(2H，s)、7.22-7.48(5H，m)、7.46(1H，s)、7.52(1H，s).
PREPARATION 401 Synthesis of- [2- (4-fluorophenyl) ethyl ] -3-methyl-4-piperidone (40-1) bis (methylpropanoyl) -4-fluorophenylethylamine
4-Fluorophenethylamine (236.87g) was dissolved in methanol (360ml), cooled with ice, and methyl acrylate (360ml) was added dropwise over 30 minutes, followed by heating under reflux for 10 hours. Concentration under reduced pressure gave the title compound (527.04g) as a colorless oil. (yield 99.5%)
1H-NMR(400NHz，CDCl3)；δ(ppm)
2.43(4H，t，J＝7.6Hz)、2.62-2.83(4H，m)、2.83(4H，t，J＝7.6Hz)、3.66(6H，s)、6.95(2H，t，J＝8.8Hz)、7.12(2H，dd，J＝4.8，8.8Hz).
(40-2)1- [2- (4-fluorophenyl) ethyl ] -3-methoxycarbonyl-4-piperidone (sodium salt)
60% sodium hydride (75g) was suspended in toluene (1400ml) under ice cooling, and a solution (30ml) of bis (methylpropiono) -4-fluorophenylethylamine (263.52g) dissolved in toluene (100ml) was added dropwise thereto while heating to an internal temperature of 110 ℃. Thereafter, methanol (3.2ml) was added dropwise so that only a small amount of bubbles were generated, and the mixture was stirred at room temperature until bubbles were not generated any more. The reaction mixture was heated again, and a solution (ml) of the remaining bis (methylpropiono) -4-fluorophenylethylamine (263.52g) dissolved in toluene (100ml) was added dropwise. After the end of the dropwise addition, the mixture was stirred for 30 minutes. Ice-cooling was performed, water (800ml) was added, and the precipitate was filtered off, washed with water (700ml), toluene (500ml), hexane (500ml), and dried to give the title compound (255.0g) as pale yellow. (yield; quantitative)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.96(2H，t，J＝6.0Hz)，2.51(2H，m)、2.72(2H，t，J＝7.6Hz)、3.15(2H，s)、3.39(3H，s)、7.08(2H，t，J＝8.8Hz)、7.26(2H，dd，J＝6.0，8.8Hz).
(40-3) 1-fluorophenethyl-4-piperidone
Hydrochloric acid (500ml) and toluene (500ml) were added to 1-fluorophenethyl-3-methoxycarbonyl-4-piperidone (sodium salt), and the mixture was refluxed at 130 ℃ for 15.5 hours. The reaction solution was cooled with ice, alkalified by addition of sodium hydroxide, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was diluted with hexane (500ml) and isopropyl ether (500ml), which was stirred under ice cooling for 1 hour, and the precipitated crystal was filtered, washed with cold hexane, and dried to give the title compound as a pale yellow crystal (133.67g) (yield 71.4%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.48(4H，t，J＝6.2Hz)、2.70(2H，m)，2.80(2H，m)，2.82(4H，t，J＝6.2Hz)、6.98(2H，t，J＝8.8Hz)、7.17(2H，dd.J＝5.2，8.8Hz).
(40-4)1- [2- (4-fluorophenyl) ethyl ] -3-methyl-4-oxo-3-piperidinecarboxylic acid methyl ester
The sodium salt (15.1g) of methyl 1- [2- (4-fluorophenyl) ethyl ] -4-oxo-3-piperidinecarboxylate was dissolved in dimethylformamide (150ml), and iodomethane (3.1ml) was added thereto under ice cooling, followed by stirring at room temperature overnight. Ice water (500ml) was added thereto, extraction was carried out 2 times with diethyl ether (200ml), and the organic phase was washed with water (100ml) and brine (100 ml). The organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silicia, NH-DM2035, hexane/ethyl acetate) to give the title compound (3.4g) as a pale yellow oil. (yield 23%)
1H-NMR(CDCl3)；δ(ppm)
1.26(3H，s)、2.16(1H，d，J＝11.5Hz)、2.45(2H，m)、2.66(2H，m)、2.78(2H，m)、2.87(1H，m)、3.09(1H，m)、3.57(1H，dd，J＝3.0Hz，11.5Hz)、3.70(3H，s)、6.97(2H，br-t)、7.17(2H，br-d).
(40-5)1- [2- (4-fluorophenyl) ethyl ] -3-methyl-4-piperidone
To a toluene solution (12ml) of methyl 1- [2- (4-fluorophenyl) ethyl ] -3-methyl-4-oxo-3-piperidinecarboxylate (3.4g) was added concentrated hydrochloric acid (12ml), and the mixture was refluxed for 2.5 hours. The reaction mixture was cooled, and a 1.5N aqueous solution (100ml) of sodium hydroxide was added under ice cooling, followed by adjusting the pH to 9 with a 5N aqueous solution of sodium hydroxide. Extraction was performed 2 times with ethyl acetate (100ml), and the organic phase was washed with water and brine, dried, and concentrated under reduced pressure to give the title compound (2.87g) as a pale yellow oil. (yield 100%)
1H-NMR(CDCl3)；δ(ppm)
1.02(3H，d，J＝7Hz)、2.16(1H，t，J＝10Hz)、2.37(2H，m)、2.45(1H，m)、2.58(1H，m)、2.65(2H，m)、2.81(2H，t，J＝7Hz)、3.17(2H，m)、6.97(2H，br-t)、7.16(2H，br-d).
PREPARATION EXAMPLE 411-Fluorophenethyl-4-formylpiperidine Synthesis
(41-1) 1-fluorophenethyl-4-methoxymethylpiperidine
Methoxymethyltriphenylphosphonium chloride (36.3g) was suspended in tetrahydrofuran (105 ml). A solution of potassium tert-butoxide (11.9g) and 1-fluorophenethyl-4-piperidone (7.8g) dissolved in tetrahydrofuran (105ml) were successively added under ice cooling. Stirring at room temperature. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (7.41g) as a yellow oil. (yield 84.2%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.12(2H，t，J＝5.6Hz)、2.36(2H，t，J＝5.6Hz)。2.49(4H，m)、2.57(4H，m)、2.79(4H，m)、3.55(3H，m)，5.81(1H，d，J＝1.2Hz)、6.96(2H，t，J＝8.8Hz)、7.15(2H，dd，J＝5.6，8.8Hz).
(41-2) 1-fluorophenethyl-4-formylpiperidine
1-Fluorophenethyl-4-methoxymethylpiperidine (1.0g) was dissolved in 1N hydrochloric acid and stirred at 70 ℃ for 4 hours. The reaction mixture was cooled, neutralized with a 5N aqueous solution of sodium hydroxide, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.240g) as a pale yellow oil. (yield 25.4%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
0.72-1.82(2H，m)、1.95-2.01(2H，m)、2.23-2.34(3H，m)、2.59-2.63(2H，m)、2.90-2.95(2H，m)、6.96(2H，t，J＝8.4Hz)、7.15(2H，dd，J＝5.6，8.4Hz).
PREPARATION 421- (4-Fluorophenethyl) -4-piperidineethanol Synthesis
The title compound (4.1g) was obtained as a colorless oil from 4-piperidineethanol (3.2g) and 4-fluorophenylethyl bromide (5.0g) in the same manner as in example 2. (yield 65%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.22-1.38(2H，m)，1.40-1.60(3H，m)、1.70-1.79(2H，m)、1.91-2.02(3H，m)、2.50-2.59(2H，m)、2.78-2.81(2H，m)、2.95-3.01(2H，m)、3.69-3.75(2H，m)、6.91-7.00(2H，m)、7.10-7.20(2H，m).
PREPARATION EXAMPLE 431- (4-fluorophenethyl) -4-piperidineacetaldehyde
A suspension of 1- (4-fluorophenethyl) -4-piperidineethanol (1.0g), pyridinium chlorochromate (2.6g) and molecular sieve (2.6g) in dichloromethane (60ml) was stirred at room temperature for 1 hour. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (260 mg). (yield 36%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.29-1.43(2H，m)、1.69-1.80(2H，m)、1.81-2.10(3H，m)、2.33-2.42(2H，m)、2.50-2.60(2H，m)、2.72-2.80(2H，m)、2.93-3.00(2H，m)、6.93-7.00(2H，m)、7.10-7.20(2H，m)、9.78-9.80(1H，m).
PREPARATION EXAMPLE 44 Synthesis of 4- (4-fluorophenethyl) -4-aminopiperidine
A suspension of 1- (4-fluorophenethyl) -4-piperidone (5.0g), hydroxylamine hydrochloride (1.9g) and anhydrous sodium acetate (4, 4g) in ethanol (50ml) was refluxed for 30 minutes, and the reaction mixture was concentrated under reduced pressure, diluted with a saturated aqueous sodium hydrogencarbonate solution and ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was diluted with tetrahydrofuran (50ml), and lithium aluminum hydride (1.7g) was added in small portions under ice cooling. Heated to reflux for 4 hours. While the reaction mixture was cooled with ice water, water (1.7ml) was added dropwise, followed by 5N aqueous sodium hydroxide solution (5.1ml), water (1.7ml) was further carefully added dropwise, the mixture was stirred vigorously, the precipitated precipitate was filtered off, the filtrate was concentrated under reduced pressure, and the filtrate was purified by NH-silica gel column chromatography (dichloromethane/methanol) to give the title compound (4.0g) as a pale yellow oil. (yield 80%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.31-1.60(4H，m)，1.80-1.89(2H，m)、2.01-2.11(2H，m)、2.50-2.58(2H，m)，2.63-2.81(3H，m)、2.91-3.00(2H，m)、6.94-7.03(2H，m)、7.14-7.25(2H，m).
PREPARATION EXAMPLE 451- (piperidin-4-yl) indoline Synthesis
A mixture of indoline (25g), 1-acetyl-4-piperidone (25g), platinum oxide (0.5g), acetic acid (20ml) and ethanol (200ml) was catalytically reduced overnight at room temperature under normal pressure. The catalyst was filtered off, concentrated under reduced pressure, and diluted with 2N-aqueous sodium hydroxide solution and ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, purified by silica gel column chromatography (dichloromethane/ethanol), and 5N hydrochloric acid (300ml) was added to the residue, followed by refluxing under heating for 2 hours, alkalinization with concentrated aqueous sodium hydroxide solution, separation with ethyl acetate, washing with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (26g) as a brown oil. (yield 61%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.51-1.69(3H，m)、1.80-1.85(2H，m)、2.66-2.72(2H，m)、2.91(2H，t，J＝8Hz)、3.11-3.22(2H，m)、3.39(2H，t，J＝8Hz)、3.40-3.52(1H，m)、6.41(1H，d，J＝8Hz)、6.60(1H，d，J＝8Hz)、7.01-7.10(2H，m).
PREPARATION EXAMPLE 461- (PIPERIDIN-4-YL) -6-FLUORO-DIHYDROINDOLE SYNTHESIS
1- (1-Benzylpiperidin-4-yl) -6-fluoroindoline (2.0g) in toluene (50ml) was added 1-chloroethyl chloroformate (2.8g), the mixture was refluxed for 2 hours, and the reaction mixture was concentrated under reduced pressure, and the mixture was separated into layers with a 5N-aqueous sodium hydroxide solution and chloroform, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.0g) as a brown oil. (yield 70%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.59-1.71(2H，m)、1.80-1.87(2H，m)、2.06(1H，br-s)、2.68-2.75(2H，m)、2.91(2H，t，J＝8Hz)、3.20-3.29(2H，m)、3.34-3.48(1H，m)、3.45(2H，t，J＝8Hz)、6.08(1H，d，J＝8Hz)、6.23(1H，t，J＝8Hz)、6.91(1H，t，J＝8Hz).
Preparation example 476-Synthesis of bromoindoline
(47-1) 6-bromo-2-oxoindole
Diethyl malonate (500g) was added dropwise to a suspension of sodium hydride (125g) in dimethylsulfoxide (800ml) under ice cooling. After the reaction mixture became a uniform solution, the reaction mixture was heated to 100 ℃ and a solution of 2, 5-dibromonitrobenzene (500g) in dimethylsulfoxide (400ml) was added dropwise thereto, followed by stirring at 100 ℃ for 5 hours. The reaction mixture was diluted with ice water (2l), the layers were separated with ethyl acetate (8l), and the organic layer was washed with water (2l) 4 times, then with saturated brine, dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, diluted with ethanol (2.5l), tin (380g) was added, and concentrated hydrochloric acid (1.5l) was added dropwise under ice cooling. After dropwise addition, the mixture was refluxed for 3 hours, diluted with ice water, and precipitated crystals were filtered off. The crystals were washed with water, hexane and air-dried at 50 ℃ for 24 hours to give the title compound (321 g). (yield 84%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.51(2H，s)、7.06(1H，s)、7.10(1H，d，J＝8Hz)、7.17(1H，d，J＝8Hz)、8.27(1H，br-s).
(47-2) 6-Bromoindoline
Under ice cooling, borane/methyl sulfide complex (300ml) was added dropwise to a toluene (1l) suspension of 6-bromo-2-oxoindole (311g), and the mixture was slowly heated and refluxed. After 2 hours, the mixture was cooled with ice, and 5N aqueous sodium hydroxide solution (500ml), 8N aqueous sodium hydroxide solution (500ml) and ethyl acetate (400ml) were added thereto, followed by vigorous stirring for 1 hour, followed by dilution with ethyl acetate (1.6l) and water (1l) to separate an organic layer. The organic layer was washed with water (1l) 2 times, then with saturated brine (0.5l), and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane/ethyl acetate). The title compound (169g) was obtained. (yield 58%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.96(2H，t，J＝8Hz)、3.58(2H，t，J＝8Hz)、6.76(1H，s)、6.80(1H，d，J＝8Hz)、6.95(1H，d，J＝8Hz).
PREPARATION 481- (PIPERIDIN-4-YL) -6-BROMO-DIHYDROINDOLE SYNTHESIS
1- (1-Benzylpiperidin-4-yl) -6-bromoindoline (14.3g) in toluene (250ml) was added 1-chloroethyl chloroformate (13.7g), and the mixture was refluxed for 2 hours, and the reaction mixture was concentrated under reduced pressure, added with methanol, and refluxed for 2 hours. After concentration under reduced pressure, 5N-aqueous sodium hydroxide solution and ethyl acetate were added to the mixture, the layers were separated, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (8.4g) as a brown oil. (yield 78%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.51-1.69(2H，m)、1.78-1.83(2H，m)、2.06(1H，br-s)、2.67-2.73(2H，m)、2.90(2H，t，J＝8Hz)、3.19-3.23(2H，m)、3.31-3.43(1H，m)、3.41(2H，t，J＝8Hz)、6.49(1H，s)、6.68(1H，t，J＝8Hz)、6.85(1H，t，J＝8Hz).
Preparation example 491- (piperidin-4-yl) -6-nitroindoline Synthesis
70% nitric acid (2.6ml) was added dropwise to a concentrated sulfuric acid (50ml) solution of 1- (piperidin-4-yl) indoline (6.9g) at 15 ℃ for 20 minutes, and then diluted with ice water, made alkaline with concentrated aqueous sodium hydroxide solution, and ethyl acetate was added thereto, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (7g) as a brown oil. (yield 83%)
1H-NMR(400MHz，CDCl3，δ(ppm)
1.53-1.69(3H，m)、1.75-1.83(2H，m)、2.69-2.78(2H，m)、3.03(2H，t，J＝8Hz)、3.16-3.23(2H，m)、3.44-3.51(1H，m)，3.52(2H，t，J＝8Hz)、7.08(1H，d，J＝8Hz)、7.10(1H，s)、7.48(1H，d，J＝8Hz).
PREPARATION 506 Synthesis of dimethylaminoindoline
(50-1) 1-acetyl-6-aminoindoline
Fuming nitric acid (11ml) was added dropwise to a concentrated sulfuric acid (250ml) solution of indoline (26.5g) at-15 ℃ for 20 minutes, then diluted with ice water, washed with ethyl acetate, the aqueous layer was made alkaline with concentrated aqueous sodium hydroxide solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and acetic anhydride (100ml) and pyridine (100ml) were added to the residue, followed by stirring at room temperature for 4 hours. Ice water was added to the reaction solution, and precipitated crystals were filtered off. A mixture of iron powder (40g), ammonium chloride (60g), water (70ml) and ethanol (300ml) was added to the crystals, and the mixture was stirred at 60 ℃ overnight. The reaction solution was filtered, concentrated under reduced pressure, added with water and stirred vigorously, and the precipitated crystals were filtered off and air-dried at 70 ℃ overnight. The title compound (19g) was obtained as a brown powder. (yield 57%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.20(3H，s)、3.08(2H，t，J＝8Hz)、3.63(2H，br-s)、4.01(2H，t，J＝8Hz)、6.33(1H，d，J＝8Hz)、6.91(1H，d，J＝8Hz)、7.67(1H，s).
(50-2) 6-Dimethylaminoindoline
1-acetyl-6-aminoindoline (1.0g), 37% formaldehyde (5.2g), acetic acid (1.0ml), platinum oxide (0.1g) and methanol were mixed and subjected to catalytic reduction at ordinary temperature and pressure. After 1 day, the catalyst was filtered off and concentrated under reduced pressure. The residue was diluted with saturated aqueous sodium hydrogencarbonate and ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, purified by silica gel column chromatography (dichloromethane/ethanol), and then 5N hydrochloric acid (30ml) was added to the mixture, and the mixture was refluxed for 1 hour. The reaction mixture was made alkaline with concentrated aqueous sodium hydroxide solution, extracted with chloroform, and purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.6g) as a brown powder. (yield 65%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.89(6H，s)、2.91(2H，t，J＝8Hz)、3.52(2H，t，J＝8Hz)、3.70(1H，br-s)、6.11(1H，d，J＝8Hz)、6.12(1H，s)、6.95(1H，d，J＝8Hz).
PREPARATION EXAMPLE 511 Synthesis of (piperidin-4-yl) -6-methoxyindoline
1- (1-Benzylpiperidin-4-yl) -6-methoxyindoline (7.9g) in toluene (200ml) was added 1-chloroethyl chloroformate (10.5g), the mixture was refluxed for 3 hours, the reaction mixture was concentrated under reduced pressure, methanol was added, the mixture was refluxed for 2 hours, concentrated under reduced pressure, then, 5N-aqueous sodium hydroxide solution and chloroform were added to separate layers, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (4.1g) as a brown oil. (yield 72%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.51-1.62(2H，m)、1.78-1.85(2H，m)、1.92(1H，br-s)、2.62-2.74(2H，m)、2.89(2H，t，J＝8Hz)、3.13-3.22(2H，m)、3.34-3.46(1H，m)、3.40(2H，t，J＝8Hz)、3.76(3H，s)、6.00(1H，s)、6.11(1H，d，J＝8Hz)、6.93(1H，d，J＝8Hz).
PREPARATION EXAMPLE 521- (PIPERIDIN-4-YL) -6-ACETAMINOMETHYLNOLIN SYNTHESIS
Acetyl chloride (1.7ml) was added dropwise to a solution of 1- [1- (4-tert-butoxycarbonyl) piperidin-4-yl ] -6-aminomethylindoline (8.3g) and triethylamine (2.4g) in acetonitrile (150ml) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and ethyl acetate to separate an organic layer, which was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, added with chloroform (100ml) and trifluoroacetic acid (50ml), and stirred at room temperature for 2 hours. After concentration under reduced pressure, a 2N aqueous solution (100ml) of sodium hydroxide and toluene (50ml) were added thereto, and the mixture was vigorously stirred and purified by NH-silica gel column chromatography (methanol/ethyl acetate) to obtain the title compound as white crystals (3.78 g). (yield 58%)
Melting point: 165-
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.64-1.86(4H，m)、2.52-2.82(2H，m)、2.93(2H，t，J＝8Hz)、3.24-3.32(2H，m)、3.42(2H，t，J＝8Hz)、3.44-3.52(1H，m)、4.33(2H，d，J＝5Hz)、5.67(1H，br-s)、6.34(1H，s)、6.51(1H，d，J＝8Hz)、7.00(1H，d，J＝8Hz).
FAB-Mass；274(MH+).
Preparation example 536 Synthesis of N-Methylsulfamoylmethyl indoline
(53-1) 1-tert-Butoxycarbonyl-6-bromoindoline
Di-tert-butyl carbonate (6.7g) was added to a tetrahydrofuran (50ml) solution of 6-bromoindoline (5.1g) and triethylamine (3.1g), and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the residue, and the organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). The title compound (5.5g) was obtained as a colorless oil. (yield 71%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.56(9H，s)、3.04(2H，t，J＝8Hz)、3.99(2H，t，J＝8Hz)、6.98(1H，d，J＝8Hz)、7.03(1H，d，J＝8Hz)、8.04(1H，s).
(53-2) 6-Hydroxymethylindoline-1-Boc-T-Butoxycarbonyl
To a solution of 1-tert-butoxycarbonyl-6-bromoindoline (3.5g) in tetrahydrofuran (100ml) at-78 ℃ was added dropwise a 2.5M n-butyllithium/hexane solution (7ml) over 5 minutes. After 10 minutes, dimethylformamide (1.4ml) was added. The temperature was raised to room temperature, and a saturated aqueous ammonium chloride solution and ethyl acetate were added to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue were added ethanol (20ml) and sodium borohydride (0.4g), and the mixture was stirred at room temperature for 1 hour. To the reaction solution were added ice water and ethyl acetate. The organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.9g) as a colorless oil. (yield 66%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.60(9H，s)、3.08(2H，t，J＝8Hz)、3.99(2H，t，J＝8Hz)、4.68(2H，s)、6.95(1H，d，J＝8Hz)、7.12(1H，d，J＝8Hz)、7.87(1H，s).
(53-3) 1-acetyl-6-chloromethylindoline
A solution of 1-tert-butoxycarbonyl-6-hydroxymethylindoline (1.9g) in concentrated hydrochloric acid (20ml) was stirred overnight at 50 ℃. The resulting mixture was made alkaline by adding concentrated aqueous sodium hydroxide solution, and ethyl acetate (40ml) and acetyl chloride (0.5ml) were added thereto and stirred at room temperature for 1 hour. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.87 g). (yield 54%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.23(3H，s)、3.20(2H，t，J＝8Hz)、4.09(2H，t，J＝8Hz)、4.59(2H，s)、7.06(1H，d，J＝8Hz)、7.16(1H，d，J＝8Hz)、8.25(1H，s).
(53-4)6- (N-Methylsulfamoylmethyl) indoline
A solution of 1-acetyl-6-chloromethylindoline (470mg), sodium sulfite (330mg) and trioctylmethylammonium chloride (50mg) in water (30ml) was heated under reflux for 1 hour. After concentration under reduced pressure, phosphorus pentachloride (500mg) and phosphorus oxychloride (5ml) were added to the residue, and the mixture was stirred at room temperature for 3 hours. Ice water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, and a 2M methylamine/tetrahydrofuran (20ml) solution was added to the residue, followed by stirring at room temperature overnight. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed with ethanol, dissolved in 5N hydrochloric acid (5ml), and refluxed for 1 hour. The reaction mixture was adjusted to pH8 with concentrated aqueous sodium hydroxide solution under ice cooling, and chloroform was added thereto to separate an organic layer. The residue was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound as white crystals (100 mg). (yield 20%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.71(3H，s)、3.01(2H，t，J＝8Hz)、3.20(1H，br-s)、3.58(2H，t，J＝8Hz)、4.15(2H，s)、4.25(1H，br-s)、6.65-6.69(2H，m)、7.08(1H，d，J＝8Hz).
Preparation example 543 Synthesis of methyldihydroindole
3-methylindole (1.0g) was dissolved in trifluoroacetic acid (30ml), and triethylsilane (2.4ml) was added dropwise under ice cooling, followed by stirring for 1 hour. After concentration under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution and ethyl acetate were added to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). The title compound (0.673g) was obtained as a pale yellow oil. (yield 66.3%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.32(3H，d，J＝6.8Hz)、3.11(1H，t，J＝8.6Hz)、3.36(1H，m)、3.70(1H，t，J＝8.6Hz)、6.65(1H，d，J＝8.0Hz)、6.73(1H，t，J＝8.0Hz)、7.03(1H，t，J＝8.0Hz)、7.09(1H，d，J＝8.0Hz).
PREPARATION EXAMPLE 553- (4-fluorophenyl) indoline Synthesis
(55-1)2- (tert-butoxy) carbonylaminobenzyl alcohol
Using 2-aminobenzyl alcohol (5g), the title compound was obtained in pale yellow (5.776g) by the method of "Synthesis" 871 (1991). (yield 60.4%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.52(9H，s)、4.69(2H，s)、7.02(1H，t，J＝8.0Hz)、7.17(1H，d、J＝8.0Hz)、7.31(1H，t，J＝8.0Hz)、7.63(1H，m)、7.91(1H，d，J＝8.0Hz).
(55-2)2- (tert-butoxy) carbonylaminobenzyl bromide
Using 2- (tert-butoxy) carbonylaminobenzyl alcohol (4.93g), triethylamine (0.58ml) was added to conduct a reaction in the same manner as in production example 1. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as pale yellow crystals (5.380 g). (yield 86.1%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.58(9H，s)、4.51(2H，s)、6.68(1H，m)、7.06(1H，t，J＝8.0Hz)、7.28(1H，d，J＝8.0Hz)、7.34(1H，t，J＝8.0Hz)、7.84(1H，d，J＝8.0Hz).
(55-3)2- (4-Fluorobenzyl) -N- (tert-butoxy) carbonylanilide
Using 2- (tert-butoxy) carbonylaminobenzyl bromide (2.98g) and 4-phenylmagnesium bromide, the title compound was obtained as pale yellow crystals (1.187g) according to the method of J.Organmet.C. 329, 133-138 (1987). (yield 39.4%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.46(9H，s)、3.93(2H，s)、6.12(1H，m)、6.91-7.12(7H，m)、7.82(1H，br-d).
(55-4)1- (tert-butoxy) carbonyl-3- (4-fluorophenyl) indole
Using 2- (4-fluorobenzyl) -N- (tert-butoxy) carbonylaniline (0.5g), the title compound (0.340g) was obtained as a pale yellow oil by the method of Synthesis 871 (1991). (yield 68.2%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.69(9H，s)、7.15(2H，t，J＝8.8Hz)、7.29(1H，t，J＝8.0Hz)、7.37(1H，t，J＝8.0Hz)、7.59(2H，dd、J＝6.0，8.8Hz)、7.67(1H，s)、7.75(1H，d，J＝8.0Hz)、8.22(1H，d，J＝8.0Hz)，
(55-5)3- (4-fluorophenyl) indoline
Deprotection of 1- (tert-butoxy) carbonyl-3- (4-fluorophenyl) indole (0.340g) with trifluoroacetic acid gave the title compound (0.184g) as a pale yellow oil in the same manner as in preparation example 54. (yield 79.0%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.45(1H，t，J＝8.8Hz)、3.92(1H，t，J＝8.8Hz)、4.48(1H，t，J＝8.8Hz)、6.72(2H，m)、6.89(1H，d，J＝8.4Hz)、6.99(2H，t，J＝8.4Hz)、7.08(1H，t，J＝8.4Hz)、7.23(2H，m).
PREPARATION EXAMPLE 563- (4-FLUOROBenzyl) indoline Synthesis
(56-1)3- (4-Fluorobenzyl) indole
The title compound was obtained as a yellow oil from 3-formylindole according to Tetrahedron Lett., 1869 (1986).
1H-NMR(400MHz，CDCl3)；δ(ppm)
4.05(2H，s)、6.84(1H，s)、6.93(2H，t，J＝8.4Hz)、7.06(1H，t，J＝8.0Hz)、7.15-7.19(3H，m)、7.46(1H，d，J＝8.0Hz)、7.97(1H，m)
(56-2)3- (4-Fluorobenzyl) indoline
3- (4-Fluorobenzyl) indoline (2.119g) was dissolved in trifluoroacetic acid (3.9ml), and under ice-cooling, 1.0M borane-tetrahydrofuran complex/tetrahydrofuran solution (18.7ml) was added dropwise thereto, followed by stirring at room temperature for 1 hour, water was added thereto, the reaction mixture was concentrated under reduced pressure, ethanol (20ml) was added thereto, a 5N aqueous sodium hydroxide solution (46ml) was added thereto, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (200ml) was added to the reaction solution, the organic layer was separated, the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.163g) · (yield 54.4%) as a yellow oil
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.80(1H，dd，J＝8.0，13.6Hz)、3.06(1H，dd，J＝4.6，13.6Hz)、3.26(1H，m)、3.55(2H，m)、6.48-6.71(2H，m)、6.92(1H，t，J＝7.6Hz)、6.99(2H，t，J＝8.8Hz)、7.05(1H，t，J＝7.6Hz)、7.15(1H，dd，J＝5.6，8.8Hz).
Preparation example 573 Synthesis of- (3-picolyl) indoline
(57-1)3- (3-picolyl) indole
Starting from 3-bromopyridine, the title compound is obtained in the form of a yellow oil, according to the method of Tetrahedron lett, 1869 (1986).
1H-NMR(400MHz，CDCl3)；δ(ppm)
4.11(2H，s)、6.92(1H，s)、7.09(1H，t，J＝8.0Hz)、7.18(2H，m)、7.46(1H，d，J＝8.0Hz)、7.48(1H，d，J＝8.0Hz)、7.54(1H，d，J＝8.0Hz)、8.33(1H，m)、8.45(1H，m)、8.60(H，m).
(57-2)3- (3-picolyl) indoline
The same procedures used in preparation example 56-2 were repeated except for using 3- (3-picolyl) indole (0.212g) to give the title compound (0.253g) as a yellow oily substance.
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.83(1H，m)、3.06(1H，m)、3.27(1H，d，J＝3.2Hz)、3.56(2H，m)、6.50(1H，d，J＝8.0Hz)，6.69(1H，t，J＝8.0Hz)、6.92(1H，d，J＝8.0Hz)、7.23(1H，m)、7.49(1H，d，J＝8.0Hz)、8.48(1H，m).
PREPARATION 583- (4-METHOXYBENZYL) INDOLINE SYNTHESIS
(58-1)3- (4-methoxybenzyl) indole
Starting from 1-diethylcarbamoyl-3-formylindole (7.33g) obtained by the method from tetrahedron letters 1869 (1986), the title compound (5.480g) was obtained as a pale yellow oil from 4-methoxyphenylmagnesium bromide by the method from tetrahedron letters 1869 (1986). (yield 77.0%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.78(3H，s)、4.06(2H，s)、6.82(2H，d，J＝6.8Hz)、6.90(1H，s)、7.07(1H，t，J＝8.0Hz)、7.18(1H，t，J＝8.0Hz)、7.20(2H，d，J＝6.8Hz)、7.36(1H，d，J＝8.0Hz)、7.51(1H，d，J＝8.0Hz)，7.89(1H，m).
(58-2)3- (4-methoxybenzyl) indoline
The title compound (0.332g) was obtained as a pale yellow oil in the same manner as in preparation example 54 using 3- (4-methoxybenzyl) indole. (yield 65.7%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.76(1H，dd，J＝8.4，14.0Hz)，3.04(1H，dd，J＝5.2，14.0Hz)、3.54(2H，m)、3.76(1H，d，J＝5.2Hz)、3.81(3H，s)、6.65(1H，d，J＝7.6Hz)、6.69(1H，t，J＝7.6Hz)、6.85(2H，d，J＝8.2Hz)、6.95(1H，d，J＝7.6Hz)、7.04(1H，t，J＝7.6Hz)、7.12(2H，d，J＝8.2Hz).
PREPARATION 593- (3-methoxyphenylethyl) indoline Synthesis
(59-1) 1-Diethylcarbamoyl-3- [2- (3-methoxyphenyl) ethenyl ] indole
From 3-methoxybenzyltriphenylphosphinium chloride and 1-diethylcarbamoyl-3-formylindole (1.71g) synthesized by the method of tetrahedron letters 1869 (1986), the reaction was carried out in tetrahydrofuran (5ml) in the same manner as in preparation example 41-1 to give the title compound (0.842g) as a brown oil. (yield 59.1%)
(59-2) 1-Diethylcarbamoyl-3- (3-methoxyphenethyl) indole
1-Diethylcarbamoyl-3- [2- (3-methoxyphenyl) vinyl ] indole (0.842g) was dissolved in methanol (20ml), and catalytically reduced with palladium on charcoal at room temperature under normal pressure for 1 hour. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (0.864g) as a brown oil. (yield: quantitative)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.19(6H，t，J＝7.2Hz)，3.01(4H，m)、3.42(4H，q，J＝7.2Hz)、3.78(3H，s)、6.72(2H，m)、6.79(1H，d，J＝8.4Hz)、6.95(1H，s)、7.18(2H，t，J＝8.4Hz)、7.27(1H，m)、7.57(1H，d，J＝8.4Hz)、7.63(1H，d，J＝8.4Hz).
(59-3)3- (3-methoxyphenylethyl) indole
Deprotection of 1-diethylcarbamoyl-3- (3-methoxyphenethyl) indole (0.864g) was carried out according to the method of tetrahedron letters 7911(1993) to give the title compound as a brown oil (0.554 g). (yield 91.1%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.00(2H，m)、3.08(2H，m)、3.78(3H，s)、6.75(2H，m)、6.82(1H，d，J＝8.0Hz)、6.93(1H，s)、7.12(1H，t，J＝8.0Hz)、7.19(2H，q，J＝8.0Hz)、7.36(1H，d，J＝8.0Hz)、7.62(1H，d，J＝8.0Hz)、7.93(1H，m).
(59-4)3- (3-methoxyphenyl) indoline
The procedure of preparation 56-2 was repeated using 3- (3-methoxyphenyl) indole (0.554g) to give the title compound (0.133g) as a pale yellow oil. (yield 23.8%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.83(1H，m)、2.15(1H，m)、2.70(2H，t，J＝8.0Hz)、3.34(1H，m)、3.71(2H，t，J＝8.0Hz)、3.80(3H，s)、6.64(1H，d，J＝8.0Hz)、6.75(3H，m)、6.80(1H，d，J＝8.0Hz)、7.03(1H，t，J＝8.0Hz)，7.10(1H，d，J＝8.0Hz)、7.20(1H，t，J＝8.0Hz).
PREPARATION EXAMPLE 603 Synthesis of 3-fluorophenethyl) indoline
(60-1)3- [2- (3-fluorophenyl) ethenyl ] indole
3-Formylindole (1.0g) was synthesized in the same manner as in production example 41-1 using 3-fluorobenzylphosphinium chloride (2.8g) to give the title compound as colorless crystals (0.598 g). (yield 73.1%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
6.51(1H，d，J＝12.0Hz)、6.80(1H，d，J＝12.0Hz)、6.89(1H，m)、7.06-7.37(7H，m)、7.47(1H，dd，J＝0.4，8.0Hz)、8.04(1H，m).
(60-2)3- (3-fluorophenethyl) indole
The procedure of preparation 59-2 was repeated except for using 3- [2- (3-fluorophenyl) vinyl ] indole (0.598g) to give the title compound (0.541g) as a brown oil. (yield: 89.7%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.04(4H，m)、6.90(2H，m)、6.98(1H，d，J＝8.0Hz)、7.13(1H，dt，J＝0.8，8.0Hz)、7.23(2H，m)、7.36(1H，d，J＝8.0Hz)、7.61(1H，dd，J＝0.8，8.0Hz)、7.89(1H，br-s).
(60-3)3- (3-fluorophenethyl) indoline
The title compound (0.582g) was obtained as a brown oil by the method of production example 56-2 using 3- (3-fluorophenethyl) indole (0.541 g). (yield; quantitative)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.87(1H，m)、2.14(1H，m)、2.72(2H，t，J＝8.0Hz)、3.26(2H，t，J＝8.0Hz)、3.30(1H，m)、3.71(1H，t，J＝8.0Hz)，6.65(1H，d，J＝8.0Hz)、6.73(1H，t，J＝8.0Hz)、6.88(2H，m)、7.03(1H，t，J＝8.0Hz)、7.13(1H，d，J＝8.0Hz)、7.23(1H，m).
PREPARATION 614- (4-fluorophenyl) indoline synthesis
A mixture of 4-bromoindole (1.0g), 4-fluorobenzeneboronic acid (1.1g), tetrakistriphenylphosphine palladium (0.24g), 10% aqueous sodium carbonate (10ml) and toluene (20ml) synthesized as described in J.org.chem. (1986, vol.5, No.26, p5106) was heated under reflux for 4 hours. Ethyl acetate was added to the reaction mixture to separate an organic layer. The reaction mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). Trifluoroacetic acid and a 1M borane/tetrahydrofuran complex solution (6.8ml) were added to the residue, and the mixture was stirred at 0 ℃ for 1 hour. Adding water, concentrating under reduced pressure, adding ethanol and sodium hydroxide water solution, and stirring for 30 min. Ethyl acetate was added to the reaction mixture to separate an organic layer. Washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). The title compound (0.5g) was obtained as a colorless oil. (yield 46%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.01(2H，t，J＝8Hz)、3.50(2H，t，J＝8Hz)、3.81(1H，br-s)、6.61(1H，d，J＝8Hz)、6.72(1H，d，J＝8Hz)、7.02-7.10(3H，m)、7.38-7.41(2H，m).
PREPARATION EXAMPLE 62 Synthesis of Thiazolo [5, 4-f ] indoline
To a solution of 1-acetyl-6-aminoindoline (6.0g) and potassium thiocyanate (9.3g) in acetic acid (100ml) was added dropwise liquid bromine (2.5ml), and the mixture was stirred at room temperature for 5 hours. Under ice-cooling, a 5N aqueous sodium hydroxide solution was added to the reaction mixture, and the precipitated crystals were filtered off. The crystals were air-dried at 60 ℃ overnight, dissolved in dimethylformamide (90ml), and isoamyl nitrite (18ml) was added dropwise thereto and stirred at 80 ℃ for 1 hour. After concentration under reduced pressure, a 5N aqueous sodium hydroxide solution and chloroform were added to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate), followed by addition of 5N hydrochloric acid (150ml) and heating under reflux for 30 minutes. 5N aqueous sodium hydroxide solution and ethyl acetate were added to the residue, the organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as brown powder crystals (1.2 g). (yield 21%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.14(2H，t，J＝8Hz)、3.65(2H，t，J＝8Hz)、4.00(1H，br-s)，7.28(1H，s)、7.58(1H，s)、8.83(1H，s).
PREPARATION EXAMPLE 636- (4-fluorobenzenesulfonylamino) indoline
1-acetyl-6-aminoindoline (1.0g) in a pyridine solution (10ml) was added dropwise 4-fluorobenzenesulfonyl chloride (1.4g) under ice cooling, and the mixture was stirred for 30 minutes. After concentration under reduced pressure, 5N hydrochloric acid was added and the mixture was refluxed for 5 hours. Adjusting the alkalinity with concentrated sodium hydroxide aqueous solution, and extracting with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by NH silica gel column chromatography (dichloromethane/ethanol) to give the title compound as white powder crystals (1.36 g). (yield 82%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.95(2H，t，J＝8Hz)，3.64(2H，t，J＝8Hz)、3.78(1H，br-s)、6.22(1H，d，J＝8Hz)、6.33(1H，br-s)、6.48(1H，s)、6.90(1H，d，J＝8Hz)、7.08-7.12(2H，m)、7.71-7.80(2H，m).
PREPARATION 644 Synthesis of methoxyindoline
Under ice-cooling, a 1M borane-tetrahydrofuran complex/tetrahydrofuran solution (6.2ml) was added dropwise to a trifluoroacetic acid (10ml) solution of 4-methoxyindole (0.46g), and the mixture was stirred for 1 hour.
Water was added, the mixture was concentrated under reduced pressure, ethanol and a 5N aqueous solution of sodium hydroxide were added, and the mixture was stirred overnight. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (130mg) as a brown oil. (yield 28%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.95(2H，t，J＝8Hz)、3.52(2H，t，J＝8Hz)、3.80(1H，s)、6.28(1H，d，J＝8Hz)、6.30(1H，d，J＝8Hz)、6.99(1H，t，J＝8Hz).
PREPARATION 651- (PIPERIDIN-4-YL) DIHYDROINDENE SYNTHESIS
(65-1) 1-hydroxy-1- (4-pyridyl) indane
To 4-bromopyridine hydrochloride (19.4g) were added 2N aqueous sodium hydroxide (120ml) and ether (300ml), and the 4-bromopyridine was extracted, and the ether layer was dried over anhydrous potassium carbonate and cooled to-70 ℃. To the solution was added dropwise, while stirring, 2.5M n-butyllithium (40 ml). After the completion of the dropwise addition, the reaction mixture was stirred for 30 minutes. To this was added an ether solution (60ml) of 1-indanone (13.0g) at-70 ℃. The reaction solution was returned to room temperature over 12 hours. Ethyl acetate and a saturated aqueous ammonium chloride solution were added to the reaction mixture to separate the layers. The ethyl acetate layer was washed with water, dried, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (7.6g) as a colorless oil. (yield 35.9%)
1H-NMR(400MHz，CDC13)；δ(ppm)
2.40-2.50(2H，m)、2.82(1H，br-s)、2.94-3.04(1H，m)、3.17-3.26(1H，m)、7.02(1H，d，J＝8.4Hz)、7.22(1H，dt，J＝8.4，2.8Hz)、7.3(2H，d，J＝8.0Hz)、7.30-7.37(2H，m)、8.47(2H，d，J＝8.0Hz).
(65-2)1- (piperidin-4-yl) indanes
A mixture of 1-hydroxy-1- (4-pyridyl) indan (6.0g), 6N hydrochloric acid (20ml) and ethanol (20ml) was heated at 100 ℃ for 30 minutes. The reaction mixture was concentrated under reduced pressure, and ethanol (200ml) and platinum oxide (0.2g) were added to the residue at a concentration of 3kg/cm2And (4) hydrogenation. After the reaction, the reaction mixture was filtered through celite and extracted with ethanol. The filtrate was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and a 2N aqueous solution of sodium hydroxide, and the ethyl acetate layer was washed with water, dried, concentrated under reduced pressure, and purified by NH-silica gel column chromatography (ethyl acetate) to give the title compound as a pale brown crystalline powder (4.2 g). (yield 73.4%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.13-1.49(3H，m)、1.51(1H，br-s)、1.62-1.70(1H，m)、1.72-1.82(1H，m)、1.90-2.00(1H，m)、2.02-2.18(1H，m)、2.50-2.64(2H，m)、2.75-2.92(2H，m)、3.01-3.13(3H，m)、7.09-7.21(4H，m).
PREPARATION EXAMPLE 661- (PIPERIDIN-4-YL) -6-CHLORO-7-AZALINOLINE SYNTHESIS
A mixture of 2, 6-dichloro-3-formylmethylpiperidine (5.6g), ethyl 4-amino-1-piperidinecarboxylate (7.6g), platinum oxide (140mg), acetic acid (1.0ml) and ethanol (100ml) was catalytically reduced under a hydrogen stream at ordinary temperature and pressure. After 6 hours, the catalyst was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with saturated aqueous sodium bicarbonate and ethyl acetate and the layers were separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (dichloromethane/ethanol). After triethylamine (1.5g) and o-dichlorobenzene (100ml) were added, the resulting mixture was heated at 180 ℃ for 2 hours. The reaction solution was then concentrated under reduced pressure and diluted with saturated aqueous sodium bicarbonate and ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and purified by silica gel column chromatography (hexane/ethyl acetate). To the residue were added potassium hydroxide (10g) and ethylene glycol (200ml), and the mixture was refluxed for 2 hours. Water and ethyl acetate were added to the reaction mixture to separate an organic layer. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off to obtain the title compound (2.3g) as a brown oil. (yield: 33%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.71-1.89(4H，m)、2.80-2.91(2H，m)、2.94(2H，t，J＝8Hz)、3.25-3.34(2H，m)、3.66(2H，t，J＝8Hz)、4.11-4.23(1H，m)、6.38(1H，d，J＝8Hz)、7.04(1H，d，J＝8Hz).
PREPARATION EXAMPLE 671- (4-PIPERIDINYL) -7-METHOXY-1, 2, 3, 4-TETRAHYDROQUINOLINE SYNTHESIS
A solution of 1- (4-piperidinyl) -7-methoxy-3, 4-dihydroquinolone (1.50g) synthesized according to the method described in JP-A-3-173870 (50ml) in THF (50ml) is cooled to 0 ℃. Lithium aluminum hydride (660mg) was added in 5 portions. The resulting reaction mixture was stirred at 0 ℃ for 10 minutes and heated under reflux for 4 hours. After completion of the reaction, the reaction mixture was cooled to 0 ℃ and water (0.66ml), a 5N aqueous solution (0.66ml) of sodium hydroxide and water (2ml) were added in this order, followed by addition of magnesium sulfate and stirring for 10 minutes. The precipitate was filtered through celite, and the filtrate was concentrated to give the title compound (1.27 g). (yield 89%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.62-1.91(6H，m)、2.02-2.12(1H，m)、2.64-2.75(3H，m)、3.07-3.22(4H，m)、3.51-3.74(1H，m)、3.77(3H，s)、6.13(1H，dt，J＝8.0，2.0Hz)、6.24(1H，t，J＝2.0Hz)、6.85(1H，d，J＝8.0Hz).
EXAMPLE 11 Synthesis of- [1- (4-fluorophenyl) piperidin-4-yl ] indoline
To a mixture of indoline (300mg), 1- (4-fluorophenyl) -4-piperidone (580mg), acetic acid (650mg) and dichloroethane (30ml) was added sodium triacetoxyborohydride (760mg), and the mixture was stirred for 2 hours. Ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added to the reaction mixture to separate an organic layer, which was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). The title compound was obtained as white prisms (470 mg). (yield 63%)
Melting point: 120 ℃ C. & 122 ℃ C
1H-NMR(400MHz，CDCl3)；δ(ppm)1.82-1.93(4H，m)、2.71-2.82(2H，m)、2.92-3.01(2H，m)、3.39-3.43(3H，m)、3.63-3.71(2H，m)、6.42-6.49(1H，m)、6.60-6.65(1H，m)、6.90-7.10(6H，m).
FAB-Mass；297(MH+).
EXAMPLE 21 Synthesis of- [1- (4-fluorobenzyl) piperidin-4-yl ] indoline
4-Fluorobenzyl bromide (0.067ml) was dissolved in N, N-dimethylformamide (2.5ml), and 4-Fluorobenzyl bromide (0.067ml) and triethylamine (0.075ml) were added thereto and stirred for 5 hours. Water and ethyl acetate were added to separate an organic layer. Washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). The title compound was obtained as colorless crystals (0.131 g). (yield 86.1%)
Hydrochloric acid was added thereto to form a salt, which was recrystallized from ethanol to obtain the titled compound hydrochloride as colorless crystals.
Melting point (hydrochloride salt): 223 deg.C
Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.84(2H，br-d)、2.14(2H，m)，2.90(2H，t，J＝8.4Hz)、3.01(2H，m)、3.33(2H，t，J＝8.4Hz)、3.40(2H，br-d)、3.72(1H，m)、4.27(2H，d，J＝4.8Hz)、6.62(1H，d，J＝7.6Hz)、6.63(1H，t，J＝7.6Hz)、7.02(1H，t，J＝7.6Hz)、7.06(1H，d，J＝7.6Hz)、7.31(2H，t，J＝8.8Hz)、7.70(2H，dd，J＝5.6，8.8Hz).
ESI-Mass；311.1(MH+).
Example 31 Synthesis of- (1-phenethylpiperidin-4-yl) indoline
Using (2-bromoethyl) benzene (0.19g), the procedure of example 2 was repeated to give the title compound (0.126g) as a colorless oil. (yield: 77.3%)
Hydrochloric acid was added thereto to form a salt, which was recrystallized from ethanol to obtain the titled compound hydrochloride as colorless crystals.
Melting point (hydrochloride salt): 234 deg.C
Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.89(2H，m)、2.10(2H，m)、2.91(2H，t，J＝8.2Hz)、3.09(4H，m)、3.26(2H，m)、3.35(2H，t，J＝8.2Hz)、3，65(2H，m)、3.76(1H，m)、6.60(1H，d，J＝7.6Hz)、6.61(1H，t，J＝7.6Hz)、7.02(1H，t，J＝7.6Hz)、7.06(1H，d，J＝7.6Hz)、7.28(3H，m)、7.3(2H，m).
FAB-Mass；307(MH+).
EXAMPLE 41 Synthesis of- [1- (4-bromophenylethyl) piperidin-4-yl ] indoline
Using 4-bromophenethyl bromide, the title compound (0.119g) was obtained as a colorless oil by the method of example 2. (yield: 63.0%)
Hydrochloric acid was added thereto to form a salt, which was recrystallized from ethanol to give the titled compound hydrochloride as colorless crystals (0.110 g).
Melting point (hydrochloride salt): 230 deg.C
Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.88(2H，br-d)、2.09(2H，m)、2.91(2H，t，J＝8.2Hz)、3.09(4H，m)、3.25(2H，m)、3.36(2H，t，J＝8.2Hz)、3.62(2H，br-d)、3.75(1H，m)、6.59(1H，d，J＝8.0Hz)、6.60(1H，t，J＝8.0Hz)、7.02(1H，t，J＝8.0Hz)、
7.05(1H，d，J＝8.0Hz)、7.27(2H，d，J＝8.4Hz)、7.55(2H，d，J＝8.4Hz).
FAB-Mass；385(MH+)
EXAMPLE 51 Synthesis of- [1- (3-Chloroethyl) piperidin-4-yl ] indoline
Using 3-chlorophenylethyl bromide (0.1g), the procedure of example 2 was repeated to give the title compound (0.119g) as a colorless oil. (yield: 63.0%)
Hydrochloric acid was added thereto to form a salt, which was recrystallized from ethanol to give the titled compound hydrochloride as colorless crystals (0.110 g).
Melting point (hydrochloride salt): 219 deg.C
Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.89(2H，br-d)、2.11(2H，m)、2.91(2H，t，J＝8.4Hz)、3.09(4H，m)、3.27(2H，m)、3.35(2H，t，J＝8.4Hz)、3.63(2H，br-d)、3.77(1H，br-t)、6.62(2H，m)、7.02(1H，t，J＝8Hz)、7.06(1H，d，J＝8Hz)、7.27(1H，d，J＝7.2Hz)、7.32-7.41(3H，m).
FAB-Mass；341(MH+).
EXAMPLE 61 Synthesis of- [1- (4-Chlorophenylethyl) piperidin-4-yl ] indoline
Using 4-chlorophenylethyl bromide (0.1g), the procedure of example 2 was repeated to give the title compound (0.125g) as a colorless oil. (yield: 74.8%)
Hydrochloric acid was added thereto to form a salt, which was recrystallized from ethanol to give the titled compound hydrochloride as colorless crystals (0.120 g).
Melting point (hydrochloride salt): 228 deg.C
Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.88(2H，br-d)、2.11(2H，m)、2.91(2H，t，J＝8.4Hz)、3.09(4H，m)、3.25(2H，m)、3.35(2H，t，J＝8.4Hz)、3.63(2H，br-d)、3.77(1H，br-t)、6.62(1H，d，J＝8.0Hz)、6.63(1H，t，J＝8.0Hz)、7.03(1H，t，J＝8.0Hz)、7.06(1H，d，J＝8.0Hz)、7.33(2H，d，J＝8.6Hz)、7.42(2H，d，J＝8.6Hz).
FAB-Mass；341(MH+).
EXAMPLE 71 Synthesis of- [1- (2-fluorophenethyl) piperidin-4-yl ] indoline
The title compound hydrochloride was obtained as white powder crystals (290mg) in the same manner as in example 2, except for using 1- (piperidin-4-yl) indoline (300mg) and 2-fluorophenethyl bromide (340mg) obtained in the same manner as in production example 1. (yield: 54%)
Melting point (hydrochloride salt): 229 + 231 deg.C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.81-1.90(2H，m)、2.00-2.12(2H，m)、2.89(2H，t，J＝8Hz)、3.01-3.16(4H，m)、3.20-3.30(2H，m)、3.33(2H，t，J＝8Hz)、3.60-3.79(3H、m)、6.53-6.60(2H，m)、6.96-7.04(2H，m)、7.16-7.23(2H，m)、7.29-7.40(2H，m)，10.80(1H，br-s).
FAB-Mass；325(MH+).
EXAMPLE 81 Synthesis of- [1- (3-fluorophenethyl) piperidin-4-yl ] indoline
Dicyclohexylcarbodiimide (560mg) was added to a solution of 1- (piperidin-4-yl) indoline (500mg) in methylene chloride (30ml), and the mixture was stirred at 0 ℃. After 1 hour, 3-fluorophenylacetic acid (420mg) was added thereto, and the mixture was stirred at room temperature for 2 hours. The precipitated crystal was filtered off, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane/ethyl acetate). The residue was diluted with tetrahydrofuran (30ml), and lithium aluminum hydride (290mg) was added in small portions under ice-cooling stirring, followed by stirring at room temperature overnight. While the reaction mixture was chilled in ice water, water (0.29ml) was carefully added dropwise, followed by a 5N aqueous solution (0.87ml) of sodium hydroxide, followed by addition of water (0.29ml), and the mixture was vigorously stirred. The precipitated precipitate was filtered off, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane/ethyl acetate). Conversion to the hydrochloride salt was carried out according to a conventional method to obtain the hydrochloride salt of the title compound as white powdery crystals (550 mg). (yield 61%)
Melting point (hydrochloride salt): 231 ℃ 234-
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.81-1.89(2H，m)、1.93-2.07(2H，m)、2.88(2H，t，J＝8Hz)、3.00-3.11(4H，m)、3.23-3.35(4H，m)、3.58-3.75(3H，m)、6.51-6.57(2H，m)、6.95-7.03(2H，m)、7.06-7.19(2H，m)、7.35-7.41(2H，m).
FAB-Mass；325(MH+).
EXAMPLE 91 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] indoline
A2.5M n-butyllithium/hexane solution (0.36ml) was added dropwise to a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline (300mg) in tetrahydrofuran (15ml) at-78 ℃ for 10 minutes, and after 10 minutes, a saturated aqueous ammonium chloride solution and ethyl acetate were added to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the reaction mixture was purified by silica gel column chromatography (dichloromethane/ethanol). Conversion to the hydrochloride salt was carried out by a conventional method to obtain the hydrochloride salt of the title compound as white needle crystals (240 mg). (yield 90%)
Melting point (hydrochloride salt): 233 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.81-1.90(2H，m)、2.00-2.13(2H，m)、2.90(2H，t，J＝8Hz)、3.00-3.14(4H，m)、3.19-3.28(2H，m)、3.30(2H，t，J＝8Hz)、3.58-3.63(2H，m)、3.69-3.79(1H，m)、6.51-6.60(2H，m)、6.94-7.08(2H，m)、7.12-7.20(2H，m)、7.29-7.39(2H，m)、10.70(1H，br-s).
FAB-Mass；325(MH+).
EXAMPLE 101 Synthesis of- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] indoline
According to the same manner as in example 8, from 1- (piperidin-4-yl) indoline (500mg) and 2, 4-difluorophenylacetic acid (470mg), the hydrochloride of the title compound was obtained as white powder crystals (720 mg). (yield: 76%)
Melting point (hydrochloride salt): 226 ℃ C. (227 ℃ C.)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.81-2.08(4H，m)、2.89(2H，t，J＝8Hz)、3.00-3.15(4H，m)、3.20-3.39(4H，m)、3.40-3.75(3H，m)、6.49-6.57(2H，m)、6.94-7.04(2H，m)、7.07-7.12(1H，m)、7.23-7.30(1H，m)、7.39-7.46(1H，m).
FAB-Mass；343(MH+).
EXAMPLE 111- [1- (3, 4-difluorophenethyl) piperidin-4-yl ] indoline synthesis
3, 4-Difluorophenylacetic acid (0.095g) 1, 1-carbonyldiimidazole (0.089g) was added to tetrahydrofuran (5.0ml), and after stirring at room temperature for 15 minutes, 1- (piperidin-4-yl) indoline (0.1g) was added. After stirring at room temperature overnight, the mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). A colorless oil was obtained. The reaction mixture was dissolved in tetrahydrofuran (2.5ml), lithium aluminum hydride (0.046g) was added thereto under ice cooling, the mixture was refluxed for 2 hours, and the reaction mixture was cooled, then water (0.05ml), a 5N aqueous solution (0.05ml) of sodium hydroxide and water (0.15ml) were added thereto, and the solid matter was filtered off, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.190g) as a colorless oil. (yield: quantitative)
Hydrochloric acid was added thereto to form a salt, which was recrystallized from ethanol to give the title compound as a hydrochloride salt (0.120 g).
Melting point (hydrochloride salt): 223 deg.C
Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.87(2H，br-d)、2.06(2H，m)、2.90(2H，t，J＝8.4Hz)、3.09(4H，m)、3.28(2H，m)、3.33(2H，t，J＝8.4Hz)、3.62(2H，br-d)、3.74(1H，br-t)、6.57(1H，d，J＝7.0Hz)、6.58(1H，t，J＝7.0Hz)、7.01(1H，t，J＝7.0Hz)、7.04(1H，d，J＝7.0Hz)、7.16(1H，m)、7.39-7.46(2H，m).
FAB-Mass；343(MH+).
EXAMPLE 121 Synthesis of- [1- (3, 5-difluorophenethyl) piperidin-4-yl ] indoline
The title compound (0.342g) was obtained as a colorless oil by the method of example 11 using 3, 5-difluorophenylacetic acid (0.189 g). (yield: quantitative)
Hydrochloric acid was added thereto to form a salt, which was recrystallized from ethanol to give the title compound as a hydrochloride salt (0.268 g).
Melting point (hydrochloride salt): 208 deg.C
Hydrochloride salt
1H-NMR(400MHz、DMSO-d6)；δ(ppm)
1.89(2H，br-d)、2.12(2H，m)、2.92(2H，t，J＝8，2Hz)、3.09(4H，m)、3.27(2H，m)、3.36(2H，t，J＝8.2Hz)、3.61(2H，br-d)、3.78(1H，m)、6.64(1H，d，J＝8.0Hz)，6.6 4(1H，t，J＝8.0Hz)、7.04(1H，t，J＝8.0Hz)、7.07(1H，d，J＝8.0Hz)、7.14-7.18(1H，m)、7.38-7.45(2H，m).
FAB-Mass；343(MH+).
EXAMPLE 131 Synthesis of 1- [1- (4-fluoropropylen) piperidin-4-yl ] indoline
Ethanol (50ml) was added to 4-fluorocinnamic acid (5g), ethyl acetate was added until complete dissolution, palladium on carbon catalyst was added, and catalytic reduction was carried out under normal pressure. After filtration through celite, a part (0.082g) of colorless crystals obtained by concentrating the filtrate under reduced pressure was dissolved in tetrahydrofuran (5.0ml), and carbonyldiimidazole (0.079g) and 1- (4-piperidyl) indoline (0.1g) were added to stir at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a pale yellow oil (0.171 g). After dissolving in tetrahydrofuran, lithium aluminum hydride (0.046g) was added thereto under ice cooling, the mixture was refluxed for 2 hours under heating, then cooled with ice, and then added with water (0.05ml), a 5N aqueous solution (0.05ml) of sodium hydroxide, and water (0.15ml), the precipitated solid was filtered off, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.113g) as a colorless oil. (yield: 68.1%)
Hydrochloric acid was added thereto to form a salt, and recrystallization was performed with ethanol to obtain the title compound as a hydrochloride salt (temperature absorption property) as colorless crystals.
Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.83(2H，br-d)、1.97-2.14(4H，m)、2.64(2H，t，J＝8.0Hz)，2.90(2H，t，J＝8.0Hz)、3.00(4H，m)、3.33(2H，t，J＝8.4Hz)、3.54(2H，br-d)，3.73(1H，m)、6.58(1H，d，J＝7.6Hz)、6.61(1H，t，J＝7.6Hz)、7.02(1H，t，J＝7.6Hz)、7.05(1H，d，J＝7.6Hz)、7.14(2H，t，J＝8.8Hz)、7.29(2H，dd，J＝5.6，8.8Hz).
ESI-Mass；339.2(MH+).
EXAMPLE 141 Synthesis of 1- {1- [2- (4-fluorophenyl) propyl ] piperidin-4-yl } indoline
1- (4-piperazinyl) indoline (0.20g) was dissolved in dimethylformamide (3ml), and 4- (2-bromo-1-methylethyl) fluorobenzene (10.0g) and triethylamine (0.14ml) were added thereto, followed by stirring at 60 ℃ overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was purified by NH-silica gel column chromatography (methanol/dichloromethane) to give the title compound (178mg) as an oil.
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.37(3H，d，J＝6.8Hz)、1.60-2.10(8H，m)、2.85-3.50(8H，m)、6.36(1H，d，J＝7.5Hz)，6.58(1H，t，J＝7.5Hz)、6.97-7.07(4H，m)、7.24-7.30(2H，m).
FAB-Mass；339(MH+).
EXAMPLE 151 Synthesis of- [1- (4-fluorobenzoyl) piperidin-4-yl ] indoline
According to the same manner as in example 8, from 1- (piperidin-4-yl) indoline (1.0g) and 4- (4-fluorophenyl) butanoic acid (0.9g), the title compound hydrochloride was obtained as white powdery crystals (0.23 g). (yield: 12%)
Melting point (hydrochloride salt): 204 ℃ and 206 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.51-1.71(4H，m)，1.79-1.86(2H，m)、1.89-2.02(2H，m)、2.60(2H，t，J＝7Hz)、2.87(2H，t，J＝8Hz)、2.92-3.07(4H，m)、3.29(2H，t，J＝7Hz)、3.47-3.53(2H，m)、3.62-3.72(1H，m)、6.48-6.56(2H，m)、6.92-7.02(2H，m)、7.06-7.12(2H，m)、7.20-7.28(2H，m)、9.99(1H，br-s).
FAB-Mass；353(MH+).
EXAMPLE synthesis of 161- [1- (4-fluorophenethyl) piperidin-4-yl ] methylindoline
1-Fluorophenethyl-4-formylpiperidine (0.240g), indoline (0.095ml) and 1, 2-dichloroethane (3.5ml) were dissolved, acetic acid (0.29ml) and sodium triacetoxyborohydride (0.36g) were added in this order, and stirring was carried out at room temperature for 2 hours, and a saturated aqueous sodium hydrogencarbonate solution and ethyl acetate were added to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). The title compound (0.211g) was obtained as a yellow oil. (yield 73.3%)
Oxalic acid (28mg) was added thereto to form a salt, which was recrystallized from acetone to obtain colorless crystals of the oxalate salt of the title compound.
Melting point (oxalate): 201 ℃ to 206 DEG C
Oxalate
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.57(2H，m)、1.90(1H，m)、1.95(2H，m)、2.92(6H，m)、3.07(2H，m)、3.23(2H，m)、3.34(2H，t，J＝8.4Hz)、3.57(2H，br-d)、6.52(1H，d，J＝7.6Hz)、6.58(1H，t，J＝7.6Hz)、6-99(1H，t，J＝7.6Hz)、7.03(1H，d，J＝7.6Hz)、7.18(2H，t，J＝8.8Hz)、7.33(2H，dd，J＝5.2、8.8Hz).
ESI-Mass；339.1(MH+).
EXAMPLE 171 Synthesis of- {2- [1- (4-fluorophenethyl) piperidin-4-yl ] ethyl } indoline
The title compound was obtained as a hydrochloride salt in the form of white prismatic crystals (270mg) from indoline (170mg), 1- (4-fluorophenethyl) -4-piperidineacetaldehyde (360mg), acetic acid (440mg) and sodium triacetoxyborohydride (490mg) in the same manner as in example 1. (yield: 48%)
Melting point (hydrochloride salt): 159 ℃ plus 161 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.45-1.70(5H，m)、1.89-1.98(2H，m)、2.80-3.10(8H，m)、3.14-3.36(4H，m)、3.50-3.58(2H，m)，6.50-6.58(2H，m)、6.96-7.0(2H，m)、7.16-7.21(2H，m)，7.30-7.38(2H，m)、10.16(1H，m).
FAB-Mass；353(MH+).
EXAMPLE 181- [1- (4-Methoxyphenethyl) piperidin-4-yl ] indoline synthesis
Using 4-methoxyphenethyl bromide (0.23g), the procedure of example 2 was followed to give the title compound (0.131g) as colorless crystals. (yield: 86.1%)
Hydrochloric acid was added thereto to form a salt, which was recrystallized from ethanol to obtain the titled compound hydrochloride as colorless crystals.
Melting point (hydrochloride salt): 244 deg.C
Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.88(2H，m)、2.02(2H，m)、2.90(2H，t，J＝8.4Hz)、3.00(2H，m)、3.10(2H，m)、3.21(2H，m)、3.33(2H，t，J＝8.4Hz)、3.63(2H，br-d)、3.73，(3H，s)、3.74(1H，m)、6.57(1H，d，J＝7.6Hz)、6.59(1H，t，J＝7.6Hz)、6.91(2H，d，J＝8.4Hz)、7.01(1H，t，J＝7.6Hz)、7.04(1H，d，J＝7.6Hz)、7.21(2H，d，J＝8.4Hz).
FAB-Mass；337(MH+).
EXAMPLE 191 Synthesis of- [1- (3-methoxyphenethyl) piperidin-4-yl ] indoline
The pale yellow oil (0.23g) obtained in the same manner as in production example 1 was extracted with 3-methoxyphenylethanol in the same manner as in example 2 to give the title compound as colorless crystals (0.150 g). (yield: 45.4%)
Hydrochloric acid was added thereto to form a salt, which was recrystallized from ethanol to obtain the titled compound hydrochloride as colorless crystals.
Melting point (hydrochloride salt): 229 DEG C
Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.88(2H，br-d)、2.14(2H，m)、2.92(2H，t，J＝8.4Hz)、3.07(4H，m)、3.25(2H，m)、3.37(2H，t，J＝8.4Hz)、3.63(2H，br-d)、3.75(3H，s)、3.77(1H，m)、6.57(1H，d，J＝7.6Hz)、6.45(1H，m)、6.81-6.88(3H，m)、7.05(2H，m)、7.26(1H，d，J＝8.0Hz).
FAB-Mass；337(MH+).
EXAMPLE 201 Synthesis of- [1- (4-Hydroxyphenylethyl) piperidin-4-yl ] indoline
1- [1- (4-Methoxyphenylethyl) piperidin-4-yl ] indoline (0.23g) was dissolved in 47% aqueous hydrobromic acid (5ml), and the mixture was refluxed for 90 minutes. After cooling, the mixture was added to a saturated aqueous sodium bicarbonate solution (pH9-10), extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate). The title compound was obtained as colorless crystals (0.113 g). (yield 75.7%)
Hydrochloric acid was added thereto to form a salt, which was recrystallized from ethanol to obtain the titled compound hydrochloride as colorless crystals.
Melting point (hydrochloride salt): 240 ℃ C
Hydrochloride
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.87(2H，m)，2.09(2H，m)，2.91(2H，t，J＝8.4Hz)，2，95(2H，m)、3.07(2H，m)、3.18(2H，m)、3.34(2H，t，J＝8.4Hz)、3.62(2H，br-d)、3.75(1H，m)、6.61(2H，m)、6.73(2H，d，J＝8.4Hz)、7.05(4H，m)、10.69(1H，br-s).
FAB-Mass；323(MH+).
EXAMPLE 211 Synthesis of- [1- (4-cyanophenylethyl) piperidin-4-yl ] indoline
1- [1- (4-Oximethylphenethyl) piperidin-4-yl ] indoline (0.466g) was dissolved in methylene chloride (6.5ml), triethylamine (0.35ml) was added, trifluoroacetic anhydride (0.14ml) was added dropwise at-78 ℃ under a nitrogen atmosphere, and the mixture was stirred for 3 hours. Adding saturated aqueous sodium bicarbonate solution, extracting with ethyl acetate, washing with saturated saline, drying over anhydrous magnesium sulfate, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography (ethyl acetate/dichloromethane/methanol). The title compound (0.126g) was obtained as a pale yellow oil. (yield 28.9%)
Hydrochloric acid was added thereto to form a salt, which was recrystallized from ethanol to obtain the title compound as a hydrochloride salt.
Melting point (hydrochloride salt): 228 deg.C
Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.89(2H，br-d)、2.12(2H，m)、2.91(2H，t，J＝8.4Hz)、3.12(2H，m)、3.21(2H，m)、3.28(2H，m)、3.34(2H，t，J＝8.4Hz)、3.63(2H，br-d)、3.76(1H，m)、6.60(1H，d，J＝7.4Hz)、6.61(1H，t，J＝7.4Hz)、7.02(1H，t，J＝7.4Hz)、7.05(1H，d，J＝7.4Hz)，7.52(2H，d，J＝8.0Hz)、7.84(2H，d，J＝8.0Hz).
FAB-Mass；332(MH+).
EXAMPLE 221- [1- (3-Hydroxymethylbenzylethyl) piperidin-4-yl ] indoline synthesis
From 3-tert-butyldimethylsilyloxymethylphenylbromide (0.22g), the procedure of example 2 was followed to give the title compound (0.116g) as a pale yellow oil. (yield: 31.9%)
Free form
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.75-1.84(4H，m)、2.15(2H，m)、2.63(2H，m)、2.84(2H，m)、2.95(2H，t，J＝8.4Hz)、3.14(2H，br-t)、3.37(1H，m)、3.39(2H，t，J＝8.4Hz)、4.68(2H，s)、6.39(1H，d)、6.60(1H，t)、7.03(2H，m)、7.12-7.35(4H，m).
Hydrochloric acid (0.372g) was added thereto to form a salt, which was recrystallized from an ethanol/acetone mixed solvent to obtain a hydrochloride salt.
Melting point (hydrochloride salt): 218 deg.C
EXAMPLE 231- [1- (4-Hydroxymethylphenylethyl) piperidin-4-yl ] indoline synthesis
From 4- (2-bromoethyl) benzyl alcohol (0.2g), the title compound was obtained as a pale yellow oil (0.177g) by the method of example 2. (yield: 53.7%)
Free form
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.79(4H，m)、2.12(2H，dt，J＝2.8，11.6Hz)、2.59(2H，m)、2.81(2H，m)、2.94(2H，t，J＝8.4Hz)、3.12(2H，br-d)、3.38(2H，t，J＝8.4Hz)、3.40(1H，m)、4.65(2H，s)，6.42(1H，d，J＝8.0Hz)、6.61(1H，t，J＝8.0Hz)、7.03(1H，t、J＝8.0Hz)、7.05(1H，d，J＝8.0Hz)、7.21(2H，d，J＝8.0Hz)、7.49(2H，d，J＝8.0Hz)、8.11(1H，s).
Hydrochloric acid was added thereto to form a salt, to obtain the hydrochloride of the title compound.
Example 241 Synthesis of- {1- [4- (2-hydroxyethyl) phenethyl ] piperidin-4-yl } indoline
From 4- [2- (tert-butyldimethylsiloxy) ethyl ] phenethyl bromide (0.2g), the procedure of example 2 was followed to give a pale yellow oil (0.113 g). The resulting solution was dissolved in tetrahydrofuran (1.0ml), and a 2.0M tetrabutylammonium fluoride/tetrahydrofuran solution (0.49ml) was added thereto, and the mixture was stirred wet at room temperature for 1.5 hours, and the reaction mixture was concentrated under reduced pressure to give the title compound (0.086g) as a yellow oil. (yield: quantitative)
Free form
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.88(4H，m)、2.31(2H，m)，2.75(2H，m)、2.85(2H，t，J＝6.4Hz)、2.95(2H，t，J＝8.4Hz)、3.21(2H，m)、3.24(2H，m)、3.40(2H，t，J＝8.4Hz)、3.85(2H，t，J＝6.4Hz)、6.41(1H，d)、6.60(1H，t)、7.03(2H，m)、7.18(4H，s).
Oxalic acid (0.372g) was added thereto to form a salt, to give an oxalate salt as a brown oil.
FAB-Mass；351(MH+).
Example Synthesis of 251- {/- [4- (1-hydroxyethyl) phenethyl ] piperidin-4-yl) indoline
From 4- (1-hydroxyethyl) phenethyl bromide (0.2g), the title compound (0.044g) was obtained as a yellow oil by the method of example 2. (yield: 12.6%)
Adding oxalic acid into the mixture to form salt, and recrystallizing the salt by using ethanol to obtain oxalate.
Melting point (oxalate): 132 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.30(3H，d，J＝6.4Hz)、1.86(4H，m)、2.88(2H，t，J＝8.0Hz)、2.92(4H，m)、3.15(2H，m)、3.32(2H，t，J＝8.4Hz)、3.54(2H，m)、3.67(1H，m)、4.69(1H，q，J＝6.7Hz)、6.51(1H，d，J＝8.0Hz)、6.55(1H，t，J＝8.0Hz)，6.99(1H，t，J＝8.0Hz)、7.02(1H，d，J＝8.0Hz)、7.22(2H，d，J＝8.0Hz)、7.30(1H，d，J＝8.0Hz).
FAB-Mass；351(MH+).
Example Synthesis of 261- {1- [4- (2-hydroxyethoxy) phenethyl ] piperidin-4-yl } indoline
To 1- [1- (4-Hydroxyphenylethyl) piperidin-4-yl ] indoline (0.1g), potassium carbonate (0.081g) and 1-bromo-2-di (tert-butyl) dimethylsiloxyethane (0.20g) was added N, N-dimethylformamide (2.5ml), and the mixture was stirred at 80 ℃ for 28 hours. After cooling, the mixture was extracted with ethyl acetate (200ml), washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). A colorless oil was obtained. Dissolved in tetrahydrofuran (1.3ml), a 2.0M tetrabutylammonium fluoride/tetrahydrofuran solution (0.88ml) was added, the mixture was stirred at room temperature for 1 hour, extracted with ethyl acetate (200ml), washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). The title compound (0.124g) was obtained as a colorless oil. (yield 69.0%)
Free form
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.80(4H，m)、2.11(2H，dt，J＝3.2，11.6Hz)、2.58(2H，m)、2.76(2H，m)、2.94(2H，t，J＝8.4Hz)、3.12(2H，br-d)、3.39(2H，t，J＝8.4Hz)、3.40(1H，m)、3.94(2H，t，J＝8.4Hz)、4.06(2H，t，J＝8.4Hz)、6.40(1H，d，J＝7.6Hz)、6.60(1H，t，J＝7.6Hz)、6.85(2H，d，J＝8.4Hz)、7.04(2H，m)、7.13(2H，d，J＝8.4Hz).
ESI-Mass；367.2(MH+).
Hydrochloric acid was added thereto to form a salt, which was recrystallized from ethanol to obtain the titled compound hydrochloride as colorless crystals.
Melting point (hydrochloride salt): 229 DEG C
EXAMPLE 271 Synthesis of- [1- (4-trifluoromethylphenethyl) piperidin-4-yl ] indoline
According to the same manner as in example 8, from 1- (piperidin-4-yl) indoline (1.0g) and 4-trifluoromethylphenylacetic acid (1.0g), the title compound hydrochloride was obtained as white powdery crystals (0.98 g). (yield: 48%)
Melting point (hydrochloride salt): 212 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.81-1.89(2H，m)、1.94-2.09(2H，m)、2.88(2H，t，J＝8Hz)、3.02-3.20(4H，m)、3.28-3.36(4H，m)、3.60-3.79(3H，m)、6.52-6.58(2H，m)、6.96-7.04(2H，m)、7.53(2H，d，J＝8Hz)、7.72(2H，d，J＝8Hz).
FAB-Mass；375(MH+).
Example 281- [1- (4-Methylsulfonylphenylethyl) piperidin-4-yl ] indoline Synthesis
According to the same manner as in example 2, from 1- (piperidin-4-yl) indoline (200mg) and 4-methanesulfonylphenethyl bromide (290mg), the title compound hydrochloride was obtained as white powder crystals (180 mg). (yield: 43%)
Melting point (hydrochloride salt): 208 ℃ C. & lt 210 ℃ C. & gt
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.69-1.86(4H，m)、2.10-2.18(2H，m)、2.61-2.67(2H，m)、2.87-2.98(4H，m)、3.04(3H，s)、3.06-3.14(2H，m)、3.35-3.44(3H，m)、6.41(1H，d，J＝8Hz)、6.60(1H，t，J＝8Hz)、7.01-7.06(2H，m)、7.41(2H，d，J＝8Hz)、7.85(2H，d，J＝8Hz).
FAB-Mass；385(MH+).
EXAMPLE 291 Synthesis of- [1- (4-Nitrophenylethyl) piperidin-4-yl ] indoline
1- (piperidin-4-yl) indoline (2.00g) was dissolved in dimethylformamide (20ml), and 4- (2-bromoethyl) nitrobenzene (10.0g) and triethylamine (2.9ml) were added thereto and the mixture was stirred at 100 ℃ overnight. Water was added to the reaction mixture, extraction was performed with ethyl acetate, the organic layer was washed with saturated brine, dried over magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). The title compound was obtained as a pale yellow solid. (1.05g)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.70-1.90(4H，m)、2.14-2.22(2H，m)、2.64-2.72(4H，m)、2.90-3.00(2H，m)、3.08-3.16(2H，m)、3.36-3.46(3H，m)、6.41(1H，d，J＝7.6Hz)、6.61(1H，d，J＝7.6Hz)、7.02-7.08(2H，m)、7.35-7.40(2H，m)、8.13-8.18(2H，m).
FAB-Mass；352(MH+).
Melting point: 95-97 deg.C
EXAMPLE 301 Synthesis of- [1- (4-Aminophenylethyl) piperidin-4-yl ] indoline
1- [1- (4-Nitrophenyl ethyl) piperidin-4-yl ] indoline (780g) was dissolved in methanol (7ml), concentrated hydrochloric acid (0.5ml) was added dropwise, and catalytic reduction was carried out under normal pressure in the presence of a palladium catalyst. The catalyst was filtered off, a 1N aqueous solution of sodium hydroxide was added thereto, extraction was performed with chloroform, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off to leave the title compound (620mg) as an oil.
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.70-1.85(4H，m)、2.06-2.15(2H，m)、2.52-2.60(2H，m)、2.67-2.75(2H，m)、2.94(2H，t，J＝8.2Hz)、3.08-3.16(2H.m)、3.35-3.45(3H，m)、3.57(2H，br-s)、6.41(1H，d，J＝8.0Hz)、6.57-6.67(3H，m)、6.97-7.02(2H，m)、7.05(1H，d，J＝8.0Hz).
FAB-Mass；322(MH+).
EXAMPLE 311 Synthesis of 1- [1- (4-methanesulfonylaminophenylethyl) piperidin-4-yl ] indoline and 1- {1- [ 4-bis (methanesulfonyl) aminophenylethyl ] piperidin-4-yl } indoline
1- [1- (4-Aminophenethyl) piperidin-4-yl ] indoline (140mg) was dissolved in methylene chloride (2ml), and methanesulfonyl chloride (0.12ml) and triethylamine (0.1ml) were added under ice cooling to stir for 45 minutes. Adding 10% potassium carbonate aqueous solution, extracting with ethyl acetate, washing the organic layer with saturated brine, drying over anhydrous magnesium sulfate, concentrating under reduced pressure, evaporating the solvent, and purifying the residue (150mg) by NH-silica gel column chromatography (hexane/ethyl acetate). This gave 1- {1- [ 4-bis (methylsulfonyl) aminophenylethyl ] piperidin-4-yl } indoline (50mg) as an oil, which gave 1- [1- (4-methylsulfonylaminophenylethyl) piperidin-4-yl ] indoline (35 mg).
(1)1- {1- [ 4-bis (methylsulfonyl) aminophenylethyl ] piperidin-4-yl } indoline
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.71-1.87(4H，m)、2.09-2.18(2H，m)、2.60-2.66(2H，m)、2.83-2.89(2H，m)、2.95(2H，t，J＝8.4Hz)、3.08-3.15(2H，m)、3.35-3.45(3H，m)、3.39(6H，s)、6.41(1H，d，J＝7.5Hz)，6.60(1H，t，J＝7.5Hz)、7.01-7.07(2H，m)、7.25-7.33(4H，m).
FAB-Mass；478(MH+).
(2)1- [1- (4-Methylsulfonylaminophenylethyl) piperidin-4-yl ] indoline
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.52-1.66(4H，m)、2.00-2.08(2H，m)、2.64-2.70(2H，m)、2.80-2.86(2H，m)、2.96-3.02(2H，m)、3.25-3.40(3H，m)、3.32(3H，s)、6.41(1H，d，J＝7.4Hz)、6.48(1H，t，J＝7.4Hz)、6.91-6.99(2H，m)、7.07-7.19(4H，m).
FAB-Mass；400(MH+).
EXAMPLE 321- [1- (4-Acetylaminophenylethyl) piperidin-4-yl ] indoline Synthesis
1- [1- (4-Aminophenethyl) piperidin-4-yl ] indoline (310mg) was dissolved in methylene chloride (3ml), and acetyl chloride (0.103ml) was added thereto under ice cooling to stir for 45 minutes. The reaction mixture was added with 10% potassium carbonate aqueous solution, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over magnesium sulfate, the solvent was evaporated, and the residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate). The title compound (200mg) was obtained as an oil.
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.70-1.86(4H，m)、2.08-2.16(2H，m)、2.17(3H，s)、2.56-2.62(2H，m)、2.76-2.82(2H，m)、2.95(2H，t，J＝8.4Hz)、3.08-3.14(2H，m)、3.35-3.44(3H，m)、6.41(1H，d，J＝7.5Hz)、6.60(1H，t，J＝7.5Hz)、7.04(1H，t，J＝7.5Hz)、7.10(1H，br-s)、7.16(2H，d，J＝8.4Hz)、7.40(2H，d，J＝8.4Hz).
FAB-Mass；364(MH+).
EXAMPLE 331 Synthesis of- [1- (4-Ethylaminophenylethyl) piperidin-4-yl ] indoline
1- [1- (4-Acetylaminophenylethyl) piperidin-4-yl ] indoline (135mg) was dissolved in tetrahydrofuran (5ml), and lithium aluminum hydride (28mg) was added thereto at room temperature and the mixture was refluxed for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing of the organic layer with saturated brine, drying over magnesium sulfate, evaporation of the solvent, and purification of the residue by NH-silica gel column chromatography (hexane/ethyl acetate). The title compound (40mg) was obtained as an oil.
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.25(3H，t，J＝7.1Hz)、1.72-1.86(4H，m)、2.06-2.14(2H，m)、2.54-2.60(2H，m)、2.68-2.76(2H，m)、2.91-2.98(2H，m)、3.09-3.16(3H，m)、3.35-3.44(4H，m)、6.41(1H，d.J＝8.0Hz)、6.54-6.70(3H，m)、7.00-7.07(4H，m).
EXAMPLE synthesis of 341- [1- (4-Oximethylphenethyl) piperidin-4-yl ] indoline
From 4- (2-bromoethyl) benzaldoxime (0.49g), the title compound was obtained as pale yellow crystals (0.480g) by following the procedure of example 2. (yield: 70.1%)
Free form
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.87(4H，m)、2.19(2H，dt，J＝3.0，11.2Hz)、2.68(2H，m)、2.89(2H，m)，2.93(2H，t，J＝8.4Hz)，3.20(2H，br-d)、3.40(2H，t，J＝8.4Hz)、3.43(1H，m)、6.42(1H，d，J＝8.0Hz)、6.61(1H，t，J＝8.0Hz)、7.03(1H，t，J＝8.0Hz)、7.05(1H，d，J＝8.0Hz)、7.21(2H，d，J＝8.0Hz)、7.49(2H，d，J＝8.0Hz)、8.11(1H，s).
Hydrochloric acid was added thereto to form a salt, to obtain the title compound hydrochloride as a hygroscopic amorphous form.
FAB-Mass；350(MH+).
EXAMPLE 351- [1- (4-Aminomethylphenylethyl) piperidin-4-yl ] indoline synthesis
1- [1- (4-Oximethylphenethyl) piperidin-4-yl ] indoline (2.71g) was dissolved in tetrahydrofuran (40ml), and lithium aluminum hydride (0.59g) was added thereto under ice cooling, followed by heating and refluxing for 2 hours. The reaction mixture was further cooled with ice, to which were added water (0.6ml), 5N aqueous sodium hydroxide solution (0.6ml) and water (1.8ml), and the precipitated precipitate was filtered off, washed with ethyl acetate and concentrated under reduced pressure. The title compound (1.462g) was obtained as a pale yellow oil. (yield 56.2%)
Free form
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.58(2H，m)、1.79(4H，m)、2.12(2H，dt，J＝3.0，11.6Hz)、2.61(2H，m)、2.81(2H，m)、2.95(2H，t，J＝8.4Hz)、3.13(2H，br-d)、3.39(2H，t，J＝8.4Hz)、3.40(1H，m)、3.84(2H，s)、6.42(1H，d，J＝7.6Hz)、6.60(1H，t，J＝7.6Hz)、7.04(1H，t，J＝7.6Hz)、7.05(1H，d，J＝7.6Hz)、7.18(2H，d，J＝8.4Hz)、7.24(2H，d，J＝8.4Hz).
Hydrochloric acid was added thereto to form a salt, to obtain the title compound hydrochloride as a hygroscopic amorphous form.
FAB-Mass；336(MH+).
EXAMPLE 361- [1- (4-Acetylaminomethyl-phenethyl) piperidin-4-yl ] indoline synthesis
1- [1- (4-Aminomethylphenylethyl) piperidin-4-yl ] indoline (0.6g) was dissolved in tetrahydrofuran (9.0ml), and acetyl chloride (0.14ml) was added dropwise under ice cooling, followed by stirring for 2 hours. The reaction mixture was added with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the solvent was evaporated, and the residue was purified by cromatotrex NH-silica gel column chromatography (hexane/ethyl acetate). The title compound (0.518g) was obtained as a pale yellow oil. (yield 79.2%)
Hydrochloric acid was added thereto to form a salt, to obtain a hygroscopic hydrochloride of the title compound as a pale yellow amorphous form.
Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.86(3H，s)、1.90(2H，m)、2.08(2H，m)、2.90(2H，t，J＝8.2Hz)，3.08(4H，m)、3.23(2H，m)、3.33(2H，t，J＝8.2Hz)、3.63(2H，br-d)、3.74(1H，m)、4.22(2H，d，J＝6.0Hz)、6.58(1H，d，J＝7.6Hz)、6.59(1H，t，J＝7.6Hz)、7.01(1H，t，J＝7.6Hz)、7.05(1H，d，J＝7.6Hz)、7.23(4H，s)、8.36(1H，t，J＝6.0Hz).
FAB-Mass；378(MH+).
EXAMPLE 371- [1- (4-Chloroacetamidomethylphenylethyl) piperidin-4-yl ] indoline synthesis
From 1- [1- (4-Aminomethylphenylethyl) piperidin-4-yl ] indoline (0.1g) and chloroacetyl chloride (0.026ml), the title compound (0.074g) was obtained as a pale yellow oil according to example 36.
(yield 62.1%)
Free form
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.79(4H，m)、2.12(2H，m)、2.61(2H，m)、2.82(2H，m)、2.94(2H，t，J＝8.4Hz)、3.12(2H，br-d)、3.39(2H，t，J＝8.4Hz)、3.40(1H，m)、4.13(2H，s)、4.46(2H，d，J＝5.6Hz)、6.41(1H，d，J＝7.6Hz)、6.60(1H，t，J＝7.6Hz)、6.83(1H，br-s)、7.04(2H，t，J＝8.0Hz)、7.20(4H，m).
Oxalic acid was added thereto to form a salt, which was recrystallized from a mixed solvent of ethanol/isopropyl ether to obtain the title compound, oxalate, as colorless crystals (0.054 g).
Melting point (oxalate): 138 deg.C
FAB-Mass；412(MH+).
EXAMPLE 381 Synthesis of- [1- (4-Methanesulfonamidomethylphenethyl) piperidin-4-yl ] indoline
From 1- [1- (4-Aminomethylphenylethyl) piperidin-4-yl ] indoline (0.120g) and methanesulfonyl chloride (0.030ml), according to example 36, the title compound (0.078g) was obtained as a pale yellow oil.
(yield 54.5%)
Free form
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.85(4H，m)、2.20(2H，m)、2.66(2H，m)、2.86(2H，m)、2.89(3H，s)、2.95(2H，t，J＝8.7Hz)、3.28(2H，m)、3.39(2H，t，J＝8.7Hz)、3.42(1H，m)、4.30(2H，d，J＝5.8Hz)、4.63(1H，m)、6.41(1H，d，J＝8Hz)、6.61(1H，t，J＝8Hz)，7.03(1H，t，J＝8Hz)、7.05(1H，d，J＝8Hz)、7.21(2H，d，J＝8Hz)、7.28(2H，d，J＝8Hz).
To this, oxalic acid was added to form a salt, and the salt was recrystallized from a mixed solvent of acetone/water to obtain the oxalate salt of the title compound.
Melting point (oxalate): 199 deg.C
FAB-Mass；414(MH+).
Example 391 Synthesis of- [1- (4-propionylaminomethylphenethyl) piperidin-4-yl ] -3-methylindoline
From 1- [1- (4-Aminomethylphenylethyl) piperidin-4-yl ] -3-methyldihydroindole (0.1g) and propionyl chloride (0.028ml), according to example 36, the title compound (0.122) was obtained as a pale yellow oil. (yield: quantitative)
Oxalic acid (13mg) was added thereto to form a salt, which was recrystallized from ethyl acetate to give the title compound, oxalate, as colorless crystals (0.064 g).
Melting point (oxalate): 96-105 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.02(3H，t，J＝8.4Hz)、1.86(2H，m)、2.10(2H，m)、2.13(2H，q，J＝8.4Hz)、2.81(2H，m)、2.88(2H，t，J＝8.4Hz)、2.91(2H，m)、3.07(2H，m)、3.10(2H，t，J＝8.4Hz)、3.49(2H，br-d)、3.64(1H，m)、4.22(2H，s)、6.52(2H，m)、7.01(2H，m)、7.20(4H，m).
FAB-Mass；392(MH+).
EXAMPLE 401 Synthesis of- [1- (4-carbamoylphenethyl) piperidin-4-yl ] indoline
From 4-carbamoylphenethyl bromide (0.135g), according to the procedure of example 2, the title compound was obtained as pale yellow crystals (0.097 g). (yield: 56.6%)
Oxalic acid (13mg) was added thereto to form a salt, to obtain an amorphous form of the oxalate salt of the title compound. Melting point (oxalate): 178-
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.78(4H，m)、2.61(2H，m)、2.87(2H，t、J＝8.4Hz)、2.94(4H，m)、3.31(2H，t，J＝8.4Hz)、3.34(2H，m)、3.55(1H，m)、6.48(1H，d，J＝7.6Hz)、6.53(1H，t，J＝7.6Hz)、6.98(1H，t，J＝7.6Hz)、7.01(1H，d，J＝7.6Hz)、7.31(1H，m)、7.34(2H，d，J＝8.4Hz)、7.82(2H，d，J＝8.4Hz)、7.93(1H，m).
ESI-Mass；350.1(MH+).
EXAMPLE 411- [1- (4-N-Isopropylcarbamoylmethylphenylethyl) piperidin-4-yl ] indoline synthesis
From N-isopropyl-4- (2-bromoethyl) phenylacetamide (0.029g), according to the method of example 2, the title compound was obtained as colorless crystals (0.040 g). (yield: 92.1%)
Oxalic acid (5mg) was added thereto to form a salt, to obtain an amorphous form of the oxalate salt of the title compound. Melting point (oxalate): 88-96 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.64(6H，d，J＝6.8Hz)、1.82(4H，m)、2.82-2.92(6H，m)、3.06(2H，m)、3.31(2H，m)、3.33(2H，s)、3.46(2H，m)、3.63(1H，m)、9.79(1H，q，J＝6.8Hz)、6.50(1H，d，J＝8Hz)、6.54(1H，t，J＝8Hz)、6.98(1H，t，J＝8Hz)、7.01(1H，d，J＝8Hz)、7.19(4H，s)、7.93(1H，d，J＝8Hz).
ESI-Mass；406.25(MH+).
EXAMPLE synthesis of 421- [1- (4-sulfamoylphenethyl) piperidin-4-yl ] indoline
From 1- (piperidin-4-yl) indoline (300mg) and 4-sulfamoylphenethyl bromide (400mg), the procedure of example 2 was followed to give the title compound as pale yellow powder crystals (60 mg).
(yield: 10%)
Melting point: 207 ℃ C. & lt 210 ℃ C. & gt
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.70-1.87(4H，m)、2.11-2.20(2H，m)、2.60-2.66(2H，m))、2.86-2.98(4H，m)、3.08-3.15(2H，m)、3.34-3.45(3H，m)、6.41(1H，d，J＝8Hz)、6.61(1H，d，J＝8Hz)、7.01-7.08(2H，m)、7.36(2H，d，J＝8Hz)，7.85(2H，d，J＝8Hz).
FAB-Mass；386(MH+).
Example 431 Synthesis of 1- {1- [3- (2-hydroxyethoxy) phenethyl ] piperidin-4-yl } indoline
From 3- [2- (tert-butyldimethylsilyloxy) ethoxy ] phenethyl bromide (0.33g), the procedure of example 24 was followed to give the title compound (0.197g) as a yellow oil. (yield: 53.8%)
Oxalic acid (48mg) was added thereto to form a salt, to give the oxalate salt of the title compound.
Melting point (oxalate): 118 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.86(4H，m)、2.88(2H，t，J＝8.2Hz)、2.92(4H，m)、3.17(2H，m)、3.31(2H，t，J＝8.2Hz)、3.53(2H，br-d)、3.67(1H，m)、3.71(2H，t，J＝9.0Hz)、3.08(2H，t，J＝9.0Hz)、6.52(1H，d，J＝7.6Hz)、6.55(1H，t，J＝7.6Hz)、6.83(2H，m)、6.87(1H，br-s)、6.99(1H，t，J＝7.6Hz)、7.02(1H，d，J＝7.6Hz)、7.24(1H，t，J＝8.4Hz).
FAB-Mass；367(MH+).
Example 441 synthesis of- {1- [4- (2-dimethylaminoethoxy) phenethyl ] piperidin-4-yl } indoline
To 1- [1- (4-Hydroxyphenylethyl) piperidin-4-yl ] indoline (0.1g), potassium carbonate (0.081g) and 2-dimethylaminoethyl chloride hydrochloride (0.078g) was added N, N-dimethylformamide (2.5ml), and the mixture was stirred at 80 ℃ overnight (12 hours). After the mixture was allowed to cool, ethyl acetate (200ml) was added thereto, the organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.052g) as a tan oil. (yield 27.0%)
Hydrochloric acid was added thereto to form a salt, to obtain the hydrochloride of the title compound.
Melting point (hydrochloride salt): 258 ℃ 259 DEG C
Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.87(2H，m)、2.12(2H，m)、2.82(6H，m)、2.91(2H，t，J＝8.4Hz)、3.06(4H，m)、3.21(2H，m)、3.34(2H，t，J＝8.4Hz)、3.48(2H，m)、3.63(2H，br-d)、3.75(1H，m)、4.37(2H，t，J＝4.8Hz)、6.59(1H，d，J＝8.0Hz)、6.60(1H，t，J＝8.0Hz)、6.98(2H，d，J＝8.6Hz)、7.01(1H，t，J＝8.0Hz)，7.05(1H，d，J＝8.0Hz)、7.24(2H，d，J＝8.6Hz).
ESI-Mass；394.2(MH+).
EXAMPLE 451 Synthesis of- {1- [3, 4-bis (hydroxymethyl) phenethyl ] piperidin-4-yl } indoline
The procedure of example 24 was followed using 3, 4- [ di (tert-butyl) dimethylsilyloxymethyl ] phenethyl bromide (0.421g) to give the title compound (0.318g) as a pale yellow oil. (yield 98.6%)
Hydrochloric acid was added thereto to form a salt, which was recrystallized from ethanol to give the titled compound hydrochloride as colorless crystals (0.617 g). (yield 47.1%)
Melting point (hydrochloride salt): 178 deg.C
Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.89(2H，m)、1.04(2H，m)、2.90(2H，t，J＝8.0Hz)、3.08(4H，m)、3.25(2H，m)、3.33(2H，t，J＝8.0Hz)、3.66(2H，br-d)、3.73(1H，m)、4.50(2H，s)、4.53(2H，s)、6.55(1H，d，J＝7.6Hz)、6.58(1H，t，J＝7.6Hz)、7.01(1H，t，J＝7.6Hz)、7.04(1H，d，J＝7.6Hz)、7.14(1H，dd，J＝1.6.8.0Hz)、7.32(1H，d，J＝1.6Hz)、7.34(1H，d，J＝8.0Hz).
FAB-Mass；367(MH+).
Example Synthesis of 461- {1- [3, 4- (methylenedioxy) phenethyl ] piperidin-4-yl } indoline
The procedure of example 11 was followed using 3, 4- (methylenedioxy) phenylacetic acid (0.198g) to give the title compound (0.304g) as a colorless oil. (yield: 89.8%)
Hydrochloric acid was added thereto to form a salt, which was recrystallized from ethanol to obtain the titled compound hydrochloride as colorless crystals.
Melting point (hydrochloride salt): 236 deg.C
Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.88(2H，br-d)、2.12(2H，m)、2.93(2H，t，J＝8.0Hz)、3.03(4H，m)、3.20(2H，m)、3.37(2H，t，J＝8.0Hz)、3.61(2H，br-d)、3.78(1H，m)、5.99(2H，s)、6.74(1H，d，J＝8.0Hz)、6.88(2H，m)、7.06(2H，m).
FAB-Mass；361(MH+).
Example 471- {1- [2- (4-Chlorophenylsulfonamido) ethyl ] piperidin-4-yl } indoline Synthesis
1- [1- (2-aminoethyl) piperazin-4-yl ] indoline (113mg) was dissolved in chloroform (3ml), 4-chlorobenzenesulfonyl chloride (97mg) was added under ice cooling, the mixture was stirred for 6 hours, water was added to the reaction solution, extraction was performed with chloroform, the organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated, and the residue (205mg) was purified by NH-silica gel column chromatography (methanol/dichloromethane) to give the title compound (134mg) as an oil.
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.54-1.66(2H，m)、1.71-1.78(2H，m)、1.99-2.07(2H，m)、2.42(2H，t，J＝5.8Hz)、2.70-2.76(2H，m)、2.94-3.02(4H，m)、3.28-3.40(3H，m)、5.30(1H，br-s)、6.36(1H，d，J＝8.0Hz)、6.59-6.63(1H，m)、7.00-7.08(2H，m)、7.47-7.52(2H，m)、7.80-7.84(2H，m).
FAB-Mass；420(MH+).
Example Synthesis of 481- {1- [2- (4-Methoxyphenylsulfonylamino) ethyl ] piperidin-4-yl } indoline
1- [1- (2-aminoethyl) piperazin-4-yl ] indoline (113mg) was dissolved in chloroform (3ml), and 4-methoxybenzenesulfonyl chloride (95mg) was added thereto under ice cooling, followed by stirring at room temperature overnight. The reaction solution was added with water, extracted with chloroform, the organic layer was washed with saturated brine, dried over magnesium sulfate, the solvent was evaporated, and the residue (80mg) was purified by NH-silica gel column chromatography (methanol/dichloromethane) to give the title compound (45mg) as an oil.
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.54-1.76(4H，m)、1.96-2.04(2H，m)、2.40(2H，t，J＝5.8Hz)、2.67-2.74(2H，m)、2.93-3.00(4H，m)，3.27-3.36(1H，m)、3.37(2H，t，J＝8.4Hz)、3.86(3H，s)、5.19(1H，br-s)、6.36(1H，d，J＝8.0Hz)、6.58-6.62(1H，m)、6.95-7.08(4H，m)、7.78-7.83(2H，m).
FAB-Mass；416(MH+).
Example 491 Synthesis of- {1- [2- (4-pyridyl) ethyl ] piperidin-4-yl } indoline
1- (4-piperidyl) indoline (0.1g) was dissolved in ethanol (5ml), and 4-vinylpyridine (0.16ml) was added thereto, followed by heating and refluxing under nitrogen for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (toluene/acetone) to give the title compound (0.064g) as a colorless oil. (yield: 42.5%)
Free form
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.74-1.85(4H，m)、2.15(2H，dt，J＝2.8，12.0Hz)、2.64(2H，m)，2.82(2H，m)、2.95(2H，t，J＝8.4Hz)、3.10(2H，br-d)、3.39(2H，t，J＝8.4Hz)、3.40(1H，m)、6.41(1H，d，J＝8.0Hz)、6.61(1H，t，J＝8.0Hz)、7.04(1H，t，J＝8.0Hz)、7.05(1H，d，J＝8.0Hz)、7.14(2H，dd，J＝2.0，4.8Hz)、8.50(2H，dd，J＝2.0，4.8Hz).
Hydrochloric acid was added to form a salt, to obtain a hygroscopic amorphous form of the hydrochloride salt of the title compound.
FAB-Mass；308(MH+).
EXAMPLE 501 Synthesis of- {1- [2- (2-pyridyl) ethyl ] piperidin-4-yl } indoline
From 2-vinylpyridine (0.16ml), the title compound (0.041) was obtained as a colorless oil by the method of example 49. (yield: 27.2%)
Hydrochloric acid was added thereto to form a salt, and the salt was recrystallized from a mixed solvent of ethanol/isopropyl ether to obtain the hydrochloride of the title compound (0.036 g).
Melting point (hydrochloride salt): 258 ℃ and 260 DEG C
Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.89(2H，br-d)、2.16(2H，m)、2.93(2H，t，J＝8.0Hz)、3.20(2H，m)、3.38(2H，t，J＝8.0Hz)、3.61(6H，m)、3.83(1H，br-t)、6.66(2H，m)、7.05(1H，t，J＝8Hz)、7，08(1H，d，J＝8Hz)、7.89(1H，m)、8.00(1H，d，J＝7.6Hz)、8.47(1H，m)、8.82(1H，d，J＝5.2Hz).
FAB-Mass；308(MH+).
Example 511 Synthesis of- {1- [2- (3-pyridyl) ethyl ] piperidin-4-yl } indoline
From 3- (2-bromoethyl) pyridine (0.481g), the title compound (0.601g) was obtained as a pale yellow oil by the method of example 2. (yield: 75.5%)
To this was added oxalic acid to form a salt, which was recrystallized from ethanol to give the oxalate salt of the title compound. Melting point (oxalate): 174 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.92(4H，m)、2.87(2H，t，J＝8.4Hz)、3.04(4H，m)、3.10(2H，m)、3.31(2H，t，J＝8.4Hz)、3.61(2H，br-d)、3.72(1H，m)、6.53(1H，d，J＝7.6Hz)、6.56(1H，t，J＝7.6Hz)、7.00(1H，t，J＝7.6Hz)、7.03(1H，d，J＝7.6Hz)、7.39(1H，dd，J＝4.8，7.6Hz)，7.74(1H，ddd，J＝1.6，1.6，7.6Hz)、8.48(1H，dd，J＝1.6，4.8Hz)、8.53(1H，J＝1.6Hz).
ESI-Mass；308(MH+).
Example Synthesis of 521- {1- [2- (2-methoxy-5-pyridyl) ethyl ] piperidin-4-yl } indoline
From 1-bromo-2- (2-methoxypyridin-5-yl) ethane (1.221g), the title compound (1.394g) was obtained as a pale yellow oil by the method of example 2. (yield: 82.6%)
Oxalic acid (0.372g) was added thereto to form a salt, which was recrystallized from ethanol to give the oxalate salt of the title compound.
Melting point (oxalate): 173 ℃ C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.83-1.95(4H，br-d)、2.88(2H，t，J＝8.4Hz)、2.94(4H，m)、3.15(2H，m)、3.31(2H，t，J＝8.4Hz)、3.53(2H，br-d)、3.68(1H，m)、3.83(3H，s)、6.52(1H，d，J＝8.0Hz)、6.55(1H，t，J＝8.0Hz)、6.81(1H，d，J＝8.4Hz)、6.99(1H，t，J＝8.0Hz)、7.02(1H，d，J＝8.0Hz)、7.64(1H，dd，J＝2.4，8.4Hz)，8.08(1H，d，J＝2.4Hz).
FAB-Mass；338(MH+).
Example 531 Synthesis of- {1- [2- (3-methoxypyridin-5-yl) ethyl ] piperidin-4-yl } indoline
From 5- (2-bromoethyl) -3-methoxypyridine (0.181g), the title compound (0.104g) was obtained as a yellow oil by the method of example 2. (yield: 37.1%)
To this was added oxalic acid to form a salt, which was recrystallized from ethanol to give the oxalate salt of the title compound. Melting point (oxalate): 220 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.89(4H，m)、2.88(2H，t，J＝8.4Hz)，3.99(2H，m)、3.22(2H，m)、3.31(2H，t，J＝8.4Hz)、3.54(2H，br-d)、3.68(1H，m)、3.83(3H，s)、6.52(1H，d，J＝7.6Hz)、6.55(1H，t，J＝7.6Hz)、6.99(1H，t，J＝7.6Hz)、7.02(1H，d，J＝7.6Hz)、7.35(1H，t，J＝2.0Hz)、8.11(1H，t，J＝2.0Hz)、8.19(1H，t，J＝2.0H).
FAB-Mass；338(MH+).
Example Synthesis of 541- {1- [2- (2-cyanopyridin-5-yl) ethyl ] piperidin-4-yl } indoline
From 1-bromo-2- (2-cyanopyridin-5-yl) ethane (0.406g), the title compound (0.068g) was obtained as a pale yellow oil by the method of example 2. (yield: 9.7%)
Oxalic acid (18mg) was added thereto to form a salt, which was recrystallized from ethanol to obtain the oxalate salt of the title compound.
Melting point (oxalate): 136 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.82(4H，m)、2.81(2H，m)、2.87(2H，t，J＝8.2Hz)、3.07(2H，m)、3.14(2H，m)、3.31(2H，t，J＝8.2Hz)，3.44(2H，br-d)、3.63(1H，m)、6.51(1H，d，J＝7.6Hz)、6.54(1H，t，J＝7.6Hz)、6.99(1H，t，J＝7.6Hz)、7.01(1H，d，J＝7.6Hz)、8.01(2H，m)、8.71(1H，d，J＝1.6Hz).
FAB-Mass；333(MH+).
Example Synthesis of 551- {1- [2- (2-hydroxymethylpyridin-5-yl) ethyl ] piperidin-4-yl } indoline
1- {1- [2- (2-cyanopyridin-5-yl) ethyl ] piperidin-4-yl } indoline (0.103g) was dissolved in toluene (1.5ml), and a 1.5M diisopropylaluminum hydride/toluene solution (0.44ml) was added under nitrogen at-78 ℃ and stirred for 1 hour. The reaction mixture was added to 5% sulfuric acid water, made alkaline with sodium hydroxide aqueous solution, and diethyl ether was added to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.066g) as a yellow oil. (yield: 64.5%)
Free form
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.79(4H，m)、2.13(2H，dt，J＝2.8，8.0Hz)、2.60(2H，m)、2.80(2H，m)、2.97(2H，d，J＝8.4Hz)、3.10(2H，br-d)、3.39(2H，t，J＝8.4Hz)、3.40(1H，m)、3.95(2H，s)、6.41(1H，d，J＝7.6Hz)、6.60(1H，t，J＝7.6Hz)、7.04(1H，t，J＝7.6Hz)、7.05(1H，d，J＝7.6Hz)、7.21(1H，d，J＝8.0Hz)、7.50(1H，dd，J＝2.0，8.0Hz)、8.42(1H，d，J＝2.0Hz).
ESI-Mass；338.3(MH+).
Oxalic acid (18mg) was added thereto to form a salt, to obtain an oxalate salt of the title compound as a hygroscopic amorphous form.
Example Synthesis of 561- {1- [2- (3-hydroxymethylpyridin-5-yl) ethyl ] piperidin-4-yl } indoline
From 5- (2-bromoethyl) -3-tert-butyldimethylsilyloxymethylpyridine (0.248g), the title compound was obtained as a pale yellow oil (0.150g) by the method of example 24. (yield: 61.4%)
Oxalic acid (40mg) was added thereto to form a salt, which was recrystallized from ethanol to give the title compound, oxalate, as colorless crystals (0.143 g).
Melting point (oxalate): 177 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.89(4H，m)、2.88(2H，t，J＝8.4Hz)、3.01(2H，m)，3.22(2H，m)、3.32(2H，t，J＝8.4Hz)、3.57(2H，br-d)、3.69(1H，m)、4.53(2H，s)、6.53(1H，d，J＝7.6Hz)、6.56(1H，t，J＝7.6Hz)、6.99(1H，t，J＝7.6Hz)、7.02(1H，d，J＝7.6Hz)、7.66(1H，s)、8.39(1H，d，J＝1.8Hz)、8.41(1H，d，J＝1.8Hz).
FAB-Mass；338(MH+).
Example 571 Synthesis of- [1- (2, 6-difluoro-3-pyridylethyl) piperidin-4-yl ] indoline
According to the same manner as in example 2, from 1- (piperidin-4-yl) indoline (300mg) and 2, 6-difluoro-3-bromoethylpyridine (330mg), the title compound hydrochloride was obtained as white powdery crystals (270 mg). (yield: 47%)
Melting point (hydrochloride salt): 202 ℃ to 204 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.82-1.91(2H，m)、2.00-2.13(2H，m)、2.88(2H，t，J＝8Hz)、3.03-3.16(4H，m)、3.24-3.34(4H，m)、3.58-3.66(2H，m)、3.68-3.78(1H，m)、6.54-6.61(2H，m)、6.96-7.05(2H，m)、7.17-7.22(1H，m)、8.10-8.18(1H，m).
FAB-Mass；344(MH+).
Example 581 Synthesis of 1- {1- [2- (2-thienyl) ethyl ] piperidin-4-yl } indoline
From 1- (4-piperidyl) indoline (0.1g), the title compound was obtained as colorless crystals (0.057g) by the method of example 2. (yield: 37.2%)
Hydrochloric acid was added thereto to form a salt, and the salt was recrystallized from a mixed solvent of ethanol/isopropyl ether to obtain the hydrochloride of the title compound as colorless crystals.
Melting point (hydrochloride salt): 243 deg.C
Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.88(2H，br-d)、2.15(2H，m)、2.93(2H，t，J＝8.4Hz)、3.09(2H，m)、3.34(6H，m)、3.64(2H，br-d)、3.78(1H，tt，J＝3.6，12Hz)、6.66(2H，m)、7.00(2H，m)、7.06(2H，m)、7.42(1H，dd，J＝1.2，4.8Hz).
FAB-Mass；313(MH+).
Example 591 Synthesis of- {1- [2- (3-thienyl) ethyl ] piperidin-4-yl } indoline
From 2- (2-bromoethyl) thiophene (0.19g), the title compound (0.105g) was obtained as a colorless oil by the method of example 2. (yield: 68.6%)
Hydrochloric acid (15mg) was added thereto to form a salt, which was recrystallized from a mixed solvent of ethanol/isopropyl ether to give the hydrochloride of the title compound as colorless crystals.
Melting point (hydrochloride salt): 248 deg.C
Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.88(2H，br-d)、2.04(2H，m)、2.90(2H，t，J＝8.4Hz)、3.08(4H，m)、3.30(2H，m)、3.32(2H，t，J＝8.4Hz)、3.63(2H，br-d)、3.74(1H，m)、6.56(1H，d，J＝7.6Hz)，6.58(1H，t，J＝7.6Hz)、7.00(1H，t，J＝7.6Hz)、7.04(1H，d，J＝7.6Hz)、7.08(1H，dd，J＝1.2，4.8Hz)、7.34(1H，m)、7.55(1H，dd，J＝2.8，4.8Hz).
FAB-Mass；313(MH+).
EXAMPLE 601 Synthesis of- [1- (2-Thiazolylethyl) piperidin-4-yl ] indoline
From 2- (2-bromoethyl) thiazole (0.46g), according to the method of example 2, the title compound was obtained as colorless crystals (0.102 g). (yield: 14.4%)
Oxalic acid (15mg) was added thereto to form a salt, which was recrystallized from a mixed solvent of ethanol/acetone to give the title compound, oxalate, as colorless crystals.
Melting point (oxalate): 149 deg.C
Oxalate
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.85(2H，m)、2.86(2H，m)、2.87(2H，t，J＝8.4Hz)、3.30(2H，m)、3.31(2H，t，J＝8.4Hz)、3.40(4H，m)、3.47(2H，br-d)、3.63(1H，m)、6.50(1H，d，J＝7.6Hz)、6.55(1H，t，J＝7.6Hz)，6.99(1H，t，J＝7.6Hz)、7.02(1H，d，J＝7.6Hz)、7.65(1H，d，J＝3.6Hz)、7.75(1H，d，J＝3.6Hz).
FAB-Mass；314(MH+).
Example 611- [1- (4-methyl-5-thiazolylethyl) piperidin-4-yl ] indoline Synthesis
According to the same manner as in example 2, from 1- (piperidin-4-yl) indoline (300mg) and 4-methyl-5-thiazole bromoethane (310mg) obtained in the same manner as in production example 1, the hydrochloride of the title compound was obtained as gray powder crystals (140 mg). (yield: 26%)
Melting point (hydrochloride salt): 222 ℃ C. -, -225 ℃ C. -)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.82-1.89(2H，m)、1.95-2.10(2H，m)、2.37(3H，s)、2.87(2H，t，J＝8Hz)、3.01-3.12(2H，m)、3.15-3.33(6H，m)、3.60-3.76(3H，m)、6.51-6.60(2H，m)、6.95-7.03(2H，m)、8.93(1H，s).
FAB-Mass；328(MH+).
Example 621 Synthesis of- {1- [ (indol-3-yl) ethyl ] piperidin-4-yl } indoline
According to the same manner as in example 2, from 1- (piperidin-4-yl) indoline (300mg) and 3- (2-bromoethyl) indole (340mg) obtained in the same manner as in production example 1, the title compound hydrochloride was obtained as brown powder crystals (410 mg). (yield: 72%)
Melting point (hydrochloride salt): 240 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.82-1.91(2H，m)、1.93-2.08(2H，m)、2.89(2H，t，J＝8Hz)、3.07-3.20(4H，m)、3.27-3.36(4H，m)、3.65-3.76(3H，m)、6.51-6.58(2H，m)、6.96-7.04(3H，m)、7.06-7.11(1H，m)、7.24(1H，s)、7.35(1H，d，J＝8Hz)、7.61(1H，d，J＝8Hz).
FAB-Mass；346(MH+).
Example 631 Synthesis of- {1- [2- (6-benzothiazolyl) ethyl ] piperidin-4-yl } indoline
From 6- (2-bromoethyl) benzothiazole (0.073g), the procedure of example 2 was followed to give the title compound (0.084g) as a pale yellow oil. (yield; 70.0%)
Oxalic acid (21mg) was added thereto to form a salt, which was recrystallized from ethanol to obtain the oxalate salt of the title compound.
Melting point (oxalate): 197 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.87(4H，m)、2.88(2H，t，J＝8.4Hz)、2.95(2H，m)、3.13(2H，m)，3.25(2H，m)、3.32(2H，t，J＝8.4Hz)、3.56(2H，m)、3.68(1H，m)、6.52(1H，d，J＝8.0Hz)、6.55(1H，t，J＝8.0Hz)、6.99(1H，t，J＝8.0Hz)、7.02(1H，d，J＝8.0Hz)、7.48(1H，dd，J＝1.6，8.4Hz)、8.06(1H，d，J＝8.4Hz)、8.09(1H，d，J＝1.6Hz)、9.37(1H，s).
FAB-Mass；364(MH+).
Example 641- [1- (5-methoxy-2-thienyl) ethylpiperidin-4-yl ] indoline synthesis
According to the same manner as in example 2, from 1- (piperidin-4-yl) indoline (300mg) and (5-methoxy-2-thienyl) ethyl bromide (400mg), the title compound hydrochloride was obtained as gray powder crystals (260 mg). (yield: 46%)
Melting point (hydrochloride salt): 204 ℃ (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.80-1.89(2H，m)、2.00-2.11(2H，m)、2.90(2H，t，J＝8Hz)、3.00-3.28(6H，m)、3.32(2H，t，J＝8Hz)、3.55-3.62(2H，m)、3.67-3.78(1H，m)、3.80(3H，s)、6.13(1H，d，J＝4Hz)、6.56-6.60(3H，m)、6.97-7.04(2H，m)、10.79(1H，br-s).
FAB-Mass；343(MH+).
Example Synthesis of 651- [1- (2-methoxy-5-thiazolyl) ethylpiperidin-4-yl ] indoline
According to the same manner as in example 2, from 1- (piperidin-4-yl) indoline (300mg) and (2-methoxy-5-thiazolyl) ethyl bromide (380mg), the title compound hydrochloride was obtained as white powder crystals (340 mg). (yield: 60%)
Melting point (hydrochloride salt): 207 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.80-1.86(2H，m)、1.92-2.03(2H，m)、2.89(2H，t，J＝8Hz)、3.00-3.12(2H，m)、3.15-3.32(6H，m)、3.67-3.75(3H，m)、3.95(3H，s)、6.50-6.59(2H，m)、6.94-7.07(3H，m)、10.36(1H，br-s).
FAB-Mass；344(MH+).
EXAMPLE 661- [1- (2-cyano-5-thiazolyl) ethylpiperidin-4-yl ] indoline synthesis
According to the same manner as in example 2, from 1- (piperidin-4-yl) indoline (190mg) and (2-cyano-5-thiazolyl) ethyl bromide (200mg), the title compound hydrochloride was obtained as gray powder crystals (21 mg). (yield: 6.1%)
Melting point (hydrochloride salt): 209 ℃ C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.81-2.00(4H，m)、2.89(2H，t，J＝8Hz)、3.01-3.15(2H，m)、3.30(2H，t，J＝8Hz)、3.36-3.78(7H，m)、6.49-6.55(2H，m)、6.92-7.03(2H，m)、8.02(1H，s).
FAB-Mass；339(MH+).
Example 671 Synthesis of- (1-pyrazinylethylpiperidin-4-yl) indoline
A solution of 1- (piperidin-4-yl) indoline (500mg) and vinyl pyrazine (260mg) in o-dichlorobenzene (5ml) was heated at 180 ℃ under reflux for 3 hours. The reaction mixture was purified by silica gel column chromatography (dichloromethane/ethanol) and converted to the oxalate salt according to a conventional method to obtain the title compound as crystals of oxalate powder (90mg) as a white powder. (yield: 9.0%)
Melting point (oxalate): 168 ℃ C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.75-1.83(4H，m)、2.80-2.91(4H，m)、3.11-3.20(2H，m)、3.21-3.33(4H，m)、3.41-3.52(2H，m)、3.55-3.69(1H，m)、6.48(1H，d，J＝8Hz)、6.53(1H，t，J＝8Hz)、6.95-7.00(2H，m)、8.53(1H，s)、8.57-8.59(1H，m)、8.63(1H，s).
FAB-Mass；309(MH+).
Example 681 Synthesis of- {1- [2- (4-bromopyrazol-1-yl) ethyl ] piperidin-4-yl } indoline
According to the same manner as in example 2, from 1- (4-piperidinyl) indoline (162mg) and 1- (2-bromoethyl) -4-bromopyrazole (200mg), the title compound hydrochloride was obtained as beige crystals (372 mg). (yield: 67%)
Melting point (hydrochloride salt): 210 ℃ and 212 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.83(2H，d，J＝11.6Hz)、2.00-2.12(2H，m)、2.88(2H，t，J＝8.4Hz)、3.07(2H，q，J＝11.2Hz)、3.31(2H，t，J＝8.4Hz)、3.46-3.54(4H，m)、3.66-3.76(1H，m)、4.63(2H，t，J＝6.8Hz)、6.56-6.64(2H，m)、6.97-7.06(2H，m)、7.64(1H，s)、8.11(1H，s)、11.10(1H，br-s).
ESI-Mass；351(MH+).
Example 691 Synthesis of- {1- [3- (4-fluorophenoxy) propyl ] piperidin-4-yl } indoline
According to the same manner as in example 2, from 1- (piperidin-4-yl) indoline (300mg) and 1-bromo-3- (4-fluorophenoxy) propane (420mg), the hydrochloride of the title compound was obtained as white needle crystals (330 mg). (yield: 56%)
Melting point (hydrochloride salt): 207 ℃ C. & lt 210 ℃ C. & gt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.80-1.87(2H，m)、1.91-2.20(4H，m)、2.88(2H，t，J＝8Hz)、3.00-3.11(2H，m)、3.13-3.21(2H，m)、3.30(2H，t，J＝8Hz)、3.52-3.61(2H，m)、3.66-3.77(1H，m)、4.04(2H，t，J＝6Hz)、6.49-6.70(2H，m)、6.92-7.03(4H，m)、7.08-7.15(2H，m).
FAB-Mass；355(MH+).
Example 701 Synthesis of- {1- [3- (4-hydroxymethylphenoxy) propyl ] piperidin-4-yl } indoline
The title compound hydrochloride was obtained as a pale yellow-orange amorphous form (422mg) from 1- (piperidin-4-yl) indoline (263mg) and 4- (3-bromo-propoxy) benzyl alcohol (389mg) in the same manner as in example 2. (yield: 92%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.20-2.35(4H，m)、2.47-2.73(4H，m)、2.55(2H，t，J＝7.4Hz)、2.94(2H，t，J＝8.4Hz)、3.07(2H，d，J＝11.2Hz)、3.35-3.43(1H，m)、3.38(2H，t，J＝8.4Hz)、4.02(2H，t，J＝6.4Hz)、4.62(2H，s)、6.41(1H，d，J＝8Hz)、6.60(1H，dt，J＝7.4Hz，0.8Hz)、6.89(2H，d，J＝8.8Hz)、7.04(1H，ddd，J＝8Hz.7.4Hz，0.8Hz)、7.05(1H，d，J＝7.4Hz)、7.29(2H，d，J＝8.8Hz).
ESI-Mass；367(MH+).
Example 711 Synthesis of- {1- [3- (4-Hydroxyethylphenoxy) propyl ] piperidin-4-yl } indoline
The title compound hydrochloride was obtained as an off-white amorphous form (500mg) from 1- (4-piperidinyl) indoline (303mg) and 4- (3-bromo-propoxy) phenethyl alcohol (389mg) in the same manner as in example 2. (yield: 80%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.84(2H，d，J＝13.2Hz)、2.40-2.22(4H，m)、2.63(2 H，t，J＝7.2Hz)、2.90(2H，t，J＝8.4Hz)、3.05(2H，q，J＝10.4Hz)、3.12-3.19(2H，m)、3.33(2H，t，J＝8.4Hz)、3.52(2H，t，J＝7.2Hz)、3.52-3.60(2H，m)、3.70-3.80(1H，m)、4.01(2H，t，J＝6Hz)、6.58-6.68(2H，br-t)、6.83(2H，d，J＝8.8Hz)、7.01(1H，d，J＝8Hz)、7.05(1H，d，J＝8Hz)、7.11(2H，d，J＝8.8Hz)、10.80(1H，br-s).
ESI-Mass；381(MH+).
Example Synthesis of 721- {1- [4- (4-fluorophenyl) -4-oxybutyl ] piperidin-4-yl } indoline
The title compound (0.5g) was obtained from 1- (piperidin-4-yl) indoline (1.0g) and 4-chloro-1- (4-fluorophenyl) -1-butanone (1.1g) by the same method as in example 2. (yield: 27%)
Hydrochloric acid was added thereto to form a salt, to obtain the title compound hydrochloride as white powdery crystals.
Melting point (hydrochloride salt): 213 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.80-1.88(2H，m)、1.94-2.10(4H，m)、2.88(2H，t，J＝8Hz)、3.00-3.10(4H，m)、3.19(2H，t，J＝8Hz)、3.30(2H，t，J＝8Hz)、3.50-3.60(2H，m)、3.67-3.78(1H，m)、6.52-6.58(2H，m)、6.96-7.03(2H，m)、7.34-7.39(2H，m)、8.03-8.07(2H，m).
FAB-Mass；367(MH+).
Example 731- {1- [4- (4-fluorophenyl) -4-hydroxybutyl ] piperidin-4-yl } indoline
To a solution of 1- {1- [4- (4-fluorophenyl) -4-oxybutyl ] piperidin-4-yl } indoline (320mg) in ethanol (20ml) was added sodium borohydride (38mg), and the mixture was stirred for 5 hours. Concentrated under reduced pressure, water and ethyl acetate were added, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, purified by silica gel column chromatography (hexane/ethyl acetate) and converted to a hydrochloride salt according to a conventional method to give the title compound as crystals (250mg) as a gray powder. (yield 71%)
Melting point (hydrochloride salt): 174- & ltSUB & gt 175- & lt/SUB & gt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.55-2.00(6H，m)、2.87(2H，t，J＝8Hz)、2.95-3.05(4H，m)、3.28(2H，t，J＝8Hz)、3.46-3.54(2H，m)、3.62-3.71(1H，m)、4.57(1H，t，J＝6Hz)、6.49-6.56(2H，m)、6.95-7.02(2H，m)、7.11-7.16(2H，m)、7.34-7.38(2H，m)、9.71(1H，br-s).
FAB-Mass；369(MH+).
EXAMPLE synthesis of 741- [1- (phthalimid-1-yl) ethylpiperidin-4-yl ] indoline
The title compound (520mg) was obtained as a colorless oil by the same procedures as in example 2 starting from 1- (piperidin-4-yl) indoline (500mg) and N- (2-bromoethyl) phthalimide (750 mg). (yield: 55%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.59-1.81(4H，m)，2.09-2.20(2H，m)，2.68(2H，t，J＝7Hz)、2.90(2H，t，J＝8Hz)、3.08-3.15(2H，m)，3.30-3.41(1H，m)、3.32(2H，t，J＝8Hz)、3.83(2H，t，J＝7Hz)、6.38(1H，d，J＝8Hz)、6.59(1H，t，J＝8Hz)、7.00-7.08(2H，m)，7.68-7.73(2H，m)、7.80-7.87(2H，m).
Example 751- [1- (4-Fluorobenzoylamino) ethylpiperidin-4-yl ] indoline synthesis
A solution of 1- [1- (phthalimid-1-yl) ethylpiperidin-4-yl ] indoline (520mg) and hydrazine (100mg) in ethanol (20ml) was heated under reflux for 5 hours. The mixture was cooled to room temperature, and precipitated crystals were filtered off. To the residue were added methylene chloride (30ml), a 2N aqueous solution (5ml) of sodium hydroxide and 4-fluorobenzoyl chloride (250mg), and the mixture was stirred vigorously at room temperature. After 1 hour, the reaction mixture was diluted with dichloromethane, the organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane/ethanol) to convert the resulting product into the hydrochloride salt, to obtain white powdery crystals of the hydrochloride salt of the title compound (160 mg). (yield: 28%)
Melting point (hydrochloride salt): 221 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.81-2.02(4H，m)、2.88(2H，t，J＝8Hz)、3.02-3.15(2H，m)、3.20-3.31(4H，m)、3.60-3.75(5H，m)、6.49-6.56(2H，m)、6.95-7.02(2H，m)、7.29-7.34(2H，m)、7.94-7.99(2H，m)、8.86(1H，t，J＝6Hz).
FAB-Mass；368(MH+).
Example 761 Synthesis of- {1- [1- (3, 4-dimethoxyphenyl) propan-2-yl ] piperidin-4-yl } indoline
A mixture of 1- (piperidin-4-yl) indoline (300mg), 3, 4-dimethoxypropiophenone (870mg), sodium cyanoborohydride (280mg) and molecular sieve (1.0g) in methanol (20ml) was stirred at room temperature for 3 days. The reaction solution was filtered, concentrated under reduced pressure, added with water and ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, purified by silica gel column chromatography (dichloromethane/ethanol) and converted to a hydrochloride salt according to a conventional method to obtain the title compound as a gray powder crystal (220 mg). (yield 35%)
Melting point (hydrochloride salt): 245 ℃ (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.00(3H，d，J＝7Hz)、1.82-1.91(2H，m)、2.01-2.13(2H，m)、2.55-2.63(1H，m)、2.88(2H，t，J＝8Hz)、3.17-3.28(4H，m)、3.43-3.61(4H，m)、3.71(3H，s)、3.74(3H，s)、3.76-3.83(1H，m)、6.52-6.56(2H，m)、6.75-6.78(1H，m)、6.87-6.90(2H，m)、6.98-7.03(2H，m)、9.90(1H，br-s).
FAB-Mass；381(MH+).
Example 771- {1- [ (1, 4-Benzodioxane-2-yl) methyl ] piperidin-4-yl } indoline Synthesis
According to the same manner as in example 2, from 1- (4-piperidinyl) indoline (303mg) and 2-bromomethyl-1, 4-benzodioxole (344mg), the title compound hydrochloride was obtained as beige crystals (372 mg). (yield: 67%)
Melting point (hydrochloride salt): 200 ℃ C. (205 ℃ C.)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.88(2H，d，J＝12.4Hz)、2.10-2.25(2H，m)、2.92(2H，t，J＝8.4Hz)、3.13-3.58(7H，m)、3.72-3.82(2H，m)、4.05(1H，dd，J＝11.4Hz，6.8Hz)、4.34(1H，dd，J＝11.4Hz，2Hz)、4.90-4.95(1H，m)，6.67(1H，d，J＝6.8Hz)、6.68(1H，dd.J＝6.8Hz，6.6Hz)、6.84-6.96(4H，m)、7.04(1H，dd，J＝9Hz，7.6Hz)、7.08(1H，d，J＝7.6Hz)、11.40(1H，br-s).
ESI-Mass；351(MH+).
Example Synthesis of 781- {1- [3- (3, 4-methylenedioxyphenoxy) propyl ] piperidin-4-yl } indoline
According to the same manner as in example 2, from 1- (4-piperidinyl) indoline (303mg) and 3-bromopropoxy-1, 2-methylenedioxybenzene (389mg), pale blue crystals (443mg) of the hydrochloride salt of the title compound were obtained. (yield: 73%)
Melting point (hydrochloride salt): 210 ℃ and 212 DEG C
1H-NMR(400MHz、DMSO-d6)；δ(ppm)
1.84(2H，d，J＝11.6Hz)、1.98-2.18(4H，m)，2.88(2H，t，J＝8.4Hz)，3.05(2H，q，J＝11.6Hz)、3.11-3.20(2H，m)、3.30(2H，t，J＝8.4Hz)、3.57(2H，d，J＝11.6Hz)、3.72(1H，m)、3.97(2H，t，J＝6Hz)、5.94(2H，s)、6.37(1H，dd，J＝8.4Hz，2.8Hz)、6.54(1H，d，J＝7.6Hz)、6.57(1H，t，J＝7.6Hz)、6.63(1H，d，J＝2.8Hz)、6.80(1H，d，J＝8.4Hz)、6.99(1H，t，J＝7.6Hz)、7.02(1H，d，J＝7.6Hz)、10.45(1H，br-s).
ESI-Mass；381(MH+).
EXAMPLE 79 Synthesis of cis-1- [1- (4-fluorophenethyl) -3-methylpiperidin-4-yl ] indoline
The title compound (100mg) was obtained as a yellow oil by the same procedures as in example 101, from indoline (238mg) and 1- [2- (4-fluorophenyl) ethyl ] -3-methyl-4-piperidone (588mg) obtained in production examples 40 to 5 and sodium triacetoxyborohydride (1.19 g). (yield: 15%) melting point (oxalate salt): 229 ℃ 230 DEG C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.09(3H，d，J＝6.5Hz)、1.69(1H，m)、2.10(2H，m)、2.26(1H，br-d)、2.30(1H，m)、2.47(1H，m)、2.56(1H，m)、2.74(2H，m)、2.81(1H，br-d)、2.98(3H，m)、3.42(1H，m)、3.56(1H，q，J＝9.0Hz)、3.64(1H，m)、6.31(1H，br-d)、6.54(1H，br-t)、6.96(2H，br-d)、7.03(2H，m)、7.17(2H，m).
FAB-Mass；339(MH+).
EXAMPLE 80 Synthesis of 11-benzyl-3-hydroxymethyl-4-piperidone
(80-1-1) 1-benzyl-4, 4-ethylenedioxy-3-piperidinecarboxylic acid ethyl ester
To a toluene solution (600ml) of ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate hydrochloride (CAS registry No. 1454-53-1, 44.7g) and ethylene glycol (100ml) was added p-toluenesulfonic acid monohydrate (1.5g), and the mixture was heated under reflux overnight. After cooling to room temperature, ice water (500ml) and a saturated aqueous sodium hydrogencarbonate solution (300ml) were added to the solution, and the mixture was extracted 3 times with ethyl acetate (400 ml). The organic phase was washed 2 times with water (200ml), then with saturated brine (300ml), and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (30.4 g). (yield 66%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.22(3H，t，J＝6.0Hz)、1.74(1H，m)、1.98(1H，m)、2.48(1H，m)、2.68(2H，m)、2.82(2H，m)，3.49(1H，d，J＝11.0Hz)、3.57(1H，d，J＝11.0Hz)、3.89(1H，d，J＝7.0Hz)、3.96(3H，m)、4.13(2H，q，J＝6.0Hz)、7.22-7.32(5H，m).
(80-1-2) 1-benzyl-4, 4-ethylenedioxy-3-piperidinemethanol
Lithium aluminum hydride (702mg) was carefully added to ice-cooled anhydrous tetrahydrofuran (100ml) under a nitrogen stream. To this was slowly added dropwise a solution of ethyl 1-benzyl-4, 4-ethylenedioxy-3-piperidinecarboxylate (4.58g) obtained in the above-item in tetrahydrofuran (30 ml). The mixture was slowly warmed to room temperature and stirred overnight. To the reaction mixture, water (0.7ml), a 5N aqueous solution (2.1ml) of sodium hydroxide, water (2.1ml), and anhydrous sodium sulfate were carefully added in this order under ice cooling. After filtration through celite, the title compound was obtained as a colorless oil (4.03 g).
(yield: 100%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.67(1H，m)、1.92(1H，m)、2.01(1H，m)、2.43-2.66(3H，m)、2.70(1H，br-d)、3.49(2H，s)、3.77(1H，d，J＝11.0Hz)、3.83(1H，d，J＝11.0Hz)、3.96(4H，br-s)、7.23-7.33(5H，m).
(80-1-3) 1-benzyl-3-hydroxymethylpiperidone
Under ice-cooling, 1-benzyl-4, 4-ethylenedioxy-3-piperidinemethanol (960mg) was dissolved in a mixed solvent of water and concentrated sulfuric acid (10ml/6ml), and the mixture was slowly warmed to room temperature and stirred for 1 day. The reaction mixture was cooled with ice while adjusting the pH to about 8 with a 5N aqueous solution of sodium hydroxide. The extract was extracted 2 times with chloroform (50ml), which was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (710mg) as a colorless oil. (yield: 89%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.47(2H，m)、2.60(2H，m)、2.70(1H，m)、3.01(2H，m)、3.62(2H，s)、3.71(1H，dd，J＝7.5Hz，13.5Hz)、3.76(1H，br-d)、7.25-7.37(5H，m).
EXAMPLE 80 Synthesis of cis-1- (1-benzyl-3-hydroxymethylpiperidin-4-yl) indoline
The title compound (140mg) was obtained as a yellow powder from indoline (300mg), 1-benzyl-3-hydroxymethyl-4-piperidone (548mg) and sodium triacetoxyborohydride (1.91g) by the same procedure as in example 1. (yield: 22%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.79(1H，br-d)、2.08(1H，br-s)、2.14(1H，dt，J＝2.8Hz，12.0Hz)，2.49(1H，br-d)、2.54(1H，dt，J＝4.5Hz，12.0Hz)、3.02(3H，m)、3.14(1H，br-d)、3.49(1H，d，J＝12.0Hz)、3.55(1H，d，J＝12.0Hz)、3.56(1H，t，J＝12.5Hz)、3.64(1H，q，J＝9.0Hz)、3.82(2H，m)、3.97(1H，br-d)、6.28(1H，d，J＝7.5Hz)、6.56(1H，t，J＝7.5Hz)、7.00(1H，t，J＝7.5Hz)、7.04(1H，d，J＝7.5Hz)、7.27-7.37(5H，m).
Example 81 Synthesis of cis-1- (3-acetoxymethylpiperidin-4-yl) indoline
(81-1-1) cis-1- (1-benzyl-3-acetoxymethylpiperidin-4-yl) indoline
Triethylamine (111mg) and acetyl chloride (86mg) were added to a solution of cis-1- (1-benzyl-3-hydroxymethylpiperidin-4-yl) indoline (322mg) in tetrahydrofuran (3ml) under ice-cooling. The reaction mixture was stirred for 30 minutes under ice-cooling, then stirred at room temperature for 1 hour, ethyl acetate (15ml) was added, and filtered through celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (340mg) as a yellow oil. (yield 93%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.76(1H，br-d)、1.83(3H，s)、1.99-2.20(3H，m)、2.44(1H，m)、2.92-3.03(4H，m)、3.40(1H，d，J＝13.0Hz)、3.48-3.56(3H，m)、3.58(1H，d，J＝13.0Hz)、4.13(1H，dd，J＝4.2Hz，10.0Hz)、4.63(1H，t，J＝10.0Hz)，6.31(1H，d，J＝7.5Hz)、6.57(1H，t，J＝7.5Hz)、7.02(2H，m)、7.21-7.31(5H，m).
(81-1-2) cis-1- (3-acetoxymethylpiperidin-4-yl) indoline
To a solution of cis-1- (1-benzyl-3-acetoxymethylpiperidin-4-yl) indoline (340mg) in dichloroethane (5ml) was added a solution of chloroformic acid (1-chloroethyl ester) (135mg) in dichloroethane (1ml) under ice-cooling. Stirred for 30 minutes and then heated to reflux for 1 hour. After the reaction mixture was cooled, it was concentrated under reduced pressure, methanol (10ml) was added, and the mixture was stirred at 50 ℃ for 10 minutes, then heated under stirring and refluxed for 30 minutes, and then cooled to room temperature. Concentrated under reduced pressure, and then a saturated aqueous sodium hydrogencarbonate solution (10ml) was added thereto, followed by extraction with chloroform (15ml) for 3 times. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (290mg) as a yellow powder. (yield: 100%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.94(1H，dd，J＝4.5Hz，13.0Hz)、1.99(3H，s)，2.45(1H，m)、2.79(1H，dt，J＝3.0Hz，12.0Hz)、2.87(1H，dd，J＝3.0Hz，12.5Hz)、2.97(3H，m)、3.19(1H，br-d)、3.26(1H，br-d，J＝13.5Hz)、3.55(2H，t，J＝9.0Hz)，3.64(1H，td，J＝5.0Hz，12.5Hz)、4.20(1H，dd，J＝4.5Hz，11.5Hz)、4.56(1H，t，J＝10.5Hz)、6.34(1H，d，J＝7.5Hz)、6.58(1H，t，J＝7.5Hz)、7.03(2H，m).
EXAMPLE 81 Synthesis of 2-cis-1- [1- (4-fluorophenethyl) -3-hydroxymethylpiperidin-4-yl ] indoline
81-2-1 cis-1- [1- (4-fluorophenethyl) -3-acetoxymethylpiperidin-4-yl ] indoline
Cis-1- (3-acetoxymethylpiperidin-4-yl) indoline (280mg) was dissolved in dimethylformamide (4ml) and methanol (1ml), followed by addition of triethylamine (222mg) and 4-fluorophenylethyl bromide (285mg), and the mixture was stirred at 50 ℃ for 2 hours. After the reaction mixture was cooled, water (50ml) was added, ether (50ml) was extracted 2 times, the organic phase was washed with water (20ml) 2 times, 2N aqueous sodium hydroxide solution (50ml) 1 time, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (100mg) as a colorless oil. (yield: 28%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.77(1H，br-d)、1.93(3H，s)、1.98(1H，dd，J＝4.0Hz，12.0Hz)、2.12-2.21(2H，m)、2.42-2.63(4H，m)、2.73(2H，m)、2.98(2H，m)、3.06(1H，br-d)、3.46-3.58(3H，m)、4.20(1H，dd，J＝3.5Hz，10.0Hz)、4.46(1H，t，J＝9.5Hz)、6.33(1H，d，J＝7.5Hz)、6.58(1H，t，J＝7.5Hz)、6.96(2H，br-t)、7.04(2H，br-d)、7.15(2H，m).
81-2-2 cis-1- [1- (4-fluorophenethyl) -3-hydroxymethylpiperidin-4-yl ] indoline
Cis-1- [1- (4-fluorophenethyl) -3-acetoxymethylpiperidin-4-yl ] indoline (100mg) obtained in the above was dissolved in methanol (6ml), and potassium carbonate (130mg) was added to stir at room temperature for 4 hours. Diethyl ether (20ml) was added thereto, the mixture was filtered through celite, the filtrate was concentrated under reduced pressure, the residue was filtered again through ethyl acetate, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (40mg) as a pale yellow powder. (yield: 45%)
Melting point (oxalate): 173 ℃ and 174 DEG C
1H-NMR(400MHz，CDCl3)；
1.82(1H，br-d)，2.08(1H，br-s)、2.18(1H，t，J＝11.0Hz)、2.50(2H，m)、2.59(2H，t，J＝7.5Hz)、2.80(2H，br-t)、3.01(2H，m)、3.16(2H，m)、3.57(1H，m)、3.64(1H，q，J＝9.0Hz)、3.82(2H，m)、3.94(1H，d，J＝10.5Hz)、6.27(1H，d，J＝7.5Hz)、6.55(1H，t，J＝7.5Hz)、6.96-7.06(4H，m)、7.14(2H，m).
FAB-Mass；355(MH+).
EXAMPLE 82 Synthesis of trans-1- [1- (4-fluorophenethyl) -3-hydroxymethylpiperidin-4-yl ] indoline
82-1 trans-1- (1-acetyl-3-hydroxymethylpiperidin-4-yl) indoline
To a solution of trans-1- (1-acetyl-3-ethoxycarbonylpiperidin-4-yl) indoline (780mg) in ethanol (40ml) was added sodium borohydride (5.7g) in 3 portions every 30 minutes, and the mixture was stirred at room temperature overnight. Sodium borohydride (3.3g) was added and stirred for an additional 4 hours. Ethyl acetate (20ml) and water (50ml) were carefully added to the reaction mixture, which was extracted 3 times with ethyl acetate (50 ml). The organic layer was washed with water (100ml) 2 times, saturated brine (100ml) 1 time, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (250mg) as a yellow powder. (yield 39%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.60(1H，m)、1.72(1H，m)、1.97(1H，m)、2.11(3H of ltautomer，s)、2.14(3H of ltautomer，s)、2.51(2H，m)、2.92-3.15(3H，m)、3.28(1H，m)、3.38-3.81(4H，m)、3.89(1H of ltautomer，br-d)、3.99(1H of ltautomer，br-d)，4.75(1H，br-d)、6.50(1H，m)、6.67(1H，m)、7.05(2H，m).
82-2 trans-1- (3-hydroxymethylpiperidin-4-yl) indoline
To a mixed solution of trans-1- (1-acetyl-3-hydroxymethylpiperidin-4-yl) indoline (250mg) in ethanol (10ml) and water (0.5ml) was added sodium hydroxide (220mg), and the mixture was refluxed for 20 hours. After cooling, water (50ml) was added and chloroform (30ml) was extracted 3 times. The organic phase was washed with water (50ml) and saturated brine (50ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (190mg) as a colorless oil. (yield: 85%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.56-1.69(2H，m)、1.95-2.07(1H，m)、2.46(1H，t，J＝11.5Hz)，2.64(1H，dt，J＝2.5Hz，11.5Hz)、2.95(2H，m)、3.17(2H，m)、3.34(1H，br-q)、3.42(1H，dt，J＝4.5Hz，10.5Hz)、3.50(1H，dt，J＝5.0Hz，8.5Hz)、3.61(1H，dd，J＝5.0Hz，11.0Hz)、3.67(1H，dd，J＝5.0Hz，11.0Hz)、6.53(1H，d，J＝7.5Hz)、6.66(1H，t，J＝7.5Hz)、7.06(2H，m).
82-3 trans-1- [1- (4-fluorophenethyl) -3-hydroxymethylpiperidin-4-yl ] indoline
Trans-1- (3-hydroxymethylpiperidin-4-yl) indoline (190mg), triethylamine (152mg) and 4-fluorophenethyl bromide (406mg) were reacted by the same way with example 2 to give the title compound (210mg) as a brown oil. (yield 72%)
Melting point (oxalate): 113 ℃ and 116 DEG C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.69(1H，m)、1.79(1H，m)、1.92(1H，t，J＝11.0Hz)、2.07(1H，br-t)、2.17(1H，m)、2.58(2H、br-t)、2.79(2H，br-t)、2.95(2H，m)、3.06(1H，br-d)、3.13(1H，br-d)、3.35(2H，m)、3.49(1H，m)、3.64(1H，dd，J＝4.5Hz，11.0Hz)、3.71(1H，dd，J＝6.0Hz，11.0Hz)、6.52(1H，d，J＝7.5Hz)、6.67(1H，t，J＝7.5Hz)、6.97(2H，t，J＝8.0Hz)、7.07(2H，br-t)、7.15(2H，m).
FAB-Mass；355(MH+).
EXAMPLE 831 Synthesis of- [2- (4-Acetylaminomethyl-phenyl) ethyl ] -4- (indan-1-yl) piperidine-1-oxide
1- [1- (4-Acylaminomethylphenethyl) piperidin-4-yl ] indoline (0.50g) obtained in example 36 was dissolved in methylene chloride (20ml), and m-chloroperbenzoic acid (0.37g) was added at 0 ℃ at 70 ℃. The reaction mixture was stirred at room temperature for 30 minutes, and sodium carbonate (5.0g) was added thereto. The reaction mixture was filtered through alumina, washed with dichloromethane/methanol (10: 1), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (0.15g) as a white powder. (yield: 28.8%)
Melting point: 130 ℃ and 131 DEG C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.77(2H，br-d)、2.03(3H，s)、2.50-2.73(5H，m)、2.97(2H，t，J＝8.0Hz)、3.16-3.26(3H，m)、3.36-3.60(5H，m)、4.40(2H，d，J＝9.6Hz)、6.32(1H，m)、6.41(1H，d，J＝8.0Hz)、6.65(1H，t，J＝7.6Hz)、7.04(1H，t.J＝7.6Hz)、7.08(1H，d，J＝7.2Hz)、7.19(2H，d，J＝8.0Hz)、7.23(2H，d，J＝8.0Hz).
FAB-Mass；394(MH+).
EXAMPLE 84 Synthesis of cis-1- [ 1-ethyl-3- (4-fluorophenoxymethyl) piperidin-4-yl ] indoline
4-fluorophenol (168mg) and triphenylphosphine (420mg) were added to a solution of cis-1- [ 1-ethyl-3-hydroxymethylpiperidin-4-yl ] indoline (300mg) in tetrahydrofuran (4ml) under a nitrogen stream. After cooling to-10 ℃, diethyl azodicarboxylate (278mg) was slowly dropped. The temperature was slowly raised to room temperature and stirred at room temperature overnight. Water (40ml) was added to the reaction mixture, and extraction was carried out 3 times with diethyl ether (40ml), and the organic phase was washed successively with a saturated aqueous sodium bicarbonate solution (40ml) and a 1N aqueous sodium hydroxide solution (40ml), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Fuji Silicia NH-DM2035 hexane/ethyl acetate). The title compound (100mg) was obtained as a colorless oil. (yield 25%)
Melting point (oxalate); 97-98 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.04(3H，t，J＝7.0Hz)、1.82(1H，m)、2.00(1H，dq，J＝3.5Hz，11.5Hz)、2.11(2H，m)、2.35(1H，m)、2.44(1H，m)、2.62(1H，m)、2.98(3H，m)、3.17(1H，br-d，J＝10.5Hz)、3.54(3H，m)、4.10(1H，dd，J＝3.5Hz，8.0Hz)、4.34(1H，t，J＝8.5Hz)、6.38(1H，d，J＝7.5Hz)、6.59(1H，t，＝7.5Hz)、6.77(2H，m)、6.88(2H，br-t)、7.01-7.06(2H，m).
FAB-Mass；355(MH+).
Example Synthesis of ethyl 85-11-acetyl-4-oxo-3-piperidinecarboxylate
(85-1-1) 4-oxo-3-piperidinecarboxylic acid ethyl ester hydrochloride
To a solution of ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate hydrochloride (30g) in methanol (500ml) was added 10% palladium-activated carbon (2g), and the mixture was stirred at room temperature under a hydrogen stream for 1 day. The reaction mixture was filtered through celite, and concentrated under reduced pressure to give the title compound (20.0g) as a white powder in a yield (97%)
1H-NMR(400MHz，CD3OD)；δ(ppm)
1.30(3H，t，J＝6.0Hz)、2.66(2H，t，J＝5.5Hz)、3.42(2H，t，J＝5.5Hz)、3.84(2H，s)、4.29(2H，q，J＝6.0Hz).
(85-1-2) 1-acetyl-4-oxo-3-piperidinecarboxylic acid ethyl ester
Ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate hydrochloride (20.0g) obtained above was dissolved in pyridine (150ml), acetic anhydride (10.2g) was added over 5 minutes, the mixture was stirred at room temperature for 2 hours, the reaction mixture was filtered by adding ethyl acetate (500ml), the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (19.9g) - (yield: 97%)
1H-NMR(400MHz，CDCl3) (ii) a Delta (ppm) tautomer mixture
Mainly: 1.34(3H, t, J ═ 6.0Hz), 2.16(3H, s), 2.39(2H, t, J ═ 5.5Hz), 3.75(2H, t, J ═ 5.5Hz), 4.10(2H, s), 4.28(2H, q, J ═ 6.0Hz), 12.08(1H, s).
Secondly: 1.32(3H, t, J ═ 6.0Hz), 2.15(3H, s), 2.44(2H, t, J ═ 5.5Hz), 3.60(2H, t, J ═ 5.5Hz), 4.23(2H, s), 4.26(2H, q, J ═ 6.0Hz), 12.06(1H, s).
EXAMPLE 85 Synthesis of cis-2-cis-1- (1-acetyl-3-ethoxycarbonylpiperidin-4-yl) indoline
The title compound (7.12g) was obtained as a pale yellow powder from indoline (12.5g), ethyl 1-acetyl-4-oxo-3-piperidinecarboxylate (22.3g) and sodium triacetoxyborohydride (48.7g) in the same manner as in example 1. (yield: 22%)
1H-NMR(400MHz，CDCl3) (ii) a Delta (ppm) tautomer mixture
1.19(3H tautomer 1, t, J ═ 6.0Hz), 1.21(3H tautomer 1, t, J ═ 6.0Hz), 2.07(3H tautomer 1, s), 2.14(3H tautomer 1, s), 2.36-3.07(5H, m), 3.19-3.62(3H, m), 3.75(1H tautomer 1, m), 3.93-4.13(3H, m), 4.66(1H tautomer 1, br-d), 4.82(1H tautomer 1, br-d), 6.34(1H, d, J ═ 7.5Hz), 6.61(1H, t, J ═ 7.5Hz), 7.05(2H, m).
EXAMPLE 85-Synthesis of trans-1- (1-acetyl-3-ethoxycarbonylpiperidin-4-yl) indoline
Cis-1- (1-acetyl-3-ethoxycarbonylpiperidin-4-yl) indoline (4.35g) in ethanol (150ml) was added potassium carbonate (138mg) and stirred at 60 ℃ for 1 day. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (200ml) was added to the residue, which was washed with water (50ml) and saturated brine (50ml) respectively for 1 time, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (4.22g) as a yellow oil. (yield: 97%)
1H-NMR(400MHz，CDCl3) (ii) a Delta (ppm) tautomer mixture
1.11(3H, t, J ═ 6.0Hz), 1.59(1H, m), 1.71(1H, m), 2.13(3H tautomer 1, s), 2.14(3H tautomer 1, s), 2.61-2.82(2H, m), 2.95(2H, m), 3.22(1H, m), 3.34(1H, m), 3.54(1H, m), 3.93(2H, m), 3.99(2H, m), 4.77(1H tautomer 1, br-d), 4.88(1H tautomer 1, br-d), 6.45(1H, m), 6.61(1H, br-t), 7.03(2H, br-t).
EXAMPLE 85-4 Synthesis of trans-1- [ 1-ethyl-3- (4-fluorobenzyloxymethyl) piperidin-4-yl ] indoline
85-4-1 trans-1- (1-ethyl-3-hydroxymethylpiperidin-4-yl) indoline
Lithium aluminum hydride (133mg) was carefully added to anhydrous tetrahydrofuran (5ml) under ice-cooling in a nitrogen stream. To this was slowly added a solution of trans-1- (1-acetyl-3-ethoxycarbonylpiperidin-4-yl) indoline (850mg) in anhydrous tetrahydrofuran (5ml), and the mixture was stirred at 0 ℃ overnight. After vigorously stirring the mixture under ice-cooling, water (0.13ml) and then a 5N aqueous solution (0.13ml) of sodium hydroxide were added in this order, water (0.4ml) was added again, the temperature was raised to room temperature, ethyl acetate was added, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (340mg) as a pale yellow powder. (yield: 49%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.11(3H，t，J＝6.0Hz)、1.68(1H，m)、1.79(2H，m)、1.96(1H，dt，J＝2.5Hz，11.0Hz)、2.17(1H，m)，2.44(2H，q，J＝6.0Hz)，2.95(2H，m)、3.05(2H，m)、3.34(2H，m)、3.48(1H，dt，J＝5.0Hz，8.0Hz)、3.63(1H，dd，J＝5.0Hz，10.0Hz)、3.69(1H，dd、J＝5.5Hz，10.5Hz)、6.51(1H，d，J＝7.5Hz)、6.65(1H，t，J＝7.5Hz)，7.06(2H，m).
85-4-2 trans-1- [ 1-ethyl-3- (4-fluorobenzyloxymethyl) piperidin-4-yl ] indoline
To a suspension of 55% sodium hydride (83mg) in dimethylformamide (3ml) were added a solution of trans-1- (1-ethyl-3-hydroxymethylpiperidin-4-yl) indoline (340mg) in dimethylformamide (2ml) and 4-fluorobenzyl bromide (378mg) under ice-cooling. The reaction mixture was slowly warmed to room temperature and stirred at room temperature overnight. Water (50ml) was added thereto, and the mixture was extracted 3 times with ethyl acetate (50ml), and the organic phase was washed 1 time with water (50ml) and saturated brine (50 ml). The residue was purified by silica gel column chromatography (Fuji Silicia NH-DM2035, hexane/ethyl acetate) to give the title compound (50mg) as a colorless oil. (yield: 10%)
Melting point (oxalate): 177 temperature 178 ℃ C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.11(3H，t，J＝6.0Hz)、1.73(1H，m)、1.96(2H，m)、2.15(1H，m)、2.45(2H，q，J＝6.0Hz)，2.83-2.97(2H，m)、3.04(1H，m)、3.23(1H，br-d)、3.32(3H，m)、3.57(1H，dd，J＝2.5Hz，9.0Hz)、4.35(1H，d，J＝11.5z)、441(1H，d，J＝11.5Hz)、4.50(2H，s)、6.37(1H，d，J＝7.5Hz)、6.57(1H，t，J＝7.5Hz)、6.95(2H，br-t)、7.02(2H，m)、7.22(2H，dd，J＝6.0Hz，9.0Hz).
FAB-Mass；369(MH+).
EXAMPLE 86 Synthesis of cis-1- [ 1-ethyl-3- (4-fluorobenzyloxymethyl) piperidin-4-yl ] indoline
86-1 cis-1- (1-ethyl-3-acetoxymethylpiperidin-4-yl) indoline
Triethylamine (1.21g) and iodoethane (1.72g) were added to a dimethylformamide (40ml) solution of cis-1- (3-acetoxymethylpiperidin-4-yl) indoline (3.5g), and the mixture was stirred at 50 ℃ for 4 hours. Water (150ml) was added to the reaction mixture under ice cooling, and the mixture was extracted 3 times with ethyl acetate (50ml), washed 2 times with water (50ml), washed 1 time with saturated brine (100ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (2.06g) as a pale yellow oil. (yield: 63%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.04(3H，t，J＝7.0Hz)、1.77(1H，m)、1.92(3H，s)、1.96-2.11(3H，m)、2.31-2.48(3H，m)、2.93-3.03(4H，m)、3.49(1H，m)，3.56(2H，m)、4.22(1H，dd，J＝4.5Hz，10.5Hz)、4.47(1H，dd，J＝9.0Hz，10.0Hz)、6.32(1H，d，J＝7.5Hz)、6.56(1H，t，J＝7.5Hz)、7.02(2H，m).
86-2 cis-1- (1-ethyl-3-hydroxymethylpiperidin-4-yl) indoline
To a methanol (120ml) solution of cis-1- (1-ethyl-3-acetoxymethylpiperidin-4-yl) indoline (2.06g) was added potassium carbonate (3.0g), and the mixture was stirred at room temperature for 4 hours. Diethyl ether (80ml) was added, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (Fuji Silicia NH-DM2035, hexane/ethyl acetate) to give the title compound (1.19g) as a pale yellow powder. (yield: 67%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.11(3H，t，J＝7.0Hz)、1.82(1H，br-d)、2.06(1H，m)、2.11(1H，dd，J＝3.0Hz、11.5Hz)、2.40(2H，q，J＝7.0Hz)、2.41(1H，m)、2.52(1H，m)、3.01(2H m)、3.10(1H m)、3.16(1H，td，J＝2.0Hz，11.5Hz)、3.56(1H，td，J＝5.0Hz，12.0Hz)、3.66(1H，q，J＝9.0Hz)、3.82(1H，dd，J＝6.0Hz，9.0Hz)、3.87(1H，br-d)、3.98(1H，td，J＝2.0Hz，11.5Hz)、6.27(1H、d，J＝7.5Hz)、6.55(1H，t，J＝7.5Hz)、7.00(1H，br-t)、7.04(1H，br-d).
86-3 cis-1- [ 1-ethyl-3- (4-fluorobenzyloxymethyl) piperidin-4-yl ] indoline
To a suspension of 65% sodium hydride (42mg) in dimethylformamide (3ml) were added a solution of cis-1- (1-ethyl-3-hydroxymethylpiperidin-4-yl) indoline (250mg) in dimethylformamide (1ml) and 4-fluorobenzyl bromide (264mg) under ice-cooling. The reaction mixture was slowly warmed to room temperature and stirred at room temperature overnight. Ice water (30ml) was added thereto, and the mixture was extracted 3 times with ethyl acetate (30ml), and the organic phase was washed 1 time with water (50ml) and saturated brine (50 ml). The residue was purified by silica gel column chromatography (Fuji Silicia NH-DM2035, hexane/ethyl acetate) to give the title compound as a pale brown amorphous substance (100 mg). (yield: 28%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.07(3H，t，J＝7.0Hz)、1.75(1H，m)、1.94(1H，m)、2.07(1H，m)，2.31-2.54(3H，m)、2.94(3H，m)、3.15(1H，br-d)、3.48(2H，m)、3.62(1H，dd，J＝4.0Hz，8.0Hz)、3.86(1H，m)、4.18(1H，d，J＝4.0Hz)，4.41(1H，d，J＝4.0Hz)、6.36(1H，d，J＝7.5Hz)、6.57(1H，t，J＝7.5Hz)、6.95(2H，br-t)、7.00-7.06(2H，m)、7.20(2H、dd.J＝6.0Hz，9.0Hz).
FAB-Mass；369(MH+).
Example 871 Synthesis of- (1-acetylpiperidin-4-yl) indoline-7-carbaldehyde
(87-1)1- (1-acetylpiperidin-4-yl) indoline
Indoline (25ml), 1-acetyl-4-piperidone (25g) and glacial acetic acid (20ml) were dissolved in methanol (300ml), and 10% palladium on charcoal (1.0g) was added to conduct hydrogenation under normal pressure. After completion of the reaction, the reaction mixture was filtered through celite, washed with methanol, and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate, made alkaline with 5N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine, dried, and concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (ethyl acetate/hexane) to give 35.6g of the title compound as a pale yellow wax. (yield: 82.2%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.50-1.62(2H，m)、1.81-1.93(2H，m)、2.12(3H，s)、2.59(1H，br-t)、2.96(2H，t，J＝7.2Hz)、3.15(1H，br-t)，3.31-3.39(2H，m)、3.57-3.64(1H，m)、3.93(1H，br-d)、4.78(1H，br-d)、6.42(1H，d，J＝8.0Hz)、6.62(1H，t，J＝8.0Hz)，7.02-7.09(2H，m).
(87-2)1- (4-piperidin-1-yl) indoline
(1) The 1- (1-acetyl-piperidin-4-yl) indoline (24.4g) obtained in (1) was dissolved in ethanol (500ml), and a 5N aqueous sodium hydroxide solution (80ml) was added to the solution, followed by heating and refluxing for 5 hours. The reaction mixture was concentrated under reduced pressure, the residue was partitioned between water and ethyl acetate, the ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by NH-silica gel column chromatography (ethyl acetate) to give 15.9g of the title compound as a meat-colored wax. (yield 78.7%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.53-1.65(2H，m)、1.77-1.85(2H，m)、2.68(2H，br-t)、2.95(2H，t.J＝7.2Hz)、3.16-3.22(1H，m)、3.39(2H，t，J＝7.2Hz)、3.40-3.50(1H，m)、6.41(1H，d，J＝8.0Hz)、6.59(1H，t，J＝8.0Hz)、7.01-7.07(2H，m).
(87-3)1- (1-acetyl-piperidin-4-yl) indoline-7-carbaldehyde
Phosphorus oxychloride (4.60g) was added to ice-cooled DMF (40ml), and stirred for 15 minutes, 1- (1-acetylpiperidin-4-yl) indoline (7.32g) obtained in (1) was added to the mixture, and the reaction mixture was heated at 80 ℃ for 3 hours with vigorous stirring. The reaction mixture was cooled, partitioned between water and ethyl acetate, the ethyl acetate layer was then washed with water and saturated brine, dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give 3.2g of the title compound as a pale yellow oil. (yield 39.0%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.62(2H，br-q)、1.81-1.92(2H，m)、2.12(3H，s)、2.61(1H，br-t)、3.04(2H，t，J＝7.2Hz)、3.16(1H，br-t)、3.50-3.60(2H，m)、3.66-3.75(1H，m)、3.95(1H，br-d)、4.81(1H，br-d)、6.40(1H，d，J＝8.0Hz)、7.53-7.59(2H，m)、9.66(1H，s).
EXAMPLE 881 Synthesis of- [1- (tert-Butoxycarbonyl) piperidin-4-yl ] -6-bromoindoline
6-Bromoindoline (8.3g), 1- (tert-butoxycarbonyl) -4-piperidone (10g, [ CAS registry No. 79099-01-3]), acetic acid (14.9g) and dichloroethane (200ml) were added to a mixture of sodium triacetoxyborohydride (11.7g) and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the pH was adjusted to 9 with ethyl acetate, 8N aqueous sodium hydroxide solution and water. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (10.3 g). (yield 64%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.48(9H，s)、1.50-1.62(2H，m)、1.75-1.82(2H，m)、2.71-2.82(2H，m)、2.90(2H，t，J＝8Hz)、3.40-3.50(1H，m)、3.42(2H，t，J＝8Hz)、4.17-4.32(2H，m)、6.52(1H，br-s)、6.75(1H，d，J＝8Hz)、6.90(1H，d，J＝8Hz).
EXAMPLE 891 Synthesis of- [1- (tert-Butoxycarbonyl) piperidin-4-yl ] -6-hydroxymethylindoline
To a solution of 1- [1- (tert-butoxycarbonyl) piperidin-4-yl ] -6-bromoindoline (10g) in tetrahydrofuran (250ml) at-78 ℃ was added dropwise a 2.5M n-butyllithium/hexane solution (16ml) over 5 minutes. After 10 minutes, dimethylformamide was added, the temperature was raised to room temperature, and a saturated ammonium chloride solution and ethyl acetate were added to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was added with ethanol (50ml) and sodium borohydride (1.0g), stirred at room temperature for 30 minutes, and then ice water and ethyl acetate were added to the reaction mixture to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (7.9 g). (yield: 91%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.48(9H，s)、1.50-1.63(2H，m)、1.75-1.83(2H，m)、2.71-2.83(2H，m)、2.91(2H，t，J＝8Hz)、3.39(2H，t，J＝8Hz)、3.50-3.60(1H，m)、4.10-4.29(2H，m)、4.31(2H，d，J＝6Hz)、6.49(1H，br-s)、6.61(1H，d，J＝8Hz)、7.03(1H，d，J＝8Hz).
EXAMPLE 901- [1- (tert-Butoxycarbonyl) piperidin-4-yl ] -6-aminomethyl indoline
To a tetrahydrofuran (250ml) solution of 1- [1- (tert-butoxycarbonyl) piperidin-4-yl ] -6-hydroxyindoline (7.9g), triphenylphosphine (6.9g) and phthalimide (3.9g) was added dropwise tetrahydrofuran (20ml) of diethyl azodicarboxylate (4.6g) under ice cooling, the mixture was stirred at room temperature for 3 hours, concentrated under reduced pressure, purified by silica gel column chromatography (ethyl acetate/hexane), added hydrazine hydrate (3.6g) and ethanol (150ml), refluxed for 2 hours under heating, cooled with ice, and then precipitated crystals were filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (8.3 g).
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.48(9H，s)、1.50-1.60(2H，m)、1.71-1.81(2H，m)、2.72-2.89(2H，m)、2.91(2H，t，J＝8Hz)、3.35(2H，t，J＝8Hz)、3.49-3.60(1H，m)、3.83(2H，5)、4.13-4.29(2H，m)、6.42(1H，br-s)、6.58(1H，d，J＝8Hz)、7.00(1H，d，J＝8Hz).
EXAMPLE synthesis of 911- (1-Benzylpiperidin-4-yl) -6-bromoindoline
To a mixture of 6-bromoindoline (10g), 1-benzyl-4-piperidone (9.5g), acetic acid (12g) and dichloroethane (200ml) was added sodium triacetoxyborohydride (14.6g) over 5 minutes, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, 8N aqueous sodium hydroxide solution and water, and the pH was adjusted to 10. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) to give the title compound (16.3g) as a brown oil. (yield 87%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.51-1.60(2H，m)、1.69-1.79(2H，m)、2.01-2.13(2H，m)、2.89(2H，t，J＝8Hz)、2.95-3.03(2H，m)，3.22-3.32(1H，m)、3.40(2H，t，J＝8Hz)、3.53(2H，s)、6.44(1H，s)、6.65(1H，t，J＝8Hz)、6.84(1H，t，J＝8Hz)、7.22-7.36(5H，m).
Example Synthesis of 92-11- (1-benzylpiperidin-4-yl) -6-fluoroindole
Referring to the method of reference example 1 of Japanese patent publication No. 40-6347, a solution of synthesized 1-benzyl-4- (3-fluorophenyl) aminopiperidine (11.7g) and oxalyl chloride (10.5g) in diethyl ether (300ml) was refluxed for 2 hours. Concentrated under reduced pressure, the residue was diluted with methylene chloride (120ml), and a solution of anhydrous aluminum chloride (27g) in methylene chloride (100ml) was carefully added dropwise at 0 ℃. After stirring for 1 hour, a saturated aqueous sodium bicarbonate solution was carefully added to the reaction solution, and the precipitated crystal was filtered off and washed with dichloromethane. The organic layer was separated from the filtrate, which was washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). The mixture was diluted with tetrahydrofuran (200ml), and a 1M (borane-tetrahydrofuran complex)/tetrahydrofuran solution (120ml) was added dropwise under ice cooling, followed by stirring at room temperature overnight. Heated to reflux for 3 hours. The reaction mixture was carefully added dropwise to a saturated aqueous sodium bicarbonate solution, ethyl acetate was added thereto, and an organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was diluted with pyridine (100ml), which was stirred at room temperature for 4 hours, a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate were added to separate an organic layer, which was washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.5g) as a yellow oil. (yield 35%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.00-2.30(6H，m)、3.02-3.18(2H，m)、3.55-3.67(2H，m)、4.09-4.19(1H，m)、6.49(1H，s)、6.81-6.89(1H，m)、7.00-7.04(1H，m)、7.20(1H，s)、7.22-7.40(5H，m)、7.49-7.56(1H，m).
Example Synthesis of 92-21- (1-benzylpiperidin-4-yl) -6-fluoroindoline
A trifluoroacetic acid (50ml) solution of 1- (1-benzylpiperidin-4-yl) -6-fluoroindole (3.5g) was added dropwise to a 1M (borane-tetrahydrofuran complex)/tetrahydrofuran solution (23ml) under ice cooling, and the mixture was stirred for 2 hours. Adding water, concentrating under reduced pressure, adding ethanol and 5N sodium hydroxide aqueous solution, adjusting alkalinity, and stirring for 2 hr. Saturated aqueous sodium hydrogencarbonate and ethyl acetate were added to the solution, the organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.0g) as a brown oil. (yield 57%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.72-1.83(4H，m)、2.89(2H，t，J＝8Hz)，3.00-3.09(2H，m)、3.23-3.44(3H，m)、3.42(2H，t，J＝8Hz)、3.52-3.61(2H，m)、6.02-6.09(1H，m)、6.20-6.28(1H，m)、6.89-6.93(1H，m)、7.23-7.40(5H，m).
Example 931 Synthesis of- (1-Benzylpiperidin-4-yl) -6-formylindoline
1- (1-Benzylpiperidin-4-yl) -6-bromoindoline (8.54g) was dissolved in tetrahydrofuran (125ml), and a 2.5M N-butyllithium/hexane solution (11.5ml) was added dropwise at-78 ℃ under a nitrogen atmosphere, followed by N, N-dimethylformamide (6.1ml) and stirring for 2 hours. Water and ethyl acetate were added to the residue, and the organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.360g) as a yellow oil. (yield 86.1%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.74-1.80(4H，m)、2.11(2H，m)、2.99-3.03(2H，m)、3.01(2H，t，J＝8.4Hz)、3.43(1H，m)、3.47(2H，t，J＝8.4Hz)、3.55(2H，s)、6.82(1H，d，J＝1.6Hz)、7.06(1H，dd，J＝1.6，7.2Hz)、7.15(1H，d，J＝7.2Hz)、7.28(1H，t，J＝4.4Hz)、7.33(1H，d，J＝4.4Hz)、9.85(1H，s).
Example 941 Synthesis of (1-benzylpiperidin-4-yl) -6-oxime methylindoline
The same procedures used in example 46 were repeated except for using 1- (1-benzylpiperidin-4-yl) -6-formylindoline (6.36g) to give the title compound (6.200g) as a yellow oil. (yield: 89.4%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.74-1.89(4H，m)、2.09(2H，dt，J＝2.4，11.6Hz)、2.91(2H，t，J＝8.4Hz)、3.02(2H，br-d)、3.40(1H，m)、3.41(2H，t，J＝8.4Hz)、3.55(2H，s)、6.66(1H，s)、6.70(1H，dd，J＝1.4，7.2Hz)、7.01(1H，d，J＝7.2Hz)、7.27(1H，m)、7.32(4H，m)、8.06(1H，s).
Example 951 Synthesis of- (1-benzylpiperidin-4-yl) -6-aminomethylindoline
The same procedures used in example 35 were repeated except for using 1- (1-benzylpiperidin-4-yl) -6-oxime methylindoline (5.5g) to give the title compound (5.598g) as a brown oil.
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.75(4H，m)，2.09(2H，m)、2.10(2H，t，J＝8.4Hz)，3.00(2H，m)，3.39(2H，t，J＝8.4Hz)、3.55(2H，s)、3.76(2H，s)、6.36(1H，t，J＝0.6Hz)、6.51(1H，dd，J＝0.6，7.2Hz)，6.99(1H，d，J＝7.2Hz)、7.27(1H，m)、7.32(4H，m).
Example 961 Synthesis of (1-benzylpiperidin-4-yl) -6-acetamidomethylindoline
The same procedures used in example 36 were repeated except for using 1- (1-benzylpiperidin-4-yl) -6-aminomethylindoline (5.598g) and acetyl chloride (1.3ml) to give the title compound (5.598g) as a brown oil.
Free form
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.76(4H，m)、1.99(3H，s)、2.12(2H，m)、2.91(2H，t，J＝8.4Hz)、3.02(2H，br-d)、3.36(1H，m)、3.40(2H，t，J＝8.4Hz)、3.57(2H，br-s)、4.31(2H，d，J＝5.6Hz)、5.65(1H，m)、6.30(1H，br-d)、6.49(1H，dd，J＝1.2，7.4Hz)、6.98(1H，d，J＝7.4Hz)、7.28(1H，m)、7.35(4H，d，J＝8.4Hz).
ESI-Mass；364.1
EXAMPLE 971 Synthesis of- [1- (4-methoxyphenylethyl) piperidin-4-yl ] -6-acetamidomethylindoline
From 1- (1-piperidin-4-yl) -6-acetamidomethylindoline (250mg) and 4-methoxyethyl bromide (240mg), according to the method of example 2, the title compound was obtained as white powder crystals (200 mg). (yield: 53%)
Melting point: 151 ℃ and 152 DEG C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.50-1.63(2H，m)、1.79-1.81(2H，m)、2.01(3H，s)、2.10-2.30(2H，m)，2.75-2.96(4H，m)，2.93(2H，t，J＝8Hz)、3.10-3.30(2H，m)、3.36-3.50(1H，m)、3.44(2H，t，J＝8Hz)、3.79(3H，s)、4.33(2H，d，J＝6Hz)、6.47(1H，s)、6.52(1H，d，J＝8Hz)、6.83-6.87(2H，m)，7.00(1H，d，J＝8Hz)、7.13-7.16(2H，m).
FAB-Mass；408(MH+).
EXAMPLE 981 Synthesis of- [1- (4-Chloroethyl) piperidin-4-yl ] -6-acetamidomethylindoline
From 1- (1-piperidin-4-yl) -6-acetamidomethylindoline (250mg) and 4-bromophenethyl bromide (240mg), according to the method of example 2, the title compound was obtained as white flaky crystals (240 mg). (yield: 63%)
Melting point: 151 ℃ and 152 DEG C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.50-1.64(2H，m)、1.54-1.90(2H，m)、2.01(3H，s)、2.04-2.34(2H，m)、2.60-3.00(4H，m)、2.93(2H，t，J＝8Hz)、3.06-3.26(2H，m)、3.36-3.48(1H，m)、3.43(2H，d，J＝8Hz)、4.33(2H，d，J＝6Hz)、6.38(1H，s)、6.51(1H，d，J＝8Hz)，7.00(1H，d，J＝8Hz)、7.11-7.20(2H，m)、7.23-7.29(2H，m).
FAB-Mass；412(MH+).
EXAMPLE 991 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -5-methoxyindoline
From 1- (4-fluorophenethyl) -4- (4-methoxyphenyl) aminopiperidine (10g) synthesized according to reference example 1 of Japanese patent publication (Kokoku) No. 40-6347, the title compound hydrochloride was obtained as white powdery crystals (180mg) according to the method of example 106. (yield: 1.4%)
Melting point (hydrochloride salt): 209 ℃ C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.83-2.09(4H，m)、2.83-2.96(2H，m)、2.98-3.10(4H，m)、3.20-3.29(2H，m)、3.31-3.45(2H，m)、3.60-3.80(3H，m)、3.69(3H，s)、4.24-4.34(1H，m)、6.58-6.70(2H，m)、6.75-6.80(1H，m)、7.11-7.20(2H，m)、7.29-7.40(2H，m).
FAB-Mass；355(MH+).
Example Synthesis of 100-11- (4-fluorophenethyl) -4- (3-bromophenyl) aminopiperidine
A solution of o-bromoaniline (17.2g) and 4-fluorophenethylpiperidone (22g) in toluene (200ml) was heated to reflux overnight on a Dean-Starke trap. After concentration under reduced pressure, the residue was diluted with 1, 2-dichloroethane (200ml), and sodium borohydride (7.6g) and acetic acid (8.0g) were added thereto and stirred at 0 ℃ for 4 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue was purified by silica gel column chromatography (dichloromethane/ethanol). The title compound (10g) was obtained as a brown oil. (yield 27%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.42-1.60(2H，m)、2.02-2.10(2H，m)、2.18-2.25(2H，m)、2.55-2.63(2H，m)，2.78-2.84(2H，m)、2.90-3.00(2H，m)、3.23-3.32(1H，m)、3.60(1H，d，J＝8Hz)，6.50(1H，d，J＝8Hz)、6.72(1H，s)、6.79(1H，d，J＝8Hz)、6.94-7.02(3H，m)、7.12-7.20(2H，m).
EXAMPLE 100 Synthesis of 21- [1- (4-fluorophenethyl) piperidin-4-yl ] -2, 3-dioxo-6-bromoindoline
A solution of 1- (4-fluorophenethyl) -4- (3-bromophenyl) aminopiperidine (10g) and oxalyl chloride (6.7g) in diethyl ether (200ml) was heated under reflux for 2 hours. Concentrated under reduced pressure, the residue was diluted with methylene chloride (200ml), and a solution of anhydrous aluminum chloride (24.7g) in methylene chloride (60ml) was added dropwise at 0 ℃. After stirring for 1 hour, the reaction solution was carefully added to a saturated aqueous sodium bicarbonate solution. The precipitated crystals were filtered off and washed with dichloromethane. The organic layer of the filtrate was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). The title compound was obtained as yellow powder crystals (7.4 g). (yield 65%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.75-1.83(2H，m)、2.15-2.25(2H，m)、2.35-2.50(2H，m)、2.60-2.69(2H，m)、2.78-2.87(2H，m)、3.11-3.20(2H，m)、4.12-4.28(1H，m)、6.95-7.03(2H，m)、7.15-7.20(2H，m)、7.28(1H，d，J＝8Hz)、7.36(1H，s)，7.49(1H，d，J＝8Hz).
EXAMPLE 100 Synthesis of 31- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindole
To a tetrahydrofuran (150ml) solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -2, 3-dioxo-6-bromoindoline (7.4g) was added dropwise a 1M borane-tetrahydrofuran complex/tetrahydrofuran solution (69ml) under ice cooling, and after stirring overnight at room temperature, the mixture was refluxed for 3 hours. The reaction mixture was carefully added dropwise with saturated aqueous sodium bicarbonate solution, and ethyl acetate was added thereto to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was diluted with pyridine (50ml), stirred at room temperature for 4 hours, and then saturated aqueous sodium hydrogencarbonate and ethyl acetate were added to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). The title compound (3.9g) was obtained as a yellow oil. (yield 57%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.01-2.12(4H，m)，2.20-2.32(2H，m)、2.61-2.69(2H，m)、2.79-2.86(2H，m)、3.13-3.21(2H，m)、4.10-4.21(1H，m)、6.48(1H，d，J＝2Hz)、6.95-7.02(2H，m)，7.12-7.23(2 H，m)、7.45-7.55(3H，m)、7.91(1H，t，J＝6Hz).
EXAMPLE 100 Synthesis of 41- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline
To a tetrahydrofuran (50ml) solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindole (3.9g) was added dropwise a 1M borane-tetrahydrofuran complex/tetrahydrofuran solution (20ml) under ice cooling, and the mixture was stirred for 3 hours. Adding water, concentrating under reduced pressure, adding ethanol and 5N sodium hydroxide aqueous solution to adjust alkalinity, and stirring for 30 minutes. Saturated aqueous sodium bicarbonate and ethyl acetate were added and the organic layer was separated. The reaction mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue was purified by silica gel column chromatography (toluene/acetone). The title compound was obtained as white powdery crystals (2.0 g). (yield 51%)
Melting point: 99-101 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.74-1.84(4H，m)、2.10-2.19(2H，m)、2.58-2.64(2H，m)、2.78-2.84(2H，m)、2.89(2H，t，J＝8Hz)、3.10-3.17(2H，m)、3.28-3.38(1H，m)、3.43(2H，t，J＝8Hz)，6.47(1H，d，J＝2Hz)、6.69(1H，dd，J＝2.8Hz)、6.87(1H，d，J＝8Hz)、6.96-7.00(2H，m)、7.15-7.18(2H，m).
FAB-Mass；404(MH+).
Example Synthesis of 1011- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline
To a mixture of 6-bromoindoline (175g), 1- (4-fluorophenethyl) -4-piperidone (194g), acetic acid (250ml) and dichloroethane (2.5l) was added sodium triacetoxyborohydride (298g) over 30 minutes, and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, which was diluted with ethyl acetate (2l), 8N aqueous sodium hydroxide (1l) and water (500 ml). The organic layer was separated, washed successively with water (0.5l) and saturated brine (0.5l), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved with ethyl acetate (500ml) while it was still hot, and after cooling with ice water, the precipitated crystal was filtered off. The title compound (205g) was obtained. (yield: 58%)
The crude crystals were recrystallized from a mixed solvent of hexane/ethyl acetate to give the title compound as white prisms.
Melting point: 99-101 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.74-1.84(4H，m)、2.10-2.19(2H，m)、2.58-2.64(2H，m)，2.78-2.84(2H，m)、2.89(2H，t，J＝8Hz)，3.10-3.17(2H，m)、3.28-3.38(1H，m)、3.43(2H，t，J＝8Hz)、6.47(1H，d，J＝2Hz)、6.69(1H，dd，J＝2.8Hz)、6.87(1H，d，J＝8Hz)、6.96-7.00(2H，m)、7.15-7.18(2H，m).
FAB-Mass；404(MH+).
Example 1021- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-chloroindoline Synthesis
1- (4-Fluorophenethyl) -4- (3-chlorophenyl) aminopiperidine (1.4g) synthesized in the same manner as in example 101 as in reference example 1 of Japanese patent publication (Kokoku) No. 40-6347 gave the hydrochloride of the title compound as white powder crystals (380 mg). (yield: 25%)
Melting point (hydrochloride salt): 236-240 deg.C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.79-1.90(2H，m)、1.99-2.12(2H，m)、2.87(2H，t，J＝8Hz)、3.00-3.13(4H，m)、3.20-3.29(2H，m)、3.36(2H，t，J＝8Hz)、3.55-3.63(2H，m)、3.70-3.80(1H，m)，6.52(1H，d，J＝8Hz)、6.57(1H，s)、6.97(1H，d，J＝8Hz)、7.13-7.20(2H，m)、7.29-7.35(2H，m).
FAB-Mass；359(MH+).
EXAMPLE 1031- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-fluoroindoline synthesis
According to the same manner as in example 2, from 1- (piperidin-4-yl) -6-fluoroindoline (200mg) and 4-fluorophenethyl bromide (220mg), the title compound was obtained as crystals (220mg) as a white powder as the hydrochloride salt. (yield: 65%)
Melting point (hydrochloride salt): 214 ℃ 216 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.81-1.90(2H，m)、1.95-2.08(2H，m)、2.85(2H，t，J＝8Hz)、2.99-3.10(4H，m)、3.20-3.29(2H，m)、3.38(2H，t，J＝8Hz)、3.67-3.75(3H，m)、6.26(1H，t，J＝8Hz)、6.39(1H，d，J＝8Hz)、6.95(1H，t，J＝8Hz)、7.14-7.19(2H，m)、7.30-7.34(2H，m).
FAB-Mass；343(MH+).
EXAMPLE 1041 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-hydroxyindoline
A solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methoxyindoline (1.6g) in concentrated hydrogen bromide (40ml) was heated at 100 ℃ for 2 hours. Adjusting the alkalinity with concentrated sodium hydroxide aqueous solution, and extracting with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/ethanol) and converted to the hydrochloride according to a conventional method to give brown prismatic crystals (1.2g) of the hydrochloride of the title compound. (yield: 68%)
Melting point (hydrochloride salt): 232 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.81-2.00(4H，m)、2.73(2H，t，J＝8Hz)、2.97-3.12(4H，m)、3.21-3.33(4H，m)、3.59-3.69(3H，m)、5.93(1H，s)、5.97(1H，d，J＝8Hz)、6.75(1H，d，J＝8Hz)、7.12-7.21(2H，m)、7.30-7.38(2H，m)、8.89(1H，s).
FAB-Mass；341(MH+).
EXAMPLE 1051- [1- (4-fluorophenethyl) piperidin-4-yl ] -4-methoxyindoline synthesis
A mixture of 4-methoxyindoline (0.25g), 1- (4-fluorophenethyl) -4-piperidone, platinum oxide (50mg), acetic acid (1.0ml) and ethanol (20ml) was catalytically reduced under a hydrogen stream at ordinary temperature and pressure. Stirring overnight, evaporating the solvent, filtering off the catalyst, and concentrating under reduced pressure. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate and ethyl acetate, the separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) and converted to the hydrochloride according to a conventional method to give the title compound as a hydrochloride salt in the form of white powder crystals (92 mg). (yield: 27%)
Melting point (hydrochloride salt); 195 ℃ C. & 198 ℃ C
1H-NMR(400MHz、DMSO-d6)；δ(ppm)
1.81-2.04(4H，m)、2.79(2H，t，J＝8Hz)、3.00-3.13(4H，m)、3.21-3.36(4H，m)、3.59-3.71(3H，m)、3.72(3H，s)、6.22(1H，d，J＝8Hz)、6.27(1H，d，J＝8Hz)、6.98(1H，t，J＝8Hz)、7.15-7.20(2H，m)、7.31-7.35(2H，m).
FAB-Mass；355(MH+).
Example Synthesis of 106-11- (1-benzylpiperidin-4-yl) -6-methoxyindoline-2, 3-dione
1-benzyl-4- (3-methoxyphenyl) aminopiperidine (1.88g) synthesized according to reference example 1 of Japanese patent publication (Kokoku) No. 40-6347 was dissolved in diethyl ether (38ml), oxalyl chloride (1.62g) was added dropwise over 30 minutes, and then the mixture was refluxed for 3.5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in methylene chloride (100ml), and the solution was added dropwise to a suspension of aluminum chloride (5.9g) in methylene chloride (20ml) at 0 ℃ over 30 minutes. After the completion of the dropwise addition, the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the reaction mixture was added to ice, neutralized with an aqueous sodium hydrogencarbonate solution, the precipitate was filtered off, the filtrate was extracted with methylene chloride, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 1- (1-benzylpiperidin-4-yl) -6-methoxyindoline-2, 3-dione (1.63g) (yield: 73%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.69-1.76(2H，m)、2.12(2H，br-t)、2.42(2H，dq，J＝12.0，4.0Hz)、3.03(2H，br-d)、3.55(2H，s)、3.93(3H，s)、4.08-4.18(1H，m)、6.54(1H，dd，J＝8.4，1.6Hz)、6.66(1H，d，J＝1.6Hz)、7.24-7.36(5H，m)、7.59(1H，d，J＝8.4Hz).
Example Synthesis of 106-21- (1-benzylpiperidin-4-yl) -6-methoxyindole
To a solution of 1- (1-benzylpiperidin-4-yl) -6-methoxyindoline-2, 3-dione (110mg) in tetrahydrofuran (2ml) was added a 2M solution of borane/dimethylsulfoxide complex in tetrahydrofuran (0.47ml), and the mixture was stirred for 1 hour and then refluxed for 4.5 hours. After the reaction, an aqueous sodium hydrogencarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate, and the solvent was distilled off. The residue was dissolved in pyridine, stirred for 4.5 hours, the pyridine was evaporated, and ethyl acetate and an aqueous solution of sodium hydrogencarbonate were added. The ethyl acetate layer was separated, dried over magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 1- (1-benzylpiperidin-4-yl) -6-methoxyindole (28 mg). (yield: 28%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.02-2.12(4H，m)、2.17-2.27(2H，m)、3.07(2H，br-d)、3.60(2H，s)、3.87(3H，s)、4.09-4.18(1H，m)、6.44(1H，d，J＝3.2Hz)、6.78(1H，dd，J＝8.8，2.0Hz)、6.82(1H，br-d)、7.13(1H，d，J＝3.2Hz)、7.25-7.37(5H，m)、7.49(1H，d，J＝8.8Hz).
Example Synthesis of 106-31- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methoxyindole
1-Chloroethyl chloroformate (32mg) was added to a solution of 1- (1-benzylpiperidin-4-yl) -6-methoxyindole (24mg) in toluene (2ml), and the mixture was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol and refluxed for 9 hours. After completion of the reaction, methanol was distilled off, the residue was dissolved in dimethylformamide (1ml), and 2- (4-fluorophenyl) ethyl bromide (19mg) was added to stir at 60 ℃ for 11 hours. After completion of the reaction, brine was added, and the mixture was extracted with ethyl acetate and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (toluene/acetone) to give the title compound (7 mg). (yield 27%).
Melting point: 230 ℃ (decomposition)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.06-2.14(4H，m)，2.25-2.33(2H，m)、2.67(2H，dd，J＝9.2；10.8Hz)、2.83(2H，dd，J＝10.8，9.2Hz)、3.20(2H，br-d，J＝11.6Hz)、3.88(3H，s)、4.12-4.21(1H，m)、6.45(1H，d，J＝3.2Hz)，6.79(1H，dd，J＝8.4，2.0Hz)、6.83(1H，d，J＝2.0Hz)、6.99(2H，t，J＝12.4Hz)、7.14(1H，d，J＝3.2Hz)、7.18(2H，dd，J＝8.4，5.6Hz)、7.50(1H，d，J＝8.4Hz).
MS；[M+H]+；m/z＝353.
EXAMPLE 106 Synthesis of 41- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methoxyindoline
To a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methoxyindole (24mg) in trifluoroacetic acid (1ml) at 0 ℃ was added dropwise 1M borane-tetrahydrofuran complex (0.18ml) over 2 minutes, followed by stirring at 0 ℃ for 30 minutes. After completion of the reaction, water (0.1ml) was added, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a 2N aqueous sodium hydroxide solution and stirred at room temperature for 10 minutes. The mixture was extracted with dichloromethane, the organic layer was separated, dried over magnesium sulfate and the solvent was concentrated under reduced pressure. The residue was purified by preparative TLC to give 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methoxyindoline (10 mg).
(yield: 35%)
Melting point: 242 deg.C (decomposition)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.75-1.90(4H，m)、2.10-2.22(2H，m)、2.58-2.70(2H，m)、2.80(2H，dd，J＝11.6，7.2Hz)、2.88(2H，t，J＝8.8Hz)、3.14(2H，br-d，J＝10.8Hz)、3.31-3.82(1H，m)、3.41(2H，t，J＝8.4Hz)、3.77(3H，s)、6.00(1H，d，J＝2.0Hz)、6.13(1H，dd，J＝8.0，2.0Hz)、6.93(1H，2H，t，J＝8.8Hz)、6.97(2H，t，J＝8.8Hz)、7.16(2H，dd，J＝8.4，5.6Hz).
MS；[M+H]+；m/z＝355.
EXAMPLE 1071 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -7-methoxyindoline
According to the same manner as in example 106, from 1- (4-fluorophenethyl) -4- (2-methoxyphenyl) aminopiperidine (3.9g) synthesized according to the method of reference example 1 of Japanese patent publication No. 40-6347, the hydrochloride of the title compound was obtained as white powdery crystals (530 mg). (yield: 11%)
Melting point (hydrochloride salt); 204 ℃ and 206 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.72-1.80(2H，m)、1.90-2.40(2H，m)、2.86(2H，t，J＝8Hz)、2.95-3.08(4H，m)、3.21-3.34(4H，m)、3.55-3.63(2H，m)、3.73(3H，s)、4.24-4.34(1H，m)、6.60-6.64(1H，m)、6.69-6.74(2H，m)、7.14-7.19(2H，m)、7.28-7.32(2H，m).
FAB-Mass；355(MH+).
EXAMPLE 1081 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6, 7-dimethoxyindoline
According to the same manner as in example 106, from 1- (4-fluorophenethyl) -4- (2, 3-dimethoxyphenyl) aminopiperidine (8.1g) synthesized according to the method of reference example 1 of Japanese patent publication No. 40-6347, the oxalate salt of the title compound was obtained as crystals (34mg) as a white powder. (yield: 1.7%)
Melting point (oxalate); 179 plus 181 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.72-1.86(4H，m)、2.79(2H，t，J＝8Hz)、2.86-2.97(2H，m)、3.04-3.18(2H，m)、3.29(2H，t，J＝8Hz)、3.40-3.58(4H，m)、3.64(3H，s)、3.69(3H，s)、4.05-4.17(1H，m)、6.25(1H，d，J＝8Hz)、6.69(1H，d，J＝8Hz)、7.13-7.18(2H，m)、7.28-7.32(2H，m).
FAB-Mass；385(MH+).
EXAMPLE 1091 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-nitroindoline
The title compound was obtained as crystals (5.1g) as a pale yellow powder from 1- (piperidin-4-yl) -6-nitroindoline (3.5g) and 4-fluorophenethyl bromide (4.1g) in the same manner as in example 2. (yield: 81%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.71-2.89(4H，m)、2.09-2.20(2H，m)、2.55-2.66(2H，m)、2.76-2.83(2H，m)、3.03(2H，t，J＝8Hz)、3.10-3.19(2H，m)、3.39-3.49(1H，m)、3.56(2H，t，J＝8Hz)、6.95-7.00(2H，m)、7.09(1H，d，J＝8Hz)、7.10(1H，s)、7.12-7.21(2H，m)、7.50(1H，d，J＝8Hz).
Example 1101 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminoindoline
A mixture of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-nitroindoline (5.1g), iron powder (5.0g), ammonium chloride (10g), water (20ml) and ethanol (100ml) was stirred at 60 ℃ for 4 hours. The reaction mixture was filtered, concentrated under reduced pressure, and 5N aqueous sodium hydroxide solution and ethyl acetate were added to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/ethanol) to give the title compound as brown powder crystals (3.4 g). (yield: 73%)
Melting point: 104 ℃ C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.69-1.88(4H，m)、2.05-2.13(2H，m)、2.53-2.60(2H，m)、2.71-2.81(2H，m)、2.83(2H，t，J＝8Hz)、3.09-3.13(2H，m)、3.29-3.35(1H、m)、3.36(2H，t，J＝8Hz)、3.50(2H，br-s)、5.82(1H，s)、5.98(1H，d，J＝8Hz)、6.81(1H，d，J＝8Hz)、6.91-7.00(2H，m)、7.12-7.20(2H，m).
FAB-Mass；340(MH+).
Example Synthesis of 1111- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methylaminoindoline
Ethyl chlorocarbonate (100mg) was added dropwise to a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminoindoline (0.3g) and triethylamine (100mg) in methylene chloride (5ml) at room temperature, followed by stirring for 30 minutes. Concentrated under reduced pressure, the residue was partitioned between ethyl acetate and water, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and a suspension of lithium aluminum hydride (67mg) in tetrahydrofuran (5ml) was added to the residue, which was then refluxed for 1 hour. While the reaction mixture was cooled with ice water, water (0.14ml), a 5N aqueous solution of sodium hydroxide (0.42ml), and water (0.14ml) were carefully added dropwise to the reaction mixture, and the mixture was vigorously stirred. The precipitated precipitate was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) and converted into a hydrochloride according to a conventional method to give a brown hygroscopic amorphous form (220mg) of the hydrochloride of the title compound. (yield: 64%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.81-1.90(2H，m)、1.99-2.13(2H，m)、2.82(3H，s)、2.90(2H，t，J＝8Hz)、3.00-3.12(4H，m)、3.20-3.33(2H，m)、3.41(2H，t，J＝8Hz)、3.59-3.69(2H，m)、3.80-3.90(1H，m)、6.56-6.62(2H，m)、7.09(1H，d，J＝8Hz)、7.12-7.20(2H，m)、7.29-7.35(2H，m).
FAB-Mass；354(MH+).
Example 1121 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-ethylaminoindoline
A mixture of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminoindoline (0.3g), pyridine (5ml) and acetic anhydride (3ml) was stirred at room temperature for 30 minutes. Concentrated under reduced pressure, and water and ethyl acetate were added. The layers were separated, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and a suspension of lithium aluminum hydride (127mg) in tetrahydrofuran (5ml) was added to the residue, followed by refluxing under heating for 1 hour. While the reaction mixture was chilled in ice water, water (0.14ml), a 5N aqueous solution of sodium hydroxide (0.42ml), and water (0.14ml) were carefully added dropwise to the reaction mixture, and the mixture was vigorously stirred. The precipitated precipitate was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) and converted to the hydrochloride according to a conventional method to give a pale brown hygroscopic amorphous form (210mg) of the hydrochloride of the title compound. (yield: 59%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.20(3H，t，J＝7Hz)、1.82-1.91(2H，m)、2.01-2.10(2H，m)、2.89(2H，t，J＝8Hz)、3.00-3.09(4H，m)、3.21-3.32(4H，m)、3.39(2H，t，J＝8Hz)、3.60-3.72(3H，m)、6.55-6.62(2H，m)、7.09(1H，d，J＝8Hz)、7.10-7.21(2H，m)、7.28-7.33(2H，m).
FAB-Mass；368(MH+).
EXAMPLE 1131 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-isopropylaminoindoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminoindoline (0.3g), acetone (0.075g), acetic acid (0.23g) and sodium triacetoxyborohydride (0.36g), a pale brown hygroscopic amorphous form (240mg) of the hydrochloride salt of the title compound was obtained in the same manner as in example 101. (yield: 65%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.23(6H，d，J＝7Hz)、1.80-1.91(2H，m)、2.02-2.20(2H，m)、2.91(2H，t，J＝8Hz)、3.00-3.13(4H，m)、3.20-3.29(2H，m)，3.40(2H，t，J＝8Hz)、3.60-3.71(4H，m)、6.61-6.69(2H，m)、7.09(1H，d、J＝8Hz)、7.11-7.20(2H，m)、7.31-7.39(2H，m).
FAB-Mass；382(MH+).
EXAMPLE 1141 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-dimethylaminoindoline
The title compound was obtained as hydrochloride salt in the same manner as in example 101 from 6-dimethylaminoindoline (0.6g), 1- (4-fluorophenethyl) -4-piperidone (0.98g), acetic acid (1.1g) and sodium triacetoxyborohydride (1.2g) as a white powdery crystal (0.77 g). (yield: 52%)
Melting point (hydrochloride salt); 205 deg.C and 208 deg.C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.81-2.03(4H，m)、2.71(2H，t，J＝8Hz)、2.80(6H，s)、2.99-3.13(4H，m)、3.20-3.31(4H，m)、3.53-3.67(2H，m)、3.70-3.80(1H，m)、5.89-5.99(2H，m)、6.80(1H，d，J＝8Hz)、7.11-7.19(2H，m)、7.29-7.36(2H，m).
FAB-Mass；367(MH+).
EXAMPLE 1151 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidoindoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminoindoline (1.0g) and acetic anhydride (1ml), the title compound was obtained as crystals (450mg) as a pale yellow powder in the same manner as in example 133.
(yield: 41%)
Melting point; 148 deg.C and 150 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.80-1.91(4H，m)、2.15(3H，s)、2.20-2.35(2H，m)、2.62-2.75(2H，m)、2.81-2.97(2H，m)、2.90(2H，t，J＝8Hz)、3.13-3.29(2H，m)、3.39-3.48(1H，m)、3.42(2H，t，J＝8Hz)、6.44(1H，d，J＝8Hz)、6.93-7.01(4H，m)、7.16-7.20(3H，m).
FAB-Mass；382(MH+).
Example 1161 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methanesulfonylaminoindoline
Methanesulfonyl chloride (0.4ml) was added dropwise to a mixture of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminoindoline (0.3g), 4-dimethylaminopyridine (0.1g) and pyridine (10ml) at 0 ℃ and stirred for 2 hours. Water and ethyl acetate were added to the reaction mixture to separate an organic layer. The organic layer was washed with water saturated brine, dried over anhydrous magnesium sulfate, purified by NH silica gel column chromatography (hexane/ethyl acetate) and converted to the hydrochloride according to a conventional method to give the title compound hydrochloride as a pale yellow hygroscopic amorphous (160 mg). (yield: 40%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.80-2.03(4H，m)、2.85(2H，t，J＝8Hz)、2.89(3H，s)、2.99-3.17(4H，m)、3.20-3.43(5H，m)、3.58-3.69(2H，m)、6.37-6.40(2H，m)、6.94(1H，d，J＝8Hz)、7.15-7.20(2H，m)、7.30-7.34(2H，m)、9.33(1H，s).
FAB-Mass；418(MH+).
EXAMPLE 1171 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-ethanesulfonylaminoindoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminoindoline (0.4g) and ethanesulfonyl chloride (0.61g), the hydrochloride salt of the title compound was obtained as a brown hygroscopic amorphous form (160mg) in the same manner as in example 116. (yield: 29%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.16(3H，t，J＝7Hz)、1.81-1.89(2H，m)、1.94-2.05(2H，m)、2.82(2H，t，J＝8Hz)、2.98(2H，q，J＝7Hz)、2.99-3.16(4H，m)、3.20-3.29(2H，m)、3.31(2H，t，J＝8Hz)、3.35-3.44(1H，m)、3.55-3.68(2H，m)、6.37-6.39(2H，m)、6.93(1H，d，J＝8Hz)、7.13-7.19(2H，m)、7.29-7.33(2H，m)、9.42(1H，s).
FAB-Mass：432(MH+).
EXAMPLE 1181 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-propanesulfonylaminoindoline
The title compound was obtained as hydrochloride salt as a white powder (210mg) from 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminoindoline (0.4g) and propanesulfonyl chloride (0.67g) in the same manner as in example 116. (yield: 37%)
Melting point (hydrochloride salt): 166 ℃ and 169 ℃ of-
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
0.91(3H，t，J＝7Hz)、1.65(2H，sextet，J＝7Hz)、1.82-2.04(4H，m)、2.84(2H，t，J＝8Hz)、2.94(2H，q，J＝7Hz)、3.00-3.16(4H，m)、3.22-3.43(5H，m)、3.59-3.68(2H，m)、6.38-6.40(2H，m)、6.91(1H，d，J＝8Hz)、7.11-7.20(2H，m)、7.30-7.38(2H，m)、9.41(1H，s).
FAB-Mass；446(MH+).
Example 1191 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (4-fluorophenylsulfonylamino) indoline
The title compound was obtained as hydrochloride salt in the same manner as in example 101 from 6- (4-fluorobenzenesulfonylamino) indoline (0.23g) and 1- (4-fluorobenzoethyl) -4-piperidone (0.33g), acetic acid (0.36g) and sodium triacetoxyborohydride (0.42g) as white powder crystals (0.29 g). (yield: 68%)
Melting point (hydrochloride salt): 140 ℃ 143 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.69-1.73(2H，m)、1.83-1.99(2H，m)、2.75(2H，t，J＝8Hz)、3.01-3.19(4H，m)，3.20-3.31(4H，m)、3.51-3.63(3H，m)、6.12(1H，d，J＝8Hz)、6.28(1H，s)、6.81(1H，d，J＝8Hz)、7.13-7.21(2H，m)、7.30-7.41(4H，m)、7.74-7.79(2H，m).
FAB-Mass；498(MH+).
EXAMPLE 1201- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (N-methylmethanesulfonylamino) indoline synthesis
The title compound was obtained as the hydrochloride salt in white prismatic crystal (100mg) from 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methylaminoindoline (150mg) and methanesulfonyl chloride (54mg) in the same manner as in example 116. (yield: 55%)
Melting point (hydrochloride salt): 136-
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.82-1.89(2H，m)、1.98-2.10(2H，m)、2.83-2.90(2H，m)、2.90(3H，s)、3.01-3.14(4H，m)、3.17(3H，s)、3.20-3.28(2H，m)、3.32-3.40(2H，m)、3.58-3.76(3H，m)、6.54-6.59(2H，m)、7.01(1H，d，J＝8Hz)、7.14-7.19(2H，m)、7.30-7.34(2H，m).
FAB-Mass；432(MH+).
Example 1211- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-hydroxyethoxyindoline Synthesis
To a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-hydroxyindoline (0.8g) in dimethylformamide (30ml) was added 60% sodium hydride (0.11g), and the mixture was stirred at 50 ℃ for 10 minutes, after which (tert-butyl) dimethylsiloxyethyl bromide (0.67g) was added to the reaction mixture and further stirred for 2 hours. After concentration under reduced pressure, the resulting solution was diluted with a 2N aqueous solution of sodium hydroxide and ethyl acetate to separate an organic layer, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, purified by silica gel column chromatography (dichloromethane/ethanol), to the residue were added a 1M tetrabutylammonium fluoride/tetrahydrofuran solution (2.4ml) and tetrahydrofuran (20ml), stirred at room temperature for 3 hours, diluted with a 2N aqueous solution of sodium hydroxide and ethyl acetate to separate an organic layer, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/ethanol) to convert the residue into a hydrochloride according to a conventional method, whereby the title compound hydrochloride was obtained as a white powder crystal (300 mg). (yield 25%)
Melting point (hydrochloride salt): 235-238 deg.C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.84-1.99(2H，m)、2.79(2H，t，J＝8Hz)、2.97-3.14(4H，m)、3.22-3.34(4H，m)、3.60-3.77(5H、m)、3.88(2H，t，J＝5Hz)、4.79(1H，br-s)、6.09(1H，d，J＝8Hz)、6.12(1H，s)、6.88(1H，d，J＝8Hz)、7.12-7.20(2H，m)、7.30-7.38(2H，m).
FAB-Mass；385(MH+).
EXAMPLE 1221 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methanesulfonyloxyindoline
A concentrated hydrogen bromide (20ml) solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methoxyindoline (1.0g) was heated at 100 ℃ for 2 hours, the mixture was made alkaline with concentrated aqueous sodium hydroxide solution, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was dissolved in pyridine (10ml), methanesulfonyl chloride (0.46g) was added dropwise under ice-cooling, and the mixture was stirred overnight. After concentration under reduced pressure, the resulting solution was diluted with a 2N aqueous solution of sodium hydroxide and ethyl acetate to separate an organic layer, which was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, purified by NH silica gel column chromatography (ethyl acetate/hexane) and converted to the hydrochloride according to a conventional method to give the title compound as a crystalline hydrochloride salt in the form of a pale brown powder (300 mg). (yield: 15%)
Melting point (hydrochloride salt): 220 ℃ and 223 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.83-1.92(2H，m)、1.94-2.06(2H，m)、2.90(2H，t，J＝8Hz)、3.00-3.14(4H，m)、3.21-3.28(2H，m)、3.30(3H，s)、3.34-3.44(2H，m)、3.59-3.66(2H，m)，3.68-3.78(1H，m)、6.46-6.48(2H，m)、7.04(1H，d，J＝8Hz)、7.15-7.19(2H，m)、7.30-7.34(2H，m).
FAB-Mass；419(MH+).
EXAMPLE 1231 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -7-hydroxyethoxyindoline
A solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -7-methoxyindoline (0.3g) in concentrated hydrogen bromide (6ml) was heated at 100 ℃ for 2 hours, the alkaline condition was adjusted to concentrated aqueous sodium hydroxide solution, extraction was performed with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, the residue was dissolved in dimethylformamide (10ml), 60% sodium hydride (32mg) was added thereto, the mixture was stirred at 50 ℃ for 30 minutes, then, (tert-butyl) dimethylsiloxyethyl bromide (0.19g) was added to the reaction mixture, and further stirred for 30 minutes. After concentration under reduced pressure, the resulting solution was diluted with a 2N aqueous solution of sodium hydroxide and ethyl acetate to separate an organic layer, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, purified by silica gel column chromatography (ethyl acetate/methanol), to the residue were added a 1M tetrabutylammonium fluoride/tetrahydrofuran solution (0.45ml) and tetrahydrofuran (10ml), stirred at room temperature overnight, diluted with a 2N aqueous solution of sodium hydroxide and ethyl acetate to separate an organic layer, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol) and converted to a hydrochloride according to a conventional method to obtain a white hygroscopic amorphous form (80mg) of the hydrochloride of the title compound. (yield 25%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.79-1.86(2H，m)、1.95-2.07(2H，m)、2.91(2H，t，J＝8Hz)、2.95-3.07(4H，m)、3.20-3.27(2H，m)，3.30-3.41(2H，m)、3.56-3.63(2H，m)、3.74(2H，t，J＝5Hz)、3.96(2H，t，J＝5Hz)、4.38-4.47(1H，m)、6.69-6.80(3H，m)、7.11-7.21(2H，m)、7.29-7.35(2H，m).
FAB-Mass；385(MH+).
EXAMPLE 1241 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-cyanoindoline
To a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-oxime methylindoline (1.5g) and triethylamine (1.2ml) in dichloromethane (1l) was added dropwise trifluoromethanesulfonic anhydride (0.72ml) at-78 ℃ and the temperature was raised to room temperature. Saturated aqueous sodium bicarbonate and chloroform were added to the solution, the organic layer was separated, dried over anhydrous magnesium sulfate, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) to give the title compound as white powder crystals (1.0 g). (yield: 67%)
A portion of the crystals was taken and converted to the hydrochloride salt according to a conventional method to obtain the title compound as hydrochloride salt as white powdery crystals.
Melting point (hydrochloride salt): 230 ℃ (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.82-1.91(2H，m)、1.95-2.09(2H，m)、2.98(2H，t，J＝8Hz)、3.00-3.13(4H，m)、3.21-3.30(2H，m)、3.41(2H，t，J＝8Hz)、3.59-3.68(2H，m)、3.74-3.83(1H，m)、6.90(1H，s)、6.96(1H，d，J＝8Hz)、7.11-7.20(3H，m)、7.30-7.39(2H，m)、10.51(1H，br-s).
FAB-Mass；350(MH+).
EXAMPLE 1251- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carbamoylindoline synthesis
A solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-cyanoindoline (1.0g) in concentrated sulfuric acid (1l) was heated at 50 ℃ for 2 hours. The reaction solution was diluted with ice water, made alkaline with concentrated aqueous sodium hydroxide solution, and ethyl acetate was added to separate an organic layer. After washing with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, the title compound was obtained as white powdery crystals (0.81 g). (yield: 77%)
A portion of the crystals was taken and converted to the hydrochloride salt according to a conventional method to obtain the title compound as hydrochloride salt as white powdery crystals.
Melting point (hydrochloride salt): 160 ℃ C. and 162 ℃ C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.87-1.95(2H，m)、1.99-2.13(2H，m)、2.94(2H，t，J＝8Hz)、3.04-3.17(4H，m)、3.24-3.31(2H，m)、3.38(2H，t，J＝8Hz)，3.60-3.68(2H，m)、3.73-3.83(1H，m)、7.01(1H，s)、7.07(1H，d，J＝8Hz)、7.12(1H，d，J＝8Hz)、7.16-7.21(3H，m)、7.32-7.36(2H，m)，7.79(1H，br-s).
FAB-Mass；368(MH+).
EXAMPLE 1261 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-pyrrolylcarbonyl) indoline
A mixture of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carbamoylindoline (0.3g), 1, 4-dichloro-1, 4-dimethoxybutane (0.7g), Amberlyst A-21(0.21g) and acetonitrile (10ml) was heated at 60 ℃ for 10 hours. The reaction solution was filtered, made alkaline with a saturated aqueous solution of sodium hydroxide, and ethyl acetate was added to separate an organic layer. After washing with saturated brine, drying over anhydrous magnesium sulfate, concentration under reduced pressure was carried out, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) and converted to the oxalate according to a conventional method to give the title compound as crystals (0.13g) of oxalate as pale yellow powder. (yield: 31%)
Melting point (oxalate): 169-171 deg.C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.83-1.94(4H，m)、2.90-2.97(4H，m)、3.02(2H，t，J＝8Hz)、3.08-3.19(2H，m)、3.41-3.55(4H，m)、3.72-3.83(1H，m)、6.37(2H，s)、6.80(1H，s)、6.89(1H，d，J＝8Hz)、7.14-7.21(3H，m)、7.28-7.34(4H，m).
FAB-Mass；418(MH+).
Example 1271 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetylindoline
A solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline (1.0g) in tetrahydrofuran (30ml) at-78 ℃ was added dropwise thereto over 5 minutes a 2.5M n-butyllithium/hexane solution (1.5 ml). After 10 minutes, dimethylacetamide (0.34ml) was added thereto, the mixture was warmed to room temperature, a saturated aqueous ammonium chloride solution and ethyl acetate were added to the mixture, an organic layer was separated, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) to give the title compound as yellow powder crystals (250 mg). (yield: 27 ℃ C.)
Melting point: 90-92 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.71-1.86(4H，m)、2.12-2.22(2H，m)、2.56(3H，s)、2.57-2.64(2H，m)、2.77-2.84(2H，m)、2.99(2H，t，J＝8Hz)、3.07-3.16(2H，m)、3.42-3.56(1H，m)、3.46(2H，t，J＝8Hz)、6.94-6.99(3H，m)、7.08(1H，d，J＝8Hz)、7.14-7.23(3H，m).
FAB-Mass；367(MH+).
EXAMPLE synthesis of 1281- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methanesulfonylindoline
A2.5M n-butyllithium/hexane solution (0.6ml) was added dropwise to a tetrahydrofuran solution (20ml) of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline (470mg) at-78 ℃ over 10 minutes. After 10 minutes, a saturated sulfur dioxide/tetrahydrofuran solution (50ml) was added and the temperature was raised to room temperature. The reaction mixture was concentrated under reduced pressure, and dimethylformamide (10ml) and methyl iodide (100mg) were added to the residue, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the mixture to separate an organic layer, which was washed with saturated brine, dried over anhydrous magnesium sulfate, purified by NH silica gel column chromatography (hexane/ethyl acetate) and converted to a hydrochloride according to a conventional method to obtain brown prismatic crystals (20mg) of the hydrochloride of the title compound. (yield: 3.8%)
Melting point (hydrochloride salt): 228 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.83-2.09(4H，m)、2.98-3.18(6H，m)、3.10(3H，s)、3.20-3.31(2H，m)，3.44(2H，t，J＝8Hz)、3.59-3.68(2H，m)、3.80-3.93(1H，m)、6.91(1H，s)、7.06(1H，d，J＝8Hz)、7.14-7.23(3H，m)、7.30-7.35(2H，m).
FAB-Mass；403(MH+).
Example 1291 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-thiocarbamoylmethylindole
A mixture of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carbamoylmethyl indoline (720mg), phosphorus pentasulfide (250mg) and pyridine (20ml) was refluxed for 1 hour, and then diluted with 5N aqueous sodium hydroxide solution and ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) and converted to the hydrochloride according to a conventional method to give the title compound hydrochloride as a white hygroscopic amorphous (170 mg). (yield: 21 ℃ C.)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.86-1.94(2H，m)、2.02-2.15(2H，m)、2.86(2H，t，J＝8Hz)、3.03-3.16(4H，m)、3.22-3.30(2H，m)、3.33(2H，t，J＝8Hz)、3.60-3.74(3H，m)、3.70(2H，s)、6.57(1H，d，J＝8Hz)、6.61(1H，s)，6.95(1H，d，J＝8Hz)、7.16-7.21(2H，m)、7.32-7.36(2H，m)、9.26(1H，br-s)、9.42(1H，br-s)、10.60(1H，br-s).
FAB-Mass；398(MH+).
Example 1301 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindoline
A solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline (40g) in tetrahydrofuran (1l) at-78 ℃ was added dropwise thereto over 10 minutes a 2.5M n-butyllithium/hexane solution (50 ml). After 10 minutes, dimethylacetamide (11.6ml) was added thereto, the mixture was warmed to room temperature, a saturated aqueous ammonium chloride solution (200ml) and ethyl acetate (500ml) were added thereto, the organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product of the title compound (37.5g), and a portion thereof was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as crystals (250mg) as a yellow powder.
Melting point: 109 ℃ and 111 DEG C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.78-1.80(4H，m)、2.10-2.29(2H，m)、2.59-2.68(2H，m)、2.79-2.90(2H，m)、3.03(2H，t，J＝8Hz)、3.10-3.19(2H，m)、3.42-3.53(1H，m)、3.50(2H，t，J＝8Hz)、6.82(1H，s)、6.91-7.00(2H，m)、7.09(1H，d，J＝8Hz)、7.13-7.19(3H，m)，9.85(1H，s).
FAB-Mass；353(MH+).
EXAMPLE 1311 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-oxime methylindoline
A suspension of crude 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindoline (35g), hydroxylamine hydrochloride (10.4g) and anhydrous sodium acetate (12.3g) in ethanol (400ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (500ml), 8N aqueous sodium hydroxide (30ml) and water (100ml), the organic layer was separated, washed with saturated brine, dried over magnesium sulfate, the solvent was evaporated, the residue was dissolved in a mixed solvent of toluene (100 ml)/isopropyl ether (100ml) while hot, cooled to room temperature, the precipitated crystals were filtered off, and dried at 50 ℃ to give the title compound as pale yellow powder crystals (31 g). (yield: 85%)
Melting point: 152 ℃ and 154 DEG C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.78-1.85(4H，m)、2.08-2.20(2H，m)、2.56-2.64(2H，m)，2.78-2.84(2H，m)、2.92(2H，t，J＝8Hz)、3.10-3.19(2H，m)、3.40-3.50(1H，m)、3.46(2H，t，J＝8Hz)、6.69(1H，s)、6.70(1H，d，J＝8Hz)、6.92-7.00(2H，m)，7.03(1H，d，J＝8Hz)、7.15-7.20(2H，m)、8.06(1，s).
FAB-Mass；368(MH+).
EXAMPLE 1321 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindoline
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-oxime methylindoline (31g) was added in small portions to a suspension of lithium aluminum hydride (8.0g) in tetrahydrofuran (500ml) under ice cooling, and heated under reflux for 3 hours. While the reaction mixture was chilled in ice water, water (8ml) was carefully added dropwise to the reaction mixture, followed by 5N aqueous sodium hydroxide solution (24ml), followed by addition of water (8ml), and the mixture was vigorously stirred. The precipitated crystals were filtered off to give the crude title compound (about 30 g). Taking part of the crude product, refining by NH-silica gel column chromatography (ethyl acetate), and recrystallizing with ethyl acetate/isopropyl ether mixed solvent to obtain the title compound as light yellow powder crystal.
Melting point: 83-85 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.52-2.02(6H，m)、2.10-2.20(2H，m)、2.56-2.63(2H，m)、2.78-2.83(2H，m)、2.91(2H，t，J＝8Hz)、3.10-3.18(2H，m)、3.37-3.50(1H，m)、3.41(2H，t，J＝8Hz)、3.69(2H，s)、6.39(1H，s)、6.51(1H，d，J＝8Hz)、6.93-7.01(3H，m)、7.12-7.20(2H，m).
FAB-Mass；354(MH+)
Example 1331 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindoline
Acetyl chloride (6.6ml) was added dropwise to an acetonitrile (500ml) solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindoline (30g) and triethylamine (9.4g) obtained in the above example under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added a 5N aqueous solution (40ml) of sodium hydroxide and water (500ml), and the precipitated crystals were filtered off. The crystals were washed with water and ethyl acetate and dried at 50 ℃ overnight to give the crude title compound (22.8 g). The crude product was recrystallized from ethyl acetate and then ethanol to give the title compound as white needles (17.9 g). (yield: 54%)
Melting point; 160 ℃ C. and 162 ℃ C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.78-1.86(4H，m)、2.01(3H，s)、2.12-2.28(2H，m)、2.58-2.72(2H，m)、2.76-2.89(2H，m)、2.93(2H，t，J＝8Hz)、3.08-3.26(2H，m)、3.35-3.46(1H，m)、3.42(2H，t，J＝8Hz)、4.33(2H，d，J＝6Hz)，5.69(1H，br-s)、6.34(1H，s)、6.51(1H，d，J＝8Hz)、6.95-7.02(3H，m)、7.14-7.20(2H，m).
FAB-Mass；396(MH+).
EXAMPLE 1341 Synthesis of- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindoline
The title compound was obtained as white powder crystals (190mg) from 1- (piperidin-4-yl) -6-acetamidomethylindoline (250mg) and 2-fluorophenethyl bromide (220mg) by the same method as in example 2. (yield: 52%)
Melting point: 160 ℃ plus 161 DEG C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.51-1.68(2H，m)、1.81-1.92(2H，m)、2.00(3H，s)、2.20-2.40(2H，m)、2.70-2.89(4H，m)、2.91(2H，t，J＝8Hz)、3.01-3.10(2H，m)、3.40-3.48(3H，m)、4.32(2H，d，J＝6Hz)、6.39(1H，s)、6.51(1H，d，J＝8Hz)、6.98-7.10(3H，m)、7.18-7.30(2H，m).
FAB-Mass；396(MH+).
Example 1351 Synthesis of- [1- (3-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindoline
The title compound was obtained as white needles (210mg) in the same manner as in example 2 from 1- (piperidin-4-yl) -6-acetamidomethylindoline (250mg) and 3-fluorophenethyl bromide (220 mg). (yield: 58%)
Melting point: 161-162 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.51-1.68(2H，m)、1.80-1.89(2H，m)、2.00(3H，s)、2.11-2.37(4H，m)、2.65-2.75(2H，m)、2.91(2H，t，J＝8Hz)、3.12-3.29(2H，m)、3.40-3.48(3H，m)、4.32(2H，d，J＝6Hz)、6.38(1H，s)、6.51(1H，d，J＝8Hz)、6.98-6.98(2H，m)、7.00-7.05(2H，m)、7.21-7.30(1H，m).
FAB-Mass；396(MH+).
Example Synthesis of 1361- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-hydroxymethylindoline
A solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline (80g) in tetrahydrofuran (2l) at-78 ℃ was added dropwise thereto over 15 minutes a 2.5M n-butyllithium/hexane solution (100 ml). After 10 minutes, dimethylacetamide (23.2ml) was added thereto, the temperature was raised to room temperature, a saturated aqueous ammonium chloride solution (400ml) and ethyl acetate (1l) were added thereto, an organic layer was separated, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, ethanol (240ml) and sodium borohydride (7.6g) were added to the residue, stirred at room temperature for 1 hour, ice water (480ml) was added to the reaction solution to filter out the precipitated crystals, washed with water, and air-dried at 50 ℃ overnight to give the title compound as yellow powder crystals (about 71g), a portion of the crude product was taken out, purified by silica gel column chromatography (ethyl acetate/methanol) and converted to the hydrochloride according to a conventional method to give pale purple powder crystals of the hydrochloride of the title compound.
Melting point (hydrochloride salt): 190 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.81-1.90(2H，m)、1.99-2.11(2H，m)、2.81-2.90(2H，m)、3.02-3.13(4H，m)、3.20-3.29(2H，m)、3.31(2H，t，J＝8Hz)、3.68-3.63(2H，m)、3.70-3.80(1H，m)、4.38(2H，s)、6.30-6.37(2H，m)、6.96(1H，d，J＝8Hz)、7.12-7.20(2H，m)、7.30-7.36(2H，m)、10.60(1H，br-s).
FAB-Mass；355(MH+).
EXAMPLE 1371 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-hydroxyethyl) indoline
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetylindoline (0.17g) in ethanol (5ml) was added hydrogen boride (0.03g), and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture to separate an organic layer, which was washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (150mg) as a colorless oil. (yield: 89%)
Oxalic acid (37mg) was added to an acetone solution of the oil to give the title compound as an oxalate salt as a gray powder. (140mg)
Melting point (oxalate): 113 ℃ and 116 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.28(3H，d，J＝6Hz)、1.84-2.05(4H，m)、2.84(2H，t，J＝8Hz)、3.00-3.35(8H，m)、3.55-3.68(2H，m)、3.70-3.80(1H，m)、4.61(1H，q，J＝6Hz)、6.52-6.54(2H，m)、6.94(1H，d，J＝8Hz)、7.16-7.21(2H，m)、7.32-7.36(2H，m).
FAB-Mass；369(MH+).
Example 1381- [1- (4-fluorophenethyl) piperidin-4-yl]Synthesis of (E) -6- (1-hydroxypropyl) indoline
To a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindoline (1.0g) in tetrahydrofuran (30ml) at-78 ℃ was added dropwise a 3M ethyl magnesium/diethyl ether solution (1.4ml), and the temperature was raised to room temperature. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) to give the title compound (710mg) as a colorless oil. (yield: 66%)
Oxalic acid (47mg) was added to an acetone solution of the oil (200mg) to give the title compound as pale brown powdery crystals (150mg).
Melting point (oxalate): 106 ℃ and 108 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
0.80(3H，t，J＝7Hz)、1.50-1.61(2H，m)、1.80-1.95(4H，m)、2.85(2H，t，J＝8Hz)、2.95-3.25(6H，m)、3.31(2H，t，J＝8Hz)，3.51-3.62(2H，m)、3.66-3.78(1H，m)、4.32(1H，t，J＝6Hz)、6.49-6.51(2H，m)、6.94(1H，d，J＝8Hz)、7.16-7.21(2H，m)、7.31-7.35(2H，m).
FAB-Mass；383(MH+).
EXAMPLE 1391 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-hydroxy-1-methylethyl) indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline (0.75g), 2.5M n-butyllithium/hexane solution (1.1ml) and acetone (0.16g), the title compound was obtained as crystals of the oxalate salt of the compound (250mg) as a pale yellow powder in the same manner as in example 130. (yield: 35%)
Melting point (oxalate): 179 plus 182 deg.C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.38(6H，s)、1.81-1.90(4H，m)、2.83(2H，t，J＝8Hz)、2.91-3.04(4H，m)、3.11-3.20(2H，m)、3.30(2H，t，J＝8Hz)、3.50-3.59(2H，m)、3.66-3.74(1H，m)、6.63-6.65(2H，m)、6.92(1H，d，J＝8Hz)、7.15-7.20(2H，m)、7.31-7.35(2H，m).
FAB-Mass；383(MH+).
Example 1401 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-hydroxycyclobutyl) indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline (0.5g), 2.5M n-butyllithium/hexane solution (0.8ml) and cyclobutanone (0.14ml), the title compound hydrochloride was obtained as white powder crystals (150mg) in the same manner as in example 130. (yield: 29%)
Melting point (hydrochloride salt): 172 ℃ C. & lt 175 ℃ C.)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.53-1.64(1H，m)，1.82-1.94(3H，m)、1.96-2.09(2H，m)、2.16-2.26(2H，m)、2.31-2.40(2H，m)、2.87(2H，t，J＝8Hz)、3.00-3.44(9H，m)、3.60-3.70(2H，m)、6.64(1H，s)、6.72(1H，d，J＝8Hz)、6.99(1H，d，J＝8Hz)、7.16-7.22(2H，m)、7.32-7.36(2H，m).
FAB-Mass；395(MH+).
EXAMPLE 1411 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-hydroxycyclopentyl) indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline (0.5g), 2.5M n-butyllithium/hexane solution (0.8ml) and cyclopentanone (0.17ml), the title compound hydrochloride was obtained as white powder crystals (240mg) in the same manner as in example 130. (yield: 45%)
Melting point (hydrochloride salt): 191 plus 194 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.64-2.00(12H，m)、2.81(2H，t，J＝8Hz)、2.96-3.04(2H，m)，3.06-3.16(2H，m)、3.20-3.31(2H，m)，3.34-3.78(5H，m)、6.59(1H，s)、6.64(1H，d，J＝8Hz)，6.90(1H，d，J＝8Hz)、7.11-7.19(2H，m)、7.30-7.38(2H，m).
FAB-Mass；409(MH+).
Example 1421 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-chloromethylindoline
Concentrated hydrochloric acid (280ml) was added to 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-hydroxymethylindoline (about 70g) in the same manner as in example 130, and the mixture was stirred at 80 ℃ for 1 day. The reaction mixture was neutralized to pH7 with concentrated aqueous sodium hydroxide solution under ice-cooling, ethyl acetate (200ml) was added, the precipitated crystals were filtered off, the crystals were dissolved in ethyl acetate (500ml) and 5N aqueous sodium hydroxide solution (500ml), the organic layer was separated, the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as pale yellow powder crystals (70 g). (yield: 94%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.76-1.90(4H，m)、2.10-2.26(2H，m)、2.58-2.70(2H，m)，2.78-2.90(2H，m)、2.94(2H，t，J＝8Hz)、3.10-3.24(2H，m)、3.36-3.51(1H，m)、3.43(2H，t，J＝8Hz)、4.53(2H，s)、6.40(1H，s)、6.60(1H，d，J＝8Hz)、6.95-7.02(3H，m)、7.14-7.19(2H，m).
EXAMPLE 1431 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-fluoromethyl indoline
Diethylaminosulfanilamide trifluoride (DAST, 160mg) was added dropwise to a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-hydroxymethylindoline (300mg) in dichloromethane (10ml) at-78 ℃ and stirred for 1 hour. Saturated aqueous sodium bicarbonate and ethyl acetate were added, and the organic layer was separated and dried over anhydrous magnesium sulfate. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) and converted to the hydrochloride according to a conventional method to give the title compound as a hydrochloride salt in the form of white powder crystals (100 mg). (yield: 30%)
Melting point (hydrochloride salt): 190 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.84-1.93(2H，m)、2.01-2.14(2H，m)、2.87-2.95(2H，m)，3.00-3.16(4H，m)、3.21-3.30(4H，m)、3.37(2H，t，J＝8Hz)、3.59-3.68(2H，m)、3.73-3.83(1H，m)、5.28(2H，d，J＝22Hz)、6.60-6.63(2H，m)、7.05(1H，d，J＝8Hz)、7.16-7.21(2H，m)、7.33-7.36(2H，m)、10.70(1H，br-s).
FAB-Mass；357(MH+).
Example 1441 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-fluoroethyl) indoline
To a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-hydroxyethylindoline (400mg) in dichloromethane (20ml) at-78 ℃ was added dropwise diethylaminosulfanilamide trifluoride (DAST, 160mg) with stirring for 1 hour, a saturated aqueous sodium hydrogencarbonate solution and chloroform were added, the organic layer was separated, dried over anhydrous magnesium sulfate, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) and converted into a hydrochloride according to a conventional method to give the title compound as a hydrochloride salt as a white hygroscopic amorphous (100mg) (yield: 23%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.55(3H，dd，J＝24,6Hz)、1.82-1.92(2H，m)，1.96-2.10(2H，m)、2.81-2.93(2H，m)、3.01-3.18(4H，m)、3.22-3.49(4H，m)、3.59-3.69(2H，m)、3.71-3.85(1H，m)、5.57(1H，dq，J＝48,6Hz)、6.5 4-
6.61(2H，m)、6.98-7.04(1H，m)、7.18-7.21(2H，m)、7.32-7.40(2H，m).
FAB-Mass；371(MH+).
EXAMPLE 1451 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-cyanomethylindoline
To 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-chloromethylindoline (about 70g) were added dimethylsulfoxide (500ml) and sodium cyanide (9.8g), and the mixture was stirred at 50 ℃ for 2 hours. Ice water (500ml) was added to the reaction mixture, followed by vigorous stirring, and the precipitated crystals were collected by filtration, washed with water, and then air-dried at 80 ℃ to give the title compound as pale yellow powder crystals (67 g). (yield: 93%)
The fractions were purified by silica gel column chromatography (ethyl acetate/hexane) and converted to the hydrochloride salt according to a conventional method to obtain the title compound as a hydrochloride salt as white powder crystals.
Melting point (hydrochloride salt): 211 ℃ C. 214 ℃ C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.83-1.91(2H，m)、1.99-2.12(2H，m)、2.90(2H，t，J＝8Hz)，3.00-3.19(4H，m)、3.21-3.32.(2H，m)、3.35(2H，t，J＝8Hz)、3.60-3.80(3H，m)、3.90(2H，s)、6.49(1H，s)、6.51(1H，d，J＝8Hz)、7.01(1H，d，J＝8Hz)、7.13-7.21(2H，m)、7.30-7.40(2H，m).
FAB-Mass；364(MH+).
Example Synthesis of 1461- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carboxymethyldihydroindole
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-cyanomethylindoline (about 67g) was dissolved in water (134ml) and concentrated sulfuric acid (134ml), and heated under reflux for 7 hours. The pH of the mixture was adjusted to 10 with concentrated aqueous sodium hydroxide solution under ice cooling, and ethyl acetate (300ml) was added thereto and the mixture was vigorously stirred. Thereafter, the pH was adjusted to about 6 with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals were washed with water and air-dried at 50 ℃ for one day and night. The title compound was obtained as white powdery crystals (58 g). (yield: 76%)
Melting point: 130 ℃ C. and 132 ℃ C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.53-1.73(4H，m)、2.70-2.90(4H，m)、3.00-3.53(12H，m)、6.31(1H，s)、6.39(1H，d，J＝8Hz)、6.90(1H，d，J＝8Hz)、7.04-7.15(2H，m)、7.22-7.30(2H，m).
FAB-Mass；383(MH+).
EXAMPLE 1471 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carbamoylmethylindoline
Crude 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-cyanomethylindoline (230mg) was dissolved in concentrated sulfuric acid (5ml), which was stirred overnight. The reaction solution was diluted with ice water. The pH was adjusted to 10 with concentrated aqueous sodium hydroxide solution under ice cooling, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/ethanol) and converted into the hydrochloride according to a conventional method to give the title compound hydrochloride as a white hygroscopic amorphous form (200 mg). (yield: 76%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.83-1.92(2H，m)、2.02-2.17(2H，m)、2.86(2H，t，J＝8Hz)、3.00-3.16(4H，m)、3.21-3.29(2H，m)、3.34(2H，t，J＝8Hz)、3.60-4.10(5H，m)、6.43-6.51(2H，m)、6.81(1H，br-s)、6.95(1H，d，J＝8Hz)、7.16-7.21(2H，m)、7.32-7.39(3H，m).
FAB-Mass；382(MH+).
EXAMPLE 1481 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (methylcarbamoylmethyl) indoline
Ethyl chlorocarbonate (87mg) was added to a mixed solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carboxymethyldihydroindole (250mg), triethylamine (81mg), dimethylformamide (6ml) and tetrahydrofuran (8ml) at-78 ℃, and the mixture was warmed to-30 ℃, added with a 2N methylamine/tetrahydrofuran solution (0.4ml), warmed to room temperature again and stirred for 30 minutes. Ice water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution and saturated brine in this order, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/ethanol) and converted into a hydrochloride according to a conventional method to give the title compound hydrochloride as a white hygroscopic amorphous form (120 mg). (yield: 45%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.83-1.92(2H，m)、2.00-2.13(2H，m)、2.55(3H，d，J＝4Hz)、2.86(2H，t、J＝8Hz)、2.99-3.16(4H，m)、3.22-3.30(4H，m)、3.33(2H，t，J＝8Hz)、3.60-3.76(3H，m)、6.45-6.50(2H，m)、6.94(1H，d，J＝8Hz)、7.16-7.22(2H，m)、7.32-7.40(2H，m)、7.84(1H，d，J＝4Hz)、10.53(1H，br-s).
FAB-Mass；396(MH+).
Example 1491 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (ethylcarbamoylmethyl) indoline
To a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carboxymethyldihydroindole (2.0g) in dimethylformamide (40ml) was added 1, 1' -carbonyldiimidazole (1.0g) under ice-cooling, followed by stirring for 2 hours, followed by addition of ethylamine hydrochloride (0.51g), warming to room temperature, and further stirring for 5 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in hot toluene (10ml), which was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound as white powdery crystals (1.3 g). (yield: 56%)
The hydrochloride salt was converted to the hydrochloride salt according to a conventional method and recrystallized from acetone to obtain the title compound as a white powdery crystal as the hydrochloride salt.
Melting point (hydrochloride salt): 161-164 deg.C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
0.99(3H，t，J＝7Hz)、1.83-1.93(2H，m)、1.96-2.11(2H，m)、2.85(2H，t.J＝8Hz)、2.98-3.17(6H，m)、3.23-3.39(6H，m)、3.61-3.75(3H，m)、6.41-6.48(2H，m)、6.93(1H，d，J＝8Hz)、7.15-7.23(2H，m)、7.30-7.37(2H，m)、7.92(1H，br-s).
FAB-Mass；410(MH+).
Example 1501 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (n-propylcarbamoylmethyl) indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carboxymethyldihydroindole (220mg), 1' -carbonyldiimidazole (110mg) and n-propylamine (41mg), the title compound was obtained as white needles (90mg) in the same manner as in example 149. (yield: 37%)
Melting point: 143 ℃ C. (145 ℃ C.)
1H-NMR(400MHz，CDCl3)；δ(ppm)
0.83(3H，t，J＝7Hz)、1.42(2H，sextet，J＝7Hz)、1.75-1.79(4H，m)、2.10-2.30(2H，m)、2.53-2.71(2H，m)、2.78-2.90(2H，m)、2.95(2H，t，J＝8Hz)、3.09-3.21(4H，m)、3.37-3.49(1H，m)、3.42(2H，t，J＝8Hz)、3.50(2H，s)、5.51(1H，br-s)、6.29(1H，s)，6.48(1H，d，J＝8Hz)、6.92-7.01(3H，m)、7.12-7.20(2H，m).
FAB-Mass；424(MH+).
Example 1511 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (isopropylcarbamoylmethyl) indoline
To a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carboxymethyldihydroindole (30g) in dimethylformamide (240ml) was added 1, 1' -carbonyldiimidazole (15g) under ice cooling, followed by stirring for 2 hours, isopropylamine (5.6g) was added, the temperature was raised to room temperature, and further stirring was carried out for 2 hours. Ice water (240ml) and ethyl acetate (300ml) were added to the reaction mixture to separate an organic layer. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution and saturated brine in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in hot ethyl acetate (80ml), which was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound as white powdery crystals (17.2 g).
The hydrochloride salt was converted to the hydrochloride salt according to a conventional method and recrystallized from ethanol to obtain the title compound as a white powdery crystal as the hydrochloride salt.
Melting point (hydrochloride salt): 153-
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.03(6H，d，J＝7Hz)、1.84-1.92(2H，m)、1.96-2.10(2H，m)、2.85(2H，t，J＝8Hz)、3.01-3.16(4H，m)、3.20-3.38(6H，m)、3.61-3.83(4H，m)、6.42-6.46(2H，m)、6.93(1H，d，J＝8Hz)、7.16-7.23(2H，m)、7.31-7.38(2H，m)、7.83(1H，d，J＝8Hz).
FAB-Mass；424(MH+).
EXAMPLE 1521 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (isobutylcarbamoylmethyl) indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carboxymethyldihydroindole (300mg), 1' -carbonyldiimidazole (150mg) and isobutylamine (69mg) in the same manner as in example 149, the hydrochloride of the title compound was obtained as white needles (270 mg). (yield: 72%)
Melting point (hydrochloride salt): 122 ℃ C. 114 ℃ C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
0.81(6H，d，J＝7Hz)、1.66(1H，septet，J＝7Hz)、1.84-1.92(2H，m)、2.00-2.15(4H，m)、2.81-2.90(4H，m)、3.02-3.15(2H.m)、3.23-3.38(4H，m)、3.44-3.73(5H，m)、6.48-6.53(2H，m)、6.95(1H，d，J＝8Hz)、7.17-7.22(2H，m)、7.29-7.40(2H，m)、7.94(1H，br-s).
FAB-Mass；438(MH+).
EXAMPLE 1531 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (tert-butylcarbamoylmethyl) indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carboxymethyldihydroindole (250mg), 1' -carbonyldiimidazole (130mg) and tert-butylamine (58mg) in the same manner as in example 151, the hydrochloride of the title compound was obtained as crystals (140mg) as a pale brown powder. (yield: 45%)
Melting point (hydrochloride salt): 189 deg.C, 192 deg.C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.24(9H，s)、1.84-1.92(2H，m)、2.03-2.16(2H，m)、2.87(2H，t，J＝8Hz)、3.03-3.15(4H，m)、3.22-3.30(4H，m)、3.34(2H，t，J＝8Hz)、3.58-3.77(3H，m)、6.47-6.50(2H，m)、6.95(1H，d，J＝8Hz)、7.16-7.21(2H，m)、7.32-7.36(2H，m)、7.58(1H，br-s)、10.69(1H，br-s).
FAB-Mass；438(MH+).
EXAMPLE 1541 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (cyclopropylcarbamoylmethyl) indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carboxymethyldihydroindole (250mg), 1' -carbonyldiimidazole (130mg) and cyclopropylamine (45mg) in the same manner as in example 151, the title compound was obtained as white powder crystals (110 mg). (yield: 40%)
Melting point: 182 ℃ and 184 DEG C
1H-NMR(400MHz，CDCl3)；δ(ppm)
0.36-0.41(2H，m)、0.69-0.74(2H，m)、1.75-1.90(4H，m)、2.10-2.30(2H，m)、2.60-2.71(3H，m)、2.75-2.90(2H，m)、2.94(2H，t，J＝8Hz)、3.10-3.25(2H，m)、3.35-3.48(5H，m)、5.60(1H，br-s)、6.26(1H，s)、6.42(1H，d，J＝8Hz)、6.96-7.01(3H，m)、7.15-7.20(2H，m).
FAB-Mass；422(MH+).
EXAMPLE 1551 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (tetramethylenecarbamoylmethyl) indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carboxymethyldihydroindole (360mg), 1' -carbonyldiimidazole (160mg) and pyrrolidine (70mg) in the same manner as in example 151, the hydrochloride of the title compound was obtained as white powder crystals (280 mg). (yield: 60%)
Melting point (hydrochloride salt): 159 ℃ plus 161 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.90-2.04(8H，m)、2.86(2H，t，J＝8Hz)、3.00-3.19(4H，m)、3.21-3.39(6H，m)、3.42(2H，t，J＝8Hz)、3.61-3.76(3H，m)，6.41(1H，s)、6.43(1H，d，J＝8Hz)、6.94(1H，d，J＝8Hz)、7.17-7.22(2H，m)、7.30-7.37(2H，m).
FAB-Mass；436(MH+).
EXAMPLE 1561 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-propionylaminomethylindoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindoline (200mg), triethylamine (69mg) and propionyl chloride (63mg) in the same manner as in example 133, the title compound was obtained as crystals (88mg) as a pale brown powder as a hydrochloride salt. (yield: 35%)
Melting point (hydrochloride salt): 157 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
0.99(3H，t，J＝7Hz)、1.82-2.10(4H，m)、2.10(2H，q，J＝7Hz)、2.84(2H，t，J＝8Hz)、2.92-3.14(4H，m)、3.21-3.35(4H，m)、3.59-3.73(3H，m)、4.12(2H，d，J＝6Hz)、6.41(1H，s)，6.44(1H，d，J＝8Hz)、6.94(1H，d，J＝8Hz)、7.15-7.20(2H，m)、7.30-7.35(2H，m)、8.12(1H，t，J＝6Hz).
FAB-Mass；410(MH+).
EXAMPLE 1571 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-n-butylaminomethyl indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindoline (200mg), triethylamine (69mg) and n-butyryl chloride (72mg) in the same manner as in example 133, the title compound was obtained as hydrochloride salt as pale yellow needles (110 mg). (yield: 46%)
Melting point: 153-
1H-NMR(400MHz，CDCl3)；δ(ppm)
0.96(3H，t，J＝7Hz)、1.68(2H，sextet，J＝7Hz)、1.75-1.83(4H，m)、2.10-2.22(2H，m)、2.17(2H，q，J＝7Hz)、2.55-2.70(2H，m)、2.74-2.90(2H，m)、2.93(2H，t，J＝8Hz)、3.05-3.20(2H，m)、3.35-3.45(1H，m)，3.42(2H，t，J＝8Hz)，4.34(2H，d，J＝6Hz)，6.33(1H，s)、6.50(1H，d，J＝8Hz)、6.95-7.00(3H，m)、7.10-7.19(2H，m).
FAB-Mass；424(MH+).
EXAMPLE 1581 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-isobutyrylaminomethylindoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindoline (300mg), triethylamine (80mg) and isobutyryl chloride (90mg) in the same manner as in example 133, the title compound was obtained as white needles (200 mg). (yield: 58%)
Melting point: 163 ℃ C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.17(6H，d，J＝7Hz)、1.51-1.66(2H，m)、1.75-1.87(2H，m)、2.10-2.25(2H，m)、2.36(1H，septet，J＝7Hz)、2.56-2.72(2H，m)、2.75-2.95(2H，m)、2.93(2H，t，J＝8Hz)、3.08-3.25(2H，m)、3.35-3.45(1H，m)、3.42(2H，t，J＝8Hz)、4.34(2H，d，J＝6Hz)、6.33(1H，s)、6.50(1H，d，J＝8Hz)、6.96-7.01(3H，m)、7.15-7.19(2H，m).
FAB-Mass；424(MH+).
EXAMPLE 1591 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-cyclopropanecarboxamidomethylindoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindoline (250mg) and cyclopropanecarbonyl chloride (81mg) in the same manner as in example 133, the title compound was obtained as a hydrochloride salt as a white powder (100 mg). (yield: 31%)
Melting point: 143 ℃ C. and 146 ℃ C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
0.60-0.69(4H，m)、1.55-1.63(1H，m)、1.83-1.90(2H，m)、1.99-2.09(2H，m)、2.86(2H，t，J＝8Hz)、3.02-3.16(4H，m)、3.22-3.30(2H，m)、3.31(2H，t，J＝8Hz)、3.60-3.79(3H，m)、4.16(2H，d，J＝6Hz)、6.47(1H，s)、6.48(1H，d，J＝8Hz)、6.98(1H，d，J＝8Hz)、7.16-7.21(2H，m)、7.32-7.38(2H，m)、8.43(1H，d，J＝6Hz).
FAB-Mass；422(MH+).
Example 1601 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methanesulfonamidomethylindoline
To a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindoline (200mg) in pyridine (20ml) was added methanesulfonyl chloride (78mg) dropwise under ice cooling, followed by stirring for 30 minutes, concentration under reduced pressure, partition of the residue between ethyl acetate and water, washing the organic layer with saturated brine, drying over anhydrous magnesium sulfate, and concentration under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/ethanol) and then converted into a hydrochloride according to a conventional method to give the hydrochloride of the title compound as a white hygroscopic amorphous form (160 mg). (yield: 60%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.81-1.91(2H，m)、2.00-2.12(2H，m)、2.78(3H，s)、2.82-2.90(2H，m)、2.97-3.15(4H，m)、3.19-3.30(2H，m)、3.33(2H，t，J＝8Hz)、3.58-3.75(3H，m)、4.02(2H，s)、6.53(1H，s)、6.55(1H，d，J＝8Hz)、6.98(1H，d，J＝8Hz)、7.14-7.19(2H，m)、7.30-7.34(2H，m)、7.42(1H，br-s)、10.70(1H，br-s).
FAB-Mass；432(MH+).
EXAMPLE 1611 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-ureidomethyl-indoline
To a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindoline (300mg) and nitrourea (90mg) in methanol (10ml) under ice cooling, was heated under reflux for 3 hours, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate. The crystals were dissolved in ethanol and converted to hydrochloride to give the title compound as a gray hygroscopic amorphous (260 mg). (yield: 71%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.83-2.02(4H，m)、2.84(2H，t，J＝8Hz)、2.98-3.16(4H，m)、3.20-3.74(7H，m)、4.04(2H，br-s)、6.42(1H，s)、6.45(1H，d，J＝8Hz)、6.94(1H，d，J＝8Hz)、7.15-7.20(2H，m)、7.31-7.34(2H，m).
FAB-Mass；397(MH+).
EXAMPLE 1621 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-N-methylaminomethylindoline
Ethyl chlorocarbonate (300mg) was added dropwise to a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindoline (800mg) and triethylamine (290mg) in methylene chloride (20ml) at room temperature, followed by stirring for 90 minutes. Concentrated under reduced pressure, the residue was partitioned between water and ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was added to a suspension of lithium aluminum hydride (260mg) in tetrahydrofuran (20ml) and heated under reflux for 1 hour. While the reaction mixture was cooled with ice water, water (0.26ml) was carefully added dropwise, followed by 5N aqueous sodium hydroxide solution (0.78ml), followed by addition of water (0.26ml), and the mixture was vigorously stirred. The precipitated crystals were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/ethanol) to give the title compound (700mg) as an oil. (yield: 83%)
The obtained fractions were converted into hydrochloride salts by a conventional method to obtain the hydrochloride salt of the title compound as a dark red hygroscopic amorphous.
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.90-1.98(2H，m)、2.06-2.20(2H，m)、2.48(3H，s)、2.89(2H，t，J＝8Hz)、2.99-3.12(4H，m)、3.22-3.31(2H，m)、3.35(2H，t，J＝8Hz)、3.58-3.68(3H，m)、3.95(2H，br-s)、6.64(1H，d，J＝8Hz)、6.87(1H，s)、7.03(1H，d，J＝8Hz)、7.10-7.19(2H，m)、7.30-7.34(2H，m)、9.22(2H，br-s)、10.79(1H，br-s).
FAB-Mass；368(MH+).
EXAMPLE 1631 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-N-methylacetamidomethyl indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-N-methylaminomethylindoline (540mg), triethylamine (200mg) and acetyl chloride (150mg), a white hygroscopic amorphous form (330mg) of the hydrochloride of the title compound was obtained in the same manner as in example 133. (yield: 50%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.81-1.89(2H，m)、1.92-2.06(2H，m)、2.02(3H，s)、2.75(1.5H，s)、2.85(1.5H，s)、2.80-2.90(2H，m)、3.00-3.14(4H，m)、3.21-3.36(4H，m)、3.58-3.73(3H，m)、4.35(1H，s)、4.40(1H，s)、6.32(0.5H，s)、6.36(0.5H，s)、6.37(0.5H，d，J＝8Hz)、6.40(0.5H，d，J＝8Hz)、6.95(0.5H，d，J＝8Hz)、6.99(0.5H，d，J＝8Hz)、7.14-7.19(2H，m)、7.30-7.34(2H，m).
FAB-Mass；410(MH+).
Example 1641 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (N-methylsulfamoylmethyl) indoline
From 6- (N-sulfamoylmethyl) indoline (100mg), 1- (4-fluorophenethyl) -4-piperidone (150mg), acetic acid (120mg) and sodium triacetoxyborohydride (140mg) in the same manner as in example 1, the title compound was obtained as white prismatic crystals (100 mg). (yield: 53%)
Melting point: 162 ℃ C. & lt 164 ℃ C. & gt
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.70-1.89(4H，m)、2.07-2.20(2H，m)，2.55-2.64(2H，m)、2.71(3H，d，J＝6Hz)、2.75-2.86(2H，m)、2.95(2H，t，J＝8Hz)、3.08-3.15(2H，m)、3.37-3.50(3H，m)、4.10-4.30(1H，m)、4.18(2H，s)、6.43(1H，s)、6.54(1H，d，J＝8Hz)、6.91-7.03(3H，m)、7.11-7.20(2H，m).
FAB-Mass；432(MH+).
EXAMPLE 1651 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-acetamidomethyl) indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-hydroxyethyl) indoline (300mg), the hydrochloride of the title compound was obtained as a pale yellow hygroscopic amorphous form (80mg) in the same manner as in example 90. (yield: 22%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.29(3H，d，J＝7Hz)、1.82(3H，s)、1.83-1.93(2H，m)、2.00-2.15(2H，m)、2.84(2H，t，J＝8Hz)、3.01-3.15(4H，m)，3.20-3.35(2H，m)、3.32(2H，t，J＝8Hz)、3.60-3.77(3H，m)、4.80(1H，quintet，J＝7Hz)、6.51-6.53(2H，m)、6.95(1H，d，J＝8Hz)、7.17-7.21(2H，m)、7.32-7.37(2H，m)、8.19(1H，d，J＝8Hz).
FAB-Mass；410(MH+).
Example 1661 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidoethylindoline
A mixture of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-cyanomethylindoline (0.25g), platinum oxide (50mg), 5N hydrochloric acid (1.0ml) and methanol (20ml) was catalytically reduced under a hydrogen stream of 3 atm. After 4 hours, the catalyst was filtered off, concentrated under reduced pressure, and the residue was added with 5N aqueous sodium hydroxide (10ml), acetyl chloride (0.2ml) and methylene chloride (20ml), and stirred vigorously for 1 hour. The mixture was diluted with water and chloroform, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) and converted into an oxalate salt according to a conventional method to give a brown hygroscopic amorphous (90mg) of the title compound oxalate. (yield: 26%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.80-1.94(4H，m)、2.08(3H，s)、2.58(2H，t，J＝7Hz)、2.84(2H，t，J＝8Hz)、2.93-3.07(4H，m)、3.15-3.24(4H，m)、3.31(2H，t，J＝8Hz)、3.51-3.59(2H，m)、3.64-3.74(1H，m)、6.36(1H，s)、6.39(1H，d，J＝8Hz)、7.15-7.21(2H，m)、7.31-7.39(2H，m)、7.88(1H，t，J＝6Hz).
FAB-Mass；410(MH+).
EXAMPLE 1671 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ (piperidin-4-yl) methyl ] indoline
A mixture of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1' -hydroxy-4-pyridylmethyl) indoline (1.2g), 10% palladium on charcoal (600mg), 5N hydrochloric acid (2.9ml) and ethanol (30ml) was catalytically reduced under a hydrogen stream of 3 atm. After 7 hours, platinum oxide (150mg) was added and catalytic reduction was carried out for 2 hours. The catalyst was filtered off and concentrated under reduced pressure. The residue was diluted with saturated aqueous sodium hydrogencarbonate and ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue was purified by NH silica gel column chromatography (ethanol/ethyl acetate) and converted to the hydrochloride according to a conventional method to give the title compound as a hydrochloride salt in the form of white powder crystals (510 mg). (yield: 33%)
Melting point (hydrochloride salt): 165 ℃ C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.27-1.40(2H，m)、1.65-1.91(5H，m)、2.03-2.17(2H，m)、2.38-2.44(2H，m)、2.51-2.84(2H，m)、2.84(2H，t，J＝8Hz)、3.01-3.45(10H，m)、3.59-3.76(3H，m)、3.36-3.39(2H，m)、6.93(1H，d，J＝8Hz)、7.16-7.21(2H，m)、7.32-7.36(2H，m)、8.68(1H，br-s)、8.85(1H，br-s)、10.79(1H，br-s).
FAB-Mass；422(MH+).
EXAMPLE 1681 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ (1-acetylpiperidin-4-yl) methyl ] indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ (piperidin-4-yl) methyl ] indoline (100mg) and acetyl chloride (0.1ml), the hydrochloride of the title compound was obtained as a pale yellow hygroscopic amorphous form (50mg) in the same manner as in example 133. (yield: 45%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
0.87-1.12(2H，m)、1.50-1.78(3H，m)、1.82-1.91(2H，m)、1.96(3H，s)、2.00-2.16(2H，m)、2.36-2.45(2H，m)、2.81-2.98(4H，m)、3.00-3.16(4H，m)、3.20-3.38(4H，m)、3.57-3.80(4H，m)、4.26-4.36(1H，m)、6.40-6.42(2H，m)、6.94(1H，d，J＝8Hz)、7.16-7.21(2H，m)、7.32-7.36(2H，m).
FAB-Mass；464(MH+).
EXAMPLE 1691 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ (1-ethylpiperidin-4-yl) methyl ] indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ (piperidin-4-yl) methyl ] indoline (190mg) and iodoethane (84mg) in the same manner as in example 2, the hydrochloride of the title compound was obtained as a pale brown hygroscopic amorphous form (50 mg). (yield: 21%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.22(3H，t，J＝7Hz)、1.43-1.56(2H，m)、1.68-1.70(5H，m)、2.04-2.19(2H，m)、2.38-2.45(2H，m)、2.69-2.83(2H，m)、2.85(2H，t，J＝8Hz)、2.95-3.18(6H，m)、3.20-3.31(2H，m)、3.32(2H，t，J＝8Hz)、3.35-3.43(2H，m)、3.57-3.70(3H，m)、6.37-6.41(2H，m)、6.94(1H，d，J＝8Hz)、7.16-7.22(2H，m)、7.30-7.37(2H，m)、10.17(1H，br-s)、10.80(1H，br-s).
FAB-Mass；450(MH+).
Example 1701- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ (1-methylpiperidin-4-yl) methyl ] indoline synthesis
A mixture of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ (piperidin-4-yl) methyl ] indoline (200mg), formaldehyde (40mg), formic acid (44mg), water (5ml) and methanol (5ml) was heated under reflux overnight. Saturated aqueous sodium hydrogencarbonate and ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) and converted to the hydrochloride according to a conventional method to give the title compound hydrochloride as a pale yellow hygroscopic amorphous form (60 mg). (yield: 25%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.40-1.54(2H，m)、1.63-1.76(3H，m)、1.82-1.90(2H，m)、2.05-2.18(2H，m)、2.38-2.44(2H，m)、2.51(3H，s)、2.64-2.65(2H，m)、2.80-2.90(2H，m)、3.01-3.17(4H，m)、3.20-3.39(6H，m)、3.58-3.70(3H，m)、6.38-6.42(2H，m)、6.94(1H，d，J＝8Hz)、7.16-7.21(2H，m)、7.32-7.36(2H，m)、10.34(1H，br-s)、10.85(1H，br-s).
FAB-Mass；436(MH+).
EXAMPLE 1711 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-pyridyl) indoline
Using 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline (0.405g) and 2-tributyltin (stanyl) pyridine (1.85g) synthesized according to Tetrahedron letters, 4407(1986) in the proceedings of Tetrahedron, the title compound (0.234g) was obtained as a pale yellow oil according to preparation example 13-2. (yield: 46.6%)
Oxalic acid (52mg) was added thereto to form a salt, which was recrystallized from acetone to give the title compound as an oxalate salt as orange crystals (0.254 g).
Melting point (oxalate): 182 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.92(4H，m)、2.95(2H，t，J＝8.4Hz)、2.99(2H，m)、3.04(2H，m)、3.17(2H，m)、3.40(2H，t，J＝8.4Hz)、3.56(2H，br-d)、3.86(1H，m)、7.17(4H，m)、7.32(4H，m)、7.85(2H，m)、8.62(1H，d，J＝4.4Hz).
FAB-Mass；402(MH+).
Example 1721 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-thiazolyl) indoline
Using 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline (0.56g) and 2-tributylstannylthiazole (2.778g) synthesized according to Synthesis, 757 (19%) by the method of preparation 13-2, the title compound (0.017g) was obtained as a pale yellow oil. (yield: 3.0%)
Oxalic acid (2mg) was added thereto to form a salt, which was recrystallized from acetone to give the oxalate of the title compound as yellow crystals.
Melting point (oxalate): 170 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.90(4H，m)、2.95(2H，t，J＝8.4Hz)、2.98(2H，m)、3.04(2H，m)、3.16(2H，m)、3.42(2H，t，J＝8.4Hz)、3.56(2H，m)、3.85(1H，m)、7.06(1H，s)、7.13(2H，m)、7.33(2H，m)、7.71(1H，d，J＝3.2Hz)、7.86(1H，d，J＝3.2Hz).
FAB-Mass；408(MH+).
Example 1731 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-methylpyrrol-2-yl) indoline
Using 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline (0.1g) and 1-methyl-2-tributylstannylpyrrole (0.37g) synthesized according to Tetrahedron letters, 4407(1986) in accordance with preparation example 13-2, the title compound (0.016g) was obtained as a yellow oil. (yield: 15.8%)
Oxalic acid (2mg) was added thereto to form a salt, which was recrystallized from acetone to give the oxalate of the title compound as yellow crystals.
Melting point (oxalate): 118 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.83(4H，m)、2.79(2H，m)，2.90(2H，t，J＝8.4Hz)、2.92(2H，m)、3.02(2H，m)、3.37(2H，t，J＝8.4Hz)、3.41(2H，m)、3.60(3H，s)、3.68(1H，m)、6.01(1H，dd，J＝2.4，3.6Hz)、6.05(1H，dd，J＝2.0，3.6Hz)、6.51(1H，d，J＝1.2Hz)、6.58(1H，dd，J＝1.2，7.6Hz)、6.78(1H，dd，J＝2.0，2.4Hz)、7.04(1H，d，J＝7.6Hz)、7.15(2H，m)、7.31(2H，m).
ESI-Mass；404.2(MH+).
EXAMPLE 1741 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-pyridyl) methyl ] indoline
The title compound (0.344g) was obtained as a yellow oil by the method of example 93 using 2-bromopyridine (0.16ml), 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindoline (0.5g) and diethyl ether as a solvent. (yield: 56.1%)
50mg of oxalic acid (10mg) was added thereto to form a salt, to give the title compound as an oxalate salt as orange crystals.
Melting point (oxalate): 105 ℃ C
Free form
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.72-1.81(4H，m)、2.08-2.19(2H，m)、2.57-5.61(2H，m)、2.78-2.82(2H，m)、2.91(1H，t，J＝8.4Hz)、3.10(2H，br-t)、3.38(2H，t，J＝8.4Hz)、3.40(1H，m)、5.21(1H，d，J＝4.0Hz)、5.66(1H，d，J＝4.0Hz)、6.43(1H.d，J＝1.2Hz)、6.56(1H，dd，J＝1.2，7.2Hz)、6.95-6.99(3H，m)、7.13-7.26(4H，m)、7.60(1H，ddd，J＝1.6，7.2，8.8Hz)、8.54(1H，ddd，J＝0.8，1.6，4.0Hz).
ESI-Mass；432.2(MH+).
EXAMPLE 1751 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [1- (2-pyridyl) methyl ] indoline
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-pyridyl) methyl ] indoline (0.321g) was dissolved in ethanol (86.4ml), and 1N hydrochloric acid (3.7ml) and palladium on charcoal were added to conduct catalytic reduction at normal pressure for 3 hours. The catalyst was filtered off from the solution and concentrated under reduced pressure. To the residue were added saturated aqueous sodium hydrogencarbonate and ethyl acetate, the organic layer was separated, which was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate/methanol) to give the title compound (0.076g) as a yellow oil. (yield: 24.6%)
Oxalic acid (16.5mg) was added thereto to form a salt, to obtain the title compound as an oxalate salt as a yellow hygroscopic amorphous form.
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.77(4H，m)、2.67(2H，m)、2.81(2H，t，J＝8.2Hz)、2.87-2.93(4H，m)、3.30(2H，t，J＝8.2Hz)、3.36(2H，br-d)、3.95(1H，m)、4.17(2H，s)、6.42-6.44(2H，m)、6.91(1H，d，J＝7.5Hz)、7.12-7.21(4H，m)、7.29-7.32(2H，m)、7.67(1H，ddd，J＝1.8，6.0，6.0Hz)、8.46(1H，dd，J＝0.8，4.8Hz).
FAB-Mass；416(MH+).
EXAMPLE 1761 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (3-pyridyl) methyl ] indoline
3-bromopyridine (0.44ml), 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindoline (0.4g) and diethyl ether as a solvent were used in the same manner as in example 93 to give the title compound (0.337g) as a yellow oily substance. (yield: 68.8%)
To this, oxalic acid was added to form a salt to obtain the oxalate salt of the title compound as an amorphous form.
Melting point (oxalate): 110-
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.88(4H，m)、2.83(2H，t，J＝8.5Hz)、3.01(4H，m)、3.19(2H，m)、3.30(2H，t，J＝8.5Hz)、3.57(2H，m)、3.71(1H，m)、5.65(1H，s)、6.56(1H，d，J＝7.6Hz)、6.59(1H，s)、6.95(1H，d，J＝7.6Hz)、7.18(2H，m)、7.32(3H，m)、7.70(1H，ddd，J＝1.6，2.0，6.0Hz)、8.40(1H，dd，J＝1.6，5.2Hz)、8.57(1H，d，J＝2.0Hz).
ESI-Mass；432.2(MH+).
EXAMPLE 1771 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [1- (3-pyridyl) methyl ] indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (3-pyridyl) methyl ] indoline (0.1g), the procedure was followed as in example 175 to give the title compound (0.018g) as a colorless oil. (yield: 18.7%)
Free form
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.79(4H，m)、2.14(2H，m)、2.61(2H，m)、2.81(2H，m)、2.91(2H，t，J＝8.4Hz)、3.13(2H，br-d)、3.25(1H，m)、3.40(2H，t，J＝8.4Hz)、3.88(2H，s)、6.19(1H，d，J＝1.2Hz)、6.41(1H，dd，J＝1.2，7.4Hz)、6.97(3H，m)、7.17(3H，m)、7.47(1H，m)、8.44(1H，dd，J＝1.2，4.8Hz)、8.51(1H，d，J＝1.2Hz).
ESI-Mass；416.2(MH+).
Oxalic acid (5mg) was added thereto to form a salt, to obtain the oxalate salt of the title compound as an amorphous form.
Example 1781 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-hydroxy-4-pyridylmethyl) indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline (700mg), 2.5M n-butyllithium/hexane solution (1.0ml) and 4-pyridinecarbaldehyde (280mg), the title compound was obtained as an oxalate salt as a brown hygroscopic amorphous form (130mg) in the same manner as in example 130. (yield: 15%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.75-1.93(4H，m)、2.83(2H，t，J＝8Hz)、2.91-3.02(4H，m)、3.11-3.19(2H，m)、3.30(2H，t，J＝8Hz)、3.48-3.57(2H，m)、3.61-3.71(1H，m)、5.57(1H，s)、6.55-6.57(2H，m)、6.94(1H，d，J＝8Hz)、7.15-7.20(2H，m)、7.31-7.36(4H，m)、8.45-8.47(2H，m).
FAB-Mass；432(MH+).
Example 1791 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (4-pyridylmethyl) indoline
A mixture of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1' -hydroxy-4-pyridylmethyl) indoline (350mg), 10% palladium on charcoal (200mg), 5N hydrochloric acid (0.8ml) and ethanol (20ml) was catalytically reduced under 3 atm. After 5 hours the catalyst was filtered off and concentrated under reduced pressure. The residue was diluted with saturated aqueous sodium hydrogencarbonate and ethyl acetate, the organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) and converted to the oxalate salt according to a conventional method to give white powdery crystals of the title compound oxalate (190 mg). (yield: 46%)
Melting point (oxalate): 195 + 197 deg.C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.79-1.94(4H，m)、2.84(2H，t，J＝8Hz)、2.92-2.90(4H，m)、3.11-3.19(2H，m)、3.32(2H，t，J＝8Hz)、3.48-3.56(2H，m)、3.59-3.69(1H，m)、3.83(2H，s)、6.41-6.43(2H，m)、6.94(1H，d，J＝8Hz)、7.15-7.22(4H，m)、7.30-7.34(2H，m)、8.42-8.44(2H，m).
FAB-Mass；416(MH+).
Example 1801- [1- (4-fluorophenethyl) piperidin-4-yl]Synthesis of (E) -6- (2-pyridylcarbonyl) indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-pyridyl) methyl ] indoline (0.895g) according to J.org.chem., 2899(1993) in the journal of organic chemistry, the title compound (0.357g) was obtained as a yellow oil. (yield: 40.1%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.81(4H，m)、2.18(2H，m)、2.60(2H，m)、2.80(2H，m)、3.01(2H，t，J＝8.4Hz)、3.11(2H，m)、3.47(2H，t，J＝8.4Hz)、3.51(1H，m)、6.97(2H，m)、7.02(1H，d，J＝0.6Hz)、7.09(1H，d，J＝7.2Hz)、7.17(3H，m)、7.45(1H，ddd，J＝1.4，5.0，7.6Hz)、7.87(1H，ddd，J＝1.8，7.6，7.6Hz)、7.93(1H，ddd，J＝0.8，1.4，7.6Hz)、8.71(1H，ddd，J＝0.8，1.8，5.0Hz).
EXAMPLE 1811 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-pyridyl) ethyl ] indoline
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-pyridylcarbonyl) indoline (0.074g) was dissolved in tetrahydrofuran (1.0ml), and 3.0M methylmagnesium bromide/diethyl ether solution was added to the solution at-78 ℃ and stirred for 1 hour. Water and ethyl acetate were added to the residue, and the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate-methanol) to give the title compound (0.029g) as a yellow oil. (yield: 37.8%)
Oxalic acid (6mg) was added thereto to form a salt, to give the title compound as a yellow amorphous form of the oxalate salt.
Melting point (oxalate): 98-108 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.84(4H，m)、2.80(2H，t，J＝8.4Hz)、2.99(2H，m)、3.11(2H，m)、3.24(2H，m)、3.28(2H，t，J＝8.4Hz)、3.59(2H，m)、3.70(1H，m)、6.61(1H，d，J＝7.4Hz)、6.69(1H，s)、6.88(1H，d，J＝7.4Hz)、7.19(3H，m)、7.36(2H，m)、7.58(1H，m)、7.71(1H，m)、8.46(1H，m).
ESI-Mass；446.3(MH+).
EXAMPLE 182 Synthesis of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-pyridyl) -2-trimethylsilylethyl ] indoline
(in the above formula, TMS represents a trimethylsilyl group.)
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-pyridyl) ethyl ] indoline (0.357g) according to the method of Synthesis, 384(1984), the title compound (0.250g) was obtained as a yellow oil. (yield: 58.3%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
-0.75(9H，s)、1.75(4H，m)、2.13(2H，m)、2.58(2H，m)、2.78(2H，m)、2.87(3H，t，J＝8.4Hz)、3.09(2H，m)、3.36(2H，t，J＝8.4Hz)、3.43(1H，m)、5.99(2H，s)、6.64(1H，d，J＝1.2Hz)、6.76(1H，dd，J＝1.2，7.6Hz)、6.94(1H，d，J＝7.6Hz)、6.97(2H，m)、7.11(1H，ddd，J＝0.8，4.8，7.6Hz)、7.15(2H，m)、7.39(1H，ddd，J＝0.8，0.8，8.0Hz)、7.59(1H，ddd，J＝1.6，7.6，8.0Hz)、8.45(1H，ddd，J＝0.8，1.6，4.8Hz).
EXAMPLE 182 Synthesis of 21- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [1- (2-pyridyl) ethenyl ] indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-pyridyl) -2-trimethylsilylethyl ] indoline (0.250g) according to J.Am.chem.Soc., 1464(1975), the title compound (0.138g) was obtained as a yellow oil. (yield: 66.6%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.80(4H，m)、2.07(2H，m)、2.56(2H，m)、2.77(2H，m)、2.97(2H，t，J＝8.4Hz)、3.08(2H，br-d)、3.36(1H，m)、3.43(2H，t，J＝8.4Hz)、5.40(1H，d，J＝1.8Hz)、5.98(1H，d，J＝1.8Hz)、6.37(1H，d，J＝1.2Hz)、6.57(1H，dd，J＝1.2，7.6Hz)、6.96(2H，m)、7.03(1H，d，J＝7.6Hz)、7.14(2H，m)、7.20(1H，ddd，0.6，5.0，7.6Hz)、7.27(1H，ddd，0.4，0.6，7.2Hz)、7.60(1H，ddd，2.0，7.2，7.6Hz)、8.64(1H，ddd，0.4，2.0，5.0Hz).
EXAMPLE 182 Synthesis of 31- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [1- (2-pyridyl) ethyl ] indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [1- (2-pyridyl) ethenyl ] indoline (0.138g), the title compound (0.110g) was obtained as a yellow oil by the method of production example 59-2. (yield: 79.3%)
Oxalic acid (23mg) was added thereto to form a salt, to give the title compound as an amorphous oxalate salt.
Melting point (oxalate): 95-102 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.58(3H，d，J＝7.2Hz)、1.83(4H，m)、2.81(2H，t，J＝8.0Hz)、2.96(2H，m)、3.16(2H，m)、3.29(2H，t，J＝8.0Hz)、3.53(2H，m)、3.67(1H、m)、4.14(1H，q，J＝7.2Hz)、6.48(2H，m)、6.91(1H，d，J＝7.6Hz)、7.18(4H，m)、7.33(2H，m)、7.66(1H，ddd，J＝1.6，7.6，7.6Hz)、8.48(1H，m).
ESI-Mass；430.3(MH+).
Example 1831 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (3-pyridylcarbonyl) indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (3-pyridyl) methyl ] indoline (0.121g) according to J.Org.chem., 2899(1993) in the journal of organic chemistry, the title compound (0.009g) was obtained as a yellow oil. (yield: 7.5%)
Free form
1H-NMR(400MHz、CDCl3)；δ(ppm)
1.84(4H，m)、2.17(2H，m)、2.61(2H，m)、2.80(2H，m)、3.04(2H，t，J＝8.4Hz)，3.14(2H，m)、3.49(1H，m)、3.51(2H，t，J＝8.4Hz)、6.87(1H，t，J＝1.6Hz)、6.93(1H，dd，J＝1.6，7.2Hz)、6.98(2H，m)、7.10(1H，d，J＝7.2Hz)、7.16(2H，m)、7.43(1H，ddd，J＝0.8，4.8，7.2Hz)、8.10(1H，ddd，J＝1.6，2.0，7.2Hz)、8.78(1H，dd，J＝0.8，4.8Hz)、8.97(1H，dd，J＝0.8，2.0Hz).
ESI-Mass；430.2(MH+).
Oxalic acid (2mg) was added thereto to form a salt, to give the oxalate salt of the title compound.
Melting point (oxalate): 115 deg.C
Example 1841 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-methoxypyridin-3-yl) methyl ] indoline
From 2-methoxypyridine (0.3ml), 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindoline (0.5g) according to J.org.chem., 1367(1988), the title compound (0.493g) was obtained as a pale yellow oil. (yield: 75.2%)
To this was added oxalic acid to form a salt to give the title compound as an amorphous oxalate salt.
Melting point (oxalate): 101 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.82(4H，m)、2.81(2H，t，J＝8.4Hz)、2.96(4H，m)、3.14(2H，m)、3.31(2H，t，J＝8.4Hz)、3.53(2H，m)、3.67(1H，m)、3.84(3H，s)、5.75(1H，s)、6.49(1H，dd，J＝0.8，7.4Hz)、6.55(1H，d，J＝0.8Hz)、6.91(1H，d，J＝7.4Hz)、6.98(1H，dd，J＝5.2，7.6Hz)、7.16(2H，m)、7.33(2H，m)、7.79(1H，dd，J＝2.0，7.6Hz)，8.02(1H，dd，J＝2.0，5.2Hz).
ESI-Mass；462.3(MH+).
EXAMPLE 1851 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [1- (2-methoxypyridin-3-yl) methyl ] indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-methoxypyridin-3-yl) methyl ] indoline (0.418g), the title compound was obtained as a pale yellow oil (0.040g) by the method of example 175. (yield: 9.9%)
Oxalic acid (8mg) was added thereto to form a salt, to give the title compound as an amorphous oxalate salt.
Melting point (oxalate): 182 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.85(4H，m)、2.83(2H，t，J＝8.4Hz)、2.96(4H，m)、3.17(2H，m)、3.31(2H，t，J＝8.4Hz)、3.54(2H，m)、3.65(1H，m)、3.75(2H，s)、3.87(3H，s)、6.39(1H，d，J＝7.6Hz)、6.41(1H，s)、6.90(1H，dd，J＝5.2，7.6Hz)、6.92(1H，d，J＝7.6Hz)、7.18(2H，m)、7.33(2H，m)、7.39(1H，dd，J＝2.0，7.6Hz)、8.01(1H，dd，J＝2.0，5.2Hz).
ESI-Mass；446.3(MH+).
Example 1861 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-methoxypyridin-6-yl) methyl ] indoline
From 6-bromo-2-methoxypyridine (0.32g) synthesized according to Tetrahedron, 1373(1985), 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindoline (0.4g), tetramethylethylenediamine (0.26ml) was added, and diethyl ether was used as a solvent in the same manner as in example 93, to give the title compound (0.401g) as colorless crystals. (yield: 76.5%)
To this was added oxalic acid to form a salt to give the title compound as an amorphous oxalate salt.
Melting point (oxalate): 95 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.84(2H，m)、2.16(2H，m)、2.82(2H，t，J＝8.4Hz)、2.99(4H，m)、3.16(2H，t)、3.30(2H，t，J＝8.4Hz)、3.54(2H，m)、3.68(1H，m)、3.81(3H，s)、5.48(1H，s)、6.52(3H，m)、6.92(1H，d，J＝7.9Hz)、7.09(1H，d，J＝7.1Hz)、7.16(3H，m)、7.34(2H，m)、7.65(1H，d，J＝7.6Hz).
FAB-Mass；462(MH+).
EXAMPLE 1871 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [1- (2-methoxypyridin-6-yl) methyl ] indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-methoxypyridin-6-yl) methyl ] indoline (0.363g), the procedure was followed as in example 175 to give the title compound (0.127g) as a pale yellow oil. (yield: 39.2%)
Oxalic acid (26mg) was added thereto to form a salt, to give the title compound as an amorphous oxalate salt.
Melting point (oxalate): 139 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.83(4H，m)、2.84(2H，t，J＝8.4Hz)、2.87(2H，m)、2.93(2H，m)、3.06(2H，m)、3.31(2H，t，J＝8.4Hz)、3.45(2H，m)、3.64(1H，m)、3.83(3H，s)、3.85(2H，s)、6.47(2H，m)、6.60(1H，d，J＝8.2Hz)、6.75(1H，d，J＝7.3Hz)、6.93(1H，d，J＝8.0Hz)、7.16(2H，m)、7.32(2H，m)、7.57(1H，dd，J＝7.3，8.2Hz).
FAB-Mass；446(MH+).
Example 1881 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-methoxypyridin-5-yl) methyl ] indoline
The title compound (0.461g) was obtained as a pale yellow oil from 5-bromo-2-methoxypyridine (0.32g) synthesized according to Tetrahedron, 1373(1985), 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindoline (0.4g) using diethyl ether as a solvent in the same manner as in example 93. (yield: 88.0%)
Free form
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.79(4H，m)、2.13(2H，m)、2.48(1H，br-d)、2.60(2H，m)、2.80(2H，m)、2.92(2H，t，J＝8.4Hz)、3.11(2H，br-d)、3.38(1H，m)、3.41(2H，t，J＝8.4Hz)、3.91(1H，ddd，J＝0.4，0.4，2.8Hz)、5.72(1H，d，J＝2.4Hz)、6.42(1H，d，J＝0.8Hz)、6.55(1H，dd，J＝0.8Hz)，6.68(1H，dd，J＝0.4，8.8Hz)、6.97(3H，m)、7.15(2H，m)、7.56(1H，ddd，J＝0.4，2.4，8.8Hz)、8.17(1H，ddd，J＝0.4，0.4，2.4Hz).
ESI-Mass；462.2(MH+).
Oxalic acid or hydrochloric acid is added thereto to form a salt, to obtain the oxalate salt of the title compound, a hygroscopic amorphous hydrochloride salt.
Oxalate salt
Melting point (oxalate): 108 deg.C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.76(4H，m)、2.63(4H，m)、2.86(2H，t，J＝8.2Hz)、3.89(4H，m)、3.31(2H，t，J＝8.2Hz)、3.33(2H，m)、3.55(1H，m)、3.80(3H，s)、5.58(1H，s)、6.54(1H，s)、6.72(1H，d，J＝8.6Hz)、6.92(1H，d，J＝7.6Hz)、7.14(2H，t，J＝8.2Hz)、7.30(2H，dd，J＝5.6，8.2Hz)、7.57(1H，dd，J＝2.2，8.6Hz)、8.13(1H，d，J＝2.2Hz).
Oxalate salt
FAB-Mass：462(MH+)
Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.86(2H，m)、2.10(2H，m)、2.86(2H，t，J＝8.4Hz)、3.11(4H，m)、3.24(2H，m)、3.34(2H，t，J＝8.4Hz)、3.64(2H，m)、3.75(1H，m)、3.82(3H，s)、5.61(1H，s)、6.55(1H，s)、6.58(1H，d，J＝7.6Hz)、6.67(1H，br-s)、6.78(1H，d，J＝8.4Hz)、6.97(1H，d，J＝7.6Hz)、7.19(2H，m)、7.34(2H，m)、7.63(1H，dd，J＝2.4，8.4Hz)、8.16(1H，d，J＝2.4Hz).
FAB-Mass；462(MH+).
EXAMPLE 1891 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [1- (2-methoxypyridin-5-yl) methyl ] indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-methoxypyridin-5-yl) methyl ] indoline (0.335g), the title compound was obtained as a pale yellow oil (0.046g) by the method of example 175. (yield: 14.2%)
Oxalic acid (10mg) was added thereto to form a salt, to give the oxalate salt of the title compound.
Melting point (oxalate): 166 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.57(4H，m)、1.85(2H，m)、2.30(2H，m)、2.80(2H，m)、2.93(2H，t，J＝8.4Hz)、3.21(2H，m)、3.42(2H，t，J＝8.4Hz)、3.46(1H，m)、4.0(3H，s)、4.89(1H，d，J＝4.2Hz)、5.59(1H，d，J＝4.2Hz)、6.45(1H，d，J＝1.1Hz)、6.60(1H，d，J＝7.3Hz)、6.62(1H，d，J＝8.2Hz)、6.71(1H，d，J＝7.3Hz)、6.99(2H，m)、7.00(1H，d，J＝7.3Hz)、7.18(2H.m)、7.50(1H，dd，J＝7.3，8.2Hz).
FAB-Mass；446(MH+).
EXAMPLE 1901 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-pyridon-5-yl) methyl ] indoline
After the formation of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-methoxypyridin-5-yl) methyl ] indoline hydrochloride (0.101g) for about 1 month, the hydrochloride was left at room temperature for 2 months, dissolved in ethyl acetate, and a saturated aqueous sodium hydrogencarbonate solution was added to separate an organic layer, which was then washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) to give the title compound as pale yellow crystals (0.033 g).
Melting point (free form): 202 deg.C
Free form
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.82(4H，m)、2.31(2H，m)、2.68(2H，m)、2.86(2H，m)、2.92(2H，t，J＝8.4Hz)、3.19(2H，m)、3.38(1H，m)、3.42(2H，t，J＝8.4Hz)、5.53(1H，s)、6.38(1H，br-s)、6.47(1H，d，J＝932Hz)、6.54(1H，dd，J＝0.8，7.2Hz)、6.95-7.01(3H，m)、7.14-7.17(2H，m)、7.32(1H，d，J＝2.4Hz)、7.44(1H，dd，J＝2.4，9.2Hz).
FAB-Mass；448(MH+).
Example Synthesis of 191-15-bromo-2-dimethylaminopyridine
2-dimethylaminopyridine (1.0ml) was dissolved in chloroform (60ml), and tributylammonium bromide (3.88g) was added thereto and the mixture was stirred for 7 minutes. The reaction mixture was washed with an aqueous sodium thiosulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate-methanol) to give the title compound as yellow crystals (1.097 g). (yield: 72.0%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.05(6H，s)、6.40(1H，dd，J＝0.8，8.8Hz)、7.48(1H，dd，J＝2.8，8.8Hz)、8.16(1H，dd，J＝0.8，2.8Hz).
Example Synthesis of 191-22-dimethylamino-5-formylpyridine
Using 5-bromo-2-dimethylaminopyridine (5.0g) and N, N-dimethylformamide (6.1ml), tetramethylethylenediamine (8.0ml) was added to the reaction solution, and diethyl ether was used as a solvent, to give the title compound as pale yellow crystals (3.273g) in the same manner as in example 93. (yield: 89.6%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.21(6H，s)、6.56(1H，dd，J＝0.4，9.2Hz)、7.91(1H，dd，J＝2.4，9.2Hz)、8.55(1H，dd，J＝0.4，2.4Hz)，9.77(1H，s).
EXAMPLE 191-31- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-dimethylaminopyridin-5-yl) methyl ] indoline synthesis
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline (0.5g) 2-dimethylamino-5-formylpyridine (0.345g), the title compound (0.376g) was obtained as a colorless oil by the method of example 130. (yield: 65.3%)
Hydrochloric acid was added thereto to form a salt, to obtain the hydrochloride salt of the title compound as an amorphous form.
Melting point (hydrochloride salt): 185 ℃ and 196 DEG C
Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.86(2H，m)、2.08-2.18(2H，m)、2.86(2H，t，J＝8.4Hz)、3.07-3.15(4H，m)、3.21(6H，s)、3.71(2H，m)、3.34(2H，t，J＝8.4Hz)、3.64(2H，br-d)、3.73(1H，m)、5.63(1H，s)、6.56(1H，d，J＝7.4Hz)、6.69(1H，s)，6.98(1H，t，J＝7.4Hz)、7.18(3H，m)、7.34(2H，m)、7.85(1H，dd，J＝2.0，9.6Hz)、7.90(1H，d，J＝2.0Hz).
ESI-Mass；475.2(MH+).
Example 192 Synthesis of 15-bromo-2-chloropyridine
Using 5-bromo-2-methoxypyridine (1.88g), the title compound (0.046g) was obtained as a pale yellow oil according to the method of synthetic communications Synth. Commun., 2971 (1990). (yield: 14.2%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
7.24(1H，dd，J＝0.4，8.1Hz)、7.77(1H，dd，J＝2.4，8.1Hz)、8.47(1H，dd，J＝0.4，2.4Hz).
EXAMPLE 192-21- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-chloropyridin-5-yl) methyl ] indoline synthesis
From 5-bromo-2-chloropyridine (0.151g), 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindoline (0.2g), the procedure of example 93 was followed to give the title compound (0.130g) as a colorless oil. (yield: 49.7%)
Hydrochloric acid was added thereto to form a salt, to obtain the hydrochloride salt of the title compound as an amorphous form.
Melting point (hydrochloride salt): 136 deg.C
Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.84(2H，m)、2.12(2H，m)、2.84(2H，t，J＝8.4Hz)、3.04-3.17(4H，m)、3.16(2H，t，J＝8.4Hz)、3.65(2H，br-d)、3.74(1H，m)、5.68(1H，s)、6.58(1H，d，J＝7.6Hz)、6.64(1H，s)、6.97(1H，d，J＝7.6Hz)、7.19(2H，m)、7.34(2H.m)、7.43(1H，d，J＝8.4Hz)、7.76(1H，dd，J＝2.4，8.4Hz)、8.42(1H，d，J＝2.4Hz).
ESI-Mass；466.1(MH+).
Example Synthesis of 1931- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [1- (2-thiazol-5-yl) -1-hydroxymethyl ] indoline
Thiazole (0.12ml) was dissolved in tetrahydrofuran (5ml), and a 1.66M n-butyllithium/n-hexane solution (1.0ml) was added dropwise at-78 ℃ under a nitrogen atmosphere, followed by stirring for 10 minutes. To this was added 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindoline (0.5g) and the resulting solution was dissolved in tetrahydrofuran (7ml), and the mixture was stirred at-78 ℃ for 3 hours. To the reaction mixture was added a saturated aqueous solution of ammonium chloride and then ethyl acetate (200ml), the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) to give the title compound (0.134g) as a pale yellow oil. (yield: 32.6%)
40mg of oxalic acid (3mg) was added thereto to form a salt, to give the title compound as a colorless amorphous form of the oxalate salt.
Melting point (oxalate): 118 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.78(4H，m)、2.84(2H，t，J＝8.6Hz)、2.89(4H，m)、2.95(2H，m)、3.32(2H，t，J＝8.6Hz)、3.37(2H，m)、3.58(1H，m)、4.81(1H，s)、5.56(1H，s)、6.00(1H，d，J＝7.2Hz)、6.95(1H，d，J＝7.2Hz)、7.15(2H，m)、7.31(2H，m)、7.59(1H，d，J＝3.0Hz)、7.66(1H，d，J＝3.0Hz).
ESI-Mass；438.2(MH+).
Example 1941- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-thiazolecarbonyl) indoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [1- (2-thiazolyl) -1-hydroxymethyl ] indoline (0.1g), the title compound (0.022g) was obtained as a yellow oil according to J.org.chem.2480 (1978). (yield: 22.1%)
Oxalic acid (5mg) was added thereto to form a salt, to give the title compound as a colorless amorphous form of the oxalate salt.
Melting point (hydrochloride salt): 132 deg.C
Free form
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.51(4H，m)、1.82(2H，m)、2.62(2H，m)、2.80(2H，m)、2.97(2H，t，J＝8.4Hz)、3.14(2H，m)、3.43(2H，t，J＝8.4Hz)、3.49(1H，m)、6.20(2H，m)、7.11(3H，m)、7.17(1H，br-s)、7.61(1H，d，J＝3.2Hz)、7.89(1H，d，J＝7.6Hz)、7.99(1H，d，J＝3.2Hz).
FAB-Mass；436(MH+).
EXAMPLE 1951 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [1- (4-thiazolyl) -1-hydroxymethyl ] indoline
From 4-bromo-2-trimethylsilylthiazole (0.2g) and 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindoline (0.2g) synthesized according to the method of J.org.chem.2480(1978) in the journal of organic chemistry, as in example 193, the title compound (0.039g) was obtained as a yellow oil. (yield: 15.7%)
Oxalic acid (4mg) was added thereto to form a salt, to obtain an amorphous form of the oxalate salt of the title compound.
Melting point (oxalate): 115 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.78(4H，m)、2.74(2H，m)、2.83(2H，t，J＝8.4Hz)、2.89(2H，m)、2.97(2H，m)、3.31(2H，t，J＝8.4Hz)、3.38(2H，m)、3.57(1H，m)、5.72(1H，s)、6.55(2H，m)、6.92(1H，d，J＝7.2Hz)、7.15(2H，m)、7.31(2H，m)、7.44(1H，dd，J＝0.4，2.0Hz)、8.96(1H，d，J＝2.0Hz).
FAB-Mass；438(MH+).
Example 1961- [1- (4-fluorophenethyl) piperidin-4-yl]-6- [1- (5-thiazolyl) -1-hydroxymethyl]Synthesis of indolines
From 2-trimethylsilylthiazole (0.134g) and 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindoline (0.2g), as in example 193, the title compound (0.145g) was obtained as a yellow oil. (yield: 58.4%)
Oxalic acid (15mg) was added thereto to form a salt, to obtain an amorphous form of the oxalate salt of the title compound.
Melting point (oxalate): 112 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.80(4H，m)、2.86(2H，t，J＝8.4Hz)、2.91(4H，m)、3.04(2H，m)、3.33(2H，t，J＝8.4Hz)、3.46(2H，m)、3.62(1H，m)、5.90(1H，s)、6.58(2H，m)、6.97(1H，d，J＝7.2Hz)、7.16(2H，m)、7.31(2H，m)、7.66(1H，s)、8.93(1H，s).
FAB-Mass；438(MH+).
Example 1971 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (pyrimidin-2-yl) methyl ] indoline
The title compound (0.038g) was obtained as a yellow oil from 2-trimethylstannylalkylpyridine (0.2g) and 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindoline (0.21g) synthesized according to J.Am.chem.Soc.1481(1978) in Tetrahedron letters 275 (1994). (yield: 16.2%)
Oxalic acid (8mg) was added thereto to form a salt, to obtain an amorphous form of the oxalate salt of the title compound.
Melting point (oxalate): 123 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.84(4H，m)、2.82(2H，t，J＝8.2Hz)、2.98(2H，m)、3.04(2H，m)、3.19(2H，m)、3.29(2H，t，J＝8.2Hz)、3.58(2H，m)、3.68(1H，m)、5.65(1H，s)、6.60(1H，d，J＝7.2Hz)、6.65(1H，s)、6.91(1H，d，J＝7.2Hz)、7.18(2H，m)、7.33(2H，m)、7.36(1H，t，J＝4.8Hz)，8.76(2H，d，J＝4.8Hz).
ESI-Mass；433.3(MH+).
EXAMPLE 1981 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (pyrimidin-5-yl) methyl ] indoline
From 5-bromopyridine (1.27g) and 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindoline (0.21g) according to Synth. Commun.253(1994), the title compound (0.624g) was obtained as a pale yellow oil. (yield: 36.1%)
0.156g of oxalic acid (32mg) was taken and added thereto to form a salt, to obtain a hygroscopic amorphous form of the oxalate salt of the title compound.
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.78-1.92(4H，m)、2.84(2H，t，J＝8.4Hz)、2.95(4H，m)、3.13(2H，m)、3.23(2H，t，J＝8.2Hz)、3.51(2H，m)、3.68(1H，m)、5.71(1H，s)、6.59(1H，d，J＝7.0Hz)、6.60(1H，s)、6.97(1H，d，J＝7.0Hz)、7.17(2H，m).7.33(2H，m)、8.75(2H，s)、9.04(1H，s).
FAB-Mass；433(MH+).
EXAMPLE 1991 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ 1-hydroxy-1- (2-pyrrolyl) methyl ] indoline
Using 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline (0.2g), 2-pyrrolecarboxaldehyde (0.44ml), the title compound (0.044g) was obtained as a colorless oil according to example 193. (yield: 21.0%)
Free substance
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.80(4H，m)，2.14(2H，m)、2.60(2H，m)、2.81(2H，m)、2.94(2H，t，J＝8.4Hz)、3.12(2H，br-d)、3.38(1H，m)、3.42(2H，t，J＝8.4Hz)、5.79(1H，s)、6.03(1H，m)、6.13(1H，m)、6.50(1H，d，J＝1.2Hz)、6.62(1H，dd，J＝1.2，7.2Hz)、6.71(1H，m)、6.97(2H，m)、7.02(1H，d，J＝7.2Hz)、7.15(2H，m)、8.33(1H，m).
Fab-Mass；420(MH+).
Example 2001- [1- (4-fluorophenethyl) piperidin-4-yl]Synthesis of (E) -6-N, N-dimethylaminomethylindoline
As in example 170, from 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindoline (500mg), formaldehyde (290mg) and formic acid (180mg), the hydrochloride of the title compound (60mg) was obtained as a pale brown hygroscopic, amorphous form. (yield: 9.3%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.94-2.03(2H，m)、2.04-2.17(2H，m)、2.66(3H，s)、2.67(3H，s)、2.92(2H，t，J＝8Hz)、3.00-3.12(4H，m)、3.26-3.35(2H，m)、3.39(2H，t，J＝8Hz)、3.58-3.70(3H，m)、4.12(2H，s)、6.65(1H，d，J＝8Hz)、6.93(1H，s)、7.08(1H，d，J＝8Hz)、7.16-7.21(2H，m)、7.32-7.36(2H，m)，10.52(1H，br-s)、10.62(1H，br-s).
FAB-Mass；382(MH+).
Example Synthesis of 201-11- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindole
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline (0.1g) was dissolved in chloroform (27ml), and manganese dioxide (2.75g) was added thereto and the mixture was refluxed for 4 hours. Manganese dioxide was filtered off, and the filtrate was distilled under reduced pressure to give the title compound (0.480g) as a yellow oil. (yield: 96.5%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.09(4H，m)、2.25(2H，m)、2.50(2H，m)、2.82(2H，m)、3.17(2H，br-d)、4.17(1H，m)、6.49(1H，d，J＝2.8Hz)、6.99(2H，m)、7.18(2H，m)、7.20(1H，d，J＝8.4Hz)、7.21(1H，d，J＝2.8Hz)、7.48(1H，d，J＝8.4Hz)、7.53(1H，br-s).
Example 201 Synthesis of 21- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (4-fluorophenyl) indole
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindole (0.1g), 4-fluorophenylboronic acid (0.067g), palladium tetrakistriphenylphosphine (0.014g) and sodium carbonate (0.12g) were dissolved in toluene (5ml) and water (1.2ml), and the mixture was stirred at 90 ℃ for 12 hours. The reaction mixture was filtered, ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added to the filtrate, and the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.075g) as pale yellow crystals. (yield: 71.6%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.19(4H，m)、2.42(2H，m)、2.75(2H，m)、2.89(2H，m)、3.27(2H，m)、4.33(1H，m)、6.51(1H，d，J＝2.4Hz)、6.98(2H，m)、7.14(6H，m)、7.30(1H，dd，J＝1.4，8.0Hz)、7.44(1H，s)、7.59(2H，m)、7.67(1H，d，J＝8.0Hz).
Example 201-31- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (4-fluorophenyl) indoline Synthesis
Using 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (4-fluorophenyl) indole (0.075g), the title compound (0.020g) was obtained as a yellow oil by the method of production example 56-2.
(yield: 26.6%)
To this was added oxalic acid to form a salt to give the oxalate salt of the title compound.
Melting point (oxalate): 130 ℃ and 145 DEG C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.93(2H，m)、2.08(2H，m)、2.93(2H，t，J＝8.2Hz)、3.10(4H，m)、3.25(2H，m)、3.39(2H，t，J＝8.2Hz)、3.64(2H，m)、3.89(1H，m)、6.77(1H，s)、6.82(1H，d，J＝7.4Hz)、7.00(1H，d，J＝7.4Hz)、7.19(2H，m)、7.25(2H，m)、7.34(2H，m)、7.65(2H，m).
FAB-Mass；417(MH+).
EXAMPLE 2021 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-pyrrolidin-1-yl) methyldihydroindole
To a solution of 2-pyrrolidone (85mg) in dimethylformamide (10ml) was added 60% sodium hydride (40mg), and after stirring at 50 ℃ for 2 hours, 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-chloromethylindoline (200mg) was added and the mixture was stirred for an additional 2 hours. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/ethanol) and hydrochloride was obtained in accordance with a conventional method to give the hydrochloride of the title compound (170mg) as a purple powder crystal. (yield: 69%)
Melting point (hydrochloride salt): 140 ℃ to 142 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.81-1.92(4H，m)、1.94-2.08(2H，m)、2.25(2H，t，J＝8Hz)、2.81-2.87(2H，m)、3.00-3.35(10H，m)、3.57-3.74(3H，m)、4.22(2H，s)、6.35(1H，s)、6.40(1H，d，J＝8Hz)、6.96(1H，d，J＝8Hz)、7.14-7.19(2H，m)、7.30-7.34(2H，m).
FAB-Mass；422(MH+).
EXAMPLE 2031 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-piperidon-1-yl) methylindoline
Starting from 2-piperidone (64mg), 60% sodium hydride (26mg) and 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-chloromethylindoline (200mg), the hydrochloride of the title compound (130mg) was obtained as example 202 which was amorphous and had a dark red color and hygroscopicity. (yield: 51%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.60-1.73(4H，m)、1.82-1.89(2H，m)、2.02-2.15(2H，m)、2.26-2.32(2H，m)、2.87(2H，t，J＝8Hz)、3.04-3.16(6H，m)、3.21-3.28(2H，m)、3.34(2H，t，J＝8Hz)、3.60-3.70(2H，m)、4.40(2H，s)、6.41(1H，s)、6.45(1H，d，J＝8Hz)、6.98(1H，d，J＝8Hz)、7.16-7.21(2H，m)、7.32-7.36(2H，m).
FAB-Mass；436(MH+).
EXAMPLE 2041 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (succinimidin-1-yl) methylindoline
As in example 202, from succinimide (64mg), 60% sodium hydride (26mg) and 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-chloromethylindoline (200mg), the title compound was obtained as a hydrochloride (140mg) as a dark purple hygroscopic amorphous form. (yield: 55%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.84-2.05(4H，m)、2.67(4H，s)、2.85(2H，t，J＝8Hz)、3.02-3.20(4H，m)、3.24-3.35(4H，m)、3.60-3.75(3H，m)、4.43(2H，s)、6.41-6.44(2H，m)、6.94(1H，d，J＝8Hz)、7.17-7.22(2H，m)、7.32-7.37(2H，m).
FAB-Mass；436(MH+).
EXAMPLE 2051 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (glutarimido-1-yl) methyldihydroindole
As in example 202, from glutarimide (73mg), 60% sodium hydride (26mg) and 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-chloromethylindoline (200mg), the oxalate salt of the title compound (240mg) was obtained as a pale brown powder crystal. (yield: 82%) melting point (oxalate salt): 109 ℃ and 111 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.80-1.91(6H，m)、2.65(4H，t，J＝6Hz)、2.83(2H，t，J＝8Hz)、2.92-3.04(4H，m)、3.12-3.22(2H，m)、3.31(2H，t，J＝8Hz)、3.49-3.71(3H，m)、4.72(2H，s)、6.35-6.37(2H，m)、6.91(1H，d，J＝8Hz)、7.15-7.20(2H，m)、7.31-7.35(2H，m).
FAB-Mass；450(MH+).
Example 2061 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-imidazolidinonyl) methylindoline
As in example 202, from 2-imidazolidinone (60mg), 60% sodium hydride (28mg) and 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-chloromethylindoline (260mg), the oxalate salt of the title compound was obtained as a white prismatic crystal (120 mg). (yield: 33%) melting point (oxalate salt): 184 ℃ and 186 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.80-1.89(4H，m)、2.86(2H，t，J＝8Hz)、2.90-2.99(4H，m)、3.08-3.24(6H，m)、3.33(2H，t，J＝8Hz)、3.47-3.55(2H，m)、3.60-3.68(1H，m)、4.10(2H，s)、6.34-6.37(2H，m)、6.43(1H，d，J＝8Hz)、6.97(1H，d，J＝8Hz)、7.15-7.19(2H，m)、7.31-7.34(2H，m).
FAB-Mass；423(MH+).
Example 2071 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2, 4-imidazolidinedion-3-yl) methyldihydroindole
As in example 202, from hydantoin (130mg), 60% sodium hydride (54mg) and 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-chloromethylindoline (400mg), the title compound (230mg) was obtained as white powder crystals. (yield: 49%)
Melting point: 191 ℃ 193 DEG C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.68-1.84(4H，m)、2.11-2.21(2H，m)、2.56-2.63(2H，m)、2.76-2.83(2H，m)，2.90(2H，t，J＝8Hz)、3.06-3.15(2H，m)、3.39(2H，t，J＝8Hz)、3.35-3.46(1H，m).3.92(2H，s)、4.57(2H，s)、5.90(1H，s)、6.47(1H，s)、6.65(1H，d，J＝8Hz)、6.94-7.00(3H，m)、7.13-7.19(2H，m)、
FAB-Mass；436(MH+).
Example 2081- [1- (4-fluorophenethyl) piperidin-4-yl]Synthesis of (E) -6- (2-oxazolidinone-3-yl) methyl indoline
As in example 202, from 2-oxazolidinone (120mg), 60% sodium hydride (54mg) and 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-chloromethylindoline (400mg), the hydrochloride of the title compound (450mg) was obtained as a pale red hygroscopic amorphous form. (yield: 92%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.82-1.90(2H，m)、2.05-2.18(2H，m)、2.89(2H，t，J＝8Hz)、3.03-3.15(4H，m)，3.19-3.28(2H，m)、3.31-3.80(7H，m)、4.21-4.29(4H，m)、6.44-6.50(2H，m)、7.01(1H，d，J＝8Hz)、7.16-7.21(2H，m)、7.32-7.36(2H，m).
FAB-Mass；424(MH+).
EXAMPLE 2091 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2, 4-thiazolidinedione-3-yl) methylindoline
As in example 202, from 2, 4-thiazolidinedione (110mg), 60% sodium hydride (40mg) and 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-chloromethylindoline (300mg), the hydrochloride of the title compound (120mg) was obtained as a red, hygroscopic amorphous form. (yield: 30%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.83-2.06(4H，m)、2.86(2H，t，J＝8Hz)、3.10-3.19(4H，m)、3.24-3.35(4H，m)、3.60-3.76(3H，m)、4.27(2H，s)、4.56(2H，s)、6.43-6.45(2H，m)，6.97(1H，d，J＝8Hz)、7.17-7.22(2H，m)、7.32-7.36(2H，m).
FAB-Mass；454(MH+).
EXAMPLE 2101 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (pyrrol-1-yl) methylindoline
As in example 202, from pyrrole (50mg), 60% sodium hydride (30mg) and 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-chloromethylindoline (250mg), the hydrochloride of the title compound (240mg) was obtained as crystals as a brown powder. (yield: 82%) melting point (hydrochloride salt): 162 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.80-1.87(2H，m)、2.06-2.19(2H，m)、2.84(2H，t，J＝8Hz)、2.99-3.12(4H，m)、3.18-3.25(2H，m)、3.33(2H，t，J＝8Hz)、3.56-3.70(3H，m)、4.92(2H，s)、5.94-5.96(2H，m)、6.41(1H，d，J＝8Hz)、6.52(1H，s)、6.75-6.77(2H，m)、6.95(1H，d，J＝8Hz)、7.14-7.19(2H，m)、7.29-7.34(2H，m)、11.06(1H，br-s).
FAB-Mass；405(MH+).
EXAMPLE 2111 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (imidazol-1-yl) methylindoline
As in example 202, from imidazole (50mg), 60% sodium hydride (30mg) and 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-chloromethylindoline (250mg), the hydrochloride of the title compound (260mg) was obtained as a red hygroscopic amorphous form. (yield: 88%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.81-1.90(2H，m)、2.15-2.28(2H，m)、2.86(2H，t，J＝8Hz)、2.99-3.14(4H，m)、3.21-3.29(2H，m)、3.36(2H，t，J＝8Hz)、3.58-3.68(3H，m)、5.25(2H，s)、6.59(1H，d，J＝8Hz)、6.81(1H，s)、7.01(1H，d，J＝8Hz)、7.14-7.19(2H，m)、7.30-7.34(2H，m)、7.66(1H，s)、7.82(1H，s)、11.07(1H，br-s).
FAB-Mass；405(MH+).
EXAMPLE Synthesis of 2121- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1, 2, 3-triazol-1-yl) methylindoline and 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1, 2, 3-triazol-2-yl) methylindoline
As in example 202, from 1, 2, 3-triazole (51mg), 60% sodium hydride (30mg) and 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-chloromethylindoline (250mg), 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1, 2, 3-triazol-1-yl) methylindoline hydrochloride (180mg) was obtained as a highly polar, dark red hygroscopic amorphous form, respectively (yield: 61%), hydrochloride of low-polarity 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1, 2, 3-triazol-2-yl) methylindoline (40mg) as a pale red hygroscopic amorphous (yield: 14%).
(1)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1, 2, 3-triazol-1-yl) methylindoline (high polarity)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.80-1.88(2H，m)、2.05-2.18(2H，m)、2.87(2H，t，J＝8Hz)、3.02-3.14(4H，m)、3.21-3.30(2H，m)、3.34(2H，t，J＝8Hz)、3.60-3.75(3H，m)、5.46(2H，s)、6.51(1H，d，J＝8Hz)、6.57(1H，s)、7.00(1H，d，J＝8Hz)、7.16-7.21(2H，m)、7.32-7.40(2H，m)、7.73(1H，s)、8.17(1H，s)、10.88(1H，br-s).
FAB-Mass；406(MH+).
(2)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1, 2, 3-triazol-2-yl) methylindoline (low polarity)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.81-1.90(2H，m)、1.94-2.10(2H，m)、2.86(2H，t，J＝8Hz)、3.01-3.18(4H，m)、3.22-3.30(2H，m)、3.33(2H，t，J＝8Hz)、3.60-3.75(3H，m)，5.49(2H，s)、6.45(1H，d，J＝8Hz)、6.48(1H，s)、6.98(1H，d，J＝8Hz)、7.17-7.22(2H，m)、7.32-7.36(2H，m)、7.78(2H，s).
FAB-Mass；406(MH+).
Example 2131 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1, 2, 4-triazol-2-yl) methylindoline
From 1, 2, 4-triazole (51mg), 60% sodium hydride (30mg) and 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-chloromethylindoline (250mg), the title compound hydrochloride (210mg) was obtained as a brown hygroscopic amorphous form, as in example 202. (yield: 71%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.81-1.90(2H，m)、1.95-2.14(2H，m)、2.87(2H，t，J＝8Hz)、3.01-3.15(4H，m)、3.21-3.32(2H，m)、3.34(2H，t，J＝8Hz)、3.60-3.74(3H，m)、5.27(2H，s)、6.48(1H，d，J＝8Hz)、6.50-6.59(1H，m)、6.99(1H，d，J＝8Hz)、7.17-7.22(2H，m)、7.32-7.40(2H，m)、7.97-8.00(1H，m)、8.64-8.72(1H，m).
FAB-Mass；406(MH+).
EXAMPLE 2141 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-thiazolyl) methylindoline
A mixture of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-thiocarbamoylmethylindole (150mg), 40% -chloroacetaldehyde (30mg), potassium carbonate (79mg) and dimethoxyethane (32ml) was stirred overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Trifluoroacetic anhydride (240mg), pyridine (210mg) and dimethoxyethane (4ml) were added to the residue, and after stirring for 30 minutes, the reaction mixture was concentrated under reduced pressure. After diluting with saturated aqueous sodium bicarbonate and ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate), and then hydrochloride was obtained by an ordinary method to give the hydrochloride of the title compound (40mg) as a brown hygroscopic amorphous form. (yield: 23%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.82-1.90(2H，m)、2.03-2.15(2H，m)、2.88(2H，t，J＝8Hz)、3.03-3.15(4H，m)、3.20-3.28(2H，m)、3.35(2H，t，J＝8Hz)、3.58-3.66(2H，m)、3.68-3.80(1H，m)、4.23(2H，s)，6.55(1H，d，J＝8Hz)、6.57(1H，s)、6.99(1H，d，J＝8Hz)、7.16-7.21(2H，m)、7.31-7.35(2H，m)、7.60(1H，s)、7.75(1H，s)、10.82(1H，br-s).
FAB-Mass；422(MH+).
Example 2151 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -3- (4-methoxybenzyl) indoline
Using 3- (4-methoxybenzyl) indoline (0.2g), 1- (4-fluorophenethyl) -4-piperidone (0.262g), as in example 16, the title compound (0.343g) was obtained as a colorless oil. (yield: 94.9%)
Oxalic acid (36mg) was added thereto to prepare an oxalate salt, to give the oxalate salt of the title compound (0.101g) as colorless crystals.
Melting point (oxalate): 187 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.80(4H，m)、2.63(1H，dd，J＝9.0，13.6Hz)、2.96(4H，m)、3.15(4H，m)、3.27(1H，t，J＝8.6Hz)、3.43(1H，m)、3.52(2H，m)、3.67(1H，m)、3.74(3H，s)、6.52(1H，d，J＝7.6Hz)、6.55(1H，t，J＝7.6Hz)、6.87(2H，d，J＝8.4Hz)、6.92(1H，d，J＝7.6Hz)、7.01(1H，t，J＝7.6Hz)、7.16(2H，d，J＝8.4Hz)、7.18(2H，d，J＝8.4Hz)、7.32(2H，dd，J＝6.0，8.4Hz).
ESI-Mass；445.3(MH+).
EXAMPLE 2161 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -3-methylindoline
Using 3-methylindoline (0.2g) and 1- (4-fluorophenethyl) -4-piperidone (0.50g), as in example 16, the title compound (0.384g) was obtained as a pale yellow oil. (yield: 70.7%)
Hydrochloric acid was added thereto to prepare a hydrochloride salt, which was recrystallized from ethanol to give the oxalate salt of the title compound (0.314g) as colorless crystals.
Melting point (hydrochloride salt): 232 ℃ C
Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.25(3H，d，J＝6.8Hz)、1.89(2H，m)、2.33(2H，m)、2.88(1H，t，J＝8.0Hz)、3.10(4H，m)、3.23(3H，m)、3.55(1H，t，J＝8.0Hz)、3.61(2H，m)、3.78(1H，m)、6.67(2H，m)、7.06(2H，m)、7.18(2H，t，J＝8.8Hz)、7.33(2H，m).
ESI-Mass；339.2(MH+).
Example 2171 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -5-chloro-6-aminoindoline
To a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminoindoline (0.5g) in acetonitrile (50ml) was added N-chlorosuccinimide (0.24g) at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was filtered, concentrated under reduced pressure, and added with 5N-aqueous sodium hydroxide solution and ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and purified by silica gel column chromatography (dichloromethane/ethanol) to give the title compound (0.19g) as a brown oil.
(yield: 34%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.69-1.83(4H，m)、2.03-2.11(2H，m)、2.51-2.60(2H，m)、2.75-2.82(2H，m)、2.83(2H，t，J＝8Hz)、3.08-3.15(2H，m)、3.20-3.32(1H，m)、3.38(2H，t，J＝8Hz)、3.85(2H，br-s)、5.89(1H，s)、6.89(1H，s)、6.92-7.00(2H，m)、7.11-7.21(2H，m).
Example 2181 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -5-chloro-6-methanesulfonylaminoindoline
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -5-chloro-6-aminoindoline (0.19g) and methanesulfonyl chloride (0.058g) as in example 116, the oxalate salt of the title compound was obtained as a pale red powder crystal (160 mg). (yield: 58%)
Melting point (oxalate): 193 ℃ 196-
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.73-1.83(4H，m)、2.81-3.00(6H，m)、2.91(3H.s)、3.09-3.15(2H，m)、3.37(2H，t，J＝8Hz)、3.42-3.56(2H，m)、3.58-3.65(1H，m)、6.49(1H，s)、7.10(1H，s)、7.12-7.20(2H，m)、7.23-7.31(2H，m).
FAB-Mass；452(MH+).
EXAMPLE synthesis of 2191- [1- (4-fluorophenethyl) piperidin-4-yl ] -5-chloro-6-methoxyindoline
To a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methoxyindoline (0.39g) in dichloromethane (5ml) was added N-chlorosuccinic acid imine (0.15g) at room temperature, followed by stirring for 20 minutes. To the reaction mixture were added 5N-aqueous sodium hydroxide solution and ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (dichloromethane/ethanol) and then hydrochloride was prepared by a conventional method to obtain the hydrochloride of the title compound (0.10g) as pale red powder crystals. (yield: 21%)
Melting point (hydrochloride salt): 135 ℃ and 138 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.83-2.08(4H，m)、2.82(2H，t，J＝8Hz)、3.00-3.12(4H，m)、3.21-3.29(2H，m)、3.34(2H，t，J＝8Hz)、3.60-3.67(2H，m)、3.72-3.84(1H，m)、3.79(3H，s)、6.34(1H，s)、6.99(1H，s)、7.15-7.20(2H，m)、7.30-7.34(2H，m).
FAB-Mass；399(MH+).
EXAMPLE 2201 Synthesis of- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-aminoindoline
From 1- (piperidin-4-yl) -6-nitroindoline (3.5g) as in example 2 or example 110, the title compound (2.4g) was obtained as pale yellow powder crystals. (yield: 40%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.69-1.88(4H，m)、2.09-2.15(2H，m)、2.52-2.60(2H，m)、2.78-2.89(2H，m)、3.07-3.11(2H，m)、3.14-3.21(1H，m)、3.22(2H，t，J＝8Hz)、3.50(2H，br-s)、5.81(1H，s)、5.98(1H，d，J＝8Hz)、6.72-6.83(3H，m)、7.10-7.20(1H，m).
EXAMPLE 2211- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-methanesulfonylaminoindoline synthesis
From 1- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-aminoindoline (0.4g) and methanesulfonyl chloride (0.51g), the hydrochloride of the title compound (240mg) was obtained as a pale yellow hygroscopic amorphous salt, as in example 116. (yield: 45%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.83-1.89(2H，m)、1.99-2.10(2H，m)、2.84(2H，t，J＝8Hz)、2.89(3H，s)、3.05-3.27(6H，m)、3.33(2H，t，J＝8Hz)、3.35-3.43(1H，m)、3.59-3.68(2H，m)、6.38-6.41(2H，m)、6.94(1H，d，J＝8Hz)、7.06-7.11(1H，m)、7.22-7.28(1H，m)、7.39-7.45(1H，m)、9.34(1H，br-s)、10.76(1H，br-s).
FAB-Mass；436(MH+).
Example 2221- [1- (2, 4-difluorophenethyl) piperidin-4-yl]Synthesis of (E) -6-acetamido-indoline
As in example 133, from 1- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-aminoindoline (0.6g) and acetic anhydride (5ml), the hydrochloride of the title compound (640mg) was obtained as white powder crystals. (yield: 87%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.83-1.98(4H，m)、1.99(3H，s)、2.81(2H，t，J＝8Hz)、3.00-3.13(4H，m)、3.22-3.33(4H，m)、3.55-3.69(3H，m)、6.58(1H，d，J＝8Hz)、6.90(1H，d，J＝8Hz)、6.95(1H，s)、7.07-7.12(1H，m)、7.24-7.30(1H，m)、7.39-7.45(1H，m)、9.69(1H，br-s).
FAB-Mass；400(MH+).
EXAMPLE 2231 Synthesis of- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-bromoindoline
From 1- (piperidin-4-yl) -6-bromoindoline (3.0g) and 2, 4-difluorophenethyl bromide (3.1g), the title compound (2.7g) was obtained as white powder crystals as in example 2.
(yield: 60%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.70-1.85(4H，m)、2.10-2.21(2H，m)、2.51-2.63(2H，m)、2.79-2.89(2H，m)、2.90(2H，t，J＝8Hz)、3.08-3.17(2H，m)、3.28-3.37(1H，m)、3.41(2H，t，J＝8Hz)、6.48(1H，s)、6.69(1H，d，J＝8Hz)、6.72-6.84(2H，m)、6.90(1H，d，J＝8Hz)、7.11-7.20(1H，m).
Example 2241 Synthesis of- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindoline
From 1- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-bromoindoline (3.5g), the hydrochloride of the title compound (0.26g) was obtained as a gray powder in the same manner as in examples 130 to 133. (yield: 7.3%)
Melting point (hydrochloride salt): 179 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.80(3H，s)、1.85-2.05(4H，m)、2.90(2H，t，J＝8Hz)、3.03-3.28(4H，m)、3.21-3.39(4H，m)、3.64-3.78(3H，m)、4.30(2H，s)、6.51-6.60(2H，m)、6.98-7.08(2H，m)、7.11-7.19(1H，m)、7.32-7.40(1H，m)、8.25(1H，br-s).
FAB-Mass；414(MH+).
Example 2251 Synthesis of- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-carbamoylmethyl indoline
From 1- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-bromoindoline (1.8g), the hydrochloride of the title compound (0.12g) was obtained as a pale green powder. (yield: 6.6%)
Melting point (hydrochloride salt): 241-
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.85-2.05(4H，m)、2.89(2H，t，J＝8Hz)、3.03-3.18(4H，m)、3.21-3.43(4H，m)、3.49(2H，s)、3.64-3.77(3H，m)、6.52-6.59(2H，m)、6.98-7.10(4H，m)、7.29-7.35(1H，m)、7.59(1H，br-s).
FAB-Mass；400(MH+).
Example 2261 Synthesis of- {1- [3- (4-fluorophenyl) propyl ] piperidin-4-yl } -6-acetamidomethylindoline
From 1- (piperidin-4-yl) -6-acetamidomethylindoline (250mg) and 3- (4-fluorophenyl) propyl bromide (240mg), the title compound (220mg) was obtained as pale yellow prisms as in example 2. (yield: 58%)
Melting point: 128-130 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.73-1.99(6H，m)、2.00(3H，s)、2.02-2.20(2H，m)、2.39-2.67(4H，m)、2.92(2H，t，J＝8Hz)、3.02-3.20(2H，m)、3.34-3.44(1H，m)、3.41(2H，t，J＝8Hz)、4.32(2H，d，J＝6Hz)、5.71(1H，br-s)、6.33(1H，s)、6.45(1H，d，J＝8Hz)、6.94-7.00(3H，m)、7.12-7.16(2H，m).
FAB-Mass；410(MH+).
Example 2271 Synthesis of- {1- [4- (4-fluorophenyl) butyl ] piperidin-4-yl } -6-acetamidomethylindoline
From 1- (piperidin-4-yl) -6-acetamidomethylindoline (250mg) and 4- (4-fluorophenyl) butyl bromide (250mg), the title compound (280mg) was obtained as white needle-like crystals as in example 2. (yield: 70%) melting Point: 119 ℃ C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.50-1.68(4H，m)、1.70-1.84(4H，m)、1.99-2.12(2H，m)、2.00(3H，s)、2.34-2.45(2H，m)、2.57-2.64(2H，m)、2.91(2H，t，J＝8Hz)、3.00-3.10(2H，m)、3.32-3.44(1H，m)、3.40(2H，t，J＝8Hz)、4.32(2H，d，J＝6Hz)、5.70(1H，br-s)、6.31(1H，s)、6.59(1H，d，J＝8Hz)、6.93-7.00(3H，m)、7.10-7.14(2H，m).
FAB-Mass；424(MH+).
EXAMPLE 2281 Synthesis of- [1- (4-Methoxyphenylethyl) piperidin-4-yl ] -6-methoxyindoline
As in example 2, from 1- (piperidin-4-yl) -6-methoxyindoline (320mg) and 4-methoxyphenethyl bromide (360mg), the oxalate salt of the title compound (220mg) was obtained as a white powder crystal. (yield: 34%)
Melting point (oxalate): 165-
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.74-1.88(4H，m)、2.79(2H，t，J＝8Hz)、2.84-2.90(4H，m)、3.03-3.12(2H，m)、3.30(2H，t，J＝8Hz)、3.47-3.69(3H，m)、3.67(3H，s)、3.71(3H，s)、6.07-6.15(2H，m)、6.84-6.93(3H，m)、7.16-7.21(2H，m).
FAB-Mass；367(MH+).
EXAMPLE 2291 Synthesis of- [1- (4-methoxyphenethyl) piperidin-4-yl ] -6-fluoroindoline
As in example 2, from 1- (piperidin-4-yl) -6-fluoroindoline (250mg) and 4-methoxyethyl bromide (290mg), the hydrochloride (120mg) of the title compound was obtained as white powder crystals. (yield: 27%)
Melting point (hydrochloride salt): 212 deg.C and 214 deg.C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.83-1.92(4H，m)、2.83(2H，t，J＝8Hz)、2.90-2.97(2H，m)、3.00-3.10(2H，m)、3.17-3.26(2H，m)、3.38(2H，t，J＝8Hz)、3.60-3.73(3H，m)、3.72(3H，s)、6.24-6.29(1H，m)、6.36-6.40(1H，m)、6.87-6.97(3H，m)、7.17-7.21(2H，m).
FAB-Mass；355(MH+).
Example 2301 Synthesis of- [1- (4-sulfamoylphenethyl) piperidin-4-yl ] -6-methoxyindoline
From 1- (piperidin-4-yl) -6-methoxyindoline (350mg) and 4-sulfamoylphenethylbromide (340mg) as in example 2, the title compound (70mg) was obtained as brown powder crystals. (yield: 13%)
Melting point: 179 plus 182 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.71-1.90(4H，m)、2.11-2.29(2H，m)、2.61-2.70(2H，m)、2.82-2.98(4H，m)、3.10-3.21(2H，m)、3.31-3.41(3H，m)、3.78(3H，s)、4.98(2H，br-s)、6.00(1H，s)、6.12(1H，d，J＝8Hz)、6.94(1H，d，J＝8Hz)、7.35(1H，d，J＝8Hz)、7.85(1H，d，J＝8Hz).
FAB-Mass；416(MH+).
Example 2311 Synthesis of- [1- (4-fluorophenoxypropyl) piperidin-4-yl ] -6-bromoindoline
From 1- (piperidin-4-yl) -6-bromoindoline (1.6g) and 4-fluorophenoxypropyl bromide (1.6g), the title compound (2.2g) was obtained as white powder crystals as in example 2. (yield: 90%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.51-1.85(2H，m)、1.87-1.89(2H，m)、1.92-2.19(4H，m)、2.52-2.62(2H，m)、2.90(2H，t，J＝8Hz)、3.03-3.14(2H，m)、3.28-3.33(1H，m)、3.42(2H，t，J＝8Hz)、3.97(2H，t，J＝6Hz)、6.45(1H，s)、6.68(1H，d，J＝8Hz)、6.80-6.89(3H，m)、6.92-7.00(2H，m).
Example 2321 Synthesis of- [1- (4-fluorophenoxypropyl) piperidin-4-yl ] -6-acetamidomethylindoline
From 1- [1- (4-fluorophenoxypropyl) piperidin-4-yl ] -6-bromoindoline (1.2g), the oxalate salt of the title compound (46mg) was obtained as a brown hygroscopic amorphous salt in the same manner as in examples 130, 131 and 133. (yield: 3.2%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.77-1.93(4H，m)、2.03-2.13(2H，m)、2.08(3H，s)、2.84(2H，t，J＝8Hz)、2.85-2.99(2H，m)、3.04-3.12(2H，m)、3.31(2H，t，J＝8Hz)、3.44-3.53(2H，m)、3.60-3.89(1H，m)、4.03(2H，t，J＝6Hz)、4.13(2H，d，J＝6Hz)、6.39(1H，s)、6.45(1H，d，J＝8Hz)、6.93-6.98(3H，m)、7.11-7.16(2H，m)、8.21(1H，t，J＝6Hz).
FAB-Mass；426(MH+).
EXAMPLE 2331 Synthesis of- {1- [2- (6-benzothiazolyl) ethyl ] piperidin-4-yl } -6-methoxyindoline
Using 6- (2-bromoethyl) benzothiazole (0.108g), 1- (piperidin-4-yl) -6-methoxyindoline (0.105g), according to example 2, the title compound (0.145g) was obtained as a yellow oil. (yield: 81.9%)
To this was added oxalic acid (37mg) to form a salt, which was recrystallized from ethanol to give the oxalate salt of the title compound (0.097 g).
Melting point: 188 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.87(4H，m)、2.82(2H，t，J＝7.6Hz)、3.21(2H，br-t)、3.18(2H，m)、3.28(2H，m)、3.34(2H，t，J＝7.6Hz)、3.58(2H，m)、3.70(3H，s)、3.72(1H.m)、6.12(1H，d，J＝7.6Hz)、6.15(1H，s)、6.91(1H.d，J＝7.6Hz)、7.50(1H，d，J＝8.4Hz)、8.08(1H，d，J＝8.4Hz)、8.10(1H，s)、9.39(1H，s).
ESI-Mass；394.2(MH+).
Example 2341 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -thiazolo [5, 4-f ] indoline
As in example 101, from thiazolo [5, 4-f ] indoline (0.2g), 1- (4-fluorophenethyl) -4-piperidone (0.6g), acetic acid (0.66g) and sodium triacetoxyborohydride (0.79g), the hydrochloride (0.34g) of the title compound was obtained as yellow powder crystals. (yield: 71%)
Melting point (hydrochloride salt): 165 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.93-2.06(4H，m)、2.98-3.06(4H，m)、3.08-3.19(2H，m)、3.24-3.32(2H，m)、3.43(2H，t，J＝8Hz)，3.60-3.70(2H，m)、3.81-3.90(1H，m)、7.16-7.20(3H，m)、7.31-7.36(2H，m)、7.70(1H，s)、9.14(1H，s).
FAB-Mass；382(MH+).
Example 2351 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminothiazolo [5, 4-f ] indoline
To a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminoindoline (1.2g) and potassium thiocyanate (1.0g) in acetic acid (12ml) was added dropwise liquid bromine (0.22ml), and the mixture was heated at 100 ℃ for 1 hour. A5N aqueous sodium hydroxide solution and chloroform were added to the reaction mixture under ice cooling, and the organic layer was separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (dichloromethane/ethanol) to give the title compound (0.20g) as brown powder crystals. (yield: 14%)
Melting point: 173 ℃ (decomposition)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.68-1.90(2H，m)、2.07-2.16(2H，m)、2.55-2.61(2H，m)、2.75-2.82(2H，m)、2.97(2H，t，J＝8Hz)、3.07-3.14(2H，m)、3.36-3.45(1H，m)、3.41(2H，t，J＝8Hz)、5.25(2H，br-s)、6.62(1H，s)、6.94-6.99(2H，m)、7.14-7.19(3H.m).
FAB-Mass；397(MH+).
EXAMPLE 2361 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -7-hydroxy- (4a, 7a) -cyclohexanoindole and 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -4-hydroxy- (3b, 6a) -cyclohexanoindole and their oxalate salts
Triethyl phosphonoacetate (2.24g) was added dropwise to a suspension of 60% sodium hydride (0.4g) in THF (30ml) under ice-cooling. After completion of hydrogen generation, a solution of 1- (1-acetylpiperidin-4-yl) -indoline-7-carbaldehyde (2.4g) in THF (20ml) was added dropwise to the reaction mixture, and the mixture was reacted at room temperature for 3 hours. The reaction mixture was partitioned between ethyl acetate and water, washed with water, dried, and concentrated under reduced pressure.
The residue was dissolved in ethanol (50ml), and 10% palladium on charcoal (0.3g) was added to hydrogenate the mixture under normal pressure. After completion of the reaction, the reaction mixture was filtered through celite and washed with ethanol. To the filtrate was added a 5N-aqueous sodium hydroxide solution (5ml), and the mixture was reacted at 50 ℃ for 1 hour. After the reaction mixture was cooled, 5N hydrochloric acid (5ml) was added thereto, and the mixture was concentrated under reduced pressure. Methylene chloride (100ml) was added to the residue, which was filtered through celite, and the filtrate was concentrated.
To the obtained crude carboxylic acid (1.8g) was added polyphosphoric acid (30g), and the reaction was carried out at 120 ℃ for 2 hours. The reaction mixture was cooled to 50 ℃ and water (200ml) was added to the reaction mixture, followed by extraction with ethyl acetate. The ethyl acetate layer was then washed with water, 10% aqueous potassium carbonate solution, water and saturated brine, dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give 0.31g of a mixture of colorless oily cyclopentanone compounds.
This mixture was dissolved in ethanol (15ml), and 8N aqueous sodium hydroxide solution (5ml) was added to the solution, followed by heating and refluxing for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and an aqueous ammonium chloride solution, and the ethyl acetate layer was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel short column chromatography (dichloromethane/methanol) to give 0.21g of a pale brown oily mixture.
This oily mixture (0.20g), 4-fluorophenethyl bromide (0.18g) and potassium carbonate (0.43g) were suspended in DMF (15ml) and reacted at 60 ℃ for 12 hours. The reaction mixture was partitioned between ethyl acetate and water, the ethyl acetate layer was washed with water and saturated brine, dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol) to give 0.12g of a colorless oily ketone mixture.
The ketone body mixture was dissolved in methanol, and sodium borohydride was added thereto at room temperature to react for 30 minutes. The solvent was evaporated under reduced pressure, the residue was partitioned between ethyl acetate and water, the ethyl acetate layer was washed with water, dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol) to give 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -7-hydroxy- (4a, 7a) -cyclohexanoindole (0.04g) and 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -4-hydroxy- (3b, 6a) -cyclohexanoindole as colorless oils (0.03 g). Dissolving in methanol, reacting with oxalic acid, evaporating solvent, adding ether to the residue, filtering to obtain precipitate, drying, and obtaining the oxalate salt of the title compound as amorphous substance.
(1)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -7-hydroxy- (4a, 7a) -cyclohexanoindoline
Oxalate salt
1H-NMR(400MHz，CD3OD)；δ(ppm)
1.87(1H，m)、2.04(4H，m)、2.39(1H，m)、2.63(1H，m)、2.86(3H，m)、3.02-3.25(4H，m)、3.30-3.40(4H，m)、3.70-3.85(3H，m)、5.06(1H，br-t)、6.56(1H，s)、6.92(1H，s)、7.05(2H，t，J＝8.0Hz)、7.31(2H，br).
FAB-Mass；381(MH+).
(2)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -4-hydroxy- (3b, 6a) -cyclohexanoindoline
Oxalate salt
1H-NMR(400MHz，CD3OD)；δ(ppm)
1.87-2.06(5H，m)、2.37(1H，m)、2.65(1H，m)、2.93(2H，m)，3.02-3.23(5H，m)、3.30-3.40(4H，m)、3.70-3.84(3H，m)、5.15(1H，br-t)、6.48(1H，d，J＝8.0Hz)、6.92(1H，d，J＝8.0Hz)、7.05(2H，t，J＝8.0Hz)、7.32(2H，br-t).
FAB-Mass；381(MH+).
Example 2371 Synthesis of- (1-methylpiperidin-4-yl) -6- (4-fluorobenzenesulfonylamino) indoline
From 6- (4-fluorobenzenesulfonylamino) indoline (0.3g), 1-methyl-4-piperidone (0.17g), acetic acid (0.36g) and sodium triacetoxyborohydride (0.41g), the hydrochloride of the title compound (0.08g) was obtained as a pale yellow powder crystal, as in example 101. (yield: 19%)
Melting point (hydrochloride salt): 170 ℃ and 172 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.63-1.71(2H，m)、1.80-1.94(2H，m)、2.71(3H，s)、2.76(2H，t，J＝8Hz)、3.03-3.14(2H，m)、3.24(2H，t，J＝8Hz)、3.40-3.56(3H，m)、6.18(1H，d，J＝8Hz)、6.22(1H，s)、6.81(1H，d，J＝8Hz)、7.35-7.39(2H，m)、7.69-7.78(2H，m).
FAB-Mass；390(MH+).
Example 2381 Synthesis of- (1-ethylpiperidin-4-yl) -6- (4-fluorobenzenesulfonylamino) indoline
From 6- (4-fluorobenzenesulfonylamino) indoline (0.3g), 1-ethyl-4-piperidone (0.19g), acetic acid (0.36g) and sodium triacetoxyborohydride (0.41g), the hydrochloride of the title compound (0.34g) was obtained as pale yellow hygroscopic amorphous in the same manner as in example 101. (yield: 77%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.22(3H，t，J＝7Hz)、1.62-1.71(2H，m)、1.80-1.99(2H，m)、2.76(2H，t，J＝8Hz)、2.95-3.19(4H，m)、3.22(2H，t，J＝8Hz)、3.48-3.80(3H，m)、6.16(1H，d，J＝8Hz)、6.23(1H，s)、6.81(1H，d，J＝8Hz)、7.31-7.40(2H，m)、7.70-7.80(2H，m).
FAB-Mass；390(MH+).
Example 2391 Synthesis of- (1-ethylpiperidinyl) -4- (4-fluorophenyl) indoline
From 4- (4-fluorophenyl) indoline (250mg), 1-ethyl-4-piperidone (230mg), acetic acid (430mg) and sodium triacetoxyborohydride (510mg), the hydrochloride of the title compound (200mg) was obtained as white powder crystals as in example 1. (yield: 46%) melting point (hydrochloride salt): 270 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.23(3H，t，J＝7Hz)、1.83-2.04(4H，m)、2.91-3.12(6H，m)、3.24-3.34(2H，m)、3.50-3.57(2H，m)、3.70-3.80(1H，m)、6.54(1H，d，J＝8Hz)、6.60(1H，d，J＝8Hz)、7.09(1H，t，J＝8Hz)、7.21-7.26(2H，m)、7.45-7.48(2H，m)、9.89(1H，br-s).
FAB-Mass；325(MH+).
Example 2401 Synthesis of- (1-ethylpiperidin-4-yl) -3- (4-fluorophenyl) indoline
The same procedures used in example 16 were repeated except for using 3- (4-fluorophenyl) indoline (0.184g) to give the title compound (0.102g) as a yellow oil. (yield: 38.0%)
To this was added oxalic acid (14mg) to form a salt, which was recrystallized from ethanol to give the oxalate salt of the title compound (0.063 g).
Melting point (oxalate): 216 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.20(3H，t，J＝6.8Hz)、1.90(4H，m)、2.96(2H，m)、3.04(2H，m)、3.23(1H，t，J＝8.2Hz)、3.48(2H，m)、3.75(2H，m)、4.42(1H，t，J＝8.2Hz)、6.58(1H，t，J＝7.6Hz)、6.64(1H，d，J＝7.6Hz)、6.78(1H，d，J＝7.6Hz)、7.06(1H，t，J＝7.6Hz)、7.14(2H，t，J＝8.4Hz)、7.28(1H，dd，J＝5.6，8.4Hz).
FAB-Mass；325(MH+).
Example 2411 Synthesis of- (1-ethylpiperidin-4-yl) -3- (4-methoxyphenyl) indoline
Using methoxymethyltriphenylphosphonium bromide (7.113g) and 4-anisaldehyde (2.6ml), production example 41-1 was repeated to give a pale yellow oil (2.235 g). This was dissolved in isopropanol (25ml) and 2N-hydrochloric acid (25ml), and phenylhydrazine (1.0ml) was added thereto, followed by heating and refluxing for 1 hour. The reaction mixture was left to cool, and then concentrated under reduced pressure. Ethyl acetate was added to the residue, and the organic layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give a yellow oil (1.249 g). The title compound (0.307g) was obtained as a yellow oil by the method of preparation 54 (0.534g), further using 1-ethyl-4-piperidone and the method of example 16. (yield: 4.4%)
To this, oxalic acid (41mg) was added to form a salt, which was recrystallized from ethanol to give the oxalate salt of the title compound as pale yellow crystals (0.151 g).
Melting point (oxalate): 143 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.20(3H，t，J＝7.2Hz)、1.89(4H，m)、2.95(2H，m)、3.04(2H，m)、3.19(1H，t，J＝8.4Hz)、3.48(2H，m)、3.72(3H，s)、3.75(2H，m)、4.34(1H，t，J＝8.4Hz)、6.57(1H，t，J＝7.6Hz)、6.62(1H，d，J＝7.6Hz)、6.75(1H，d，J＝7.6Hz)、6.88(2H，d，J＝8.8Hz)、7.05(1H，t，J＝7.6Hz)、7.16(2H，t，J＝8.8Hz).
ESI-Mass；337.1(MH+).
Example 2421 Synthesis of- (1-ethylpiperidin-4-yl) -3- (4-methoxybenzyl) indoline
Using 3- (4-methoxybenzyl) indoline (0.332g) and 1-ethyl-4-piperidine (0.28ml), the title compound (0.380g) was obtained as a pale yellow oil according to example 16. (yield: 78.0%)
To this was added oxalic acid (49mg) to form a salt, which was recrystallized from acetone to give the oxalate salt of the title compound (0.150 g).
Melting point (oxalate): 136 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.18(3H，t，J＝7.6Hz)、1.80(4H，m)、2.63(1H，dd，J＝9.2，13.6Hz)、2.89(2H，m)、2.99(4H，m)、3.23(1H，t，J＝8.6Hz)、3.44(3H，m)、3.67(1H，m)、3.73(3H，5)、6.51(1H，d，J＝7.6Hz)、6.55(1H，t，J＝7.6Hz)、6.87(2H，d，J＝8.4Hz)、6.92(1H，d，J＝7.6Hz)、7.01(1H，t，J＝7.6Hz)、7.15(2H，d，J＝8.4Hz).
ESI-Mass；351.3(MH+).
Example 243 Synthesis of 11- (4-pyridylmethyl) -3- (4-methoxybenzyl) indoline
Using 3- (4-methoxybenzyl) indoline (2.0g) and 4-pyridinecarboxaldehyde (1.2ml), the title compound (1.474g) was obtained as a pale yellow oil according to Experimental example 16. (yield: 53.44%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.27(1H，d，J＝8.8，14.0Hz)、3.08(2H，m)、3.36(1H，t，J＝8.8Hz)、3.55(1H，m)、3.79(3H，s)、4.20(2H，d，J＝7.6Hz)、7.00(1H，d，J＝7.6Hz)、7.06(3H，m)、7.20(2H，m)、8.53(2H，dd，J＝1.6，4.8Hz).
Example Synthesis of 243-21- [ (1-ethylpyridin-3-en-4-yl) methyl ] -3- (4-methoxybenzyl) indoline
1- (4-pyridylmethyl) -3- (4-methoxybenzyl) indoline (0.7g) was dissolved in acetonitrile (10ml), ethyl iodide (0.29ml) was added, and the mixture was heated at 70 to 90 ℃ for 9 hours in a sealed tube. The reaction mixture was cooled and concentrated under reduced pressure. To the residue were added ethanol (20ml) and sodium borohydride (0.40g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (200ml), washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.115g) as a pale yellow oil. (yield: 15.0%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.12(3H，t，J＝7.2Hz)、2.14(2H，m)、2.48(2H，q，J＝7.2Hz)、2.56(2H，m)、2.73(1H，dd，J＝9.2，14.4Hz)、2.96(2H，br-d)、3.01(2H，m)、3.40(2H，t，J＝9.2Hz)、3.53(2H，br-s)、3.79(3H，s)、5.58(1H，br-s)、6.47(1H，d，J＝9.1Hz)、6.61(1H，d，J＝9.1Hz)、6.83(2H，m)、6.83(2H，m)、6.91(1H，d，J＝8.0Hz)、6.47(1H，d，J＝9.1Hz)、7.07(3H，m).
Example Synthesis of 243-31- [ (1-ethylpiperidin-4-yl) methyl ] -3- (4-methoxybenzyl) indoline
1- [ (1-ethylpiperidin-3-en-4-yl) methyl ] -3- (4-methoxybenzyl) indoline (0.115g) was dissolved in ethanol (3.2ml), and catalytically reduced at room temperature for 54 hours under normal pressure by adding a palladium-on-carbon catalyst. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.053g) as a pale yellow oil. (yield: 45.8%)
To this was added oxalic acid (6mg) to form a salt, which was recrystallized from a mixed solvent of ethyl acetate/isopropyl ether to give the oxalate salt of the title compound (0.313g) as colorless crystals.
Melting point (oxalate): 78 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.17(3H，t，J＝7.2Hz)、1.38(2H，m)、1.82(2H，br-t)、2.64(1H，dd，J＝8.6，14.0Hz)、2.75(2H，br-t)、2.83(1H，m)、2.97(4H，m)、3.29(1H，t，J＝8.6Hz)、3.34(2H，br-d)、3.45(1H，m)、3.73(3H，s)、6.48(1H，d，J＝7.6Hz)、6.55(1H，t，J＝7.6Hz)、6.86(2H，d，J＝8.4Hz)、6.94(1H，d，J＝7.6Hz)、6.99(1H，t，J＝7.6Hz)、7.14(2H，d，J＝8.4Hz).
FAB-Mass；365(MH+).
Example 2441 Synthesis of- (1-ethylpiperidin-4-yl) -3- (4-fluorobenzyl) indoline
Using 3- (4-fluorobenzyl) indoline (1.163g) and 1-ethyl-4-piperidone (1.0ml), the title compound (1.614g) was obtained as yellow oil according to example 16. (yield: 93.7%)
To this was added oxalic acid (21mg) to form a salt, which was recrystallized from ethanol to give the oxalate salt of the title compound.
Melting point (oxalate): 203 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.20(3H，t，J＝7.2Hz)、1.82(4H，m)、2.70(1H，dd，J＝8.8，13.2Hz)、2.90-3.07(6H，m)、3.26(1H，t，J＝8.8Hz)、3.41-3.50(3H，m)、3.68(1H.m)、6.54(2H，m)、6.91(1H，d，J＝7.6Hz)、7.02(1H，t，J＝7.6Hz)、7.12(2H，t，J＝8.8Hz)、7.27(1H，dd，J＝5.6，8.8Hz).
ESI-Mass；339.2(MH+).
Example 2451 Synthesis of- (1-ethylpiperidin-4-yl) -3- (3-pyridylmethyl) indoline
The same procedures used in example 16 were repeated except for using 3- (3-pyridylmethyl) indoline (0.253g) to give the title compound (0.233g) as a yellow oil. (yield: 71.0%)
To this was added oxalic acid (65mg) to form a salt, which was recrystallized from ethanol to give the oxalate salt of the title compound (0.191g, 45.5%).
Melting point (oxalate): 149 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.20(3H，t，J＝7.6Hz)、1.83(4H，m)、2.76(1H，dd，J＝8.8，11.6Hz)、3.04(6H，m)、3.29(1H，t，J＝8.8Hz)、3.50(3H，m)、3.68(1H，m)、6.52(1H，d，J＝7.6Hz)、6.56(1H，t，J＝7.6Hz)、6.92(1H，d，J＝7.6Hz)，7.02(1H，t，J＝7.6Hz)、7.32(1H，dd，J＝4.8，8.0Hz)、7.65(1H，dt，J＝2.0，8.0Hz)、8.43(2H，m).
ESI-Mass；322.2(MH+).
Example Synthesis of 2461- (1-ethylpiperidin-4-yl) -3- (3-methoxyphenylethyl) indoline
Using 3- (3-methoxyphenethyl) indoline (0.133g), the title compound (0.132g) was obtained as a pale yellow oil in accordance with example 16. (yield: 52.3%)
Hydrochloric acid was added thereto to form a salt, to obtain a hygroscopic amorphous hydrochloride of the title compound. Hydrochloride salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.26(3H，t，J＝8.0Hz)、1.74(1H，m)、1.86(2H，m)、2.07(3H，m)、2.63(2H，t，J＝8.0Hz)、2.99-3.07(5H，m)、3.14(1H，m)、3.52(3H，t，J＝8.0Hz)、3.72(1H，m)、3.74(3H，s)、6.59(2H，m)、7.02(1H，t，J＝8.0Hz)、7.08(1H，d，J＝8.0Hz)、7.20(1H，d，J＝8.0Hz).
ESI-Mass；365.2(MH+).
Example 2471 Synthesis of- (1-ethylpiperidin-4-yl) -3- (3-fluorophenethyl) indoline
Using 3- (3-fluorophenethyl) indoline (0.582g), the title compound (0.641g) was obtained as a yellow oil according to example 16. (yield: 66.2%)
To this was added oxalic acid (68mg) to form a salt, which was recrystallized from ethyl acetate to give the oxalate salt of the title compound (0.313g) as colorless crystals.
Melting point (oxalate): 138 deg.C
Oxalate salt
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.22(3H，t，J＝7.2Hz)、1.72(1H，m)、1.89(4H，m)、2.07(1H，m)、2.67(2H，t，J＝8.4Hz)、2.97(2H，br-t)、3.12(1H，m)、3.50(3H，t，J＝8.4Hz)、3.70(1H，m)、6.53(1H，d，J＝7.6Hz)、6.58(1H，d，J＝7.6Hz)、7.00(2H，m)、7.06(1H，d，J＝7.6Hz)、7.09(2H，m)、7.32(1H，q，J＝7.6Hz).
ESI-Mass；353.1(MH+).
EXAMPLE 2481 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] indane
From 1- (piperidin-4-yl) indane (300mg) and 4-fluorophenethyl bromide (370mg) as in example 2, the hydrochloride of the title compound (250mg) was obtained as white powder crystals. (yield: 46%)
Melting point (hydrochloride salt): 222 ℃ and 224 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.50-1.98(6H，m)、2.01-2.12(1H，m)、2.72-2.94(4H，m)、2.98-3.04(2H，m)、3.08-3.22(3H，m)、3.46-3.57(2H，m)、7.11-7.22(6H，m)、7.28-7.31(2H，m)、10.33(1H，br-s).
FAB-Mass；324(MH+).
EXAMPLE 2491 Synthesis of- [1- (4-methoxyphenethyl) piperidin-4-yl ] indane
From 1- (piperidin-4-yl) indane (300mg) and 4-methoxyphenethyl bromide (390mg) as in example 2, the hydrochloride of the title compound (260mg) was obtained as a white powder crystal. (yield: 47%)
Melting point (hydrochloride salt): 191 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.48-1.57(1H，m)、1.60-1.97(5H，m)、2.01-2.11(1H，m)、2.71-3.00(6H，m)、3.08-3.18(3H，m)、3.45-3.56(2H，m)、3.70(3H，s)、6.87(2H，d，J＝8Hz)、7.11-7.23(6H，m)、10.43(1H，br-s).
FAB-Mass；336(MH+).
Example Synthesis of 2501- {4- [2- (4-fluorophenyl) ethyl ] piperazin-1-yl } -6-methoxyindane hydrochloride
(250-1)1- (piperazin-1-yl) -6-methoxyindane
The intermediate 1- (4-acetylpiperazin-1-yl) -6-methoxyindane (2.20g) obtained in the above example and 8N-sodium hydroxide (8.0ml) were heated under reflux in ethanol. The reaction mixture was concentrated under reduced pressure, extracted with dichloromethane, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (1.48g) as a wax. (yield: 73%)
(250-2)1- [4- (4-Fluorobenzoylmethyl) piperazin-1-yl ] -6-methoxyindane
1- (piperazin-1-yl) -6-methoxyindane (0.41g) and 4-fluorobenzoylmethyl chloride (0.46g) are reacted in dichloromethane at 0 ℃ in the presence of 5N sodium hydroxide (2.0 ml). Extraction with dichloromethane, washing of the dichloromethane layer with water, drying, concentration under reduced pressure, and purification of the residue by silica gel column chromatography (toluene/acetone) gave the title compound (0.60 g).
(250-3)1- {4- [2- (4-fluorophenyl) ethyl ] piperazin-1-yl } -6-methoxyindane hydrochloride
Lithium aluminum hydride (0.13g) was suspended in THF, and a THF solution of 1- [4- (4-fluorobenzoylmethyl) piperazin-1-yl ] -6-methoxyindane (0.60g) was added dropwise thereto, and the reaction was monitored by TLC while heating to reflux. The reaction mixture was cooled with ice, to which were added water (0.13ml), a 5N aqueous solution (0.13ml) of sodium hydroxide and water (0.39ml) in this order, followed by stirring at room temperature for 1 hour. The precipitated precipitate was filtered off, washed with THF, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol) to give an oil (0.48 g). (yield: 83%)
The oily substance was converted into hydrochloride according to a conventional method to obtain the title compound as a white powder. Melting point: 213 deg.C (decomposition)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.03-2.19(2H，m)、2.49-2.66(10H，m)、2.69-2.90(4H，m)、3.80(3H，s)，4.32(1H，t，J＝7.2Hz)、6.77(1H，dd，J＝8.4，2.8Hz)、6.90(1H，d，J＝2.8Hz)、6.93-6.99(2H，m)，7.11(1H，d，J＝8.4Hz)、7.12-7.17(2H，m).
FAB-Mass；355(MH+).
Example Synthesis of 2511- (4-ethylpiperazin-1-yl) -6-methoxyindane hydrochloride
(251-1) 1-chloro-6-methoxyindane
6-Methoxyindan-1-one (5.0g) was dissolved in methanol (50ml), and sodium borohydride (1.41g) was added thereto at 0 ℃ to react at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned with ethyl acetate and water, and the ethyl acetate layer was washed with water, dried and concentrated under reduced pressure to give 6-methoxyindan-1-ol (5.1g) as an oil. This alcohol form was not purified, and was reacted with thionyl chloride (4.5ml) in diethyl ether at room temperature for 6 hours. The reaction mixture was poured into ice water, extracted with ether, and the ether layer was washed with water, dried and concentrated under reduced pressure to give the title compound (2.76 g).
(251-2)1- (4-acetylpiperazin-1-yl) -6-methoxyindane
1-chloro-6-methoxyindane (2.76g), 1-acetylpiperazine (2.30g) and potassium carbonate (2.90g) were refluxed in acetone overnight. The reaction mixture was cooled, filtered, washed with acetone, and the filtrate was concentrated under reduced pressure. The residue was partitioned with ethyl acetate and water, the ethyl acetate layer was then washed with water, dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (toluene/acetone system) to give the title compound (2.70g) as an oil.
(251-3)1- (4-ethylpiperazin-1-yl) -6-methoxyindane hydrochloride
Lithium aluminum hydride (0.14g) was suspended in THF, and a THF solution of 1- (4-acetylpiperazin-1-yl) -6-methoxyindane (0.50g) was added dropwise thereto, and the reaction was monitored by TLC while heating under reflux. The reaction mixture was cooled with ice, to which were added water (0.14ml), a 5N aqueous solution (0.14ml) of sodium hydroxide and water (0.42ml) in this order, followed by stirring at room temperature for 1 hour. The precipitated precipitate was filtered off, washed with THF, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol) to give 1- (4-ethylpiperazin-1-yl) -6-methoxyindane (0.30g) as an oil. (yield: 63%)
The hydrochloride salt was prepared in accordance with a conventional method to obtain the title compound as a white powder.
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.08(3H，t，J＝7.2Hz)、2.02-2.19(2H，m)、2.41(2H，q，J＝7.2Hz)、2.43-2.65(8H，m)、2.69-2.90(2H，m)、3.80(3H，s)、4.92(1H，t，J＝7.2Hz)、6.77(1H，dd，J＝8.4，2.8Hz)、6.90(1H，d，J＝2.8Hz)、7.09(1H，d，J＝8.4Hz).
FAB-Mass；261(MH+).
EXAMPLE 252 Synthesis of trans-1- (4-ethylpiperazin-1-yl) -2-ethoxycarboxyaminoindane
A mixture of (+ -) - (Z) -ethoxy-3 a, 8 b-dihydro-4H-indeno [2, 1-d ] oxazole (1.4g), ethylpiperazine (1.3ml), scandium trifluoromethanesulfonate (50mg) and toluene (40ml) synthesized according to WO95/04028 was stirred under a nitrogen stream at 70 ℃ for 17 hours according to example 13 of WO95/04028 and the method of tetrahedron letters 1627-1628, 35 (1994). After cooling to room temperature, ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by Chromatorex NH-silica gel chromatography (hexane/ethyl acetate) to give the title compound (675mg) (yield: 31%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.07(3H，t，J＝7.2Hz)、1.23(3H，m)、2.40(2H，q，J＝7.2Hz)、2.45(4H，br-s)、2.68(6H，m)、3.37(1H，dd，J＝16.2，7.4Hz)、4.02(1H，d，J＝4.8Hz)、4.12(2H，m)、7.16-7.23(3H，m)、7.33(1H，m).
EXAMPLE 253 Synthesis of trans-1- (4-ethylpiperazin-1-yl) -2-methylaminoindane
Trans-1- (4-ethylpiperazin-1-yl) -2-ethoxycarboxyaminoindane (670mg) was dissolved in dehydrated ether (20ml), and lithium aluminum hydride (410mg) was added at room temperature. After stirring under a nitrogen stream for 21 hours, water (0.4ml), a 5N-sodium hydroxide aqueous solution (0.4ml), and water (1.2ml) were added and stirred. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (503 mg).
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.08(3H，t，J＝7.2Hz)、2.42(2H，q，J＝7.2Hz)、2.47(4H，m)、2.69(5H，m)、3.18(1H，dd，J＝16.2，7.4Hz)、3.48(1H，dt，J＝7.4，4.8Hz)、4.03(1H，d，J＝4.8Hz)、7.14-7.21(3H，m)、7.36(1H，m).
EXAMPLE 254 Synthesis of trans-1- (4-ethylpiperazin-1-yl) -2- [ methyl- (4-trifluorobenzyl) amino ] indane
The title compound (670mg) was obtained from N-methylamine (500mg), 4-fluorobenzaldehyde (0.52ml), acetic acid (0.6ml) and dichloromethane (20ml) as in example 101. (yield: 95%)
This was dissolved in 10ml of ethyl acetate, and a 4N-HCl/ethyl acetate solution (2ml) was added. After concentrating the solvent under reduced pressure, diethyl ether was added and the mixture was concentrated again. Drying on vacuum tube gave the title compound as a white crystal as the hydrochloride salt (821 mg).
Free form
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.08(3H，t，J＝7.2Hz)、2.10(3H，s)、2.41(2H，q，J＝7.2Hz)、2.45(4H，br-s)、2.64(4H，br-s)、2.95(2H，m)、3.48(3H，s)、3.73(1H，ddd，J＝7.4，7.2，4.4Hz)、4.33(1H，d，J＝4.4Hz)、6.98(2H，m)、7.19(3H，m)、7.29(3H，m)、7.36(1H，m).
Hydrochloride salt
Melting point: 196 ℃ 198 DEG C
FAB-Mass：368(MH+)
Example 2557 Synthesis of- [ 4-hydroxy-1- (4-fluorophenethyl) piperidin-4-yl ] -5, 6-dihydro-7H-azaindene
6, 7-dihydro-5H-cyclopenta [ B ] pyridine (1.00g, CAS registry No. 533-37-9) was dissolved in tetrahydrofuran (15ml), and a 1.6M- (n-butyllithium)/hexane solution (5.8ml) was added dropwise under a nitrogen stream while cooling to-55 ℃ or lower. After stirring for 5 minutes, a solution of 1- (4-fluorophenethyl) -4-piperidone (204g) in tetrahydrofuran (10ml) was added dropwise thereto over 20 minutes at the same temperature. After stirring for 30 minutes, the mixture was cooled to room temperature, water was added thereto, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the obtained residue (3.17g) was purified by silica gel column chromatography (methanol/dichloromethane) to give the title compound (600mg) as a slightly brown oil.
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.72-2.08(4H，m)、2.22-3.10(12H，m)、3.37(1H，d，J＝9.5Hz)、5.81(1H，br-s)、6.93-7.01(2H，m)、7.08(1H，dd，J＝8.0，5.5Hz)、7.12-7.20(2H，m)、7.33(1H，d，J＝8.0Hz)、8.28(1H，d，J＝5.5Hz).
FAB-Mass；341(MH+).
Example 2567- [1- (4-fluorophenethyl) piperidin-4-ylidene]Synthesis of (E) -5, 6-dihydroazaindene
7- [ 4-hydroxy-1- (4-fluorophenethyl) piperidin-4-yl ] -5, 6-dihydro-7H-azaindene (350mg) was dissolved in tetrahydrofuran (3ml), and thionyl chloride (0.11ml) and triethylamine (0.50ml) were added dropwise under ice-cooling. After stirring at room temperature for 15 minutes, water was added, extraction was performed with ethyl acetate, and the organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off, and the resulting residue (250mg) was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (45mg) as an oil.
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.45-2.50(2H，m)、2.58-2.68(6H，m)、2.75-2.95(6H，m)、3.48(2H，br-s)、6.93-7.00(3H，m)、7.14-7.20(2H，m)、7.48(1H，d，J＝7.6Hz)、8.40(1H，d，J＝4.4Hz).
FAB-Mass；323(MH+).
Example 2577 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -5, 6-dihydro-7H-azaindene
Reacting 7- [1- (4-fluorophenethyl) piperidin-4-ylidene]-5, 6-dihydroazaindene (100mg) was dissolved in methanol (5ml), 2 drops of acetic acid were added dropwise thereto, and then the mixture was reacted under a hydrogen pressure of 3kg/cm in the presence of a palladium catalyst2The vibration was vigorously carried out for 12 hours. After the catalyst was filtered off, water was added thereto, and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off to leave the title compound (45mg) as an oil.
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.22-1.52(2H，m)、1.94-2.40(4H，m)、2.55-2.96(4H，m)、3.00-3.30(6H，m)、3.45-3.70(2H，m)、6.97-7.02(2H，m)、7.07(1H，dd，J＝5.2，7.6Hz)、7.19-7.25(2H，m)、7.52(1H，d，J＝7.6Hz)、8.34(1H，d，J＝5.2Hz).
FAB-Mass；325(MH+).
Example 2587 Synthesis of- [4- (4-fluorophenethyl) piperidin-1-yl ] -5, 6-dihydro-7H-azaindene
7-hydroxy-6, 7-dihydro-5H-cyclopenta [ B ] pyridine (247mg) synthesized in Japanese patent application laid-open No. Hei 1-211581 was dissolved in methylene chloride (5ml), and thionyl chloride (0.147ml) was added thereto under ice cooling to stir for 25 minutes. The reaction mixture was evaporated to dryness under reduced pressure. To this solution, a dimethylformamide (5ml) solution of 1- (4-fluorophenethyl) piperazine (570mg) synthesized according to Japanese patent application laid-open No. Sho 54-92979 and triethylamine (0.38ml) were added, and the mixture was heated at 60 ℃ for 5 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the obtained residue was purified by NH-silica gel column chromatography (hexane/dichloromethane) to give the title compound (200mg) as an oil.
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.15-2.25(2H，m)、2.50-3.00(14H，m)、4.28(1H，t，J＝7.0Hz)、6.92-7.00(2H，m)、7.08(1H，dd，J＝5.0，7.4Hz)、7.12-7.18(2H，m)、7.50(1H，d，J＝7.4Hz)、8.46(1H，d，J＝5.0Hz).
FAB-Mass；326(MH+).
Example 259 Synthesis of cis-and trans-2, 6-dichloro-3-methoxyvinylpyridines
To a solution of methoxymethyltriphenylphosphonium chloride (62.5g) in tetrahydrofuran (250ml) was added potassium tert-butoxide (22.2g), and the mixture was stirred at 0 ℃ for 20 minutes. Then, a tetrahydrofuran (100ml) solution of 2, 6-dichloro-3-formylpyridine (24.7g) synthesized according to the description of J.CHEM.SOC.PERKIN TRANS.1(1990, NO.9, p2409) was added dropwise thereto, and the mixture was stirred for 2 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give a mixture of geometric isomers of the title compound (21.5g) as a pale yellow oil. (yield: 75%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.71(3H，s)、3.82(3H，s)、5.53(1H，d，J＝7Hz)、5.93(1H，d，J＝12Hz)、6.38(1H，d，J＝7Hz)、7.03(1H，d，J＝12Hz)、7.17(1H，d，J＝8Hz)、7.19(1H，d.J＝8Hz)、7.60(1H，d，J＝8Hz)、8.36(1H，d，J＝8Hz).
Example 259 Synthesis of 3-formylmethylpyridine-22, 6-dichloro-6
Cis-and trans-2, 6-dichloro-3-methoxyvinylpyridine (21.5g) and a solution of 35% homoalanine (100 ml)/diethyl ether (200ml) were stirred at room temperature for 1 day. After the reaction solution was made alkaline with a concentrated aqueous sodium hydroxide solution, ethyl acetate was added to separate an organic layer. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (15g) as a pale yellow oil. (yield: 56%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.90(2H，s)、7.31(1H，d，J＝8Hz)、7.55(1H，d，J＝8Hz)、9.81(1H，s).
Example 259 Synthesis of 3-hydroxyethyl-3-dichloro-pyridine
A solution of cis-and trans-2, 6-dichloro-3-methoxyvinylpyridine (2.0g) and 35% perchloric acid (10 ml)/diethyl ether (30ml) was stirred at room temperature for 1 day. After the reaction solution was made alkaline with a concentrated aqueous sodium hydroxide solution, ethyl acetate was added to separate an organic layer. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was evaporated. To the residue were added ethanol (20ml) and sodium borohydride (0.076g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium bicarbonate and ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.3g) as a pale yellow oil. (yield: 69%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.50(1H，t，J＝6Hz)、2.99(2H，t，J＝6Hz)、3.95(1H，q，J＝6Hz)、7.23(1H，d，J＝8Hz)、7.62(1H，d，J＝8Hz).
Example 259-41- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-chloro-7-azaindoline Synthesis
Methanesulfonyl chloride (0.45g) was added dropwise to pyridine (10ml) of 2, 6-dichloro-3-hydroxyethylpyridine (0.65g) under ice-cooling, and the mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium bicarbonate and ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was evaporated. To the residue were added 1- (4-fluorophenethyl) -4-aminopiperidine (0.75g) and dichlorobenzene (20ml), and the mixture was heated at 180 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium bicarbonate and ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.43g) as a colorless oil. (yield: 35%)
A part of the compound was converted to a hydrochloride salt by a conventional method to obtain the title compound as a white powdery crystal.
Melting point (hydrochloride salt): 225 ℃ (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.81-1.90(2H，m)、1.99-2.10(2H，m)、2.93(2H，t，J＝8Hz)、3.00-3.08(2H，m)、3.10-3.27(4H，m)、3.52(2H，t，J＝8Hz)、3.55-3.64(2H，m)、4.00-4.12(1H，m)、6.44(1H，d，J＝8Hz)、7.12-7.20(2H，m)、7.23(1H，d，J＝8Hz)、7.29-7.34(2H，m).
FAB-Mass；360(MH+).
Example 2601- [1- (4-fluorophenethyl) piperidin-4-yl]Synthesis of (E) -7-azaindoline
Starting from 2-chloro-3-formylpyridine (1.5g) synthesized according to the description of J.CHEM.SOC.PERKIN TRANS.1(1990.No.9, p2409), the title compound was obtained as a hydrochloride salt (0.21g) as a white powdery crystal in the same manner as in examples 259-1, 259-3 and 259-4. (yield: 4.9%)
Melting point (hydrochloride salt): 223 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.79-2.00(2H，m)、2.03-2.21(2H，m)、2.95-3.10(4H，m)、3.22-3.36(4H，m)、3.60-3.69(4H，m)、4.15-4.24(1H，m)、6.51-6.60(1H，m)、7.12-7.20(2H，m)、7.29-7.37(3H，m)、7.67-7.73(1H，m).
FAB-Mass；326(MH+).
Example Synthesis of 261-12, 6-difluoro-3-bromoethylpyridine
Triphenylphosphine (3.1g) and N-bromosuccinimide (1.9g) were added to a dichloromethane (100ml) solution of 2, 6-difluoro-3-hydroxyethylpyridine (1.58g) obtained as in example 259-3 under ice-cooling, and the mixture was stirred for 2 hours. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.6g) as a colorless oil. (yield: 73%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
3.20(1H，t，J＝6Hz)、3.59(2H，t，J＝6Hz)、6.80-6.85(1H，m)，7.75-7.83(1H，m).
EXAMPLE 261-21- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-fluoro-7-azaindoline synthesis
A mixture of 2, 6-difluoro-3-bromoethylpyridine (0.3g), 1- (4-fluorophenethyl) -4-aminopiperidine (0.3g), triethylamine (0.27g) and o-dichlorobenzene (20ml) was heated at 180 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium bicarbonate and ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and then hydrochloride was obtained by a conventional method to obtain the hydrochloride of the title compound (0.14g) as a white powder crystal. (yield: 30%)
Melting point (hydrochloride salt): 202 ℃ to 204 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.81-1.90(2H，m)、1.99-2.11(2H，m)、2.91(2H，t，J＝8Hz)、3.00-3.19(4H，m)、3.20-3.30(2H，m)、3.51(2H，t，J＝8Hz)、3.58-3.65(2H，m)、3.93-4.03(1H，m)、6.03(1H，d，J＝8Hz)、7.14-7.21(2H，m)、7.29-7.35(3H，m).
FAB-Mass；344(MH+).
EXAMPLE synthesis of 2621- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-chloro-7-azaindoline
Starting from 1- (piperidin-4-yl) -6-chloro-7-azaindoline (0.5g) and 2, 4-difluorophenethyl bromide (0.43g), the hydrochloride of the title compound (74mg) was obtained as a brown powder crystal as in example 2. (yield 7.8%) melting point (hydrochloride salt): 221 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.81-1.91(2H，m)、2.00-2.15(2H，m)、2.91(2H，t，J＝8Hz)、3.03-3.39(6H，m)、3.53(2H，t，J＝8Hz)、3.60-3.68(2H，m)、4.01-4.12(1H，m)、6.46(1H，d，J＝8Hz)、7.08-7.17(1H，m)、7.21-7.31(2H，m)、7.40-7.48(1H，m).
FAB-Mass；378(MH+).
EXAMPLE 2631 Synthesis of- [1- (4-methoxyphenylethyl) piperidin-4-yl ] -6-chloro-7-azaindoline
As in example 2, from 1- (piperidin-4-yl) -6-chloro-7-azaindoline (0.8g) and 4-methoxyethyl bromide (0.72g), the hydrochloride of the title compound (220mg) was obtained as a pale yellow powder crystal. (yield 16%)
Melting point (hydrochloride salt): 199 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.82-1.91(2H，m)、1.97-2.09(2H，m)、2.89-2.98(4H，m)、3.08-3.24(4H，m)、3.52(2H，t，J＝8Hz)、3.56-3.64(2H，m)、4.00-4.10(1H，m)、6.44(1H，d，J＝7Hz)、6.90(1H，d，J＝9Hz)、7.18(1H，d，J＝9Hz)、7.22(1H，d，J＝7Hz).
FAB-Mass；372(MH+).
EXAMPLE 2641 Synthesis of- [1- (-fluorophenethyl) piperidin-4-yl ] -6-azaindoline
A mixture of 6-azaindoline (180mg), 1- (4-fluorophenethyl) -4-piperidone (530mg), platinum oxide (20mg), acetic acid (0.5ml) and ethanol (10ml) synthesized according to the description in tetrahedron (1998, vol.44, No.10, p2977) was subjected to catalytic reduction under a stream of hydrogen gas at ordinary temperature and pressure. After stirring overnight, the catalyst was filtered off and concentrated under reduced pressure. The mixture was diluted with saturated aqueous sodium bicarbonate and ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate) to obtain an oxalate salt of the title compound (35mg) as a pale yellow powder crystal according to the conventional method. (yield: 5.2%)
Melting point (oxalate): 196 ℃ 198 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.83-1.91(4H，m)、2.90-3.05(6H，m)、3.18-3.27(2H，m)、3.38(2H，t，J＝8Hz)、3.51-3.60(2H，m)、3.69-3.79(1H，m)、7.10(1H，d，J＝5Hz)、7.14-7.19(2H，m)、7.30-7.34(2H，m)、7.83(1H，d，J＝5Hz)、7.86(1H，s).
FAB-Mass；326(MH+).
EXAMPLE 2655 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-ylidene ] -7-methyl-5, 6-dihydrocyclopentapyrazine
5-methyl-6, 7-dihydro-5 (H) -cyclopenta [ B ] pyrazine (2.82g, CAS registry No. 23747-48-0) was dissolved in tetrahydrofuran (30ml), and 1.6M- (n-butyllithium)/hexane solution (13.4ml) was added dropwise under a nitrogen stream while cooling to-55 ℃ or lower. After stirring for 5 minutes, a solution of 1- (4-fluorophenethyl) -4-piperidone (3.72g) in tetrahydrofuran (10ml) was added dropwise thereto over 5 minutes at the same temperature. After stirring for 5 minutes, the reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off, and the obtained residue (6.5g) was purified by NH-silica gel column chromatography (hexane/ethyl acetate) to give 5- [ 4-hydroxy-1- (4-fluorophenethyl) piperidin-4-yl ] -7-methyl-5, 6-dihydrocyclopentapyrazine as an oily isomer A (1.48g) and isomer B (2.94 g).
Isomer a:
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.40(3H，d，J＝6.8Hz)、1.48-1.85(5H，m)、2.47-2.65(5H，m)、2.72-2.85(4H，m)、3.14-3.24(1H，m)、3.32-3.38(1H，m)、4.48(1H，s)、6.93-7.00(2H，m)、7.12-7.19(2H，m)、8.24(1H，dd，J＝1.2，2.8Hz)、8.36(1H，dd，J＝1.2，2.8Hz).
isomer B:
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.33(3H，d，J＝7.2Hz)、1.65-1.97(5H，m)、2.27-2.86(9H，m)、3.25-3.36(1H，m)、3.38-3.44(1H，m)、4.11(1H，s)、6.93-7.01(2H，m)、7.12-7.20(2H，m)、8.27(1H，dd，J＝0.8，2.8Hz)、8.36(1H，dd，J＝0.8，2.8Hz).
example isomer a (1.48g) was dissolved in acetic acid (10ml), concentrated sulfuric acid (2.0ml) was added under cooling in a water bath, and stirred at room temperature for 2 hours. The reaction solution was made alkaline with 10% potassium carbonate and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The residue obtained by evaporation of the solvent was purified by NH-silica gel column chromatography (hexane/ethyl acetate) to give the title compound (680mg) as an oil.
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.38(3H，d，J＝6.8Hz)、2.12-2.40(1H，m)、2.45-2.50(2H，m)、2.56-2.69(6H，m)、2.79-2.86(2H，m)、3.06-3.14(1H，m)、3.20-3.30(1H，m)、3.33-3.39(1H，m)、6.94-7.00(2H，m)、7.15-7.19(2H，m)、8.18(1H，d，J＝2.7Hz)，8.36(1H，dd，J＝0.8，2.7Hz).
FAB-Mass；338(MH+).
Example 2665- [1- (4-fluorophenethyl) piperidin-4-yl]Synthesis of (E) -7-methyl-5, 6-dihydro-5H-cyclopentanopyrazine
Reacting 5- [1- (4-fluorophenethyl) piperidin-4-ylidene]-7-methyl-5, 6-dihydrocyclopentapyrazine (300mg) was dissolved in methanol (10ml), 5 drops of acetic acid were dropped, and then in the presence of a palladium catalyst, under a hydrogen pressure of 4.2kg/cm2The vibration was vigorously carried out for 13 hours. After the catalyst was filtered off, water was added thereto, and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off to leave the titled compound (200mg) as an oilVolume mixture (about 5: 1).
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.34(d, J ═ 7.2Hz) and 1.40(d, J ═ 6.8Hz) 1: 5 total 3H, 1.44-1.56(3H, m), 1.62-1.90(2H, m), 2.00-2.20(3H, m), 2.43-2.51(1H, m), 2.54-2.66(2H, m), 2.76-2.88(2H, m), 3.04-3.20(4H, m), 6.93-7.00(2H, m), 7.13-7.19(2H, m), 8.30(s) and 8.31(s) 5: 1 total 2H, m
FAB-Mass；340(MH+).
EXAMPLE 2671 Synthesis of- {1- [2- (4-methoxyphenyl) ethyl ] piperidin-4-yl } -7-methoxy-1, 2, 3, 4-tetrahydroquinoline hydrochloride
A solution of 1- (piperidin-4-yl) -7-methoxy-1, 2, 3, 4-tetrahydroquinoline (250mg), 2- (4-methoxyphenyl) ethyl bromide (260mg) and diisopropylethylamine (270mg) in DMF (5ml) was stirred with heating at 60 ℃ for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water was added thereto, and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (toluene/acetone system) to give 1- {1- [2- (4-methoxyphenyl) ethyl ] piperidin-4-yl } -7-methoxy-1, 2, 3, 4-tetrahydroquinoline as an oil. The free body is dissolved in ethyl acetate, 8.5 percent-HCl/ethyl acetate is added, and hydrochloride is separated out. Recrystallization from ethanol/diethyl ether gave the title compound (225 mg). (yield: 53%)
Melting point: 232 ℃ and 235 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.72-1.84(4H，m)、2.10-2.24(2H，m)、2.57(2H，t，J＝6.0Hz)、2.96-3.03(2H，m)、3.09(2H，t，J＝5.6Hz)、3.11-3.21(4H，m)、3.58(2H，br-d)、3.66(3H，s)、3.71(3H，s)、3.90-4.00(1H，m)、6.11(1H，dd，J＝8.4，2.4Hz)、6.28(1H，d，J＝2.4Hz)、6.78(1H，d，J＝8.4Hz)、6.89(2H，d，J＝8.4Hz)、7.18(2H，d，J＝8.4Hz)、10.68-10.81(1H，br-s).
MS；381(M+H)+.
Example 268-274 was obtained as in example 267.
Example 2681- {1- [2- (4-fluorophenyl) ethyl ] piperidin-4-yl } -7-methoxy-1, 2, 3, 4-tetrahydroquinoline hydrochloride
(yield: 75%)
Melting point: 258 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.74-1.84(4H，m)、2.23(2H，qd，J＝12，2Hz)、2.569(2H，t，J＝6.4Hz)、3.04-3.23(6H，m)、3.57(2H，d，J＝11.6Hz)、3.66(3H，s)、3.93-4.03(1H，m)、6.14(1H，dd，J＝8，1.6Hz)、6.32(1H，d，J＝1.6Hz)、6.79(1H，d，J＝7.6Hz)、7.16(2H，t，J＝9.2Hz)、7.32(2H，dd，J＝8.8，5.6Hz)、11.05-11.20(1H，br-s).
MS；369(M+H)+.
Example 2691- [1- (4-cyanopropyl) piperidin-4-yl ] -7-methoxy-1, 2, 3, 4-tetrahydroquinoline hydrochloride
(yield: 55%)
Melting point: 180 ℃ C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.71-1.82(4H，m)、1.97-2.12(2H，m)、2.15-2.28(2H，m)、2.56(2H，t，J＝6.4Hz)、2.67(2H，t，J＝7.2Hz)、2.99-3.18(6H，m)、3.51(2H，br-d，J＝11.6Hz)、3.66(3H，s)、3.90-4.01(1H，m)、6.12(1H，dd，J＝8.4，1.0Hz)、6.29(1H，d，J＝1.0Hz)、6.78(1H，d，J＝8.4Hz)、10.94-11.12(1H，br-s).
MS；314(M+H)+.
Example 2701- {1- [2- (2-thienyl) ethyl ] piperidin-4-yl } -7-methoxy-1, 2, 3, 4-tetrahydroquinoline hydrochloride
(yield: 35%)
Melting point: 232 ℃ in 235 ℃ (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.73-1.84(4H，m)、2.16-2.29(2H，m)、2.57(2H，t，J＝6.4Hz)、3.10(2H，t，J＝5.2Hz)、3.13-3.40(6H，m)、3.58(2H，br-d)、3.66(3H，s)、3.91-4.02(1H，m)、6.15(1H，br-d)、6.32(1H，br-s)、6.80(1H，d，J＝8.0Hz)、6.97(1H，d，J＝1.6Hz)、6.99(1H，d，J＝5.2Hz)、7.40(1H，dd，J＝5.2，1.6Hz)、11.21-11.33(1H，br-s).
MS；357(M+H)+.
Example 2711- {1- [2- (4-fluorophenyl) ethyl ] piperidin-4-yl } -7, 8-dimethoxy-1, 2, 3, 4-tetrahydroquinoline hydrochloride
(yield: 82%)
Melting point: 213-
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.62-1.89(4H，m)、2.11-2.31(2H，m)、2.57-2.69(2H，m)、2.88-3.23(8H，m)、3.51-3.69(2H，m)、3.62(3H，s)、3.71(3H，s)、6.40-6.62(1H，br-d)、6.63-6.75(1H，br-d)、7.15(2H，t，J＝8.8Hz)、7.29(2H，dd，J＝7.6，5.2Hz)、10.50-10.77(1H，br-s).
MS；399(M+H)+.
Example 2721- {1- [2- (4-fluorophenyl) ethyl ] piperidin-4-yl } -7, 8-methylenedioxy-1, 2, 3, 4-tetrahydroquinoline hydrochloride
(yield: 55%)
Melting point: 225 ℃ 227 ℃ (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.71-1.83(4H，m)、2.24(2H，qd，J＝12.4，3.2Hz)、2.58(2H，t，J＝6.0Hz)、2.92-3.10(6H，m)、3.18-3.25(2H，m)，3.58(2H，br-d)、4.14-4.23(1H，m)、5.83(2H，s)、6.23(1H，d，J＝8.0Hz)、6.46(1H，d，J＝8.0Hz)、7.16(2H，t，J＝8.8Hz)，7.29(2H，dd，J＝8.8，5.6Hz)、10.84-10.91(1H，m).
MS；383(M+H)+.
Example 2731- {1- [2- (4-fluorophenyl) ethyl ] piperidin-4-yl } -7-methoxy-8-methyl-1, 2, 3, 4-tetrahydroquinoline oxalate
(yield: 68%)
Melting point: 176-
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.66-1.75(4H，m)、1.97-2.09(2H，m)、2.02(3H，s)、2.58(2H，t，J＝6.8Hz)、2.79-3.22(9H，m)、3.40-3.51(2H，m)、3.71(3H，s)、6.47(1H，d，J＝8.4Hz)、6.76(1H，d，J＝8.4Hz)、7.13(2H，t，J＝8.8Hz)、7.29(2H，dd，J＝11.2，8.8Hz).
MS；383(M+H)+.
Example 2741- {1- [2- (4-fluorophenyl) -2-oxyethyl ] piperidin-4-yl } -7-methoxy-1, 2, 3, 4-tetrahydroquinoline hydrochloride
(yield: 60%)
Melting point: 153 ℃ and 155 ℃ (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.70-1.83(4H，m)、2.15-2.29(2H，m)、2.54(2H，t，J＝6.4Hz)、3.08(2H，t，J＝6.0Hz)、3.17-3.32(2H，m)、3.56(2H，br-d，J＝12.0Hz)、3.62(3H，s)、3.92-4.03(1H，m)、4.98(2H，d，J＝4.4Hz)、6.11(1H，dd，J＝7.2，1.0Hz)、6.32(1H，d，J＝1.0Hz)、6.76(1H，d，J＝7.2Hz)、7.41(2H，t，J＝8.8Hz)、8.04(2H，dd，J＝8.8，5.6Hz)、10.22-10.39(1H，m).
MS；383(M+H)+.
Example 2751- {1- [2- (4-fluorophenyl) -2-hydroxyethyl ] piperidin-4-yl } -7-methoxy-1, 2, 3, 4-tetrahydroquinoline oxalate
To a solution of 1- {1- [2- (4-fluorophenyl) -2-oxyethyl ] piperidin-4-yl } -7-methoxy-1, 2, 3, 4-tetrahydroquinoline (400mg) in methanol (10ml) was added sodium borohydride (73mg) at 0 ℃. After stirring at this temperature for 1 hour, further stirring was carried out at room temperature for 1 hour. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The residue was purified by column chromatography (hexane/ethyl acetate) to give 1- {1- [2- (4-fluorophenyl) -2-hydroxyethyl ] piperidin-4-yl } -7-methoxy-1, 2, 3, 4-tetrahydroquinoline as an oil. It is dissolved in ethanol and oxalic acid is added. The precipitated salt was recrystallized from ethanol/diethyl ether to give the title compound (280 mg). (yield: 68%)
Melting point: 170 ℃ and 172 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.62-2.01(6H，m)、2.55(2H，t，J＝6.4Hz)、2.58-2.90(4H，m)、3.09(2H，t，J＝5.6Hz)、3.21-3.39(2H，m)、3.64(3H，s)、3.65-3.78(1H，m)、4.82-4.91(1H，m)、6.06(1H，dd，J＝8.4，2.4Hz)、6.20(1H，d，J＝2.4Hz)、6.75(1H，d，J＝8.4Hz)、7.17(2H，t，J＝8.8Hz)、7.42(2H，dd，J＝8.8，6.0Hz).
MS；385(M+H)+.
Example 2761- {1- [2- (4-fluorophenyl) -2-fluoroethyl ] piperidin-4-yl } -7-methoxy-1, 2, 3, 4-tetrahydroquinoline hydrochloride
A solution of 1- {1- [2- (4-fluorophenyl) -2-hydroxyethyl ] piperidin-4-yl } -7-methoxy-1, 2, 3, 4-tetrahydroquinoline (250mg) in dichloromethane (5ml) was cooled to-78 ℃ and diethylaminosulfur trifluoride (DAST, 0.1ml) was added. The reaction mixture was stirred at this temperature for 45 minutes. After completion of the reaction, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was returned to room temperature with stirring. The reaction mixture was extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane/hexane) to give 1- {1- [2- (4-fluorophenyl) -2-fluoroethyl ] piperidin-4-yl } -7-methoxy-1, 2, 3, 4-tetrahydroquinoline as an oil. This was dissolved in ethyl acetate, hydrochloric acid was added, and the precipitated salt was recrystallized from ethanol/diethyl ether to give the title compound (60 mg). (yield: 24%)
Melting point 227-
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.72-1.88(4H，m)、2.10-2.34(2H，m)、2.57(2H，t，J＝6.0Hz)、3.11(2H，t，J＝5.2Hz)，3.17-3.80(6H，m)、3.66(3H，s)、3.93-4.03(1H，m)、6.13(1H，dd，J＝8.0Hz)、6.31(1H，dd，J＝50，8.6Hz)、6.32(1H，s)、6.79(1H，d，J＝8.0Hz)、7.31(2H，t，J＝8.8，6.0Hz)、7.53(2H，dd，J＝8，5.6Hz)、11.46-11.72(1H，m).
MS；387(M+H)+.
EXAMPLE 2771 Synthesis of- [2- (4-fluorophenethyl) ethyl ] -4- (6-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) piperidine
(277-1)4- (1-hydroxy-6-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) pyridine
7.04g (1.0 equivalent) of 4-bromopyridine hydrochloride was partitioned between an aqueous sodium hydroxide solution and ether, and the organic layer was separated and dried over magnesium sulfate. The solution was cooled to-78 ℃ under a nitrogen atmosphere. 25.0ml (1.0 equivalent) of a 1.6M n-butyllithium/hexane solution was added dropwise thereto, followed by stirring for 30 minutes. Then, 7.049g (4.0mmol) of 6-methoxytetralone dissolved in 50ml of tetrahydrofuran was added thereto, and the mixture was slowly warmed to room temperature with stirring. Saturated aqueous ammonium chloride was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was reprecipitated with chloroform/n-hexane to obtain 4.019g of the title compound as a pale tan powder. (yield: 39.4%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.58-1.68(1H，m)、1.91-2.00(3H，m)、2.81(2H，br-s)、3.72(3H，s)、5.69(1H，s)、6.65-6.70(2H，m)、6.77(1H，d，J＝8.8Hz)、7.22(2H，d，J＝6.0Hz)、8.45(2H，d，J＝6.0Hz).
(277-2) 1- [2- (4-fluorophenyl) ethyl ] -4- (6-methoxy-3, 4-dihydronaphthalen-1-yl) pyridinium bromide
A mixture of 3.978g (15.6mmol) of 4- (1-hydroxy-6-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) pyridine (compound 1-1), 3.322g (1.05 equiv.) of 4-fluorophenylethyl bromide and 100ml of acetonitrile was stirred under nitrogen at 80 ℃ for 26 hours. 6.327g (2.0 equivalents) of 4-fluorophenylethyl bromide was added thereto, and the mixture was stirred for another 12 hours. Ethyl acetate and water were added to the reaction solution, and the insoluble precipitate was collected by filtration and dried with warm air at 50 ℃ to obtain 5.785g of the title compound as a pale brown powder. (yield: 84.3%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
2.42-2.47(2H，m)、2.79(2H，br-t)、3.28(2H，br-t)、3.79(3H，s)、4.83(2H，t，J＝7.4Hz)、6.54(1H，t，J＝4.8Hz)、6.78(1H，dd，J＝2.8，8.4Hz)、6.86(1H，d，J＝8.4Hz)、6.90(1H，d，J＝2.8Hz)、7.15-7.20(2H，m)、7.30-7.33(2H，m)、8.06(2H，d，J＝6.8Hz)，8.96(2H，d，J＝6.8Hz).
(277-3)1- [2- (4-fluorophenyl) ethyl ] -4- (6-methoxy-3, 4-dihydronaphthalen-1-yl) -1, 2, 3, 6-tetrahydropyridine
5.710g (13mmol) of 1- [2- (4-fluorophenyl) ethyl ] -4- (6-methoxy-3, 4-dihydronaphthalen-1-yl) pyridinium bromide (compound 1-2) was dissolved in 50ml of methanol, and the solution was stirred under ice-cooling. To this was added 0.49g of sodium borohydride, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and water was added to the residue to conduct extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 4.169g of the title compound as a pale brown viscous oil. (yield 88.5%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.21-2.27(2H，m)、2.33-2.38(2H，m)、2.66-2.74(6H，m)，2.84-2.88(2H，m)、3.19(2H，br-q)、3.80(1H，s)、5.71(1H，br-quintet)、5.84(1H，t，J＝4.8Hz)、6.69(1H，dd，J＝2.4，8.4Hz)、6.73(1H，d，J＝2.4Hz)、6.96-7.00(2H，m)、7.11(1H，d，J＝8.4Hz)、7.17-7.20(2H，m).
(277-4)1- [2- (4-fluorophenyl) ethyl ] -4- (6-methoxy-1, 2, 3, 4-tetrahydrofuran-1-yl) piperidine
1.035g (2.85mmol) of 1- [2- (4-fluorophenyl) ethyl ] -4- (6-methoxy-3, 4-dihydronaphthalen-1-yl) -1, 2, 3, 6-tetrahydropyridine (Compound 1-3) was dissolved in 100ml of methanol, 0.11g of 10% Pd-C was added, and catalytic reduction was carried out under normal pressure for 12 hours. The catalyst was filtered off, the solvent was evaporated under reduced pressure, then 0.11g of 10% Pd-C was added, and catalytic reduction was carried out for 6 hours under normal pressure. The catalyst was filtered off, and the solvent was evaporated under reduced pressure to give 0.910g of the title compound as a pale brown amorphous substance. (yield: 93.9%)
This was converted to the hydrochloride salt by a conventional method, and recrystallized from ethanol/diisopropyl ether to obtain the title compound as a colorless powder.
An episome:
melting point: 190 ℃ 191 DEG C
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.58-1.90(8H，m)、2.27(2H，br-s)、2.66-2.64(4H，m)、2.84(2H，br-s)、3.01(2H，br-s)、3.33(2H，br-s)、3.77(3H，s)、6.62(1H，d，J＝2.8Hz)、6.68(1H，dd，J＝2.8，8.4Hz)，6.96-6.70(2H，m)、7.03(1H，d，J＝8.4Hz)、7.16-7.20(2H，m).
FAB-MS：[M+H]+；m/z＝368.
Example 2781 Synthesis of- [2- (4-fluorophenyl) ethyl ] -4- [6- (2-hydroxy) ethoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl ] piperidine
(278-1)1- [2- (4-fluorophenyl) ethyl ] -4- [ 6-hydroxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl ] piperidine
To 2.718g (7.57mmol) of 1- [2- (4-fluorophenyl) ethyl ] -4- (6-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) piperidine was added 45ml of 47% hydrobromic acid, and the mixture was refluxed for 1 hour. 20ml of glacial acetic acid was added thereto, and the mixture was refluxed for 1.5 hours. After cooling, water was added and the precipitated precipitate was filtered off. Chloroform and a saturated aqueous sodium hydrogencarbonate solution were added thereto, and the organic layer was separated. The resulting solution was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.043g of the title compound in a brown amorphous state. (yield: 76.4%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.35-2.04(10H，m)、2.52-2.70(6H，m)、2.77-2.82(2H，m)、3.08(2H，br-t)、6.45(1H，d，J＝2.8Hz)、6.59(1H，dd，J＝2.8，8.0Hz)、6.93-6.97(2H，m)、7.00(1H，d，J＝8.0Hz)、7.11-7.14(2H，m).
(278-2)1- [2- (4-fluorophenyl) ethyl ] -4- [6- (2-tert-butyldimethylsilyloxy) ethoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl ] piperidine
0.055g (1.1 equivalent) of 55% sodium hydride was washed with N-hexane, and suspended in 3ml of N, N-dimethylformamide, followed by stirring under ice cooling. To this was added a solution of 2.718g (7.57mmol) of 1- [2- (4-fluorophenyl) ethyl ] -4- [ 6-hydroxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl ] piperidine (compound 2-1) in 1ml of N, N-dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. Then, the mixture was cooled with ice, and a solution of 0.410g (1.5 equivalents) of (2-tert-butyldimethylsilyloxy) ethanol dissolved in 1ml of N, N-dimethylformamide was added thereto, followed by stirring at 50 ℃ for 25 hours under a nitrogen atmosphere. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine in this order, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 0.371g of the title compound as a colorless viscous oil. (yield: 63.4%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
0.10(6H，s)、0.91(9H，s)、1.36-1.98(12H，m)、2.40-2.54(2H，m)、2.60-2.79(4H.m)、2.99-3.06(2H，m)、3.93-3.96(2H，m)、3.98-4.01(2H，m)、6.61(1H，d，J＝2.4Hz)、6.68(1H，dd，J＝2.4，8.4Hz)、6.93-6.97(2H，m)、7.04(1H.d，J＝8.4Hz)、7.12-7.16(2H，m).
(278-3)1- [2- (4-fluorophenyl) ethyl ] -4- [6- (2-hydroxy) ethoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl ] piperidine
0.350g (0.684mmol) of 1- [2- (4-fluorophenyl) ethyl ] -4- [6- (2-t-butyldimethylsilyloxy) ethoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl ] piperidine (compound 2-2) was dissolved in 5ml of tetrahydrofuran, 821ml (1.2 equiv.) of a 1.0M-tetra-n-butylammonium fluoride/tetrahydrofuran solution was added, and the mixture was stirred at room temperature for 9.5 hours. Adding water, and extracting with ethyl acetate. The extract was washed with water (3 times) and saturated brine in this order, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol) to give 0.242g of the title compound as a colorless viscous oil. (yield: 89.0%)
This was converted to the hydrochloride salt by a conventional method, and recrystallized from ethanol/diisopropyl ether to obtain the title compound as a colorless powder.
An episome:
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.21-1.88(12H，m)、2.41-2.45(2H，m)、2.51-2.70(4H，m)、2.90-2.97(2H，m)、3.83(2H，t，J＝9.2Hz)、3.95(2H，t，J＝9.2Hz)、6.53(1H，d，J＝2.8Hz)、6.60(1H，dd，J＝2.8，8.8Hz)、6.83-6.87(2H，m)、6.96(1H，d，J＝8.8Hz)、7.02-7.05(2H，m).
FAB-MS：[M+H]+；m/z＝398.
melting point: 213-
EXAMPLE 279 Synthesis of trans-1- (4-ethylpiperazin-1-yl) -7-methoxy-2- (4-trifluoromethylphenoxy) -1, 2, 3, 4-tetrahydronaphthalene
(279-1) Trans-1- (4-ethylpiperazin-1-yl) -2-hydroxy-7-methoxy-1, 2, 3, 4-tetrahydronaphthalene
7-methoxy-3, 4-dihydronaphthalene-1, 2-oxide (5.28g) synthesized according to the method described in tetrahedron, 33, 85-94 was dissolved in n-butanol (100ml), ethylpiperazine (3.42g) was added, and the mixture was refluxed for 12 hours. The solvent was evaporated under reduced pressure, the residue was recrystallized from ethyl acetate (5ml) and diethyl ether (80ml), and the collected crystals were washed with diethyl ether to give the title compound (6.88g) as pale yellow crystals. (yield: 79%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.73-1.85(1H，m)、2.09-2.16(1H，m)、2.48(4H，br-s)、2.77(2H，m)、2.91(4H，br-s)、3.16(1H，br-s)、3.68(1H，d，J＝8.5Hz)、3.78(3H，s)、3.95(1H，ddd，J＝3.0Hz，8.5Hz，10.5Hz)、6.71(1H，br-d)、6.99(1H，d，J＝10.0Hz)、7.12(1H，br-s).
(279-2) Trans-1- (4-ethylpiperazin-1-yl) -7-methoxy-2- (4-trifluoromethylphenoxy) -1, 2, 3, 4-tetrahydronaphthalene
To a solution of trans-1- (4-ethylpiperazin-1-yl) -2-hydroxy-7-methoxy-1, 2, 3, 4-tetrahydronaphthalene (435mg) in dimethylformamide (3ml) were slowly added a solution of potassium tert-butoxide (247mg) and 4-fluorobenzyl trifluoride (492mg) in dimethylformamide (1ml) at room temperature, and the mixture was stirred for 4 hours. Water (50ml) was added to the reaction mixture, which was extracted 3 times with ethyl acetate (50 ml). The organic phase was washed with water (50ml) 2 times and saturated brine (50ml) 1 time, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji silica NH-DM2035, hexane/ethyl acetate) to give the title compound (190mg) as a colorless oil. (yield: 29%)
Melting point (oxalate): 207 ℃ C. & lt 210 ℃ C. & gt
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.03(3H，t，J＝7.0Hz)、1.85-1.96(1H，m)、2.15-2.22(1H，m)、2.39(2H，q，J＝7.0Hz)、2.42(4H，br-s)、2.70(2H，br-s)、2.77(2H，br-s)、2.80(2H，t，J＝6.0Hz)、3.81(3H，s)、4.05(1H，d，J＝7.5Hz)、4.79(1H，m)、6.76(1H，dd，J＝3.0Hz，8.0Hz)、6.97(2H，d，J＝8.5Hz)、7.02(1H，d，J＝8.0Hz)、7.33(1H，d，J＝3.0Hz)、7.53(2H，d，J＝8.5Hz).
FAB-Mass；435(MH+).
Example 2801 Synthesis of- {4- [2- (4-fluorophenyl) ethyl ] piperazin-1-yl } -7-methoxy-1, 2, 3, 4-tetrahydronaphthalene hydrochloride
(280-1) 1-hydroxy-7-methoxy-1, 2, 3, 4-tetrahydronaphthalene
7-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-one (5g) was dissolved in methanol, and sodium borohydride (1.3g) was added at 0 ℃ to react at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and water, and the ethyl acetate layer was washed with water, dried and concentrated under reduced pressure to give 5.19g of the title compound as a colorless oil.
(280-2)1- (4-acetylpiperazin-1-yl) -7-methoxy-1, 2, 3, 4-tetrahydronaphthalene
1-hydroxy-7-methoxy-1, 2, 3, 4-tetrahydronaphthalene (5.19g) and thionyl chloride (4.3ml) were reacted in diethyl ether at room temperature for 3 hours. The reaction mixture was partitioned between ether and water, and the ether layer was washed successively with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried and concentrated under reduced pressure. The resulting residue was refluxed with 1-acetylpiperazine and potassium carbonate in acetone for 10 hours, the reaction mixture was filtered, the waste was washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (3.0g) as a pale yellow oil.
(280-3) 7-methoxy-1- (piperazin-1-yl) -1, 2, 3, 4-tetrahydronaphthalene
1- (4-acetylpiperazin-1-yl) -7-methoxy-1, 2, 3, 4-tetrahydronaphthalene (0.85g) was dissolved in ethanol (10ml), and 8N aqueous sodium hydroxide solution (3ml) was added to the solution, followed by heating and refluxing for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (ethyl acetate) to give the title compound (0.6g) as a pale brown oil.
(280-4)1- [4- (4-fluorophenylacetyl) piperazin-1-yl ] -7-methoxy-1, 2, 3, 4-tetrahydronaphthalene
An acid chloride prepared from 7-methoxy-1- (piperazin-1-yl) -1, 2, 3, 4-tetrahydronaphthalene (0.6g), 4-fluorophenylacetic acid (0.44g) and thionyl chloride (0.21ml) was reacted in dichloromethane for 2 hours. The reaction mixture was partitioned between dichloromethane and water, extracted with dichloromethane, dried, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (toluene/acetone) to give the title compound (0.56g) as an oil.
(280-5)1- {4- [2- (4-fluorophenyl) ethyl ] piperazin-1-yl } -7-methoxy-1, 2, 3, 4-tetrahydronaphthalene
1- [4- (4-Fluorophenylacetyl) piperazin-1-yl ] -7-methoxy-1, 2, 3, 4-tetrahydronaphthalene (0.41g) and lithium aluminium hydride (0.05g) in THF (15ml) were heated to reflux for 6 h. The reaction mixture was cooled, and water (50ml), a 5N aqueous solution (50ml) of sodium hydroxide and water (150ml) were sequentially added thereto, followed by stirring at room temperature for 1 hour. The precipitate was filtered through celite, washed with THF, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (toluene/acetone) to give the title compound (0.38g) as an oil.
Melting point: 205 deg.C (decomposition)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.60-1.70(2H，m)、1.93-2.02(2H，m)、2.48-2.81(14H，m)、3.76-3.83(1H，m)、3.79(3H，s)、6.71(1H，dd，J＝8.4，2.8Hz)、6.96(2H，t，J＝8.4Hz)、7.12-7.19(3H，m)、7.32(1H，d，J＝2.8Hz).
FAB-Mass；269(MH+).
Example 2811 Synthesis of- {4- [2- (4-fluorophenyl) -2-oxyethyl ] piperazin-1-yl } -7-methoxy-1, 2, 3, 4-tetrahydronaphthalene hydrochloride
7-methoxy-1- (piperazin-1-yl) -1, 2, 3, 4-tetrahydronaphthalene (0.27g), 4-fluorobenzoylmethyl bromide (0.24g) and diisopropylethylamine (0.43g) were dissolved in DMF (15ml) and reacted at room temperature for 12 hours. The reaction mixture was partitioned between ethyl acetate and water, the ethyl acetate layer was washed with water, dried, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give an oil (0.34 g). This was converted to the hydrochloride salt by a conventional method to obtain the title compound as a white powder.
Melting point: 194 deg.C (decomposition)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.60-1.69(2H，m)、1.92-2.01(2H，m)、2.53-2.68(8H，m)、3.76(2H，s)、3.79(3H，s)、6.70(1H，dd，J＝8.4，2.8Hz)、6.97(1H，d，J＝8.4Hz)、7.09-7.15(2H，m)、7.31(1H，d，J＝2.8Hz)、8.04-8.10(2H，m).
FAB-Mass；383(MH+).
EXAMPLE 282 Synthesis of 18-aminobenzcycloheptanone
Ammonium nitrate (24g) was added little by little to a chloroform (400ml) solution of benzocycloheptane (40g) and trifluoroacetic anhydride (85ml) at-10 ℃ and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution and ethyl acetate were added to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, purified by silica gel column chromatography (hexane/ethyl acetate), and catalytically reduced with palladium on carbon (5g) and ethanol (300ml) at 50 ℃ in a hydrogen stream. After stirring overnight, the catalyst was filtered off, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (10 g). (yield: 24%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.71-1.89(4H，m)、2.67-2.72(2H，m)、2.80-2.85(2H，m)、3.70(2H，br-s)、6.76(1H，dd，J＝8.3Hz)、6.97(1H，d，J＝8Hz)、7.04(1H，t，J＝3Hz).
EXAMPLE 282 Synthesis of 28-methoxybenzcycloheptanone
To a mixture of 8-aminobenzcycloheptanone (4.0g), concentrated sulfuric acid (3ml) and water (47ml) was added dropwise an aqueous solution (15ml) of sodium nitrite (9.0g) at a temperature below 5 ℃. After 30 minutes, the reaction solution was dropped into a saturated aqueous copper sulfate solution (25ml) heated to 90 ℃ and stirred for 30 minutes. After the reaction solution was cooled to room temperature, ethyl acetate was added to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and methyl iodide, potassium carbonate, and dimethylformamide were added to the residue, followed by stirring at room temperature for 7 hours. After the reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.5 g). (yield: 80%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.78-1.90(4H，m)、2.70-2.75(2H，m)、2.87-2.92(2H，m)、3.81(3H，s)、6.99(1H，dd，J＝8,3Hz)、7.11(1H，d，J＝8Hz)、7.29(1H，t，J＝3Hz).
Example Synthesis of 282-31- (4-fluorophenethyl) -4- (2-methoxybenzcycloheptan-9-yl) piperazine
To a solution of 8-methoxybenzcycloheptanone (3.5g) in ethanol (40ml) was added sodium borohydride (0.7g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium bicarbonate and ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was evaporated. Toluene (50ml) and thionyl chloride (2.4g) were added to the residue, and after stirring for 2 hours, the mixture was concentrated under reduced pressure. Dimethylformamide (50ml), 1- (4-fluorophenethyl) piperazine (2.1g) synthesized in Japanese patent application laid-open No. Sho 54-92979, and triethylamine (0.7g) were added to the residue, and the mixture was stirred at 100 ℃ for 3 hours. After concentration under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution and ethyl acetate were added to separate an organic layer. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and purified by silica gel column chromatography (dichloromethane/ethanol) to give a hydrochloride salt according to a conventional method, to obtain a hydrochloride salt (230mg) of the title compound as a white powdery crystal (yield: 11%) having a melting point (hydrochloride salt): 188 ℃ plus 190 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.20-1.35(1H，m)、1.50-1.65(2H，m)、1.74-1.98(4H，m)、2.06-2.19(2H，m)、2.21-2.67(4H，m)、2.96-3.06(3H，m)、3.20-3.35(3H，m)、3.49-3.80(2H，m)、3.74(3H，s)、6.69-6.89(2H，m)、7.00-7.09(1H，m)、7.12-7.20(2H，m)、7.28-7.40(2H，m).
FAB-Mass；383(MH+).
Example 2835 Synthesis of- {4- [2- (4-fluorophenyl) ethyl ] piperazin-1-yl } -5, 6, 7, 8-tetrahydroisoquinoline hydrochloride
(283-1)5, 6, 7, 8-tetrahydroisoquinoline-2-oxide
5, 6, 7, 8-tetrahydroisoquinoline (10g) was added to dichloromethane (100ml) and 10% aqueous sodium carbonate solution (100ml), and a solution of 70% m-chloroperbenzoic acid (20g) in dichloromethane (100ml) was added dropwise with vigorous stirring at 0 ℃. The reaction mixture was extracted with dichloromethane, and the dichloromethane layer was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol) to give 7.50g of the title compound as a colorless oil.
(283-2)5, 6, 7, 8-tetrahydroisoquinolin-5-ol
5, 6, 7, 8-tetrahydroisoquinoline-2-oxide (7.50g) was dissolved in acetic anhydride (30ml) and reacted at 120 ℃ for 6 hours. The reaction mixture was concentrated under reduced pressure, and 10% hydrochloric acid (30ml) was added to the residue, followed by heating at 100 ℃ for 2 hours. The reaction solution was cooled, made alkaline with a 5N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give 1.90g of the title compound.
(283-3)5- {4- [2- (4-fluorophenyl) ethyl ] piperazin-1-yl } -5, 6, 7, 8-tetrahydroisoquinoline hydrochloride
5, 6, 7, 8-tetrahydroisoquinolin-5-ol (1.90g), methanesulfonyl chloride (1.48g), and triethylamine (5.0ml) were reacted in THF (50ml) at 0 ℃ for 6 hours. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution, and the ethyl acetate layer was washed with water, dried, and concentrated under reduced pressure to give a pale yellow oil. This was dissolved in DMF, and 4- [2- (4-fluorophenyl) ethyl ] -piperazine (2.0g) and potassium carbonate (2.0g) were added to the solution to conduct a reaction for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methane) to give 0.71g of a pale yellow oil. This was converted to the hydrochloride salt by a conventional method to obtain 0.52g of the title compound as a white powder.
Melting point: 174 deg.C 176 deg.C
1H-NMR(400MHz，D2O)；δ(ppm)
1.77(2H，m)、1.99-2.16(2H，m)、2.87(2H，m)、3.03(4H，m)、3.38(4H，m)、4.19(1H，m)、7.05(2H，t，J＝8.4Hz)、7.26(2H，dd，J＝8.4，7.2Hz)、8.28(1H，d，J＝8.0Hz)、8.43(1H，d，J＝8.0Hz)、8.45(1H，s).
FAB-Mass；340(MH+).
EXAMPLE synthesis of 2841- [1- (4-fluorophenethyl) piperidin-4-yl ] -5, 6-methylenedioxyindoline
From 1- (4-fluorophenethyl) -4- (3, 4-methylenedioxyphenyl) aminopiperidine (10g) synthesized according to the method of reference example 1 of Japanese patent publication No. 40-6347 in the same manner as in example 106, the hydrochloride of the title compound was obtained as dark red prismatic crystals (330 mg). (yield: 2.8%) melting point (hydrochloride salt): 229 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.80-2.09(4H，m)、2.72-2.85(2H，m)、2.99-3.19(4H，m)、3.19-3.35(4H.m)、3.55-3.61(3H，m)、5.82(2H，s)、6.44(1H，s)、6.71(1H，s)、7.12-7.20(2H，m)、7.29-7.38(2H，m).
FAB-Mass；369(MH+).
EXAMPLE synthesis of 2851- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindole
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindoline (7.5g) obtained in example 133 was dissolved in acetone (500ml) at 50 ℃. The solution was added little by little with stirring to active manganese dioxide (35.6 g). The suspension was refluxed for 1.5 hours, filtered through celite, and washed with acetone. The filtrate was concentrated under reduced pressure, and the resulting pale yellow solid was recrystallized from ethyl acetate to give 4.2g of the title compound as a white powder crystal. (yield: 56%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.86(s，3H)、1.88-2.04(m，4H)、2.23(dt，J＝11.2，2.4Hz，2H)、2.55-2.62(m，2H)、2.74-2.81(m，2H)、3.09(br-d，2H)，4.26-4.36(m，1H)、4.33(d，J＝5.6Hz，2H)、6.41(d，J＝3.2Hz.1H)、6.94(d，J＝7.2Hz.1H)、7.08-7.15(m，2H)、7.26-7.33(m，2H)、7.41(br-s，1H)、7.45-7.49(m，2H)、8.26-8.32(m，1H).
Melting point: 127 ℃ C
Mass；FAB+ 394(M+H).
EXAMPLE synthesis of 2861- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (N-isopropylcarbamoylmethyl) indole
A suspension of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (isopropylcarbamoylmethyl) indoline (1g) obtained in example 151, activated manganese dioxide (4g) and 1, 2-dichloroethane (100ml) was refluxed for 1.5 hours, filtered through celite and concentrated under reduced pressure. The resulting pale yellow solid was recrystallized from ethyl acetate to give 0.4g of the title compound as a white powder crystal. (yield: 40%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.04(d，J＝6.0Hz，6H)、2.04-2.18(m，4H)、2.25-2.40(m，2H)、2.63-2.74(m，2H)、2.80-2.91(m，2H)、3.15-3.28(m，2H)、3.68(s，2H)、4.02-4.12(m，1H)、4.20-4.31(m，1H)、5.20-5.32(m，1H)、6.53(d，J＝3Hz，1H)、6.95-7.02(m，3H)、7.18-7.21(m，2H)、7.26-7.28(m，2H)、7.61(d，J＝8Hz，1H).
Melting point: 146- & ltSUB & gt 148- & lt/SUB & gt
Mass：ESI 422(M+)
EXAMPLE synthesis of 2871- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-methylpyrrol-2-yl) indole
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindole (0.2g) was dissolved in toluene (2.50ml), and 1-methyl-2-tributylstannylpyrrole (1.44g) synthesized by the method of tetrahedron letters, 4407(1986) using 1-methylpyrrole and tributyltin chloride was added to the solution and heated under reflux for 3 hours under a nitrogen atmosphere. Ethyl acetate was added thereto, and the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 0.115g of the title compound as a yellow oil. (yield: 57.28%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.92-1.99(4H，m)、2.05-2.13(2H，m)、2.47-2.51(2H，m)、2.64-2.68(2H，m)、3.32(2H，br-d)、3.50(3H，s)、4.05-4.13(1H，m)、6.16-6.19(2H，m)、6.38(1H，d，J＝3.6Hz)、6.57(1H，t，J＝2.2Hz)、6.82(2H，t，J＝8.6Hz)、6.98-7.03(3H，m)、7.11(1H，d，J＝3.6Hz)、7.23(1H，s)、7.48(1H，d，J＝8.8Hz).
ESI-Mass；402.
EXAMPLE 2881 Synthesis of- [1- (4-Acetylaminomethyl-phenethyl) piperidin-4-yl ] indole
A chloroform (30ml) suspension of 1- [1- (4-acetamidomethylphenylethyl) piperidin-4-yl ] indoline (0.80g) obtained in example 36 and activated manganese dioxide (1.32g) was refluxed for 6 hours while being vigorously stirred. The reaction mixture was filtered through celite, and the residue was washed with chloroform, and then the filtrate was concentrated under reduced pressure. The residue was crystallized from an ethyl acetate/hexane mixture to obtain 0.64g of the title compound as a white powder. (yield: 80.4%)
Melting point: 134 ℃ of 133-
1H-NMR(400MHz，CDCl3)；δ(ppm)2.02(3H，s)、2.06-2.35(5H，m)、2.64-2.73(2H，m)、2.82-2.90(2H，m)、3.15-3.25(2H，br-d)、4.22-4.32(1H，m)、4.41(2H，d，J＝5.6Hz)、6.53(1H，d，J＝3.6Hz)、7.07-7.13(1H，m)、7.18-7.26(5H，m)、7.38(1H，d，J＝8.0Hz)、7.63(2H，d，J＝8.0Hz).
FAB-Mass；376(MH+).
EXAMPLE synthesis of 2891- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-cyanoindole
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-cyanoindoline obtained in example 124 (0.50g) and activated manganese dioxide (1.00g) were subjected to the same treatment as in example 288 to give 0.42g of the title compound as a white powder. (yield: 83.8%)
Melting point: 131 ℃ C. and 132 ℃ C
1H-NMR(400MHz，CDCl3)；δ(ppm)2.06-2.16(3H，m)、2.25-2.34(2H，m)、2.64-2.70(2H，m)、2.79-2.87(2H，m)、3.16-3.24(2H，m)、4.21-4.31(1H，m)、4.41(2H，d，J＝5.6Hz)、6.60(1H，d，J＝3.2Hz)，6.97-7.03(2H，m)、7.16-7.22(2H，m)、7.33(1H，dd，J＝8.0，1.2Hz)、7.44(1H，d，J＝3.2Hz)、7.67(2H，d，J＝8.0Hz)、7.73(1H，br-s).
FAB-Mass；378(MH+).
EXAMPLE 290 Synthesis of cis-1- [1- (4-fluorophenethyl) -3-methylpiperidin-4-yl ] indole
As a by-product produced upon synthesis of cis-1- [1- (4-fluorophenethyl) -3-methylpiperidin-4-yl ] indoline from indoline (560mg), 1- [2- (4-fluorophenyl) ethyl ] -3-methyl-4-piperidone (1.19mg) and sodium triacetoxyborohydride (2.40g) in the same manner as in example 79-4, 30mg of the title compound was obtained as a white amorphous form. (yield: 3%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
0.80(3H，d，J＝6.5Hz)、1.88(1H，br-d)、2.26(1H，dt，J＝12.0，3.5Hz)、2.35-2.67(5H，m)、2.74-2.82(2H，m)、2.89(1H，br-d)、3.14(1H，br-d)、4.46(1H，dt，J＝120.5，4.0Hz)、6.49(1H，d，J＝3.1Hz)、6.98(2H，br-t)、7.10(1H，br-d)、7.16-7.22(4H，m)、7.36(2H，d，J＝8.0Hz)、7.64(2H，d，J＝8.0Hz).
FAB-Mass；337(MH+).
EXAMPLE 2911 Synthesis of- [1- (4-fluorophenethyl) homopiperidin-4-yl ] -6-methoxyindoline
(291-1)1- (4-fluorophenethyl) -4- (3-methoxyphenylamino) homopiperidine
4-Fluorophenylacetic acid (1.5g) was dissolved in tetrahydrofuran (44ml), and N, N-carbonyldiimidazole (1.6g) was added to stir at room temperature for 15 minutes. To this was added 4-homopiperidinone hydrochloride (1.0g) synthesized from 1- (tert-butoxycarbonyl) -4-piperidone according to Synth. Commun.1249 (1992), followed by addition of triethylamine (1.2ml) and stirring at room temperature for 12 hours. Water was added to the reaction solution, which was partitioned with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran, and lithium aluminum hydride was added thereto under ice cooling, followed by heating and refluxing, followed by treatment in a conventional manner. The product was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain a brown oil.
Using m-anisidine (0.39ml), it was treated in the same manner as in example 1 to give a yellow oil. This was dissolved in tetrahydrofuran (30ml), and lithium aluminum hydride (0.72g) was added under ice cooling, followed by heating and refluxing for 2.5 hours. Water (0.72ml), a 5N aqueous solution (0.72ml) of sodium hydroxide and water (2.2ml) were added under ice cooling, and the precipitated solid was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give 1.348g of the title compound as a brown oil. (yield: 44.6%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.62-1.79(5H，m)、1.95-2.04(1H，m)、2.59-2.67(2H，m)、2.70-2.85(6H，m)、3.66(1H，m)、3.76(3H，s)、4.02(1H，br-s)、6.00(1H，t，J＝2.4Hz)、6.12(1H，ddd，J＝0.8，2.4，8.0Hz).6.23(1H，ddd，J＝0.8，2.4，8.0Hz)、6.98(2H，t，J＝8.8Hz)、7.05(1H，t，J＝8.0Hz)、7.16(2H，dd，J＝4.2，8.8Hz).
(291-2)1- (4-fluorophenethyl) -4- (6-methoxyisatin-1-yl) homopiperidine
Using 1- (4-fluorophenethyl) -4- (3-methoxyphenylamino) homopiperidine (1.148g), the title compound is obtained as an orange oil by the method of j.prakt.chem., 137(1922) 1.203 g. (yield: 90.6%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.83-2.00(3H，m)、2.10(2H，m)、2.78(7H，br-s)、2.87(2H，br-s)、3.93(3H，s)、3.43(1H，m)、4.40(1H，br-s)、6.52(1H，s)、6.53(1H，d，J＝8.8Hz)、6.99(1H，t，J＝8.8Hz)、7.18(1H，dd，J＝5.6，8.8Hz)、7.59(1H，d，J＝8.8Hz).
(291-3)1- [1- (4-fluorophenethyl) homopiperidin-4-yl ] -6-methoxyindoline
1- (4-Fluorophenethyl) -4- (6-methoxyisatin-1-yl) homopiperidine (0.4g) was dissolved in tetrahydrofuran (1.0ml), and a 2.0M boron-tetrahydrofuran complex/tetrahydrofuran solution (4.0ml) was added dropwise in an ice bath under a nitrogen atmosphere, followed by refluxing with heating for 3 hours. The reaction solution was ice-cooled, water was added thereto, and the mixture was partitioned with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in pyridine (5.0ml), and the mixture was stirred at room temperature for 11 hours. Water was added to the reaction mixture, which was partitioned with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) to give 1- (4-fluorophenethyl) -4- (6-methoxyindol-1-yl) homopiperidine as a yellow oil. This was treated in the same manner as in production example 64 to obtain 0.095g of the free form of the title compound as a yellow oil. (yield: 27.2%)
This was treated with oxalic acid in accordance with a conventional method to obtain the hygroscopic oxalate salt of the title compound. An episome:
1H-NMR(400MHz.CDCl3)；δ(ppm)
1.61-1.99(6H，m)、2.66-2.90(10H，m)、3.38(2H，dt，J＝1.6，8.6Hz)、3.63(1H，m)、3.76(3H，s)、6.00(1H，d，J＝2.4Hz)、6.12(1H，dd，J＝2.4，7.6Hz)、6.92(1H，d，J＝7.6Hz)、6.97(2H，t，J＝8.4Hz)、7.15(2H，dd.J＝5.6，8.4Hz).
ESI-Mass；369.1
EXAMPLE 2921 Synthesis of- [1- (4-fluorophenethyl) pyrrolidin-3-yl ] -6-methoxyindoline
(292-1) 1-benzyl-3- (6-methoxyindolin-1-yl) pyrrolidine
The same procedures used in example 1 were repeated except for using 1-benzyl-3-pyrrolidone (10.0g) and m-anisidine (0.39ml) to give a brown oil. This was treated in the same manner as in 291-2) above to obtain red crystals. The same procedures as 291-3) were repeated to give 2.301g of the title compound as a pale yellow oil. (yield: 13.1%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
2.00(1H，br-s)、2.21(1H，br-s)、2.68-2.98(4H，br-s)、2.86(1H，t，J＝8.0Hz)、3.42(1H，q，J＝8.0Hz)、3.60-3.90(2H，br-s)、3.75(3H，s)、4.24(1H，br-s)、6.09(1H，d，J＝2.4Hz)、6.16(1H，dd，J＝2.4，8.0Hz)、6.92(1H，d，J＝8.0Hz)、7.27-7.42(5H，m).
(292-2)1- [1- (4-fluorophenethyl) pyrrolidin-3-yl ] -6-methoxyindoline
Using 1-benzyl-3- (6-methoxyindolin-1-yl) pyrrolidine (0.5g), a yellow oil was obtained according to the method of tetrahedron letters, 1567 (1977). The reaction mixture was reacted with 4-fluorophenethyl bromide (0.15g) in the same manner as in example 2 to give 2.301g as a free form of the title compound as a pale yellow oil (yield: 13.1%)
This free body was treated with oxalic acid in acetone according to a conventional method to obtain the oxalate salt of the title compound in a hygroscopic amorphous form.
Oxalate salt:
1H-NMR(400MHz，DMSO-d6)；δ(ppm)
1.89(1H，m)、2.08(1H，m)、2.62-3.06(10H，m)、3.32(2H，t，J＝8.2Hz)、3.65(3H，s)、4.30(1H，m)、6.10(1H，dd，J＝2.0，8.0Hz)、6.15(1H，d，J＝2.0Hz)、6.87(1H，d，J＝8.0Hz)、7.10(2H，t，J＝8.4Hz)、7.27(2H，dd，J＝5.4，8.4Hz).
ESI-Mass；341.1
EXAMPLE 2933 Synthesis of 3-dimethyl-1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline
(293-1)3, 3-dimethyl-6-bromoindolin-2-one
A THF solution (50ml) of 6-bromoindolin-2-one (3.18g) was cooled to-78 ℃ and 1.5M lithium diisopropylamide (20ml) was added dropwise thereto, followed by stirring for 15 minutes, and methyl iodide (0.92ml) was added thereto. The reaction mixture was returned to room temperature and stirred for 1 hour. The reaction mixture was again cooled to-78 ℃ and 1.5M lithium diisopropylamide (10ml) was added dropwise thereto, followed by stirring for 15 minutes and then methyl iodide (0.92ml) was added thereto. The reaction mixture was returned to room temperature with stirring. To this was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The residue was washed with hexane to give 3.35g of the title compound as a white amorphous form. (yield: 93.0%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.38(6H，s)、7.05(1H，d，J＝8.0Hz)、7.096(1H，d，J＝1.6Hz)、7.169(1H，d，J＝1.6Hz)、8.41(1H，m).
(293-2)3, 3-dimethyl-6-bromoindoline
To a toluene solution (80ml) of 3, 3-dimethyl-6-bromoindolin-2-one (3.35g) was added dropwise borane/dimethyl sulfoxide complex (3ml) with stirring at 60 ℃. After the reaction mixture was refluxed for 3 hours, a 5N aqueous sodium hydroxide solution (20ml) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate, washed with water and saturated brine, dried, and the extract was concentrated under reduced pressure to give 3.10g of the title compound as a yellow oil. (yield: 98.3%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.28(6H，s)、3.35(2H，s)、6.83-6.91(3H，m).
(293-3)3, 3-dimethyl-1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline
The same procedures used in example 16 were repeated except for using 3, 3-dimethyl-6-bromoindoline (3.10g), 1- [2- (4-fluorophenyl) ethyl ] -4-piperidone (2.81g) and sodium triacetoxyborohydride (5.70g) to give 2.72g of the title compound as a white amorphous substance. (yield: 49.8%)
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.24(6H，s)、1.80(4H，br-s)、2.13-2.24(2H，m)、2.58-2.67(2H，m)、2.79-2.86(2H，m)、3.11-3.21(2H，m)、3.17(2H，s)、3.28-3.40(1H，m)、6.44(1H，s)、6.72(1H，d，J＝8.0Hz)、6.80(1H，d，J＝8.0Hz)、6.93-7.01(2H，m)、7.13-7.20(2H，m).
FAB-Mass；432(MH+).
EXAMPLE 2941 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (ethylcarbamoylmethyl) indole
A chloroform (30ml) suspension of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (ethylcarbamoylmethyl) indoline (0.41g) obtained in example 149 and activated manganese dioxide (0.40g) was stirred vigorously at 50 ℃ for 6 hours. The reaction mixture was filtered through celite, and the residue was washed with chloroform, and then the filtrate was concentrated under reduced pressure. The residue was recrystallized from chloroform/hexane to give 0.33g of the title compound as white needle crystals. (yield: 89.5%)
Melting point: 159.6-160.1 DEG C
1H-NMR(400MHz，CDCl3)；δ(ppm)1.02(3H，t，J＝7.2Hz)、2.07-2.13(4H，m)、2.25-2.32(2H，m)、2.64-2.68(2H，m)、2.81-2.85(2H，m)、3.17-3.26(4H，m)、3.70(2H，s)、4.21-4.29(1H，m)、5.40(1H，br-t)、6.53(1H，d，J＝3.2Hz)、6.95-7.01(3H，m)、7.17-7.21(2H，m)、7.26-7.28(2H，m)、7.61(1H，d，J＝8.0Hz).
ESI-Mass；408(MH+).
EXAMPLE 2951 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ N- (cyclopropylcarbamoyl) methyl ] indole
A chloroform (30ml) suspension of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ (cyclopropylcarbamoyl) methyl ] indoline (0.04g) obtained in example 154 and activated manganese dioxide (0.04g) was stirred vigorously at 50 ℃ for 10 hours. The reaction mixture was filtered through celite, and the residue was washed with chloroform, and then the filtrate was concentrated under reduced pressure. The residue was recrystallized from chloroform/hexane to give 0.03g of the title compound as a white powder. (yield: 81.9%)
Melting point: 156.4-156.8 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)0.34-0.38(2H，m)、0.68-0.73(2H，m)、2.06-2.14(4H，m)、2.25-2.32(2H，m)、2.62-2.68(3H，m)、2.81-2.85(2H，m)、3.18(2H，br-d)、3.68(2H，s)、4.20-4.28(1H，m)、5.50(1H，br-s)、6.52(1H，d，J＝3.2Hz)、6.93(1H，dd，J＝1.4，8.2Hz)、6.97-7.01(2H，m)、7.17-7.20(2H，m)、7.25-7.27(2H，m)、7.60(1H，d，J＝8.2Hz).
ESI-Mass；420(MH+).
EXAMPLE 2961 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ N- (isobutylcarbamoyl) methyl ] indole
A chloroform (30ml) suspension of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ (isobutylcarbamoyl) methyl ] indoline (0.07g) obtained in example 152 and activated manganese dioxide (0.07g) was stirred vigorously at 50 ℃ overnight. The reaction mixture was filtered through celite, the residue was washed with chloroform, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from chloroform/hexane to give 0.05g of the title compound as a white powder. (yield: 70.0%)
Melting point: 131.8-132.2 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)0.79(6H，d，J＝6.8Hz)、1.61-1.71(1H，m)、2.07-2.13(4H，m)、2.24-2.31(2H，m)、2.64-2.68(2H，m)、2.81-2.85(2H，m)、3.01(2H，t，J＝6.4Hz)、3.18(2H，br-d)、3.72(2H，s)、4.20-4.28(1H，m)、5.46(1H，br-t)、6.53(1H，d，J＝2.8Hz)、6.96-7.01(3H，m)、7.17-7.20(2H，m)、7.26-7.27(2H，m)、7.61(1H，d，J＝8.0Hz).
ESI-Mass；436(MH+).
EXAMPLE 2971 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (N-N-propylcarbamoylmethyl) indole
A chloroform (30ml) suspension of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ (n-propylcarbamoyl) methyl ] indoline (0.04g) obtained in example 150 and activated manganese dioxide (0.08g) was vigorously stirred, and stirred at 50 ℃ overnight. The reaction mixture was filtered through celite, and the residue was washed with chloroform, and then the filtrate was concentrated under reduced pressure. The residue was recrystallized from chloroform/hexane to give 0.03g of the title compound as white needle crystals. (yield: 84.6%)
Melting point: 131.3-131.9 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)0.81(3H，t，J＝7.4Hz)、1.41(2H，tq，J＝7.4，7.4Hz)、2.07-2.12(4H，m)、2.25-2.31(2H，m)、2.64-2.68(2H，m)、2.81-2.85(2H，m)、3.71(2H，s)、4.20-4.28(1H，m)、5.43(1H，br-t)、6.53(1H，d，J＝3.2Hz)、6.96-7.01(3H，m)、7.17-7.21(2H，m)、7.25-7.27(2H，m)、7.61(1H，d，J＝8.0Hz).
ESI-Mass；422(MH+).
EXAMPLE 2981 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (tetramethylenecarbamoylmethyl) indole oxalate
A chloroform (30ml) suspension of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (tetramethylenecarbamoylmethyl) indoline (0.08g) obtained in example 155 and activated manganese dioxide (0.07g) was stirred vigorously at 50 ℃ overnight. The reaction mixture was filtered through celite, and the residue was washed with chloroform, and then the filtrate was concentrated under reduced pressure. The residue was recrystallized from chloroform/hexane to obtain 0.06g of the free form of the title compound as a pale brown viscous compound. (yield: 87.0%)
This was converted into oxalate by a conventional method, and reprecipitated with methanol/diethyl ether to obtain the title compound as a colorless powder.
An episome:
1H-NMR(400MHz，CDCl3)；δ(ppm)1.78-1.93(4H，m)、2.09(4H，br-s)、2.25-2.33(2H，m)、2.64-2.68(2H，m)、2.81-2.85(2H，m)、3.17(2H，br-d)、3.45-3.51(4H，m)、3.78(2H，s)、4.24-4.32(1H，m)、6.49(1H，d，J＝3.0Hz)、6.97-7.01(3H，m)、7.17-7.20(2H，m)、7.22(1H，d，J＝3.0Hz)、7.38(1H，s)、7.55(1H，d，J＝8.0Hz).
oxalate salt:
melting point: 171.5-172.1 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)1.72-1.79(2H，m)、1.83-1.90(2H，m)、2.09-2.21(4H，m)、2.92-3.18(6H，m)、3.29(2H，t，J＝7.0Hz)、3.49(2H，t，J＝7.0Hz)、3.49-3.56(2H，m)、3.70(2H，s)、4.58(1H，br-s)、6.45(1H，d，J＝3.2Hz)、6.93(1H，dd，J＝1.2，8.4Hz)、7.16-7.20(2H，m)、7.33-7.37(2H，m)、7.39-7.42(2H，m)、7.46(1H，d，J＝8.4Hz).
ESI-Mass；434(MH+).
EXAMPLE 2991 Synthesis of- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-carbamoylmethylindole
A chloroform (30ml) suspension of 1- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-carbamoylmethylindoline (0.05g) obtained in example 225 and activated manganese dioxide (0.10g) was vigorously stirred, and stirred at 50 ℃ overnight. The reaction mixture was filtered through celite, and the residue was washed with chloroform, and then the filtrate was concentrated under reduced pressure. The residue was recrystallized from chloroform/hexane to obtain 0.02g of the title compound as a white powder. (yield: 41.7%)
Melting point: 156.9-157.8 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)2.03-2.12(4H，m)、2.25-2.31(2H，m)、2.63-2.67(2H，m)、2.84-2.88(2H，m)、3.17(2H，br-d)、4.22-4.30(1H，m)、5.54(2H，br-s)、6.52(1H，dd，J＝0.8，3.2Hz)、6.88(1H，dt，J＝1.2，8.6Hz)、7.10(1H，ddd，J＝0.8，7.0，8.0Hz)、7.13-7.22(2H，m)、7.24(1H.d，J＝3.6Hz)、7.38(1H，dd，J＝0.4，8.4Hz)、7.62-7.65(1H，m).
ESI-Mass；398(MH+).
EXAMPLE 3001 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-hydroxyethyl) carbamoylmethylindole
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 146 (0.20g) was dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.104g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. 320ml of ethanolamine was added thereto, and the mixture was further stirred overnight. After the solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.15g of a pale brown viscous oil.
The residue was dissolved in chloroform (30 ml). Manganese dioxide (0.31g) was added thereto, and the mixture was stirred at 50 ℃ overnight. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. The residue was recrystallized from chloroform/n-hexane to give the title compound (0.13 g) as a pale yellow powder.
Melting point: 140.0-141.2 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)2.08-2.21(4H，m)、2.28(2H，br-t)、2.64-2.68(2H，m)、2.81-2.85(2H，m)、3.19(2H，br-d)、3.35-3.39(2H，m)、3.67(2H，t，J＝5.0Hz)、3.74(2H，s)、4.19-4.28(1H，m)、5.90(1H，br-t)、6.51(1H，br-d)、6.96-7.02(3H，m)、7.17-7.21(2H，m)、7.25(1H，d，J＝3.2Hz)、7.31(1H，br-s)、7.61(1H，d，J＝8.4Hz).
ESI-Mass；424(MH+).
EXAMPLE 3011 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-dimethylcarbamoylmethylindole oxalate
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 146 (0.19g) was dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.10g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. To this was added 2M dimethylamine/tetrahydrofuran solution (2.50ml) and stirred overnight. The solvent was evaporated under reduced pressure. To the residue were added water and ethyl acetate, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.13g of a pale brown viscous oil.
The residue was dissolved in chloroform (30 ml). Manganese dioxide (0.28g) was added thereto, and the mixture was stirred at 50 ℃ overnight. Manganese dioxide (0.14g) was added thereto and stirred for 5 hours. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. Free form of the title compound was obtained as a light brown viscous oil in an amount of 0.15 g. It is made into oxalate by conventional method.
Melting point: 170.1-170.6 deg.C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)2.14-2.24(4H，m)、2.83(3H，s)、2.95-3.10(4H，m)、3.03(3H，s)、3.15(2H，br-s)、3.53(2H，br-d)、3.76(2H，s)、4.58(1H，br-s)、6.45(1H，d，J＝3.2Hz)、6.91(1H，d，J＝8.2Hz)、7.15-7.20(2H，m)、7.33-7.37(2H，m)、7.40(2H，br-s)、7.47(1H，d，J＝8.2Hz).
ESI-Mass；408(MH+).
EXAMPLE 3021 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (4-hydroxypiperidin-1-yl) carbonylmethylindole
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 146 (0.21g) was dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.11g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. To this was added 4-hydroxypiperidine (0.56g), followed by stirring overnight. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.18g of a pale brown viscous oil.
The residue (0.13g) was dissolved in chloroform (30 ml). Manganese dioxide (0.33g) was added thereto, and the mixture was stirred at 50 ℃ for 10 hours. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. The residue was recrystallized from chloroform/n-hexane to give the title compound (0.16 g) as colorless mica-like crystals.
Melting point: 190.5-192.2 deg.C (decomposition)
1H-NMR(400MHz，CDCl3)；δ(ppm)1.22-1.50(2H，m)、1.62-1.69(1H，m)、1.82-1.89(1H，m)、2.05-2.11(4H，m)、2.24-2.31(2H，m)、2.63-2.67(2H，m)、2.80-2.84(2H，m)、3.15-3.24(4H，m)、3.76-3.88(2H，m)、3.88(2H，s)、4.11-4.17(2H，m)、4.21-4.29(1H，m)、6.49(1H，d，J＝3.6Hz)、6.95-7.01(3H，m)、7.17-7.20(2H，m)、7.22(1H，d，J＝3.6Hz)、7.30(1H，s)、7.56(1H，d，J＝8.4Hz).
ESI-Mass；464(MH+).
EXAMPLE 3031 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ bis (2-hydroxyethyl) ] carbamoylmethylindole oxalate
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 146 (0.20g) was dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.10g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. A solution of diethanolamine (0.56g) in N, N-dimethylformamide (1ml) was added thereto, and the mixture was stirred overnight. The solvent was evaporated under reduced pressure. To the residue were added water and ethyl acetate, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.16g of a pale brown viscous oil.
The residue was dissolved in chloroform (30 ml). Manganese dioxide (0.30g) was added thereto, and the mixture was stirred at 50 ℃ overnight. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol system) to obtain 0.10g of the free form of the title compound as a pale brown viscous oil. It is made into oxalate by conventional method.
1H-NMR(400MHz，DMSO-d6)；δ(ppm)2.10(2H，br-d)、2.29(2H，br-q)、3.98-3.08(4H，m)、3.16-3.21(2H，m)、3.39(2H，br-t)、3.45-3.58(8H，m)、3.83(2H，s)、4.57-4.65(1H，m)、6.45(1H，d，J＝3.2Hz)，6.91(1H，d，J＝8.0Hz)、7.17(2H，br-t)、7.33-7.37(2H，m)、7.40(2H，br-s)、7.47(1H，d，J＝8.0Hz).
ESI-Mass；468(MH+).
Example 3041 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1, 3-dihydroxypropan-2-yl) carbamoylmethylindole oxalate
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 146 (0.23g) was dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.11g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. 2-amino-1, 3-propanediol (Serinol, 0.27g) was added thereto, and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.20g of a pale brown viscous oil.
The residue was dissolved in chloroform (30 ml). Manganese dioxide (0.27g) was added thereto, and the mixture was stirred at 50 ℃ overnight. Manganese dioxide (0.19g) was added thereto and stirred for 6 hours. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 0.09g of the free form of the title compound as a pale brown viscous oil. It is made into oxalate by conventional method.
Melting point: 213.1-214.5 deg.C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)2.06-2.23(4H，m)、2.81-3.09(6H，m)、3.41-3.47(6H，m)、3.52(2H，s)、3.67-3.75(1H，m)、4.49-4.57(1H，m)、6.43(1H，d，J＝3.2Hz)、6.95(1H，d，J＝8.4Hz)、7.17(2H，br-t)、7.32-7.36(2H，m)、7.41-7.46(3H，m)、7.72(1H，d，J＝8.4Hz).
ESI-Mass；454(MH+).
Example 3051 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carbamoylmethylindole
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 146 (0.22g) was dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.11g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. To this was added a saturated ammonia/methanol solution (2ml) and stirred overnight. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated, washed with water, saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.11g of a pale brown viscous oil.
This residue was dissolved in chloroform (30ml), to which manganese dioxide (0.24g) was added, and stirred at 50 ℃ for 4 hours. Manganese dioxide (0.12g) was added thereto, and the mixture was stirred overnight, manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. The residue was recrystallized from chloroform/n-hexane to give the title compound (0.08 g) as a pale yellow powder.
Melting point: 159.1-160.8 DEG C
1H-NMR(400MHz，CDCl3)；δ(ppm)2.07-2.13(4H，m)、2.25-2.31(2H，m)、2.64-2.68(2H，m)、2.81-2.85(2H，m)、3.18(2H，br-d)、3.73(2H，s)、4.21-4.29(1H，m)、5.33(1H，br-s)、4.43(1H，br-s)、6.52(1H，dd，J＝3.2Hz)、6.97-7.01(3H，m)、7.17-7.20(2H，m)、7.26(1H，d，J＝3.2Hz)、7.29(1H，s)、7.62(1H，d，J＝8.0Hz).
ESI-Mass；380(MH+).
EXAMPLE 3061 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (carbamoylmethyl) carbamoylmethylindole oxalate
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 146 (0.22g) was dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.11g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. A suspension of glycinamide hydrochloride (0.31g), triethylamine (395ml) and N, N-dimethylformamide (10ml) was added thereto, and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.10g of a pale brown viscous oil.
The residue was dissolved in chloroform (30ml). Manganese dioxide (0.14g) was added thereto, and the mixture was stirred at 50 ℃ overnight. Manganese dioxide (0.10g) was added thereto and stirred for 3.5 hours. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 0.06g of the free form of the title compound as a pale brown amorphous substance. It is made into oxalate by conventional method.
1H-NMR(400MHz，DMSO-d6)；δ(ppm)2.06-2.22(4H，m)、2.86-3.07(6H，m)、3.57(2H，s)、3.65(2H，d，J＝5.6Hz)、4.56(1H，br-s)、7.44(1H，d，J＝2.8Hz)、6.96(1H，d，J＝7.8Hz)、7.04(1H，br-s)、7.17(1H，br-t)、7.33-7.36(3H，m)、7.41(1H，br-s)、7.46(1H，d，J＝7.8Hz)、7.50(1H，s)、8.13(1H，br-t).
ESI-Mass；437(MH+).
EXAMPLE 3071 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-dimethylaminoethyl) carbamoylmethylindole
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 146 (0.22g) was dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.11g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. N, N-dimethylethylenediamine (310ml) was added thereto, and stirred overnight. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.18g of a pale brown viscous oil.
The residue was dissolved in chloroform (30 ml). Manganese dioxide (0.24g) was added thereto, and stirred at 50 ℃ for 9 hours. Manganese dioxide (0.28g) was added thereto, and the mixture was stirred overnight. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. The residue was recrystallized from chloroform/n-hexane to give the title compound (0.12 g) as a pale brown powder.
Melting point: 111.8-112.9 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)2.07-2.14(4H，m)、2.13(6H，s)、2.24-2.32(2H，m)、2.32(2H，t，J＝6.0Hz)、2.64-2.68(2H，m)、2.81-2.85(2H，m)、3.18(2H，br-d)、3.28(2H，dt，J＝6.0，6.0Hz)、3.69(2H，s)、4.21-4.29(1H，m)、5.98(1H，br-t)、6.51(1H，d，J＝3.4Hz)、6.97-7.01(3H，m)、7.17-7.20(2H，m)、7.24(1H，d，J＝3.4Hz)、7.30(1H，s)、7.59(1H，d，J＝8.0Hz).
ESI-Mass；451(MH+).
EXAMPLE 3081 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-cyanomethylcarbamoylmethylindole oxalate
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 146 (0.22g) was dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.11g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. To this was added a solution of aminoacetonitrile hydrochloride (0.26g) in N, N-dimethylformamide (10ml), and further added triethylamine (394ml), and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.17g of a pale brown viscous oil.
The residue was dissolved in chloroform (30 ml). Manganese dioxide (0.25g) was added thereto, and the mixture was stirred at 50 ℃ for 8 hours. Manganese dioxide (0.28g) was added thereto, and the mixture was stirred overnight. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) and further by NH silica gel column chromatography (chloroform/ethyl acetate), to give 0.04g of an isolated product of the title compound as a pale brown viscous oil. It is made into oxalate by conventional method.
1H-NMR(400MHz，DMSO-d6)；δ(ppm)2.04-2.21(4H，m)、2.77-3.06(6H，m)、3.41-3.46(2H，m)、3.58(2H，s)、4.13(2H，d，J＝5.6Hz)、4.53(1H，br-s)、6.45(1H，d，J＝3.2Hz)、6.94(1H，d，J＝8.6Hz)、7.16(2H，br-t)、7.32-7.36(2H，m)、7.44(2H，br-s)、7.48(1H，d，J＝8.6Hz)、8.69(1H，br-t).
ESI-Mass；419(MH+).
EXAMPLE 3091 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-methoxyethyl) carbamoylmethylindole
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 146 (0.22g) was dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.11g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. To this was added 2-methoxyethylamine (245ml) and stirred for an additional 4 hours. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.19g of a pale brown viscous oil.
The residue was dissolved in chloroform (30 ml). Manganese dioxide (0.31g) was added thereto, and the mixture was stirred at 50 ℃ overnight. Manganese dioxide (0.27g) was added thereto and stirred for 5 hours. Manganese dioxide (0.19g) was added again, and the mixture was stirred for 1 hour. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. The residue was recrystallized from chloroform/n-hexane to give the title compound (0.13 g) as a colorless powder. It is made into oxalate by conventional method.
Melting point: 113.2-114.4 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)2.07-2.13(4H，m)、2.25-2.31(2H，m)、2.64-2.68(2H，m)、2.81-2.85(2H，m)、3.18(2H，br-d)、3.26(3H，s)、3.39(4H，br-d)、3.71(2H，s)、4.21-4.29(1H，m)、5.81(1H，br-s)、6.52(1H，d，J＝3.4Hz)、6.96-7.01(3H，m)、7.17-7.21(2H，m)、7.26(1H，d，J＝3.4Hz)，7.28(1H，s)、7.60(1H，d，J＝8.0Hz).
ESI-Mass；438(MH+).
EXAMPLE 3101 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-fluoroethyl) carbamoylmethylindole
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 146 (0.22g) was dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.11g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. To this was added a solution of 2-fluoroethylamine hydrochloride (0.30g) in N, N-dimethylformamide (5ml), and further triethylamine (397ml) was added and stirred for 4 hours. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.19g of pale brown crystals.
The crystals were dissolved in chloroform (30 ml). Manganese dioxide (0.30g) was added thereto, and the mixture was stirred at 50 ℃ overnight. Manganese dioxide (0.26g) was added thereto and stirred for 5 hours. Manganese dioxide (0.19g) was added again, and the mixture was stirred for 2 hours. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. The residue was recrystallized from chloroform/n-hexane to give the title compound (0.15 g) as a colorless powder. It is made into oxalate by conventional method.
Melting point: 163.3-163.8 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)2.05-2.13(4H，m)、2.25-2.31(2H，m)、2.64-2.68(2H，m)、2.81-2.85(2H，m)、3.18(2H，br-d)、3.50(2H，ddt，J＝4.8，28.0，4.8Hz)、3.74(2H，s)、4.21-4.29(1H，m)、4.43(2H，dt，J＝47.2，4.8Hz)、5.80(1H，br-t)、6.53(1H，d，J＝3.2Hz)、6.97-7.01(3H，m)、7.17-7.20(2H，m)、7.26-7.28(2H，m)、7.62(1H，d，J＝8.0Hz).
ESI-Mass；426(MH+).
EXAMPLE 3111 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [2- (ethylcarbamoyl) ethyl ] indole oxalate
(311-1)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [2- (ethoxycarbonyl) ethenyl ] indole
55% oily sodium hydride (0.46g) was washed with n-hexane, suspended in tetrahydrofuran (1ml), and stirred under ice-cooling. To this was added a solution of ethyl diethylphosphonoacetate (2.37g) in tetrahydrofuran (7ml), and the mixture was stirred at room temperature for 30 minutes. Then, a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindole (3.53g) obtained in example 130 in tetrahydrofuran (10ml) was added thereto, and the mixture was stirred at room temperature for 2 days under a nitrogen atmosphere. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give the title compound (3.59 g) as yellow crystals.
1H-NMR(400MHz，CDCl3)；δ(ppm)1.36(3H，t，J＝7.2Hz)、2.08-2.14(4H，m)、2.26-2.33(2H，m)、2.65-2.69(2H，m)、2.81-2.85(2H，m)、3.20(2H，br-d)、4.28(2H，q，J＝7.2Hz)、4.23-4.32(1H，m)、6.47(1H，d，J＝16.0Hz)、6.53(1H，d，J＝3.2Hz)、6.97-7.02(2H，m)、7.17-7.21(2H，m)、7.32(1H，d，J＝3.2Hz)、7.34(1H，d，J＝8.4Hz)、7.52(1H，s)、7.61(1H，d，J＝8.4Hz)、7.84(1H，d，J＝16.0Hz).
(311-2)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [2- (ethoxycarbonyl) ethyl ] indole
To the above 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [2- (ethoxycarbonyl) ethenyl ] indole (1.89g) were added 40ml of ethanol and 20ml of ethyl acetate, and they were dissolved. 10% Pd/C (0.10g) was added thereto, and catalytic reduction was carried out overnight under normal pressure. The solvent was filtered off, and the solvent was evaporated under reduced pressure to give the title compound 1.87g as a colorless viscous oil.
1H-NMR(400MHz，CDCl3)；δ(ppm)1.25(3H，t，J＝7.2Hz)、2.06-2.12(4H，m)、2.24-2.31(2H，m)、2.64-2.70(4H，m)、2.81-2.85(2H，m)、3.08(2H，t，J＝8.0Hz)、3.18(2H，br-d)、4.14(2H，q，J＝7.2Hz)、4.19-4.27(1H，m)、6.48(1H，d，J＝3.2Hz)、6.95-7.01(3H，m)、7.17-7.20(4H，m)，7.54(1H，d，J＝8.0Hz).
(311-3)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-carboxyethyl) indole
To the above 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [2- (ethoxycarbonyl) ethyl ] indole (1.85g) was added 25ml of methanol, and the mixture was dissolved. To this was added a 5N aqueous solution (1.75ml) of sodium hydroxide, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, neutralized with 5N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 1.70g of the title compound as a pale brown amorphous form.
1H-NMR(400MHz，CDCl3)；δ(ppm)1.79-1.82(2H，m)、2.32-2.43(4H，m)、2.78-2.84(4H，m)、2.92-2.97(2H，m)、3.13(2H，t，J＝7.4Hz)、3.20(2H，br-d)、4.14-4.22(1H，m)、6.40(1H，d，J＝3.2Hz)、6.96-7.03(3H，m)、7.05(1H，d，J＝3.2Hz)、7.16-7.20(2H，m)、7.33(1H，s)、7.49(1H，d，J＝8.0Hz).
(311-4)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [2- (ethylcarbamoyl) ethyl ] indole oxalate
The above 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-carboxyethyl) indole (0.10g) was dissolved in N, N-dimethylformamide (2 ml). To the solution was added 1, 1-carbonyldiimidazole (0.05g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. To this was added 70% aqueous ethylamine (106ml), and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/n-hexane) to give 0.05g of an isolated product of the title compound as a colorless viscous oil. It is made into oxalate by conventional method.
1H-NMR(400MHz，DMSO-d6)；δ(ppm)2.05(2H，br-d)、2.13-2.22(2H，m)、2.39(2H，t，J＝7.8Hz)、2.81(2H，br-t)、2.89-2.95(4H，m)、3.01-3.09(4H，m)、3.42(2H，br-d)、4.48-4.56(1H，m)、6.41(1H，d，J＝3.2Hz)、6.89(1H，d，J＝8.0Hz)、7.16(2H，br-t)、7.32-7.37(3H，m)、7.39(1H，d，J＝3.2Hz)、7.43(1H，d，J＝8.0Hz)、7.82(1H，t，J＝5.4Hz).
ESI-Mass；422(MH+).
EXAMPLE 3121 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ (2-pyrrolidin-1-yl) ethyl ] carbamoylmethylindole oxalate
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 146 (0.21g) was dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.11g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. To this was added 1- (2-aminoethyl) pyrrolidine (353ml), and the mixture was stirred for another 4.5 hours. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 0.19g of a pale brown viscous oil.
The residue was dissolved in chloroform (30 ml). Manganese dioxide (0.17g) was added thereto, and the mixture was stirred at 50 ℃ overnight. Manganese dioxide (0.17g) was added thereto and stirred for 7 hours. Manganese dioxide (0.17g) was added again, and the mixture was stirred for 5 hours. Manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure to give 0.19g of the free form of the title compound as a pale brown viscous oil. It is made into oxalate by conventional method.
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.78-1.82(4H，m)、1.95(2H，br-d)、2.06-2.16(2H，m)、2.41(2H，br-t)、2.70-2.74(2H，m)、2.81-2.85(2H，m)、2.93-2.98(6H，m)、3.20(2H，br-d)、3.28-3.34(2H，m)、3.50(2H，s)、4.32-4.40(1H，m)、6.40(1H，d，J＝3.2Hz)、6.94(1H，d，J＝9.2Hz)、7.12(2H，br-t)、7.28-7.32(2H，m)、7.42-7.45(3H，m)、8.30(1H，br-t).
ESI-Mass；477(MH+).
EXAMPLE 3131 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [2- (morpholin-4-yl) ethyl ] carbamoylmethylindole oxalate
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 146 (0.22g) was dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.11g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. To this was added 4- (2-aminoethyl) morpholine (379ml) and stirred for an additional 4 hours. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 0.19g of a pale brown viscous oil.
The residue was dissolved in chloroform (30 ml). Manganese dioxide (0.17g) was added thereto, and the mixture was stirred at 50 ℃ overnight. Manganese dioxide (0.17g) was added thereto and stirred for 8 hours. Manganese dioxide (0.17g) was added thereto, and the mixture was stirred for 3 hours. Manganese dioxide (0.08g) was added thereto, and the mixture was stirred for 1.5 hours. Manganese dioxide (0.08g) was added again, and the mixture was stirred for 5 hours. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. Free form of the title compound was obtained as a light brown viscous oil in an amount of 0.20 g. It is made into oxalate by conventional method.
1H-NMR(400MHz，DMSO-d6)；δ(ppm)2.04(2H，br-d)、2.17-2.27(4H，m)、2.40-2.44(6H，m)、2.79(2H，br-t)、2.91-2.95(2H，m)、2.98-3.03(2H，m)、3.19(2H，br-q)、3.42(2H，br-d)、3.50(2H，s)、3.53(4H，br-t)、4.47-4.55(1H，m)、6.43(1H，d，J＝3.2Hz)、6.96(1H，dd，J＝0.8，8.0Hz)、7.13-7.18(2H，m)、7.32-7.35(2H，m)、7.42(1H，d，J＝3.2Hz)、7.45-7.47(2H，m)、7.93(1H，t，J＝5.6Hz).
ESI-Mass；493(MH+).
EXAMPLE 3141 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (pyridin-4-yl) methylcarbamoylmethylindole
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 146 (0.21g) was dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.11g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. To this was added 4-aminomethylpyridine (283ml), and the mixture was stirred for 6 hours. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 0.20g of a pale brown viscous oil.
The residue was dissolved in chloroform (30 ml). Manganese dioxide (0.37g) was added thereto, and the mixture was stirred at 50 ℃ overnight. Manganese dioxide (0.18g) was added thereto and stirred for 3 hours. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. The title compound was obtained in the form of a pale yellow amorphous 0.16 g.
1H-NMR(400MHz，CDCl3)；δ(ppm)2.07-2.16(4H，m)、2.24-2.31(2H，m)、2.64-2.68(2H，m)、2.81-2.85(2H，m)、3.18(2H，br-d)、3.81(2H，s)、4.19-4.27(1H，m)、4.39(2H，d，J＝6.0Hz)、5.89(1H，t，J＝6.0Hz)、6.53(1H，d，J＝3.2Hz)、6.97-7.01(3H，m)、7.06(2H，d，J＝5.8Hz)、7.17-7.20(2H，m)、7.27(1H，d，J＝3.2Hz)、7.29(1H，s)、7.63(1H，d，J＝8.0Hz)、8.48(2H，d，J＝5.8Hz).
ESI-Mass；471(MH+).
EXAMPLE 3151 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [2- (pyridin-2-yl) ethyl ] carbamoylmethylindole oxalate
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 146 (0.23g) was dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.11g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. To this was added 2- (2-aminoethyl) pyridine (352ml), and the mixture was stirred for 6 hours. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 0.23g of a pale brown viscous oil.
The residue was dissolved in chloroform (30 ml). Manganese dioxide (0.42g) was added thereto, and the mixture was stirred at 50 ℃ overnight. Manganese dioxide (0.21g) was added thereto and stirred for 7.5 hours. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. Free form of the title compound was obtained as a light brown viscous oil in an amount of 0.23 g. This was converted into the oxalate salt according to a conventional method to obtain the title compound.
1H-NMR(400MHz，CDCl3)；δ(ppm)2.08(2H，br-d)、2.23-2.34(2H，m)、2.06(2H，t，J＝7.2Hz)、2.93-3.00(4H，m)、3.11-3.15(2H，m)、3.41(2H，br-q)、3.48(2H，s)、3.52(2H，br-d)、4.54-4.62(1H，m)、6.44(1H，d，J＝3.0Hz)、6.91(1H，d，J＝9.2Hz)、7.15-7.20(4H，m)、7.33-7.36(2H，m)、7.42(1H，d，J＝3.0Hz)、7.44-7.46(2H，m)、7.61(1H，dt，J＝2.0，8.6Hz)、8.07(1H，t，J＝5.6Hz)、8.44(1H，br-d).
ESI-Mass；485(MH+).
EXAMPLE 3161 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methylcarbamoylmethylindole
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 146 (0.29g) was dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.15g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. 40% aqueous methylamine solution (662ml) was added thereto, and stirred overnight. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.22g of pale brown crystals.
The crystals were dissolved in chloroform (30 ml). Manganese dioxide (0.49g) was added thereto, and the mixture was stirred at 50 ℃ overnight. Manganese dioxide (0.24g) was added thereto and stirred for 2 hours. Manganese dioxide (0.19g) was added again, and the mixture was stirred for 2 hours. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. The residue was recrystallized from chloroform/n-hexane to give the title compound (0.18 g) as a pale brown powder.
Melting point: 149.4-150.5 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)2.05-2.13(4H，m)、2.25-2.31(2H，m)、2.64-2.68(2H.m)、2.73(3H，d，J＝4.8Hz)、2.81-2.85(2H，m)、3.18(2H.br-d)、3.72(2H，s)、4.20-4.28(1H，m)、5.40(1H，br-s)、6.53(1H，d，J＝3.2Hz)、6.95-7.01(3H，m)、7.17-7.20(2H，m)、7.26-7.27(2H，m)、7.61(1H，d，J＝7.6Hz).
ESI-Mass；394(MH+).
EXAMPLE 3171 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-methoxypyridin-5-yl) carbonylindole oxalate
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ (2-methoxypyridin-5-yl) hydroxymethyl ] indoline obtained in example 189 (0.16g) was dissolved in chloroform (30 ml). Manganese dioxide (0.30g) was added thereto, and the mixture was stirred at 50 ℃ overnight. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to obtain 0.07g of the free form of the title compound as a pale brown viscous oil. It is made into oxalate by conventional method.
1H-NMR(400MHz，DMSO-d6)；δ(ppm)2.04-2.11(2H，m)、2.16-2.25(2H，m)、2.75(2H，br-t)、2.89-2.97(4H，m)、3.98(3H，s)、4.68-4.76(1H，m)、6.65(1H，d，J＝3.2Hz)、7.00(1H，d，J＝8.8Hz)、7.15(2H，br-t)、7.31-7.34(2H，m)、7.44(1H，d，J＝8.4Hz)、7.70(1H，d，J＝8.4Hz)、7.80(1H，d，J＝3.2Hz)、8.07(1H，s)、8.11(1H，dd，J＝2.4，8.8Hz)、8.60(1H，d，J＝2.4Hz).
ESI-Mass；458(MH+).
EXAMPLE 3181 Synthesis of [1- (4-fluorophenethyl) pyridin-4-yl ] -6- [ (2-methoxypyridin-5-yl) hydroxymethyl ] indole oxalate
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6- (2-methoxypyridin-5-ylcarbonyl) indole (0.07g) obtained in example 317 was dissolved in methanol (10 ml). To this was added sodium borohydride little by little. The disappearance of the starting material was confirmed by thin layer chromatography and the solvent was evaporated off under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 0.11g of the free form of the title compound as a colorless viscous oil. It is made into oxalate by conventional method.
1H-NMR(400MHz，DMSO-d6)；δ(ppm)2.03-2.08(2H，m)、2.13-2.21(2H，m)、2.75-3.00(6H，m)、3.40(2H，br-d)、3.80(2H，s)、4.52-4.60(1H，m)、6.42(1H，d，J＝3.2Hz)、6.72(1H，d，J＝8.6Hz)、6.96(1H，d，J＝8.6Hz)、7.16(2H，br-t)、7.32-7.35(2H，m)、7.44-7.46(2H，m)、7.62(1H，dd，J＝2.2，8.6Hz)、7.65(1H，s)、8.19(1H，d，J＝2.2Hz).
ESI-Mass；460(MH+).
EXAMPLE 3191 Synthesis of 1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-hydroxypropyl) indole oxalate
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-formylindoline (0.10g) obtained in example 130 was dissolved in tetrahydrofuran (5ml), and the solution was stirred under ice-cooling. To this solution was added a 1.0M ethylmagnesium bromide/tetrahydrofuran solution (0.5ml), and the mixture was stirred for 25 minutes. A1.0M ethylmagnesium bromide/tetrahydrofuran solution (0.5ml) was added thereto, and the mixture was stirred for another 15 minutes. To the reaction mixture were added a saturated aqueous ammonium chloride solution, water and ethyl acetate, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give the free body of the title compound as a pale brown viscous oil (0.10 g). It is made into oxalate by conventional method.
1H-NMR(400MHz，DMSO-d6)；δ(ppm)0.85(3H，t，J＝7.4Hz)、1.62-1.75(2H，m)，2.08(2H，br-d)、2.19-2.29(2H，m)、2.93-2.99(4H，m)、3.08-3.12(2H，m)、3.49(2H，br-d)、4.54(1H，t，J＝6.4Hz)、4.59-4.65(1H，m)、6.43(1H，d，J＝3.0Hz)、7.00(1H，d，J＝8.0Hz)、7.17(2H，br-t)、7.33-7.36(2H，m)、7.41(1H，d，J＝3.0Hz)、7.47(1H，d，J＝8.0Hz)、7.49(1H，s).
ESI-Mass；381(MH+).
EXAMPLE 3201 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-hydroxy-1-methylethyl) indoline
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-hydroxy-1-methylethyl) indoline (0.1g) obtained in example 139 and activated manganese dioxide (0.5g) were treated in the same manner as in example 288 to give the title compound (0.07g) as a pale yellow oil. (yield: 70.3%)
It is made into oxalate by conventional method.
Oxalate salt:
melting point: 97-99 deg.C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.49(6H，s)、2.04-2.15(2H，m)、2.16-2.30(2H，m)、2.92-3.06(4H，m)、3.08-3.19(2H，m)、3.47-3.56(2H，m)、4.58-4.68(1H，m)、6.42(1H，d，J＝3.2Hz)、7.13(1H，dd，J＝8.4，1.2Hz)、7.13-7.21(2H，m)、7.32-7.37(2H，m)、7.40(1H，d，J＝3.2Hz)、7.50(1H，d，J＝8.4Hz)、7.63(2H，br-s).
FAB-Mass；381(MH+).
Example 3211 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (3-hydroxypropyl) indole
To a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindole (0.20g) obtained in example 130 in tetrahydrofuran (2ml) was added dropwise ethyl triethylphosphonoacetate (0.14g) at room temperature to a solution prepared by adding sodium hydride (0.03g) in tetrahydrofuran (5 ml). After 1 hour, saturated aqueous ammonium chloride (10ml) was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in ethanol (10ml), and the solution was hydrogenated in the presence of 10% palladium on carbon (0.05g) at normal temperature and pressure. After 2 hours, the reaction solution was filtered, and the filtrate was concentrated. The residue was dissolved in tetrahydrofuran (3ml), and a suspension of lithium aluminum hydride (0.03g) in tetrahydrofuran (5ml) was added dropwise. After the reaction mixture was stirred at room temperature for 1 hour, water (0.03ml), 5N sodium hydroxide (0.09ml) and water (0.03ml) were added to the reaction mixture in this order. The precipitated precipitate was filtered off, washed with ethyl acetate, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (0.05g) as a pale yellow powder. (yield: 23%)
Melting point: 131 ℃ and 133 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.90-2.05(4H，m)、2.20-2.29(2H，m)、2.55-2.62(2H，m)、2.74-2.81(2H，m)、2.81(3H，s)、3.06-3.13(2H，m)、4.25(2H，d，J＝6.4Hz)、4.26-4.38(1H，m)、6.42(1H，d，J＝3.2Hz)、7.02(1H，dd，J＝8.0，1.2Hz)、7.08-7.14(2H，m)、7.27-7.33(2H，m)、7.47-7.53(3H，m).
ESI-Mass；381(MH+).
Example 3221- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methanesulfonamidomethylindole Synthesis
(322-1)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindole
A chloroform (100ml) suspension of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindoline (3.60g) obtained in example 130 and activated manganese dioxide (15.0g) was refluxed for 6 hours while vigorously stirring. The reaction mixture was filtered through celite, and the residue was washed with chloroform, and then the filtrate was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give the title compound (2.45g) as a yellow powder. (yield: 68.4%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.09-2.42(6H，m)、2.67-2.75(2H，m)、2.83-2.91(2H，m)、3.19-3.28(2H，br-d)、4.35-4.45(1H，m)、6.61(1H，d，J＝3.2Hz)、6.95-7.05(2H，m)、7.16-7.23(2H，m)、7.48(1H，d，J＝3.2Hz)、7.62(1H，dd，J＝8.0，1.2Hz)、7.72(1H，d，J＝8.0Hz)、7.98(1H，s)、10.07(1H，s).
(322-2)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-hydroxyiminomethylindole
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindole (3.78g), hydroxylamine hydrochloride (0.90g) and anhydrous sodium acetate (1.06g) were stirred in ethanol (60ml) at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate (150ml) and 1N aqueous sodium hydroxide solution (30 ml). The ethyl acetate layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether/hexane, filtered, washed with hexane and dried to give the title compound (3.60g) as a pale yellow powder. (yield: 91.3%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.03-37(6H，m)、2.61-2.74(2H，m)、2.81-2.91(2H，m)、3.15-3.27(2H，m)、4.20-4.32(1H，m)、6.51(0.5H，d，J＝3.2Hz)、6.68(0.5H，d，J＝3.2Hz)、6.95-7.02(2H，m)、7.14-7.22(2H，m)、7.31(0.5H，d，J＝3.2Hz)、7.32(0.5H，dd，J＝8.0，1.2Hz)、7.38(0.5H，dd，J＝8.0，1.2Hz)、7.45(0.5H，d，J＝3.2Hz)、7.58-7.63(1H，m)、7.66(0.5H，d，J＝8.0Hz)、7.74(0.5H，br-s)、8.32(0.5H，s).
(322-3)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindole
To a suspension of lithium aluminum hydride (1.0g) in tetrahydrofuran (100ml) was added dropwise a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-hydroxyiminomethylindole (3.60g) in tetrahydrofuran (50ml) at room temperature with stirring under ice cooling, and then the mixture was refluxed for 3 hours. While the reaction mixture was chilled in ice water, water (1ml), a 5N-sodium hydroxide aqueous solution (3ml), and water (1ml) were carefully added dropwise to the reaction mixture, and the mixture was stirred vigorously. The precipitated precipitate was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (ethyl acetate) to give the title compound (2.56g) as a pale yellow powder. (yield: 73.9%)
1H-NMR(400MHz，CDCl3)；δ(ppm)1.86-2.18(4H，m)、2.22-2.32(2H，m)、2.61-2.70(2H，m)、2.78-2.87(2H，m)、3.10-3.18(2H，m)、4.05(2H，d，J＝4.2Hz)、4.20-4.28(1H，m)、6.46(1H，d，J＝3.2Hz)、6.95-7.03(2H，m)、7.05(1H，dd，J＝8.4，1.6Hz)、7.14-7.19(2H，m)、7.21(1H，d，J＝3.2Hz)、7.50-7.53(1H，m)、7.53(1H，d，J＝8.4Hz).
(322-4)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methanesulfonamidomethylindole
To a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindoline (0.12g) and triethylamine (0.5g) obtained in the previous example in ethyl acetate (15ml) was added dropwise methanesulfonyl chloride (0.08ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added 1N aqueous sodium hydroxide (2ml) and water (15ml), followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether/hexane, filtered, washed with hexane and dried to give the title compound (0.11g) as a white powder.
(yield: 75%)
Melting point: 121-
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.90-2.05(4H，m)、2.20-2.29(2H，m)、2.55-2.62(2H，m)、2.74-2.81(2H，m)、2.81(3H，s)、3.06-3.13(2H，m)、4.25(2H，d，J＝6.4Hz)、4.26-4.38(1H，m)、6.42(1H，d，J＝3.2Hz)、7.02(1H，dd，J＝8.0，1.2Hz)、7.08-7.14(2H，m)、7.27-7.33(2H，m)、7.47-7.53(3H，m).
ESI-Mass；430(MH+).
Example 3231 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-isopropylsulfonylaminomethylindole
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindoline (0.20g), triethylamine (0.3ml) and isopropylsulfonyl chloride (0.1ml), as in example 322-4), the title compound (0.06g) was obtained as a white powder. (yield: 23%)
Melting point: 90-92 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)1.38(6H，d，J＝7.2Hz)、2.05-2.18(4H，m)，2.22-2.36(2H，m)，2.60-2.75(2H，m)、2.79-2.90(2H，m)、3.05-3.25(3H，m)、4.20-4.35(1H，m)、4.35-4.50(3H，m)、6.52(1H，d，J＝3.2Hz)、6.99(2H，t，J＝8.8Hz)、7.05(1H，d，J＝8.0Hz)、7.19(2H，dd，J＝5.4，8.8Hz)、7.27(1H，d，J＝3.2Hz)、7.38(1H，s)、7.60(1H，d，J＝8.0Hz).
MS m/e；458(MH+).
Example 3241 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-n-propylsulfonylaminomethylindole
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindoline (0.25g), triethylamine (0.4ml) and n-propylsulfonyl chloride (0.3ml), as in example 322-4), the title compound (0.17g) was obtained as a beige powder. (yield: 53%)
Melting point: 80-81 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)0.99(3H，t，J＝7.4Hz)、1.76-1.88(2H，m)、2.02-2.20(4H，m)、2.34-2.37(2H，m)、2.60-2.74(2H，m)、2.76-3.00(4H，m)、3.12-3.28(2H，m)、4.20-4.34(1H，m)、4.43(2H，d，J＝5.6Hz)、4.48(1H，br-s)、6.52(1H，d，J＝3.2Hz)、6.99(2H，t，J＝8.4Hz)、7.05(1H，d，J＝8.0Hz)、7.19(2H，dd，J＝5.8，8.4Hz)、7.28(1H，d，J＝3.2Hz)、7.38(1H，s)、7.61(1H，d，J＝8.0Hz).
MS m/e；458(MH+).
Example Synthesis of 3251- (1- (4-fluorophenethyl) piperidin-4-yl ] -6- (3-chloropropyl) sulfonylaminomethylindole
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindoline (0.25g), triethylamine (0.4ml) and 3-chloropropylsulfonyl chloride (0.1ml), the title compound (0.25g) was obtained as a white powder in the same manner as in example 322-4). (yield: 71%)
Melting point: 143 ℃ C. (145 ℃ C.)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.06-2.16(4H，m)、2.19-2.36(4H.m)、2.63-2.72(2H，m)、2.79-2.88(2H，m)、3.09(2H，t，J＝7.4Hz)、3.15-3.24(2H，m)、3.59(2H，t，J＝6.4Hz)、4.20-4.34(1H，m)、4.44(2H，d，J＝5.6Hz)、4.56(1H，br-s)、6.52(1H.d，J＝3.2Hz)、6.99(2H，t，J＝8.4Hz)、7.05(1H，d，J＝8.4Hz)、7.19(2H，dd，J＝5.6，8.4Hz)、7.28(1H，d，J＝3.2Hz)、7.38(1H，s)、7.62(1H，d，J＝8.4Hz).
MS m/e；492，494(MH+).
EXAMPLE 3261 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1, 3-propanesul-tam-2-yl) methylindole
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (3-chloropropyl) sulfonylaminomethylindole (144mg) obtained in example 325 above was dissolved in N, N-dimethylformamide (4ml), and sodium hydride (40mg, 60 to 70% oily) was added thereto at room temperature and stirred for 20 minutes. Water was added, and the mixture was extracted with ethyl acetate and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (110mg) as a colorless amorphous form. (yield 83%)
This amorphous material was dissolved in ethanol (5ml), and a solution of oxalic acid (20mg) in ethanol (1ml) was added. The precipitated salt was powdered by addition of ethyl acetate and collected by filtration to give the oxalate salt of the title compound as a white powder (82 mg).
Oxalate salt:
melting point: 171 ℃ 172 ℃
An episome:
1H-NMR(400MHz，CDCl3)；δ(ppm)2.10-2.38(4H，m)、2.22-2.36(4H，m)、2.62-2.72(2H，m)、2.78-2.88(2H，m)、3.06-3.28(6H，m)、4.20-4.38(1H，m)、4.30(2H，s)、6.52(1H，d，J＝3.2Hz)、6.99(2H，t，J＝8.4Hz)、7.07(1H，d，J＝8.0Hz)、7.19(2H，dd，J＝5.6 and 8.4Hz)、7.27(1H，d，J＝3.2Hz)、7.37(1H，s)、7.59(1H，d，J＝8.0Hz).
MS m/e；456(MH+).
EXAMPLE 3271 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-propionylaminomethylindole
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-propionylaminomethylindoline (0.16g) obtained in example 156 and activated manganese dioxide (0.8g), the same procedures as in example 288 were repeated to give the title compound (0.12g) as a white powder. (yield: 75.3%)
Melting point: 141-142 DEG C
1H-NMR(400MHz，CDCl3)；δ(ppm)1.18(3H，t，J＝7.2Hz)、2.06-2.15(2H，m)、2.51(2H，q，J＝7.2Hz)、2.28-2.50(2H，m)、2.64-2.98(4H，m)、3.16-3.35(2H，m)、4.22-4.34(1H，m)、4.56(2H，d，J＝6Hz)、6.51(1H，d，J＝3.2Hz)、6.96-7.05(2H，m)、7.16-7.23(2H，m)、7.24(1H，d，J＝3.2Hz)、7.36(1H，br-s)、7.58(1H，d，J＝8.0Hz).
ESI-Mass；408(MH+).
EXAMPLE 3283 Synthesis of chloro-1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindole
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindole (0.1g) obtained in example was reacted with 1-chlorosuccinimide (0.04g) in benzene (10ml) at 80 ℃ for 1 hour. The reaction mixture was diluted with ethyl acetate (20ml), which was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether/hexane, filtered, washed with hexane and dried to give the title compound (0.04g) as a white powder. (yield: 36.8%)
Melting point: 101-102 deg.C
1H-NMR(400MHz、CDCl3)；δ(ppm)1.95-2.15(4H，m)、2.03(3H，s)、2.20-2.50(2H，m)、2.72-3.00(4H，m)、3.28-3.40(2H，m)、4.20-4.30(1H，m)、4.54(2H，d，J＝6.4Hz)、6.95-7.04(2H，m)、7.10(1H，d，J＝8.0Hz)、7.17-7.24(3H，m)、7.35(1H，s)、7.55(1H，d，J＝8.0Hz).
ESI-Mass；428(MH+).
Example 3291 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (4-hydroxybutyramidomethyl) indole oxalate
4-acetoxybutyric acid (0.07g) synthesized according to the literature (Tetrahedron, 45(24), 7783-7794, 1989) and 1, 1' -carbonyldiimidazole (0.08g) were reacted in chloroform (5ml), to which 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindole (0.13g) obtained in example 322-3) was added, and stirred at room temperature for 3 hours. The reaction mixture was concentrated, and 5N aqueous sodium hydroxide (2ml) and methanol (10ml) were added to the residue to conduct a reaction at 50 ℃ for 1 hour. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol). The pale yellow oil was oxalate according to a conventional method, and the oxalate salt of the title compound (0.04g) was obtained as a pale brown amorphous substance. (yield: 20.5%)
Oxalate salt:
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.68(2H，m)、2.08-2.34(4H，m)、2.18(2H，t，J＝7.6Hz)、2.96-3.29(6H，m)、3.39(2H，t，J＝6.8Hz)、3.56-3.66(2H，m)、4.36(2H，d，J＝5.2Hz)、4.58-4.70(1H，m)，6.46(1H，d，J＝3.6Hz)、6.96(1H，d，J＝8.0Hz)、7.15-7.23(2H，m)、7.32-7.46(3H，m)、7.50(1H，d，J＝8.0Hz)、8.26-8.33(1H，m).
ESI-Mass；438(MH+).
EXAMPLE 3301 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-hydroxyethoxyindole
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-hydroxyethoxyindoline (25.2mg) obtained in example 121 was dissolved in chloroform (5 ml). To this solution was added activated manganese dioxide (138 mg). The suspension was stirred at room temperature for 22 hours, filtered through celite, and washed with chloroform. The filtrate was concentrated under reduced pressure and crystallized from ethyl acetate/hexane to give the title compound as a white solid, 12.0 mg. (yield: 48%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.05-2.13(4H，m)、2.22-2.30(2H，m)、2.64(2H，t，J＝7.5Hz)、2.83(2H，t，J＝7.5Hz)、3.18(2H，br-d，J＝12.1Hz)、4.00(2H，t，J＝4.6Hz)、4.09-4.17(1H，m)，4.17(2H，t，J＝4.6Hz)、6.46(1H，d，J＝3.3Hz)、6.80(1H，dd，J＝8.6，2.2Hz)、6.88(1H，d，J＝2.2Hz)、6.99(2H，t，J＝8.4Hz)、7.15(1H，d，J＝3.3Hz)、7.18(2H，dd，J＝8.4，5.5Hz)、7.51(1H，d，J＝8.6Hz).
Melting point: 118-119 deg.C
Mass：FAB+383(M+H)+
Example 3311 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methanesulfonylindole
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methanesulfonylindoline obtained in example 128 (19.2mg) was dissolved in chloroform (5 ml). To this solution was added activated manganese dioxide (100 mg). The suspension was stirred at room temperature for 22 hours and then at 60 ℃ for 22 hours. After completion of the reaction, the reaction mixture was filtered through celite, and washed with chloroform. The filtrate was concentrated under reduced pressure and crystallized from ethyl acetate/hexane to give the title compound as a white solid, 5.0 mg. (yield: 26%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.06-2.24(4H，m)、2.32(2H，td，J＝11.6，2.0Hz)、2.66(2H，t，J＝7.2Hz)、2.83(2H，t，J＝7.2Hz)、3.19(2H，br-d，J＝9.9Hz)、4.33-4.42(1H，m)、6.64(1H，d，J＝3.3Hz)、6.99(2H，t，J＝8.8Hz)、7.19(2H，dd，J＝8.8，5.5Hz)、7.49(1H，d，J＝3.3Hz)、7.61(1H，dd，J＝7.3，1.1Hz)、7.77(1H，d，J＝7.3Hz)、8.04(1H，br-s).
Melting point: 135 ℃ of 133-
Mass：FAB+401(M+H)+
EXAMPLE 3321 Synthesis of- [1- (2, 6-difluoro-3-pyridylethyl) piperidin-4-yl ] indole
1- [1- (2, 6-difluoro-3-pyridylethyl) piperidin-4-yl ] indoline obtained in example 57 (30.5mg) was dissolved in chloroform (5 ml). To this solution was added activated manganese dioxide (185 mg). The suspension was stirred at room temperature for 22 hours, filtered through celite, and washed with chloroform. The filtrate was concentrated under reduced pressure to give the title compound as an oil 27.4 mg. (yield: 90%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.00-2.15(4H，m)、2.28(2H，td，J＝11.7，3.1Hz)、2.66(2H，t，J＝8.1Hz)、2.85(2H，t，J＝8.1Hz)、3.14(2H，br-d，J＝11.7Hz)、4.24-4.30(1H，m)、6.52(1H，d，J＝3.1Hz)、6.79(1H，dd，J＝8.1，2.7Hz)、7.10(1H，t，J＝7.9Hz)、7.21(1H，t，J＝7.9Hz)、7.23(1H，d，J＝3.1Hz)，7.37(1H，d，J＝7.9Hz)、7.63(1H，d，J＝7.9，5.3Hz)、7.76(1H，dd，J＝17.2，8.1Hz).
Mass；FAB+ 341(M+H).
EXAMPLE 3331 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-fluoroindole
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-fluoroindoline obtained in example 103 (28.8mg) was dissolved in chloroform (5 ml). To this solution was added active manganese dioxide (160 mg). The suspension was stirred at room temperature for 22 hours, filtered through celite, and washed with chloroform. The filtrate was concentrated under reduced pressure to give 20.1mg of the title compound as an oil. (yield: 70%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.04-2.15(4H，m)、2.26(2H，td，J＝11.4，3.3Hz)、2.65(2H，t，J＝8.8Hz)、2.82(2H，t，J＝8.8Hz)、3.18(2H，br-d，J＝11.4Hz)、4.08-4.17(1H，m)、6.50(1H，d，J＝3.3Hz)、6.87(1H，td，J＝8.8，1.6Hz)、6.99(2H，t，J＝8.6Hz)、7.03(2H，dd，J＝10.4，1.6Hz)、7.18(2H，dd，J＝8.6，5.5Hz)、7.22(1H，d，J＝3.3Hz)、7.52(1H，dd，J＝8.8，5.3Hz).
Mass；FAB：340(M+H)+.
Synthesis of indole
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] thiazolo [5, 4-f ] indoline (23.7mg) obtained in example 234 was dissolved in chloroform (5 ml). To this solution was added activated manganese dioxide (130 mg). After the suspension was stirred at room temperature for 22 hours, the reaction mixture was filtered through celite and washed with chloroform. The filtrate was concentrated under reduced pressure, and crystallized from ethyl acetate/hexane to give the title compound as a pale yellow solid, 12.6 mg. (yield: 53%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.07-2.18(4H，m)、2.24-2.35(2H，m)、2.66(2H，t，J＝7.0Hz)、2.83(2H，t，J＝7.0Hz)、3.21(2H，br-d，J＝12.1Hz)、4.36(1H，tt，J＝11.7，4.4Hz)、6.60(1H，d，J＝3.5Hz)、7.00(2H，t，J＝8.6Hz)、7.19(2H，dd，J＝8.6，5.5Hz)、7.49(1H，d，J＝3.5Hz)、8.13(2H，s)、8.92(1H，s).
Melting point: 152 ℃ and 154 DEG C
Mass：FAB+380(M+H)+
EXAMPLE 3351 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (N-methylmethanesulfonylamino) indole
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (N-methylmethanesulfonylamino) indoline obtained in example 120 (34.6mg) was dissolved in chloroform (5 ml). To this solution was added activated manganese dioxide (190 mg). After the suspension was stirred at room temperature for 22 hours, the reaction mixture was filtered through celite and washed with chloroform. The filtrate was concentrated under reduced pressure and crystallized from ethyl acetate/hexane to give the title compound as a white solid, 24.7 mg. (yield: 72%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.01-2.17(4H，m)、2.28(2H，td，J＝11.7，3.3Hz)、2.65(2H，t，J＝8.2Hz)、2.83(2H，t，J＝8.2Hz)、2.88(3H，s)、3.17(2H，br-d，J＝12.1Hz)、3.39(3H，s)、4.25(1H，tt，J＝11.2，5.2Hz)、6.52(1H，d，J＝3.3Hz)、6.99(2H，t，J＝8.6Hz)、7.04(1H，dd，J＝8.4，1.8Hz)、7.19(2H，dd，J＝8.6，5.5Hz)、7.30(1H，d，J＝3.3Hz)、7.47(1H，d，J＝1.8Hz)、7.61(1H，d，J＝8.4Hz).
Melting point: 192 ℃ C
Mass：FAB+430(M+H)+
EXAMPLE 3361 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methanesulfonyloxyindole
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methanesulfonyloxyindoline (53.4mg) obtained in example 122 was dissolved in chloroform (5 ml). To this solution was added activated manganese dioxide (300 mg). After the suspension was stirred at room temperature for 22 hours, the reaction mixture was filtered through celite and washed with chloroform. The filtrate was concentrated under reduced pressure and crystallized from ethyl acetate/hexane to give the title compound as a white solid, 40.0 mg. (yield: 75%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.87-2.01(4H，m)、2.22(2H，br-t，J＝10.6Hz)、2.55(2H，t，J＝7.9Hz)、2.75(2H，t，J＝7.9Hz)、3.06(2H，br-d，J＝11.2Hz)、3.34(3H，s)、4.32-4.41(1H，m)、6.50(1H，d，J＝2.6Hz)、6.98(1H，dd，J＝8.4，1.5Hz)、7.09(2H，t，J＝9.0Hz)、7.27(2H，dd，J＝9.0，5.7Hz)、7.57(1H，d，J＝1.5Hz)、7.56(1H，d，J＝8.4Hz)、7.60(1H，d，J＝2.6Hz).
Melting point: 213-215 deg.C
Mass：FAB+417(M+H)+
EXAMPLE 3371 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carbamoylindole
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carbamoylindoline (14.1mg) obtained in example 125 was dissolved in chloroform (5 ml). To this solution was added activated manganese dioxide (80 mg). After the suspension was stirred at room temperature for 22 hours, the reaction mixture was filtered through celite and washed with chloroform. The filtrate was concentrated under reduced pressure and crystallized from ethyl acetate/hexane to give the title compound as a white solid, 5.0 mg. (yield: 36%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.05-2.14(4H，m)、2.22-2.31(2H，m)、2.62-2.67(2H，m)、2.78-2.84(2H，m)、3.18(2H，br-d，J＝10.3Hz)、4.35-4.44(1H，m)、6.57(1H，d，J＝3.3Hz)、6.99(2H，t，J＝8.2Hz)、7.18(2H，dd，J＝8.2，5.3Hz)、7.39(1H，d，J＝3.3Hz)、7.40(1H，d，J＝8.1Hz)、7.64(1H，d，J＝8.1Hz)、8.10(1H，br-s).
Melting point: 238 deg.C and 240 deg.C
Mass；FAB+366(M+H)+.
EXAMPLE 3381 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (N-methylsulfamoylmethyl) indole
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (N-methylsulfamoylmethyl) indoline (30.4mg) obtained in example 164 was dissolved in chloroform (5 ml). To this solution was added active manganese dioxide (165 mg). After the suspension was stirred at room temperature for 22 hours, the reaction mixture was filtered through celite and washed with chloroform. The filtrate was concentrated under reduced pressure, and crystallized from ethyl acetate/hexane to give the title compound as a white solid, 24mg (yield: 79%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.99-2.04(4H，m)、2.17-2.25(2H，m)、2.54(2H，d，J＝4.8)、2.55(2H，t，J＝8.4Hz)、2.76(2H，t，J＝8.4Hz)、3.08(2H，br-d，J＝11.7Hz)、4.25-4.35(1H，m)、4.37(2H，s)、6.43(1H，d，J＝3.1Hz)、6.83(1H，q，J＝4.8Hz)、7.01(1H，d，J＝8.4Hz)、7.09(2H，t，J＝8.8Hz)、7.27(2H，dd，J＝8.8，5.7Hz)、7.50(1H，d，J＝8.4Hz)、7.51(1H，s)、7.52(1H，d，J＝3.1Hz).
Melting point: 172 ℃ C. & lt 175 ℃ C.)
Mass：FAB+430(M+H)+
EXAMPLE 3391 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidoindole
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidoindoline obtained in example 115 (32mg) was dissolved in chloroform (5 ml). To this solution was added active manganese dioxide (160 mg). After the suspension was stirred at room temperature for 22 hours, the reaction mixture was filtered through celite and washed with chloroform. The filtrate was concentrated under reduced pressure and crystallized from ethyl acetate/hexane to give the title compound as a pale red solid, 23 mg. (yield: 72%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.85-2.00(4H，m)、2.02(3H，s)、2.13-2.23(2H，m)、2.55(2H，t，J＝7.7Hz)、2.75(2H，t，J＝7.7Hz)、3.08(2H，br-d，J＝11.7Hz)、4.07-4.18(1H，m)、6.35(1H，d，J＝2.2Hz)、7.05(1H，d，J＝8.6Hz)、7.09(2H，t，J＝9.0Hz)、7.27(2H，dd，J＝9.0，6.0Hz)、7.39(1H，d，J＝2.2Hz)，7.40(1H，d，J＝8.6Hz)、7.92(1H，s)、9.85(1H，br-s).
Melting point: 195-196 deg.C
Mass；FAB+380(M+H)+
EXAMPLE 3401 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1, 2-dihydroxypropan-3-yl) carbamoylmethylindole oxalate
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 146 (0.17g) was dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.09g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. To this was added a solution of 1-amino-2, 3-propanediol (0.40g) in N, N-dimethylformamide (1ml), and the mixture was stirred for 7.5 hours. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.14g of a pale brown viscous oil.
The residue was dissolved in chloroform (30 ml). Manganese dioxide (0.27g) was added thereto, and the mixture was stirred at 50 ℃ overnight. Manganese dioxide (0.13g) was added thereto and stirred for 3 hours. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 0.07g of the free form of the title compound as a pale brown amorphous substance. It is made into oxalate by conventional method.
1H-NMR(400MHz，DMSO-d6)；δ(ppm)2.07(2H，br d)、2.18-2.27(2H，m)、2.84-3.06(7H，m)、3.17-3.28(3H，m)、3.45-3.53(3H，m)、3.53(2H，s)、4.50-4.58(1H，m)、6.43(1H，d，J＝3.2Hz)、6.95(1H，d，J＝8.8Hz)、7.16(2H，br-t)、7.32-7.36(2H，m)、7.41-7.46(3H，m)、7.99(1H，t，J＝5.4Hz).
ESI-Mass；454(MH+).
EXAMPLE 3411 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (pyridin-2-yl) methylcarbamoylmethylindole oxalate
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 146 (0.21g) was dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.11g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. To this was added 2-aminomethylpyridine (287ml) and stirred for an additional 4 hours. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.20g of a pale brown viscous oil.
The residue was dissolved in chloroform (30 ml). Manganese dioxide (0.36g) was added thereto, and the mixture was stirred at 50 ℃ overnight. Manganese dioxide (0.18g) was added thereto and stirred for 6 hours. Manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure to give 0.18g of the free form of the title compound as a pale brown viscous oil. It is made into oxalate by conventional method.
1H-NMR(400MHz，DMSO-d6)；δ(ppm)2.09(2H，br-d)、2.25-2.34(2H，m)、2.92-3.00(4H，m)、3.09-3.17(2H，m)、3.52(2H，br-d)、3.62(2H，s)、4.37(2H，d，J＝5.8Hz)、4.54-4.64(1H，m)、6.45(1H，d，J＝3.4Hz)、7.01(1H，d，J＝8.0Hz)、7.17(2H，br-t)、7.22-7.25(2H，m)、7.33-7.36(2H，m)、7.42(1H，d，J＝1.6Hz)、7.48(1H，d，J＝8.0Hz)、7.50(1H，s)、7.68-7.72(1H，m)、7.48(1H，d，J＝3.4Hz)、8.63(1H，t，J＝5.8Hz).
ESI-Mass；471(MH+).
EXAMPLE 3421 Synthesis of- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-methylcarbamoylmethylindole
(342-1)1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-hydroxymethylindoline
To 1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-formylindoline (6.85g) obtained in example 348-3 were added methanol (50ml) and tetrahydrofuran (25ml), and the mixture was dissolved and stirred under ice cooling. To this was added sodium borohydride little by little. The disappearance of the starting material was confirmed by thin layer chromatography, and the solvent was evaporated under reduced pressure. Ethyl acetate and 8N aqueous sodium hydroxide solution were added to separate an organic layer. After washing with water and saturated brine, the mixture was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 8.10g of the title compound as colorless crystals.
1H-NMR(400MHz，CDCl3)；δ(ppm)1.72-1.84(4H，m)、2.13-2.19(2H，m)、2.60-2.64(2H，m)、2.84-2.88(2H，m)、2.93(2H，t，J＝8.4Hz)、3.13(2H，br-d)、3.42(2H，t，J＝8.4Hz)、3.38-3.46(1H，m)、4.59(2H，s)、6.44(1H，s)、6.57(1H，d，J＝7.2Hz)、6.99-7.04(2H，m)、7.04-7.08(1H，m)、7.16-7.23(2H，m).
(342-2)1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-chloromethylindoline
To the above-mentioned 1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-hydroxymethylindoline (7.49g) was added 30ml of concentrated hydrochloric acid, and the mixture was stirred at 80 ℃ overnight. The mixture was neutralized with a 5N aqueous sodium hydroxide solution under ice cooling, a 10% aqueous sodium carbonate solution was added to adjust the pH to about 10, and the mixture was extracted with ethyl acetate. After washing with saturated brine, the mixture was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 8.10g of the title compound as pale brown crystals.
1H-NMR(400MHz，CDCl3)；δ(ppm)1.72-1.85(4H，m)、2.14-2.21(2H，m)、2.60-2.65(2H，m)、2.84-2.89(2H，m)、2.93(2H，t，J＝8.4Hz)、3.14(2H，br-d)、3.37-3.44(1H，m)、3.43(2H，t，J＝8.4Hz)、4.52(2H，s)、6.40(1H，d，J＝1.2Hz)、6.59(1H，dd，J＝1.2，7.4Hz)、6.99-7.04(2H，m)、7.05-7.09(1H，m)、7.16-7.24(2H，m).
(342-3)1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-cyanomethylindoline
To the above 1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-chloromethylindoline (6.51g) was added dimethyl sulfoxide (50ml), which was dissolved, and sodium cyanide (0.94g) was added and stirred at 50 ℃ for 2 hours. Ice water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with a dilute saline solution, washed with a saturated saline solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/n-hexane) to give 4.95g of the title compound as a pale yellow viscous oil.
1H-NMR(400MHz，CDCl3)；δ(ppm)1.72-1.83(4H，m)、2.14-2.21(2H，m)、2.61(2H，m)、2.84-2.88(2H.m)、2.94(2H，t，J＝8.4Hz)、3.13(2H，br-d)、3.35-3.44(1H，m)、3.44(2H，t，J＝8.4Hz)、3.65(2H，s)、6.30(1H，s)、6.50(1H，d，J＝7.2Hz)、6.99-7.04(2H，m)、7.05-7.09(2H，m)、7.16-7.24(2H，m).
342-4)1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline
To the above 1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-cyanomethylindoline (6.51g) were added water (10ml) and concentrated sulfuric acid (10ml), followed by dissolution and reflux with heating. The reaction solution was cooled with ice, neutralized with an 8N aqueous sodium hydroxide solution, adjusted to pH 6 with 1N hydrochloric acid, and then extracted with chloroform. After washing with saturated brine, the mixture was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 0.93g of the title compound as a pale green powder.
1H-NMR(400MHz，CDCl3)；δ(ppm)1.91-1.95(2H，m)、2.52(2H，br-s)、2.80(2H，br-s)、2.90(2H，t，J＝8.4Hz)、3.13-3.17(2H，m)、3.27-3.31(2H，m)、3.40(2H，t，J＝8.4Hz)、3.54-3.73(3H，m)、3.55(2H，s)、6.39(1H，s)、6.55(1H，d，J＝7.6Hz)、6.97-7.13(3H，m)、7.25-7.35(2H，m).
ESI-Mass；383(MH+).
(342-5)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methylcarbamoylindole
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 146 (0.16g) was dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.08g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. To this was added a 2N methylamine/tetrahydrofuran solution (1.02ml), and the mixture was stirred for 2 hours. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.09g of pale brown crystals.
The crystals were dissolved in chloroform (20 ml). Manganese dioxide (0.20g) was added thereto, and the mixture was stirred at 50 ℃ overnight. Manganese dioxide (0.20g) was added thereto and stirred for 7 hours. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. The residue was recrystallized from chloroform/n-hexane to give the title compound (0.06 g) as a pale brown powder.
Melting point: 136.5-137.4 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)2.08-2.13(4H，m)、2.28-2.35(2H，m)、2.67-2.71(2H，m)、2.73(3H，d，J＝4.8Hz)、2.88-2.92(2H，m)、3.20(2H，br-d)、3.72(2H，s)、4.21-4.28(1H，m)、5.40(1H，br-s)、6.53(1H，d，J＝3.2Hz)、6.96(1H，dd，J＝1.2，8.0Hz)、7.01-7.06(1H，m)、7.06-7.10(1H，m)、7.18-7.24(4H，m)、7.61(1H，d，J＝8.0Hz).
ESI-Mass；394(MH+).
EXAMPLE 3431 Synthesis of- [1- (2-fluorophenethyl) piperidin-4-yl ] -6- (1-acetylpiperidin-4-yl) methylcarbamoylmethylindole oxalate
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 146 (0.20g) was dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.10g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. To this was added a solution of 1-acetyl-4-aminomethylpiperidine (0.25g) in N, N-dimethylformamide (1ml), and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.20g of a pale brown viscous oil.
The residue was dissolved in chloroform (30 ml). Manganese dioxide (0.33g) was added thereto, and the mixture was stirred at 50 ℃ overnight. Manganese dioxide (0.17g) was then added thereto, and the mixture was stirred for another 6 hours. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. This gave 0.26g of the title compound as a pale yellow amorphous product.
1H-NMR(400MHz，CDCl3)；δ(ppm)0.94-1.09(2H，m)、1.55-1.83(3H，m)、2.04(3H，s)、2.08-2.13(4H，m)、2.25-2.31(2H，m)、2.46(1H，dt，J＝2.4，12.8Hz)、2.64-2.68(2H，m)、2.81-2.85(2H，m)、2.92-3.03(2H，m)、3.11-3.20(3H，m)、3.72(2H，s)、3.75(1H，br-d)、4.20-4.28(1H，m)、4.55(1H，br-d)、5.55(1H，t，J＝6.0Hz)、6.53(1H，d，J＝2.8Hz)、6.95-7.01(3H，m)、7.17-7.20(2H，m)、7.26-7.27(2H，m)、7.62(1H，d，J＝8.0Hz).
ESI-Mass；519(MH+).
EXAMPLE 3441 Synthesis of- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-ethylcarbamoylmethylindole
1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 342-4) (0.16g) is dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.08g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. To this was added a 2N ethylamine/tetrahydrofuran solution (1.06ml), and the mixture was stirred for 2 hours. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain light brown crystals (0.11 g).
The crystals were dissolved in chloroform (20 ml). Manganese dioxide (0.23g) was added thereto, and the mixture was stirred at 50 ℃ overnight. Manganese dioxide (0.23g) was then added thereto, and the mixture was stirred for another 7 hours. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. The residue was recrystallized from chloroform/n-hexane to give 0.07g of the title compound as a pale brown powder.
Melting point: 147.0-148.6 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)1.02(3H，t，J＝7.4Hz)、2.08-2.13(4H，m)、2.28-2.35(2H，m)、2.67-2.71(2H，m)、2.88-2.92(2H，m)、3.19-3.26(4H，m)、3.70(2H，s)、4.21-4.29(1H，m)、5.40(1H，br-t)、6.53(1H，d，J＝3.2Hz)、6.97(1H，dd，J＝1.6，8.0Hz)、7.01-7.06(1H，m)、7.06-7.10(1H，m)、7.18-7.27(4H，m)、7.61(1H，d，J＝8.0Hz).
ESI-Mass；408(MH+).
EXAMPLE 3451 Synthesis of- [1- (2-fluorophenethyl) piperidin-4-yl ] -6- (1-ethylpiperidin-4-yl) methylcarbamoylmethylindole oxalate
345-1) 1-acetyl-4-aminomethylpiperidine
To 4-aminomethylpiperidine (10.00g), benzene (70ml) was added and dissolved. To this was added 9.30g of benzaldehyde, which was then placed in a Dean-Stark trap and heated under reflux for 3 hours. The solvent was evaporated under reduced pressure, and 70ml of benzene was added to the residue to dissolve it. To this was added triethylamine (67ml) and anhydrous acetic acid (9.1ml), and the mixture was stirred at room temperature under nitrogen for 3 days. The solvent was evaporated under reduced pressure.
Sodium hydrogen sulfate-1 hydrate (13.3g) was dissolved in water (80ml), and the above residue was added thereto and stirred at room temperature for 2.5 hours. The reaction solution was washed with diethyl ether. The aqueous layer was cooled with ice, adjusted to pH 11 with 5N aqueous sodium hydroxide solution, and extracted with chloroform under salting out. Drying over magnesium sulfate and evaporation of the solvent under reduced pressure gave the title compound as a brown oil (12.81 g).
1H-NMR(400MHz，CDCl3)；δ(ppm)1.04-1.19(2H，m)、1.50-1.57(1H，m)、1.74-1.84(2H，m)、2.09(3H，s)、2.54(1H，dt，J＝2.8，12.8Hz)、2.62(2H，d，J＝6.8Hz)、3.04(1H，dt，J＝2.8，12.8Hz)、3.80-3.86(1H，m)、4.61-4.67(1H，m).
(345-2) 1-Ethyl-4-aminomethylpiperidine
Lithium aluminum hydride (1.06g) was suspended in tetrahydrofuran (70ml), and the suspension was stirred under nitrogen atmosphere and ice-cooling. To this was added a solution of 1-acetyl-4-aminomethylpiperidine (4.14g) in tetrahydrofuran (30ml), and the mixture was stirred at room temperature for 10 minutes. Then heated to reflux overnight. The reaction mixture was cooled with ice, and water (1.06ml), a 5N aqueous solution of sodium hydroxide (1.06ml) and water (3.18ml) were added in this order and stirred. The mixture was diluted with ethyl acetate, and insoluble matter was filtered off. The residue was purified by NH silica gel column chromatography (chloroform/methanol) to give 3.15g of the title compound as a pale brown oil.
(345-3)1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-ethylpiperidin-4-yl) methylcarbamoylmethylindole oxalate
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 146 (0.29g) was dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.15g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. To this was added a solution of 1-ethyl-4-aminomethylpiperidine (0.32g) in N, N-dimethylformamide (1ml), and the mixture was stirred for 3 hours. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.30g of a pale brown viscous oil.
The residue was dissolved in chloroform (30 ml). Manganese dioxide (0.51g) was added thereto, and the mixture was stirred at 50 ℃ overnight. Manganese dioxide (0.51g) was added thereto and stirred for 13.5 hours. Manganese dioxide (0.51g) was added again, and the mixture was stirred overnight. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 0.26g of an episome of the title compound as a brown viscous oil. It is made into oxalate by conventional method.
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.12(3H，t，J＝6.6Hz)、1.27-1.35(2H，m)、1.54-1.64(1H，m)、1.73(2H，br-d)、1.92-2.08(4H，m)、2.30(2H，br-t)、2.55(2H，br-t)、2.62-2.66(2H，m)、2.78-2.86(4H，m)、2.97(2H，br-t)、3.14(2H，br-d)、3.23(2H，br-d)、3.50(2H，s)、4.26-4.34(1H，m)、6.40(1H，d，J＝3.2Hz)、6.93(1H，d，J＝8.0Hz)、7.12(2H，br-t)、7.28-7.32(2H，m)、7.41-7.45(2H，m)、8.09(1H，t，J＝5.8Hz).
ESI-Mass；505(MH+).
EXAMPLE 3461 Synthesis of- [1- (2-fluorophenethyl) piperidin-4-yl ] -6- (2-hydroxyethyl) carbamoylmethylindole
1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 342-4) (0.20g) is dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.10g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. Ethanolamine (161ml) was added thereto, and stirred overnight. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain light brown crystals (0.14 g).
The crystals were dissolved in chloroform (30 ml). Manganese dioxide (0.28g) was added thereto, and the mixture was stirred at 50 ℃ overnight. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. The residue was recrystallized from chloroform/n-hexane to give 0.07g of the title compound as a pale gray powder.
Melting point: 127.7-128.6 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)2.08-2.21(4H，m)、2.31(2H，br-t)、2.68-2.71(2H，m)、2.88-2.92(2H，m)、3.21(2H，br-d)、3.37(2H，dt，J＝4.8，4.8Hz)、3.67(2H，t，J＝4.8Hz)、3.74(2H，s)、4.20-4.27(1H，m)、5.90(1H，br-s)、6.51(1H，d，J＝3.2Hz)、6.96-7.10(3H，m)、7.18-7.26(3H，m)、7.32(1H，s)、7.61(1H，d，J＝8.0Hz).
ESI-Mass；424(MH+).
EXAMPLE 3471 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1, 3-dioxolan-2-yl) methylcarbamoylmethylindole
1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-carboxymethylindoline obtained in example 342-4) (0.22g) is dissolved in 5ml of N, N-dimethylformamide. To the solution was added 1, 1-carbonyldiimidazole (0.11g), and the mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. To this was added a solution of 2-aminomethyl-1, 3-dioxolane (0.12g) in N, N-dimethylformamide (1ml), and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain light brown crystals (0.20 g).
The crystals were dissolved in chloroform (20 ml). Manganese dioxide (0.38g) was added thereto, and the mixture was stirred at 50 ℃ overnight. Manganese dioxide (0.38g) was added thereto, and the mixture was stirred for 10.5 hours. The manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure. The residue was recrystallized from chloroform/n-hexane to give 0.15g of the title compound as colorless needle crystals.
Melting point: 173.8-174.6 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)2.05-2.12(4H，m)、2.25-2.31(2H，m)、2.64-2.68(2H，m)、2.81-2.85(2H，m)、3.18(2H，br-d)、3.43(2H，dd，J＝3.6，6.0Hz)、3.73(2H，s)、3.75-3.79(4H，m)、4.21-4.29(1H，m)、4.90(1H，t，J＝3.6Hz)、5.67(1H，t，J＝6.0Hz)、6.51(1H，d，J＝3.2Hz)、6.96-7.01(3H，m)、7.17-7.20(2H，m)、7.25-7.28(2H，m)、7.60(1H，d，J＝8.0Hz).
ESI-Mass；466(MH+).
EXAMPLE 3481 Synthesis of- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindole
(348-1)1- (2-fluorophenethyl) piperidin-4-one
To a solution of 2-fluorophenethylamine (25g), potassium carbonate (56.6g), water (400ml) and ethanol (800ml) was added dropwise an aqueous solution (400ml) of N, N-dimethyl-4-oxopiperidinium iodide (49.6g) under reflux. After completion of the dropwise addition, the reaction mixture was heated under reflux for 45 minutes. Ethanol was evaporated under reduced pressure, the residue was extracted with chloroform, and the chloroform layer was washed with saturated brine and was dried over magnesium sulfate. The solvent was evaporated, and the residue was dissolved in a mixture of ethyl acetate/chloroform (1: 1) and filtered through silica gel. The filtrate was concentrated under reduced pressure to give the title compound (31.2g) as a yellow oil. (yield: 80.2%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.46-2.55(4H，m)、2.71-2.80(2H.m)、2.80-2.93(6H，m)、6.98-7.10(2H，m)、7.16-7.25(2H，m).
(348-2)1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline
Sodium triacetoxyborohydride (15.0g) was added to a mixture of 6-bromoindoline (9.0g), 1- (2-fluorophenethyl) piperidin-4-one (11.0g) and acetic acid (12.5ml) in 1, 2-dichloroethane (140ml) under ice-cooling. The reaction was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (400ml), and 8N aqueous sodium hydroxide solution (70ml) was added thereto. The organic layer was separated, extracted with 5N hydrochloric acid (100ml), and made alkaline with 8N aqueous sodium hydroxide solution. Extracting with ethyl acetate, and washing with water and saturated saline. The ethyl acetate layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (12.2g) as a pale yellow solid. (yield: 66.6%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.52-1.66(4H，m)、2.10(2H，dt，J＝7.6，2.8Hz)、2.48-2.53(2H，m)、2.77(2H，t，J＝8.4Hz)、2.83(2H，t，J＝8.4Hz)、2.96-3.03(2H，br-d)、3.37(2H，t，J＝8.4Hz)、3.34-3.43(1H，m)、6.57(1H，d，J＝1.2Hz)、6.61(1H，dd，J＝7.6，1.2Hz)、6.90(1H，d，J＝7.6Hz)、7.10-7.16(2H，m)、7.21-7.28(1H，m)、7.33(1H，dt，J＝7.6，1.2Hz).
ESI-Mass；404(MH+).
(348-3)1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-formylindoline
To a tetrahydrofuran (200ml) solution of 1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline (12g) obtained in example 348-2 was added dropwise a 1.6M- (n-butyllithium)/hexane solution (24ml) at-78 ℃ over a period of 10 minutes. After 10 minutes, dimethylformamide (3.5ml) was added thereto and the mixture was allowed to return to room temperature, then saturated aqueous ammonium chloride (100ml) and ethyl acetate (200ml) were added thereto to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/ethanol) to give the title compound (9.6g) as yellow powder crystals. (yield: 91.5%)
Melting point: 86-87 deg.C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.56-1.71(4H，m)、2.07-2.16(2H，m)、2.48-2.56(2H，m)、2.77(2H，t，J＝8.0Hz)、2.94-3.06(4H，m)、3.39-3.50(3H，m)、6.82(1H，s)、7.10-7.17(3H，m)、7.20-7.29(2H，m)、7.31-7.37(1H，m)、9.83(1H，s).
ESI-Mass；353(MH+).
(348-4)1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-formylindole
A chloroform (100ml) suspension of 1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-formylindoline (2.50g) obtained in example 348-3) and activated manganese dioxide (5.0g) was refluxed for 4 hours while being vigorously stirred. Then, manganese dioxide (5.0 g. times.1, 2.5 g. times.2) was added to the reaction mixture every 1 hour, and reacted for another 2 hours. The reaction mixture was filtered through celite, and the residue was washed with chloroform, and the filtrate was concentrated under reduced pressure to give the title compound (1.94g) as a yellow powder. (yield: 78.0%)
Melting point: 128-129 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)2.09-2.42(6H，m)、2.67-2.75(2H，m)、2.83-2.91(2H，m)、3.19-3.28(2H，br-d)、4.35-4.45(1H，m)、6.61(1H，d，J＝3.2Hz)、6.95-7.05(2H，m)、7.16-7.23(2H，m)、7.48(1H，d，J＝3.2Hz)、7.62(1H，dd，J＝8.0，1.2Hz)、7.72(1H，d，J＝8.0Hz)、7.98(1H，s)、10.07(1H，s).
Mass；351(MH+).
(348-5)1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindole
A mixture of 1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-formylindole (1.94g) obtained in example 348-4), hydroxylamine hydrochloride (0.5g) and anhydrous sodium acetate (0.55g) in methanol (60ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate (150ml) and 1N aqueous sodium hydroxide solution (30 ml). The ethyl acetate layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-hydroxyiminomethylindole (1.96g) as ivory powder. (yield: 96.8%)
A solution of 1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-hydroxyiminomethylindole (1.95g) in tetrahydrofuran (50ml) was added dropwise to a suspension of lithium aluminum hydride (0.4g) in tetrahydrofuran (100ml) with stirring under ice cooling, and then the mixture was refluxed for 3 hours. While the reaction mixture was chilled in ice water, water (1ml), a 5N-sodium hydroxide aqueous solution (3ml), and water (1ml) were carefully added dropwise to the reaction mixture in this order, and the mixture was stirred vigorously. The precipitated precipitate was collected by filtration, washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to give the title compound (0.92g) as a brown wax. (yield: 49.1%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.80-2.04(4H，m)、2.22-2.30(2H，m)、2.56-2.62(2H，m)、2.79-2.85(2H，m)、3.06-3.13(2H，m)、3.80(2H，s)、4.27-4.38(1H，m)、6.38(1H，d，J＝2.8Hz)、6.97(1H，br-d)、7.12-7.18(2H，m)、7.23-7.29(1H，m)、7.34-7.39(1H，m)、7.41-7.45(2H，m)、7.47(1H，br-s).
EXAMPLE 3491 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindole
From 1- [1- (4-chlorophenylethyl) piperidin-4-yl ] -6-acetamidomethylindoline (120mg) obtained in example 98, activated manganese dioxide (480mg) and chloroform (10ml), the title compound (95 mg) was obtained as white powder crystals in the same manner as in example 285. (yield: 80%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.03(3H，s)、2.04-2.16(4H，m)、2.24-2.40(2H，m)、2.64-2.76(2H，m)、2.81-2.95(2H，m)、3.12-3.29(2H，m)、4.23-4.33(1H，m)、4.55(2H，d，J＝5.6Hz)、5.79(1H，br-s)、6.51(1H，d，J＝3.6Hz)、7.03(1H，d，J＝8.0Hz)、7.17(2H，d，J＝8.4Hz)、7.25(1H，d，J＝3.6Hz)、7.28(2H，d，J＝8.4Hz)、7.36(1H，s)、7.59(1H，d，J＝8.0Hz).
Melting point: 148 ℃ 149 DEG C
Mass；FAB+410(M+H)
EXAMPLE 3501 Synthesis of- [1- (3-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindole
From 1- [1- (3-chlorophenylethyl) piperidin-4-yl ] -6-acetamidomethylindoline (130mg) obtained in example 135, activated manganese dioxide (520mg) and chloroform (10ml) was obtained the title compound 110mg as white powder crystals in the same manner as in example 285. (yield: 85%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.03(3H，s)、2.04-2.16(4H，m)、2.24-2.40(2H，m)、2.60-2.78(2H，m)、2.80-2.99(2H，m)、3.11-3.33(2H，m)、4.22-4.33(1H，m)、4.55(2H，d，J＝5.2Hz)、5.78(1H，br-s)、6.51(1H，d，J＝3.2Hz)、6.89-6.98(2H，m)、7.00-7.11(2H，m)、7.24-7.30(2H，m)、7.36(1H，s)、7.59(1H，d，J＝8.0Hz).
Melting point: 134 ℃ and 135 DEG C
Mass；FAB+394(M+H)
EXAMPLE 3511 Synthesis of- [1- (4-methoxyphenylethyl) piperidin-4-yl ] -6-acetamidomethylindole
From 1- [1- (4-methoxyphenylethyl) piperidin-4-yl ] -6-acetamidomethylindoline (110mg) obtained in example 97, activated manganese dioxide (440mg) and chloroform (10ml), the title compound 90mg3 was obtained as pale yellow prisms (yield: 82%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.03(3H，s)、2.05-2.15(4H，m)、2.25-2.35(2H，m)、2.63-2.76(2H，m)、2.79-2.90(2H，m)、3.17-3.30(2H，m)、3.80(3H，s)、4.22-4.31(1H，m)、4.52(2H，d，J＝5.2Hz)、5.73(1H，br-s)、6.51(1H，d，J＝3.6Hz)、6.86(2H，d，J＝8.4Hz)、7.03(1H，d，J＝8.0Hz)、7.16(2H，d，J＝8.4Hz)、7.25(1H，d，J＝3.6Hz)、7.36(1H，s)、7.59(1H，d，J＝8.0Hz).
Melting point: 101-102 deg.C
Mass；FAB+406(M+H)
EXAMPLE 3521 Synthesis of- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindole
From 1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindoline (110mg) obtained in example 134, activated manganese dioxide (440mg) and chloroform (10ml) was obtained the title compound as pale yellow needle crystals (90 mg) in the same manner as in example 285. (yield: 82%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.03(3H，s)、2.05-2.16(4H，m)、2.31-2.43(2H，m)、2.69-2.82(2H，m)、2.86-2.99(2H，m)、3.17-3.31(2H，m)、4.23-4.35(1H，m)、4.55(2H，d，J＝5.6Hz)、5.75(1H，br-s)、6.51(1H，d，J＝3.6Hz)、6.99-7.13(3H，m)、7.15-7.27(3H，m)、7.37(1H，s)、7.59(1H，d，J＝8.0Hz).
Melting point: 101-102 deg.C
Mass；FAB+394(M+H)
EXAMPLE 3531 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2, 4-imidazolidinedion-3-yl) methylindole
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2, 4-imidazolidinedion-3-yl) methylindoline (110mg) obtained in example 207, activated manganese dioxide (550mg) and chloroform (10ml) as in example 285, 80mg of the title compound was obtained as pale yellow powder crystals. (yield: 74%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.05-2.13(4H，m)、2.26-2.36(2H，m)、2.63-2.70(2H，m)、2.80-2.87(2H，m)、3.14-3.20(2H，m)、3.93(2H，s)、4.21-4.33(1H，m)、4.79(2H，s)、5.83(1H，br-s)、6.49(1H，d，J＝3.2Hz)、6.96-7.03(2H，m)、7.15-7.22(3H，m)、7.25(1H，d，J＝3.2Hz)、7.48(1H，s)、7.56(1H，d，J＝8.0Hz).
Melting point: 157 ℃ of 156-
Mass；FAB+435(M+H)
EXAMPLE 3541 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-isobutyrylaminomethylindole
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-isobutyrylaminomethylindoline (110mg) obtained in example 158, activated manganese dioxide (550mg) and chloroform (10ml) as in example 285, 95mg of the title compound was obtained as white needle-like crystals. (yield: 87%)
1H-NMR(400MHz，CDCl3)；δ(ppm)1.19(6H，d，J＝7.6Hz)、2.06-2.15(4H，m)、2.26-2.43(2H，m)、2.38(1H，septet，J＝7.6Hz)、2.65-2.75(2H，m)、2.81-2.91(2H，m)、3.18-3.27(2H，m)、4.22-4.31(1H，m)、4.56(2H，d，J＝5.6Hz)、5.75(1H，br-s)、6.51(1H，d，J＝3.2Hz)、6.96-7.05(3H，m)、7.16-7.22(2H，m)、7.25(1H，d，J＝3.2Hz)、7.33(1H，s)、7.59(1H，d，J＝8.0Hz).
Melting point: 97-98 deg.C
Mass；FAB+422(M+H)
EXAMPLE 3551 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-imidazolidinonyl) methylindole
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-imidazolidinonyl) methylindoline (80mg) obtained in example 206, activated manganese dioxide (400mg) and chloroform (10ml) as in example 285, 32mg of the title compound was obtained as pale yellow powder crystals.
(yield: 48%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.04-2.18(4H，m)、2.28-2.42(2H，m)、2.65-2.78(2H，m)、2.81-2.96(2H，m)、3.12-3.41(6H.m)、4.25-4.36(2H，m)、4.49(2H，s)、6.52(1H，d，J＝3.2Hz)、6.99(1H，d，J＝8.0Hz)、7.00-7.09(2H，m)、7.17-7.23(2H，m)、7.26(1H，d，J＝3.2Hz)、7.33(1H，s)、7.58(1H，d，J＝8.0Hz).
Melting point: 130 ℃ and 131 DEG C
Mass；FAB+421(M+H)
Example Synthesis of 3561- {1- [4- (4-fluorophenyl) butyl ] piperidin-4-yl } -6-acetamidomethylindole
From 1- {1- [4- (4-fluorophenyl) butyl ] piperidin-4-yl } -6-acetamidomethylindoline (110mg) obtained in example 227, activated manganese dioxide (550mg) and chloroform (10ml) were obtained 56mg of the title compound as white powder crystals as in example 285. (yield: 51%)
1H-NMR(400MHz，CDCl3)；δ(ppm)1.62-1.72(4H，m)、2.04(3H，s)、2.05-2.17(4H，m)、2.24-2.39(2H，m)、2.60-2.79(2H，m)、2.81-2.92(2H，m)、3.10-3.22(2H，m)、4.23-4.35(1H，m)、4.55(2H，d，J＝5.6Hz)、5.83(1H，br-s)、6.50(1H，d，J＝3.2Hz)、6.95-7.01(2H，m)、7.03(1H，d，J＝8.0Hz)、7.12-7.17(2H，m)、7.23(1H，d，J＝3.2Hz)、7.26(1H，s)、7.58(1H，d，J＝8.0Hz).
Melting point: 59-60 deg.C
Mass；FAB+422(M+H)
EXAMPLE 3571 Synthesis of- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindole
From 1- [1- (2, 4-difluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindoline (100mg) obtained in example 224, activated manganese dioxide (500mg) and chloroform (10ml) as in example 285, 83mg of the title compound was obtained as an oil. This oil was dissolved in ethyl acetate and crystallized from oxalic acid (15mg) to give 46mg of the oxalate salt of the title compound as pale yellow prismatic crystals. (yield: 42%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)2.00-2.28(4H，m)、2.05(3H，s)、2.81-3.16(6H，m)、3.44-3.54(2H，m)、4.28(2H，d，J＝5.2Hz)、4.52-4.63(1H，m)、6.47(1H，d，J＝3.6Hz)、6.99-7.16(3H，m)、7.32-7.40(1H，m)、7.44(1H，d，J＝3.6Hz)、7.51-7.58(2H，m)、8.23(1H，t，J＝5.2Hz).
Melting point: 103 deg.C and 106 deg.C
Mass；FAB+412(M+H)
EXAMPLE 3581 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-pyrrolidin-1-yl) methylindole
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (2-pyrrolidone-1-yl) methylindoline (80mg) obtained in example 202, activated manganese dioxide (400mg) and chloroform (10ml) as in example 285, 69mg of the title compound was obtained as an oil. This oil was dissolved in ethyl acetate and crystallized from oxalic acid (13mg) to give 54mg of the oxalate salt of the title compound as a white powder crystal. (yield: 61%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.83-1.92(2H，m)、2.05-2.25(4H，m)、2.27(2H，t，J＝8.0Hz)、2.89-3.24(6H，m)、3.20(2H，t，J＝8.0Hz)、3.46-3.56(2H，m)、4.44(2H，s)、4.54-4.66(1H，m)、6.45(1H，d，J＝2.8Hz)、6.89(1H，d，J＝8.0Hz)、7.13-7.19(2H，m)、7.30-7.36(2H，m)、7.40-7.46(2H，m)、7.50(1H，d，J＝8.0Hz).
Melting point: 179 plus 180 DEG C
Mass；FAB+420(M+H)
EXAMPLE 3591 Synthesis of 1- (4-fluorophenethyl) piperidin-4-yl ] -6-N-methylacetamidomethyl indole
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-N-methylacetamidomethyl indoline (140mg) obtained in example 163, activated manganese dioxide (700mg) and chloroform (10ml) as in example 285, 120mg of the title compound was obtained as an oil. This oil was dissolved in ethyl acetate and crystallized from oxalic acid (24mg) to give 90mg of the oxalate salt of the title compound as pale red powder crystals. (yield: 58%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)2.05(1.5H，s)、2.10(1.5H，s)、2.05-2.26(4H，m)、2.78(1.5H，s)、2.87(1.5H，s)、2.90-3.04(4H，m)、3.09-3.18(2H，m)、3.46-3.56(2H，m)、4.52-4.66(3H，m)、6.44(0.5H，d，J＝2.8Hz)、6.47(0.5H，d，J＝2.8Hz)、6.86-6.92(1H，m)、7.13-7.20(2H，m)、7.30-7.46(4H，m)、7.48(0.5H，d，J＝8.0Hz)、7.53(0.5H，d，J＝8.0Hz).
Melting point: 148 ℃ 149 DEG C
Mass；FAB+408(M+H)
Example Synthesis of 3601- {1- [3- (4-fluorophenyl) propyl ] piperidin-4-yl } -6-acetamidomethylindole
From 1- {1- [3- (4-fluorophenyl) propyl ] piperidin-4-yl } -6-acetamidomethylindoline (110mg) obtained in example 226, activated manganese dioxide (550mg) and chloroform (10ml) as in example 285, 113mg of the title compound was obtained as an oil. This oil was dissolved in diethyl ether and crystallized from oxalic acid (25mg) to give 90mg of the oxalate salt of the title compound as a pale red amorphous form. (yield: 67%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.84(3H，s)、1.87-1.97(2H，m)、2.01-2.09(2H，m)、2.14-2.26(2H，m)、2.60-2.67(2H，m)、2.86-2.99(4H，m)、3.41-3.50(2H，m)、4.32(2H，d，J＝5.6Hz)、4.53-4.61(1H，m)、6.43(1H，d，J＝3.2Hz)、6.94(1H，d，J＝8.0Hz)、7.08-7.15(2H，m)、7.24-7.30(2H，m)、7.39(1H，d，J＝3.2Hz)、7.40(1H，s)、7.47(1H，d，J＝8.0Hz)、8.30(1H，t，J＝5.6Hz).
Mass；FAB+ 408(M+H).
EXAMPLE 3611 Synthesis of- [1- (4-fluorophenyl) piperidin-4-yl ] -6-N-methylaminomethylindole
A mixture of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindole (400mg) obtained in example 130, methylamine hydrochloride (150mg), sodium triacetoxyborohydride (480mg), acetic acid (300mg) and dichloroethane (10ml) was stirred at room temperature for 2 days. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the organic layer was separated and washed with a saturated saline solution. After drying over anhydrous magnesium sulfate, concentration under reduced pressure was performed, and the residue was purified by Chromatorex NH silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as an oil (140 mg). This oil was dissolved in ethyl acetate and crystallized from oxalic acid (34mg) to give 140mg of the oxalate salt of the title compound as a white powder crystal. (yield: 27%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.88-2.05(4H，m)、2.16-2.25(2H，m)、2.41(3H，s)、2.53-2.60(2H，m)、2.73-2.78(2H，m)、3.04-3.12(2H，m)、3.96(2H，s)、4.20(1H，br-s)、4.24-4.34(1H，m)、6.42(1H，d，J＝3.2Hz)、7.02(1H，d，J＝8.0Hz)、7.06-7.13(2H，m)、7.25-7.30(2H，m)、7.49(1H，d，J＝3.2Hz)、7.50(1H，d，J＝8.0Hz)、7.55(1H，s).
Melting point: 195-196 deg.C
Mass；FAB+366(M+H)
EXAMPLE 3621 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (n-butyryl) aminomethylindole
A mixture of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindole (200mg), n-butyric anhydride (158mg) and pyridine (3ml) obtained in example 322-3) was stirred at room temperature for 2 days. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the organic layer was separated and washed with a saturated saline solution. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 170mg of the title compound as an oil. This oil was dissolved in ethyl acetate and crystallized from oxalic acid (36mg) to give 170mg of the oxalate salt of the title compound as a white amorphous form. (yield: 58%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)0.85(3H，t，J＝7.2Hz)、1.53(2H，q，J＝7.2Hz)、1.98-2.18(6H，m)、2.69-3.02(6H，m)、3.35-3.44(2H，m)、4.34(2H，d，J＝6.0Hz)、4.41-4.53(1H，m)、6.42(1H，d，J＝3.2Hz)、6.93(1H，d，J＝8.4Hz)、7.10-7.18(2H，m)、7.27-7.35(2H.m)、7.39(1H，s)、7.42(1H，d，J＝3.2Hz)、7.47(1H，d，J＝8.4Hz)、8.26(1H，t，J＝6.0Hz).
Mass；FAB+422(M+H).
EXAMPLE 3631 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-cyclopropaneamidomethylindole
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-cyclopropanecarboxamidomethylindoline (90mg) obtained in example 159, activated manganese dioxide (450mg) and chloroform (10ml) as in example 285, 60mg of the title compound was obtained as white powder crystals. (yield: 73%)
1H-NMR(400MHz，CDCl3)；δ(ppm)0.72-0.79(2H，m)、0.99-1.04(2H，m)、1.31-1.42(1H，m)、2.05-2.17(4H，m)、2.22-2.35(2H，m)、2.63-2.75(2H，m)、2.82-2.93(2H，m)、3.12-3.25(2H，m)、4.23-4.34(1H，m)、4.58(2H，d，J＝5.6Hz)、5.89(1H，br-s)、6.51(1H，d，J＝3.2Hz)、6.97-7.03(2H，m)、7.06(1H，d，J＝8.0Hz)、7.17-7.23(2H，m)、7.25(1H，d，J＝3.2Hz)、7.36(1H.s)，7.60(1H，d，J＝8.0Hz).
Melting point: 116 ℃ C. (117 ℃ C.)
Mass；FAB+420(M+H)
EXAMPLE 3641 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-hydroxyacetamidomethyl indole
A mixture of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindole (150mg), acetoxyacetyl chloride (64mg), pyridine (3ml) and tetrahydrofuran (5ml) obtained in example 322-3) was stirred under ice-cooling for 30 minutes. Ice water and ethyl acetate were added to the reaction mixture, and the organic layer was separated and washed with saturated brine. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and methanol (10ml) and potassium carbonate (100mg) were added to the residue, followed by stirring for 30 minutes. After an organic layer was separated by adding ice water and ethyl acetate, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (ethyl acetate/ethanol) to give 140mg of the title compound as white flaky crystals. (yield: 80%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.87-1.99(4H，m)、2.19-2.25(2H，m)、2.52-2.59(2H，m)、2.72-2.78(2H，m)、3.03-3.11(2H，m)、3.82(2H，d，J＝6.0Hz)、4.23-4.33(1H，m)、4.37(2H，d，J＝6.0Hz)、5.48(1H，t，J＝6.0Hz)、6.38(1H，d，J＝3.2Hz)、6.95(1H，d，J＝8.0Hz)、7.06-7.13(2H，m)、7.24-7.30(2H，m)、7.42(1H，d，J＝8.0Hz)、7.45(1H，d，J＝3.2Hz)、7.46(1H，s)、8.14(1H，t，J＝6.0Hz).
Melting point: 76-78 deg.C
Mass；FAB+410(M+H)
EXAMPLE 3651 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-difluoroacetamidomethylindole
To a solution of difluoroacetic acid (96mg) in dimethylformamide (5ml) was added N, N, -carbonyldiimidazole (160mg) under ice-cooling, and the mixture was stirred for 30 minutes. Then, a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindole (150mg) obtained in example 322-3) in dimethylformamide (5ml) was added thereto, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the organic layer was separated and washed with a saturated saline solution. After drying over anhydrous magnesium sulfate, the resulting residue was concentrated under reduced pressure and purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 120mg of the title compound as white powder crystals. (yield: 65%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.05-2.15(4H，m)、2.24-2.35(2H，m)、2.63-2.70(2H，m)、2.79-2.86(2H，m)、3.14-3.22(2H，m)、4.20-4.30(1H，m)、4.62(2H，d，J＝5.6Hz)、5.95(1H，t，J＝54.2Hz)、6.52(1H，d，J＝3.6Hz)、6.61(1H，br-s)、6.96-7.02(2H，m)、7.03(1H，d，J＝8.0Hz)、7.15-7.21(2H，m)、7.27(1H，d，J＝3.6Hz)、7.33(1H，s)、7.61(1H，d，J＝8.0Hz).
Melting point: 79-80 deg.C
Mass；FAB+430(M+H)
EXAMPLE 3661 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-fluoroacetamidomethyl indole
Ethyl chlorocarbonate (96. mu.l) was added to a suspension of sodium fluoroacetate (100mg) in dimethylformamide (5ml) under ice-cooling, and the mixture was stirred for 20 minutes. Then, a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindole (150mg) obtained in example 322-3) in dimethylformamide (5ml) was added thereto, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the organic layer was separated and washed with a saturated saline solution. After drying over anhydrous magnesium sulfate, the resulting residue was concentrated under reduced pressure and purified by silica gel column chromatography (hexane/ethyl acetate), whereby 100mg of the title compound was crystallized as a white powder. (yield: 57%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.08-2.16(4H，m)、2.26-2.35(2H，m)、2.64-2.71(2H，m)、2.81-2.88(2H，m)、3.16-3.24(2H，m)、4.21-4.31(1H，m)、4.63(2H，d，J＝5.6Hz)、4.85(2H，d，J＝47.6Hz)、6.52(1H，d，J＝3.2Hz)、6.60(1H，br-s)、6.96-7.02(2H，m)、7.04(1H，d，J＝8.0Hz)、7.16-7.21(2H，m)、7.27(1H，d，J＝3.2Hz)、7.34(1H，s)、7.61(1H，d，J＝8.0Hz).
Melting point: 106 ℃ and 108 DEG C
Mass；FAB+412(M+H)
EXAMPLE 3671 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (3-chloropropylamino) methylindole
A mixture of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindole (150mg), 3-chloropropionyl chloride (70mg) and pyridine (5ml) obtained in example 322-3) was stirred under ice-cooling for 2 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the organic layer was separated and washed with a saturated saline solution. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound as white powder crystals (30 mg). (yield: 16%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.04-2.15(4H，m)、2.22-2.32(2H，m)、2.62-2.69(2H，m)、2.65(2H，t，J＝6.4Hz)、2.80-2.87(2H，m)、3.13-3.22(2H，m)、3.86(2H，t，J＝6.4Hz)、4.20-4.30(1H，m)、4.59(2H，d，J＝5.6Hz)、5.99(1H，br-s)、6.51(1H，d，J＝3.2Hz)、6.97(1H，d，J＝8.0Hz)、6.98-7.04(2H，m)、7.16-7.21(2H，m)、7.24(1H，d，J＝3.2Hz)、7.35(1H，s)、7.58(1H，d，J＝8.0Hz).
Melting point: 121-
Mass；FAB+442(M+H)
EXAMPLE 3681 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-imidazolecarbonylaminomethylindole
To a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindole (150mg) obtained in example 322-3) in dimethylformamide (5ml) was added N, N' -carbonyldiimidazole (160mg) under ice-cooling, and the mixture was stirred for 30 minutes. Ice water and ethyl acetate were added to the reaction mixture, and the organic layer was separated and washed with saturated brine. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/ethanol) to give the title compound (140 mg) as an oil. This oil was dissolved in ethyl acetate and crystallized from oxalic acid (28mg) to give 150mg of the oxalate salt of the title compound as a white powder crystal. (yield: 65%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.99-2.23(4H，m)、2.69-2.81(2H，m)、2.84-3.02(4H，m)、3.33-3.43(2H，m)、4.47-4.57(1H，m)、4.54(2H，d，J＝5.6Hz)、6.44(1H，d，J＝2.8Hz)、7.01(1H，s)、7.03(1H，d，J＝8.0Hz)、7.10-7.18(2H，m)、7.27-7.35(2H，m)、7.45(1H，d，J＝2.8Hz)、7.51(1H，d，J＝8.0Hz)、7.53(1H，s)、7.71(1H，s)、8.27(1H，s)、9.08(1H，t，J＝5.6Hz).
Melting point: 157 ℃ of 156-
Mass；FAB+446(M+H)
EXAMPLE 3691 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (3-hydroxypropionylamino) methylindole
A mixture of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindole (150mg), β -propiolactone (30mg) and toluene (10ml) obtained in example 322-3) was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/ethanol) to give 150mg of the title compound as an oil. This oil was dissolved in ethyl acetate and crystallized from oxalic acid (32mg) to give 100mg of the oxalate salt of the title compound as a pale yellow amorphous form. (yield: 45%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)2.03-2.25(4H，m)、2.29(2H，t，J＝6.8Hz)、2.91-2.98(4H，m)、3.05-3.16(2H，m)、3.44-3.54(2H，m)、3.64(2H，t，J＝6.8Hz)、4.35(2H，d，J＝6.0Hz)、4.50-4.60(1H，m)、6.43(1H，d，J＝3.2Hz)、6.94(1H，d，J＝8.4Hz)、7.12-7.20(2H，m)、7.29-7.36(2H，m)、7.41(1H，d，J＝3.2Hz)、7.43(1H，s)、7.46(1H，d，J＝8.4Hz)、8.28(1H，t，J＝6.0Hz).
Mass；FAB+ 424(M+H).
Example 3701 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -3-formyl-6-acetamidomethylindole
To a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindole (0.22g) obtained in example 285 in N, N' -dimethylformamide (5ml) was added phosphorus oxychloride (0.1g) at 0 ℃ and, after stirring for 10 minutes, the mixture was reacted at 70 ℃ for 2 hours. To the reaction mixture was added a 2N aqueous solution (20ml) of sodium hydroxide, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was filtered through silica gel (15g), which was washed with ethyl acetate/methanol, and the filtrate was concentrated to give the title compound (0.16g) as a pale yellow amorphous form. (yield: 67.9%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)2.04(3H，s)、2.14-2.37(4H，m)、2.37-2.49(2H，m)、2.73-2.82(2H，m)、2.87-2.95(2H，m)、3.25-3.35(2H，m)、4.28-4.38(1H，m)、4.55(2H，d，J＝5.6Hz)、6.00-6.12(1H，m)、6.97-7.04(2H，m)、7.17-7.24(3H，m)、7.44(1H，br-s)、7.84(1H，s)、8.25(1H，d，J＝8.0Hz)、9.97(1H，s).
ESI-Mass；422(MH+).
EXAMPLE 3711 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -3-hydroxyimino-6-acetamidomethylindole
A mixture of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -3-formyl-6-acetylaminomethylindole (0.09g) obtained in example 370, hydroxylamine hydrochloride (0.02g) and anhydrous sodium acetate (0.03g) in methanol (10ml) was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was partitioned between ethyl acetate (20ml) and a 1N aqueous solution (10ml) of sodium hydroxide. The ethyl acetate layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether/hexane, filtered, washed with hexane and dried to give the title compound (0.08g) as a pale yellow powder. (yield: 88.5%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.87(3H，s)、1.91-2.03(4H，m)、2.20-2.30(2H，m)、2.56-2.62(2H，m)、2.74-2.80(2H，m)、3.06-3.3(2H，m)、4.33-4.38(1H，m)、7.03-7.15(3H，m)、7.27-7.33(2H，m)、7.45-7.50(1H，m)、7.77(1H，d，J＝8.0Hz)、7.83(0.5H，d，J＝8.0Hz)、7.91(0.5H，d，J＝8.0Hz)、8.20(0.5H，s)、8.26(0.5H，s)、8.30-8.35(1H，m)、10.54(0.5H，s)、11.27(0.5H，s).
EXAMPLE 3721 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -3-hydroxymethyl-6-acetamidomethylindole
To a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -3-formyl-6-acetamidomethylindole (0.04g) obtained in example 370 in methanol (10ml) was added sodium borohydride (0.01g), and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate (40ml) and water (10 ml). The ethyl acetate layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was treated with diethyl ether/hexane to give the title compound (0.03g) as a pale yellow amorphous form. (yield: 74.6%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.86(3H，s)、1.87-2.00(4H，m)、2.18-2.27(2H，m)、2.54-2.61(2H，m)、3.05-3.12(2H，m)、4.22-4.32(1H，m)、4.33(2H，d，J＝5.6Hz)、4.60(2H，d，J＝5.6Hz)、4.76(1H，t，J＝5.6Hz)、6.94(1H，dd，J＝8.0，1.2Hz)、7.08-7.15(2H，m)、7.25-7.33(2H，m)、7.36(1H，br-d)、8.26-8.32(1H，m).
EXAMPLE 3731 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-chloroacetamidomethylindole
A mixture of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindole (150mg), chloroacetyl chloride (60mg), triethylamine (50mg) and acetonitrile (5ml) obtained in example 322-3) was stirred under ice-cooling for 2 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the organic layer was separated and washed with a saturated saline solution. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 90mg of the title compound as white needle crystals. (yield: 49%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.06-2.13(4H，m)、2.24-2.33(2H，m)、2.63-2.69(2H，m)、2.80-2.86(2H，m)、3.14-3.22(2H，m)、4.09(2H，s)、4.20-4.30(1H，m)、4.59(2H，d，J＝5.6Hz)、6.52(1H，d，J＝3.2Hz)、6.89(1H，br-s)、6.90-7.02(2H，m)、7.04(1H，d，J＝8.0Hz)、7.16-7.21(2H，m)、7.26(1H，d，J＝3.2Hz)、7.33(1H，s)、7.61(1H，d，J＝8.0Hz).
Melting point: 143 ℃ C. -
Mass；FAB+428(M+H)
EXAMPLE 3741 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoacetamidomethylindole
And example 373, from 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindole (370mg) obtained in example 322-3), bromoacetyl chloride (220mg), triethylamine (140mg) and acetonitrile (10ml), 320mg of the title compound was obtained as an oil. (yield: 65%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.05-2.13(4H，m)、2.25-2.33(2H，m)、2.62-2.70(2H，m)、2.79-2.85(2H，m)、3.15-3.24(2H，m)、3.92(2H，s)、4.19-4.29(1H，m)、4.58(2H，d，J＝5.6Hz)、6.53(1H，d，J＝3.2Hz)、6.90(1H，br-s)、6.92-7.04(3H，m)、7.15-7.21(2H，m)、7.25(1H，d，J＝3.2Hz)、7.34(1H，s)、7.60(1H，d，J＝8.0Hz).
EXAMPLE 3751 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (N, N-dimethylaminoacetamido) methylindole
A mixture of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoacetamidomethylindole (170mg), 2M dimethylamine/tetrahydrofuran solution (2.2ml) and dimethylformamide (5ml) obtained in example 374 was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated and washed with saturated brine. After drying over anhydrous magnesium sulfate, concentration under reduced pressure was performed, and the residue was purified by Chromatorex NH silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound 35mg as an oil.
This oil was dissolved in ethyl acetate and crystallized from oxalic acid (7mg) to give 18mg of the oxalate salt of the title compound as a white powder crystal. (yield: 94%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.96-2.16(4H，m)、2.39-2.44(2H，m)、2.60(6H，s)、2.82-2.94(4H，m)、3.30-3.71(4H，m)、4.41(2H，d，J＝5.6Hz)、4.42-4.52(1H，m)、6.43(1H，d，J＝2.8Hz)、6.96(1H，d，J＝8.0Hz)、7.10-7.19(2H，m)、7.27-7.34(2H，m)、7.45(1H，s)、7.46(1H，d，J＝2.8Hz)、7.49(1H，d，J＝8.0Hz)、8.53(1H，t，J＝5.6Hz).
Melting point: 112 ℃ and 113 DEG C
Mass；FAB+437(M+H)
EXAMPLE 3761 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [ (piperidin-1-yl) acetamido ] methylindole
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoacetamidomethylindole (150mg), piperidine (187mg) and dimethylformamide (5ml) obtained in example 374, 20mg of the oxalate salt of the title compound was obtained as crystals as a white powder, as in example 375. (yield: 11%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.40-1.50(2H，m)、1.60-1.71(4H，m)、2.00-2.08(2H，m)、2.12-2.26(2H，m)、2.37-2.52(2H，m)、2.70-3.10(8H，m)、3.39-3.49(2H，m)、3.52-3.63(2H，m)、4.42(2H，d，J＝6.0Hz)、4.45-4.58(1H，m)、6.43(1H，d，J＝3.2Hz)、6.96(1H，d，J＝8.0Hz)、7.10-7.19(2H，m)、7.26-7.34(2H，m)、7.44(1H，d，J＝3.2Hz)、7.47(1H，s)、7.49(1H，d，J＝8.0Hz)、8.76(1H，t，J＝6.0Hz).
Melting point: 113 ℃ and 114 DEG C
Mass；FAB+477(M+H)
EXAMPLE 3771 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (3-bromopropionylamino) methylindole
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindole (370mg) obtained in example 322-3), 3-bromopropionyl chloride (240mg), triethylamine (140mg) and acetonitrile (10ml) as in example 373, the title compound was obtained as an oil at 290 mg. (yield: 57%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.02-2.10(2H，m)、2.14-2.26(2H，m)、2.29-2.40(2H，m)、2.68-2.76(2H，m)、2.80(2H，t，J＝6.4Hz)、2.85-2.92(2H，m)、3.18-3.26(2H，m)、3.70(2H，t，J＝6.4Hz)、4.20-4.30(1H，m)、4.62(2H，d，J＝6.0Hz)、6.15(1H，br-s)、6.50(1H，d，J＝3.2Hz)、6.96-7.04(3H，m)、7.16-7.24(2H，m)、7.25(1H，d，J＝3.2Hz)、7.37(1H，s)、7.58(1H，d，J＝8.0Hz).
Example 3781 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (3-N, N-dimethylaminopropionyl) aminomethylindole
A mixture of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (3-bromopropionylamino) methylindole (150mg), 2M dimethylamine/tetrahydrofuran solution (5.0ml) and toluene (5ml) obtained in example 377 was heated at 80 to 90 ℃ for a whole day and night. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated and washed with saturated brine. After drying over anhydrous magnesium sulfate, concentration was performed under reduced pressure, and the residue was purified by chromatoreexnh silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as an oil (140 mg). This oil was dissolved in ethyl acetate and crystallized from oxalic acid (28mg) to give 110mg of the oxalate salt of the title compound as a white powder crystal. (yield: 66%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.90-1.99(2H，m)、2.00-2.12(2H，m)、2.38-2.45(2H，m)、2.55(2H，t，J＝7.2Hz)、2.61(6H，s)、2.70-2.76(2H，m)、2.78-2.85(2H，m)、3.11(2H，t，J＝7.2Hz)、3.16-3.24(2H，m)、4.37(2H，d，J＝5.6Hz)、4.38-4.42(1H，m)、6.40(1H，d，J＝2.8Hz)、6.94(1H，d，J＝8.0Hz)、7.08-7.14(2H，m)、7.25-7.32(2H，m)、7.42(1H，s)、7.45(1H，d，J＝2.8Hz)、7.47(1H，d，J＝8.0Hz)、8.58(1H，t，J＝5.6Hz).
Melting point: 104-
Mass；FAB+451(M+H)
EXAMPLE 3791 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- [3- (piperidin-1-yl) propionylamino ] methylindole
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (3-bromopropionylamino) methylindole (140mg), piperidine (85mg) and toluene (5ml) obtained in example 377, 80mg of the oxalate salt of the title compound was obtained as white powder crystals as in example 378. (yield: 44%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.39-1.49(2H，m)、1.57-1.66(4H，m)、1.90-2.11(4H，m)、2.35-2.60(4H，m)、2.71-3.01(8H，m)、3.06-3.14(2H，m)、3.18-3.25(2H，m)、4.36(2H，d，J＝4.8Hz)、4.37-4.45(1H，m)、6.41(1H，d，J＝3.2Hz)、6.94(1H，d，J＝8.0Hz)、7.06-7.14(2H，m)、7.23-7.31(2H，m)、7.42(1H，s)、7.45(1H，d，J＝3.2Hz)、7.47(1H，d，J＝8.0Hz)、8.56(1H，t，J＝4.8Hz).
Melting point: 108 temperature 109 deg.C
Mass；FAB+491(M+H)
Example 3801 Synthesis of- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-propionylaminomethylindole
From 1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindole (150mg), propionyl chloride (43mg), triethylamine (47mg) and acetonitrile (5ml) obtained in example 348 as in example 373, the title compound was obtained as white powder crystals (105 mg). (yield: 60%)
1H-NMR(400MHz，CDCl3)；δ(ppm)1.19(3H，t，J＝7.6Hz)、2.00-2.16(4H，m)、2.25(2H，q，J＝7.6Hz)、2.26-2.50(2H，m)、2.61-2.82(2H，m)、2.85-3.05(2H，m)、3.20-3.34(2H，m)、4.19-4.33(1H，m)、4.56(2H，d，J＝5.6Hz)、5.75(1H，br-s)、6.51(1H，d，J＝3.2Hz)、7.06-7.13(3H，m)、7.15-7.29(3H，m)、7.36(1H，s)、7.59(1H，d，J＝8.4Hz).
Melting point: 118-119 deg.C
Mass；FAB+ 408(M+H)
Example 3811 Synthesis of- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-fluoroacetamidomethylindole
From 1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindole (150mg), sodium fluoroacetate (100mg), ethyl chlorocarbonate (96. mu.l) and dimethylformamide (10ml) obtained in example 348 as in example 373, 100mg of the oxalate salt of the title compound was obtained as crystals as a white powder. (yield: 46%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)2.05-2.12(2H，m)、2.15-2.28(2H，m)、2.93-3.05(4H，m)、3.09-3.17(2H，m)、3.49-3.58(2H，m)、4.41(2H，d，J＝6.0Hz)、4.52-4.63(1H，m)、4.83(2H，d，J＝47.2Hz)、6.44(1H，d，J＝3.2Hz)、6.98(1H，d，J＝8.4Hz)、7.15-7.22(2H，m)、7.27-7.35(1H，m)、7.36-7.46(3H，m)、7.48(1H，d，J＝8.4Hz)、8.68(1H，t，J＝6.0Hz).
Melting point: 168 deg.C and 169 deg.C
Mass；FAB+412(M+H)
Example 3821 Synthesis of- [1- (2-fluorophenethyl) piperidin-4-yl ] -6- (3-hydroxypropionylamino) methylindole
From 1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindole (110mg), β -propiolactone (23mg) and toluene (10ml) obtained in example 348 as in example 373, the title compound was obtained as crystals as a white powder (90 mg). (yield: 69%)
1H-NMR(400MHz，CDCl3)；δ(ppm)1.99-2.06(4H，m)、2.28-2.39(2H，m)、2.51(2H，t，J＝5.2Hz)、2.69-2.78(2H，m)、2.91-2.99(2H，m)、3.23-3.30(2H.m)、3.95(2H，t，J＝5.2Hz)、4.14-4.24(1H，m)、4.63(2H，d，J＝6.0Hz)、6.28(1H，br-s)、6.45(1H.d，J＝3.2Hz)、6.98(1H，d，J＝8.8Hz)、7.02-7.12(2H，m)、7.14(1H，d，J＝3.2Hz)、7.19-7.27(2H，m)、7.57(1H，d，J＝8.8Hz)、7.58(1H，s).
Melting point: 58-59 deg.C
Mass；FAB+424(M+H)
Example 3831 Synthesis of- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-hydroxyacetamidomethylindole
From 1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindole (150mg) obtained in example 348 and acetoxyacetyl chloride (64mg) as in example 373, 110mg of the title compound was obtained as white powder crystals. (yield: 62%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.87-2.03(4H，m)、2.19-2.26(2H，m)、2.54-2.60(2H，m)、2.76-2.83(2H，m)、3.04-3.11(2H，m)、3.82(2H，d，J＝6.0Hz)、4.23-4.33(1H，m)、4.37(2H，d，J＝6.0Hz)、5.47(1H，t，J＝6.0Hz)、6.38(1H，d，J＝3.2Hz)、6.95(1H，d，J＝8.0Hz)、7.10-7.17(2H，m)、7.21-7.28(1H，m)、7.32-7.38(1H，m)、7.42(1H，d，J＝8.0Hz)、7.44(1H，d，J＝3.2Hz)、7.45(1H，s)、8.14(1H，t，J＝6.0Hz).
Melting point: 151 ℃ and 152 DEG C
Mass；FAB+ 410(M+H)
EXAMPLE 3841 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methoxycarbonylaminomethyl indole
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindole (150mg), methylcarbonate (47mg), triethylamine (50mg) and acetonitrile (5ml) obtained in example 322-3) was obtained the title compound as white needle crystals (120 mg) as in example 373. (yield: 68%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.02-2.12(4H，m)、2.20-2.31(2H，m)、2.60-2.68(2H，m)、2.78-2.85(2H，m)、3.12-3.20(2H，m)、3.70(3H，s)、4.19-4.29(1H，m)、4.48(2H，d，J＝6.0Hz)、5.13(1H，br-s)、6.49(1H，d，J＝3.2Hz)、6.95-7.01(2H，m)、7.03(1H，d，J＝8.0Hz)、7.15-7.20(2H，m)、7.22(1H，d，J＝3.2Hz)、7.31(1H，s)、7.58(1H，d，J＝8.0Hz).
Melting point: 117 ℃ C. and 118 ℃ C
Mass；FAB+ 410(M+H)
EXAMPLE 3851 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-N, N-dimethylaminocarbonylaminomethyl indole
From 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindole (150mg), dimethylcarbamoyl chloride (54mg), triethylamine (50mg) and acetonitrile (5ml) obtained in example 322-3) as in example 373, the title compound was obtained as white powder crystals (130 mg). (yield: 72%)
1H-NMR(400MHz，CDCl3)；δ(ppm)2.04-2.11(4H，m)、2.23-2.30(2H，m)、2.62-2.68(2H，m)、2.79-2.85(2H，m)、2.90(6H，s)、3.13-3.20(2H，m)，4.20-4.30(1H，m)、4.53(2H，d，J＝5.2Hz)、4.70(1H，br-s)、6.49(1H，d，J＝3.2Hz)、6.95-7.02(2H，m)、7.07(1H，d，J＝8.0Hz)、7.16-7.21(2H，m)、7.23(1H，d，J＝3.2Hz)、7.35(1H，s)、7.58(1H，d，J＝8.0Hz).
Melting point: 115 ℃ and 116 DEG C
Mass；FAB+ 423(M+H)
Example 3861 Synthesis of- {1- [2- (3-pyridyl) ethyl ] piperidin-4-yl } -6-acetamidomethylindole
Synthesis of (386-1)1- (piperidin-4-yl) -6-acetamidomethylindole
1- (piperidin-4-yl) -6-acetamidomethylindoline (0.6g) obtained in production example 52 and activated manganese dioxide (3.0g) were refluxed with heating in chloroform (30ml) for 8 hours. The reaction mixture was filtered through celite, the residue was washed with chloroform, the filtrate was concentrated under reduced pressure, and the residue was purified by NH-silica gel chromatography (ethyl acetate/methanol) to give the title compound (0.45g) as a brown amorphous form. (yield: 75.5%)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.75-1.90(4H，m)、1.86(3H，s)、2.64-2.74(2H，m)、3.04-3.10(2H，m)、4.30-4.39(1H，m)、4.33(2H，d，J＝6.0Hz)、6.41(1H，d，J＝3.0Hz)、6.93(1H，dd，J＝8.0，1.2Hz)、7.41(1H，br-s)、7.42(1H，d，J＝3.0Hz)、7.47(1H，d，J＝8.0Hz)、8.24-8.31(1H，m).
(386-2)1- {1- [2- (3-pyridinyl) ethyl ] piperidin-4-yl } -6-acetamidomethylindole
To a solution of 1- (piperidin-4-yl) -6-acetamidomethylindole (0.10g) obtained in example 386-1) and 3- (2-bromoethyl) pyridine (0.07g) obtained in production example 26-2 in N, N-dimethylformamide (5ml) was added potassium carbonate (0.5g), and the mixture was stirred at 70 (. degree.C.) for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (40ml) and water (15ml), which was then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform/methanol) to give the title compound (0.06g) as a pale yellow wax. (yield: 75.5%)
This was oxalate-treated according to the usual method to give the oxalate salt of the title compound as a pale yellow amorphous form (0.06 g).
Oxalate salt:
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.87(3H，s)、2.00-2.09(2H，m)、2.14-2.27(2H，m)、2.75-2.86(2H，m)、2.93-3.09(4H，m)、3.38-3.46(2H，m)、4.35(2H，d，J＝6.0Hz)、4.47-4.60(1H，m)、6.44(1H，d，J＝3.2Hz)、6.96(1H，d，J＝8.0Hz)、7.36(1H，dd，J＝8.0，4.4Hz)、7.43-7.47(2H，m)、7.49(1H，d，J＝8.0Hz)、7.71-7.76(1H，m)、8.30-8.37(1H.m)、8.46(1H，dd，J＝8.0，1.6Hz)、8.53(1H，d，J＝1.6Hz).
ESI-Mass；377(MH+).
EXAMPLE 3873 Synthesis of cyano-1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindole
To a chloroform (10ml) solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -3-hydroxyimino-6-acetamidomethylindole (0.07g) obtained in example 371 was added 1, 1' -carbonyldiimidazole (0.04g), and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate (40ml) and water (10 ml). The ethyl acetate layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (ethyl acetate) to give the title compound (0.04g) as a white powder. (yield: 57.6%)
Melting point: 130 ℃ and 131 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.88(3H，s)、2.09-2.29(4H，m)、2.82-3.14(6H，m)、3.42-3.52(2H，m)、4.39(2H，d，J＝5.2Hz)、4.64-4.74(1H，m)、7.14-7.24(3H，m)、7.32-7.38(2H，m)、7.62(1H，d，J＝8.4Hz)、7.68(1H，s)、8.43(1H，s).
Example 3881 Synthesis of- {4- [ (1-hydroxyethyl) phenethyl ] piperidin-4-yl } -6-acetamidomethylindole
To a solution of 1- (piperidin-4-yl) -6-acetamidomethylindole (0.10g) obtained in example 386-1) and 4- (1-hydroxyethyl) phenethylbromide (0.07g) obtained in production example 19 in N, N-dimethylformamide (5ml) was added potassium carbonate (0.5g), and the mixture was stirred at 70 ℃ for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between chloroform (40ml) and water (15 ml). The chloroform layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.07g) as a pale yellow wax. (yield: 45.3%)
This was oxalate-treated according to the usual method to give the oxalate salt of the title compound as a pale yellow powder (0.06 g).
Oxalate salt:
melting point: 105 ℃ C. and 107 ℃ C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.31(2H，d，J＝6.4Hz)、1.87(3H，s)、2.09-2.17(2H，m)、2.30-2.43(2H，m)、2.99-3.05(2H，m)、3.16-3.33(4H，m)、3.62-3.70(2H，m)、4.35(2H，d，J＝6.0Hz)、4.64-4.74(2H，m)、6.47(1H，d，J＝3.2Hz)、6.97(1H，d，J＝8.0Hz)、7.25(2H，d，J＝8.0Hz)、7.32(2H，d，J＝8.0Hz)、7.43(1H，d，J＝3.2Hz)、7.48(1H，br-s)、7.50(1H，d，J＝8.0Hz)、8.33-8.38(1H，m).
ESI-Mass；420(MH+).
Example 3891 Synthesis of- [1- (4-bromophenylethyl) piperidin-4-yl ] -6-acetamidomethylindole
To a solution of 1- (piperidin-4-yl) -6-acetamidomethylindole (0.20g) obtained in example 386-1) and 4-bromophenethyl bromide (0.16g) obtained in production example 4 in N, N-dimethylformamide (15ml) was added potassium carbonate (1.0g), and the mixture was stirred at 70 ℃ for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between chloroform (40ml) and water (15 ml). The chloroform layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) and recrystallized from ethyl acetate/hexane to give 0.25g of the title compound as a pale yellow powder. (yield: 74.6%)
Melting point: 140 ℃ 141 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.86(3H，s)、1.88-2.03(4H，m)、2.19-2.28(2H，m)、2.56-2.62(2H，m)、2.73-2.79(2H，m)、3.05-3.12(2H，m)、4.26-4.35(1H，m)、4.34(2H，d，J＝6.0Hz)、6.41(1H，d，J＝3.2Hz)、6.97(1H，d，J＝8.0Hz)、7.25(2H，d，J＝8.0Hz)、7.32(2H，d，J＝8.0Hz)、4.64-6.93(1H，dd，J＝8.0，1.2Hz)、7.23(2H，d，J＝8.0Hz)、7.40(1H，br-s)、7.45-7.50(4H，m)、8.25-8.31(1H，m).
ESI-Mass；455(MH+).
Example 3901 Synthesis of- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-formylindole
1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-hydroxymethylindoline (0.49g) obtained in example 342-1 was dissolved in chloroform (40 ml). Manganese dioxide (1.20g) was added thereto, and the mixture was stirred at 50 ℃ overnight. Manganese dioxide (0.60g) was added thereto, and the mixture was stirred for 7 hours. Manganese dioxide (0.60g) was added again, and the mixture was stirred overnight. Manganese dioxide (0.60g) was added thereto and stirred for 10 hours. Manganese dioxide (0.60g) was added again, and the mixture was stirred overnight. Manganese dioxide was filtered off, and the solvent was evaporated under reduced pressure to give the title compound (0.40 g) as a pale yellow powder.
1H-NMR(400MHz，CDCl3)；δ(ppm)2.07-2.13(4H，m)、2.27-2.34(2H，m)、2.67-2.71(2H，m)、2.87-2.91(2H，m)、3.19(2H，br-d)、4.32-4.40(1H，m)、6.59(1H，d，J＝3.2Hz)、7.00-7.03(1H，m)、7.05-7.10(1H，m)、7.17-7.25(2H，m)、7.46(1H，d，J＝3.2Hz)、7.61(1H，dd，J＝0.8，8.0Hz)、6.71(1H，d，J＝8.0Hz)、7.97(1H，s)、10.06(1H，s).
ESI-Mass；351(MH+).
EXAMPLE 3911 Synthesis of- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-hydroxymethylindole
To 1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-formylindole (0.21g) obtained in example 348-4) were added methanol (10ml) and tetrahydrofuran (5ml), and the mixture was dissolved and stirred under ice cooling. To this was added sodium borohydride little by little. The disappearance of the starting material was confirmed by thin layer chromatography, and the solvent was evaporated under reduced pressure. To the residue was added a 2N aqueous solution of sodium hydroxide, followed by extraction with ethyl acetate. The extract was washed with water, washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from chloroform/n-hexane to give 0.17g of the title compound as a colorless powder.
Melting point: 116.8-117.5 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)2.07-2.16(4H，m)、2.26-2.33(2H，m)、2.66-2.70(2H，m)、2.87-2.91(2H，m)、3.19(2H，br-d)、4.23-4.31(1H，m)、4.82(2H，s)、6.51(1H，d，J＝3.6Hz)、7.01-7.11(3H，m)、7.17-7.26(3H，m)、7.43(1H，s)、7.61(1H，d，J＝8.0Hz).
ESI-Mass；353(MH+).
Example 3921 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (1-hydroxyethyl) indole oxalate
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-formylindoline (0.15g) obtained in example 130 was dissolved in tetrahydrofuran (5ml), and the solution was stirred under ice-cooling. To the solution was added 1.0M methylmagnesium bromide/diethyl ether solution (0.5ml), and the mixture was stirred for 30 minutes, saturated aqueous ammonium chloride solution, water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give the titled compound as a pale brown viscous oil in an amount of 0.13g free form, which was prepared into an oxalate salt according to a conventional method.
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.38(3H，d，J＝6.4Hz)、2.10(2H，br-d)、2.24-2.33(2H，m)、2.98-3.02(2H，m)、3.06(2H，br-t)、3.16-3.20(2H，m)、3.56(2H，br-d)、4.63-4.70(1H，m)、6.44(1H，d，J＝3.2Hz)、7.03(1H，d，J＝8.4Hz)、7.18(2H，br-t)、7.34-7.37(2H，m)、7.41(1H，d，J＝3.2Hz)、7.47(1H，d，J＝8.4Hz)、7.53(1H，s).
ESI-Mass；367(MH+).
Example 3931 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-ureidomethyl indole
1, 1-carbonyldiimidazole (0.16g) and imidazole (0.13g) were added to tetrahydrofuran (5ml), and the mixture was stirred under nitrogen atmosphere and ice cooling. To this was added a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindoline (0.33g) obtained in example 132 in tetrahydrofuran (3 ml). After stirring for another 15 minutes, a saturated solution (2ml) of ammonia in ethanol was added thereto, and the mixture was stirred for 10 minutes under ice cooling and then at room temperature overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound as colorless crystals. It was recrystallized from chloroform/ethyl acetate/n-hexane to obtain 0.07g of the title compound as colorless needle crystals.
Melting point: 171.9-172.8 deg.C
1H-NMR(400MHz，CDCl3)；δ(ppm)2.02-2.10(4H，m)、2.20-2.26(2H，m)、2.60-2.64(2H，m)、2.78-2.82(2H，m)、3.12(2H，br-d)、4.16-4.24(1H，m)、4.37(2H，d，J＝5.4Hz)、4.58(2H，s)、5.34(1H，t，J＝5.4Hz)、6.47(1H，d，J＝3.2Hz)、6.96-7.00(3H，m)、7.15-7.18(2H，m)、7.21(1H，d，J＝3.2Hz)、7.29(1H，s)、7.54(1H，d，J＝8.0Hz).
ESI-Mass；395(MH+).
Example 3941 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (3-methylureido) methylindole
1- [1- (4-Fluorophenethyl) piperidin-4-yl ] -6-aminomethylindoline (0.17g) obtained in example 132 was dissolved in tetrahydrofuran (5ml), and the mixture was stirred under a nitrogen atmosphere. Methyl isothiocyanate (40.4ml) was added thereto, and stirred for 50 minutes. Methyl isothiocyanate (40.4ml) was added thereto, and the mixture was stirred for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/n-hexane system) to give 0.14g of the title compound as a peach-colored amorphous form.
1H-NMR(400MHz，CDCl3)；δ(ppm)2.07-2.12(4H，m)、2.26-2.33(2H，m)、2.64-2.68(2H，m)、2.81-2.85(2H，m)、2.96(3H，br-d)、3.17(2H，br-d)、4.22-4.30(1H，m)、4.71(2H，br-s)、5.87(1H，br-s)、6.09(1H，br-s)、6.52(1H，d，J＝3.2Hz)、6.99(2H，br-t)、7.05(1H，d，J＝8.0Hz)、7.17-7.20(2H，m)、7.27(1H，d，J＝3.2Hz)、7.37(1H，s)、7.61(1H，d，J＝8.0Hz).
ESI-Mass；425(MH+).
Example 3953 Synthesis of 3-dimethyl-1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidoindoline
(395-1)3, 3-dimethyl-1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindoline
To a solution of 3, 3-dimethyl-1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-bromoindoline (1.50g) obtained in example 293 in tetrahydrofuran (50ml) was added dropwise a 1.6M n-butyllithium/hexane solution (3ml) at-78 ℃. After 10 minutes, dimethylformamide (0.3ml) was added thereto, and after warming to room temperature, a saturated aqueous ammonium chloride solution (20ml) and ethyl acetate (100ml) were added to separate an organic layer. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate) to give 3, 3-dimethyl-1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-formylindoline (0.68g), which was suspended in a solution of hydroxylamine hydrochloride (0.15g) and anhydrous sodium acetate (0.18g) in ethanol (20ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, which was diluted with ethyl acetate (50ml), 2N aqueous sodium hydroxide (10ml) and water (10ml), and the organic layer was separated. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was evaporated. The resulting tetrahydrofuran (5ml) solution of 3, 3-dimethyl-1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-hydroxyiminomethyl indoline (0.55g) was added dropwise to a tetrahydrofuran (50ml) suspension of lithium aluminum hydride (0.07g) under ice cooling, and then refluxed for 3 hours. While the reaction mixture was chilled in an ice water bath, water (0.07ml), a 5N aqueous solution of sodium hydroxide (0.21ml) and water (0.07ml) were carefully added dropwise to the reaction mixture in this order, and the mixture was stirred vigorously. The precipitated precipitate was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/methanol) to give 0.23g of the title compound as a brown amorphous form. (Total yield: 17.4%)
1H-NMR(400MHz，CDCl3)；δ(ppm)1.24(6H，s)、1.78-2.10(4H，m)、2.38-2.51(2H，m)、2.72-2.83(2H，m)、2.89-2.98(2H，m)、3.17(2H，s)、3.20-3.35(2H，m)、3.42-3.55(1H，m)、6.61(1H，s)、6.88(1H，d，J＝8.0Hz)、6.94-7.01(3H，m)、7.14-7.20(2H，m).
(395-2)3, 3-dimethyl-1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-acetamidomethylindoline
Acetyl chloride (0.05ml) was added dropwise to a tetrahydrofuran (10ml) solution of 3, 3-dimethyl-1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindoline (0.22g) and triethylamine (0.5ml) obtained in the above example under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added a 1N aqueous solution (5ml) of sodium hydroxide and water (10ml), and the mixture was extracted with ethyl acetate, washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform/methanol) and crystallized from ethyl acetate/hexane to give 0.18g of the title compound as an off-white powder. (yield: 73.7%)
Melting point: 131 ℃ and 133 DEG C
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.21(6H，s)、1.83(3H，s)、1.80-2.06(4H，m)、2.98-3.20(4H，m)、3.07(2H，s)、3.21-3.42(2H，m)、3.58-3.68(1H，m)、4.14(2H，d.J＝6Hz)、6.41(1H，s)、6.50(1H，br-d)、6.94(1H，br-d)、7.14-7.22(2H，m)、7.28-7.38(2H，m)、8.17-8.21(1H，m).
ESI-Mass；428(MH+).
Example Synthesis of 3962, 2-dimethyl-1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methoxyindoline
(396-1) N- (1-acetylpiperidin-4-yl) -3-methoxyaniline
To a mixture of m-anisidine (4.40g), 1-acetylpiperidin-4-one (5.0g) and acetic acid (8ml) in dichloroethane (80ml) was added sodium triacetoxyborohydride (12.0g) under ice cooling. The reaction was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (200ml), and 5N aqueous sodium hydroxide (35ml) was added thereto. The organic layer was separated, washed with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane system) to give 7.80g of the title compound as a brown oil. (yield: 87.9%)
1H-NMR(400MHz，CDCl3)；δ(ppm)1.30-1.45(2H，m)、2.06-2.18(2H，m)、2.11(3H，s)、2.76-2.85(1H，m)、3.13-3.22(1H，m)、3.43-3.51(1H，m)、3.78(3H，s)、3.76-3.93(1H，m)、4.46-4.53(1H，m)、6.24(1H，br-s)、6.28-6.36(2H，m)、7.11(1H，t，J＝8.0Hz).
(396-2) N- (1-acetylpiperidin-4-yl) -N- (2-methyl-2-propen-1-yl) -3-methoxyaniline
A mixture of N- (1-acetylpiperidin-4-yl) -3-methoxyaniline (2.0g), 3-chloro-2-methylpropene (10ml) and potassium carbonate (5.0g) in dimethylformamide (50ml) was reacted at 80 ℃ for 6 hours. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and saturated brine, and was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1.55g of the title compound as a yellow oil. (yield: 63.6%)
1H-NMR(400MHz，CDCl3)；δ(ppm)1.46-1.60(2H，m)、1.73(3H，s)、1.86-1.98(2H，m)、2.11(3H，s)、2.58(1H，dt，J＝8.8，2.4Hz)、3.14(1H，dt，J＝8.8，2.4Hz)、3.59(2H，s)、3.77(3H，s)、3.80-3.94(2H，m)、4.73-4.81(1H，s)、4.87(2H，d，J＝9.2Hz)、6.22-6.37(3H，m)、7.12(1H，t，J＝8.0Hz).
(396-3)2, 2-dimethyl-1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-methoxyindoline
N- (1-acetylpiperidin-4-yl) -N- (2-methyl-2-propen-1-yl) -3-methoxyaniline (1.50g) was heated under reflux in xylene (30ml) in the presence of zinc chloride (2.0g) under nitrogen for 4 hours. The reaction mixture was cooled, and 5N aqueous sodium hydroxide (20ml) and ethyl acetate (100ml) were added thereto and the mixture was stirred for 30 minutes. The ethyl acetate layer was separated, washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was dissolved in ethanol (30ml), and a 5N aqueous solution (10ml) of sodium hydroxide was added to the solution, followed by refluxing under heating for 2.5 hours. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 0.91g of a yellow oily mixture containing 2, 2-dimethyl-1- (piperidin-4-yl) -6-methoxyindoline.
This mixture was reacted with 4-fluorophenethyl bromide (0.8g) in N, N-dimethylformamide (20ml) in the presence of potassium carbonate (1.5g) at 70 ℃ for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (ODS column, acetonitrile/water/70% perchloric acid). The solvent was concentrated, made alkaline, extracted with ethyl acetate, washed with water, dried and concentrated to obtain 0.31g of the title compound as a pale yellow oil.
This was made into oxalate according to a conventional method to obtain light green cyan powder.
Oxalate salt:
melting point: 228 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.22(6H，s)、1.58-1.69(2H，m)、2.50-2.75(4H，m)、2.94-3.11(4H，m)、3.15-3.25(2H，m)、3.36-3.61(3H，m)、3.66(3H，s)、6.01(1H，d，J＝8Hz)、6.22(1H，s)、6.82(1H，d，J＝8Hz)、7.14-7.24(2H，m)、7.30-7.38(2H，m).
ESI-Mass；383(MH+).
Example 3975 Synthesis of- [1- (4-fluorophenethyl) piperidin-4-yl ] -6- (3-methylureido) methylindole
To a solution of 1- [1- (4-fluorophenethyl) piperidin-4-yl ] -6-aminomethylindoline (0.09g) obtained in example 132 in ethyl acetate (10ml) was added dropwise methyl isocyanate (0.02g) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The precipitated precipitate was collected by filtration, washed with diethyl ether/hexane and dried to obtain 0.07g of the title compound as a white powder. (yield: 67%) melting Point: 192 deg.C (decomposition)
1H-NMR(400MHz，DMSO-d6)；δ(ppm)1.88-2.04(4H，m)、2.19-2.27(2H，m)、2.54-2.61(2H，m)、2.57(3H，d，J＝4.4Hz)、2.74-2.80(2H，m)、3.09(2H，br-d)、4.25-4.34(1H，m)、4.28(2H，d，J＝6.0Hz)、5.73-5.78(1H，m)，6.26-6.32(1H，m)、6.40(1H，d，J＝3.2Hz)、6.94(1H，d，J＝8.0Hz)、7.08-7.14(2H，m)、7.27-7.32(2H，m)、7.39(1H，s)、7.44-7.48(2H，m).
ESI-Mass；409(MH+).
Further, structural formulae of the compounds of examples 294 to 397 are shown below.
Reference example 11 Synthesis of- {1- [2- (5-oxo-7-methyl-5H-pyrimido [2, 1-b ] [1, 3] thiazol-6-yl) ethyl ] piperidin-4-yl } indoline
[ Compound 5(Co. No.5) disclosed in WO96/23784 ]
1- [1- (2-aminoethyl) piperazin-4-yl ] indoline (192mg) was dissolved in DMF (5ml), and 7-methyl-6- (2-chloroethyl) -5H-pyrimido [2, 1-b ] [1, 3] thiazol-5-one (239mg) and triethylamine (0.159ml) were added to the solution, followed by stirring with heating at 80 ℃ for 11 hours and at 100 ℃ for 8 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (methanol/dichloromethane) to give the title compound (46mg) as an oil.
1H-NMR(400MHz，CDCl3)；δ(ppm)
1.60-1.89(6H，m)、2.15-2.24(2H，m)、2.45(3H，s)、2.51-2.58(2H，m)、2.82-2.88(2H，m)、2.94(2H，t，J＝8.2Hz)、3.14-3.22(2H，m)、3.39(2H，t，J＝8.2Hz)、3.36-3.44(1H，m)、6.41(1H，d，J＝7.6Hz)、6.60(1H，t，J＝7.6Hz)、6.92(1H，d，J＝4.8Hz)、7.01-7.07(2H，m)、7.91(1H，d，J＝4.8Hz).
FAB-Mass；395(MH+).

Claims (11)

1. 1, 4-substituted cyclic amine derivatives (I) represented by the following general formula:
the bond represented by the following general formula has the meaning of a single bond or a double bond:
y, Z are the same or different and each represents a methine group, a nitrogen atom, a group represented by the formula
A group of the formula
A group represented by (a) wherein at least one is a nitrogen atom;
R1、R2the same or different, represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkylsulfonylaminoalkyl group, a lower haloalkylsulfonylaminoalkyl group, a 2-pyrrolidone-1-yl group, a 1-hydroxy-1- (methoxypyridyl) methyl group, a methoxypyridylcarbonyl group, a 1, 3-propanesul onamido-2-yl group, a lower hydroxypiperidinylcarbonylalkyl group, a lower hydroxyalkylamidoalkyl group, a lower haloalkylamidoalkyl group, a lower dihaloalkylamidoalkyl group, a lower heteroarylamidoalkyl group, a lower hydroxyalkylamidoalkyl group, an optionally substituted amino group, a nitro group, a lower alkyl group, a lower alkoxy group, a lower acyl group, a lower alkoxyalkoxy group, a cyano group, a lower alkylsulfonyl group, a sulfonamido group, a hydroxy lower alkyl group, a hydroxy lower alkoxy group, a lower alkoxycarbonyla, Lower alkylsulfonylamino, N-lower alkylsulfonylamino, lower acylamino, optionally substituted aminoalkyl, optionally nitrogen substituted lower acylaminoalkyl, optionally substituted aryl, optionally substituted arylsulfonylamino, lower alkylsulfonyloxy, hydroxyiminomethyl, (2-pyrrolidin-1-yl) methyl, (2-piperidone-1-yl) methyl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, cycloalkylcarbonylaminoalkyl, optionally substituted ureido lower alkyl, succinimidyl, (succinimidyl-1-yl) lower alkyl, amido, optionally substituted carbamoyl lower alkyl, optionally substituted thiocarbamoyl lower alkyl, substituted, Formyl, aroyl, heteroarylcarbonyl, halogenated lower alkyl, (2-imidazolidin-1-yl) ) Methyl, (2, 4-imidazolidinedion-3-yl) methyl, (2-oxazolidin-3-yl) methyl, (glutarimide-1-yl) methyl, optionally substituted heteroarylhydroxyalkyl, cyano lower alkyl, 1-hydroxy lower cycloalkyl, (2, 4-thiazolidinedione-3-yl) methyl, optionally substituted 4-piperidinylmethyl, heteroarylacyl, pyrrolidinylcarbonyl lower alkyl, optionally substituted aminosulfonylalkyl, carboxy lower alkyl or lower alkylamidoalkyl; in addition, R1And R2Optionally substituted alicyclic rings, optionally substituted heterocyclic rings or alkylenedioxy groups may also be formed, and the rings may also be substituted;
R3represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl lower alkyl group, a lower alkoxy group, a formyl group, an optionally substituted aralkyloxy group, a hydroxyl lower alkoxy group, an optionally substituted sulfamoyl group or a sulfamoyl lower alkyl group in which the nitrogen atom is optionally substituted;
R4represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxyalkyl group, an aryloxyalkyl group in which the aryl group is optionally substituted, or an aralkyloxyalkyl group in which the aryl group is optionally substituted;
R5represents lower alkyl, lower acyl, lower alkoxycarbonyl, aromatic acyl or the formula
-Q1-(CH2)s-Q2-R6
A group represented by (a);
in the formula Q1、Q2May simultaneously represent a single bond, or either one of them represents a single bond, the other represents an oxygen atom, a carbonyl group, a group represented by the formula-NHCO-, a group represented by the formula-NHSO2A group represented by-or of the formula > CH-R7A group represented by (wherein R is7Represents a hydroxyl group, a lower alkyl group or a halogen atom);
s represents 0 or an integer of 1 to 6;
R6represents optionally substituted aryl, optionally substituted pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, imidazolyl, pyrazolyl, quinolinyl, isoquinolinyl, furanyl, thienyl, thiazolyl, optionally substituted benzoheteroaryl, 1, 4-benzodioxanyl, 1,3-benzodioxolyl, benzothiazolyl, or cyano;
m represents 0 or an integer of 1 to 6,
p represents an integer of 1 to 3.
2. The 1, 4-substituted cyclic amine derivative according to claim 1, wherein m is 0 and p is 2, or a pharmacologically acceptable salt thereof.
3. The 1, 4-substituted cyclic amine derivative according to claim 1 or 2, wherein Y is a methine group and Z is a nitrogen atom, or a pharmacologically acceptable salt thereof.
4. A1, 4-substituted cyclic amine derivative (III) according to claim 3 represented by the following general formula:
wherein the bond is represented by the following general formula:
And R1、R2、R3、R4、R5Have the same meanings as described above.
5. A1, 4-substituted cyclic amine derivative (IV) according to claim 4 represented by the following general formula:
wherein the bond is represented by the following general formula:
and R1、R2、R3、R4、R6、Q1、Q2And s have the same meanings as described above.
6. A1, 4-substituted cyclic amine derivative (V) according to claim 5 represented by the following general formula:
in the formula R1、R2、R3、R4、R6And s have the same meanings as described above.
7. A1, 4-substituted cyclic amine derivative (VI) according to claim 5 represented by the following general formula:
in the formula R1、R2、R3、R4、R6And s have the same meanings as described above.
8. The 1, 4-substituted cyclic amine derivative according to claim 1, which is 1- [1- (2-fluorophenethyl) piperidin-4-yl ] -6-methylcarbamoylmethylindole or a pharmacologically acceptable salt thereof.
9. A pharmaceutical agent comprising the 1, 4-substituted cyclic amine derivative according to claim 1 or a pharmacologically acceptable salt thereof.
10. The pharmaceutical agent according to claim 9, which is a therapeutic, ameliorating or prophylactic agent for spastic paralysis.
11. The medicament according to claim 9, which is a muscle relaxant.
HK00105871.3A 1997-03-31 1998-03-31 1,4-substituted cyclic amine derivatives or dihydroindole derivatives and medicament thereof HK1026700B (en)

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JP9843397 1997-03-31
JP98433/1997 1997-03-31
JP366764/1997 1997-12-26
JP36676497 1997-12-26
PCT/JP1998/001481 WO1998043956A1 (en) 1997-03-31 1998-03-31 1,4-substituted cyclic amine derivatives

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HK1026700B true HK1026700B (en) 2005-08-26

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