WO2010079668A1 - Olefin compound - Google Patents

Abstract

Disclosed is a compound represented by general formula (I) or a pharmacologically acceptable salt thereof. (In the formula, R1, R2, R2', R4, R5, R6, R7, R8 and R8' each represents a hydrogen atom or the like; and R3 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group or the like.)

Description

Olefin compounds

The present invention relates to an olefin compound or a pharmacologically acceptable salt thereof, particularly a compound having activity as an α ₂ δ ligand and having an affinity for the α ₂ δ subunit of a voltage-dependent calcium channel, or a pharmacologically thereof. Relates to acceptable salts. The present invention further relates to a pharmaceutical composition comprising such a compound or a pharmacologically acceptable salt thereof as an active ingredient.

Compounds that exhibit high affinity binding to the α ₂ δ subunit of the voltage-gated calcium channel have been shown to be effective, for example, in the treatment of neuropathic pain (eg, Non-Patent Document 1 and Non-Patent Document 1). Patent Document 2). Here, neuropathic pain is chronic pain caused by nerve tissue damage, etc., and is a disease that significantly impairs the quality of life, such as a patient becoming depressed when a painful attack is severe. .

Currently, several types of α ₂ δ ligands are known as therapeutic agents for such neuropathic pain, and examples of α ₂ δ ligands include gabapentin and pregabalin. Α ₂ δ ligands such as these compounds are useful for the treatment of epilepsy, neuropathic pain and the like (for example, Patent Document 1).

However, for example, in the case of gabapentin, the effective treatment rate by patient self-assessment in postherpetic neuralgia is about 60% (for example, see Non-Patent Document 3), and in the case of pregabalin, the patient's self in painful diabetic neuropathy It is reported that the therapeutic effective rate by evaluation is about 50% (for example, refer nonpatent literature 4).

As other compounds, for example, disclosed in Patent Document 2, Patent Document 3, Patent Document 4, and the like, but the main compounds disclosed in these Patent Documents are saturated hydrocarbon bicyclic compounds. This is clearly different from the compounds of the present invention.

WO04 / 006836 pamphlet WO99 / 21824 pamphlet International Publication No. 01/28978 Pamphlet International Publication No. 02/085839 Pamphlet

J Biol. Chem. 271 (10): 5768-5776, 1996 J Med. Chem. 41: 1838-18445, 1998 Acta Nerurol. Scand. 101: 359-371, 2000 Drugs 64 (24): 2813-2820, 2004

Providing a compound that further enhances the therapeutic effect over a compound having activity as an α ₂ δ ligand conventionally used in treatment is considered to have great significance in the treatment.

Therefore, the present invention has an excellent therapeutic effect and / or preventive effect on disorders such as olefin compounds having excellent activity as α ₂ δ ligands or pharmacologically acceptable salts thereof, pain, central nervous system disorders, etc. It aims at providing a pharmaceutical composition and a manufacturing intermediate.

［式中、各置換基は、以下のように定義される。
Ｒ^１は、水素原子又はＣ１－Ｃ６アルキル基を示す。
Ｒ^２は、水素原子、Ｃ１－Ｃ６アルキル基又はＣ３－Ｃ６シクロアルキル基を示す。
Ｒ^３は、水素原子、Ｃ１－Ｃ６アルキル基又はＣ３－Ｃ６シクロアルキル基を示す。
Ｒ^４及びＲ^４’は、それぞれ独立して、同一又は異なって、水素原子、Ｃ１－Ｃ６アルキル基又はＣ３－Ｃ６シクロアルキル基を示し、あるいは、Ｒ^４及びＲ^４’は、それらが結合する炭素原子と一緒になって、Ｃ３－Ｃ６シクロアルキル基を示す。
Ｒ^５は、水素原子又はＣ１－Ｃ６アルキル基を示す。
Ｒ^６は、水素原子、Ｃ１－Ｃ６アルキル基又はアミノ基の保護基を示す。
Ｒ^７は、水素原子、Ｃ１－Ｃ６アルキル基又はカルボキシ基の保護基を示す。
Ｒ^８及びＲ^８’は、それぞれ独立して、同一又は異なって、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基又はＣ１－Ｃ６アルキルチオ基を示し、あるいは、Ｒ^８及びＲ^８’は、それらが結合する炭素原子と一緒になって、Ｃ３－Ｃ６シクロアルキル基を示す。］
　本発明として、好適には、以下に示す発明である。 The present invention is the invention described below.
(1)
A compound having the general formula (I) or a pharmacologically acceptable salt thereof.

[Wherein each substituent is defined as follows.
R ¹ represents a hydrogen atom or a C1-C6 alkyl group.
R ² represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group.
R ³ represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group.
R ⁴ and R ^{4 ′} are independently the same or different and each represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group, or R ⁴ and R ^{4 ′} are bonded to each other. Together with the carbon atom represents a C3-C6 cycloalkyl group.
R ⁵ represents a hydrogen atom or a C1-C6 alkyl group.
R ⁶ represents a hydrogen atom, a C1-C6 alkyl group or an amino protecting group.
R ⁷ represents a hydrogen atom, a C1-C6 alkyl group or a protecting group for a carboxy group.
R ⁸ and R ^{8 ′} are independently the same or different and each represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group or a C1-C6 alkylthio group, or R ⁸ and R ^{8 ′ 8 ′} , together with the carbon atom to which they are attached, represents a C3-C6 cycloalkyl group. ]
The present invention is preferably the following invention.

(2)
The compound according to (1) or a pharmacologically acceptable salt thereof, wherein R ¹ is a hydrogen atom.
(3)
The compound or a pharmacologically acceptable salt thereof according to (1) or (2), wherein R ² is a hydrogen atom, a methyl group, an ethyl group, a propyl group or a cyclopropyl group.
(4)
The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (3), wherein R ³ is a hydrogen atom or a C1-C6 alkyl group.
(5)
The compound or a pharmacologically acceptable salt thereof according to any one of (1) to (3), wherein R ³ is a hydrogen atom, a methyl group, an ethyl group or a propyl group.
(6)
The compound according to any one of (1) to (5) or a pharmacologically acceptable salt thereof, wherein R ⁴ and R ^{4 ′} are a hydrogen atom or a carbon atom to which they are bonded, and are a cyclopropyl group Salt.
(7)
The compound or a pharmacologically acceptable salt thereof according to any one of (1) to (5), wherein R ⁴ and R ^{4 ′} are a hydrogen atom.
(8)
The compound or a pharmacologically acceptable salt thereof according to any one of (1) to (7), wherein R ⁵ is a hydrogen atom.
(9)
The compound or a pharmacologically acceptable salt thereof according to any one of (1) to (8), wherein R ⁶ is a hydrogen atom.
(10)
10. The compound or a pharmacologically acceptable salt thereof according to any one of (1) to (9), wherein R ⁷ is a hydrogen atom.
(11)
The compound or a pharmacologically acceptable salt thereof according to any one of (1) to (10), wherein R ⁸ and R ^{8 ′} are a hydrogen atom.

(12)
The compound according to (1) or a pharmacologically acceptable salt thereof, wherein the compound having the general formula (I) is a compound selected from the group consisting of:
[(1S ^* , 5R ^* , 6S ^* )-6- (aminomethyl) bicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
[(1R, 5S, 6R) -6 (aminomethyl) bicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
[(1S, 5R, 6S) -6 (aminomethyl) bicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
[(1R ^* , 5S ^* , 6S ^* , 7R ^* )-6- (aminomethyl) -7- (methylthio) bicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
[(1S ^* , 5S ^* , 6S ^* , 7R ^* )-6- (aminomethyl) -7-methylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
[(1R ^* , 5R ^* , 7R ^* )-7- (aminomethyl) spiro [bicyclo [3.2.0] heptane-2,1′-cyclopropane] -3-en-7-yl] acetic acid,
[(1R ^* , 5S ^* , 6R ^* )-6- (aminomethyl) -3-methyl-bicyclo [3.2.0] hept-3-en-6-yl] acetic acid,
[(1R ^* , 5S ^* , 6R ^* )-6- (aminomethyl) -3-ethylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
[(1S ^* , 5S ^* , 6R ^* )-6- (aminomethyl) -2-methylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid hydrochloride,
[(1R ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -2-ethylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
(−)-[(1R ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -2-ethylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
(+)-[(1R ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -2-ethylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
[(1R ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -2-propylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
[(1R ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -2-cyclopropylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
[(1S ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -3-propylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
[(1S ^* , 5R ^* , 6R ^* )-6- (aminomethyl) bicyclo [3.2.0] hept-2-en-6-yl] acetic acid In the title of the compound name in this specification, “ “ ^* ” ^Indicates that the asymmetric carbon indicated is a racemic mixture. However, in the case of marking such as “(1S ^* , 5R ^* , 6R ^* ) −”, the relative arrangement indicates the relationship. In addition, when it is marked as “(−)-[(1R ^* , 5R ^* , 6S ^* )-”, it indicates that it is an optically active substance from its optical rotation, but its absolute configuration is not yet The decision structure is shown.

(13)
(1)-(12) A pharmaceutical composition comprising the compound according to any one of the above items or a pharmacologically acceptable salt thereof as an active ingredient.
(14)
The pharmaceutical composition according to (13), for treating and / or preventing pain.
(15)
Acute pain, chronic pain, pain arising from soft tissue or peripheral injury, postherpetic neuralgia, occipital neuralgia, trigeminal neuralgia, medullary or intercostal neuralgia, central pain, neuropathic pain, migraine, osteoarthritis or joint Pain associated with rheumatism, pain associated with contusion, sprains or trauma, spinal pain, pain due to spinal cord or brainstem injury, low back pain, sciatica, toothache, myofascial pain syndrome, perineal incision pain, gout pain, burn Related to pain, heart pain, muscle pain, eye pain, inflammatory pain, oral and facial pain, abdominal pain, dysmenorrhea, pain associated with labor pain or endometriosis, somatic pain, nerve or root injury Pain, amputation, painful tics, pain associated with neuroma or vasculitis, pain resulting from diabetic neuropathy (or diabetic peripheral neuropathic pain), pain resulting from chemotherapy-induced neuropathy, atypical facial pain , Neuropathy Lumbar pain, trigeminal neuralgia, occipital neuralgia, medullary or intercostal neuralgia, HIV-related neuralgia, AIDS-related neuralgia, hyperalgesia, burn pain, idiopathic pain, chemotherapy pain, occipital neuralgia, psychogenic pain, gallstones Pain, neuropathic or non-neuropathic pain associated with cancer, phantom limb pain, functional abdominal pain, headache, acute or chronic tension headache, sinus headache, cluster headache, temporal mandibular pain, maxillary sinus pain, Pain resulting from ankylosing spondyloarthritis, postoperative pain, scarring, chronic non-neuropathic pain, fibromyalgia, amyotrophic lateral sclerosis, epilepsy (partial epilepsy, partial seizures in adults, partial seizures in epileptic patients) ), A pharmaceutical composition according to (13) for treating and / or preventing a disease selected from the group consisting of generalized anxiety disorder and restless leg syndrome.
(16)
The pharmaceutical composition according to (13) for treating and / or preventing pain resulting from diabetic neuropathy.
Furthermore, the present invention includes the following inventions.
(17)
Use of the compound according to any one of (1) to (12) or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition.
(18)
(1)-(12) A method for treating and / or preventing pain, comprising administering an effective amount of the compound or pharmacologically acceptable salt thereof according to any one of (1) to a mammal.
It is.

According to the present invention, an olefin compound having an excellent activity as an α ₂ δ ligand or a pharmacologically acceptable salt thereof, a pharmaceutical composition having an excellent therapeutic effect and / or preventive effect for disorders such as pain and central nervous system disorders Products as well as manufacturing intermediates.

The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom.

The “C1-C6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec -Butyl group, tert-butyl group, pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, hexyl group, isohexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methyl Pentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2 , 3-dimethylbutyl group, 2-ethylbutyl group, etc., preferably methyl group, ethyl group, propyl group, isopropyl group or butyl group.

The “C3-C6 cycloalkyl group” is a cyclic alkyl group having 3 to 6 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and preferably a cyclopropyl group or Cyclobutyl group.

The “halogeno C1-C6 alkyl group” is a group in which the “halogen atom” is substituted on the “C1-C6 alkyl group”. For example, a trifluoromethyl group, a trichloromethyl group, a difluoromethyl group, a dichloromethyl group , A dibromomethyl group, a fluoromethyl group, a 2,2,2-trifluoroethyl group, a 2,2,2-trichloroethyl group, and the like, and preferably a trifluoromethyl group.

The “C1-C6 alkylthio group” is a group in which a sulfur atom is substituted on the “C1-C6 alkyl group”, and examples thereof include a methylthio group, an ethylthio group, a propylthio group, and the like, and preferably a methylthio group .

The “C1-C6 alkoxy group” is a group in which an oxygen atom is substituted on the “C1-C6 alkyl group”, and examples thereof include a methoxy group, an ethoxy group, and a propoxy group, and a methoxy group is preferable. .

“Carboxy protecting group” means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, hexyl, bromo-tert-butyl, trichloroethyl Group, benzyl group, p-nitrobenzyl group, o-nitrobenzyl group, p-methoxybenzyl group, p-tert-butylbenzyl group, acetoxymethyl group, propionyloxymethyl group, butyryloxymethyl group, isobutyryloxy Methyl group, valeryloxymethyl group, pivaloyloxymethyl group, acetoxyethyl group, acetoxypropyl group, acetoxybutyl group, propionyloxyethyl group, propionyloxypropyl group, butyryloxyethyl group, isobutyryloxyethyl group , Pivaloyloxyethyl group, hexanoyloxyethyl group, isobutyryl Xymethyl group, ethylbutyryloxymethyl group, dimethylbutyryloxymethyl group, pentanoyloxyethyl group, methoxycarbonyloxymethyl group, ethoxycarbonyloxymethyl group, propoxycarbonyloxymethyl group, tert-butoxycarbonyloxymethyl group, methoxy Carbonyloxyethyl group, ethoxycarbonyloxyethyl group, isopropoxycarbonyloxyethyl group, tert-butyldimethylsilyl group, trimethylsilyl group, methoxymethyl group, ethoxymethyl group, propoxymethyl group, isopropoxymethyl group, (2-methylthio) -Ethyl group, 3-methyl-2-butenyl group, 5-indanyl group, 3-phthalidyl group and the like.

“Amino group protecting group” means formyl group, phenylcarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, phenyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, adamantyloxycarbonyl group, benzyloxycarbonyl group, Benzylcarbonyl group, benzyl group, benzhydryl group, trityl group, phthaloyl group and the like.

“The pharmacologically acceptable salt” refers to a salt that can be used as a medicine. In the compound of this invention, when it has an acidic group or a basic group, since it can be made into a basic salt or an acidic salt by making it react with a base or an acid, the salt is shown.

The pharmacologically acceptable “basic salt” of the compound of the present invention is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as magnesium salt or calcium salt. Organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt or glycine salt; Amino acid salts such as lysine salts, arginine salts, ornithine salts, glutamates, and aspartates, and alkali metal salts are preferred.
The pharmacologically acceptable “acid salt” of the compound of the present invention is preferably a hydrohalide salt such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, Inorganic acid salts such as nitrates, perchlorates, sulfates, phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p- Organics such as aryl sulfonates such as toluene sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc. Acid salts; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, aspartate, and most preferably hydrohalide salt.

The compound of the present invention or a pharmacologically acceptable salt thereof may absorb moisture, adhere to adsorbed water, or become a hydrate when left in the air or by recrystallization. The present invention also includes such various hydrates, solvates and polymorphic compounds.

The light compounds of the present invention, salts thereof or solvates thereof may be isomers such as cis isomers and trans isomers, tautomers or optical isomers such as d isomers and l isomers, depending on the type and combination of substituents. The compounds of the present invention include all isomers, stereoisomers and any ratios of these isomers and stereoisomer mixtures, unless otherwise specified. Is. A mixture of these isomers can be separated by a known resolution means.
The compound of the present invention also includes a label, that is, a compound in which one or more atoms of the compound of the present invention are substituted with a radioisotope (for example, ³ H, ¹⁴ C, ³⁵ S, etc.).

The present invention also includes pharmacologically acceptable prodrugs of the compounds of the present invention. A pharmacologically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like of the compound of the present invention by hydrolysis or under physiological conditions. Drug-forming groups are described in Prog. Med., Volume 5, pages 2157-2161, 1985, “Development of Drugs” (Yodogawa Shoten, 1990), Volume 7, Molecular Design pages 163-198 It is the basis of. As the prodrug, more specifically, when an amino group is present in the compound of the present invention, a compound in which the amino group is acylated, alkylated or phosphorylated (for example, the amino group is eicosanoylated). Alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert- In the case where a hydroxyl group is present in the compound of the present invention, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated or borated (for example, The hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylated. Le aminomethyl carbonylated compounds and the like.), And the like. In addition, when a carboxy group is present in the compound of the present invention, a compound in which the carboxy group is esterified or amidated (for example, the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethyl Aminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, amidation, or methylamidated compounds, etc.).

The compound having the general formula (I) of the present invention is preferably a compound having a combination of the following substituents.
R ¹ is a hydrogen atom,
R ² is a hydrogen atom, a methyl group, an ethyl group, a propyl group or a cyclopropyl group,
R ³ is a hydrogen atom, a methyl group, an ethyl group or a propyl group,
R ⁴ and R ^{4 ′} are hydrogen atoms,
R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{8 ′} are hydrogen atoms.
The compounds having the general formula (I) of the present invention are more preferably the compounds described in the examples.

(Production method)
The compound of the present invention can be produced by applying various known synthesis methods using characteristics based on the basic skeleton or the type of substituent. Known methods include, for example, the methods described in “ORGANIC FUNCTIONAL GROUP PREPARATIONS”, 2nd edition, ACADEMIC PRESS, INC., 1989, “Comprehensive Organic Transformations”, VCH Publishers Inc., 1989, and the like.
In this case, depending on the type of functional group, it is effective in terms of production technology to protect the functional group with a suitable protecting group at the raw material or intermediate stage, or to replace it with a group that can be easily converted to the functional group. There are cases.
Examples of such a functional group include an amino group, a hydroxyl group, a carboxyl group, and the like, and examples of protective groups thereof include, for example, “Protective Groups in Organic Synthesis (3rd edition, 1999) by TW Greene and PG Wuts. ) ”, And may be appropriately selected and used depending on the reaction conditions. According to such a method, after carrying out the reaction by introducing the substituent, the desired compound can be obtained by removing the protective group or converting it to a desired group as necessary.
Further, a prodrug of the compound of the present invention is produced by introducing a specific group at the raw material or intermediate stage, or reacting with the obtained compound of the present invention, in the same manner as the above protecting group. it can. The reaction can be carried out by applying methods known to those skilled in the art, such as ordinary esterification, amidation, dehydration, hydrogenation and the like.
The production method of the compound of the present invention is described below. However, the manufacturing method is not limited to the following method.

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^４’、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８及びＲ^８’は、前記と同意義を示し、Ｐ^１はカルボキシ基の保護基を表し、Ｐ^２及びＰ^３はアミノ基の保護基を示す。］ [Method A and Method B]

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ^{4 ′} , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{8 ′} are as defined above, and P ¹ is a carboxy group] Represents a protecting group, P ² and P ³ represent amino protecting groups. ]

[Step A-1]
Step A-1 is a step for producing compound (2) by subjecting compound (1) to an alkenylation reaction.
The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent. For example, aromatic, ether, ester, halogenated hydrocarbon, nitrile, amide And sulfoxide-based solvents, ether solvents are preferred, and tetrahydrofuran is more preferred.
Examples of the auxiliary material used include Horner Emmons reagent; Dialkylphosphonic acid alkyl ester such as diethylphosphonic acid ethyl ester; Phosphorus ylide reagent; Phosphonium ylide such as ethoxycarbonylmethylenetriphenylphosphorane.
Reagents used include inorganic bases, alkali metal alkoxides, organic bases, organic metal bases, etc., preferably inorganic bases, and more preferably sodium hydride.
The reaction temperature varies depending on the kind of the raw material compound, solvent, auxiliary raw material, reagent and the like, but is usually 0-100 ° C., preferably 0 ° C.-room temperature.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, if necessary, the reaction is stopped by decomposing excess reagent, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration and then mixed with water and ethyl acetate. The organic layer containing the target compound is separated, washed with water and the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate and the like, and then the solvent is distilled off. If necessary, the obtained target compound is appropriately combined with conventional methods such as recrystallization and reprecipitation, which are usually used for separation and purification of organic compounds as appropriate, and applied with chromatography to obtain an appropriate eluent. To be separated and purified.
Thereafter, usually after completion of the reaction in each step, the target compound of each reaction is collected from the reaction mixture in the same manner as in the post-treatment in step A-1.

[Step A-2]
Step A-2 is a step for producing compound (3) from compound (2).
The solvent to be used is the same solvent as in step A-1, preferably an ether solvent or a nitrile solvent, more preferably tetrahydrofuran or acetonitrile.
An example of the auxiliary material used is nitromethane.
Examples of the reagent used include the same reagents as in step A-1, preferably organic bases or organometallic bases, and more preferably diazabicycloundecene or tetraalkylammonium halide.
The reaction temperature varies depending on the kind of the raw material compound, solvent, auxiliary raw material, reagent and the like, but is usually 0-100 ° C., preferably 0-60 ° C.

[Step A-3]
Step A-3 is a step for producing compound (5) by reducing compound (3).
The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting material to some extent. A solvent or an aqueous solvent, more preferably ethanol or water.
Examples of the reagent used include radium-carbon, palladium hydroxide-carbon, nickel chloride, tin chloride, sodium borohydride, iron powder, tin, zinc, hydrogen and the like, preferably iron powder or tin.
While the reaction temperature varies depending on the kind of raw material compound, solvent, reagent and the like, it is generally 0-100 ° C., preferably 60-80 ° C.

[Step B-1]
Step B-1 is a step for producing compound (4) from compound (2).
Examples of the solvent used include the same solvents as in step A-1, alcohol solvents, aqueous solvents, etc., preferably amide solvents, and more preferably N, N-dimethylformamide.
Examples of the reagent used include cyanating agents; metal cyanides such as aluminum cyanide reagents, preferably cyanating agents, and more preferably sodium cyanide or potassium cyanide.
While the reaction temperature varies depending on the kind of raw material compound, solvent, reagent and the like, it is generally 0-100 ° C., preferably 60-80 ° C.

[Step B-2]
Step B-2 is a step of producing compound (5) by reducing compound (4).
As the solvent to be used, there are the same solvents as in Step B-1, preferably an alcohol solvent or an ether solvent, more preferably methanol or tetrahydrofuran.
The catalyst used is a transition metal catalyst, preferably nickel chloride or cobalt chloride.
Examples of the reagent used include a boron reagent, preferably sodium borohydride.
While the reaction temperature varies depending on the kind of the raw material compound, solvent, catalyst, reagent and the like, it is generally 0-100 ° C., preferably 0 ° C.-room temperature.

[Step A-4]
If necessary, the compound (6) may be obtained by carrying out a step (A-4 step) for protecting the amino group of the compound (5).
As the solvent to be used, there are the same solvents as in step A-3, preferably an alcohol solvent or an aqueous solvent, more preferably ethanol or water.
Examples of the reagent used include ditert-butyl dicarbonate, chloroformate, acid halide, acid anhydride, sulfonyl chloride, inorganic bases, alkali metal alkoxides, organic bases, and organic metal bases. Is di-tert-butyl dicarbonate, inorganic bases or organic bases, more preferably di-tert-butyl dicarbonate, sodium hydroxide or triethylamine.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually 0-100 ° C., preferably 0 ° C.-room temperature.

[Step A-5]
Step A-5 is a step for producing compound (7) from compound (5) or (6) by deprotection of the protecting group.
As the solvent to be used, there are the same solvents as in step A-3, preferably an ether solvent or an ester solvent, more preferably dioxane or ethyl acetate.
The reagent used is an inorganic acid, an inorganic base or an organic acid, more preferably hydrochloric acid, acetic acid or trifluoroacetic acid.
The reaction temperature varies depending on the kind of the raw material compound, solvent, auxiliary raw material, reagent and the like, but is usually 0-100 ° C., preferably 0 ° C.-room temperature.

[Step A-6]
Step A-6 is a step for producing compound (8) by protecting the amino group of compound (7).
As the solvent to be used, there are the same solvents as in step A-3, preferably an alcohol solvent or an aqueous solvent, more preferably ethanol or water.
Examples of the reagent used include the same reagents as in step A-4, preferably ditert-butyl dicarbonate, inorganic bases or organic bases, more preferably ditert-butyl dicarbonate, sodium hydroxide. Or triethylamine.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually 0-100 ° C., preferably 0 ° C.-room temperature.

[Step A-7]
Step A-7 is a step of producing compound (9) by alkylating compound (8).
As the solvent to be used, there are the same solvents as in step A-1, and an ether solvent is preferable.
An auxiliary material used is an alkyl halide.
The reagent used is the same reagent as in step A-1, preferably sodium hydride.
While the reaction temperature varies depending on the kind of the raw material compound, solvent, auxiliary material, reagent and the like, it is generally −78 ° C.-room temperature, preferably 0 ° C.-room temperature.

[Step A-8]
If necessary, step A-8 may be performed after step A-7. Step A-8 is a step for producing compound (10) by alkylating compound (9).
As the solvent to be used, there are the same solvents as those in the step A-1, preferably an ether solvent or an amide solvent.
As an auxiliary material used, there is an alkyl halide.
The reagent used is the same reagent as used in step A-1, and is preferably sodium carbonate or potassium carbonate.
While the reaction temperature varies depending on the kind of the raw material compound, solvent, auxiliary material, reagent and the like, it is generally −78 ° C.-room temperature, preferably 0 ° C.-room temperature.

[Step A-9]
Step A-9 is a step of producing a compound having the general formula (I) from the compound (9) by deprotecting the protecting group.
As the solvent to be used, there are the same solvents as in step A-3, preferably an ether solvent or an ester solvent, more preferably dioxane or ethyl acetate.
The reagent used is the same reagent as in step A-4, preferably hydrochloric acid, acetic acid or trifluoroacetic acid.
The reaction temperature varies depending on the kind of the raw material compound, solvent, auxiliary raw material, reagent and the like, but is usually 0-100 ° C., preferably 0 ° C.-room temperature.

The compound (4) in the above production method can also be produced by the following methods C, E and the like.

[Method C and Method D]

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ^{4 ′} , R ⁵ , P ¹ , R ⁸ and R ^{8 ′} are as defined above, and P ⁴ represents a protecting group for an amide group. Show. ]

[Step C-1]
Step C-1 is a step of producing an alpha and beta unsaturated amide compound (11) from the compound (1).
The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent. For example, aromatic, ether, ester, halogenated hydrocarbon, nitrile, amide And sulfoxide-based solvents, ether solvents are preferred, and tetrahydrofuran is more preferred.
Examples of auxiliary materials used include Horner Emmons reagent; dialkylphosphonic acid derivatives such as diethyl (2-benzoyl-2-oxoethyl) phosphonate.
Reagents used include inorganic bases, alkali metal alkoxides, organic bases, organic metal bases, etc., preferably organic metal bases, and more preferably butyl lithium.
The reaction temperature varies depending on the kind of the raw material compound, solvent, auxiliary raw material, reagent and the like, but is usually 0-100 ° C., preferably 0 ° C.-room temperature.

[Step C-2]
Step C-2 is a step of producing compound (12) from compound (11).
The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent. For example, aromatic, ether, ester, halogenated hydrocarbon, nitrile, amide And sulfoxide solvents, preferably aromatic solvents, more preferably toluene. Examples of reagents used include cyanating agents; metal cyanides such as aluminum cyanide reagents, and trialkyl silylates. Examples thereof include rucyanide, preferably trialkylsilylcyanide, and more preferably trimethylsilylcyanide.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually 0-100 ° C., preferably 40-60 ° C.

[Step C-3]
Step C-2 is a step of producing compound (13) by hydrolysis from compound (12).
The solvent used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent. For example, aromatic, ether, halogenated hydrocarbon, nitrile, amide, sulfoxide There are solvents such as alcoholic, alcoholic and aqueous solvents, preferably alcoholic solvents, aqueous solvents or mixed solvents thereof, more preferably methanol-water.
Reagents used include inorganic bases, preferably potassium hydroxide, sodium hydroxide or lithium hydroxide.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually 0-100 ° C., preferably 0 ° C.-room temperature.

[Step C-4]
Step C-4 is a step for producing compound (4) by protecting carboxylic acid from compound (13).
The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent. For example, aromatic, ether, halogenated hydrocarbon, nitrile, amide, sulfoxide There are solvents such as those based on alcohols, alcohols, and waters, preferably the royal family or mixed solvents thereof, more preferably benzene or toluene.
Examples of reagents used include alkylating agents such as alkyl halides, alkylating agents such as amide dialkyl sweat tar, and preferably alkylating agents such as N, N-dimethylformamide di-t-butyl acetal.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually 0-100 ° C., preferably 60-80 ° C.

Compound (1) in the above production method can also be produced by Method D, Method E, Method F, or the like. Compounds (16), (24) and (30) can be used in place of compound (1) in production method A.

[Step D-1]
Step D-1 is a step of producing the bicyclic compound (15) by reacting the substituted cyclopentadiene (14) with trichloroacetyl chloride or dichloroacetyl chloride.
The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent. For example, hydrocarbon, aromatic, ether, halogenated hydrocarbon, nitrile, There are amide-based, sulfoxide-based, alcohol-based and water-based solvents, preferably hydrocarbon-based or ether-based solvents, and more preferably ether-based solvents and diethyl ether.
The reagent used is a metal catalyst such as zinc, and is preferably zinc or a copper-zinc complex.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually 0-100 ° C., preferably 0 ° C.-room temperature.

[Step D-2]
Step D-2 is a step of producing compound (16) from compound (15) by carrying out a reduction reaction.
The solvent used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent, for example, hydrocarbon, aromatic, ether, halogenated hydrocarbon, nitrile, There are amide-based, sulfoxide-based, alcohol-based and water-based solvents, preferably alcohol-based solvents, and more preferably methanol.
As a reagent to be used, a metal catalyst such as zinc and ammonium chloride are used. The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually 0-100 ° C., preferably 0 ° C.-room temperature.

If necessary, R8 and R8 'can be introduced by performing steps D-3 and D-4.

[Step D-3]
Step D-3 is a step of producing compound (17) from compound (16).
The solvent used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent, for example, hydrocarbon, aromatic, ether, halogenated hydrocarbon, nitrile, There are amide-based, sulfoxide-based, alcohol-based and water-based solvents, preferably amide-based or ether-based solvents.
Examples of auxiliary materials to be used include alkylating agents such as alkyl halides and alkylating agents such as dialkyl sulfuric acid. Preferably, it is an alkyl halide.
Reagents used include inorganic bases, alkali metal alkoxides, organic bases, organic metal bases, etc., preferably inorganic bases, and more preferably sodium hydride.
As a reagent to be used, a metal catalyst such as zinc and ammonium chloride are used. The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually 0-100 ° C., preferably 0 ° C.-room temperature.

[Step D-4]
Step D-4 is a step for producing compound (1) from compound (17).
The solvent used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent, for example, hydrocarbon, aromatic, ether, halogenated hydrocarbon, nitrile, There are amide-based, sulfoxide-based, alcohol-based and water-based solvents, preferably amide-based or ether-based solvents.
Examples of auxiliary materials to be used include alkylating agents such as alkyl halides and alkylating agents such as dialkyl sulfuric acid. Preferably, it is an alkyl halide.
Reagents used include inorganic bases, alkali metal alkoxides, organic bases, organic metal bases, etc., preferably inorganic bases, and more preferably sodium hydride.
As a reagent to be used, a metal catalyst such as zinc and ammonium chloride are used. The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually 0-100 ° C., preferably 0 ° C.-room temperature.

［式中、Ｒ^２、Ｒ^３は、前記と同意義を示し、Ｐ^５、Ｐ^６及びＰ^７は、水酸基基の保護基を示す。］ [Method E and Method F]

[Wherein R ² and R ³ represent the same meaning as described above, and P ⁵ , P ⁶ and P ⁷ represent a protecting group for a hydroxyl group. ]

[Step E-1]
Step E-1 is a method for producing compound (19) from compound (18) by a reduction reaction. Compound (18) was prepared according to J. Org. Chem. Soc. Perkin. It can be produced by the method of Trans I (1980) 852-857.
Examples of the solvent used include the same solvents as in step A-1, alcohol solvents, aqueous solvents, etc., preferably ether solvents, alcohol solvents, or a mixed solvent thereof, more preferably tetrahydrofuran.
Reagents used include boron hydride reagents and aluminum hydride reagents, preferably water aluminum hydride reagents and lithium aluminum hydride.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually 0-100 ° C., preferably 0 ° C.-room temperature.

[Step E-2]
Step E-2 is a method for producing compound (20) by subjecting compound (19) to an oxidation reaction.
The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent. For example, hydrocarbon, aromatic, ether, halogenated hydrocarbon, nitrile, There are amide-based, sulfoxide-based, alcohol-based and water-based solvents, preferably halogenated hydrocarbon-based or ether-based solvents.
The reagent used is a commonly used oxidizing agent such as a chromic reagent, a manganese reagent, or an iodine reagent, preferably a chromic reagent, pyridinium chromate, or pyridinium dichromate.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually 0-100 ° C., preferably 0 ° C.-room temperature.

[Step E-3]
Step E-3 is a method for producing compound (21) from compound (20).
The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent, for example, hydrocarbon, aromatic, ether, halogenated hydrocarbon, nitrile, There are amide-based, sulfoxide-based, alcohol-based and water-based solvents, and ether-based solvents such as diethyl ether and tetrahydrofuran are preferred.
Examples of the reagent used include a Grignard reagent, an alkyl lithium reagent, and an alkyl zinc reagent, and preferably a Grignard reagent and an alkyl lithium reagent.
While the reaction temperature varies depending on the kind of starting compound, solvent, reagent and the like, it is generally -78 ° C-100 ° C, preferably -78 ° C-0 ° C.

[Step E-5]
Step E-5 is a method for producing compound (23) from compound (21) by a dehydration reaction.
The solvent used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent, for example, hydrocarbon, aromatic, ether, halogenated hydrocarbon, nitrile, There are amide-based, sulfoxide-based, alcohol-based, aqueous-based and pyridine-based solvents, and pyridine-based solvents and pyridine are preferred.
As a reagent to be used, phosphorus oxychloride or the like is used.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually −78 ° C.-100 ° C., preferably 0 ° C.-room temperature.

[Step E-4]
Step E-4 is a method for producing compound (22) from compound (20).
The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent. For example, hydrocarbon, aromatic, ether, halogenated hydrocarbon, nitrile, There are amide-based, sulfoxide-based, alcohol-based, aqueous-based and pyridine-based solvents, and ether-based solvents such as diethyl ether and tetrahydrofuran are preferred.
Examples of auxiliary materials used include sulfonic acid anhydrides, sulfonyl chlorides, sulfonic acid imides, and preferably sulfonic acid imides such as N-phenylbis (trifluoromethanesulfonylimide).
In addition, the reagents used are inorganic bases, alkali metal alkoxides, organic bases, organic metal bases, etc., preferably organic metal bases, more preferably sodium bis (trimethylsilyl) amide or potassium. Bis (trimethylsilyl) amide.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually −78 ° C.-100 ° C., preferably 0 ° C.-room temperature.

[Step E-6]
Step E-6 is a method for producing compound (23) from compound (22) by a dehydration reaction.
The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent. For example, hydrocarbon, aromatic, ether, halogenated hydrocarbon, nitrile, There are amide-based, sulfoxide-based, alcohol-based, aqueous-based and pyridine-based solvents, and ether-based solvents such as diethyl ether and tetrahydrofuran are preferred.
The reagent used is a Grignard reagent, an alkyl lithium reagent, an alkyl zinc reagent, or the like, and preferably a Grignard reagent.
Moreover, when a palladium catalyst, a rhodium catalyst, or the like is added as a catalyst, the reaction may be accelerated.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually −78 ° C.-100 ° C., preferably 0 ° C.-room temperature.

[Step E-7]
Step E-7 is a method for producing compound (24) by deprotecting compound (23).
The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent. For example, hydrocarbon, aromatic, ether, halogenated hydrocarbon, nitrile, There are amide-based, sulfoxide-based, alcohol-based, aqueous-based and pyridine-based solvents, and a mixed solvent system such as alcohol-water and acetonitrile-water is preferable.
The reagent used is not particularly limited as long as it is an acid such as a hard acid such as hydrochloric acid or sulfuric acid, or an organic acid such as camphorsulfonic acid or toluenesulfonic acid, but is preferably a hard acid such as sulfuric acid.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually −78 ° C.-100 ° C., preferably 0 ° C.-room temperature.

[Step F-1]
Step F-1 is a method for producing compound (25) from compound (18) by a reduction reaction.
Examples of the solvent used include the same solvents as in step A-1, alcohol solvents, aqueous solvents, etc., preferably ether solvents, alcohol solvents, or a mixed solvent thereof, more preferably tetrahydrofuran.
Reagents used include boron hydride reagents and aluminum hydride reagents, preferably water aluminum hydride reagents and lithium aluminum hydride.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually 0-100 ° C., preferably 0 ° C.-room temperature.

[Step F-2]
Step F-2 is a method for producing compound (26) by subjecting compound (25) to an oxidation reaction.
The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent. For example, hydrocarbon, aromatic, ether, halogenated hydrocarbon, nitrile, There are amide-based, sulfoxide-based, alcohol-based and water-based solvents, preferably halogenated hydrocarbon-based or ether-based solvents.
The reagent used is a commonly used oxidizing agent such as a chromic reagent, a manganese reagent, or an iodine reagent, preferably a chromic reagent, pyridinium chromate, or pyridinium dichromate.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually 0-100 ° C., preferably 0 ° C.-room temperature.

[Step F-3]
Step F-3 is a method for producing compound (27) from compound (26).
The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent, for example, hydrocarbon, aromatic, ether, halogenated hydrocarbon, nitrile, There are amide-based, sulfoxide-based, alcohol-based and water-based solvents, and ether-based solvents such as diethyl ether and tetrahydrofuran are preferred.
Examples of the reagent used include a Grignard reagent, an alkyl lithium reagent, and an alkyl zinc reagent, and preferably a Grignard reagent and an alkyl lithium reagent.
While the reaction temperature varies depending on the kind of starting compound, solvent, reagent and the like, it is generally -78 ° C-100 ° C, preferably -78 ° C-0 ° C.

[Step F-5]
Step F-5 is a method for producing compound (29) from compound (27) by a dehydration reaction.
The solvent used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent, for example, hydrocarbon, aromatic, ether, halogenated hydrocarbon, nitrile, There are amide-based, sulfoxide-based, alcohol-based, aqueous-based and pyridine-based solvents, and pyridine-based solvents and pyridine are preferred.
As a reagent to be used, phosphorus oxychloride or the like is used.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually −78 ° C.-100 ° C., preferably 0 ° C.-room temperature.

[Step F-4]
Step F-4 is a method for producing compound (28) from compound (26).
The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent. For example, hydrocarbon, aromatic, ether, halogenated hydrocarbon, nitrile, There are amide-based, sulfoxide-based, alcohol-based, aqueous-based and pyridine-based solvents, and ether-based solvents such as diethyl ether and tetrahydrofuran are preferred.
Examples of auxiliary materials used include sulfonic acid anhydrides, sulfonyl chlorides, sulfonic acid imides, and preferably sulfonic acid imides such as N-phenylbis (trifluoromethanesulfonylimide).
In addition, the reagents used are inorganic bases, alkali metal alkoxides, organic bases, organic metal bases, etc., preferably organic metal bases, more preferably sodium bis (trimethylsilyl) amide or potassium. Bis (trimethylsilyl) amide.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually −78 ° C.-100 ° C., preferably 0 ° C.-room temperature.

[Step F-6]
Step F-6 is a method for producing compound (29) from compound (28) by a dehydration reaction.
The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent. For example, hydrocarbon, aromatic, ether, halogenated hydrocarbon, nitrile, There are amide-based, sulfoxide-based, alcohol-based, aqueous-based and pyridine-based solvents, and ether-based solvents such as diethyl ether and tetrahydrofuran are preferred.
The reagent used is a Grignard reagent, an alkyl lithium reagent, an alkyl zinc reagent, or the like, and preferably a Grignard reagent.
Moreover, when a palladium catalyst, a rhodium catalyst, or the like is added as a catalyst, the reaction may be accelerated.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually −78 ° C.-100 ° C., preferably 0 ° C.-room temperature.

[Step F-7]
Step F-7 is a method for producing compound (30) by deprotecting compound (29).
The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent. For example, hydrocarbon, aromatic, ether, halogenated hydrocarbon, nitrile, There are amide-based, sulfoxide-based, alcohol-based, aqueous-based and pyridine-based solvents, and a mixed solvent system such as alcohol-water and acetonitrile-water is preferable.
The reagent used is not particularly limited as long as it is an acid such as a hard acid such as hydrochloric acid or sulfuric acid, or an organic acid such as camphorsulfonic acid or toluenesulfonic acid, but is preferably a hard acid such as sulfuric acid.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually −78 ° C.-100 ° C., preferably 0 ° C.-room temperature.

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^４’、Ｒ^５、Ｐ^４、Ｒ^８及びＲ^８’は、前記と同意義を示す。］ [G method]

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ^{4 ′} , R ⁵ , P ⁴ , R ⁸ and R ^{8 ′} have the same meaning as described above. ]

[Step G-1]
Step G-1 is a step of producing compound (31) by reducing compound (1).
The solvent used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting material to some extent, but is not limited to aromatic, ether, ester, halogenated hydrocarbon, nitrile, amide, There are sulfoxide type, hydrocarbon type solvent and the like, preferably aromatic type solvent, halogenated hydrocarbon type solvent or hydrocarbon type solvent, more preferably tetrahydrofuran.
Examples of the reagent used include a boron reagent and an aluminum reagent, and trimethoxyaluminum hydride is preferable.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually −78 ° C.-room temperature, preferably −78-0 ° C.

[Step G-2]
Step G-2 is a method for obtaining compound (32a) or (32b) by optically resolving compound (31) using an enzyme such as lipase.
The solvent used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent, but is not limited to aromatic, ether, ester, halogenated hydrocarbon, nitrile, amide, There are sulfoxide-based and hydrocarbon-based solvents, preferably aromatic-based solvents, halogenated hydrocarbon-based solvents or hydrocarbon-based solvents, and more preferably hexane.
Reagents used include ester reagents, preferably vinyl esters, and more preferably vinyl acetate.
Examples of the enzyme used include Candida Antarctica lipase, Pseudomonas fluorescens lipase, Pseudomonas cepacia lipase, porcine pancreatic lipase, porcine liver esterase, and Candida rugosa lipase.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent, enzyme and the like, but is usually 0 to 150 ° C., preferably room temperature to 40 ° C.

In addition, the G-2 step can be led to a diastereomer using an appropriate asymmetric auxiliary group and resolved by an appropriate method such as recrystallization, distillation, column chromatography, etc. On reaction (II) of organic compounds (November 25, 1957, publisher Maruzen Co., Ltd., Editor, The Chemical Society of Japan) p. 503-556 or the like. More specifically, a carboxylic acid reagent such as phthalic anhydride is reacted with the compound (31), and the resulting mixture of the carboxylic acid derivatives (32a) and (32b) is converted into phenethylamine, quinine, cinchosine, methylbenzylamine. It can be divided by recrystallization using naphthylethylamine or the like.

[Step G-3]
Step G-3 is a method of synthesizing compound (33a) or (33b) by hydrolyzing compound (32a) or (32b).
The solvent used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent, but is not limited to aromatic, ether, ester, halogenated hydrocarbon, nitrile, amide, There are sulfoxide-based, hydrocarbon-based, alcohol-based, aqueous-based, mixed solvents thereof, etc., preferably ether-based solvents, alcohol-based solvents, aqueous-based solvents or mixed solvent systems thereof, more preferably methanol, ethanol or water. is there.
Reagents used include inorganic bases, preferably potassium carbonate, sodium hydroxide or potassium hydroxide.
While the reaction temperature varies depending on the kind of starting compound, solvent, reagent and the like, it is generally 0-60 ° C., preferably 0 ° C.-room temperature.

[Step G-4]
Step G-4 is a method of synthesizing compound (1a) or (1b) by oxidizing compound (33a) or (33b).
The solvent used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent, but is not limited to aromatic, ether, ester, halogenated hydrocarbon, nitrile, amide, There are sulfoxide-based and hydrocarbon-based solvents, preferably halogenated hydrocarbon-based solvents, and more preferably dichloromethane.
The reagent used is acid chloride, preferably oxalyl chloride.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually −78 ° C.-room temperature, preferably −78-0 ° C.

[Method H]
Method H is a method for producing compound (1a) or (1b) which is an optical isomer of compound (1) by optical resolution prior to Step A-1 in Method A above.

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^４’、Ｒ^５、Ｐ^４、Ｒ^８及びＲ^８’は、前記と同意義を示す。Ｒ^Ｐは、Ｃ１－Ｃ６アルキル基又は２つのＲ^Ｐが一緒になって、Ｃ１－Ｃ６アルキレン基を示す。］ [Method H]

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ^{4 ′} , R ⁵ , P ⁴ , R ⁸ and R ^{8 ′} have the same meaning as described above. R ^P represents a C1-C6 alkyl group or two R ^{P taken} together to represent a C1-C6 alkylene group. ]

[Step H-1]
Step H-1 is a step of producing compound (34) from compound (1).
The solvent used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent, but is not limited to aromatic, ether, ester, halogenated hydrocarbon, nitrile, amide, There are sulfoxide type, hydrocarbon type solvent, etc., preferably aromatic type solvent, halogenated hydrocarbon type solvent or hydrocarbon type solvent, more preferably benzene or toluene.
Examples of the reagent used include ethanediol and propanediol, preferably hydrobenzoin.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually −78 ° C. under reflux conditions, and preferably 60 ° C. under reflux conditions.

[Step H-2]
Step H-2 is a step of optically resolving compound (34) to produce compound (34a) or (34b).
Examples of the solvent used include the same solvents as in step A-1, hydrocarbon-based, alcohol-based, mixed solvents of hydrocarbon-based and alcohol-based solvents, preferably hexane-isopropanol or hexane-ethanol.
As a column used for optical resolution, there is a column similar to the F method.
The use temperature is usually 0-40 ° C., preferably 20-40 ° C.
After completion of the reaction, the target compound of this reaction can be obtained by distilling off the eluate (solvent).

[Step H-3]
Step H-3 is a step of synthesizing compound (1a) or (1b) from compound (34a) or (34b).
The solvent used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent, but is not limited to aromatic, ether, ester, halogenated hydrocarbon, nitrile, amide, There are sulfoxide-based, hydrocarbon-based, ketone-based, aqueous-based solvents and the like, preferably ketone-based solvents and aqueous-based solvents, more preferably acetone or water.
Examples of reagents used include acid catalysts such as inorganic acids such as hydrochloric acid, acetic acid, sulfuric acid, toluenesulfonic acid, and camphorsulfonic acid, and organic acids.
The reaction temperature varies depending on the kind of the raw material compound, solvent, reagent and the like, but is usually 0-100 ° C., preferably 60-100 ° C.

The compound having the general formula (I) obtained by the above method or a pharmacologically acceptable salt thereof shows activity as an α ₂ δ ligand and has an affinity for the α ₂ δ subunit of the voltage-dependent calcium channel. It is useful as an active ingredient in pharmaceutical compositions used for the treatment and / or prevention of pain, central nervous system disorders, and other disorders.

“Pain” includes, for example, acute pain, chronic pain, pain resulting from soft tissue or peripheral injury, postherpetic neuralgia, occipital neuralgia, trigeminal neuralgia, medullary or intercostal neuralgia, central nervous pain, neuropathic pain, fragment Pain associated with headache, osteoarthritis or rheumatoid arthritis, pain associated with contusion, sprain or trauma, spinal pain, pain due to spinal cord or brainstem injury, low back pain, sciatica, tooth pain, myofascial pain syndrome, society Pain incision, gout pain, pain resulting from burns, heart pain, muscle pain, eye pain, inflammatory pain, oral and facial pain, abdominal pain, dysmenorrhea, pain associated with labor pain or endometriosis, somatic pain Pain associated with nerve or root injury, amputation, painful tics, pain associated with neuroma or vasculitis, pain resulting from diabetic neuropathy (or diabetic peripheral neuropathic pain), chemotherapy-induced neuropathy Arise from Atypical facial pain, neuropathic back pain, trigeminal neuralgia, occipital neuralgia, medullary or intercostal neuralgia, HIV-related neuralgia, AIDS-related neuralgia, hyperalgesia, burn pain, idiopathic pain, chemotherapy pain, occipital Neuralgia, psychogenic pain, pain associated with gallstones, neuropathic or non-neuropathic pain associated with cancer, phantom limb pain, functional abdominal pain, headache, acute or chronic tension headache, sinus headache, cluster headache, Temporal mandibular pain, maxillary sinus pain, pain resulting from ankylosing spondyloarthritis, postoperative pain, scar pain, chronic non-neuropathic pain, tendon pain associated with hyperlipidemia, fibromyalgia, fibromyalgia, etc. is there.

“Central nervous system disorders” include, for example, fainting attacks, epilepsy (particularly partial epilepsy, partial seizures in adults, partial seizures in epileptic patients), asphyxia, general anoxia, hypoxia, spinal cord injury, trauma Brain injury, head trauma, cerebral ischemia, stroke, cerebral vascular disorder, neurocardiac syncope, nervous syncope, irritable carotid sinus, neurovascular syndrome, arrhythmia, mood disorder (such as depression), treatment resistance Depression, seasonal emotional disorder, childhood depression, premenstrual syndrome, premenstrual dysphoric disorder, hot flash, bipolar disorder, manic depression, behavioral disorder, disruptive behavioral disorder, stress-related physical disorder, anxiety disorder, Borderline personality disorder, schizophrenia, schizophrenia disorder, paranoid disorder, simple psychotic disorder, shared psychotic disorder, substrate-induced psychotic disorder, psychosis related anxiety, psychotic mood disorder, schizophrenia Continual mood disorder, behavioral disorder related to mental retardation, insomnia (primary insomnia, secondary insomnia, transient insomnia, etc.), sleepwalking, sleep deprivation, REM sleep disorder, sleep apnea, hyperactivity There are sleepiness, parasomnia, sleep-wake cycle disorder, jet lag, narcolepsy, generalized anxiety disorder.

“Other disorders” include, for example, chronic obstructive airway disease, bronchial pneumonia, chronic bronchitis, cystic fibrosis, adult respiratory distress syndrome, bronchospasm, cough, pertussis, allergy, contact dermatitis, atopic Dermatitis, hives, pruritus, pruritus related to hemodialysis, inflammatory bowel disease, psoriasis, osteoarthritis, cartilage damage, rheumatoid arthritis, psoriatic arthritis, asthma, sunburn, hypersensitivity disorder, Parkinson's disease, Huntington's disease, Alzheimer's disease, delirium, dementia, amnesia disorder, autism, attention deficit hyperactivity disorder, Reiter syndrome, Down syndrome, Sjogren's syndrome, hypertension, hematopoiesis, postoperative neuroma, benign prostatic hypertrophy, periodontal disease, hemorrhoids , Anal fissure, infertility, reflex sympathetic dystrophy, hepatitis, vasodilatation, fibrosis, collagen disease, angina, migraine, Raynaud's disease, dry eye syndrome , Conjunctivitis, spring catarrh, proliferative vitreoretinopathy, multiple sclerosis, amyotrophic lateral sclerosis, pervasive developmental disorder, human immunodeficiency virus infection, HIV encephalopathy, dissociative disorder, eating disorder, ulcer Colitis, Crohn's disease, irritable bowel syndrome, chronic pancreatitis, chronic fatigue syndrome, sudden infant death syndrome, overactive bladder, chronic cystitis, chemotherapy-induced cystitis, primary movement disorder, ataxia, dyskinesia, Spasticity, Tourette syndrome, Scott syndrome, paralysis, extrapyramidal movement disorder, restless leg syndrome, breast pain syndrome, motion sickness, lupus erythematosus, immunodeficiency, inflammatory gastrointestinal disorders, gastritis, proctitis, gastroduodenum Examples include ulcers, peptic ulcers, dyspepsia, vomiting, breast cancer, gastric cancer, gastric lymphoma, ganglion cell blastoma, and small cell carcinoma.

When the pharmaceutical composition containing the compound having the general formula (I) or a pharmacologically acceptable salt thereof is administered to a mammal (eg, human, horse, cow, pig, etc., preferably human), It is administered systemically or locally, orally or parenterally.

The pharmaceutical composition of the present invention can be prepared by selecting an appropriate form according to the administration method and preparing various preparations usually used.

Oral pharmaceutical compositions include tablets, pills, powders, granules, capsules, liquids, suspensions, emulsions, syrups, elixirs and the like. The preparation of such a pharmaceutical composition includes excipients, binders, disintegrants, lubricants, swelling agents, swelling aids, coating agents, plasticizers, stabilizers, antiseptics, anti-fouling agents, ordinarily used as additives. An oxidizing agent, a coloring agent, a solubilizing agent, a suspending agent, an emulsifier, a sweetening agent, a preservative, a buffering agent, a diluent, a wetting agent and the like are appropriately selected as necessary, and are carried out according to a conventional method.

The forms of parenteral pharmaceutical compositions include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, and inhalations. There are agents. Preparation of the pharmaceutical composition in such a form involves the use of stabilizers, preservatives, solubilizers, moisturizers, preservatives, antioxidants, flavoring agents, gelling agents, neutralizing agents, and dissolution agents that are commonly used as additives. Adjuvants, buffering agents, isotonic agents, surfactants, colorants, buffering agents, thickeners, wetting agents, fillers, absorption enhancers, suspending agents, binders, etc. are selected as necessary. And carried out in accordance with conventional methods.

The dose of the compound having the general formula (I) or a pharmacologically acceptable salt thereof varies depending on symptoms, age, body weight and the like, but in the case of oral administration, adults (body weight of about 60 kg) 1 to several times a day. As a compound, the compound equivalent is 1-2000 mg per person, preferably 10-600 mg. In the case of parenteral administration, the compound equivalent is 0.1-1000 mg per adult once a day or once per adult. The preferred amount is 1 to 300 mg.

（構造式は、相対配置を示す。）
（１－ａ）（±）－Ｎ－｛（２Ｅ）－２－［（１Ｓ^＊，５Ｒ^＊）－ビシクロ［３．２．０］ヘプタ－２－エン－６－イリデン］アセチル｝ベンズアミド
［２－（ベンゾイルアミノ）－２－オキソエチル］ホスホン酸ジエチル（Ａｄｖ．Ｓｙｎｔｈ．Ｃａｔａｌ．２００２，３４４，９５３）（１４．５ｇ，４８．６ｍｍｏｌ）のテトラヒドロフラン溶液（６０ｍＬ）に，－７８℃攪拌下，ｎ－ブチルリチウムのヘキサン溶液（１．５８Ｍ，６１．５ｍＬ，９７．１ｍｍｏｌ）を滴下し，そのままの温度で１０分攪拌した。０℃に昇温してさらに２０分攪拌した後，（１Ｓ^＊，５Ｒ^＊）－ビシクロ［３．２．０］ヘプタ－２－エン－６－オン（５．００ｇ，４６．２ｍｍｏｌ）のテトラヒドロフラン溶液（２０ｍＬ）を滴下し，そのままの温度で６時間攪拌した。反応液に０．５Ｍ塩酸を加え，ジエチルエーテルで抽出した。有機層を飽和食塩水で洗浄し，無水硫酸ナトリウムで乾燥した。ろ過，減圧濃縮後，残渣を酢酸エチルとヘキサンから再結晶することにより，目的物を白色固体として得た（７．７７ｇ，６６％）。
¹H NMR (CDCl₃, 400 MHz):
δ 2.51-2.58 (1H, m), 2.66-2.74 (1H, m), 2.94-3.01 (1H, m), 3.37 (1H, dd, J = 2.7, 8.2 Hz), 3.46-3.53 (1H, m), 3.68-3.73 (1H, m), 5.76-5.78 (1H, m), 5.82-5.86 (1H, m), 7.13 (1H, ddd, J = 2.4, 2.4, 2.4 Hz), 7.47-7.51 (2H, m), 7.57-7.61 (1H, m), 7.84-7.87 (2H, m), 8.49 (1H, br s). Example 1 [(1S ^* , 5R ^* , 6S ^* )-6- (aminomethyl) bicyclo [3.2.0] hept-2-en-6-yl] acetic acid (racemic)

(Structural formula indicates relative arrangement.)
(1-a) (±) -N-{(2E) -2-[(1S ^* , 5R ^* )-bicyclo [3.2.0] hept-2-en-6-ylidene] acetyl} benzamide [2 -(Benzoylamino) -2-oxoethyl] diethyl phosphonate (Adv. Synth. Catal. 2002, 344, 953) (14.5 g, 48.6 mmol) in tetrahydrofuran (60 mL) was stirred at -78 ° C under n -A solution of butyllithium in hexane (1.58 M, 61.5 mL, 97.1 mmol) was added dropwise and stirred at the same temperature for 10 minutes. After raising the temperature to 0 ° C. and stirring for another 20 minutes, (1S ^* , 5R ^* )-bicyclo [3.2.0] hept-2-en-6-one (5.00 g, 46.2 mmol) in tetrahydrofuran was obtained. The solution (20 mL) was added dropwise and stirred at the same temperature for 6 hours. 0.5M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was recrystallized from ethyl acetate and hexane to obtain the desired product as a white solid (7.77 g, 66%).
¹ H NMR (CDCl ₃ , 400 MHz):
δ 2.51-2.58 (1H, m), 2.66-2.74 (1H, m), 2.94-3.01 (1H, m), 3.37 (1H, dd, J = 2.7, 8.2 Hz), 3.46-3.53 (1H, m) , 3.68-3.73 (1H, m), 5.76-5.78 (1H, m), 5.82-5.86 (1H, m), 7.13 (1H, ddd, J = 2.4, 2.4, 2.4 Hz), 7.47-7.51 (2H, m), 7.57-7.61 (1H, m), 7.84-7.87 (2H, m), 8.49 (1H, br s).

(1-b) (±) -N- {2-[(1S ^* , 5R ^* )-6-cyanobicyclo [3.2.0] hept-2-en-6-yl] acetyl} benzamide N- { (2E) -2-[(1S ^* , 5R ^* )-bicyclo [3.2.0] hept-2-en-6-ylidene] acetyl} benzamide (2.50 g, 9.87 mmol) was added to diethylaluminum cyanide. A toluene solution of nido (1.0 M, 29.6 mL, 29.6 mmol) and trimethylsilylcyanide (97%, 8.14 mL, 59.2 mmol) were added, and the mixture was stirred at 48 ° C. overnight. Saturated sodium hydrogen carbonate and water were added to the reaction solution while cooling with ice, and insoluble materials were removed by Celite filtration. After liquid separation and extraction with methylene chloride, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the target product as a yellow solid (1.73 g, 63%, Major / Minor = 66/34).
¹ H NMR (CDCl ₃ , 400 MHz):
Major isomer:
δ 2.00 (1H, dd, J = 3.9, 12.9 Hz), 2.46-2.49 (1H, m), 2.60-2.67 (1H, m), 2.87-2.96 (1H, m), 2.98 (1H, dd, J = 9.0, 12.9 Hz), 3.42-3.49 (1H, m), 3.49 (1H, d, J = 18.8 Hz), 3.56 (1H, d, J = 18.8 Hz), 3.57-3.59 (1H, m), 5.82- 5.84 (2H, m), 7.52-7.56 (2H, m), 7.62-7.66 (1H, m), 7.87-7.89 (1H, m), 8.93 (1H, s).
Minor isomer:
δ 2.41 (1H, dd, J = 3.9, 12.9 Hz), 2.51-2.52 (1H, m), 2.68-2.76 (1H, m), 2.87-2.96 (1H, m), 3.28-3.35 (1H, m) , 3.42-3.49 (1H, m), 3.55-3.56 (1H, m), 3.59-3.61 (2H, m), 5.82-5.85 (1H, m), 5.93-5.95 (1H, m), 7.52-7.56 ( 2H, m), 7.62-7.66 (1H, m), 7.87-7.89 (1H, m), 8.93 (1H, s).

(1-c) [(1S ^* , 5R ^* )-6-cyanobicyclo [3.2.0] hept-2-en-6-yl] acetic acid N- {2-[(1S ^* , 5R ^* )- To a tetrahydrofuran solution (20 mL) of 6-cyanobicyclo [3.2.0] hept-2-en-6-yl] acetyl} benzamide (1.52 g, 5.42 mmol) was added 1M aqueous sodium hydroxide solution (7.1 mL). ) And stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was washed with methylene chloride. The aqueous layer was neutralized with 2M hydrochloric acid, extracted with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the desired product as an oily substance (1.22 g,> 99%, Major / Minor = 63/37).
¹ H NMR (CDCl ₃ , 400 MHz):
Major isomer:
δ 1.99 (1H, dd, J = 3.9, 12.9 Hz), 2.43-2.49 (1H, m), 2.59-2.66 (1H, m), 2.83-2.85 (1H, m), 2.89-2.90 (1H, m) , 2.92-2.98 (1H, m), 3.39-3.46 (1H, m), 3.52-3.56 (1H, m), 5.81-5.86 (2H, m).
Minor isomer:
δ 2.37 (1H, dd, J = 3.9, 12.9 Hz), 2.43-2.49 (1H, m), 2.68-2.76 (1H, m), 2.79-2.85 (2H, m), 2.89-2.90 (1H, m) , 2.92-2.98 (1H, m), 3.27-3.34 (1H, m), 5.83-5.86 (1H, m), 5.91-5.94 (1H, m).

(1-d) [(1S ^* , 5R ^* )-6-cyanobicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate [(1S ^* , 5R ^* )-6- To a benzene solution (17 mL) of cyanobicyclo [3.2.0] hept-2-en-6-yl] acetic acid (500 mg, 2.82 mmol) under stirring at 80 ° C., N, N-dimethylformamide ditert-butyl Acetal (2.70 mL, 11.3 mmol) was added dropwise. After stirring as it was at 80 ° C. for 2 hours, the reaction solution was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the desired product as an oily substance (423 mg, 64%, Major / Minor = 62/38).
¹ H NMR (CDCl ₃ , 400 MHz):
Major isomer:
δ 1.47 (9H, s), 1.95 (1H, dd, J = 3.9, 12.9 Hz), 2.40-2.43 (1H, m), 2.45-2.47 (1H, m), 2.66-2.69 (1H, m), 2.72 -2.75 (1H, m), 2.90 (1H, dd, J = 8.6, 12.9 Hz), 3.37-3.44 (1H, m), 3.48-3.52 (1H, m), 5.79-5.82 (2H, m).
Minor isomer:
δ 1.48 (9H, s), 2.33 (1H, dd, J = 3.9, 12.9 Hz), 2.56-2.64 (2H, m), 2.66-2.69 (1H, m), 2.72-2.75 (1H, m), 2.78 -2.85 (1H, m), 2.92-2.95 (1H, m), 3.25-3.32 (1H, m), 5.80-5.84 (1H, m), 5.90-5.93 (1H, m).

(1-e) {(1S ^* , 5R ^* )-6-[(tert-butoxycarbonyl) amino] bicyclo [3.2.0] hept-2-en-6-yl} tert-butyl acetate [(1S ^* , 5R ^* )-6-cyanobicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate (150 mg, 0.64 mmol) in methylene chloride solution (6.9 mL) While stirring at 78 ° C., a toluene solution of diisobutylaluminum hydride (0.99 M, 0.84 mL, 0.84 mmol) was added dropwise. After stirring at the same temperature for 10 minutes, sodium borohydride (73.0 mg, 1.93 mmol) and methanol (2.3 mL) were added, and the temperature was raised to room temperature. After stirring for 1 hour, potassium carbonate (107 mg, 0.77 mmol) and ditert-butyl dicarbonate (281 mg, 1.29 mmol) were added and stirred overnight. A 30% aqueous solution of potassium sodium tartrate (7.0 mL) was added to the reaction mixture, and the mixture was stirred for a while, then separated and extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the desired product as an oily substance (49.7 mg, 23%, Major / Minor = 50/50).
¹ H NMR (CDCl ₃ , 400 MHz):
Mixture of two isomers:
δ 1.41-1.44 (18H, m), 1.57-1.63 (1.5H, m), 1.83-1.92 (0.5H, m), 2.07 (0.5H, dd, J = 8.6, 12.1 Hz), 2.15-2.24 (0.5 H, m), 2.32-2.51 (3H, m), 2.72-2.77 (0.5H, m), 2.79-2.85 (0.5H, m), 3.17-3.36 (3H, m), 4.95 (1H, br s) , 5.70-5.79 (2H, m).

(1-f) [(1S ^* , 5R ^* , 6S ^* )-6- (aminomethyl) bicyclo [3.2.0] hept-2-en-6-yl] acetic acid {(1S ^* , 5R ^* ) -6-[(tert-Butoxycarbonyl) amino] bicyclo [3.2.0] hept-2-en-6-yl} tert-butyl acetate (49.7 mg, 0.15 mmol) in 4N hydrochloric acid-ethyl acetate ( 2.0 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, methylene chloride (1.5 mL) and triethylamine (25 μL, 0.18 mmol) were added to the residue, and the mixture was stirred at room temperature for 2 hr. The precipitated solid was washed with methylene chloride to obtain the desired product (single isomer) as a white solid (13.9 mg, 52%).
Mp: 170-172 ℃
¹ H-NMR (400 MHz, CD ₃ OD): δ ppm: 1.61 (1H, dd, J = 4.4, 12.4 Hz), 2.14 (1H, dd, J = 8.9, 12.4 Hz), 2.53-2.50 (1H, m ), 2.54 (1H, dd, J = 3.0, 12.4Hz), 2.54 (1H, d, J = 16.1Hz), 2.62 (1H, d, J = 16.1Hz), 2.80-2.84 (1H, m), 3.08 (1H, d, J = 12.9Hz), 3.12 (1H, d, J = 12.9Hz), 3.21-3.27 (1H, m), 5.79-5.83 (2H, m).
IR (KBr): cm ^-1 : 2935, 2853, 2199, 1634, 1511, 1415, 1399, 1290, 1169.
MS (EI): m / z: 181 (M) ⁺ .
Anal.calcd for C ₁₀ H ₁₅ NO ₂ : C, 66.27; H, 8.34; N, 7.73; Found C, C, 65.53; H, 8.21; N, 7.63.

Example 2 [(1R, 5S, 6R) -6 (aminomethyl) bicyclo [3.2.0] hept-2-en-6-yl] acetic acid (optically active substance)

市販の（１Ｒ、５Ｓ）ビシクロ［３．２．０］へプタ－２－エン－６－オン（１．００ｇ、９．２４ｍｍｏｌ）より同様に合成した（白色固体　６４２．３ｍｇ）。
Mp: 177-178℃
[α]²⁵ _D-39.1° (c 0.871, MeOH).
¹H-NMR(400MHz、CD₃OD) :δ ppm: 1.61(1H, dd, J=4.4, 12.4Hz), 2.14(1H, dd, J= 8.9, 12.4Hz), 2.53-2.50(1H, m), 2.54(1H, dd, J=3.0, 12.4Hz), 2.54(1H, d, J=16.1Hz), 2.62(1H, d, J=16.1Hz), 2.80-2.84(1H, m), 3.08(1H, d, J=12.9Hz), 3.12(1H, d, J=12.9Hz), 3.21-3.27(1H, m), 5.79-5.83(2H, m).
IR (KBr) : cm^-1: 2946, 2902, 1644, 1577, 1522, 1384, 1303.
MS (FAB) : m/z : 182 (M+H)⁺, 220 (M+K)⁺.
Anal. calcd for C₁₀H₁₅NO₂: C, 66.27; H, 8.34; N, 7.73; Found C, C, 65.79; H, 8.31; N, 7.73.

It was synthesized in the same manner from commercially available (1R, 5S) bicyclo [3.2.0] hept-2-en-6-one (1.00 g, 9.24 mmol) (white solid 642.3 mg).
Mp: 177-178 ℃
[α] ²⁵ _D -39.1 ° (c 0.871, MeOH).
¹ H-NMR (400 MHz, CD ₃ OD): δ ppm: 1.61 (1H, dd, J = 4.4, 12.4 Hz), 2.14 (1H, dd, J = 8.9, 12.4 Hz), 2.53-2.50 (1H, m ), 2.54 (1H, dd, J = 3.0, 12.4Hz), 2.54 (1H, d, J = 16.1Hz), 2.62 (1H, d, J = 16.1Hz), 2.80-2.84 (1H, m), 3.08 (1H, d, J = 12.9Hz), 3.12 (1H, d, J = 12.9Hz), 3.21-3.27 (1H, m), 5.79-5.83 (2H, m).
IR (KBr): cm ^-1 : 2946, 2902, 1644, 1577, 1522, 1384, 1303.
MS (FAB): m / z: 182 (M + H) ⁺ , 220 (M + K) ⁺ .
Anal.calcd for C ₁₀ H ₁₅ NO ₂ : C, 66.27; H, 8.34; N, 7.73; Found C, C, 65.79; H, 8.31; N, 7.73.

市販の（１Ｓ、５Ｒ）ビシクロ［３．２．０］へプタ－２－エン－６－オン（１．００ｇ、９．２４ｍｍｏｌ）より合成した（白色固体　８４０．５ｍｇ）。
Mp: 176-177℃
[α]²⁵ _D+43.9° (c 1.13, MeOH).
¹H-NMR(400MHz、CD₃OD) :δ ppm: 1.61(1H, dd, J=4.4, 12.4Hz), 2.14(1H, dd, J= 8.9, 12.4Hz), 2.53-2.50(1H, m), 2.54(1H, dd, J=3.0, 12.4Hz), 2.54(1H, d, J=16.1Hz), 2.62(1H, d, J=16.1Hz), 2.80-2.84(1H, m), 3.08(1H, d, J=12.9Hz), 3.12(1H, d, J=12.9Hz), 3.21-3.27(1H, m), 5.79-5.83(2H, m).
IR (KBr) : cm^-1: 2946, 2902, 1644, 1577, 1522, 1384, 1303.
MS (FAB) : m/z : 182 (M+H)⁺, 220 (M+K)⁺.
Anal. calcd for C₁₀H₁₅NO₂: C, 66.27; H, 8.34; N, 7.73; Found C, C, 65.80; H, 8.33; N, 7.68. Example 3 [(1S, 5R, 6S) -6 (aminomethyl) bicyclo [3.2.0] hept-2-en-6-yl] acetic acid (optically active substance)

Synthesized from commercially available (1S, 5R) bicyclo [3.2.0] hept-2-en-6-one (1.00 g, 9.24 mmol) (840.5 mg of white solid).
Mp: 176-177 ℃
[α] ²⁵ _D + 43.9 ° (c 1.13, MeOH).
¹ H-NMR (400 MHz, CD ₃ OD): δ ppm: 1.61 (1H, dd, J = 4.4, 12.4 Hz), 2.14 (1H, dd, J = 8.9, 12.4 Hz), 2.53-2.50 (1H, m ), 2.54 (1H, dd, J = 3.0, 12.4Hz), 2.54 (1H, d, J = 16.1Hz), 2.62 (1H, d, J = 16.1Hz), 2.80-2.84 (1H, m), 3.08 (1H, d, J = 12.9Hz), 3.12 (1H, d, J = 12.9Hz), 3.21-3.27 (1H, m), 5.79-5.83 (2H, m).
IR (KBr): cm ^-1 : 2946, 2902, 1644, 1577, 1522, 1384, 1303.
MS (FAB): m / z: 182 (M + H) ⁺ , 220 (M + K) ⁺ .
Anal.calcd for C ₁₀ H ₁₅ NO ₂ : C, 66.27; H, 8.34; N, 7.73; Found C, C, 65.80; H, 8.33; N, 7.68.

（構造式は、相対配置を示す。）
（４－ａ）（１Ｒ^＊、５Ｓ^＊、７Ｒ^＊）－７－（メチルチオ）ビシクロ［３．２．０］へプタ－２－エン－６－オン
　（１Ｒ^＊、５Ｓ^＊、７Ｒ^＊）－７－クロロビシクロ［３．２．０］へプタ－２－エン－６－オン（２．８４ｇ、１６ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（２０ｍＬ）溶液に、ナトリウムチオメトキシド（１．５４ｇ、２２ｍｍｏｌ）を加えた後、室温で３時間攪拌した。飽和食塩水を加え、ジエチルエーテルで抽出した。有機層を飽和食塩水で洗浄し無水硫酸マグネシウムで乾燥後、ろ液を減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィーにより精製し標記化合物を淡黄色油状物質として得た（０．７５ｇ、３０％）。
MS (EI) : m/z : 154 (M)^+
1H-NMR(400MHz、CDCl₃) :δ ppm: 2.18(3H, s), 2.47(1H, dddd, J=2.9, 4.4, 8.5, 17.1Hz), 2.73(1H, d, J=17.1Hz), 3.81-3.89(2H, m), 4.38(1H, dd, J=2.9, 8.5Hz), 5.86-5.88(1H, m), 5.91-5.92(1H, m). Example 4 [(1R ^* , 5S ^* , 6S ^* , 7R ^* )-6- (aminomethyl) -7- (methylthio) bicyclo [3.2.0] hept-2-en-6-yl ] Acetic acid (racemic)

(Structural formula indicates relative arrangement.)
(4-a) (1R ^* , 5S ^* , 7R ^* )-7- (methylthio) bicyclo [3.2.0] hept-2-en-6-one (1R ^* , 5S ^* , 7R ^* )- To a solution of 7-chlorobicyclo [3.2.0] hept-2-en-6-one (2.84 g, 16 mmol) in N, N-dimethylformamide (20 mL) was added sodium thiomethoxide (1.54 g, 22 mmol) was added, followed by stirring at room temperature for 3 hours. Saturated brine was added and extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound as a pale yellow oil (0.75 g, 30%).
MS (EI): m / z: 154 (M) ^+
1 H-NMR (400 MHz, CDCl ₃ ): δ ppm: 2.18 (3H, s), 2.47 (1H, dddd, J = 2.9, 4.4, 8.5, 17.1 Hz), 2.73 (1H, d, J = 17.1 Hz) , 3.81-3.89 (2H, m), 4.38 (1H, dd, J = 2.9, 8.5Hz), 5.86-5.88 (1H, m), 5.91-5.92 (1H, m).

(4-b) (1R ^* , 5S ^* , 7R ^* )-7- (methylthio) bicyclo [3.2.0] hept-2-ene-6-ylidene acetate tert-butyl dimethoxyphosphoryl acetate tert-butyl ( 1.01 g, 4.5 mmol) dimethoxyethane solution (10 mL) and sodium hydride (> 63% oily, 171.4 mg, 4.5 mmol) to a reaction solution prepared in advance (1R ^* , 5S ^* , 7R ^* ) A tetrahydrofuran solution (10 mL) of -7- (methylthio) bicyclo [3.2.0] hept-2-en-6-one (0.70 g, 4.5 mmol) was added dropwise under ice cooling. After gradually returning to room temperature and stirring for 1 hour, a saturated aqueous ammonium chloride solution and saturated brine were sequentially added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound as a pale yellow oil (0.62 g, 55%, E , Z-form mixture).
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm: Major isomer 1.45 (9H, S), 2.29 (3H, m), 2.29-2.32 (1H, m), 2.69-2.72 (1H, m), 3.36- 3.40 (1H, m), 3.71-3.81 (1H, m), 5.71-5.94 (3H, m): Minor isomer 1.48 (9H, s), 2.11 (3H, s), 2.29-2.32 (1H, m), 2.69-2.72 (1H, m), 3.32-3.40 (2H, m), 4.22-4.24 (1H, m), 5.71-5.94 (3H, m).

(4-c) [(1R ^* , 5S ^* , 7R ^* )-7- (methylthio) -6- (nitromethyl) bicyclo [3.2.0] hept-2-en-6-yl] acetic acid tert- Butyl (1R ^* , 5S ^* , 7R ^* )-7- (methylthio) bicyclo [3.2.0] hept-2-ene-6-ylidene acetate tert-butyl acetate (0.62 g, 2.46 mmol) was added to nitromethane (5 mL), 1,8-diazabicyclo [5.4.0] undec-7-ene (0.37 mL, 2.46 mmol) was added, and the mixture was stirred with heating at 50-60 ° C. for 6 hr. The mixture was allowed to cool, diluted with 1N hydrochloric acid and saturated brine, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product as a colorless oil (0.13 g, 17%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm: 1.46 (9H, s), 1.98 (3H, s), 2.42-2.44 (1H, m), 2.50-2.56 (1H, m), 2.63 (1H, d, J = 18.4Hz), 2.80 (1H, d, J = 18.4Hz), 2.82 (1H, d, J = 15.6Hz), 3.60 (1H, d, J = 9.0Hz), 3.60-3.72 (1H, m), 5.00 (2H, s), 5.77-5.79 (1H, m), 5.91-5.93 (1H, m).

(4-d) [(1R ^* , 5S ^* , 7R ^* )-6- (aminomethyl) -7- (methylthio) bicyclo [3.2.0] hept-2-en-6-yl] acetic acid tert- Butyl [(1R ^* , 5S ^* , 7R ^* )-7- (methylthio) -6- (nitromethyl) bicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate (0. 13 g, 0.42 mmol) was dissolved in ethanol (8 mL) and water (4 mL), and iron powder (306.2 mg, 6.4 mmol) and ammonium chloride (22.3 mg, 0.42 mmol) were added. Stir for half an hour. The mixture was allowed to cool, diluted with saturated brine, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate, and insoluble material was removed by celite filtration. The filtrate was separated into an organic layer and an aqueous layer. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the desired product as a pale yellow solid (0.12 g, < 100%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm:
1.42-1.49 (1H, m), 1.44 (9H, s), 2.03 (3H, s), 2.43-2.52 (1H, m), 2.46 (1H, d, J = 16.1Hz), 2.61-2.63 (1H, m), 2.63 (1H, d, J = 16.1Hz), 2.90 (1H, d, J = 13.2Hz), 3.06 (1H, d, J = 13.2Hz), 3.39 (1H, d, J = 8.8Hz) , 3.61 (1H, d, J = 8.8Hz), 5.76-5.79 (1H, m), 5.90-5.93 (1H, m).

(4-e) [(1R ^* , 5S ^* , 6S ^* , 7R ^* )-6- (aminomethyl) -7- (methylthio) bicyclo [3.2.0] hept-2-en-6-yl ] Acetic acid [(1R ^* , 5S ^* , 7R ^* )-6- (aminomethyl) -7- (methylthio) bicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate (0 4N hydrochloric acid ethyl acetate solution (10 mL) was added to .12 g, 0.42 mmol), and the mixture was stirred at room temperature for 1 hour, and then the solvent was distilled off under reduced pressure. Dichloromethane was added to the residue to suspend it, and then triethylamine was added dropwise, and the resulting powder was collected by filtration. After washing with dichloromethane and drying under reduced pressure, the desired product was obtained as a white powder (38.8 mg, 40%).
Mp: 176-178 ℃
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm:
1.99 (3H, s), 2.48 (1H, dddd, J = 2.0, 4.3, 8.5, 21.0Hz), 2.49 (1H, d, J = 17.1Hz), 2.60-2.67 (1H, m), 2.90 (dt, J = 1.3, 8.8Hz), 2.98 (1H, dd, J = 1.3, 17.1Hz), 3.10 (1H, d, J = 12.8Hz), 3.20 (1H, dd, J = 1.3, 12.8Hz), 3.42 ( 1H, d, J = 8.8Hz), 3.60-3.66 (1H, m), 5.72-5.75 (1H, m), 5.90-5.93 (1H, m).
IR (KBr): cm ^-1 : 3042, 2300, 2947, 2914, 1625, 1562, 1529, 1393, 1174.
MS (FAB): m / z: 228 (M + H) ⁺ , 250 (M + Na) ⁺ .
Anal.calcd for C ₁₁ H ₁₇ NO ₂ S: C, 58.12; H, 7.54; N, 6.16; S, 14.11; Found C, 53.05; H, 7.05; N, 5.71; S, 12.49.

（構造式は、相対配置を示す。）
（５－ａ）［（１Ｓ^＊，５Ｓ^＊，６Ｓ^＊，７Ｒ^＊）－７－メチル－６－（ニトロメチル）ビシクロ［３．２．０］ヘプタ－２－エン－６－イル］酢酸ｔｅｒｔ－ブチル
　水素化ナトリウム（６３％，１．１５ｇ，３１．６ｍｍｏｌ）のジメトキシエタン懸濁液（２０ｍＬ）に，０℃攪拌下，Ｐ，Ｐ－ジメチルホスホノ酢酸ｔｅｒｔ－ブチル（６．７６ｇ，３０．１ｍｍｏｌ）のジメトキシエタン溶液（３．０ｍＬ）を加えた後，（１Ｓ^＊，５Ｓ^＊，７Ｒ^＊）－７－メチルビシクロ［３．２．０］ヘプタ－２－エン－６－オン（Ｊ．Ｏｒｇ．Ｃｈｅｍ．　２０００，６５，５３６９）（３．５０ｇ，２８．７ｍｍｏｌ）のジメトキシエタン溶液（３．０ｍＬ）を加えた。室温に昇温しながら２時間攪拌した後，水を加え，酢酸エチルで抽出した。有機層を水，飽和食塩水で洗浄し，無水硫酸ナトリウムで乾燥した。ろ過，減圧濃縮後，残渣をニトロメタン（４０ｍＬ）に溶解させ，１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（６．１８ｍＬ，４１．４ｍｍｏｌ）を加え，６０℃にて５時間攪拌した。反応液に飽和りん酸二水素カリウム水溶液を加え，酢酸エチルで抽出した。有機層を飽和りん酸二水素カリウム水溶液，飽和食塩水で洗浄し，無水硫酸ナトリウムで乾燥した。ろ過，減圧濃縮後，シリカゲルカラムクロマトグラフィーにて精製することにより，目的物を油状物質として得た（２．８８ｇ，３６％）。
¹H NMR (CDCl₃, 400 MHz):
δ 0.87 (3H, d, J = 7.0 Hz), 1.44 (9H, s), 2.32-2.40 (1H, m), 2.46-2.54 (1H, m), 2.47 (1H, d, J = 18.0 Hz), 2.58 (1H, d, J = 18.0 Hz), 2.65-2.72 (1H, m), 2.79-2.83 (1H, m), 3.34-3.40 (1H, m), 4.82 (1H, d, J = 12.1 Hz), 4.94 (1H, d, J = 12.1 Hz), 5.71-5.74 (1H, m), 5.86-5.90 (1H, m). Example 5 [(1S ^* , 5S ^* , 6S ^* , 7R ^* )-6- (aminomethyl) -7-methylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid ( Racemic)

(Structural formula indicates relative arrangement.)
(5-a) [(1S ^* , 5S ^* , 6S ^* , 7R ^* )-7-methyl-6- (nitromethyl) bicyclo [3.2.0] hept-2-en-6-yl] acetic acid tert- Butyl butyl hydride (63%, 1.15 g, 31.6 mmol) in dimethoxyethane suspension (20 mL) with stirring at 0 ° C., tert-butyl P, P-dimethylphosphonoacetate (6.76 g, 30. 1 mmol) dimethoxyethane solution (3.0 mL) was added, and (1S ^* , 5S ^* , 7R ^* )-7-methylbicyclo [3.2.0] hept-2-en-6-one (J. (Org. Chem. 2000, 65, 5369) (3.50 g, 28.7 mmol) in dimethoxyethane (3.0 mL) was added. The mixture was stirred for 2 hours while warming to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was dissolved in nitromethane (40 mL), 1,8-diazabicyclo [5.4.0] undec-7-ene (6.18 mL, 41.4 mmol) was added, and 5 ° C. was added at 5 ° C. Stir for hours. A saturated aqueous potassium dihydrogen phosphate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous potassium dihydrogen phosphate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, purification by silica gel column chromatography gave the desired product as an oily substance (2.88 g, 36%).
¹ H NMR (CDCl ₃ , 400 MHz):
δ 0.87 (3H, d, J = 7.0 Hz), 1.44 (9H, s), 2.32-2.40 (1H, m), 2.46-2.54 (1H, m), 2.47 (1H, d, J = 18.0 Hz), 2.58 (1H, d, J = 18.0 Hz), 2.65-2.72 (1H, m), 2.79-2.83 (1H, m), 3.34-3.40 (1H, m), 4.82 (1H, d, J = 12.1 Hz) , 4.94 (1H, d, J = 12.1 Hz), 5.71-5.74 (1H, m), 5.86-5.90 (1H, m).

(5-b) [(1S ^* , 5S ^* , 6S ^* , 7R ^* )-6- (aminomethyl) -7-methylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid tert -Butyl [(1S ^* , 5S ^* , 6S ^* , 7R ^* )-7-methyl-6- (nitromethyl) bicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate (2 .88 g, 10.2 mmol) is dissolved in a mixed solvent of ethanol (44 mL) and water (11 mL), and ammonium chloride (0.55 g, 10.2 mmol) and iron powder (5.70 g, 102 mmol) are added for 6 hours. Refluxed. The reaction mixture was filtered through celite and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the desired product as an oily substance (1.92 g, 75%).
¹ H NMR (CDCl ₃ , 400 MHz):
δ 0.85 (3H, d, J = 7.4 Hz), 1.44 (9H, s), 2.30 (1H, d, J = 14.9 Hz), 2.32-2.38 (1H, m), 2.39 (1H, d, J = 14.9 Hz), 2.45-2.59 (3H, m), 2.85 (1H, d, J = 13.1 Hz), 2.89 (1H, d, J = 13.1 Hz), 3.25-3.32 (1H, m), 5.66-5.69 (1H , m), 5.84-5.88 (1H, m).

(5-c) [(1S ^* , 5S ^* , 6S ^* , 7R ^* )-6- (aminomethyl) -7-methylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid [ (1S ^* , 5S ^* , 6S ^* , 7R ^* )-6- (Aminomethyl) -7-methylbicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate (1.92 g , 7.64 mmol) was added 4N hydrochloric acid-ethyl acetate (45 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, methylene chloride (31 mL) and triethylamine (2.12 mL, 15.3 mmol) were added to the residue, and the mixture was stirred at room temperature for 2 hr. The precipitated solid was washed with methylene chloride to obtain the target product as a white solid (1.43 g, 96%).
Mp: 172-173 ^o C.
¹ H NMR (D ₂ O, 400 MHz):
δ 0.88 (3H, d, J = 7.4 Hz), 2.40-2.50 (4H, m), 2.58 (1H, d, J = 16.8 Hz), 2.74 (1H, dt, J = 3.1, 7.4 Hz), 3.24 ( 2H, s), 3.33-3.40 (1H, m), 5.80-5.84 (1H, m), 5.92-5.96 (1H, m).
MS (EI): m / z: 195 (M) ⁺ .
Anal.Calcd for C ₁₁ H ₁₇ NO ₂ : C 67.66; H 8.78; N 7.17; Found: C 66.05; H 8.72; N 7.01.
IR (KBr): cm ^-1 : 2953, 1627, 1541, 1452, 1400.

（構造式は、相対配置を示す。）
（６－ａ）（２Ｅ）－（１Ｓ^＊，５Ｒ^＊）－スピロ［ビシクロ［３．２．０］ヘプタン－２，１’－シクロプロパン］－３－エン－７－イリデン酢酸ｔｅｒｔ－ブチル
水素化ナトリウム（６３％，１．９０ｇ，５０．０ｍｍｏｌ）のテトラヒドロフラン懸濁液（３５ｍＬ）に，０℃攪拌下，Ｐ，Ｐ－ジメチルホスホノ酢酸ｔｅｒｔ－ブチル（１１．２ｇ，５０．０ｍｍｏｌ）のテトラヒドロフラン溶液（１０ｍＬ）を加えた後，（１Ｓ^＊，５Ｒ^＊）－スピロ［ビシクロ［３．２．０］ヘプタン－２，１’－シクロプロパン］－３－エン－７－オン（Ｍｏｎａｔｓｈ．Ｃｈｅｍ．　１９８４，１１５，６０５）（６．９１ｇ，５０．０ｍｍｏｌ）のテトラヒドロフラン溶液（１５ｍＬ）を加えた。そのままの温度で１時間攪拌した後，水を加え，酢酸エチルで抽出した。有機層を水，飽和食塩水で洗浄し，無水硫酸ナトリウムで乾燥した。ろ過，減圧濃縮後，得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製することにより，目的物を油状物質として得た（４．０２ｇ，３５％）。
¹H NMR (CDCl₃, 500 MHz):
δ0.60-0.70 (2H, m), 0.71-0.77 (1H, m), 0.89-0.95 (1H, m), 1.44 (9H, s), 2.83-2.90 (1H, m), 3.04-3.08 (1H, m), 3.24-3.31 (1H, m), 3.53-3.59 (1H, m), 5.25 (1H, d, J = 5.4 Hz), 5.56-5.59 (1H, m), 5.76 (1H, dd, J = 2.0, 5.4 Hz). Example 6 [(1R ^* , 5R ^* , 7R ^* )-7- (aminomethyl) spiro [bicyclo [3.2.0] heptane-2,1'-cyclopropane] -3-ene-7- Yl] acetic acid (racemic)

(Structural formula indicates relative arrangement.)
(6-a) (2E)-(1S ^* , 5R ^* )-spiro [bicyclo [3.2.0] heptane-2,1′-cyclopropane] -3-ene-7-ylidene tert-butyl hydrogen acetate To a tetrahydrofuran suspension (35 mL) of sodium halide (63%, 1.90 g, 50.0 mmol), tert-butyl P, P-dimethylphosphonoacetate (11.2 g, 50.0 mmol) was stirred at 0 ° C. After adding tetrahydrofuran solution (10 mL), (1S ^* , 5R ^* )-spiro [bicyclo [3.2.0] heptane-2,1′-cyclopropane] -3-en-7-one (Monatsh. Chem) 1984, 115, 605) (6.91 g, 50.0 mmol) in tetrahydrofuran (15 mL) was added. After stirring at the same temperature for 1 hour, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the desired product as an oily substance (4.02 g, 35%).
¹ H NMR (CDCl ₃ , 500 MHz):
δ0.60-0.70 (2H, m), 0.71-0.77 (1H, m), 0.89-0.95 (1H, m), 1.44 (9H, s), 2.83-2.90 (1H, m), 3.04-3.08 (1H , m), 3.24-3.31 (1H, m), 3.53-3.59 (1H, m), 5.25 (1H, d, J = 5.4 Hz), 5.56-5.59 (1H, m), 5.76 (1H, dd, J = 2.0, 5.4 Hz).

(6-b) [(1R ^* , 5R ^* , 7R ^* )-7- (Nitromethyl) spiro [bicyclo [3.2.0] heptane-2,1′-cyclopropane] -3-en-7-yl Tert-butyl acetate (2E)-(1S ^* , 5R ^* )-spiro [bicyclo [3.2.0] heptane-2,1′-cyclopropane] -3-ene-7-ylidene tert-butyl acetate ( 4.02 g, 17.3 mmol) was dissolved in nitromethane (25 mL), 1,8-diazabicyclo [5.4.0] undec-7-ene (3.87 mL, 26.0 mmol) was added, and Stir for 5 hours. A saturated aqueous potassium dihydrogen phosphate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous potassium dihydrogen phosphate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, purification by silica gel column chromatography gave the desired product as an oily substance (1.73 g, 34%).
¹ H NMR (CDCl ₃ , 400 MHz):
δ 0.54-0.61 (2H, m), 0.77 (1H, ddd, J = 4.7, 7.0, 9.0 Hz), 0.87-0.95 (1H, m), 1.45 (9H, s), 1.98 (1H, dd, J = 3.5, 13.1 Hz), 2.18 (1H, dd, J = 9.0, 13.1 Hz), 2.74 (1H, d, J = 17.2 Hz), 2.74 (1H, d, J = 7.4 Hz), 2.93 (1H, d, J = 17.2 Hz), 3.42-3.49 (1H, m), 4.48 (1H, d, J = 11.7 Hz), 4.92 (1H, d, 11.7 Hz), 5.30 (1H, dd, J = 1.4, 5.5 Hz) , 5.80 (1H, dd, J = 2.4, 5.5 Hz).

(6-c) [(1R ^* , 5R ^* , 7R ^* )-7- (Aminomethyl) spiro [bicyclo [3.2.0] heptane-2,1′-cyclopropane] -3-ene-7- Yl] tert-butyl acetate [(1R ^* , 5R ^* , 7R ^* )-7- (nitromethyl) spiro [bicyclo [3.2.0] heptane-2,1′-cyclopropane] -3-ene-7- Yl] tert-butyl acetate (1.71 g, 5.83 mmol) was dissolved in a mixed solvent of ethanol (25 mL) and water (6.0 mL), and ammonium chloride (0.31 g, 5.83 mmol) and iron powder (3 .26 g, 58.3 mmol) was added and refluxed for 4 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the desired product as an oily substance (1.31 g, 85%).
¹ H NMR (CDCl ₃ , 400 MHz):
δ0.49-0.57 (2H, m), 0.71 (1H, ddd, J = 5.1, 6.3, 9.4 Hz), 0.94 (1H, ddd, J = 5.1, 7.0, 9.4 Hz), 1.43 (9H, s), 1.92 (1H, dd, J = 9.0, 12.5 Hz), 2.00 (1H, dd, J = 3.5, 12.5 Hz), 2.27 (1H, d, J = 7.4 Hz), 2.61-2.69 (3H, m), 2.78 (1H, d, J = 13.3 Hz), 3.33-3.39 (1H, m), 5.24 (1H, dd, J = 1.2, 5.5 Hz), 5.82 (1H, dd, J = 2.4, 5.5 Hz).

(6-d) (±) [(1R ^* , 5R ^* , 7R ^* )-7- (aminomethyl) spiro [bicyclo [3.2.0] heptane-2,1′-cyclopropane] -3-ene -7-yl] acetic acid [(1R ^* , 5R ^* , 7R ^* )-7- (aminomethyl) spiro [bicyclo [3.2.0] heptane-2,1'-cyclopropane] -3-ene-7 To the tert-butyl acetate (700 mg, 2.66 mmol) was added 4N hydrochloric acid-ethyl acetate (15 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, methylene chloride (16 mL) and triethylamine (0.55 mL, 3.99 mmol) were added to the residue, and the mixture was stirred at room temperature for 2 hr. The precipitated solid was washed with methylene chloride and then recrystallized from isopropanol and water to obtain the desired product as a white solid (136 mg, 43%).
Mp: 184-186 ^o C.
¹ H NMR (CD ₃ OD, 500 MHz):
δ0.52-0.56 (2H, m), 0.78-0.83 (1H, m), 0.96-1.02 (1H, m), 1.80 (1H, dd, J = 3.4, 12.7 Hz), 2.25 (1H, dd, J = 8.8, 12.7 Hz), 2.29 (1H, d, J = 7.3 Hz), 2.69 (1H, d, J = 16.1 Hz), 2.94 (1H, d, J = 12.7 Hz), 3.02 (1H, d, J = 16.1 Hz), 3.07 (1H, d, J = 12.7 Hz), 3.40-3.45 (1H, m), 5.32 (1H, dd, J = 1.5, 5.4 Hz), 5.79 (1H, dd, J = 2.4, 5.4 Hz).
MS (FAB): m / z: 298 (M + H) ⁺ .
Anal.Calcd for C ₁₂ H ₁₇ NO ₂ : C 69.54; H 8.27; N 6.76; Found: C 68.64; H 8.37; N 6.75.
IR (KBr): cm ^-1 : 2931, 1556, 1518, 1393, 1299.

（構造式は、相対配置を示す。）
（７－ａ）［（１Ｒ^＊、５Ｓ^＊）－３－メチル－ビシクロ［３．２．０］ヘプター２－エン－６－イリデン］酢酸　ｔ－ブチルエステル
　（１Ｒ^＊、５Ｓ^＊）－３－メチル－ビシクロ［３．２．０］ヘプター２－エン－６－オン（３．０ｇ、２４．６ｍｍｏｌ）の無水テトラヒドロフラン溶液（１０ｍＬ）をｔｅｒｔ－ブチル－Ｐ，Ｐ－ジメチルホスホノ酢酸メチル（５．５１ｇ、２４．６ｍｍｏｌ）の無水テトラヒドロフラン溶液（５０ｍＬ）と水素化ナトリウム（＞６３％油性、９３６ｍｇ、２４．６ｍｍｏｌ）から予め調整した反応液に氷冷攪拌下で滴下した後、室温で１時間半攪拌した。反応液をクエン酸水溶液で希釈した後、酢酸エチルで抽出した。有機層を水、飽和重曹水、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去して得られた残留物を、シリカゲルカラムクロマトグラフィーにより精製し、目的物粗体を無色油状物質として得た（４．９０ｇ）。
¹H-NMR(400MHz、CDCl₃) :δ ppm:1.45 and 1.48(total 9H, each s), 1.73(3H, s), 2.24-3.25(4H, m), 3.28-3.39(1H, m), 3.53-3.59 and 3.84-3.90(total 1H, each m), 5.31-5.67(2H, m) Example 7 [(1R ^* , 5S ^* , 6R ^* )-6- (Aminomethyl) -3-methyl-bicyclo [3.2.0] hept-2-en-6-yl] acetic acid (racemic body)

(Structural formula indicates relative arrangement.)
(7-a) [(1R ^* , 5S ^* )-3-methyl-bicyclo [3.2.0] hepter-2-ene-6-ylidene] acetic acid t-butyl ester (1R ^* , 5S ^* )-3- A solution of methyl-bicyclo [3.2.0] hept-2-en-6-one (3.0 g, 24.6 mmol) in anhydrous tetrahydrofuran (10 mL) was added methyl tert-butyl-P, P-dimethylphosphonoacetate (5 0.51 g, 24.6 mmol) in anhydrous tetrahydrofuran (50 mL) and sodium hydride (> 63% oily, 936 mg, 24.6 mmol) was added dropwise to the reaction solution prepared in advance under ice-cooling and stirring for 1 hour at room temperature. Half stirred. The reaction mixture was diluted with aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography. Obtained as a colorless oil (4.90 g).
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm: 1.45 and 1.48 (total 9H, each s), 1.73 (3H, s), 2.24-3.25 (4H, m), 3.28-3.39 (1H, m), 3.53-3.59 and 3.84-3.90 (total 1H, each m), 5.31-5.67 (2H, m)

(7-b) [(1R ^* , 5S ^* , 6R ^* )-3-Methyl-6-nitromethyl-bicyclo [3.2.0] hept-2-en-6-yl] acetic acid t-butyl ester (± )-[(1R ^* , 5S ^* )-3-methyl-bicyclo [3.2.0] hepter-2-ene-6-ylidene] acetic acid t-butyl ester (4.9 g, 22.2 mmol) was added to nitromethane (50 mL). ), 1,8-diazabicyclo [5.4.0] undec-7-ene (4.98 mL, 33.4 mmol) was added, and the mixture was stirred with heating at 80 ° C. for 10 hours, and then allowed to stand overnight at room temperature. The reaction mixture was diluted with dipotassium hydrogen phosphate aqueous solution and extracted with ethyl acetate. The organic layer was further washed with a dipotassium hydrogen phosphate aqueous solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product as a colorless oil (3.70 g).
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm: 1.44 and 1.45 (total 9H, each s), 1.74-1.76 (3H, m), 2.19-2.30 (2H, m), 2.43-2.52 (1H, m ), 2.94-2.64 (2H, m), 2.96-3.02 (1H, m), 3.18-3.25 (1H, m), 4.75 and 4.76 (total 2H, each s), 5.33-5.36 and 5.39-5.42 (total 1H , each m)

(7-c) [(1R ^* , 5S ^* , 6R ^* )-6-[(tert-butoxycarbonylamino) methyl-3-methylbicyclo [3.2.0] hept-2-en-6-yl ] Acetic acid tert-butyl ester [(1R ^* , 5S ^* , 6R ^* )-3-methyl-6-nitromethyl-bicyclo [3.2.0] hepter-2-en-6-yl] acetic acid t-butyl ester (3 .70 g, 13.2 mmol) is dissolved in ethanol (30 mL) and water (10 mL), iron powder (3.67 g, 65.8 mmol) and ammonium chloride (703 mg, 13.2 mmol) are added, and the oil bath is heated at 80 ° C. Stir for 4 hours. Since the raw nitro compound remained, iron powder (1.84 g, 32.9 mmol) was added and stirred in an oil bath at 80 ° C. After 2.5 hours, iron powder (1.84 g, 32.9 mmol) was further added, and the mixture was stirred in an oil bath at 80 ° C. for 2 hours. After allowing to cool, (Boc) 2 O (4.31 g, 19.7 mmol) and triethylamine (5.50 mL, 39.5 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes and allowed to stand overnight. The insoluble material was removed by filtration, and the filtrate was diluted with ethyl acetate, washed with aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain the desired crude product as a colorless oil (3.70 g).
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm: 1.45 (18H, s), 1.61-1.65 (1H, m), 1.67 and 1.74 (total 3H, each s), 2.03-2.07 (1H, m), 2,24-2.46 (2H, m), 2.37 (2H, s), 2.77-2.81 (1H, m), 2.96-3.01 and 3.13-3.19 (total 1H, each m), 3.24-3.37 (2H, m) , 5.29 and 5.40 (total 1H, each s)

(7-d) [(1R ^* , 5S ^* , 6R ^* )-6-[(tert-butoxycarbonylamino) methyl-3-methylbicyclo [3.2.0] hept-2-en-6-yl ] Acetic acid [(1R ^* , 5S ^* , 6R ^* )-6-[(tert-butoxycarbonylamino) methyl-3-methylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid tert To a solution of butyl ester (2.65 g, 7.54 mmol) in tetrahydrofuran (50 mL), methanol (16 mL) and water (16 mL) was added lithium hydroxide monohydrate (1.58 g, 37.7 mmol) The mixture was stirred for 7 hours in an oil bath. The reaction mixture was allowed to cool, diluted with water, neutralized with 1N hydrochloric acid (38 mL), and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by diol column chromatography to give the desired product as a colorless oil (1). .7g).
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm: 1.46 (9H, s), 1.66, 1.73 and 1,75 (total 3H, each s), 1.78-1.97 (2H, m), 2.16-2.24 (1H , m), 2.38-2.55 (3H, m), 2.68-2.75 (1H, m), 3.12-3.22 (2H, m), 3.41-3.48 (1H, m), 5.29, 5.38 and 5.43 (total 1H, each s)

(7-e) [(1R ^* , 5S ^* , 6R ^* )-6- (aminomethyl) -3-methylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid [(1R ^* , 5S ^* , 6R ^* )-6-[(tert-butoxycarbonylamino) methyl-3-methylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid (1.9 g, 6 4N hydrochloric acid ethyl acetate solution (20 mL) was added to .43 mmol), and the mixture was stirred at room temperature for 30 minutes, and then concentrated under reduced pressure. The residue was dissolved in methylene chloride (50 mL), and triethylamine (0.9 mL, 6.43 mmol) was added dropwise at room temperature, stirred for 4 hours, and allowed to stand overnight. The resulting powder was collected by filtration and recrystallized from methanol to obtain the desired product as colorless crystals (418 mg). Purity: about 75% (H-NMR) [(1S ^* , 5R ^* , 6R ^* )-6- (aminomethyl) -3-methylbicyclo [3.2.0] hept-2-ene-6 as an impurity -Yl] acetic acid.
¹ H-NMR (400 MHz, CD ₃ OD): δ ppm: 1.59 (1H, dd, J = 4.4, 12.2 Hz), 1.76 (3H, s), 2.09 (1H, dd, 8.3, 12.2 Hz), 2.42- 2.45 (2H, m), 2.55 (1H, d, J = 16.6Hz), 2.63 (1H, d, J = 16.6Hz), 2.83 (1H, dd, 5.9, 13.2Hz), 3.08 (2H, dd, J = 12.7, 18.1Hz), 3.17-3.24 (1H, m), 5.40 (1H, s)
IR (KBr): cm ^-1 : 2904, 1568, 1516, 1395, 1381
MS (FAB): m / z: 196 (M + H) ⁺ , 234 (M + K) ⁺
Anal.calcd for C ₁₀ H ₁₅ NO ₂ : C, 67.66; H, 8.78; N, 7.17; Found C, 67.32; H, 8.80; N, 7.14
Mp 166-169 ℃

（構造式は、相対配置を示す。）
（８－ａ）（１Ｒ^＊、５Ｓ^＊）－７，７－ジクロロ－３－エチルビシクロ［３．２．０］ヘプタ－２－エン－６－オン
ジエチルジシクロペンタジエンの熱分解によって調製したエチルシクロペンタジエン（６．３５ｇ，６７．４ｍｍｏｌ）及びトリエチルアミン（７．４０ｍＬ，５３．４ｍｍｏＬ）のヘキサン溶液（１５０ｍＬ）に，室温攪拌下，ジクロロアセチルクロリド（４．７０ｍＬ，４８．８ｍｍｏＬ）のヘキサン溶液（５０ｍＬ）をゆっくり加え，そのまま４時間攪拌した。反応液をセライトろ過，濃縮した後，シリカゲルカラムクロマトグラフィーにて精製することにより，（１Ｒ^＊、５Ｓ^＊）－７，７－ジクロロ－３－エチルビシクロ［３．２．０］ヘプタ－２－エン－６－オン，（１Ｒ^＊，５Ｓ^＊）－７，７－ジクロロ－２－エチルビシクロ［３．２．０］ヘプタ－２－エン－６－オン，（１Ｒ^＊，５Ｓ^＊）－７，７－ジクロロ－１－エチルビシクロ［３．２．０］ヘプタ－２－エン－６－オンの混合物を得た（７．８９ｇ，７９％，異性体比＝７０／２０／１０）。
¹H NMR (CDCl₃, 400 MHz):
Major isomer (3-ethyl):
δ 1.07 (3H, t, J = 7.4 Hz), 2.06-2.20 (2H, m), 2.46-2.57 (1H, m), 2.65-2.72 (1H, m), 3.96-4.01 (1H, m), 4.21-4.28 (1H, m), 5.40-5.44 (1H, m).
Minor isomer (2-ethyl, detectable peaks):
δ 1.12 (3H, t, J = 7.4 Hz), 2.73-2.82 (1H, m), 3.89-3.94 (1H, m), 5.61-5.64 (1H,m).
Minor isomer (1-ethyl, detectable peaks):
δ 1.00 (3H, t, 7.4 Hz), 3.70-3.73 (1H, m), 5.75-5.78 (1H, m), 5.99-6.02 (1H, m). Example 8 [(1R ^* , 5S ^* , 6R ^* )-6- (Aminomethyl) -3-ethylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid (racemic)

(Structural formula indicates relative arrangement.)
(8-a) (1R ^* , 5S ^* )-7,7-dichloro-3-ethylbicyclo [3.2.0] hept-2-en-6-one ethyl prepared by thermal decomposition of diethyldicyclopentadiene To a hexane solution (150 mL) of cyclopentadiene (6.35 g, 67.4 mmol) and triethylamine (7.40 mL, 53.4 mmol), hexane solution (4.70 mL, 48.8 mmol) of dichloroacetyl chloride (4.70 mL, 48.8 mmol) was stirred at room temperature. (50 mL) was added slowly and stirred as such for 4 hours. The reaction solution is filtered through celite, concentrated, and purified by silica gel column chromatography to obtain (1R ^* , 5S ^* )-7,7-dichloro-3-ethylbicyclo [3.2.0] hepta-2- En-6-one, (1R ^* , 5S ^* )-7,7-dichloro-2-ethylbicyclo [3.2.0] hept-2-en-6-one, (1R ^* , 5S ^* )-7 , 7-dichloro-1-ethylbicyclo [3.2.0] hept-2-en-6-one was obtained (7.89 g, 79%, isomer ratio = 70/20/10).
¹ H NMR (CDCl ₃ , 400 MHz):
Major isomer (3-ethyl):
δ 1.07 (3H, t, J = 7.4 Hz), 2.06-2.20 (2H, m), 2.46-2.57 (1H, m), 2.65-2.72 (1H, m), 3.96-4.01 (1H, m), 4.21 -4.28 (1H, m), 5.40-5.44 (1H, m).
Minor isomer (2-ethyl, detectable peaks):
δ 1.12 (3H, t, J = 7.4 Hz), 2.73-2.82 (1H, m), 3.89-3.94 (1H, m), 5.61-5.64 (1H, m).
Minor isomer (1-ethyl, detectable peaks):
δ 1.00 (3H, t, 7.4 Hz), 3.70-3.73 (1H, m), 5.75-5.78 (1H, m), 5.99-6.02 (1H, m).

(8-b) [(1R ^* , 5S ^* , 6R ^* )-3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate (1R ^* , 5S ^* )-7,7-dichloro-3-ethylbicyclo [3.2.0] hept-2-en-6-one (7.89 g, 38.5 mmol) in tetrahydrofuran (110 mL), methanol (30 mL ) To the mixed solution were added zinc powder (10.1 g, 154 mmol) and ammonium chloride (8.24 g, 154 mmol), and the mixture was heated to reflux for 10 hours. After allowing to cool, cerite filtration and concentration under reduced pressure gave a crude product of (±) -3-ethylbicyclo [3.2.0] hept-2-en-6-one. To a tetrahydrofuran suspension (70 mL) of sodium hydride (63%, 1.47 g, 38.5 mmol) under stirring at 0 ° C., a tetrahydrofuran solution of tert-butyl P, P-dimethylphosphonoacetate (8.62 g) ( 40 mL) was added, and then the resulting crude product in tetrahydrofuran (30 mL) was added. The mixture was stirred for 4 hours while warming to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, concentration under reduced pressure, and purification by silica gel column chromatography, [(1R ^* , 5S ^* )-3-ethylbicyclo [3.2.0] hept-2-ene-6-ylidene] acetic acid tert- Butyl was obtained (including 2-ethyl and 1-ethyl as minor isomers). The obtained product was dissolved in nitromethane (35 mL), 1,8-diazabicyclo [5.4.0] undec-7-ene (4.19 mL, 28.0 mmol) was added, and the mixture was stirred at 60 ° C. for 7 hours. . A saturated aqueous potassium dihydrogen phosphate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous potassium dihydrogen phosphate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, concentration under reduced pressure, and purification by silica gel column chromatography, the desired product was obtained as an oily substance (3.06 g, 27%, including 2-ethyl and 1-ethyl compounds as minor isomers). Further, the product was purified by preparative HPLC (Inertsil ODS-3, acetonitrile: water = 9: 1) (2.02 g). 2-ethyl isomers are included as minor isomers (Major / Minor = 76/24).
¹ H NMR (CDCl ₃ , 400 MHz):
Major isomer:
δ 1.08 (3H, t, 7.4 Hz), 1.45 (9H, s), 1.72 (1H, dd, J = 4.3, 13.3 Hz), 2.05-2.14 (2H, m), 2.23-2.37 (2H, m), 2.44-2.54 (1H, m), 2.57-2.65 (2H, m), 2.94-3.00 (1H, m), 3.19-3.26 (1H, m), 4.74 (1H, d, J = 11.7 Hz), 4.79 ( 1H, d, J = 11.7 Hz), 5.41-5.44 (1H, m).
Minor isomer (detectable peaks):
δ 1.04 (3H, t, J = 7.4 Hz), 3.08-3.17 (1H, m), 5.35-5.37 (1H, m).

(8-c) [(1R ^* , 5S ^* , 6R ^* )-6- (aminomethyl) -3-ethylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid [(1R ^* , 5S ^* , 6R ^* )-3-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate (862 mg, 2.92 mmol) in ethanol (13 mL ) And water (3 mL), iron powder (1.63 g, 29.2 mmol) and ammonium chloride (156 mg, 2.92 mmol) were added, and the mixture was stirred for 4 hours and a half with heating under reflux. After standing to cool, insolubles were removed by Celite filtration. The filtrate was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. [(1R ^* , 5S ^* , 6R ^* )-6- (aminomethyl) -3-ethylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid was obtained by filtration and concentration under reduced pressure. A crude product of tert-butyl was obtained. To a mixed solution of the crude product in tetrahydrofuran: methanol: water (3: 1: 1, 15 mL), lithium hydroxide monohydrate (599 mg, 14.3 mmol) was added, and the mixture was heated to reflux for 4 hours. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and dichloromethane (10 mL) and water (10 mL) were added to the residue. After separation, the aqueous layer was neutralized with 1M hydrochloric acid, and concentrated. The resulting crude product was eluted with a cation exchange resin (Dowex 50W-X8, 28% ammonia water: water = 0: 100 to 15:85). ) To obtain the desired product as a pale yellow solid (93.1 mg, 16%). 2-Ethyl is included as a minor isomer (Major / Minor = 78/22).
¹ H NMR (CD ₃ OD, 400 MHz):
Major isomer:
δ 1.09 (3H, t, J = 7.4 Hz), 1.60 (1H, dd, J = 4.5, 12.3 Hz), 2.06-2.19 (3H, m), 2.45-2.52 (2H, m), 2.55 (1H, d , J = 16.0 Hz), 2.64 (1H, d, J = 16.0 Hz), 2.79-2.86 (1H, m), 3.06-3.14 (2H, m), 3.17-3.27 (1H, m), 5.41-5.45 ( 1H, m).
Minor isomer (detectable peaks):
δ 1.05 (3H, t, J = 7.4 Hz), 1.66 (1H, dd, J = 4.7, 12.5 Hz), 5.18-5.40 (1H, m).
MS (FAB): m / z: 210 (M + H) ⁺ .

　（構造式は、相対配置を示す。）
（９－ａ）（１Ｓ^＊，２Ｓ^＊、５Ｓ^＊）－スピロ［ビシクロ［３．２．０］ヘプタン－６、２’－［１，３］ジオキソラン］－２－オール
　（１Ｓ^＊，２Ｓ^＊、５Ｓ^＊）－２－ヒドロキシビシクロ［３．２．０］ヘプタン－オン（２．３３ｇ、１８．５ｍｍｏｌ）、エチレングリコール（２０．５ｍＬ、３６８ｍｍｏｌ）、オルト蟻酸トリメチル（６．０６ｍＬ、５５．４ｍｍｏｌ）及びパラートルエンスルホン酸一水和物（３５１ｍｇ、１．８５ｍｍｏｌ）を無水トルエン（１００ｍＬ）に溶解させ、室温で４時間攪拌した後、一夜放置した。反応液は水で希釈し、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧下留去、残留物をシリカゲルカラムクロマトグラフィーにて精製して目的物を無色油状物として得た（１．９４ｇ）。
¹H-NMR(400MHz、CDCl₃) :δ ppm:1.71-1.87(4H, m), 1.99-2.06(1H, m), 2.40-2.51(2H, m), 2.94-3.01(1H, m), 3.78-3.93(4H, m), 4.09-4.15(1H, m) Example 9 [(1S ^* , 5S ^* , 6R ^* )-6- (aminomethyl) -2-methylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid hydrochloride ( Racemate)

(Structural formula indicates relative arrangement.)
(9-a) (1S ^* , 2S ^* , 5S ^* )-spiro [bicyclo [3.2.0] heptane-6,2 ′-[1,3] dioxolane] -2-ol (1S ^* , 2S ^* 5S ^* )-2-hydroxybicyclo [3.2.0] heptan-one (2.33 g, 18.5 mmol), ethylene glycol (20.5 mL, 368 mmol), trimethyl orthoformate (6.06 mL, 55.4 mmol) ) And para-toluenesulfonic acid monohydrate (351 mg, 1.85 mmol) were dissolved in anhydrous toluene (100 mL), stirred at room temperature for 4 hours, and then allowed to stand overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product as a colorless oil (1.94 g). ).
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm: 1.71-1.87 (4H, m), 1.99-2.06 (1H, m), 2.40-2.51 (2H, m), 2.94-3.01 (1H, m), 3.78-3.93 (4H, m), 4.09-4.15 (1H, m)

(9-b) (1S ^* , 5S ^* )-2H-spiro [bicyclo [3.2.0] heptane-6,2 ′-[1,3] dioxolane] -2-one dimethylsulfoxide (2.43 mL, 34.2 mmol) in anhydrous methylene chloride (20 mL) was added dropwise with a solution of oxalyl chloride (1.47 mL, 17.1 mmol) in anhydrous methylene chloride (10 mL) in a −78 ° C. bath, and the mixture was stirred in the same bath for 30 minutes. Later, (1S ^* , 2S ^* , 5S ^* )-spiro [bicyclo [3.2.0] heptane-6,2 ′-[1,3] dioxolane] -2-ol (1.94 g, 11.4 mmol) Of anhydrous methylene chloride (10 mL) was added dropwise. The mixture was further stirred at the same temperature for 2 hours and then slowly heated (2 hours, −20 ° C.). Triethylamine (6.35 mL, 45.6 mmol) was added dropwise, and the mixture was warmed to room temperature, stirred for 2 hours, and allowed to stand overnight. The reaction mixture was diluted with ethyl acetate, washed with water, aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain the desired product as a yellow oil (1.50 g).
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm: 1.91-2.00 (1H, m), 2.13-2.20 (1H, m), 2.23-2.31 (2H, m), 2.53-2.59 (1H, m), 2.66-2.81 (2H, m), 3.15-3.20 (1H, m), 3.88-3.98 (4H, m)

(9-c) (1S ^* , 2R ^* , 5S ^* )-2-methylspiro [bicyclo [3.2.0] heptane-6,2 ′-[1,3] dioxolane] -2-ol (1S ^* , 5S ^* )-2H-spiro [bicyclo [3.2.0] heptane-6, 2 ′-[1,3] dioxolane] -2-one (1.50 g, 8.92 mmol) in anhydrous tetrahydrofuran (30 mL) To the solution, methyl lithium in diethyl ether (1 mol / L, 13.4 mL) was added dropwise in a −78 ° C. bath. After stirring at the same temperature for 30 minutes, an aqueous ammonium chloride solution was added dropwise to stop the reaction. The reaction mixture was warmed to room temperature and extracted with ethyl acetate. The organic layer was washed with aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain the desired product as a colorless oil (1.08 g).
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm: 1.25 and 1.26 (total 3H, each s), 1.55-1.67 (2H, m), 1.78-1.85 (1H, m), 1.95-2.05 (1H, m ), 2.16-2.23 (1H, m), 2.30-2.35 (2H, m), 2.74-2.80 (1H, m), 3.78-3.95 (4H, m)

(9-d) (1S ^* , 5S ^* )-2-methylspiro [bicyclo [3.2.0] hepta-2-ene-6,2 ′-[1,3] dioxolane]
(1S ^* , 2R ^* , 5S ^* )-2-Methylspiro [bicyclo [3.2.0] heptane-6,2 ′-[1,3] dioxolane] -2-ol (1.08 g, 5.86 mmol) To a solution of pyridine (20 mL), phosphorus oxychloride (1.37 mL, 14.7 mmol) was added dropwise with stirring under ice cooling. After stirring for 1 hour in the same bath, the reaction mixture was diluted with ethyl acetate and washed with aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate, and saturated brine. After drying over anhydrous magnesium sulfate, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain the desired crude product (a mixture of three structural isomers) as a colorless oil (970 mg).

(9-e) [(1S ^* , 5S ^* )-2-Methylbicyclo [3.2.0] hepta-2-ene-6-ylidene] acetic acid t-butyl ester (1S ^* , 5S ^* )-2-methylspiro [Bicyclo [3.2.0] hepta-2-ene-6,2 ′-[1,3] dioxolane] crude (1.26 g, 7.58 mmol) was mixed in a mixed solvent of acetic acid (20 mL) and water (5 mL). Dissolve and stir in a 70 ° C. oil bath for 1 hour. After standing to cool, it was diluted with water and extracted with toluene. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. After removing inorganic substances by filtration, tert-butyl-P, P-dimethylphosphonoacetic acid methyl ester (1.70 g, 7.58 mmol) in anhydrous tetrahydrofuran (20 mL) and sodium hydride (> 63% oily, 289 mg, 7.58 mmol) was added dropwise to the reaction solution prepared in advance under ice-cooling and stirring. The reaction solution was stirred at room temperature for 30 minutes, washed with an aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain the desired crude product (mixture of three kinds of structural isomers) as a colorless oil (773 mg).

(9-f) [(1S ^* , 5S ^* , 6R ^* )-2-Methyl-6- (nitromethyl) -bicyclo [3.2.0] hepta-2-en-6-yl] acetic acid t-butyl ester [ (1S ^* , 5S ^* )-2-Methylbicyclo [3.2.0] hepta-2-en-6-ylidene] acetic acid t-butyl ester crude (770 mg, 3.50 mmol) dissolved in nitromethane (10 mL) 1,8-diazabicyclo [5.4.0] undec-7-ene (0.78 mL, 5.24 mmol) was added, and the mixture was stirred with heating in an oil bath at 80 ° C. for 8 hours, and then allowed to stand overnight at room temperature. The reaction solution was diluted with disodium hydrogen phosphate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and further by reverse layer preparative HPLC to obtain the desired product as a colorless oil (237 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm: 1.44 (9H, s), 1.67-1.69 (3H, m), 1.76 (1H, dd, 4.0, 13.3 Hz), 2.26-2.33 (2H, m) , 2.46-2.56 (1H, m), 2.61 and 2.62 (total 2H, each s), 2.95-3.09 (2H, m), 4.76 (2H, s), 5.33-5.36 (1H, m)

(9-g) [(1S ^* , 5S ^* , 6R ^* )-6-[(tert-butoxycarbonylamino) methyl-2-methylbicyclo [3.2.0] hept-2-en-6-yl ] Acetic acid tert-butyl ester [(1S ^* , 5S ^* , 6R ^* )-2-methyl-6- (nitromethyl) -bicyclo [3.2.0] hepta-2-en-6-yl] acetic acid t-butyl ester ( 237 mg, 0.84 mmol) was dissolved in ethanol (10 mL) and water (4 mL), and iron powder (470 mg, 8.42 mmol) and ammonium chloride (45 mg, 0.84 mmol) were added. Stir. Since the starting nitro compound remained, iron powder (235 mg, 0.42 mmol) was added, and the mixture was further stirred in an oil bath at 80 ° C. for 3 hours. After allowing to cool, (Boc) 2 O (276 mg, 1.26 mmol) and triethylamine (0.35 mL, 2.53 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The insoluble material was removed by filtration, and the filtrate was diluted with water, extracted with ethyl acetate, washed with aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate, saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain the target compound as a colorless solid (232 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm: 1.44 (9H, s), 1.45 (9H, s), 1.67 (3H, s), 1.63-1.69 (1H, m), 2.03-2.13 (1H, m), 2,29-2.50 (2H, m), 2.38 (2H, s), 2.73-2.80 (1H, m), 2.95-3.02 (1H, m), 3.25-3.38 (2H, m), 5.29 ( 1H, s)

(9-h) [(1S ^* , 5S ^* , 6R ^* )-6-[(tert-butoxycarbonylamino) methyl-2-methylbicyclo [3.2.0] hept-2-en-6-yl ] Acetic acid [(1S ^* , 5S ^* , 6R ^* )-6-[(tert-butoxycarbonylamino) methyl-2-methylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid tert -To a solution of butyl ester (230 mg, 0.65 mmol) in tetrahydrofuran (4.5 mL), methanol (1.5 mL) and water (1.5 mL) was added lithium hydroxide monohydrate (137 mg, 3.27 mmol). And stirred for 7 hours under reflux. The reaction mixture was allowed to cool, neutralized with 1N hydrochloric acid (3.27 mL), and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by diol column chromatography to obtain the desired product as a white solid (133 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm: 1.46 (9H, s), 1.68 (3H, s), 1.85-1.97 (2H, m), 2.22-2.29 (1H, m), 2.40 (1H, d, J = 13.2Hz), 2.44-2.52 (1H, m), 2.55 (1H, d, J = 13.7Hz), 2.67-2.73 (1H, m), 2.95-3.02 (1H, m), 3.16 (1H , dd, J = 5.4, 15.6Hz), 3.49 (1H, dd, J = 7.8, 15.1Hz), 5.30 (1H, s)

(9-i) [(1S ^* , 5S ^* , 6R ^* )-6- (Aminomethyl) -2-methylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid hydrochloride [ (1S ^* , 5S ^* , 6R ^* )-6-[(tert-butoxycarbonylamino) methyl-2-methylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid (130 mg, 0 (.04 mmol) was added 4N hydrochloric acid ethyl acetate solution (4 mL) and stirred at room temperature for 30 minutes. The resulting powder was collected by filtration and dried under reduced pressure to obtain the desired product as a white powder (85 mg).
¹ H-NMR (400 MHz, CD ₃ OD): δ ppm: 1.68-1.74 (4H, m), 2.20 (1H, dd, J = 9.0, 12.9 Hz), 2.30-2.38 (1H, m), 2.46-2.56 (1H, m), 2.64 (2H, s), 2.84 (1H, t, J = 8.2Hz), 3.02-3.10 (1H, dd, m), 3.27 (2H, d, J = 3.1Hz), 5.38 ( 1H, s)
IR (KBr): cm ^-1 : 2928, 1714, 1206, 1192
Mp 188-192 ℃
MS (FAB): m / z: 196 (M + H) ⁺ , 234 (M + K) ⁺

（構造式は、相対配置を示す。）
（１０－ａ）（１Ｒ^＊，２Ｓ^＊，５Ｒ^＊）－スピロ［ビシクロ［３．２．０］ヘプタン－６，２’－［１，３］ジオキソラン］－２－オール
水素化リチウムアルミニウム（５．０８ｇ，１３４ｍｍｏｌ）のテトラヒドロフラン懸濁液（３６０ｍＬ）に，０℃攪拌下，（１’Ｒ^＊，２’Ｒ^＊，４’Ｓ^＊，６’Ｒ^＊）－スピロ［１，３－ジオキソラン－２，７’－［３］オキサトリシクロ［４．２．０．０^２，４］オクタン］（Ｊ．Ｃｈｅｍ．Ｓｏｃ．Ｐｅｒｋｉｎ　Ｔｒａｎｓ．１，１９８０，８５２）（１５．０ｇ，８９ｍｍｏｌ）のテトラヒドロフラン溶液（９０ｍＬ）をゆっくりと滴下した。室温にて終夜攪拌した後，反応液を氷冷しながらテトラヒドロフラン（１００ｍＬ），水（５．１ｍＬ），１５％水酸化ナトリウム水溶液（５．１ｍＬ），水（１５．３ｍＬ）を加え，室温にて３時間攪拌した。セライトろ過，減圧濃縮後，得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製（ヒドロキシル基に関する位置異性体と分離）することにより，目的物を油状物質として得た（５．５３ｇ，３６％）。
¹H NMR (CDCl₃, 400 MHz):
δ 1.48-1.58 (1H, m), 1.76-1.96 (3H, m), 2.16 (1H, br s), 2.25 (1H, ddd, J = 3.1, 9.4, 14.1 Hz), 2.35 (1H, dd, J = 5.9, 14.5 Hz), 2.49-2.56 (1H, m), 2.74-2.79 (1H, m), 3.79-3.94 (4H, m), 6.24 (1H, dt, J = 6.7, 9.8 Hz). Example 10 [(1R ^* , 5R ^* , 6S ^* )-6- (Aminomethyl) -2-ethylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid (racemic)

(Structural formula indicates relative arrangement.)
(10-a) (1R ^* , 2S ^* , 5R ^* )-spiro [bicyclo [3.2.0] heptane-6,2 ′-[1,3] dioxolane] -2-ol lithium aluminum hydride (5 0.08 g, 134 mmol) in a tetrahydrofuran suspension (360 mL) with stirring at 0 ° C., (1′R ^* , 2′R ^* , 4 ′S ^* , 6′R ^* )-spiro [1,3-dioxolane- 2,7 ′-[3] oxatricyclo [4.2.0.0 ^2,4 ] octane] (J. Chem. Soc. Perkin Trans. 1, 1980, 852) (15.0 g, 89 mmol) in tetrahydrofuran The solution (90 mL) was slowly added dropwise. After stirring overnight at room temperature, tetrahydrofuran (100 mL), water (5.1 mL), 15% aqueous sodium hydroxide solution (5.1 mL), and water (15.3 mL) were added while cooling the reaction mixture with ice. And stirred for 3 hours. After filtration through celite and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (separated from the positional isomer with respect to the hydroxyl group) to obtain the desired product as an oily substance (5.53 g, 36% ).
¹ H NMR (CDCl ₃ , 400 MHz):
δ 1.48-1.58 (1H, m), 1.76-1.96 (3H, m), 2.16 (1H, br s), 2.25 (1H, ddd, J = 3.1, 9.4, 14.1 Hz), 2.35 (1H, dd, J = 5.9, 14.5 Hz), 2.49-2.56 (1H, m), 2.74-2.79 (1H, m), 3.79-3.94 (4H, m), 6.24 (1H, dt, J = 6.7, 9.8 Hz).

(10-b) (1R ^* , 5R ^* )-spiro [bicyclo [3.2.0] heptane-6,2 ′-[1,3] dioxolane] -2-one (1R ^* , 2S ^* , 5R ^* ) -Spiro [bicyclo [3.2.0] heptane-6,2 ′-[1,3] dioxolane] -2-ol (5.53 g, 32.5 mmol) in methylene chloride (260 mL) was added to celite ( 70 g), molecular sieves 4A (15 g) and pyridinium dichromate (98%, 37.4 g, 97.5 mmol) were added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was filtered through celite, washed with saturated aqueous copper sulfate solution, water and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the desired product as an oily substance (3.68 g, 67%).
¹ H NMR (CDCl ₃ , 500 MHz):
δ 1.91-2.00 (1H, m), 2.14-2.19 (1H, m), 2.23-2.30 (2H, m), 2.54-2.58 (1H, m), 2.67-2.80 (2H, m), 3.16-3.19 ( 1H, m), 3.89-3.96 (4H, m).

(10-c) (1R ^* , 5R ^* )-2-ethylspiro [bicyclo [3.2.0] hept-2-ene-6,2 ′-[1,3] dioxolane]
Toluene (80 mL) was added potassium bis (trimethylsilyl) amide in toluene (0.5 M, 85.3 mL, 42.7 mmol), and (1R ^* , 5R ^* )-spiro [bicyclo [3. 2.0] Heptane-6,2 '-[1,3] dioxolane] -2-one (2.87 g, 17.1 mmol) in tetrahydrofuran (40 mL) was slowly added dropwise. After stirring at the same temperature for 2 hours, a tetrahydrofuran solution (40 mL) of N-phenylbis (trifluoromethanesulfonimide) (12.2 g, 34.1 mmol) was slowly added dropwise. After warming to room temperature and stirring overnight, the reaction was stopped by adding saturated aqueous ammonium chloride and water, and the mixture was separated and extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting crude product is purified by silica gel column chromatography to obtain (1R ^* , 5S ^* )-spiro [bicyclo [3.2.0] hept-2-ene-6, 2 ′-[1,3] Dioxolane] -2-yl trifluoromethanesulfonate was obtained as a mixture with impurities (11.0 g). This was dissolved in diethyl ether (60 mL), and [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride-dichloromethane complex (0.84 g, 1.02 mmol) was added with stirring at room temperature. A solution of ethylmagnesium bromide in tetrahydrofuran (1.0 M, 51.2 mL, 51.2 mmol) was added slowly. After stirring overnight, a saturated aqueous ammonium chloride solution and water were added for liquid separation, extracted with diethyl ether, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, purification by silica gel column chromatography gave the desired product as an oily substance (2.71 g, 88%).
¹ H NMR (CDCl ₃ , 500 MHz):
δ 1.05 (3H, t, J = 7.8 Hz), 1.93-2.01 (1H, m), 2.08-2.16 (2H, m), 2.35 (1H, dd, J = 9.3, 16.6 Hz), 2.50 (1H, dd , J = 2.0, 16.6 Hz), 2.63 (1H, dd, J = 8.8, 13.2 Hz), 2.91-2.95 (1H, m), 3.14-3.18 (1H, m), 3.79-3.95 (4H, m), 5.38 (1H, br s).

(10-d) (1R ^* , 5R ^* )-2-ethylbicyclo [3.2.0] hept-2-ene-6-ylidene] tert-butyl acetate (1R ^* , 5R ^* )-2-ethylspiro [ Bicyclo [3.2.0] hept-2-ene-6,2 ′-[1,3] dioxolane] (2.71 g, 15.0 mmol) was dissolved in a mixed solvent of acetonitrile (50 mL) and water (20 mL). 2M sulfuric acid (8.0 mL) was added with stirring at room temperature. After stirring overnight at room temperature, the reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (14 mL), and this was dissolved in sodium hydride (63%, 0.60 g, 15.8 mmol) and tert-butyl P, P-dimethylphosphonoacetate (3.54 g, 15.8 mmol) was added to a tetrahydrofuran solution (22 mL) prepared at 0 ° C. with stirring. After stirring at the same temperature for 1 hour, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the desired product as an oily substance (3.39 g, 96%, Major / Minor = 74/26).
¹ H NMR (CDCl ₃ , 400 MHz):
Major isomer:
δ 1.06 (3H, t, J = 7.4 Hz), 1.46 (9H, s), 1.96-2.05 (1H, m), 2.08-2.17 (1H, m), 2.33-2.38 (1H, m), 2.57-2.65 (1H, m), 2.84-2.90 (1H, m), 3.22 (1H, dd, J = 2.7, 8.2 Hz), 3.24-3.29 (1H, m), 3.53-3.59 (1H, m), 5.33 (1H , br s), 5.65-5.67 (1H, m).
Minor isomer:
δ 1.06 (3H, t, J = 7.4 Hz), 1.47 (9H, s), 1.96-2.05 (1H, m), 2.08-2.17 (1H, m), 2.47-2.54 (1H, m), 2.70-2.78 (1H, m), 3.00-3.07 (1H, m), 3.24-3.29 (1H, m), 3.80-3.90 (2H, m), 5.37 (1H, br s), 5.50-5.52 (1H, m).

(10-e) [(1R ^* , 5R ^* , 6S ^* )-2-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate (± )-(1R ^* , 5R ^* )-2-ethylbicyclo [3.2.0] hept-2-ene-6-ylidene] tert-butyl acetate (3.39 g, 14.5 mmol) in nitromethane (30 mL) After dissolution, 1,8-diazabicyclo [5.4.0] undec-7-ene (3.25 mL, 21.7 mmol) was added, and the mixture was stirred at 65 ° C. for 7 hr. A saturated aqueous potassium dihydrogen phosphate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous potassium dihydrogen phosphate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, purification by silica gel column chromatography gave the desired product as an oily substance (3.21 g, 75%).
¹ H NMR (CDCl ₃ , 400 MHz):
δ 1.04 (3H, t, J = 7.4 Hz), 1.45 (9H, s), 1.75 (1H, dd, J = 4.3, 12.9 Hz), 1.91-2.02 (1H, m), 2.06-2.15 (1H, m ), 2.29-2.36 (2H, m), 2.48-2.56 (1H, m), 2.59 (1H, d, J = 17.2 Hz), 2.64 (1H, d, J = 17.2 Hz), 2.96-3.00 (1H, m), 3.10-3.15 (1H, m), 4.75 (1H, d, J = 12.1 Hz), 4.78 (1H, d, J = 12.1 Hz), 5.36 (1H, br s).

(10-f) [(1R ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -2-ethylbicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate [ (1R ^* , 5R ^* , 6S ^* )-2-Ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate (3.21 g, 10.9 mmol) ) Was dissolved in a mixed solvent of ethanol (40 mL) and water (10 mL), ammonium chloride (1.16 g, 21.7 mmol) and iron powder (6.68 g, 120 mmol) were added, and the mixture was refluxed for 6 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the desired product as an oily substance (2.20 g, 76%).
¹ H NMR (CDCl ₃ , 400 MHz):
δ 1.04 (3H, t, J = 7.4 Hz), 1.43 (9H, s), 1.71 (1H, dd, J = 4.7, 12.1 Hz), 1.96 (1H, dd, J = 8.6, 12.1 Hz), 1.96- 2.02 (1H, m), 2.06-2.14 (1H, m), 2.33-2.39 (1H, m), 2.39 (1H, d, J = 13.7 Hz), 2.43 (1H, d, J = 13.7 Hz), 2.43 -2.51 (1H, m), 2.64-2.69 (1H, m), 2.79 (2H, s), 3.00-3.05 (1H, m), 5.31 (1H, br s).

(10-g) [(1R ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -2-ethylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid [(1R ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -2-ethylbicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate (1.00 g, 3.77 mmol) To the benzene solution (8.5 mL), p-toluenesulfonic acid monohydrate (0.86 g, 4.52 mmol) was added and refluxed for 1 hour. After allowing to cool, the precipitated solid was washed with methylene chloride to obtain the target p-toluenesulfonate (1.24 g). This was suspended in methylene chloride (20 mL), and triethylamine (0.55 mL, 3.96 mmol) was added with stirring at room temperature. After stirring for 3 hours as it was, the precipitated solid was washed with methylene chloride to obtain the desired product as a white solid (610 mg, 77%).
Mp: 178-180 ℃
¹ H NMR (CD ₃ OD, 400 MHz):
δ 1.05 (3H, t, J = 7.4 Hz), 1.65 (1H, dd, J = 4.3, 12.1 Hz), 1.94-2.04 (1H, m), 2.08-2.14 (1H, m), 2.14 (1H, dd , J = 8.6, 12.1 Hz), 2.47-2.52 (2H, m), 2.56 (1H, d, J = 16.4 Hz), 2.63 (1H, d, J = 16.4 Hz), 2.82 (1H, dt, J = 3.1, 7.8 Hz), 3.08 (1H, d, J = 12.9 Hz), 3.12 (1H, d, J = 12.9 Hz), 3.12-3.16 (1H, m), 5.38 (1H, br s).
MS (FAB): m / z: 210 (M + H) ⁺ .
Anal.Calcd for C ₁₂ H ₁₉ NO ₂ : C 68.87; H 9.15; N 6.69; Found: C 68.70; H 9.31; N 6.89.
IR (KBr): cm ^-1 : 2929, 1631, 1509, 1403, 1286, 1166.

（構造式は、相対配置を示す。）
（１１－ａ）［（１Ｒ^＊，５Ｒ^＊，６Ｓ^＊）－２－エチル－６－（ニトロメチル）ビシクロ［３．２．０］ヘプタ－２－エン－６－イル］酢酸ｔｅｒｔ－ブチルの光学分割
　実施例（１０－ｅ）で得られた［（１Ｒ^＊，５Ｒ^＊，６Ｓ^＊）－２－エチル－６－（ニトロメチル）ビシクロ［３．２．０］ヘプタ－２－エン－６－イル］酢酸ｔｅｒｔ－ブチル（６．１５ｇ）をキラルカラムＨＰＬＣによって光学分割することにより，第１ピーク（２．８９ｇ）及び第２ピーク（２．６６ｇ）を得た。
分析条件: Daicel CHIRALPAC IC 0.46 x 25 cm, hexane/ethanol = 100/1, 1.0 mL/min, 210 nm, t_R = 6.1 min (第1ヒ゜ーク), t_R = 8.5 min (第2ヒ゜ーク). Example 11 (−)-[(1R ^* , 5R ^* , 6S ^* )-6- (Aminomethyl) -2-ethylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid (Optically active)

(Structural formula indicates relative arrangement.)
(11-a) [(1R ^* , 5R ^* , 6S ^* )-2-ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-2-en-6-yl] optical of tert-butyl acetate Resolution [(1R ^* , 5R ^* , 6S ^* )-2-Ethyl-6- (nitromethyl) bicyclo [3.2.0] hept-2-en-6-yl obtained in Example (10-e) The first peak (2.89 g) and the second peak (2.66 g) were obtained by optical resolution of tert-butyl acetate (6.15 g) by chiral column HPLC.
Analytical conditions: Daicel CHIRALPAC IC 0.46 x 25 cm, hexane / ethanol = 100/1, 1.0 mL / min, 210 nm, t _R = 6.1 min (first peak), t _R = 8.5 min (second peak).

(11-b) (−)-[(1R ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -2-ethylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid In the same manner as in Examples (10-f) and (10-g), from the first peak obtained in Example (11-a), (−)-[(1R ^* , 5R ^* , 6S ^* ) − 6- (Aminomethyl) -2-ethylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid (absolute configuration undecided) was obtained as a white solid.
[α] _D = -5.5 (c 1.00, MeOH).
Mp: 172-174 ℃
MS (FAB): m / z: 210 (M + H) ⁺ .
Anal.Calcd for C ₁₂ H ₁₉ NO ₂ : C 68.87; H 9.15; N 6.69; Found: C 68.04; H 9.18; N 6.70.

（構造式は、相対配置を示す。）
実施例（１０－ｆ），（１０－ｇ）と同様にして，実施例（１１－ａ）で得られた第２ピークから，（＋）－［（１Ｒ^＊，５Ｒ^＊，６Ｓ^＊）－６－（アミノメチル）－２－エチルビシクロ［３．２．０］ヘプタ－２－エン－６－イル］酢酸（絶対配置未決定）を白色固体として得た。
[α]_D = +3.9 (c 1.10, MeOH).
Mp: 171-172 ^oC.
MS (FAB): m/z: 210 (M + H)⁺.
Anal. Calcd for C₁₂H₁₉NO₂: C 68.87; H 9.15; N 6.69; Found: C 68.25; H 9.38; N 6.74. Example 12 (+)-[(1R ^* , 5R ^* , 6S ^* )-6- (Aminomethyl) -2-ethylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid (Optically active substance)

(Structural formula indicates relative arrangement.)
In the same manner as in Examples (10-f) and (10-g), from the second peak obtained in Example (11-a), (+)-[(1R ^* , 5R ^* , 6S ^* )- 6- (Aminomethyl) -2-ethylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid (absolute configuration undecided) was obtained as a white solid.
[α] _D = +3.9 (c 1.10, MeOH).
Mp: 171-172 ^o C.
MS (FAB): m / z: 210 (M + H) ⁺ .
Anal.Calcd for C ₁₂ H ₁₉ NO ₂ : C 68.87; H 9.15; N 6.69; Found: C 68.25; H 9.38; N 6.74.

（構造式は、相対配置を示す。）
（１３－ａ）（１Ｒ^＊，５Ｒ^＊）－２－プロピルスピロ［ビシクロ［３．２．０］ヘプタ－２－エン－６，２’－［１，３］ジオキソラン］
　実施例（１０－ｃ）と同様にして，（１Ｒ^＊，５Ｒ^＊）－スピロ［ビシクロ［３．２．０］ヘプタン－６，２’－［１，３］ジオキソラン］－２－オン（１．７３ｇ，１０．３ｍｍｏｌ）及び臭化ｎ－プロピルマグネシウムのテトラヒドロフラン溶液（１．０Ｍ，３０．９ｍＬ，３０．９ｍｍｏｌ）から，目的物を油状物質として得た（不純物込みで２．５７ｇ）。
¹H NMR (CDCl₃, 400 MHz):
δ 0.90 (3H, t, J = 7.4 Hz), 1.37-1.53 (2H, m), 1.97-2.08 (2H, m), 2.10 (1H, ddd, J = 1.2, 3.9, 13.3 Hz), 2.32-2.39 (1H, m), 2.47-2.53 (1H, m), 2.62 (1H, ddd, J = 2.0, 8.6, 13.3 Hz), 2.89-2.94 (1H, m), 3.12-3.17 (1H, m), 3.79-3.95 (4H, m), 5.38 (1H, br s). Example 13 [(1R ^* , 5R ^* , 6S ^* )-6- (Aminomethyl) -2-propylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid (racemic)

(Structural formula indicates relative arrangement.)
(13-a) (1R ^* , 5R ^* )-2-propylspiro [bicyclo [3.2.0] hept-2-ene-6,2 ′-[1,3] dioxolane]
In the same manner as in Example (10-c), (1R ^* , 5R ^* )-spiro [bicyclo [3.2.0] heptane-6,2 ′-[1,3] dioxolane] -2-one (1 The desired product was obtained as an oily substance (2.57 g including impurities) from a tetrahydrofuran solution (1.0 M, 30.9 mL, 30.9 mmol) of n-propylmagnesium bromide and .73 g, 10.3 mmol).
¹ H NMR (CDCl ₃ , 400 MHz):
δ 0.90 (3H, t, J = 7.4 Hz), 1.37-1.53 (2H, m), 1.97-2.08 (2H, m), 2.10 (1H, ddd, J = 1.2, 3.9, 13.3 Hz), 2.32-2.39 (1H, m), 2.47-2.53 (1H, m), 2.62 (1H, ddd, J = 2.0, 8.6, 13.3 Hz), 2.89-2.94 (1H, m), 3.12-3.17 (1H, m), 3.79 -3.95 (4H, m), 5.38 (1H, br s).

(13-b) (1R ^* , 5R ^* )-2-propylbicyclo [3.2.0] hept-2-ene-6-ylidene] tert-butyl acetate In the same manner as in Example (10-d), From (1R ^* , 5R ^* )-2-propylspiro [bicyclo [3.2.0] hept-2-ene-6,2 ′-[1,3] dioxolane] (2.57 g including impurities) The product was obtained as an oil (1.67 g, 4 steps 65%, Major / Minor = 72/28).
¹ H NMR (CDCl ₃ , 400 MHz):
Major isomer:
δ 0.92 (3H, t, J = 7.4 Hz), 1.40-1.57 (2H, m), 1.46 (9H, s), 2.00-2.09 (2H, m), 2.32-2.38 (1H, m), 2.54-2.64 (1H, m), 2.84-2.90 (1H, m), 3.19-3.26 (2H, m), 3.53-3.57 (1H, m), 5.33 (1H, br s), 5.65-5.67 (1H, m).
Minor isomer:
δ 0.92 (3H, t, J = 7.4 Hz), 1.40-1.57 (2H, m), 1.47 (9H, s), 2.00-2.09 (2H, m), 2.50 (1H, ddt, J = 2.0, 3.9, 17.2 Hz), 2.54-2.64 (1H, m), 2.70-2.78 (1H, m), 2.99-3.06 (1H, m), 3.19-3.26 (1H, m), 3.84-3.90 (1H, m), 5.37 (1H, br s), 5.50 (1H, ddd, J = 2.4, 2.4, 2.4 Hz).

(13-c) [(1R ^* , 5R ^* , 6S ^* )-6- (nitromethyl) -2-propylbicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate (1R ^* , 5R ^* )-2-propylbicyclo [3.2.0] hept-2-ene-6-ylidene] tert-butyl acetate (1.67 g, 6.72 mmol) was dissolved in nitromethane (15 mL) and 1 , 8-diazabicyclo [5.4.0] undec-7-ene (1.51 mL, 10.1 mmol) was added, and the mixture was stirred at 65 ° C. for 7 hours. A saturated aqueous potassium dihydrogen phosphate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous potassium dihydrogen phosphate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, purification by silica gel column chromatography gave the desired product as an oily substance (1.69 g, 81%).
¹ H NMR (CDCl ₃ , 500 MHz):
δ 0.91 (3H, t, J = 7.3 Hz), 1.37-1.50 (2H, m), 1.44 (9H, s), 1.75 (1H, dd, J = 3.9, 12.7 Hz), 1.94-2.05 (2H, m ), 2.29 (1H, dd, J = 8.8, 12.7 Hz), 2.30-2.35 (1H, m), 2.48-2.55 (1H, m), 2.61 (2H, s), 2.95-2.98 (1H, m), 3.08-3.13 (1H, m), 4.76 (2H, s), 5.36 (1H, br s).

(13-d) [(1R ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -2-propylbicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate [ (1R ^* , 5R ^* , 6S ^* )-6- (Nitromethyl) -2-propylbicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate (1.69 g, 5.46 mmol) ) And Raney nickel (KAWAKEN, NDHT-90, 1.50 g) in ethanol suspension (25 mL) was added hydrazine monohydrate (1.59 mL, 32.8 mmol) with stirring at room temperature. After stirring at room temperature for 3 hours, filtration through celite and concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography to obtain the desired product as an oily substance (1.30 g, 85%). .
¹ H NMR (CDCl ₃ , 400 MHz):
δ 0.91 (3H, t, J = 7.4 Hz), 1.37-1.49 (2H, m), 1.43 (9H, s), 1.71 (1H, dd, J = 4.3, 12.5 Hz), 1.93-2.05 (3H, m ), 2.33-2.39 (1H, m), 2.39 (1H, d, J = 14.1 Hz), 2.44 (1H, d, 14.1 Hz), 2.44-2.52 (1H, m), 2.64-2.68 (1H, m) , 2.79 (2H, s), 2.98-3.05 (1H, m), 5.31 (1H, br s).

(13-e) [(1R ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -2-propylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid [(1R ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -2-propylbicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate (1.30 g, 4.65 mmol) To the benzene solution (9.0 mL), p-toluenesulfonic acid monohydrate (0.97 g, 5.12 mmol) was added and refluxed for 1 hour. After allowing to cool, the precipitated solid was washed with benzene to obtain the desired p-toluenesulfonate (1.70 g). This was suspended in methylene chloride (18 mL), and triethylamine (0.66 mL, 4.73 mmol) was added with stirring at room temperature. After stirring for 3 hours as it was, the precipitated solid was washed with methylene chloride to obtain the desired product as a white solid (900 mg, 87%).
Mp: 178-180 ℃
¹ H NMR (CD ₃ OD, 400 MHz):
δ 0.91 (3H, t, J = 7.4 Hz), 1.37-1.54 (2H, m), 1.65 (1H, dd, J = 4.7, 12.1 Hz), 1.98-2.08 (2H, m), 2.13 (1H, dd , J = 8.6, 12.1 Hz), 2.48-2.55 (2H, m), 2.57 (1H, d, J = 16.4 Hz), 2.64 (1H, d, J = 16.4 Hz), 2.79-2.84 (1H, m) , 3.08 (1H, d, J = 12.9 Hz), 3.12 (1H, d, J = 12.9 Hz), 3.12-3.15 (1H, m), 5.39 (1H, br s).
MS (FAB): m / z: 224 (M + H) ⁺ .
Anal.Calcd for C ₁₃ H ₂₁ NO ₂ : C 69.92; H 9.48; N 6.27; Found: C 69.60; H 9.72; N 6.31.
IR (KBr): cm ^-1 : 2929, 1632, 1506, 1402, 1295, 1167.

（構造式は、相対配置を示す。）
（１４－ａ）（１Ｒ^＊，５Ｒ^＊）－２－シクロプロピルスピロ［ビシクロ［３．２．０］ヘプタ－２－エン－６，２’－［１，３］ジオキソラン］
　実施例（１０－ｃ）と同様にして，（１Ｒ^＊，５Ｒ^＊）－スピロ［ビシクロ［３．２．０］ヘプタン－６，２’－［１，３］ジオキソラン］－２－オン（１．７３ｇ，１０．３ｍｍｏｌ）及び臭化シクロプロピルマグネシウムのテトラヒドロフラン溶液（１．０Ｍ，３０．９ｍＬ，３０．９ｍｍｏｌ）から，目的物を油状物質として得た（不純物込みで２．１２ｇ）。
¹H NMR (CDCl₃, 400 MHz):
δ 0.32-0.36 (1H, m), 0.47-0.51 (1H, m), 0.58-0.64 (2H, m), 1.40-1.46 (1H, m), 2.16 (1H, ddd, J = 1.2, 3.9, 13.3 Hz), 2.30-2.37 (1H, m), 2.48-2.54 (1H, m), 2.62 (1H, ddd, J = 2.0, 8.6, 13.3 Hz), 2.78-2.83 (1H, m), 3.80-3.96 (4H, m), 5.40 (1H, br s). Example 14 [(1R ^* , 5R ^* , 6S ^* )-6- (Aminomethyl) -2-cyclopropylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid (racemate )

(Structural formula indicates relative arrangement.)
(14-a) (1R ^* , 5R ^* )-2-cyclopropylspiro [bicyclo [3.2.0] hept-2-ene-6,2 ′-[1,3] dioxolane]
In the same manner as in Example (10-c), (1R ^* , 5R ^* )-spiro [bicyclo [3.2.0] heptane-6,2 ′-[1,3] dioxolane] -2-one (1 .73 g, 10.3 mmol) and a solution of cyclopropylmagnesium bromide in tetrahydrofuran (1.0 M, 30.9 mL, 30.9 mmol) were obtained as an oily substance (2.12 g including impurities).
¹ H NMR (CDCl ₃ , 400 MHz):
δ 0.32-0.36 (1H, m), 0.47-0.51 (1H, m), 0.58-0.64 (2H, m), 1.40-1.46 (1H, m), 2.16 (1H, ddd, J = 1.2, 3.9, 13.3 Hz), 2.30-2.37 (1H, m), 2.48-2.54 (1H, m), 2.62 (1H, ddd, J = 2.0, 8.6, 13.3 Hz), 2.78-2.83 (1H, m), 3.80-3.96 ( 4H, m), 5.40 (1H, br s).

(14-b) (1R ^* , 5R ^* )-2-cyclopropylbicyclo [3.2.0] hept-2-ene-6-ylidene] tert-butyl acetate In the same manner as in Example (10-d) , (1R ^* , 5R ^* )-2-cyclopropylspiro [bicyclo [3.2.0] hept-2-ene-6,2 ′-[1,3] dioxolane] (2.12 g including impurities) The target product was obtained as an oily substance (730 mg, 4 steps 29%, Major / Minor = 72/28).
¹ H NMR (CDCl ₃ , 500 MHz):
Major isomer:
δ 0.33-0.40 (1H, m), 0.47-0.52 (1H, m), 0.64-0.66 (2H, m), 1.40-1.46 (1H, m), 1.46 (9H, s), 2.34-2.37 (1H, m), 2.55-2.62 (1H, m), 2.91-2.96 (1H, m), 3.10-3.18 (1H, m), 3.22-3.28 (1H, m), 3.55-3.58 (1H, m), 5.36 ( 1H, br s), 5.64-5.66 (1H, m).
Minor isomer:
δ 0.33-0.40 (1H, m), 0.47-0.52 (1H, m), 0.64-0.66 (2H, m), 1.40-1.46 (1H, m), 1.47 (9H, s), 2.55-2.62 (2H, m), 2.74 (1H, dd, J = 8.8, 17.1 Hz), 3.00-3.05 (1H, m), 3.10-3.18 (1H, m), 3.86-3.89 (1H, m), 5.39 (1H, br s ), 5.49-5.51 (1H, m).

(14-c) [(1R ^* , 5R ^* , 6S ^* )-2-cyclopropyl-6- (nitromethyl) bicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate ( ±)-(1R ^* , 5R ^* )-2-cyclopropylbicyclo [3.2.0] hept-2-ene-6-ylidene] tert-butyl acetate (730 mg, 2.96 mmol) was added to nitromethane (6.0 mL) 1,8-diazabicyclo [5.4.0] undec-7-ene (0.66 mL, 4.45 mmol) was added, and the mixture was stirred at 75 ° C. for 7 hours. A saturated aqueous potassium dihydrogen phosphate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous potassium dihydrogen phosphate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, purification by silica gel column chromatography gave the desired product as an oily substance (432 mg, 47%).
¹ H NMR (CDCl ₃ , 400 MHz):
δ 0.29-0.34 (1H, m), 0.44-0.49 (1H, m), 0.62-0.67 (2H, m), 1.40-1.44 (1H, m), 1.45 (9H, s), 1.82 (1H, dd, J = 4.3, 12.9 Hz), 2.28-2.35 (2H, m), 2.47-2.54 (1H, m), 2.61 (2H, s), 2.94-3.05 (2H, m), 4.74 (1H, d, J = 12.1 Hz), 4.77 (1H, d, J = 12.1 Hz), 5.37 (1H, br s).

(14-d) [(1R ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -2-cyclopropylbicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate [(1R ^* , 5R ^* , 6S ^* )-2-cyclopropyl-6- (nitromethyl) bicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate (432 mg, 1.41 mmol ) In a mixed solvent of ethanol (5.0 mL) and water (1.3 mL), ammonium chloride (0.15 g, 2.81 mmol) and iron powder (0.78 g, 14.1 mmol) were added for 6 hours. Refluxed. The reaction mixture was filtered through celite and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the desired product as an oily substance (240 mg, 62%).
¹ H NMR (CDCl ₃ , 500 MHz):
δ 0.31-0.35 (1H, m), 0.45-0.49 (1H, m), 0.60-0.64 (2H, m), 1.43 (9H, s), 1.43-1.45 (1H, m), 1.76 (1H, dd, J = 4.9, 12.2 Hz), 1.96 (1H, dd, J = 8.8, 12.2 Hz), 2.36-2.42 (3H, m), 2.47 (1H, dd, J = 9.3, 17.6 Hz), 2.64-2.68 (1H , m), 2.78 (2H, s), 2.88-2.94 (1H, m), 5.35 (1H, br s).

(14-e) (±)-[(1R ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -2-cyclopropylbicyclo [3.2.0] hept-2-en-6-yl] Acetic acid [1R ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -2-cyclopropylbicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate (0.24 g, To a benzene solution (0.8 mL) of 0.86 mmol), p-toluenesulfonic acid monohydrate (0.18 g, 0.95 mmol) was added and refluxed for 1 hour. After standing to cool, the residue obtained by concentration was purified with a cation exchange resin (InertSepSCX, eluted with water: methanol = 1: 1 to 10% aqueous ammonia: methanol = 1: 1), and then isolated from isopropanol and water. Recrystallization gave the desired product as a white solid (29.1 mg, 15%).
Mp: 178-181 ^o C.
¹ H NMR (CD ₃ OD, 500 MHz):
δ 0.29-0.33 (1H, m), 0.46-0.50 (1H, m), 0.60-0.64 (2H, m), 1.38-1.44 (1H, m), 1.70 (1H, dd, J = 4.4, 12.2 Hz) , 2.13 (1H, dd, J = 8.8, 12.2 Hz), 2.43-2.53 (2H, m), 2.57 (1H, d, J = 16.6 Hz), 2.63 (1H, d, J = 16.6 Hz), 2.79- 2.82 (1H, m), 3.00-3.05 (1H, m), 3.07 (1H, d, J = 16.1 Hz), 3.10 (1H, d, J = 16.1 Hz), 5.38 (1H, br s).
MS (FAB): m / z: 222 (M + H) ⁺ .
Anal.Calcd for C ₁₃ H ₁₉ NO ₂ : C 70.56; H 8.65; N 6.33; Found: C 68.07; H 8.54; N 6.03.
IR (KBr): cm ^-1 : 2932, 1740, 1567, 1517, 1394, 1381.

（構造式は、相対配置を示す。）
（１５－ａ）（１Ｒ^＊，５Ｒ^＊）－スピロ［ビシクロ［３．２．０］ヘプタン－６，２’－［１，３］ジオキソラン］－３－オン
　水素化リチウムアルミニウム（６．７７ｇ，１７８ｍｍｏｌ）のテトラヒドロフラン懸濁液（４８０ｍＬ）に，０℃攪拌下，（１’Ｒ^＊，２’Ｒ^＊，４’Ｓ^＊，６’Ｒ^＊）－スピロ［１，３－ジオキソラン－２，７’－［３］オキサトリシクロ［４．２．０．０^２，４］オクタン］（Ｊ．Ｃｈｅｍ．Ｓｏｃ．Ｐｅｒｋｉｎ　Ｔｒａｎｓ．１，１９８０，８５２）（２０．０ｇ，１１９ｍｍｏｌ）のテトラヒドロフラン溶液（１２０ｍＬ）をゆっくりと滴下した。室温にて終夜攪拌した後，反応液を氷冷しながらテトラヒドロフラン（２００ｍＬ），水（６．８ｍＬ），１５％水酸化ナトリウム水溶液（６．８ｍＬ），水（２０．４ｍＬ）を加え，室温にて３時間攪拌した。セライトろ過，減圧濃縮後，得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製（ヒドロキシル基に関する位置異性体と分離）することにより，（１Ｒ^＊，３Ｒ^＊，５Ｒ^＊）－スピロ［ビシクロ［３．２．０］ヘプタン－６，２’－［１，３］ジオキソラン］－３－オールを油状物質として得た（７．７８ｇ，３８％）。オキサリルクロリド（５．５０ｍＬ，６４．２ｍｍｏｌ）の塩化メチレン溶液（１１０ｍＬ）に，－７８℃攪拌下，ジメチルスルホキシド（９．１１ｍＬ，１２８ｍｍｏｌ）を加え，そのままの温度で５分攪拌した後，先に得られたアルコール（７．２８ｇ，４２．８ｍｍｏｌ）の塩化メチレン溶液（３０ｍＬ）を加えた。そのままの温度で１５分攪拌した後，トリエチルアミン（２３．７ｍＬ，１７１ｍｍｏｌ）を加え，室温に昇温して攪拌した。０．１Ｍ塩酸を加えて分液し，有機層を０．１Ｍ塩酸，水，飽和食塩水で洗浄した後，無水硫酸ナトリウムで乾燥した。ろ過，減圧濃縮後，得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製することにより，目的物を油状物質として得た（６．６１ｇ，９２％）。
¹H NMR (CDCl₃, 400 MHz):
δ 2.05 (1H, dd, J = 4.7, 12.5 Hz), 2.18-2.23 (1H, m), 2.32 (1H, ddd, J = 2.0, 10.2, 19.6 Hz), 2.44-2.55 (2H, m), 2.68-2.82 (2H, m), 3.17-3.22 (1H, m), 3.80-3.95 (4H, m). Example 15 [(1S ^* , 5R ^* , 6S ^* )-6- (Aminomethyl) -3-propylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid (racemic)

(Structural formula indicates relative arrangement.)
(15-a) (1R ^* , 5R ^* )-spiro [bicyclo [3.2.0] heptane-6,2 ′-[1,3] dioxolane] -3-one lithium aluminum hydride (6.77 g, 178 mmol) in a tetrahydrofuran suspension (480 mL) with stirring at 0 ° C., (1′R ^* , 2′R ^* , 4 ′S ^* , 6′R ^* )-spiro [1,3-dioxolane-2,7 '-[3] oxatricyclo [4.2.0.0 ^2,4 ] octane] (J. Chem. Soc. Perkin Trans. 1, 1980, 852) (20.0 g, 119 mmol) in tetrahydrofuran (120 mL) ) Was slowly added dropwise. After stirring overnight at room temperature, tetrahydrofuran (200 mL), water (6.8 mL), 15% aqueous sodium hydroxide (6.8 mL), and water (20.4 mL) were added to the reaction solution while cooling with ice. And stirred for 3 hours. After filtration through celite and concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography (separated from the positional isomers related to the hydroxyl group) to give (1R ^* , 3R ^* , 5R ^* )-spiro [bicyclo [ 3.2.0] Heptane-6,2 ′-[1,3] dioxolane] -3-ol was obtained as an oil (7.78 g, 38%). Dimethyl sulfoxide (9.11 mL, 128 mmol) was added to a methylene chloride solution (110 mL) of oxalyl chloride (5.50 mL, 64.2 mmol) with stirring at −78 ° C., and the mixture was stirred at that temperature for 5 minutes. A methylene chloride solution (30 mL) of the obtained alcohol (7.28 g, 42.8 mmol) was added. After stirring at the same temperature for 15 minutes, triethylamine (23.7 mL, 171 mmol) was added, and the mixture was warmed to room temperature and stirred. 0.1M hydrochloric acid was added for liquid separation, and the organic layer was washed with 0.1M hydrochloric acid, water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the desired product as an oily substance (6.61 g, 92%).
¹ H NMR (CDCl ₃ , 400 MHz):
δ 2.05 (1H, dd, J = 4.7, 12.5 Hz), 2.18-2.23 (1H, m), 2.32 (1H, ddd, J = 2.0, 10.2, 19.6 Hz), 2.44-2.55 (2H, m), 2.68 -2.82 (2H, m), 3.17-3.22 (1H, m), 3.80-3.95 (4H, m).

(15-b) (1S ^* , 5R ^* )-spiro [bicyclo [3.2.0] hept-2-ene-6,2 ′-[1,3] dioxolane] -3-yl trifluoromethanesulfonate tetrahydrofuran ( 180 mL) was added a solution of potassium bis (trimethylsilyl) amide in tetrahydrofuran (0.5 M, 96.8 mL, 48.4 mmol), and (1R ^* , 5R ^* )-spiro [bicyclo [3.2. 0] Heptane-6,2 ′-[1,3] dioxolane] -3-one (6.11 g, 36.3 mmol) in tetrahydrofuran (85 mL) was slowly added dropwise. After stirring at the same temperature for 2 hours, a tetrahydrofuran solution (95 mL) of N-phenylbis (trifluoromethanesulfonimide) (17.3 g, 48.4 mmol) was slowly added dropwise. After warming to room temperature and stirring overnight, the reaction was stopped by adding saturated aqueous ammonium chloride and water, and the mixture was separated and extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (separated from regioisomers related to olefins) to obtain the desired product as an oily substance (2.80 g, 26%).
¹ H NMR (CDCl ₃ , 400 MHz):
δ 2.23 (1H, ddd, J = 1.2, 3.9, 13.7 Hz), 2.64 (1H, ddt, J = 2.0, 9.4, 16.4 Hz), 2.71 (1H, ddd, J = 1.6, 8.6, 13.7 Hz), 2.76 -2.82 (1H, m), 3.05-3.11 (1H, m), 3.20-3.25 (1H, m), 3.80-3.91 (3H, m), 3.95-4.00 (1H, m), 5.69-5.70 (1H, m).

(15-c) (1S ^* , 5R ^* )-3-propylspiro [bicyclo [3.2.0] hept-2-ene-6,2 ′-[1,3] dioxolane]
(1S ^* , 5R ^* )-spiro [bicyclo [3.2.0] hept-2-ene-6,2 ′-[1,3] dioxolan] -3-yl trifluoromethanesulfonate (2.80 g, 9. [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride-dichloromethane complex (0.46 g, 0.56 mmol) was added to a diethyl ether solution (33 mL) of 33 mmol) with stirring at room temperature. A tetrahydrofuran solution of n-propylmagnesium bromide (1.0 M, 28.0 mL, 28.0 mmol) was slowly added. After stirring overnight, a saturated aqueous ammonium chloride solution and water were added for liquid separation, extracted with diethyl ether, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, purification by silica gel column chromatography gave the desired product as an oily substance (500 mg, 28%).
¹ H NMR (CDCl ₃ , 400 MHz):
δ 0.91 (3H, t, J = 7.4 Hz), 1.49 (2H, tq, J = 7.4, 7.4 Hz), 2.03-2.12 (3H, m), 2.28-2.34 (1H, m), 2.41-2.46 (1H , m), 2.58 (1H, ddd, J = 2.0, 8.6, 13.3 Hz), 2.98-3.04 (1H, m), 3.11-3.15 (1H, m), 3.77-3.89 (3H, m), 3.91-3.95 (1H, m), 5.34-5.36 (1H, m).

(15-d) (1S ^* , 5R ^* )-3-propylbicyclo [3.2.0] hept-2-en-6-one (1S ^* , 5R ^* )-3-propylspiro [bicyclo [3. 2.0] hept-2-ene-6,2 ′-[1,3] dioxolane] (500 mg, 2.57 mmol) was dissolved in a mixed solvent of acetonitrile (7.4 mL) and water (3.4 mL), 2M sulfuric acid (1.2 mL) was added with stirring at room temperature. After stirring overnight at room temperature, the reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the desired product as an oily substance (330 mg, 85%).
¹ H NMR (CDCl ₃ , 400 MHz):
δ 0.89 (3H, t, J = 7.4 Hz), 1.46 (2H, tq, J = 7.4 Hz), 2.03-2.07 (2H, m), 2.38-2.46 (1H, m), 2.54-2.60 (1H, m ), 2.68 (1H, dt, J = 2.7, 17.2 Hz), 3.26 (1H, ddd, J = 2.7, 8.2, 17.2 Hz), 3.40-3.46 (1H, m), 3.82-3.88 (1H, m), 5.44-5.46 (1H, m).

(15-e) [(1S ^* , 5R ^* , 6S ^* )-6- (Nitromethyl) -3-propylbicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate hydrogenation A tetrahydrofuran solution (5 mg) of sodium (63%, 92.1 mg, 2.42 mmol) in tetrahydrofuran (5 mL) with tert-butyl P, P-dimethylphosphonoacetate (542 mg, 2.42 mmol) was stirred at 0 ° C. 5 mL), followed by the addition of (1S ^* , 5R ^* )-3-propylbicyclo [3.2.0] hept-2-en-6-one (330 mg, 2.20 mmol) in tetrahydrofuran (5 mL). It was. After stirring at the same temperature for 3 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was dissolved in nitromethane (5.0 mL), 1,8-diazabicyclo [5.4.0] undec-7-ene (494 μL, 3.30 mmol) was added, and the mixture was heated at 60 ° C. for 7 hours. Stir. A saturated aqueous potassium dihydrogen phosphate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous potassium dihydrogen phosphate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the desired product as an oily substance (513 mg, 75%).
¹ H NMR (CDCl ₃ , 400 MHz):
δ 0.93 (3H, t, J = 7.4 Hz), 1.45 (9H, s), 1.46-1.52 (2H, m), 1.71 (1H, dd, J = 4.3, 12.9 Hz), 2.02-2.09 (2H, m ), 2.24-2.29 (2H, m), 2.44-2.51 (1H, m), 2.56 (1H, d, J = 16.8 Hz), 2.63 (1H, d, J = 16.8 Hz), 2.94-2.98 (1H, m), 3.19-3.25 (1H, m), 4.73 (1H, d, J = 12.1 Hz), 4.78 (1H, d, J = 12.1 Hz), 5.41-5.44 (1H, m).

(15-f) [(1S ^* , 5R ^* , 6S ^* )-6- (Aminomethyl) -3-propylbicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate [ (1S ^* , 5R ^* , 6S ^* )-6- (nitromethyl) -3-propylbicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate (513 mg, 1.66 mmol) Hydrazine monohydrate (482 μL, 9.94 mmol) was added to an ethanol suspension (10 mL) of Raney nickel (KAWAKEN, NDHT-90, 500 mg) with stirring at room temperature. After stirring at room temperature for 6 hours, filtration through celite and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the desired product as an oily substance (341 mg, 74%).
¹ H NMR (CDCl ₃ , 500 MHz):
δ 0.93 (3H, t, J = 7.3 Hz), 1.43 (9H, s), 1.45-1.53 (2H, m), 1.65 (1H, dd, J = 4.4, 12.2 Hz), 1.93 (1H, dd, J = 8.8, 12.2 Hz), 2.04-2.07 (2H, m), 2.30-2.34 (1H, m), 2.36 (1H, d, J = 13.7 Hz), 2.42 (1H, d, J = 13.7 Hz), 2.42 -2.47 (1H, m), 2.64-2.67 (1H, m), 2.76 (1H, d, = J = 13.2 Hz), 2.79 (1H, d, J = 13.2 Hz), 3.09-3.15 (1H, m) , 5.42 (1H, br s).

(15-g) (±)-[(1S ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -3-propylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid ([(1S ^* , 5R ^* , 6S ^* )-6- (Aminomethyl) -3-propylbicyclo [3.2.0] hept-2-en-6-yl] tert-butyl acetate (341 mg, 1. P-Toluenesulfonic acid monohydrate (302 mg, 1.58 mmol) was added to a benzene solution (3.0 mL) of 22 mmol), and the mixture was refluxed for 1 hour. The target p-toluenesulfonate was obtained (315 mg), suspended in methylene chloride (3.0 mL), and triethylamine (121 μL, 0.87 mmol) was added with stirring at room temperature for 3 hours. After 拌, the precipitated solid by washing with methylene chloride to obtain the desired product as a white solid (127mg, 46%).
Mp: 189-192 ^o C.
¹ H NMR (CD ₃ OD, 400 MHz):
δ 0.94 (3H, t, J = 7.4 Hz), 1.45-1.61 (3H, m), 2.03-2.15 (4H, m), 2.45-2.51 (1H, m), 2.54 (1H, d, J = 16.4 Hz ), 2.64 (1H, d, J = 16.4 Hz), 2.80-2.89 (1H, m), 3.08-3.13 (1H, m), 3.14 (1H, d, J = 13.3 Hz), 3.19 (1H, d, J = 13.3 Hz), 5.39 (1H, br s).
MS (FAB): m / z: 224 (M + H) ⁺ .
Anal.Calcd for C ₁₃ H ₂₁ NO ₂ : C 69.92; H 9.48; N 6.27; Found: C 69.56; H 9.76; N 6.34.
IR (KBr): cm ^-1 : 3153, 2956, 1566, 1518, 1396, 1382.

（構造式は、相対配置を示す。） Example 16 [(1S ^* , 5R ^* , 6R ^* )-6- (aminomethyl) bicyclo [3.2.0] hept-2-en-6-yl] acetic acid (racemic)

(Structural formula indicates relative arrangement.)

(16-a) (1S ^* , 5R ^* )-6- (Nitromethyl) bicyclo [3.2.0] hept-2-en-6-ol (diastereomeric mixture)
To a solution of (1S ^* , 5R ^* )-bicyclo [3.2.0] hept-2-en-6-one (5.41 g, 50.0 mmol) in nitromethane (28 mL) was added 1,8-diazabicyclo [5 .4.0] Undec-7-ene (9.42 g, 60.0 mmol) was added and stirred for 2 hours. The mixture was treated with saturated aqueous potassium dihydrogen phosphate solution, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product as a pale yellow oil (6.00 g, 71%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm: diastereomer mixture 1.90 (isomer1H, dd, J = 4.4, 13.7 Hz), 2.07 (isomer1H, dd, J = 3.9, 13.2 Hz), 2.30 (isomer1H, d, J = 18.6Hz), 2.44 (isomer1H, dd, J = 9.3, 12.7Hz), 2.56-3.39 (3H + isomer2H, m), 4.50 (isomer1H, d, J = 13.7Hz), 4.56 (isomer2H, s), 4.62 (isomer1H, d, J = 13.7Hz), 5.79-5.93 (2H, m).

(16-b) (1S ^* , 5R ^* )-6- (nitromethylene) bicyclo [3.2.0] hept-2-ene (E / Z mixture)
(1S ^* , 5R ^* )-6- (Nitromethyl) bicyclo [3.2.0] hept-2-en-6-ol (6.00 g, 35.5 mmol) and triethylamine (10.87 g, 106.4 mmol) ) In dichloromethane (100 mL) was added dropwise methanesulfonyl chloride (12.19 g, 106.4 mmol) at 0 ° C. over 20 minutes, followed by stirring at room temperature for 2 hours. Water treatment was performed, and the separated organic layer was dried over anhydrous magnesium sulfate. The volatile matter was distilled off under reduced pressure, and then the desired product was obtained by silica gel column chromatography (2.90 g, 54%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm: E / Z mixture 2.59-2.78 (2H, m), 2.92 (1H, dd, J = 10.3, 17.6 Hz), 3.20 (1H, dd, J = 8.3 , 18.1Hz), 3.47-3.55 (1H, m), 4.12 (1H, m), 5.80-5.90 (2H, m), 6.92 (isomerA1H, s), 7.07 (isomerB1H, s).

(16-c) [(1S ^* , 5R ^* , 6S ^* )-6- (nitromethyl) bicyclo [3.2.0] hept-2-en-6-yl] diethyl malonate sodium hydride (0. To a suspension of 88 g, 63%, 23.0 mmol) in N, N-dimethylformamide (35 mL), diethyl malonate (3.69 g, 23.0 mmol) was added dropwise at 0 ° C. for 10 minutes, and then (1S ^* , 5R ^* )-6- (nitromethylene) bicyclo [3.2.0] hept-2-ene (2.90 g, 19.2 mmol) was added dropwise at 0 ° C. for 2 minutes and stirred at 0 ° C. for 30 minutes. did. The mixture was treated with 1N hydrochloric acid, ethyl acetate was added, the separated organic layer was dried over anhydrous magnesium sulfate, the volatile matter was distilled off under reduced pressure, and the residue was obtained by silica gel column chromatography (4.08 g, 68%). ).
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm: 1.31 (6H, t, J = 7.3 Hz), 2.00 (1H, dd, J = 3.9, 13.7 Hz), 2.46 (1H, d, J = 18.1 Hz) ), 2.56 (1H, dd, J = 9.3, 13.7Hz), 2.64 (1H, ddq, J = 8.8, 18.1, 2.0Hz), 3.21 (1H, br), 3.44 (1H, t, J = 8.3Hz) , 3.85 (1H, s), 4.22-4.31 (4H, m), 4.78 (1H, d, J = 12.7Hz), 4.96 (1H, d, J = 12.7Hz), 5.83 (1H, m), 5.92 ( 1H, m).

(16-d) [(1S ^* , 5R ^* , 6S ^* )-5′-oxospiro [bicyclo [3.2.0] hept-2-ene-6,3′-pyrrolidine] -4′-carbonate [ (1S ^* , 5R ^* , 6S ^* )-6- (Nitromethyl) bicyclo [3.2.0] hept-2-en-6-yl] diethyl malonate (3.75 g, 12.1 mmol) and iron powder An aqueous solution (20 mL) of ammonium chloride (0.64 g, 12.1 mmol) was added to an ethanol (40 mL) suspension of (3.36 g, 60.2 mmol), and the mixture was stirred at 80 ° C. for 4 hours. Insolubles were removed by Celite filtration, volatiles were distilled off under reduced pressure, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting mixture was made into an ethanol (20 mL) solution. 2N Aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred at room temperature for 6.5 hr. The mixture was neutralized with 1N aqueous hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the desired product (2.26 g, 91%).
¹ H-NMR (500 MHz, CDCl ₃ ): δ ppm: 1.74 (isomerA1H, dd, J = 2.9, 12.7 Hz), 1.87 (isomerB1H, dd, J = 2.9, 12.2 Hz), 2.30-2.39 (1H, m) , 2.51-2.78 (2H, m), 3.12-3.77 (4H, m), 5.81 (1H, m), 5.84 (1H, m), 5.95 (1H, br).

(16-e) [(1S ^* , 5R ^* , 6R ^* )-5′H-spiro [bicyclo [3.2.0] hept-2-ene-6,3′-pyrrolidin] -5′-one [(1S ^* , 5R ^* , 6R ^* )-5′-oxospiro [bicyclo [3.2.0] hept-2-ene-6,3′-pyrrolidine] -4′-carbonate (2.26 g, 10 .9 mmol) of toluene (20 mL) was stirred at 140 ° C. for 3 hours. After allowing to cool, impurities were dissolved in ethyl acetate and suction filtered to obtain the desired product as a yellow solid (1.18 g, 75%).
¹ H-NMR (500 MHz, CDCl ₃ ): δ ppm: 1.82 (1H, dd, J = 3.4, 12.2 Hz), 2.35 (1H, d, J = 18.1 Hz), 2.42 (1H, dd, J = 8.8, 12.7Hz), 2.45 (2H, s), 2.55 (1H, ddq, J = 8.3, 18.1, 2.0Hz), 2.90 (1H, t, J = 7.8Hz), 3.15 (1H, d, J = 9.8Hz) , 3.22 (1H, m), 3.43 (1H, d, J = 9.8Hz), 5.50 (1H, br), 5.79 (1H, m), 5.82 (1H, m).

(16-f) [(1S ^* , 5R ^* , 6R ^* )-6-{[(tert-butoxycarbonyl) amino] methyl} bicyclo [3.2.0] hept-2-en-6-yl] acetic acid [(1S ^* , 5R ^* , 6R ^* )-5′H-spiro [bicyclo [3.2.0] hept-2-ene-6,3′-pyrrolidin] -5′-one (0.99 g, A solution of 6.1 mmol) in N, N-dimethylacetamide (0.15 mL) and water (3.62 mL) in a solution of benzenesulfonic acid monohydrate (3.21 g, 18.2 mmol) in water (0.89 mL) And heated to reflux at 110 ° C. for 1 day. After allowing to cool, toluene was added, the organic layer was removed, and neutralized with a saturated aqueous sodium hydrogen carbonate solution. Di-tert-butyl dicarbonate (4.00 g) was added to the filtrate and stirred at room temperature for 2.5 hours, and di-tert-butyl dicarbonate (10.00 g) was further added and stirred at room temperature for 4 hours. After evaporating volatile components under reduced pressure, ethyl acetate was added. The obtained organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain the desired product as a yellow liquid (0.88 g, 52%). ).
¹ H-NMR (500 MHz, CDCl ₃ ): δ ppm: 1.47 (9H, s), 1.63 (1H, dd, J = 3.9, 12.7 Hz), 2.13 (1H, dd, J = 9.3, 12.7 Hz), 2.40 (1H, d, J = 17.6Hz), 2.51-2.58 (3H, m), 3.03 (1H, t, J = 8.3Hz), 3.25-3.33 (2H, m), 3.45 (1H, dd, J = 6.8 , 14.6Hz), 4.86 (1H, m), 5.80 (1H, m), 5.85 (1H, m).

(16-g) [(1S ^* , 5R ^* , 6R ^* )-6- (aminomethyl) bicyclo [3.2.0] hept-2-en-6-yl] acetic acid [(1S ^* , 5R ^* , 6R ^* )-6-{[(tert-butoxycarbonyl) amino] methyl} bicyclo [3.2.0] hept-2-en-6-yl] acetic acid dissolved in 4N hydrochloric acid-ethyl acetate solution (20 mL) After stirring at room temperature for 1 hour, the volatile matter was distilled off under reduced pressure, and dichloromethane was added to suspend, then triethylamine was added dropwise, and the resulting powder was collected by filtration and dried under reduced pressure to obtain the desired product. Obtained as a white powder (0.24 g, 42%).
Mp: 167-169 ° C;
¹ H-NMR (500 MHz, CDCl ₃ ): δ ppm: 1.72 (1H, dd, J = 3.9, 12.7 Hz), 2.21 (1H, dd, J = 8.8, 12.7 Hz), 2.41 (1H, d-quint, 18.1, 2.4Hz), 2.58 (1H, dddd, J = 2.0, 3.9, 8.8, 18.1Hz), 2.67 (1H, d, J = 15.6Hz), 2.73 (1H, d, J = 15.6Hz), 2.84 ( 1H, t, J = 7.8Hz), 3.05 (1H, d, J = 12.7Hz), 3.14 (1H, d, J = 12.7Hz), 3.30 (1H, br), 5.82 (1H, m), 5.89 ( 1H, m).
MS (ESI ⁺ ): m / z: 204 (M + Na) ⁺ , 182 (M + H) ⁺ .
HRMS (ESI ⁺ ) calcd for (M + H) ⁺ : 182.11810.Found 182.11560 (-2.51 mmu).

Formulation Example 1 (Powder)
A powder is obtained by mixing 5 g of the compound of this invention, 895 g of lactose, and 100 g of corn starch with a blender.
Formulation Example 2 (granule)
After mixing 5 g of the compound of the present invention, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose, 300 g of 10% hydroxypropylcellulose aqueous solution is added and kneaded. This is granulated using an extrusion granulator and dried to obtain granules.
Formulation Example 3 (tablet)
5 g of the compound of the present invention, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate are mixed with a blender, and then tableted by a tablet machine to obtain a tablet.

(Test Example 1) Construction of human calcium channel α ₂ δ ₁ subunit (hereinafter referred to as human Cacna2d1) gene expression plasmid and preparation of human Cacna2d1 expression cell membrane fraction a) Construction of human Cacna2d1 expression plasmid pRK / hCacna2d1 a-1 ) Preparation of DNA fragment The human Cacna2d1 gene was obtained by dividing it into a first half fragment and a second half fragment. PCR was carried out using the cDNA library (QUICK-Clone cDNA Human Brain (Clontech Laboratories, Inc)) as a template and the enzyme KOD polymerase (TOYOBO) according to the protocol attached to this enzyme. As a PCR primer, a primer having the following sequence in the first half fragment:
Primer 1: 5'-agctgcggcc gctagcgcca ccatggctgg ctgcctgctg gc-3 '(SEQ ID NO: 1)
Primer 2: 5'-attaggatcg attgcaaagt aataccc-3 '(SEQ ID NO: 2)
The latter fragment has primers with the following sequences:
Primer 3: 5'-aatgggtatt actttgcaat cgatcc-3 '(SEQ ID NO: 3)
Primer 4: 5'-agtcggatcc tcataacagc cggtgtgtgc tg-3 '(SEQ ID NO: 4)
Was purchased from Sigma Genesis and used. In the first and second half of the PCR reaction, a thermal cycler (GeneAmp PCR System 9700 (Applied Biosystems)) was used, and after heating at 94 ° C for 1 minute, temperature cycling (94 ° C for 15 seconds, 60 ° C for 30 seconds, 68 ° C) 2 minutes) was repeated 35 times, followed by 5 minutes at 68 ° C and cooling to 4 ° C.

These two reaction products were purified with a PCR product purification kit (MiniElute PCR Purification Kit (QIAGEN)) according to the protocol attached to this kit. The obtained first half fragment was digested with the restriction enzyme Not1 (TOYOBO). The latter half was digested with restriction enzymes Cla1 (TOYOBO) and BamH1 (TOYOBO). These were then purified with a reaction product purification kit (MiniElute® Reaction® Cleanup® Kit (QIAGEN)) according to the protocol attached to this kit.

a-2) Preparation of vector A vector was prepared in which the multicloning site (hereinafter referred to as MCS) of the animal cell expression vector pRK5 (Pharmingen) was changed to MCS of the vector pBluescript 2 (STRATAGENE). That is, pRK5 was subjected to restriction enzyme treatment with Cla 1 (TOYOBO) and Hind 3 (TOYOBO), and then both ends of the DNA were smoothed using Klenow Fragment (TAKARA). Furthermore, after dephosphorylating both ends using bovine small intestine alkaline phosphatase (hereinafter referred to as CIAP: TAKARA), purification was performed using MiniElute Reaction Cleanup Kit (QIAGEN). Then, the enzyme-treated DNA was electrophoresed on a 1.0% agarose gel, the gel after electrophoresis was stained with ethidium bromide, and a band corresponding to about 4.7 kbp was irradiated with ultraviolet rays using a razor blade. After separation, DNA was extracted using a gel extraction purification kit (MiniElute Gel Extraction Kit (QIAGEN)) according to the protocol attached to this kit.

In order to obtain a DNA fragment corresponding to MCS of pBluescript 2, pBluescript 2 is subjected to restriction enzyme treatment with Sac 1 (TOYOBO) and Kpn 1 (TOYOBO), then both ends of DNA are smoothed using Klenow Fragment (TAKARA) Turned into. The enzyme-treated DNA was electrophoresed on a 2.0% agarose gel, the gel after electrophoresis was stained with ethidium bromide, and the band portion corresponding to about 100 bp was separated with a razor blade under ultraviolet irradiation. Then, using a gel extraction purification kit (MiniElute Gel Extraction Kit (QIAGEN)), DNA was extracted according to the protocol attached to this kit.

The obtained DNA fragment and cleaved pRK5 were ligated using a DNA ligation kit (TAKARA) according to the protocol attached to the kit. E. coli DH5α competent cells (TOYOBO) were transformed with this reaction product to obtain ampicillin resistant colonies. After collecting several colonies, a plasmid was extracted from the cells obtained by culturing the collected colonies, and the base sequence was analyzed using a DNA sequencer (Model 3700 (Applied Biosystems)). Has been confirmed to be introduced into pRK5. At this time, the orientation of the MCS sequence is upstream from the CMV promoter and the downstream direction is as follows: 5'-ccaccgcggtggcggccgctctagaactagtggatcccccgggctgcaggaattcgatatcaagcttatcgataccgtcgacctcgagggggggggcccg-3 '(SEQ ID NO: 5). Was named pRK-KS.

a-3) Plasmid construction pRK-SK obtained in a-2) was treated with the restriction enzyme Xba1 (TOYOBO), both ends of the DNA were blunted using Klenow Fragment (TAKARA), and the blunted DNA Was digested with restriction enzyme Not 1 (TOTOBO) and purified in the same manner as in a-2). The linearized pRK-SK and the first half of the human Cacna2d1 gene DNA fragment obtained in a-1) were electrophoresed on a 1.0% agarose gel, and about 4.7 kbp and about 1.5 kbp DNA was extracted from the gel and purified. The obtained two DNAs were ligated in the same manner as in a-2), and E. coli was transformed. A plasmid was extracted from the obtained Escherichia coli clone, and its base sequence was analyzed using a DNA sequencer (Model 3700 (Applied Biosystems)) to confirm that the sequence shown in SEQ ID NO: 6 was introduced. . Next, the obtained plasmid was treated with restriction enzymes Cla 1 (TOYOBO) and BamH 1 (TOYOBO), and CIAP treatment and purification were performed in the same manner as in a-2). The linearized plasmid DNA and the second half DNA fragment of the human Cacna2d1 gene obtained in a-1) were electrophoresed on a 1.0% agarose gel, and about 6.2 kbp and about 1.8 kbp as in a-2). kbp DNA was extracted from the gel and purified. The obtained two DNAs were ligated in the same manner as in a-2), and E. coli was transformed. A plasmid was extracted from the obtained Escherichia coli clone, the base sequence was analyzed using a DNA sequencer (Model 3700 (Applied Biosystems)), and the sequence shown in SEQ ID NO: 7 was introduced into the vector pRK-SK. I confirmed. The obtained plasmid was named pRK / hCacna2d1.

b) Acquisition of 293 cell line expressing human Cacna2d1 The human Cacna2d1 expression plasmid pRK / hCacna2d1 constructed in a) was introduced into 293 cells, and a human Cacna2d1 stable expression cell line was obtained using human Cacna2d1 protein expression as an index. Specifically, 2 × 10 ⁶ cells of 293 cells were seeded in a φ6 cm dish, and after culturing for 12 hours, using the gene transfer reagent LipofectaminePlus (Invitrogen), 5 μg of pRK / hCacna2d1 and 0.5 μg according to the protocol attached to the reagent The neomycin resistant gene expression plasmid pSV2neo (Clontech) was simultaneously introduced.

After gene transfer, cells were collected, diluted to φ15 cm dish, seeded, and cultured for 2 weeks in DMEM (Invitrogen) supplemented with 10% fetal bovine serum (Cansera Inc.) and 500 μg / ml G418 (Invitrogen). . The neomycin-resistant cells that formed colonies were isolated and expanded, and the cells were collected. The cell lysate was evaluated by the Western assay method to obtain a 293 cell line expressing human Cacna2d1. In Western® assay, anti-hCacna2d1 antibody (Chemicon® Inc.) was used as the primary antibody.

c) Preparation of cell membrane fraction of human Cacna2d1-expressing 293 cells DMEM (Invitrogen) supplemented with 10% fetal calf serum (Cansera International Inc.) and 500 μg / ml G418 (Invitrogen) from human Cacna2d1-expressing 293 cells obtained in b) ) And cultured in large quantities. Add a recommended amount of protease inhibitor (Comlpete EDTA free (Roche)) to Binding Assay Buffer (10 mM MOPS (pH7.4), 10 mM HEPES (pH7.4), 100 mM NaCl) did. The collected cells were washed with a membrane fraction preparation buffer, and then disrupted using an ultrasonic disrupter. Thereafter, centrifugation was performed at 12,000 rpm, 4 ° C. for 1 hour using a centrifuge, and the supernatant was discarded and the precipitate was suspended in a membrane fraction preparation buffer. The process from sonication using an ultrasonic crusher to suspension of the precipitate after centrifugation was repeated three more times, and the resulting suspension was used as a human Cacna2d1-expressing cell membrane fraction. The total amount of protein contained in the membrane fraction was calculated from the absorbance of UV at a wavelength of 280 nm.

(Test Example 2) Construction of detection system for binding reaction between Cacna2d1 and Gabapentin (hereinafter referred to as GBP) and detection of Cacna2d1 / GBP binding reaction inhibitory activity by example compounds a) Construction of detection system for binding reaction between Cacna2d1 and GBP Human Cacna2d1 expression GBP labeled with cell membrane fraction and radioisotope ³ H (hereinafter referred to as ³ H-GBP: Tocris Cookson) Binding Assay Buffer (10 mM MOPS (pH 7.4), 10 mM HEPES (pH 7.4), 100 mM NaCl) The total amount of protein was diluted to a final concentration of 2.5 mg / ml and a final concentration of ³ H-GBP of 4.5 nM to prepare 120 μl of a reaction solution, which was allowed to stand at 4 ° C. for 3 hours. This reaction product was added to the well of a filter plate (UniFilter350 GF / B (Whatman)) and filtered. Thereafter, 350 μl of Binding Assay Buffer (10 mM MOPS (pH 7.4), 10 mM HEPES (pH 7.4), 100 mM NaCl) was added and the washing operation for filter filtration was repeated three times. The filter plate was thoroughly dried, the bottom was sealed, 50 μl of Microscint 20 (PerkinElmer) was added, the top was also sealed, and the radioisotope ³ H-derived radiation remaining on the filter was counted with TopCount (PerkinElmer). The value obtained when non-labeled GBP (SIGMA-ALDRICH) at a final concentration of 20 μM was added to this assay was subtracted from nonspecific adsorption, and the specific amount of ³ H-GBP bound to Cacna2d1 (units) "Count").

b) Detection of Cacna2d1 / GBP binding reaction inhibitory activity by the test compound The test compound was added at various concentrations to the detection assay for the Cacna2d1 / GBP binding reaction constructed in a), and the amount of binding was determined by the method described in a). It was measured. Thereafter, the amount of Cacna2d1 / GBP specific binding when the compound was added to x nM was defined as “binding amount [x]”, and the Cacna2d1 / GBP binding inhibition rate at that time was defined as “inhibition rate [x]”.
Inhibition rate [x] (%) = (1- (binding amount [x] / binding amount [0])) × 100
(In the formula, the binding amount [0] represents the binding amount of ³ H-GBP when no compound is added)
The inhibition rate (%) was obtained based on the above, and the inhibition rate was plotted against the concentration. From this result, the concentration of the test compound necessary to inhibit Cacna2d1 / GBP binding by 50%, “IC ₅₀ value” was calculated. The test results of the test compound are shown in Table 2.

Test Example 3 Mechanical Hyperalgesia Assay It has been reported that peripheral nerve injured animals and diabetes model animals exhibit hyperalgesia and allodynia symptoms to mechanical and thermal stimuli. In the present invention, mice that developed mechanical hyperalgesia were used for evaluation.
Mice were acclimated for 30 minutes in the plastic cage for measurement, and then the test compound was orally administered, and mechanical hyperalgesia was evaluated at the measurement time determined by the investigator. Mechanical hyperalgesia was evaluated by partially modifying the method of Takasaki et al. (Pain 86 95-101, 2000) to confirm the effect of the test compound on mechanical hyperalgesia. That is, mechanical hyperalgesia was evaluated by scoring the behavior induced by pressing 1.4 g of von Frey filament against the sole of the animal according to the criteria described below.
(0: no response, 1: escape from von Frey filament, 2: shake or lick the hind limb immediately after stimulation)
In one measurement, six stimulations were performed and the total score was taken as the pain score.
The test compound was evaluated by calculating a dose (ID ₅₀ ) that improves the pain score of the vehicle administration group by 50%. In the above model, for example, the compound described in Example 2 exhibited an ID _{50 of} 10.4 mg / kg.
Test Example 4 Thermal Hyperalgesia Assay In the present invention, mice and rats that develop thermal hyperalgesia are used for evaluation.
Test compounds are orally administered to animals and thermal hyperalgesia is assessed at the measurement time specified by the study director. In other words, a heat stimulus is applied to the sole of the hind limb of the animal, and the latency until escaping behavior such as licking the foot or swinging the foot is measured.
(Test Example 5) Cold plate test In the present invention, mice and rats that develop cold arodinia are used for evaluation.
Evaluation of cold arodinia is performed according to the method of Tanimoto-Mori et al. (Behabioural Pharmacology 19, 85-90, 2008). That is, the animal is placed on a low-temperature metal plate, and the latency until the hind limb lifting action is observed and the duration of the raising action are measured.
(Test Example 5) Mouse acetic acid writhing test The test compound was orally administered to mice, and 0.6% acetic acid was administered intraperitoneally at the measurement time determined by the person in charge of the test. The total number of writhing behaviors for 10 minutes after 5 to 15 minutes Count.
(Test Example 6) Rat Adjuvant Arthritis Pain Test An adjuvant is prepared by pulverizing Mycobacterium butyricum heat-killed cells in an agate mortar, suspending in liquid paraffin sterilized by dry heat, and further sonicating.
This adjuvant (100 μg / 0.05 mL / paw as a heated dead cell) is injected into the right hind paw skin of a rat to induce arthritis. A pain test is performed 18 days after adjuvant treatment. That is, the test compound is orally administered to the animal, and the tarsal tibial joint is bent 5 times at the measurement time determined by the investigator, and the number of squeals (0-5) is recorded as a pain score.

(Test Example 7) Electric shock-induced convulsion test A test compound was orally administered to a mouse, and electrical stimulation (60 Hz, 50 mA) was performed on the binocular cornea using an electric stimulator and a bipolar electrode at a measurement time determined by the person in charge of the test. 0.2 seconds), and observe and record the presence or absence of tonic extension of the hind limbs.
(Test Example 8) Pentylenetetrazole-induced convulsions test A test compound is orally administered to mice and a pentyleneretrazole solution (85 mg / 10 ml / kg, dissolved in physiological saline) is administered subcutaneously at the measurement time determined by the person in charge of the test. And observe and record the presence or absence of clonic convulsions for 30 minutes.
(Test Example 9)
In addition, the effect of the present invention can be confirmed by performing an evaluation according to the method described in the homepage of the National Institutes of Health (NIH).

The compound of the present invention or a pharmacologically acceptable salt thereof can be used as an active ingredient in a pharmaceutical composition for treating and / or preventing disorders such as pain and central nervous system disorders.

SEQ ID NO: 1 is a PCR sense primer for the first half of human Cacna2d1.
SEQ ID NO: 2 is a PCR antisense primer in the first half of human Cacna2d1.
SEQ ID NO: 3 is a PCR sense primer in the latter half of human Cacna2d1.
SEQ ID NO: 4 is a PCR antisense primer in the latter half of human Cacna2d1.
SEQ ID NO: 5 is the multicloning site of vector pBluescript 2.

Claims (18)

A compound represented by formula (I) or a pharmacologically acceptable salt thereof.

[Wherein each substituent is defined as follows.
R ¹ represents a hydrogen atom or a C1-C6 alkyl group.
R ² represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group.
R ³ represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group.
R ⁴ and R ^{4 ′} are independently the same or different and each represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group, or R ⁴ and R ^{4 ′} are bonded to each other. Together with the carbon atom represents a C3-C6 cycloalkyl group.
R ⁵ represents a hydrogen atom or a C1-C6 alkyl group.
R ⁶ represents a hydrogen atom, a C1-C6 alkyl group or an amino protecting group.
R ⁷ represents a hydrogen atom, a C1-C6 alkyl group or a protecting group for a carboxy group.
R ⁸ and R ^{8 ′} are independently the same or different and each represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group or a C1-C6 alkylthio group, or R ⁸ and R ^{8 ′ 8 ′} , together with the carbon atom to which they are attached, represents a C3-C6 cycloalkyl group. ] The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R ¹ is a hydrogen atom. The compound or pharmacologically acceptable salt thereof according to claim 1 or 2, wherein R ² is a hydrogen atom, a methyl group, an ethyl group, a propyl group or a cyclopropyl group. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein R ³ is a hydrogen atom or a C1-C6 alkyl group. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein R ³ is a hydrogen atom, a methyl group, an ethyl group or a propyl group. The compound according to any one of claims 1 to 5, wherein R ⁴ and R ^{4 '} together with a hydrogen atom or a carbon atom to which they are bonded are a cyclopropyl group or a pharmacologically acceptable salt thereof salt. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 5, wherein R ⁴ and R ^{4 '} are a hydrogen atom. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 7, wherein R ⁵ is a hydrogen atom. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 8, wherein R ⁶ is a hydrogen atom. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 9, wherein R ⁷ is a hydrogen atom. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 10, wherein R ⁸ and R ^{8 '} are a hydrogen atom. The compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein the compound having the general formula (I) is a compound selected from the group consisting of:
[(1S ^* , 5R ^* , 6S ^* )-6- (aminomethyl) bicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
[(1R, 5S, 6R) -6 (aminomethyl) bicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
[(1S, 5R, 6S) -6 (aminomethyl) bicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
[(1R ^* , 5S ^* , 6S ^* , 7R ^* )-6- (aminomethyl) -7- (methylthio) bicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
[(1S ^* , 5S ^* , 6S ^* , 7R ^* )-6- (aminomethyl) -7-methylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
[(1R ^* , 5R ^* , 7R ^* )-7- (aminomethyl) spiro [bicyclo [3.2.0] heptane-2,1′-cyclopropane] -3-en-7-yl] acetic acid,
[(1R ^* , 5S ^* , 6R ^* )-6- (aminomethyl) -3-methyl-bicyclo [3.2.0] hept-3-en-6-yl] acetic acid,
[(1R ^* , 5S ^* , 6R ^* )-6- (aminomethyl) -3-ethylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
[(1S ^* , 5S ^* , 6R ^* )-6- (aminomethyl) -2-methylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid hydrochloride,
[(1R ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -2-ethylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
(−)-[(1R ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -2-ethylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
(+)-[(1R ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -2-ethylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
[(1R ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -2-propylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
[(1R ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -2-cyclopropylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
[(1S ^* , 5R ^* , 6S ^* )-6- (aminomethyl) -3-propylbicyclo [3.2.0] hept-2-en-6-yl] acetic acid,
[(1S ^* , 5R ^* , 6R ^* )-6- (aminomethyl) bicyclo [3.2.0] hept-2-en-6-yl] acetic acid A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 or a pharmacologically acceptable salt thereof as an active ingredient. 14. The pharmaceutical composition according to claim 13, for treating and / or preventing pain. Acute pain, chronic pain, pain resulting from soft tissue or peripheral injury, postherpetic neuralgia, occipital neuralgia, trigeminal neuralgia, medulla or intercostal neuralgia, central nervous pain, neuropathic pain, migraine, osteoarthritis or joint Pain associated with rheumatism, pain associated with contusion, sprains or trauma, spinal pain, pain due to spinal cord or brainstem injury, low back pain, sciatica, toothache, myofascial pain syndrome, perineal incision pain, gout pain, burn Pain resulting from, heart pain, muscle pain, eye pain, inflammatory pain, orofacial pain, abdominal pain, dysmenorrhea, pain associated with labor pain or endometriosis, somatic pain, related to nerve or root injury Pain, amputation, painful tics, pain associated with neuroma or vasculitis, pain resulting from diabetic neuropathy (or diabetic peripheral neuropathic pain), pain resulting from chemotherapy-induced neuropathy, indefinite Facial pain, neuropathic back pain, trigeminal neuralgia, occipital neuralgia, medullary or intercostal neuralgia, HIV related neuralgia, AIDS related neuralgia, hyperalgesia, burn pain, idiopathic pain, chemotherapy pain, occipital neuralgia, psychogenic Pain, gallstone-related pain, cancer-related neuropathic or non-neuropathic pain, phantom limb pain, functional abdominal pain, headache, acute or chronic tension headache, sinus headache, cluster headache, temporal mandible Pain, maxillary sinus pain, pain resulting from ankylosing spondyloarthritis, postoperative pain, scar pain, chronic non-neuropathic pain, fibromyalgia, amyotrophic lateral sclerosis, epilepsy (partial epilepsy, partial seizure in adult epilepsy) 14. A pharmaceutical composition according to claim 13, for treating and / or preventing a disease selected from the group consisting of: partial seizures in epileptic patients), generalized anxiety disorder and restless leg syndrome. 14. A pharmaceutical composition according to claim 13 for treating and / or preventing pain resulting from diabetic neuropathy. Use of a compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition. A method for treating and / or preventing pain, which comprises administering an effective amount of the compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 12 to a mammal.