JPH09140396A - Production of optical activator by bacterium - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently obtain an optical activator useful as a medicine such as a compound having affinity for a melatonin receptor, by bringing a cultured product of a bacterium or its treated material into contact with a recemic compound of a specific indane to asymmetrically hydrolyze the compound. SOLUTION: A cultured product of a bacterium (e.g. Corynebacterium ammoniagenes IFO12, 612) or its treated material is brought into contact with a racemic compound (salt) of an indane of formula I [R<1> and R<2> are each H, a (substituted) hydrocarbon, a (substituted) heterocyclic group or R<1> and R<2> form a (substituted) spiro ring together with an adjoining carbon atom; R<3> is an acyl; ring A is a (substituted) benzene ring; (m) is an integer of 1-5; (n) is an integer of 1-4] e.g. 1-[2-(propionylamino)ethyl]-6-methoxyindane} to efficiently give an optical activator of a compound of formula I or an optical activator of a compound of formula II [e.g. 1-(2-aminoethyl)-6-methoxyindane, etc.] (salt).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active substance of an indane derivative.

[0002]

BACKGROUND OF THE INVENTION Optically active forms of indane derivatives are useful as drugs or raw materials for synthesizing drugs. Recently, as an example thereof, a derivative having an excellent affinity for melatonin receptor (see Reference Example 8) was found, and various compounds are disclosed in Japanese Patent Application No. 7-232981.

[0003]

Since these derivatives have an asymmetric carbon at the 1-position, it is necessary to perform optical resolution using high performance liquid chromatography (HPLC) to obtain optical isomers. However, optical resolution by high performance liquid chromatography has a high manufacturing cost and is extremely difficult to industrially use. Therefore, the establishment of a more efficient and inexpensive optical resolution method has been desired.

[0004]

[Means for Solving the Problems] The present inventors have studied the optical resolution of indane derivatives by utilizing the stereospecificity of microbial enzymes. The present invention has been completed as a result of the finding that the above can be achieved and further diligent efforts. That is, the present invention provides (1) formula (I)

Embedded image [Wherein R ¹ and R ² each represent a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, or R ¹ and R ² are It may form a spiro ring which may have a substituent together with the adjacent carbon atom, R ³ is an acyl group, Ring A is an optionally substituted benzene ring, and m is 1 to An integer of 5 and n represent an integer of 1 to 4. ] The optically active isomer of the compound represented by formula (I) or its salt, or formula (II), characterized in that a culture of a microorganism or a treated product thereof is contacted with the racemic compound represented by

Embedded image [In the formula, each symbol has the same meaning as described above. ] The manufacturing method of the optically active substance of the compound represented by these, or its salt, (2) R ¹ and R ² are respectively

A hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-6 cycloalkyl group or a C _6-14 aryl group, which are halogen atoms, Nitro group, cyano group, hydroxyl group, optionally halogenated C
_1-6 alkyl group, C _1-6 alkoxy group, amino group, mono-
C _1-6 alkylamino group, di-C _1-6 lower alkylamino group, carboxyl group, C _1-6 alkyl-carbonyl group,
C _1-6 alkoxy-carbonyl group, carbamoyl group, mono-C _1-6 alkylcarbamoyl group, di-C _1-6 alkylcarbamoyl group, C _6-10 arylcarbamoyl group, C
_6-10 aryl group, C _6-10 aryloxy group, or optionally substituted C _1-6 alkylcarbonylamino group, or other than carbon atom, nitrogen atom, oxygen atom, and sulfur A 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group and a C _2-6 alkynyl group. , C
_2-6 alkenyl group, C _7-11 aralkyl group, C _6-10 aryl group, C _1-6 alkoxy group, C _6-10 aryloxy group,
C _1-6 alkanoyl group, benzoyl group, naphthoyl group,
C _1-6 alkanoyloxy group, C _6-10 arylcarbonyloxy group, carboxyl group, C _1-6 alkoxycarbonyl group, C _7-11 aralkyloxycarbonyl, carbamoyl group, mono-, di- or tri-halogeno-C _1-4 alkyl group, oxo group, amidino group, imino group, amino group, mono-C _1-4 alkylamino group, di-C _1-4 alkylamino group, oxygen atom in addition to carbon atom and one nitrogen atom ,
A 3 to 6 membered cyclic amino group optionally containing 1 to 3 heteroatoms selected from sulfur atom, nitrogen atom, etc.,
C _1-3 alkylenedioxy group, hydroxyl group, nitro group, cyano group, mercapto group, sulfo group, sulfino group, phosphono group, sulfamoyl group, mono-C _1-6 alkylsulfamoyl group, di-C _{1- 6} alkylsulfamoyl group, C _1-6 alkylthio group, C _6-10 arylthio group, C _1-6 alkylsulfinyl group, C _6-10 arylsulfinyl group, C _1-6 alkylsulfonyl group or C
_6-10 arylsulfonyl groups may be substituted, or R ¹ and R ² together with adjacent carbon atoms

Embedded image Halogen atom, C _1-6 alkyl group, C _3-6 cycloalkyl group, C _2-6 alkynyl group, C _2-6 alkenyl group, C _7-11 aralkyl group, C _6-10 aryl group, C _1-6 An alkoxy group,
C _6-10 aryloxy group, C _1-6 alkanoyl group, benzoyl group, naphthoyl group, C _1-6 alkanoyloxy group, C _6-10 arylcarbonyloxy group, carboxyl group, C _1-6 alkoxycarbonyl group, C _7-11 Aralkyloxycarbonyl, carbamoyl group, mono-, di- or tri-halogeno-C _1-4 alkyl group, oxo group, amidino group, imino group, amino group, mono-C _1-4 alkylamino group, di -C _1-4 alkylamino group, which may contain 1 to 3 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like in addition to carbon atom and 1 nitrogen atom 3
To 6-membered cyclic amino group, C _1-3 alkylenedioxy group, hydroxyl group, nitro group, cyano group, mercapto group, sulfo group, sulfino group, phosphono group, sulfamoyl group, mono-C _1-6 alkylsulfa group Moyl group, di-
C _1-6 alkylsulfamoyl group, C _1-6 alkylthio group, C _6-10 arylthio group, C _1-6 alkylsulfinyl group, C _6-10 arylsulfinyl group, C _1-6 alkylsulfonyl group or C _{6 -10} arylsulfonyl group may be substituted, and R ³ is of the formula —COR ⁴ [wherein R ⁴ is a C _1-6 alkyl group, a C _3-6 cycloalkyl group, a C _2-6 alkenyl group, C _6-10 aryl group, C _1-6 lower alkylamino group, C _6-10 arylamino group, 5- or 6-membered nitrogen-containing heterocyclic group or C _1-6 alkoxy group,
These groups may be substituted with halogen. ] A ring A is selected from a C _1-6 alkoxy group optionally substituted by a halogen atom, a lower alkyl group or an aryl group, a hydroxyl group and a mono-C _1-6 alkylamino group. The benzene ring optionally substituted with 1 to 3 substituents as described above,

(3) Formula (III)

Embedded image [In the formula, A, R ⁴ and n have the same meanings as described in (2) above. ] The optically active substance of the compound represented by the formula (III) or a salt thereof, or the formula (IV), which comprises contacting a culture of a microorganism or a treated product thereof with the racemic compound represented by

Embedded image [In the formula, A and n have the same meanings as described in (2) above. ] The production method according to the above (1), which is a method for producing an optically active compound of the compound or a salt thereof, (4) above, wherein R ⁴ is an optionally halogenated C _1-6 alkyl group. 3) The production method described, (5) Ring A is

Embedded image [R ⁵ represents a C _1-6 alkoxy group. ] Above (3)
(6) The production method according to (1) above, wherein the microorganism is a bacterium having an ability to asymmetrically hydrolyze compound (I).

(7) Bacteria are Corynebacterium
The production method according to (6) above, which is a microorganism belonging to the genus bacterium, the genus Klebsiella or the genus Serratia, and (8) the microorganism belonging to the genus Corynebacterium is Corynebacterium ammoniagenes. Above (7)
The production method described in (9) Corynebacterium ammoniagenes IFO
The production method according to (8) above, which is 12612, (10)
The method according to (7) above, wherein the microorganism belonging to the genus Klebsiella is Klebsiella planticola, (11) The method according to (10) above, wherein Klebsiella planticola is Klebsiella planticola IFO 3317,

(12) The method according to (7) above, wherein the microorganism belonging to the genus Serratia is Serratia marcescens, (13) The method according to (12) wherein Serratia marcescens is Serratia marcescens IFO 12648. Method, (14) N- [2- (6-methoxyindan-1-yl) ethyl] acetamide or a salt thereof, and Corynebacterium ammoniagenes IF
(R) -N- [2- (6-methoxyindane-1) characterized by contacting O 12612 or a treated product thereof.
-Yl) ethyl] acetamide and (S) -2- (6-methoxyindan-1-yl) ethylamine or a salt thereof, and (15) 1- (2-propionylaminoethyl) -6-methoxyindane Or its salt,
Corynebacterium ammoniagenes IFO 126
12 or a treated product thereof is contacted
(R) -1- (2-propionylaminoethyl) -6-methoxyindane and (S) -1- (2-aminoethyl) -6
-Provides a method for producing methoxyindane or a salt thereof.

In the present invention, the formula (I)

Embedded image [Wherein R ¹ and R ² each represent a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, or R ¹ and R ² are It may form a spiro ring which may have a substituent together with the adjacent carbon atom, R ³ is an acyl group, Ring A is an optionally substituted benzene ring, and m is 1 to An integer of 5 and n represent an integer of 1 to 4. ] A racemic compound represented by the following formula or a salt thereof is brought into contact with a culture of a microorganism or a treated product thereof, and asymmetric hydrolysis is carried out to obtain an optically active substance of the compound represented by the formula (I) or a salt thereof, or a formula (II )

Embedded image [In the formula, each symbol has the same meaning as described above. ] The optically active substance of the compound or its salt represented by these is manufactured.

The compound (I) has the formula (Ia)

Embedded image [In the formula, each symbol has the same meaning as described above. ] Formula (Ib)

Embedded image [Wherein each symbol has the same meaning as defined above], which is a mixture (racemic mixture) of the compound represented by the formula (Ia)
Both and the compound (Ib) are optically active substances.

The compound (II) has the formula (IIa)

Embedded image [Wherein each symbol has the same meaning as defined above] and a compound of formula (IIb)

Embedded image [In the formula, each symbol has the same meaning as described above. ] It is a mixture (racemic form) of the compound represented by
Both a) and compound (IIb) are optically active substances.

According to the production method of the present invention, compound (Ib) and compound (IIa) can be selectively produced, and compound (Ia) and compound (IIb) can be selectively produced. However, it is preferable to produce the former compound group. Compound (III), which is a preferred example of compound (I), has the formula (IIIa)

Embedded image [In the formula, each symbol has the same meaning as described above. ] Formula (IIIb)

Embedded image [Wherein each symbol has the same meaning as defined above], which is a mixture (racemate) in an equal amount with the compound (III
Both a) and compound (IIIb) are optically active substances.

The compound (IV) has the formula (IVa)

Embedded image [Wherein each symbol has the same meaning as defined above], and a compound of the formula (IVb)

Embedded image [In the formula, each symbol has the same meaning as described above. ] The compound represented by the formula (IV)
Both a) and compound (IVb) are optically active substances.
In the above formulas (IIIa), (IIIb), (IVa) and (IVb), (S) represents the S-absolute configuration and (R) represents the R-absolute configuration.

In formulas (I), (Ia) and (Ib),
Examples of the “hydrocarbon group” of the “hydrocarbon group which may have a substituent” represented by R ¹ and R ² include, for example, an aliphatic hydrocarbon group, a monocyclic saturated hydrocarbon group and an aromatic hydrocarbon group. Examples thereof include a hydrogen group, and those having 1 to 16 carbon atoms are preferable. Specifically, for example, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group and an aryl group are used. The “alkyl group” is preferably, for example, a lower alkyl group, and examples thereof include C _1-6 such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl and hexyl.
Alkyl groups are commonly used. The "alkenyl group" is preferably, for example, a lower alkenyl group, such as vinyl,
Commonly used are C _2-6 alkenyl groups such as 1-propenyl, allyl, isopropenyl, butenyl and isobutenyl. The “alkynyl group” is preferably, for example, a lower alkynyl group, and for example, a C _2-6 alkynyl group such as ethynyl, propargyl and 1-propynyl is commonly used. The "cycloalkyl group" is preferably, for example, a lower cycloalkyl group and the like, for example, C such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
_{A 3-6} cycloalkyl group is commonly used. "Aryl group" means, for example, phenyl, xylyl, 1-naphthyl, 2
-Naphthyl, biphenylyl, 2-indenyl and 2-
A C _6-14 aryl group such as anthryl is preferable, and for example, a phenyl group is widely used.

The substituent which the “hydrocarbon group” of the “hydrocarbon group which may have a substituent” represented by R ¹ and R ² may have, for example, a halogen atom (eg,
Fluorine, chlorine, bromine, iodine, etc.), nitro group, cyano group, hydroxyl group, optionally halogenated lower alkyl group (eg, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2 -Bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 4,4,4-tri Fluorobutyl, pentyl, isopentyl, neopentyl,
5,5,5-trifluoropentyl, hexyl, 6,6.6
An optionally halogenated C _1-6 alkyl group such as trifluorohexyl), a lower alkoxy group (for example,
Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy and other C _1-6 alkoxy groups), amino groups, mono-
A lower alkylamino group (eg, a mono-C _1-6 alkylamino group such as methylamino, ethylamino, etc.), a di-lower alkylamino group (eg, a di-C _1-6 alkylamino group such as dimethylamino, diethylamino, etc.) ), A carboxyl group, a lower alkyl-carbonyl group (eg, C _1-6 alkyl-carbonyl group such as acetyl, propionyl, etc.), a lower alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.) the C _1-6 alkoxy - carbonyl group), a carbamoyl group, a mono - lower alkylcarbamoyl group (e.g., methylcarbamoyl, mono- -C such ethylcarbamoyl
_1-6 alkylcarbamoyl group), di-lower alkylcarbamoyl group (eg, di-C _1-6 alkylcarbamoyl group such as dimethylcarbamoyl, diethylcarbamoyl, etc.), arylcarbamoyl group (eg, phenylcarbamoyl, naphthylcarbamoyl, etc.) C _6-10 aryl-carbamoyl group), aryl group (for example, C _6-10 aryl group such as phenyl and naphthyl), aryloxy group (for example, C _6-10 aryloxy group such as phenyloxy and naphthyloxy), An optionally halogenated lower alkylcarbonylamino group (eg, an optionally halogenated C _1-6 alkyl-carbonylamino group such as acetylamino, trifluoroacetylamino, etc.) and the like are used. The "hydrocarbon group" of the "hydrocarbon group optionally having substituent (s)" has 1 to 5, preferably 1 to 3 of the above-mentioned substituents at substitutable positions of the hydrocarbon group. When the number of substituents is two or more, each substituent may be the same or different.

The "heterocyclic group" of the "optionally substituted heterocyclic group" represented by R ¹ and R ² is, for example, selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon atom. 5 to 14-membered (preferably 5 to 10-membered) monocyclic to tricyclic, containing 1 to 4 (preferably 1 to 3) 1 or 2 heteroatoms, (preferably monocyclic) Or bicyclic) heterocyclic group and the like.
For example, 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, 2-, 4- or 5-oxazolyl, 3-, 4- Or 5-isoxazolyl, 2-, 4
-Or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 3-, 4- or 5-pyrazolyl, 2-3
-Or 4-pyrazolidinyl, 2-, 4- or 5-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, etc. in addition to a carbon atom, an oxygen atom, a sulfur atom, 5-membered ring group containing 1 to 4 heteroatoms selected from nitrogen atom and the like, for example, 2-,
3- or 4-pyridyl, N-oxide-2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxide-2-, 4- or 5-pyrimidinyl, thiomorpholinyl, morpholinyl, piperidino Two
-, 3- or 4-piperidyl, thiopyranyl, 1,4
-Oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, triazinyl, 3- or 4-pyridazinyl, pyrazinyl, N-oxide-3- or 4-
In addition to carbon atoms such as pyridazinyl, oxygen atom, sulfur atom,
6-membered ring group containing 1 to 4 heteroatoms selected from nitrogen atom and the like, for example, indolyl, benzofuryl, benzothiazolyl, benzoxazolyl, benzimidazolyl,
Quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolidinyl,
In addition to carbon atoms such as 1,8-naphthyridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromanyl, phenothiazinyl, and phenoxazinyl, 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like. A bicyclic or tricyclic fused ring group containing 1 to 4 heterocyclic groups (preferably the above 5- to 6-membered ring contains 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom, etc. in addition to carbon atoms. And a group formed by condensing 1 or 2 5- to 6-membered ring groups). Among them, a 5- to 7-membered (preferably 5- or 6-membered) heterocyclic group containing 1 to 3 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like in addition to carbon atom is preferable.

The "heterocyclic group which may have a substituent (s)"
Examples of the substituent which the “heterocyclic group” may have include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) and a lower alkyl group (eg, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec-
C such as butyl, tert-butyl, pentyl and hexyl
_1-6 alkyl group, etc.), cycloalkyl group (eg, C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), lower alkynyl group (eg, ethynyl, 1-propynyl, propargyl, etc. _2-6 alkynyl group, etc.), lower alkenyl group (eg, C _2-6 alkenyl group such as vinyl, allyl, isopropenyl, butenyl, isobutenyl, etc.), and aralkyl group (eg, C _2-6 such as benzyl, α-methylbenzyl, phenethyl and the like). _7-11 aralkyl group, etc.), aryl group (for example, C _6-10 aryl group such as phenyl, naphthyl and the like, preferably phenyl group), lower alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy,
C _1-6 alkoxy groups such as butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc., aryloxy groups (eg, C _6-10 aryloxy groups such as phenoxy, etc.), lower alkanoyl groups (eg, formyl, acetyl). C _1-6 , such as propionyl, butyryl, isobutyryl, etc.
Alkanoyl group), benzoyl group, naphthoyl group,
Lower alkanoyloxy groups (eg formyloxy,
Acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc., C _1-6 alkanoyloxy groups, etc.), arylcarbonyloxy groups (eg, benzoyloxy, naphthoyloxy, etc., C _6-10 arylcarbonyloxy groups, etc.), Carboxyl group, lower alkoxycarbonyl group (for example, C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.), aralkyloxycarbonyl (e.g., C _7-11 aralkyloxycarbonyl group such as benzyloxycarbonyl), carbamoyl group, mono-, - di - or tri - halogeno - lower alkyl group (e.g., chloromethyl, dichloro Methyl, trifluoromethyl, mono-, such 2,2,2-trifluoroethyl -, di - or tri - such as halogeno -C _1-4 alkyl group), an oxo group, amidino group, an imino group, an amino group, a mono - Lower alkylamino group (eg, methylamino, ethylamino,
Propylamino, isopropylamino, butylamino, etc. mono-C _1-4 alkylamino groups, etc., Di-lower alkylamino groups (eg, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, etc. di-C) _1-4 alkylamino group, etc.), 3- to 6-membered ring which may contain 1 to 3 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom, etc. in addition to carbon atom and 1 nitrogen atom An amino group (eg, 3 to 6 membered aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolidinyl, piperidyl, morpholinyl, dihydropyridyl, pyridyl, N-methylpiperazinyl, N-ethylpiperazinyl, etc. Cyclic amino groups, etc.), alkylenedioxy groups (eg, methyl groups) Njiokishi and C _1-3 alkylenedioxy group such as ethylenedioxy), a hydroxyl group, a nitro group, a cyano group, a mercapto group, a sulfo group,
Sulfino group, phosphono group, sulfamoyl group, monoalkylsulfamoyl group (for example, N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfyl) Mono-C _1-6 alkylsulfamoyl group such as famoyl), dialkylsulfamoyl group (eg, N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, N,
Di-C _1-6 alkylsulfamoyl groups such as N-dipropylsulfamoyl and N, N-dibutylsulfamoyl),
Alkylthio group (eg, C _1-6 alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.), arylthio group (eg, C _6-10 arylthio group such as phenylthio, naphthylthio, etc.) Etc.), lower alkylsulfinyl group (eg, C _1-6 alkylsulfinyl group such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.), arylsulfinyl group (eg, C _6-10 such as phenylsulfinyl, naphthylsulfinyl, etc.) Arylsulfinyl group, etc., lower alkylsulfonyl group (eg, C _1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.), arylsulfonyl group (eg, For example, C _6-10 arylsulfonyl groups such as phenylsulfonyl and naphthylsulfonyl) and the like are used. The “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” is
The heterocyclic group may have 1 to 5, preferably 1 to 3, at substitutable positions, and when the number of substituents is 2 or more, each substituent may be the same or different.

As used herein, the term "spiro ring" in the term "optionally substituted spiro ring" means, for example, R
¹ and R ² together represent a 3- to 8-membered ring in which adjacent carbon atoms are formed with spiro atoms as adjacent carbon atoms, such as a lower cycloalkane (eg, C ₃ such as cyclopropane, cyclobutane, cyclopentane, cyclohexane). _-8 cycloalkane), lower cycloalkene (eg, C _3-8 cycloalkene such as cyclopropene, cyclobutene, cyclopentene, cyclohexene, etc.) and the like are widely used. Preferred is C _3-8 cycloalkane. Examples of the substituent that the "spiro ring" may have include, for example, the substituent that the "heterocyclic group that may have a substituent" represented by R ¹ and R ² may have. The same number is used for the same number. Further, the "spiro ring" may be condensed with an aromatic ring (for example, a 6-membered aromatic ring such as a benzene ring or a pyridine ring).

As used herein, the term "optionally substituted benzene ring" includes, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) and a carbon atom which may have a substituent. Hydrogen group, hydroxyl group having a substituent (preferably a lower alkoxy group optionally having a substituent (eg, C _1-6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy etc.)), hydroxyl group, substitution Optionally having a group, an amide group [eg, a C _1-6 acylamino group such as acetamide (preferably C 2-5 alkanoylamino etc.)], a lower alkylenedioxy group (eg methylenedioxy) ,
And a benzene ring having 1 to 3 substituents selected from C _1-6 alkylenedioxy groups such as ethylenedioxy) at substitutable positions. Examples of the above-mentioned "hydrocarbon group which may have a substituent (s)" include those similar to the "hydrocarbon group which may be substituted" represented by R ¹ and R ² . The above "hydroxyl group having a substituent" is
A hydroxyl group having one “hydrocarbon group which may have a substituent” represented by R ¹ and R ² instead of the hydrogen atom of the hydroxyl group is shown. "Hydroxyl group having a substituent"
For example, a hydroxyl group having one lower alkyl group which may have a substituent and the like are preferable. As the "lower alkyl group", for example, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl is used, and the "lower alkyl group" is included. As the optionally substituted substituent, for example, the same substituents as the optionally substituted “hydrocarbon group optionally substituted” represented by R ¹ and R ² are used. The above "amino group which may have a substituent (s)" means, for example, R ¹
And an amino group optionally having 1 or 2 “hydrocarbon groups optionally having substituent (s)” represented by R ² . Preferred examples of the substituent which the “amino group” may have include, for example, a C _1-6 alkyl group which may have a substituent and a C _6-10 which may have a substituent. And an aryl group. Examples of the substituent which the “C _1-6 alkyl group” and “C _6-10 aryl group” may have are the “ _optionally substituted carbonized group” represented by R ¹ and R ^2. The same substituents as the “hydrogen group” may have are used. These "hydrocarbon groups",
When the "hydroxyl group" and the "amino group" have two or more substituents, the substituents may be the same or different.

The "optionally substituted benzene ring" is, for example, a halogen atom (eg fluorine, chlorine etc.), a C _1-6 alkyl group (eg methyl, ethyl etc.), a C _6-10 aryl group. A benzene ring substituted with 1 to 3 substituents selected from a C _1-6 alkoxy group (eg, methoxy, ethoxy, etc.) which may have a hydroxyl group and a mono-C _1-6 alkylamino group. And the like, and particularly preferred is a benzene ring substituted with one C _1-6 alkoxy group (eg, methoxy).

In the above formula, R ¹ and R ² each represent a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent. Further, R ¹ and R ² may form a spiro ring which may have a substituent together with the adjacent carbon atom. R ¹ and R ² are each, for example, a hydrogen atom, a lower alkyl group (eg, C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, etc.) or an aryl group (eg, phenyl, 1
-Naphthyl, 2-naphthyl, and other _C6-10 aryl groups, etc.) are preferred, and hydrogen atoms or lower alkyl groups are especially commonly used. In addition, R ¹ and R ² may be fused together with the adjacent carbon atom, for example, and condensed with an aromatic ring (eg, benzene ring).

Embedded image It is preferable when a spiro ring represented by, for example, is formed. Among them, R ¹ and R ² are preferably hydrogen atoms.

The acyl group represented by R ³ is, for example, the formula —COR ⁴ [wherein R ⁴ is a hydrocarbon group which may have a substituent,
It represents an amino group which may have a substituent, a hydroxyl group having a substituent or a heterocyclic group which may have a substituent. A group represented by or wherein -S (O) _j R ⁴ [wherein,, R ⁴ are as defined above, j represents 0 or 1. Indicates a group represented by the], among others, wherein -COR ⁴ [wherein, R ⁴ is as defined above. ] The group represented by these is preferable. The “hydrocarbon group” of the “hydrocarbon group which may have a substituent” represented by R ⁴ includes R ¹ and R ²
The same as the "hydrocarbon group" represented by are mentioned, but preferable examples thereof include alkyl groups (for example, C such as methyl, ethyl, propyl and isopropyl).
_1-6 alkyl group, etc.), alkenyl group (eg, C _2-6 alkenyl group such as vinyl), alkynyl group (eg, C _2-6 alkynyl group such as ethynyl), cycloalkyl group (eg, cyclopropyl) , Cyclobutyl,
Especially alkyl groups (eg, C _1-6 alkyl groups such as methyl), such as C _3-6 cycloalkyl groups such as cyclopentyl and cyclohexyl, and aryl groups (eg, C _6-14 aryl groups such as phenyl). And cycloalkyl groups (eg, C _3-6 cyclopropyl such as cyclopropyl) and the like are widely used. The "alkyl group", "alkenyl group", "alkynyl group", "cycloalkyl group" and "aryl group" have 1 to 5, preferably 1 to 3 halogen atoms such as fluorine. May be. As the substituent of the "optionally substituted amino group" represented by R ⁴ . Examples of the “hydrocarbon group” represented by R ¹ and R ² include an amino group which may be substituted by 1 to 2 groups. Preferred examples include a lower alkyl group which may have a substituent and One or two aryl groups which may have a substituent are used, and particularly one lower alkyl group which may have a substituent is used. As the "lower alkyl group", for example, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like can be used. The "lower alkyl group" may have 1 to 5, preferably 1 to 3 halogen atoms such as fluorine. As the “aryl group”, for example, a C _6-10 aryl group such as a phenyl group is used. The "aryl group"
Is, for example, 1 to 5 for a halogen atom such as fluorine.
It may have one, preferably 1 to 3. Examples of the “optionally substituted amino group” include 1
To a phenyl group optionally substituted with 3 to 3 halogen atoms and a lower alkyl group optionally substituted with 1 to 3 halogen atoms (eg, C such as methyl, ethyl, propyl, butyl and tert-butyl). _Examples thereof include a hydroxyl group substituted with one substituent selected from ( _1-4 alkyl group etc.), and an amino group which may be substituted is generally used.

"Hydroxyl group having a substituent" represented by R ⁴
The substituent which has is a “hydrocarbon group” represented by R ¹ and R ² , and preferable examples thereof include a lower alkyl group which may have a substituent. As the "lower alkyl group", for example, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like can be used. The “lower alkyl group” may have 1 to 3 halogen atoms such as fluorine.
Preferred examples of the "hydroxyl group having a substituent" include, for example, a lower alkoxy group which may have a substituent (for example, a C _1-6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.) and the like. Is commonly used. As the substituent of the "lower alkoxy group",
For example, a halogen atom such as fluorine is used.

Preferred examples of the “heterocyclic group” of the “optionally substituted heterocyclic group” represented by R ⁴ are:
For example, a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom is used. Specifically, for example, 1-, 2- or 3-pyrrolidinyl, 2- or 4-imidazolinyl, 2-, 3- or 4-pyrazolidinyl,
Piperidino, 2-, 3- or 4-piperidyl, 1- or 2-piperazinyl, morpholinyl, 2- or 3-
Thienyl, 2-, 3- or 4-pyridyl, 2-furyl or 3-furyl, pyrazinyl, 2-pyrimidinyl, 3
-Pyrrolyl, 3-pyridazinyl, 3-isothiazolyl,
3-isoxazolyl and the like. Particularly preferably, a 6-membered nitrogen-containing heterocyclic group (eg, pyridyl and the like) is used. As the substituent of the “heterocyclic group which may have a substituent” represented by R ⁴ , for example, a halogen atom such as fluorine is used.

R ⁴ has, for example, (i) a lower alkyl group which may have a substituent, (ii) a lower cycloalkyl group which may have a substituent, and (iii) a substituent. Optionally lower alkenyl group, (iv) optionally substituted aryl group, (v) optionally substituted lower alkylamino group, (vi) optionally substituted Good arylamino group, (vii) optionally substituted 5 or 6
A membered nitrogen-containing heterocyclic group or (viii) a lower alkoxy group which may have a substituent is preferable. The “lower alkyl group” is preferably, for example, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, pentyl and hexyl. "Lower cycloalkyl group"
For example, C _3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are preferable. The “lower alkenyl group” is, for example, vinyl,
C _2-6 alkenyl groups such as 1-propenyl and butenyl are preferable. “Aryl group” is, for example, phenyl, 1
A C _6-10 aryl group such as -naphthyl and 2-naphthyl is preferable. "Lower alkylamino group" means, for example, mono- or di-C _1-6 alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, dimethylamino, diethylamino, methylethylamino and the like. A group and the like are preferable. The “arylamino group” is preferably a C _6-10 arylamino group such as phenylamino. The "5- or 6-membered nitrogen-containing heterocyclic group" is, for example, 2-, 3- or 4-
A 5- or 6-membered nitrogen-containing heterocyclic group such as -pyridyl is preferable. "Lower alkoxy group", for example, methoxy, ethoxy, propoxy, C _1-6 alkoxy groups such as isopropoxy preferred. As the substituent which these groups may have, for example, 1 to 5 halogen atoms are used.

Further preferred examples of R ⁴ are i) C _1-6 alkyl group optionally substituted with 1 to 4 halogens, ii) C _3-6 cycloalkyl group, iii) C _2-6 alkenyl. A group, iv) a C _6-10 aryl group, each of which may be substituted with 1 to 4 halogen atoms, v) a mono- or di-C _1-6 alkylamino group, vi) C _{6- 10} arylamino groups, vii) 6-membered nitrogen-containing heterocyclic groups, or viii) C
_1-6 alkoxy groups and the like. In particular, for example, an optionally halogenated C _1-6 alkyl group (eg methyl,
Chloromethyl, difluoromethyl, trichloromethyl,
Trifluoromethyl, ethyl, 2-bromoethyl, 2,
2,2-trifluoroethyl, pentafluoroethyl,
Propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 4,4,4-trifluorobutyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoro Pentyl, hexyl, 6,6,6-trifluorohexyl etc.), C _3-6 cycloalkyl group (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.) or mono-C _1-6 alkylamino group (eg methyl) (Amino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, etc.)
Is commonly used. Of these, an optionally halogenated C _1-6 alkyl group or a mono-C _1-6 alkylamino group, particularly a halogeno C _1-3 alkyl group (eg, chloromethyl) is preferable.

In the above formula, the optionally substituted benzene ring represented by ring A is, for example,

Embedded image [R ⁵ represents a lower alkoxy group which may have a substituent (for example, a C _1-6 alkoxy group such as methoxy and ethoxy). ] Are preferred. R ⁵ is, for example, C
_A C _1-6 alkoxy group which may have a _6-10 aryl group and the like is preferable. Among them, a C _1-6 alkoxy group (for example,
Such as methoxy) is preferred.

Embedded image [In the formula, each symbol has the same meaning as described above. ].
n is preferably an integer of 1 to 3, and particularly preferably n is 1. m represents an integer of 1 to 5. m is preferably an integer of 1 to 4. Further, m is preferably 2 or 3, and particularly preferably m is 2.

As the compound (I) of the present invention, those having the following structural formulas are particularly widely used.

Embedded image [In the formula, each symbol has the same meaning as described above. ]

Preferred examples of the compound (I) include compounds of the formula

Embedded image [In the formula, each symbol has the same meaning as described above. And the like. As a preferable example of the compound (II), for example, a compound represented by the formula:

Embedded image [In the formula, each symbol has the same meaning as described above. And the like. Particularly preferred compounds (I) to (IV) are R ¹ and R ² each being a hydrogen atom,
R ⁴ is an optionally halogenated C _1-6 alkyl group or a mono-C _1-6 alkylamino group (in particular, an optionally halogenated C _1-6 alkyl group, especially halogenated C _1-4 alkyl group), A ring is C _1-3
A benzene ring substituted with an alkoxy group, and m is 2,
For example, a compound in which n is 1.

Examples of the compound (I) or a salt thereof include 1- [2- (acetylamino) ethyl] -6-methoxyindane, 1- [2- (trifluoroacetylamino) ethyl] -6-methoxyindane, 1- [2- (cyclopropylcarbonylamino) ethyl] -6-methoxyindane, 1- [2- (propionylamino) ethyl] -6-methoxyindane, 1- [2- (isobutyrylamino) ethyl]- 6-methoxyindane, 1- [2
-(Acetylamino) ethyl] -7-methoxy-1,2,
3,4-tetrahydronaphthalene, 7-methoxy-1-
[2- (trifluoroacetylamino) ethyl] -1,
Preferred examples include 2,3,4-tetrahydronaphthalene and 1- [2- (cyclopropylcarbonylamino) ethyl] -7-methoxy-1,2,3,4-tetrahydronaphthalene.

The salts of the compounds (I) to (IV) of the present invention include, for example, pharmaceutically acceptable salts. Examples include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferable examples of the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and aluminum salt and ammonium salt. Preferred examples of the salt with an organic base include:
For example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine,
Examples thereof include salts with diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like. Preferred examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfone Acids and salts with p-toluenesulfonic acid and the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be Among them, pharmaceutically acceptable salts are preferred, and examples thereof include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid when the compound (I) has a basic functional group. Examples thereof include salts with organic acids such as acetic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid. Examples thereof include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, ammonium salt and the like.

The compounds of the present invention (I) or of a salt thereof, and R ³ is represented by -COR ⁴ or for the salts, the first 32 pages to pages 46 Specification No. Hei 7-232981 The compound or a salt thereof, which can be obtained according to the method described and in which R ³ is —S (O) _j R ⁴ , is described in Japanese Patent Application No. 7-232981.
Compound (V) described on pages 34 to 34 can be obtained by subjecting it to an acylation reaction known per se.

Any microorganism can be used in the present invention as long as it has the ability to asymmetrically hydrolyze compound (I), and examples thereof include bacteria. Examples of bacteria include microorganisms belonging to the genus Corynebacterium, Klebsiella, and Serratia. Examples of microorganisms belonging to the genus Corynebacterium include Corynebacterium ammoniagenes, more specifically, Corynebacterium ammoniagenes I.
FO 12612 and the like. As a microorganism belonging to the genus Klebsiella, Klebsiella planticola (Kl
ebsiella planticola) and the like, more specifically Klebsiella planticola IFO 3317 and the like. Examples of microorganisms belonging to the genus Serratia include Serratia marcescens, and more specifically Serratia marcescens IFO 12468. The above IFO 12612, IFO 331
7 and IFO 12648 are described in LIST OF CULTURES, 9th edition, 1992 (Fermentation Research Institute), and can be obtained from the research institute. The above-mentioned microorganism may be used as it is, but may be subjected to a mutation treatment for the purpose of further improving the conversion rate or optical purity of the asymmetric hydrolysis reaction.

In the present invention, the medium to be used for culturing the microorganism having the ability to asymmetrically hydrolyze the compound (I) may be any medium as long as the microorganism can grow. As a carbon source of the medium, glucose, sucrose, maltose, dextrin, starch, glycerol, oils (eg, soybean oil, olive oil), various fatty acids (eg, palmitic acid, stearic acid, oleic acid, etc.) are used. Examples of the nitrogen source include meat extract, yeast extract, peptone, dry yeast, soybean powder, defatted soybean powder, corn steep liquor, peptone, casein, cottonseed flour, urea, ammonium salts (for example, ammonium sulfate, ammonium chloride, ammonium nitrate). , Ammonium acetate, etc.) is used. Examples of the inorganic salt include monopotassium phosphate,
Dipotassium phosphate, monosodium phosphate, disodium phosphate, sodium nitrate, magnesium sulfate, calcium carbonate, sodium chloride, and other sodium,
Potassium, calcium, magnesium salts and the like, and salts of iron, manganese, zinc, cobalt, nickel and the like are appropriately used. In addition, amino acids, peptides, vitamins, nucleic acids and the like may be contained. Inorganic or organic acids and alkalis are added for the purpose of adjusting the pH of the medium, and appropriate amounts of fats and oils, surfactants, etc. are added to the medium for the purpose of defoaming. The pH of the medium is 5-9, more preferably 6-
8 The cultivation is performed by static culture or aeration and agitation culture. The temperature is about 20 to 45 ° C, more preferably about 2
8 to 37 ° C. Culture time is about 10 to 96 hours,
More preferably, it is about 16 to 72 hours.

The "culture" used in the present invention is a culture solution obtained by culturing the above-mentioned microorganism. "Processed material" refers to cells or culture supernatant obtained by filtration or centrifugation of the culture, ultrasonic treatment of the cells, French press treatment,
Ammonium sulfate fractionation, ion exchange chromatography, adsorption chromatography, gel from cell lysate or cell extract, culture supernatant or cell extract obtained by alumina grinding, lytic enzyme treatment, surfactant, organic solvent treatment, etc. Filtration,
An enzyme preparation obtained by affinity chromatography or the like. Alternatively, a cell obtained by immobilizing cells or enzymes on a carrier such as celite may be used. In the present invention, the optically active compound (I) or compound (II) can be obtained by mixing the compound (I), which is a substrate, with the above-mentioned culture product or a treated product thereof and carrying out a reaction. . When the culture obtained by culturing the above-mentioned microorganism is a culture solution, a substrate may be added to the culture solution to carry out the reaction. At this time, the substrate may be added before or before inoculating the microorganism into the medium, or may be added simultaneously with the growth of the microorganism. The substrate may be added to the reaction solution as it is, but may be adjusted to an appropriate concentration in an organic solvent (eg, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, ethanol, methanol, toluene, etc.). It is better to add after dissolving. When the enzyme obtained from the processed product of the culture of the above microorganism is used for the reaction with the substrate, the enzyme is dissolved in an appropriate solvent (eg, saline, phosphate buffer, Tris-HCl buffer, etc.). Then, it may be subjected to the reaction with the substrate.
At this time, the substrate may be dissolved in an appropriate solvent as described above. The enzyme may be added after the substrate is dissolved in a suitable solvent. At this time, the enzyme may be dissolved in an appropriate solvent as described above. Further, both the enzyme and the substrate may be simultaneously dissolved in a suitable solvent to carry out the reaction.

This reaction can be carried out in an aqueous solution, but an organic solvent (for example, toluene, ethyl acetate, acetic acid n-
Propyl, n-butyl acetate, isopropyl ether, dichloromethane, etc.) or a two-phase system of an aqueous solution and an organic solvent. In this reaction, the concentration of the starting compound (substrate) in the reaction solution is about 0.1 to 200 mg / ml, preferably about 5 to 50 mg / ml. The amount of the microbial culture or the treated product added is 1 to 50 mg per 1 ml of the reaction solution, with the microbial cells or a corresponding amount of the treated product being the weight of wet microbial cells
Is appropriate. The reaction temperature is about 15 to 80 ° C, more preferably about 24 to 40 ° C. pH is about 4-11,
More preferably, it is about 5-8. The reaction time is about 10 minutes to 120 hours, more preferably about 1 to 96 hours. In the reaction solution, if desired, an organic solvent reaction accelerator,
An enzyme stabilizer or the like may be added. The reaction may be performed under any conditions of standing, shaking, and stirring. If necessary, cells or enzymes may be immobilized on a suitable carrier and reacted in a bioreactor.

In the reaction of the present invention, the conversion rate of compound (I) to compound (II) can be determined by the following method.

(Equation 1) [In the formula, compound (Ia), compound (Ib), compound (IIa)
And the amount of compound (IIb) are shown after the respective reactions. ] Also, the optical purity of the product (or substrate) (enantiomeric excess%
ee) is, for example, when a compound represented by the general formula (IIa) is produced,

(Equation 2) [Wherein the compounds (Ia), (Ib), (IIa) and (IIb) have the same meanings as described above]. Compound (Ia), Compound (I
The amounts of b), the compound (IIa), and the compound (IIb) after the reaction can be determined, for example, as follows. After the reaction, the reaction solution is adjusted to be basic, an appropriate amount (eg, equal amount) of an organic solvent (eg, ethyl acetate) is added thereto, and the mixture is stirred. The resulting organic solvent layer is applied to a suitable chiral column [eg
ULTRON ES-CD (Shinwa I), CHRAL-AGP (Sumitomo Chemical Analysis Service, etc.)] to obtain a compound (Ia), compound (Ib), compound (IIa) , Each amount of compound (IIb) can be measured. Compounds (Ia), (Ib), (IIa) and (IIb) are obtained from the reaction solution obtained by the above reaction by known methods such as solvent extraction, phase transfer, crystallization, recrystallization and chromatography. be able to. The obtained compound (Ia) or compound (Ib) can be hydrolyzed using a chemical method or an enzyme to obtain compound (IIa) or compound (IIb), respectively.

The optically active indane derivative obtained by the method of the present invention is useful as a drug or a raw material for synthesizing a drug.

Embedded image (S) -N- [2- (6-methoxyindan-1-yl) ethyl] acetamide (Reference Example 3) and

Embedded image Obtained from (S) -2- (6-methoxyindan-1-yl) ethylamine as a synthetic raw material

Embedded image 2,2,2-trifluoro-N- [2- (6-methoxyindan-1-yl) ethyl] acetamide (Reference Example 5),

Embedded image (S) -N- [2- (6-methoxyindan-1-yl) ethyl] propionamide (Reference Example 6),

Embedded image (S) -N- [2- (6-methoxyindan-1-yl) ethyl] butyramide (Reference Example 7) exhibits excellent melatonin receptor affinity, particularly melatonin receptor agonistic activity (see Reference Example 8). ). The compound (I) or compound (Ia) of the present invention has a high affinity for the melatonin receptor, has low toxicity, and has few side effects, and is therefore useful as a pharmaceutical. The optically active substance of the compound represented by the general formula (I) or (III) or a salt thereof of the present invention is a mammal (for example, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, It acts as a melatonin agonist or antagonist on humans, etc., and is useful as a melatonin receptor affinity composition, particularly as a melatonin receptor agonist composition or melatonin receptor antagonist composition, and is useful for melatonin such as biological rhythm regulation disorder. Diseases that may be affected, such as sleep-wake rhythm disorders, jet lag, physical condition changes due to shift work, seasonal depression, reproductive and neuroendocrine disorders, senile dementia, Alzheimer's disease, aging Various disorders (for example, aging prevention), cerebral circulation disorder,
It can be used for prevention and treatment of stress, epilepsy, convulsions, anxiety, depression, Parkinson's disease, hypertension, glaucoma, cancer, insomnia, diabetes, etc., and also immune regulation, intelligence, mental stability or ovulation regulation (eg. , Contraception) is also effective.
The optically active substance of the compound represented by the general formula (I) or (III) or a salt thereof is, for example, a biological rhythm regulator,
Preferably, a sleep disorder therapeutic agent (for example, a sleep induction agent), a sleep / wake rhythm regulator (including a sleep / wake rhythm regulator), a time band change syndrome, a so-called jet lag (je
t lag) Used as a therapeutic agent or the like.

[0039]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described in more detail below with reference to Reference Examples and Examples, but the present invention is not limited thereto.

[0040]

【Example】

Reference Example 1 N- [2- (6-methoxyindan-1-yl) ethyl] acetamide 2- (6-methoxyindan-1-yl) ethylamine (0.80 g, 4.18 mmol) and triethylamine (0.44 g, 4.39 mmol) of dichloromethane (15 m
l) solution, acetyl chloride (0.33g, 4.18mmo
l) was gradually added dropwise under ice cooling. After stirring at room temperature for 10 minutes, the reaction solution was poured into water and the organic matter was extracted with chloroform. The extract was washed with water, 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The obtained residue is ethyl acetate /
Recrystallization from isopropyl ether gave the title compound (yield 0.68 g, 70% yield). Melting point 73-74 ° C (recrystallized from ethyl acetate / isopropyl ether) NMR (CDCl ₃ ) δ: 1.50-1.80 (2H, m), 1.93-2.15 (1
H, m), 1.97 (3H, s), 2.22-2.40 (1H, m), 2.68-2.86 (2H, m), 3.
05-3.18 (1H, m), 3.33 (2H, q, J = 5.8Hz), 3.78 (3H, s), 5.49 (1
H, br s), 6.67-6.76 (2H, m), 7.11 (1H, d, J = 8.0Hz). Elemental analysis: C ₁₄ H ₁₉ NO ₂ Calculated:. C, 72.07; H, 8.21; N, 6.00 Found: C, 72.16; H, 7.94 ; N, 6.17.

Reference Example 2 (R) -N- [2- (6-Methoxyindan-1-yl) ethyl] acetamide N- [2- (6-Methoxyindan-1-yl) ethyl] acetamide was analyzed by high performance liquid chromatography. Graphography (pump, L-6000; detector, L-4000; data processor, D-2500; autosampler, AS-200
0; column, Ceramospher RU-1; mobile phase, methanol; flow rate, 0.6 ml / min; column temperature, 50 ° C .; detection wavelength, 290 nm; sample concentration, 6%; injection volume 0.1 m1; injection frequency, 100 injections ) To give the title compound (yield 99 mg). [Α] _Hg365 -61.3 ° (c 0.
3, CHCl ₃ ). Melting point 95-96 ° C

Reference Example 3 (S) -N- [2- (6-Methoxyindan-1-yl) ethyl] acetamide In the same manner as in Reference Example 2, N- [2- (6-methoxyindan-1-yl). ) Ethyl] acetamide was optically resolved using high performance liquid chromatography to obtain the title compound (yield 119 mg). [Α] _Hg365 + 80.7 ° (c 0.
3, CHCl ₃ ). Melting point 93-94 ° C Reference Example 4 (R) -2,2,2-trifluoro-N- [2
-(6-Methoxyindan-1-yl) ethyl] acetamide (R) -N- [2- (6-methoxyindan-1-yl) ethyl] acetamide (50 mg, 0.21 mmol) and hydrazine hydrate (1 ml). The mixture was heated under reflux for 26 hours under an argon atmosphere. The reaction solution was cooled, saturated saline was added, and the mixture was extracted with chloroform. The extract was washed with saturated saline and then dried over anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure to give (R) -2- (6-methoxyindan-1-yl) ethylamine 39 mg (yield 95
%). Oily. This was dissolved in chloroform (0.8 ml), triethylamine (57 μl, 0.41 mmol) was added, and the mixture was ice-cooled. Trifluoroacetic anhydride (43
μl, 0.31 mmol) was added dropwise and stirred for 20 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate, 7: 3) to give 41 mg (yield 70%) of the title compound. [Α] _Hg365 −51.
8 ° (c 0.3, CHCl ₃ ). Melting point 65-66 ° C (recrystallized from isopropyl ether / hexane)

Reference Example 5 (S) -2,2,2-Trifluoro-N- [2- (6-methoxyindan-1-yl) ethyl] acetamide In the same manner as in Reference Example 4, (S) -N -[2- (6-Methoxyindan-1-yl) ethyl] acetamide (50
mg, 0.21 mmol) to (S) -2- (6-methoxyindan-1-yl) ethylamine 38 mg (yield 93%)
I got After dissolving a portion of this in a hydrogen chloride ethanol solution, diethyl ether was added, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain (S) -2- (6-methoxyindan-1-yl).
Ethylamine hydrochloride was obtained. [Α] _D −30.0 ° (c
0.15, H ₂ O). Melting point 180-181 ° C. Further, (S) -2- (6-methoxyindan-1-yl) ethylamine was trifluoroacetylated in the same manner as in Reference Example 4 to obtain the title compound. 63% yield. [Α] _Hg365
+ 54.9 ° (c 0.3, CHCl ₃ ). Melting point 65-66 ° C (recrystallized from isopropyl ether / hexane)

Reference Example 6 (S) -N- [2- (6-Methoxyindan-1-yl) ethyl] propionamide (S) -2- (6-methoxyindan-1-yl) ethylamine hydrochloride (3) To a suspension of 0.000 g (13.2 mmol) in tetrahydrofuran (15 mL), 1N aqueous sodium hydroxide solution (30 mL) was added under ice cooling, and propionyl chloride (1.37 mL, 15.8 mmol) was further added dropwise. The mixture was stirred at room temperature for 1 hour, water was added, and this was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
The residue was recrystallized from ethyl acetate / isopropyl ether to give the title compound (2.30 g, yield 70%).
[Α] _{Hg365 +} 57.8 ° (c 1.0, CHCl ₃ ). 78-79 ° C. NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.6Hz), 1.50-1.80
(2H, m), 1.98-2.40 (2H, m), 2.20 (2H, q, J = 6.7Hz), 2.68-2.9
5 (2H, m), 3.04-3.20 (1H, m), 3.34-3.43 (2H, m), 3.79 (3H,
s), 5.45 (1H, br s), 6.68-6.76 (2H, m), 7.12 (1H, d, J = 8.0H
z). Elemental analysis: C ₁₅ H ₂₁ NO ₂ Calculated: C, 72.84; H, 8.56 ; N, 5.66. Found: C, 72.69; H, 8.64; N, 5.70.

Reference Example 7 (S) -N- [2- (6-Methoxyindan-1-yl) ethyl] butyramide In the same manner as in Reference Example 6, (S) -2- (6-methoxyindan-1-). The title compound was obtained from (yl) ethylamine hydrochloride and butyryl chloride (yield 94%) [α] _Hg365 + 58.4 ° (c 1.0, CHCl ₃ ). Melting point 98-99 [deg.] C. (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ; 0.94 (3H, t, J = 7.2Hz), 1.50-1.80
(4H, m), 1.96-2.13 (1H, m), 2.14 (2H, t, J = 7.4Hz), 2.22-2.4
0 (1H, m), 2.70-2.95 (2H, m), 3.03-3.19 (1H, m), 3.33-3.45
(2H, m), 3.79 (3H, s), 5.44 (1H, br s), 6.67-6.75 (2H, m), 7.
11 (1H, d, J = 8.0 Hz). Elemental analysis: C ₁₆ H ₂₃ NO ₂ Calculated: C, 73.53; H, 8.87 ; N, 5.36. Found: C, 73.28; H, 8.81; N, 5.23. The residue was purified by column chromatography (ethyl acetate / methanol: 95: 5) using silica gel (Kieselgel 60, manufactured by Merck) as a simple substance, and then (R) -N- [2- (6
2.55 g (yield 46%) of -methoxyindan-1-yl) ethyl] acetamide was obtained. [Α] _Hg365 −61.
6 ° (c 0.3, CHCl ₃ ). Melting point 95-96 [deg.] C (recrystallized from ethyl acetate / isopropyl ether). NMR (CDCl ₃ ) δ: 1.50-1.80 (2H, m), 1.93-2.11 (1
H, m), 1.97 (3H, s), 2.24-2.40 (1H, m), 2.67-2.90 (2H, m), 3.
02-3.20 (1H, m), 3.32-3.44 (2H, m), 3.79 (3H, s), 5.51 (1H, b
rs), 6.67-6.76 (2H, m), 7.11 (1H, d, J = 8.0Hz).

Reference Example 8 Inhibitory Action of 2- [ ¹²⁵ I] Iodomelanin Binding The forebrain was excised from a 7-day-old chick (white leghorn).
Ice-cold assay buffer (50 mM Tris-HCl, p
H7.7, 25 ° C.) to prepare a homogenate
A sediment was obtained by centrifugation at 0 × g for 10 minutes. This was washed once with the same buffer solution and then 0.3-0.4 mg protein /
A membrane sample was obtained by homogenizing with an assay buffer so as to have a volume of ml. Ask the examiner for drug solution, membrane sample, ligand (80 pM 2- [ ¹²⁵ I] iodomelatonin, about 100,
000 dpm) was mixed in a total volume of 0.5 ml and incubated at 25 ° C. for 90 minutes. Add 3 ml of ice-cold assay buffer and immediately filter by suction onto Whatman GF / B. The filter is 3 ml of ice-cold assay buffer.
After washing twice with, the radioactivity was measured with a γ-counter. The value obtained by subtracting the binding in the presence of 10 μM melatonin as a non-specific binding was defined as a specific binding. The 50% inhibitory concentration (IC ₅₀ ) was calculated by the log-probit method.

[0047]

[Table 1] Inhibitory action of 2- [ ¹²⁵ I] iodomelanin binding Reference Example Compound IC ₅₀ (nM) 3 0.75 5 0.16 6 0.26 Melatonin 1.1 [Table 1] It can be seen that the compounds obtained in 3, 5 and 6 have excellent melatonin receptor affinity. Example 1 5 ml Trypticase Soy Broth (Becton Dickens) placed in a test tube.
on and Company, USA) were inoculated with bacteria and cultured at 28 ° C. for 1 day under shaking. 500 μl of the obtained culture broth was taken, and Tris-hydrochloric acid buffer (50 μl) and 2% N were added to it.
-[2- (6-Methoxyindan-1-yl) ethyl]
Add a methanol solution containing acetamide (25 μl),
The reaction was carried out at 28 ° C. for 1 day under shaking. In this reaction liquid
Add 500 μl of methanol and centrifuge.
High-performance liquid chromatography (HPLC) using CHIRAL-AGP (Sumitomo Chemical Analysis Service) as a column was used for analysis to quantify the acetyl form as the substrate and the free form as the hydrolyzate. [Table 2] shows the conversion rate and optical purity of asymmetric hydrolysis by each strain.

[0048]

[Table 2]  Optical purity (%) Strain Conversion rate (%) Free form Acetyl form A 55.9 (S) 71.8 (R) 92.8 B 61.3 (S) 74.3 (R) 100C 22.3 (S) 100 (R) 26.4 A: Crevenella planticola IFO 3317 B: Corynebacterium ammoniagenes IFO 12612 C: Serratia marcescens IFO 12648 Free form: 2- (6-methoxyindan-1-yl) ethylamino acetyl form: N- [2- ( 6-Methoxyindan-1-yl) ethyl] acetamide (S): S-absolute configuration (R): R-absolute configuration From the above results, the above-mentioned microorganism is N- [2- (6-meth)
Asymmetric xyindan-1-yl) ethyl] acetamide
Hydrolyzed to give optically active form
Was.

Example 2 In the same manner as in Example 1, 1- [2- (propionyl urea
Mino) ethyl-6-methoxyindane was reacted. Addition
Conversion of water splitting reaction and the resulting hydrolyzate 1- (2
-Aminoethyl) -6-methoxyindane optical purity
It shows in [Table 3]. Strain conversion rate (%) Optical purity (%) Klebsiella planticola IFO 3317 8.4> 99 Corynebacterium ammoniagenes IFO 12612 14.1> 99Serratia marcescens IFO 12648 9.1> 99

[Example 3] Corynebacterium ammoniagenes IFO
12612 200ml Erlenmeye
r) Inoculate 40 ml of Trypticase Soy Broth (BBL) in a flask and inoculate 2
Culturing was carried out at 8 ° C. for 1 day under shaking to obtain a seed culture solution. 40
0.4 ml of the above seed culture was transferred to 138 200 ml Erlenmeyer flasks containing ml trypticase soy broth and cultured at 28 ° C. for 1 day under shaking to obtain a main culture. . N- [2- (6-methoxyindan-1-yl) ethyl] acetamide (5.52 g) was dissolved in methanol (276 ml), and the methanol solution was added to 138 200 ml Erlenmeyer flasks containing 40 ml of the main culture solution. 2 ml each was dispensed, and the reaction was carried out by shaking at 28 ° C. for 3 days. Obtained reaction solution (5.52 l)
Was adjusted to pH 5.0 with 2N HCl and extracted twice with 5.5 l of ethyl acetate. Obtained ethyl acetate layer (total 11
l) was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / methanol: 95: 5) using silica gel (Kieselgel 60 manufactured by Merck) as a carrier to obtain (R) -N- [2- (6-methoxyindan-1-
2.55 g (yield) ethyl] acetamide (46% yield)
I got [Α] _Hg365 -61.6 ° (c 0.3, CHC
l ₃₎ mp 95-96 ° C. (recrystallized from ethyl acetate / isopropyl ether). NMR (CDCl ₃ ) δ: 1.50-1.80 (2H, m), 1.93-2.11 (1
H, m), 1.97 (3H, s), 2.24-2.40 (1H, m), 2.67-2.90 (2H, m), 3.
02-3.20 (1H, m), 3.32-3.44 (2H, m), 3.79 (3H, s), 5.51 (1H,
m, br s), 6.67-6.76 (2H, m), 7.11 (1H, d, J = 8.0 Hz). Elemental analysis: C ₁₄ H ₁₉ NO ₂ Calculated: C, 72.07; H, 8.21 ; N, 6.00. Found: C, 72.11; H, 8.09; N, 5.86. Meanwhile, the aqueous layer was adjusted to pH 9.0 with 30% NaOH, and the volume was adjusted to 6 l.
It was extracted twice with ethyl acetate. The ethyl acetate layer (12 l in total) was concentrated under reduced pressure. The residue was dissolved in ethanol (5 mL) and diethyl ether (30 mL), and 5N hydrogen chloride ethanol solution (15 mL) was added thereto. The precipitated crystals were filtered out and then recrystallized from ethanol / diethyl ether to give (S) -2- (6
1.37 g (yield 26%) of -methoxyindan-1-yl) ethylamine hydrochloride was obtained. [Α] _D −30.0 ° (c 0.15, CHCl ₃ ). Melting point 180-181 [deg.] C. NMR (DMSO-d ₆ ) δ: 1.57-1.88 (2H, m), 2.01-2.
36 (2H, m), 2.62-2.92 (4H, m), 3.07-3.23 (1H, m), 3.73 (3H,
s), 6.68-6.78 (2H, m), 7.12 (1H, d, J = 8.2Hz), 8.14 (2H, br
s). Elemental analysis: C ₁₂ H ₁₈ ClNO Calculated: C, 63.29; H, 7.97 ; N, 6.15. Found: C, 63.14; H5 7.70; N5 6.14.

[0051]

INDUSTRIAL APPLICABILITY In the method of the present invention, an optically active substance of an indane derivative represented by the general formula (I) or a salt thereof and a compound represented by the general formula (II) or a compound thereof by asymmetric hydrolysis by a microorganism. An optically active salt can be efficiently produced.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location (C12P 41/00 C12R 1:43)

Claims (15)

[Claims] 1. A compound of the formula (I) [Wherein R ¹ and R ² each represent a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, or R ¹ and R ² are It may form a spiro ring which may have a substituent together with the adjacent carbon atom, R ³ is an acyl group, Ring A is an optionally substituted benzene ring, and m is 1 to An integer of 5 and n represent an integer of 1 to 4. ] The optically active substance of the compound represented by formula (I) or its salt, or formula (II), which comprises contacting a culture of a microorganism or a treated product thereof with the racemic compound represented by [Chemical 2] [In the formula, each symbol has the same meaning as described above. ] The manufacturing method of the optically active substance of the compound or its salt represented by these. 2. R ¹ and R ² are each (1) hydrogen atom, (2) C _1-6 alkyl group, C _2-6 alkenyl group, C
_2-6 alkynyl group, C _3-6 cycloalkyl group or C _6-14
Aryl groups, these groups include halogen atoms, nitro groups,
Cyano group, hydroxyl group, optionally halogenated C _1-6 alkyl group, C _1-6 alkoxy group, amino group, mono-C _1-6 alkylamino group, C _1-6 di-lower alkylamino group , Carboxyl group, C _1-6 alkyl-carbonyl group, C _1-6 alkoxy-carbonyl group, carbamoyl group, mono-C _1-6 alkylcarbamoyl group, C _1-6 di-alkylcarbamoyl group, C _6-10 aryl A carbamoyl group, a C _6-10 aryl group, a C _6-10 aryloxy group, or an optionally halogenated C _1-6 alkylcarbonylamino group, or (3) other than carbon atom 5- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, and these groups are halogen atom, C _1-6 alkyl group, C
_3-6 cycloalkyl group, C _2-6 alkynyl group, C _2-6 alkenyl group, C _7-11 aralkyl group, C _6-10 aryl group, C
_1-6 alkoxy group, C _6-10 aryloxy group, C _1-6 alkanoyl group, benzoyl group, naphthoyl group, C _1-6 alkanoyloxy group, C _6-10 arylcarbonyloxy group, carboxyl group, C _{1- 6} alkoxycarbonyl group,
C _7-11 aralkyloxycarbonyl, carbamoyl group,
Mono-, di- or tri-halogeno-C _1-4 alkyl group, oxo group, amidino group, imino group, amino group, mono-C _1-4 alkylamino group, di-C _1-4 alkylamino group, carbon In addition to the atom and one nitrogen atom, a 3- to 6-membered cyclic amino group optionally containing 1 to 3 hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom and the like, C _1-3
Alkylenedioxy group, hydroxyl group, nitro group, cyano group, mercapto group, sulfo group, sulfino group, phosphono group, sulfamoyl group, mono-C _1-6 alkylsulfamoyl group, di-C _1-6 alkylsulfa group Moyle group,
Substituted with a C _1-6 alkylthio group, a C _6-10 arylthio group, a C _1-6 alkylsulfinyl group, a C _6-10 arylsulfinyl group, a C _1-6 alkylsulfonyl group or a C _6-10 arylsulfonyl group Good or (4)
R ¹ and R ² together with the adjacent carbon atom are Halogen atom, C _1-6 alkyl group, C _3-6 cycloalkyl group, C _2-6 alkynyl group, C _2-6 alkenyl group, C _7-11 aralkyl group, C _6-10 aryl group, C _1-6 An alkoxy group,
C _6-10 aryloxy group, C _1-6 alkanoyl group, benzoyl group, naphthoyl group, C _1-6 alkanoyloxy group, C _6-10 arylcarbonyloxy group, carboxyl group, C _1-6 alkoxycarbonyl group, C _7-11 Aralkyloxycarbonyl, carbamoyl group, mono-, di- or tri-halogeno-C _1-4 alkyl group, oxo group, amidino group, imino group, amino group, mono-C _1-4 alkylamino group, di -C _1-4 alkylamino group, which may contain 1 to 3 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like in addition to carbon atom and 1 nitrogen atom 3
To 6-membered cyclic amino group, C _1-3 alkylenedioxy group, hydroxyl group, nitro group, cyano group, mercapto group, sulfo group, sulfino group, phosphono group, sulfamoyl group, mono-C _1-6 alkylsulfa group Moyl group, di-
C _1-6 alkylsulfamoyl group, C _1-6 alkylthio group, C _6-10 arylthio group, C _1-6 alkylsulfinyl group, C _6-10 arylsulfinyl group, C _1-6 alkylsulfonyl group or C _{6 -10} arylsulfonyl group may be substituted, and R ³ is of the formula —COR ⁴ [wherein R ⁴ is a C _1-6 alkyl group, a C _3-6 cycloalkyl group, a C _2-6 alkenyl group, C _6-10 aryl group, C _1-6 lower alkylamino group, C _6-10 arylamino group, 5- or 6-membered nitrogen-containing heterocyclic group or C _1-6 alkoxy group,
These groups may be substituted with halogen. ] A group represented by the following formula, wherein ring A is (1) C which may be substituted with a halogen atom, a lower alkyl group or an aryl group.
_1-6 alkoxy group, (2) hydroxyl group and (3)
1 to 3 selected from mono-C _1-6 alkylamino groups
The method according to claim 1, which is a benzene ring which may be substituted with one substituent. 3. Formula (III): [In the formula, A, R ⁴ and n have the same meanings as in claim 2. ] The optically active compound of the compound represented by formula (III) or its salt, or formula (IV), which comprises contacting a culture of a microorganism or a treated product thereof with the racemic compound represented by [Chemical 5] [In the formula, A and n have the same meaning as in claim 2. ]
The method according to claim 1, which is a method for producing an optically active compound of the compound represented by or a salt thereof. 4. The process according to claim 3, wherein R ⁴ is an optionally halogenated C _1-6 alkyl group. 5. Ring A is [R ⁵ represents a C _1-6 alkoxy group. ] The manufacturing method of Claim 3 which is these. 6. The method according to claim 1, wherein the microorganism is a bacterium having an ability to asymmetrically hydrolyze compound (I). 7. The method according to claim 6, wherein the bacterium is a microorganism belonging to the genus Corynebacterium, the genus Klebsiella or the genus Serratia. 8. The method according to claim 7, wherein the microorganism belonging to the genus Corynebacterium is Corynebacterium ammoniagenes. 9. Corynebacterium ammoniagenes IFO 126
The method according to claim 8, which is 12. 10. The method according to claim 7, wherein the microorganism belonging to the genus Klebsiella is Klebsiella planticola. 11. The Klebsiella planticola is Klebsiella planticola IFO 3317.
Production method as described. 12. A microorganism belonging to the genus Serratia is Serratia.
The method according to claim 7, which is marcescene. 13. The method according to claim 12, wherein the Serratia marcescens is Serratia marcescens IFO 12648. 14. N- [2- (6-methoxyindan-1)
-Ryl) ethyl] acetamide or a salt thereof is contacted with Corynebacterium ammoniagenes IFO 12612 or a treated product thereof (R) -N
-[2- (6-Methoxyindan-1-yl) ethyl]
Acetamide and (S) -2- (6-methoxyindane-1)
-Yl) A method for producing ethylamine or a salt thereof. 15. 1- (2-propionylaminoethyl)
Corynebacterium ammoniagenes IFO 12612 or a treated product thereof is brought into contact with -6-methoxyindane or a salt thereof (R) -1- (2
A method for producing -propionylaminoethyl) -6-methoxyindane and (S) -1- (2-aminoethyl) -6-methoxyindane or a salt thereof.