Method for producing optically active compounds

Abstract

The purpose of the present invention is to provide a method for more efficiently producing specific optically active compounds including optically active 1-acetyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline.　The present invention provides a method for producing an optically active compound represented by formula (3) (wherein R5 represents a hydrogen atom, etc., R6 and R7 each independently represent a hydrogen atom, etc., R8 represents a C1-C6 alkyl group, R9, R10, and R11 each independently represent a hydrogen atom, etc., and the asterisked carbon atom is an asymmetric carbon atom), the method comprising reacting a compound represented by formula (2) (wherein R5, R6, R7, R8, R9, R10, and R11 respectively have the same meanings as defined above) with hydrogen in the presence of an asymmetric cobalt complex.

Description

[Technical field]

[0001] The present invention relates to a method for producing an optically active compound and an asymmetric cobalt complex effective therefor. [Background technology]

[0002] Patent Document 1 describes a method for producing optically active 1-acetyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline, in which 1-acetyl-1,2-dihydro-2,2,4-trimethyl-1-quinoline is reacted with hydrogen in the presence of an asymmetric iridium catalyst. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2015 / 141564 Summary of the Invention [Problem to be solved by the invention]

[0004] An object of the present invention is to provide a more efficient method for producing certain optically active compounds, including optically active 1-acetyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline. [Means for solving the problem]

[0005] Under these circumstances, the present inventors have conducted extensive research and have arrived at the present invention. [1] In the presence of an asymmetric cobalt complex, the compound of formula (2): [ka] (In the formula, R 5 represents a hydrogen atom or a C1-C6 alkyl group which may have one or more substituents, R 6 and R 7each independently represents a hydrogen atom or a C1-C6 alkyl group; R 8 represents a C1-C6 alkyl group, and R 9 , R 10 and R 11 each independently represents a hydrogen atom, a halogen atom, an amino group, a hydroxy group, a C1-C6 alkyl group which may have one or more substituents, a C1-C6 alkoxy group which may have one or more substituents, a C2-C7 alkylcarbonyl group which may have one or more substituents, or a C6-C10 aryl group which may have one or more substituents. and reacting a compound represented by formula (3): [ka] (In the formula, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 have the same meaning as above. The carbon atom marked with * represents an asymmetric carbon atom.) A method for producing an optically active compound represented by the formula: [2] The asymmetric cobalt complex according to [1] has the formula (1): [ka] (In the formula, R 1 R each independently represents a C1-C10 alkyl group which may have one or more substituents, a C3-C10 cycloalkyl group which may have one or more substituents, or a C6-C10 aryl group which may have one or more substituents. 2 and R 3 each independently represents a hydrogen atom, a C1-C10 alkyl group which may have one or more substituents, or a C6-C10 aryl group which may have one or more substituents, or R 2 and R 3 and are bonded to each other to form a ring together with the carbon atoms to which they are attached. 4represents a C1-C10 alkyl group optionally having one or more substituents, a C1-C10 alkoxy group optionally having one or more substituents, a C1-C10 alkylthio group optionally having one or more substituents, a C2-C11 alkoxycarbonyl group optionally having one or more substituents, a C2-C11 alkylcarbonyl group optionally having one or more substituents, a C6-C10 aryl group optionally having one or more substituents, a halogen atom, an amino group optionally mono- or di-alkylated with a C1-C10 alkyl group, a nitro group, a hydroxy group, a sulfo group, a C1-C10 alkylsulfonyl group, a C6-C10 arylsulfonyl group, or a halosulfonyl group. n represents 0, 1, 2, or 3. When n is 0 or 1, multiple R 4 may be the same or different. X represents a chlorine atom, a bromine atom, or an iodine atom. And, the carbon atom marked with * represents an asymmetric carbon atom.) The method according to [1], wherein the monovalent cobalt complex is obtained by reacting an asymmetric cobalt complex represented by the formula: [3] The method according to [2], wherein the reducing agent is a hydride reducing agent and the asymmetric monovalent cobalt complex is a hydride complex. [4] The method according to [3], wherein the hydride reducing agent is an alkali metal trialkylborohydride. [5] The method according to [3] or [4], further comprising carrying out the reaction in the presence of a divalent cobalt halide salt. [6] The method according to [5], wherein the amount of the divalent cobalt halide salt used is 2 moles or less per mole of the hydride complex. [7] The method according to [3] or [4], further comprising carrying out the reaction in the presence of a trialkylamine. [8] The method according to [7], wherein the amount of trialkylamine used is in the range of 0.5 to 3 moles per mole of the compound represented by formula (2). [9] The method according to [2], wherein the reducing agent is an alkyllithium and the monovalent cobalt complex is an alkyl complex.

[10] A step of obtaining an optically active compound represented by formula (3) by the production method according to any one of [1] to [9]; [1] to [9], the optically active compound represented by formula (3) obtained by the production method according to any one of the above [1] to [9] is reacted with an acid to obtain a compound represented by formula (4): [ka] (In the formula, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 have the same meaning as above. The carbon atom marked with * represents an asymmetric carbon atom.) obtaining an optically active compound represented by the formula: The obtained optically active compound represented by formula (4) is reacted with water to obtain a compound represented by formula (5): [ka] (In the formula, R 6 , R 7 , R 8 , R 9 , R 10 and R 11 have the same meaning as above. The carbon atom marked with * represents an asymmetric carbon atom.) A method for producing an optically active compound, comprising the step of obtaining an optically active compound represented by the formula:

[11] R in Equation (5) 6 , R 7 and R 8 is a methyl group, and R 9 , R 10 and R 11 is a hydrogen atom.

[12] A step of obtaining optically active 1,1,3-trimethyl-4-aminoindan by the production method according to

[11] ,

[11] A method for producing optically active 1,1,3-trimethyl-4-aminoindan, comprising a step of dissolving the optically active 1,1,3-trimethyl-4-aminoindan obtained by the production method according to claim 1 in a solvent, and then optically resolving the resulting product using optically active tartaric acid.

[13] A process for obtaining optically active 1,1,3-trimethyl-4-aminoindan by the process according to

[11] ,

[11] A method for producing optically active 1,1,3-trimethyl-4-aminoindan, comprising a step of dissolving the optically active 1,1,3-trimethyl-4-aminoindan obtained by the production method according to claim 1 in a solvent, and then adding an acid to cause preferential crystallization.

[14] The method according to

[13] , wherein the acid has an acid dissociation constant (pKa) of less than 2.8.

[15] The method according to any one of

[12] to

[14] , wherein the enantiomeric ratio of the optically active 1,1,3-trimethyl-4-aminoindan subjected to optical resolution or preferential crystallization is 70 / 30 or more in terms of R- / S-form.

[16] A process for obtaining optically active 1,1,3-trimethyl-4-aminoindan by the process according to any one of

[12] to

[15] ,

[12] to

[15] , and an optically active 1,1,3-trimethyl-4-aminoindan of the formula (6): [ka] (In the formula, R 12 and R 13 each independently represents a C1-C6 alkyl group optionally substituted with one or more halogen atoms, or a hydrogen atom, and R 14 represents a halogen atom, a hydroxy group, or a C1-C6 alkoxy group optionally substituted with one or more halogen atoms. and a compound represented by formula (7): [ka] (In the formula, R 12 , R 13 and * have the same meaning as above.) A method for producing an optically active compound, comprising the step of obtaining an optically active compound represented by the formula:

[17] Formula (1'): [ka] (In the formula, R 1 represents an isopropyl group or a tert-butyl group. The carbon atom marked with * represents an asymmetric carbon atom. An asymmetric cobalt complex represented by the formula:

[18] Formula (1'): [ka] (In the formula, R 1 represents an isopropyl group or a tert-butyl group. The carbon atom marked with * represents an asymmetric carbon atom. The hydride complex is obtained by reacting an asymmetric cobalt complex represented by the following formula with a hydride reducing agent.

[19] Formula (1'): [ka] (In the formula, R 1 represents an isopropyl group or a tert-butyl group. The carbon atom marked with * represents an asymmetric carbon atom. An alkyl complex obtained by reacting an asymmetric cobalt complex represented by the formula: with an alkyl lithium. Effect of the Invention

[0006] According to the present invention, the optically active compound represented by the above formula (3) can be efficiently produced. In addition, by reacting the obtained optically active compound represented by the formula (3) with an acid and then reacting with water, the optically active compound represented by the above formula (5) can be efficiently produced. Furthermore, by subjecting the obtained optically active 1,1,3-trimethyl-4-aminoindan, which is one of the optically active compounds represented by the formula (5), to optical resolution or preferential crystallization with an acid, 1,1,3-trimethyl-4-aminoindan with high optical purity can be efficiently produced, and by reacting the obtained 1,1,3-trimethyl-4-aminoindan with high optical purity with the compound represented by the above formula (6), the optically active compound represented by the above formula (7) can be efficiently produced. Such an optically active compound represented by the formula (7) is known to have plant disease control effects (see International Publication No. WO 2011 / 162397). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] The present invention will be described in detail below.

[0008] In this specification, the notation "CX-CY" means that the number of carbon atoms is X to Y. For example, the notation "C1-C4" means that the number of carbon atoms is 1 to 4.

[0009] In this specification, examples of the C1-C10 alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group. Examples of the substituents that these C1-C10 alkyl groups may have include C6-C10 aryl groups that may have one or more C1-C10 alkyl groups or C1-C10 alkoxy groups, such as a phenyl group, a naphthyl group, a 4-methylphenyl group, and a 4-methoxyphenyl group; C1-C10 alkoxy groups that may have one or more fluorine atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butyloxy group, a tert-butoxy group, and a trifluoromethoxy group; C1-C10 alkoxy groups having C6-C10 aryl groups that may have one or more C1-C10 alkyl groups or C1-C10 alkoxy groups, such as a benzyloxy group, a 4-methylbenzyloxy group, and a 4-methoxybenzyloxy group; and one or more C6-C10 aryloxy groups, such as a 3-phenoxybenzyloxy group. C1-C10 alkoxy groups having a C6-C10 aryl group having one or more C1-C10 alkyl groups or C1-C10 alkoxy groups, such as a phenoxy group, a 2-methylphenoxy group, a 4-methylphenoxy group, and a 4-methoxyphenoxy group; C6-C10 aryloxy groups having one or more C6-C10 aryloxy groups, such as a 3-phenoxyphenoxy group; C2-C10 acyl groups having a C6-C10 aryl group which may have one or more C1-C10 alkyl groups or C1-C10 alkoxy groups, such as an acetyl group, a propionyl group, a benzylcarbonyl group, a 4-methylbenzylcarbonyl group, a 4-methoxybenzylcarbonyl group, a benzoyl group, a 2-methylbenzoyl group, a 4-methylbenzoyl group, and a 4-methoxybenzoyl group; a carboxy group; and a fluorine atom. Examples of C1-C10 alkyl groups having one or more substituents include a fluoromethyl group, a trifluoromethyl group, a methoxymethyl group, an ethoxymethyl group, a methoxyethyl group, a benzyl group, a 4-fluorobenzyl group, a 4-methylbenzyl group, a phenoxymethyl group, a 2-oxopropyl group, a 2-oxobutyl group, a phenacyl group, and a 2-carboxyethyl group.

[0010] In this specification, examples of a C3-C10 cycloalkyl group include a cyclopropyl group, a 2,2-dimethylcyclopropyl group, a cyclopentyl group, a cyclohexyl group, and a menthyl group. Examples of the substituents that these C3-C10 cycloalkyl groups may have include C6-C10 aryl groups that may have one or more C1-C10 alkyl groups or C1-C10 alkoxy groups, such as a phenyl group, a naphthyl group, a 4-methylphenyl group, and a 4-methoxyphenyl group; C1-C10 alkoxy groups that may have one or more fluorine atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butyloxy group, a tert-butoxy group, and a trifluoromethoxy group; C1-C10 alkoxy groups having C6-C10 aryl groups that may have one or more C1-C10 alkyl groups or C1-C10 alkoxy groups, such as a benzyloxy group, a 4-methylbenzyloxy group, and a 4-methoxybenzyloxy group; and one or more C6-C10 aryloxy groups, such as a 3-phenoxybenzyloxy group. C1-C10 alkoxy groups having a C6-C10 aryl group having one or more C1-C10 alkyl groups or C1-C10 alkoxy groups, such as a phenoxy group, a 2-methylphenoxy group, a 4-methylphenoxy group, and a 4-methoxyphenoxy group; C6-C10 aryloxy groups having one or more C6-C10 aryloxy groups, such as a 3-phenoxyphenoxy group; C2-C10 acyl groups having a C6-C10 aryl group which may have one or more C1-C10 alkyl groups or C1-C10 alkoxy groups, such as an acetyl group, a propionyl group, a benzylcarbonyl group, a 4-methylbenzylcarbonyl group, a 4-methoxybenzylcarbonyl group, a benzoyl group, a 2-methylbenzoyl group, a 4-methylbenzoyl group, and a 4-methoxybenzoyl group; a carboxy group; and a fluorine atom. Examples of the substituted C3-C10 cycloalkyl group include a fluorocyclopropyl group, a 4-trifluorocyclohexyl group, a 4-methoxycyclopentyl group, and a 4-phenylcyclohexyl group.

[0011] As used herein, C6-C10 aryl groups include, for example, phenyl and naphthyl groups. Examples of the substituents that these C6-C10 aryl groups may have include one or more C1-C10 alkoxy groups or C1-C10 alkyl groups which may have a fluorine atom, such as a methyl group, a fluoromethyl group, a trifluoromethyl group, a methoxymethyl group, an ethoxymethyl group, and a methoxyethyl group; one or more C1-C10 alkoxy groups or C1-10 alkoxy groups which may have a fluorine atom, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutyloxy group, a sec-butyloxy group, a tert-butyloxy group, a pentyloxy group, a fluoromethoxy group, a trifluoromethoxy group, a methoxymethoxy group, an ethoxymethoxy group, and a methoxyethoxy group; a C3-C10 cycloalkyloxy group such as a cyclopentyloxy group; and halogen atoms such as a fluorine atom and a chlorine atom. Examples of the C6-C10 aryl group having one or more substituents include a 2-methylphenyl group, a 4-methylphenyl group, a 4-chlorophenyl group and a 4-methoxyphenyl group.

[0012] In this specification, a C1-C10 alkoxy group which may have one or more substituents refers to a group in which the hydrogen atom constituting the hydroxy group (-OH) is replaced by a C1-C10 alkyl group which may have one or more substituents as described above, and examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, an n-butoxy group, a sec-butoxy group, a pentyloxy group, a decyloxy group, a fluoromethoxy group, a trifluoromethoxy group, a methoxymethoxy group, an ethoxymethoxy group, a benzyloxy group, a 4-fluorobenzyloxy group, a 4-methylbenzyloxy group, a phenoxymethoxy group, a 2-oxopropoxy group, and a 2-oxobutoxy group.

[0013] In this specification, a C1-C10 alkylthio group which may have one or more substituents refers to a group in which the hydrogen atom constituting the sulfanyl group (-SH) is replaced by a C1-C10 alkyl group which may have one or more substituents as described above, and examples thereof include a methylthio group, an ethylthio group, an n-propylthio group, an n-butylthio group, a sec-butylthio group, a pentylthio group, a tydecylthio group, a fluoromethylthio group, a trifluoromethylthio group, a methoxymethylthio group, an ethoxymethylthio group, a benzylthio group, a 4-fluorobenzylthio group, a 4-methylbenzylthio group, a phenoxymethylthio group, a 2-oxopropylthio group, and a 2-oxobutylthio group.

[0014] In this specification, a C2-C11 alkoxycarbonyl group which may have one or more substituents refers to a group in which the hydrogen atom constituting a formyl group (-CHO) is replaced with a C1-C10 alkoxy group which may have one or more substituents as described above, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an n-butoxycarbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonyl group, a decyloxycarbonyl group, a fluoromethoxycarbonyl group, a trifluoromethoxycarbonyl group, a methoxymethoxycarbonyl group, an ethoxymethoxycarbonyl group, a benzyloxycarbonyl group, a 4-fluorobenzyloxycarbonyl group, a 4-methylbenzyloxycarbonyl group, a phenoxymethoxycarbonyl group, a 2-oxopropoxycarbonyl group, and a 2-oxobutoxycarbonyl group.

[0015] In this specification, a C2-C11 alkylcarbonyl group which may have one or more substituents refers to a group in which the hydrogen atom constituting a formyl group (-CHO) is replaced with a C1-C10 alkyl group which may have the above-mentioned substituents, and examples thereof include an acetyl group, an ethylcarbonyl group, a propylcarbonyl group, a butylcarbonyl group, a sec-butylcarbonyl group, a tert-butylcarbonyl group, a pentylcarbonyl group, a decylcarbonyl group, a fluoromethylcarbonyl group, a trifluoromethylcarbonyl group, a methoxymethylcarbonyl group, an ethoxymethylcarbonyl group, a benzylcarbonyl group, a 4-fluorobenzylcarbonyl group, a 4-methylbenzylcarbonyl group, a phenoxymethylcarbonyl group, a 2-oxopropylcarbonyl group, and a 2-oxobutylcarbonyl group.

[0016] In the present specification, a mono- or di-alkylated amino group refers to an amino group (-NH 2 ) is a group in which at least one of the two hydrogen atoms constituting the alkyl group is replaced with the above-mentioned C1-C10 alkyl group, and examples thereof include a methylamino group, a dimethylamino group, an ethylamino group, and a diethylamino group.

[0017] In the present specification, a C1-C10 alkylsulfonyl group refers to a sulfo group (-SO 2 OH) is a group in which the OH is replaced by the above-mentioned C1-C10 alkyl group, and examples thereof include a methylsulfonyl group and an ethylsulfonyl group.

[0018] In the present specification, the C6-C10 arylsulfonyl group refers to a sulfo group (-SO 2 OH) is a group in which the OH is replaced by the above-mentioned C6-C10 aryl group, and examples thereof include a phenylsulfonyl group and a 4-methylphenylsulfonyl group.

[0019] In this specification, a halosulfonyl group refers to a sulfo group (-SO 2OH) is a group in which the OH in the alkyl group is replaced by a halogen atom, and examples thereof include a fluorosulfonyl group and a chlorosulfonyl group.

[0020] The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0021] Next, a method for producing an optically active compound represented by the above formula (3) (hereinafter sometimes referred to as "optically active compound (3)") by reacting a compound represented by the above formula (2) (hereinafter sometimes referred to as "compound (2)") with hydrogen in the presence of an asymmetric cobalt complex will be described.

[0022] The asymmetric cobalt complex used in the present invention may be any complex in which an optically active ligand is coordinated to cobalt metal or cobalt ion. For example, the asymmetric cobalt complexes described in J. Amer. Chem. Soc., 2012, Vol. 134, pp. 4561-4564 and the complex represented by the above formula (1) (hereinafter sometimes referred to as "complex (1)") may be used. However, it is preferable to use a complex obtained by reacting complex (1) with a reducing agent (hereinafter sometimes referred to as "monovalent cobalt complex (1)").

[0023] In the above formula (1), R 2 and R 3 Examples of the ring formed by combining with the carbon atom to which they are bonded include cycloalkane rings such as a cyclopentane ring, a cyclohexane ring, and a cycloheptane ring. These rings may be substituted with a C1-C10 alkyl group which may have one or more of the above-mentioned substituents, or with a substituent which a C1-C10 alkyl group may have.

[0024] In the above formula (1), R 1 As the alkyl group, a C1-10 alkyl group which may have one or more substituents is preferable, and a C1-C4 alkyl group which may have one or more substituents is more preferable. R 2 and R 3 are preferably each independently a hydrogen atom or a C1-C4 alkyl group. R 4 is preferably a C1-C4 alkoxy group or a halogen atom. Preferably, n is 2 or 3, and more preferably 3. X is preferably a chlorine atom or a bromine atom. R 1 , R 2 , R 3 and X is preferably a combination of these.

[0025] The complex (1) may be dichloro[2,6-bis[4-(S)-isopropyl-2-oxazolyl]pyridine]cobalt, dichloro[2,6-bis[4-(R)-isopropyl-2-oxazolyl]pyridine]cobalt, dibromo[2,6-bis[4-(S)-isopropyl-2-oxazolyl]pyridine]cobalt, dibromo[2,6-bis[4-(R)-isopropyl-2-oxazolyl]pyridine]cobalt, diiodo[2,6-bis[4-(S)-isopropyl-2-oxazolyl]pyridine]cobalt, diiodo[2,6-bis [4-(R)-isopropyl-2-oxazolyl]pyridine]cobalt, dichloro[2,6-bis[4-(S)-tert-butyl-2-oxazolyl]pyridine]cobalt, dichloro[2,6-bis[4-(R)-tert-butyl-2-oxazolyl]pyridine]cobalt, dibromo[2,6-bis[4-(S)-tert-butyl-2-oxazolyl]pyridine]cobalt, dibromo[2,6-bis[4-(R)-tert-butyl-2-oxazolyl]pyridine]cobalt, diiodo[2,6-bis[4-(S)-tert-butyl dichloro[2,6-bis[4-(R)-ethyl-2-oxazolyl]pyridine]cobalt, dibromo[2,6-bis[4-(S)-ethyl-2-oxazolyl]pyridine]cobalt, dibromo[2,6-bis[4-(R)-ethyl-2-oxazolyl]pyridine]cobalt, diiodo[2,6-bis[4-(R)-tert-butyl-2-oxazolyl]pyridine]cobalt, [4-(S)-ethyl-2-oxazolyl]pyridine]cobalt, diiodo[2,6-bis[4-(R)-ethyl-2-oxazolyl]pyridine]cobalt, dichloro[2,6-bis[4-(S)-methyl-2-oxazolyl]pyridine]cobalt, dichloro[2,6-bis[4-(R)-methyl-2-oxazolyl]pyridine]cobalt, dibromo[2,6-bis[4-(S)-methyl-2-oxazolyl]pyridine]cobalt, dibromo[2,6-bis[4-(R)-methyl-2-oxazolyl]pyridine]cobalt, diiodo[2,6-Bis[4-(S)-methyl-2-oxazolyl]pyridine]cobalt, diiodo[2,6-bis[4-(R)-methyl-2-oxazolyl]pyridine]cobalt, dichloro[2,6-bis[4-(S)-phenyl-2-oxazolyl]pyridine]cobalt, dichloro[2,6-bis[4-(R)-phenyl-2-oxazolyl]pyridine]cobalt, dibromo[2,6-bis[4-(S)-phenyl-2-oxazolyl]pyridine]cobalt, dibromo[2,6-bis[4-(R)-phenyl-2-oxazolyl]pyridine]cobalt, diiodo [2,6-bis[4-(S)-phenyl-2-oxazolyl]pyridine]cobalt, diiodo[2,6-bis[4-(R)-phenyl-2-oxazolyl]pyridine]cobalt, dichloro[2,6-bis[4-(S)-naphthyl-2-oxazolyl]pyridine]cobalt, dichloro[2,6-bis[4-(R)-naphthyl-2-oxazolyl]pyridine]cobalt, dibromo[2,6-bis[4-(S)-naphthyl-2-oxazolyl]pyridine]cobalt, dibromo[2,6-bis[4-(R)-naphthyl-2-oxazolyl]pyridine]cobalt, Diiodo[2,6-bis[4-(S)-naphthyl-2-oxazolyl]pyridine]cobalt, diiodo[2,6-bis[4-(R)-naphthyl-2-oxazolyl]pyridine]cobalt, dichloro[2,6-bis[4-(S)-isopropyl-2-oxazolyl]-4-chloropyridine]cobalt, dichloro[2,6-bis[4-(R)-isopropyl-2-oxazolyl]-4-chloropyridine]cobalt, dibromo[2,6-bis[4-(S)-isopropyl-2-oxazolyl]-4-chloropyridine]cobalt, dibromo[2,6-bis[4 -(R)-isopropyl-2-oxazolyl]-4-chloropyridine]cobalt, diiodo[2,6-bis[4-(S)-isopropyl-2-oxazolyl]-4-chloropyridine]cobalt, diiodo[2,6-bis[4-(R)-isopropyl-2-oxazolyl]-4-chloropyridine]cobalt, dichloro[2,6-bis[4-(S)-tert-butyl-2-oxazolyl]-4-chloropyridine]cobalt, dichloro[2,6-bis[4-(R)-tert-butyl-2-oxazolyl]-4-chloropyridine]cobalt, dibromo[2,6-Bis[4-(S)-tert-butyl-2-oxazolyl]-4-chloropyridine]cobalt, dibromo[2,6-bis[4-(R)-tert-butyl-2-oxazolyl]-4-chloropyridine]cobalt, diiodo[2,6-bis[4-(S)-tert-butyl-2-oxazolyl]-4-chloropyridine]cobalt, diiodo[2,6-bis[4-(R)-tert-butyl-2-oxazolyl]-4-chloropyridine]cobalt, dichloro[2,6-bis[4-(S)-tert-butyl-2-oxazolyl]- 4-Methoxypyridine]cobalt, dichloro[2,6-bis[4-(R)-tert-butyl-2-oxazolyl]-4-methoxypyridine]cobalt, dibromo[2,6-bis[4-(S)-tert-butyl-2-oxazolyl]-4-methoxypyridine]cobalt, dibromo[2,6-bis[4-(R)-tert-butyl-2-oxazolyl]-4-methoxypyridine]cobalt, diiodo[2,6-bis[4-(S)-tert-butyl-2-oxazolyl]-4-methoxypyridine]cobalt, diiodo[2,6-bis [4-(R)-tert-butyl-2-oxazolyl]-4-methoxypyridine]cobalt, dichloro[2,6-bis[4-(S)-isopropyl-2-oxazolyl]-4-trifluoromethylpyridine]cobalt, dichloro[2,6-bis[4-(R)-isopropyl-2-oxazolyl]-4-nitropyridine]cobalt, dibromo[2,6-bis[4-(S)-isopropyl-2-oxazolyl]-4-trifluoromethylpyridine]cobalt, dibromo[2,6-bis[4-(R)-isopropyl-2-oxazolyl] -4-nitropyridine]cobalt, diiodo[2,6-bis[4-(S)-isopropyl-2-oxazolyl]-4-nitropyridine]cobalt, diiodo[2,6-bis[4-(R)-isopropyl-2-oxazolyl]-4-trifluoromethylpyridine]cobalt, dichloro[2,6-bis[4-(S)-tert-butyl-2-oxazolyl]-4-nitropyridine]cobalt, dichloro[2,6-bis[4-(R)-tert-butyl-2-oxazolyl]-4-trifluoromethylpyridine]cobalt, dibromo[2,6-Bis[4-(S)-tert-butyl-2-oxazolyl]-4-nitropyridine]cobalt, dibromo[2,6-bis[4-(R)-tert-butyl-2-oxazolyl]-4-trifluoromethylpyridine]cobalt, diiodo[2,6-bis[4-(S)-tert-butyl-2-oxazolyl]-4-nitropyridine]cobalt, diiodo[2,6-bis[4-(R)-tert-butyl-2-oxazolyl]-4-trifluoromethylpyridine]cobalt, dichloro[2,6-bis[4-(S)-isopropyl-2-oxazolyl] -4-hydroxypyridine]cobalt, dichloro[2,6-bis[4-(R)-isopropyl-2-oxazolyl]-4-methylpyridine]cobalt, dibromo[2,6-bis[4-(S)-isopropyl-2-oxazolyl]-4-phenylmethylpyridine]cobalt, dibromo[2,6-bis[4-(R)-isopropyl-2-oxazolyl]-4-methoxypyridine]cobalt, diiodo[2,6-bis[4-(S)-isopropyl-2-oxazolyl]-4-carbomethoxypyridine]cobalt, diiodo[2,6-bis[4-(R)-isopropyl-2-oxazolyl]-4-carbomethoxypyridine]cobalt dichloro[2,6-bis[4-(R)-tert-butyl-2-oxazolyl]-4-methylsulfonylpyridine]cobalt, dibromo[2,6-bis[4-(S)-tert-butyl-2-oxazolyl]-4-hydroxypyridine]cobalt, dibromo[2,6-bis[4-(R)-tert-butyl-2-oxazolyl]-4-bromopyridine]cobalt balt, diiodo[2,6-bis[4-(S)-tert-butyl-2-oxazolyl]-2-chloropyridine]cobalt, diiodo[2,6-bis[4-(R)-tert-butyl-2-oxazolyl]-2-fluoropyridine]cobalt, dichloro[2,6-bis[4-(S)-tert-butyl-5,5-dimethyl-2-oxazolyl]pyridine]cobalt, dichloro[2,6-bis[4-(R)-tert-butyl-5,5-dimethyl-2-oxazolyl]pyridine]cobalt, dibromo[2,6-bis[4-(S)-tert-butyl-5,5-diphenyl-2-oxazolyl]pyridine]cobalt, dibromo[2,6-bis[4-(R)-tert-butyl-5,5-diphenyl-2-oxazolyl]pyridine]cobalt, etc.

[0026] Complex (1) can be synthesized, for example, by mixing an optically active bisoxazolinylpyridine derivative, which is a precursor, with a divalent cobalt halide in a solvent in accordance with the method described in the experimental section of the supplementary material in Angew. Chem. Int. Ed., Vol. 55, p. 10839 (2016). The optically active bisoxazolinylpyridine derivative, which is a precursor, can be produced, for example, according to the method described in Scheme 1 of Tetrahedron Letters, vol. 45, p. 8988 (2004), etc. That is, a 2,6-dicarboxypyridine derivative is reacted with thionyl chloride to obtain a corresponding carboxylic acid chloride, which is then reacted with an optically active aminoalcohol to obtain a diamide, which is then reacted with thionyl chloride to chlorinate the hydroxy group, and then a ring-closing reaction to obtain an oxazoline ring is carried out in NaOH / methanol, whereby an optically active bisoxazolinylpyridine derivative can be produced.

[0027] Among the complexes (1), the asymmetric cobalt complex represented by the above formula (1') (hereinafter, sometimes referred to as "complex (1')") is preferred. In the above formula (1'), R 1 is preferably a tert-butyl group. When the asymmetric hydrogenation reaction of the present invention is carried out using a monovalent cobalt complex obtained by reducing the S-complex (1'), an optically active compound (3) having a high ratio of R-complex is usually obtained. It is known that the R-complex of the optically active compound represented by the above formula (7) has a higher plant disease control effect (see WO 2011 / 162397), and from the viewpoint of obtaining the optically active compound (3) to be used as an intermediate therefor, it is preferable that the complex (1') is an S-complex. Hereinafter, the complex obtained by reacting the complex (1') with a reducing agent may be referred to as a monovalent cobalt complex (1').

[0028] In this specification, when the compounds represented by formula (3), formula (4), formula (5), and formula (7) are referred to as "optically active compounds" or "optically active compounds," unless otherwise specified, this means a mixture of the R and S forms in which either the R or S form is enantiomerically enriched, as described below, or either the R or S form itself.

[0029] An optically active bisoxazolinylpyridine ligand is obtained by the method described in Scheme 1 (R is an isopropyl group or a tert-butyl group) in the above Tetrahedron Letters, Vol. 45, p. 8988 (2004), and then, in accordance with the experimental section of the supplementary material in Angew. Chem. Int. Ed., Vol. 55, p. 10839 (2016), complex (1') is obtained by mixing the ligand with cobalt bromide instead of divalent cobalt chloride.

[0030] The reducing agent to be reacted with the complex (1) includes a hydride reducing agent, an alkyllithium compound, and a Grignard reagent, and is preferably a hydride reducing agent. The hydride reducing agent may be any reducing agent capable of reducing the divalent cobalt atom of complex (1) to produce a hydride complex having a monovalent cobalt atom, and examples thereof include alkali metal trialkylborohydrides such as lithium triethylborohydride, sodium triethylborohydride, potassium triethylborohydride, lithium trimethylborohydride, sodium trimethylborohydride, lithium tripropylborohydride, sodium tripropylborohydride, lithium tributylborohydride, and sodium tributylborohydride. The amount of the hydride reducing agent used is usually in the range of 2 to 20 moles, preferably 4 to 10 moles, per mole of Complex (1). The reaction is carried out by mixing the complex (1) with a hydride reducing agent in a solvent inert to the hydride reducing agent under an inert gas atmosphere, or may be carried out in the presence of the compound (2). Examples of such solvents include ether solvents such as diethyl ether, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, and methyl tert-butyl ether; aliphatic hydrocarbon solvents such as n-hexane, n-heptane, and cyclohexane; aromatic hydrocarbon solvents such as toluene, xylene, and chlorobenzene; and halogenated hydrocarbon solvents such as dichloromethane and dichloroethane, with ether solvents being preferred. The amount of the solvent used is usually within the range of 2 to 100 parts by weight per part by weight of the complex (1). The reaction temperature is usually in the range of -70°C to 100°C. Reaction times typically range from 10 minutes to 4 hours. After completion of the reaction, the obtained hydride complex may be isolated, but is usually used in the reaction of compound (2) with hydrogen without isolation.

[0031] The alkyllithium compound may be any reducing agent capable of reducing the divalent cobalt atom of complex (1) to produce an alkyl complex having a monovalent cobalt atom, and examples thereof include methyllithium, ethyllithium, n-propyllithium, and n-butyllithium. The amount of the alkyllithium compound used is usually in the range of 2 to 20 moles, preferably 3 to 10 moles, per mole of Complex (1). The reaction is carried out by mixing the complex (1) with the alkyllithium compound in a solvent inert to the alkyllithium compound under an inert gas atmosphere, or may be carried out in the presence of the compound (2). Examples of such solvents include ether solvents such as diethyl ether, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, and methyl tert-butyl ether; aliphatic hydrocarbon solvents such as n-hexane, n-heptane, and cyclohexane; aromatic hydrocarbon solvents such as toluene, xylene, and chlorobenzene; and halogenated hydrocarbon solvents such as dichloromethane and dichloroethane, with ether solvents being preferred. The amount of the solvent used is usually within the range of 2 to 100 parts by weight per part by weight of the complex (1). The reaction temperature is usually in the range of -70°C to 100°C. Reaction times typically range from 10 minutes to 4 hours. After completion of the reaction, the resulting alkyl complex may be isolated, but is usually used in the reaction of compound (2) with hydrogen without isolation.

[0032] The Grignard reagent may be any reducing agent capable of reducing the divalent cobalt atom of complex (1) to produce an alkyl complex having a monovalent cobalt atom, and examples thereof include methylmagnesium bromide, ethylmagnesium bromide, n-propylmagnesium bromide, and n-butylmagnesium bromide. The amount of the Grignard reagent used is usually in the range of 2 to 20 moles, preferably 3 to 10 moles, per mole of Complex (1). The reaction is carried out by mixing the complex (1) with the Grignard reagent in a solvent inert to the Grignard reagent under an inert gas atmosphere, or may be carried out in the presence of the compound (2). Examples of such solvents include ether solvents such as diethyl ether, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, and methyl tert-butyl ether; aliphatic hydrocarbon solvents such as n-hexane, n-heptane, and cyclohexane; aromatic hydrocarbon solvents such as toluene, xylene, and chlorobenzene; and halogenated hydrocarbon solvents such as dichloromethane and dichloroethane, with ether solvents being preferred. The amount of the solvent used is usually within the range of 2 to 100 parts by weight per part by weight of the complex (1). The reaction temperature is usually in the range of -70°C to 100°C. Reaction times typically range from 10 minutes to 4 hours. After completion of the reaction, the resulting alkyl complex may be isolated, but is usually used in the reaction of compound (2) with hydrogen without isolation.

[0033] Compound (2) can be synthesized, for example, according to the method described in J. Chem. Soc. (C), 1966, p. 514. Alternatively, a commercially available product can be used.

[0034] Examples of compound (2) include 1-acetyl-1,2-dihydro-2,2,4-trimethyl-1-quinoline, 1-acetyl-1,2-dihydro-2,2,4-trimethyl-6-fluoro-1-quinoline, 1-acetyl-1,2-dihydro-2,2,4-trimethyl-6-ethoxy-1-quinoline, 1-acetyl-2,2-dimethyl-4-ethyl-1-quinoline, 1-acetyl-1,2-dihydro-2,2-dimethyl-4-propyl-1-quinoline, 1-acetyl-1,2-dihydro-2,2-dimethyl-4-butyl-1-quinoline, 1-acetyl-1,2-dihydro-2,2-diethyl-4-methyl-1-quinoline, 1-acetyl-1,2-dihydro-2,2-dipropyl-4-methyl-1-quinoline, 1-ethylcarbonyl 1,2-dihydro-2,2,4-trimethyl-1-quinoline, 1-ethylcarbonyl-1,2-dihydro-2,2-dimethyl-4-ethyl-1-quinoline, 1-ethylcarbonyl-1,2-dihydro-2,2-dimethyl-4-propyl-1-quinoline, 1-ethylcarbonyl-1,2-dihydro-2,2-dimethyl-4-butyl-1-quinoline, 1-ethylcarbonyl-1,2-dihydro-2,2-diethyl-4-methyl-1-quinoline, 1-ethylcarbonyl-1,2-dihydro-2,2-dipropyl-4-methyl-1-quinoline, 1-acetyl-1,2-dihydro-2,2,4,7-tetramethyl-1-quinoline, and 1-acetyl-1,2-dihydro-2,2,4,6,7-pentamethyl-1-quinoline.

[0035] The reaction of compound (2) with hydrogen in the presence of an asymmetric cobalt complex (hereinafter sometimes referred to as "asymmetric hydrogenation reaction") is usually carried out in the presence of a solvent. Examples of such solvents include ether solvents such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, and methyltetrahydrofuran, halogenated hydrocarbon solvents such as chloroform and chlorobenzene, aromatic solvents such as toluene and xylene, and nitrile solvents such as acetonitrile and propionitrile. Ether solvents are preferred, and tetrahydrofuran or 1,4-dioxane is particularly preferred. The amount of the solvent used is not particularly limited, and in consideration of volume efficiency and the like, it is practically 100 parts by weight or less per part by weight of compound (2).

[0036] When a monovalent cobalt complex (1) is used as the asymmetric cobalt complex, the asymmetric hydrogenation reaction of the present invention is more preferably carried out further in the presence of a divalent cobalt halide salt or a trialkylamine. Such divalent cobalt halide salts include, for example, CoCl 2 , CoBr 2 and CoI 2 Preferably, CoBr 2 It is. The amount of the divalent cobalt halide salt used is usually 2 moles or less per mole of the hydride complex (1). Examples of such trialkylamines include trimethylamine, triethylamine, tripropylamine and tributylamine. Triethylamine is preferred. The amount of triethylamine used is usually 0.5 to 3 moles per mole of compound (2).

[0037] The asymmetric hydrogenation reaction of the present invention is usually carried out by stirring a mixture containing the asymmetric cobalt catalyst and compound (2) under a hydrogen atmosphere. The pressure during the reaction may be normal pressure or elevated pressure. The amount of hydrogen used is usually within the range of 1 to 10 moles per mole of compound (2). The reaction temperature is usually in the range of -40°C to 100°C, preferably in the range of -20°C to 80°C.

[0038] When a monovalent cobalt complex (1) is used as the asymmetric cobalt complex, the asymmetric hydrogenation reaction may be carried out by adding a separately prepared monovalent cobalt complex (1) and, if necessary, a divalent cobalt halide salt or trialkylamine to a solution obtained by dissolving compound (2) in a solvent, and then supplying hydrogen thereto; the asymmetric hydrogenation reaction may be carried out by preparing a monovalent cobalt complex (1) in the presence of a solvent, adding, if necessary, a divalent cobalt halide salt or trialkylamine to the mixture obtained, then adding compound (2), and then supplying hydrogen thereto; or the asymmetric hydrogenation reaction may be carried out by adding a hydride reducing agent, an alkyllithium compound, or a Grignard reagent to a mixture containing complex (1), compound (2), a solvent, and, if necessary, a divalent cobalt halide salt or trialkylamine to reduce complex (1), and then supplying hydrogen thereto.

[0039] The degree of progress of the reaction can be confirmed by analytical means such as gas chromatography, high performance liquid chromatography, thin layer chromatography, nuclear magnetic resonance spectroscopy, and infrared absorption spectroscopy.

[0040] Examples of the optically active compound (3) include 1-acetyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline, 1-acetyl-2,2,4-trimethyl-6-fluoro-1,2,3,4-tetrahydroquinoline, 1-acetyl-2,2,4-trimethyl-6-ethoxy-1,2,3,4-tetrahydroquinoline, and 1-acetyl-2,2-dimethyl-4-ethyl-1,2,3,4-tetrahydroquinoline. 1-acetyl-2,2-dimethyl-4-propyl-1,2,3,4-tetrahydroquinoline, 1-acetyl-2,2-dimethyl-4-butyl-1,2,3,4-tetrahydroquinoline, 1-acetyl-2,2-diethyl-4-methyl-1,2,3,4-tetrahydroquinoline, 1-acetyl-2,2-dipropyl-4-methyl-1,2,3,4-tetrahydroquinoline, 1-ethyl 1-ethylcarbonyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline, 1-ethylcarbonyl-2,2-dimethyl-4-ethyl-1,2,3,4-tetrahydroquinoline, 1-ethylcarbonyl-2,2-dimethyl-4-propyl-1,2,3,4-tetrahydroquinoline, 1-ethylcarbonyl-2,2-dimethyl-4-butyl-1,2,3,4-tetrahydroquinoline, 1-ethyl carbonyl-2,2-diethyl-4-methyl-1,2,3,4-tetrahydroquinoline, 1-ethylcarbonyl-2,2-dipropyl-4-methyl-1,2,3,4-tetrahydroquinoline, 1-acetyl-2,2,4,7-tetramethyl-1,2,3,4-tetrahydroquinoline, and 1-acetyl-2,2,4,6,7-pentamethyl-1,2,3,4-tetrahydroquinoline.

[0041] The resulting reaction mixture usually contains the optically active compound (3), and after completion of the reaction, the optically active compound (3) can be separated and extracted by concentration, washing, crystallization, etc. When the optically active compound (3) is subjected to the reaction of an acid with an optically active compound (3) described below, the reaction mixture is usually concentrated and used as it is.

[0042] Next, the process of reacting the optically active compound (3) with an acid to obtain the optically active compound represented by the above formula (4) (hereinafter, sometimes referred to as "optically active compound (4)") and then reacting the optically active compound (4) with water to obtain the optically active compound represented by the above formula (5) (hereinafter, sometimes referred to as "optically active compound (5)") will be described. Hereinafter, the reaction of the optically active compound (3) with an acid may be referred to as an isomerization reaction, and the reaction of the optically active compound (4) with water may be referred to as a hydrolysis reaction.

[0043] The isomerization reaction can be carried out, for example, according to the method described in J. Chem. Soc. (C), 1966, p. 514 or JP-A-7-215921. The acid is preferably sulfuric acid. The sulfuric acid concentration is usually in the range of 90% by weight to 98% by weight, and preferably in the range of 92% by weight to 97% by weight in terms of yield. The reaction of the optically active compound (3) with an acid is carried out in the absence of an organic solvent, and the reaction temperature is usually in the range of 20°C to 80°C. The amount of the acid used is usually within the range of 1 to 10 parts by weight per part by weight of the optically active compound (3). Examples of the optically active compound (4) obtained include N-acetyl-1,1,3-trimethyl-4-aminoindan, N-acetyl-7-fluoro-1,1,3-trimethyl-4-aminoindan, N-acetyl-7-ethoxy-1,1,3-trimethyl-4-aminoindan, N-acetyl-1,1-dimethyl-3-ethyl-4-aminoindan, N-acetyl-1,1-dimethyl-3-propyl-4-aminoindan, N-acetyl-1,1-dimethyl-3-butyl-4-aminoindan, N-acetyl-1,1-dipropyl-3-methyl-4-aminoindan, and N-ethylcarbonyl-1,1,3-trimethyl-4-aminoindan. trimethyl-4-aminoindan, N-ethylcarbonyl-1,1-dimethyl-3-ethyl-4-aminoindan, N-ethylcarbonyl-1,1-dimethyl-3-propyl-4-aminoindan, N-ethylcarbonyl-1,1-dimethyl-3-butyl-4-aminoindan, N-ethylcarbonyl-1,1-diethyl-3-methyl-4-aminoindan, N-ethylcarbonyl-1,1-dipropyl-3-methyl-4-aminoindan, N-acetyl-1,1,3,6-tetramethyl-4-aminoindan, and N-acetyl-1,1,3,6,7-pentamethyl-4-aminoindan.

[0044] After the isomerization reaction is completed, the optically active compound (4) may be isolated from the resulting reaction mixture, but usually, water is added to the resulting reaction mixture to effect hydrolysis. The reaction temperature for the hydrolysis reaction is usually in the range of 50°C to 110°C. The amount of water used is usually within the range of 1 to 10 parts by weight per part by weight of the optically active compound (4). Examples of the optically active compound (5) obtained include 1,1,3-trimethyl-4-aminoindan, 7-fluoro-1,1,3-trimethyl-4-aminoindan, 7-ethoxy-1,1,3-trimethyl-4-aminoindan, 1,1-dimethyl-3-ethyl-4-aminoindan, 1,1-dimethyl-3-propyl-4-aminoindan, 1,1-dimethyl-3-butyl-4-aminoindan, 1,1-dipropyl-3-methyl-4-aminoindan, 1,1-diethyl-3-methyl-4-aminoindan, 1,1,3,6-tetramethyl-4-aminoindan, and 1,1,3,6,7-pentamethyl-4-aminoindan. The reaction mixture is neutralized with an alkali and extracted with a water-immiscible organic solvent such as toluene to obtain a solution containing optically active compound (5). The enantiomeric ratio (R / S or S / R) of optically active compound (5) is usually in the range of 60 / 40 to 90 / 10.

[0045] Next, among the optically active compounds (5) obtained above, optically active 1,1,3-trimethyl-4-aminoindan (R 6 , R 7 and R 8 is a methyl group, and R 9 , R 10 and R 11 The process of dissolving a compound in which R is a hydrogen atom) in a solvent and then optically resolving it using optically active tartaric acid (hereinafter, this may be referred to as "optical resolution") will be described.

[0046] The optical resolution of 1,1,3-trimethyl-4-aminoindan is described in International Publication No. WO 2015 / 118793, and the optical resolution of the present invention can be performed in accordance with the description in this International Publication. This International Publication describes that 1,1,3-trimethyl-4-aminoindan having an optical purity in the range of 0% ee to 25% ee (i.e., an enantiomer ratio (R-form / S-form or S-form / R-form) of 50 / 50 to 62.5 / 37.5) is subjected to optical resolution. In the present invention, 1,1,3-trimethyl-4-aminoindan with a high optical purity obtained through the asymmetric hydrogenation reaction, isomerization reaction, and hydrolysis reaction described above is subjected to optical resolution, whereby 1,1,3-trimethyl-4-aminoindan with an even higher optical purity can be obtained more efficiently. The optical purity of 1,1,3-trimethyl-4-aminoindan subjected to the optical resolution of the present invention is usually in the range of 40%ee to 80%ee (for example, 66%ee or more) (i.e., the enantiomer ratio (R-isomer / S-isomer or S-isomer / R-isomer) is 70 / 30 to 90 / 10). It is known that the R-isomer of the optically active compound represented by the above formula (7) has a higher plant disease control effect (see International Publication No. 2011 / 162397), and from the viewpoint of using it as an intermediate, it is preferable that 1,1,3-trimethyl-4-aminoindan has a high ratio of the R-isomer. That is, the enantiomer ratio of the R-isomer / S-isomer of 1,1,3-trimethyl-4-aminoindan subjected to the optical resolution of the present invention is preferably 70 / 30 or more, more preferably in the range of 70 / 30 to 90 / 10.

[0047] In order to optically resolve 1,1,3-trimethyl-4-aminoindan, which has a high ratio of R-isomers, and increase the ratio of the R-isomer, D-tartaric acid is used as the optically active tartaric acid, and in order to optically resolve 1,1,3-trimethyl-4-aminoindan, which has a high ratio of S-isomers, and increase the ratio of the S-isomer, L-tartaric acid is used as the optically active tartaric acid. As the optically active tartaric acid, commercially available products can usually be used. The amount of optically active tartaric acid used is usually in the range of 0.7 to 1.3 mol, preferably 0.8 to 1.2 mol, per mol of optically active 1,1,3-trimethyl-4-aminoindan (total of R- and S-isomers).

[0048] Examples of the solvent include alcohol solvents such as methanol, ethanol, and 2-propanol; ether solvents such as tetrahydrofuran; nitrile solvents such as acetonitrile; ester solvents such as ethyl acetate; aromatic hydrocarbon solvents such as toluene, xylene, and ethylbenzene; halogenated aromatic hydrocarbon solvents such as monochlorobenzene; aliphatic hydrocarbon solvents such as heptane and hexane; alicyclic hydrocarbon solvents such as cyclopentane and cyclohexane; and water. Two or more types of solvents may be used in combination. An alcohol solvent or water, or a mixture thereof, is preferred. The amount of the solvent used is usually within the range of 0.5 to 10 parts by weight per part by weight of the optically active 1,1,3-trimethyl-4-aminoindan.

[0049] The optical resolution of the present invention is preferably carried out by mixing optically active 1,1,3-trimethyl-4-aminoindan, optically active tartaric acid, and a solvent. The mixing temperature is usually in the range of 20°C to 70°C. The order of mixing is not particularly limited, and optically active 1,1,3-trimethyl-4-aminoindan, optically active tartaric acid, and a solvent may be mixed at once, optically active 1,1,3-trimethyl-4-aminoindan may be added to a mixture of optically active tartaric acid and a solvent, a mixture of optically active tartaric acid and a solvent may be added to optically active 1,1,3-trimethyl-4-aminoindan, or optically active tartaric acid may be added to a mixture of optically active 1,1,3-trimethyl-4-aminoindan and a solvent. When a mixed solvent of an alcohol solvent and water is used, optically active 1,1,3-trimethyl-4-aminoindan, optically active tartaric acid, methanol and water may be mixed at once, optically active 1,1,3-trimethyl-4-aminoindan may be added to a mixture of optically active tartaric acid, an alcohol solvent and water, a mixture of optically active tartaric acid, an alcohol solvent and water may be added to optically active 1,1,3-trimethyl-4-aminoindan, water may be added to a mixture of optically active tartaric acid, an alcohol solvent and optically active 1,1,3-trimethyl-4-aminoindan, or optically active tartaric acid may be added to a mixture of optically active 1,1,3-trimethyl-4-aminoindan, an alcohol solvent and water. In these mixing orders, the later-added substance may be added all at once, may be added in several divided portions (e.g., dropwise), or may be added continuously. When optically active tartaric acid is added to a mixture of optically active 1,1,3-trimethyl-4-aminoindan and a solvent, it is preferable to add the optically active tartaric acid continuously.

[0050] Usually, when the mixing is completed, the resulting mixture is a solution, and by cooling the solution, crystals containing optically active 1,1,3-trimethyl-4-aminoindan and optically active tartrate are precipitated. When an alcohol solvent is used, the precipitated crystals are usually solvates.

[0051] The temperature after cooling is lower than the above-mentioned mixing temperature, and is preferably in the range of -20°C to 30°C, more preferably in the range of -10°C to 20°C. The cooling rate is usually in the range of 1° C. / hour to 10° C. / hour, and by cooling the mixture at such a cooling rate, crystals containing 1,1,3-trimethyl-4-aminoindan with high optical purity and optically active tartaric acid can be precipitated. The cooling rate is preferably in the range of 1° C. / hour to 8° C. / hour, more preferably in the range of 3° C. / hour to 6° C. / hour.

[0052] The resulting mixture is filtered to obtain crystals containing optically active 1,1,3-trimethyl-4-aminoindan and optically active tartaric acid. When 1,1,3-trimethyl-4-aminoindan having a high ratio of R isomer is mixed with D-tartaric acid and methanol for optical resolution, the mixture can be separated by filtration into crystals containing the methanol solvate of the D-tartrate salt of (R)-1,1,3-trimethyl-4-aminoindan and a solution containing (S)-1,1,3-trimethyl-4-aminoindan and its D-tartrate salt.

[0053] The obtained crystals may be washed with the solvent used in the optical resolution or with a solvent other than those mentioned above as a solvent that can be used in the optical resolution, and may be dried as necessary. By mixing the crystals thus obtained with an aqueous solution of an alkali metal hydroxide, the crystals can be decomposed into optically active 1,1,3-trimethyl-4-aminoindan and an optically active alkali metal salt of tartaric acid. Alkali metal hydroxides include sodium hydroxide and potassium hydroxide. The amount of the alkali metal hydroxide used is usually in the range of 1 to 3 moles, calculated as the alkali metal, per mole of the optically active tartaric acid used in the optical resolution.

[0054] The mixing temperature is usually in the range of 10°C to 80°C. The mixing of the aqueous solution of the alkali metal hydroxide may be carried out in the presence of an organic solvent, such as aromatic hydrocarbon solvents such as toluene, xylene, and ethylbenzene, halogenated aromatic hydrocarbon solvents such as monochlorobenzene, aliphatic hydrocarbon solvents such as heptane and hexane, alicyclic hydrocarbon solvents such as cyclopentane and cyclohexane, ether solvents such as diethyl ether and tert-butyl methyl ether, and ester solvents such as ethyl acetate. The amount of the organic solvent used is usually 10 parts by weight or less per part by weight of the crystals containing optically active 1,1,3-trimethyl-4-aminoindan and the optically active tartrate.

[0055] The order of mixing may be such that the crystals containing optically active 1,1,3-trimethyl-4-aminoindan and optically active tartrate, an aqueous solution of an alkali metal hydroxide, and, if necessary, an organic solvent are mixed at once, or the aqueous solution of an alkali metal hydroxide may be added to a mixture of the crystals and an organic solvent, or the crystals may be added to a mixture of an aqueous solution of an alkali metal hydroxide and an organic solvent. Among these, it is preferable to add the crystals to a mixture of an alkali metal hydroxide and an organic solvent.

[0056] After the mixing is completed, the aqueous layer is removed from the mixture, and the organic solvent is distilled off from the organic layer, if necessary, to obtain optically active 1,1,3-trimethyl-4-aminoindan. The optical activity of the obtained 1,1,3-trimethyl-4-aminoindan is higher than that of the 1,1,3-trimethyl-4-aminoindan subjected to optical resolution.

[0057] Next, the method of preferential crystallization with an acid will be described. The preferential crystallization of the present invention includes a first step of mixing optically active 1,1,3-trimethyl-4-aminoindan with an achiral acid in the presence of a solvent to precipitate an acid salt thereof, and a second step of mixing the acid salt obtained in the first step with a base to obtain optically active 1,1,3-trimethyl-4-aminoindan. First, the first step in which a solution containing optically active 1,1,3-trimethyl-4-aminoindan is mixed with an acid to precipitate an acid salt will be described.

[0058] The optically active 1,1,3-trimethyl-4-aminoindan subjected to the first step is preferably one having an optical purity of 40% ee or more (e.g., 66% ee or more) since the optical purity of the optically active 1,1,3-trimethyl-4-aminoindan obtained in the second step is likely to be high (usually 89% ee or more, e.g., 91% ee or more, 92% ee or more, 96% ee or more, 97% ee or more, 99% ee or more). The optically active 1,1,3-trimethyl-4-aminoindan is preferably one having a large amount of R-isomers, since it is useful as a synthetic intermediate of the compound having the plant disease prevention effect described in the above Patent Document 1. When the optically active 1,1,3-trimethyl-4-aminoindan subjected to the first step is more likely to be R-isomers, the optically active 1,1,3-trimethyl-4-aminoindan obtained in the second step is usually one having a large amount of R-isomers.

[0059] The structural formulas of the R and S forms of 1,1,3-trimethyl-4-aminoindan are shown below. TIFF0007662640000011.tif47122

[0060] As a method for producing optically active 1,1,3-trimethyl-4-aminoindan, 2,2,4-trimethyl-1-quinoline is acylated with an optically active acylating agent, then hydrogenated to obtain an optically active 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline derivative, which is then isomerized using sulfuric acid and then hydrolyzed (see, for example, JP-A-7-215921). It is also known that the optically active 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline derivative can be obtained by asymmetric hydrogenation of the 2,2,4-trimethyl-1-quinoline derivative (see, for example, WO 2015 / 141564), which can then be isomerized with sulfuric acid and then hydrolyzed to obtain optically active 1,1,3-trimethyl-4-aminoindan. In the first step of the present invention, optically active 1,1,3-trimethyl-4-aminoindan obtained by these methods can be provided.

[0061] The acid may be an achiral acid, and may be any acid that can preferentially precipitate an optically active salt of the optically active substance contained in the optically active 1,1,3-trimethyl-4-aminoindan in a larger amount. To form such salts, acids having an acid dissociation constant (pKa) of less than 2.8 are typically used. Here, the acid dissociation constant is an index of the strength of an acid, expressed by the equilibrium constant (Ka) of the ionization equilibrium of an acid when considering an acid dissociation reaction in which hydrogen ions are released from the acid, or the dissociation constant (pKa), which is its negative common logarithm. The larger the equilibrium constant Ka value, or the smaller the dissociation constant pKa value, the stronger the acid is. In the present invention, when a calculated value (a value calculated using Advanced Chemistry Development (ACD / Labs) Software V11.02) is recorded in SciFinder, a database provided by Chemical Abstracts Service, as the acid dissociation constant (pKa), the value is adopted. Such values ​​can be searched, for example, from the website of the Japan Association of Chemical Information (https: / / www.jaici.or.jp / SCIFINDER / ). For acids whose calculated values ​​are not recorded in SciFinder, data published on the Chemical Book website (https: / / www.chemicalbook.com / ) is adopted, and for acids not published on the website, the value described in Applied Catalysis A: General 492 (2015) 252-261 is adopted. If the acid is not published in the journal, the value calculated using Advanced Chemistry Development (ACD / Labs) Software V11.02 is adopted.

[0062] Examples of acids having an acid dissociation constant (pKa) of less than 2.8 include sulfuric acid, hydrogen sulfates, sulfamic acid, organic sulfonic acids, hydrohalic acids, phosphoric acid, organic phosphoric acids, nitric acid, tetrafluoroboric acid, and carboxylic acids, and it is preferable to use one or more acids selected from the group consisting of these acids. Hydrogen sulfates include alkali metal hydrogen sulfates such as sodium hydrogen sulfate, lithium hydrogen sulfate, and potassium hydrogen sulfate. Examples of organic sulfonic acids include methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and taurine. Hydrohalic acids include hydrochloric acid, hydrobromic acid, and hydroiodic acid. The organic phosphoric acids include phenyl dihydrogen phosphate, ethyl dihydrogen phosphate, phenylphosphonic acid, and methylphosphonic acid. Examples of the carboxylic acid include oxalic acid, trichloroacetic acid, trifluoroacetic acid, dichloroacetic acid, monochloroacetic acid, monobromoacetic acid, 2-nitrobenzoic acid, and pentafluorophenylcarboxylic acid. Among these, it is more preferable to use one or more acids selected from the group consisting of sulfuric acid, hydrogen sulfate, sulfamic acid, organic sulfonic acid, hydrohalic acid, phosphoric acid, organic phosphoric acid, nitric acid, tetrafluoroboric acid, and carboxylic acid. It is even more preferable to use one or more acids selected from the group consisting of sulfuric acid, sodium hydrogen sulfate, potassium hydrogen sulfate, sulfamic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, phenylphosphoric acid, phenyl dihydrogen phosphate, nitric acid, tetrafluoroboric acid, oxalic acid, trifluoroacetic acid, trichloroacetic acid, 2-nitrobenzoic acid, chloroacetic acid, and bromoacetic acid. It is even more preferred to use one or more acids selected from the group consisting of sulfuric acid, sodium hydrogen sulfate, potassium hydrogen sulfate, sulfamic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, phenylphosphoric acid, phenyl dihydrogen phosphate, nitric acid, tetrafluoroboric acid, oxalic acid, trifluoroacetic acid, trichloroacetic acid, and 2-nitrobenzoic acid. The amount of acid used is usually 0.7 to 1.5 mol, preferably 0.7 to 1.0 mol, per mol of optically active 1,1,3-trimethyl-4-aminoindan in the case of acids other than sulfuric acid, and usually 0.35 to 0.5 mol, preferably 0.35 to 0.45 mol in the case of sulfuric acid.

[0063] Examples of the solvent include alcohol solvents such as methanol, ethanol, and 2-propanol; water; ether solvents such as tetrahydrofuran; nitrile solvents such as acetonitrile; ester solvents such as ethyl acetate; aromatic hydrocarbon solvents such as toluene, xylene, and ethylbenzene; halogenated aromatic hydrocarbon solvents such as monochlorobenzene; aliphatic hydrocarbon solvents such as heptane and hexane; and alicyclic hydrocarbon solvents such as cyclopentane and cyclohexane. Among these, alcohol solvents, aromatic hydrocarbon solvents, and water are preferred. Two or more of these solvents may be used in combination. The amount of the solvent used is usually in the range of 0.5 to 20 parts by weight, preferably 1.0 to 10 parts by weight, per part by weight of 1,1,3-trimethyl-4-aminoindan.

[0064] The mixing temperature is usually in the range of 20°C to 100°C. The mixing order may be 1,1,3-trimethyl-4-aminoindan, acid, and solvent mixed at once, or 1,1,3-trimethyl-4-aminoindan may be added to the mixture obtained after mixing the acid and solvent. A mixture of acid and solvent may be added to 1,1,3-trimethyl-4-aminoindan. Also, 1,1,3-trimethyl-4-aminoindan and solvent may be mixed, and then an acid or a mixture of acid and solvent may be added to the mixture obtained. A method of mixing 1,1,3-trimethyl-4-aminoindan and solvent, and then adding an acid or a mixture of acid and solvent to the mixture obtained is preferable. Also, if crystals do not precipitate even after cooling after mixing, the solvent may be partially distilled off to precipitate crystals.

[0065] The mixing may be performed all at once, continuously, or in portions (for example, dropwise). When an acid is added to a mixture of 1,1,3-trimethyl-4-aminoindan and a solvent, the acid may be added all at once or continuously, but is preferably added in portions.

[0066] Although an acid salt of optically active 1,1,3-trimethyl-4-aminoindan may precipitate simply by mixing a solution of optically active 1,1,3-trimethyl-4-aminoindan with an acid, the resulting mixture is usually cooled to precipitate an acid salt of optically active 1,1,3-trimethyl-4-aminoindan. By separating the precipitated salt from the mixture by a solid-liquid separation process such as filtration, the acid salt of optically active 1,1,3-trimethyl-4-aminoindan and a solution containing the remaining 1,1,3-trimethyl-4-aminoindan and its acid salt can be separated. If an acid salt of optically active 1,1,3-trimethyl-4-aminoindan does not precipitate even after cooling, the salt may be precipitated by partially distilling off the solvent.

[0067] The temperature after cooling is lower than the above-mentioned mixing temperature, and is preferably in the range of -20°C to 30°C, more preferably in the range of -10°C to 20°C. The cooling rate is not particularly limited, but is usually in the range of about 1° C. / hour to 100° C. / hour.

[0068] The optically active acid salt of 1,1,3-trimethyl-4-aminoindan isolated in the first step may be directly subjected to the second step, or may be washed with at least one solvent selected from the above-mentioned solvents before being subjected to the second step, or may be dried as necessary before being subjected to the second step.

[0069] Next, the second step in which the acid salt obtained in the first step is mixed with a base to obtain optically active 1,1,3-trimethyl-4-aminoindan will be described.

[0070] There are no particular limitations on the base that can be used, so long as it has a basic strength sufficient to decompose the acid salt of optically active 1,1,3-trimethyl-4-aminoindan. The base includes inorganic bases and organic bases. Examples of the inorganic base include alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, and alkali metal phosphates. Alkali metal hydroxides include sodium hydroxide and potassium hydroxide. Alkaline earth metal hydroxides include calcium hydroxide and magnesium hydroxide. Alkali metal carbonates include potassium carbonate and sodium carbonate. Alkaline earth metal carbonates include calcium carbonate and magnesium carbonate. Alkali metal phosphates include trisodium phosphate and tripotassium phosphate. Preferred is an alkali metal hydroxide. Organic bases include tertiary amines, secondary amines, and primary amines. Tertiary amines include triethylamine, tripropylamine, and tributylamine. The secondary amines include diethylamine, dipropylamine, dibutylamine, and the like. Primary amines include butylamine and benzylamine. Preferably it is a tertiary amine. The amount of the base is usually in the range of 0.5 to 3 moles in terms of base relative to 1 mole of the acid used in the first step. The mixing temperature is usually in the range of 10°C to 80°C.

[0071] The mixing of the salt obtained in the first step with the base may be carried out in the presence of an organic solvent and / or water. Examples of the organic solvent include, but are not limited to, aromatic hydrocarbon solvents such as toluene, xylene, and ethylbenzene; halogenated aromatic hydrocarbon solvents such as monochlorobenzene; aliphatic hydrocarbon solvents such as heptane and hexane; alicyclic hydrocarbon solvents such as cyclopentane and cyclohexane; ether solvents such as diethyl ether and tert-butyl methyl ether; and ester solvents such as ethyl acetate; and mixtures of two or more of these. The amount of the organic solvent and / or water used is usually 10 parts by weight or less in total per part by weight of the salt.

[0072] The order of mixing may be a mixture of an optically active acid salt of 1,1,3-trimethyl-4-aminoindan, a base in an aqueous solution as required, and an organic solvent as required all at once, or a mixture of the acid salt and an organic solvent as required and an aqueous solution of the base as required may be mixed. The acid salt may also be added to a mixture of the base in an aqueous solution as required and an organic solvent as required. It is particularly preferred to add the acid salt to a mixture of an organic solvent and a base in an aqueous solution as required.

[0073] After the mixing is completed, the mixture is usually separated into an organic layer and an aqueous layer, which are separated to obtain the organic layer, and the organic solvent is distilled off as necessary to obtain optically active 1,1,3-trimethyl-4-aminoindan. As described above, the optical purity of the optically active 1,1,3-trimethyl-4-aminoindan thus obtained is usually higher than that of the optically active 1,1,3-trimethyl-4-aminoindan used in the first step. Furthermore, when optically active 1,1,3-trimethyl-4-aminoindan is used in the amidation reaction D described below, the acid salt is reacted with the compound represented by formula (1-3) as it is, whereby the acid salt is first neutralized by the base in the reaction system to give optically active 1,1,3-trimethyl-4-aminoindan, which then reacts with the compound represented by formula (1-3), thereby allowing the second step of the present invention and the amidation reaction D to be carried out continuously.

[0074] Finally, the process of reacting the optically active 1,1,3-trimethyl-4-aminoindan obtained through the above asymmetric hydrogenation, isomerization, and hydrolysis reactions, and optical resolution (or preferential crystallization) as necessary, with the compound represented by the above formula (6) (hereinafter, sometimes referred to as "compound (6)") to obtain the optically active compound represented by the above formula (7) (hereinafter, sometimes referred to as "optically active compound (7)"). Hereinafter, the reaction between the optically active 1,1,3-trimethyl-4-aminoindan and compound (6) may be referred to as "amidation reaction".

[0075] R in the above formula (6) 12 is preferably a hydrogen atom or a methyl group, and more preferably a hydrogen atom. R 13 is preferably a methyl group, a monofluoromethyl group, a difluoromethyl group or a trifluoromethyl group, and more preferably a difluoromethyl group. R 14 is preferably a chlorine atom, an ethoxy group, or a hydroxy group, more preferably a chlorine atom. Examples of compound (6) include 1-methyl-3-difluoromethylpyrazole-4-carboxylate, 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid, and 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid chloride.

[0076] The resulting optically active compound (7) may be (R)-(-)-N-(1,1,3-trimethylindan-4-yl)-1-methyl-3-difluoromethylpyrazole-4-carboxylic acid amide.

[0077] The amidation reaction may be carried out under conditions in which optically active 1,1,3-trimethyl-4-aminoindan reacts with compound (6), and is preferably the following amidation reaction A, B, C or D.

[0078] <Amidation reaction A> The amidation reaction A is a reaction between optically active 1,1,3-trimethyl-4-aminoindan and R 14 is a hydroxy group (hereinafter sometimes referred to as “compound (6-1)”) in the presence of a dehydrating condensation agent to obtain optically active compound (7). TIFF0007662640000012.tif38170 (in the formula, R 12 and R 13 has the same meaning as above.)

[0079] Examples of the dehydration condensation agent include carbodiimide compounds such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1,3-dicyclohexylcarbodiimide, and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate. The amount of the dehydration condensation agent used is usually within the range of 1 to 5 moles per mole of compound (6-1). The amount of optically active 1,1,3-trimethyl-4-aminoindan used is usually within the range of 0.5 to 3 moles per mole of compound (6-1).

[0080] The reaction of optically active 1,1,3-trimethyl-4-aminoindan with compound (6-1) is usually carried out in the presence of a solvent inert to the reaction. Examples of such solvents include ether solvents such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, and tert-butyl methyl ether; aliphatic hydrocarbon solvents such as hexane, heptane, and octane; aromatic hydrocarbon solvents such as toluene, xylene, and ethylbenzene; halogenated hydrocarbon solvents such as chlorobenzene; ester solvents such as butyl acetate and ethyl acetate; nitrile solvents such as acetonitrile; acid amide solvents such as N,N-dimethylformamide; sulfoxide solvents such as dimethyl sulfoxide, and nitrogen-containing aromatic compound solvents such as pyridine; and mixed solutions of two or more of these. The amount of the solvent used is usually in the range of 1 part by weight to 20 parts by weight per part by weight of compound (6-1). The reaction temperature is usually in the range of -20°C to 150°C, and the reaction time is usually in the range of 1 hour to 24 hours.

[0081] After the reaction is completed, the resulting reaction mixture is mixed with water; an aqueous solution of a base such as an aqueous solution of sodium hydrogen carbonate, an aqueous solution of sodium carbonate, an aqueous solution of ammonium chloride, an aqueous solution of sodium hydroxide, or an aqueous solution of potassium hydroxide; or an aqueous solution of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid, a solid is precipitated, and the resulting mixture is filtered to obtain the optically active compound (7). If no solid is precipitated, the resulting mixture is extracted with an organic solvent, and the organic layer is separated, dried, concentrated, or other post-treatment operations are performed to obtain the optically active compound (7). The organic layer may be washed with water; an aqueous solution of an alkali metal hydrogen carbonate such as an aqueous solution of sodium hydrogen carbonate; an aqueous solution of an alkali metal carbonate such as an aqueous solution of sodium carbonate; an aqueous solution of ammonium chloride; an aqueous solution of an alkali metal hydroxide such as an aqueous solution of sodium hydroxide and an aqueous solution of potassium hydroxide; or an aqueous solution of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid. The washing of the organic layer is usually performed in the range of 0° C. to 70° C., preferably 20° C. to 60° C. The extracted optically active compound (7) can be further purified by column chromatography, recrystallization, or the like.

[0082] <Amidation reaction B> The amidation reaction B is a step in which optically active 1,1,3-trimethyl-4-aminoindan is reacted with compound (6-1) in the presence of a Lewis acid to obtain optically active compound (7).

[0083] Examples of Lewis acids include metal chlorides such as titanium tetrachloride, zirconium tetrachloride, and aluminum chloride; metal alkoxide compounds such as titanium ethoxide, titanium propoxide, zirconium ethoxide, zirconium propoxide, aluminum ethoxide, aluminum propoxide, antimony ethoxide, and antimony propoxide; metal amide compounds such as tetrakis(dimethylamino)titanium, dichlorobis(dimethylamino)titanium, and tetrakis(diethylamino)titanium; boron compounds such as boric acid, 3,5-bis(trifluoromethyl)phenylboronic acid, 2,4-bis(trifluoromethyl)phenylboronic acid, and pentafluorophenylboronic acid; and borate compounds such as triphenylmethyltetrakis(pentafluorophenyl)borate, triphenylmethyltetrakis(3,5-bistrifluoromethylphenyl)borate, and N,N-dimethylanilinium tetrakis(pentafluorophenyl)borate. The amount of the Lewis acid used is usually within the range of 0.001 to 3 moles per mole of compound (6-1). The amount of optically active 1,1,3-trimethyl-4-aminoindan used is usually within the range of 0.5 to 3 moles per mole of compound (6-1).

[0084] The reaction of optically active 1,1,3-trimethyl-4-aminoindan with compound (6-1) is usually carried out in the presence of a solvent inert to the reaction. Examples of such a solvent include those mentioned above as solvents that can be used in the amidation reaction A. The amount of the solvent used is usually in the range of 1 to 20 parts by weight per part by weight of compound (6-1). The reaction temperature is usually in the range of -20°C to 150°C, and the reaction time is usually in the range of 1 to 120 hours. It is preferable to carry out the reaction while removing the by-produced water. After completion of the reaction, the optically active compound (7) can be isolated by carrying out the same treatment as in the amidation reaction A.

[0085] <Amidation reaction C> The amidation reaction C is a reaction of optically active 1,1,3-trimethyl-4-aminoindan with R 14 is a C1-C10 alkoxy group optionally substituted with one or more halogen atoms (hereinafter sometimes referred to as "compound (6-2)") in the presence of a Lewis acid or a Lewis base to obtain optically active compound (7). TIFF0007662640000013.tif38170 (in the formula, R 12 and R 13 has the same meaning as above, R 14’ represents a C1-C10 alkoxy group optionally substituted with one or more halogen atoms.

[0086] Lewis acids include metal chlorides such as titanium tetrachloride, zirconium tetrachloride, and aluminum chloride, and metal alkoxide compounds such as titanium ethoxide, titanium propoxide, zirconium ethoxide, zirconium propoxide, aluminum ethoxide, aluminum propoxide, antimony ethoxide, and antimony propoxide. The amount of the Lewis acid used is usually within the range of 0.01 to 3 moles per mole of the compound (6-2). The amount of optically active 1,1,3-trimethyl-4-aminoindan used is usually within the range of 0.5 to 3 moles per mole of compound (6-2).

[0087] Examples of Lewis bases include metal alkoxide compounds such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, and potassium tert-butoxide; metal hydrides such as sodium hydride; lithium compounds such as lithium diisopropylamide and tert-butyllithium; silicon compounds such as sodium hexamethyldisilazane and potassium hexamethyldisilazane; and aluminum compounds such as trimethylaluminum, triethylaluminum, and triisobutylaluminum. The amount of the Lewis base used is usually within the range of 0.01 to 3 moles per mole of compound (6-2). The amount of optically active 1,1,3-trimethyl-4-aminoindan used is usually within the range of 0.5 to 3 moles per mole of compound (6-2).

[0088] The reaction of optically active 1,1,3-trimethyl-4-aminoindan with compound (6-2) is usually carried out in the presence of a solvent inert to the reaction. Examples of such a solvent include those mentioned above as solvents that can be used in the amidation reaction A. The amount of the solvent used is usually in the range of 1 to 20 parts by weight per part by weight of compound (6-2). The reaction temperature is usually in the range of -20°C to 150°C, and the reaction time is usually in the range of 1 to 110 hours. It is preferable to carry out the reaction while removing the by-produced alcohol. After completion of the reaction, the optically active compound (7) can be isolated by carrying out the same treatment as in the amidation reaction A.

[0089] <Amidation reaction D> The amidation reaction D is a reaction between optically active 1,1,3-trimethyl-4-aminoindan and R 14 is a halogen atom (hereinafter sometimes referred to as “compound (6-3)”) in the presence of a base to obtain optically active compound (7). TIFF0007662640000014.tif38170 (in the formula, R 12 and R 13 has the same meaning as above, R 14’’ represents a halogen atom.)

[0090] The base includes alkali metal carbonates such as sodium carbonate and potassium carbonate; tertiary amines such as triethylamine and diisopropylethylamine; and nitrogen-containing aromatic compounds such as pyridine and 4-dimethylaminopyridine. The amount of the base used is usually in the range of a catalytic amount to 5 moles, preferably 1 mole to 3 moles, per mole of optically active 1,1,3-trimethyl-4-aminoindan. The amount of compound (6-3) used is usually 0.5 to 1.5 moles, preferably 0.8 to 1.3 moles, more preferably 1.0 to 1.2 moles, per mole of optically active 1,1,3-trimethyl-4-aminoindan.

[0091] The reaction of optically active 1,1,3-trimethyl-4-aminoindan with compound (6-3) is usually carried out in the presence of a solvent. The solvent may be any solvent inert to the reaction, such as aliphatic hydrocarbon solvents such as pentane, hexane, heptane, octane and cyclohexane; aromatic hydrocarbon solvents such as toluene, xylene and ethylbenzene; halogenated aliphatic hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane and carbon tetrachloride; halogenated aromatic hydrocarbon solvents such as chlorobenzene, dichlorobenzene and trichlorobenzene; ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclohexyl methyl ether, ethylene glycol dimethyl ether, tetrahydrofuran and dioxane; ester solvents such as ethyl acetate and butyl acetate; nitrile solvents such as acetonitrile; and mixtures of two or more of these, with aromatic hydrocarbon solvents, halogenated aromatic hydrocarbon solvents and ether solvents being preferred, and toluene, xylene, ethylbenzene, chlorobenzene and tetrahydrofuran being more preferred. The amount of the solvent used is preferably in the range of 1 to 20 parts by weight, more preferably 2 to 10 parts by weight, per part by weight of the optically active 1,1,3-trimethyl-4-aminoindan.

[0092] The reaction temperature is usually in the range of -20°C to 80°C, preferably 0°C to 70°C, more preferably 20°C to 60°C, and the reaction time is usually in the range of 0.1 hours to 24 hours. After completion of the reaction, the optically active compound (7) can be isolated by carrying out the same treatment as in the amidation reaction A. The isolated optically active compound (7) can be, and is preferably, further purified by column chromatography, recrystallization, or the like. A preferred purification method is to dissolve the optically active compound (7) in a solvent to prepare a solution, and then recrystallize the compound using the solution. Seed crystals may be used during recrystallization. Examples of such solvents include aliphatic hydrocarbon solvents such as pentane, hexane, heptane, octane, and cyclohexane; aromatic hydrocarbon solvents such as toluene, xylene, and ethylbenzene; halogenated aliphatic hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane, and carbon tetrachloride; halogenated aromatic hydrocarbon solvents such as chlorobenzene, dichlorobenzene, and trichlorobenzene; ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclohexyl methyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, and dioxane; ester solvents such as ethyl acetate and butyl acetate; nitrile solvents such as acetonitrile; alcohol solvents such as methanol, ethanol, and 2-propanol; and mixed solutions of two or more of these. Among these, aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents, halogenated aromatic hydrocarbon solvents, and ester solvents are preferred, and toluene, xylene, ethylbenzene, hexane, heptane, and ethyl acetate are more preferred. EXAMPLES

[0093] The present invention will now be described in further detail with reference to examples. In the examples, the ratio of R / S isomers was analyzed by high performance liquid chromatography (area percentage method) using a chiral column. The contents of 1,1,3-trimethyl-4-aminoindan and (R)-(-)-N-(1,1,3-trimethylindan-4-yl)-1-methyl-3-difluoromethylpyrazole-4-carboxylic acid amide were analyzed by liquid chromatography (internal standard method).

[0094] Example 1 <Synthesis of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt> 2.37g of 2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine and 43g of tetrahydrofuran were charged into a 100mL flask equipped with a nitrogen-substituted reflux condenser, and the mixture was stirred at 25°C to confirm that 2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine had dissolved. 1.31g of cobalt(II) bromide was added to the resulting solution at 25°C, and the mixture was heated and refluxed for 2 hours. After cooling to room temperature, the solvent was distilled off from the resulting reaction mixture, 8g of tetrahydrofuran was added to make a slurry, and 185g of methyl-t-butyl ether was added, and the mixture was refluxed for 1 hour. The mixture was cooled to room temperature to precipitate crystals, and the resulting crystals were filtered, washed with 150g of methyl-t-butyl ether, and then dried to obtain 3.41g of a blue-green powder. The obtained powder was confirmed to be dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt by EI-MS. Yield: 88% EI-MS=546, 548, 550

[0095] Example 2 <Synthesis of dibromo[2,6-bis[4-(S)-isopropyl-2-oxazolyl]pyridine]cobalt> The same procedure as in Example 1 was carried out except that 2.16 g of 2,6-bis[4-(S)-isopropyl-2-oxazolyl]pyridine was used instead of 2.37 g of 2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine in Example 1, and 3.17 g of a blue-green powder was obtained. Yield: 85%

[0096] Example 3 <Synthesis of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]-4-methoxypyridine]cobalt> The same procedure as in Example 1 was carried out except that 2.59 g of 2,6-bis[4-(S)-isobutyl-2-oxazolyl]-4-methoxypyridine was used instead of 2.37 g of 2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine, and 3.54 g of a blue-green powder was obtained. Yield: 85%

[0097] Example 4 <Asymmetric hydrogenation reaction using hydride reduction complex of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt> In a 100 mL autoclave equipped with a glass inner cylinder, 88 mg of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt, 3.44 g of 1-acetyl-1,2-dihydro-2,2,4-trimethyl-1-quinoline, and 11.5 g of tetrahydrofuran were charged. After nitrogen replacement, the mixture was heated to 35°C, 0.64 mL of 1 M sodium triethylborohydride / tetrahydrofuran solution was added to the resulting mixture, hydrogen replacement was performed, and the mixture was pressurized to 0.95 MPa with hydrogen, and stirred at 35°C for 1 hour under pressure. After the reaction, the mixture was cooled to 15°C and replaced with nitrogen. The R-form ratio of the resulting reaction mixture and the yield of 1-acetyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline were analyzed using high performance liquid chromatography. R-form ratio = 82.5%, yield = 99%

[0098] Example 5 <Asymmetric hydrogenation reaction using hydride reduction complex of dichloro[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt> In a 100 mL autoclave equipped with a glass inner cylinder, 74 mg of dichloro[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt, 3.44 g of 1-acetyl-1,2-dihydro-2,2,4-trimethyl-1-quinoline, and 11.5 g of tetrahydrofuran were charged. After nitrogen replacement, the mixture was heated to 35°C, 0.64 mL of 1 M sodium triethylborohydride / tetrahydrofuran solution was added to the mixture, hydrogen replacement was performed, and the mixture was pressurized to 0.95 MPa with hydrogen, and stirred at 35°C for 1 hour under pressure. After the reaction, the mixture was cooled to 15°C and replaced with nitrogen. The R-form ratio of the reaction mixture and the yield of 1-acetyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline were analyzed using high performance liquid chromatography. R-form ratio = 70%, yield = 99%

[0099] Example 6 <Asymmetric hydrogenation reaction using hydride reduction complex of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt> In a 100 mL autoclave equipped with a glass inner cylinder, 44 mg of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt, 6.89 g of 1-acetyl-1,2-dihydro-2,2,4-trimethyl-1-quinoline, 17.5 mg of cobalt(II) bromide, and 11.5 g of tetrahydrofuran were charged. After nitrogen replacement, the mixture was heated to 40°C, 0.8 mL of 1 M sodium triethylborohydride / tetrahydrofuran solution was added to the resulting mixture, hydrogen replacement was performed, and the mixture was pressurized to 0.95 MPa with hydrogen, and the mixture was stirred under pressure at 40°C for 2 hours. After the reaction, the mixture was cooled to 15°C and then replaced with nitrogen. The R-form ratio of the resulting reaction mixture and the yield of 1-acetyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline were analyzed using high performance liquid chromatography. R-form ratio: 75.0%, yield: 100%

[0100] Example 7 <Asymmetric hydrogenation reaction using hydride reduction complex of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt> The reaction was carried out in the same manner as in Example 6, except that cobalt (II) bromide was not added. After the reaction, the mixture was cooled to 15°C and purged with nitrogen. The R-isomer ratio of the resulting reaction mixture and the yield of 1-acetyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline were analyzed by high performance liquid chromatography. R-isomer ratio: 58.0%, yield: 85%.

[0101] Example 8 <Asymmetric hydrogenation reaction using hydride reduction complex of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt> In a 100 mL autoclave equipped with a glass inner cylinder, 88 mg of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt, 6.89 g of 1-acetyl-1,2-dihydro-2,2,4-trimethyl-1-quinoline, 35 mg of cobalt(II) bromide, and 11.5 g of tetrahydrofuran were charged. After nitrogen replacement, the mixture was heated to 40°C, and 1.6 mL of 1 M sodium triethylborohydride / tetrahydrofuran solution was added to the resulting mixture, which was then replaced with hydrogen. The mixture was pressurized to 0.95 MPa with hydrogen, and the mixture was stirred at 40°C for 2 hours under pressure. After the reaction, the mixture was cooled to 15°C and replaced with nitrogen. The R-form ratio of the resulting reaction mixture and the yield of 1-acetyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline were analyzed using high performance liquid chromatography. R-form ratio: 72.5%, yield: 100%

[0102] Example 9 <Asymmetric hydrogenation reaction using hydride reduction complex of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt> In a 100 mL autoclave equipped with a glass inner cylinder, 44 mg of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt, 6.89 g of 1-acetyl-1,2-dihydro-2,2,4-trimethyl-1-quinoline, 3.85 g of triethylamine, and 8.2 g of 1,4-dioxane were charged. After nitrogen replacement, the mixture was heated to 40°C, and 0.64 mL of 1 M sodium triethylborohydride / tetrahydrofuran solution was added to the resulting mixture, which was then stirred at 40°C for 1 hour. After 1 hour, the reaction solution was cooled to 15°C, replaced with hydrogen, and pressurized to 0.95 MPa with hydrogen, and the mixture was stirred at 15°C for 5 hours under pressure. After the reaction, the atmosphere was replaced with nitrogen, and the R-isomer ratio of the resulting reaction mixture and the yield of 1-acetyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline were analyzed by high performance liquid chromatography. R-isomer ratio: 90.0%, yield: 100%.

[0103] Example 10 <Asymmetric hydrogenation reaction using hydride reduction complex of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt> In a 100 mL autoclave equipped with a glass inner cylinder, 22 mg of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt, 3.44 g of 1-acetyl-1,2-dihydro-2,2,4-trimethyl-1-quinoline, 1.93 g of triethylamine, and 4.1 g of 1,4-dioxane were charged. After nitrogen replacement, the mixture was heated to 40°C, and 0.4 mL of 1 M sodium triethylborohydride / tetrahydrofuran solution was added to the resulting mixture, which was then stirred at 40°C for 1 hour. After 1 hour, the reaction solution was cooled to 25°C, replaced with hydrogen, and pressurized to 0.95 MPa with hydrogen, and the mixture was stirred under pressure at 25°C for 3 hours. After the reaction, the atmosphere was replaced with nitrogen, and the R-isomer ratio of the resulting reaction mixture and the yield of 1-acetyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline were analyzed by high performance liquid chromatography. R-isomer ratio: 86.5%, yield: 99%

[0104] Example 11 <Asymmetric hydrogenation reaction using hydride reduction complex of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt> In a 100mL autoclave equipped with a glass inner cylinder, 88mg of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt, 13.8g of 1-acetyl-1,2-dihydro-2,2,4-trimethyl-1-quinoline, 35mg of cobalt(II) bromide and 16.5g of 1,4-dioxane were charged. After nitrogen replacement, the mixture was heated to 40°C, and 1.2mL of 1M sodium triethylborohydride / tetrahydrofuran solution was added to the mixture, which was then stirred at 40°C for 1 hour. After 1 hour, the reaction solution was cooled to 25°C, replaced with hydrogen, and pressurized to 0.95MPa with hydrogen, and the mixture was stirred at 25°C for 4 hours under pressure. After the reaction, the atmosphere was replaced with nitrogen, and the R-isomer ratio of the resulting reaction mixture and the yield of 1-acetyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline were analyzed by high performance liquid chromatography. R-isomer ratio: 86.0%, yield: 100%.

[0105] Example 12 <Asymmetric hydrogenation reaction using hydride reduction complex of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt> In a 100 mL autoclave equipped with a glass inner cylinder, 44 mg of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt, 6.89 g of 1-acetyl-1,2-dihydro-2,2,4-trimethyl-1-quinoline, and 8.2 g of 1,4-dioxane were charged. After nitrogen replacement, the temperature was raised to 40°C, and 0.6 mL of 1 M sodium triethylborohydride / tetrahydrofuran solution was added to the resulting mixture, which was then kept warm and stirred at 40°C for 1 hour. After 1 hour, the mixture was cooled to 25°C, replaced with hydrogen, and pressurized to 0.95 MPa with hydrogen, and the mixture was stirred under pressure at 25°C for 4 hours. After the reaction, the mixture was replaced with nitrogen, and the R-form ratio of the resulting reaction mixture and the yield of 1-acetyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline were analyzed using high performance liquid chromatography. R-form ratio: 83.6%, yield: 100%

[0106] Example 13 <Asymmetric hydrogenation reaction using hydride reduction complex of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt> In a 100mL autoclave equipped with a glass inner cylinder, 44mg of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt, 7.5g of 1-acetyl-1,2-dihydro-2,2,4-trimethyl-6-fluoro-1-quinoline, and 8.2g of 1,4-dioxane were charged. After nitrogen replacement, the mixture was heated to 40°C, and 0.6mL of 1M sodium triethylborohydride / tetrahydrofuran solution was added to the resulting mixture, which was then stirred at 40°C for 1 hour. After 1 hour, the mixture was cooled to 25°C, replaced with hydrogen, pressurized to 0.95MPa with hydrogen, and stirred under pressure at 25°C for 4 hours. After the reaction, the atmosphere was replaced with nitrogen, and the R-isomer ratio of the resulting reaction mixture and the yield of 1-acetyl-2,2,4-trimethyl-6-fluoro-1,2,3,4-tetrahydroquinoline were analyzed by high performance liquid chromatography. R-isomer ratio: 84%, yield: 91%

[0107] Example 14 <Asymmetric hydrogenation reaction using hydride reduction complex of dibromo[2,6-bis[4-(S)-isopropyl-2-oxazolyl]pyridine]cobalt> In a 100 mL autoclave equipped with a glass inner cylinder, 52 mg of dibromo[2,6-bis[4-(S)-isopropyl-2-oxazolyl]pyridine]cobalt prepared in Example 2, 4.31 g of 1-acetyl-1,2-dihydro-2,2,4-trimethyl-1-quinoline, 2.6 g of triethylamine, and 10.1 g of 1,4-dioxane were charged. After nitrogen replacement, the mixture was heated to 40°C, and 0.8 mL of 1 M sodium triethylborohydride / toluene solution was added to the resulting mixture, which was then stirred at 40°C for 1 hour. After 1 hour, the mixture was cooled to 25°C, replaced with hydrogen, pressurized with hydrogen to 0.95 MPa, and stirred under pressure at 25°C for 3 hours. After the reaction, the atmosphere was replaced with nitrogen, and the R-isomer ratio of the resulting reaction mixture and the yield of 1-acetyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline were analyzed by high performance liquid chromatography. R-isomer ratio: 66.3%, yield: 65%

[0108] Example 15 <Asymmetric hydrogenation reaction using hydride reduction complex of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]-4-methoxypyridine]cobalt> In a 100 mL autoclave equipped with a glass inner cylinder, 58 mg of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]-4-4 methoxypyridine]cobalt prepared in Example 3, 4.31 g of 1-acetyl-1,2-dihydro-2,2,4-trimethyl-1-quinoline, 2.6 g of triethylamine, and 10.1 g of 1,4-dioxane were charged. After nitrogen replacement, the temperature was raised to 40°C, and 0.8 mL of 1 M sodium triethylborohydride / tetrahydrofuran solution was added to the resulting mixture, which was then stirred at 40°C for 1 hour. After 1 hour, the mixture was cooled to 25°C, replaced with hydrogen, pressurized to 0.95 MPa with hydrogen, and stirred under pressure at 25°C for 3 hours. After the reaction, the atmosphere was replaced with nitrogen, and the R-isomer ratio of the resulting reaction mixture and the yield of 1-acetyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline were analyzed by high performance liquid chromatography. R-isomer ratio: 78.6%. Yield = 100%

[0109] Example 16 <Asymmetric hydrogenation reaction using methyl-reduced complex of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt> In a Schlenk flask under a nitrogen atmosphere, 219 mg of dibromo[2,6-bis[4-(S)-t-butyl-2-oxazolyl]pyridine]cobalt, 2 g of 1,4-dioxane, and 2 g of toluene were added and cooled to -40° C. To this mixture, 2 ml of a 1.1 M methyllithium / diethyl ether solution was added, and stirring was continued for 3 hours until the mixture reached room temperature, to prepare a methyl complex. In a 100 mL autoclave equipped with a glass inner cylinder, 8.61 g of 1-acetyl-1,2-dihydro-2,2,4-trimethyl-1-quinoline, 10 g of 1,4-dioxane, and 4.9 g of triethylamine were charged. After replacing with nitrogen, the entire amount of the methyl complex solution prepared in the Schlenk tube was added to the resulting mixture at 25°C. The atmosphere was replaced with hydrogen, and the mixture was pressurized to 0.95 MPa with hydrogen, and stirred under pressure at 25°C for 4 hours. After the reaction, the atmosphere was replaced with nitrogen, and the R-isomer ratio of the resulting reaction mixture and the yield of 1-acetyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline were analyzed using high performance liquid chromatography. R-isomer ratio = 54.6%, yield = 32%

[0110] Example 17 <Synthesis of optically active 1,1,3-trimethyl-4-aminoindan> A 300 mL flask purged with nitrogen was charged with 50 g of a tetrahydrofuran solution of 1-acetyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline having an R isomer ratio of 77.7% obtained in the same manner as in Example 4 or 6, and the tetrahydrofuran was distilled off. After purging the flask with nitrogen in which 13.3 g (content 85%) of the concentrated solution remained, 22.7 g of 98% sulfuric acid and 260 mg of water were charged at room temperature, and the mixture was heated and stirred at 45 °C for 6 hours. After the reaction, 23 g of water was added, and the mixture was further heated and stirred at 110 °C for 2 hours. After completion of the reaction, 85 g of a 27% aqueous sodium hydroxide solution was added to the reaction solution, and extraction was performed twice with 50 g of toluene. The toluene layers were combined, washed once with 10 g of water, and then the toluene was distilled off. The obtained concentrated solution was optically active 1,1,3-trimethyl-4-aminoindane, and 9.6 g was obtained. Internal standard substance method content analysis and optical purity analysis were performed by liquid chromatography to determine the content and optical purity. Content 90%, optical isomer ratio R:S = 78.1:21.9%, yield = 95%

[0111] Example 18 <Optical Resolution of 1,1,3-Trimethyl-4-aminoindane Using d-Tartaric Acid> A 300 mL flask purged with nitrogen was charged with 9.6 g of 1,1,3-trimethyl-4-aminoindane (R isomer / S isomer = 78 / 22) obtained in Example 17 and 36 g of methanol, and the mixture was heated to 60 °C. A solution obtained by dissolving 7.4 g of d-tartaric acid in 20 g of water was added dropwise at 60 °C over 30 minutes. After cooling the reaction mixture to 38 °C, 20 mg of (R)-1,1,3-trimethyl-4-aminoindane·d-tartrate was added, and crystals precipitated, so the mixture was cooled to 10 °C over 3 hours. This reaction solution was filtered under reduced pressure with a Nutsche, and the crystals were further washed and drained twice with 10 g of toluene under reduced pressure on the Nutsche. The crystals were dried to obtain 11.4 g of a methanol solvate salt of (R)-1,1,3-trimethyl-4-aminoindane·d-tartaric acid. Optical purity analysis was performed by liquid chromatography to determine the optical purity of (R)-1,1,3-trimethyl-4-aminoindane. Optical isomer ratio R:S = 98.1:1.9, yield = 65%

[0112] Example 19 <Synthesis of Optically Active 1,1,3-Trimethyl-4-aminoindane> A 300 mL flask substituted with nitrogen was charged with 53 g of a tetrahydrofuran solution of 1-acetyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline (R form / S form = 80.7 / 19.3) obtained in the same manner as in Example 4 or 6, and the tetrahydrofuran was distilled off. After the flask in which 15.8 g (content 85%) of the concentrated solution remained was substituted with nitrogen, 26.9 g of 98% sulfuric acid and 180 mg of water were charged at room temperature, and the mixture was heated and stirred at 45 °C for 7 hours. After the reaction, 27.3 g of water was added, and the mixture was further heated and stirred at 110 °C for 2 hours. After the reaction was completed, 100 g of a 27% aqueous sodium hydroxide solution was added to the reaction solution, and extraction was performed twice with 60 g of toluene. The toluene layers were combined, washed once with 12 g of water, and then the toluene was distilled off. The obtained concentrated solution was optically active 1,1,3-trimethyl-4-aminoindane, and 12.1 g was obtained. The content analysis by the internal standard substance method and the optical purity analysis were performed by liquid chromatography to determine the content and the optical purity. Content 90%, optical isomer ratio R:S = 80.7:19.3, yield = 98%

[0113] Example 20 <Optical Resolution of 1,1,3-Trimethyl-4-aminoindane Using d-Tartaric Acid> In a 300 mL flask purged with nitrogen, 12 g of 1,1,3-trimethyl-4-aminoindan (R / S = 80.7 / 19.3) obtained in Example 19 and 46 g of methanol were charged, and the mixture was heated to 60°C. A solution obtained by dissolving 9.8 g of d-tartaric acid in 23 g of water was added dropwise at 60°C over 30 minutes. After cooling the reaction mixture to 40°C, 20 mg of (R)-1,1,3-trimethyl-4-aminoindan·d-tartrate was added, and crystals were precipitated, so the mixture was cooled to 10°C over 3 hours. The reaction solution was filtered under reduced pressure using a Nutsche filter, and the crystals were washed twice with 10 g of toluene on the Nutsche filter under reduced pressure and dehydrated. The crystals were dried to obtain 12.5 g of methanol solvate salt of (R)-1,1,3-trimethyl-4-aminoindan·d-tartaric acid. The optical purity was determined by liquid chromatography. The optical isomer ratio R:S=98.1:1.9, yield=70.6%.

[0114] Example 21 <First step of preferential crystallization using sodium hydrogen sulfate (pKa=1.99)> In a 300 mL flask purged with nitrogen, 17.5 g of 1,1,3-trimethyl-4-aminoindan (R / S = 83 / 17) and 60 g of methanol were charged, and the mixture was heated to 60°C. A solution obtained by dissolving 9.6 g of sodium hydrogen sulfate monohydrate in 15 g of water was added dropwise at 60°C over 30 minutes, and crystals precipitated. The reaction solution was kept at 60°C for 3 hours, cooled to room temperature for 3 hours, and then cooled to 10°C for 1 hour. The reaction solution was filtered under reduced pressure using a Nutsche filter, and the crystals were washed twice with 15 g of toluene on the Nutsche filter under reduced pressure and dehydrated. The crystals were dried to obtain 19.3 g of (R)-1,1,3-trimethyl-4-aminoindan sodium hydrogen sulfate. The optical purity was determined by liquid chromatography. Optical isomer ratio R:S=96.4:3.6, yield=66%

[0115] Example 22 <Second step of preferential crystallization> In a nitrogen-purged 100 mL flask, 19 g of (R)-1,1,3-trimethyl-4-aminoindan sodium hydrogen sulfate obtained in Example 21, 14.2 g of 27% aqueous sodium hydroxide solution, and 40 g of toluene were charged, and the mixture was stirred at room temperature for 30 minutes. The toluene layer was washed once with 5 g of water, and the toluene was distilled off to obtain 11.2 g of (R)-1,1,3-trimethyl-4-aminoindan. Content analysis by internal standard method and optical purity analysis by liquid chromatography were performed to determine the content and optical purity. Optical isomer ratio R:S=96.4:3.6, content 98%, yield=98%

[0116] Example 23 <First step of preferential crystallization using sodium hydrogen sulfate (pKa=1.99)> In a 300 mL flask purged with nitrogen, 17.5 g of 1,1,3-trimethyl-4-aminoindan (R / S = 83 / 17) and 60 g of methanol were charged, and the mixture was heated to 60°C. A solution obtained by dissolving 9.3 g of sodium hydrogen sulfate monohydrate in 20 g of water was added dropwise at 60°C over 30 minutes, and crystals precipitated. The reaction solution was kept at 70°C for 3 hours, cooled to room temperature for 3 hours, and then cooled to 10°C for 1 hour. The reaction solution was filtered under reduced pressure using a Nutsche filter, and the crystals were washed twice with 15 g of toluene on the Nutsche filter under reduced pressure and dehydrated. The crystals were dried to obtain 19.6 g of (R)-1,1,3-trimethyl-4-aminoindan sodium hydrogen sulfate. The optical purity was determined by liquid chromatography. Optical isomer ratio R:S=96.8:3.2, yield=66.5%

[0117] Example 24 <First step of preferential crystallization using sodium hydrogen sulfate (pKa=1.99)> In a 300 mL flask purged with nitrogen, 17.5 g of 1,1,3-trimethyl-4-aminoindan (R / S = 90 / 10) and 60 g of methanol were charged, and the mixture was heated to 60°C. A solution obtained by dissolving 11.5 g of sodium hydrogen sulfate monohydrate in 18 g of water was added dropwise at 60°C over 30 minutes, and crystals precipitated. The reaction solution was kept at 60°C for 2 hours, cooled to room temperature for 3 hours, and then cooled to 10°C for 1 hour. The reaction solution was filtered under reduced pressure using a Nutsche filter, and the crystals were washed twice with 15 g of toluene on the Nutsche filter under reduced pressure and dehydrated. The crystals were dried to obtain 23.5 g of (R)-1,1,3-trimethyl-4-aminoindan sodium hydrogen sulfate. The optical purity was determined by liquid chromatography. Optical isomer ratio R:S=98.4:1.6, yield=80%

[0118] Example 25 <Synthesis of (R)-1,1,3-trimethyl-4-aminoindan by decomposition of (R)-1,1,3-trimethyl-4-aminoindan·d-tartrate methanol solvate> In a nitrogen-purged 100 mL flask, 5 g of the methanol solvate salt of (R)-1,1,3-trimethyl-4-aminoindan·d-tartaric acid obtained in Example 18, 5.2 g of 27% aqueous sodium hydroxide solution, and 10 g of toluene were charged, and the mixture was stirred at room temperature for 30 minutes. The toluene layer was washed once with 5 g of water, and the toluene was distilled off to obtain 2.4 g of (R)-1,1,3-trimethyl-4-aminoindan. Content and optical purity were determined by liquid chromatography using the internal standard method. Optical isomer ratio R:S=98.1:1.9, content 98%, yield=98%

[0119] Example 26 <Amidation reaction D> Under a nitrogen atmosphere, 14.0 parts of 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid and 35.1 parts of xylene were mixed at room temperature. The resulting mixture was heated to 100°C. 11.2 parts of thionyl chloride were added dropwise to the resulting mixture over 5 hours. The resulting mixture was stirred at 100°C for 15 hours and then cooled to 40°C. Thionyl chloride and xylene were distilled off from the resulting reaction mixture under reduced pressure to obtain brown 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid chloride. A solution was prepared by mixing 14.6 parts of (R)-1,1,3-trimethyl-4-aminoindan, 9.2 parts of triethylamine, and 38.1 parts of xylene. A solution of the 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid chloride obtained above dissolved in 13.2 parts of xylene was added dropwise to the obtained solution at 45°C to 50°C over 2 hours. The obtained mixture was stirred at 45°C to 50°C for 15 hours. The obtained reaction mixture was mixed with a 20% aqueous sodium hydroxide solution, and then the organic layer was separated. The obtained organic layer was washed successively with water, 18% hydrochloric acid, water, a 1% aqueous sodium hydroxide solution, and water, and then concentrated under reduced pressure conditions to obtain 27.5 parts of (R)-(-)-N-(1,1,3-trimethylindan-4-yl)-1-methyl-3-difluoromethylpyrazole-4-carboxylic acid amide. Example 27 <Amidation reaction D> Under a nitrogen atmosphere, 1.8 g of 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid was mixed with 10 g of toluene at room temperature. The resulting mixture was heated to 100°C. 30 mg of dimethylformamide was added to the resulting mixture, and then a mixture of 1.57 g of thionyl chloride dissolved in 5 g of toluene was added dropwise over 30 minutes. The resulting mixture was stirred at 100°C for 2 hours and then cooled to 40°C. Thionyl chloride and toluene were distilled off from the resulting reaction mixture under reduced pressure to obtain brown 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid chloride. The entire amount of this brown 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid chloride solution, 3 g of (R)-1,1,3-trimethyl-4-aminoindan-sodium hydrogen sulfate obtained in Example 23, and 10 g of toluene were mixed and heated to 50°C. A mixture of 2.26 g of triethylamine and 5 g of toluene was added dropwise to this solution over 30 minutes, and the mixture was stirred while keeping the temperature at 40°C for 2 hours. The resulting reaction mixture was mixed with water, and the organic layer was separated. The resulting organic layer was washed three times with water and then concentrated under reduced pressure to obtain 3.3 g of (R)-(-)-N-(1,1,3-trimethylindan-4-yl)-1-methyl-3-difluoromethylpyrazole-4-carboxylic acid amide. [Industrial Applicability]

[0120] According to the present invention, optically active (R)-1,1,3-trimethyl-4-aminoindan can be efficiently produced. Such a compound is useful as an intermediate for the production of (R)-(-)-(1,1,3-trimethylindan-4-yl)-1-methyl-3-difluoromethylpyrazole-4-carboxylic acid amide having a plant disease prevention effect. The present invention also provides an asymmetric cobalt complex that can be used for the production of a precursor of such an intermediate.

Claims

1. Formula (1): 【Chemistry 1】 (In the formula, each R 1 independently represents a C1-C10 alkyl group which may have one or more substituents, a C3-C10 cycloalkyl group which may have one or more substituents, or a C6-C10 aryl group which may have one or more substituents. R 2 and R 3 independently represent a hydrogen atom, a C1-C10 alkyl group which may have one or more substituents, or a C6-C10 aryl group which may have one or more substituents, or R 2 and R 3 are bonded to each other to form a ring together with the carbon atoms to which they are bonded. R 4 represents a C1-C10 alkyl group which may have one or more substituents, a C1-C10 alkoxy group which may have one or more substituents, a C1-C10 alkylthio group which may have one or more substituents, a C2-C11 alkoxycarbonyl group which may have one or more substituents, a C2-C11 alkylcarbonyl group which may have one or more substituents, a C6-C10 aryl group which may have one or more substituents, a halogen atom, an amino group which may be mono- or di-alkylated with C1-C10 alkylation, a nitro group, a hydroxy group, a sulfo group, a C1-C10 alkylsulfonyl group, a C6-C10 arylsulfonyl group, or a halosulfonyl group. n represents 0, 1, 2, or 3. When n is 0 or 1, the multiple R 4 s may be the same or different from each other. X represents a chlorine atom, a bromine atom, or an iodine atom. And the carbon atom marked with * represents an asymmetric carbon atom.) In the presence of a monovalent asymmetric cobalt complex obtained by reacting an asymmetric cobalt complex represented by the formula (2): 【Chemistry 2】 (In the formula, R ５ represents a hydrogen atom or a C1-C6 alkyl group which may have one or more substituents, R ６ and R ７ each independently represents a hydrogen atom or a C1-C6 alkyl group; R ８ represents a C1-C6 alkyl group, and R ９ , R １０ and R １１ each independently represents a hydrogen atom, a halogen atom, an amino group, a hydroxy group, a C1-C6 alkyl group which may have one or more substituents, a C1-C6 alkoxy group which may have one or more substituents, a C2-C7 alkylcarbonyl group which may have one or more substituents, or a C6-C10 aryl group which may have one or more substituents. and reacting a compound represented by formula (3): 【Chemistry 3】 (In the formula, R ５ , R ６ , R ７ , R ８ , R ９ , R １０ and R １１ have the same meaning as above. The carbon atom marked with * represents an asymmetric carbon atom.) A method for producing an optically active compound represented by the formula:

2. 2. The process according to claim 1, wherein the reducing agent is a hydride reducing agent and the monovalent cobalt complex is a hydride complex.

3. 3. The process of claim 2, wherein the hydride reducing agent is an alkali metal trialkylborohydride.

4. The method according to claim 2 or 3, further comprising carrying out the reaction in the presence of a divalent cobalt halide salt.

5. 5. The process according to claim 4, wherein the amount of the divalent cobalt halide salt used is 2 moles or less per mole of the hydride complex.

6. The method according to claim 2 or 3, further comprising carrying out the reaction in the presence of a trialkylamine.

7. The process according to claim 6, wherein the amount of trialkylamine used is in the range of 0.5 to 3 moles per mole of the compound represented by formula (2).

8. 2. The process according to claim 1, wherein the reducing agent is an alkyllithium and the monovalent cobalt complex is an alkyl complex.

9. A step of obtaining an optically active compound represented by formula (3) by the production method according to any one of claims 1 to 8; The optically active compound represented by formula (3) obtained by the method according to any one of claims 1 to 8 is reacted with an acid to obtain a compound represented by formula (4): 【Chemistry 4】 (In the formula, R ５ , R ６ , R ７ , R ８ , R ９ , R １０ and R １１ have the same meaning as above. The carbon atom marked with * represents an asymmetric carbon atom.) obtaining an optically active compound represented by the formula: The obtained optically active compound represented by formula (4) is reacted with water to obtain a compound represented by formula (5): 【Chemistry 5】 (In the formula, R ６ , R ７ , R ８ , R ９ , R １０ and R １１ have the same meaning as above. The carbon atom marked with * represents an asymmetric carbon atom.) A method for producing an optically active compound, comprising the step of obtaining an optically active compound represented by the formula:

10. R in formula (5) ６ , R ７ and R ８ is a methyl group, and R ９ , R １０ and R １１ The method according to claim 9 , wherein is a hydrogen atom.

11. A process for producing optically active 1,1,3-trimethyl-4-aminoindan by the process according to claim 10, A method for producing optically active 1,1,3-trimethyl-4-aminoindan, comprising the steps of dissolving the optically active 1,1,3-trimethyl-4-aminoindan obtained by the method according to claim 10 in a solvent, and then optically resolving the resulting mixture using optically active tartaric acid.

12. A process for producing optically active 1,1,3-trimethyl-4-aminoindan by the process according to claim 10, A method for producing optically active 1,1,3-trimethyl-4-aminoindan, comprising the steps of dissolving the optically active 1,1,3-trimethyl-4-aminoindan obtained by the method according to claim 10 in a solvent, and then adding an acid to cause preferential crystallization.

13. The process according to claim 12, wherein the acid has an acid dissociation constant (pKa) of less than 2.

8.

14. The method according to any one of claims 11 to 13, wherein the enantiomeric ratio of the optically active 1,1,3-trimethyl-4-aminoindan subjected to optical resolution or preferential crystallization is 70 / 30 or more in terms of R-isomer / S-isomer.

15. A step of obtaining optically active 1,1,3-trimethyl-4-aminoindan by the production method according to any one of claims 11 to 14, and The optically active 1,1,3-trimethyl-4-aminoindan obtained by the method according to any one of claims 11 to 14 and a compound of the formula (6): 【Chemistry 6】 (In the formula, R １２ and R １３ each independently represents a C1-C6 alkyl group optionally substituted with one or more halogen atoms, or a hydrogen atom, and R １４ represents a halogen atom, a hydroxy group, or a C1-C6 alkoxy group optionally substituted with one or more halogen atoms. and a compound represented by formula (7): 【Chemistry 7】 (In the formula, R １２ , R １３ and * have the same meanings as above.) A method for producing an optically active compound, comprising the step of obtaining an optically active compound represented by the formula:

16. Formula (1'): 【Chemistry 8】 (In the formula, R １ represents an isopropyl group or a tert-butyl group. The carbon atom marked with * represents an asymmetric carbon atom. An asymmetric cobalt complex represented by the formula:

17. Formula (1'): 【Chemistry 9】 (In the formula, R １ represents an isopropyl group or a tert-butyl group. The carbon atom marked with * represents an asymmetric carbon atom. The hydride complex is obtained by reacting an asymmetric cobalt complex represented by the following formula with a hydride reducing agent.

18. Formula (1'): 【Chemistry 10】 (In the formula, R １ represents an isopropyl group or a tert-butyl group. The carbon atom marked with * represents an asymmetric carbon atom. An alkyl complex obtained by reacting an asymmetric cobalt complex represented by the formula: with an alkyl lithium.

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