JP2014031327A - Production method of optically active cis-2-amino-cyclohexane carboxylic acid derivative and precursor of the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To easily and efficiently produce an optically active cis-2-amino-cyclohexane carboxylic acid derivative that is important as a raw material of pharmaceutical products from an easily available starting material.SOLUTION: An optically active cis-2-amino-cyclohexane carboxylic acid derivative can be efficiently produced by preparing a solid of an optically active cis-2-carbamoyl-cyclohexane carboxylic acid derivative by crystallizing a salt formed from a racemic-cis-2-carbamoyl-cyclohexane carboxylic acid and an optically active amine, into a solid from a solvent, then decomposing the salt and converting the carbamoyl group into an amino group.

Description

  The present invention relates to a method for producing an optically active cis-2-amino-cyclohexanecarboxylic acid derivative and a precursor thereof.

  The following method has been reported as a method for producing an optically active cis-2-amino-cyclohexanecarboxylic acid derivative.

  (1) By reductive amination with ethyl 2-oxocyclohexanecarboxylate and (R) -phenethylamine, followed by purification by silica gel chromatography, salt crystallization, dephenethylation, hydrolysis, and then t-butoxycarbonylation , (1S, 2R) -2- (t-butoxycarbonylamino) -cyclohexanecarboxylic acid (Patent Document 1).

  (2) A method for producing (1S, 2R) -2-amino-cyclohexanecarboxylic acid by converting ethyl 2-oxocyclohexanecarboxylate into benzyl ester, followed by enamineation with (R) -phenethylamine, reduction and hydrogenation ( Non-patent document 1).

  (3) (1S, 2R) -2-amino-cyclohexanecarboxylic acid is produced by optical resolution of racemic-cis-2-aza-3-oxobicyclo [4,2,0] octane using an enzyme. Method (Non-patent Document 2).

JP 2010-534670 A

Tetrahedron Asymmetry, 2007, Vol. 18, 1906-1910 Organic Letters, 2003, Vol. 5,1209-1212

  In the prior art (1), a multi-stage reaction is performed, which is not suitable for industrial implementation such as using silica gel column chromatography for purification. The prior art (2) is also a multistage reaction and requires special equipment for hydrogenation under high pressure conditions of 50 atm. The prior art (3) has a problem of using a large excess amount of enzyme with respect to the reaction substrate and a long-time reaction.

  As a result of intensive studies, the present inventors have found that by using racemic cis-2-carbamoyl-cyclohexanecarboxylic acid, an optically active cis-2-amino-cyclohexanecarboxylic acid derivative can be obtained simply and efficiently, The present invention has been completed.

  That is, the present invention provides the following formula (1):

An optically active cis-2-carbamoyl-cyclohexane characterized by forming a salt from an optically active amine and a racemic-cis-2-carbamoyl-cyclohexanecarboxylic acid represented by the formula: The present invention relates to a method for producing a carboxylic acid derivative. In particular, the optically active amine is represented by the following formula (2):

(In the formula, R ¹ represents an alkyl group having Cl -C 12, cycloalkyl group of C3-C12, or .R ² in which an aralkyl group C7~C12 a hydrogen atom, an alkyl group having Cl -C 12, cycloalkyl of C3-C12 Alkyl group, C7-C12 aralkyl group, C2-C12 alkenyl group, hydroxyl group, C1-C12 alkyloxy group, C3-C12 cycloalkyloxy group, C7-C12 aralkyloxy group, C2-C12 alkenyloxy A C6 to C12 aryloxy group, R ¹ and R ² may be combined to form a ring, Ar represents a C6 to C12 aryl group, and * represents an asymmetric carbon atom. It is an optically active amine represented by the following formula (3):

(Wherein R ¹ , R ² , Ar and * are the same as defined above). The compound (3) is converted to the following formula (5) by converting the carbamoyl group after salt removal:

(Wherein R ³ represents a hydrogen atom, a C2 to C12 alkyloxycarbonyl group, a C8 to C12 aralkyloxycarbonyl group, or a C7 to C12 aryloxycarbonyl group. * Is the same as above). It can be an optically active cis-2-amino-cyclohexanecarboxylic acid derivative represented by the formula, or a salt thereof.

  Further, the present invention provides the following formula (3):

(In the formula, R ¹ represents an alkyl group having Cl -C 12, cycloalkyl group of C3-C12, or .R ² in which an aralkyl group C7~C12 a hydrogen atom, an alkyl group having Cl -C 12, cycloalkyl of C3-C12 Alkyl group, C7 to C12 aralkyl group, C2 to C12 alkenyl group, hydroxyl group, C1 to C12 alkyloxy group, C1 to C12 cycloalkyloxy group, C7 to C12 aralkyloxy group, C2 to C12 alkenyloxy A C6 to C12 aryloxy group, R ¹ and R ² may be combined to form a ring, Ar represents a C6 to C12 aryl group, and * represents an asymmetric carbon atom. The optically active cis-2-carbamoyl-cyclohexanecarboxylic acid derivative represented by:

  The optically active cis-2-amino-cyclohexanecarboxylic acid derivative is important as a raw material for pharmaceuticals and agricultural chemicals, and in particular, (1S, 2R) -2- (t-butoxy) described in Patent Document WO2009 / 015166. Carbonylamino) -cyclohexanecarboxylic acid is useful, for example, as an intermediate for rheumatoid arthritis drugs from Bristol-Myers Squibb.

  According to the method of the present invention using a cis-2-carbamoyl-cyclohexanecarboxylic acid derivative, an optically active cis-2-amino-cyclohexanecarboxylic acid derivative is easily and efficiently produced by a method suitable for industrial practice. be able to.

X-ray powder analysis spectrum of (1S, 2R) -cis-2-carbamoyl-cyclohexanecarboxylic acid / (S) -N- (p-methyloxybenzyl) -1-phenethylamine salt measured in Example 22 of the present invention It is. The vertical axis represents the X-ray intensity (cps), and the horizontal axis represents the diffraction angle (2θ).

  Below, the method concerning this invention is described in detail.

  In the present invention, a salt is formed from racemic-cis-2-carbamoyl-cyclohexanecarboxylic acid and an optically active amine to obtain an optically active cis-2-carbamoyl-cyclohexanecarboxylic acid derivative. Further, the optically active cis-2-amino-cyclohexanecarboxylic acid derivative is converted to a salt by converting salt of the optically active cis-2-carbamoyl-cyclohexanecarboxylic acid derivative and converting the carbamoyl group. The production method of the optically active cis-2-amino-cyclohexanecarboxylic acid derivative is illustrated as follows. Below, each process is demonstrated in order. In the present application, unless otherwise specified, each step can be performed independently.

Process 1
In this step, a salt is formed from the racemic-cis-2-carbamoyl-cyclohexanecarboxylic acid represented by the formula (1) and an optically active amine, and an optically active cis-2-carbamoyl-cyclohexanecarboxylic acid derivative (optically active) Cis-2-carbamoyl-cyclohexanecarboxylic acid and a salt of optically active amine), and then precipitated as a solid from the solvent.

  The racemic-cis-2-carbamoyl-cyclohexanecarboxylic acid represented by the above formula (1), which is a starting material of the present invention, is according to the method described in, for example, Bioorganic and Medicinal Chemistry, 19, 4967-4970 (2009). Can be manufactured. Specifically, it can be easily produced by a method of producing a corresponding racemic-cis-2-carbamoyl-cyclohexanecarboxylic acid by causing ammonia to act on cis-cyclohexanedicarboxylic acid anhydride.

  The optically active amine used in the present invention is not particularly limited. Specifically, for example, cinchona alkaloids such as cinchonidine and cinchonine; quinaalkaloids such as quinidine and quinine; 2-methylpyrrolidine and 2-methylpiperidine , 3-benzyloxypyrrolidine, 1-amino-2-benzyloxycyclohexane and other optically active cyclic amines; 1,2-diphenyl-1,2-ethylenediamine, 1,2-dimethyl-1,2-diphenyl-1, Optically active diamines such as 2-ethylenediamine and 1,2-diaminocyclohexane; 3-aminopyrrolidine, 3-aminopiperidine, 2-methylpiperazine, 3-methylpiperazine, 2-phenylpiperazine, 3-phenylpiperazine, N-methyl -3-aminopyrrolidine, N-methyl-3-aminopi Optically active cyclic diamines such as peridine, 1-methyl-2-methylpiperazine, 1-methyl-3-methylpiperazine, 1-methyl-2-phenylpiperazine, 1-methyl-3-phenylpiperazine; prolinol, 1, Optically active amino alcohols such as 1-diphenylpyrrolidinemethanol, bis (3,5-ditrifluoromethylphenyl) pyrrolidinemethanol, ephedrine, norephedrine, 4-hydroxynorephedrine; alanine methyl ester, valine methyl ester, phenylalanine methyl ester, Examples include optically active amino acid esters such as dimethyl aspartate, proline methyl ester, 4-hydroxyproline methyl ester, and the following formula (2):

The optically active amine represented by these is mentioned.

Here, R ¹ represents a C1-C12 alkyl group, a C3-C12 cycloalkyl group, or a C7-C12 aralkyl group. These may have one or more substituents. Examples of the substituent include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom; hydroxyl group; alkoxy group such as methoxy group and ethoxy group; methylthio group; trifluoromethyl group; acetyl group; A nitro group; a carboxyl group; an alkoxycarbonyl group such as a methoxycarbonyl group and an ethoxycarbonyl group;

Specific examples of R ¹ include methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, cyclobutyl group, and n-pentyl. Group, cyclohexyl group, benzyl group and the like. A methyl group or an ethyl group is preferable, and a methyl group is more preferable.

R ² is a hydrogen atom, a C1-C12 alkyl group, a C3-C12 cycloalkyl group, a C7-C12 aralkyl group, a C2-C12 alkenyl group, a hydroxyl group, a C1-C12 alkyloxy group, a C3-C12 cyclohexane. An alkyloxy group, a C7 to C12 aralkyloxy group, a C2 to C12 alkenyloxy group, or a C6 to C12 aryloxy group is represented. These may have one or more substituents. Examples of the substituent include the same as those for R ¹ .

Specific examples of R ² include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a t-butyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, and a vinyl group. Allyl group, methallyl group, benzyl group, p-methylbenzyl group, p-chlorobenzyl group, p-methyloxybenzyl group, p-nitrobenzyl group, 3,4-dichlorobenzyl group, 1-phenethyl group, hydroxyl group, Methyloxy group, ethyloxy group, n-propyloxy group, isopropyloxy group, n-butyloxy group, isobutyloxy group, t-butyloxy group, cyclopropyloxy group, cyclopentyloxy group, cyclohexyloxy group, vinyloxy group, allyloxy group, Methallyloxy group, benzyloxy group, 1-phenethyloxy Group, and the like.

R ² is preferably a hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, cyclopropyl group, vinyl group, allyl group, benzyl group, p -Methylbenzyl group, p-chlorobenzyl group, p-methyloxybenzyl group, p-nitrobenzyl group, 3,4-dichlorobenzyl group, 1-phenethyl group, hydroxyl group, methyloxy group, ethyloxy group, n-propyloxy Group, isopropyloxy group, n-butyloxy group, isobutyloxy group, t-butyloxy group, cyclopropyloxy group, vinyloxy group, allyloxy group, or benzyloxy group, more preferably hydrogen atom, methyl group, ethyl group, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, cycl Propyl group, vinyl group, allyl group, benzyl group, p-methylbenzyl group, p-chlorobenzyl group, p-methyloxybenzyl group, p-nitrobenzyl group, 3,4-dichlorobenzyl group, or 1-phenethyl group And particularly preferably a hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, vinyl group, allyl group, benzyl group, p-methylbenzyl group, p-chlorobenzyl group, p- A methyloxybenzyl group, a p-nitrobenzyl group, a 3,4-dichlorobenzyl group, or a 1-phenethyl group, particularly preferably a hydrogen atom, a p-methylbenzyl group, or a p-methyloxybenzyl group.

In addition, R ¹ and R ² may be bonded to form an optically active amine to form a cyclic amine. Specifically, R ¹ and R ² bonded to each other may be a methylene group, an ethylene group, or a propylene group. And a butylene group. A propylene group is preferred.

Ar represents a C6-C12 aryl group, and may have one or more substituents. Examples of the substituent include the same as those for R ¹ .

  Specific examples of Ar include a phenyl group, p-methylphenyl group, p-chlorophenyl group, p-methoxyphenyl group, p-nitrophenyl group, 3,5-bis (trifluoromethyl) phenyl group, 1- A naphthyl group, 2-naphthyl group, etc. are mentioned. A phenyl group, a p-methylphenyl group, a p-chlorophenyl group, a p-methoxyphenyl group, or a p-nitrophenyl group is preferable, and a phenyl group is more preferable.

  * Represents an asymmetric carbon atom.

  The optically active amine is preferably the compound (2), more preferably (S) -1-phenethylamine, N-benzyl- (S) -1-phenethylamine, N- (p-methylbenzyl)-(S ) -1-phenethylamine or N- (p-methyloxybenzyl)-(S) -1-phenethylamine, particularly preferably N- (p-methyloxybenzyl)-(S) -1-phenethylamine.

  When the compound (2) is used as an optically active amine, the optically active cis-2-carbamoyl-cyclohexanecarboxylic acid derivative that is a product of this step is represented by the following formula (3):

It is represented by Here, R ¹ , R ² , Ar, * are the same as described above.

  The optically active cis-2-carbamoyl-cyclohexanecarboxylic acid derivative is preferably (1S, 2R) -cis-2-carbamoyl-cyclohexanecarboxylic acid / (S) -1-phenethylamine salt, (1S, 2R) -cis- 2-carbamoyl-cyclohexanecarboxylic acid / (S) -N- (p-methylbenzyl) -1-phenethylamine salt or (1S, 2R) -cis-2-carbamoyl-cyclohexanecarboxylic acid / (S) -N- ( p-methyloxybenzyl) -1-phenethylamine salt, more preferably (1S, 2R) -cis-2-carbamoyl-cyclohexanecarboxylic acid / (S) -1-phenethylamine salt, (1S, 2R) -cis- 2-carbamoyl-cyclohexanecarboxylic acid / (S) -N- (p-methylbenzyl) -1 Phenethylamine salt or (1S, 2R) -cis-2-carbamoyl-cyclohexanecarboxylic acid / (S) -N- (p-methyloxybenzyl) -1-phenethylamine salt, particularly preferably (1S, 2R)- Cis-2-carbamoyl-cyclohexanecarboxylic acid / (S) -N- (p-methyloxybenzyl) -1-phenethylamine salt.

  Subsequently, the optically active cis-2-carbamoyl-cyclohexanecarboxylic acid derivative is formed by forming a salt from the racemic-cis-2-carbamoyl-cyclohexanecarboxylic acid represented by the formula (1) and the optically active amine. A method of depositing as a solid from a solvent will be described.

  The upper limit of the amount of the optically active amine is preferably 5 moles, more preferably 3 moles, and particularly preferably 2 moles relative to 1 mole of the compound (1). Preferably as a minimum, it is 0.02 mol with respect to 1 mol of said compounds (1), More preferably, it is 0.05 mol, Especially preferably, it is 0.1 mol.

  For precipitation of the solid, for example, the compound (1) and the optically active amine are mixed in a solvent as in the solid precipitation methods (a) to (e) described later.

  Although there is no restriction | limiting in particular as a solvent to be used, Specifically, for example, water; Alcohol solvents, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, ethylene glycol; Ethyl acetate, n-acetate Ester solvents such as propyl and isopropyl acetate; Ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl t-butyl ether, diisopropyl ether and ethylene glycol dimethyl ether; Ketone solvents such as acetone and methyl ethyl ketone; Acetonitrile, Pro Nitrile solvents such as pionitrile; aromatic hydrocarbon solvents such as benzene, toluene and xylene; aliphatic hydrocarbon solvents such as pentane, hexane, heptane, cyclohexane and methylcyclohexane; Halogen solvents such as tylene, 1,2-dichloroethane, chlorobenzene; sulfoxide solvents such as dimethyl sulfoxide; amide solvents such as N, N-dimethylformamide and N, N-dimethylacetamide; urea solvents such as dimethylpropylene urea A phosphonic acid triamide solvent such as hexamethylphosphonic acid triamide can be used. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited.

  Preferably, water; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, ethylene glycol; ester solvents such as ethyl acetate, n-propyl acetate, isopropyl acetate; tetrahydrofuran, diethyl Ether solvents such as ether, 1,4-dioxane, methyl t-butyl ether, diisopropyl ether and ethylene glycol dimethyl ether; ketone solvents such as acetone and methyl ethyl ketone; nitrile solvents such as acetonitrile and propionitrile; benzene, toluene and xylene Aromatic hydrocarbon solvents such as pentane, hexane, heptane, cyclohexane, methylcyclohexane, etc .; methylene chloride, 1,2-dichloroethane, chloroform A halogen-based solvent such as Zen; more preferably water; alcohol-based solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, ethylene glycol; tetrahydrofuran, diethyl ether, 1,4-dioxane Ether solvents such as methyl t-butyl ether, diisopropyl ether and ethylene glycol dimethyl ether; ketone solvents such as acetone and methyl ethyl ketone; nitrile solvents such as acetonitrile and propionitrile, particularly preferably water, ethanol, tetrahydrofuran and acetonitrile. Or acetone, particularly preferably ethanol.

  If the amount of the solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore the upper limit is preferably 100 parts by weight, more preferably 50 parts by weight with respect to 1 part by weight of the compound (1). Particularly preferred is 20 parts by weight. Preferably as a minimum, it is 0.1 weight part with respect to 1 weight part of said compound (1), More preferably, it is 0.5 weight part, Especially preferably, it is 1 weight part.

The method for depositing the optically active cis-2-carbamoyl-cyclohexanecarboxylic acid derivative of the present invention as a solid is not particularly limited, and examples thereof include the following methods.
(A) A method of precipitating a solid by mixing the compound (1) and the optically active amine in the solvent.
(B) A method in which the compound (1) and the optically active amine are mixed in the solvent and then cooled to precipitate a solid.
(C) A method in which the compound (1) and the optically active amine are mixed in the solvent and then concentrated to precipitate a solid.
(D) A method in which a solid is precipitated by adding a poor solvent after mixing the compound (1) and the optically active amine in the solvent.
(E) A method in which a solid is precipitated by mixing the compound (1) and the optically active amine in the solvent and then concentrating and replacing with a poor solvent.

  Further, solids may be precipitated by appropriately combining the methods (a) to (e). Further, when the solid is precipitated, a seed solid may be added.

  Examples of the poor solvent used in the methods (d) and (e) include isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl t-butyl ether, diethyl ether, acetone, methyl ethyl ketone, acetonitrile, toluene, methylene chloride, 1,2- Examples include dichloroethane, chlorobenzene, hexane, heptane, cyclohexane, and methylcyclohexane.

  The implementation temperature in the method of precipitating the solids (a) to (e) is not particularly limited, and may be appropriately selected depending on the type of salt to be generated and the type of solvent to be used. Preferably, the temperature is set below the temperature at which the optically active cis-2-carbamoyl-cyclohexanecarboxylic acid derivative is dissolved in the solvent species or mixed solvent species to be used, depending on the target precipitation amount and solid quality.

  The optically active cis-2-carbamoyl-cyclohexanecarboxylic acid derivative deposited by the method of depositing the solids of (a) to (e) is separated and obtained by a method such as vacuum filtration, pressure filtration, or centrifugation. Can do. Further, when the mother liquor remains in the obtained solid and the solid enantiomeric excess (% ee) decreases, the quality can be improved by further washing with an organic solvent as necessary.

  There is no particular limitation on the method for drying the solid, but it is desirable to dry under reduced pressure (vacuum drying) at about 60 ° C. or less while avoiding thermal decomposition and melting.

  If the enantiomeric excess (% ee) is not improved sufficiently, it is again subjected to the method of precipitating any of the solids (a) to (e) or the optically active cis-2- The carbamoyl-cyclohexanecarboxylic acid derivative may be washed with a solvent, or a solid may be precipitated again by a method according to any one of the above (a) to (e).

  In addition, the said compound (3) obtained by this invention is a novel compound which has not been described in literature, and naturally it is not known that it becomes solid.

Process 2
The optically active cis-2-carbamoyl-cyclohexanecarboxylic acid derivative is an optically active cis-2-carbamoyl-cyclohexanecarboxylic acid represented by the above formula (4) having an improved enantiomeric excess (% ee) by salting. It can be obtained as an acid.

  As the salt-dissociation method, for example, the compound (5) can be prepared by adding an acid aqueous solution such as hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, citric acid to the optically active cis-2-carbamoyl-cyclohexanecarboxylic acid derivative. The compound (5), which has been released by freeing the solvent, is collected by filtration, or the released compound (5) is extracted using an organic solvent such as ethyl acetate, toluene, methyl t-butyl ether, and the extraction solvent is distilled off under reduced pressure. The method of leaving is mentioned. Preferably, it is a method of collecting the solid of the compound (5) precipitated by liberation.

Process 3
In this step, the carbamoyl group of the compound (4) is converted to produce an optically active cis-2-amino-cyclohexanecarboxylic acid derivative represented by the formula (5) or a salt thereof.

  Here, * is the same as described above.

R ³ represents a hydrogen atom, a C2 to C12 alkyloxycarbonyl group, a C8 to C12 aralkyloxycarbonyl group, or a C7 to C12 aryloxycarbonyl group. These may have one or more substituents. Examples of the substituent include the same as those for R ¹ .

Specific examples of R ³ include hydrogen atom, methyloxycarbonyl group, ethyloxycarbonyl group, n-propyloxycarbonyl group, isopropyloxycarbonyl group, n-butyloxycarbonyl group, isobutyloxycarbonyl group, s-butyloxycarbonyl group. Group, t-butyloxycarbonyl group, n-pentyloxycarbonyl group, benzyloxycarbonyl group, phenyloxycarbonyl and the like. Preferably a hydrogen atom, methyloxycarbonyl group, ethyloxycarbonyl group, n-propyloxycarbonyl group, isopropyloxycarbonyl group, n-butyloxycarbonyl group, isobutyloxycarbonyl group, t-butyloxycarbonyl group, or benzyloxycarbonyl More preferably a hydrogen atom, a methyloxycarbonyl group, an ethyloxycarbonyl group, a t-butyloxycarbonyl group, or a benzyloxycarbonyl group, and particularly preferably a hydrogen atom.

  The compound (5) is preferably (1S, 2R) -cis-2-amino-cyclohexanecarboxylic acid, (1S, 2R) -cis-2- (methyloxycarbonylamino) -cyclohexanecarboxylic acid, (1S, 2R) ) -Cis-2- (ethyloxycarbonylamino) -cyclohexanecarboxylic acid, (1S, 2R) -cis-2- (n-propyloxycarbonylamino) -cyclohexanecarboxylic acid, (1S, 2R) -cis-2- (Isopropyloxycarbonylamino) -cyclohexanecarboxylic acid, (1S, 2R) -cis-2- (n-butyloxycarbonylamino) -cyclohexanecarboxylic acid, (1S, 2R) -cis-2- (isobutyloxycarbonylamino) -Cyclohexanecarboxylic acid, (1S, 2R) -cis-2- (t-butyl) Oxycarbonylamino) -cyclohexanecarboxylic acid or (1S, 2R) -cis-2- (benzyloxycarbonylamino) -cyclohexanecarboxylic acid, more preferably (1S, 2R) -cis-2-amino-cyclohexanecarboxylic acid Acid, (1S, 2R) -cis-2- (methyloxycarbonylamino) -cyclohexanecarboxylic acid, (1S, 2R) -cis-2- (ethyloxycarbonylamino) -cyclohexanecarboxylic acid, (1S, 2R)- Cis-2- (t-butyloxycarbonylamino) -cyclohexanecarboxylic acid or (1S, 2R) -cis-2- (benzyloxycarbonylamino) -cyclohexanecarboxylic acid, particularly preferably (1S, 2R)- Cis-2-amino-cyclohexanecarboxylic acid.

  The method for converting the carbamoyl group of the compound (4) is not particularly limited. For example, a halogenating agent may be allowed to act on the compound (4) in the presence of a base.

  The base is not particularly limited. Specifically, for example, triethylamine, tri-n-butylamine, N-methylmorpholine, N-methylpiperidine, diisopropylethylamine, pyridine, N, N-dimethylaminopyridine, 1,4 -Tertiary amines such as diazabicyclo [2,2,2] octane; Alkali alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide; lithium hydroxide, sodium hydroxide, potassium hydroxide, hydroxide Examples thereof include metal hydroxides such as barium and magnesium hydroxide; metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. Preferably triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydroxide, potassium carbonate, or sodium bicarbonate, more preferably triethylamine, sodium methoxide, sodium ethoxide, sodium hydroxide, Or it is potassium carbonate, Especially preferably, it is sodium hydroxide.

  As the amount of the base used, if it is too large, it is not preferable in terms of cost and post-treatment, so the upper limit is preferably 15 moles, more preferably 10 moles, more preferably 10 moles, especially 1 mole of the compound (4). Preferably it is 7 mol. The lower limit is preferably 0.5 mol, more preferably 1 mol, and particularly preferably 1.5 mol with respect to 1 mol of the compound (4).

  The halogenating agent is not particularly limited, and specifically, for example, sodium hypochlorite, potassium hypochlorite, sodium hypobromite, potassium hypobromite, chlorine, bromine, iodine, N -Chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, N-chloroisocyanuric acid and the like. Preferably sodium hypochlorite, potassium hypochlorite, sodium hypobromite, potassium hypobromite, bromine, N-chlorosuccinimide, or N-bromosuccinimide, more preferably sodium hypochlorite, Sodium hypobromite, bromine, or N-bromosuccinimide, particularly preferably sodium hypochlorite.

  The halogenating agent may be prepared in the system. For example, a sodium hypobromite methanol solution can be prepared by allowing bromine to act on sodium methoxide in a methanol solvent.

  An excessive amount of the halogenating agent is not preferable in terms of cost and post-treatment, so that the upper limit is preferably 10 mol, more preferably 7 mol, per 1 mol of the compound (4). Particularly preferred is 5 moles. The lower limit is preferably 0.02 mol, more preferably 0.05 mol, and particularly preferably 0.1 mol with respect to 1 mol of the compound (4).

  The solvent is not particularly limited as long as it does not affect the reaction. Specifically, for example, water; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, and ethylene glycol Solvent; ester solvents such as ethyl acetate, n-propyl acetate, isopropyl acetate; ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl t-butyl ether, diisopropyl ether, ethylene glycol dimethyl ether; acetone, methyl ethyl ketone, etc. Ketone solvents; nitrile solvents such as acetonitrile and propionitrile; aromatic hydrocarbon solvents such as benzene, toluene and xylene; pentane, hexane, heptane, cyclohexane, methylcyclohexane Aliphatic hydrocarbon solvents; halogen solvents such as methylene chloride, 1,2-dichloroethane and chlorobenzene; sulfoxide solvents such as dimethyl sulfoxide; amide solvents such as N, N-dimethylformamide and N, N-dimethylacetamide A urea solvent such as dimethylpropylene urea; a phosphonic acid triamide solvent such as hexamethylphosphonic acid triamide can be used. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited.

  Preferably, water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, benzyl alcohol, ethylene glycol, tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl t-butyl ether, diisopropyl ether, Or ethylene glycol dimethyl ether, more preferably water, methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, benzyl alcohol, tetrahydrofuran, methyl t-butyl ether, or ethylene glycol dimethyl ether, particularly preferably. Water, methanol, ethanol, t-butanol, benzyl alcohol, or tetrahydrofuran, particularly preferably water A.

  If the amount of the solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore the upper limit is preferably 100 parts by weight, more preferably 50 parts by weight with respect to 1 part by weight of the compound (4). Particularly preferred is 20 parts by weight. The lower limit is preferably 0.1 parts by weight, more preferably 0.5 parts by weight, and particularly preferably 1 part by weight with respect to 1 part by weight of the compound (4).

  The reaction temperature in this reaction is not particularly limited and may be set as appropriate. However, in order to reduce the production of by-products, the upper limit is preferably 200 ° C., more preferably 150 ° C., and particularly preferably 100 ° C. The lower limit is preferably −50 ° C., more preferably −30 ° C., and particularly preferably −10 ° C.

  The reaction time in this reaction is not particularly limited and may be set as appropriate. The upper limit is preferably 120 hours, more preferably 100 hours, and particularly preferably 80 hours. The lower limit is preferably 0.001 hour, more preferably 0.01 hour, and particularly preferably 0.1 hour.

  There is no restriction | limiting in particular about the mixing order of the said compound (4), a base, a halogenating agent, and a solvent.

  What is necessary is just to perform the general process for acquiring a product from a reaction liquid as a process after reaction. For example, the reaction solution after completion of the reaction is subjected to an extraction operation using water, a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane and the like. When the reaction solvent and the extraction solvent are distilled off from the resulting extract by an operation such as heating under reduced pressure, the desired product is obtained. The target product obtained in this way has sufficient purity that can be used in the subsequent steps, but for the purpose of further increasing the purity, crystallization, fractional distillation, inversion cleaning (by salt formation and salt removal). The purity may be further increased by a general purification method such as a washing method using movement of a compound between an organic layer and an aqueous layer), column chromatography, or a method of precipitating a solid from a solvent.

  In addition, the solid manufactured by this invention represents a crystal | crystallization, an amorphous, or those mixtures, The mixing ratio is arbitrary, All shall be contained in the scope of the present invention.

  Hereinafter, the present invention will be described in more detail with reference to examples, but these examples do not limit the present invention in any way.

The purity of the cis-2-carbamoyl-cyclohexanecarboxylic acid derivative and cis-2-amino-cyclohexanecarboxylic acid derivative described in the examples was analyzed by the following HPLC method.
In the following, “wt%” which is a title of purity means wt%.

[ Chemical purity analysis method and content analysis method (gradient HPLC method) ]
Column: Nacalai Tesque {Cosmocil 5C18 ARII 4.6 mm × 250 mm}
Mobile phase A: 0.1% phosphoric acid aqueous solution, mobile phase B: acetonitrile (mobile phase A / mobile phase B = 90/10 to 40/60) (volume ratio)
Flow rate: 1.0 ml / min
Detection: UV 210nm
Column temperature: 40 ° C
Retention time:
Cis-2-carbamoyl-cyclohexanecarboxylic acid: 8.6 minutes The optical purity of the optically active cis-2-carbamoyl-cyclohexanecarboxylic acid was analyzed by the following HPLC method.

[ Optical purity analysis method (Isocratech HPLC method) ]
Column: Daicel Chemical Industries, Ltd. {CHIRALCEL OJ-H 4.6 mm x 250 mm}
Mobile phase: hexane / isopropanol / trifluoroacetic acid = 90/10 / 0.5 (volume ratio)
Flow rate: 0.3 ml / min
Detection: UV 210nm
Column temperature: 25 ° C
Retention time:
(1R, 2S) -2-carbamoyl-cyclohexanecarboxylic acid: 32.5 minutes (1S, 2R) -2-carbamoyl-cyclohexanecarboxylic acid: 34.1 minutes

Reference Example 1 Production of racemic-cis-2-carbamoyl-cyclohexanecarboxylic acid

A solution consisting of 25.00 g (162 mmol) of cis-cyclohexanedicarboxylic anhydride and 25.00 g of tetrahydrofuran (THF) was added dropwise to 110.46 g (1.62 mol) of 25 wt% aqueous ammonia at 5 ° C. After stirring at 5 ° C. for 2 hours, the reaction solution was concentrated under reduced pressure to 41.67 g, and 93.79 g of distilled water was added. When this solution was cooled to 5 ° C. and 15.54 g (149 mmol) of concentrated hydrochloric acid was added, a solid was precipitated and further stirred at 5 ° C. for 1 hour. The solid was filtered off under reduced pressure, washed with 150 ml of distilled water, and vacuum dried to obtain the title compound as a white solid 25.93 g (yield 92%, purity 98.4 wt%).
Title compound:
¹ H-NMR (DMSO-d6): δ (ppm) 1.62 (m, 8H), 2.56 (m, 2H), 6.71 (s, 1H), 7.12 (s, 1H), 11.89 (s, 1H)

Example 1 Production of (1S, 2R) -cis-2-carbamoyl-cyclohexanecarboxylic acid / (S) -1-phenethylamine salt

To 171 mg (1.0 mmol) of the racemic cis-2-carbamoyl-cyclohexanecarboxylic acid produced in Reference Example 1, 0.77 g of THF and 0.77 g of distilled water were added. When 121 mg (1.0 mmol) of (S) -1-phenethylamine was added to this solution, a solid was precipitated and further stirred at 25 ° C. for 16 hours. The solid was filtered off under reduced pressure, washed with 0.5 ml of ethanol and dried in vacuo to give 194 mg of the title compound as a white solid (yield 23%, optical purity 11.7% ee). That is, (1S, 2R) -cis-2-carbamoyl-cyclohexanecarboxylic acid contained in 171 mg of the crude product was 85 mg, of which 59 mg was recovered in the crystals (recovery rate 69%).
Title compound:
¹ H-NMR (DMSO-d6): δ (ppm) 1.60 (m, 11H), 2.54 (m, 2H), 4.01 (m, 1H), 6.68 (s, 1H), 7.20 (m, 1H), 7.33, (m, 5H)

Examples 2 to 13 Production of (1S, 2R) -cis-2-carbamoyl-cyclohexanecarboxylic acid / (S) -1-phenethylamine salt

  The same reaction operation was carried out except that the solvent (THF) of Example 1 was replaced with the solvent represented below and the stirring time was changed.

Example 14 Production of (1S, 2R) -cis-2-carbamoyl-cyclohexanecarboxylic acid / (S) -N- (p-methyloxybenzyl) -1-phenethylamine salt

To 2.00 g (11.7 mmol) of the racemic cis-2-carbamoyl-cyclohexanecarboxylic acid produced in Reference Example 1, 8.00 g of ethanol was added. When 2.26 g (9.4 mmol) of (S) -N- (p-methyloxybenzyl) -1-phenethylamine was added to this solution, a solid was precipitated and further stirred at 25 ° C. for 39 hours. The solid was filtered off under reduced pressure, washed with 2.0 ml of ethanol and dried in vacuo to give the title compound as a white solid 2.26 g (yield 47%, optical purity 47.2% ee). That is, 1.00 g of (1S, 2R) -cis-2-carbamoyl-cyclohexanecarboxylic acid contained in 2.00 g of the crude product was recovered, and 692 mg of this was recovered in the crystals (recovery rate 69%).
Title compound:
¹ H-NMR (DMSO-d6): δ (ppm) 1.60 (m, 11H), 2.56 (m, 2H), 3.41 (m, 2H), 3.66 (m, 1H), 3.72 (s, 3H), 7.03 (m, 11H)

Examples 15 to 17 Production of (1S, 2R) -cis-2-carbamoyl-cyclohexanecarboxylic acid / (S) -N- (p-methyloxybenzyl) -1-phenethylamine salt

  The same reaction operation was carried out except that the solvent (ethanol) of Example 14 was replaced with the solvent represented below and the amount of the solvent and the stirring time were changed.

Example 18 Production of (1S, 2R) -cis-2-carbamoyl-cyclohexanecarboxylic acid / (S) -N- (p-methyloxybenzyl) -1-phenethylamine salt

  To 500 mg of the solid containing (1S, 2R) -cis-2-carbamoyl-cyclohexanecarboxylic acid / (S) -N- (p-methyloxybenzyl) -1-phenethylamine salt prepared in Example 14, 1.10 g of ethanol was added. Was added. When heated to 70 ° C., the crystals dissolved and further stirred at 70 ° C. for 1 hour. As the reaction solution was cooled, crystals were precipitated at approximately 50 ° C., and further stirred at 50 ° C. for 0.5 hour, and then stirred at 25 ° C. for 1 hour. The solid was filtered off under reduced pressure, washed with 0.5 ml of ethanol and dried in vacuo to give the title compound as a white solid 283 mg (yield 57%, optical purity 100% ee).

Example 19 Production of (1S, 2R) -cis-2-carbamoyl-cyclohexanecarboxylic acid / (S) -N- (p-methylbenzyl) -1-phenethylamine salt

To 172 mg (1.0 mmol) of cis-2-carbamoyl-cyclohexanecarboxylic acid produced in Reference Example 1, 1.54 g of ethanol was added. When (S) -N- (p-methylbenzyl) -1-phenethylamine (203 mg, 0.9 mmol) was added to this solution, a solid was precipitated and further stirred at 25 ° C. for 38 hours. The solid was filtered off under reduced pressure, washed with ethanol (0.3 ml), and dried in vacuo to give the title compound as a white solid (121 mg, yield 30%, optical purity 29.9% ee). That is, 86 mg of (1S, 2R) -cis-2-carbamoyl-cyclohexanecarboxylic acid contained in 172 mg of the crude product was recovered, of which 34 mg was recovered in the crystals (recovery rate 40%).
Title compound:
¹ H-NMR (DMSO-d6): δ (ppm) 1.60 (m, 11H), 2.26 (s, 3H), 2.56 (m, 2H), 3.43 (m, 2H), 3.66 (m, 1H), 6.72 (s, 1H), 7.12 (m, 5H), 7.22 (m, 1H), 7.33 (m, 4H)

Example 20 Production of (1S, 2R) -cis-2-carbamoyl-cyclohexanecarboxylic acid

  To 206 mg (0.5 mmol) of the solid containing (1S, 2R) -cis-2-carbamoyl-cyclohexanecarboxylic acid / (S) -N- (p-methyloxybenzyl) -1-phenethylamine salt prepared in Example 18 1.00 g of distilled water was added. When 78 mg (0.8 mmol) of concentrated hydrochloric acid was added thereto, a solid was precipitated and further stirred at 25 ° C. for 30 minutes. The solid was filtered off under reduced pressure, washed with 0.5 ml of distilled water, and dried in vacuo to give the title compound as a white solid 86 mg (yield 100%, optical purity 100% ee).

Example 21 Production of (1S, 2R) -cis-2-amino-cyclohexanecarboxylic acid

To 24 mg (0.14 mmol) of (1S, 2R) -cis-2-carbamoyl-cyclohexanecarboxylic acid produced by the production method described in Example 20, 170 mg of distilled water was added and cooled to 5 ° C. A 30 wt% aqueous sodium hydroxide solution (54 mg, 0.41 mmol) and a 13.5 wt% aqueous sodium hypochlorite solution (89 mg, 0.16 mmol) were added, and the mixture was stirred at 5 ° C. for 1 hour, and further stirred at 25 ° C. for 3 hours. The reaction solution was added dropwise to 605 mg (5.8 mmol) of concentrated hydrochloric acid at 5 ° C. and stirred at 25 ° C. for 1 hour. The reaction solution was adjusted to pH 7 with a 30 wt% aqueous sodium hydroxide solution and concentrated under reduced pressure. The concentrate was purified with an ion exchange resin column and vacuum dried to obtain 13 mg of the title compound (yield 66%).
¹ H-NMR (DMSO-d6): δ (ppm) 1.30-1.85 (m, 8H), 2.30 (m, 1H), 3.17 (m, 1H)

(Example 22)
The X-ray analysis spectrum of the (1S, 2R) -cis-2-carbamoyl-cyclohexanecarboxylic acid / (S) -N- (p-methyloxybenzyl) -1-phenethylamine salt prepared in Example 18 is shown in FIG. .

2θ is about 6.3 °, 9.2 °, 9.8 °, 12.7 °, 15.3 °, 16.6 °, 18.3 °, 18.7 °, 18.8 °, 19. At 0 °, 20.2 °, 21.3 °, 21.7 °, 25.1 °, and 29.9 °, unique peaks are observed in XRD, and in particular, 2θ is about 6.3 °, 9 .2 °, 9.8 °, 12.7 °, 15.3 °, 16.6 °, 18.3 °, 19.0 °, 20.2 °, 21.3 °, 21.7 °, and The peak at 25.1 ° is prominent, especially 2θ is about 6.3 °, 9.2 °, 9.8 °, 12.7 °, 15.3 °, 16.6 °, 20.2 °. Peaks at 21.7 ° and 25.1 ° were most prominent. From this result, it was suggested that the solid had a crystal structure.
X-ray powder analyzer: MiniFlex-ll manufactured by Rigaku Corporation
Measurement conditions: CuKα ₁ wire
Tube voltage 30 kV
Current between 15 mA

Claims (8)

Following formula (1):
An optically active cis-2-carbamoyl-cyclohexane characterized by forming a salt from an optically active amine and a racemic-cis-2-carbamoyl-cyclohexanecarboxylic acid represented by the formula: A method for producing a carboxylic acid derivative. The optically active amine is represented by the following formula (2):
(In the formula, R ¹ represents an alkyl group having Cl -C 12, cycloalkyl group of C3-C12, or .R ² in which an aralkyl group C7~C12 a hydrogen atom, an alkyl group having Cl -C 12, cycloalkyl of C3-C12 Alkyl group, C7-C12 aralkyl group, C2-C12 alkenyl group, hydroxyl group, C1-C12 alkyloxy group, C3-C12 cycloalkyloxy group, C7-C12 aralkyloxy group, C2-C12 alkenyloxy A C6 to C12 aryloxy group, R ¹ and R ² may be combined to form a ring, Ar represents a C6 to C12 aryl group, and * represents an asymmetric carbon atom. The optically active cis-2-carbamoyl-cyclohexanecarboxylic acid derivative is represented by the following formula (3):
(Wherein, R ¹ , R ² , Ar, * are the same as defined above). The production method according to claim 1 or 2, wherein R ¹ is a methyl group, R ² is a hydrogen atom, a p-methylbenzyl group, or a p-methyloxybenzyl group, and Ar is a phenyl group. The following formula (4) in which optical purity is improved by salting out the compound (3):
4. The production method according to claim 2, wherein an optically active cis-2-carbamoyl-cyclohexanecarboxylic acid represented by (wherein * is the same as defined above) is produced. By converting the carbamoyl group of the compound (4), the following formula (5):
(Wherein R ³ represents a hydrogen atom, a C2 to C12 alkyloxycarbonyl group, a C8 to C12 aralkyloxycarbonyl group, or a C7 to C12 aryloxycarbonyl group. * Is the same as above). The production method according to claim 4, comprising a step of forming an optically active cis-2-amino-cyclohexanecarboxylic acid derivative or a salt thereof. Following formula (3):
(In the formula, R ¹ represents an alkyl group having Cl -C 12, cycloalkyl group C3-C12, or .R ² in which an aralkyl group C7~C12 a hydrogen atom, an alkyl group having Cl -C 12, cyclo C3-C12 Alkyl group, C7 to C12 aralkyl group, C2 to C12 alkenyl group, hydroxyl group, C1 to C12 alkyloxy group, C1 to C12 cycloalkyloxy group, C7 to C12 aralkyloxy group, C2 to C12 alkenyloxy A C6 to C12 aryloxy group, R ¹ and R ² may be combined to form a ring, Ar represents a C6 to C12 aryl group, and * represents an asymmetric carbon atom. An optically active cis-2-carbamoyl-cyclohexanecarboxylic acid derivative represented by: R ¹ is a methyl group, R ² is a p-methyloxybenzyl group, Ar is a phenyl group, the absolute configuration of the asymmetric carbon atom bonded to R ¹ is S, and cis-2-carbamoyl- The optically active cis-2-carbamoyl-cyclohexanecarboxylic acid derivative according to claim 6, wherein the absolute configuration of the asymmetric carbon atom of cyclohexanecarboxylic acid is 1S, 2R.   Specific at 2θ = 6.3 °, 9.2 °, 9.8 °, 12.7 °, 15.3 °, 16.6 °, 20.2 °, 21.7 °, and 25.1 ° The optically active cis-2-carbamoyl-cyclohexanecarboxylic acid derivative according to claim 6 or 7, which has an X-ray powder analysis pattern showing a peak.