Method for producing 4-(aminomethyl)cyclohexanecarboxylic acid

Abstract

Provided is a method for efficiently producing 4-(aminomethyl)cyclohexane carboxylic acid with a low production cost.　According to the present invention, 4-(aminomethyl)cyclohexane carboxylic acid is obtained through synthesis using, as a raw material, 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexane carboxylate or a hydrolysis product thereof.

Description

[Technical field]

[0001] The present invention relates to a novel method for inexpensively and simply synthesizing 4-(aminomethyl)cyclohexanecarboxylic acid, which is useful as a functional chemical, particularly as a raw material for polyamide production, various polymer modifiers, and a raw material for polymerization reactions and pharmaceuticals. [Background technology]

[0002] 4-(Aminomethyl)cyclohexanecarboxylic acid is produced by going through numerous structural transformation steps using p-xylene and its oxidized compound terephthalic acid as raw materials.

[0003] When p-xylene is used as a starting material, a typical production method involves appropriately combining a step of oxidizing a methyl group to convert it to a carboxylic acid group or an aldehyde group, a step of reducing the aromatic ring to generate a cyclohexane ring, and, if necessary, a step of converting the cis / trans mixture of the generated cyclohexane ring into the desired geometric isomer (Patent Document 1, etc.).

[0004] These methods produce a large amount of by-product waste, use expensive precious metal catalysts, and require high temperature and pressure conditions under extreme liquid conditions such as strong acids or strong alkalis, resulting in high production costs and a large environmental impact, making them extremely inefficient from an industrial standpoint.

[0005] On the other hand, methods that do not have the drawbacks of the above-mentioned manufacturing methods have been reported as laboratory synthesis research. However, these methods use catalysts or reagents that are not suitable for industrial use, require special equipment, or have difficulty in obtaining starting materials, and therefore are not feasible for industrial mass production (Non-Patent Document 1, etc.).

[0006] Also known is a method for producing 4-(aminomethyl)cyclohexanecarboxylic acid, which comprises amminating one hydroxy group of trans-1,4-cyclohexanedimethanol and oxidizing the other hydroxymethyl group (Patent Document 2, etc.).

[0007] However, even with this production method, the regioselectivity of the two reactions, amination and oxidation, is poor, and the target compound cannot be obtained in high purity. As a result, there are limitations to obtaining inexpensive 4-(aminomethyl)cyclohexanecarboxylic acid.

[0008] For this reason, there has been a demand for the development of an efficient and cost-effective method for producing 4-(aminomethyl)cyclohexanecarboxylic acid. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] Japanese Patent Application Publication No. 58-32848 [Patent Document 2] Patent No. 3763598 [Non-patent literature]

[0010] [Non-Patent Document 1] Tetrahedron, 1958, vol. 3, 175p Summary of the Invention [Problem to be solved by the invention]

[0011] An object of the present invention is to provide a method for obtaining 4-(aminomethyl)cyclohexanecarboxylic acid at low cost. [Means for solving the problem]

[0012] In order to solve the above problems, the present inventors have conducted intensive research and have found a novel synthetic route for producing 4-(aminomethyl)cyclohexanecarboxylic acid using 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate or a hydrolysate thereof, thereby completing the present invention. That is, the present invention is achieved by the following means.

[0013] (1) The first invention of the present invention is a method for producing 4-aminomethylcyclohexanecarboxylic acid (2) from 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate (1) or a hydrolysate thereof, the method comprising the steps of converting a hydroxy group of 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate (1) to a primary amine precursor A to obtain an intermediate (1), and decomposing the intermediate (1), which is represented by the following formula 1.

[0014] [ka]

[0015] (2) The second invention of the present invention is a method for producing 4-aminomethylcyclohexanecarboxylic acid (2) from 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate (1) or a hydrolysate thereof, the method comprising the steps of: converting the hydroxy group of 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate (1) into primary amine precursor A to obtain intermediate (1); substituting primary amine precursor A of intermediate (1) with an amino group to obtain 4-(aminomethyl)cyclohexylmethyl 4'-(aminomethyl)cyclohexanecarboxylate; and decomposing 4-(aminomethyl)cyclohexylmethyl 4'-(aminomethyl)cyclohexanecarboxylate.

[0016] (3) The third invention of the present invention is a method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) from 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate (1) or a hydrolysate thereof, the method comprising the steps of converting a hydroxy group of 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate (1) to a primary amine precursor A to give intermediate (1) and hydrolyzing the intermediate (1) to substitute the primary amine precursor A of intermediate (1) with an amino group.

[0017] (4) A fourth aspect of the present invention is a method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) according to any one of (1) to (3), wherein the step of converting the hydroxy group into a primary amine precursor A is a step of converting the hydroxy group into a substitutable leaving group X, and then converting the leaving group X into a primary amine precursor A to which a nitrogen atom is bonded.

[0018] (5) A fifth aspect of the present invention is a method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) according to any one of (1) to (4), wherein the step of converting the hydroxy group into a primary amine precursor A is a step of converting the hydroxy group into a replaceable leaving group X and then substituting the leaving group X with an azide group.

[0019] (6) A sixth aspect of the present invention is a method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) according to any one of (1) to (4), wherein the step of converting the hydroxy group into a primary amine precursor A is a step of converting the hydroxy group into a replaceable leaving group X, and then substituting the leaving group X with hexamethylenetetramine.

[0020] (7) A seventh aspect of the present invention is a method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) according to any one of (1) to (4), wherein the step of converting the hydroxy group into a primary amine precursor A is a step of converting the hydroxy group into a replaceable leaving group X and then substituting the leaving group X with an imide group.

[0021] (8) An eighth aspect of the present invention is a method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) according to any one of (1), (4) to (7), wherein the step of decomposing the intermediate (1) includes hydrolyzing the intermediate (1) to obtain a mixture of a carboxylic acid derivative and an aminoalcohol derivative.

[0022] (8(A)) The invention of item 8(A) of the present invention is the method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) according to item (2), wherein the step of decomposing the 4-(aminomethyl)cyclohexylmethyl 4'-(aminomethyl)cyclohexanecarboxylate is a step of hydrolyzing the 4-(aminomethyl)cyclohexylmethyl 4'-(aminomethyl)cyclohexanecarboxylate.

[0023] (9) A ninth aspect of the present invention is a method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) according to (8), further comprising a step of converting a hydroxy group of the aminoalcohol derivative into a carboxy group.

[0024] (9(A)) The invention of the present invention 9(A) is a method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) according to (7), which comprises, after a step of hydrolyzing the intermediate (1), oxidizing an aminoalcohol derivative in a mixture of a carboxylic acid derivative and an aminoalcohol derivative to convert it into a carboxylic acid derivative.

[0025] (9(B)) The invention of the present invention 9(B) is a method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) according to (7), which comprises, after the step of hydrolyzing the intermediate (1), separating a carboxylic acid derivative and an aminoalcohol derivative from a mixture of the carboxylic acid derivative and the aminoalcohol derivative, and oxidizing the separated aminoalcohol derivative to obtain a carboxylic acid derivative.

[0026] (10) A tenth aspect of the present invention is a method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) according to any one of (1) to (4), wherein the step of converting the hydroxy group into a primary amine precursor A is a step of converting the hydroxy group into a replaceable leaving group X, and then substituting the leaving group X with an alkoxycarbonylamino group.

[0027] (11) The eleventh aspect of the present invention is a method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2a), which comprises converting a hydroxy group of 4-(hydroxymethyl)cyclohexanecarboxylic acid (1a), which is a hydrolysis product of 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate (1), into a primary amine, The method for converting the hydroxy group into a primary amine is a method in which the hydroxy group is converted into a replaceable leaving group X, and then the leaving group X is converted into a primary amino group with ammonia, or a method in which the leaving group X is replaced with a primary amine precursor A to which a nitrogen atom is bonded, and the primary amine precursor A is converted into a primary amine.

[0028] [ka]

[0029] (12) A twelfth aspect of the present invention is the method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2a) according to (11), wherein the method for converting the hydroxy group into a primary amine comprises converting the hydroxy group into a replaceable leaving group X, substituting the leaving group X with an azide group, and reducing the azide group to convert the azide group into the primary amine.

[0030] (13) A thirteenth aspect of the present invention relates to the method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2a) according to (11), in which the method for converting the hydroxy group into a primary amine comprises converting the hydroxy group into a replaceable leaving group X, substituting the leaving group X with hexamethylenetetramine, and decomposing the hexamethylenetetramine to convert into the primary amine.

[0031] (14) A fourteenth aspect of the present invention is the method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2a) according to (11), wherein the method for converting the hydroxy group into a primary amine comprises converting the hydroxy group into a replaceable leaving group X, substituting the leaving group X with an imide group, and reacting and treating the imide group with at least one selected from an acid, a base, a reducing agent, a hydrazine, and an alkylamine to convert the imide group into a primary amine.

[0032] (15) A fifteenth aspect of the present invention relates to the method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2a) according to (11), in which the method for converting the hydroxy group into a primary amine is a method in which the hydroxy group is converted into a substitutable leaving group X, the leaving group X is substituted with an alkoxycarbonylamino group, and the alkoxycarbonylamino group is hydrolyzed to convert the hydroxy group into a primary amine.

[0033] (16(A)) The invention 16(A) of the present invention is a method for producing trans-4-(aminomethyl)cyclohexanecarboxylic acid (2c), which comprises converting a hydroxy group of trans-4-(hydroxymethyl)cyclohexanecarboxylic acid (1c) into a replaceable leaving group X, substituting the leaving group X with an azide group, and reducing the azide group to convert it into a primary amine.

[0034] (17(A)) The invention of the present invention 17(A) is a method for producing trans-4-(aminomethyl)cyclohexanecarboxylic acid (2c), which comprises converting a hydroxy group of trans-4-(hydroxymethyl)cyclohexanecarboxylic acid (1c) into a replaceable leaving group X, substituting the leaving group X with hexamethylenetetramine, and converting the hexamethylenetetramine into a primary amine.

[0035] (18(A)) The 18(A) invention of the present invention is a method for producing trans-4-(aminomethyl)cyclohexanecarboxylic acid (2c), which comprises converting a hydroxy group of trans-4-(hydroxymethyl)cyclohexanecarboxylic acid (1c) into a replaceable leaving group X, imidizing the leaving group X, and reacting the imidized leaving group with at least one selected from an acid, a base, a reducing agent, a hydrazine, or an alkylamine to convert the imidized leaving group into a primary amine. Effect of the Invention

[0036] According to the first to tenth aspects of the present invention, 4-(aminomethyl)cyclohexanecarboxylic acid can be produced in large quantities inexpensively and simply. According to the inventions 11 to 15 and 16(A) to 18(A) of the present invention, 4-(aminomethyl)cyclohexanecarboxylic acid can be supplied in large quantities inexpensively and simply from 4-(hydroxymethyl)cyclohexylmethyl-4'-(hydroxymethyl)cyclohexanecarboxylic acid, which was previously a by-product. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] [Method for producing 4-(aminomethyl)cyclohexanecarboxylic acid using 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate as starting material] The present invention is described in detail below. The present invention is a method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (hereinafter, also simply referred to as "production method").

[0038] Specifically, the first production method according to the present invention is a method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) from 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate, and includes a step of converting a hydroxy group of 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate (1) into a primary amine precursor A to obtain an intermediate (1), and a step of decomposing the intermediate (1).

[0039] A second production method according to the present invention is a method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) from 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate, and includes the steps of converting the hydroxy group of 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate (1) into primary amine precursor A to obtain intermediate (1), substituting primary amine precursor A of intermediate (1) with an amino group to obtain 4-(aminomethyl)cyclohexylmethyl 4'-(aminomethyl)cyclohexanecarboxylate, and decomposing 4-(aminomethyl)cyclohexylmethyl 4'-(aminomethyl)cyclohexanecarboxylate.

[0040] In the first and second production methods according to the present invention, the starting material 4-(hydroxymethyl)cyclohexylmethyl-4'-(hydroxymethyl)cyclohexanecarboxylate is obtained as a by-product during the production of 1,4-cyclohexanedimethanol, which is supplied in extremely large quantities and stably and used as a modifier for general-purpose polymer materials such as polyesters.

[0041] Therefore, in the first and second production methods according to the present invention, by using 4-(hydroxymethyl)cyclohexylmethyl-4'-(hydroxymethyl)cyclohexanecarboxylate, which was previously a by-product as described above, as a starting material, 4-(aminomethyl)cyclohexanecarboxylic acid can be produced inexpensively and simply.

[0042] Here, 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate ((I) in the following reaction formula 3 is obtained as a by-product in the production of 1,4-cyclohexanedimethanol (hereinafter referred to as CHDM, (III) in the following reaction formula 3)) is hydrolyzed to obtain 4-hydroxymethylcyclohexanecarboxylic acid and CHDM. A specific production method thereof is disclosed in Japanese Patent No. 5372258. When the CHDM obtained by this method is used to produce 4-(aminomethyl)cyclohexanecarboxylic acid, it is necessary to convert one of the two equivalent hydroxymethyl groups into an aminomethyl group and the other into a carboxylic acid. However, the reaction selectivity of each substituent is naturally low, and it is extremely difficult to obtain 4-(aminomethyl)cyclohexanecarboxylic acid in high yield and high purity. [ka]

[0043] In contrast, according to the present invention, by taking advantage of the characteristic that 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate has two 2-substituted cyclohexane rings, two molecules of 4-(aminomethyl)cyclohexanecarboxylic acid can be produced in an inexpensive, simple and efficient manner from 2-substituted cyclohexane compounds having different substituents obtained by substituting hydroxy groups at both ends of one molecule of 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate with amino group derivatives and then decomposing the resulting compound.

[0044] <1> Regarding the first manufacturing method according to the present invention The first production method according to the present invention is a method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) from 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate (1), and includes a step <1-1> of converting a hydroxy group of 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate to a primary amine precursor A to form an intermediate (1), and a step <1-2> of decomposing the intermediate (1).

[0045] Regarding step <1-1> The first production method according to the present invention includes a step of converting the hydroxy group of 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate (1) into a primary amine precursor A to obtain an intermediate (1).

[0046] A specific example of a method for converting the hydroxy group of 4-(hydroxymethyl)cyclohexylmethyl-4'-(hydroxymethyl)cyclohexanecarboxylate to a primary amine precursor A is a reaction in which the hydroxy group is replaced with a replaceable leaving group X such as a halogen, an alkylsulfonyloxy, an arylsulfonyloxy, or a tosyl group, and then the replaceable leaving group X is replaced with a primary amine precursor A to which a nitrogen atom is bonded. In addition, examples of a reaction in which the replaceable leaving group X is replaced with a primary amine precursor A to which a nitrogen atom is bonded, and the primary amine precursor A is converted to a primary amine include a method in which an azidation reaction is followed by a reduction reaction, an imidation reaction is followed by a decomposition reaction, a decomposition reaction after substitution with hexamethylenetetramine, and a decomposition reaction after substitution with an alkoxycarbonylamino group, are carried out.

[0047] The term "substitutable leaving group X" means that the leaving group X can be substituted by a substituent. The leaving group X is not particularly limited as long as it can be substituted by a substituent. Specifically, it represents a halogen atom, an alkylsulfonyloxy group, or an arylsulfonyloxy group.

[0048] Here, the halogen atom means an element belonging to Group 7 in the periodic table, and at least one selected from fluorine, chlorine, bromine, and iodine is preferably used. Methods for substituting a hydroxyl group with a halogen atom include, for example, thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, phosphorus oxybromide, carbon tetrachloride / triphenylphosphine, carbon tetrabromide / triphenylphosphine, etc.

[0049] The alkyl in the alkylsulfonyloxy group is, but not limited to, C1 to C 20 Among them, those having at least one group selected from methyl, ethyl, or a C3 to C8 linear or branched alkyl group are preferably used. In addition, the aryl in the arylsulfonyloxy is not particularly limited, but may be any of C6 to 10 Examples of the aryl group include the above aryl groups. Among these, phenyl and toluyl groups are preferably used. As a method for substituting a hydroxyl group with a substitutable leaving group X such as halogen, alkylsulfonyloxy, arylsulfonyloxy, or tosyl group, for example, a method of reacting with a sulfonic acid chloride such as thionyl chloride, methanesulfonic acid chloride, benzenesulfonic acid chloride, or p-toluenesulfonic acid chloride (tosyl chloride) in a solvent such as acetonitrile or in the presence of a base such as pyridine or triethylamine without using a solvent is exemplified. The solvent used may be a polar aprotic solvent or a mixture of a plurality of polar aprotic solvents, and is industrially available.

[0050] As the base, both organic and inorganic bases can be used. For example, alkali metal alcoholates such as pyridine, triethylamine, potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, and sodium methoxy, and metal hydrides such as sodium hydride can be mentioned. In particular, pyridine and triethylamine are preferably used.

[0051] When the leaving group X is an alkylsulfonyloxy or arylsulfonyloxy group, it can undergo a substitution reaction with a halogen ion to form X = a halogen atom. Examples of halogen ions include fluorine ions (F - ), iodine ion (I - ), bromide ion (Br - ), chloride ion (Cl - ), but iodine ions are preferred. As compounds containing halogen ions, NaI, NaBr, NaCl, KI, KBr, KCl, CuI2, MgI2, etc. are preferably used. Thus, the substitution of sulfonyloxy groups with ions of halogen atoms is preferably carried out in the presence of a polar organic solvent, and the polar organic solvent that can be used in this case is not particularly limited, but for example, acetone, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide, and acetonitrile are preferably used.

[0052] In addition, the "primary amine precursor A" is not particularly limited as long as it contains a nitrogen atom that can be finally converted into a primary amine, and examples of the primary amine precursor A include an azide group, an imide group, a hexamethylenetetramine group, and an alkoxycarbonylamino group. Examples of the imide group include a succinimide group, a maleimide group, and a phthalimide group. Furthermore, examples of the primary amine precursor A include those in which the leaving group X is converted into a secondary amine, a tertiary amine, and the like.

[0053] Examples of a method for substituting the hydroxy group of 4-(hydroxymethyl)cyclohexanecarboxylic acid with a displaceable leaving group X such as halogen, alkylsulfonyloxy, arylsulfonyloxy, or tosyl include a method of reacting with a sulfonyl chloride such as thionyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride, or p-toluenesulfonyl chloride (tosyl chloride) in a solvent such as acetonitrile or in the presence of a base such as pyridine or triethylamine without using a solvent. The solvent used may be a polar aprotic solvent or a mixture of a plurality of polar aprotic solvents, and is industrially available.

[0054] Examples of polar aprotic solvents include amides, sulfoxides, ethers, nitriles, and mixtures thereof. Examples of solvents include N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, cyclopentyl methyl ether, anisole, tetrahydrofuran, acetonitrile, and mixtures thereof. Acetonitrile is particularly preferred.

[0055] As the base, both organic and inorganic bases can be used. For example, alkali metal alcoholates such as pyridine, triethylamine, potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, and sodium methoxy, and metal hydrides such as sodium hydride can be mentioned. In particular, pyridine and triethylamine are preferably used.

[0056] Methods for converting the replaceable leaving group X to the primary amine precursor A include a method of replacing the replaceable leaving group X with an azide, imide, hexamethylenetetramine, or alkoxycarbonylamino group, or a method of replacing the replaceable leaving group X with a secondary amine or tertiary amine.

[0057] A method for converting the displaceable leaving group X into an azide group includes, for example, reacting with a sulfonyl chloride such as methanesulfonyl chloride, benzenesulfonyl chloride, or p-toluenesulfonyl chloride (tosyl chloride) in a solvent such as acetonitrile or in the presence of a base such as triethylamine to form a sulfonate ester, followed by reaction with a suitable azide compound including, but not limited to, a metal azide such as sodium azide, lithium azide, zinc azide, tributyltin azide, aluminum azide, or trialkylsilyl azide.

[0058] Examples of the solvent used in the azidization method include alcohol solvents such as branched or straight-chain alcohols having carbon numbers of C1 to C4, such as methanol, ethanol, and isopropyl alcohol; aromatic hydrocarbon solvents such as toluene and xylene; ether solvents such as diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, and dioxane; aprotic polar solvents such as N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, and dimethylsulfoxide; and mixtures thereof.

[0059] An example of a method for imidizing the displaceable leaving group X to form an imide group is a method in which the hydroxy group of 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate (1) is substituted with the displaceable leaving group X, and then the imide is reacted in an aprotic solvent or without using a solvent.

[0060] Aprotic solvents include amides, sulfoxides, alcohol ethers, nitriles, and mixtures thereof. Examples of some specific solvents include aprotic polar solvents such as N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, and dimethylsulfoxide, alcohol solvents such as branched or straight-chain C1 to C4 alcohols such as methanol, ethanol, and isopropyl alcohol, cyclopentyl methyl ether, tetrahydrofuran, and acetonitrile, and mixtures thereof. Dimethylformamide is particularly preferably used.

[0061] As the imide, succinimide, maleimide, phthalimide, etc. can be used. The succinimide, maleimide, or phthalimide may have a succinimide, maleimide, or phthalimide skeleton, and includes, for example, phthalimide, 4,5-dichlorophthalimide, 4-nitrophthalimide, 3-acetyloxysuccinimide, tetramethylsuccinimide, hexahydrophthalimide, maleimide, 2,3-dimethylmaleimide, succinimide derivatives, maleimide derivatives, and phthalimide derivatives. In addition, the succinimide, maleimide, or phthalimide also includes salt forms such as sodium salts and potassium salts. In particular, the potassium salt of phthalimide is preferably used from the viewpoint of reactivity.

[0062] As a method for substituting the displaceable leaving group X with hexamethylenetetramine, for example, the hydroxy group of 4-(hydroxymethyl)cyclohexanecarboxylic acid is substituted with a halogen atom. Examples of the substitution method include thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, phosphorus oxybromide, carbon tetrachloride / triphenylphosphine, carbon tetrabromide / triphenylphosphine, etc. After the substitution with a halogen atom, a method of reacting with hexamethylenetetramine in a polar solvent or without a solvent is exemplified. As the halogen atom, iodine is preferably used from the viewpoint of reactivity in the substitution reaction with hexamethylenetetramine. When the substituent is other than iodine, it may be substituted with chlorine, bromine, alkylsulfonyloxy, or arylsulfonyloxy group with sodium iodide or the like.

[0063] The polar solvent is not particularly limited as long as it is inactive in the reaction of the present invention, and examples thereof include halogen-based solvents such as chloroform and methylene chloride, alcohol-based solvents such as methanol, ethanol, n-propanol, and isopropanol, ether-based solvents such as diethyl ether, tetrahydrofuran, and dioxane, nitrile-based solvents such as acetonitrile and propionitrile, aprotic polar solvents such as dimethyl sulfoxide and N,N-dimethylacetamide, and water, and these can be used alone or as a mixed solvent. Alcohol-based solvents or water are preferred, and halogen-based solvents and alcohol-based solvents are more preferred.

[0064] As a method for converting the displaceable leaving group X into an alkoxycarbonylamino group, for example, the hydroxy group of 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate (1) is substituted with a halogen atom. Examples of the substitution method include thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, phosphorus oxybromide, carbon tetrachloride / triphenylphosphine, carbon tetrabromide / triphenylphosphine, etc. After the substitution with a halogen atom, a method of reacting with an alkali cyanate and an alcohol in a polar aprotic solvent is exemplified. As the halogen atom, bromine and iodine are preferably used from the viewpoint of reactivity in the substitution reaction with an alkali cyanate and an alcohol. When the substituent is chlorine, it may be substituted with bromine or iodine using potassium bromide, sodium iodide, etc. Examples of the alkali cyanate include sodium cyanate, potassium cyanate, etc. The alcohol is not particularly limited as long as it has a monovalent, divalent, or trivalent hydrocarbon group, and examples thereof include methanol, ethanol, isopropanol, t-butanol, and benzyl alcohol. Of these, methanol is preferably used. Examples of polar aprotic solvents include amides, sulfoxides, ethers, and nitriles, as well as mixtures thereof. Specific examples of solvents include N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, cyclopentyl methyl ether, anisole, tetrahydrofuran, and acetonitrile, as well as mixtures thereof. Of these, N,N-dimethylformamide is preferably used.

[0065] Regarding step <1-2> The first production method of the present invention includes a step of decomposing the intermediate (1).

[0066] Examples of the process for decomposing the intermediate (1) include hydrolysis and catalytic hydrogenolysis. A preferred example is hydrolysis, and the hydrolysis method can be preferably a method of hydrolysis in a basic solution or a method of hydrolysis in an acidic solution. Examples of the basic solution include, but are not limited to, hydroxides of alkali metals or alkaline earth metals, ammonia, and amines. Examples of the alkali metal include, for example, sodium hydroxide or potassium hydroxide, and examples of the alkaline earth metal include, for example, calcium hydroxide. Sodium hydroxide or potassium hydroxide is preferably used because of its ease of availability and ease of handling. Examples of the acid include, but are not limited to, inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as acetic acid and formic acid. Among them, a solution containing hydrochloric acid is preferably used. The reaction temperature is not particularly limited, but is preferably carried out within a range of 0°C to 100°C, and the reaction time is preferably 1 hour to 48 hours. This allows the hydrolysis reaction to be carried out in a high yield.

[0067] The step of decomposing the intermediate (1) further includes a step of converting the primary amine precursor to a primary amine. Methods for converting the primary amine precursor to a primary amine include a reduction reaction of a secondary amino group or a tertiary amino group, a reduction reaction of an azide group, a decomposition reaction of an imide group, or a method of subjecting a hexamethylenetetramine-substituted product to a decomposition reaction.

[0068] Any reduction method can be used as the method for reducing the secondary or tertiary amination, but for example, the primary amine can be obtained by hydrogenolysis using a catalyst such as palladium on carbon (hereinafter, also simply referred to as "Pd / C"), or by reduction using a reducing agent such as sodium borohydride or lithium aluminum hydride.

[0069] Any reduction method can be used for the reduction after azidation, and examples of such reduction methods include reduction methods using reducing agents such as sodium borohydride, lithium aluminum hydride, and triphenylphosphine, and catalytic hydrogen reduction methods using reduction catalysts such as platinum carbon and Pd / C.

[0070] Examples of the reaction for decomposition after imidization include hydrolysis under basic conditions using a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., or hydrolysis under acidic conditions using an acid such as hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, etc. Alternatively, a method using a reducing agent such as sodium borohydride, lithium aluminum hydride, etc., a method using a hydrazine such as hydrazine, methylhydrazine, phenylhydrazine, etc., or a method using an alkylamine such as methylamine, ethylamine, ethanolamine, etc. can be used as necessary.

[0071] The decomposition reaction after the substitution with hexamethylenetetramine may be carried out under acidic conditions, for example, with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., and organic acids such as acetic acid, formic acid, etc. Among these, hydrochloric acid is particularly preferably used.

[0072] The decomposition reaction after substitution with an alkoxycarbonylamino group may be carried out under acidic conditions, for example, with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., and organic acids such as acetic acid, formic acid, etc. Among these, hydrochloric acid is particularly preferably used.

[0073] The step of decomposing intermediate (1) includes hydrolyzing intermediate (1) to obtain a mixture of a carboxylic acid derivative and an amino alcohol derivative.

[0074] The term "carboxylic acid derivative" refers to a compound represented by the following formula 4.

[0075] [ka]

[0076] The term "amino alcohol derivative" refers to a compound represented by the following formula 5.

[0077] [ka]

[0078] The "mixture" refers to a mixture containing a carboxylic acid derivative and an aminoalcohol derivative. The mixture may contain starting materials and reaction by-products other than the carboxylic acid derivative and the aminoalcohol derivative.

[0079] Regarding the carboxylic acid derivative, 4-(aminomethyl)cyclohexanecarboxylic acid can be obtained by converting the primary amine precursor A into a primary amine. On the other hand, the aminoalcohol derivative has two asymmetric substituents, and by converting this hydroxymethyl group into a carboxylic acid, the production of symmetric disubstituted cyclohexanedicarboxylic acid (also called 1,4-cyclohexyldicarboxylic acid), which is a by-product in the conventional process of producing 4-(aminomethyl)cyclohexanecarboxylic acid from cyclohexanedimethanol (hereinafter also called CHDM), and the remaining unreacted CHDM are not generated.

[0080] In the first production method of the present invention, when the carboxylic acid derivative or amino alcohol derivative contains a primary amine precursor, the step of converting the primary amine precursor to a primary amine can be a method of carrying out a reduction reaction of a secondary amino group or a tertiary amino group, a reduction reaction of an azide group, a decomposition reaction of an azide group, or a decomposition reaction of a hexamethylenetetramine-substituted compound, etc. As a specific method, a method used in the case where the step of decomposing intermediate (1) further includes a step of converting the primary amine precursor to a primary amine can be used.

[0081] The step of decomposing the intermediate (1) further comprises the step of converting the hydroxy group of the amino alcohol derivative to a carboxy group.

[0082] The hydroxy group of the obtained amino alcohol derivative can be converted to a carboxy group to produce a carboxylic acid derivative. The step of converting the hydroxy group of the amino alcohol derivative to a carboxy group may be carried out in a state of a mixture of the carboxylic acid derivative and the amino alcohol derivative, or the hydroxy group of the amino alcohol derivative may be converted to a carboxy group after isolating the carboxylic acid derivative or the amino alcohol derivative or separating the carboxylic acid derivative and the amino alcohol derivative.

[0083] As used herein, "isolation" refers to removing one component from a mixture, and "separation" refers to removing one or more components from a mixture.

[0084] As a method for isolating or separating the amino alcohol derivative and / or the carboxylic acid derivative, a conventionally known method such as solvent extraction, recrystallization, chromatographic separation, etc. Among these, the solvent extraction and recrystallization methods are preferably used because of the simplicity of the operation.

[0085] The solvent extraction method includes extraction with an aqueous solvent and an organic solvent. The aqueous solvent includes not only water but also alcohol-based solvents that are miscible with water. The organic solvent is not particularly limited as long as it is a solvent that is not miscible with water. For example, the organic solvent includes toluene, ether, etc. Among them, toluene is preferably used.

[0086] Examples of the recrystallization method include dissolving the crude crystals in a solvent, utilizing the difference in solubility between the target compound and impurities due to temperature, concentrating the solution, adding other solvents, etc. to reduce the solubility, and finally extracting the target crystals. The solvent used is not particularly limited as long as it dissolves the target crude crystals. For example, the solvent may be water, acetone, etc. Among them, water, acetone, and water-acetone mixed solvents are preferably used.

[0087] The step of converting the hydroxy group of the amino alcohol derivative to a carboxy group includes an oxidation method. The oxidation can be carried out using an oxidizing agent, such as hydrogen peroxide, potassium permanganate (hereinafter referred to as KMnO4), 2,2,6,6-tetramethylpiperidine-1-oxyl free radical (hereinafter also simply referred to as "TEMPO") or its analogues, Jones reagent, PDC in DMF, and ruthenium tetroxide (RuO4). In particular, the oxidation method using hydrogen peroxide, KMnO4, TEMPO or its analogues is preferred, and from the viewpoint of safety, hydrogen peroxide, TEMPO or its analogues are particularly preferred.

[0088] Oxidation with KMnO4 occurs when an alkaline aqueous solution of KMnO4 is added to a solution or suspension of the amino alcohol derivative. The solution or suspension is stirred until the oxidation is complete. For the reaction to proceed efficiently, the amino alcohol derivative must be at least partially dissolved. Therefore, the reaction can be driven by the addition of an organic co-solvent such as dioxane, pyridine, acetone or t-BuOH. The oxidation is generally carried out under strongly alkaline conditions with 1N sodium hydroxide or potassium hydroxide.

[0089] The oxidation with hydrogen peroxide is preferably carried out in the presence of tungstic acids and a phase transfer catalyst, and the amount of hydrogen peroxide used is usually 1.5 to 5 times by mol, preferably 2.0 to 2.7 times by mol, relative to the amino alcohol derivative, to oxidize to a carboxylic acid. There is no particular limitation on the concentration of hydrogen peroxide, and a commercially available 30% aqueous solution is sufficient, but it may be used after dilution. Examples of tungstic acids include alkali tungstates such as sodium tungstate dihydrate and potassium tungstate dihydrate, ammonium tungstate, tungsten trioxide, tungsten trisulfide, tungsten hexachloride, and phosphotungstic acid, and alkali tungstates such as sodium tungstate dihydrate and potassium tungstate dihydrate are preferred.

[0090] As the phase transfer catalyst, a quaternary ammonium hydrogen sulfate, for example, tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium hydrogen sulfate, benzyltriethylammonium hydrogen sulfate, lauryltrimethylammonium hydrogen sulfate, stearyltrimethylammonium hydrogen sulfate, methyltrioctylammonium hydrogen sulfate, ethyltrioctylammonium hydrogen sulfate, is preferable. As the quaternary ammonium halide, a quaternary ammonium halide having a chloride or bromide is preferable, for example, tetramethylammonium chloride, tetramethylammonium bromide, tetraethylammonium chloride, tetraethylammonium bromide, tetrapropylammonium, Examples of quaternary ammonium salts include N-lauryl pyridinium chloride, tetrapropyl ammonium bromide, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, benzyl triethyl ammonium chloride, benzyl triethyl ammonium bromide, lauryl trimethyl ammonium chloride, stearyl trimethyl ammonium chloride, dilauryl dimethyl ammonium chloride, methyl trioctyl ammonium chloride, ethyl trioctyl ammonium chloride, N-lauryl pyridinium chloride, N-cetyl pyridinium chloride, N-lauryl picolinium chloride, N-cetyl picolinium chloride, N-lauryl quinolium chloride, and N-cetyl quinolium chloride. These quaternary ammonium salts may be hydrates. The amount of the quaternary ammonium salt used is usually 0.01 to 5 mol%, preferably 0.05 to 3 mol% relative to the amino alcohol derivative.

[0091] The reaction is usually carried out in the range of 30 to 130° C., and may be carried out without a solvent, or in an aqueous solvent or an organic solvent. Examples of the organic solvent include ether solvents such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, diglyme, etc., ester solvents such as ethyl acetate, etc., tertiary alcohol solvents such as tert-butanol, nitrile solvents such as acetonitrile, propionitrile, etc., aromatic hydrocarbon solvents such as toluene, xylene, ethylbenzene, etc., aliphatic hydrocarbon solvents such as heptane, and amide solvents such as 1,3-dimethyl-2-imidazolidinone, N,N-dimethylformamide, 1-methyl-2-pyrrolidone, N,N-dimethylacetamide, etc.

[0092] The oxidation by TEMPO or its analogues will be described in detail. The catalytic amount of TEMPO or its analogues may be a chain-like one, but a cyclic nitroxide radical is preferred. Specifically, 2,2,6-tetramethylpiperidine-1-oxyl, 4-oxo-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 3-carbamoylproxyl, 4-carboxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 3-carboxy-2,2,5,5-tetramethylpyrrolidine-1-oxyl, di-t-butyl nitroxide, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl benzoate, 4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl, and the like are mentioned, and 2,2,6,6-tetramethylpiperidine-1-oxyl free radical is most preferably used.

[0093] Co-oxidants used with TEMPO and its analogues include hypochlorites (such as sodium hypochlorite) and chlorate salts (such as sodium chlorite), as well as hydrogen peroxide, iodine, N-chlorosuccinimide, N-bromosuccinimide, persulfates (such as sodium persulfate), chloramine B, chloramine T, peracids, N,N-dibromobenzenesulfonamide, 1,3-dibromo-5,5-dimethylhydantoin, 1,3-dichloro-5,5-dimethylhydantoin, and 1,3-dichloro-5,5-dimethylhydantoin. Examples of suitable disinfectants include toin, dichloramine B, dichloramine T, sodium dichloroisocyanurate, t-butyl hypochlorite, iodosobenzenes (such as PhI(OAc)2), oxone, and trichloroisocyanuric acid. However, hypochlorites, chlorites, hydrogen peroxide, iodine, N-chlorosuccinimide, and N-bromosuccinimide are more preferred, and from the standpoints of safety and cost, hypochlorites and chlorites are most preferably used alone or in combination.

[0094] The most preferred reaction solvent is a two-phase system of water and an organic solvent, and preferred organic solvents include halogenated solvents (dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc.), toluene, chlorobenzene, ethyl acetate, butyl acetate, acetonitrile, propionitrile, butyronitrile, etc.

[0095] It is also preferable to add various salts to control the pH during the reaction to pH 7-9. As these salts, those having a buffering effect are preferable, and any salt having a buffering effect can be used, but in addition to sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, borates, phosphates, etc. are also preferable, and these can be used in appropriate mixtures. Furthermore, in order to complete the reaction, KBr, a phase transfer catalyst, etc. can be used.

[0096] Here, the isolation or separation of an amino alcohol derivative and / or a carboxylic acid derivative from a mixture obtained by hydrolyzing intermediate (1) has been described. However, the first production method of the present invention may include, as a process step, a process step of isolating an amino alcohol derivative or a carboxylic acid derivative after the process step of hydrolyzing intermediate (1), or a process step of converting a hydroxy group of the amino alcohol derivative to a carboxy group after isolating the amino alcohol derivative.

[0097] In addition, in the first production method of the present invention, the hydroxy group of the amino alcohol derivative contained in the mixture obtained by hydrolyzing the intermediate (1) may be converted to a carboxy group in one pot without separating the resulting mixture of a carboxylic acid derivative and an amino alcohol derivative into the carboxylic acid derivative and the amino alcohol derivative.

[0098] <2> Regarding the second manufacturing method according to the present invention The second production method according to the present invention is a method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) from 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate (1), and includes a step <2-1> of converting the hydroxy group of 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexacarboxylate (1) to a primary amine precursor A to obtain an intermediate (1), a step <2-2> of substituting the primary amine precursor A of the intermediate (1) with an amino group to obtain 4-(aminomethyl)cyclohexylmethyl 4'-(aminomethyl)cyclohexanecarboxylate, and a step <2-3> of decomposing 4-(aminomethyl)cyclohexylmethyl 4'-(aminomethyl)cyclohexanecarboxylate.

[0099] Regarding step <2-1> The second production method according to the present invention comprises converting the hydroxy group of 4-(hydroxymethyl)cyclohexylmethyl-4'-(hydroxymethyl)cyclohexanecarboxylate into a primary amine precursor A.

[0100] A method for converting the hydroxy group of 4-(hydroxymethyl)cyclohexylmethyl-4'-(hydroxymethyl)cyclohexanecarboxylate into the primary amine precursor A includes a reaction in which the hydroxy group is substituted with a replaceable leaving group X such as a halogen, an alkylsulfonyloxy, an arylsulfonyloxy, or a tosyl group, and then the replaceable leaving group X is substituted with a primary amine precursor A to which a nitrogen atom is bonded. The specific method is the same as the method described in step <1-1>.

[0101] The method for converting the replaceable leaving group X to the primary amine precursor A includes a method for replacing the replaceable leaving group X with azide, imide, or hexamethylenetetramine, or a method for replacing the replaceable leaving group X with a secondary amine or a tertiary amine. The specific method is the same as the method described in step <1-1>.

[0102] Regarding step <2-2> The second production method according to the present invention includes a step of substituting a primary amine precursor A of intermediate (1) with an amino group to obtain 4-(aminomethyl)cyclohexylmethyl 4'-(aminomethyl)cyclohexanecarboxylate.

[0103] The method of substituting the primary amine precursor A of the intermediate (1) with an amino group can be a method of carrying out a reduction reaction of an azide group, a decomposition reaction of an imide group, or a decomposition reaction of a compound substituted with hexamethylenetetramine, etc. As a specific method, a method used in the case where the step of decomposing the intermediate (1) in the step <1-2> further includes a step of converting the primary amine precursor into a primary amine can be used.

[0104] Regarding step <2-3> The method includes a step of decomposing 4-(aminomethyl)cyclohexylmethyl 4'-(aminomethyl)cyclohexanecarboxylate.

[0105] Methods for decomposing 4-(aminomethyl)cyclohexylmethyl 4'-(aminomethyl)cyclohexanecarboxylate include hydrolysis and catalytic hydrogenolysis. A preferred method is hydrolysis, and the hydrolysis method can be preferably a method of hydrolysis in a basic solution or a method of hydrolysis in an acidic solution. As a specific method, the hydrolysis method or the like used in the step of decomposing intermediate (1) in step <1-2> can be used.

[0106] Thus, 4-(aminomethyl)cyclohexylmethyl 4'-(aminomethyl)cyclohexanecarboxylate can be hydrolyzed to give 4-(aminomethyl)cyclohexanecarboxylic acid.

[0107] In the first and second production methods of the present invention, a cis / trans mixture of 4-(aminomethyl)cyclohexanecarboxylic acid may be isomerized to produce a trans isomer, or a cis / trans mixture of 4-(hydroxymethyl)cyclohexanecarboxylic acid may be separated by column chromatography to obtain only the trans isomer. Note that, as a method for isomerizing a cis / trans mixture to a trans isomer, the methods described in, for example, JP-A-2009-263336, JP-B-41-14830, JP-B-42-23018, JP-B-54-3867, and JP-B-54-7784 may also be used.

[0108] [A method for producing 4-(aminomethyl)cyclohexanecarboxylic acid using 4-(hydroxymethyl)cyclohexanecarboxylic acid, which is a hydrolysis product of 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate, as a starting material] The present invention is described in detail below. The present invention is a method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (hereinafter, also simply referred to as "production method").

[0109] Specifically, the production method according to the present invention is a method comprising converting a hydroxy group of 4-(hydroxymethyl)cyclohexanecarboxylic acid to a primary amine.

[0110] In the production method according to the present invention, the starting material 4-(hydroxymethyl)cyclohexanecarboxylic acid is easily and inexpensively obtained by hydrolyzing 4-(hydroxymethyl)cyclohexylmethyl-4'-(hydroxymethyl)cyclohexanecarboxylate (CAS number 1278692-42-9, (I) in the following reaction formula 6) ((II) in the following reaction formula 6). A specific production method is disclosed in Japanese Patent No. 5372258. The 4-(hydroxymethyl)cyclohexylmethyl-4'-(hydroxymethyl)cyclohexanecarboxylate is obtained as a by-product in the production of 1,4-cyclohexanedimethanol ((III) in the following reaction formula 6), which is supplied in a large amount and stably and used as a modifier for general-purpose polymer materials such as polyester.

[0111] [ka]

[0112] Therefore, in the production method according to the present invention, 4-(aminomethyl)cyclohexanecarboxylic acid can be produced inexpensively and simply by using, as a starting material, a compound that can be easily obtained by hydrolyzing 4-(hydroxymethyl)cyclohexylmethyl-4'-(hydroxymethyl)cyclohexanecarboxylate, which was previously a by-product, as described above.

[0113] As described above, the production method according to the present invention includes converting the hydroxy group of 4-(hydroxymethyl)cyclohexanecarboxylic acid to a primary amine. Specific examples of the method for converting the hydroxy group of 4-(hydroxymethyl)cyclohexanecarboxylic acid to a primary amine include a reaction of substituting the hydroxy group with a replaceable leaving group X such as halogen, alkylsulfonyloxy, arylsulfonyloxy, or tosyl group, followed by amination with ammonia, and a reaction of substituting the replaceable leaving group X with a primary amine precursor A to which a nitrogen atom is bonded, and converting the primary amine precursor A to a primary amine. In addition, examples of the reaction of substituting the replaceable leaving group X with a primary amine precursor A to which a nitrogen atom is bonded, followed by conversion to a primary amine include a reduction reaction followed by azidation, a decomposition reaction followed by imidization, a decomposition reaction after conversion to hexamethylenetetramine, and a decomposition reaction after conversion to an alkoxycarbonylamino group.

[0114] The term "substitutable leaving group X" means that the leaving group X can be substituted by a substituent. The leaving group X is not particularly limited as long as it can be substituted by a substituent, and examples thereof include halogen, alkylsulfonyloxy, and arylsulfonyloxy. The term "halogen" as used herein means an element belonging to Group 17 in the periodic table, and at least one selected from fluorine, chlorine, bromine, and iodine is preferably used. The alkyl in "alkylsulfonyloxy" is not particularly limited, and may be any of C1 to C6. 20 Among them, those having at least one group selected from methyl, ethyl, or a C3 to C8 linear or branched alkyl group are preferably used. In addition, the aryl in "arylsulfonyloxy" is not particularly limited, but may be any of C6 to 10 Among these, phenyl is preferably used.

[0115] The "primary amine precursor A" is not particularly limited as long as it contains a nitrogen atom that can be ultimately converted into a primary amine, and examples of the primary amine precursor A include an azide group, a succinimide group, a maleimide group, a phthalimide group, a hexamethylenetetramine group, an alkoxycarbonylamino group, etc. Also included are those in which the leaving group X has been converted into a secondary amine, a tertiary amine, etc.

[0116] Examples of a method for substituting the hydroxy group of 4-(hydroxymethyl)cyclohexanecarboxylic acid with a displaceable leaving group X such as halogen, alkylsulfonyloxy, arylsulfonyloxy, or tosyl include a method of reacting with a sulfonyl chloride such as thionyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride, or p-toluenesulfonyl chloride (tosyl chloride) in a solvent such as acetonitrile or in the presence of a base such as pyridine or triethylamine without using a solvent. The solvent used may be a polar aprotic solvent or a mixture of a plurality of polar aprotic solvents, and is industrially available.

[0117] Examples of polar aprotic solvents include amides, sulfoxides, ethers, nitriles, and mixtures thereof. Examples of solvents include N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, cyclopentyl methyl ether, anisole, tetrahydrofuran, acetonitrile, and mixtures thereof. Acetonitrile is particularly preferred.

[0118] As the base, both organic and inorganic bases can be used. For example, alkali metal alcoholates such as pyridine, triethylamine, potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, and sodium methoxy, and metal hydrides such as sodium hydride can be mentioned. In particular, pyridine and triethylamine are preferably used.

[0119] As a method for substituting the hydroxy group of 4-(hydroxymethyl)cyclohexanecarboxylic acid and / or an ester thereof with a substitutable leaving group X and then amminating the resulting product, a method for adding ammonia to the substitutable leaving group X and allowing the product to react can be given.

[0120] The ammonia may be ammonia gas or liquid ammonia, or may be ammonia water or an organic solvent solution of ammonia dissolved in an organic solvent capable of dissolving ammonia, such as methanol.

[0121] The reaction temperature is usually 15 to 100° C., preferably 20 to 90° C. The reaction pressure is not particularly limited, but is usually carried out under normal pressure or pressurized conditions. The reactor may be sealed to prevent ammonia from leaking out of the reaction system, and is preferably a pressure-resistant vessel, but is not limited thereto.

[0122] The reaction may be carried out without a solvent, but is preferably carried out in a solvent. The solvent is not particularly limited as long as it is inert in the reaction of the present invention, and examples thereof include alcoholic solvents such as methanol, ethanol, n-propanol, and isopropanol, aromatic hydrocarbon solvents such as toluene and xylene, halogenated hydrocarbon solvents such as chlorobenzene and dichlorobenzene, aliphatic hydrocarbon solvents such as hexane, heptane, and cyclohexane, ether solvents such as diethyl ether, tetrahydrofuran, and dioxane, aprotic polar solvents such as acetonitrile, propionitrile, dimethyl sulfoxide, and N,N-dimethylacetamide, and water, and these can be used alone or as a mixed solvent. An alcoholic solvent or water is preferred, and water is more preferred.

[0123] Examples of the method for replacing the replaceable leaving group X with the primary amine precursor A include a method for replacing the replaceable leaving group X with an azide, imide, hexamethylenetetramine, or alkoxycarbonylamino group, or a method for converting the replaceable leaving group X into a secondary amine or a tertiary amine. When the replaceable leaving group X is converted into a secondary amine or a tertiary amine, the primary amine can be obtained by hydrogenolysis using a catalyst such as palladium carbon, or reduction using a reducing agent such as sodium borohydride or lithium aluminum hydride.

[0124] Examples of a method for azidizing a displaceable leaving group X to form an azide group include a method in which the displaceable leaving group X is reacted with a sulfonyl chloride such as methanesulfonyl chloride, benzenesulfonyl chloride, or p-toluenesulfonyl chloride (tosyl chloride) in a solvent such as acetonitrile or in the presence of a base such as triethylamine in the absence of a solvent to form a monosulfonate ester, which is then reacted with sodium azide, lithium azide, or the like.

[0125] Examples of the solvent used in the azidation method include relatively low polarity solvents such as acetonitrile, dichloromethane, and chloroform, and mixtures thereof. Among these, acetonitrile is preferably used.

[0126] Next, the above azide group can be reduced to an amino group by any reduction method, and examples of the method include a reduction method using a reducing agent such as sodium borohydride, lithium aluminum hydride, or triphenylphosphine, and a catalytic hydrogen reduction method using a reduction catalyst such as platinum on carbon or palladium on carbon.

[0127] An example of a method for imidizing the displaceable leaving group X is a method in which the hydroxy group of 4-(hydroxymethyl)cyclohexanecarboxylic acid and / or an ester thereof is substituted with the displaceable leaving group X, and then the imide is reacted in an aprotic solvent or without using a solvent.

[0128] The aprotic solvents include amides, sulfoxides, ethers, nitriles, and mixtures thereof. Some specific examples of solvents include N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, cyclopentyl methyl ether, anisole, tetrahydrofuran, acetonitrile, and mixtures thereof. Dimethylformamide is particularly preferred.

[0129] The above-mentioned imide may be succinimide, maleimide, or phthalimide, and the succinimide, maleimide, or phthalimide may have a succinimide, maleimide, or phthalimide skeleton, and includes succinimide derivatives, maleimide derivatives, and phthalimide derivatives. The succinimide, maleimide, or phthalimide may also be in the form of a salt such as a sodium salt or potassium salt. In particular, the potassium salt of phthalimide is preferably used from the viewpoint of reactivity.

[0130] Examples of the reaction for decomposition after imidization include hydrolysis under basic conditions using a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., or hydrolysis under acidic conditions using an acid such as hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, etc. Alternatively, a reduction method using a reducing agent such as sodium borohydride, lithium aluminum hydride, etc., a method using a hydrazine such as hydrazine, methylhydrazine, phenylhydrazine, etc., or a method using an alkylamine such as methylamine, ethylamine, ethanolamine, etc. can be used as necessary.

[0131] A method for substituting the displaceable leaving group X with hexamethylenetetramine includes, for example, substituting the hydroxy group of 4-(hydroxymethyl)cyclohexanecarboxylic acid with a halogen, and then reacting with hexamethylenetetramine in a polar solvent or without using a solvent. The halogen is preferably iodine in view of reactivity in the substitution reaction with hexamethylenetetramine. When the substituent is chlorine, the chlorine may be substituted with sodium iodide or the like.

[0132] The polar solvent is not particularly limited as long as it is inactive in the reaction of the present invention, and examples thereof include alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, etc., etheric solvents such as diethyl ether, tetrahydrofuran, dioxane, etc., aprotic polar solvents such as acetonitrile, propionitrile, dimethyl sulfoxide, N,N-dimethylacetamide, etc., water, etc., and these can be used alone or as a mixed solvent. Alcoholic solvents or water are preferred, and alcoholic solvents are more preferred.

[0133] The decomposition reaction after the substitution with hexamethylenetetramine may be carried out under acidic conditions, for example, with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., and organic acids such as acetic acid, formic acid, etc. Among these, hydrochloric acid is particularly preferably used.

[0134] As a method for making the displaceable leaving group X into an alkoxycarbonylamino group, for example, the hydroxy group of 4-(hydroxymethyl)cyclohexanecarboxylic acid is substituted with a halogen atom. Examples of the substitution method include thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, phosphorus oxybromide, carbon tetrachloride / triphenylphosphine, carbon tetrabromide / triphenylphosphine, etc. After the substitution with a halogen atom, a method of reacting with an alkali cyanate and an alcohol in a polar aprotic solvent is exemplified. As the halogen atom, bromine and iodine are preferably used from the viewpoint of reactivity in the substitution reaction with an alkali cyanate and an alcohol. When the substituent is chlorine, it may be substituted with bromine or iodine by potassium bromide, sodium iodide, etc. Examples of the alkali cyanate include sodium cyanate and potassium cyanate. Examples of the alcohol include, but are not limited to, any alcohol having a monovalent, divalent, or trivalent hydrocarbon group, and examples thereof include methanol, ethanol, isopropanol, t-butanol, and benzyl alcohol. Among these, methanol is preferably used. Examples of polar aprotic solvents include amides, sulfoxides, ethers, nitriles, and mixtures thereof. Specific examples of solvents include N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, cyclopentyl methyl ether, anisole, tetrahydrofuran, acetonitrile, and mixtures thereof. Among these, N,N-dimethylformamide is preferably used.

[0135] The decomposition reaction after substitution with an alkoxycarbonylamino group may be carried out under acidic conditions, for example, with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., and organic acids such as acetic acid, formic acid, etc. Among these, hydrochloric acid is particularly preferably used.

[0136] The production method of the present invention may include a step of converting the starting material, an ester or an esterified product during production, into a carboxylic acid as necessary. Examples of methods for converting an ester into a carboxylic acid include hydrolysis and catalytic hydrogenolysis. As a method for hydrolysis, a method of hydrolysis in a basic solution or a method of hydrolysis in an acidic solution can be preferably used. Examples of basic solutions include, but are not limited to, hydroxides of alkali metals or alkaline earth metals, ammonia, and amines. Examples of alkali metals include, for example, sodium hydroxide or potassium hydroxide, and examples of alkaline earth metals include, for example, calcium hydroxide. Sodium hydroxide or potassium hydroxide is preferably used because of its ease of availability and ease of handling. Examples of acids include, but are not limited to, inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as acetic acid and formic acid. Among them, a solution containing hydrochloric acid is preferably used. Although the reaction temperature is not particularly limited, it is preferably carried out within a range of 0°C to 100°C, and the reaction time is preferably 1 hour to 48 hours. This allows the hydrolysis reaction to be carried out in a high yield.

[0137] In the production method of the present invention, the trans isomer can be used as 4-(hydroxymethyl)cyclohexanecarboxylic acid, and the trans isomer can be produced by isomerizing a cis / trans mixture of 4-(hydroxymethyl)cyclohexanecarboxylic acid to the trans isomer, or the trans isomer can be obtained by isolating only the trans isomer by column chromatography of the cis / trans mixture of 4-(hydroxymethyl)cyclohexanecarboxylic acid. Note that the method of isomerizing the cis / trans mixture to the trans isomer can also be the method described in JP-A-2009-263336, for example. EXAMPLES

[0138] The present invention will be described in more detail below by showing examples, but the present invention is not limited to the following examples in any way.

[0139] The identification of compounds was mainly 1 H-NMR was used. 1 In the H-NMR measurements, s means a singlet, d means a doublet, and m means a multiplet.

[0140] [Method for producing 4-(aminomethyl)cyclohexanecarboxylic acid using 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate as starting material]

[0141] Example 1 Synthesis of 4-(chloromethyl)cyclohexylmethyl 4'-(chloromethyl)cyclohexanecarboxylate To a solution of 20 g (70.3 mmol) of 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate and 350 ml of acetonitrile, add 12.0 g (151.7 mmol) of pyridine, and dropwise add 17.6 g (147.9 mmol) of thionyl chloride at 5°C or less under ice water cooling. Stir for 1 hour under ice water cooling, then at room temperature for 4 hours, then heat under reflux for 3 hours, and allow to cool. The reaction mixture is cooled under ice water cooling, and 5 ml of water is slowly dropped. Then, add 100 ml of ice water and add 250 ml of ethyl acetate for extraction. The aqueous layer is further extracted with 100 ml of ethyl acetate, combined with the previous ethyl acetate layer, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 19.7 g (61.3 mmol) of 4-chloromethylcyclohexylmethyl 4'-(chloromethyl)cyclohexanecarboxylate as white crystals. Yield: 82.2%

[0142] Example 2 Synthesis of 4-(methylsulfonyloxy)methylcyclohexylmethyl 4'-[(methylsulfonyloxy)methyl]cyclohexanecarboxylate To a solution of 20 g (70.3 mmol) of 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate and 350 ml of acetonitrile, add 15.70 g (155.2 mmol) of triethylamine, add 16.9 g (147.5 mmol) of methanesulfonyl chloride dropwise at 5°C or less under ice water cooling, stir for 4 hours under ice cooling, and then stir at room temperature for 1 hour. The reaction mixture is poured into 500 g of ice water, and then 250 ml of ethyl acetate is added and extracted. The aqueous layer is further extracted with 100 ml of ethyl acetate, and the mixture is combined with the previous ethyl acetate layer, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 25.2 g (57.2 mmol) of crude 4-(methylsulfonyloxy)methylcyclohexylmethyl 4'-[(methylsulfonyloxy)methyl]cyclohexanecarboxylate as a yellow oil. Yield: 81.4%

[0143] Example 3 Synthesis of 4-(phthalimido)methylcyclohexylmethyl 4'-[(phthalimido)methyl]cyclohexanecarboxylate 15.0 g (46.7 mmol) of 4-chloromethylcyclohexylmethyl 4'-(chloromethyl)cyclohexanecarboxylate was added to a solution of 200 ml of N,N-dimethylformamide and 21.6 g (116.6 mmol) of potassium phthalimide, heated to 70-85°C, and stirred for 6 hours. The mixture was then allowed to cool and stirred overnight. The reaction mixture was poured into water, and then extracted with 300 ml of toluene. The toluene layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 23.2 g (43.7 mmol) of crude 4-(phthalimido)methylcyclohexylmethyl 4'-[(phthalimido)methyl]cyclohexanecarboxylate. Yield: 93.6%

[0144] Example 4 Hydrolysis of 4-(phthalimido)methylcyclohexylmethyl 4'-[(phthalimido)methyl]cyclohexanecarboxylate and synthesis of 4-(aminomethyl)cyclohexanecarboxylic acid from the mixture (A) Synthesis of ester hydrolysis mixture To a solution of 7 g (12.9 mmol) of crude 4-(phthalimido)methylcyclohexylmethyl 4'-[(phthalimido)methyl]cyclohexanecarboxylate, 100 ml of isopropanol, and 10 ml of water, add 10 ml of 25% sodium hydroxide, stir under reflux until hydrolysis is complete, and then allow to cool.

[0145] The reaction mixture is concentrated under reduced pressure, 2N hydrochloric acid is added to adjust the pH to below 4, and the mixture is extracted with 200 ml of ethyl acetate. The aqueous layer is further extracted with 100 ml of ethyl acetate. The extract is combined with the previous ethyl acetate layer, washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 7.2 g of an ester hydrolysis mixture, 4-(phthalimido)methylcyclohexanecarboxylic acid and 4-(phthalimido)methylcyclohexanol.

[0146] (a) Oxidation of the ester hydrolysis mixture A mixture of 7.2 g of the obtained ester hydrolysis mixture, 75 ml of acetonitrile, and 50 ml of phosphate buffer (pH = 6.8 1M) is heated to 35-40 ° C. After adding 84.4 mg (0.54 mmol) of 2,2,6,6-tetramethylpiperidine-1-oxyl free radical (TEMPO), 4.41 g of sodium chlorite (purity: 80%, 39 mmol) dissolved in 15 ml of water and 0.30 ml of sodium hypochlorite (12% aqueous solution, 0.58 mmol) dissolved in 10 ml of water are simultaneously added dropwise over 1 hour. The reaction mixture is further heated and stirred at 35-40 ° C for 3 hours. The reaction mixture is then allowed to cool to room temperature. After that, 150 ml of water is added, and the pH is adjusted to 8.0 with 2N sodium hydroxide. Next, the mixture is cooled under ice cooling, and an aqueous sodium sulfite solution is added to decompose the excess sodium chlorite and sodium hypochlorite, thereby stopping the reaction. The reaction mixture is then cooled to room temperature, acidified to pH 2-4 by adding 2N hydrochloric acid, and stirred at room temperature to precipitate crystals. The crude crystals are filtered, washed with water, and dried to obtain 6.2 g (21.6 mmol) of crude crystals of 4-(phthalimido)methylcyclohexanecarboxylic acid. Yield: 167.4% MP: 190-194°C

[0147] (c) Synthesis of 4-(aminomethyl)cyclohexanecarboxylic acid from 4-(phthalimido)methylcyclohexanecarboxylic acid After 6g (20.9mmol) of crude crystals of 4-(phthalimido)methylcyclohexanecarboxylic acid, 60ml of isopropanol, and 10ml of water are charged, 2.4g (63.3mmol) of sodium borohydride is added while stirring at room temperature, and the mixture is stirred at room temperature for a whole day. In order to decompose the excess sodium borohydride, 2N hydrochloric acid is added to the reaction mixture at room temperature to adjust the pH to 2-3, and the mixture is stirred at 80°C for 3 hours and allowed to cool to room temperature. 100ml of water is added to the reaction mixture, which is then washed with 100ml of toluene. The aqueous layer is filtered to remove insoluble matter, and passed through a weakly basic ion exchange resin and then a weakly acidic ion exchange resin, and the filtrate is concentrated under reduced pressure. The residue was recrystallized from water / acetone to give 2.6 g (16.7 mmol) of 4-(aminomethyl)cyclohexanecarboxylic acid. Yield: 79.9%.

[0148] Example 5 Synthesis of 4-(phthalimido)methylcyclohexanecarboxylic acid by isolating 4-(phthalimido)methylcyclohexanemethanol from the hydrolysis mixture of 4-(phthalimido)methylcyclohexylmethyl 4'-[(phthalimido)methyl]cyclohexanecarboxylate and then oxidizing it. (a) Synthesis and isolation of 4-(phthalimido)methylcyclohexanemethanol To a solution of 7 g (12.9 mmol) of crude 4-(phthalimido)methylcyclohexylmethyl 4'-[(phthalimido)methyl]cyclohexanecarboxylate, 100 ml of isopropanol, and 10 ml of water, add 10 ml of 25% sodium hydroxide, and stir under reflux until hydrolysis is complete, then allow to cool. To this reaction mixture, add 150 ml of toluene and 100 ml of water for extraction. The toluene layer is further washed with 100 ml of water and 10 ml of 25% sodium hydroxide. The toluene layer is then washed with a saturated saline solution and diluted with anhydrous sulfuric acid. Dry over magnesium and concentrate under reduced pressure to obtain 3.3 g (12.1 mmol) of 4-(phthalimido)methylcyclohexanemethanol. Yield: 93.8%

[0149] On the other hand, the aqueous layer obtained after two water washes is concentrated under reduced pressure to remove the organic solvent, and then 2N hydrochloric acid is added to adjust the pH to below 4, causing crystals to precipitate. The crude crystals are filtered, washed with water, and dried to obtain 2.6 g (9.05 mmol) of crude crystals of 4-(phthalimido)methylcyclohexanecarboxylic acid. Yield: 74.9%

[0150] (a) Oxidation of isolated 4-(phthalimido)methylcyclohexanemethanol The mixture of 3.3g (12.1mmol) of the obtained 4-(phthalimido)methylcyclohexanemethanol, 70ml of acetonitrile, and 50ml of phosphate buffer (pH=6.8 1M) is heated to 35-40℃. After adding 79.1mg (0.51mmol) of TEMPO, 4.13g (purity: 80%, 36.5mmol) of sodium chlorite dissolved in 15ml of water and 0.28ml of sodium hypochlorite (12% aqueous solution, 0.54mmol) dissolved in 10ml of water are added dropwise over 1 hour. The reaction mixture is further heated and stirred at 35-40℃ for 3 hours. The reaction mixture is then allowed to cool to room temperature. After that, 150ml of water is added, and the pH is adjusted to 8.0 with 2N sodium hydroxide. The mixture is then cooled under ice cooling, and an aqueous sodium sulfite solution is added to decompose the excess sodium chlorite and sodium hypochlorite, thereby terminating the reaction. The reaction mixture is then cooled to room temperature, acidified to pH 2-4 by adding 2N hydrochloric acid, and stirred at room temperature to precipitate crystals. The crude crystals are filtered, washed with water, and dried to obtain 2.8 g (9.7 mmol) of crude crystals of 4-(phthalimido)methylcyclohexanecarboxylic acid. Yield: 80.2% MP: 190-193°C

[0151] Example 6 Synthesis of 4-(aminomethyl)cyclohexanecarboxylic acid from 4-(methylsulfonyloxy)methylcyclohexylmethyl 4'-[(methylsulfonyloxy)methyl]cyclohexanecarboxylate via 4-(azidomethyl)cyclohexylsilmethyl 4'-(azidomethyl)cyclohexanecarboxylate (a) Synthesis of 4-(azidomethyl)cyclohexylmethyl 4'-(azidomethyl)cyclohexanecarboxylate To a solution of 24 g (54.5 mmol) of 4-(methylsulfonyloxy)methylcyclohexylmethyl 4'-[(methylsulfonyloxy)methyl]cyclohexanecarboxylate and 75 ml of N,N-dimethylformamide, add 10.6 g (163.1 mmol) of sodium azide [NaN3] at room temperature. The reaction mixture is stirred at 80°C for 5 hours under nitrogen. After cooling, the reaction mixture is poured into 300 ml of water and extracted with 100 ml of toluene. The aqueous layer is further extracted twice with 100 ml of toluene, and the mixture is combined with the previous toluene layer, washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 16 g (47.8 mmol) of crude 4-(azidomethyl)cyclohexylmethyl 4'-(azidomethyl)cyclohexanecarboxylate as a yellow oil.

[0152] (a) Synthesis of 4-azidomethylcyclohexanecarboxylic acid To a solution of 16 g (47.8 mmol) of crude 4-(azidomethyl)cyclohexylmethyl 4'-(azidomethyl)cyclohexanecarboxylate, 200 ml of isopropanol, and 20 ml of water, 30 ml of 25% sodium hydroxide is added, and the mixture is refluxed and stirred until hydrolysis is complete, and then allowed to cool. The reaction mixture is added with 150 ml of water, washed three times with 100 ml of toluene, and the aqueous layer is adjusted to pH 3-4 with 2N hydrochloric acid, and extracted three times with 100 ml of dichloromethane. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 7.7 g (42 mmol) of crude crystals of 4-azidomethylcyclohexanecarboxylic acid. Yield from 4-(methylsulfonyloxy)methylcyclohexylmethyl 4'-[(methylsulfonyloxy)methyl]cyclohexanecarboxylate: 77.8%

[0153] (c) Synthesis of 4-(aminomethyl)cyclohexanecarboxylic acid To a solution of 7.5 g (40.1 mmol) of crude crystalline 4-(azidomethyl)cyclohexanecarboxylic acid and 150 ml of methanol, 1.5 g of 10% Pd / C is added and hydrogenated at room temperature under atmospheric pressure for 6 hours. The reaction mixture is filtered to remove the Pd / C, and concentrated under reduced pressure to dryness to obtain 6.1 g of 4-(aminomethyl)cyclohexanecarboxylic acid. This is recrystallized from water / acetone to obtain 5.9 g (37.5 mmol) of 4-(aminomethyl)cyclohexacarboxylic acid. Yield: 93.5%

[0154] Example 7 Synthesis of 4-(aminomethyl)cyclohexanecarboxylic acid by hydrolysis of 4-(phthalimido)methylcyclohexylsilmethyl 4'-[(phthalimido)methyl]cyclohexanecarboxylate via 4-(aminomethyl)cyclohexylsilmethyl 4'-(aminomethyl)cyclohexanecarboxylate (a) Synthesis of 4-(aminomethyl)cyclohexylmethyl 4'-(aminomethyl)cyclohexanecarboxylate 20g (36.9mmol) of 4-(phthalimido)methylcyclohexylsilmethyl 4'-[(phthalimido)methyl]cyclohexanecarboxylate, 240ml of isopropanol, and 40ml of water are charged, and then 4.18g (110.6mmol) of sodium borohydride is added while stirring at room temperature, and the mixture is stirred at room temperature for 24 hours. In order to decompose the excess sodium borohydride, 2N hydrochloric acid is added to this reaction mixture at room temperature to adjust the pH to 2-3, and the mixture is stirred at 80°C for 4 hours and allowed to cool to room temperature. The reaction mixture is concentrated under reduced pressure to remove the organic solvent, and 2N sodium hydroxide is added to adjust the pH to 7-8. 250ml of toluene is added to this reaction mixture for extraction. The toluene layer is washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 9.8g of crude 4-aminomethylcyclohexylsilmethyl 4'-(aminomethyl)cyclohexanecarboxylate.

[0155] (a) Synthesis of 4-(aminomethyl)cyclohexanecarboxylic acid from 4-(aminomethyl)cyclohexylmethyl 4'-(aminomethyl)cyclohexanecarboxylate To a solution of 9.8 g of 4-(aminomethyl)cyclohexylmethyl 4'-(aminomethyl)cyclohexanecarboxylate, 250 ml of isopropanol, and 20 ml of water, add 30 ml of 25% sodium hydroxide, reflux and stir until hydrolysis is complete, then allow to cool. The reaction mixture is added with 150 ml of water, washed twice with 100 ml of toluene, and the aqueous layer is The insoluble matter is filtered off, and the mixture is passed through a weakly acidic ion exchange resin and then a weakly basic ion exchange resin, and the filtrate is concentrated under reduced pressure. The residue is recrystallized from water / acetone to give 3.95 g (25.1 mmol) of 4-aminomethylcyclohexanecarboxylic acid (4). Yield from 4-(phthalimido)methylcyclohexylmethyl 4'-[(phthalimido)methyl]cyclohexanecarboxylate: 68.1%

[0156] Example 8 Synthesis of 4-(aminomethyl)cyclohexanecarboxylic acid from 4-(aminomethyl)cyclohexylmethyl 4'-(aminomethyl)cyclohexanecarboxylate (a) Synthesis of 4-(aminomethyl)cyclohexylmethyl 4'-(aminomethyl)cyclohexanecarboxylate To a solution of 16 g (47.8 mmol) of crude 4-(azidomethyl)cyclohexylsilmethyl 4'-(azidomethyl)cyclohexanecarboxylate and 150 ml of methanol, 3 g of 10% Pd / C was added and hydrogenated overnight under atmospheric pressure. The reaction mixture was filtered to remove the Pd / C, and then concentrated under reduced pressure to dryness to obtain 12.0 g (42.5 mmol) of crude 4-aminomethylcyclohexylsilmethyl 4'-(aminomethyl)cyclohexanecarboxylate. Yield: 89% (a) Synthesis of 4-aminomethylcyclohexanecarboxylic acid from 4-(aminomethyl)cyclohexylmethyl 4'-(aminomethyl)cyclohexanecarboxylate To a solution of 12.0 g of 4-(aminomethyl)cyclohexylmethyl 4'-(aminomethyl)cyclohexanecarboxylate, 250 ml of isopropanol, and 20 ml of water, add 30 ml of 25% sodium hydroxide, reflux and stir until hydrolysis is complete, then allow to cool. The reaction mixture is added with 150 ml of water, washed twice with 100 ml of toluene, and the aqueous layer is The insoluble matter is filtered off, and the mixture is passed through a weakly acidic ion exchange resin and then a weakly basic ion exchange resin, and the filtrate is concentrated under reduced pressure. The residue is recrystallized from water / acetone to give 5.14 g (32.7 mmol) of 4-aminomethylcyclohexanecarboxylic acid. Yield: 77%

[0157] Example 9 Synthesis of 4-(aminomethyl)cyclohexanecarboxylic acid by hydrolysis of hexamethylenetetramine adduct and deprotection of hexamethylenetetramine in one step To a solution of 15.0 g (46.7 mmol) of 4-(chloromethyl)cyclohexylmethyl 4'-(chloromethyl)cyclohexanecarboxylate and 250 ml of methanol, add 19.6 g (139.8 mmol) of hexamethylenetetramine and 1.5 g (10.0 mmol) of sodium iodide, and stir at room temperature for one day and night. After confirming that 4-chloromethylcyclohexylmethyl 4'-(chloromethyl)cyclohexanecarboxylate has disappeared from the reaction mixture and that the hexamethylenetetramine form has been produced, concentrate. Add 50 ml of methanol and 30 ml of concentrated hydrochloric acid to the reaction mixture, stir under reflux for 10 hours, and allow to cool and return to room temperature. Neutralize with 2N aqueous sodium hydroxide solution, add 100 ml of toluene, and extract twice. Filter the aqueous layer to remove insoluble matter, pass it through a weakly acidic ion resin, and concentrate the filtrate under reduced pressure. The residue was recrystallized from water / acetone to give 5.5 g (35 mmol) of 4-aminomethylcyclohexanecarboxylic acid.

[0158] Example 10 Synthesis of 4-(aminomethyl)cyclohexanecarboxylic acid from 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate a) Synthesis of 4-(chloromethyl)cyclohexylmethyl 4'-(chloromethyl)cyclohexanecarboxylate A mixture of 25 g (87.9 mmol) of 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate, 50 g of toluene, and 5.56 g (70.32 mmol) of pyridine is slowly dripped into a solution of 25.1 g (0.21 mol) of thionyl chloride in 40 g of toluene at 10°C or less under ice cooling over about 30 minutes. The mixture is then heated at 70-80°C for 4 hours, allowed to cool, quenched with water, washed with a dilute aqueous solution of sodium hydroxide and an aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. As the residue, 25.9 g (80.7 mmol) of crude 4-(chloromethyl)cyclohexylmethyl 4'-(chloromethyl)cyclohexanecarboxylate is obtained as an oil. Yield: 90.5% a) Synthesis of 4-(methoxycarbonylaminomethyl)cyclohexylmethyl 4'-(methoxycarbonylaminomethyl)cyclohexanecarboxylate When reacting with 25g (77.8mmol) of 4-(chloromethyl)cyclohexylmethyl 4'-(chloromethyl)cyclohexanecarboxylate, 18.33g (0.233mol) of potassium cyanate, and 15g (0.468mol) of methanol, in the presence of 22g (0.185mol) of KBr for halogenation exchange, the mixture is heated to 100°C in 160g of DMF, reacted for 15 hours or more, cooled, added with water, extracted with 200ml of ethyl acetate, washed with dilute hydrochloric acid, and dried over anhydrous magnesium sulfate. The residue obtained by concentration is separated and purified by silica gel chromatography to obtain 23.2g (58.2mmol) of 4-(methoxycarbonylaminomethyl)cyclohexylmethyl 4'-(methoxycarbonylaminomethyl)cyclohexanecarboxylate as an oil. Yield: 75% c) Synthesis of 4-(aminomethyl)cyclohexanecarboxylic acid Add 10.0 g (25 mmol) of 4-(methoxycarbonylaminomethyl)cyclohexylmethyl 4'-(methoxycarbonylaminomethyl)cyclohexanecarboxylate and 25 ml of 35% hydrochloric acid (12N HCl), and heat under reflux for 6 hours. Cool to room temperature. Neutralize with 2N sodium hydroxide solution, filter out insoluble matter, add 50 ml of toluene, and extract twice. Pass the aqueous layer through a weakly acidic ion resin, and concentrate the filtrate under reduced pressure. Recrystallize the concentrate from water / acetone / methanol to obtain 3.3 g (0.021 mmol) of 4-aminomethylcyclohexanecarboxylic acid. Yield: 84%.

[0159] [A method for producing 4-(aminomethyl)cyclohexanecarboxylic acid using 4-(hydroxymethyl)cyclohexanecarboxylic acid, which is a hydrolysis product of 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate, as a starting material] The trans-4-(hydroxymethyl)cyclohexanecarboxylic acid used as the starting material in the following examples can be obtained by isomerizing CHDM to the trans form by a known method.

[0160] Example 1A Synthesis of trans-4-chloromethylcyclohexanecarboxylic acid To a solution of 15 g (94.8 mmol) of trans-4-(hydroxymethyl)cyclohexanecarboxylic acid (1c) and 300 ml of acetonitrile, add 16.5 g (208.5 mmol) of pyridine, and dropwise add 28.15 g (208.5 mmol) of thionyl chloride at 5°C or less under ice water cooling. Stir for 1 hour under ice water cooling, then at room temperature for 4 hours, then heat under reflux for 3 hours, and allow to cool. The reaction mixture is cooled under ice water cooling, and 5 ml of water is slowly added dropwise. Then, add 100 ml of ice water, and add 100 ml of chloroform for extraction. The aqueous layer is further extracted twice with 100 ml of chloroform, combined with the previous chloroform layer, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 13.8 g (78.2 mmol) of trans-4-chloromethylcyclohexanecarboxylic acid as a white crystalline substance. Yield: 82.5%1 H-NMR(CDCl3) 3.36 (2H d)

[0161] Example 2A Synthesis of trans-4-(hydroxymethyl)cyclohexanecarboxylic acid methyl ester To a solution of 15 g (94.8 mmol) of trans-4-(hydroxymethyl)cyclohexanecarboxylic acid (1c) and 300 ml of methanol, 0.5 g of concentrated sulfuric acid is added, and the reaction mixture is refluxed and stirred for 6 hours, then allowed to cool. The reaction mixture is neutralized with an aqueous solution of sodium bicarbonate and concentrated under reduced pressure. 150 ml of ethyl acetate and 50 ml of water are added to the concentrated reaction mixture for extraction. The aqueous layer is further extracted with 100 ml of ethyl acetate, and the resulting mixture is combined with the previous ethyl acetate layer, washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 15.2 g (88.2 mmol) of crude trans-4-(hydroxymethyl)cyclohexanecarboxylic acid methyl ester as a yellow oil. Yield: 93.0% 1 H-NMR(Methanol-d4) 3.38-3.43(2H m) 3.67(3H s)

[0162] Example 3A Synthesis of trans-4-(methylsulfonyloxy)methylcyclohexanecarboxylic acid methyl ester To a solution of 15 g (87.1 mmol) of trans-4-(hydroxymethyl)cyclohexane carboxylic acid methyl ester and 250 ml of acetonitrile, add 9.70 g (95.8 mmol) of triethylamine, add 11.4 g (95.8 mmol) of methanesulfonic acid chloride dropwise at 5°C or less under ice water cooling, stir for 2.5 hours under ice cooling, and then stir at room temperature for 2 hours. The reaction mixture is poured into 500 g of ice water, and then 200 ml of ethyl acetate is added for extraction. The aqueous layer is further extracted with 100 ml of ethyl acetate, combined with the previous ethyl acetate layer, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 19.1 g (76.1 mmol) of trans-4-(methylsulfonyloxy)methylcyclohexane carboxylic acid methyl ester as a yellow oil. Yield: 87.4% 1H-NMR(Methanol-d4) 3.07(3H S) 3.65(3H s) 4.04-4.09(2H m)

[0163] Example 4A Synthesis of trans-4-chloromethylcyclohexanecarboxylic acid methyl ester To a solution of 15 g (87.1 mmol) of trans-4-(hydroxymethyl)cyclohexane carboxylic acid methyl ester used in Example 2A and 70 ml of chloroform, add 7.7 g (99.3 mmol) of pyridine, and dropwise add 11.4 g (95.8 mmol) of thionyl chloride to the reaction mixture at 5°C or less under ice water cooling. Stir for 1 hour under ice water cooling, then at room temperature for a day and night, reflux for another 4 hours, and then allow to cool. Pour the reaction mixture into water and extract. Further extract the aqueous layer with 100 ml of chloroform, combine with the previous chloroform layer, wash with saturated saline solution, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure to obtain 13.1 g (68.7 mmol) of crude trans-4-chloromethylcyclohexane carboxylic acid methyl ester as a yellow oil. 1 H-NMR(CDCl3) 3.37 (2H d) 3.65(3H s)

[0164] Example 5A Synthesis of trans-4-chloromethylcyclohexanecarboxylic acid propyl ester To a solution of 15 g (94.8 mmol) of trans-4-(hydroxymethyl)cyclohexanecarboxylic acid (1c) and 300 ml of acetonitrile, add 16.5 g (208.5 mmol) of pyridine, and dropwise add 28.15 g (208.5 mmol) of thionyl chloride at 5°C or less under ice water cooling. Stir for 1 hour under ice water cooling, then at room temperature for 4 hours, then heat under reflux for 3 hours, and allow to cool. Cool the reaction mixture under ice water cooling, add 10.5 g (103.8 mmol) of triethylamine, and then dropwise add 10 g of isopropanol. React for 0.5 hours under ice water cooling, return to room temperature, and stir overnight. Add 300 ml of water to the reaction mixture, and then add 200 ml of ethyl acetate to extract. After washing with water, the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 16.0 g (73.1 mmol) of oily trans-4-chloromethylcyclohexanecarboxylic acid isopropyl ester. Yield: 77.2%

[0165] Example 6A Synthesis of trans-4-(aminomethyl)cyclohexanecarboxylic acid (2c) from ammonia and trans-4-chloromethylcyclohexanecarboxylic acid 13.5g (76.4mmol) of trans-4-chloromethylcyclohexanecarboxylic acid, 200ml of water, and 28% aqueous ammonia are added to an autoclave and reacted at 80°C and 1.2MPa for 12 hours. After the reaction, the mixture is allowed to cool and return to room temperature, and the reaction mixture is removed from the autoclave. Air is slowly blown in to remove the ammonia, and the pH is adjusted to 6-7 using hydrochloric acid. The mixture is concentrated under reduced pressure to dryness. Water is added to the crude product to dissolve it, acetone is added, and the mixture is allowed to cool, yielding 7.9g (50.2mmol) of trans-4-(aminomethyl)cyclohexanecarboxylic acid (hereinafter also referred to as tranexamic acid). Yield: 65.7% The 1H-NMR (D2O) data of the obtained trans-4-(aminomethyl)cyclohexanecarboxylic acid was consistent with the 1H-NMR (D2O) data of tranexamic acid.

[0166] ·Tranexamic acid 1H-NMR(D2O) data 1.01-1.11 (m 2H), 1.33-1.40 (m 2H), 1.64-1.68 (m 1H), 1.82-1.84 (m 2H), 1.91-1.93 (m 2H), 2.08-2.16 (m 1H), 2.86 (d 2H)

[0167] Example 7A Synthesis of trans-4-(aminomethyl)cyclohexanecarboxylic acid (2c) from trans-4-(methylsulfonyloxy)methylcyclohexanecarboxylic acid methyl ester i) Synthesis of trans-4-(azido)methylcyclohexanecarboxylic acid methyl ester To a solution of 18.0 g (71.9 mmol) of trans-4-(methylsulfonyloxy)methylcyclohexane carboxylic acid methyl ester and 75 ml of N,N-dimethylformamide, add 7.2 g (110.7 mmol) of sodium azide at room temperature. The reaction mixture is stirred at 80°C under nitrogen for 5 hours. After cooling, the reaction mixture is poured into 300 ml of water and extracted with 100 ml of toluene. The aqueous layer is further extracted twice with 100 ml of toluene, and the mixture is combined with the previous toluene layer, washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 14 g (65.6 mmol) of crude trans-4-(azido)methylcyclohexane carboxylic acid methyl ester as a yellow oil. 1H-NMR (Methanol-d4) 3.13-3.17 (2H m) 3.66 (3H s) ii) Synthesis of trans-4-(aminomethyl)cyclohexanecarboxylic acid (2c) To a solution of 10 g (46.9 mmol) of trans-4-(azido)methylcyclohexane carboxylic acid methyl ester and 200 ml of methanol, add 1.7 g of 10% Pd / C (palladium on carbon) and hydrogenate at room temperature under atmospheric pressure for 6 hours. The reaction mixture is filtered to remove Pd / C and concentrated under reduced pressure to obtain 7.5 g of oily trans-4-(aminomethyl)cyclohexane carboxylic acid methyl ester. This can be confirmed as hydrochloride by a conventional method. Melting point: 167-171°C. Add 50 ml of isopropanol to this, then add 2N sodium hydroxide, and stir under reflux for 2.5 hours. Allow to cool to room temperature, filter out insolubles from the reaction mixture, dilute the filtrate three times with water, pass it through a weak acid ion exchange resin and then a weak base ion exchange resin, and concentrate the filtrate under reduced pressure. The residue is recrystallized from water / acetone to obtain 6.8 g (43.2 mmol) of trans-4-(aminomethyl)cyclohexane carboxylic acid. Yield: 92.1%. The 1H-NMR (D2O) data of the obtained trans-4-(aminomethyl)cyclohexanecarboxylic acid was consistent with the 1H-NMR (D2O) data of tranexamic acid.

[0168] Example 8A Synthesis of 4-(aminomethyl)cyclohexanecarboxylic acid (2c) from 4-chloromethylcyclohexanecarboxylic acid methyl ester To a solution of 14.0 g (73.4 mmol) of 4-chloromethylcyclohexane carboxylic acid methyl ester and 250 ml of methanol, add 14.5 g (103.4 mmol) of hexamethylenetetramine and 1.5 g (10.0 mmol) of sodium iodide, and stir at room temperature for 24 hours. After confirming that 4-chloromethylcyclohexane carboxylic acid methyl ester has disappeared from the reaction mixture and that hexamethylenetetramine has been produced, concentrate. Add 30 ml of concentrated hydrochloric acid to the reaction mixture, stir under reflux for 4 hours, and allow to cool and return to room temperature. Neutralize with 2N aqueous sodium hydroxide solution, add 100 ml of toluene, and extract twice. Filter insoluble matter from the aqueous layer, pass it through a weak acid ion exchange resin, then a weak base ion exchange resin, and concentrate the filtrate under reduced pressure. Recrystallize the residue from water / acetone to obtain 10.3 g (65.5 mmol) of 4-(aminomethyl)cyclohexane carboxylic acid. Yield from 4-chloromethylcyclohexanecarboxylic acid methyl ester: 93%

[0169] Example 9A Synthesis of trans-4-(aminomethyl)cyclohexanecarboxylic acid (2c) from trans-4-chloromethylcyclohexanecarboxylic acid isopropyl ester A solution of 11.5g (52.6mmol) of trans-4-chloromethylcyclohexane carboxylic acid isopropyl ester and 80ml of N,N-dimethylformamide is added to 14.1g (76.1mmol) of potassium phthalimide, heated to 70-85℃, and stirred for 6 hours. Then, it is stirred overnight. After cooling, the reaction mixture is poured into water and extracted with 250ml of toluene. The toluene layer is washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 16.5g of crude trans-4-(phthalimido)methylcyclohexane carboxylic acid isopropyl ester. After charging 16.5g of this crude trans-4-(phthalimido)methylcyclohexane carboxylic acid isopropyl ester, 90ml of isopropanol, and 15ml of water, 5.7g (150mmol) of sodium borohydride is added under stirring at room temperature, and the mixture is stirred overnight at room temperature. 150 ml of 2N hydrochloric acid is added dropwise to this reaction mixture at room temperature to decompose excess sodium borohydride, and the mixture is stirred at 80°C for 3 hours and allowed to cool to room temperature. The pH of the reaction mixture is adjusted to 11 with 25% sodium hydroxide and stirred at 80°C for 4 hours. After allowing to cool to room temperature, the reaction mixture is filtered to remove insoluble matter, and the aqueous layer is washed with 100 ml of toluene. The aqueous layer is passed through a weak acid ion exchange resin and then a weak base ion exchange resin, and the filtrate is concentrated under reduced pressure. The residue is recrystallized from water / acetone to obtain 6.4 g (40.7 mmol) of trans-4-(aminomethyl)cyclohexanecarboxylic acid. Yield: 77.4%. Note that the amount of the obtained 4-(aminomethyl)cyclohexanecarboxylic acid is 1 H-NMR (D2O) data for tranexamic acid 1 The H-NMR (DO) data was consistent.

[0170] The reaction scheme of Examples 1A to 9A is outlined in the following Reaction Scheme 7.

[0171] [ka]

[0172] Example 10A Synthesis of 4-(aminomethyl)cyclohexanecarboxylic acid from 4-(hydroxymethyl)cyclohexanecarboxylic acid 1 i) Synthesis of methyl-4-(hydroxymethyl)cyclohexanecarboxylate A solution of 25 g (0.158 mol) of 4-(hydroxymethyl)cyclohexanecarboxylic acid and 125 g of methanol was cooled to 0°C, and 9.4 g (0.079 mol) of thionyl chloride was added dropwise using a dropping funnel. The reaction solution was slowly warmed to room temperature and stirred overnight. After 4-(hydroxymethyl)cyclohexanecarboxylic acid was consumed (by TLC), the solution was concentrated under reduced pressure to give 27.2 g of the desired methyl-4-(hydroxymethyl)cyclohexanecarboxylate as an oil. Yield: 100% ii) Synthesis of methyl-4-(chloromethyl)cyclohexanecarboxylate A mixture of 27.2 g (0.158 mol) of methyl-4-(hydroxymethyl)cyclohexanecarboxylate, 40 g of toluene, and 5 g (63.2 mmol) of pyridine is slowly dripped into a solution of 22.6 g (0.19 mol) of thionyl chloride in 10 g of toluene at 10°C or less under ice cooling over about 30 minutes. The mixture is then heated at 70-80°C for 4 hours, allowed to cool, quenched with water, washed with a dilute aqueous solution of sodium hydroxide and an aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. As the residue, 27.2 g (0.143 mol) of crude methyl-4-(chloromethyl)cyclohexanecarboxylate is obtained as an oil. Yield: 90.5% iii) Synthesis of methyl [(4-methoxycarbonylcyclohexyl)methyl]carbamate When reacting with 27g (0.14mol) of methyl-4-(chloromethyl)cyclohexanecarboxylate, 17g (0.21mol) of potassium cyanate, and 18g (0.56mol) of methanol, in the presence of 20g (0.168mol) of KBr for halogenation exchange, the mixture is heated to 100℃ in 160g of DMF, reacted for 10 hours, cooled, added with water, extracted with 200ml of ethyl acetate, washed with dilute hydrochloric acid, and dried over anhydrous magnesium sulfate. The residue obtained by concentration is separated and purified by silica gel chromatography to obtain 25g (0.109mol) of methyl [(4-methoxycarbonylcyclohexane-yl)methyl]carbamate as an oil. Yield: 77.9% iv) Synthesis of 4-(aminomethyl)cyclohexanecarboxylic acid Add 5.0 g (21.8 mmol) of methyl [(4-methoxycarbonylcyclohexyl)methyl]carbamate and 25 ml of 35% hydrochloric acid (12N HCl) and heat to reflux for 3 hours. Remove insoluble matter by filtration, pass the reaction solution through a weakly basic ion exchange resin (OH type) to remove hydrochloric acid and inorganic ions, concentrate the effluent, and recrystallize from water / acetone / methanol to obtain 2.87 g of 4-(aminomethyl)cyclohexanecarboxylic acid. Yield: 83.6% In this example, a cis / trans mixture of 4-(hydroxymethyl)cyclohexanecarboxylic acid was used as the starting material, and the products obtained in the above reactions i) to iv) were separated into cis and trans isomers using gas chromatography. When separation was possible, the ratio of cis / trans isomers was determined. As a result, the cis / trans ratios of the products obtained in the reactions i), ii), and iii) were 5.3 / 1, 6 / 1, and 0.9 / 1, respectively. From these experimental results, it was found that the reaction iii) can be used to isomerize a cis / trans mixture of cyclohexane rings and convert it into a predominantly trans isomer.

[0173] Example 11A Synthesis of 4-(aminomethyl)cyclohexanecarboxylic acid from 4-(hydroxymethyl)cyclohexanecarboxylic acid 2 i) Synthesis of methyl-4-(hydroxymethyl)cyclohexanecarboxylate Methyl-4-(hydroxymethyl)cyclohexanecarboxylate is prepared analogously to Example 10A i). ii) Synthesis of methyl-4-(bromomethyl)cyclohexanecarboxylate 7.28 g (0.042 mol) of methyl-4-(hydroxymethyl)cyclohexanecarboxylate, 70 g of toluene, and 1.17 g (0.0148 mol) of pyridine were quenched in cold water. 4.275 g (=1.5 ml, 0.0158 mol) of phosphorus tribromide in 30 g of toluene was added dropwise to the cooled mixture, and the reaction was stirred for 30 minutes, warmed to room temperature, and stirred overnight. After carefully quenching the reaction with saturated sodium bicarbonate solution and diluting with water, the organic extract was washed with saturated sodium bicarbonate solution, then with brine, dried over MgSO4, and concentrated under reduced pressure to give 8.4 g (0.0357 mol) of the desired methyl-4-(bromomethyl)cyclohexanecarboxylate. Yield: 85%. iii) Synthesis of methyl [(4-methoxycarbonylcyclohexyl)methyl]carbamate When reacting with 8g (0.034mol) of methyl-4-(bromomethyl)cyclohexanecarboxylate, 4.14g (0.051mol) of potassium cyanate, and 4.36g (0.136mol) of methanol, the mixture is heated to 100℃ in 48g of DMF, reacted for 6 hours, cooled, added with water, extracted with 60g of ethyl acetate, washed with dilute hydrochloric acid, and dried over anhydrous magnesium sulfate. The residue obtained by concentration is separated and purified by silica gel chromatography to obtain 6.4g (0.028mol) of methyl [(4-methoxycarbonylcyclohexane-yl)methyl]carbamate as an oil. Yield: 82.4% iv) Synthesis of 4-(aminomethyl)cyclohexanecarboxylic acid 4-(Aminomethyl)cyclohexanecarboxylic acid is synthesized analogously to Example 10A iv).

[0174] Examples 10A and 11A are outlined in Scheme 8 below. [ka]

[0175] As described above, according to the present invention, 4-(aminomethyl)cyclohexanecarboxylic acid can be obtained under mild conditions by substituting the hydroxy group of 4-(hydroxymethyl)cyclohexanecarboxylic acid with a substitutable leaving group such as halogen, alkylsulfonyloxy, arylsulfonyloxy, or tosylation, followed by amination with ammonia, reduction reaction following azidation, decomposition reaction following imidation, decomposition reaction after substitution with hexamethylenetetramine, or decomposition reaction after substitution with an alkoxycarbonyl group, and the like, and thus it becomes unnecessary to reduce or use expensive noble metal catalysts, etc., as in the conventional method for reducing the cyclohexane moiety with a benzene ring, and therefore no special equipment is required. That is, according to the production method of the present invention, 4-(aminomethyl)cyclohexanecarboxylic acid can be produced from inexpensive raw materials. [Industrial Applicability]

[0176] According to the present invention, 4-(aminomethyl)cyclohexanecarboxylic acid can be produced from inexpensive raw materials, and can be synthesized under mild conditions. Since no special equipment is required and expensive catalysts are hardly used, industrialization is easy. Therefore, the present invention can be usefully applied to the industrial production of tranexamic acid. Therefore, the industrial applicability of the present invention is extremely high.

Claims

1. The method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) from 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate (1) or a hydrolysate thereof includes a step of converting a hydroxy group of 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate (1) to a primary amine precursor A to give intermediate (1), and a step of decomposing the intermediate (1), to produce 4-(aminomethyl)cyclohexanecarboxylic acid (2) represented by the following formula 1. 【Chemistry 1】

2. The method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) from 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate (1) or a hydrolysate thereof includes the steps of: converting a hydroxy group of 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate (1) to a primary amine precursor A to obtain an intermediate (1); substituting the primary amine precursor A of the intermediate (1) with an amino group to obtain 4-(aminomethyl)cyclohexylmethyl 4'-(aminomethyl)cyclohexanecarboxylate; and decomposing 4-(aminomethyl)cyclohexylmethyl 4'-(aminomethyl)cyclohexanecarboxylate, which is represented by the following formula 1: 【Chemistry 2】

3. A method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) from 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate (1) or a hydrolysate thereof, the method comprising the steps of converting a hydroxy group of 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate (1) to a primary amine precursor A to give an intermediate (1), and hydrolyzing the intermediate (1) to substitute the primary amine precursor A of the intermediate (1) with an amino group, to produce 4-(aminomethyl)cyclohexanecarboxylic acid (2) represented by the following formula 1. 【Chemistry 3】

4. The method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) according to any one of claims 1 to 3, wherein the step of converting the hydroxy group into a primary amine precursor A is a step of converting the hydroxy group into a substitutable leaving group X, and then converting the leaving group X into a primary amine precursor A to which a nitrogen atom is bonded.

5. The method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) according to any one of claims 1 to 4, wherein the step of converting the hydroxy group into a primary amine precursor A is a step of converting the hydroxy group into a replaceable leaving group X, and then substituting the leaving group X with an azide group.

6. The method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) according to any one of claims 1 to 4, wherein the step of converting the hydroxy group into a primary amine precursor A is a step of converting the hydroxy group into a replaceable leaving group X, and then substituting the leaving group X with hexamethylenetetramine.

7. The method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) according to any one of claims 1 to 4, wherein the step of converting the hydroxy group into a primary amine precursor A is a step of converting the hydroxy group into a replaceable leaving group X, and then substituting the leaving group X with an imide group.

8. The method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) according to any one of claims 1 and 4 to 7, wherein the step of decomposing the intermediate (1) comprises hydrolyzing the intermediate (1) to obtain a mixture of a carboxylic acid derivative and an amino alcohol derivative.

9. The method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) according to claim 8, further comprising a step of converting a hydroxy group of the aminoalcohol derivative into a carboxy group.

10. The method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2) according to any one of claims 1 to 4, wherein the step of converting the hydroxy group into a primary amine precursor A is a step of converting the hydroxy group into a replaceable leaving group X, and then substituting the leaving group X with an alkoxycarbonylamino group.

11. A method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2a), comprising converting a hydroxy group of 4-(hydroxymethyl)cyclohexanecarboxylic acid (1a), which is a hydrolysis product of 4-(hydroxymethyl)cyclohexylmethyl 4'-(hydroxymethyl)cyclohexanecarboxylate (1), into a primary amine, The method for converting the hydroxy group into a primary amine is a method of converting the hydroxy group into a replaceable leaving group X, and then converting the leaving group X into a primary amino group with ammonia, or a method of substituting the leaving group X with a primary amine precursor A to which a nitrogen atom is bonded, and then converting the primary amine precursor A into a primary amine. 【Chemistry 4】

12. The method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2a) according to claim 11, wherein the method for converting the hydroxy group into a primary amine is a method in which the hydroxy group is converted into a replaceable leaving group X, the leaving group X is then substituted with an azide group, and the azide group is reduced to convert the azide group into the primary amine.

13. The method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2a) according to claim 11, wherein the method for converting the hydroxy group into a primary amine is a method in which the hydroxy group is converted into a replaceable leaving group X, the leaving group X is then substituted with hexamethylenetetramine, and the hexamethylenetetramine is decomposed to convert the hydroxy group into a primary amine.

14. The method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2a) according to claim 11, wherein the method for converting the hydroxy group into a primary amine is a method for converting the hydroxy group into a replaceable leaving group X, and then substituting the leaving group X with an imide group, and converting the imide group into the primary amine by reacting with at least one selected from an acid, a base, a reducing agent, a hydrazine, or an alkylamine.

15. The method for producing 4-(aminomethyl)cyclohexanecarboxylic acid (2a) according to claim 11, wherein the method for converting the hydroxy group into a primary amine is a method for converting the hydroxy group into a replaceable leaving group X, and then substituting the leaving group X with an alkoxycarbonylamino group, which is then hydrolyzed to convert into the primary amine.

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