JP2008260723A - Method for producing cis-4-alkylcyclohexylamine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for isolating a cis-form substance from a cis/trans form-mixed material of 4-alkylcyclohexylamine. <P>SOLUTION: This method for producing the cis-4-alkylcyclohexylamine comprises a process of mixing (I) the cis/trans form-mixed material with (II) an acid in a solvent used for crystallization to form (III) an acid adduct salt and then crystallizing. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an acid addition salt of cis-4-alkylcyclohexylamine which is useful as an intermediate for pharmaceuticals and the production thereof.

  Cis-4-alkylcyclohexylamine is a useful intermediate for pharmaceuticals and the like, and conventionally, various methods listed below are known as its production method.

Non-Patent Document 1 discloses a method for obtaining a mixture of cis / trans isomers of 4-isopropylcyclohexylamine from 4-isopropylaniline by reduction by hydrogenation at 80 to 120 ° C. under a pressure of 100 bar. . Specifically, when Ru / Al ₂ O ₃ was used as a catalyst, a mixture having a cis / trans isomer ratio of 1.1 to 1.4: 1 was obtained, and Ru / C was used. In some cases, it was reported that although a 2: 1 ratio mixture was obtained, it contained about 50% of the by-product of bicyclohexylamine shown below. When Rh / Al ₂ O ₃ was used as a catalyst, a mixture having a cis / trans isomer ratio of 3: 1 was obtained, but the reaction was incomplete, and 11% of bicyclohexylamine was present. It is reported that it was included. Further, when Rh / C was used, it was reported that although a mixture having the ratio of 4: 1 was obtained, about 50% of bicyclohexylamine was contained. However, there is no description of a method for isolating high purity cis-4-alkylcyclohexylamine from the reaction mixture.

  In Patent Document 1, 4-butylaniline having a cis / trans isomer ratio of 1: 1 was synthesized by hydrogenating 4-butylaniline in Example 1 with glacial acetic acid in the presence of platinum oxide. Is disclosed.

  Non-Patent Document 2 describes a method for producing cis-4-alkylcyclohexylamine by reducing 4-alkylcyclohexanone oxime, but describes that a trans isomer is mixed.

R = methyl, chemical yield 54%; trans isomer content <30%
R = ethyl, chemical yield 62%; trans isomer content = about 40%
R = i-propyl, chemical yield 57%; trans isomer content <40%
R = s-butyl, chemical yield 68%; trans isomer content <15%
R = c-hexyl, chemical yield 40%; trans isomer content <15%

  Patent Document 2 describes a method for producing high-purity cis-4-alkylcyclohexylamine by performing reductive amination and hydrogenolysis of 4-alkylcyclohexanone using benzylamine or the like.

  However, as described above, there is no known method for isolating the cis isomer in high purity and high yield from a cis / trans isomer mixture of 4-alkylcyclohexylamine. Furthermore, in the method for producing cis-4-alkylcyclohexylamine using 4-alkylcyclohexanones as starting materials, each step requires complicated operations, or materials that are difficult to obtain commercially are used. Therefore, it is not necessarily an industrially advantageous method. Also, benzoic acid salts of cis-4-alkylcyclohexylamine or benzenesulfonic acid salts and production methods are not known.

US Pat. No. 3,671,642 WO99 / 47487 pamphlet J. Med. Chem., 46, 255 (2003) J. Chem. Soc. (B), 1047 (1971)

  The present invention provides a method for isolating cis isomers in high purity from a mixture of cis and trans isomers (also referred to herein as cis / trans isomers) of 4-alkylcyclohexylamines. With the goal.

  As a result of intensive studies to achieve the above-mentioned problems, the present inventors have mixed a specific acid with a cis / trans isomer mixture of 4-alkylcyclohexylamines having a cis isomer content of more than 50%, and a crystallization solvent. It was found that a high-purity cis-4-alkylcyclohexylamine acid addition salt could be efficiently and easily isolated by forming a salt therein and crystallizing it, thereby completing the present invention.

  That is, the present invention provides the following method for producing an acid addition salt of cis-4-alkylcyclohexylamine.

  [Item 1] The following formula (I):

[Wherein, R ¹ represents a C _2-6 alkyl group. ]
A cis isomer and a trans isomer (cis / trans isomer) mixture of 4-alkylcyclohexylamine represented by the formula (II), wherein the cis isomer content of the mixture is more than 50%, and the following formula (II): ):

[Wherein, A represents —CO— or —SO ₂ —, and R ² , R ³ or R ⁴ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a halogen atom. ]
And a compound represented by the following formula (III):

[Wherein, A, R ¹ , R ² , R ³ and R ⁴ are the same as above. ]
The manufacturing method of compound (III) including the process of forming and crystallizing the acid addition salt of cis-4-alkyl cyclohexylamine represented by these.

[Item 2] The production method according to item 1, wherein R ¹ represents a C _3-5 alkyl group.

[Claim 3] hydrogen atom R ² is to be bonded to either position para to A, a methyl group, an ethyl group or a chlorine atom, both R ³ and R ⁴ according to claim 1 or 2 represents a hydrogen atom Manufacturing method.

[Item 4] The method according to Item 3, wherein A represents —SO ₂ —.

  CLAIM | ITEM 5 The manufacturing method as described in any one of claim | item 1 -4 whose cis-isomer content rate of the cis / trans isomer mixture represented by Formula (I) is 55% or more.

  CLAIM | ITEM 6 The manufacturing method as described in any one of claim | item 1 -5 whose purity of compound (III) is 95% or more.

  CLAIM | ITEM 7 The manufacturing method as described in any one of claim | item 1 -6 which uses 0.8-2.0 equivalent for compound (II) with respect to the cis / trans isomer mixture represented by Formula (I).

  [Item 8] The production method according to any one of Items 1 to 7, wherein the amount of the crystallization solvent is 10 to 60 parts by volume based on 1 part by weight of the cis / trans isomer mixture represented by the formula (I). .

  [Item 9] The following formula (III):

[Wherein, A represents —CO— or —SO ₂ —, R ¹ represents a C _2-6 alkyl group, and R ² , R ³ or R ⁴ are the same or different and represent a hydrogen atom, C _{1 -6 represents} an alkyl group or a halogen atom. An acid addition salt of cis-4-alkylcyclohexylamine represented by the formula:

  According to the present invention, a highly pure acid addition salt of cis-4-alkylcyclohexylamine can be obtained industrially advantageously.

  The present invention will be described below. Note that the following abbreviations may be used to simplify the description in this specification. Me: methyl, Et: ethyl, Pr: propyl, Bu: butyl, Pen: pentyl, t-: tert-, s-: sec-, i-: iso-, n-: normal, c-: cyclo, THF: Tetrahydrofuran, DME: 1,2-dimethoxyethane, IPA: 2-propanol, EAC: ethyl acetate, HEP: heptane, TOL: toluene, ACE: acetone

  The mixture of cis isomer and trans isomer of 4-alkylcyclohexylamine represented by the formula (I) is the following formula (I-1):

[Wherein, R ¹ is the same as defined in item 1. ]
Cis-4-alkylcyclohexylamine represented by the following formula (I-2):

[Wherein, R ¹ is the same as defined in item 1. ]
And a mixture with trans-4-alkylcyclohexylamine represented by the formula:

  In the above mixture according to the present invention, the cis isomer content (%) [cis isomer abundance ratio / (cis isomer abundance ratio + trans isomer abundance ratio)] × 100 exceeds 50%. Preferably, the cis isomer content of the mixture is 55% or more, more preferably 60% or more. When one having a cis isomer content of 50% or less is used, a highly pure acid addition salt of cis-4-alkylcyclohexylamine cannot be obtained by the production method of the present invention.

In the present specification, the “alkyl group” means a linear or branched saturated hydrocarbon, for example, “C _3-5 alkyl group”, “C _2-6 alkyl group” or “C _The “ _1-6 alkyl group” means an alkyl group having 3 to 5, 2 to 6 or 1 to 6 carbon atoms. Specific examples thereof include “C _3-5 alkyl group”, propyl group, i-propyl group, butyl group, i-butyl group, s-butyl group, t-butyl group, pentyl group, i-pentyl group. When the group, neopentyl group or the like is “C _2-6 alkyl group”, in addition to the above, when the ethyl group, hexyl group or the like is “C _1-6 alkyl”, in addition to the above, a methyl group Is mentioned.

  “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferably, it is a chlorine atom.

Preparation of cis / trans isomer mixture of formula (I) The cis / trans isomer mixture of formula (I) can be prepared by the method of reducing 4-alkylaniline (IV) shown in the following scheme. Specifically, a compound having a cis isomer content of more than 50% is obtained by adding a specific amount of acid to the reaction solution of compound (IV) and hydrogenating the benzene ring in the presence of a hydrogenation catalyst. The cis / trans isomer mixture of (I) is produced in high yield. Specifically, according to this method, a cis / trans isomer mixture of the formula (I) having a cis isomer content of 70 to 85% can be obtained.

[Wherein, R ¹ is the same as defined in item 1. ]
Compound (IV) as a raw material is industrially easily available and inexpensive compared to 4-alkylcyclohexanones, which are raw materials described in Patent Document 2. Specific examples include 4-ethylaniline, 4-propylaniline, 4-isopropylaniline, 4-butylaniline, 4-isobutylaniline, 4-s-butylaniline, 4-pentylaniline, 4-hexylaniline and the like. .

  Examples of the hydrogenation catalyst include at least one metal catalyst selected from the group consisting of palladium, platinum, nickel, rhodium, ruthenium, iridium, osmium, and the like. From the viewpoint of reactivity and selectivity, the platinum catalyst Is preferred.

  Specific examples of metal catalysts include zero-valent metals, nitrates, sulfates, acetates, chlorides, bromides, oxides, hydroxides, and other metal-containing organic substances, amine complexes, phosphine complexes, and carbonyl compounds. Examples of the metal-containing complex compound such as platinum are preferable, and platinum oxide which is an oxide of platinum is preferable. These may be used alone or in combination.

  The metal-based catalyst can be used as it is, but can also be used as a carrier-supported catalyst. The carrier-supported catalyst may be a conventionally known or commercially available catalyst and is not particularly limited as long as it is a catalyst that can hydrogenate an aromatic ring. Specific examples of the carrier include diatomaceous earth, pumice, activated carbon, silica gel, alumina, zirconium oxide, titanium oxide, and mixtures thereof.

  The amount of the catalyst used varies depending on the type of the catalyst, but the amount of the catalyst containing no carrier is usually 0.005 parts by weight or more per 1 part by weight of the compound (IV), and there is no particular upper limit. However, if it is too much, it tends to be economically disadvantageous, so it is practically 0.1 parts by weight or less, preferably 0.05 parts by weight or less.

  In the hydrogenation reaction, a cis / trans isomer mixture of formula (I) having a high cis isomer content can be produced by adding a specific amount of acid to the reaction solution relative to compound (IV). it can. Specific examples of the acid that can be used include organic acids such as acetic acid, formic acid and propionic acid, and mineral acids such as hydrochloric acid and sulfuric acid, with acetic acid being preferred. The amount of the acid added is 0.5 to 3.0 equivalents, preferably 0.9 to 2.2 equivalents, relative to compound (IV).

  The hydrogenation reaction is carried out without solvent or using a suitable solvent. The reaction solvent used is not particularly limited as long as it is an inert solvent for the hydrogenation reaction, but preferably THF, dioxane, DME, ethyl acetate, acetone, acetonitrile or methanol, ethanol, IPA, t-butanol and the like. Examples thereof include organic solvents such as alcohols and water, and these can be used alone or as a mixed solvent. Preferably, alcohols are used, and the amount of the solvent used is usually 3 parts by volume or more, preferably 5 parts by volume or more with respect to 1 part by weight of the compound (IV). If the amount is too large, the volumetric efficiency is deteriorated, so that it is practically 20 parts by volume or less. In addition, 1 volume part with respect to 1 weight part means 1 mL with respect to 1 g.

  The reaction temperature varies depending on the compound (IV) used, the solvent, the catalyst, the type of acid, etc., but is usually −10 to 120 ° C., preferably 10 to 50 ° C.

  The reaction pressure is in the range of 0.1 to 1.0 MPa, preferably in the range of 0.1 to 0.5 MPa, as the hydrogen partial pressure of the reaction system.

  While the reaction time varies depending on the amount of catalyst and various conditions, it is generally 0.5 to 48 hours, preferably 2 to 24 hours.

  In addition to the above method, specific examples of the method for producing a cis / trans isomer mixture of the formula (I) having a cis isomer content of more than 50% include conventionally known methods such as the above-mentioned Patent Document 2, Non-Patent Document 2. The method of patent document 1 and nonpatent literature 2 is mentioned. In addition, a method of increasing the cis isomer by isomerizing the trans isomer in the obtained isomer mixture or a method of increasing the cis isomer by removing the trans isomer from the isomer mixture can be used.

  From the hydrogenation reaction crude product obtained by the above method, the catalyst is removed by a usual method such as filtration or centrifugation, and purified by a known method such as distillation, whereby the cis isomer content exceeds 50%. A cis / trans isomer mixture of (I) can be obtained.

Production of Compound (III) Next, the production method of the compound (III) of the present invention will be described. The production method of the present invention comprises a step of mixing a cis / trans isomer mixture of formula (I) and compound (II) in a suitable crystallization solvent to form a salt of compound (III) and crystallizing. It is characterized by including.

  Examples of the crystallization solvent include THF, dioxane, DME, ethyl acetate, toluene, acetone, heptane, organic solvents such as methanol, ethanol, IPA, and t-butanol, or water. Can be used as Preferably, THF or IPA is used, and the amount used is usually 10 parts by volume or more, preferably 20 parts by volume or more, based on 1 part by weight of the cis / trans isomer mixture of formula (I), and the upper limit is Although there is no particular, the volumetric efficiency is deteriorated if it is too much, so it is practically 60 parts by volume or less.

  The following formula (II) used for the production of compound (III):

[Wherein, A, R ² , R ³ and R ⁴ are the same as defined in item 1. Specific examples of the compound represented by formula (I) include benzenesulfonic acids such as p-toluenesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 4-ethylbenzenesulfonic acid, and 2-mesitylenesulfonic acid, benzoic acid, 4 -Benzoic acids such as methylbenzoic acid, 4-chlorobenzoic acid and 3-chlorobenzoic acid. Preferably, a compound in which R ² is bonded to a position para to the A, represents a hydrogen atom, a methyl group, an ethyl group or a chlorine atom, and R ³ and R ⁴ represent a hydrogen atom is preferable. Specifically, benzenesulfonic acids such as p-toluenesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid and 4-ethylbenzenesulfonic acid, and benzoic acids such as benzoic acid, 4-methylbenzoic acid and 4-chlorobenzoic acid. Is mentioned. More preferably, benzenesulfonic acids in which A represents —SO ₂ — are preferable. Compound (II) may exist in hydrates and / or solvates, and these hydrates and / or solvates may be used. The amount of compound (II) used is from 0.8 to 2.0 equivalents, preferably from 0.9 to 1.5 equivalents, particularly preferably from 0.8 to 2.0 equivalents, based on the cis / trans isomer mixture of formula (I). It is in the range of 9 to 1.2 equivalents.

  The salt formation / crystallization step is performed under normal pressure, reduced pressure, or increased pressure. This step may be performed in an inert gas atmosphere such as nitrogen or argon. The temperature in the salt formation / crystallization step is preferably in the range of 0 to 120 ° C., particularly 20 to 100 ° C., particularly preferably under reflux. In the present invention, the cis / trans isomer mixture of the formula (I) and the compound (II) are dissolved in a crystallization solvent to form a uniform solution to form a salt of the compound (III) for crystallization. preferable.

  In the salt formation / crystallization step in the present invention, stirring is not essential, but stirring is preferable. The time required for this step varies depending on various conditions, but is usually 0.5 to 24 hours, preferably, 1 to 12 hours.

  The salt formation and crystallization operations are performed by concentrating and / or cooling the above solution. By obtaining precipitated crystals, the acid addition salt of the target product, cis-4-alkylcyclohexylamine, is obtained with high purity. be able to. The step of obtaining the crystal is not particularly limited and can be performed by a conventionally known method. For example, these crystals can be taken out by ordinary methods such as filtration and decantation. Compound (III) produced by this method is of high purity. For example, from a cis / trans isomer mixture of formula (I) having a cis isomer content of 80%, the cis isomer content is 90% or more, preferably 95% or more, more preferably 97% or more. Manufactured by.

  Further, the thus obtained compound (III) is purified by recrystallization, column chromatography or the like to obtain an acid addition salt of cis-4-alkylcyclohexylamine having a very low trans isomer content. be able to.

  Since the compounds of the present invention may exist as hydrates and / or solvates, these hydrates and / or solvates are also encompassed in the compounds of the present invention.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, reference examples, and comparative examples, but the present invention is not limited to these examples. In addition, the compound was identified from ¹ H-NMR measurement (300 MHz or 400 MHz). In addition, the ratio of cis isomer and trans isomer of 4-alkylcyclohexylamines is represented by the cis isomer content in the cis / trans isomer mixture, and the cis isomer content is the cis isomer in the NMR spectrum and Calculation was based on the integral ratio derived from the α-position proton of the amino group of the trans isomer. In addition, the combined yield of the mixture of cis isomer and trans isomer was distinguished and expressed as a chemical yield.

When “cis isomer content> 99%” is indicated, the trans isomer is below the detection limit in the ¹ H-NMR measurement.

Reference example 1
Production of 4-butylcyclohexylamine:
15.0 g of 4-butylaniline is dissolved in ethanol (100 mL), 8.63 mL of acetic acid (1.5 equivalents relative to 4-butylaniline) and 0.40 g of platinum oxide are added, and under a hydrogen atmosphere (0.4 MPa) And stirred at room temperature for 16 hours. The reaction mixture was filtered through celite, and the solvent was distilled off under reduced pressure. To the residue, 100 mL of diethyl ether and 150 mL of water were added for extraction, and the organic layer was removed. 16 g of sodium hydroxide was added to the obtained aqueous layer, and extracted with 200 mL of diethyl ether. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 13.0 g of the desired product (chemical yield 83%, cis isomer content 85%).

Reference example 2
Production of 4-butylcyclohexylamine:
15.0 g of 4-butylaniline is dissolved in ethanol (100 mL), 8.63 mL of acetic acid (1.5 equivalents with respect to 4-butylaniline) and 1.0 g of platinum oxide are added, and under a hydrogen atmosphere (0.4 MPa) And stirred at room temperature for 17 hours. The reaction mixture was filtered through celite, and the solvent was distilled off under reduced pressure. To the residue, 100 mL of diethyl ether and 150 mL of water were added for extraction, and the organic layer was removed. 17 g of sodium hydroxide was added to the obtained aqueous layer, and extracted with 200 mL of diethyl ether. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 14.5 g of the desired product (chemical yield 92%, cis isomer content 81%).

Reference Examples 3-5
Production of 4-butylcyclohexylamine:
The cis isomers shown in Table 1 were reacted and treated in the same manner as in Reference Example 2 except that the amount of acetic acid in Reference Example 2 was 1.0, 1.2, or 2.0 equivalents relative to 4-butylaniline. A 4-butylcyclohexylamine content was obtained.

Reference Example 6
Production of 4-butylcyclohexylamine:
According to Patent Document 1, 7.50 g of 4-butylaniline was dissolved in 75.3 mL of acetic acid, 0.4 g of platinum oxide was added, and the mixture was stirred at room temperature for 18 hours in a hydrogen atmosphere (0.4 MPa). The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. To the residue, 50 mL of diethyl ether and 100 mL of water were added for extraction, and the organic layer was removed. To the resulting aqueous layer, 9 g of sodium hydroxide was added and extracted with 120 mL of diethyl ether. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 6.25 g (chemical yield 80%, cis isomer content 50%) of the desired product.

Reference Examples 7-10
Production of various 4-alkylcyclohexylamines:
Using various 4-alkylanilines, the reaction and treatment were performed in the same manner as in Reference Example 2 to obtain 4-alkylcyclohexylamine having the cis isomer content shown in Table 2.

Example 1
Preparation of cis-4-butylcyclohexylamine p-toluenesulfonate:
1.00 g of 4-butylcyclohexylamine obtained in Reference Example 2 (cis isomer content 81%) was dissolved in THF (35 mL), and 1.22 g of p-toluenesulfonic acid monohydrate (4-butylcyclohexyl). 1.0 equivalent) relative to the amine was added and dissolved under heating to reflux, and then allowed to cool with stirring for 2 hours. The precipitated crystals were collected by filtration, washed with THF, and dried to obtain 1.48 g of the desired product (chemical yield 70%, cis isomer content> 99%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.87 (t, 3H), 1.18-1.32 (m, 6H), 1.33-1.78 (m, 9H), 2.29 (s, 3H), 3.10-3.21 (m, 1H), 7.11 (d, 2H), 7.47 (d, 2H), 7.60 (brs, 3H).

Examples 2-6
Preparation of cis-4-butylcyclohexylamine p-toluenesulfonate:
Instead of 4-butylcyclohexylamine in Example 1 (cis isomer content 81%), 4-butylcyclohexylamine obtained in Reference Example 2 and Reference Example 6 was mixed in various ways, and the cis isomer content was different. By using the mixture and forming a salt and crystallizing in the same manner as in Example 1 except that a crystallization solvent having a volume part shown in Table 3 with respect to 1 part by weight of 4-butylcyclohexylamine was used, the cis isomer contained in Table 3 was contained. A cis-4-butylcyclohexylamine p-toluenesulfonate having a ratio was obtained.

Examples 7-15
Production of various acid addition salts of cis-4-butylcyclohexylamine:
Using 1 part by weight of 4-butylcyclohexylamine, a crystallization solvent having a volume part shown in Table 4 was used to form a salt and crystallize in the same manner as in Example 1, whereby the cis isomer content shown in Table 4 was obtained. Various acid addition salts of -4-butylcyclohexylamine were obtained.

Example 7
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.87 (t, 3H), 1.13-1.31 (m, 6H), 1.32-1.78 (m, 9H), 1.70-1.93, 3.10-3.20 (m, 1H), 7.35 (d, 2H), 7.59 (d, 2H), 7.64 (brs, 3H).

Example 9
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.87 (t, 3H), 1.18-1.31 (m, 6H), 1.32-1.78 (m, 9H), 3.10-3.20 (m, 1H), 7.28 -7.36 (m, 3H), 7.57-7.63 (m, 2H), 7.67 (brs, 3H).

Example 11
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.86 (t, 3H), 1.16-1.31 (m, 6H), 1.32-1.68 (m, 9H), 2.31 (s, 3H), 3.02-3.12 (m, 1H), 7.11 (d, 2H), 7.75 (d, 2H), 7.90 (brs, 3H).

Example 13
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.86 (t, 3H), 1.16-1.31 (m, 6H), 1.32-1.70 (m, 9H), 3.08-3.17 (m, 1H), 7.34 (d, 2H), 7.85 (d, 2H), 8.23 (brs, 3H).

Example 15
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.86 (t, 3H), 1.16-1.31 (m, 6H), 1.32-1.71 (m, 9H), 3.09-3.18 (m, 1H), 7.28 -7.38 (m, 3H), 7.80-7.91 (m, 2H), 8.20 (brs, 3H).

The ¹ H-NMR data of the compounds obtained in Examples 8, 10, 12 and 14 showed the same data as in Examples 7, 9, 11 and 13, respectively.

Comparative Example 1
Preparation of 4-butylcyclohexylamine p-toluenesulfonate:
Example 1 was used except that 4-butylcyclohexylamine (cis isomer content 50%) obtained in Reference Example 6 was used instead of 4-butylcyclohexylamine (cis isomer content 81%) in Example 1. In the same manner as above, salt formation and crystallization gave 1.15 g of the desired product (chemical yield 55%, cis isomer content 69%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.87 (t, 3H), 1.10-1.33 (m, 6H), 1.33-1.68 (m, 5H + 4Hx69 / 100), 1.70-1.93 (m, 4Hx31 / 100), 2.29 (s, 3H), 2.89 (tt, 1Hx31 / 100), 3.10-3.20 (m, 1Hx69 / 100), 7.11 (d, 2H), 7.47 (d, 2H), 7.68 (brs, 3H).

Comparative Examples 2-9
Production of various acid addition salts of 4-butylcyclohexylamine:
In place of p-toluenesulfonic acid monohydrate in Example 1, various acids shown in Table 5 were used, and salt formation / crystals were formed in the same manner as in Example 1 except that the crystallization solvent having a volume part shown in Table 5 was used. By analysis, various acid addition salts of 4-butylcyclohexylamine having the cis isomer content shown in Table 5 were obtained.

Comparative Example 2
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.87 (t, 3H), 1.10-1.32 (m, 6H), 1.33-1.68 (m, 5H + 4Hx73 / 100), 1.70-1.96 (m, 4Hx27 / 100), 2.33 (s, 3H), 2.90 (tt, 1Hx27 / 100), 3.11-3.20 (m, 1Hx73 / 100), 7.71 (brs, 3H).

Comparative Example 3
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.87 (t, 3H), 1.10-1.32 (m, 6H), 1.33-1.68 (m, 5H + 4Hx71 / 100), 1.70-1.96 (m, 4Hx29 / 100), 2.33 (s, 3H), 2.90 (tt, 1Hx29 / 100), 3.11-3.20 (m, 1Hx71 / 100), 7.72 (brs, 3H).

Comparative Example 4
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.87 (t, 3H), 1.10-1.32 (m, 6H), 1.33-1.69 (m, 5H + 4Hx78 / 100), 1.70-1.97 (m, 4Hx22 / 100), 2.87 (tt, 1Hx22 / 100), 3.08-3.17 (m, 1Hx78 / 100), 8.00 (brs, 3H).

Comparative Example 5
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.87 (t, 3H), 1.10-1.32 (m, 6H), 1.33-1.69 (m, 5H + 4Hx80 / 100), 1.70-1.97 (m, 4Hx20 / 100), 2.87 (tt, 1Hx20 / 100), 3.08-3.17 (m, 1Hx80 / 100), 7.97 (brs, 3H).

Comparative Example 6
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.87 (t, 3H), 1.10-1.31 (m, 6H), 1.32-1.69 (m, 5H + 4Hx86 / 100), 1.70-1.92 (m, 4Hx14 / 100), 2.91 (tt, 1Hx14 / 100), 3.10-3.20 (m, 1Hx86 / 100), 7.77 (brs, 3H).

Comparative Example 7
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.87 (t, 3H), 1.10-1.30 (m, 6H), 1.31-1.70 (m, 5H + 4Hx79 / 100), 1.72-1.90 (m, 4Hx21 / 100), 2.70 (tt, 1Hx21 / 100), 2.91-3.01 (m, 1Hx79 / 100), 4.88 (brs, 3H), 6.31 (s, 1H).

Comparative Example 8
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.87 (t, 3H), 1.10-1.30 (m, 6H), 1.31-1.70 (m, 5H + 4Hx67 / 100), 1.72-1.90 (m, 4Hx33 / 100), 2.70 (tt, 1Hx33 / 100), 2.91-3.01 (m, 1Hx67 / 100), 4.88 (brs, 3H), 6.31 (s, 1H).

Comparative Example 9
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.87 (t, 3H), 1.10-1.30 (m, 6H), 1.31-1.61 (m, 5H + 4Hx80 / 100), 1.68-1.87 (m, 4Hx20 / 100), 2.69 (tt, 1Hx20 / 100), 2.93-3.03 (m, 1Hx80 / 100), 5.20 (brs, 3H), 6.01 (s, 1H).

Examples 16-23
Preparation of cis-4-alkylcyclohexylamine p-toluenesulfonate:
In place of 4-butylcyclohexylamine in Example 1 (cis isomer content 81%), various 4-alkylcyclohexylamines obtained in Reference Examples 7 to 10 were used, and the crystallization solvent of the capacity parts shown in Table 6 In the same manner as in Example 1 except that cis was used, salt formation and crystallization were performed to obtain various cis-4-alkylcyclohexylamine p-toluenesulfonates having the cis isomer content shown in Table 6.

Example 16
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.85 (t, 3H), 1.21-1.42 (m, 5H), 1.43-1.70 (m, 6H), 2.29 (s, 3H), 3.12-3.21 (m, 1H), 7.11 (d, 2H), 7.47 (d, 2H), 7.68 (brs, 3H).

Example 18
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.85 (d, 6H), 1.01-1.11 (m, 1H), 1.35-1.62 (m, 5H), 1.63-1.80 (m, 4H), 2.29 (s, 3H), 3.20-3.30 (m, 1H), 7.11 (d, 2H), 7.47 (d, 2H), 7.66 (brs, 3H).

Example 20
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.85 (d, 6H), 1.11 (dd, 2H), 1.26-1.50 (m, 2H), 1.51-1.76 (m, 8H), 2.29 (s , 3H), 3.11-3.20 (m, 1H), 7.11 (d, 2H), 7.47 (d, 2H), 7.68 (brs, 3H).

Example 22
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.86 (t, 3H), 1.18-1.31 (m, 8H), 1.32-1.78 (m, 9H), 2.29 (s, 3H), 3.10-3.21 (m, 1H), 7.11 (d, 2H), 7.47 (d, 2H), 7.67 (brs, 3H).

The ¹ H-NMR data of the compounds obtained in Examples 17, 19, 21 and 23 showed the same data as in Examples 16, 18, 19 and 22, respectively.

  As described above, according to the present invention, there is provided an industrial process for producing a high-purity cis-4-alkylcyclohexylamine acid addition salt represented by the formula (III) useful as an intermediate of a pharmaceutical product. Is done. In addition, it can be expected to provide pharmaceutical production using the intermediates provided by these production methods.

Claims (9)

The following formula (I):

[Wherein, R ¹ represents a C _2-6 alkyl group. ]
A cis isomer and a trans isomer (cis / trans isomer) mixture of 4-alkylcyclohexylamine represented by the formula (II), wherein the cis isomer content of the mixture is more than 50%, and the following formula (II): ):

[Wherein, A represents —CO— or —SO ₂ —, and R ² , R ³ or R ⁴ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a halogen atom. ]
And a compound represented by the following formula (III):

[Wherein, A, R ¹ , R ² , R ³ and R ⁴ are the same as above. ]
The manufacturing method of compound (III) including the process of forming and crystallizing the acid addition salt of cis-4-alkyl cyclohexylamine represented by these. The production method according to claim 1, wherein R ¹ represents a C _3-5 alkyl group. The production method according to claim 1 or 2, wherein R ² represents a hydrogen atom, a methyl group, an ethyl group, or a chlorine atom bonded to a position para to the A, and R ³ and R ⁴ both represent a hydrogen atom. . The method according to claim 3 showing a - A is -SO _2.   The production method according to any one of claims 1 to 4, wherein the cis isomer content of the cis / trans isomer mixture represented by the formula (I) is 55% or more.   The production method according to any one of claims 1 to 5, wherein the purity of the compound (III) is 95% or more.   The production method according to any one of claims 1 to 6, wherein the compound (II) is used in an amount of 0.8 to 2.0 equivalents based on the cis / trans isomer mixture represented by the formula (I).   The production method according to any one of claims 1 to 7, wherein 10 to 60 parts by volume of the crystallization solvent is used with respect to 1 part by weight of the cis / trans isomer mixture represented by the formula (I). Formula (III) below:

[In the formula, A represents —CO— or —SO ₂ —, R ¹ represents a C _2-6 alkyl group, R ² , R ³ or R ⁴ are the same or different and represent a hydrogen atom, C _{1 -6 represents} an alkyl group or a halogen atom. An acid addition salt of cis-4-alkylcyclohexylamine represented by the formula: