KR820001613B1 - Process for the preparation of 4'-(2-carboxyethyl)phenyl trans-4-aminomethyl cyclohexanecarboxylate - Google Patents

Abstract

Title compd.(I), useful for treatment of ulcer, was prepd. by hydrolsis of compd.(IV) which was obtained from the reaction of trans-4-aminomethylcyclohexane carbonylhalide(II; X = halogen) and compd.(III; R1 = lower alkyl, substituted lower alkyl, aryl, alkoxy, amino; R2 = H, lower alkyl,aryl, acyl, alkoxycarbonyl, cyano), Thus, 4'-(2-acetoxyloxy,carbonylethyl)phenyl-trans-4-aminomethylcyclohexane carboxylate HCI salts 4.97 g and sodium bicarbonate 2.10 g were recdted at 40≰C for 40 hr. The obtained ppt.was filtered and dried to give 4'-(2-carboxyethyl)phenyl-trans-4-aminomethylcyclohexane carboxylate (CEP-ester) 3.56 g.

Description

Method for preparing 4 '-(2-carboxyethyl) phenyl trans-4-aminomethyl cyclohexanecarboxylate

The present invention relates to 4 '-(2-carboxyethyl) phenyl trans-4-aminomethyl cyclohexanecarboxylate or therapeutically useful acid addition salts useful as antipramine or anti-digestive ulcer (hereinafter referred to as "CEP-ester"). It relates to a novel manufacturing method of).

The following three manufacturing methods are known as a manufacturing method of the conventional CEP-ester.

(i) an intermediate 4'- obtained by condensing trans-4-N-benzyloxycarbonylaminomethyl cyclohexanecarbonyl chloride or trans-4-aminomethylcyclohexane carbonyl chloride with 4-hydroxy phenylpropionic acid benzyl ester 2-benzyloxycarbonylethyl) phenyl trans-4-N-benzyloxycarbonyl aminomethyl cyclohexane carboxylate hydrochloride or 4 '-(2-benzyloxycarbonylethyl) phenyl trans-4-aminomethylcyclohexane carboxyl A method for obtaining CEP-ester by catalytic reduction of late hydrochloride and leaving a protecting group, i.e., benzyl group, (see Japanese Patent Publication Nos. 46-19950 and 52-48978).

(ii) Intermediate 4 '-(2-tert-butoxycarbonylethyl) phenyl trans- by reacting trans-4-aminomethyl cyclohexanecarbonyl chloride with tert-butyl 4-hydroxyphenylpropionate hydrochloride Preparation of 4-aminomethyl cyclohexanecarboxylate and hydrochloride, followed by treatment of this intermediate with hydrofluoric acid-acetic acid to remove the group protecting the carbonyl group, i.e. tertiary butyl group, to prepare CEP-ester ( See Japanese Patent Laid-Open No. 48-78143).

The reason for requiring a special protecting group in these prior arts is as follows. The phenyl ester linkages in the CEP-ester molecules are much easier to hydrolyze than common ester bonds. However, in the preparation of the above-mentioned intermediates which have been commonly used, the carboxy group of P-hydroxyphenylpropionic acid, which is one of the starting materials of the intermediate, must be protected with a suitable protecting group. Thus in their intermediate two ester moieties coexist. In order to obtain the desired product, CEP-ester, the ester bond of the terminal carbonyl group of the intermediate must be selectively hydrolyzed. For this reason, the protecting group of terminal carbonyl must be a special protecting group which is easily released by conditions other than contact reduction or normal hydrolysis.

Next, the third prior art will be described, but it will be apparent that the yield is extremely poor when the terminal carboxyl group is not protected by a special protecting group.

(iii) 4 '(2-alkoxycarbonylethyl) phenyl trans-4-aminomethyl cyclohexane carboxylate obtained by reacting 4-hydroxyphenyl propionic acid alkyl ester with trans-4-aminomethyl cyclohexane carbonyl chloride or The acid addition salt is hydrolyzed in the presence of an acid catalyst to obtain a CEP-ester (see Japanese Patent Laid-Open No. 52-17447).

This method (iii) is the simplest method for producing CEP-esters in the prior art. However, the yield is less than 35%, and cannot be said to be industrially advantageous. The reason for the poor yield is that, as described above, the intermediate has two kinds of ester bonds, ie, phenyl ester and alkyl ester in the molecule.

In the hydrolysis reaction, the alkyl ester bond in the molecule is slightly unstable than the phenyl ester bond, but the difference is extremely small. Therefore, since only an alkyl ester cannot be hydrolyzed without hydrolyzing a phenyl ester bond, a yield cannot be reduced.

None of the above conventional techniques can be satisfied.

The inventors of the present invention have repeatedly studied the preparation method of the CEP-ester and react the trans-4-aminomethylcyclohexane carbonyl halide with the novel compound represented by the formula (i) as shown in the following reaction formula to formula (ii). The present invention was completed to find a method for preparing a CEP-ester represented by the formula (iii) by preparing a new compound represented by the formula (I), followed by hydrolysis of the compound of the formula (ii) by a conventional method. It was.

Wherein X is a halogen atom, R ₁ is an alkyl group, a substituted alkyl group, an aryl group, an alkoxy group, or an amino group and R ₂ is a hydrogen atom, an alkyl group, an aryl group, an acyl group, a lower alkoxycarbonyl group or a cyano group. )

The present invention will be described in more detail. The first process of the present invention is a process for producing a novel intermediate (ii) and the second process is a process for producing CEP-ester by hydrolyzing the intermediate (ii).

First, the first step will be described.

The novel intermediate (ii) is obtained by condensation of a trans-4-aminomethyl cyclohexanecarbonyl halide or acid addition salt thereof in a suitable solvent with the compound represented by formula (i).

What is necessary is just a solvent which does not inhibit the reaction as a solvent used for this reaction. For example, dichloroethane, chloroform, benzene, toluene, dioxane and the like are used. The reaction proceeds in the range of 30 to 110 ° C, but more preferably in the range of 50 to 80 ° C. The desired intermediate (ii) after the reaction can be easily separated from the reaction mixture according to conventional methods described in the following examples.

The obtained intermediate (ii) shows a significant advantage in the next hydrolysis reaction in the second step. That is, the intermediate (ii) has two ester bonds in the molecule, and each bond has a very significant difference in the binding force for hydrolysis conditions. Therefore, when the intermediate (ii) is hydrolyzed under mild hydrolysis reaction conditions, for example, in a weak acid or weakly basic solution at room temperature, the phenyl ester moiety is not hydrolyzed, while the acetonyl ester moiety is easily separated. Furthermore, the acetonyl moiety refers to the moiety except X in the compound of formula (iv). In this respect, intermediate (ii) is an extremely useful and important compound in the industrial production of CEP-esters.

The starting material (i) necessary for the above production method can be easily produced in good yield by reacting 4-hydroxyphenylpropionic acid with the compound represented by the formula (iv).

(Wherein X represents a halogen atom and R ₁ and R ₂ are the same as above).

In addition, the detailed manufacturing method of the compound of Formula (i) is as having described in the following reference example.

The second step of the present invention relates to a hydrolysis reaction step of the intermediate (ii) obtained in the first step. This hydrolysis reaction proceeds by suspending intermediate (ii) in water with or without base. The reaction is usually carried out in the range of pH 5-12. Examples of bases that can be used include hydroxides of alkali or alkaline earth metals such as sodium carbonate, sodium bicarbonate, sodium acetate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, barium hydroxide or salts of their weak acids or pyridine, triethylamine, Organic bases such as trimethylamine, diethylamine, dimethylamine, monoethylamine, monomethylamine, or weak salts thereof; and the like can be given. There is no particular limitation on the amount of base used. For example, in the case of hydrolyzing the acid addition salt of intermediate (ii), the reaction proceeds sufficiently in the presence of an equimolar amount or a slight excess of base. As the solvent, water, alcohols and other organic solvents such as acetone, dioxane and the like are used, and an aqueous organic solvent can also be used.

On the other hand, the temperature of the hydrolysis reaction depends on the kind of protecting group of the intermediate (ii) or the kind of base used and its concentration or the pH of the reactor. Generally, however, the reaction proceeds at 0 ° C to 100 ° C, preferably at 20 ° C to 70 ° C.

After the reaction, the target CEP-ester can be separated into crystals according to a conventional method as described in the following examples.

Starting material (i) is also easily obtained by the method described in the following reference.

[Reference Example]

49.9 g of 4-hydroxyphenylpropionic acid is dissolved in 160 ml of dimethylformamide, and then 21.8 g of potassium carbonate is added at room temperature. 29.1 g of monochloroacetone was added dropwise to the solution at 60 DEG C and then reacted with 4-hydroxyphenylpropionic acid at 80 to 90 DEG C for 1 hour. After the reaction, dimethylformamide is distilled from the reaction solution to obtain a residue. The residue was dissolved in dichloroethane, washed with water, the dichloroethane layer was removed and the solvent was distilled off to give 64.7 g (yield 97%) of acetonyl 4-hydroxyphenyl propionate. Recrystallization in isopropyl ether gives a product of colorless crystals with a melting point of 64.5 ° C.

Elemental Analysis for C ₁₂ H ₁₄ O ₄

Calculated Value: C 64.85, H 9.35

Found: C 64.99, H 6.39

Similarly, other starting materials (i) can be prepared. Their melting point and elemental analysis are shown in Table 1.

Melting point and elemental analysis of starting material (i)

TABLE 1

Example 1

A solution of 60.4 g of trans-4-amino methyl cyclohexanecarboxylic acid chloride hydrochloride in 260 ml of 1,2-dichloroethane while stirring 63.3 g of acetonyl 4-hydroxyphenyl propionet for 2.5 hours at 60 to 70 ° C React with After the reaction, the crystalline precipitate was removed by filtration and dried to give 105.5 g (yield 93.1%) of 4 '-(2-acetonyloxycarbonylethyl) phenyl trans-4-aminomethylcyclohexane carboxylate hydrochloride. The product is recrystallized in aqueous isopropyl alcohol to give colorless crystals having a melting point of 199 ° C. (decomposition).

Elemental Analysis for C ₂₀ H ₂₈ NO ₅ Cl

Calculated Value: C 60.37, H 7.09, N 3.52, Cl 8.91

Found: C 60.45, H 7.02, N 3.61, Cl 9.04

The aqueous solution containing 4.97 g of 4 '-(2-acetonyloxycarbonylethyl) phenyl trans-4-aminomethyl cyclohexane carboxylate hydrochloride and 2.10 g of sodium bicarbonate obtained above was mixed with an aqueous solution at 40 캜. The reaction is stirred for 40 hours at. After the reaction, precipitated crystals were filtered and dried to obtain 3.56 g (yield 93.4%) of 4 '-(2-carboxyethyl) phenyl trans-4-aminomethylcyclohexanecarboxylate (CEP-ester).

The product was identified by NMR and infrared spectra and then treated with dilute hydrochloric acid to give 3.84 g of the corresponding hydrochloric acid addition salt having a melting point of 235 DEG C (decomposition) (89.9% yield).

Example 2

The hydrochloric acid addition salt of 4 '-(2acetonyloxycarbonylethyl) phenyl trans-4-aminomethylcyclohexanecarboxylate obtained in Example 1 was dissolved in water, and a diluted aqueous solution of sodium bicarbonate was added at room temperature to neutralize it. Get a decision. The crystals are removed by filtration and recrystallized in aqueous metalol to give a free form of 4 '-(2-acetonyloxycarbonylethyl) phenyl trans-4-aminomethyl cyclohexanecarboxylate having a melting point of 144 ° C (decomposition). .

Elemental Analysis for C ₂₀ H ₂₇ NO ₅

Calculated Value: C 66.46, H 7.53, N 3.88

Found: C 66.34, H 7. 34 N 3.98

4.52 g of 4 '-(2-acetonyloxycarbonylethyl) phenyl trans-4-aminomethylcyclohexane carboxylate obtained above was dissolved in 60 ml of water, and stirred at 40 ° C. for 40 hours to carry out a hydrolysis reaction. Do. The solution was treated by the latter method of Example 1 to yield 3.25 g of CEP-ester (85.1% yield). The product is confirmed by NMR and IR spectra.

Example 3

8.50 g of α-methylacetonyl 4-hydroxyphenyl propionate is stirred at 65 to 70 ° C. for 3.5 hours with 6.37 g of trans-4-aminomethyl cyclohexane carbonyl chloride in 50 ml of 1,2-dichloroethane. The hydrochloride is reacted with the dissolved solution. The solvent was distilled off from the reaction solution and the residue was recrystallized from isopropyl alcohol to give 4 '-[2-(?-Methyl-acetonyloxycarbonyl) -ethyl] phenyl trans-4- having a melting point of 187 DEG C (decomposition). 9.74 g (78.4% yield) of aminomethylcyclohexanecarbolate hydrochloride are obtained.

Elemental Analysis for C ₂₁ H ₃₀ NO ₅ Cl

Calculated Value: C 61.23, H 7.43, N 3.40, Cl 8.61

Found: C 61.20, H 7.29, N 3.46, Cl 8.64

5.15 g of the product 4 '-[2- (α-methyl-acetonyloxycarbonyl) ethyl] phenyl trans-4-aminomethylcyclohexanecarbosylate hydrochloride was added to 100 ml of an aqueous solution of 5% sodium bicarbonate and then Hydrolyze with stirring for 24 hours. The reaction solution was treated by the latter method of Example 1 to obtain an ester of 3.17 g (83.0% yield) CEP-. This product is confirmed by NMR and IR-spectrum.

Example 4

15.86 g of α-acetylacetonyl 4-hydroxy phenylpropionate is stirred at 65 to 70 ° C. for 3 hours with 10.60 g of trans-4-aminomethylcyclohexanecarbonyl chloride in 50 ml of 1,2-dichloroethane. The hydrochloride is reacted with the dissolved solution. After the reaction, the solvent was distilled off, and the obtained residue was dissolved in ether and the crystalline precipitate was removed by filtration and dried to obtain 21.0 g (yield 95.5%) of 4 '-[2- (α-acetylacetonyloxycarbonyl). Ethyl] phenyl trans-4-aminomethylcyclohexane carboxylate hydrochloride is obtained. The product is recrystallized in isopropyl alcohol to give a pale yellow crystal with a melting point of 144 ° C. (decomposition).

Elemental Analysis for C ₂₂ H ₃₀ NO ₆ Cl

Calculated Value: C 60.06, H 6.87, N 3.18, Cl 8.06

Found: C 59.95, H 6.80, N 3.46, Cl 8.09

5.50 g of the product 4- [2- (α-acetyl-acetonyloxycarbonyl) ethyl] phenyl trans-4-aminomethylcyclohexane carboxylate hydrochloride was added to 100 ml of a 5% aqueous solution of sodium bicarbonate, followed by 29 hours at 40 ° C. Hydrolyze with stirring. The reaction solution was treated by the latter method of Example 1 to obtain 2.79 g (yield 73.0%) of CEP-ester. The product is confirmed by NMR and IR-spectrum.

Example 5

17.70 g of α-ethoxycarbonylacetonyl 4-hydroxyphenyl propionate was stirred at 65 to 70 ° C., and 10.60 g of trans-4-aminomethylcyclohexane carbonyl chloride hydrochloride was dissolved in 50 ml of ethylene dichloride. React with solution. After the reaction, the solvent is distilled off, the resulting residue is dissolved in ether, and the crystalline precipitate is removed by filtration. The obtained precipitate was recrystallized in isopropyl alcohol-n-hexane to give 4 '-[2-(?-Ethoxycarbonyl-acetonyloxycarbonyl) ethyl] phenyl trans-4-amino having a melting point of 140 캜 (decomposition). 17.05 g (72.6% yield) of methylcyclohexane carboxylate hydrochloride are obtained.

Elemental Analysis for C ₂₃ H ₃₂ NO ₇ Cl

Calculated Value: C 58.78, H 6.86, N 2.96, Cl 7.54

Found: C 58.62, H 6.98, N 2.88, Cl 7.44

5.87 g of 4- [2- (α-ethoxycarbonyl-acetonyloxycarbonyl) ethyl] -phenyl trans-4-aminomethylcyclohexane carboxylate hydrochloride was dissolved in 100 ml of 5% aqueous solution of sodium bicarbonate, followed by The latter method of Example 3 gave 2.7 g (71.9% yield) of CEP-ester. This product is confirmed by NMR and IR-spectrum.

Example 6

1.80 g of γ-chloro-acetonyl 4-hydroxyphenylpropionate was stirred at 65 to 70 ° C. for 3 hours, and 1.48 g of trans-4-aminomethylcyclohexanecarbonyl chloride hydrochloride was dissolved in 10 ml of ethylene chloride. After reacting with the solution, the crystalline reaction product was filtered and dried to obtain 2.62 g (yield 86.8%) of 4 '-[2- (γ-chloro acetonyloxycarbonyl) -ethyl] phenyl trans-4-aminomethylcyclohexane. Obtained carboxylate hydrochloride.

Recrystallization from aqueous isopropyl alcohol gives the product a colorless crystal with a melting point of 200 ° C. (decomposition).

Elemental Analysis for C ₂₀ H ₂₇ NO ₅ Cl ₂

Calculated Value: C 55.56, H 6.29, N 3.24, Cl 16.40

Found: C 55.63, H 6.20, N 3.44, Cl 16.17

The latter of Example 3 was dissolved after dissolving 5.40 g of 4 '-[2- (γ-chloroacetonyloxycarbonyl) ethyl] phenyl trans-4-aminomethyl cyclohexane carboxylate hydrochloride in 100 ml of 5% sodium bicarbonate. The process yields 1.98 g (52.0% yield) of CEP-ester. This product is confirmed by NMR and IR-spectrum.

Example 7

12.0 g of phenacyl 4-hydroxy phenyl propionate was reacted with a solution of 8.49 g of trans-4-amino methylcyclohexanecarbonyl chloride hydrochloride in 50 ml of ethylene chloride, followed by the former method of Example 1. 16.09 g (yield: 87.4%) of 4 '-(2-phenacyloxycarbonylmethyl) phenyl trans-4-aminomethyl cyclohexane carboxylate hydrochloride was obtained. Recrystallization from water gives the product a colorless crystal with melting point 205 ° C (decomposition).

Elemental Analysis for C ₂₅ H ₃₀ NO ₅ Cl

Calculated Value: C 65.28, H 6.57, N 3.05, Cl 7.71

Found: C 65.22, H 6.49, N 3.00, Cl 7.43

5.75 g of 4 '-(2-phenacyloxycarbonylethyl) phenyl trans-4-aminomethyl cyclohexane carboxylate hydrochloride and 5.3 g of sodium bicarbonate obtained above were dissolved in 100 ml of 5% aqueous acetone. The reaction is stirred at 45 ° C. for 45 hours. The reaction solution was treated by the latter method of Example 1 to yield 1.83 g (yield 47.9) of CEP-ester. This product is confirmed by NMR and IR-spectrum.

Example 8

2.23 g of carbamylmethyl 4-hydroxyphenylpropionate was stirred at 75 to 80 ° C. for 1.5 hours to react with a solution of 2.11 g of trans-4-aminomethylcyclohexanecarbonyl chloride hydrochloride in 30 ml of dioxane. After filtration, the crystalline precipitate was separated by filtration and dried to obtain 2.80 g (yield 70.5%) of 4 '-(2-carbamylmethoxycarbonylethyl) phenyl trans-4-aminomethyl cyclohexane carboxylate hydrochloride. The material is recrystallized in methanol to give colorless crystals having a melting point of 242 ° C. (decomposition).

Elemental Analysis for C ₂₀ H ₂₇ N ₂ O ₅ Cl

Calculated Value: C 57.21, H 6.82, N 7.02, Cl 8.89

Found: C 57.02, H 6.74, N 7.01, Cl 9.16

The 4 '-(2carbamylmethyloxy carbonylethyl) phenyl trans-4-aminomethyl cyclohexane carboxylate hydrochloride obtained above was dissolved in 50 ml of a 5% aqueous solution of sodium bicarbonate, and then stirred at 50 ° C. for 10 hours for hydrolysis. do. The reaction solution was treated by the latter method of Example 1 to obtain 1.32 g (34.6% yield) of CEP-ester. This product is confirmed by NMR and IR-Spectra.

Example 9

4.76 g of methoxycarbonylmethyl 4-hydroxyphenyl propionate was added to 4.23 g of trans-4-aminomethylcyclohexane in 30 ml of 1,2-dichloroethane under the reaction conditions described in the former method of Example 4. Reaction with the solution of carbonyl chloride hydrochloride yields 7.30 g (88.5% yield) of 4 '-(2-methoxycarbonylmethyloxycarbonylethyl) phenyl trans-4-aminomethylcyclohexane carboxylate hydrochloride.

This product is recrystallized in ethanol to give colorless crystals having a melting point of 198 ° C. (decomposition).

Elemental Analysis for C ₂₀ H ₂₈ NO ₆ Cl

Calculated Value: C 58.04, H 6.82, N 3.38, Cl 8.57

Found: C 58.12, H 6.87, N 3.33, Cl 8.35

Example 10

10.8 g of diethoxycarbonylmethyl 4-hydroxyphenylpropionate was added to 6.36 g of trans-4-aminomethyl in 30 ml of 1,2-dichloroethane under the same reaction conditions as described in the former method of Example 4. Reaction with a solution of cyclohexanecarbonyl chloride hydrochloride yielded 12.7 g (yield 84.7%) of 4 '-(2-diethoxycarbonylmethyloxycarbonylethyl) phenyl trans-4-amino methylcyclohexane carboxylate hydrochloride do. Recrystallization from isopropyl alcohol yields a colorless crystal product having a melting point of 131 ° C (decomposition).

Elemental Analysis for C ₂₄ H ₃₄ NO ₈ Cl

Calculated Value: C 57.65, H 6.85, N 2.80, Cl 7.09

Found: C 57.35, H 6.61, N 2.77, Cl 6.98

Example 11

The 4 '-[2-acetonyloxycarbonylethyl) phenyl trans-4-aminomethylcyclohexane carboxylate hydrochloride obtained according to the former method of Example 1 was dissolved in 100 ml of water, 6.0 ml of% aqueous solution is added. The solution was hydrolyzed with stirring at 40 ° C. for 3 hours and then treated by the latter method of Example 1 to yield 2.32 g (yield 60.9%) of CEP-ester.

This product is confirmed by NMR and IR-spectrum.

Example 12

4.97 g of 4 '-(2-acetonyloxycarbonylethyl) phenyl trans-4-aminomethylcyclohexane carboxylate hydrochloride obtained according to the former method of Example 1 was dissolved in 50 ml of water, followed by a 2% aqueous solution of sodium carbonate. 35 ml are added.

The reaction mixture was hydrolyzed with stirring at room temperature for 43 hours and then treated by the latter method of Example 1 to yield 31.4 g (82.4% yield) of CEP-ester.

The product is confirmed by NMR and IR-spectrum.

Example 13

4.97 g of 4 '-(2-acetonyloxycarbonylethyl) phenyl trans-4-aminomethylcyclohexane carboxylate hydrochloride obtained according to the former method of Example 1 was dissolved in 50 ml of water, followed by 1.34 g of triethyl. Add amine. The solution was hydrolyzed with stirring at 40 ° C. for 17 hours and then treated by the latter method of Example 1 to yield 2.89 g (yield 75.5%) of CEP-ester. This product is confirmed by NMR and IR-spectrum.

Claims (1)

The trans-4-aminomethylcyclo hexanecarbonyl halide of the following formula (II) is reacted with the following formula (III) to obtain a compound of the following formula (IV), and then hydrolyzed. A process for preparing 4 '-(2-carboxyethyl) phenyltrans-4-aminomethylcyclohexanehexanecarboxylate of I).

The general formula R ₁ is selected from the group consisting of lower alkyl, substituted lower alkyl, aryl, alkoxy or amino and R ₂ is selected from hydrogen, lower alkyl, aryl, acyl, alkoxycarbonyl or cyano consisting of the group and , X is a halogen atom.