GB1580783A

GB1580783A - Process for producing 4' - (2 - carboxyethyl)phenyl trans - 4 - aminomethyl-cyclohexanecarboxylate or the acid-additsalts thereof and intermediates for producing the same

Info

Publication number: GB1580783A
Application number: GB16683/78A
Authority: GB
Original assignee: Daiichi Pharmaceutical Co Ltd
Current assignee: Daiichi Pharmaceutical Co Ltd
Priority date: 1978-04-27
Filing date: 1978-04-27
Publication date: 1980-12-03

Description

(54) PROCESS FOR PRODUCING 4 -(2-CARBOXYETHYL) PHENYL TRANS-4-AMINOMETHYLCYCLOHEXANE CARBOXYLATE OR THE ACID-ADDITION SALTS THEREOF AND INTERMEDIATES FOR PRODUCING THE SAME (71) We, DAIICHI SEIYAKU CO., LTD., No. 14-10, Nihonbashi 3chome, Chuo-ku, Tokyo, Japan, a Japanese Company, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to a process for producing 4'-(2-carboxyethyl) phenyl trans-4-aminomethylcyclohexanecarboxylate (hereinafter referred to as "SEP-ester") or a therapeutically useful acid-addition salt thereof which is useful as an anti-plasmic agent or anti-peptic ulcer agent and relates to useful novel intermediates for producing CEP-ester.

Three conventional processes for producing CEP-ester are known as follows: (i) Catalytic reduction of 4' - (2 - benzyloxycarbonylethyl) phenyl trans - 4 N - benzyloxycarbonylaminomethylcydohexanecarboxylate hydrochloride or 4' - (2benzyloxycarbonylethyl) phenyl trans - 4 - aminomethylcyclohexanecarboxylate hydrochloride, which is obtained by condensing trans - 4 - N - benzyloxycarbonylaminomethylcyclohexanecarbonyl chloride or trans - 4 - aminomethylcyclohexanecarbonylchloride, respectively, with benzyl 4 - hydroxyphenylpropionate, and successive removal of the protective group, i.e., a benzyl group, to produce CEP-ester, as described in Japanese Published Patent Applications Nos. 19950/71 and No. 48978/77.

(ii) Condensation of trans - 4 - aminomethylcyclohexanecarbonyl chloride with tert-butyl 4-hydroxyphenylpropionate hydrochloride to produce an intermediate, 4' (2 - tert - butoxycarbonylethyl) phenyl trans - 4 - aminomethylcyclohexanecarboxylate hydrochloride, and then treatment of the intermediate with hydrogen halide-acetic acid for the purpose of removing the carbonyl-protective group, i.e., a tert-butyl group to obtain CEP-ester, as described in Japanese Published Patent Application No. 78143/73.

The reason why these specific protective groups are essential in these conventional processes is because the phenyl ester-bond in the CEP-ester molecule tends to be hvdrolyzed more easily than a general ester bond. Further, in the condensation reactions described in (i) and (ii) above for synthesis of the intermediates used, the carboxyl moiety of one of the starting materials, i.e. p-hydroxyphenylpropionic acid must be protected with a suitable protective group.

Accordingly, after the condensation reaction, the protective group on the terminal carboxyl moiety of these resulting intermediates must be selectively removed to obtain the desired CEP-ester. For this purpose the terminal carboxyl moiety must, as a result, be protected with a fairly specific protective group which can be easily removed by catalytic reduction or under conditions other than those used in an ordinary hydrolysis.

This can be well understood from the poor yield resulting from the third conventional method described below in which such a specific protective group was not employed as the terminal carboxy moiety protective group but rather an ordinary alkyl ester was employed.

(iii) An intermediate, 4' - (2 - alkoxycarbonylethyl) phenyl trans - 4 - amino methylcyclohexanecarboxylate or the acid-addition salts thereof, which was obtained by reacting an alkyl 4 - hydroxyphenylpropionate with trans - 4 - aminomethylcyclohexane carbonyl chloride, was hydrolyzed in the presence of an acid catalyst to produce a CEP-ester, as disclosed in Japanese Published Patent Application No. 17447/77.

The above method (iii) is the simplest known method which can be used to produce CEP-ester using conventional processes. However, since the yield according to this method (iii) is less than 35%, the method is not industrially advantageous.

The intermediate has, as stated before, two kinds of ester-bonds, i.e. a phenyl esterbond and an alkyl ester-bond, in the molecule. In a hydrolysis reaction, the alkyl esterbond in the molecule is less stable by only a narrow margin than the phenyl ester-bond.

Since there is only a slight difference, the alkyl ester-bond can not be hydrolyzed alone and selectively without hydrolyzing the phenyl ester-bond as well.

As a result of intensive investigations on processes for producing CEP-ester, it has now been found that the end product CEP-ester, represented by the formula (I)

can be quite easily obtained by reacting a trans - 4 - aminomethylcyclohexanecarbonyl halide represented by the formula (II)

or an acid-addition salt thereof, with a compound represented by the formula (III)

to produce a compound represented by the formula (IV)

or an acid-addition salt thereof and then hydrolyzing the compound represented by the formula (IV) or the acid-addition salt thereof, wherein in the above formulae (I) to (IV), X represents a halogen atom, R1 represents an alkyl group having 1 to 6 carbon atoms a halogenated alkyl group having 1 to 6 carbon atoms in the alkylmoiety thereof, an aryl group, an alkoxy group having 1 to 6 atoms or an amino group, and2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, an acyl group, an alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety thereof or a cyano group.

As a result, this invention also provides a novel intermediate represented by the formula (IV).

The present invention further provides a process for producing 4' - (2 - carboxyethyl) phenyl trans - 4 - aminomethylcyclohexanecarboxylate or a therapeutically useful acid-addition salt thereof, comprising hydrolyzing a compound of the formula (IV) or an acid-addition salt thereof.

The process of this invention to produce the end product CEP-ester represented by the formula (I) can be schemactically summarized as follows:-

wherein X, Rl and R2 are each as described above.

The first step in the process of this invention comprises the reaction for producing a novel intermediate compound represented by the formula (IV). The useful novel intermediate compound represented by the formula (IV) can be obtained by condensing a trans - 4 - aminomethylcyclohexanecarbonyl halide or an acid-addition salt thereof represented by the formula (II) with a compound represented by the formula (III) with heating in a suitable solvent. Any solvent can be used in the above reaction, if the solvent does not inhibit the reaction. For example, dichloroethane, trichloroethane, chloroform, benzene, toluene or dioxane can be used. The reaction will proceed at a temperature in the range of 30 to 1100 C, preferably 50 to 800C. After completion of the reaction, the desired intermediate compound represented the formula (IV) can be easily separated from the reaction mixture in a conventional manner as hereinafter described in detail in the Examples.

The intermediate represented by the formula (IV) obtained as above provides a remarkable advantage in the subsequent hydrolysis step. That is, the intermediate represented by the formula (IV) has two ester-bonds in the molecule, and each ester bond exhibits distinguishable differences in strength against the conditions for hydrolysis.

So, when the intermediate represented by the formula (IV) is subjected to hydrolysis under mild hydrolysis conditions such as in a weakly acidic or weakly alkaline solution at normal temperature, the acetonyl ester moiety can be easily cleaved, while the phenyl ester moiety remains unhydrolyzed. The acetonyl group is represented by the moiety of the formula (V)

Thus, the intermediate represented by the formula (IV) is a very useful and important compound in the industrial production of CEP-ester.

The starting material represented by the formula (II), i.e., a trans - 4 - aminomethylcyclohexanecarbonyl halide or an acid-addition salt thereof, is a known compound as disclosed in Japanese Published Patent Application No. 48978/77.

The starting material represented by the formula (III) employed in the above step can be easily prepared in good yield by reacting 4-hydroxyphenylpropionic acid with a compound represented by the formula (VI)

wherein X represents a halogen atom and R1 and R2 are as defined above. A detailed description of the preparation of the hydroxyphenylpropionic ester represented by the formula (III) is described hereinafter in the Reference Example.

The second step of this invention comprises hydrolyzing the intermediate represented by the formula (IV) obtained in the first step. The hydrolysis reaction may be effected simply by suspending the intermediate represented by the formula (IV) in water, in the presence or absence of a base. The hydrolysis can be carried out usually atapHof5to 12.

Examples of suitable and preferred bases which can be used in the hydrolysis are hydroxides of alkali metals or alkaline earth metals or alkali metal or alkaline earth metal salts of weak acids such as sodium carbonate, sodium bicarbonate, sodium acetate, sodium hydroxide, potassium carbonate, potassium bicarbonate potassium hydroxide or barium hydroxide or organic bases such as pyridine, triethylamine tri methylamine, diethylamine, dimethylamine, momoethylamine or monomethylamine or the weakly acidic bases thereof. The amount of the base to be used is not particularly limited. For example, in case of hydrolyzing acid-addition salts of the intermediate represented by the formula (IV), an equimolar or a slightly molar excess amount of the base to the intermediate represented by the formula (IV) is sufficient for the hydrolysis reaction to proceed. As described above, a suitable solvent is water, and an aqueous organic solvent such as alcohols, acetone or dioxane also can be used.

The hydrolysis reaction temperature will depend on the type of protective group employed for the intermediate represented by the formula (IV) or on the type and amount of the base to be used or the pH of the reaction system. However, the hydrolysis reaction commonly proceeds at a temperature of 0 C to 100"C, more preferably in a range of 20"C to 700 C.

After the hydrolysis reaction described above, the desired product (CEP-ester) can be separated in the form of crystals thereof using conventional techniques, e.g., as described in the examples given hereinafter.

The starting materials represented by the formula (II) and (III) can be easily prepared in accordance with the method described in the Reference Example given below.

In the Reference Example and other Examples, all parts percentages and ratios are by weight unless otherwise indicated.

REFERENCE EXAMPLE.

After 49.9 g of 4-hydroxyphenylpropionic acid was dissolved in 160 ml of dimethylformamide, 21.8 g of potassium caibonate was added to the solution at room temperature (about 250C). Then 29.1 g of monochloroacetone was added dropwise to the above solution at 60"C and reacted with the 4-hydroxyphenylpropionic acid at 80--90"C for 1 hour. After the reaction, the dimethylformamide was distilled off from the reaction solution to obtain a residue. The residue was dissolved in dichloroethane and then the solution was washed with water. The layer of dichloroethane was removed and the solvent was distilled off to obtain 64.7 g (yield: 97%) of acetonyl 4-hydroxyphenylpropionate. After recrystallization from diisopropyl ether, colorless crystals having a melting point 64.5 C were obtained.

Elemental Analysis: Calcd. (%) for C12HO4: C, 64.85; H, 6.35.

Found (%): C, 64.99; H, 6.39.

Other starting material compounds represented by the formula (III) can be prepared in the same manner as described in the Reference Example above. The melting points and elemental analysis values of representative examples of starting material compounds represented by the formula (III) are shown in Table I below.

TABLE I

(Calcd.

Melting Elemental Analysis Found) R1 R2 Point( C) C H N Cl (or product form) CH3 -CH3 (oil) 66.09 6.82 6 82 - - 65.81 6.74 CH3 -COCH3 (oil) 63.63 6.10 6 03 63.41 6.03 -CH3 -COOC2H5 (oil) 61.22 6.16 25 61.15 6.25 -CH2Cl -H 86.5 56.15 5.10 - 13.81 56.43 5.08 13.80 -NH2 -H 149.5 59.19 5.87 6.27 - 59.39 5.99 6.30 -C6H5 -H 78.5 71.82 5.67 - - 71.56 5.65 -OCH3 -H (oil) 60.50 5.92 - - 61.00 6.20 -OC2H5 -COOC2H5 (oil) 59.25 6.22 - - 58.98 6.25 Example 1.

(a) 63.3 g of acetonyl 4 - hydroxyphenylpropionate prepared as described above was reacted with 60.4 g of trans - 4 - aminomethylcyclohexanecarboxylic acid chloride hydrochloride in 260 ml of 1,2-dichloroethane at 60 to 70 C for 2.5 hours with stirring. After completion of the reaction, a crystalline precipitate was removed by filtration and dried to obtain 105.5 g (yield: 93.1% of 4' - (2 - acetonyloxycarbonylethyl)phenyl trans - 4 - aminomethylcyclohexanecarboxylate hydrochloride. This product was recrystallized from 5% aqueous isopropyl alcohol to obtain colorless crystals having a melting point of 199 C (decomp.).

Elemental Analysis: Calcd. (%) for C2H,NO,Cl: 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.

(b) 4.97 g of 4' - (2 - acetonyloxycarbonylethyl)phenyl trans - 4 - amino methylcyclohexanecarboxylate hydrochloride obtained as described above and an aqueous solution (60 ml) containing 2.10 g of sodium bicarbonate were mixed and reacted at 40 C for 40 hours with stirring. After completion of the reaction, the precipitated crystals were filtered off and dried to obtain 3.56 g (yield 93.4%) of 4' (2-carboxyethyl)phenyl trans - 4 - aminomethylcyclohexanecarboxylate (CEP-ester).

This product was identified by its nuclear magnetic resonance (NMR) spectra and infrared (IR) spectra. Then, the product was treated in a dilute hydrochloric acid aqueous solution to obtain 3.84 g (yield: 89.9%) of the corresponding hydrochloric acid-addition salt having a melting point of 235 C (decomp.).

Example 2.

The 4' - (2 - acetonyloxycarbonylethyl)phenyl trans - 4 - amino - methylcyclohexanecarboxylate hydrochloride obtained as described in Example 1 (a) was dissolved in water and the resulting aqueous solution was rendered neutral with a dilute aqueous solution of sodium bicarbonate at room temperature to obtain crystals. The crystals were removed by filtration and recrystallized from aqueous methanol to obtain free 4' - (2 - acetonyloxycarbonylethyl)phenyl trans-4-aminomethylcyclohexanecarboxylate having a melting point of 144"C (decomp.).

Elemental Analysis: Calcd. (%) for C20H,7NO5! 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 - aminomethylcyclohexanecarboxylate obtained as described above was suspended in 60 ml of water and, then, hydrolyzed at 40"C for 40 hours with stirring. After completion of the reaction, the solution was treated in the same manner as described in Example 1 (b) to obtain 3.25g (yield: 85.1%) of CEP-ester. The product obtained was identified by its NMR and IR-spectra.

Example 3.

(a) 8.50 g of a - methylacetonyl 4 - hydroxyphenylpropionate was reacted with 6.37 g of trans-4-aminomethylcyclohexanecarbonyl chloride hydrochloride in 50 ml of 1,2-dichloroethane at 65 to 700C for 3.5 hours with stirring. After completion of the reaction, the solvent was removed from the reaction solution by distillation and the residue thus obtained was recrystallized from isopropyl alcohol to obtain 9.74 g (yield: 78.4%) of 4' - [2 - (a - methyl - acetonyloxycarbonyl)ethyl]phenyl trans - 4 - aminomethylcyclohexanecarboxylate hydrochloride having a melting point of 187"C (de comp.).

Elemental Analysis: Calcd. (%) for C,0H,0NO5Cl: 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.

(b) 5.15 g of 4' - [2 - (a - methyl - acetonyloxycarbonyl)ethyl]phenyl trans - 4aminomethylcyclohexanecarboxylate hydrochloride obtained as described in (a) above was added to 100 ml of a 5% sodium bicarbonate aqueous solution and the mixture was treated in the same manner as described in Example 1 (b) to obtain 3.17 g (yield: 83.0%) of CEP-ester. This product was identified by its NMR and IR-spectra.

Example 4.

(a) 15.86 g of a-acetylacetonyl 4-hydroxyphenylpropionate was reacted with 10.60 g of trans - 4 - aminomethylcyclohexanecarbonyl chloride hydrochloride in 50 ml of 1,2-dichloroethane at 65 to 700C for 3 hours with stirring. After completion of the reaction, the solvent was distilled off and the residue thus obtained was dissolved in diethyl ether. The resulting crystalline precipitate was removed by filtration and dried to obtain 21.0 g (yield: 95.5%) of 4' - [2 - (a - acetylacetonyloxycarbonyl)ethyl]phenyl trans - 4 - aminomethylcyclohexanecarboxylate hydrochloride. This product was recrystallized from isopropyl alcohol to obtain pale-yellow crystals having a melting point of 1440C (decomp.).

Elemental Analysis: Calcd. ( /O) for C?,H,,,,NO,,C1: C, 66.06; H, 6.87; N, 3.18; Cl, 8.06.

Found ( /n) C, 59.95; H, 6.80; N, 3.46; Cl, 8.09.

(b) 5.50 g of 4 - [2 - (a - acetvl - acetonyloxycarbonyl)ethyll phenyl trans - 4 aminomethylcyclohexanecarboxylate hydrochloride obtained as described in above (a) was added to 100 ml of a 5% sodium bicarbonate aqueous solution, and hydrolyzed at 40"C for 29 hours with stirring. The reaction solution was treated in the same manner as described in Example 1 (b) to obtain 2.79 g (yield: 73.0%) of CEP-ester. This product was identified by its NMR and IR-spectra.

Example 5.

(a) 17.70 g of ct - ethoxycarbonylacetonyl 4 - hydroxyphenylpropionate was reacted with 10.60 g of trans - 4 - aminomethylcyclohexanecarbonyl chloride hydrochloride in 50 ml of ethylene dichloride at 65 to 700C for 3 hours with stirring. After completion of the reaction, the solvent was distilled off and the residue obtained was dissolved in diethyl ether. The resulting crystalline precipitate was removed by filtration and recrystallized from isopropyl alcohol/n-hexane to obtain 17.05 g (yield: 72.6%) of 4' - [2 - (Q - ethoxycarbonyl - acetonyloxycarbonyl)ethyl]phenyl trans - 4 - aminomethylcyclohexanecarboxylate hydrochloride having a melting point of 140"C (de comp.).

Elemental Analysis: Calcd. (%) for C23HS2NO7Cl: C, 58.78; H, 6.86; N, 2.98; Cl, 7.54.

Found (%): C, 58.62; H, 6.88; N, 2.88; Cl, 7.44.

(b) 5.87 g of 4' - [2- (ez - ethoxycarbonyl - acetonyloxycarbonyl)ethyl]phenyl trans - 4 - aminomethylcyclohexanecarboxylate hydrochloride obtained as described in (a) above was dissolved in 100 ml of a 5% aosium bicarbonate aqueous solution, and the resulting solution was treated in the same manner as described in Example 3 (a) to obtain 2.74 g (yield: 71.9%) of CEP-ester. This product was identified by its NMR and IR-spectra.

Example 6.

(a) 1.80 g of y - chloro acetonyl 4 - hydroxyphenylpropionate was reacted with 1.48 g of trans - 4 - aminomethylcyclohexanecarbonylchloride hydrochloride in 10 ml of ethylene dichloride at 65 to 70"C for 3 hours with stirring. After completion of the reaction, the crystalline reaction product was filtered off and dried to obtain 2.62 g (yield: 86.8%) of 4' - [2 - y - chloroacetonyloxycarbonylethyl]phenyl trans - 4aminomethylcyclohexanecarboxylate hydrochloride. On recrystallization from aqueous isopropyl alcohol, the product was obtained as colorless crystals having a melting point of 200"C (decomp.).

Elemental Analysis: Calcd. (%) for C20H2NO,Cl2: 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.

(b) 5.40 g of 4' - [2 - y - chloroacetonyloxycarbonyl )ethyl] phenyi trans - 4aminomethylcyclohexanecarboxylate hydrochloride obtained as described in (a) above was dissolved in 100 ml of a 5% sodium bicarbonate aqueous solution. Then, the solution was treated in the same manner as described in Example 3 (b) to obtain 1.98 g (yield: 52.0% ) of CEP-ester. This product was identified by its NMR and IR-spectra.

Example 7.

(a) 12.0 g of phenacyl 4 - hydroxyphenylpropionate was reacted with 8.49 g of trans - 4 - aminomethylcyclohexanecarbonyl chloride hydrochloride in 50 ml of ethylene dichloride. The reaction solution was treated in the same manner as described in Example 1 (a) to obtain 16.09 g (yield: 87.4%) of 4' - (2 - phenacyloxycarbonyl ethyl )phenyl trans - 4 - aminomethylcyclohexanecarboxylate hydrochloride. On recrystallization from water, the product was obtained as colorless crystals having a melting point of 205"C (decomp.).

Elemental Analysis: Calcd. (%) for C25HS NO-CI: 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.

(b) 5.75 g of 4' - phenacyloxycarbonylethyl)phenyl trans - 4 - aminomethylcyclohexanecarboxylate hydrochloride obtained as described in (a) above and 5.3 g of sodium bicarbonate were dissolved in 100 ml of a 50% aqueous acetone solution and were reacted at 50"C for 45 hours with stirring. After completion of the reaction, the reaction solution was treated in the same manner as described in Example 1 (b) to obtain 1.83 g (yield: 47.9 ,/O) of CEP-ester. This product was identified by its NMR and IR-spectra.

Exampie 8.

(a) 2.23 g of carbamylmethyl 4 - hydroxyphenylpropionate was reacted with 2.11 g of trans - 4 - aminomethylcyclohexanecarbonyl chloride hydrochloride in 30 ml of dioxane at 75 to 800C for 1.5 hours with stirring. After completion of the reaction, the resulting crystalline precipitate was removed by filtration and dried to obtain 2.80 g (yield: 70.5%) of 4' - (2 - carbamylmethoxycarbonylethyl]phenyl trans - 4 - aminomethylcyclohexanecarboxylate hydrochloride. This product was recrystallized from methanol to obtain colorless crystals having a melting point of 2420C (decomp.).

Elemental Analysis: Calcd. (%) Cl9H27N2OsCl C, 57.21; H, 6.82; N, 7.02; C1, 8.89.

Found (%): C, 57.02; H, 6.74; N, 7.01; Cl, 9.16.

(b) 4.99 g of 4' - (2 - carbamylmethyloxycarbonyfethyl)phenyl trans - 4 - aminomethvlcyclohexanecarboxylate hydrochloride obtained as described in (a) above was dissolved in 50 ml of a 5% sodium bicarbonate aqueous solution and hydrolyzed at 50"C for 10 hours with stirring. Then the reaction solution was treated in the same manner as described in Example 1 (b) to obtain 1.32 g (yield: 34.6%) of CEP-ester.

This product was identified by its NMR and IR-spectra.

Example 9.

4.76 g of methoxycarbonylmethyl 4 - hydroxyphenylpropionate was reacted with 4.23 g of trans - 4 - aminomethylcyclohexanecarbonyl chloride hydrochloride in 30 ml of 1,2-dichloroethane under the same reaction conditions as described in Example 4 (a) to obtain 7.30 g (yield: 88.5%) of 4' - (2 - methoxycarbonylmethyloxycarbonylethyl)phenyl trans - 4 - aminomethylcyclohexanecarboxylate hydrochloride. This product was recrystallized from ethanol to obtain colorless crystals having a melting point of 1980C (decomp.).

Elemental Analysis: Calcd. (%) C20H28NO6Cl: 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 reacted with 6.36 g of trans - 4 - aminomethylcyclohexanecarbonyl chloride hydrochloride in 30 ml of 1,2-dichloroethane under the same conditions as described in Example 4 (a) to obtain 12.7 g (yield: 84.7%) of 4 - (2 - diethoxycarbony]methyloxycarbonylethyl)- phenyl trans - 4 - aminomethylcyclohexanecarboxylate hydrochloride. On crystallization from isopropyl alcohol, the product was obtained as colorless crystals having a melting point of 1310C (decomp.).

Elemental Analysis: Calcd. (%) for C24H34NO8CI: C, 57.65; H, 6.85; N, 2.80; C1, 7.()9.

Found (%): C, 57.35; H, 6.61; N, 2.77; Cl, 6.98.

Example 11.

4.97 g of 4' - (2 - acetonyloxycarbonylethyl)phenyl trans - 4 - aminomethylcyclohexanecarboxylate hydrochloride obtained as described in Example 1 (a) was dissolved in 100 ml of water, and 6.0 ml of a 10% sodium hydroxide aqueous solution was added thereto. Then, the mixture was stirred at 400C for 3 hours to effect the hydrolysis. The reaction solution was treated in the same manner as described in Example 1 (b) to obtain 2.32 g (yield: 60.9%) of CEP-ester. This product was identified by its NMR and IR-spectra.

Example 12.

4.97 g of 4' - (2 - acetonyloxycarbonylethyl)phenyl trans - 4 - aminomethylcyclohexanecarboxylate hydrochloride obtained as described in Example 1 (a) was dissolved in 50 ml of water, and 35 ml of a 2% sodium carbonate aqueous solution was added thereto. Then, the mixture was stirred at room temperature for 43 hours to effect the hydrolysis and then the reaction solution was treated in the same manner as described in Example 1 (b) to obtain 3.14 g (yield: 82.4%) of CEP-ester.

This product was identified by its NMR and IR-spectra.

EXAMPLE 13.

4.97 g of 4' - (2 - acetonyloxycarbonylethyl)phenyl trans - 4 - aminomethylcyclohexanecarboxylate hydrochloride obtained as described in Example 1 (a) was dissolved in 50 ml of water, and 1.34 g of triethylamine was added thereto. Then, the mixture was stirred at 40"C for 17 hours to effect the hydrolysis. After completion of the hydrolysis, the reaction solution was treated in the same manner as described in Example 1 (b) to obtain 2.89 g (yield: 75.9%) of CEP-ester. This product was identified by its NMR and IR-spectra.

WHAT WE CLAIM IS: 1. A process for producing 4' - (2 - carboxyethyl)phenyl trans - 4 - aminomethylcyclohexanecarboxylate, or a therapeutically useful acid-addition salt thereof, comprising hydrolyzing a compound represented by the formula (IV)

wherein Rl is an alkyl group having 1 to 6 carbon atoms, a halogenated alkyl group having 1 to 6 carbon atoms in the alkyl moiety thereof, an aryl group, an alkoxy group having 1 to 6 carbon atoms or an amino group, and R2 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, an acyl group an alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety thereof or a cyano group, or an acid-addition salt of the compound represented by the formula (IV).

2. A process for producing 4' - (2 - carboxyethyl) phenyl trans - 4 - aminomethylcyclohexanecarboxylate, or a therapeutically useful acid-addition salt thereof, comprising reacting a trans - 4 - aminomethylcyclohexanecarbonyl halide represented by the formula (II)

wherein X is a halogen atom, or an acid-addition salt thereof with a compound represented by the formula (III)

wherein R1 is an alkyl groun having 1 to 6 carbon atoms. a hay enacted alkvl on,iD having 1 to 6 carbon atoms in the alkyl moiety thereof, an aryl group, an alkoxy group or an amino group, and R2 is a hydrogen atom, an alkyl grou

Claims

**WARNING** start of CLMS field may overlap end of DESC **. Example 12. 4.97 g of 4' - (2 - acetonyloxycarbonylethyl)phenyl trans - 4 - aminomethylcyclohexanecarboxylate hydrochloride obtained as described in Example 1 (a) was dissolved in 50 ml of water, and 35 ml of a 2% sodium carbonate aqueous solution was added thereto. Then, the mixture was stirred at room temperature for 43 hours to effect the hydrolysis and then the reaction solution was treated in the same manner as described in Example 1 (b) to obtain 3.14 g (yield: 82.4%) of CEP-ester. This product was identified by its NMR and IR-spectra. EXAMPLE 13. 4.97 g of 4' - (2 - acetonyloxycarbonylethyl)phenyl trans - 4 - aminomethylcyclohexanecarboxylate hydrochloride obtained as described in Example 1 (a) was dissolved in 50 ml of water, and 1.34 g of triethylamine was added thereto. Then, the mixture was stirred at 40"C for 17 hours to effect the hydrolysis. After completion of the hydrolysis, the reaction solution was treated in the same manner as described in Example 1 (b) to obtain 2.89 g (yield: 75.9%) of CEP-ester. This product was identified by its NMR and IR-spectra. WHAT WE CLAIM IS:

1. A process for producing 4' - (2 - carboxyethyl)phenyl trans - 4 - aminomethylcyclohexanecarboxylate, or a therapeutically useful acid-addition salt thereof, comprising hydrolyzing a compound represented by the formula (IV)

wherein R1 is an alkyl groun having 1 to 6 carbon atoms. a hay enacted alkvl on,iD having 1 to 6 carbon atoms in the alkyl moiety thereof, an aryl group, an alkoxy group or an amino group, and R2 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, an acyl group, an alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety thereof or a cyano group, to produce a compound represented by the formula (IV)

wherein R and R2 are as defined above, or an acid addition salt thereof, and then hydrolyzing the compound represented by the formula (IV) or the acid-addition salt thereof.

3. A compound represented by the formula (IV)

wherein R1 is an alkyl group having 1 to 6 carbon atoms, a halogenated alkyl group having 1 to 6 carbon atoms in the alkyl moiety thereof, an aryl group, an alkoxy group or an amino group, and R2 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, an acyl group an alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy group thereof and a cyano group, or an acid-addition salt of the compound represented by the formula (IV).

4. 4' - (2 - Acetonyloxycarbonylethyl)phenyl trans - 4 - aminomethylcyclohexanecarboxylate or an acid-addition salt thereof.

5. 4' - [2 - (a - Methyl - acetonyloxycarbonyl)ethyl] phenyl trans - 4 - aminomethylcyclohexandecarboxylate or an acid-addition salt thereof.

6. 4' - [2 - (e - Acetyl - acetonyloxycarbonyl)ethyl]phenyl trans - 4 - aminomethylcyclohexanecarboxylate or an acid-addition salt thereof.

7. 4' - [2 - ( - Ethoxycarbonyl - acetonyloxycarbonyl)ethyl]phenyl - trans - 4aminomethylcyclohexanecarboxylate or an acid-addition salt.

8. 4' - [2 - ( - Chloro - acetonyloxycarbonyl)ethyljphenyl - trans - 4 - aminomethylcyclohexanecarboxylate or an acid-addition salt thereof.

9. 4' - (2 - Phenacyloxycarbonylethyl)phenyl trans - 4 - aminomethylcyclohexanecarboxylate or an acid-addition salt thereof.

10. 4' - (2 - Carbamylmethoxycarbonylethyl)phenyl trans - 4 - aminomethyl- cyclohexanecarboxylate or an acid addition salt thereof.

11. 4' - (2 - Methoxycarbonylmethyloxycarbonylethyl) phenyl trans - 4 - aminomethylxyxlohexanecarboxylate or an acid-addition salts thereof.

12. 4' - (2 - Diethoxycarbonylmethyloxycarbonylethyl)phenyl trans - 4 - aminomethylcyclohexanecarboxylate or an acid-addition salt thereof.

13. A process as claimed in Claim 1, substantially as hereinbefore described in any one of Examples 1 to 13.

14. A process as claimed in Claim 2, substantially as hereinbefore described in any one of Examples 1 to 13.

15. A compound as claimed in Claim 3, when produced by the method in Claim 2 or 14.

16. A compound when produced by the method as claimed in Claim 1 or 13.