FI68611B - TRANSMISSION OF OIL FRAMSTAELLNING AV EN TRANS-4-AMINOMETHYLCYKLOHEXANKARBOXYLSYRAESTER - Google Patents

Description

NOTICE OF PUBLICATION, «, Λ 1 B (11) UTLÄGGNINGSSKRIFT ΟΟΟΊΊ C (45) Patent granted 10 10 1985 Patent coddelat ^ ~ ^ (51) Kv.lk.> t.Ci. 'C 07 C IOI / I8, 99/00 ( 21) Patent application - Patentansdknlng 800713 (22) Application date - Ansöknlngsdag 07 · 03.8 0 (EN) (23) Starting date - Glltlghetsdag 07-03.80 (41) Has become public - Blivit offentlig 08.09 .81

National Board of Patents and Registration of Finland Date of publication and hearing publication - 28.06.85

Patent and registration authorities Anslikan utlagd och utl.skrlften publicerad (32) (33) (31) Privilege claimed - Begärd prloritet (71) Daiichi Seiyaku Co., Ltd., No 1 * »- 10, Nihonbashi 3-chome, Chuo -ku, Tokyo, Japan-Japan (JP) (72) Tadamasa Hirayama, Tokyo, Hiroki Kuroda, Tokyo,

Moriaki Iwase, Tokyo, Japan-Japan (JP) (7 * 0 Oy Koi ster Ab (5 * 0 Method for the preparation of trans- * i-aminomethyl isyclohexanecarboxylic acid ester - Förfarande för f ramstäl lning av en trans - * »- amino-methy1cyk1ohexanka rboxy1sy This invention relates to a novel process for the preparation of trans-4-aminomethylcycloheecanecarboxylic acid 4 '- (2 "-carboxyethyl) phenyl ester (hereinafter referred to as" CEP ester ") / which has the formula

TT / ,, \ - - - / (\\ - CH-CH-COOH

h2nh2c · - <h - - - coo ----— \ v_y · 2 2 and which is excellently active as an antiulcer and oligoplasmic agent, a method which is advantageous in production on a technical scale. More specifically, the present invention relates to a process for the preparation of a CEP ester, which process is characterized in that it comprises a trans-4-aminomethylcyclohexanecarboxylic acid ester represented by the formula (I) 2 68611 n2NCH2- \ H / ------ C0 ° - ^ - CH 2 CH 2 COOR (I) wherein R represents a benzyl group / "wherein the compound is hereinafter referred to as compound (Ia) - / or a methyl group [hereinafter referred to as compound (Ib) J7, or the terminal carboxylic acid ester part of the acid addition salt of the ester of formula (I) is cleaved with benzyl - or a methyl group in the presence of a Lewis acid and a nucleophilic reagent.

The starting material of formula (I) used in the process of this invention has two ester bonds, a phenyl ester moiety and a terminal carboxylic ester moiety, and therefore, by hydrolyzing the starting ester in the usual manner with an acid or alkali commonly used to prepare a carboxylic acid from the corresponding carboxylic acid ester, also the phenyl ester moiety, which makes it impossible to selectively prepare only the desired CEP ester.

Accordingly, in preparing a compound having a free carboxyl group, a reaction in which only the protecting group of the terminal carboxyl group is specifically cleaved without causing cleavage of the phenyl ester moiety must be used. For this purpose, some conventional methods have been proposed, for example, a process for cleaving a benzyl CEP ester having a benzyl group protected by a terminal carboxyl group of the CEP ester by catalytic reduction as disclosed in Japanese Patent Publication JP 19 950/71 and Japanese Patent Application (OP). JP 75 547/73 (term "OPI" = Open to Public Inspection "; the same applies to the later part of the text), a process for deprotecting a tertiary butyl CEP ester in which the terminal carboxyl groups of the CEP ester are protected by a tertiary butyl group, a hydrogen halide -acetic acid mixture as disclosed in Japanese Patent Application No. 3,68611 (OPI) JP 78 143/73 or a process for hydrolyzing a CEP ester having a terminal carboxyl group protected by a special protecting group as disclosed in Japanese Patent Application (OPI) JP 56 643/78, which is the subject of Norwegian advertisement publication No. 148 521. These conventional men however, the methods are not satisfactory in the context of the technical manufacturing process, given the disadvantages associated with these conventional methods. For example, the first conventional method mentioned above requires the use of an expensive palladium catalyst in the deprotection step, the second conventional method mentioned above requires the use of tertiary butyl CEP ester as a starting material, which is very complicated and difficult to prepare and yields only in small yields, and the third conventional method. the process requires the use of a specially protected CEP ester as a starting material, the preparation of which is very complex.

As a result of extensive studies on a process for the preparation of CEP ester applicable to industrial scale production, the inventors of the present invention found that when treating a starting material having a terminal carboxylic acid ester represented by formula (I) above with Lewis acid in the presence of a nucleophilic reagent under relatively mild reaction conditions, a very interesting reaction takes place in which only the protecting group of the terminal carboxyl group is cleaved specifically and selectively so that the phenyl ester moiety is not cleaved. The present invention is based entirely on the above finding.

The starting material used in the process of this invention can be readily prepared by condensing trans-4-aminomethyl-cyclohexanecarboxylic acid chloride hydrochloride with a 4-hydroxy-phenylpropionic acid ester of formula (II) wherein R is as defined in formula (I), in the usual manner is illustrated in the reference examples described later.

The process of this invention can be carried out by suspending the starting material of formula (I) in a suitable solvent, and stirring the mixture in the presence of a Lewis acid and a nucleophilic reagent to give a uniform and complete reaction, the product obtained can be isolated from the reaction mixture by a conventional method to give the desired CEP ester in maximum yields.

Reaction solvents can be all types of solvents, and generally useful are halogenated hydrocarbons, for example, methylene chloride, chloroform, carbon tetrachloride, ethylene dichloride, and the like, as well as aromatic hydrocarbons, for example, benzene, toluene, and the like.

Preferred examples of nucleophilic reagents include thiols such as alkylthio, for example CH 3 SH, C 2 H, -SH, CH 3 (CH 2) 2 SH, n-C 1 H 2 SH and the like, and alkyl dithiols, for example HSCl 2 CH 2 SH and the like dithiols; sulfides such as (CH 2 Cl 2, (C 2 H 2) 2 S, CH 2 -SC 2 H 2 Cl 2, (m-propyl) 2 S, (isopropyl) 2 S and the like sulfides, thiophenols such as thiophenol (SH), thioanisole (^ -SCH ^) and the like thiophenols, disulfides such as CH2-SS-CH-j, C2H4-SS-C2Hg and the like disulfides, and phenols such as phenol (^ -HH) 'cresols (^ OH) , chlorophenols (^ OH), anisole (^ -OCH ^) and the like.

These nucleophilic reagents are mainly used in an amount of about 1 to about 10 moles per mole of starting material (I).

Examples of Lewis acids useful in the present invention include metal halides such as AlCl 2, AlBr 2 68611

SnCl 2, FeCl 2, ZnCl 2 and the like metal halides.

These Lewis acids can be used in an amount of about 2 to about 4 moles per mole of starting material (I).

The reaction temperature used in the process of this invention is not critical, provided that the temperature is below the boiling point of the solvent used, and is generally in the range of about 0 ° C to about 30 ° C.

The reaction rate varies depending on the reaction conditions used, i.e. the reaction temperature as well as the nature and amount of Lewis acid and nucleophilic reagent used, but in general, the reaction can be completed within about 1 to about 30 hours by selecting a combination of these reaction conditions as appropriate.

The process of this invention can be carried out under the above conditions, and after completion of the reaction, the desired CEP ester product can be easily obtained in very pure yields by conventional methods, for example, distilling off the reaction solvent, decomposing the remaining metal complex residue and crystallizing the product apart.

From the foregoing description, it will be apparent to one skilled in the art that the process of the present invention is technically and economically very useful, given that the process allows the desired CEP esters to be prepared in very pure and high yields with simple work, despite relatively mild reaction conditions. and cheap reagents.

The present invention is further illustrated in more detail by the following Reference Examples and Examples.

Reference Example 1 3.7 g of trans-4-aminomethylcyclohexanecarboxylic acid was reacted with 3.0 g of thionyl chloride in 35 ml of ethylene dichloride at 50-60 ° C with stirring for two hours. Then, 6.3 g of benzyl 4-hydroxyphenylpropionate was added to the reaction mixture, after which the mixture was allowed to react at that temperature with stirring for two hours. The reaction solution was evaporated to dryness in vacuo to give 6,686,11, and the residue was recrystallized from ethanol to give 8.7 g of trans-4-aminomethylcyclohexanecarboxylic acid 41- (2 "-benzyloxycarbonylethyl) phenyl ester hydrochloride having a decomposition point of 198-200 °.

Reference Example 2 7.08 g of trans-4-aminomethylcyclohexanecarboxylic acid were reacted with 6.45 g of thionyl chloride in 60 ml of ethylene dichloride at 55-65 ° C with stirring for 1.5 hours. Then, 8.52 g of methyl 4-hydroxyphenylpropionate was added to the reaction mixture, after which the mixture was allowed to react at that temperature for 2.5 hours with stirring. The reaction mixture was cooled, and the precipitate was filtered off and dried, yielding 15.5 g of trans-4-aminomethylcyclohexanecarboxylic acid 4 '(2 "-methoxycarbonylethyl) phenyl ester hydrochloride. Recrystallization from water gave colorless flake-like crystals, which had colorless crystals. C.

Example 1 8.64 g of trans-4-aminomethylcyclohexanecarboxylic acid 4 '- (2 "-benzyloxycarbonylethyl) phenyl ester (Ia) hydrochloride was suspended in 90 ml of ethylene chloride, and 1.9 g of methyl sulfide was added to the suspension, followed by adding to the mixture 8 g of anhydrous aluminum chloride were allowed to react for 7 hours at room temperature, the insoluble matter was filtered off, dried and dissolved in a mixture of isopropyl alcohol and water, adjusted to pH 2.5 with concentrated hydrochloric acid and treated with charcoal. to dryness in vacuo and the precipitated crystals were filtered off and dried to give 6.5 g of white crystals, the crystals thus obtained were dissolved in a mixture of isopropyl alcohol and water and, after treatment with activated carbon, the pH of the solution was adjusted to 7.0 to precipitate crystals with sodium hydroxide. the obtained crystals were filtered and dried to give 5.61 g (91.8% yield) of trans-4-aminomethyl-cyclohexanecarboxylic acid 7,686,11-poly '- (2 "-carboxyethyl) -phenyl ester with a decomposition point higher than 280 ° C. . The IR and NMR spectra of the product were found to be quite consistent with the corresponding spectra of the authentic sample.

The product obtained above was suspended in a mixture of isopropyl alcohol and water, and the pH of the solution was adjusted to 2.5. After treatment with activated carbon, the clear filtrate was evaporated to dryness in vacuo. The precipitated crystals were filtered off and dried, yielding 6.0 g (87.7% yield) of trans-4-aminomethylcyclohexanecarboxylic acid 41- (2 "-carboxyethyl) phenyl ester hydrochloride, m.p. 238 ° C (decomposed).

Elemental analysis for C 17 H 24 NO 4 Cl: Calculated: C 59.73 H 7.08 N 4.10 Cl 10.37 Found: C 59.48 H 7.19 N 4.24 Cl 10.23

In addition, the IR and NMR spectra of the product were found to be completely consistent with the corresponding spectra of the authentic sample.

Example 2 8.64 g of compound (Ia) was dissolved in 200 ml of methylene dichloride, and 10 g of ethanethiol and then 15.6 g of dry stannous chloride were added to the solution under cooling. The mixture was then allowed to react at room temperature for one hour with stirring. After completion of the reaction, the formed insoluble matter was filtered off, dried and dissolved in a mixture of isopropyl alcohol and water. The solution was adjusted to pH 2.5 with concentrated hydrochloric acid and treated with activated carbon. The filtrate was evaporated to dryness in vacuo, and the precipitated crystals were filtered off and dried to give 6.6 g of crude CEP ester hydrochloride crystals. The obtained crude crystals were then treated in the same manner as described in Example 1 to give 5.7 g (93.5% yield) of pure CEP ester, which was then treated in the same manner as described in Example 1 to give 6.1 g. (89.2% yield) of pure CEP ester hydrochloride.

8,68611

Example 3 8/64 g of compound (Ia) was suspended in 200 ml of ethylene dichloride, and 10.8 g of anisole was added to the suspension, and then 8 g of dry aluminum chloride was added to the mixture under cooling. The mixture was then allowed to react at room temperature with stirring for three hours. Upon completion of the reaction, the reaction mixture was treated in the same manner as described in Example 1 to give 5.0 g (81.8% yield) of pure CEP ester, which was then treated in the same manner as described in Example 1 to give 5.31 g ( 77.6% yield) of pure CEP ester ester hydrochloride.

Example 4 7.12 g of trans-4-aminomethylcyclohexanecarboxyl-4 '- (2 "-methoxycarbonylethyl) phenyl ester hydrochloride (Ib) were suspended in 200 ml of ethylene chloride, and 12.5 g of methyl sulfide was added to the suspension, and then 8 g of dry matter was added to the mixture under cooling. The mixture was then allowed to react with stirring for 30 hours at 30. At the end of the reaction, the reaction mixture was treated in the same manner as described in Example 1 to give 5.18 g (84.4% yield) of pure CEP ester, which was then treated in the same manner as described in Example 1 to give 5.5 g (80.4% yield) of pure CEP ester hydrochloride.

Claims (1)

Process for the preparation of trans-4-aminomethylcyclohexanecarboxylic acid 4 '(2 "-carboxyethyl) phenyl ester of the formula h2nh2c - ^ h ^ ------ coo_-ch2ch2cooh and its acid addition salt, characterized in that the trans- A benzyl or methyl ester of a 4-aminomethylcyclohexanecarboxylic acid ester represented by the formula H2NCH2 - ^ H ----- -COO -_CH2CH2COOR wherein R corresponds to a benzyl group or a methyl group, or an acid addition salt of said benzyl or methyl ester, is cleaved in the presence of a nucleophilic reagent.