Process for the preparation of 1,5-benzothiazepines by ring closure of amino esters

Abstract: A process for the preparation of 1,5-benzothiazepines which comprises the cyclization of aminoesters of formula wherein R₁ and R₃ have the meanings reported in the specification, is described.

Description: The present invention relates to a process for the preparation of 1,5-benzothiazepines and, more particularly, it relates to a process for the preparation of 1,5-benzothiazepines useful as intermediates in the synthesis of optically active 2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)ones of formula wherein R represents a hydrogen atom or acetyl, R 1 represents a hydrogen atom or chlorine atom, the asterisks mark the asymmetric carbon atoms. Specific examples of the compounds of formula I are Diltiazem, (+)-(2S,3S)-3-acetoxy-5-[2-(dimethylamino)-ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (Merck Index, X Ed., No. 3189, page 466) and TA-3090, (+)-(2S,3S)-3-acetoxy-8-chloro-5-[2-(dimethylamino)-ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (Annual Drug Data Report 1987, page 507). Various methods for the preparation of the compounds of formula I are known in the literature such as for example those described in British patent No. 1,234,467, in European patent applications No. 127,882 and No. 158,340 and in the British patent application No. 2,167,036 all in the name of Tanabe Seiyaku Co. Ltd. Most of these methods substantially foresee the following reaction scheme. wherein R 1 represents a hydrogen or chlorine atom, R 2 represents a lower alkyl and the asterisks mark the asymmetric carbon atoms. EP-A-378455 is a relevant prior art only as far as Art. 54(3) EPC is concerned. The cyclization of methyl (2S,3S)-2-hydroxy-3-(2-aminophenylthio)-3-(4-methylphenyl)-propionate which can bear a chlorine substituent on the 2-aminophenylthio moiety by heating in the presence of a chlorinated solvent having a boiling point higher than 70°C and of methanesulfonic acid is described therein. Chem. Pharm. Bull., vol 18, No. 10, 1970, pages 2028-2037 generally describes the cyclization of esters of formula by heating in the presence of sulfuric or acetic acid. This paper clearly states that the cyclization of the corresponding carboxylic acids gives better results than the cyclization of the esters of formula (E). The only example reported in detail in the Chem. Pharm. Bull. article concerns the cyclization of an ester unsubstituted on the phenyl ring adjacent to the C-OH group by heating in 20% sulphuric acid or in acetic acid without other solvents. Object of the present invention is a process for the preparation of compounds of formula wherein R represents a hydrogen atom or acetyl, R 1 represents a hydrogen atom or chlorine atom, the asterisks mark the asymmetric carbon atoms; which comprises the cyclization of the optically active amino ester of formula wherein R 1 represents a hydrogen atom or chlorine atom, R 3 represents a C 1 -C 3 alkyl, the asterisks mark the asymmetric carbon atoms; by heating preferably in the presence of a solvent such as xylene or toluene and of small amounts of an acid, e.g. p.toluenesulfonic acid, sulfuric acid in water being excluded and the cyclization of methyl (2S,3S)-2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)-propionate which can bear a chlorine substituent on the 2-aminophenylthio moiety by heating in the presence of a chlorinated solvent having a boiling point higher than 70°C and methanesulfonic acid being excluded too. The process object of the present invention represents an extremely advantageous process, simple and unexpensive, for the preparation of the compound of formula 1. By a practical point of view, the process object of the invention allows, in fact, to avoid the subsequent hydrolysis of the amino ester IV, reported in scheme 1, by carrying out the cyclization directly on the amino ester. With the aim to better illustrate the present invention the following example is given, Example Cyclization of methyl (2S,3S)-2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)-pronionate To a suspension of methyl (2S,3S)-2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)-propionate (19.4 g; 0.058 moles) in xylene (223 ml), monohydrate p.toluenesulfonic acid (1.1 g) was added. The mixture was heated to reflux under stirring for 5 hours. Then it was cooled and the insoluble was filtered and dried in an oven under vacuum at 70°C to give (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (16.1 g - 90% yield) with titre 98% weight/weight.

Claims: A process for the preparation of compounds of formula wherein R represents a hydrogen atom or acetyl, R 1 represents a hydrogen atom or chlorine atom, the asterisk mark the asymmetric carbon atoms; which comprises the cyclization of the optically active amino ester of formula wherein R 1 represents a hydrogen atom or chlorine atom, R 3 represents a C 1 -C 3 alkyl, the asterisk mark the asymmetric carbon atoms; by heating in the presence of a solvent and of an acid, sulfuric acid in water being excluded and the cyclization of methyl (2S,3S)-2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)propionate which can bear a chlorine substituent on the 2-aminophenylthio moiety by heating in the presence of a chlorinated solvent having a boiling point higher than 70°C and of methanesulfonic acid being excluded too. A process according to claim 1 wherein the solvent is xylene or toluene. A process according to claim 1 wherein the acid is present in a molar amount of about 10%. A process according to claim 1 wherein the acid is p.toluenesulphonic acid. A process for the preparation of compounds of formula wherein R represents a hydrogen atom or acetyl, R 1 represents a hydrogen atom or chlorine atom, the asterisks mark the asymmetric carbon atoms; which comprises the cyclization according to claim 1 to afford the compound of formula (VI-cis) and the further alkylation and optional acetylation.

Inventors: TENTORIO DARIO, TENTORIO, DARIO
Applicants: ZAMBON SPA, ZAMBON GROUP S.P.A.
Application year: 1990
Main classification: C07D281
IPC codes: C07D281, C07C319, C07C323