Process for preparing 1,5-benzothiazepine derivatives

Abstract: There is disclosed a process for preparing 1,5-benzothiaze­ pine derivatives represented by the formula: wherein R is a lower alkyl group, which comprises subjecting a propionic acid compound represented by the formula: wherein R has the same meaning as defined above, to intramolecular ring closing reaction in the presence of a sulfonic acid compound represented by the formula: R¹SO₃H (III) wherein R¹ represents a lower alkyl group or a sub­ stituted or unsubstituted phenyl group.

Description: This invention relates to a novel process for preparing 1,5-benzothiazepine derivatives represented by the formula: wherein R represents a C 1 -C 4 alkyl group. The above 1,5-benzothiazepine derivatives (I) are useful compounds as intermediates for the synthesis of medical compounds, for example, (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(β-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (generic name: Diltiazem) having excellent coronary vasodilating activity. Heretofore, as a process for preparing 1,5-benzothiazepine derivatives (I), for example, the method in which 2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)propionic acid is subjected to intramolecular ring closing reaction in xylene under reflux (Japanese Patent Publication No. 18038/1978) has been known. However, this method is disadvantageous in that a long time (12 hours in Examples of the above publication is required for completing the reaction. EP-A-343 474 and EP-A-378 455 are comprised in the state of the art in accordance with Article 54(3) EPC. Furthermore, EP-A-343 474 (which was published after the Japanese Priority date of this present application) relates to a process for preparing an acid of the general formula wherein R 1 and R 2 are each, independently, hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of I to 4 carbon atoms, halogen, trifluoromethyl or nitro or R 1 and R 2 taken together with the benzene ring to which they are attached, are naphthalene and Ar is phenyl which unsubstituted or substituted by one to three substituents selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms and halogen, which comprises hydrolyzing a compound of the general formula wherein R 1 and R 2 and Ar are as described above, by reacting same with a base in a polar, protic solvent; the compound of general formula A is cyclized to provide a compound of general formula C wherein R 1 , R 2 and Ar are as described above. The cyclization is stated on page 4, lines 21 to 37 to be effected preferably in an organic solvent such as benzene, toluene, or more preferably a mixture of xylene at about the reflux termperature of the solvent for about 5 to 30 hours with nitrogen being bubbled through the reaction mixture and in the presence of an organic catalyst such as p-toluene sulphonic acid monohydrate. Also, EP-A-0 343 474 describes in Example 14B the cyclization of (2S,3S)-3-(2-aminophenyl)thio-2-hydroxy-3-(4-methoxybenzene)-propanoic acid with p-toluene sulphonic acid monohydrate with xylene as solvent with mixing at reflux under argon for 16 hours. Also, EP-A-378 455 (which was published after the filing date of the present application) discloses a process for the preparation of a compound of the general formula in which X represents one atom of hydrogen or chlorine, comprising firstly causing a 2-aminothiophenol of the general formula in which X is defined above, to react with (-)-(2R,3S)-2,3-epoxy-3-(4-methoxylproprionate of formula then cyclising the intermediate compound thus obtained, of general formula in the presence of acid, which process is characterised in that the two reaction steps are carried out, without isolation the intermediate compound, using a solvent chosen from among the chlorinated solvents having a boiling point above 70°C. The solvent used in these two reaction steps may be 1,2,3-trichloropropane, dichlorobenzene and is preferably chlorobenzene. The acid used to effect the cyclization may be anyone of a number of disclosed acids including p-toluene sulphonic acid, but is preferably methane sulphonic acid. The present inventors have carried out various researches and as a result, they have found that, when the intramolecular ring closing reaction of a specific propionic acid compound (II) is carried out in the presence of a specific sulfonic acid compound, the reaction time can be remarkably shortened and the compound (I) can be prepared in good yield. That is, according to the present invention there is provided a process for preparing 1,5-benzothiazepine derivatives represented by the formula: wherein R is a C 1-4 alkyl group, which comprises subjecting a propionic acid compound represented by the formula: wherein R has the same meaning as defined above, to intramolecular ring closing reaction in the presence of a sulfonic acid compound represented by the formula: R 1 SO 3 H wherein R 1 represents a C 1-4 alkyl group or a phenyl group which may be substituted by at least one selected from methyl group, ethyl group, propyl group and butyl group; provided that the intramolecular cyclization of the stereoisomer or a mixture of stereoisomers of 2-hydroxy-3-(2-aminophenyl)thio-3-(p-methoxyphenyl)-propionic acid is not carried out in an organic solvent such as benzene, toluene or xylene at reflux temperature with nitrogen being bubbled through the reaction mixture in the presence of an organic acid catalyst such as p-toluenesulfonic acid monohydrate, nor is it carried out in xylene at reflux temperature under argon in the presence of p-toluenesulfonic acid monohydrate. Of the sulfonic acid compounds (III) to be used in the intramolecular ring closing reaction of the present invention preferred are methanesulfonic acid and p-toluenesulfonic acid. An amount of the said sulfonic acid is not particularly limited but generally, it is preferably used at an amount of 0.5 to 10 w/w %, more preferably about 1 to 6 w/w % based cn the compound (II). The above reaction is preferably carried out in a high boiling point solvent such as xylene, toluene, etc. under reflux. The desired compound (I) formed can be isolated as a pure product containing no sulfonic acid compound (III) by simple and easy operations as, for example, cooling the reaction mixture, collecting precipitated crystals by filtration, and washing them with a suitable solvent (e.g. ethanol, aqueous ethanol, etc.). The invention also includes the use of a compound according to formula 1 produced in accordance with this invention in the production of the corresponding 3-acetoxy-5-(β-dimethylaminoethyl) -1,5-benzothiazepine derivatives represented by the formula: wherein R is C 1 -C 4 alkyl, or a pharmaceutically acceptable salt thereof in a known method, for example, in a method described in Japanese Patent Publications (examined) No. 18038/1978 and No. 43785/1971 and U.S. Patents No. 3,562,257 and No. 4,438,035, the contents of which are hereby incorporated herein by reference. According to the process of the present invention as mentioned above, a time required for the intramolecular ring closing reaction can be markedly shortened and the desired compound can be obtained in high yield and high purity. Therefore, the process of the present invention is excellent as an industrial process. Throughout the specification and claims, the term "lower alkyl" should be interpreted as referring to an alkyl having one to four carbon atoms. Experimental example For forming (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one by refluxing by heating 12.75 g of (+)-threo-2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)propionic acid in 52 ml of xylene or toluene, under continuous removal of formed water, the effects of presence of a sulfonic acid compound in the reaction system were examined. The results are shown in Tables 1 and 2. In the tables, the amount of the sulfonic acid compound is based on the starting compound, and p-toluenesulfonic acid is used as a monohydrate. (in xylene) Sulfonic acid compound Amount used (w/w %) Reaction time Yield of desired product (%) Process of this invention p-Toluenesulfonic acid 5.4 30 min 94 2.7 60 min 93.9 1.1 1 hr & 15 min 95.5 0.6 2 hrs & 15 min 95.4 Methanesulfonic acid 5.4 45 min 93 Control - - 12 hrs 82.2 (in toluene) Sulfonic acid compound Amount used (w/w %) Reaction time Yield of desired product (%) Process of this invention p-Toluenesulfonic acid 5.4 5 hrs 92 Methanesulfonic acid 5.4 5 hrs 92 Control - - 7 hrs < 50 As seen from the above Table 1 and Table 2, it can be understood that by the existance of p-toluenesulfonic acid or methanesulfonic acid in the reaction system, the desired product can be obtained within extremely short time in good yield. Example 1 A mixture of 12.75 g of (+)-threo-2-hydroxy-3-(2-aminophenyl) thio -3-(4-methoxyphenyl)propionic acid, 140 mg of p-toluenesulfonic acid monohydrate and 52 ml of xylene is refluxed by heating for about 1 hour and 15 minutes. During the reaction, water formed is continuously removed. After cooling, precipitated crystals are collected by filtration and washed with cooled ethanol to give 11.5 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. Yield: 95.5 % m.p.: 203 to 204 °C [α] 20 / D + 116 ° (c = 0.5, dimethylformamide) Example 2 A mixture of 12.75 g of (+)-threo-2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)propionic acid, 690 mg of p-toluenesulfonic acid monohydrate and 52 ml of toluene is refluxed by heating for about 5 hours. During the reaction, water formed is continuously removed. After cooling, precipitated crystals are collected by filtration and washed with cooled ethanol to give 11 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. Yield: 92 % m.p.: 203 to 204.5 °C [α] 20 / D + 118 ° (c = 0.5, dimethylformamide)

Claims: A process for preparing 1,5-benzothiazepine derivatives represented by the formula: wherein R is a C 1-4 alkyl group, which comprises subjecting a propionic acid compound represented by the formula: wherein R has the same meaning as defined above, to intramolecular ring closing reaction in the presence of a sulfonic acid compound represented by the formula: R 1 SO 3 H wherein R 1 represents a C 1-4 alkyl group or a phenyl group which may be substituted by at least one selected from methyl group, ethyl group, propyl group and butyl group; provided that the intramolecular cyclization of the stereoisomer or a mixture of stereoisomers of 2-hydroxy-3-(2-aminophenyl)thio-3-(p-methoxyphenyl)-propionic acid is not carried out in an organic solvent such as benzene, toluene or xylene at reflux temperature with nitrogen being bubbled through the reaction mixture in the presence of an organic acid catalyst such as p-toluenesulfonic acid monohydrate, nor is it carried out in xylene at reflux temperature under argon in the presence of p-toluenesulfonic acid monohydrate. A process for preparing 1,5-benzothiazepine derivatives according to claim 1, wherein the sulfonic acid compound (III) is methanesulfonic acid or p-toluenesulfonic acid. A process for preparing 1,5-benzothiazepine derivatives according to any one of the preceding claims, wherein the reaction is carried out in an appropriate solvent under reflux. A process for preparing 1,5-benzothiazepine derivatives according to claim 3, wherein the solvent is at least one selected from xylene, toluene and dichlorobenzene. A process for preparing 1,5-benzothiazepine derivatives according to any one of the preceding claims, wherein the sulfonic acid (III) is used in an amount of 0.5 to 10 w/w % based on the compound (II). A process for preparing 1,5-benzothiazepine derivatives according to claim 5, wherein the sulfonic acid (III) is used in an amount of 1 to 6 w/w % based on the propionic acid compound (II). A process for preparing 3-acetoxy-5-(β-dimethylaminoethyl)-1,5-benzothiazepine derivatives represented by the formula: wherein R is a C 1-4 alkyl group, or pharmaceutically acceptable salt thereof which comprises the steps of: subjecting a propionic acid compound represented by the formula: wherein R has the same meaning as defined above, to an intramolecular ring closing reaction in the presence of a sulfonic acid compound represented by the formula: R 1 SO 3 H wherein R 1 represents a C 1-4 alkyl group or a phenyl group, which may be substituted by at least one selected from methyl group, ethyl group, propyl group and butyl group, to give a compound represented by the formula: wherein R has the same meaning as defined above, and converting the compound (I) to the corresponding 3-acetoxy-5-(β-dimethylaminoethyl)-1,5-benzothiazepine derivative or a pharmaceutically acceptable salt thereof in a known method; provided that the intramolecular cyclization of the stereoisomer or a mixture of stereoisomers of 2-hydroxy-3-(2-aminophenyl)thio-3-(p-methoxyphenyl)-propionic acid is not carried out in an organic solvent such as benzene, toluene or xylene at reflux temperature with nitrogen being bubbled through the reaction mixture in the presence of an organic acid catalyst such as p-toluenesulfonic acid monohydrate, nor is it carried out in xylene at reflux temperature under argon in the presence of p-toluenesulfonic acid monohydrate.

Inventors: HAYASHI HIRONORI, KITANO MASASHI, MAEDA SADAO, NISHIMOTO SHIGERU, OKUNO TAMOTSU, HAYASHI, HIRONORI, KITANO, MASASHI, MAEDA, SADAO, NISHIMOTO, SHIGERU, OKUNO, TAMOTSU
Applicants: TANABE SEIYAKU CO, TANABE SEIYAKU CO., LTD.
Application year: 1990
Main classification: C07D281
IPC codes: C07B61, C07D281