Method for preparing (+)-(2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-one and chlorinated derivatives thereof

.Iadd.

This application is a continuation-in-part of application Ser. No. 07/408,042, filed Sep. 14, 1989, now U.S. Pat. No. 5,013,835. .Iaddend.

The subject of the present invention is a method for preparing (+)-(2S,3S)-3-hydroxy-2-(4-methoxyphenyl-2,3-dihydro-5H-1,5-benzothiazepine-4-one, bearing optionally a chlorine atom on the aromatic ring.

These optically pure compounds are synthetic intermediates of compounds with therapeutic activities, such as (+)-(2S,3S)-3-acetyloxy-5-(2-dimethylaminoethyl)-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-one and its chlorinated derivatives.

The reaction scheme is shown on the following page. In the formulae, X denotes hydrogen or chlorine.

The first step comprises reacting a 2-aminothiophenol derivative of general formula II with methyl (-). (2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate of formula III. A methyl (2S,3S)-3-[(2-aminophenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propionate derivative of general formula IV is obtained via opening the epoxide ring.

The second step comprises the cyclization of this compound in the presence of an acid.

The reaction principles of each of the two steps are well known.

They are found, for example, in Chem. Pharm. Bull., 18, 2028-2037 (1970), where the ester of formula III is used in racemic form. The first step necessitates several hours of heating to 150°-160° C., and after separation and purification of the ester of formula IV, the second step is performed by hydrolyzing this ester and cyclizing the acid obtained in the presence of sulfuric or acetic acid, in refluxing xylene.

U.S. Pat. No. 4,416,819 describes the first step, where the (racemic) ester of formula III reacts with the aminothiophenol (II) in toluene after six hours of heating at reflux.

Japanese Patent Application 145160/1986, which describes the synthesis of the optically pure ester of formula III, likewise. ##STR1## describes the reaction of the latter with aminothiophenol of formula II, under toluene reflux for 10 hours.

Finally, European Patent Application 0154838 describes among others a method that combines the two steps. The reactions are performed without solvent, requiring 16 hours of heating to 160° C., and furnishing a mixture of optical isomers of the final compound and is intermediate.

Thus it is clear that none of the known methods are suitable for economic industrial manufacture of the compounds of formula I, for various reasons: poor yields, elevated temperatures, the need to purify the intermediate and/or final compounds, and long reaction times.

The present invention therefore proposes a method that overcomes the disadvantages of the known art, and affords the following advantages:

the two reaction steps can be performed in the one and same reactor, so that emptying and cleaning it between the two steps, or using a second reactor, is unnecessary (for reasons of convenience, the two steps can be performed in separate reactors, but anyway it is not necessary to isolate the intermediate ester);

the total yield is high compared with the yields of the known methods;

energy consumption is reduced, in particular during the first step;

the reaction times are short; and

the final compound is pure.

The operating conditions of the method according to the invention, which make it possible to attain all the advantages listed above, are described below.

The starting ester of formula III is used in optically pure form. It is described in Japanese Patent Applications 145159/1986, 145160/1986 and 145174/1986.

The possibility of carrying out the two steps of the reaction in the same vessel, without evacuation or intermediate transfer to another vessel, is due to the selection of a unique solvent which is highly suitable for each of the steps.

Specific solvents for each of the two steps are naturally already known (dichloroethane, toluene, xylene, etc.), but they are different for each step and so do not permit the entire method to take place within the same reactor. The solvents to be used according to the invention are chlorinated organic solvents having a boiling point of more than 70° C. Examples of suitable solvents are 1,2,3-trichloropropane, dichlorobenzenes and, preferably, chlorobenzene.

These solvents are not only--and unexpectedly--highly favorable to a good overall yield, but further/more they are so efficient that the first step necessitates heating only for startup, because the exothermic nature of the reaction is sufficient for it to be maintained without adding external energy. This particular feature was entirely unforeseeable, because it had never been found with other solvents.

Additionally, the use of these solvents promotes the threoerythro selectivity of the first step. With other solvents, it is in fact found that an unfavorable mixture of diastereoisomers of formula IV is obtained.

Another particular feature of the invention is due to the catalyst used in the second step. While it is known that cyclization takes place better in an acid medium (sulfuric or acetic), the catalyst to be used according to the invention is selected from methanesulfonic acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, perchloric acid, paratoluenesulfonic acid. The preferred catalyst is methanesulfonic acid.

These acids, which make it possible to obtain an excellent yield of the cyclized compound (I), are simple to add to the reaction medium as soon as the first step is completed.

The following examples provide a detailed illustration of the method according to the invention.