KR0143805B1 - Method for preparing (+)-(2s,3s)-3-rydroxg-2-(4-methoxy phenyl)-2,3-dihydro-5h-1.5-bengothiage pine-4-one and chlorinated derivatives thereof - Google Patents

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Description

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

It is an object of the present invention to provide (+)-(2S, 3S) -3-hydroxy-2- (4-methoxyphenyl) -2, 3-dihydro-5H-1, optionally having a chlorine atom in the aromatic ring, It is a manufacturing method of 5-benzothiazepin-4-one. Their optically pure compounds are (+)-(2S, 3S) -3-acetyloxy-5- (2-dimethylaminoethyl) -2- (4-methoxyphenyl) -2, 3-dihydro-5H Synthetic intermediates of therapeutically active compounds such as -1, 5-benzothiazepin-4-one and chlorinated derivatives thereof. The reactivity is shown on the next page. In the formula, X represents hydrogen or chlorine.

The first step is to react the 2-aminothiophenol derivative of formula II with (-)-(2R, 3S) -2, 3-epoxy-3- (4-methoxyphenyl) propionate of formula III. Is done. Ring opening of the epoxide ring results in methyl (2S, 3S) -3-[(2-aminophenyl) thio] -2-hydroxy-3- (4-methoxyphenyl) propionate of general formula IV. . The second step consists of the cyclization of this compound in the presence of an acid. The reaction principle of each of the two steps is well known. They are found, for example, in Chem, Pharm, Bull., 18, 2028-2037 (1970), wherein the esters of formula III are used in racemic form. The first step requires heating for several hours to 150-160% and after separation and purification of the ester of formula IV, the second step is a ring of the acid obtained in the presence of sulfuric acid or acetic acid in xylene hydrolyzing and refluxing the ester. Is done by US Pat. No. 4,116,819 describes the first step, wherein the (racemic) ester of formula III is reacted with aminothiophenol (II) in toluene after heating for 6 hours under reflux. Japanese Patent Application No. 145160/1986 describes the synthesis of optically pure esters of formula III and likewise describes the reaction with the latter aminothiophenols of formula II for 10 hours under toluene reflux. Finally, European patent application 0154838 describes a method of combining two steps among others. The reaction is carried out without solvent and requires 16 hours of heating to 160 ° C. to give a mixture of optical isomers and intermediates of the final compound. Thus, it is evident that none of the known methods are suitable for the economical industrial preparation of the compounds of formula I for a variety of reasons: poor yield, high temperature, intermediate and / or final compound needs and long reaction times. The present invention therefore proposes a method which overcomes the disadvantages of the known art and provides the following advantages. In other words,

Since two reaction steps can be carried out in one and the same reactor, it is unnecessary to empty and wash the reactor or use a second reactor between the two steps. (Conveniently, the two steps can be carried out in separate reactors, but do not require any separation of intermediate esters.)-The total yield is high compared to the yield of known methods.

The energy consumption is particularly reduced during the first phase.

-Short reaction time.

The final compound is pure.

The operating conditions of the method according to the invention make it possible to achieve these points listed above, which are described below. The starting ester of formula III is used in optically pure form. It is described in Japanese Patent Application Nos. 145159/1986, 145160/1986 and 145174/1986. The possibility of carrying out two stage reactions in the same vessel without emptying the intermediates in another vessel is due to the selection of a unique solvent which is highly suitable for each of the two stages. Solvents specific for each of the two steps are already known as such (dichloroethane, toluene, xylene, etc.) but they are different for each step and thus do not allow the whole process to occur in the same reactor. Solvents used according to the invention are chlorinated organic solvents having a boiling point of at least 70 ° C. Examples of suitable solvents are 1, 2, 3-trichloropropane, dichlorobenzel and preferably chlorobenzene. These solvents are unexpectedly highly desirable with good overall yields, and furthermore they are efficient enough to require heating only at the start, since the first step is sufficient to maintain the exothermic nature of the reaction without participation of external energy. This specific feature is unexpected because it was never found in other solvents. In addition, the use of these solvents promotes the selectivity with the threo-erythrite of the first step. It is actually found that other solvents result in undesirable mixtures of the diastereomers of formula IV. Another specific feature of the invention is due to the catalyst used in the second step. It is known that cyclization is better at acidic solvents (sulfuric acid or acetic acid), while the catalysts used according to the invention are from methane sulfonic acid, phosphoric acid, trifluoro acetic acid, trifluoro methanesulfonic acid, perchloric acid, paratoluene sulfonic acid Is selected. Preferred catalyst is methanesulfonic acid. These acids make it possible to obtain excellent yields of the cyclized compound (I), which are simply added 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.

Example 1

3 kg of methyl (-)-(2R, 3S) -2, 3-epoxyl- (4-methoxyphenyl) propionate and 10 liters of chlorobenzene were introduced into a 25-liter reactor purged with nitrogen. The mixture is heated to 100 ° C. The heating is stopped, a solution of 1900 g of 20 aminothiophenol in 1.5 l of chlorobenzene is introduced at an interval of 30 minutes, the temperature not exceeding 120 ° C., and 3.5 l of chlorobenzene also added to rinse the inlet funnel and tube. . Maintain the temperature for approximately 30 minutes at 115 ° C, then add 37.5 ml of methanesulfonic acid and heat the mixture under reflux for 8 hours, but distill the methanol and chloro by distillation so that the temperature does not drop below 132 ° C (boiling point of chlorobenzene). Remove the mixture of benzene. The heating is stopped and the mixture is returned to 20 ° C. and cooled to 5 ° C. for 1 hour and the crystals formed are filtered off, rinsed with chlorobenzene and dried in vacuo at 100 ° C. Yield of 3463 g of pure (+)-(2S, 3S) -3-hydroxy-2- (4-methoxyphenyl) -2, 3-dihydro-5H-1,5-benzothiazepin-4-one Obtained. Melting point: 200.3 -201.8 ° C. [α] ² _D ^0- + 114 ° (c = 0.1; DMF).

Example 2

50 g of methyl (-)-(2R, 3S) -2, 3-epoxy-3- (4-methoxyphenyl) propionate and 350 ml of dichlorobenzene (0-, m- in a 1 liter flask under argon atmosphere And a commercially available mixture of p-isomers) and the mixture is heated at l15 ° C. Next, 31.8 g of 2-aminothiophenol is introduced at an interval of 30 minutes while the temperature does not exceed 120 ° C. The temperature is held at 120 ° C. for another 30 minutes and then 0.62 ml of methasulfonic acid is added and the mixture is heated at 150 ° C. for 3 hours. (The reaction is complete after 2 hours.) The mixture is left to cool and cooled to 5 ° C. for 1 hour, the crystals are filtered off, washed with dichlorobenzene and dried in vacuo. 49.5 g of pure (+)-(2S, 3S) -3-hydroxy-2 (4-methoxyphenyl) -2, 3-dihydro-5H-1, 5-benzothiazepin-4-one are obtained Lose. Melting Point: 203-2O4 ℃

Example 3

18.8 g of 2-aminothiothenol was mixed with 30 g of methyl (-)-(2R, 3S) -2, 3-epoxy-3- () in 200 ml of 1, 2, 3-trichloropropane at 110-l15 ° C. Dropwise to a solution of 4-methoxyphenyl) propionate. After 30 minutes 0.35 g of methanesulfonic acid is added and the mixture is heated at 145-1 50 ° C. for 6 hours. Allow the mixture to cool, then cool and filter. The crystals are washed with 1, 2, 3-trichloropropane and dried in vacuo at 50 ° C. 33.8 g of pure (+)-(2S, 3S) -3-hydroxy-2- (4-methoxyphenyl) -2, 3-dihydro-5H-1, 5-benzothiazepin-4-one Obtained. Melting Point: 202.8-204.1 ℃

Example 4

In the same manner as in Example 1, the reaction between 2-amino-5-chlorothiophenol and methyl (-)-(2R, 3S) -2, 3-epoxy-3- (4-methoxyphenyl) propionate Silver (+)-(2S, 3S) -8-chloro-3-hydroxy-2- (4-methoxyphenyl) -2, 3-dihydro-5H-1, 5-benzothiazepin-4-one Provide for. Melting point: 237-241 ° C. [α] ² _D ⁰ = + 91.9。 (c = 0.1; DMF)

Claims (6)

Formula (II)

To a compound of the general formula (III)

First reacted with a compound of

Wherein the intermediate compound of is cyclized in the presence of an acid, the process being characterized in that two reaction steps are carried out without separation of the intermediate compound by using a solvent selected from chlorinated organic solvents having a boiling point of at least 70 ° C. (I)

Process for the preparation of the compound. In the formulas, X represents hydrogen or chlorine. The method of claim 1 wherein X is hydrogen. The method of claim 1 wherein the solvent is chlorobenzene. The method of claim 1 wherein the solvent is dichlorobenzene. The method of claim 1 wherein the solvent is 1,2,3-trichloropropane. The method of claim 1 wherein methanesulfonic acid is used to catalyze the cyclization of the intermediate compound of formula (IV).