JPH05202013A - Preparation of 1,5-benzothiazepine derivative - Google Patents

Abstract

PURPOSE:To profitably and simply obtain the intermediate of diltiazem hydrochloride having a coronary vasodilating action and useful for treating ischemic cardiac diseases simply in one process and in a good yield without requiring any prelimanary treatment. CONSTITUTION:(A) A phenylpropionic acid derivative of formula I (R is methyl, ethyl) is reacted with (B) N,N-dimethylaminoethyl chloride or its acid salt in an amount of equimolar or slightly excessive mole, preferably 1-2 times mole, in the presence of an alkali metal hydroxide, especially potassium hydroxide, in an amount of 1-5 times mole, especially 1.3-3 times mole, in an etheric solvent (preferably a cyclic ether such as dioxane or tetrahydrofuran) preferably at approximately 50 deg.C; to the boiling point of the solvent to advantageously obtain 5-[2-(dimethylamino)-ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro- 1,5- benzothiazepine-4 (5H)-one of formula II useful as the intermediate of medicines.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an industrially advantageous process for producing a synthetic intermediate compound useful for the production of diltiazem hydrochloride, which has a coronary vasodilatory effect and is useful as a therapeutic drug for ischemic heart disease. ..

[0002]

Conventionally, 5- [2- (dimethylamino) -ethyl] -3-hydroxy-2- (4-
Various production methods of methoxyphenyl) -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one are known, and in particular, chemical formula 4 (in the formula, R represents a lower alkyl group).
As a method of using the phenylthiopropionic acid ester derivative represented by the formula (1), the phenylthiopropionic acid ester derivative is subjected to ring closure by heating to give a 1,5-benzothiazepine derivative, and then N
-Method of alkylating. (For example, Japanese Patent Publication No. 45-938
No. 3, JP-B-16749, etc.) (2) A method in which a phenylthiopropionate derivative is saponified to give an acid, which is then subjected to ring closure by heating to give a 1,5-benzothiazepine derivative, followed by N-alkylation. (For example, Japanese Patent Publication No. 46-8922 and Japanese Patent Laid-Open No. 61-658.
No. 75, etc.) (3) A method of reacting a phenylthiopropionate derivative with dimethylaminoethyl chloride in the presence of a metal hydride in an aprotic polar solvent. (For example, JP-A-60-78973) and the like are known.

[0003]

[Chemical 3]

[0004]

[Chemical 4]

[0005]

However, the above methods (1) and (2) require many steps and the method is complicated, which is not industrially satisfactory. In addition, the method (3) is a one-step method, but using a metal hydride that is difficult to use industrially, one of the raw materials N,
N-dimethylaminoethyl chloride is usually provided as a salt, but it has the drawbacks that it must be converted into the free form and subjected to the reaction once, and the yield is not satisfactory, and it is industrially available. I was not satisfied.

[0006]

Means for Solving the Problems The inventors of the present invention have made earnest studies to overcome such drawbacks, and as a result, phenylthiopropion represented by the formula 4 (in the formula, R represents a methyl group or an ethyl group). By reacting an acid derivative with N, N-dimethylaminoethyl chloride or an acid addition salt thereof in an ether solvent such as dioxane or tetrahydrofuran in the presence of a solid alkali metal hydroxide, surprisingly no pretreatment is performed. And the like, 5- [2- (dimethylamino) -ethyl] -3-hydroxy-2- (4-methoxyphenyl) -2,3-dihydro-1, which is easily represented by Chemical formula 3, It was found that 5-benzothiazepin-4 (5H) -one was produced all at once in good yield, and the present invention was completed. That is, the present invention provides 5- [2- (dimethylamino) -ethyl] -3-hydroxy-2- (4-methoxyphenyl) -2,3-dihydro-1,5-benzothiazepine-4 (5H)-. The present invention provides a simple, industrially advantageous manufacturing method.

The phenylthiopropionic acid derivative represented by the above chemical formula 4, which is the starting material of the present invention, is a known compound which can be easily produced. For example, 2-aminothiophenol and 3
It is easily produced by reacting with-(4-methoxyphenyl) glycidic acid ester by heating, and an optically active substance is also known. (For example, Japanese Patent Publication No. 45-9383, Japanese Patent Application Laid-Open No. 2-6468, Japanese Patent Application Laid-Open No. 2-17168, etc.) One starting material, N, N-dimethylaminoethyl chloride, is free of hydrochloride and sulfuric acid. Although any salt such as a salt can be used for the reaction, it is preferable to use the salt as it is, and it is preferable to use the salt as it is, and it is preferable to use an equimolar to a slight excess of the phenylthiopropionic acid derivative, for example, 1 to 2 times.

The present invention is carried out in an ether solvent in the presence of a solid alkali metal hydroxide. The ether solvent used is preferably a cyclic ether, and examples thereof include dioxane and tetrahydrofuran. As the alkali metal hydroxide, potassium hydroxide,
Although sodium hydroxide and the like can be mentioned, potassium hydroxide is preferable. The alkali metal hydroxide is, for example, in the case where N, N-dimethylaminoethyl chloride used in the reaction is a hydrochloride, the molar ratio of N, N-dimethylaminoethyl chloride hydrochloride is 1 to 5 times, preferably 1.5 to It is preferable to use a 3-fold molar amount. The reaction is carried out under heating, preferably at a reaction temperature of about 50 ° C. to the boiling point of the solvent, and a reaction time of about 30 minutes to several hours is sufficient, although it varies depending on the reaction conditions. After completion of the reaction, the desired product can be obtained by a conventional method, for example, by concentrating the reaction solution under reduced pressure, extracting the residue with a suitable organic solvent such as ethyl acetate, toluene, chloroform, etc., and concentrating the mixture with a suitable solvent such as isopropanol. Or the like, or by converting to a hydrochloride with hydrochloric acid and then crystallizing from ethanol or the like. Further, as shown in Reference Example, it is also possible to use for the next reaction simply by concentrating after extracting with an organic solvent.

[0009]

The present invention will be described in detail below with reference to examples. Example 1 2-hydroxy-3- (2-aminophenylthio) -3
5 g of methyl- (4-methoxyphenyl) -propionate
Was dissolved in 50 ml of dioxane, and 2.6 g of dimethylaminoethyl chloride hydrochloride and 2.7 g of potassium hydroxide were added to the solution.
g was added, and the mixture was stirred at 100 to 105 ° C. for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, water and ethyl acetate were added to the residue and the organic layer was extracted. After drying the organic layer over anhydrous sodium sulfate,
After concentration under reduced pressure, ethanol-hydrochloric acid was added to the residue to dissolve it, ether was added to precipitate the crystals, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give 5- [2- (dimethylamino) -ethyl] -3-. 4.3 g of hydroxy-2- (4-methoxyphenyl) -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one hydrochloride were obtained. Melting point
225 to 7 ° C. TLC Rf = 0.46 (CHCl ₃ : MeOH = 10: 1) The structure of this compound was confirmed by a fusion test with a standard sample and comparison of infrared absorption spectrum.

Example 2 5 g of methyl (2s, 3s) -2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxyphenyl) -propionate was dissolved in 50 ml of dioxane, and dimethylamino was added thereto. 2.6 g of ethyl chloride hydrochloride and 2.7 g of potassium hydroxide were added, and the mixture was stirred at 100 to 105 ° C for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was extracted. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, the residue was dissolved in isopropanol, seeds were inoculated, the mixture was stirred overnight under cooling, and the precipitated crystals were collected by filtration (+)-(2s, 3s ) -5
[2- (Dimethylamino) -ethyl] -3-hydroxy-2- (4-methoxyphenyl) -2,3-dihydro-
1,5-Benzothiazepin-4 (5H) -one 2.73
g was obtained. By treating the mother liquor in the same manner, 0.6
7 g was recovered. Melting point 83-7 ° C. Optical rotation [α] _D 162.7 ° (C = 1, methanol) The structure of this compound was confirmed by a fusion test with a standard sample and comparison of infrared absorption spectra.

Reference Example 1 5 g of methyl (2s, 3s) -2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxyphenyl) -propionate was dissolved in 50 ml of dioxane, and dimethylamino was added thereto. 2.6 g of ethyl chloride hydrochloride and 2.7 g of potassium hydroxide were added, and the mixture was stirred at 100 to 105 ° C for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was extracted. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the residue was mixed with 15 ml of acetic anhydride.
1.5 ml of concentrated hydrochloric acid (35%) with cooling and stirring.
Was added and the mixture was stirred at 80 ° C. for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol to give (+)-(2s, 3s) -3-acetoxy-5- [2-.
(Dimethylamino) -ethyl] -2- (4-methoxyphenyl) -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one hydrochloride (4.7 g) was obtained. Melting point 206-7 ° C. The structure of this compound was confirmed by a fusion test with a standard sample and comparison of infrared absorption spectrum.

[0012]

As described above, according to the method of the present invention, 2-hydroxy-3- (2-aminophenylthio)
Pretreatment, etc., of 3--3- (4-methoxyphenyl) -propionic acid ester and dimethylaminoethyl chloride or an acid addition salt thereof by using an alkali metal hydroxide in an ether solvent 5 without
-[2- (Dimethylamino) -ethyl] -3-hydroxy-2- (4-methoxyphenyl) -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one can be prepared. it can.

Claims (1)

[Claims] 1. A phenylthiopropionic acid derivative represented by Chemical Formula 1 (wherein R represents a methyl group or an ethyl group) in an ether solvent in the presence of a solid alkali metal hydroxide, N, 5- [2- (dimethylamino) -ethyl] -3-hydroxy-2- (4-methoxyphenyl) represented by Chemical formula 2 characterized by reacting with N-dimethylaminoethyl chloride or an acid addition salt thereof A method for producing 2,3-dihydro-1,5-benzothiazepin-4 (5H) -one. [Chemical 1] [Chemical 2]