JPS6165875A - Production of 1,5-benzothiazepine derivative - Google Patents

Abstract

PURPOSE:To obtain the titled substance useful as an intermediate for a compound having vasodilating on coronary vessel in high yield, by reacting a 2- hydroxy-3-(2-aminophenylthio)-3-phenylpropionic acid with an active acetic ester in the presence of a base in a solvent under heating. CONSTITUTION:A 2-hydroxy-3-(2-aminophenylthio)-3-phenylpropionic acid shown by the formula I (Ar is lower alkoxy group-substituted phenyl) is reacted with an active acetic ester in the presence of a base (e.g., triethylamine, pyridine, etc.) to give a compound shown by the formula II. The compound shown by the formula I is easily synthesized by condensing 2-aminothiophenol with a glycidic ester shown by the formula III (R is ester residue). An acetic ester of a phenol having electron attractive substituent group such as pen tachlorophenyl acetate, etc. may be used as the active acetic ester.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention discloses an important intermediate of diltiazem hydrochloride, an excellent pharmaceutical compound having coronary vasodilatory action, (I) (in the formula, M represents a phenyl group substituted with a lower flukoxy group). The present invention relates to a new method for producing a 1,5-benzothiazepine derivative represented by:

2-7 Minothiophenol and the general formula n> (wherein k represents the same group as above and R represents an ester residue) 2-hydroxy-3-(2-7minophenylthio) represented by (Ar represents the same group as above)
JP-A-57-136581 is known as a method for producing compound (I) from -3-phenylpropionic acid, but in this method, compound (2) is first converted into an alkali salt, and then the React the anhydride.

The present inventors have developed a more excellent method for producing compound (I) from compound (2). According to the method of the invention,
Compound (I) of high purity can be obtained in a higher yield than conventionally by simple operations without forming a salt of compound ω0 in advance. That is, the desired compound (I) is obtained by simply adding compound ω1), an active ester of acetic acid, and a base into a suitable solvent and heating.

The active esters of acetic acid used include acetic acid esters of phenols having electron-withdrawing substituents such as pentachlorophenylacetate and p-nitrophenyl acetate, N-hydroxysuccinimide-〇-acetate and N-hydroxyphthalimide-〇-acetate. N like
-Acetates of hydroxy compounds can be used. As the base, ordinary bases such as triethylamine and pyridino can be used, and as the reaction solvent, there is no particular restriction as long as it does not adversely affect the reaction, but examples include acetonitrile, N-dimethylformamide, acetone, etc. Lysine or tertiary amine may be used directly as a solvent if it directly participates in the reaction.

After the reaction, if the reaction solvent is miscible with water, the compound (I) can be isolated by simply pouring it into water, removing the phenol residue with an aqueous alkali solution, and dividing the resulting crystals. If the reaction solvent is immiscible with water, the desired product can be obtained by performing the same operation after distilling off the solvent or by solvent extraction.

This will be specifically explained below by giving examples.

Example 1 1.276 g of threo-2-hydroxy-3-(2-7minophenylthio)-3-(4-methoxyphenyl)furopionic acid, pentachlorophenylacetate)2.
59 g of pyridine, 0.32 g of pyridine, and 0.4 g of triethylamine were added to 12-g of acetonitrile and heated under reflux for 6 hours.

After cooling, acetonitrile is distilled off and the residue is carbonated using H ram 1.
．． 7 g was matched with that of a standard of water phenyl)-3-7setoxy2,3-dihydro-1,5-benzothiazepin-4(5H)-one.

m, p, 195-198°C Example 2 Threo-type d/-2-hydroxy-3-(2-7minophenylthio)-3-(4-methoxyphenyl)furopionic acid 1.276 g, pentachlorophenylacetate 2.
591 g and 2.56 g of pyridine were dissolved in 7cetonitroxy 2,3-dihydro-1,5-benzothiazepine-4 (5
H)-one was obtained.

m, p, 197-199°C Example 3 Threo-type dz-2-hydroxy-3-(2-7minophenylthio)-3-(4-methoxyphenyl)propion e 1.276 g% p-nitrophenyl acetate 1 .52 g, 0.64 g of pyridine and 0.2 g of triethylamine were dissolved in N,N-dimethylformamide 12
ml and stirred at 100°C for 6 hours. After cooling, 3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4 (
1.13 g of crystals of 5H)-one were obtained.

m, p, 195-199°C Example 4 d-2-hydroxy-3-(2-aminophenylthio)
-3-(4-methoxypheni Jv) propionic acid 1.2
76 g, acetone 12-j, pentachlorophenylacetate 2.59 g, ) ethylamine 0.4 g, and pyridine 0.32 g were mixed and heated under reflux for 7.5 hours.

Hereafter, 1.30 g of d-2-
(4-methoxyphenyl)-3-acetoxy-2,3-
Dihydro-1,5-benzothiazepin-4(5H)-one was obtained.

m, p, 145-148°C Example 5 d-2-hydroxy-3-(2-aminophenylthio)
-3-(4-methoxyphenyl)propionic acid 1.27
6 g, DMF 1217゜ p-nitrophenyl acetate 1.52 g and pyridine 0.64 g were mixed;
The mixture was heated under reflux for 5 hours. The following treatment was carried out in the same manner as in Example 3.
．． 23 g of d-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one were obtained.

m, p, 144-147°C Example 6 d-2-hydroxy-3-(2-7minophenylthio)
-3-(4-methoxyphenyl)propion l11.2
1.52 g of 76g% p-nitrophenyl acetate and 20 m of pyridine were mixed and heated under reflux for 5 hours. Thereafter, 1.21 g of d-2-(4-methoxypheny)L/)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine to 4(5H) was treated in the same manner as in Example 3. - Got on.

m, p, 149-151°C Example 7 d-2-hydroxy-3-(2-aminophenylthio)
-3-(4-methquinphenyl)propionic acid 1.27
6g, acetonitrile 121I11pentachlorophenylacetate 2.591g,) ethylamine 0.4
g and 0.32 g of pyridine were mixed and heated under reflux for 5.5 hours. Thereafter, 130 g of d was treated in the same manner as in Example 3.
-2-(4-methoxyphenyl)-3-acetoxy-2
,3-dihydro-1,5-benzothiazepine-4 (5H
)-on was obtained.

m, p, 149-151'c Example 8 d-2-hydroxy-3-(2-7minophenylthio)
-3-(4-methoxyphenyl)propionic acid 1.27
6 gt DMF 12d1 Pentachlorophenylacetate 2.591g, Triethylamine 0.4g
and 0.32g of pyridine were mixed and heated to 3.5g at 100'C.
The mixture was heated and stirred for hours. The following steps were performed in the same manner as in Example 3.
27 g of d-2-(4-methoxyphenyl)-3-7setoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was obtained.

m, p, 148-I50°C Example 9 d-2-hydroxy-3-(2-7minophenylthio)
-3-(4-methoxyphenyl)propionic acid 1.27
6g, acetic acid 2,4-dinitrophenyl ester 1.8g
0.64 g of pyridine was added to the suspension of acetonitrile l2IE/ while stirring at room temperature, and then stirred at the same temperature for 3 hours. Thereafter, 1.09 g of d-2-(4-methoxyphenyl)-3-acetoxy-
2,3-dihydro-1,5-benzothiazepine-4 (5
H)-one was obtained.

m, p, 144-147°C Procedural amendment (voluntary) 5゜ October 9, 1982

Claims (1)

[Claims] 2-hydroxy-3-(2-aminophenyl) represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, Ar represents a phenyl group substituted with a lower alkoxy group) General formula characterized by reacting thio)-3-phenylpropionic acid with an active ester of acetic acid in the presence of a base ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, Ar represents the same group as above) A method for producing a 1,5-benzothiazepine derivative represented by