JPS60146884A - Production of 1,5-benzothiazepine derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as pharmaceuticals, by condensing a specific thiophenol derivative with a propionic acid derivative, reacting with acetic anhydride after hydrolysis, and cyclizing the resultant threo-type propionic acid derivative with DCC. CONSTITUTION:The objective compound of formula V, i.e. cis-2-(4'-methoxy- phenyl )-3-acetoxy-5-( N,N-dimethylaminoethyl )-2, 3-dihydro-1, 5-benzothiazepin-4- 5(H)one, is produced by (1) condensing the 2-(N,N-dimethylaminoethyl)aminothiophenol alkali metal salt of formula I (M is Na or K) with the erythro-type 3-(4- methoxy-phenyl)-3-chloro-2-hydroxypropionic acid methyl ester of formula II, (2) hydrolyzing the resultant threo-type propionic acid derivative with an alkali, (3) reacting with acetic anhydride in the presence of a base to obtain the compound of formula IV, and (4) carrying out the intramolecular cyclization reaction of the threo-type propionic acid derivative of formula IV with DCC (N,N'-dicyclohexylcarbodiimide).

Description

[Detailed description of the invention]

The present invention relates to cis-1,5-benzothiazepine derivatives represented by the following formula (■), specifically cis-2-(4'-methoxyphenyl)-3-acetoxy-5-(NN dimethylaminoethyl) The present invention relates to a method for producing -2,3-dihydro-1,5benzothiazepine-4-(5H)one and its salts. C) Lt CH. More specifically, the present invention relates to a novel production method in which the hydrogen atoms bonded to the 2- and 3-position carbon atoms have a cis configuration in the 1,5-benzothiazepine derivative represented by formula (V). Cis-1,5-benzothiazepine derivatives (V
1 is a useful pharmaceutical compound containing coronary vasodilator action, psychotropic action, etc. The compound of formula (V) of the present invention is disclosed in Japanese Patent Publication No. 46-43785, Japanese Patent Application Publication No. 57-136581, and Japanese Patent Application Publication No. 58-1948.
It can be manufactured by the method described in No. 72 etc. When produced by these methods, in the final step, all reaction reagents such as sodium hydride and NN-dimethylaminochloride are used, but hydride (II) reacts explosively with water, and It is a compound that must be handled with care as it decomposes when exposed to moisture in the air, and NN dimethylamine ethyl chloride must be used after dehydrochlorinating commercially available NN dimethylamino chloride hydrochloride or its aqueous solution. Moreover, there are inconveniences such as the fact that the solvent used in the reaction must be sufficiently dried. The present inventor invented a new manufacturing method to solve the above manufacturing inconvenience. That is, 2-, (
The problem was solved by using N,N dimethylamine ethyl) aminothiophenol as the starting material. (In the formula, M represents an alkali metal such as sodium or potassium))
7 pages, and 88 volumes, 1638 pages). Matata (
V) To subvert the cis form of the compound, the intermediate substance (111
1 and (the compound of the formula (It) must have a threo-type configuration) HI CH-,
3-(4'-,7')*diphenyl)-3chloro-2-
The problem was solved by using hydroxypropionic acid methyl ester as one of the starting materials. Compounds of formula (11) are prepared by known methods (J, C, S, Perkin n 1973, p. 653 and (: hemistry and ind.
ustry, Vol. 1963, p. 1985). The production method of JP-A-58-194872 does not mention stereoisomerism. The manufacturing method of the present invention will be explained in detail below. The reaction between the compound of formula (1) and the compound of formula (II) is expressed by the formula (
The compound of formula (+) is added to hydrous methyl alcohol, ethyl alcohol, isopropyl alcohol, preferably aqueous ethyl alcohol, and 1 to 1.1 equivalents of sodium hydroxide or potassium hydroxide, preferably hydroxide. The compound of formula (1) is added and dissolved in an alcohol bath solution in which 11 um of alcohol is dissolved. This may then be equivalent to the proportion of the compound of formula (If). The compound of formula (In) produced in this reaction can proceed to the next reaction without isolation. The hydrolysis of the compound of formula (m) is carried out in a hydrous alcohol containing 11 um of sodium hydroxide or potassium hydroxide, and the reaction time is 30 minutes to 1 hour. The reaction temperature is preferably 20 to 80°C, especially 45 to 1 hour. 55°C is suitable. Next, the compound (the cup is a threo-type 3-(4'methoxyphe-nyl)-3-C which is a hydrolysis product of the compound (no)
It is obtained by acetylating (2-NN dimethylaminoethylamine) phenylthio]-2-hydroxypropionic acid by a conventional method. That is, the compound CF/)' can be easily obtained by reacting the above 10 pionic acid derivatives with acetic anhydride in the presence of a base. Here, as the base, pyridine, tertiary amine, alkali metal, etc. are used, and pyridine is particularly suitable. The amount of acetic anhydride used is preferably 1 to 1.5 equivalents, and the amount of base used is preferably 2 equivalents or more. Furthermore, it is advantageous to use a solvent that does not affect the reaction, such as benzene, chloroform, or NN dimethylformamide, in order to make the reaction proceed more smoothly. The reaction process proceeds in the range of 20 to 50°C, and the reaction time varies depending on the type of base used, but the reaction is completed in 1 to 3 hours. By adding L, N, N' dicyclohexylcarbodiimide (hereinafter simply abbreviated as CC), 70
It can be obtained with a higher yield than 1. That is, by adding 1.1 to 1.5 equivalents of CC to a dioxane solution of compound (IV), separating the resulting NN dicyclohexyl urea kF, and distilling off the dioxane, the desired compound of formula (V) is obtained. Compound (V) can be converted into a salt such as a hydrochloride or an aqueous bromide salt depending on the purpose. Next, the present invention will be specifically explained using examples. Example (1) Threo type, 2-acetoxy-3-(4-methoxyphenyl)-3-[(2-NN dimethylamino xf)
v amine) phenylthio]propionic acid [compound (m)
] Synthesis of Potassium hydroxide 62% water-containing ethyl alcohol 50ml
1VC2 (NN dimethylaminoethyl) aminothiophenol zywm was dissolved and while stirring at room temperature, 2-hydroxy-3-(4methoxyphenyl)-3-chlor 10
Pionic acid methyl ester was dissolved in 2.45fk ethyl alcohol 5-, added and reacted for 1 hour. Then, a solution of 92% II hydroxide and 18tnt of water was added, and the mixture was stirred at 50°C for 30 minutes. After the reaction, ethyl alcohol was distilled off under reduced pressure, cooled, added 50 f' of water, neutralized with acetic acid, and extracted with chloroform.

[-After washing with water and drying, chloroform was distilled off under total vacuum to obtain a yellow oily substance (3.52%). This oil was dissolved in 50 ml of chloroform, 5f of pyridine was added thereto, and the mixture was stirred at room temperature for 30 minutes, and then 1v of acetic anhydride was slowly added thereto, and the mixture was further stirred at room temperature for 1 hour. After the reaction, the chloroform was washed with water and the chloroform was distilled off under reduced pressure, leaving 100 m7 of water! Crystals that precipitate by adding and neutralizing with hydrochloric acid? It was dried and reconstituted from ethyl alcohol to obtain a threo-type compound (M13.5. m, p, 95-98°C, yield 80:2).
cis 2-(4'-methoxyphenyl)-3-acetoxy-5-(NNdimethylamineethyl)-2,3-dihydro-1,5-benzothiazepine-4-(5H)★one (
Synthesis of compound (Vn) Threo-type compound (ri') 4.3fi dioxane 50r
After stirring at room temperature for 5 hours and standing overnight, the precipitated crystals were filtered and dioxane was distilled off under reduced pressure to give an oily product of 4.2 liters.
'I got it. Diisoglobyl ether was added to this and crystallized to give compound (V) 3. m, p, 133-135°C.
I got 3f'i. Yield: 80% This substance was dissolved in diethyl ether and a hydrogen chloride saturated diethyl ether solution was added to precipitate crystals. When the mixture was removed and dried, a cis-type compound (Vl hydrochloride 3v) with m, p, and a temperature of 185 to 187°C was obtained.

Claims (1)

[Claims] A 2-(N,N dimethylaminoethyl)aminothiophenol alkali metal salt represented by the following formula (r) (wherein M represents an alkali of ketorium or potassium) and the following: Formula (n) 1) Toro type, 3-(4-methoxy phenyl)-
By condensing 3-chloro-2-hydroxypropionic acid methyl ester, a threo type represented by the following formula (Ill),
3-(4'-methoxyphenyl)-3-((2-N,N
dimethylaminoethylamino)phenylthio]-2-hydroxy propionic acid methyl ester, and the threo-type globionic acid salt conductor represented by formula (II) was subjected to alkali hydrolysis and then reacted with acetic anhydride in the presence of a base to form the following formula ( Seki CM. Threo type, 2-acetoxy-3-(4'-
methoxyphenyl)-3-[2-(N,N dimethylaminoethylamino)phenylthio]-propionic acid, and the threo-type propionic acid derivative represented by the formula (F/) has N, N' dicyclohexyl Cis-2-(4'-methoxyphenyl)- represented by the following formula (V) CH, which is characterized by carrying out an intramolecular ring-closing reaction using carbodiimide.
3-acetoxy-5-(NNdimethylaminoethyl)-
2,3-dihydro-1,5benzothiazepine-4-(5
H) Process for producing on and its salts.