JPS6078973A - Production of 1,5-benzothiazepine derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a coronary vasodilator, etc. in high yield in one stage, by condensing a partially novel specific propionic acid ester derivative with a halide of a tertiary amine in the presence of a metal hydride in an aprotic polar solvent. CONSTITUTION:A partially novel substance of formula I (Ar is phenyl substituted by a lower alkoxyl; R is H or lower acyl; R1 is lower alkyl) which is novel when R is lower acyl is condensed with a compound of formula II (R2 and R3 are lower alkyl; Y is lower alkylene; Z is halogen) in the presence of a metal hydride, e.g. sodium hydride, in an aprotic polar solvent, preferably dimethyl sulfoxide at 5-70 deg.C, preferably 10-40 deg.C to afford industrially and advantageously the aimed compound of formula III useful as medicines such as a psychotropic agent in addition to those described above or an intermediate thereof, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel method for producing 1,5-benzothiazepine derivatives. , R is a hydrogen atom or lower acylno, (R2 and R3 are each a lower alkyl group and Y is a lower alkylene group) 1,5-penzothiazepi/conductor represented by The present invention relates to a method for manufacturing in series.

Among the 1+5-benzothiazepine derivatives represented by the general formula (1'), there are compounds useful as pharmaceuticals with pharmacological effects such as coronary vasodilator and psychotropic effects, or as intermediates thereof. , is an extremely important derivative.

The 1,5-benzothiazepine derivative represented by the general formula (1) can be obtained by many methods proposed in the literature (Japanese Patent Publication No. 8982-1982, Japanese Patent Publication No. 16749-1974, Japanese Patent Publication No. 46-16749, 4.3785 Publication, JP-A-57-13
6581, JP-A-58-99471, JP-A-58-29779, etc.).

However, all of these methods are basic (but complicated methods with long steps as shown below), and cannot be said to be economically satisfactory methods. When producing the 1,5-benzothiazepine derivative represented by 1), the steps are as follows: General formula (II) Ar (wherein Ar and R have the same meanings as above, R1 is a lower alkyl group) The propionic acid ester derivative represented by
1 to 1 to form a propionic acid derivative represented by the general formula (Ill) Ar (Ar and R in the formula are the same as above, and have a taste), and then ring-closed to obtain the general formula) Ar (in the formula Ar and 1,5-benzothiazepine derivative (R has the same formula as above)
, R5 and Y have the same meanings as above, and Z is a halogen atom), and further acylation as required, the 1,5-benzothiamine represented by the general formula (1) can be obtained. An azepine derivative is obtained.

As described above, following the conventionally proposed method requires a long process (complicated) and is economically disadvantageous.

The present inventors have improved the shortcomings of such conventionally proposed methods, and have advantageously produced the 1,5-benzothiazepine derivative represented by the general formula (1) in a short process and economically. As a result of intensive research to provide a method for producing the compound, the compound represented by the general formula (If) is combined with the compound represented by the general formula (V) in the presence of a metal hydride in an aprotic polar solvent. By carrying out a condensation reaction, the general formula (
It has been found that the 1,5-benzothiazepine derivative represented by 0 can be obtained in good yield and that the object can be achieved, and based on this knowledge, the present invention has been completed.

That is, the present invention provides a compound represented by the general formula (If) Ar (wherein Ar is a phenyl group substituted with a lower alkylene group, R is a hydrogen atom or a lower acyl group, and R1 is a lower alkyl group) , in the presence of a hydrogenated metal in an aprotic polar bath medium, expressed by the general formula (■) (wherein R2 and R3 are each a lower argyl group, Y is a lower alkylene group, and 2 is a halogeno atom) 'Cj jl
The present invention provides a method for producing a 1,5-benzothiazepine derivative represented by the general formula (1) (wherein Ar, R, R2, R3, and Y have the same meanings as above), where t is represented by the following formula.

The compound represented by the general formula (■) used in the method of the present invention is a propionic acid compound in which Ar is a phenyl group substituted with a lower alkoxy group, R is a hydrogen atom or a lower acyl group, and R1 is a lower alkyl group. In the ester derivatives, examples of the lower alkokino groups include methoxy and ethoxy groups, examples of the lower acyl groups include acetyl and propionyl groups, and examples of the lower alkyl groups include methyl and ethyl groups.

Among these propionic acid ester derivatives, the general formula (
The 2-hydroxypropio/acid ester derivative in which R in II) is a hydrogen atom can be prepared by a known method (Japanese Patent Publication No. 45-1989).
9383).

For example, 2-aminothiophenol and a glycitic acid ester represented by the general formula (in which Ar and R1 have the same meanings as above) are mixed in a solvent-free solution at a concentration of 100 to 130%.
By reacting at a temperature of 0.degree. C., the desired 2-hydroxypropionic acid ester derivative can be obtained. There are two stereoisomers of this compound, the /s type and the trans type, but 1) According to the production method described in II, the cis type is produced in high yield (
47.

Furthermore, the 2-acyloxy/propio/acid ester derivative in which R in the general formula (n) is a lower acyl group may be a new compound, and the 2-hydroxypropionate derivative obtained as described above may be acylated. Nitro derivative C represented by the general formula 〇■ (Ar and R1 in the formula have the same meanings as above), which can also be obtained by
It can also be produced by acylating a resin synthesized by the method described in JP-A-8982 and then reducing the nitro group. In this production method, acid anhydrides such as acetic acid and propionic acid, acid halides, etc. are used as acylating agents, and the reaction between these acylating agents and the nitro derivative represented by the above general formula (to) is carried out without a solvent. Or directly in an organic solvent such as benzene or chloroform,
Alternatively, it is carried out in the presence of a base such as pyridine. The reaction temperature in this case varies depending on the type of solvent, acylating agent, etc., but is usually in the range of 0 to 100°C.

The reduction of the acylogycin nitro derivative of the novel compound represented by the general formula (in which Ar and R1 have the same meanings as above, and R4 is a lower alkyl group) is usually carried out using nitro Methods used for the reduction of groups, such as the method of reacting metals such as zinc, iron, tin, or their metal salts with acids or alkalis, or the catalytic reduction method using palladium-carbon as a catalyst. 1. In this way, the general formula (■
) in which ■ (is a lower acyl group) 2-acyloki/
A propionic acid ester visiting conductor is obtained.

In the compound represented by the general formula (V) used in the method of the present invention, R2 and "(5) in the formula are each a lower alkyl group, Y is a lower alkylene group, and Z is a halogen atom, and as a lower alkyl group, Examples of lower alkylene groups include methylene, ethylene, trimethylene, and the like; examples of halogen atoms include chlorine, bromine, and the like.

Examples of the aprotic polar mother medium used in the method of the present invention include dimethyl sulfoxide, N,N-dimethylformamide, sulfolane, acetonitrile, N,N
-dimethylacetamide and the like, among which dimethylsulfoquinide is preferred. Further, as the metal hydride, for example, sodium hydride is used.

In order to suitably carry out the method of the present invention, for example, the general formula (
After dissolving the propionic acid ester derivative represented by II) in the aprotic polar solvent, a hydrogenation metal such as sodium hydride is added in an amount of 1 to 3 molar equivalents, preferably 1 to 3 times the molar equivalent of the propionic acid ester derivative. ~1.2 times the molar equivalent is added, and then a compound represented by the general formula (g) is added in a 1 to 3 times molar equivalent, preferably 1 to 1.5 times the molar equivalent of the propionic acid ester derivative, and reacted. After that, the generated 1,5 shown in the general formula (1)
- The benzothiazepine derivative may be isolated from the reaction solution and purified according to a conventional method. In this case, the reaction temperature varies depending on the solvent and the type of the propionic acid ester derivative;
A range of 70°C to 70°C is desirable, and a range of 10 to 40°C is particularly suitable.

The method for producing 1,5-benzothiazepine derivatives of the present invention requires only one step, whereas the conventional method requires three steps.
Furthermore, the desired product can be obtained in good yield, making it extremely advantageous as an industrial method. 1 Next, the present invention will be explained in more detail with reference to Examples.

Example 1 Cis-2-(4-methoxyphenyl)-3-hydroxy-5-(2-(dimethylamino)ethyl]-z,a-dihydro-1,5-benzothiazepine-4(51()- Synthesis of 1-hydrochloride cis-2-hydroxy-3-(2-aminophenyl+,
+)-3-(4-methoxyphenyl)-7-methyl lopionate 3.31 to dimethyl sulfoxide.

20% by weight of sodium hydride.
．． Add 48 f and stir at room temperature for 30 minutes.

Then N,N-dimethylaminoethyl chloride 1.37
was added, stirred at room temperature for 7 hours, and then neutralized with acetic acid.
Add 100 d of water. Next, extract twice with 50 g of chloroform, combine the extracts, wash with water, dry with anhydrous sulfuric acid, and concentrate.

The obtained oil was dissolved in ethanol, hydrochloric acid gas was introduced, ether was added, the crystals were collected by filtration, and then recrystallized from ethanol to give cis-2-(4-methoxyphenyl)-3- as needle-shaped crystals. 3.12 of hydroxy-s-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride were obtained. Yield 75%, melting point 226-228°C (decomposition), crystals were synthesized by a known method, and TLC and 1. Complete agreement with R.

Example 2 60% by weight sodium hydride in Example 1 0.48
The operation was carried out in exactly the same manner as in Example 1 except that 0.9Or was used instead of r. As a result, cis-2-(
4-methoxyphenyl)-3-hydroxy-5-[2-
(dimethylamino)ethylcou-2,3-dihydro-1,
5-Benzothiazepine-4(5H)-one hydrochloride 1.9
2 was obtained 1, yield 46% Example 3 N-2-(4-methoxyphenyl)-3-acetoxy-5-1:2-(dimethylamine)ethyl)-2,3-
Dihydro-1,5-benzothiazepine-4(511)-
Synthesis of 1-hydrochloride 7 1.9 g of methyl 2-acetyloxy-3-(2-aminophenylthio)-3-(4-methogyaphenyl)-propionate was dissolved in 207 g of dimethyl sulfoxide! After dissolving in 60% sodium hydride, 0.1% sodium hydride.
Add 249 and stir at room temperature for 10 minutes. Then N,
Add 0.72 of N-dimethylaminoethyl chloride and stir for 7 hours at room temperature for 1 hour, then neutralize with acetic acid.
Add 100ml of water. Next, the mixture is extracted twice with 50 rnl of chloroform, the extracts are combined, washed with water, dried over anhydrous sodium sulfate, and concentrated.

The obtained oil was subjected to column chromatography using silica gel, and a chloroform-methanol mixture (3:2
V/V) to give an oil.

Next, this oily substance was dissolved in ethanol, hydrochloric acid gas was introduced to form a hydrochloride salt, and ether was added to crystallize it, resulting in cis-2-(4-methoxyphenyl)-3-acetoxy-5-( 2-(dimethylamino)ethyl:]-
]2.3-dihydro1,5-benzothiazepine 4(5
1.32 of H)-one hydrochloride was obtained. The yield was 48%, the melting point was 188-182°C, and the crystals were completely identical to the standard product synthesized by a known method by TLC and engineering.

Reference Example 1 Synthesis of methyl cis-2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)-propionate 2-aminothiophenol 14. Or and 20.82 g of methyl 3-(4-methquinphenyl)glysitate were placed in an oil bath at 110° C. under a nitrogen gas stream and stirred for 10 hours. After the reaction, add methanol to crystallize,
When collected by filtration and recrystallized from methanol, cis-2-hydroxy-3-(2-aminephenylthio)-3-(4-
Methoxyphenyl)-propionate 24.8 f
was gotten.

Yield 74%, melting point 92-9:3°C Reference Example 2 Synthesis of cis-2-acetyloxy-3-(4-methoxyphenyl)-3-(2-nitrophenylthio)-methyl phlopionate cis-2- Hydroxy-3-(4-methogyaphenyl)
Methyl -3-(2-nitrophenylthio)-furopionate20. OS', pyridine 50++ and acetic anhydride 20m
Add 1 and boil at 60℃ for 3 hours.

After cooling to room temperature, the mixture was added to 2.00111e of ice water, extracted twice with 300d of ethyl acetate, and the extracts were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated.

The concentrate was internally crystallized with ethanol to give yellow cylindrical crystals of cis-2.
-acetyloki/-3-(4-meI-quinphenyl)-
Add 20.5 f of methyl 3-(2-nitrophenylthio)-propionate. Yield 95%, melting point 103-1
05°C, IRv”'cm': 17 (30°173
8.1508.1338.1210 Reference Example 3 Synthesis of cis-2-acetyloxy-3-(2-aminophenylthio)-a-(4-methoxyphenyl)-methyl propionate cis-2-acetyloxy-3- 3.02 methyl (4-methoxyphenyl)-3-(2-nitrophenylthio)-propionate was suspended in 50me of methanol, and 5%
P(1-Cx, oy is added and catalytic reduction is carried out at room temperature for 6 hours. After the reaction, it is filtered and the filtrate is concentrated under reduced pressure to produce an oily substance, cis-2-acetyl-oxy-3-(2-aminophenylthio). Methyl -3-(4-methoxyphenyl)-furopionate 2.8KI3r -1.

t was obtained. 100% yield, IRv1naXcrn.

3450.3350.1608.1508 Patent Applicant
Toshin Chemical Co., Ltd. Agent Akira Agata

Claims (1)

[Claims] ■ A compound represented by the general formula (in the formula, Ar is a phenyl group substituted with a lower alkogine group, R is a hydrogen atom or a lower alkyl group, and R1 is a lower alkyl group), Condensation reaction with a compound represented by the general formula (in the formula, R2 and R3 are each a lower argyl group, Y is a lower alkylene group, and Z is a halogen atom) in the presence of a metal hydride in an aprotic polar crystal medium. characterized by causing
A process for producing a 1,5-benzothiacebin derivative represented by the general formula (Ar, R, R2, R3 and Y in the formula have the same meanings as above) Claims in which the aprotic polar solvent is dimethyl sulfoxide The manufacturing method described in paragraph 1. 3. The manufacturing method according to claim 1 or 2, wherein the hydriding metal is IJium.