JPS62123182A - Novel process for production of 1,5-benzothiazepine derivative, novel intermediate and its preparation - Google Patents

Abstract

PURPOSE:A novel diketone is used as a starting substance to effect reduction reaction to form a hydroxylated compound, the product is subjected to the condensation reaction with a carboxylic acid to give an alkanoyl compound whereby the titled compound with is used as a hypotensor is readily obtained. CONSTITUTION:The intramolecular ring closure of a compound of formula I (R<1>, R<3> and R<4> are H, lower alkyl; R<6> is lower alkyl; one of X<1> and X<2> is H, and the other is Cl) gives a novel compound of formula II. The product or its salt is treated with a reducing agent or catalytically hydrogenated to form a hydroxyl compound of formula II. The compound is subjected to condensation reaction with a compound of formula IV (R<5> is lower alkyl) or its reactive derivative to give an alkanoyl compound of formula V. When needed, the compounds of formula III and IV are converted into their salts to give the objective compound of formula IV (R<2> is H, lower alkanoyl) which is used as cerebral or coronary vasodilator.

Description

DETAILED DESCRIPTION OF THE INVENTION [Technical Field] The present invention relates to a new method for producing 8- or 9-chloro-1,5-benzothiazepine derivatives, a new intermediate used in the method, and a method for producing the same.

[Prior art]

2-(4-Me)xyphenyl) -3-7/l/Kalyloxy (or hydroxy)-5-C2-(dialkylamino)ethyl2-8-chloro-2゜3-dihydro-
1,5-benzothiazepine-4(5H)-one has excellent antihypertensive effect and/or cerebral/coronary vasodilatory effect, and the above pen is based on the fact that zothiazebin@conductor≠the corresponding thiazepine ring at the 5th position. It is known that it can be produced by reacting an unsubstituted compound at the N-position with dialkylaminoethyl halide (Japanese Patent Laid-Open No. 59-225174).

[Purpose of the invention]

The object of the present invention is to provide a new method for producing 8- or 9-talolo-1,5-benzothiazepine derivatives. Another object of the present invention is to provide a synthetic intermediate for the benzothiazepine derivative and a method for producing the same.

[Structure and effects of the invention]

As a result of various researches, the present inventors found that
- (However, R1,
Rn and R4 are the same or different and represent a lower alkyl group spanning a hydrogen atom, R2 represents a hydrogen atom or a lower alkanoyl group; XI and X2 represent one of them being a hydrogen atom and the other being a chlorine atom) The inventors succeeded in synthesizing the indicated compound and completed the present invention.

A compound in which R3 and R4 are both lower alkyl groups in the above compound CI) is useful as an antihypertensive agent 2 and/or a cerebral/coronary vasodilator.

In addition, compounds in which R3 and R4 are both hydrogen atoms or one of them is a lower alkyl group and the other is a hydrogen atom are useful pharmaceutical compounds that exhibit a strong and long-lasting platelet aggregation inhibiting effect even when administered orally.

For example, (c)-cis-2-(4-methoxyphenyl)-
3-Hydroxy-5-(2-(N-methylamino)ethyl-8-chloro-2,3-dihydro-1°5-benzothiazepin-4(5H)-one hydrochloride and (→-cis-2- (4-methoxyphenyl)-3-hydroxy-
5-C2-(N-methylamino)ethyl-9-chloro-2,3-dihydro-1,5-benzothiazepine-4 (
When 5H)-one hydrochloride was orally administered to SD rats (dose: 10 mg/kg), all compounds inhibited collagen-induced rat platelet aggregation by 50% or more.

According to the method of the present invention, the compound represented by the general formula [■] or its salt is reduced to form the general formula (wherein R', R'i R', X'i% and X2 have the same meanings as above), and if necessary, prepare a compound represented by the formula %) or a salt thereof, represented by the general formula %) (where RS represents a lower alkyl group). compound or a reactive derivative thereof to form a compound of the general formula (wherein R1, R2, R4, Rli, XI and X2
has the same meaning as above), and if necessary, the compound [I-A]
Alternatively, it can be produced by using [IB) as its salt.

This will be explained in detail below.

This can be carried out by treating [■] with a reducing agent or by catalytic reduction.

The reaction of treating the diketone compound Cl1) with a reducing agent can be carried out in a suitable solvent, and the reducing agent may be an alkali metal borohydride such as sodium borohydride, potassium borohydride, or sodium borohydride. Preferred examples include methanol, ethanol,
Examples include lower alkanols of propyl alcohols, mixtures of lower alkanol hydrates, tetrahydrofuran, and dioxane.

Catalytic reduction of diketone compound (II) can be carried out in a suitable solvent in the presence of a catalyst.

As the catalyst, palladium carbon, palladium black, etc. can be used, and as the solvent, the one used in the reaction between the diketone compound (II) and the reducing agent can be suitably used.

The reaction proceeds suitably at about 0 to 40C, whether using a reducing agent or catalytic reduction.

The hydroxy compound CI-A) is obtained as a racemate, and the racemate is optically resolved by a conventional method to split the optically active form of the hydroxy compound CI-A). be able to. For example, the hydroxy compound CI-
The racemic form of A) is P-hydroxyphenylglycine ester, cinchonidine.

An optical resolving agent such as 7-earth sulfonic acid and a suitable solvent (
acetone, methyl ethyl ketone, ethyl acetate, methanol, etc.) to form two diastereomeric salts, and then fractional crystallization of the diastereomeric salts;
The poorly soluble salt is collected as a crystal and the easily soluble salt is collected from the solution, and the obtained diastereomeric salt is treated with an acid (for example, hydrochloric acid) to form an optically active hydroxy compound CI.
-A] can be produced. In addition, the optically active form of hydroxy compound CI-A) is hydroxy compound CI-A)
Racemic form of and optically active 1-(2-7tylsulfonyl)
Reacting pyrrolidine-2″-carbonyltalolide,
It can also be produced by forming two diastereomers, separating the diastereomers by fractional crystallization or column chromatography, and hydrolyzing.

Hydroxy compound CI-A) can be converted into a salt by subjecting it to a salt-forming reaction according to a conventional method.

CI-A) + (III)-→(I-B) The degree of comparison f3 between the hydroxy compound CI-A) and the reactive derivative of the carboxylic acid compound [11) is determined in the presence or absence of a deoxidizing agent in the solvent. can be implemented. Carboxylic acid compound CI [l]
Examples of the reactive derivatives include acid anhydrides (eg, acetic anhydride, propionic anhydride, butyric anhydride) or acid halides (eg, ayatyl chloride, propionyl chloride, butyryl chloride). Examples of the solvent include pyridine, tetrahydrofuran, and dioxane.

Mention may be made of benzene, toluene, methylene chloride or acetic acid. An example of a deoxidizing agent is pyridine.

Triethylamine, N-methylpiperidine, N-
Examples include methylmorpholine, N-methylpyrrolidine, and N-ethyl-N,N-diisopropylamine.

When acetic anhydride is used as the reactive derivative of carboxylic acid compound (III) during the reaction, it is not necessarily necessary to use a solvent since it also serves as a solvent. Anti-Ff5 is carried out at about 20 to 130 °C when an acid anhydride is used as the reactive derivative of the carboxylic acid compound (I[[), and at about -10 to 60 °C when an acid halide is used. preferable.

Furthermore, in this method, the condensation reaction between carboxylic acid compound (III) (free carboxylic acid) and hydroxy compound CI-A) or a salt thereof can be carried out in a solvent in the presence of a condensing agent. Condensing agents include, for example, dicyclohexylcarbodiimidobonyldiimidazole, 1-methyl-2-halohyridinicum iodide (e.g. 1-methyl-2-promopyridinicum iodide), methoxyacetylene or triphenyl 7-osphine-tetrachloride US. Examples of solvents include methylene chloride, taloloform, 1.2
-dichloroethane, benzene, toluene, tetrahydrofuran, dioxane, etc. can be used.

Preferably, the reaction is carried out at a temperature of about 0-50°C, especially about 0-25°C.

Since this reaction proceeds without racemization, the optically active form of the alkanoyloxy compound (1-B:) can be produced by using the optically active form of the hydroxy compound CI-A). Alkanoyloxy compound CI-B
E can be made into a salt by subjecting it to a salt-forming reaction according to a conventional method.

In addition, the diketone compound CHI) is a novel compound and is a useful synthetic intermediate in the method of the present invention.As the diketone compound (II), for example, R1, R1 and R4 are the same or different and are hydrogen atoms, or methyl groups, Examples include compounds in which the group is a lower alkyl group such as an ethyl group, a propyl group, or a butyl group, and one of XI and x2 is a hydrogen atom and the other is a chlorine atom. Among these, preferred compounds include compounds in which R1 is a lower alkyl group, R1 is a hydrogen atom or a lower alkyl group, R4 is a lower alkyl group, and one of XI and X2 is a hydrogen atom and the other is a chlorine atom. Furthermore, as a more preferable compound, R1 is a methyl group and R3 is a hydrogen atom.

or methyl group, ethyl group, propyl group or butyl group, R4 is methyl group, ethyl group or butyl group.

Examples include compounds in which one of Xl and X2 is a hydrogen atom and the other is a chlorine atom. The most preferred eight compounds include R1 crabmethyl group R2 in the general formula [■]
is a hydrogen atom or a methyl group, R4 is a methyl group,
Examples include compounds in which XI is a chlorine atom, X2 is a hydrogen atom, or Xl is a hydrogen atom and X2 is a chlorine atom.

The compound of the present invention (III) can form a salt.

Examples of such salts include salts with inorganic acids such as hydrochloric acid and perchlorates, and salts with organic acids such as succinic acid, fumaric acid and maleic acid.

Compound (II) of the present invention has one asymmetric carbon atom,
Although there are two types of optical isomers, the present invention includes any of these optical isomers or racemates.

The compound [■] can be produced by the following reaction formulas [A] and [B].

(:ff) [:n) Reaction formula [
B] (If-A)
(V) (However, R", R" and R6 each represent a lower alkyl group, R7 represents either R3+ or R41, R8 represents a halogen atom or an ester radical, and R', R".

(R4, x+ and X2 have the same meanings as above) That is, according to method A, the compound [IV] can be produced by intramolecular ring closure of compound (IV). In addition, the compound (It) in which one of R1 or R4 is a lower alkyl group and the other is a hydrogen atom [:II-B) is a compound [■-A
] with an acid halide or ester of halogenoformic acid to produce compound (V).

It can also be produced by subsequently removing the N-acyl group from this.

This will be explained in detail below.

The intramolecular ring closure reaction of compound [■] takes place in the presence of a base.

It can be carried out in a suitable solvent.

As the base, for example, lyticum diimprovira, ether, tetrahydro7rane, hexamethylphosphoric acid triamide, dioxane, or a mixture thereof can be suitably used. The reaction proceeds suitably at -70 to -25°C, particularly at -60 to -20°C.

(I[-A)-Gin[v] The reaction between compound (n-A) and the acid halide or ester of halogenoformic acid can be carried out in a suitable solvent in the presence or absence of a base.

As the acid/ride of halogenformic acid, any of the acid halides of fluoroformic acid, the acid halides of chloroformic acid, the acid halides of bromoformic acid, and the acid halides of fluoroformic acid can be used. is carbonyl di7fluoride.

It is preferable to use phosgene, carbonyl dibromide, and carbonyl dibromide, with phosgene being particularly preferable. Examples of esters of halogenoformic acid include hepano-, di-, or tri-halogenoalkyl esters of the above-mentioned halogenoformic acids, with trichloroalkyl esters being preferred. Particularly preferred is trichloromethyl ester of halogenformic acid, and a specific example is trichloromethylchlormate.

As a base, 1 such as triethylamine, pyridine, 2
-Methylpyridine, 2,6-dimethylpyridine, tetramethylurea, hexamethylphosphoric acid triamide, quinoline, and the like.

Examples of solvents include benzene, toluene, xylene, chloroform, carbon tetrachloride, 1j2-dichloroethane, acetonitrile, methyl acetate, ethyl acetate, dioxane,
Tetrahydrofuran, acetone, methylethylgtone,
Hexane, cyclohexane, etc. can be used.

The reaction can be carried out in the presence of a base at about -20 DEG to 60 DEG C., particularly around room temperature. In addition, the reaction in the absence of a base is approximately O~6 when using logenoformic acid halide.
The process preferably proceeds at 0°C, particularly around room temperature, and when an ester of halogenoformic acid is used, it preferably proceeds at temperatures ranging from about -20°C to reflux temperature and about 20 to 60°C.

[Y)-→CII-BE The N-acyl group can be removed from the thus obtained compound [v] by a conventional method.

Specifically, for example, compound [v] may be treated with an acid or alkali in an appropriate solvent, or heated in an appropriate solvent, or when the acyl group is a β, β, β-trihaloethoxycarbonyl group. This can be carried out by treatment with zinc-acetic acid.

When removing an acyl group by acid treatment or alkali treatment, examples of acids include hydrochloric acid, hydrobromic acid, 'Ii/
Examples of alkalis include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide, sodium carbonate, potassium carbonate, and carbonate. Alkali metal carbonates such as chikum.

Hydrogen carbonate) Alkali metal hydrogen carbonates such as IJ cum, potassium hydrogen carbonate, and thicum hydrogen carbonate can be used. As the solvent, alkanols such as methanol, ethanol, propatool, butanol, acetonitrile, diocypne, detrahydrofuran, water, or a mixture thereof can be used. 2. When the reaction is carried out with an acid treatment,
0-100℃.

Particularly preferred is S carried out at 20 to 60°C.

In the case of alkali treatment, the temperature is 0 to 100°C, especially 10°C.
Preferably it is carried out at a temperature of -50°C. When the acyl group is removed by heating, the reaction proceeds suitably by heating the compound [v] in the solvent used in the above acid or alkali treatment at about θ to the reflux temperature, particularly at the reflux temperature. Also, the acyl group is β.

+ 2 β, β-trihaloequitonocarbonyl &'>;
The zinc-acetic acid treatment is preferably carried out at about 10 DEG to 50 DEG C., especially at room temperature.

The starting compounds (■) of the present invention are all new compounds and can be produced, for example, according to the following reaction formula.

Reaction formula % Formula % (However, XR to X5 are respectively norogen atoms, R
1゜R2, R4, R6, xl and X2 have the same meanings as above) That is, the reaction between compound [)1] and [■] is carried out using a suitable solvent (lower alkanol, tetrahydrofuran, etc.).

Dioxane, acetonitrile, benzene, toluene,
deoxidizing agent (alkali metal carbonate, alkali metal hydrogen carbonate, etc.) in dimethylformamide or mixtures thereof).
In the presence of alkali metal hydroxides, alkali metal hydrides, organic bases such as pyridine, triethylamine, alkali metal alkoxides).

It can be carried out at 0-80°C, especially at 20-60°C.

Compound CX'l) can be prepared. Compound [■
] can be achieved by catalytic reduction in a solvent (lower alkanol, tetrahydrofuran, dioxane, etc.) in the presence of a catalyst (palladium carbon, palladium black, etc.) to produce compound [ff]. The reaction between compound [■] and [x] is carried out in the presence of a deoxidizer (alkali metal carbonate, alkali bicarbonate salt, alkali metal hydroxide, organic base, etc.) in the presence of a solvent (methylene chloride, chloroform, etc.).

Ethyl acetate, tetrahydro7ran, dioxane.

acetone or a mixture of these and water) from 0 to 40°C
, especially at 0 to 25°C, and compound [XI] can be produced. The reaction between compound CXl, dimethylformamide, dioxane, dimethyl sulfoxide) at 20-100°C, especially 20-70'C.
T% can be applied, and compound IYI can be prepared.

Example 1 (1) N-(4-chloro-2-((4-methoxybenzyl)thio)phenyl 1-N-[2-(dimethylamino)
Ethyl]oxamic acid ethyl ester (Reference example (5)
) 0.2 g of a mixture of tetrahydro7ran65- and 0.075 g of hexamethylphosphoric triamide
Cool to 0°C. Lyticum diisoprobylamide [prepared by a conventional method using 103 g of diinpropylamine, n-butyl lyticum o, 64 rrt (1,6 molar hexane solution) and tetrahydro7rane 3] is added dropwise to this. After stirring for 10 minutes at the same temperature, the reaction solution was poured into a saturated ammonium chloride aqueous solution. Extract this with ethyl acetate.

Wash with water, dry and remove the solvent. Remove the remaining residue with silica gel 2-(
dimethylamino)ethyl)-2-(4-methoxyphenyl)-1,5-benzothiazepine-3゜4(2H,5
0.102 g of H) dione are obtained as a pale yellow oil.

Yield 56.7% IRν"""(cm-'): 1720.1660ax NMR (ppm, CDCZa)' 2.20 (
6H9S, N (CHi) 2) +3.75
(3H,S, 0CH3), 5.38 (broad
peak IH, CH)) (2) To a solution of 0.1 g of the compound (free) obtained above, 5 tIt of ethanol, and 1 - of water was added 0.01 g of sodium borohydride under water cooling, and the mixture was heated at room temperature for 1 hour. Stir. The reaction solution was then diluted with water and extracted with ethyl acetate.

After washing the extract with saturated saline and drying.

The solvent is distilled off. By recrystallizing the residue with ethanol, cis-8-chloro-5(2-('; methylamino)
0.081 g of ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as needles.

Yield 80.6% M, P, 169.5 N170C hydrochloride 1/2C7H6OH M, P, 136-139°C (recrystallized from a mixture of chloroform-ethanol-ether) (3) Obtained in (2) above A mixture of 1 g of the compound (hydrochloride), 2-acetic anhydride and 2-acetic acid is stirred at 110°C for 4 hours. The reaction mixture is concentrated under reduced pressure to remove the solvent.

By adding ether to the residue and filtering out the precipitated crystals,
cis-8-chloro-2-(4-methoxyphenyl)-3
-acetoxy-5-C2-(dimethylamino)ethyl)
-2,3-dihydro-1,5-benzothiazepine-4 (
1.08 g of 5H)-one hydrochloride are obtained. When Honjima is recrystallized from a mixture of chloroform, ethanol, and ether, it becomes needle-shaped crystals (ethanol adduct).

M, P, 159-161°C Example 2 8-chloro-5-C2-(dimethylamino)ethyl)-
Dissolve 200 mg of 2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione in 2 swjK of toluene, and add 3 ml of triethylamine under water cooling.
Add 5 mg. Next, 100 mg of trichloromethyl chloroformate (trichloromethyl chloroformate) was added thereto, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform and ether. The organic solvent layer is washed with 1096 hydrochloric acid and then with water.

After drying, the solvent is distilled off.

The resulting residue (8-chloro-5-(2-(N-methyl-
N-chloroformylamino)ethyl]-2-(4-methoxyphenyl)'-1.5-pen l-f-mg and water 1.
5- and acetonitrile 1.5- are added and heated under reflux for 30 minutes. The resulting (8-taloro-5-(2-(methylamino)ethyl)-2-(4-methoxyphenyl)-1
, 5-benzothiazepine-3,4(2H,5H)-dione) is cooled, 60 mg of sodium fluoride hydride is added under water cooling, and the mixture is stirred at room temperature for 1 hour.

The reaction solution was extracted with chloroform, washed with water, and dried. Then, the solvent was distilled off and the residue was subjected to silica gel column chromatography (solvent:
Make ↑4- with chloroform:ethanol = 95:5). The resulting compound was recrystallized from succinate dimethylformamide-phenol-ether to give cis-8-chloro-2,3-si'-drow-5-(2-(methylamino)ethyl]-3- Hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepine-4(5
Obtain 70 mg of H)-one succinate.

LP, 190-194 (decomposition) Example 3 (1) 9-diRoro-5-[2-(dimethylamino)ethyl)- prepared from 2-90-6-nitrothiophenol in the same manner as in the reference example. 2-(4-methoxyphenyl)
-1,5-penzothiacepine-3,4(2H,5H)
cis-9-chloro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2, 3-dihydro-1,5-benzothiazepine-4
(5H)-one is obtained.

M, P, 143-144°C Hydrochloride monohydrate M, P, 228-230°C (decomposed) (wet from 143°C) (recrystallized from methanol) (2) Above M Compound obtained in (1) (free) obtained by optical resolution using optically active 1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl chloride (+)-
Cis-9-chloro-5-(2-(dimethylamino)ethylcou-3-hydroxy-2-(4-methoxyphenyl)
-2,3-dihydro-1゜5-penzothiasebin-
Using 4(5H)-one.

By treating in the same manner as in Example 1-(3) and converting it into a hydrochloride, (t)-cis-9-chloro-5-C2-(dimethylamino)ethylcy-3-acetoxy-2-(4-methoxyphenyl) -2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride hydrate is obtained.

M, P, 140-143°C [α) D+13.0' (C=0.347.methanol) Examples 4-40 The compounds shown in the table below are obtained by treating in the same manner as in Examples 1-3.

Reference example (1) 3-chloro-6-nitrothiophenol 3.3g
, 5.3 g of sodium ethylate was added to a mixture of 50 - ethanol and 20 - tetrahydrofuran under water cooling, and the mixture was stirred for 10 minutes. Then, 3 g of paramethoxybenzyl chloride was added and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, water was added to the residue, and the precipitated crystals were collected by filtration.
By recrystallizing from ethanol)) 1-(4-methoxybenzylthio)-3-chloro-6-nidropense
4.5 g of yellow needles are obtained.

M, P, 122-123.5°C (2-1> 1 g of the compound obtained in (1) above was dissolved in ethanol 4
3.8 g of stannous chloride dihydrate was added, and the mixture was stirred at 70°C for 1.5 hours. After the reaction is cooled, the two reaction solutions are poured into water ice and sodium bicarbonate is added to adjust the pH to 7-8.

Extract with chloroform and dry the extract. The solvent was distilled off and the residue was purified using silica gel column chromatography (solvent: benzene:
Hexadi=2:1) to obtain 0.78 g of 1-(4-methoxybenzylthio)-3-chloro-6-aminobenzene.

M, P, 84-85.5°C (2-2) 1 g of the compound obtained in (1) above, 1 methanol
A mixture of 5-, 15 rnt of tetrahydro 7-ran, concentrated hydrochloric acid 1- and 0.2 g of 10% Balazicum carbon was added at room temperature.
Catalytic reduction at normal pressure. After the reaction, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and ethanol to obtain 0.84 g of 1-(4-methoxybenzylthio)-3-chloro-6-amine benzene hydrochloride.

Δ1. P, 191-193°C (3) Compound obtained in (2-1) above (free) 1.53
g9 0.92 g of baking soda, 20 g of water and 30 g of methylene chloride
While vigorously stirring the mixture of d, add talologlioxalic acid ethyl ester (C4COCOOC2H5) 1,3
Drop 6 g. After stirring for 30 minutes, the methylene chloride layer is separated. Extract the aqueous layer with methylene chloride. After combining the methylene chloride layers, washing with water and drying, the solvent was distilled off.

By recrystallizing the residual from isopropanol, N-
(4-chloro-2-[(4-methoxybenzyl)thio]
1.81 g of phenyl)-oxamic acid ethyl ester are obtained as colorless needles.

M, P, 99.5-100°C (4) A mixture of 1.5 g of the compound obtained in (3) above, 1.27 g of dimethylaminoethyl chloride + 1.64 g of potassium potassium chloride and 30-acetonitrile was
Stir at 0°C for 3 hours. After the reaction, cool and add 2 reaction solutions to 5 parts of water.
Pour into 〇− and extract with ethyl acetate. Wash the extract with water.

Dry and evaporate the solvent. The residue was purified by silica gel column chromatography (G medium: chloroform:ethanol = 10 = 1) to obtain N-(4-chloro-2-((4-methoxybenzyl)thio]phenyl)-N-[2-( Dimethylamino)ethyl]-oxamic acid ethyl ester 1.
7 g are obtained as a yellow oil.

1Rtt0Hc'3 (cm'): 1740.167
0aX NMR (ppm, CDC13): 1.04 (3H, t,
J=7Hz+CH,CH8), 2.17 (6H,S
, N(CH,)2), 3.79(3H,S, 0C
H3), 3.97 (2H, q, J”8H2゜0C
H2CH, ), 4.11 (2H,S, S-CH2
) Agent Patent Attorney Seiji Nakaho [-,,1

Claims (1)

[Claims] 1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [II] (However, R^1, R^3 and R^4 are the same or different and represent a hydrogen atom or a lower alkyl group. ,X^1
and X^2 means that either one is a hydrogen atom and the other is a chlorine atom) The general formula ▲ Numerical formulas, chemical formulas, tables, etc. are obtained by reducing the compound or its salt represented by ▼ [ I - A] (However, R^1, R^3, R^4, X^1 and X^2
has the same meaning as above), and if necessary, the compound [I-A]
Or, by condensing its salt with a compound represented by the general formula R^5COOH[III] (where R^5 represents a lower alkyl group) or its reactive derivative, there are the general formula ▲ mathematical formula, chemical formula, table, etc. ▼ [I-B] (However, R^1, R^3, R^4, R^5, X^1 and X^2 represent the same meanings as above), and if necessary, a compound [I-A
] or [ I −B] as its salt ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [ I ] (However, R^2 represents a hydrogen atom or a lower alkanoyl group, and R^ 1, R^3, R^4, X^1 and X^2
has the same meaning as above) A method for producing an 8- or 9-chloro-1,5-benzothiazepine derivative or a salt thereof. 2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] (However, R^1, R^3 and R^4 are the same or different and represent a hydrogen atom or a lower alkyl group, and X^1
and X^2 represents that either one is a hydrogen atom and the other is a chlorine atom) or a salt thereof. 3) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] (However, R^1, R^3 and R^4 are the same or different and represent a hydrogen atom or a lower alkyl group, and R^6
represents a lower alkyl group, and X^1 and X^2 represent one of which is a hydrogen atom and the other a chlorine atom). There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by their salts ▼ [II] (However, R^1, R^3, R^4, X^1 and X^2
has the same meaning as above) A method for producing a benzothiazepine derivative or a salt thereof. 4) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [II-A] (However, R^1 represents a hydrogen atom or a lower alkyl group, and R^3^l and R^4^l each represent a lower alkyl group. X^1 and X^2 represent one of which is a hydrogen atom and the other is a chlorine atom) or a salt thereof, and an acid halide or ester of halogenoformic acid are reacted. There are general formulas▲mathematical formulas, chemical formulas, tables, etc.▼[V] (However, R^7 represents either R^3^l or R^4^l, and R^8 represents a halogen atom or (representing an ester residue, and R^1, There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by the fact that is its salt ▼ [II-B] (However, R^1, R^7, X^1 and X^2 have the same meanings as above. ) A method for producing a benzothiazepine derivative or a salt thereof.