DD257426A5 - PROCESS FOR THE PREPARATION OF 1,5-BENZOTHIAZEPINE DERIVATIVES - Google Patents

Abstract

A process for the preparation of 1,5-benzothiazepine derivatives having antihypertensive and coronary and cerebral vasodilator activity and inhibiting aggregation of platelets of general formula (I) wherein R 1 is lower alkyl, R 2 is hydrogen or lower alkanoyl and X 1 is hydrogen or a lower alkyl radical, and their salts. Formula (I)

Description

(II)

in which R ^{3 is} a hydrogen atom or a lower alkanoyl radical and X ^{2 is} a hydrogen atom, a lower alkyl radical or an amino-protecting group, alkylated, ii) when the radical X ^{2 is} a protective group, cleaves this protective group, iii) when the radical R ³ a lower alkanoyl radical, optionally cleaving this radical

iv) optionally converting the product obtained by reaction with an acid in the salt.

2. The method according to claim 1, characterized in that the alkylation is carried out with a lower alkanol at 0 to 40 ^C C in the presence of a dehydrating agent,

3. The method according to claim 1, characterized in that the alkylation is carried out with a lower alkyl sulfate, lower alkyl sulfonate or lower alkyl halide at a temperature of 0 ° C to the reflux temperature in the presence of a base and in an inert solvent.

4. The method according to claim 1, characterized in that the alkylation is carried out with a quaternary lower alkylammonium compound, a lower alkylsulfonium or sulfoxonium compound or a lower Alkylselenoniumverbindung at a temperature of 1O ⁰ C to the reflux temperature.

5. The method according to claim 1, characterized in that the alkylation is carried out with a lower diazoalkane at 0 to 40 ° C, preferably at 20 to 30 ⁰ C, in an inert solvent.

Field of application of the invention

The application of the present invention is in the field of drugs with hypotensive action and cerebral vascular and coronary vasodilator effect as well as the platelet aggregation inhibitory effect.

Characteristic of the known technical solutions

Benzothiazepine derivatives are known from US-PS 3562257, including γ-chloro-i.δ-benzothiazepine derivatives such as 2- (4-methoxyphenyl) -3-hydroxy (or acetoxy) -5- [2- (dimethylamino) ethyl] -7-chloro-2,3-dihydro-1,5-benzothiazepine-4- (5H) -one. These benzothiazepine derivatives are antidepressants, tranquilizers and / or they have coronary vasodilator activity.

Object of the invention

The object of the invention is to provide novel drugs which have antihypertensive activity and cerebral vascular and coronary vasodilating action, as well as to provide those drugs which inhibit platelet aggregation

Explanation of the essence of the invention

The invention has for its object to provide new drugs that have hypotensive effect and cerebral vascular and coronary vessel dilating effect and inhibit platelet aggregation.

The invention thus relates to a process for the preparation of 1,5-benzothiazepine derivatives of the general formula

one yy ago ¹

C ll V ^0RZ

--- ~ ^ ν - (\ (D

I 0 .CH ₃ C Il ₂ C Il ζ Ν C ^

in which R ^{1 is} a lower alkyl radical, R ^{2 is} a hydrogen atom or a lower alkanoyl radical and X ^{1 is} a hydrogen atom or a lower alkyl radical, and their salts, which are characterized in that a compound of the general formula II,

(II)

wherein R ^{3 represents} a hydrogen atom or a lower alkanoyl group and X ^{2 represents} a hydrogen atom, a lower alkyl group or an amino-protecting group, when X ^{2 is} an amino-protecting group, this protecting group is alkylated when R ^{3 is} a lower alkanoyl group, optionally splits off this residue and, if appropriate, converts the compound obtained into a salt. The alkylation is preferably carried out by reaction with a lower aliphatic alcohol at temperatures of 0 to 40 ⁰ C in the presence of a dehydrating agent. The alkylating agent used is preferably a lower alkyl sulfate, a lower alkyl sulfonate or a lower alkyl halide, and the alkylation is carried out at temperatures between 0 ° C. and the reflux temperature. The reaction is preferably carried out in the presence of a base and in an inert solvent. Preferably, the alkylation is carried out with a lower alkyl quaternary ammonium compound, a lower alkyl sulfonium or sulfoxonium compound or a lower alkyl selenonium compound at temperatures between 10 ° C and the reflux temperature. The alkylation can also be carried out preferably with a lower diazoalkene at temperatures of 0 to 40 ⁰ C, in particular 20 to 30 ⁰ C, in an inert solvent. ,

In comparison to the known compounds have the inventively prepared compounds of general formula I in which X ¹ represents a lower alkyl group, a stronger hypotensive and cerebral or herzkranzgefäßerweiternde effect. It is therefore more suitable for the treatment and / or prophylaxis of hypertension, cerebral diseases such as cerebral vascular spasms or cerebral infarction, and for the treatment of cardiac diseases such as angina pectoris, arrhythmia or myocardial infarction. On the other hand, compounds of the general formula I which can be prepared according to the invention, in which X ¹ denotes a hydrogen atom, show inhibition in platelet aggregation. They are therefore suitable for the treatment and / or prophylaxis of thrombotic diseases, such as cerebral infarction, transient cerebral ischemia, coronary thrombosis (myocardial infarction), pulmonary embolism, peripheral blood vessel embolism, thromboangiitis and / or other thromboses, as described, for. B. can occur after replacement of the heart valves.

According to the invention, the compounds of the general formula can be prepared as follows: i) alkylation of a compound of the general formula II,

(II)

in which R ^{3 is} a hydrogen atom or a lower alkanoyl radical and X ^{2 is} a hydrogen atom, a lower alkyl radical or an amino-protecting group.

ii) When the radical X ^{2 is} an amino-protecting group, this protective group is cleaved, iii) If the radical R ^{3 is} a lower alkanoyl radical, it can optionally be eliminated and iv) if appropriate, the product obtained can be converted into a salt.

In the process according to the invention, a wide variety of amino-protecting groups can be used. Specific examples of these groups are unsubstituted or substituted benzyloxycarbonyl groups such as the benzyloxycarbonyl or p-methoxybenzyloxycarbonyl group, unsubstituted or substituted lower alkoxycarbonyl groups such as the tert-butoxycarbonyl, β, β, β-trichloroethoxycarbonyl or iodoethoxycarbonyl group, and unsubstituted or substituted phenyl lower alkyl groups such as the benzyl, p-methoxybenzyl or 3,4-dimethoxybenzyl group. The alkylation can be carried out according to the invention with a lower alkylating agent. Examples of lower alkylating agents are lower aliphatic alcohols, lower alkyl sulfates such as dimethyl sulfate, lower alkyl esters of alkyl or aryl sulfonates such as toluenesulfonate, methanesulfonate and 2-oxo-i, 3-propandisulfonsäuredimethylester, lower alkyl halides such as methyl iodide and methyl bromide, lower alkyl quaternary Ammonium compounds such as trimethylphenylammonium hydroxide, lower alkylsulfonium or sulfoxonium compounds such as trimethylsulfonium hydroxide and trimethylsulfoxonium iodide, lower alkylselenonium compounds such as trimethylselenonium hydroxide, and lower diazoalkanes such as diazomethane.

When using lower aliphatic alcohols as alkylating agents, the reaction is preferably carried out in the presence of a dehydrating agent. Specific examples of dehydrating agents are dicyclohexylcarbodiimide or a mixture of triphenylphosphine and diethyl azodicarboxylate. Preferably, the reaction is carried out at temperatures of from 0 to 40 ° C.

When using lower alkyl sulfates, lower alkyl esters of alkyl or aryl sulfonates or lower alkyl halides as alkylating agents, the reaction is preferably carried out in the presence of a base. Examples of suitable bases are inorganic bases such as alkali metal oxides, carbonates, bicarbonates, hydrides or alkoxides, and organic bases such as ethyldiisopropylamine. Preferably, the reaction at temperatures between ^{0 0} C under reflux temperatures, in particular bejJemperaturen of 10 to 40 ⁰ C in an inert solvent such as acetone, acetonitrile, methanol, benzene, dioxane, tetrahydrofuran, dimethyl sulfoxide or dimethylformamide performed. Preferably the reaction is in the presence of a phase transfer catalyst, wieTetrabutylammoniumfluorid, carried out when using quartärenNieder-alkylammonium, lower alkyl sulfonium or -sulfoxoniumverbindungen or low-alkylselenoniumverbindungen as the alkylating agent, the reaction is preferably performed at temperatures between 1O ⁰ C and the reflux temperature, especially at temperatures of about 50 to 100 ⁰ C carried out either in an inert solvent or without solvent. Examples of suitable solvents are toluene, dioxane, methanol, dimethylformamide and dimethyl sulfoxide.

When using a lower Diazolalkans as alkylating agent, the reaction is preferably carried out at temperatures of 0 to 40 ⁰ C, in particular 20 to 30 ⁰ C, in an inert solvent. Examples of suitable solvents are dioxane, tetrahydrofuran, methanol and mixtures thereof. When the radical R ^{3 of} the starting compounds of the general formula II is a lower alkanoyl radical, the reaction is preferably carried out in the presence of fluoboric acid or silica gel. In carrying out the alkylation reaction, it is particularly preferable that a lower alkyl sulfate, a lower alkyl sulfonate or a lower alkyl halide is used as the alkylating agent when the X ^{2 group of} the starting compounds of the general formula II is a hydrogen atom and R ^{3 is} a lower alkanoyl group. On the other hand, when both X ² and R ^{3 of} the starting compounds of the general formula II are hydrogen, it is preferable to use a lower alkyl quaternary ammonium compound, a lower alkylsulfonium or sulfoxonium compound or a lower alkylselenonium compound or a lower diazoalkane Alkylating agent used.

When the radical X ^{2 of} the product obtained represents an amino-protecting group, this protecting group is usually split off. For example, an unsubstituted or substituted benzyloxycarbonyl group or an unsubstituted lower alkoxycarbonyl group can be cleaved by treatment with an acid such as hydrogen bromide, hydrogen chloride or trifluoroacetic acid in a solvent. When the protecting group is a substituted lower alkoxycarbonyl group, this group can be cleaved by treatment with zinc in a solvent. When the protecting group is an unsubstituted or substituted phenyl-lower alkyl group, this group may be cleaved by first reacting it with another protecting group, e.g. As a benzyloxycarbonyl, replaced, which is easily cleavable with an acid, and then splits off the latter group in the manner described above. Substitution of the unsubstituted or substituted phenyl-lower alkyl group with a benzyloxycarbonyl group is preferably carried out by treating the product, ie the compound whose imino group is protected by the unsubstituted or substituted phenyl-lower alkyl group, with a benzyloxycarbonyl halide such as benzyloxycarbonyl chloride at temperatures of 50 to 130 ⁰ C are carried out in a solvent.

When the group R ^{3 is} a lower alkanoyl group, the protective group and the lower alkanoyl group can be simultaneously cleaved off. However, the protective group can also be cleaved off without cleavage of the lower alkanoyl radical. These reactions can be achieved by changing the reaction conditions, eg. B. control the amount of reagents, the reaction time and / or the solvent.

Optionally, the compounds of general formula I obtained can be converted by treatment with an acid into the corresponding salts. Examples of the acids usable for salt formation are inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, perchloric acid, sulfuric acid and phosphoric acid, and organic acids such as oxalic acid, maleic acid, fumaric acid and methanesulfonic acid.

Since the reactions described above proceed without racemization, when using an optically active isomer of the compounds of general formula II, the compounds of general formula I can be obtained in optically active form.

The starting compounds of the general formula II can be prepared, for example, as follows: Methyl 3- (4-benzoyloxyphenyl) glycidate is converted with 5-chloro-2-aminothiophenol to 2- (4-benzyloxyphenyl) -3-hydroxy-8-chloro-2,3 dihydro-1,5-benzothiazepine-4 (5H) -one or its salt. This compound is reacted with a compound of general formula III.

' CH ₃

Y-CH ₂ CH ₂ N →. ( "Ι,

in which Y is a halogen atom and X ^{2 have} the abovementioned meaning, or its salt is converted into a compound of the general formula IV.

CH ₂ CH ₂

X ² has the meaning given above. The benzyl group is then cleaved off and optionally the hydroxyl group of the product obtained in the 3-position of the benzodiazepine ring is converted into a lower alkanoyloxy group before or after cleavage of the benzyl group. The compounds of the general formula I and the starting compounds of the general formula II may be in the form of two diastereoisomers (eg, ice and trans) or four optical isomers (eg (+) - cis, (+) - trans and ( -) - trans) due to the two asymmetric carbon atoms. The invention includes all isomers and mixtures thereof. Of the isomers, the cis-isomers of the compounds of general formula I are particularly preferred as drugs.

embodiment example 1

690 mg (+) - cis-2- (4-hydroxyphenyl) -3-hydroxy-5- [2- (N, N-dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine -4 (5H) -one are dissolved in 20 ml of tetrahydrofuran. The mixture is added at room temperature with 78 mg sodium hydride (as a 60% dispersion in mineral oil) and stirred for 30 minutes at the same temperature. Then a solution of 245 mg of dimethyl sulfate in 10 ml of dimethylformamide is added. The mixture is stirred for a further hour at room temperature. Then the reaction mixture is poured into water and extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried and evaporated. The residue is recrystallized from a mixture of ethyl acetate and η-hexane. Yield 509 mg (+) - cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (N, N-dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5- benzothiazepine-4 (5H) -one

 F. 122 to 124 ° C (decomp.)

"C (C = 0.85, methanol)

Examples 2 to 4.

The corresponding starting compounds are reacted in the same manner as in Example 1 to the compounds listed below in Table I.

Table I

3CH ₃ CH ₂ CH ₂ N. <(Π) ^X X ²

I 0 CH ₃ CH ₂ CH ₂ N <f (I) X '

(R ¹ , χ 'and χ ² = -CH ₃ , R ³ =

Example no.

Compound (I)

optical activity properties

-H

cis - (-)

F.121-123 ° C (dec.) [A ° ° -142.7 ° C (C = 1.04Methanol)

Example no. Compound (I) optical activity properties 3 -COCH ₃ cis - <+) ' Maieat (recrystallized from ethanol-diethyl ether) F. 158-160 ⁰ C [a] +75.4 ⁰ g ° C (C = 1.0, methanol) 4 -COCH ₃ cis - (-) Hydrochloric! F.128-132 ° C (dec.) [A] g ° -93.3 ° C (C = 0.872, ethanol)

Example 5

210mg (+) - cis-2- (4-hydroxyphenyl) -3-acetoxy-5- [2- (N -methyl-amino) -ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine -4 (5H) -one, 250 mg of potassium carbonate and 140 mg of dimethyl sulfate are dissolved in 5 ml of methanol. The solution is stirred for 12 hours at room temperature. Then insoluble substances are filtered off. The filtrate is evaporated. The residue is purified by chromatography on silica gel (mobile phase benzene / ethyl acetate 4: 1). The eluate is evaporated, converted by reaction with maleic acid in the Maieat and crystallized from a mixture of ethanol and diethyl ether. Yield: 212 mg (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (N, N-dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5- benzothiazepin-4 (5H) -one maleate. ,.

The physicochemical properties of the product are identical to those of the product of Example 3.

Example 6

(a) (-) - Cis-2- (4-Hydroxyphenyl) -3-hydroxy-5- [2- (N-benzyl-N-methylamino) -ethyl] -8-chloro-2,3-dihydro-1 5-benzothiazepine-4 (5H) -one is converted to (-) - cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (N, -benzyl-N -methylamino) -ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one. With perchloric acid, the perchlorate is produced, which melts after decomposition from ethanol at 161 to 163 ° C with decomposition.

[a] g ° C -76.4 ⁰ (C = 0.589, methanol)

(b) 4.3 g of the product obtained in step (a) are dissolved in 50 ml of benzene and heated to reflux. Within 15 minutes, a solution of 4.55g Benzyloxycarbonylchlorid is added dropwise in 10 ml of benzene. The mixture is refluxed for 1 hour, then cooled to room temperature and evaporated. The residue is mixed with 30 ml of ethanol and 50 ml of 5% sodium hydroxide solution and stirred for 2 hours at room temperature. Thereafter, the reaction mixture is diluted with water and extracted with chloroform. The chloroform extract is washed with water, dried and evaporated. There are added 4.76 g of (-) - cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (N-benzyloxycarbonyl-N-methylamino) -ethyl] -8-chloro-2,3- dihydro-1,5-benzothiazepine-4 (5H) -one.

IRvSaS ' ³ (cm ^-1 ): 3510.1695.1660 [a] g ° -133.3 ⁰ C (C = 0.582, methanol)

(c) Dissolve 1.07 g of the product obtained in step (b) in 2 ml of benzene and add 1.7 ml of a 25% solution of hydrogen bromide in acetic acid. The mixture is stirred for 2 hours at room temperature. Then diethyl ether is added and the precipitate is filtered off and washed with diethyl ether. The precipitate is then treated with water and benzene and the mixture is made alkaline with potassium carbonate. The benzene solution is washed with water, dried and evaporated. The residue is mixed with diethyl ether. The resulting precipitate is filtered off and recrystallized from a mixture of ethyl acetate and η-hexane. Yield 0.47 g (-) - cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (N-methylamino) ethyl] -8-chloro-2,3-dihydro-1,5- benzothiazepine (5H) -one, mp 142-145 ° C.

[a] g -147.7 ° C ⁰ (C = 0.814, chloroform)

The fumarate melts after recrystallization from ethanol at 164 to 167 ° C with decomposition.

Examples 7 to 9

(a) The corresponding starting compounds are reacted in the same manner as in Example 6 (a) to the compounds listed below in Table II.

Table II

(Π) (R ¹ = -CH ₃ , X ² = -CH ₂ C ₆ H ₅ )

Example no. Connection V optical activity properties 7 -H cis - (+) Perchlorate (umkristallisiertaus ethanol) F.161-163 ° C (dec.) [A] + 76.5 ° § ⁰ C (C = 0.446, methanol) δ -COCH ₃ cis - (-) Oxalate (recrystallized from ethanol) mp 192-194 ° C (dec.) [A] § ⁰ -96.5 ° C (C = 1, O, dimethylformamide) 9 -COCH _{3 (} 'CiS- (H-) Oxalate (recrystallized from ethanol) F.191-194 ° C (dec.) [A] § ° + 96, e ° C (C = 0.73, dimethylformamide)

(b) The products of formula V are reacted in the same manner as in Example 6 (b) to the compounds listed in Table III below.

Table II!

CH ₂ CH ₂ N

(V-a)

^N CH, - // \)

OR ³

I 0, CH ₃ CH ₂ CH ₂ N

(V-b)

^ COOCH - / ⁷ ^

(R ¹ = -CH ₃ )

Example no. Compound Vb R ^a optical activity properties 7 -H CiS (H) [a] § ° + 132.6 ⁰ C (C = 0.50, methanol) δ -COCH ₃ * ¹ cis - (-) IR & ^{C '3} (cm- ^1): 1740.1685 [a] § ° -115.4 ⁰ C (C = 1, O.Methanol) 9 -COCH ₃ * ¹ cis (H) [a] § ° +115.5 X (C = 1.0, methanol)

Note: After the reaction, the residue is not treated with a mixture of ethanol and caustic soda.

(c) the products (V-b) are reacted in the same manner as in Example 6 (c) to the compounds listed below in Table IV.

Table IV

O .CH ₃ CH ₂ CH ₂ NC

(V-b)

XOOCH

(Ia) (R ¹ = -CH ₃ , R ² = -H ₁ R ³ = -H or -COCHj)

Ex

 No.

Compound (I-a) optical activity

properties

Hydrochloride 0.5 hydrate

(recrystallized from a

Mixture of ethanol and

Diethyl ether).

F. 137-14O ⁰ C

[a] ° ° + 83.4 ° C (C = 0.415, methanol)

cis - (-)

identical to the product of Example 6 (c)

identical to the product of Example 7 (c)

Example 10

(a) 450mg (-) - cis-2- (4-hydroxyphenyl) -3-hydroxy-5- [2- (N-benzyl-N-methylamino) -ethyl] -8-chloro-2,3-dihydro- 1,5-benzothiazepin-4 (5H) -one are dissolved in 20 ml toluene and treated at 8O ⁰ C with a solution of 490mg of benzyloxycarbonyl chloride in 10ml of toluene. The mixture is stirred at 8O ⁰ C for 5 hours. After completion of the reaction, the solvent is distilled off. The residue is mixed with 10 ml of 5% sodium hydroxide solution and 10 ml of methanol and stirred for 2 hours at room temperature. Thereafter, the mixture is extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried and evaporated. The residue is purified by chromatography on silica gel. The eluent used is a mixture of chloroform and methanol (9: 1). There are 410mg (-) - cis-2- (4-hydroxyphenyl) -3-hydroxy-5- [2- (N-benzyloxycarbonyl-N-methylamino) -ethyl] -8-chloro-2,3-dihydro-1 , 5-benzothiazepine-4 (5 H) -one obtained.

(b) A mixture of 410 mg of the product obtained in step (a), 340 mg of potassium carbonate, 170 mg of methyl iodide and 10 ml of methanol is stirred for 40 hours at room temperature. After completion of the reaction, the reaction mixture is evaporated and the residue taken up in ethyl acetate. The solution is washed with 10% sodium hydroxide solution and water, dried and evaporated. Yield 315 mg (-) - cis -2- (4-methoxyphenyl) -3-hydroxy-5- [2- (N-benzyloxycarbonyl-N-methylamino) ethyl] -8-chloro-2,3-dihydro-1, 5-benzothiazepine-4 (5H) -one.

The physicochemical properties of this product are identical to the product of Example 6 (b).

(c) The product obtained in step (b) is converted in the manner described in Example 6 (c) to (-) - cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (N-methylamino ) -ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one.

Example 11

(a) (-) - Cis-2- (4-Hydroxyphenyl) -3-acetoxy-5- [2- (N-benzyl-N-methylamino) -ethyl] -8-chloro-2,3-dihydro-1 5-benzothiazepine-4 (5H) -one is converted to (-) - cis-2- (4-hydroxyphenyl) -3-acetoxy-5- [2- (N -benzyloxy) in the manner described in Example 8 (b) -carbonyl-N-methylamino) -ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one.

[a] £ ⁰ ° C -106.0 (C = 0.50, chloroform)

(b) The product obtained in step (a) is converted in the manner described in Example 10 (b) to (-) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (N -benzyloxycarbonyl-N-methylamino) -ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one.

(c) 37.5 g of the product obtained in step (b) and 75 ml of a 25% solution of hydrogen bromide in acetic acid and 95 ml of dichloromethane are mixed together under ice-cooling. The mixture is stirred for 3 hours at room temperature. After completion of the reaction, dichloromethane is distilled off and the residue is treated with diethyl ether. The resulting

Precipitation is washed with diethyl ether. Thereafter, the precipitate is dissolved in water. The solution is neutralized with potassium carbonate and extracted with diethyl ether. The ether extract is washed with water, dried and evaporated. The residue is converted by reaction with oxalic acid in the oxalate, which is recrystallized from methanol. Yield 18.7 g of (-) - cis -2- (4-methoxyphenyl) -3-acetoxy-5- [2- (N-methylamino) ethyl] -8-chloro-2,3-dihydro-1,5 benzothiazepine-4 (5H) -one oxalate, mp 174-176 ° C.

[cc] 1 ° -74.2 ° C (C = 0.814, methanol)

Example 12

A solution of sodium methylate, prepared from 46mg sodium and 4.5ml methanol, is added with 645mg trimethylammonium tosylate. The mixture is stirred for 3 hours at room temperature. Insoluble substances are filtered off and the filtrate is added to a solution of 570 mg of (-) - cis-2- (4-hydroxyphenyl) -3-hydroxy-5- [2- (N-methylamino) -ethyl] -8-chloro-2, 3-dihydro-1,5-benzothiazepine-4 (5H) -one in 20 ml of toluene. Thereafter, the methanol is distilled off and the solution is heated under reflux for 2 hours. After completion of the reaction, the mixture is evaporated. The residue is purified by chromatography on silica gel (mobile phase chloroform: ethanol = 95: 5). The product is recrystallized from a mixture of ethyl acetate and η-hexane. Yield 275 mg (-) - cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (N -methylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine 4 (5H) -On.

The physico-chemical properties of this product are identical to the product prepared according to Example 6 (c). Preparation of the Starting Compounds: Preparation 1 '

(a) A mixture of (±) -trans-3- (4-benzyloxyphenyl) -glycidic acid methyl ester and 5-chloro-2-aminothiophenol is heated to 16O ⁰ C for 16 hours. Then, the reaction solution is added with (S) -N- (2-naphthalenesulfonyl) -pyrrolidine-2-carbonyl chloride and pyridine. The mixture is stirred. After completion of the reaction, the product is separated by chromatography on silica gel (solvent benzene: ethyl acetate = 4: 1) in the (+ Hsomerunddas (-) - isomer After separation, the isomers are added in each case with potassium carbonate, water and methanol, and the mixture The product is recrystallized from ethyl acetate to give the (+) and (-) isomers of cis-2- (4-benzyloxyphenyl) -3-hydroxy-8-chloro-2,3- dihydro-1,5-benzothiazepine-4 (5H) -one Vs ethyl acetate.

(+ (- isomer ¹ A ethyl acetate:

[α] -74.2 ° § ⁰ C (C = 1.00, dimethylformamide)

(-) - isomer ^1/5 ethyl acetate:

[a \ l -75 °, ⁰ ° C (C = 1.00, dimethylformamide)

(b) A mixture of (+) - cis-2- (4-benzyloxyphenyl) -3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one, 2 (N -Benzyl-N-methylamino) -ethyl chloride hydrochloride, potassium carbonate, acetone, ethyl acetate and water is heated under reflux. After completion of the reaction, insoluble substances are filtered off. The filtrate is evaporated. The residue is converted by reaction with oxalic acid in the oxalate, which is recrystallized from a mixture of methanol and diethyl ether. It is the (+) - cis-2- (4-benzyloxyphenyl) -3-hydroxy-5- [2- (N-benzyl-N-methylamino) -ethyl] -8-chloro-2,3-dihydro-1 , 5-benzothiazepine-4 (5H) -one oxalate obtained from mp 108-115 ° C.

[a] § ° +85.8 ⁰ C (C = 1.00, methanol)

(c) The product of step (b) in the form of the free base is dissolved in pyridine and treated with a solution of acetyl chloride in dichloromethane. The mixture is stirred. After completion of the reaction, the mixture is evaporated and the residue dissolved in ethyl acetate. The solution is washed with water, 5% aqueous sodium bicarbonate solution and water. The solution is then dried and evaporated. The residue is converted into the oxalate and recrystallized from a mixture of methanol and diethyl ether. It is the (+) - cis-2- (4-benzyloxyphenyl) -3-acetoxy-5- [2- (N-benzyl-N-methylamino) -ethyl] -8-chloro-2,3-dihydro-1 , 5-benzothiazepine-4 (5H) -one oxalate, mp 173-175 ⁰ C.

Ia] I ⁰ +78.4 ⁰ C (C = 1.00, methanol) (-) - cis isomer oxalate, mp 172-175 ⁰ C

(d) The product obtained in step (c) is dissolved as the free base in toluene and treated dropwise with a solution of benzyloxycarbonyl chloride in toluene. The mixture is heated and stirred. After completion of the reaction, the solvent is distilled off. The residue is purified by chromatography on silica gel (solvent chloroform: ethyl acetate = 95: 5). The purified product is recrystallized from a mixture of ethyl acetate and η-hexane. It becomes the (+) - cis-2- (4-benzyloxyphenyl) -3-acetoxy-5- [2- (N-benzyloxycarbonyl-N-methylamino) -ethyl] -8-chloro-2,3-dihydro-1 , 5-benzothiazepine-4 (5H) -one obtained.

Ia] I ⁰ +79.0 ⁰ C (C = 1.00, chloroform)

(-) - isomer,

Hg ⁰ -79.2 ° C (C = 1.00, chloroform)

(E) The product obtained in step (d) is dissolved in ethyl acetate and treated with cooling with a 25% solution of hydrogen bromide in acetic acid. After completion of the reaction, the solvent is distilled off. The residue is washed with diethyl ether and neutralized with concentrated aqueous ammonia solution. The corresponding free base is obtained, which is extracted with chloroform. The chloroform extract is washed with water, dried and evaporated. The residue is purified by chromatography on silica gel and the purified product is converted to the oxalate. It becomes the (+) - cis-2- (4-hydroxyphenyl) -3-acetoxy-5- [2- (N-methylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine -4 (5H) -one oxalatvom F. 186 get to 189 ⁰ C.

Ia] I ⁰ + 81.2 ° C (C = 0.50, methanol) (-) - cis-isomer, mp 187-189 ° C, [αψ ⁰ -81.6 C (C = 0.50, methanol)

(aT ( ^P +) ^r -ds-2- (4-benzyloxyphenyl) -3-hydroxy-5- [2- (N-benzyl-N-methylamino) -ethyl] -8-chloro-2,3-dihydro- 1,5-benzothiazepine-4 (5 H) -one is converted to the (+) - cis-2- (4-benzyloxyphenyl) -3-hydroxy-5- [2- (N -benzyloxycarbonyl-N-methylamino) -ethyl-8,3-chloro-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one of mp. 94-96 ° C.

[a] o ° C ⁰ +126.0 (C = 1.00, chloroform)

(-) - cis-isomer, m.p. 93-95 ⁰ C,

[α] ² , ⁰ -125.6 ° C (C = 1.00, chloroform)

(b) The product of step (a) is reacted in the same manner as in Preparation 1 (e). The resulting free base is converted to the corresponding 2- (4-hydroxybenzoyl) benzoate and recrystallized from aqueous ethanol. The (+) - cis- 2- (4-hydroxyphenyl) -3-hydroxy-5-t2- (N-methylamino) -ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine is obtained. 4 (5H) -one-2- (4-hydroxybenzoyl) benzoate- ³ / 2hydrate from mp 124 to 127 ° C; [α] ² , ⁰ +198.1 ⁰ C (C = 0.120, methanol) (-) - cis-isomer 2- (4-hydroxybenzoyl) -benzoate ³ /2-hydrate, mp 124-127 ° C; [α] ² , ⁰ -197.5 ° C (C = 0.120, methanol)

Preparation 3

(a) (+) - cis-2- (4-benzyloxyphenyl) -3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one and 2- (N, N-) Dimethylamino) -ethyl chloride hydrochloride are reacted in the manner described in Preparation 1 (b). The (+) - cis-2- (4-benzyloxyphenyl) -3-hydroxy-5- [2- (N, N-dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5 is obtained benzothiazepine-4 (5H) -one oxalate from F. 148 to 151 ° C (dec.).

M ² , ⁰ +94.0 ⁰ C (C = 1.00, methanol) (-) - cis isomer oxalate; F. 149 to 152 ⁰ C (dec.) [A] ^{2 0 0} -94.2 C (C = 1.00, methanol)

(b) A mixture of the product obtained in the step (a) as the free base, acetic anhydride and pyridine is heated and stirred. After completion of the reaction, the solvent is distilled off and the residue is converted into the oxalate, which is recrystallized from a mixture of methanol and diethyl ether. The (+) - cis-2- (4-benzyloxyphenyl) -3-acetoxy-5- [2- (N, N-dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5 is obtained -benzothiazepin-4 (5H) -one V2 oxalate, melting 168-172 ⁰ C (dec.). [α] ² , ⁰ +78.4 ⁰ C (C = 1.00, methanol)

(-) - cis-isomer V2 oxalate; F. 168-171 ⁰ C (dec.) [All ⁰ -78.8 ° C (C = 1.00, methanol)

(c) The product obtained in step (b) is dissolved as the free base in acetic acid and treated with cooling and stirring with a 25% solution of hydrogen bromide in acetic acid. After completion of the reaction, the solvent is distilled off. The residue is washed with diethyl ether and neutralized with concentrated aqueous ammonia solution. The resulting free base is extracted with chloroform. The chloroform extract is washed with water, dried and evaporated. The residue is converted into the oxalate and recrystallized from ethanol. The (+) - cis-2- (4-hydroxyphenyl) -3-acetoxy-5- [2- (N, N-dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5 is obtained benzothiazepine-4 (5H) -one oxalate · H ₂ O, mp 142-149X; [a] l ° + 79.2 ° C (C = 0.50, methanol)

(-) - cis-isomer oxalate · H ₂ O, mp 143-149 ⁰ C; [a] g ° C -78.3 ⁰ (C = 0.50, methanol) Preparations 4 to 6

The corresponding starting compounds are synthesized in the same manner as in Preparation 3 (c) to those shown in Table V below

reacted compounds listed.

Table V

O- CH

(IV)

prep

 No.

Connection (H)

X ²

optical activity

properties

2- (4-hydroxybenzoyl) benzoate (recrystallized from a mixture of acetone and diisopropyl ether), mp 165-17O ⁰ C (dec.); [α] ² , ⁰ +79.8 ⁰ C (C = 1.00, methanol)

-H

XH ₃

cis - (-)

2- (4-hydroxybenzoyl) benzoate

(recrystallized from a mixture

of acetone and diisopropyl ether),

F.166-170 ° C (dec.);

[α] ² , ⁰ -80.1 X (C = 1.00, methanol)

Prep. Compound (I II) X ² optical properties No. ^RJ activity cis - (+) Oxalate (recrystallized from a mixture of ethanol and diethyl ether), mp 130-135 ⁰ C (dec.); [α] ² , ⁰ +97.6 ⁰ C (C = 0.50, methanol)

-H

cis - (-)

Oxalate (recrystallized from a mixture of ethanol and diethyl ether),

F. 130-135 ⁰ C (Zers.); Mg ⁰ -97.5 ° C (C = 0.50, methanol)

V2 oxalate H ₂ O

(recrystallized from a mixture of acetone and diethyl ether).

F: iO3-113 ° C (dec.); [a] ² , ⁰ +78.4 ⁰ C (C = 1.00, methanol)

-COCH ₃

-CH ₂ C ₆ H ₅

cis - (-)

V ₂ oxalate -H ₂ O

(recrystallized from a mixture of acetone and diethyl ether), mp. 103-114 ° C (dec.); [α] ^{2 0 0} -78.8 C (C = 1.00, methanol)

Claims (1)

1. A process for the preparation of 1,5-behzothiazepine derivatives of the general formula \\ W I 0 CH ₃ CH ₂ CH ₂ N <^ in which R ^{1 is} a lower alkyl radical, R ^{2 is} a hydrogen atom or a lower alkanoyl radical and X ^{1 is} a hydrogen atom or a lower alkyl radical, and salts thereof, characterized in that i) a compound of the general formula