FI91965C - Method for alkylation of the phenolic hydroxy group of a 1,5-benzothiazepine derivative without racemization of the starting material - Google Patents

Description

91965

The present invention relates to a process for the preparation of compounds of the present invention. 'N - (I) I 0 CHa CII z CII z N ς X' 1. In R 3, R is a lower alkyl group, R is a hydrogen atom or a lower alkanoyl group, and X 1 is a hydrogen atom or a lower alkyl group, or a salt thereof.

U.S. Patent 3,562,257 discloses various benzothiazepine derivatives, including 7-chloro-1,5-benzothiazepine derivatives such as 2- (4-methoxyphenyl) -3-hydroxy (or acetoxy) -5- (2- (dimethylamino) ethyl) - 7-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one. It is also stated in this U.S. patent that these benzothiazepine derivatives have antidepressant, tranquilizing and / or cardiovascular dilating activity.

Compared to these known compounds, the present compound (I) of the present invention wherein X 1 is lower. alkyl group, has a stronger hypotensive and cerebral vasodilatory activity, and is more useful in the treatment, alleviation and / or prophylaxis of the following diseases: Hypertension; brain diseases such as cerebral vasoconstriction or cerebral infarction and cerebral infarction; angina pectoris, arrhythmia or myocardial infarction.

* · · 91965 2

The compound (I) of this invention in which X 1 is a hydrogen atom also has antiplatelet activity and is useful in the treatment, alleviation and / or prophylaxis of the following diseases: Thrombotic diseases such as cerebral thrombosis (a myocardial infarction), transient cerebral ischemia thrombosis (myocardial infarction), pulmonary embolism, peripheral vascular embolism, thromboangitis, and / or other thromboembolism (e.g., post-myocardial thromboembolism).

According to the present invention, compound (I) may be prepared by the step or steps of: i) alkylating a compound of formula (II)

C I 0II

yrsV

;; - (\ (ii) I o cn 3 c ii? c n z n

Xx2 3] in which R is a hydrogen atom or a lower alkanoyl group and 2 X is a hydrogen atom, a lower alkyl group or a protecting group, 2 ii) when X is a protecting group, removing this protecting group, iii) when RJ is a lower alkanoyl group, optionally removing this lower alkanoyl group, (iv) if necessary, the product is further converted into salt.

A variety of protecting groups commonly used to protect the amino group can be used in the above 2 reactions as protecting group X. Examples of such protecting groups include unsubstituted or substituted benzyloxycarbonyl groups such as benzyloxycarbonyl or p-methoxybenzyloxycarbonyl groups; unsubstituted or substituted lower alkoxycarbonyl groups such as tert-91965 butoxycarbonyl, β, β, β-trichloroethoxycarbonyl or iodoethoxycarbonyl groups; and unsubstituted or substituted phenyl-lower alkyl groups such as benzyl, p-methoxybenzyl or 3,4-dimethoxybenzyl groups.

The alkylation according to this invention can be carried out by treating the compound (II) with a lower alkylating agent. Alkylating agents include, for example, a lower alkanol, a lower alkyl sulfate such as dimethyl sulfate, a lower alkyl ester of an alkyl or aryl sulfonate such as methyl tosylate, methyl methanesulfonate and dimethyl 2-oxo-1,3-propane disulfonate, a lower alkyl halide, a lower alkyl halide such as methyl halide such as methyl such as trimethylphenylammonium hydroxide, a lower alkylsulfonium or sulfoxonium compound such as trimethylsulfonium hydroxide, trimethylsulfonium iodide, a lower alkylsilonium compound such as trimethylsilonium hydroxide and a diazo lower alkane such as diazomane.

When a lower alkanol is used as the alkylating agent, the reaction is best carried out in the presence of a dehydrating agent. For this purpose, conventional dehydrating agents, such as dicyclohexylcarbodiimide or a mixture of triphenylphosphine and diazenedicarboxylic acid diethyl ester, can be used. The reaction is best carried out at a temperature of 0 to 40 ° C.

When the above-mentioned lower alkyl sulfate, lower alkyl ester of alkyl or aryl sulfonate or lower alkyl halide is used as the alkylating agent, the reaction is best carried out in the presence of a base. Examples of such bases include inorganic bases such as alkali metal oxide, alkali metal carbonate, alkali metal bicarbonate, alkali metal hydride or alkali metal alkoxide, and organic bases such as ethyl di-. 91965 isopropylamine. The reaction is best carried out at a lamp temperature between 0 ° C and a reflux temperature, especially at 10 to 40 ° C in an inert solvent (e.g. acetone, acetonitrile, methanol, benzene, dioxane, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide). It is further recommended to carry out the reaction in the presence of a phase transfer catalyst such as tetrabutylammonium fluoride.

On the other hand, if the alkylating agent is a lower alkyl quaternary ammonium compound, a lower alkylsulfonium or sulfoxonium compound or a lower alkyl selonium compound, the reaction is best carried out at a temperature between 10 ° C and reflux, especially at 50-100 ° C in an inert solvent or solvent. Suitable solvents include toluene, dioxane, methanol, dimethylformamide and dimethyl sulfoxide.

When a diazo lower alkane is used as the alkylating agent, the reaction is best carried out at a temperature of 0 to 40 ° C, especially 20 to 30 ° C in an inert solvent. Suitable solvents include dioxane, tetrahydrofuran, methanol 3 and mixtures thereof. When the R of the starting compound (II) is a lower alkanoyl group, the reaction is best carried out in the presence of fluoroboric acid or silica gel.

In carrying out the above alkylation reaction, it is particularly preferable to use a lower alkyl sulfate, a lower alkyl sulfonate or a lower alkyl halide as the alkylating agent when X is a hydrogen atom of the starting compound (II) and R is a lower alkanoyl group; or alternatively the alkylating agent used is a lower alkyl quaternary ammonium compound, a lower alkylsulfonium or sulfoxonium compound, a lower alkylcellonium compound or a diazo lower alkane when both X and R of the starting compound 2 (II) are hydrogen atoms.

5 91965 2 ......

When the product X thus obtained is a protecting group, this protecting group can be removed in the usual manner. For example, when the protecting group is unsubstituted or substituted benzyloxycarbonyl or unsubstituted lower alkoxycarbonyl, this group can be easily removed by treatment with an acid such as hydrogen bromide, hydrogen chloride or trifluoroacetic acid in a solvent. When the protecting group is substituted lower alkoxycarbonyl, this group can be removed by treatment with zinc in a solvent. On the other hand, if the protecting group is unsubstituted or substituted phenyl lower alkyl, this group can be removed by first substituting it with a protecting group (for example, a benzyloxycarbonyl group) which can be easily removed with an acid, and then treating the latter group as mentioned above. Substitution of unsubstituted or substituted phenyl lower alkyl with a benzyloxycarbonyl group is best accomplished by treating the product (i.e., a compound whose imino group is protected with an unsubstituted or substituted phenyl at the lower alkyl group) with a benzyl oxycarbonyl halide such as benzyloxycarbonyl halide such as

3

When R is a lower alkanoyl group, a protecting group and the like. the lower alkanoyl group may be removed simultaneously, or the protecting group may be removed without removing that lower alkanoyl group. These reactions can be controlled by varying the reaction conditions, such as the number of reaction components, the reaction time and / or the reaction solvent used.

: The compound (I) of the present invention thus obtained can, if desired, be converted into its acid addition salts by treating it with an acid. Examples of acid addition salts include inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate or phosphate, organic acid addition salts, such as oxalate, maleate, fumarate tax methanesulfonate, and the like.

Since the above-mentioned reactions of the invention can be carried out without racemization, the optically active form of the compound (I) can be easily obtained by using the optically active isomer of the compound (II) as a starting material.

The starting compound (II) is prepared, for example, by a step or steps of reacting 3- (4-benzyloxyphenyl) glycidic acid methyl ester with 5-chloro-2-aminothiophenol to give 2- (4-benzyloxyphenyl) -3-hydroxy-8- chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one or a salt thereof, condensing the product with a compound of formula (III) () Λ 2 wherein Y is a halogen atom and X is as defined above, or a salt thereof to give a compound of formula (IV) CI JT 0 -CH 2 -N-N (IV) 10 CH a C II; C II: v ς

; J

2 wherein X is as defined above, the benzyl group of compound (IV) is removed and, if necessary, the hydroxy group of the product thus obtained, which is in the 3-position of the benzo-91965 7 thiazepine ring, is converted to a lower alkanoyloxy group before or after removal of said benzyl group.

Since the compound (I) and the starting compound (II) can exist as two diastereoisomers (e.g., cis and trans) or as four optical isomers (e.g., (+) - cis, (-) - cis, (+) - trans and (-) - trans) due to the two asymmetric carbon atoms in the compounds, all of these isomers or mixtures thereof are included within the scope of the invention. However, of these isomers, the cis isomer of compound (I) is considered to be the preferred one in medical use.

Example 1 690 mg of (+) - cis-2- (4-hydroxyphenyl) -3-hydroxy-5- [2- (N, N-dimethylamino) ethyl) -8-chloro-2,3-dihydro-1,5 - benzothiazepin-4 (5H) -one is dissolved in 20 ml of tetrahydrofuran. 78 mg of sodium hydride (60%, oil) are added to the paste at room temperature and stirred for 30 minutes at the same temperature. A solution of 245 mg of dimethyl sulfate in 10 ml of dimethylformamide is added and the mixture is stirred for one hour at room temperature.

The reaction mixture is poured into water and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove the solvent. The residue is recrystallized from a mixture of ethyl acetate and n-hexane. 509 mg of (+) - cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (N, N-dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5-5 benzothiazepin-4 (5H) -one.

M.p .: 122-124 ° C (dec.) (A) 20 + 144.6 ° (C = 0.85, methanol)

D

Examples 2-4

The following starting compounds are treated as described in Example 1 to give the compounds given in Table 1.

8 91 965

Table 1 '' i 0H C1 ^ / ° R3 N ^ iC «Z ^ oR 'I' oc II3 -> I XX0 CII 3 CHjCHzN'CII2CII2; and X2 = -CH3, R3 = R2) -, 1-j -: - K> · -

Eg Compound (I) Optical Properties 2 No. R activity 2 -H cis - (-) Sp. 121-123 ° (dec.) (A) 20-142.7 ° (C = 1.04, methanol) 3 -COCH 2 cis - (+) Maleate (recrystallized from ethanol-ether)

Sp. 158-160 ° (a) 20 + 75.4 ° (C = 1.0, ____-methanol) 4 -COCH 2 cis - (-) Hydrochloride

Sp. 128-132 ° (dec.) (Α) 20 -93.3 ° (C = 0.872, D ethanol): 1 - ^ - 1-9 91 965

Example 5 210 mg of (+) - cis-2- (4-hydroxyphenyl) -3-acetoxy-5- (2- (N-methylamino) ethyl) -8-chloro-2,3-dihydro-1,5 -Benzothiazetpin-4 (5H) -one, 250 mg of potassium carbonate and 140 mg of dimethyl sulfate are dissolved in 5 ml of methanol and the solution is stirred in a room 1 arn patient overnight. The insoluble matter is filtered off and the filtrate is evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; benzene: ethyl acetate = 4: 1), converted into maleate and recrystallized from a mixture of ethanol and ether. 212 mg of (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (N, N-dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5 are obtained. -benzothiazepin-4 (5H) -one maleate.

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

Example 6

Solution of 1.8 g of (+) - cis-2- (4-hydroxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5 -Benzothiazepin-4 (5H) -one in 20 ml of tetrahydrofuran was added to a suspension of 168 mg of sodium hydride (60% dispersion in mineral oil) in 20 ml of tetrahydrofuran at 26-27 ° C. A solution of 485 mg of methyl methanesulfonate in 3 ml of tetrahydrofuran was added to the mixture, followed by dropwise addition of 40 ml of dimethylformamide to the solution, which then began to foam. After stirring at room temperature for 30 minutes, the reaction mixture was poured into ice water. The solution was extracted with ethyl acetate, and the extract was washed with water, dried and evaporated to remove the solution. The residue was purified by silica gel column chromatography (solvent; chloroform: methanol = 50: 1) to give 870 mg of (+) - cis-2- (4-methoxyphenyl) -2-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one as an oil. The product was converted to the maleate, recrystallized from a mixture of ethanol and ether to give 1.05 g of (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2-dimethylamino) ethyl] -8-chloro -2,3-dihydro-l, 5-benzothiazepin-4 (5H) -onimaleaattia. Sp. 158-160oC.

91965 10

Example 7

A solution of 1.05 g of diazomethane in 65 ml of methylene chloride was added to a solution of 220 mg of (+) - cis-2- (4-hydroxy-phenyl) -3-acetoxy-5- [2- ( dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one in 10 ml of methanol, and the mixture was stirred at room temperature overnight. A few drops of ethyl acetate were added to the reaction mixture and the mixture was condensed. The residue was converted into a maleate, and recrystallized from a mixture of ethanol and ether to give 214 mg of (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro. -2,3-dihydro-1,5-benzothiazepin-4 (5H) -onimaleaattia. Yield 75%,

Sp. 158-160oC.

Example 8

A mixture of 2.2 g of (+) - cis-2- (4-hydroxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5 -benzothiazepin-4 (5H) -one, 160 mg of methanol, 1.03 g of dicyclohexylcarbodiimide and 5 ml of dimethylformamide were stirred at room temperature for 2 weeks. Water was added to the reaction mixtures, and the solution was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to remove the solvent. The residue was purified by silica gel column chromatography (solvent; chloroform: methanol = 50: 1). (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepin-4 ( The 5H) -one obtained above was converted to the maleate, recrystallized from a mixture of ethanol and ether to give 0.57 g of (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [ 2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -onimaleaattia.

Sp. 158 - 160oc.

[Preparation of starting compounds] Preparation Example 1 • (1) A mixture of (±) -trans-3- (4-benzyloxy-phenyl) -glycidic acid methyl ester and 5-chloro-2-aminothiophenol is heated at 160 ° C for 16 hours. To the reaction solution is added (S) -N- (2-naphthalenesulfonyl-1i) pyrrolidine-2-carbonyl chloride and pyridine, and the solution is stirred. After the reaction, the product is separated by column chromatography on silica gel 11å (solvent; benzene: ethyl acetate = 4: 1) to its (+) isomer and (-) isomer. After separation i: "91965 Potassium carbonate, water and methanol are added to each isomer and the mixture is stirred at room temperature overnight. Recrystallization of each product from ethyl acetate gives cis-2- (4-benzyloxyphenyl) -3-hydroxy-8-chloro-2, The corresponding (+) and (-) isomers of 3-dihydro-1,5-benzothiazepin-4 (5H) -one-1,5-ethyl acetate.

(+) - isomer 1/5 ethyl acetate: (α) D -74.2 ° (C = 1.00, dimethylformamide) (-) - isomer 1/5 ethyl acetate: (α-75.0 ° (C = 1 , 00, dimethylformamide) (2) (+) - cis-2- (4-benzyloxyphenyl) -3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one, 2 A mixture of - (N-benzyl-N-methylamino) ethyl chloride hydrochloride, potassium carbonate, acetone, ethyl acetate and water is refluxed, the insoluble matter is filtered off and the solvent is removed by evaporation. The residue is decanted from oxalate and recrystallized from ) -cis-2- (4-benzyloxyphenyl) -3-hydroxy-5- / 2- (n-benzyl-n-methylamino) ethyl / -8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one oxalate.

Sp. 108-115 ° C

(a) + 85.8 ° (c = 1.00, methanol) (3) The product obtained in (2) (free base) is dissolved in pyridine, a solution of acetyl chloride in dichloromethane is added and the mixture is stirred. After the reaction: the solvent is removed from the mixture by evaporation and the portion is dissolved in ethyl acetate. The solution is washed successively with water, 5% aqueous sodium bicarbonate and water. The solution is then dried and the solvent is removed by evaporation. The residue is converted into oxalate 91965 and recrystallized from a mixture of methanol and ether. (+) - Cis-2- (4-benzyloxyphenyl) -3-acetoxy-5- [2- (N-benzyl-N-methylamino) ethyl] -chloro-2,3-dihydro-1,5-benzothiazepine is obtained. 4 (5H) -one oxalate.

Sp. 108-115 ° C

(a) mp + 85.8 ° (c = 1.00, methanol)

Sp. 173-175 ° C

(α) λ max + 78.4 ° (C = 1.00, methanol)

(-) - cis isomer oxalate Sp. 172-175 ° C

(4) The product obtained in paragraph (3) (free base) is dissolved in toluene and a solution of benzyloxycarbonyl chloride in toluene is added dropwise. The mixture is stirred with heating. After the reaction, the solvent is distilled off. The residue is purified by column chromatography on silica gel (solvent; chloroform: ethyl acetate = 95: 5) and recrystallized from a mixture of ethyl acetate and n-hexane. (+) - Cis-2- (4-benzyloxyphenyl) -3-acetoxy-5- [2- (N-benzyloxycarbonyl-N-methylamino) ethyl] -8-chloro-2,3-dihydro-1,5 benzodiazepin-4 (5H) -one.

(a + 79.0 ° (C = 1.00, chloroform) (-) - isomer (a) ^ -79.2 ° (C = 1.00, chloroform) (5) The product obtained in paragraph (4) is dissolved 25% Hydrogen bromide-acetic acid is added to the ethyl acetate and the solution under cooling, after which the solvent is distilled off * The residue is washed with ether, neutralized with stable aqueous ammonia to give the corresponding free base and extracted with chloroform, the extract is washed with water and dried. The residue is purified by column chromatography on silica gel 13 91565 and converted into the oxalate to give (+) - cis-2- (4-hydroxyphenyl) -3-acetoxy-5- [2- (N-methylamino) ethyl] -8-chloro- 2,3-dihydro-l, 5-benzothiazepin-4 (5H) -one oxalate.

Sp. 186-189 ° C

(α) E + + 81.2 ° (C = 0.50, methanol)

The (-) - cis-isomer Sp. 187-189 ° C

(α) ^ -81.6 ° (C = 0.50, methanol)

Preparation Example 2 (1) (+) - cis-2- (4-benzyloxyphenyl) -3-hydroxy-5- [2- (N-benzyl-N-methylamino) ethyl] -8-chloro-2,3-dihydro- 1,5-Benzothiazepin-4 (5H) -one is treated as described in Example 1- (4) to give (+) - cis-2- (4-benzyloxyphenyl) -3-hydroxy-5- [2- (N- bentsyylioksikarbo-phenyl-n-methylamino) ethyl / -8-chloro-2,3-dihydro-l, 5-benzothiazepin-4 (5H) -one.

mp. 9 4 -9 6 ° C

(α) ^ ° + 126.0 ° (C = 1.00, chloroform)

(-) - cis-isomer Sp. 93-95 ° C

(a) ^ ° -125.6 ° (C = 1.00, chloroform) (2) The product obtained in paragraph (1) is treated as described in Preparation Example 1 to (5). The resulting free base is converted to the corresponding 2- (4-hydroxybenzoyl) benzoate and recrystallized from aqueous ethanol to give (+) - cis-2- (4-hydroxyphenyl) -3-hydroxy-5- [2- (N-methylamino). ) ethyl / -8-chloro-2,3-dihydro-5-benzo-thiazepin-4 (5H) -one-2- (4-hydroxybenzyl) benzoate 3/2-hydrate.

Sp. 124-127 ° C

14 91965 (alp + + 198.1 ° (c = 0.120, methanol))

(-) - cis-isomer 2- (4-hydroxy-benzoyl) benzoate 3/2-hydrate M.p. 124-127 ° C

(a) mp -197.5 ° (C = 0.120, methanol)

Preparation Example 3 (1) (+) - cis-2- (4-benzyloxyphenyl) -3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one and 2- (N , N-dimethylamino) ethyl chloride hydrochloride is treated as described in Preparation Example 1- (2) to give (+) - cis-2- (4-benzyloxyphenyl) -3-hydroxy-5- [2- (N, N-dimethylamino) ethyl / -8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one oxalate.

Sp. 148-151 ° C (dec.) (A) mp + 94.0 ° (C = 1.00, methanol) (-) - cis-isomer oxalate M.p. 149-152 ° C (dec.) (A) ^ ° -94.2 ° (C = 1.00, methanol) (2) A mixture of the product obtained in paragraph (1) (free base), acetic anhydride and pyridine is stirred under heating. .

After the reaction, the solvent is distilled off and the residue is converted into oxalate and recrystallized from a mixture of methanol and ether. (+) - cis-2- (4-benzyloxyphenyl) -3-acetoxy-5- [2- (N, N-dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine is obtained. 4 (5H) -one-1/2-oxalate.

Sp. 168-172 ° C (dec.) (A) mp + 78.4 ° (C = 1 # 00, methanol) (-) - cis-isomer 1/2 oxalate 15 91965

Sp. 168-171 ° C (dec.) (Α) -78.8 ° (C = 1.00, methanol)

D

(3) The product obtained in (2) (free base) is dissolved in acetic acid and added to the solution under cooling with 25% hydrobromic acid and mixed. After the reaction, the solvent is distilled off. The portion is washed with ether, neutralized with concentrated ammonia to give the free base. This is extracted with chloroform and the extract is washed with water, dried and evaporated to remove the solvent. The residue is converted into oxalate and recrystallized from ethanol. (+) - cis-2- (4-hydroxyphenyl) -3-acetoxy-5- [2- (N, N-dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine is obtained. 4 (5H) -one oksalaaati-1-hydrate.

Sp. 142-149 ° C

(+) + 79.2 ° C (C = 0.50, methanol)

(-) - cis-isomer oxalate-1-hydrate M.p. 143-149 ° C

(a) mp -78.3 ° (C = 0.50, methanol)

Illustrative Examples 4-6

The corresponding starting compounds are treated as described in Preparation Example 3 to (3) to give the compounds given in Table 5.

1 6 91965

Table 5

Cl ° 'C 11 z ~ ^ V) VV] fS Vor 3 n - <\ I 0 C li,

C II * C 11 z N

(IV) Xz

Cl 2 O-OH

xjVvrs y ° R3 -> ^ N - <\ I 0 CII 3 CII 2 CII 2 N ^ (U) xz

Eg Compound (II) Optical Properties 3 2 No. R X activity 2- (4-hydroxybenzoyl) benzoate (crystallized from a mixture of acetone and isopropyl cis - (+) ethenate)

Sp. 165-170 ° C (dec.) (A) mp + 79.8 ° (C = 1.00, 4-H-CH 3 -methanol) -2- (4-hydroxybenzoyl) benzoate (crystallized from acetone and isopropyl: * from a mixture of ether)

Sp. 166-170 ° C (dec.) (A) ^ ° -80.1 ° (C = 1.00f methanol) 17 91 965

Oxalate (recrystallized from a mixture of ethanol and cis - (+) ether)

Sp. 13 0-13 5 ° C (dec.) (A) p ° + 97.6 ° (0 = 0.50, 5 -H-CH 2 Cl 2 -Hr- methanol) 2 b 5 ------ -

Oxalate (recrystallized from a mixture of ethanol and ether)

Sp. 13 0-13 5 ° C (dec.) (A) p ° -97.5 ° (0 = 0.50, methanol) 1/2 oxalate 1 hydrate (recrystallized from a mixture of cis - (+) acetone and ether)

Sp. 103-113 ° C (dec.) (A) mp + 78.4 ° (0 = 1.00, _methanol) _ 6 -COCH .. -CH 2 C.Hr 1/2 oxalate 1 hydrate (recrystallized from cis - (-) of a mixture of acetone and ether)

Sp. 10 3 -114 ° C (dec.) (A) p ° -78.8 ° (0 = 1.00, methanol) 91,965 18

In the present invention, the process relates to the alkylation of the hydroxy group of the 2-position phenyl ring of the 1,5-benzothiazepine nucleus.

This implies alkylation of aromatic hydroxy group does not require låsnåoloa emåksisen agent and alkylating agent may be kåyttåå sample at the lower Si-alkyylikvaternååriammoniumyhdistettå and diazo (lower) alkanes, but alkylation may be carried out mybskin alem-by dihydratointiaineen låsnåollessa alkanol, or a lower alkyl sulfate, lower alkyl sulfonate or halide, alempialkyy-emåksen låsnåollessa , selected from the group consisting of alkali metal carbonate, alkali metal bicarbonate, alkali metal hydride, alkali metal alkoxide and ethyl isopropylamine.

In the process according to the application, the carbon atom in the 2-position of the starting compound's 1,5-benzothiazepine nucleus, to which the phenol is substituted, is located next to the sulfur atom of the 1,5-benzothiazepine nucleus, and this allows tautomerism in ring opening and closing.

^ I 0 'Ϊ °, C », CH2CH2N ^ CHiCHjN ^ emås i V r I 0 CH1 / CH3 i / ch2ch2n <CH2CH2N <^ Xri R1 19>' I> 65

For example, when a cis-1,5-benzothiazepine compound having a hydroxyphenyl group in the 2-position used as a starting material was alkylated with dimethyl sulfate in the presence of KOH, a steric inversion was obtained in the 2-position and the trans isomer B was obtained in contrast to the present invention. When NaOH was used, the desired compound was not formed, but the product obtained was a quaternary salt (Comparative Example A).

In the process of the invention, the phenolic hydroxy group is alkylated while maintaining the 2-position of the 1,5-benzothiazepine ring unchanged. The isomerism of the 2-position can thus be influenced by the choice of certain bases.

Comparative Examples H (^ Y0H OMe

C1 H fY

"0.>,” yi.

^ - NMe0 \ I N— NMe 2

Comparative Example A

1.9 g of (+) - cis-β-chloro-2,3-dihydro-5- [2- (dimethylamino) ethyl] -3-hydroxy-2- (4-hydroxyphenyl) -1,5- benzothiazepin-4 (5H) -one was dissolved in 2 mL of DMF, and aqueous NaOH (NaOH 210 mg, H 2 O 5 mL) was added. After stirring, 630 mg of dimethyl sulfate was added over 5 minutes, stirring was continued for 30 minutes at 10 ° C and then for one hour at 60 ° C. By monitoring the reaction solution by thin layer chromatography, it was found that the desired compound was not formed even though the compound used as starting material> 1> 65 20 disappeared in the reaction mixture. The main product was a compound with a low Rf value (quaternary salt). The material was diluted with water and extracted with CHCl 3. The fraction extracted with CHCl3 was very small in quantity, the largest amount of material was in the aqueous fraction. It was also checked by thin layer chromatography that a cavernous salt with a low Rf value was included in the aqueous phase.

Comparative Example B

1.9 g of (+) - cis-8-chloro-2,3-dihydro-5- [2- (dimethylamino) ethyl] -3-hydroxy-2- (4-hydroxyphenyl) -1,5- benzothiazepin-4 (5H) -one was dissolved in 5 mL of DMSO, followed by the addition of 292 mg of comminuted KOH (97%). Stirring was continued for 30 minutes at room temperature to form K salt. To the solution was then added 630 mg of dimethyl sulfate over 5 minutes, and stirring was continued for 1 hour at room temperature and 2 hours at 60 ° C. Examination of the reaction solution by thin layer chromatography showed, as in Comparative Example A, respectively, that the starting material disappeared and most of the product was a low Rf quaternary salt and the reaction solution was treated in the same manner as in Comparative Example A and extracted with 300 mg of CHCl 3. by thin layer chromatography on silica gel for separation and purification to give 70 mg (3.5%) of trans-8-chloro-2,3-dihydro-5- [2- (dimethylamino) ethyl] -3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one and 120 mg (6%) of trans-8-chloro-2,3-dihydro-5- [2- (dimethylamino) ethyl] -3-hydroxy-2- (4-hydroxyphenyl) -1,5-benzothiazepin-4 (5H) -one. The products thus obtained were compounds which were isomerized at the 2-position.

Claims (5)

9. b'65 A process for preparing a cis isomer of a 1,5-benzothiazepine derivative of formula (I) wherein F1 is OR1 C1 IV OR2 (I) wherein R1 is a lower alkyl group, R2 is a hydrogen atom or a lower alkanoyl group, and X1 is a lower alkyl group, or a salt thereof, characterized in that the process comprises the step or steps of: i) alkylating a cis compound of formula (II) Cl 'Y-OR3 (II) I ^ ch3 CHOCH9N2 2 \ X2 wherein R3 is a hydrogen atom or a lower alkanoyl group and X 2 is a hydrogen atom or a lower alkyl group; alkali metal bicarbonate, alkali metal hydride, alkali metal alkoxide and ethyl isopropylamine, ii) when R 3 is a lower alkanoyl group, optionally removing this lower alkanoyl group, and iii) further converting the product to a salt, if necessary. Process according to Claim 1, characterized in that the alkylation is carried out by treatment with a lower alkanol at 0 to 40 ° C in the presence of a dehydrating agent. A process according to claim 1, characterized in that the alkylation is carried out by treatment with a lower alkyl sulphate, a lower alkyl sulphonate or a lower alkyl halide at a temperature between OOC and refluxyl alcohalide as an alkali metal alkali, an alkali metal oxide, an alkali metal oxide, an alkali metal carbide solvent. Process according to Claim 1, characterized in that the alkylation is carried out by treating the lower alkyl with a quaternary ammonium compound, a lower alkylsulfonium or sulfoxonium compound or a lower alkylcellonium compound at a temperature between 10 ° C and reflux. Process according to Claim 1, characterized in that the alkylation is carried out by treatment with a diazoalemalkane at 0 to 40 ° C, in particular at 20 to 30 ° C in an inert solvent. i. 23 91965