FI77240C - FRAMSTAELLNINGSFOERFARANDE AV 1,5-BENZOTHIAZEPINDERIVAT. - Google Patents

Description

1,77240 Method for preparing 1,5-benzothiazepine derivatives. -Framställningsförfarande av 1,5-benzothiazepinderivater.

The present invention relates to a process for the preparation of 1,5-benzothiazepine derivatives having excellent coronary vasodilatory and psychoneurotic activities. More specifically, it relates to a process for the preparation of 1,5-benzothiazepine derivatives of the formula I.

NZY ^ 0 ° Cor

^ (I) / H1

V-N

\ r2 where

Ar is phenyl substituted with lower alkoxy, R is lower alkyl, and R 1 is each lower alkyl, and Y is lower alkylene.

In this specification, the term "lower alkoxy" means alkoxy of 1 to 4 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy). "Lower alkyl" means alkyl of 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl). "Lower alkyl" means alkylene of 1 to 4 carbon atoms (e.g., methylene, ethylene, propylene, butylene).

A particularly preferred 1,5-benzothiazepine according to the present invention is a compound of formula (I) wherein Ar is p-methoxyphenyl, R is methyl, Y is ethylene, and R 1 and r 2 each represent methyl. This compound has excellent coronary vasodilatory activity and is particularly useful as a Ca ++ antagonist coronary vasodilator.

U.S. Patent 3,155,649 describes 6- (2-dimethylaminoethyl) -3,4-2,77240 dihydro-2-1,6-benzothiazosin-5 (6H) -ones which are useful as sedatives and are prepared by cyclization of 4- (O) -aminophenylthio) -4-phenylbutyric acid with thionyl chloride followed by alkylation with dimethylaminoethyl chloride.

DE-AS-18 05 714 describes 2- (p-methoxyphenyl) -3-acetoxy-5- (N, N-dimethylaminoethyl) -2,3-dihydro-1,5-benzothiazepine-4- (5H) - which are useful as coronary vasodilators and are prepared by reacting 2-aminothiophenol with ethyl 3- (p-methoxyphenyl) 2,3-epoxypropionate and alkylating 2- (p-methoxyphenyl) -3-hydroxy-2, 3-dihydro-1,5-benzothiazepin-4- (5H) -ones with dimethylaminoethyl halides followed by alkylation. In addition, it is known that optically active 2- (4-chlorophenyl) -3-hydroxy-5- (N, N-dimethylaminoethyl) -7-chloro-2,3-dihydro-1,5-benzothiazepine-4- ( 5H) -one is useful as an anticonvulsant and is prepared by dissolving racemic 3- (2-amino-4-chlorophenylthio) -3- (4-chlorophenyl) -2-hydroxypropionic acid, the optically active isomer thus obtained being subjected to intramolecular ring closure followed by alkylone (JP-A-78-43517). In addition, 2- (p-methoxyphenyl) -3-acetoxy-5- (N, N-dimethylaminoethyl) -2,3-dihydro-1,5-benzothiazepin-4- (5H) -one is prepared by carrying out 3 - (2-Aminophenylthio) -3- (p-methoxyphenyl) -2-hydroxypropionic acid Intramolecular ring closure and acylation of 2- (p-methoxyphenyl) -3-hydroxy-2,3-dihydro-1,5-benzothiazepine 4 (5H) -one at its 3-position followed by alkylation (JP-A-78-18038 and JP-A-71-43785).

A new method has now been found which is industrially and economically useful for the preparation of the above-mentioned benzothiazepine derivatives.

According to the present invention, a compound of formula (I) is prepared by reacting a 1,5-benzothiazepine derivative of formula (II), preferably its alkali metal protecting at the 5-position nitrogen atom, with a compound of formula (III) according to the following Reaction Scheme I.

Reaction Scheme I

With pl

I V-OCOR + Z-Y-N

\ 2 - ^

H O R

(II) (III) 1 2 wherein Ar, R, R, R and Y are as defined above and Z is halogen such as chlorine or bromine.

Condensation reaction, i.e. The N-alkylation in this Reaction Scheme I, can usually be performed in an aprotic polar solvent, preferably in the presence of silica gel and / or alumina. Compound (II) is best reacted with compound (III) after being converted to its alkali metal salt at the 5-position nitrogen atom by treating compound (II) with 1 to 1.5 moles of alkali metal hydride (e.g., sodium hydride) per mole of compound (II). . The alkali metal salt of the compound (II) can be formed in the reaction system, i. the reaction is carried out by dissolving compound (II) in an aprotic polar solvent, adding silica gel and / or alumina, adding alkali metal hydride thereto (whereby compound (II) is converted into an alkali metal salt), and then adding compound (III), whereby compound (III) can be added to the reaction system before compound (II) is converted to its alkali metal salt. Compound (III) is used in the reaction in 1 to 3 moles per mole of compound (II). The reaction is usually carried out at a temperature of 5 to 60 ° C, preferably 15 to 40 ° C, which temperature may be varied depending on the nature of the solvent and the compound (III), for about 1 to 24 hours, preferably 3 to 10 hours.

The silica gel and alumina used in the previous reaction may be any commercially available products, but are best used after dehydration by calcination. The amount of silica gel and alumina is not critical, but is usually between 0.01 and 2 parts by weight per part by weight of the compound. The particle size of the silica gel and 4,77240 alumina is also not critical, and any product useful in dry chromatography can be used.

Aprotic polar solvents include, for example, dimethyl sulfoxide, sulfolane, N, N-dimethylformamide, N-N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone, hexamethyl phosphorus triamide, or the like. Of these, dimethyl sulfoxide is considered particularly good.

The compound (I) thus prepared can be isolated from the reaction mixture by conventional methods, e.g., neutralizing the reaction mixture, removing residual reagents (e.g., silica gel, alumina, etc.) by filtration, adding a non-polar solvent to the filtrate, and crystallizing the solvent after possible washing and drying. According to this method, the desired compound (I) can be obtained in good yield (e.g. 70-80%) and in high purity.

The 1,5-benzothiazepine derivative of formula (II) used as a starting material is best prepared by treating 2-hydroxy-3- (2'-aminophenylthio) -3-phenylpropionic acid of formula (IV) with an acylating agent as shown in the following Reaction Scheme II:

Reaction Scheme II

Ar r Ar '-s Γ ιΓ \ base | "Γ \ acylating agent WU2 λ-0Η —- ^ ilNH Voh - c ° OH NH2 cooh base (IV) (IV ·,

Γ Ar Ί U J

C / Ar | V- OCOR. . . . .. \

/ acid anhydride j | ) -0C0R

^ COOH.base ^ - /

B

"(V) J (II) 5 77240 wherein Ar and R are as defined above.

Compound (IV) is first converted into a salt (IV) of a base such as a pyridine compound, a tertiary amine, an alkali metal or an alkaline earth metal and then reacted with an acylating agent in a suitable solvent.

Bases used are, for example, pyridine compounds (e.g. pyridine, α-picoline, β-picoline, γ-picoline, halogen-substituted pyridine, quinoline, isoquinoline), tertiary amines (e.g. trimethylamine, triethylamine), alkali metal (lithium, sodium, potassium ) carbonates, bicarbonates or salts of an organic acid, (eg acetate) carbonates of alkaline earth metals (eg magnesium), bicarbonates or salts of an organic acid (eg acetate), of which pyridine and lithium compounds are considered to be particularly good. The base is usually used in an amount of 0.2 to 3 equivalents, preferably 0.5 to 2 equivalents in the case of alkali metal or alkaline earth metal compounds, and one or more equivalents in the case of pyridine compounds and tertiary amines, based on compound (IV). .

Acylating agents include, for example, an anhydride compound of a lower alkanoic acid having 2 to 4 carbon atoms (e.g., acetic anhydride, propionic anhydride, butyric anhydride) and a halogen compound of a lower alkali acid (e.g., acetyl chloride, acetyl bromide), propyl bromide, propyl bromide. Of these, acylating agents are used in an equivalent amount or more relative to compound (IV) or (IV).

The solvent is not limited unless it adversely affects the reaction. Solvents include, for example, benzene, chloroform, ethyl acetate, N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone or the like. When pyridine compounds or tertiary amines are used as the base, they can also be used as a solvent.

The reaction of Reaction Scheme II proceeds differently depending on the nature and amount of the acylating agent. When 2 equivalents or more, usually 2-2.5 equivalents, of lower alkanoic anhydride are used relative to compound (IV) or (IV), the desired compound (II) is obtained directly from compound (IV), i. Acylation and cyclization of the 2-position hydroxy group occur as a single operation. In this method, the process is carried out by dissolving the compound (IV) in a Solvent, adding a base (thereby converting the compound (IV) to a salt of the base (IV) by adding two equivalents or more of a lower alkanoic anhydride, usually 2-2.5 equivalents of the compound (IV)). ) or (IV) and then reacting the mixture at a temperature of 0-50 ° C, preferably 15-35 ° C, for a few hours to several hours, usually 2-3 hours In this method, compound (IV) may first be acylated with one equivalent of anhydride, to form an intermediate of formula (IV) and intermediate (IV) can be cyclized in the presence of the remaining acid anhydride, however, this acylation and cyclization occur approximately simultaneously for a short period of time such as 2-3 hours to give the desired compound (II) in good yield, e.g. With a yield of 70% or more.

When the lower alkanoic acid anhydride is used as the acylating agent less than two equivalents (e.g. 1-1.5 equivalents), the reaction takes place at least partially incomplete, i. at least some of the intermediates (IV) are not cyclized and the reaction product obtained is a mixture of intermediate (V) and compound (II). In addition, when 1 to 1.5 equivalents of the lower alkanoic acid halide is used as the acylating agent, only intermediate (V) is obtained. Intermediate (V) can be easily cyclized to the desired compound (II) by treatment with 1-1.5 equivalents of acid anhydride.

Alternatively, compound (II) can be prepared by acylation of a compound of formula (IV) with an acylating agent followed by deacylation of the resulting intermediate (VII) with an amine according to the following reaction scheme III:

Reaction Scheme III

7 77240

Ar Ar

, χΓ'Ύ-δ <acylating agent y 7Γ \ _OCOB

f lL r -: - ^ Λνη / -

2 Anm I COOH

C °° H COR

(IV) L (VI) J

Ar acylating agent r '/' V'S \ amine, ττλ _ ^ | f) —OCOR _ ^ (11) _ / (VII) J \)

the COR

wherein Ar and R have the same meaning as above.

The acylation of compound (IV) is usually carried out in a suitable solvent such as toluene, xylene, ethylbenzene using lower alkali anhydride 3 equivalents or more at 100-150 ° C, preferably 110-140 ° C, for a few hours to several hours, preferably 2-3 hours within. When an excess of acid anhydride is used, it can also be used as a solvent without using any other solvent. When less than 3 equivalents of anhydride or 2 equivalents or more of a lower alkanoic acid halide are used as the acylating agent, or when the reaction is carried out at a temperature below 100 ° C, intermediate (VI) and optionally a compound in which only the 21-position amino group is acylated without cyclization are formed. Intermediate (VI) can be cyclized to intermediate (VII) by treatment with one or more equivalents of lower alkanoic anhydride at 110-140 ° C.

Intermediate (VII) can be easily de-acylated to compound (II) by treatment with an amine in a suitable solvent, whereby only the acyl group at the 5-position nitrogen atom is selectively de-acylated.

Amines used in said deacylation include e.g. ammonia, hydrazine, aliphatic primary amines (e.g. methylamine, ethylamine, n-butylamine), aromatic primary amines (e.g. aniline, toluidine), aliphatic secondary amines (e.g. dimethylamine). , di-n-propylamine, di-n-butylamine), cyclic amines (e.g. morpholine, pyrrole, imidazole) or the like. Of these, aliphatic secondary amines such as dimethylamine or diethylamine are preferred. These amines are used in equal molar amounts or in excess compared to compound (VII).

There is no restriction on the solvent used in the de-acylation unless it adversely affects the de-acylation reaction. These solvents include, for example, chloroform, benzene, toluene, xylene, N, N-dimethylformamide and the like.

According to this de-acylation reaction, intermediate (VII) can be quantitatively converted to the desired compound (II).

Compound (II) obtained in the above Reaction Schemes II or III can be used in a condensation reaction with Compound (III) in Reaction Scheme I after being isolated from the reaction mixture or without isolating it. Thus, in a preferred embodiment of the present invention, the reaction of Reaction Scheme II or III and the reaction of Reaction Scheme I are carried out continuously in the same reaction system.

The starting compounds (IV) used in the above Reaction Scheme II are also known (cf. Japanese Patent Publication No. 9383/1970) or can be prepared by the method disclosed in this publication. Compound (IV) can thus be prepared by reacting 2-aminothiophenol (IX) and a glycidic acid ester of formula (X) according to the following reaction scheme IV:

Reaction Scheme IV

(/ y-SH + Ar-CH-CH-COOR3 - »nh2 (IX) (X)

Ar φζ - ^ _ οΗ hydrolysisl ^ (lv) H2 coor3 (XI) 9 77240 wherein Ar is as defined above and is an ester residue.

This reaction is usually carried out in a suitable solution such as toluene, xylene and ethylbenzene at a temperature of 100-140 ° C for 5-20 hours, after which the obtained compound (IX) is hydrolysed in the usual manner, e.g. by treatment with an acid e.g. hydrochloric acid, sulfuric acid or alkali ( e.g. sodium hydroxide, potassium hydroxide).

Compound (IV) has two asymmetric carbon atoms in the 2- and 3-positions and thus has two stereoisomers of the threoisomer and the erythro isomer. According to the method of the above reaction scheme (IV), compound (IV) is obtained as a threo isomer. The threo isomer comprises two further optically active isomers, i. the d-isomer and the A-isomer, and is usually obtained as a racemic mixture (dl form). The final compound of formula (I) is also optically active. The d-isomer of Compound (I) is particularly useful because of its stronger pharmacological activities. Although the racemic mixture of compound (I) can be separated into optically active isomers, this separation is best performed with compound (IV) because the desired optically active compound (I) can be obtained from optically active compound (IV) without racemization in the acylation and cyclization steps of Schemes II and III above. and also in the N-alkylation step of Reaction Scheme I.

The inventors have found that the optical resolution of the compound (IV) can be advantageously carried out using an optically active α-phenylethyl amine as follows.

The racemic mixture of compound (IV) is reacted with 1-1.2 equivalents of optically active α-phenylethylamine, i. d-α-phenylethylamine or A-α-phenylethylamine, in a suitable Liu. This gives two diastereomeric salts which can be separated into each optically active salt by taking advantage of their different solubilities in the solvent. When d-α-phenylethylamine is used, the salt of the d-isomer of compound (IV) is isolated as a sparingly soluble salt, and when A-α-phenylethylamine is used, the salt of the A-isomer of compound (IV) is isolated as a sparingly soluble salt.

10 77240

Solvents used in optical separation include, for example, water, a hydrophilic organic solvent (e.g., methanol, ethanol, acetone), a mixture of water and a hydrophilic organic solvent, and a hydrophobic organic solvent (e.g., benzene, ethyl acetate). Of these, water is considered to be particularly good from an economic and industrial point of view because the two diastereomeric salts have a greater difference in solubility in water and, in addition, the sparingly soluble diastereomeric salt has a lower solubility in water.

The sparingly soluble diastereomeric salt thus obtained can be isolated from the reaction mixture by mixing it in the usual manner, e.g. by cooling the reaction mixture, concentrating and then cooling the reaction mixture or by changing the solvent component, i.e. by adding one or more other solvents, followed by separating the precipitated salt by a conventional liquid-solid separation method, e.g. by filtration, decantation or the like. The sparingly soluble diastereomeric salt thus isolated has a high optical purity, usually 95% or more, and when recrystallized from a suitable solvent (e.g., water, aqueous alcohol, ethyl acetate), an optically pure and stereomeric salt is obtained.

The optically active, sparingly soluble diastereomeric salt thus obtained can be easily converted to the corresponding free acid by conventional hydrolysis, e.g. by dissolving the sparingly soluble salt in water under heating, adding a mineral acid (e.g. hydrochloric acid) and separating the precipitated crystals by filtration.

As mentioned above, when using d- or ε-phenylethylamine, the salt of the d- or α-isomer of compound (IV) is isolated as a sparingly soluble salt. After separation of such a sparingly soluble salt, a second soluble isomeric salt thus remains in the mother liquor, i. the 1-isomeric salt of compound (IV) when using d-α-phenylethylamine or the d-isomeric salt of compound (IV) when using α-α-phenylethylamine. The optically active compound (IV) can also be obtained from the mother liquor by adding a mineral acid (e.g. hydrochloric acid) to a mother liquor containing a porous, optically active diastereomeric salt and separating the obtained crystals, whereby the desired optically active compound (IV) can be isolated as the free acid. .

The optically active α-phenylethylamine used in this optical separation can be recovered almost quantitatively from the solution after separating the optically active compound (IV) by filtration in a conventional manner, e.g. by basifying the acidic filtrate obtained after separation of the optically active compound (IV) with alkali. (e.g. sodium hydroxide, potassium hydroxide), extracting the solution with a hydrophobic organic solvent (e.g. benzene, ethyl acetate, ether) and removing the solvent from the extract.

The optically active compound (IV) is best used as a starting material in the acylation and cyclization reaction shown in Reaction Schemes II and III, but the starting compound (IV) can also be used as an optically active diastereomeric salt with optically active α-phenylethylamine without conversion to the free acid.

The present invention is illustrated by the following examples, which are not to be construed as limiting.

Example 1 (1) Preparation of 2-hydroxy-3- (21-aminophenylthio) -3- (4 "-methoxyphenyl) propionic acid (compound (iv) in threo form): 2-aminothiophenol (14.38 g) and methyl 3- (4-Methoxyphenyl) glycidate (20.80 g) is dissolved in toluene (100 ml) and the solution is refluxed for 6 hours under nitrogen gas, and the reaction mixture is concentrated and methanol is added under heating, and after cooling, the precipitated crystals are filtered off and recrystallized. from ethanol to give methyl trio-2-hydroxy-3- (21-aminophenylthio) -3- (4 "-methoxyphenyl) propionate (27.31 g, 82%), m.p. 92-93 ° C.

The product (16.65 g) is added to 5% aqueous sodium hydroxide (80 ml) and the mixture is stirred for 30 minutes at 50 ° C. After cooling to room temperature 772 40, the reaction mixture is neutralized with hydrochloric acid. The precipitated crystals are filtered off, washed with water and dried to give a racemic mixture of the title compound (IV) in the threo form (15.63 g, 98%), m.p. 169-172 ° C.

(2) Optical separation of compound (IV):

The racemic mixture of compound (IV) obtained above in the threo form (6.38 g) and d-α-phenylethylamine (2.58 g) is dissolved with heating in water (100 ml) and the mixture is stirred at room temperature for five hours. The precipitated crystals are filtered off and recrystallized from water (60 ml) to give an optically pure salt of the d-isomer of threo compound (IV) with diphenylethylamine (3.95 g), m.p. 157-158 ° C. = + 376 ° (c = 0.511, ethanol). The previous procedure is repeated except that the solvents shown in Table 1 are used instead of water. The results are shown in Table 1.

Table 1__ Working _Solvent__ Salt Salt / a / £ (eta-

Quality Amount (ml) yield (g) nanol ethanol δ 0.36 + 362.4 ° (c = 0.521) 50% ethanol-H 2 O 10 0.70 + 374.0 ° (c = 0.475) 25% ethanol-H 2 O 20 0.89 + 369.4 ° (c = 0.438) isopropanol 4 0.89 + 333.8 ° (c = 0.535) benzene 0.58 + 333.0 ° (c = 0.565) ethyl acetate 2.5 0.59 + 337.2 ° (c = 0.522)

The product obtained above is dissolved by heating in water (180 ml) and 1N hydrochloric acid (8.9 ml) is added to the solution, and the mixture is cooled. The precipitated crystals are separated by filtration, washed with water and dried to give optically pure d-isomer (IV) of the threo compound (2.68 g, 84%), melting point 138-139 ° C, / α / λ = + 346 ° (c = 0.355, ethanol).

To the mother liquor, which has separated the salt of the d-isomer of compound (IV) and diphenylethylamine, 1N hydrochloric acid (8.5 ml) is added and the precipitated crystals of 13,77240 are separated by filtration, washed with water and dried to give threo-compound (IV). isomer (2.40 g), (α / β3 = 306 ° (c = 0.360, ethanol), optical purity: 88.7% (as the?, isomer of compound (IV)).

(3) Preparation of optically active 2- (4'-methoxyphenyl) -3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one (Compound (II)):

Threo-d-2-hydroxy-3- (2'-aminophenylthio) -3- (4 "-methoxyphenyl) propionic acid / compound (IV) / (3.19 g) is dissolved in N, N-dimethylformamide (5 ml). and pyridine (0.80 ml) is added to the solution, the mixture is stirred at room temperature for 30 minutes, acetic anhydride (2.04 g) is added dropwise to the mixture and the reaction mixture is stirred continuously for 1 hour, ice-water (200 ml) is added and the precipitated crystals are filtered off. , dried to give d-cis compound (II) (2.80 g, 81.6%), m.p. 150-152 ° C. This product is chromatographed on silica gel (developer, benzene: ethyl acetate = 4: 1), to give the title compound as a pure product, melting point 152-153 ° C, / oi / 1'5 = + 39 ° (c = 0.500, CHCl 3).

When the above procedure is repeated, except that a salt of propionic acid compound (IV) with diphenylethylamine (0.50 g) is used instead of the free propionic acid compound (IV), the title d-cis compound (II) (0.27 g, 69 , 3%), [α] 33 = + 38.1 ° (c = 0.486, CHCl 3) (optical purity 97.7%).

(4) Preparation of optically active 2- (4'-methoxyphenyl) -3-acetoxy-5- (N, N-dimethylaminoethyl) -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one / Compound (I ) /:

To dry dimethyl sulfoxide (10 ml) are added the d-cis compound (II) obtained above (1.0 g) and dried silica gel (Wako-gel C-200) (0.50 g) suitable for column chromatography. To the mixture is added 60% by weight of sodium hydride (0.14 g), and the mixture is stirred for 30 minutes at room temperature. To the reaction mixture is added a 50% by weight solution of N, N-dimethylamino-14,77240 ethyl chloride (0.75 g) in ether. After stirring at room temperature for 5 hours, the reaction mixture is neutralized with acetic acid and then the silica gel is filtered off. Benzene is added to the filtrate, and the benzene solution is washed with water and dried. Benzene is distilled off from solution to give an oily substance (1.27 g).

The oily substance thus obtained is dissolved in ether and ether saturated with hydrochloric acid is added thereto. The obtained crystals were separated by filtration and recrystallized from ethanol-isopropanol to give the title compound (I) in d-cis hydrochloride (1.01 g, 76.9%), m.p. 206-207 ° C, m.p. = + 96.6 ° (c = 0.613, methanol).

Example 2 Preparation of 2-acetoxy-3- (2'-aminophenylthio) -3- (4 "-methoxyphenyl) propionic acid (free acid of compound (V)): 2 - (1) 2-hydroxy-3- (21) -aminophenylthio) -3- (4 "-methoxyphenyl) propionic acid / compound (IV) / (3.19 g) is dissolved in pyridine (10 ml) and acetic anhydride (1.02 g) is added dropwise to the solution at 10 ° C. The mixture is stirred at the same temperature for 2 hours. The reaction mixture is added to ice water (200 ml), neutralized with hydrochloric acid and extracted with benzene (50 ml x 2). The benzene extracts are combined, washed with water and dried, and then the benzene is removed by evaporation to give the free acid of compound (V) (3.07 g, 85.0%), m.p. 104-107 ° C. 1 2 - (3). Proceed in the same manner as in Example 2- (1), except that triethylamine (1.50 g) is used instead of pyridine.

- (2). Proceed in the same manner as in Example 2- (1), except that acetyl chloride (0.79 g) is used instead of acetic anhydride and that the reaction mixture is extracted with chloroform (50 ml) instead of benzene. The reaction affords the free acid of compound (V) (3.14 g, 87%).

15 77240

The reaction is carried out to give the free acid of compound (IV) (2.89 g, 80%).

Example 3 Preparation of 2- (4'-methoxyphenyl) -3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one / Compound (II) /: 3- (1). 1-Acetoxy-3- (2'-aminophenylthio) -3- (4 "-methoxyphenyl) propionic acid / free acid of compound (V) / (3.00 g) is dissolved in pyridine (6 ml) and the mixture is stirred at room temperature for 30 minutes. acetic anhydride (0.85 g) was added dropwise, followed by stirring at room temperature for a further 30 minutes, the reaction mixture was added to ice water (100 ml) and the precipitated crystals were filtered off, washed with water and dried to give the title compound (11) (2.42 g, 84 .9%), melting point 198-200 ° C.

3- (2). 2-Hydroxy-3- (21-aminophenylthio) -3- (4 "-methoxyphenyl) propionic acid / compound (IV) / (0.5 g) is dissolved in pyridine (2 ml) and the mixture is stirred at room temperature for 1 hour. acetic anhydride (0.32 g) was added dropwise, followed by stirring at room temperature for 1.5 hours, and the reaction mixture was treated in the same manner as in 3- (1) above to give the title compound (II) (0.48 g, 89%), m.p. 198-200 ° C. When this product is recrystallized from ethanol to give the pure product, melting point 200-202 ° C.

3- (3). The same compound (IV) as in 3 to (2) above (1.00 g) is dissolved in N, N-dimethylformamide (2 ml). Triethylamine (0.32 g) is added to the solution, and the mixture is stirred at room temperature for 30 minutes. Acetic anhydride (0.64 g) is added and then the mixture is stirred for a further 2 hours at room temperature. The reaction mixture is treated in the same manner as in 3- (1) above to give the title compound (II) (0.75 g, 69.8%), m.p. 193-195 ° C.

16 772 4 0 3- (4). The procedure of 3- (3) is repeated except that 1,3-dimethyl-2-imidazolidinone is used as solvent instead of N, Ν-dimethylformamide and pyridine (0.26 g) is used instead of triethylamine. There is thus obtained the title compound (II) (0.09 g, 83.7%), m.p. 198-200 ° C.

3- (5). The same compound (IV) as in 3- (2) above (3.19 g) is dissolved in N, N-dimethylformamide (25 ml). Lithium carbonate (0.37 g) is added to the solution, and the mixture is stirred for one hour at room temperature. A solution of acetic anhydride (2.20 g) in N, N-dimethylformamide (5 ml) is added dropwise, followed by stirring for a further two hours at room temperature. The reaction mixture is added to ice water (800 ml), and the precipitated crystals are filtered off, washed with water and dried to give the title compound (II) (2.81 g, 81.9%), m.p. 196-198 ° C.

3 - (6). The procedure of 3 to (5) above is repeated except that 50% by weight of sodium hydride (0.53 g) is used instead of lithium carbonate to give the title compound (II) (2.13 g, 62.1%), melting point. 192-196 ° C.

3- (7). The same compound (IV) as in 3 to (2) above (0.50 g) is dissolved in α-picoline (2 ml). The mixture is stirred for 30 minutes at room temperature. Acetic anhydride (0.32 g) is added dropwise over one hour and then the mixture is stirred for another hour at room temperature. The reaction mixture is treated in the same manner as in 3 to (1) above to give the title compound (II) (0.38 g, 70.7%), m.p. 198-200 ° C.

3- (8). The same compound (IV) as in 3- (2) above (0.30 g) is dissolved in quinoline (1 ml), and the mixture is stirred at room temperature for 30 minutes. Acetic anhydride (0.192 g) is added dropwise over 30 minutes and then the mixture is stirred for a further two hours at room temperature. The reaction mixture is added to ice water (100 ml) and neutralized with hydrochloric acid. The precipitated crystals are filtered off, washed with water and dried to give the title compound (II) (0 24 g, 74.4%), m.p. 198-200 ° C.

17 7 7240 3- (9). The procedure of 3 to (5) above is repeated, except that the different metal salts shown in Table 2 are used instead of lithium carbonate. The results are shown in Table 2.

Table 2__

Metal Salt__ Compound (II)

Quality Amount yield basic magnesium carbonate 2.91 2.23 g (65.0%) sodium bicarbonate 2.52 2.40 g (70.0%) lithium acetate 1.30 2.50 g (72.9%)

Example 4 Preparation of 2- (4'-methoxyphenyl) -3-propionyloxy-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one / Propionated Compound (II) /: 4- (1). 2-Hydroxy-3- (2'-aminophenylthio) -3- (4 "-methoxyphenyl) propionic acid / compound (IV) / (3.19 g) and pyridine (0.79 g) are dissolved in N, N-dimethylformamide (5 ml) and the solution are stirred for 30 minutes at room temperature, propionic anhydride (2.60 g) is added dropwise, followed by stirring for a further 1.5 hours at room temperature, the reaction mixture is added to ice water (200 ml) and the precipitated crystals are filtered off, washed with water and dried. to give the title propionated compound (II) (3.19 g, 89.4%), mp 155-156 ° C.

4 - (2). The same compound (IV) as in 4 to (1) above (3.19 g) is dissolved in 1,3-dimethyl-2-imidazolidinone (30 ml). Lithium carbonate (0.74 g) is added to the solution, and the mixture is stirred at room temperature for one hour. Propionic anhydride (2.86 g) is added dropwise, followed by stirring for a further two hours at room temperature. The reaction mixture is added to ice water (800 ml), and the precipitated crystals are filtered off, washed with water and dried to give the title propionated compound (II) (3.29 g, 92.2%), m.p. 155-156 ° C.

is 77240

Example 5 Preparation of 2- (4'-methoxyphenyl) -3- (acetoxy-5- (N, N-dimethylaminoethyl) -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one / Compound (I) /: 5- (1) 2- (4'-methoxyphenyl) -3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one / Compound (II) / (1, 0 g) and dry silica gel suitable for column chromatography (obtained by calcining commercially available silica gel (Wako gel C-200) at 300 ° C for 8 hours under nitrogen) (0.5 g) are added to dimethyl sulfoxide (10 ml). Sodium hydride (60% by weight) (0.14 g) is added and the mixture is stirred for 30 minutes at room temperature, a solution of 50% by weight of N, N-dimethylaminoethyl chloride (0.75 g) in ether is added and the mixture is stirred for a further 5 hours at room temperature. It is then neutralized with acetic acid and the silica gel is filtered off, benzene is added to the filtrate and the benzene solution is washed with water, dried and the benzene is removed by evaporation to give a solid (1.20 g). e is added to diisopropyl ether. The insoluble matter is removed by filtration, and then the filtrate is allowed to stand at room temperature. The precipitated crystals are filtered off to give the title compound (I) (0.92 g, 76.2%), m.p. 134-135 ° C. The hydrochloride of this product has a melting point of 187-188 ° C.

The above procedure is repeated, except that commercially available silica gel is used as such instead of dried silica gel and 0.16 g of sodium hydride is used. There is thus obtained the title compound (I) in a yield of 67.9%.

5 - {2). The procedure of (5-) above is repeated, except that dried alumina suitable for column chromatography (obtained by calcining commercially available alumina at 300 ° C for 8 hours under nitrogen) (200 mesh, 0.5 g) is used instead of silica gel, whereby to give the title compound (I) (0.87 g, 72.1%).

i9 7 7240

The above procedure is repeated, except that commercially available alumina is used as such instead of dried alumina and 0.18 g of sodium hydride is used. There is thus obtained the title compound (I) in a yield of 57.1%.

5- (3). The procedure of 5- (1) above is repeated, except that various aprotic polar solvents shown in Table 3 are used instead of dimethyl sulfoxide and the reaction time is 20 hours. Thus, the title compound (I) is obtained in the yields shown in Table 3.

Table 3___

Aprotic Polar Silica Gel or Solvents of Compound (I) alumina yield N, N-dimethylformamide dried silica gel 70% N, N-dimethylformamide dried alumina 65% n-methylpyrrolidone dried silica gel 72% N, N'-dimethylimidazolidinone 63% dried silica

Hexamethylphosphoryltramide dried silica gel 71% N, N'-dimethylacetamide dried silica gel 68% sulfolane dried silica gel 71%

Example 6 Preparation of 2- (4'-methoxyphenyl) -3-acetoxy-5-acetyl-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one / Compound (VII) /: 6- ( 1). 2-Hydroxy-3- (2'-aminophenylthio) -3- (4 "-methoxyphenyl) propionic acid / compound (IV) / (3.19 g) and acetic anhydride (6.12 g) are added to xylene (10 ml) and the mixture reflux for 2 hours while removing the acetic acid formed by azeotropic distillation After quenching, the reaction mixture is cooled to room temperature and the precipitated crystals are filtered off, washed and dried to give the title compound 2o 772 40 (VII) (3.28 g, 85.2%), melting point 158-160 ° C. When this product is recrystallized from xylene to give pure product, melting point 160-161 ° C.

6 - {2) - The same compound (IV) as above 6 - (1) (3.19 g) and acetic anhydride (1.22 g) are added to xylene (10 ml) and the mixture is stirred for 1 hour at 50 ° C. . After the reaction, the precipitated crystals are separated by filtration, washed and dried to give 2-hydro-3- (2'-N-acetylaminophenylthio) -3- (4 "-methoxyphenyl) propionic acid (3.43 g, 94 .0%), melting point 170-171 ° C.

This product (3.0 g) and acetic anhydride (3.39 g) are added to xylene (10 ml) and the mixture is reacted in the same manner as in 6- (1) above to give the title compound (VII) (2.7 g, 84 .5%), melting point 158-160 ° C.

6- (3). To toluene (20 ml) are added the N-acetyl derivative of compound (IV) (7.22 g) and acetic anhydride (2.44 g), and the mixture is reacted for 1 hour at 80 ° C. After cooling the reaction mixture, the precipitated crystals are filtered off, washed and dried to give 2-acetoxy-3- (2'-N-acetylaminophenylthio) -3- (4 "-methoxyphenyl) propionic acid / compound (IV) / (7.40 g, 91.8%), melting point 164-166 [deg.] C. This product (3.70 g) of glacial acetic anhydride (1.87 g) is added to xylene (10 ml) and the mixture is reacted in the same manner as in 6- ( 1) to give the title compound (VII) (3.0 g, 84.9%), mp 158-160 ° C.

Example 7 Preparation of 2- (4'-methoxyphenyl) -3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one / Compound (II) /: 7- (1). 2- (4'-methoxyphenyl) -3-acetoxy-5-acetyl-2,3-dihydro-1,5-bisothiazepin-4 (5H) -one / compound (VII) / (1.93 g) and di- ethylamine (0.44 g) is added to chloroform (20 ml) and the mixture is stirred for one hour at room temperature. Chloroform is distilled off with 2i 77240 and then water is added to the residue. The precipitated crystals are filtered off, washed with water and dried to give the title compound (II) (1.63 g, 94.8%), m.p. 198-220 ° C.

7 - (2). Proceed in the same manner as in 7- (1) above, except that dimethylamine (0.27 g) and benzene (90 ml) are used instead of diethylamine. The reaction gives the title compound (II) (1.54 g, 89.6%), m.p. 196-199 ° C.

7- (3). Compound (VII) (200 mg) and aniline (63 ml) are added to chloroform (10 ml), and the mixture is stirred at room temperature for two hours. The chloroform solution was concentrated and thin layer chromatographed on silica gel (developer, benzene: ethyl acetate = 1: 1) to give acetanilide (62 mg, 88.3%) and the title compound (II) (159 mg, 89.2%), mp 196-198 °. C.

7 - (4). The procedure of 7- (1) above is repeated, except that various amines shown in Table 4 are used instead of dimethylamine. This gives the title compound (II) in the yields shown in Table 4.

Table 4__

Amine__ Yield of compound (II)

Quality Amount * ammonia 0.15 1.20 g (69.8%) phenylhydrazine 0.65 1.35 g (78.6%) n-butylamine 0.50 1.40 g (81.4%) imidazole 0, 40 1.50 g (87.3%) morpholine 0.55 1.42 g (82.6%) *) Prepared by introducing ammonia gas into chloroform.

Claims (11)

1 COOH. wherein Ar and R are the same as above are reacted with one or more equivalents of the lower alkanoic acid anhydride. A process for the preparation of 1,5-benzothiatesepine derivatives according to the formula I Is, / Ar Cs. Y (OC) R 1 (I) YN XR 2 wherein Ar is a lower alkoxy substituted phenyl, R is a lower alkyl, R 1 and R 2 are each an alkyl and Y is a lower alkylene, characterized in that a 2 -hydroxy-3- (2'-amino-phenylthio) -3-phenylpropionic acid, which is a base with a base, is ~ C ° H / (IV) COOH 11 in which Ar is the same as above, reacted with an acylation reaction. agent and the obtained 1,5-benzothiatesepine derivative of formula 'I' Ar '- OCOR' / H O (II) in which Ar and R are the same as above, or its alkali metal salt is reacted with a compound of formula III Process according to claim 1, characterized in that a reaction between the compound (II) and the compound (III) is carried out in the presence of a silica gel and / or aluminum oxide. 2-Y-N \ r 2 (III) which R 1, R 2 and Y are the same as above and Z is a 2 halogen. 26 7 7 2 4 0 3. A process according to claim 1, characterized in that the base, which will form a site with the compound (IV), is selected from the group consisting of a pyridine compound, tertiary amine, alkali metal and alkaline earth metal. 4. A process according to claim 1, characterized in that the acylating agent is an anhydride of a lower alkanoic acid, which is used in two equivalents or more in relation to the compound (IV). 5. A process according to claim 1, characterized in that a reaction is carried out in the first stage by reacting the compound (IV) with under two equivalents of the lower alkanoic acid anhydride or one or more equivalents of the lower alkanoic acid halide and the obtained intermediate compound of the formula V _ Ar k Ϊ \ - OCOR m 6. A process according to claim 1, characterized in that the 2-hydroxy-3- / 2'-amino-phenyl-thio) -3-phenylpropionic acid (IV) used as starting agent is used as free acid, which is reacted with three or more equivalents. of acylating agent, and the obtained compound of formula VII