HU185725B - Process for preparing 1,5-benzothiazepine derivatives - Google Patents

Abstract

The present invention relates to a novel process of the general formula (I) wherein Ar is lower alkoxy, R is lower alkyl, R * and R 2 are both lower alkyl and Y is lower alkylene to produce 1,5-benzothiazepine derivatives. 2-hydroxy-3- (2'-amino-fend mercapto) - 3 - phenyl of formula IV. starting from a propionic acid derivative, then the cyclized and acylated 1,5-benzothiazepine derivative of formula (II) or an alkali metal salt thereof is reacted with a compound of formula (I). According to the present invention, a) the starting compound of formula IV is reacted in one step with a lower alkanoic anhydride in the form of a base salt thereof in an amount equal to or greater than 2 equivalents, or b) a starting compound of formula IV as a base salt with a short chain an anhydride of an alkanoic acid is reacted with an amount of 1 equivalent or greater, but less than 2 equivalents, or an equivalent of 1 or more of the lower alkanoic acid, and the intermediate of formula (V) thus obtained is an Ar-1-

Description

The present invention relates to a novel process for the preparation of 1,5-benzothiazepine derivatives having excellent coronary vasodilator and psychoneurotic activity. More particularly, the present invention relates to a process of formula (I) wherein:

Ar is phenyl substituted with lower alkoxy,

R is lower alkyl,

R ¹ and R ² are both a lower alkyl group, and

Y is lower alkylene,

For the preparation of 1,5-benzothiazepine derivatives.

As used herein, the term "lower alkoxy" means an alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, η-propoxy, isopropoxy, η-butoxy, isobutoxy, secondary butoxy and tert-butoxy. . The term "lower alkyl" refers to alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, η-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. The term "lower alkylene group" means an alkylene group containing from 1 to 4 carbon atoms, such as methylene, ethylene, propylene or butylene.

this compound has an excellent coronary vasodilator effect and is particularly useful as a calcium antagonist coronary vasodilator.

A 43 785/1971. Japanese Patent Laid-Open Publication No. 2- (4'-Methoxyphenyl) -3-acetoxy-5- (2-dimethylaminoethyl) -2,3-dihydro-1,5-benzothiazepine-4 (5H) - on is prepared by cyclizing 2-hydroxy-3- (2-aminophenylthio) -3- (4 '' methoxyphenyl) propionic acid to form 2- (4'-methoxyphenyl) ) -3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4- (5H) -one is then 0-acetylated and the resulting 0-acetylated compound is reacted with 2-dimethyl20 aminoethyl halide and the above benzothiazepine reaction with dimethylaminoethyl halide followed by 0-acylation. However, prior art literature does not disclose a reaction involving simultaneous ring closure and O-acylation. Surprisingly, our experiments have found that when treating 2-hydroxy-3- (2'-aminophenylthio) -3- (4-alkoxyphenyl) propionic acid with acetic anhydride, the desired 2- (4-alkoxy) phenyl) -3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4- (5H) -one can be obtained in better yields than those known in the art, in addition, the ring closure and the 0-acylation can be carried out in one step. It has also been found that when N-alkylation of the above benzothiazepine is carried out in the presence of silica gel or aluminum oxide, the N-alkylation also provides better yields than those known to date. According to the present invention, the compounds of formula (I) are prepared by reacting a 1,5-benzothiazepine derivative of formula (II), preferably an alkali metal salt thereof at position 5, with an alkali metal. ) as shown in Reaction A. In the reaction equation, formulas II and III

Ar, R, R ¹ and R ² and Y are as defined above and Z is halogen such as chlorine or bromine.

According to a preferred embodiment of the process of this invention, this condensation reaction, i.e. the N-alkylation reaction illustrated by Reaction equation A, is generally carried out in an aprotic polar solvent, preferably in the presence of silica gel and / or alumina. Preferably, the compound of formula (II) is reacted with the compound of formula (III) by first converting the compound of formula (II) into an alkali metal salt at its 5-position 5 nitrogen atom and, for this purpose, the compound of formula (II) Compound II is treated with 1 to 1.5 moles of an alkali metal hydride (e.g., sodium hydride) relative to the compound of formula (II). The alkali metal salt of the compound of formula II can be formed in the reaction mixture itself, i.e., by reacting the compound of formula II in an aprotic polar solvent, adding silica gel and / or alumina. the alkali metal hydride and thus the formula II

185 725 are converted to the alkali metal salt. The compound of formula (III) is then added. The compound of formula (III) may also be added to the reaction mixture prior to forming the alkali metal salt of the compound of formula (II). For the reaction, the compound of formula (III) is used in an amount of 1 to 3 moles relative to the compound of formula (II). The reaction is generally carried out at a temperature between 5 ° C and 60 ° C, preferably between 15 ° C and 40 ° C, depending on the nature of the solvent and the compound of formula III and may last from about 1 hour to 24 hours. is preferably from 3 to 10 hours.

Any of the commercially available silica gel or alumina formulations may be used for the above reaction, but preferably dehydrated (dehydrated) such materials by calcination (heating). The amount of silica gel and alumina is not critical, but is generally used in an amount of from 0.01 to 2 parts by weight of the compound of formula II. The particle size of silica gel and alumina is also not critical, any column may be used. silica gel or aluminum oxide.

Examples of aprotic polar solvents include dimethyl sulfoxide, sulfolane, N, N-dimethylformamide, Ν, Ν-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone, hexamethylphosphoric triamide and the like. and the like, dimethyl sulfoxide being a particularly preferred solvent.

. The compound of formula (I) thus obtained can be isolated from the reaction mixture in a manner known per se, for example by neutralizing the reaction mixture, filtering off insoluble material (e.g. silica gel, alumina and the like) and adding a non-polar solvent to the filtrate. the mixture is washed with water and dried, if necessary, and the solvent is distilled off and the product is crystallized. By this process, the desired compounds of formula I can be prepared in high yield (e.g., 70-80% yield) and high purity.

The starting 1,5-benzothiazepine derivatives of formula II are prepared by processes a) and b) by reacting the 2-hydroxy-3- (2'-aminophenylmercapto) -3-alkoxyphenyl compound of formula IV the propionic acid derivative is reacted with an acylating agent as shown in Reaction B. In the general formulas in the reaction equations

Ar and R are as defined above.

This reaction is carried out by first preparing a salt of the compound of formula IV with a base such as a pyridine dehydrogenase, a tertiary amine, an alkali metal or an alkaline earth metal (formula IV ') and then reacting in a suitable solvent with the acylating agent.

Suitable bases include pyridine derivatives (e.g., pyridine, α-picoline, β-picoline, γ-picoline, halogen substituted pyridine derivative, quinoline, isoquinoline), tertiary amine oxate (e.g., trimethylamine, triethylamine), alkali metal (lithium, sodium or potassium) carbonates, hydrogen carbonates or organic acid salts (e.g. acetates), _(as well as alkaline earth metals (e.g. magnesium) carbonates, hydrogen carbonates or organic acid salts (e.g. acetates) such bases Pyridine and lithium derivatives are particularly preferred .The base is used in an amount of from 0.2 equivalents to 3 equivalents relative to the amount of the compound of formula IV, and preferably from about 0.5 equivalents to 2 equivalents of the alkali metal and alkaline earth metal compounds. pyridine derivatives and tertiary amines are used in an amount of 1 equivalent or more.

Acylating agents include, for example, anhydride of a lower alkanoic acid having from 2 to 4 carbon atoms (e.g. acetic anhydride, propionic anhydride, butyric anhydride) or halides of these lower alkanoic acids (e.g., acetyl chloride, propionyl azide, It is used in an amount of 1 equivalent or more, based on the amount of compound of formula IV or formula IV ⁷ .

A variety of solvents may be used in the reaction provided that the solvent does not adversely affect the reaction, such as benzene, chloroform, ethyl acetate, Ν, Ν-dimethylformamide, 1,3-dimethyl-2-imidazolidinone and the like. like. If a base is a pyridine derivative or a tertiary amine, they may also be used as a solvent.

The reaction illustrated by Reaction B can take place in many ways, depending on the nature and amount of the acylating agent. When the acylating agent is an anhydride of a lower alkanoic acid of formula IV. or two equivalents or more, typically 2 to 2.5 equivalents, relative to the amount of compound of formula IV ', the starting compound of formula IV' is used to give the desired compound of formula 11 directly, i.e. acylation of the hydroxy group at position 3 and the ring closure reaction proceeds in a single step (process a). In such cases, the reaction is carried out by dissolving the compound of formula (IV) in a solvent, adding the base to convert the compound of formula (IV) to the salt of formula (IV *), and adding 2 equivalents of the anhydride of lower alkanoic acid. or more, typically 2 to 2.5 equivalents, of the compound of formula IV or formula IV ', followed by reaction at a temperature of 0 ° C to 50 ° C, preferably 15 ° C to 35 ° C. At a temperature of from about C to about a few hours, usually 2-3 hours. First, 1 equivalent of anhydride megacylates the compound of formula (IV ') to form intermediate (V), then the excess acid anhydride encapsulates this intermediate of formula (V), but this is the acylation and ring closure step. at about the same time, in a short time, for example 2-3 hours, to give the desired compound of formula II in high yield, for example 70% or higher.

By using less than 2 equivalents of anhydride of a lower alkanoic acid (e.g., 1-1.5 equivalents) as the acylating agent IIa, the reaction is at least partially incomplete, i.e. at least in part is not ring-closed, and the reaction is yielding a mixture of intermediate (V) and compound (II). In addition, if the acylating agent is short3

Use of 1 to 1.5 equivalents of the halide of 185,725 alkanoic acids yields only the intermediate of formula (V). The intermediate of formula (V) is readily ring-linked to provide the desired compound of formula (II) by treating the intermediate of formula (V) with 1 to about 1.5 equivalents of the acid anhydride (process b).

Alternatively, process (c) may also be prepared by acylating a compound of formula (IV) with an acylating agent and then deacylating the resulting intermediate of formula (VII) as described in C. reaction equation. In the general formulas of C, Ar and R are as defined above.

The acylation of the compound of formula (IV) is generally carried out in a suitable solvent, such as toluene, xylene or ethylbenzene, in an amount of 3 equivalents or more of said lower alkanoic acid, at a temperature of 100 ° C to 150 ° C, and preferably 110 ° C. C and 140 ° C. Under these conditions, the reaction proceeds within a few hours, preferably 2-3 hours. If excess acid anhydride is used, it may be used as a solvent, so no other solvent is used. If the acid anhydride is used in an amount of less than 3 equivalents, or 2 equivalents or more of the lower alkylating agent halide is used as the acylating agent, or if the reaction is carried out at a temperature below 100 ° C, intermediate (VI) is obtained. in the case of a compound in which only the amino group at the 2'-position has been acylated but the ring closure has not taken place. The intermediate of formula (VI) can be ring-formed and the intermediate of formula (VII) may be prepared by treating the intermediate of formula (VI) with 1 equivalent or more of anhydride of a lower alkanoic acid at a temperature of 110 ° C to 140 ° C. .

The intermediate of formula (VII) can be easily deacylated to give the compound of formula (II) by treating the compound of formula (VII) with an amine in a suitable solvent, whereby only the acyl group at position 5 is present. cleaves selectively.

Amines used in the above deacylation reaction include, for example, ammonia, hydrazine, aliphatic primary amines (e.g., methylamine, ethylamine, n-butylamine), aromatic primary amines (e.g., aniline, toluidine), aliphatic secondary amines (e.g., dimethylamine, diethylamine, di-n-propylamine, di-n-butylamine), cyclic amines (e.g. morpholine, pyrrole, imidazole) and the like, aliphatic secondary amines such as dimethylamine being preferred. and diethylamine. Such amines are used in an amount equal to or greater than that of the compound of formula (VII).

The deacylation can be carried out in a variety of solvents, provided that the solvent does not adversely affect the deacylation reaction, such as chloroform, benzene, toluene, xylene, N, N-dimethylformamide and the like.

In this deacylation reaction, intermediate (VII) can be converted to the desired compound (II) by quantitative production.

The compounds of formula (II) prepared by the methods illustrated in Reaction B and Reaction C may be used for the condensation reaction of Reaction A with compounds of Formula (III) by first isolating the compounds of Formula (II) or and without isolating them from the reaction mixture used for their preparation. Thus, in a preferred embodiment of the process of the invention, the reaction illustrated by Reaction B or Reaction C, followed by the reaction illustrated by Reaction A, is carried out continuously in the same reaction mixture.

The starting compounds of formula (IV) used for the above reaction illustrated by reaction equation (B) are also known (see Japanese Patent Application No. 9383/1970) or may be prepared by the procedure described therein. That is, the compounds of formula (IV) may be prepared by reacting an aminothiophenol of formula (IX) and a glycidic acid ester of formula (X) as illustrated in Reaction D. In the general formulas in the D reaction equation

Ar is as defined above, and

R ³ is an esterifying group.

This reaction is generally carried out in a suitable solvent, such as toluene, xylene or ethylbenzene, at a temperature between 100 ° C and 140 ° C for 5 to 20 hours, and the compound of formula IX thus obtained is known per se, e.g. hydrolyzed by treatment with an acid (e.g. hydrochloric acid, sulfuric acid) or a base (e.g. sodium hydroxide, potassium hydroxide).

The compounds of formula (IV) have two asymmetric centers at positions 2 and 3 and thus exist in the form of their threo and erythro isomers. In the above reaction illustrated by Reaction D, the threoisomers of the compounds of formula (IV) are formed. These threo isomers have two other optically active isomers, the d-isomers and the 1-isomers, and the reaction generally produces a racemic mixture (d1-form) of these isomers. The final products of formula (I) also have optically active forms, and the d-isomers of the compounds of formula (I) are particularly preferred because of their greater pharmacological activity. Although a racemic mixture of a compound of formula (I) can be resolved to provide optically active isomers, the optical resolution is preferably performed on a compound of formula (IV), since the desired optically active compound of formula (I) can be prepared optically. from the compound of formula (IV), since the above acylation and ring closure steps illustrated by Reaction B and C and the N-alkylation step represented by Reaction A are not racemized.

It has been found that the compounds of formula (IV) can advantageously be resolved using α-phenylethylamine as follows:

A racemic mixture of a compound of formula (IV)

185 725 optically active alpha-phenylethylamine, i.e. 1-to-1.2 equivalents of d-phenylethylamine or 1-a-phenylethylamine, in a suitable solvent, and the resulting two diastereomeric salts, It can be separated. When daphenylethylamine is used for the salt formation, the d-isomer salt of the compound of formula IV is obtained as a poorly soluble salt, whereas when Ι-α-phenylethylamine is used, the salt of (IV) is obtained. ) as a poorly soluble salt.

Solvents for optical resolution 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); water is preferred because the water solubility of the two diastereomeric salts is greater than that of other solvents, and the less soluble diastereomeric salt is less soluble in water than other solvents.

The poorly soluble diastereomeric salt thus obtained may be isolated from the reaction mixture by precipitation in a manner known per se, for example by cooling or concentrating the reaction mixture and then cooling, or by changing the proportion of a particular solvent, for example one or more additional solvents. to the reaction mixture. The precipitated salt can then be isolated by methods known per se for solid-liquid separation, such as filtration, decantation and the like. The thus-isolated poorly soluble diastereomeric salt has a high optical purity, generally 95% or higher, and is recrystallized from a suitable solvent (e.g. water, aqueous alcohol or ethyl acetate) to give the optically pure diastereomeric salt.

The resulting optically active, sparingly soluble, diastereomeric salt is readily converted to the corresponding free acid by hydrolytic methods known per se, for example, by dissolving the poorly soluble salt in water, adding a mineral acid (e.g., hydrochloric acid) and precipitating crystalline material. filtration.

In addition, as mentioned above, when either 1-α-phenylethyl-araline is used, either the d-isomer or the 1-isomer of the compound of formula IV is obtained in the form of a poorly soluble salt. Accordingly, after isolation of the poorly soluble salt, the other, more soluble isomeric salt, i.e., the 1-isomeric salt of the compound of formula (IV) and the 1-phenylethylamine, For example, the salt of the d-isomer of the compound of formula IV remains in the mother liquor. Alternatively, the optically active compound of formula (IV) can be isolated from the mother liquor by adding a mineral acid (e.g. hydrochloric acid) to the soluble optically active diastereomeric salt and filtering off the precipitated crystals, thereby obtaining the desired optically active compound of formula (IV). The compound of Formula I may be isolated as the free acid.

Almost all of the optically active α-phenylethylamine used in the optical resolution process described above can be recovered after filtration of the optically active compound of formula (IV). This can be done in a manner known per se, for example by basifying the acidic filtrate obtained after filtration of the optically active compound of formula (IV) with a base such as sodium hydroxide or potassium hydroxide, a solution of a hydrophobic organic solvent such as benzene, ethyl extraction with ethyl acetate or diethyl ether and distilling off the organic solvent.

In the acylation and ring closure reactions illustrated by Reaction B and Reaction C, the optically active compound of formula (IV) is preferably used as starting material, but the optically active compound of formula (IV) may be used as an optically active compound. also the active diastereomeric salt without liberating the acid.

The invention is further illustrated by the following non-limiting Examples.

Example 1

the step

Hydroxy-3- (2'-amino-phenyl-mercapto) -3- (4-methoxy-phenyl) -propionic acid [Compound (IV), threoform]

14.38 g of 2-aminothiophenol and 20.80 g of 3- (4'-methoxyphenyl) glycidic acid methyl ester are dissolved in 100 ml of toluene and the solution is refluxed for 6 hours under nitrogen. The solvent was then distilled off and the residue was heated with ethanol. After cooling, the precipitated crystalline material is filtered off and recrystallized from ethanol. In this way, 27.31 g (82%) of methyl threo-2-hydroxy-3- (2'-amino-phenyl-mercapto) -3- (4 '-methoxy-phenyl) -propionic acid, m.p. 92-93 ° C.

16.65 g of the product obtained as described in the previous paragraph are added to 80 ml of a 5% aqueous sodium hydroxide solution and the mixture is stirred for half an hour at 50 ° C. The reaction mixture was cooled to room temperature and then neutralized with hydrochloric acid. The precipitated crystalline material is filtered off, washed with water and dried. In this way, a racemic mixture of the threo form of the title compound of formula IV is obtained. Yield: 15.63 g, 98%, m.p. 169-172 ° C.

Step b)

Optical resolution of a compound of formula (IV)

The racemic mixture of the threo form of the compound of formula IV obtained in step a) (6.38 g) and 2.58 g of daphenylethylamine were warmly dissolved in 100 ml of water and stirred for 5 hours at room temperature. The precipitated crystalline material is filtered off and recrystallized from 60 ml of water. In this way, an optically pure salt of the d-isomer of the threoform of the compound of formula IV with d-α-phenylethylamine is obtained. Yield:

3.95 g, m.p. 157-158 ° C, fa], = + 376 '(c = 0.511, ethane').

Using all the procedures described above, but employing the solvents given in Table I instead of water, the results shown in Table I are obtained.

-5185 725

Table I

Solvent Amount of solvent (ml) Yield of salt (g) 23 Optical rotation of the salt [a] _D (in ethanol) ethanol 6 0.36 + 362.4 ° (c = 0.521) Ethanol-water = 1: 1 10 0.70 + 374.0 ° (c = 0.475) Ethanol-water = 1: 3 20 0.89 + 369.4 ° ( _C = 0.438) isopropanol 4 0.89 + 333.8 ° (c = 0.535) Benzene 30 0.58 + 333.0 ° (c = 0.565) Ethyl acetate 2.5 0.59 + 337.2 ° (c = 0.522)

The product obtained as described above is dissolved in 180 ml of water with heating, 8.9 ml of 1N hydrochloric acid are added and the mixture is cooled. The precipitated crystalline material is filtered off, washed with water and dried. In this way, the optically pure d-isomer of the threo form of the compound of formula (IV) was obtained: 2.68 g, 84%, m.p. 138-139 ° C, [α] _D = + 346 ° (c = 0.355). , ethanol).

8.5 ml of 1N hydrochloric acid are added to the mother liquor obtained by filtration of the d-isomer of the d-isomer of the compound of formula IV and the precipitated crystalline material is filtered off, washed with water and dried. In this way, the treg form I of the compound of formula IV is obtained, weighing 2.40 g, [α] D = -306 ° (c = 0.360, ethanol), optical purity: 88.7% [α 1-isomer of compound of formula IV.

step c)

Optically active 2- (4'-methoxyphenyl) -3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one (compound of formula II)

3.19 g of threo-d-2-hydroxy-3- (2'-aminophenyl mercapto) 3- (4 '-methoxyphenyl) propionic acid (compound of formula IV) are dissolved in 5 ml of Ν, Ν dimethylformamide and 0.80 ml of pyridine was added to the solution. After stirring for half an hour at room temperature, 2.04 g of acetic anhydride was added dropwise. After stirring for 1 hour, 200 ml of ice water was added. The precipitated crystalline material is filtered off, washed with water and dried. Yield: 2.80 g (81.6%) of d-cis II, m.p. 150-152 ° C. Purify by TLC on silica gel (eluent: benzoethyl acetate = 4: 1) to give the title compound in pure state, m.p. 152-153 ° C, [α] D = + 39 ° (c = 0.500, chloroform). ).

When the propionic acid derivative of formula (IV) is used in the above process, not as the free acid, but as its salt with d-aphenylethylamine (0.50 g), 0.27 g (69.3%) is obtained. of the title compound d-cis, [α] D = + 38.1 ° (c = 0.486, chloroform), (optical purity:

97.7%).

Step d)

Optically Active 2- (4'-Methoxyphenyl) -3-acetoxy-5- (N, N-dimethylaminoethyl) -2,3-dihydro-1,5-benzothiazepin4 (5H) -one [(I) Compound II] To anhydrous dimethyl sulfoxide (1.0 ml) was added 1.0 g of d-cis compound (II) obtained in step c) and 0.50 g of dried silica gel Wakogel C-200 for column chromatography. followed by 0.14 g of 60% sodium hydride and the mixture was stirred for half an hour at room temperature. A solution of 0.75 g of N, N-dimethylaminoethyl chloride in 50% by weight in diethyl ether is then added. After stirring for 5 hours at room temperature, the reaction mixture was neutralized with acetic acid and the silica gel filtered. Benzene is added to the filtrate, the benzene solution is washed with water and dried. The benzene was distilled off to give 1.27 g of an oily product.

The oily product was dissolved in diethyl ether and diethyl ether saturated with hydrogen chloride gas was added to the solution. The precipitated crystalline material is filtered off and recrystallized from a mixture of ethanol and isopropanol. This gives the hydrochloride salt of the d-cis form of the title compound (1.01 g, 76.9% yield, m.p. 206207 ° C, [α] _D = + 96.6). ° (c = 0.613, methanol).

Example 2

2-Acetoxy-3- ^{(2-amino-phenylthio)} -3- (4 ^/, methoxyphenyl) propionic acid [free acid form of the compound of formula (V)]

Method A)

3.19 g of 2-hydroxy-3- (2'-amino-phenylthio) -3- (4 ^,, methoxy-phenyl) -propionic acid [(IV), a compound of formula] are dissolved in 10 ml of pyridine and treated with 10 1.02 g of acetic anhydride was added dropwise at 0 ° C, and the reaction mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into 200 ml of ice water, neutralized with hydrochloric acid and extracted twice with 50 ml of benzene. The benzene fractions were combined, washed with water and dried, and the benzene was distilled off. Yield: 3.07 g, 85.0%, mp 104-107 ° C.

-6185 725

Method B

All procedures were carried out as described in Method A above, except that 0.79 g of acetyl chloride was used in place of acetic anhydride and the reaction mixture was shaken with 50 ml of chloroform instead of benzene. In this way, 3.14 g (87%) of V are obtained in the form of the free acid.

Method C

All of the procedures described in Method A were repeated except that 1.50 g of triethylamine was used in place of pyridine to give 2.89 g (80% yield) of the compound of formula V as the free acid.

Example 3

2- (4'-Methoxyphenyl) -3-acetoxy-2- _[ 3-dihydro-1,5-benzothiazepin-4 (5H) -one [Compound II]

Method A)

2-Acetoxy-3- (2'-aminophenyl-mercapto) -3- (4-methoxyphenyl) -propionic acid (3.00 g, free acid form) is dissolved in 6 ml of pyridine and the solution is stirred for 30 minutes. stirring at room temperature. Subsequently, 0.85 g of acetic anhydride was added dropwise and the mixture was stirred at room temperature for another half hour and then poured into 100 ml of ice water. The precipitated crystalline material is filtered off, washed with water and dried. Yield: 2.42 g (84.9%) of the title compound (II), m.p. 198-200 ° C.

Method B

Dissolve 0.5 g of 2-hydroxy-3- (2'-aminophenyl-mercapto) -3- (4-methoxyphenyl) -propionic acid (IV) in 2 ml of pyridine and stir at room temperature for 1 hour. and 0.32 g of acetic anhydride are added dropwise over half an hour, and the mixture is stirred at room temperature for a further 1.5 hours. The mixture was then worked up as described in Method A above to give 0.48 g (89%) of the title compound II, m.p. 198200 ° C. This product was recrystallized from ethanol to give pure product, mp 200-202 ° C.

Method C

1.00 g of 2-hydroxy-3- (2'-aminophenyl mercapto) -3- (4'-methoxyphenyl) propionic acid (compound of formula V) are dissolved in 2 ml of dimethylformamide, 32 g of triethylamine and the mixture is stirred for half an hour at room temperature. 0.64 g of acetic anhydride is then added and the reaction mixture is stirred for a further 2 hours at room temperature. The mixture was then worked up as described in Method A above to give 0.75 g (69.8%) of the title compound, m.p. 193-195 ° C.

Method D

All of the procedures described in Method C above are repeated except that 1,3-dimethyl-2-imidazolidinone is substituted for dimethylformamide and 0.26 g of pyridine is used instead of triethylamine. Yield: 0.90 g (83.7%) of the title compound II, m.p. 198-200 ° C.

Method E)

2.19 g of 2-hydroxy-3- (2'-aminophenylmercapto} -3- (4-methoxyphenyl) propionic acid (IV) are dissolved in 25 ml of dimethylformamide, Lithium carbonate (37 g) was stirred at room temperature for 1 hour, then a solution of acetic anhydride (2.20 g) in dimethylformamide (5 ml) was added dropwise and the reaction mixture was poured into ice water (800 ml). filtered, washed with water and dried to give 2.81 g (81.9%) of the title compound II, m.p. 196-198 ° C.

Method F

All procedures were carried out as described in Method E above, except that 0.53 g of 50% w / w sodium hydride was used in place of lithium carbonate. Yield: 2.13 g (62.1%) of the title compound (II), m.p. 192-196 ° C.

Method G)

0.50 g of 2-hydroxy-3- (2'-aminophenyl mercapto) -3- (4'-methoxyphenyl) -propionic acid (compound of formula IV) is dissolved in 2 ml of α-picoline, After stirring for half an hour at room temperature, 0.32 g of acetic anhydride was added dropwise over 1 hour. Then the reaction ^! The mixture was stirred for an additional 1 hour at room temperature and worked up as described in Method A above. Yield: 0.38 g (70.7%) of the title compound II, m.p. 198-200 ° C.

Method 11)

0.30 g of 2-hydroxy-3- (2'-aminophenyl mercapto) -3- (4-methoxyphenyl) propionic acid is dissolved in 1 ml of quinoline and the solution is stirred for half an hour at room temperature. Thereafter, 0.192 g of acetic anhydride was added dropwise over half an hour, and the reaction mixture was stirred at room temperature for a further 2 hours. It is then poured into 100 ml of ice water and neutralized with hydrochloric acid. The precipitated crystalline material is filtered off, washed with water and dried. Yield: 0.24 g (74.4%) of the title compound II, m.p. 198-200 ° C.

Method I

In each of the methods described in Method E above. except that, instead of lithium carbonate, the following compounds of formula II are used. The metal salts shown in Table II are used. The results are shown in Table II. are summarized in Table

185,725

II. Spreadsheet

salt Quantity of metal salt, (g) Yield of compound (II) 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

2- (4'-Methoxyphenyl) -3-propionyloxy-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one [Compound (H) wherein R = Propyl]

Method A)

2.19 g of 2-hydroxy-3 '- (2'-aminophenyl-kidney capto) -3- (4-methoxyphenyl) -propionic acid (compound of formula IV) and 0.79 g of pyridine are dissolved in 5 ml of dimethylformamide , and the solution is stirred for half an hour at room temperature. Propionic anhydride (2.60 g) was added dropwise and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into ice-water (200 ml), the precipitated crystals were filtered off, washed with water and dried. Yield: 3.19 g (89.4%), m.p. 155-156 ° C.

Method B

3.19 g of 2-hydroxy-3- (2 ^, aminophenyl mercapto) -3- (4 'methoxyphenyl) propionic acid are dissolved in 30 ml of 1,3-dimethyl-2-imidazolidinone and 0.74 g of lithium are added. carbonate. After stirring for 1 hour at room temperature, propionic anhydride (2.86 g) was added dropwise and the mixture was stirred at room temperature for an additional 2 hours. It was then poured into 800 ml of ice water and the precipitated crystalline material was filtered off, washed with water and dried. 3.29 g (92.2%) of the title compound (II) are obtained, m.p. 155-156 ° C.

Example 5

2- (4'-Methoxyphenyl) -3-acetoxy-5- (N, N-dimethylaminoethyl) 2,3-dihydro-1,5-benzothiazepin-4 (5H) -one [(I) compound of general formula]

Method A)

1.0 g of 2- (4'-methoxyphenyl) -3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one (II) and 0.5 g of Silica gel for chromatography, obtained by calcining commercial grade Wako gel C-200 silica gel at 300 ° C for 8 hours under nitrogen atmosphere, is added to ml of dimethyl sulfoxide and then 0.14 g of 60% sodium chloride is added. hydride was added and the reaction mixture was stirred for half an hour at room temperature. A solution of 0.75 g of N, N-dimethylaminoethyl chloride in 50% by weight in diethyl ether is then added and the reaction mixture is stirred for 5 hours at room temperature. The mixture was then quenched with acetic acid and filtered through silica gel. Benzene was added to the filtrate and the benzene mixture was washed with water, dried and the benzene was distilled off. The resulting solid (1.20 g) was dissolved in diisopropyl ether, the insolubles were filtered off and the filtrate was allowed to stand at room temperature. The precipitated crystalline material was filtered off to give 0.92 g (76.2%) of the title compound, m.p. 134-135 ° C. The hydrochloride salt of this product melts at 187-188 ° C.

If the above experiment is repeated using commercially available silica instead of dry silica gel and using 0.16 g of sodium hydride, the title compound (Ϊ) is obtained in a yield of 67.9%.

Method B

All procedures are carried out as described in Method A above, except that silica gel (0.5 g, 4 ₀ 200 mesh, alumina suitable for column chromatography (prepared by commercially available alumina) is used instead of silica gel. The oxide was heated at 300 ° C under nitrogen for 8 hours to give 0.87 g (yield: 45.1%) of the title compound.

If the experiment described in the previous paragraph is carried out using commercial grade alumina instead of dried alumina, using 50 and 0.18 g of sodium hydride, the yield of the title compound (I) is 57.1%. a compound of the general formula.

Method C

All of the procedures described in Method A above are repeated except that dimethylsulfoxide is replaced by the procedure set forth below in Method III. The aprotic polar solvents shown in Table 1 are used and the reaction time is 20 hours. The yield of the title compound of formula I is a

III. table.

185,725

III. Spreadsheet

Aprotic polar solvent Silica gel or alumina Yield of compound (I) Ν, Ν-dimethylformamide dried silica gel 70% Ν, Ν-dimethylformamide dried alumina 65% N-methylpyrrolidone dried silica gel 72% N, N'-dimethylimidazolidinone dried silica gel 63% Hexamethylphosphoric triamide dried silica gel 71% N, N-dimethyl-acetamide dried silica gel 68% sulfolane dried silica gel 71%

Example 6

2- ^{(4-Methoxyphenyl)} -3-acetoxy-5-acetyl-2,3-dihydro-5benzotiazepin-4 (5H) -one [(VII) with a compound of formula]

Method A)

2.19 g of 2-hydroxy-3- (2'-aminophenyl mercapto) -3- (4-methoxyphenyl) propionic acid and 6.12 g of acetic anhydride are added to 10 ml of xylene and the mixture is refluxed for 2 hours. by removing the resulting acetic acid by azeotropic distillation. The reaction mixture was then cooled to room temperature, and the precipitated crystalline material was filtered off, washed and dried. 3.28 g (85.2%) of the title compound of formula VII are obtained, m.p. 158-160 ° C. The product is recrystallized from Kilograms to give a pure product, m.p. 160-161 ° C.

Method B

2-Hydroxy-3- (2'-aminophenyl mercapto) -3- (4-methoxyphenyl) propionic acid (3.19 g) and acetic anhydride (1.22 g) in xylene (10 ml) were added and the mixture was stirred for 50 hours. Stir at 0 ° C. The precipitated crystalline material is then filtered off, washed and dried. Dryness to yield 3.43 g (95.0%) of 2-hydroxy-3- [2 ^'- (N-acetylamino) -fenilmerkapto] -3- (4-methoxyphenyl) propionic acid, mp. Mp 170-171 ° C.

The product obtained as described in the previous paragraph (3.0 g) and acetic anhydride (3.39 g) are added to 10 ml of xylene and the mixture is reacted as described in Method A above. 2.7 g (84.5% yield) of the title compound of formula VII are obtained, m.p. 158-160 ° C.

The product obtained as described in the previous paragraph (3.70 g) is treated with 10 ml of xylene in 1.87 g of acetic anhydride as described in Method A above. This gave 3.1 g (84.9%) of the title compound (VII), m.p. 158-160 ° C.

Example 7

2- (4'-Methoxyphenyl) -3-acetoxy-2,3-dihydro-5benzotiazepin-4 (5H) -one [(II) compound of formula _30]

Method A To a solution of chloroform in ml is added 1.93 g of 2- (4'-methoxyphenyl) -3-acetoxy-5-acetyl-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one [(VII) of the formula] and 0.44 g of diethylamine and the mixture is stirred for 1 hour at room temperature. The chloroform is then distilled off, water is added to the residue, the precipitated crystals are filtered off, washed with water and dried. Yield: 1.63 g (94.8%) of the title compound II, m.p. 198-200 ° C.

Method B

All the procedures described in Method A above were repeated except that 0.27 g of dimethylamine was used instead of diethylamine and 90 ml of benzene was used instead of chloroform. Yield: 1.54 g (89.6%) of the title compound II, m.p. 196-199 ° C.

Method C

The N-acetyl derivative of the compound of formula IV (7.22 g) and 2.44 g of acetic anhydride in 20 ml of toluene are reacted at 80 ° C for 1 hour. The mixture was cooled, and the precipitated crystalline material was filtered off, washed and dried. In this way, 7.40 g (yield:

91.8%) of 2-acetoxy-3- [2 '- (N-acetylamino) phenyl mercapto] 3- (4-methoxyphenyl) propionic acid (compound of formula VI), m.p. Mp: 164-166 ° C.

Method C

200 mg of the compound of formula VII and 63 mg of aniline are added to 10 ml of chloroform and the mixture is stirred for 2 hours at room temperature. The solvent was then distilled off and the residue was chromatographed on a thin layer of silica gel plate. Running solvent: benzene: ethyl acetate = 1: 1. This gave 62 mg (88.3%) of acetanilide and 150 mg (89.2%) of the title compound II, m.p. 196-198 ° C.

185,725

Method D

All of the procedures described in Method A above were repeated except that dimethylamine was replaced by the procedure described in Example IV below. The various amines given in Table II are used. The yield of the title compound (II) is shown in Table IV. is shown in Table.

ARC. Spreadsheet

Amin Amine content (g) Yield of compound (II) 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%)

* = Gaseous ammonia is introduced into chloroform.

Claims (6)

A process of the formula I wherein Ar is phenyl substituted with lower alkoxy, R is lower alkyl, R ¹ and R ² are both a lower alkyl group, and Y is lower alkylene, 1.5-benzothiazepine derivatives, which process comprises the preparation of a compound of formula IV wherein: Ar has the meaning above, Starting from the 2-hydroxy-3- (2'-amino-phenyl-mercapto) -3-phenyl-propionic acid derivative, the acylated and acylated formula (II) Ar and R are as defined above, A 1.5-benzothiazepine derivative or an alkali metal salt thereof, having the formula: R ^1, R ² and Y are as defined above, and Z is a halogen atom, is reacted with a compound, characterized in that a) Acylating and deprotecting the starting compound of formula IV in the form of its base with 2 equivalents or less of lower alkanoic anhydride. b) a lower alkanoic acid as the base salt of the starting compound of formula IV 1 anhydride of 5 equivalents or more, but less than 2 equivalents, or 1 equiv. Or 1 equivalent of cut, or c) the starting 2-hydroxy-3- (2'-aminophenyl mercapto) -3-phenylpropionic acid of the formula IV 15, with 3 equivalents or more of the anhydride or halide of the lower alkanoic acid, and then deacylating the compound of formula VII, wherein Ar and R are as defined above, The compound of formula (II) obtained by process (a), (b) or (c) is further reacted with the compound of formula (III), optionally in situ or in the form of a salt thereof. Method a) according to claim 1, which is an embodiment 25. A process comprising reacting a compound of formula II with a compound of formula III in the presence of silica gel and / or alumina. 3. A process according to claim 1, wherein the process is a) or b) The salt of a compound of formula (30) with a base is pyridine or a tertiary amine salt, an alkali metal salt or an alkaline earth metal salt. A process for carrying out process c) according to claim 1, characterized in that the amine is ammonia, 35 hydrazine, an aliphatic primary amine, an aromatic primary amine, an aliphatic secondary amine or a cyclic amine are used. 5. A method according to any one of claims 1 to 6, characterized in that We start from the optically active variant of the threo form of the compound of formula IV. 6. The process of claim 5, wherein the compound is a threo-d form of a compound of formula IV. 7. A process according to claim 5 or 6, wherein the optically active compound of formula IV is prepared by resolution of a racemic mixture of the threo form of the compound of formula IV by: the The racemic mixture of compound (IV) is treated with optically active α-phenylethylamine, followed by isolation of the optically active salt of compound (IV) with optically active α-phenylethylamine, optionally optically active salt 55 with a mineral acid.