DK154077B - PROCEDURE FOR THE PREPARATION OF 1,5-BENZOTHIAZEPINE DERIVATIVES - Google Patents

Description

in

DK 154077 B

The present invention relates to a process for the preparation of 1,5-benzothiazepine derivatives of the general formula: 5 CIC V * ° coR (i) o / r1

Y-N

\ R2

10 R

wherein Ar represents phenyl substituted with alkoxy of 1-4 carbon atoms, R

1 2 represents all alkyl of 1-4 carbon atoms, R and R each represent all alkyl of 1-4 carbon atoms, and Y represents all alkyl of 1-4 carbon atoms in racemic or optical form, which derivatives exhibit coronary vasodilatory and psychoneurotic activity.

The process of the present invention is characterized by reacting (A-1) a 2-hydroxy-3- (2'-aminophenylthio) -3-phenylpropionic acid of the general formula (IV) OC

COOH

Wherein Ar is as defined above, which compound (IV) is in the form of a salt with a base, having two or more equivalents of a lower alkanoic anhydride or (A-2) reacting said compound (IV) with less than two equivalents -30 l enter of a lower alkanoic anhydride or with one or more equivalents of a lower alkanoic acid halide, after which the resulting product of the general formula (V)

Ar 35 lu \ -OCOR (V) COOH base wherein Ar and R have the above meanings are reacted with one or

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2 more equivalents of a lower alkanoic anhydride, or (A-3) reacting said compound (IV) in the form of the free acid with three or more equivalents of a lower alkanoic anhydride, after which the obtained compound of the general formula (VII) 5

Ar Γ. n V0C0R (vii) I 0

COR

Wherein Ar and R are as defined above, react with an amine and (B) then react the resulting 1,5-benzothiazepine derivative of the general formula (II)

Ar I Π V ° COR (II) _ /

20 H ^ O

wherein Ar and R are as defined above or an alkali metal salt thereof, having 1-3 molar equivalents of a compound of general formula 25 (III) R 1: ZYN (III) R 2 Y has the meaning defined above and Z represents halogen in the presence of silica gel and / or alumina in an aprotic solvent.

From the specification of Danish Patent No. 123,942, it is known to prepare 1,5-benzothiazepine derivatives of the general formula (I). However, the process of the present invention has surprising advantages over known processes for the preparation of benzothiazepine derivatives.

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According to the present invention, either the 2-hydroxy group of compound (IV) is acylated during simultaneous cyclization, or the 2-hydroxy group is first acylated selectively, after which the product is cyclized.

This process has the advantage that the reaction can be carried out at normal or relatively low temperature (0-50 ° C) under atmospheric pressure and that compound (II) can be obtained from compound (IV) in high yield.

As will be known to those skilled in the art, the amino group is preferably acylated in a compound containing both amino and hydroxy. It is therefore surprising that, in the process of the invention, O-acylation is preferably obtained when the compound (IV) is converted to a salt thereof and then reacted with a certain amount of a lower alkanoic anhydride.

Further, from the specification of US Patent No. 3,155,649, it is known to carry out a corresponding cyclization reaction by reacting 3- (0-aminophenylthio) -3-phenylpropionate with thienyl chloride and from the description to Danish Patent No. 123,942 to perform a cyclization reaction by reacting 2-aminothiophenols with epoxyalkanoic acid esters. However, the cyclization reaction of the present invention carried out using alkanoic anhydride or acid halide in place of thionyl chloride or epoxyalkanoic acid esters is not known, and one skilled in the art will not expect that the cyclization reaction can be carried out while simultaneously acylating the hydroxy group of the amino group.

Furthermore, when the reaction is carried out under the conditions referred to in step (A1), the O-acylation takes place in one course at usual or relatively low temperature (0-50 ° C) under atmospheric pressure, and even when the reaction is carried out according to step (A-2). the two-step reaction is carried out at usual or relatively low temperature under atmospheric pressure, whereby the preferred O-acylation and cyclization can occur in one run. That the preferred O-acylation and ring closure of the present invention can be performed in one go is a surprising advantage not known from the methods disclosed in the above-mentioned patents.

The reactions under steps (A-1) and (A-2) depend on the amount of acylating agent, i.e. lower alkanoic anhydride or lower alkanoic acid halide.

In step (A-3), a compound (IV) is reacted with a lower alkanoic anhydride and the resulting compound (VII) treated with a 4

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amine, preferably removing only the N-acyl group. Thus, this step provides a method whereby the N-acyl group is preferably removed (without removing the O-acyl group) from the O- and N-acylated compound, which is surprising and not previously described.

During step (B), the compound (II) is N-alkylated to give the desired compound (I) in the presence of silica gel or alumina. The disclosures of US Patent No. 3,155,649 and Danish Pat.

123,942 also discloses an N-alkylation of benzothiazepine compounds, but these patents do not indicate that the N-alkylation is carried out in the presence of silica gel or alumina.

In the process of the invention, surprisingly high yields in the order of 70-80% are obtained in step (B). Such high yields have not been achieved by known methods. Furthermore, the process according to the invention differs with respect to the starting materials used in the N-alkylation from previously known methods. Thus, the starting compound (II) of the process of the invention contains an alkanoyloxy group (-COOR) at the 3-position of the benzothiazepine nucleus, whereas the starting compounds of the known methods 20 contain no substituent at the 3-position of the benzothiazepine nucleus.

In this specification, alkoxy of 1 to 4 carbon atoms comprises e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, alkyl of 1-4 carbon atoms e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl and alkyl of 1 to 4 carbon atoms e.g. methylene, ethylene, propylene, butylene.

A particularly preferred 1,5-benzothiazepine derivative prepared by the process of the invention is a compound of formula (I) wherein Ar represents p-methoxyphenyl, R represents methyl, Y represents ethyl one, and R 1 and R 2 are both methyl, which compound has excellent coronary vasodilatory activity and is particularly valuable as a Ca ++ antagonistic coronary vasodilator.

According to the present invention, the compound of formula (I) is prepared by reacting a 1,5-benzothiazepine derivative of formula (II), preferably an alkali metal salt thereof, at the nitrogen atom at the 5-35 position, with a compound of formula (III) as depicted in the present invention. subsequent reaction scheme (i).

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Scheme (I)

Ar '1 r ^ rs ~ \ / Μ VOCOR + Z-Y-N - * (I) 5' ^ N- / \ 2

0 H O K

(II) (III) 1 2 wherein Ar, R, R, R and Y have the meaning defined above and 10 Z represents halogen such as chlorine or bromine.

The condensation reaction, i.e. The N-alkylation in the above reaction scheme (I) can usually be carried out in an aprotic polar solvent, preferably in the presence of si 1 in a bullet and / or aluminum oxide. Compound (II) is preferably reacted with compound (III) after being converted to an alkali metal salt thereof on the nitrogen atom of 5-stage, which is prepared by treating compound (II) with an all potassium metal hydride (e.g., sodium hydride) in a amount of 1 to 1.5 moles to 1 mole of compound (II). All the potassium salt of compound (II) can be formed in the reaction system, i.e., the reaction is carried out by dissolving compound (II) in an aprotic polar solvent, adding silica gel and / or alumina, adding an all potassium hydride (whereby compound (II) is converted to an all potassium salt) and then reacted with compound (III), compound (III) may be added to the reaction system before compound (II) is converted to an alkali metal salt thereof. In the reaction, compound (III) is used in an amount of 1 to 3 moles to 1 mole of compound (II). The reaction is usually carried out at a temperature of 5 to 60 ° C, preferably 15 to 40 ° C for approx. 1 to 24 hours, preferably 3 to 10 hours, the temperature varying according to the nature of the solvent and compound 30 (III).

Si 1 in ball one and the alumina used in the above reaction may be any of the commercially available products, but they are preferably used after being dehydrated by calcination (heating). The amount of silica gel and alumina is not critical, but is usually in the range of 0.01 to 2 parts by weight to 1 part by weight of compound (II). The particle size of the silica gel and the alumina is also not critical, and any product useful for column chromatography can be used.

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The aprotic polar solvent includes, for example, dimethyl sul foxide, sulfolane, Ν, Ν-dimethylformamide, N, N-dimethylacetamide, 1,3-di methyl-2-i dazoli di non, N-methyl pyrroli don, hexamethyl-phosphorotriamide or similar, among which dimethyl sul foxide is especially preferred.

The compound (I) thus prepared can be isolated from the reaction mixture by conventional methods, for example, by neutralizing the reaction mixture, removing the remaining reagents (e.g., silica gel, alumina, etc.), filtering, adding a non-polar solvent for the filtrate and, if necessary, washing the mixture with water and drying, and crystallization of the product by evaporation of the solvent. According to this method, the desired compound (I) can be obtained in high yield (e.g., 70 to 80%) and in high purity.

The 1,5-benzothiazepine derivative of formula (II) used as starting material is preferably prepared by treating a 2-hydroxy-3- (2'-aminophenylthio) -3-phenylpropionic acid of formula (IV) with an acylating agent, as shown. in the following reaction scheme (II) 20 f ^ VS (_OH base% (tjf5-S "OH acylating agent ^ Δ COOH COOH.base (IV) (IV) _ Ar Ί s-- <Ar

rtf 'OCOR acid anhydride \ jT * \ -OCOR

-ζ

_ COOH.base H O

25 (V) (II) p. Wherein Ar and R have the meaning defined above.

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

The base used includes, for example, pyridine compounds (e.g., pyridine, o-picoline, β-picoline, γ-picoline, a halogen-substituted pyridine, quinoline, isoquinoline), tertiary amines (e.g., trimethylamine, triethylamine), carbonates, hydrogen carbonates or salts of organic acids (eg acetate) with alkali metal (lithium, sodium, potassium) and carbonates, hydrogen carbonates or salts with organic acids (eg acetate) of alkaline earth metals (eg magnesium) , including pyridine and 7

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lithium compounds are particularly preferred. 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 terrestrial potassium pastes and one or more equivalents in the case of pyridine compounds 5 and tertiary amines, calculated in relation to compound (IV).

The acylating agent includes, for example, an anhydride compound of a lower alkanoic acid having 2 to 4 carbon atoms (eg acetic anhydride, propionic anhydride, butyric anhydride) and a halide compound of the lower alkanoic acid (e.g. acetyl chloride, acetyl bromide, propionyl chloride) which is used in an amount equivalent to compound (IV) or (IV ') or greater.

There are no restrictions on the solvent unless it has an undesirable effect on the reaction and includes, for example, benzene, chloroform, ethyl acetate, Ν, Ν-dimethylformamide, 1,3-15 dimethyl-2-imidazolidinone or the like. When pyridine compounds or tertiary amines are used as a base, they can also be used as a solvent.

The reaction of the above reaction scheme (II) proceeds in various ways according to the nature and amount of the acylating agent. When an anhydride of a lower alkanoic acid is used in an amount of 2 equivalents or more, usually 2 to 2.5 equivalents to compound (IV) or (IV '), the desired compound (II) is obtained directly from compound ( IV '), that is, the acylation of the hydroxy group at the 2-position and the ring closure is done in a single procedure. In this embodiment, the procedure is carried out by dissolving compound (IV) in a solvent, adding a base (whereby compound (IV) is converted to a salt (IV ') of the base), adding an anhydride of a lower alkanoic acid in an amount of two equivalents or more, usually 2 to 2.5 equivalents of compound (IV) or (IV ') and then reacting the mixture at a temperature of 0 to 50 ° C, preferably 15 to 35 ° C, for a few for several hours, usually 2 to 3 hours. In accordance with this procedure, compound (IV ') may first be acylated with an equivalent of the acid anhydride to form an intermediate of formula (V), and the intermediate (V) may be cyclized in the presence of the remaining acid anhydride, but this acylation and cyclization will be performed. approximately simultaneously within a short period of time, such as two to three hours, and the desired compound is thereby obtained in high yield, such as 70% or more.

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When less than two equivalents (e.g., 1 to 1.5 equivalents) of anhydrous alkanoic acid are used as the acylating agent, the reaction is at least partially incomplete, i.e., at least part of the intermediate (V) is not cyclized and the reaction product is obtained in a mixture of the intermediate (V) and compound (II). Furthermore, only the intermediate (V) is obtained when 1 to 1.5 equivalents of halide of a lower alkanoic acid are used as acylating agent. The intermediate (V) can be readily cyclized to give the desired compound (II) by treatment with 1 to 1.5 equivalents of the acid anhydride.

Alternatively, compound (II) can be prepared by acylating a compound of formula (IV) with an acylating agent and subsequently deacylating the resulting intermediate (VII) with an amine as shown in the following reaction scheme (III). s /

L li „„ V- ° H means || V_0C0R

^^ NH2 / -> ^ ΛνΗ / -> COOH I qooh

COR

(Iv) L (VI) ^ acylating Ar agent r ^ / TS \ am-in - »Q £ NyocoR ~~>; ii) 1-¾

25 C0R

(VII) wherein Ar and R have the meaning defined above.

The acylation of compound (IV) is usually carried out in a suitable solvent such as toluene, xylene or ethylbenzene using three equivalents or more of an anhydride of a lower alkanoic acid as mentioned above at a temperature of 100 to 150 ° C, preferably 110 to 140 ° C for a few to several hours, preferably 2 to 3 hours. When an excess of the acid anhydride is used, it can also be used as a solvent without the use of any other solvent. When less than three equiv 9 is used as an acylating agent

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or the two or more equivalents of a halide of a lower alkanoic acid or when the reaction is carried out at a temperature lower than 100 ° C, an intermediate (VI) and optionally a compound wherein only the amino group of 2'- position 5 is acylated without being closed. The intermediate (VI) may be cyclized to obtain the intermediate (VII) by treatment with one or more equivalents of an anhydride of a lower alkanoic acid, also at a temperature of 110 to 140 ° C.

The intermediate (VII) can be readily deacylated to Compound (II) by treatment with an amine in a suitable solvent, thereby selectively deacylating only the acyl group on the 5-nitrogen nitrogen atom.

The amine used in the above deacylation includes, for example, ammonia, hydrazine, aliphatic primary amines (e.g., methylamine, ethylamine, n-butylamine), aromatic primary amines (e.g., aniline, toluidine), aliphatic secondary amines. amines (e.g., dimethylamine, diethylamine, di-n-propylamine, di-n-butylamine), cyclic amines (e.g., morpholine, pyrrole, imidazole), or the like, among which aliphatic secondary amines such as dimethylamine or diethylamine, is preferred.

These amines are used in equimolar amount or in excess of compound (VII).

There are no restrictions on the solvent used in the deacylation unless it has an undesirable effect on the deacylation reaction and it includes, for example, chloroform, benzene, toluene, xylene, N, N-dimethyl formamide or the like.

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

Compound (II) thus obtained in the above reaction scheme (II) or (III) can be used for condensation reaction with compound (III) in reaction scheme (I) after being isolated or without isolation from the reaction mixture. According to a preferred embodiment of the present invention, the reaction in Reaction Scheme (II) or (III) and the reaction in Reaction Scheme (I) are thus carried out continuously in the same reaction system.

The starting compound (IV) used in the above Reaction Scheme 35 (II) is also known (cf. Japanese Patent Publication No. 9383/1970) or can be prepared by the same method as described therein.

That is, compound (IV) can be prepared by reacting a 2-aminothiophenol (IX) and a glycolic acid ester of formula (X) as shown in

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The following reaction scheme (IV): (γ-SH + Ar-CH-CH-COOR 3

c M

5 m2 ° (IX) (X)

Ar f ^ S \ n "Hydrolysis 10 / -" - * (IV) H2 coor3 (XI) 15

ISLAND

wherein Ar has the meaning defined above and R is an ester residue.

The above reaction is usually carried out in a suitable solvent such as toluene, xylene or ethyl benzene at a temperature of 100 to 140 ° C for 5 to 20 hours, followed by hydrolysis of the resulting compound (IX) in a conventional manner, for example by treatment. with an acid (e.g. hydrochloric or sulfuric acid) or an alkali (e.g., sodium hydroxide or potassium hydroxide).

Compound (IV) has two asymmetric carbon atoms in the 2- and 3-positions, and therefore there are two stereomers of threoisomers and erythro isomers. According to the method of the above reaction scheme (IV), compound (IV) is obtained in the form of a threoisomer. The threoisomer further includes two optically active isomers, i.e., d-isomer and 1-isomer, and it is usually obtained in a racemic mixture (d1-form). The final compound of formula (I) also has optical activity and the d-isomer 30 of compound (I) is particularly valuable by virtue of higher pharmacological activity. Although the racemic mixture of compound (I) can be dissolved in optically active isomers, the optical solution is preferably carried out on compound (IV) because the desired optically active compound (I) can be obtained from an optically active compound (IV) without racemia. in the acylation and cyclization steps of the above reaction schemes (II) and (III) and in the N-alkylation step of the above reaction scheme (I).

The present inventors have found that the optical solution of compound (IV) can be advantageously made using an optical

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active α-phenylethylamine as follows.

A racemic mixture of compound (IV) is reacted with 1 to 1.2 equivalents of an optically active α-phenylethylamine, i.e. d-α-phenyl-ethylamine or Ι-α-phenyl-ethylamine in a suitable solvent to obtain two diastereomeric salts which can be dissolved in each optically active salt using the difference in solubility in the solvent. When da-phenylethylamine is used, a salt of the d-isomer of compound (IV) is isolated as a heavy-soluble salt, and when 1-a-phenyl-ethylamine is used, a salt of the 1-isomer of compound (IV) 10 is isolated as a heavy-soluble salt.

The solvent used in the optical solution includes, 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 15 (f. eg benzene, ethyl acetate), of which water is especially preferred from an economic and industrial point of view, because the two diastereomeric salts show a greater solubility difference in water and the heavily soluble diastereomer salt further has less solubility in water.

The thus-soluble diastereomer salt thus obtained can be isolated from the reaction mixture by precipitation in a conventional manner, for example by cooling the reaction mixture, by concentrating and subsequently cooling the reaction mixture, or by varying the solvent component, that is, by adding one or more other solvents followed by separation. of the precipitated salt by a conventional solid-liquid separation method, for example, by filtration, decanting or the like. The thus-insoluble heavy-soluble diastereomer salt 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 30 diastereomer salt is obtained.

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

When d- or Ι-α-phenyl ethylamine is used, as mentioned above, a heavily soluble salt of d- or 1-isomer of compound (IV) is isolated, respectively. After separation of such a heavy soluble salt 12

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is otherwise soluble isomeric salt, ie. a salt of 1-isomer of compound (IV) with d-α-phenylethylamine or a salt of d-isomer of compound (IV) with Ι-α-phenyl ethylamine, contained in the remaining mother liquor. The optically active compound (IV) can also be obtained from the mother liquor by adding 5 a mineral acid (e.g. hydrochloric acid) to the mother liquor containing a soluble, optically active diastereomeric salt and separation of the resulting crystals, whereby the desired crystals are obtained. optically active compound (IV) can be isolated in the form of a free acid.

The optically active α-phenylethylamine used in the above optical solution can, after separation of the optically active compound (IV), be recovered almost quantitatively from the solution by filtration in a conventional manner, for example by doing so after the separation of the optically active compound (IV) obtained acidic filtrate alkaline with an alkali (e.g., sodium hydroxide, potassium hydroxide), extract the solution with a hydrophobic organic solvent (e.g., benzene, ethyl acetate, ether) and remove the solvent from the extract.

The optically active compound (IV) is preferably used as starting material in the acylation and cyclization reaction as shown in Scheme (II) or (III), but the starting compound (IV) can also be used in the form of an optically active diastereomeric salt having an optically active α phenylethylamine without being converted to a free acid thereof.

The present invention is further illustrated by the following Examples.

25

Example 1 (1) Preparation of 2-hydroxy-3- (2β-amino-phenylthiol-3- (4 "-methoxyphenylpropionic acid v compound IIV) in threoforml 2-aminothiophenol (14.38 g) and methyl-3 - ( 4'-Methoxyphenyl) glycidate 30 (20.80 g) is dissolved in toluene (100 ml) and refluxed under nitrogen gas for 6 hours. The reaction mixture is concentrated and ethanol is added under heating. After cooling the mixture, the precipitated crystals are separated by filtration and is recrystallized from ethanol to give methyl-threo-2-hydroxy-3- (2'-aminophenylthio) -3- (4 "-35 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 at 50 ° C for 30 minutes. After cooling to room temperature, the reaction mixture is neutralized with hydrochloric acid. The precedent 13

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pitted crystals are separated by filtration, washed with water and dried to give a racemic mixture of the title compound (IV) in threoform (15.63 g, 98%), mp 169-172 ° C.

12) Optical resolution of compound (IV)

The above-obtained racemic mixture of compound (IV) in threoform (6.38 g) and d-α-phenylethylamine (2.58 g) is dissolved in water (100 ml) under heating and the mixture is stirred at room temperature for 5 hours. The precipitated crystals were separated by filtration and recrystallized from water (60 ml) to give an optically pure salt of d-isomer of threo compound (IV) with da-phenylethylamine (3.95 g), mp 157-158 ° C. , [α] D 23 = + 376 ° (c = 0.511, ethanol).

The above procedure is repeated except that instead of water, the solvents shown in Table 1 are used. The results are shown in Table 1.

Table 1 20 r ---- oo

Solvent Yield of [a] D (in ethanol)

Species Amount of salt (g) of salt ___ (ml) __ * __

Ethanol 60/36 + 362.4 ° (c = 0.521) 50% ethanol-HgO 0.70 + 37470 ° (c = 0.475) 25% ethanol-H 2 O 0.89 + 369.4 ° (c = 0.438)

Isopropamoil 4 0.89 + 333.8 ° (c-0.535)

Benzene I 0.58 + 333.0 ° (c-0.565)

Ethyl acetate 2.5 0.59 + 337.2 ° (c = 0.522) 30 1 ----- 35 The product obtained above is dissolved in water (180 ml) under heating, 1N HCl (8.9 ml) is added and the mixture is cooled. The precipitated crystals are separated by filtration, washed with water and dried to give an optically pure d-isomer of the threo compound (IV) 14

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(2.68 g, 84%), mp 138-139 ° C, [α] β23 = + 346 ° (c = 0.355, ethanol).

To the mother liquor obtained after separation of the salt of d-isomer of compound (IV) and da-phenylethylamine, IN HCl (8.5 ml) is added and the precipitated crystals are separated by filtration, washed with water and dried to give 1 -isomer of threo compound (IV) (2.40 g), [α] D = -306 (c = 0.360, ethanol), optical purity: 88.7% [as 1-isomer of compound (IV)].

(3) Preparation of Optically Active 2- (4'-Methoxyphenyl) -3-Acetoxy-2,3-Dihydro-1,5-BenzothiazeDin-4-5Hl-One (Compound (ΙΙΠ)

Threo-d-2-hydroxy-3- (2'-aminophenylthio) -3- (4 "-methoxyphenyl) propionic acid [compound (IV)] (3.19 g) is dissolved in N, N-dimethyl formamide (5 ml ) and pyridine (0.80 ml) are added. The mixture is stirred at room temperature for 30 minutes. After dropwise addition of acetic anhydride (2.04 g) to the mixture, the reaction mixture is stirred continuously for one hour. (200 ml) and the precipitated crystals are separated by filtration, washed with water and dried to give a d-cis compound (II) (2.80 g, 81.6%), mp 150-152 ° C. product is subjected to thin layer chromatography on silica gel (developer, benzene: ethyl acetate = 4: 1) to give a pure product of the title compound, mp 152-153 ° C, [a] D21.5 = + 39 ° (c = 0.500, CHCl 3).

When the above procedure is repeated except that a salt of the propionic acid starting compound (IV) with da-phenylethylamine (0.50 g) is used instead of the free propionic acid compound (IV), the title d-cis compound ( II) (0.27 g, 69%), [α] D 23 = + 38.1 ° (c = 0.486, CHCl 3) (optical purity: 97.7%).

Preparation of Optically Active 2- (4'-Methoxyphenyl-3-acetoxy-5- (N, N-dimethylaminoethyl-2,3-dihydro-1 ♦ 5-benzothi azeoin-4) 5Hl-one compound (111

The above-obtained d-cis compound (II) (1.0 g) and dried silica gel ("Wako gel C-200") suitable for column chromatography (0.50 g) are added to dried dimethyl sulfoxide (10 g). ml) and 60% by weight sodium hydride (0.14 g) is added and the mixture is stirred at room temperature for 30 minutes. To the reaction mixture is added 50 wt% solution (0.75 g) of Ν, Ν-dimethylaminoethyl chloride in ether. After stirring at 15

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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. The benzene is distilled from the 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. The resulting crystals are separated by filtration and recrystallized from ethanol-isopropanol to give a d-cis hydrochloride product of the title compound (I) (1.01 g, 76.9%), mp 206-207 ° C = 10 + 96.6 ° (c = 0.613, methanol).

Example 2

Preparation of 2-acetoxy-3- (2β-aminophenylthio) -3-1,4-methoxyphenyl) propionic acid Free acid of Compound (Will 15 2- (1). 2-Hydroxy-3- (2'-aminophenylthio) 3 - (4 "-methoxyphenyl) propionic acid [compound (IV)] (3.19 g) is dissolved in pyridine (10 ml), acetic anhydride (1.02 g) is added dropwise at 10 ° C and the mixture is stirred at Add the reaction mixture to ice water (200 ml), neutralize with hydrochloric acid and extract with benzene (50 ml x 2).

The benzene extracts are combined, washed with water and dried, and then evaporated to remove benzene to give the free acid of compound (V) (3.07 g, 85.0%), mp 104-107 ° C.

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

2- (3). The reaction is carried out in the same manner as described in Example 2 (1) above, except that triethylamine (1.50 g) is used instead of pyridine to give the free acid of compound (V) (2.89 g). 80%).

Example 3

Preparation of 2- (4 H -methoxyphenyl) -3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one [compound (11) 1 3- (1). 2-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 After 16

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dropwise addition of acetic anhydride (0.85 g), the mixture is further stirred at room temperature for 30 minutes. The reaction mixture is added to ice water (100 ml) and the precipitated crystals are separated by filtration, washed with water and dried to give the title compound (II) (2.42 g, 84.9%), m.p. 200 ° C.

3- (2). 2-hydroxy-3- (2-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 one hour After dropwise addition of acetic anhydride (0.32 g) over 30 minutes, the mixture is further stirred at room temperature for 1.5 hours. The reaction mixture is treated in the same manner as described under 3- (1) to give the title Compound (II) (0.48 g, 89%), mp 198-200 ° C.

When this product is recrystallized from ethanol, a pure product thereof is obtained, mp 200-202 ° C.

3- (3). The same compound (IV) as used under 3- (2) above (1.00 g) is dissolved in Ν, Ν-dimethylformamide (2 ml), triethylamine (0.32 g) added and the mixture stirred at room temperature for 30 minutes. After addition of acetic anhydride (0.64 g), the mixture is further stirred at room temperature for 2 hours. The reaction mixture is treated in the same manner as described under 3- (1) above to give the title compound (II) (0.75 g, 69.8%), mp 193-195 ° C.

3- (4). The procedure under 3- (3) above is repeated except that 1,3-dimethyl-2-imidazolidinone is used as a solvent instead of Ν, Ν-dimethylformamide and that pyridine (0.26 g) is used instead of tri-25 ethylamine to give the title compound (II) (0.90 g, 83.7%), mp 198-200 ° C.

3- (5). The same compound (IV) as used under 3- (2) above (3.19 g) is dissolved in Ν, Ν-dimethylformamide (25 ml), lithium carbonate (0.37 g) added and the mixture stirred at room temperature for one hour.

After dropwise addition of a solution of acetic anhydride (2.20 g) in Ν, Ν-dimethylformamide (5 ml), the mixture is further stirred for 2 hours at room temperature. The reaction mixture is added to ice water (800 ml) and the precipitated crystals are separated by filtration, washed with water and dried to give the title compound (II) 35 (2.81 g, 81.9%), mp 196-198 ° C.

3- (6). The procedure under 3- (5) above is repeated except that 50 wt% sodium hydride (0.53 g) is used in place of lithium carbonate to give the title compound (II) (2.13 g, 17).

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62.1%), mp 192-196 ° C.

3- (7) * The same compound (IV) as used under 3- (2) above (0.50 g) is dissolved in α-picoline (2 ml) and the mixture is stirred at room temperature for 30 minutes. After dropwise addition of acetic anhydride (0.32 g) over one hour, the mixture is further stirred for one hour at room temperature. The reaction mixture is treated in the same manner as described under 3- (1) above to give the title compound (II) (0.38 g, 70.7%), mp 198-200 ° C.

3- (8). The same compound (IV) used under 3- (2) (0.30 g) is dissolved in quinoline (1 ml) and the mixture is stirred at room temperature for 30 minutes. After dropwise addition of acetic anhydride (0.192 g) over 30 minutes, the mixture is further stirred for two hours at room temperature. The reaction mixture is added to ice-water (100 ml) and neutralized with hydrochloric acid. The precipitated crystals are separated by filtration, washed with water and dried to give the title compound (II) (0.24 g, 74.4%), mp 198-200 ° C.

3- (9). The procedure under 3- (5) above is repeated except that instead of lithium carbonate various metal salts are used as shown in Table 2. The results are shown in Table 2.

20

Table 2

Metal salt Yield of

Art Quantity (g) Compound (II) _ 25 - ----—— "------

Basic Magnesium Carbonate 2.91 2.23 g (65.0%)

2.52 2.40 g (70.0%) 2Q Lithium Acetate 1.30 2.50 g (72.9%)

Example 4 Preparation of 2- (4-Methoxyphenyl) -3-Dropionyloxy-2,3-Hydro-1,5-benzothiazepine-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

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18 Ν, Ν-dimethylformamide (5 ml) and the solution is stirred at room temperature for 30 minutes. After the dropwise addition of propionic anhydride (2.60 g), the mixture is further stirred for an hour and a half at room temperature. The reaction mixture is added to ice water (200 ml) and the precipitated 5 crystals are separated by filtration, washed with water and dried to give the title propionate compound (II) (3.19 g, 89.4%), m.p. 155-156 ° C.

4- (2). The same compound (IV) as used under 4- (1) above (3.19 g) is dissolved in 1,3-dimethyl-2-imidazolidinone (30 ml), lithium carbonate (0.74 g) added and the mixture stirred. at room temperature for one hour. After dropwise addition of propionic anhydride (2.86 g), the mixture is further stirred for two hours at room temperature. The reaction mixture is added to ice-water (800 ml) and the precipitated crystals are separated by filtration, washed with water and dried to give the title propionic compound (II) (3.29 g, 92.2%), m.p. 155 -156 ° C.

Example 5

Preparation of 2- (4β-methoxyphenyl) -3- (acetoxy-5- (NN-dimethylamino-ethylH-2,3-dihydro-1,5-benzothiaze-din-4 (5H-one) Γ compound (D1-5 (1)) (4'-methoxyphenyl) -3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one [compound (II)] - (1.0 g) and dried sieve of column chromatography grade (which is obtained by calcining commercially available sieve 1 in a kugel ("Wako gel C-200") at 300 ° C under nitrogen for 8 hours) (0.5 g) is added to dimethyl sulfoxide (10 ml ), 60 wt% sodium hydride (0.14 g) is added and the mixture is stirred at room temperature for 30 minutes. A 50 wt% solution (0.75 g) of Ν, Ν-dimethylaminoethyl chloride in ether is added to the mixture, and the mixture is further stirred for 5 hours at room temperature and neutralized with acetic acid, then 30 sieve is filtered off in a boiler, to the filtrate is added benzene and the benzene solution is washed with water, dried and evaporated to remove benzene to give a solid (1.20 g) The solid is added to di isopropyl ether. After removal of insoluble material by filtration, the filtrate is left to stand at room temperature. The precipitated 35 crystals are separated by filtration to give the title compound (I) (0.92 g, 76.2%), mp 134-135 ° C. The hydrochloride of this product: mp 187-188 ° C.

The above procedure is repeated, except in the case of trade 19

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available silica gel is used as it is in place of the dried sieve 1 in the ball, and sodium hydride is used in an amount of 0.16 g. As a result, the title compound (I) is obtained in a yield of 67.9%.

5- (2). The procedure under 5 - (1) above is repeated except that instead of silica gel, a dried alumina of column chromatography grade is used (which is obtained by calcining commercially available alumina at 300 ° C under nitrogen for 8 hours) ( 200 mesh, 0.5 g) to give the title compound (I) (0.87 g, 72.1%).

The above procedure is repeated except that a commercially available alumina is used as it is in place of the dried alumina and sodium hydride is used in an amount of 0.18 g. As a result, the title compound (I) is obtained in a yield of 57.1%.

5- (3). The procedure under 5- (1) above is repeated except that instead of dimethyl sul foxide, different aprotic polar solvents are used as shown in Table 3 and the reaction time is 20 hours.

As a result, the title compound (I) is obtained in a yield as shown in Table 3.

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Table 3

Aprot polar Silica gel or solvent alumina compound (I) 25 -------- Ν, Ν-dimethylformamide Dried silica gel 70% Ν, Ν-dimethylformamide Dried alumina 65% N-methylpyrrolidone Dried silica gel 72% N, N ' -dimethylimidazolidinone 63%

Hexamethylphosphoryl triamide "71% Ν, Ν'-dimethylacetamide" 68%

Sulfolane "71% 35 —-- L-- 20

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Example 6

Preparation of 2- (4-Methoxyphenyl) -3-acetoxy-5-acetyl-2,3-dihydro-1 <5-benzothiazepine-4 (5H-one-compound Compound III-6- (1). 2-Hydroxy-3- (2 ') -aminophenylthio) -3- (4 "-metboxyphenyl) -5-propionic acid [compound (IV)] (3.19 g) and acetic anhydride (6.12 g) was added to xylene (10 ml) and the mixture refluxed for 2 hours. The acetic acid is removed by azeotropic distillation. After completion of the reaction, the reaction mixture is cooled to room temperature and the precipitated crystals are separated by filtration, washed and dried to give the title compound (VII) (3.28 g, 85.2 %), mp 158-160 ° C. When this product is recrystallized from xylene, the pure product, mp 160-161 ° C, is obtained.

6- (2). The same compound (IV) as used under 6- (1) above (3.19 g) and acetic anhydride (1.22 g) was added to xylene (10 ml) and the mixture stirred at 50 ° C for one hour. After the reaction, the precipitated crystals are separated by filtration, washed and dried to give 2-hydroxy-3- (2'-N-acetylamino-nophenylthio) -3- (4 "-methoxyphenyl) -propionic acid ( 3.43 g, 95.0%), mp 170-171 ° C.

This product (3.0 g) and acetic anhydride (3.39 g) is added to 20 xylene (10 ml) and the mixture is reacted in the same manner as described under 6- (1) above to give the title compound (VII). ) (2.7 g, 84.5%), mp 158-160 ° C.

6- (3). An N-acetylderivate of compound (IV) (7.22 g) and acetic anhydride (2.44 g) is added to toluene (20 ml) and the mixture is reacted at 80 ° C for one hour. After cooling the reaction mixture, the precipitated crystals are separated by filtration, washed and dried to give 2-acetoxy-3- (2'-N-acetylaminophenylthio) -3- (4 "-methoxyphenyl) propionic acid [compound (VI) ] (7.40 g, 91.8%), mp 164-166 ° C.

This product (3.70 g) and acetic anhydride (1.87 g) are added to xylene (10 ml) and the mixture is reacted in the same manner as described under 6- (1) above 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-benzothiazepine-4 (5H-one compound) ΙΙΠ 7- (1). 2- (4'-methoxyphenyl) ) -3-Acetoxy-5-acetyl-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one [compound (VII)] (1.93 g) and diethylamine \ 21

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(0.44 g) is added to chloroform (20 ml) and the mixture is stirred at room temperature for one hour. After distillation of chloroform, water is added to the residue and the precipitated crystals are separated by filtration, washed with water and dried to give the title compound (II) · (1.63 g, 94.8%), m.p. 200 ° C.

7- (2). The reaction is carried out in the same manner as described under 7- (1) above, except that dimethylamine (0.27 g) is used in place of diethylamine and that benzene (90 ml) is used in place of chloroform, thus giving the title compound (II) is obtained (1.54 g, 89.6%), m.p. 196-199 ° C.

7 - (3). Compound (VII) (200 mg) and aniline (63 mg) are added to chloroform (10 ml) and the mixture is stirred at room temperature for 2 hours. The chloroform solution is concentrated and subjected to thin layer chromatography using 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 under 7- (1) above is repeated, except that different amines are used instead of dimethylamine as shown in Table 4. As a result, the title compound (II) is obtained in the yields shown in Table 4.

Table 4 25 - - Amine

Species Quantity (g) bond (II)

Ammonia * 0.15 1.20 g (69.8%)

Phenyfhydrazine 0.65 i, 35 g (78.6%) n-butylamine 0.50 1/40 g (8i / 4%)

Imidazole 0.40 1/50 g (87.3%) ΜθΓΡΗοΙ? Η 0.55 1/42 g (82.6%) *) Prepared by passing ammonia gas in chloroform.

35

Claims (3)

A process for the preparation of 1,5-benzothiazepine derivatives of the general formula (I) 5 Ar r | T V-OCOR (I) o / r1 10 YN \ r 2 wherein Ar represents phenyl substituted with alkoxy of 1-4 carbon atoms, 1 2 R represents all alkyl of 1-4 carbon atoms, R and R each represent 15 alkyl of 1-4 carbon atoms, and Y represents all alkyl of having 1-4 carbon atoms in racemic or optically active form, characterized by reacting (Al) a 2-hydroxy-3- (2'-aminophenylthio) -3-phenylpropionic acid of the general formula (IV) Ar - (y iT y_ oh (IV) Å COOH wherein Ar has the meaning given above, which compound 25 (IV) is in the form of a salt with a base, having two or more equivalents of a lower alkanoic anhydride or (A-2) reacting said compound (IV) with less than two equivalents of a lower alkanoic anhydride or with one or more equivalents of a lower alkanoic acid halide, after which the resulting product of the general formula (V) Ar \ 11 \ - OCOR (V ) / COOH base 35 wherein Ar and R have the above meanings are reacted with one or more equivalents of a lower alkane acid anhydride, or (A-3) reacting said compound (IV) in the form of the free acid with DK 154077 B three or more equivalents of a lower alkanoic anhydride, after which the obtained compound of the general formula (VII) 5 L uf V0 CO ) wherein COR and R are as defined above are reacted with an amine and (B) then reacted with the resulting 1,5-benzothiazepine derivative of the general formula (II) Ar J if V-OCOR / TT H ~~% 20 wherein Ar and iR have the meaning given above or an alkali metal salt thereof 'forged 1-3 molar equivalents of a compound of the general formula (131;), 25 ^ r1 zyn (in) XR2 1 2 Wherein R, R and Y are as defined above and Z represents halogen in the presence of silica gel and / or alumina in an aprotic solvent. 2. A process according to claim 1, characterized in that the reaction in step (B) is carried out in the presence of 0.01 to 2 parts by weight of silica gel and / or 35 alumina per minute. part by weight of compound (II). 3. A process according to claim 1 or 2, characterized in that the base used to form a salt of compound (IV) is selected from the group consisting of pyridine, tertiary amine, alkali metal and alkaline earth metal and the amine is selected from the group consisting of ammonia, hydrazine, aliphatic primary amine, aromatic amine, aliphatic secondary amine and cyclic amine. 5 10 15 20 25