MXPA00003820A - Process for the recycle of a waste product of diltiazem synthesis - Google Patents

Abstract

A process which allows the re-use of compounds of formula (III-(2R, 3R)) in diltiazem synthesis through a process of conversion to a mixture of enantiomers III-(2R,3R) and III-(2S,3S) is described.

Description

PROCESS FOR THE RECYCLING OF A RESIDUAL PRODUCT OF THE SYNTHESIS OF DILTIAZEM The present invention relates to a method for the recycling of a residual product from the synthesis of diltiazem and, more particularly, relates to a method for the preparation of esters of threo-2-hydroxy-3- (2- aminophenylthio) -3- (4-methoxyphenyl) propionic intermediates useful for the synthesis of diltiazem, starting from (2R, 3R) -2-hydroxy-3- (2-aminophenylthio) -3- (-methoxyphenyl) propionic acid or derivatives of the same. Diltiazem, (+) - (2S, 3S) -3-acetoxy-5- [2- (dimethylamino) ethyl] -2,3-dihydro-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 ( 5H) -one (The Merck Index, XII ed., No. 3247, page 541), is a known drug with calcium antagonist activity described in British Patent 1236467 (Tanabe Seiyaku Co. Ltd.). Various methods for. the preparation of diltiazem, such as, for example, those described in British Patent 1236467 cited above, in European Patent Application 0 059 335 and in Japanese Patent no. 71/8982, all in the name of Tanabe Seiyaku Co. Ltd., are described in the literature.

Most of these methods substantially provide the following synthesis scheme.

Scheme 1 N * 'Diltiazem where R is a hydrogen atom or a lower alkyl and the asterisk marks the stereogenic carbon atoms. These methods use the compound of formula III-threo in racemic form, as an intermediate. However, diltiazem shows stereocenters with S configuration and then, after the scheme reported above, a separation step of the (2S, 3S) enantiomer of the ona (2R, 3R) is necessary. The separation of the two enantiomers can be carried out on the intermediate (III) in the form of an ester (R = alkyl), as well as in the acid form (R = H). For example, the separation of the enantiomers (2S, 3S) and (2R, 3R) at the level of ester III can be carried out using an optically active acid as a resolving agent (US Patent 5,144,025 - Zambon Group S.p.A.) or by spontaneous resolution (Patent United States 5,097,059 - Zambón Group S.p.A.). In the case of separation at the level of acid III, the methods described in the literature provide, inter alia, resolution with optically active bases such as a-phenylethylamine (patent application).

European 0 098 892 - Tanabe Seiyaku Co. Ltd.) or L-lysine (British patent application 2130578 - Istituto Luso Fármaco d 'Italia S.p.A.) or acylation in the presence of a lipase (European patent application 0 617 130 - Orion-Yhtyma Oy Fermion). It is evident that the resolution methods have the disadvantage of giving the (2S, 3S) isomer with a maximum theoretical yield of 50% over the racemate and also giving the corresponding (2R, 3R) isomer at the same time. The isomers with configuration (2R, 3R), unsuitable for the synthesis of diltiazem, are then a residual product in the industrial synthesis. As a consequence, a process for the recycling of such compounds to recover them for the synthesis of diltiazem would be useful. As far as we know, the only method described in the literature to recycle an intermediary with configuration (2R, 3R) is the process called in the U.S. Patent 5,102,999 (Zambón Group S.p.A.), which provides the racemization of the IV-cis intermediate (2R, 3R). We have now found a process for the conversion of the intermediates III- (2R, 3R) to a mixture of enantiomers III- (2R, 3R) and III- (2S, 3S) which allows to reuse the enantiomers with configuration (2R, 3R ) of the intermediates of formula III for the synthesis of diltiazem. Therefore, the object of the present invention is a. process for the conversion of threo- (2R, 3R) -2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxyphenylthio) -3- (4-methoxyphenyl) propionic acid derivatives of the formula "formula wherein R1 is a linear or branched C? -C3 alkyl or a hydrogen atom; in a mixture of enantiomers III- (2R-3R) and III- (2S, 3S). characterized by the steps of: (a) cyclization of compound III- (2R, 3R) to give the corresponding compound of formula (b) the conversion of the compound of formula wherein R2 is a hydrogen atom or a C2-C4 acyl group. (c) the reduction to give the compound of formula (d) the opening reaction by treatment with a strong acid or a strong base in an alcoholic or aqueous solvent. The mixture of the two enantiomers III- (2R, 3R) and III- (2S, 3S) obtained with the process object of the present invention, can be solved according to the methods already reported to separate the (2S, 3S) enantiomers useful for the synthesis of diltiazem.

In the present context, if not otherwise specified, the term enantiomer mixture means a substantially racemic mixture (ratio of 2R, 3R: 2S, 3S of about 1: 1) or a mixture where the 2S, 3S enantiomer prevails. Analogously, if the absolute configuration of the compounds of formula III or IV is not indicated, it means that the compounds are in a substantially racemic mixture (ratio of 2R, 3R: 2S, 3S of about 1: 1) or a mixture where the 2S, 3S enantiomer prevails. The term "straight or branched C1-C3 alkyl" means methyl, ethyl, propyl, isopropyl and the term "C2-C4 acyl group" means acetyl, propionyl, butyryl, isobutyryl. The intermediates of formula III- (2R, 3R) used as initial products in the process object of the present invention are known compounds and are obtained as residual products in the process of optical separation for the synthesis of diltiazem. In general, the compounds of formula III are in the form of acid (R1 = H) or in the form of methyl (RX = CH3) or ethyl (R1 = CH2-CH3) ester. Preferably, in the process object of the present invention, the compounds of formula III are methyl esters.

Cyclization of compound III- (2R, 3R) to give the compound of formula IV- (2R, 3R) can be carried out according to the known methods for cyclization of the corresponding (2S, 3S) enantiomer. For example, the cyclization of the esters of formula III- (2R, 3R) can be carried out by treating with phosphonic acids (US Pat. No. 5,223,612 - Zambon Group SpA) or by treating with sulfonic acids (European patent application 0 447 135 - Tanabe Seiyaku Co. Ltd.). Similarly, the cyclisation of the acid of formula III- (2R, 3R) can be carried out by treating with sulphonic acids (European patent application 0 395 323 Tanabe Seiyaku Co. Ltd.) or with bases (European patent application 0 450 705 - Stamicarbon BV). In the process object of the present invention, the cyclization reaction is preferably carried out starting from the methyl ester of formula III- (2R, 3R) by treating with cis-propenyl phosphonic acid. The subsequent conversion reaction to the derivative V can be carried out according to known methods as well. For example, the methods described in J. Org. Chem., 1996. 8586-8590 or in the aforementioned U.S. Patent 5,102,999. Preferably, in the process object of the present invention, the acetyl derivative of formula V (R2 = COCH3) is prepared, then hydrolyzed to give the compound Va, which will be in equilibrium with the tautomer (Vb) as it is reported here later.

Va Vb The following reduction reaction allows obtaining the IV-cis compound. Optionally, the hydrolysis and reduction reactions can be carried out in a vessel, ie in a single reaction environment, without isolating the compound Va or (Vb). The preparation of the acetyl derivative V is preferably carried out by treating with acetic anhydride in dimethyl sulfoxide, in the presence of catalytic amounts of pyridine. Optional hydrolysis can be carried out by treating with bases such as sodium hydroxide or sodium mesylate. The reduction of the compound of formula V can be carried out with known methods, for example, by treating with hydrams according to that reported in the aforementioned US Patent 5,102,999. The resulting IV-cis compound can then be converted to the corresponding compound of formula III-threo by treating with strong acid or with a strong base in an alcoholic or aqueous solvent. The amount of acid or base is at least equimolar, preferably in excess, with respect to the IV-cis compound. In general, the reaction is carried out using an excess of acid or base equal to 10% -30% by mole with respect to compound IV. The strong acids used in the process of the invention are inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids or organic acids such as sulfonic acids, preferably methanesulfonic acid, p-toluenesulfonic acid and camphorsulfonic acid. Preferably, sodium hydroxide is used as the strong base. Methanesulfonic acid is preferably used in the process object of the present invention. The reaction is carried out in an alcohol solvent, such as, for example, methane or ethanol, preferably in methanol or water optionally in admixture with a suitable cosolvent, such as dimethylsulfoxide. Depending on the alcohol used as a solvent, the corresponding ester of formula III-threo is obtained, which can then be used again in the preparation of diltiazem according to the synthetic route illustrated in scheme 1 above. When an aqueous solvent is used, the acid (R1 = H) of formula III-threo is obtained and used according to the synthetic route illustrated in scheme 1 as well. The initial reaction of the compound of formula IV-cis represents the most outstanding characteristic of the process object of the present invention. In fact, as far as we know, this reaction has never been described in the literature. On the contrary, cyclizations of the compound III-threo to give the compound IV-cis using acids or bases have been widely described in the literature. In addition, it is evident that the possibility of racemizing the residual products with configuration (2R, 3R) of the process for the preparation of diltiazem at the level of one of the first synthetic intermediates represents a relevant advantage from a practical and economic point of view.

A particularly preferred embodiment of the process object of the present invention is the following. The methyl ester of formula III- (2R, 3R), obtained by resolution of the corresponding racemic mixture, is cyclized with cis-propenyl-phosphonic acid and then oxidized by treatment with acetic anhydride / dimethylsulfoxide / pyridine to obtain the acetyl derivative of formula V. After hydrolysis and basic reduction with sodium borohydride, the racemic compound IV-cis is obtained and treated with an excess of methanesulfonic acid in methanol until the racemic methyl ester III-threo is obtained. The resolution of the racemic methyl ester? Ll-threo allows obtaining the compound III- (2S, 3S) which is used for the synthesis of diltiazem and the enantiomer III- (2R, 3R), which may undergo an additional recycling phase according to the object of the process of the present invention. To better illustrate the present invention, the following examples are now given.

Example 1 A mixture of methyl (2R, 3R) -2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxy) -propionate (5 g, "15 mmol) and cis-propenyl phosphonic acid (0.183 g; 1. 5 mmoles) 'in xylene (35 ml), heated under reflux and stirred for 5.5 hours. After distilling a mixture of xylene / methanol (at about 3%), the reaction mixture was cooled to 15 ° C. The resulting precipitate was filtered under vacuum, washed with xylene (2x5 ml) and then dried in an oven at 65 ° C to obtain (2R, 3R) -2, 3-dihydro-3-hydroxy-2- (4- methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one (42 g, 89.6% yield).

Example 2 A catalytic amount of pyridine (19.5 g, 0.25 mole) was added to a solution of (2R, 3R) -2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepine- 4 (5H) -one (500 g, 1.6 moles) in dimethylsulfoxide (1100 g, 14.1 moles) and acetic anhydride (425 g, 4.17 moles). After maintaining the solution under stirring at room temperature for 24 hours, water (1000 rcl) was added slowly and the mixture was kept under stirring for 30 minutes. The crystalline precipitate was filtered, washed with methanol and dried to obtain 3-acetoxy-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one (481.6 g, yield 84.7%).

Example 3 A suspension of 3-acetoxy-2- (methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one (17.1 g, 0.05 mmol) in methanol (51 ml) was cooled in ice and then added a solution of NaOH (5 g, 0.125 mmol) in water (63 ml). The solution was then kept under stirring for 2 hours at room temperature. t After neutralizing with 2N HCl (50 ml) and extraction with ethyl acetate, the organic phase was washed twice, dried and concentrated to obtain a viscous oil. The oil was treated with ethyl ether to obtain 2- (4-methoxyphenyl) -1,5-benzothiazepin-3,4 (4H, H) -dione (12.98 g, 86.7% yield) as a crystalline solid.

Example 4 Sodium borohydride (0.567 g, 15 mmol) was added to a solution of 2- (4-methoxyphenyl) -1,5-benzothiazepin-3,4 (2H, 5H) -dione (4.25 g, 14.2 mmol) in methanol (65 ml) was kept under stirring at 15 ° C. 1 hour later, the reaction mixture was poured into a buffer solution (100 ml) at pH 7 and the methanol was removed by distillation under vacuum.

The resulting mixture was extracted with methylene chloride (2x30 ml). After evaporation of the solvent under reduced pressure, cis-2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one was obtained (4.15 g; 97%) as a racemic mixture.

Example 5 In a 500 ml flask, equipped with thermometer and condenser, cis-2, 3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one was suspended ( 50 g, 165.9 mmol) in methanol (200 ml) and methanesulfonic acid (19.2, 200 mmol) was added to the mixture. The reaction mixture was brought to reflux and the progress of the reaction was followed by TLC (Thin Layer Chromatography) (eluent ethyl acetate: hexane = 6: 4). After heating for 7 hours, the content of the initial product was about 1%. The reaction mixture was then cooled to room temperature before adding, with a dropping funnel, an 8% sodium bicarbonate solution (208 g, final pH = 7.0). The resulting precipitate was filtered and washed three times with water (3x50 ml). The resulting solid was then dried at 50 ° C under vacuum to a constweight to obtain methyl threo-2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxyphenyl) -propionate (54 g, 94.2 molar yield). %, CLAP title 96.5%).

Example 6 30% sodium methylate in methanol was added (0.1 ml, 0.5 mmol) and, 15 minutes later, sodium borohydride (54 mg, 1.42 mmol) to a suspension of 3-acetoxy-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) - Ona (1 g, 2.9 mmol) in methanol (5 ml). After maintaining the mixture under stirring at room temperature for 5 hours, methanesulfonic acid (0.6 ml, 9.3 mmol) was added and the mixture was stirred under reflux for 5 hours. After cooling to room temperature, 8% sodium bicarbonate (9 ml) was added. After adding toluene, the resulting solid was filtered, washed with water (3x1 ml) and dried at 50 ° C under vacuum to obtain threo-2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxyphenyl) Methyl propionate (0.92 g, 90% molar yield, CLAP 95% title).

Example 7 30% sodium methylate in methanol (0.5 ml, 2.5 mmol) was added and, 15 minutes later, sodium borohydride (0.28 g, 7.35 mmol) to a suspension of 3-acetoxy-2- (4-methoxyphenyl). -1,5-benzothiazepin-4 (5H) -one (5 g, 14.7 mmol) in methanol (25 ml). After maintaining the mixture under stirring at room temperature for 5 hours, a 6.5 M solution of hydrochloric acid in methanol (2.7 ml; 17. 6 mmoles) and the mixture was heated under reflux for hours . After cooling to room temperature, 8% sodium bicarbonate (16 ml) was added. The resulting precipitate was filtered, washed with water (3x5 ml) and dried at 50 ° C under vacuum to obtain methyl threo-2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxyphenyl) -propionate ( 5 g, 85% molar yield, XH-NMR 75% title). It is noted that in relation to this date, the best method known to the applicto carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (9)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A process for the conversion of threo- (2R, 3R) -2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxyphenylthio) -3- (4-methoxyphenyl) propionic acid derivatives and their derivatives of the formula where R1 is a linear or branched C? -C3 alkyl or a hydrogen atom; in a mixture of enantiomers III- (2R-3R) and III- (2S, 3S), characterized by the following steps: (a) cyclization of compound III- (2R, 3R) to give the corresponding compound of formula (b) ) the conversion of the compound of formula where R is a hydrogen atom or a C2-C4 acyl group. (c) the reduction to give the compound of formula rv-c / s (d) the opening reaction by treatment with a strong acid or with a strong base in an alcoholic or aqueous solvent.

2. The process according to claim 1, characterized in that it serves for the conversion of threo- (2R, 3R) -2-hydroxy-3- (2-aminophenylthio) -3- (-methoxyphenyl) propionic acid methyl ester.

3. The process according to claim 1, characterized in that the compound of formula V wherein R2 is acetyl is used.

4. The process according to claim 1, characterized in that the opening reaction is carried out by treating with a strong acid.

5. The process according to claim 4, characterized in that the strong acid is hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, p-toluenesulfonic or camphorsulfonic acid.

6. The process according to claim 5, characterized in that the strong acid is methanesulfonic acid.

7. The process according to claim 4, characterized in that an alcohol solvent is used.

8. The process according to claim 7, characterized in that the solvent is methanol.

9. Diltiazem, (+) - (2S, 3S) -3-acetoxy-5- [2- (dimethylamino) ethyl] -2,3-dihydro-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 ( 5H) -one, characterized in that it is obtained by using an intermediate of formula III prepared with the process according to claim 1.