CS269330B1 - Method of dilthiazeme production - Google Patents

Abstract

Oiltlazea of Formula I, a drug of the group Calcium antagoniatl, ee new scorpion such that the crude product is prepared by alkylacl and acetylating compound II to dissolve! in water and this solution is extracted into organic the solvents are free of non-polar solvents impurities. From the aqueous phase ee equivalent the amount of pH provided by the pH temperatures of 0 ° C to + 20 ° C release crystalline the compound I which is isolated after isolation e) dissolution dissolves in an organic solvent β by means of hydrogen chloride converted to dlltlase at least 99% pure in yield about 85% (based on the amount used compound II).

Description

The present invention relates to a process for the preparation of cls - (+) - 3-acetoxy-2,3-dihydro-5- (2-dimethylaminoethyl) -2- (4-methoxyfexyl) -1,5-bensothiazepin-4 (5H) -one hydrochloride (diltiazem, compound I) with a purity of at least 99% by a process starting from cia- (+) - 2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothlazepin-4 (5H) -one (compound II) without isolation and purification of intermediates. .

Several methods for preparing diltiazem from compound II are currently known. They mostly use in the first phase of the preparation the alkylation of nitrogen in position 5 and the subsequent acetylation of the hydroxyl in position 3. GB patent δ. U.S. Pat. No. 1,236,467 describes, for example, the abovementioned alkylation by the action of alkali metals, alkali metal hydrides or alkali metal amides on compound II and the subsequent reaction with 2- (dimethylaminoethyl chloride in dioxane, toluene, xylene or dimethyl sulfoxide). - (dimethylamino) ethyl chloride in the presence of anhydrous potassium carbonate using solvents such as acetone, ethyl acetate or mixtures thereof with water, optionally in the presence of potassium hydroxide in acetone (European Patent No. 0 081 234).

The product of both of the above-mentioned routes is a substance from which direct acetylation cannot be prepared by diltiazem of the desired quality, and high losses occur by purification of the product thus prepared by known routes. This problem seems to be solved by the work describing the above-mentioned alkylation in a two-phase system consisting of water and chlorinated hydrocarbons in the presence of calcium or barium hydroxide with the addition of phase transfer catalysts of quaternary ammonium salts (European Patent No. 0 153 303). which gives high purity diltiazem without further purification after subsequent acetylation. However, the reported ee results could not be confirmed both quantitatively and qualitatively.

The essence of the invention is a new highly efficient method for the production of diltiazem. The process consists in using the N-alkylated compound II directly in the crude state for the subsequent acetylation. The crude compound I thus prepared, which is in the form of a salt with acetic acid after the reaction, is dissolved in water, and non-polar impurities are removed from this solution by extraction with an organic solvent. The organic phase after shaking can be extracted with water, thereby selectively extracting compound I, which is partially converted to a non-polar phase. The aqueous solution thus freed of non-polar impurities is basified with an equivalent amount of ammonia. It is also possible to use an alkali metal carbonate or bicarbonate or an alkali metal hydroxide for alkalization. In this operation, it is essential to observe the equivalence condition for the release of the base of compound I from its salt, which is ensured by the indication of the pH on alkalization. Non-alkalization reduces the yield of the production process, over-alkalization leads to the destruction of the molecule by deeacetylation. Kugita et al. (Chern. Pharm. Bull., 19, 595 (1971)) describe, for example, the quantitative preparation of a desacetylated product by reacting Compound I with an excess of sodium hydroxide in water: ethanol at room temperature. For this reason, it is additionally suitable to work at reduced temperatures when preparing the base of compound I. The preparation of the base according to the described method of production ensures a very effective removal of polar impurities. The base of the compound I thus obtained is converted into the compound X with the aid of hydrogen chloride in an ethyl acetate medium. Alcohols having 1 to 3 carbon atoms, dimethylformamide or mixtures of these solvents can also be used as the hydrochloride-forming medium.

The process of the invention allows the final steps of the synthesis to be combined without isolation and purification of intermediates, thereby substantially increasing the yield of production. European Patent No. 0 081 234, which uses a similar arrangement of reaction steps, but with the isolation of alkylated compound II gives an average of 90.7% of theory for alkylation and 71% for acetylation. The total yield is therefore 64.4 ¢. The average total yield of 59.3% was achieved during the reproduction (laboratory, pilot plant). Another advantage is the implementation of these production steps in half the time with respect to the current state of the production method, thereby

CS 269 330 B1 increases the capacity of the production facility. In addition, by replacing the environment of organic solvents for the purification of intermediates with water, the working environment and work safety are improved. Another advantage of the production process is the possibility of applying the final operations of the process to purify analytically unsatisfactory fractions of compound I obtained from the mother liquors in the production of the substance.

The process according to the invention is carried out by alkylating compound IX in the presence of acetone and in the presence of potassium carbonate with 2- (dimethylamino) ethyl chloride. After the reaction, the inorganic portion is filtered off and the filtrate is freed from the solvent by distillation. Acetic anhydride is added to the residue and acetylation is carried out in position 3. Excess reagent is then distilled off and the crude diltiazem is extracted with an organic solvent after dissolution in water. The organic ee extract is re-extracted with water and the combined aqueous phases, after cooling to +5 to -> 10 ° C, are basified with an indication of pH with an equivalent amount of the above base to a final pH of 7.2 to 7 * 4. The crystalline base of compound I thus obtained, after isolation and drying, is dissolved in ethyl acetate (optionally in an alcohol having 1 to 3 carbon atoms or dimethylformamide or in a mixture of these substances) and, after filtration with activated carbon, acidified with hydrogen chloride to a final pH of 3 to 3.5. . The precipitated crystalline substance is filtered off with suction, washed with pure solvent and dried. Obtained by diltiazem of at least 99% purity ·

The production method according to the invention has been successfully tested in practice. By treating about 1 kg of compound II, diltiazem of 99.95% and 99.55% purity was prepared in two quarter-run batches in an average yield of about 83% of theory. By processing the mother liquors, the yield increased by an average of about 7% of theory. The overall average yield of the reaction was thus about 90% of theory.

The process according to the invention can be used for the production of diltiazem, a drug from the group of calcium antagonists.

The following examples illustrate but do not limit the method according to the invention.

Example 1.

15.0 g of compound II, 8.7 g of dimethylaminoethyl hydrochloride hydrochloride and 16.0 g of anhydrous potassium carbonate ee are suspended in 100 ml of acetone, the suspension is heated to boiling with stirring and maintained under these conditions for 30 minutes. A solution of 20 ml of acetone and 5 ml of water is then added dropwise over a period of 10 to 15 minutes and reflux is continued for 6 hours. After completion of the reaction, the solid is filtered off and washed with 3 x 20 ml of acetone. The filtrate is distilled off from the solvent.

6.35 g of acetic anhydrite are added to the residue and the solution is kept at 95 DEG C. for 5 hours. Then the excess reagent is distilled off under reduced pressure and the residue is dissolved in 75 ml of water. ml of toluene and the combined toluene phases are extracted with 15 ml and 10 ml of water. The combined aqueous phases are cooled to +5 to +10 DEG C. and basified with dilute ammonia solution (pca 10%) to a final pH of 7.2 to 10. 7.4 · The crystallization of diltiazem base is terminated after standing at the above temperature for 2 hours. The solid is filtered off with suction, washed with 3 * 10 ml of water and dried. About 19.0 g of diltiazem base with a melting point of 101 DEG C. to 102 DEG C. and a content of at least 98.0% are obtained.

This is dissolved in 90 ml of ethyl acetate and, after the addition of 0.25 g of activated carbon, filtered and the filter is washed with 10 ml of ethyl acetate. The combined ethyl acetate phases are acidified with a solution of hydrogen chloride in ethanol to a final pH of 3 to 3.5. Crystallization, which begins already during the acidification, is completed by standing at + 5 ° C for 2 hours. The precipitate is filtered off with suction, washed with 2 * 10 ml of ethyl acetate and dried. For example, 19.6 g of diltiazem with a content of 99.72% * are obtained.

Example 2

According to Example 1, 19.12 g of diltiazem of 99.87% purity were prepared, but for alkalized aqueous solution of the crude product in the preparation of the base of compound I, a saturated solution of potassium carbonate was used and the hydrochlorides were prepared in ethanol.

Example 3

According to Example 1, 18.40 g of diltiazem of 99.45% purity were prepared, but ethyl acetate was extracted from the aqueous solution from an aqueous solution, and ethyl acetate was prepared and the hydrochloride was prepared in methanol.

Example 4

According to Example 1, 19.36 g of diltlazein with a purity of 99.53% were prepared, but a 10% solution of sodium hydroxide in distilled water was used to alkalize the aqueous solution of the crude product in the preparation of the base of compound I and the hydrochlorides were prepared in 2-propanol by introducing hydrogen chloride gas at +10 ° C to + 20 ° C.

Example 5

According to Example 1, 18.79 g of diltiazem with a purity of 99.72% were prepared, but extraction gasoline was used to extract non-polar impurities from the aqueous solution and the hydrochloride was prepared in dimethylformamide: ethyl acetate in a volume ratio of 1 to 5.

Example 6

According to Example 1, 19.17 g of diltiazem with a purity of 99.42% were prepared, but a saturated aqueous solution of sodium bicarbonate was used at +20 ° C to alkalize an aqueous solution of the crude product in the preparation of the base of compound I.

Claims (1)

OBJECT OF THE INVENTION Process for the preparation of diltiazem of at least 99% purity by alkylation and acetylation of compound II and subsequent purification, characterized in that the crude N-alkylated compound II is directly acetylated and the crude product thus obtained is dissolved in water, extracted with toluene, optionally ethyl acetate or extraction gasoline and after alkalization with an equivalent amount of ammonia, optionally an alkali metal carbonate or bicarbonate or an alkali metal hydroxide at a temperature of 0 ° C to + 20 ° C, compound I is isolated in the form of a crystalline base which is dissolved in ethyl acetate or alcohol having 1 to 3 carbon atoms, dimethylformamide or mixtures of these solvents at 0 ° C to + 20 ° C with hydrochloric acid are converted into the hydrochloride of compound I,