CS210018B1 - Process for the preparation of purely pure 11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo / b, e / thiepine hydrochloride - Google Patents

Abstract

The invention relates to the industrial production of a pharmacopoeially pure substance with ataractic and antidepressant activity. Its aim is to improve the efficiency of the purification methods known to date and at the same time reduce material costs in production. The essence of the invention lies in the crystallization of a crude or contaminated product from a mixture of organic solvents. The production procedure is as follows: the crude substance is dissolved in a mixture of toluene and methanol in a volume ratio of 6:1 to 15:1 at the boiling point of the above mixtures and the insoluble components are filtered off. The filtrate is then enriched with the addition of an alcohol selected from the group comprising cyclohexanol, n-butanol, isobutyl alcohol, isopropyl alcohol and ethanol, the amount of this addition, based on the amount of toluene used, being 3 to 25%. Methanol is then removed from the resulting solvent mixture by distillation under normal pressure. The pharmacopoeially pure product crystallizes from the remaining solvent mixture, usually during distillation. After one hour of crystallization at 20 °C, the product can be separated. It is washed with pure toluene and dried at 70 °C to constant weight. The yield is 93 to 96%.

Description

The present invention relates to the preparation of pharmacologically pure 11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, n] thiepine, thymoleptics and antidepressants known under the synonyms of dosulepin hydrochloride, dothiepine hydrochloride or prothiaden. The invention finds application particularly in the industrial production of said substance, at the end of the multi-stage synthesis in the final purification phase of the crude product »

The known prior art methods for purifying crude 11- (3-dimethylaminopropylene) -6,11-dihyd rhodibenzo [b, e] thiepine hydrochloride are crystallization from a mixture of organic solvents, one component being ethanol and the other components being, for example, chlorinated solvents, aliphatic hydrocarbons, ketones or esters. The common drawback of these steps is that they do not reliably remove all impurities and chemical impurities from the crude or otherwise pre-treated product. Moreover, these processes are not characterized by very good yields.

Newer procedure Purification of the crude product according to Cs. No. 204103 Crystallization of 11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] thiepine hydrochloride (Kugler R.), based on crystallization from a mixture of n-butanol and acetone, no longer has the above drawbacks; in terms of process cost, however, it does not differ significantly from these procedures.

It differs from the previous processes for purification of crude 1- (3-dimethylamino-tert-butylidene) -6,11-dihydrodibenzo [b, e] thiepine hydrochloride both in the manner of implementation and in the resultant effect of the process for preparing a pharmacopoeically pure product according to the invention. It is based on crystallization from a mixture of organic solvents and is carried out by dissolving the crude material in a toluene / methanol mixture in a volume ratio of 6: 1 to 15: 1 at the boiling point of the mixture used and filtering off the insolubles.

It is advantageous to combine this filtration with decolorizing the solution with activated carbon. An alcohol selected from the group consisting of cyclohexanol, n-butanol, isobutyl alcohol, isopropyl alcohol and ethanol is added to the filtrate in an amount of 3 to 25% of the amount of toluene used, and the solvent mixture is now removed by distillation at normal pressure. methanol in the form of an azeotropic mixture with toluene.

The pharmacologically pure product usually crystallizes from the remaining solvent mixtures already during the distillation. Upon completion, the mixture was cooled to 20 ° C and after stirring for one hour at this temperature the product was filtered off with suction. Wash with a small amount of filtered toluene and dry at 70 ° C to constant weight. The yield varies from 93 to 96%.

This basic procedure can be altered so that the alcohol from the group of said alcohols can be added to the toluene / methanol mixture at the start of the dissolution of the product to be purified.

The process for the preparation of the pharmacologically pure 11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] thiepine hydrochloride according to the invention is very simple and conventional equipment is sufficient.

Its greatest advantage over other processes is that, due to the specific composition of the crystallization mixture, it yields sufficiently high yields for the first crystallization fraction, so that there is no need to process higher product fractions. , wage and energy.

It is also advantageous in view of the possibility of using inexpensive and commercially available solvents.

The quality of the product complies in all respects with the pharmacopoeial requirements. In industrial application, its speed and low energy demand are applied because crystallization is carried out at room temperature. The choice and composition of the crystallization mixture also results in high process reliability, which eliminates the possibility of premature crystallization during filtration.

The following examples illustrate but do not limit the manner in which the present invention may be practiced.

He did

100.0 g of crude 11- (3-dimethylaminopropylidyl) -6,11-dihydrodibenzo [b, e] thiepine hydrochloride is dissolved in the mixture at boiling point

1000 ml toluene and 90 ml methanol. Add g of activated carbon, filter the solution and wash the funnel with a mixture of 150 ml of toluene and 10 ml of methanol. 50 ml of cyclohexanol are then added to the filtrate and methanol is distilled off under normal pressure from a solvent mixture of methanol in the form of a binary mixture of toluene-methanol, b.p. 63.8 ° C. The product crystallizes as a rule before distillation during heating, sometimes during distillation.

The distillation process is terminated when the vapor temperature rises to approximately 105 ° C. The volume of distillate is usually 130 to 140 ml. The product suspension in solvents was cooled to 20 ° C and stirred at this temperature for 1 hour. The product is filtered off with suction, washed with toluene and dried at 70 ° C. The purity of the product corresponds to the pharmacopoeial requirements, for example the pharmacopoeia of the CsL 3. Yield: 95.9 g;

95.9

Example 2

100.0 g of crude 11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] thiepine hydrochloride is dissolved in boiling in a mixture of 1000 ml of toluene and 90 ml of methanol. Add g of activated carbon, filter the solution and wash the funnel with a mixture of 150 ml of toluene and 10 ml of methanol. To the filtrate was then added 0 ml of n-butanol and continued as in Example 1. Yield: 94.5 g; 94,5%,

Example 3

100.0 g of crude 11- (3-dimethylarainopropylidene) -6,11-dihydrodibenzo [b, e] thiepine hydrochloride were dissolved in boiling in a mixture of 1000 ml of toluene and 100 ml of methanol. 5 g of activated carbon are added, the solution is filtered and the funnel is washed with a mixture of 150 ml of toluene and 10 ml of methanol. 70 ml of isobutyl alcohol are then added to the filtrate and the procedure is continued as in Example 1. Yield: 93.9 g;

93.9 7 ..

Example 4

100.0 g of crude 11- (3-dimethylaminopropylidene) -6,11-dihydrochloride give benzo (b, e) thiepine at boiling in a mixture of 1000 ml of toluene and 95 ml of methanol. 5 g of activated carbon are added, the solution is filtered and the funnel is washed with a mixture of 150 ml of toluene and 10 ml of methanol. The filtrate was then treated with 60 ml of isopropyl alcohol and continued as in Example 1. Yield: 94.8 g; 94.8

Example5

100.0 g of crude 11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo [210018] b, e) thiepine are dissolved in boiling in a mixture of 1000 ml of toluene and 100 ml of methanol. 6 g of activated carbon are added, the solution is filtered and the funnel is washed with a mixture of 150 ml of toluene and 10 ml of methanol. 60 ml of ethanol are then added to the filtrate and methanol is distilled off from the solvent mixture under normal pressure in the form of a binary mixture with toluene. A packed column of about 30 .mu.m long is used to sharply separate the low-boiling fraction. The product crystallizes when the vast majority of methanol is already removed from the environment. Upon completion of the distillation, proceed as in Example 1. Yield;

93.1 g; 93.1%.

Claims (2)

SUBJECT V Process for the preparation of pharmacologically pure 11- (3-dimethylaminopropylidene-6,11-dihydrodibenzo [b, e] thiepine hydrochloride by crystallization of a crude product, characterized in that the crude product is dissolved in a toluene / methanol mixture in a 6: 1 to 15: v / v 1 boiling, insoluble matter is filtered off, the filtrate is enriched with an alcohol selected from the group consisting of: Example 6 100.0 g of 11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] thiepine hydrochloride containing small amounts of impurities are dissolved in boiling in a mixture of 1000 ml of toluene, 90 ml of methanol and 60 ml of cyclohexanol. 6 g of activated carbon are added, the solution is filtered and the funnel is washed with a mixture of 150 ml of toluene and 10 ml of methanol. Methanol was distilled off from the filtrate under normal pressure as a binary mixture with toluene, and then continued as in Example 1. Yield 93.1 g; 93.1%. BACKGROUND OF THE INVENTION cyclohexanol, n-hutanol, isobutyl alcohol, isopropyl alcohol and ethanol in an amount of 3 to 25% based on the amount of toluene used, and crystallization in the resulting mixture by distilling off methanol at normal pressure. 2. A process according to claim 1, characterized in that the alcohol enrichment is carried out before the impurities are removed by filtration. Severogr * fia. n. line 7. Moet