CS214979B1 - A method of purifying dosulepinium chloride - Google Patents

Abstract

The method of purifying dosulepinium chloride of structural formula I, a psychotropic drug from the group of thymolytics and anxiolytics, not meeting the requirements imposed on this drug by the analytical specification and pharmacopoeia, containing various amounts of ballast substances, products of side and subsequent reactions of synthesis, products of oxidation and subsequent decomposition of the original substances, consists in converting the contaminated dosulepinium chloride in the presence of a medium polar solvent of the general formula CHjCOO.R, in which R represents a group of the formula C2H5-, n- or iso- C3H7- or n- or iso- C4H9-, preferably in the presence of ethyl acetate, to a dosulepinium base and its solution, after washing with water and purification with 0.5 to 3.5% activated carbon, at a temperature of 0 to 20 “C, without isolation, is converted again in the same solvent with a 30 to 35% solution of hydrogen chloride in alcohol with 1 to 4 carbon atoms, preferably ethanol, to dosulepinium chloride, of the quality prescribed for this drug.

Description

214873

BACKGROUND OF THE INVENTION The present invention relates to a process for the purification of ultrafine chloride obtained by treating the master batches from the main reaction sequence contaminated with by-products.

Dosulepinium chloride [synonyms pro-thiadene chloride, dothiepine chloride, trans-3- (6,11-dihydrodibenzo / b, e-thiepin-11-ylidene) propyldimethylammonium chloride] of structural formula I and

C19H22ClNS represents a significant thymolytic psychopharmaceutical (B. Melichar et al., Chemical Drugs, Aviation, Prague 1972). In the synthesis of this important drug, especially in its final phase, chloridosulepinium is obtained, which is difficult to purify for its pharmacological use. For this purpose, processes are used in which dosing adhesive is purified by crystallization from suitable solvents, or mixtures thereof, e.g. from ethanol, isopropanol or methyl ethyl ketone (K. Stacha F. Bickelhaupt, Monatsch. 83, 896, 1962 or from a mixture of n-butanol with acetone, or the base, isolated from dosulepinium chloride, is purified by crystallization from petroleum ether, or purified from the isolated chloride via crystalline oxalate [F. Gadient et al., Helv. Chim. Acta 45, 1860, (1962) and Belgian Patent 607,503 to Sandoz SA). In processes that use a base isolation to purify the chloride, non-polar solvents such as chloroform [F. Gadient et al., Helv. Chim Acta 45,1860, (1962), Belgian Patent 607,503 to San-doz SA], petroleum ether, ether, benzene, trichloroethylene [M. Rajshner, Lab. Prescription Prothiaden (1963)].

The ballast substances contained in the unsatisfactory chloride dosulepinia originate from the earlier stages and can be derived from a diphthalide which accompanies the synthesis starting material in an amount of 6-10% [JH Brewster et al., J. Org. Chem., 488, (1963)]. In the next phase of preparation, the transferase was active by the action of thiophenolate in the acid-bound substance, the structure of which corresponds to 2- (2-carboxy-phenyl) -indane-1,3-dione of structural formula II.

This compound was first described by M. Protiva sespol. in Collectlon 37, 3660, (1972).

This by-product of the synthesis is converted into further by-products in further stages of the production (by Grignard reaction), which are then accompanied by fat portions of dosulepinia. Removal of these feed materials from dosulepinia by mere crystallization is not successful and the number of recrystallization from different solvents and their mixtures result in considerable losses of expensive product. Another disadvantage of recrystallization is the need to use a significant amount of activated carbon at a higher temperature of the dosulepinia solutions, leading to oxidation of sulfur heteroatoms to oxide or dioxidosulepinium, respectively. In addition, a large amount of adsorbent makes it difficult to filter the final product solutions and significantly reduces the process yield. N-butanol is used as the solvent for the recrystallization of the highly contaminated components, but is particularly disadvantageous because it fumes the working environment by separating the final product.

The above-mentioned disadvantages are eliminated by the method of cleaning the dosulepinium chloride according to the invention so as to purify the dosulepinium chloride, containing 2 to 10% of the ballast substances in varying proportions, the oxide and the dosulepinium dioxide, the decomposition of the main substance and another up to four, by thin layer chromatography. proven, closely-determined by-products of the synthesis of formula (II) and the decomposition of the compound of formula (I) are converted in the presence of a medium polar solvent of the formula CH 3 COOR where R is a group of formula (C 2 H 5 ', n - or iso) - C3H7- or non-C4-9H9-, preferably ethyl acetate, in the dosulepinia base which, after purification with 0.5 to 3.5% activated carbon, is converted again without isolation in the same solvent with a hydrogen chloride-alcohol solution with 1 to 4 carbon atoms in a satisfactory dosule-pinium chloride.

The subject matter of the process is the use of a suitable organic solvent to decompose its disodium chloride, which at the same time permits further purification of the product, without isolation, with activated charcoal at 0 to 20 ° C, thereby limiting the oxidation of the sulfur heteroatom. furthermore, it has the property that dosulepinium chloride is a suitable crystallization medium with a solution of hydrogen chloride in a C 1 -C 4 -alcohol or optionally other organic solvents, preferably acetone. By utilizing both of these solvents, crystalline dosulepinium chloride is obtained of high purity, satisfying the requirements of both the analytical specification and the drug. A further advantage of this process is the fact that the purification operations of the product are carried out in both the basic region (decomposition of chloridudosulepinium) and in the acidic region (crystallization of dosulepinium chloride). 2

Claims (1)

214979 The present process for purifying dosulepinium provides the advantage of an easy and quantitative re-generation of the solvent used. The examples illustrate, but do not limit, the subject matter of the invention. EXAMPLE 1 20 g of polluted dosulepinium chloride (from fat liquors) containing 92% of the C19H22ClNS total sample containing 2% of oxide and 1% of dosulepinium dioxide and another about 5% of unidentified impurities, as evidenced by thin layer chromatography, dissolve at a temperature of 40 DEG. C in 100 ml of water and filtered. 80 ml of ethyl acetate and an aqueous solution of ammonia are added to the solution to alkaline pH 10. After removal of the aqueous layer, the organic phase is drained and the organic phase is shaken with 100 ml of water. The separated, 15 ° C, base-ethylsulphonium acetate solution is purified by filtration with 0.2 g of active charcoal and acidified to room temperature at 30 ° -35 ° C with an ethanolic hydrogen chloride solution to pH 0. 22 ml of liquid are then distilled off from the reaction mixture, and the reaction mixture is cooled to -5 DEG C. After 8 hours of crystallization, the precipitated product is washed and washed with 10 ml of cooled acetone. The yield is 16.2 g (88% of theory) of white crystalline dosulepinium chloride, satisfying the analytical specification. prescribed for this drug and pharmacopoeia requirements. EXAMPLE 2 20 g of polluted dosulepinium chloride having a content of 94.5% of a compound of formula C19H22ClNS, further containing 1% of dosulepinium oxide, 0.5% of dosulepinium dioxide and 4% of unidentified impurities, as shown by thin layer chromatography, are dissolved at 40 DEG C. 80 ml of water. Ethyl acetate (80 ml) and aqueous ammonia solution were added to the solution to pH 10. After separation of the aqueous layer, the ethyl acetate solution was shaken with 80 ml of water. The cooled base solution was purified by filtration with 0.2 g of charcoal and acidified at room temperature with 30-35% hydrogen chloride in ethanoluna pH 0. 22 mL of the mixture was then distilled off, the reaction mixture was cooled to 55 ° C, 22 was added. ml of acetone and cooled to 55 ° C. OBJECT OF THE INVENTION A method for purifying dosulepinium chloride of structural formula I After 8 h of crystallization, the product is filtered off with suction and washed with 10 ml of acetone. The yield is 16.3 g (86.5% of the theory) of white crystalline dosulepinium chloride, meeting the conditions prescribed for the drug. EXAMPLE 3 20 g of polluted dosulepinium chloride containing 92% of the compound of formula C19H22ClNS, containing 2% of dosulepinium oxide and 1% of dosulepinium dioxid and another about 5% of non-identified, thin layered, impurities, Dissolve at 40 ° C in 80 mL of water. To the solution was added 70 mL of butyl acetate and aqueous ammonia to pH 10. After separation of the aqueous layer, the butyl acetate solution of the base was dried with 80 mL of water. The cooled base solution was purified by filtration with 0.2 g of activated charcoal and acidified at room temperature with 30-35% hydrogen chloride / methanol solution. After 8 h of crystallization at 0 ° C, the product is filtered off with suction, washed with 15 ml of acetone and dried at room temperature. Yield: 16.0 g (87%) of white, crystalline dosulepinium chloride, satisfying the conditions prescribed for this drug. EXAMPLE 4 50 g of polluted dosulepinium chloride having a content of 94.5% of the compound of formula C19H22ClNS, further containing 1% of dosulepinium oxide, 0.5% of dosulepinium dioxide and 4% of unidentified impurities, as shown by thin layer chromatography, are dissolved at 40 DEG C. 200 ml of water are added. The solution is treated with 180 ml of isobutyl acetate and adjusted to pH 10 with an aqueous 20-26% ammonia solution. After separation of the aqueous layer, the isobutyl acetate solution of the base is dried with 180 ml of water. After purification of the solution by filtration with 1 g of activated charcoal, the base is converted to a dosylepinium chloride solution at room temperature with a 30-35% solution of hydrochloric acid in butanol. After addition of 84 ml of acetone and 8 hrs crystalliz. at 0-5 ° C, dosulep chloride. It is filtered off with suction, washed with acetone and dried at room temperature. The yield is 44.5 g (94.2% of theory) of white, crystalline dosulepinium chloride, satisfying the criteria prescribed for this drug. OUT of the side-reaction products of synthesis, oxidation products and subsequent decomposition of the originals in an amount of 0.5 to 10% and 1 to 8, which can be demonstrated by thin layer chromatography, characterized in that the starting material is converted to the presence of a medium polar solvent of the general formula CH3COO.R in which R is a group of the formula c2h5-, n- or iso- C3H7- nebon- or iso- C4H9-, 3 214979 preferably in the presence of ethyl acetate, for baseidosulinium, washing the solution with water and purifying with 0.5 to 3.5% activated carbon, preferably 1 to 2%, at 0 to 20 ° C, preferably at 15 ° C, and directly re-converting with a 30 to 35% solution of hydrogen chloride in alcohol and 1 to 4 carbon atoms , preferably ethanol, dosulepinium chloride, the quality prescribed for the drug. Print 52 139-83