CS229882B1 - A method for isolating methyl 3a, 7a-diacetoxy-12-methanesulfonyloxy-5? -cholanové - Google Patents

Abstract

3alpha,7alpha-diacetoxy-12alpha-methanesulfonyloxy-5beta-cholanic acid methyl ester is isolated after the reaction of methanesulfonyl chloride with 3alpha,7alpha-diacetoxy-12alpha-hydroxy-5beta-cholanic acid methyl ester in pyridine by pouring the reaction mixture into an ice-cold aqueous solution of mineral acid, after which the product is filtered off with suction, washed to neutrality and dried.

Description

The present invention relates to a process for the isolation of 3alpha, 7alpha-diacetoxy-12alpha-methanesulfonyloxy-5beta-cholanic acid methyl ester, which is an important intermediate of the partial synthesis of chenodesoxycholic acid and ursodesoxycholic acid, steroid drugs for dissolving gallstones.

The first to utilize the title compound in the synthesis of chenodesoxycholic acid was Chen (U.S. Patent No. 3,998,859 to Synthesis 1976, 125). The title compound is prepared by a conventional method of reacting methanesulfonyl chloride with 3alpha, 7alpha-diacetoxy-12alpha-hydroxy-5beta-cholanic acid methyl ester in pyridine under anhydrous conditions and under an inert atmosphere. The isolated title compound is then subjected to cleavage of methanesulfonic acid to give 3alpha, 7alpha-diacetoxy-5beta-shol-11-enoic acid methyl ester which, after hydrogenation and hydrolysis, provides chenodesoxycholic acid.

Isolation of the title compound from the reaction mixture after completion of the reaction of methanesulfonyl chloride with 3alpha, 7alpha-diacetoxy-12alpha-hydroxy-5beta-cholanic acid methyl ester in pyridine is poured into ice water saturated with sodium chloride and extracted several times with ether. The combined ether extracts were then concentrated to a syrupy product, which was extracted continuously with hexane at elevated temperature for 20 hours, from which the crystalline title compound was isolated, m.p. 85-88 ° C.

The disadvantage of this procedure of isolation of the title compound is its lengthiness and complexity. For the extraction it is necessary to use class I combustibles, for the technological use of the process it is necessary to use a complex device and the product always contains a certain amount of pyridine, which causes the product volatility. The product should only be stored at reduced temperature or used immediately in the next reaction step, otherwise it will rapidly become contaminated by decomposition products.

These disadvantages are overcome by a process for the isolation of 3alpha, 7alpha-diacetoxy-12alpha-methanesulfonyloxy-5beta-cholanic acid methyl ester according to the invention, characterized in that the reaction mixture after the reaction of methanesulphonyl chloride with 3alpha, 7alpha-diacetoxy-12alpha-hydroxy-5beta- of choline in pyridine is poured with stirring into an ice-cooled, dilute aqueous solution of mineral acid, whereupon the precipitate formed is filtered off with suction, washed neutral with water and dried. The reaction mixture is decomposed at 0 to 5 ° C, preferably at 0 ° C, with an aqueous medium containing at least 1.1 equivalents of mineral acid based on the amount of pyridine used. The product thus obtained is completely devoid of pyridine and is therefore stable at room temperature. The product obtained by the process according to the invention is in all respects identical to the product isolated by the earlier process, excluding the higher melting points (134-136 ° C). The product isolated by the process of the invention is sufficiently pure for the next reaction step and can be obtained in almost quantitative yield.

Any mineral acid, preferably hydrochloric acid diluted to about 3% solution, used in excess to the amount of pyridine present in the reaction mixture can be used to neutralize pyridine and isolate the product from the reaction mixture. The maximum concentration by weight of hydrochloric acid is 5%, since at a higher concentration, the product is generally not excreted in a solid, well filterable form.

The process according to the invention is illustrated by the following examples without limiting the process according to the invention.

He did

45.2 g of 3alpha, 7alpha-diaoethoxy-12alpha-hydroxy-5beta-cholanic acid methyl ester are dissolved in 136ml of pyridine under exclusion of atmospheric humidity and an inert atmosphere. The solution is cooled to 0 ° C and 14.5 g of methanesulfonyl chloride is added dropwise with stirring and cooling at a rate such that the temperature of the reaction mixture does not exceed +2 ° C. After complete addition of methane-3-sulfonyl chloride, the reaction mixture was allowed to warm to room temperature and stirred for an additional 24 hours. After completion of the reaction, the mixture was added dropwise to 2.3 liters of ice-cold 3% hydrochloric acid with stirring. The precipitated solid product is suction filtered, washed to neutrality with water and dried to constant weight in an oven at a temperature of up to 50 ° C. 50.5 g of 3alpha, 7alpha-diacetoxy-12alpha-methanesulfonyloxy-5beta-cholanic acid methyl ester, m.p. 134-136 ° C, [α] 2 ° = + 54 ° (dioxane), are obtained.

Example 2 /

The experiment was carried out analogously to Example 1, but after completion of the reaction, the mixture was added dropwise with stirring to 3.4 L of a 2% hydrochloric acid solution cooled to 5 ° C. Yield and product quality are the same as in Example 1.

Claims (2)

A process for isolating 3alpha, 7alpha-diacetoxy-12alpha-methanesulfonyloxy-5beta-cholanic acid methyl ester from the reaction mixture after the reaction of methanesulphonyl chloride with 3alpha, 7alpha-diacetoxy-12alpha-hydroxy-5beta-eholanic acid methyl ester in pyridine medium is complete. The process according to claim 1, characterized in that the reaction mixture is decomposed at 0 to 5 ° C, preferably at 0 ° C, with an aqueous medium containing at least 1.1 equivalents of mineral acid, based on the amount of pyridine used, whereupon the precipitated product is isolated. 2. The process according to claim 1, wherein the aqueous medium containing mineral acid is an aqueous hydrochloric acid solution having a maximum concentration of 5% by weight, preferably 3% by weight.