CS219404B1 - A method for selectively acetylating a mixture of cortisol and its 11-epimer - Google Patents

Abstract

The invention relates to the selective acetylation of a mixture of cortisol and its 11-epimer by the action of acetic anhydride in a mixture of anhydrous acetone, chloroform and potassium acetate at the boiling point of the mixture.

Description

The present invention relates to a process for the selective acetylation of a mixture of cortisol and its 11-epimer, obtained by transforming Reichstein's compound S, ( ^{4 4} -pregnene) 17,21,2-di'O1,2,210-diomi, e.g. U.S. Pat. No. 95,309. This mixture, containing the individual components in a weight ratio of 3 to 6 to 4 to 7, was reported by selective acetylation and separation of the obtained crystalline acetates.

To date, selective acetylation of steroid compounds, including the mixture of cortisol and its 1111-epimer, has been carried out by treatment with an equivalent amount of acetic anhydride in pyridine, mostly at a temperature not exceeding 20 degrees Celsius. This method was able to process the mixture in an average yield of 52-55%, a maximum of 60%, since at the same time 11,2'-diacetates were produced in an amount of 25% which could not be reduced.

Selective acetylation of 11-epicortisol is described in DD Pat. No. 22,448, using acetic anhydride in acetic acid, in the presence of basic reacting catalysts, for example, alkali metal acetates. Application of this method to mixtures of cortisol and its 11-epimer has shown that in this case it is not completely selective and that undesired diacetates are formed which reduce the yield and make it difficult to isolate the desired products.

Also other methods known from the chemistry of steroid compounds (Cerny se sp., Chemistry of Steroid Compounds, Prague, Czechoslovak Academy of Sciences, p. 172; Groggins, Fundamentals of Organic Synthesis, SNTL, Prague 1958, p. 552), for example acetylation with acetic anhydride in the presence of acetate Potassium ¹ , resulting in the esterification of all hydroxyl groups contained in the steroid compound molecule, or the use of acetyl chloride in the presence of dimethylaniline in boiling chloroform, did not reliably lead to a target as demonstrated by reproduction attempts.

In an effort to streamline production, novel selective acetylation pathways have been sought which could be applied primarily to said cortisol / 11-epimer mixture, or to other steroid compounds with similar functional groups.

A systematic study of the reaction conditions has succeeded in developing a process for the selective acetylation of a mixture of cortisol and its 11-epimer by the action of acetic anhydride in the organic solvent environment of the present invention.

The process according to the invention consists in that the acetylation is carried out in a mixture of anhydrous acetone, chloroform and potassium acetate at the boiling point of the reaction mixture.

As the medium for acetylation, it is preferred to use 1: 1 by volume of anhydrous acetone and chloroform in an amount of 10 ml per g of the starting mixture of cortisol and its 11-epimer.

Conducting acetylation under these conditions is very simple, the reaction generally takes about 10 hours at low boiling. The course is quantitative, and although an excess of acetic anhydride is used, diacetate formation does not occur, which is a surprising phenomenon.

As shown by the comparison with the known methods, the process according to the invention is indeed selective for the acetylation of a mixture of cortisol a, its 11-epimer. It depends on the combination of all the reagents used in the amounts indicated. Potassium acetate acts as a catalyst of acetylation at position 21, chloroform in acetone protects the hydroxyl at position 11 by formation of an adduct from acetylation.

The process according to the invention has proven to be very hot in operation and has achieved, with simplified technology, an increase in yields of an average of 2.2% over the prior art, so that a higher technical effect has been demonstrated. Example g of a mixture of cortisol and its 11-epimer, containing 97% of both components in a ratio of 32 ': 6.8 percent, was refluxed (capped and anhydrous CaCl 2) for 10 hours in a mixture of 50 ml of anhydrous, freshly precooled acetone. (dried over calcium chloride J, 50 ml of anhydrous chloroform, TO · ml of acetic anhydride and 5 g of calcined potassium acetate). Then 10 ml of methanol are added to the reaction mixture and boiled for 30 minutes, then cooled and allowed to stand at temperature. The precipitated cortisol acetate is filtered off with suction, washed with cold chloroform, stirred in lukewarm distilled water, filtered off with suction and washed with water. 6.12 g of cortisol acetate of satisfactory quality are obtained in a vacuum and oxidized in a known manner, yielding in total 85 % of the product, based on the amount of the starting mixture.

Claims (2)

SUBJECT A process for the selective acetylation of a mixture of cortisol and its 11-epimer by treatment with acetic anhydride in an organic solvent, characterized in that the acetylation is carried out in a mixture of anhydrous acetone, chloroform and potassium acetate at the boiling point of the reaction mixture. invention 2. The process of claim 1 wherein the mixture is anhydrous acetone / chloroform in a 1: 1 by volume ratio and in an amount of 10 ml per g of the starting mixture of cortisol and its 11-epimer.