Synthesis of hydrocortisone butyrate

Abstract

The invention relates to synthesis of hydrocortisone butyrate, which comprises the following steps of: A. carrying out acylation reaction on hydrocortisone acetate adopted as a raw material and butyl chloride in an organic solvent I under the condition of existence of a catalyst; after the reaction is finished, adding acid to adjust a pH value being smaller than 5; diluting or recrystallizing to obtain hydrocortisone 17alpha-butyrate-21-acetate; and B. adopting the hydrocortisone 17alpha-butyrate-21-acetate as a raw material, adding inorganic alkali in an organic solvent II and carrying out selective hydrolysis reaction to obtain hydrocortisone 17alpha-butyrate.

Description

field of invention The invention relates to a preparation method of hydrocortisone 17-butyrate. Background technique: Hydrocortisone 17α-butyrate (Hydrocortisone-17-butyrate, CAS: 13609-67-1) is a common skin drug and should be widely used in China (the application of hydrocortisone butyrate in dermatology , "Continuing Medical Education", 2006, Vol. 20, No. 33, No. 59), preparations with hydrocortisone 17-butyrate as the active ingredient are relatively common in the market, for example, the product produced by Tianjin Pharmaceutical Group Co., Ltd. is named "Udrole" cream. The synthesis technology of hydrocortisone 17-butyrate has been studied by scientists in the seventies of last century, such as JP52136157, JP 56040700, Synthesis, (8), 700-1 1984, JP 60048998 and other documents all show that the compound The synthesis of hydrocortisone is reacted with triethyl orthobutyrate to form 17,21 cyclic orthoester, which is formed by acid-selective ring opening at position 2...

AI Technical Summary

Problems solved by technology

But because acid is to 17,21 cyclic orthoesters ring-opening process, although most of them generate corresponding 17-esters, some corresponding 21-esters will also occur, resulting in impure products, especially 17-esters and 21-esters. The polarity of esters is similar, and it is not easy to separate by recrystallization. In order to obtain the desired product, the number of refining times will be increased accordingly, and the yield will be reduced.

In fact, there are many methods for synthesizing esters. For example, the corresponding esters can be directly obtained by reacting alcohols with acids, acid anhydrides or acid chlorides. Since the above-mentioned methods have obvious problems, why are the above-mentioned methods with obvious problems still used? The reason is that there is a β-acetone side chain and an α-hydroxyl group at the 17th position of the pregnant compound. Due to the existence of the β-acetone side chain, the direct esterification of the α-hydroxyl group has a large steric hindrance, especially when the β-acetone side chain This is especially true when there is an ester group (ie 21-ester) at the other end of the 17α-hydroxyl group, which causes the 17α-hydroxyl group to be unable to be esterified by a direct method. It will also be esterified at the same time, causing more impurities and not obtaining high-purity products

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