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Synthesis of hydrocortisone butyrate

A technology of hydrocortisone acetate and hydrocortisone, which is applied in the fields of steroids and organic chemistry, and can solve the problems of product impurity, increased refining times, and failure to obtain high purity.

Active Publication Date: 2012-05-23
TIANJIN JINYAO GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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.
[0007] 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

Method used

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  • Synthesis of hydrocortisone butyrate
  • Synthesis of hydrocortisone butyrate
  • Synthesis of hydrocortisone butyrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Acylation:

[0049]Take 1mmol of hydrocortisone acetate and place it in 10ml of dichloromethane, cool the resulting solution to 0-5°C, and add 4ml of triethylamine and 0.05mmol DMAP at this temperature, and then put it under the condition of 0-5°C slowly add 1.5 mmol of butyryl chloride, then stir the resulting mixture at 0°C, react for 3 hours, add hydrochloric acid to adjust the pH to 2, stir for 10 minutes, wash with water until neutral, and then wash with dichloromethane 10ml×3 The aqueous phase was extracted and the organic phase was combined, concentrated, poured into methanol for recrystallization, cooled and filtered to obtain 0.86 mmol of hydrocortisone 17α-butyrate-21-acetate (acylate).

[0050] Before hydrochloric acid was added to the reaction, samples were taken and analyzed by HPLC to find that the ratio of hydrocortisone 17α-butyrate-21-acetate to 11β, 17α-bisbutyrate-acetate hydrocortisone was 1:0.16.

[0051] In the product obtained after the reaction,...

Embodiment 2

[0055] Acylation:

[0056] Take 1 mmol of hydrocortisone acetate and place it in 10 ml of chloroform, cool the resulting solution to 0-5 °C, and add 4 ml of pyridine and 0.1 mmol of pyridine hydrobromide at this temperature, and then Under the condition of ℃, slowly add 1.3 mmol of butyryl chloride, then stir the obtained mixture under the condition of 0 ℃, add hydrochloric acid to adjust to 2 after reacting for 3 hours, after stirring for 10 minutes, wash with water until neutral, and then wash with dichloromethane 10ml ×3 times extract the aqueous phase and combine the organic phases, concentrate, pour into methanol for recrystallization, and obtain 0.83 mmol of hydrocortisone 17α-butyrate-21-acetate (acylate).

[0057] hydrolysis:

[0058] Dissolve the acylate in dichloromethane, add an equal amount of methanol, pass N 2 For protection, add 0.1g of potassium carbonate dissolved in methanol. After the reaction is complete at -20°C, the reaction solution is neutralized to n...

Embodiment 3

[0060] Acylation:

[0061] Take 1 mmol of hydrocortisone acetate and place it in 10 ml of dichloromethane, cool the resulting solution to 0-5 ° C, and add 4 ml of pyridine and 0.05 mmol DMAP at this temperature, and then at a temperature of 0-5 ° C, Slowly add 1.3mmol of butyryl chloride, then stir the resulting mixture at 0°C, add acetic acid to adjust to 5 after reacting for 3 hours, stir for 10 minutes, wash with water until neutral, and then extract the water with 10ml of dichloromethane×3 times phase, the organic phases were combined, concentrated, poured into methanol for recrystallization, and obtained 0.9 mmol of hydrocortisone 17α-butyrate-21-acetate (acylate).

[0062] Before hydrochloric acid was added to the reaction, samples were taken and analyzed by HPLC to find that the ratio of hydrocortisone 17α-butyrate-21-acetate to 11β, 17α-bisbutyrate-acetate hydrocortisone was 1:0.19.

[0063] In the product obtained after the reaction, the ratio of hydrocortisone 17α-b...

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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 [0001] The invention relates to a preparation method of hydrocortisone 17-butyrate. Background technique: [0002] 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. [0003] 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 ri...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J21/00
Inventor 孙亮陈松赵琳
Owner TIANJIN JINYAO GRP
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