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A kind of preparation method of fluticasone propionate

A technology of fluticasone propionate and halohalomethanes, which is applied in the field of preparation of fluticasone propionate, and can solve the problems of complex post-treatment process, mercapto oxide impurities, disulfide compounds and haloalkylation impurities, etc.

Active Publication Date: 2022-08-09
TIANJIN PHARMA GROUP CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The object of the present invention is to take compound 5 as starting material, prepare the compound 1 of high standard and high yield, solve the mercapto oxide impurity, disulfide compound and haloalkylation caused in the process of preparing fluticasone propionate by compound 6 Excessive impurities and complex post-treatment process

Method used

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  • A kind of preparation method of fluticasone propionate
  • A kind of preparation method of fluticasone propionate
  • A kind of preparation method of fluticasone propionate

Examples

Experimental program
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Effect test

Embodiment 1

[0038] Preparation of Example 1 Compound 6

[0039] Add 20.0g of compound 5, 14.5g of sodium carbonate and 100ml of methanol to the reaction flask, stir to dissolve and then cool down to 25°C, react for 4h, add 150ml of distilled water, extract with toluene (3x50ml), and adjust the pH of the aqueous layer to 1 with 2mol / L HCl .0~1.5, filtered, the filter cake was washed with water until neutral, and dried under vacuum to obtain 17.3 g of compound 6.

Embodiment 2

[0040] The preparation of embodiment 2 fluticasone propionate (compound 1)

[0041] 10.0g of compound 6 and 50ml of hydroxypropyl methacrylate were added to a four-neck reaction flask, cooled to 10°C, 6.0g of potassium thiosulfate was added, 2.2ml of chlorofluoromethane was added dropwise, and 500ml of purified water was added after the reaction was complete. , the solid was precipitated, and 10.2 g of crude fluticasone propionate was obtained by suction filtration, with a content of 99.1%, a mercapto oxide content of 0.38%, a haloalkylated impurity content of 0.15%, and no disulfide compounds were detected.

Embodiment 3

[0042] The preparation of embodiment 3 fluticasone propionate (compound 1)

[0043] 10g of compound 6 and 50ml of dimethylacetamide were added to a four-neck reaction flask, cooled to -5°C, 2.9g of sodium sulfite was added, then 2.0ml of bromofluoromethane was added dropwise, 500ml of purified water was added after the reaction was complete, a solid was precipitated, and the mixture was extracted. 10.4 g of crude fluticasone propionate was obtained by filtration, the content of compound 1 was 98.8%, the content of sulfhydryl oxide was 0.38%, the halogenated impurities were 0.19%, and the disulfide compound was not detected. Crystallization, suction filtration, and drying to obtain 10.1 g of fine fluticasone propionate with a content of 99.7%.

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Abstract

The present invention provides a preparation method of fluticasone propionate, comprising the following steps: 1) compound 5 is hydrolyzed in the presence of a base and an alcohol solvent to obtain compound 6; 2) compound 6 is mixed with fluorine under the condition that a reducing salt is used as a catalyst The halomethane reaction affords fluticasone propionate (compound 1). The invention uses a reducing inorganic salt as a catalyst, which greatly reduces the generation of impurities, such as disulfide impurities, mercapto oxide impurities and halogenated alkylate impurities introduced by mercapto oxides.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, in particular to a preparation method of fluticasone propionate. Background technique [0002] Fluticasone propionate is a new type of glucocorticoid developed by GSK and first listed in the UK in 1993. The main dosage forms are powder inhalation, aerosol, spray, nasal drops and cream, etc. The product shows high affinity with human glucocorticoid receptor in vitro, has strong anti-inflammatory effect, and can be used for the treatment of allergic rhinitis, asthma, COPD and other respiratory diseases. Fluticasone propionate is an effective inhaled corticosteroid drug for the treatment of asthma, which greatly improves lung function. It has been marketed for nearly 20 years and has good effectiveness. It has high selectivity for glucocorticoid receptors and produces few side effects at clinically recommended doses. [0003] The synthesis of fluticasone propionate reported in domestic and foreig...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J31/00
CPCC07J31/006Y02P20/55
Inventor 李亚玲齐海迪韩昆颖
Owner TIANJIN PHARMA GROUP CORP
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