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Fluoroalkylation method of steroid 17 beta-thiocarboxylic acid

A technology of thiocarboxylic acid and fluoroalkylation, which is applied in the production of steroids, organic chemistry, and bulk chemicals, and can solve the problems of low and high content of fluoroformation products, and uncontrollable reaction conditions. Achieve the effect of reducing the residue of impurities and reducing the difficulty of refining

Active Publication Date: 2019-10-18
TIANJIN PHARMA GROUP CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the compound of formula I containing mercapto is easily oxidized, disulfide compound (-S-S-), mercapto oxide (-SOH), haloalkylated impurity (SOCH) introduced by mercapto oxidation 2 X), the existing reaction conditions cannot be effectively controlled, the content of fluoroformation products obtained is low, the content of impurity disulfide compounds and mercapto oxides is high, and it needs to be washed or crystallized many times, and the post-treatment procedure is complicated

Method used

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  • Fluoroalkylation method of steroid 17 beta-thiocarboxylic acid
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  • Fluoroalkylation method of steroid 17 beta-thiocarboxylic acid

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Experimental program
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Effect test

Embodiment 1

[0063]

[0064] Add 50ml of dimethylacetamide and 10g of compound 1 into a four-necked reaction flask, cool down to -5°C, add 2.9g of sodium sulfite, and then dropwise add 2.0ml of bromofluoromethane. After the reaction is complete, add 500ml of purified water to precipitate a solid. 10.4g of crude compound 2 was obtained by filtration. The detected compound 2 content was 98.8%, the mercapto oxide content was 0.38%, the haloalkylated impurities were 0.19%, and the disulfide compound was not detected. The solid compound 2 crude product obtained was recrystallized by adding absolute ethanol , suction filtration, and drying to obtain 10.1 g of compound 2, with a content of 99.7%.

Embodiment 2

[0068]

Embodiment 2-1

[0070] Add 100ml of acetonitrile and 10g of compound 3 into a four-necked reaction flask, cool down to -15°C, add 4.0g of potassium carbonate and 1.0g of potassium sulfite, then dropwise add 2.0ml of fluoroiodomethane, after complete reaction, add 500ml of purified water to precipitate As a solid, 10.3 g of crude compound 4 was obtained by suction filtration, with a content of 98.8%, a content of mercapto oxides of 0.40%, haloalkylated impurities of 0.21%, and no disulfide compounds were detected. The obtained crude solid compound 4 was recrystallized by adding absolute ethanol, suction filtered, and dried to obtain 9.8 g of refined compound 4 with a content of 99.2%.

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Abstract

The invention provides a fluoroalkylation method of steroid 17 beta-thiocarboxylic acid. The method comprises the following step that a compound represented by a formula I reacts with an F-CH2-X reagent under the condition that a reducing salt is used as a catalyst, so that a fluoroalkylated compound, represented by a formula II, of 17 beta-thiocarboxylic acid is obtained, wherein X is halogen. According to the invention, the inorganic salt with reducibility is used as the catalyst, so that generation of disulfide impurities, thiol oxide impurities and thiol oxide introduced haloalkylated impurities are greatly reduced.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, in particular to a method for fluoroalkylation of steroidal 17β-thiocarboxylic acid. Background technique [0002] Carbon-fluorine bonds are ubiquitous in pharmaceutical products, such as fluticasone propionate, fluticasone furoate, fluoroquinone, etc. Fluoroalkylation is one of the main synthetic methods for the preparation of fluorinated organic compounds. This reaction is generally based on the mercapto (-SH) structure compound with fluorobromomethane (fluorochloromethane, fluoroiodomethane) under the catalysis of organic amine or inorganic carbonate. The reaction introduces a fluoromethyl group. Since the compound of formula I containing mercapto is easily oxidized, disulfide compound (-S-S-), mercapto oxide (-SOH), haloalkylated impurity (SOCH) introduced by mercapto oxidation 2 X), the existing reaction conditions cannot be effectively controlled, and the content of fluoroformation produ...

Claims

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Application Information

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IPC IPC(8): C07J31/00C07J71/00
CPCC07J31/006C07J71/0015C07J71/0031C07J71/0068Y02P20/55
Inventor 李亚玲张亮
Owner TIANJIN PHARMA GROUP CORP
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