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Preparation method of fluticasone propionate intermediate

A technology for fluticasone propionate and intermediates, which is applied in the field of preparation of fluticasone propionate intermediates, and can solve problems such as throat and bronchospasm, inflammation and edema, separation and purification operations that affect reaction efficiency, human respiratory mucosa and tissue damage, etc. , to avoid irritating and corrosive problems, simplify operation, and have no by-products

Pending Publication Date: 2020-06-19
夏同生物科技(苏州)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, there are multiple active hydroxyl groups in the molecule of 6α,9α-difluoro-11β,17α,21-trihydroxy-16α-methylandrost-1,4-diene-3,20-dione, and periodic acid is strong The oxidation activity of 11-OH will also oxidize 11-OH to form by-products, which will affect the efficiency of the reaction and subsequent separation and purification operations
[0006] In addition, periodic acid itself is highly irritating and corrosive, and can seriously damage human respiratory mucosa and tissues. Inhalation can cause spasm, inflammation, and edema in the throat and bronchus, and can cause eye and skin burns. Skin absorption, greater harm to the human body, higher production costs

Method used

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  • Preparation method of fluticasone propionate intermediate
  • Preparation method of fluticasone propionate intermediate
  • Preparation method of fluticasone propionate intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0037] A preparation method of fluticasone propionate intermediate, comprising the following steps:

[0038] 1) Add 1.5631g (7.3mmol, 3.0eq) of sodium periodate into 1.5mL of water, heat it to 100°C with an electric heat gun to fully dissolve it, then add 5g of silica gel (200 mesh), shake and mix well, Obtain silica gel supported sodium periodate;

[0039] 2) Add 1 g (2.436 mmol, 1.0 eq) of flumetasone into a mixed solvent composed of 7 mL of dichloromethane and 1 mL of methanol, and ultrasonically disperse to obtain a flumetasone solution;

[0040] 3) Add sodium periodate loaded on silica gel into 2.5 mL of dichloromethane, then add flumetasone solution, stir and react at room temperature for 1 h to obtain a reaction solution;

[0041] 4) The reaction solution was filtered with 1.5 g of diatomaceous earth, and rinsed several times with dichloromethane-methanol mixed solvent (the volume ratio of dichloromethane and methanol was 10:1), then the filtrate was spin-dried and vac...

Embodiment 2

[0047] A preparation method of fluticasone propionate intermediate, comprising the following steps:

[0048] 1) Add 15.631g of sodium periodate into 15mL of water, heat it to 100°C with an electric heat gun to fully dissolve it, then add 50g of silica gel (200 mesh), oscillate and mix well to obtain silica gel-loaded sodium periodate;

[0049] 2) adding 10 g of flumetasone to a mixed solvent composed of 70 mL of dichloromethane and 10 mL of methanol, and ultrasonically dispersing to obtain a flumetasone solution;

[0050] 3) Add sodium periodate loaded on silica gel into 25 mL of dichloromethane, then add flumetasone solution, stir and react at room temperature for 1 h to obtain a reaction solution;

[0051] 4) The reaction solution was filtered with 15 g of diatomaceous earth, and rinsed several times with dichloromethane-methanol mixed solvent (the volume ratio of dichloromethane and methanol was 10:1), then the filtrate was spin-dried and vacuum-dried. Obtained 9.22 g of f...

Embodiment 3

[0053] A preparation method of fluticasone propionate intermediate, comprising the following steps:

[0054] 1) Add 0.5133g (2.4mmol, 1.0eq) of sodium periodate into 1.5mL of water, heat it to 100°C with an electric heat gun to fully dissolve, then add 3g of silica gel (200 mesh), oscillate and mix well, Obtain silica gel supported sodium periodate;

[0055] 2) Add 1 g (2.436 mmol, 1.0 eq) of flumetasone into a mixed solvent composed of 7 mL of dichloromethane and 1 mL of methanol, and ultrasonically disperse to obtain a flumetasone solution;

[0056] 3) Add sodium periodate loaded on silica gel into 2.5 mL of dichloromethane, then add flumetasone solution, stir and react at room temperature for 2 hours to obtain a reaction solution;

[0057] 4) The reaction solution was filtered with 1.5 g of diatomaceous earth, and rinsed several times with dichloromethane-methanol mixed solvent (the volume ratio of dichloromethane and methanol was 10:1), then the filtrate was spin-dried an...

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Abstract

The invention discloses a preparation method of a fluticasone propionate intermediate. The preparation method comprises the following steps: firstly, preparing silica gel loaded sodium periodate, andthen oxidizing flumetasone by utilizing the silica gel loaded sodium periodate so as to obtain a fluticasone propionate intermediate 6alpha, 9alpha-difluoro-11beta, 17alpha-dyhydroxy-16alpha-methyl-3-oxoandrostane-1, 4-diene-17beta-carboxylic acid. The method has the advantages of readily available reaction raw materials, simple operation, good selectivity, no by-product, stable process, low price, safety, high reaction yield and the like and is beneficial to reduction of the production cost of enterprises and subsequent commercial production and batch supply.

Description

technical field [0001] The invention relates to a preparation method of a fluticasone propionate intermediate, belonging to the technical field of organic synthesis. Background technique [0002] The chemical name of fluticasone propionate is 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-1,4-diene-17α-propionyloxy-androstane -17β-fluoromethyl mercaptoformate (chemical formula I), is a new type of glucocorticoid developed by Glaxo Smith Kline (Glaxo Smith Kline) in the UK. It has strong anti-inflammatory and anti-allergic effects and was obtained in 2000. Approved by the US FDA, it is used to treat and alleviate bronchial asthma and control inflammation and disease progression. [0003] Compound 6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrost-1,4-diene-17β-carboxylic acid (chemical formula II) is fluticasone propionate and many The important synthetic intermediates of derivatives, the traditional synthetic method is to adopt periodate oxidized flumethasone (chemical ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J3/00
CPCC07B2200/07C07J3/005
Inventor 肖奇才高理钱周全明石子寒汪伟向梦华谢刘幸杨芬罗川朝
Owner 夏同生物科技(苏州)有限公司