Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Preparation method of fluticasone furoate

An acid regulation and compound technology, applied in the direction of steroids, organic chemistry, etc., can solve the problems of increasing the difficulty of refining, affecting the yield, and difficult to purify, and achieving the effect of reducing the difficulty of refining, ensuring safety, and reducing residues

Inactive Publication Date: 2017-01-04
CHIA TAI TIANQING PHARMA GRP CO LTD
View PDF8 Cites 7 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] In the above synthetic method, the intermediate steps will produce more by-products, especially intermediate II is unstable and difficult to purify. If the next step reaction is not refined, impurities will remain in the final product fluticasone furoate, which needs to be refined. It can be removed several times, increasing the difficulty of refining and affecting the yield

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of fluticasone furoate
  • Preparation method of fluticasone furoate
  • Preparation method of fluticasone furoate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] 6α,9α-Difluoro-17α-[(2-furylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androst-1,4-diene-17β-thiocarboxy Preparation of Acid-S-N,N-Dimethylcarbamoyl Ester

[0040]

[0041] Add 2-butanone (3.33L) into a 10L round-bottomed glass flask, add compound VII (222g, 0.453mol) under stirring, control the temperature at 10-20°C and stir evenly, then add triethylamine (190mL, 1.359mol) dropwise ); after 10 min, N,N-dimethylthiocarbamoyl chloride (140 g, 1.133 mol) was added, and after another 10 min, an aqueous solution of sodium iodide (81.5 g, 0.544 mol) was added; stirred at 15°C to 20°C for 5h, TLC Monitor until the reaction is complete. Add N,N-dimethylacetamide (1.78L) to the reaction solution, stir for 10 minutes, then add dropwise purified water pre-cooled to below 5°C, stir for 1.0h at 0°C to 10°C after dropping, filter with suction, use for filter cake After washing with purified water and suction filtration, the obtained wet product was air-dried at 45°C±3°C for 12...

Embodiment 2

[0043] 6α,9α-Difluoro-17α-[(2-furylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androst-1,4-diene-17β-thiocarboxy acid preparation

[0044]

[0045] Anhydrous methanol (2.195L) was added to a 3L round bottom glass flask, and intermediate VIII (219.5g, 0.38mol) and potassium carbonate (157.6g, 1.14mol) were added successively, N 2 Under protection, control the temperature at 40-45° C. and stir for 4.0 h, and monitor by TLC until the reaction is complete. In a 10L three-necked flask, add the reaction solution to purified water pre-cooled to 0-5°C, and slowly add 2mol / L hydrochloric acid (0.222L hydrochloric acid / 1.11L water) at 0-10°C under temperature control. Stir for 1.0 h, filter with suction, wash the solid with purified water, and filter with suction, the obtained crude product is analyzed by HPLC, the purity is ≥96%, and the proportions of impurities IX and VIII are greater than 1.2% and 1.0%, respectively.

[0046] Add the crude product to Na with stirring 2 CO 3 (5...

Embodiment 3

[0048] 6α,9α-Difluoro-17α-[(2-furylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androst-1,4-diene-17β-thiocarboxy acid preparation

[0049]

[0050] Intermediate VIII (1.00g, 1.73mmol) and potassium phosphate (1.10g, 5.20mmol) were dissolved in 10mL of anhydrous methanol; N 2 Under protection, control the temperature at 40-45°C and stir for 4.0 hours until the reaction of intermediate VIII is completed; add the reaction solution to 25 mL of pre-cooled purified water, add 8.6 mL of 2 mol / L hydrochloric acid solution dropwise under stirring; filter with suction and wash with water to obtain the intermediate Ⅱ crude product. Add the crude product to a mixed solution of sodium carbonate (0.5g) / purified water (11mL), add 4mL of ethyl acetate and stir to dissolve it, then separate the liquids, then stir and wash the water phase with 4mL of ethyl acetate, and add the water phase 8.6 mL of 2 mol / L hydrochloric acid solution was suction filtered, washed with water, and dried under r...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention relates to a preparation method of fluticasone furoate, especially preparation and purification of an intermediate 6alpha, 9alpha-difluoro-17alpha-[(2-furylcarbonyl)oxy]-11beta-hydroxy-16alpha-methyl-3-oxo-androstane-1,4-diene-17beta-thiocarboxylic acid. The preparation method comprises the following steps: in the presence of alkali and alcoholic solvent, a compound as shown in the formula VIII is converted into a mixture containing the compound of formula II; the mixture containing the compound of formula II is mixed with an aqueous solution of inorganic base and an ester solvent; a water phase is separated; pH value of the water phase is regulated by the use of acid until a solid is precipitated out; and the solid is separated. The invention provides a preparation method capable of remarkably raising purity of fluticasone furoate. Safety of drug application is guaranteed.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a preparation method of a drug compound, in particular to a preparation method of fluticasone furoate, a glucocorticoid receptor agonist. Background technique [0002] Glucocorticoids have anti-inflammatory properties and are widely used in the treatment of inflammatory diseases such as asthma and rhinitis. US patent US4335121 discloses 6α, 9α-difluoro-17α-(1-oxopropoxy)-11β-hydroxyl-16α-methyl-3-oxo-androst-1,4-diene-17β- Thiocarboxylic acid-S-fluoromethyl ester (common name is fluticasone propionate) and its derivatives, WO2002 / 012265 discloses a new fluticasone derivative, i.e. fluticasone furoate or fluticasone furoate, the structural formula is as follows: [0003] [0004] The chemical name of fluticasone furoate (Ⅰ) is: 6α,9α-difluoro-17α-[(2-furylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androst-1 , 4-diene-17β-thiocarboxylate-S-fluoromethyl ester, a glucocorticoid recep...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07J31/00
Inventor 高鹏孟庆义李阳张喜全
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com