Preparation method of high-purity fluticasone furoate

Abstract

The invention relates to a preparation method of high-purity fluticasone furoate. The method comprises the steps as follows: adding a compound in formula III, an alcohol solvent and alkali to a reaction flask for an alcoholysis reaction to prepare a mixture of a compound in formula II, and performing after-treatment to prepare a solution of the compound in formula II; adding the solution of the compound in formula II, organic alkali and a fluoro-halogen methylation reagent to a reaction flask for a substitution reaction to prepare a crude product of a compound in formula I, and performing recrystallization to obtain a refined product of the compound in formula I. The target product is prepared by improving the after-tretament method of the compound in formula II and improving preparation methods of the compound in formula II to the compound in formula I, and the method is simple to operate, can effectively control methyl esters and oxidation impurities, is high in yield, high in purityand lower in cost, and can better meet the requirement of medicinal materials and the requirement of industrial enlargement.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of high-purity fluticasone furoate. Background technique [0002] Fluticasone furoate (compound of formula Ⅰ, Fluticasone furoate), the chemical name is 6α,9α-difluoro-17α-[(2-furylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo- Androst-1,4-diene-17β-thiocarboxylate-S-fluoromethyl ester is a synthetic corticosteroid derived from fluticasone, which has anti-inflammatory and anti-allergic properties. Fluticasone furoate has been widely used in inflammatory diseases, allergic diseases, such as asthma and allergic rhinitis. [0003] [0004] Fluticasone furoate nasal spray developed by GlaxoSmithKline was launched in the United States in April 2007, and then successively launched in many European countries, Japan and China. The fluticasone furoate compound has been disclosed in WO2002012265. At present, there are three main methods for the...

AI Technical Summary

Problems solved by technology

[0012] 1) The starting materials are rarely commercially available and can only be obtained through synthesis;

[0013] 2) Hydrogen sulfide or similar compounds are used in the synthesis process of starting materials, therefore, there is a relatively large safety hazard in the scale-up production process;

[0014] 3) The compound of formula II needs to be formed into an organic amine salt (such as triethylamine salt, DIPEA salt, etc.) to achieve the purification effect, but the process is very complicated, and the compound of formula II is relatively unstable, and has been oxidized to Impurities, core impurities methyl ester and oxidized impurities are not well controlled, and the removal efficiency is low, which directly affects the purity of the finished product

In actual operation, it is found that the precipitated compound of formula II is difficult to filter, and the yield of this step is low, only 70%-75%

[0018] In summary, although the prior art has disclosed some methods for preparing fluticasone furoate, these methods can produce more by-products in the process of synthesizing fluticasone furoate (compound of formula I), especially the compound of formula II is unstable and relatively Difficult to purify, it needs to be refined many times to remove, resulting in difficult subsequent refining and low yield purity

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