Preparation method of high-purity fluticasone furoate

A fluticasone furoate and high-purity technology, which is applied in the field of preparation of high-purity fluticasone furoate, can solve the problems of complex process, low yield, and low removal efficiency, and achieve the goals of shortening the existence time, high conversion rate, and improving yield Effect

Active Publication Date: 2019-03-08
GUANGZHOU JOINCARE RESPIRATORY DRUG ENG TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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

Method used

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  • Preparation method of high-purity fluticasone furoate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] The preparation of formula III compound:

[0069] 1) Add the compound of formula V (50.0g), butanone (500mL) and diethylamine (38.29g) into the reaction flask at a temperature of ≦30°C; then add furoyl chloride (32.74 g), react for 0.5-1h until the reaction is complete (HPLC detection, calculated by the peak area according to the normalization method, if the compound of formula V in the raw material is ≦1.0%, the reaction can be considered complete). Then add a mixed solution of diethanolamine (19.89g) and water (250mL) and react for 1-1.5h; then add water (250mL), and adjust the pH value to 2-3 with 10% hydrochloric acid (72g). ℃ temperature, stirring for 30min, a large amount of solid precipitated. Filter the solid, rinse with water (100mL); add water (250mL) and acetone (250mL) to the solid, stir for 30min at a temperature of 20-30°C, filter, rinse with water (100mL), and then dissolve the solid at a temperature of 70-80°C After drying, 61.80 g of the compound of f...

Embodiment 2

[0072] 1) Add the compound of formula III (50.0g) prepared in Example 1 and methanol (250mL) into the reaction flask at a temperature ≦30°C under nitrogen protection, then add potassium carbonate (35.88g), and heat up to 25-35°C , reacted for 16h until the reaction was complete (HPLC detection, calculated by the normalization method with the peak area, the compound of formula III≦1.0% in the raw material, the reaction can be considered complete), and a mixture containing the compound of formula II was prepared.

[0073] 2) Add purified water (375mL), methanol (125mL), ethyl acetate (125mL) and toluene (125mL) to the mixture containing the compound of formula II prepared in the previous step, stir for 10min, and stand to separate the phases. Add ethyl acetate (125mL) and toluene (125mL) to the water phase, stir for 10min, and let stand to separate the phases; the water phase is then cooled to 10-20°C, and the pH value is adjusted to 2- 3; add methyl ethyl ketone (750mL) and sod...

Embodiment 3

[0077] With reference to the preparation method of Example 2, respectively adopt the conditions listed in the following table to prepare the compound of formula I (except the conditions listed in the table below, other conditions are the same as in Example 2)

[0078]

[0079] Using the conditions in experimental group a, the refined product of the compound of formula I was finally obtained, with a yield of 81.12%, a purity of 99.43%, and total impurities of 0.57%.

[0080] Using the conditions in the experimental group b, the refined product of the compound of formula I was finally obtained, with a yield of 85.50%, a purity of 98.75%, and total impurities of 1.27%.

[0081] Using the conditions in experimental group c, more solids were precipitated and phase separation was impossible, which made it difficult to carry out the subsequent steps.

[0082] Using the conditions in the experimental group d, the refined product of the compound of formula I was finally obtained, wi...

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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...

Claims

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Application Information

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IPC IPC(8): C07J31/00
CPCC07J31/006
Inventor 俞雄谢福胜陈与华
Owner GUANGZHOU JOINCARE RESPIRATORY DRUG ENG TECH CO LTD
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