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Preparation method of difluprednate beta form crystal

A technology of difluprednate and crystal form, which is applied in the field of preparation of difluprednate crystal form β, can solve problems such as crystal form instability, and achieve the effects of stable impurities, high yield, and simple preparation process

Active Publication Date: 2016-05-25
CHINA RESOURCES ZIZHU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0005] The crystalline form α of difluprednate is obtained by crystallization with conventional low-toxicity solvents such as methanol, ethyl acetate, acetone, ethanol, etc., which is unstable

Method used

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  • Preparation method of difluprednate beta form crystal

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Effect test

Embodiment 1

[0021] Add 10 g of difluprednate and 80 ml of absolute ethanol to the reaction flask, heat to 75-80° C. to dissolve, and filter. Transfer the filtrate and the precipitated solids to a one-necked bottle, heat in a water bath at 60°C and concentrate by rotary evaporation until the remaining volume is about 50ml, then reheat to reflux to dissolve. Cool down and crystallize at a rate of 0.5°C / min. Stir at -10°C for 30 minutes, filter, and dry in the air to obtain the crystal form β of difluprednate. Yield 92%, purity 99%.

Embodiment 2

[0023] Add 10 g of difluprednate and 40 ml of absolute ethanol to the reaction flask, heat to 75-80° C. to dissolve, and filter. Transfer the filtrate and the precipitated solids to a one-necked bottle, heat in a water bath at 55°C and concentrate by rotary evaporation until the remaining volume is about 45ml, then reheat to reflux to dissolve. Cool down and crystallize at a rate of 0.3°C / min. Stir at -10°C for 30 minutes, filter, and dry in the air to obtain the crystal form β of difluprednate. Yield 91.5%, purity 99.1%.

Embodiment 3

[0025] Add 10 g of difluprednate and 100 ml of absolute ethanol to the reaction flask, heat to 75-80° C. to dissolve, and filter. Transfer the filtrate and the precipitated solid into a one-necked bottle, heat and concentrate in a water bath at 65°C by rotary evaporation until the remaining volume is about 55ml, and reheat to reflux to dissolve. Cool down at a rate of 2°C / min for crystallization. Stir at -10°C for 30 minutes, filter, and dry in the air to obtain the crystal form β of difluprednate. Yield 91%, purity 98.5%

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Abstract

The invention relates to a preparation method of difluprednate beta form crystal. In the preparation method, absolute ethyl alcohol is taken as a solvent to prepare difluprednate beta form crystal. The preparation method is simple and economical, and is high in yield; the prepared difluprednate beta form crystal is stable and contains less impurity; and the preparation method is suitable for industrialized mass production.

Description

technical field [0001] The invention relates to a preparation method of difluprednate crystal form β, belonging to the field of medicinal chemistry. Background technique [0002] Difluprednate is a glucocorticoid receptor agonist and a fluorinated derivative of prednisolone, which has anti-inflammatory activity and is mainly used in the treatment of postoperative ocular infection and pain. [0003] The crystal forms of difluprednate that have been reported so far include α crystal form, β crystal form and γ crystal form, among which the most stable is the β crystal form. [0004] "Difuprednate: Morethanmeetstheeye" in "Journal of Pharmaceutical and Biomedical Analysis" by GarlottaGiacobe et al. in 2015 disclosed a method for preparing difluprednate crystalline form β by crystallization from acetonitrile. According to the classification of ICHQ3C and the technical guidelines for the study of residual solvents in chemical drugs, acetonitrile belongs to the second-class solven...

Claims

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Application Information

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IPC IPC(8): C07J5/00
Inventor 李志峰蒋彬孙玉霞赵红欣
Owner CHINA RESOURCES ZIZHU PHARMA
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