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Preparation method of 6alpha, 9alpha-difluoroprednisolone

A technology of difluoroprednisolone and fluorination is applied in the field of preparation of 6α,9α-difluoroprednisolone, which can solve the problems of increasing the cost of raw materials and achieve the effect of low price

Active Publication Date: 2020-04-07
HUNAN NORCHEM PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In the above route, the hydroxyl positions of 17 and 21 are firstly esterified, and then the epoxy at the 9 and 11 positions is carried out. Since the epoxy at the 9 and 11 positions needs to be carried out under alkaline conditions, this will inevitably lead to 17, 21 The ester group is hydrolyzed, introducing impurities, and placing it at the back end of the route will cause a significant increase in the cost of raw and auxiliary materials for the product

Method used

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  • Preparation method of 6alpha, 9alpha-difluoroprednisolone
  • Preparation method of 6alpha, 9alpha-difluoroprednisolone
  • Preparation method of 6alpha, 9alpha-difluoroprednisolone

Examples

Experimental program
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Effect test

Embodiment 1

[0023] Preparation of Intermediate 1

[0024] At 0-5°C, add 313g of acetone, 180g of water and 120g of dehydroacetate to the reaction flask, and then dropwise add 4.8g of 50% fluoroboric acid. After the dropwise addition, the temperature is controlled at 0-5°C, 66g Dibromohydantoin, stir for 2-3 hours after the addition, TLC spot plate detection, the reaction of the raw materials is complete, pour the reaction solution into 720g of water, a white solid is precipitated, filter, collect the filter cake, dissolve in 1043g of acetone, dropwise at room temperature Add potassium carbonate aqueous solution (60g potassium carbonate and 180g water), dropwise temperature does not exceed 25 ℃, after dropping, be warming up to 40 ℃, stir for 16 hours, TLC detects the raw material reaction is complete, pour the reaction solution into 4800g ice water, separate out The white solid was washed with water until neutral, and the filter cake was collected and dried at 50° C. to obtain 110 g of a ...

Embodiment 2

[0032] The difference between this example and Example 1 is that the steps for preparing intermediate 3 are as follows.

[0033] Preparation of Intermediate 3

[0034] Add 5000g dichloromethane, 750g intermediate 2 and 40g tert-butyl hydroquinone to the reaction flask, cool down to about -10~-5℃, add 3000g hydrofluoric acid dropwise, keep the reaction for 2h, TLC spot plate detection, raw material The reaction is complete, pour the reaction solution into 15000g ice water, at 0-5°C, under stirring, neutralize the excess hydrofluoric acid with an aqueous solution of KOH, adjust the pH to 6-8, filter, collect the filter cake, wash with water until neutral, Dry at 45°C, use a mixed solvent of 299g methylene chloride and 410g methanol for the crude product, heat at 40°C to dissolve and stir for 1 hour, concentrate to a thick substance, cool to 0-5°C, filter, and dry at 55°C to obtain 637.5g of light The yellow solid (Intermediate 3), the liquid phase showed a purity of 99.1% and a...

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Abstract

The invention belongs to the technical field of steroid hormone preparation, and particularly relates to a preparation method of 6alpha, 9alpha-difluoroprednisolone. Anecortave dehydroacetate used asa starting raw material undergoes bromo-hydroxy epoxidation, 6-positon fluoridation, 9-position fluoridation and hydrolysis to prepare the 6alpha, 9alpha-difluoroprednisolone. The method taking the anecortave dehydroacetate as the starting raw material has the advantages of low prices, few isomers, few impurities and short reaction route.

Description

technical field [0001] The invention belongs to the technical field of preparation of steroid hormones, in particular to a preparation method of 6α,9α-difluoroprednisolone. Background technique [0002] Difluprednate, also known as difluprednate, is a difluorinated derivative of prednisolone with potent anti-inflammatory activity, similar in structure to other corticosteroids , fluorinated at carbon 6 and carbon 9. On June 23, 2008, the US FDA approved 0.05% difluprednate ophthalmic lotion (Difluprednate, Durezol) developed by Sirion Therapeutics for listing for the treatment of postoperative local inflammation and pain. [0003] The main synthetic literatures of difluprednate currently reported are found in Ercoli and Gardi's 1968 patent ZA6803686, 1973 US patent 3780177 and patents of the same family, 2012 Chinese patent CN103509075, and 2014 Chinese patent CN201410209590. There are three main routes: [0004] Route one: [0005] [0006] Route two: [0007] [...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J5/00
CPCC07J5/0053
Inventor 靳志忠刘喜荣曾春玲曹旭
Owner HUNAN NORCHEM PHARMACEUTICAL CO LTD
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