Preparation method of hepatitis drug intermediate

A technology for intermediates and drugs, applied in the field of preparation of drug intermediates, can solve the problems of high price, difficult recycling, expensive catalysts, etc., and achieves the effects of low reaction conditions, high yield and few side reactions.

Active Publication Date: 2020-04-28
SUZHOU JINGYE MEDICINE & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The disadvantage of this method is that the procurement of starting materials is difficult and expensive
At the same time, after a multi-step reaction, the chlorine in the molecule needs to be converted into a substituted amino group. The substitution reaction requires the use of 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene, Tris(dibenzylideneacetone) dipalladium (0) catalyst, which is expensive and difficult to recycle, thus resulting in high production costs

Method used

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  • Preparation method of hepatitis drug intermediate
  • Preparation method of hepatitis drug intermediate
  • Preparation method of hepatitis drug intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Embodiment 1: Preparation of 3-fluoroacetanilide

[0040]

[0041] Add 220ml of acetic acid and 55.5g (0.5M) of m-fluoroaniline into a 500ml four-neck bottle, stir to form a homogeneous one, and slowly add 53.6g (0.525M) of acetic anhydride (with obvious temperature rise). After the addition, heat up to 105°C. Insulation reaction 2hrs.

[0042] After the heat preservation is over, remove the acetic acid and acetic anhydride under reduced pressure, and remove to 110°C (-0.095MPa). Slightly cool to 85°C, add 55g of ethyl acetate, stir until uniform, and cool. Cool to room temperature, add 110g of n-hexane dropwise, freeze after dropping, cool to 0°C, stir for 2hrs to crystallize. Suction filtration, washing with n-hexane, and drying to obtain 75.0 g of partial solids, and 3-fluoroacetanilide with a content of more than 99.5% and a yield of about 98%.

Embodiment 2

[0043] Embodiment 2, the preparation of 2-fluoro-4-acetamidoacetophenone

[0044]

[0045] Add 104g of anhydrous aluminum trichloride (0.78M) and 150ml of carbon disulfide to a 500ml four-necked bottle, stir and cool to 0°C, slowly add 39.3g of acetyl chloride (0.5M), after the addition, raise the temperature to 20°C, and stir for 30min . Freeze to 0°C, and add 30.6 g (0.20 M) of m-fluoroacetanilide in batches. After the addition, the temperature was raised to room temperature and stirred for 30 min. Then heated to reflux for 48hrs.

[0046]After reflux, cool to room temperature. Remove the supernatant (to recover carbon disulfide), pour the reaction solution into 500g of crushed ice and 50ml of hydrochloric acid, and stir for hydrolysis. The hydrolyzate was extracted twice with 150ml and 100ml dichloroethane. The extracts were combined and washed twice with 100ml×2 water. The organic phase is a dichloroethane solution of the F-C product.

[0047] The solvent was rem...

Embodiment 3

[0048] Embodiment 3, the preparation of 2-fluoro-4-acetamidoacetophenone

[0049] According to the method of Example 2, nitrobenzene was used instead of carbon disulfide as a solvent. After the reaction was over, it was cooled, poured into crushed ice, stirred and hydrolyzed, and then the organic layer was separated, dried over sodium sulfate, and nitrobenzene was recovered by distillation under reduced pressure. Appropriate amount of methyl chloride, heated to dissolve. Cool to room temperature, slowly add n-hexane dropwise, stir for 1 hr (around 25°C), filter with suction, and wash with dichloromethane / n-hexane (1 / 3). The solid was dried to obtain the Fuke acylation product with a content of more than 97%. Yield 60.1%.

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Abstract

The invention discloses a preparation method of a hepatitis drug intermediate, which is characterized in that m-fluoroaniline is used as an initial raw material, and subjected to acetylation amino protection, a Friedel-Crafts acylation reaction, a nitration reaction and a bromination reaction, and finally coupling is performed to obtain 1,4-bis-[(4-acetamido-2-fluoro-5-nitro)phenyl]butane-1,4-dione. According to the method, the raw materials are easy to obtain, the reaction condition requirements are low, side reactions are few, the yield is high, and the 1,4-bis-[(4-acetamido-2-fluoro-5-nitro)phenyl]butane-1,4-dione can be used as a drug intermediate for preparing pibrentasvir.

Description

technical field [0001] The present invention relates to a preparation method of a pharmaceutical intermediate, in particular to the preparation of 1,4-bis-[(4-acetylamino-2-fluoro-5-nitro)phenyl]butane-1,4-dione method. Background technique [0002] Hepatitis C is considered to be a chronic liver viral disease. Mavyret, a pan-gene hepatitis C compound drug launched by American biotechnology giant AbbVie, is used to treat all 6 genotypes (GT1-6) of chronic hepatitis C virus ( HCV) adult patients, the drug treatment course is 8 weeks. After HCV patients take Maviret according to the course of treatment, the virological cure rate reaches 98%. [0003] Mavyret is a compound composed of an NS3 / 4A protease inhibitor glecaprevir and an NS5A inhibitor pibrentasvir, among which pibrentasvir is a new compound that is listed for the first time. The synthesis method of pirentasvir reported in the literature (WO2012051361A1) is to use 4-chloro-2-fluoro-5-nitrobenzoic acid as a raw mat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C233/43
CPCC07C231/12C07C231/02C07C233/43C07C233/33C07C233/15
Inventor 沈建伟吴和明
Owner SUZHOU JINGYE MEDICINE & CHEM
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