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Preparation method for hepatitis C virus resisting drug sofosbuvir intermediates

A technology of sofosbuvir and intermediates, which is applied in the field of preparation of anti-hepatitis C virus drug sofosbuvir intermediates, and can solve the problems of long reaction routes and high costs of compounds 9 and 11

Inactive Publication Date: 2016-01-06
CONSCI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In order to solve the existing problem of long reaction route and high cost of industrialized preparation of compounds 9 and 11, the inventors of the present invention achieved through the following technical scheme:

Method used

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  • Preparation method for hepatitis C virus resisting drug sofosbuvir intermediates
  • Preparation method for hepatitis C virus resisting drug sofosbuvir intermediates
  • Preparation method for hepatitis C virus resisting drug sofosbuvir intermediates

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0012] Example 1 (preparation of compound IV)

[0013] Add 94g of compound I and 42g of methyl propiolate, 250mL of 50% ethanol solvent, 152g of 1,8-diazabicycloundec-7-ene into a 500mL reaction bottle, heat up and reflux for 4 hours, then cool down to room temperature After concentrating the solvent to half, 100 mL of isopropanol was slowly added dropwise to precipitate crystals, filtered, and the filter cake was vacuum-dried for 5 hours to obtain 110 g of a white solid with a yield of 91.7% and a purity of 98%. H-NMR (MeOD400MHz): δ1.64 (3H, s), 3.49-3.54 (1H, dd), 3.58-3.63 (1H, dd), 4.05-4.09 (1H, dd), 4.33 (1H, d), 5.90 (1H, s), 6.05 (1H, d), 7.76 (1H, d).

example 2

[0014] Example 2 (preparation of compound 11)

[0015] Add 80g of compound IV, 19.31g of potassium fluoride, 160mL of DMF, 160mL of toluene, and 1g of benzo-18-crown-6-ether into a 500mL reaction flask. Add 200mL of 1,4-dioxane dropwise, precipitate needle-like crystals, cool to 5-10°C, filter, filter the cake with 200mL of ethyl acetate for 1 hour and filter, vacuum-dry at 45°C for 5 hours to obtain 80g of white needle-like crystals , yield 92.3%, purity 98.5%. H-NMR (DMSO-d 6 ): δ11.44(br, s, 1H, NH), 7.95(d, 1H), 5.97(d, 1H), 5.64(d, 1H), 3.84-3.77(m, 3H), 3.63-3.60(m , 1H), 1.23(d, 3H).

example 3

[0016] Example 3 (preparation of compound V)

[0017] Add 180g of I, 240mL of N,N-dimethylacetamide to a 500mL reaction bottle, control the temperature at 15-20°C and add 40g of propylonitrile, about 1.5 hours, the system turns dark reddish brown, add 50mL of 48% hydrogen fluoride, 10mL of water, After reacting at 20-25°C for 2 hours, 80 mL of 1,4-dioxane was slowly added dropwise, and 85 g of crystalline solid (V) was precipitated, with a yield of 84% and a purity of 97%. H-NMR (DMSO-d 6 ): δ1.63(s, 3H), 1.72(d, 1H), 3.39(dd, 2H), 3.88(s, 1H), 4.53(d, 1H), 4.95(s, 1H), 5.47(s, 1H), 5.71 (s, 1H), 4.95 (s, 1H), 6.55 (m, 1H).

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Abstract

The invention relates to a preparation method for sofosbuvir intermediates 9, 11. The preparation method comprises the following steps: by taking a compound I as an initial material, carrying out an additive reaction with electrophilic reagents acrylonitrile, cyanoacetylene, propargyl ester and acrylate and carrying out ring-closing reaction to prepare corresponding intermediates (VII, V, IV and II); carrying out a ring-opening reaction on the intermediates (VII, V, IV and II) and a fluorination reagent to obtain corresponding intermediates (VIII, VI, II and III), carrying out a reaction on the intermediate VIII and benzoyl chloride in an alkaline condition to prepare an intermediate IX, and further carrying out dehydrogenation reaction on the intermediate IX in the presence of an oxidizing agent to prepare an intermediate 9; carrying out a reaction on the intermediate VI and benzoyl chloride in the alkaline reaction to prepare the intermediate 9; and further carrying out dehydrogenation reaction on the intermediate III in the presence of an oxidizing agent to prepare the intermediate 11.

Description

technical field [0001] The invention relates to a preparation method of an anti-hepatitis C virus medicine sofosbuvir intermediate. Background technique [0002] Sofosbuvir is a new generation of antiviral drug developed by Gilead Famoxet Co., Ltd., and its structural formula is as follows. [0003] [0004] Compounds 9 and 11 are important intermediates for the synthesis of sofosbuvir. Currently, CN101437524B reports the synthesis method of compound 9 (such as route 1). For the method of synthesizing intermediate 11 from intermediate 9, see CN102858790A. [0005] [0006] This reaction has problems such as long reaction route, incomplete reaction and low reaction selectivity in the preparation of compound (9), which lead to high production cost and raw material cost of the whole route. Contents of the invention [0007] In order to solve the existing problem of long reaction route and high cost of industrialized preparation of compounds 9 and 11, the inventors of t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/073C07H1/00
Inventor 牟祥刘念
Owner CONSCI PHARMA
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