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Method for preparing sofosbuvir intermediate

A technology for intermediates and crude products, applied in the field of medicinal chemistry, can solve the problems of harsh reaction conditions, high equipment requirements, low yield, etc., and achieve the effect of simple and convenient post-processing and mild reaction

Active Publication Date: 2017-02-22
江苏阿尔法集团福瑞药业(宿迁)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] To sum up, the reported route still has problems such as harsh reaction conditions, high equipment requirements and low yield. In view of the fact that the infection rate of hepatitis C has been increasing year by year in recent years, the treatment of hepatitis C has attracted more and more attention from scientists. , so it is necessary to develop a synthetic route of the key intermediate I of sofosbuvir that is more convenient and suitable for industrialized production

Method used

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  • Method for preparing sofosbuvir intermediate
  • Method for preparing sofosbuvir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Part 1: Preparation of N-dichlorophosphoryl-L-alanine isopropyl ester (II)

[0040]

[0041] Step a), L-alanine isopropyl ester hydrochloride (8.4g, 50mmol), add 100ml of diethyl ether, cool down in an ice bath, control the temperature at 0°C, slowly add phosphorus oxychloride (7.7g, 50mmol), dropwise After the addition, triethylamine (10.1g, 100mmol) was slowly added dropwise. After the dropwise addition, the insulation reaction was carried out for 1 hour. After the reaction was completed, it was gradually raised to room temperature, and the insolubles were removed by suction filtration. The filtrate was concentrated under reduced pressure to obtain a yellow solid ( Compound shown in formula II), this crude product is directly used in the next step reaction without refining;

[0042] Part II: Preparation of N-[(S)-(2,3,4,5,6-pentafluorophenoxy)]phenoxyphosphoryl-L-alanine isopropyl ester

[0043]

[0044]Step b), the crude product (12.4g, 50mmol) of the compound...

Embodiment 2

[0047] Part 1: Preparation of N-dichlorophosphoryl-L-alanine isopropyl ester (II)

[0048]

[0049] Step a), L-alanine isopropyl ester hydrochloride (8.4g, 50mmol), add 100ml of tetrahydrofuran, cool down in an ice bath, control the temperature at 0°C, slowly add phosphorus oxychloride (7.7g, 50mmol), dropwise After the addition, triethylamine (10.1g, 100mmol) was slowly added dropwise. After the dropwise addition, the insulation reaction was carried out for 1 hour. After the reaction was completed, it was gradually raised to room temperature, and the insolubles were removed by suction filtration. The filtrate was concentrated under reduced pressure to obtain a yellow solid ( Compound shown in formula II), this crude product is directly used in the next step reaction without refining;

[0050] Part II: Preparation of N-[(S)-(2,3,4,5,6-pentafluorophenoxy)]phenoxyphosphoryl-L-alanine isopropyl ester

[0051]

[0052] Step b), the crude product of the compound represented ...

Embodiment 3

[0055] Part 1: Preparation of N-dichlorophosphoryl-L-alanine isopropyl ester (II)

[0056]

[0057] Step a), L-alanine isopropyl ester hydrochloride (10.0g, 50mmol), add 100ml of tetrahydrofuran, cool down in an ice bath, control the temperature at 0°C, slowly add phosphorus oxychloride (7.7g, 50mmol), dropwise After the addition, N,N-diisopropylethylenediamine (14.4g, 100mmol) was slowly added dropwise. After the dropwise addition was completed, the reaction was incubated for 1 hour. Concentration under reduced pressure gave a yellow solid (compound shown in formula II), and the crude product was directly used in the next step without purification;

[0058] Part II: Preparation of N-[(S)-(2,3,4,5,6-pentafluorophenoxy)]phenoxyphosphoryl-L-alanine isopropyl ester

[0059]

[0060] Step b), the crude product of the compound represented by formula II in step a) (12.4g, 50mmol), add 50ml of dichloromethane, cool down in an ice bath, control the temperature at 0°C, and slowl...

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Abstract

The invention relates to the technical field of medicinal chemistry, and in particular to a method for preparing a sofosbuvir intermediate N-[(S)-(2,3,4,5,6-pentafluorophenyl) phenoxyl phosphoryl-L-alanine isopropyl ester. According to the method, a compound II prepared from L-alanine isopropyl ester hydrochloride and phosphorus oxychloride is adopted as an initial raw material, the compound II is reacted with phenol and pentafluorophenol, and thus a target product can be prepared. The compound II is adopted as the initial raw material for a first time, and the whole process adopts gentle reaction conditions, the operation is simple and convenient, the yield is high in yield, the purity is good and the method is applicable to large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a sofosbuvir intermediate N-[(S)-(2,3,4,5,6-pentafluorophenoxy)]phenoxyphosphoryl- The preparation method of L-alanine isopropyl ester. Background technique [0002] Sofosbuvir (also translated as Sofosbuvir, English name Sofosbuvir, trade name Sovaldi), developed by Pharmasset and acquired by Gilead, is used to treat chronic hepatitis C. On December 6, 2013, it was approved by the US Food and Drug Administration (FDA) for marketing in the United States, and on January 16, 2014, it was approved by the European Medicines Agency (EMEA) for marketing in EU countries. The structure of Sofosbuvir is as follows: [0003] [0004] International patent WO2010135569, US2011251152, WO2011123645 and literature "J.Org.Chem., 2011,76,8311-8319" reported the synthesis method of sofosbuvir: intermediate I N-[(S)-(2,3 ,4,5,6-Pentafluorophenoxy)]phenoxyphosphoryl-L-alanine isopr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/24
CPCC07B2200/07C07F9/242C07F9/2458
Inventor 陈本顺
Owner 江苏阿尔法集团福瑞药业(宿迁)有限公司
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