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Method for preparing sofosbuvir intermediate through one-step process

An intermediate and step technology, applied in the field of one-step preparation of sofosbuvir intermediates, can solve the problems of long process route, poor product quality, difficult to handle and the like, and achieve the advantages of short process flow, good quality and reduced reaction steps. Effect

Inactive Publication Date: 2017-06-09
苏州诚和医药化学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Purpose of the invention: Aiming at the deficiencies in the prior art, the present invention provides a method for preparing the intermediate of sofosbuvir in one step, which solves the problems of long process route, low yield, poor product quality and three wastes in the prior art. Large and difficult to handle and other shortcomings, more suitable for industrial production requirements

Method used

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  • Method for preparing sofosbuvir intermediate through one-step process
  • Method for preparing sofosbuvir intermediate through one-step process

Examples

Experimental program
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Effect test

Embodiment 1

[0017] like figure 2 The synthetic route of the sofosbuvir intermediate shown, will add 300g dichloromethane, α-picoline 70g, raw material 2-C-methyl-4,5-O-(1- Methylvinyl)-D-ethyl arabinonic acid ester (1) 150g (0.57mol), cooled to below 15°C, slowly add 81g (0.60mol) of sulfuryl chloride dropwise under stirring condition and maintain 10-20°C, sulfuryl chloride After the dropwise addition, slowly raise the temperature to 20-25°C, and keep warm at this temperature for 8 hours, add 300ml of water to wash and separate the organic phase, dry the organic phase with anhydrous magnesium sulfate, and then concentrate to dryness to obtain the target product (3) , 171.2g (0.53mol), yield 92.98%, GC purity 99.16%. (GC Analysis Conditions Detector: Hydrogen Flame Ionization (FID) Detector; Chromatographic Column Model: DM-5, 30m0.25mmID0.25µm; Carrier Gas / Flow: Nitrogen / 0.1Mpa; Hydrogen: 0.1Mpa; Column Temperature: 150 ℃; Injector temperature: 180℃; Detector temperature: 190℃; Injecti...

Embodiment 2

[0019] like figure 2 The synthetic route of the sofosbuvir intermediate shown, will add 100g dichloromethane, α-picoline 25g, raw material 2-C-methyl-4,5-O-(1- Methylvinyl)-D-ethyl arabinonic acid ester (1) 50g (0.19mol), cooled to below 15°C, slowly add 31.0g (0.23mol) of sulfuryl chloride dropwise under stirring condition and maintain 10-20°C, sulfur After the addition of acid chloride, slowly raise the temperature to 25-30°C, and keep it at this temperature for 5 hours, add 100ml of water to wash and separate the organic phase, and then dry and concentrate the organic phase with anhydrous magnesium sulfate to obtain this product, 50.4g (0.18mol), yield 94.74%, GC purity 99.04%. (GC Analysis Conditions Detector: Hydrogen Flame Ionization (FID) Detector; Chromatographic Column Model: DM-5, 30m0.25mmID0.25µm; Carrier Gas / Flow: Nitrogen / 0.1Mpa; Hydrogen: 0.1Mpa; Column Temperature: 150 ℃; Injector temperature: 180℃; Detector temperature: 190℃; Injection volume: 0.5µl)

Embodiment 3

[0021] like figure 2 The synthetic route of the sofosbuvir intermediate shown, will add 250g dichloromethane, α-picoline 60g, raw material 2-C-methyl-4,5-O-(1- Methylvinyl)-D-ethyl arabinonic acid ester (1) 100g (0.38mol), cooled to below 15°C, slowly add 59.4g (0.44mol) of sulfuryl chloride dropwise under stirring condition and maintain 10-20°C, sulfur After the addition of the acid chloride, slowly raise the temperature to 15-20°C, and keep warm at this temperature for 10 hours, add 200ml of water to wash and separate the organic phase, and then dry and concentrate the organic phase with anhydrous magnesium sulfate to obtain this product, 113.5g (0.35mol), yield 92.10%, GC purity 99.31%. (GC Analysis Conditions Detector: Hydrogen Flame Ionization (FID) Detector; Chromatographic Column Model: DM-5, 30m0.25mmID0.25µm; Carrier Gas / Flow: Nitrogen / 0.1Mpa; Hydrogen: 0.1Mpa; Column Temperature: 150 ℃; Injector temperature: 180℃; Detector temperature: 190℃; Injection volume: 0.5µ...

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Abstract

The invention provides a method for preparing a sofosbuvir intermediate through a one-step process. The method includes: adopting sulfuryl chloride (SO2Cl2) to esterify 2-C-methyl-4, 5-O-(1-methylvinyl)-D-arabinic acid ethyl ester. The method is short in synthesis route, and synthesis of the sofosbuvir intermediate which is a target product is completed through one step, so that reaction steps are reduced, the oxidation step in the prior art is omitted, raw material consumption is reduced substantially, and high-salinity wastewater is reduced.

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis, and in particular relates to a method for preparing a sofosbuvir intermediate in one step. Background technique [0002] Sofosbuvir is an anti-hepatitis C patent drug newly developed by Gilead Sciences, Inc. (hereinafter referred to as "Gilead"). This product was approved by the US Food and Drug Administration (FDA) in December 2013. Approved by the European Union in January 2014, it is the first drug approved for the full oral treatment of hepatitis C. Synthetic routes of prior art, such as figure 1 Synthesis of sulfinate from starting material 2-C-methyl-4,5-O-(1-methylvinyl)-D-arabininate ethyl ester (1) using thionyl chloride as shown (2), and then oxidized by sodium hypochlorite to obtain sulfonate (3). This process has a long synthetic route and requires a complicated post-treatment process. Because the process uses a large amount of excessive sodium hypochlorite, a la...

Claims

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Application Information

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IPC IPC(8): C07D411/04
CPCC07D411/04
Inventor 夏秋景
Owner 苏州诚和医药化学有限公司
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