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Method for preparing sofosbuvir intermediate

A technology for intermediates and compounds, applied in the field of drug synthesis, can solve problems such as high cost and many side reactions, and achieve the effects of low cost, few side reactions and simple handling

Active Publication Date: 2019-04-05
湖南千金湘江药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The existing synthetic methods all have the problems of high cost and many side reactions

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Take 2-C-methyl-4,S-O-(1-methylethylene)-D-ethyl arabinonic acid cyclic sulfate and 4-phenyl-2-oxazolidinone according to the molar ratio of 1:1.5 , add toluene to react, the reaction temperature is 60°C, and the reaction time is 12 hours. After the reaction, the temperature was lowered to 20° C., washed twice with saturated brine, and the organic phases were combined and concentrated to obtain a yellow oil (the first compound) with a yield of 90%, which was directly used in the next reaction. The reaction formula is as follows:

[0042]

[0043] Add the first compound, tetraethylammonium fluoride, and anhydrous 1,4-dioxane in the reaction flask, the molar ratio of the first compound and tetraethylammonium fluoride is 1:2.0, and the resulting reaction mixture is heated to 105°C, the solvent was refluxed, and the reaction was stirred for 16 hours. After TLC (thin-layer chromatography) monitors the complete reaction of the raw materials, the reaction mixture is coole...

Embodiment 2

[0050] Take 2-C-methyl-4,S-O-(1-methylethylene)-D-ethyl arabinonic acid cyclic sulfate and 4-phenyl-2-oxazolidinone according to the molar ratio of 1:2.0 , add toluene to react, the reaction temperature is 80°C, and the reaction time is 8 hours. After the reaction, the temperature was lowered to 30° C., washed twice with saturated brine, and the organic phases were combined and concentrated to obtain a yellow oil (the first compound) with a yield of 95%, which was directly used in the next reaction.

[0051] Add the first compound, tetraethylammonium fluoride, and anhydrous 1,4-dioxane in the reaction flask, the molar ratio of the first compound and tetraethylammonium fluoride is 1:2.0, and the resulting reaction mixture is heated to 115°C, the solvent was refluxed, and the reaction was stirred for 18 hours. After TLC (thin-layer chromatography) monitors the complete reaction of the raw materials, the reaction mixture is cooled to room temperature, and 2,2-dimethoxypropane (1...

Embodiment 3

[0055] Take 2-C-methyl-4,S-O-(1-methylethylene)-D-ethyl arabinonic acid cyclic sulfate and 4-phenyl-2-oxazolidinone according to the molar ratio of 1:1.8 , add toluene to react, the reaction temperature is 70°C, and the reaction time is 10 hours. After the reaction, the temperature was lowered to 25° C., washed twice with saturated brine, and the organic phases were combined and concentrated to obtain a yellow oil (the first compound) with a yield of 92%, which was directly used in the next reaction.

[0056] Add the first compound, tetraethylammonium fluoride, and anhydrous 1,4-dioxane in the reaction flask, the molar ratio of the first compound and tetraethylammonium fluoride is 1:1.9, and the resulting reaction mixture is heated to 110°C, the solvent was refluxed, and the reaction was stirred for 17 hours. After TLC (thin-layer chromatography) monitors the complete reaction of the raw materials, the reaction mixture is cooled to room temperature, and 2,2-dimethoxypropane (...

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Abstract

The invention provides a method for preparing a sofosbuvir intermediate. The method includes following steps: allowing 2-C-methyl-4, S-O-(1-methylethylene)-D-arabonic acid ethyl cyclosulfate and 4-phenyl-2-oxazolidone to be in condensation reaction to obtain a first compound; allowing the first compound and a fluorinating agent for fluorinating reaction, and adding acid for deprotection reaction to obtain a second compound; allowing the second compound to react with sodium ethoxide to obtain a third compound; allowing the third compound to be in rearrangement reaction, and allowing a rearrangement product to react with benzoyl chloride to obtain the sofosbuvir intermediate. The method provides a new idea for synthesizing the sofosbuvir intermediate.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for preparing a sofosbuvir intermediate. Background technique [0002] Sofosbuvir (English name Sofosbuvir, trade name Sovaldi) is a drug developed by Gilead for the treatment of chronic hepatitis C. It is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor. It is suitable for treating chronic hepatitis C (CHC) infection as a combined component in a combined antiviral therapy regimen. In December 2013, it was approved by the US Food and Drug Administration (FDA) for marketing in the United States, and in January 2014 it was approved by the European Medicines Agency (EMEA) for marketing in EU countries. Launched in China in 2017. In 2017, the total global sales of the drug reached 9 billion US dollars, which has huge social and commercial value. [0003] During the synthesis of sofosbuvir, 2R-2-deoxy-2-fluoro-2-methyl-D-erythropentanoic acid-γ-lactone-3,...

Claims

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Application Information

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IPC IPC(8): C07D307/33
CPCC07D307/33
Inventor 宿亮袁红波金秉德袁秀菊姚亮元王玲兰邹斌彬龙承基
Owner 湖南千金湘江药业股份有限公司
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