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Synthesis method of sofosbuvir intermediate

A synthesis method and intermediate technology, applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of sodium hypochlorite sensitization, nail thinning, hair loss, etc., achieve huge industrial production prospects, save production costs, and increase the effect of reaction intensity

Active Publication Date: 2019-03-08
JIANGSU COBEN PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The oxidizing agent that this reaction is used is sodium hypochlorite or sodium periodate, and the shortcoming that it shows is: sodium periodate is irritating to eyes, upper respiratory tract, mucous membrane and skin, needs to wear suitable protective clothing, gloves and Use protective glasses or face shields; sodium hypochlorite is absorbed through inhalation, ingestion, and skin contact. Workers who often touch sodium hypochlorite with their hands will sweat profusely in their palms, their nails will become thinner, and their hair will fall off.
When sodium hypochlorite or sodium periodate is used for oxidation reaction, there will be by-products NaCl or NaI, which is not conducive to subsequent processing

Method used

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  • Synthesis method of sofosbuvir intermediate
  • Synthesis method of sofosbuvir intermediate
  • Synthesis method of sofosbuvir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] A kind of synthetic method of Sofosbuvir intermediate (I), concrete steps are as follows:

[0026] Step 1, the synthesis of compound (Ⅲ): under the condition of 0-5°C, add 24.8g (0.1mol) of compound (Ⅱ), 200g of dichloromethane and 20.2g (0.2mol) of triethylamine into a dry three-necked flask, and stir To 0°C, slowly add thionyl chloride 17.9g (0.15mol), react for 30min, add ice water 100g, dichloromethane 200g, stir for 30min, separate the organic layer, then use 100g of water and 20% The organic layer was washed with brine to obtain a dichloromethane solution of compound (Ⅲ).

[0027] Step 2, the synthesis of compound (Ⅳ): Add 1.65 g (0.05 mol) of sodium tungstate dihydrate to the dichloromethane solution of compound (Ⅲ) in step 1, and add 28.3 g of 30% hydrogen peroxide dropwise at 23°C (0.25mol), continue the reaction for 9h until the compound (Ⅲ) disappears, filter and recover sodium tungstate dihydrate, and wash the filtrate with 50g of 10% sodium bisulfite and 5...

Embodiment 2

[0032] A kind of synthetic method of Sofosbuvir intermediate (I), concrete steps are as follows:

[0033] Step 1, the synthesis of compound (Ⅲ): under the condition of 0-5°C, add 22.6g (0.09mol) of compound (Ⅱ), 180g of dichloromethane and 18.2g (0.18mol) of triethylamine into a dry three-necked flask, and stir To 0°C, slowly add thionyl chloride 15.5g (0.13mol), react for 20min, add ice water 100g, dichloromethane 200g, stir for 30min, separate the organic layer, then use 100g of water and 20% The organic layer was washed with brine to obtain a dichloromethane solution of compound (Ⅲ).

[0034]Step 2, the synthesis of compound (Ⅳ): Add 15 g (0.045 mol) of sodium tungstate dihydrate to the methylene chloride solution of compound (Ⅲ) in step 1, and add 26.4 g of 35% hydrogen peroxide dropwise at 20° C. ( 0.27mol), continue the reaction for 8 hours until compound (Ⅲ) disappears, filter and recover sodium tungstate dihydrate, and wash the filtrate with 50 g of 10% sodium bisulfi...

Embodiment 3

[0039] A kind of synthetic method of Sofosbuvir intermediate (I), concrete steps are as follows:

[0040] Step 1, synthesis of compound (Ⅲ): under low temperature conditions, add 29.76g (0.12mol) of compound (Ⅱ), 230g of dichloromethane and 21.2g (0.21mol) of triethylamine into a dry three-necked flask, and stir to 0°C , slowly add thionyl chloride 18.6g (0.156mol), react for 40min, add ice water 100g, dichloromethane 200g, stir for 30min, separate the organic layer, then wash with 100g of water and 20% brine respectively organic layer to obtain a dichloromethane solution of compound (Ⅲ).

[0041] Step 2, synthesis of compound (Ⅳ): add 1.75 g (0.053 mol) of sodium tungstate dihydrate to the dichloromethane solution of compound (Ⅲ) in step 1, and add 29.9 g of 25% hydrogen peroxide dropwise at 25°C (0.22mol), continue to react for 10h until compound (Ⅲ) disappears, filter and recover sodium tungstate dihydrate, and wash the filtrate with 50g of 10% sodium bisulfite and 50g of ...

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Abstract

The invention relates to a synthesis method of a sofosbuvir intermediate shown as a formula (I). The synthesis method comprises the following steps: with a compound (2S,3R)-ethyl-3-((R)-2,2-dimethyl-1,3-dioxocyclopent-4-yl)-2,3-dihydroxy-2-methyl propionate (II) as a starting material, cyclizing by using sulfoxide chloride to form a compound (III); then, oxidizing the compound (III) by using hydrogen peroxide / sodium tungstate to produce a compound (IV); and synthesizing the sofosbuvir intermediate 3,5-dibenzoyl-2-deoxy-2-fluoro-2methyl-D-ribose-gamma-lactone (I) from the obtained compound (IV)through fluorination, hydrolysis and benzoylation. By the synthesis method, the sofosbuvir intermediate is synthesized; and the synthesis method is environmentally friendly and economical and has a huge industrial production prospect.

Description

technical field [0001] The present invention relates to a kind of synthetic method of medicine intermediate, relate in particular to a kind of synthetic method of the intermediate of sofosbuvir. technical background [0002] Sofosbuvir (also translated as Sofosbuvir, English name Sofosbuvir, trade name Sovaldi) is a new drug developed by Gilead for the treatment of chronic hepatitis C. It was approved by the US Food and Drug Administration (FDA) on December 6, 2013. ) was approved for marketing in the United States, and was approved for marketing in EU countries by the European Medicines Agency (EMEA) on January 16, 2014. Not yet available in China. The drug is the first to safely and effectively treat certain types of hepatitis C without the need for interferon. Clinical trials have confirmed that for hepatitis C types 1 and 4, the overall sustained virological response rate (SVR) of the drug combined with peginterferon and ribavirin is as high as 90%; for hepatitis C typ...

Claims

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Application Information

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IPC IPC(8): C07D307/33
CPCC07D307/33
Inventor 游金宗蒋善会史磊胡建隆何牮石
Owner JIANGSU COBEN PHARMA CO LTD
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