Preparation method of sofosbuvir impurity

A technology for sofosbuvir and impurities, which is applied in the field of preparation of sofosbuvir impurities and achieves the effects of mild reaction conditions, simple operation and good impurity purity

Pending Publication Date: 2021-04-20
JIANGSU COBEN PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It can be seen from the literature search that there are no substantive literature reports on the preparation method of the impurity SM1-Q7. Therefore, it is necessary to invent the preparation method of the above-mentioned impurity to obtain related impurities, so as to meet the needs of drug research and quality control.

Method used

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  • Preparation method of sofosbuvir impurity
  • Preparation method of sofosbuvir impurity
  • Preparation method of sofosbuvir impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Add 42g of 2-methoxyethanol, 85g of DBU, and 150g of DMF in sequence in a 250mL reaction bottle, stir rapidly at room temperature for 15 minutes, add 30g of sulfonyl chloride dropwise, control the reaction temperature below 40°C, and add dropwise for 30 minutes. Finally, react at about 40°C for 3 hours, then raise the temperature to about 60°C for 3 hours. After the reaction is completed, concentrate under reduced pressure below 95°C until there is no distillate, add 150g of dichloromethane and 30g of water, stir and dissolve for 30 minutes, separate the layers, wash the organic layer with water twice, and then separate the layers, and concentrate the organic layer under reduced pressure below 50°C. Layer until there is no fraction, and the residue is obtained, which is the crude product of SM1-Q7. The crude product was separated by silica gel column flash chromatography (eluent: ethyl acetate / n-hexane=8 / 1), and the fractions were collected and concentrated to obtain ab...

Embodiment 2

[0040]Add 37g of 2-methoxyethanol, 37g of DBU, and 100g of tetrahydrofuran to a 250mL reaction flask in sequence, stir rapidly at room temperature for 15 minutes, add 30g of sulfuryl chloride dropwise, control the reaction temperature below 40°C, and add dropwise for 30 minutes. After completion, react at about 40°C for 3 hours, then raise the temperature to about 50°C for 3 hours. After the reaction is complete, concentrate under reduced pressure below 50°C until there is no distillate, add 150g of dichloromethane and 30g of water, stir and dissolve for 40 minutes, separate the layers, wash the organic layer with water twice, and then separate the layers, and concentrate the organic layer under reduced pressure below 50°C. Layer until there is no fraction, and the residue is obtained, which is the crude product of SM1-Q7. The crude product was separated by silica gel column flash chromatography (eluent: ethyl acetate / n-hexane=8 / 1), and the fractions were collected and concent...

Embodiment 3

[0042] Add 37g of 2-methoxyethanol, 74g of DBU, and 150g of acetonitrile to a 500mL reaction flask in sequence, stir rapidly at room temperature for 15 minutes, add 30g of sulfonyl chloride dropwise, control the reaction temperature below 40°C, and add dropwise for 30 minutes. After completion, react at about 40°C for 3 hours, then raise the temperature to about 50°C for 3 hours. Post-treatment was carried out according to Example 2 (eluent: ethyl acetate / n-hexane=8 / 1), and about 36 g of the colorless liquid target SM1-Q7 was obtained with a purity of 98.9%.

[0043] The structure of the prepared compound was confirmed by hydrogen spectroscopy, and it was confirmed to be the impurity SM1-Q7. The analysis is as follows: 1 HNMR (500MHz, d-DMSO); δ: 3.291 (S, 3H), equivalent to 6H, in line with the number of protons of two symmetrical methyl groups in the molecule; δ: 3.609-3.626 (m, 2H), equivalent to 4H, in line with The number of protons of the two symmetrical methylene group...

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Abstract

The invention discloses a preparation method of a sofosbuvir impurity, the sofosbuvir impurity is an impurity SM1-Q7, and the sofosbuvir impurity is prepared by one of the following two synthesis routes. The method has the advantages of easily available raw materials, mild reaction conditions and simple operation, and the obtained SM1-Q7 has good purity and meets the requirements of research and control of sofosbuvir impurities.

Description

technical field [0001] The invention relates to a preparation process of sofosbuvir impurities, belonging to the technical field of drug synthesis. Background technique [0002] Sofosbuvir, the English name is Sofosbuir, the trade name is Sovaldi, and the dosage form is tablet (400mg). It was approved by the US FDA in December 2013. It is a hepatitis C drug developed by Gilead Sciences. Viral (HCV) nucleotide analogue NS5B polymerase inhibitor, used for the treatment of chronic hepatitis C virus (HCV) infection, clinically used as a combined antiviral therapy for the treatment of chronic hepatitis C (CHC) infection, in In subjects infected with HCV genotypes 1, 2, 3, or 4, including those with hepatocellular carcinoma, HCV / HIV-1 co-infection, treatment with sofosbuvir achieved favorable results. Clinical trials have confirmed that for hepatitis C types 1 and 4, the overall sustained virological response rate (SVR) of sofosbuvir combined with peginterferon and ribavirin is a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C303/28C07C305/10
Inventor 史磊游金宗蔡金元蒋善会
Owner JIANGSU COBEN PHARMA CO LTD
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