Preparation method of remdesivir

A compound and organic base technology, applied in the field of preparation of remdesivir, can solve the problems of increasing the risk of genotoxic impurities and achieve the effect of reducing the risk of genotoxic impurities

Inactive Publication Date: 2020-05-08
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

This method uses a genotoxic nitro substitute, increasing the risk of genotoxic impurities

Method used

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  • Preparation method of remdesivir

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Experimental program
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Effect test

Embodiment 1

[0026] Preparation of Compound IV:

[0027] Under the protection of nitrogen, add compound V (16.48g, 47.4mmol) and pentafluorophenol (8.28g, 45.0mmol) into the round bottom flask, cool down to 0°C, then slowly add triethylamine (6.85mL) dropwise Dichloromethane solution (30mL), keep the temperature of the solution in the round bottom flask not higher than 5°C, after the dropwise addition, slowly return to room temperature (15~20°C), and stir at room temperature for 24h; add cold water (ice + water 100g in total, cool down the system to 0~5°C, pay attention to add ice to cool down first, but do not have solid ice, other examples are the same), after stirring, separate layers, wash the organic layer with saturated saline, and wash the organic layer with 10gMg 2 SO 4 Stir dry. After filtration, the organic layer was concentrated, then 100 mL of toluene was added, and evaporated to dryness under reduced pressure to obtain 21.18 g of crude compound IV. The crude product was dir...

Embodiment 2

[0035] Preparation of Compound IV:

[0036] Under the protection of nitrogen, add compound V (18.95g, 54.5mmol) and pentafluorophenol (8.28g, 45.0mmol) into the round bottom flask, cool down to 0°C, then slowly add triethylamine (8.18mL) dropwise Dichloromethane solution (30mL), keep the temperature of the solution in the round bottom flask not higher than 10°C, after the dropwise addition, slowly return to room temperature (15~20°C), and stir at room temperature for 12h; add cold water (ice + water (total 100g, the system was cooled to 0~5°C), after stirring, the layers were separated, the organic layer was washed with saturated brine, and the organic layer was washed with 10gMg 2 SO 4 Stir dry. After filtration, the organic layer was concentrated, then 100 mL of toluene was added, and evaporated to dryness under reduced pressure to obtain 21.62 g of crude compound IV. The crude product was directly used for the next step of resolution without further purification, and the ...

Embodiment 3

[0043] Preparation of Compound IV:

[0044] Under nitrogen protection, compound V (22.71g, 65.3mmol) and pentafluorophenol (8.28g, 45.0mmol) were added to a round bottom flask, cooled to 0°C, and then slowly added dropwise with triethylamine (7.68mL) Dichloromethane solution (30mL), keep the temperature of the solution in the round bottom flask not higher than 5°C, after the dropwise addition, slowly return to room temperature (15~20°C), and stir at room temperature for 16h; add cold water (ice + water (total 100g, the system was cooled to 0~5°C), after stirring, the layers were separated, the organic layer was washed with saturated brine, and the organic layer was washed with 10gMg 2 SO 4 Stir dry. After filtration, the organic layer was concentrated, then 100 mL of toluene was added, and evaporated to dryness under reduced pressure to obtain 20.95 g of crude compound IV. The crude product was directly used for the next step of resolution without further purification, and t...

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Abstract

The invention discloses a preparation method of remdesivir, and belongs to the field of pharmaceutical chemicals; the preparation method comprises the steps: carrying out a reaction on a compound V with pentafluorophenol under the action of an alkali to obtain a compound IV; further splitting the compound IV to obtain a compound III; carrying out a reaction on the compound III with a compound II under the action of organic base with large steric hindrance, and carrying out acid hydrolysis to obtain a compound I. According to the method disclosed by the invention, the use of genotoxic nitro substitutes is avoided, the risk of genotoxic impurities is reduced, and the method is suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of remdesivir. Background technique [0002] The current outbreak of novel coronavirus pneumonia is expanding, and there is no clear specific drug available for treatment. [0003] Recently, some scientists from the Washington State Department of Health in the United States reported how they treated the first patient with new coronary pneumonia in the United States. They mentioned a drug called remdesivir. On the seventh day of the patient’s hospitalization, the doctors gave him an intravenous injection of remdesivir, and the patient’s condition improved the next day: blood oxygen concentration Rise, pulmonary rales disappeared, and appetite also recovered. The new type of coronavirus is closely related to atypical pneumonia coronavirus (SARS-CoV). In vitro and animal models, remdesivir is effective against both SARS-CoV and MERS-Co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561
CPCC07F9/6561
Inventor 陈本顺江涛朱萍杨涛
Owner 江苏阿尔法集团福瑞药业(宿迁)有限公司
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