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Preparation method of retegravir

A compound, trifluoromethoxyphenol 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

Active Publication Date: 2020-06-05
JIANGSU ALPHA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses genotoxic nitro substitutes, which are also explosive substances, increasing the risk of genotoxic impurities

Method used

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  • Preparation method of retegravir
  • Preparation method of retegravir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The preparation of compound IV:

[0028] Under the protection of nitrogen, add dichloromethane (100mL), compound V (16.48g, 47.4mmol) and 4-trifluoromethoxyphenol (8.01g, 45.0mmol) into the round bottom flask, cool down to 0°C, and slowly Slowly drop dichloromethane solution (30mL) containing triethylamine (6.28mL), keep the temperature of the solution in the round bottom flask not higher than 5°C, after the dropwise addition, slowly rise to room temperature (15~20°C), And stir at room temperature for 24 hours; add cold water (100g of ice + water in total, cool down the system to 0~5°C, note that ice is added first to cool down, and the final temperature is below 5°C, but no solid ice exists. Other examples are the same), After stirring, the layers were separated, and the organic layer was washed with saturated brine, and then 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 d...

Embodiment 2

[0036] The preparation of compound IV:

[0037] Under the protection of nitrogen, add compound V (15.62g, 45mmol), 4-trifluoromethoxyphenol (8.01g, 45.0mmol), dichloromethane (100mL) into a round bottom flask, cool down to 5°C, and Ethylamine (6.28mL) in dichloromethane solution (30mL) was slowly added dropwise to the reaction system, keeping the temperature of the solution in the round bottom flask below 10°C, after the dropwise addition was completed, slowly rise to room temperature (15~20°C) , and stirred at room temperature for 12 hours; add cold water (100g of ice + water, the system cools down to 0~5°C), cool the system down to 5°C, stir and separate layers, wash the organic layer with saturated brine, wash 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 21.1 g of crude compound IV, with a molar yield of 95.8% (0.958 moles of crude compound IV ...

Embodiment 3

[0044] The preparation of compound IV:

[0045] Under nitrogen protection, compound V (18.74g, 54mmol), 4-trifluoromethoxyphenol (8.01g, 45.0mmol), dichloromethane (100mL) were added to a round bottom flask, cooled to 5°C, and then slowly Add dropwise a dichloromethane solution (30mL) containing triethylamine (6.28mL), keep the temperature of the solution in the round bottom flask below 10°C, after the dropwise addition, slowly rise to room temperature (15~20°C), and Stir at room temperature for 16 hours; add cold water (100g of ice + water in total, cool down the system to 0~5°C), stir and separate layers, wash the organic layer with saturated brine, wash with 10g Mg 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 21.2 g of crude compound IV, with a molar yield of 96.3% (0.963 moles of crude compound IV per mole of 4-trifluoromethoxyphenol), without further pu...

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Abstract

The invention discloses a preparation method of retegravir, which belongs to the field of pharmaceutical chemicals, and comprises the following steps: reacting a compound V with 4-trifluoromethoxyphenol under the action of alkali to obtain a compound IV; further performing chiral resolution on the compound IV to obtain a compound III; and carrying out an acid hydrolysis reaction on the compound III and the compound II under the action of organic base with large steric hindrance to obtain a compound I. According to the method disclosed by the invention, the use of genotoxic nitro substitutes isavoided, 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] At present, there is no clear specific drug available for the treatment of the novel coronavirus pneumonia epidemic. Recently, some scientists from the Washington State Department of Health reported that a drug called remdesivir may be effective in the treatment of new coronaviruses, and proposed a possible mechanism of action for this drug, which inhibits the production of the viral RdRP protein . [0003] Remdesivir is a nucleoside analog with antiviral activity. In HAE cells, it has an EC50 value of 74 nM against ARS-CoV and MERS-CoV. In delayed brain tumor cells, it has anti-mouse hepatitis virus activity. The EC50 value is 30 nM. In vitro and in animal models, Remdesivir has demonstrated activity against viral pathogens of SARS and MERS, which also belong to coronaviruses and are re...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
CPCC07F9/65616
Inventor 陈本顺江涛朱萍程刚
Owner JIANGSU ALPHA PHARM CO LTD
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