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Preparation method of balosavir intermediate

An intermediate and central control technology, applied in the field of medicine, can solve the problems of high cost, poor product purity and chromaticity, long steps, etc., and achieve the effect of facilitating industrial production and good product quality

Active Publication Date: 2021-01-26
南京法恩化学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The problems with this method are long steps, high cost, poor product purity and chromaticity

Method used

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  • Preparation method of balosavir intermediate
  • Preparation method of balosavir intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0029] A kind of preparation method of baloxavir intermediate specifically comprises the following steps:

[0030] (1) Add 1L tetrahydrofuran to the reaction flask, add 1.68kg dicyclohexylcarbodiimide, 1kg 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid and 1.5kg 2, -(2-Aminoethoxy)-1,1-dimethoxyethane, start stirring, raise the temperature to 60°C for reaction, and track with central control. After completion of the reaction, cool down to room temperature, add 3L of water, then extract with 5L of ethyl acetate, and concentrate the organic phase to obtain 1.33kg of Intermediate I, with a yield of 87%.

[0031] (2) Add 4L of N,N-dimethylacetamide into the reaction flask, then add 1.33kg of intermediate I and 2.3kg of pyridinium p-toluenesulfonate, start stirring, raise the temperature to 60°C, and drop tert-butoxycarbonylhydrazine 0.6 kg and 2L N,N-dimethylacetamide mixed solution, temperature control 60 ℃ reaction, central control tracking. After the reaction was completed, l...

Embodiment 2

[0034] A kind of preparation method of baloxavir intermediate specifically comprises the following steps:

[0035] (1) Add 1L 1,4-dioxane to the reaction flask, add 0.63kg 1-ethyl-3(3-dimethylpropylamine) carbodiimide, 1kg 3-(benzyloxy)-4- Oxo-4H-pyran-2-carboxylic acid and 0.6kg 2,-(2-aminoethoxy)-1,1-dimethoxyethane, started stirring, raised the temperature to 80°C to react, and followed the central control. After the reaction was completed, cool down to room temperature, add 3L of water, then extract with 5L of ethyl acetate, and concentrate the organic phase to obtain 1.30kg of Intermediate I.

[0036] (2) Add 4L of N,N-dimethylformamide into the reaction flask, then add 1.30kg of intermediate I and 2.3kg of pyridinium p-toluenesulfonate, start stirring, raise the temperature to 80°C, and drop tert-butoxycarbonylhydrazine 0.6 kg and 2L N,N-dimethylformamide mixed solution, temperature control 80 ℃ reaction, central control tracking. After the reaction was completed, lowe...

Embodiment 3

[0039] A kind of preparation method of baloxavir intermediate specifically comprises the following steps:

[0040] (1) Add 1L N,N-dimethylformamide, 1.02kg diisopropylcarbodiimide, 1kg 3-(benzyloxy)-4-oxo-4H-pyran- 2-Carboxylic acid and 1.5kg 2,-(2-aminoethoxy)-1,1-dimethoxyethane, start stirring, raise the temperature to 50°C and react with central control. After completion of the reaction, cool down to room temperature, add 3L of water, then extract with 5L of ethyl acetate, and concentrate the organic phase to obtain 1.33kg of Intermediate I.

[0041] (2) Add 4L of N,N-dimethylacetamide into the reaction flask, then add 1.33kg of intermediate I and 2.3kg of pyridinium p-toluenesulfonate, start stirring, raise the temperature to 80°C, and drop tert-butoxycarbonylhydrazine 0.6 kg and 2L N,N-dimethylacetamide mixed solution, temperature control 80 ℃ reaction, central control tracking. After the reaction was completed, lower the temperature to 0°C, add 2L of ethanol and 8L of...

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Abstract

The invention relates to a preparation method of a baloxavir intermediate, in particular to a method for efficiently synthesizing the baloxavir intermediate by taking 3-(benzyloxy)-4-oxo-4H-pyran- 2-carboxylic acid as a raw material through three steps of condensation reaction, hydrazinolysis reaction and cyclization reaction. The preparation method of the balosavir intermediate provided by the invention is a preparation method which is high in yield, low in cost, less in three wastes, high in product purity and suitable for industrialization.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation method of a baloxavir intermediate. Background technique [0002] The chemical name of the intermediate of baloxavir is 7-(benzyloxy)-3,4,12,12A-tetrahydro-1H-[1,4]oxazin[3,4-C]pyrido[2,1 -F][1,2,4]triazine-6,8dione, an intermediate in the synthesis of the anti-influenza drug baloxavir. In February 2018, Baloxavir marboxil (trade name: Xofluza), a new anti-influenza drug developed by Shionogi in Japan and jointly researched with Roche in Switzerland, received accelerated approval in Japan and was approved for marketing. Baloxavir dipivoxil is an innovative Cap-dependent endonuclease inhibitor and one of the few new drugs in the world that can inhibit the proliferation of influenza virus. In June 2018, the U.S. Food and Drug Administration (FDA) accepted the new drug application for baloxavir dipivoxil and granted it a priority review qualification. [0003] Th...

Claims

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Application Information

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IPC IPC(8): C07D498/14
CPCC07D498/14
Inventor 王坤鹏
Owner 南京法恩化学有限公司
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