Preparation method of baloxavir intermediate

An intermediate, dimethoxyethane technology, applied in the field of preparation of baloxavir intermediates, can solve the problems of low conversion rate of compound E, difficult crystallization, low purity of compound D, etc., and achieve high product purity, Simple operation and mild effect

Pending Publication Date: 2021-10-22
HEADING NANJING PHARMTECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] (1) Compound C has good water solubility, and water needs to be added for treatment, and the organic solvent used in the reaction system is tetrahydrofuran, so what is obtained is a tetrahydrofuran solution of compound C, and it is difficult to separate the pur...

Method used

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  • Preparation method of baloxavir intermediate
  • Preparation method of baloxavir intermediate
  • Preparation method of baloxavir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Add 247.6g of ethanolamine and 272.7g of sodium tert-butoxide into a 2L three-necked flask, stir, raise the temperature to 80-90°C, stir for 3h, add 101.0g of 2-chloroacetaldehyde dimethyl acetal dropwise, react at 90°C for 3h, and control in GC The detection reaction is complete.

[0033] Post-treatment: add 12L of ice water, then add 12L of dichloromethane, stir for 30min, let stand to separate the liquid, wash the organic phase with 500ml of sodium sulfate solution, separate the liquid, concentrate the organic phase, and rectify with an oil pump to obtain 63.3g of the product, namely ( 2,-(2-Aminoethoxy)-1,1-dimethoxyethane, yield 52%, hydrogen spectrum, GC spectrum as Figure 1-2 shown.

Embodiment 2

[0035] Add 29.5g of ethanolamine and 31g of sodium tert-butoxide into a 500mL three-necked flask, stir, raise the temperature to 80-90°C, stir for 3h, add 10g of 2-chloroacetaldehyde dimethyl acetal dropwise, react at 90°C for 3h, and detect the reaction in GC End.

[0036] Post-processing: add 1L of ice water, then add 1L of dichloromethane, stir for 30min, let stand to separate the liquid, wash the organic phase with 50ml of sodium sulfate solution, separate the liquid, concentrate the organic phase, and rectify with an oil pump to obtain 6.6g of the product, namely ( 2,-(2-aminoethoxy)-1,1-dimethoxyethane, yield 55%.

Embodiment 3

[0038] Add 3.43g of ethanolamine and 3.47g of sodium tert-butoxide into a 100mL three-necked flask, stir, raise the temperature to 80-90°C, stir for 3h, add 1g of 2-chloroacetaldehyde dimethyl acetal dropwise, react at 90°C for 3h, and detect in GC The reaction is over.

[0039] Post-processing: add 100mL of ice water, then add 100mL of dichloromethane, stir for 30min, let stand to separate the liquid, wash the organic phase with 50ml of sodium sulfate solution, separate the liquid, concentrate the organic phase, and rectify with an oil pump to obtain 0.6g of the product, namely ( 2,-(2-aminoethoxy)-1,1-dimethoxyethane, yield 50%.

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Abstract

The invention relates to the technical field of synthesis of medical intermediates, in particular to a preparation method of a baloxavir intermediate, wherein the baloxavir intermediate is 2,-(2-aminoethoxy)-1, 1-dimethoxyethane. The synthesis route of the baloxavir intermediate specifically comprises the following steps: 1) mixing an alkaline reagent and ethanolamine to obtain a mixed solution, and heating; 2) adding chloroacetaldehyde dimethyl acetal into the mixed solution, stirring, and reacting; and 3) after the reaction is finished, adding ice water and dichloromethane for post-treatment, concentrating an organic phase, and rectifying to obtain the 2,-(2-aminoethoxy)-1, 1-dimethoxyethane. The method is high in product purity, low in cost, simple to operate, mild in condition and suitable for industrial popularization.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a method for preparing a baloxavir intermediate. Background technique [0002] Baloxavir is a new drug against influenza A and B viruses discovered by Shionogi Co in Japan and jointly developed by it and Roche. Baloxavir, a novel cap-dependent endonuclease inhibitor, was approved by the U.S. Food and Drug Administration (FDA) on October 24, 2018, for the treatment of children 12 years of age and older with flu symptoms of prolonged duration. Acute uncomplicated influenza patients over 48 hours. It is also one of the few new drugs in the world that can inhibit the proliferation of influenza virus. Because it has no effect on host cells and has few side effects, it is expected to replace oseltamivir and become the ace drug in the field of influenza. [0003] Baloxavir Marvoxil was first seen in PCT patent WO20161752224, and its structural formula is as fol...

Claims

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Application Information

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IPC IPC(8): C07C213/06C07C217/08
CPCC07C213/06C07C217/08
Inventor 李文森
Owner HEADING NANJING PHARMTECH CO LTD
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