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A kind of synthetic method of favipiravir

A technology of favipiravir and synthetic route, applied in the direction of organic chemistry and the like, can solve problems such as being unfavorable to industrialized production, and achieve the effects of low production cost, short reaction period and easy operation

Active Publication Date: 2017-06-20
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Not conducive to industrial production

Method used

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  • A kind of synthetic method of favipiravir
  • A kind of synthetic method of favipiravir
  • A kind of synthetic method of favipiravir

Examples

Experimental program
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Effect test

Embodiment 1

[0041] The preparation of embodiment 1 compound III

[0042] molecular weight Feeding amount Moles / mmol equivalent Ⅱ 218.01 50.1g 230 1 98.3% concentrated sulfuric acid 98.08 133g 1380 6 Methanol 2.2L sodium bicarbonate 84.01 231.9g 2760 12

[0043] Add 50.1g II and 2L methanol to the 3L reaction flask. At 0-5°C, slowly add 133g of 98.3% concentrated sulfuric acid dropwise thereto, after the drop is complete, raise the temperature to 40°C, and react for about 48 hours until the reaction of raw material II is basically completed.

[0044] Spin-dry methanol, add 200mL methanol and 500g ice-water mixture to it at 0-5°C, and add saturated aqueous sodium bicarbonate solution dropwise thereto to adjust the pH to 6-7. After suction filtration, the filter cake was vacuum-dried at 45° C. for 12 hours to obtain 43.2 g of brown solid III, with a yield of 80.1%.

[0045] MS(m / z):233[M+H] + ; 1 H NMR (DMSO-d 6 )δ: 3.95(s,3H), ...

Embodiment 2

[0046] The preparation of embodiment 2 compound IV

[0047] molecular weight Feeding amount Moles / mmol equivalent Ⅲ 232.03 43g 185.3 1 98.3% concentrated sulfuric acid 98.08 43mL sodium nitrite 69.0 25.6g 371 2

[0048] Add 43g III and 43mL 98.3% concentrated sulfuric acid into a 250mL reaction flask, and stir. At -10~-5°C, add 25.6g of sodium nitrite to it, raise the temperature to 20~25°C after adding, keep stirring for about 0.5h until the reaction of the raw materials is basically completed.

[0049] Slowly add the reaction solution dropwise into 430g of ice water, and keep stirring for about 1.5h until the reaction is complete. After suction filtration, the filter cake was air-dried at 50° C. for 6 hours to obtain 36.7 g of orange solid IV with a yield of 85%.

[0050] MS(m / z):232[M-H] - ; 1 H NMR (DMSO-d 6 )δ: 3.95(s,3H), 8.21(s,1H), 11.52(s,1H).

Embodiment 3

[0051] The preparation of embodiment 3 compound IV

[0052] molecular weight Feeding amount Moles / mmol equivalent Ⅲ 232.03 43g 185.3 1 98.3% concentrated sulfuric acid 98.08 21.5mL 0.5 sodium nitrite 69.0 12.8g 371 1

[0053] Add 43g III and 43mL 98.3% concentrated sulfuric acid into a 250mL reaction flask, and stir. At -20-0°C, add 25.6g of sodium nitrite to it, raise the temperature to 55-60°C after the addition, keep stirring for about 30 minutes until the raw materials are basically reacted.

[0054] Slowly add the reaction solution dropwise into 430g of ice water, and keep stirring for about 1.5h until the reaction is complete. After suction filtration, the filter cake was air-dried at 50° C. for 6 hours to obtain 37.6 g of orange solid IV with a yield of 87%.

[0055] MS(m / z):232[M-H] - ;1 H NMR (DMSO-d 6 )δ: 3.95(s,3H), 8.21(s,1H), 11.52(s,1H).

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Abstract

The invention belongs to the field of medicinal chemistry and particularly relates to a new synthesis method of Favipiravir. The method comprises the following steps: carrying out carboxyl protection on raw material shown in the formula (II) to generate a compound (III); carrying out diazotization hydrolysis reaction in the presence of concentrated sulfuric acid and sodium nitriteto generate a compound (IV); carrying out benzyl protection reaction to generate a compound (V), and then generating a compound (VI) in the presence of potassium fluoride and tetrabutylammonium bromide; removing a benzyl protection group to generate a compound (VII); and then adding an aminating agent to carry out amination to generate Favipiravir shown in the formula I. The method disclosed by the invention has the advantages that the reaction cycle is short, the operation is simple, the production cost is low, and the product is high in quality; therefore, the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, in particular to a method for synthesizing Favipiravir. Background technique [0002] Favipiravir (favipiravir, 1), chemically named 6-fluoro-3-hydroxypyrazine-2-carboxamide, is a new type of RNA polymerase inhibitor developed by Toyama Chemical Pharmaceutical Company in Japan, completed in Japan in March 2011 Phase III clinical trial, and submission of marketing application, it can be used clinically for the treatment of influenza. [0003] [0004] Literature [Furuta Y.Nitrogenous heterocyclic carboxamide derivatives orsalts thereof and antiviral agents containing both:WO,00 / 10569[P].2003-03-02.] with 6-bromo-3-aminopyrazine-2-carboxylic acid methyl ester ( 4) 6-amino-3-methoxypyrazine-2-carboxamide was obtained by diazotization alcoholysis, palladium-catalyzed amino substitution and amidation reaction, and then substituted by diazotized fluorine, and then in trimethyl The target mo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D241/24
CPCC07D241/24
Inventor 包金远黄辉蒋玉伟张孝清
Owner NANJING HUAWE MEDICINE TECH DEV
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