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Favipiravir intermediate and synthetic method for favipiravir

A compound and reaction technology, applied in the field of organic chemical synthesis, can solve the problems of unsuitability for industrial production, harsh reaction conditions, cumbersome post-processing, etc., and achieve the effects of stable yield, increased yield, and simplified post-processing process

Inactive Publication Date: 2018-01-30
富乐马鸿凯(大连)医药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] However, in the above synthetic route, there are problems such as harsh reaction conditions, cumbersome post-treatment, unsuitability for industrial production and low yield.

Method used

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  • Favipiravir intermediate and synthetic method for favipiravir
  • Favipiravir intermediate and synthetic method for favipiravir
  • Favipiravir intermediate and synthetic method for favipiravir

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0059] Preparation Example 1: Synthesis of 3,6-difluoro-2-cyanopyrazine

[0060] Step a): Under nitrogen protection, 35 g of 3-hydroxy-2-pyrazinamide, 33.6 g of pyridine and 0.3 liter of acetonitrile were mixed and heated to 80°C-85°C. 40 g of NCS was added dropwise in batches while keeping the temperature of the reaction system at 80°C to 85°C. After the addition was complete, the reaction was maintained at this temperature for 4 hours. Subsequently, the solvent was recovered by concentration. Then 0.6 liter of water was added, the resulting suspension was stirred at 20° C. to 25° C. for 2 hours, and filtered to obtain a wet product of 6-chloro-3-hydroxy-2-pyrazinamide. The wet product was vacuum-dried at 50°C-55°C to obtain 38.8 g of off-white solid 6-chloro-3-hydroxy-2-pyrazinamide. The yield was 88.7%, and the purity determined by HPLC was 99.1%.

[0061] Step b): Mix 36.7 g of 6-chloro-3-hydroxy-2-pyrazinamide and 0.3 liter of chlorobenzene, and cool to 0°C to 5°C. A...

preparation example 2

[0065] Preparation Example 2: Synthesis of 3,6-difluoro-2-cyanopyrazine

[0066] Step a): Under the protection of nitrogen, take 175 grams of 3-hydroxy-2-pyrazinamide, 168 grams of pyridine and 1.7 liters of N,N-dimethylformamide, mix and heat to 80 ° C ~ 85 ° C, and then dropwise add 290 gram of bromine while keeping the temperature of the reaction system at 80°C to 85°C. After the addition was complete, the reaction was maintained at this temperature for 2 hours. Subsequently, the solvent was recovered by concentration. Then 1.5 liters of water was added, the resulting suspension was stirred at 20° C. to 25° C. for 2 hours, and filtered to obtain a wet product of 6-bromo-3-hydroxy-2-pyrazinamide. The wet product was vacuum-dried at 50°C-55°C to obtain 220 g of off-white solid 6-bromo-3-hydroxy-2-pyrazinamide. The yield was 80.1%, and the purity determined by HPLC was 100%.

[0067] Step b): Mix 220 g of 6-bromo-3-hydroxy-2-pyrazinamide and 1.8 liters of acetonitrile, and...

preparation example 3

[0071] Preparation Example 3: Synthesis of Favipiravir

[0072] Mix 39.9 g of 3,6-difluoro-2-cyanopyrazine and 72 g of anhydrous sodium acetate in 0.35 liter of water and 0.35 liter of tetrahydrofuran, and heat to reflux for 20 hours. After the reaction is complete, the reaction solution is concentrated, and then the pH value of the system is adjusted to 2.0 to 2.5 with 20% dilute sulfuric acid. Then it was extracted with 0.2 liter of ethyl acetate. The resulting organic phase was concentrated under reduced pressure to obtain an oil. Add 0.2 liter of acetone and 50 g of dicyclohexylamine, stir the resulting suspension at 0° C. to 5° C. for 2 hours, and filter to obtain a wet product of 6-fluoro-3-hydroxy-2-cyanopyrazine dicyclohexylamine salt. Then vacuum-dried at 50° C. for 3 hours to obtain 62.4 g of a light brown solid with a yield of 70.3% and a purity of 99.2% as determined by HPLC.

[0073] 1 H NMR(DMSO)δ1.06(m,2H),1.23(m,8H),1.61(m,2H),1.73(m,4H),1.98(m,4H),3.08(m,2H)...

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Abstract

The invention relates to a favipiravir intermediate and a synthetic method for favipiravir, and specifically discloses a method for synthesizing 3,6-difluoro-2-cyanopyrazine with a formula 4 as shownin the specification. The method comprises the following steps: a) allowing a compound with a formula 1 as shown in the specification to react with a chlorinated reagent or a brominated reagent so asto obtain a compound with a formula 2 as shown in the specification; b) allowing the compound with the formula 2 as shown in the specification to react with phosphorus oxychloride in the presence of organic base so as to obtain a compound with a formula 3 as shown in the specification; and c) allowing the compound with the formula 3 as shown in the specification to react with a fluorinated reagentso as to obtain the compound with the formula 4 as shown in the specification. The invention also relates to a method for synthesizing the favipiravir by using the above-mentioned method.

Description

technical field [0001] The invention relates to the field of organic chemical synthesis, in particular to a method for synthesizing favipiravir intermediate 3,6-difluoro-2-cyanopyrazine and a method for synthesizing favipiravir through the method. Background technique [0002] Favipiravir (favipiravir) is a new type of RNA polymerase inhibitor broad-spectrum antiviral drug developed by Toyama Chemical Pharmaceutical Co., Ltd. in Japan. It has a good therapeutic effect on influenza virus. Nile virus and arenavirus also have good curative effect. Its structural formula is as follows: [0003] [0004] So far, a variety of methods for synthesizing favipiravir have been reported, among which the methods reported in EP1256588, WO2013180149 and WO2010087117 have more industrial value. In the above-mentioned documents, Favipiravir is synthesized by the following route. [0005] [0006] It can be seen from the above route that 3,6-difluoro-2-cyanopyrazine is the key interm...

Claims

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Application Information

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IPC IPC(8): C07D241/24
Inventor 陈有刚于双赵新俊冯言枢高汉荣
Owner 富乐马鸿凯(大连)医药有限公司
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