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Favipiravir intermediate 3, 6-dichloro-2-cyanopyrazine synthesis process

A synthetic process, favipiravir technology, is applied in the field of synthetic process of favipiravir intermediate 3,6-dichloro-2-cyanopyrazine, which can solve the problems of reducing production costs, long synthetic route steps, and yield. Low efficiency and other problems, to achieve the effects of reduced energy consumption, low cost, and convenient production

Active Publication Date: 2021-07-16
白银康寓信生物科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In order to overcome the problems of long steps and low yield in the synthesis route of favipiravir intermediate 3,6-dichloro-2-cyanopyrazine in the prior art, the present invention proposes a brand-new synthetic 3,6-dichloropyrazine The route of chloro-2-cyanopyrazine, using 2-chloropyrazine as raw material, only requires two steps of reaction to obtain the product 3,6-dichloro-2-cyanopyrazine, with a total yield of more than 55% , reduces the production cost, and is a synthetic process suitable for industrial production of 3,6-dichloro-2-cyanopyrazine

Method used

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  • Favipiravir intermediate 3, 6-dichloro-2-cyanopyrazine synthesis process
  • Favipiravir intermediate 3, 6-dichloro-2-cyanopyrazine synthesis process
  • Favipiravir intermediate 3, 6-dichloro-2-cyanopyrazine synthesis process

Examples

Experimental program
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Effect test

Embodiment 1

[0044](1) Weigh 100g (0.873mol) of dry 2-chloropyrazine into a 1-liter three-neck flask, replace the nitrogen, add 57.4g (0.786mol) of freshly steamed DMF, control the temperature in an ice bath, and add sulfuryl chloride dropwise at a temperature below 20°C 589g (4.36mol), gas is released, and the addition is completed in about 2 hours; keep at about 20°C for 30 minutes, then raise the temperature to 70°C for 4 hours; HPLC monitors the end of the reaction. Stop the reaction, cool to room temperature, slowly pour the system into 1500g of crushed ice with stirring, extract 300mL of methyl tert-butyl ether each time, extract 3 times in total, dry with anhydrous sodium sulfate, and spin dry to obtain light yellow flaky crystals 125.5 g, purity 97.2%, yield 76.43%. 1 HNMR spectrum see figure 1 .

[0045] (2) Weigh 50g (0.275mol) 2,3,5-trichloropyrazine into a 500ml three-necked flask, add 0.3g (0.55mmol) 1,3-bis(diphenylphosphinopropane) nickel dichloride and 3.3g (8.25mmol) PE...

Embodiment 2

[0047] The other steps are the same as in Example 1, except that 1,3-bis(diphenylphosphinopropane)nickel dichloride is replaced by an equimolar amount of [1,1'-bis(diphenylphosphino)ferrocene]dichloride nickel chloride. The purity of the target product 3,6-dichloro-2-cyanopyrazine was 97.4%, and the total yield was 55.38%.

Embodiment 3

[0049] Other steps are the same as in Example 1, except that PEG400 is replaced by PEG800 in an equimolar amount. The purity of the target product 3,6-dichloro-2-cyanopyrazine was 98.1%, and the total yield was 56.72%.

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Abstract

The present invention relates to a favipiravir intermediate 3, 6-dichloro-2-cyanopyrazine synthesis process, which is characterized in that the synthesis route is as follows as described in the specification. The cheap 2-chloropyrazine is used as the raw material, the product 3, 6-dichloro-2-cyanopyrazine can be obtained only through two-step reaction, the total yield is 55% or above, all the used reagents can be common reagents which can be purchased commercially, the production cost is reduced, and a synthesis process for large-scale industrial production of the 3, 6-dichloro-2-cyanopyrazine is achieved. According to the method disclosed by the invention, the synthesis process conditions are optimized, and particularly, the catalyst and the cocatalyst in the step (2) are selected, so that the yield and the purity of the product are further improved.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a synthesis process of a favipiravir intermediate 3,6-dichloro-2-cyanopyrazine. Background technique [0002] Favipiravir (T-705), the chemical name is 6-fluoro-3-hydroxypyrazine-2-carboxamide, researched and developed by Japan Toyama Chemical Co., Ltd., approved for marketing in 2014, is an RNA polymerase inhibitor broad-spectrum antiviral drugs. Favipiravir selectively disrupts the viral RNA replication and transcription processes in infected cells, thereby halting the infection cycle. It has obvious effects in the treatment of common influenza, H1N1, Ebola and other viruses. [0003] At present, the routes of synthesizing Favipiravir at home and abroad mainly contain the following types: [0004] Patent WO2010 / 087117 reports that from ethyl aminomalonate hydrochloride as the starting material, favipiravir is obtained through 7 steps of reaction, and it...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/24
CPCC07D241/24
Inventor 王林善王有为张巧兰张锋
Owner 白银康寓信生物科技有限公司
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