A kind of synthesis technique of favipiravir intermediate 3,6-dichloro-2-cyanopyrazine

A synthetic process, favipiravir technology, applied in the field of synthetic process of favipiravir intermediate 3,6-dichloro-2-cyanopyrazine, can solve low yield, reduce production cost, synthetic route Long steps and other problems, to achieve the effect of reducing energy consumption, low cost, and shortening the production cycle

Active Publication Date: 2021-11-30
白银康寓信生物科技有限公司
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  • Description
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  • 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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  • A kind of synthesis technique of favipiravir intermediate 3,6-dichloro-2-cyanopyrazine
  • A kind of synthesis technique of favipiravir intermediate 3,6-dichloro-2-cyanopyrazine
  • A kind of synthesis technique of favipiravir intermediate 3,6-dichloro-2-cyanopyrazine

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 kind of synthetic technology of favipiravir intermediate 3,6-dichloro-2-cyanopyrazine, it is characterized in that, synthetic route is as follows. The present invention uses relatively cheap 2-chloropyrazine as a raw material, and only needs two steps of reaction to obtain the product 3,6-dichloro-2-cyanopyrazine, with a total yield of more than 55%, and the reagents used can be It is a common reagent that can be purchased commercially, which reduces the production cost, and is a very large-scale synthetic process for the industrial production of 3,6-dichloro-2-cyanopyrazine. The method of the invention optimizes the synthesis process conditions, especially selects the catalyst and co-catalyst in the step (2), and further improves the yield and purity of the product.

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 Patents(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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