ciffeFamipiravir is a novel broad-spectrum antiviral drug that can selectively inhibit the RNA polymerase related to virus replication. It can be phosphorylated by host cell enzymes to form the bioactive famipiravir RTP; the famipiravir RTP is wrongly recognized by the viral RNA polymerase and then inserted into the viral RNA chain or binds to the viral RNA polymerase domain, thereby hindering the replication and transcription of the viral RNA chain. Famipiravir is truly a "chemical weapon against viruses". Experimental evidence shows that famipiravir can inhibit Ebola virus, yellow fever, chikungunya virus, norovirus and enterovirus, and can also effectively inhibit drug-resistant (amantadine, oseltamivir, zanamivir) influenza viruses. Therefore, it has been included in Japan's national strategic reserve drugs. Research also indicates that in in vitro cell experiments, the IC50 of famipiravir against influenza virus is 341 nM, and the EC50 against the novel coronavirus reaches 61.88 μM, indicating its extremely strong antiviral ability.
3,6-Difluoro-2-cyanopyrazine is a pharmaceutical intermediate that can be used to prepare favipiravir. Favipiravir was developed by Fujisaki Chemical Co., Ltd. of Japan. In 2011, it completed the Phase III clinical trial in Japan and was approved for market in 2014. Clinically, it is mainly used for the treatment of influenza. It is a broad-spectrum antiviral drug of the RNA-dependent RNA polymerase inhibitor type. Studies have shown that favipiravir forms favipiravir-5'-furanosyl-5'-triphosphate (T-705RTP) under the action of intracellular enzymes, competitively inhibiting the RNA-dependent RNA polymerase of the virus, thereby inhibiting the replication and transcription of the viral genome; at the same time, it can also penetrate into the viral genes and induce mutations to exert antiviral effects.
Famipiravir was developed by Fujifilm Fuji Chemicals in Japan (with the Chinese licensor being "Zhejiang Haitong Pharmaceutical Co., Ltd."). This drug was approved for sale in Japan in March 2014 and is used for antiviral treatment of influenza A and B. Studies have shown that in addition to the influenza virus, this drug (Chemicalbook) also exhibits good antiviral effects against various RNA viruses, such as Ebola virus, sandfly virus, bunyavirus, rabies virus, etc. 3,6-Difluoro-2-cyanopyrazine is mainly used as an intermediate for the production of famipiravir in the chemical and pharmaceutical synthesis process.
1) Preparation of 1,4-dioxopyrazineamide: Control the temperature at -5 to 5℃. Mix 5.25g of 2-cyanopyrazine with 29.95g of glacial acetic acid and 45.30g of 30% hydrogen peroxide evenly. Heat to 95℃ and conduct a reflux reaction for 22 hours. TLC shows no raw materials after that. Reduce the pressure and perform a vacuum distillation at 40℃ to remove the solvent. Add 15ml of water, conduct a vacuum distillation again, repeat several times to remove glacial acetic acid, then add 15ml of water. Add hot chloroform extraction (15ml * 3), reduce the pressure and dry the aqueous layer. Recrystallize with 90% methanol, filter, and vacuum dry the filter cake to obtain white powder-like 1,4-dioxopyrazineamide 4.45g. The melting point is greater than 300℃, and the yield is 57.43%. 2) Preparation of 3,6-dichloro-2-cyanopyrazine by Chemicalbook: Mix 6.20g of 1,4-dioxopyrazineamide with 24.53g of tri-chlorophosphorus after re-distillation evenly. Stir at 50℃ for 50 minutes, then heat to 70℃ for 1 hour. Cool to room temperature, then add 4.86g of triethylamine. After adding, heat to 96℃ and conduct a reflux reaction for 6 hours. TLC shows that the reaction is completed. Reduce the pressure and dry, then add 10mL of ice water, extract with ethyl acetate (15mL * 3), combine the organic phases, wash twice with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and reduce the pressure and dry the filtrate. Purify and separate by column chromatography, then vacuum dry to obtain a pale yellow solid 3,6-dichloro-2-cyanopyrazine 3.14g. The yield is 45.15%, and the melting point is 90-91℃.
