Synthesis Of Favipirarir And Cethromycin Intermediate

Favipiravir(T-705;6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is a RNA antiviral drug which is developed by Japan Toyama chemical and pharmaceutical company and approved in 2014. It treats flu at clinic and selectively inhibits the RNA-dependent RNA polymerase of influenza virus to achieve antiviral effect. Favipiravir is active against a broad range of favipiravir for influenza, including A(H1N1), A(H5N1) and the recently emerge A(H7N9) avian virus. It also inhibits influenza strains resistant to current antiviral drugs. In addition, favipiravir blocks the replication of many other RNA viruses, including arenaviruses, yellow fever virus,west Nile virus,foot and mouth virus and so on. It has been reported that T-705 suppressed replication of Zaire EBOV in cell culture with an IC90 of 110 ?M, With its unique mechanism of action and borad range of antiviral activity, favipiravir is a good drug for influenza and many other RNA viral diseases.At present, there are few domestic and foreign literatures reports on the preparation of the scale of favipirair, thus it is necessary to explore a suitable scale preparation of synthesise route, In this paper, we have c desiged a the synthetic route of T-705. The commercial available diethyl aminomalonate hydrochloride was selected as the starting material. The product of aminolysis was cyclized with glyoxal to yield 3-hydroxy-2-pyraziamide, which was subjected to nitration with KNO3, chlorination and dehydration with POCl3 andfluorination with KF to afford 3,6-difluoropyrazin-2-carbonnitrile. The difluorate product was further hydrolyzed and oxidized to give Favipirair.The target compound was efficiently prepared by above synthetic route. The reaction conditions are mild except the fluoro-substitution, in which all reagents should be dried completely. The synthetic procedure is simple, high-yield(the total yield was 5.6%), and is of importance for the scale preparation of T-705.Cethromycin(ABT-773) is third-generation macrolide antibiotics, which has developed by the United States Abbott. It has a very good inhibitory activity to many bacterium including marolides sensitive, resistant respiratory pathogens(such as Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, mycoplasma pneumoniae, Legionella bacteria). In addition, it has good pharmacokinetics, low toxicity and is currently in clinical trial Ⅲ.In this paper, through the analysis of domestic and foreign synthetic route of cethromycin, we started to synthesize cethromycin using erythromycin A as the starting material. The target compound was synthesized through oximation, esterification, alkylation, deoximation, cyclocarbamation, acid hydrolysis, oxidation and deprotection.Because of time limits, we only synthezied the key intermediates, which is really helpful for the further study on the preparation of cethromycin and related derivatives.