Synthesis Of The Key Intermediate Of Famciclovir

This paper summarized the research and development of antiviral drugs. The research and development and clinical applications of nucleoside analogues antiviral drugs as well as the synthetic methods and clinical applications of a new antiviral drug, famciclovir, were described in detail.A new synthetic route of famciclovir in which the key intermediate propanedioic acid,2-[2-(2-amino-6-chloro-9H-purin-9-yl)ethyl]-1,3-diethyl ester underwent reduction, esterification and dechlorination to give famciclovir was designed to overcome the shortcomings of the present synthetic routes due to their formation of N-7position isomer.Two synthetic routes were designed to synthesize the key intermediate. In the first route it was prepared through Mitsunobu reaction between 2-hydroxyethyl diethyl malonate(self-made) and 2-amino-6-chloropurine used as the starting material. In the second route, it was prepared by alkylation of diethyl malonate with 2-amino-6-chloro-9-chloroethyl purine which was obtained through Mitsunobu reaction of 2-amino-6-chloropurine with chloroethyl alcohol in the presence of DIAD and PPh3.The Mitsunobu reaction is the key reaction step in the two synthetic routes. This reaction proceeds in neutral conditions where N-7position isomer of 2-amino-6-chloropurine doesn't exist, thus N-7position isomer of 2-amino-6-chloro-9-chloroethyl purine is avoided, which means that N-7position isomer of famciclovir is avoided.Simultaneously, the necessary intermediate 2-hydroxyethyl diethyl malonate in the first route was synthesized by two methods and the synthetic conditions were optimized. In the first method the total yield of which was 52.2%, bromorthanol underwent protection of hydroxyl group, alkylation with diethyl malonate and deprotection of the hydroxyl group to obtain 2-hydroxyethyl diethyl malonate. In the process of alkylation catalyzed by quaternary ammonium salt and potassium iodide to significantly increase the reaction rate toluene was used as solvent and potassium carbonate other than sodium hydride or sodium ethoxide as the base so that dialkylation of diethyl malonate was avoided. In the second method of which the total yield was 40.2% 2-benzyloxyethanol was used as the starting material which underwent bromination, alkylation and deprotection to produce 2-hydroxyethyl diethyl malonate.At last, 2-amino-6-chloro-9-chloroethylpurine was synthesized through Mitsunobu reaction between 2-amino-6-chloropurine and ethylene chlorohydrin in the presence of DIAD and PPh3, which then reacted with diethyl malonate to produce the object product propanedioic acid,2-[2-(2-amino-6-chloro-9H-purin-9-yl) ethyl]-1,3-diethyl ester with a total yield of 59%. Its structure was confirmed by NMR and MS.