Studies On Critical Technology Of Industrial Production Of Nucleoside APIs

This paper developed a new route for Adenine synthesis.Adenosine(I)was acetylated to produce Acetylated Adenine(II)and 1,2,3,5-Tetra-O-Acetyl-D-Ribose(III),then II was hydrolyzed by hydrochloric acid to produce Adenine Hydrochloride which was neutralized to produce Adenine(IV).RA acid was selected to be catalytic agent in acetylation reaction,yield of II and III was 94.23% and 87.88% respectively;acid hydrolysis and alkali hydrolysis was investigated in hydrolytic reaction of II,the yield of which was 97.37%.Comparing to the exited industrialized process route,Acetyl Hypoxanthine route(200yuan/kg)and Diethyl Malonate route(230yuan/kg),the material cost of new synthesis route sharply declined to 60yuan/kg,which made it great values of industrialization and economy.This paper investigated that the Adenine(IV)of new process was used as starting material to produce Adefovir dipivoxil(VII)which was obtained via condensation reaction,hydrolytic reaction and esterification.The new method of removing 3-[2-[[bis(isopropoxy)-phosphiny]methoxy]ethyl]adenine(V')had been developed in condensation reaction,and high purity 9-[2-[[bis(isopropoxy)-phosphiny]methoxy]ethyl]adenine(V)of ?99% was obtained.The high purity Adefovir of ?99% was obtained via hydrolytic reaction of high purity V and RC acid of high yield.VI was esterified to produce Adefovir dipivoxil(VII),post-processing of liquid reaction had been greatly simplified,which got rid of purifying operation with silica gel chromatographic column.The new process route was lower cost and easier to be industrialized that made a solid technology foundation for application of API process change.The new process,creating great values of industrialization and economy,had produced advanced intermediate Adefovir(VI)which complied with specifications of abroad Clients for the first time.The side product 1,2,3,5-Tetra-O-Acetyl-D-Ribose(III)of the new process for Adenine(II)in this paper was produced simultaneously,which was the material of Ribavirin(?)production.III reacting with methyl triazole carboxylate(?)in melt condensation produced Triacetyl Ribavirin methyl ester(?).This paper focused on the choosing of catalysator for the condensation reaction,yield of condensation had been increased to 87% from 81% compared with old process,therefore the cost for Ribavirin production reduced.The industry chain of Adenosine had been investigated and developed in this paper that inCluded development of new process of Adenine and Adefovir Dipivoxil,catalysator optimization of condensation reaction in Ribavirin production.Greater economic benefits would be created for the enterprise,for the new product industrialization,increased yield and deClined cost for existing products.