Study On The Process For The Preparation Of Tenofovir Disoproxil Fumarate

Tenofovir disoproxil fumarate(TDF)is a new type of nucleotide reverse transcriptional inhibitor,which is used for the effective treatment of AIDS and hepatitis B.In this paper,the synthetic route of tenofovir disoproxil fumarate was analyzed,and the process using R-propylene carbonate as raw material was studied and developed.For the impurity problems existed in the manufacture of the key intermediate of(R)-9-(2-hydroxypropyl)adenine(HPA),which is not solve yet in the literature,we synthesized all the possible isomers of the impurities using(R)-9-(2-hydroxypropyl)adenine(HPA)and R-propulrnr carbonate alkylation reaction.The specific structure of impurietes in the process using high performance liquid chromatography(HPLC)analysis and its mechanism are analyzed.The synthesis and process optimization of Tenofovir disoproxil fumarate were completed according to the mechanism analysis.The process of tenofovir disoproxil fumarate was optimized by optimizing the reaction using various bases,solvents,and temperatures.The optimal reaction conditions were obtained,and the reaction yield of 91% was obtained,an increase of 10% over the literature.In order to solve the problem that the solvent is difficult to remove during the alkylation reaction of(R)-9-(2-hydroxypropyl)adenine and diethyl p-toluenesulfonyloxymethylphosphonate,after several attempts we found that the reaction yelid could be achieved 85% by using cyclohexane as a co-solvents.For the problem of expensive silylation reagents and product difficult to separate after hydrolysis,we found that problem could be efficiently solved using hydrochloric acid in the reaction.The optimal water consumption for the secondary crystallization of tenofovir was optimized.The problem of low yields during esterification of tenofovir and isopropyl chloromethyl carbonate,by comparing different acid-binding agents,it was found that when tri-n-butylamine was used as the acid-binding agent,the yield was 81% by changing the feeding mode,which was 20% higher than that in the literature.For the case where salt of tenofovir disoproxil: fumarate=1:0.5 occurs during the salt formation of tenofovir disoproxil with fumaric acid(tenofovir disoproxil: fumaric acid = 1:1),using different post-treatment methods,it was found that pure Tenofovir disoproxil fumarate can be obtained by re-salting the mixed salt after alkalization.The new process of tenofovir disoproxil fumarate was developed.The new process has the advantages of using cheap raw materials,short steps,and the total reaction yield reaches 68%,which is 24% higher than the literature,and has practical industrial application value.