Synthesis Of Fosamprenavir Calcium

Acquired immunodeficiency syndrome (AIDS) is a sort of contagious disease caused by human immunodeficiency virus (HIV). The common therapeutic drugs can be classified into three categories:nucleotide reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor and proteinase inhibitor. Fosamprenavir (the brand name is Lexiva) is one of quite effective proteinase inhibitor. Fosamprenavir is an inactive phosphate ester that is a highly water soluble prodrug of amprenavir. It allows more convenient dosing as compared to amprenavir and it has been selected for further development. The Vertex Pharmaceutical prepared Fosamprenavir and licensed it to GlaxoSmithKline for development. It was granted by FDA and came into the U.S. market in October 2003.This dissertation provides a novel and viable route which is designed according to the literature for the synthesis of Fosamprenavir Calcium. Starting with the L-phenylalanine, the product is finally obtained after thirteen reaction steps (including the synthesis of side chain). The whole process includes the reaction of protection of amino group, esterification, the addition of sulfer ylide, asymmetric reduction, condensation, acylation, phosphine acylation, salt formation etc.. Compared with processes reported in the literature, the process in this dissertation has the following merits:fewer reaction steps, milder reaction conditions, more available reagents and catalysts, more convenient separation of final product. The total yield is 26.2%.For the synthesis of the key intermediate (2R,3S)-3-tert-butoxycarbonylamino-2-h-ydroxy-1-(N-isobutyl)amino-4-phenylbutane, several reduction conditions of the a-chloro ketone were tested and investigated. The product (S)-α-chloro alcohol was finally obtained in 78.7% yield and 100% enantiomeric purity.For the synthesis of (S)-3-hydroxyl-tetra-hydrofuranyl carbonate, triphosgene, phenyl chloroformate, N,N-carbonyldiimidazole and N,N-succinimidyl carbonate were examined. Finally, N,N- succinimidyl carbonate was selected for the acylation reaction and the yield was 82.45%.In sum, a novel and viable process for the total synthesis of Fosamprenavir was designed and experimentally confirmed.