Synthesis Of The Key Intermediate Of Maraviroc

Maraviroc is a chemokine receptor5(CCR5) receptor antagonist, it can block HIV from entering into the host cell, thus slowing the aggravation of the disease. Nowadays, the Pfizer Company has extensively reported the synthesis and reaction improvements for this drug, and its multi-kilogram scale-up was also realized in order to support the toxicology and clinical trials of this drug.In this thesis, Great efforts were made for the synthesis and reaction improvements of8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-aza-bicyclo [3.2.1] octane21, which was the key intermediate of Maraviroc. Finally, the target21was synthesized and an innovative method, namely the3rd improved method, was put forward sucessfully.After series of improvements, better results were obtained:Yield of the oximation reaction was improved from95%to97.5%; Yield from oxime15to N-(8-benzyl-8-aza-bicyclo [3.2.1] octan-3-yl) isobutyramide18was improved from72%to75.4%due to the successful removal of the impurity in the reduction reaction; Yield from N-(8-benzyl-8-aza-bicyclo [3.2.1] octan-3-yl) isobutyramide18to21was improved from72%to76.6%owing to the3rd improved method. This new method could avoid the unstable problem of chloromethylene amide19with water, which may seriously affect the recrystalization of21and dramatically decrease the yield of pure21.Improvements were also made to enhance the chemical process. For example, the amount of n-pentanol was decreased in the reduction reaction of oxime15; the tert-amyl alcohol/AcOH was subustituted by the econimcal and clean solvent of EtOH in the cyclic condensation reaction of N-acetylamidrazone20and the neutralization for AcOH could also be omitted in the post-processing etc. Many methods were also tried concerning the safty issues brought by the usage of Na in the reduction reaction.