Synthesis Of The Intermediate Of Saquinavir And Synthesis Of Tenofovir Alafenamide

This thesis consists of two parts.The synthesis of(2S,3S)-3-[(tert-butoxycarbonyl)amino]-1,2-epoxy-4-phenylbutane,an key intermediate of saquinavir for anti-AIDS,was mainly studied in the first part.And the second part is the synthesis of tenofovir alafenamide.(2S,3S)-3-[(tert-Butoxycarbonyl)amino]-1,2-epoxy-4-phenylbutaneis is a key intermediate of navemycin for the HIV-1 protease inhibitors.The feasibility of using continuoustubular reactor to synthesize chloro-ketone((3S)-3-(tert-Butoxycarbonylamino)-1-chloro-4-phenyl-2-butanone)with(2S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropionic acid as the raw material,diluting diazomethane with nitrogen gas,was studied,which was compared with the traditional method of organic magnesium reagent.The conditions for the synthesis of chloro-ketone and chloro-alcohol((2S,3S)-N-tert-Butoxycarbonyl-3-amino-1-chloro-2-hydroxy-4-phenylbu tane)were explored,the diastereoselectivity involved in the synthesis of chloro-alcohol was optimized.And the undesired diastereomers was also recovered.As a new drug,tenofovir alafenamide,developed by Gilead Sciences Company in 2016,was used in the treatment of AIDS and anti-hepatitis B virus.Based on the existing literature,anti-HIV pharmacology,toxicology and security of TAF were summarized,and the methods for the synthesis of TAF were also introduced.The synthetic technique of HPA with adenine and(2R)-2-methyloxirane as raw materials was mainly investigated also and the chief reaction conditions,such as solvent,reactant ratio and catalyst etc,were optimized.The catalytic effect for synthesis of R-9-(2-hydroxypropyl)adenine over various base and the reaction condition for synthesis of TAF-1 with PMPA and triphenyl phosphite as raw material and pyridine as solvent were also investigated in detail.