Synthesis And Structure Confirmation Of The Anti-AIDS Drug Of Atazagavir

Atazanavir is an azapeptide HIV protease inhibitor that has a high inhibitory activity against the HIV-1 virus and is used to treat AIDS.This article mainly uses pinacol as raw material,reacts with bromine to form 1-bromopinatone,and then uses BH3 as a reducing agent to reduce to obtain a chiral hydroxyl group,and then reacts with succinimide by Mitsunobu reaction to obtain a hydrolysis reaction(S)-2-Amino-3,3-dimethyl-1-butanol,reoxidation to give L-tert-leucine,continued reaction with methyl chloroformate to give MOC-L-tert-leucine,and finally the condensation reaction Atazanavir.Comparing several existing synthetic routes of atazanavir,synthesize an industrialized,green,non-polluting synthetic route and optimize it.The use of pinacol as raw material,bromination,toluene as a solvent,control the amount of bromine,low temperature 0 ℃ can effectively control the formation of impurities,to obtain a 1-bromonaphtha yield of 93%;reduction reaction,tetrahydrofuran As a solvent,(1S,2R)-(-)-cis-l-amino-2-furfuryl alcohol as a chiral catalyst,low temperature-10 ℃,.can better control the formation of racemate,higher than the highest yield reported in the literature The yield is increased by 26%and the yield is 87%.The Mitsunobu reaction is delayed,toluene is used as the solvent,and the chiral inversion of the amino compound is obtained with succinimide.The temperature is 0℃,the generation of side reactions is effectively suppressed,and the ratio of the materials is adjusted to decrease.The three wastes saved cost and yield was 82%;hydrolysis reaction,water as solvent,hydrolysis with hydrochloric acid,the reaction time was shortened from 24h to 5h,and the amount of hydrochloric acid was adjusted,and all the raw materials and intermediates were completely reacted with a yield of 95%;oxidation Reaction,water as a solvent,reaction with Boc2O to give(S)-N-BOC-2-amino-3,3-dimethyl-1-butanol,adjusting the ratio,controlling excessive reaction impurities,and then oxidizing with sodium hypochlorite,Adjust the amount of sodium hypochlorite so that the reaction between the raw material and the intermediate is complete.At low temperature 0 ℃ obtain L-Tert-leucine,yield 81%.The prepared L-tert-leucine chiral purity was 90%,and the total yield was 51%.L-tert-leucine was used as raw material,water was used as solvent,and it was incubated with methyl chloroformate at 20 ℃ for 3 h to obtain a yield of MOC-L-tert-leucine of 93%.MOC-L-tert-leucine was used as raw material.Tetrahydrofuran was used as a solvent and EDCI·HCl was used as a condensing agent to obtain atazanavir monomer with a yield of 87.8%.The product was characterized by elemental analysis,infrared spectroscopy and nuclear magnetic resonance spectroscopy,and the structure was confirmed to be correct.After the process optimization,a process route for synthesizing atazanavir with the prospect of industrialization is obtained.The raw materials are economically and easily available,and the conditions are mild,safe and stable,and the overall yield is 41.7%.