Research On The Synthesis Of Leitgewei

Raltegravir is a new anti-HIV drug that is the world’s first HIV integrase inhibitor for clinical use.The function of the integrase is mainly to insert the viral DNA into the chromosome of the host cell,and then the virus uses the replication function of the host cell gene to complete the replication of the virus.Therefore,the inhibition of integrase can effectively inhibit the replication of HIV;and the integrase is only present in the virus and does not exist in the human body,so the raltegravir is characterized by low toxicity and high efficiency.In this paper,through the study of the synthesis route of Raltegravir,2-amino-2-methylpropionitrile hydrochloride(4)was selected as the raw material,Cbz protected amino group,reacted with hydroxylamine,Michael addition,closing ring,methylation,aminolysis with p-fluorobenzylamine,deprotection of Cbz to form intermediate(2);using 5-methyl-1H-tertazole(10)and ethyl oxalyl monochloride as the starting material,the obtained amide is heated to remove nitrogen then rearrange,hydrolysis synthesis to get intermediate(13);with oxalyl chloride to form acid chloride(3)and then reacted with intermediate(2)to obtain the target product raltegravir(1).This paper focuses on some of the unit reactions:1)Optimizing the purification method of intermediate products to reduce the human cost and material consumption;2)Seeking for the optimized reaction conditions of key steps by controlling single factor variable experiments;3)Discussing the effect of different solvents and temperatures on the Z/E ratio of the Michael addition product of intermediate(6)and dimethyl acetylenedicarboxylate;4)According to the yield of the two synthetic routes of the intermediate(13),discussing their advantages and disadvantages,and selecting a better route to synthesize the intermediate(13).