Synthetic Study Of Anti-hiv-i Protease Inhibitors Ritonavir And Carbon Intermediates Of Carbapenem Antibiotics

The first part of this paper relates to a synthetic research of protease inhibitor of HIV-I Ritonavir(marked as Norvir), which is a strong protease inhibitor developed by U. S. A. ABBOTT Company. In March of 1996, the U. S. A. FDA gave approval of Ritonavir for the treatment of patients with advanced HIV disease as well as for patientes with less advanced HIV disease.We synthesized Ritonavir from L-phenylalanine, and have optimized two synthesis routes and researched in detail: Through adjusting the proportion of material and change the treatment of reaction, the yield of enaminone (20) can rise to 95% from 70%. And We find that enaminone (20) is easy to form 1:1 complex compound with ethanol, and change the order of addition will cause to less diastereoselectivity;We put forward the mechanism of asymmetric reduction of enaminones(20) and perfectly explain the result.Through controlling the conditions of reaction, the diastereoselectivity is improved greatly, the content of 10 rised to 94%;Optimizing the process of While formating of 5-hydroxyl thiazole, We can prevent the catalyst from being poisonned and improve the producing rate;Through change the condition of formating of 11, reduce the danger; We find the best conditions of removing the two benzyl groups of intermediate 13. The result is obviously better than document value. The purity of the final product Ritonavir make be up to 99. 79%.The second part of this paper is the synthetic research of pivotal intermediates for carbapenera of antibiotics. Carbapenem antibiotics is a new class of 3-lactam antibiotics, developed in the seventies of the 20th century, have already become an important group of drugs and the object of ongoing pharmaceutical development because of it's antibiotic activation. Inparticular, carbapenems bearing a 1 P-methyl substituent, examplified by Meropenem, have an excellent spectrum of activity and good resistance to renal dehydropeptidase I(DHP).We researched on the prepartion of pivotal intermediate 2 and 3 for 1 P-methyl carbapenem antibiotics from intermediate 1, which is subjected to Reformastky reaction, N-alkylation, Dieckmann-type cyclisation, enolization, ester condensation etc. in sequence. The synthesis route of document is optimized by us. We tested two new synthesis routes for intermediate 3 and 36. Through reaction of P -keto ester with intermediate 1, We get two compound , which was proved to be new compounds and belong to pyridine, one of them may have potential medical value . And We put forward the mechanism of the reaction.