Anti-hiv Drug To Labbe Set And Hypolipidemic New Drugs, Nk-104, The Synthetic Research

This paper relates to the study of the synthesis of the novel lipid-lowering medicine pitavastatin (NK-104) and the antiviral HIV-1 medicine delavirdine.Pitavastatin ( NK-104) is a synthetic inhibitor of the HMG-CoA reductase (statin) and is used in the treatment of hypercholesterolemia, heterozygous dyslipidemia and homozygous hypertriglyceridemia. This drug was developed by the Nissan Company Ltd. and first lunched in Japan in 2003.In the present thesis, we brought forward a novel synthetic route. NK-104 was synthesized via a series of reaction steps. Firstly, the substituted quinolinedelyde was synthesized from anthranillic acid via cyclization, reduction, oxidation etc. Secondly, the chiral wittig reagent was synthesized from 3-[ (tert-butyldimethylsily) oxy] pentanedioic anhydride via selective asymmetric ring-opening reaction , debenzylation, esteration etc. Finally, NK-104 was prepared from the substituted quinolinedelyde and the chiral wittig reagent via wittig-horner reaction, deprotection, asymmetric reduction and hydrolyzation etc. During the study, we synthesized intermediate with high chiral purity by investigating the condition of the selectiveasymmetric ring-opening reaction. Furthermore, we increased the overall yield and decreased the cost greatly by optimizing the condition of the witting-horner reaction and oxidation, which made it appropriate to be used in the industrial production.Delavirdine is an antiviral HIV-1 non-nucleoside reverse transcriptase inhibitor, which was developed by Pharmacia & Upjiohn. Delavirdine is indicated in combination with protease inhibitors and nucleoside reverse transcriptase inhibitor for the treatment of HIV-infection.We synthesized delavirdine from 2-choro-3-nitropyridine by substituted reaction, reduction, alkylation, acylation and methanesulfonylation. During the study, we improved the condensation condition of the carboxylic acid and the amine, which increased the overall yield by 9 times. Moreover, we substituted potassium carbonate and Raney Ni for some expensive reagents. We made progress in the basic work ofsynthesization of ethyl pyruvate p-nitro-phenylthydrazone and indol. Through above improvement, the simple and convenient process with lower costs make it appropriate to be used in the industrial production.