| Delavirdine mesylate, brand Rescriptor, made by pharmacia & upjohn company in American, is a new non-nucleoside HIV-1 reverse transcriptase inhibitors coming into the market in 1997, which name in chemistry is 1-[3-(isopropylamino)-2-pyridyl]-4-[5-(methanesulfonamido)-1H-indol-2–yl carbonyl] piperazine monomethanesulfonate. Delavirdine mesylate is a member of the bis(heteroaryl) piperazine(BHAP) class of non-nucleoside HIV-1 reverse transcriptase inhibitors (RTIs). This class of compounds was discovered through anextensive broad screening and resultant analog program which systematically explored the relationship between chemical structure and RT inhibitors activity. Such non-nucleoside RT inhibitors (NNRTIs) differ from nucleoside RTIs (AZT, ddI, ddC) which operate by simulating the natural deoxynucleoside triphosphate substrates of the enzyme and thereby act as chain terminators. The BHAPs have some properties in common with other NNRTI described in the literature, such as the dipyridodiazepinones, TIBO compounds and pyridinones. The BHAPs and these other NNRTIs bind to a common region of RT and are susceptible to certain amino acid substitutions in RT that confer resistance. The synthesis of Delavirdine Mesylate reported by literature is that 2-(1-piperazine)-3-[(1-methylethyl)amino]pyridine(4) was synthesized from 2-chloro-3-nitropyridine by substitution, BOC protection, catalytic hydrogenation, nucleophilic addition, removal of the protection, and Delavirdine Mesylate was synthesized from intermediates 4 and 5-nitroindole-2-carboxylic acid by coupling reaction,catalytic hydrogenation,methanesulfonylation,acidification with methanesulfonic acid. Because of the higher price of 2-chloro-3-nitropyridine and the limit resource of 5-nitro indole-2-carboxylic acid ethyl ester(8), we designed that the key intermediates 4 and 8 were synthesized by nicotinamide, 4-nitrophenyl-hydrazine and 2-oxo-propionic acid ethyl ester. The compound 4 was synthesized by hoffman degradation, nucleophilic addition, reduction, nucleophilic substitution by total yield 37.8%, which avioded BOC protection, removal of the protection, catalytic hydrogenation and decreased the reaction step when using the expensive 2-chloro-3-nitropyridine as beginning material. The compound 8 was synthesized by 4-nitrophenyl-hydrazine and 2-oxo-propionic acid ethyl ester by nucleophilic addition, rearrangement by total yield 67.9%, and the cost was decreased. In the experiment of acidification with methanesulfonic acid, we find a new method to prepare crystal form VIII(U-90152) with large scale and stable yield ,which increased the yield by 25%, simplified the operation and decreased the cost again. The structure of the target molecule and the key intermediates was confirmed by IR, 1H NMR, 13C NMR, Ms, and element analysis. The synthesis of delavirdine mesylate provides reasonable synthetic route and safe quality standard and ensures the feasibility forindustrialized synthesis. The patent of the synthesis of delavirdine mesylate is applying. The method described in this paper provides a simplified synthetic route and resultes in dramatically reducing the cost of material drug, which will serve a vast of AIDS patients. Therefor, the research and the development of delavirdine mesylate will have great economic and societal significance. During the course of these studies,tow new chemistries had been synthesized ,modeled the molecule of delavirdine that HIV inhibitors with resveratrol. The two molecules were connected together by Sunccinic anhydride or p-Phthaloyl chloride. We first try to investigate the effect of reseveratrol on improvement of humen immunity and the inhibitor delavirdine.Different synthetic routes were planned and discussed.
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