Synthesis Of A New Anti-AIDS Drug Delavirdine Mesylate

Delavirdine mesylate, brand Rescriptor, made by pharmacia & upjohncompany in American, is a new non-nucleoside HIV-1 reverse transcriptaseinhibitors coming into the market in 1997, which name in chemistry isl-[3-(isopropylamino)-2-pyridyl]-4-[5-(methanesulfonamido)-1H-indol-2-ylcarbonyl] piperazine monomethanesulfonate.Delavirdine mesylate is a member of the bis(heteroaryl) piperazine(BHAP)class of non-nucleoside HIV-1 reverse transcriptase inhibitors (RTIs). Thisclass of compounds was discovered through anextensive broad screening andresultant analog program which systematically explored the relationshipbetween chemical structure and RT inhibitors activity. Such non-nucleoside RTinhibitors (NNRTIs) differ from nucleoside RTIs (AZT, ddl, ddC) whichoperate by simulating the natural deoxynucleoside triphosphate substrates of theenzyme and thereby act as chain terminators. The BHAPs have some propertiesin common with other NNRTI described in the literature, such as thedipyridodiazepinones, TIBO compounds and pyridinones. The BHAPs andthese other NNRTIs bind to a common region of RT and are susceptible tocertain amino acid substitutions in RT that confer resistance.The synthesis of Delavirdine Mesylate reported by literature is that2-(l-piperazine)-3-[(l-methylethyl)amino]pyridine(4) was synthesized from2-chloro-3-nitropyridine by substitution, BOC protection, catalytichydrogenation, nucleophilic addition, removal of the protection, andDelavirdine Mesylate was synthesized from intermediates 4 and5-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 limitresource of 5-nitro indole-2-carboxylic acid ethyl ester(8), we designed that thekey intermediates 4 and 8 were synthesized by nicotinamide,4-nitrophenyl-hydrazine and 2-oxo-propionic acid ethyl ester. The compound 4was 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 reactionstep when using the expensive 2-ehloro-3-nitropyridine as beginning material.The compound 8 was synthesized by 4-nitrophenyl-hydrazine and2-oxo-propionic acid ethyl ester by nucleophilic addition, rearrangement bytotal yield 67.9%, and the cost was decreased. In the experiment of acidification with methanesulfonic acid, we find anew method to prepare crystal form VIII(U-90152) with large scale and stableyield ,which increased the yield by 25%, simplified the operation and decreasedthe cost again. The structure of the target molecule and the key intermediateswas confirmed by IR, 1H NMR, I3C NMR, Ms, and element analysis. The synthesis of delavirdine mesylate provides reasonable synthetic routeand safe quality standard and ensures the feasibility forindustrialized synthesis. The patent of the synthesis of delavirdine mesylate isapplying. The method described in this paper provides a simplified synthetic routeand resultes in dramatically reducing the cost of material drug, which will servea vast of AIDS patients. Therefor, the research and the development of...