Research On The Synthesis Of The Chiral Intermediate Of A New Anti-HIV Drug Fosamprenavir

Fosamprenavir (GW433908, the brand name is Lexiva), developed by Glaxo Wellcome Inc. and Vertex Inc., is an effective therapeutic agents for the treatment of HIV infection in children and adults. As the phosphate ester pro-drug of the protease inhibitor (PI) amprenavir, fosamprenavir has improved solubility and bioavailability over the parent PI, allowing for dosing easily and with a bright future. It was granted by FDA and came into the U.S. market in October 2003.(2R,3S)-3 -tert-Butoxycarbonylamino-2-hydroxy-1 -(N-isobutyl-4-nit rophenylsulfon)-amino-4-phenylbutane, a key chiral intermediate of fosamprenavir, containing pivotal hydroxyethylamine structure with two asymmetric centers, was synthesized from L-phenylalanine in this paper. According to the reports, we designed a new synthetic route of the intermediate, which is proved to be suitable for potential manufacture inindustrial scale.We start from the L-phenylalanine and eventually finish the synthesis work in a six-step of reactions including: nucleophilic substitution, reductions of carbonyl and nitryl and nucleophilic addition dehydration, etc. The total yield is 47%, much higher than traditional routes. Moderate conditions, cheap reagents and catalysts, easy purification of products and high yields make this route an excellent one. Especially in the asymmetric reduction of a-nitro ketone structure, the key step of this route, we improved the yield from 34% to 77% and made the ratio of (2R, 35) to (2S, 35) diastereoisomers arise from 74:26 to 85:15. All the intermediates and final product are conformed by NMR.Two methods were employed in the reduction of nitryl, one is using NaBH4/NiCl2 6H2O, and the other is using Pd/C to catalyze hydrogenation. Though they have comparative yield, about 95%, the latter is more suitable to large-scale preparation for its' slight pollution, convenient process and good quality.We discussed two different processes separately between "one-step reduction", which is related to reduce a-nitro ketone to a-amino alcohol directly, and "two-step reduction" , which means reducing carbonyl and nitryl successively. At last, we found that the step-wise reduction has more satisfied results, for its total yield is 10% higher than the "one-step method" and the d.e. is 8% over. We also found that temperature effectlittle on the selectivity and the yield, while various Lewis acids make the reductive effects different.At the same time, we carried out mounts of experiments about nucleophilic substitution and addition of carbonyl as well as the substitution and condensation of nitryl. By analyzing the mechanism and controlling the conditions, we made the reactions accomplished with good yields.In all, herein we made progresses in the total synthesis of the key intermediate of fosamprenavir, and the research results are believed to offer a valuable route to its industrial production.