Synthesis of key intermediates towards HIV protease inhibitors

Abstract

HIV protease inhibitors (PIs) are considered to be a highly potent class of drugs in AIDS therapy. The commercial anti-HIV drug Kaletra, patented by Abbott Laboratories, is the combination of two highly effective PIs; Ritonavir and Lapinavir. These two molecules contain the same 2S,5S-diamino-1,6-diphenyl-3-hexanol as their core structure. The rather complicate synthesis of this diamino alcohol core molecule effectively raises the price of Kaletra and limits the patients’ access to this drug. Consequently, a shorter and more effective strategy is needed. In this research, a derivative of L-phenylalanine was used as the starting material. Functional group manipulations gave the N-[(tert-benzyloxy)carbonyl]-L-phenylalaninal as the main substrate. By using McMurry coupling as the key step, the diastereomeric mixture of 2,5-bis[[(tert-butyloxy)carbonyl]amino]-3,4-dihydroxy-1,6-diphenylhexane from the homocoupling of the starting aldehydes was obtained. After column chromatography gave 0.12% yield of SSSS isomer and 0.2% yield of diastereomeric mixture of SRRS and SRSS in 1:1 ratio. In addition, the synthesis of the west and the east sides of Lopinavir, 2,6-Dimethylphenoxyacetic acid and urea derivative have been accomplished in 65% and 5.1% yield respectively.