Development of a Large-Scale Process for an HIV Protease Inhibitor

An efficient large-scale process to prepare the HIV protease inhibitor urea intermediate, N-[3(S)-[bis(phenylmethyl)amino-2(R)-hydroxy-4-phenylbutyl]-N ‘-(1,1-dimethylethyl)-N-(2methylpropyl)urea was developed. The protected alcohol, β(S)-[bis(phenylmethyl)amino]benzenepropanol, was obtained in 95% yield in one step by the benzylation of l-phenylalaninol with benzyl bromide under aqueous conditions. Oxidation of protected alcohol with sulfur trioxide pyridine complex in DMSO at 15 °C gave the corresponding aldehyde in quantitative yield. The dimethyl sulfide byproduct was easily removed by nitrogen sparging and treatment of the effluent gas stream with bleach solution. Diastereoselective reaction of the chiral amino aldehyde with (chloromethyl)lithium at −35 °C followed by warming to room temperature gave the desired epoxide stereoselectively in good yield. A DOE (statistical design of experiment) study indicated that the reaction concentration and halogen reagent were important factors for this reaction. To simplify the operations and to increase the productivity of epoxide, a continuous process was developed. Regioselective ring opening of epoxides with isobutylamine followed by reaction of the resulting amine with tert-butyl isocyanate in isopropyl alcohol gave the urea N-[3(S)-[bis(phenylmethyl)amino]-2(R)-hydroxy-4-phenylbutyl]-N ‘-(1,1-dimethylethyl)-N-(2-methylpropyl)urea, in good yield. The process improvements for the crystallization of urea are also discussed.