DEVELOPMENT OF A LARGE-SCALE PROCESS FOR AN HIV PROTEASE INHIBITOR

An efficient large-scale process to prepare the HIV protease inhibitor urea intermediate, tyl]-N'-(1,1-dimethylethyl)-N-(2-methylpropyl)urea was developed, The protected alcohol, beta-(S)-[bis(phenylmethyl)amin o]benzenepropanol, was obtained in 95% yield in one step by the benzyl ation of L-phenylalaninol with benzyl bromide under aqueous conditions , Oxidation of protected alcohol with sulfur trioxide pyridine complex in DMSO at 15 degrees C gave the corresponding aldehyde in quantitati ve yield. The dimethyl sulfide byproduct was easily removed by nitroge n sparging and treatment of the effluent gas stream with bleach soluti on, Diastereoselective reaction of the chiral amino aldehyde with (chl oromethyl)lithium at -35 degrees C followed by warming to room tempera ture gave the desired epoxide stereoselectively in good yield. A DOE ( statistical design of experiment) study indicated that the reaction co ncentration and halogen reagent were important factors for this reacti on, To simplify the operations and to increase the productivity of epo xide, a continuous process was developed. Regioselective ring opening of epoxides with isobutylamine followed by reaction of the resulting a mine with tert-butyl isocyanate in isopropyl alcohol gave the urea yl] -N'-(1,1-dimethylethyl)-N-(2-methylpropyl)urea, in good yield. The pro cess improvements for the crystallization of urea are also discussed.