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-(2-methylpropyl)urea was developed, The protected alcohol, beta-(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 degrees 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 degrees 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.

A series of delta 17 unsaturated cycloalkyl and cycloalkenyl analogues of enisoprost was synthesized to investigate the effects of omega chain unsaturation on gastric antisecretory activity and diarrheogenic side effects. Of these, the 17E, 18-cyclopentenyl analogue 5d displayed potent gastric antisecretory activity in dogs but very weak diarrheogenic properties in rats and is the most selective prostaglandin compound discovered in these laboratories. Structurally, 5d contains both a conjugated diene and tertiary allylic alcohol in the omega chain, and these chemical features impart some interesting oxidative and acid-catalyzed epimerization and allylic rearrangement reactivities, respectively.