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

Abstract

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.

The Hitchhiker’s Guide to Flow Chemistry

“…The reduction of esters to aldehydes with diisobutylaluminum hydride (DIBAL-H) is attractive in theory. However, in practice it generally leads to unacceptable levels of overreduction leading to the primary alcohol − or is completely avoided because of its erratic reactivity. − Various groups identified that DIBAL-H performs better in a flow reactor. ,− Jamison’s group incorporated an inline quench was incorporated to prevent overreduction to the alcohol (Scheme ). In this reaction, T-mixers outperformed Y-mixers.…”

Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences

“…Reaction of the lithium anion of N-Boc pyrrole with aldehyde 3 19 provided the corresponding alcohol as a single diastereomer. 20 Hydrogenation of the pyrrole ring provided a 1:1 mixture of the two diastereomers at the new chiral center, 4a and 4b, which were separated by chromatography.…”

Continuous Flow Aerobic Alcohol Oxidation Reactions Using a Heterogeneous Ru(OH)x/Al2O3 Catalyst

“…Conversion of alcohols to carbonyl compounds is one of the most common transformations in organic chemistry. Process-scale alcohol oxidations are often done using stoichiometric or catalytic reagents, such as pyridine·SO 3 − and NaOCl/TEMPO (TEMPO = 2,2,6,6-tetramethyl-1-piperidinyloxyl); − however, there has been long-standing interest in the development of aerobic methods that generate essentially no byproducts. Applications of aerobic alcohol oxidation in the pharmaceutical and fine-chemical industries have been limited, often because the performance of existing catalytic methods does not match or exceed that of traditional oxidation methods and/or because mixtures of oxygen gas and organic solvents represent a potential safety hazard …”