Process Research on [(2S)-(3-Fluorophenyl)-(1S)-(5-oxotetrahydrofuran- 2-yl)ethyl]carbamic Acid tert-Butyl Ester, a Lactone Intermediate for an Aspartyl Protease Inhibitor

Abstract

Two processes for the preparation of lactone [2S-(3-fluorophenyl)-1S-(5-oxotetrahydrofuran-2-yl)ethyl]carbamic acid tert-butyl ester 1 starting from S-BOC-(3-fluorophenyl)alanine 3 are described. (S)-(3-Fluorophenyl)alanine N-methyl-N-methoxy amide 10, the Weinreb amide of 3, was reacted with 2-(2-1,3-dioxanyl)ethylmagnesium bromide to provide key intermediate ketoacetal 11. To achieve high yields for this conversion, the N−H of the BOC group in Weinreb amino acid amide 10 was deprotonated first with a simple Grignard reagent (methyl or benzylmagnesium halide) followed by Barbier reaction with magnesium metal and 2-(2-bromoethyl)-1,3-dioxane. The acetal group in 11 was opened oxidatively with ozone, and the resulting ester 15 was reduced selectively at low temperature with N-Selectride. Alternatively, the ketone moiety in 11 was reduced diastereoselectively with aluminum triisopropoxide in 2-propanol to give the undesired (R,S)-diastereomeric alcohol. The alcohol was converted to the mesylate which was heated in solution to cause formation of oxazolidinone 19 through displacement of the mesylate group by the carbonyl moiety of the BOC group with loss of tert-butyl alcohol. This intramolecular reaction provided the desired (S,S)-diastereomer. Finally, acetal 19 was converted to nitrile 20 with hydroxylamine hydrochloride in ethanol with catalytic toluenesulfonic acid at reflux. Basic aqueous hydrolysis of nitrile 20 followed by treatment with di-tert-butyl dicarbonate provided 1. While the second process was longer, the inexpensive reagents, simple reaction conditions, and high yields made it the process of choice. Both processes have been run on a multikilogram scale.