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

Autor:	Frank J. Urban, V. John Jasys
Rok vydání:	2003
Předmět:	chemistry.chemical_classification Barbier reaction Ketone Organic Chemistry Acetal Alcohol chemistry.chemical_compound Carbamic acid chemistry Ethylmagnesium bromide Amide Organic chemistry Physical and Theoretical Chemistry Lactone
Zdroj:	Organic Process Research & Development. 8:169-175
ISSN:	1520-586X 1083-6160
DOI:	10.1021/op030207n
Popis:	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 he...
Databáze:	OpenAIRE
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