J. Rizzo, B. Anderson, L. J. Heinz
Feb 1, 2000
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Journal
Organic Preparations and Procedures International
Abstract
An ongoing drug development program required the design of a reliable synthetic route to the oxazole-containing coupling partner 6 which was to be employed in displacement reactions with oxygen nucleophiles. Serine-derived oxazoles containing a C-2 aryl substituent are common pharmacophores present in a number of biologically important agents including the neuroprotective antioxidant compounds currently under investigation in these laboratories.' The original approach while strategically sound, employed a number of transformations which were not amenable to large scale production of 6.' We describe herein tactical modifications which not only significantly reduced waste generation and eliminated the need for purification by chromatography but provided generally applicable methodology for the production of related oxazole derivatives. The free base of 41-serine methyl ester hydrochloride was coupled with 3,5-di-ferr-butyl-4hydroxybenzoic acid 1 using 1 equiv of 2-chloro-4,6-dimethoxy1,3,5-triazine (CDMT)? to give the amide 2a in 75% yield. Cyclodehydration of hydroxyamides similar to 2a with thionyl chloride is well precedented,' the cyclization being conducted in neat thionyl chloride or with a large excess in order to drive the reaction to completion. Suprisingly, treatment of 2a with neat thionyl chloride gave the chloride derivative 2b instead of the desired oxazoline 3. The use of 2 equivalents of thionyl chloride afforded a mixture of the desired oxazoline 3 and 2b. The use of 1.05 equivalent of thionyl chloride yielded the desired oxazoline in 90% yield with less than 5% of 2b (Eq. I ) .