An improved method for the synthesis of an alpha-alkoxy ketone using the Weinreb amide and Grignard reagent is described.  Efforts to reduce raw material cost through formation of an aryl lithium reagent by direct deprotonation with subsequent Weinreb amide quench were abandoned due to poor yield and low temperature constraints.  Development was then shifted to optimizing the Grignard reagent chemistry using either the morpholine or Weinreb amide.  The Weinreb amide was prioritized over the morpholine amide due to higher yields.  Utilizing DOE, improved reaction conditions were identified for the Weinreb amide Grignard chemistry.  The improved process gave consistent yields of 80% on lab and plant scale while allowing for forward processing of the product solution without further purification.

Improved synthesis of an alpha-alkoxy ketone using the Weinreb amide and Grignard reagent

246th National Meeting (2013)

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