Chemical development of Cl-1008, an enantiomerically pure anticonvulsant

Chemical development of Cl-1008, an enantiomerically pure anticonvulsant

Hoekstra, Marvin S. and Sobieray, Denis M. and Schwindt, Mark A. and Mulhern, Thomas A. and Grote, Todd M. and Huckabee, Brian K. and Hendrickson, Valerie S. and Franklin, Lloyd C. and Granger, Eric J. and Karrick, Gregory L.

Organic Process Research and Development 1997

Abstract : Development of a manufacturing process for (S)-3-(aminomethyl)-5-methylhexanoic acid, an anticonvulsant, is described. Initial preparation employed an Evans chiral alkylation on (4R,5S)-4-methyl-3-(1-oxo-4-methylpentyl)-5-phenyl-2-oxazolidinone, using benzyl bromoacetate. Use of tert-butyl bromoacetate proved advantageous for large-scale preparation. Route selection for a low-cost manufacturing process was based on “ideal process” cost projections. Four routes were evaluated in the laboratory. Of the four, two were scaled up in the pilot plant, resulting in selection of a route based on synthesis of racemic 3-(aminomethyl)-5-methylhexanoic acid, followed by resolution with (S)-(+)-mandelic acid.