Scalable Asymmetric Syntheses of Foslevodopa and Foscarbidopa Drug Substances for the Treatment of Parkinson’s Disease

Abstract

Foslevodopa (FLD, levodopa 4'-monophosphate, <b>3</b>) and foscarbidopa (FCD, carbidopa 4'-monophosphate, <b>4</b>) were identified as water-soluble prodrugs of levodopa (LD, <b>1</b>) and carbidopa (CD, <b>2</b>), respectively, which are useful for the treatment of Parkinson's disease. Herein, we describe asymmetric syntheses of FLD (<b>3</b>) and FCD (<b>4</b>) drug substances and their manufacture at pilot scale. The synthesis of FLD (<b>3</b>) employs a Horner-Wadsworth-Emmons olefination reaction followed by enantioselective hydrogenation of the double bond as key steps to introduce the α-amino acid moiety with the desired stereochemistry. The synthesis of FCD (<b>4</b>) features a Mizoroki-Heck reaction followed by enantioselective hydrazination to install the quaternary chiral center bearing a hydrazine moiety.