An Efficient, Safe, and Scalable Method for the Preparation of D- and L-Penicillamines

Abstract

The present work describes a simple, efficient and scalable route for the synthesis of D- and L-penicillamines from commercially available ethyl isocyanoacetate. The four-step synthesis mainly includes condensation of acetone with ethyl isocyanoacetate to form α-formylaminoacrylate 18. The key intermediate β-sulfido carbonyl compound 22, was synthesized via the Rongalite and base-promoted cleavage of disulfides and subsequent thia-Michael addition. Consequent removal of formyl and p-Methoxybenzyl ether groups afforded racemic penicillamine 3. Finally, the chiral resolution of racemic penicillamine furnished enantiomerically pure D- and L-penicillamines in good yields. The salient features of the developed protocol are odorless, high efficiency, inexpensive starting materials and excellent yield without the need for chromatographic purification processes. Current synthesis eliminates hazardous reaction conditions, use of heavy metals, and toxic cyanide.