Efficient Enantioselective Synthesis of the NMDA 2B Receptor Antagonist Ro 67-8867

Abstract

An efficient, enantioselective, and scalable eight-step synthesis for the NMDA 2B receptor antagonist Ro 67-8867 (S,S)-1 selected for the treatment of acute ischemic stroke is described based on the coupling reaction of the amino alcohol (S,S)-6 with the sulfone building block 7. The synthesis of the amino alcohol (S,S)-6 was achieved by the highly selective asymmetric hydrogenation of the piperidinone 4*HCl proceeding with concomitant dynamic kinetic resolution to (S,S)-5. Subsequent debenzylation afforded the enantiomerically pure amino alcohol (S,S)-6 after ee-enhancement by simple crystallization in good yield. The hydrogenation substrate 4*HCl was prepared as a stable hydrochloride in two steps from ethyl N-benzyl-3-oxo-4-piperidinecarboxylate hydrochloride (2) for which a new, short, efficient, and cheap synthesis was developed. To bypass a mutagenic intermediate, a revised safe protocol for the sulfone building block 7 was established. The new synthesis allows the access to Ro 67-8867 (S,S)-1 in an overall yield of 53% compared to 3.5% of the Discovery Chemistry approach.