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

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• 作者：Michelangelo Scalone and Pius Waldmeier
• 刊名：Organic Process Research & Development
• 出版年：2003
• 出版时间：May 2003
• 年：2003
• 卷：7
• 期：3
• 页码：418 - 425
• 全文大小：152K
• 年卷期：v.7,no.3(May 2003)
• ISSN：1520-586X

文摘

An efficient, enantioselective, and scalable eight-step synthesisfor the NMDA 2B receptor antagonist Ro 67-8867 (S,S)-1selected for the treatment of acute ischemic stroke is describedbased on the coupling reaction of the amino alcohol (S,S)-6 withthe 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 goodyield. The hydrogenation substrate 4*HCl was prepared as astable 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 bypassa mutagenic intermediate, a revised safe protocol for the sulfonebuilding block 7 was established. The new synthesis allows theaccess to Ro 67-8867 (S,S)-1 in an overall yield of 53%compared to 3.5% of the Discovery Chemistry approach.