Process Development for a Key Synthetic Intermediate of LY2140023, a Clinical Candidate for the Treatment of Schizophrenia

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• 作者：Mario Waser ; Eric D. Moher ; Sandy S. K. Borders ; Marvin M. Hansen ; David W. Hoard ; Michael E. Laurila ; Michael E. LeTourneau ; Richard D. Miller ; Michael L. Phillips ; Kevin A. Sullivan ; Jeffrey A. Ward ; Chaoyu Xie ; Cheryl A. Bye ; Tanja Leitner ; Brigitte Herzog-Krimbacher ; Marcus Kordian ; Martin M眉llner
• 刊名：Organic Process Research & Development
• 出版年：2011
• 出版时间：November 18, 2011
• 年：2011
• 卷：15
• 期：6
• 页码：1266-1274
• 全文大小：911K
• 年卷期：v.15,no.6(November 18, 2011)
• ISSN：1520-586X

文摘

To fuel clinical development of the experimental CNS medicine LY2140023, we developed a scalable route for the multistep synthesis of a pivotal synthetic intermediate. The core of the conformationally restricted glutamic acid-based amino acid analogue was built via a Rh-catalyzed cyclopropanation of thiophene. Regioselective functionalization of the remaining double bond was achieved by a hydroboration/oxidation sequence followed by a Bucherer鈥揃ergs reaction to give a hydantoin with the targeted l-glutamic acid configuration. Subsequent resolution, oxidation state, and protecting group manipulations gave the key intermediate in an overall nine-step scalable streamlined route starting from thiophene.