A Mechanistic Insight into a Simple C−N Bond Formation via SN2 Displacement: A Synergistic Kinetics and Design of Experiment Approach

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• 作者：Luca Massari ; Laura Panelli ; Mark Hughes ; Federica Stazi ; William Maton ; Pieter Westerduin ; Federico Scaravelli ; Sergio Bacchi
• 刊名：Organic Process Research & Development
• 出版年：2010
• 出版时间：November 19, 2010
• 年：2010
• 卷：14
• 期：6
• 页码：1364-1372
• 全文大小：437K
• 年卷期：v.14,no.6(November 19, 2010)
• ISSN：1520-586X

文摘

A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes was recently identified as new highly potent and selective dopamine (DA) D₃ receptor antagonists. This class of molecules deserved the Chemical Development special attention to quantify the reliability and robustness of the pivotal S_N2 displacement step between the 1,2,4-triazol-3-yl-halide derivative (4) and variously substituted azabicyclo[3.1.0]hexanes (5). To reach this goal we applied the classical Design of Experiment (DoE) approach, simultaneously trying to build up a descriptive kinetic model of the chemistry. The synergistic use of these two techniques allowed us to select new, higher-yielding and more robust reaction conditions and, at the same time, to identify their Design Space.