期刊
ORGANIC PROCESS RESEARCH & DEVELOPMENT
卷 13, 期 2, 页码 209-224出版社
AMER CHEMICAL SOC
DOI: 10.1021/op800247w
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A commercial synthesis was developed for the production of (4-benzylmorpholin-2-(S)-yl)-(tetrahydropyran-4-yl)methanone mesylate, 1 a, a key starting material for a phase 2, new investigational drug candidate at Eli Lilly and Company. The target compound was produced in the clinical pilot plant by the combination of two key steps: resolution of a morpholine amide intermediate to install the S-morpholino stereocenter in 35% yield and a high-yielding (89%) Grignard reaction to generate the title compound la, isolated as a mesylate salt. The Grignard reaction was found to proceed optimally when using a combination of I-2 and DIBAL-H for the initiation. In addition, the Grignard reagent formation was monitored by ReactMax calorimetry, and proof of-concept studies were completed, demonstrating that the Grignard step could potentially be run as a continuous process with magnesium recycling.
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