Practical Synthesis of Chiral 2-Morpholine: (4-Benzylmorpholin-2-(S)-yl)-(tetrahydropyran-4-yl)methanone Mesylate, a Useful Pharmaceutical Intermediate

Autor:	Mark A. Pietz, Michael M. Murray, Michael E. Kopach, Thierry Giard, Thierry Defrance, Utpal K. Singh, Vincent Mancuso, Michel Vanmarsenille, Gregory A. Stephenson, William G. Trankle, Kobierski Michael Edward, Mindy B. Forst
Rok vydání:	2009
Předmět:	Chemistry Magnesium Mesylate Organic Chemistry Grignard reaction chemistry.chemical_element Tetrahydropyran Combinatorial chemistry Stereocenter chemistry.chemical_compound Morpholine Amide Yield (chemistry) Organic chemistry Physical and Theoretical Chemistry
Zdroj:	Organic Process Research & Development. 13:209-224
ISSN:	1520-586X 1083-6160
DOI:	10.1021/op800247w
Popis:	A commercial synthesis was developed for the production of (4-benzylmorpholin-2-(S)-yl)-(tetrahydropyran-4-yl)methanone mesylate, 1a, 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 1a, isolated as a mesylate salt. The Grignard reaction was found to proceed optimally when using a combination of I2 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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::59ea8393476d33dcd3c13cfa6038449d https://doi.org/10.1021/op800247w Zobrazit plný text záznamu