Enantioselective Synthesis of a Key Intermediate in a New Process for Orlistat Using Asymmetric Hydrogenation and a Grignard Reagent Promoted Lactone Cyclization

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• 作者：Mark A. Schwindt ; Michael P. Fleming ; Yeun-Kwei Han ; Lewis M. Hodges ; David A. Johnston ; Roger P. Micheli ; Chris R. Roberts ; Roger Snyder ; Robert J. Topping ; Kurt Pü ; ntener ; Michelangelo Scalone
• 刊名：Organic Process Research & Development
• 出版年：2007
• 出版时间：May 2007
• 年：2007
• 卷：11
• 期：3
• 页码：524 - 533
• 全文大小：150K
• 年卷期：v.11,no.3(May 2007)
• ISSN：1520-586X

文摘

A new enantioselective synthesis of Orlistat suitable for large-scale preparation is described. Therein, the first isolated keyintermediate (R)-3-hexyl-5,6-dihydro-4-hydroxy-6-undecyl-2H-pyran-2-one (12) is prepared via (a) the asymmetric hydrogenation of methyl 3-oxotetradecanoate to (S)-3-hydroxytetradecanoate (9); (b) the acylation of 9 with 2-bromooctanoyl halide(bromide/chloride) to (R)-3-[(2-bromo-1-oxooctyl)oxy]-tetradecanoic acid methyl ester (11) and finally (c) the tert-butylmagnesium chloride promoted cyclization of 11 to the singleenantiomer 12. The single enantiomer intermediate 12, previously published as a mixture of enantiomers 2, has been carriedon through several steps to Orlistat (1) without any processchanges.