沙沙利汀
化学
酰胺
胺气处理
组合化学
酰胺
有机化学
氨基酸
磷酸西他列汀
生物化学
医学
内分泌学
糖尿病
二甲双胍
作者
Scott A. Savage,Gregory S. Jones,Sergei Kolotuchin,Shelly Ann Ramrattan,Truc Vu,Robert E. Waltermire
摘要
The commercial-scale synthesis of the DPP-IV inhibitor, saxagliptin (1), is described from the two unnatural amino acid derivatives 2 and 3. After the deprotection of 3, the core of 1 is formed by the amide coupling of amino acid 2 and methanoprolinamide 4. Subsequent dehydration of the primary amide and deprotection of the amine affords saxagliptin, 1. While acid salts of saxagliptin have proven to be stable in solution, synthesis of the desired free base monohydrate was challenging due to the thermodynamically favorable conversion of the free amine to the six-membered cyclic amidine 9. Significant process modifications were made late in development to enhance process robustness in preparation for the transition to commercial manufacturing. The impetus and rationale for those changes are explained herein.
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