Chung John Y L, Cvetovich Raymond J, Tsay Fuh-Rong, Dormer Peter G, DiMichele Lisa, Mathre David J, Chilenski Jennifer R, Mao Bing, Wenslow Robert
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA.
J Org Chem. 2003 Nov 14;68(23):8838-46. doi: 10.1021/jo034835e.
A six-step preparation of thrombin inhibitor drug candidate 1 from pyrazinone 7 in 47% overall yield is described. The problem of low reactivity between weak amine nucleophile 4 and poor electrophile 3-bromopyrazinone 17 was overcome with the use of pyridinylthioimidate 27 in the presence of ZnCl(2) to afford adduct 3 in high yield. Several zinc complexes were characterized by solution and solid-state NMR and X-ray crystallographic analyses, and provided insight into the reaction mechanism. Preparation of pyridine N-oxide amine 4 was accomplished via a selective oxidation of the corresponding pyridinylamine 6. Pyridinylthioimidate 27 was prepared from pyrazinone 7 via a two-step one-pot process in near quantitative yield. Chlorination of the pyrazinone ring in 3 followed by hydrolysis and amide coupling completed the synthesis of 1. This chromatography-free synthesis was used successfully to prepare multikilogram quantities of the drug with reproducibility and high purity.
描述了一种从吡嗪酮7制备凝血酶抑制剂候选药物1的六步方法，总产率为47%。在ZnCl₂存在下使用吡啶硫代亚氨酸酯27克服了弱胺亲核试剂4与不良亲电试剂3-溴吡嗪酮17之间反应活性低的问题，以高产率得到加合物3。通过溶液和固态NMR以及X射线晶体学分析对几种锌配合物进行了表征，并深入了解了反应机理。吡啶N-氧化物胺4是通过相应的吡啶胺6的选择性氧化制备的。吡啶硫代亚氨酸酯27是由吡嗪酮7通过两步一锅法以接近定量的产率制备的。3中吡嗪酮环的氯化，随后水解和酰胺偶联完成了1的合成。这种无色谱合成方法成功地用于制备多公斤量的药物，具有可重复性和高纯度。
