磷酸西他列汀
化学
产量(工程)
联氨(抗抑郁剂)
水解
组合化学
磷酸西他列汀
劈理(地质)
对映选择合成
立体化学
有机化学
催化作用
2型糖尿病
色谱法
糖尿病
内分泌学
材料科学
医学
复合材料
冶金
断裂(地质)
作者
Karl B. Hansen,Jaume Balsells,Spencer D. Dreher,Yi Hsiao,Michele Kubryk,Michael Palucki,Nelo R. Rivera,Dietrich Steinhuebel,Joseph D. Armstrong,David Askin,Edward J. J. Grabowski
摘要
A new synthesis of sitagliptin (MK-0431), a DPP-IV inhibitor and potential new treatment for type II diabetes, suitable for the preparation of multi-kilogram quantities is presented. The triazolopyrazine fragment of sitagliptin was prepared in 26% yield over four chemical steps using a synthetic strategy similar to the medicinal chemistry synthesis. Key process developments were made in the first step of this sequence, the addition of hydrazine to chloropyrazine, to ensure its safe operation on a large scale. The beta-amino acid fragment of sitagliptin was prepared by asymmetric reduction of the corresponding beta-ketoester followed by a two-step elaboration to an N-benzyloxy beta-lactam. Hydrolysis of the lactam followed by direct coupling to the triazolopiperazine afforded sitagliptin after cleavage of the N-benzyloxy group and salt formation. The overall yield was 52% over eight steps.
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