First Generation Process for the Preparation of the DPP-IV Inhibitor Sitagliptin

IF 3.1 3区 化学 Q2 CHEMISTRY, APPLIED
Karl B. Hansen, Jaume Balsells, Spencer Dreher, Yi Hsiao, Michele Kubryk, Michael Palucki, Nelo Rivera, Dietrich Steinhuebel, Joseph D. Armstrong, David Askin, Edward J. J. Grabowski
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引用次数: 122

Abstract

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.

Abstract Image

第一代DPP-IV抑制剂西格列汀的制备工艺
西格列汀(MK-0431)是一种DPP-IV抑制剂,是治疗II型糖尿病的潜在新方法,适合制备多公斤量。采用类似于药物化学合成的合成策略,经过四个化学步骤以26%的收率制备了西格列汀的三唑吡嗪片段。关键的工艺发展是在该序列的第一步,在氯吡嗪中添加肼,以确保其大规模安全运行。西格列汀的β -氨基酸片段是通过不对称还原相应的β -酮酯,然后两步精化成n -苯氧基β -内酰胺制备的。内酰胺水解后与三唑哌嗪直接偶联得到西格列汀后,n -苄氧基的裂解和盐的形成。八个步骤的总收率为52%。
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来源期刊
CiteScore
6.90
自引率
14.70%
发文量
251
审稿时长
2 months
期刊介绍: The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools,process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.
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