Development of the Enabling Route for Glecaprevir via Ring-Closing Metathesis,Organic Process Research & Development

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Development of the Enabling Route for Glecaprevir via Ring-Closing Metathesis
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2020-01-14 , DOI: 10.1021/acs.oprd.9b00469
Russell D. Cink ₁ , Kirill A. Lukin ₁ , Richard D. Bishop ₁ , Gang Zhao ₁ , Matthew J. Pelc ₁ , Timothy B. Towne ₁ , Bradley D. Gates ₁ , Matthew M. Ravn ₁ , David R. Hill ₁ , Chen Ding ₁ , Steven C. Cullen ₁ , Jianzhang Mei ₁ , M. Robert Leanna ₁ , Jeremy Henle ₁ , José G. Napolitano ₁ , Nandkishor K. Nere ₁ , Shuang Chen ₁ , Ahmad Sheikh ₁ , Jeffrey M. Kallemeyn ₁

Affiliation

Glecaprevir was identified as a potent HCV NS3/4A protease inhibitor, and an enabling synthesis was required to support the preclinical evaluation and subsequent Phase I clinical trials. The enabling route to glecaprevir was established through further development of the medicinal chemistry route. The key steps in the synthesis involved a ring-closing metathesis (RCM) reaction to form the 18-membered macrocycle and a challenging fluorination step to form a key amino acid. The enabling route was successfully used to produce 41 kg of glecaprevir, sufficient to support the preclinical evaluation and early clinical development.

中文翻译：

通过环复分解开发格列卡韦的赋能途径

Glecaprevir被鉴定为有效的HCV NS3 / 4A蛋白酶抑制剂，需要进行有效的合成以支持临床前评估和随后的I期临床试验。通过进一步发展药物化学途径，确立了格列卡韦的赋能途径。合成中的关键步骤涉及闭环复分解（RCM）反应以形成18元大环，而挑战性的氟化步骤则是形成关键氨基酸。该成功途径已成功用于生产41千克格列卡韦韦，足以支持临床前评估和早期临床开发。

更新日期：2020-01-15

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