Optimization and Development of a Scalable Palladium-Catalyzed C–H Activation Process for the Geometry-Selective Preparation of Kilograms of YLF466D, a Potent AMP-Activated Protein Kinase Activator,Organic Process Research & Development

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Optimization and Development of a Scalable Palladium-Catalyzed C–H Activation Process for the Geometry-Selective Preparation of Kilograms of YLF466D, a Potent AMP-Activated Protein Kinase Activator
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2021-09-27 , DOI: 10.1021/acs.oprd.1c00150
Jianpeng Yin ₁ , Desheng Zhan ₁ , Hui Ma ₂ , Huanan Liu ₂ , Lifang Yu ₂ , Yangming Zhang _{1,

2} , Fajun Nan _{1,

2,

3}

Affiliation

Adenosine 5′-monophosphate-activated protein kinase (AMPK) activator YLF466D is a promising preclinical drug candidate to treat metabolic diseases and myocardial ischemia-reperfusion injury (MIRI). Herein, we report our efforts on optimization and development of a practical and scalable process for the preparation of YLF466D in kilogram scale. The process features a palladium-catalyzed C–H activation under mild reaction conditions, geometry selectivity, effective impurities purging, and low levels of residual solvents in the final active pharmaceutical ingredient (API). We applied this process successfully to prepare more than 17 kg (3.0–3.6 kg per batch) of YLF466D to support its preclinical study.

中文翻译：

用于几何选择性制备 YLF466D（一种有效的 AMP 激活蛋白激酶激活剂）的可扩展钯催化 C-H 活化过程的优化和开发

腺苷 5'-单磷酸活化蛋白激酶 (AMPK) 激活剂 YLF466D 是一种有前景的临床前候选药物，可用于治疗代谢疾病和心肌缺血再灌注损伤 (MIRI)。在此，我们报告了我们在优化和开发用于制备千克级 YLF466D 的实用且可扩展的过程方面所做的努力。该工艺具有在温和反应条件下钯催化的 C-H 活化、几何选择性、有效的杂质清除以及最终活性药物成分 (API) 中残留溶剂含量低的特点。我们成功地应用该工艺制备了超过 17 公斤（每批 3.0-3.6 公斤）的 YLF466D，以支持其临床前研究。

更新日期：2021-10-15

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