Development of a Scalable Synthesis of Mevidalen (LY3154207), an Orally Available Positive Allosteric Modulator of the Human Dopamine D1 Receptor,Organic Process Research & Development

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Development of a Scalable Synthesis of Mevidalen (LY3154207), an Orally Available Positive Allosteric Modulator of the Human Dopamine D1 Receptor
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2020-09-22 , DOI: 10.1021/acs.oprd.0c00229
Jeffery Richardson ₁ , Kevin P. Cole ₂ , Amy C. DeBaillie ₂ , Junliang Hao ₃ , Jared Piper ₂ , Peter Houghton ₂ , John Rizzo ₂ , Mo Jia ₄ , Peng Liu ₄ , Ping Huang ₄ , Katarina Kadlecikova ₅ , Conchita F. Garcia ₅ , Daniel S. Richards ₆

Affiliation

The evolution from early medicinal chemistry to large-scale production of the chemical synthesis of Lilly D1-positive allosteric modulator (PAM) mevidalen (LY3154207) and its hydroxybenzoate co-crystal is outlined. The issues and steps taken to resolve them are outlined across several generations of synthesis, including unexpected issues that arose during cryogenic addition of MeLi to a key imine intermediate and the use of flow chemistry to enable large-scale production. Ultimately, a process that was used to deliver >100 kg of API to support ongoing clinical trials is described.

中文翻译：

人多巴胺D1受体的口服可用的正构构调节剂美维达仑（LY3154207）的可扩展合成的发展。

概述了礼来D1阳性变构调节剂（PAM）甲维达烯（LY3154207）及其羟基苯甲酸酯共晶体从早期药物化学到大规模生产化学合成的过程。在几代合成过程中概述了解决这些问题所采取的问题和步骤，包括在将MeLi低温加至关键亚胺中间体中以及使用流化法实现大规模生产过程中出现的意外问题。最终，描述了一种用于输送> 100千克API以支持正在进行的临床试验的过程。

更新日期：2020-11-21

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