Kinetic Investigations To Enable Development of a Robust Radical Benzylic Bromination for Commercial Manufacturing of AMG 423 Dihydrochloride Hydrate,Organic Process Research & Development

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Kinetic Investigations To Enable Development of a Robust Radical Benzylic Bromination for Commercial Manufacturing of AMG 423 Dihydrochloride Hydrate
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2020-07-15 , DOI: 10.1021/acs.oprd.0c00256
James I. Murray ₁ , Maria V. Silva Elipe ₂ , Andrew Cosbie ₁ , Kyle Baucom ₁ , Kyle Quasdorf ₁ , Seb Caille ₁

Affiliation

During development of a radical benzylic bromination, observation of polymerized byproducts and variation in isolated yields warranted an in-depth mechanistic investigation to ensure process understanding and robustness. In situ kinetic studies using multinuclear CryoFree NMR spectroscopy revealed molecular bromine to be the active brominating species and variable time normalization analysis allowed accurate determination of the order of each reagent in this process. These kinetic studies allowed for accurate reaction modeling and were used to demonstrate that adoption of a simple procedural change ensured reliability and reproducibility during manufacturing.

中文翻译：

动力学研究，以开发用于工业生产AMG 423二盐酸盐水合物的鲁棒的自由基苯甲基溴化反应

在自由基苄基溴化反应的开发过程中，观察到聚合副产物和分离产率的变化，因此有必要进行深入的机械研究，以确保对工艺的理解和可靠性。使用多核CryoFree NMR光谱进行的原位动力学研究表明分子溴是活性溴化物种，可变时间归一化分析可以准确确定此过程中每种试剂的顺序。这些动力学研究可以进行准确的反应建模，并用于证明采用简单的程序更改可确保制造过程中的可靠性和可重复性。

更新日期：2020-08-21

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