Systematic Optimization of a Robust Telescoped Process for a BTK Inhibitor with Atropisomer Control by High-Throughput Experimentation, Design of Experiments, and Linear Regression
Systematic Optimization of a Robust Telescoped Process for a BTK Inhibitor with Atropisomer Control by High-Throughput Experimentation, Design of Experiments, and Linear Regression
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DOI：
10.1021/acs.oprd.8b00398
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发表时间：
2019-06-01
影响因子：
3.4
通讯作者：
Razler, Thomas M.
中科院分区：
文献类型：
--
作者：
Gonzalez, Federico Lora;Wisniewski, Steven R.;Razler, Thomas M.
报道了一种用于BTK可逆抑制剂路线上的API步骤的伸缩工艺的开发。尽管之前实施了强大而有效的反应和结晶，但对倒数第二种材料的储存和稳定性的担忧导致了对伸缩过程的研究。利用实验设计(DoE)了解对原料药反应的影响，并利用高通量提取(HTEx)优化工作，快速开发了一种工艺，以获得相同质量的原料药，总收率提高13%，工艺质量强度(PMI)提高41%。
The development of a telescoped process for the API step in the route to a reversible inhibitor of BTK is reported. Although a robust and effective reaction and crystallization was previously implemented, concerns around the storage and stability of the penultimate material led to investigating a telescoped process. Utilizing design of experiments (DoE) to understand impacts to the API reaction and high-throughput extractions (HTEx) to optimize the workup, a process was rapidly developed to achieve the same quality API with an overall 13% improvement to yield and 41% improvement in the process mass intensity (PMI).