Development of a Multi-Step Synthesis and Workup Sequence for an Integrated, Continuous Manufacturing Process of a Pharmaceutical
Development of a Multi-Step Synthesis and Workup Sequence for an Integrated, Continuous Manufacturing Process of a Pharmaceutical
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DOI：
10.1021/op400294z
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发表时间：
2014-03-01
影响因子：
3.4
通讯作者：
Jensen, Klavs F.
中科院分区：
文献类型：
--
作者：
Heider, Patrick L.;Born, Stephen C.;Jensen, Klavs F.
介绍了用于合成小分子药物阿利吉仑的完全集成的连续制造工厂的合成和后处理步骤的开发和操作。该工厂从高级中间体开始，距离最终的活性药物成分还有两个合成步骤，最后是成品片剂。整个过程多次运行，本文提供的数据对应于阿利吉仑标称吞吐量 41 g·h(-1) 下运行 240 小时。第一个反应是在高温熔融条件下无溶剂进行的，实现了高产率 (90%)，并避免了固体处理和较长的停留时间（由于在溶剂中较低温度下运行时与稀释条件相比浓度更高）。使用液液萃取和基于微流体设计的基于膜的分离器对所得流进行在线处理。第二个反应涉及 Boc 脱保护，使用 HCl 水溶液，然后用 NaOH 水溶液快速淬灭，并使用在线 pH 测量来控制 NaOH 的添加。尽管存在过程干扰，该反应在闭环控制下仍保持高产率（90-95%）。
The development and operation of the synthesis and workup steps of a fully integrated, continuous manufacturing plant for synthesizing aliskiren, a small molecule pharmaceutical, are presented. The plant started with advanced intermediates, two synthetic steps away from the final active pharmaceutical ingredient, and ended with finished tablets. The entire process was run on several occasions, with the data presented herein corresponding to a 240 h run at a nominal throughput of 41 g h(-1) of aliskiren. The first reaction was performed solvent-free in a molten condition at a high temperature, achieving high yields (90%) and avoiding solid handling and a long residence time (due to higher concentrations compared to dilute conditions when run at lower temperatures in a solvent). The resulting stream was worked-up inline using liquid liquid extraction with membrane-based separators that were scaled-up from microfluidic designs. The second reaction involved a Boc deprotection, using aqueous HCl that was rapidly quenched with aqueous NaOH using an inline pH measurement to control NaOH addition. The reaction maintained high yields (90-95%) under closed-loop control despite process disturbances.