Rapid Development and Scale-Up of a 1H-4-Substituted Imidazole Intermediate Enabled by Chemistry in Continuous Plug Flow Reactors

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• 作者：Scott A. May ; Martin D. Johnson ; Timothy M. Braden ; Joel R. Calvin ; Brian D. Haeberle ; Amy R. Jines ; Richard D. Miller ; Edward F. Plocharczyk ; Gregory A. Rener ; Rachel N. Richey ; Christopher R. Schmid ; Radhe K. Vaid ; Hannah Yu
• 刊名：Organic Process Research & Development
• 出版年：2012
• 出版时间：May 18, 2012
• 年：2012
• 卷：16
• 期：5
• 页码：982-1002
• 全文大小：910K
• 年卷期：v.16,no.5(May 18, 2012)
• ISSN：1520-586X

文摘

The development of reactions in a continuous fashion in plug flow tube reactors (PFR) offers unique advantages to the drug development and scale-up process and can also enable chemistry that would be difficult to perform via batch processing. Herein, we report the development of two different continuous flow approaches to a key 1H-4-substituted imidazole intermediate (5). In a first generation approach, rapid optimization and scale-up of a challenging cyclization reaction was demonstrated in a PFR under GMP conditions to afford 29 kg of protected product 2. This material was further processed in batch equipment to deliver di-HCl salt 4. This first generation approach highlights the rapid development of chemistry in research-scale PFRs and speed to material delivery through linear scale up to a pilot-scale PFR under GMP conditions. In a second generation effort, a more efficient synthetic route was developed, and PFRs with automated sampling, dilution, and analytical analysis allowed for rapid and data-rich reaction optimization of both a key cyclization reaction and thermal removal of a Boc protecting group. This work culminated in 1 kg demonstration runs in a 0.22 L PFR for both continuous steps and shows the potential of commercialization from a lab hood footprint (1鈥? MT/year).