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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 (1−2 MT/year).

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4-Methoxyphenylbutyric acid (2) is smoothly demethylated in 3 h at 180 °C when melted with pyridinium hydrochloride (Pyr·HCl), affording 4-hydroxyphenylbutyric acid (3), a key starting material for the preclinical candidate LY518674 (1). The adaptation of this chemistry to 22-L and pilot-plant scale is described, including findings to facilitate product isolation, selection of a compatible extraction solvent, and observation of an unusual relationship between the number of solvent extractions and the Pyr·HCl stoichiometry. To the best of our knowledge, this represents the first literature report of the use of this classic demethylation chemistry on multikilogram scale.

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