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).
A practical method for palladium-catalyzed cyanation of aryl halides using Pd/C is described. The new method can be applied to a variety of aryl bromide and active aryl chloride substrates to effect efficient conversions. The process features many advantages over existing cyanation conditions and the practical utility of the process has been demonstrated on scale.
The large-scale manufacture of complex
synthetic peptides is challenging
due to many factors such as manufacturing risk (including failed product
specifications) as well as processes that are often low in both yield
and overall purity. To overcome these liabilities, a hybrid solid-phase
peptide synthesis/liquid-phase peptide synthesis (SPPS/LPPS) approach
was developed for the synthesis of tirzepatide. Continuous manufacturing
and real-time analytical monitoring ensured the production of high-quality
material, while nanofiltration provided intermediate purification
without difficult precipitations. Implementation of the strategy worked
very well, resulting in a robust process with high yields and purity.
A novel, potent series of indole analogs were recently developed as MR antagonists, culminating in 14. This compound represents the first MR antagonist in this class of molecules, exhibiting picomolar binding affinity and in vivo blood pressure lowering at pharmaceutically relevant doses.
The
development of a route for a key building block in the synthesis
of abemaciclib is described. The route proceeds through a Leuckart–Wallach
reductive amination in flow followed by an Ullmann amination with
aqueous ammonia. Key to the Leuckart–Wallach reductive amination
was the addition of trimethyl orthoformate for water removal, running
the reaction continuously in a pipes-in-series reactor for rapid heat-up,
and building a kinetic model to understand time and temperature parameters
for the feed tank storage. The product of the Leuckart–Wallach
reductive amination is forward processed in batch and telescoped with
the Ullmann amination and subsequent workup. The development resulted
in a robust process that has successfully been run on the production
scale.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.