Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.
The development and scale-up of a synthetic route to tasisulam sodium (5-bromo-thiophene-2-sulfonic acid 2,4dichlorobenzoylamide sodium salt, hereafter referred to as tasisulam) utilizing continuous Schotten−Baumann reaction conditions is disclosed. A new synthetic route for the cytotoxic API amenable to continuous processing was envisioned that would minimize potential worker exposure by reducing the number of unit operations and would allow commercial-scale API production in laboratory fume hoods with inexpensive glassware. The developed Schotten−Baumann conditions contained fewer unit operations than the existing batch process by utilizing the direct formation of the final sodium salt from a sulfonamide and acid chloride without isolation of the free acyl sulfonamide. Batch development, continuous proof of concept studies, 5.2 g/h labscale demonstration and 5 kg/day commercial-scale runs will be discussed. Very stringent release specifications were in place for the tasisulam API batch process, and the challenges of meeting these requirements for the continuous process are detailed. Finally, the quality of material generated during startup and shutdown transitions will be addressed.
The design, development,
and scale up of a continuous iridium-catalyzed
homogeneous high pressure reductive amination reaction to produce 6, the penultimate intermediate in Lilly’s CETP inhibitor
evacetrapib, is described. The scope of this report involves initial
batch chemistry screening at milligram scale through the development
process leading to full-scale production in manufacturing under GMP
conditions. Key aspects in this process include a description of drivers
for developing a continuous process over existing well-defined batch
approaches, manufacturing setup, and approaches toward key quality
and regulatory questions such as batch definition, the use of process
analytics, start up and shutdown waste, “in control”
versus “at steady state”, lot genealogy and deviation
boundaries, fluctuations, and diverting. The fully developed continuous
reaction operated for 24 days during a primary stability campaign
and produced over 2 MT of the penultimate intermediate in 95% yield
after batch workup, crystallization, and isolation.
Two routes for the synthesis of cis-N-protected-3-methylamino-4-methylpiperidine (3) were examined: a route hinging on the
electrochemical oxidation of carbamate 1 to install a ketone at
the 3 position of the piperidine followed by reductive amination
(disconnection A), and a route involving the hydrogenation of
an appropriately functionalized pyridine (disconnection B).
While both routes to the desired compound were ultimately
successful, the pyridine hydrogenation approach proved to be
more amenable to kilogram-scale preparations due to the
crystallinity and purity of intermediates in that route.
[reaction: see text] A simple, one-pot procedure is described for the direct conversion of quinoline N-oxides to alpha-amidoquinolines with primary amides. This methodology is complimentary to the Abramovich reaction, which is limited to the introduction of secondary amides via imidoyl chlorides. Although reaction conditions are quite similar, omission of the base is key for successful reaction with primary amides, which were found not to proceed through the intermediacy of an imidoyl chloride but rather through an acyl isocyanate.
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