Richard D. Miller

Photochemical Perfluoroalkylation with Pyridine N-Oxides: Mechanistic Insights and Performance on a Kilogram Scale

The direct trifluoromethylation of (hetero)arenes is a process of high importance to the pharmaceutical industry. Many reagents exist for this purpose and have found widespread use in discovery efforts; however, the step-intensive preparation of these reagents and their corresponding cost have resulted in minimal use of these methods in large-scale applications. For the ready transition of direct trifluoromethylation methodologies to large-scale application, the further development of processes utilizing inexpensive CF3 sources available on a metric ton scale is highly desirable. We report the use of pyridine N-oxide derivatives in concert with trifluoroacetic anhydride to promote a high-yielding and scalable trifluoromethylation reaction. Key mechanistic insights include the observation of electron donor-acceptor complexes in solution as well as a high dependence on photon flux. These observations have culminated in the application of this chemistry on a kilogram scale, demonstrating the utility of this reagent combination for preparative applications.

Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions.

Continuous-flow technology is devised and implemented for manufacture of a drug candidate in clinical trials. Go with the flow in drug manufacturing Although many commodity chemicals are manufactured using continuous flow techniques, pharmaceuticals are still mostly produced in large single batches. Cole et al. report a protocol for the small-volume continuous preparation of multi-kilogram quantities of a cancer drug candidate, prexasertib monolactate monohydrate, under current good manufacturing practices. Advantages of the approach include safer handling of hazardous reagents and intermediates, as well as yield and selectivity improvements in both the reaction and purification stages. Concurrent analytical monitoring also facilitated rapid trouble-shooting during the manufacturing process. Science, this issue p. 1144 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.

A diastereoselective tandem metalloenamine alkylation/aza-annulation of β-tetralones expedites the synthesis of benzoquinolinones

Abstract In one operation, metalloenamines derived from R -phenylethylamine (PEA) and a β-tetralone were treated with an electrophile followed by acrylic anhydride. The unpurified lactams were reduced to give 10b-angular benzoquinolinones (BQs).

Reagent-free continuous thermal tert-butyl ester deprotection

Continuous processing enables the use of non-standard reaction conditions such as high temperatures and pressures while in the liquid phase. This expands the chemists toolbox and can enable previously unthinkable chemistry to proceed with ease. For a series of amphoteric amino acid derivatives, we have demonstrated the ability to hydrolyze the tert-butyl ester functionality in protic solvent systems. Using a continuous plug flow reactor at 120-240°C and 15-40min reaction times, no pH modification or additional reagents are needed to achieve the desired transformation. The method was then expanded to encompass a variety of more challenging substrates to test selectivity and racemization potential. The acid products were generally isolated as crystalline solids by simple solvent exchange after the deprotection reaction in good to high yield and purity.