Scott A. May

Development of Pd/C-Catalyzed Cyanation of Aryl Halides

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.

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.

Rhodium-Catalyzed and Zinc(II)-Triflate-Promoted Asymmetric Hydrogenation of Tetrasubstituted α,β-Unsaturated Ketones

The asymmetric hydrogenation of tetrasubstituted α,β-unsaturated ketones has been accomplished using an in situ formed rhodium-Josiphos catalyst. The reaction is enhanced by addition of catalytic zinc(II) triflate, which significantly improves turnover frequency while suppressing epimerization of the products.

Development of a Stepwise Reductive Deoxygenation Process by Ru‐Catalysed Homogeneous Ketone Reduction and Pd‐Catalysed Hydrogenolysis in the Presence of Cu Salts

A stepwise catalytic reduction of ketone 1 to alcohol 2 and subsequently to aryl(imidazo[1,2‐b]pyridazinyl)methane 3 is described, which provides synthetically useful chemoselectivity at acceptably low catalyst loadings. Undesired reactive sites include an aryl chloride, heteroarylchloride and benzylic amine group. The presence of these functional groups presents a significant challenge to chemoselectivity for both reduction steps. For selective CO reduction of highly functionalised 1, high chemoselectivity was observed at low catalyst loading by using Wills’ tethered Ru transfer‐hydrogenation catalyst 13. The selective hydrogenolysis of 2 was then accomplished under acidic hydrogenation conditions by using a Pd/C catalyst in the presence of Cu salts. This procedure has been demonstrated on a multi‐gram scale, which makes this approach a viable method to use a combination of homogeneous and heterogeneous catalysis.

Flow chemistry, continuous processing, and continuous manufacturing: A pharmaceutical perspective

Flow chemistry has become a vibrant area for research over the past decade. This perspective is intended to capture insights on how these advances have and will continue to impact the development and commercialization of active pharmaceutical ingredients. A series of chemistry examples from a number of pharmaceutical companies will highlight the influence of flow chemistry on this industry.

Chapter 6.1 Six-membered ring systems: Pyridines and benzo derivatives

Publisher Summary This chapter describes six-membered ring systems particularly pyridines and benzo derivatives. Pyridines and their benzo-derivatives have played an important role in the synthesis of biologically active synthetic and natural substances. As a result, the construction of this molecular architecture has attracted the attention of a diverse array of synthetic methodologies.Transition metal catalysis, radical reactions, and cycloaddition chemistry-based methods have been developed for the construction of this important ring system. Several strategies for pyridine synthesis involving cycloaddition reactions have been reported. Zhu and co-workers have disclosed full details of their ammonium chloride-promoted four-component synthesis of fused pyridines. Intermolecular cycloaddition strategies have also been used successfully. Moody and co-workers have reported the synthesis of a core piece of the thiopeptide antibiotics through a cycloaddition—for example, 2-azadiene and 2-thiazolyl dienophile were submitted to microwave heating for 15 minutes. The substituted pyridine product was isolated in modest yield.

Continuous Platform To Generate Nitroalkanes On-Demand (in Situ) Using Peracetic Acid-Mediated Oxidation in a PFA Pipes-in-Series Reactor

The synthetic utility of the aza-Henry reaction can be diminished on scale by potential hazards associated with the use of peracid to prepare nitroalkane substrates, and the nitroalkanes themselves. In response, a continuous and scalable chemistry platform to prepare aliphatic nitroalkanes on-demand is reported, using the oxidation of oximes with peracetic acid and direct reaction of the nitroalkane intermediate in an aza-Henry reaction. A uniquely designed pipes-in-series plug flow tube reactor addresses a range of process challenges including stability and safe handling of peroxides and nitroalkanes. The subsequent continuous extraction generates a solution of purified nitroalkane which can be directly used in the following enantioselective aza-Henry chemistry to furnish valuable chiral diamine precursors in high selectivity, thus, completely avoiding isolation of potentially unsafe low molecular weight nitroalkane intermediate. A continuous campaign (16 h) established that these conditions were effective in processing 100 g of the oxime and furnishing 1.4 L of nitroalkane solution.