Asymmetric hydrogenation is one of the key strategies for achieving the stereoselective synthesis of pharmaceuticals. In the synthesis of eslicarbazepine acetate, a stereoselective reduction approach was employed to convert oxcarbazepine into eslicarbazepine with 99% ee and 93% yield. This article provides a comprehensive, complementary density functional theory (DFT) calculation to gain mechanistic insight into the observed high enantioselectivity. Furthermore, crystallographic analysis of the final product offers distinctive evidence of a stereochemical outcome. By employing Quality by Design (QbD) principles and Design of Experiments (DoE), we identified the critical quality attributes (CQAs) and established relationships among material attributes (MAs), critical process parameters (CPPs), and CQAs. Environmental impact was assessed using green metrics to ensure process sustainability. This study also highlights an efficient, scalable, and robust process, developed through DoE techniques to afford eslicarbazepine acetate with 99.9% ee and 81% yield.

Data-rich synthetic chemistry, enabled by high-throughput experimentation (HTE) and automation, allows the acquisition of concentration data across the full time-course of multiparallel reactions. This approach is both time- and material-efficient and can be leveraged for strategies beneficial to pharmaceutical process development, including reaction profiling, visual kinetic analysis, and predictive kinetic and hybrid reaction modeling. Here, we describe the development and adoption of HTE kinetics workflows within AstraZeneca’s process chemistry department and the advantages realized.

The application of chemical transformations to substrates that surpass the scope of the original method for either steric or electronic reasons can often lead to failure. The chances of succeeding in reoptimizing that method can vary and are increased when the existing method is well-defined in terms of critical parameters and mechanism. As part of efforts to develop a sustainable and scalable synthesis of a functionalized indole intermediate en route to the TLR7/8 antagonist afimetoran, reoptimization of a previously developed (phenoxyimine)nickel-catalyzed C(sp2)–C(sp3) Suzuki–Miyaura coupling led to conditions which presented significant advantages over the alternatives in terms of purity and yield. When combined with a nickel-catalyzed borylation, a streamlined two-step telescope was demonstrated which shows the potential for successful and rapid extension of existing methodologies to challenging substrates when starting reoptimization from a mechanistically well-defined starting point.

GS-2278 (1) is a lysophosphatidic acid receptor 1 (LPAR1) antagonist with a complex form landscape (15 freebase polymorphs) that was selected for development as a treatment of idiopathic pulmonary fibrosis (IPF). The thermodynamically most stable unsolvated polymorph, 1-A, was selected for initial development, but due to low solubility and poor pharmacokinetics (PK), a salt form was desired for long-term development. Ultimately, the dihydrate hydrochloride salt, 1-HCl 2H2O, became the desired API for development. However, impurity carryover in this salt-forming step remained high throughout development, placing the burden of impurity control on the penultimate reaction and isolation of freebase 1. During the early process development of 1, several generations of reaction, isolation, and crystallization were designed to ensure form control, chemical purity, and high yield. This manuscript details the challenges faced and overcome during the continuous development of the freebase 1 across a complex form landscape as well as the development and isolation of 1-HCl 2H2O.

The discovery and process development for the synthesis of diastereopure sultam (1), a key chiral intermediate in route to a clinical candidate, are disclosed. Continuous route development to access (1) was required to satisfy both time and dynamic material needs during successive campaigns. Three distinct methods were developed to obtain diastereopure material. The first-generation process invoked time-intensive supercritical fluid chromatography (SFC) to access the diastereopure (2). Subsequent route development enabled a scalable, time-effective classical resolution approach that provided >20 kg of (1). Lastly, a Ruthenium-catalyzed diastereoselective hydrogenation approach was demonstrated on a hundred-gram scale and then coupled to the resolution technology to access (1), both reducing step count and improving overall yield relative to the resolution approach.

This report presentsa rapid, ecofriendly technique for the formationof commonly used N-bromo and N-iodinatingreagents by reacting readily available N-chloro derivativeswith inorganic bromide and iodide salts. All reagents were easilyhandled, commercially available, and bench stable. This strategy illustratesthe expeditious formation of these halogenating reagents in multigramscale in high-yields and purity with an operationally straightforwardrecrystallization. The mechanistic details suggest an in situ generationof an interhalogen species.

A continuous flow approach for the aerobic photo-oxidation of benzylic substrates to ketone and aldehyde products is presented. The resulting process exploits UV-A LEDs (375 nm) in combination with a Corning AFR reactor that ensures effective gas-liquid mixing and leads to short residence times of 1 min. A variety of benzylic substrates are converted to their corresponding carbonyl products, and scalability is demonstrated to produce multigram quantities of products within a few hours. Overall, this continuous flow approach offers several improvements over alternative oxidation methods due to the combined use of air as an oxidant and SAS (sodium anthraquinone-2 sulfonate) as a water-soluble photocatalyst. The use of greener and safer conditions together with process intensification principles renders this flow approach attractive for further industrial applications.

A software platform for the computer vision-enabled analysis of mixing phenomena of relevance to process scale-up is described. By bringing new and known time-resolved mixing metrics under one platform, hitherto unavailable comparisons of pixel-derived mixing metrics are exemplified across non-chemical and chemical processes. The analytical methods described are applicable using any camera and across an appreciable range of reactor scales, from development through to process scale-up. A case study in nucleophilic aromatic substitution run on a 5 L scale in a stirred tank reactor shows how camera and offline concentration analyses can be correlated. In some cases, it can be shown that camera data hold the power to predict reaction progress.

Csp2–Csp2 Suzuki–Miyauracouplings(SMCs) are ubiquitous in the synthesis of small molecules, but analogousCsp2–Csp3 bond-forming SMCs are rare,especially asymmetric variants. Recently, we developed a series ofRh-catalyzed couplings between racemic sp3-hybridized allylchlorides and heteroaryl boronic acids. Here, we demonstrate thatthese catalytic asymmetric reactions can be scaled-up to give over100 g of a product. The reaction we chose to test couples a heteroaromaticboronic acid derivative and a racemic bicyclic electrophile to givea product with three contiguous stereogenic centers. The SMC productwas obtained as a single diastereomer in 90% yield and 98% ee. Kineticanalysis of the reaction reveals two exothermic steps in the reactionsetup and revealed the means by which to prevent the generation ofheat spikes detrimental to the stability of the catalyst.