Organic Process Research & Development最新文献

New synthetic methodologies that access complex saturated building blocks enable the synthesis of drug molecules with unique properties. Here, we report collaborative efforts between Pfizer’s Medicinal Chemistry, Medicinal Chemistry Synthesis Development, and Pharmaceutical Sciences Small Molecule (PSSM) groups for the development of kilogram-scale-enabled synthesis of a type II brain penetrant cMET inhibitor, PF-07907063. The chemistry presented herein demonstrates the importance of implementing a green chemistry approach for developing and applying new transformations throughout the drug development pipeline. Specifically, synthetic planning rooted in the 12 Principles of Green Chemistry led to advancements in deoxygenative photoredox-nickel dual catalysis and cross-electrophile nickel catalysis. The final route significantly lowered the process mass intensity (PMI), increased the yield of the final API, and allowed for the purification of key intermediates through crystallization versus purging impurities via column chromatography, among other improvements.

The synthesis of active pharmaceutical ingredients (APIs) demands extensive resources, with solvents playing a pivotal role in shaping the safety, health, waste, and environmental impacts of chemical processes. To address the absence of a tailored metric for the requirements of the pharmaceutical industry to rapidly quantify and compare these impacts, we developed a novel tool providing concrete operational guidance to enhance sustainability, cost-effectiveness, and operational efficiency. This metric leverages a comprehensive data set, prioritizes critical impact categories, and evaluates solvent quantities relative to the product output. These features enable it to effectively identify areas of improvement in chemical processes and guide sustainable development initiatives. The experience of the application of the metric by a contract development and manufacturing organization to its processes is presented, demonstrating the effectiveness of the metric for internal benchmarking and establishing sustainability criteria. Furthermore, the metric provided structured, actionable guidelines to support daily process development activities, ultimately serving as a practical tool to achieve corporate environmental, social, and governance (ESG) objectives. While the described benchmarking is not proposed as a general industry standard, the method is adaptable to the unique context and requirements of any chemical or pharmaceutical company. Case studies underscore its capability to pinpoint high-impact solvents, support targeted interventions, and achieve notable reductions in sustainability impacts. Aligned with the United Nations Sustainable Development Goal for responsible production, this metric integrates seamlessly into process evaluation tools, enabling consistent, data-driven improvements. Designed to complement existing methodologies rather than replace them, it enhances chemical process assessments with a rapid, decision-focused approach tailored to the priorities and key impact categories of the pharmaceutical industry. This practical tool fosters sustainability and operational efficiency, addressing critical industry needs.

Here we report the development of a large-scale manufacturing process for the synthesis of the Northern Fragment of enlicitide decanoate (MK-0616), an orally bioavailable inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9). The key topics covered are (1) process development for the selective tryptophan allylation; (2) development of the one-pot process for two consecutive peptide coupling reactions; (3) process development for the one-pot cleavage of two N-tert-butyloxycarbonyl (N-Boc) groups and a tert-butyl ester; and (4) process development of the magnesium chloride (MgCl₂)-mediated selective macrolactamization. This optimized process was demonstrated to produce the key fragment at >150 kg scale per batch in the synthesis of enlicitide.

Process development and scale-up of the synthesis of a pyridazinyl imidazolidinone intermediate for the production of an imidazo[1,2-b]pyridazine IL-17A inhibitor are described. A transamination process was developed for the preparation of (S)-3,3,3-trifluoropropane-1,2-diamine, eliminating an unstable enamine intermediate that significantly limited the scalability of the original asymmetric hydrogenation route. A CSTR continuous flow process was developed for the carbonylation of N-(6-chloropyridazin-3-yl)pivalamide under cryogenic conditions that successfully suppressed product decomposition, improving the isolated yield to ∼60% from the ∼40% yield of the batch mode process. A robust KRED process was developed for the reduction of N-(6-chloro-5-(2-methoxyacetyl)pyridazin-3-yl)pivalamide to the corresponding chiral alcohol, which was further derivatized as its triflate for the S_N2 reaction with (S)-3,3,3-trifluoropropane-1,2-diamine and treated with carbonyl diimidazole to assemble the target pyridazinyl imidazolidinone intermediate. The developed process was successfully scaled up to deliver 157 kg of the pyridazinyl imidazolidinone intermediate to support the production of the final drug substance, demonstrating the robustness of the optimized process.

A 5-step cGMP sequence for the preparation of an IL-17A inhibitor 1 was optimized and scaled up to deliver a total of 66 kg of the final drug substance 1 to support clinical and product development studies. Salt formation and polymorph screening identified a suitable polymorph of the hemiedisylate salt that provided desirable physical properties. Key impurities in the final drug substance were identified, and control strategies were developed and executed to control them to acceptable levels in the production batches.