Organic Process Research & Development最新文献

NMR plays a “detective role” that through observation and data analysis acts as a “magnifying lens” facilitating the visualization of chemical problems in detail to provide solutions; therefore, NMR is an essential part of analytical control strategies during scaling up drug development stages in preparation of commercial regulatory approval. NMR is a critical analytical technique for the structure characterization of organic impurities during drug development, supporting the work of process chemists for analytical control strategies. During the past decade, NMR has played an important role in investigating reaction mechanisms for process understanding and improvement on scale-up drug processes to support clinical trials in the pharmaceutical industry. Those mechanistic investigation studies are key to improving the quality, efficiency, and yield of materials in the APIs syntheses, providing mitigation pathways that directly impact the performance of scale-up processes and their analytical control strategies. Structure elucidation of drug impurities and investigations of reaction mechanisms during scale-up chemical reactions have become the principal “detective roles” of NMR, providing better control strategies for drugs during process development. In addition, other existing NMR methodologies and technologies may provide impact expanding the “detective role” of NMR as part of the analytical control strategies for process chemists. Those methodologies are NMR anisotropy for the determination of relative configuration of stereoisomers of chiral drugs, quantitation by low field time-domain (TD) NMR of fluorinated drug substances in their formulated drug products, low field TD-NMR for the water content of lyophilized materials in sealed vials as a nondestructive and not invasive technique, and the application of low field benchtop NMR and high field cryogen-free NMR as PAT tools in real-time reaction monitoring of chemical processes in the manufacturing plant. The “detective role” of NMR in drug development provides solutions based on knowledge of process understanding for improvement, which plays a critical role in implementing appropriate analytical control strategies for process chemists.

An efficient and scalable synthesis of two small-molecule renal outer medullary potassium (ROMK) inhibitors 1 and 2 was developed from readily available raw material. The alternative approach includes a newly developed asymmetric reduction of the keto intermediate to access compound 1 and a chiral resolution of an amine intermediate for the synthesis of compound 2, respectively, which circumvented the large-scale supercritical fluid chromatography (SFC) separation of the homochiral intermediates. A safe, robust, and scalable synthesis of 1 and 2 was successfully demonstrated.

The compound (S)-oxetan-2-ylmethyl tosylate 1 was identified as a key synthetic fragment for the introduction of the 2-substituted oxetane functionality in potential drug candidates under development in our laboratories. The focus of this paper is to highlight methodologies evaluated in our quest for synthetic routes to 2-substituted oxetanes suitable for enabling manufacture. Of the five routes investigated, three (Route 1A, Route 2, and Route 3) were successfully demonstrated in the laboratory. Subsequently, Route 3 was executed at scale to deliver metric ton quantities of the oxetane tosylate 1 as a solution in EtOAc, which was integrated into the synthesis of 2 and aforementioned drug candidates.

A second-generation synthesis of CT1812, a sigma-2 receptor modulator (ligand), was developed from readily available starting materials to support late-stage clinical needs. An AIBN-induced thermal benzylic bromination in DCE was replaced by a visible-light-induced continuous flow process in MeCN operating at room temperature. High throughput screening was employed to overcome the unexpected challenges encountered in the hydrogenation of alkyne 13 in the penultimate step. The rationale for a polymorph switch from the originally developed monofumarate anhydrate to the more thermodynamically stable hemifumarate dihydrate is also described. The new convergent route proceeds in eight steps (longest linear sequence (LLS) = 6) as compared to the original med chem route (12 steps; LLS = 9) and has been successfully demonstrated on a 100 kg scale.

This article presents the results of a comprehensive survey on the adoption of electrochemistry among 17 major pharmaceutical companies. The study examined key areas, including motivation, vision, personnel, utilization, explored reactions, scale-up experience, and equipment, with a focus on identifying gaps that hinder the realization of electrochemistry’s full potential. The survey findings suggest that although the adoption of electrochemistry is still in its early stages, it is viewed as a promising area that could lead to novel, better, and differentiated chemical transformations and disruptive routes. None of the surveyed companies reported having commercialized electrochemical processes; however, many anticipate reaching late-stage development or commercialization within a few years. The survey provides valuable insights for both industrial and academic laboratories seeking to pursue research in this field. Addressing gaps in knowledge and technology is essential to realizing the potential benefits of electrochemistry, ultimately contributing to the development of more efficient and sustainable manufacturing processes in the pharmaceutical industry.