Organic Process Research & Development最新文献

We investigate the influence of oligomeric impurities on the crystallization of ritlecitinib tosylate, an active pharmaceutical compound, using a combined experimental and molecular modeling approach. Ritlecitinib oligomers, particularly hexamers, were identified as key species hindering crystal growth. Experimental outcomes highlighted the inhibitory effects of oligomers on crystallization kinetics, yield, and physical properties. Simplified free energy methods based on the linear interaction energy model revealed a nonmonotonic relationship between oligomer size and surface affinity, with hexamers having the most prominent tendency to block the surface of ritlecitinib tosylate crystals, thus impacting crystal growth. A competitive Langmuir adsorption isotherm model quantified the reduction in crystal growth rates due to oligomer adsorption, providing a systematic approach to understanding these inhibitory effects. This research enhances our understanding of the molecular mechanisms governing oligomer adsorption, and more generally, impurity adsorption, on crystal surfaces and offers insights for designing crystal growth inhibitors in pharmaceutical applications.

Flow chemistry is a method of conducting a reaction in continuous flow through channels by pumping the reactants into the system. This advanced method offers rapid and efficient mixing, precise control of reaction conditions, high-throughput screening, and rapid optimization of the reaction as compared to batch conditions. In the current times, various pharmaceutical intermediates are being produced efficiently using flow chemistry. One of the most important reactions emerging is the carbon–carbon cross coupling reaction using transition metal catalysis especially palladium. Cross-coupling reactions are vital in the creation of advanced materials with tailored properties desired for pharmaceuticals, agrochemicals, and fine chemicals. Over the years, numerous Pd-catalyzed cross-coupling reactions, such as Suzuki-Miyaura coupling, Mizoroki-Heck coupling, Sonogashira coupling, Stille coupling, Negishi coupling, etc., have been explored and widely applied. Continuous-flow methods for heterogeneous catalysis have enhanced the reaction by integrating the separation process into a single step using packed bed reactors and eliminating the need for additional steps for catalyst recovery. The focus of this review is to address various catalysts developed for Pd-catalyzed cross-coupling reactions in a flow reaction, followed by optimization such as flow rate, residence time, temperature, Pd loading, solvent, base, and concentration of starting material. This review presents a comprehensive study of these catalysts used for C–C coupling using flow chemistry.

Perylene diimides (PDI) have an extraordinary ability to activate both energy and electron transfer processes upon light excitation; however, their extremely low solubility has hindered their wide use as photocatalysts. Here, we show that the combination of solid-supported PDIs with continuous flow photochemistry offers a promising strategy for process intensification and a scalable platform for heterogeneous photocatalysis. The photocatalyst immobilized onto glass beads is highly efficient, easy to separate, and extremely reusable, with a broad synthetic application range. Using the photo-oxidation of n-butyl sulfide as a benchmark reaction, we demonstrate that immobilized PDI are highly active, outperforming reported homogeneous photosensitizers, and capable of extensive reuse (turnover number (TON) >57,000 over 2 months). Transferring the process from batch to flow results in a 10-fold reduction in irradiation time and an increase in the space-time yield by a factor of 33 (40 vs 1338 mmol^–1 h^–1 L^–1 batch vs flow). What is more, the same catalyst sample can be used for the preparation of a range of sulfoxides, the aza-Henry reaction between nitromethane and N–Ar tetrahydroisoquinolines, and the photo-oxidation of furfural with high catalytic activity. Overall, our work combines the remarkable photocatalytic properties of PDI with inert, easy-to-handle glass beads, producing hybrid materials that are reusable and can be adapted for performing heterogeneous photocatalysis in a range of scalable photochemical reactors.

A robust and scalable synthesis process for Nerandomilast (1, BI 1015550), a selective PDE4B inhibitor with potential therapeutic properties for the treatment of respiratory diseases, was developed and implemented at a pilot plant on a multikilogram scale. Key aspects of the process include the efficient synthesis of intermediate (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (4) by means of a regioselective S_NAr reaction between (1-aminocyclobutyl)methanol (6) and 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (5), a new convergent synthesis of 5-chloro-2-(piperidin-4-yl)pyrimidine (3) by means of a Suzuki coupling, and a highly enantioselective sulfide oxidation to give chiral nonracemic (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (2).