Organic Process Research & Development最新文献

An experimental study was performed for a fed-batch catalytic hydrogenation for the production of Argatroban. The penultimate expensive and scarcely available intermediate is characterized by a slow dissolution rate that evolves in parallel with the reaction process. The study investigated the coupling between the reaction and dissolution kinetics. In these circumstances, the standard Area Percentage method in HPLC was found to be misleading, requiring calibration and then absolute peak area measurements to correctly identify the dissolution rate and thus the actual chemical kinetics. Experiments quantified the role of the temperature, stirring rate, and catalyst loading. Shifting from 40 to 80 °C reduced the batch time by 58%, although higher temperatures promoted the formation of undesired impurities. Stirring rate controlled the initial reaction phases when reagent dissolution is critical. Catalyst loading is key in reducing batch time. The increase in catalyst loading was proved to affect the reagent dissolution rate, by increasing the collision frequency between reagent and catalyst particles. A refined first-principles model, incorporating the effect of the catalyst amount on the dissolution mass transfer coefficient, significantly improved the accuracy of dissolution predictions and enabled better identification of the intrinsic reaction kinetics. The addition of a microkinetic description further improved the predictions of intermediates and products.

An efficient large-scale synthesis of 2a·HCl, a key fragment to several KRAS inhibitors, is described. Optimization to a previously reported racemic route by Merck includes the development of a catalytic exocyclic olefin oxidation using RuCl₃/NaIO₄, followed by a highly diastereoselective reduction of the resulting ketone. A second-generation approach was then developed. The highlight of this synthesis includes a one-step intramolecular nucleophilic ring cyclization of 35a or 35b via a stable chelate with lithium cation 38 to give a stereoselective product, bicyclic scaffold 36a, with excellent diastereoselectivity and good yields. Consecutive deoxyfluorination followed by the reduction of benzyl ester 37a afforded 2a·HCl without the need for chiral separation utilized in the first-generation approach.

Daprodustat is a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor indicated for treating anemia in patients with chronic kidney disease (CKD). This study describes a novel, efficient, and robust kilogram-scale manufacturing process for daprodustat starting from commercially available malonic acid by implementing quality by design (QbD) principles. A novel synthetic approach was adopted for the synthesis of methyl (1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl)glycinate by avoiding the use of ethyl isocyanatoacetate and replacing it with methyl glycinate and CDI. To our delight, we achieved a throughput of 76% with over 99% purity for daprodustat, compared to the previously reported throughput of 52%. This approach has enabled us to develop a more environmentally friendly process for synthesizing daprodustat than the prior method.

Triflumezopyrim (TFM) is a novel class of mesoionic insecticides. Herein, a novel synthetic process for TFM was developed via imidization, reductive amination, and cyclization. Based on toluene as a universal solvent and simplifying postprocessing operations, TFM could be obtained in approx. 26 h with about 40% overall isolated yield, while the E-factor was decreased to 158, which improved the reaction efficiency and eco-friendliness. Subsequently, the synthetic route was attempted in continuous flow, and TFM was prepared in about 32 min with about 30% total isolated yield. Furthermore, by connecting to our previous research, TFM could also be obtained in less than 35 min total reaction time with about 30% yield based on continuous flow total synthesis, which shortened the total reaction residence time by about 48-fold compared to the batch mode and manifested a significant advantage of reaction efficiency in continuous flow.

Ethyl 2-(4-aminophenoxy)thiazole-5-carboxylate is a key intermediate of several P2X₃ antagonists required for clinical trials. The synthesis at the early R&D stage delivered this thiazole derivative via a nucleophilic aromatic substitution reaction in highly variable yields, from 7 to 85%. We describe the process development of the initial route of synthesis carefully considering the reaction conditions, process robustness and safety, operational improvement, and the impact on downstream steps. The optimized process was successfully replicated on a multikg scale in a pilot plant, allowing for the supply of the key intermediate in 90% isolated yield with high purity (>99 area%).