Organic Process Research & Development最新文献

Herein, we describe the development of steps 5–7for a large-scaleprocess to synthesize muvalaplin, a small-molecule lipoprotein(a)inhibitor for the potential reduction of major adverse cardiovascularevents in participants with established cardiovascular disease orat risk for a first cardiovascular event. Each step was optimized,leading to improvements in safety, robustness, and cost of goods thatultimately resulted in a 41% yield increase over three steps and a60% reduction in PMI compared to the original discovery synthesis.The process was safely scaled to >100 kg, thus ensuring clinicalsupplyand laying the foundation for a commercial route.

Olutasidenib is a potent, selective,and orally administeredsmall-moleculeinhibitor of mutant isocitrate dehydrogenase 1. The traditional syntheticmethods suffer from several drawbacks including prolonged reactiontimes, safety concerns, and low yields. Herein, we describe a four-stepcontinuous-flow synthesis of olutasidenib via oxidation reaction,Katada reaction, methylation reaction, and nucleophilic substitutionreaction. The coil reactor enables a shorter reaction time and reducesthe risk of hydrogen peroxide decomposition due to its enhanced heatand mass transfer. Meanwhile, Bayesian optimization is used to acceleratethe optimization of the continuous-flow. The level of N-methylation product of 2-pyridone was effectively increased to 93%by using methyl trifluoromethanesulfonate as a methylating agent inhexafluoroisopropanol. This continuous-flow process, featuring a totalresidence time of 86 min and a total yield of 44.1%, substantiallyreduces the reaction time and improves process safety while also achievinga lower Process Mass Intensity (PMI) than batch reactions.

Ibuzatrelviris a second-generation, orally administered proteaseinhibitor of the SARS-CoV-2 M^Pro virus that is currentlybeing evaluated for the treatment of Covid-19. The molecule containsa substituted trans-trifluoromethylproline fragmentthat, although it had been the focus of previous synthetic efforts,was still identified as a target for improvement. Herein, we describea route featuring the late-stage introduction of a stereocenter viaa mechanistically distinct diastereoselective kinetic hydrolysis.This bold strategy has resulted in significant efficiency, environmental,and process dividends, underscoring the impact of a continuous-improvementapproach to chemical development.

Chiral N, P ligands represent privilegedscaffoldsin asymmetric catalysis, yet their scalable synthesis suffers fromtraditional batch constraints: ultra-cryogenic conditions (−100to −120 °C), competitive benzyne formation, low yields,and poor scalability. Herein, a concise continuous-flow protocol forthe efficient synthesis of (S)-DPPNH₂-derivedchiral N, P ligands via sequential Br/Li exchangeis reported. Precise spatiotemporal control in a microreactor systemenables selective monolithiation, phosphination, and stereoselectivenucleophilic addition at a mild −70 °C, with a total residencetime of only 17.8 s. This flow platform effectively suppresses benzyneside reactions and eliminates the need for ultra-cryogenic infrastructurewhile maintaining a low in-process inventory of hazardous intermediates.The corresponding ligand precursors are obtained in yields of up to71% with good to excellent diastereoselectivities (up to 98:2 dr).Preparative-scale synthesis (1.17 g in a 2 min collection) and subsequentacid-catalyzed deprotection highlight the potential for further scale-up.This modular continuous-flow strategy offers a practical route todiverse chiral N, P ligands, addressing key manufacturingchallenges in asymmetric catalyst development.

Palladium-catalyzed thermal C–O cross-couplingreactionsrepresent first-choice methodologies for alkyl (hetero)aryl etherformation in both academia and industry, especially when commencingfrom otherwise challenging (hetero)aryl chloride or bromide electrophilesand aliphatic alcohol coupling partners. While highly effective thermalnickel-catalyzed processes of this type have emerged owing to advancesin ancillary ligand design, their use as competitive drop-in alternativesto palladium in such applications in the context of high-throughputexperimentation (HTE) has not been demonstrated. In targeting theformation of alkyl heteroaryl ethers of biological relevance, we discloseherein a comparative HTE screening study focused on thermal palladium-or nickel-catalyzed C–O cross-couplings of primary, secondary,or tertiary aliphatic alcohols with heteroaryl chlorides or bromides.We demonstrate that appropriate DalPhos-ligated nickel precatalystscan offer catalytic performance in such transformations that is competitivewith (e.g., for primary and secondary alcohols) or superior to (e.g.,for tertiary alcohols) that achieved by use of otherwise best-in-classpalladium catalysts (e.g., featuring biarylmonophosphine, JosiPhos,or other ligation).

Cu-catalyzed cross-coupling of aryl halides and malonatesusinghydroxypicolinamide ligands to furnish the corresponding aryl malonatesis disclosed herein. Malonates are commonly coupled with aryl halidesvia Pd catalysis, with a few reports of classic Hurtley-type Cu-mediatedcouplings. The Cu-MPBS system, originally designed for C–Ncoupling, has been further developed for the Cu-catalyzed couplingof diethyl malonate with aryl bromides and less precedented aryl chlorides.Our hydroxypicolinamide ligand scaffold promotes the Hurtley-typecoupling of diethyl malonate under mild conditions for aryl bromides(20–40 °C) and aryl chlorides (60–80 °C) withlow Cu loading (2–4 mol %). Reaction conditions are compatiblewith a wide variety of functional groups and heterocycles to providethe desired malonate. Furthermore, we demonstrated a telescoped processto the α-aryl ester simply by heating to drive subsequent decarboxylation.

The synthesis of a picolinamide ligand is demonstratedon a 70g scale in a process-friendly solvent, and its application in a copper-catalyzedC–N cross-coupling on a 20 g scale is reported. The ligandcan be accessed in one step via an amide coupling using inexpensive,commercially available 6-hydroxypicolinic acid and 6-methylquinolin-5-amine.A simple aqueous workup followed by a pH-swing-induced crystallizationaffords the ligand without the need for column chromatography. Thecombination of the scalable access to the ligand and its excellentperformance in copper-catalyzed C–N cross-coupling on decagramscale renders this ligand attractive for deployment in process chemistryapplications.