Organic Process Research & Development最新文献

A novel approach has been utilized in a continuous flow auto-optimizer for multistep apixaban (APX) synthesis, cutting residence time to 17.2 min and boosting overall yield by 78%. This AI-driven tool bypasses traditional trial-and-error methods, streamlining reactivity space navigation and enhancing productivity. It is designed to reduce APX production costs, improve space-time yield, and facilitate the transition from batch to continuous manufacturing, addressing critical gaps in the industry and advancing the field of digital smart workflows.

The optimization of a ruthenium-catalyzed catechol, terminal-alkyne coupling reaction to form a key benzodioxolane intermediate toward Lotiglipron is described. This transformation required the use of 3-butyn-2-ol, a valuable yet thermally hazardous reagent. Manual reaction condition optimization delivered a good yield but a poor process safety profile. Further reaction understanding was gained by performing a design of experiments (DoE) screening of relevant reaction conditions while using differential scanning calorimetry output data as well as productivity optimization parameters to strike a balance of process safety and chemical yield. To the best of our knowledge, this work represents the first report of using process safety data as DoE output to guide safe reaction condition selection. Finally, the optimal conditions were demonstrated in a lab-scale flow reactor with good translation of results from the batch reaction.

We report the initial studies toward the continuous processing of Baloxavir Marboxil, the active pharmaceutical ingredient (API) of Roche’s commercial product Xofluza. The motivation behind this effort is to transition to integrated continuous manufacturing (ICM) as a platform to create an agile and on-demand supply chain capability for a drug that has highly variable market demand. The work described herein includes an improved late-stage synthetic route to Baloxavir Marboxil that (1) reduced a four-step synthesis down to two steps, (2) identified key diastereomeric crystallization conditions to reach required material specifications, and (3) removed the use of N,N-dimethylacetamide in exchange for a more environmentally benign solvent mixture of acetonitrile and water. After a full revision of the two-step synthetic route in batch mode, key unit operations were translated to continuous mode to evaluate their performance. Collectively, this work eliminated 16 unit operations, significantly simplified the process, and is projected to reduce the lead time from 12 months to several days using ICM.

This article presents the development of an improved synthetic process for a crucial intermediate in the production of the antiviral drug baloxavir marboxil. The focus is on optimizing the telescoped synthesis of methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)-amino)-4-oxo-1,4-dihydropyridine-2-carboxylate (compound 7) built on the original method, which used polar aprotic solvents to improve selectivity in the acid-catalyzed dehydration-condensation reaction between intermediate ester 6 and tert-butyl carbazate. This process encountered difficulties related to high-boiling solvent recovery and the generation of nitrogen-rich wastewater. To overcome these challenges, we evaluated three optimization strategies. Notably, the use of a PPTS-organic base buffering system (Strategy III) enabled the replacement of the polar aprotic solvent DMAc with readily recoverable THF under the acidity adjustment and Lewis base catalysis effect of triethylamine (TEA). Design of experiments (DoE) further optimized the reaction parameters, significantly reducing the level of impurities, including the identification of three previously unreported process impurities. The optimized process was successfully scaled up to 135 g in the laboratory, yielding the monohydrate form of compound 7 with a purity of 98.3% and an overall yield improved from 78.6% to 85.1%.

The chemical development and production of sufficient amounts of IL-17A inhibitor LY3509754 to enable preclinical toxicology studies is described. LY3509754 is a complex small molecule that features three stereocenters, which comprised much of the synthetic challenge. Stereoselective hydrogenation and biocatalysis enabled access to all stereocenters. The most significant challenge was installation of the chiral methoxymethyl side chain, specifically, formation of the sp2–sp3 C–C bond from reasonable raw materials and establishment of the benzylic amine stereocenter. Given prior experience with structural analogs, we were able to use a hybrid approach to the synthesis, with key building blocks being available on large-scale from the previous efforts. Historical knowledge combined with rapid route scouting and development allowed us to invent a scalable route to LY3509754 in about seven months and deliver 430 g to accelerate the preclinical toxicology studies.

We report the iodoamination of alkenes in continuous flow under metal-free, visible-light-mediated conditions with commercially available N-iodosuccinimide and protected amines. Unactivated and activated alkenes as well as Michael acceptors are amenable substrate classes for this process, allowing the synthesis of 1,2-iodoamines with a broad scope and in high yields (59–94%). The steadiness of the protocol is demonstrated in a continuous flow experiment over 4.5 h for the coupling of styrene, NIS, and N-tosyl-amine, which gave rise to 14 g (91%) of the iodoaminated product, corresponding to a productivity of 3.1 g h^–1. Additionally, the direct conversion of the products without prior isolation into aziridines, enamines, amino alcohols, or azidoamines is possible, underscoring the synthetic value of this approach. Variation of the reaction conditions by adding typical impurities in reagents or solvents or changing the irradiation from green to blue light had a minimal effect on the yield, giving credit to the robustness of the process.