Organic Process Research & Development最新文献

A change to EU law is proposed that would lead to a ban on manufacture, supply, and use of most per- and polyfluorinated alkyl substance (PFAS) materials. The proposed EU definition of PFAS is extremely broad, including most fluoroalkyl materials, regardless of molecular weight. Thus, reagents as simple as trifluoroacetic acid through fluorinated intermediates to polymers such as PTFE, PVDF, and Viton could be entirely banned, with the exception of API molecules themselves. The implications of such a ban for the chemical and (bio)pharma industries in Europe cannot be overstated. The EU Proposal is currently out for public consultation, and the purpose of this Perspective is both to raise awareness and to encourage contributions to the consultation process. Comments to the EU must be received by the deadline of 23:59 (Helsinki time) on September 25, 2023.

High-throughput experimentation is a common practice in the optimization of chemical synthesis. Chemists design reaction arrays to optimize the yield of couplings between building blocks. Popular reactions used in pharmaceutical research include the amide coupling, Suzuki coupling, and Buchwald–Hartwig coupling. We show how the artificial intelligence (AI) language model ChatGPT can automatically formulate reaction arrays for these common reactions based on the literature corpus it was trained on. Critically, we showcase how ChatGPT results can be directly translated into inputs for the management software phactor, which enables automated execution and analysis of assays. This workflow is experimentally demonstrated, with modest to excellent yields of products obtained in each instance on the first attempt.

Stereoinvertive deoxyamination involving Bose–Mitsunobu azidation and the Staudinger reaction, which proceeds under mild conditions in the presence of a neighboring group, was successfully applied for the synthesis of edoxaban. The one-pot process allowed access to key intermediates of edoxaban without isolating azide intermediates. Furthermore, the efficiency of the Bose–Mitsunobu azidation was dramatically improved by changing the substituent on the neighboring group from the Boc group to a thiazole carbonyl unit.

We describe the development of a triphasic quench-crystallization operation to isolate an intermediate in the manufacture of the sotorasib drug substance. Using this case study, unique aspects of the quench-crystallization operation are highlighted and contrasted with the development of more commonly discussed cooling/antisolvent crystallization operations. A workflow for exploring and developing complex, reactive crystallization operations for commercial drug substance manufacture is proposed and illustrated. Within this framework, the utility of applying process analytical technology (PAT) is demonstrated.

While large-scale crystallizer design profits from many years of accumulated knowledge, traditional fabrication technologies limit the possibilities for easy and rapid lab-scale design, fabrication, and subsequently testing of crystallizer design variants. Additive manufacturing (three-dimensional (3D) printing) affords an opportunity to overcome the challenges associated with scaling down equipment using traditional fabrication technologies and materials of construction such as glass or metal alloys. Moreover, additive manufacturing provides flexibility in design and the ability to rapidly redesign and prototype novel designs, limited, perhaps, only by the suitability of available materials of construction. Surprisingly, this technology has not yet found widespread use in crystallizer design. In this contribution, we present a concept study for a 3D-printed prototype crystallizer. We discuss additive manufacturing as a tool for rapid design and fabrication of down-scaled crystallizers based upon a design using the classic Oslo-type crystallizer as a starting point. The initial crystallizer design and fabrication process, subsequent design modifications, and investigation of the crystallizer characteristics are discussed here with a view to applications in pharmaceutical continuous crystallization.

This paper presents the development of two generations of routes for the synthesis of the key intermediate 8-Cl of siponimod. The first generation focuses on a cyanation reaction followed by alkaline hydrolysis to introduce the benzoic acid group, replacing the hazardous nucleophilic carboxylation mediated by n-BuLi in the reported manufacturing route. Furthermore, the use of LiAlH₄ for the carboxylic acid reduction is substituted with a milder acid anhydride reduction enabled by NaBH₄. Overall, the first-generation route demonstrates an 11.6% increase in yield over 8 steps, effectively addressing concerns related to scale-up effects and safety-critical operations. In the second generation, a two-step synthesis involving nickel-catalyzed Kumada–Corriu coupling and Blanc chloromethylation is devised to produce benzyl chloride 8-Cl, starting from the readily available and cost-effective material 1-halo-2-(trifluoromethyl)benzene 9. The second-generation route is successfully demonstrated at large scales ranging from hundreds to kilo grams, resulting in a remarkable 32.5% yield increase and approximately 65% reduction in process mass intensity for the synthesis of intermediate 8-Cl.

Two improved routes to BIIB091 key tetrahydrobenzoazepine core (1) were developed to support tox and early clinical demands. The first improved route takes advantage of a diastereoselective Ellman’s sulfinimine reduction as the key step of chiral amine synthesis. This route was successfully scaled up to support API manufacturing for early clinical trials. The second improved route uses an amine transaminase (ATA) biocatalysis reaction of an N-Boc ketone (15) precursor, which was prepared by applying a trifluoroacetamide-protecting group for effective azepine ring construction and protecting group swap. The ATA route is demonstrated at a subkilogram scale and has the potential to become a late clinical and commercial route due to its significant improvements in synthetic efficiency, overall yield, and process greenness.

The traditional batch production process for methyl sulfone (MSM) from dimethyl sulfoxide (DMSO) is highly exothermic and poses serious safety risks. In this work, we present a continuous-flow synthesis strategy using microchannel reactors to enhance the safety and efficiency of industrial-scale MSM production. Four specifications of microchannel reactors have been constructed and then were applied for the continuous-flow synthesis of MSM with both high yield and purity. The effects of the channel diameter, water bath temperature, catalytic dosage, residence time, and segmented temperature control on MSM yield were systematically investigated. By gradually optimizing the design parameters, the yield of MSM in the industrialized microchannel reactor reached 95.3%, and the average annual time yield of MSM was 18.36 t·a^–1. In addition, the maximum overlimit temperature in the continuous flow does not exceed 10 °C, and the overtemperature time is less than 20 s. Dual temperature-controlled continuous-flow process was more beneficial to increase the yield of MSM. The microchannel continuous-flow amplification process can greatly improve the productivity of MSM while ensuring the high yield of MSM, which is a promising strategy for the efficient and safe production of MSM at an industrial scale.