Organic Process Research & Development最新文献

A catalyst-in-bag system facilitates the recovery and recycling of chiral dirhodium carboxylate catalysts used for enantioselective, intermolecular cyclopropanation. The catalyst-in-bag system incorporates a soluble enantioselective dirhodium complex catalyst within a reusable, commercial dialysis membrane. Dirhodium catalysts of different sizes are examined, and two catalysts with molecular weights above 2400 Da are well-retained by the membrane. The catalyst Rh₂(S-TPPTTL)₄ [TPPTTL = (1,3-dioxo-4,5,6,7-tetraphenylisoindolin-2-yl)-3,3-dimethylbutanoate] is explored in enantioselective cyclopropanation reactions under a variety of conditions. The Rh₂(S-TPPTTL)₄ catalyst, when contained in the catalyst-in-bag system, provides high yields and enantioselectivities, akin to the homogeneous catalyst in solution, with negligible rhodium permeation out of the bag over five catalytic cycles. The catalyst-in-bag approach facilitates recovery of the expensive rhodium metal and ligand, with only ppm level Rh detected in the reaction products. The flexible and expandable catalyst-in-bag system can be accommodated in vessels of different shapes and dimensions.

A four chemical step route to 2′-deoxy-2′-fluoro-N⁶,3′-dipivaloylarabinoadenosine and 2′-deoxy-2′-fluoro-N⁶-pivaloylarabinoadenosine from adenosine was developed for the preparation of ulevostinag in our STING (Stimulator of Interferon Genes) program. This 4-step route is based on the selective protection of adenosine with a dynamic kinetic crystallization of the desired N⁶,3′,5′-tripivaloyladenosine. This is followed by activation of the 2′-alcohol as its triflate without pivalate migration. Subsequently, the triflate is displaced with fluoride under mild conditions. Selective deprotection of the esters can give a variety of mono- and diacylated products including the 3′- or 5′-protected 2′-fluoroarabinonucleoside in the presence of the N⁶-pivalamide.

Sonocrystallization is a promising technology for improving the reproducibility and productivity of the crystallization process because of the unique cavitation effect of ultrasound as well as for controlling crystal polymorphs and particle size. Despite these advantages, the use of ultrasound for crystallization has typically been limited to laboratory studies and has not been widely adopted on an industrial scale by the pharmaceutical industry. In this study, ultrasound was combined with continuous crystallization using a mixed-suspension, mixed-product removal (MSMPR) crystallizer, and this technology was applied to the crystallization of perampanel, demonstrating the effects of ultrasound and its practicality. Finally, the continuous sonocrystallization process was successfully scaled up using a 10 L ultrasonic crystallizer capable of direct ultrasound irradiation, providing a methodology for the scale-up of the continuous sonocrystallization process.

The development of sustainable trifluoromethylations of enamides is of great interest to the pharmaceutical industry. Herein, we demonstrate a sustainable direct electrochemical trifluoromethylation method in a microflow cell, using Langlois reagent, without the need for a supporting electrolyte, oxidants, or any additive under mild conditions. This method can be applied to various substrates with a yield of up to 84%. Additionally, the batch process yielded significantly less (22%), highlighting the microflow cell’s efficiency.

An electrochemical synthesis of mono- and 1,1-disubstituted cyclopropanes is demonstrated. Starting from readily available 1,3-dialkyl bromides, this method hinges on the integration of a sacrificial reductant alongside cost-effective cathode and anode materials. The refined approach eliminates the necessity for a divided cell and the use of hazardous or costly electrodes, thereby streamlining the transition of this protocol to a continuous flow system. In addition, an alternative protocol that utilizes a simple sacrificial anode is also described.

Alectinib (marketed as Alecensa) is an oral, highly potent ALK inhibitor for the treatment of ALK-positive, non–small-cell lung cancer (NSCLC). This paper describes the evolution from a medicinal chemistry synthetic process to a process enabling the scaled-up supply of a high-quality drug substance. A characteristic structural feature of alectinib is its indole-containing tetracyclic core, the construction of which was effectively achieved through intramolecular reductive cyclization and an intramolecular Friedel–Crafts reaction. Furthermore, the optimized synthetic route and conditions were designed to suppress the formation of impurities containing the same tetracyclic scaffold that are difficult to purge in downstream processes. The established manufacturing process could consistently produce alectinib on a multikilogram scale, typically with an overall yield of 29% and purity exceeding 99.9 area%.

A simple and widely applicable technique to avoid precipitation-induced clogging in continuous-flow processes involving gas and liquid reagents (such as hydrogenations) has been developed. Management of solid compounds poses one of the largest scale-up risks in the flow manufacturing of pharmaceuticals and fine chemicals. As noted in this study, compounds with limited solubility in low-boiling solvents can be susceptible to precipitation when mixed with a gas stream in a standard tee-mixer. The prescribed technique, whereby the gas stream is prewetted with a solvent prior to contacting with the feed solution, has been successfully applied both in lab and scale-up platforms to enhance the stable (clog-free) operating run time of continuous-flow synthesis of an active pharmaceutical ingredient (API) intermediate from minutes to days.

The development of an efficient and general telescoped nickel-catalyzed Suzuki–Miyaura coupling (SMC) process from a nickel-catalyzed borylation reaction to form Csp²–Csp² bonds without isolation of the intermediate aryl boronate has been a long-standing interest for process chemists. Most scalable borylation/SMC sequences currently use palladium catalysts in subsequent catalytic steps, yet the ability to utilize nickel has the potential to greatly improve efficiency and decrease cost while also improving sustainability. This work introduces nickel-catalyzed SMC methodology that operates under homogeneous biphasic conditions to minimize inhibition from reaction byproducts of borylation and benefits from the addition of methanol as a cosolvent. These findings enabled the development of a one-pot, two-reaction method, which is demonstrated with a variety of complex heterocyclic coupling partners as both the nucleophilic aryl boronic acid and the electrophilic aryl halide, including an array of bioactive molecules that are representative of pharmaceutical synthetic targets. A comparison of this nickel-catalyzed telescoped process to the analogous palladium-catalyzed telescoped process is included to guide future use cases. A decagram scale telescoped process utilizing pharmaceutically relevant aryl halides demonstrates its scalability.

The demand for a cost-effective in-line particle measurement device is high, and the image analysis of particles in flow represents a promising concept to meet these expectations. In this work, we present an in-house developed image analysis flow cell to track particle size distributions in a process stream, including the necessary code and printing files for open-source use. For benchmarking of the flow cell, premade seeded solutions were prepared and analyzed by comparing the results to already applied and commercially available particle measurement devices. Furthermore, the results of six mixed-suspension, mixed-product-removal crystallization experiments were evaluated with the new measurement system.

CXCR4 is a seven-transmembrane chemokine receptor that is intimately involved in stem cell niche maintenance and immune cell trafficking. Among several other pathophysiological states for which CXCR4 mis regulation is implicated, various hematological malignancies and solid tumors hijack this chemokine network by dramatically overexpressing CXCR4 and its cognate chemokine ligand CXCL12. Upregulation of the CXCR4/CXCL12 axis in cancer drives tumor progression through several mechanisms, which makes CXCR4 a promising target for the development of anticancer therapeutics. Herein, we report the preparative scale synthesis of a novel, best-in-class, orally bioavailable small molecule CXCR4 antagonist, EMU-116. Two synthetic strategies for production of EMU-116 were pursued. While the first discovery-focused synthesis facilitated late-stage diversification to drive structure–activity relationship determinations, the second process-focused synthesis delivered EMU-116 more efficiently in higher overall yield with enhanced stereocontrol. For both synthetic routes, Buchwald–Hartwig amination of key aryl bromide intermediates enabled installation of the N-methylpiperazine appendage of EMU-116. Synthetic methods devised to prepare (R)-9-bromo-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one, the key aryl bromide intermediate required for the process-focused synthesis, are reported. In addition, an improved preparative method of known synthon (S)–N-methyl-5,6,7,8-tetrahydroquinolin-8-amine is highlighted by elevated overall yield, enhanced diastereoselectivity, and robust purification by crystallization. Further elaboration of these two intermediates, coupling via reductive amination to furnish the full EMU-116 scaffold, removal of protecting groups, and final product purification techniques are also reported. Overall, the synthetic methods described herein enabled reliable and efficient production of multigram quantities of EMU-116 and are anticipated to be amenable to larger scale production.