Organic Process Research & Development最新文献

{"title":"Facile Recovery and Recycling of a Soluble Dirhodium Catalyst in Asymmetric Cyclopropanation via a Catalyst-in-Bag System","authors":"UnJin Ryu, Duc Ly, Kristin Shimabukuro, Huw M. L. Davies, Christopher W. Jones","doi":"10.1021/acs.oprd.4c00400","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00400","url":null,"abstract":"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(<i>S</i>-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(<i>S</i>-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.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electrochemical Trifluoromethylation of Enamides under Microflow Conditions","authors":"Anna Vanluchene, Tomas Horsten, Eli Bonneure, Christian V. Stevens","doi":"10.1021/acs.oprd.4c00311","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00311","url":null,"abstract":"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.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electrochemical Cyclopropanation of 1,3-Dialkyl Bromides","authors":"Sylvain Charvet, Clément Jacob, Aurore Dietsch, Guillaume Tintori, Pierre-Georges Echeverria, Julien C. Vantourout","doi":"10.1021/acs.oprd.4c00302","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00302","url":null,"abstract":"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.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a Scalable Manufacturing Process for Alectinib with a Concise Preparation of the Indole-Containing Tetracyclic Core","authors":"Tomohiro Oki, Masao Tsukazaki, Junichi Shiina, Hiroshi Fukuda, Minoru Yamawaki, Yasushi Kito, Takenori Ishizawa, Kazutomo Kinoshita, Sosuke Hara, Noriyuki Furuichi, Hatsuo Kawada, Toshiya Ito, Kota Tanaka, Noriaki Maruyama, Daisuke Tamaru, Takahiro Ichige, Masatoshi Koizumi, Yosuke Hosoya, Masahiro Kimura, Mami Yamaguchi, Shigeki Sato, Yuta Miyazaki, Azusa Toya, Hiroshi Iwamura, Kenji Maeda","doi":"10.1021/acs.oprd.4c00376","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00376","url":null,"abstract":"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%.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Solving Gas–Liquid Mixing-Induced Clogging in Continuous-Flow Hydrogenation Synthesis of an API Intermediate","authors":"Jadid E. Samad, Douglas Connolly, Zheng Zhao, Joel M. Hawkins","doi":"10.1021/acs.oprd.4c00324","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00324","url":null,"abstract":"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.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing Base-Metal Catalysis: Developing Nickel Catalysis for the Direct Telescope of Miyaura Borylation and Suzuki–Miyaura Cross-Coupling Reactions","authors":"Henrique Alves Esteves, Matthew J. Goldfogel, Andrii Shemet, Cheng Peng, Benjamin Hritzko, Eric M. Simmons, Steven R. Wisniewski","doi":"10.1021/acs.oprd.4c00327","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00327","url":null,"abstract":"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.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a 3D Printed Flow Cell for Application as an In-line Optical Particle Analysis Tool","authors":"Sebastian Soritz, Nico Nys, Matteo Thierrichter, Lorenz Buchgraber, Richard Amering, Peter Neugebauer, Heidrun Gruber-Woelfler","doi":"10.1021/acs.oprd.4c00168","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00168","url":null,"abstract":"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.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expansion of the Green Chemistry Principles: Inclusion of Greenhouse Gases and Carbon Footprint","authors":"Kai Rossen, Krishna Ganesh, Kai Oliver Donsbach","doi":"10.1021/acs.oprd.4c00428","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00428","url":null,"abstract":"There is growing agreement among scientists that the world may face catastrophic climatic developments in the coming decades, caused primarily by the massive emission of greenhouse gases such as CO&lt;sub&gt;2&lt;/sub&gt; and methane. Many governments are already beginning to face the challenge on how to manage and minimize the calamitous effects. The topic is a complex interplay of many facets, and the sheer size of the successive meetings of the Conference of Parties─UN Climate Change, with tens of thousands of attendees, bears witness that the management of the ongoing climate change will require a massive input of creative ideas and resources. The topic is central to the ability of humans to survive on Earth, so minimization and mitigation of climate change will be the driver for several decisions in the next decades. It is clear that we are at the beginning of a new modern industrial revolution which will completely change the way we live and how our economies function. The coming decades will experience a massive shift to renewable energies, with replacement of energy-intensive chemical manufacturing processes such as the Haber–Bosch ammonia synthesis and the petrol-based polymer industry by renewable materials and sustainable technologies. We will also have to find strategies on how to deal with limiting supplies of critical elements such as P, Pd, and Li, and critically, the construction industry will have to find replacements for concrete. These are massive challenges and will amount to a new analogous industrial revolution that requires unabated efforts in defining our future economies that will alter the fabric of our societies. Health (new medicines) and materials (to improve living standards) are central to modern human existence. Transforming science, engineering, and technologies should play a critical role by providing solutions and new opportunities. Toward this end, chemistry will play a vital and decisive role as the central science, since the material world is dependent on finite chemical resources on and within Earth. We need to acknowledge the fact that the ability of humankind to continue living on this planet depends on chemists and their creativity to bring forward solutions. The chemical community should responsibly and proudly embrace this responsibility. How will all these demands effect the production and affordability of medicines? Let us look at how the existing processes and prevailing industrial revolution will affect the production of different types of medicines and what the decarbonized industrial landscape will mean for the manufacture of these. One should never forget that medicines should not only extend patients’ lifetimes but also improve the quality of our lives. Medicines cover a vast range of different modalities, each associated with characteristic production technologies. Very importantly, all technologies are associated with widely varying business models. Let us keep in mind that the economics of a recently lau","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expansion of the Green Chemistry Principles: Inclusion of Greenhouse Gases and Carbon Footprint","authors":"Kai Rossen*,&nbsp;Krishna Ganesh and Kai Oliver Donsbach,&nbsp;","doi":"10.1021/acs.oprd.4c0042810.1021/acs.oprd.4c00428","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00428https://doi.org/10.1021/acs.oprd.4c00428","url":null,"abstract":"","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Scale-Up Preparation of Best-In-Class Orally Bioavailable CXCR4 Antagonist EMU-116 in an Academic Setting","authors":"Leon Jacobs, Eric J. Miller, Robert J. Wilson, Edgars Jecs, Paul Joseph Tholath, Huy H. Nguyen, Manohar T. Saindane, Yesim Altas-Tahirovic, Lawrence J. Wilson, Dennis C. Liotta","doi":"10.1021/acs.oprd.4c00246","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00246","url":null,"abstract":"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 <i>N</i>-methylpiperazine appendage of EMU-116. Synthetic methods devised to prepare (<i>R</i>)-9-bromo-1,5,10,10<i>a</i>-tetrahydro-3<i>H</i>-oxazolo[3,4<i>-b</i>]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 (<i>S</i>)–<i>N</i>-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.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}