Organic Process Research & Development最新文献

{"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<sub>2</sub> 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*, Krishna Ganesh and Kai Oliver Donsbach, ","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}

{"title":"An Alternate, Efficient Synthetic Process for a Hemolytic Anemia Drug: Mitapivat Sulfate","authors":"Ramesh Goura, Surendra Babu Manabolu Surya, Naresh Kumar Katari, Ramprasad Achampeta Kodanda, Pradeep Rebelly, Nagaraju Chakilam","doi":"10.1021/acs.oprd.4c00319","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00319","url":null,"abstract":"A new commercial manufacturing process for producing mitapivat sulfate, crucial for treating hemolytic anemia, is described. Starting from 4-nitrobenzoic acid (<b>14</b>) and N-Boc piperazine (<b>6</b>), the process involves sequential reactions to obtain <i>tert</i>-butyl 4-[4-(quinoline-8-sulfonamido)benzoyl]piperazine-1-carboxylate (<b>7</b>). This compound is then deprotected to yield <i>N</i>-[4-(piperazine-1-carbonyl)phenyl]naphthalene-1-sulfonamide (<b>8</b>), which undergoes reductive amination to produce mitapivat-free base (<b>9</b>). Finally, mitapivat sulfate is obtained with high quality and an overall yield of 81%. The synthesis prevents impurity formation and employs cost-effective raw materials, adhering to environmental sustainability and ICH product quality standards.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439602","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 Process for the Synthesis of Cyclopropyl-Methyl-Proline with Complex Stereochemistry: A Key Building Block of Factor D Inhibitors","authors":"Akihiro Hashimoto, Antonio C. Ferretti, Suresh K. Tipparaju, Justin L. Burt, Ashish Soman, Avinash Phadke, Prabu Chandran, Anand M. Lahoti, Devaraju Bilidegalu N, Anbazhagan Mani, Swarup Datta, Sankappa Rai, Sameerana Huddar, Prasanna Kumara, Tirumani Raju, Guruprasad AN, Suman Ganapathy, Tanish Chukka","doi":"10.1021/acs.oprd.4c00223","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00223","url":null,"abstract":"The development of a scalable process for a complex intermediate featuring a chiral, quaternary cyclopropane moiety presented significant challenges. We report two generations of synthetic strategies appropriate for the respective stages of development. The initial approach utilized a stereoselective Simmons–Smith cyclopropanation of (<i>R</i>)-pyroglutamic acid ester, which predominantly yielded the undesired stereoisomer. To circumvent this issue, we implemented a strategy that combined isomerization, recycling of the undesired isomer, and selective crystallization to improve the yield of the desired product. An important insight was that the Simmons–Smith cyclopropanation exhibited opposite stereoselectivity with a benzoyl ester of a prolinol substrate, resulting in the desired stereoisomer as the major product. This understanding enabled the development of a second-generation process that facilitated the large-scale production of the targeted intermediate, thus supporting the advancement of clinical trials.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436515","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":"Analytical Artifact Due to Residual HCN in Acetonitrile: Identification and Control Strategies","authors":"Vasantha Krishna Kadambar, Bhoopendra Singh Kushwah, Riddhi Gupta, Denna Sunny, Himanshu Vachhani, Joel Young, Lakshmikant Bajpai","doi":"10.1021/acs.oprd.4c00336","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00336","url":null,"abstract":"Mismatch in the potency from quantitative ¹H NMR (∼96%) and the calculated potency (∼94%) of an aldehyde intermediate led to the investigation of an unknown impurity peak observed in the chromatography. The HR-MS/MS analysis of the unknown impurity suggested it to be the cyanohydrin derivative of the corresponding aldehyde intermediate with the addition of ∼27 amu. Further investigation was performed using analogous 3-methyl iso-nicotinaldehyde as a model compound. A postcolumn hydrogen to deuterium exchange (H/D exchange) experiment further supported the proposed impurity structure as cyanohydrin. The source of HCN for the possible generation of this impurity was traced to certain brands of acetonitrile used duirng the analysis, where the presence of HCN as a contaminant was confirmed and quantified using ion chromatography. The aforementioned model compound was used to investigate the effect of other parameters like diluent composition, sample temperature and storage time, pH of the diluent, and duration of sonication, which impact the formation of such artifact impurity. Based on the results of all the experiments, mitigation strategies were proposed to avoid/control the formation of these impurities during the analytical processing such as use of methanol or HCN-free acetonitrile as a sample diluent, reduced composition of acetonitrile in the diluent, and use of freshly prepared solutions for injections to avoid longer storage time specially when certain sensitive substrates like aldehydes and ketones are analyzed. To evaluate if the formation of this impurity is limited to the compound of interest or if it is a common artifact peak for other similar compounds, various substrates involving aldehyde and ketone functional groups were analyzed under similar analytical conditions. The results indicated that aldehydes were more reactive than ketones, specifically the aldehydes containing a heterocyclic ring such as pyridine were prone to generate the cyanohydrin impurity.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431242","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":"Unraveling Lipase’s Promiscuous Behavior: Insights into Organic Acid Inhibition during Solventless Ester Production","authors":"Wouter Van Hecke, Marta Martinez-Garcia, Yamini Satyawali, Christof Porto-Carrero, Heleen De Wever","doi":"10.1021/acs.oprd.4c00274","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00274","url":null,"abstract":"Production of esters using chemical catalysts often entails off-odors, colors, or environmentally harmful reagents. Lipases play a pivotal role in enhancing product purity and sustainability. Despite their acknowledged substrate promiscuity, quantitative characterization of biocatalytic ester production remains scarce. Moreover, their behavior in solvent-free conditions, particularly in the presence of potentially inhibitory organic acids, is unknown. A systematic quantitative approach was conducted, which culminated in the development of a substrate preference heat map. A subsequent in-depth examination led to the identification and validation of a novel rate equation. While mechanistic in nature, an empirical adjustment is incorporated to account for inhibition effects. Specifically, this adjustment involves raising the acid concentration within the inhibition term to the power of n. This advancement is poised to facilitate scale-up endeavors to produce biocatalytic esters derived from short-chain fatty acids.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431750","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}