Organic Process Research & Development最新文献

{"title":"Continuous Flow Synthesis and Kinetic Study of Diphenyl Sulfoxide in a Microreactor","authors":"Hongrui Zhang, Feng Xu, Xiang Zhou, Zhiquan Chen, Juncheng Jiang, Gang Fu, Lei Ni","doi":"10.1021/acs.oprd.5c00018","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00018","url":null,"abstract":"The oxidation of diphenyl sulfide (DPS) by hydrogen peroxide (H₂O₂) to synthesize diphenyl sulfoxide (DPSO) is extremely exothermic and has a high thermal risk. When thermal runaway happens, it may lead to equipment damage or even explosions. Therefore, in this work, a microreactor was adopted to reduce reaction thermal risk and process conditions were optimized. Phosphotungstic acid (PTA) was used as the catalyst, and the effects of process conditions, including reaction temperature, residence time, catalyst concentration, and molar ratio on the conversion and yield were systematically investigated. The results showed that the DPSO yield could reach up to 84.3% under the condition of 0.75% catalyst loading, 25 min residence time, 70 °C reaction temperature, and H₂O₂–DPS molar ratio of 2. Then, apparent reaction kinetics were studied, and a kinetic model was established and validated. By varying the initial concentrations of H₂O₂ and DPS, the reaction was determined to be of second-order, with an activation energy of 57.5 kJ·mol^–1 and a pre-exponential factor of 2.96 × 10⁷ mol^–1·L·min^–1. Furthermore, the temperature distribution along the microreactor was estimated by combining the thermal equilibrium with the reaction kinetics. The results indicated that in a 1/16 in. microreactor, the reaction was nearly isothermal. Temperature distributions were also predicted for microreactors with different diameters and materials. It was demonstrated that the reaction could be safely scaled up to a 3/8 in. microreactor at a reaction temperature of 55 °C, with the maximum temperature rise remaining below 5 °C and no decline in DPSO yield. This study provided a convenient method to guide the safe sizing-up of the reaction in flow reactors.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"74 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836950","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":"Access to Phenolic Pyridopyridazinones and Phthalazinones Using THP Ether-Directed Ortho Lithiation","authors":"Helena Leuser, Subhash Pithani, Staffan Karlsson, Carl-Johan Aurell, Marcus Malmgren, Per-Ola Norrby, Okky D. Putra","doi":"10.1021/acs.oprd.4c00541","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00541","url":null,"abstract":"Route scouting, process research and development, and large-scale synthesis of phenol-substituted pyridopyridazinones (azaphthalazinones) and phthalazinones are reported. For the introduction of one of our key building blocks, 3-(trifluoromethyl)phenol, our identified large-scale route initially employed an unstable aryllithium, generated by bromine lithium exchange next to a phenolic hydroxy group protected as <i>p</i>-methoxybenzyl (PMB) ether. We found that instead, protecting the phenolic hydroxy group as tetrahydropyran (THP) ether in a bromine-free substrate and applying directed ortho metalation (DoM) generated the desired aryllithium in a stable form, suitable for use in a batch process on a large scale, which significantly facilitated the synthesis of our target molecules. The final process, a palladium-free, telescoped two-step sequence consisting of ketone formation by acylation with a mixed diester and cyclization with hydrazine, was demonstrated in our kilogram laboratory on a 0.5 kg scale for the pyridopyridazinone scaffold. Routes to the analogous phthalazinone scaffold were also investigated, and here, both phthalic anhydride and a mixed diester can serve as starting material. DFT calculations support our rationale regarding experimentally found differences between pyridine- and benzene-based intermediates. The target molecules were isolated as crystalline solids, and their structures were further confirmed by single crystal X-ray diffraction.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"284 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832495","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":"Shackles Off: A Kilo Scale Synthesis of Rawal’s Diene","authors":"Oleksii I. Shamrai, Ievgenii A. Iermolenko, Eugeniy N. Ostapchuk, Dmytro O. Leha, Evgenij V. Zarudnitskii, Serhiy V. Ryabukhin, Dmytro M. Volochnyuk","doi":"10.1021/acs.oprd.5c00039","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00039","url":null,"abstract":"Compared to Danishefsky’s diene, Rawal’s diene suffers from low commercial availability, limited scalability, and obscure stability issues, which strictly limits its usability. Herein, we present an optimized, scalable synthetic protocol that achieves yields suitable for the diene’s semi-industrial production, with adjustments to reagent concentrations, reaction conditions, and isolation procedures to enhance efficiency. Complementing synthetic advancements, this work explores the diene’s physicochemical stability under diverse storage conditions. Rigorous quality control methodologies exploiting nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy facilitate precise monitoring of purity and degradation pathways, establishing robust analytical standards. Additionally, the work demonstrates the utility and advantages of Rawal’s diene in multigram syntheses of 2-alkyl-2,3-dihydro-4<i>H</i>-pyran-4-ones, showcasing its applicability for medicinal chemistry purposes. The findings disclosed in the paper establish a foundation for the broader adoption and commercialization of Rawal’s diene, enabling its integration into academic and industrial workflows.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"183 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827286","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":"Continuous Dihydrolevoglucosenone Recovery Using Commercial Membrane Technology","authors":"Andreas Dejaegere, Alessandro Napoli, Thomas S.A. Heugebaert, Christian V. Stevens","doi":"10.1021/acs.oprd.4c00494","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00494","url":null,"abstract":"Cyrene, or dihydrolevoglucosenone (DHL), is a biobased and biodegradable solvent that can be produced in two steps from cellulose. It has properties similar to dipolar aprotic solvents such as NMP and DMF, both of which raise significant concerns regarding environmental and human health. As such, dihydrolevoglucosenone offers a promising alternative. The use of this sustainable solvent enhances the environmental profile of chemical reactions. However, target compounds synthesized in dihydrolevoglucosenone are mainly purified using an aqueous workup, leading mostly to the disposal of DHL in an aqueous waste stream. This study focuses on recovering dihydrolevoglucosenone through back-extraction processes.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"1 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806150","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":"Continuous Dihydrolevoglucosenone Recovery Using Commercial Membrane Technology","authors":"Andreas Dejaegere,&nbsp;Alessandro Napoli,&nbsp;Thomas S.A. Heugebaert and Christian V. Stevens*,&nbsp;","doi":"10.1021/acs.oprd.4c0049410.1021/acs.oprd.4c00494","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00494https://doi.org/10.1021/acs.oprd.4c00494","url":null,"abstract":"<p >Cyrene, or dihydrolevoglucosenone (DHL), is a biobased and biodegradable solvent that can be produced in two steps from cellulose. It has properties similar to dipolar aprotic solvents such as NMP and DMF, both of which raise significant concerns regarding environmental and human health. As such, dihydrolevoglucosenone offers a promising alternative. The use of this sustainable solvent enhances the environmental profile of chemical reactions. However, target compounds synthesized in dihydrolevoglucosenone are mainly purified using an aqueous workup, leading mostly to the disposal of DHL in an aqueous waste stream. This study focuses on recovering dihydrolevoglucosenone through back-extraction processes.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 4","pages":"1076–1082 1076–1082"},"PeriodicalIF":3.1,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842431","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":"Kilo-Scale-Enabled Route toward PF-07907063, a Type II Brain Penetrant cMET Inhibitor","authors":"Grace McKenna, Cole Cruz, Bryon Simmons, James T. Brewster, II, Anna M. Benz-Weeden, Thomas A. Brandt, Quinn A. Bumpers, Adam Cook, Mohamed Saad Abdullah Elsayed, Daniel Golec, Nicholas Lewandowski, Phong Nguyen, Robert W. Pipal, Pavel Savechenkov, Christina E. Wong, Eugene Tarlton, John J. Gaudino, Ronald J. Hinklin, Tony P. Tang","doi":"10.1021/acs.oprd.4c00441","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00441","url":null,"abstract":"New synthetic methodologies that access complex saturated building blocks enable the synthesis of drug molecules with unique properties. Here, we report collaborative efforts between Pfizer’s Medicinal Chemistry, Medicinal Chemistry Synthesis Development, and Pharmaceutical Sciences Small Molecule (PSSM) groups for the development of kilogram-scale-enabled synthesis of a type II brain penetrant cMET inhibitor, PF-07907063. The chemistry presented herein demonstrates the importance of implementing a green chemistry approach for developing and applying new transformations throughout the drug development pipeline. Specifically, synthetic planning rooted in the 12 Principles of Green Chemistry led to advancements in deoxygenative photoredox-nickel dual catalysis and cross-electrophile nickel catalysis. The final route significantly lowered the process mass intensity (PMI), increased the yield of the final API, and allowed for the purification of key intermediates through crystallization versus purging impurities via column chromatography, among other improvements.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"168 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143798411","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":"Kilo-Scale-Enabled Route toward PF-07907063, a Type II Brain Penetrant cMET Inhibitor","authors":"Grace McKenna,&nbsp;Cole Cruz,&nbsp;Bryon Simmons*,&nbsp;James T. Brewster II*,&nbsp;Anna M. Benz-Weeden,&nbsp;Thomas A. Brandt,&nbsp;Quinn A. Bumpers,&nbsp;Adam Cook,&nbsp;Mohamed Saad Abdullah Elsayed,&nbsp;Daniel Golec,&nbsp;Nicholas Lewandowski,&nbsp;Phong Nguyen,&nbsp;Robert W. Pipal,&nbsp;Pavel Savechenkov,&nbsp;Christina E. Wong,&nbsp;Eugene Tarlton,&nbsp;John J. Gaudino,&nbsp;Ronald J. Hinklin* and Tony P. Tang,&nbsp;","doi":"10.1021/acs.oprd.4c0044110.1021/acs.oprd.4c00441","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00441https://doi.org/10.1021/acs.oprd.4c00441","url":null,"abstract":"<p >New synthetic methodologies that access complex saturated building blocks enable the synthesis of drug molecules with unique properties. Here, we report collaborative efforts between Pfizer’s Medicinal Chemistry, Medicinal Chemistry Synthesis Development, and Pharmaceutical Sciences Small Molecule (PSSM) groups for the development of kilogram-scale-enabled synthesis of a type II brain penetrant cMET inhibitor, PF-07907063. The chemistry presented herein demonstrates the importance of implementing a green chemistry approach for developing and applying new transformations throughout the drug development pipeline. Specifically, synthetic planning rooted in the 12 Principles of Green Chemistry led to advancements in deoxygenative photoredox-nickel dual catalysis and cross-electrophile nickel catalysis. The final route significantly lowered the process mass intensity (PMI), increased the yield of the final API, and allowed for the purification of key intermediates through crystallization versus purging impurities via column chromatography, among other improvements.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 4","pages":"1048–1057 1048–1057"},"PeriodicalIF":3.1,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842338","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":"Solvent Eco-Impact Metric: A Tool for Chemists to Drive Sustainability in Chemical Processes across Safety, Health, Waste, and Environmental Aspects","authors":"Marco Ferrara*,&nbsp;Federico Della Negra and Massimo Verzini,&nbsp;","doi":"10.1021/acs.oprd.4c0054610.1021/acs.oprd.4c00546","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00546https://doi.org/10.1021/acs.oprd.4c00546","url":null,"abstract":"<p >The synthesis of active pharmaceutical ingredients (APIs) demands extensive resources, with solvents playing a pivotal role in shaping the safety, health, waste, and environmental impacts of chemical processes. To address the absence of a tailored metric for the requirements of the pharmaceutical industry to rapidly quantify and compare these impacts, we developed a novel tool providing concrete operational guidance to enhance sustainability, cost-effectiveness, and operational efficiency. This metric leverages a comprehensive data set, prioritizes critical impact categories, and evaluates solvent quantities relative to the product output. These features enable it to effectively identify areas of improvement in chemical processes and guide sustainable development initiatives. The experience of the application of the metric by a contract development and manufacturing organization to its processes is presented, demonstrating the effectiveness of the metric for internal benchmarking and establishing sustainability criteria. Furthermore, the metric provided structured, actionable guidelines to support daily process development activities, ultimately serving as a practical tool to achieve corporate environmental, social, and governance (ESG) objectives. While the described benchmarking is not proposed as a general industry standard, the method is adaptable to the unique context and requirements of any chemical or pharmaceutical company. Case studies underscore its capability to pinpoint high-impact solvents, support targeted interventions, and achieve notable reductions in sustainability impacts. Aligned with the United Nations Sustainable Development Goal for responsible production, this metric integrates seamlessly into process evaluation tools, enabling consistent, data-driven improvements. Designed to complement existing methodologies rather than replace them, it enhances chemical process assessments with a rapid, decision-focused approach tailored to the priorities and key impact categories of the pharmaceutical industry. This practical tool fosters sustainability and operational efficiency, addressing critical industry needs.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 4","pages":"1110–1124 1110–1124"},"PeriodicalIF":3.1,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.oprd.4c00546","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Solvent Eco-Impact Metric: A Tool for Chemists to Drive Sustainability in Chemical Processes across Safety, Health, Waste, and Environmental Aspects","authors":"Marco Ferrara, Federico Della Negra, Massimo Verzini","doi":"10.1021/acs.oprd.4c00546","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00546","url":null,"abstract":"The synthesis of active pharmaceutical ingredients (APIs) demands extensive resources, with solvents playing a pivotal role in shaping the safety, health, waste, and environmental impacts of chemical processes. To address the absence of a tailored metric for the requirements of the pharmaceutical industry to rapidly quantify and compare these impacts, we developed a novel tool providing concrete operational guidance to enhance sustainability, cost-effectiveness, and operational efficiency. This metric leverages a comprehensive data set, prioritizes critical impact categories, and evaluates solvent quantities relative to the product output. These features enable it to effectively identify areas of improvement in chemical processes and guide sustainable development initiatives. The experience of the application of the metric by a contract development and manufacturing organization to its processes is presented, demonstrating the effectiveness of the metric for internal benchmarking and establishing sustainability criteria. Furthermore, the metric provided structured, actionable guidelines to support daily process development activities, ultimately serving as a practical tool to achieve corporate environmental, social, and governance (ESG) objectives. While the described benchmarking is not proposed as a general industry standard, the method is adaptable to the unique context and requirements of any chemical or pharmaceutical company. Case studies underscore its capability to pinpoint high-impact solvents, support targeted interventions, and achieve notable reductions in sustainability impacts. Aligned with the United Nations Sustainable Development Goal for responsible production, this metric integrates seamlessly into process evaluation tools, enabling consistent, data-driven improvements. Designed to complement existing methodologies rather than replace them, it enhances chemical process assessments with a rapid, decision-focused approach tailored to the priorities and key impact categories of the pharmaceutical industry. This practical tool fosters sustainability and operational efficiency, addressing critical industry needs.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"38 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143798412","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":"Process Development toward a Key Fragment of the PCSK9 Inhibitor Enlicitide Decanoate","authors":"Kai-Jiong Xiao*,&nbsp;Yonggang Chen,&nbsp;Yingju Xu,&nbsp;Gao Shang,&nbsp;Lushi Tan,&nbsp;Fangzhou Xie,&nbsp;Chengqian Xiao,&nbsp;Yongpeng Yuan,&nbsp;Baoqiang Wan,&nbsp;Guiquan Liu and Jingjun Yin,&nbsp;","doi":"10.1021/acs.oprd.4c0050410.1021/acs.oprd.4c00504","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00504https://doi.org/10.1021/acs.oprd.4c00504","url":null,"abstract":"<p >Here we report the development of a large-scale manufacturing process for the synthesis of the Northern Fragment of enlicitide decanoate (MK-0616), an orally bioavailable inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9). The key topics covered are (1) process development for the selective tryptophan allylation; (2) development of the one-pot process for two consecutive peptide coupling reactions; (3) process development for the one-pot cleavage of two <i>N</i>-<i>tert</i>-butyloxycarbonyl (<i>N</i>-Boc) groups and a <i>tert</i>-butyl ester; and (4) process development of the magnesium chloride (MgCl₂)-mediated selective macrolactamization. This optimized process was demonstrated to produce the key fragment at &gt;150 kg scale per batch in the synthesis of enlicitide.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 4","pages":"1083–1092 1083–1092"},"PeriodicalIF":3.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842386","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}