Organic Process Research & Development最新文献

{"title":"Can a Simple Surrogate Model System Be Used to Develop a Continuous Flow Packed Bed Hydrogenation for a Complex Molecule?","authors":"Stefano Martinuzzi,&nbsp;Martin Mex,&nbsp;Jelena Milic,&nbsp;Christopher A. Hone* and C. Oliver Kappe*,&nbsp;","doi":"10.1021/acs.oprd.4c0041110.1021/acs.oprd.4c00411","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00411https://doi.org/10.1021/acs.oprd.4c00411","url":null,"abstract":"<p >Catalytic hydrogenations are key processes in the fine chemical and pharmaceutical industries, but the development of such processes is challenging due to aspects such as catalyst deactivation, metal leaching, mass transfer limitations, solubility issues, and the formation of side products. Processes are particularly difficult to develop when a substrate is a large molecule containing multiple functional groups. These difficulties are significant obstacles for the identification of robust operating conditions; thus, workflows are necessary to speed up development timelines. The use of a more cost-effective and commercially available surrogate in development is an alternative strategy to find the optimized conditions, which can then be subsequently validated on the real molecule only at a later stage in development. The approach we apply herein is designed to use less of the real compound while minimizing the perceived risk of failure when transferring the conditions to the complex molecule. In this article, we apply our workflow for the catalytic hydrogenolysis of a large glycopeptide molecule, Cbz-protected glycopeptide (Cbz-GP), in a packed bed reactor. As part of the workflow, we use a robustness screening approach, introduced by Collins and Glorius, to show that a surrogate molecule, Cbz-protected lysine (Cbz-Lys), in the presence of additives can mimic secondary functional groups present in Cbz-GP or represent residual impurities generated upstream in the synthesis of Cbz-GP. The data generated for Cbz-Lys enabled the identification of the operating conditions for the successful deprotection of Cbz-GP after minor modification. Gratifyingly, only a few additional experiments were necessary using the Cbz-protected GP molecule to modify the conditions to achieve &gt;95% conversion under mild conditions and within &lt;10 s of contact time for stable performance over &gt;6 h operation time.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 2","pages":"363–372 363–372"},"PeriodicalIF":3.1,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452675","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":"Can a Simple Surrogate Model System Be Used to Develop a Continuous Flow Packed Bed Hydrogenation for a Complex Molecule?","authors":"Stefano Martinuzzi, Martin Mex, Jelena Milic, Christopher A. Hone, C. Oliver Kappe","doi":"10.1021/acs.oprd.4c00411","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00411","url":null,"abstract":"Catalytic hydrogenations are key processes in the fine chemical and pharmaceutical industries, but the development of such processes is challenging due to aspects such as catalyst deactivation, metal leaching, mass transfer limitations, solubility issues, and the formation of side products. Processes are particularly difficult to develop when a substrate is a large molecule containing multiple functional groups. These difficulties are significant obstacles for the identification of robust operating conditions; thus, workflows are necessary to speed up development timelines. The use of a more cost-effective and commercially available surrogate in development is an alternative strategy to find the optimized conditions, which can then be subsequently validated on the real molecule only at a later stage in development. The approach we apply herein is designed to use less of the real compound while minimizing the perceived risk of failure when transferring the conditions to the complex molecule. In this article, we apply our workflow for the catalytic hydrogenolysis of a large glycopeptide molecule, Cbz-protected glycopeptide (Cbz-GP), in a packed bed reactor. As part of the workflow, we use a robustness screening approach, introduced by Collins and Glorius, to show that a surrogate molecule, Cbz-protected lysine (Cbz-Lys), in the presence of additives can mimic secondary functional groups present in Cbz-GP or represent residual impurities generated upstream in the synthesis of Cbz-GP. The data generated for Cbz-Lys enabled the identification of the operating conditions for the successful deprotection of Cbz-GP after minor modification. Gratifyingly, only a few additional experiments were necessary using the Cbz-protected GP molecule to modify the conditions to achieve &gt;95% conversion under mild conditions and within &lt;10 s of contact time for stable performance over &gt;6 h operation time.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"31 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981920","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":"Scaling Up Gas–Liquid Photo-Oxidations in Flow Using Rotor-Stator Spinning Disc Reactors and a High-Intensity Light Source","authors":"Arnab Chaudhuri, Wouter F.C. de Groot, Jasper H.A. Schuurmans, Stefan D.A. Zondag, Alessia Bianchi, Koen P.L. Kuijpers, Rémy Broersma, Amin Delparish, Matthieu Dorbec, John van der Schaaf, Timothy Noël","doi":"10.1021/acs.oprd.4c00458","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00458","url":null,"abstract":"Photochemical transformations have garnered renewed interest over the past decade for their ability to enable unique reactions under mild conditions. However, scaling up such processes, particularly in multiphase systems (e.g., gas–liquid), remains challenging. Previously, we demonstrated the potential of the photochemical rotor-stator spinning disc reactor (pRS-SDR) for scaling the photooxidation of α-terpinene to ascaridole, though the system was limited by the light source, resulting in suboptimal operation in a photon-limited regime. In this work, we unlock the full potential of the pRS-SDR by integrating a high-powered light source (up to 652 W optical output) specifically designed for the reactor. The results show that the high gas–liquid mass transfer rates achievable in the pRS-SDR allow for significant productivity improvements under high irradiance (16.3 kg day^–1 at 92% α-terpinene conversion and 2.52 W cm^–2 in a 27 mL irradiated volume), representing an order of magnitude increase compared to our previous study. However, the photooxidation of β-citronellol exhibited notable limitations, highlighting the importance of selecting appropriate model reactions when evaluating intensified photochemical reactors.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142975666","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":"A Continuous Hydrogenation Reactor Based on a Powdered Catalyst Enmeshed in an Expanded Poly(tetrafluoroethylene) Matrix","authors":"Sean Breen, Purnima Barua, Yuan-Qing Fang, David D. Ford, Ali Hasan, Manish Joshi, Sara Mason, Kevin D. Nagy, Sifat bin Quadery, Grace Russell, Vladimiros Nikolakis, John D. Holcombe, Andrea Adamo, Lorenzo Milani","doi":"10.1021/acs.oprd.4c00303","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00303","url":null,"abstract":"Fixed bed catalytic reactors are commonly used for hydrogenation in the commodity chemical industry, but adoption in the pharmaceutical industry has been limited by the lack of available catalyst pellets in sizes suitable both for process research and development at scales of 1–50 g substrate per experiment and also for to manufacturing at the metric ton scale. Herein, we describe an approach for continuous flow hydrogenation using catalytic cartridges of powdered catalysts (palladium on carbon in this example) enmeshed in an expanded poly(tetrafluoroethylene) (ePTFE) matrix. Using a modular design, the catalytic layers and supplemental components can be arranged to suit specific reaction conditions, desired results, and throughput. The reactor was demonstrated with three classes of hydrogenation reactions: nitro reduction, debenzylation, and alkene reduction. All substrates could achieve high or full conversion after optimization. The study also includes longevity experiments to understand the long-term reliability of the reactor as well as preliminary results for scaling up to a larger membrane size. The results make this technology promising for scale-up opportunities by using the same modular design.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"5 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142975664","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":"Scaling Up Gas–Liquid Photo-Oxidations in Flow Using Rotor-Stator Spinning Disc Reactors and a High-Intensity Light Source","authors":"Arnab Chaudhuri,&nbsp;Wouter F.C. de Groot,&nbsp;Jasper H.A. Schuurmans,&nbsp;Stefan D.A. Zondag,&nbsp;Alessia Bianchi,&nbsp;Koen P.L. Kuijpers,&nbsp;Rémy Broersma,&nbsp;Amin Delparish,&nbsp;Matthieu Dorbec,&nbsp;John van der Schaaf* and Timothy Noël*,&nbsp;","doi":"10.1021/acs.oprd.4c0045810.1021/acs.oprd.4c00458","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00458https://doi.org/10.1021/acs.oprd.4c00458","url":null,"abstract":"<p >Photochemical transformations have garnered renewed interest over the past decade for their ability to enable unique reactions under mild conditions. However, scaling up such processes, particularly in multiphase systems (e.g., gas–liquid), remains challenging. Previously, we demonstrated the potential of the photochemical rotor-stator spinning disc reactor (pRS-SDR) for scaling the photooxidation of α-terpinene to ascaridole, though the system was limited by the light source, resulting in suboptimal operation in a photon-limited regime. In this work, we unlock the full potential of the pRS-SDR by integrating a high-powered light source (up to 652 W optical output) specifically designed for the reactor. The results show that the high gas–liquid mass transfer rates achievable in the pRS-SDR allow for significant productivity improvements under high irradiance (16.3 kg day^–1 at 92% α-terpinene conversion and 2.52 W cm^–2 in a 27 mL irradiated volume), representing an order of magnitude increase compared to our previous study. However, the photooxidation of β-citronellol exhibited notable limitations, highlighting the importance of selecting appropriate model reactions when evaluating intensified photochemical reactors.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 2","pages":"460–471 460–471"},"PeriodicalIF":3.1,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.oprd.4c00458","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452608","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":"A Continuous Hydrogenation Reactor Based on a Powdered Catalyst Enmeshed in an Expanded Poly(tetrafluoroethylene) Matrix","authors":"Sean Breen,&nbsp;Purnima Barua,&nbsp;Yuan-Qing Fang,&nbsp;David D. Ford*,&nbsp;Ali Hasan,&nbsp;Manish Joshi,&nbsp;Sara Mason,&nbsp;Kevin D. Nagy,&nbsp;Sifat bin Quadery,&nbsp;Grace Russell,&nbsp;Vladimiros Nikolakis*,&nbsp;John D. Holcombe,&nbsp;Andrea Adamo and Lorenzo Milani,&nbsp;","doi":"10.1021/acs.oprd.4c0030310.1021/acs.oprd.4c00303","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00303https://doi.org/10.1021/acs.oprd.4c00303","url":null,"abstract":"<p >Fixed bed catalytic reactors are commonly used for hydrogenation in the commodity chemical industry, but adoption in the pharmaceutical industry has been limited by the lack of available catalyst pellets in sizes suitable both for process research and development at scales of 1–50 g substrate per experiment and also for to manufacturing at the metric ton scale. Herein, we describe an approach for continuous flow hydrogenation using catalytic cartridges of powdered catalysts (palladium on carbon in this example) enmeshed in an expanded poly(tetrafluoroethylene) (ePTFE) matrix. Using a modular design, the catalytic layers and supplemental components can be arranged to suit specific reaction conditions, desired results, and throughput. The reactor was demonstrated with three classes of hydrogenation reactions: nitro reduction, debenzylation, and alkene reduction. All substrates could achieve high or full conversion after optimization. The study also includes longevity experiments to understand the long-term reliability of the reactor as well as preliminary results for scaling up to a larger membrane size. The results make this technology promising for scale-up opportunities by using the same modular design.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 2","pages":"299–310 299–310"},"PeriodicalIF":3.1,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452605","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":"Achieving New Scales: The First Successful Pilot Plant Spherical Crystallization","authors":"Stephanie C. Kosnik, Zeno Leuter, Kevin Schwickert","doi":"10.1021/acs.oprd.4c00350","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00350","url":null,"abstract":"Spherical crystallization is a widely used technique for the preparation of spherically shaped agglomerates of crystalline material, which results in free-flowing powders with improved micromeritic properties. In this study, we applied this technique to the reactive crystallization of 3-iodo-7-methyl-1<i>H</i>-indazole, a critical early intermediate for one of our Active Pharmaceutical Ingredients at Boehringer Ingelheim. We utilized a traditional spherical agglomeration approach to identify a bridging liquid that could be easily implemented into the current crystallization process. Our experiments showed that the amount and rate of antisolvent addition were important for the crystallization; however, the stir rate and the amount of bridging liquid were the most critical factors. We successfully scaled up this process to a 300 L pilot plant reactor, keeping a constant power per unit mass during scale-up. The results showed that the spherical crystallizations for both 300 L batches were highly successful with almost identical particle sizes.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"47 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968524","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":"Predicting Shock Sensitivity from Differential Scanning Calorimetry Data and Molecular Structure: Beyond the Yoshida Correlation","authors":"Eric L. Margelefsky, Benjamin C. Dobson, Tao Chen, Nelson Lee Afanador","doi":"10.1021/acs.oprd.4c00439","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00439","url":null,"abstract":"The Yoshida correlation is widely used in the pharmaceutical and fine chemical industry to predict explosivity and shock sensitivity of chemical substances based on the initiation temperature and enthalpy of differential scanning calorimetry (DSC) exotherms. We investigate the origins and accuracy of this correlation (and commonly used modifications thereof) by applying it to a large data set of 383 compounds, which are relevant to the pharmaceutical industry, and demonstrate that the initiation temperature and enthalpy variables are not good predictors for shock sensitivity. By incorporating structural information (for the 292 compounds where it was available), we used machine learning to inform and guide a logistic regression technique to develop a shock sensitivity model which has a higher overall accuracy (63%) and a higher accuracy for shock-sensitive compounds (97%) compared to the original Yoshida correlation (52% overall accuracy, 82% accuracy for shock-sensitive compounds). This logistic regression model includes both the original Yoshida variables (DSC initiation temperature and enthalpy) and also incorporates the oxygen balance (OB₁₀₀) and the number of energetic nitrogen groups in the molecule.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"4 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968525","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":"Predicting Shock Sensitivity from Differential Scanning Calorimetry Data and Molecular Structure: Beyond the Yoshida Correlation","authors":"Eric L. Margelefsky*,&nbsp;Benjamin C. Dobson,&nbsp;Tao Chen and Nelson Lee Afanador,&nbsp;","doi":"10.1021/acs.oprd.4c0043910.1021/acs.oprd.4c00439","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00439https://doi.org/10.1021/acs.oprd.4c00439","url":null,"abstract":"<p >The Yoshida correlation is widely used in the pharmaceutical and fine chemical industry to predict explosivity and shock sensitivity of chemical substances based on the initiation temperature and enthalpy of differential scanning calorimetry (DSC) exotherms. We investigate the origins and accuracy of this correlation (and commonly used modifications thereof) by applying it to a large data set of 383 compounds, which are relevant to the pharmaceutical industry, and demonstrate that the initiation temperature and enthalpy variables are not good predictors for shock sensitivity. By incorporating structural information (for the 292 compounds where it was available), we used machine learning to inform and guide a logistic regression technique to develop a shock sensitivity model which has a higher overall accuracy (63%) and a higher accuracy for shock-sensitive compounds (97%) compared to the original Yoshida correlation (52% overall accuracy, 82% accuracy for shock-sensitive compounds). This logistic regression model includes both the original Yoshida variables (DSC initiation temperature and enthalpy) and also incorporates the oxygen balance (OB₁₀₀) and the number of energetic nitrogen groups in the molecule.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 2","pages":"418–429 418–429"},"PeriodicalIF":3.1,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452523","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":"Achieving New Scales: The First Successful Pilot Plant Spherical Crystallization","authors":"Stephanie C. Kosnik*,&nbsp;Zeno Leuter and Kevin Schwickert,&nbsp;","doi":"10.1021/acs.oprd.4c0035010.1021/acs.oprd.4c00350","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00350https://doi.org/10.1021/acs.oprd.4c00350","url":null,"abstract":"<p >Spherical crystallization is a widely used technique for the preparation of spherically shaped agglomerates of crystalline material, which results in free-flowing powders with improved micromeritic properties. In this study, we applied this technique to the reactive crystallization of 3-iodo-7-methyl-1<i>H</i>-indazole, a critical early intermediate for one of our Active Pharmaceutical Ingredients at Boehringer Ingelheim. We utilized a traditional spherical agglomeration approach to identify a bridging liquid that could be easily implemented into the current crystallization process. Our experiments showed that the amount and rate of antisolvent addition were important for the crystallization; however, the stir rate and the amount of bridging liquid were the most critical factors. We successfully scaled up this process to a 300 L pilot plant reactor, keeping a constant power per unit mass during scale-up. The results showed that the spherical crystallizations for both 300 L batches were highly successful with almost identical particle sizes.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 2","pages":"311–321 311–321"},"PeriodicalIF":3.1,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452524","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}