Organic Process Research & Development最新文献

筛选
英文 中文
Industrial Case Studies Demonstrating Applicability of ICH M7 Control Options 3 and 4 for Nitrosamine Control
IF 3.1 3区 化学
Organic Process Research & Development Pub Date : 2025-03-21 DOI: 10.1021/acs.oprd.5c0004210.1021/acs.oprd.5c00042
Michael W. Urquhart*, Michael J. Burns*, Frank Bernardoni, Hugh F. Clark, Jean-Philippe Crochard, Alessandro De Benedetti, Olivier Dirat, Jared W. Fennell, Malcolm A. Y. Gall, Marzia Galli, Stefan Hildbrand, Jeffrey M. Kallemeyn, Nadine Kuhl, Daniel J. Mack, Christian Moessner, David D. Pascoe, Alessandro Pozzoli, Philippe Risch, Alastair J. Roberts, Andrew Teasdale, Oliver R. Thiel, Paula Tomlin and Andrew Whitehead, 
{"title":"Industrial Case Studies Demonstrating Applicability of ICH M7 Control Options 3 and 4 for Nitrosamine Control","authors":"Michael W. Urquhart*,&nbsp;Michael J. Burns*,&nbsp;Frank Bernardoni,&nbsp;Hugh F. Clark,&nbsp;Jean-Philippe Crochard,&nbsp;Alessandro De Benedetti,&nbsp;Olivier Dirat,&nbsp;Jared W. Fennell,&nbsp;Malcolm A. Y. Gall,&nbsp;Marzia Galli,&nbsp;Stefan Hildbrand,&nbsp;Jeffrey M. Kallemeyn,&nbsp;Nadine Kuhl,&nbsp;Daniel J. Mack,&nbsp;Christian Moessner,&nbsp;David D. Pascoe,&nbsp;Alessandro Pozzoli,&nbsp;Philippe Risch,&nbsp;Alastair J. Roberts,&nbsp;Andrew Teasdale,&nbsp;Oliver R. Thiel,&nbsp;Paula Tomlin and Andrew Whitehead,&nbsp;","doi":"10.1021/acs.oprd.5c0004210.1021/acs.oprd.5c00042","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00042https://doi.org/10.1021/acs.oprd.5c00042","url":null,"abstract":"<p >The assessment and control of potential mutagenic impurities (PMIs) within pharmaceutical products are managed in accordance with the ICH M7 guideline “Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk”. This guidance highlights four control options that can be used to give assurance of control of PMIs to below a level of toxicological concern for the intended use. These control options range from testing to confirm that impurity levels within the active pharmaceutical ingredient or product are below an acceptable limit (ICH M7 Option 1 Control) to a control strategy that relies on process controls and scientific principles (e.g., purging) to demonstrate impurity presence to below a level of concern in lieu of analytical testing (option 4). While ICH M7 control option 4 is an established approach to justify that levels of a potential mutagenic impurity are below an acceptable limit, there have been health authority challenges that the use of ICH M7 control option 4 rationales is not appropriate for <i>N</i>-nitrosamines without included confirmatory analytical testing data to confirm absence. The reasons behind this lack of acceptance for ICH M7 control option 4 alone may include (i) a higher perceived potency for nitrosamines over other mutagenic impurities as they alert as part of the cohort of concern and (ii) inappropriate application of purge rationales such that, in some instances, confirmatory testing data highlighted higher levels for the impurity than had been predicted to be present. Through the inclusion of industry relevant case studies, this publication outlines that, while some nitrosamines may require control to lower levels than the ICH M7 threshold of toxicological concern, the concept of the ICH M7 option 4 control is scientifically justified when the properties for the nitrosamine are considered and an appropriate conservative purge rationale is applied.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 4","pages":"1152–1167 1152–1167"},"PeriodicalIF":3.1,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842479","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}
引用次数: 0
Surface Defects and Crystal Growth of Apremilast Benzoic Acid Cocrystals
IF 3.4 3区 化学
Organic Process Research & Development Pub Date : 2025-03-19 DOI: 10.1021/acs.oprd.4c00480
Jan Jirát, Vít Zvoníček, Luděk Ridvan, Miroslav Šoóš
{"title":"Surface Defects and Crystal Growth of Apremilast Benzoic Acid Cocrystals","authors":"Jan Jirát, Vít Zvoníček, Luděk Ridvan, Miroslav Šoóš","doi":"10.1021/acs.oprd.4c00480","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00480","url":null,"abstract":"A cocrystallization process of the active pharmaceutical ingredient apremilast with benzoic acid is explored in this work. The aim of the study is to adjust operating conditions during the crystallization to purposefully tune the dissolution properties of the final product. Understanding the cocrystallization is key to obtaining a consistent, high-quality product, as well as tuning other properties such as powder flowability or dissolution properties. It was discovered early in development that the studied cocrystallization process does not follow the common rules of crystallization. Better crystals were obtained at faster cooling rates and worse crystals at slower cooling rates. Interestingly, this can be explained by crystal collisions and a two-phase growth of the crystals. Standard operating conditions were further tested, resulting in different shapes and sizes of the product. Different types of produced crystals were tested in a dissolution apparatus and provided significantly modified dissolution profiles.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"61 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143654052","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}
引用次数: 0
Surface Defects and Crystal Growth of Apremilast Benzoic Acid Cocrystals
IF 3.1 3区 化学
Organic Process Research & Development Pub Date : 2025-03-19 DOI: 10.1021/acs.oprd.4c0048010.1021/acs.oprd.4c00480
Jan Jirát, Vít Zvoníček, Luděk Ridvan and Miroslav Šoóš*, 
{"title":"Surface Defects and Crystal Growth of Apremilast Benzoic Acid Cocrystals","authors":"Jan Jirát,&nbsp;Vít Zvoníček,&nbsp;Luděk Ridvan and Miroslav Šoóš*,&nbsp;","doi":"10.1021/acs.oprd.4c0048010.1021/acs.oprd.4c00480","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00480https://doi.org/10.1021/acs.oprd.4c00480","url":null,"abstract":"<p >A cocrystallization process of the active pharmaceutical ingredient apremilast with benzoic acid is explored in this work. The aim of the study is to adjust operating conditions during the crystallization to purposefully tune the dissolution properties of the final product. Understanding the cocrystallization is key to obtaining a consistent, high-quality product, as well as tuning other properties such as powder flowability or dissolution properties. It was discovered early in development that the studied cocrystallization process does not follow the common rules of crystallization. Better crystals were obtained at faster cooling rates and worse crystals at slower cooling rates. Interestingly, this can be explained by crystal collisions and a two-phase growth of the crystals. Standard operating conditions were further tested, resulting in different shapes and sizes of the product. Different types of produced crystals were tested in a dissolution apparatus and provided significantly modified dissolution profiles.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 4","pages":"1067–1075 1067–1075"},"PeriodicalIF":3.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.oprd.4c00480","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842475","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}
引用次数: 0
Imine Reductase-Catalyzed Synthesis of a Key Intermediate of Avacopan: Enzymatic Oxidative Kinetic Resolution with Ex Situ Recovery and Dynamic Kinetic Reduction Strategies toward 2,3-Disubstituted Piperidine
IF 3.4 3区 化学
Organic Process Research & Development Pub Date : 2025-03-17 DOI: 10.1021/acs.oprd.4c00511
Zsuzsa Juhász Pótáriné, Tihamér Paál, Lajos Mészáros, Gergely Bánóczi, Zoltán Kondor, Napsugár Kavalecz, Andrea Zsuzsanna Ujvárosi, János Végh, Dániel Eszenyi, Gábor J. Zahuczky, Ram Prajapaty, Rushikesh Kadu, Vadivelan Rengasamy, Imre Gyűjtő
{"title":"Imine Reductase-Catalyzed Synthesis of a Key Intermediate of Avacopan: Enzymatic Oxidative Kinetic Resolution with Ex Situ Recovery and Dynamic Kinetic Reduction Strategies toward 2,3-Disubstituted Piperidine","authors":"Zsuzsa Juhász Pótáriné, Tihamér Paál, Lajos Mészáros, Gergely Bánóczi, Zoltán Kondor, Napsugár Kavalecz, Andrea Zsuzsanna Ujvárosi, János Végh, Dániel Eszenyi, Gábor J. Zahuczky, Ram Prajapaty, Rushikesh Kadu, Vadivelan Rengasamy, Imre Gyűjtő","doi":"10.1021/acs.oprd.4c00511","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00511","url":null,"abstract":"Imine reductase (IRED) enzymes catalyze the asymmetric reduction of cyclic imines and have recently gained attention due to their reductive aminase (RedAm) activity. Herein, we demonstrated their ability to control the two vicinal stereogenic centers in an N-heterocyclic system. By reversing their usual mode of action, the oxidative kinetic resolution (KR) of the <i>rac-cis</i>-<b>1</b> piperidine intermediate of avacopan was used to leave the (2<i>R</i>,3<i>S</i>)-<b>1</b> desired enantiomer untouched, whereas the undesired enantiomer was oxidized and tautomerized to enamine <b>4</b>. The synthesis was improved by using alcohol dehydrogenase (ADH) for cofactor regeneration, and <b>4</b> was recycled by catalytic hydrogenation to <i>rac-cis</i>-<b>1</b>. Hence, KR was carried out on a 1 kg scale with 99.5% <i>ee</i> and 37.2 g/L/d space-time yield (STY). One cycle of recycling of <b>4</b> enamine was confirmed at the kg scale in 83.7% yield, which resulted after the bioconversion of (2<i>R</i>,3<i>S</i>)-<b>1</b> with a total yield of 57.8% (theoretical maximum KR of 50%). Repetitive sequences of KR with ex situ recycling of <b>4</b> afforded an overall theoretical yield of 72%. Moreover, an enantiocomplementary enzyme was utilized for the dynamic kinetic reduction of <b>4</b> to (2<i>R</i>,3<i>S</i>)-<b>1</b> with excellent diastereoselectivity.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"197 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143640917","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}
引用次数: 0
Imine Reductase-Catalyzed Synthesis of a Key Intermediate of Avacopan: Enzymatic Oxidative Kinetic Resolution with Ex Situ Recovery and Dynamic Kinetic Reduction Strategies toward 2,3-Disubstituted Piperidine
IF 3.1 3区 化学
Organic Process Research & Development Pub Date : 2025-03-17 DOI: 10.1021/acs.oprd.4c0051110.1021/acs.oprd.4c00511
Zsuzsa Juhász Pótáriné, Tihamér Paál*, Lajos Mészáros, Gergely Bánóczi, Zoltán Kondor, Napsugár Kavalecz, Andrea Zsuzsanna Ujvárosi, János Végh, Dániel Eszenyi, Gábor J. Zahuczky, Ram Prajapaty, Rushikesh Kadu, Vadivelan Rengasamy and Imre Gyűjtő, 
{"title":"Imine Reductase-Catalyzed Synthesis of a Key Intermediate of Avacopan: Enzymatic Oxidative Kinetic Resolution with Ex Situ Recovery and Dynamic Kinetic Reduction Strategies toward 2,3-Disubstituted Piperidine","authors":"Zsuzsa Juhász Pótáriné,&nbsp;Tihamér Paál*,&nbsp;Lajos Mészáros,&nbsp;Gergely Bánóczi,&nbsp;Zoltán Kondor,&nbsp;Napsugár Kavalecz,&nbsp;Andrea Zsuzsanna Ujvárosi,&nbsp;János Végh,&nbsp;Dániel Eszenyi,&nbsp;Gábor J. Zahuczky,&nbsp;Ram Prajapaty,&nbsp;Rushikesh Kadu,&nbsp;Vadivelan Rengasamy and Imre Gyűjtő,&nbsp;","doi":"10.1021/acs.oprd.4c0051110.1021/acs.oprd.4c00511","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00511https://doi.org/10.1021/acs.oprd.4c00511","url":null,"abstract":"<p >Imine reductase (IRED) enzymes catalyze the asymmetric reduction of cyclic imines and have recently gained attention due to their reductive aminase (RedAm) activity. Herein, we demonstrated their ability to control the two vicinal stereogenic centers in an N-heterocyclic system. By reversing their usual mode of action, the oxidative kinetic resolution (KR) of the <i>rac-cis</i>-<b>1</b> piperidine intermediate of avacopan was used to leave the (2<i>R</i>,3<i>S</i>)-<b>1</b> desired enantiomer untouched, whereas the undesired enantiomer was oxidized and tautomerized to enamine <b>4</b>. The synthesis was improved by using alcohol dehydrogenase (ADH) for cofactor regeneration, and <b>4</b> was recycled by catalytic hydrogenation to <i>rac-cis</i>-<b>1</b>. Hence, KR was carried out on a 1 kg scale with 99.5% <i>ee</i> and 37.2 g/L/d space-time yield (STY). One cycle of recycling of <b>4</b> enamine was confirmed at the kg scale in 83.7% yield, which resulted after the bioconversion of (2<i>R</i>,3<i>S</i>)-<b>1</b> with a total yield of 57.8% (theoretical maximum KR of 50%). Repetitive sequences of KR with ex situ recycling of <b>4</b> afforded an overall theoretical yield of 72%. Moreover, an enantiocomplementary enzyme was utilized for the dynamic kinetic reduction of <b>4</b> to (2<i>R</i>,3<i>S</i>)-<b>1</b> with excellent diastereoselectivity.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 4","pages":"1093–1102 1093–1102"},"PeriodicalIF":3.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842432","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}
引用次数: 0
Assessing the Industrial Edge of the Lipase-Mediated Oxidation of 2,5-Diformylfuran to 2,5-Furandicarboxylic Acid: Rotating Bed Reactors, an “Acyl-Donor-Free” Oxidation Concept, and Environmental Aspects 评估脂肪酶介导的 2,5-二甲酰呋喃氧化成 2,5-呋喃二甲酸的工业优势:旋转床反应器、"无酰基供体 "氧化概念和环境问题
IF 3.4 3区 化学
Organic Process Research & Development Pub Date : 2025-03-14 DOI: 10.1021/acs.oprd.4c00474
Milica Milić, Guillem Vernet, Hai Yen Le, Ningning Zhang, Emil Byström, Pablo Domínguez de María, Selin Kara
{"title":"Assessing the Industrial Edge of the Lipase-Mediated Oxidation of 2,5-Diformylfuran to 2,5-Furandicarboxylic Acid: Rotating Bed Reactors, an “Acyl-Donor-Free” Oxidation Concept, and Environmental Aspects","authors":"Milica Milić, Guillem Vernet, Hai Yen Le, Ningning Zhang, Emil Byström, Pablo Domínguez de María, Selin Kara","doi":"10.1021/acs.oprd.4c00474","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00474","url":null,"abstract":"The lipase-mediated oxidation of 2,5-diformylfuran (DFF) to 2,5-furandicarboxylic acid (FDCA) via peracid formation is a promising alternative to valorizing furans from biorefineries. In this chemoenzymatic reaction, <i>Candida antarctica</i>lipase B (CALB) uses hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) and ethyl acetate as an acyl donor to form peracetic acid <i>in situ</i>, which subsequently performs the oxidation of DFF to FDCA, via the intermediate 5-formyl-2-furancarboxylic acid (FFCA). This study explores the reaction en route to its industrial application, identifying strengths and limitations. First, the origin of DFF is considered since it can proceed from biorefineries either in organic media or in aqueous solutions. The reaction is assessed in ethyl acetate with different water contents, showing that oxidations can be achieved in wet nonaqueous media. Moreover, a mixture of ethyl acetate and <i>tert</i>-butanol improves the FDCA yield 2-fold. Subsequently, the reaction is conducted using a rotating bed reactor (RBR), which may enable straightforward downstream processing while showing hints for future scale-up. Once H<sub>2</sub>O<sub>2</sub> dosage, rotating rate, and enzyme and substrate loadings are optimized, FDCA production of up to ∼27 g/L is achieved, yet still at low DFF selectivity (∼50%). To improve the atom economy of the reaction and enhance the option of organic media recycling, which saves significant CO<sub>2</sub> generation during incineration, an “acyl-donor-free” concept of the lipase-mediated oxidation of DFF to FDCA is proposed, which uses catalytic amounts of FDCA to be taken by the lipase to generate per-FDCA, to oxidize DFF to form the desired product subsequently. Overall, the enzyme-mediated oxidation of DFF to FDCA may become relevant in biorefineries if improvements in the enzyme stability (against H<sub>2</sub>O<sub>2</sub> and peracids), as well as in process conditions (e.g., H<sub>2</sub>O<sub>2</sub> and substrate addition, downstream, etc.) are adequately tuned.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"69 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627710","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}
引用次数: 0
Assessing the Industrial Edge of the Lipase-Mediated Oxidation of 2,5-Diformylfuran to 2,5-Furandicarboxylic Acid: Rotating Bed Reactors, an “Acyl-Donor-Free” Oxidation Concept, and Environmental Aspects
IF 3.1 3区 化学
Organic Process Research & Development Pub Date : 2025-03-14 DOI: 10.1021/acs.oprd.4c0047410.1021/acs.oprd.4c00474
Milica Milić, Guillem Vernet, Hai Yen Le, Ningning Zhang, Emil Byström, Pablo Domínguez deMaría* and Selin Kara*, 
{"title":"Assessing the Industrial Edge of the Lipase-Mediated Oxidation of 2,5-Diformylfuran to 2,5-Furandicarboxylic Acid: Rotating Bed Reactors, an “Acyl-Donor-Free” Oxidation Concept, and Environmental Aspects","authors":"Milica Milić,&nbsp;Guillem Vernet,&nbsp;Hai Yen Le,&nbsp;Ningning Zhang,&nbsp;Emil Byström,&nbsp;Pablo Domínguez deMaría* and Selin Kara*,&nbsp;","doi":"10.1021/acs.oprd.4c0047410.1021/acs.oprd.4c00474","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00474https://doi.org/10.1021/acs.oprd.4c00474","url":null,"abstract":"<p >The lipase-mediated oxidation of 2,5-diformylfuran (DFF) to 2,5-furandicarboxylic acid (FDCA) via peracid formation is a promising alternative to valorizing furans from biorefineries. In this chemoenzymatic reaction, <i>Candida antarctica</i>lipase B (CALB) uses hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) and ethyl acetate as an acyl donor to form peracetic acid <i>in situ</i>, which subsequently performs the oxidation of DFF to FDCA, via the intermediate 5-formyl-2-furancarboxylic acid (FFCA). This study explores the reaction en route to its industrial application, identifying strengths and limitations. First, the origin of DFF is considered since it can proceed from biorefineries either in organic media or in aqueous solutions. The reaction is assessed in ethyl acetate with different water contents, showing that oxidations can be achieved in wet nonaqueous media. Moreover, a mixture of ethyl acetate and <i>tert</i>-butanol improves the FDCA yield 2-fold. Subsequently, the reaction is conducted using a rotating bed reactor (RBR), which may enable straightforward downstream processing while showing hints for future scale-up. Once H<sub>2</sub>O<sub>2</sub> dosage, rotating rate, and enzyme and substrate loadings are optimized, FDCA production of up to ∼27 g/L is achieved, yet still at low DFF selectivity (∼50%). To improve the atom economy of the reaction and enhance the option of organic media recycling, which saves significant CO<sub>2</sub> generation during incineration, an “acyl-donor-free” concept of the lipase-mediated oxidation of DFF to FDCA is proposed, which uses catalytic amounts of FDCA to be taken by the lipase to generate per-FDCA, to oxidize DFF to form the desired product subsequently. Overall, the enzyme-mediated oxidation of DFF to FDCA may become relevant in biorefineries if improvements in the enzyme stability (against H<sub>2</sub>O<sub>2</sub> and peracids), as well as in process conditions (e.g., H<sub>2</sub>O<sub>2</sub> and substrate addition, downstream, etc.) are adequately tuned.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 4","pages":"1058–1066 1058–1066"},"PeriodicalIF":3.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842401","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}
引用次数: 0
From Lab Procedure to Industrial Reality: Continuous Flow Diisobutylaluminum Hydride Reduction of Esters to Aldehydes
IF 3.1 3区 化学
Organic Process Research & Development Pub Date : 2025-03-13 DOI: 10.1021/acs.oprd.4c0035710.1021/acs.oprd.4c00357
Marina Ciriani*, Bas Ritzen, Thomas Schmitges, Raf Reintjens, Peter Hermsen and Ruben van Summeren, 
{"title":"From Lab Procedure to Industrial Reality: Continuous Flow Diisobutylaluminum Hydride Reduction of Esters to Aldehydes","authors":"Marina Ciriani*,&nbsp;Bas Ritzen,&nbsp;Thomas Schmitges,&nbsp;Raf Reintjens,&nbsp;Peter Hermsen and Ruben van Summeren,&nbsp;","doi":"10.1021/acs.oprd.4c0035710.1021/acs.oprd.4c00357","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00357https://doi.org/10.1021/acs.oprd.4c00357","url":null,"abstract":"<p >The selective partial reduction of esters to the corresponding aldehydes has been a long-standing challenge in the field of chemistry due to rapid reaction kinetics, high exothermicity, and generation of unstable intermediates. Batch reactors, with their limited heat transfer capabilities, necessitate careful temperature control and prolonged dosing of DIBAL-H, typically at very low temperatures (−70 to −50 °C). This process, especially on a plant scale, can take several hours and often results in considerable over-reduction to the alcohol product despite the cryogenic conditions. As industries aim to increase productivity and efficiency, the transition from laboratory-scale processes to larger-scale manufacturing becomes crucial. Herein, we report a pilot-scale DIBAL-H reduction of an ester to the corresponding aldehyde with product output ranging from 0.72 to 1.2 kg/h using the benefits of continuous flow chemistry. Furthermore, we demonstrate the advantages of 3D metal printing in fabricating the flow reactor, heat exchangers, and static mixers, leading to a straightforward scale-up of this highly reactive and exothermic chemical process demanding excellent heat and mass transfer properties.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 3","pages":"640–649 640–649"},"PeriodicalIF":3.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666901","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}
引用次数: 0
From Lab Procedure to Industrial Reality: Continuous Flow Diisobutylaluminum Hydride Reduction of Esters to Aldehydes
IF 3.4 3区 化学
Organic Process Research & Development Pub Date : 2025-03-13 DOI: 10.1021/acs.oprd.4c00357
Marina Ciriani, Bas Ritzen, Thomas Schmitges, Raf Reintjens, Peter Hermsen, Ruben van Summeren
{"title":"From Lab Procedure to Industrial Reality: Continuous Flow Diisobutylaluminum Hydride Reduction of Esters to Aldehydes","authors":"Marina Ciriani, Bas Ritzen, Thomas Schmitges, Raf Reintjens, Peter Hermsen, Ruben van Summeren","doi":"10.1021/acs.oprd.4c00357","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00357","url":null,"abstract":"The selective partial reduction of esters to the corresponding aldehydes has been a long-standing challenge in the field of chemistry due to rapid reaction kinetics, high exothermicity, and generation of unstable intermediates. Batch reactors, with their limited heat transfer capabilities, necessitate careful temperature control and prolonged dosing of DIBAL-H, typically at very low temperatures (−70 to −50 °C). This process, especially on a plant scale, can take several hours and often results in considerable over-reduction to the alcohol product despite the cryogenic conditions. As industries aim to increase productivity and efficiency, the transition from laboratory-scale processes to larger-scale manufacturing becomes crucial. Herein, we report a pilot-scale DIBAL-H reduction of an ester to the corresponding aldehyde with product output ranging from 0.72 to 1.2 kg/h using the benefits of continuous flow chemistry. Furthermore, we demonstrate the advantages of 3D metal printing in fabricating the flow reactor, heat exchangers, and static mixers, leading to a straightforward scale-up of this highly reactive and exothermic chemical process demanding excellent heat and mass transfer properties.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"22 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143608543","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}
引用次数: 0
Efficient and Scalable Diastereoselective Synthesis of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol Hydrochloride
IF 3.4 3区 化学
Organic Process Research & Development Pub Date : 2025-03-11 DOI: 10.1021/acs.oprd.4c00462
Rulin Zhao, Zhenqiu Hong, Bei Wang, Daniel Smith, Joseph M. Pawluczyk, Shishir Chourey, Roshan Y Nimje, Basavraj Koli, Manibalan Chidambaram, Ramakrishna Panchakharla, Anuradha Gupta, Pravin Shirude, Brian Fink, James Kempson, Arvind Mathur
{"title":"Efficient and Scalable Diastereoselective Synthesis of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol Hydrochloride","authors":"Rulin Zhao, Zhenqiu Hong, Bei Wang, Daniel Smith, Joseph M. Pawluczyk, Shishir Chourey, Roshan Y Nimje, Basavraj Koli, Manibalan Chidambaram, Ramakrishna Panchakharla, Anuradha Gupta, Pravin Shirude, Brian Fink, James Kempson, Arvind Mathur","doi":"10.1021/acs.oprd.4c00462","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00462","url":null,"abstract":"An efficient large-scale synthesis of <b>2a</b>·HCl, a key fragment to several KRAS inhibitors, is described. Optimization to a previously reported racemic route by Merck includes the development of a catalytic exocyclic olefin oxidation using RuCl<sub>3</sub>/NaIO<sub>4</sub>, followed by a highly diastereoselective reduction of the resulting ketone. A second-generation approach was then developed. The highlight of this synthesis includes a one-step intramolecular nucleophilic ring cyclization of <b>35a</b> or <b>35b</b> via a stable chelate with lithium cation <b>38</b> to give a stereoselective product, bicyclic scaffold <b>36a,</b> with excellent diastereoselectivity and good yields. Consecutive deoxyfluorination followed by the reduction of benzyl ester <b>37a</b> afforded <b>2a</b>·HCl without the need for chiral separation utilized in the first-generation approach.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"49 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599047","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}
引用次数: 0
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
相关产品
×
本文献相关产品
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信