Organic Process Research & Development最新文献

{"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}

{"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}

{"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 (H₂O₂) 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 H₂O₂ 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 CO₂ 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 H₂O₂ and peracids), as well as in process conditions (e.g., H₂O₂ 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}

{"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}

{"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}

{"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 RuCl₃/NaIO₄, 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}

{"title":"Some Issues and Their Solutions in the Process Development of Ethyl 2-(4-Aminophenoxy)thiazole-5-carboxylate: A Key Intermediate of P2X3 Antagonist","authors":"Masahiro Hosoya, Toshikatsu Maki, Takayuki Tsuritani","doi":"10.1021/acs.oprd.5c00015","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00015","url":null,"abstract":"Ethyl 2-(4-aminophenoxy)thiazole-5-carboxylate is a key intermediate of several P2X₃ antagonists required for clinical trials. The synthesis at the early R&amp;D stage delivered this thiazole derivative via a nucleophilic aromatic substitution reaction in highly variable yields, from 7 to 85%. We describe the process development of the initial route of synthesis carefully considering the reaction conditions, process robustness and safety, operational improvement, and the impact on downstream steps. The optimized process was successfully replicated on a multikg scale in a pilot plant, allowing for the supply of the key intermediate in 90% isolated yield with high purity (&gt;99 area%).","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"68 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143600019","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":"Impact of Reactant Dissolution in the Kinetics of a Catalytic Hydrogenation for the Production of Argatroban","authors":"Filippo Nanto*,&nbsp;Dario Ciato,&nbsp;Mariano Stivanello and Paolo Canu,&nbsp;","doi":"10.1021/acs.oprd.4c0047910.1021/acs.oprd.4c00479","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00479https://doi.org/10.1021/acs.oprd.4c00479","url":null,"abstract":"<p >An experimental study was performed for a fed-batch catalytic hydrogenation for the production of Argatroban. The penultimate expensive and scarcely available intermediate is characterized by a slow dissolution rate that evolves in parallel with the reaction process. The study investigated the coupling between the reaction and dissolution kinetics. In these circumstances, the standard Area Percentage method in HPLC was found to be misleading, requiring calibration and then absolute peak area measurements to correctly identify the dissolution rate and thus the actual chemical kinetics. Experiments quantified the role of the temperature, stirring rate, and catalyst loading. Shifting from 40 to 80 °C reduced the batch time by 58%, although higher temperatures promoted the formation of undesired impurities. Stirring rate controlled the initial reaction phases when reagent dissolution is critical. Catalyst loading is key in reducing batch time. The increase in catalyst loading was proved to affect the reagent dissolution rate, by increasing the collision frequency between reagent and catalyst particles. A refined first-principles model, incorporating the effect of the catalyst amount on the dissolution mass transfer coefficient, significantly improved the accuracy of dissolution predictions and enabled better identification of the intrinsic reaction kinetics. The addition of a microkinetic description further improved the predictions of intermediates and products.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 3","pages":"735–747 735–747"},"PeriodicalIF":3.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.oprd.4c00479","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666960","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":"Impact of Reactant Dissolution in the Kinetics of a Catalytic Hydrogenation for the Production of Argatroban","authors":"Filippo Nanto, Dario Ciato, Mariano Stivanello, Paolo Canu","doi":"10.1021/acs.oprd.4c00479","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00479","url":null,"abstract":"An experimental study was performed for a fed-batch catalytic hydrogenation for the production of Argatroban. The penultimate expensive and scarcely available intermediate is characterized by a slow dissolution rate that evolves in parallel with the reaction process. The study investigated the coupling between the reaction and dissolution kinetics. In these circumstances, the standard Area Percentage method in HPLC was found to be misleading, requiring calibration and then absolute peak area measurements to correctly identify the dissolution rate and thus the actual chemical kinetics. Experiments quantified the role of the temperature, stirring rate, and catalyst loading. Shifting from 40 to 80 °C reduced the batch time by 58%, although higher temperatures promoted the formation of undesired impurities. Stirring rate controlled the initial reaction phases when reagent dissolution is critical. Catalyst loading is key in reducing batch time. The increase in catalyst loading was proved to affect the reagent dissolution rate, by increasing the collision frequency between reagent and catalyst particles. A refined first-principles model, incorporating the effect of the catalyst amount on the dissolution mass transfer coefficient, significantly improved the accuracy of dissolution predictions and enabled better identification of the intrinsic reaction kinetics. The addition of a microkinetic description further improved the predictions of intermediates and products.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"32 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143600005","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":"Efficient and Scalable Diastereoselective Synthesis of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol Hydrochloride","authors":"Rulin Zhao*,&nbsp;Zhenqiu Hong,&nbsp;Bei Wang,&nbsp;Daniel Smith,&nbsp;Joseph M. Pawluczyk,&nbsp;Shishir Chourey,&nbsp;Roshan Y Nimje*,&nbsp;Basavraj Koli,&nbsp;Manibalan Chidambaram,&nbsp;Ramakrishna Panchakharla,&nbsp;Anuradha Gupta,&nbsp;Pravin Shirude,&nbsp;Brian Fink,&nbsp;James Kempson and Arvind Mathur,&nbsp;","doi":"10.1021/acs.oprd.4c0046210.1021/acs.oprd.4c00462","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00462https://doi.org/10.1021/acs.oprd.4c00462","url":null,"abstract":"<p >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 RuCl₃/NaIO₄, 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.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 3","pages":"704–715 704–715"},"PeriodicalIF":3.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143667113","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}