Organic Process Research & Development最新文献

{"title":"Selective and Scalable O-Alkylation of Serine and Threonine Enabled by Chelation-Controlled Reductive C–N Cleavage of N,O-Acetals","authors":"Keisuke Nogi, Masao Tsukazaki, Hiroshi Iwamura, Kenji Maeda","doi":"10.1021/acs.oprd.4c00543","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00543","url":null,"abstract":"A selective and scalable <i>O</i>-alkylation method has been developed for the synthesis of a series of <i>O</i>-alkyl serine and threonine derivatives as useful unnatural amino acids. The use of Ti(IV) species capable of bis-ligation enables chelation-controlled reductive C–N cleavage of <i>N</i>,<i>O</i>-acetal intermediates to afford the corresponding <i>O</i>-alkylated product. Moreover, <i>N</i>-alkylated byproducts are selectively decomposed under basic conditions and removed by extraction and crystallization, thus eliminating laborious column chromatography processes in scale-up synthesis.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"71 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703679","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":"On Scalability, Synthetic Efficiency, and Convergency","authors":"Vittorio Farina","doi":"10.1021/acs.oprd.5c00030","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00030","url":null,"abstract":"Terms like <i>scalability</i>, <i>synthetic efficiency</i>, and <i>convergency</i> are often used by development chemists to qualify the merits of their processes. However, these are often qualitative designations, devoid of any quantitative assessment. We propose some guidelines to support the judicious use of these terms. In particular, we would like to bring to the attention of process chemists the work of J. B. Hendrickson, who─almost 50 years ago─first proposed a meaningful quantitative evaluation of a synthetic plan and defined <i>consistency</i> and <i>convergency</i> in a quantitative way. After a brief analysis of the term <i>scalability</i>, this perspective presents a simplified version of Hendrickson’s ideas and extends it to multicomponent reactions. The metrics proposed herein are very easy to use and should allow chemists to verify the efficiency of their synthetic plan by calculating a <i>consistency index</i> and a <i>convergency index</i> which could complement qualitative descriptors like “efficient process” or “highly convergent synthesis”.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"33 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666357","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":"Industrial Case Studies Demonstrating Applicability of ICH M7 Control Options 3 and 4 for Nitrosamine Control","authors":"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, Andrew Whitehead","doi":"10.1021/acs.oprd.5c00042","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00042","url":null,"abstract":"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.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"70 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666358","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":"Excellence in Industrial Organic Synthesis 2024","authors":"Bernd Schaefer, Shashank Shekhar, James Murray","doi":"10.1021/acs.oprd.5c00049","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00049","url":null,"abstract":"Published as part of &lt;i&gt;Organic Process Research &amp; Development&lt;/i&gt; special issue “Excellence in Industrial Organic Synthesis 2024”. In the chemical industry, alongside the discovery of new substances and their properties, the development and optimization of chemical reactions and processes play a decisive role, not least for economic reasons. (1,2) This is nothing new. The interplay between research and development, and thus the pursuit of excellence in chemistry, has characterized the industry from the very beginning and will certainly continue to make a decisive contribution in the future, mastering the major challenges we are currently facing, from the demand for increased sustainability and efficient CO&lt;sub&gt;2&lt;/sub&gt; management to the changes in the supply of raw materials and energy. The conceptual foundations of excellence in chemistry can be traced back to the principle of parsimony by William of Ockham (1286–1347), a medieval Franciscan monk, and on his proverbial razor, in which he summed up the motivation of optimization in a single sentence: “It is futile to do with more what can be done with fewer” (Lat.: “&lt;i&gt;Frustra fit per plura, quod potest fieri per pauciora&lt;/i&gt;”). (3,4) In accordance with this concept, James B. Hendrickson (1928–2018) outlined his ideas on the logic of organic chemistry and &lt;i&gt;ideal synthesis&lt;/i&gt; already in 1975. (5,6) Barry Trost’s thoughts on &lt;i&gt;atom economy&lt;/i&gt; followed in the early 1990s, while Paul A. Wender came up with function-oriented synthesis and &lt;i&gt;step economy&lt;/i&gt; in 2008 (7) and Phil Baran and Reinhard Hoffmann with &lt;i&gt;redox economy&lt;/i&gt; at almost the same time. (8) In parallel, Roger A. Sheldon emphasized the need for a new paradigm in the evaluation of efficiency in chemical production, assigning value not only to chemical yield but also to waste minimization. By developing the E-factor concept, which is now used throughout the industry in one form or another, he brought &lt;i&gt;elegance and precision&lt;/i&gt; to large-scale production. (9−11) In this respect, it is perhaps not too surprising that some of these elegant processes have already been in operation for a while. As examples one may consider Evonik’s methionine production, BASF’s citral synthesis, and Rhodia’s vanillin process. (12) Taking James Hendrickson’s thoughts on the &lt;i&gt;ideal synthesis&lt;/i&gt; as a starting point, this year we can indeed celebrate 50 years of excellence in industrial organic synthesis. Articles included in this Special Issue cover a wide variety of research topics such as discussion on strategies for kilogram-scale synthesis with emphasis on safety, robustness, and sustainability, flow and impinging-jet technologies, new catalytic methods, integration of Process Analytical Technologies (PAT) for solid-phase peptide synthesis, and green chemistry to name a few. These outstanding contributions provide an exquisite overview of the current state of the art and certainly pave the way for further improvements. Consistent with earlie","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"34 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666359","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":"Excellence in Industrial Organic Synthesis 2024","authors":"Bernd Schaefer*,&nbsp;Shashank Shekhar* and James Murray*,&nbsp;","doi":"10.1021/acs.oprd.5c0004910.1021/acs.oprd.5c00049","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00049https://doi.org/10.1021/acs.oprd.5c00049","url":null,"abstract":"","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 3","pages":"601–602 601–602"},"PeriodicalIF":3.1,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666977","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":"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}