Organic Process Research & Development最新文献_第2页

Stereoselective and Scalable Synthesis of Potent Antibiotic RSC-435830 Through a Key Intermediate C2 (S)-Methylcephalosporin 通过关键中间体C2 (S)-甲基头孢菌素立体选择性和可扩展合成强效抗生素RSC-435830

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-05-30 DOI: 10.1021/acs.oprd.5c00111

Shinya Hisakawa, Katsuki Yokoo, Shinichiro Hara, Toshiaki Aoki, Jun Sato, Hiroki Kusano, Yoshifumi Kusumoto, Kenji Yamawaki

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Up-Scale Pseudotelescopic Photoinduced Arndt-Eistert α-Amino Acid Homologation in a Flow Reactor Cascade 流动反应器级联中伪伸缩光诱导α-氨基酸同源性的研究

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-05-30 DOI: 10.1021/acs.oprd.5c00061

Viacheslav V. Pendiukh, Hanna V. Yakovleva, Ivan A. Stadniy, Olexandr Ye Pashenko, Olesia B. Volovenko, Alexander B. Rozhenko, Serhiy V. Ryabukhin, Dmytro M. Volochnyuk

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Rapid Development of a Scalable Reduction of R-Carvone Utilizing Commercially Available Biocatalysts 利用市售生物催化剂可伸缩还原r -香芹酮的快速发展

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-05-29 DOI: 10.1021/acs.oprd.5c00116

Shane M. McKenna, David T. George, Yichen Tan

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Exploring New Reactions with an Accessible High-throughput Screening (Open-HTS) Chemical Robotic System 利用可访问的高通量筛选（Open-HTS）化学机器人系统探索新反应

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-05-28 DOI: 10.1021/acs.oprd.5c00027

Heming Jiang, Ying Chen, Meirong Huang, Tingjun Liu, Yun-Dong Wu, Xinhao Zhang

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Scaling Helicene Synthesis via Photochemical Oxidation─A Comparison between Batch and Flow Reactors 光化学氧化催化合成螺旋烯─间歇反应器与流动反应器之比较

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-05-28 DOI: 10.1021/acs.oprd.5c00038

Patrick Hewitt, John H. Dunlap, Vikas Varshney, Luke A. Baldwin, Davide L. Simone

{"title":"Scaling Helicene Synthesis via Photochemical Oxidation─A Comparison between Batch and Flow Reactors","authors":"Patrick Hewitt, John H. Dunlap, Vikas Varshney, Luke A. Baldwin, Davide L. Simone","doi":"10.1021/acs.oprd.5c00038","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00038","url":null,"abstract":"Helicenes are a class of helically chiral, aromatic molecules that are often functionalized and are of interest for a variety of applications due to their axial chirality. However, their syntheses are typically conducted under high dilution conditions to prevent undesirable side reactions and require large volumes of solvent, which makes scaling up a challenge. This study discusses the challenges of scaling helicene syntheses and offers facile strategies to address some of these challenges. The increased interest for using helicenes to address materials, sensing, and electronic applications necessitates that strategies for scaling them effectively with high purity need to be developed. It is well-known that flow chemistry facilitates more reproducible, scalable, safe, and efficient options for chemical synthesis, making it a valuable tool in both academic and industrial settings, as it allows for precise control over reaction conditions such as stoichiometry, mixing, temperature, and reaction time, leading to greater yields and better selectivity for a variety of reaction classes. Using quantitative 1H-NMR and isolated yields of the desired product and notable side products, we evaluated three reactor systems: 1L-batch, 5L-batch, and flow reactors towards the synthesis of a [5]-helicene tetraester (5HLTE). After initial optimization, the optimal conditions were used to demonstrate the scalability and provided throughput of ∼5 g/day in a 5 mL reactor flow system, scaling linearly with reactor volume. Discrete control of purity is vital for these applications in that impurities may provide incorrect structure–property conclusions when applied to organic electronics and polymer mechanical properties.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"4 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153432","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}

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Lessons Learned in Developing a Manufacturing Facility for Flow Chemistry 开发流动化学制造设备的经验教训

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-05-28 DOI: 10.1021/acs.oprd.5c00082

Hirotsugu Usutani

{"title":"Lessons Learned in Developing a Manufacturing Facility for Flow Chemistry","authors":"Hirotsugu Usutani","doi":"10.1021/acs.oprd.5c00082","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00082","url":null,"abstract":"Specific designs are necessary when installing manufacturing facilities for active pharmaceutical ingredient (API) plants, especially for scaling up manufacturing using flow chemistry. Each flow reactor is a device focused on an intended reaction. However, due to the required heat exchange (heating or cooling), the parts responsible for carrying out the reactions (the flow reactor itself) are often enclosed in a jacket or setup in a way that makes it difficult to verify the internal structure from the external view. In this paper, we present a case where a piping error made during the installation of a flow system, designed for oxidation reactions with heating, led to a subsequent manufacturing failure, as the error went undetected before operation was started. In retrospect, it would have been possible to identify the piping error ahead of starting manufacture, based on data, such as the internal pressures, obtained during the premanufacturing test. Specifically, the mistake highlighted the importance of identifying the flow lines with ″synchronized internal pressures″ and prediction of the flow lines where the internal pressure is expected to be at its highest or lowest. It is thought that our observations regarding the failure offer an example for OPR&D’s special issue on ‘Lessons Learned in Organic Process Chemistry’ and the details will be disclosed.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"101 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144165686","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}

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Quantitative Gas Evolution Analysis via Combination of Online Thermal Mass Flow and Mass Spectrometry Data 结合在线热质量流和质谱数据的定量气体演化分析

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-05-27 DOI: 10.1021/acs.oprd.5c00098

Frank Dixon, Jr., Roy C. Flanagan

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Drug Substance and Drug Product Workflows for Quality Risk Management for the Presence of Nitrosamines in Medicines 药品中存在亚硝胺的原料药和药品质量风险管理工作流程

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-05-23 DOI: 10.1021/acs.oprd.5c00097

Olivier Dirat, Michael W. Urquhart, Heather Akehurst, Michael J. Burns, Krista L. Dobo, James Harvey, Nadine Kuhl, Joerg Schlingemann, Paula Tomlin, Christian Wetter

{"title":"Drug Substance and Drug Product Workflows for Quality Risk Management for the Presence of Nitrosamines in Medicines","authors":"Olivier Dirat, Michael W. Urquhart, Heather Akehurst, Michael J. Burns, Krista L. Dobo, James Harvey, Nadine Kuhl, Joerg Schlingemann, Paula Tomlin, Christian Wetter","doi":"10.1021/acs.oprd.5c00097","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00097","url":null,"abstract":"The ICH M7 guidance “Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk” requires that drug substances and drug products be assessed for potential mutagens including N-nitroso compounds. N-Nitrosamines are a class of N-nitroso compounds within the cohort of concern as defined in ICH M7 because they can display carcinogenic potency with acceptable intakes in the range of ng/day rather than μg/day. Therefore, control to levels below the ICH M7 threshold of toxicological concern may be required. Following the detection of certain simple N-nitrosamines in marketed medicines between 2018 and 2019, health authorities requested that marketing authorization holders assess all their products (both chemical entities and biologics) for the presence of N-nitrosamines. It became important to establish scientifically robust and reliable approaches for the assessment of small molecule drug substances and products for the potential presence or formation of N-nitrosamines. Included are workflows and associated guidance to enable the reader to risk assess drug substances and drug products that contain chemical entities for the potential presence or formation of N-nitrosamines. These workflows and guidance are the culmination of five years of cross industry collaborations. They are based on known and emerging risk factors for the presence and formation of N-nitrosamines. In combination with regulatory guidance, these are considered as a “best practice” within the Pharmaceutical Industry for conducting drug substance and drug product assessments.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"12 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144130442","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

Coamorphous Solid Dispersion of a Soluble Epoxide Hydrolase Inhibitor t-TUCB with Amino Acid l-Arginine 可溶性环氧化物水解酶抑制剂t-TUCB与l-精氨酸的共晶固体分散

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-05-21 DOI: 10.1021/acs.oprd.5c00096

Sung Hee Hwang, Karen M. Wagner, Jun Yang, Christophe Morisseau, Debin Wan, James C. Fettinger, Marilyn M. Olmstead, Bruce D. Hammock

{"title":"Coamorphous Solid Dispersion of a Soluble Epoxide Hydrolase Inhibitor t-TUCB with Amino Acid l-Arginine","authors":"Sung Hee Hwang, Karen M. Wagner, Jun Yang, Christophe Morisseau, Debin Wan, James C. Fettinger, Marilyn M. Olmstead, Bruce D. Hammock","doi":"10.1021/acs.oprd.5c00096","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00096","url":null,"abstract":"Inhibitors of soluble epoxide hydrolase (sEHIs) have been of interest for treating various diseases in humans and animals. Therefore, various sEHIs have been investigated in several clinical trials. Here, we report the development of a coamorphous solid dispersion of an sEHI t-TUCB with the amino acid l-arginine. t-TUCB has a very low aqueous equilibrium solubility (0.031 ± 0.013 μg/mL in pH 6.6 DI water) but possesses free carboxylic acid. Thus, converting t-TUCB to the corresponding sodium salt improved the water solubility (1.2 mg/mL). However, the sodium salt tended to form insoluble t-TUCB sodium salt aggregates, which is problematic for the scale-up of the sodium salt. However, adding l-arginine can deaggregate t-TUCB sodium salt aggregates. Moreover, the basicity of l-arginine allows us to prepare solid dispersion of t-TUCB directly, which forms a coamorphous system. The coamorphous solid dispersion of t-TUCB with l-arginine at a ratio of 1:3 (t-TUCB/Arg (1:3) solid dispersion) not only improved the water solubility (2.2 mg/mL) and dissolution profile (>80% in 10 min) of t-TUCB but also solved the problem of forming insoluble heavy aggregates associated with the sodium salt of t-TUCB. Therefore, the t-TUCB/Arg (1:3) solid dispersion obtained showed 87.1% bioavailability and alleviated LPS-induced pain in rats when orally administered.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"136 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114425","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

Machine Learning-Driven Optimization of Continuous-Flow Photoredox Amine Synthesis 连续流光氧化还原胺合成的机器学习驱动优化

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-05-21 DOI: 10.1021/acs.oprd.4c00533

Perman Jorayev, Sebastian Soritz, Simon Sung, Mohammed I. Jeraal, Danilo Russo, Alexandre Barthelme, Frédéric C. Toussaint, Matthew J. Gaunt, Alexei A. Lapkin

{"title":"Machine Learning-Driven Optimization of Continuous-Flow Photoredox Amine Synthesis","authors":"Perman Jorayev, Sebastian Soritz, Simon Sung, Mohammed I. Jeraal, Danilo Russo, Alexandre Barthelme, Frédéric C. Toussaint, Matthew J. Gaunt, Alexei A. Lapkin","doi":"10.1021/acs.oprd.4c00533","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00533","url":null,"abstract":"Photoredox catalysis plays an important role in the synthesis of pharmaceutically relevant compounds such as C(sp3)-rich tertiary amines. The difficulty of identifying underlying mechanistic models for such novel transformations, coupled with the large reaction space of this reaction class, means that developing a robust process is challenging. In this work, we demonstrate the machine learning-driven optimization of a photoredox tertiary amine synthesis with six continuous variables (e.g., concentration, temperature, residence time) and solvent choice as a discrete variable, in a semiautomated continuous flow setup. Starting with a large library of solvents, the workflow included multiple steps of a priori knowledge generation (e.g., solubility predictions) to narrow the discrete space. A novel Bayesian optimization algorithm, nomadic exploratory multiobjective optimization (NEMO), was then deployed to identify and populate the Pareto front for the two reaction objectives─yield and reaction cost. Permutation feature importance and partial dependence plots identified the most important parameters for high yield, sig3, the asymmetry of the s-profile for the discrete space, and equivalences of alkene and Hantzsch ester for the continuous variables. Catalyst loading and residence time were found to be correlated to absorbed photon equivalence, while catalyst loading was additionally the main parameter to drive cost. Even though productivity was not an optimization objective, the best result achieved in flow was ∼25 times higher than reactions in batch, which equals to ∼12 g per day throughput.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"11 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144104020","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