Organic Process Research & Development最新文献

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

引用次数: 0

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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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}

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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

Development of a Manufacturing Process for S-892216 Part I: A Novel Method for Constructing a Multi-Substituted Barbiturate Skeleton for Scalable Synthesis S-892216制备工艺的发展第一部分：构建多取代巴比妥酸盐骨架的新方法

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-05-20 DOI: 10.1021/acs.oprd.5c00071

Naoto Sahara, Yoichi Hirano, Thien Phuc Le, Katsuya Yamakawa, Eisaku Ohashi, Satoru Shibuya, Kazuo Komano, Keiichiro Hirai, Moriyasu Masui, Go Kato, Takafumi Higuchi, Yuto Shimazaki, Takahiro Kawajiri, Tadashi Oohara, Naoki Tsuno, Takafumi Ohara

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MicroPhotoGas Reactor: High-Throughput Experimentation for Photoinduced Reactions under a Gas Atmosphere 微光气反应器：气体环境下光诱导反应的高通量实验

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-05-19 DOI: 10.1021/acs.oprd.5c00118

Sylvain Foucquart, Taline Kerackian, Géraud Chacktas, Jean-Christophe Cintrat, Eugénie Romero

引用次数: 0

Determining the Influence of Particle Size and Surface Area on the Measured Minimum Ignition Energy of Pharmaceutical Powders 测定粒径和表面积对药粉最小点火能的影响

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-05-15 DOI: 10.1021/acs.oprd.5c00052

Rafaela Costa Carmona, Rachel Duong, John F. Gamble, Lauren N. Grant, Helen Hughes, Simon Shun Wang Leung, Michael Tobyn, Linda Zheng

{"title":"Determining the Influence of Particle Size and Surface Area on the Measured Minimum Ignition Energy of Pharmaceutical Powders","authors":"Rafaela Costa Carmona, Rachel Duong, John F. Gamble, Lauren N. Grant, Helen Hughes, Simon Shun Wang Leung, Michael Tobyn, Linda Zheng","doi":"10.1021/acs.oprd.5c00052","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00052","url":null,"abstract":"Dust explosions constitute a significant risk in many industries. To identify materials for which mitigation strategies are required, information about the relative risk for each material is required. Such information will include characteristics such as the minimum ignition energy (MIE), but material availability represents a significant challenge for the pharmaceutical industry at early stages of development. These challenges contrast with the relatively high material requirements for risk characterization. To this end, there is significant interest in the application of models to predict MIE. The aims of this study were 2-fold. The first stage was to assess the predictive strength of a published MIE prediction model for a range of pharmaceutical powders. The second stage of the study was to investigate the role of particle size for a series of samples of ‘constant chemistry’ and varying size. The results demonstrate that the model provided ‘safe’ results for half the materials tested while the accuracy of the model was unsatisfactory. The results showed that the risk was often overestimated; thereby, the work required for safety mitigation would not add value to the process, or underestimated, raising the risk of inadequate safety mitigation. When the chemistry of the materials was maintained constant, significant differences in the relationship of particle size and surface area with the measured MIE were demonstrated. Overall, the work suggests that the relative influence of chemistry and particle properties on MIE shows notable differences between materials, thereby affecting the ability of the assessed model to accurately predict MIE.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"53 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144000630","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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A Concise Flow Synthesis of the IKZF2 Glue Degrader DKY709 IKZF2型胶水降解剂DKY709的简洁流动合成

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-05-15 DOI: 10.1021/acs.oprd.4c00476

Xu You, Xu-Lun Huang, Hailong Ren, Chunrui Wu, Dahai Wang

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