Organic Process Research & Development最新文献_第6页

Autonomous Optimization of Continuous-Flow Clothianidin Synthesis via Dynamic Kinetic Modeling and Multiobjective Bayesian Optimization 基于动力学建模和多目标贝叶斯优化的噻虫胺连续流合成自主优化

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-09-18 Epub Date: 2026-08-14 DOI: 10.1021/acs.oprd.6c00272

Jiapeng Guo, Xiaorong Lu, Kang Cao, Guihua Luo, Bin Shen, Yuwei Song, Weike Su, An Su

{"title":"Autonomous Optimization of Continuous-Flow Clothianidin Synthesis via Dynamic Kinetic Modeling and Multiobjective Bayesian Optimization","authors":"Jiapeng Guo, Xiaorong Lu, Kang Cao, Guihua Luo, Bin Shen, Yuwei Song, Weike Su, An Su","doi":"10.1021/acs.oprd.6c00272","DOIUrl":"10.1021/acs.oprd.6c00272","url":null,"abstract":"We report the continuous flow synthesisof clothianidinas a modelsystem, in which a reaction kinetic model was rapidly establishedthrough dynamic experiments. However, kinetic modeling alone providesno strategy for resolving trade-offs between conflicting objectives.Multiobjective Bayesian optimization (MOBO) addresses this gap bymapping the Pareto front across the parameter space, with the kineticmodel serving as a virtual experiment surrogate within the iterativecycle to replace physical experiments entirely. The coupled frameworksimultaneously minimized the E-factor and maximized the productionrate, yielding a well-resolved Pareto front that quantifies the trade-offbetween these two objectives. Optimization was further extended toa pilot-scale continuous flow system incorporating a static mixer,with transfer learning employed to leverage prior knowledge and reduceexperimental burden at the new scale. A maximum production rate of1.32 g/min and a minimum E-factor of 1.53 were achieved via Meta-Learning-assistedMOBO (Meta-MOBO), with an average reaction yield of approximately79.8% across the scale-up optimization. These results demonstratethat coupling kinetic modeling with MOBO and transfer learning offersan efficient and scalable strategy for bridging laboratory-scale synthesisand industrial production.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 9","pages":"2565–2575"},"PeriodicalIF":3.3,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148726402","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 Scalable and Safe Synthesis of Ramelteon: Integrating Batch Steps with Asymmetric Hydrogenation and Microreactor Technology 一种可扩展和安全的Ramelteon合成方法：不对称加氢和微反应器技术集成的间歇步骤

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-09-18 Epub Date: 2026-08-17 DOI: 10.1021/acs.oprd.5c00521

Renbing Wang, Wenjie Yu, Chen Yang, Kaiyu Gao, Jiale Hu, Rui Zhang, Junyin Liu, Ruitong Zhao, Lexi Niao, Chengyang Li, Liuxiang Zhu, Zhiyu Li, Xi Xu, Zhisheng Zhang, Jubo Wang

{"title":"A Scalable and Safe Synthesis of Ramelteon: Integrating Batch Steps with Asymmetric Hydrogenation and Microreactor Technology","authors":"Renbing Wang, Wenjie Yu, Chen Yang, Kaiyu Gao, Jiale Hu, Rui Zhang, Junyin Liu, Ruitong Zhao, Lexi Niao, Chengyang Li, Liuxiang Zhu, Zhiyu Li, Xi Xu, Zhisheng Zhang, Jubo Wang","doi":"10.1021/acs.oprd.5c00521","DOIUrl":"10.1021/acs.oprd.5c00521","url":null,"abstract":"Ramelteon,a melatonin receptor agonist approved by the FDA in2005 for the treatment of insomnia, serves as the focus of this study.We present a comprehensive investigation into the development of anadvanced and efficient synthetic route for ramelteon, enabling batch-scaleproduction of the active pharmaceutical ingredient (API) to meet commercialdemands. The four-step synthetic sequence commences with commerciallyavailable 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (2), proceeding through: Wittig–Hornerreaction, asymmetric hydrogenation of the α,β-unsaturated nitrile double bond, continuous-flow microfluidic hydrogenationfor nitrile reduction, and N-propionylation. Thesynthesized ramelteon exhibited exceptional quality, with a chromatographicpurity exceeding 99.9% (by area normalization), enantiomeric excess(ee) >99.9%, and an overall yield of 40%. A key advantage of thisapproach is its circumvention of the conventional high-pressure batchhydrogenation typically employed in industrial ramelteon synthesis.Furthermore, the developed protocol demonstrates potential applicabilityfor the reduction of other α,β-unsaturatednitrile pharmaceutical intermediates. This scalable and high-efficiencysynthetic strategy not only establishes safer production conditionsfor ramelteon manufacturing but also provides novel insights intothe catalytic reduction of α,β-unsaturatednitriles in pharmaceutical synthesis.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 9","pages":"2435–2446"},"PeriodicalIF":3.3,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148767011","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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Synthesis of N-Linked Amino-Hexyl Fluorotryptophan for Enlicitide, Part 1: Route Scouting enenicitide的N-Linked氨基己基氟色氨酸合成，第一部分：路线探索

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-09-18 Epub Date: 2026-09-02 DOI: 10.1021/acs.oprd.6c00255

Jeffrey T. Kuethe, Byron K. Peters, Keywan A. Johnson, Kai-Jiong Xiao, Yingju Xu, Stephen M. Dalby, Artis Klapars, Yonghee Lee, Weidong Tong, Erica L. Schwalm, Yongqian Zhang

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Recent Advances in the Synthesis of Citronellal from Citral 以柠檬醛为原料合成香茅醛的研究进展

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-09-18 Epub Date: 2026-08-17 DOI: 10.1021/acs.oprd.6c00235

Xingxing Zhang, Yetao Hu, Yang Yang, Hao Zhan, Liuzeng Chen, Bin Li, Xue Song, Banfeng Ruan

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Evolution of a Synthetic Strategy toward Highly Substituted Isoindolinone Glutarimide Fragments 高取代异吲哚酮戊二酰亚胺片段合成策略的演变

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-09-18 Epub Date: 2026-08-31 DOI: 10.1021/acs.oprd.6c00316

Anthony T. Tam, Allen Y. Hong, Yu-Hsiang Chang, Jacob C. Timmerman, Matthew M. Pompeo, Robert D. Gilbert, Haiming Zhang, Chong Han

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Synthesis of N-Linked Amino-Hexyl Fluorotryptophan for Enlicitide, Part 2: Process Improvements toward Commercial Manufacture enenicitide的N-Linked氨基己基氟色氨酸合成，第二部分：商业化生产的工艺改进

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-09-18 Epub Date: 2026-08-31 DOI: 10.1021/acs.oprd.6c00256

Kai-Jiong Xiao, Yingju Xu, Alexandra C. Sun, Eric Sirota, Byron K. Peters, Jeffrey T. Kuethe, Timothy J. Wright, Ralph Zhao, Gurpreet Longia, Erica L. Schwalm, Yongqian Zhang, Chengqian Xiao, Yongtuan Bao, Sarah S. Co

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Recent Advances in Nonprecious Metal Catalysis 非贵金属催化研究进展

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Organic Process Research & Development Pub Date : 2026-09-18 Epub Date: 2026-08-13 DOI: 10.1021/acs.oprd.6c00229

Kristen Berger, Nathan Faialaga, Jessica Hurtak, Ruihao Li, Xu Ma, Jenna L. Payne, Jonathan R. Hall, Xuan Wu

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Practical Scale-Up of Trickle Bed Continuous Hydrogenation for Pharmaceuticals 滴流床连续加氢工艺的实际放大

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-09-18 Epub Date: 2026-08-18 DOI: 10.1021/acs.oprd.5c00499

Onkar N Manjrekar, Gregory E. Storer, Brian Kotecki, Bradley Greiner, Moiz Diwan

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Spectroscopic Monitoring and Chemometric-Based Feedback Control of the Diazotization Reaction 重氮化反应的光谱监测与化学计量学反馈控制

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-08-21 Epub Date: 2026-07-09 DOI: 10.1021/acs.oprd.6c00030

Máté Fent, Attila Farkas, Hajnalka Pataki, Zsombor K. Nagy, István Csontos

{"title":"Spectroscopic Monitoring and Chemometric-Based Feedback Control of the Diazotization Reaction","authors":"Máté Fent, Attila Farkas, Hajnalka Pataki, Zsombor K. Nagy, István Csontos","doi":"10.1021/acs.oprd.6c00030","DOIUrl":"10.1021/acs.oprd.6c00030","url":null,"abstract":"Inline Raman spectroscopy-basedmonitoring enables thedevelopmentof control systems that allow the implementation of Process AnalyticalTechnology (PAT) principles even in chemical reactions, thereby improvingquality, efficiency, and safety. There are only a few articles inthe literature that discuss such control systems. This may be dueto the numerous challenges involved, including the need for robustmeasurement setups and the development of chemometric algorithms capableof delivering accurate and stable real-time evaluations. Thus, thisstudy presents the Raman spectroscopic monitoring and chemometric-basedfeedback control of a highly exothermic and potentially hazardousdiazotization reaction, namely, the synthesis of phenyldiazonium chloridefrom aniline, hydrochloric acid, and sodium nitrite. Raman spectrawere analyzed offline using Multivariate Curve Resolution-AlternatingLeast Squares (MCR-ALS) and in real-time using Classical Least Squares(CLS) chemometric methods to monitor and control key reaction components.The developed feedback system successfully controlled concentrationlevels during both acid–base and diazotization phases. Thereduction of the Raman signal-to-noise ratio, induced by the decompositionof the diazonium salt, was also observed. This factor significantlyaffected the monitoring of the diazotization experiment. Furthermore,a calibration was established to quantify the molar concentrationsof key components based on Raman spectra. The calibration experimentsuccessfully demonstrated well-fitted linear molar–spectralrelationships for both aniline (R2homogeneous = 0.997; R2heterogeneous = 0.9947) and aniline hydrochloride (R2 = 0.9987). For aniline, the molar–spectral relationship exhibiteda distinct change in tendency that precisely correlated with its solubilitylimit in water, marking the transition from homogeneous solution toemulsion.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 8","pages":"2149–2158"},"PeriodicalIF":3.3,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148408354","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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Versatile Construction of a 4-Substituted Piperidine by Continuous Preparation of a Complex Grignard and Addition to an In Situ Generated Pyridinium Species 通过连续制备络合物Grignard和添加原位生成的吡啶类化合物构建4-取代哌啶的多用途结构

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-08-21 Epub Date: 2026-07-27 DOI: 10.1021/acs.oprd.6c00252

Tyler K. Allred, Matthew Cook, Moshood Ganiu, Francesco Manoni, Nicholas Klitzing, Daniel J. Griffin, Michael J. Frohn, James I. Murray, Matthew G. Beaver, David Bauer

{"title":"Versatile Construction of a 4-Substituted Piperidine by Continuous Preparation of a Complex Grignard and Addition to an In Situ Generated Pyridinium Species","authors":"Tyler K. Allred, Matthew Cook, Moshood Ganiu, Francesco Manoni, Nicholas Klitzing, Daniel J. Griffin, Michael J. Frohn, James I. Murray, Matthew G. Beaver, David Bauer","doi":"10.1021/acs.oprd.6c00252","DOIUrl":"10.1021/acs.oprd.6c00252","url":null,"abstract":"A robust and enabling synthesis ofa sterically encumbered4-substitutedpiperidine, a common motif in a novel KRAS G12C inhibitor series,was developed. It was discovered that the critical congested C–Cbond could be forged by the regioselective addition of a functionalizedGrignard reagent to an N-carbamyl pyridinium species.Kinetic studies demonstrated that the Grignard species was inherentlyunstable, leading to diminished yields in large-scale batch processes.A semicontinuous reactor train was developed to generate the Grignardcontinuously using a plug flow reactor, which flowed directly intoa stirred reactor containing the preformed pyridinium species. Thissystem was utilized to produce >100 g quantities of the Grignardadductin a single operation, which could be converted to the desired 4-substitutedpiperidine in two additional steps. Further studies determined thatregioselectivity was governed by the steric environment of the nucleophilicGrignard species.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 8","pages":"2367–2376"},"PeriodicalIF":3.3,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148596104","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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