Organic Process Research & Development最新文献

Scalable Synthesis of Naldemedine Tosylate via O-to-C Ethoxycarbonyl Group Transfer of Carbonate

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2026-11-10 DOI: 10.1021/acs.oprd.6c00318

Youngdo Jeong,Gopathi Ramu,Yura Choe,Seung Jong Lee,Hyesung Ryu,Seung Woo Kim,Jinho Kwag,Ganganna Bogonda,Kee-Young Lee,Hyunik Shin

引用次数: 0

Continuous-Flow Chemistry at Hundreds of Grams to Hundreds of Kilogram Scale: Recent Advances in Pharmaceutical Intermediates, APIs, and Selected Fine Chemicals 数百克至数百公斤规模的连续流动化学：医药中间体，原料药和精选精细化学品的最新进展

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2026-11-09 DOI: 10.1021/acs.oprd.6c00352

Bimbisar K. Desai,Arun Asokan Vinodini

{"title":"Continuous-Flow Chemistry at Hundreds of Grams to Hundreds of Kilogram Scale: Recent Advances in Pharmaceutical Intermediates, APIs, and Selected Fine Chemicals","authors":"Bimbisar K. Desai,Arun Asokan Vinodini","doi":"10.1021/acs.oprd.6c00352","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00352","url":null,"abstract":"Continuous-flow chemistry has emerged as a transformative technology for the development and manufacture of active pharmaceutical ingredients (APIs) and advanced pharmaceutical intermediates, offering enhanced process safety, improved heat and mass transfer, reduced reactor inventory, and efficient scale-up. Numerous reviews have highlighted advances in flow chemistry methodology and laboratory-scale applications that demonstrate the potential for future scale-up; however, a critical review of recent examples demonstrating successful implementation at preparative, pilot, and manufacturing scales is of considerable interest to flow enthusiasts, and scientific and industrial communities. This review aims to summarize and critically evaluate advances reported between 2023 and 2025 in the continuous-flow synthesis of pharmaceutical intermediates, API precursors, APIs, and selected fine chemicals, with a particular focus on processes demonstrated at scales ranging from hundreds of grams to hundreds of kilograms. By focusing specifically on manufacturing-relevant published examples, this review highlights key strategies enabling successful industrial implementation and underscores the expanding role of continuous-flow technologies in pharmaceutical and fine chemical production. Representative examples are categorized into: (1) organometallic and cryogenic-sensitive chemistry, (2) hazardous and energetic transformations, (3) integrated continuous manufacturing, (4) catalytic/multiphase/reactor engineering-driven transformations, and (5) flow photochemistry.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"17 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149368392","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

Bio-Based Support for Trypsin Immobilization: Cost and Environmental Perspectives 胰蛋白酶固定化的生物支持：成本和环境观点

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2026-11-03 DOI: 10.1021/acs.oprd.6c00365

Juan D. Galvis-Nieto,Natalia Salgado,Danya K. Jurado E,Carlos E. Orrego

{"title":"Bio-Based Support for Trypsin Immobilization: Cost and Environmental Perspectives","authors":"Juan D. Galvis-Nieto,Natalia Salgado,Danya K. Jurado E,Carlos E. Orrego","doi":"10.1021/acs.oprd.6c00365","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00365","url":null,"abstract":"Enzyme immobilization remains as a pivotal strategy for enhancing the sustainability and economic viability of biocatalytic processes, yet the gap between academic developments and industrial implementation persists due to the lack of standardized tools for early-stage techno-economic and environmental assessment. This work presents a comprehensive technical, economic, and environmental evaluation of trypsin immobilized on a novel biobased epoxy foam, alongside the proposal of a new decision-making indicator─the Minimum Recycle Number─designed to connect catalytic performance with economic feasibility. The immobilized system developed exhibited excellent catalytic properties, including an activity recovery of 82%, operational stability retaining over 80% activity after 10 reuse cycles, and storage stability of up to 86%–88% over 45 days under ambient conditions. The techno-economic analysis, based on SuperPro Designer simulations and standard cost estimation methodologies, revealed a manufacturing cost of 61.50 USD/kg, with enzyme loading identified as the most influential variable on economic viability, followed by process scale and activity recovery. The proposed indicator effectively prioritized these variables and established that the immobilized system becomes economically competitive within 17–27 recycles under realistic scenarios, well within industrially achievable ranges. The environmental assessment (Life Cycle Assessment methodology trough ISO 14044) identified epoxy resin production as the main hotspot, contributing significantly to climate change (4.64 kg CO2 eq) and fossil depletion (2.21 kg oil eq) per kg of an immobilized biocatalyst. These findings demonstrate that the proposed indicator serves as a robust and versatile tool for bridging laboratory-scale developments with industrial applications, while the environmental analysis provides critical insights for designing more sustainable immobilization strategies through the substitution of fossil-based components with biodegradable alternatives.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"3 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149305471","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

Digital-Assisted Workflow for Organic Solvent Nanofiltration: Accelerating Process Development in Pharmaceutical Manufacturing 有机溶剂纳滤的数字化辅助工作流程：加速制药工艺的发展

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2026-11-02 DOI: 10.1021/acs.oprd.6c00337

Yiran Li,Ida F. Amura,Petros Neoptolemou,Andrew G. Livingston

{"title":"Digital-Assisted Workflow for Organic Solvent Nanofiltration: Accelerating Process Development in Pharmaceutical Manufacturing","authors":"Yiran Li,Ida F. Amura,Petros Neoptolemou,Andrew G. Livingston","doi":"10.1021/acs.oprd.6c00337","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00337","url":null,"abstract":"Organic solvents contribute more than 80% of total process mass intensity (PMI) in pharmaceutical manufacturing. Although organic solvent nanofiltration (OSN) diafiltration processes can improve sustainability, achieving high product yield typically requires large solvent volume to operate. Here, we present a digital-assisted workflow, built on the OSN Designer framework, that enables rapid screening of OSN process configurations to identify architectures that minimize solvent consumption while maintaining API recovery. The framework integrates a solution-diffusion transport model, film theory for concentration polarization, and non-steady-state mass balances, calibrated from crossflow experiments with compound A on the Borsig oNF-3 membrane in 2-methyltetrahydrofuran. Validated with average concordance correlation coefficient (ccc) of 0.72 across steady-state and dynamic operating regimes, the model was applied without recalibration to evaluate four process configurations. A two-stage membrane cascade with closed-loop permeate recycling achieved a process mass intensity (PMI) of 7.76─a 92.4% reduction relative to the single-stage constant-volume diafiltration baseline (PMI 101.5). The formalized four-phase workflow reduces experimental effort to approximately 3 weeks from more than 6–8 months and is directly transferable to other pharmaceutical OSN systems.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"320 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149304796","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

Cold Plasma-Induced Nucleation of Paracetamol in a Batch Stirred Tank Reactor 间歇式搅拌釜反应器中对乙酰氨基酚冷等离子体诱导成核

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2026-11-02 DOI: 10.1021/acs.oprd.6c00342

Hanan El Hadjaji,Arthur Salmon,Isabelle Ziri,Jean-Philippe Jelin,Guillaume Levilain,François Puel

{"title":"Cold Plasma-Induced Nucleation of Paracetamol in a Batch Stirred Tank Reactor","authors":"Hanan El Hadjaji,Arthur Salmon,Isabelle Ziri,Jean-Philippe Jelin,Guillaume Levilain,François Puel","doi":"10.1021/acs.oprd.6c00342","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00342","url":null,"abstract":"Cold plasma generates multiple physical and chemical phenomena that can promote crystal nucleation. However, its use for crystallization under process-relevant conditions remains unexplored. In this work, cold plasma was evaluated as a novel strategy to initiate the crystallization of paracetamol, a model pharmaceutical active ingredient (API), in acetonitrile within a stirred tank reactor. An in-house probe was designed to generate nanosecond repetitively pulsed (NRP) discharges inside nitrogen bubbles injected into the solution. Above a supersaturation threshold within the metastable zone, cold plasma treatment significantly decreased the induction time and improved its reproducibility. Enhancing the number of plasma-treated bubbles further reduced the induction time and increased the desupersaturation rate. Surprisingly, no significant effect on the final particle size distribution was observed, probably due to agglomeration. This work demonstrates, for the first time, that cold plasma is an effective tool to trigger the crystallization of API on-demand, automatically, and without seed preparation. It offers a promising nonintrusive alternative to conventional seeding.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"64 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149304919","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

Process Development of ABBV-576: A C2 Corrector for the Treatment of Cystic Fibrosis 治疗囊性纤维化的C2矫正剂ABBV-576的工艺开发

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2026-10-30 DOI: 10.1021/acs.oprd.6c00264

Nicholas J. Hafeman,Stephen P. Lathrop,Aleksandra Holownia,Kartik Kamat,Louis R. Redfern,Geoff G. Z. Zhang,Nick Rosano,Jeffrey M. Kallemeyn,Kenneth M. Engstrom,John R. Bellettini,John Hartung

{"title":"Process Development of ABBV-576: A C2 Corrector for the Treatment of Cystic Fibrosis","authors":"Nicholas J. Hafeman,Stephen P. Lathrop,Aleksandra Holownia,Kartik Kamat,Louis R. Redfern,Geoff G. Z. Zhang,Nick Rosano,Jeffrey M. Kallemeyn,Kenneth M. Engstrom,John R. Bellettini,John Hartung","doi":"10.1021/acs.oprd.6c00264","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00264","url":null,"abstract":"The development and execution of a second-generation process for the manufacture of ABBV-576, a CFTR C2 corrector for the treatment of cystic fibrosis, are described. Strategic considerations are outlined that address challenges encountered during the manufacture of the phase I-enabling delivery of ABBV-576. The new route features a highly branched-selective Mizoroki–Heck coupling, a Sharpless asymmetric dihydroxylation/cyclization sequence, an alcohol-to-carboxylic acid oxidation on a challenging substrate prone to oxidative decomposition, and an amide coupling to forge the active pharmaceutical ingredient (API). An improved API crystallization addresses issues with solvent removal observed in the original process, and crystallization development work provided insights into a stereoisomeric impurity that was difficult to purge in the penultimate intermediate and API isolations. This paper details the development work performed to establish the second-generation route as well as its execution on a 3 kg scale.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"10 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149304139","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

Retrospective Analysis of Pharmaceutically Relevant Palladium-Catalyzed Cross-Coupling Reactions for Machine Learning-Guided Ligand Selection 用于机器学习引导配体选择的药学相关钯催化交叉偶联反应回顾性分析

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2026-10-30 DOI: 10.1021/acs.oprd.6c00317

Jacob Werth,Sergei Tcyrulnikov,Melissa Lee

引用次数: 0

Improved Two-Step Synthesis of d-Penicillamine: Mechanistic Insights and Structural Identification of Key Process-Related Substances 改进的两步法合成d-青霉胺：关键工艺相关物质的机理和结构鉴定

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2026-10-30 DOI: 10.1021/acs.oprd.6c00130

Xiangping Luo,Zijian Gong,Renfa Fu,Yu Hu,Xiaoxia Sun,Yuai Zhang

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Development of a Synthetic Process for Cyphenovaline: A Potent, Selective Abscisic Acid Receptor Agonist 一种强效选择性脱落酸受体激动剂——环苯缬氨酸合成工艺的发展

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2026-10-29 DOI: 10.1021/acs.oprd.6c00287

Chuantao Zhu,Shen Yang,Bowei Yang,Jia-Qi Li,Xianjun Tang,Yumei Xiao,Zhaohai Qin

{"title":"Development of a Synthetic Process for Cyphenovaline: A Potent, Selective Abscisic Acid Receptor Agonist","authors":"Chuantao Zhu,Shen Yang,Bowei Yang,Jia-Qi Li,Xianjun Tang,Yumei Xiao,Zhaohai Qin","doi":"10.1021/acs.oprd.6c00287","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00287","url":null,"abstract":"Abscisic acid is one of the six major naturally occurring phytohormones and has substantial potential for agricultural applications. However, its practical use in agriculture remains highly limited in both scale and scope because of the challenges associated with its synthesis and its intrinsic structural instability. Consequently, the development of abscisic acid analogs with improved properties has become an important and active area of research. Cyphenovaline, a selective abscisic acid receptor agonist developed by our group, exhibits strong antidrought activity and inhibits seed germination, among other desirable functions. Nevertheless, an industrial-scale manufacturing process for this compound has not yet been established. Here, we report a more economical and efficient four-step synthetic route than the original process. The route comprises glyoxylic acid-mediated electrophilic dibromination, deaminative cyanation, EDCI-mediated amide bond formation followed by methyl ester saponification, and a final Suzuki coupling to install the dicyclopropyl group, affording cyphenovaline. The reaction conditions for each step were systematically screened and optimized. In addition, a scale-up experiment conducted on the 100 g scale demonstrated the feasibility of the process, confirming its suitability for industrial production.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"15 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149281823","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

A Practical and Chromatography-Free Process for Sabizabulin (VERU-111) via an Acylaminoisoxazole Intermediate 酰基氨基异恶唑中间体制备Sabizabulin （VERU-111）的实用无层析工艺

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2026-10-29 DOI: 10.1021/acs.oprd.6c00308

Olga I. Adaeva,Dmitry V. Demchuk,Victor V. Semenov

引用次数: 0