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

Process Development and Scale-Up of BIIB129, a Covalent, Selective and Brain Penetrant BTK Inhibitor for the Treatment of Multiple Sclerosis BIIB129是一种共价、选择性和脑渗透的BTK抑制剂，用于治疗多发性硬化症

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2026-10-28 DOI: 10.1021/acs.oprd.6c00250

Steven Mathieu,Chaomin Li,Nicolette Fernandes,Lianyong Shi,Ye Ji,Shuo Qiao,Deju Shang,Cuicui Yuan,Dong Wang,Ziliang Liu,Zhu Liang,Fei Tong,Martin K. Himmelbauer,H. George Vandeveer,Brian T. Hopkins

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Data-Guided Descriptor Rebalancing for Monophosphine Ligand Training Set Development 单膦配体训练集开发的数据导向描述符再平衡

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2026-10-28 DOI: 10.1021/acs.oprd.6c00355

Jamie A. Cadge,Neal W. Sach,Louise Bernier,Matthew S. Sigman

{"title":"Data-Guided Descriptor Rebalancing for Monophosphine Ligand Training Set Development","authors":"Jamie A. Cadge,Neal W. Sach,Louise Bernier,Matthew S. Sigman","doi":"10.1021/acs.oprd.6c00355","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00355","url":null,"abstract":"Data-guided optimization strategies increasingly rely on well-designed training sets and meaningful chemical space representations, yet identifying appropriate descriptors and ensuring domain applicability remain persistent challenges. Here, we present an iterative workflow for refining monodentate phosphine-based training sets by coupling experimental reaction data with systematic feature evaluation. Using a pharmaceutically relevant cross-coupling reaction as a case study, we demonstrate how imbalances in steric and electronic descriptors of monodentate phosphines derived from the kraken database, along with limited feature overlap between training and validation sets, can challenge classification models and virtual screening performance. By rebalancing descriptor types, we generated a more chemically intuitive representation that improved predictive performance in a classification model. This approach enables the development of a redesigned monophosphine ligand screening set with an enhanced coverage of key structural and electronic dimensions. The resulting workflow provides a generalizable template for constructing more robust, diverse, and application-ready training sets for catalyst screening and reaction optimization within process chemistry.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"15 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149275031","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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Development of a Continuous Trickle-Flow Hydrogenation Process for Cbz Deprotection in Dipeptide Synthesis 二肽合成中Cbz脱保护的连续滴流加氢工艺的开发

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2026-10-27 DOI: 10.1021/acs.oprd.6c00369

Michael Whittington,Longrui Chen,Jacob H. Waldman,Michael J. Di Maso,Byron K. Peters,Mark Weisel,Gerard Klinzing,Tuyen Cao,François Lévesque

{"title":"Development of a Continuous Trickle-Flow Hydrogenation Process for Cbz Deprotection in Dipeptide Synthesis","authors":"Michael Whittington,Longrui Chen,Jacob H. Waldman,Michael J. Di Maso,Byron K. Peters,Mark Weisel,Gerard Klinzing,Tuyen Cao,François Lévesque","doi":"10.1021/acs.oprd.6c00369","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00369","url":null,"abstract":"The synthesis of enlicitide decanoate (MK-0616), a first-in-class oral PCSK9 inhibitor, requires efficient Cbz deprotection of a proline–threonine dipeptide intermediate, presenting safety and economic challenges for traditional batch hydrogenation. Here, we report the development of a continuous trickle-bed flow reactor with customized components that addresses these manufacturing constraints through systematic process optimization. This paper reports the development of a laboratory-scale trickle-bed flow reactor with customized components on a commercially available system along with catalyst characterization and continuous temperature mapping. The optimized process achieved complete conversion with 3.8% catalyst loading (24% reduction versus batch processing) and maintained a robust performance over extended operations. This comprehensive development establishes a scalable, safer alternative to batch hydrogenation while reducing precious-metal usage, providing a template for pharmaceutical flow chemistry applications requiring heterogeneous catalysis.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"65 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149251018","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

High-Throughput Experimentation in Practice: Hidden Bottlenecks and Digital Gaps 实践中的高通量实验：隐藏的瓶颈和数字差距

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2026-10-27 DOI: 10.1021/acs.oprd.6c00266

Kaiman A. Cheung,Henrique Magri Marçon,Matthew T. Pratley,Daniel Wigh,Alexander Pomberger,Connor J. Taylor

{"title":"High-Throughput Experimentation in Practice: Hidden Bottlenecks and Digital Gaps","authors":"Kaiman A. Cheung,Henrique Magri Marçon,Matthew T. Pratley,Daniel Wigh,Alexander Pomberger,Connor J. Taylor","doi":"10.1021/acs.oprd.6c00266","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00266","url":null,"abstract":"High-throughput experimentation (HTE) has become an increasingly important approach for reaction discovery, optimization, and AI-ready data generation in synthetic chemistry. However, despite rapid adoption, many practical limitations associated with implementing HTE workflows remain underreported, particularly outside industrial settings. In practice, experimental reliability is frequently constrained by factors such as solvent compatibility, evaporation, sealing performance, plate geometry, liquid handling limitations, and the physical constraints introduced through miniaturization. These effects can strongly influence reproducibility and data quality, yet are often treated as secondary implementation details rather than core considerations. Alongside these operational challenges, digital HTE workflows remain fragmented, with limited interoperability between software, hardware, analytical systems, and data structures. In this perspective, we discuss a range of practical and digital bottlenecks encountered during plate-based HTE, drawing on direct experimental experience, supporting experimental data, and recent developments across the field. In particular, we present new observations relating to solvent evaporation and sealing performance in common HTE formats, highlighting how seemingly minor physical effects can substantially influence experimental reliability and downstream interpretation. By making these practical considerations more explicit, we aim to support the development of more reproducible, interoperable, and scalable HTE workflows across academic and industrial chemistry.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"23 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149251016","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

Technical Note: On the Selection of Precooling Loops for Low-Temperature Continuous Flow Chemistry 技术说明：关于低温连续流化学预冷回路的选择

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2026-10-22 DOI: 10.1021/acs.oprd.6c00246

James A. K. Cochrane,Raminder S. Mulla

引用次数: 0

Process Development of a Key Chiral Intermediate toward the Synthesis of ABBV-576 合成ABBV-576关键手性中间体的工艺开发

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2026-10-22 DOI: 10.1021/acs.oprd.6c00265

Jesse T. C. Brown,Nick Rosano,Stephen P. Lathrop,Ryan M. Phelan,Jeffrey M. Kallemeyn,Kenneth M. Engstrom,John R. Bellettini,Aleksandra Holownia,Louis R. Redfern,Nicholas J. Hafeman

引用次数: 0

Synthesis of a Crystalline Acylated Lysine Building Block for Retatrutide Manufacture 一种用于利特鲁肽生产的晶体酰化赖氨酸构建块的合成

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2026-10-22 DOI: 10.1021/acs.oprd.6c00240

Jingyao Wang,Jing Teng,Emily Guinn,Ryan W. Curtis,Rachel N. Richey,Sergey V. Tsukanov,Joel R. Calvin,Gordon Randall Lambertus,Mark A. Strege,Ankur Jalan,Michael E. Kopach

{"title":"Synthesis of a Crystalline Acylated Lysine Building Block for Retatrutide Manufacture","authors":"Jingyao Wang,Jing Teng,Emily Guinn,Ryan W. Curtis,Rachel N. Richey,Sergey V. Tsukanov,Joel R. Calvin,Gordon Randall Lambertus,Mark A. Strege,Ankur Jalan,Michael E. Kopach","doi":"10.1021/acs.oprd.6c00240","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00240","url":null,"abstract":"Retatrutide contains a structurally complex lipidated side chain that presents significant challenges for efficient large-scale synthesis and isolation. We report the development of a novel and highly efficient commercial synthetic route to the lipidated side chain, designed to enable robust and sustainable manufacture at multimetric-ton scale. A central innovation of this process is the successful crystallization of an acylated lysine building block─a rare outcome for lipidated amino-acid-derived materials─which enables a chromatography-free isolation strategy and provides consistent solid-state quality. The optimized route leverages flow chemistry for key transformations in combination with crystallization-based purification, resulting in improved convergence, throughput, and operational robustness. Process mass intensity (PMI) analysis indicates a total raw material usage of 152 kg per kg of acylated lysine, with solvent consumption dominated by water and acetonitrile. Compared to a solid-phase synthetic route to the same intermediate, the liquid-phase process reduces total PMI by more than 65% and eliminates piperidine from the synthesis, representing a substantive improvement in manufacturing efficiency. Solvent usage in the final transformation was evaluated with an emphasis on process flexibility; preliminary studies demonstrate that DMSO provided comparable solubility and impurity profiles under manufacturing conditions, offering a potential path to complete elimination of DMF from the synthesis and further reduction of PMI. The process has been successfully incorporated into the retatrutide validation supply chain and is expected to support multimetric-ton-scale manufacture. The route consistently delivers ≥99% purity crystalline acylated lysine, which serves as a critical registered starting material for the commercial manufacture of retatrutide.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"76 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149230333","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

Bioinformatics-Guided Immobilization of a Peptiligase Variant for Continuous-Flow Chemoenzymatic Synthesis of Semaglutide 生物信息学指导下固定化连续流化学酶合成半聚脲的肽酶变体

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2026-10-20 DOI: 10.1021/acs.oprd.6c00249

Cristina Lía Fernández Regueiro,Marco Macis,Claudia Arnofi,Ana Toplak,Walter Cabri,Francesca Paradisi,David Roura Padrosa,Antonio Ricci

{"title":"Bioinformatics-Guided Immobilization of a Peptiligase Variant for Continuous-Flow Chemoenzymatic Synthesis of Semaglutide","authors":"Cristina Lía Fernández Regueiro,Marco Macis,Claudia Arnofi,Ana Toplak,Walter Cabri,Francesca Paradisi,David Roura Padrosa,Antonio Ricci","doi":"10.1021/acs.oprd.6c00249","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00249","url":null,"abstract":"Chemoenzymatic peptide synthesis offers a sustainable alternative to traditional solid-phase peptide synthesis for manufacturing therapeutic peptides such as semaglutide. However, cost-efficient industrial implementation requires enzyme immobilization to enable the catalyst recovery and continuous processing. This work presents the first demonstration of a bioinformatics-guided immobilization strategy for a peptiligase variant, successfully applied in a continuous-flow packed-bed reactor for semaglutide fragment ligation. Using computational tools, we predicted optimal immobilization sites and systematically screened covalent and noncovalent methods. EP400/SS-aldehyde emerged as the superior support, maintaining >85% of the immobilized activity after 10 reuse cycles. Translation to continuous flow revealed substrate hydrolysis as a competing side reaction at high enzyme loads. Optimization of the protein loading, to 2.5 mg/g, suppressed this unwanted reaction, achieving 95% conversion with 30 min of residence time, matching solution-phase performance. This establishes a robust framework for immobilizing peptiligases in industrial bioprocesses.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"12 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221700","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

Synthesis of the pan-TEAD Inhibitor GDC-8025 via a Flow Chan–Evans–Lam Coupling and Enantioselective Biocatalytic α-Ketoester Reduction 流动Chan-Evans-Lam偶联及α-酮酯还原法制备泛tead抑制剂GDC-8025

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-10-16 Epub Date: 2026-09-29 DOI: 10.1021/acs.oprd.6c00216

Nicholas A. White, Matthew M. Pompeo, Kyle Clagg, Jeff Shen, Di Xu, Carmela Molinaro, Lauren E. Sirois, Francis Gosselin

{"title":"Synthesis of the pan-TEAD Inhibitor GDC-8025 via a Flow Chan–Evans–Lam Coupling and Enantioselective Biocatalytic α-Ketoester Reduction","authors":"Nicholas A. White, Matthew M. Pompeo, Kyle Clagg, Jeff Shen, Di Xu, Carmela Molinaro, Lauren E. Sirois, Francis Gosselin","doi":"10.1021/acs.oprd.6c00216","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00216","url":null,"abstract":"GDC-8025 is a potentpan-TEAD inhibitor that featuresa functionalized 1H-pyrazolo[3,4-b]pyridine core and a reactive acrylamide warhead. The first-generationsynthesis of GDC-8025 relied on a Sharpless asymmetricdihydroxylation of 7 to install the chiral diol moiety(8). This chemistry was not suitable for large scalemanufacturing due to the instability of the requisite 4-vinylpyridineintermediate (7) and occupational toxicity concerns ofosmium tetroxide. To address these challenges, a second-generationroute utilizing a biocatalytic enantioselective reduction of an α-ketoestersubstrate (18) was developed. Together with optimizationof a Chan–Evans–Lam coupling in flow, a tandem ester/nitrilereduction, and a chemoselective acrylamidation, implementation ofthis new route facilitated the robust multikilogram synthesis of GDC-8025 in 8 chemical steps.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 10","pages":"2755–2766"},"PeriodicalIF":3.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149188020","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

Telescoped Two-Step Continuous-Flow Synthesis of Nevirapine Enabled by the On-Demand Generation of NaHMDS 由NaHMDS按需生成的奈韦拉平的伸缩两步连续流合成

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-10-16 Epub Date: 2026-10-01 DOI: 10.1021/acs.oprd.6c00277

Maksim Vasilev, Rajasekar Reddy Annapureddy, Chengfeng Ye, Sridhar Regati, Praveen Kumar Gajula, Jonathan Bietsch, Zhirui Wang, Jack D. Brown, Gopal Sirasani, Aravind S. Gangu, Paul Guo, Bo Qu, Chris H. Senanayake

{"title":"Telescoped Two-Step Continuous-Flow Synthesis of Nevirapine Enabled by the On-Demand Generation of NaHMDS","authors":"Maksim Vasilev, Rajasekar Reddy Annapureddy, Chengfeng Ye, Sridhar Regati, Praveen Kumar Gajula, Jonathan Bietsch, Zhirui Wang, Jack D. Brown, Gopal Sirasani, Aravind S. Gangu, Paul Guo, Bo Qu, Chris H. Senanayake","doi":"10.1021/acs.oprd.6c00277","DOIUrl":"10.1021/acs.oprd.6c00277","url":null,"abstract":"A telescoped two-step fully continuous-flow process forthe synthesisof nevirapine (trade name: Viramune), a key therapeutic agent forthe prevention and treatment of HIV-1 infection, has been developed.The process employs, for the first time, sodium bis(trimethylsilyl)amide(NaHMDS) as a homogeneous, process-friendly base for both reactionstages and enables direct conversion of methyl 2-(cyclopropylamino)nicotinateand 2-chloro-3-amino-4-picoline to nevirapine without isolation ofthe cyclization intermediate. The optimized process operates witha total residence time of 10 min and delivers crude nevirapine in91.9% overall isolated yield across two reaction steps, with a space-timeyield of ∼365 g/h/L and 99.6 A% HPLC purity. Furthermore, wedeveloped an on-demand continuous generation of NaHMDS in diglyme(up to ∼2.0 M) using a sodium packed-bed column reactor. Usingon-demand generated NaHMDS, the telescoped synthesis yielded crudenevirapine in 90.7% isolated yield (∼340 g/h/L space-time yieldand 99.5 A% purity), providing a scalable and cost-effective alternativeto NaH applied in the current commercial synthesis.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 10","pages":"2822–2832"},"PeriodicalIF":3.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149092228","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