Organic Process Research & Development最新文献

{"title":"Toward the Development of a Commercial Process to Produce Muvalaplin. Part II: Preparation of the Drug Substance","authors":"Daniel P. Walker,&nbsp;John R. Rizzo,&nbsp;Mai Khanh Hawk,&nbsp;Matthew J. Genzink,&nbsp;Antonio Navarro,&nbsp;Dajiang Jing,&nbsp;Srinivas Gangula,&nbsp;Silong Zhang,&nbsp;Jianfei Dai,&nbsp;Panpan Sun","doi":"10.1021/acs.oprd.6c00323","DOIUrl":"10.1021/acs.oprd.6c00323","url":null,"abstract":"<p>Herein, we describe the development of steps 5–7for a large-scaleprocess to synthesize muvalaplin, a small-molecule lipoprotein(a)inhibitor for the potential reduction of major adverse cardiovascularevents in participants with established cardiovascular disease orat risk for a first cardiovascular event. Each step was optimized,leading to improvements in safety, robustness, and cost of goods thatultimately resulted in a 41% yield increase over three steps and a60% reduction in PMI compared to the original discovery synthesis.The process was safely scaled to &gt;100 kg, thus ensuring clinicalsupplyand laying the foundation for a commercial route.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 10","pages":"2850–2866"},"PeriodicalIF":3.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149022372","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}

{"title":"Bayesian Optimization Assisted Multistep Continuous-Flow Synthesis of Olutasidenib","authors":"Tengfei Gong,&nbsp;Fei Ji,&nbsp;Zhihao Chen,&nbsp;Yuting Geng,&nbsp;Xi Yang,&nbsp;Xu Ye,&nbsp;Xiaoming Zha","doi":"10.1021/acs.oprd.6c00251","DOIUrl":"10.1021/acs.oprd.6c00251","url":null,"abstract":"<p>Olutasidenib is a potent, selective,and orally administeredsmall-moleculeinhibitor of mutant isocitrate dehydrogenase 1. The traditional syntheticmethods suffer from several drawbacks including prolonged reactiontimes, safety concerns, and low yields. Herein, we describe a four-stepcontinuous-flow synthesis of olutasidenib via oxidation reaction,Katada reaction, methylation reaction, and nucleophilic substitutionreaction. The coil reactor enables a shorter reaction time and reducesthe risk of hydrogen peroxide decomposition due to its enhanced heatand mass transfer. Meanwhile, Bayesian optimization is used to acceleratethe optimization of the continuous-flow. The level of <em>N</em>-methylation product of 2-pyridone was effectively increased to 93%by using methyl trifluoromethanesulfonate as a methylating agent inhexafluoroisopropanol. This continuous-flow process, featuring a totalresidence time of 86 min and a total yield of 44.1%, substantiallyreduces the reaction time and improves process safety while also achievinga lower Process Mass Intensity (PMI) than batch reactions.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 10","pages":"2794–2802"},"PeriodicalIF":3.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088564","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}

{"title":"High-Throughput Screening of Conditions for Gas–Liquid Reactions Involving Ozone Gas: A Workflow for Rapid Development and Optimization of Scalable Conditions","authors":"Vanna D. Blasczak,&nbsp;Christopher W. Mitchell,&nbsp;Kevin Barry,&nbsp;Louis Edwards Caceres-Martinez,&nbsp;Brian R. Clark,&nbsp;Nicolette Fernandes,&nbsp;Gabriel Kuklis,&nbsp;Steven Mathieu,&nbsp;Michael C. Nicastri,&nbsp;Nicholas Venditto,&nbsp;Chao Wang,&nbsp;Chaomin Li,&nbsp;Daniel B. Patience","doi":"10.1021/acs.oprd.6c00209","DOIUrl":"10.1021/acs.oprd.6c00209","url":null,"abstract":"<p>Ozone is an attractive, sustainable oxidant for organicsynthesis,yet its adoption in pharmaceutical process development is often limitedby safety concerns, poor gas–liquid mass transfer, solventincompatibilities, and challenges in scaling. Herein, a robust, high-throughputworkflow for the rapid development and optimization of scalable ozonolysisreactions is reported. Miniaturized screening using a 96-well high-pressurereaction block in which ozone-containing gas flows through the headspaceenabled rapid evaluation of solvent systems, cosolvents, and quenchingagents under controlled low-temperature conditions, allowing hundredsof experiments to be conducted with minimal material consumption.Key reaction parameters were efficiently translated to larger-scalesparged tube and bubble reactor platforms, demonstrating a consistentperformance across scales. Reaction progress monitoring and temperature-dependentstudies suggest that the ozonolysis reaction is influenced by gas–liquidmass-transfer control rather than intrinsic kinetic limitation. Theuse of immiscible solvent mixtures and sodium sulfite as a quenchingagent provided clean phase separations and operationally simple workupswhile mitigating the safety risks associated with peroxide formation.Collectively, this workflow enables the identification, scale-up,and validation of practical ozone-based oxidations within weeks, providinga general and scalable approach for integrating ozone chemistry intosustainable pharmaceutical process development.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 10","pages":"2726–2734"},"PeriodicalIF":3.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149050196","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}

{"title":"Late-Stage Kinetic Hydrolysis to Prepare an Advanced Intermediate for Ibuzatrelvir","authors":"Russell F. Algera,&nbsp;Christophe Allais,&nbsp;Aaron F. Baldwin,&nbsp;Gabrielle E. Cabrera,&nbsp;María González-Esguevillas,&nbsp;Michael Herr,&nbsp;Chintelle James,&nbsp;Johnny W. Lee,&nbsp;Melissa Lee,&nbsp;Emily Lennert,&nbsp;Jeffrey M. Massicott,&nbsp;Lesly Mejia,&nbsp;Robert J. Pearson,&nbsp;Dylan Pedro,&nbsp;David W. Place,&nbsp;Philipp C. Roosen,&nbsp;R. Matthew Weekly,&nbsp;Gerald A. Weisenburger,&nbsp;Shu Yu","doi":"10.1021/acs.oprd.6c00096","DOIUrl":"10.1021/acs.oprd.6c00096","url":null,"abstract":"<p>Ibuzatrelviris a second-generation, orally administered proteaseinhibitor of the SARS-CoV-2 M^Pro virus that is currentlybeing evaluated for the treatment of Covid-19. The molecule containsa substituted <em>trans</em>-trifluoromethylproline fragmentthat, although it had been the focus of previous synthetic efforts,was still identified as a target for improvement. Herein, we describea route featuring the late-stage introduction of a stereocenter viaa mechanistically distinct diastereoselective kinetic hydrolysis.This bold strategy has resulted in significant efficiency, environmental,and process dividends, underscoring the impact of a continuous-improvementapproach to chemical development.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 10","pages":"2625–2636"},"PeriodicalIF":3.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148933626","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}

{"title":"Continuous Flow Br/Li Exchange Enables Scalable Synthesis of Chiral N, P Ligands for Asymmetric Catalysis","authors":"Rixin Shao,&nbsp;Liming Cao,&nbsp;Jianan Mao,&nbsp;Junzheng Xian,&nbsp;Mingchen Zheng,&nbsp;Maolin Sun,&nbsp;Ruihua Cheng,&nbsp;Yanxiong Ke,&nbsp;Jinxing Ye","doi":"10.1021/acs.oprd.6c00194","DOIUrl":"10.1021/acs.oprd.6c00194","url":null,"abstract":"<p>Chiral <em>N, P</em> ligands represent privilegedscaffoldsin asymmetric catalysis, yet their scalable synthesis suffers fromtraditional batch constraints: ultra-cryogenic conditions (−100to −120 °C), competitive benzyne formation, low yields,and poor scalability. Herein, a concise continuous-flow protocol forthe efficient synthesis of (<em>S</em>)-DPPNH₂-derivedchiral <em>N, P</em> ligands via sequential Br/Li exchangeis reported. Precise spatiotemporal control in a microreactor systemenables selective monolithiation, phosphination, and stereoselectivenucleophilic addition at a mild −70 °C, with a total residencetime of only 17.8 s. This flow platform effectively suppresses benzyneside reactions and eliminates the need for ultra-cryogenic infrastructurewhile maintaining a low in-process inventory of hazardous intermediates.The corresponding ligand precursors are obtained in yields of up to71% with good to excellent diastereoselectivities (up to 98:2 dr).Preparative-scale synthesis (1.17 g in a 2 min collection) and subsequentacid-catalyzed deprotection highlight the potential for further scale-up.This modular continuous-flow strategy offers a practical route todiverse chiral <em>N, P</em> ligands, addressing key manufacturingchallenges in asymmetric catalyst development.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 10","pages":"2709–2716"},"PeriodicalIF":3.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148974117","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}

{"title":"Nickel as a Competitive Drop-In Alternative to Palladium in Thermal C–O Cross-Couplings of Aliphatic Alcohols with Heteroaryl Halides: A High-Throughput Experimentation Study","authors":"Kathleen M. Morrison,&nbsp;Emily C. Jackson,&nbsp;Alexis Lavallée,&nbsp;Faral Akhtar,&nbsp;Martin Priester,&nbsp;Devin Deussen,&nbsp;Philipp M. Holstein,&nbsp;Mark Stradiotto","doi":"10.1021/acs.oprd.6c00228","DOIUrl":"10.1021/acs.oprd.6c00228","url":null,"abstract":"<p>Palladium-catalyzed thermal C–O cross-couplingreactionsrepresent first-choice methodologies for alkyl (hetero)aryl etherformation in both academia and industry, especially when commencingfrom otherwise challenging (hetero)aryl chloride or bromide electrophilesand aliphatic alcohol coupling partners. While highly effective thermalnickel-catalyzed processes of this type have emerged owing to advancesin ancillary ligand design, their use as competitive drop-in alternativesto palladium in such applications in the context of high-throughputexperimentation (HTE) has not been demonstrated. In targeting theformation of alkyl heteroaryl ethers of biological relevance, we discloseherein a comparative HTE screening study focused on thermal palladium-or nickel-catalyzed C–O cross-couplings of primary, secondary,or tertiary aliphatic alcohols with heteroaryl chlorides or bromides.We demonstrate that appropriate DalPhos-ligated nickel precatalystscan offer catalytic performance in such transformations that is competitivewith (e.g., for primary and secondary alcohols) or superior to (e.g.,for tertiary alcohols) that achieved by use of otherwise best-in-classpalladium catalysts (e.g., featuring biarylmonophosphine, JosiPhos,or other ligation).</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 10","pages":"2783–2793"},"PeriodicalIF":3.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149022371","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}

{"title":"Copper-Catalyzed Cross-Coupling of Malonates with Aryl Halides Using Hydroxypicolinamide Ligands","authors":"Ian Hotham,&nbsp;Daniel W. Widlicka","doi":"10.1021/acs.oprd.6c00215","DOIUrl":"10.1021/acs.oprd.6c00215","url":null,"abstract":"<p>Cu-catalyzed cross-coupling of aryl halides and malonatesusinghydroxypicolinamide ligands to furnish the corresponding aryl malonatesis disclosed herein. Malonates are commonly coupled with aryl halidesvia Pd catalysis, with a few reports of classic Hurtley-type Cu-mediatedcouplings. The Cu-MPBS system, originally designed for C–Ncoupling, has been further developed for the Cu-catalyzed couplingof diethyl malonate with aryl bromides and less precedented aryl chlorides.Our hydroxypicolinamide ligand scaffold promotes the Hurtley-typecoupling of diethyl malonate under mild conditions for aryl bromides(20–40 °C) and aryl chlorides (60–80 °C) withlow Cu loading (2–4 mol %). Reaction conditions are compatiblewith a wide variety of functional groups and heterocycles to providethe desired malonate. Furthermore, we demonstrated a telescoped processto the α-aryl ester simply by heating to drive subsequent decarboxylation.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 10","pages":"2735–2742"},"PeriodicalIF":3.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148564927","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}

{"title":"Decagram Scale Synthesis and Deployment of a Picolinamide Ligand for a Copper-Catalyzed C–N Cross-Coupling","authors":"Andrew McGrath,&nbsp;Dan Lehnherr","doi":"10.1021/acs.oprd.6c00198","DOIUrl":"10.1021/acs.oprd.6c00198","url":null,"abstract":"<p>The synthesis of a picolinamide ligand is demonstratedon a 70g scale in a process-friendly solvent, and its application in a copper-catalyzedC–N cross-coupling on a 20 g scale is reported. The ligandcan be accessed in one step via an amide coupling using inexpensive,commercially available 6-hydroxypicolinic acid and 6-methylquinolin-5-amine.A simple aqueous workup followed by a pH-swing-induced crystallizationaffords the ligand without the need for column chromatography. Thecombination of the scalable access to the ligand and its excellentperformance in copper-catalyzed C–N cross-coupling on decagramscale renders this ligand attractive for deployment in process chemistryapplications.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 10","pages":"2717–2725"},"PeriodicalIF":3.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088490","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}

{"title":"Toward Organosolv\u0000Biorefineries Based on γ-Valerolactone\u0000Recycling via Salting-Out Extraction","authors":"Giacomo Fabbrizi,Leonardo Lorenzi,Mattia Gelosia,Gianfrancesco Russo,Ilaria Armentano,Andrea Nicolini","doi":"10.1021/acs.oprd.6c00063","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00063","url":null,"abstract":"Abstract This study presents an alternative approach for solvent regeneration in γ-valerolactone (GVL) based organosolv fractionation of lignocellulosic biomass through a two-stage salting-out assisted liquid–liquid extraction (SALLE) mediated by Na2SO4. Cynara cardunculus L. altilis (cardoon) stems were treated via microwave-assisted GVL/water extraction, followed by sequential washing and SALLE steps to separate and quantify cellulose, lignin, and hemicellulose fractions while regenerating GVL and Na2SO4. The regenerated GVL was reused over six consecutive cycles, and its performance was assessed through pulp composition and solvent purity analyses. Results show that SALLE enables consistent GVL regeneration (82%), high-purity cellulose pulps (&amp;gt;90 wt % cellulose), and lignin recovery (about 78%) without significant solvent degradation or undesired solute accumulation. The findings demonstrate that SALLE provides an efficient and reproducible method for GVL recovery, which could be implemented in a GVL-based biorefinery.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"292 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210334","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}

{"title":"Recent Advances\u0000in the Synthesis of Therapeutic Peptides\u0000and Oligonucleotides","authors":"Adithya Ramesh,Priyanka Behera,Rathod Siddija,Shreya Ghosh,Om Shanker Tiwari","doi":"10.1021/acs.oprd.6c00322","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00322","url":null,"abstract":"Abstract Peptide and oligonucleotide synthesis is an emerging indispensable molecular platform in modern medicine due to their inherent property of exceptional target specificity and broad therapeutic potential. However, their synthetic complexity, inefficiency in production, and issues related to sequence length and structural diversity have restricted their large-scale manufacture. This review presents a broad survey of recent developments in synthetic methodologies that have revolutionized the synthesis of these biomacromolecules, with special emphasis on process-oriented innovations that bridge laboratory synthesis and industrial manufacture. This review discusses the recent development of solid-phase methodologies, improvements in ligation chemistry, orthogonal protecting-group strategies, and chemo-selective conjugation methods that enable the efficient assembly of structurally complex peptide and oligonucleotide architectures, along with emerging technologies, including continuous-flow processing, microwave-assisted synthesis, and atom-economical reaction platforms, which are highlighted for their ability to improve reaction kinetics, reduce solvent consumption, and enhance reproducibility. Furthermore, the growing integration of enzymatic and chemoenzymatic methodologies, including engineered polymerases and template-independent nucleic acid synthesis systems, is redefining the preparation of next-generation oligonucleotides. Particular attention is given to sustainability-driven synthetic innovations that address longstanding limitations related to scalability, purification, stereochemical control, and environmental impact. By comparing the strengths and limitations of conventional synthetic platforms, this review establishes a unified perspective on the evolving manufacturing landscape for peptide and oligonucleotide production, as well as the therapeutic applications of versatile peptide and oligonucleotide substrates. Collectively, these advances provide a foundation for the accelerated development of increasingly sophisticated biomolecular constructs and offer practical insights for translating synthetic innovations into clinically and industrially relevant applications.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"11 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210332","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}