Organic Process Research & Development最新文献

{"title":"Kilogram-Scale Synthesis and Impurity Profiling of a COPD Candidate LY104: Optimization of Salt Forms for Enhanced Purity and Pharmaceutical Potential","authors":"Jilong Zhang, Kaile Li, Xiaokun Liu, Ping Zhang, Wanli Meng, Shengbiao Wan, Guanhua Du, Jiejie Hao, De Wang","doi":"10.1021/acs.oprd.5c00123","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00123","url":null,"abstract":"This study describes a synthetic route to access <b>LY104</b>, a structurally novel compound investigated for the treatment of chronic obstructive pulmonary disease (COPD). Our approach to <b>LY104</b> encompasses (i) a concise and efficient synthetic strategy for this COPD candidate and (ii) a scalable process with structural characterization of related impurities. The synthesis of <b>LY104</b> was accomplished in four steps, during which three key impurity structures were identified. Through careful optimization of the chemical process, <b>LY104</b> acetate salt was consistently obtained in a high purity (&gt;99.85%) for pharmacological studies.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"15 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144312127","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":"Multigram-Scale Synthesis and Study of Reactivity of Two Difluoromethylating Reagents Based on Sulfoximine Skeletons","authors":"Gabriel Goujon, Marina Briand, Nathalie Leclerc, Bruce Pégot, Guillaume Dagousset, Elsa Anselmi, Emmanuel Magnier","doi":"10.1021/acs.oprd.5c00148","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00148","url":null,"abstract":"Hu’s reagent is widely known for the electrophilic and radical difluoromethylation reactions of various compounds of interest for the pharmaceutical and agrochemical fields. Recently, our group described a cyclic version of this sulfoximine. In this article, the gram-scale synthesis of these two reagents, as well as a comparison of their reactivity in electrophilic and radical transformation, is disclosed. DSC and TGA measurements were carried out on the pure final compounds to assess the safety of the process.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"87 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144312128","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":"Production of Active Pharmaceutical Ingredients Encapsulating Ferritin Using Rapid Reassembly Technology via a Flow Microreactor","authors":"Yuta Endo, Yuichi Nakahara, Takahiro Okasora, Junko Yamazaki, Sachise Karakawa, Akira Nakayama, Yutaka Matsuda, Ippei Inoue","doi":"10.1021/acs.oprd.5c00031","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00031","url":null,"abstract":"The encapsulation of active pharmaceutical ingredients (APIs) within ferritin represents a promising approach for drug delivery systems (DDS) due to ferritin’s unique self-assembling hollow structure. However, encapsulating nucleic acids such as DNA and siRNA remains challenging due to molecular size, charge balance, and the risks of protein aggregation and misassembly during the reassembly process. To address these limitations, this study developed and evaluated a novel ferritin disassembly and reassembly process using a sequential-mode flow microreactor (FMR), which offers precise control over mixing and reaction conditions. The FMR system demonstrated superior performance over traditional batch methods by ensuring uniform protein concentrations and reducing misassembly levels across varying scales. By optimizing flow rates and solution conditions, the misassembly ratio was significantly reduced to 3–4%, even at higher flow rates, while maintaining high yields. Moreover, the FMR system successfully encapsulated model DNA, within ferritin, achieving encapsulation efficiencies unattainable with batch processing. These findings establish the sequential-mode FMR as a robust and scalable platform for the production of ferritin-based therapeutics, paving the way for innovative applications in nucleic acid delivery and large-molecule biopharmaceuticals. The study underscores the potential of FMR technology to revolutionize protein reassembly techniques, offering transformative solutions for bio- and nanomedicine.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"89 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269411","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":"Data-Driven Modeling for the Enhanced Understanding for the Crystallization of an Active Pharmaceutical Ingredient","authors":"Andrea Angulo, Jonathan P. McMullen","doi":"10.1021/acs.oprd.5c00036","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00036","url":null,"abstract":"Extensive research efforts are dedicated to studying and understanding the dynamics of the crystallization of an active pharmaceutical ingredient (API), aiming to optimize product quality, yield, and robustness. In this study, we developed, tuned, and demonstrated a data-rich experimentation workflow that can be used to characterize and model the dynamic behavior of an antisolvent crystallization of an API. First, automated, parallel experiment technology and empirical models are used to describe the API solubility as a function of temperature and solvent composition. Next, an efficient protocol that leverages laboratory automation and process analytical technologies was used to generate an accurate chemometric model to quantify API supernatant concentration with <i>in situ</i> Fourier-transformed infrared spectroscopy. Using a 2² full-factorial design and data-rich experimentation, supernatant concentration profiles were obtained to characterize the impact of the crystallization temperature and antisolvent charge rate on the isolation procedure. These multivariate, time-series data profiles were subsequently modeled using dynamic response surface methodology (DRSM). This approach provided a comprehensive understanding of the sensitivity of the operating parameters on the crystallization process to enable rapid process development. The DRSM model successfully predicted the concentration dynamics based on antisolvent fraction, addition rate, and temperature for the training data set from the initial design of the experiment as well as a separate validation experiment. This study highlights how the combination of data-rich experimentation and process modeling can lead to valuable process knowledge for optimization and control strategies for crystallization in pharmaceutical manufacturing.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"25 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144278639","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":"Optimization of the Industrial-Scale Manufacturing Process for Arformoterol through Classical Resolution of Formoterol","authors":"Kishor More, Akshay Chile, Prashant B. Patil, Mustapha Mandewale, Mohan Anand Chandavarkar","doi":"10.1021/acs.oprd.5c00092","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00092","url":null,"abstract":"Brovana Inhalation Solution is a sterile, clear, colorless aqueous solution of the tartrate salt of arformoterol. Arformoterol, the <i>R</i>,<i>R</i>-enantiomer of formoterol, is a highly effective medication with improved pharmacodynamic properties, including increased receptor binding affinity and prolonged bronchodilation. This report describes the development of a robust, efficient, cost-effective, and commercially scalable process for the production of the targeted (<i>R,R</i>)-isomer of formoterol featuring a chiral resolution of inexpensive and readily available formoterol fumarate. This newly developed resolution process proved its efficacy by providing &gt;99.90% chiral pure arformoterol with 74% overall yield.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"520 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144237597","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":"Development of an Automated High-Throughput Screening Platform for the Dynamic Phase Separation Analysis of Microemulsion Systems with AI Image Recognition","authors":"Karsten Duch, Markus Illner, Jens-Uwe Repke","doi":"10.1021/acs.oprd.5c00083","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00083","url":null,"abstract":"Increasing efforts are undertaken to develop new sustainable production processes, and homogeneous catalysis offers many advantages regarding selectivity and energy efficiency in new chemical production routes. A major factor often limiting the application of homogeneous catalysis is the retention of valuable catalysts. One promising option to introduce superior reaction performance and catalyst recovery in organic reactions is the use of water-soluble catalysts in aqueous reaction media with surfactants. However, these surfactant-based microemulsion systems (MES) exhibit a complex phase separation behavior that is dependent on various parameters such as temperature and component concentrations, while its prediction is currently not possible due to the complex thermodynamics. The characterization of the phase behavior hence requires extensive and time-consuming experimental investigation due to a lack of fundamental modeling approaches. To facilitate the acquisition of experimental data, this contribution presents the development of a high-throughput screening platform for dynamic phase separation analysis with an automated experimental procedure, AI analysis of separation images, and automated result data handling. The platform enables a fast characterization of MES separation behavior, which is required for process development and operation. The functionalities of the screening platform are demonstrated in a case study for the hydroformylation of decene. The image detection is performed with a Mask R-CNN model achieving a ±1.5% accuracy in phase height detection with a classification confidence threshold of 96%. The new setup enables a fast evaluation of over 722 measurement runs each with a different combination of separation temperature and mixture composition that only required at total of 38 manual dosing steps. The gathered data is also used to derive a correlation for a soft-sensor with interpretable machine learning, enabling online insights into otherwise inaccessible process variables in an MES plant and enabling its operability.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"39 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144219527","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":"Quality Management of Diastereomeric Impurity for Complex Peptide Manufacturing: A Case Study of Corticorelin Ovine","authors":"Yi Yang, Lena Hansen, Jean-Marie Receveur","doi":"10.1021/acs.oprd.5c00144","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00144","url":null,"abstract":"Diastereomeric impurities are ubiquitous in peptide synthesis and should be controlled with the highest degree of scrutiny in peptide API manufacturing. Diastereomeric impurity reference standards are normally prepared, and the corresponding analytical methods are developed to quantify the diastereomer impurities in the peptide product. This strategy suits the process development for short- to medium-sized peptide molecules containing no more than 15 amino acid residues. However, when the peptides of interest contain more amino acids, they will pose substantial challenges to the preparation of individual diastereomeric impurity reference standards and the development of corresponding analytical methods. In such cases, alternative strategies for controlling peptide diastereomeric impurities should be pursued to ensure the chiral integrity of the peptide product. A deuterated HCl (DCl) hydrolysis-based GC-MS (termed chiral amino acid analysis) strategy has been applied to manage diastereomeric impurity control in the development of a corticorelin ovine manufacturing process. Process optimization was accomplished on this basis.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"24 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210999","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":"Development of Scalable Synthesis of Chiral Tetralol via Hydrogen Borrowing and Dynamic Kinetic Resolution","authors":"Seung Wook Kim, Maura MacTaggart, Michael A. Schmidt, William J. Wolf, Eric M. Simmons, Carolyn S. Wei, Sloan Ayers, Rebecca A. Green, Candice L. Joe, Jeffrey Nye, Scott A. Savage","doi":"10.1021/acs.oprd.5c00090","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00090","url":null,"abstract":"Herein, we describe a two-step alkylation and asymmetric transfer hydrogenation telescope process for the synthesis of an enantioenriched substituted tetralol, a key intermediate in the synthesis of active pharmaceutical ingredient udifitimod (BMS-986166). A hydrogen borrowing alkylation catalyzed by an iridium catalyst was developed to replace an asymmetric alkylation that utilized an alkyl iodide with a costly stoichiometric chiral auxiliary under cryogenic conditions. In the following step, construction of the key stereocenter on the tetralin core was enabled by dynamic kinetic resolution using Ru-catalyzed asymmetric transfer hydrogenation. Process optimization allowed for a telescoped process that delivered the chiral alcohol product with high yield, purity, and enantio- and diastereoselectivity as well as controlled levels of residual metal content acceptable for downstream processing.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"4 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192977","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 Purification of a Conjugated Short Interfering RNA Therapeutic Using Anion Exchange Twin-Column Chromatography (MCSGP)","authors":"Richard Weldon, Tobias Vandermeersch, Thomas Müller-Späth","doi":"10.1021/acs.oprd.4c00513","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00513","url":null,"abstract":"Multicolumn Countercurrent Solvent Gradient Purification (MCSGP) process technology improves yields and production efficiency in clinical and commercial manufacturing of therapeutic APIs such as peptides and oligonucleotide drugs (ONDs). In this case study, we developed an MCSGP process for the purification of a sugar-conjugated sense strand of a therapeutic siRNA (short interfering RNA) using anion exchange (AIEX) chromatography and state-of-the-art twin-column chromatography equipment. MCSGP is relatively complex and requires specialized process development tools to optimize and implement. We describe a simplified, software-aided MCSGP method development procedure for fast transfer from batch to continuous-mode chromatography. As expected with MCSGP, the yield improved from 80% to 93% compared to single-column chromatography, allowing for proportional downscaling of steps preceding and including oligonucleotide synthesis. This greatly decreases manufacturing costs and reduces waste (e.g., byproducts, solvents, and reagents). In addition to increasing the OND yield, throughput was increased by 87%. Other generic benefits of implementing MCSGP are also outlined; for example, due to automation, process robustness is improved; column dimensions and resin volumes are downscaled; laborious side-fraction rechromatography is eliminated; and fewer “in-process control” samples are generated, reducing the manufacturing support burden. The automation enabled by MCSGP is a significant advancement in the commercial-scale manufacturing of APIs.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"45 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144211000","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":"Development of an Improved Process To Prepare a Key Intermediate in the Manufacture of Sotorasib","authors":"Kyle W. Quasdorf, Michal Achmatowicz, Padmini Ananthoji, Joshua Bolger, Derek B. Brown, Seb Caille, Junlong Chen, Ying Chen, Brian M. Cochran, John T. Colyer, Michael Corbett, Xi-Jie Dai, Brendan Dalbey, Yongbo Dan, Daniel J. Griffin, Yajun Han, Hsiao-Wu Hsieh, Kai Liu, Vilmali Lopez-Mejias, William Powazinik, IV, Jo Anna Robinson, Austin Smith, Amanda E. Stahl, Jason S. Tedrow, Tianhui Shi, Maria V. Silva Elipe, Laszlo Visontai, Zuquan Wang, Andrew T. Parsons","doi":"10.1021/acs.oprd.5c00043","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00043","url":null,"abstract":"Sotorasib is a first-in-class KRAS^G12C inhibitor with a unique carbon–nitrogen atropisomer. Described herein is the development of an improved second-generation process to manufacture a key sotorasib intermediate, <i>rac-</i><b>4</b>. Notable improvements to the second-generation process include the development of a three-step fully telescoped sequence in acetonitrile and the use of phosgene as an isocyanating agent, which allowed for dichloromethane, aqueous extractive work-ups, and distillations to be completely removed from the process. Compared to the first-generation process, these process improvements led to a 97% reduction in organic solvent usage and a 71% reduction in wastewater generation and still maintains a 75% yield and &gt;99.5% purity of <i>rac</i>-<b>4</b> in the overall process.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"5 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192976","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}