Organic Process Research & Development最新文献

{"title":"Evolution of Synthetic Strategies for Lilly’s Clinical BACE Inhibitors: From Discovery Concepts to Manufacturing-Ready Routes","authors":"Michael O. Frederick*,&nbsp;Pablo Garcia-Losada,&nbsp;Dustin J. Mergott,&nbsp;Erik J. Hembre and Jeffery Richardson,&nbsp;","doi":"10.1021/acs.oprd.6c00179","DOIUrl":"10.1021/acs.oprd.6c00179","url":null,"abstract":"<p >Alzheimer’s disease (AD) remains a critical unmet medical need that Eli Lilly and Company has been working to address for many years. This manuscript details the evolution of Lilly’s BACE inhibitor program, highlighting the iterative synthetic strategies that enabled the advancement of multiple clinical development candidates. The work underscores how strategic retrosynthetic analysis and process optimization facilitated the translation of intricate medicinal chemistry targets into robust manufacturing processes, ultimately supporting clinical development efforts in AD despite the inherent challenges and program terminations encountered along the way.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 7","pages":"2075–2084"},"PeriodicalIF":3.3,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148336273","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":"Four-Step Continuous-Flow Total Synthesis of 4-Chloro-6,7-dimethoxyquinoline, a Key Intermediate for Tyrosine Kinase Inhibitors","authors":"Xiaobin Liang,&nbsp;Xiaorong Zhou,&nbsp;Yian Luo,&nbsp;An Su,&nbsp;Hanqi Zhou,&nbsp;Jianli Chen,&nbsp;Fengfan Liu* and Weike Su,&nbsp;","doi":"10.1021/acs.oprd.6c00170","DOIUrl":"10.1021/acs.oprd.6c00170","url":null,"abstract":"<p >Tivozanib and cabozantinib are important oral tyrosine kinase inhibitors for the clinical treatment of advanced renal cell carcinoma. In this study, 4-chloro-6,7-dimethoxyquinoline, a common intermediate for two drug syntheses, was designed to be prepared from readily available 1,2-dimethoxybenzene through a sequence of Friedel–Crafts acylation, nitration, hydrogenation, and chlorination. Furthermore, the fully continuous-flow technology was applied to optimize the process and reduce safety risks, achieving the four-step “end-to-end” reaction by concatenating the synthesis, quenching, and phase-separation steps. In the nitration step, the byproduct of 3,4-dimethoxynitrobenzene could isolate by recrystallization. A kinetic model for the nitration reaction was established, indicating that &gt;99% conversion could be achieved at 30 °C with a residence time of 6 min. In the chlorination step, triphosgene (BTC) was used in place of conventional chlorinating reagents (POCl₃, (COCl)₂), enabling one-step synthesis of 4-chloro-6,7-dimethoxyquinoline in 73% isolated yield with 99% HPLC purity. Compared with the batch process, the fully continuous-flow synthesis of 4-chloro-6,7-dimethoxyquinoline shortened the total reaction time from 480 to 70 min, increased the overall yield from 46.6% to 53.7%, and reduced PMI by 26%.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 7","pages":"2054–2066"},"PeriodicalIF":3.3,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148385129","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":"Hydroxyapatite as an Enzyme Carrier in Continuous-Flow Biocatalysis: An Improved Synthesis of γ-Glutamyl Derivatives","authors":"Leonardo Gelati,&nbsp;Fabrizio Medici,&nbsp;Sebastiano Campisi,&nbsp;Cinzia Calvio,&nbsp;Maurizio Benaglia,&nbsp;Antonella Gervasini,&nbsp;Marco Rabuffetti,&nbsp;Giovanna Speranza* and Carlo F. Morelli*,&nbsp;","doi":"10.1021/acs.oprd.6c00083","DOIUrl":"10.1021/acs.oprd.6c00083","url":null,"abstract":"<p >Biocatalysis has proved to be of great importance to pursue a more sustainable production of fine chemicals, and enzyme immobilization is a crucial tool to achieve this goal. In this work, hydroxyapatite, an eco-friendly material, was used as a support for the immobilization of a γ-glutamyltransferase from <i>Escherichia coli</i>, an enzyme that catalyzes the synthesis of bioactive γ-glutamyl derivatives, exploiting the noncovalent interactions between the support and the enzyme. After screening the immobilization conditions, the storage (up to 90 days) and the thermal stability (50 °C) of the obtained immobilized biocatalyst were studied, as well as its reuse in up to 10 consecutive reactions of γ-glutamylation of <i>S</i>-allyl-<span>l</span>-cysteine, to give γ-<span>l</span>-glutamyl-<i>S</i>-allyl-<span>l</span>-cysteine (<b>3</b>), a flavor enhancer occurring in garlic extract. Finally, the immobilized enzyme was used to prepare a packed-bed reactor and <b>3</b> was synthesized under continuous-flow conditions improving both the productivity (from 19.4 to 35.1 μmol·h^–1) and the space-time yield (9.7 vs 381 μmol·h^–1·mL^–1) of the reaction.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 7","pages":"1894–1902"},"PeriodicalIF":3.3,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.oprd.6c00083","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148291452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of Kilogram-Scale Electrochemical Ni-Catalyzed Cross Electrophile Coupling in Flow","authors":"Megan Kelly,&nbsp;Luana Cardinale,&nbsp;Karrin V. Sackett,&nbsp;Suqi Zhang,&nbsp;Gregory L. Beutner,&nbsp;Benjamin Cohen,&nbsp;Shannon S. Stahl and Marcel Schreier*,&nbsp;","doi":"10.1021/acs.oprd.6c00110","DOIUrl":"10.1021/acs.oprd.6c00110","url":null,"abstract":"<p >Organic electrosynthesis opens novel routes for pharmaceutical production; however, limited knowledge and experience with the scale up of this technique have hindered its industrial implementation. In this work, we report a kilogram-scale flow electrochemical Ni-catalyzed cross-electrophile coupling (XEC) to prepare a key intermediate in the synthesis of the toll-like receptor (TLR) 7/8 inhibitor afimetoran. We successfully demonstrate scalability across 2 orders of magnitude while maintaining reaction performance. We also conduct a continuous 120 h reaction, highlighting compatibility with industrially relevant time scales. Key design aspects of our custom parallel-plate reactor are discussed that enabled kilogram-scale synthesis with a single electrode stack. This report showcases that with proper reaction engineering, electrochemical Ni-catalyzed XEC is a viable alternative to existing Pd-catalyzed cross-coupling methods.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 7","pages":"1926–1936"},"PeriodicalIF":3.3,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.oprd.6c00110","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148291656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kilogram-Scale Process Development of Formoterol Fumarate: Synthesis, Identification, and LC–MS/MS Method Development for Trace-Level Quantification of N-Nitroso Impurity","authors":"Kishor More*,&nbsp;Vinayak Vele,&nbsp;Rajesh Kamath,&nbsp;Mustapha Mandewale and Mohan Anand Chandavarkar,&nbsp;","doi":"10.1021/acs.oprd.6c00146","DOIUrl":"10.1021/acs.oprd.6c00146","url":null,"abstract":"<p >Formoterol fumarate is a long-acting, selective <i>β</i>_<i>2</i>-adrenergic agonist with a rapid onset of action, widely used in the treatment of bronchospastic disorders. An improved, kilogram-scale synthetic route to formoterol fumarate was developed, featuring an enhanced chiral resolution of a key intermediate using <span>l</span>-(+)-tartaric acid followed by a selective formylation step. The optimized process demonstrated consistent performance under batch manufacturing conditions and improved the overall yield up to 60%. Moreover, a sensitive and selective liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed and validated for trace-level quantification of the <i>N</i>-nitroso impurity associated with formoterol. The validated method exhibited stringent linearity and enabled reliable quantification of <i>N</i>-nitroso-formoterol in the range of 3.60–15.50 ppb. This sensitivity and reliability ensured effective monitoring and control of the <i>N</i>-nitroso-formoterol throughout the process development and commercial API manufacturing.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 7","pages":"1996–2007"},"PeriodicalIF":3.3,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148336319","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":"Automation in Pharmaceutical Crystallization","authors":"Giovanni Aprile,&nbsp;Peter Sagmeister,&nbsp;Cedric Devos,&nbsp;Aniket Udepurkar,&nbsp;Francesco Destro,&nbsp;Fateme Molajafari,&nbsp;Torsten Stelzer,&nbsp;Hamza Youssef Ismail,&nbsp;Daniel J. Griffin,&nbsp;Richard D. Braatz and Allan S. Myerson*,&nbsp;","doi":"10.1021/acs.oprd.6c00057","DOIUrl":"10.1021/acs.oprd.6c00057","url":null,"abstract":"<p >Crystallization is a key unit operation in the pharmaceutical industry for separation, purification, solid-form selection, and particle design. Yet, developing robust crystallization processes can be resource-intensive, since thermodynamics and kinetics both govern system behavior, resulting in numerous process parameters that must be optimized. Automation offers a powerful means to accelerate this development, but the very complexity that makes crystallization challenging─nonlinear responses, multiphase behavior, and a large design space, among other factors─also complicates automation. This review discusses how automation technologies are applied for resource-efficient crystallization process development, focusing on their contributions to the core process development activities: design space mapping, modeling, process control, optimization, and scale-up. Many automation tools─ranging from process analytical technology hardware to algorithmic experiment-selection and control software─are already widely used in crystallization, but typically in isolation. This review focuses on automation tools for pharmaceutical crystallization, emphasizing their role in accelerating process understanding, improving resource efficiency, enabling reproducible data generation, and supporting intelligent decision-making.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 7","pages":"1746–1780"},"PeriodicalIF":3.3,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148336334","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":"Applications of Raman Spectroscopy in Early Phase Chemical Development","authors":"Ravikumar Ramachandran,&nbsp;Sudhakar Alla,&nbsp;Lakshmikant Bajpai,&nbsp;Joel Young and Karthik Jayaraman*,&nbsp;","doi":"10.1021/acs.oprd.5c00376","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00376","url":null,"abstract":"<p >Raman spectroscopy has emerged as a powerful process analytical technology (PAT) tool in early phase pharmaceutical synthesis, offering real-time, nondestructive analysis without the need for sample preparation. This study explores the application of Raman spectroscopy across six case studies in early phase active pharmaceutical ingredient (API) development to enhance reaction monitoring, optimize synthesis efficiency, and ensure process safety. The case studies demonstrate the versatility of Raman spectroscopy in various contexts, including the monitoring of highly toxic reagents, detection of UV-inactive compounds, and analysis of reactive intermediates. In the first case study, Raman spectroscopy monitored the synthesis of 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP), overcoming limitations of liquid chromatography (LC) and ensuring safety by avoiding the use of water with sodium azide. The second case study highlighted the optimization of an esterification reaction in a pilot plant, where Raman data indicated reaction completion within 6 h, significantly reducing process time. The third case study focused on real-time optimization of reductive amination by precise imine monitoring, facilitating timely addition of sodium triacetoxyborohydride (STAB) to maximize yield. The fourth case study utilized Raman spectroscopy to assess the stability of an amine intermediate, identifying degradation and prompting immediate downstream processing. In the fifth case study, Raman-based compatibility testing ensured reactor safety by detecting active species in oxone without the drawbacks of conventional iodometric titration. The final case study demonstrated rapid impurity detection in raw materials, simplifying quality checks and reducing labor. Overall, this manuscript underscores the significant advantages of Raman spectroscopy in early phase chemical synthesis, including real-time monitoring, reduced need for extensive method development, and enhanced safety. By integrating Raman spectroscopy, pharmaceutical companies can accelerate development timelines, improve process understanding, and achieve more efficient manufacturing.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 7","pages":"1781–1788"},"PeriodicalIF":3.3,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148458408","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":"Optimized Kilogram-Scale Synthesis and Impurity Identification of Clascoterone","authors":"Yang Yang,&nbsp;Yaotian Zhang,&nbsp;Xiaoyan Shan,&nbsp;Lin Lin,&nbsp;Donghao Xi,&nbsp;Fuli Zhang* and Pengcheng Qiu*,&nbsp;","doi":"10.1021/acs.oprd.6c00022","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00022","url":null,"abstract":"<p >Clascoterone is a first-in-class topical androgen receptor inhibitor for acne treatment. We describe an optimized three-step kilogram-scale synthesis of clascoterone. By optimizing the reaction parameters, we developed a new strategy that utilizes NH₄Cl or Lewis acids to mediate the site-selective hydrolysis to solve the issues of acyl migration and overhydrolysis pathways. This process utilizes the selective coordination of the Lewis acid with the substrate to precisely activate its cyclic ketal structure, thereby significantly suppressing the formation of Impurity 5 (from C-21 propionyl isomerization) and Impurity 2 (from 17,21-dihydroxy hydrolysis). As a result, both impurities were consistently maintained below 0.1%. Eight process-related impurities were synthesized and characterized, including four previously unreported impurities, and corresponding control strategies were established. Validated at the 10 kg scale, the process delivered a 72.9% overall yield and API with ≥99.5% HPLC purity, meeting ICH Q6A specifications. The optimized process has mild reaction conditions, simple postprocessing, high yield, high purity, quality control, and cost-effectiveness and is suitable for large-scale industrial production.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 7","pages":"1833–1843"},"PeriodicalIF":3.3,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148458452","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":"A Concise and Efficient Synthesis of 25(S)-Δ7-Dafachronic Acid, a Lead Compound for the Development of Antiparasitic Agents","authors":"Federico Paccoia,&nbsp;Luigi Franchini,&nbsp;Giada Ceccarelli,&nbsp;Bruno Cerra and Antimo Gioiello*,&nbsp;","doi":"10.1021/acs.oprd.6c00188","DOIUrl":"10.1021/acs.oprd.6c00188","url":null,"abstract":"<p >25(<i>S</i>)-Δ⁷-Dafachronic acid is the endogenous ligand of the nuclear receptor DAF-12 and a key chemical probe for the discovery and development of new anthelmintic agents. Reliable access to multigram quantities of this natural steroid is crucial to enable chemical biology studies, improved analogue synthesis, and in vivo evaluations. Herein, we report the optimization of an eight-step synthetic route to 25(<i>S</i>)-Δ⁷-dafachronic acid from renewable, inexpensive, and readily available ergosterol, delivering the target compound in 44% overall yield on a multigram scale. Key process features include side chain oxidative cleavage via ozonolysis reaction and telescoping of the resulting C22-aldehyde into a Horner–Wadsworth–Emmons olefination without intermediate purification. A comparative assessment using process-relevant metrics, including safety, efficiency, and sustainability, demonstrates the superior performance of this route compared to previously reported synthetic approaches. Overall, this synthesis provides a practical and scalable access to 25(<i>S</i>)-Δ⁷-dafachronic acid for biological investigations and medicinal chemistry studies toward new antiparasitic agents.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 7","pages":"2085–2095"},"PeriodicalIF":3.3,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.oprd.6c00188","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148385584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Case Studies on Enabling Data-Rich, Parallelized Kinetic Analysis for Process Optimization with the ReactALL Platform","authors":"Vaishnavi N. Nair,&nbsp;Andreas R. Rötheli,&nbsp;Alan H. Cherney,&nbsp;Madeleine C. Deem,&nbsp;Melodie Christensen,&nbsp;Kevin Stone,&nbsp;Lu Han,&nbsp;Sebastien Monfette* and Truong N. Nguyen*,&nbsp;","doi":"10.1021/acs.oprd.6c00131","DOIUrl":"10.1021/acs.oprd.6c00131","url":null,"abstract":"<p >Automated, scale-predictive reaction profiling is often constrained by material limitations, sampling fidelity, and/or reactor mixing artifacts. We report the application of ReactALL, a five-reactor automated platform with a 5 mL working volume that integrates overhead agitation with built-in sampling, to generate reproducible, data-rich time-course reaction profiles. The performance of ReactALL was validated through three industry-relevant case studies: (1) the rapid, material-efficient development of an amidation reaction (Sanofi), (2) variable time normalization analysis (VTNA) of a Pd-catalyzed Suzuki–Miyaura coupling reaction (MSD), and (3) kinetic modeling of an S_NAr reaction (Pfizer). In each case, data sets obtained from ReactALL closely matched those obtained from established laboratory reactors while offering &gt;10-fold savings in material consumption compared to conventional automated laboratory reactors. The analysis of the generated data provided valuable and actionable insights into reaction behavior, accelerating effective process optimization and predictive modeling across a range of reaction types. Collectively, these results demonstrate that ReactALL enables material-efficient, parallelized generation of high-quality kinetic data, supporting mechanistic analysis, predictive modeling, and scalable process development.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 7","pages":"1976–1986"},"PeriodicalIF":3.3,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148385131","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}