Organic Process Research & Development最新文献

{"title":"Lessons Learned in Organic Process Chemistry","authors":"Hirotsugu Usutani, Makoto Michida, Yasumasa Hayashi, Margaret M. Faul","doi":"10.1021/acs.oprd.5c00353","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00353","url":null,"abstract":"Published as part of <i>Organic Process Research &amp; Development</i> special issue “Lessons Learned in Organic Process Chemistry”. The saying “<i>failure is the mother of success</i>” is familiar across cultures, and nowhere is it more relevant than in the practice of process chemistry. Behind every successful scale-up or robust manufacturing route lies a history of experiments that did not work as planned. These moments, though often left unspoken, are not wasted efforts. They are the foundation on which durable processes we develop and commercialize are built. In our field, progress rarely follows a straight line. The pursuit of an optimal process for a novel pharmaceutical or agrochemical entity requires navigating unexpected outcomes, revisiting assumptions, and adapting strategies. Impurities emerge without warning, crystallization pathways never meet our expectations, and reaction conditions that seem ideal on paper or even small scale can unravel at scale. Each challenge becomes a source of learning─insight that shapes the next experiment, the next campaign, and ultimately, the success of a program. What distinguishes process chemistry is not only the ingenuity of its technical solutions but also the willingness of its experts in the field to learn from the difficulties they have encountered and share those learnings. Communication is our most powerful tool. By recording and exchanging the lessons of setbacks as well as successes, we accelerate discovery, avoid repeating costly detours, and collectively raise the standard of our discipline. Traditionally, the academic record has emphasized positive results and final outcomes, while the equally important “negative data” have remained within individual laboratories or organizations. This Special Issue of <i>Organic Process Research &amp; Development</i> takes a different approach. It shines a light on the knowledge gained from failures, unexpected results, and the insights that arise from them. By curating these experiences, we aim to transform private lessons into a positive experience so that then shared wisdom can benefit the broader community. We hope that the case studies presented in this Special Issue will serve as both guideposts and encouragement. For the next generation of process chemists, they demonstrate that setbacks are not end points but turning points. For experienced practitioners, they provide a reminder that our discipline advances most when we are candid about the full journey of development, not just its successes. May these contributions inspire all of us to continue learning, recording, and sharing the lessons that shape the art and science of process chemistry. This article has not yet been cited by other publications.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"5 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153926","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":"Use of In Situ FTIR to Ensure Safe Quench of Phenylsilane","authors":"Blanka M. Hodur, Nisha P. Shah","doi":"10.1021/acs.oprd.5c00137","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00137","url":null,"abstract":"A process using phenylsilane was scaled in a multipurpose pilot plant, and a thorough understanding of the conditions under which it hydrolyzes, releasing flammable hydrogen gas, was required to enable safe processing and quenching procedures. Studies utilizing in situ FTIR, reaction calorimetry, and gas flow data determined that the hydrolysis of phenylsilane can be catalyzed by a small amount of base or metal and the rate of hydrolysis can vary widely with the solvent. The results highlight the necessity for a full hazard evaluation under the specific reaction conditions when working with hydrosilanes.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"80 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117215","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":"Process Development and Scale-Up of a Novel Route to 8-Aminooctanoic Acid","authors":"Peter Hermsen, Niels Krogsgaard-Larsen, Swarup De, Brian Rasmussen, Dennis Heemskerk, Michael Raunkjær, Bert Dielemans, Paul L. Alsters, Marijn Rijkers, Thomas Schmitges, Martin Schürmann","doi":"10.1021/acs.oprd.5c00109","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00109","url":null,"abstract":"A robust and scalable process for the production of 8-aminooctanoic acid has been developed. Starting from commercially available azelaic acid, the target compound was obtained in four steps in a 62% overall yield. The process starts with a Fischer esterification, followed by a highly selective enzymatic hydrolysis of dimethyl azelate to methyl hydrogen azelate. Ammonolysis of the latter using aqueous ammonia and subsequent Hofmann rearrangement yields 8-aminooctanoic acid. The scalability of the process has been demonstrated through the successful production of 25 kg of 8-aminooctanoic acid (5 kg batches). Furthermore, a proof of principle has been demonstrated for a further streamlined process in which the first three steps are telescoped.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"2 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103778","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":"Streamlined Atom-Economical Synthesis of Escitalopram: Kilogram-Scale Process Optimization and Industrial-Scale Implementation","authors":"Peng Yang, Xiyong Li, Jianghua He, Cailang Lai, Yan Sheng, Yue Huang, Xianxin Li, Hailong Wang, Yu Wan","doi":"10.1021/acs.oprd.5c00188","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00188","url":null,"abstract":"A straightforward, efficient, atom-economical, and scalable commercial manufacturing process was developed for the treatment of depression via commercial available starting materials. Citalopram, a selective serotonin reuptake inhibitor introduced in 1989, is a racemic mixture whose entire inhibitory activity resides in the S-(+)-enantiomer, also known as escitalopram. While the original six-step route suffered from sub-30% overall yield, inefficient diol resolution (&lt;40%), nonrecyclable solvents, and problematic reaction byproduct management, our redesigned process achieves three critical advancements: (1) controlled impurity profiles, enhanced reaction efficiency (over 90% yield per step), streamlined postprocessing and recyclable solvents for preparation of racemic diol; (2) effective stereoinvertive cyclization strategy for converting R-diol byproducts into escitalopram via S_N²; (3) closed-loop resolution agent recovery and valorization of escitalopram enantiomeric byproduct. Safety-optimized scale-up enabled production of 446 kg batches with exceptional purity (&gt;99.7%), enantiomeric excess (&gt;99.8% ee), and 81.6% overall yield─representing 3.9-fold process intensification versus legacy methods. This sustainable platform demonstrates unprecedented atom utilization efficiency (&gt;90%) while eliminating stereochemical waste, establishing new benchmarks for escitalopram manufacturing.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"79 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084097","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":"Thermal Hazard Evaluation and Safety Considerations for the Use of O-Benzoyl-N-alkyl Hydroxylamines as Synthetic Reagents","authors":"Joseph J. Topczewski, Hayden Cheek, Joseph M. Gruber, Brett M. Marsh, Daniel J. Valco","doi":"10.1021/acs.oprd.5c00177","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00177","url":null,"abstract":"Numerous synthetic methods utilize <i>O</i>-benzoyl-<i>N</i>-alkyl hydroxylamines (BzO-NR₂) as electrophilic aminating reagents. The need for gram scale quantities of these reagents prompted a detailed reactive chemistry evaluation. This report provides information on the thermal hazards associated with this class of BzO-NR₂ reagent. Several of these reagents demonstrated low detected onset temperatures, as determined by differential scanning calorimetry (DSC). The observed detected onset temperature was below the reported operating temperatures for some synthetic methods. Variable scan rate DSC data indicated a high probability of autocatalytic decomposition. These data were modeled by using Advanced Kinetics and Technology Solutions (AKTS) software to predict and confirm autocatalytic behavior. Accelerating rate calorimetry (ARC) was performed to confirm the low thermal onset, high exotherm, and gas generation of the decomposition. Finally, micro reaction calorimetry and analytical methods were used to confirm the initial steps of the decomposition pathway. Taken together, these results indicate that care should be taken in the synthesis, use, transport, and storage of these reagents.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"81 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078498","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":"Improved Process Understanding of Filtration Drying via a Rotary Evaporator-Based Process Analytical Technology (PAT) Interface","authors":"Jason Yu, Eduardo Madrigal, Lady Mae Alabanza, Derek M. Dalton, Zhenqi Shi","doi":"10.1021/acs.oprd.5c00161","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00161","url":null,"abstract":"The filtration drying of chemical solids is a critical unit operation in the isolation of active pharmaceutical ingredients and intermediates during the manufacturing process. Due to its central role in API isolation, it is important to understand the kinetics of filtration and drying processes to ensure minimal timeline impact and, importantly, the quality of the API produced. Process analytical technologies (PAT), such as Raman spectroscopy, near-infrared spectroscopy (NIRS), gas chromatography (GC), and mass spectrometry (MS), have been used to monitor filtration drying operations to provide real-time solvent content concentrations. However, each instrument has limitations, such as the need for at-scale calibration experiments with Raman and NIRS, and for GC and MS, the difficulty of correlating the headspace solvent concentration to the wet cake. Furthermore, current PAT methods to assess drying kinetics have large material demands, in even the smallest scale-down filter dryers, and lack representative measurements in a heterogeneous gas–solid sample matrix. To address some of these challenges, a drying workflow using a rotary evaporator (rotavap) with PAT interfaces has been developed in our lab. This unique rotavap PAT interface improves upon existing PAT drying methods because it reduces the material demand to as little as 1 g and, due to the rotational mechanism of the rotavap, ensures representative sampling by PAT of the wet cake during the drying curve collection. Three different drying case studies were carried out using the rotavap PAT interface and are illustrated herein. Initial slurry and final solid residual solvent concentrations were measured by GC or Karl Fischer (KF) methods and served not only as reference measurements for calibrating PAT sensors but were also used to rescale predicted solvent content by vibrational spectroscopy to capture accurate drying dynamics. Such PLS models were then applied to different experimental conditions across all three case studies, such as various drying temperatures and nitrogen sweep rates, to inform process understanding of the normal operating range of the filtration drying step. The alignment between the model predictions and offline reference measurements successfully demonstrates the value of the rotava p-based PAT interface for collecting filtration drying data in a material-sparing manner. This approach is expected to streamline the process development of API filtration drying steps by helping to determine the drying end point and also providing real-time drying data for kinetic modeling that could be used to predict drying outcomes at variable scales and across different filtration dryer designs.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"88 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078500","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":"Investigation of Pd Catalyst for Key Coupling Reaction in Asciminib Synthesis and Impurity Characterization","authors":"Kiran Aluri, Hrithvik Reddy Pullagurla, Syam Prasad Reddy Annareddy, Bhaskar Reddy Pitta","doi":"10.1021/acs.oprd.5c00192","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00192","url":null,"abstract":"Asciminib, marketed as Scemblix, is approved for treating adults with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP), as well as for those previously treated with two or more tyrosine kinase inhibitors (TKIs). Existing literature on Asciminib manufacturing processes involves considerable quantities of preformed Pd complex catalysts for the key coupling reaction. We optimized the commercial production process by identifying dichlorobis[di<i>tert</i>-butyl(4-dimethylaminophenyl)phosphine]palladium(II) PdCl₂(Amphos)₂ as the most effective catalyst for the key coupling reaction. By fine-tuning the Pd complex quantity to a 0.0035 weight ratio relative to the key starting material─approximately one-third of the previously reported amount─we achieved complete conversion and obtained the desired coupling product in high yield. Additionally, we developed a highly effective and commercially viable method combining <span>l</span>-cystine and activated carbon to efficiently remove Pd metal impurities from the final product. The optimized process was successfully validated under GMP conditions at the multikilogram level and has proven to be easily scalable for larger quantities. This report also addresses the lack of detailed information on potential process and degradation impurities of Asciminib. We identified and synthesized potential process impurities (P-1 to P-5) and degradation impurities (DP-1 to DP-3), confirming their structures using ¹H NMR, ¹³C NMR, mass spectrometry, and IR spectroscopy. This comprehensive impurity identification enhances the quality and safety of Asciminib and supports the development of robust analytical methods for impurity quantification and validation.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"53 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078501","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":"Kinetic Modeling of Solid-Phase Oligonucleotide Synthesis: Mechanistic Insights and Reaction Dynamics","authors":"David E. Pfister*,&nbsp;Airy Tilland,&nbsp;Ludivine Larue,&nbsp;Kilian Kobl,&nbsp;Philipp Weber and Martin Olbrich,&nbsp;","doi":"10.1021/acs.oprd.5c00199","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00199","url":null,"abstract":"<p >Solid-phase oligonucleotide synthesis is a cornerstone of modern biotechnology, enabling the production of custom DNA and RNA sequences for therapeutic, diagnostic, and research applications. Despite its widespread use, the kinetics of this process remain incompletely understood, limiting efforts to enhance efficiency and yield and reduce environmental impact. This study presents a comprehensive kinetic model of solid-phase oligonucleotide synthesis, integrating mechanistic insights into the stepwise coupling, capping, oxidation, and detritylation reactions. Using a combination of computational simulations and experimental data, we identify rate-limiting steps and quantify the influence of reaction conditions─such as concentrations, step duration, and stoichiometry─on synthesis performance. The model is a first step to predicting strategies for process optimization, including adjusted cycle times and excess ratios. Validation against experimental synthesis runs demonstrates that the proposed model can be used for predictive purposes. These findings offer a quantitative framework for improving solid-phase oligonucleotide synthesis with implications for scalable production and cost-effective design of nucleic acid–based technologies.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 9","pages":"2298–2309"},"PeriodicalIF":3.5,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094420","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":"An Alternate and Efficient Synthetic Process for a Metabolic Dysfunction-Associated Steatohepatitis Drug: Resmetirom","authors":"Youbao Cui,&nbsp;Jiachen Zhang,&nbsp;Shuyu Liu,&nbsp;Zhenhang Zhao,&nbsp;Mengya Shan,&nbsp;Nan Jiang* and Xin Zhai*,&nbsp;","doi":"10.1021/acs.oprd.5c00149","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00149","url":null,"abstract":"<p >A novel, efficient, and streamlined process was developed for resmetirom, a first-in-class THR-β agonist for the treatment of MASH. The key innovation of this novel process was the ingenious utilization of a “one-pot” reaction, which simultaneously accomplished aromatic cyclization and the hydrolysis of 3-chloro-4-isopropylpyridazine. This breakthrough circumvented steps of amino protection and deprotection, effectively streamlining the synthetic route from eight linear steps to four steps while maintaining mild reaction conditions. Using commercially available raw materials, the optimized process provided a rapid pathway to synthesize multigram quantities of resmetirom with an assay purity of 98.8% and a corrected overall yield of 44.3%.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 9","pages":"2230–2237"},"PeriodicalIF":3.5,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094421","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 a Scalable Process for an LPAR1 Antagonist with a Complex Form Landscape, GS-2278","authors":"Dane Holte*,&nbsp;Kathy Dao,&nbsp;Nathaniel Kadunce,&nbsp;Henry Morrison,&nbsp;David A. Siler and Anna M. Wagner,&nbsp;","doi":"10.1021/acs.oprd.5c00251","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00251","url":null,"abstract":"<p ><b>GS-2278</b> (<b>1</b>) is a lysophosphatidic acid receptor 1 (LPAR1) antagonist with a complex form landscape (15 freebase polymorphs) that was selected for development as a treatment of idiopathic pulmonary fibrosis (IPF). The thermodynamically most stable unsolvated polymorph, <b>1-A</b>, was selected for initial development, but due to low solubility and poor pharmacokinetics (PK), a salt form was desired for long-term development. Ultimately, the dihydrate hydrochloride salt, <b>1-HCl 2H</b>_<b>2</b><b>O</b>, became the desired API for development. However, impurity carryover in this salt-forming step remained high throughout development, placing the burden of impurity control on the penultimate reaction and isolation of freebase <b>1</b>. During the early process development of <b>1</b>, several generations of reaction, isolation, and crystallization were designed to ensure form control, chemical purity, and high yield. This manuscript details the challenges faced and overcome during the continuous development of the freebase <b>1</b> across a complex form landscape as well as the development and isolation of <b>1-HCl 2H</b>_<b>2</b><b>O</b>.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 9","pages":"2378–2387"},"PeriodicalIF":3.5,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094712","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}