Organic Process Research & Development最新文献

{"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}

{"title":"Development of Scalable Synthesis of Chiral Sultam via a Chiral Phosphoric Acid-Promoted tert-Butyl Carbamate Deprotection–Resolution Sequence or Diastereoselective Hydrogenation","authors":"Caroline A. Blakemore,&nbsp;Adam R. Brown,&nbsp;Todd W. Butler,&nbsp;Christopher W. am Ende,&nbsp;Nahian Khan,&nbsp;Sarai Lara-Boykin,&nbsp;Bryan Li,&nbsp;Guochun Ma,&nbsp;Javier Magano,&nbsp;Subham Mahapatra,&nbsp;Peter D. Morse,&nbsp;Giselle P. Reyes,&nbsp;Colin Rose,&nbsp;Neal W. Sach,&nbsp;Liam S. Sharninghausen,&nbsp;Jared Van Haitsma,&nbsp;Pengzhi Wang,&nbsp;Daniel W. Widlicka and Zebediah C. Girvin,&nbsp;","doi":"10.1021/acs.oprd.5c00263","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00263","url":null,"abstract":"<p >The discovery and process development for the synthesis of diastereopure sultam (<b>1</b>), a key chiral intermediate in route to a clinical candidate, are disclosed. Continuous route development to access (<b>1</b>) was required to satisfy both time and dynamic material needs during successive campaigns. Three distinct methods were developed to obtain diastereopure material. The first-generation process invoked time-intensive supercritical fluid chromatography (SFC) to access the diastereopure (<b>2</b>). Subsequent route development enabled a scalable, time-effective classical resolution approach that provided &gt;20 kg of (<b>1</b>). Lastly, a Ruthenium-catalyzed diastereoselective hydrogenation approach was demonstrated on a hundred-gram scale and then coupled to the resolution technology to access (<b>1</b>), both reducing step count and improving overall yield relative to the resolution approach.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 9","pages":"2410–2422"},"PeriodicalIF":3.5,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094713","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":"Novel and Efficient Synthesis of Potassium-Competitive Acid Blocker Fexuprazan","authors":"Wei Qian,&nbsp;Fangyuan Hu,&nbsp;Qianxi Feng,&nbsp;Jiahui Ren,&nbsp;Qiaohong Huang,&nbsp;Shiling Liu,&nbsp;Fei Ling,&nbsp;Chunlin Wen,&nbsp;Yu Feng* and Weihui Zhong*,&nbsp;","doi":"10.1021/acs.oprd.5c00255","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00255","url":null,"abstract":"<p >Fexuprazan is a novel potassium-competitive acid blocker (P-CAB). The conventional synthesis route involves preparing methyl 5-(2,4-difluorophenyl)-4-methoxy-1<i>H</i>-pyrrole-3-carboxylate (<b>7</b>), a key intermediate associated with toxicity concerns, environmental pollution, and low yields. This article aims to develop an innovative synthetic strategy to overcome these limitations. Our approach utilizes 3-aminopropionitrile and methyl 2-(2,4-difluorophenyl)-2-oxoacetate (<b>20</b>) as key precursors for a streamlined one-pot synthesis of the cyano-containing pyrrole <b>23</b>, achieving a 90.0% yield. A significant advancement is the subsequent implementation of hydrogen gas as an ecofriendly reductant for direct cyano-to-aldehyde conversion. Starting from cost-effective 1,3-difluorobenzene (<b>18</b>), the optimized six-step route delivers fexuprazan hydrochloride (<b>1</b>) with an overall yield of 42.6% at kilogram scale. This improved protocol demonstrates significant advantages in process economics, operational simplicity, and environmental sustainability, establishing a robust platform for industrial-scale manufacture.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 9","pages":"2400–2409"},"PeriodicalIF":3.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094658","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":"Manufacturing Process for HIF-2α Inhibitor Casdatifan (AB521): Creating Five Chiral Centers with High Stereoselectivity","authors":"Zhiguo Jake Song*,&nbsp;Xiaopeng Yin,&nbsp;Vimal Varghese,&nbsp;Jaroslaw Kalisiak,&nbsp;Michael T. Corbett,&nbsp;Bruce Kowalczyk,&nbsp;Zhongzhen Li,&nbsp;Hongfeng Li,&nbsp;Weikai Wang,&nbsp;Yinhe Bao,&nbsp;Jie Wang,&nbsp;Xiong Xiong and Yafei Hu,&nbsp;","doi":"10.1021/acs.oprd.5c00214","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00214","url":null,"abstract":"<p >A manufacturing process for HIF-2α inhibitor casdatifan suitable on a multikilogram scale and beyond is presented. Key features include the convergent coupling of two fragments (<b>A7</b> and <b>B4</b>) of similar complexity, followed by diastereoselective olefin hydrogenation to introduce the tetralin central C-8 chiral center of intermediate <b>C4</b>. Double electrophilic alpha fluorination of the diketone <b>C4</b>, followed by double Noyori transfer hydrogenation enables the introduction of the additional four chiral centers to produce the penultimate diol intermediate <b>C6</b>. Chemo and stereoselective deoxyfluorination of one of the two benzylic alcohols produces casdatifan.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 9","pages":"2346–2360"},"PeriodicalIF":3.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094382","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":"Review of the Synthesis of Gatifloxacin and Ofloxacin Drug Substances Used for the Treatment of Eye Infections","authors":"Rajarathnam E. Reddy*,&nbsp;Alexander S. Wong,&nbsp;David J. Babinski and Michael A. Haley,&nbsp;","doi":"10.1021/acs.oprd.5c00225","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00225","url":null,"abstract":"<p >A variety of eye infections are caused by microorganisms such as bacteria, viruses, fungi, and parasites, and they have a significant impact on eyes in all ages of population worldwide ranging from inconvenience, visual impairment, blindness, and death. The objective of this review is to provide a brief overview of eye infectious diseases, with an emphasis on the importance of quinolone antibiotics in eye care. Gatifloxacin (<b>1</b>) and ofloxacin (<b>2</b>) are important anti-infectious agents widely used for the treatment of ocular infections. A literature review of various synthetic approaches for the preparation of gatifloxacin (<b>1</b>) and ofloxacin (<b>2</b>) drug substances is presented. In addition, the reported gatifloxacin (<b>1</b>) and ofloxacin (<b>2</b>) synthetic routes were assessed for their strengths and weaknesses from a process chemistry perspective. A comparative summary is provided based on drug substance batch size, quality, process and manufacturability, safety, and environmental considerations.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 9","pages":"2146–2160"},"PeriodicalIF":3.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094336","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 Reduction of an Ester to Aldehyde in CSTR: From Laboratory to Industrial Plant","authors":"Matteo Baudino*,&nbsp;Debora Rossini,&nbsp;Ludovico Marinoni,&nbsp;Davide Gornati,&nbsp;Fabio Morana and Jacopo Roletto,&nbsp;","doi":"10.1021/acs.oprd.5c00265","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00265","url":null,"abstract":"<p >The reduction of an ester to the corresponding aldehyde using DIBAL-H is a classic example of a reaction that is difficult to scale in batch mode. The highly exothermic nature of the reduction, combined with DIBAL-H’s limited selectivity toward the ester substrate, often results in significant formation of the corresponding alcohol as an over-reduced byproduct. This paper presents the optimization and scale-up of ester reduction to aldehyde using a continuous stirred tank reactor (CSTR) technology under cryogenic conditions. Optimal reaction conditions were determined through a design of experiments (DoE) approach, employing multivariate analysis to evaluate the impact of the following key parameters: DIBAL-H equivalents, residence time, temperature. After identifying the optimal conditions to minimize the formation of over-reduced byproducts, the reaction enthalpy was experimentally measured to ensure safe and efficient operation at scale. The process was ultimately scaled successfully from the laboratory scale to multiton industrial production.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 9","pages":"2423–2428"},"PeriodicalIF":3.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094597","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":"Cu-Catalyzed C–N Couplings with Benzilamide Ligands","authors":"Ian Hotham,&nbsp;Daniel W. Widlicka,&nbsp;Robert A. Singer*,&nbsp;David J. Bernhardson and Zheng Wang,&nbsp;","doi":"10.1021/acs.oprd.5c00257","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00257","url":null,"abstract":"<p >A linker fragment used in the preparation of an oncology candidate is efficiently synthesized via Cu-catalyzed C–N coupling. The original route required a Cu-catalyzed coupling, followed by an oxidation and protection sequence. After the evaluation of hydroxypicolinamide ligands and other amide ligands as inefficient for a more desirable C–N coupling sequence, screening of new ligands commenced. With a new catalyst derived from Cu salts and dimethoxyphenylbenzilamide (DMPB), the linker fragment can be directly prepared with commodity chemicals, avoiding oxidation. The DMPB ligand for the Cu catalyst is readily prepared from benzilic acid and 2,6-dimethoxyaniline. A brief survey of the scope of this Cu-DMPB system is explored for secondary and primary amines.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 9","pages":"2388–2399"},"PeriodicalIF":3.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094470","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":"Methanol Steam Reforming Controls the Selective Transfer Hydrogenation vs N-Methylation of Nitrobenzene Using a PVP-Stabilized IrO2 Nanoparticle Catalyst","authors":"Elizabeth Lee,&nbsp;Jessica Clore,&nbsp;Hailey Catania,&nbsp;Samantha Seifert,&nbsp;Emma Elinski and Meng Zhou*,&nbsp;","doi":"10.1021/acs.oprd.5c00210","DOIUrl":"10.1021/acs.oprd.5c00210","url":null,"abstract":"<p >Polyvinylpyrrolidone-stabilized iridium oxide nanoparticles (<b>PVP</b>_<b>1.7</b><b>IrO</b>_<b>2</b>) catalyzed the transfer hydrogenation and <i>N</i>-methylation of nitrobenzene, where the water content controlled the selectivity between aniline and <i>N</i>-methylaniline (NMA). Methanol served as the source of hydrogen and carbon in these reactions. When 1:1 methanol/water was used as the solvent, aniline was formed in a ratio of 13:1 over NMA. Without water, the chemoselectivity is reversed using an organic superbase, 1,8-diazabicyclo(5.4.0)undec-7-ene, instead of KOH. Both reactions achieved quantitative substrate conversion at 160 °C in 1 h. In control experiments under otherwise identical conditions, IrO₂ and metallic Ir powder led to ineffective and unselective reactions, respectively. In contrast to <b>PVP</b>_<b>1.7</b><b>IrO</b>_<b>2</b>, these microcrystalline solids could not form a homogenized colloidal suspension in solution. At the end of the <b>PVP</b>_<b>1.7</b><b>IrO</b>_<b>2</b>-catalyzed reactions, up to 5,131 ppm of CO₂ was detected in the gas phase by nondispersive infrared analysis. The amount of CO₂ in the solution phase was determined using the precipitation of BaCO₃ from Ba(OH)₂. The BaCO₃ was verified by powder X-ray diffraction and quantified by gravimetric analysis to reveal an 88% yield of CO₂ relative to the substrate for the aniline-selective reaction and an 87% yield for the NMA-selective reaction with KOH. A control experiment without methanol under otherwise identical conditions in pure H₂O solvent gave only a 5% yield of CO₂. When the reaction temperature was lowered to 100 °C, potassium formate was detected in 34% yield at the end of the reaction in methanol, consistent with a pathway of methanol steam reforming. Overall, the formation of C1 products from methanol and the water effect on chemoselectivity suggest that methanol steam reforming is key to the catalytic transfer hydrogenation and <i>N</i>-methylation of nitrobenzene.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 9","pages":"2327–2338"},"PeriodicalIF":3.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144931376","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}