Pub Date : 2026-03-24DOI: 10.1021/acs.oprd.5c00400
Shrivatsa Shrirang Korde,Gintaras V. Reklaitis,Zoltan K. Nagy
The global rise in pharmaceutical use over the past two decades has led to more unused drug products and a corresponding surge in pharmaceutical waste. Thus, there is an impetus to develop processes for recovering active pharmaceutical ingredients (APIs) from unused drugs. This study introduces a multiobjective optimization framework for solvent screening to enable sustainable recovery of APIs using a general separation train with cooling crystallization as the final step. The objectives considered are recovery during crystallization, the relative solubilities of API and excipients, and process mass intensity (PMI), which accounts for process sustainability. The framework is demonstrated using various commercial formulations of paracetamol (PA) for experimental validation. The recoveries obtained were in the range 57–63%, and the recovered API samples were of high chemical purity based on characterization using Raman spectroscopy and powder X-ray diffraction (PXRD).
{"title":"Generalized Digital Framework for the Sustainable Recovery of Active Pharmaceutical Ingredients from Solid Drug Formulations","authors":"Shrivatsa Shrirang Korde,Gintaras V. Reklaitis,Zoltan K. Nagy","doi":"10.1021/acs.oprd.5c00400","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00400","url":null,"abstract":"The global rise in pharmaceutical use over the past two decades has led to more unused drug products and a corresponding surge in pharmaceutical waste. Thus, there is an impetus to develop processes for recovering active pharmaceutical ingredients (APIs) from unused drugs. This study introduces a multiobjective optimization framework for solvent screening to enable sustainable recovery of APIs using a general separation train with cooling crystallization as the final step. The objectives considered are recovery during crystallization, the relative solubilities of API and excipients, and process mass intensity (PMI), which accounts for process sustainability. The framework is demonstrated using various commercial formulations of paracetamol (PA) for experimental validation. The recoveries obtained were in the range 57–63%, and the recovered API samples were of high chemical purity based on characterization using Raman spectroscopy and powder X-ray diffraction (PXRD).","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"3 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506232","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}
Pub Date : 2026-03-24DOI: 10.1021/acs.oprd.5c00409
Jeffrey S. Derrick,Stasik Popov,Cecilia Bottecchia,Ben W. H. Turnbull,François Lévesque,Andrew J. Neel,Nastaran Salehi Marzijarani,Chibueze I. Onyeagusi,Douglas A. L. Otte,Brittany Holden,Yining Ji,Alex Confer,Gilmar A. Brito,Yingju Xu,Michelle Zheng,Yu-hong Lam,Jamie M. McCabe Dunn,Mark Brower
We report the development and scale-up of a Claisen condensation en route to MK-7845, a small molecule evaluated for the treatment of COVID-19. Compared with other synthetic approaches, the Claisen sequence described herein provides access to a key 1,3-ketoester intermediate in excellent yield, starting from readily available and inexpensive reagents. The solutions identified to overcome the reactivity challenges associated with this transformation include the design and selection of an appropriate electrophile coupling partner and the implementation of a continuous-flow cascade for the generation and immediate consumption of unstable reactive intermediates. The Claisen sequence was demonstrated on a kilogram scale, highlighting its viability, efficiency, and robustness.
{"title":"Development of a Claisen Condensation in Flow toward the Synthesis of MK-7845","authors":"Jeffrey S. Derrick,Stasik Popov,Cecilia Bottecchia,Ben W. H. Turnbull,François Lévesque,Andrew J. Neel,Nastaran Salehi Marzijarani,Chibueze I. Onyeagusi,Douglas A. L. Otte,Brittany Holden,Yining Ji,Alex Confer,Gilmar A. Brito,Yingju Xu,Michelle Zheng,Yu-hong Lam,Jamie M. McCabe Dunn,Mark Brower","doi":"10.1021/acs.oprd.5c00409","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00409","url":null,"abstract":"We report the development and scale-up of a Claisen condensation en route to MK-7845, a small molecule evaluated for the treatment of COVID-19. Compared with other synthetic approaches, the Claisen sequence described herein provides access to a key 1,3-ketoester intermediate in excellent yield, starting from readily available and inexpensive reagents. The solutions identified to overcome the reactivity challenges associated with this transformation include the design and selection of an appropriate electrophile coupling partner and the implementation of a continuous-flow cascade for the generation and immediate consumption of unstable reactive intermediates. The Claisen sequence was demonstrated on a kilogram scale, highlighting its viability, efficiency, and robustness.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"33 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506231","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}
Pub Date : 2026-03-24DOI: 10.1021/acs.oprd.5c00507
Bhoopendra Singh Kushwah,Vasantha Krishna Kadambar,Michael B. Peddicord,Jonathan Marshall,Ashok Kumar Rajendran,Vajir Fakirsab Tamboli,Saravanan Natarajan,Lakshmikant Bajpai,Joel Young
B2(neo)2 is emerging as the preferred borylating reagent for Suzuki coupling reactions, outperforming widely used alternatives such as bis(pinacolato)diboron (B2pin2) and tetrahydroxy diboron (BBA). This preference is attributed to its greater reactivity and ease of handling, notably because it minimizes the risk of hydrogen evolution. Moreover, the lower stability and presence of oligomers in boronic acids further highlight the advantages of B2(neo)2. However, many boronic acid and ester reagents pose a risk as potential genotoxic impurities (GTIs), requiring stringent control strategies in drugs and formulated drug products. This article presents the first highly selective and specific analytical method for the precise quantification of bis(neopentyl glycolato)diboron [B2(neo)2] in active pharmaceutical ingredients (APIs) and intermediates using gas chromatography–mass spectrometry (GC–MS). Although the analyte of interest did not exhibit an M•+ ion in GC–MS, its fragments were well-characterized by gas chromatography-high-resolution mass spectrometry. Quantification relied on the signature fragment of m/z 211 and another intense fragment of m/z 69, while additional fragments of m/z 55, 56, and 70 were utilized for qualification. A systematic method optimization was conducted in the selected ion monitoring mode involving column screening, gas flow, and oven program optimization using the most intense fragment of m/z 69. The final optimized method was validated in compliance with ICH guidelines, using Losartan as a model API. It achieved a limit of detection of 2 ppm (0.01 ppm) and a limit of quantification of 10 ppm (0.05 ppm). The method demonstrated linearity from 10 ppm (0.05 ppm) to 200 ppm (1 ppm), with recovery values between 88 and 106%.
{"title":"First Method for Trace-Level Quantification of the Potential Genotoxic Impurity Bis(neopentyl glycolato)diboron Using GC–MS","authors":"Bhoopendra Singh Kushwah,Vasantha Krishna Kadambar,Michael B. Peddicord,Jonathan Marshall,Ashok Kumar Rajendran,Vajir Fakirsab Tamboli,Saravanan Natarajan,Lakshmikant Bajpai,Joel Young","doi":"10.1021/acs.oprd.5c00507","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00507","url":null,"abstract":"B2(neo)2 is emerging as the preferred borylating reagent for Suzuki coupling reactions, outperforming widely used alternatives such as bis(pinacolato)diboron (B2pin2) and tetrahydroxy diboron (BBA). This preference is attributed to its greater reactivity and ease of handling, notably because it minimizes the risk of hydrogen evolution. Moreover, the lower stability and presence of oligomers in boronic acids further highlight the advantages of B2(neo)2. However, many boronic acid and ester reagents pose a risk as potential genotoxic impurities (GTIs), requiring stringent control strategies in drugs and formulated drug products. This article presents the first highly selective and specific analytical method for the precise quantification of bis(neopentyl glycolato)diboron [B2(neo)2] in active pharmaceutical ingredients (APIs) and intermediates using gas chromatography–mass spectrometry (GC–MS). Although the analyte of interest did not exhibit an M•+ ion in GC–MS, its fragments were well-characterized by gas chromatography-high-resolution mass spectrometry. Quantification relied on the signature fragment of m/z 211 and another intense fragment of m/z 69, while additional fragments of m/z 55, 56, and 70 were utilized for qualification. A systematic method optimization was conducted in the selected ion monitoring mode involving column screening, gas flow, and oven program optimization using the most intense fragment of m/z 69. The final optimized method was validated in compliance with ICH guidelines, using Losartan as a model API. It achieved a limit of detection of 2 ppm (0.01 ppm) and a limit of quantification of 10 ppm (0.05 ppm). The method demonstrated linearity from 10 ppm (0.05 ppm) to 200 ppm (1 ppm), with recovery values between 88 and 106%.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"42 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506230","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}
Pub Date : 2026-03-19DOI: 10.1021/acs.oprd.5c00357
Chiara Colletto
Since its discovery by H. C. Brown and H. I. Schlesinger in 1943, sodium borohydride (NaBH4, SBH) has become one of the most widely used organometallic reducing agents, with applications in the synthesis of pharmaceuticals, agrochemicals, flavors and fragrances, and other industrial sectors like electronics, pulp and paper industry, water treatment and metal recovery, surfactants, textiles, in the hops processing and as a hydrogen carrier. This review focuses on its recent applications in organic synthesis, emphasizing the advantages of SBH over alternative reducing agents and discussing its relevance across key industrial sectors.
{"title":"Reductive Transformations with Sodium Borohydride and Their Applications","authors":"Chiara Colletto","doi":"10.1021/acs.oprd.5c00357","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00357","url":null,"abstract":"Since its discovery by H. C. Brown and H. I. Schlesinger in 1943, sodium borohydride (NaBH<sub>4</sub>, SBH) has become one of the most widely used organometallic reducing agents, with applications in the synthesis of pharmaceuticals, agrochemicals, flavors and fragrances, and other industrial sectors like electronics, pulp and paper industry, water treatment and metal recovery, surfactants, textiles, in the hops processing and as a hydrogen carrier. This review focuses on its recent applications in organic synthesis, emphasizing the advantages of SBH over alternative reducing agents and discussing its relevance across key industrial sectors.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"312 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479017","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}
This study addresses the significant exothermic risk associated with the scaled-up synthesis of a key chemical intermediate, 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane. To precisely control the reaction heat distribution and optimize the reaction parameters, we developed a continuous-flow process optimization method guided by computational fluid dynamics (CFD) and enhanced through the combined application of kinetic modeling and machine learning (ML). A cross-platform cooperative optimization strategy was employed, which successfully identified the optimal reaction parameters: a reactant concentration of 1.013 mol/L, a temperature of 50 °C, a catalyst loading of 0.17 mol/L, and a residence time of 15 min. Under these conditions, the continuous-flow system operated stably, achieving the product in >90% yield and >99% purity. Scale-up experiments confirmed a space-time yield (STY) of 244.17 g·L–1·h–1. These results demonstrate that the integrated “continuous-flow-ML” strategy not only significantly improves the safety and product quality of highly exothermic reactions but also provides a general theoretical framework and a technical pathway for the development and optimization of continuous-flow processes.
{"title":"Bayesian Optimization and Kinetic Modeling for Continuous-Flow Synthesis of 4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane Directed by Computational Fluid Dynamics","authors":"Nian Chen, Junfeng Zhi, Qiuming Yan, Zhichao Wu, Yichen Shi, Zhixiang Wang, Xiaoming Zha","doi":"10.1021/acs.oprd.6c00049","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00049","url":null,"abstract":"This study addresses the significant exothermic risk associated with the scaled-up synthesis of a key chemical intermediate, 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane. To precisely control the reaction heat distribution and optimize the reaction parameters, we developed a continuous-flow process optimization method guided by computational fluid dynamics (CFD) and enhanced through the combined application of kinetic modeling and machine learning (ML). A cross-platform cooperative optimization strategy was employed, which successfully identified the optimal reaction parameters: a reactant concentration of 1.013 mol/L, a temperature of 50 °C, a catalyst loading of 0.17 mol/L, and a residence time of 15 min. Under these conditions, the continuous-flow system operated stably, achieving the product in >90% yield and >99% purity. Scale-up experiments confirmed a space-time yield (STY) of 244.17 g·L<sup>–1</sup>·h<sup>–1</sup>. These results demonstrate that the integrated “continuous-flow-ML” strategy not only significantly improves the safety and product quality of highly exothermic reactions but also provides a general theoretical framework and a technical pathway for the development and optimization of continuous-flow processes.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"13 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147490123","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}
Pub Date : 2026-03-18DOI: 10.1021/acs.oprd.5c00402
Lili Virág Bereczki-Horváth, Botond Szilágyi
Wet milling is increasingly employed as a process-intensification tool in pharmaceutical batch crystallization, not only as a terminal particle-size reduction step but also as an integrated unit operation synchronized with the crystallizer to enhance process robustness and expand the attainable range of particle-size and shape distributions. Designing a high-performance batch crystallization process is challenging because of the large number of design variables that often require repeated crystallization and dissolution cycles. Synchronizing the crystallizer and wet-milling operations adds further complexity. Direct nucleation control (DNC) is widely used to automatically design cycles of crystal growth and dissolution for single-input, single-output systems─for example, adjusting the temperature to maintain the relative number density within a predefined range. This study extends the DNC principle to handle an integrated system. We propose a sequential split-range controller that regulates the relative number density by employing cooling and heating as the primary manipulated variables. When the target particle count cannot be achieved by cooling alone, a wet-milling cycle is automatically initiated to increase the count through high shear, thereby enhancing the nucleation, attrition, and breakage. Experimental results indicate that this control strategy can drive the process beyond the limits of conventional DNC, producing repeated cycles of growth and nucleation (by cooling or sequential cooling and milling) and dissolution (by heating). In addition to generating larger crystals, the automatic milling cycles also reduced the aspect ratio of rod-like particles, demonstrating the potential for simultaneous crystal-shape control. Repeated implementation of the integrated operation discovered by split-range DNC exhibited high reproducibility, underscoring the potential of the method not only as a control strategy but also as a rapid process-design tool.
{"title":"Automatic Design of Wet-Milling-Integrated Batch Crystallization Processes by Process Analytical Technology-Based Split-Range Direct Nucleation Control","authors":"Lili Virág Bereczki-Horváth, Botond Szilágyi","doi":"10.1021/acs.oprd.5c00402","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00402","url":null,"abstract":"Wet milling is increasingly employed as a process-intensification tool in pharmaceutical batch crystallization, not only as a terminal particle-size reduction step but also as an integrated unit operation synchronized with the crystallizer to enhance process robustness and expand the attainable range of particle-size and shape distributions. Designing a high-performance batch crystallization process is challenging because of the large number of design variables that often require repeated crystallization and dissolution cycles. Synchronizing the crystallizer and wet-milling operations adds further complexity. Direct nucleation control (DNC) is widely used to automatically design cycles of crystal growth and dissolution for single-input, single-output systems─for example, adjusting the temperature to maintain the relative number density within a predefined range. This study extends the DNC principle to handle an integrated system. We propose a sequential split-range controller that regulates the relative number density by employing cooling and heating as the primary manipulated variables. When the target particle count cannot be achieved by cooling alone, a wet-milling cycle is automatically initiated to increase the count through high shear, thereby enhancing the nucleation, attrition, and breakage. Experimental results indicate that this control strategy can drive the process beyond the limits of conventional DNC, producing repeated cycles of growth and nucleation (by cooling or sequential cooling and milling) and dissolution (by heating). In addition to generating larger crystals, the automatic milling cycles also reduced the aspect ratio of rod-like particles, demonstrating the potential for simultaneous crystal-shape control. Repeated implementation of the integrated operation discovered by split-range DNC exhibited high reproducibility, underscoring the potential of the method not only as a control strategy but also as a rapid process-design tool.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"20 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478187","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}
Pub Date : 2026-03-16DOI: 10.1021/acs.oprd.6c00006
Unjila Afrin, Aaron Baldwin, Arlene P. Bartolome, Nga M. Do, Andres R. Faria Quintero, David F. Fernández, Jonathan Fifer, Steven J. Fussell, Shanjun Huang, Gary R. Jolin, Md Kamrul Hasan Khan, Melissa Lee, Taegyo Lee, Laura McGivern, Giselle P. Reyes, Rachel Ruest, Adam Scott, Ursula Sheridan, Steven J. R. Twiddle, Angela L. A. Puchlopek-Dermenci, Chase Anthony Salazar, Sergei Tcyrulnikov, Gerald A. Weisenburger, Bianca Williams, Yexenia Nieves-Quinones
Danuglipron tromethamine (1), a glucagon-like peptide-1 receptor (GLP-1R) agonist candidate, was investigated by Pfizer for the treatment of type 2 diabetes mellitus (T2DM) and obesity. Given the anticipated high clinical and commercial demand for danuglipron tromethamine, the development of a robust, efficient, and sustainable manufacturing process was critical. This work describes the optimization and development of a telescoped process for the initial steps of the synthesis, featuring a Pd-catalyzed C–O coupling and an acidic t-butoxycarbamate deprotection. This is the first of two papers describing the commercial route for danuglipron tromethamine.
{"title":"Synthesis of Danuglipron: Design and Development of a Robust Telescoped C–O Coupling─Deprotection Sequence","authors":"Unjila Afrin, Aaron Baldwin, Arlene P. Bartolome, Nga M. Do, Andres R. Faria Quintero, David F. Fernández, Jonathan Fifer, Steven J. Fussell, Shanjun Huang, Gary R. Jolin, Md Kamrul Hasan Khan, Melissa Lee, Taegyo Lee, Laura McGivern, Giselle P. Reyes, Rachel Ruest, Adam Scott, Ursula Sheridan, Steven J. R. Twiddle, Angela L. A. Puchlopek-Dermenci, Chase Anthony Salazar, Sergei Tcyrulnikov, Gerald A. Weisenburger, Bianca Williams, Yexenia Nieves-Quinones","doi":"10.1021/acs.oprd.6c00006","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00006","url":null,"abstract":"Danuglipron tromethamine (<b>1</b>), a glucagon-like peptide-1 receptor (GLP-1R) agonist candidate, was investigated by Pfizer for the treatment of type 2 diabetes mellitus (T2DM) and obesity. Given the anticipated high clinical and commercial demand for danuglipron tromethamine, the development of a robust, efficient, and sustainable manufacturing process was critical. This work describes the optimization and development of a telescoped process for the initial steps of the synthesis, featuring a Pd-catalyzed C–O coupling and an acidic <i>t</i>-butoxycarbamate deprotection. This is the first of two papers describing the commercial route for danuglipron tromethamine.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"100 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147461999","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}
Starting from kanamycin B, the important 3′,4′-alkene intermediate is synthesized through selective N-Boc protection, regioselective 4″,6″-O-benzylidene acetalization and Garegg–Samuelsson reaction. Within the framework of response surface methodology (RSM), the central composite design (CCD) was used to systematically optimize the process parameters of the key step in the Garegg–Samuelsson reaction, aiming to improve the selectivity of the target product. Density functional theory (DFT) calculations, in conjunction with steric hindrance analysis (% Vbur), were applied to elucidate the pathways of impurity formation and site reactivity during the iodination–elimination step. A telescoped cascade deprotection and hydrogenation process ultimately yielded dibekacin (1) with an overall yield of 35.8% and a purity of 99.4%. The streamlined process eliminates the need for resin-based purification and significantly reduces the production cycle, thereby underscoring its strong industrial applicability.
从卡那霉素B开始，通过选择性N-Boc保护、区域选择性4″，6″- o -苄基缩醛化和Garegg-Samuelsson反应合成了重要的3 ',4 ' -烯烃中间体。在响应面法（RSM）框架下，采用中心复合设计（CCD）对Garegg-Samuelsson反应关键步骤的工艺参数进行系统优化，以提高目标产物的选择性。密度泛函理论（DFT）计算，结合空间位阻分析（% Vbur），用于阐明碘消除步骤中杂质形成和位点反应性的途径。伸缩式级联脱保护加氢工艺最终得到地贝卡星(1)，总收率为35.8%，纯度为99.4%。流线型工艺消除了树脂基净化的需要，大大缩短了生产周期，从而强调了其强大的工业适用性。
{"title":"Streamlined Synthesis of Dibekacin: RSM-Guided Process Refinement and DFT-Based Mechanistic Study","authors":"Hongsen Zhang,Kai Liu,Hao Chang,Chunxiao Wang,Chao Li,Renzhong Qiao","doi":"10.1021/acs.oprd.6c00041","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00041","url":null,"abstract":"Starting from kanamycin B, the important 3′,4′-alkene intermediate is synthesized through selective N-Boc protection, regioselective 4″,6″-O-benzylidene acetalization and Garegg–Samuelsson reaction. Within the framework of response surface methodology (RSM), the central composite design (CCD) was used to systematically optimize the process parameters of the key step in the Garegg–Samuelsson reaction, aiming to improve the selectivity of the target product. Density functional theory (DFT) calculations, in conjunction with steric hindrance analysis (% Vbur), were applied to elucidate the pathways of impurity formation and site reactivity during the iodination–elimination step. A telescoped cascade deprotection and hydrogenation process ultimately yielded dibekacin (1) with an overall yield of 35.8% and a purity of 99.4%. The streamlined process eliminates the need for resin-based purification and significantly reduces the production cycle, thereby underscoring its strong industrial applicability.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"96 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462283","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}
Pub Date : 2026-03-15DOI: 10.1021/acs.oprd.5c00512
Sean T. Neville, Todd A. Wenderski, W. Stacy Bremner, Sara A. Bonderoff, Lina Chan, Matthew R. Chin, Nolan D. Griggs, Blanka M. Hodur, Zilin Huang, Trevor C. Johnson, Matthew M. Logan, Robert R. Milburn, B. Michael O’Keefe, Christopher S. Regens, Andrew C. Stevens, Nick Uhlig, Tiago Vieira, Laura Zilke
Herein are reported strategies to achieve the global deprotection of an advanced intermediate in the synthesis of remdesivir, the active pharmaceutical ingredient of Veklury and the first antiviral medication approved (October 2020) for the treatment of COVID-19. Three strategies to improve the efficiency of the BCl3-mediated debenzylation reaction were explored: 1) enhanced control over processing conditions via flow chemistry; 2) attenuation of the reactivity of the BCl3 with additive B(OMe)3; and 3) replacement of BCl3/CH2Cl2 with AlCl3/anisole. These three strategies were developed in parallel in pursuit of improved yield and process robustness to expedite the large-scale manufacturing of remdesivir during the COVID-19 outbreak.
{"title":"A Three-Pronged Approach to the Global Debenzylation of an Advanced Furanoside Intermediate en Route to Remdesivir","authors":"Sean T. Neville, Todd A. Wenderski, W. Stacy Bremner, Sara A. Bonderoff, Lina Chan, Matthew R. Chin, Nolan D. Griggs, Blanka M. Hodur, Zilin Huang, Trevor C. Johnson, Matthew M. Logan, Robert R. Milburn, B. Michael O’Keefe, Christopher S. Regens, Andrew C. Stevens, Nick Uhlig, Tiago Vieira, Laura Zilke","doi":"10.1021/acs.oprd.5c00512","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00512","url":null,"abstract":"Herein are reported strategies to achieve the global deprotection of an advanced intermediate in the synthesis of remdesivir, the active pharmaceutical ingredient of Veklury and the first antiviral medication approved (October 2020) for the treatment of COVID-19. Three strategies to improve the efficiency of the BCl<sub>3</sub>-mediated debenzylation reaction were explored: 1) enhanced control over processing conditions via flow chemistry; 2) attenuation of the reactivity of the BCl<sub>3</sub> with additive B(OMe)<sub>3</sub>; and 3) replacement of BCl<sub>3</sub>/CH<sub>2</sub>Cl<sub>2</sub> with AlCl<sub>3</sub>/anisole. These three strategies were developed in parallel in pursuit of improved yield and process robustness to expedite the large-scale manufacturing of remdesivir during the COVID-19 outbreak.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"3 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462000","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}
Herein, we report a scalable and robust route for the synthesis of 6-bromo-2,4,5-trichloropyrrolo[2,1-f][1,2,4]triazine 1. The developed process involves modification of the known method for pentachlorination, followed by aromatization and N-amination, which has only been reported on a smaller scale and may not be safe to scale. The new method discussed in this paper is safe, scalable, and efficient, as inferred from safety and engineering studies using the Advanced Reactive System Screening Tool (ARSST) and Reaction Calorimeter (RC1mx). The highlight of this protocol involves regioselective bromination of a key fragment and the development of operationally simple workup and purification strategies to synthesize compound 1 with an overall yield of 26%.
{"title":"A Practical and Scalable Route to 6-Bromo-2,4,5-trichloropyrrolo[2,1-f][1,2,4]triazine: Process Optimization Guided by Thermal Safety Insights","authors":"Debabrata Bhattasali, Premsai Rai Neithnadka, Jayaraman Dhineshkumar, Prakasam Kuppusamy, Sivaprasad Dhanukoti, Thirupala Reddy, Prakasa Rao, Thirumalai Lakshminarasimhan, Lan-Ying Qin, Brian Fink, Arvind Mathur, Anuradha Gupta","doi":"10.1021/acs.oprd.5c00446","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00446","url":null,"abstract":"Herein, we report a scalable and robust route for the synthesis of 6-bromo-2,4,5-trichloropyrrolo[2,1-<i>f</i>][1,2,4]triazine <b>1</b>. The developed process involves modification of the known method for pentachlorination, followed by aromatization and <i>N</i>-amination, which has only been reported on a smaller scale and may not be safe to scale. The new method discussed in this paper is safe, scalable, and efficient, as inferred from safety and engineering studies using the Advanced Reactive System Screening Tool (ARSST) and Reaction Calorimeter (RC1mx). The highlight of this protocol involves regioselective bromination of a key fragment and the development of operationally simple workup and purification strategies to synthesize compound <b>1</b> with an overall yield of 26%.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"8 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147439758","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}
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