Pub Date : 2026-01-24DOI: 10.1021/acs.oprd.5c00342
Seema Bag, Allen Qinglin Che, Andre Lescarbeau, Daniel Jones, Vishnu Karnati, Jing He, Alexander Merton Taylor, Charles Heap, Tim Briggs, Jianglin Colin Liang, Jay Larrow, Lingzhu Kong, Jin Zhang, Song Guo, Liyu Wang, Licheng Song, Surendra Singh
RLY-2139 is a potent and selective orthosteric CDK2/Cyclin E inhibitor in development for the treatment of ER+/HER2– breast cancer. It showed an on target IC50 of 4 nM for CDK2/CycE and good biochemical selectivity, e.g., 100× for CDK1/CycB, 320× for CDK6/CycD3, and 2400× for CDK9/CycT1. We report the route optimization and scale-up of a robust, cGMP-compliant synthesis for RLY-2139 to support preclinical and early clinical supply. The convergent route couples two advanced intermediates 1 and 2 followed by deprotections and functional group transformations to deliver the drug substance. Key optimizations included replacing T3P with CMPI to address operational constraints, substituting HF·TEA with aqueous TBAF to improve safety, and employing N,N′-disuccinimidyl carbonate (DSC) in place of phenyl chloroformate to eliminate phenolic byproducts and enable telescoping. Rearranging late-stage steps improved impurity control and process robustness, while scalable recrystallization replaced column chromatography. The optimized sequence was successfully demonstrated on multi-kilogram scale, delivering 14.7 kg of crystalline RLY-2139 (67% overall yield from 1) with >99.9% chemical purity (LCAP) and 100% chiral purity.
{"title":"Process Development and Scale-Up of RLY-2139: A Selective CDK2 Inhibitor Targeting ER+/HER2– Breast Cancer","authors":"Seema Bag, Allen Qinglin Che, Andre Lescarbeau, Daniel Jones, Vishnu Karnati, Jing He, Alexander Merton Taylor, Charles Heap, Tim Briggs, Jianglin Colin Liang, Jay Larrow, Lingzhu Kong, Jin Zhang, Song Guo, Liyu Wang, Licheng Song, Surendra Singh","doi":"10.1021/acs.oprd.5c00342","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00342","url":null,"abstract":"<b>RLY-2139</b> is a potent and selective orthosteric CDK2/Cyclin E inhibitor in development for the treatment of ER+/HER2– breast cancer. It showed an on target IC<sub>50</sub> of 4 nM for CDK2/CycE and good biochemical selectivity, e.g., 100× for CDK1/CycB, 320× for CDK6/CycD3, and 2400× for CDK9/CycT1. We report the route optimization and scale-up of a robust, cGMP-compliant synthesis for <b>RLY-2139</b> to support preclinical and early clinical supply. The convergent route couples two advanced intermediates <b>1</b> and <b>2</b> followed by deprotections and functional group transformations to deliver the drug substance. Key optimizations included replacing T3P with CMPI to address operational constraints, substituting HF·TEA with aqueous TBAF to improve safety, and employing <i>N</i>,<i>N′</i>-disuccinimidyl carbonate (DSC) in place of phenyl chloroformate to eliminate phenolic byproducts and enable telescoping. Rearranging late-stage steps improved impurity control and process robustness, while scalable recrystallization replaced column chromatography. The optimized sequence was successfully demonstrated on multi-kilogram scale, delivering 14.7 kg of crystalline <b>RLY-2139</b> (67% overall yield from <b>1</b>) with >99.9% chemical purity (LCAP) and 100% chiral purity.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"273 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034109","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}
Polymer agglomeration shows promising potential for increasing the particle size of polybutadiene latex (PBL) and has garnered significant attention in the field of agglomeration. Current PBL agglomeration processes predominantly employ batch stirred reactors, which face challenges such as low agglomeration efficiency and significant batch-to-batch variability. In this study, the continuous flow reactor was served as reactor for PBL agglomeration. The effects of mixer configuration, flow rate, agglomeration temperature, and agglomerant dosage on the PBL agglomeration process and particle size were systematically examined. The results demonstrated that the average particle size of agglomerated PBL decreased from 320 to 280 nm with increasing mixing angle in Y-shaped mixers, while the particle size of agglomerated PBL using multi-inlet vortex mixer (MIVM) could reach 350 nm. Over a range of 0.16 to 1.27 m/min, the fluid flow rate did not significantly influence the agglomeration process. Meanwhile, elevated temperatures accelerated the agglomeration of PBL and yielded smaller final particle sizes. Moreover, increasing the agglomerating agent content shortened the time required to complete agglomeration. However, when the agent-to-PBL ratio was below 1:11, the system struggled to achieve stability. Scale-up experiments indicated strong potential for industrial application of this technology. Compared to traditional batch stirred reactors, the continuous flow system demonstrated superior agglomeration efficiency and product quality, achieving stability within 30 min and maintaining consistent particle size over 2 weeks of storage at room temperature. This study not only develops a novel and efficient continuous technique for PBL agglomeration but also provides a means to precisely control operational parameters, thereby enhancing the product quality of agglomerated PBL.
{"title":"Study on PBL Agglomeration in Continuous Flow Reactor Based on Polymer Agglomerating Agent","authors":"Junlin Ge, Shulai Lu, Yuchao Wang, Ming Chen, Pinzhe Luo, Liqi Zhuang, Changlu Zhou, Shicheng Zhao","doi":"10.1021/acs.oprd.5c00456","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00456","url":null,"abstract":"Polymer agglomeration shows promising potential for increasing the particle size of polybutadiene latex (PBL) and has garnered significant attention in the field of agglomeration. Current PBL agglomeration processes predominantly employ batch stirred reactors, which face challenges such as low agglomeration efficiency and significant batch-to-batch variability. In this study, the continuous flow reactor was served as reactor for PBL agglomeration. The effects of mixer configuration, flow rate, agglomeration temperature, and agglomerant dosage on the PBL agglomeration process and particle size were systematically examined. The results demonstrated that the average particle size of agglomerated PBL decreased from 320 to 280 nm with increasing mixing angle in Y-shaped mixers, while the particle size of agglomerated PBL using multi-inlet vortex mixer (MIVM) could reach 350 nm. Over a range of 0.16 to 1.27 m/min, the fluid flow rate did not significantly influence the agglomeration process. Meanwhile, elevated temperatures accelerated the agglomeration of PBL and yielded smaller final particle sizes. Moreover, increasing the agglomerating agent content shortened the time required to complete agglomeration. However, when the agent-to-PBL ratio was below 1:11, the system struggled to achieve stability. Scale-up experiments indicated strong potential for industrial application of this technology. Compared to traditional batch stirred reactors, the continuous flow system demonstrated superior agglomeration efficiency and product quality, achieving stability within 30 min and maintaining consistent particle size over 2 weeks of storage at room temperature. This study not only develops a novel and efficient continuous technique for PBL agglomeration but also provides a means to precisely control operational parameters, thereby enhancing the product quality of agglomerated PBL.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"214 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034108","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}
We report a scalable and operationally simple synthesis of cetrorelix acetate, a clinically used decapeptide GnRH antagonist (Ac-D-2′Nal1-D-(4-Cl)Phe2-D-3′Pal3-Ser4-Tyr5-D-Cit6-Leu7-Arg8-Pro9-d-Ala10-NH2) employed in in vitro fertilization (IVF) regimens. The peptide was assembled through a convergent [5-mer +5-mer] strategy using tailor-made hydrophobic tags to facilitate fragment anchorage and handling. Pentapeptide intermediates and the final product were constructed via iterative Fmoc-based couplings of suitably protected amino acids. The hydrophobic tags enabled efficient, chromatography-free isolation of intermediates through precipitation and liquid–liquid extraction. This approach provides a practical and scalable route to cetrorelix acetate and demonstrates the utility of tag-assisted peptide synthesis for complex therapeutic peptides.
{"title":"Scalable Hydrophobic Tag-Assisted Convergent Synthesis of Cetrorelix Acetate","authors":"Veeranjaneyulu Avula, Ranjithkumar Murugan, Archanadevi Kumaran, Nagendra Govindappa, H. Surya Prakash Rao","doi":"10.1021/acs.oprd.5c00284","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00284","url":null,"abstract":"We report a scalable and operationally simple synthesis of cetrorelix acetate, a clinically used decapeptide GnRH antagonist (Ac-D-2′Nal<sup>1</sup>-D-(4-Cl)Phe<sup>2</sup>-D-3′Pal<sup>3</sup>-Ser<sup>4</sup>-Tyr<sup>5</sup>-D-Cit<sup>6</sup>-Leu<sup>7</sup>-Arg<sup>8</sup>-Pro<sup>9</sup>-<span>d</span>-Ala<sup>10</sup>-NH<sub>2</sub>) employed in in vitro fertilization (IVF) regimens. The peptide was assembled through a convergent [5-mer +5-mer] strategy using tailor-made hydrophobic tags to facilitate fragment anchorage and handling. Pentapeptide intermediates and the final product were constructed via iterative Fmoc-based couplings of suitably protected amino acids. The hydrophobic tags enabled efficient, chromatography-free isolation of intermediates through precipitation and liquid–liquid extraction. This approach provides a practical and scalable route to cetrorelix acetate and demonstrates the utility of tag-assisted peptide synthesis for complex therapeutic peptides.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"56 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146022037","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 : 2026-01-20DOI: 10.1021/acs.oprd.5c00349
Jinnai Liu, Jiawei Tang, Hao Chen, Li Zhang, Ganlan Li, Fuli Zhang, Shaoxin Chen, Jun Yu
(S)-3-Bromo-2-(1-methoxyethyl)pyridine 1 is a key intermediate of RMC-6236. In this report, we detail the development and optimization of a highly enantioselective chemoenzymatic and kilogram-scale process for 1. The developed process for intermediate (S)-1-(3-Bromopyridin-2-yl)ethanol 3 was performed on 1 kg scale with a substrate concentration of 70.0 g/L, achieving a yield of 93.0% and an ee value of >99.9%. Subsequently, a simple and effective NaHMDS/CH3I methylation system afforded the title compound 1, in 95.0% yield and with >99.9% ee, achieving 88.4% overall yield from intermediate 1-(3-bromopyridin-2-yl)ethanone 2. This represents a notable increase compared to the early stage process (overall yield 55.5%). This optimized highly efficient and sustainable process was demonstrated during kilogram-scale production of 1.
{"title":"Highly Enantioselective Chemoenzymatic and Kilogram-Scale Process Development of (S)-3-Bromo-2-(1-methoxyethyl)pyridine","authors":"Jinnai Liu, Jiawei Tang, Hao Chen, Li Zhang, Ganlan Li, Fuli Zhang, Shaoxin Chen, Jun Yu","doi":"10.1021/acs.oprd.5c00349","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00349","url":null,"abstract":"(<i>S</i>)-3-Bromo-2-(1-methoxyethyl)pyridine <b>1</b> is a key intermediate of RMC-6236. In this report, we detail the development and optimization of a highly enantioselective chemoenzymatic and kilogram-scale process for <b>1</b>. The developed process for intermediate (<i>S</i>)-1-(3-Bromopyridin-2-yl)ethanol <b>3</b> was performed on 1 kg scale with a substrate concentration of 70.0 g/L, achieving a yield of 93.0% and an <i>ee</i> value of >99.9%. Subsequently, a simple and effective NaHMDS/CH<sub>3</sub>I methylation system afforded the title compound <b>1</b>, in 95.0% yield and with >99.9% <i>ee</i>, achieving 88.4% overall yield from intermediate 1-(3-bromopyridin-2-yl)ethanone <b>2</b>. This represents a notable increase compared to the early stage process (overall yield 55.5%). This optimized highly efficient and sustainable process was demonstrated during kilogram-scale production of <b>1</b>.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"6 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146001533","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 : 2026-01-18DOI: 10.1021/acs.oprd.5c00396
Yuya Orito
This paper demonstrates the application of a mechanistic investigation approach that combines an experiment-based extrapolatable reaction kinetic modeling with DFT analysis through mechanism elucidation of a condition-insensitive nucleophilic aromatic substitution reaction involving a solvent-dependent mechanistic transition. The “double-checking” methodology revealed a significant discrepancy between activation energies obtained experimentally from the kinetic model and those calculated by DFT using implicit solvation models. This suggests unaccounted effects on the transition state, particularly arising from interference in the hydrogen bond network when using NaOMe as a nucleophile in methanol, resulting in reduced reaction rates and low regioselectivity. These mechanistic insights led efficiently to switching to proton-free conditions, resulting in significant changes in the reaction time course profiles and improved regioselectivity. The results highlight the benefits of kinetic modeling combined with in-depth reaction understanding in the reaction development of condition-insensitive systems.
{"title":"Solvent Effect Elucidation in Nucleophilic Aromatic Substitution: Cross-Validation of the Mechanism through Kinetic Analysis and Quantum Calculations","authors":"Yuya Orito","doi":"10.1021/acs.oprd.5c00396","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00396","url":null,"abstract":"This paper demonstrates the application of a mechanistic investigation approach that combines an experiment-based extrapolatable reaction kinetic modeling with DFT analysis through mechanism elucidation of a condition-insensitive nucleophilic aromatic substitution reaction involving a solvent-dependent mechanistic transition. The “double-checking” methodology revealed a significant discrepancy between activation energies obtained experimentally from the kinetic model and those calculated by DFT using implicit solvation models. This suggests unaccounted effects on the transition state, particularly arising from interference in the hydrogen bond network when using NaOMe as a nucleophile in methanol, resulting in reduced reaction rates and low regioselectivity. These mechanistic insights led efficiently to switching to proton-free conditions, resulting in significant changes in the reaction time course profiles and improved regioselectivity. The results highlight the benefits of kinetic modeling combined with in-depth reaction understanding in the reaction development of condition-insensitive systems.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"88 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145995099","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 : 2026-01-18DOI: 10.1021/acs.oprd.5c00396
Yuya Orito
This paper demonstrates the application of a mechanistic investigation approach that combines an experiment-based extrapolatable reaction kinetic modeling with DFT analysis through mechanism elucidation of a condition-insensitive nucleophilic aromatic substitution reaction involving a solvent-dependent mechanistic transition. The “double-checking” methodology revealed a significant discrepancy between activation energies obtained experimentally from the kinetic model and those calculated by DFT using implicit solvation models. This suggests unaccounted effects on the transition state, particularly arising from interference in the hydrogen bond network when using NaOMe as a nucleophile in methanol, resulting in reduced reaction rates and low regioselectivity. These mechanistic insights led efficiently to switching to proton-free conditions, resulting in significant changes in the reaction time course profiles and improved regioselectivity. The results highlight the benefits of kinetic modeling combined with in-depth reaction understanding in the reaction development of condition-insensitive systems.
{"title":"Solvent Effect Elucidation in Nucleophilic Aromatic Substitution: Cross-Validation of the Mechanism through Kinetic Analysis and Quantum Calculations","authors":"Yuya Orito","doi":"10.1021/acs.oprd.5c00396","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00396","url":null,"abstract":"This paper demonstrates the application of a mechanistic investigation approach that combines an experiment-based extrapolatable reaction kinetic modeling with DFT analysis through mechanism elucidation of a condition-insensitive nucleophilic aromatic substitution reaction involving a solvent-dependent mechanistic transition. The “double-checking” methodology revealed a significant discrepancy between activation energies obtained experimentally from the kinetic model and those calculated by DFT using implicit solvation models. This suggests unaccounted effects on the transition state, particularly arising from interference in the hydrogen bond network when using NaOMe as a nucleophile in methanol, resulting in reduced reaction rates and low regioselectivity. These mechanistic insights led efficiently to switching to proton-free conditions, resulting in significant changes in the reaction time course profiles and improved regioselectivity. The results highlight the benefits of kinetic modeling combined with in-depth reaction understanding in the reaction development of condition-insensitive systems.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"5 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145995104","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 : 2026-01-16DOI: 10.1021/acs.oprd.5c00431
Liangguang Yi, Lorenzo V. White, Claudia Pessoa, José de Brito Vieira Neto, Martin G. Banwell
A four-step (three-pot) and biomimetic total synthesis of the title compound (+)-1, a pterocarpan-type natural product and microtubule destabilizing agent, was achieved using readily available starting materials. The tetramethoxy-substituted isoflavone 17 was prepared (via ketone 16) from these and on treatment with AlCl3 and sodium iodide this underwent regioselective mono-demethylation to give congener 20. This was subjected to asymmetric transfer hydrogenation (ATH) and then an acidic workup. By such means the title pterocarpan (+)-1 was obtained in multigram quantities and >99% ee.
{"title":"Biomimetic, Multigram, and Enantioselective Total Synthesis of the Microtubule Destabilizing Pterocarpan (6aS,11aS)-2,3,9-Trimethoxy-6a,11a-dihydro-6H-benzofuro[3,2-c]chromene","authors":"Liangguang Yi, Lorenzo V. White, Claudia Pessoa, José de Brito Vieira Neto, Martin G. Banwell","doi":"10.1021/acs.oprd.5c00431","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00431","url":null,"abstract":"A four-step (three-pot) and biomimetic total synthesis of the title compound (+)-<b>1</b>, a pterocarpan-type natural product and microtubule destabilizing agent, was achieved using readily available starting materials. The tetramethoxy-substituted isoflavone <b>17</b> was prepared (via ketone <b>16</b>) from these and on treatment with AlCl<sub>3</sub> and sodium iodide this underwent regioselective mono-demethylation to give congener <b>20</b>. This was subjected to asymmetric transfer hydrogenation (ATH) and then an acidic workup. By such means the title pterocarpan (+)-<b>1</b> was obtained in multigram quantities and >99% ee.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"269 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145993303","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 : 2026-01-15DOI: 10.1021/acs.oprd.5c00382
Zhiwei Yin, Victor W. Rosso, Frederick Roberts, Ariel Furman, Jason M. Stevens, Taylor Watts, Cameron Cook, Anisha Patel, Jun Qiu
High-throughput crystallization (HTC) polymorph screening is pivotal for exploring the crystal polymorph landscape, but the sheer volume and complexity of powder X-ray diffraction (PXRD) and Raman spectroscopy data present significant data-processing challenges. Traditional approaches, which rely on human interpretation aided by software, are often constrained by limited clustering accuracy. To address these limitations, we developed EZClust, a lightweight machine-learning model designed for rapid PXRD and Raman batch data analysis. A key algorithm in the model is shape-based distance (SBD), which provides robust performance for processing data with distortion and minimal parameter tuning. In this work, we compare EZClust’s performance to existing mainstream commercial software (Jade Pro) and the open-source AutoFIDEL implementation, demonstrating its robustness through cluster analysis of HTC datasets for the model compounds ROY and carbamazepine. Herein, we disclose the core algorithms of EZClust, robust preprocessing coupled with an SBD metric, to streamline cluster analysis for PXRD and Raman datasets in HTC workflows.
{"title":"EZClust: A Robust Machine Learning-Based Powder X-Ray Diffraction and Raman Cluster Analysis Model for Efficient High-Throughput Crystallization Polymorph Screening","authors":"Zhiwei Yin, Victor W. Rosso, Frederick Roberts, Ariel Furman, Jason M. Stevens, Taylor Watts, Cameron Cook, Anisha Patel, Jun Qiu","doi":"10.1021/acs.oprd.5c00382","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00382","url":null,"abstract":"High-throughput crystallization (HTC) polymorph screening is pivotal for exploring the crystal polymorph landscape, but the sheer volume and complexity of powder X-ray diffraction (PXRD) and Raman spectroscopy data present significant data-processing challenges. Traditional approaches, which rely on human interpretation aided by software, are often constrained by limited clustering accuracy. To address these limitations, we developed EZClust, a lightweight machine-learning model designed for rapid PXRD and Raman batch data analysis. A key algorithm in the model is shape-based distance (SBD), which provides robust performance for processing data with distortion and minimal parameter tuning. In this work, we compare EZClust’s performance to existing mainstream commercial software (Jade Pro) and the open-source AutoFIDEL implementation, demonstrating its robustness through cluster analysis of HTC datasets for the model compounds ROY and carbamazepine. Herein, we disclose the core algorithms of EZClust, robust preprocessing coupled with an SBD metric, to streamline cluster analysis for PXRD and Raman datasets in HTC workflows.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"39 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968888","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 : 2026-01-15DOI: 10.1021/acs.oprd.5c00406
Jianxun He, Dong Zuo, Jun Tang, Zhen Wang, Bo Wang, Bing Liu, Qiang Zhang, Guangwei He, Yungen Xu
An improved synthesis of HY-072808 (1), a highly potent and selective PDE4B inhibitor developed as a clinical candidate, is reported, achieving an overall yield of 42.9% and a purity of 99.98%. Starting from readily available and inexpensive 4-(trifluoromethyl)aniline (10) and 2-bromo-5-hydroxybenzaldehyde (5), HY-072808 was effectively and conveniently synthesized without chromatographic purification in any steps. Key improvements include enhanced control over impurity formation, increased productivity of the SNAr reaction, efficient purification of the product through acidification, effective removal of palladium via recrystallization, and a reliable method for identifying the crystal morphology. This process has been successfully scaled up to produce over 3 kg of HY-072808.
{"title":"Development of a Scalable Synthetic Route and a Crystal Morphology Characterization Method for the PDE4B Inhibitor HY-072808","authors":"Jianxun He, Dong Zuo, Jun Tang, Zhen Wang, Bo Wang, Bing Liu, Qiang Zhang, Guangwei He, Yungen Xu","doi":"10.1021/acs.oprd.5c00406","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00406","url":null,"abstract":"An improved synthesis of HY-072808 (<b>1</b>), a highly potent and selective PDE4B inhibitor developed as a clinical candidate, is reported, achieving an overall yield of 42.9% and a purity of 99.98%. Starting from readily available and inexpensive 4-(trifluoromethyl)aniline (<b>10</b>) and 2-bromo-5-hydroxybenzaldehyde (<b>5</b>), HY-072808 was effectively and conveniently synthesized without chromatographic purification in any steps. Key improvements include enhanced control over impurity formation, increased productivity of the S<sub>N</sub>Ar reaction, efficient purification of the product through acidification, effective removal of palladium via recrystallization, and a reliable method for identifying the crystal morphology. This process has been successfully scaled up to produce over 3 kg of HY-072808.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"57 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145993182","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 : 2026-01-14DOI: 10.1021/acs.oprd.5c00354
Seema Bag, Andre Lescarbeau, Allen Qinglin Che, Vishnu Karnati, Zhongbo Fei, Liyang Wang, Dehai Zhang, Jun Liu, Fan Jiang, Hai Wang, Gang Huang, Pengfei Shen, Jing Wang, Mingying Zhu, Yonghui Lu, Fanfan Meng, Baldip Kang, Surendra Singh, David Tschaen
The development of RLY-2139, a selective orthosteric CDK2 inhibitor for ER+/HER2– breast cancer, necessitates a scalable and enantioselective synthesis of a key chiral intermediate, the chiral tetrahydrofuran pyrazolamine (compound 2). The initial synthetic route, culminating in a low-yielding final-step chiral separation of rac-2a, provided 2a in only a 2% overall yield. Recognizing the need for improved efficiency and sustainability, we explored several alternative strategies, including biocatalysis and various asymmetric routes. However, these were limited by challenges such as epimerization, poor diastereoselectivity, or limited scalability. Ultimately, a robust and scalable process was established using hydrolytic kinetic resolution (HKR) of terminal epoxide 27, delivering enantiomerically pure 2b. This intermediate was successfully converted to 3 in a kilo-lab campaign with an overall yield of 11%. The optimized 8-step route toward 2b was highly telescoped, chromatography-free, incorporating multiple impurity purges, making the process highly efficient. This process was successfully demonstrated on a multikilogram scale, providing a practical and industrially viable method for large-scale production of a critical pharmaceutical intermediate.
{"title":"From Chiral Separation to Asymmetric Synthesis: Route Scouting and Early Process Development of a Chiral Tetrahydrofuran–Pyrazolamine Intermediate of CDK2 Inhibitor RLY-2139","authors":"Seema Bag, Andre Lescarbeau, Allen Qinglin Che, Vishnu Karnati, Zhongbo Fei, Liyang Wang, Dehai Zhang, Jun Liu, Fan Jiang, Hai Wang, Gang Huang, Pengfei Shen, Jing Wang, Mingying Zhu, Yonghui Lu, Fanfan Meng, Baldip Kang, Surendra Singh, David Tschaen","doi":"10.1021/acs.oprd.5c00354","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00354","url":null,"abstract":"The development of <b>RLY-2139</b>, a selective orthosteric CDK2 inhibitor for ER+/HER2– breast cancer, necessitates a scalable and enantioselective synthesis of a key chiral intermediate, the chiral tetrahydrofuran pyrazolamine (compound <b>2</b>). The initial synthetic route, culminating in a low-yielding final-step chiral separation of <b>rac-2a</b>, provided <b>2a</b> in only a 2% overall yield. Recognizing the need for improved efficiency and sustainability, we explored several alternative strategies, including biocatalysis and various asymmetric routes. However, these were limited by challenges such as epimerization, poor diastereoselectivity, or limited scalability. Ultimately, a robust and scalable process was established using hydrolytic kinetic resolution (HKR) of terminal epoxide <b>27</b>, delivering enantiomerically pure <b>2b</b>. This intermediate was successfully converted to <b>3</b> in a kilo-lab campaign with an overall yield of 11%. The optimized 8-step route toward <b>2b</b> was highly telescoped, chromatography-free, incorporating multiple impurity purges, making the process highly efficient. This process was successfully demonstrated on a multikilogram scale, providing a practical and industrially viable method for large-scale production of a critical pharmaceutical intermediate.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"124 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968403","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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