Organic Process Research & Development最新文献_第8页

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2025-07-18

Hao Li, Jin-Xi Wu, Guang-Yuan Zhang, Ning-Ning Du, Le-Wu Zhan, Jing Hou* and Bin-Dong Li*,

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IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2025-07-18

Hui Liu*, Shixiang Zeng, Yujin Li and Zhiping Liu,

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IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2025-07-18

Yu Qi, Cheng-Cheng Gu, Hao-Xing Xu, Yu-Hong Tao and Xiao Wang*,

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IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2025-07-18

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IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2025-07-18

Frédéric Pin*, Julien Picard* and Sylvie Dhulut*,

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SDMA (Synhydrid, Red-Al, Vitride): A Chemoselective and Safe Solution for Reduction Reactions SDMA（红铝玻璃体合化物）：一种化学选择性和安全的还原反应溶液

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-07-16 DOI: 10.1021/acs.oprd.5c00114

Chiara Colletto*, Arnaud Tessier* and Jacques Lebreton*,

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TCCA-Mediated Oxidative Deprotection of a Benzylamine tcca介导的一种苯胺氧化脱保护作用

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-07-15 DOI: 10.1021/acs.oprd.5c00130

Augustin Villotet, Anne-Laure Revelli, Pierre-Georges Echeverria* and Clément Jacob*,

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Biocatalytic Aerobic Oxidation for Large-Scale Production of trans-3-Hydroxy-l-Proline 大规模生产反式-3-羟基-l-脯氨酸的生物催化好氧氧化

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-07-14 DOI: 10.1021/acs.oprd.5c00136

Kai-Jiong Xiao*, Christopher K. Prier, Anna Fryszkowska, Yangzhong Qin, Alexandra C. Sun, Yingju Xu, Jonathan Vroom, Jeffrey T. Kuethe, Michelle Zheng, Yonggang Chen, Lushi Tan, Teng Peng, Erica L. Schwalm, Summer A. Baker Dockrey, Keith A. Mattern, Mengbin Chen, Eric Sirota, Mary Stanik, Jack Liang, Gregory A. Cope, Nikki D. Kruse, Wenbing Xi, Sriram Saripalli, Jianjun Duan, David A. Thaisrivongs and Sarah S. Co,

{"title":"Biocatalytic Aerobic Oxidation for Large-Scale Production of trans-3-Hydroxy-l-Proline","authors":"Kai-Jiong Xiao*, Christopher K. Prier, Anna Fryszkowska, Yangzhong Qin, Alexandra C. Sun, Yingju Xu, Jonathan Vroom, Jeffrey T. Kuethe, Michelle Zheng, Yonggang Chen, Lushi Tan, Teng Peng, Erica L. Schwalm, Summer A. Baker Dockrey, Keith A. Mattern, Mengbin Chen, Eric Sirota, Mary Stanik, Jack Liang, Gregory A. Cope, Nikki D. Kruse, Wenbing Xi, Sriram Saripalli, Jianjun Duan, David A. Thaisrivongs and Sarah S. Co, ","doi":"10.1021/acs.oprd.5c00136","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00136","url":null,"abstract":"Direct, stereoselective hydroxylation of unactivated C–H bonds has the potential to dramatically streamline organic synthesis, and enzymes are particularly well-suited for facilitating these transformations, enabling clean and efficient processes that are scalable for industrial applications. Here, we report the development of a chemoenzymatic process for producing trans-3-hydroxy-l-proline (1), a key intermediate in synthesizing the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor enlicitide decanoate (MK-0616). This process proceeds by direct biocatalytic aerobic C(sp3)–H hydroxylation of l-proline, mediated by an engineered Fe(II)- and α-ketoglutarate (α-KG)-dependent oxygenase. Through integrated enzyme discovery, protein engineering, and process development, we achieved a robust large-scale biocatalytic oxidation using minimal enzyme loading at high substrate concentrations. In combination with a high-yielding in situ protection and an efficient isolation procedure, this methodology has been used to produce high-purity N-Cbz-trans-3-hydroxy-l-proline 5 at >400 kg scale.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 8","pages":"2076–2085"},"PeriodicalIF":3.5,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840675","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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Overcoming Scale-Dependent Impurity Escalation in Epalrestat Synthesis: Identification, Mechanistic Elucidation, and Robust Process Control 克服依帕司他合成中规模依赖的杂质升级：鉴定，机理阐明和鲁棒过程控制

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-07-09 DOI: 10.1021/acs.oprd.5c00104

Yao Feng, Zhike Tian, Jincheng Yang, Xiang Ma, Hailin Su, Wencheng Ma, Yongsheng An, Zhaolin Li, Rui Ma, Xuefeng Fu*, Zhining Ma*, Yan Kang* and Pingtian Ding*,

{"title":"Overcoming Scale-Dependent Impurity Escalation in Epalrestat Synthesis: Identification, Mechanistic Elucidation, and Robust Process Control","authors":"Yao Feng, Zhike Tian, Jincheng Yang, Xiang Ma, Hailin Su, Wencheng Ma, Yongsheng An, Zhaolin Li, Rui Ma, Xuefeng Fu*, Zhining Ma*, Yan Kang* and Pingtian Ding*, ","doi":"10.1021/acs.oprd.5c00104","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00104","url":null,"abstract":"Epalrestat is a clinically vital aldose reductase inhibitor for diabetic neuropathy. An unknown impurity exhibited an unacceptable increase from laboratory batches to approximately 2% in 100 kg pilot-scale batches, accompanied by a 20% yield reduction. This study investigates the impurity’s origin, structure, and control strategies. Through high-resolution mass spectrometry (HRMS) and NMR analyses, the impurity was identified as 4-methyl-5-phenyl-2-thiophenecarboxylic acid, a previously unreported impurity in Epalrestat synthesis. Mechanistic studies revealed that the impurity forms through base-mediated hydrolysis of rhodanine-N-acetic acid, followed by a Michael addition with α-methylcinnamaldehyde, and subsequent cyclization with concurrent hydrolysis and oxidation, ultimately leading to the impurity. Corresponding control strategies were established. Critical process parameters (CPPs), including NH3·H2O equivalents, reaction temperature, and EtOH volume, were optimized to suppress the impurity generation. Implementing these control strategies in scale-up lab batches suppressed this unknown impurity to undetectable levels while achieving >95% yield and >97% purity, and enabled transfer to pilot-scale facility. This systematic investigation of impurity profiling, combined with mechanism-driven process optimization, presents an effective strategy for pilot-scale process development of Epalrestat.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 7","pages":"1749–1756"},"PeriodicalIF":3.5,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144807822","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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Synthesis of Nitroso Derivatives of Dihydropyridine Calcium Channel Blockers 二氢吡啶类钙通道阻滞剂亚硝基衍生物的合成

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-07-07 DOI: 10.1021/acs.oprd.5c00153

Hui Liu*, Shixiang Zeng, Yujin Li and Zhiping Liu,

{"title":"Synthesis of Nitroso Derivatives of Dihydropyridine Calcium Channel Blockers","authors":"Hui Liu*, Shixiang Zeng, Yujin Li and Zhiping Liu, ","doi":"10.1021/acs.oprd.5c00153","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00153","url":null,"abstract":"Regulatory authorities issued guidance on acceptable intake limits for nitrosoamine drug substance-related impurities. However, the formation of these potential nitrosamine contaminants in the dihydropyridine class of drugs has not been clearly established. In this work, the nitrosation of six dihydropyridine calcium channel blockers was investigated under a set of conditions. The nitrosation products were isolated and characterized by MS, NMR, and XRD. The results show that nitrosation occurred on the carbon atom instead of the nitrogen atom. Nifedipine exhibited the highest reactivity via oxidative aromatization and reduction to produce a C-nitroso compound. Treatment with nitrite in either 1 M hydrochloric acid or 30% acetic acid resulted mainly in pyridine products via oxidation. In contrast, the other dihydropyridine derivatives studied generated C-nitrosated products in addition to aromatized products upon treatment with butyl nitrite. The findings provide direct evidence to rule out the possibility of N-nitroso impurities being present in the dihydropyridine class of drug substances and products.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 7","pages":"1837–1842"},"PeriodicalIF":3.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144807839","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}

引用次数: 0