Organic Process Research & Development最新文献_第7页

Development of a Scalable Anodic Oxidation Process for (R)-Troloxamide Quinone (EPI-589) Using a Continuous Flow Approach 连续流动法制备(R)-Troloxamide醌（EPI-589）可扩展阳极氧化工艺

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2025-03-28 DOI: 10.1021/acs.oprd.5c0001610.1021/acs.oprd.5c00016

Hirotsugu Usutani*, Jun Hirabayashi, Kenji Yamamoto, Xinlong Gao, Jianghong Chen, Jianye Jiao, Hsiao Yi, Pan Wang* and Kazuki Hashimoto,

{"title":"Development of a Scalable Anodic Oxidation Process for (R)-Troloxamide Quinone (EPI-589) Using a Continuous Flow Approach","authors":"Hirotsugu Usutani*, Jun Hirabayashi, Kenji Yamamoto, Xinlong Gao, Jianghong Chen, Jianye Jiao, Hsiao Yi, Pan Wang* and Kazuki Hashimoto, ","doi":"10.1021/acs.oprd.5c0001610.1021/acs.oprd.5c00016","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00016https://doi.org/10.1021/acs.oprd.5c00016","url":null,"abstract":"Electrochemical methods in organic synthesis hold significant potential for next-generation chemical processes and are gaining attention not only in the pharmaceutical sector but also across the broader chemical industry. From an electrochemical perspective, electrons can be regarded as a reagent, which can be utilized in various oxidation and reduction reactions. Anodic oxidation is one example, by which it is possible to oxidatively cleave troloxamide to form troloxamide quinone. Thus, an electrochemical process can contribute to the synthesis of the active pharmaceutical ingredient (API) EPI-589, a drug candidate for the treatment of amyotrophic lateral sclerosis (ALS). Process development using electrochemical methods is often regarded as challenging for scale-up and manufacturing, but here we describe the establishment of a manufacturing method by combining the concepts of anodic oxidation (electroorganic chemistry) and continuous processing are described. The results of a scale-up proof-of-concept experiment are shown, in which the API was obtained with excellent quality on a kilogram scale.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 5","pages":"1211–1217 1211–1217"},"PeriodicalIF":3.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067836","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

Development of a Scalable Anodic Oxidation Process for (R)-Troloxamide Quinone (EPI-589) Using a Continuous Flow Approach 连续流动法制备(R)-Troloxamide醌（EPI-589）可扩展阳极氧化工艺

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-03-28 DOI: 10.1021/acs.oprd.5c00016

Hirotsugu Usutani, Jun Hirabayashi, Kenji Yamamoto, Xinlong Gao, Jianghong Chen, Jianye Jiao, Hsiao Yi, Pan Wang, Kazuki Hashimoto

{"title":"Development of a Scalable Anodic Oxidation Process for (R)-Troloxamide Quinone (EPI-589) Using a Continuous Flow Approach","authors":"Hirotsugu Usutani, Jun Hirabayashi, Kenji Yamamoto, Xinlong Gao, Jianghong Chen, Jianye Jiao, Hsiao Yi, Pan Wang, Kazuki Hashimoto","doi":"10.1021/acs.oprd.5c00016","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00016","url":null,"abstract":"Electrochemical methods in organic synthesis hold significant potential for next-generation chemical processes and are gaining attention not only in the pharmaceutical sector but also across the broader chemical industry. From an electrochemical perspective, electrons can be regarded as a reagent, which can be utilized in various oxidation and reduction reactions. Anodic oxidation is one example, by which it is possible to oxidatively cleave troloxamide to form troloxamide quinone. Thus, an electrochemical process can contribute to the synthesis of the active pharmaceutical ingredient (API) EPI-589, a drug candidate for the treatment of amyotrophic lateral sclerosis (ALS). Process development using electrochemical methods is often regarded as challenging for scale-up and manufacturing, but here we describe the establishment of a manufacturing method by combining the concepts of anodic oxidation (electroorganic chemistry) and continuous processing are described. The results of a scale-up proof-of-concept experiment are shown, in which the API was obtained with excellent quality on a kilogram scale.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"19 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723985","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

Multistep Continuous Heterogeneous Synthesis of C.I. Reactive Red 195 and Safety Evaluation of the Continuous Diazotization Process 多步连续多相合成C.I.活性红195及连续重氮化工艺的安全性评价

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2025-03-27 DOI: 10.1021/acs.oprd.5c0005510.1021/acs.oprd.5c00055

Lei Li, Xinyu Ye, Huaixi Liu, Rongwen Lu, Bingtao Tang and Shufen Zhang*,

{"title":"Multistep Continuous Heterogeneous Synthesis of C.I. Reactive Red 195 and Safety Evaluation of the Continuous Diazotization Process","authors":"Lei Li, Xinyu Ye, Huaixi Liu, Rongwen Lu, Bingtao Tang and Shufen Zhang*, ","doi":"10.1021/acs.oprd.5c0005510.1021/acs.oprd.5c00055","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00055https://doi.org/10.1021/acs.oprd.5c00055","url":null,"abstract":"Integrating the diazotization and coupling reactions in solid–liquid heterogeneous systems to achieve large-scale, multistep continuous flow synthesis of water-soluble azo dyes remains a significant challenge. During the diazotization process of water-soluble azo dyes, considerable diazonium salt may precipitate, posing potential safety risks. In this study, we established a continuous dynamic tubular reaction system to achieve the multistep continuous heterogeneous synthesis of C.I. Reactive Red 195, a representative water-soluble azo dye. The optimal conditions for continuous diazotization and coupling reactions were determined, achieving a high throughput of 120 L/h and a yield of up to 736 kg/day. The purity of the synthesized dye increased by 20% compared to the commercial C.I. Reactive Red 195, with the K/S value rising from 19.07 to 22.16, indicating enhanced dyeing performance. Density functional theory (DFT) calculations and ab initio molecular dynamics (AIMD) simulations show that 2-naphthylamine-1,5-disulfonic acid diazonium salt (NADA-DS) spontaneously aggregates into stable clusters due to dispersion forces, which leads to precipitation. Furthermore, the thermal stability, impact sensitivity, explosive propagation, and decomposition activation energy of NADA-DS were investigated. The severity and possibility of thermal runaway during the continuous diazotization process are classified as level 1. The risk matrix indicates that the continuous diazotization process risk is acceptable, with the Stoessel criticality diagram categorizing the hazard level as grade 1, signifying a low level of risk. This study promotes safer, more efficient, and sustainable production of water-soluble azo dyes.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 4","pages":"1168–1178 1168–1178"},"PeriodicalIF":3.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842450","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

Development of a Convergent and Scalable Synthetic Route to Long-Acting RSV Inhibitor JNJ-7950 长效RSV抑制剂JNJ-7950聚合可扩展合成途径的建立

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2025-03-27 DOI: 10.1021/acs.oprd.4c0043710.1021/acs.oprd.4c00437

Kiran Matcha*, William M. Maton*, Peter Reniers, Robert Geertman, Bart Bueken, Philip Pye, Stijn Wuyts and Ed Cleator,

{"title":"Development of a Convergent and Scalable Synthetic Route to Long-Acting RSV Inhibitor JNJ-7950","authors":"Kiran Matcha*, William M. Maton*, Peter Reniers, Robert Geertman, Bart Bueken, Philip Pye, Stijn Wuyts and Ed Cleator, ","doi":"10.1021/acs.oprd.4c0043710.1021/acs.oprd.4c00437","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00437https://doi.org/10.1021/acs.oprd.4c00437","url":null,"abstract":"JNJ-7950 is a potent small-molecule respiratory syncytial virus (RSV) inhibitor with a long-acting profile in preclinical species. The design and development of a convergent synthetic route accelerated the discovery and development of JNJ-7950. First, the new synthetic route supported the lead candidate (JNJ-7950) selection process and later was adapted to provide a large-scale clinical batch. A shorter and cost-effective synthetic route to the key spiro-azetidine moiety exploited an intramolecular copper-catalyzed C–N coupling. The development of an efficient and sustainable process for telescoping three steps in a single solvent provided the benzimidazole moiety with an 85% overall yield. The spiro-azetidine and the benzimidazole moieties were coupled to provide JNJ-7950 in 48% overall yield with excellent purity over the six longest linear steps. Two GMP batches (6 and 12 kg) of JNJ-7950 were manufactured in parenteral grade quality to support long-acting injectable formulation development and early clinical need.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 4","pages":"1036–1047 1036–1047"},"PeriodicalIF":3.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842315","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

Multistep Continuous Heterogeneous Synthesis of C.I. Reactive Red 195 and Safety Evaluation of the Continuous Diazotization Process 多步连续多相合成C.I.活性红195及连续重氮化工艺的安全性评价

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-03-27 DOI: 10.1021/acs.oprd.5c00055

Lei Li, Xinyu Ye, Huaixi Liu, Rongwen Lu, Bingtao Tang, Shufen Zhang

{"title":"Multistep Continuous Heterogeneous Synthesis of C.I. Reactive Red 195 and Safety Evaluation of the Continuous Diazotization Process","authors":"Lei Li, Xinyu Ye, Huaixi Liu, Rongwen Lu, Bingtao Tang, Shufen Zhang","doi":"10.1021/acs.oprd.5c00055","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00055","url":null,"abstract":"Integrating the diazotization and coupling reactions in solid–liquid heterogeneous systems to achieve large-scale, multistep continuous flow synthesis of water-soluble azo dyes remains a significant challenge. During the diazotization process of water-soluble azo dyes, considerable diazonium salt may precipitate, posing potential safety risks. In this study, we established a continuous dynamic tubular reaction system to achieve the multistep continuous heterogeneous synthesis of C.I. Reactive Red 195, a representative water-soluble azo dye. The optimal conditions for continuous diazotization and coupling reactions were determined, achieving a high throughput of 120 L/h and a yield of up to 736 kg/day. The purity of the synthesized dye increased by 20% compared to the commercial C.I. Reactive Red 195, with the K/S value rising from 19.07 to 22.16, indicating enhanced dyeing performance. Density functional theory (DFT) calculations and ab initio molecular dynamics (AIMD) simulations show that 2-naphthylamine-1,5-disulfonic acid diazonium salt (NADA-DS) spontaneously aggregates into stable clusters due to dispersion forces, which leads to precipitation. Furthermore, the thermal stability, impact sensitivity, explosive propagation, and decomposition activation energy of NADA-DS were investigated. The severity and possibility of thermal runaway during the continuous diazotization process are classified as level 1. The risk matrix indicates that the continuous diazotization process risk is acceptable, with the Stoessel criticality diagram categorizing the hazard level as grade 1, signifying a low level of risk. This study promotes safer, more efficient, and sustainable production of water-soluble azo dyes.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"36 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723984","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

Development of a Convergent and Scalable Synthetic Route to Long-Acting RSV Inhibitor JNJ-7950 长效RSV抑制剂JNJ-7950聚合可扩展合成途径的建立

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-03-27 DOI: 10.1021/acs.oprd.4c00437

Kiran Matcha, William M. Maton, Peter Reniers, Robert Geertman, Bart Bueken, Philip Pye, Stijn Wuyts, Ed Cleator

引用次数: 0

Novel Baeyer–Villiger Oxidation of Nucleosides Applied to the Large-Scale Synthesis of MeMOP: A Key Amidite in the GalXC Platform 新型Baeyer-Villiger氧化核苷在大规模合成MeMOP中的应用：GalXC平台上的关键中间体

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2025-03-27 DOI: 10.1021/acs.oprd.5c0002110.1021/acs.oprd.5c00021

John R. Rizzo, Prem Kumar Begari, Deepak Kalita, Jiancai Gu, Scott A. Frank, Nour Eddine Fahmi and Hem Raj Khatri*,

引用次数: 0

Novel Baeyer–Villiger Oxidation of Nucleosides Applied to the Large-Scale Synthesis of MeMOP: A Key Amidite in the GalXC Platform 新型Baeyer-Villiger氧化核苷在大规模合成MeMOP中的应用：GalXC平台上的关键中间体

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-03-27 DOI: 10.1021/acs.oprd.5c00021

John R. Rizzo, Prem Kumar Begari, Deepak Kalita, Jiancai Gu, Scott A. Frank, Nour Eddine Fahmi, Hem Raj Khatri

引用次数: 0

Decagram-Scale Synthesis of the Novel Bacterial Topoisomerase Inhibitor OSUAB-0284 新型细菌拓扑异构酶抑制剂OSUAB-0284的十克级合成

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-03-26 DOI: 10.1021/acs.oprd.5c00033

Jason S. West, Chelsea A. Mann, Mark J. Mitton-Fry

引用次数: 0

Decagram-Scale Synthesis of the Novel Bacterial Topoisomerase Inhibitor OSUAB-0284 新型细菌拓扑异构酶抑制剂OSUAB-0284的十克级合成

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2025-03-26 DOI: 10.1021/acs.oprd.5c0003310.1021/acs.oprd.5c00033

Jason S. West, Chelsea A. Mann and Mark J. Mitton-Fry*,

引用次数: 0