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

Development of a Manufacturing Process for a Key (S)-5-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-1H-indole Intermediate for Orforglipron. Part III. Development of a Telescoped Phase-Transfer-Catalyzed Alkylation and Cyclopropanation Process 甲氟格列酮中间体(S)-5-（2,2-二甲基四氢- 2h -吡喃-4-基）- 1h -吲哚的制备工艺研究第三部分。缩合相转移催化烷基化和环丙烷化工艺的发展

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-08-05 DOI: 10.1021/acs.oprd.5c00185

Qiang Yang*, Derek R. Starkey, Jingfan Yang, Radhe K. Vaid, Peng-Kai Kao, Charles B. Held, Mark D. Argentine, Derek Berglund, Alison Campbell Brewer, Jonas Y. Buser, Kayla L. Mathews, Ping Huang, Mo Jia, Peng Liu, Jing Chen and Fangyun Yang,

{"title":"Development of a Manufacturing Process for a Key (S)-5-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-1H-indole Intermediate for Orforglipron. Part III. Development of a Telescoped Phase-Transfer-Catalyzed Alkylation and Cyclopropanation Process","authors":"Qiang Yang*, Derek R. Starkey, Jingfan Yang, Radhe K. Vaid, Peng-Kai Kao, Charles B. Held, Mark D. Argentine, Derek Berglund, Alison Campbell Brewer, Jonas Y. Buser, Kayla L. Mathews, Ping Huang, Mo Jia, Peng Liu, Jing Chen and Fangyun Yang, ","doi":"10.1021/acs.oprd.5c00185","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00185","url":null,"abstract":"A scalable 8-step route for a key (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole intermediate for orforglipron was developed to support clinical trials. Highlights of process development results in this contribution include the following: (1) approximately 50% reduction of a key des-carbonyl impurity in the reductive removal of the Evans auxiliary by the introduction of MgCl2 as a chelating agent for the reduction with LiBH4, (2) a telescoped process for PTC alkylation with chloroacetonitrile and subsequent cyclopropyl ring formation with an asymmetric cyclic sulfate avoiding the problematic isolation of the alkylation product, and (3) significantly improved isolated yield and stereoselectivity of the cyclopropyl ring formation by replacing KHMDS with LiOt-Bu as the base for the reaction. The developed process was successfully scaled up to >400 kg scale for each step to deliver a high-quality product in an overall yield of 22%, demonstrating the robustness of the optimized process.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 8","pages":"2018–2029"},"PeriodicalIF":3.5,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840480","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

An Expedient Approach for the Synthesis of TAM and MET Receptor Kinase Inhibitor’s Core (R)-2-((4-(4-Amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)amino)propan-1-ol TAM和MET受体激酶抑制剂核心(R)-2-（（4-（4-氨基-2-氟苯氧基）-1-（4-甲氧基）- 1h -吡唑[3,4-b]吡啶-3-基）氨基）丙烷-1-醇的一种便捷合成方法

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-08-04 DOI: 10.1021/acs.oprd.5c00219

Xingyong Zhu*, Bairong Liu, Biao Li, Shovan Mondal and Sudarshan Debnath*,

引用次数: 0

Development of a Manufacturing Process for a Key (S)-5-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-1H-indole Intermediate for Orforglipron. Part II. Development of a CSTR Process for Evans Auxiliary-Assisted Asymmetric 1,4-Addition 甲氟格列酮中间体(S)-5-（2,2-二甲基四氢- 2h -吡喃-4-基）- 1h -吲哚的制备工艺研究第二部分。Evans辅助-非对称1,4加成CSTR工艺的发展

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-08-04 DOI: 10.1021/acs.oprd.5c00184

Qiang Yang*, Derek R. Starkey, Radhe K. Vaid, Xavier Ortiz-Medina, Charles B. Held, Mark D. Argentine, Derek Berglund, Molly Hess, Alison Campbell Brewer, Kayla L. Mathews, Ping Huang, Mo Jia, Peng Liu, Jing Chen, Chaoyi Deng and Fangyun Yang,

{"title":"Development of a Manufacturing Process for a Key (S)-5-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-1H-indole Intermediate for Orforglipron. Part II. Development of a CSTR Process for Evans Auxiliary-Assisted Asymmetric 1,4-Addition","authors":"Qiang Yang*, Derek R. Starkey, Radhe K. Vaid, Xavier Ortiz-Medina, Charles B. Held, Mark D. Argentine, Derek Berglund, Molly Hess, Alison Campbell Brewer, Kayla L. Mathews, Ping Huang, Mo Jia, Peng Liu, Jing Chen, Chaoyi Deng and Fangyun Yang, ","doi":"10.1021/acs.oprd.5c00184","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00184","url":null,"abstract":"A scalable 8-step route incorporating Evans auxiliary-assisted asymmetric 1,4-addition was developed for a key (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole intermediate of orforglipron. The main challenges of the batch process included the copper complex’s stability, the high exothermicity of the reaction, and the control of a key diastereomeric impurity. These challenges were addressed by developing a CSTR process to prepare the copper complex, enabling “on-demand” preparation and improved heat transfer to control the reaction temperature. A simple slurry purification was devised to isolate a metastable polymorph that effectively reduced the diastereomeric impurity to acceptable levels. The optimized process was successfully scaled up to >400 kg, demonstrating its robustness.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 8","pages":"2005–2017"},"PeriodicalIF":3.5,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840613","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

Discovery of Oxazole Byproduct Formation in the Modified Dakin–West Reaction and Efficient Synthesis of Diastereomeric α-Ketoamide Cysteine Protease Inhibitors 修饰Dakin-West反应中恶唑副产物的发现及α-酮酰胺半胱氨酸蛋白酶非对映体抑制剂的高效合成

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-07-30 DOI: 10.1021/acs.oprd.4c00512

Takashi Imada*, Chiho Fukiage and Mitsuyoshi Azuma,

引用次数: 0

Full Oxidation of an α-Arylated Isochromane: Development of a Two-Step Sequence as an Alternative to the Carcinogenic Jones Reagent and Application to the Manufacturing Process of Servier Phase II Clinical Candidate S44819 α-芳基化异色胺的完全氧化：两步序列的开发作为致癌琼斯试剂的替代品以及在施维雅II期临床候选物S44819的生产过程中的应用

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-07-29 DOI: 10.1021/acs.oprd.5c00193

Jean-Francois Giffard, Sylvain Lemaitre, François Bariere, Anthony Craquelin, Christophe Hardouin, Chloé Copin* and Alexandre Jean*,

引用次数: 0

α-Bromination of Aldehydes by Continuous Flow Chemistry and Its Application to the Flow Synthesis of 2-Aminothiazoles 连续流动化学α-溴化反应及其在2-氨基噻唑流动合成中的应用

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-07-28 DOI: 10.1021/acs.oprd.5c00076

Yong Lu, Zilong Yan, Yu Jiang, Haibing He, Jian Zhou, Shuanhu Gao and Dong Xing*,

引用次数: 0

Establishment of a Simple and Efficient Screening Protocol for Optical Resolution by Diastereomeric Salt Crystallization: Analyzing Success-Related Factors and Constructing Reliable Procedures from Previous Studies 建立一种简单有效的非对映体盐结晶光学分辨筛选方案：分析成功的相关因素并从以往研究中构建可靠的程序

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-07-25 DOI: 10.1021/acs.oprd.5c00201

Keisuke Suzuki*, Tomokazu Ogura*, Masaki Hayashi and Tsuyoshi Ueda,

{"title":"Establishment of a Simple and Efficient Screening Protocol for Optical Resolution by Diastereomeric Salt Crystallization: Analyzing Success-Related Factors and Constructing Reliable Procedures from Previous Studies","authors":"Keisuke Suzuki*, Tomokazu Ogura*, Masaki Hayashi and Tsuyoshi Ueda, ","doi":"10.1021/acs.oprd.5c00201","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00201","url":null,"abstract":"This paper presents a simple and efficient screening protocol for optical resolution by diastereomeric salt crystallization, developed from an analysis of our historical data. Original screening kits have been created utilizing selected commercially available chiral acids and bases, which encompass all reagents that have demonstrated promising results in the diastereomeric salt crystallization of 30 intermediates examined in our laboratories. The influence of various conditions such as crystallization solvents, the equivalents of the resolving agent, additives, and temperature was analyzed to establish clear procedures for the first screening experiments. The advantages of this procedure include its simplicity, accessibility, and high likelihood of success supported by historical achievements, as demonstrated in the optical resolution of the PTDSS1 inhibitor’s intermediate. Overall, this research offers valuable insights into the techniques of diastereomeric salt crystallization and contributes to the efficient acquisition of chiral compounds and advancement of process chemistry.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 8","pages":"2097–2106"},"PeriodicalIF":3.5,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840591","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

A Methodological Review of Extraction, Purification, and Identification Techniques for Natural Bioactive Compounds 天然生物活性化合物的提取、纯化和鉴定技术的方法学综述

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-07-23 DOI: 10.1021/acs.oprd.5c00080

Ali Rajabiyan*, Danial Bakhshi and Seyed Abolfazl Hosseini,

{"title":"A Methodological Review of Extraction, Purification, and Identification Techniques for Natural Bioactive Compounds","authors":"Ali Rajabiyan*, Danial Bakhshi and Seyed Abolfazl Hosseini, ","doi":"10.1021/acs.oprd.5c00080","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00080","url":null,"abstract":"Natural resources, both land and sea, contain many bioactive compounds. Today, these compounds have attracted the attention of many researchers due to their many therapeutic, medical, and other industrial applications. Due to their important health effects, extracting, purifying, and identifying the properties and structural descriptions of natural compounds show great attention in their analytical science. A crucial initial step in generating high-quality research results is preparing medicinal plants for testing. Prior to performing the intended biological test, biologically active chemicals must be extracted, purified, and their concentration and purity determined. Examples of popular extraction methods include percolation, Soxhlet, maceration, ultrasonic, enzymatic, and microwave extraction. On the other hand, the separation and purification of herbal substances is accomplished using numerous very efficient chromatography methods, including thin-layer chromatography, gas chromatography, and liquid chromatography. Ultimately, the resulting compounds are characterized using a range of identification techniques, like nuclear magnetic resonance spectroscopy, infrared spectroscopy, ultraviolet spectroscopy, and mass spectrometry. Here we review and provide an invaluable tool for researchers, business leaders, and legislators seeking to use natural bioactive chemicals to promote human health and environmental sustainability.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 8","pages":"1885–1915"},"PeriodicalIF":3.5,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840558","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

Expeditious and Automated Dispensing of ChemBeads for High-Throughput Experimentation in 384-Well Microtiter Plates 快速和自动分配化学珠高通量实验在384孔微量滴定板

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-07-23 DOI: 10.1021/acs.oprd.5c00232

Vincent Porte*, Philipp Hirschle*, Kilian Frank, Luca Hepp, Philipp Kollmus, Eloisa Serrano, Christian Ziegler*, Roland Heinrich, Simon Seebacher, Christoph Weiss, James M. Fordham and Marco Santagostino*,

{"title":"Expeditious and Automated Dispensing of ChemBeads for High-Throughput Experimentation in 384-Well Microtiter Plates","authors":"Vincent Porte*, Philipp Hirschle*, Kilian Frank, Luca Hepp, Philipp Kollmus, Eloisa Serrano, Christian Ziegler*, Roland Heinrich, Simon Seebacher, Christoph Weiss, James M. Fordham and Marco Santagostino*, ","doi":"10.1021/acs.oprd.5c00232","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00232","url":null,"abstract":"A unique automated dispensing robot to dose chemical-coated beads in microtiter plates (MTPs) at unprecedented speed is reported. With its novel dosing head design, ChemBeads can be reliably dosed volumetrically into 96- and 384-well MTPs. The platform features an intuitive graphical user interface, rendering the dosing protocol easy and flexible while ensuring traceability. This technology eliminates the need for multiple precatalyst/ligand stock solutions and overcomes the time constraint typically associated with automated gravimetric solid dosing. We also introduce a general workflow for performing metal-catalyzed reactions in 384-well glass MTPs under demanding conditions. The streamlined process was validated with a challenging C–N cross coupling reaction, conducted at elevated temperatures under heterogeneous conditions and using solvents rarely utilized in ultrahigh-throughput experimentation.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 8","pages":"2124–2131"},"PeriodicalIF":3.5,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840559","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

IF 3.1 3区化学

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

Yuya Orito*,

引用次数: 0