Organic Process Research & Development最新文献

Economic, One-Pot Synthesis of Diethyl Furoxan Dicarboxylate 经济、一步法合成呋喃香烷二甲酸二乙酯

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-09-25 DOI: 10.1021/acs.oprd.4c00191

Michael Thoenen, Nicholas F. Scherschel, Davin G. Piercey

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Highly Selective Electrosynthesis of 1H-1-Hydroxyquinol-4-ones–Synthetic Access to Versatile Natural Antibiotics 1H-1-羟基喹啉-4-酮的高选择性电合成--合成多功能天然抗生素的途径

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-09-24 DOI: 10.1021/acs.oprd.4c00337

Tobias Prenzel, Nils Schwarz, Jasmin Hammes, Franziska Krähe, Sarah Pschierer, Johannes Winter, María de Jesús Gálvez-Vázquez, Dieter Schollmeyer, Siegfried R. Waldvogel

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Risk of Formaldehyde Contamination in Amines from Residual Dichloromethane 残留二氯甲烷造成胺中甲醛污染的风险

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-09-24 DOI: 10.1021/acs.oprd.4c00323

Henrique A. Esteves, Subha Mukherjee, James Chadwick, Jennifer Albaneze-Walker, Whitney Nikitczuk, Jonathan Marshall, Joanne Ly, Antonio Ramirez, Emanuele Petruzzella, Junhe Ma

{"title":"Risk of Formaldehyde Contamination in Amines from Residual Dichloromethane","authors":"Henrique A. Esteves, Subha Mukherjee, James Chadwick, Jennifer Albaneze-Walker, Whitney Nikitczuk, Jonathan Marshall, Joanne Ly, Antonio Ramirez, Emanuele Petruzzella, Junhe Ma","doi":"10.1021/acs.oprd.4c00323","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00323","url":null,"abstract":"Understanding the mechanism of the formation of impurities in pharmaceutical intermediates and starting materials is crucial for a successful control strategy in the manufacturing of active pharmaceutical ingredients. This paper describes how amines containing residual dichloromethane can form substantial levels of formaldehyde during short-term storage. An investigation involving 22 different amines presents evidence underpinning the role of dichloromethane (DCM) in forming formaldehyde. Additionally, control experiments combined with existing knowledge on the reactivity of DCM with amine nucleophiles provide a mechanistic discussion on the generation of formaldehyde via known adducts from the reaction between amines, dichloromethane, and water. Finally, a case study involving a key intermediate of a drug candidate under investigation at Bristol Myers Squibb demonstrates the impact of residual DCM-derived formaldehyde in amine starting material on the formation of a daughter impurity during an amidation step.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317779","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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Impurities from Hydroxyproline Derivatives in the Synthesis of Modified Oligonucleotides 合成修饰寡核苷酸过程中来自羟脯氨酸衍生物的杂质

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-09-22 DOI: 10.1021/acs.oprd.4c00295

Hao Liang, Dalong Hou, Siming Li, Simin Chen, Yaru Ma, Haiqi Liu, Fushun Fan, Yuqiang Wang, Changgeng Qian, Xinjian Liu

{"title":"Impurities from Hydroxyproline Derivatives in the Synthesis of Modified Oligonucleotides","authors":"Hao Liang, Dalong Hou, Siming Li, Simin Chen, Yaru Ma, Haiqi Liu, Fushun Fan, Yuqiang Wang, Changgeng Qian, Xinjian Liu","doi":"10.1021/acs.oprd.4c00295","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00295","url":null,"abstract":"This study explores the challenges of synthesizing modified oligonucleotides, particularly focusing on the impurities introduced when using hydroxyproline derivatives. We found that incorporating amino linkers, specifically the trans-4-hydroxy-l-prolinol backbone, leads to the formation of specific difficult-to-remove impurities. To address these issues, we recommend preloading the linker onto the solid-phase carrier to prevent the generation of phosphoramide impurities. Additionally, using a scavenger during the cleavage and deprotection steps is suggested to minimize unwanted reactions. A significant finding is the crucial role of triethylamine in the washing steps, where increasing its amount effectively prevents the formation of acrylonitrile and acetylation adducts. Through a series of experiments, we have identified the causes of these impurities and proposed strategies for their mitigation. These strategies ensure the efficient synthesis of oligonucleotides with improved purity, enhancing their potential for broader applications in biomedical research and biotechnology.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306299","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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Highlights from the Third National Edition of the French Industrial Chemistry Symposium (FICS 2024), Paris, France, April 2024 第三届法国工业化学研讨会（FICS 2024）亮点，法国巴黎，2024 年 4 月

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2024-09-20 DOI: 10.1021/acs.oprd.4c0030810.1021/acs.oprd.4c00308

Fanny Coumes, Philippe Mackiewicz, Michael Parmentier, Laurent Petit and Morgan Donnard*,

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Highlights from the Third National Edition of the French Industrial Chemistry Symposium (FICS 2024), Paris, France, April 2024 第三届法国工业化学研讨会（FICS 2024）亮点，法国巴黎，2024 年 4 月

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-09-20 DOI: 10.1021/acs.oprd.4c00308

Fanny Coumes, Philippe Mackiewicz, Michael Parmentier, Laurent Petit, Morgan Donnard

{"title":"Highlights from the Third National Edition of the French Industrial Chemistry Symposium (FICS 2024), Paris, France, April 2024","authors":"Fanny Coumes, Philippe Mackiewicz, Michael Parmentier, Laurent Petit, Morgan Donnard","doi":"10.1021/acs.oprd.4c00308","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00308","url":null,"abstract":"Figure 1. Organizing Committee of FICS 2024 (from left to right: M. Donnard, P. Mackiewicz, F. Coumes, L. Petit, M. Parmentier). Figure 2. Anthony Lapray (right) received the OPR&D Best Poster Award from the hands of Fanny Coumes and Michael Parmentier. Figure 3. Jérémy Paris was named Laureate of the DCI Industrial Prize 2024. Figure 4. Péroline Helbling has been awarded the DCI Young Chemist Prize 2024. The organizing committee is grateful to the École Nationale Supérieure de Chimie de Paris (Chimie Paris Tech - PSL), especially Dr. Michael Tatoulian, for hosting this event and providing all the logistical resources required to ensure that it ran smoothly. This event would not have been possible without the financial support of our sponsors, and therefore, the organizing committee sincerely thanks EUROAPI, Novartis, Paris Flow Tech, Seqens, Oril, TÜV SÜD, Sanofi, AtlanChim Pharma, Samabriva, Minakem, Corning, SON SAS, Charles Friedel Consulting, pmc isochem, Nuvisan, Magritek, Merck, SpiroChem, Société Chimique de France, CNRS, and OPR&D. This article has not yet been cited by other publications.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247231","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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Development of a Robust Pd-Catalyzed C–S Coupling for the Synthesis of Janus Kinase Inhibitor GDC-9918 开发用于合成 Janus 激酶抑制剂 GDC-9918 的稳健 Pd 催化 C-S 偶联反应

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-09-20 DOI: 10.1021/acs.oprd.4c00268

Derek M. Dalton, Juno Castillo Siu, Marcelino Varona-Ortiz, C. Gregory Sowell, Francis Gosselin

{"title":"Development of a Robust Pd-Catalyzed C–S Coupling for the Synthesis of Janus Kinase Inhibitor GDC-9918","authors":"Derek M. Dalton, Juno Castillo Siu, Marcelino Varona-Ortiz, C. Gregory Sowell, Francis Gosselin","doi":"10.1021/acs.oprd.4c00268","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00268","url":null,"abstract":"The development of an in situ formed (Xantphos)Pd oxidative addition complex made possible a robust, scalable C–S coupling of a functionalized aryl bromide with 2-mercaptoethanol that ultimately enabled the synthesis of Janus Kinase inhibitor GDC-9918 on a kilogram scale. An insoluble, catalytically inactive, [12]metallacrown-6 palladium(II) complex, [Pd6(μ2-SCH2CH2OH)12], was found to form quickly under most reaction conditions in the presence of 2-mercaptoethanol and a Pd catalyst and required up to 12 mol % Pd for full conversion in our generation route. A second-generation process was developed to minimize the formation of the [12]metallacrown-6 palladium(II) complex and enabled the decrease in catalyst loading to 2 mol % Pd. A soluble Pd scavenger, PIX, effectively removed Pd to <5 ppm. Catalytic sodium tungstate oxidation of the resulting thioether smoothly provided crude GDC-9918 that was recrystallized to the desired polymorph and micronized to a particle size distribution suitable for development as an inhalable treatment for asthma.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247232","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

Reactivities of N-Nitrosamines against Common Reagents and Reaction Conditions N-亚硝胺与常见试剂和反应条件的反应活性

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-09-18 DOI: 10.1021/acs.oprd.4c00217

George A. Hodgin, Michael J. Burns, Benjamin J. Deadman, Christopher S. Roberts, King Kuok Mimi Hii, Bao N. Nguyen

{"title":"Reactivities of N-Nitrosamines against Common Reagents and Reaction Conditions","authors":"George A. Hodgin, Michael J. Burns, Benjamin J. Deadman, Christopher S. Roberts, King Kuok Mimi Hii, Bao N. Nguyen","doi":"10.1021/acs.oprd.4c00217","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00217","url":null,"abstract":"The knowledge of the reactivity of N-nitrosamines (NSAs) with common organic reagents in synthesis is essential in determining their presence in pharmaceutical products, if formed and retained during synthesis. In this study, we carried out a comprehensive survey of the Reaxys database for all reactions in which the NSA functional group is consumed. Very different reactivities for different classes of NSAs, e.g., N,N-dialkylnitrosamines and N,N-diphenylnitrosamine, were identified, suggesting substrates which should be included in any future reactivity screening. A classification of NSAs based on their reactivities, and corresponding reagents and transformations, was drawn up based on the data. Furthermore, the survey identified missing areas in the reported reactivities of NSAs with different reagents. This led to an experimental reactivity screening of 8 commercial NSAs with common synthetic reagents in the Mirabilis tool for purge assessment. The results showed Na2S2O4 in 1 M aqueous NaOH at 50 °C to be highly effective at destroying NSAs without damaging other organic compounds.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142237101","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

Process Development for the First GMP Synthesis of SGD-9501-TFA, Part 1: Synthesis of Two Oligopeptide Fragments SGD-9501-TFA 首次 GMP 合成的工艺开发，第 1 部分：两个寡肽片段的合成

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-09-16 DOI: 10.1021/acs.oprd.4c00317

Noah Porter, William Guy, Brooke Gill, Kareem Bdeir, Minh Nguyen, Jared Abbruzzese, Malcolm Reider, Lorenzo Pontini, Gabriele Cerai, Jacopo Roletto, Aaron M. Whittaker

{"title":"Process Development for the First GMP Synthesis of SGD-9501-TFA, Part 1: Synthesis of Two Oligopeptide Fragments","authors":"Noah Porter, William Guy, Brooke Gill, Kareem Bdeir, Minh Nguyen, Jared Abbruzzese, Malcolm Reider, Lorenzo Pontini, Gabriele Cerai, Jacopo Roletto, Aaron M. Whittaker","doi":"10.1021/acs.oprd.4c00317","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00317","url":null,"abstract":"The discovery of novel auristatin-derived antibody drug conjugates (ADCs) with attenuated bystander activity is an area of intense research. Recently, drug-linker SGD-9501 emerged as a promising clinical candidate possessing favorable off-target toxicity. To support the clinical supply of ADCs based on this drug-linker, we set out to develop a first-in-human (FIH) amenable GMP manufacturing route. This report describes the process development of two oligopeptide fragments covering four synthetic steps in the seven-step convergent solution phase synthesis of SGD-9501 from commercial reagents. The highlights within this report include the discovery and development of three crystallizations, the use of PAT to control impurities formed in a direct coupling of N,N-dimethyl-O-unprotected serine, and the development of mild acid promoted boc and tert-butyl ester deprotection conditions that optimized impurity control and subsequent isolation. Each step was performed on a >500 g scale for the GMP campaign and achieved a >75% yield and >98% LC area percent (LCAP) purity.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142235412","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 Practical Telescoped Process to Prepare (P)-7-(2-Amino-6-fluorophenyl)-4-hydroxy-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one: a Key Intermediate of KRASG12C Inhibitor GH35 开发制备(P)-7-(2-氨基-6-氟苯基)-4-羟基-6-(三氟甲基)吡啶并[3,4-d]嘧啶-8(7H)-酮的实用远程工艺：KRASG12C 抑制剂 GH35 的关键中间体

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-09-13 DOI: 10.1021/acs.oprd.4c00279

Gaolei Zuo, Haojie Xu, Yaobin Zhang, Zhi Liu, Jinyue Tu, Donghui Gou, Peng Fu, Haifeng Huang, Jianhua Ren, Yuanyuan Hu, Feng Liu, Jie Jack Li, Guiping Zhang

{"title":"Development of a Practical Telescoped Process to Prepare (P)-7-(2-Amino-6-fluorophenyl)-4-hydroxy-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one: a Key Intermediate of KRASG12C Inhibitor GH35","authors":"Gaolei Zuo, Haojie Xu, Yaobin Zhang, Zhi Liu, Jinyue Tu, Donghui Gou, Peng Fu, Haifeng Huang, Jianhua Ren, Yuanyuan Hu, Feng Liu, Jie Jack Li, Guiping Zhang","doi":"10.1021/acs.oprd.4c00279","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00279","url":null,"abstract":"GH35 is a potent irreversible covalent inhibitor of KRASG12C that is currently undergoing phase I clinical trials for the treatment of patients with advanced solid tumors. Herein, we describe an efficient and cost-effective telescoped process to produce an atropisomeric intermediate, GH35-RSM, for the synthesis of GH35. Iterative optimization based on medicinal chemistry synthetic route resulted in significant improvement of several key reactions, such as two-step chiral resolution affording highly pure atropisomer (P)-methyl 1-(2-fluoro-6-nitrophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (5-P) in 99.9% e.e. and 35% yield and introduction of a nitrile group into (P)-3-amino-1-(2-amino-6-fluorophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-4-carbonitrile (17) by use of an environment-friendly catalyst system identified by high throughput screening. The telescoped six-step process was robustly performed to provide hundreds of kilograms of GH35-RSM in plants to support clinical studies.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231590","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