Pub Date : 2025-03-27DOI: 10.1021/acs.oprd.5c00021
John R. Rizzo, Prem Kumar Begari, Deepak Kalita, Jiancai Gu, Scott A. Frank, Nour Eddine Fahmi, Hem Raj Khatri
The Baeyer–Villiger reaction is an established oxidative process that is applied for structural and functional group modification. We have applied the Baeyer–Villiger process to prepare 4′-oxo nucleosides. The application of Baeyer–Villiger oxidation to prepare MeMOP, a complex amidite used in the reported GalXC platform, will be discussed. A large-scale process to prepare MeMOP with an improved economic and operational safety risk profile will be highlighted. This novel application of the Baeyer–Villiger reaction to nucleoside platforms was used to scale up the MeMOP phosphoramidite process, which supported multiple clinical trials enabling siRNA campaigns.
{"title":"Novel Baeyer–Villiger Oxidation of Nucleosides Applied to the Large-Scale Synthesis of MeMOP: A Key Amidite in the GalXC Platform","authors":"John R. Rizzo, Prem Kumar Begari, Deepak Kalita, Jiancai Gu, Scott A. Frank, Nour Eddine Fahmi, Hem Raj Khatri","doi":"10.1021/acs.oprd.5c00021","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00021","url":null,"abstract":"The Baeyer–Villiger reaction is an established oxidative process that is applied for structural and functional group modification. We have applied the Baeyer–Villiger process to prepare 4′-oxo nucleosides. The application of Baeyer–Villiger oxidation to prepare MeMOP, a complex amidite used in the reported GalXC platform, will be discussed. A large-scale process to prepare MeMOP with an improved economic and operational safety risk profile will be highlighted. This novel application of the Baeyer–Villiger reaction to nucleoside platforms was used to scale up the MeMOP phosphoramidite process, which supported multiple clinical trials enabling siRNA campaigns.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"50 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713635","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 : 2025-03-26DOI: 10.1021/acs.oprd.5c00033
Jason S. West, Chelsea A. Mann, Mark J. Mitton-Fry
Medicinal chemistry efforts identified OSUAB-0284 (2) as a preclinical candidate to treat staphylococcal infections, especially those caused by methicillin-resistant Staphylococcus aureus (MRSA). Herein, we describe a fit-for-purpose route that enabled the production of >20 g of API for toxicology studies and further preclinical characterization. Process improvements include a 16-fold increase in yield over the longest sequence, a 21-fold increase in efficiency for the cost-limiting reagent, and reduction of chromatography to one silica plug across an 18-step route.
{"title":"Decagram-Scale Synthesis of the Novel Bacterial Topoisomerase Inhibitor OSUAB-0284","authors":"Jason S. West, Chelsea A. Mann, Mark J. Mitton-Fry","doi":"10.1021/acs.oprd.5c00033","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00033","url":null,"abstract":"Medicinal chemistry efforts identified OSUAB-0284 (<b>2</b>) as a preclinical candidate to treat staphylococcal infections, especially those caused by methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). Herein, we describe a fit-for-purpose route that enabled the production of >20 g of API for toxicology studies and further preclinical characterization. Process improvements include a 16-fold increase in yield over the longest sequence, a 21-fold increase in efficiency for the cost-limiting reagent, and reduction of chromatography to one silica plug across an 18-step route.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"18 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703638","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 : 2025-03-26DOI: 10.1021/acs.oprd.5c0003310.1021/acs.oprd.5c00033
Jason S. West, Chelsea A. Mann and Mark J. Mitton-Fry*,
Medicinal chemistry efforts identified OSUAB-0284 (2) as a preclinical candidate to treat staphylococcal infections, especially those caused by methicillin-resistant Staphylococcus aureus (MRSA). Herein, we describe a fit-for-purpose route that enabled the production of >20 g of API for toxicology studies and further preclinical characterization. Process improvements include a 16-fold increase in yield over the longest sequence, a 21-fold increase in efficiency for the cost-limiting reagent, and reduction of chromatography to one silica plug across an 18-step route.
{"title":"Decagram-Scale Synthesis of the Novel Bacterial Topoisomerase Inhibitor OSUAB-0284","authors":"Jason S. West, Chelsea A. Mann and Mark J. Mitton-Fry*, ","doi":"10.1021/acs.oprd.5c0003310.1021/acs.oprd.5c00033","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00033https://doi.org/10.1021/acs.oprd.5c00033","url":null,"abstract":"<p >Medicinal chemistry efforts identified OSUAB-0284 (<b>2</b>) as a preclinical candidate to treat staphylococcal infections, especially those caused by methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). Herein, we describe a fit-for-purpose route that enabled the production of >20 g of API for toxicology studies and further preclinical characterization. Process improvements include a 16-fold increase in yield over the longest sequence, a 21-fold increase in efficiency for the cost-limiting reagent, and reduction of chromatography to one silica plug across an 18-step route.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 4","pages":"1136–1151 1136–1151"},"PeriodicalIF":3.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842449","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 : 2025-03-25DOI: 10.1021/acs.oprd.4c0054310.1021/acs.oprd.4c00543
Keisuke Nogi*, Masao Tsukazaki, Hiroshi Iwamura and Kenji Maeda,
A selective and scalable O-alkylation method has been developed for the synthesis of a series of O-alkyl serine and threonine derivatives as useful unnatural amino acids. The use of Ti(IV) species capable of bis-ligation enables chelation-controlled reductive C–N cleavage of N,O-acetal intermediates to afford the corresponding O-alkylated product. Moreover, N-alkylated byproducts are selectively decomposed under basic conditions and removed by extraction and crystallization, thus eliminating laborious column chromatography processes in scale-up synthesis.
{"title":"Selective and Scalable O-Alkylation of Serine and Threonine Enabled by Chelation-Controlled Reductive C–N Cleavage of N,O-Acetals","authors":"Keisuke Nogi*, Masao Tsukazaki, Hiroshi Iwamura and Kenji Maeda, ","doi":"10.1021/acs.oprd.4c0054310.1021/acs.oprd.4c00543","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00543https://doi.org/10.1021/acs.oprd.4c00543","url":null,"abstract":"<p >A selective and scalable <i>O</i>-alkylation method has been developed for the synthesis of a series of <i>O</i>-alkyl serine and threonine derivatives as useful unnatural amino acids. The use of Ti(IV) species capable of bis-ligation enables chelation-controlled reductive C–N cleavage of <i>N</i>,<i>O</i>-acetal intermediates to afford the corresponding <i>O</i>-alkylated product. Moreover, <i>N</i>-alkylated byproducts are selectively decomposed under basic conditions and removed by extraction and crystallization, thus eliminating laborious column chromatography processes in scale-up synthesis.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 4","pages":"1103–1109 1103–1109"},"PeriodicalIF":3.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842208","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}
A selective and scalable O-alkylation method has been developed for the synthesis of a series of O-alkyl serine and threonine derivatives as useful unnatural amino acids. The use of Ti(IV) species capable of bis-ligation enables chelation-controlled reductive C–N cleavage of N,O-acetal intermediates to afford the corresponding O-alkylated product. Moreover, N-alkylated byproducts are selectively decomposed under basic conditions and removed by extraction and crystallization, thus eliminating laborious column chromatography processes in scale-up synthesis.
{"title":"Selective and Scalable O-Alkylation of Serine and Threonine Enabled by Chelation-Controlled Reductive C–N Cleavage of N,O-Acetals","authors":"Keisuke Nogi, Masao Tsukazaki, Hiroshi Iwamura, Kenji Maeda","doi":"10.1021/acs.oprd.4c00543","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00543","url":null,"abstract":"A selective and scalable <i>O</i>-alkylation method has been developed for the synthesis of a series of <i>O</i>-alkyl serine and threonine derivatives as useful unnatural amino acids. The use of Ti(IV) species capable of bis-ligation enables chelation-controlled reductive C–N cleavage of <i>N</i>,<i>O</i>-acetal intermediates to afford the corresponding <i>O</i>-alkylated product. Moreover, <i>N</i>-alkylated byproducts are selectively decomposed under basic conditions and removed by extraction and crystallization, thus eliminating laborious column chromatography processes in scale-up synthesis.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"71 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703679","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 : 2025-03-21DOI: 10.1021/acs.oprd.5c00030
Vittorio Farina
Terms like scalability, synthetic efficiency, and convergency are often used by development chemists to qualify the merits of their processes. However, these are often qualitative designations, devoid of any quantitative assessment. We propose some guidelines to support the judicious use of these terms. In particular, we would like to bring to the attention of process chemists the work of J. B. Hendrickson, who─almost 50 years ago─first proposed a meaningful quantitative evaluation of a synthetic plan and defined consistency and convergency in a quantitative way. After a brief analysis of the term scalability, this perspective presents a simplified version of Hendrickson’s ideas and extends it to multicomponent reactions. The metrics proposed herein are very easy to use and should allow chemists to verify the efficiency of their synthetic plan by calculating a consistency index and a convergency index which could complement qualitative descriptors like “efficient process” or “highly convergent synthesis”.
开发化学家经常使用可扩展性、合成效率和收敛性等术语来评价其工艺的优劣。然而，这些术语通常都是定性的，缺乏任何定量评估。我们提出了一些指导原则，以支持合理使用这些术语。特别是，我们希望提请工艺化学家注意 J. B. Hendrickson 的工作，他在近 50 年前首次提出了对合成计划进行有意义的定量评估，并以定量的方式定义了一致性和收敛性。在简要分析了可扩展性这一术语之后，本章提出了亨德里克森思想的简化版本，并将其扩展到多组分反应。本文提出的指标非常容易使用，化学家可以通过计算一致性指数和收敛性指数来验证其合成计划的效率，从而补充 "高效工艺 "或 "高收敛性合成 "等定性描述。
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Pub Date : 2025-03-21DOI: 10.1021/acs.oprd.5c0003010.1021/acs.oprd.5c00030
Vittorio Farina*,
Terms like scalability, synthetic efficiency, and convergency are often used by development chemists to qualify the merits of their processes. However, these are often qualitative designations, devoid of any quantitative assessment. We propose some guidelines to support the judicious use of these terms. In particular, we would like to bring to the attention of process chemists the work of J. B. Hendrickson, who─almost 50 years ago─first proposed a meaningful quantitative evaluation of a synthetic plan and defined consistency and convergency in a quantitative way. After a brief analysis of the term scalability, this perspective presents a simplified version of Hendrickson’s ideas and extends it to multicomponent reactions. The metrics proposed herein are very easy to use and should allow chemists to verify the efficiency of their synthetic plan by calculating a consistency index and a convergency index which could complement qualitative descriptors like “efficient process” or “highly convergent synthesis”.
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Pub Date : 2025-03-21DOI: 10.1021/acs.oprd.5c00042
Michael W. Urquhart, Michael J. Burns, Frank Bernardoni, Hugh F. Clark, Jean-Philippe Crochard, Alessandro De Benedetti, Olivier Dirat, Jared W. Fennell, Malcolm A. Y. Gall, Marzia Galli, Stefan Hildbrand, Jeffrey M. Kallemeyn, Nadine Kuhl, Daniel J. Mack, Christian Moessner, David D. Pascoe, Alessandro Pozzoli, Philippe Risch, Alastair J. Roberts, Andrew Teasdale, Oliver R. Thiel, Paula Tomlin, Andrew Whitehead
The assessment and control of potential mutagenic impurities (PMIs) within pharmaceutical products are managed in accordance with the ICH M7 guideline “Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk”. This guidance highlights four control options that can be used to give assurance of control of PMIs to below a level of toxicological concern for the intended use. These control options range from testing to confirm that impurity levels within the active pharmaceutical ingredient or product are below an acceptable limit (ICH M7 Option 1 Control) to a control strategy that relies on process controls and scientific principles (e.g., purging) to demonstrate impurity presence to below a level of concern in lieu of analytical testing (option 4). While ICH M7 control option 4 is an established approach to justify that levels of a potential mutagenic impurity are below an acceptable limit, there have been health authority challenges that the use of ICH M7 control option 4 rationales is not appropriate for N-nitrosamines without included confirmatory analytical testing data to confirm absence. The reasons behind this lack of acceptance for ICH M7 control option 4 alone may include (i) a higher perceived potency for nitrosamines over other mutagenic impurities as they alert as part of the cohort of concern and (ii) inappropriate application of purge rationales such that, in some instances, confirmatory testing data highlighted higher levels for the impurity than had been predicted to be present. Through the inclusion of industry relevant case studies, this publication outlines that, while some nitrosamines may require control to lower levels than the ICH M7 threshold of toxicological concern, the concept of the ICH M7 option 4 control is scientifically justified when the properties for the nitrosamine are considered and an appropriate conservative purge rationale is applied.
药品中潜在致突变杂质（PMIs）的评估和控制是根据 ICH M7 指导原则 "评估和控制药品中 DNA 活性（致突变）杂质以限制潜在致癌风险 "进行管理的。该指南强调了四种控制方案，可用于确保将 PMIs 控制在预定用途的毒理学关注水平以下。这些控制方案包括通过检测确认活性药物成分或产品中的杂质含量低于可接受的限度（ICH M7 方案 1 控制），以及依靠工艺控制和科学原理（如净化）来证明杂质含量低于关注水平的控制策略，以代替分析检测（方案 4）。虽然 ICH M7 控制选项 4 是证明潜在致突变杂质水平低于可接受限值的既定方法，但有卫生当局提出质疑，认为在没有包含确认不存在的确证分析测试数据的情况下，使用 ICH M7 控制选项 4 的理由不适合亚硝胺类化合物。仅 ICH M7 控制选项 4 不被接受的原因可能包括：(i) 亚硝胺的效力高于其他致突变杂质，因为它们是受关注群组的一部分；(ii) 不适当地应用清除原理，例如，在某些情况下，确认测试数据显示杂质含量高于预测含量。通过纳入行业相关案例研究，本出版物概述了虽然某些亚硝胺可能需要控制在低于 ICH M7 毒理学关注阈值的水平，但如果考虑到亚硝胺的特性并采用适当的保守净化原理，ICH M7 选项 4 控制的概念是科学合理的。
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Pub Date : 2025-03-21DOI: 10.1021/acs.oprd.5c00049
Bernd Schaefer, Shashank Shekhar, James Murray
Published as part of <i>Organic Process Research & Development</i> special issue “Excellence in Industrial Organic Synthesis 2024”. In the chemical industry, alongside the discovery of new substances and their properties, the development and optimization of chemical reactions and processes play a decisive role, not least for economic reasons. (1,2) This is nothing new. The interplay between research and development, and thus the pursuit of excellence in chemistry, has characterized the industry from the very beginning and will certainly continue to make a decisive contribution in the future, mastering the major challenges we are currently facing, from the demand for increased sustainability and efficient CO<sub>2</sub> management to the changes in the supply of raw materials and energy. The conceptual foundations of excellence in chemistry can be traced back to the principle of parsimony by William of Ockham (1286–1347), a medieval Franciscan monk, and on his proverbial razor, in which he summed up the motivation of optimization in a single sentence: “It is futile to do with more what can be done with fewer” (Lat.: “<i>Frustra fit per plura, quod potest fieri per pauciora</i>”). (3,4) In accordance with this concept, James B. Hendrickson (1928–2018) outlined his ideas on the logic of organic chemistry and <i>ideal synthesis</i> already in 1975. (5,6) Barry Trost’s thoughts on <i>atom economy</i> followed in the early 1990s, while Paul A. Wender came up with function-oriented synthesis and <i>step economy</i> in 2008 (7) and Phil Baran and Reinhard Hoffmann with <i>redox economy</i> at almost the same time. (8) In parallel, Roger A. Sheldon emphasized the need for a new paradigm in the evaluation of efficiency in chemical production, assigning value not only to chemical yield but also to waste minimization. By developing the E-factor concept, which is now used throughout the industry in one form or another, he brought <i>elegance and precision</i> to large-scale production. (9−11) In this respect, it is perhaps not too surprising that some of these elegant processes have already been in operation for a while. As examples one may consider Evonik’s methionine production, BASF’s citral synthesis, and Rhodia’s vanillin process. (12) Taking James Hendrickson’s thoughts on the <i>ideal synthesis</i> as a starting point, this year we can indeed celebrate 50 years of excellence in industrial organic synthesis. Articles included in this Special Issue cover a wide variety of research topics such as discussion on strategies for kilogram-scale synthesis with emphasis on safety, robustness, and sustainability, flow and impinging-jet technologies, new catalytic methods, integration of Process Analytical Technologies (PAT) for solid-phase peptide synthesis, and green chemistry to name a few. These outstanding contributions provide an exquisite overview of the current state of the art and certainly pave the way for further improvements. Consistent with earlie
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Pub Date : 2025-03-21DOI: 10.1021/acs.oprd.5c0004910.1021/acs.oprd.5c00049
Bernd Schaefer*, Shashank Shekhar* and James Murray*,
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