Organic Process Research & Development最新文献

{"title":"Accelerating the Development of Sustainable Catalytic Processes through Data Science","authors":"Jason M. Stevens, Jacob M. Ganley, Matthew J. Goldfogel, Ariel Furman, Steven R. Wisniewski","doi":"10.1021/acs.oprd.4c00434","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00434","url":null,"abstract":"Herein, we describe the optimization of reaction conditions for a nickel-catalyzed borylation using a combination of machine learning, high-throughput experimentation, and Bayesian optimization. A machine learning model, trained on a data set from Bristol Myers Squibb, was employed to predict the yields of 144 potential reaction conditions across three potential substrates for the target borylation reaction. These predictions guided a high-throughput experimentation study, which identified promising conditions for further development. The most promising condition underwent four rounds of Bayesian optimization, resulting in reaction conditions optimized for both chemical yield (>99%) and cost efficiency. The entire hit-identification and optimization process was completed in just 120 experiments over the course of 1 week by a single scientist. These optimized conditions were successfully validated on a 40 g scale to achieve 83.5% isolated yield.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"26 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911596","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}

{"title":"Accelerating the Development of Sustainable Catalytic Processes through Data Science","authors":"Jason M. Stevens*,&nbsp;Jacob M. Ganley,&nbsp;Matthew J. Goldfogel,&nbsp;Ariel Furman and Steven R. Wisniewski,&nbsp;","doi":"10.1021/acs.oprd.4c0043410.1021/acs.oprd.4c00434","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00434https://doi.org/10.1021/acs.oprd.4c00434","url":null,"abstract":"<p >Herein, we describe the optimization of reaction conditions for a nickel-catalyzed borylation using a combination of machine learning, high-throughput experimentation, and Bayesian optimization. A machine learning model, trained on a data set from Bristol Myers Squibb, was employed to predict the yields of 144 potential reaction conditions across three potential substrates for the target borylation reaction. These predictions guided a high-throughput experimentation study, which identified promising conditions for further development. The most promising condition underwent four rounds of Bayesian optimization, resulting in reaction conditions optimized for both chemical yield (&gt;99%) and cost efficiency. The entire hit-identification and optimization process was completed in just 120 experiments over the course of 1 week by a single scientist. These optimized conditions were successfully validated on a 40 g scale to achieve 83.5% isolated yield.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 1","pages":"189–199 189–199"},"PeriodicalIF":3.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143089395","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}

{"title":"Impurity Control Strategy of TMS-Triol in the Manufacture Development of Islatravir","authors":"Weidong Tong*,&nbsp;Victor L. Schultz,&nbsp;Yingying Yang,&nbsp;Junyong Jo,&nbsp;Yu He,&nbsp;Marco E. Armenante,&nbsp;Sandra A. Robaire,&nbsp;Samantha A. Burgess,&nbsp;Yun Chen,&nbsp;Erica L. Schwalm,&nbsp;Matthew Gunsch,&nbsp;Xiao Wang,&nbsp;Qi Gao,&nbsp;Cyndi Q. He,&nbsp;Mikhail Reibarkh,&nbsp;Jeffrey T. Kuethe and Gregory J. Hughes,&nbsp;","doi":"10.1021/acs.oprd.4c0036810.1021/acs.oprd.4c00368","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00368https://doi.org/10.1021/acs.oprd.4c00368","url":null,"abstract":"<p >The identification, quantification, understanding, and control of impurities in starting materials, intermediates, and substances are crucial during the evaluation of new molecular entities in the clinical development of the pharmaceutical industry. Through process characterization development in islatravir (MK-8591), two impurities from the regulatory starting material, TMS-Triol, were discovered in a late stage that persisted in the product. However, they were not detectable by the gas chromatography (GC) method that the process used. This paper describes the use of orthogonal analytical approaches for impurity investigations, which aim to provide a comprehensive understanding of the impurity profile of a drug substance with a particular emphasis on comprehending the origin and fate of impurities from upstream steps. The understanding serves as a guide for making decisions on process controls and optimizations of the islatravir drug substance. This paper also outlines quality control strategies for the starting material of the islatravir drug substance commercial process. The knowledge gained from these investigations forms a solid foundation for establishing specifications for impurities in regulatory starting materials.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 1","pages":"92–99 92–99"},"PeriodicalIF":3.1,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143086018","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}

{"title":"Impurity Control Strategy of TMS-Triol in the Manufacture Development of Islatravir","authors":"Weidong Tong, Victor L. Schultz, Yingying Yang, Junyong Jo, Yu He, Marco E. Armenante, Sandra A. Robaire, Samantha A. Burgess, Yun Chen, Erica L. Schwalm, Matthew Gunsch, Xiao Wang, Qi Gao, Cyndi Q. He, Mikhail Reibarkh, Jeffrey T. Kuethe, Gregory J. Hughes","doi":"10.1021/acs.oprd.4c00368","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00368","url":null,"abstract":"The identification, quantification, understanding, and control of impurities in starting materials, intermediates, and substances are crucial during the evaluation of new molecular entities in the clinical development of the pharmaceutical industry. Through process characterization development in islatravir (MK-8591), two impurities from the regulatory starting material, TMS-Triol, were discovered in a late stage that persisted in the product. However, they were not detectable by the gas chromatography (GC) method that the process used. This paper describes the use of orthogonal analytical approaches for impurity investigations, which aim to provide a comprehensive understanding of the impurity profile of a drug substance with a particular emphasis on comprehending the origin and fate of impurities from upstream steps. The understanding serves as a guide for making decisions on process controls and optimizations of the islatravir drug substance. This paper also outlines quality control strategies for the starting material of the islatravir drug substance commercial process. The knowledge gained from these investigations forms a solid foundation for establishing specifications for impurities in regulatory starting materials.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"22 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142874512","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}

{"title":"Design, Development, and Scale-Up of a Stereoselective Synthesis of (1R,3R)-3-(3,5-Bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane Carboxylic Acid","authors":"Pablo J. Cabrera, Fangzheng Li, Nakyen Choy, Tay Rosenthal, Steffen Good, Jeffrey Nissen, Avery Sader","doi":"10.1021/acs.oprd.4c00425","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00425","url":null,"abstract":"This report describes the design, development, and scale-up of a stereoselective synthesis of (1<i>R</i>,3<i>R</i>)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane carboxylic acid (<b>1)</b>, a key intermediate toward the synthesis of a promising developmental agrochemical. The synthesis features <span>d</span>-mannitol as a sustainable chiral pool starting material, a double Heck coupling reaction, and the invention of diastereoselective dichlorocyclopropanation. Details disclosed include the route design, development of enabling steps, and learnings from a kilogram-scale campaign. The nine-step route was used to produce 1.5 kg of (1<i>R</i>,3<i>R</i>)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane carboxylic acid in 13% overall yield, 97.8% purity, and excellent enantiopurity (&gt;99.5% <i>ee)</i>.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"15 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867613","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}

{"title":"Thank You","authors":"Kai Rossen*,&nbsp;","doi":"10.1021/acs.oprd.4c0047510.1021/acs.oprd.4c00475","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00475https://doi.org/10.1021/acs.oprd.4c00475","url":null,"abstract":"","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 12","pages":"4173 4173"},"PeriodicalIF":3.1,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867905","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}

{"title":"Predictive Methodology for Selecting the “Fit-for-Purpose” LC-HRMS Method for Quality Assessment in Peptide Synthesis","authors":"Pavan Ingle,&nbsp;Naveen Chandrasekar,&nbsp;Sumit Kumar,&nbsp;Cherukuri Venkata Apparao,&nbsp;Bichismita Sahu* and Ravi P. Shah*,&nbsp;","doi":"10.1021/acs.oprd.4c0039310.1021/acs.oprd.4c00393","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00393https://doi.org/10.1021/acs.oprd.4c00393","url":null,"abstract":"<p >Peptides are essential in pharmaceuticals and function as therapeutic agents for a wide range of conditions. The chemical synthesis process of peptides often leaves impurities, such as inorganic salts and residual reagents, which can interfere with the analysis and contaminate the mass spectrometer’s source in in-process quality control (IPQC). Moreover, process monitoring using short liquid chromatography-high-resolution mass spectrometry (LC-HRMS) runtimes presents challenges due to the presence of multiple organic impurities. To address this, four distinct LC-HRMS templates were developed to accommodate a diverse range of peptides. A principal component analysis (PCA)-based methodology was then developed and validated to select the appropriate LC-HRMS method based on the peptides’ physicochemical properties, including sequence length, hydrophobicity, isoelectric point, molecular weight, and clog <i>P</i>. The PCA methodology efficiently classified peptides into distinct quadrants, guiding the selection of the appropriate short LC-HRMS method without the need for trial-and-error LC-HRMS method development. With a success rate exceeding 90%, the methodology accurately predicted the appropriate LC-HRMS method for the peptides. This systematic approach streamlines method selection and ensures the precise elution of peptides. Furthermore, by directing the initial LC flow to waste, the short methods minimize the risk of mass source contamination from inorganic impurities. This developed methodology is suitable for peptides with sequence lengths ranging from tetrapeptides to octapeptides, providing a robust tool for peptide analysis in IPQC workflows.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 1","pages":"137–145 137–145"},"PeriodicalIF":3.1,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143085565","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}

{"title":"Predictive Methodology for Selecting the “Fit-for-Purpose” LC-HRMS Method for Quality Assessment in Peptide Synthesis","authors":"Pavan Ingle, Naveen Chandrasekar, Sumit Kumar, Cherukuri Venkata Apparao, Bichismita Sahu, Ravi P. Shah","doi":"10.1021/acs.oprd.4c00393","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00393","url":null,"abstract":"Peptides are essential in pharmaceuticals and function as therapeutic agents for a wide range of conditions. The chemical synthesis process of peptides often leaves impurities, such as inorganic salts and residual reagents, which can interfere with the analysis and contaminate the mass spectrometer’s source in in-process quality control (IPQC). Moreover, process monitoring using short liquid chromatography-high-resolution mass spectrometry (LC-HRMS) runtimes presents challenges due to the presence of multiple organic impurities. To address this, four distinct LC-HRMS templates were developed to accommodate a diverse range of peptides. A principal component analysis (PCA)-based methodology was then developed and validated to select the appropriate LC-HRMS method based on the peptides’ physicochemical properties, including sequence length, hydrophobicity, isoelectric point, molecular weight, and clog <i>P</i>. The PCA methodology efficiently classified peptides into distinct quadrants, guiding the selection of the appropriate short LC-HRMS method without the need for trial-and-error LC-HRMS method development. With a success rate exceeding 90%, the methodology accurately predicted the appropriate LC-HRMS method for the peptides. This systematic approach streamlines method selection and ensures the precise elution of peptides. Furthermore, by directing the initial LC flow to waste, the short methods minimize the risk of mass source contamination from inorganic impurities. This developed methodology is suitable for peptides with sequence lengths ranging from tetrapeptides to octapeptides, providing a robust tool for peptide analysis in IPQC workflows.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"97 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857759","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}

{"title":"Thank You","authors":"Kai Rossen","doi":"10.1021/acs.oprd.4c00475","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00475","url":null,"abstract":"My term as Editor-in-Chief for &lt;i&gt;Organic Process Research &amp; Development&lt;/i&gt; comes to an end in December 2024. I had the great honor to take over this role from Trevor Laird 10 years ago. Trevor had started the journal almost 20 years before and brought it into the family of American Chemical Society journals. The process chemistry community should be grateful to Trevor for having realized the need for a scientific journal covering topics relevant to industrial chemists, often from the pharmaceutical and agrochemical industry. It is fair to say that the journal is doing well. The number and quality of submissions is excellent and overall very interesting to our readership. This is reflected in the number of downloads─we can expect to come close to 2.7 million downloads in 2024, which makes &lt;i&gt;OPR&amp;D&lt;/i&gt; one of the most read ACS journals. The process chemistry community can be proud of this fact, as it reflects what we already know: we are doing interesting science at the highest level, and we do this for the ultimate benefit of patients, in the case of pharmaceuticals, or to assure the food supply, in the case of agrochemicals. It is good that our work is also read more widely than just in industry and that academic groups are contributing actively and creatively to our field. I want to thank all the authors who have submitted and published papers with us, something that requires a very high engagement for industrial chemists on top of their “day job” of driving research projects, not forgetting the challenges to obtain the permission to publish. I have tried to be as accommodating as possible to the constraints of industrial scientists, and I hope that we have been able to make the publishing process as smooth as possible. The scientific publishing process hinges on reviewers. The review process is an anonymous activity that is performed without any public recognition but requires commitment and effort. I want to use this opportunity to thank the countless reviewers who have kept the process of the journal going over the last 10 years. Running a journal also requires significant back-office work. &lt;i&gt;OPR&amp;D&lt;/i&gt; has been more than fortunate to have been supported all these years by Jelena Vukadinovic. It would have been impossible for me to fulfill the EIC role without Jelena keeping me on track. The journal has had multiple managing editors at the ACS, and my great thanks go to all of them. I want to mention especially Steve Ritter, who retired in May of this year and who made a big difference for the journal by establishing a good working relationship with sister ACS journals. I was fortunate that I could convince Prof. Qilong Shen from the Shanghai Institute of Organic Chemistry to join us as an associate editor (AE) almost 10 years ago. Prof. Shen’s tenure as an AE is also coming to an end in 2024, and I am very grateful for the opportunity to have worked with a such great scientist and person. The other AEs are active scientists fro","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"82 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857760","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}

{"title":"Three-Step Continuous Flow Synthesis of the Intermediate 4-Fluoro-2-methoxy-5-nitrophenol of Linzagolix","authors":"Tengfei Gong, Fei Ji, Yichen Shi, Yiyang Dong, Yu Xia, Fawen Wu, Xiaoming Zha","doi":"10.1021/acs.oprd.4c00405","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00405","url":null,"abstract":"4-Fluoro-2-methoxy-5-nitrophenol is a key intermediate of the GnRH receptor antagonist Linzagolix. The traditional synthetic methods have several disadvantages including prolonged reaction time and safety issues. Herein, we describe a three-step continuous flow synthesis of 4-fluoro-2-methoxy-5-nitrophenol via esterification, nitration, and hydrolysis. The total residence time was 234 s, and the total yield was 85.6%, which substantially reduced the reaction time and considerably improved the process safety as well as the total yield.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"86 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841804","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}