Ruchi Chauhan, Abhilash Rana, Amirreza Mottafegh, Dong Pyo Kim and Ajay K. Singh*,
{"title":"Manual to Auto-Optimization Platform of Multistep Apixaban Synthesis","authors":"Ruchi Chauhan, Abhilash Rana, Amirreza Mottafegh, Dong Pyo Kim and Ajay K. Singh*, ","doi":"10.1021/acs.oprd.4c0053510.1021/acs.oprd.4c00535","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00535https://doi.org/10.1021/acs.oprd.4c00535","url":null,"abstract":"<p >A novel approach has been utilized in a continuous flow auto-optimizer for multistep apixaban (APX) synthesis, cutting residence time to 17.2 min and boosting overall yield by 78%. This AI-driven tool bypasses traditional trial-and-error methods, streamlining reactivity space navigation and enhancing productivity. It is designed to reduce APX production costs, improve space-time yield, and facilitate the transition from batch to continuous manufacturing, addressing critical gaps in the industry and advancing the field of digital smart workflows.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 3","pages":"881–888 881–888"},"PeriodicalIF":3.1,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666922","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}
James Clarke, Duncan Farr, Jimmy Wang, Heather Ingram, Caroline Chapman, Harriet Field, Christopher P. Breen, Eva M. Gulotty, Sara Mason, Grace Russell, Oliver Williams, Shruti Kumta, Jerry Britto, Li-Jen Ping
{"title":"Thermally Hazardous 1,3-Dioxolane Coupling Reaction Required for a Pharmaceutical Candidate Starting Material, Made Safer by Employing Process Safety Data as Key Design of Experiments Output Variables","authors":"James Clarke, Duncan Farr, Jimmy Wang, Heather Ingram, Caroline Chapman, Harriet Field, Christopher P. Breen, Eva M. Gulotty, Sara Mason, Grace Russell, Oliver Williams, Shruti Kumta, Jerry Britto, Li-Jen Ping","doi":"10.1021/acs.oprd.4c00519","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00519","url":null,"abstract":"The optimization of a ruthenium-catalyzed catechol, terminal-alkyne coupling reaction to form a key benzodioxolane intermediate toward Lotiglipron is described. This transformation required the use of 3-butyn-2-ol, a valuable yet thermally hazardous reagent. Manual reaction condition optimization delivered a good yield but a poor process safety profile. Further reaction understanding was gained by performing a design of experiments (DoE) screening of relevant reaction conditions while using differential scanning calorimetry output data as well as productivity optimization parameters to strike a balance of process safety and chemical yield. To the best of our knowledge, this work represents the first report of using process safety data as DoE output to guide safe reaction condition selection. Finally, the optimal conditions were demonstrated in a lab-scale flow reactor with good translation of results from the batch reaction.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"16 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599064","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}
James Clarke*, Duncan Farr, Jimmy Wang, Heather Ingram, Caroline Chapman, Harriet Field, Christopher P. Breen, Eva M. Gulotty, Sara Mason, Grace Russell, Oliver Williams, Shruti Kumta, Jerry Britto and Li-Jen Ping,
{"title":"Thermally Hazardous 1,3-Dioxolane Coupling Reaction Required for a Pharmaceutical Candidate Starting Material, Made Safer by Employing Process Safety Data as Key Design of Experiments Output Variables","authors":"James Clarke*, Duncan Farr, Jimmy Wang, Heather Ingram, Caroline Chapman, Harriet Field, Christopher P. Breen, Eva M. Gulotty, Sara Mason, Grace Russell, Oliver Williams, Shruti Kumta, Jerry Britto and Li-Jen Ping, ","doi":"10.1021/acs.oprd.4c0051910.1021/acs.oprd.4c00519","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00519https://doi.org/10.1021/acs.oprd.4c00519","url":null,"abstract":"<p >The optimization of a ruthenium-catalyzed catechol, terminal-alkyne coupling reaction to form a key benzodioxolane intermediate toward Lotiglipron is described. This transformation required the use of 3-butyn-2-ol, a valuable yet thermally hazardous reagent. Manual reaction condition optimization delivered a good yield but a poor process safety profile. Further reaction understanding was gained by performing a design of experiments (DoE) screening of relevant reaction conditions while using differential scanning calorimetry output data as well as productivity optimization parameters to strike a balance of process safety and chemical yield. To the best of our knowledge, this work represents the first report of using process safety data as DoE output to guide safe reaction condition selection. Finally, the optimal conditions were demonstrated in a lab-scale flow reactor with good translation of results from the batch reaction.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 3","pages":"836–845 836–845"},"PeriodicalIF":3.1,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666895","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}
Ruchi Chauhan, Abhilash Rana, Amirreza Mottafegh, Dong Pyo Kim, Ajay K. Singh
{"title":"Manual to Auto-Optimization Platform of Multistep Apixaban Synthesis","authors":"Ruchi Chauhan, Abhilash Rana, Amirreza Mottafegh, Dong Pyo Kim, Ajay K. Singh","doi":"10.1021/acs.oprd.4c00535","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00535","url":null,"abstract":"A novel approach has been utilized in a continuous flow auto-optimizer for multistep apixaban (APX) synthesis, cutting residence time to 17.2 min and boosting overall yield by 78%. This AI-driven tool bypasses traditional trial-and-error methods, streamlining reactivity space navigation and enhancing productivity. It is designed to reduce APX production costs, improve space-time yield, and facilitate the transition from batch to continuous manufacturing, addressing critical gaps in the industry and advancing the field of digital smart workflows.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"56 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143598769","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}
Keith S. Barbato*, Qinglin Su, Youhua Li, Anjana Ramnath, Wei Wu, Chuntian Hu, Stephen C. Born, Paul Hermant, Paul Stonestreet, Michael Berg, Bayan Takizawa and Salvatore Mascia*,
{"title":"Process Development toward the Continuous Manufacturing of Baloxavir Marboxil","authors":"Keith S. Barbato*, Qinglin Su, Youhua Li, Anjana Ramnath, Wei Wu, Chuntian Hu, Stephen C. Born, Paul Hermant, Paul Stonestreet, Michael Berg, Bayan Takizawa and Salvatore Mascia*, ","doi":"10.1021/acs.oprd.4c0051710.1021/acs.oprd.4c00517","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00517https://doi.org/10.1021/acs.oprd.4c00517","url":null,"abstract":"<p >We report the initial studies toward the continuous processing of Baloxavir Marboxil, the active pharmaceutical ingredient (API) of Roche’s commercial product Xofluza. The motivation behind this effort is to transition to integrated continuous manufacturing (ICM) as a platform to create an agile and on-demand supply chain capability for a drug that has highly variable market demand. The work described herein includes an improved late-stage synthetic route to Baloxavir Marboxil that (1) reduced a four-step synthesis down to two steps, (2) identified key diastereomeric crystallization conditions to reach required material specifications, and (3) removed the use of <i>N,N</i>-dimethylacetamide in exchange for a more environmentally benign solvent mixture of acetonitrile and water. After a full revision of the two-step synthetic route in batch mode, key unit operations were translated to continuous mode to evaluate their performance. Collectively, this work eliminated 16 unit operations, significantly simplified the process, and is projected to reduce the lead time from 12 months to several days using ICM.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 3","pages":"794–803 794–803"},"PeriodicalIF":3.1,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666896","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":"Improved Synthesis for the 4-Pyridone Intermediate of Baloxavir Marboxil: Elimination of Polar Aprotic Solvents and Optimization Through Design of Experiments (DoE)","authors":"Jianwu Lu, Yinfei Shi, Kongcheng Huang, Yuebin Liu, Shun Yuan, Xiaolong Yang, Yansheng Xu, Xun Sun, Taizhi Wu","doi":"10.1021/acs.oprd.4c00473","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00473","url":null,"abstract":"This article presents the development of an improved synthetic process for a crucial intermediate in the production of the antiviral drug baloxavir marboxil. The focus is on optimizing the telescoped synthesis of methyl 3-(benzyloxy)-1-((<i>tert</i>-butoxycarbonyl)-amino)-4-oxo-1,4-dihydropyridine-2-carboxylate (compound <b>7</b>) built on the original method, which used polar aprotic solvents to improve selectivity in the acid-catalyzed dehydration-condensation reaction between intermediate ester <b>6</b> and <i>tert</i>-butyl carbazate. This process encountered difficulties related to high-boiling solvent recovery and the generation of nitrogen-rich wastewater. To overcome these challenges, we evaluated three optimization strategies. Notably, the use of a PPTS-organic base buffering system (Strategy III) enabled the replacement of the polar aprotic solvent DMAc with readily recoverable THF under the acidity adjustment and Lewis base catalysis effect of triethylamine (TEA). Design of experiments (DoE) further optimized the reaction parameters, significantly reducing the level of impurities, including the identification of three previously unreported process impurities. The optimized process was successfully scaled up to 135 g in the laboratory, yielding the monohydrate form of compound <b>7</b> with a purity of 98.3% and an overall yield improved from 78.6% to 85.1%.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"52 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575126","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":"Improved Synthesis for the 4-Pyridone Intermediate of Baloxavir Marboxil: Elimination of Polar Aprotic Solvents and Optimization Through Design of Experiments (DoE)","authors":"Jianwu Lu, Yinfei Shi, Kongcheng Huang, Yuebin Liu, Shun Yuan, Xiaolong Yang, Yansheng Xu, Xun Sun* and Taizhi Wu*, ","doi":"10.1021/acs.oprd.4c0047310.1021/acs.oprd.4c00473","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00473https://doi.org/10.1021/acs.oprd.4c00473","url":null,"abstract":"<p >This article presents the development of an improved synthetic process for a crucial intermediate in the production of the antiviral drug baloxavir marboxil. The focus is on optimizing the telescoped synthesis of methyl 3-(benzyloxy)-1-((<i>tert</i>-butoxycarbonyl)-amino)-4-oxo-1,4-dihydropyridine-2-carboxylate (compound <b>7</b>) built on the original method, which used polar aprotic solvents to improve selectivity in the acid-catalyzed dehydration-condensation reaction between intermediate ester <b>6</b> and <i>tert</i>-butyl carbazate. This process encountered difficulties related to high-boiling solvent recovery and the generation of nitrogen-rich wastewater. To overcome these challenges, we evaluated three optimization strategies. Notably, the use of a PPTS-organic base buffering system (Strategy III) enabled the replacement of the polar aprotic solvent DMAc with readily recoverable THF under the acidity adjustment and Lewis base catalysis effect of triethylamine (TEA). Design of experiments (DoE) further optimized the reaction parameters, significantly reducing the level of impurities, including the identification of three previously unreported process impurities. The optimized process was successfully scaled up to 135 g in the laboratory, yielding the monohydrate form of compound <b>7</b> with a purity of 98.3% and an overall yield improved from 78.6% to 85.1%.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 3","pages":"723–734 723–734"},"PeriodicalIF":3.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666994","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}
Thomas J. Beauchamp*, Kevin P. Cole*, Howard B. Broughton, David A. Coates, Graham Robert Cumming, Jose Eugenio de Diego, Kwame Frimpong, Julio Gutierrez, William Holloway, Ian Hotham, Spencer Jones, Talbi Kaoudi, Peter Lander, Adam M. Levinson, Yu Lu, Charles Lugar, Katherine Partridge, J. Craig Ruble, Sofiane Saouane, Narasimha Rao Ummaneni, H. George Vandeveer and Brian Watson,
{"title":"Preclinical Toxicology Supply for a Complex API Enabled by Asymmetric Catalysis and Rapid Chemical Development: IL-17A Inhibitor LY3509754","authors":"Thomas J. Beauchamp*, Kevin P. Cole*, Howard B. Broughton, David A. Coates, Graham Robert Cumming, Jose Eugenio de Diego, Kwame Frimpong, Julio Gutierrez, William Holloway, Ian Hotham, Spencer Jones, Talbi Kaoudi, Peter Lander, Adam M. Levinson, Yu Lu, Charles Lugar, Katherine Partridge, J. Craig Ruble, Sofiane Saouane, Narasimha Rao Ummaneni, H. George Vandeveer and Brian Watson, ","doi":"10.1021/acs.oprd.4c0053910.1021/acs.oprd.4c00539","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00539https://doi.org/10.1021/acs.oprd.4c00539","url":null,"abstract":"<p >The chemical development and production of sufficient amounts of IL-17A inhibitor LY3509754 to enable preclinical toxicology studies is described. LY3509754 is a complex small molecule that features three stereocenters, which comprised much of the synthetic challenge. Stereoselective hydrogenation and biocatalysis enabled access to all stereocenters. The most significant challenge was installation of the chiral methoxymethyl side chain, specifically, formation of the sp2–sp3 C–C bond from reasonable raw materials and establishment of the benzylic amine stereocenter. Given prior experience with structural analogs, we were able to use a hybrid approach to the synthesis, with key building blocks being available on large-scale from the previous efforts. Historical knowledge combined with rapid route scouting and development allowed us to invent a scalable route to LY3509754 in about seven months and deliver 430 g to accelerate the preclinical toxicology studies.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 3","pages":"889–908 889–908"},"PeriodicalIF":3.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143667146","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}
Viktor Klöpfer, Leonie Roithmeier, Manuel Kobras, Peter Kreitmeier and Oliver Reiser*,
{"title":"Catalyst-Free, Scalable, Green-Light-Mediated Iodoamination, and Further Transformation of Olefins Under Continuous Flow Conditions","authors":"Viktor Klöpfer, Leonie Roithmeier, Manuel Kobras, Peter Kreitmeier and Oliver Reiser*, ","doi":"10.1021/acs.oprd.4c0048910.1021/acs.oprd.4c00489","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00489https://doi.org/10.1021/acs.oprd.4c00489","url":null,"abstract":"<p >We report the iodoamination of alkenes in continuous flow under metal-free, visible-light-mediated conditions with commercially available <i>N</i>-iodosuccinimide and protected amines. Unactivated and activated alkenes as well as Michael acceptors are amenable substrate classes for this process, allowing the synthesis of 1,2-iodoamines with a broad scope and in high yields (59–94%). The steadiness of the protocol is demonstrated in a continuous flow experiment over 4.5 h for the coupling of styrene, NIS, and <i>N</i>-tosyl-amine, which gave rise to 14 g (91%) of the iodoaminated product, corresponding to a productivity of 3.1 g h<sup>–1</sup>. Additionally, the direct conversion of the products without prior isolation into aziridines, enamines, amino alcohols, or azidoamines is possible, underscoring the synthetic value of this approach. Variation of the reaction conditions by adding typical impurities in reagents or solvents or changing the irradiation from green to blue light had a minimal effect on the yield, giving credit to the robustness of the process.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 3","pages":"755–759 755–759"},"PeriodicalIF":3.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.oprd.4c00489","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thomas J. Beauchamp, Kevin P. Cole, Howard B. Broughton, David A. Coates, Graham Robert Cumming, Jose Eugenio de Diego, Kwame Frimpong, Julio Gutierrez, William Holloway, Ian Hotham, Spencer Jones, Talbi Kaoudi, Peter Lander, Adam M. Levinson, Yu Lu, Charles Lugar, Katherine Partridge, J. Craig Ruble, Sofiane Saouane, Narasimha Rao Ummaneni, H. George Vandeveer, Brian Watson
{"title":"Preclinical Toxicology Supply for a Complex API Enabled by Asymmetric Catalysis and Rapid Chemical Development: IL-17A Inhibitor LY3509754","authors":"Thomas J. Beauchamp, Kevin P. Cole, Howard B. Broughton, David A. Coates, Graham Robert Cumming, Jose Eugenio de Diego, Kwame Frimpong, Julio Gutierrez, William Holloway, Ian Hotham, Spencer Jones, Talbi Kaoudi, Peter Lander, Adam M. Levinson, Yu Lu, Charles Lugar, Katherine Partridge, J. Craig Ruble, Sofiane Saouane, Narasimha Rao Ummaneni, H. George Vandeveer, Brian Watson","doi":"10.1021/acs.oprd.4c00539","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00539","url":null,"abstract":"The chemical development and production of sufficient amounts of IL-17A inhibitor LY3509754 to enable preclinical toxicology studies is described. LY3509754 is a complex small molecule that features three stereocenters, which comprised much of the synthetic challenge. Stereoselective hydrogenation and biocatalysis enabled access to all stereocenters. The most significant challenge was installation of the chiral methoxymethyl side chain, specifically, formation of the sp2–sp3 C–C bond from reasonable raw materials and establishment of the benzylic amine stereocenter. Given prior experience with structural analogs, we were able to use a hybrid approach to the synthesis, with key building blocks being available on large-scale from the previous efforts. Historical knowledge combined with rapid route scouting and development allowed us to invent a scalable route to LY3509754 in about seven months and deliver 430 g to accelerate the preclinical toxicology studies.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"16 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143561263","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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