Pub Date : 2024-06-07DOI: 10.1021/acs.oprd.4c00135
Matthew R. Tatton*, Gordon S. Currie*, Bradley Adams, Carl-Johan Aurell, Karl Broberg, Andrew D. Campbell, Kuangchu Dai, Marcus Malmgren, Andrew Ikin, Sophie L. M. Janbon, Martin Sims, Joanna Hemming-Taylor and Victoria Winterbottom,
Camizestrant is currently being investigated in multiple Phase 3 clinical trials for ER+ breast cancer. This article describes our efforts toward the first manufacture of clinical material. Strategic process development focused on delivering robust processes and control points that could be scaled to deliver kilograms of material of the right quality and meet expedited project timelines. Highlights include optimization of an efficient Buchwald–Hartwig amination, development of a diastereoselective Pictet–Spengler reaction followed by an efficient isolation, and a significant reduction in the number of chromatography stages from five to one. The processes were used to deliver 8.5 kg of material in an overall yield of 44%.
{"title":"First Multikilogram Synthesis of the Next-Generation Oral Selective ERα Degrader Camizestrant","authors":"Matthew R. Tatton*, Gordon S. Currie*, Bradley Adams, Carl-Johan Aurell, Karl Broberg, Andrew D. Campbell, Kuangchu Dai, Marcus Malmgren, Andrew Ikin, Sophie L. M. Janbon, Martin Sims, Joanna Hemming-Taylor and Victoria Winterbottom, ","doi":"10.1021/acs.oprd.4c00135","DOIUrl":"10.1021/acs.oprd.4c00135","url":null,"abstract":"<p >Camizestrant is currently being investigated in multiple Phase 3 clinical trials for ER+ breast cancer. This article describes our efforts toward the first manufacture of clinical material. Strategic process development focused on delivering robust processes and control points that could be scaled to deliver kilograms of material of the right quality and meet expedited project timelines. Highlights include optimization of an efficient Buchwald–Hartwig amination, development of a diastereoselective Pictet–Spengler reaction followed by an efficient isolation, and a significant reduction in the number of chromatography stages from five to one. The processes were used to deliver 8.5 kg of material in an overall yield of 44%.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141287305","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 : 2024-06-07DOI: 10.1021/acs.oprd.4c00067
Yangmu Chloe Liu, Suresh K. Tipparaju, Michael R. Tracey, Robert Carr, Anil Damarancha, Akihiro Hashimoto, Stephen Hubbs, Chad Keyes, John Lucas, Vidya Nandialath, Mark Stevens, Mareena Thottakara
Technology transfer and Current Good Manufacturing Practice (cGMP) manufacture of danicopan are described. During the acquisition of Achillion Pharmaceuticals (Achillion) by Alexion Pharmaceuticals (Alexion), a staged approach for technology transfer to Cambrex Charles City (CCC) was developed. The difference in Alexion’s and CCC’s approaches to process-validation-enabling studies as well as strategies to bridge the gap and meet both organizations’ expectations within a compressed timeline are discussed. The differences are best illustrated with an example step that was successfully validated concurrently at 45 and 210 kg scales in different work centers at the CCC facility to support multiple indications and programs for an advanced pharmaceutical intermediate. Key learnings are offered from the perspective of a sponsor organization and a contract manufacturer, highlighting a collaborative approach and partnership that allowed a successful execution with ambitious timelines while navigating the challenges of a global pandemic.
{"title":"Technology Transfer and Process Development of Danicopan to Enable Process Validation","authors":"Yangmu Chloe Liu, Suresh K. Tipparaju, Michael R. Tracey, Robert Carr, Anil Damarancha, Akihiro Hashimoto, Stephen Hubbs, Chad Keyes, John Lucas, Vidya Nandialath, Mark Stevens, Mareena Thottakara","doi":"10.1021/acs.oprd.4c00067","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00067","url":null,"abstract":"Technology transfer and Current Good Manufacturing Practice (cGMP) manufacture of danicopan are described. During the acquisition of Achillion Pharmaceuticals (Achillion) by Alexion Pharmaceuticals (Alexion), a staged approach for technology transfer to Cambrex Charles City (CCC) was developed. The difference in Alexion’s and CCC’s approaches to process-validation-enabling studies as well as strategies to bridge the gap and meet both organizations’ expectations within a compressed timeline are discussed. The differences are best illustrated with an example step that was successfully validated concurrently at 45 and 210 kg scales in different work centers at the CCC facility to support multiple indications and programs for an advanced pharmaceutical intermediate. Key learnings are offered from the perspective of a sponsor organization and a contract manufacturer, highlighting a collaborative approach and partnership that allowed a successful execution with ambitious timelines while navigating the challenges of a global pandemic.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141287361","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 : 2024-06-06DOI: 10.1021/acs.oprd.4c00164
A. Filipa Almeida, Sofia Branco, Luisa C. R. Carvalho, Andre Raposo Moreira Dias, Emília P. T. Leitão, Rui M. S. Loureiro, Susana D. Lucas, Ricardo F. Mendonça, Rudi Oliveira, Inês L. D. Rocha, Joao Sardinha, Saúl Silva, Luís M. S. Sobral, Nuno M. T. Lourenço, Pedro C. Valente
This study benchmarks diverse strategies in sustainable process chemistry development, ranging from human subject matter expertise to advanced computational models, including machine learning, Bayesian optimization, and quantum mechanics simulations. Through a “virtual laboratory” case study simulating a Pd-catalyzed C–H arylation reaction, the efficiency, sustainability, and practical application of these methodologies were compared. The study highlights the nuanced interplay between traditional expertise and computational tools, offering insights into their complementary roles in accelerating development and achieving green-by-design principles in pharmaceutical synthesis. Our findings suggest that no single approach universally outperforms others; instead, a hybrid strategy leveraging both human intuition and computational power appears to be the most promising approach when combining powerful tools in the complex field of modern organic synthesis.
{"title":"Benchmarking Strategies of Sustainable Process Chemistry Development: Human-Based, Machine Learning, and Quantum Mechanics","authors":"A. Filipa Almeida, Sofia Branco, Luisa C. R. Carvalho, Andre Raposo Moreira Dias, Emília P. T. Leitão, Rui M. S. Loureiro, Susana D. Lucas, Ricardo F. Mendonça, Rudi Oliveira, Inês L. D. Rocha, Joao Sardinha, Saúl Silva, Luís M. S. Sobral, Nuno M. T. Lourenço, Pedro C. Valente","doi":"10.1021/acs.oprd.4c00164","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00164","url":null,"abstract":"This study benchmarks diverse strategies in sustainable process chemistry development, ranging from human subject matter expertise to advanced computational models, including machine learning, Bayesian optimization, and quantum mechanics simulations. Through a “virtual laboratory” case study simulating a Pd-catalyzed C–H arylation reaction, the efficiency, sustainability, and practical application of these methodologies were compared. The study highlights the nuanced interplay between traditional expertise and computational tools, offering insights into their complementary roles in accelerating development and achieving green-by-design principles in pharmaceutical synthesis. Our findings suggest that no single approach universally outperforms others; instead, a hybrid strategy leveraging both human intuition and computational power appears to be the most promising approach when combining powerful tools in the complex field of modern organic synthesis.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141287345","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 : 2024-06-06DOI: 10.1021/acs.oprd.4c00015
Nicholas R. Deprez*, Jonathan M. E. Hughes*, Shorouk O. Badir, Stasik Popov, Teresa Andreani, Rachel S. Bade, Clara Hartmanshenn, Thomas Tai-min Kwok, Donald R. Gauthier Jr., Nastaran Salehi Marzijarani, Zeinab Sakhaei, Riki Drout, Steve Castro, David J. Schenk, Charles Wolstenholme, Nilusha Padivitage, Cody Welch, Jason R. Kowalski, Brittany Kassim, Yong Liu, Ryan D. Cohen, Alex M. Confer, Guilherme Dal Poggetto, Andrew P. J. Brunskill, Feng Peng, Ji Qi, Jing Xu, Mingxiang Lin and Jamie M. McCabe Dunn,
We describe the rapid end-game process development for the first good manufacturing process (GMP) delivery of the 3C-like protease inhibitor MK-7845 (1), an experimental treatment for SARS-CoV-2. Three operations, including an amide-coupling, oxidation, and crystallization, were rapidly developed and implemented on a kilogram scale to enable critical safety studies and phase 1 clinical trials to move forward on a highly accelerated timeline. Key to the success of this undertaking was our focus on purging key impurities formed in the amide-coupling step, identifying a safe and scalable TEMPO/NaOCl oxidation to access 1, and developing an active pharmacutical ingredient (API) crystallization that addressed challenges associated with gumming, oiling, and agglomeration. Notably, this delivery was completed within an approximately six-week time frame, and challenges associated with this highly accelerated delivery are also discussed.
{"title":"Rapid End-Game Process Development and First GMP Production of MK-7845: An Experimental Antiviral Treatment for COVID-19","authors":"Nicholas R. Deprez*, Jonathan M. E. Hughes*, Shorouk O. Badir, Stasik Popov, Teresa Andreani, Rachel S. Bade, Clara Hartmanshenn, Thomas Tai-min Kwok, Donald R. Gauthier Jr., Nastaran Salehi Marzijarani, Zeinab Sakhaei, Riki Drout, Steve Castro, David J. Schenk, Charles Wolstenholme, Nilusha Padivitage, Cody Welch, Jason R. Kowalski, Brittany Kassim, Yong Liu, Ryan D. Cohen, Alex M. Confer, Guilherme Dal Poggetto, Andrew P. J. Brunskill, Feng Peng, Ji Qi, Jing Xu, Mingxiang Lin and Jamie M. McCabe Dunn, ","doi":"10.1021/acs.oprd.4c00015","DOIUrl":"10.1021/acs.oprd.4c00015","url":null,"abstract":"<p >We describe the rapid end-game process development for the first good manufacturing process (GMP) delivery of the 3C-like protease inhibitor MK-7845 (<b>1</b>), an experimental treatment for SARS-CoV-2. Three operations, including an amide-coupling, oxidation, and crystallization, were rapidly developed and implemented on a kilogram scale to enable critical safety studies and phase 1 clinical trials to move forward on a highly accelerated timeline. Key to the success of this undertaking was our focus on purging key impurities formed in the amide-coupling step, identifying a safe and scalable TEMPO/NaOCl oxidation to access <b>1</b>, and developing an active pharmacutical ingredient (API) crystallization that addressed challenges associated with gumming, oiling, and agglomeration. Notably, this delivery was completed within an approximately six-week time frame, and challenges associated with this highly accelerated delivery are also discussed.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141265052","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 : 2024-06-06DOI: 10.1021/acs.oprd.4c00171
Matthew L. Maddess*, Ed Cleator*, Mariko Morimoto, Adrian Goodyear, Alejandro Dieguez-Vazquez, Andrew Gibb, Andy Kirtley, Melodie Christensen, Chaohui Song, Feng Peng, Mahbub Alam, Stephen P. Keen and Steven F. Oliver,
Process development to improve synthetic access to a potent, selective, and brain-penetrant tricyclic diazepine clinical candidate that inhibits mutant IDH1 is described. A variety of disconnections were evaluated to determine the preferred sequence of fragment coupling. The optimized route involves a metal-catalyzed C–N coupling/reductive cascade to form the central diazepine core, improved entries to both the zigzag morpholine and cyclohexyl acid peripheral pieces, and an efficient end-game sequence of acylation, C–N coupling, and deprotection. In addition, a dynamic acylation process that enables selective acylation at N6 of an unprotected diazepine core is described.
{"title":"Process Development of a Tricyclic Diazepine-Based IDH1 Mutant Inhibitor","authors":"Matthew L. Maddess*, Ed Cleator*, Mariko Morimoto, Adrian Goodyear, Alejandro Dieguez-Vazquez, Andrew Gibb, Andy Kirtley, Melodie Christensen, Chaohui Song, Feng Peng, Mahbub Alam, Stephen P. Keen and Steven F. Oliver, ","doi":"10.1021/acs.oprd.4c00171","DOIUrl":"10.1021/acs.oprd.4c00171","url":null,"abstract":"<p >Process development to improve synthetic access to a potent, selective, and brain-penetrant tricyclic diazepine clinical candidate that inhibits mutant IDH1 is described. A variety of disconnections were evaluated to determine the preferred sequence of fragment coupling. The optimized route involves a metal-catalyzed C–N coupling/reductive cascade to form the central diazepine core, improved entries to both the zigzag morpholine and cyclohexyl acid peripheral pieces, and an efficient end-game sequence of acylation, C–N coupling, and deprotection. In addition, a dynamic acylation process that enables selective acylation at N6 of an unprotected diazepine core is described.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141265091","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 : 2024-05-31DOI: 10.1021/acs.oprd.4c00047
Thomas M. Bass, Daniel Zell, Sean M. Kelly, Thomas C. Malig, José G. Napolitano, Lauren E. Sirois, Chong Han, Francis Gosselin
Herein, we describe the development of two continuous manufacturing processes for the synthesis of 6-chloro-1H-pyrazolo[3,4-b]pyrazine, which is a key intermediate en route to the SHP2 inhibitor GDC-1971 (migoprotafib). The reaction sequence starts with a plug-flow metalation/formylation of readily available 2,6-dichloropyrazine using i-Pr2NMgCl·LiCl (MgDA) as the base, whereupon the resulting unstable heteroaryl aldehyde intermediate is isolated as its easier-to-handle and bench-stable bisulfite adduct. The ensuing cyclization step to the pyrazolopyrazine product necessitates the use of excess amounts of hydrazine reagent, and involves the accumulation of highly energetic, nitrogen-rich intermediates. A continuous stirred-tank reactor (CSTR) process was engineered to address the associated safety concerns while accommodating for the heterogeneity of the reaction mixture. These two safe and robust continuous processes have been demonstrated on multikilogram scale, and serve as enabling contributions toward large-scale manufacturing of GDC-1971.
{"title":"Scalable Synthesis of 6-Chloro-1H-pyrazolo[3,4-b]pyrazine via a Continuous Flow Formylation/Hydrazine Cyclization Cascade","authors":"Thomas M. Bass, Daniel Zell, Sean M. Kelly, Thomas C. Malig, José G. Napolitano, Lauren E. Sirois, Chong Han, Francis Gosselin","doi":"10.1021/acs.oprd.4c00047","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00047","url":null,"abstract":"Herein, we describe the development of two continuous manufacturing processes for the synthesis of 6-chloro-1<i>H</i>-pyrazolo[3,4-<i>b</i>]pyrazine, which is a key intermediate en route to the SHP2 inhibitor <b>GDC-1971</b> (<i>migoprotafib</i>). The reaction sequence starts with a plug-flow metalation/formylation of readily available 2,6-dichloropyrazine using <i>i</i>-Pr<sub>2</sub>NMgCl·LiCl (MgDA) as the base, whereupon the resulting unstable heteroaryl aldehyde intermediate is isolated as its easier-to-handle and bench-stable bisulfite adduct. The ensuing cyclization step to the pyrazolopyrazine product necessitates the use of excess amounts of hydrazine reagent, and involves the accumulation of highly energetic, nitrogen-rich intermediates. A continuous stirred-tank reactor (CSTR) process was engineered to address the associated safety concerns while accommodating for the heterogeneity of the reaction mixture. These two safe and robust continuous processes have been demonstrated on multikilogram scale, and serve as enabling contributions toward large-scale manufacturing of <b>GDC-1971</b>.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141182628","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 : 2024-05-30DOI: 10.1021/acs.oprd.4c00108
Daniel W. Widlicka, Robert A. Singer, Ian Hotham, David J. Bernhardson, Samantha Grosslight
Hydroxylation of haloarenes is a fundamental transformation in synthetic organic chemistry. Hydroxypicolinamide ligands enable the efficient Cu-catalyzed hydroxylation of heteroaryl halides with a wide functional group tolerance. The Cu-MPBS system, originally designed for C–N coupling, enables the Cu-catalyzed hydroxylation of aryl bromides. A related derivative, Cu-HMPS, provides exceptional reactivity and purity for hydroxylation of aryl bromides, aryl iodides, and activated aryl chlorides. Ortho-activated substrates have shown exceptionally high reactivity and selectivity for Cu-catalyzed hydroxylation. More difficult aryl chlorides, substrates that require a higher activation temperature (120 °C), may be hydroxylated by the Cu-DMPS system that has superior intrinsic ligand stability. Reaction conditions may be tuned to target substrates through ligand, solvent, and base selection. Safe and robust processing conditions have been designed utilizing aqueous KOH, K2CO3, or K3PO4 in sulfolane or sulfolane and alcohol blends.
{"title":"Copper-Catalyzed Hydroxylation of Aryl Halides Using Hydroxypicolinamide Ligands","authors":"Daniel W. Widlicka, Robert A. Singer, Ian Hotham, David J. Bernhardson, Samantha Grosslight","doi":"10.1021/acs.oprd.4c00108","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00108","url":null,"abstract":"Hydroxylation of haloarenes is a fundamental transformation in synthetic organic chemistry. Hydroxypicolinamide ligands enable the efficient Cu-catalyzed hydroxylation of heteroaryl halides with a wide functional group tolerance. The Cu-MPBS system, originally designed for C–N coupling, enables the Cu-catalyzed hydroxylation of aryl bromides. A related derivative, Cu-HMPS, provides exceptional reactivity and purity for hydroxylation of aryl bromides, aryl iodides, and activated aryl chlorides. <i>Ortho-</i>activated substrates have shown exceptionally high reactivity and selectivity for Cu-catalyzed hydroxylation. More difficult aryl chlorides, substrates that require a higher activation temperature (120 °C), may be hydroxylated by the Cu-DMPS system that has superior intrinsic ligand stability. Reaction conditions may be tuned to target substrates through ligand, solvent, and base selection. Safe and robust processing conditions have been designed utilizing aqueous KOH, K<sub>2</sub>CO<sub>3</sub>, or K<sub>3</sub>PO<sub>4</sub> in sulfolane or sulfolane and alcohol blends.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141177892","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 : 2024-05-30DOI: 10.1021/acs.oprd.4c00102
Thomas. W. Lyons*, David A. Thaisrivongs*, Nadine Kuhl, Cheol K. Chung, Angie Angeles, Dietrich Steinhuebel, Erik Guetschow, Andrew P. J. Brunskill, Timothy J. Henderson, Brandon D. Cash and Andrew Haidle,
The first GMP synthesis of MK-2118, a small molecule agonist of the stimulator of interferon genes (STING) is described. The small molecule represents a dramatic change in the chemical matter from the more complex cyclic dinucleotides previously disclosed. In this article, we detail the route-scouting, decision-making, and development details of a first GMP campaign typical for a first delivery on an accelerated timeline. The route chosen involves a key copper-mediated Negishi coupling using a chiral organozinc reagent and subsequent direct isolation. Several unexpected challenges are outlined, which highlight the difficulty in developing a first scale-up process.
{"title":"The First GMP Synthesis of MK-2118, a Small Molecule Agonist for Stimulator of Interferon Genes","authors":"Thomas. W. Lyons*, David A. Thaisrivongs*, Nadine Kuhl, Cheol K. Chung, Angie Angeles, Dietrich Steinhuebel, Erik Guetschow, Andrew P. J. Brunskill, Timothy J. Henderson, Brandon D. Cash and Andrew Haidle, ","doi":"10.1021/acs.oprd.4c00102","DOIUrl":"10.1021/acs.oprd.4c00102","url":null,"abstract":"<p >The first GMP synthesis of MK-2118, a small molecule agonist of the stimulator of interferon genes (STING) is described. The small molecule represents a dramatic change in the chemical matter from the more complex cyclic dinucleotides previously disclosed. In this article, we detail the route-scouting, decision-making, and development details of a first GMP campaign typical for a first delivery on an accelerated timeline. The route chosen involves a key copper-mediated Negishi coupling using a chiral organozinc reagent and subsequent direct isolation. Several unexpected challenges are outlined, which highlight the difficulty in developing a first scale-up process.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141177930","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 : 2024-05-30DOI: 10.1021/acs.oprd.4c00159
Shasha Zhang, Simon Shun Wang Leung, Dale Vanyo
Despite the widespread application of diboron reagents in Suzuki–Miyaura borylation reactions, the thermal stability of diboron compounds is poorly understood. Seven commonly used diboron reagents were selected to investigate their thermal stability using Differential Scanning Calorimetry (DSC). Tetrahydroxydiboron (BBA) was specifically chosen for comprehensive safety characterization, considering the high thermal risk identified during the DSC screening. The decomposition of BBA was further explored using DSC in conjunction with Advanced Thermokinetics Software (AKTS), as well as Accelerating Rate Calorimetry (ARC) and Differential Accelerating Rate Calorimetry (DARC). Key safety parameters, such as the temperature at which the time to the maximum rate is 24 h (TMR24 and TD24), were estimated. Consistent results for TMR24 were obtained across various methods, affirming the reliability of these techniques in the kinetic analysis. DARC and ARC testing reveal an exceptionally rapid thermal runaway for BBA to the extent that the self-heating rate cannot be tracked within the instrument’s limits. Furthermore, BBA was found to be insensitive to impact or friction. This study presents the general methodology and specific findings for BBA, with the aim of providing industry guidance for conducting process safety assessment and ensuring the safe utilization of diboron reagents during process development and scale-up.
{"title":"Thermal Stability of Tetrahydroxydiboron","authors":"Shasha Zhang, Simon Shun Wang Leung, Dale Vanyo","doi":"10.1021/acs.oprd.4c00159","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00159","url":null,"abstract":"Despite the widespread application of diboron reagents in Suzuki–Miyaura borylation reactions, the thermal stability of diboron compounds is poorly understood. Seven commonly used diboron reagents were selected to investigate their thermal stability using Differential Scanning Calorimetry (DSC). Tetrahydroxydiboron (BBA) was specifically chosen for comprehensive safety characterization, considering the high thermal risk identified during the DSC screening. The decomposition of BBA was further explored using DSC in conjunction with Advanced Thermokinetics Software (AKTS), as well as Accelerating Rate Calorimetry (ARC) and Differential Accelerating Rate Calorimetry (DARC). Key safety parameters, such as the temperature at which the time to the maximum rate is 24 h (TMR<sub>24</sub> and <i>T</i><sub>D24</sub>), were estimated. Consistent results for TMR<sub>24</sub> were obtained across various methods, affirming the reliability of these techniques in the kinetic analysis. DARC and ARC testing reveal an exceptionally rapid thermal runaway for BBA to the extent that the self-heating rate cannot be tracked within the instrument’s limits. Furthermore, BBA was found to be insensitive to impact or friction. This study presents the general methodology and specific findings for BBA, with the aim of providing industry guidance for conducting process safety assessment and ensuring the safe utilization of diboron reagents during process development and scale-up.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141177889","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 : 2024-05-29DOI: 10.1021/acs.oprd.4c00144
Louise M. Guard, John R. Rizzo
Somatostatin receptor subtype 4 (SSTR4) antagonists are potential clinical targets for pain. We describe the efforts toward a robust large-scale synthesis of certain small-molecule SSTR4 agonist compounds. Previous routes used metal-mediated reactions and produced stereochemical mixtures. The molecule has a 3-azabicyclo[3.1.0]hexane ring system with cis-stereochemistry. A unique tandem cyclization at the multi-kilogram scale was employed to generate the fused ring system with exclusive cis-stereochemistry observed. The potential commercial synthesis is an efficient, economical process with good control points. This novel tandem cyclization was implemented to swiftly scale up a similar compound for early-phase studies.
{"title":"Large-Scale Tandem Cyclization Applied to Potentially High-Volume SSTR4 Agonists","authors":"Louise M. Guard, John R. Rizzo","doi":"10.1021/acs.oprd.4c00144","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00144","url":null,"abstract":"Somatostatin receptor subtype 4 (SSTR4) antagonists are potential clinical targets for pain. We describe the efforts toward a robust large-scale synthesis of certain small-molecule SSTR4 agonist compounds. Previous routes used metal-mediated reactions and produced stereochemical mixtures. The molecule has a 3-azabicyclo[3.1.0]hexane ring system with <i>cis-</i>stereochemistry. A unique tandem cyclization at the multi-kilogram scale was employed to generate the fused ring system with exclusive <i>cis-</i>stereochemistry observed. The potential commercial synthesis is an efficient, economical process with good control points. This novel tandem cyclization was implemented to swiftly scale up a similar compound for early-phase studies.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141177898","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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