Here we report the development of a large-scale manufacturing process for the synthesis of the Northern Fragment of enlicitide decanoate (MK-0616), an orally bioavailable inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9). The key topics covered are (1) process development for the selective tryptophan allylation; (2) development of the one-pot process for two consecutive peptide coupling reactions; (3) process development for the one-pot cleavage of two N-tert-butyloxycarbonyl (N-Boc) groups and a tert-butyl ester; and (4) process development of the magnesium chloride (MgCl2)-mediated selective macrolactamization. This optimized process was demonstrated to produce the key fragment at >150 kg scale per batch in the synthesis of enlicitide.
{"title":"Process Development toward a Key Fragment of the PCSK9 Inhibitor Enlicitide Decanoate","authors":"Kai-Jiong Xiao, Yonggang Chen, Yingju Xu, Gao Shang, Lushi Tan, Fangzhou Xie, Chengqian Xiao, Yongpeng Yuan, Baoqiang Wan, Guiquan Liu, Jingjun Yin","doi":"10.1021/acs.oprd.4c00504","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00504","url":null,"abstract":"Here we report the development of a large-scale manufacturing process for the synthesis of the Northern Fragment of enlicitide decanoate (MK-0616), an orally bioavailable inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9). The key topics covered are (1) process development for the selective tryptophan allylation; (2) development of the one-pot process for two consecutive peptide coupling reactions; (3) process development for the one-pot cleavage of two <i>N</i>-<i>tert</i>-butyloxycarbonyl (<i>N</i>-Boc) groups and a <i>tert</i>-butyl ester; and (4) process development of the magnesium chloride (MgCl<sub>2</sub>)-mediated selective macrolactamization. This optimized process was demonstrated to produce the key fragment at >150 kg scale per batch in the synthesis of enlicitide.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"41 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766881","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 : 2025-04-03DOI: 10.1021/acs.oprd.5c00003
Qiang Yang, Yu Lu, Thomas J. Beauchamp, Kevin P. Cole, Jiang Wang, Srinivas Gangula, Silong Zhang, Zhaoshan Cui, Guopeng Wang, Lei Shi, Dajiang Jing, Fuliang Wei, Xuecheng Jiao, Xiang Li, Na Zhang, Xiangjun Jiang, Yulei Ma
Process development and scale-up of the synthesis of a pyridazinyl imidazolidinone intermediate for the production of an imidazo[1,2-b]pyridazine IL-17A inhibitor are described. A transamination process was developed for the preparation of (S)-3,3,3-trifluoropropane-1,2-diamine, eliminating an unstable enamine intermediate that significantly limited the scalability of the original asymmetric hydrogenation route. A CSTR continuous flow process was developed for the carbonylation of N-(6-chloropyridazin-3-yl)pivalamide under cryogenic conditions that successfully suppressed product decomposition, improving the isolated yield to ∼60% from the ∼40% yield of the batch mode process. A robust KRED process was developed for the reduction of N-(6-chloro-5-(2-methoxyacetyl)pyridazin-3-yl)pivalamide to the corresponding chiral alcohol, which was further derivatized as its triflate for the SN2 reaction with (S)-3,3,3-trifluoropropane-1,2-diamine and treated with carbonyl diimidazole to assemble the target pyridazinyl imidazolidinone intermediate. The developed process was successfully scaled up to deliver 157 kg of the pyridazinyl imidazolidinone intermediate to support the production of the final drug substance, demonstrating the robustness of the optimized process.
{"title":"Development of a Scalable Process for an IL-17A Inhibitor LY3509754: Part I: Synthesis of the Pyridazinyl Imidazolidinone Intermediate Enabled by Biocatalysis and CSTR Technologies","authors":"Qiang Yang, Yu Lu, Thomas J. Beauchamp, Kevin P. Cole, Jiang Wang, Srinivas Gangula, Silong Zhang, Zhaoshan Cui, Guopeng Wang, Lei Shi, Dajiang Jing, Fuliang Wei, Xuecheng Jiao, Xiang Li, Na Zhang, Xiangjun Jiang, Yulei Ma","doi":"10.1021/acs.oprd.5c00003","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00003","url":null,"abstract":"Process development and scale-up of the synthesis of a pyridazinyl imidazolidinone intermediate for the production of an imidazo[1,2-<i>b</i>]pyridazine IL-17A inhibitor are described. A transamination process was developed for the preparation of (<i>S</i>)-3,3,3-trifluoropropane-1,2-diamine, eliminating an unstable enamine intermediate that significantly limited the scalability of the original asymmetric hydrogenation route. A CSTR continuous flow process was developed for the carbonylation of <i>N</i>-(6-chloropyridazin-3-yl)pivalamide under cryogenic conditions that successfully suppressed product decomposition, improving the isolated yield to ∼60% from the ∼40% yield of the batch mode process. A robust KRED process was developed for the reduction of <i>N</i>-(6-chloro-5-(2-methoxyacetyl)pyridazin-3-yl)pivalamide to the corresponding chiral alcohol, which was further derivatized as its triflate for the S<sub>N</sub>2 reaction with (<i>S</i>)-3,3,3-trifluoropropane-1,2-diamine and treated with carbonyl diimidazole to assemble the target pyridazinyl imidazolidinone intermediate. The developed process was successfully scaled up to deliver 157 kg of the pyridazinyl imidazolidinone intermediate to support the production of the final drug substance, demonstrating the robustness of the optimized process.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"35 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143767124","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 : 2025-04-02DOI: 10.1021/acs.oprd.5c00005
Qiang Yang, Ryan J. Linder, Yu Lu, Thomas J. Beauchamp, Timothy A. Woods, David A. Coates, Brandon J. Reizman, Jonas Y. Buser, Michael E. Laurila, Nicholas A. Magnus, Yongjie Yu, Lili Han, Ping Huang
A 5-step cGMP sequence for the preparation of an IL-17A inhibitor 1 was optimized and scaled up to deliver a total of 66 kg of the final drug substance 1 to support clinical and product development studies. Salt formation and polymorph screening identified a suitable polymorph of the hemiedisylate salt that provided desirable physical properties. Key impurities in the final drug substance were identified, and control strategies were developed and executed to control them to acceptable levels in the production batches.
{"title":"Development of a Scalable Process for an IL-17A Inhibitor LY3509754: Part III. Assembly of Drug Substance, Salt Formation, and Impurity Control","authors":"Qiang Yang, Ryan J. Linder, Yu Lu, Thomas J. Beauchamp, Timothy A. Woods, David A. Coates, Brandon J. Reizman, Jonas Y. Buser, Michael E. Laurila, Nicholas A. Magnus, Yongjie Yu, Lili Han, Ping Huang","doi":"10.1021/acs.oprd.5c00005","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00005","url":null,"abstract":"A 5-step cGMP sequence for the preparation of an IL-17A inhibitor <b>1</b> was optimized and scaled up to deliver a total of 66 kg of the final drug substance <b>1</b> to support clinical and product development studies. Salt formation and polymorph screening identified a suitable polymorph of the hemiedisylate salt that provided desirable physical properties. Key impurities in the final drug substance were identified, and control strategies were developed and executed to control them to acceptable levels in the production batches.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"73 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758663","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}
The following affiliations should be designated in the exact order shown below for Gaolei Zuo. This change is reflected in the authorship of this Correction. 1. Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China 2. Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China 3. Center for Drug Design and Development Suzhou, Genhouse Bio Co., Ltd., Suzhou, Jiangsu 215123, China This article has not yet been cited by other publications.
{"title":"Correction to “Development of a Practical Telescoped Process to Prepare (P)-7-(2-Amino-6-fluorophenyl)-4-hydroxy-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one: A Key Intermediate of KRASG12C Inhibitor GH35”","authors":"Gaolei Zuo, Haojie Xu, Yaobin Zhang, Zhi Liu, Jinyue Tu, Donghui Gou, Peng Fu, Haifeng Huang, Jianhua Ren, Yuanyuan Hu, Feng Liu, Jie Jack Li, Guiping Zhang","doi":"10.1021/acs.oprd.5c00106","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00106","url":null,"abstract":"The following affiliations should be designated in the exact order shown below for Gaolei Zuo. This change is reflected in the authorship of this Correction. 1. Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China 2. Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China 3. Center for Drug Design and Development Suzhou, Genhouse Bio Co., Ltd., Suzhou, Jiangsu 215123, China This article has not yet been cited by other publications.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"107 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758662","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 : 2025-04-01DOI: 10.1021/acs.oprd.5c00004
Qiang Yang, Yu Lu, Thomas J. Beauchamp, Scott A. Frank, Xavier Ortiz-Medina, Jing Chen, Lixuan Liang, Xin Zhang, Ping Huang
A route to the key α-bromoketone intermediate for the synthesis of an imidazo[1,2-b]pyridazine IL-17A inhibitor via Horner–Wadsworth–Emmons condensation of commercially available 4,4-difluorocyclohexan-1-one (8) and methyl 2-(((benzyloxy)carbonyl)amino)-2-(dimethoxyphosphoryl)acetate (7) was developed and scaled up to support the production of drug substance for toxicology and clinical studies. The α,β-didehydroamino acid ester product 13 from Horner–Wadsworth–Emmons condensation was hydrolyzed under basic conditions to afford the corresponding N-protected α,β-didehydroamino acid 14, which was asymmetrically hydrogenated in the presence of the Ru-S-Xyl-Segphos dimer to afford the desired chiral amino acid 15. After activation with carbonyl diimidazole, the resulting acyl imidazole was reacted with the magnesium ethyl malonate complex to afford a β-oxo ester 17, which was brominated followed by concomitant decarboxylation after enzymatic ester hydrolysis with Lipozyme TL IM to afford the desired α-bromoketone intermediate 5. Stress tests and range-finding studies were carried out for all steps to support production. The optimized process was successfully scaled up to deliver 110 kg of α-bromoketone intermediate 5 to support the production of an IL-17A inhibitor. The overall yield of the optimized process was significantly improved to 46.5% from the 19.1% of the preclinical supplies process.
{"title":"Development of a Scalable Process for an IL-17A Inhibitor LY3509754. Part II: Synthesis of the α-Bromoketone Intermediate Leveraging Concomitant Decarboxylation Following Enzymatic Ester Hydrolysis","authors":"Qiang Yang, Yu Lu, Thomas J. Beauchamp, Scott A. Frank, Xavier Ortiz-Medina, Jing Chen, Lixuan Liang, Xin Zhang, Ping Huang","doi":"10.1021/acs.oprd.5c00004","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00004","url":null,"abstract":"A route to the key α-bromoketone intermediate for the synthesis of an imidazo[1,2-<i>b</i>]pyridazine IL-17A inhibitor via Horner–Wadsworth–Emmons condensation of commercially available 4,4-difluorocyclohexan-1-one (<b>8</b>) and methyl 2-(((benzyloxy)carbonyl)amino)-2-(dimethoxyphosphoryl)acetate (<b>7</b>) was developed and scaled up to support the production of drug substance for toxicology and clinical studies. The α,β-didehydroamino acid ester product <b>13</b> from Horner–Wadsworth–Emmons condensation was hydrolyzed under basic conditions to afford the corresponding <i>N</i>-protected α,β-didehydroamino acid <b>14</b>, which was asymmetrically hydrogenated in the presence of the Ru-<i>S</i>-Xyl-Segphos dimer to afford the desired chiral amino acid <b>15</b>. After activation with carbonyl diimidazole, the resulting acyl imidazole was reacted with the magnesium ethyl malonate complex to afford a β-oxo ester <b>17</b>, which was brominated followed by concomitant decarboxylation after enzymatic ester hydrolysis with Lipozyme TL IM to afford the desired α-bromoketone intermediate <b>5</b>. Stress tests and range-finding studies were carried out for all steps to support production. The optimized process was successfully scaled up to deliver 110 kg of α-bromoketone intermediate <b>5</b> to support the production of an IL-17A inhibitor. The overall yield of the optimized process was significantly improved to 46.5% from the 19.1% of the preclinical supplies process.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"32 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758479","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 : 2025-03-28DOI: 10.1021/acs.oprd.5c00016
Hirotsugu Usutani, Jun Hirabayashi, Kenji Yamamoto, Xinlong Gao, Jianghong Chen, Jianye Jiao, Hsiao Yi, Pan Wang, Kazuki Hashimoto
Electrochemical methods in organic synthesis hold significant potential for next-generation chemical processes and are gaining attention not only in the pharmaceutical sector but also across the broader chemical industry. From an electrochemical perspective, electrons can be regarded as a reagent, which can be utilized in various oxidation and reduction reactions. Anodic oxidation is one example, by which it is possible to oxidatively cleave troloxamide to form troloxamide quinone. Thus, an electrochemical process can contribute to the synthesis of the active pharmaceutical ingredient (API) EPI-589, a drug candidate for the treatment of amyotrophic lateral sclerosis (ALS). Process development using electrochemical methods is often regarded as challenging for scale-up and manufacturing, but here we describe the establishment of a manufacturing method by combining the concepts of anodic oxidation (electroorganic chemistry) and continuous processing are described. The results of a scale-up proof-of-concept experiment are shown, in which the API was obtained with excellent quality on a kilogram scale.
{"title":"Development of a Scalable Anodic Oxidation Process for (R)-Troloxamide Quinone (EPI-589) Using a Continuous Flow Approach","authors":"Hirotsugu Usutani, Jun Hirabayashi, Kenji Yamamoto, Xinlong Gao, Jianghong Chen, Jianye Jiao, Hsiao Yi, Pan Wang, Kazuki Hashimoto","doi":"10.1021/acs.oprd.5c00016","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00016","url":null,"abstract":"Electrochemical methods in organic synthesis hold significant potential for next-generation chemical processes and are gaining attention not only in the pharmaceutical sector but also across the broader chemical industry. From an electrochemical perspective, electrons can be regarded as a reagent, which can be utilized in various oxidation and reduction reactions. Anodic oxidation is one example, by which it is possible to oxidatively cleave troloxamide to form troloxamide quinone. Thus, an electrochemical process can contribute to the synthesis of the active pharmaceutical ingredient (API) EPI-589, a drug candidate for the treatment of amyotrophic lateral sclerosis (ALS). Process development using electrochemical methods is often regarded as challenging for scale-up and manufacturing, but here we describe the establishment of a manufacturing method by combining the concepts of anodic oxidation (electroorganic chemistry) and continuous processing are described. The results of a scale-up proof-of-concept experiment are shown, in which the API was obtained with excellent quality on a kilogram scale.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"19 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723985","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 : 2025-03-27DOI: 10.1021/acs.oprd.5c00055
Lei Li, Xinyu Ye, Huaixi Liu, Rongwen Lu, Bingtao Tang, Shufen Zhang
Integrating the diazotization and coupling reactions in solid–liquid heterogeneous systems to achieve large-scale, multistep continuous flow synthesis of water-soluble azo dyes remains a significant challenge. During the diazotization process of water-soluble azo dyes, considerable diazonium salt may precipitate, posing potential safety risks. In this study, we established a continuous dynamic tubular reaction system to achieve the multistep continuous heterogeneous synthesis of C.I. Reactive Red 195, a representative water-soluble azo dye. The optimal conditions for continuous diazotization and coupling reactions were determined, achieving a high throughput of 120 L/h and a yield of up to 736 kg/day. The purity of the synthesized dye increased by 20% compared to the commercial C.I. Reactive Red 195, with the K/S value rising from 19.07 to 22.16, indicating enhanced dyeing performance. Density functional theory (DFT) calculations and ab initio molecular dynamics (AIMD) simulations show that 2-naphthylamine-1,5-disulfonic acid diazonium salt (NADA-DS) spontaneously aggregates into stable clusters due to dispersion forces, which leads to precipitation. Furthermore, the thermal stability, impact sensitivity, explosive propagation, and decomposition activation energy of NADA-DS were investigated. The severity and possibility of thermal runaway during the continuous diazotization process are classified as level 1. The risk matrix indicates that the continuous diazotization process risk is acceptable, with the Stoessel criticality diagram categorizing the hazard level as grade 1, signifying a low level of risk. This study promotes safer, more efficient, and sustainable production of water-soluble azo dyes.
{"title":"Multistep Continuous Heterogeneous Synthesis of C.I. Reactive Red 195 and Safety Evaluation of the Continuous Diazotization Process","authors":"Lei Li, Xinyu Ye, Huaixi Liu, Rongwen Lu, Bingtao Tang, Shufen Zhang","doi":"10.1021/acs.oprd.5c00055","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00055","url":null,"abstract":"Integrating the diazotization and coupling reactions in solid–liquid heterogeneous systems to achieve large-scale, multistep continuous flow synthesis of water-soluble azo dyes remains a significant challenge. During the diazotization process of water-soluble azo dyes, considerable diazonium salt may precipitate, posing potential safety risks. In this study, we established a continuous dynamic tubular reaction system to achieve the multistep continuous heterogeneous synthesis of C.I. Reactive Red 195, a representative water-soluble azo dye. The optimal conditions for continuous diazotization and coupling reactions were determined, achieving a high throughput of 120 L/h and a yield of up to 736 kg/day. The purity of the synthesized dye increased by 20% compared to the commercial C.I. Reactive Red 195, with the <i>K</i>/<i>S</i> value rising from 19.07 to 22.16, indicating enhanced dyeing performance. Density functional theory (DFT) calculations and ab initio molecular dynamics (AIMD) simulations show that 2-naphthylamine-1,5-disulfonic acid diazonium salt (NADA-DS) spontaneously aggregates into stable clusters due to dispersion forces, which leads to precipitation. Furthermore, the thermal stability, impact sensitivity, explosive propagation, and decomposition activation energy of NADA-DS were investigated. The severity and possibility of thermal runaway during the continuous diazotization process are classified as level 1. The risk matrix indicates that the continuous diazotization process risk is acceptable, with the Stoessel criticality diagram categorizing the hazard level as grade 1, signifying a low level of risk. This study promotes safer, more efficient, and sustainable production of water-soluble azo dyes.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"36 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723984","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 : 2025-03-27DOI: 10.1021/acs.oprd.4c00437
Kiran Matcha, William M. Maton, Peter Reniers, Robert Geertman, Bart Bueken, Philip Pye, Stijn Wuyts, Ed Cleator
JNJ-7950 is a potent small-molecule respiratory syncytial virus (RSV) inhibitor with a long-acting profile in preclinical species. The design and development of a convergent synthetic route accelerated the discovery and development of JNJ-7950. First, the new synthetic route supported the lead candidate (JNJ-7950) selection process and later was adapted to provide a large-scale clinical batch. A shorter and cost-effective synthetic route to the key spiro-azetidine moiety exploited an intramolecular copper-catalyzed C–N coupling. The development of an efficient and sustainable process for telescoping three steps in a single solvent provided the benzimidazole moiety with an 85% overall yield. The spiro-azetidine and the benzimidazole moieties were coupled to provide JNJ-7950 in 48% overall yield with excellent purity over the six longest linear steps. Two GMP batches (6 and 12 kg) of JNJ-7950 were manufactured in parenteral grade quality to support long-acting injectable formulation development and early clinical need.
{"title":"Development of a Convergent and Scalable Synthetic Route to Long-Acting RSV Inhibitor JNJ-7950","authors":"Kiran Matcha, William M. Maton, Peter Reniers, Robert Geertman, Bart Bueken, Philip Pye, Stijn Wuyts, Ed Cleator","doi":"10.1021/acs.oprd.4c00437","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00437","url":null,"abstract":"JNJ-7950 is a potent small-molecule respiratory syncytial virus (RSV) inhibitor with a long-acting profile in preclinical species. The design and development of a convergent synthetic route accelerated the discovery and development of JNJ-7950. First, the new synthetic route supported the lead candidate (JNJ-7950) selection process and later was adapted to provide a large-scale clinical batch. A shorter and cost-effective synthetic route to the key spiro-azetidine moiety exploited an intramolecular copper-catalyzed C–N coupling. The development of an efficient and sustainable process for telescoping three steps in a single solvent provided the benzimidazole moiety with an 85% overall yield. The spiro-azetidine and the benzimidazole moieties were coupled to provide JNJ-7950 in 48% overall yield with excellent purity over the six longest linear steps. Two GMP batches (6 and 12 kg) of JNJ-7950 were manufactured in parenteral grade quality to support long-acting injectable formulation development and early clinical need.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"183 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713634","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 : 2025-03-27DOI: 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}
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