Organic Process Research & Development最新文献_第10页

A Scalable Flow Electrolysis of Heterogeneous Mixtures Using a Rotating Cylinder Electrode Reactor: Access to a Chiral Iminophosphorane 使用旋转圆柱电极反应器的非均质混合物的可扩展流动电解：获得手性亚磷烷

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2025-02-27 DOI: 10.1021/acs.oprd.4c0053210.1021/acs.oprd.4c00532

Felix Xu, Longrui Chen*, Dan Lehnherr* and François Lévesque,

{"title":"A Scalable Flow Electrolysis of Heterogeneous Mixtures Using a Rotating Cylinder Electrode Reactor: Access to a Chiral Iminophosphorane","authors":"Felix Xu, Longrui Chen*, Dan Lehnherr* and François Lévesque, ","doi":"10.1021/acs.oprd.4c0053210.1021/acs.oprd.4c00532","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00532https://doi.org/10.1021/acs.oprd.4c00532","url":null,"abstract":"We report the application of rotating cylinder electrode (RCE) reactors for the electrolysis of heterogeneous reactions in batch and in recirculating flow. A scalable method for the synthesis of an N-cyano iminophosphorane ligand in an RCE reactor is also reported. In the development of this process, a graphite felt attached to the inner impervious graphite was used as a rotating anode, and the outer stainless steel wall of the reactor was used as the cathode. The reaction was first evaluated in batch using a small RCE reactor to optimize the spinning rate, supporting electrolyte, and current density. The optimal batch condition was then scaled up in a medium-sized RCE reactor with modifications to adapt it to a flow process. The electrosynthesis was demonstrated up to a 100 g scale, and the impact of the reaction temperature was investigated. Finally, an operationally simple direct crystallization using water as the antisolvent provided a chiral N-cyano iminophosphorane ligand in 74% isolated yield on a 100 g scale from commercially available (S)-BINAP and bis(trimethylsilyl)carbodiimide.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 3","pages":"872–880 872–880"},"PeriodicalIF":3.1,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143667144","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}

引用次数: 0

Safe and Efficient Continuous Flow Synthesis of (3S,4S)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[(R)-1-carboxyethyl]-2-azetizinone via Vertical Dynamic Reactor 垂直动态反应器安全高效连续流合成(3S,4S)-3-[(R)-1-（t-丁基二甲基硅氧基）乙基]-4-[(R)-1-羧乙基]-2-氮杂tizinone

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-02-27 DOI: 10.1021/acs.oprd.4c00507

Kai Fu, Guangbing Zheng, Xibo Guan, Haibo Mu, Xianqiang Meng, Shouxiang Jiang, Bin Wang, Guangkun Dong, Gengxiu Zheng

{"title":"Safe and Efficient Continuous Flow Synthesis of (3S,4S)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[(R)-1-carboxyethyl]-2-azetizinone via Vertical Dynamic Reactor","authors":"Kai Fu, Guangbing Zheng, Xibo Guan, Haibo Mu, Xianqiang Meng, Shouxiang Jiang, Bin Wang, Guangkun Dong, Gengxiu Zheng","doi":"10.1021/acs.oprd.4c00507","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00507","url":null,"abstract":"The H2O2-mediated cleavage of chiral auxiliary as a mild and selective method is commonly used in the pharmaceutical industry but they can also introduce unexpected safety hazards due to the O2 release. Here, a novel safe and efficient continuous flow synthesis process for (3S,4S)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(R)-1-carboxyethyl]-2-azetizinone (4-BMA), a key intermediate of meropenem was reported. The vertical dynamic reactor (VDR) effectively addresses the safety risk by preventing electrostatic accumulation and eliminating gas-phase space within the reactor. Compared to the current batch process, the continuous flow synthesis method reported in this paper not only significantly improved the safety of the process but also greatly shortened the reaction time (from 600 to 20 min) and increased the yield (from 85 to 91%) due to its high mass and heat transfer efficiency. These results indicated that the VDR provides great potential for the industrial scale-up of 4-BMA.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518608","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}

引用次数: 0

Development of a Scalable Synthetic Route to (1R,5R)-2,2-Dimethoxybicyclo[3.1.0]hexan-3-one: An Important Intermediate in the Synthesis of Lenacapavir Lenacapavir合成重要中间体(1R,5R)-2,2-二甲氧基双环[3.1.0]己烷-3- 1的可扩展合成路线的建立

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2025-02-26 DOI: 10.1021/acs.oprd.4c0052710.1021/acs.oprd.4c00527

Aline Nunes De Souza, Nagaraju Sakkani, Daryl Guthrie, Rajkumar Lalji Sahani, John M. Saathoff, Samuel R. Hochstetler, Justina M. Burns, Saeed Ahmad, G. Michael Laidlaw, B. Frank Gupton, Douglas A. Klumpp and Limei Jin*,

引用次数: 0

Industry Perspective on the Selection of Regulatory Starting Materials for Synthetic Peptides 合成多肽起始原料选择的行业展望

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-02-26 DOI: 10.1021/acs.oprd.4c00426

Subha Mukherjee, David A. Thaisrivongs, Paridhi Agrawal, Mark R. Berglund, Alec Fettes, Zack Guo, Martin N. Kenworthy, Rasmus Lewinsky, John Lopez, Ogonna Nwajiobi, Yasuhiro Sawai, Kevin D. Seibert

{"title":"Industry Perspective on the Selection of Regulatory Starting Materials for Synthetic Peptides","authors":"Subha Mukherjee, David A. Thaisrivongs, Paridhi Agrawal, Mark R. Berglund, Alec Fettes, Zack Guo, Martin N. Kenworthy, Rasmus Lewinsky, John Lopez, Ogonna Nwajiobi, Yasuhiro Sawai, Kevin D. Seibert","doi":"10.1021/acs.oprd.4c00426","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00426","url":null,"abstract":"This Perspective from the Synthetic Peptide Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium or IQ) Drug Substance Leadership Group discusses the selection of regulatory starting materials (RSMs) for peptide manufacture. Given the ubiquity of solid-phase peptide synthesis (SPPS), it has been common practice to simply default to individual amino acids or dipeptides as RSMs. However, as the field of synthetic peptide research has grown and new synthesis technologies have been more widely adopted, this team proposes that there are cases where significant scientific and technical justification exists to consider larger peptide fragments as RSMs that remain consistent with ICH Q11. This framework would provide greater flexibility and support for the adoption of new and superior peptide synthesis technologies, increasing manufacturing process and supply chain robustness and offering opportunities for industry to address sustainability challenges inherent to current practices in synthetic peptide manufacture.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"1 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143496165","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}

引用次数: 0

Development of a Scalable Synthetic Route to (1R,5R)-2,2-Dimethoxybicyclo[3.1.0]hexan-3-one: An Important Intermediate in the Synthesis of Lenacapavir Lenacapavir合成重要中间体(1R,5R)-2,2-二甲氧基双环[3.1.0]己烷-3- 1的可扩展合成路线的建立

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-02-26 DOI: 10.1021/acs.oprd.4c00527

Aline Nunes De Souza, Nagaraju Sakkani, Daryl Guthrie, Rajkumar Lalji Sahani, John M. Saathoff, Samuel R. Hochstetler, Justina M. Burns, Saeed Ahmad, G. Michael Laidlaw, B. Frank Gupton, Douglas A. Klumpp, Limei Jin

引用次数: 0

Industry Perspective on the Selection of Regulatory Starting Materials for Synthetic Peptides 合成多肽起始原料选择的行业展望

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2025-02-26 DOI: 10.1021/acs.oprd.4c0042610.1021/acs.oprd.4c00426

Subha Mukherjee*, David A. Thaisrivongs*, Paridhi Agrawal, Mark R. Berglund, Alec Fettes, Zack Guo, Martin N. Kenworthy, Rasmus Lewinsky, John Lopez, Ogonna Nwajiobi, Yasuhiro Sawai and Kevin D. Seibert,

{"title":"Industry Perspective on the Selection of Regulatory Starting Materials for Synthetic Peptides","authors":"Subha Mukherjee*, David A. Thaisrivongs*, Paridhi Agrawal, Mark R. Berglund, Alec Fettes, Zack Guo, Martin N. Kenworthy, Rasmus Lewinsky, John Lopez, Ogonna Nwajiobi, Yasuhiro Sawai and Kevin D. Seibert, ","doi":"10.1021/acs.oprd.4c0042610.1021/acs.oprd.4c00426","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00426https://doi.org/10.1021/acs.oprd.4c00426","url":null,"abstract":"This Perspective from the Synthetic Peptide Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium or IQ) Drug Substance Leadership Group discusses the selection of regulatory starting materials (RSMs) for peptide manufacture. Given the ubiquity of solid-phase peptide synthesis (SPPS), it has been common practice to simply default to individual amino acids or dipeptides as RSMs. However, as the field of synthetic peptide research has grown and new synthesis technologies have been more widely adopted, this team proposes that there are cases where significant scientific and technical justification exists to consider larger peptide fragments as RSMs that remain consistent with ICH Q11. This framework would provide greater flexibility and support for the adoption of new and superior peptide synthesis technologies, increasing manufacturing process and supply chain robustness and offering opportunities for industry to address sustainability challenges inherent to current practices in synthetic peptide manufacture.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 3","pages":"671–677 671–677"},"PeriodicalIF":3.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143667103","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}

引用次数: 0

Development of an Innovative Three-Component Optical Resolution and a Flow Chemistry Process for (R)-Troloxamide Quinone (EPI-589) (R)-Troloxamide醌（EPI-589）创新三组分光学分辨及流动化学工艺的建立

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-02-25 DOI: 10.1021/acs.oprd.4c00540

Hirotsugu Usutani, Kiichi Kuroda, Kiyoto Sawamura, Jun Hirabayashi, Kenji Yamamoto, Masahiko Tanaka, Masayuki Ohira, Shigeaki Masuda, Takuya Nakagiri, Rui Ono, Tetsuji Kawamoto, Kazuki Hashimoto

{"title":"Development of an Innovative Three-Component Optical Resolution and a Flow Chemistry Process for (R)-Troloxamide Quinone (EPI-589)","authors":"Hirotsugu Usutani, Kiichi Kuroda, Kiyoto Sawamura, Jun Hirabayashi, Kenji Yamamoto, Masahiko Tanaka, Masayuki Ohira, Shigeaki Masuda, Takuya Nakagiri, Rui Ono, Tetsuji Kawamoto, Kazuki Hashimoto","doi":"10.1021/acs.oprd.4c00540","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00540","url":null,"abstract":"(R)-Troloxamide quinone (EPI-589) is a compound that is under development as a therapeutic agent for Parkinson’s disease and amyotrophic lateral sclerosis (ALS). The compound is derived from Trolox, a vitamin E derivative, using optical resolution and subsequent chemical conversion processes to obtain the active pharmaceutical ingredient (API). However, in the initially developed manufacturing method, pseudoephedrine was used as the optical resolution reagent, although it is restricted for use as a stimulant drug raw material in several countries, and the reproducibility of the optical resolution was not high. Thus, it was necessary to find an alternative chiral amine, which would be more freely usable and give high reproducibility. Among several optical resolution conditions investigated, an unusual three-component complex between (R)-Trolox, (R)-phenylethylamine, and N-methyl-2-pyrrolidone (NMP) was identified as most effective. However, although the optical resolution process showed both high reproducibility and optical purity, the manufacturing method came with the risk of introducing nitrosamines into the active pharmaceutical ingredient, so further extensive investigations were conducted to address this issue. As a result, a flow chemistry process was developed, which could avoid the use of a nitrate reagent in the oxidation step, and thus eliminate the risk of nitrosamine generation. This paper discloses the process development studies and discusses the successful manufacturing of EPI-589 on a scale of several hundred kilograms, utilizing the novel optical resolution and flow chemistry process under GMP conditions.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"26 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486331","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}

引用次数: 0

Development of a Scalable Manufacturing Process for AB-343 Drug Substance: A Potential Candidate for the Treatment of Coronavirus Infections AB-343原料药可扩展制造工艺的开发：治疗冠状病毒感染的潜在候选药物

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-02-25 DOI: 10.1021/acs.oprd.4c00528

Jeremy D. Mason, Jan M. Spink, Mahesh Pallerla, Zhenhua Wu, Rajeev K. Singh, Aravind B. Pulipaka, Jia Liu, Marvin Marcus Vega, Xu Wang, Michael J. Sofia, Ganapati Reddy Pamulapati

引用次数: 0

Development of a Scalable Manufacturing Process for AB-343 Drug Substance: A Potential Candidate for the Treatment of Coronavirus Infections AB-343原料药可扩展制造工艺的开发：治疗冠状病毒感染的潜在候选药物

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2025-02-25 DOI: 10.1021/acs.oprd.4c0052810.1021/acs.oprd.4c00528

Jeremy D. Mason*, Jan M. Spink, Mahesh Pallerla, Zhenhua Wu, Rajeev K. Singh, Aravind B. Pulipaka, Jia Liu, Marvin Marcus Vega, Xu Wang, Michael J. Sofia and Ganapati Reddy Pamulapati*,

引用次数: 0

Comprehensive Synthetic Route Redesign of AZD5991: A High-Complexity Atropisomeric Macrocycle AZD5991合成路线的再设计：一个高复杂度的atrosom异构大环

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-02-25 DOI: 10.1021/acs.oprd.4c00524

Gareth P. Howell, Lauren R. Agnew, Christoph Bauer, Fiona J. Bell, Andrew D. Campbell, Kuangchu Dai, David Dave, Sam R. Ellis, Matthew J. Foulkes, Malcolm A. Y. Gall, Kilian Garrec, Huajun Ge, Barry R. Hayter, Martin F. Jones, George Karageorgis, Mairi Littleson, Thomas W. Lloyd-Hughes, Harriet C. McNicholl, David T. Mooney, Bethany J. Moore, Rachel H. Munday, Emily Noone, David Perkins, Lyn Powell, Okky Dwichandra Putra, Simone Tomasi, Miriam Turner, Hongxu Wang, Hucheng Zhao, Oliver T. Ring

{"title":"Comprehensive Synthetic Route Redesign of AZD5991: A High-Complexity Atropisomeric Macrocycle","authors":"Gareth P. Howell, Lauren R. Agnew, Christoph Bauer, Fiona J. Bell, Andrew D. Campbell, Kuangchu Dai, David Dave, Sam R. Ellis, Matthew J. Foulkes, Malcolm A. Y. Gall, Kilian Garrec, Huajun Ge, Barry R. Hayter, Martin F. Jones, George Karageorgis, Mairi Littleson, Thomas W. Lloyd-Hughes, Harriet C. McNicholl, David T. Mooney, Bethany J. Moore, Rachel H. Munday, Emily Noone, David Perkins, Lyn Powell, Okky Dwichandra Putra, Simone Tomasi, Miriam Turner, Hongxu Wang, Hucheng Zhao, Oliver T. Ring","doi":"10.1021/acs.oprd.4c00524","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00524","url":null,"abstract":"We describe our approach to the total synthesis of AZD5991 (1) from a process development perspective through the complete redesign of our synthetic strategy from the ground up. The size and complexity of small-molecule therapeutic targets have continued to increase over recent decades. One such example, 1, is arguably the most complex active pharmaceutical ingredient (API) in AstraZeneca’s small molecule development portfolio to date and poses formidable synthetic challenges. The previous racemic synthesis of 1 was sufficient to supply early clinical activities; however, the route was not deemed commercially viable and had significant environmental challenges. The identification of a long-term sustainable route was therefore critical to enable the robust manufacture of drug substance for later clinical activities and launch. We report exploration of asymmetric approaches toward the atropisomeric core, new routes toward each of the four heterocyclic building blocks, including a divergent pyrazole functionalization, and final assembly in a scalable and controlled macrocyclization process. These improvements resulted in a 49% reduction in step count and 95% reduction in projected waste generation.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"1 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486330","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}

引用次数: 0