Cameron T. Armstrong, Katharina Grohowalski, Grace Russell, Sara Mason, Kakasaheb Y. Nandiwale, DaQuawn Edwards, Jillian Sheeran, Talia J. Steiman, Douglas J. Critcher, Christopher P. Ashcroft, Angel R. Diaz, Steven M. Guinness
{"title":"Early-Stage Flow Process Development of a Key Intermediate toward PF-07265807, an AXL-MER Inhibitor Oncology Candidate","authors":"Cameron T. Armstrong, Katharina Grohowalski, Grace Russell, Sara Mason, Kakasaheb Y. Nandiwale, DaQuawn Edwards, Jillian Sheeran, Talia J. Steiman, Douglas J. Critcher, Christopher P. Ashcroft, Angel R. Diaz, Steven M. Guinness","doi":"10.1021/acs.oprd.4c00112","DOIUrl":null,"url":null,"abstract":"The application of continuous processing can afford certain advantages during development and scale-up, such as enhanced risk mitigation of hazardous compounds and reducing both manufacturing cycle time and solvent waste through telescoping steps and avoiding intermediate isolations. While telescoping is not unique to flow, the operating windows enabled by the process intensification only possible in flow are notable, and they often possess the additional benefit of accessing chemistries not feasible in a batch. In this work, we highlight efforts to translate an early-stage batch route for the AXL-MER inhibitor oncology candidate PF-07265807 into a viable continuous flow process. The route to the key intermediate of interest features two S<sub>N</sub>Ar reactions, the latter utilizing aqueous hydrazine to enable an intramolecular cascade reaction, followed by a Boc deprotection. Efforts were made to assess and demonstrate the suitability of the process for telescoping steps in flow by finding a solvent/base system that maintained the solubility of all species and led to efficacious reactions. Additional studies were performed to reduce the concentration of aqueous hydrazine solution used as a feed in the continuous process to 5 wt % hydrazine, adding to the various safety advantages not amenable to a traditional batch process. Furthermore, an automated D-optimal design of experiment study was carried out for the aqueous hydrazine step to increase process understanding and screen effects during this early stage of development.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1000,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Organic Process Research & Development","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1021/acs.oprd.4c00112","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
引用次数: 0
Abstract
The application of continuous processing can afford certain advantages during development and scale-up, such as enhanced risk mitigation of hazardous compounds and reducing both manufacturing cycle time and solvent waste through telescoping steps and avoiding intermediate isolations. While telescoping is not unique to flow, the operating windows enabled by the process intensification only possible in flow are notable, and they often possess the additional benefit of accessing chemistries not feasible in a batch. In this work, we highlight efforts to translate an early-stage batch route for the AXL-MER inhibitor oncology candidate PF-07265807 into a viable continuous flow process. The route to the key intermediate of interest features two SNAr reactions, the latter utilizing aqueous hydrazine to enable an intramolecular cascade reaction, followed by a Boc deprotection. Efforts were made to assess and demonstrate the suitability of the process for telescoping steps in flow by finding a solvent/base system that maintained the solubility of all species and led to efficacious reactions. Additional studies were performed to reduce the concentration of aqueous hydrazine solution used as a feed in the continuous process to 5 wt % hydrazine, adding to the various safety advantages not amenable to a traditional batch process. Furthermore, an automated D-optimal design of experiment study was carried out for the aqueous hydrazine step to increase process understanding and screen effects during this early stage of development.
期刊介绍：
The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.
京公网安备 11010802042870号
京ICP备2023020795号-1
分享
求助内容：
应助结果提醒方式：
扫码关注我们
