Christopher P. Ashcroft, Alexander M. Berne, Florian Blasberg, Kelly Catlin, Michael R. Collins, Doug J. Critcher, Jean-Nicolas Desrosiers*, Adam Goetz, Cheryl Hayward, Ricky A. Jones, Michael J. Karmilowicz, Nandell Keene, Carlos A. Martinez, Sebastien Monfette, Sebastian David Pattavina, Hahdi H. Perfect, John A. Ragan, Blake Rauschenberger*, Neal W. Sach, Gemma Scotney, Scott C. Sutton, Courtney Talicska, Steven J.R. Twiddle, Jared Van Haitsma and Richard Wisdom,
{"title":"Development of a Cost-Efficient Process Toward a Key Synthetic Intermediate of the EZH2 Inhibitor PF-06821497","authors":"Christopher P. Ashcroft, Alexander M. Berne, Florian Blasberg, Kelly Catlin, Michael R. Collins, Doug J. Critcher, Jean-Nicolas Desrosiers*, Adam Goetz, Cheryl Hayward, Ricky A. Jones, Michael J. Karmilowicz, Nandell Keene, Carlos A. Martinez, Sebastien Monfette, Sebastian David Pattavina, Hahdi H. Perfect, John A. Ragan, Blake Rauschenberger*, Neal W. Sach, Gemma Scotney, Scott C. Sutton, Courtney Talicska, Steven J.R. Twiddle, Jared Van Haitsma and Richard Wisdom, ","doi":"10.1021/acs.oprd.3c00477","DOIUrl":null,"url":null,"abstract":"<p >A cost-efficient approach for the synthesis of a key intermediate of the EZH2 inhibitor PF-06821497 was identified after performing process chemistry development. A wide route scouting effort was initially deployed to finally identify a successful oxidative decyanation approach. Widely available raw materials were utilized to access a desired oxetanyl-ketone as a precursor for a KRED process to generate the enantioenriched alcohol in 99% ee. Subsequent methylation followed by a carboxylation led to our targeted building block in seven steps with an overall yield of 28%. This process was demonstrated on a large scale to produce up to 50 kg of our key intermediate in the synthesis of PF-06821497.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 6","pages":"2260–2268"},"PeriodicalIF":3.1000,"publicationDate":"2024-02-26","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://pubs.acs.org/doi/10.1021/acs.oprd.3c00477","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
A cost-efficient approach for the synthesis of a key intermediate of the EZH2 inhibitor PF-06821497 was identified after performing process chemistry development. A wide route scouting effort was initially deployed to finally identify a successful oxidative decyanation approach. Widely available raw materials were utilized to access a desired oxetanyl-ketone as a precursor for a KRED process to generate the enantioenriched alcohol in 99% ee. Subsequent methylation followed by a carboxylation led to our targeted building block in seven steps with an overall yield of 28%. This process was demonstrated on a large scale to produce up to 50 kg of our key intermediate in the synthesis of PF-06821497.
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.
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