{"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":null,"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":3.1000,"publicationDate":"2024-05-29","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.4c00144","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
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.
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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