Steven A. Weissman, Christopher J. Kassl, Siead Zegar, Sarah M. Pound, Nori Ikemoto, William Reid, Thorsten Rosner, Xican He, Xianda Chen, Junfei Wen, Liang Han, Xiaojun Huang, Chaoyang Chen, Yuehui Liu, Prithvi Vangal, Hongkun Lin, David D. Ford, Yuan-Qing Fang
{"title":"Commercial Route Development of Sigma-2 Receptor Modulator, CT1812 Leveraging Photoflow, and HTS Technologies","authors":"Steven A. Weissman, Christopher J. Kassl, Siead Zegar, Sarah M. Pound, Nori Ikemoto, William Reid, Thorsten Rosner, Xican He, Xianda Chen, Junfei Wen, Liang Han, Xiaojun Huang, Chaoyang Chen, Yuehui Liu, Prithvi Vangal, Hongkun Lin, David D. Ford, Yuan-Qing Fang","doi":"10.1021/acs.oprd.4c00412","DOIUrl":null,"url":null,"abstract":"A second-generation synthesis of CT1812, a sigma-2 receptor modulator (ligand), was developed from readily available starting materials to support late-stage clinical needs. An AIBN-induced thermal benzylic bromination in DCE was replaced by a visible-light-induced continuous flow process in MeCN operating at room temperature. High throughput screening was employed to overcome the unexpected challenges encountered in the hydrogenation of alkyne <b>13</b> in the penultimate step. The rationale for a polymorph switch from the originally developed monofumarate anhydrate to the more thermodynamically stable hemifumarate dihydrate is also described. The new convergent route proceeds in eight steps (longest linear sequence (LLS) = 6) as compared to the original med chem route (12 steps; LLS = 9) and has been successfully demonstrated on a 100 kg scale.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"7 1","pages":""},"PeriodicalIF":3.5000,"publicationDate":"2025-01-29","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.4c00412","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 second-generation synthesis of CT1812, a sigma-2 receptor modulator (ligand), was developed from readily available starting materials to support late-stage clinical needs. An AIBN-induced thermal benzylic bromination in DCE was replaced by a visible-light-induced continuous flow process in MeCN operating at room temperature. High throughput screening was employed to overcome the unexpected challenges encountered in the hydrogenation of alkyne 13 in the penultimate step. The rationale for a polymorph switch from the originally developed monofumarate anhydrate to the more thermodynamically stable hemifumarate dihydrate is also described. The new convergent route proceeds in eight steps (longest linear sequence (LLS) = 6) as compared to the original med chem route (12 steps; LLS = 9) and has been successfully demonstrated on a 100 kg scale.
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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