Gabriel Schäfer*, Tony Fleischer, Nicole Blumer, Megan Udry, Stefan Reber, Ian Stansfield, Yuanhua Liu, Yan Li, Pixu Li
{"title":"对茴香胺和2-氟丙二酸多公斤生产3-氟-6-甲氧基喹啉的初步路线探索和最终工艺开发","authors":"Gabriel Schäfer*, Tony Fleischer, Nicole Blumer, Megan Udry, Stefan Reber, Ian Stansfield, Yuanhua Liu, Yan Li, Pixu Li","doi":"10.1021/acs.oprd.1c00414","DOIUrl":null,"url":null,"abstract":"<p >A scalable route to 3-fluoro-6-methoxyquinoline needed to be developed as multi-kg amounts of this heterocycle were required. Initial route development focused on the formation of the key C–F bond via a Balz–Schiemann reaction or electrophilic fluorination using Selectfluor. Both routes were developed on laboratory scale and provided gram amounts of 3-fluoro-6-methoxyquinoline. However, due to process safety concerns and high step counts, both routes were not suitable for further scale up. Therefore, a third approach was developed, in which the desired heterocycle was formed via condensation of <i>p</i>-anisidine with 2-fluoromalonic acid, two inexpensive and commercially available starting materials. After intensive optimization and safety studies, this POCl<sub>3</sub>-mediated process was successfully scaled up to a 32 kg scale. After final hydrodechlorination, 12 kg of 3-fluoro-6-methoxyquinoline with excellent purity was produced.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"26 2","pages":"347–357"},"PeriodicalIF":3.5000,"publicationDate":"2022-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":"{\"title\":\"Initial Route Scouting and Final Process Development for the Multi-Kg Production of 3-Fluoro-6-methoxyquinoline from p-Anisidine and 2-Fluoromalonic Acid\",\"authors\":\"Gabriel Schäfer*, Tony Fleischer, Nicole Blumer, Megan Udry, Stefan Reber, Ian Stansfield, Yuanhua Liu, Yan Li, Pixu Li\",\"doi\":\"10.1021/acs.oprd.1c00414\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >A scalable route to 3-fluoro-6-methoxyquinoline needed to be developed as multi-kg amounts of this heterocycle were required. Initial route development focused on the formation of the key C–F bond via a Balz–Schiemann reaction or electrophilic fluorination using Selectfluor. Both routes were developed on laboratory scale and provided gram amounts of 3-fluoro-6-methoxyquinoline. However, due to process safety concerns and high step counts, both routes were not suitable for further scale up. Therefore, a third approach was developed, in which the desired heterocycle was formed via condensation of <i>p</i>-anisidine with 2-fluoromalonic acid, two inexpensive and commercially available starting materials. After intensive optimization and safety studies, this POCl<sub>3</sub>-mediated process was successfully scaled up to a 32 kg scale. After final hydrodechlorination, 12 kg of 3-fluoro-6-methoxyquinoline with excellent purity was produced.</p>\",\"PeriodicalId\":55,\"journal\":{\"name\":\"Organic Process Research & Development\",\"volume\":\"26 2\",\"pages\":\"347–357\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2022-01-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Organic Process Research & Development\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.oprd.1c00414\",\"RegionNum\":3,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, APPLIED\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Organic Process Research & Development","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.oprd.1c00414","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
Initial Route Scouting and Final Process Development for the Multi-Kg Production of 3-Fluoro-6-methoxyquinoline from p-Anisidine and 2-Fluoromalonic Acid
A scalable route to 3-fluoro-6-methoxyquinoline needed to be developed as multi-kg amounts of this heterocycle were required. Initial route development focused on the formation of the key C–F bond via a Balz–Schiemann reaction or electrophilic fluorination using Selectfluor. Both routes were developed on laboratory scale and provided gram amounts of 3-fluoro-6-methoxyquinoline. However, due to process safety concerns and high step counts, both routes were not suitable for further scale up. Therefore, a third approach was developed, in which the desired heterocycle was formed via condensation of p-anisidine with 2-fluoromalonic acid, two inexpensive and commercially available starting materials. After intensive optimization and safety studies, this POCl3-mediated process was successfully scaled up to a 32 kg scale. After final hydrodechlorination, 12 kg of 3-fluoro-6-methoxyquinoline with excellent purity was produced.
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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