Pawan Kumar, Premnath Dhande, Muhammad Taufiq F. Mazlee, S. M. Yaman, Nurul Syazwani Nadirah Binti Muhammad Syafiq Chandran, M. Makhtar, Dhramveer Singh Shekhawat, S. V. Lanke, R. Kumar, Sandeep Mhetre
{"title":"A controlled, efficient and robust process for the synthesis of an epidermal growth factor receptor inhibitor: Afatinib Dimaleate","authors":"Pawan Kumar, Premnath Dhande, Muhammad Taufiq F. Mazlee, S. M. Yaman, Nurul Syazwani Nadirah Binti Muhammad Syafiq Chandran, M. Makhtar, Dhramveer Singh Shekhawat, S. V. Lanke, R. Kumar, Sandeep Mhetre","doi":"10.25082/CR.2019.01.001","DOIUrl":null,"url":null,"abstract":"A simple, controlled, robust and scalable three-stage manufacturing process of Afatinib Dimaleate was assessed and optimized leading to improved yield and quality. The synthetic process involves sequence of reactions as nitro-reduction, amidation and salification. The developed and optimized route was demonstrated on 300g scale with over all isolated yield of 84% for Afatinib free base. The developed process has the capability to control not only the process related impurities but also the degradation impurities. One new impurity was identified during the process development studies and characterized as acetamide impunity, chemically known as (S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) acetamide. Other impurities were identified as degradation impurities, Process impurity impurities and were labeled as 1-(4-((3-chloro-4-fluorophenyl) amino)-7-(((S)-tetrahydrofuran-3-yl) oxy) quinazoline-6-yl)-5-Hydroxypyrrolidin-2-one (hydroxy impurity), Afatinib N-Oxide impurity and N4-(3-chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furanyl] oxy]-4,6-quinazolinediamine (Intermediate-1).","PeriodicalId":66475,"journal":{"name":"化学报告(英文)","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2019-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"化学报告(英文)","FirstCategoryId":"1089","ListUrlMain":"https://doi.org/10.25082/CR.2019.01.001","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 1
Abstract
A simple, controlled, robust and scalable three-stage manufacturing process of Afatinib Dimaleate was assessed and optimized leading to improved yield and quality. The synthetic process involves sequence of reactions as nitro-reduction, amidation and salification. The developed and optimized route was demonstrated on 300g scale with over all isolated yield of 84% for Afatinib free base. The developed process has the capability to control not only the process related impurities but also the degradation impurities. One new impurity was identified during the process development studies and characterized as acetamide impunity, chemically known as (S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) acetamide. Other impurities were identified as degradation impurities, Process impurity impurities and were labeled as 1-(4-((3-chloro-4-fluorophenyl) amino)-7-(((S)-tetrahydrofuran-3-yl) oxy) quinazoline-6-yl)-5-Hydroxypyrrolidin-2-one (hydroxy impurity), Afatinib N-Oxide impurity and N4-(3-chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furanyl] oxy]-4,6-quinazolinediamine (Intermediate-1).