Open Access

Peer-reviewed

Research Article

Main Article Content

Pawan kumarcorresponding author
Premnath Dhande
Muhammad Taufiq F. Mazlee
Suhaila M. Yaman
Nurul Syazwani Nadirah Binti Muhammad Syafiq Chandran
Mohd Zulfadli Bin Makhtar
Dhramveer Singh Shekhawat
Sunil Vasudeorao Lanke
Ramesh Kumar
Sandeep Mhetre

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).

Keywords
Afatinib Dimaleate, HPLC, degradation impurities, NMR, LC-MS, new process impurity, improved process

Article Details

How to Cite
kumar, P., Dhande, P., Mazlee, M., Yaman, S. M., Chandran, N., Makhtar, M., Shekhawat, D., Lanke, S., Kumar, R., & Mhetre, S. (2019). A controlled, efficient and robust process for the synthesis of an epidermal growth factor receptor inhibitor: Afatinib Dimaleate. Chemical Reports, 1(1), 3-12. https://doi.org/10.25082/CR.2019.01.001

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