A controlled, efficient and robust process for the synthesis of an epidermal growth factor receptor inhibitor: Afatinib Dimaleate

• 作者: Dhramveer Singh Shekhawat Mohd Zulfadli Bin Makhtar Muhammad Taufiq F. Mazlee Nurul Syazwani Nadirah Binti Muhammad Syafiq Chandran Pawan Kumar Premnath Dhande Ramesh Kumar Sandeep Mhetre Suhaila M. Yaman Sunil Vasudeorao Lanke
• 来源期刊: 化学报告(英文)
• 学科: 地球科学
• 关键词: AFATINIB Dimaleate HPLC degradation IMPURITIES NMR LC-MS new PROCESS IMPURITY improved PROCESS
• 年，卷（期）: 2019,（1）
• 页码范围: 3-12
• 页数: 10页
• 分类号: X

摘要

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 300 g 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 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).