Process for the preparation of afatinib.
Publication Date: 2015-Sep-30
The IP.com Prior Art Database
The present disclosure relates to a process for the preparation of afatinib or its pharmaceutically acceptable salts that employs novel intermediates
The present disclosure relates to a process for the preparation of afatinib or its pharmaceutically acceptable salts that employs novel intermediates.
Afatinib dimaleate is an orally administered irreversible inhibitor of both the epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinases. Afatinib dimaleate is used to treat patients with several solid tumors including non-small cell lung cancer (NSCLC), breast, head and neck cancer, and a variety of other cancers.
GILOTRIF® tablets contain afatinib, a tyrosine kinase inhibitor which is a 4-anilinoquinazoline. Afatinib is presented as the dimaleate salt, with the chemical name 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]7-[[(3S)-tetrahydro-3-furanyl] -oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2E)-, (2Z)-2-butenedioate (1:2). Its structural formula is:
The present disclosure is to provide a process for the preparation of afatinib or its pharmaceutically acceptable salts, which is as shown in scheme-I.
Preparation of 7-Chloro-4-(3-chloro-4-Fluoro phenyl amino)-6-Nitro quinazoline (4):
5.0g of 7-Chloro-4-Hydroxy-6-Nitro-Quinazoline, Acetonitrile (20ml), POCl3 (5.0ml) to this added TEA (7.5ml) and heated to 70-800C for 3hrs then added 3-Cloro-4-Fluoro aniline (3.39g) solution in 15ml acetonitrile. Maintained for 1hr and volatile parts were recovered by distillation to that added toluene 35ml cooled to 100C and added sodium hydroxide solution in water 7.9g in 50ml followed by water 20ml. Product filtered and washed with water 50m...