SYNTHESIS OF QUINAZOLINE DERIVATIVES AS GEFITINIB INTERMEDIATES

• Main Author: Auliya Hafizah, Raysa
• Format: Final Project
• Language: Indonesia
• Subjects: Kimia
• Online Access: https://digilib.itb.ac.id/gdl/view/81485
• Institution: Institut Teknologi Bandung

Cancer appears to be the second cause of death in the worldwide. Lung cancer is the second most common cancer variety with the highest death rate. Lung cancer is a disease caused by gene mutations in the Epidermal Growth Factor Receptor (EGFR) signalling pathway which causes excessive phosphorylation. One of the medications used for lung cancer is gefitinib. Gefitinib is a molecule that has an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor activity. In the previous study, the most important step in the synthesis of gefitinib was the demethylation process of the methoxy group at position 6 of 6,7-dimethoxy-3,4-dihydroquinazolin-4-one (1) using L-methionine and methanesulfonic acid to produce 6-hydroxy-7- methoxy-3,4-dihydroquinazoline-4-one (2), with a yield of 46%. Therefore, this study aims to optimize the demethylation process of 6-hydroxy-7- methoxy-3,4-dihydroquinazolin-4-one (2) by varying the temperature and equivalent, then the optimization results ware reacted with 4-(3-chloro-4-fluorophenylamino)-6,7-dimethoxy quinazoline (3) to produce 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxy quinazoline (4). Subsequently, the Williamson ether reaction was carried out to produce the intermediates N-(3- chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazoline-4-amine (5) and 6-(4- bromobutoxy)-N-(3 -chloro-4-fluorophenyl)-7-methoxyquinazoline-4-amine (6). In this study, compound (2) was successfully synthesized with optimum reaction conditions at a temperature 120°C and equivalent ratio of precursor and L-methionine of 1:1,5 for 1 hour reaction with a HPLC yield of 74,4%, compound (4) with a yield of 49% , compound (5) with a yield of 31%, and compound (6) with a yield of 3.5%. The synthesized product was characterized by NMR spectroscopy (1H and 13C) and mass spectrometry