A new method for synthesis of N-\[3-chloro-4-(3-fluorophenzyloxy)phenyl\]-6-iodoquinazolin-4-amine
JIA Yu-cai, LU Jun-jin, ZHENG Yan-jun, LI Bao-lin*
(Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, College of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi′an 710062, Shaanxi, China)
Abstract:
N-\[3-chloro-4-(3-fluorophenzyloxy)phenyl\]-6-iodoquinazolin-4-amine, a necessary intermediate of antitumor durg lapatinib, was synthesized from o-nitrobenzaldehyde as a cheap starting material through cyanogenation, reduction, iodination, formamidine formation and Dimroth rearrangement with an overall yield of 52.2%. There are two improvements in the process including the iodination of 2-aminobenzonitrile using NH4I-H2O2 system, and the direct preparation of N′-(2-cyano-4-iodio-phenyl)-N,N-dimethylforamidine through the reaction between 2-amino-4-iodobenzonitrile and imine salt generated from dimethyl sulfate and N,N-dimethylformamide. The protocol exhibits obvious advantages such as low cost, high efficiency and low environmental impact.
KeyWords:
lapatinib intermediate; NH4I-H2O2; formamidine; Dimroth rearrangement; quinazoline derivative
