Clinical Use
Icotinib hydrochloride, developed by the Chinese pharmaceutical
company Zhejiang Bata Pharma Inc., is a potent small molecule
epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor
for the treatment of non-small cell lung cancer (NSCLC). It was first
approved by the SFDA of China, and launched under the brand
name Conmana in the middle of 2011, representing an important
milestone for Chinese pharmaceutical research and development.
As the third EGFR-TKI drug targeting NSCLS therapy, icotinib
hydrochloride possesses a similar structure to gefitinib (Iressa,
AstraZeneca) and erlotinib (Tarceva, OST & Roche). Interestingly,
a randomized, double-blind phase III clinical study of icotinib
versus gefitinib in 399 patients with advanced NSCLC demonstrated
that icotinib provides similar efficacy to gefitinib, but with
better tolerability in NSCLC patients previously treated with one or
two chemotherapy agents.
Synthesis
Icotinib was prepared by a similar process approach to that of
erlotinib. Beginning from commercially available
2,20-(ethylenedioxy)diethanol (162), bis-tosylation to 163, followed
by bis-alkylation with commercially available catechol
derivative 164 provided crown-4-ether 165 in 96% yield. Nitration
of polyether 165 using concentrated nitric acid and concentrated
sulfuric acid provided nitroarene 166 in 65% yield. Reduction of the nitroarene under catalytic hydrogenation conditions gave
amine 167 in 85% yield. Condensation of the amine 167 with formamide
in the presence of ammonium formate afforded quinazolinone
168 in 80% yield. The chlorination of 168 using POCl3
furnished quinazolyl chloride 169 in 77% yield. The treatment of
chloride 169 with amine 170 followed by the HCl salt formation
produced icotinib hydrochloride (XIV) in good yield.
