Erlotinib Hydrochloride → Oxalyl chloride

Participants

Reaction Steps

As per the process described in U.S. Pat. No. 5,747,498 (hereinafter “the '498 patent”), erlotinib hydrochloride can be prepared by the reaction of 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline, obtained by reaction of 6,7-bis(2-methoxy-ethoxy)-quinazolone with oxalylchloride in a solvent system containing chloroform and dimethylformamide, with 3-ethynylaniline or its hydrochloride salt in a solvent such as a (C1-C6)-alcohol, dimethylformamide, N-methylpyrrolidin-2-one, chloroform, acetonitrile, tetrahydrofuran, 1,4-dioxane, pyridine or another aprotic solvent, preferably isopropyl alcohol; in the presence or absence of a base, preferably an alkali or alkaline earth metal carbonate or hydroxide or a tertiary amine base, such as pyridine, 2,6-lutidine, collidine, N-methyl-morpholine, triethylamine, 4-dimethylamino-pyridine or N,N-dimethylaniline; at a temperature from about ambient to about the reflux temperature of the solvent, preferably from about 35° C. to about reflux; under an inert atmosphere such as dry nitrogen. The crude erlotinib hydrochloride (residue) obtained is then basified with saturated aqueous NaHCO3 in the presence of methanol and chloroform followed by flash chromatography on silica using 30% acetone in hexane to afford erlotinib free base, which is further treated with hydrochloric acid in the presence of diethyl ether and chloroform to give erlotinib hydrochloride.

Provenance & Evidence