反应详情

PCT Patent Publication No. WO 2007/060691 A2 describes an improved process for the preparation of erlotinib hydrochloride, which comprises: i) reacting 6,7-dimethoxy-4-(3H)-quinazolinone with aqueous hydrobromic acid or pyridine hydrochloride at an elevated temperature to get a hydrobromide or hydrochloride salt of 6,7-dihydroxy-4-(3H)-quinazolinone which on neutralization with a base gives 6,7-dihydroxy-4-(3H)-quinazolinone; ii) acylating the dihydroxy compound using an acylating agent at a temperature in the range of 20-150° C. and in the presence of a catalyst to give 6,7-diacetoxy-4-(3H)-quinazolinone; iii) reacting the diacetoxy compound with oxalyl chloride at a temperature of 10-100° C. to give 4-chloro-6,7-diacetoxy-quinazoline; iv) condensing the reaction mass containing the chloro compound with 3-ethynylaniline in an organic solvent selected from chloroform, methylene chloride, acetonitrile, isopropyl alcohol, toluene, tetrahydrofuran, dioxane, cyclohexane and dimethylformamide, at a temperature of 10-100° C. to give N-(3-ethynylphenyl)-6,7-diacetoxy-4-quinazolinamine hydrochloride which on further treatment with a base such as aqueous sodium or potassium hydroxide, or aqueous ammonia solution in alcohols at a temperature of 20-60° C. gives N-(3-ethynylphenyl)-6,7-hydroxy-4-quinazolinamine; v) reacting the N-(3-ethynylphenyl)-6,7-hydroxy-4-quinazolinamine with 2-halo-ethylmethyl ether in the presence of a base at a temperature of 25-100° C. to give crude erlotinib base; vi) recrystallizing the crude erlotinib base from different solvents like ethyl acetate, acetonitrile, isopropyl alcohol, methanol, ethanol, acetone, methyl ethyl ketone, water or a mixture thereof to give pure erlotinib base; vii) reacting pure erlotinib base by dissolving or suspending in an organic solvent or water or a mixture thereof with aqueous hydrochloric acid or hydrogen chloride gas dissolved in an organic solvent selected from chloroform, toluene, ethanol, methanol, isopropyl alcohol, acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, dimethylformamide, dimethyl ether, diethyl ether and tetrahydrofuran to give erlotinib hydrochloride.