Processes and intermediates for preparing anti-cancer quinazoline compounds

摘要

A method of preparing a compound of formula 1 comprising: (a) treating a compound of formula 5 with thionyl chloride in anhydrous dichloromethane to forma compound of formula 3; (b) reacting a compound of formula 3 with a compound of formula 4 to form a compound of formula 2; and (c) treating a compound of formula 2 with either an alkali-metal or alkaline-metal hydroxide in a solvent comprising hydroxy-substituted alkyl or a tetra-alkylammonium fluoride compound in an aprotic solvent. A method for preparing a compound of formulae 6 or 7 comprising: (a) treating a compound of formula 8 with a primary or secondary alcohol of the formula R7-OH in the presence of an alkali-metal or alkaline-metal hydroxide to form a compound of formula 7; or (b) treating a compound of formula 8 with a secondary alcohol of the formula R7-OH in the presence of an alkali-metal or alkaline-metal hydroxide to form a compound of formula 6. In formulae 1-8: R1 and R2 are each independently selected from alkyl and alkoxy which are optionally substituted by up to two substituents independently selected from hydroxy and alkoxy; R15 is hydrogen, alkyl or -(CH2)q-aryl wherein q is an integer from 0-4; G is blocking group -C(OH)R3R4 or -SiR3R4R5; G is blocking group -C(OH)R3R4; R3, R4 and R5 are each independently alkyl; R6 is alkyl or -(CH2)mO(CH2)nCH3; each m is independently an integer from 1-6 and each n is an integer from 0-3; and R7 is -alkyl or -alkylaryl optionally substituted with 1-3 substituents independently selected from halo, nitro, trifluoromethoxy, sulfonyl, alkyl, alkoxy, aryloxy and arylsulfonyl.