Chloroacetyl chloride → 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[1-(3,3-difluoropyrrolidin-1-ylacetyl)piperidin-3-yloxy]quinazoline

Participants

Reaction Steps

Chloroacetyl chloride (47 μl) was added to a solution of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline dihydrochloride (250 mg) and diisopropylethylamine (373 μl) in methylene chloride (10 ml) and the mixture was stirred at room temperature for 1 hour. 3,3-Difluoropyrrolidine hydrochloride (Synthetic Letters, 1995, 1, 55-57; 328 mg) was added, and the solution stirred for 1 hour before being washed with saturated aqueous sodium bicarbonate (10 ml) and purified by flash column chromatography eluting with increasingly polar mixtures of methylene chloride methanol (100/0 to 9515) to give a foam. This was dissolved in methylene chloride (5 ml) and crystallised by the addition of isohexane (50 ml) to give the title product (102 mg). NMR Spectrum (DMSO d6) 1.45-1.57 (m, 1H), 1.73-1.95 (m, 2H), 1.98-2.18 (m, 2H), 2.18-2.33 (m, 1H), 2.63-2.75 (m, 1H), 2.77-2.85 (m, 1H), 2.85-2.99 (m, 1H), 3.04-3.19 (m, 1H), 3.21-3.29 (m, 1H), 3.37-3.50 (m, 2H), 3.52-3.70 (m, 2H), 3.77-3.99 (m, 4H), 4.63 (m, 1H), 7.21-7.29 (m, 2H), 7.47-7.57 (m, 2H), 7.87 (d, 1H), 8.39 (s, 1H), 9.55 (d, 1H); Mass Spectrum: (M+H)+ 550.

Provenance & Evidence