Diisopropylethylamine → 4-(3-Chloro-2-fluoroanilino)-6-{[(2S)-1-(3,4-methylenedioxypyrrolidin-1-ylacetyl)pyrrolidin-2-yl]methoxy}-7-methoxyquinazoline

Participants

Reaction Steps

3,4-methylenedioxypyrrolidine hydrochloride (87 mg) was added to a stirred solution of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl)pyrrolidin-2-yl]methoxy}quinazoline (0.25 g; prepared as described in Example 43) and diisopropylethylamine (0.2 ml) in acetonitrile (10 ml) and the mixture heated at reflux for 2 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/isopropanol/triethylamine (97/2/1) to (95/4/1). The fractions containing the expected product were evaporated under vacuum to give the title product as a yellow solid (0.203 g; 70%); 1H NMR Spectrum: (CDCl3) 1.92-222 (m, 4H), 2.54-2.61 (m, 2H), 3.05-3.15 (m, 2H), 3.26-3.38 (q, 2H), 3.42-3.47 (m, 1H), 3.58-3.65 (m, 1H), 4.00-4.10 (m, 4H), 4.47-4.55 (m, 3H), 4.65-4.72 (m, 1H), 4.84 (s, 1H), 5.02 (s, 1H), 7.11-7.22 (m, 2H), 7.24 (s, 1H), 7.96-8.02 (m, 1H), 8.38 (s, 1H), 8.61 (s, 1H), 8.63 (s, 1H); Mass Spectrum: (M+H)+ 558.

Provenance & Evidence