Diisopropylethylamine → 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{1-[(2S)-1-methylpyrrolidin-2-ylcarbonyl]piperidin-3-yloxy}quinazoline

Participants

Reaction Steps

HATU (0.26 g) was added to a solution of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline dihydrochloride (250 mg; prepared as described in Example 45), diisopropylethylamine (210 μl) and N-methyl-L-proline (0.120 g) in DMF (7.5 ml) and the mixture was stirred at room temperature for 2.5 hours. The DMF was removed under reduced pressure and the residue dissolved in methylene chloride (50 ml) and washed with sodium bicarbonate (50 ml) then water (50 ml). Purification by flash column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (9614). The fractions containing the expected product were evaporated to give a foam. This foam was dissolved in methylene chloride (5 ml) and crystallised by the addition of isohexane (50 ml) to give the title product as a mixture of two diastereoisomers (0.130 g). 1H NMR Spectrum: (DMSO d6) 1.43-1.62 (m, 2H), 1.66-1.95 (m, 4H), 1.96-2.18 (m, 4H), 2.20-2.29 (m, 2H), 2.67-2.80 (m, 1H), 2.96 (m, 1H), 3.03-3.20 (m, 1H), 3.51-3.80 (m, 2H), 3.80-4.05 (m, 4H), 4.51-4.68 (m, 1H), 7.22-7.31 (2H), 7.47-7.59 (m, 2H), 7.89 (m, 1H), 8.39 (s, 1H), 9.55 (m, 1H); Mass Spectrum: (M+H)+ 514.

Provenance & Evidence