Formaldehyde → 4-(3-Chloro-2-fluoroanilino)-6-[(2S,4S)-2-(N,N-dimethylcarbamoyl)-1-methylpyrrolidin-4-yloxy]-7-methoxyquinazoline

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Reaction Steps

4-(3-chloro-2-fluoroanilino)-6-[(2S,4S)-1-(tert-butoxycarbonyl)-2-(N,N-dimethylcarbamoyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline (prepared as described in Example 24; 0.18 g), formic acid (0.31 ml) and formaldehyde (0.51 ml) were heated at 85° C. for 6 hours. The reaction mixture was cooled and evaporated under vacuum. The resulting residue was partitioned between methylene chloride/n-propanol and saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, adsorbed onto silica and purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10). The fractions containing the desired product were combined and evaporated under vacuum to yield a white crystalline solid. The solid was washed with water, dissolved in methylene chloride and dried over magnesium sulfate. The solvent was removed under vacuum to give the title product (0.11 g); 1H NMR Spectrum: (DMSO d6) 1.87 (t, 1H), 2.24 (s, 3H), 2.61-2.68 (m, 1H), 2.83 (s, 3H), 2.85-2.94 (m, 1H), 3.10 (s, 3H), 3.22-3.31 (m, 2H), 3.92 (s, 3H), 5.04 (m, 1H), 7.22 (s, 1H), 7.29 (t, 1H), 7.45-7.56 (m, 2H), 7.64 (s, 1H), 8.35 (s, 1H), 9.56 (s, 1H); Mass Spectrum: (M+H)+ 474.

Provenance & Evidence