Formaldehyde → HCID 58318671, compound

Participants

Reaction Steps

Methyl (2S,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxylate (13) (0.35 g, 0.76 mmol) was dissolved in a solution of 15% Acetic acid/methylene chloride (6.1 ml). To this was then added powdered 4A° molecular sieves (0.63 g) and the resulting suspension stirred for 5 minutes. 37% formaldehyde in water (0.56 ml) was added drop-wise and the mixture stirred a further 2 minutes. Sodium triacetoxyborohydride (0.29 g) was added in one portion. The reaction mixture was stirred a further 2 hours at room temperature, filtered and evaporated. The residues were partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The combined organics were washed with brine, dried over MgSO4, filtered and evaporated. The crudes were purified by column chromatography on SiO2 eluting with increasingly polar mixtures of DCM/methanol (100/0-95/5). The fractions containing the desired product were combined and evaporated to give methyl (2S,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-1-methylpiperidine-2-carboxylate (14) as a foam (252 mg, 70%): 1H NMR Spectrum: (DMSO-d6) δ1.72-1.78 (2H, m), 2.05-2.35 (6H, m), 2.95-3.04 (2H, m), 3.63 (3H, s), 3.94 (3H, s), 4.51-4.59 (1H, m), 7.23 (1H, s), 7.29-7.31 (1H, m), 7.49-7.56 (2H, m), 7.84 (1H, s), 8.39 (1H, s), 9.55 (1H, s); Mass Spectrum: (M+H)+ 475.

Provenance & Evidence