反应详情

N-(3-Chloro-2-fluorophenyl)-6-(chloromethyl)-7-methoxyquinazolin-4-amine (360 mg, 0.93 mmol, prepared as described in Example 62) was added portionwise over 2 hours to a solution of tert-butyl 3-(aminocarbonyl)-3-(ethylamino)azetidine-1-carboxylate (294 mg, 1.21 mmol) and diisopropylethylamine (0.5 ml, 2.79 mmol) in DMF (1 ml) at 120° C. The resulting product was purified on preparative HPLC (standard basic conditions) to give tert-butyl 3-(aminocarbonyl)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(ethyl)amino]azetidine-1-carboxylate as a solid (100 mg, 19%); Mass Spectrum: (M+H)+ 559. This was dissolved in 1,4-dioxan (3 ml) and a solution of concentrated hydrochloric acid (5 ml) in 1,4-dioxan (25 ml) was added dropwise. The reaction mixture was stirred overnight and concentrated under reduced pressure. The residues were triturated with a mixture of methanol/dichloromethane/diethylether to give a hydrochloride salt of 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(ethyl)amino]azetidine-3-carboxamide as a solid (89 mg, 100%); 1H NMR Spectrum: (CDCl3) 1.16 (t, 3H), 2.59 (q, 2H), 3.41 (d, 2H), 3.76 (d, 2H), 3.89 (s, 2H), 3.98 (s, 3H), 5.47 (brs, 1H), 7.15 (m, 2H), 7.24 (s, 1H), 7.77 (s, 1H), 7.90 (s, 1H), 8.44 (m, 1H), 8.72 (s, 1H); Mass Spectrum: (M+H)+ 459.

1. customThe resulting product was purified on preparative HPLC (standard basic conditions)