反应详情

To a solution of N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methyl-4-piperidinyl)methoxy]-4-quinazolinamine (ZD6474; Hennequin et al, J Med Chem, 2002, 45, 1300-1312) (250 mg, 0.53 mmol) in NMP (1 mL) was added 5-(bromomethyl)-1-methyl-4-nitro-1H-imidazole (105) (139 mg, 0.63 mmol) according to general procedure C, except the reaction was stirred for 48 hours and EtOAc was used instead of MeCN in the work-up to give 4-({[4-(4-bromo-2-fluoroanilino)-6-methoxy-7-quinazolinyl]oxy}methyl)-1-methyl-1-[(1-methyl-4-nitro-1H-imidazol-5-yl)methyl]piperidinium bromide (392 mg), which was further purified by preparative HPLC eluting with CH3CN/H2O/TFA to give 4-({[4-(4-bromo-2-fluoroanilino)-6-methoxy-7-quinazolinyl]oxy}methyl)-1-methyl-1-[(1-methyl-4-nitro-1H-imidazol-5-yl)methyl]piperidinium trifluoroacetate (146) (246 mg, 64%) as a mixture of trans/cis isomers in a ratio of ˜2:5 by 1H NMR, hereafter named as A for the minor isomer and B for the major isomer, m.p. 185-188° C. (dec.). 1H NMR [(CD3)2SO] δ 10.42 (br, 1H), 8.60 (s, 1H), 8.114 & 8.110 (s×2, A & B isomers, 1H), 7.74-7.71 (m, 1H), 7.56-7.53 (m, 1H), 7.34 & 7.27 (s×2, A & B isomers, 1H), 5.07 (br, 2H), 4.29 & 4.14 (d×2, A & B isomers, J=6.6 Hz, 2H), 3.99 & 3.97 (s×2, A & B isomers, 3H), 3.88 (s, 3H), 3.75-3.60 (m, 4H), 3.15 & 3.01 (s×2, A & B isomers, 3H), 2.33-1.82 (m, 5H).