Ethyl Acetate → 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

HRID 1520733Notes

Reaction equation

HRID 1520733 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:30])[CH:3]=1.BrC[C:33]1[N:34]([CH3:41])[CH:35]=[C:36]([N+:38]([O-:40])=[O:39])[N:37]=1.[CH3:42]COC(C)=O>CN1C(=O)CCC1>[Br-:1].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][N+:26]([CH3:42])([CH2:29][C:35]5[N:34]([CH3:41])[CH:33]=[N:37][C:36]=5[N+:38]([O-:40])=[O:39])[CH2:25][CH2:24]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:30])[CH:3]=1

Participants

5

Reactant 3

HCID 8857Ethyl AcetateHCID 3081361VandetanibHCID 668237632-(bromomethyl)-1-methyl-4-nitro-1H-imidazole

Product 1

HCID 866636034-({[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

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

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).

Sources & evidence

ORD record
ord-b184a413e0cb4b8db624cbf34a0160df
Source dataset
uspto-grants-2015_07
Patent number
US09073916B2

Reaction notes

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