Water → N-ethyl-6-{4-[2-methyl-7-(methyloxy)quinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1H-benzimidazol-2-amine

HRID 241181Notes

Reaction equation

HRID 241181 reaction equation
Cl.Cl.[CH2:3]([NH:5][C:6]1[NH:10][C:9]2[CH:11]=[CH:12][C:13]([C:15]3[CH:16]=[CH:17][C:18]4[O:24][CH2:23][CH2:22][NH:21][CH2:20][C:19]=4[CH:25]=3)=[CH:14][C:8]=2[N:7]=1)[CH3:4].Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=2)[N:30]=[C:29]([CH3:39])[N:28]=1.C(N(C(C)C)CC)(C)C.O>CN1C(=O)CCC1>[CH2:3]([NH:5][C:6]1[NH:7][C:8]2[CH:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]4[O:24][CH2:23][CH2:22][N:21]([C:27]5[C:36]6[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=6)[N:30]=[C:29]([CH3:39])[N:28]=5)[CH2:20][C:19]=4[CH:25]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH3:4]

Participants

6

Reactant 4

HCID 962WaterHCID 81531DiisopropylethylamineHCID 722070634-Chloro-7-methoxy-2-methylquinazolineHCID 178463378HCID 178463378, compound

Product 1

HCID 59586403N-ethyl-6-{4-[2-methyl-7-(methyloxy)quinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1H-benzimidazol-2-amine

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
90 °C

Procedure

To a mixture of N-ethyl-5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-amine dihydrochloride (50 mg, 0.13 mmol) and 4-chloro-7-methoxy-2-methylquinazoline (27 mg, 0.13 mmol) in NMP (1 mL) was added diisopropylethylamine (91 uL, 0.52 mmol). The mixture was heated to 90° C. and stirred for 1 h. After cooling to rt, water was added, and the resulting aqueous mixture was extracted twice with 10% methanol in ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered, and then concentrated. The residue was purified by reverse-phase preparative HPLC to provide N-ethyl-6-{4-[2-methyl-7-(methyloxy)quinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1H-benzimidazol-2-amine as an acetate salt (34.2 mg, 0.063 mmol, 49% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.91 (br s, 1H), 10.83 (br s, 1H), 7.92 (d, 1H), 7.58 (d, 1H), 7.43 (dd, 1H), 7.35 (s, 1H), 7.20-7.10 (m, 3H), 7.05-6.97 (m, 2H), 6.61 (br s, 1H), 4.99 (s, 2H), 4.44-4.38 (m, 2H), 4.18-4.11 (m, 2H), 3.33-3.25 (m, 2H), 2.44 (s, 3H), 1.91 (s, 4H), 1.19 (t, 3H); MS (EI) for C28H28N6O2: 481 (MH+).

Workup

  1. temperatureAfter cooling to rt
  2. extractionthe resulting aqueous mixture was extracted twice with 10% methanol in ethyl acetate
  3. dry with materialdried over magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue was purified by reverse-phase preparative HPLC

Sources & evidence

ORD record
ord-56a73412365641879699665fdc09c440
Source dataset
uspto-grants-2014_02
Patent number
US08648066B2

Reaction notes

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