Diisopropylethylamine → 7-[4-(1H-imidazol-2-yl)phenyl]-4-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepine

HRID 473855Notes

Reaction equation

HRID 473855 reaction equation
CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([N:21]4[CH2:26][CH2:25][CH:24]([C:27]([F:30])([F:29])[F:28])[CH2:23][CH2:22]4)=[O:20])[CH2:14][C:13]=3[CH:31]=2)O1.Br[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41](C(OCC(C)C)=O)[CH:42]=[CH:43][N:44]=2)=[CH:36][CH:35]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.O>[NH:41]1[CH:42]=[CH:43][N:44]=[C:40]1[C:37]1[CH:38]=[CH:39][C:34]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([N:21]4[CH2:22][CH2:23][CH:24]([C:27]([F:28])([F:30])[F:29])[CH2:25][CH2:26]4)=[O:20])[CH2:14][C:13]=3[CH:31]=2)=[CH:35][CH:36]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 66820246isobutyl 2-(4-bromophenyl)-1H-imidazole-1-carboxylateHCID 675139857-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-4-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepine

Product 1

HCID 497871697-[4-(1H-imidazol-2-yl)phenyl]-4-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepineYield 14%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepine (0.4 g, 0.88 mmol) and isobutyl 2-(4-bromophenyl)-1H-imidazole-1-carboxylate (0.6 g, 1.86 mmol) in dioxane (4 mL) and water (0.5 ml) was added diisopropylethylamine (0.34 g, 2.64 mmol). The solution was sparged with N2(g) for ten minutes before the addition of dichloro[1,1-bis-(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (0.072 g, 10 mol %). The resulting suspension was heated at 120° C. for 2 hours in a sealed tube on a CEM Explorer microwave synthesizer. On cooling to room temperature the mixture was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate (70 mL), brine (50 mL) then dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel chromatography (97:3 dichloromethane/methanol) then preparative reverse phase HPLC of the combined product containing fractions (0.1% aqueous ammonium acetate-acetonitrile) to afford 7-[4-(1H-imidazol-2-yl)phenyl]-4-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepine (0.058 g, 12% yield) as a white solid. 1H NMR (400 MHz, methanol-d4): 7.92 (d, 2H), 7.70 (d, 2H), 7.58-7.50 (m, 2H), 7.15 (s, 2H), 7.05 (d, 1H), 4.52 (s, 2H), 4.22 (t, 2H), 3.77 (d, 2H), 3.71 (t, 2H), 2.87 (t, 2H), 2.39 (m, 1H), 1.86 (d, 2H), 1.59 (m, 2H); MS (EI) for C25H25F3N4O2: 471 (MH+).

Workup

  1. customThe solution was sparged with N2(g) for ten minutes before the addition of dichloro[1,1-bis-(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (0.072 g, 10 mol %)
  2. temperatureOn cooling to room temperature the mixture
  3. additionwas diluted with ethyl acetate (100 mL)
  4. washwashed with saturated sodium bicarbonate (70 mL), brine (50 mL)
  5. dry with materialthen dried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe resulting residue was purified by silica gel chromatography (97:3 dichloromethane/methanol)
  9. additionpreparative reverse phase HPLC of the combined product containing fractions (0.1% aqueous ammonium acetate-acetonitrile)

Sources & evidence

ORD record
ord-b34f78b41bfb49a9b0c53ea77d43d2f1
Source dataset
uspto-grants-2014_01
Patent number
US08637499B2

Reaction notes

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