Isobutyl chloroformate → 1,1-dimethylethyl 7-(2-[(2-fluoroethyl)amino]-1-{[(2-methylpropyl)oxy]carbonyl}-1H-benzimidazol-5-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate

HRID 473881Notes

Reaction equation

HRID 473881 reaction equation
Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]([C:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])[C:7]([NH:9][CH2:10][CH2:11][F:12])=[N:8][C:4]=2[CH:3]=1.[CH3:22][C:23]([O:26][C:27]([N:29]1[CH2:35][C:34]2[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:33]=2[O:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C.ClC(OCC(C)C)=O>C(OCC)(=O)C.O.O1CCOCC1>[F:12][CH2:11][CH2:10][NH:9][C:7]1[N:6]([C:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])[C:5]2[CH:20]=[CH:21][C:2]([C:37]3[CH:38]=[CH:39][C:33]4[O:32][CH2:31][CH2:30][N:29]([C:27]([O:26][C:23]([CH3:24])([CH3:22])[CH3:25])=[O:28])[CH2:35][C:34]=4[CH:36]=3)=[CH:3][C:4]=2[N:8]=1

Participants

8

Reactant 4

HCID 62365Isobutyl chloroformateHCID 81531Diisopropylethylamine2×HCID 59604707(4-(Tert-butoxycarbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)boronic acidHCID 86647855Isobutyl 5-bromo-2-(2-fluoroethylamino)-1H-benzo[d]imidazole-1-carboxylate

Product 1

HCID 866720291,1-dimethylethyl 7-(2-[(2-fluoroethyl)amino]-1-{[(2-methylpropyl)oxy]carbonyl}-1H-benzimidazol-5-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylateYield 75.2%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
85 °C

Procedure

Isobutyl 5-bromo-2-(2-fluoroethylamino)-1H-benzo[d]imidazole-1-carboxylate (55 mg, 0.15 mmol) and (4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (example 1, step 2) (50 mg, 0.17 mmol) were taken into dioxane (1 mL) and water (0.2 mL) followed by addition of dichloro[1,1-bis-(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (8.5 mg) and DIPEA (0.11 mL, 0.6 mmol) and the mixture was heated to 85° C. for 12 h. The mixture was then cooled and diluted with ethyl acetate then dried over anhydrous sodium sulfate and filtered through a plug of silica gel with an ethyl acetate wash. The organic solution was then concentrated to an oil. The residue was taken into THF (2 mL) followed by sequential addition of DIPEA (0.05 mL, 0.29 mmol) and isobutyl chloroformate (0.01 mL, 0.08 mmol) then the mixture was stirred for 30 minutes. The mixture was concentrated and the residue purified by silica gel chromatography (1.5:1 hexanes:ethyl acetate) to give 1,1-dimethylethyl 7-(2-[(2-fluoroethyl)amino]-1-{[(2-methylpropyl)oxy]carbonyl}-1H-benzimidazol-5-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (59.4 mg, 75% yield) as a colorless amorphous residue. MS (EI) for C28H35FN4O5: 528 (MH+).

Workup

  1. temperatureThe mixture was then cooled
  2. dry with materialthen dried over anhydrous sodium sulfate
  3. filtrationfiltered through a plug of silica gel with an ethyl acetate
  4. washwash
  5. concentrationThe organic solution was then concentrated to an oil
  6. concentrationThe mixture was concentrated
  7. customthe residue purified by silica gel chromatography (1.5:1 hexanes:ethyl acetate)

Sources & evidence

ORD record
ord-edee7bf5a2da4fe091b14884f9b560a0
Source dataset
uspto-grants-2014_01
Patent number
US08637499B2

Reaction notes

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