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 473881Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 473881
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

Komponenten

8

Edukt 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

Produkt 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)-carboxylateAusbeute 75,2 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 962WaterLösungsmittelHCID 8857Ethyl AcetateLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
85 °C

Versuchsvorschrift

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+).

Aufarbeitung

  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)

Quellen und Nachweise

ORD-Eintrag
ord-edee7bf5a2da4fe091b14884f9b560a0
Quelldatensatz
uspto-grants-2014_01
Patentnummer
US08637499B2

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