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 473881노트

반응식

HRID 473881 반응식
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

참가 물질

8

반응물 4

HCID 62365Isobutyl chloroformateHCID 81531Diisopropylethylamine2회HCID 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

생성물 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)-carboxylate수율 75.2%

시약·촉매·용매 3

HCID 962Water용매HCID 8857Ethyl Acetate용매HCID 312751,4-Dioxane용매

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온도
85 °C

실험 절차

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+).

후처리

  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)

출처 및 근거

ORD 기록
ord-edee7bf5a2da4fe091b14884f9b560a0
출처 데이터셋
uspto-grants-2014_01
특허 번호
US08637499B2

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