Toluene → methyl 6-chloro-5-[3-fluoro-4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylate

HRID 1054668노트

반응식

HRID 1054668 반응식
[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]2([OH:34])[CH2:33][CH2:32][CH2:31]2)=[C:26]([F:35])[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30]2([OH:34])[CH2:31][CH2:32][CH2:33]2)=[C:26]([F:35])[CH:25]=1

참가 물질

8

반응물 4

HCID 1140TolueneHCID 11430Potassium CarbonateHCID 687191711-(4-Bromo-2-fluorophenyl)cyclobutanolHCID 86698665methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate

생성물 1

HCID 86698672methyl 6-chloro-5-[3-fluoro-4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylate수율 57%

시약·촉매·용매 3

HCID 178418807HCID 178418807, 화합물촉매HCID 702Ethanol용매HCID 8857Ethyl Acetate용매

실험 절차

A mixture of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (75 mg, 0.23 mmol), 1-(4-bromo-2-fluorophenyl)cyclobutanol (57 mg, 0.23 mmol), 4 M aqueous potassium carbonate (0.47 mL, 0.9 mmol), toluene (3 mL), and ethanol (1 mL) was sparged with nitrogen for 10 minutes, then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (9 mg, 0.011 mmol). The reaction mixture was placed in a pre-heated oil bath at 105° C. and stirred for 2 hours. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water and saturated brine (lx each), dried over magnesium sulfate, filtered and concentrated in vacuo to afford a brown semi-solid, which was purified by flash chromatography (12 g silica, 10-50% ethyl acetate/heptane, 21 column volumes). The product fractions were combined and concentrated in vacuo to afford the title compound as a colorless solid (49 mg, 56% yield). MS (ES−) 372.2 (M−H)−. 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1 H), 8.10 (s, 1 H), 7.94 (d, J=2.93 Hz, 1 H), 7.54 (s, 1 H), 7.38-7.44 (m, 1 H), 7.18-7.28 (m, 2 H), 3.89 (s, 3 H), 2.66-2.77 (m, 2 H), 2.42 (m, 2 H), 2.11-2.22 (m, 1 H), 1.74-1.86 (m, 1 H).

후처리

  1. customwas sparged with nitrogen for 10 minutes
  2. customThe reaction mixture was placed in a pre-heated oil bath at 105° C.
  3. washwashed with water and saturated brine (lx each),
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customto afford a brown semi-solid, which
  8. customwas purified by flash chromatography (12 g silica, 10-50% ethyl acetate/heptane, 21 column volumes)
  9. concentrationconcentrated in vacuo

출처 및 근거

ORD 기록
ord-aa6fae4e18cf43349665e30a5d4250e8
출처 데이터셋
uspto-grants-2016_07
특허 번호
US09394285B2

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