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3-Bromopyridine → N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-6-(pyridin-3-yloxy)-1H-indole-3-carboxamide

HRID 40168
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HRID 40168 반응식
[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:10]=1[CH:26]([CH3:28])[CH3:27])=[O:8].[OH-].[K+].Br[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>CN(C)C(=O)C.[Cu]>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:10]=1[CH:26]([CH3:28])[CH3:27])=[O:8]
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6

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HCID 122863-BromopyridineHCID 14797Potassium HydroxideHCID 59762365N-(3,4-Difluorobenzyl)-6-hydroxy-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide2회

생성물 1

HCID 59762343N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-6-(pyridin-3-yloxy)-1H-indole-3-carboxamide수율 6.5%

시약·촉매·용매 2

HCID 23978
Copper
촉매
HCID 31374Dimethylacetamide용매

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온도
130 °C

실험 절차

General Procedure G. To a solution of N-(3,4-difluorobenzyl)-2-isopropyl-6-hydroxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 220, 30 mg, 0.069 mmol) in N,N-dimethylacetamide (1.50 ml) stirring at room temperature, was added potassium hydroxide (80 mg, 1.43 mmol) and the reaction stirred for 5 minutes. 3-bromopyridine (0.05 mL, 0.08 g, 0.51 mmol) and then Copper powder (9.0 mg, 0.14 mmol) was then directly added and the resulting mixture heated at 120-140° C. for 18 h. The reaction was cooled to room temperature, quenched with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (50% EtOAc-hexanes, 100 % EtOAc) to yield N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-6-(pyridin-3-yloxy)-1H-indole-3-carboxamide (Compound 222) as a yellow solid (2.3 mg). 1H NMR (300 MHz, METHANOL-d4) δ ppm 1.34 (d, J=7.0 Hz, 6 H), 4.59 (s, 2 H), 5.55 (s, 2 H), 6.72 (d, J=8.2 Hz, 1 H), 6.92 (dd, J=8.6, 2.2 Hz, 1 H), 7.02 (d, J=2.0 Hz, 1 H), 7.19-7.42 (m, 6 H), 7.62-7.74 (m, 2 H), 8.14-8.24 (m, 2 H), 8.49 (d, J=5.0 Hz, 1 H).

후처리

  1. temperatureThe reaction was cooled to room temperature
  2. customquenched with water
  3. extractionextracted with EtOAc
  4. washwashed with brine
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by flash column chromatography on silica gel (50% EtOAc-hexanes, 100 % EtOAc)

출처 및 근거

ORD 기록
ord-187f0a3d3b89426ab4bda23413f732ec
출처 데이터셋
uspto-grants-2013_09
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US08524917B2

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