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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
Notes
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Reaction equation

HRID 40168 reaction equation
[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]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 122863-BromopyridineHCID 14797Potassium HydroxideHCID 59762365N-(3,4-Difluorobenzyl)-6-hydroxy-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide2×

Product 1

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

Reagents, catalysts & solvents 2

HCID 23978
Copper
Catalyst
HCID 31374DimethylacetamideSolvent

Conditions

Temperature
130 °C

Procedure

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).

Workup

  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)

Sources & evidence

ORD record
ord-187f0a3d3b89426ab4bda23413f732ec
Source dataset
uspto-grants-2013_09
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08524917B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes