Ethyl 7-(4-(6-bromopyridin-2-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate → 6-Chloro-7-(4-(6-isobutylpyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid

HRID 1626453Notes

Reaction equation

HRID 1626453 reaction equation
Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28]CC)=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[Cl:31])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1.[Br-].[CH2:35]([Zn+])[CH:36]([CH3:38])[CH3:37]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:31][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][C:14]1[CH:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH2:35][CH:36]([CH3:38])[CH3:37])[N:7]=3)=[CH:33][CH:32]=1)[O:23][CH2:22][CH2:21][CH:20]2[C:26]([OH:28])=[O:27]

Participants

5

Reactant 2

HCID 86664393Ethyl 7-(4-(6-bromopyridin-2-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylateHCID 178448254HCID 178448254, compound

Product 1

HCID 672878986-Chloro-7-(4-(6-isobutylpyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic acidYield 68%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

To ethyl 7-(4-(6-bromopyridin-2-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (Example 52, Step A, 0.021 g, 0.039 mmol) in THF (0.5 ml) was added 0.5 isobutylzinc bromide in THF (0.12 ml, 0.059 mmol) followed by bis(tri-t-butylphosphine)palladium (0) (0.0010 g, 0.0020 mmol) and the reaction was stirred at ambient temperature for 1 hour. The reaction was loaded onto silica gel and the product eluted using 3:1 hexanes/ethyl acetate. The resulting oil was dissolved in THF/MeOH/1N NaOH (0.5 ml/0.5 ml/0.25 ml) and stirred at ambient temperature for 3 hours. The reaction was diluted with DCM (35 ml) and washed with water with made acidic (pH=5) with 1N HCl. The organic layer was washed with brine (10 ml), dried over magnesium sulfate and concentrated to give the title compound (0.013 g, 0.027 mmol, 68% yield) as a white solid. MS (ESI) m/z=481.31 (M+H).

Workup

  1. washthe product eluted
  2. dissolutionThe resulting oil was dissolved in THF/MeOH/1N NaOH (0.5 ml/0.5 ml/0.25 ml)
  3. stirringstirred at ambient temperature for 3 hours
  4. additionThe reaction was diluted with DCM (35 ml)
  5. washwashed with water with made acidic (pH=5) with 1N HCl
  6. washThe organic layer was washed with brine (10 ml)
  7. dry with materialdried over magnesium sulfate
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-ac1e280af3544245a0f0adc4c7b2f6b1
Source dataset
uspto-grants-2014_07
Patent number
US08785445B2

Reaction notes

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