Potassium Carbonate → 1-(3-((4-(Piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzyl)-1H-indole-4-carboxylic acid

HRID 1408014Notes

Reaction equation

HRID 1408014 reaction equation
[NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12]C)=[O:11])[C:4]=2[CH:3]=[CH:2]1.Cl[CH2:15][C:16]1[CH:17]=[C:18]([CH:54]=[CH:55][CH:56]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][C:23]=1[C:34]1[CH:35]=[C:36]([CH:51]=[CH:52][N:53]=1)[C:37]([NH:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=1)=[O:38])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:28]1([C:25]2[CH:26]=[CH:27][C:22]([NH:21][C:19]([C:18]3[CH:17]=[C:16]([CH:56]=[CH:55][CH:54]=3)[CH2:15][N:1]3[C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=[O:11])[C:4]=4[CH:3]=[CH:2]3)=[O:20])=[C:23]([C:34]3[CH:35]=[C:36]([C:37](=[O:38])[NH:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:48])([F:49])[F:50])[CH:42]=4)[CH:51]=[CH:52][N:53]=3)[CH:24]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 2733668methyl 1H-indole-4-carboxylateHCID 665867362-(2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)-isonicotinamide

Product 1

HCID 665881211-(3-((4-(Piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzyl)-1H-indole-4-carboxylic acidYield 48.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of 10.5 mg of methyl 1H-indole-4-carboxylate, 18.2 mg of 2-(2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)-isonicotinamide 8.1a, and excess potassium carbonate in 300 μL of DMF was stirred for 24 h. The solvent was evaporated and the residue was purified by silica gel chromatography. The product was dissolved in 1 mL of 4:1 THF/water and treated with 10 mg of LiOH.H2O. After stirring 4 days at 70° C. the reaction mixture was acidified with 3.0 N hydrochloric acid and then extracted with ethyl acetate. The aqueous phase was washed with ethyl acetate, and the combined organic extracts washed with brine and dried (NaSO4). The residue was purified by reverse phase HPLC eluting with 0.1% TFA in a water/acetonitrile gradient to give 10.6 mg of product. MS (ES, m/z) 732.4 [M+H]+.

Workup

  1. customThe solvent was evaporated
  2. customthe residue was purified by silica gel chromatography
  3. dissolutionThe product was dissolved in 1 mL of 4:1 THF/water
  4. additiontreated with 10 mg of LiOH.H2O
  5. stirringAfter stirring 4 days at 70° C. the reaction mixture
  6. extractionextracted with ethyl acetate
  7. washThe aqueous phase was washed with ethyl acetate
  8. washthe combined organic extracts washed with brine
  9. dry with materialdried (NaSO4)
  10. customThe residue was purified by reverse phase HPLC
  11. washeluting with 0.1% TFA in a water/acetonitrile gradient

Sources & evidence

ORD record
ord-b69f838b2d914d0083965d902af38d98
Source dataset
uspto-grants-2014_12
Patent number
US08916569B2

Reaction notes

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