Dabco → 3-[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoic acid

HRID 1512936Notes

Reaction equation

HRID 1512936 reaction equation
[CH2:1]1N2CCN(CC2)C1.[Cl:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:33]=[C:32]4[C:28]([C:29]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:30][NH:31]4)=[CH:27][CH:26]=3)[N:21]=2)[CH:13]=[N:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18]>C(=O)(OC)OC.CN(C=O)C>[Cl:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:33]=[C:32]4[C:28]([C:29]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:30][N:31]4[CH3:1])=[CH:27][CH:26]=3)[N:21]=2)[CH:13]=[N:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18]

Participants

5

Reactant 2

HCID 9237DabcoHCID 445468613-[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid

Product 1

HCID 445470173-[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoic acidYield 29%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 12021Dimethyl CarbonateSolvent

Conditions

Temperature
90 °C

Procedure

DABCO (64 mg) was added to a solution of 3-[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E81) (60 mg) in dimethyl carbonate (3 mL) and DMF (2 mL). The resulting mixture was heated at reflux for 5 days. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was dissolved in iPrOH (3 mL) and water (3 mL). Sodium hydroxide (20 mg) was added to the mixture. The resulting mixture was heated at 90° C. for 1 hour. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoic acid (E82) (18 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 2.60 (2H, t), 2.96 (2H, t), 3.84 (3H, s), 5.46 (1H, m), 7.32 (1H, s), 7.75 (2H, m), 8.12 (1H, s), 8.57 (1H, d), 8.94 (1H, d), 12.08 (1H, br s). MS (ES): C22H21ClN4O4 requires 440. found 441.1.

Workup

  1. temperatureThe resulting mixture was heated
  2. temperatureat reflux for 5 days
  3. temperatureAfter cooling
  4. customthe reaction was quenched with water
  5. extractionextracted with EtOAc for 3 times
  6. washThe combined organic solution was washed with brine
  7. dry with materialdried over anhydrous sodium sulfate
  8. concentrationThe dried solution was concentrated
  9. dissolutionThe residue was dissolved in iPrOH (3 mL)
  10. additionSodium hydroxide (20 mg) was added to the mixture
  11. additionThen 0.5 M HCl solution was added until pH was about 6
  12. concentrationThe solvent was concentrated
  13. dissolutionthe residue was dissolved in water
  14. customThe precipitated solid was purified by Mass Directed Auto Prep

Sources & evidence

ORD record
ord-bed8452947844564af68b46f89e33725
Source dataset
uspto-grants-2012_07
Patent number
US08217028B2

Reaction notes

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