Hydrochloric Acid → 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1-methyl-1H-indol-3-yl]propanoic acid

HRID 1512956Notes

Reaction equation

HRID 1512956 reaction equation
[OH-].[K+].[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[C:21]([F:36])=[CH:22][CH:23]=[C:24]4[C:28]=3[NH:27][CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4].I[CH3:38].[OH-].[Na+].Cl>CS(C)=O.C1COCC1.O>[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[C:21]([F:36])=[CH:22][CH:23]=[C:24]4[C:28]=3[N:27]([CH3:38])[CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:13])[CH3:14])#[N:4]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 6328Methyl iodideHCID 14797Potassium HydroxideHCID 14798Sodium HydroxideHCID 59146092Ethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoate

Product 1

HCID 445473203-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1-methyl-1H-indol-3-yl]propanoic acid

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

Potassium hydroxide (237 mg) was added to a solution of ethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoate (D148) (450 mg) and iodomethane (0.76 mL) in DMSO (5 mL) at RT. The reaction mixture was stirred at RT for 4 hours. Then the reaction was quenched with saturated ammonium chloride, 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 to afford the crude product as a brown oil. This oil was dissolved in THF (4 mL) and water (4 mL). Sodium hydroxide (100 mg) was then added to the mixture. The reaction mixture was stirred at 90° C. for 1 hour, and then at RT for another 24 hours. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by MDAP to afford 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1-methyl-1H-indol-3-yl]propanoic acid (E106) (249 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 1.31 (6H, d), 2.53 (2H, t), 2.88 (2H, t), 3.33 (3H, s), 4.89-4.95 (1H, m), 7.02 (1H, t), 7.11 (1H, s), 7.50 (1H, d), 7.75 (1H, dd), 8.36 (1H, dd), 8.49 (1H, d), 12.06 (1H, br s); δF (DMSO-d6, 376 MHz): −123.0; MS (ES): C24H21FN4O4 requires 448; found 449.1 (M+H+).

Workup

  1. customThen the reaction was quenched with saturated ammonium chloride
  2. extractionextracted with EtOAc for 3 times
  3. washThe combined organic solution was washed with brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. concentrationThe dried solution was concentrated
  6. customto afford the crude product as a brown oil
  7. stirringThe reaction mixture was stirred at 90° C. for 1 hour
  8. waitat RT for another 24 hours
  9. concentrationThe solvent was concentrated
  10. dissolutionthe residue was dissolved in water
  11. customThe precipitated solid was purified by MDAP

Sources & evidence

ORD record
ord-cd4b0f5252d64cbf8a830a9be7f2b203
Source dataset
uspto-grants-2012_07
Patent number
US08217028B2

Reaction notes

Loading…