Sodium Hydroxide → 6-Chloro-5-[4-(tetrahydro-2H-pyran-4-yl)phenyl]-1H-indole-3-carboxylic acid

HRID 1054847Notes

Reaction equation

HRID 1054847 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:19][CH:20]=1

Participants

4

Reactant 2

HCID 14798Sodium Hydroxide2×HCID 86698838HCID 86698838, compound

Product 1

HCID 717660976-Chloro-5-[4-(tetrahydro-2H-pyran-4-yl)phenyl]-1H-indole-3-carboxylic acidYield 34.4%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Conditions

Temperature
70 °C

Procedure

To a solution of methyl 6-chloro-5-[4-(tetrahydro-2H-pyran-4-yl)phenyl]-1H-indole-3-carboxylate (360 mg, 0.973 mmol) in methanol (10 mL) was added sodium hydroxide (1 M, 4.0 mL, 4 mmol) and the reaction was heated to 70° C. for 24 hours. The reaction was concentrated under reduced pressure. The crude reaction was diluted with methanol (9 mL) to which was added additional sodium hydroxide (1M, 6.0 mL, 6 mmol) and heated to 70° C. for 24 hours. The reaction was concentrated under reduced pressure and acidified using 1N aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified using the Biotage Isolera One (SNAP 50 g silica gel column) and eluting with a gradient of 0-20% methanol/dichloromethane yielding 215 mg of the title compound as a solid. To a round bottom flask containing the title compound was added methanol (10 mL) and the reaction was heated to reflux. Additional methanol (5 mL) was added and the solution was allowed to cool to room temperature and stirred overnight at room temperature. The resulting precipitate was filtered and washed with 1 mL of methanol and dried by pulling high vacuum yielding 119 mg of the title compound. MS (ES−) 354.0 (M−H)−. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.10 (s, 1 H), 11.93 (br. d, 1 H), 8.07 (d, 1 H), 7.93 (s, 1 H), 7.62 (s, 1 H), 7.21-7.46 (m, 4 H), 3.86-4.02 (m, 2H), 3.46 (td, 2 H), 2.71-2.93 (m, 1 H), 1.60-1.85 (m, 4 H).

Workup

  1. concentrationThe reaction was concentrated under reduced pressure
  2. customThe crude reaction
  3. temperatureheated to 70° C. for 24 hours
  4. concentrationThe reaction was concentrated under reduced pressure
  5. extractionextracted three times with ethyl acetate
  6. washThe combined organic layers were washed with brine
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe crude material was purified
  11. washeluting with a gradient of 0-20% methanol/dichloromethane yielding 215 mg of the title compound as a solid
  12. additionTo a round bottom flask containing the title compound
  13. additionwas added methanol (10 mL)
  14. temperaturethe reaction was heated to reflux
  15. additionAdditional methanol (5 mL) was added
  16. temperatureto cool to room temperature
  17. filtrationThe resulting precipitate was filtered
  18. washwashed with 1 mL of methanol
  19. customdried

Sources & evidence

ORD record
ord-6876ed6555f549d9a17c12deade3ba9d
Source dataset
uspto-grants-2016_07
Patent number
US09394285B2

Reaction notes

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