Formic Acid → 6-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic acid

HRID 1689816Notes

Reaction equation

HRID 1689816 reaction equation
C(O)=O.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[C:12]1[C:16]([CH2:17][O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:33]=[C:32]4[C:28]([C:29]([C:35]([O:37]C(C)(C)C)=[O:36])=[CH:30][N:31]4[CH3:34])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)=[C:15]([CH:42]2[CH2:44][CH2:43]2)[O:14][N:13]=1>O>[CH:42]1([C:15]2[O:14][N:13]=[C:12]([C:6]3[C:5]([Cl:4])=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:11])[C:16]=2[CH2:17][O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:33]=[C:32]4[C:28]([C:29]([C:35]([OH:37])=[O:36])=[CH:30][N:31]4[CH3:34])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[CH2:43][CH2:44]1

Participants

4

Reactant 2

HCID 284Formic AcidHCID 59369339tert-Butyl 6-(4-{[3-(2,6-dichlorophenyl)-5-cyclopropylisoxazol-4-yl]methoxy}piperidyl)-1-methylindole-3-carboxylate

Product 1

HCID 252047676-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic acidYield 73%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent3×

Conditions

Temperature
25 °C

Procedure

To formic acid (116.5 Kg), add tert-butyl 6-(4-{[3-(2,6-dichlorophenyl)-5-cyclopropylisoxazol-4-yl]methoxy}piperidyl)-1-methylindole-3-carboxylate (19.102 Kg, 34.45 mol) under a nitrogen atmosphere. Stir the mixture at 20-30° C. for 24-72 hours. Follow by HPLC until no starting material is observed. Add water (286.5 Kg) and stir for at least 1 hour. Add water (133.7 Kg) and stir for at least 30 minutes, repeat with a further addition of water (133.7 Kg) with stirring for at least 30 minutes. Collect the solids by filtration and rinse the filter cake with water (3×30 Kg). Add the wet solids to methanol (75.5 Kg) and stir the suspension for at least 12 hours. Cool the suspension to 0-5° C. and stir for at least 1 hour. Collect the solids by filtration. Wash the solids with a solution of methanol (9.1 Kg) and water (1.1 Kg) cooled to 0-5° C. and repeat. Dry solids at 50-55° C. for 12-72 hours under vacuum. Add the solids to formic acid (28.5 Kg) and water (2.3 Kg) and stir for 10-20 minutes. Filter the mixture. Add water (49.7 Kg) and stir for 30-60 minutes. Add water (2×36.6 Kg) and stir for at least 30 minutes. Collect solids by filtration and rinse with water (3×15.9 Kg). Add collected solids to methanol (58.2 Kg). Stir for at least 12 hours, cool to 0-5° C. and stir for at least 1 hour. Collect solids by filtration. Wash solids with a solution of methanol (8.1 Kg) and water (1.1 Kg) cooled to 0-5° C., repeat once. Add the collected solids to a solution of methanol (115.6 Kg) and water (14.6 Kg). Heat the suspension to reflux for 2-3 hours, cool to 0-5° C. and stir 1 hour. Collect the solids by filtration. Wash the solids with a solution of methanol (17.3 Kg) and water (2.2 Kg) cooled to 0-5° C., repeat once. Dry collected solids at 60-65° C. for 12-72 hours under vacuum to give 13.584 Kg (73%) of the title compound.

Workup

  1. stirringwith stirring for at least 30 minutes
  2. customCollect the solids
  3. filtrationby filtration
  4. washrinse the filter cake with water (3×30 Kg)
  5. additionAdd the wet solids to methanol (75.5 Kg)
  6. stirringstir the suspension for at least 12 hours
  7. temperatureCool the suspension to 0-5° C.
  8. stirringstir for at least 1 hour
  9. customCollect the solids
  10. filtrationby filtration
  11. washWash the solids with a solution of methanol (9.1 Kg) and water (1.1 Kg)
  12. temperaturecooled to 0-5° C.
  13. customDry solids at 50-55° C. for 12-72 hours under vacuum
  14. additionAdd the solids to formic acid (28.5 Kg) and water (2.3 Kg)
  15. stirringstir for 10-20 minutes
  16. filtrationFilter the mixture
  17. stirringAdd water (49.7 Kg) and stir for 30-60 minutes
  18. stirringAdd water (2×36.6 Kg) and stir for at least 30 minutes
  19. customCollect solids
  20. filtrationby filtration
  21. washrinse with water (3×15.9 Kg)
  22. additionAdd
  23. customcollected solids to methanol (58.2 Kg)
  24. stirringStir for at least 12 hours
  25. temperaturecool to 0-5° C.
  26. stirringstir for at least 1 hour
  27. customCollect solids
  28. filtrationby filtration
  29. washWash solids with a solution of methanol (8.1 Kg) and water (1.1 Kg)
  30. temperaturecooled to 0-5° C.
  31. additionAdd the collected solids to a solution of methanol (115.6 Kg) and water (14.6 Kg)
  32. temperatureHeat the suspension
  33. temperatureto reflux for 2-3 hours
  34. temperaturecool to 0-5° C.
  35. stirringstir 1 hour
  36. customCollect the solids
  37. filtrationby filtration
  38. washWash the solids with a solution of methanol (17.3 Kg) and water (2.2 Kg)
  39. temperaturecooled to 0-5° C.
  40. customDry
  41. customcollected solids at 60-65° C. for 12-72 hours under vacuum

Sources & evidence

ORD record
ord-dca2ca6441f5464cb51272dc201e93c2
Source dataset
uspto-grants-2012_04
Patent number
US08153624B2

Reaction notes

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