Methanol → Ammonia methanol

HRID 730006Notes

Reaction equation

HRID 730006 reaction equation
[C:1]([C:5]1[NH:6][C:7]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[C:8]([C:10]2[N:15]=[C:14]3[N:16]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:17]([NH2:19])=[N:18][C:13]3=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CS(O)(=O)=O.[CH3:38][OH:39]>>[NH3:6].[CH3:38][OH:39].[C:1]([C:5]1[NH:6][C:7]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[C:8]([C:10]2[N:15]=[C:14]3[N:16]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:17]([NH2:19])=[N:18][C:13]3=[CH:12][CH:11]=2)[N:9]=1)([CH3:2])([CH3:3])[CH3:4]

Participants

5

Reactant 3

HCID 887Methanol2×HCID 6395Methanesulfonic AcidHCID 178446130HCID 178446130, compound

Product 2

HCID 21705897Ammonia methanolYield 2%HCID 178446130HCID 178446130, compound

Procedure

Mix 5-[2-tert-butyl-5-(2,4-difluoro-phenyl)-1H-imidazol-4-yl]-3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine (11.55 g, 26.33 mmol) in MeOH (150 mL), and then add a solution of methanesulfonic acid (2.53 g, 26.33 mmol) in MeOH (10 mL) dropwise. Stir the resulting reaction mixture at room temperature for 20 minutes, then concentrate under reduced pressure. Slurry the residue in Et2O, then filter and wash with fresh Et2O. Dry the resulting solid in a drying oven at room temperature under house vacuum overnight, then at 80° C. for 1.5 h. Dissolve the salt in MeOH and then treat with NaHCO3 until basic. Extract the resulting solution with EtOAc, dry the combined organics over Na2SO4, filter, then concentrate under reduced pressure. Purify by column chromatography, eluting with neat EtOAc, then 1% of 2N ammonia/MeOH in EtOAc, then 2% of 2N ammonia/MeOH in EtOAc to give 9.38 g of 5-[2-tert-butyl-5-(2,4-difluoro-phenyl)-1H-imidazol-4-yl]-3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine. Mix 5-[2-tert-butyl-5-(2,4-difluoro-phenyl)-1H-imidazol-4-yl]-3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine (9.38 g, 21.39 mmol) in anhydrous MeOH (150 mL), and then add a solution of methanesulfonic acid (2.06 g, 21.43 mmol) in MeOH (10 mL) dropwise. Allow the resulting reaction mixture to stir at room temperature for 30 minutes, then concentrate under reduced pressure. Slurry the residue in Et2O, then filter and wash with fresh Et2O. Dry the resulting solid in a drying oven at room temperature under house vacuum for 48 h to give 10.695 g (76% yield) of the title compound as a tan solid.

Workup

  1. customthe resulting reaction mixture at room temperature for 20 minutes
  2. concentrationconcentrate under reduced pressure
  3. filtrationfilter
  4. washwash with fresh Et2O
  5. customDry the resulting solid in a drying oven at room temperature under house vacuum overnight
  6. dissolutionDissolve the salt in MeOH
  7. additiontreat with NaHCO3 until basic
  8. extractionExtract the resulting solution with EtOAc
  9. dry with materialdry the combined organics over Na2SO4
  10. filtrationfilter
  11. concentrationconcentrate under reduced pressure
  12. customPurify by column chromatography
  13. washeluting with neat EtOAc

Sources & evidence

ORD record
ord-9935302bc9214dbeb9c633f5fa3431fd
Source dataset
uspto-grants-2009_09
Patent number
US07582652B2

Reaction notes

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