Methanol → HCID 178420310, compound

HRID 2204644Notes

Reaction equation

HRID 2204644 reaction equation
[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14](=[N:25][NH2:26])[C:15]2[C:20](Cl)=[CH:19][N:18]=[C:17]3[NH:22][CH:23]=[CH:24][C:16]=23)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].CO>CN1C(=O)CCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[C:15]3=[C:16]4[CH:24]=[CH:23][NH:22][C:17]4=[N:18][CH:19]=[C:20]3[NH:26][N:25]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 3

HCID 887MethanolHCID 23676156Sodium t-butoxideHCID 866371884-((1-benzylpiperidin-3-yl)(hydrazono)methyl)-5-chloro-1H-pyrrolo[2,3-b]pyridine

Product 1

HCID 178420310HCID 178420310, compoundYield 19%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalyst3×HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
160 °C

Procedure

A mixture of 4-((1-benzylpiperidin-3-yl)(hydrazono)methyl)-5-chloro-1H-pyrrolo[2,3-b]pyridine (1.04 g, 2.84 mmol), sodium tert-butoxide (0.652 g, 6.78 mmol), palladium acetate (0.0064 g, 0.028 mmol) and (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butyl phosphine (0.016 g, 0.028 mmol) in NMP (10 mL) was heated in the microwave at about 160° C. for about 30 min. Additional palladium acetate (0.0064 g, 0.028 mmol) and (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butyl phosphine (0.016 g, 0.028 mmol) were added and the mixture was heated in a microwave at about 160° C. for about 15 min. Additional palladium acetate (0.003 g, 0.014 mmol) and (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butyl phosphine (0.008 g, 0.014 mmol) were added and the mixture was again heated at about 160° C. for about 8 min. The solvent was removed under reduced pressure and the residue was partitioned between water (25 mL) and EtOAc (25 mL). The organic phase was washed with brine (20 mL), dried over anhydrous MgSO4, decolorized with charcoal and filtered. The solvent was removed under reduced pressure and the residue purified by silica gel chromatography, eluting first with DCM (1 L), a mixture of 98:1:1 DCM:TEA:MeOH (1 L) and then with a mixture of 97:1:2 DCM:TEA:MeOH (1 L) to yield 1-(1-benzylpiperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.18 g, 0.54 mmol, 19%) as a brown solid: LC/MS (Table 2, Method a) Rt=1.36 min; MS m/z: 332 (M+H)+.

Workup

  1. temperaturethe mixture was heated in a microwave at about 160° C. for about 15 min
  2. temperaturethe mixture was again heated at about 160° C. for about 8 min
  3. customThe solvent was removed under reduced pressure
  4. customthe residue was partitioned between water (25 mL) and EtOAc (25 mL)
  5. washThe organic phase was washed with brine (20 mL)
  6. dry with materialdried over anhydrous MgSO4
  7. filtrationfiltered
  8. customThe solvent was removed under reduced pressure
  9. customthe residue purified by silica gel chromatography
  10. washeluting first with DCM (1 L)
  11. additiona mixture of 98:1:1 DCM
  12. additionTEA:MeOH (1 L) and then with a mixture of 97:1:2 DCM

Sources & evidence

ORD record
ord-41db7af93d0c472497f015a06c933dff
Source dataset
uspto-grants-2016_06
Patent number
US09365579B2

Reaction notes

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