Sodium hydride → Tert-butyl 3-(((3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)piperidine-1-carboxylate

HRID 1253545Notes

Reaction equation

HRID 1253545 reaction equation
[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([OH:17])[C:6]=12.Br[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([O:17][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:21]3)[C:6]=12

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 211885311-Boc-3-bromomethylpiperidineHCID 673753833-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol

Product 1

HCID 58404902Tert-butyl 3-(((3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)methyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol (60.0 mg, 0.205 mmol), tert-butyl 3-(bromomethyl)piperidine-1-carboxylate (114 mg, 0.410 mmol), and NaH (29.5 mg, 0.737 mmol) were suspended in DMF (2 ml), then heated to 60° C. After 2 h, the reaction mixture was quenched with 1 ml of saturated aqueous ammonium chloride, diluted in ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine. The combined aqueous layers were extracted with ethyl acetate (1×30 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/ethyl acetate gradient) afford a yellow oil. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate, filtered and concentrated to afford tert-butyl 3-({[3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]oxy}methyl)piperidine-1-carboxylate.

Workup

  1. customthe reaction mixture was quenched with 1 ml of saturated aqueous ammonium chloride
  2. additiondiluted in ethyl acetate
  3. washwashed with saturated aqueous sodium bicarbonate and brine
  4. extractionThe combined aqueous layers were extracted with ethyl acetate (1×30 mL)
  5. dry with materialthe combined organic layers were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by column chromatography on silica gel (methanol/ethyl acetate gradient)
  9. customafford a yellow oil
  10. customThe residue was purified by preparative HPLC Reverse phase (C-18)
  11. washeluting with Acetonitrile/Water+0.05% TFA
  12. additionThe fractions containing product
  13. additiondiluted in ethyl acetate
  14. washwashed with aqueous sodium bicarbonate
  15. dry with materialdried over sodium sulfate
  16. filtrationfiltered
  17. concentrationconcentrated

Sources & evidence

ORD record
ord-32981d77af3846d793959015f118871f
Source dataset
uspto-grants-2013_06
Patent number
US08455477B2

Reaction notes

Loading…