Cesium carbonate → 3-(1-(4-Cyclobutoxymethyl-benzyl)-1H-pyrazol-4-yl)-pyridin-2-ylamine

HRID 78214Notes

Reaction equation

HRID 78214 reaction equation
Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1.O1[CH2:26][CH2:25][O:24][CH2:23]C1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:33]1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:34]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[CH:25]1([O:24][CH2:23][C:2]2[CH:20]=[CH:19][C:5]([CH2:6][N:7]3[CH:11]=[C:10]([C:12]4[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=4)[CH:9]=[N:8]3)=[CH:4][CH:3]=2)[CH2:26][CH2:34][CH2:33]1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 634876Binap, (A+-)-HCID 59255492HCID 59255492, compound

Product 1

HCID 592550883-(1-(4-Cyclobutoxymethyl-benzyl)-1H-pyrazol-4-yl)-pyridin-2-ylamineYield 16%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

To a mixture of 3-(1-(4-bromo-benzyl)-1H-pyrazol-4-yl)-pyridin-2-ylamine (24 mg, 0.073 mmol) described in Manufacturing Example 195-1-1 and 1,4-dioxane (1.5 mL) were added water (150 mL), cesium carbonate (95 mg, 0.29 mmol), potassium cyclobutoxymethyl trifluoroborate (21 mg, 0.11 mmol) described in Manufacturing Example 197-1-2, palladium(II) acetate (1.6 mg, 0.0073 mmol), and (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.5 mg, 0.0073 mmol) at room temperature, which was stirred under nitrogen atmosphere for 6 hours at 100° C. The reaction mixture was cooled to room temperature, after which water and ethyl acetate were added and the mixture was filtered through a Celite pad. The organic layer of the filtrate was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue thus obtained was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (5.2 mg, 16%) as a trifluoroacetic acid salt.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. filtrationthe mixture was filtered through a Celite pad
  3. washThe organic layer of the filtrate was washed with saturated aqueous sodium chloride
  4. concentrationwas concentrated under a reduced pressure
  5. customThe residue thus obtained
  6. customwas purified by reverse-phase high performance liquid chromatography (
  7. additioncontaining 0.1% trifluoroacetic acid)

Sources & evidence

ORD record
ord-484c2a8ebc784370a185ecce93357e0b
Source dataset
uspto-grants-2014_09
Patent number
US08841327B2

Reaction notes

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