Cesium carbonate → 5-Bromo-3-(5-(3-hydroxyazetidin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one

HRID 1772137Notes

Reaction equation

HRID 1772137 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)=[CH:4][CH:3]=1.Br[C:14]1[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:20][C:18]1[CH:19]=[C:14]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:9][CH:10]([OH:12])[CH2:11]3)=[CH:6][N:7]=2)[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 36143503,5-Dibromo-1-methylpyridin-2(1H)-oneHCID 580438121-(6-Aminopyridin-3-yl)azetidin-3-ol

Product 1

HCID 580439235-Bromo-3-(5-(3-hydroxyazetidin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-oneYield 40%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Procedure

A 100-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 120b (270 mg, 1.64 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (435 mg, 1.64 mmol), cesium carbonate (1.18 g, 3.61 mmol), and 1,4-dioxane (20 mL). After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (142 mg, 0.246 mmol) and tris(dibenzylidene-acetone)dipalladium(0) (150 mg, 0.164 mmol) were added, and the reaction mixture was heated at reflux for 3 h. After this time, the mixture was cooled to room temperature and filtered, and the filter cake was washed with methylene chloride (2×20 mL). The filtrates were combined and concentrated under reduced pressure, and the resulting residue was purified by column chromatography to afford a 40% yield (217 mg) of 120c as a yellow solid: 210° C. dec; 1H NMR (500 MHz, DMSO-d6) δ 8.50 (d, 1H, J=4.0 Hz), 8.44 (s, 1H), 7.54 (d, 1H, J=5.0 Hz), 7.42 (d, 1H, J=5.0 Hz), 7.20 (d, 1H, J=14.5 Hz), 6.89 (dd, 1H, J=14.5, 4.0 Hz), 5.59 (d, 1H, J=11.0 Hz), 4.54 (m, 1H), 4.05 (dd, 2H, J=13.0, 11.0 Hz), 3.50-3.44 (m, 5H); MS (APCI+) m/z 351.6 (M+H).

Workup

  1. customA 100-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet
  2. customAfter bubbling nitrogen through the resulting suspension for 30 min
  3. temperaturethe reaction mixture was heated
  4. temperatureat reflux for 3 h
  5. filtrationfiltered
  6. washthe filter cake was washed with methylene chloride (2×20 mL)
  7. concentrationconcentrated under reduced pressure
  8. customthe resulting residue was purified by column chromatography

Sources & evidence

ORD record
ord-adfd593b13e04a1e99ab39f00f35522c
Source dataset
uspto-grants-2016_02
Patent number
US09249123B2

Reaction notes

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