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

HRID 1918855Notes

Reaction equation

HRID 1918855 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>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.CO.CCOC(C)=O.O>[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

10

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 53.2%

Reagents, catalysts & solvents 5

HCID 9832798Tris(dibenzylideneacetone) dipalladiumCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A sealed tube was equipped with a magnetic stirrer and charged with 128b (375 mg, 2.3 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (848 g, 3.2 mmol) and cesium carbonate (1.7 g, 5 mmol) in 1,4-dioxane (24 mL). After bubbling nitrogen through the solution for 30 min, Xantphos (160 mg, 0.3 mmol) and tris(dibenzylideneacetone) dipalladium(0) (150 mg, 0.2 mmol) were added, and the reaction mixture was heated to 100° C. for 5 days. After this time, H2O (20 mL) and EtOAc (20 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine (50 mL) and dried over sodium sulfate. The resulting residue was purified by column chromatography eluting with a gradient of CH2Cl2-9:1 CH2Cl2:MeOH to afford a 39% yield (430 mg) of 128c.

Workup

  1. customA sealed tube was equipped with a magnetic stirrer
  2. customAfter bubbling nitrogen through the solution for 30 min
  3. customThe aqueous layer was separated
  4. extractionextracted with ethyl acetate (2×20 mL)
  5. washThe combined organic extracts were washed with brine (50 mL)
  6. dry with materialdried over sodium sulfate
  7. customThe resulting residue was purified by column chromatography
  8. washeluting with a gradient of CH2Cl2-9:1 CH2Cl2

Sources & evidence

ORD record
ord-f30531b256c64b03bf05a9acfb4fe549
Source dataset
uspto-grants-2013_12
Patent number
US08618107B2

Reaction notes

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