Cesium carbonate → Gne-3511

HRID 1057045Notes

Reaction equation

HRID 1057045 reaction equation
Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19]2)[N:3]=1.[NH2:25][C:26]1[CH:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.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]>[F:23][C:20]1([F:24])[CH2:21][CH2:22][N:18]([C:4]2[N:3]=[C:2]([NH:25][C:26]3[CH:31]=[C:30]([CH:29]=[CH:28][N:27]=3)[C:32]#[N:33])[CH:7]=[C:6]([CH:8]3[CH2:13][CH2:12][N:11]([CH:14]4[CH2:17][O:16][CH2:15]4)[CH2:10][CH2:9]3)[CH:5]=2)[CH2:19]1

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 70155242-AminoisonicotinonitrileHCID 900154052-Chloro-6-(3,3-difluoropyrrolidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridine

Product 1

HCID 72547959Gne-3511Yield 77%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

To a 50-mL recovery flask charged with 2-chloro-6-(3,3-difluoropyrrolidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridine (216 mg, 0.603 mmol, 1 equiv), 2-amino-4-cyanopyridine (122 mg, 1.03 mmol, 1.70 equiv), cesium carbonate (399 mg, 1.22 mmol, 2.03 equiv) in 1,4-dioxane was added tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.031 mmol, 0.051 equiv). The reaction flask was fitted with a microreflux condenser, and the reaction mixture was heated at reflux under nitrogen for 13 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (10 mL). The organic was separated and the aqueous wash was further extracted with ethyl acetate (2×10 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (3% methanol in dichloromethane+0.1% ammonium hydroxide) provided product as a yellow solid (205 mg (77% yield). 1H NMR (400 MHz, DMSO-d6), δ: 9.72 (s, 1H), 8.46 (s, 1H), 8.41 (d, J=5.0 Hz, 1H), 7.20 (dd, J=5.1, 1.2 Hz, 1H), 6.60 (s, 1H), 6.00 (s, 1H), 4.54 (t, J=6.4 Hz, 2H), 4.44 (t, J=6.0 Hz, 2H), 3.85 (t, J=13.2 Hz, 2H), 3.65 (t, J=7.2 Hz, 2H), 3.40 (m, 1H), 2.80 (m, 2H), 2.56 (m, 2H), 2.39 (m, 1H), 1.84 (m, 2H), 1.61-1.76 (m, 4H). m/z (ESI-pos) M+1=441

Workup

  1. customThe reaction flask was fitted with a microreflux condenser
  2. temperaturethe reaction mixture was heated
  3. temperatureat reflux under nitrogen for 13 h
  4. washwashed with water (10 mL)
  5. customThe organic was separated
  6. washthe aqueous wash
  7. extractionwas further extracted with ethyl acetate (2×10 mL)
  8. dry with materialThe combined organic was dried over anhydrous sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customPurification by flash column chromatography (3% methanol in dichloromethane+0.1% ammonium hydroxide)
  12. customprovided product as a yellow solid (205 mg (77% yield)

Sources & evidence

ORD record
ord-b0397f62349a4f2c8d7dcda75fe5fdb4
Source dataset
uspto-grants-2016_07
Patent number
US09399636B2

Reaction notes

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