Cesium carbonate → 7-((Dimethylamino)methyl)-N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

HRID 79451Notes

Reaction equation

HRID 79451 reaction equation
C(=O)([O-])[O-].[Cs+].[Cs+].C1(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=CC=1.Br[C:54]1[CH:59]=[CH:58][N:57]2[C:60]([C:63]([NH:65][C:66]3[CH:74]=[CH:73][CH:72]=[C:71]4[C:67]=3[C:68]([CH2:83][CH3:84])=[N:69][N:70]4[CH2:75][C:76]3[CH:81]=[CH:80][CH:79]=[C:78]([CH3:82])[N:77]=3)=[O:64])=[CH:61][N:62]=[C:56]2[CH:55]=1.[CH3:85][N:86]([CH2:88][B-](F)(F)F)[CH3:87].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:85][N:86]([CH2:88][C:54]1[CH:59]=[CH:58][N:57]2[C:60]([C:63]([NH:65][C:66]3[CH:74]=[CH:73][CH:72]=[C:71]4[C:67]=3[C:68]([CH2:83][CH3:84])=[N:69][N:70]4[CH2:75][C:76]3[CH:81]=[CH:80][CH:79]=[C:78]([CH3:82])[N:77]=3)=[O:64])=[CH:61][N:62]=[C:56]2[CH:55]=1)[CH3:87]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 45588179Potassium dimethylaminomethyl trifluoroboronateHCID 672595577-Bromo-N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Product 1

HCID 672612127-((Dimethylamino)methyl)-N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideYield 59.1%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Procedure

A round bottom flask equipped with a reflux condenser and a nitrogen line was charged with palladium acetate (3.4 mg, 0.015 mmol), cesium carbonate (300 mg, 0.92 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (19 mg, 0.030 mmol), 7-bromo-N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 127, Step A; 150 mg, 0.307 mmol), and potassium (dimethylaminomethyl)trifluoroborate (Frontier Scientific; 101 mg, 0.613 mmol). To the reaction flask was added a 1,4-dioxane:water mixture (10:1; 1.1 mL) and the reaction flask was immediately evacuated and refilled with nitrogen three times. The reaction mixture was heated at reflux for 16 hours under nitrogen. After cooling to ambient temperature, the reaction mixture was diluted with water, and extracted multiple times with dichloromethane. The combined dichloromethane extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (silica, 2% 7N ammonia-MeOH:8% MeOH:DCM) to afford the product (84.8 mg) as a white solid. 1H NMR (CDCl3) δ 9.5 (d, 1H), 8.35 (s, 1H), 8.20 (s, 1H), 7.84 (d, 1H), 7.62 (m, 1H), 7.40 (t, 1H), 7.32 (t, 1H), 7.12 (m, 2H), 7.01 (d, 1H), 6.48 (d, 1H), 5.65 (s, 2H), 3.52 (s, 2H), 3.23 (q, 2H), 2.29 (s, 6H), 1.51 (t, 3H).

Workup

  1. customA round bottom flask equipped with a reflux condenser
  2. customwater mixture (10:1; 1.1 mL) and the reaction flask was immediately evacuated
  3. additionrefilled with nitrogen three times
  4. temperatureThe reaction mixture was heated
  5. temperatureat reflux for 16 hours under nitrogen
  6. additionthe reaction mixture was diluted with water
  7. extractionextracted multiple times with dichloromethane
  8. dry with materialThe combined dichloromethane extracts were dried over anhydrous sodium sulfate
  9. concentrationconcentrated under reduced pressure
  10. customThe crude residue was purified by preparative thin-layer chromatography (silica, 2% 7N ammonia-MeOH:8% MeOH:DCM)

Sources & evidence

ORD record
ord-cf6bf1bb57c8476ba94f276a7c0063ce
Source dataset
uspto-grants-2014_09
Patent number
US08841455B2

Reaction notes

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