Cesium carbonate → 2-[(5-Chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]-3-fluorobenzonitrile

HRID 62541

Reaction equation

HRID 62541 reaction equation
Cl[C:2]1[CH:7]=[C:6](I)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14].[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+].C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:77][C:78]1[CH:82]=[C:81]([NH2:83])[N:80]([CH:84]([CH3:86])[CH3:85])[N:79]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:9][C:5]1[C:6]([NH:10][C:11]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])=[CH:7][C:2]([NH:83][C:81]2[N:80]([CH:84]([CH3:86])[CH3:85])[N:79]=[C:78]([CH3:77])[CH:82]=2)=[N:3][CH:4]=1

Participants

9

Reactant 6

HCID 10796Cesium carbonateHCID 61695Pentapotassium TriphosphateHCID 1210181-Isopropyl-3-methyl-1H-pyrazol-5-amineHCID 27833922-Amino-3-fluorobenzonitrileHCID 4285986Bis[2-(diphenylphosphino)phenyl] ether2×HCID 534009652,5-Dichloro-4-iodopyridine

Product 1

HCID 667697122-[(5-Chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]-3-fluorobenzonitrileYield 53.4%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalyst2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
50 °C

Procedure

To a degassed solution of 2,5-dichloro-4-iodopyridine (8 g, 29.2 mmol), 2-amino-3-fluorobenzonitrile (3.98 g, 29.2 mmol) and potassium triphosphate (18.60 g, 88 mmol) in 1,4-dioxane (60 ml) stirred under nitrogen at the room temperature was added DPEPhos (1.258 g, 2.337 mmol) and palladium acetate (0.262 g, 1.168 mmol) The reaction mixture was stirred at reflux for 18 hr. The reaction mixture was filtered. 3-Methyl-1-(1-methylethyl)-1H-pyrazol-5-amine (4.07 g, 29.2 mmol) and cesium carbonate (28.6 g, 88 mmol) were added. The reaction mixture was degassed and palladium acetate (0.262 g, 1.168 mmol) and DPEPhos (1.258 g, 2.337 mmol) were added. The reaction mixture was refluxed overnight. The reaction mixture was filtered and the solid was dissolved in water, heated to 50° C. and stirred for 10 minutes, then filtered again. 2-[(5-Chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]-3-fluorobenzonitrile (6 g, 15.59 mmol, 53.4% yield) was isolated as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (d, J=6.57 Hz, 6 H) 2.07 (s, 3 H) 4.32 (quin, J=6.57 Hz, 1 H) 5.64 (d, J=2.02 Hz, 1 H) 5.83 (s, 1 H) 7.39-7.58 (m, 1 H) 7.63-7.82 (m, 2 H) 7.88 (s, 1 H) 8.26 (br. s., 1 H) 8.41 (br. s., 1 H); HPLC Rt=2.35 min, MS (ESI): 385.0 [M+H]+.

Workup

  1. temperatureat reflux for 18 hr
  2. filtrationThe reaction mixture was filtered
  3. customThe reaction mixture was degassed
  4. temperatureThe reaction mixture was refluxed overnight
  5. filtrationThe reaction mixture was filtered
  6. dissolutionthe solid was dissolved in water
  7. stirringstirred for 10 minutes
  8. filtrationfiltered again

Sources & evidence

ORD record
ord-6e3639a55755478ca870328a0ec3630d
Source dataset
uspto-grants-2016_09
Patent number
US09446034B2

Linked notes

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