Cesium carbonate → 2-[(2,5-dichloropyridin-4-yl)amino]-6-fluoro-N-methylbenzamide

HRID 1045932Notes

Reaction equation

HRID 1045932 reaction equation
CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:49][C:50]1[CH:59]=[CH:58][CH:57]=[C:56]([F:60])[C:51]=1[C:52]([NH:54][CH3:55])=[O:53].[Cl:61][C:62]1[CH:67]=[C:66](I)[C:65]([Cl:69])=[CH:64][N:63]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:61][C:62]1[CH:67]=[C:66]([NH:49][C:50]2[CH:59]=[CH:58][CH:57]=[C:56]([F:60])[C:51]=2[C:52]([NH:54][CH3:55])=[O:53])[C:65]([Cl:69])=[CH:64][N:63]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 208067942-amino-6-fluoro-N-methylbenzamideHCID 534009652,5-Dichloro-4-iodopyridine

Product 1

HCID 866551412-[(2,5-dichloropyridin-4-yl)amino]-6-fluoro-N-methylbenzamideYield 26%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
80 °C

Procedure

A mixture of palladium(II) acetate (53.4 mg, 0.24 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (206 mg, 0.36 mmol), cesium carbonate (3875 mg, 11.89 mmol), 2-amino-6-fluoro-N-methylbenzamide (1000 mg, 5.95 mmol) and 2,5-dichloro-4-iodopyridine (1710 mg, 6.24 mmol) in dioxane (50 mL) under an atmosphere of nitrogen was heated at 80° C. for 18 hours. The mixture was allowed to cool to room temperature, filtered and then evaporated. The residue was dissolved in EtOAc (150 mL) and the mixture washed sequentially with a saturated solution of NaHCO3 (2×100 mL), water (100 mL) and then with a saturated solution of NaCl (100 mL). The organic layer was dried over MgSO4 and then evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 0-100% EtOAc in isohexane. Fractions containing product were combined and evaporated to afford 2-[(2,5-dichloropyridin-4-yl)amino]-6-fluoro-N-methylbenzamide (486 mg, 26% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 2.74 (3H, d), 6.96 (1H, d), 7.15 (1H, ddd), 7.37 (1H, d), 7.54 (1H, td), 8.26 (1H, s), 8.54 (1H, m), 9.09 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+ =314.26 and 316.21 and 318.23.

Workup

  1. temperatureto cool to room temperature
  2. filtrationfiltered
  3. customevaporated
  4. dissolutionThe residue was dissolved in EtOAc (150 mL)
  5. washthe mixture washed sequentially with a saturated solution of NaHCO3 (2×100 mL), water (100 mL)
  6. dry with materialThe organic layer was dried over MgSO4
  7. customevaporated
  8. customThe residue was purified by chromatography on silica
  9. washeluting with a gradient of 0-100% EtOAc in isohexane
  10. additionFractions containing product
  11. customevaporated

Sources & evidence

ORD record
ord-a5311303dfaf4c9db5567c6bf2495b7d
Source dataset
uspto-grants-2013_10
Patent number
US08569298B2

Reaction notes

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