Cesium carbonate → Ethyl 6-(3-ethylureido)-4-(phenylamino)nicotinate

HRID 2174234Notes

Reaction equation

HRID 2174234 reaction equation
Cl[C:2]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[CH2:20]([NH:22][C:23]([NH2:25])=[O:24])[CH3:21].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].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>[CH2:20]([NH:22][C:23](=[O:24])[NH:25][C:2]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1)[CH3:21]

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 12254EthylureaHCID 59212513Ethyl 6-chloro-4-(phenylamino)nicotinate

Product 1

HCID 89650713Ethyl 6-(3-ethylureido)-4-(phenylamino)nicotinateYield 92%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of ii (6.40 g, 23.18 mmol) in 1,4-dioxane (200 mL) was added N-ethylurea (2.60 g, 29.0 mmol) followed by Cs2CO3 (11.50 g, 34.80 mmol). The resulting solution was purged with nitrogen for 15 min followed by addition of Pd(OAc)2 (0.16 g, 0.70 mmol) and Xantphos (0.81 g, 1.40 mmol). The reaction mixture was again purged with nitrogen for 15 min and then heated at 80° C. for 16 h. The reaction mass was cooled to room temperature and filtered through a celite bed. The celite bed was washed with EtOAc and the combined filtrates concentrated under reduced pressure. Water was added to the residue and extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over silica gel (60-120 M, 50-75% EtOAc-hexane) to obtain a solid residue. This was purified further by trituration with 25% ether-hexane to afford compound iii as an off-white solid (7.0 g, 92%). 1H-NMR (400 MHz, DMSO-d6): δ 9.14 (s, 1H) and 9.64 (s, 1H), 8.61 (s, 1H), 7.70 (br s, 1H), 7.27-7.45 (m, 5H), 7.21 (t, J=7.20 Hz, 1H), 4.32 (q, J=7.20 Hz, 2H), 3.11 (m, 2H), 1.34 (t, J=7.20 Hz, 3H), 1.04 (t, J=7.20 Hz, 3H). [M+H]+ m/z=329.14.

Workup

  1. customThe resulting solution was purged with nitrogen for 15 min
  2. customThe reaction mixture was again purged with nitrogen for 15 min
  3. temperatureThe reaction mass was cooled to room temperature
  4. filtrationfiltered through a celite bed
  5. washThe celite bed was washed with EtOAc
  6. concentrationthe combined filtrates concentrated under reduced pressure
  7. additionWater was added to the residue
  8. extractionextracted with EtOAc (3×20 mL)
  9. washThe combined organic phase was washed with brine
  10. dry with materialdried (Na2SO4)
  11. filtrationfiltered
  12. concentrationconcentrated under reduced pressure
  13. customThe crude residue was purified over silica gel (60-120 M, 50-75% EtOAc-hexane)
  14. customto obtain a solid residue
  15. customThis was purified further by trituration with 25% ether-hexane

Sources & evidence

ORD record
ord-8fc9b1dfd29440d7884716804b972cef
Source dataset
uspto-grants-2015_06
Patent number
US09060515B2

Reaction notes

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