Water → N-methyl-4-(4-ureidophenoxy)picolinamide

HRID 885099Notes

Reaction equation

HRID 885099 reaction equation
COC1C=CC(C(F)(F)F)=CC=1N.C1N=C[N:16]([C:19](N2C=NC=C2)=[O:20])C=1.[CH3:26][NH:27][C:28]([C:30]1[CH:35]=[C:34]([O:36][C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)[CH:33]=[CH:32][N:31]=1)=[O:29].O>C(Cl)Cl>[CH3:26][NH:27][C:28]([C:30]1[CH:35]=[C:34]([O:36][C:37]2[CH:43]=[CH:42][C:40]([NH:41][C:19]([NH2:16])=[O:20])=[CH:39][CH:38]=2)[CH:33]=[CH:32][N:31]=1)=[O:29]

Participants

6

Reactant 4

HCID 962WaterHCID 682631,1'-CarbonyldiimidazoleHCID 6006372-Methoxy-5-(trifluoromethyl)anilineHCID 166551294-(4-Aminophenoxy)-N-methylpicolinamide

Product 1

HCID 25221151N-methyl-4-(4-ureidophenoxy)picolinamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.15 g) in anh CH2Cl2 (15 mL) at 0° C. is added CDI (0.13 g). The resulting solution is allowed to warm to room temp. over 1 h, is stirred at room temp. for 16 h, then is treated with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g) from Step 2. The resulting yellow solution is stirred at room temp. for 72 h, then is treated with H2O (125 mL). The resulting aqueous mixture is extracted with EtOAc (2×150 mL). The combined organics are washed with a saturated NaCl solution (100 mL), dried (MgSO4) and concentrated under reduced pressure. The residue is triturated (90% EtOAc/10% hexane). The resulting white solids are collected by filtration and washed with EtOAc. The filtrate is concentrated under reduced pressure and the residual oil purified by column chromatography (gradient from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane to 100% EtOAc) to give N-(2-methoxy-5-(trifluoromethyl)phenyl)-N)-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea as a light tan solid: TLC (100% EtOAc) Rf 0.62; 1H NMR (DMSO-d6) δ 2.76 (d, Hz, 3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 (m, 11H), 8.75 (d, J=4.8 Hz, 1H), 9.55 (s, 1H); FAB-MS m/z 461 ((M+H)+).

Workup

  1. temperatureto warm to room temp. over 1 h
  2. stirringThe resulting yellow solution is stirred at room temp. for 72 h
  3. extractionThe resulting aqueous mixture is extracted with EtOAc (2×150 mL)
  4. washThe combined organics are washed with a saturated NaCl solution (100 mL)
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated under reduced pressure
  7. customThe residue is triturated (90% EtOAc/10% hexane)
  8. filtrationThe resulting white solids are collected by filtration
  9. washwashed with EtOAc
  10. concentrationThe filtrate is concentrated under reduced pressure
  11. customthe residual oil purified by column chromatography (gradient from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane to 100% EtOAc)

Sources & evidence

ORD record
ord-6b84c9b12ce24e56b4b5b2c4376dc22c
Source dataset
uspto-grants-2012_08
Patent number
US08242147B2

Reaction notes

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