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Water → 4-(4-(3-(2-methoxy-5-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide

HRID 78331
Notes
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Reaction equation

HRID 78331 reaction equation
[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:4]=1[NH2:5].C1N=CN([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>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:4]=1[NH:5][C:19]([NH:41][C:40]1[CH:42]=[CH:43][C:37]([O:36][C:34]2[CH:33]=[CH:32][N:31]=[C:30]([C:28](=[O:29])[NH:27][CH3:26])[CH:35]=2)=[CH:38][CH:39]=1)=[O:20]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

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

Product 1

HCID 101276604-(4-(3-(2-methoxy-5-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamideYield 30%

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. was added CDI (0.13 g). The resulting solution was allowed to warm to room temp. over 1 h, was stirred at room temp. for 16 h, then was treated with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g). The resulting yellow solution was stirred at room temp. for 72 h, then was treated with H2O (125 mL). The resulting aqueous mixture was extracted with EtOAc (2×150 mL). The combined organics were washed with a saturated NaCl solution (100 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration and washed with EtOAc. The filtrate was 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 (0.098 g, 30%): TLC (100% EtOAc) Rf 0.62; 1H NMR (DMSO-d6) δ 2.76 (d, J=4.8 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 was stirred at room temp. for 72 h
  3. extractionThe resulting aqueous mixture was extracted with EtOAc (2×150 mL)
  4. washThe combined organics were washed with a saturated NaCl solution (100 mL)
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was triturated (90% EtOAc/10% hexane)
  8. filtrationThe resulting white solids were collected by filtration
  9. washwashed with EtOAc
  10. concentrationThe filtrate was 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-2857cc8ccf7b47feab4e812313b967b6
Source dataset
uspto-grants-2014_09
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08841330B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes