N-[4-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-phenyl]-2,2-dimethyl-succinamic acid → 1-[2-(4-aminophenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]urea

HRID 221897Notes

Reaction equation

HRID 221897 reaction equation
[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[O:12])[N:7]([C:27]2[CH:32]=[CH:31][C:30]([NH:33]C(=O)CC(C)(C)C(O)=O)=[CH:29][CH:28]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[NH2:33][C:30]1[CH:31]=[CH:32][C:27]([N:7]2[C:8]([NH:10][C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=4)=[CH:16][CH:15]=3)=[O:12])=[CH:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]2)=[CH:28][CH:29]=1

Participants

3

Reactant 1

HCID 11519796N-[4-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-phenyl]-2,2-dimethyl-succinamic acid

Product 1

HCID 536301891-[2-(4-aminophenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]ureaYield 54.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of N-[4-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-phenyl]-2,2-dimethyl-succinamic acid (190 mg, 0.33 mmol) in 3 mL THF was treated with borane-methylsulfide complex (2M, 1.0 mL, 2.0 mmol, 6 eq). The reaction mixture was heated at reflux under nitrogen for 4 h. The reaction mixture was then cooled to room temperature, slowly quenched by the addition of 0.6 mL EtOH and 2 mL 2N HCl. The reaction mixture was heated again at reflux for 1 hr, then cooled to room temperature, basified by the addition of 1N NaOH, extracted with DCM, and concentrated at reduced pressure. The crude residue was purified by MPLC (eluting with 2% to 6% MeOH in DCM) to afford 80 mg of semi-pure 1-[2-(4-amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea. Preparative HPLC purification using 5-80% H2O in acetonitrile (containing 0.5% TFA) afforded 33 mg (18%) of the desired product. 1H-NMR (DMSO-d6) δ 9.14 (s, 1H), 8.40 (dd, J=1.6 & 4.8 Hz, 2H), 8.17 (s, 1H), 7.47 (d, J=8.9 Hz, 2H), 7.11 (d, J=8.6 Hz, 2H), 7.07 (d, J=9 Hz, 2H), 6.85 (dd, J=1.5 & 4.9 Hz, 2H), 6.62 (d, J=8.9 Hz, 2H), 6.28 (s, 1H), 5.83 (t, J=5.2 Hz, 1H), 4.58 (t, J=5.2 Hz, 1H), 3.14 (d, J=5.4 Hz, 2H), 3.06-3.01 (m, 2H), 1.52-1.48 (m, 2H), 1.25 (s, 9H), 0.87 (s, 6H); MS LC-MS [M+H]+=543.2, RT=2.31 min.

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureat reflux under nitrogen for 4 h
  3. customslowly quenched by the addition of 0.6 mL EtOH and 2 mL 2N HCl
  4. temperatureThe reaction mixture was heated again
  5. temperatureat reflux for 1 hr
  6. temperaturecooled to room temperature
  7. additionbasified by the addition of 1N NaOH
  8. extractionextracted with DCM
  9. concentrationconcentrated at reduced pressure
  10. customThe crude residue was purified by MPLC (eluting with 2% to 6% MeOH in DCM)

Sources & evidence

ORD record
ord-26c07c05e52840728951602cd2614a40
Source dataset
uspto-grants-2012_06
Patent number
US08207166B2

Reaction notes

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