Urea → Pexmetinib

HRID 1665991Notes

Reaction equation

HRID 1665991 reaction equation
NC(N)=O.CO[CH:7]([O:28]C)[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH2:26][NH2:27])=[CH:15][CH:16]=2)[CH:11]=[N:10]1.[C:30]([C:34]1[CH:38]=[C:37]([NH:39][C:40](=O)[O:41]CC(Cl)(Cl)Cl)[N:36]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)[N:35]=1)([CH3:33])([CH3:32])[CH3:31].C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[C:30]([C:34]1[CH:38]=[C:37]([NH:39][C:40]([NH:27][CH2:26][C:20]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=2[O:18][C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[N:9]([CH2:8][CH2:7][OH:28])[N:10]=[CH:11]3)=[O:41])[N:36]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)[N:35]=1)([CH3:33])([CH3:32])[CH3:31]

Participants

6

Reactant 4

HCID 1176UreaHCID 81531DiisopropylethylamineHCID 99310942,2,2-Trichloroethyl 3-tert-butyl-1-P-tolyl-1H-pyrazol-5-ylcarbamateHCID 57552285(2-(1-(2,2-dimethoxyethyl)-1H-indazol-5-yloxy)-5-fluorophenyl)methanamine

Product 1

HCID 24765037Pexmetinib

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
80 °C

Procedure

Preparation of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(241-(2,2-dimethoxyethyl)-1H-indazol-5-yloxy)-5-fluorobenzyl)urea 70: (2-(1-(2,2-dimethoxyethyl)-1H-indazol-5-yloxy)-5-fluorophenyl)methanamine (2.00 g, 5.791 mmol), 2,2,2-trichloroethyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (3.516 g, 8.686 mmol) and N,N-diisopropylethylamine (3.026 mL, 17.37 mmol) were suspended in N,N-dimethylacetamide (50 mL) and heated at 80° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue diluted with EtOAc and saturated aqueous NH4Cl. The organics were washed with water (3×), brine, dried (MgSO4) and then concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant 35-45% EtOAc/Hexanes). After evaporation of the solvent, the desired product was obtained as a pale yellow foam (2.57 g, 74%). MS (APCI+) m/z 602 (M+1) was detected. 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.43 (d, 1H, J=9 Hz), 6.72-7.30 (m, 9H), 6.18 (s, 1H), 6.01 (br, 1H), 5.47 (t, 1H, J=6.1 Hz), 4.76 (t, 1H, J=5.3 Hz), 4.44 (t, 4H, J=5.6 Hz), 3.38 (s, 6H), 2.37 (s, 3H), 1.30 (s, 9H).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. additionthe residue diluted with EtOAc and saturated aqueous NH4Cl
  3. washThe organics were washed with water (3×), brine
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated under reduced pressure
  6. customto afford the crude material, which
  7. customwas purified by flash column chromatography (eluant 35-45% EtOAc/Hexanes)
  8. customAfter evaporation of the solvent

Sources & evidence

ORD record
ord-731aac986d4848e5ba1c5dce4a61a843
Source dataset
uspto-grants-2011_10
Patent number
US08039639B2

Reaction notes

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