Diisopropylethylamine → 1-(2-(3,3-dimethylbutyl)-4-(trifluoromethyl)benzyl)-3-(1H-indazol-4-yl)urea

HRID 2410071Notes

Reaction equation

HRID 2410071 reaction equation
[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[CH2:15][NH2:16].C(N(C(C)C)CC)(C)C.COC([N:32]1[C:40]2[C:35](=[C:36]([NH:41][C:42](ON3C(=O)CCC3=O)=[O:43])[CH:37]=[CH:38][CH:39]=2)[CH:34]=[N:33]1)=O>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:6]=1[CH2:15][NH:16][C:42]([NH:41][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:35]=1[CH:34]=[N:33][NH:32]2)=[O:43]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 11313556methyl 4-({[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl}amino)-1H-indazole-1-carboxylateHCID 44235013(2-(3,3-Dimethylbutyl)-4-(trifluoromethyl)phenyl)methanamine

Product 1

HCID 468906011-(2-(3,3-dimethylbutyl)-4-(trifluoromethyl)benzyl)-3-(1H-indazol-4-yl)urea

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To the product of Example 1B dissolved in DMF (80 mL) was added diisopropylethylamine (5.6 mL, 32.1 mmol, 1.2 eq), followed by the addition of the product of Example 1C (8.82 g, 26.5 mmol, 1 eq). The mixture was stirred for 1 hour, diluted with ethyl acetate (600 mL) and the resulting solution washed sequentially with H2O (1×250 mL) and saturated aqueous NH4Cl (1×250 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was taked up in 2:1 methanol:THF (90 mL) and 1 N NaOH (30 mL) was added. The solution was stirred 45 minutes, concentrated under reduced pressure to remove the organic solvents. The residue was diluted with ethyl acetate (600 mL), washed sequentially with H2O (2×200 mL), brine (1×200 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude solid was filtered through SiO2 (80 mL) with 4% ethanol in ethyl acetate, stirred over charcoal, filtered and concentrated under reduced pressure, triturated with 4:1 hexane and ethyl ether (150 mL). The solid was recrystallized from methanol and water, filtered and dried under reduced pressure to provide the title compound. 1H-NMR (DMSO-d6) δ 12.99 (brs, 1H), 8.79 (brs, 1H), 8.08 (s, 1H), 7.61 (d, 1H), 7.50-7.59 (m, 3H), 7.20 (t, 1H), 7.02 (d, 1H), 6.81 (t, 1H), 4.45 (d, 2H), 2.70 (ddd, 2H), 1.45 (ddd, 2H), 0.97 (s, 9H).

Workup

  1. washthe resulting solution washed sequentially with H2O (1×250 mL) and saturated aqueous NH4Cl (1×250 mL)
  2. dry with materialdried (Na2SO4)
  3. filtrationfiltered
  4. concentrationconcentrated under reduced pressure
  5. additionTHF (90 mL) and 1 N NaOH (30 mL) was added
  6. stirringThe solution was stirred 45 minutes
  7. concentrationconcentrated under reduced pressure
  8. customto remove the organic solvents
  9. additionThe residue was diluted with ethyl acetate (600 mL)
  10. washwashed sequentially with H2O (2×200 mL), brine (1×200 mL)
  11. dry with materialdried (Na2SO4)
  12. filtrationfiltered
  13. concentrationconcentrated under reduced pressure
  14. filtrationThe crude solid was filtered through SiO2 (80 mL) with 4% ethanol in ethyl acetate
  15. stirringstirred over charcoal
  16. filtrationfiltered
  17. concentrationconcentrated under reduced pressure
  18. customtriturated with 4:1 hexane and ethyl ether (150 mL)
  19. customThe solid was recrystallized from methanol and water
  20. filtrationfiltered
  21. customdried under reduced pressure

Sources & evidence

ORD record
ord-3e5c130926f34292b3319d052b4955a4
Source dataset
uspto-grants-2014_08
Patent number
US08815930B2

Reaction notes

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