Methane → 3-(4-Fluorophenyl)-1-methyl-1-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yloxy)urea

HRID 1895925Notes

Reaction equation

HRID 1895925 reaction equation
[CH3:1][NH:2][O:3][CH:4]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5]1.ClC([O:26][C:27](Cl)(Cl)Cl)=O.C.[F:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[F:32][C:33]1[CH:39]=[CH:38][C:36]([NH:37][C:27](=[O:26])[N:2]([CH3:1])[O:3][CH:4]2[CH2:5][CH2:6][N:7]([S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)(=[O:12])=[O:11])[CH2:8][CH2:9]2)=[CH:35][CH:34]=1

Participants

7

Reactant 5

HCID 297MethaneHCID 97314-FluoroanilineHCID 10426DiphosgeneHCID 81531DiisopropylethylamineHCID 86652730N-methyl-O-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)hydroxylamine

Product 1

HCID 866527313-(4-Fluorophenyl)-1-methyl-1-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yloxy)ureaYield 49%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of N-methyl-O-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)hydroxylamine (130 mg, 0.384 mmol) in tetrahydrofuran (10 ml) was added to a suspension of trichloromethyl chloroformate (91.3 mg, 0.46 mmol) and activated charcoal (20 mg) in tetrahydrofuran (35 ml) at 0° C. over 30 minutes. After stirring at room temperature for 18 hours, the reaction mixture was filtered over silicagel and the filtrate was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (15 ml), 4-fluoroaniline (65 mg, 1.13 mmol) and N,N-diisopropylethylamine (148 mg, 1.15 mmol) were added and the whole was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (50 ml), washed with H2O (20 ml×2), brine (20 ml×2), dried over Na2SO4 and concentrated in vacuo. The residual solid was recrystallized from diethyl ether to give 3-(4-fluorophenyl)-1-methyl-1-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yloxy)urea (89.5 mg, 49%) as a white solid. LCMS: 476 [M+1]+. 1H NMR (DMSO-d6) δ: 1.79 (m, 2H), 1.98 (m, 2H), 2.59 (m, 2H), 3.0 (s, 3H), 3.62 (d, 2H), 3.89 (m, 1H), 7.11 (t, 2H), 7.50 (m, 2H), 7.94 (q, 2H), 8.12 (q, 2H), 8.70 (s, 1H).

Workup

  1. filtrationthe reaction mixture was filtered over silicagel
  2. concentrationthe filtrate was concentrated in vacuo
  3. dissolutionThe residue was dissolved in tetrahydrofuran (15 ml)
  4. stirringthe whole was stirred at room temperature for 18 hours
  5. concentrationThe reaction mixture was concentrated in vacuo
  6. additionthe residue was diluted with ethyl acetate (50 ml)
  7. washwashed with H2O (20 ml×2), brine (20 ml×2)
  8. dry with materialdried over Na2SO4
  9. concentrationconcentrated in vacuo
  10. customThe residual solid was recrystallized from diethyl ether

Sources & evidence

ORD record
ord-5536c3b488614e68b9c38278af3bed00
Source dataset
uspto-grants-2013_08
Patent number
US08518934B2

Reaction notes

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