Cesium carbonate → 1-[(2-Ethylphenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]methyl]urea

HRID 1772499Notes

Reaction equation

HRID 1772499 reaction equation
[F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[C:25](=[O:36])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.C([O-])(=O)C.[Na+].[CH2:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH:50][C:51]([NH2:53])=[S:52])[CH3:43].C(=O)([O-])[O-].[Cs+].[Cs+]>ClCCl.O.C(#N)C>[CH2:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH:50][C:51]([NH:53][C:25]([NH:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:23])[F:24])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[O:36])=[S:52])[CH3:43]

Participants

9

Reactant 5

HCID 10796Cesium carbonateHCID 94429TriphosgeneHCID 517045Sodium AcetateHCID 2758895(2-Ethylphenyl)thioureaHCID 904040894-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenylmethanamine

Product 1

HCID 904042641-[(2-Ethylphenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]methyl]ureaYield 51.5%

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent3×

Procedure

A fine suspension of (4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methanamine (C16) (0.300 g, 0.897 mmol) in dichloromethane (4.0 mL) was added, in a slow dropwise fashion, to a biphasic solution of bis(trichloromethyl) carbonate (0.107 g, 0.359 mmol) and sodium acetate (0.221 g, 2.69 mmol) in dichloromethane (4.0 mL) and water (2.0 mL). The reaction was allowed to stir for 30 minutes. The reaction was passed through a phase separator, washing with additional dichloromethane and the organic layer was concentrated. The resulting residue was diluted with acetonitrile (4.0 mL), and 1-(2-ethylphenyl)thiourea (0.178 g, 0.987 mmol) and cesium carbonate (0.351 g, 1.08 mmol) were added as solids. The reaction was allowed to stir at room temperature overnight. The reaction mixture was diluted with dichloromethane and water and passed through a phase separator. The organic layer was concentrated on to Celite® and purified by reverse phase flash column chromatography (C18) using 20-100% acetonitrile/water as eluent providing the title compound as a white solid (0.100 g, 16%) contaminated with ˜20% of the dimer urea: 1H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 10.24 (s, 1H), 9.41 (s, 1H), 9.40 (d, J=1.0 Hz, 1H), 8.18-8.03 (m, 6H), 7.63 (dddd, J=9.2, 4.3, 2.0, 1.0 Hz, 3H), 7.54 (ddd, J=12.1, 7.0, 4.8 Hz, 2H), 7.50-7.38 (m, 3H), 7.35-7.26 (m, 1H), 7.26-7.20 (m, 2H), 4.44 (d, J=5.8 Hz, 2H), 2.56 (q, J=7.6 Hz, 2H), 1.14 (t, J=7.6 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 541 ([M+H]+), 539 ([M−H]−).

Workup

  1. washwashing with additional dichloromethane
  2. concentrationthe organic layer was concentrated
  3. additionwere added as solids
  4. stirringto stir at room temperature overnight
  5. concentrationThe organic layer was concentrated on to Celite®
  6. custompurified by reverse phase flash column chromatography (C18)

Sources & evidence

ORD record
ord-b5be35de3af14d8bbc7ebe1463d34940
Source dataset
uspto-grants-2016_02
Patent number
US09249133B2

Reaction notes

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