Triethylamine → 1-(2-(4-Bromophenyl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(2,2,2-trifluoroethyl)urea

HRID 1712755Notes

Reaction equation

HRID 1712755 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)C(O)=O)=[CH:4][CH:3]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:42])C=CC=CC=1.C([N:54]([CH2:57]C)CC)C.[F:59][C:60]([F:64])([F:63])[CH2:61][NH2:62]>C1(C)C=CC=CC=1.CCOC(C)=O.CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:54][C:57]([NH:62][CH2:61][C:60]([F:64])([F:63])[F:59])=[O:42])([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:32])[F:33])[CH:25]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)=[CH:6][CH:7]=1

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 9773Ethanamine, 2,2,2-trifluoro-HCID 199401P,P-Diphenylphosphinic azideHCID 594584643-(4-Bromophenyl)-2,2-bis(3-(trifluoromethoxy)phenyl)propanoic acid

Product 1

HCID 235820251-(2-(4-Bromophenyl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(2,2,2-trifluoroethyl)ureaYield 65%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolventHCID 22242641Methanol--water (1/1)Solvent

Procedure

To a solution of 3-(4-bromophenyl)-2,2-bis(3-(trifluoromethoxy)phenyl)propanoic acid (260 mg, 0.47 mmol) in toluene (10 mL) was added diphenylphosphoryl azide (0.409 mL, 1.9 mmol) followed by triethylamine (0.264 mL, 1.9 mmol). The reaction mixture was heated at reflux for 1 h, then trifluoroethylamine was added and the reaction mixture was heated at reflux for another 1 h. The reaction mixture was allowed to cool to rt and diluted with EtOAc (30 mL) and washed successively with sat. NH4Cl (10 mL), sat. NaHCO3 (10 mL) and sat. NaCl (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified on a ISCO silica gel column (12 g) with elution at 0 to 20% EtOAc/hexane over 20 min, then further purified by preparative HPLC YMC ODS S5 30×100 mm column 40-100% MeOH/H2O (90% in water, 0.1% TFA) gradient over 10 mm with flow rate 40 mL/min and UV detection at 220 nm to yield 1-(2-(4-bromophenyl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(2,2,2-trifluoroethyl)urea (Example 278) as a white solid (200 mg, yield 65%). LCMS: RT=2.24 mm [M+H] 645.0 (2 mm Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=4.476 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 3.68-3.77 (m, 2H), 3.81 (s, 2H), 4.80 (t, J=6.15 Hz, 1H), 5.15 (s, 1H), 6.52 (d, J=7.91 Hz, 2H), 6.97 (s, 2H), 7.09-7.17 (m, 4H), 7.23-7.27 (m, 3H), 7.34 (t, J=7.91 Hz, 2H).

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureat reflux for 1 h
  3. temperaturethe reaction mixture was heated
  4. temperatureat reflux for another 1 h
  5. washwashed successively with sat. NH4Cl (10 mL), sat. NaHCO3 (10 mL) and sat. NaCl (20 mL)
  6. dry with materialThe organic layer was dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe crude product was purified on a ISCO silica gel column (12 g) with elution at 0 to 20% EtOAc/hexane over 20 min
  10. customfurther purified by preparative HPLC YMC ODS

Sources & evidence

ORD record
ord-6130dd935b9546d8aa2f87ba2dd3b9fa
Source dataset
uspto-grants-2010_09
Patent number
US07790770B2

Reaction notes

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