N-Hydroxyacetamidine → Methyl [3,5-bis(trifluoromethyl)benzyl]{[2'-methoxy-5'-(3-methyl-1,2,4-oxadiazol-5-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate

HRID 17092

Reaction equation

HRID 17092 reaction equation
C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:48])([F:47])[C:9]1[CH:10]=[C:11]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:12][N:13]([CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]([C:37]([OH:39])=O)[CH:30]=1)[C:14]([O:16][CH3:17])=[O:15].[C:49](=[N:52]O)([NH2:51])[CH3:50]>CN(C)C=O.C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]1[CH:40]=[C:11]([CH:10]=[C:9]([C:8]([F:7])([F:48])[F:47])[CH:42]=1)[CH2:12][N:13]([CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:30]=[C:31]([C:37]2[O:39][N:52]=[C:49]([CH3:50])[N:51]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[C:14](=[O:15])[O:16][CH3:17]

Participants

6

Reactant 3

HCID 30926N-HydroxyacetamidineHCID 65578Oxalyl chlorideHCID 115924972'-{[[3,5-Bis(trifluoromethyl)benzyl](methoxycarbonyl)amino]methyl}-6-methoxy-4'-(trifluoromethyl)biphenyl-3-carboxylic acid

Product 1

HCID 11563674Methyl [3,5-bis(trifluoromethyl)benzyl]{[2'-methoxy-5'-(3-methyl-1,2,4-oxadiazol-5-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalyst2×HCID 6344DichloromethaneSolvent

Procedure

Oxalyl chloride (0.14 mL, 0.28 mmol) and a few drops of dimethylformamide were added to a solution of the title compound from Example 145 (86 mg, 0.14 mmol) in methylene chloride. The reaction mixture was stirred at room temperature for 1 h then concentrated in vacuo. The crude product was re-dissolved in anhydrous dichloroethane, and acetamide oxime (16 mg, 0.21 mmol) was added along with a few drops of dimethylformamide to increase solubility. The reaction was heated to and maintained at reflux overnight. Once the reaction cooled to room temperature, the solvent was removed through evaporation. The oil was taken up in methylene chloride, washed with water, then brine, dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was obtained by preparative thin layer chromatography using 50% EtOAc/hexane. 1H NMR (CDCl3, 600 MHz) δ 8.15 (s, 1H), 7.86 (s, 1H), 7.71 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.43-7.56 (m, 3H), 7.35 (d, J=7.8 Hz, 1H), 7.07 (m, 1H), 4.20-4.60 (m, 4H), 3.81 (s, 3H), 3.70 (m, 3H), 2.46 (s, 3H). LC-MS (M+1) 647.9 (4.40 min).

Workup

  1. concentrationthen concentrated in vacuo
  2. dissolutionThe crude product was re-dissolved in anhydrous dichloroethane
  3. temperatureto increase solubility
  4. temperatureThe reaction was heated to and
  5. temperaturemaintained
  6. temperatureat reflux overnight
  7. temperatureOnce the reaction cooled to room temperature
  8. customthe solvent was removed through evaporation
  9. washwashed with water
  10. dry with materialbrine, dried over anhydrous sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-3b966f8e234140ce9a70b189ec935769
Source dataset
uspto-grants-2010_06
Patent number
US07737295B2

Linked notes

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