Citric Acid → N-Methyl-N-(6-methyl-4-o-tolyl-pyridin-3-yl)-3,5-bis-trifluoromethyl-benzamide

HRID 878131Notes

Reaction equation

HRID 878131 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:3]=1.[Cl-].C[Zn+].[CH3:36]N1CCN(C)C1=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CC(C1C=CC=C(C(C)C)C=1N1[CH-]N(C2C(C(C)C)=CC=CC=2C(C)C)CC1)C.C1C=NC=C(Cl)C=1.Cl[Pd]Cl.CCOC(C)=O>[CH3:25][N:8]([C:5]1[CH:6]=[N:7][C:2]([CH3:36])=[CH:3][C:4]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1

Participants

8

Reactant 4

HCID 311Citric AcidHCID 66611,3-Dimethyl-2-imidazolidinoneHCID 60197100N-(6-Chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamideHCID 178477797HCID 178477797, compound

Product 1

HCID 86670748N-Methyl-N-(6-methyl-4-o-tolyl-pyridin-3-yl)-3,5-bis-trifluoromethyl-benzamide

Reagents, catalysts & solvents 3

HCID 588388791,3-Bis[2,6-di(propan-2-yl)phenyl]imidazolidin-2-ide;3-chloropyridine;dichloropalladiumCatalystHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (0.15 g, 0.317 mmol, example 12) in THF (2 mL) were added methylzinc chloride (0.238 mL, 0.476 mmol, 2M solution in THF), 1,3-dimethyl-2-imidazolidinone (0.4 mL, CAS RN 80-73-9) and (1,3-bis(2,6-diisopropylphenyl)imidazolidene) (3-chloropyridyl)palladium(II) dichloride (4.31 mg, 0.00635 mmol, Sigma-Aldrich) and the reaction was stirred at 50° C. (oil bath temperature) for 1 h. The reaction mixture was poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc and the organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Colorless oil (0.122 g; 85%). MS (ESI): m/z=453.14 [M+H]+.

Workup

  1. customthe layers were separated
  2. extractionThe aqueous layer was extracted twice with EtOAc
  3. washthe organic layers were washed with brine
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. additiontreated with silica gel
  7. customevaporated
  8. customThe compound was purified by silica gel chromatography on a 10 g column
  9. washeluting with a gradient of n-heptane:EtOAc (100:0 to 50:50)

Sources & evidence

ORD record
ord-64dffa1722b84c568825df8db32a1f95
Source dataset
uspto-grants-2015_03
Patent number
US08987307B2

Reaction notes

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