Citric Acid → N-[4-(4-Fluoro-2-methoxy-phenyl)-2-methyl-pyridin-3-yl]-3-methanesulfonyl-N-methyl-5-trifluoromethyl-benzamide

HRID 878264Notes

Reaction equation

HRID 878264 reaction equation
Cl[C:2]1[C:7]([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]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=2)=[C:6]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[O:33][CH3:34])[CH:5]=[CH:4][N:3]=1.[Cl-].C[Zn+].[CH3:38]N1CCN(C)C1=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCOC(C)=O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:38])[C:7]=2[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]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=2)=[C:27]([O:33][CH3:34])[CH:28]=1

Participants

7

Reactant 4

HCID 311Citric AcidHCID 66611,3-Dimethyl-2-imidazolidinoneHCID 60196902N-[2-Chloro-4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-3-methanesulfonyl-N-methyl-5-trifluoromethyl-benzamideHCID 178477797HCID 178477797, compound

Product 1

HCID 70663619N-[4-(4-Fluoro-2-methoxy-phenyl)-2-methyl-pyridin-3-yl]-3-methanesulfonyl-N-methyl-5-trifluoromethyl-benzamide

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of N-(2-chloro-4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-3-(methylsulfonyl)-5-(trifluoromethyl)benzamide (0.1 g, 193 μmol, Example 212) in THF (3 mL) were added methylzinc(II)chloride (193 μL, 387 μmol), 1,3-dimethyl-2-imidazolidinone (DMI) (0.6 mL) and PEPPSI-IPr (CAS 905459-27-0) (2.7 mg, 3.87 μmol) and the reaction mixture was heated at 50° C. for 3 hours. 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. The organic layers were washed with brine, dried over MgSO4, filtered and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.05% triethylamine) (20:80 to 60:40). Colorless solid (0.035 g; 36%). MS (ESI): m/z=497.12 [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. customevaporated
  7. customThe compound was purified by silica gel chromatography on a 10 g column
  8. washeluting with a gradient of n-heptane:EtOAc (100:0 to 0:100)
  9. customThe product was purified by preparative HPLC (Gemini NX column)
  10. customThe product was purified by preparative HPLC (Gemini NX column)

Sources & evidence

ORD record
ord-66b8e345bbf34691897fc5b2e42eb143
Source dataset
uspto-grants-2015_03
Patent number
US08987307B2

Reaction notes

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