Citric Acid → N-[4-(4-Fluoro-2-methoxy-phenyl)-6-methyl-pyridin-3-yl]-3-methanesulfonyl-N-methyl-5-trifluoromethyl-benzamide

HRID 878224Notes

Reaction equation

HRID 878224 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]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[O:33][CH3:34])[CH:3]=1.[Cl-].C[Zn+].[CH3:38]N1CCN(C)C1=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.ClC1C([Pd-](Cl)Cl)=NC=CC=1.CCOC(C)=O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:4]2[CH:3]=[C:2]([CH3:38])[N:7]=[CH:6][C:5]=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:21])=[O:22])[CH:11]=2)=[C:27]([O:33][CH3:34])[CH:28]=1

Participants

8

Reactant 4

HCID 311Citric AcidHCID 66611,3-Dimethyl-2-imidazolidinoneHCID 86670793N-[6-Chloro-4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-3-methanesulfonyl-N-methyl-5-trifluoromethyl-benzamideHCID 178477797HCID 178477797, compound

Product 1

HCID 70663183N-[4-(4-Fluoro-2-methoxy-phenyl)-6-methyl-pyridin-3-yl]-3-methanesulfonyl-N-methyl-5-trifluoromethyl-benzamide

Reagents, catalysts & solvents 3

HCID 178478202HCID 178478202, compoundCatalystHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of N-(6-chloro-4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-3-(methylsulfonyl)-5-(trifluoromethyl)benzamide (0.1 g, 0.193 mmol, example 201) in THF (2 mL) were added methylzinc chloride (0.145 mL, 0.29 mmol, 2M solution in THF, CAS RN 5158-46-3), 1,3-dimethyl-2-imidazolidinone (0.4 mL, CAS RN 80-73-9) and (1,3-bis(2,6-diisopropyl-phenyl)imidazolidene) (3-chloropyridyl) palladium(II) dichloride (PEPPSI-IPr, 2.63 mg, 3.87 μmol, Aldrich). The reaction mixture was stirred at 50° C. for 30 min. and then 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, 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 0:100), followed by a second chromatography, using preparative HPLC (Gemini NX column) eluting with a gradient of methanol:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless solid (0.073 g; 76%). MS (ESI): m/z=497.11 [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 0:100)
  10. washeluting with a gradient of methanol

Sources & evidence

ORD record
ord-4abd4eb371d3490ba2c2c6dd72ea943a
Source dataset
uspto-grants-2015_03
Patent number
US08987307B2

Reaction notes

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