Dichloromethane → Difluoro-[4-(3-trifluoromethyl-benzoylamino)-phenyl]-acetic acid ethyl ester

HRID 1818930Notes

Reaction equation

HRID 1818930 reaction equation
[CH2:1]([O:3][C:4](=[O:17])[C:5]([F:16])([F:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)[CH3:2].ClCCl.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27].CCN(C(C)C)C(C)C>CCOC(C)=O.[Pd].O>[CH2:1]([O:3][C:4](=[O:17])[C:5]([F:16])([F:15])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=2)=[CH:8][CH:7]=1)[CH3:2]

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 752573-(Trifluoromethyl)benzoyl chlorideHCID 81531DiisopropylethylamineHCID 10586437Ethyl 2,2-difluoro-2-(4-nitrophenyl)acetate3×

Product 1

HCID 68422864Difluoro-[4-(3-trifluoromethyl-benzoylamino)-phenyl]-acetic acid ethyl ester

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

Difluoro-(4-nitro-phenyl)-acetic acid ethyl ester (compound 32.1) is reacted according to Sato, K. et. al. Chem. Pharm. Bull. 1999, 47, 1013). Briefly, compound 32.1 and catalytic Pd/C in EtOAc are placed under an atmosphere of hydrogen for 3 hours. The reaction mixture is filtered, concentrated and taken on crude to the next reaction. The crude compound, dichloromethane, 3-(trifluoromethyl)benzoyl chloride and DIEA are stirred at room temperature for 10 minutes. Water is added after which the mixture partitioned between EtOAc and water. The organic layer is separated, washed with brine, dried, filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel using a gradient of EtOAc/hexanes provides difluoro-[4-(3-trifluoromethyl-benzoylamino)-phenyl]-acetic acid ethyl ester (compound 32.2).

Workup

  1. filtrationThe reaction mixture is filtered
  2. concentrationconcentrated
  3. customtaken on crude to the next reaction
  4. custompartitioned between EtOAc and water
  5. customThe organic layer is separated
  6. washwashed with brine
  7. customdried
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customPurification by flash column chromatography on silica gel using a gradient of EtOAc/hexanes

Sources & evidence

ORD record
ord-09cc051c8560489eba71c29024446eb6
Source dataset
uspto-grants-2009_10
Patent number
US07601725B2

Reaction notes

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