1,2-Dichloroethane → 2-(4-Amino-phenyl)-2,2-difluoro-1-(4-methyl-piperazin-1-yl)-ethanone

HRID 1262415Notes

Reaction equation

HRID 1262415 reaction equation
[F:1][C:2]([F:15])([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.S(Cl)(Cl)=O.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C.ClCCCl>CCOC(C)=O.O.[Cl-].[Na+].O.C([O-])(O)=O.[Na+].[Pd].CO>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]([F:1])([F:15])[C:3]([N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)=[O:5])=[CH:7][CH:8]=1

Participants

10

Reactant 5

HCID 111,2-DichloroethaneHCID 24386Thionyl ChlorideHCID 531671-MethylpiperazineHCID 81531DiisopropylethylamineHCID 467392012,2-Difluoro-2-(4-nitrophenyl)acetic acid

Product 1

HCID 667124682-(4-Amino-phenyl)-2,2-difluoro-1-(4-methyl-piperazin-1-yl)-ethanoneYield 86%

Reagents, catalysts & solvents 4

HCID 23938PalladiumCatalystHCID 887MethanolSolventHCID 8857Ethyl AcetateSolventHCID 131727349Sodium bicarbonate brine waterSolvent

Conditions

Temperature
79 °C

Procedure

Difluoro-(4-nitro-phenyl)-acetic acid (106 mg, 0.488 mmol) was suspended in Thionyl chloride (1.00 mL, 13.7 mmol) and heated at 79° C. in a vial for 5 h. Conc. and azeotroping with toluene afforded a residue, which was dried in vacuo. 1-Methyl-piperazine (0.100 mL, 0.902 mmol), N,N-Diisopropylethylamine (0.250 mL, 1.44 mmol) and 1,2-Dichloroethane (1.00 mL, 12.7 mmol) were added to the residue. The mixture was diluted with EtOAc (10 mL) and water:brine:NaHCO3 (1:3:2, 6 mL), the layers separated and the aq. extr. with DCM (2×3 mL). The comb. org. were dried, filtered and conc. in vacuo to give an oil which very slowly crystallizes. The crude amide (124 mg) was shaken under an atmosphere of Hydrogen (15 psi) over 10% Palladium on Carbon (50% Wet) (24 mg, 0.011 mmol) in Methanol (10.0 mL) overnight. Filtration and conc. afforded 2-(4-Amino-phenyl)-2,2-difluoro-1-(4-methyl-piperazin-1-yl)-ethanone (0.113 g; Yield=86.0%) as a film.

Workup

  1. customConc. and azeotroping with toluene
  2. customafforded a residue, which
  3. customwas dried in vacuo
  4. customthe layers separated
  5. customwere dried
  6. filtrationfiltered and conc. in vacuo
  7. customto give an oil which
  8. customvery slowly crystallizes
  9. filtrationFiltration

Sources & evidence

ORD record
ord-b772bcf33bb841bf9f32f6949be32c87
Source dataset
uspto-grants-2013_06
Patent number
US08471005B2

Reaction notes

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