Pyrrolidine → 3-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenyl)-N,N-dimethylprop-2-yn-1-amine

HRID 83840

Reaction equation

HRID 83840 reaction equation
Br[C:2]1[CH:33]=[C:32]([F:34])[C:5]([CH2:6][S:7][C:8]2[N:9]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:10]([C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[CH:17]=3)([CH3:15])[CH3:14])=[CH:11][N:12]=2)=[C:4]([F:35])[CH:3]=1.[CH3:36][N:37]([CH3:41])[CH2:38][C:39]#[CH:40].N1CCCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]([C:10]2[N:9]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:8]([S:7][CH2:6][C:5]3[C:32]([F:34])=[CH:33][C:2]([C:40]#[C:39][CH2:38][N:37]([CH3:41])[CH3:36])=[CH:3][C:4]=3[F:35])=[N:12][CH:11]=2)([CH3:15])[CH3:14])=[CH:17][C:18]=1[O:23][CH3:24]

Participants

6

Reactant 3

HCID 31268PyrrolidineHCID 81643N,N-DimethylpropargylamineHCID 667405782-(4-bromo-2,6-difluorobenzylthio)-5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole

Product 1

HCID 672365113-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenyl)-N,N-dimethylprop-2-yn-1-amineYield 95%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst

Conditions

Temperature
80 °C

Procedure

To a solution of 2-(4-bromo-2,6-difluorobenzylthio)-5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (250 mg, 0.43 mmol, 1.0 eq), N,N-dimethylprop-2-yn-1-amine (0.07 mL, 0.64 mmol, 1.5 eq) and pyrrolidine (0.05 mL, 0.64 mmol, 1.5 eq) in dry, degassed DMF (2 mL) were added PdCl2(dppf)2 (16 mg, 0.022 mmol, 5 mol %) and CuI (8 mg, 0.043 mmol, 10 mol %). The reaction mixture was heated at 80° C. for 16 h, at which time LCMS showed complete consumption of starting material. The mixture was diluted with EtOAc, washed with brine, dried and concentrated. Purification by column chromatography (0 to 15% MeOH/DCM) furnished 238 mg (95% yield) of 3-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenyl)-N,N-dimethylprop-2-yn-1-amine as a brown oil: MS (EI): 584 (MH+).

Workup

  1. customdegassed DMF (2 mL)
  2. customconsumption of starting material
  3. additionThe mixture was diluted with EtOAc
  4. washwashed with brine
  5. customdried
  6. concentrationconcentrated
  7. customPurification by column chromatography (0 to 15% MeOH/DCM)

Sources & evidence

ORD record
ord-23485bfa6a9a4682ae91505b2978e3ce
Source dataset
uspto-grants-2014_09
Patent number
US08846739B2

Linked notes

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