Propargyl alcohol → 3-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenyl)prop-2-yn-1-ol

HRID 1627284Notes

Reaction equation

HRID 1627284 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.[CH2:36]([OH:39])[C:37]#[CH:38].N1CCCC1>CN(C=O)C.[Cu]I.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]>[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:38]#[C:37][CH2:36][OH:39])=[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

7

Reactant 3

HCID 7859Propargyl alcoholHCID 31268PyrrolidineHCID 667405782-(4-bromo-2,6-difluorobenzylthio)-5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole

Product 1

HCID 667400453-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenyl)prop-2-yn-1-olYield 94.9%

Reagents, catalysts & solvents 3

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+)CatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 2-(4-bromo-2,6-difluorobenzylthio)-5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (0.79 g, 1.35 mmol), propargyl alcohol (122 μL, 2.03 mmol), pyrrolidine (169 μL, 2.03 mmol), CuI (26 mg, 0.13 mmol) and PdCl2(dppf)2 (50 mg, 0.07 mmol) in DMF (6.80 mL) was purged with argon and then heated to 80° C. for 3 h. The reaction mixture was filtered through Celite™ to remove solids. The filter agent was rinsed with EtOAc (3×75 mL). The filtrate was washed with water and brine, dried over anhyd Na2SO4, concentrated and purified by flash chromatography (80% EtOAc/Hex) to give the title compound (714 mg, 94%) as a yellow solid. MS (EI) m/z 557 (MH+).

Workup

  1. customwas purged with argon
  2. filtrationThe reaction mixture was filtered through Celite™
  3. customto remove solids
  4. washThe filter agent was rinsed with EtOAc (3×75 mL)
  5. washThe filtrate was washed with water and brine
  6. dry with materialdried over anhyd Na2SO4
  7. concentrationconcentrated
  8. custompurified by flash chromatography (80% EtOAc/Hex)

Sources & evidence

ORD record
ord-2d2aa97044b947dead593ee7a5600bba
Source dataset
uspto-grants-2014_07
Patent number
US08785488B2

Reaction notes

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