Propargyl alcohol → methyl 5-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)-2-(3-hydroxyprop-1-ynyl)benzoate

HRID 1627286Notes

Reaction equation

HRID 1627286 reaction equation
Br[C:2]1[CH:11]=[CH:10][C:9]([CH2:12][S:13][C:14]2[N:15]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([O:37][CH3:38])[CH:31]=3)[C:16]([C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)([CH3:21])[CH3:20])=[CH:17][N:18]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:39]([OH:42])[C:40]#[CH:41].N1CCCC1>CCOC(C)=O.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:29][C:24]1[CH:23]=[C:22]([C:19]([C:16]2[N:15]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([O:37][CH3:38])[CH:31]=3)[C:14]([S:13][CH2:12][C:9]3[CH:10]=[CH:11][C:2]([C:41]#[C:40][CH2:39][OH:42])=[C:3]([CH:8]=3)[C:4]([O:6][CH3:7])=[O:5])=[N:18][CH:17]=2)([CH3:21])[CH3:20])[CH:27]=[CH:26][C:25]=1[Cl:28]

Participants

7

Reactant 3

HCID 7859Propargyl alcoholHCID 31268PyrrolidineHCID 66740663HCID 66740663, compound

Product 1

HCID 66740390methyl 5-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)-2-(3-hydroxyprop-1-ynyl)benzoateYield 78%

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 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

To a stirred solution of methyl 2-bromo-5-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)benzoate (506 mg, 0.79 mmol, 1.0 eq), propargyl alcohol (0.07 mL, 1.2 mmol, 1.5 eq) and pyrrolidine (0.1 mL, 1.2 mmol, 1.5 eq) in dry, degassed DMF (4 mL) was added PdCl2(dppf)2 (30 mg, 0.04 mmol, 5 mol %) and CuI (15 mg, 0.08 mmol, 10 mol %). The reaction mixture was heated at 80° C. for 5 h at which time LCMS showed 85% conversion. The mixture was diluted with EtOAc, washed with brine, dried and concentrated. Purification by column chromatography (0 to 75% EtOAc/Hexanes) provided 378 mg (78% yield) of methyl 5-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)-2-(3-hydroxyprop-1-ynyl)benzoate. MS (EI) m/z 615 (MH+).

Workup

  1. customdegassed DMF (4 mL)
  2. washwashed with brine
  3. customdried
  4. concentrationconcentrated
  5. customPurification by column chromatography (0 to 75% EtOAc/Hexanes)

Sources & evidence

ORD record
ord-2eb7c2c9074e451b97456a3b88577e2b
Source dataset
uspto-grants-2014_07
Patent number
US08785488B2

Reaction notes

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