1-Ethynylcyclohexanol → 3-Cyclopentyl-2-[4-(1-hydroxy-cyclohexylethynyl)-phenyl]-propionic acid methyl ester

HRID 1936227Notes

Reaction equation

HRID 1936227 reaction equation
[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:19]([C:21]1([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)#[CH:20]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C.[I-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:20]#[C:19][C:21]2([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1

Participants

7

Reactant 2

HCID 65251-EthynylcyclohexanolHCID 674834473-Cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester

Product 1

HCID 674839653-Cyclopentyl-2-[4-(1-hydroxy-cyclohexylethynyl)-phenyl]-propionic acid methyl esterYield 109.2%

Reagents, catalysts & solvents 4

HCID 8471TriethylamineCatalystHCID 30165Iodide IonCatalystHCID 6102075Dichlorobis(triphenylphosphine)palladiumCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (716 mg, 2.0 mmol) and triethylamine (2 mL, 0.01 mmol) in N,N-dimethylformamide (2 mL) was treated with 1-ethynyl cyclohexanol (621 mg, 5.0 mmol). The resulting reaction mixture was degassed with argon and then treated with cooper iodide (10 mg, 0.05 mmol) and bis(triphenylphosphine)palladium (II) chloride (15 mg, 0.02 mmol). The reaction was then heated at 70° C. for 24 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and then washed with a half-saturated aqueous sodium chloride solution (1×20 mL). The aqueous layer was back extracted with ethyl acetate (1×40 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 ethyl acetate/hexanes) afforded 3-cyclopentyl-2-[4-(1-hydroxy-cyclohexylethynyl)-phenyl]-propionic acid methyl ester (774 mg, 98%) as a cream solid: mp 76-78° C.; EI-HRMS m/e calcd for C23H30O3 (M+) 354.2194, found 354.2194.

Workup

  1. customThe resulting reaction mixture
  2. customwas degassed with argon
  3. temperatureAt this time, the reaction was cooled to 25° C.
  4. concentrationconcentrated in vacuo
  5. additionThe residue was diluted with ethyl acetate (40 mL)
  6. washwashed with a half-saturated aqueous sodium chloride solution (1×20 mL)
  7. extractionThe aqueous layer was back extracted with ethyl acetate (1×40 mL)
  8. dry with materialThe combined organic extracts were dried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-3d2c98cd46cd4dcd805481311b86c44c
Source dataset
uspto-grants-2002_05
Patent number
US06388071B2

Reaction notes

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