Tributylphosphine → 3-[2-fluoro-4-({4-[(2-phenyl-1H-indol-1-yl)methyl]benzyl}oxy)phenyl]propanoic acid

HRID 2110889Notes

Reaction equation

HRID 2110889 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13]CC)=[O:12].[C:16]1([C:22]2[N:23]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([CH2:38]O)=[CH:34][CH:33]=3)[C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[OH-].[Na+]>C(OCC)(=O)C.O1CCCC1.CO.C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:38][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][N:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:30]=[C:22]3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:37][CH:36]=2)[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12]

Participants

10

Reactant 5

HCID 13831TributylphosphineHCID 14798Sodium HydroxideHCID 730421,1'-(Azodicarbonyl)dipiperidineHCID 23082888Ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoateHCID 23111705{4-[(2-phenyl-1H-indol-1-yl)methyl]phenyl}methanol

Product 1

HCID 115981523-[2-fluoro-4-({4-[(2-phenyl-1H-indol-1-yl)methyl]benzyl}oxy)phenyl]propanoic acidYield 79%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a mixture of ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate (0.29 g, 1.34 mmol), {4-[(2-phenyl-1H-indol-1-yl)methyl]phenyl}methanol (0.38 g, 1.22 mmol), tributylphosphine (0.46 mL, 1.83 mmol) and tetrahydrofuran (7.6 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.46 g, 1.83 mmol) with stirring at 0° C., and the mixture was stirred at room temperature for 18 hr. Diethyl ether was added to the reaction mixture. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/1) to give a colorless oil. Then, a mixture of the obtained oil, 1 N aqueous sodium hydroxide solution (2.5 mL), methanol (5.0 mL) and tetrahydrofuran (10.0 mL) was stirred at room temperature for 14 hr. The reaction mixture was diluted with ethyl acetate, and the mixture washed with 1 N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/2) to give the title compound (0.46 g, yield 79%) as colorless crystals. MS (APCI−): 478 (M−H), 1H NMR (CDCl3) δ: 2.64 (2H, t, J=7.8 Hz), 2.91 (2H, t, J=7.8 Hz), 4.96 (2H, s), 5.38 (2H, s), 6.61-6.70 (3H, m), 7.01-7.20 (6H, m), 7.32 (2H, d, J=8.1 Hz), 7.34-7.47 (5H, m), 7.67 (1H, m).

Workup

  1. stirringthe mixture was stirred at room temperature for 18 hr
  2. filtrationThe insoluble material was filtered off
  3. concentrationthe filtrate was concentrated under reduced pressure
  4. customThe residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/1)
  5. customto give a colorless oil
  6. stirringwas stirred at room temperature for 14 hr
  7. washthe mixture washed with 1 N hydrochloric acid, water and saturated brine
  8. dry with materialdried over anhydrous magnesium sulfate
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/2)

Sources & evidence

ORD record
ord-7c0b70abcf7e4022b44a9e3a1a22f8ab
Source dataset
uspto-grants-2009_04
Patent number
US07517910B2

Reaction notes

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