(3,4-Dimethoxyphenyl)acetic acid → HCID 22315298, compound

HRID 398626Notes

Reaction equation

HRID 398626 reaction equation
C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].I[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH:25]1([CH2:24][CH:19]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([O:10][CH3:9])[CH:12]=2)[C:20]([OH:22])=[O:21])[CH2:29][CH2:28][CH2:27][CH2:26]1

Participants

6

Reactant 3

HCID 7139(3,4-Dimethoxyphenyl)acetic acidHCID 2724682Lithium diisopropylamideHCID 2762531(Iodomethyl)cyclopentane

Product 1

HCID 22315298HCID 22315298, compoundYield 63.9%

Reagents, catalysts & solvents 2

HCID 816462(1H)-Pyrimidinone, tetrahydro-1,3-dimethyl-SolventHCID 22565281tetrahydrofuran 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinoneSolvent

Conditions

Temperature
25 °C

Procedure

A solution of freshly prepared lithium diisopropylamide (58.5 mL of a 0.91M stock solution, 53.2 mmol) cooled to −78° C. was treated with (3,4-dimethoxy-phenyl)-acetic acid (4.97 g, 25.3 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (25.3 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min and at 25° C. for 15 min. At this time, the reaction was cooled to 0° C. and was treated with a solution of iodomethylcyclopentane (5.87 g, 27.8 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The reaction mixture was stirred at 0° C. for 30 min. The reaction was then warmed to 25° C. and was stirred at 25° C. for 18 h. The reaction mixture was then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (10 mL). The resulting mixture was concentrated in vacuo. The residue was diluted with water (100 mL) and acidified to pH=1 with a 1N aqueous hydrochloric acid solution. This solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dimethoxy-phenyl)-propionic acid (4.5 g, 63.8%) as a yellow solid: mp 111-112° C.; EI-HRMS m/e calcd for C16H22O4 (M+) 278.1518 found 278.1517.

Workup

  1. temperatureAt this time, the reaction was cooled to 0° C.
  2. stirringThe reaction mixture was stirred at 0° C. for 30 min
  3. temperatureThe reaction was then warmed to 25° C.
  4. stirringwas stirred at 25° C. for 18 h
  5. customThe reaction mixture was then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (10 mL)
  6. concentrationThe resulting mixture was concentrated in vacuo
  7. additionThe residue was diluted with water (100 mL)
  8. extractionThis solution was extracted with ethyl acetate (3×50 mL)
  9. washThe combined organic layers were washed with a saturated aqueous lithium chloride solution (1×100 mL)
  10. dry with materialdried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-869e219f070640249021996e7e169132
Source dataset
uspto-grants-2003_08
Patent number
US06610846B1

Reaction notes

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