Lithium diisopropylamide → 3-Cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-propionic acid methyl ester

HRID 1355217Notes

Reaction equation

HRID 1355217 reaction equation
C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=1.I[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:22])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=1)[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1

Participants

6

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 2762531(Iodomethyl)cyclopentaneHCID 14897830Methyl 2-(3-fluoro-4-methoxyphenyl)acetate

Product 1

HCID 544984353-Cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-propionic acid methyl esterYield 83.9%

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
-78 °C

Procedure

A solution of freshly prepared lithium diisopropylamide (21.6 mL of 0.31M stock solution, 6.69 mmol) cooled to −78° C. was treated with a solution of (3-fluoro-4-methoxy-phenyl)-acetic acid methyl ester (1.26 g, 6.38 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.47 g, 7.02 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was warmed to 25° C. and stirred at 25° C. for 48 h. The reaction mixture was then quenched by the slow addition of a saturated aqueous ammonium chloride solution (10 mL). The reaction mixture was then poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-propionic acid methyl ester (1.50 g, 83.8%) as a clear oil: EI-HRMS m/e calcd for C16H21FO3(M+) 280.1477 found 280.1474.

Workup

  1. stirringThe reaction mixture was stirred at −78° C. for 4 h
  2. temperatureThe reaction was warmed to 25° C.
  3. stirringstirred at 25° C. for 48 h
  4. customThe reaction mixture was then quenched by the slow addition of a saturated aqueous ammonium chloride solution (10 mL)
  5. additionThe reaction mixture was then poured into water (100 mL)
  6. extractionextracted with ethyl acetate (3×50 mL)
  7. washThe combined organic layers were washed with a saturated aqueous lithium chloride solution (1×50 mL)
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-00d7802641aa4c63b0ae2c118f611bb7
Source dataset
uspto-grants-2007_05
Patent number
US07223868B2

Reaction notes

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