Lithium diisopropylamide → 3-Cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid

HRID 398580Notes

Reaction equation

HRID 398580 reaction equation
C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21].I[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH:26]1([CH2:25][CH:16]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[C:11]([C:20]([F:21])([F:22])[F:23])[CH:12]=2)[C:17]([OH:19])=[O:18])[CH2:30][CH2:29][CH2:28][CH2:27]1

Participants

6

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 27375934-Fluoro-3-(trifluoromethyl)phenylacetic acidHCID 2762531(Iodomethyl)cyclopentane

Product 1

HCID 120695003-Cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acidYield 55.4%

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 (141.28 mL of a 0.31M stock solution, 43.8 mmol) cooled to −78° C. was treated with (4-fluoro-3-trifluoromethyl-phenyl)-acetic acid (4.44 g, 20.0 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (49.68 mL, 3:1). The resulting solution was then stirred at −78° C. for 1 h. At this time, the reaction was treated with a solution of iodomethylcyclopentane (4.64 g, 22.09 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4.6 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 48 h. This solution was then quenched by the slow addition of the reaction mixture to a 2N aqueous hydrochloric acid solution. The product was extracted into ethyl acetate (3×400 mL) and diethyl ether (1×200 mL). The combined organic layers were dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate with acetic acid) afforded 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (3.37 g, 55.4%) as a white solid: mp 66-68° C.; EI-HRMS m/e calcd for C15H16F4O2 (M+) 305.1165, found 305.1174.

Workup

  1. stirringThe reaction mixture was stirred at −78° C. for 4 h
  2. temperatureThe reaction was then warmed to 25° C.
  3. stirringwas stirred at 25° C. for 48 h
  4. customThis solution was then quenched by the slow addition of the reaction mixture to a 2N aqueous hydrochloric acid solution
  5. extractionThe product was extracted into ethyl acetate (3×400 mL) and diethyl ether (1×200 mL)
  6. dry with materialThe combined organic layers were dried over magnesium sulfate and sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-863d13987e974b6e92846130c7e9cb04
Source dataset
uspto-grants-2003_08
Patent number
US06610846B1

Reaction notes

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