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

HRID 1860212Notes

Reaction equation

HRID 1860212 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 84.3%

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 (35.3 mL of a 0.31 M stock solution, 10.9 mmol) cooled to −78° C. was treated with (4-fluoro-3-trifluoromethyl-phenyl)-acetic acid (1.11 g, 5.0 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (12.4 mL, 3:1). The resulting solution was stirred at −78° C. for 1 h. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.16 g, 5.52 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.2 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 an aqueous solution of 2N hydrochloric acid (50 mL). The product was extracted into ethyl acetate (3×100 mL) and diethyl ether (1×50 mL). The organics 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 (1.28 g, 84.3%) 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 an aqueous solution of 2N hydrochloric acid (50 mL)
  5. extractionThe product was extracted into ethyl acetate (3×100 mL) and diethyl ether (1×50 mL)
  6. dry with materialThe organics were dried over magnesium sulfate and sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-808cc4d72b834b74813277e404d2f0b5
Source dataset
uspto-grants-2003_03
Patent number
US06528543B1

Reaction notes

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