Diisopropylamine → 2-(3-Chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid ethyl ester

HRID 398434Notes

Reaction equation

HRID 398434 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:27])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[C:20]([Cl:26])[CH:19]=1)[CH3:14].I[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1.CN1CCCN(C)C1=O>[CH2:13]([O:15][C:16](=[O:27])[CH:17]([C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[C:20]([Cl:26])[CH:19]=1)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[CH3:14]

Participants

7

Reactant 4

HCID 7912DiisopropylamineHCID 2762531(Iodomethyl)cyclopentaneHCID 54095555(3-Chloro-4-methylsulfanyl-phenyl)-acetic acid ethyl esterHCID 178418339Butyllithium

Product 1

HCID 543204802-(3-Chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid ethyl esterYield 56%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 816462(1H)-Pyrimidinone, tetrahydro-1,3-dimethyl-Solvent

Conditions

Temperature
-78 °C

Procedure

A solution of diisopropylamine (457 μL, 3.26 mmol) in tetrahydrofuran (5 mL) was cooled to −78° C. under a nitrogen atmosphere and then treated with a 2.5M solution of n-butyllithium in hexanes (1.3 mL, 3.26 mmol). The mixture was stirred at −78° C. for 30 min, at which time, a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid ethyl ester (0.67 g, 2.75 mmol) in tetrahydrofuran (8 mL) was slowly added to the reaction mixture. The reaction mixture turned deep yellow in color. The reaction mixture was then further stirred at −78° C. for 30 min, at which time, a solution of iodomethylcyclopentane (0.65 g, 3.09 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (1 mL) was added via syringe. The reaction mixture was then allowed to warm to 25° C. where it was stirred for 16 h. The reaction mixture turned red in color during this time period. The reaction mixture was quenched with a 6N aqueous hydrochloric acid solution (5 mL) and further diluted with water (20 mL). The reaction mixture was then extracted with methylene chloride (3×20 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid ethyl ester (0.50 g, 56%) as a light yellow oil.

Workup

  1. stirringThe reaction mixture was then further stirred at −78° C. for 30 min, at which time
  2. temperatureto warm to 25° C. where it
  3. stirringwas stirred for 16 h
  4. customThe reaction mixture was quenched with a 6N aqueous hydrochloric acid solution (5 mL)
  5. additionfurther diluted with water (20 mL)
  6. extractionThe reaction mixture was then extracted with methylene chloride (3×20 mL)
  7. washThe combined organic layers were washed with a saturated aqueous sodium chloride solution (1×25 mL)
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-26958ffd29d045d3b73486b512f97a22
Source dataset
uspto-grants-2003_08
Patent number
US06610846B1

Reaction notes

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