Diisopropylamine → Methyl 4-chloro-α-(cyclopentylmethyl)-3-nitrobenzeneacetate

Temperature

-78 °C

A solution of diisopropylamine (3.35 mL, 23.9 mmol) in dry tetrahydrofuran (45 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (15 mL) cooled to −78° C. was treated dropwise with a 2.5M solution of n-butyllithium in hexanes (9.56 mL, 23.9 mmol) over a 10 min period. The pale yellow reaction mixture was stirred at −78° C. for 20 min. At this time, the reaction was treated with a solution of 4-chloro-3-nitrophenylacetic acid methyl ester (5.00 g, 21.8 mmol) in a small amount of tetrahydrofuran over a 15 min period. The reaction mixture turned deep purple (almost black) in color. The reaction mixture was then stirred at −78° C. for 1 h. At this time, the reaction was treated with a solution of iodomethylcyclopentane (4.58 g, 21.8 mol) in a small amount of dry tetrahydrofuran. The reaction mixture was then stirred at −78° C. and then allowed to warm to 25° C., where it was stirred for 48 h. The reaction mixture was then quenched with a saturated aqueous ammonium chloride solution (50 mL), and the resulting reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The residue was diluted with ethyl acetate (150 mL) and water (50 mL). The organic phase was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacua. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionic acid methyl ester (2.17 g, 32%) as a yellow oil: EI-HRMS m/e calcd for C5H18ClNO4 (M+) 311.0924, found 311.0927.

1. stirringThe reaction mixture was then stirred at −78° C. for 1 h
2. stirringThe reaction mixture was then stirred at −78° C.
3. temperatureto warm to 25° C.
4. stirringwhere it was stirred for 48 h
5. customThe reaction mixture was then quenched with a saturated aqueous ammonium chloride solution (50 mL)
6. customthe resulting reaction mixture
7. concentrationwas concentrated in vacuo
8. customto remove tetrahydrofuran
9. additionThe residue was diluted with ethyl acetate (150 mL) and water (50 mL)
10. washThe organic phase was washed with a saturated aqueous sodium chloride solution
11. dry with materialdried over magnesium sulfate
12. filtrationfiltered
13. concentrationconcentrated in vacua

ORD record

ord-07f17ad4b3c94be1bddd8fd31b4cb4f8

Source dataset

uspto-grants-2003_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06528543B1