Diisopropylamine → Methyl 2-(oxolan-3-yl)propanoate

Temperature

-78 °C

A solution of diisopropylamine (0.84 mL, 5.98 mmol) in tetrahydrofuran (10 mL) was cooled to −78° C. under an argon atmosphere and then was treated with a 2.5M solution of n-butyllithium in hexanes (2.29 mL, 5.72 mmol). The reaction mixture was stirred at −78° C. for 15 min. At this time, the reaction was slowly treated with a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in Example 4, 1.20 g, 5.20 mmol) in tetrahydrofuran (5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.75 mL). The bright yellow solution was allowed to stir at −78° C. for 1 h, after which time, a solution of 3-iodomethyl-tetrahydro-furan (2.21 g, 10.4 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.69 mL) and tetrahydrofuran (5 mL) was added via a cannula. The reaction mixture was then allowed to warm to 25° C., where it was stirred for 48 h. The reaction mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were then combined and washed with a 10% aqueous sulfuric acid solution (25 mL) and a saturated aqueous sodium bicarbonate solution (25 mL). The combined organic layers were then dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 75/25 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-3-yl-propionic acid methyl ester (663 mg, 41%) as a light yellow oil: EI-HRMS m/e calcd for C15H19ClO3S (M+) 314.0743, found 314.0729.

1. stirringto stir at −78° C. for 1 h
2. temperatureto warm to 25° C.
3. stirringwhere it was stirred for 48 h
4. customThe reaction mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (30 mL)
5. extractionextracted with ethyl acetate (3×30 mL)
6. washwashed with a 10% aqueous sulfuric acid solution (25 mL)
7. dry with materialThe combined organic layers were then dried over sodium sulfate
8. filtrationfiltered
9. concentrationconcentrated in vacuo

ORD record

ord-669a97af6a0d4f0a9945390b13ac0de6

Source dataset

uspto-grants-2006_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07105671B2