Diisopropylamine → 2-(3,4-Dichloro-phenyl)-3-(6,10-dioxa-spiro[4.5]dec-2-yl)-propionic acid methyl ester

Temperature

-78 °C

A solution of diisopropylamine (2.5 mL, 17.80 mmol) in dry tetrahydrofuran (26 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (7.1 mL, 17.80 mmol). The reaction mixture was stirred at −78° C. for 45 min and then treated dropwise with a solution of (3,4-dichloro-phenyl)-acetic acid methyl ester (prepared as in Example 1, 3.00 g, 13.69 mmol) in dry tetrahydrofuran (26 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8 mL). The reaction mixture turned dark yellow in color and was allowed to stir at −78° C. for 10 min and then at 0° C. for 30 min. The reaction mixture was then cooled to −78° C., at which time, a solution of 2-iodomethyl-6,10-dioxa-spiro[4.5]decane (5.79 g, 20.54 mmol) in dry tetrahydrofuran (13 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8 mL) was added dropwise. The reaction mixture stirred at −78° C. for 15 min, and was then allowed to warm to 25° C., where it was stirred for 20 h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (100 mL) and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with a saturated aqueous lithium chloride solution (2×200 mL), water (200 mL) and a saturated aqueous sodium chloride solution (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 15% ethyl acetate/hexanes) afforded 2-(3,4-dichloro-phenyl)-3-(6,10-dioxa-spiro[4.5]dec-2-yl)-propionic acid methyl ester (3.92 g, 77%) as a yellow oil.

1. stirringto stir at −78° C. for 10 min
2. waitat 0° C. for 30 min
3. temperatureThe reaction mixture was then cooled to −78° C., at which time
4. stirringThe reaction mixture stirred at −78° C. for 15 min
5. temperatureto warm to 25° C.
6. stirringwhere it was stirred for 20 h
7. customThe reaction mixture was quenched with a saturated aqueous ammonium chloride solution (100 mL)
8. concentrationconcentrated in vacuo
9. customto remove tetrahydrofuran
10. extractionThe aqueous residue was extracted with ethyl acetate (2×150 mL)
11. washThe combined organic extracts were washed with a saturated aqueous lithium chloride solution (2×200 mL), water (200 mL)
12. dry with materiala saturated aqueous sodium chloride solution (200 mL), dried over sodium sulfate
13. filtrationfiltered
14. concentrationconcentrated in vacuo

ORD record

ord-aa057fc5221a43d28b4e39228129de04

Source dataset

uspto-grants-2006_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07105671B2