Hydrochloric Acid → (2,5-Dichloro-pyridin-3-yl)-acetic Acid Methyl Ester

Temperature

0 °C

To a −78° C. solution of diisopropyl amine (1.21 mL, 9.0 mmol) in tetrahydrofuran (100 mL) was added n-butyl lithium (3.45 mL, 2.5 M in hexanes, 9.0 mmol). The reaction mixture was stirred at −78° C. for 20 minute and 0° C. for 15 minutes, and then cooled to −110° C. To the cooled reaction mixture was added dimethoxymethyl diphenyl phosphine oxide (2.18 g, 8.0 mmol) in tetrahydrofuran (120 mL) and then 2,5-dichloro-pyridine-3-carbaldehyde (1.37 g, 8.0 mmol) in tetrahydrofuran (15 mL) while keeping the reaction temperature less than −100° C. The reaction mixture was stirred at −110° C. for 45 minutes and then quenched with water (50 mL), extracted with diethyl ether and washed with brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was azeotroped with toluene and then dissolved in tetrahydrofuran (80 mL) and treated with potassium tert-butoxide (0.97 g, 9.0 mmol) at ambient temperature. After stirring for 2 hours the dark solution was treated with 1N hydrochloric acid and extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.61 g).

1. temperaturecooled to −110° C
2. customTo the cooled reaction mixture
3. customthe reaction temperature less than −100° C
4. stirringThe reaction mixture was stirred at −110° C. for 45 minutes
5. customquenched with water (50 mL)
6. extractionextracted with diethyl ether
7. washwashed with brine
8. dry with materialThe organic layer was dried over magnesium sulfate
9. concentrationconcentrated in vacuo
10. customThe resulting residue was azeotroped with toluene
11. dissolutiondissolved in tetrahydrofuran (80 mL)
12. stirringAfter stirring for 2 hours the dark solution
13. extractionextracted with diethyl ether
14. washThe organic layer was washed with saturated aqueous sodium hydrogen carbonate
15. dry with materialdried over magnesium sulfate
16. filtrationfiltered
17. concentrationconcentrated in vacuo

ORD record

ord-ce115b89ef7c4a62af9e81aebfac046c

Source dataset

uspto-grants-2006_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07098212B2