Diethyl Ether → Ethyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate

Temperature

-10 °C

To a stirred mixture of 3,5-dibromo-4-chloro-2,6-dimethylpyridine (14.94 g, 49.9 mmol) and Cu(I)Br Me2S (0.513 g, 2.495 mmol) in THF (50 mL) was added drop wise 2M iPrMgCl/THF (26.2 ml, 52.4 mmol) at −30° C. over 5 min. Then, the resulting slurry was warmed to −10° C. over 30 min and stirred for 30 min. The homogeneous brown reaction mixture was rapidly transferred via cannula to a solution of ethyl 2-chloro-2-oxoacetate (6.14 ml, 54.9 mmol, degassed for 5 min by bubbling N2 through the solution) in THF (50 mL) maintained at −30° C. The resulting reaction mixture was stirred (1.5 h) while warming to 0° C. Then, taken up in to Et2O (200 mL), washed with 1:1 sat Na2CO3/1M NH4Cl (3×50 mL), dried (MgSO4), filtered and concentrated to give brown viscous oil. Flash chromatography using 2.5, 5 and 7.5% EtOAc/Hex afforded ethyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (14.37 g, 44.8 mmol, 90% yield) as white solid. 1H NMR (400 MHz, CDCl3) δ 4.42 (q, J=7.0 Hz, 2H), 2.76 (s, 3H), 2.46 (s, 3H), 1.41 (t, J=7.2 Hz, 3H). LCMS (M+H)=322.1.

1. customdegassed for 5 min
2. customby bubbling N2 through the solution) in THF (50 mL)
3. temperaturemaintained at −30° C
4. customThe resulting reaction mixture
5. stirringwas stirred (1.5 h)
6. temperaturewhile warming to 0° C
7. washwashed with 1:1
8. dry with materialdried (MgSO4)
9. filtrationfiltered
10. concentrationconcentrated
11. customto give brown viscous oil

ORD record

ord-83b85c0c7a984034895bf0b86b43b437

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09193720B2