3,5-Dibromo-4-chloro-2,6-dimethylpyridine → Isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate

Temperature

-10 °C

A solution of 2M isopropyl magnesium chloride (84 mL, 168 mmol) was added drop wise over 20 min to a cold (−70° C.), nitrogen purged solution of 3,5-dibromo-4-chloro-2,6-dimethylpyridine (48 g, 160 mmol) and copper(I)bromide-dimethyl sulfide complex (1.65 g, 8.02 mmol) in THF (240 mL), which was then allowed to warm to −10° C. over 60 min. The reaction mixture was transferred via cannula into a 1 L RB-flask containing isopropyl 2-chloro-2-oxoacetate (26.6 g, 176 mmol) in THF (160 mL) maintained at −60° C., and the reaction stirred an additional 2.5 h while being allowed to warm to −10° C. The reaction was quenched upon diluted with a mixture of 10% NH4Cl solution (80 mL) in ether (320 mL). The organic layer was washed with 160 mL of sat'd NaHCO3/10% NH4Cl solution (1:1), brine, and dried (Na2SO4). The crude product was charged (DCM solution) to a 330 g ISCO silica gel cartridge and gradient eluted (5-20% EtOAc/hexanes) using an Isolera chromatography station gave isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate 40.38 g (76%). 1H NMR (500 MHz, CDCl3) δ 5.28-5.21 (m, 1H), 2.77 (s, 3H), 2.47 (s, 3H), 1.40 (d, J=6.3 Hz, 6H). LCMS (M+H)=336.04.

1. temperaturemaintained at −60° C.
2. temperatureto warm to −10° C
3. customThe reaction was quenched
4. additionupon diluted with a mixture of 10% NH4Cl solution (80 mL) in ether (320 mL)
5. washThe organic layer was washed with 160 mL of sat'd NaHCO3/10% NH4Cl solution (1:1), brine
6. dry with materialdried (Na2SO4)
7. additionThe crude product was charged (DCM solution) to a 330 g ISCO silica gel cartridge and gradient
8. washeluted (5-20% EtOAc/hexanes)

ORD record

ord-f04c39f226b944e3883e56162a5e75e1

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09193720B2