6-Bromomethyl-2-chloronicotinic acid methyl ester → 2-Chloro-6-diformylaminomethylnicotinic acid methyl ester

To a solution of crude 6-bromomethyl-2-chloronicotinic acid methyl ester (235 g) in DMF (500 mL) was added sodium diformamide (82 g, 0.878 mol) portion wise, maintaining the temperature below 30° C., and the reaction mixture stirred at room temperature for 16 hours (N.B. the reaction mixture rapidly darkened and a small exotherm was observed). The reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate (400 mL). The resultant solution was washed with water (2×400 mL) and the aqueous layer extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with brine (200 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was dry-loaded onto silica (200 g) and the residue subjected to flash chromatography (SiO2 300 g, 10-30% ethyl acetate in cyclohexane) to yield the title compound as a yellow solid (90.2 g, 44% over two steps). 1H NMR (CDCl3, 400 MHz) 8.46 (2H, br s), 7.56 (1H, d, J=7.7 Hz), 6.66 (1H, d, J=7.9 Hz), 4.39 (2H, br s), 3.36 (3H, s).

1. temperaturemaintaining the temperature below 30° C.
2. concentrationThe reaction mixture was concentrated in vacuo
3. dissolutionthe residue dissolved in ethyl acetate (400 mL)
4. washThe resultant solution was washed with water (2×400 mL)
5. extractionthe aqueous layer extracted with ethyl acetate (2×300 mL)
6. washThe combined organic extracts were washed with brine (200 mL)
7. dry with materialdried (MgSO4)
8. concentrationconcentrated in vacuo

ORD record

ord-fa34b6da21344bb1aeec0ea2e1c904b7

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09206174B2