6-Bromomethyl-2-chloronicotinic acid methyl ester → 2-Chloro-6-diformylaminomethylnicotinic acid methyl ester
Reaction equation
[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[N:6][C:5]=1[Cl:12].[CH:14]([NH2:16])=[O:15].[CH:17](N)=[O:18].[Na]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:16]([CH:17]=[O:18])[CH:14]=[O:15])=[N:6][C:5]=1[Cl:12]Participants
4
Reactant 2
Product 1
Reagents, catalysts & solvents 1
Procedure
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).