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 (<138 g, <0.54 mol) in DMF (400 mL) was added sodium diformamide (56.3 g, 0.59 mol) and the reaction mixture stirred at room temperature for 16 hours. 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 (200 mL). The resultant solution was washed with water (400 mL) and the aqueous layer extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was dry-loaded onto silica (150 g) and the residue subjected to flash chromatography (SiO2 400 g, 40% ethyl acetate in cyclohexane) to yield the title compound as a yellow solid (46 g, 33% 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).