The general procedure for the synthesis of methyl 4,6-dichloronicotinate from methyl 4,6-dihydroxynicotinate was as follows: to a solution of methyl 4,6-dihydroxynicotinate (900 g, 5.3 mol) in phosphoryl chloride (4000 mL) was added N,N-diethylaniline (1035 mL, 6.4 mol). The reaction mixture was heated to 120 °C and maintained for 2 h, followed by cooling to room temperature. The reaction mixture was concentrated under vacuum and poured slowly into ice in batches. The mixture was extracted with ethyl acetate (2×). The organic extracts were combined, dried with anhydrous sodium sulfate and subsequently concentrated under vacuum. Purification of the crude product by rapid chromatography on silica gel (solvent gradient: 0% to 5% petroleum ether solution of ethyl acetate) afforded methyl 4,6-dichloronicotinate (400 g, 42% yield).LCMS (ESI) [M + H] = 206.1; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 7.98 (s, 1H) 3.90 (s, 3H).
