Step 3: Preparation of ethyl 4,6-dichloro-5-nitronicotinate (16)
Ethyl 4,6-dihydroxy-5-nitronicotinate (15) (20.0 g, 87.7 mmol) was dissolved in phosphoryl chloride (80 mL, 874 mmol). The reaction mixture was stirred at 80 °C for 24 hours. Upon completion of the reaction, about half the volume of phosphoryl chloride was evaporated under reduced pressure. The residue was slowly poured into ice water and extracted twice with ethyl acetate. The organic phases were combined and washed sequentially with aqueous sodium carbonate, water and saturated saline. The organic layers were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a brown oily crude product. The crude product was purified by silica gel column chromatography with petroleum ether/ethyl acetate (3:1, v/v) as eluent to give white crystalline solid 16 (14.2 g, yield 61.1%). The melting point of the product was 36-38 °C. 1H NMR (300 MHz, DMSO-d6) δ: 9.07 (s, 1H), 4.39 (q, J = 6.0 Hz, 2H), 1.34 (t, J = 6.0 Hz, 3H). m/z MS (ESI (+) 70 V): 264 [M + H]+.
