Synthesis
Step 3: Preheated 2-hydroxy-6-trifluoromethylnicotinonitrile (45 g, 0.24 mol) was mixed with phosphoryl chloride (90 mL) and phosphorus pentachloride (74.6 g, 0.359 mol) was slowly added. Violent foaming was observed on initial addition. After addition, the reaction mixture was gently refluxed for 22 hours. Complete conversion of the feedstock to 2-chloro-6-trifluoromethylnicotinonitrile was confirmed by TLC (detected as a small amount of the reaction mixture quenched with saturated sodium bicarbonate solution). Subsequently, the reaction mixture was cooled to 50-55 °C and the excess phosphoryl chloride was removed by distillation under reduced pressure. The residue was poured into crushed ice (~100 g) and neutralized with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (3 x 200 mL), the organic layers were combined and washed sequentially with water (200 mL) and brine (200 mL) and dried over anhydrous magnesium sulfate. The organic solvent was concentrated under reduced pressure to obtain a brown liquid crude product, which was purified by column chromatography (eluent: 10% ethyl acetate in hexane solution) to obtain 2-chloro-6-trifluoromethylnicotinonitrile (36g, yield 73%) as a light brown liquid.
References
[1] Patent: US2013/79373, 2013, A1. Location in patent: Paragraph 0265; 0268
[2] Patent: WO2013/45452, 2013, A1. Location in patent: Page/Page column 40
