Thionyl Chloride → 2,6-Dichloro-5-fluoronicotinyl chloride

Participants

Reaction Conditions

Reaction Steps

2,6-Dichloro-5-fluoronicotinic acid (2) (14 g) was dissolved in thionyl chloride (70 mL). The mixture was heated at 85° C. with stirring for 2.5 h and the thionyl chloride was removed under reduced pressure, yielding a yellowish oil, 2,6-dichloro-5-fluoronicotinyl chloride (3). Monoethyl malonate (27 g) and 6 mg of biquinoline was dissolved in 560 mL of dry THF and cooled to −30° C. A solution of 2.5 M of n-butyllithium in hexane was added until a pink color remained at −5° C. (160 mL). The suspension was then cooled to −50° C. The acid chloride obtained as described above, dissolved in 50 mL THF was then added to the suspension dropwise with stirring. The dry ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction was acidified with 400 mL of 1N HCl and was extracted with ether. It was washed with aqueous sodium bicarbonate solution and water. The ether solution was dried, evaporated to dryness and washed with hexane to give 27 g of (4). m.p=63-66° C.

Provenance & Evidence