Thionyl Chloride → 2-Chloro-3-chloromethyl-pyridine

Temperature

10 °C

To a 500 mL, round-bottom, 3-necked flask equipped with dropping funnel and magnetic stirrer and set for reflux was prepared a solution of 2-chloro-3-(hydroxymethyl)-pyridine (25.0 g, 174 mmol) in DCM (250 mL) under positive nitrogen atmosphere. The solution was cooled to 10° C. and thionyl chloride (31.0 g) was added dropwise over 25 minutes (exothermic). The reaction was then heated to reflux for 90 minutes, at which point the reaction was deemed complete by HPLC. The reaction mixture was cooled below boiling point and the equipment set for distillation. A total of 110 mL of DCM was initially removed and replenished with fresh DCM (110 mL), followed by another 80 mL of DCM before cooling the solution to 5-10° C. The acidic mixture was treated with a saturated solution of sodium bicarbonate (3 volumes) to pH 10. The lower organic phase was separated and the aqueous phase extracted with DCM (2 volumes). The organic phases were gathered, dried on sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a pale yellow oil in excellent purity and yield (24.8 g, 88%). δH (d6-DMSO, 300 MHz) 8.45 (1H, dd), 8.10 (1H, dd), 7.50 (1H, dd), 4.85 (2H, s). LCMS (ES)+ RT 3.00 min, m/e 162.1.

1. customTo a 500 mL, round-bottom, 3-necked flask equipped
2. temperatureset for reflux
3. temperatureThe reaction was then heated
4. temperatureto reflux for 90 minutes, at which
5. temperatureThe reaction mixture was cooled
6. distillationthe equipment set for distillation
7. customA total of 110 mL of DCM was initially removed
8. temperaturebefore cooling the solution to 5-10° C
9. additionThe acidic mixture was treated with a saturated solution of sodium bicarbonate (3 volumes) to pH 10
10. customThe lower organic phase was separated
11. extractionthe aqueous phase extracted with DCM (2 volumes)
12. customdried on sodium sulfate
13. filtrationfiltered
14. concentrationconcentrated in vacuo

ORD record

ord-78041e3f568148c9838699148ea7e334

Source dataset

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08487101B2