反应详情

温度

0 °C

A mixture of THF (1050 mL) and diisopropylamine (320 mL, 2.29 mol) was cooled to 0° C., and potassium tert-butoxide (129 g, 1.095 mol; 95% pure) was added. The solution was cooled to −50° C. and n-butyllithium solution (2.5M in hexane, 925 mL, 2.312 mol) was added, keeping the temperature below −40° C. The solution was then stirred at −50° to −40° C. prior to the addition of a solution of 3-methylpicolinic acid of Formula I (150 g, 1.095 mol) in THF (300 mL) and triethylamine (55.3 g, 0.547 mol) at −45° to −35° C. Use of the triethylamine reduces the amount of THF needed to dissolve the compound of Formula I. The purple solution was stirred at −45° to −35° C., and 3-chlorobenzyl chloride of Formula IV (176.3 g, 1.095 mol) was added. The suspension was allowed to warm to ambient temperature overnight. The suspension was poured into a solution of potassium carbonate (150 g, 1.09 mol) in water (1150 mL), washed with an additional 200 mL of water and stirred. The suspension was filtered and the solid washed with 200 mL water. The bottom phase containing the product as the potassium salt was separated and the organic phase, washed with 100 mL water. The aqueous-solution was heated under vacuum to 60° C. to remove dissolved organic volatiles and cooled to 40° C. Concentrated hydrochloric acid (585 mL of 37%) was slowly added. The resulting suspension was cooled to 0° to 10° C., filtered and washed with 10% aqueous HCl (200 mL) to remove salts. The suspension was washed with acetone and dried to give 286.5 g (88%) of 3-(3-chlorophenethyl)-picolinic acid hydrochloride 3-CPPA.HCl (Formula IIa).

1. temperatureThe solution was cooled to −50° C.
2. customthe temperature below −40° C
3. customat −45° to −35° C
4. dissolutionto dissolve the compound of Formula I
5. stirringThe purple solution was stirred at −45° to −35° C.
6. temperatureto warm to ambient temperature overnight
7. washwashed with an additional 200 mL of water
8. stirringstirred
9. filtrationThe suspension was filtered
10. washthe solid washed with 200 mL water
11. additionThe bottom phase containing the product as the potassium salt
12. customwas separated
13. washthe organic phase, washed with 100 mL water
14. temperatureThe aqueous-solution was heated under vacuum to 60° C.
15. customto remove
16. dissolutiondissolved organic volatiles
17. temperaturecooled to 40° C
18. additionConcentrated hydrochloric acid (585 mL of 37%) was slowly added
19. temperatureThe resulting suspension was cooled to 0° to 10° C.
20. filtrationfiltered
21. washwashed with 10% aqueous HCl (200 mL)
22. customto remove salts
23. washThe suspension was washed with acetone
24. customdried