Hydrochloric Acid → 2,6-Dichloro-5-fluoro-4-methylpyridine-3-carboxylic acid

Temperature

-70 °C

To a solution of 0.516 moles of lithiodiisopropyl amine in 390 mL hexane and 200 mL tetrahydrofuran, cooled to -70° C., was added dropwise a solution of 40 g (0.229 moles) 2,6-dichloro-5-fluoronicotinic acid in 600 mL tetrahydrofuran, over a 1-hour period. The reaction mixture was stirred at -70° C. for 1 hour, then warmed to -60° C. for 1.5 hours at which time a light colored precipitate formed. The slurry was briefly warmed to -50° C., then recooled to -70° C., at which point a solution of 84 mL (1.34 moles) methyl iodide in 90 mL tetrahydrofuran was added dropwise. After the addition was complete, the reaction mixture was allowed to slowly warm to -20° C. over approximately 1 hour. The solution was acidified with dilute HCl pH 1-2 diluted with diethyl ether and allowed to warm to room temperature. The aqueous layer was extracted twice with ether. The combined ether washes were washed with H2O, dried with MgSO4, and evaporated in vacuo to yield a crude solid. The crude material was recrystallized from toluene to yield 31.7 g of the title compound.

1. waitover a 1-hour period
2. temperaturewarmed to -60° C. for 1.5 hours at which time a light colored precipitate
3. customformed
4. temperatureThe slurry was briefly warmed to -50° C.
5. customrecooled to -70° C., at which point
6. additionwas added dropwise
7. additionAfter the addition
8. temperatureto slowly warm to -20° C. over approximately 1 hour
9. temperatureto warm to room temperature
10. extractionThe aqueous layer was extracted twice with ether
11. washThe combined ether washes were washed with H2O
12. dry with materialdried with MgSO4
13. customevaporated in vacuo
14. customto yield a crude solid
15. customThe crude material was recrystallized from toluene

ORD record

ord-de914676ada4450bb6e1f3acb07409e7

Source dataset

uspto-grants-1996_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05585491