Methyl iodide → 2-Fluoro-4-iodo-3,5-dimethylpyridine

Temperature

-18 °C

Diisopropylamine (88 mL) was added to THF (1.2 L), and the mixture was cooled to −18° C. in a nitrogen atmosphere. A 2.69 M solution of n-butyllithium in hexane (215 mL) was added dropwise to the solution. After completion of the dropwise addition, the mixture was warmed to −5° C. with stirring over 30 minutes. The reaction mixture was cooled to −72° C. A solution of 2-fluoro-3-iodo-5-methylpyridine (109.69 g) in TIE (240 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at −74° C. for 1.5 hours. A solution of methyl iodide (36 mL) in THF (160 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at −70° C. to −74° C. for two hours. After completion of the reaction, water (200 mL) was added to the reaction mixture at the same temperature. The mixture was stirred at the same temperature for two minutes. The reaction mixture was returned to room temperature, and water (1.2 L) was then added. The mixed solution was stirred for three minutes. Water (300 mL) was further added. The mixture was extracted with MTBE (1.2 L). The organic layer was washed with brine (500 mL). The combined aqueous layers were extracted with MTBE (1 L). The combined organic layers were dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. n-heptane (100 mL) was added to the residue, followed by cooling. The precipitated solid was collected by filtration. The residue was washed with n-heptane. The filtrate was cooled, and the precipitated solid was collected by filtration. This operation was repeated twice to give the title compound (86.9 g).

1. additionAfter completion of the dropwise addition
2. temperaturethe mixture was warmed to −5° C.
3. temperatureThe reaction mixture was cooled to −72° C
4. stirringThe reaction mixture was stirred at −74° C. for 1.5 hours
5. stirringThe reaction mixture was stirred at −70° C. to −74° C. for two hours
6. additionwas added to the reaction mixture at the same temperature
7. stirringThe mixture was stirred at the same temperature for two minutes
8. customwas returned to room temperature
9. stirringThe mixed solution was stirred for three minutes
10. extractionThe mixture was extracted with MTBE (1.2 L)
11. washThe organic layer was washed with brine (500 mL)
12. extractionThe combined aqueous layers were extracted with MTBE (1 L)
13. dry with materialThe combined organic layers were dried over anhydrous magnesium sulfate
14. customThe desiccant was removed by filtration
15. concentrationthe filtrate was concentrated under reduced pressure
16. additionn-heptane (100 mL) was added to the residue
17. temperatureby cooling
18. filtrationThe precipitated solid was collected by filtration
19. washThe residue was washed with n-heptane
20. temperatureThe filtrate was cooled
21. filtrationthe precipitated solid was collected by filtration

ORD record

ord-6bf5989c27744e37876eba2721aa9989

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08563565B2