Methyl iodide → 2-Chloro-3-fluoro-5-iodo-4-methylpyridine

To a solution of 2.0 M of lithium diisopropylamide in tetrahydrofuran (5.5 mL) in tetrahydrofuran (20 mL, 200 mmol) at −78° C. was slowly added 2-chloro-3-fluoro-4-iodopyridine (2.589 g, 10.06 mmol) as a solution in tetrahydrofuran (8 mL). The reaction mixture was then stirred at −78° C. for 4 hours. Methyl iodide (0.70 mL, 11 mmol) was then added. After an additional 1 hour, the reaction was then quenched with saturated aqueous NH4Cl and warmed to room temp. The reaction mixture was poured into ethyl acetate and washed sequentially with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (80 g silica, solvent gradient: 0-30% ethyl acetate in heptanes) to yield 2.212 g (57%) of 2-chloro-3-fluoro-5-iodo-4-methylpyridine. LCMS (ESI): M+H=272.0; 1H NMR (500 MHz, CDCl3) δ 8.46 (s, 1H), 2.44 (d, J=1.2 Hz, 3H).

1. customat −78° C.
2. waitAfter an additional 1 hour
3. customthe reaction was then quenched with saturated aqueous NH4Cl
4. temperaturewarmed to room temp
5. additionThe reaction mixture was poured into ethyl acetate
6. washwashed sequentially with water and brine
7. dry with materialdried over MgSO4
8. filtrationfiltered
9. customevaporated in vacuo
10. customThe crude product was purified via flash chromatography on silica gel (80 g silica, solvent gradient: 0-30% ethyl acetate in heptanes)

ORD record

ord-996761c735ce4a4b878a4af5003d5575

Source dataset

uspto-grants-2014_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08623889B2