Nitrogen → 4-Iodo-2-methoxynicotinaldehyde

Temperature

-10 °C

To a solution of diisopropylamine (345 mL, 249 g, 2.46 mol) in anhydrous THF (5 L) at −8 to −10° C. under a blanket of N2 was added n-BuLi (880 mL, 158 g, 2.46 mol) dropwise via cannula. The mixture was stirred at −10° C. for 30 min, cooled to −78° C. and treated with a solution of 2-fluoro-3-iodopyridine (500 g, 2.24 mol) in dry THF (2 L) dropwise. After the addition, the reaction mixture was warmed to −60° C. and this temperature was maintained for 2 h. The mixture was then cooled to −78° C., treated with ethyl formate (183 g, 2.47 mol) dropwise, followed by sodium methoxide (149 g, 2.75 mol) in MeOH (1.5 L) and warmed to ambient temperature. The reaction mixture was quenched with ice water and extracted with EtOAc. The layers were separated and the organic phase was washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to afford 4-iodo-2-methoxynicotinaldehyde (380 g, 64%) as a solid. Alternatively, 4-iodo-2-methoxynicotinaldehyde can be prepared according to the procedure described in U.S. Pat. No. 5,491,237 (WO 95/29917).

1. temperaturecooled to −78° C.
2. additionAfter the addition
3. temperaturethe reaction mixture was warmed to −60° C.
4. temperaturethis temperature was maintained for 2 h
5. temperatureThe mixture was then cooled to −78° C.
6. temperaturewarmed to ambient temperature
7. customThe reaction mixture was quenched with ice water
8. extractionextracted with EtOAc
9. customThe layers were separated
10. washthe organic phase was washed with water and brine
11. dry with materialdried (Na2SO4)
12. concentrationconcentrated in vacuo
13. customThe residue was purified by flash chromatography on silica gel

ORD record

ord-3b894b44f4634575b68cb929d61dd209

Source dataset

uspto-grants-2013_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08536200B2