Diisopropylamine → 4-Chloropyridine-3-carbaldehyde

Temperature

-70 °C

4-Chloropyridine hydrochloride (15 g, 99.9 mmol) is free-based by stirring in 1000 mL 1:1 saturated NaHCO3/ether for 1 h. The layers are allowed to separate, the aqueous layer is extracted with ether (2×175 mL), and the combined organic layer is dried over MgSO4, filtered, and concentrated to an oil. THF (300 mL) is chilled to −70° C. in a dry flask. N-butyllithium (105.1 mL, 168.2 mmol) is added drop-wise, and the mixture is placed in an ice bath. Diisopropylamine (23.6 mL. 168.4 mmol) in THF (50 mL) is added drop-wise, the yellow solution is stirred for 30 min, and the reaction is cooled to −70° C. The free-based 4-chloropyridine oil (9.55 g, 84.1 mmol) is dissolved in THF (50 mL) and added drop-wise to the chilled yellow solution, that turned dark red after the addition. The reaction is stirred at −70° C. for 2 h. Ethyl formate (13.6 mL, 168.3 mmol) in THF (25 mL) is then added drop-wise to the dark solution at −70° C. After 2 hours, the reaction is warmed to −10° C. and quenched with water (450 mL). The layers are allowed to separate, and the aqueous layer is extracted with ether (3×200 mL). The combined organic layer is dried over MgSO4, filtered, and concentrated in vacuo to an oil. The crude material is chromatographed over 320 g slurry-packed silica eluting with 30% EtOAc/hexane to afford 4-chloropyridine-3-carboxaldehyde (C140) an orange oil which solidified under vacuum to an orange solid (21% yield).

1. customto separate
2. extractionthe aqueous layer is extracted with ether (2×175 mL)
3. dry with materialthe combined organic layer is dried over MgSO4
4. filtrationfiltered
5. concentrationconcentrated to an oil
6. customthe mixture is placed in an ice bath
7. temperaturethe reaction is cooled to −70° C
8. additionadded drop-wise to the chilled yellow solution, that
9. additionred after the addition
10. stirringThe reaction is stirred at −70° C. for 2 h
11. waitAfter 2 hours
12. temperaturethe reaction is warmed to −10° C.
13. customquenched with water (450 mL)
14. customto separate
15. extractionthe aqueous layer is extracted with ether (3×200 mL)
16. dry with materialThe combined organic layer is dried over MgSO4
17. filtrationfiltered
18. concentrationconcentrated in vacuo to an oil
19. customThe crude material is chromatographed over 320 g slurry-packed silica eluting with 30% EtOAc/hexane

ORD record

ord-9d22a4feebe049afbfa54899eb6af03e

Source dataset

uspto-grants-2005_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06911543B2