Diethyl Malonate → 2-Methyl-3-nitropyridine

Temperature

90 °C

Add sodium metal (3.5 g) portion-wise over 1 hour to a 3 neck flask containing 79 mL of diethyl malonate heated to 90° C. under nitrogen. Lower the temperature to 60° C. and add 2-chloro-3-nitropyridine (1a-1, 25.0 g) portion-wise over 15 min. The reaction color turns to dark red. Keep the solution for 3 h at 60° C. and then allow to stand at rt overnight. Tlc indicates remaining starting material. Heat the solution to 80° C. for an additional 3 h (completion of the reaction). Remove the diethyl malonate under reduced pressure and take-up the dark brown residue in a mixture of conc. H2SO4 (18 mL) and H2O (32 mL). Heat the mixture for 7 h at 105° C. (decarboxylation) and then allow to stand at rt overnight. Wash the mixture with 3×150 mL of Et2O and 2×200 mL of EtOAc, and discard the washings. Basify the aqueous phase to pH 8-9 with NaOH and extract with 3×200 mL EtOAc. Filter the combined organic extracts over Celite® (diatomaceous earth) (Celite Corporation, 137 West Central Avenue, Lompor, Calif. 93436) and remove the solvent under reduced pressure. The residue crystallizes to give 2a-1 (15.0 g, 68%), mp 29-31° C.

1. customfor 3 h
2. customat 60° C.
3. temperatureHeat the solution to 80° C. for an additional 3 h (
4. customcompletion of the reaction)
5. customRemove the diethyl malonate under reduced pressure
6. additionin a mixture of conc. H2SO4 (18 mL) and H2O (32 mL)
7. temperatureHeat the mixture for 7 h at 105° C. (decarboxylation)
8. waitto stand at rt overnight
9. washWash the mixture with 3×150 mL of Et2O and 2×200 mL of EtOAc
10. extractionBasify the aqueous phase to pH 8-9 with NaOH and extract with 3×200 mL EtOAc
11. filtrationFilter the combined organic extracts over Celite® (diatomaceous earth) (Celite Corporation, 137 West Central Avenue, Lompor, Calif. 93436)
12. customremove the solvent under reduced pressure
13. customThe residue crystallizes
14. customto give 2a-1 (15.0 g, 68%), mp 29-31° C.

ORD record

ord-cf1f01134438479fadb093abb5440192

Source dataset

uspto-grants-2008_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07402672B2