Dimethylformamide → 5-Cyano-3-methyl-pyridine-2-carboxylic acid tert-butyl ester

Temperature

69 °C

To a solution of 5-bromo-3-methyl-pyridine-2-carboxylic acid tert-butyl ester (48 g, 176 mmol) in DMF (253 mL) under N2 atmosphere was sequentially added Zn powder (1.15 g, 17.6 mmol), Pd2(dba)3 (4.04 g, 4.4 mmol), tri-tert-butylphosphine (214 g, 10.6 mmol, 10 wt % in n-hexane). The mixture was then heated to 50˜60° C. with stirring, at this point, Zn(CN)2 (14.5 g, 123.5 mmol) was added to the mixture in one portion. The reaction mixture was then heated at 69° C. with stirring. After 1 h, the reaction mixture was allowed to cool to below 30° C. and filtered. The filter cake was washed with DMF. To the filtrate was added 2-methyltetrahydrofuran with stirring and the mixture was cooled to <20° C., to the mixture was added slowly 3N aqueous ammonia solution with stirring and the mixture was then stirred vigorously for 30 min at 20˜30° C. before layer separation. The organic layer was washed with brine and concentrated in vacuo to give the title compound as a yellowish crystalline solid: ESIMS: 219; [(M+H)+]; 1H NMR (400 MHz, acetone-d6): δ 8.79 (d, 1H), 8.20 (d, 1H), 2.49 (s, 3H), 1.60 (s, 9H).

1. temperatureThe mixture was then heated to 50˜60° C.
2. additionwas added to the mixture in one portion
3. temperatureto cool to below 30° C.
4. filtrationfiltered
5. washThe filter cake was washed with DMF
6. additionTo the filtrate was added 2-methyltetrahydrofuran
7. stirringwith stirring
8. temperaturethe mixture was cooled to <20° C., to the mixture
9. additionwas added slowly 3N aqueous ammonia solution
10. stirringwith stirring
11. stirringthe mixture was then stirred vigorously for 30 min at 20˜30° C. before layer separation
12. washThe organic layer was washed with brine
13. concentrationconcentrated in vacuo

ORD record

ord-0082fe7efc854e2a89905b0a2731c854

Source dataset

uspto-grants-2012_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08338413B1