Hydrochloric Acid → 1H-Indazole-5-carbonitrile

Temperature

35 °C

To a 1-L beaker was added 20.0 g (150 mmol) of 5-aminoindazole, and 150 g of ice. The mixture was stirred with a magnetic stir bar and cooled on an ice-water bath. To this mixture was added 37.5 mL of concentrated aqueous hydrochloric acid, followed by a solution of 10.5 g (152 mmol, 1.01 equiv.) of sodium nitrite in 30 mL of H2O, dropwise over 15 min. The mixture was vigorously stirred for 30 min. and then carefully neutralized to pH ca. 7.0 with 9.5 g of solid sodium carbonate (Na2CO3). This mixture was transferred to a 1-L separatory funnel, kept cold by the addition of ice, and added dropwise to an ice cooled, magnetically stirred mixture of 16.8 g (188 mmol, 1.24 equiv.) of copper (I) cyanide (CuCN), 24.4 g (498 mmol, 3.32 equiv.) of sodium cyanide (NaCN), 112 mL H2O, and 250 mL of ethyl acetate (EtOAc) in a 2-L erlenmeyer flask over 20 min. Nitrogen gas was evolved from the reaction. The mixture turned dark quickly, and was stirred on ice for 30 min. and then the ice was removed. Stirring was continued for 3.5 h. The mixture was then heated on a hot plate until the internal temperature was 50° C. The reaction was removed from the hot plate and allowed to cool to 35° C., and filtered through filter paper. The layers were separated, and the organic layer was washed with saturated aqueous NaCl, and dried (Na2SO4). The organic layer was poured directly onto a 65 mm column containing 200 g of silica gel and eluted with EtOAc. Fractions of 500 mL were collected, and all product containing fractions were combined and concentrated to give the title compound (19.60 g, 91% yield): ES-MS (m/z) 144 [M+1]+.

1. temperaturecooled on an ice-water bath
2. stirringThe mixture was vigorously stirred for 30 min.
3. customThis mixture was transferred to a 1-L separatory funnel
4. additionkept cold by the addition of ice
5. temperaturecooled
6. customNitrogen gas was evolved from the reaction
7. stirringwas stirred on ice for 30 min.
8. customthe ice was removed
9. stirringStirring
10. temperatureThe mixture was then heated on a hot plate until the internal temperature
11. customwas 50° C
12. customThe reaction was removed from the hot plate
13. filtrationfiltered
14. filtrationthrough filter paper
15. customThe layers were separated
16. washthe organic layer was washed with saturated aqueous NaCl
17. dry with materialdried (Na2SO4)
18. additionThe organic layer was poured directly onto a 65 mm column
19. additioncontaining 200 g of silica gel
20. washeluted with EtOAc
21. customFractions of 500 mL were collected
22. additionall product containing fractions
23. concentrationconcentrated

ORD record

ord-5c9ebeee59fe4383a7fff4d43bec648d

Source dataset

uspto-grants-2007_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07211594B2