Ammonium Hydroxide → 4-Amino-3-chloro-5,6-difluoropicolinonitrile

A solution of 3-chloro-4,5,6-trifluoropicolinonitrile (200 g) in ethyl acetate (EtOAc; 3 L) was cooled to 10° C. To this was slowly added 14% aqueous ammonium hydroxide (NH4OH; 1296 g) keeping the temperature between 18-23° C. The aqueous solution was separated from the organic solution. The organic phase was washed sequentially with a 50/50 solution of aqueous saturated NaCl and water (500 mL) and saturated NaCl solution (250 mL). The organic phase was concentrated under vacuum at 50° C. to about 500 mL volume as the product crystallized out. To this slurry was added heptane (1 L), and the remaining EtOAc was removed under vacuum to give the final slurry. The solids were collected by filtration. This solid was washed with pentane and dried under vacuum to give 4-amino-3-chloro-5,6-difluoropicolinonitrile (173.8 g, 90%, 99.6% purity) as a white crystalline solid: mp 190-191.5° C.; 13C{1H} NMR (101 MHz, DMSO-d6) δ 150.03 (dd, J=232.4, 12.5 Hz, C6), 144.29 (dd, J=11.4, 6.9 Hz, C4), 133.72 (dd, J=257.9, 30.8 Hz, C5), 122.14 (dd, J=19.6, 4.9 Hz, C2), 119.31 (s, C3), 114.25 (s, CN); 19F NMR (376 MHz, DMSO-d6) δ −91.24 (d, J=24.2 Hz), −154.97 (d, J=24.2 Hz); EIMS m/z 189 ([M]+). Anal. Calcd for C6H2ClF2N3: C, 38.02; H, 1.06; N, 22.17. Found: C, 37.91; H, 1.00; 22.02.

1. custombetween 18-23° C
2. customThe aqueous solution was separated from the organic solution
3. washThe organic phase was washed sequentially with a 50/50 solution of aqueous saturated NaCl and water (500 mL) and saturated NaCl solution (250 mL)
4. concentrationThe organic phase was concentrated under vacuum at 50° C. to about 500 mL volume as the product
5. customcrystallized out
6. additionTo this slurry was added heptane (1 L)
7. customthe remaining EtOAc was removed under vacuum
8. customto give the final slurry
9. filtrationThe solids were collected by filtration
10. washThis solid was washed with pentane
11. customdried under vacuum

ORD record

ord-35abc848c2e34b92a02f0e2cf3f068c6

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08609853B2