2-Chloronicotinamide

Chemical Properties

BEIGE FINE CRYSTALLINE POWDER

Uses

2-Chloronicotinamide is an off-white gracile crystal powder and serves as an important drug intermediate. 2-Chloronicotinamide acts as a substrate and precursor to produce 2-chloronicotinic acid through amidase-mediated hydrolysis and biocatalytic processes. 2-Chloronicotinamide is applied as a precursor in the synthesis of 2-piperazin-1-ylnicotinamide, 2-chloropyridine-3-carbothioamide, and 2-chloro-N-iso-butylnicotinamide[6-8].

Synthesis

General procedure for the synthesis of 2-chloronicotinamide from 2-chloro-3-cyanopyridine: 400 mL of concentrated sulfuric acid was added to a 1000 mL three-necked flask, followed by the addition of 2-chloro-3-cyanopyridine (138 g, 1 mol), which was stirred until completely dissolved. The reaction system was warmed up to 90 °C and the reaction was maintained at this temperature with stirring for 2 hours. Upon completion of the reaction, the reaction mixture was slowly poured into a mixture containing 1000 mL of ammonia and 1 kg of ice and stirring was continued for 1 hour. The precipitated crude product was collected by filtration. The crude product was transferred to 1000 mL of ethyl acetate and stirred for 1 hour to wash and subsequently separated by filtration to give a white solid product. Finally, the white solid was dried by blowing at 50 °C to give 153 g of the intermediate 2-chloronicotinamide as a white solid in 98% yield.

References

[1] Patent: CN105367571,  2017,  B. Location in patent: Paragraph 0014; 0037; 0038
[2] Tetrahedron Letters,  2012,  vol. 53,  # 4,  p. 449 - 452
[3] Journal of Chemical Research,  2011,  vol. 35,  # 8,  p. 480 - 483
[4] Synlett,  2018,  vol. 29,  # 15,  p. 2061 - 2065
[5] Journal of Organic Chemistry,  1954,  vol. 19,  p. 1633,1636
[6] Tang, X.-L., Jin, J.-Q., Wu, Z.-M., Jin, L.-Q., Zheng, R.-C., Zheng, Y.-G. (2019). Structure-Based Engineering of Amidase from Pantoea sp. for Efficient 2-Chloronicotinic Acid Biosynthesis. Applied and Environmental Microbiology, 85(5). https://doi.org/10.1128/aem.02471-18
[7] Zheng, R.-C., Jin, J.-Q., Wu, Z.-M., Tang, X.-L., Jin, L.-Q., Zheng, Y.-G. (2018). Biocatalytic hydrolysis of chlorinated nicotinamides by a superior AS family amidase and its application in enzymatic production of 2-chloronicotinic acid. Bioorganic Chemistry, 76, 81–87. https://doi.org/10.1016/j.bioorg.2017.11.001
[8] He, H., Zhang, J., Niu, X., Wan, B., Lv, M., Li, F., Gao, X., Wan, Y., Yu, Y. (2025). Solubility determination, molecular simulation and thermodynamic analysis of 2-chloronicotinamide in three binary solvents from 278.15 K to 328.15 K. Journal of Molecular Liquids, 422, 126929. https://doi.org/10.1016/j.molliq.2025.126929