Synthesis of 5-chloro-thiosulfadiazine Compounds Using Two-Phase Systems of Organic Solvents

  • Sarah M. Maashi Department of Chemistry & Biochemistry, University of the Sciences in Philadelphia, Philadelphia, PA, 19104, United States,Department of Chemistry, Jazan University, Jazan, 82817, Saudi Arabia.
  • James R. McKee Department of Chemistry & Biochemistry, University of the Sciences in Philadelphia, Philadelphia, PA, 19104, United States.
Keywords: Sulfadiazine, Thiophene, Na2CO3, NaOAc, H2O


We report a direct and simple protocol for the synthesis of 5-chloro-thiosulfadiazine compounds. This reaction has been achieved using two-phase systems of organic solvents (NaOAc/ H2O and Na2CO3/ H2O. The use of NaOAc or Na2CO3 for the preparation of chloro compounds provided all the advantages of cost, safety, and environmental concerns; thus, this method will give broad utility to the organic/medicinal chemist that is pursuing the synthesis of sulfonamides derivatives.


Ajeet, A.; Mishra, A. K.; Kumar, A. Recent Advances in Development of Sulfonamide Derivatives and Their Pharmacological Effects- A Review. Am. J. Pharmacol. Sci. 2015, 3 (1), 18–24.

Zhao, Y.; Shadrick, W. R.; Wallace, M. J.; Wu, Y.; Griffith, E. C.; Qi, J.; Yun, M.-K.; White, S. W.; Lee, R. E. Pterin-Sulfa Conjugates as Dihydropteroate Synthase Inhibitors and Antibacterial Agents. Bioorg. Med. Chem. Lett. 2016, 26 (16), 3950–3954.

Alsughayer, A.; Elassar, A.-Z. A.; Mustafa, S.; Sagheer, F. Al. Synthesis, Structure Analysis and Antibacterial Activity of New Potent Sulfonamide Derivatives. J. Biomater. Nanobiotechnol. 2011, 02 (02), 143–148.

Naaz, F.; Srivastava, R.; Singh, A.; Singh, N.; Verma, R.; Singh, V. K.; Singh, R. K. Molecular Modeling, Synthesis, Antibacterial and Cytotoxicity Evaluation of Sulfonamide Derivatives of Benzimidazole, Indazole, Benzothiazole and Thiazole. Bioorg. Med. Chem. 2018, 26 (12), 3414–3428.

Mansour, A. M.; Soliman, F. A.; Shehab, O. R.; Abdel-Ghani, N. T. Photodegradation of Sulfadiazine Catalyzed by P-Benzoquinones and Picric Acid: Application to Charge Transfer Complexes. RSC Adv. 2017, 7 (63), 39989–39996.

Blanchard, C.; Brooks, L.; Ebsworth-Mojica, K.; Didione, L.; Wucher, B.; Dewhurst, S.; Krysan, D.; Dunman, P. M.; Wozniak, R. A. F. Zinc Pyrithione Improves the Antibacterial Activity of Silver Sulfadiazine Ointment. mSphere. 2016, 1 (5).

Winters, K. J.; Janney, F. R. SULFADIAZINE: REVIEW OF ITS USE IN TREATMENT OF CHILDREN. Am. J. Dis. Child. 1943, 65 (5), 702–711.

Woods, D. D. The Relation of P-Aminobenzoic Acid to the Mechanism of the Action of Sulphanilamide. Br J Exp Pathol 1940, 21 (2), 74–90.

Mabkhot, Y. N.; Alatibi, F.; El-Sayed, N. N. E.; Kheder, N. A.; Al-Showiman, S. S. Synthesis and Structure-Activity Relationship of Some New Thiophene-Based Heterocycles as Potential Antimicrobial Agents. Molecules 2016, 21 (8).

Hu, Y.; Yang, S.; Shilliday, F. B.; Heyde, B. R.; Mandrell, K. M.; Robins, R. H.; Xie, J.; Reding, M. T.; Lai, Y.; Thompson, D. C. Novel Metabolic Bioactivation Mechanism for a Series of Anti-Inflammatory Agents (2,5-Diaminothiophene Derivatives) Mediated by Cytochrome P450 Enzymes. Drug Metab. Dispos. 2010, 38 (9), 1522–1531.

Jha, K.; Kumar, S.; Tomer, I.; Mishra, R. Thiophene: The Molecule of Diverse Medicinal Importance. J. Pharm. Res. 2012, 5 (1), 560–566.

Ryabova, V.; Ignatovich, L. Thiophene Substitution Chemistry. In Thiophenes; Joule, J. A., Ed.; Topics in Heterocyclic Chemistry; Springer International Publishing: Cham, 2015; pp 43–108.

Kamboj, A. Pharmacological Action and Sar of Thiophene Derivatives: A Review. J. Pharm. Res. 2012, (5), 7.

Żołnowska, B.; Sławiński, J.; Brzozowski, Z.; Kawiak, A.; Belka, M.; Zielińska, J.; Bączek, T.; Chojnacki, J. Synthesis, Molecular Structure, Anticancer Activity, and QSAR Study of N-(Aryl/Heteroaryl)-4-(1H-Pyrrol-1-Yl)Benzenesulfonamide Derivatives. Int. J. Mol. Sci. 2018, 19 (5), 1482.

Deng, X.; Mani, N. S. A Facile, Environmentally Benign Sulfonamide Synthesis in Water. Green Chem. 2006, 8 (9), 835.