A COMPARATIVE STUDY OF METHODS OF THE SALICYLIC ACID CHLORINATION FOR FURTHER PRODUCTION OF ANTIHELMINTHIC DRUGS
Abstract
With the help of thin-layer and high-performance liquid chromatography, the change in the composition of the reaction mass during the chlorination of salicylic acid was studied by three methods: molecular chlorine in acetic acid, sodium hypochlorite in an aqueous alkaline solution and oxidative chlorination with a mixture of hydrogen peroxide and hydrochloric acid in an acetic acid environment. It is shown that the most complete transformation of salicylic acid into 3,5-dichlorosalicylic acid is observed in the reaction with sodium hypochlorite, and the least complete - in the reaction of oxidative chlorination. It was found that the adverse reaction of the ipso-replacement of the carboxyl group with the formation of 2,4,6-trichlorophenol to the greatest extent occurs in chlorination of salicylic acid with gaseous chlorine in the acetic acid and with sodium hypochlorite in the aqueous alkaline medium. It is established that recrystallization technical 3,5-dichlorosalicylic acid of 50% aqueous 2-propanol to most effectively allows you to remove the admixture of 2,4,6-trichlorophenol, and to a lesser extent, admixture chlorosalicylic acids.
About the Authors
V. G. Dudarev
Saint-Petersburg State Chemical and Pharmaceutical University of the Ministry of Healthcare
Russian Federation
Russian Federation
M. R. Kuzminykh
Saint-Petersburg State Chemical and Pharmaceutical University of the Ministry of Healthcare
Russian Federation
Russian Federation
G. M. Alekseeva
Saint-Petersburg State Chemical and Pharmaceutical University of the Ministry of Healthcare
Russian Federation
Russian Federation
References
1. Mahajan T., Kumar L., Dwivedi K., Agarwal D. D. Sodium Lauryl Sulfate-Catalyzed Oxidative Chlorination of Aromatic Compounds // Synthetic Communications. 2012. V. 42. P. 3655-3663.
2. Solakyildirim K., Bulloch D. N., Larive C. K. 1H and 13C NMR spectral assignments of halogenated transformation products of pharmaceuticals and related environmental contaminants // Magn. Reson. Chem. 2014. V. 52. P. 310-317.
3. Swan G. E. The pharmacology of halogenated salicylanilides and their anthelmintic use in animals // J. S. Afr. Vet. Ass. 1999. V. 70. Iss. 2. P. 61-70.
4. Патент РФ № 2476424, МПК А 61К 31/609, А 61 Р 33/10, С 07 С 235/66. N-(3-хлор-4-пропилоксифенил)-3,5-дихлорсалициламид, обладающий антигельминтной активностью / Бурякина А. В., Гицу Г. А., Малахова А. Ю., Михайлицын Ф. С., Сафарова А. Я., Севбо Д. П., Трусов С. Н.; заявитель и патентообладатель ФГБОУ ВО «Санкт-Петербургская государственная химико-фармацевтическая академия» Министерства здравоохранения и социального развития Российской Федерации. - Заявл. 22.12.2011; опубл. 10.05.2013. 4 с.
5. Mikhailitsyn F. S., Sevbo D. P., Trusov S. N. i dr. Obtaining and antihymenopelodic activity of compound MST-25 // Med. parasitol. and parasitic diseases. 2011. № 2. S. 41-42.
6. Патент РФ № 2481327, МПК C07C235/44, A61P33/10, A61K31/609. N - (3,4 -дих лорфенил) -2- (ацетилокси) -3, 5 -дихлорбензамид, обладающий антигельминтной активностью / Михайлицын Ф. С., Архипов И. А., Севбо Д. П., Трусов С. Н., Мусаев М. Б., Козлов С. А., Архипова Д. Р., Садов К. М., Белова Е. Е., Гицу Г. А.; заявитель и патентообладатель ГНУ Всероссийский научно-исследовательский институт гельминтологии имени К. И. Скрябина. - Заявл. 27.12.2011; опубл. 10.05.2013. 3 с.
7. Avgustinovich D. F., Vishnivetskaya G. B., Pirozhkova D. S. i dr. Effect of N- (4-methyl-3-chlorophenyl) -2-acetoxy-3,5dichlorobenzamide on sexually mature and juvenile O. felineus in vitro and in vivo. // Sibirskii nauchnyi meditsinskii zhurnal. 2017. T. 37. № 3. S. 17-26.
8. Pilyugin V. S., Sapozhnikov Yu. E., Sapozhnikova N. A. Acyl derivatives of 2-aminobenzimidazole and their fungicidal activity. Zh. obshchei khimii. 2004. T. 74. Vyp. 5. S. 804-810.
9. Mahajan T., Kumar L., Dwivedi K., Agarwal D. D. Efficient and facile chlorination of industrially-important aromatic compounds using NaCl/p-TsOH/NCS in aqueous media // Ind. Eng. Chem. Res. 2012. V. 51. P. 3881-3886.
10. Sharma S. K. Chlorination of aromatic compounds in aqueous media using N-chlorosuccinimide // Res. J. Chem. Sci. 2015. V. 5. Iss. 12. P. 54-73.
11. Eckstein Z. Porownanie metod otrzymywania kwasu 3,6-dwuchloro-2-metoksybenzoesowego (dikamby) // Przemysl chemiczny. 1979. V. 58. P. 533-536.
12. Sharma S. K., Agarwal D. D. Oxidative Chlorination of Aromatic Compounds in aqueus media // Int. J. Sci. Res. Publ. 2014. V. 4. Iss. 7. P. 1-18.
13. Патент РФ № 2053217, МПК C07C65/05, C07C51/363. Способ получения 5-хлорсалициловой кислоты / Красюк И. И., Литвин Б. Л.; заявитель и патентообладатель Ивано-Франковская фирма «Барва». - Заявл. 12.11.1990; опубл. 27.01.1996. 3 с.
14. Broadwater M. A., Swanson T. L., Sivey J. D. Comparing the inherent reactivity of oftenoverlooked aqueous chlorinating and brominating agents toward salicylic acid // Environ. Sci.: Water Res. Technol. 2018. Advance Article. First published on 04 Jan 2018. URL: http://dx.doi.org/10.1039/C7EW00491E.
15. Prutz W. A. Reactions of hypochlorous acid with biological substrates are activated catalytically by tertiary amines // Arch. Biochem. Biophys. 1998. V. 357. № 2. P. 265-273.
16. Quintana J. B., Rodil R., Lopez-Mahia P. et al. Investigating the chlorination of acidic pharmaceuticals and by-product formation aided by an experimental design methodology // Water Res. 2010. V. 44. P. 243-255.
Review
For citations:
Dudarev V.G., Kuzminykh M.R., Alekseeva G.M. A COMPARATIVE STUDY OF METHODS OF THE SALICYLIC ACID CHLORINATION FOR FURTHER PRODUCTION OF ANTIHELMINTHIC DRUGS. Drug development & registration. 2018;(3):82-87. (In Russ.)
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