A Different Method for Synthesis of 2-(2-Methyl-5-nitro-1H-imidazol-1-yl)acetaldehyde

Öz

Metronidazole was discovered for the first time in 1959 at the Rhone Poulanc Research laboratory in France. It is an antibiotic and antiprotozoal drug active substance, which is on the World Health Organization's list of essential drugs. It has been shown by the studies carried out since 1975 that metronidazole was oxidized to the related aldehyde or further oxidized to the related acid by the bacteria in the human body and in the research laboratories by various methods. Many scientists have published many articles, containing schiff base synthesis, oxime formation and reductive amination reactions, using as a reactive substance aldehyde, the subject of this article. The oxidation of metronidazole is important for aquatic environments. On this subject, various computational and experimental studies are available in the literature in order to treat wastewater with various oxidation methods. In this study, 2-(2-methyl-5-nitro-1H-imidazol-1- yl)acetaldehyde was obtained by the controlled oxidation reaction method which was different from the literature. In this method in a round bottom flask, equal equivalent metronidazole and pyridinium chlorochromate were solved in dichloromethane. The solution was stirred magnetically for 24 hours at room temperature. The crude product contains approximately half-and-half unreacted metronidazole and the product aldehyde. The product was purified by TLC method for 1H-NMR, FTIR spectroscopic analysis and melting point determination.

Anahtar Kelimeler

• 2-(2-methyl-5-nitro1H-imidazol-1-yl) acetaldehyde
• Metronidazole
• Oxidation
• FTIR
• NMR
• TLC

Farklı Bir Yöntemle 2-(2-Metil-5-nitro-1H-imidazol-1-il)asetaldehit Eldesi

Öz

Metronidazol Dünya Sağlık Örgütünün temel ilaçlar listesinde yer alan ilk defa 1959 yılında Fransa'da Rhone Poulanc Araştırma laboratuvarında keşfedilen antibiyotik ve antiprotozoal ilaç etkin maddesidir. Metronidazolün insan vücudunda bulunan bakteriler tarafından ve araştırma laboratuvarlarında çeşitli metotlarla kontrollü olarak yükseltgenerek ilgili aldehite veya daha da yükseltgenerek ilgili asite yükseltgendiği 1975 yılından günümüze yayınlanan çalışmalarda gösterilmiştir. Birçok bilim insanı makalenin konusu aldehiti reaktif olarak kullanarak schiff bazı eldesi, oksim oluşumu ve redüktif aminasyon reaksiyonlarını yayınlamıştır. Metronidazolün yükseltgenmesi sucul ortamlar için önemlidir. Atık sulardaki metronidazolün arıtılması amacıyla, çeşitli yöntemlerle metronidazolün yükseltgenmesi için hesaplamalı ve deneysel çalışmalar literatürde mevcuttur. Bu çalışmada, literatürden farklı bir yöntemle 2-(2-metil-5-nitro-1H-imidazol-1- il)asetaldehit, metronidazolün kontrollü yükseltgenmesi reaksiyonu ile elde edilmiştir. Bu reaksiyon, dibi yuvarlak bir reaksiyon balonunda oda sıcaklığında eşit ekivalentlerde metronidazol ve piridinyum klorokromatın diklorometan içindeki çözeltisinin 24 saat manyetik olarak karıştırılmasıyla gerçekleştirilmiştir. Yükseltgenme reaksiyonu sonucunda elde edilen ham ürün yaklaşık yarı yarıya reaksiyona girmemiş metronidazolü ve yükseltgenmiş ürün aldehiti içermektedir. Ürünün 1H-NMR, FTIR spektroskopik analizleri ve erime noktası tayini amacıyla saflaştırılması için İTK yöntemi kullanılmıştır.

Anahtar Kelimeler

• 2-(2-Metil-5-nitro1H-imidazol-1-il) asetaldehit
• Metronidazol
• Yükseltgeme
• FTIR
• NMR
• İTK

Kaynakça

1. [1] Cosar, C., Julou, L. 1959. Activity of (Hydroxy2'Ethyl)-1 Methyl-2 Nitro-5 Imidazole (8823, RP) in Experimental Trichomonas vaginalis Infections. Ann. Inst. Pasteur, 96(2), 238-41.
2. [2] Leitsch, D. 2019. A review on metronidazole: an old warhorse in antimicrobial chemotherapy. Parasitology, 146(9), 1167-1178.
3. [3] Nicol, C. S., Barrow, J., Redmond, A. 1960. Flagyl (8823 RP) in the treatment of trichomoniasis. British Journal of Venereal Diseases, 36(3), 152.
4. [4] Rodin, P., King, A. J., Nicol, C. S., Barrow, J. 1960. Flagyl in the treatment of trichomoniasis. British Journal of Venereal Diseases, 36(3), 147.
5. [5] Leitsch, D. 2019. A review on metronidazole: an old warhorse in antimicrobial chemotherapy. Parasitology, 146(9), 1167-1178.
6. [6] Rustia, M., Shubik, P. 1979. Experimental induction of hepatomas, mammary tumors, and other tumors with metronidazole in noninbred Sas: MRC (WI) BR rats. Journal of the National Cancer Institute, 63(3), 863-868.
7. [7] Cavaliere, A., Bacci, M., Amorosi, A., Del Gaudio, M., Vitali, R. 1983. Induction of lung tumors and lymphomas in BALB/c mice by metronidazole. Tumori Journal, 69(5), 379-382.
8. [8] Bendesky, A., Menéndez, D., Ostrosky-Wegman, P. 2002. Is metronidazole carcinogenic? Mutation Research/Reviews in Mutation Research, 511(2), 133-144.

9. [9] Cavaliere, A., Bacci, M., Vitali, R. 1984. Induction of mammary tumors with metronidazole in female Sprague-Dawley rats. Tumori Journal, 70(4), 307-311.
10. [10] Adil, M., Iqbal, W., Adnan, F., Wazir, S., Khan, I., Khayam, M. U., Kamal, M.A., Ahmad, S., Ahmed, J., Khan, I. N. 2018. Association of metronidazole with cancer: a potential risk factor or inconsistent deductions? Current Drug Metabolism, 19(11), 902-909.
11. [11] Code of Federal Regulation. 1987. Title 21, Chapter l, Part 530, Subpart E, § 530.41 Drugs prohibited for extralabel use in animals. 21 CFR 530.41(a)(6) and https://www.ecfr.gov/current/title-21/chapterI/subchapter-E/part-530/subpart-E/section530.41#p-530.41(a)(6) (Erişim Tarihi: 13.01.2023)
12. [12] Commission Regulation. 2010. (EU) No 37/2010, on pharmacologically active substances and their classification regarding maximum residue limits in foodstuffs of animal origin, Official Journal of the European Union, L 15/1. https://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ :L:2010:015:0001 :0072:en:PDF (Erişim Tarihi: 13.01.2023)
13. [13] Sales of veterinary antimicrobial agents in 31 European countries in 2019 and 2020, Trends from 2010 to 2020 Eleventh ESVAC report. https://www.ema.europa.eu/en/documents/re port/sales-veterinary-antimicrobial-agents-31- european-countries-2019-2020-trends-2010- 2020-eleventh_en.pdf (Erişim Tarihi: 13.01.2023)
14. [14] Kalinowska-Lis, U., Felczak, A., Chęcińska, L., Zawadzka, K., Patyna, E., Lisowska, K., Ochocki, J. 2015. Synthesis, characterization and antimicrobial activity of water-soluble silver (I) complexes of metronidazole drug and selected counter-ions. Dalton Transactions, 44(17), 8178- 8189.
15. [15] Athar, F., Husain, K., Abid, M., Agarwal, S. M., Coles, S. J., Hursthouse, M. B. Maurya, M.R., & Azam, A. 2005. Synthesis and Anti‐Amoebic Activity of Gold (I), Ruthenium (II), and Copper (II) Complexes of Metronidazole. Chemistry & biodiversity, 2(10), 1320-1330.
16. [16] Ahmadi, F., Shabrandi, N., Hosseinzadeh, L., Azizian, H. 2019. Two DNA binding modes of a zinc-metronidazole and biological evaluation as a potent anti-cancer agent. Nucleosides, Nucleotides and Nucleic Acids, 38(7), 449-480.
17. [17] BERG, S. S., BW, S. 1975. Derıvatıves of 4-and 5- nitro-2-methylimidazol-1-yl-acetaldehyde. European Journal of Medicinal Chemistry, 10(2), 171-177.
18. [18] Singh, S. K., Khan, M. U., Swami, M. N., Parihar, S.S., Tiwari, S., Nigam, S. K. 2013. Kinetics of oxidation of metronidazole with Nbromophthalimide in aqueous acetic acid medium, International Journal of Green and Herbal Chemistry, 2(3), 535-542.
19. [19] Craighead, M., Palin, R., Murray, N., Lindsay, D. 2012. Preparation and use of redox derivatives of known pharmaceutical compounds. World Intellectual Property Organization, WO2012063085 A2 2012-05-18.
20. [20] Yang, L.X., Hofer, K.G., 1998. Pharmaceutical compounds comprising polyamines substituted with electron-affinic groups, World Intellectual Property Organization, WO9814190 A1 1998-04- 09.
21. [21] Yang, L. X., Hofer, K. G. 1996. Reductive amination of nitroimidazole aldehyde with diamines using sodium triacetoxyborohydride. Tetrahedron letters, 37(34), 6081-6084.
22. [22] Baxter, E. W., Reitz, A. B. 2004. Reductive aminations of carbonyl compounds with borohydride and borane reducing agents. Organic reactions, 59, 1-714.
23. [23] Goerlitzer, K., Klanck, S. 2000. Metronidazole Derivatives with Intramolecular Equivalents of Reduction. Chem Inform, 31(10), no-no.
24. [24] Ding, C.Z., Kim, I.H., Wang, J., Ma, Z., Jin, Y., Combrink, K.D., Lu, G., Lynch, A.S., 2008. Preparation of nitroheteroaryl-containing rifamycin derivatives as antibacterial agents, World Intellectual Property Organization, WO2008008480 A2 2008-01-17.
25. [25] Xu, B., Ding, X., Wu, Y., Cui, L., Qian, P., Wang, D., Zhao, Y. 2018. Synthesis and antibacterial activity of oxazolidinone derivatives containing nitro hetero aromatic moiety. Chemical Research in Chinese Universities, 34(1), 51-56.
26. [26] Ma, Z., He, S., Yuan, Y., Zhuang, Z., Liu, Y., Wang, H., Chen, J., Xu, X., Ding, C., Molodtsov, V., Lin, W., Robertson, G.T., Weiss, W.J., Pulse, M., Nguyen, P., Duncan, L., Doyle, T., Ebright, R.H., Lynch, A. S. 2022. Design, Synthesis, and Characterization of TNP-2198, a Dual-Targeted RifamycinNitroimidazole Conjugate with Potent Activity against Microaerophilic and Anaerobic Bacterial Pathogens. Journal of medicinal chemistry, 65(6), 4481-4495.
27. [27] Lee, R.E., Cherian, P.T., Hurdle, J.G., Wu, X. 2015. Treatments for gastrointestinal conditions, World Intellectual Property Organization, WO2015138753 A1 2015-09-17.
28. [28] K Hijazi, A., A Taha, Z., M Ajlouni, A., M Al-Momani, W., M Idris, I., A Hamra, E. 2017. Synthesis and biological activities of lanthanide (III) nitrate complexes with N-(2-hydroxynaphthalen-1-yl) methylene) nicotinohydrazide Schiff Base. Medicinal Chemistry, 13(1), 77-84.
29. [29] Soğukömeroğulları, H. G., Başaran, E. 2022. Hidrazon Türevi Yeni Fe (II), Co (II), Ni (II) ve Cu (II) Komplekslerinin Sentezi ve Karakterizasyonu. Süleyman Demirel Üniversitesi Fen Bilimleri Enstitüsü Dergisi, 26(2), 216-222.
30. [30] Anderson, R. F., Smaill, J. B., Patterson, A. V., Ashoorzadeh, A., Ackerley, D. F., Copp, J. N., Mowday, A.M., Williams, E.M., Guise, C.P., Koch, C., Kachur, A., Dolbier Jr, W. R. 2015. U.S. Patent Application No. 14/368,261.
31. [31] Khan, A. A. P., Khan, A., Asiri, A. M., Azum, N., Rub, M. A., Khan, S. B., Rahman, M.M., Al-Youbi, A. O. 2014. Study of the base-catalysed oxidation of the anti-bacterial and anti-protozoal agent metronidazole by permanganate ion in alkaline medium. Research on Chemical Intermediates, 40(4), 1703-1714.
32. [32] Johnson, M. B., Mehrvar, M. 2008. Aqueous metronidazole degradation by UV/H2O2 process in single-and multi-lamp tubular photoreactors: kinetics and reactor design. Industrial & engineering chemistry research, 47(17), 6525- 6537.
33. [33] Watkinson, A. J., Murby, E. J., Kolpin, D. W., Costanzo, S. D. 2009. The occurrence of antibiotics in an urban watershed: from wastewater to drinking water. Science of the total environment, 407(8), 2711-2723.
34. [34] Elmolla, E. S., Chaudhuri, M. 2009. Degradation of the antibiotics amoxicillin, ampicillin and cloxacillin in aqueous solution by the photoFenton process. Journal of hazardous materials, 172(2-3), 1476-1481.
35. [35] Elmolla, E. S., Chaudhuri, M. 2010. Degradation of amoxicillin, ampicillin and cloxacillin antibiotics in aqueous solution by the UV/ZnO photocatalytic process. Journal of hazardous materials, 173(1-3), 445-449.
36. [36] Luo, Y. I., Mao, D., Rysz, M., Zhou, Q., Zhang, H., Xu, L., JJ Alvarez, P. 2010. Trends in antibiotic resistance genes occurrence in the Haihe River, China. Environmental science & technology, 44(19), 7220-7225.
37. [37] Chee‐Sanford, J. C., Mackie, R. I., Koike, S., Krapac, I. G., Lin, Y. F., Yannarell, A. C. Maxwell, S., Aminov, R. I. 2009. Fate and transport of antibiotic residues and antibiotic resistance genes following land application of manure waste. Journal of environmental quality, 38(3), 1086-1108.
38. [38] Mohajerani, M., Mehrvar, M., Ein-Mozaffari, F. 2010. CFD modeling of metronidazole degradation in water by the UV/H2O2 process in single and multilamp photoreactors. Industrial & Engineering Chemistry Research, 49(11), 5367- 5382.
39. [39] Wang, Q. Q., Wang, D. X., Wu, Y. L., Li, L. X., Sun, X. Y. 2022. Synthesis of polyoxometalate-based complexes and photocatalytic degradation of metronidazole. Journal of Solid State Chemistry, 309, 122966.
40. [40] Yıldız, B., Yücel, A., & Hanay, Ö. 2022. In-situ generation of H2O2 in heterogeneous Fenton-like process with Fe/Ni bimetallic particle for Metronidazole degradation. Separation Science and Technology, 1-15