Study of N-Alkyl Derivatives of Theophylline by Gas Chromatography-Mass Spectrometry
Keywords:
theophylline, mass spectrometry, fragmentation, 7-(2, 3-dibromopropyl)theophylline, 7-[2-(2-chloroethoxy)ethyl]theophylline, 7-[2-(2-hydroxyethoxy)ethyl]theophylline, 7-methallyltheophyllineAbstract
In the study fragmentation under electron ionization of 7-allyl-, 7-propargyl-, 7-(2-(4-bromophenyl)-2-hydroxy-oxoethyl)-, 7-methallyl-, 7-(2-bromoethyl)-, 7-(2-hydroxyethyl)-, 7-[2-(2-chloroethoxy)ethyl]-, 7-[2-(2-hydroxyethoxy)ethyl]-, 7-(2,3-dibromopropyl)theophylline and 7,7'-ethane-1,2-diylbis(theophylline) was investigated by gas chromatography-mass spectrometry analysis, the main mass fragmentation ways were revealed. 7-(2,3-Dibromopropyl)theophylline was prepared by the addition of bromine to the double bond of 7-allyl-thophylline in acetic acid at room temperature for 24 hours. 7-[2-(2-Chloroethoxy)ethyl]- and 7-[2-(2-hydroxyethoxy)ethyl] theophyllines were obtained by the interaction of theophylline with 2,2'-dichlorodiethyl ether in DMF in the presence of anhydrous potassium carbonate under reflux for 8 h. 7-Methallyltheophylline was synthesized by the interaction of theophylline with a methallylchloride in DMF in the presence of anhydrous potassium carbonate under reflux for 6 h. The structure of 7-methallyltheophylline was confirmed by 1H NMR spectroscopy. The mass spectra of all studied compounds contain peaks characteristic for the fragmentation of theophylline. In almost all mass-spectra there are peaks of theophylline cation radical with m/z 180. This indicates a disruption of the N–CH2 bond. In the cases of 7-propargyl- and 7-(2-(4-bromophenyl)-2-oxoethyl)theophyllines this peak is absent. In the cases of 7-allyl- and 7-methallyltheophyllines peaks with m/z 180 have low intensity, because of higher stability of the N-alkyl bond. 7-Methallyl- and 7-propargyltheophyllines are thermally rearranged under chromatographic conditions in a spectrometer. There is characteristic distribution of isotope peaks of the molecular ion in the mass spectra of halogen-containing compounds: a doublet with an intensity ratio of approximately 1:1 for compounds with one bromine atom, a triplet of peaks in the case of two bromine atoms, and a doublet with an intensity ratio 3:1 for chlorine-containing derivatives. These multiplets usually have low intensity. The peak of the bromo radical detachment in the case of 7-(2-bromoethyl)- and 7-(2,3-dibromopropyl)-theophyllines has maximum intensity. The elimination of methyl isocyanate, carbon monoxide and hydrogen cyanide molecules is a characteristic feature of all studied mass spectra.References
Synthesis and physicochemical and biological properties of 8-amino-substituted 7-(2-aryl-2-oxoethyl)xanthines / N.I. Romanenko, M.V. Nazarenko, V.I. Kornienko, B.A. Samura // Pharmaceutical Chemistry Journal. – 2014. – V. 48, № 8. – P. 509–512. DOI: 10.1007/s11094-014-1142-3
Synthesis and biological activity of 8-benzylidenehydrazino-3-methyl-7-b-methoxyethylxanthines / N.I. Romanenko, O.A. Pakhomova, D.G. Ivanchenko et al. // Pharmaceutical Chemistry Journal. – 2014. – V. 48, № 7. – P. 444–447. DOI: 10.1007/s11094-014-1128-1
The synthesis and the biological evaluation of new thiazolidin-4-one derivatives containing a xanthine moiety / F.G. Lupascu, O.M. Dragostin, L. Foia et al. // Molecules. – 2013. – V. 8, № 18. – P. 9684–9703. DOI: 10.3390/molecules18089684
Synthesis and biological activities of novel methyl xanthine derivatives / Ch. Youwei, W. Baolei, G. Yanjun et al. // Chemical Research in Chinese Universities. – 2014. – V. 30, № 1. – P. 98–102. DOI: 10.1007/s40242-014-3173-4
Torres, A.C. Design of a new hypoxanthine biosensor: xanthine oxidase modified carbon film and multi-walled carbon nanotube/carbon film electrodes / A.C. Torres, M.E. Ghica, Ch.M.A. Brett // Analytical and Bioanalytical Chemistry. – 2013. – V. 405, № 11. – P. 3813–3822. DOI: 10.1007/s00216-012-6631-1
Synthesis and antiaggregant activity of 8-substituted 1-alkyl-3-methyl-7-(1-oxothietan-3-yl)xanthines / Yu.V. Shabalina, F.A. Khaliullin, A.A. Spasov et al. // Pharmaceutical Chemistry Journal. – 2013. – V. 47, № 3. – P. 151–153. DOI: 10.1007/s11094-013-0915-4
www.slovar.cc/med/sprav-lek/2519465.html
Tanabe, T. The N-alkylation of xanthine derivatives with trialkyl phosphates / T. Tanabe, K. Yamauchi, M. Kinoshita // Bulletin of the Chemical Society of Japan. – 1976. – V. 49, № 11. – P. 3224–3226. DOI: 10.1246/bcsj.49.3224
Solid liquid phase transfer catalysis: alkylation of theophylline / G. Bram, Y. Bensaid, C. Combet-Farnoux et al. // Pharmazie. – 1986. – V. 41, № 6. – P. 431–432. DOI: 10.1002/chin.198646250
Daly, J.W. Analogs of caffeine and theophylline: effect of structural alterations on affinity at adenosine receptors / J.W. Daly, W.L. Padgett, M.T. Shamim // Journal of Medicinal Chemistry. – 1986. – V. 29, № 7. – P. 1305–1308. DOI: 10.1021/jm00157a035
Caffeine-Based Gold(I) N-Heterocyclic carbenes as possible anticancer agents: synthesis and biological properties / B. Bertrand, L. Stefan, M. Pirrotta et al. // Inorganic Chemistry. – 2014. – V. 53, № 4. –P. 2296–2303. DOI: 10.1021/ic403011h
Lysakowska, M. Design, synthesis, antiviral, and cytostatic evaluation of novel isoxazolidine analogs of homonucleotides / M. Lysakowska, J. Balzarini, D.G. Piotrowska // Archiv der Pharmazie. – 2014. –V. 347, № 5. – P. 341–353. DOI: 10.1002/ardp.201300382
Design, synthesis, anticancer, antimicrobial activities and molecular docking studies of theophylline containing acetylenes and theophylline containing 1,2,3-triazoles with variant nucleoside derivatives / R.R. Ruddarraju, A.Ch. Murugulla, R. Kotla et al. // European Journal of Medicinal Chemistry. – 2016. – V. 123. – P. 379–396. DOI: 10.1016/j.ejmech.2016.07.024
‘Click Synthesis’ of 1H-1,2,3-triazolyl-based oxiconazole (=(1Z)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanone O-[(2,4-Dichlorophenyl)methyl]oxime) analogs / S. Rad, M. Navid, A. Zeinab et al. // Helvetica Chimica Acta. – 2011. –V. 94, № 12. – P. 2194–2206. DOI: 10.1002/hlca.201100189
Click reaction based synthesis, antimicrobial, and cytotoxic activities of new 1,2,3-triazoles / M.R. Sayed Aly, S. Hosam Ali, M. Mosselhi, A. Mosselhi // Bioorganic and Medicinal Chemistry Letters. – 2015. – V. 25, № 14. – P. 2824–2830. DOI: 10.1016/j.bmcl.2015.04.096
1,4-Dihydroxyanthraquinone-copper(II) nanoparticles immobilized on silica gel: a highly efficient, copper scavenger and recyclable heterogeneous nanocatalyst for a click approach to the three-component synthesis of 1,2,3-triazole derivatives in water / S. Hashem, K. Abbas, D. Mohammad Mahdi, Kh. Reza // Journal of the Iranian Chemical Society. – 2012. – V. 9, № 2. – P. 231–250. DOI: 10.1007/s13738-011-0046-3
Copper/graphene/clay nanohybrid: a highly efficient heterogeneous nanocatalyst for the synthesis of novel 1,2,3-triazolyl carboacyclic nucleosidesvia‘click’huisgen1,3-dipolar cycloaddition / N.S.R. Mohammad, B. Somayeh, J. Hoseini et al. // Helvetica Chimica Acta. – 2015. –V. 98, № 9. – P. 1210–1224. DOI: 10.1002/hlca.201500149
Reactions of xanthinium N(7)-ylides with olefinic dipolarophiles / M. Hori, T. Kataoka, H. Shimizu et al. // Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry. – 1987. – P. 1211–1220. DOI: 10.1039/P19870001211
New antihistamines: substituted piperazine and piperidine derivatives as novel H1-antagonists / M. Abou-Gharbia, J.A. Moyer, S.T. Nielsen et al. // Journal of Medicinal Chemistry. – 1995. – V. 38, № 20. – P. 4026–4032. DOI: 10.1021/jm00020a018
Ing-Jun Ch., Cho-Jan L. Theophylline-based soluble guanylyl cyclase activators KMUP-1 analogues enhanced cyclic GMP and K+ channel activities on rabbit corpus cavernosum smooth muscle and intercavernous pressure activities. Patent US, no. 209243; 2005.
Penny, J. Synthesis and characterization of novel 1,2,3- triazole-linked theophylline and coumarin S-triazines / J. Penny, T. Mohit, R.S. Diwan // Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry. – 2014. – V. 53, № 3. – P. 311–318. DOI: 10.1246/bcsj.67.203
Bayer, F. Verfahren zur darstellung oxalkylsubstituierter derivate von xanthinbasen. Patent DE, no. 193799, 1906.
Itahara, T. Preparation and NMR study of 7,7′-(α,ω-alkanediyl)bis[theophylline], 1,1′-(α,ω-alkanediyl)bis[theobromine], and 1,1′-(α,ω-alkanediyl)bis[3-methyluracil] / T. Itahara, K. Imamura // Bulletin of the Chemical Society of Japan. – 1994. – V. 67, № 1. – P. 203–209.
Chou, Ch.-H. Isolation and identification by mass spectrometry of phytotoxines in coffea Arabica / Ch.-H. Chou, G.R. Waller // Bot. Bull. Academia Sinica. – 1980. – № 21. – P. 25–34.
Фролова, Т.В. Синтез тиазолопиримидиновых и пиримидотиазиновых систем гетероциклизацией S- и N-производных 2-тиоурацилов: дис. … канд. хим. наук / Т.В. Фролова. – Челябинск, 2016. – 150 с.
