Bir Etkili Tek Ortamda Üç Bileşenli Yeni Kinazolin-4-Karboksilik Asit ve Onun Ester ve Amit Türevlerinin Sentezi

Abstract

İlaç adayları olabilecek bir dizi yeni kinazolin türevleri sentezlendi ve yapıları IR, 1H NMR, 13C NMR ve Q-TOF LC/MS spektrometresi ile karakterize edildi. Önce amonyum asetat ve 4-klorobenzaldehit ile isatinin (indol-2,3-dion) hidrolizinden elde edilen (2-amino-fenil)-okso-asetik asit sodyum tuzunun aynı ortamda üç bileşenli kondenzasyon reaksiyonundan 2-(4-kloro-fenil)-kinazolin-4-karboksilik asit (2) sentezlendi. Karboksilik asit bileşiği 2, ester, asit klorür ve amit türevlerinin sentezine izin verdi. Yeni kinazolin ester türevleri (3-6, 8), 2 bileşiği ve çeşitli alkollerin reaksiyonlarından sentezlendi. Daha sonra kinazolin amit türevleri (9-13), çeşitli alifatik ve aromatik aminlerin 2 bileşiği ve SOCl2’ün reaksiyonundan oluşan 2-(4-kloro-fenil)-kinazolin-4-karbonil klorürün (7) reaksiyonundan elde edildi.

Keywords

• İsatin
• kinazolin-4-karboksilik asit
• amit
• ester

An Efficient One-Pot Three-Component Synthesis of Novel Quinazoline-4-Carboxylic Acid and Its Ester and Amide Derivatives

Abstract

A series of novel quinazoline derivatives, which may be drug candidates, were synthesized, and their structures were characterized by IR, 1H NMR, 13C NMR and Q-TOF LC/MS spectrometry. First, 2-(4-chloro-phenyl)-quinazoline-4-carboxylic acid (2) was synthesized from a one-pot three-component condensation reaction of (2-amino-phenyl)-oxo-acetic acid sodium salt obtained from alkaline hydrolysis of isatin (indole-2,3-dione) with 4-chlorobenzaldehyde and ammonium acetate. The carboxylic acid compound 2 allowed the synthesis of the ester, acid chloride and amide derivatives. New quinazoline ester derivatives (3-6, 8) were synthesized by the reactions of compound 2 and various alcohols. Quinazoline amide derivatives (9-13) were then obtained from the reaction of different aliphatic and aromatic amines and 2-(4-chloro-phenyl)-quinazoline-4-carbonyl chloride (7) formed from the reaction of SOCl2 and compound 2.

Keywords

• Isatin
• quinazoline-4-carboxylic acid
• amide
• ester

References

1. G.F. Xu, B.A. Song, P.S. Bhadury, S. Yang, P.Q. Zhang, L.H. Jin, W. Xue, D.Y. Hu, P. Lu, Synthesis and antifungal activity of novel s-substituted 6-fluoro-4-alkyl(aryl)thioquinazoline derivatives, Bioorgan Med Chem, 15 (2007) 3768-3774.
2. J. Jampilek, R. Musiol, J. Finster, M. Pesko, J. Carroll, K. Kralova, M. Vejsova, J. O'Mahony, A. Coffey, J. Dohnal, J. Polanski, Investigating Biological Activity Spectrum for Novel Styrylquinazoline Analogues, Molecules, 14 (2009) 4246-4265.
3. J. Odingo, T. O'Malley, E.A. Kesicki, T. Alling, M.A. Bailey, J. Early, J. Ollinger, S. Dalai, N. Kumar, R.V. Singh, P.A. Hipskind, J.W. Cramer, T. Ioerger, J. Sacchettini, R. Vickers, T. Parish, Synthesis and evaluation of the 2,4-diaminoquinazoline series as anti-tubercular agents, Bioorgan Med Chem, 22 (2014) 6965-6979.
4. D. Giardina, D. Martarelli, G. Sagratini, P. Angeli, D. Ballinari, U. Gulini, C. Melchiorre, E. Poggesi, P. Pompei, Doxazosin-Related alpha(1)-Adrenoceptor Antagonists With Prostate Antitumor Activity, J Med Chem, 52 (2009) 4951-4954.
5. C. Mendoza-Martinez, J. Correa-Basurto, R. Nieto-Meneses, A. Marquez-Navarro, R. Aguilar-Suarez, M.D. Montero-Cortes, B. Nogueda-Torres, E. Suarez-Contreras, N. Galindo-Sevilla, A. Rojas-Rojas, A. Rodriguez-Lezama, F. Hernandez-Luis, Design, synthesis and biological evaluation of quinazoline derivatives as anti-trypanosomatid and anti-plasmodial agents, Eur J Med Chem, 96 (2015) 296-307.
6. H. Xiao, P. Li, D.Y. Hu, B.A. Song, Synthesis and anti-TMV activity of novel beta-amino acid ester derivatives containing quinazoline and benzothiazole moieties, Bioorg Med Chem Lett, 24 (2014) 3452-3454.
7. E. Jafari, M.R. Khajouei, F. Hassanzadeh, G.H. Hakimelahi, G.A. Khodarahmi, Quinazolinone and quinazoline derivatives: recent structures with potent antimicrobial and cytotoxic activities, Res Pharm Sci, 11 (2016) 1-14.
8. P. Verhaeghe, N. Azas, M. Gasquet, S. Hutter, C. Ducros, M. Laget, S. Rault, P. Rathelot, P. Vanelle, Synthesis and antiplasmodial activity of new 4-aryl-2-trichloromethylquinazolines, Bioorg Med Chem Lett, 18 (2008) 396-401.

9. R.A. Smits, M. Adami, E.P. Istyastono, O.P. Zuiderveld, C.M.E. van Dam, F.J.J. de Kanter, A. Jongejan, G. Coruzzi, R. Leurs, I.J.P. de Esch, Synthesis and QSAR of Quinazoline Sulfonamides As Highly Potent Human Histamine H-4 Receptor Inverse Agonists, J Med Chem, 53 (2010) 2390-2400.
10. V. Alagarsamy, U.S. Pathak, Synthesis and antihypertensive activity of novel 3-benzyl-2-substituted-3H-[1,2,4]triazolo[5,1-b]quinazolin-9-ones, Bioorgan Med Chem, 15 (2007) 3457-3462.
11. M.S. Malamas, J. Millen, Quinazolineacetic Acids and Related Analogs as Aldose Reductase Inhibitors, J Med Chem, 34 (1991) 1492-1503.
12. A. Rosowsky, J.E. Wright, C.M. Vaidya, R.A. Forsch, The effect of side-chain, para-aminobenzoyl region, and B-ring modifications on dihydrofolate reductase binding, influx via the reduced folate carrier, and cytotoxicity of the potent nonpolyglutamatable antifolate N-alpha-(4-amino-4-deoxypteroyl)-N-delta-hemiphthaloyl-L-ornithine, Pharmacol Therapeut, 85 (2000) 191-205.
13. A.M.F. Kersemaekers, G.J. Fleuren, E.G. Kenter, L.J.C.M. Van den Broek, S.M. Uljee, J. Hermans, M.J. Van de Vijver, Oncogene alterations in carcinomas of the uterine cervix: Overexpression of the epidermal growth factor receptor is associated with poor prognosis, Clinical Cancer Research, 5 (1999) 577-586.
14. D.W. Fry, A.J. Kraker, A. Mcmichael, L.A. Ambroso, J.M. Nelson, W.R. Leopold, R.W. Conners, A.J. Bridges, A Specific Inhibitor of the Epidermal Growth-Factor Receptor Tyrosine Kinase, Science, 265 (1994) 1093-1095.
15. P. Chaturvedula, G.M. Dubowchik, A.P. Degan, X.J. Han, C.M. Conway, D. Cook, C. Davis, R. Denton, R. Macci, N.R. Mathias, S. Pin, L. Signor, G. Thalody, R. Schartman, K.A. Widmann, C. Xu, J.E. Macor, MEDI 220-Design and synthesis of potent cgrp antagonists for migraine, Abstr Pap Am Chem S, 234 (2007).
16. J.P. Xu, X.Y. Liu, S. Yang, C.G. Zhang, L. Wang, Y.K. Shi, Icotinib as initial treatment in lung adenocarcinoma patients with brain metastases, Thoracic Cancer, 7 (2016) 437-441.
17. J.A. Taylor, T.M. Twomey, M.S. von Wittenau, The metabolic fate of prazosin, Xenobiotica, 7 (1977) 357-364.
18. D. Cameron, M. Casey, M. Press, D. Lindquist, T. Pienkowski, C.G. Romieu, S. Chan, A. Jagiello-Gruszfeld, B. Kaufman, J. Crown, A. Chan, M. Campone, P. Viens, N. Davidson, V. Gorbounova, J.I. Raats, D. Skarlos, B. Newstat, D. Roychowdhury, P. Paoletti, C. Oliva, S. Rubin, S. Stein, C.E. Geyer, A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses, Breast Cancer Res Tr, 112 (2008) 533-543.
19. R.T. Dungo, G.M. Keating, Afatinib: first global approval, Drugs, 73 (2013) 1503-1515.
20. K.L. Reckamp, G. Giaccone, D.R. Camidge, S.M. Gadgeel, F.R. Khuri, J.A. Engelman, M. Koczywas, A. Rajan, A.K. Campbell, D. Gernhardt, A. Ruiz-Garcia, S. Letrent, J. Liang, I. Taylor, J.P. O'Connell, P.A. Janne, A phase 2 trial of dacomitinib (PF-00299804), an oral, irreversible pan-HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non-small cell lung cancer after failure of prior chemotherapy and erlotinib, Cancer-Am Cancer Soc, 120 (2014) 1145-1154.
21. B. Han, X.L. Yang, C. Wang, Y.W. Bai, T.C. Pan, X. Chen, W. Yu, CuCl/DABCO/4-HO-TEMPO-Catalyzed Aerobic Oxidative Synthesis of 2-Substituted Quinazolines and 4H-3,1-Benzoxazines, J Org Chem, 77 (2012) 1136-1142.
22. V.L. Truong, M. Morrow, Mild and efficient ligand-free copper-catalyzed condensation for the synthesis of quinazolines, Tetrahedron Lett, 51 (2010) 758-760.
23. Z.Y. Chen, J.X. Chen, M.C. Liu, J.C. Ding, W.X. Gao, X.B. Huang, H.Y. Wu, Unexpected Copper-Catalyzed Cascade Synthesis of Quinazoline Derivatives, J Org Chem, 78 (2013) 11342-11348.
24. J.T. Zhang, C.M. Yu, S.J. Wang, C.F. Wan, Z.Y. Wang, A novel and efficient methodology for the construction of quinazolines based on supported copper oxide nanoparticles, Chem Commun, 46 (2010) 5244-5246.
25. C. Wang, S.F. Li, H.X. Liu, Y.Y. Jiang, H. Fu, Copper-Catalyzed Synthesis of Quinazoline Derivatives via Ullmann-Type Coupling and Aerobic Oxidation, J Org Chem, 75 (2010) 7936-7938.
26. R. Sarma, D. Prajapati, Microwave-promoted efficient synthesis of dihydroquinazolines, Green Chem, 13 (2011) 718-722.
27. D. Gok, One-pot three-component synthesis of novel 2-(3-nitro-phenyl)-quinazoline-4-carboxylic acid derivatives, J Heterocyclic Chem, 56 (2019) 3343-3353.
28. C. Derabli, R. Boulcina, G. Kirsch, B. Carboni, A. Debache, A DMAP-catalyzed mild and efficient synthesis of 1,2-dihydroquinazolines via a one-pot three-component protocol, Tetrahedron Lett, 55 (2014) 200-204.