A convenient approach to the synthesis of substituted 2-(methylamino)quinoline-3-carboxamides

L. V. Muzychka, O. B. Smolii, I. I. Biletskiy, O. M. Vasilenko


The paper is devoted to the synthesis of new 2-(methylamino)quinoline-3-carboxamide derivatives by the pyrimidine cycle hydrolytic cleavage of pyrimido[4,5-b]quinoline-2,4(1H,3H)-diones. These later were synthetized in high yields by interaction of available 1,3-dimethyl-6-piperidinyl-5-formyluracil with aromatic amines. The reactions with participation of ortho- and para-substituted aromatic amines proceed regioselectively to give 1,3-dimethylpyrimido[4,5-b] quinoline-2,4(1H,3H)-diones with substituents in positions 7 and 9 of the heterocycle. The use of metha-methoxyand metha-fluoroaniline leads to the mixture of 6- and 8-substituted 1,3-dimethylpyrimido[4,5-b]quinoline-2,4(1H,3H)- diones, which under basic conditions were cleaved into amides of quinoline-3-carboxylic acid. The mixture of 2-(methylamino)quinoline-3-carboxamides obtained was separated by column chromatography. Application of the correlation NMR spectroscopy method (NOESY, COSY, HSQC, HMBC) has allowed to reliably determine the structures of 1,3-dimethyl-5-formyluracil derivatives with aromatic amines condensation products. The amino-imino prototropic tautomerism occurs at 120°C. It facilitates syn-anti-isomerization promoted cyclization and leads to 1,3-dimethylpyrimido[4,5-b]quinoline-2,4(1H,3H)-dione. The structure of the compounds obtained has been proven using the methods of NMR 1 Н, 13C-spectroscopy, mass-spectra and elemental analysis.


condensation; pyrimido[4,5-b]quinoline-2;4(1H,3H)-dione; 5-deazaalloxazine; 2-(methylamino)quinoline- 3-carboxamide


Chuhan K., Singh P., Kumar V., Shukla P., Siddiqi M., Chauhan P. Eur. J. Med. Chem., 2014, Vol. 78, pp.442-454.

Protogeraki C., Andreadou E., Perdih F., Turel I., Pantazaki A., Psomas G. Eur. J. Med. Chem., 2014, Vol. 86, pp.189-201.

Rameshkumar N., Ashokkumar M., Subramanian E., Ilavarasan R., Sridhar K. Eur. J. Med. Chem., 2003, Vol. 38, pp.1001-1004.

Cui Sh.-F., Peng L.-P., Zhang H.-Z., Rasheed S., Kumar V., Zhou Ch. Eur. J. Med. Chem., 2014, Vol. 86, pp.318-334.

Al-Trawneh S., El-Abadelah M., Al-Abadleh M., Zani F., Incerti M., Vicini P. Eur. J. Med. Chem., 2014, Vol. 86, pp.364-367.

Cociorva O., Li B., Nomanbhoy T., Li Q., Nakamura A., Nakamura K., Nomura M. Bioorg. Med. Chem., 2011, Vol. 21, pp.5948-5951.

El-Sayed O. A., Al-Bassam B. A., Hussein M. E. Arch. Pharm. Med. Chem., 2002, Vol. 9, pp.403-410.

Vaitilingam B., Nayyar A., Palbe P. B. et al. Bioorg. Med. Chem., 2004, Vol. 12, pp.4179-4188.

Surech N., Naresh H., Renuka J., Rajput V., Sharma R., Ali Khahn I. Eur. J. Med. Chem., 2014, Vol. 71, pp.324-332.

Hu L., Yan S., Luo Z., Wang Y., Wang Z., Zeng Ch. Molecules, 2012, Vol. 17, pp.10652-10666.

Chen Y.-L., Zacharias J., Vince R., Geraghty R., Wang Z. Bioorg. Med. Chem., 2012, Vol. 20, pp.4790-4800.

Pat. US 8470852 B2, 2013.

Liu P., Niu Y., Wang Ch., Sun Q., Zhai Y., Yu J., Sun J. Eur. J. Med. Chem., 2014, Vol. 79, pp.413-421.

Ţînţaş M., Foucout L., Petit S., Oudeyer S., Gourand G., Barré L., Papamicaël C., Levacher V. Eur. J. Med. Chem., 2014, Vol. 81, pp.218-226.

Pathuri G., Li Q., Mohammed A., Gali H., Pento Th., Rao Ch. Bioorg. Med. Chem., 2014, Vol. 24, pp.1380-1382.

Pasquini S., De Rosa М., Ligrest A., Mugnaini C., Brizzi A., Caradonna N., Grazia Cascio M., Bolognini D., Pertwee R., Di Marzo V., Corelli F. Eur. J. Med. Chem., 2012, Vol. 58, pp.30-43.

Pasquin S., Ligresti A., Mugnaini C., Semeraro T., Cicione L., De Rosa M., Guida F., Luongo L., De Chiaro M., Grazia Cascio M., Bolognini D., Marini P., Pertwee R., Maione S., Di Marzo V., Corelli F. J. Med. Chem., 2010, Vol. 53, pp.5915-5928.

Manera C., Saccomanni G., Malfitano A. M. et al. Eur. J. Med. Chem., 2012, Vol. 52, pp.284-294.

Pasquini S., Botta L., Semeraro T., Mugnaini C., Ligresti A., Palazzo E., Maione S., Di Marzo V., Corelli F. J. Med. Chem., 2008, Vol. 51, pp.5075-5084.

Wang K., Herdtweck E., Domlung A. ACS Comb. Sci., 2012, Vol. 14, pp.316-322.

Rajanarendar E., Reddy M. N., Krishna S. R., Murthy K. R., Reddy Y. N., Rajam M. V. Eur. J. Med. Chem., 2012, Vol. 55, pp.273-283.

Ukhun L. Yu., Belov E. G. Izvestiya Akademii Nauk, Seriya Khimicheskaja – Russian Chem. Bull., 2008, No.2, pp.418-421.

Senga K., Shimizu K., Nishigaki S., Yonega F. A. Heterocycles, 1977, Vol. 6, pp.1361-1364.

Nishigaki S., Sato J., Shimizu K., Furukawa K., Senga K., Yonega F. Chem. Pharm. Bull., 1980, Vol. 28, pp.142-149.

Van Tinh D., Fischer M., Stadlbauer W. J. Heterocycl. Chem, 1996, Vol. 33, pp.905-910.

Yonega F., Takayama F., Koshiro A. Chem. Pharm. Bull., 1979, Vol. 27, pp.2507-2510.

Hirota K., Maruhashi K., Asao T., Kitamura N., Maki Y., Senda S. Chem. Pharm. Bull., 1983, Vol. 31, pp.3959-3966.

Tominaga Y., Okuda H., Kohra S., Mazume H. J. Heterocycl. Chem., 1991, Vol. 24, pp.1245-1255.

GOST Style Citations

DOI: https://doi.org/10.24959/ophcj.15.855

Abbreviated key title: Ž. org. farm. hìm.

ISSN 2518-1548 (Online), ISSN 2308-8303 (Print)