DOI: https://doi.org/10.24959/ophcj.18.935

The study of the interaction of 4,6-dichloropyrimidine-5-carbaldehyde with glycine esters

H. M. Zinchenko, L. V. Muzychka, I. I. Biletskiy, O. B. Smolii

Abstract


Aim. To study the interaction of 4,6-dichloropyrimidine-5-carbaldehyde with methyl- and with tert-butylglycinate depending on the reaction conditions.
Results and discussion. It has been found that the reaction of 4,6-dichloro-5-formylpyrimidine with hydrochlorides of glycine esters in the presence of triethylamine leads to obtaining derivatives of N-(5-formylpyrimidin-4-yl)glycinate and cyclization products: pyrrolo[2,3-d]pyrimidine and pyrido[2,3-d]pyrimidine.
Experimental part. The interaction of 4,6-dichloropyrimidine-5-carbaldehyde with methyl or tert-butyl glycinate in methanol in the presence of triethylamine depending on the molar ratio gives the mixture of 5-hydroxy-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine and 6-amino-4-chloro-7-oxopyrido[2,3-d]pyrimidine-8(7H)-yl)acetate.
The composition and structure of the compounds synthesized have been confirmed by NMR-spectroscopy, chromatography mass-spectrometry and elemental analysis.
Conclusions. The previously unknown derivatives of pyrrolo[2,3-d]pyrimidine and pyrido[2,3-d]pyrimidine have been obtained as a result of the interaction of 4,6-dichloro-5-formylpyrimidine with methyl and tert-butylglycinate.
The reaction features depending on the reactants ratio have been studied. The prospects for the synthesis of potential biologically active compounds from 6-amino-4-chloro-7-oxopyrido[2,3-d]pyrimidine-8(7H)-yl)acetate have been described.


Keywords


4,6-dichloropyrimidine-5-carbaldehyde; pyrido[2,3-d]pyrimidin-7-one; pyrrolo[2,3-d]pyrimidines; cyclization

References


Morrill, C., Babu, S., Almstead, N. G., Moon. Y.–C. (2013). Synthesis of 1,4–disubstituted pyrazolo[3,4–d]pyrimidines from 4,6–dichloropyrimidine–5–carboxaldehyde: Insights into selectivity and reactivity. Synthesis, 45 (13), 1791–1806. doi: 10.1055/s–0033–1338862

Wang, H., Zhang, Y., Ye, W., Schneller, S. W. (2014). Preparation of 8–Aza–7–deazaaristeromycin and –neplanocin A and Their 5′–Homologs. Journal of Heterocyclic Chemistry, 52 (4), 1132–1135. doi: 10.1002/jhet.2137

Babu, S., Morrill, C., Almstead, N. G., Moon, Y.–C. (2013). Selective Synthesis of 1–Substituted 4–Chloropyrazolo[3,4–d]pyrimidines. Organic Letters, 15 (8), 1882–1885. doi: 10.1021/ol4005382

Fu, Y., Wang, Y., Wan, S., Li, Z., Wang, G., Zhang, J., Wu, X. (2017). Bisarylureas Based on 1H–Pyrazolo[3,4–d]pyrimidine Scaffold as Novel Pan–RAF Inhibitors with Potent Anti–Proliferative Activities: Structure–Based Design, Synthesis, Biological Evaluation and Molecular Modelling Studies. Molecules, 22 (4), 542. doi: 10.3390/molecules22040542

Deng, X., Okram, B., Ding, Q., Zhang, J., Choi, Y., Adrián, F. J., Gray, N. S. (2010). Expanding the Diversity of Allosteric Bcr–Abl Inhibitors. Journal of Medicinal Chemistry, 53 (19), 6934–6946. doi: 10.1021/jm100555f

Lawhorn, B. G., Philp, J., Zhao, Y., Louer, C., Hammond, M., Cheung, M., Kallander, L. S. (2015). Identification of Purines and 7–Deazapurines as Potent and Selective Type I Inhibitors of Troponin I–Interacting Kinase (TNNI3K). Journal of Medicinal Chemistry, 58 (18), 7431–7448. doi: 10.1021/acs.jmedchem.5b00931

Wang, T., Liu, X., Hao, M., Qiao, J., Ju, C., Xue, L., Zhang, C. (2016). Design, synthesis and evaluation of pyrrolo[2,3– d ]pyrimidine–phenylamide hybrids as potent Janus kinase 2 inhibitors. Bioorganic & Medicinal Chemistry Letters, 26 (12), 2936–2941. doi: 10.1016/j.bmcl.2016.04.027

Yang, H.–Z., Pan, M.–Y., Jiang, D.–W., He, Y. (2011). Synthesis of Janus type nucleoside analogues and their preliminary bioactivity. Organic & Biomolecular Chemistry, 9 (5), 1516. doi: 10.1039/c0ob00495b

Kawakita, Y., Seto, M., Ohashi, T., Tamura, T., Yusa, T., Miki, H., Ishikawa, T. (2013). Design and synthesis of novel pyrimido[4,5– b ]azepine derivatives as HER2/EGFR dual inhibitors. Bioorganic & Medicinal Chemistry, 21 (8), 2250–2261. doi: 10.1016/j.bmc.2013.02.014

Verves, E. V., Kucher, A. V., Muzychka, L. V., Smolii, O. B. (2013). Synthesis of 7–alkyl–4–amino–7H–pyrrolo–[2,3–d]pyrimidine–6–carboxylic acids. Chemistry of Heterocyclic Compounds, 48 (12), 1844–1852. doi: 10.1007/s10593–013–1218–0

Zinchenko, A. N., Muzychka, L. V., Biletskii, I. I., Smolii, O. B. (2017). Synthesis of new 4–amino–substituted 7–iminopyrido[2,3–d]pyrimidines. Chemistry of Heterocyclic Compounds, 53 (5), 589–596. doi: 10.1007/s10593–017–2096–7

Xiang, J., Wen, D., Xie, H., Dang, Q., Bai, X. (2010). Synthesis of Novel 8,9–Dihydro–5H–pyrimido[4,5–e][1,4]diazepin–7(6H)–ones. Journal of Combinatorial Chemistry, 12 (4), 503–509. doi: 10.1021/cc100039w

Lavecchia, M. J., Puig de la Bellacasa, R., Borrell, J. I., Cavasotto, C. N. (2016). Investigating molecular dynamics–guided lead optimization of EGFR inhibitors. Bioorganic & Medicinal Chemistry, 24 (4), 768–778. doi: 10.1016/j.bmc.2015.12.046

Wurz, R. P., Pettus, L. H., Ashton, K., Brown, J., Chen, J. J., Herberich, B., Tasker, A. S. (2015). Oxopyrido[2,3–d]pyrimidines as Covalent L858R/ T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors. ACS Medicinal Chemistry Letters, 6 (9), 987–992. doi: 10.1021/acsmedchemlett.5b00193

Xu, T., Peng, T., Ren, X., Zhang, L., Yu, L., Luo, J., Ding, K. (2015). C5–substituted pyrido[2,3–d]pyrimidin–7–ones as highly specific kinase inhibitors targeting the clinical resistance–related EGFRT790M mutant. MedChemComm, 6 (9), 1693–1697. doi: 10.1039/c5md00208g

Yu, L., Huang, M., Xu, T., Tong, L., Yan, X., Zhang, Z., Lu, X. (2017). A structure–guided optimization of pyrido[2,3– d ]pyrimidin–7–ones as selective inhibitors of EGFR L858R/T790M mutant with improved pharmacokinetic properties. European Journal of Medicinal Chemistry, 126, 1107–1117. doi: 10.1016/j.ejmech.2016.12.006

Toogood, P. L., Harvey, P. J., Repine, J. T., Sheehan, D. J., VanderWel, S. N., Zhou, H., Fry, D. W. (2005). Discovery of a Potent and Selective Inhibitor of Cyclin–Dependent Kinase 4/6. Journal of Medicinal Chemistry, 48 (7), 2388–2406. doi: 10.1021/jm049354h

Reddy, M. V. R., Akula, B., Cosenza, S. C., Athuluridivakar, S., Mallireddigari, M. R., Pallela, V. R., Reddy, E. P. (2014). Discovery of 8–Cyclopentyl–2–[4–(4–methyl–piperazin–1–yl)–phenylamino]–7–oxo–7,8–dihydro–pyrido[2,3–d]pyrimidine–6–carbonitrile (7x) as a Potent Inhibitor of Cyclin–Dependent Kinase 4 (CDK4) and AMPK–Related Kinase 5 (ARK5). Journal of Medicinal Chemistry, 57 (3), 578–599. doi: 10.1021/jm401073p

Rudolph, J., Murray, L. J., Ndubaku, C. O., O’Brien, T., Blackwood, E., Wang, W., Zhong, Y. (2016). Chemically Diverse Group I p21–Activated Kinase (PAK) Inhibitors Impart Acute Cardiovascular Toxicity with a Narrow Therapeutic Window. Journal of Medicinal Chemistry, 59 (11), 5520–5541. doi: 10.1021/acs.jmedchem.6b00638

Camarasa, M., Puig de la Bellacasa, R., González, À. L., Ondoño, R., Estrada, R., Franco, S., Borrell, J. I. (2016). Design, synthesis and biological evaluation of pyrido[2,3–d]pyrimidin–7–(8H)–ones as HCV inhibitors. European Journal of Medicinal Chemistry, 115, 463–483. doi: 10.1016/j. ejmech.2016.03.055

Simon–Szabó, L., Kokas, M., Greff, Z., Boros, S., Bánhegyi, P., Zsákai, L., Kéri, G. (2016). Novel compounds reducing IRS–1 serine phosphorylation for treatment of diabetes. Bioorganic & Medicinal Chemistry Letters, 26 (2), 424–428. doi: 10.1016/j.bmcl.2015.11.099

Cheng, H., Hoffman, J. E., Le, P. T., Pairish, M., Kania, R., Farrell, W., Rahavendran, S. V. (2013). Structure–based design, SAR analysis and antitumor activity of PI3K/mTOR dual inhibitors from 4–methylpyridopyrimidinone series. Bioorganic & Medicinal Chemistry Letters, 23 (9), 2787–2792. doi: 10.1016/j.bmcl.2013.02.020

Puig de la Bellacasa, R., Roué, G., Balsas, P., Pérez–Galán, P., Teixidó, J., Colomer, D., Borrell, J. I. (2014). 4–Amino–2–arylamino–6–(2,6–dichlorophenyl)– pyrido[2,3–d]pyrimidin–7–(8H)–ones as BCR kinase inhibitors for B lymphoid malignancies. European Journal of Medicinal Chemistry, 86, 664–675. doi: 10.1016/j.ejmech.2014.09.018

Zinchenko, A. N., Muzychka, L. V., Smolii, O. B., Bdzhola, V. G., Protopopov, M. V., Yarmoluk, S. M. (2017). Synthesis and biological evaluation of novel amino–substituted derivatives of pyrido[2,3–d]pyrimidine as inhibitors of protein kinase CK2. Biopolymers and Cell, 33 (5), 367–378. doi: 10.7124/bc.000960


GOST Style Citations


1. Synthesis of 1,4–disubstituted pyrazolo[3,4–d]pyrimidines from 4,6–dichloropyrimidine–5–carboxaldehyde : Insights into selectivity and reactivity / C. Morrill, S. Babu, N. G. Almstead, Y.–C. Moon // Synthesis. – 2013. – Vol. 45, Issue 13. – P. 1791–1806. doi: 10.1055/s–0033–1338862

2. Preparation of 8–aza–7–deazaaristeromycin and –neplanocin A and their 5′–homologs / H. Wang, Y. Zhang, W. Ye, S. W. Schneller // J. Heterocycl. Chem. – 2014. – Vol. 52, Issue 4. – P. 1132–1135. doi: 10.1002/jhet.2137

3. Selective synthesis of 1–substituted 4–chloropyrazolo[3,4–d]pyrimidines / S. Babu, C. Morrill, N. G. Almstead, Y.–C. Moon // Org. Lett. – 2013. – Vol. 15, Issue 8. – P. 1882–1885. doi: 10.1021/ol4005382

4. Bisarylureas based on 1H–pyrazolo[3,4–d]pyrimidine scaffold as novel Pan–RAF inhibitors with potent anti–proliferative activities : Structure– based design, synthesis, biological evaluation and molecular modelling studies / Y. Fu, Y. Wang, S. Wan et al. // Molecules. – 2017. – Vol. 22, Issue 4. – 542 p. doi: 10.3390/molecules22040542

5. Expanding the diversity of allosteric Bcr–Abl inhibitors / X. Deng, B. Okram, Q. Ding et al. // J. Med. Chem. – 2010. – Vol. 53, Issue 19. – P. 6934–6946.
doi: 10.1021/jm100555f

6. Identification of purines and 7–deazapurines as potent and selective type I inhibitors of Troponin I–Interacting kinase (TNNI3K) / B. G. Lawhorn, J. Philp, Y. Zhao et al. // J. Med. Chem. – 2015. – Vol. 58, Issue 18. – P. 7431–7448. doi: 10.1021/acs.jmedchem.5b00931

7. Design, synthesis and evaluation of pyrrolo[2,3–d]pyrimidine–phenylamide hybrids as potent Janus kinase 2 inhibitors / T. Wang, X. Liu, M. Hao et al. // Bioorg. Med. Chem. Lett. – 2016. – Vol. 26, Issue 12. – P. 2936–2941. doi: 10.1016/j.bmcl.2016.04.027

8. Synthesis of Janus type nucleoside analogues and their preliminary bioactivity / H. Z.Yang, M. Y. Pan, D. W. Jiang, Y. He // Org. Biomol. Chem. – 2011. – Vol. 9, Issue 5. – 1516 p. doi: 10.1039/c0ob00495b

9. Design and synthesis of novel pyrimido[4,5–b]azepine derivatives as HER2/EGFR dual inhibitors / Y. Kawakita, M. Seto, T. Ohashi et al. // Bioorg. Med. Chem. – 2013. – Vol. 21, Issue 8. – P. 2250–2261. doi: 10.1016/j.bmc.2013.02.014

10. Synthesis of 7–alkyl–4–amino–7H–pyrrolo–[2,3–d]pyrimidine–6–carboxylic acids / E. V. Verves, A. V. Kucher, L. V. Muzychka, O. B. Smolii // Chem. Heterocycl. Compd. – 2013. – Vol. 48, Issue 12. – P. 1844–1852. doi: 10.1007/s10593–013–1218–0

11. Synthesis of new 4–amino–substituted 7–iminopyrido[2,3–d]pyrimidines / A. N. Zinchenko, L. V. Muzychka, I. I. Biletskii, O. B. Smolii // Chem. Heterocycl. Compd. – 2017. – Vol. 53, Issue 5. – P. 589–596. doi: 10.1007/s10593–017–2096–7

12. Synthesis of novel 8,9–dihydro–5H–pyrimido[4,5–e][1,4]diazepin–7(6H)–ones / J. Xiang, D. Wen, H. Xie et al. // J. Comb. Chem. – 2010. – Vol. 12, Issue 4. – P. 503–509. doi: 10.1021/cc100039w

13. Investigating molecular dynamics–guided lead optimization of EGFR inhibitors / M. J. Lavecchia, R. P. Bellacasa et al. // Bioorg. Med. Chem. – 2016. – Vol. 24, Issue 4. – P. 768–778. doi: 10.1016/j.bmc.2015.12.046

14. Oxopyrido[2,3–d]pyrimidines as covalent L858R/T790M mutant selective Epidermal Growth Factor Receptor (EGFR) inhibitors / R. P. Wurz, L. H. Pettus, K. Ashton et al. // ACS Med. Chem. Lett. – 2015. – Vol. 6, Issue 9. – P. 987–992. doi: 10.1021/acsmedchemlett.5b00193

15. C5–substituted pyrido[2,3–d]pyrimidin–7–ones as highly specific kinase inhibitors targeting the clinical resistance–related EGFRT790M mutant / T. Xu, T. Peng, X. Ren et al. // Med. Chem. Commun. – 2015. – Vol. 6, Issue 9. – P. 1693–1697. doi: 10.1039/C5MD00208G

16. A structure–guided optimization of pyrido[2,3–d]pyrimidin–7–ones as selective inhibitors of EGFRL858R/T790M mutant with improved pharmacokinetic properties / L. Yu, M. Huang, T. Xu et al. // Eur. J. Med. Chem. – 2017. – Vol. 126. – P. 1107–1117. doi: 10.1016/j.ejmech.2016.12.006

17. Discovery of a Potent and Selective Inhibitor of Cyclin–Dependent Kinase 4/6 / P. L. Toogood, P. J. Harvey, J. T. Repine et al. // J. Med. Chem. – 2005. – Vol. 48, Issue 7. – P. 2388–2406. doi: 10.1021/jm049354h

18. Discovery of 8–Cyclopentyl–2–[4–(4–methyl–piperazin–1–yl) phenylamino]–7–oxo–7,8–dihy dro–pyrido[2,3–d]pyrimidine–6–carbonitrile (7x) as a Potent Inhibitor of Cyclin–Dependent Kinase 4 (CDK4) and AMPK–Related Kinase 5 (ARKS) / M. V. R. Reddy, B. Akula, S. C. Cosenza et al. // J. Med. Chem. – 2014. – Vol. 57, Issue 3. – P. 578−599. doi: 10.1021/jm401073p

19. Chemically diverse Group I p21–activated kinase (PAK) inhibitors impart acute cardiovascular toxicity with a narrow therapeutic window / J. Rudolph, L. J. Murray, C. O. Ndubaku et al. // J. Med. Chem. – 2016. – Vol. 59, Issue 11. – P. 5520–5541. doi: 10.1021/acs.jmedchem.6b00638

20. Design, synthesis and biological evaluation of pyrido[2,3–d]pyrimidin–7–(8H)–ones as HCV inhibitors / M. Camarasa, R. Puig de la Bellacasa, À. L. González et al. // Eur. J. Med. Chem. – 2016. – Vol. 115. – P. 463–483. doi: 10.1016/j.ejmech.2016.03.055

21. Novel compounds reducing IRS–1 serine phosphorylation for treatment of diabetes / L. Simon–Szabó, M. Kokas, Z. Greff et al. // Bioorg. Med. Chem. Lett. – 2016. – Vol. 26, Issue 2. – P. 424–428. doi: 10.1016/j.bmcl.2015.11.099

22. Structure–based design, SAR analysis and antitumor activity of PI3K/mTOR dual inhibitors from 4–methylpyridopyrimidinone series / H. Cheng, J. E. Hoffman, P. T. Le et al. // Bioorg. Med. Chem. Lett. – 2013. – Vol. 23, Issue 9. – P. 2787–2792. doi: 10.1016/j.bmcl.2013.02.020

23. 4–Amino–2–arylamino–6–(2,6–dichlorophenyl)–pyrido[2,3–d]pyrimidin–7–(8H)–ones as BCR kinase inhibitors for B lymphoid malignancies / R. Puig de la Bellacasa, G. Roué, P. Balsas et al. // Eur. J. Med. Chem. – 2014. – Vol. 86. – P. 664–675. doi: 10.1016/j.ejmech.2014.09.018

24. Synthesis and biological evaluation of novel amino–substituted derivatives of pyrido[2,3–d]pyrimidine as inhibitors of protein kinase CK2 / A. N. Zinchenko, L. V. Muzychka, O. B. Smolii et al. // Biopolym. Cell. – 2017. – Vol. 33, Issue 5. – P. 367–378. doi: 10.7124/bc.000960





Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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

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