The synthesis of a tricyclic system with the 7-deazaadenine nucleus

L. V. Muzychka, I. O. Yaremchuk, Ye. V. Verves, O. B. Smolii

Abstract


Aim. To develop new convenient approaches to the synthesis of new tricyclic compounds with the 7-deazaadenine nucleus as promising synthons for the search of biologically active compounds.
Results and discussion. A new simple approach to the synthesis of 4-amino substituted pyrrolo[2,3-d]pyrimidine-6-carboxylic acids was found. A tricyclic derivative of 7-deazadenine was obtained by the intramolecular cyclization of methyl 7-oxiranylmethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate.
Experimental part. Treatment of 4-methoxypyrrolo[2,3-d]pyrimidine with ammonium acetate while heating leads to 4-aminopyrolo[2,3-d]pyrimidine-6-carboxylic acid. This acid reacts with iodine in acetic acid producing 8-iodomethylpyrimido[5’,4’:4,5]pyrrolo[2,1-c][1,4]oxazine with a high yield. Treatment of oxazine with sodium methylate gives 7-(oxiran-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate; when it is heated with triethylamine hydrochloride in acetonitrile, 10-amino-5,6-dihydro-4H-1-deazapyrimido[1,2,3-cd]purine-2-carboxylate previously unknown is obtained. The structure and composition of the substances obtained were confirmed by NMR-spectroscopy, chromatography mass-spectrometry and elemental analysis.
Conclusions. A new convenient approach to the synthesis of 10-amino-5,6-dihydro-4H-1-deazapyrimido[1,2,3-cd]purine-2-carboxylate has been developed. This compound is a tricyclic system with the 7-deazaadenine nucleus. Its further modification may produce potential biologically active substances.


Keywords


pyrrolo[2,3-d]pyrimidine; 7-deazaadenine; iodolactonization; 1-deazapyrimido[1,2,3-cd]purine

References


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GOST Style Citations


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2. Synthesis and cytostatic and antiviral activities of 2’–deoxy–2’,2’–difluororibo– and 2’–deoxy–2’–fluororibonucleosides derived from 7–(het)aryl–7– deazaadenines / P. Perlikova, L. Eberlin, P. Menova et al. // Chem. Med. Chem. – 2013. – Vol. 8, Issue 5. – P. 832–846. doi: 10.1002/cmdc.201300047

3. Practical synthesis of a potent hepatitis C virus RNA replication inhibitor / M. M. Bio, F. Xu, M. Waters et al. // J. Org. Chem. – 2004. – Vol. 69, Issue 19. – P. 6257–6266. doi: 10.1021/jo0491096

4. Structure−activity relationship of heterobase–modified 2‘–C–methyl ribonucleosides as inhibitors of hepatitis C virus RNA replication / A. B. Eldrup, M. Prhavc, J. Brooks et al. // J. Med. Chem. – 2004. – Vol. 47, Issue 21. – P. 5284–5297. doi: 10.1021/jm040068f

5. Synthesis and anti–hepatitis B virus and anti–hepatitis C virus activities of 7–deazaneplanocin A analogues in vitro / H–J. Kim, A. Sharon, C. Bal et al. // J. Med. Chem. – 2009. – Vol. 52, Issue 1. – P. 206–213.doi: 10.1021/jm801418v

6. Synthesis and antiviral activity of 7–deazaneplanocin A against orthopoxviruses (vaccinia and cowpox virus) / B. Arumughama, H–J. Kima, M. N. Prichardb et al. // Bioorg. Med. Chem. Lett. – 2006. – Vol. 16, Issue 2. – P. 285–287. doi: 10.1016/j.bmcl.2005.10.007

7. Discovery and synthesis of novel 4–aminopyrrolopyrimidine Tie–2 kinase inhibitors for the treatment of solid tumors / J. T. Arcari, J. S. Beebe, M. A. Berliner et at. // Bioorg. Med. Chem. Lett. – 2013. – Vol. 23, Issue 10. – P. 3059–3063. doi: 10.1016/j.bmcl.2013.03.012

8. Optimisation of a 5–[3–phenyl–(2–cyclic–ether)–methyl–ether]–4–aminopyrrolopyrimidine series of IGF–1R inhibitors / R. A. Fairhursta, T. H. Marsilje, S. Stutz et al. // Bioorg. Med. Chem. Lett. – 2016. – Vol. 26, Issue 8. – P. 2057–2064. doi: 10.1016/j.bmcl.2016.02.075

9. Pyrrolo[2,3–d]pyrimidines containing diverse N–7 substituents as potent inhibitors of Lck / D. J. Calderwood, D. N. Johnston, R. Munschauer, P. Rafferty // Bioorg. Med. Chem. Lett. – 2002. – Vol. 12, Issue 12. – P. 1683–1686. doi: 10.1016/S0960–894X(02)00195–6

10. Discovery of novel, potent, and selective inhibitors of 3–phosphoinositide–dependent kinase (PDK1) / S. T. Murphy, G. Alton, S. Bailey et al. // J. Med. Chem. – 2011. – Vol. 54, Issue 24. – P. 8490–8500. doi: 10.1021/jm201019k

11. 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

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18. Synthesis of a 4’,4’–spirothietane–2’, N3–cycloadenosine as a highly constrained analogue of 5’–deoxy–5’–methylthioadenosine (MTA) / G. S. G. De Carvalho, J.–L. Fourrey, R. H. Dodd et al. // Tetrahedron Lett. – 2009. – Vol. 50, Issue 4. – P. 463–466. doi: 10.1016/j.tetlet.2008.11.039





DOI: https://doi.org/10.24959/ophcj.18.936

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