INTRODUCTION:

Azaheterocycles constitute a very important class of compounds. In particular, pyrimidine derivatives include a large number of natural products, pharmaceuticals and functional materials. Several examples of pharmaceutically important compounds include trimethoprim [1] sulfadiazine [2], Gleevec (imatinib mesilate) [3], and Xeloda (capecitabine) [4]. In nature, the pyrimidine ring is synthesized from glutamine, bicarbonate, and aspartate [5]. These starting materials are converted to orotate. Several (mainly uracil, thymine and cytosine) pyrimidines have been isolated from the nucleic acid hydrolyses. The nucleic acid are essential constituent of all cell and thus of all living matter cytosine is found to be present in both types of nucleic acid i.e. ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) while uracil present only in RNA and thymine only in DNA [6].

In addition, Pyrimidine ring is also found in vitamin like thiamine, riboflavin and folic acid [7] Barbitone1, the first barbiturate hypnotic sedative and anticonvulsant is a pyrimidine derivative [8]. There are a large number of pyrimidine-based antimetabolites. They are usually structurally related to the endogenous substrates that they antagonize. One of the early metabolites prepared was 5-fluorouracil [9], a pyrimidine derivative. 5-Thiouracil also exhibits some useful antineoplastic activities [10].

There are many more in recent times, like nimustine [11], uramustine [12] and trimetrixate [13]. It is mainly used as an anticancer agent and also exhibits significant therapeutic effects in patients with herpes virus infections and herpes encephalitis. In 1948, Hitchings made an important observation that a large number of 2, 4- diaminopyrimidines and some 2-amino-4-hydroxypyrimidines are antagonists of folic acid [14]. Since then, a large number of 2, 4-diaminopyrimidines have been synthesized as antifolates. It was eventually proved that these pyrimidines are inhibitors of the enzyme dihydrofolate reductase (DHFR) [15]. Notable amongst the 2, 4- diaminopyrimidine drugs are pyrimethamine, a selective inhibitor of the DHFR of malarial plasmodia; trimethoprim, an antibacterial drug which selectively inhibits bacterial DHFR.

MATERIALS AND METHODS:

All commercial chemicals and solvents were reagent grade and used without further purification unless otherwise specified. Melting points were determined on a Fargo melting point apparatus and are uncorrected. Thin-layer chromatography was performed on silica gel G60 - F₂₅₄ (Merck) with short-wavelength UV light for visualization. All reported yields are isolated yields after chromatography or crystallization. Mass spectra were recorded on Shimadzu GC-MS QP-2010 model using direct injection probe technique. The molecular ion peak was found in agreement with molecular weight of the respective compound. ¹H NMR spectra were recorded on a 400 MHz, Brucker Top-Spin spectrometers in the indicated solvent. The chemical shifts were reported in ppm (δ) relative to TMS and coupling constants (J) in Hertz (Hz) and s, d, t, m, brs, refer to singlet, doublet, triplet, multiplet, broad respectively.

RESULTS AND DISCUSSION:

While development of important methodologies for the synthesis of pyrimidines enjoys a rich history, the discovery of new strategies for the convergent synthesis of pyrimidines remains a vibrant area of chemical research. At present there are no reports for the use of such reactions on guanidines, in this work, the three component condensation of benzoimidazole-2-guanidines with ortho-esters and active methylene compounds containing a carbonyl function were studied.

The synthetic route for substituted 2-[(1H-benzo[d]imidazol-2-yl) amino] - pyrimidine derivatives are shown in Scheme. The known 2- benzimidazolylguanidine was synthesized from substituted o-phenylenediamine and cyano guanidin by following literature procedure. Compound was treating with tri ethyl orthoformate (CH (OC₂H₅)₃) and active methylene compounds containing carbonyl function (1, 3-diketones) to furnish substituted 2-[(1H-benzo[d]imidazol-2-yl) amino]-pyrimidine.

Synthetic scheme

Experimental Section

Preparation of 2-benzimidazolylguanidine (3).

A mixture of o-phenylenediamine (1, 10.8 g, 100 mmol), cyanoguanidine (2, 8.4 g, 100 mmol) and concentrate hydrochloric acid (20mL) in H₂O (200 mL) was heated under reflux for 1 h. The reaction mixture was cooled at 0°C and KOH (10%; 50 mL) was added slowly. The precipitates of 2-guanidinobenzimidazole were collected by filtration, washed with H₂O, dried, and used in next reactions without further purification. Yield 14 g (80 %); mp 240–242 °C; MS m/z = 175 (M⁺).

Preparation of 1-(2-(1H-benzo[d]imidazol-2-ylamino)-4-methylpyrimidin-5-yl) ethanone (4a)

A mixture of 2-guanidinobenzimidazole (3, 1.75 g, 10 mmol), acetyl acetone (1g, 10 mmol) and tri ethyl orthoformate (15 mL) was stirred at reflux temperature for 120 min. Upon the completion of the reaction (monitored by TLC, ethyl acetate: hexane (1:1)), the reaction mixture was concentrated under reduced pressure, and 1 mL of water was added. The separated solid product was collected by filtration and recrystallized from ethanol to give 4a 2.3 g (88 %); mp > 300 °C; MS m/z = 267 (M⁺).

Preparation of methyl 2-(1H-benzo[d]imidazol-2-ylamino)-4-methylpyrimidine-5-carboxylate (4b)

Yield, 81%; mp 210–211°C. ¹H NMR (DMSO-d₆) δ 2.78 (3H, s, Me), 3.85(3H, s, OMe), 7.09–7.11 (2H, m, 2 × ArH), 7.51–7.53 (2H, m, 2 × ArH), 8.96 (1H, s, ArH), 11.99 (2H, br s, exchangeable NH). MS m/z = 283 (M⁺).

Preparation of ethyl 2-(1H-benzo[d]imidazol-2-ylamino)-4-methylpyrimidine-5-carboxylate (4c)

Yield, 80 %; mp 221–222°C. ¹H NMR (DMSO-d₆) δ 1.34 (3H, t, J = 7.2 Hz, Me), 2.77 (3H, s, Me), 4.31 (2H, q, J = 7.2 Hz, OCH2), 7.08–7.10 (2H, m, 2 × ArH), 7.47–7.49 (2H, m, 2 × ArH), 8.96 (1H, s, ArH), 11.87 (2H, br s, exchangeable NH). MS m/z = 297 (M+).

ACKNOWLEDGEMENT:

The authors express their thanks to Jawaharlal Nehru Technological University, for providing my research work.

CONCLUSION:

This is three component condensations of benzoimidazole-2-guanidines, orthoester and active methylene carbonyl compounds leading to several novel new chemical entities substituted-(1H-benzo[d]imidazol-2-yl)amino-pyrimidine derivatives.

REFERENCES:

1. Joffe, A. M.; Farley, J. D.; Linden, D.; Golds and, G. Am. J. Med. 1989, 87, 332.

2. Petersen, E.; Schmidt, D. R. Expert Rev. Anti-Infect. Ther. 2003, 1, 175.

3. Nadal, E.; Olavarria, E. Int. J. Clin. Pract. 2004, 58, 511.

4. Blum, J. L. Oncologist. 2001, 6, 56.

5. Lagoja, I. M. Chem. Biodiversity 2005, 2, 1.

6. Agarwal O. P. Organic Chemistry, Reaction and Reagent 2006, 735.

7. Cox, R. A. Quart. Rev. 1968, 22, 499.

8. Jain, M. K.; Sharnevas, S. C.; Organic Chemistry 2008, 997.

9. Callery, P.; Gannett, P. Cancer and Cancer Chemotherapy. Williams, D. A.; Lemke, T. L. Eds, Philadelphia, 2002, 934.

10. Al Safarjalani, O. N.; Zhou, X. J.; Ras, R. H.; Shi, J.; Schinazi, R. F.; Naguib, F. N.; El Kouni, M. H. Cancer Chemother. Pharmacol. 2005, 55, 541.

11. Weller, M.; Muller, B.; Koch, R.; Bamberg, M.; Krauseneck, P. J. Clin. Oncol. 2003, 21, 3276.

12. Kennedy, B. J.; Torkelson, J. L.; Torlakovic, E. Cancer 1999, 85, 2265.

13. Bertino, J. R. et al. Biochem. Pharmacol. 1979, 28, 1983.

14. Hitchings, G. H.; Elion, G. B.; Wanderers, H.; Falco, E. A. J. Biol. Chem. 1948, 174, 765.

15. Jain, K. S.; Chitre, T. S.; Miniyar, P. B.; Kathiravan, M. K.; Bendre, V. S.; Veer, V. S.; Shahane, S. R.; Shishoo, C. J. Curr. Science 2006, 90, 793.

Received on 15.12.2013 Modified on 14.01.2014

Asian J. Research Chem. 7(3): March 2014; Page 293-294