Synthesis of 5-Methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one in Supercritical Carbon Dioxide

Article abstract of DOI:10.1134/S1070363219010274

5-Methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one, an intermediate product in the synthesis of the antiviral drug Triazid, was obtained for the first time by condensation of 3H-1,2,4-triazol-5-amine with ethyl acetoacetate in the presence of a catalytic a

Full text of DOI:10.1134/S1070363219010274

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 1, pp. 151–152. © Pleiades Publishing, Ltd., 2019.
Russian Text © A.V. Baklykov, G.L. Rusinov, V.L. Rusinov, V.N. Charushin, D.S. Kopchuk, G.V. Zyryanov, G.A. Artem’ev, 2019, published in Zhurnal
Obshchei Khimii, 2019, Vol. 89, No. 1, pp. 140–142.
LETTERS
TO THE EDITOR
Synthesis of 5-Methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one
in Supercritical Carbon Dioxide
A. V. Baklykova,b, G. L. Rusinova,b, V. L. Rusinova,b, V. N. Charushina,b,
D. S. Kopchuka,b, G. V. Zyryanova,b*, and G. A. Artem’eva
a Postovskii Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences,
ul. S. Kovalevskoi/Akademicheskaya 22/20, Yekaterinburg, 620990 Russia
*e-mail: gvzyryanov@gmail.com
b Yeltsin Ural Federal University, ul. Mira 19, Yekaterinburg, 620002 Russia
Received August 2, 2018; revised August 2, 2018; accepted August 10, 2018
Abstract—5-Methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one, an intermediate product in the synthesis of the
antiviral drug Triazid®, was obtained for the first time by condensation of 3H-1,2,4-triazol-5-amine with ethyl
acetoacetate in the presence of a catalytic amount of ZnCl2 in supercritical carbon dioxide (200 bar) under
solvent-free conditions. Depending on the temperature and reaction time, the conversion was 90%.
Keywords: 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one, supercritical carbon dioxide, solvent-free synthesis
DOI: 10.1134/S1070363219010274
Development of pharmaceutical industry is closely
related to the problem of disposal of large amounts of
industrial wastes [1]. Implementation of the “green
chemistry” principles provides favorable conditions for
the solution of this problem. For example, the use of
large amounts of organic solvents in industrial
processes creates a high environmental hazard [2].
Therefore, replacement of organic solvents by super-
critical fluids that are non-flammable, low toxic, and
chemically inert, e.g., by carbon dioxide, may be
environmentally benign [3].
of 3H-1,2,4-triazol-5-amine (2) with ethyl acetoacetate
(3) (Scheme 1) in boiling acetic acid was described in
[5, 6]. We believed it reasonable to replace acetic acid
by a Lewis acid such as zinc(II) chloride and to use
supercritical carbon dioxide (200 bar) to dissolve all
the reactants. The reaction conditions were optimized
by varying the reaction temperature and time. The
results are given in the table.
Obviously, increase of the reaction temperature or
time increases the yield. However, unlike the con-
ventional procedure, we have synthesized compound 1
in a higher yield, which indicates that carrying out the
reaction in supercritical carbon dioxide is more
advantageous.
Herein, we report the first synthesis of 5-methyl-
1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one (1), an inter-
mediate product in the preparation of the antiviral drug
Triazid® [4], in supercritical carbon dioxide. The
synthesis of 1 in up to 83% yield by cyclocondensation
Thus, we were the first to demonstrate that 5-
methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one can
Scheme 1.
Synthesis of 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-
one (1) in supercritical carbon dioxide in the presence of
ZnCl2
N
NH
ZnCl2
scCO2
O
Yield,a %
N
Reaction time, min
NH2
110°C 150°C
190°C
75 (69)
–
N
N
2
N
60
44
–
60
+
O
O
N
H
CH3
180
90 (85)
a
H3C
OC2H5
Determined by HPLC according to the procedure described in
[7]; the isolated yields are given in parentheses.
CH3CO2H, Δ
3
1
151

152
BAKLYKOV et al.
be synthesized in supercritical carbon dioxide in the
presence of zinc(II) chloride. The effects of
temperature and reaction time on the product yield
were shown. The proposed procedure is advantageous
since it does not require the use of organic solvents but
ensures a comparable yield.
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
REFERENCES
1. Larsson, D.G.J., Philos. Trans. R. Soc., B, 2014, vol. 369,
article no. 20130571. doi 10.1098/rstb.2013.0571
2. Grodowska, K. and Parczewski, A., Acta Pol. Pharm.,
The synthesis was performed under microwave irra-
diation in a Waters TI-ReacSyS-250-200 supercritical
fluid laboratory setup with a working pressure of 200 bar.
2010, vol. 67, p. 3.
3. Budisa, N. and Schulze-Makuch, D., Life, 2014, vol. 4,
5-Methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one
(1). A mixture of aminotriazole 2 (42 mg, 0.5 mmol),
ethyl acetoacetate (3, 73 mg, 0.56 mmol), and ZnCl2
(7 mg, 0.05 mmol) in supercritical carbon dioxide was
kept under the conditions indicated in Table 1. The
mixture was analyzed by HPLC according to the
procedure described in [7]. To isolate the product, the
mixture was cooled to room temperature, and the
precipitate was filtered off, washed with 40% aqueous
ethanol, and dried. All physicochemical characteristics
of the product were consistent with those reported in
[5, 6].
p. 331. doi 10.3390/life4030331
4. Chupakhin, O.N., Charushin, V.N., Rusinov, V.L., Ulom-
skii, E.N., Kotovskaya, S.K., Kiselev, O.I., Deeva, E.G.,
Savateev, K.V., and Borisov, S.S., RU Patant no. 2529487.
5. Gujjar, R., Mazouni, F.E., White, K.L., White, J.,
Creason, S., Shackleford, D.M., Deng, X., Charman, W.N.,
Bathurst, I., Burrows, J., Floyd, D.M., Matthews, D.,
Buckner, F.S., Charman, S.A., Phillips, M.A., and
Rathod, P.K., J. Med. Chem., 2011, vol. 54, p. 3935. doi
10.1021/jm200265b
6. Savateev, K.V., Ulomsky, E.N., Fedotov, V.V., Rusinov, V.L. ,
Sivak, K.V., Lyubishin, M.M., Kuzmich, N.N., and
Aleksandrov, A.G., Russ. J. Bioorg. Chem., 2017, vol. 43,
p. 421. doi 10.1134/S1068162017040094
FUNDING
7. Baklykov, A.V., Tumashov, A.A., Kotovskaya, S.K.,
Ulomskii, E.N., Rusinov, G.L., Rusinov, V.L. Chupa-
khin, O.N., and Charushin, V.N., Razrab. Registr. Lek.
Sredstv, 2017, no. 2 (19), p. 44.
This study was performed under financial support
by the Ministry of Education and Science of the
Russian Federation (project no. 4.6351.2017/8.9).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 1 2019