CC BY
2UDK 547.272
THREE-STEP SYNTHESIS OF TRICYCLIC TRIAZOLO PYRIMIDINONES FROM
ANILINE DERIVATIVES
Z.Murtazaeva, A.Nasrullaev, D. Tukhtaev, D.Turaeva, Z.Khushnazarov, Kh.Bozorov*
Keywords: cancer, triazole, cyanoacetate, ethyl esters of 5-amino-1-N-aryl-1H-1,2,3-triazole, synthesis.
1. Introduction. Cancer is an increasingly serious public health problem that affects people of all ages. An estimated 1.9 million new cases of cancer will be diagnosed in the United States in 2022, of which 609,360 will result in cancer-related deaths. According to an analysis by the National Cancer Institute (NCI), the number of people affected by cancer could reach 23.6 million by 2030, of which 14 million will die from the disease [1]. The development of novel small molecules with both potency and selectivity remains a challenge for pharmaceutical chemists [2,3]. According to the World Health Organisation (WHO), breast and liver diseases are among the leading causes of mortality [4] (Fig.1).
Although many small molecule drugs have existed in clinical trials [5-7], nowadays, tremendous intention have been appealed to discover of novel anticancer medication with superior efficiency and lower drug resistance. So, hybridization came up as a promising approach to achieve this aim [7-9]. Among the different superior mechanisms for anticancer drugs such as alkylating agents [10], tyrosine kinase [11], aromatase inhibitors [12], DNA-intercalating antitumor agents [13], cyclooxygenase-2 inhibitors [14,15], histone acetyltransferases (HATs) [16], histone deacetylase (HDACs) [17-21], Hsp90 inhibitors [22], topoisomerase inhibitors [23] and tubulin inhibitors [24,25]; multidrug resistance protein 2 (MRP2) inhibitors [26]. Chemical compounds that prevent the assembly of microtubules are included in this class and have attracted much attention in recent research. More than 75 % of drugs accepted by FDA and at present accessible in the market have nitrogen-containing heterocycles moiety with proper characteristics and demands have increased greatly in the fields of biological and medicinal chemistry and drug manufacturing. In addition, electron-rich nitrogen heterocycles are not only capable of willingly accepting a proton but they can also form diverse weak interactions.
Among the 5-membered heterocyclic compounds, triazole is the primary heterocyclic molecule. Triazole derivatives have attracted interest in the last few decades due to their biological properties such as anticancer [27], antiviral, antimalarial [28], antioxidant [29], anticonvulsant [30], antileishmanial [31], antidiabetic [32], antifungal [33] and antibacterial [34] activities. The unique structure and properties of triazoles make them useful in various fields such as organic catalysts, materials science, pharmaceutical chemistry, agrochemistry, supramolecular chemistry [35] and nanomaterials. This heterocyclic structure is a major component of various drugs available for clinical therapy such as the antibiotics Tazobactam [36], Radezolid [37], Cefatrizine [38], Tertbutyldimethylsilylspiroaminooxathioledioxide (TSAO) [39], and the Carboxyamidotriazole (CAI) [40] fluconazole [41], ribavirin [42], isavuconazole [43] shown in (Fig. 3) which are frequently used in the pharmaceutical field. The triazole molecule shows inhibitory activity against some common enzymes such as tyrosinase [44], acetylcholinesterase [45], P-lactamase, carbonic anhydrase and a-glucosidase [46].
*Z.Murtazaeva, A.Nasrullaev, D. Tukhtaev, D. Turaeva, Z. Khushnazarov, Kh. Bozorov - Samarkand State University named after Sh.Rashidov.
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In particular, 1,2,3-triazole-containing hybrids can exert dual or multiple anticancer mechanisms of action, representing an important source for the development of new anticancer candidates.
Fig. 3. Schematic structure of triazole ring-containing drugs.
In this context, our research group presents novel condensed tricyclic compound containing 1,2,3-triazole ring.
2. Results and discussion. 2.1 Preparation of phenyl azides (2a-2i) and preparation of ethyl 1-phenyl-5-amino-4-ethoxycarbonyl-1,2,3-triazole-4-carboxylate (3a-3i):
Under the condition of the ice bath, substituting aniline (30 mmol) and hydrochloric acid (6 mol/l, 50 ml) were added into a 250 ml reaction bottle, stirred for 10 min, NaNO2 (2.8 g) aqueous solution of 25 ml was added slowly dropwise, stirred for 30 min, sodium azide (2.6 g) aqueous solution 50 ml was added slowly dropwise. The stirring was continued until the raw materials disappeared, the reaction solution was extracted with ethyl acetate and the organic phases were combined, dried with anhydrous sodium sulfate, and concentrated in a vacuum to obtain the intermediate phenyl azide (2a-2i). The reaction solution was extracted with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate and concentrated in a vacuum to obtain the intermediate phenyl azide (2a-2i). The product is used directly without further purification.
Take 0.26 g of sodium, shear it in petroleum ether and dry it with filter paper, place it carefully/slowly in 15 ml of anhydrous ethanol and leave it to dissolve all together (to form ethanol sodium solution) and set aside. To the reaction flask, ethyl cyanoacetate (1.17 ml, 0.11 mol), substituted phenyl azide (0.1 mol) were added sequentially, and the freshly prepared sodium ethanol solution was added drop by drop with stirring, the reaction gradually precipitated solid, and the reaction was monitored for completeness by TLC. The residual ethanol was removed under reduced pressure, saturated aqueous NH4Q solution was added to the reaction solution, extracted with 100 ml of dichloromethane, the organic layer was washed three times with 100 ml of saturated saline, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized in 20 ml of ethanol to obtain the yellowish solid product (3a-3i) (Scheme 1) [47].
iNH2;
R 1a
NaN3, NaN02 HCI, 4 s
a: R=4-H, b: R=4-Me, c: R=4-Et,
R
4
2a-i
d: R=4-F, e: R=4-CI, f: R=4-Br,
O-^ C2H5ONa
rt-40°C
g: R=4-OMe, h: R=4-CF3, i: R=3,4-CI
Scheme 1. General scheme for the synthesis of 5-amino-1-N-aryl-1H-1,2,3-triazoles ethyl esters derivatives
2.3. Synthesis of tricyclic triazolo[4,5-d]pyrimidinone derivatives: Intermediates 3a-3i (0.4 mmol) were dissolved in 2 ml of anhydrous 1,4-dioxane, anhydrous phosphorous oxychloride (0.8 mmol, 73 ^L) was added, stirred at room temperature for 10 min, the piperidin-2-one (0.44 mmol, 1.1 times the amount of substance) was added, heated to reflux, and the reaction was monitored for completeness by TLC. The system was reduced to room temperature, the solvent was removed under reduced pressure, the product was dissolved in 100 ml of water and extracted with 50 ml of ethyl acetate, the organic layer was washed with 50 ml of saturated saline, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography [V(petroleum ether): V(ethyl acetate) = 3:1 - 1:1] to afford the target compounds (4a-4i) (Scheme 2).
nA'
<X
h poci3,
^-o 1,4-dioxane
nh2 I J reflux,
overnight
3a-i
a: R=4-H, d: R=4-F, g: R=4-OMe,
b: R=4-Me, e: R=4-CI, h: R=4-CF3,
c: R=4-Et, f: R=4-Br, i: r=3j4-ci,
Scheme 2: General scheme for the synthesis of tricyclic derivatives of triazolo[4,5-d]pyrimidinone
Table 1 shows the schematic structure of the synthesized tricyclic triazolo [4,5-d]pyrimidinone derivatives (4a-i).
All newly synthesized heterocycles were fully elucidated by both computational and spectral evaluations.
3-phenyl-5,6,7,8-tetrahydropyrido[1,2-a][1,2,3]triazolo[4,5-d]pyrimidin-10(3H)-one
(4a)
Yield 28.7%, m.p. 171 - 172 °C, ^-NMR (400 MHz, CDCb) 5 8.11 (d, J = 7.4 Hz, 2H, Ar-H), 7.59 - 7.53 (m, 2H, Ar-H), 7.50 - 7.41 (m, 1H, Ar-H), 4.16 (t, J = 6.1 Hz, 2H, CH2), 3.06 (t, J = 6.6 Hz, 2H, CH2), 2.09 - 1.91 (m, 4H, CH2 x 2); 13C-NMR (100 MHz, CDCb) 5 160.9, 156.1, 147.0, 136.0, 129.6, 128.9, 128.8, 121.9, 42.4, 32.5, 21.9, 19.0; HRMS (ESI): calcd for [M + H]+: 268.1193, found 268.1194.
3-(p-tolyl)-5,6,7,8-tetrahydropyrido[1,2-a][1,2,3]triazolo[4,5-d]pyrimidin-10(3H)-one
(4b)
Yield 24.8%, m.p. 185 - 186 °C, 1H-NMR (400 MHz, CDCb) 5 7.95 (d, J = 8.4 Hz, 2H, Ar-H), 7.35 (d, J = 8.1 Hz, 2H, Ar-H), 4.15 (t, J = 6.1 Hz, 2H, CH2), 3.05 (t, J = 6.6 Hz, 2H, CH2), 2.44 (s, 3H, CH3), 2.07 - 1.92 (m, 4H, CH2 x 2); 13C-NMR (100 MHz, CDCb) 5 160.8, 156.2, 147.0, 139.0, 133.6, 130.3, 128.9, 122.0, 42.4, 32.6, 22.0, 21.5, 19.1; HRMS (ESI): calcd for [M + H]+: 282.1349, found 282.1351.
3-(4-ethylphenyl)-5,6,7,8-tetrahydropyrido[1,2-a][1,2,3]triazolo[4,5-d]pyrimi-din-10(3H)-one (4c)
Yield 25.9%, m.p. 148-149 °C, 1H-NMR (400 MHz, CDCb) 5 7.97 (d, J = 8.2 Hz, 2H, Ar-H), 7.38 (d, J = 8.2 Hz, 2H, Ar-H), 4.15 (t, J = 6.1 Hz, 2H, CH2), 3.05 (t, J = 6.6 Hz, 2H, CH2), 2.73 (q, J = 7.6 Hz, 2H, CH2), 2.07 - 1.93 (m, 4H, CH2 x 2), 1.29 (t, J = 7.6 Hz, 3H, CH3); 13C-NMR (100 MHz, CDCls) 5 160.7, 156.1, 146.9, 145.2, 133.7, 129.0, 128.8, 122.0, 42.3, 32.5, 28.7, 21.9, 19.0, 15.6; HRMS (ESI): calcd for [M + H]+: 296.1506, found 296.1508.
3-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[1,2-a][1,2,3]triazolo[4,5-d]pyri-midin-10(3H)-one (4d)
Yield 24.9%, m.p. 169 - 170 °C, 1H-NMR (400 MHz, CDCb) 5 8.11 (dd, J = 8.8, 4.7 Hz, 2H, Ar-H), 7.25 (s, 2H, Ar-H), 4.16 (t, J = 6.1 Hz, 2H, CH2), 3.05 (t, J = 6.7 Hz, 2H, CH2), 2.06 - 2.01 (m, 2H, CH2), 2.00 - 1.95 (m, 2H, CH2); 13C-NMR (100 MHz, CDCb) 5 162.7 (d, Jc-f = 247.5 Hz), 161.2, 156.1, 1467.0, 132.2 (d, Jc-f = 3.0 Hz), 128.9, 123.9 (d, Jc-f = 9.1 Hz), 116.7 (d, Jc-f = 24.2 Hz), 42.6, 32.7, 22.0, 19.1; HRMS (ESI): calcd for [M + H]+: 286.1099, found 286.1099.
3-(4-chlorophenyl)-5,6,7,8-tetrahydropyrido[1,2-a][1,2,3]triazolo[4,5-d]pyrim-idin-10(3H)-one (4e)
Yield 25.7%, m.p. 187 - 188 °C, 1H-NMR (400 MHz, CDCb) 5 8.12 (d, J = 8.8 Hz, 2H, Ar-H), 7.53 (d, J = 8.8 Hz, 2H, Ar-H), 4.16 (t, J = 6.0 Hz, 2H, CH2), 3.06 (t, J = 6.6 Hz, 2H, CH2), 2.08 - 1.95 (m, 4H, CH2 x 2); 13C-NMR (100 MHz, CDCb) 5 161.2, 156.0, 146.9, 134.5, 134.5, 129.8, 128.9, 122.8, 42.5, 32.6, 21.9, 19.0; HRMS (ESI): calcd for [M + H]+:302.0803, found 302.0805.
3-(4-bromophenyl)-5,6,7,8-tetrahydropyrido[1,2-a][1,2,3]triazolo[4,5-d]pyri-midin-10(3H)-one (4f)
Yield 25.3%, m.p. 198 - 199 °C, 1H-NMR (400 MHz, CDCb) 5 8.06 (d, J = 8.8 Hz, 2H, Ar-H), 7.68 (d, J = 8.8 Hz, 2H, Ar-H), 4.15 (t, J = 6.1 Hz, 2H, CH2), 3.06 (t, J = 6.6 Hz, 2H, CH2), 2.09 -1.92 (m, 4H, CH2 x 2); 13C-NMR (100 MHz, CDCb) 5 161.2, 155.9, 146.9, 135.0, 132.8, 128.9, 123.0, 122.4, 42.5, 32.6, 21.9, 19.0; HRMS (ESI): calcd for [M + H]+:346.0298, found 346.0303.
3-(4-methoxyphenyl)-5,6,7,8-tetrahydropyrido[1,2-a][1,2,3]triazolo[4,5-d]-pyrimidin-10(3H)-one (4g)
Yield 25.3%, m.p. 175 - 176 °C, 1H-NMR (400 MHz, CDCb) 5 7.96 (d, J = 9.0 Hz, 2H, Ar-H), 7.06 (d, J = 9.0 Hz, 2H, Ar-H), 4.15 (t, J = 6.2 Hz, 2H), 3.88 (s, 3H, CH2), 3.04 (t, J = 6.7 Hz, 2H, CH2), 2.04 - 2.00 (m, 2H, CH2), 1.99 - 1.93 (m, 2H, CH2); 13C-NMR (100 MHz, CDCb) 5 160.7, 159.9, 156.1, 146.7, 129.1, 128.7, 123.6, 114.8, 55.8, 42.3, 32.5, 22.0, 19.0; HRMS (ESI): calcd for [M + H]+:298.1299, found 298.1300.
3-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[1,2-a][1,2,3]triazolo-[4,5-d]pyrimidin10(3H) -one (4h)
Yield 25.7%, m.p. 164 - 165 °C, 1H-NMR (400 MHz, CDCb) 5 8.39 (d, J = 8.4 Hz, 2H, Ar-H), 7.84 (d, J = 8.3 Hz, 2H, Ar-H), 4.17 (t, J = 6.0 Hz, 2H, CH2), 3.09 (t, J = 6.7 Hz, 2H, CH2), 2.07 - 1.98 (m, 4H, CH2 x 2); 13C-NMR (100 MHz, CDCb) 5 161.3, 155.7, 147.1, 138.7, 130.4 (q, Jc-f =3.3 Hz), 128.9, 120.8 (q, Jc-f =3.0 Hz), 123.7 (q, Jc-f =272.5 Hz), 121.4, 42.5, 32.5, 21.8, 18.9; HRMS (ESI): calcd for [M + H]+:336.1067, found 336.1068.
3-(3,4-dichlorophenyl)-5,6,7,8-tetrahydropyrido[1,2-a][1,2,3]triazolo[4,5-d]pyrimidin-10(3H)-one (4i)
Yield 22.3%, m.p. 190 - 191 °C, 1H-NMR (400 MHz, CDCb) 5 8.40 (d, J = 2.5 Hz, 1H, Ar-H), 8.11 (dd, J = 8.8, 2.5 Hz, 1H, Ar-H), 7.64 (d, J = 8.7 Hz, 1H, Ar-H), 4.16 (t, J = 6.1 Hz, 2H, CH2), 3.09 (t, J = 6.6 Hz, 2H, CH2), 2.10 - 1.94 (m, 4H, CH2 x 2); 13C-NMR (100 MHz, CDCb) 5 161.5, 160.8 155.8, 135.3, 133.8, 132.8, 131.4, 130.8, 123.1, 120.5, 42.6, 32.6, 21.9, 19.0; HRMS (ESI): calcd for [M + H]+:336.0413, found 336.0411.
Conclusion.
1. A series of tricyclic triazolo[4,5-d]pyrimidinone derivatives have been synthesized by condensation reaction of ethyl esters of 5-amino-1-N-aryl-1H-1,2,3-triazoles and piperidin-2-one.
2. The structures of the new pyrimidines were identified by 1H-, 13C-NMR and HRMS analysis.
The research work was funded on the basis of the practical project No. ALM-202310062530 on the theme "Organization of a laboratory for the creation of anticancer drugs", conducted at the Samarkand State University named after Sharof Rashidov.
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ANILINHOSILALARIDAN TRISIKLIK TRIAZOLO PIRIMIDINONLARNING UCH BOSQICHLISINTEZI
5-Amino-1-N-aril-1H-1,2,3-triazol etil efirlarining piperidin-2-on bilan kondensatsiya reaksiyasi 3 bosqichda olib borildi. Birinchi bosqichda fenil azid hosilalari, ikkinchi bosqichda 5-amino-1-N-aril-1H-1,2,3-triazol etil efirlari va uchinchi bosqichda yangi trisiklik triazolo[4,5-d]pirimidinon hosilalari olindi. Sintez qilingan yangi birikmalarning strukturaviy tuzilishi 1H, 13C YaMR va HRMS analizi yordamida o'rnatildi.
ТРЕХСТАДИЙНЫЙ СИНТЕЗ ТРИЦИКЛИЧЕСКИХ ТРИАЗОЛОПИРИМИДИНОНОВ ИЗ ПРОИЗВОДНЫХ АНИЛИНА
Реакцию конденсации этиловых эфиров 5-амино-1-^арил-1Н-1,2,3-триазола с пиперидин-2-оном проводили в 3 стадии. На первой стадии были получены производные фенилазида, на второй стадии - этиловые эфиры 5-амино-1-^арил-1Н-1,2,3-триазола, а также новые трициклические производные триазоло[4,5^]пиримидинона. полученное на третьем этапе. Строение полученных соединений установлено на основе 1H и 13C ЯМР спектроскопии и HRMS анализом.
THREE-STEP SYNTHESIS OF TRICYCLIC TRIAZOLO PYRIMIDINONES FROM ANILINE DERIVA TIVES
The condensation reaction of 5-amino-1-N-aryl-1H-1,2,3-triazole ethyl ethers with piperidin-2-one was carried out in 3 steps. Phenyl azide derivatives were obtained in the first step, 5-amino-1-N-aryl-1H-1,2,3-triazole ethyl ethers in the second step, and new tricyclic triazolo[4,5-d]pyrimidinone derivatives were obtained in the third step, and their structures were determined by 1H, 13C NMR and HRMS analysis.
