6-trifluoroacetylated aza-uracil as well as visible light catalysis preparation method and application thereof

Abstract

The invention belongs to the field of organic synthesis, relates to a photocatalytic reaction, and in particular relates to 6-trifluoroacetylated aza-uracil as well as a visible light catalysis preparation method and application thereof, and realizes C-6-site trifluoroacetylation of aza-uracil. According to the method, oxygen in air is directly used as an oxidizing agent, additional addition of additives is avoided, and the method has the advantages of good functional group tolerance, easily available raw materials, simple operation, low experimental cost and the like. The method fills the gap of trifluoroacetylation of a 6-site C-H bond of azuracil, and post-modification of active molecules containing an azuracil skeleton can be realized through the trifluoroacetylation reaction of the method.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and relates to a photocatalytic reaction. BACKGROUND

[0002] Fluorine-containing compounds have unique physical and chemical properties. Among them, trifluoromethyl ketone is one of the important fluorine-containing skeletons, and widely exists in biologically active molecules (Chem. Commun., 2013, 49, 11133-11148). Azauracil is a basic structural unit of various biologically active molecules, and azauracil compounds modified based on the skeleton exhibit special physiological activity, including antiviral, antibacterial and antitumor activities (Poultry Science, 1989, 68, 489-495). Related drugs include diclazuril for treating coccidiosis, D-amino acid oxidase inhibitor for treating schizophrenia, and antiepileptic drugs. Therefore, it has important research significance and wide application prospect to introduce a trifluoroacetyl group into azauracil for modification.

[0003] However, there is currently no effective method to introduce a trifluoroacetyl group into 6-azauracil compounds for modification under mild conditions. There are two major challenges, namely, polarity mismatch and trifluoroacetyl radical instability, as follows:

[0004] (1) Azauracil compounds are a kind of electron-deficient azauracil, while trifluoroacetyl radicals have strong electrophilicity due to the strong electron-withdrawing effect of the trifluoromethyl group;

[0005] (2) Trifluoroacetyl radicals are unstable and can easily decarbonylate to form trifluoromethyl radicals.

[0006] Therefore, it has important research value and significance to solve the above problems and achieve trifluoroacetylation of azauracil under mild conditions. SUMMARY

[0007] To solve the above technical problems, the present application provides a 6-trifluoroacetylated azauracil and a visible light catalytic preparation method and application thereof.

[0008] The technical scheme of the present application is as follows:

[0009] The present application provides a preparation method for 6-masked trifluoroacetylated azauracil under visible light catalysis:

[0010] A series of 6-trifluoroacetylated azauracil derivatives (6-masked trifluoroacetylated azauracil) were efficiently synthesized by using masked trifluoroacetyl reagent as trifluoroacetyl radical precursor, azauracil as radical acceptor, under visible light catalysis, using oxygen in air as oxidant, cesium carbonate as base, 2,4,5,6-tetra(9-carbazolyl)-1,3-benzenediol as photocatalyst, dimethyl sulfoxide as solvent, under 460 nm, 10 W blue light irradiation for 12 hours at room temperature.

[0011] The specific steps are as follows:

[0012] A magnetic stirrer, a photocatalyst 2,4,5,6-tetra(9-carbazolyl)-1,3-benzenediol 4CzIPN, an azauracil compound, a masked trifluoroacetylated reagent, cesium carbonate Cs2CO3, and dimethyl sulfoxide DMSO are sequentially added to a general glass reaction tube, and a reaction is performed under 460 nm, 10 W blue light irradiation at room temperature in open air for 3-12 hours; after the reaction is completed, a saturated sodium chloride solution and dichloromethane are added for extraction, and an organic phase is collected. The obtained crude product is purified by silica gel column chromatography to obtain the product 6-masked trifluoroacetylated azauracil.

[0013] The technical route of step (1) is as follows:

[0014]

[0015] The structure of the prepared 6-masked trifluoroacetylated azauracil is as follows:

[0016]

[0017] wherein R 1 ,R 2 is Bn, Et, CH3CHCH2, CH2CHCH2, CH2CHCH;

[0018] The structure of the prepared 6-trifluoroacetylated azauracil is as follows:

[0019]

[0020] wherein R 1 ,R 2 is Bn, Et, CH3CHCH2, CH2CHCH2, CH2CHCH;

[0021] The structure of the azauracil is as follows:

[0022]

[0023] wherein R 1 ,R 2Bn, Et, CH3CHCH2, CH2CHCH2, CH2CHCH;

[0024] The trifluoroacetylated peroxide structural formula is as follows:

[0025]

[0026] Prepared according to the method reported in the literature (J. Am. Chem. Soc. 2023, 145, 11530-11536);

[0027] The photocatalyst 2,4,5,6-tetrakis (9-carbazolyl) -m-dinitrile, abbreviated as 4CzIPN, has the following structural formula:

[0028]

[0029] The molar ratio of the azauracil, the masked trifluoroacetylation reagent, cesium carbonate and 4CzIPN is 1:1.5-3:1.5-3:0.02-0.05.

[0030] The solvent is dimethyl sulfoxide. Dimethyl sulfoxide is abbreviated as DMSO.

[0031] The method for preparing 6-trifluoroacetylated azauracil using the above-mentioned 6-masked trifluoroacetylated azauracil,

[0032] The technical route is:

[0033] The step is: 6-masked trifluoroacetylated azauracil and boron tribromide are subjected to a deprotection reaction in dichloromethane to obtain 6-trifluoroacetylated azauracil.

[0034] The molar ratio of the above-mentioned 6-masked trifluoroacetylated azauracil and boron tribromide is 1:3.

[0035] The structural formula of the above-mentioned 6-trifluoroacetylated azauracil is as follows:

[0036] wherein R 1 is any one of Bn, Et, CH3CHCH2, CH2CHCH2 and CH2CHCH. 2

[0037] This method not only avoids the use of metal catalysts but also can directly use oxygen in the air as an oxidant, has mild conditions, raw materials are easy to obtain, is simple to operate, has low experimental cost, and for the first time provides a mild and efficient new method for trifluoroacetylation of azauracil at the C-6 position.

[0038] ​Further, the method can be used to realize post-modification of some bioactive molecules, including post-modification of ibuprofen and olsalazine after azauracil modification.

[0039] In addition, the application also provides application of the above-mentioned 6-masked trifluoroacetylated azauracil or the above-mentioned 6-trifluoroacetylated azauracil in preparation of a drug for inhibiting cancer cells.

[0040] The application has the following beneficial effects:

[0041] The application provides a method for constructing 6-trifluoroacetylated azauracil, which realizes trifluoroacetylation of C-6 of azauracil by using 4CzIPN as a photocatalyst under visible light irradiation. The method directly uses oxygen in air as an oxidant, avoids additional addition of additives, has good functional group tolerance, raw materials are easy to obtain, operation is simple, and experimental cost is low. The method fills the vacancy of trifluoroacetylation of C-H bond at 6 of azauracil, and the trifluoroacetylation reaction by the method can realize post-modification of active molecules containing an azauracil skeleton. Preliminary experimental results show that the method can realize fragment connection and trifluoroacetylation of drug molecules with a plurality of small organic molecules having drug activity. DETAILED DESCRIPTION

[0042] The technical solutions of the application will be described clearly and completely below with reference to the embodiments of the application. Obviously, the described embodiments are only some of the embodiments of the application, but not all the embodiments. Based on the embodiments in the application, all other embodiments obtained by those skilled in the art without creative effort fall within the protection scope of the application.

[0043] In the following experimental examples, the test methods are conventional methods unless otherwise specified; and the materials, reagents and the like used are reagents and materials that can be obtained through commercial channels unless otherwise specified.

[0044] Example 1

[0045] The preparation method of the 6-masked trifluoroacetylated azauracil in the embodiment is as follows:

[0046] A magnetic stirrer, N-benzyl-N'-benzylazauracil, i.e. 2,4-dibenzyl-1,2,4-triazine-3,5(2H,4H)-dione 0.2 mmol, masked trifluoroacetylation reagent 0.3 mmol, cesium carbonate 0.3 mmol, catalyst 4CzIP 2 mol%, and DMSO 2 mL were sequentially added to a general glass reaction tube, and the reaction was carried out under the irradiation of blue light of 460 nm, 10 W, at room temperature for 12 hours in an open air condition; after the reaction was completed, a saturated sodium chloride solution was added and dichloromethane was extracted, and the organic phase was collected. The obtained crude product was purified by silica gel column chromatography to obtain the product 6-masked trifluoroacetylated azauracil, with a yield of 78%.

[0047]

[0048] 1 H NMR (600 MHz, Chloroform-d) δ 7.43-7.42 (m, 2H), 7.41-7.39 (m, 2H), 7.33-7.31 (m, 3H), 7.30-7.27 (m, 3H), 5.07 (s, 2H), 5.02 (s, 2H), 4.47-4.45 (m, 2H), 4.28-4.26 (m, 2H). 13 C NMR (151 MHz, Chloroform-d) δ 153.2, 148.4, 135.8, 135.1, 134.8, 129.3, 129.2, 128.8, 128.6, 128.5, 128.1, 122.3 (q, J = 290.4 Hz), 104.2 (q, J = 31.6 Hz), 68.5, 55.9, 44.3. 19 F NMR (565 MHz, Chloroform-d) δ -78.36. HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 21 H 18 F3N3O4Na + 456.1142; Found 456.1124.

[0049] Example 2

[0050] The preparation method of 6-masked trifluoroacetylated azauracil of the present example is as follows:

[0051] A magnetic stir bar, 2-phenyl-4-benzyl-1,2,4-triazine-3,5(2H,4H)-dione 0.2 mmol, masked trifluoroacetylation reagent 0.3 mmol, cesium carbonate 0.6 mmol, catalyst 4CzIPN 5 mol%, and DMSO 2 mL were sequentially added to a common glass reaction tube, and the reaction was carried out under the irradiation of blue light at 460 nm, 10 W, at room temperature for 12 hours in an open air condition; after the reaction was completed, a saturated sodium chloride solution was added and dichloromethane was extracted, and the organic phase was collected. The obtained crude product was purified by silica gel column chromatography to obtain the product 6-masked trifluoroacetylated azauracil, with a yield of 61%.

[0052]

[0053] 1 H NMR (600 MHz, Chloroform-d) δ 7.52-7.50 (m, 4H), 7.45-7.42 (m, 2H), 7.38-7.36 (m, 1H), 7.33-7.30 (m, 3H), 5.14 (s, 2H), 4.54-4.52 (m, 2H), 4.33-4.31 (m, 2H). 13 CNMR (151 MHz, Chloroform-d) δ 152.9, 147.9, 139.8, 136.5, 135.1, 129.7, 128.9, 128.7, 128.3, 124.6, 122.3 (q, J = 290.2 Hz), 104.2 (q, J = 31.7 Hz), 68.6, 44.5. 19 F NMR (565 MHz, Chloroform-d) δ -78.5. HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 20 H 16 F3N3O4Na + 442.0985; Found 442.0965.

[0054] Example 3

[0055] The preparation method of 6-masked trifluoroacetylated azauracil of the present example is as follows:

[0056] A magnetic stirrer, 2-propyl-4-ethyl-1,2,4-triazine-3,5(2H,4H) dione 0.2 mmol, masked trifluoroacetylation reagent 0.6 mmol, cesium carbonate 0.3 mmol, catalyst 4CzIPN 5 mol%, and DMSO 2 mL were sequentially added into a common glass reaction tube, and the reaction was carried out under the irradiation of blue light at 460 nm, 10 W, at room temperature for 12 hours under open air conditions; after the reaction was completed, a saturated sodium chloride solution was added and dichloromethane was extracted, and the organic phase was collected. The obtained crude product was purified by silica gel column chromatography to obtain the product 6-masked trifluoroacetylated azauracil, with a yield of 52%.

[0057]

[0058] 1 H NMR (600 MHz, Chloroform-d) δ 4.50-4.48 (m, 2H), 4.32-4.30 (m, 2H), 4.04 (q, J = 7.2 Hz, 2H), 3.88-3.85 (m, 2H), 1.70-1.63 (m, 2H), 1.33 (t, J = 7.2 Hz, 3H), 0.96 (t, J = 7.5 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 153.3, 148.3, 135.4, 122.3 (q, J = 290.3 Hz), 104.2 (q, J = 31.5 Hz), 68.5, 47.1, 42.6, 20.5, 13.1, 11.3. 19 F NMR (565 MHz, Chloroform-d) δ -78.5. HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 12 H 16 F3N3O4Na + 346.0985; Found 346.0970.

[0059] Example 4

[0060] The preparation method of 6-masked trifluoroacetylated azauracil in this example is as follows:

[0061] Subsequently, a magnetic stirrer, 2,4-diallyl-1,2,4-triazine-3,5(2H,4H) dione 0.2 mmol, masked trifluoroacetylation reagent 0.4 mmol, cesium carbonate 0.3 mmol, catalyst 4CzIPN 2 mol%, and DMSO 2 mL were sequentially added to a general glass reaction tube, and the reaction was performed under the irradiation of blue light of 460 nm, 10 W, at room temperature for 12 hours under open air conditions; after the reaction was completed, saturated sodium chloride solution was added and dichloromethane was extracted, and the organic phase was collected. The obtained crude product was purified by silica gel column chromatography to obtain the product 6-masked trifluoroacetylated azauracil, with a yield of 56%.

[0062]

[0063] 1 H NMR (600 MHz, Chloroform-d) δ 5.96 - 5.91 (m, 1H), 5.90 - 5.81 (m, 1H), 5.33 (s, 1H), 5.30 (s, 2H), 5.28 - 5.25 (m, 1H), 4.57 (d, J = 6.2 Hz, 2H), 4.52 (d, J = 6.0 Hz, 2H), 4.50 - 4.48 (m, 2H), 4.31 - 4.29 (m, 2H). 13 C NMR (151 MHz, Chloroform-d) δ 152.9, 148.0, 135.8, 130.6, 129.9, 122.2 (q, J = 290.2 Hz), 120.1, 119.6, 104.1 (q, J = 31.6 Hz), 68.5, 54.4, 43.0. 19 F NMR (565 MHz, Chloroform-d) δ -78.5. HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 13 H 14 F3N3O4Na + 356.0829; Found 356.0809.

[0064] Example 5

[0065] The preparation method of 6-masked trifluoroacetylated azauracil of the present example is as follows:

[0066] Subsequently, a magnetic stirrer, 2,4-dipropargyl-1,2,4-triazine-3,5(2H,4H) dione 0.2 mmol, masked trifluoroacetylation reagent 0.3 mmol, cesium carbonate 0.3 mmol, catalyst 4CzIPN 2 mol%, and DMSO 2 mL were sequentially added to a general glass reaction tube, and the reaction was performed under the irradiation of blue light of 460 nm, 10 W, at room temperature for 12 hours under open air conditions; after the reaction was completed, saturated sodium chloride solution was added and dichloromethane was extracted, and the organic phase was collected. The obtained crude product was purified by silica gel column chromatography to obtain the product 6-masked trifluoroacetylated azauracil, with a yield of 71%.

[0067]

[0068] 1 H NMR (600 MHz, Chloroform-d) δ 4.77 (d, J = 2.5 Hz, 2H), 4.68 (d, J = 2.5 Hz, 2H), 4.52 - 4.50 (m, 2H), 4.33 - 4.31 (m, 2H), 2.40 (t, J = 2.5 Hz, 1H), 2.25 (t, J = 2.5 Hz, 1H). 13 CNMR (151 MHz, Chloroform-d) δ 152.2, 147.1, 136.4, 122.1 (q, J = 290.1 Hz), 103.9 (q, J = 32.1 Hz), 76.0, 75.8, 74.3, 72.1, 68.6, 42.0, 30.1. 19 F NMR (565 MHz, Chloroform-d) δ -78.59. HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 13 H 10 F3N3O4Na + 352.0516; Found 352.0496.

[0069] Example 6

[0070] The preparation method of 6-masked trifluoroacetylated azauracil of the present example is as follows:

[0071] A magnetic stirrer, 2-(2-hydroxyethyl)-4-(4-methylbenzyl)-1,2,4-triazine-3,5(2H,4H) dione 0.2 mmol, masked trifluoroacetylation reagent 0.3 mmol, cesium carbonate 0.3 mmol, catalyst 4CzIPN 2 mol%, and DMSO 2 mL were sequentially added to a general glass reaction tube, and the reaction was carried out under the irradiation of blue light of 460 nm, 10 W, at room temperature for 12 hours under open air conditions; after the reaction was completed, saturated sodium chloride solution was added and dichloromethane was extracted, and the organic phase was collected. The obtained crude product was purified by silica gel column chromatography to obtain the product 6-masked trifluoroacetylated azauracil, with a yield of 65%.

[0072]

[0073] 1 H NMR (600 MHz, DMSO-d6) δ 7.23 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 7.9 Hz, 2H), 4.93 (s, 2H), 4.85-4.83 (m, 1H), 4.41-4.38 (m, 2H), 4.25-4.23 (m, 2H), 3.97-3.95 (m, 2H), 3.68-3.65 (m, 2H), 2.27 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 153.5, 149.1, 137.2, 135.0, 133.1, 129.4, 128.5, 122.8 (q, J = 290.7 Hz), 104.1 (q, J = 30.7 Hz), 68.7, 58.4, 54.2, 43.9, 21.1. 19 F NMR (565 MHz, DMSO-d6) δ -77.30. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 17 H 19 F3N3O5 + 402.1271; Found 402.1258.

[0074] Example 7

[0075] The preparation method of 6-masked trifluoroacetylated azauracil 6 of this example is as follows:

[0076]

[0077] A magnetic stir bar, compound 5 0.2 mmol, masked trifluoroacetylation reagent 0.3 mmol, cesium carbonate 0.3 mmol, catalyst 4CzIPN 2 mol%, and DMSO 2 mL were sequentially added to a common glass reaction tube, and the reaction was carried out under the irradiation of blue light at 460 nm, 10 W, at room temperature for 12 hours in an open air condition; after the reaction was completed, saturated sodium chloride solution was added and dichloromethane was extracted, and the organic phase was collected. The obtained crude product was purified by silica gel column chromatography to obtain the product 6-masked trifluoroacetylated azauracil 6, with a yield of 84%.

[0078]

[0079] 1 H NMR (600 MHz, Chloroform-d) δ 7.44-7.43 (m, 2H), 7.33-7.28 (m, 3H), 7.11 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H), 5.03 (s, 2H), 4.50-4.48 (m, 2H), 4.47-4.44 (m, 1H), 4.31-4.25 (m, 2H), 4.24-4.20 (m, 2H), 4.14-4.10 (m, 1H), 3.58-3.55 (m, 1H), 2.42 (d, J = 7.1 Hz, 2H), 1.86-1.79 (m, 1H), 1.41 (d, J = 7.2 Hz, 3H), 0.89 (d, J = 6.6 Hz, 6H). 13 C NMR (151 MHz, Chloroform-d) δ 174.5, 153.0, 148.5, 140.6, 137.4, 136.1, 135.1, 129.34, 129.29, 128.6, 128.2, 127.1, 122.3 (q, J = 290.3 Hz), 104.1 (q, J = 31.7 Hz), 68.5, 61.1, 50.9, 45.1, 44.8, 44.2, 30.2, 22.4, 18.3. 19 F NMR (565 MHz, Chloroform-d) δ -78.46. HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 29 H 32 F3N3O6Na + 598.2135; Found 598.2114.

[0080] Example 8

[0081] The preparation method of 6-masked trifluoroacetylated azauracil 8 of this example is as follows:

[0082]

[0083] A magnetic stir bar, compound 7 0.2 mmol, masked trifluoroacetylation reagent 0.3 mmol, cesium carbonate 0.3 mmol, catalyst 4CzIPN 2 mol%, and DMSO 2 mL were sequentially added to a common glass reaction tube, and the reaction was carried out under the irradiation of blue light of 460 nm, 10 W, at room temperature for 12 hours in an open air condition; after the reaction was completed, a saturated sodium chloride solution was added and dichloromethane was extracted, and the organic phase was collected. The obtained crude product was purified by silica gel column chromatography to obtain product 6-masked trifluoroacetylated azauracil 8, with a yield of 75%.

[0084]

[0085] 1 H NMR (600 MHz, Chloroform-d) δ 7.63 (d, J = 7.1 Hz, 2H), 7.57 (d, J = 7.0 Hz, 2H), 7.37 - 7.31 (m, 8H), 7.11 (s, 2H), 5.02 (s, 2H), 4.49 - 4.47 (m, 2H), 4.44 - 4.42 (m, 2H), 4.29 - 4.27 (m, 2H), 4.25 - 4.23 (m, 2H), 3.13 - 3.11 (m, 2H), 2.84 - 2.81 (m, 2H), 2.27 (s, 3H). 13 CNMR (151 MHz, Chloroform-d) δ 171.8, 161.6, 153.0, 148.6, 145.4, 138.0, 136.1, 135.1, 132.5, 132.1, 129.29, 129.28, 128.63, 128.55, 128.4, 128.1, 127.9, 126.5, 122.3 (q, J = 290.5 Hz), 104.1 (q, J = 31.5 Hz), 68.5, 61.3, 51.0, 44.0, 30.7, 23.3, 21.1. 19 F NMR (565 MHz, Chloroform-d) δ -78.5. HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 35 H 31 F3N4O7Na + 699.2037; Found 699.2043.

[0086] Example 9

[0087] The preparation method of the 6-masked trifluoroacetylated azauracil 9 of the present embodiment is as follows:

[0088]

[0089] A magnetic stirrer, compound 8 0.2 mmol, masked trifluoroacetylated reagent 0.3 mmol, cesium carbonate 0.3 mmol, catalyst 4CzIPN 2 mol%, and DMSO 2 mL were sequentially added to a general glass reaction tube, and the reaction was carried out under the irradiation of blue light of 460 nm, 10 W, at room temperature for 12 hours under open air conditions; after the reaction was completed, saturated sodium chloride solution and dichloromethane were added for extraction, and the organic phase was collected. The obtained crude product was purified by silica gel column chromatography to obtain the product 6-masked trifluoroacetylated azauracil 9, with a yield of 74%.

[0090]

[0091] 1 H NMR (600 MHz, Chloroform-d) δ 7.40 (d, J = 7.7 Hz, 2H), 7.28 (d, J = 7.3 Hz, 3H), 7.08-7.07 (m, 2H), 6.73-6.72 (m, 2H), 4.96 (s, 2H), 4.51-4.48 (m, 2H), 4.44 (t, J = 4.5 Hz, 2H), 4.32-4.29 (m, 2H), 4.25-4.18 (m, 2H), 2.82 (d, J = 10.6 Hz, 1H), 1.93 (d, J = 10.7 Hz, 1H), 1.78-1.75 (m, 1H), 1.50 (s, 6H). 13 C NMR (151 MHz, Chloroform-d) δ 174.0, 154.8, 152.9, 148.4, 136.2, 135.0, 129.7, 129.3, 128.6, 128.2, 122.2 (q, J = 290.1 Hz), 118.6, 104.1 (q, J = 31.6 Hz), 79.0, 68.6, 61.8, 60.9, 50.4, 44.3, 34.8, 25.9, 25.3, 25.1. 19 F NMR (565 MHz, Chloroform-d) δ -78.4. HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 29 H 28 Cl2F3N3O7Na + 680.1149; Found 680.1117.

[0092] Example 10

[0093] The preparation method of 6-masked trifluoroacetylated azauracil 9 of this example is as follows:

[0094]

[0095] A magnetic stirrer, compound 9 0.2 mmol, masked trifluoroacetylated reagent 0.3 mmol, cesium carbonate 0.3 mmol, catalyst 4CzIPN 2 mol%, and DMSO 2 mL were sequentially added to a general glass reaction tube, and the reaction was carried out under the irradiation of blue light of 460 nm, 10 W, at room temperature for 12 hours under open air conditions; after the reaction was completed, saturated sodium chloride solution and dichloromethane were added for extraction, and the organic phase was collected. The obtained crude product was purified by silica gel column chromatography to obtain the product 6-masked trifluoroacetylated azauracil 10, with a yield of 81%.

[0096]

[0097] 1 H NMR (600 MHz, Chloroform-d) δ 8.46 (d, J = 7.9 Hz, 1H), 8.19 (d, J = 7.5, Hz, 1H), 7.78-7.77 (m, 2H), 7.51 (d, J = 7.4 Hz, 3H), 7.40-7.37 (m, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 7.8 Hz, 2H), 4.94 (s, 2H), 4.65-4.64 (m, 2H), 4.43-4.41 (m, 2H), 4.35-4.34 (m, 2H), 4.25-4.23 (m, 2H), 2.29 (s, 3H), 2.25 (s, 3H). 13 C{ 1 H} NMR (151 MHz, Chloroform-d) δ 178.2, 163.7, 161.0, 154.7, 152.9, 148.6, 138.0, 136.4, 136.2, 133.0, 132.0, 131.1, 130.5, 129.3, 129.24, 129.23, 128.4, 123.9, 123.2, 122.1 (q, J = 290.5 Hz), 119.6, 117.6, 104.0 (q, J = 31.7 Hz), 68.5, 61.9, 51.2, 44.0, 21.2, 11.8. 19 F NMR (565 MHz, Chloroform-d) δ -78.56. HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C34 H 28 F3N3O8Na + 686.1721 ; Found 686.1697.

[0098] Application Example 1

[0099] The preparation method of 6-trifluoroacetylated azauracil 4 is as follows:

[0100]

[0101] A magnetic stirrer, compound 3 0.2 mmol, and DCM 2 mL were sequentially added to a general glass reaction tube, and cooled to 0°C and stirred. Then, BBr3(0.6 mmol) was slowly added dropwise, and reacted at 0°C for 30 minutes; after the reaction was completed, 10 mL of water was slowly added dropwise to quench the reaction, and the mixture was allowed to warm to room temperature while stirring, and then saturated sodium chloride solution and dichloromethane were added to extract, and the organic phase was collected. The obtained crude product was purified by silica gel column chromatography to obtain the product 6-trifluoroacetylated azauracil 4, with a yield of 73%.

[0102]

[0103] 1 H NMR (600 MHz, Chloroform-d) δ 7.47 (d, J = 7.0 Hz, 2H), 7.43 (d, J = 6.8 Hz, 2H), 7.37 - 7.33 (m, 3H), 7.29 - 7.24 (m, 3H), 5.21 (s, 2H), 5.03 (s, 2H). 13 C NMR (151 MHz, Chloroform-d) δ 173.8 (q, J = 36.0 Hz), 152.0, 147.7, 134.5, 133.6, 131.4, 129.9, 129.4, 129.1, 129.0, 128.7, 128.6, 115.7 (q, J = 292.1 Hz), 57.1, 44.7. 19 F NMR (565 MHz, Chloroform-d) δ -72.05. HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 19 H 14 F3N3O3Na + 412.0879; Found 412.0860.

[0104] Implementation Effect Example

[0105] Example 1-10 prepared 6-masked trifluoroacetylated azauracil 10, and the application of example 1 prepared 6-trifluoroacetylated azauracil 4 in the study of anticancer activity:

[0106] (1) with cervical cancer cell Hela system as a model, using CellTiter-Glo (Promega, USA) test method, the specific test method is as follows:

[0107] After the cancer cell suspension was diluted to the appropriate concentration with the culture medium, 95 μL was added to the 96-well plate. After adding 5 μL of different concentrations of test compounds to it, the culture plate was incubated at 37℃, 5% CO2 for 72 hours. The culture plate was taken out and placed at room temperature to start testing. 20 μL of CellTiter-Glo reagent was added to each well, mixed on a shaker for 2 minutes to induce cell lysis. Incubate at room temperature for 10 minutes to stabilize the fluorescence signal. Use a multifunctional enzyme marker to record the fluorescence intensity. According to the formula and the fluorescence intensity of the blank control group, the cell viability was calculated, and then the IC50 of the target compound was calculated.

[0108] (2) with human colon cancer cell HCT116 system as a model, using CellTiter-Glo (Promega, USA) test method, the specific test method is as follows:

[0109] After the cancer cell suspension was diluted to the appropriate concentration with the culture medium, 95 μL was added to the 96-well plate. After adding 5 μL of different concentrations of test compounds to it, the culture plate was incubated at 37℃, 5% CO2 for 72 hours. The culture plate was taken out and placed at room temperature to start testing. 20 μL of CellTiter-Glo reagent was added to each well, mixed on a shaker for 2 minutes to induce cell lysis. Incubate at room temperature for 10 minutes to stabilize the fluorescence signal. Use a multifunctional enzyme marker to record the fluorescence intensity. According to the formula and the fluorescence intensity of the blank control group, the cell viability was calculated, and then the IC50 of the target compound was calculated.

[0110] The results are shown in Table 1:

[0111]

[0112] As shown in Table 1, the masked 6-masked trifluoroacetylated azauracil in the examples showed certain anticancer activity against cervical cancer and colon cancer, among which the masked 6-masked trifluoroacetylated azauracil 10 showed the best anticancer activity against HELA cervical cancer cells, with an IC 50 = 10.356 μmol / L, and also had good anticancer activity against human colon cancer cells HCT116, with an IC 50= 10.01 μmol / L. The 6-trifluoroacetylated azalide 4 prepared in Application Example 1 also showed certain anticancer activity against cervical cancer and colon cancer, with IC 50 were 10.356 μmol / L and 15.325 μmol / L, respectively, compared with the IC 50 were 34.788 μmol / L and 21.056 mol / L, respectively, which was 2.36 times the anticancer activity against cervical cancer and 0.27 times the anticancer activity against colon cancer. Thus, the above results show that the compound prepared in the present application has certain antitumor activity.

[0113] The above merely describes preferred embodiments of the present application and is not intended to limit the present application, and any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.

Claims

1. A method for preparing 6-masked trifluoroacetylated azauracil by visible light photocatalysis, characterized in that, The steps are as follows: Azauracil compounds, masked trifluoroacetylation reagents, cesium carbonate, 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile and dimethyl sulfoxide are mixed and stirred to react. The resulting reaction solution is purified by extraction and silica gel column chromatography to obtain 6-masked trifluoroacetylated azauracil.

2. The method for preparing 6-masked trifluoroacetylated azauracil by visible light catalysis according to claim 1, characterized in that, The structural formula of the azauracil compounds is as follows: In the formula R 1 , R 2 It is any one of Bn, Et, CH3CHCH2, CH2CHCH2, and CH2CHCH; The structural formula of the masked trifluoroacetylation reagent is: .

3. The method for preparing 6-masked trifluoroacetylated azauracil by visible light catalysis according to claim 2, characterized in that: The molar ratio of the azauracil compound, the masked trifluoroacetylated reagent, cesium carbonate, and 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile is 1:1.5-3:1.5-3:0.02-0.

05.

4. The method for preparing 6-masked trifluoroacetylated azauracil by visible light catalysis according to claim 3, characterized in that, The conditions for the stirring reaction are: irradiation with 460nm, 10W blue light at room temperature, and a reaction time of 3-12 hours.

5. A 6-masked trifluoroacetylazuraidine prepared by the method according to any one of claims 1-4, characterized in that, The structural formula of the 6-masked trifluoroacetylated azauramine is: In the formula R 1 , R 2 It is any one of Bn, Et, CH3CHCH2, CH2CHCH2 and CH2CHCH.

6. A method for preparing 6-trifluoroacetazolarimidine using the 6-masked trifluoroacetazolarimidine of claim 5, characterized in that, The steps are as follows: 6-masked trifluoroacetylazuraidine and boron tribromide undergo a deprotection reaction in dichloromethane to obtain 6-trifluoroacetylazuraidine.

7. The method according to claim 6, characterized in that: The molar ratio of the 6-masked trifluoroacetylazuraidine to boron tribromide is 1:

3.

8. The method according to claim 7, characterized in that: The structural formula of the 6-trifluoroacetylated azauracil is as follows: , where R 1 , R 2 It is any one of Bn, Et, CH3CHCH2, CH2CHCH2 and CH2CHCH.

9. 6-Trifluoroacetylazuracil prepared by the method of claim 8.

10. The use of the 6-masked trifluoroacetylazuracil of claim 5 or the 6-trifluoroacetylazuracil of claim 9 in the preparation of a drug for inhibiting cancer cells.

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