Method for synthesizing methylated aza-uracil derivative
By using DMSO and fluorescein to achieve the methylation reaction of azauracil under photocatalytic conditions, the dependence of traditional reactions on metal catalysts and strong oxidants is solved, and efficient, environmentally friendly and economical methylation effect is achieved.
Patent Information
- Application Number
- CN202411685427.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-22
- Publication Date
- 2025-02-28
AI Technical Summary
Traditional Fenton methylation reactions rely on metal catalysts and strong oxidants, limiting the mildness of the reaction conditions and increasing environmental pollution and cost burden.
Under photocatalytic conditions, DMSO is used as the methyl source and solvent, fluorescein as the photocatalyst and DABCO as the base to achieve the methylation reaction of azauracil, avoiding the use of metal catalysts and strong oxidants.
This method achieves efficient methylation of azauracil at room temperature, simplifies the reaction steps, reduces energy consumption and costs, and significantly improves the environmental protection and economicality of the reaction.
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Abstract
Description
Technical Field
[0001] The invention belongs to the field of organic synthetic chemistry, and specifically relates to a method for synthesizing methylated azauracil derivatives. Background Art
[0002] As the shining pearls in the chemical world, nitrogen heterocyclic compounds are widely active in many fields such as pharmaceutical chemistry and materials science. Their unique chemical structure and biological activity make many drug molecules and advanced materials use them as the core skeleton (LD Pennington, et al. Med. Chem. Res. 2023, 32, 1278–1293.). For example, nitrogen heterocyclic compounds are ubiquitous in caffeine, imidazole antifungal drugs and many anticancer drugs, and they protect human health with their excellent efficacy. Azauracil, as an important member of the nitrogen heterocyclic family, not only shows unique optoelectronic properties in materials science, but also shines in the fields of pharmaceuticals and biochemistry. Azauracil compounds, such as some antiviral drugs and DNA intercalators, have become star molecules in new drug development due to their specific biological activities (Pontillo J., et al, Bioorg. Med. Chem. Lett., 2005, 15 , 4363–4366; Hin N., et al, J. Med. Chem., 2015, 58 , 7258–7272.). In view of the wide application and important value of azauracil, the effective modification of its structure is of great significance for expanding its application range and improving drug activity. Direct CH bond functionalization reaction, as an efficient and green synthetic strategy, is undoubtedly the best way to achieve structural modification of azauracil.
[0003] As a multifunctional compound, dimethyl sulfoxide (DMSO) plays an important role in chemical synthesis (Q. Li., et al, Chem–Eur. J., 2023, 29 , e202302542.). Its importance is not only reflected in its role as an efficient solvent to promote the reaction, but also in its unique value as a methyl source, which provides rich possibilities for chemical modification. In particular, the application of DMSO in the Fenton methylation reaction (E. Jones-Mensah., et al, Synthesis, 2016, 48, 1421–1436; R. Caporaso., et al, Chem. Commun., 2016, 52, 12486–12489) demonstrates its great potential as a methyl donor. However, the traditional Fenton methylation reaction relies on metal catalysts and requires an equivalent amount of strong oxidant (such as hydrogen peroxide), which not only limits the mildness of the reaction conditions, but also increases environmental pollution and cost burden.
[0004] In view of this, our research work is dedicated to exploring new application pathways for DMSO as a methyl source, and has successfully achieved the methylation reaction of aza-uracil under photocatalytic conditions. In this innovative system, DMSO not only plays the role of a solvent, but also directly acts as a methylation reagent. Through photocatalysis and in situ generation of hydrogen peroxide strategies, a Fenton-like methylation reaction occurs, which effectively avoids the use of metal catalysts. There is no need to add a large amount of strong oxidants, and the reaction can be successfully completed at room temperature. This breakthrough not only simplifies the reaction steps, reduces energy consumption and costs, but also significantly improves the environmental friendliness and economy of the reaction, opening up a broader and greener prospect for the application of DMSO as a methyl source. Our research results have undoubtedly taken an important step in the field of DMSO chemistry and provided a more efficient and environmentally friendly new strategy for chemical synthesis. Summary of the invention
[0005] The present invention aims to break through the application limitation of DMSO as a methyl source, develop a photocatalytic methylation reaction of aza-uracil with DMSO, and construct diversified methylated aza-uracil derivatives through a direct CH bond activation strategy.
[0006] The idea of the present invention is to use azauracil as the starting material, DMSO as both a solvent and a methyl source, fluorescein as an efficient photocatalyst, DABCO as a base, and stir the reaction at room temperature under 10-watt 455-nanometer wavelength blue light irradiation. The present invention successfully achieves the efficient synthesis of methylated azauracil derivatives. This strategy cleverly uses the photocatalytic reaction mechanism to simulate the Fenton-like methylation process, effectively avoiding the use of metal catalysts and a large amount of strong oxidants. More importantly, the reaction can be successfully completed at room temperature and exhibits excellent functional group tolerance.
[0007] The purpose of the present invention is achieved through the following technical solutions.
[0008] A method for synthesizing methylated azauracil derivatives comprises the following steps:
[0009] In a glass reaction container, azauracil derivatives, DMSO, photocatalyst and base are added in proportion, and the reaction is stirred at room temperature under 10 watts of 455 nm wavelength blue light. After the reaction is completed, filtering is performed. Subsequently, the filtrate is extracted multiple times with ethyl acetate, and all organic phases containing the target component are combined. Then, the solvent is removed by reduced pressure rotary evaporation technology to obtain a preliminary product. Finally, column chromatography is used for separation and purification to obtain the target methylated azauracil derivative;
[0010] Further, the chemical reaction equation for preparing methylated azauracil derivatives is shown below:
[0011]
[0012] In the formula, R 1 is selected from the group consisting of benzyl, 4-methylbenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-trifluoromethylbenzyl, propyl, cyclohexyl, methyl, allyl and propargyl; R 2 One selected from the group consisting of benzyl, 4-methylphenyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-trifluoromethylbenzyl, ethyl, methyl, allyl and propargyl.
[0013] Furthermore, the photocatalyst is one of eosin Y, eosin Y disodium salt, rhodamine B, rhodamine 6G, rose Bengal, 4CzIPN, 9,10-phenanthrenequinone and fluorescein, preferably fluorescein.
[0014] Furthermore, the base is one of quinuclidine, Na2CO3, NaHCO3, K2CO3, morpholine, DBU, DABSO, TMEDA and DABCO, preferably DABCO.
[0015] Furthermore, the molar ratio of the azauracil derivative to DMSO is 1:15-50, preferably 1:26.
[0016] Furthermore, the molar ratio of the azauracil derivative to the photocatalyst is 1:0.01-0.5, preferably 1:0.08.
[0017] Furthermore, the molar ratio of the azauracil derivative to the base is 1:0.1-3, preferably 1:1.5.
[0018] Furthermore, the reaction time of the preparation method is 5 to 30 hours, preferably 22 hours.
[0019] Furthermore, the target product methylated azauracil derivative is purified by column chromatography, and the selected eluent is a composite solvent system of petroleum ether and ethyl acetate, the volume ratio of petroleum ether to ethyl acetate is between 1 and 100:1, and the preferred developing agent ratio is petroleum ether: ethyl acetate = 10:1.
[0020] The principle of the present invention is as follows: Fluorescein and DABCO first form an active catalyst EDA complex in the reaction system, and under the catalysis of the EDA complex, the azauracil derivative undergoes a single electron transfer and dehydrogenation reaction to produce an aryl radical intermediate; at the same time, oxygen in the air generates superoxide radical anions under the induction of the photocatalyst, and finally forms hydroxyl radicals under the action of water, and the hydroxyl radicals undergo a Fenton-like methylation reaction with DMSO to produce active methyl radicals. Finally, the methyl radicals capture the aryl radicals to generate methylated azauracil derivatives.
[0021] Compared with the prior art, the present invention has the following advantages and beneficial effects:
[0022] (1) The present invention realizes the photocatalytic coupling reaction of aza-uracil and DMSO, and constructs a series of methylated aza-uracil derivatives that are difficult to prepare. The reaction can be completed at room temperature and has excellent substrate universality;
[0023] (2) The present invention uses DMSO as a methyl source and achieves an efficient methylation reaction of aza-uracil in one step by a Fenton-like reaction. Compared with the prior art, the use of transition metal catalysts and strong oxidants is avoided, which significantly improves the economy and environmental protection of using DMSO as a methyl source. BRIEF DESCRIPTION OF THE DRAWINGS
[0024] Figure 1 , Figure 2 are the hydrogen spectrum and carbon spectrum of the target product obtained in Example 1;
[0025] Figure 3 , Figure 4 are the hydrogen spectrum and carbon spectrum of the target product obtained in Example 2;
[0026] Figure 5 , Figure 6 are the hydrogen spectrum and carbon spectrum of the target product obtained in Example 3;
[0027] Figure 7 , Figure 8 are the hydrogen spectrum and carbon spectrum of the target product obtained in Example 4; DETAILED DESCRIPTION
[0028] The present invention is further described below by means of specific examples, but the protection scope and implementation modes of the present invention are not limited thereto.
[0029] Example 1
[0030] In a glass test tube, weighed 2,4-dibenzylazauracil (0.1 mmol), DMSO (26 mmol), fluorescein (0.08 mmol) and DABCO (0.15 mmol) were added in sequence, and a stirrer was added. The reaction was stirred under magnetic stirring for 22 hours under 10-watt 455-nm wavelength blue light. After the reaction was completed, filtration was performed. Subsequently, the filtrate was extracted multiple times with ethyl acetate, and all organic phases containing the target component were combined. Then, the solvent was removed by reduced pressure rotary evaporation technology to obtain a preliminary product. Finally, the final product 6-methyl-2,4-dibenzylazauracil was purified by column chromatography with a yield of 82%.
[0031] The hydrogen and carbon spectra of the obtained target product are as follows Figure 1 and Figure 2 The structural characterization data are shown below:
[0032] 1 H NMR(500 MHz, Chloroform-d) δ 7.52 (d, J = 6.8 Hz, 2H), 7.43 (d, J= 7.0 Hz, 2H), 7.40-7.31 (m, 6H), 5.12 (d, J = 4.3 Hz, 4H), 2.27 (s, 3H). 13 CNMR (126 MHz, Chloroform-d) δ 156.21, 149.12, 142.84, 135.84, 135.61, 129.37,128.64, 128.56, 128.50, 128.11, 127.99, 55.10, 44.13, 16.89. HRMS calcd forC 18 H 17 N3O2H + [M+H] + : 308.1394; found 308.1392.
[0033] The structure of the target compound is inferred from the above characterization data as follows:
[0034]
[0035] Example 2
[0036] In a glass test tube, weighed 2,4-di(4-methylbenzyl)azauracil (0.1 mmol), DMSO (26 mmol), fluorescein (0.08 mmol) and DABCO (0.15 mmol) were added in sequence, and a stirrer was added. The reaction was stirred under 10-watt 455-nm wavelength blue light for 22 hours. After the reaction was completed, filtration was performed. Subsequently, the filtrate was extracted multiple times with ethyl acetate, and all organic phases containing the target component were combined. Then, the solvent was removed by reduced pressure rotary evaporation technology to obtain a preliminary product. Finally, the final product 6-methyl-2,4-di(4-methylbenzyl)azauracil was purified by column chromatography with a yield of 76%.
[0037] The hydrogen and carbon spectra of the obtained target product are as follows Figure 3 and Figure 4 The structural characterization data are shown below:
[0038] 1 H NMR (500 MHz, Chloroform-d) δ 7.40 (d, J = 7.7 Hz, 2H), 7.32 (d, J= 7.6 Hz, 2H), 7.17 (d, J = 7.6 Hz, 2H), 7.14 (d, J = 7.7 Hz, 2H), 5.06 (d, J= 6.1 Hz, 4H), 2.35 (s, 3H), 2.34 (s, 3H), 2.24 (s, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 156.22, 149.10, 142.74, 137.87, 137.74, 132.90, 132.71,129.40, 129.29, 129.14, 128.57, 54.83, 43.84, 21.09, 16.86. HRMS calcd forC 20 H 21 N3O2H + [M+H] + : 336.1707; found 336.1704.
[0039] The structure of the target compound is inferred from the above characterization data as follows:
[0040]
[0041] Example 3
[0042] In a glass test tube, weighed 2,4-di(4-fluorobenzyl)azauracil (0.1 mmol), DMSO (26 mmol), fluorescein (0.08 mmol) and DABCO (0.15 mmol) were added in sequence, and a stirrer was added. The reaction was stirred under 10-watt 455-nm wavelength blue light for 22 hours. After the reaction was completed, filtration was performed. Subsequently, the filtrate was extracted multiple times with ethyl acetate, and all organic phases containing the target component were combined. Then, the solvent was removed by reduced pressure rotary evaporation technology to obtain a preliminary product. Finally, the final product 6-methyl-2,4-di(4-fluorobenzyl)azauracil was purified by column chromatography with a yield of 73%.
[0043] The hydrogen and carbon spectra of the obtained target product are as follows Figure 5 and Figure 6 The structural characterization data are shown below:
[0044] 1 H NMR (400 MHz, Chloroform-d) δ 7.47 (ddd, J = 8.6, 5.3, 2.6 Hz,2H), 7.42-7.36 (m, 2H), 7.06-6.95 (m, 4H), 5.04 (d, J = 2.5 Hz, 4H), 2.23 (s,3H). 13 C NMR (101 MHz, Chloroform-d) δ 163.87, 163.73, 161.41, 161.28, 156.14,149.03, 143.03, 131.60, 131.57, 131.49, 131.41, 130.59, 130.51, 115.69,115.50, 115.48, 115.29, 54.45, 43.44, 16.90. 19 F NMR (376 MHz, Chloroform-d) δ-113.68 (d, J = 16.4 Hz). HRMS calcd for C 18 H 15 F2N3O2H + [M+H] + : 344.1205; found344.1208.
[0045] The structure of the target compound is inferred from the above characterization data as follows:
[0046]
[0047] Example 4
[0048] In a glass test tube, weighed 2,4-di(4-chlorobenzyl)azauracil (0.1 mmol), DMSO (26 mmol), fluorescein (0.08 mmol) and DABCO (0.15 mmol) were added in sequence, and a stirrer was added. The reaction was stirred under 10-watt 455-nm wavelength blue light for 22 hours. After the reaction was completed, filtration was performed. Subsequently, the filtrate was extracted multiple times with ethyl acetate, and all organic phases containing the target component were combined. Then, the solvent was removed by reduced pressure rotary evaporation technology to obtain a preliminary product. Finally, the final product 6-methyl-2,4-di(4-chlorobenzyl)azauracil was purified by column chromatography with a yield of 69%.
[0049] The hydrogen and carbon spectra of the obtained target product are as follows Figure 7 and Figure 8 The structural characterization data are shown below:
[0050] 1 H NMR (500 MHz, Chloroform-d) δ 7.44 (d, J = 8.0 Hz, 2H), 7.35 (t, J= 6.5 Hz, 4H), 7.30 (d, J = 8.4 Hz, 2H), 5.05 (d, J = 2.5 Hz, 4H), 2.26 (s,3H). 13 C NMR 13 C NMR (126 MHz, Chloroform-d) δ 156.08, 148.99, 143.10, 134.22,134.15, 134.06, 133.96, 130.92, 130.06, 128.88, 128.71, 54.48, 43.50, 16.89.HRMS calcd for C 18 H 15 Cl2N3O2H + [M+H] + : 376.0614; found 376.0613.
[0051] The structure of the target compound is inferred from the above characterization data as follows:
[0052]
[0053] Example 5
[0054] In a glass test tube, weighed 2,4-di(4-bromobenzyl)azauracil (0.1 mmol), DMSO (26 mmol), fluorescein (0.08 mmol) and DABCO (0.15 mmol) were added in sequence, and a stirrer was added. The reaction was stirred under 10-watt 455-nm wavelength blue light for 22 hours. After the reaction was completed, filtration was performed. Subsequently, the filtrate was extracted multiple times with ethyl acetate, and all organic phases containing the target component were combined. Then, the solvent was removed by reduced pressure rotary evaporation technology to obtain a preliminary product. Finally, the final product 6-methyl-2,4-di(4-bromobenzyl)azauracil was purified by column chromatography with a yield of 73%.
[0055] The structural characterization data of the obtained target product are shown below:
[0056] 1 H NMR (500 MHz, Chloroform-d) δ 7.49 (d, J = 8.3 Hz, 2H), 7.45 (d, J= 8.4 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 7.30 (s, 1H), 7.28 (s, 1H), 5.04 (d,J = 2.7 Hz, 4H), 2.25 (s, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 156.05,148.97, 143.10, 134.64, 134.45, 131.84, 131.68, 131.23, 130.37, 122.36,122.24, 54.53, 43.55, 16.89. HRMS calcd for C 18 H 15 Br2N3O2H + [M+H] + : 463.9604; found 463.9601.
[0057] The structure of the target compound is inferred from the above characterization data as follows:
[0058]
[0059] Example 6
[0060] In a glass test tube, weighed 2,4-bis(4-trifluoromethylbenzyl)azauracil (0.1mmol), DMSO (26 mmol), fluorescein (0.08 mmol) and DABCO (0.15 mmol) were added in sequence, and a stirrer was added. The reaction was stirred under 10-watt 455-nm wavelength blue light for 22 hours. After the reaction was completed, filtration was performed. Subsequently, the filtrate was extracted multiple times with ethyl acetate, and all organic phases containing the target component were combined. Then, the solvent was removed by reduced pressure rotary evaporation technology to obtain a preliminary product. Finally, the final product 6-methyl-2,4-bis(4-trifluoromethylbenzyl)azauracil was purified by column chromatography with a yield of 69%.
[0061] The structural characterization data of the obtained target product are shown below:
[0062] 1 H NMR (400 MHz, Chloroform-d) δ 7.66 (s, 1H), 7.64 (s, 1H), 7.62 (s,4H), 7.56 (s, 1H), 7.54 (s, 1H), 5.17 (s, 4H), 2.29 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 156.04, 149.05, 143.34, 139.50, 139.27, 130.69, 130.54,130.37, 130.21, 129.69, 128.90, 128.01, 125.77, 125.73, 125.69, 125.65,125.61, 125.58, 125.54, 125.50, 125.30, 122.60, 119.89, 54.66, 43.73, 16.89. 19 F NMR (376 MHz, Chloroform-d) δ -62.69 (d, J = 5.8 Hz). HRMS calcd forC 20 H 15 F6N3O2H + [M+H] + : 444.1141; found 444.1143.
[0063] The structure of the target compound is inferred from the above characterization data as follows:
[0064]
[0065] Example 7
[0066] In a glass test tube, weighed 2-ethyl-4-benzylazauracil (0.1 mmol), DMSO (26 mmol), fluorescein (0.08 mmol) and DABCO (0.15 mmol) were added in sequence, and a stirrer was added. The reaction was stirred under 10-watt 455-nm wavelength blue light for 22 hours. After the reaction was completed, filtration was performed. Subsequently, the filtrate was extracted multiple times with ethyl acetate, and all organic phases containing the target component were combined. Then, the solvent was removed by reduced pressure rotary evaporation technology to obtain a preliminary product. Finally, the final product 6-methyl-2-ethyl-4-benzylazauracil was purified by column chromatography with a yield of 68%.
[0067] The structural characterization data of the obtained target product are shown below:
[0068] 1 H NMR (500 MHz, Chloroform-d) δ 7.43 (d, J = 7.3 Hz, 2H), 7.36 (dt,J = 11.9, 6.6 Hz, 3H), 5.10 (s, 2H), 4.01 (q, J = 7.1 Hz, 2H), 2.26 (s, 3H),1.25 (t, J = 7.1 Hz, 3H). 13 HRMScalcd for C 13 H 15 N3O2H + [M+H] + : 246.1237; found 246.1237.
[0069] The structure of the target compound is inferred from the above characterization data as follows:
[0070]
[0071] Example 8
[0072] In a glass test tube, weighed 2-ethyl-4-propyl azauracil (0.1 mmol), DMSO (26 mmol), fluorescein (0.08 mmol) and DABCO (0.15 mmol) were added in sequence, and a stirrer was added. The reaction was stirred under 10-watt 455-nm wavelength blue light for 22 hours. After the reaction was completed, filtration was performed. Subsequently, the filtrate was extracted multiple times with ethyl acetate, and all organic phases containing the target component were combined. Then, the solvent was removed by reduced pressure rotary evaporation technology to obtain a preliminary product. Finally, the final product 6-methyl-2-ethyl-4-propyl azauracil was purified by column chromatography with a yield of 72%.
[0073] The structural characterization data of the obtained target product are shown below:
[0074] 1 H NMR (500 MHz, Chloroform-d) δ 3.99 (q, J = 7.0 Hz, 2H), 3.88 (t, J= 7.4 Hz, 2H), 2.23 (s, 3H), 1.76 (h, J = 7.3 Hz, 2H), 1.23 (t, J = 7.1 Hz,3H), 0.94 (t, J = 7.4 Hz, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 156.24,148.87, 142.23, 52.97, 36.04, 21.56, 16.81, 12.48, 10.91. HRMS calcd forC9H 15 N3O2H + [M+H] + : 198.1237; found 198.1238.
[0075] The structure of the target compound is inferred from the above characterization data as follows:
[0076]
[0077] Example 9
[0078] In a glass test tube, weighed 2-ethyl-4-cyclohexylazauracil (0.1 mmol), DMSO (26 mmol), fluorescein (0.08 mmol) and DABCO (0.15 mmol) were added in sequence, and a stirrer was added. The reaction was stirred under 10-watt 455-nm wavelength blue light for 22 hours. After the reaction was completed, filtration was performed. Subsequently, the filtrate was extracted multiple times with ethyl acetate, and all organic phases containing the target component were combined. Then, the solvent was removed by reduced pressure rotary evaporation technology to obtain a preliminary product. Finally, the final product 6-methyl-2-ethyl-4-cyclohexylazauracil was purified by column chromatography with a yield of 66%.
[0079] The structural characterization data of the obtained target product are shown below:
[0080] 1 H NMR (500 MHz, Chloroform-d) δ 4.53-4.46 (m, 1H), 3.98 (q, J = 7.1Hz, 2H), 2.22 (s, 3H), 1.87-1.77 (m, 4H), 1.71-1.63 (m, 3H), 1.39 (d, J =13.2 Hz, 2H), 1.24-1.16 (m, 4H). 13 C NMR (126 MHz, Chloroform-d) δ 155.88,148.70, 141.81, 57.41, 36.12, 30.74, 25.44, 25.14, 16.95, 12.49. HRMS calcdfor C 12 H 19 N3O2H + [M+H] + : 238.1550; found 238.1549.
[0081] The structure of the target compound is inferred from the above characterization data as follows:
[0082]
[0083] Example 10
[0084] In a glass test tube, weighed 2,4-dimethylazauracil (0.1 mmol), DMSO (26 mmol), fluorescein (0.08 mmol) and DABCO (0.15 mmol) were added in sequence, and a stirrer was added. The reaction was stirred under magnetic stirring for 22 hours under 10-watt 455-nm wavelength blue light. After the reaction was completed, filtration was performed. Subsequently, the filtrate was extracted multiple times with ethyl acetate, and all organic phases containing the target component were combined. Then, the solvent was removed by reduced pressure rotary evaporation technology to obtain a preliminary product. Finally, the final product 2,4,6-trimethylazauracil was purified by column chromatography with a yield of 80%.
[0085] The structural characterization data of the obtained target product are shown below:
[0086] 1 H NMR (500 MHz, Chloroform-d) δ 3.59 (s, 3H), 3.34 (s, 3H), 2.23 (s, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 156.68, 149.36, 141.96, 39.18, 27.05,16.71. HRMS calcd for C6H9N3O2H + [M+H] + : 156.0768; found 156.0770.
[0087] The structure of the target compound is inferred from the above characterization data as follows:
[0088]
[0089] Embodiment 11
[0090] In a glass test tube, weighed 2,4-diallylazauracil (0.1 mmol), DMSO (26 mmol), fluorescein (0.08 mmol) and DABCO (0.15 mmol) were added in sequence, and a stirrer was added. The reaction was stirred under magnetic stirring for 22 hours under 10-watt 455-nm wavelength blue light. After the reaction was completed, filtration was performed. Subsequently, the filtrate was extracted multiple times with ethyl acetate, and all organic phases containing the target component were combined. Then, the solvent was removed by reduced pressure rotary evaporation technology to obtain a preliminary product. Finally, the final product 6-methyl-2,4-diallylazauracil was purified by column chromatography with a yield of 68%.
[0091] The structural characterization data of the obtained target product are shown below:
[0092] 1 H NMR (500 MHz, Chloroform-d) δ 5.98-5.80 (m, 2H), 5.32-5.21 (m,4H), 4.53 (d, J = 6.6 Hz, 4H), 2.24 (s, 3H). 13 C NMR (126 MHz, Chloroform-d) δ156.04, 148.60, 142.77, 131.51, 130.36, 119.16, 118.87, 53.87, 42.87, 16.85.HRMS calcd for C 10 H 13 N3O2H + [M+H] + : 208.1081; found 208.1078.
[0093] The structure of the target compound is inferred from the above characterization data as follows:
[0094]
[0095] Example 12
[0096] In a glass test tube, weighed 2,4-propargyl azauracil (0.1 mmol), DMSO (26 mmol), fluorescein (0.08 mmol) and DABCO (0.15 mmol) were added in sequence, and a stirrer was added. The reaction was stirred under magnetic stirring for 22 hours under 10-watt 455-nm wavelength blue light. After the reaction was completed, filtration was performed. Subsequently, the filtrate was extracted multiple times with ethyl acetate, and all organic phases containing the target component were combined. Then, the solvent was removed by reduced pressure rotary evaporation technology to obtain a preliminary product. Finally, the final product 6-methyl-2,4-propargyl azauracil was purified by column chromatography with a yield of 54%.
[0097] The structural characterization data of the obtained target product are shown below:
[0098] 1 H NMR (500 MHz, Chloroform-d) δ 4.73 (s, 2H), 4.70 (s, 2H), 2.36 (s,1H), 2.30 (s, 3H), 2.22 (s, 1H). 13C NMR (126 MHz, Chloroform-d) δ 155.33,147.71, 143.52, 76.57, 73.37, 71.69, 41.13, 30.04, 16.86. HRMS calcd forC 10 H9N3O2H + [M+H] + : 204.0768; found 204.0771.
[0099] The structure of the target compound is inferred from the above characterization data as follows:
[0100]
[0101] The above-mentioned implementation modes are partial embodiments of the method of the present invention, but they do not limit the specific implementation modes of the present invention. Any other substitutions, basic skeleton changes, and condition simplifications made without departing from the spirit and principle of the present invention should be classified as equivalent replacement methods and are included in the protection scope of the present invention.
Claims
1. A method for synthesizing a methylated azauracil derivative, characterized in that: The following steps are included: In a glass reaction container, an aza-uracil derivative, DMSO, a photocatalyst and a base are added in proportion, and the reaction is stirred at room temperature under the irradiation of a 10-watt blue light, and the wavelength of the blue light is 455 nm; after the reaction is completed, a filtering operation is performed; then, the filtrate is extracted multiple times with ethyl acetate, and all organic phases containing the target component are combined; then, the solvent is removed by a reduced pressure rotary evaporation technique to obtain a preliminary product; finally, column chromatography is used for separation and purification to obtain the target methylated aza-uracil derivative; The above reaction is shown in the following formula: ； In the formula, R 1 is selected from the group consisting of benzyl, 4-methylbenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-trifluoromethylbenzyl, propyl, cyclohexyl, methyl, allyl and propargyl; R 2 The photocatalyst is selected from one of eosin Y, eosin Y disodium salt, rhodamine B, rhodamine 6G, Bengal rose red, 4CzIPN, 9,10-phenanthrenequinone and fluorescein; the base is selected from one of quinuclidine, Na2CO3, NaHCO3, K2CO3, morpholine, DBU, DABSO, TMEDA and DABCO.
2. The preparation method according to claim 1, characterized in that: The feeding molar ratio of the azauracil derivative to DMSO is 1:15-50.
3. The preparation method according to claim 1, characterized in that: The molar ratio of the aza-uracil derivative to the photocatalyst is 1:0.01-0.
5.
4. The preparation method according to claim 1, characterized in that: The molar ratio of the azauracil derivative to the base is 1:0.1-3.
5. The preparation method according to claim 1, characterized in that: The reaction time of the preparation method is 5 to 30 hours.
6. The preparation method according to claim 1, characterized in that: The target product, methylated azauracil derivative, is purified by column chromatography, and the selected eluent is a composite solvent system of petroleum ether and ethyl acetate, and the specific ratio is: the volume ratio of petroleum ether to ethyl acetate is 1-100:1.