A process for the preparation of 6-alkylazauracil compounds

Abstract

The present application relates to the technical field of drug molecule modification methodology, in particular to a preparation method of 6-alkyl azauracil compound, comprising: mixing azauracil derivative, iodine reagent, alkylating reagent and solvent, and performing reaction under light irradiation, then sequentially performing extraction, reduced pressure distillation and purification after the reaction is completed, to obtain the 6-alkyl azauracil compound. The present application breaks the C-C bond of the alkylating reagent (alcohol) to form alkyl radicals based on the efficient and universal method, to realize the C-H alkylation reaction of azauracil, to obtain the target product with excellent yield, and the substrate is widely applicable, without metal catalysis, inert gas protection and additional photocatalyst, and the alcohol raw material does not need pre-functionalization, to provide a new method for azauracil alkylation.

Description

Technical Field

[0001] This invention relates to the field of drug molecule modification methodology, and in particular to a method for preparing a 6-alkylazauracil compound. Background Technology

[0002] Azauracil is a dominant nitrogen-containing heterocyclic skeleton widely found in natural products and drug molecules, and is recognized as one of the core pharmacodynamic groups in medicinal chemistry. Many marketed and investigational drug molecules, including the anticoccidial drug diclazuril and cMet kinase inhibitors, all contain an azauracil core in their core pharmacodynamic structure. Therefore, developing green, efficient, and simple synthetic methods to achieve precise structural modification of the azauracil skeleton is of great practical significance for new drug development and the optimization of drug molecules' late-stage drug-like properties.

[0003] Direct CH functionalization of the azauracil core is a core strategy for rapidly constructing structurally diverse azauracil derivatives. However, existing direct CH alkylation reactions of the azauracil skeleton still have the following drawbacks: Alkylating reagents used for the CH alkylation of azauracil in existing technologies mainly include thioylides, halogenated hydrocarbons, 1,4-dihydropyridines (DHPs), diacid peroxides, N-hydroxyphthalimide (NHPI) carboxylates, cyclobutanone oxime esters, and alkylpyridinium salts. Most of these reagents are not commercially available on a large scale and require pre-synthesis from aldehydes, carboxylic acids, or halogenated hydrocarbons, resulting in long synthetic routes, high raw material costs, and difficulty in meeting the cost control requirements of industrial production. Secondly, to achieve the above alkylation conversion, existing technologies mainly employ transition metal catalysis and photocatalysis. Transition metal catalytic systems typically use manganese, iridium, and cobalt compounds as catalysts, which are expensive, and the metal residues in the reaction products are difficult to remove completely, failing to meet the stringent quality control standards for metal impurities in drug intermediates in the pharmaceutical field.

[0004] In photocatalytic systems, the addition of precious metal photocatalysts such as iridium and ruthenium, or photosensitizers such as organic dyes, not only further increases production costs but also adds to the difficulty of post-processing purification and environmental burden. Furthermore, existing uracil and azauracil CH alkylation reactions generally suffer from excessively long reaction times, with most systems taking tens of hours. This not only leads to low overall production efficiency and high energy consumption but also easily triggers side reactions and reduces product purity, making it difficult to meet the needs of large-scale industrial production.

[0005] In summary, existing aziridine CH alkylation technology has consistently failed to simultaneously achieve the balance between raw material availability, environmental friendliness of the reaction, and high production efficiency. Summary of the Invention

[0006] The purpose of this invention is to provide a method for preparing 6-alkylazauracil compounds, so as to overcome the defects existing in the preparation process of 6-alkylazauracil compounds in the prior art.

[0007] To achieve the above objectives, the present invention provides a method for preparing a 6-alkylazauracil compound, comprising the following steps: The aziridine derivative, iodine reagent, alkylating agent and solvent were mixed and subjected to Minisci reaction under light. After the reaction was completed, the mixture was extracted, distilled under reduced pressure and purified to obtain the 6-alkylaziridine compound. The structural formula of the azauracil derivative is shown in Formula 1: ; R1 is selected from hydrogen, benzyl, naphthalenebenzyl, alkyl, alkenyl-substituted alkyl, alkynyl-substituted alkyl, or ester-substituted alkyl. R2 is selected from hydrogen, benzyl, naphthalenebenzyl, alkyl, alkenyl-substituted alkyl, alkynyl-substituted alkyl, or ester-substituted alkyl; The structural formula of the alkylating agent is shown in Formula 2: ; R3 is selected from cyclic hydrocarbons, cyclic hydrocarbon derivatives, or alcohols. The structural formula of the 6-alkylazine uracil compound is shown in Formula 3: .

[0008] In this invention, the alkyl group R1 includes methyl, propyl, butyl, or hexyl; the alkenyl-substituted alkyl group R1 includes allyl or 1-butenyl; the alkynyl-substituted alkyl group R1 includes propynyl or butynyl; the ester-substituted alkyl group R1 includes propyl-2-(4-isobutylphenyl)-propionate; the alkyl group R2 includes methyl, propyl, butyl, or hexyl; the alkenyl-substituted alkyl group R2 includes allyl or 1-butenyl; the alkynyl-substituted alkyl group R2 includes propynyl or butynyl; the ester-substituted alkyl group R2 includes propyl-2-(4-isobutylphenyl)-propionate.

[0009] In this invention, the cyclic hydrocarbon R3 includes cyclobutane, cyclohexane, or cyclopentane; the cyclic hydrocarbon derivative includes cyclooctane-methanol; and the alcohol compound includes primary alcohol, secondary alcohol, or tertiary alcohol.

[0010] In this invention, the primary alcohol includes tert-butylmethanol (CAS No. 75-84-3), hydroxyacetone (CAS No. 204-124-8), 2-hydroxyacetophenone (CAS No. 582-24-1), or ester-substituted hydroxymethanol; the ester-substituted hydroxymethanol includes 1,2-ethylene glycol monoacetate (CAS No. 542-59-6); the secondary alcohol includes 2,4-dimethyl-3-pentanol (CAS No. 600-36-2), sec-butanol (CAS No. 78-92-2), 3-pentanol (CAS No. 584-02-1), or 2,2,4-trimethyl-1,3-pentanediol (CAS No. 144-19-4); and the tertiary alcohol includes 2-hydroxy-2-methylpropanone (CAS No. 7473-98-5).

[0011] In this invention, the iodine reagent is selected from iodophenyldiacetic acid (CAS No. 3240-34-4), benzyl iodide (CAS No. 887144-94-7), sodium iodide, tetrabutylammonium iodide (CAS No. 311-28-4), N-iodosuccinimide (CAS No. 516-12-1), or [bis(trifluoroacetoxy)iodo]benzene (CAS No. 2712-78-9), preferably [bis(trifluoroacetoxy)iodo]benzene. The solvent is selected from ethanol, acetonitrile, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide, or N,N-dimethylacetamide, preferably acetonitrile.

[0012] In this invention, the alkylating agent is preferably isobutanol (CAS No. 78-83-1), neopentyl alcohol (CAS No. 75-84-3), acetone alcohol (CAS No. 116-09-6), adamantane methanol (CAS No. 770-71-8), 1,2-propanone glycerol (CAS No. 100-79-8), cyclobutylmethanol (CAS No. 4415-82-1), 2-methylbutanol (CAS No. 137-32-6), 2,4-dimethyl-3-pentanol (CAS No. 600-36-2), or isopropanol (CAS No. 67-63-0).

[0013] In this invention, the molar ratio of the azauracil derivative to the iodine reagent is 1:1-9, preferably 1:3.

[0014] In this invention, the molar ratio of the azauracil derivative to the alkylating agent is 1:1-20, preferably 1:1-10.

[0015] In this invention, under the illumination conditions, the emission wavelength of the light source is 360-525 nm, preferably 360 nm, 390 nm, 395 nm, 400 nm, or 420 nm.

[0016] In this invention, the Minisci reaction time is 0.1-3 h, preferably 1 h.

[0017] In this invention, the purification method is column chromatography purification, and the eluent used in the column chromatography purification includes petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is 1-100:1, preferably 20:1.

[0018] The present invention has the following beneficial effects: This invention provides a method for preparing a 6-alkylazirauracil compound, comprising the following steps: mixing an azauracil derivative, an iodine reagent, an alkylating agent, and a solvent, and carrying out a Minisci reaction under light irradiation; after the reaction is completed, sequentially performing extraction, vacuum distillation, and purification to obtain the 6-alkylazirauracil compound.

[0019] This invention selects alcohol compounds of Formula 2 as alkylating agents. Compared with traditional techniques that require the use of special reagents such as thioyl ylide, NHP ester, and cyclobutanone oxime ester, which require multiple synthesis steps, the alkylating agent raw materials selected in this invention are simple and readily available, do not require pre-synthesis, greatly simplify the synthesis steps, reduce raw material costs, and solve the problem of limited alkylating agent sources in the traditional direct CH alkylation reaction of azauracil.

[0020] This invention employs a catalytic system of "light conditions + iodine reagent", which does not rely on expensive transition metal catalysts (such as manganese, iridium, and cobalt complexes) or noble metal photocatalysts (such as Ir and Ru complexes) or organic dyes, thus reducing production costs.

[0021] The present invention requires only 0.1-3 hours of reaction time under room temperature and light conditions, which is much faster than the reaction time of tens of hours of traditional technology, greatly improving the synthesis efficiency and reducing energy consumption.

[0022] This invention utilizes a highly efficient and universal method to break the C-C bonds of alkylating reagents (alcohols) to form alkyl radicals, thereby achieving the CH alkylation reaction of aziridines. The target product is obtained in excellent yield. The substrates are widely applicable, and no metal catalysis, inert gas protection, or external photocatalyst is required. The alcohol feedstock does not require pre-functionalization, providing a new method for the alkylation of aziridines.

[0023] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0024] Figure 1 The 1H NMR spectrum of 2,4-dibenzyl-6-isopropyl-1,2,4-triazine-3,5(2H,4H)-dione prepared in Example 1 of this invention; Figure 2 This is the carbon NMR spectrum of 2,4-dibenzyl-6-isopropyl-1,2,4-triazine-3,5(2H,4H)-dione obtained in Example 1 of this invention. Figure 3 This is the 1H NMR spectrum of 2,4-dibenzyl-6-(tert-butyl)-1,2,4-triazine-3,5(2H,4H)-dione obtained in Example 2 of this invention; Figure 4 This is the carbon NMR spectrum of 2,4-dibenzyl-6-(tert-butyl)-1,2,4-triazine-3,5(2H,4H)-dione obtained in Example 2 of this invention; Figure 5 This is the 1H NMR spectrum of 6-acetyl-2,4-dibenzyl-1,2,4-triazine-3,5(2H,4H)-dione obtained in Example 3 of this invention; Figure 6 This is the carbon NMR spectrum of 6-acetyl-2,4-dibenzyl-1,2,4-triazine-3,5(2H,4H)-dione obtained in Example 3 of the present invention; Figure 7 This is the 1H NMR spectrum of 6-(adamantane-1-yl)-2,4-dibenzyl-2,4-triazine-3,5(2H,4H)-dione obtained in Example 4 of this invention; Figure 8 This is the carbon NMR spectrum of 6-(adamantane-1-yl)-2,4-dibenzyl-2,4-triazine-3,5(2H,4H)-dione obtained in Example 4 of this invention. Detailed Implementation

[0025] The present invention will be further described below with reference to the accompanying drawings and embodiments. Unless otherwise defined, the technical or scientific terms used in this invention should be understood in their ordinary sense by those skilled in the art. The features mentioned above or in the specific examples mentioned in this invention can be combined arbitrarily, and these specific embodiments are only used to illustrate the invention and are not intended to limit the scope of the invention.

[0026] Example 1 This embodiment provides a method for preparing a 6-alkylazauracil compound, the steps of which are as follows: 0.2 mmol of 2,4-dibenzylazuracil (azuracil derivative), 0.6 mmol of [bis(trifluoroacetoxy)iodo]benzene (iodine reagent), and 2.0 mmol of isobutanol (alkylating agent) were dissolved in 2 mL of acetonitrile. The mixture was stirred at room temperature for 1 h at an emission wavelength of 390 nm, and the reaction was monitored by TCL. After the reaction was completed, the mixture was extracted successively with ethyl acetate and saturated brine. The organic phases were combined and distilled under reduced pressure at 40 °C. The organic phases were then separated by column chromatography (eluent composed of petroleum ether and ethyl acetate in a volume ratio of 20:1) to give the final product 2,4-dibenzyl-6-isopropyl-1,2,4-triazine-3,5(2H,4H)-dione (yield 89%), with the structure shown in Formula I: .

[0027] The 1H NMR spectrum of the 2,4-dibenzyl-6-isopropyl-1,2,4-triazine-3,5(2H,4H)-dione obtained in this example is as follows: Figure 1 As shown, the carbon spectrum is as follows Figure 2 As shown.

[0028] 1 H NMR (400 MHz, Chloroform-d) δ 7.47 – 7.35 (m, 2H), 7.36 – 7.29 (m,2H), 7.29 – 7.15 (m, 6H), 4.99 (s, 2H), 4.98 (s, 2H), 3.12-3.03 (m, 1H),1.11(s, 3H) 1.10 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 154.5, 148.4, 147.9, 134.8,134.7, 128.4, 127.7, 127.6, 127.5, 127.1, 126.9, 54.2, 43.2, 28.2, 19.0. HRMSm / z calcd for C 20 H 22 N3O2 + (M+H) + : 336.17065, found 336.17047.

[0029] Example 2 This embodiment provides a method for preparing a 6-alkylazauracil compound, the steps of which are as follows: 0.2 mmol of 2,4-dibenzylazauracil (azauracil derivative), 0.6 mmol of [bis(trifluoroacetoxy)iodo]benzene (iodine reagent), and 2.0 mmol of neopentyl alcohol (alkylating reagent) were dissolved in 2 mL of acetonitrile. The mixture was stirred at room temperature for 1 h at an emission wavelength of 390 nm, and the reaction was monitored by TCL. After the reaction was completed, the mixture was extracted successively with ethyl acetate and saturated brine. The organic phases were combined and subjected to vacuum distillation at 40 °C. The organic phases were then separated by column chromatography (eluent consisting of petroleum ether and ethyl acetate in a volume ratio of 20:1) to give the final product 2,4-dibenzyl-6-(tert-butyl)-1,2,4-triazine-3,5(2H,4H)-dione (yield 82%), with the structure shown in Formula II. .

[0030] The 1H NMR spectrum of the 2,4-dibenzyl-6-(tert-butyl)-1,2,4-triazine-3,5(2H,4H)-dione obtained in this example is as follows: Figure 3 As shown, the carbon spectrum is as follows Figure 4 As shown.

[0031] 1 H NMR (600 MHz, Chloroform-d) δ 7.49–7.45 (m, 1H), 7.44–7.39 (m,1H), 7.37–7.23 (m, 3H), 5.06 (s, 2H), 1.32 (s, 5H). 13 HRMS m / z calcd for C 21 H 24 N3O2 + (M+H) + :350.18630, found350.18610.

[0032] Example 3 This embodiment provides a method for preparing a 6-alkylazauracil compound, the steps of which are as follows: 0.2 mmol of 2,4-dibenzylazuracil (azuracil derivative), 0.6 mmol of [bis(trifluoroacetoxy)iodo]benzene (iodine reagent), and 2.0 mmol of acetone alcohol (alkylating agent) were dissolved in 2 mL of acetonitrile. The mixture was stirred at room temperature for 1 h at an emission wavelength of 390 nm, and the reaction was monitored by TCL. After the reaction was completed, the mixture was extracted successively with ethyl acetate and saturated brine. The organic phases were combined and subjected to vacuum distillation at 40 °C. The organic phases were then separated by column chromatography (eluent consisting of petroleum ether and ethyl acetate in a volume ratio of 20:1) to give the final product 6-acetyl-2,4-dibenzyl-1,2,4-triazine-3,5(2H,4H)-dione (yield 55%), with the structure shown in Formula III. .

[0033] The 1H NMR spectrum of the 6-acetyl-2,4-dibenzyl-1,2,4-triazine-3,5(2H,4H)-dione obtained in this example is as follows: Figure 5 As shown, the carbon spectrum is as follows Figure 6 As shown.

[0034] 1 H NMR (400 MHz, Chloroform-d) δ 7.51 – 7.46 (m, 2H), 7.43 – 7.33 (m,5H), 7.32-7.26 (m, 3H), 5.18 (s, 2H), 5.07 (s, 2H), 2.50 (s, 3H). 13 C NMR (101MHz, CDCl3) δ 192.6, 152.9, 148.5, 137.1, 135.0, 134.6, 129.8, 129.0, 128.9,128.8, 128.6, 128.3, 56.28, 44.4, 27.6. HRMS m / z calcd for C 19 H 18 N3O3 + (M+H) + :336.13427, found 336.13426.

[0035] Example 4 This embodiment provides a method for preparing a 6-alkylazauracil compound, the steps of which are as follows: 0.2 mmol of 2,4-dibenzylazuracil (azuracil derivative), 0.6 mmol of [bis(trifluoroacetoxy)iodo]benzene (iodine reagent), and 2.0 mmol of adamantane methanol (alkylating reagent) were dissolved in 2 mL of acetonitrile. The mixture was stirred at room temperature for 1 h at an emission wavelength of 390 nm, and the reaction was monitored by TCL. After the reaction was completed, the mixture was extracted successively with ethyl acetate and saturated brine. The organic phases were combined and subjected to vacuum distillation at 40 °C. The organic phases were then separated by column chromatography (eluent consisting of petroleum ether and ethyl acetate in a volume ratio of 20:1) to give the final product 6-(adamantane-1-yl)-2,4-dibenzyl-2,4-triazine-3,5(2H,4H)-dione (yield 50%), with the structure shown in Formula IV. .

[0036] The 1H NMR spectrum of the 6-(adamantane-1-yl)-2,4-dibenzyl-2,4-triazine-3,5(2H,4H)-dione obtained in this example is as follows: Figure 7 As shown, the carbon spectrum is as follows Figure 8 As shown.

[0037] 1 H NMR (400 MHz, Chloroform-d) δ 7.49 – 7.44 (m, 2H), 7.41 – 7.37 (m,2H), 7.36 – 7.27 (m, 6H), 5.08 (s, 2H), 5.07 (s, 2H), 2.47 (d, J = 7.1 Hz,2H), 2.07 (dq, J = 13.5, 6.7 Hz, 1H), 0.93 (s, 3H), 0.91 (s, 3H). 13 C NMR (101MHz, CDCl3) δ 154.7, 150.0, 148.9, 136.0, 135.9, 129.4, 129.0, 128.7, 128.5,128.1, 127.9, 55.3, 43.9, 39.6, 39.0, 36.8, 28.3. HRMS m / z calcd for C 27 H 30 N3O2 + (M+H) + : 428.23325, found 428.23325.

[0038] Example 5 This embodiment provides a method for preparing a 6-alkylazauracil compound, the steps of which are as follows: 0.2 mmol of 2,4-dibenzylazuracil (azuracil derivative), 0.6 mmol of [bis(trifluoroacetoxy)iodo]benzene (iodine reagent), and 2.0 mmol of 1,2-acetone glycerol (alkylating reagent) were dissolved in 2 mL of acetonitrile. The mixture was stirred at room temperature for 1 h at an emission wavelength of 390 nm, and the reaction was monitored by TCL. After the reaction was completed, the mixture was extracted successively with ethyl acetate and saturated brine. The organic phases were combined and subjected to vacuum distillation at 40 °C. The organic phases were then separated by column chromatography (eluent consisting of petroleum ether and ethyl acetate in a volume ratio of 20:1) to give the final product (R)-2,4-dibenzyl-6-(2,2-dimethyl-1,3-dioxocyclobutane-4-yl)-1,2,4-triazine-3,5(2H,4H)-dione (yield 60%), with the structure shown in Formula V: .

[0039] The structural characterization data of the (R)-2,4-dibenzyl-6-(2,2-dimethyl-1,3-dioxocyclobutane-4-yl)-1,2,4-triazine-3,5(2H,4H)-dione obtained in this embodiment are as follows: 1 H NMR (600 MHz, Chloroform-d) δ 7.49 – 7.45 (m, 2H), 7.40 (dt, J =5.8, 1.6 Hz, 2H), 7.35 – 7.28 (m, 6H), 5.23 – 5.17 (m, 2H), 5.08 – 5.03 (m,3H), 4.28 (dd, J = 8.6, 6.8 Hz, 1H), 4.14 (dd, J = 8.6, 5.8 Hz, 1H), 1.46 (s,3H), 1.44 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 155.4, 148.7, 141.9, 135.4,135.3, 129.5, 128.9, 128.8, 128.6, 128.4, 128.2, 110.8, 72.5, 67.2, 55.6,44.3, 26.3, 25.7. HRMS m / z calcd for C 22 H 24 N3O4 + (M+H) + : 394.17613, found394.17611.

[0040] Example 6 This embodiment provides a method for preparing a 6-alkylazauracil compound, the steps of which are as follows: 0.2 mmol of 2,4-dibenzylazuracil (azuracil derivative), 0.6 mmol of [bis(trifluoroacetoxy)iodo]benzene (iodine reagent), and 2.0 mmol of cyclobutylmethanol (alkylating reagent) were dissolved in 2 mL of acetonitrile. The mixture was stirred at room temperature for 1 h at an emission wavelength of 390 nm, and the reaction was monitored by TCL. After the reaction was completed, the mixture was extracted successively with ethyl acetate and saturated brine. The organic phases were combined and subjected to vacuum distillation at 40 °C. The organic phases were then separated by column chromatography (eluent consisting of petroleum ether and ethyl acetate in a volume ratio of 20:1) to give the final product 2,4-dibenzyl-6-cyclobutyl-1,2,4-triazine-3,5(2H,4H)-dione (yield 40%), with the structure shown in Formula VI: .

[0041] The structural characterization data of the 2,4-dibenzyl-6-cyclobutyl-1,2,4-triazine-3,5(2H,4H)-dione obtained in this embodiment are as follows: 1 H NMR (600 MHz, Chloroform-d) δ 7.48-7.45 (m, 2H), 7.44-7.41 (m,2H), 7.37 – 7.33 (m, 2H), 7.33 – 7.26 (m, 4H), 5.11 (s, 2H), 5.06 (s, 2H), 3.69-3.61 (m, 1H), 2.28 – 2.19 (m, 4H), 2.07-1.98 (m, 1H), 1.88 – 1.83 (m, 1H). 13 C NMR (151 MHz, CDCl3) δ 155.7, 149.0, 147.4, 135.9, 135.8, 129.5,128.8, 128.7, 128.6, 128.2, 128.0, 55.3, 44.1, 35.2, 26.3, 18.3. HRMS(ESI-TOF) m / z calcd for C 21 H 22 N3O2 + (M+H) + : 348.17065, found 348.17066.

[0042] Example 7 This embodiment provides a method for preparing a 6-alkylazauracil compound, the steps of which are as follows: 0.2 mmol of 2,4-dibenzylazuracil (azuracil derivative), 0.6 mmol of [bis(trifluoroacetoxy)iodo]benzene (iodine reagent), and 2.0 mmol of 2-methylbutanol (alkylating agent) were dissolved in 2 mL of acetonitrile. The mixture was stirred at room temperature for 1 h at an emission wavelength of 390 nm, and the reaction was monitored by TCL. After the reaction was completed, the mixture was extracted successively with ethyl acetate and saturated brine. The organic phases were combined and subjected to vacuum distillation at 40 °C. The organic phases were then separated by column chromatography (eluent consisting of petroleum ether and ethyl acetate in a volume ratio of 20:1) to give the final product 6-acetyl-2,4-dibenzyl-1,2,4-triazine-3,5(2H,4H)-dione (yield 70%), with the structure shown in Formula VII. .

[0043] The structural characterization data of the 6-acetyl-2,4-dibenzyl-1,2,4-triazine-3,5(2H,4H)-dione obtained in this embodiment are as follows: 1 H NMR (600 MHz, Chloroform-d) δ 7.50 – 7.45 (m, 2H), 7.41 – 7.37 (m,2H), 7.35-7.24 (m, 6H), 5.12 – 5.02 (m, 4H), 3.04-2.96 (m, 1H), 1.78-1.69 (m,1H), 1.51 – 1.44 (m, 1H), 1.16 (d, J = 6.9 Hz, 3H), 0.87 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 155.8, 148.9, 148.9, 135.9, 135.9, 129.5, 129.4,128.8, 128.7, 128.7, 128.7, 128.6, 128.2, 128.1, 128.0, 128.0, 55.3, 44.2,35.6, 27.2, 17.5, 11.7, 11.7. HRMS m / z calcd for C 21 H 24 N3O2 + (M+H) + : 350.18630,found350.18631.

[0044] Example 8 This embodiment provides a method for preparing a 6-alkylazauracil compound, the steps of which are as follows: 0.2 mmol of 2,4-dibenzylazuracil (azuracil derivative), 0.6 mmol of [bis(trifluoroacetoxy)iodo]benzene (iodine reagent), and 2.0 mmol of 2,4-dimethyl-3-pentanol (alkylating agent) were dissolved in 2 mL of acetonitrile. The mixture was stirred at room temperature for 1 h at an emission wavelength of 390 nm, and the reaction was monitored by TCL. After the reaction was completed, the mixture was extracted successively with ethyl acetate and saturated brine. The organic phases were combined and subjected to vacuum distillation at 40 °C. The organic phases were then separated by column chromatography (eluent consisting of petroleum ether and ethyl acetate in a volume ratio of 20:1) to give the final product 2,4-dibenzyl-6-isopropyl-1,2,4-triazine-3,5(2H,4H)-dione (yield 90%), with the structure shown in Formula VIII: .

[0045] The structural characterization data of the 2,4-dibenzyl-6-isopropyl-1,2,4-triazine-3,5(2H,4H)-dione obtained in this embodiment are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.47 – 7.35 (m, 2H), 7.36 – 7.29 (m,2H), 7.29 – 7.15 (m, 6H), 4.99 (s, 2H), 4.98 (s, 2H), 3.12-3.03 (m, 1H),1.11(s, 3H) 1.10 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 154.5, 148.4, 147.9, 134.8,134.7, 128.4, 127.7, 127.6, 127.5, 127.1, 126.9, 54.2, 43.2, 28.2, 19.0. HRMSm / z calcd for C 20 H 22 N3O2 + (M+H) + : 336.17065, found 336.17047.

[0046] Example 9 This embodiment provides a method for preparing a 6-alkylazauracil compound, the steps of which are as follows: 0.2 mmol of 4-methyl-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione (azauracil derivative), 0.6 mmol of [bis(trifluoroacetoxy)iodo]benzene (iodine reagent), and 2.0 mmol of isopropanol (alkylating agent) were dissolved in 2 mL of acetonitrile. The mixture was stirred at room temperature for 1 h at an emission wavelength of 390 nm, and the reaction was monitored by TCL. After the reaction was completed, the mixture was extracted successively with ethyl acetate and saturated brine. The organic phases were combined and subjected to vacuum distillation at 40 °C. The organic phases were then separated by column chromatography (eluent consisting of petroleum ether and ethyl acetate in a volume ratio of 20:1) to give the final product 6-isopropyl-4-methyl-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione (yield 60%), with the structure shown in Formula IX: .

[0047] The structural characterization data of the 6-isopropyl-4-methyl-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione obtained in this embodiment are as follows: 1 H NMR (600 MHz, Chloroform-d) δ 7.50 (t, J = 7.6 Hz, 2H), 7.47 –7.43 (m, 1H), 7.25 – 7.19 (m, 2H), 3.66 (s, 3H), 3.25-3.18 (m, 1H), 1.25 (s,3H), 1.24 (s,3H). 13 C NMR (151 MHz, CDCl3) δ 155.8, 149.9, 149.0, 133.3,129.5, 129.2, 127.9, 39.5, 29.4, 20.0. HRMS m / z calcd for C 12 H 15 N2O + (M+H) + :203.1179, found 203.1176.

[0048] Example 10 This embodiment provides a method for preparing a 6-alkylazauracil compound, the steps of which are as follows: 0.2 mmol of 2-(4-chlorophenyl)-2-(2,6-dichloro-4-(4-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)phenyl)acetonitrile (azauracil derivative), 0.6 mmol of [bis(trifluoroacetoxy)iodo]benzene (iodine reagent), and 2.0 mmol of isopropanol (alkylating agent) were dissolved in 2 mL of acetonitrile. The mixture was placed under an emission wavelength of 390 nm and stirred at room temperature for 1 h. The reaction was monitored by TCL. After the reaction was complete, the organic phases were extracted sequentially with ethyl acetate and saturated brine. The combined organic phases were then subjected to vacuum distillation at 40 °C, followed by column chromatography separation (eluent consisting of petroleum ether and ethyl acetate in a volume ratio of 20:1) to obtain the final product 2-(4-chlorophenyl)-2-(2,6-dichloro-4-(6-isopropyl-4-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)phenyl)propionitrile (yield 50%), with the structure shown in Formula X: .

[0049] The structural characterization data of the 2-(4-chlorophenyl)-2-(2,6-dichloro-4-(6-isopropyl-4-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)phenyl)propionitrile prepared in this embodiment are as follows: 1 H NMR (600 MHz, Chloroform-d) δ 7.79 (s, 2H), 7.36 – 7.34 (m, 2H), 7.33 – 7.30 (m, 2H), 6.18 (s, 1H), 3.42 (s, 3H), 3.33-3.27 (m, 1H), 1.28 (s,3H), 1.27 (s,3H). 13 C NMR (151 MHz, CDCl3) δ 155.0, 151.2, 148.1, 141.8,135.7, 134.3, 130.9, 129.9, 129.7, 129.5, 129.2, 128.3, 124.7, 116.3, 37.0,29.8, 27.55, 19.9. HRMS m / z calcd for C 21 H 17 Cl3N4NaO2 + (M+Na) + : 485.03093, found485.030944.

[0050] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical solutions of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. A method for preparing a 6-alkylazauracil compound, characterized in that, Includes the following steps: The aziridine derivative, iodine reagent, alkylating agent and solvent were mixed and subjected to Minisci reaction under light. After the reaction was completed, the mixture was extracted, distilled under reduced pressure and purified to obtain the 6-alkylaziridine compound. The structural formula of the azauracil derivative is shown in Formula 1: ； R1 is selected from hydrogen, benzyl, naphthalenebenzyl, methyl, propyl, butyl, hexyl, allyl, 1-butenyl, propynyl, butynyl or propyl-2-(4-isobutylphenyl)-propionate; R2 is selected from hydrogen, benzyl, naphthylbenzyl, methyl, propyl, butyl, hexyl, allyl, 1-butenyl, propynyl, butynyl or propyl-2-(4-isobutylphenyl)-propionate; The structural formula of the alkylating agent is shown in Formula 2: ； R3 is selected from cyclobutyl, cyclohexyl, or cyclopentyl; Alternatively, the alkylating agent may be isobutanol, neopentyl alcohol, acetone alcohol, adamantane methanol, 1,2-acetone glycerol, 2-methylbutanol, or 2,4-dimethyl-3-pentanol. The structural formula of the 6-alkylazine uracil compound is shown in Formula 3: ； The iodine reagent is [bis(trifluoroacetoxy)iodide]benzene; Under the aforementioned illumination conditions, the emission wavelength of the light source is 360-525 nm.

2. The method for preparing a 6-alkylazauracil compound according to claim 1, characterized in that, The solvent is selected from ethanol, acetonitrile, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide, or N,N-dimethylacetamide.

3. The method for preparing a 6-alkylazauracil compound according to claim 1, characterized in that, The molar ratio of the azauracil derivative to the iodine reagent is 1:1-9.

4. The method for preparing a 6-alkylazauracil compound according to claim 1, characterized in that, The molar ratio of the azauracil derivative to the alkylating agent is 1:1-20.

5. The method for preparing a 6-alkylazauracil compound according to claim 1, characterized in that, The Minisci reaction time is 0.1-3 h.

6. The method for preparing a 6-alkylazauracil compound according to claim 1, characterized in that, The purification method is column chromatography purification, and the eluent used in the column chromatography purification includes petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1-100:1.

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