Dihydropyrimidone-coumarin derivative and preparation method thereof

Abstract

The invention discloses a dihydropyrimidone-coumarin derivative and a preparation method thereof, and belongs to the technical field of dihydropyrimidone-coumarin derivates. The preparation method comprises the steps that firstly, aromatic aldehyde with different substituent groups and containing hydroxyl, urea and a beta-dicarbonyl compound are subjected to a reaction under the conditions that DES serves as a solvent and p-toluenesulfonic acid monohydrate serves as a catalyst; dihydropyrimidone compounds are obtained through Biginelli condensation, and the dihydropyrimidone compounds and bromomethyl coumarin are synthesized into a series of target compounds through a Williamson ether synthesis method. According to the method, a series of target products capable of efficiently removing DPPH free radicals are obtained, the reaction process is simple, and the used catalyst is non-toxic, harmless, low in price and free of burden on the environment; the structural diversity of the target compound is enriched, and a certain theoretical basis is provided for subsequent development of novel coumarin drugs.

Description

Technical Field

[0001] The invention relates to the technical field of dihydropyrimidone-coumarin derivatives, and in particular to a dihydropyrimidone-coumarin derivative and a preparation method thereof. Background Art

[0002] Dihydropyrimidone compounds are widely present in nature and the human body. They are an extremely important class of compounds. Cytosine, uracil, thymine and other nucleotides in organisms belong to this class of compounds. Dihydropyrimidone and its derivatives have a variety of biological activities, such as antioxidant, antibacterial, antitumor, antihypertensive and antiviral activities. Biochemists use dihydropyrimidone as a target drug for clinical trial drug candidates. RV Chikhale et al. synthesized 15 new 6-methyl-2-methoxy-3-(substituted 1-phenylacetophenone)-4-substituted phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate compounds. All compounds were tested for their antihypertensive activity by non-invasive rat tail artery pressure measurement and carotid artery catheterization. The results showed that some compounds have new antihypertensive activity structures. E. Rajanarendar et al. synthesized a series of new 1-aryl-4-methyl-3,6-di(5-methylisoxazol-3-yl)-2-thio-2,3,6,10b-tetrahydro-1H-pyrimidine-[5,4-c]-quinolin-5-ones and tested their performance against Bacillus subtilis (MTCC441), Bacillus sphaericus (MTCC 511), Staphylococcus aureus (MTCC 96), Pseudomonas aeruginosa (MTCC741), Klebsiella pneumoniae (MTCC 39) and Chromobacterium violaceum (MTCC2656). The results showed that the compounds showed the same or better antibacterial activity as the standard drug ciprofloxacin. It is the first dihydropyrimidine-based small molecule, identified as an inhibitor of the mitotic spindle protein Eg5, which helps the formation of the spindle during mitosis. It is a dihydropyrimidone compound. Monastrol binds to the kinesin Eg5 to form the Monastrol spindle, which stops mitosis and causes cell death after apoptosis. At the same time, Monastrol can also inhibit the release of adenosine diphosphate (ADP) from Eg5 through conformational changes, so Monastrol is also a non-competitive inhibitor of adenosine triphosphate (ATP); Monastrol can bind to a hydrophobic region in the head power domain of Eg5, hindering the release of ADP and the binding of ATP, and interfering with the biological function of Eg5 protein by inhibiting the ATPase activity of Eg5. At the same time, due to the specificity of Eg5 protein expression, all biological processes involving microtubules will not be affected, so by inhibiting the kinesin Eg5, the normal cell division cycle will be terminated, causing cell apoptosis, and there will be no neurotoxic side effects, which provides a new idea for the development of anti-tumor drugs in the future.

[0003] The application of coumarin compounds in the medical field has also attracted much attention. Its special aromatic oxygen heterocyclic structure can easily bind to a variety of biological enzymes and receptors through covalent bonds, thus showing anti-coagulation, anti-inflammatory, anti-acute biliary infection, antibacterial, antifungal, antiviral and other effects. Some natural coumarin antibacterial compounds such as novobiocin, chlorobiocin and coumermycin have been used in clinical practice to treat Gram-positive bacteria.

[0004] In order to further improve the biological activity of the above-mentioned dihydropyrimidone compounds and coumarin compounds, researchers synthesized dihydropyrimidone-coumarin compounds by a series of reactions. However, the biological activity of the dihydropyrimidone-coumarin compounds reported so far still cannot meet expectations and needs to be further improved, and the existing synthesis reaction process is relatively cumbersome. To this end, the present invention provides a dihydropyrimidone-coumarin derivative and a preparation method thereof. Summary of the invention

[0005] The invention provides a dihydropyrimidone-coumarin derivative and a preparation method thereof. A series of dihydropyrimidone-coumarin derivatives are obtained by adopting a Williamson ether synthesis method, and not only a series of target products capable of efficiently removing DPPH free radicals are obtained, but also the reaction process is simple, the catalyst used is non-toxic and harmless, the price is low, and no burden is generated on the environment; the invention not only enriches the structural diversity of the target compound, but also provides a certain theoretical basis for the subsequent development of new coumarin drugs.

[0006] The first object of the present invention is to provide a dihydropyrimidone-coumarin derivative, characterized in that its general structural formula is:

[0007] Wherein, R1 is selected from methyl or ethyl, R2 is selected from methyl or phenyl, and R3 is selected from

[0008] Preferably, the structural formula of the dihydropyrimidone-coumarin derivative is the following compound: (6-methyl-5-ethoxycarbonyl-4-aryl-[4'-phenol ether-(6'-substituted coumarin)]-3,4-dihydropyrimidin-2-one), (6-methyl-5-methoxycarbonyl-4-aryl-[4'-phenol ether-(6'-substituted coumarin)]-3,4-dihydropyrimidin-2-one), (6-phenyl-5-ethoxycarbonyl-4-aryl-[4'-phenol ether-(6'-substituted coumarin)]-3,4-dihydropyrimidin-2-one), (6-phenyl-5-ethoxycarbonyl-4-aryl-[3'-methoxy-4'-phenol ether-(6'-substituted coumarin)]-3,4-dihydropyrimidin-2-one), (6-difluoromethyl-5-ethoxycarbonyl-4-aryl-[3'-methoxy-4'-phenol ether-(6'-substituted coumarin)]-3,4-dihydropyrimidin-2-one), (6-methyl-5-methoxycarbonyl-4-aryl-[2'-phenol ether-(6'-substituted coumarin)]-3,4-dihydropyrimidin-2-one), (6-phenyl-5-ethoxycarbonyl-4-aryl-[2'-phenol ether-(6'-substituted coumarin)]-3,4-dihydropyrimidin-2-one), (6-phenyl-5-ethoxycarbonyl-4-aryl-[3'-bromo-2'-phenol ether-(6'-substituted coumarin)]-3,4-dihydropyrimidin-2-one), (6-methyl-5-ethoxycarbonyl-4-aryl-[4'-phenol ether-(7'-substituted coumarin)]-3,4-dihydropyrimidin-2-one), (6-methyl-5-methoxycarbonyl-4-aryl-[4'-phenol ether-(7'-substituted coumarin)]-3,4-dihydropyrimidin-2-one) (6-phenyl-5-ethoxycarbonyl-4-aryl-[4'-phenol ether-(7'-substituted coumarin)]-3,4-dihydropyrimidin-2-one), (6-methyl-5-ethoxycarbonyl-4-aryl-[3'-phenol ether-(7'-substituted coumarin)]-3,4-dihydropyrimidin-2-one), (6-phenyl-5-ethoxycarbonyl-4-aryl-[3'-phenol ether-(7'-substituted coumarin)]-3,4-dihydropyrimidin-2-one), (6-phenyl-5-ethoxycarbonyl-4-aryl-[2'-phenol ether-(7'-substituted coumarin)]-3,4-dihydropyrimidin-2-one), (6-phenyl-5-ethoxycarbonyl-4-aryl-[3'-bromo-2'-phenol ether-(7'-substituted coumarin)]-3,4-dihydropyrimidin-2-one), (6-methyl-5-methoxycarbonyl-4-aryl-[3'-bromo-2'-phenol ether-(7'-substituted coumarin)]-3,4-dihydropyrimidin-2-one) or (6-phenyl-5-ethoxycarbonyl-4-aryl-[3'-methoxy-4'-phenol ether-(7'-substituted coumarin)]-3,4-dihydropyrimidin-2-one).

[0009] The second object of the present invention is to provide a method for preparing the above-mentioned dihydropyrimidone-coumarin derivatives, comprising the following steps:

[0010] Aromatic aldehydes, urea, and β-dicarbonyl compounds with different substituents and containing hydroxyl groups are added to a deep eutectic solvent and reacted with p-toluenesulfonic acid monohydrate to obtain dihydropyrimidone compounds through Biginelli condensation at room temperature;

[0011] The dihydropyrimidone compound, bromomethyl coumarin, anhydrous potassium carbonate and 18-crown ether-6 are dissolved in acetonitrile, and a dihydropyrimidone-coumarin derivative is obtained by Williamson ether synthesis method;

[0012] The aromatic aldehydes with different substituents and containing hydroxyl groups are

[0013] The general structural formula of the β-dicarbonyl compound is Wherein, R1 is selected from methyl or ethyl, and R2 is selected from methyl or phenyl.

[0014] Preferably, the deep eutectic solvent is obtained by mixing choline chloride and ethylene glycol in a molar ratio of 1:2 and heating in an oil bath at 80° C. for 2 hours.

[0015] Preferably, the ratio of the mixture of aromatic aldehydes with different substituents and containing hydroxyl groups, urea, and β-dicarbonyl compounds to the low eutectic solvent is 20 mmol:10 mL.

[0016] Preferably, the aromatic aldehyde containing hydroxyl groups and having different substituents, urea and β-dicarbonyl compound are added to the low eutectic solvent in a molar ratio of 1:1:1.

[0017] Preferably, the molar ratio of the aromatic aldehydes containing hydroxyl groups and having different substituents to p-toluenesulfonic acid monohydrate is 1:0.2.

[0018] Preferably, the usage ratio of the dihydropyrimidone compound, bromomethylcoumarin, anhydrous potassium carbonate, 18-crown ether-6 and acetonitrile is 1.2 mmol:1 mmol:1.5 mmol:0.2 mmol:18 mL.

[0019] Preferably, the Williamson ether synthesis method is specifically as follows: dissolving the dihydropyrimidone compound, bromomethyl coumarin, anhydrous potassium carbonate and 18-crown ether-6 in acetonitrile, and refluxing at 70° C. for 2.5 hours.

[0020] Preferably, the bromomethylcoumarin is 6-bromomethylcoumarin or 7-bromomethylcoumarin.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] The present invention provides a dihydropyrimidone-coumarin derivative and a preparation method thereof. The present invention first uses a low eutectic solvent (DES) as a solvent, p-toluenesulfonic acid monohydrate as a catalyst, and obtains a dihydropyrimidone compound by Biginelli condensation. The dihydropyrimidone compound and bromomethyl coumarin are synthesized into a series of target compounds by Williamson ether synthesis. The present invention not only obtains a series of target products that can efficiently remove DPPH free radicals, but also has a simple reaction process, and the catalyst used is non-toxic, harmless, low-priced, and will not burden the environment; the present invention not only enriches the structural diversity of the target compound, but also provides a certain theoretical basis for the subsequent development of new coumarin drugs. DETAILED DESCRIPTION

[0023] In order to enable those skilled in the art to better understand the technical solution of the present invention and implement it, the present invention is further described below in conjunction with specific examples, but the examples are not intended to limit the present invention. The following test methods and detection methods, unless otherwise specified, are conventional methods; the reagents and raw materials, unless otherwise specified, are commercially available.

[0024] The present invention will now be further described with reference to specific embodiments.

[0025] 1. Synthesis process of dihydropyrimidone-coumarin derivatives of the present invention

[0026] Synthesis of dihydropyrimidone-coumarin derivatives: Aromatic aldehydes, urea, and β-dicarbonyl compounds with different substituents and containing hydroxyl groups are added to a low eutectic solvent, and dihydropyrimidone compounds are obtained by Biginelli condensation under the catalysis of p-toluenesulfonic acid monohydrate; dihydropyrimidone compounds are synthesized with bromomethyl coumarin by Williamson ether synthesis. The specific route is as follows:

[0027]

[0028] 2. The present invention synthesized the following 17 dihydropyrimidone-coumarin derivatives:

[0029] The specific structural formulas of the 17 derivatives of Examples 1 to 17 are shown in Table 1.

[0030] Table 117 Specific structural formulas of derivatives

[0031]

[0032]

[0033]

[0034] 1. The specific preparation steps of the derivative of the structural formula of Example 1 are:

[0035] S1, Preparation of intermediate 4a: Aromatic aldehyde containing hydroxyl group Urea and β-dicarbonyl compounds The reaction mixture was added to a DES solvent and catalyzed by p-toluenesulfonic acid monohydrate to obtain intermediate 4a (6-methyl-5-ethoxycarbonyl-4-(4'-hydroxy)-3,4-dihydropyrimidin-2-one) through Biginelli condensation.

[0036] S2, 1.2mmol of intermediate 4a, 1mmol of 6-bromomethylcoumarin, 1.5mmol of anhydrous potassium carbonate, 0.2mmol of 18-crown ether-6 (compared to 6-bromomethylcoumarin) were dissolved in 18mL of acetonitrile, added to a three-necked flask, refluxed at 70°C for 2.5h (TLC detection of reaction progress, developing solvent: PE:EA=4 / 1, V:V), after the reaction, filtered, evaporated the solvent, added dichloromethane and NaHCO3 saturated solution for extraction three times, combined the organic phases, added an appropriate amount of anhydrous magnesium sulfate and dried for 20min, filtered, evaporated the solvent to obtain the crude target compound, and the detection yield was 86%. Finally, acetonitrile was used for recrystallization, and vacuum drying was used to obtain the pure target compound 7a (6-methyl-5-ethoxycarbonyl-4-aryl-[4'-phenol ether-(6'-substituted coumarin)]-3,4-dihydropyrimidin-2-one).

[0037] 2. The specific preparation steps of the derivative of the structural formula of Example 2 are:

[0038] Referring to the preparation steps of Example 1, the difference is that in step S2, 1.2 mmol of 4b (6-methyl-5-methoxycarbonyl-4-(4'-hydroxy)-3,4-dihydropyrimidin-2-one) and 1 mmol of 6-bromomethylcoumarin are used as raw materials to obtain the target compound 7b (6-methyl-5-methoxycarbonyl-4-aryl-[4'-phenol ether-(6'-substituted coumarin)]-3,4-dihydropyrimidin-2-one) with a yield of 62%.

[0039] 3. The specific preparation steps of the derivative of the structural formula of Example 3 are:

[0040] Referring to the preparation steps of Example 1, the difference is that in step S2, 1.2 mmol of 4c (6-phenyl-5-ethoxycarbonyl-4-phenyl (4'-hydroxy) -3,4-dihydropyrimidin-2-one) and 1 mmol of 6-bromomethyl coumarin are used as raw materials to obtain the target compound 7c (6-phenyl-5-ethoxycarbonyl-4-aryl-[4'-phenol ether-(6'-substituted coumarin)]-3,4-dihydropyrimidin-2-one) with a yield of 60%.

[0041] 4. The specific preparation steps of the derivative of the structural formula of Example 4 are:

[0042] Referring to the preparation steps of Example 1, the difference is that in step S2, 1.2 mmol of 4d (6-phenyl-5-ethoxycarbonyl-4-(4'-hydroxy-3'-methoxy)-3,4-dihydropyrimidin-2-one) and 1 mmol of 6-bromomethylcoumarin are used as raw materials to obtain the target compound 7d (6-phenyl-5-ethoxycarbonyl-4-aryl-[3'-methoxy-4'-phenol ether-(6'-substituted coumarin)]-3,4-dihydropyrimidin-2-one) in a yield of 29%.

[0043] 5. The specific preparation steps of the derivative of the structural formula of Example 5 are:

[0044] Referring to the preparation steps of Example 1, the difference is that in step S2, 1.2 mmol of 4e (6-difluoromethyl-5-ethoxycarbonyl-4-(4'-hydroxy-3'-methoxy)-3,4-dihydropyrimidin-2-one) and 1 mmol of 6-bromomethylcoumarin are used as raw materials to obtain the target compound 7e (6-difluoromethyl-5-ethoxycarbonyl-4-aryl-[3'-methoxy-4'-phenol ether-(6'-substituted coumarin)]-3,4-dihydropyrimidin-2-one) with a yield of 48%.

[0045] 6. The specific preparation steps of the derivative of the structural formula of Example 6 are:

[0046] Referring to the preparation steps of Example 1, the difference is that in step S2, 1.2 mmol of 4f (6-methyl-5-methoxycarbonyl-4-phenyl (2-hydroxy) -3,4-dihydropyrimidin-2-one) and 1 mmol of 6-bromomethylcoumarin are used as raw materials to obtain the target compound 7f (6-methyl-5-methoxycarbonyl-4-aryl-[2'-phenol ether-(6'-substituted coumarin)]-3,4-dihydropyrimidin-2-one) in a yield of 33%.

[0047] 7. The specific preparation steps of the derivative of the structural formula of Example 7 are:

[0048] Referring to the preparation steps of Example 1, the difference is that in step S2, 1.2 mmol of 4g (6-phenyl-5-ethoxycarbonyl-4-phenyl (2-hydroxy) -3,4-dihydropyrimidin-2-one) and 1 mmol of 6-bromomethyl coumarin are used as raw materials to obtain 7g of the target compound (6-phenyl-5-ethoxycarbonyl-4-aryl-[2'-phenol ether-(6'-substituted coumarin)]-3,4-dihydropyrimidin-2-one) with a yield of 63%.

[0049] 8. The specific preparation steps of the derivative of the structural formula of Example 8 are:

[0050] Referring to the preparation steps of Example 1, the difference is that in step S2, 1.2 mmol of 4h (6-phenyl-5-ethoxycarbonyl-4-phenyl (2'-hydroxy-3'-bromo) -3,4-dihydropyrimidin-2-one) and 1 mmol of 6-bromomethyl coumarin are used as raw materials to react for 10 hours to obtain the target compound 7h (6-phenyl-5-ethoxycarbonyl-4-aryl-[3'-bromo-2'-phenol ether-(6'-substituted coumarin)]-3,4-dihydropyrimidin-2-one) with a yield of 53%.

[0051] 9. The specific preparation steps of the derivative of the structural formula of Example 9 are:

[0052] Referring to the preparation steps of Example 1, the difference is that in step S2, 1.2 mmol of 4a (6-methyl-5-ethoxycarbonyl-4-(4'-hydroxy)-3,4-dihydropyrimidin-2-one) and 1 mmol of 7-bromomethylcoumarin are used as raw materials to obtain the target compound 8a (6-methyl-5-ethoxycarbonyl-4-aryl-[4'-phenol ether-(7'-substituted coumarin)]-3,4-dihydropyrimidin-2-one) with a yield of 68%.

[0053] 10. The specific preparation steps of the derivative of the structural formula of Example 10 are:

[0054] Referring to the preparation steps of Example 1, the difference is that in step S2, 1.2 mmol of 4b (6-methyl-5-methoxycarbonyl-4-(4'-hydroxy)-3,4-dihydropyrimidin-2-one) and 1 mmol of 7-bromomethylcoumarin are used as raw materials to obtain the target compound 8b (6-methyl-5-methoxycarbonyl-4-aryl-[4'-phenol ether-(7'-substituted coumarin)]-3,4-dihydropyrimidin-2-one) with a yield of 67%.

[0055] 11. The specific preparation steps of the derivative of the structural formula of Example 11 are:

[0056] Referring to the preparation steps of Example 1, the difference is that in step S2, 1.2 mmol of 4c (6-phenyl-5-ethoxycarbonyl-4-phenyl (4'-hydroxy) -3,4-dihydropyrimidin-2-one) and 1 mmol of 7-bromomethyl coumarin are used as raw materials to obtain the target compound 8c (6-phenyl-5-ethoxycarbonyl-4-aryl-[4'-phenol ether-(7'-substituted coumarin)]-3,4-dihydropyrimidin-2-one) with a yield of 47%.

[0057] 12. The specific preparation steps of the derivative of the structural formula of Example 12 are:

[0058] Referring to the preparation steps of Example 1, the difference is that in step S2, 1.2 mmol of 4i (6-methyl-5-ethoxycarbonyl-4-phenyl (3'-hydroxy) -3,4-dihydropyrimidin-2-one) and 1 mmol of 7-bromomethyl coumarin are used as raw materials to obtain the target compound 8d (6-methyl-5-ethoxycarbonyl-4-aryl-[3'-phenol ether-(7'-substituted coumarin)]-3,4-dihydropyrimidin-2-one) with a yield of 48%.

[0059] 13. The specific preparation steps of the derivative of the structural formula of Example 13 are:

[0060] Referring to the preparation steps of Example 1, the difference is that in step S2, 1.2 mmol of 4j (6-phenyl-5-ethoxycarbonyl-4-phenyl (3'-hydroxy) -3,4-dihydropyrimidin-2-one) and 1 mmol of 7-bromomethyl coumarin are used as raw materials to obtain the target compound 8e (6-phenyl-5-ethoxycarbonyl-4-aryl-[3'-phenol ether-(7'-substituted coumarin)]-3,4-dihydropyrimidin-2-one) with a yield of 48%.

[0061] 14. The specific preparation steps of the derivative of the structural formula of Example 14 are:

[0062] Referring to the preparation steps of Example 1, the difference is that in step S2, 1.2 mmol of 4g (6-phenyl-5-ethoxycarbonyl-4-phenyl (2'-hydroxy) -3,4-dihydropyrimidin-2-one) and 1 mmol of 7-bromomethyl coumarin are used as raw materials to obtain the target compound 8f (6-phenyl-5-ethoxycarbonyl-4-aryl-[2'-phenol ether-(7'-substituted coumarin)]-3,4-dihydropyrimidin-2-one) with a yield of 68%.

[0063] 15. The specific preparation steps of the derivative of the structural formula of Example 15 are:

[0064] Referring to the preparation steps of Example 1, the difference is that in step S2, 1.2 mmol of 4h (6-phenyl-5-ethoxycarbonyl-4-phenyl (2'-hydroxy-3'-bromo) -3,4-dihydropyrimidin-2-one) and 1 mmol of 7-bromomethyl coumarin are used as raw materials to react for 10 hours to obtain 8 g of the target compound (6-phenyl-5-ethoxycarbonyl-4-aryl-[3'-bromo-2'-phenol ether-(7'-substituted coumarin)]-3,4-dihydropyrimidin-2-one) with a yield of 40%.

[0065] 16. The specific preparation steps of the derivative of the structural formula of Example 16 are:

[0066] Referring to the preparation steps of Example 1, the difference is that in step S2, 1.2 mmol of 4k (6-methyl-5-methoxycarbonyl-4-phenyl (2'-hydroxy-3'-bromo) -3,4-dihydropyrimidin-2-one) and 1 mmol of 7-bromomethyl coumarin are used as raw materials and reacted for 10 hours to obtain the target compound 8h (6-methyl-5-methoxycarbonyl-4-aryl-[3'-bromo-2'-phenol ether-(7'-substituted coumarin)]-3,4-dihydropyrimidin-2-one) with a yield of 21%.

[0067] 17. The specific preparation steps of the derivative of the structural formula of Example 17 are:

[0068] Referring to the preparation steps of Example 1, the difference is that in step S2, 1.2 mmol of 4d (6-phenyl-5-ethoxycarbonyl-4-(4'-hydroxy-3'-methoxy)-3,4-dihydropyrimidin-2-one) and 1 mmol of 7-bromomethylcoumarin are used as raw materials to obtain the target compound 8i (6-phenyl-5-ethoxycarbonyl-4-aryl-[3'-methoxy-4'-phenol ether-(7'-substituted coumarin)]-3,4-dihydropyrimidin-2-one) with a yield of 20%.

[0069] In order to further illustrate the effect of the present invention, the present invention also sets a comparative example, as follows:

[0070] Comparative Example 1 (4)

[0071] Only intermediate 4 is used:

[0072] Comparative Example 2 (5)

[0073] Only compound 5: 6-bromomethylcoumarin was used:

[0074] Comparative Example 3(6)

[0075] Only compound 6: 7-bromomethylcoumarin was used:

[0076] III. The hydrogen spectra of the dihydropyrimidone-coumarin derivatives and intermediates 4a-4k of the structural formulas of Examples 1-17 are shown in Tables 2 and 3 below.

[0077] Table 2 Hydrogen spectra of 17 derivatives

[0078]

[0079]

[0080]

[0081]

[0082] Table 3 Intermediates 4a to 4k

[0083]

[0084]

[0085]

[0086]

[0087] 4. DPPH free radical scavenging rate results

[0088] L-ascorbic acid was used as a positive control to detect its scavenging rate for DPPH free radicals. The results are shown in Table 4. Linear fitting gave a regression equation of Y=0.3996X-4.5471, and the IC50 of L-ascorbic acid under the experimental conditions was calculated to be 113.75 μg / mL. The IC50 values ​​of the derivatives 7a-7h, 8a-8i of Examples 1-17 were calculated according to the formula, and the results are shown in Table 5.

[0089] Table 4 Scavenging rate of DPPH free radical by L-ascorbic acid

[0090]

[0091] According to Table 4, with different concentrations of L-ascorbic acid as the horizontal coordinate and the scavenging rate of DPPH free radicals by L-ascorbic acid as the vertical coordinate, a standard curve Y=0.3996X-4.5471 can be obtained, and the IC50 of L-ascorbic acid is calculated to be 113.75 μg / mL.

[0092] Table 5 DPPH free radical scavenging rates and IC50 values ​​of derivatives 7a-7h, 8a-8i of Examples 1-17 and Comparative Examples 1-3

[0093]

[0094]

[0095] As shown in Table 5, compared with the IC50 of the positive control group L-ascorbic acid, the different types of dihydropyrimidone-coumarin derivatives prepared by the present invention all have better scavenging effects on DPPH free radicals. Taking 100 μg / mL of any one of the dihydropyrimidone-coumarin derivatives 7a to 8i as an example, the scavenging rate of the DPPH free radical is higher than that of 125 μg / mL L-ascorbic acid (63.05%).

[0096] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A dihydropyrimidone-coumarin derivative, characterized in that: Its general structural formula is: Wherein, R1 is selected from methyl or ethyl, R2 is selected from methyl or phenyl, and R3 is selected from 2. The dihydropyrimidone-coumarin derivative according to claim 1, characterized in that: The structural formula of the dihydropyrimidone-coumarin derivative is specifically:

3. A method for preparing the dihydropyrimidone-coumarin derivatives according to claim 1, characterized in that: The following steps are involved: Aromatic aldehydes, urea, and β-dicarbonyl compounds with different substituents and containing hydroxyl groups are added to a deep eutectic solvent and reacted with p-toluenesulfonic acid monohydrate to obtain dihydropyrimidone compounds through Biginelli condensation at room temperature; The dihydropyrimidone compound, bromomethyl coumarin, anhydrous potassium carbonate and 18-crown ether-6 are dissolved in acetonitrile, and a dihydropyrimidone-coumarin derivative is obtained by Williamson ether synthesis method; The aromatic aldehydes with different substituents and containing hydroxyl groups are The general structural formula of the β-dicarbonyl compound is Wherein, R1 is selected from methyl or ethyl, and R2 is selected from methyl or phenyl.

4. The preparation method according to claim 3, characterized in that: The deep eutectic solvent is obtained by mixing choline chloride and ethylene glycol in a molar ratio of 1:2 and heating the mixture in an oil bath at 80° C. for 2 hours.

5. The preparation method according to claim 3, characterized in that: The dosage ratio of the mixture of aromatic aldehydes with different substituents and containing hydroxyl groups, urea, and β-dicarbonyl compounds to the low eutectic solvent is 20 mmol:10 mL.

6. The preparation method according to claim 3, characterized in that The aromatic aldehydes with different substituents and containing hydroxyl groups, urea and β-dicarbonyl compounds are added to the deep eutectic solvent in a molar ratio of 1:1:

1.

7. The preparation method according to claim 3, characterized in that: The molar ratio of the aromatic aldehydes with different substituents and containing hydroxyl groups to p-toluenesulfonic acid monohydrate is 1:0.

2.

8. The preparation method according to claim 3, characterized in that: The usage ratio of the dihydropyrimidone compound, bromomethylcoumarin, anhydrous potassium carbonate, 18-crown ether-6 and acetonitrile is 1.2mmol:1mmol:1.5mmol:0.2mmol:18mL.

9. The preparation method according to claim 3, characterized in that: The Williamson ether synthesis method is specifically as follows: dissolving the dihydropyrimidone compound, bromomethyl coumarin, anhydrous potassium carbonate and 18-crown ether-6 in acetonitrile, and refluxing the mixture at 70° C. for 2.5 hours.

10. The preparation method according to claim 3, characterized in that: The bromomethylcoumarin is 6-bromomethylcoumarin or 7-bromomethylcoumarin.

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