Green synthesis method of polycyclic dihydroquinazolinone derivative with antiviral activity

Abstract

The invention provides a green synthesis method of a polycyclic dihydroquinazolinone derivative with antiviral activity, which comprises the following steps: mixing a compound with a structure as shown in a formula (I), a photocatalyst, an additive, a reducing agent, a hydrogen atom transfer reagent and a solvent, and reacting under sunlight or blue light irradiation conditions to obtain the polycyclic dihydroquinazolinone derivative with antiviral activity. According to the present invention, the polycyclic dihydroquinazolinone derivative having the antiviral activity and having the structure represented by the formula (II) is obtained by using the compound represented by the formula (I) as the raw material, and the experiment results show that the reaction conversion can be completed by using the long wavelength blue light (467 nm) or sunlight, the use amount of the photocatalyst is only 0.2 mol%, and the catalytic efficiency is high; meanwhile, a specific photocatalyst and a specific reducing agent are selected, so that the yield is increased, and reactants are clean and pollution-free; and the method is suitable for large-scale production, and has a good application prospect and a good research value.

Description

Technical Field

[0001] The invention relates to the field of drug synthesis, and in particular to a green synthesis method of polycyclic dihydroquinazolinone derivatives with antiviral activity. Background Art

[0002] Polycyclic quinazolinone and its derivatives are an important class of nitrogen-containing heterocyclic structures and are also important skeletons of many natural alkaloids. The reported polycyclic quinazolinones all have various biological activities, such as: the natural products and drug molecules containing polycyclic quinazolinone skeletons shown in the following structural formulas have antiviral activity, antibacterial activity, anticancer activity, antidepressant activity, or anti-Alzheimer's disease activity, etc.

[0003]

[0004] Therefore, the synthesis method of polycyclic quinazolinone and its derivatives is favored by many drug synthesis researchers; in particular, in recent years, the free radical cascade reaction triggered by photochemical, electrochemical induction or peroxide, metal salt and other conditions has become a popular research method for preparing polycyclic dihydroquinazolinone derivatives (Org. Lett. 2023, 25, 1683-1688; Chem. Commun., 2018, 54, 10160-10163). Although there are many reports on the synthesis method of polycyclic quinazolinone and its derivatives, it is summarized as follows Two reaction pathways:

[0005] Path A: The functional group-activated small molecule RX undergoes homolysis under metal catalysts, peroxides or ultraviolet conditions to generate R-based free radicals, which then add to the alkenyl double bond of the N-alkyl-substituted quinazolinone QN to generate the intermediate Int-I, which then undergoes cyclization to obtain the polycyclic quinazolinone product QN-1.

[0006] Path B: Under 420 nm violet light, the protonated N-alkyl-substituted quinazolinone QN under acidic conditions is reduced by a single electron by an excited photosensitizer to give the intermediate Int-II, which then undergoes an intramolecular free radical cycloaddition to the side chain double bond to give the polycyclic quinazolinone product QN-2.

[0007] Path B (Path C): N-alkyl substituted quinazolinone QN is catalyzed by heavy metal compound SmI2 to obtain cycloquinazolinone product QN-3.

[0008]

[0009] From the above reactions, it can be seen that these current methods all have certain shortcomings and cannot meet the requirements of green chemistry. For example, some of these reactions require harsh conditions such as high temperature, some require the use of oxidants or catalysts containing heavy metals, some use equivalent amounts of peroxides, organic acids or have poor atom economy, etc. Therefore, it is of great significance to develop a synthetic method with mild conditions and green environmental protection. Summary of the invention

[0010] In view of this, the technical problem to be solved by the present invention is to provide a green synthesis method for polycyclic dihydroquinazolinone derivatives with antiviral activity. The method provided by the present invention not only has mild reaction conditions and is environmentally friendly, but also has wide applicability to substrates.

[0011] Compared with the prior art, the present invention provides a green synthesis method of a polycyclic dihydroquinazolinone derivative with antiviral activity. The method provided by the present invention comprises the following steps: mixing a compound of a structure of formula (I), a photocatalyst, an additive, a reducing agent, a hydrogen atom transfer reagent and a solvent, and reacting the mixture under sunlight or blue light irradiation conditions to obtain a polycyclic dihydroquinazolinone derivative with antiviral activity of a structure of formula (II). Experiments show that the method provided by the present invention can complete the reaction conversion under the use of longer wavelength blue light (467nm) or sunlight, and the amount of the photocatalyst required is only 0.2mol%, with high catalytic efficiency. At the same time, the specific photocatalyst and reducing agent are selected, which not only improves the yield, but also makes the reactants clean and pollution-free. Moreover, the yield of the amplified reaction is not significantly reduced, and the method is suitable for large-scale production, and has good application prospects and research value. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 This is the hydrogen spectrum of the compound prepared in Example 1 of the present invention;

[0013] Figure 2 This is the carbon spectrum of the compound prepared in Example 1 of the present invention;

[0014] Figure 3 This is an X-ray image of the compound prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0015] The present invention provides a method for preparing a polycyclic dihydroquinazolinone derivative having antiviral activity, comprising:

[0016] The compound of formula (I), a photocatalyst, an additive, a reducing agent, a hydrogen atom transfer agent and a solvent are mixed and reacted under sunlight or blue light to obtain a compound of formula (II), which is a polycyclic dihydroquinazolinone derivative with antiviral activity;

[0017]

[0018] in,

[0019] The n is 0 or 1;

[0020] R1 is hydrogen or a C1-C6 alkyl group;

[0021] R2 is hydrogen, C6-C12 aryl, C1-C6 alkyl or halogen;

[0022] R3 is hydrogen, C6-C12 aryl, C1-C6 alkyl or halogen;

[0023] R4 is hydrogen, C1-C6 alkyl or halogen;

[0024] R is hydrogen, C1-C3 alkyl with substituents, C1-C3 alkyl without substituents, C1-C3 alkoxy, halogen or amino;

[0025] The photocatalyst is one or more of 4DPIPN, 4CzIPN and 3CzCIIPN;

[0026]

[0027] The hydrogen atom transfer reagent is a sulfur-containing and nitrogen-containing organic compound or a salt of a sulfur-containing and nitrogen-containing organic compound;

[0028] The additive is one or more of water, formic acid, acetic acid, benzoic acid and p-toluenesulfonic acid;

[0029] The reducing agent is one or more of sodium formate, potassium formate and cesium formate.

[0030] According to the present invention, the R is preferably hydrogen, methyl, ethyl, propyl, trifluoromethyl, trifluoroethyl, fluorine, chlorine, bromine, methoxy, ethoxy or amino, wherein the R can be at any position of the benzene ring where it is located, and there can be 1, 2 or 3 R substituents on the benzene ring; the R1 is preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl or n-hexyl; the R2 is preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, phenyl or fluorine; the R3 is preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, phenyl or fluorine; the R4 is preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl or fluorine; more preferably, the compound of formula (II) has the following structure:

[0031]

[0032]

[0033] According to the present invention, the compound of formula (I), a photocatalyst, a hydrogen atom transfer reagent, an additive, a reducing agent and a solvent are mixed and reacted under sunlight or blue light to obtain a compound of formula (II); wherein the wavelength of the blue light is preferably 465 to 470 nm, more preferably 20 w 467nm blue light source; the molar ratio of the compound with formula (I) structure to the photocatalyst is preferably 1: (0.001-0.005), more preferably 1: (0.002-0.003); the molar ratio of the compound with formula (I) structure to the hydrogen atom transfer reagent is preferably 1: (0.01-0.05), more preferably 1: (0.02-0.04); the molar ratio of the compound with formula (I) structure to the additive is preferably 1: (1-8), more preferably 1: (5-7); the molar ratio of the compound with formula (I) structure to the reducing agent is 1: (2-5), and the molar ratio of the compound with formula (I) structure to the reducing agent is 1: (2.5-3); the amount ratio of the compound with formula (I) structure to the solvent is preferably 1 mmol: (8-20) mL, more preferably 1 mol: (10-15) mL.

[0034] According to the present invention, the photocatalyst is preferably one or more of 4DPIPN and 4CzIPN; the hydrogen atom transfer reagent is preferably one or more of 2-mercaptobenzoic acid methyl ester, 4-thiolbenzoic acid methyl ester, 2-methoxybenzenethiol, triethylamine, diisopropylethylamine, triethylenediamine, thiol, thiolate and thiol, more preferably one or more of 2-mercaptobenzoic acid methyl ester, 4-thiolbenzoic acid methyl ester and 2-methoxybenzenethiol; the additive is preferably water or formic acid; the solvent is preferably one or more of DMSO, DMF, THF and CH3CN, more preferably DMSO or DMF.

[0035] According to the present invention, there is no special requirement for the mixing method, and any method known to those skilled in the art can be used. The reaction is preferably carried out under a nitrogen atmosphere; wherein the method for providing the nitrogen atmosphere is to remove the air in the reaction solution and the reaction bottle by filling with nitrogen, so that the nitrogen fills the entire reaction system; the reaction time is preferably 3 to 12 hours, more preferably 4 to 10 hours; the reaction temperature is preferably 20 to 30° C., more preferably 25 to 28° C.; after the reaction is completed, the present invention preferably adds saturated salt water and an organic solvent for extraction, and extracts the aqueous phase 2 to 3 times, and combines the organic phases for distillation and concentration to obtain a compound of formula (II), wherein the organic solvent for extraction is preferably ethyl acetate; the present invention also preferably purifies the obtained concentrate again by column chromatography to obtain a high-purity compound of formula (II), wherein the column chromatography washing machine is preferably petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is preferably (3 to 5):1.

[0036] The present invention provides a green synthesis method of a polycyclic dihydroquinazolinone derivative with antiviral activity. The method provided by the present invention is to react a compound with a structure of formula (I), a photocatalyst, an additive, a hydrogen atom transfer reagent and a solvent mixture under sunlight or blue light irradiation conditions to obtain a compound with a structure of formula (II) with antiviral activity. The results show that the method provided by the present invention can complete the reaction conversion under the use of longer wavelength blue light (465-470nm) or sunlight, and the amount of the photocatalyst is only 0.2mol%, with high catalytic efficiency; at the same time, a specific photocatalyst is selected and additive water is added during the reaction, which not only improves the yield, but also makes the reactants clean and pollution-free; and the amplified reaction yield is not significantly reduced, so the method is suitable for large-scale production and has good application prospects and research value.

[0037] The following will be described clearly and completely in conjunction with the technical solutions of the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0038] All chemicals and solvents were commercially available and used without further purification. Analytical thin layer chromatography (TLC) was performed on silica gel plates (GF254) using UV light (254 nm). For flash chromatography, 200-300 mesh silica gel (Qingdao, China) was used. Recording was at 400 MHz 1 H NMR spectra. Chemical shifts are in ppm relative to DMSO-d6 (δ = 2.50 ppm), CDCl3 (δ = 7.26 ppm), Acteone-d6, and CF3COOD (δ = 11.5 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), integral, and coupling constant J (Hz). 13 C NMR spectra were recorded at 100 MHz with complete proton decoupling. Chemical shifts are reported in ppm relative to DMSO-d6 (δ = 39.6 ppm), CDCl3 (δ = 77.2 ppm), 200Acteone-d6 (δ = 29.8 ppm). 19 F NMR was recorded at 376 MHz. High resolution mass spectra (HRMS) were recorded on a Bruker Apex IV FTMS spectrometer.

[0039] The reaction substrates involved in this embodiment are shown in Table 1:

[0040] Table 1: Substrates involved in the embodiments of the present invention

[0041]

[0042]

[0043] The substrates involved in the present invention are prepared according to the methods disclosed in the prior art:

[0044] (a) The references used for the synthesis of the substrate are as follows: Xiao, H.-X.; Li, P.-P.; Pan, B.; Liang, W.; Du, F.; Yu, Y. Photoinduced, Silver (I)-Mediated Synthesis of Ester-Substituted Fused Quinazolinones via Cascade Alkoxycarbonylation / Cyclization of Heterocycles Bearing Unactivated Alkenes. J. Org. Chem. 2023, 88, 5861-5874. The synthesis reaction equation is:

[0045]

[0046] (b) The method for synthesizing the brominated compound is as follows: Nikas, SP; D'Souza, M.; Makriyannis, A. Enantioselective Synthesis of (10S)- and (10R)-Methyl-anandamides. Tetrahedron, 2012, 68, 6329-6337. The reaction equation is as follows:

[0047]

[0048] Example 1

[0049]

[0050] Substrate 1a (0.2 mmol, 1.0 equiv), photocatalyst 0.0004 mmol 4DPAIPN (0.2 mol%), hydrogen atom transfer reagent 0.004 mmol 2-mercaptobenzoic acid methyl ester (2.0 mol%), additive 1 mmol water (5.0 equiv), reducing agent 0.5 mmol sodium formate (2.5 equiv) and solvent DMSO (2.0 mL) were added to a schlenk sealed tube and mixed. The reaction solution was heated with 20 w The mixture was irradiated with a 467 nm blue LED lamp at room temperature (25° C.) for 12 hours. After the reaction was completed, saturated saline water and ethyl acetate were added to the mixture for extraction, and the aqueous phase was extracted three times with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and then concentrated by distillation under reduced pressure to remove the solvent to obtain a yellow oily substance. The yellow oily substance was separated by column chromatography using a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1 as an eluent for column chromatography. The eluate containing the target compound was collected, the solvent was evaporated and dried to obtain 41.48 mg of a white solid 2a with a yield of 97%. Its chemical structure is:

[0051]

[0052] Characterization data: White solid, its hydrogen spectrum is as follows Figure 1 As shown, Figure 1 The hydrogen spectrum of the compound prepared in Example 1 of the present invention; the carbon spectrum is as follows Figure 2 As shown, Figure 2 This is the carbon spectrum of the compound prepared in Example 1 of the present invention; Figure 3 This is an X-ray image of the compound prepared in Example 1 of the present invention;

[0053] 1 H NMR (400MHz, CDCl3): δ8.19 (d, J=8.0Hz, 1H), 7.64 (t, J=8.0Hz, 1H), 7.58 (d, J=8.0Hz, 1H), 7.35 (t, J=8.0Hz, 1H), 4.24-4.19 ( m, 1H), 3.88-3.83 (m, 1H), 3.00-2.98 (m, 1H), 2.07-2.04 (m, 1H), 1.98-1.89 (m, 2H), 1.59-1.55 (m, 1H), 1.43 (d, J=4.0Hz, 3H);

[0054] 13 C NMR (100MHz, CDCl3): δ162.2, 158.4, 147.4, 134.0, 126.7, 126.5, 126.0, 120.1, 42.1, 35.4, 27.6, 20.1, 19.4.

[0055] Embodiments 2 to 19

[0056] Consistent with the preparation method and substrate of Example 1, Example 2N16 uses the same amount of raw materials, and changes the type of photocatalyst, the type of hydrogen atom transfer agent, the type of reducing agent or the reaction solvent to obtain 2a. Example 17, based on the reaction conditions of Example 1, changes the amount of photocatalyst to 0.02 mol%, to obtain 2a; Example 18, based on the reaction conditions of Example 1, changes the reducing agent to 2 equiv., to obtain 2a; Example 19, based on the reaction conditions of Example 1, changes the irradiation light source to 20W 530nm green LEDs lamp; the reaction results are shown in Table 2, which is a summary table of reaction conditions and yields of Examples 1 to 14.

[0057] Table 2

[0058]

[0059]

[0060] Among them, ArSH, ArSH-1 and ArSH-2 are methyl 2-mercaptobenzoate, 2-methoxythiophenol and methyl 4-mercaptobenzoate, respectively.

[0061] It can be seen from the table that the photocatalysts 4DPAIPN, 4CzIPN and 3CzClIPN have good catalytic effects, the reaction effects of ArSH, ArSH-1 and ArSH-2 among the hydrogen atom transfer agents are better, and the reaction effects of DMSO, THF and DMF as reaction solvents are better. It can be seen from Example 14 that after adding water as an additive, the reaction yield is significantly improved; when the reducing agent is sodium formate, potassium formate or cesium formate, the reaction effect is better, and when the reducing agent is used in an amount of 2.5 equivalents, the reaction yield is significantly better than 2 equivalents; when the reaction light source is green light, the reaction cannot proceed.

[0062] Embodiment 20

[0063] According to the preparation method of Example 1, different substrates were changed to obtain a series of polycyclic dihydroquinazolinone derivatives, and the results and characterization data are as follows:

[0064]

[0065] Characterization data: white solid, (43.7 mg, yield 95%).

[0066] w NMR (400MHz, CDCl3): δ7.10 (t, J=7.6Hz, 1H), 6.59 (d, J=7.6Hz, 1H), 6.45 (d, J=7.6Hz, 1H), 4.66-4.62 (m, 1H), 4.38 (bs, 1H), 4.25 (d, J=8.8Hz, 1H), 2.68 (s, 3H), 2.65-2.57 (m, 1H), 1.87-1.83 (m, 2H), 1.70-1.68 (m, 1H), 1.26-1.21 (m, 1H), 1.01 (d, J=6.4Hz, 3H); 13 C NMR (100MHz, CDCl3): δ164.8, 146.9, 142.5, 132.3, 122.8, 113.3, 112.4, 73.9, 42.6, 36.6, 31.8, 24.2, 23.1, 17.4; HRMS (ESI) m / z calcdfor C 14 H 19 N2O[M+H + ]: 231.1492, found 231.1493.

[0067]

[0068] Characterization data: white solid, (42.8 mg, 93% yield). 1 H NMR (400MHz, CDCl3): δ7.79 (d, J=7.6Hz, 1H), 7.14 (d, J=7.6Hz, 1H), 6.72 (t, J=7.6Hz, 1H), 4.70-4.65 (m, 1H), 4.35 (d, J=9.2Hz, 1 H), 4.24 (bs, 1H), 2.66-2.59 (m, 1H), 2.13 (s, 3H), 1.90-1.86 (m, 2H), 1.67-1.63 (m, 2H), 1.31-1.21 (m, 1H), 1.01 (d, J=6.4Hz, 3H); 13 C NMR (100MHz, CDCl3): δ163.8, 143.4, 134.1, 126.4, 121.2, 118.1, 114.6, 74.6, 43.3, 36.8, 32.2, 24.2, 17.4, 16.2; HRMS (ESI) m / zcalcd for C 14 H 19 N2O[M+H + ]: 231.1492, found 231.1486.

[0069]

[0070] Characterization data: white solid, (45.1 mg, yield 98%).

[0071] 1 H NMR (400MHz, CDCl3): δ7.76 (d, J=7.6Hz, 1H), 6.60 (d, J=7.6Hz, 1H), 6.40 (s, 1H), 4.70-4.65 (m, 1H), 4.45 (bs, 1H), 4.30 (d, J =9.2Hz, 1H), 2.64-2.57 (m, 1H), 2.26 (s, 3H), 1.88-1.83 (m, 2H), 1.66-1.62 (m, 2H), 1.26-1.23 (m, 1H), 0.99 (d, J = 6.4Hz, 3H); 13 CNMR (100MHz, CDCl3): δ163.8, 145.4, 144.1, 128.5, 119.9, 114.1, 112.5, 74.8, 43.1, 36.8, 32.1, 24.2, 21.6, 17.3; HRMS (ESI) m / z calcd for C 14 H 19 N2O[M+H+ ] :231.1492, found231.1491.

[0072]

[0073] Characterization data: white solid, (44.4 mg, yield 91%).

[0074] 1 H NMR (400MHz, CDCl3): δ7.61 (s, 1H), 6.99 (s, 1H), 4.69-4.65 (m, 1H), 4.32-4.30 (m, 1H), 4.06 (bs, 1H), 2.68-2.60 (m, 1H), 2. 24(s, 3H), 2.12(s, 3H), 1.90-1.89(m, 2H), 1.68-1.63(m, 1H), 1.61-1.60(m, 1H), 1.31-1.24(m, 1H), 1.01(d, J=6.4Hz, 3H); 13 C NMR (100MHz, CDCl3): δ164.2, 141.1, 135.22, 127.7, 126.3, 121.6, 115.0, 74.8, 43.4, 36.7, 32.2, 24.2, 20.4,

[0075] 17.6, 16.2; HRMS(ESI)m / z calcd for C 15 H 21 N2O[M+H+]: 245.1648, found245.1645.

[0076]

[0077] Characterization data: white solid, (41.8 mg, yield 85%).

[0078] 1 H NMR (400MHz, CDCl3): δ7.42 (d, J=3.0Hz, 1H), 6.87 (dd, J=8.4, 3.0Hz, 1H), 6.49 (d, J=8.4Hz, 1H), 4.97 (d, J=3.0Hz, 1H), 4.74- 4.70 (m, 1H), 3.77 (s, 3H), 2.62-2.60 (m, 1H), 1.95-1.90 (m, 1H), 1.78-1.73 (m, 3H), 1.52-1.49 (m, 1H), 1.06 (d, J=6.8Hz, 3H); 13 CNMR (100MHz, CDCl3): δ163.4, 152.3, 140.2, 122.0, 114.8, 114.5, 110.7, 72.0, 55.8, 42.6, 35.4, 29.6, 18.8, 11.9; HRMS (ESI) m / z calcd for C 14 H 20 N2O3[M+H + ]:247.1441,found247.1433.

[0079]

[0080] Characterization data: white solid, (43.3 mg, yield 88%).

[0081] 1 H NMR (400MHz, CDCl3): δ7.49 (d, J=8.0Hz, 1H), 6.83 (d, J=8.0Hz, 1H), 6.72-6.68 (m, 1H), 4.86 (bs, 1H), 4.72-4.68 (m, 1H), 4.39 (d , J=9.2Hz, 1H), 3.85 (s, 3H), 2.65-2.58 (m, 1H), 1.91-1.84 (m, 2H), 1.68-1.58 (m, 2H), 1.30-1.24 (m, 1H), 1.01 (d, J=6.4Hz, 3H); 13C NMR (100MHz, CDCl3): δ163.5, 145.5, 135.9, 119.9, 117.1, 114.3, 112.8, 75.0, 55.6, 43.1, 36.9, 32.0, 24.1, 17.2; HRMS (ESI) m / z calcd for C 14 H 19 N2O2[M+H + ]: 247.1441, found 247.1434.

[0082]

[0083] Characterization data: white solid, (43.0 mg, yield 78%).

[0084] 1 H NMR (400MHz, CDCl3): δ7.39 (s, 1H), 6.16 (s, 1H), 4.64-4.60 (m, 1H), 4.31 (bs, 1H), 4.29-4.26 (m, 1H), 3.85 (s, 6H), 2 .66-2.58(m, 1H), 1.88-1.83(m, 2H), 1.73-1.68(m, 1H), 1.70-1.61(m, 2H), 1.29-1.19(m, 1H), 1.03(d, J=6.4Hz, 3H); 13 C NMR (100MHz, CDCl3): δ164.2, 153.8, 142.7, 140.9, 110.2, 110.1, 107.4, 97.8, 74.9, 56.2, 55.9, 42.9, 36.5, 31.9, 24.0, 17.5; HRMS (ESI) m / z calcd for C15H21N2O3[M+H + ]:277.1547, found277.1543.

[0085] Characterization data: white solid, (39.8 mg, yield 85%).

[0086] 1 H NMR (400MHz, CDCl3): δ7.18-7.12 (m, 1H), 6.45-6.36 (m, 2H), 4.70-4.64 (m, 1H), 4.29 (d, J=9.2Hz, 1H ), 2.63-2.55(m, 1H), 1.88-1.84(m, 2H), 1.67-1.62(m, 2H), 1.29-1.22(m, 1H), 1.00(d, J=6.4Hz, 3H);13 C NMR (100MHz, CDCl3): δ164.4, 161.8, 161.0, 147.6, 134.0 (d, J=11.6Hz), 109.6 (d, J=3.6Hz), 106.5 (d, J=22.2Hz), 103.8, 74.1, 42.7, 36.7, 32.0, 24.0, 17.3; 19 F NMR (376MHz, CDCl3): δ-111.7; HRMS (ESI) m / z calcd for C 13 H 16 FN2O[M+H + ]: 235.1241, found 235.1241.

[0087]

[0088] Characterization data: white solid, (44.0 mg, yield 94%). 1 H NMR (400MHz, CDCl3): 7.59 (dd, J=8.8, 3.0Hz, 1H), 6.99 (td, J=8.4, 3.0 Hz, 1H), 6.57 (dd, J=8.8, 3.6Hz, 1H), 4.68-4.62 (m, 1H), 4.33-4.31 (d, J=9.2Hz, 1H), 4.31 (bs, 1H), 2.69-2.6 1 (m, 1H), 1.89-1.85 (m, 2H), 1.71-1.70 (m, 1H), 1.67-1.62 (m, 1H), 1.31-1.24 (m, 1H), 1.02 (d, J=6.4Hz, 3H); 13 C NMR (100MHz, CDCl3): δ162.8, 157.5, 155.2, 141.6, 120.7 (d, J=22.6Hz), 116.3 , 115.5 (d, J=6.6Hz), 114.3 (d, J=22.7Hz), 74.7, 43.2, 36.8, 32.0, 24.1, 17.5; 19 F NMR (376MHz, CDCl3): δ-124.8; HRMS (ESI) m / z calcd for C 13 H 16 FN2O[M+H + ]: 235.1241, found 235.1238.

[0089]

[0090] Characterization data: white solid, (45.9 mg, yield 98%).

[0091] 1 H NMR (400MHz, CDCl3): 7.63 (d, J=8.0Hz, 1H), 7.03-7.01 (m, 1H), 6.63-6.58 (m, 1H), 5.13-5.12 (m, 1H), 4.80-4.76 (m, 1 H), 4.29 (bs, 1H), 2.60-2.54 (m, 1H), 1.98-1.97 (m, 1H), 1.78-1.76 (m, 3H), 1.51-1.49 (m, 1H), 1.06 (d, J=6.8Hz, 3H); 13 C NMR (100MHz, CDCl3): δ161.9, 150.2, 147.8, 134.6 (d, J=13.7Hz), 123.5 (d, J=2.7 Hz), 118.2 (d, J=17.2Hz), 116.3 (d, J=5.9Hz), 72.1, 42.7, 35.9, 29.5, 18.8, 11.3; 19 F NMR (376MHz, CDCl3): δ-140.0; HRMS (ESI) m / z calcd for C 13 H 16 FN2O[M+H + ]: 235.1241, found 235.1246.

[0092]

[0093] Characterization data: white solid, (48.8 mg, yield 86%)

[0094] 1 H NMR (400MHz, CDCl3): δ8.14 (s, 1H), 7.46-7.43 (m, 1H), 6.63 (d, J=8.4Hz, 1H), 4.90 (bs, 1H), 4.75-4.70 (m, 1H), 4.44-4.41 ( m, 1H), 2.66-259 (m, 1H), 1.92-1.88 (m, 2H), 1.73-1.69 (m, 1H), 1.66-1.55 (m, 1H), 1.34-1.23 (m, 1H), 1.02 (d, J=6.4Hz, 3H); 13C NMR (100MHz, CDCl3): δ161.9, 147.5, 130.1 (d, J=2.9Hz), 126.3 (d, J=4.2Hz), 125.7, 123.0, 120.3 (q, J=32.8Hz), 113.7, 74.6, 43.4, 37.4, 32.2, 24.2, 17.1; 19 F NMR (376MHz, CDCl3): δ-61.5; HRMS (ESI) m / z calcd for C 14 H 16 F3N2O[M+H + ]: 285.1209, found 285.1200.

[0095]

[0096] Characterization data: white solid, (55.5 mg, yield 95%).

[0097] 1 H NMR (400MHz, CDCl3): δ7.88-7.86 (m, 1H), 7.33-7.29 (m, 2H), 7.26-7.24 (m, 1H), 7.20-7 .14 ​​(m, 3H), 6.78 (t, J = 8.0Hz, 1H), 6.19 (d, J = 8.0Hz, 1H), 4.70-4.65 (m, 1H), 4.55-4.52 (m, 1H), 4.25 (bs, 1H), 2.85-2.80 (m, 1H), 2.65-2.57 (m, 1H), 2.55-2.50 (m, 1H), 2.09-2 .06(m, 1H), 1.83-1.75(m, 1H), 1.75-1.66(m, 1H), 1.57-1.53(m, 1H), 1.29-1.21(m, 1H); 13 CNMR (100MHz, CDCl3): δ163.6, 145.1, 139.2, 133.3, 128.9, 128.8, 128.4, 12 6.5, 118.7, 115.0, 114.1, 74.3, 43.2, 43.1, 39.3, 30.0, 24.0; HRMS (ESI) m / z calcd for C 19 H 21 N2O[M+H + ]: 293.1648, found 293.1648.

[0098]

[0099] Characterization data: white solid, (59.9 mg, yield 93%).

[0100] 1 H NMR (400MHz, CDCl3): δ7.87 (dd, J=7.6, 1.4Hz, 1H), 7.20-7.19 (m, 1H), 7.06 (d, J=8.4Hz, 2H), 6.85 (d, J=8.4Hz, 2H), 6.78-6.75 (m, 1H), 6.23 (d, J=7.6Hz, 1H), 4.69-4.65 (m, 1H), 4.54-4.51 (m, 1H), 4.21 (bs, 1H), 3.81 (s, 3H), 2.79-2.74 (m, 1H), 2.64-2.58 (m, 1H), 2.52-2.47 (m, 1H), 2 .18-2.05(m, 1H), 1.85-1.84(m, 1H), 1.70-1.67(m, 1H), 1.57-1.54(m, 1H), 1.28-1.22(m, 1H); 13 C NMR (100MHz, CDCl3): δ163.7, 158.3, 145.2, 133.3, 131.0, 129.9, 128.5, 118.8 , 115.1, 114.2, 114.0, 74.2, 55.3, 43.2, 43.0, 38.4, 29.9, 24.0; HRMS (ESI) m / z calcd for C 20 H 23 N2O2[M+H + ]: 323.1754, found 323.1757.

[0101]

[0102] Characterization data: white solid, (45.1 mg, yield 98%).

[0103] 1 H NMR (400MHz, CDCl3): δ7.90-7.88 (m, 1H), 7.27-7.23 (m, 1H), 6.81-6.77 (m, 1H), 6.57 (d, J=8.0Hz, 1H), 4.65-4.59 (m, 1H), 4.29(bs, 1H), 2.79-2.71(m, 1H), 2.12-2.10(m, 1H), 1.76-1.69(m, 3H), 1.40-1.37(m, 4H), 1.02(d, J=6.4Hz, 3H); 13C NMR (100MHz, CDCl3): δ163.8, 144.2, 133.4, 128.7, 118.7, 115.0, 114.1, 74.0, 41.2, 38.9, 29.5, 24.2, 17.1, 16.2; HRMS (ESI) m / z calcd for C 14 H 19 N2O[M+H + ]: 231.1492, found 231.1492.

[0104]

[0105] Characterization data: white solid, (47.3 mg, yield 97%).

[0106] 1 H NMR (400MHz, CDCl3): δ7.83 (dd, J=8.0, 1.6Hz, 1H), 7.22-7.17 (m, 1H), 6.68 (t, J=7.6Hz, 1H), 6.46 (d, J=8.0Hz, 1H), 4.80-4.76 (m, 1H), 4.07 ( bs, 1H), 2.69-2.62 (m, 1H), 2.25-2.20 (m, 2H), 1.79-1.74 (m, 1H), 1.66 -1.63(m, 2H), 1.44-1.51(m, 1H), 1.37-1.34(m, 1H), 0.98-0.92(m, 6H); 13 C NMR (100MHz, CDCl3): δ163.1, 145.0, 133.5, 128.6, 117.4, 113.1, 112.6, 77.1, 41.6, 38.6, 30.2, 25.1, 24.4, 15.7, 7.1; HRMS (ESI) m / z calcdforC 15 H 21 N2O[M+H + ]: 245.1648, foand 245.1642.

[0107]

[0108] Characterization data: white solid, (18.2 mg, yield 45%).

[0109] 1H NMR (400MHz, DMSO-d6): δ7.59 (dd, J=8.0, 1.2Hz, 1H), 7.25-7.23 (m, 1H), 6.93 (bs, 1H), 6.78 (d, J=8.0Hz, 1H), 6.7 4-6.69 (m, 1H), 4.48-4.46 (m, 1H), 3.55-3.41 (m, 2H), 2.07-2.04 (m, 2H), 1.56-1.50 (m, 1H), 1.14 (d, J=6.4Hz, 3H); 13 C NMR (100 MHz, DMSO-d6 ) : δ161.5, 149.1, 133.2, 127.6, 118.3, 117.3, 115.1, 75.3, 43.4, 40.1, 29.8, 15.6; HRMS (ESI) m / z calcd for C 12 H 15 N2O[M+H + ]: 203.1179, found 203.1177.

[0110]

[0111] Characterization data: white solid, (24.1 mg, yield 47%).

[0112] 1 H NMR (400MHz, DMSO-d6): δ7.60 (dd, J=7.6Hz, 1.6Hz, 1H), 7.50 (m, 1H), 7.28-7.24 (m, 1H), 6.73 (d, J=7.6Hz, 1H), 6.65 (d, J=8. 0Hz, 1H), 5.30-5.24(m, 1H), 5.21-5.02(m, 1H), 4.57-4.53(m, 1H), 2.84-2.80(m, 1H), 2.25-2.23(m, 1H), 1.70-1.63(m, 1H); 13 C NMR (100MHz, DMSO-d6): δ161.7, 146.3, 133.9, 127.3, 117.0, 113.7, 111.8, 8 8.8-88.4(m), 86.9-86.5(m), 67.7-67.2(m), 37.3-37.2(m), 28.0-27.7(m); 19 F NMR (376MHz, DMSO-d6): δ-123.6--124.2(m), -139.8--140.6(m), -199.3--199.4(m); HRMS(ESI)m / z calcd forC12 H12F3N2O[M+H + ]: 257.0896, found 257.0899.

[0113]

[0114] Characterization data: white solid, (24.1 mg, yield 44%).

[0115] 1 H NMR (400MHz, acetone-d6): δ7.29-7.23 (m, 1H), 6.96 (s, 1H), 6.64-6.62 (m, 1H), 6.42-6.38 (m, 1H), 5.30-5 .23(m, 1H), 5.30-5.01(m, 1H), 4.78-4.71(m, 1H), 2.89-2.82(m, 1H), 2.30-2.23(m, 1H), 1.94-1.80(m, 1H); 13 C NMR (100MHz, acetone-d6): δ165.0, 162.4, 159.7, 149.5, 135.6, 135.4, 110.5, 11.0 5, 106.1, 105.9, 89.8, 88.1-87.7(m), 69.5-69.0(m), 38.2-38.1(m), 28.9-28.6(m); 19 F NMR (376MHz, acetone-d6): δ-112.4--112.5(m), -125.7--126.3(m), -141.2--142.0(m), -201.3--201.5(m); HRMS(ESI)m / z calcd forC 12 H 11 F4N2O[M+H + ]: 275.0802, found 275.0809.

[0116]

[0117] Characterization data: white solid, (22.7 mg, yield 42%).

[0118] 1H NMR (400MHz, acetone-d6): δ7.72 (dd, J=7.6Hz, 1.6Hz, 1H), 7.26 (dt, J=7.6Hz, 1.6Hz, 1H), 6.74 (d, J=8.0Hz, 1H), 6.71 (dt, J=7.6Hz, 0.8Hz , 1H), 6.51 (bs, 1H), 5.40-5.20 (m, 1H), 4.83-4.76 (m, 1H), 3.07 (t, J= 13.6Hz, 1H), 2.30-2.26(m, 1H), 2.06-2.04(m, 1H), 1.77-1.76(m, 1H); 13 C NMR (100MHz, acetone-d6): δ162.7, 146.3, 134.6, 128.7, 118.1, 114.1, 112.7, 88.8-8 8.4(m), 86.9-86.5(m), 75.6-75.1(m), 35.1-34.9(m), 29.8-29.22(m), 23.1-23.1(m); 19 F NMR (376MHz, acetone-d6): δ-128.0--128.7(m), -133.7--134.3(m), -200.7--200.8(m); HRMS(ESI)m / z calcd for C 13 H14F3N2O[M+H + ]: 271.1053, found 271.1056.

[0119]

[0120] Characterization data: white solid, (38.9 mg, yield 90%).

[0121] 1 H NMR (400MHz, CDCl3): δ7.87-7.85 (m, 1H), 7.28-7.23 (m, 1H), 6.83-6.81 (m, 1H), 4.50 (bs, 1H), 3.87-3. 55 (m, 2H), 2.30-2.21 (m, 2H), 1.70-1.62 (m, 1H), 1.43 (s, 2.2H), 1.27 (s, 1.1H), 1.11 (d, J=6.8Hz, 3H); 13C NMR (100MHz, CDCl3): δ161.7, 146.2, 145.6, 133.0, 127.9, 118.9, 118.5, 116.6, 115.9, 114.9, 114.9, 114.9, 77.3, 45.1, 43.4, 42.6, 42.6, 29.4, 28.7, 26.1, 19.6, 15.3, 13.2; HRMS (ESI) m / z calcd for C 13 H 17 N2O[M+H + ]:217.1335, found217.1332.

[0122]

[0123] Characterization data: white solid, (38.9 mg, yield 90%).

[0124] 1 H NMR (400MHz, CDCl3): δ7.68 (m, 1H), 7.07 (d, J=8.0Hz, 1H), 6.60 (d, J=8.0Hz, 1H), 4.25 (bs, 1H), 3.89-3.51 (m, 2H), 2.30 -2.26 (m, 1H), 2.26 (s, 3H), 2.15-2.09 (m, 1H), 1.69-1.56 (m, 1H), 1.41 (s, 2.2H), 1.25 (s, 1.1H), 1.11 (d, J=6.8Hz, 3H); 13 C NMR (100MHz, CDCl3): δ161.8, 161.7, 143.8, 143.2, 133.8, 128.4, 128.0, 127.9, 116.9, 116.0, 115.1 , 115.1, 77.2, 77.7, 45.1, 43.5, 42.7, 42.5, 29.6, 28.8, 25.9, 20.3, 19.5, 15.2, 13.2; HRMS (ESI) m / z calcd for C 13 H 17 N2O[M+H + ]: 231.1492, found 231.1493.

[0125]

[0126] Characterization data: white solid, (56.6 mg, yield 97%).

[0127] 1H NMR (400MHz, CDCl3): δ7.91 (dd, J=7.6Hz, 1.6Hz, 1H), 7.34-7.32 (m, 2H), 7.27-7.23 (m, 4H), 6.87-6.83 (m, 1H), 6.62 (d, J=8.0 Hz, 1H), 4.10 (bs, 1H), 3.96-3.89 (m, 1H), 3.56-3.55 (m, 1H), 3.14-3.10 (m, 1H), 2.62-2.55(m, 2H), 2.03-1.99(m, 1H), 1.79-1.77(m, 1H), 1.48(s, 3H); 13 C NMR (100MHz, CDCl3): δ161.5, 145.7, 140.0, 133.1, 129.0, 128.7, 128.2, 126.4, 1 19.1, 116.0, 114.9, 77.5, 50.5, 42.7, 35.6, 29.7, 26.9, 26.8; HRMS(ESI)m / zcalcd for C 19 H 21 N2O[M+H + ]:293.1648.found 293.1651.

[0128] Embodiment 21

[0129] Substrate 1a (10 mmol, 2.14 g), photocatalyst 0.02 mmol 4DPAIPN (0.2 mol%), hydrogen atom transfer reagent 0.2 mmol methyl 2-mercaptobenzoate (2.0 mol%), additive 50 mmol water (1.0 equiv), reducing agent 25 mmol sodium formate (2.5 equiv) and solvent DMSO (40 mL) were added to a round-bottom flask and mixed. The reaction solution was heated with 20 w The reaction mixture was irradiated with a 467 nm blue LED lamp at room temperature (25°C) for 12 hours. After the reaction was completed, saturated brine and ethyl acetate were added to the mixture for extraction, and the aqueous phase was extracted three times with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and then concentrated by distillation under reduced pressure to remove the solvent to obtain a yellow oil. The yellow oil was separated by column chromatography using a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1 as an eluent for column chromatography. The eluate containing the target compound was collected, the solvent was evaporated and dried to obtain 1.72 g of white solid 2a with a yield of 81%.

Claims

1. A method for preparing a polycyclic dihydroquinazolinone derivative having antiviral activity, include: The compound of formula (I), a photocatalyst, a reducing agent, a hydrogen atom transfer agent, an additive and a solvent are mixed and reacted under sunlight or blue light to obtain a compound of formula (II), which is a polycyclic dihydroquinazolinone derivative with antiviral activity; in, The n is 0 or 1; R is hydrogen, C1-C3 alkyl with substituents, C1-C3 alkyl without substituents, C1-C3 alkoxy, halogen or amino; The R 1 is hydrogen or a C1-C6 alkyl group; The R 2 is hydrogen, C6-C12 aryl, C1-C6 alkyl or halogen; The R 3 is hydrogen, C6-C12 aryl, C1-C6 alkyl or halogen; The R 4 is hydrogen, C1-C6 alkyl or halogen; The photocatalyst is one or more of 4DPIPN, 4CzIPN and 3CzCIIPN; The hydrogen atom transfer reagent is a sulfur-containing and nitrogen-containing organic compound or a salt of a sulfur-containing and nitrogen-containing organic compound; The additive is one or more of water, formic acid, acetic acid, benzoic acid and p-toluenesulfonic acid; The reducing agent is one or more of sodium formate, potassium formate and cesium formate.

2. The preparation method according to claim 1, It is characterized in that The R is hydrogen, methyl, ethyl, propyl, trifluoromethyl, trifluoroethyl, fluorine, chlorine, bromine, methoxy, ethoxy or amino.

3. The preparation method according to claim 1, It is characterized in that The R 1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl or n-hexyl.

4. The preparation method according to claim 1, It is characterized in that The R 2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, phenyl or fluorine; The R 3 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, phenyl or fluorine; The R 4 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl or fluorine.

5. The preparation method according to claim 1, It is characterized in that The molar ratio of the compound of formula (I) to the photocatalyst is 1:(0.001-0.005).

6. The preparation method according to claim 1, It is characterized in that The hydrogen atom transfer reagent is one or more of 4-mercaptobenzoic acid, methyl thiosalicylate, 2-methoxythiophenol, triethylamine, diisopropylethylamine, triethylenediamine, thiolate and thiol. The molar ratio of the compound of formula (I) to the hydrogen atom transfer reagent is 1:(0.01N0.05).

7. The preparation method according to claim 1, It is characterized in that The molar ratio of the compound of formula (I) to the reducing agent is 1:(2-5).

8. The preparation method according to claim 1, It is characterized in that The solvent is DMSO, DMF, THF and CH 3 One or more of CN.

9. The preparation method according to claim 1, It is characterized in that The molar ratio of the compound of formula (I) to the additive is 1:(1-8).

10. The preparation method according to claim 1, It is characterized in that The compound of formula (II) has the following structure:

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