Synthesis method of polycyclic quinazolinone derivative with antiviral activity

Abstract

The invention provides a synthesis method of a polycyclic quinazolinone derivative with antiviral activity, which comprises the following steps: mixing an N-alkyl olefin quinazolinone compound, a compound with a structure as shown in a formula (II), a photocatalyst, an additive and a solvent, and reacting under a blue light irradiation condition to obtain the polycyclic quinazolinone derivative with a structure as shown in a formula (III), results show that according to the method provided by the invention, by selecting the specific additive and the photocatalyst, the application range of the reaction to the substrate is wide, the reaction can be carried out without activating a high-activity functional group near the reaction site of the substrate, the reaction condition is mild and green, the reaction conversion can be completed under the irradiation of blue light, and the method is suitable for industrial production. The dosage of the photocatalyst is only about 0.5 mol%, and the catalytic efficiency is high; meanwhile, a specific photocatalyst is selected, so that the yield is increased, and reactants are clean and pollution-free; good application prospects and research values are realized.

Description

Technical Field

[0001] The invention relates to the field of drug synthesis, and in particular to a method for synthesizing a polycyclic quinazolinone derivative with antiviral activity. Background Art

[0002] Polycyclic quinazolinone and its derivatives are important skeletons of many natural alkaloids. So far, there are about 200 natural products and commercial drugs containing quinazolinone, especially in polycyclic quinazolinone natural products, compounds containing ester and ketone groups on the C ring of the skeleton often show anti-tumor, anti-viral and anti-bacterial activities, such as: the natural products and drug molecules containing polycyclic quinazolinone skeleton shown in the following structural formula have anti-viral activity, anti-bacterial activity, anti-cancer activity, anti-depressant activity, anti-Alzheimer's disease activity, etc. Therefore, they have received widespread attention from medicinal chemists and chemists.

[0003]

[0004] Polycyclic quinazolinone derivatives containing functional groups such as carboxyl, amide, ketone or cyano can also be used as important chemical building blocks and widely used in functional group transformation, functional material synthesis and drug discovery. Therefore, it is of great significance to synthesize polycyclic quinazolinone derivative molecules containing functional groups.

[0005] Traditional methods for constructing polycyclic quinazolinones often require transition metals, such as heavy metal catalysts such as Cu, Ni, and Ru, organotin reagents or equivalent oxidants, resulting in poor atom economy and the generation of toxic waste. In the past few years, the synthesis of polycyclic quinazolinone core skeletons has been mainly based on quinazoline-4-one substrates with N-alkylene side chains, which are prepared by tandem cyclization reactions of free radicals initiated under various conditions. For example, the C(sp) cyclization of alkyl esters was directly induced by di-tert-butyl peroxide (DTBP) or tert-butyl peroxide (TBHP) at 120°C. 3 )-H bond activation, and the polycyclic quinazolinone containing an ester structure is synthesized through a free radical tandem reaction. In addition, since the photochemical reaction has the outstanding characteristics of simple operation, environmental protection and low cost, the photosynthesis method of polycyclic quinazolinone compounds containing an ester structure has attracted much attention. However, the current photochemical synthesis of polycyclic quinazolinone containing an ester structure still faces certain shortcomings. For example: the need to use ultraviolet light, the narrow scope of application of the substrate, the need to add an oxidant, and the use of unstable sulfur ylide substrates.

[0006] Therefore, it is of great significance to improve the adaptability of substrates and develop green and environmentally friendly synthesis methods with mild reaction conditions. Summary of the invention

[0007] In view of this, the technical problem to be solved by the present invention is to provide a green synthesis method for polycyclic quinazolinone 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.

[0008] Compared with the prior art, the present invention provides a method for synthesizing a polycyclic quinazolinone derivative with antiviral activity. The method provided by the present invention comprises the steps of mixing an N-alkyl olefin quinazolinone compound, a compound of a structure of formula (II), a photocatalyst, an additive and a solvent, and reacting the mixture under blue light irradiation to obtain a polycyclic quinazolinone derivative of a structure of formula (III). Experiments have shown that the method provided by the present invention has a wide range of application for substrates by selecting specific additives and photocatalysts, and that the reaction can occur without activating highly active functional groups near the reaction sites of the substrate of formula (II), and that the reaction is mild and green. The reaction conversion can be completed under blue light irradiation, and the amount of the photocatalyst used is only about 0.5 mol%, with high catalytic efficiency. At the same time, the use of a specific photocatalyst not only improves the yield, but also makes the reactants clean and pollution-free. The method has good application prospects and research value. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 This is the hydrogen spectrum of the compound prepared in Example 1 of the present invention;

[0010] Figure 2 This is the carbon spectrum of the compound prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0011] The present invention provides a method for synthesizing a polycyclic quinazolinone derivative having antiviral activity, comprising:

[0012] The compound of formula (I), the compound of formula (II), a photocatalyst, an additive and a solvent are mixed and reacted under blue light irradiation to obtain a polycyclic quinazolinone derivative of formula (III);

[0013]

[0014] in,

[0015] The n is selected from 1, 2 or 3;

[0016] The R is selected from hydrogen, C1-C6 alkyl with substituents, C1-C6 alkyl without substituents, C1-C3 alkoxy, halogen, C2-C15 carboxylate, C2-C5 alkoxycarbonyl;

[0017] R1 is hydrogen or a C1-C3 alkyl group without a substituent;

[0018] R2 is hydrogen or a C1-C3 alkyl group without a substituent;

[0019] R3 is hydrogen or a C1-C3 alkyl group without a substituent;

[0020] R4 is cyano or Wherein, Ra is a hydroxyl group, a C1-C6 alkyl group without a substituent, a C1-C3 alkoxy group, a C1-C8 amine group or a C6-C30 aromatic group;

[0021] The additive is a carbonate or a bromide salt;

[0022] The photocatalyst is one or both of 4DPAIPN and 4CzIPN;

[0023]

[0024] According to the present invention, R is preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, propionate or isobutylbenzene propionate, more preferably hydrogen, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, fluorine or chlorine; R1 is preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl or n-hexyl. R2 is preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl or n-hexyl; R3 is preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl or n-hexyl; R a Preferred are hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, dimethylamino, diethylamino, phenyl, naphthyl, biphenyl or anthracenyl.

[0025] More specifically, the polycyclic quinazolinone derivative of formula (III) has the following structure:

[0026]

[0027] It should be noted that the R group in the general formula of the compound of formula (I) of the present invention may be a substituent at any one or two positions on the benzene ring.

[0028] According to the present invention, the compound of formula (I), the compound of formula (II), a photocatalyst, an additive and a solvent are mixed and reacted under blue light irradiation to obtain a polycyclic quinazolinone derivative of formula (III); wherein the molar ratio of the compound of formula (I) to the compound of formula (II) is preferably 1: (1.5-4), more preferably 1: (2-3); the molar ratio of the compound of formula (I) to the photocatalyst is preferably 1: (0.001-0.02), more preferably 1: (0.005-0.015); the additive is one or more of sodium bromide, potassium bromide, sodium carbonate and potassium carbonate, more preferably sodium bromide or potassium bromide; the molar ratio of the compound of formula (I) to the additive is preferably 1: (0.5-0.015); 4), more preferably 1:(1-3); the solvent is preferably one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran and CH3CN, more preferably one or two of N,N-dimethylformamide and N,N-dimethylacetamide; the compound of formula (I) and the solvent are preferably 1mmol:(2-12)mL, more preferably 1mmol:(6-10)mL; the present invention has no special requirements for the blue light used for reflection, and any blue light source known in the art can be used, preferably a blue LED lamp with a wavelength of 420-460nm, and more preferably a 20w, 430nm blue LED lamp. The present invention has no special requirements 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 5 to 36 hours, more preferably 10 to 24 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 saline to quench the reaction, extracts the reaction solution with an organic solvent, and extracts the aqueous phase 2 to 3 times, combines the organic phases, dries, and distills and concentrates to obtain a polycyclic quinazolinone derivative with a structure of formula (III), wherein the organic solvent for extraction is preferably ethyl acetate; the drying agent for drying is preferably anhydrous magnesium sulfate; the present invention also preferably purifies the obtained concentrate again by column chromatography to obtain a high-purity polycyclic quinazolinone derivative with a structure of formula (III), wherein the column chromatography eluent 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, more preferably 4:1.

[0029] The invention provides a method for synthesizing a polycyclic quinazolinone derivative. The method provided by the invention comprises the steps of mixing an N-alkyl olefin quinazolinone compound, a compound of a structure of formula (II), a photocatalyst, an additive and a solvent, and reacting the mixture under blue light irradiation to obtain a polycyclic quinazolinone derivative of a structure of formula (III). The results show that the method provided by the invention has a wide range of application to substrates, and that the reaction can occur without activating a highly active functional group near the reaction site of the substrate, and that the reaction is mild and green. The reaction conversion can be completed under blue light irradiation, and that the amount of the photocatalyst used is only about 0.5 mol%, and that the catalytic efficiency is high. At the same time, the use of a specific photocatalyst not only improves the yield, but also makes the reactants clean and pollution-free. The method has good application prospects and research value.

[0030] 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.

[0031] 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 (δ = 2.05 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), Acteone-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.

[0032] The reaction substrates involved in this embodiment are shown in Table 1:

[0033] Table 1: Substrates involved in the embodiments of the present invention

[0034]

[0035] The substrates involved in the present invention are prepared according to the methods disclosed in the prior art:

[0036] The references used for the synthesis of substrates 1a-1j are as follows: L. Dong, XQ Wang, YH Gou, ZS Yu, Org. Lett., 2024, 26, 8756; the synthesis reaction equation is:

[0037]

[0038] Under N2 condition, in 50mL round-bottom flask, 1a (1.0 g, 5.0 mmol), methyl chloroacetate 2a (1.1 g, 10.0 mmol), 4CzIPN (19.7 mg, 0.5 mol%), NaBr (0.5 g, 5.0 mmol) mixture was dissolved in 20 mL DMA, and irradiated at room temperature for 24 hours with blue LED (430 nm, 20 W) lamp. Then, 40 mL saturated NaCl quenched reaction mixture was extracted three times with EA (3x30 mL). Organic layer was dried with anhydrous MgSO4, concentrated under reduced pressure. Residue obtained by silica gel column chromatography (PE / EA=4 / 1) purification, light yellow oily liquid 3a, and productive rate was 85%.

[0039] 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.

[0040] Its characterization data are as follows:

[0041] 1 H NMR (400MHz, CDCl3): δ8.26 (dd, J=8.0, 1.2Hz, 1H), 8.02 (s, 1H), 7.71 (td, J=8.0, 1.2Hz, 1H), 7.66 (dd, J=8.0, 1.2Hz, 1H), 7.43 (td, J=8.0, 1.2Hz, 1H), 4.29-4.23(m, 1H), 4.03-3.96(m, 1H), 3.68(s, 3H), 3.29- 3.25(m, 1H), 2.64-2.61(m, 1H), 2.47-2.37(m, 2H), 1.98-1.87(m, 2H);

[0042] 1 3C NMR (100MHz, CDCl3): δ173.3, 160.9, 160.7, 149.1, 134.0, 127.1, 126.3, 126.3, 120.7, 51.7, 44.6, 42.9, 31.5, 27.3, 26.5;

[0043] HRMS(ESI)m / z calcd for C 15 H 17 N2O3[M+H + ]: 273.1234, found 273.1231.

[0044] Example 2

[0045] Consistent with the preparation method and substrate of Example 1, when the amount of each raw material used is the same, the type of reaction catalyst, the type of additive or no additive is added, to obtain polycyclic quinazolinone derivatives (see Table 2 Series 2 to Series 10); in Series 11N13, the amount of the additive sodium bromide is changed to 0.2 equivalents (0.2 equiv.), 0.5 equivalents (0.5 equiv.) and 2 equivalents (2 equiv.), respectively; the reaction results are shown in Table 2, which is the condition screening results of the present invention.

[0046] Table 2

[0047]

[0048] Wherein, a represents the isolated yield.

[0049] It can be seen from Table 2 that when no additive is used, the product is basically the by-product 4, and the yield is better when sodium bromide is used as the additive, and the amount of the additive has a greater impact on the reaction yield. When 1 equivalent of the additive is used, the reaction effect is best.

[0050] Example 3

[0051] According to the preparation method of Example 1, different substrates 1 and 2 were selected to prepare a series of polycyclic quinazolinone derivatives of formula (III), and the results and characterization data are as follows:

[0052]

[0053] Characterization data: yellow oily liquid, yield 76%;

[0054] 1H NMR (400MHz, CDCl3): δ8.22 (dd, J=8.0, 1.2Hz, 1H), 7.67 (td, J=8.0, 1.2Hz, 1H), 7.59 (d, J=8.0, 1H), 7.39 (t, J=8.0, 1H), 4.30-4.23 (m , 1H), 3.90-3.88(m, 1H), 3.62(s, 3H), 2.91-2.88(m, 2H), 2.61-2.56(m, 1H), 2.44-2.42(m, 1H), 1.99-1.97(m, 3H), 1.67-1.58(m, 1H);

[0055] 13 C NMR (100MHz, CDCl3): δ173.8, 162.0, 156.7, 147.1, 133.9, 126.8, 126.5, 126.1, 120.2, 51.5, 41.3, 39.5, 31.7, 28.1, 25.0, 20.1;

[0056] HRMS(ESI)m / z calcd for C 16 H19N2O3[M+H+]: 287.1390, found 287.1388.

[0057]

[0058] Characterization data: white solid, yield 83%;

[0059] 1 H NMR (400MHz, DMSO-d6): δ12.19 (bs, 1H), 8.13 (d, J=8.0Hz, 1H), 7.80 (t, J=7.6Hz, 1H), 7.66 (d, J=8.0Hz, 1H), 7.49 (t, J=7.6Hz, 1H), 4 .17-4.12(m, 1H), 3.94-3.87(m, 1H), 3.33-3.27(m, 1H), 2.52-2.48(m, 2H), 2.40-2.38(m, 1H), 2.29-2.26(m, 1H), 1.89-1.77(m, 2H);

[0060] 13 C NMR (100MHz, DMSO-d6): δ174.2, 161.8, 159.9, 149.0, 134.0, 126.9, 126.0, 125.7, 120.4, 44.5, 42.4, 31.2, 26.7, 25.6;

[0061] HRMS(ESI)m / z calcd for C 14 H15N2O3[M+H+]: 259.1077, found 259.1075.

[0062]

[0063] Characterization data: white solid, yield 74%;

[0064] 1 H NMR (400MHz, DMSO-d6): δ12.06 (bs, 1H), 8.09 (d, J=8.8Hz, 1H), 7.77 (t, J=8.8Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.46 (t, J=7.2Hz, 1H), 4.18-4.12 (m, 1H), 3.84-3.77 (m, 1H), 2.95-2.87 (m, 1H), 2.45-2.42 (m , 2H), 2.38-2.29(m, 1H), 2.09-2.02(m, 1H), 1.95-1.84(m, 2H), 1.82-1.78(m, 1H), 1.57-1.50(m, 1H);

[0065] 13 C NMR (100MHz, DMSO-d6): δ174.5, 161.0, 157.8, 146.9, 134.1, 126.7, 126.0, 126.0, 119.8, 41.0, 38.9, 31.4, 27.6, 24.1, 19.7;

[0066] HRMS (ESI) m / z calculation for C 15 H 17 N2O3[M+H + ]: 273.1234, found 273.1229.

[0067] The above embodiments are only used to help understand the method and core idea of ​​the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A method for synthesizing a polycyclic quinazolinone derivative having antiviral activity, comprising: The compound of formula (I), the compound of formula (II), a photocatalyst, an additive and a solvent are mixed and reacted under blue light irradiation to obtain a polycyclic quinazolinone derivative of formula (III); in, The n is selected from 1, 2 or 3; The R is selected from hydrogen, C1-C6 alkyl with substituents, C1-C6 alkyl without substituents, C1-C3 alkoxy, halogen, C2-C15 carboxylate or C2-C5 alkoxycarbonyl; R1 is hydrogen or a C1-C3 alkyl group without a substituent; R2 is hydrogen or a C1-C3 alkyl group without a substituent; R3 is hydrogen or a C1-C3 alkyl group without a substituent; R4 is cyano or Wherein, Ra is a hydroxyl group, a C1-C6 alkyl group without a substituent, a C1-C3 alkoxy group, a C1-C8 amine group or a C6-C30 aromatic group; The additive is a carbonate or a bromide salt; The photocatalyst is one or both of 4DPAIPN and 4CzIPN; 2. The preparation method according to claim 1, characterized in that: The R is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, propionate or isobutylpropionate.

3. The preparation method according to claim 1, characterized in that: The R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl or n-hexyl.

4. The preparation method according to claim 1, characterized in that: The R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl or n-hexyl; The R3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl or n-hexyl.

5. The preparation method according to claim 1, characterized in that: The Ra is selected from hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, dimethylamino, diethylamino, phenyl, naphthyl, biphenyl or anthracenyl.

6. The preparation method according to claim 1, characterized in that: The molar ratio of the compound of the formula (I) to the compound of the formula (II) is 1:(1.5-4).

7. The preparation method according to claim 1, characterized in that: The molar ratio of the compound of formula (I) to the photocatalyst is 1:(0.001-0.010).

8. The preparation method according to claim 1, characterized in that: The solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran and CH3CN.

9. The preparation method according to claim 2, characterized in that: The additive is one or more of sodium bromide, potassium bromide, sodium carbonate and potassium carbonate.

10. The preparation method according to claim 1, characterized in that: The polycyclic quinazolinone derivative of formula (III) has the following structure:

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