A tetranuclear ring derivative and a method for preparing the same

Abstract

The application belongs to the technical field of tetra-cyclic ring derivative preparation, and particularly relates to a tetra-cyclic ring derivative and a preparation method thereof. The preparation method of the tetra-cyclic ring derivative comprises the following steps: (1) adding two substrates, a photocatalyst and a solvent into a quartz tube and stirring; (2) placing the quartz tube under ultraviolet light to perform a photocatalytic reaction; and (3) evaporating the reaction liquid and separating the target compound through column chromatography. The application uses cis-olefin as a starting material to perform a cycloaddition reaction, has high regioselectivity and diastereoselectivity, effectively inhibits homodimerization of the olefin through a reversible cis-trans isomerization reaction, and thus efficiently obtains the tetra-cyclic ring derivative. The tetra-cyclic ring derivative prepared by the application plays a basic role in drug design and provides a solid structural support for a pharmaceutical molecule.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of tetra-cyclic ring derivative preparation, and particularly relates to a tetra-cyclic ring derivative and a preparation method thereof. BACKGROUND

[0002] Cyclobutane, oxetane and azetidine derivatives are an important class of cyclic compounds, which not only have extensive chemical properties, important biological activities and irreplaceable functions, but also are key active structural units in amino acids, alkaloids, natural and synthetic drugs. However, the preparation of tetra-cyclic compounds still faces challenges.

[0003] At present, the methods for preparing tetra-cyclic compounds include free radical cyclization, ring contraction, rearrangement and monomolecular cyclization reaction. Compared with these methods, the light-driven [2+2] cycloaddition method has obvious advantages such as high efficiency and simple operation. However, the light-driven [2+2] cycloaddition needs to go through a series of complex conversion processes: the first mechanism is to generate a transient p-p* excited singlet state by directly exciting the olefin substrate under light, and the reaction is carried out within its short life limit, therefore, this type of reaction needs to be carried out in concentrated solution or solid state, and the developed template guidance, crystal engineering and other strategies are mainly used for synthesizing homodimeric tetra-cyclic derivatives, which show excellent stereoselectivity, however, these strategies cannot effectively prepare asymmetric cyclobutane and heteroatom-containing tetra-cyclic ring; the other mechanism is to add a photosensitizer, which generates a long-lived triplet state intermediate under the action of the photosensitizer to participate in the subsequent reaction, and a number of methods for constructing tetra-cyclic ring have been successfully obtained by using this mechanism, but due to the difficulty in accurate control of high-energy excited states (such as olefin molecules, ketones and imines) under light excitation, the method is limited to the preparation of a single type of tetra-cyclic derivative. Therefore, it is urgent to realize an efficient and widely applicable tetra-cyclic ring construction strategy. SUMMARY

[0004] The application aims to provide a tetra-cyclic ring derivative and a preparation method and application thereof. The method can realize the catalytic synthesis of tetra-cyclic ring derivatives in homogeneous solution under mild conditions through the confinement effect of aza-cyclophane template.

[0005] The implementation process of the application is as follows:

[0006] A tetra-cyclic ring derivative, the structural formula of which is as follows:

[0007]

[0008] wherein X is selected from any one of C, O or N; n is 1 or 2.

[0009] R1 is selected from any one of phenyl, substituted phenyl, anthracenyl, acetyl, methoxycarbonyl, carboxyl, N-methylcarbamoyl, N-phenylcarbamoyl or N-naphthylcarbamoyl;

[0010] R2 is selected from any one of hydrogen, alkyl group having 1 to 6 carbon atoms, phenyl or

[0011] R3 is selected from any one of hydrogen, hydroxyl group, alkyl group having 1 to 6 carbon atoms, phenyl-substituted alkyl group having 1 to 6 carbon atoms, halogen-substituted phenyl-substituted alkyl group having 1 to 6 carbon atoms, naphthyl group, aldehyde group,

[0012] Further, the substituent of the substituted phenyl group is selected from any one of alkyl group having 1 to 6 carbon atoms, halogen group, halogenated carbon group, cyano group, cyano-substituted alkyl group having 1 to 6 carbon atoms, N-cycloalkyl-substituted carbamoyl group or

[0013] Further, the N-cycloalkyl-substituted carbamoyl group is

[0014] The preparation method of the tetranuclear ring derivative includes the following steps:

[0015] (1) adding substrate 1, substrate 2, a photo-catalyst and a solvent into a quartz tube and stirring;

[0016] (2) placing the quartz tube under ultraviolet light to perform photo-catalytic reaction, and stopping the reaction after the substrate 1 is completely reacted;

[0017] (3) evaporating the reaction solution, and separating and obtaining the target compound through column chromatography;

[0018]

[0019] R1 is selected from any one of phenyl, substituted phenyl, anthracenyl, acetyl, methoxycarbonyl, carboxyl, N-methylcarbamoyl, N-phenylcarbamoyl or N-naphthylcarbamoyl;

[0020] X in the substrate 2 is selected from any one of C, O or N; R2 is selected from any one of hydrogen, alkyl group having 1 to 6 carbon atoms, phenyl or

[0021] R3 is selected from any one of hydrogen, hydroxyl group, alkyl group having 1 to 6 carbon atoms, phenyl-substituted alkyl group having 1 to 6 carbon atoms, halogen-substituted phenyl-substituted alkyl group having 1 to 6 carbon atoms, naphthyl group, aldehyde group, ​​​​​​

[0022] The preparation method of the above-mentioned four-membered ring derivative comprises the following steps:

[0023] (1) adding the substrate 3, the substrate 4, a photo-catalyst and a solvent into a quartz tube and stirring;

[0024] (2) placing the quartz tube under ultraviolet light to perform a photo-catalytic reaction, and stopping the reaction after the substrate 3 is completely reacted;

[0025] (3) evaporating the reaction solution, and separating and obtaining the target compound through column chromatography;

[0026]

[0027] In the substrate 3, R1 is selected from any one of a phenyl group, a substituted phenyl group, an anthracene group, an acetyl group, a methoxycarbonyl group, a carboxyl group, an N-methyl carbamoyl group, an N-phenyl carbamoyl group or an N-naphthyl carbamoyl group;

[0028] In the substrate 4, X is selected from any one of C, O or N; n is 1 or 2; and R3 is selected from any one of a hydrogen group, a hydroxyl group, an alkyl group with 1-6 carbon atoms, a phenyl-substituted alkyl group with 1-6 carbon atoms, a halogen-substituted benzene-substituted alkyl group with 1-6 carbon atoms, a naphthyl group, an aldehyde group, In the substrate 4, X is selected from any one of C, O or N; n is 1 or 2; and R3 is selected from any one of a hydrogen group, a hydroxyl group, an alkyl group with 1-6 carbon atoms, a phenyl-substituted alkyl group with 1-6 carbon atoms, a halogen-substituted benzene-substituted alkyl group with 1-6 carbon atoms, a naphthyl group, an aldehyde group,

[0029] Further, in the step (1), the solvent is selected from any one of dimethyl sulfoxide, N,N-dimethylformamide or acetonitrile;

[0030] The substituent group of the substituted phenyl group is selected from any one of an alkyl group with 1-6 carbon atoms, a halogen group, a halogenated carbon group, a cyano group, a cyano-substituted alkyl group with 1-6 carbon atoms, The substituent group of the substituted phenyl group is selected from any one of an alkyl group with 1-6 carbon atoms, a halogen group, a halogenated carbon group, a cyano group, a cyano-substituted alkyl group with 1-6 carbon atoms,

[0031] Further, in the step (1), the structure of the photo-catalyst is The molar ratio of the substrate 1 to the substrate 2 is (0.09-0.11):1, and the molar ratio of the substrate 2 to the photo-catalyst is 1:(0.0015-0.0025).

[0032] Further, in the step (1), the structure of the photo-catalyst is The molar ratio of the substrate 3 to the substrate 4 is (0.09-0.11):1, and the molar ratio of the substrate 3 to the photo-catalyst is 1:(0.0015-0.0025).

[0033] Further, in the step (2), the wavelength of the ultraviolet light is 365 nm; and whether the substrate 1 is completely reacted is monitored by TLC.

[0034] Further, in step (3), the column chromatography filler is neutral alumina; and the developing agent in the column chromatography separation process is a mixed solution of petroleum ether, dichloromethane and triethylamine in a volume ratio of 2:1:1.

[0035] Advantages of the present application:

[0036] (1) The present application utilizes the confinement effect of the azacyclic carbene template to increase the local concentration of cis-olefin raw materials in homogeneous solution, providing conditions for the [2+2] photochemical cycloaddition reaction of short-lived intermediates. Meanwhile, cis-olefin is used as the starting material, and the concentration of trans-olefin is adjusted through controllable cis-trans isomerization, and the homodimerization reaction is further inhibited through ligand competition. Further, high-selectivity tetra-membered ring derivatives are prepared.

[0037] (2) The present application uses cis-olefin as the starting material for cycloaddition reaction, which has high regioselectivity and diastereoselectivity; the homodimerization reaction of olefins is effectively inhibited through reversible cis-trans isomerization, thereby efficiently obtaining tetra-membered ring derivatives.

[0038] (3) The tetra-membered ring derivatives obtained by the present application play a fundamental role in drug design, providing a solid structural support for pharmaceutical molecules, thereby widening their application potential in the field of medicine. BRIEF DESCRIPTION OF DRAWINGS

[0039] Figure 1 A schematic diagram of the reaction mechanism of the method of the present application;

[0040] Figure 2 A crystal structure of cyclobutane derivative 4a; 1 H NMR nuclear magnetic resonance spectrum;

[0041] Figure 3 A crystal structure of cyclobutane derivative 4a; 13 C NMR nuclear magnetic resonance spectrum;

[0042] Figure 4 A crystal structure of cyclobutane derivative 4a;

[0043] Figure 5 A crystal structure of oxetane derivative 5a; 1 H NMR nuclear magnetic resonance spectrum;

[0044] Figure 6 A crystal structure of oxetane derivative 5a; 13 C NMR nuclear magnetic resonance spectrum;

[0045] Figure 7 A crystal structure of azetidine derivative 6a; 1 H NMR nuclear magnetic resonance spectrum;

[0046] Figure 8azetidine derivative 6a 13 C NMR nuclear magnetic spectrum;

[0047] Figure 9 Cell survival rate chart of the target product obtained from Example 19 in human liver cancer cells (Hep G2) and human breast cancer cells (MCF-7). DETAILED DESCRIPTION

[0048] The application will be further described below in combination with examples.

[0049] The application realizes the preparation of a series of cyclobutane, oxetane and azetidine derivatives by the confinement effect of the azetidine carbene template, so that the short-lived intermediates perform the photocycloaddition reaction under low concentration conditions, and the preparation of the tetra-membered ring derivatives is realized with high selectivity, thereby providing a new idea for the preparation of tetra-membered ring derivatives.

[0050] The structural formula of the tetra-membered ring derivative is as follows:

[0051]

[0052] The preparation method of the above-mentioned tetra-membered ring derivative comprises the following steps:

[0053] (1) The substrate 1, substrate 2, photocatalyst and solvent are added to the quartz tube and stirred at room temperature; the solvent is selected from any one of dimethyl sulfoxide, N,N-dimethylformamide or acetonitrile. The amount of the solvent added is not limited, which can only dissolve the substrate 1 and substrate 2. The structure of the photocatalyst is The catalyst is derived from the binuclear gold carbene compound in the declared patent 202210274173.7. The molar ratio of the substrate 1 to the substrate 2 is (0.09-0.11):1, and the molar ratio of the substrate 2 to the photocatalyst is 1:(0.0015-0.0025). The stirring time at room temperature is not limited, as long as the mixture is uniform.

[0054] (2) The quartz tube is placed under ultraviolet light with a wavelength of 365 nm for photocatalytic reaction, and the reaction is terminated after the complete reaction of the substrate 1 is monitored by TLC;

[0055] (3) The reaction solution is evaporated to dryness, a mixture of petroleum ether, dichloromethane and triethylamine with a volume ratio of 2:1:1 is used as the developing agent, and neutral alumina is used for column chromatography separation to obtain the target compound.

[0056]

[0057] wherein R1 in substrate 1 is selected from any one of phenyl, substituted phenyl, anthracenyl, acetyl, methoxycarbonyl, carboxyl, N-methyl carbamoyl, N-phenyl carbamoyl or N-naphthyl carbamoyl; and the solvent is selected from any one of dimethyl sulfoxide, N,N-dimethylformamide or acetonitrile;

[0058] the substituent of the substituted phenyl is selected from any one of alkyl having carbon number 1-6, halogen, halogenated carbon, cyano, cyano-substituted alkyl having carbon number 1-6, any one of the above.

[0059] X in substrate 2 is selected from any one of C, O or N; R2 is selected from any one of hydrogen, alkyl having carbon number 1-6, phenyl or any one of the above;

[0060] R3 is selected from any one of hydrogen, hydroxyl, alkyl having carbon number 1-6, phenyl-substituted alkyl having carbon number 1-6, halogenated benzene-substituted alkyl having carbon number 1-6, naphthyl, aldehyde, any one of the above.

[0061] The second method for preparing the above tetranuclear ring derivative is different from the first method in that the compounds of substrate 1 and substrate 2 are replaced by substrate 3 and substrate 4.

[0062]

[0063] wherein R1 in substrate 3 is selected from any one of phenyl, substituted phenyl, anthracenyl, acetyl, methoxycarbonyl, carboxyl, N-methyl carbamoyl, N-phenyl carbamoyl or N-naphthyl carbamoyl; and the solvent is selected from any one of dimethyl sulfoxide, N,N-dimethylformamide or acetonitrile;

[0064] the substituent of the substituted phenyl is selected from any one of alkyl having carbon number 1-6, halogen, halogenated carbon, cyano, cyano-substituted alkyl having carbon number 1-6, any one of the above.

[0065] X in substrate 2 is selected from any one of C, O or N;

[0066] R3 is selected from any one of hydrogen, hydroxyl, alkyl having carbon number 1-6, phenyl-substituted alkyl having carbon number 1-6, halogenated benzene-substituted alkyl having carbon number 1-6, naphthyl, aldehyde, any one of the above.

[0067] Preparation of cyclobutane derivative 4a in Example 1

[0068] any one of the above.

[0069] A solution of 1e (0.10 mmol), 2a (1 mmol) and photocatalyst (0.002 mmol) in CH3CN (5 mL) was placed in a quartz tube and stirred at room temperature for 20 min, then the quartz tube was irradiated under UV light (λ = 365 nm) for 20 h to carry out the photocatalytic reaction. The reaction was monitored by TLC and stopped after the complete reaction of the substrate 1e. The reaction solution was evaporated by rotary evaporation under reduced pressure. The cyclobutane derivative 4a was purified by column chromatography on neutral Al2O3 with petroleum ether / dichloromethane / triethylamine (v / v / v, 2 / 1 / 1) as the developing agent to give 40.8 mg of cyclobutane derivative 4a in 99% yield. The structure of the photocatalyst is

[0070] Cyclobutane derivative 4a: 1 H NMR (CD3CN, 400 MHz) δ = 8.32-8.30 (m, 2H, Ar-H), 8.26-8.25 (m, 2H, Ar-H), 7.69-7.67 (m, 2H, Ar-H), 7.15-7.10 (m, 4H, Ar-H), 6.93 (d, 2H, J = 6.0 Hz, Ar-H), 4.26-4.16 (m, 2H, H cyclobutane ), 4.03-3.98 (m, 1H, H cyclobutane ), 2.78-2.63 (m, 2H, H cyclobutane ). 13 C{ 1 H} NMR (CD3CN, 100 MHz) δ = 150.6, 150.4, 150.3, 149.3, 144.7, 138.6, 130.0, 124.7, 124.0, 92.1, 51.1, 42.5, 41.2, 30.5 ppm. HRMS (ESI, positive ions): m / z = 413.0500 (calcd for [4a+H] + = 413.0509).

[0071] Example 2: Preparation of cyclobutane derivative 4b

[0072]

[0073] A solution of 1a (0.10 mmol), 2a (1 mmol) and photocatalyst (0.002 mmol) in CH3CN (5 mL) was placed in a quartz tube and stirred at room temperature for 10 min, then the quartz tube was irradiated under UV light (λ = 365 nm) for 20 h to carry out the photocatalytic reaction. The reaction was monitored by TLC and stopped after the complete reaction of the substrate 1a. The reaction solution was evaporated by rotary evaporation under reduced pressure. The cyclobutane derivative 4b was obtained by column chromatography on neutral Al2O3 with petroleum ether / dichloromethane / triethylamine (v / v / v, 2 / 1 / 1) as the developing agent, and the yield was 97%. The structure of the photocatalyst is

[0074] Cyclobutane derivative 4b: 1 H NMR (CD3CN, 400 MHz) δ = 8.32 (d, J = 5.2 Hz, 2H, Ar-H), 8.26 (d, J = 5.2 Hz, 2H, Ar-H), 7.37-7.31 (m, 4H, Ar-H), 7.24-7.21 (m, 1H, Ar-H), 7.13 (d, J = 5.2 Hz, 2H, Ar-H), 6.96 (d, J = 5.2 Hz, 2H, Ar-H), 4.31-4.20 (m, 2H, H cyclobutane ), 4.04-4.00 (m, 1H, H cyclobutane ), 2.79-2.67 (m, 2H, H cyclobutane ). 13 C{ 1 H} NMR (CD3CN, 100 MHz) δ = 150.8, 150.4, 150.3, 149.6, 144.7, 129.6, 127.6, 124.8, 124.1, 51.3, 42.5, 41.7, 30.7 ppm. HRMS (ESI, positive ions): m / z = 287.1544 (calcd for [4b + H] + 287.1543).

[0075] Example 3: Preparation of oxetane derivative 5a

[0076]

[0077] A mixture of 1a (0.11 mmol), 2b (1 mmol) and photocatalyst (0.0025 mmol) in N,N-dimethylformamide (6 mL) was placed in a quartz tube and irradiated under UV light (λ = 365 nm) at room temperature for 28 h. The reaction was monitored by TLC and stopped when the substrate 1a was completely consumed. The reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography on neutral Al2O3 with petroleum ether / dichloromethane / triethylamine (v / v / v, 2 / 1 / 1) as eluent to give the oxetane derivative 5a 18.4 mg in 61% yield. The structure of the photocatalyst is

[0078]

[0079] Cyclobutane derivative 5a: 1 H NMR (CD3CN, 400 MHz) δ = 8.40 (dd, J = 4.4, 1.6 Hz, 2H, Ar-H), 8.32 (dd, J = 4.8, 2.0 Hz, 2H, Ar-H), 7.54-7.52 (m, 2H, Ar-H), 7.45-7.41 (m, 2H, Ar-H), 7.38-7.34 (m, 1H, Ar-H), 7.15 (dd, J = 4.5, 1.6 Hz, 2H, Ar-H), 6.97 (dd, J = 4.4, 1.6 Hz, 2H, Ar-H), 5.96 (d, J = 8.4 Hz, 1H, H oxetane ), 4.24 (d, J = 8.4 Hz, 1H, H oxetane ), 1.92 (s, 3H, CH3). 13 C{ 1 H} NMR (CD3CN, 100 MHz) δ = 152.8, 150.6, 150.5, 145.5, 142.7, 129.8, 129.5, 126.6, 124.6, 121.7, 86.8, 80.0, 60.6, 30.9 ppm. HRMS (ESI, positive ions): m / z = 303.1487 (calcd for [5a + H] + = 303.1492).

[0080] Example 4: Preparation of oxetane derivative 5b

[0081]

[0082] A solution of 1b (0.09 mmol), 2b (1 mmol) and a photo-catalyst (0.0015 mmol) in dimethyl sulfoxide (5 mL) was placed in a quartz tube and irradiated under UV light (λ = 365 nm) at room temperature for 21 h. The reaction was monitored by TLC and stopped when the substrate 1b was completely consumed. The reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography on neutral Al2O3 with petroleum ether / dichloromethane / triethylamine (v / v / v, 2 / 1 / 1) as eluent to give the cyclobutane derivative 5b 22.4 mg, yield 70%. The structure of the photo-catalyst is

[0083]

[0084] Cyclobutane derivative 5b: 1 H NMR (CD3CN, 400 MHz) δ = 8.40 (dd, J = 4.4, 1.6 Hz, 2H, Ar-H), 8.31 (dd, J = 4.4, 1.6 Hz, 2H, Ar-H), 7.61-7.51 (m, 2H, Ar-H), 7.21-7.11 (m, 4H, Ar-H), 6.96 (dd, J = 4.4, 1.6 Hz, 2H, Ar-H), 5.94 (d, J = 8.5 Hz, 1H, H oxetane ), 4.24 (d, J = 8.5 Hz, 1H, H oxetane ), 1.92 (s, 3H, CH3). 13 C{ 1 H} NMR (CD3CN, 100 MHz) δ = 152.2, 150.6, 150.5, 145.3, 138.6, 128.9, 128.8, 124.5, 121.7, 116.6, 116.4, 87.2, 80.0, 60.6, 30.5 ppm. HRMS (ESI, positive ions): m / z = 321.1391 (calcd for [5b + H] + = 321.1398).

[0085] Example 5: Preparation of azetidine derivative 6a

[0086]

[0087] A mixture of 1a (0.10 mmol), 2d (1 mmol) and photocatalyst (0.0015 mmol) in N,N-dimethylformamide (7 mL) was placed in a quartz tube and irradiated under UV light (λ = 365 nm) at room temperature for 18 h. The reaction was monitored by TLC and stopped when the substrate 1c was completely consumed. The reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography on neutral Al2O3 with petroleum ether / dichloromethane / triethylamine (v / v / v, 2 / 1 / 1) as eluent to give the cyclobutane derivative 6a 22.9 mg in 68% yield. The structure of the photocatalyst is

[0088]

[0089] Azetidine derivative 6a: 1 H NMR (CD3CN, 400 MHz) δ = 8.35-8.30 (m, 4H, Ar-H), 7.65-7.62 (m, 2H, Ar-H), 7.49-7.45 (m, 2H, Ar-H), 7.25 (d, J = 5.8 Hz, 2H, Ar-H), 7.17 (d, J = 5.6 Hz, 2H, Ar-H), 6.65 (s, 1H, O-H), 5.43 (d, J = 9.7 Hz, 1H, H azetidine ), 5.17 (br, 1H, H azetidine ), 4.14 (dd, J = 9.5, 5.1 Hz, 1H, H azetidine ). 13 C{ 1 H} NMR (CD3CN, 100 MHz) δ = 150.5, 150.2, 134.4, 131.6, 129.4, 124.9, 124.1, 74.6, 73.8, 45.5 ppm. HRMS (ESI, positive ions): m / z = 338.1052 (calcd for [6a + H] + = 338.1055).

[0090] Example 6: Preparation of azetidine 6b derivative

[0091]

[0092] A mixture of 1a (0.11 mmol), 2d (1 mmol) and photocatalyst (0.002 mmol) in dimethyl sulfoxide (5 mL) was placed in a quartz tube and irradiated under UV light (λ = 365 nm) at room temperature for 17 h. The reaction was monitored by TLC and stopped when the substrate 1d was completely consumed. The reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography on neutral Al2O3 with petroleum ether / dichloromethane / triethylamine (v / v / v, 2 / 1 / 1) as the eluent to give the cyclobutane derivative 6b 24.8 mg in 65% yield. The structure of the photocatalyst is

[0093]

[0094] Azetidine derivative 6b: 1 H NMR (CD3CN, 400 MHz) δ = 8.35-8.30 (m, 4H, Ar-H), 7.64-7.55 (m, 4H, Ar-H), 7.25 (d, J = 5.9 Hz, 2H, Ar-H), 7.17 (d, J = 5.6 Hz, 2H, Ar-H), 6.66 (br, 1H, O-H), 5.43 (d, J = 9.6 Hz, 1H, H azetidine ), 5.16 (br, 1H, H azetidine ), 4.14 (dd, J = 9.5, 5.1 Hz, 1H, H azetidine ). 13 C{ 1 H} NMR (CD3CN, 100 MHz) δ = 150.4, 150.1, 147.9, 147.4, 132.4, 132.0, 124.9, 123.9, 122.6, 74.6, 73.7, 45.4 ppm. HRMS (ESI, positive ions): m / z = 382.0555 (calcd for [6b + H] + = 382.0550).

[0095] The preparation methods and parameters of Examples 7-9 are the same as those of Example 1, except that the substrates 1 and 2 are as shown in the following table, and the target products also change as shown in the following table due to the changes in substrates 1 and 2.

[0096] The preparation methods and parameters of Examples 10-63 are the same as those of Example 2, except that the substrates 1 and 2 are as shown in the following table, and the target products also change as shown in the following table due to the changes in substrates 1 and 2.

[0097] The preparation method and parameters of Example 64 are the same as those of Example 3, except that the substrate 3 and substrate 4 are shown in the following table, and the target product also changes as shown in the following table due to the change of the substrate 3 and substrate 4.

[0098] The preparation method and parameters of Example 65 are the same as those of Example 4, except that the substrate 3 and substrate 4 are shown in the following table, and the target product also changes as shown in the following table due to the change of the substrate 3 and substrate 4.

[0099] The preparation method and parameters of Example 66 are the same as those of Example 5, except that the substrate 3 and substrate 4 are shown in the following table, and the target product also changes as shown in the following table due to the change of the substrate 3 and substrate 4.

[0100] Table 1 Substrate 1 or 3, substrate 2 or 4 and target product of Example 7-Example 65

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109] Performance test:

[0110] The target product tetra-cyclic ring derivative obtained by the present application has wide chemical properties, important biological activity and irreplaceable function, and is a key active structure unit in amino acids, alkaloids, natural and synthetic drugs. The present application focuses on the structural design and synthesis research of tetra-cyclic ring derivative, and its performance is tested as follows.

[0111] The target product obtained in Example 19 is taken as an example to study its toxic effect on Hep G2 and MCF-7 cells.

[0112] (1) Cell culture

[0113] Human hepatoma (Hep G2) cells and human breast cancer (MCF-7) cells were cultured in a cell incubator at 37°C with 5% carbon dioxide, using DMEM high-sugar culture solution containing 1% penicillin / streptomycin stock solution and 10% fetal bovine serum (FBS).

[0114] (2) Cytotoxicity study

[0115] The cytotoxicity of the target product tetra-ring derivative obtained in Example 19 on Hep G2 and MCF-7 cells was detected by using a Cell Counting Kit-8 (CCK-8) method. When the cells entered the logarithmic growth phase, they were trypsinized with EDTA, centrifuged, and resuspended by blowing with DMEM high-sugar culture solution containing 10% FBS. Then, 10,000 cells per well were inoculated into a 96-well plate and incubated in a cell incubator for 24 h. After that, the culture solution in the wells was discarded, and DMEM culture solution containing different concentrations of the target product tetra-ring derivative obtained in Example 19 (0, 5, 10, 20, 50, and 100 μM) was added to the wells for co-incubation with the Hep G2 cells for 24 h. After 24 h, the culture solution containing the drug was discarded, 100 μL of 10% CCK8 / DMEM solution was added, and the plate was incubated in a cell incubator for 2 h. Then, the absorbance of each well was detected by using a microplate reader at a wavelength of 450 nm, and the survival rate of the cells was calculated.

[0116] The calculation formula of the cell survival rate is as follows:

[0117]

[0118] The cell survival rate values at different concentrations were introduced into GraphPad Prism software, and the half-inhibitory concentration (IC 50 ) of the target product tetra-ring derivative obtained in Example 19 in human hepatoma (Hep G2) cells and human breast cancer (MCF-7) cells was calculated by using nonlinear fitting. The half-inhibitory concentration (IC 50 ) refers to the concentration at which a certain substance inhibits a certain biological process by 50%. In this case, it refers to the concentration at which the target product tetra-ring derivative obtained in Example 19 induces apoptosis of tumor cells by 50%.

[0119] Similarly, the cytotoxicity of the target product tetra-ring derivative obtained in Example 19 on human breast cancer (MCF-7) cells was detected by using the same cell inoculation density, the same drug concentration, and the same cell treatment process and time. The half-inhibitory concentration (IC 50 ) of the target product tetra-ring derivative obtained in Example 19 in human hepatoma (Hep G2) cells was greater than 100 μmol / L, and the half-inhibitory concentration (IC 50 ) of the target product tetra-ring derivative obtained in Example 19 in human breast cancer (MCF-7) cells was 52.13 μmol / L.

[0120] Figure 1 Schematic diagram of reaction mechanism of the method of the present application.

[0121] Figure 2 NMR hydrogen spectrum of compound 4a in Example 1 of the present application is shown in Figure 1. Figure 2 It can be concluded that the structure of compound 4a is consistent with the NMR hydrogen spectrum information, and the specific spectrum information is as follows: 1 H NMR (CD3CN, 400 MHz) δ = 8.32-8.30 (m, 2H, Ar-H), 8.26-8.25 (m, 2H, Ar-H), 7.697.67 (m, 2H, Ar-H), 7.15-7.10 (m, 4H, Ar-H), 6.93 (d, 2H, J = 6.0 Hz, Ar-H), 4.26-4.16 (m, 2H, H cyclobutane ), 4.03-3.98 (m, 1H, H cyclobutane ), 2.78-2.63 (m, 2H, H cyclobutane ).

[0122] Figure 3 NMR carbon spectrum of compound 4a in Example 1 of the present application is shown in Figure 2. Figure 3 It can be concluded that the structure of compound 4a is consistent with the NMR carbon spectrum information, and the specific spectrum information is as follows: 13 C{ 1 H} NMR (CD3CN, 100 MHz) δ = 150.6, 150.4, 150.3, 149.3, 144.7, 138.6, 130.0, 124.7, 124.0, 92.1, 51.1, 42.5, 41.2, 30.5 ppm.

[0123] Figure 4 Crystal structure of compound 4a in Example 1 of the present application is shown in Figure 3. Figure 4 It can be concluded that the structure of compound 4f is consistent with the crystal structure information, and the obtained compound has single regioselectivity and diastereoselectivity, and the product is syn-HH configuration.

[0124] Figure 5 NMR hydrogen spectrum of compound 5a is shown in Figure 4. Figure 5 It can be seen that the structure of compound 5a is consistent with the NMR hydrogen spectrum information, and the specific spectrum information is as follows: 1H NMR (CD3CN, 400MHz) δ=8.40(dd,J=4.4,1.6Hz,2H,Ar-H),8.32(dd,J=4.8,2.0Hz,2H,Ar-H),7.54–7.52(m,2H,Ar-H),7.45–7.41( m,2H,Ar-H),7.38–7.34(m,1H,Ar-H),7.15(dd,J=4.5,1.6Hz,2H,Ar-H),6.97(dd,J=4.4,1.6Hz,2H,Ar-H),5.96(d,J=8.4Hz,1H,H oxetane ), 4.24 (d, J = 8.4 Hz, 1H, H oxetane ),1.92(s,3H,CH3).

[0125] Figure 6 For the carbon NMR characterization of oxobutane derivative 5a, from Figure 6 It can be seen that the structure of compound 5a is consistent with the information in its carbon NMR spectrum, and its specific spectral information is as follows: 13 C{ 1 H} NMR (CD3CN, 100MHz) δ = 152.8, 150.6, 150.5, 145.5, 142.7, 129.8, 129.5, 126.6, 124.6, 121.7, 86.8, 80.0, 60.6, 30.9ppm.

[0126] Figure 7 For the characterization of the nitrogen-containing heterocyclic butane derivative 6a by 1H NMR, from Figure 7 It can be seen that the structure of compound 6a is consistent with the information in its 1H NMR spectrum. The specific spectral information is as follows: 1 H NMR(CD3CN,400MHz)δ=8.35–8.30(m,4H,Ar-H),7.65–7.62(m,2H,Ar-H),7.49–7.45(m,2H,Ar-H) ,7.25(d,J=5.8Hz,2H,Ar-H),7.17(d,J=5.6Hz,2H,Ar-H),6.65(s,1H,OH),5.43(d,J=9.7Hz,1H,H azetidine ),5.17(br,1H,H azetidine ), 4.14(dd, J = 9.5, 5.1 Hz, 1H, H azetidine ).

[0127] Figure 8 For the carbon NMR characterization of the azacyclic butane derivative 6a, from Figure 8 It can be seen that the structure of compound 6a is consistent with the information in its carbon NMR spectrum. The specific spectral information is as follows: 13C{ 1 H}NMR (CD3CN, 100 MHz) δ = 150.5, 150.2, 134.4, 131.6, 129.4, 124.9, 124.1, 74.6, 73.8, 45.5 ppm.

[0128] Figure 9 The cell survival rate graph of the target product obtained from Example 19 in human liver cancer cells (Hep G2) and human breast cancer cells (MCF-7) is shown in Figure 2. Figure 9 It can be seen that the tetra ring derivative of the target product obtained from Example 19, when co-incubated with human liver cancer (Hep G2) cells and human breast cancer (MCF-7) cells at a low concentration, exhibits a high cell survival rate, and the cytotoxicity is low. However, when the concentration of the tetra ring derivative of the target product obtained from Example 19 is increased to 100 μM, the cell survival rate in human liver cancer cells (Hep G2) is higher than 70%, but the cell survival rate in human breast cancer cells (MCF-7) is only about 40%, and a certain cytotoxicity is exhibited at a high concentration.

[0129] The above is a further detailed description of the present application in combination with specific preferred embodiments, and it cannot be determined that the specific implementation of the present application is limited to these descriptions. For ordinary skilled persons in the art to which the present application belongs, without departing from the concept of the present application, a number of simple deductions or substitutions can be made, and all should be considered to belong to the protection scope of the present application.

Claims

1. A process for the preparation of a tetra cyclic ring derivative, characterized by, The method comprises the following steps: (1) Substrate 1, substrate 2, a photocatalyst, and a solvent are added to a quartz tube and stirred, the structure of the photocatalyst being ; the molar ratio of substrate 1 to substrate 2 is (0.09-0.11): 1, and the molar ratio of substrate 2 to the photocatalyst is 1:(0.0015-0.0025); (2) placing the quartz tube under ultraviolet light with a wavelength of 365 nm to perform a photocatalytic reaction, and terminating the reaction after the substrate 1 is completely reacted; (3) evaporating the reaction solution, and separating the target compound through column chromatography; ； In the substrate 1, R1 is selected from any one of a phenyl group, a substituted phenyl group, an anthracene group, an acetyl group, a methoxycarbonyl group, a carboxyl group, an N-methyl carbamoyl group, an N-phenyl carbamoyl group or an N-naphthyl carbamoyl group; X in substrate 2 is selected from any one of CH, O or N, R3 is absent when X is O; R2 is selected from any one of hydrogen, an alkyl group having a carbon number of 1 to 6, a phenyl group or any one of R3is selected from any one of hydrogen, hydroxyl, alkyl group having 1 to 6 carbon atoms, phenyl-substituted alkyl group having 1 to 6 carbon atoms, halogenated benzene-substituted alkyl group having 1 to 6 carbon atoms, naphthyl group, aldehyde group, or group having 1 to 6 carbon atoms, phenyl-substituted alkyl group having 1 to 6 carbon atoms, halogenated benzene-substituted alkyl group having 1 to 6 carbon atoms, naphthyl group, aldehyde group, 2. The process for the preparation of the tetranuclear derivative according to claim 1, characterized in that, The method comprises the following steps: (1) substrate 1, substrate 2 are replaced by substrate 3, substrate 4, and a photocatalyst and a solvent are added into a quartz tube, and stirring is carried out, the structure of the photocatalyst is ; the molar ratio of substrate 3 to substrate 4 is (0.09-0.11):1, and the molar ratio of substrate 3 to the photocatalyst is 1:(0.0015-0.0025); (2) placing the quartz tube under ultraviolet light with a wavelength of 365 nm to perform a photocatalytic reaction, and terminating the reaction after the substrate 3 is completely reacted; (3) evaporating the reaction solution, and separating the target compound through column chromatography; ； In the substrate 3, R1 is selected from any one of a phenyl group, a substituted phenyl group, an anthracene group, an acetyl group, a methoxycarbonyl group, a carboxyl group, an N-methyl carbamoyl group, an N-phenyl carbamoyl group or an N-naphthyl carbamoyl group; X in substrate 4 is selected from any one of CH, O or N, R3is absent when X is O; n is 1 or 2; R3is selected from any one of hydrogen, hydroxyl, alkyl of 1-6 carbon atoms, phenyl-substituted alkyl of 1-6 carbon atoms, halogenated benzene-substituted alkyl of 1-6 carbon atoms, naphthyl, aldehyde, or groups.

3. Process for the preparation of the tetranuclear ring derivative according to claim 1 or 2, characterized in that: In step (1), the solvent is selected from any one of dimethyl sulfoxide, N,N-dimethylformamide or acetonitrile; the substituent of the substituted phenyl group is selected from the group consisting of alkyl group having 1 to 6 carbon atoms, halogen group, halogenated carbon group, cyano group, cyano-substituted alkyl group having 1 to 6 carbon atoms, , , , , or .

4. The process for the preparation of the tetranuclear ring derivative according to claim 1, characterized by the fact that: In step (2), whether the substrate 1 is completely reacted is monitored through TLC.

5. A process for the preparation of the tetranuclear ring derivative according to claim 1 or 2, characterized by: In step (3), the column chromatography filler is neutral alumina, and the developing agent in the column chromatography separation process is a mixed solution of petroleum ether, dichloromethane and triethylamine with a volume ratio of 2:1:1.

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