A dihydroisoxazole molecule and its synthesis method

Abstract

This invention discloses a dihydroisoxazole molecule, a method for synthesizing the compound, and its pharmaceutical applications. The dihydroisoxazole molecule of this invention contains a pyridine group, which is significant for molecule modification in the later stages of pyridine drug synthesis and for accelerating the screening of clinical drug candidates. The dihydroisoxazole molecule contains coordinating nitrogen and oxygen atoms; as a ligand, the synthesized nitrogen-containing bicyclic compound can be used to design metal catalysts; as a molecular probe, the dihydroisoxazole molecule can be used for drug candidate discovery; and as a scaffold, the dihydroisoxazole molecule can be used in materials science.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a pyridine-substituted isoxazole molecule. BACKGROUND

[0002] Pyridine and isoxazole and other nitrogen-containing heterocycles are important structural units in bioactive natural products, drug molecules and functional materials. Chemical modification of the pyridine core skeleton, especially modification of the molecule in the late stage of drug synthesis, can accelerate the screening of clinical candidate drugs. Due to the relatively low reactivity of the pyridine group, the introduction efficiency of the traditional method is low, which restricts the further development of the pyridine group in the field of applied chemistry. At the same time, the synthesis of pyridine derivatives is still focused on the attack of some relatively stable alkyl radicals on pyridinium salts, such as secondary alkyl radicals and tertiary alkyl radicals, and the coupling reaction of primary alkyl radicals with pyridinium salts is still a challenging work. SUMMARY

[0003] To solve the above technical problems, the purpose of the present application is to provide a synthesis method of a pyridine-substituted heterocyclic compound with high selectivity, which effectively solves the problem of low reactivity of pyridine.

[0004] To achieve the above purpose, the present application provides a compound of formula I, and the structural formula is as follows:

[0005]

[0006] wherein R 1 , R 2 is an alkyl group or H, R 3 , R 4 is any one of an aromatic group, an alkyl group, a halogen, H.

[0007] Preferably, wherein R 1 , R 2 is a C1-4 alkyl group or H, R 3 is any one of a phenyl group, H, CN-, halomethyl, Cl, F, Br, MeCO-, MeCO2-, C1-4 alkyl group; R 4 is any one of a C1-4 alkyl group, a phenyl group, H.

[0008] Preferably, wherein R 1 , R 2 is a methyl group or H, R 3 is any one of a phenyl group, H, CN-, CF3, Cl, MeCO-, MeCO2-, a methyl group; R 4 is any one of a methyl group, a phenyl group, H.

[0009] Preferably, the compound of formula I is selected from 4,4-dimethyl-3-phenyl-5-(pyridine-2-methyl)-4,5-dihydroisoxazole, 4,4-dimethyl-3-phenyl-5-(pyridine-4-methyl)-4,5-dihydroisoxazole, 4,4-dimethyl-3-phenyl-5-(4-(trifluoromethyl)pyridine-2-methyl)-4,5-dihydroisoxazole, 5-(4-chloropyridine-2-methyl)-4,4-dimethyl-3-phenyl-4,5-dihydroisoxazole, 4,4-dimethyl-5-(4-methylpyridine-2-methyl)-3-phenyl-4,5-dihydroisoxazole, 4,4-dimethyl-3-phenyl-5-(4-phenylpyridine-2-methyl)-4,5-dihydroisoxazole, 4,4-dimethyl-3-phenyl-5-(6-phenylpyridine-2-methyl)-4,5-dihydroisoxazole, 4,4-dimethyl-3-phenyl-5-(2-phenylpy-4-methyl)-4,5-dihydroisoxazole or 5-(2,6-dimethylpyridine-4-methyl)-4,4-dimethyl-3-phenyl-4,5-dihydroisoxazole.

[0010] The present application also provides a synthesis method of the compound of formula I, which comprises the following steps: using an oxime and an N-methoxypyridinium salt as raw materials, and synthesizing the compound of formula I by visible light catalysis.

[0011] Preferably, the synthesis method is as follows:

[0012]

[0013] Preferably, the oxime, the N-methoxypyridinium salt, manganese acetate dihydrate and a photocatalyst are mixed, an organic solvent is added under an inert gas environment, blue light is irradiated, and magnetic stirring is performed until the reaction is completed. After the reaction, the solution is extracted with ethyl acetate, the combined organic phase is washed with saturated brine, then dried with anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the concentrated crude product is separated and purified by silica gel column chromatography to obtain the compound of formula I.

[0014] Preferably, the photocatalyst is bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bipyridine]iridium di(hexafluorophosphate) salt.

[0015] Preferably, the mass concentration ratio of the oxime and the N-methoxypyridinium salt is 1:2.5.

[0016] Preferably, the organic solvent comprises any one of dichloromethane, acetonitrile and 1,2-dichloroethane.

[0017] Preferably, the wavelength of the blue light is 440 nm or 456 nm, the light intensity is 10 watts, and the irradiation time is 10-16 hours.

[0018] Preferably, in a 10 mL reaction tube, oxime 1 (0.1 mmol, 1.0 equiv.), N-methoxy pyridinium salt 2 (0.25 mmol, 2.5 equiv.), manganese acetate dihydrate (32.2 mg, 0.12 mmol) and photocatalyst bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bipyridine]iridium dihexafluorophosphate (2.0 mg, 2 mol%) are added. The reaction solution is protected by nitrogen and 1 mL of organic solvent is added, which can be dichloromethane, acetonitrile, 1,2-dichloroethane, among which dichloromethane is the best. The reaction is irradiated under blue light (wavelength 440 nm or 456 nm, light intensity 10 watts) and magnetically stirred for 16 hours. After the reaction is completed, ethyl acetate is used for extraction (3 x 25 mL), the combined organic phase is washed with saturated brine (1 x 30 mL), then dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the concentrated crude product is separated and purified by silica gel column chromatography (petroleum ether and ethyl acetate as eluent) to obtain the methylene bridged double heterocyclic compound.

[0019] The present application also provides the use of the compound of formula I in the preparation of a medicament for treating liver cancer, breast cancer or colon cancer.

[0020] Compared with the prior art, the technical scheme of the present application has the following innovative points:

[0021] The advantage of the present application is that the alkoxyl radical generated under visible light catalysis based on N-methoxy pyridinium salt is used as a further single electron transfer initiator, and at the same time, the electron-deficient pyridinium salt can also be used as a radical acceptor, and the synthesis route is simple and economical.

[0022] The pyridinium salt has high reactivity, and the raw material is easy to synthesize. Using pyridinium salt as a precursor molecule for introducing pyridine can effectively solve the problem of low reactivity of pyridine.

[0023] The synthesized dihydroisoxazole molecule contains a pyridine group, which is important for modifying the molecule in the later stage of pyridine drug synthesis, and speeding up the screening of clinical candidate drugs.

[0024] The synthesized pyridine-substituted isoxazole molecule contains a coordination functional nitrogen atom and an oxygen atom, which can be used as a ligand. The synthesized nitrogen-containing double heterocyclic compound can be used for designing metal catalysts; as a molecular probe, the synthesized nitrogen-containing double heterocyclic compound can be used for the exploration of candidate drugs; as a scaffold, the synthesized nitrogen-containing double heterocyclic compound can be used for material science.

[0025] Through activity test, the synthesized nitrogen-containing double heterocyclic compound exhibits different degrees of anti-cancer effect on typical liver cancer cells (HepG2), breast cancer cells (MCF7) and colon cancer cell lines (Caco2). BRIEF DESCRIPTION OF DRAWINGS

[0026] In order to make the technical problems solved by the present application, the technical means adopted and the technical effects obtained more clear, specific embodiments of the present application will be described in detail below with reference to the drawings. However, it should be pointed out that the drawings described below are only the drawings of exemplary embodiments of the present application, and for those skilled in the art, other drawings can be obtained from these drawings without creative labor.

[0027] Figure 1 Trend chart of relative cell viability of breast cancer cells (MCF7) corresponding to each concentration of compound 3a in Example 12.

[0028] Figure 2 Trend chart of relative cell viability of liver cancer cells (HepG2) corresponding to each concentration of compound 3a in Example 12.

[0029] Figure 3 Trend chart of relative cell viability of colon cancer cell line (Caco2) corresponding to each concentration of compound 3a in Example 12. DETAILED DESCRIPTION

[0030] Exemplary embodiments of the present application will now be described more fully with reference to the accompanying drawings, in which exemplary embodiments can be embodied in various forms. However, the present application should not be construed as being limited to the embodiments set forth herein. Rather, these exemplary embodiments are provided so that the present application will be thorough and complete, and will fully convey the scope of the application to those skilled in the art. The structures, properties, effects, or other features described in a certain exemplary embodiment can be combined with those of one or more other exemplary embodiments in any appropriate manner.

[0031] In the introduction of the specific embodiments, the detailed description of the structures, properties, effects or other features is to make the embodiments fully understood by those skilled in the art. However, it does not exclude that those skilled in the art can implement the present application without the above-mentioned structures, properties, effects or other features in specific cases.

[0032] The flowchart in the drawings is only an exemplary flow demonstration, and does not represent that all the contents, operations and steps in the flowchart must be included in the scheme of the present application, nor does it represent that the execution must be performed in the order shown in the figure. For example, some operations / steps in the flowchart can be decomposed, some operations / steps can be combined or partially combined, etc. The execution order shown in the flowchart can be changed according to the actual situation without departing from the inventive concept of the present application.

[0033] The block in the drawings Figure 1Generally, the functions described herein can be implemented as software, firmware, hardware (e.g., fixed-logic circuitry), or a combination of these implementations. The term "software" can include a computer program, a piece of code, an instruction, or some combination thereof, for being executed by a processing unit. The term "hardware" can include a microprocessor, a microcontroller, a central processing unit (CPU), a graphics processing unit (GPU), a field-programmable gate array (FPGA), an application-specific integrated circuit (ASIC), a programmable logic device (PLD), a digital signal processor (DSP), a read-only memory (ROM), a random-access memory (RAM), a programmable logic device (PLD), a memory chip, a register, a processor, a controller, a microcontroller, a microprocessor, a processor core, a system on a chip (SoC), or a similar device or any combination thereof. The term "software" can include a computer program, a piece of code, an instruction, or some combination thereof, for being executed by a processing unit. The term "hardware" can include a microprocessor, a microcontroller, a central processing unit (CPU), a graphics processing unit (GPU), a field-programmable gate array (FPGA), an application-specific integrated circuit (ASIC), a programmable logic device (PLD), a digital signal processor (DSP), a read-only memory (ROM), a random-access memory (RAM), a programmable logic device (PLD), a memory chip, a register, a processor, a controller, a microcontroller, a microprocessor, a processor core, a system on a chip (SoC), or a similar device or any combination thereof.

[0034] The same reference numbers in different drawings represent the same or similar elements, components, or parts and the description thereof can be omitted. It should also be understood that, although the first, second, third, etc. adjectives are used herein to describe various devices, elements, components, or parts, these adjectives should not be limited by these descriptors. That is, a first device can also be called a second device without departing from the spirit of the technical solutions of the present application. In addition, the terms "and / or" and "and / or" refer to all combinations of one or more of the listed items.

[0035] The present application utilizes the abstraction of active hydrogen in the oxime molecule by methoxy radicals to achieve the synthesis of pyridine-substituted heterocyclic compounds. The present application uses N-methoxy pyridinium salt as the raw material, and under visible light catalysis, the N-O bond of pyridinium salt is broken, and the obtained methoxy radical can be used as the power source for abstracting active hydrogen, thereby designing and synthesizing substituted pyridine derivatives. The molecular structure of oxime contains nitrogen / oxygen atoms with nucleophilic properties, so it has been widely concerned by organic chemists as a precursor molecule for the synthesis of nitrogen-containing or oxygen-containing heterocyclic compounds. The hydroxyl hydrogen in the oxime molecule can generate an oxygen radical intermediate by the abstraction of hydrogen by other heteroatom radicals, so the present application reports a photochemical reaction to construct substituted pyridine derivatives.

[0036] Example 1

[0037] In a 10 mL reaction tube, add oxime 1a (18.9 mg, 0.1 mmol), N-methoxy pyridinium salt 2a (49.3 mg, 0.25 mmol), manganese acetate dihydrate (32.2 mg, 0.12 mmol) and photo-catalyst bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bipyridine]iridium di(hexafluorophosphate) (2.0 mg, 2 mol%). The reaction solution is protected with nitrogen and 1 mL of organic solvent dichloromethane is added. The reaction is irradiated under blue light (wavelength 456 nm, light intensity 10 watts) with magnetic stirring for 16 hours. After the reaction is completed, extract with ethyl acetate (3 x 25 mL), wash the combined organic phase with saturated brine (1 x 30 mL), then dry over anhydrous sodium sulfate, concentrate to dryness under reduced pressure, and purify the crude product obtained after concentration by silica gel column chromatography (eluent, petroleum ether: ethyl acetate = 2:1) to obtain pyridine-substituted isoxazole molecules 3a-C2 (17.8 mg, 67%) and 3a-C4 (5.6 mg, 21%), with a total yield of 88%. The reaction equation is as follows:

[0038]

[0039] 4,4-Dimethyl-3-phenyl-5-(pyridin-2-ylmethyl)-4,5-dihydroisoxazole (3a) (C2:C4 = 3.2:1). Rf = 0.4 in 2:1 v / v petroleum ether / ethyl acetate) to give the compound 3a-C2 (17.8 mg, 67%) as a light yellow oil (major). 1 H NMR (500 MHz, CDC13) δ 8.56 (d, J = 4.0 Hz, 1H), 7.69 (td, J = 7.7, 1.8 Hz, 1H), 7.64 (dd, J = 7.5, 2.2 Hz, 2H), 7.42 - 7.38 (m, 4H), 7.21 (dd, J = 7.6, 5.0 Hz, 1H), 4.60 (dd, J = 8.4, 4.9 Hz, 1H), 3.18 - 3.16 (m, 2H), 1.39 (s, 3H), 1.36 (s, 3H); 13 C{ 1 H} NMR (126 MHz, CDC13) δ 165.4, 157.9, 148.8, 137.3, 129.8, 129.5, 128.7, 127.5, 124.7, 122.1, 90.0, 51.5, 37.0, 24.2, 19.9; IR (ATR) v max 2968, 2927, 1590, 1467, 1438, 902, 766, 696 cm –1 ; HRMS (ESI) Calcd for C 17 H 19 N2O: [M+H]+ = 267.1492. Found: 267.1488.

[0040] 4,4-Dimethyl-3-phenyl-5-(pyridin-4-ylmethyl)-4,5-dihydroisoxazole (3a) (C2:C4 = 3.2:1). Rf = 0.2 in 2:1 v / v petroleum ether / ethyl acetate) gave compound 3a-C4 (5.6 mg, 21%) as a pale yellow oil (minor). 1 H NMR (300 MHz, CDC13) δ 8.55 (d, J = 5.3 Hz, 2H), 7.65 - 7.61 (m, 2H), 7.40 (dd, J = 5.3, 2.0 Hz, 3H), 7.32 (d, J = 6.1 Hz, 2H), 4.32 (dd, J = 10.0, 3.2 Hz, 1H), 3.05 (dd, J = 14.5, 10.0 Hz, 1H), 2.86 (dd, J = 14.5, 3.2 Hz, 1H), 1.37 (s, 3H), 1.33 (s, 3H); 13 C{ 1 H} NMR (75 MHz, CDC13) δ 165.3, 149.3, 147.9, 130.0, 129.2, 128.8, 127.5, 124.9, 90.0, 51.6, 34.1, 24.1, 19.8; IR (ATR) v^x 2925, 2855, 1603, 1558, 1463, 904, 775, 702 cm –1 ; HRMS (ESI) Calcd for C 17 H 19 N2O: [M+H] + = 267.1492. Found: 267.1486.

[0041] Example 2

[0042] 10 mL reaction tube, add oxime (18.9 mg, 0.1 mmol), N-methoxy pyridinium salt (55.5 mg, 0.25 mmol), manganese acetate dihydrate (32.2 mg, 0.12 mmol) and photocatalyst bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bipyridine]iridium di(hexafluorophosphate) (2.0 mg, 2 mol%). The reaction solution is protected with nitrogen and 1 mL of organic solvent dichloromethane is added. The reaction is irradiated under blue light (wavelength 456 nm, light intensity 10 watts) with magnetic stirring for 16 hours. After the reaction is completed, extract with ethyl acetate (3 x 25 mL), wash the combined organic phase with saturated brine (1 x 30 mL), then dry over anhydrous sodium sulfate, concentrate to dryness under reduced pressure, and purify the concentrated crude product by silica gel column chromatography (eluent, petroleum ether: ethyl acetate = 2:1) to obtain pyridine-substituted isoxazole molecule 3b (22.4 mg) with a total yield of 77%.

[0043] 2-(4,4-dimethyl-3-phenyl-4,5-dihydroisoxazole-5-ylmethyl)isonicotinonitrile (3b). Subsequent standard work-up on silica gel and flash column chromatography with (3:1 v / v) petroleum ether / ethyl acetate eluent, Rf= 0.2 in 3:1 v / v petroleum ether / ethyl acetate) gave compound 3b as a pale yellow oil (22.4 mg, 77%), m.p. = 96.1-96.5 °C. 1 H NMR (500 MHz, CDC13) δ 8.75 (d, J = 3.8 Hz, 1H), 7.69 (s, 1H), 7.64 (dd, J = 7.5, 1.6 Hz, 2H), 7.47 (d, J = 2.6 Hz, 1H), 7.41 (q, J = 5.4 Hz, 3H), 4.58 (dd, J = 8.4, 4.1 Hz, 1H), 3.21 - 3.17 (m, 2H), 1.44 (s, 3H), 1.37 (s, 3H); 13 C{ 1 H} NMR (126 MHz, CDC13) δ 165.3, 159.8, 149.6, 130.0, 129.2, 128.8, 127.5, 126.5, 123.7, 121.8, 116.4, 89.4, 51.7, 36.9, 24.4, 19.9; IR (ATR) v max3060, 2969, 2931, 2238, 1719, 1595, 1550, 1467, 1402, 891, 767, 696 cm –1 ; HRMS (ESI) Calcd for C 18 H 18 N3O: [M+H] += 292.1444. Found: 292.1433.

[0044] Example 3

[0045] In a 10 mL reaction tube, oxime (18.9 mg, 0.1 mmol), N-methoxy pyridinium salt (66.3 mg, 0.25 mmol), manganese acetate dihydrate (32.2 mg, 0.12 mmol) and photocatalyst bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bipyridine]iridium di(hexafluorophosphate) (2.0 mg, 2 mol%) were added. The reaction was protected with nitrogen and 1 mL of organic solvent dichloromethane was added. The reaction was irradiated under blue light (wavelength 456 nm, light intensity 10 watt) with magnetic stirring for 16 hours. After the reaction was completed, the reaction was extracted with ethyl acetate (3 x 25 mL), the combined organic phase was washed with saturated brine (1 x 30 mL), then dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the concentrated crude product was purified by silica gel column chromatography (eluent, petroleum ether: ethyl acetate = 2: 1) to obtain pyridine-substituted isoxazole molecule 3c (24.4 mg) with a total yield of 73%.

[0046] 4,4-Dimethyl-3-phenyl-5-((4-(trifluoromethyl)pyridin-2-yl)methyl)-4,5-dihydroisoxazole (3c). Standard work-up on silica gel and flash column chromatography with (4:1 v / v) petroleum ether / ethyl acetate eluent, Rf = 0.5 in 4:1 v / v petroleum ether / ethyl acetate) gave compound 3c as a light yellow oil (24.4 mg, 73%). 1 H NMR (600 MHz, CDC13) δ 8.73 (d, J = 5.2 Hz, 1H), 7.64 (dd, J = 7.3, 2.1 Hz, 2H), 7.60 (s, 1H), 7.40 - 7.39 (m, 4H), 4.61 (dd, J = 10.1, 3.2 Hz, 1H), 3.23 (dd, J = 14.2, 10.1 Hz, 1H), 3.16 (dd, J = 14.2, 3.2 Hz, 1H), 1.41 (s, 3H), 1.36 (s, 3H); 13 C{ 1 H} NMR (151 MHz, CDC13) δ 165.3, 159.9, 150.3, 138.9 (q, J = 33.9 Hz), 129.9, 129.3, 128.7, 127.5, 122.9 (q, J = 273.3 Hz), 119.9 (q, J = 3.6 Hz), 117.5 (q, J = 3.7 Hz), 89.6, 51.5, 37.3, 24.2, 19.8; 19F NMR (565 MHz, CDC13) δ -64.7; IR (ATR) vmax 2969, 1613, 1411, 1331, 1132, 897, 765, 693 cm –1 ; HRMS (ESI) Calcd for C 18 H 18 F3N2O: [M+H] + = 335.1366. Found: 335.1361.

[0047] Example 4

[0048] In a 10 mL reaction tube, the oxime (18.9 mg, 0.1 mmol), N-methoxy pyridinium salt (57.8 mg, 0.25 mmol), manganese acetate dihydrate (32.2 mg, 0.12 mmol) and the photocatalyst bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bipyridine]iridium di(hexafluorophosphate) (2.0 mg, 2 mol%) were added. The reaction was protected with nitrogen and 1 mL of the organic solvent dichloromethane was added. The reaction was irradiated under blue light (wavelength 456 nm, light intensity 10 watt) with magnetic stirring for 16 hours. After the reaction was completed, the reaction was extracted with ethyl acetate (3 x 25 mL), the combined organic phase was washed with saturated brine (1 x 30 mL), then dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the concentrated crude product was purified by silica gel column chromatography (eluent, petroleum ether: ethyl acetate = 2: 1) to obtain the pyridine-substituted isoxazole molecule 3d (17.1 mg) with a total yield of 57%.

[0049] 5-((4-Chloropyridin-2-yl)methyl)-4,4-dimethyl-3-phenyl-4,5-dihydroisoxazole (3d). Standard work-up on silica gel and flash column chromatography with (3:1 v / v) petroleum ether / ethyl acetate eluent, Rf= 0.3 in 3:1 v / v petroleum ether / ethyl acetate) gave compound 3d as a light yellow oil (17.1 mg, 57%), m.p. = 75.9-76.6 °C. 1 H NMR (500 MHz, CDC13) δ 8.44 (d, J = 5.4 Hz, 1H), 7.64 - 7.62 (m, 2H), 7.42 (d, J = 1.7 Hz, 1H), 7.41 - 7.37 (m, 3H), 7.19 (dd, J = 5.4, 1.8 Hz, 1H), 4.57 (dd, J = 9.0, 4.2 Hz, 1H), 3.14 - 3.06 (m, 2H), 1.39 (s, 3H), 1.34 (s, 3H); 13 C{ 1H}NMR (126 MHz, CDC13) δ 165.1, 159.6, 149.7, 144.7, 129.7, 129.2, 128.5, 127.3, 124.6, 122.2, 89.4, 51.3, 36.8, 24.1, 19.7; IR (ATR) vmax 3056, 2968, 2930, 1575, 1555, 1466, 896, 766, 696 cm –1 ; HRMS (ESI) Calcd for C 17 H 18 ClN2O: [M+H] + = 301.1102. Found: 301.1091

[0050] Example 5

[0051] In a 10 mL reaction tube, the oxime (18.9 mg, 0.1 mmol), N-methoxy pyridinium salt (59.8 mg, 0.25 mmol), manganese acetate dihydrate (32.2 mg, 0.12 mmol) and the photocatalyst bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bipyridine]iridium di(hexafluorophosphate) (2.0 mg, 2 mol%) were added. The reaction was protected with nitrogen and 1 mL of the organic solvent dichloromethane was added. The reaction was irradiated under blue light (wavelength 456 nm, light intensity 10 watt) with magnetic stirring for 16 hours. After the reaction was completed, the reaction was extracted with ethyl acetate (3 x 25 mL), the combined organic phase was washed with saturated brine (1 x 30 mL), then dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the crude product after concentration was purified by silica gel column chromatography (eluent, petroleum ether: ethyl acetate = 2: 1) to obtain the pyridine-substituted isoxazole molecule 3e (20.0 mg) with a total yield of 65%.

[0052] 1-(2-((4,4-dimethyl-3-phenyl-4,5-dihydroisoxazol-5-yl)methyl)pyridin-4-yl)ethan-1-one (3e). Subsequent standard work-up on silica gel and flash column chromatography eluting with (3:1 v / v) petroleum ether / ethyl acetate, Rf = 0.2 in 3:1 v / v petroleum ether / ethyl acetate) gave needle-like crystals of 3e (20.0 mg, 65%), m.p. = 69.1-69.8 °C. 1H NMR (400 MHz, CDC13) δ 8.75 (d, J = 5.1 Hz, 1H), 7.86 (s, 1H), 7.68 (dd, J = 5.1, 1.3 Hz, 1H), 7.65 - 7.63 (m, 2H), 7.43 - 7.39 (m, 3H), 4.62 (dd, J = 9.1, 4.1 Hz, 1H), 3.29 - 3.20 (m, 2H), 2.66 (s, 3H), 1.43 (s, 3H), 1.38 (s, 3H); 13 C{ 1 H} NMR (101 MHz, CDC13) δ 197.2, 165.4, 159.5, 149.5, 144.2, 130.0, 129.3, 128.8, 127.5, 122.7, 119.9, 89.7, 51.6, 36.8, 27.0, 24.3, 19.9; IR (ATR) v^ 2968, 2922, 1695, 1556, 1409, 1271, 768, 697 cm –1 ; HRMS (ESI) Calcd for C 19 H 21 N2O2: [M + H] + = 309.1598. Found: 309.1591.

[0053] Example 6

[0054] In a 10 mL reaction tube, the oxime (18.9 mg, 0.1 mmol), N-methoxy pyridinium salt (63.8 mg, 0.25 mmol), manganese acetate dihydrate (32.2 mg, 0.12 mmol) and photocatalyst bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bipyridine]iridium di(hexafluorophosphate) (2.0 mg, 2 mol%) were added. The reaction was protected with nitrogen and 1 mL of organic solvent dichloromethane was added. The reaction was irradiated under blue light (wavelength 456 nm, light intensity 10 watts) with magnetic stirring for 16 hours. After the reaction was completed, it was extracted with ethyl acetate (3 x 25 mL), the combined organic phase was washed with saturated brine (1 x 30 mL), then dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the concentrated crude product was purified by silica gel column chromatography (eluent, petroleum ether: ethyl acetate = 2:1) to obtain the pyridine-substituted isoxazole molecule 3f (25.3 mg) with a total yield of 78%.

[0055] 2-((4,4-dimethyl-3-phenyl-4,5-dihydroisoxazol-5-yl)methyl)isonicotinic acid methyl ester (3f). Standard work-up followed by flash column chromatography on silica gel eluting with (3:1 v / v) petroleum ether / ethyl acetate, Rf= 0.4 in 3:1 v / v petroleum ether / ethyl acetate) afforded compound 3f as a pale yellow oil (25.3 mg, 78%). 1 H NMR (400 MHz, CDC13) δ 8.73 (dd, J = 5.2, 0.6 Hz, 1H), 8.01 (s, 1H), 7.83 (dd, J = 5.2, 1.4 Hz, 1H), 7.65 - 7.63 (m, 2H), 7.43 - 7.39 (m, 3H), 4.63 (dd, J = 9.8, 3.5 Hz, 1H), 3.97 (s, 3H), 3.33 - 3.21 (m, 2H), 1.43 (s, 3H), 1.38 (s, 3H); 13 C{ 1 H} NMR (101 MHz, CDC13) δ 165.2, 165.1, 158.8, 150.1, 148.7, 139.0, 129.8, 129.2, 128.6, 127.4, 124.3, 123.1, 121.6, 89.5, 52.9, 51.5, 36.5, 24.2, 19.8; IR (ATR) v^ 2965, 2923, 1731, 1438, 1299, 1216, 764, 695 cm –1 ; HRMS (ESI) Calcd for C 19 H 21 N2O3: [M+H] + = 325.1547. Found: 325.1534.

[0056] Example 7

[0057] In a 10 mL reaction tube, add the oxime (16.1 mg, 0.1 mmol), N-methoxy pyridinium salt (63.8 mg, 0.25 mmol), manganese acetate dihydrate (32.2 mg, 0.12 mmol) and the photocatalyst bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bipyridine]iridium di(hexafluorophosphate) (2.0 mg, 2 mol%). The reaction is protected with nitrogen and 1 mL of the organic solvent dichloromethane is added. The reaction is irradiated with blue light (wavelength 456 nm, light intensity 10 watts) for 16 hours with magnetic stirring. After the reaction is complete, the reaction is extracted with ethyl acetate (3 x 25 mL), the combined organic phases are washed with saturated brine (1 x 30 mL) and then dried over anhydrous sodium sulfate. The reaction is concentrated to dryness under reduced pressure and the crude product is purified by column chromatography on silica gel (eluent, petroleum ether: ethyl acetate = 2: 1) to give the pyridine substituted isoxazole molecule 3g (21.3 mg) in a total yield of 72%.

[0058] 2-((3-phenyl-4,5-dihydroisoxazol-5-yl)methyl)isonicotinic acid methyl ester (3g). Standard work-up and flash column chromatography on silica gel with (3:1 v / v) petroleum ether / ethyl acetate eluent, Rf= 0.3 in 3:1 v / v petroleum ether / ethyl acetate) gave compound 3g as a pale yellow oil (21.3 mg, 72%). 1 H NMR (300 MHz, CDC13) δ 8.69 (dd, J = 5.1, 0.9 Hz, 1H), 7.83 (s, 1H), 7.71 (dd, J = 5.1, 1.6 Hz, 1H), 7.66 - 7.63 (m, 2H), 7.40 - 7.36 (m, 3H), 5.22 (ddd, J = 13.9, 10.3, 6.4 Hz, 1H), 3.95 (s, 3H), 3.50 - 3.15 (m, 4H); 13 C{ 1 H} NMR (75 MHz, CDC13) δ 165.8, 158.7, 156.8, 150.3, 138.0, 130.2, 129.7, 128.8, 126.8, 123.5, 121.2, 80.5, 52.8, 43.4, 39.9; IR (ATR) v^ 2954, 2923, 1723, 1437, 1293, 761, 692 cm –1 ; HRMS (ESI) Calcd for C 17 H 17 N2O3: [M+H] + = 297.1234. Found: 297.1227.

[0059] Example 8

[0060] 10 mL reaction tube, add oxime (18.9 mg, 0.1 mmol), N-methoxy pyridinium salt (52.8 mg, 0.25 mmol), manganese acetate dihydrate (32.2 mg, 0.12 mmol) and photocatalyst bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bipyridine]iridium di(hexafluorophosphate) (2.0 mg, 2 mol%). The reaction solution is protected with nitrogen and 1 mL of organic solvent dichloromethane is added. The reaction is irradiated under blue light (wavelength 456 nm, light intensity 10 watts) with magnetic stirring for 16 hours. After the reaction is completed, extract with ethyl acetate (3 x 25 mL), wash the combined organic phase with saturated brine (1 x 30 mL), then dry over anhydrous sodium sulfate, and concentrate to dryness under reduced pressure. The concentrated crude product is separated and purified by silica gel column chromatography (eluent, petroleum ether: ethyl acetate = 2:1) to obtain pyridine-substituted isoxazole molecule 3h (18.8 mg) with a total yield of 67%.

[0061] 4,4-Dimethyl-5-((4-methylpyridin-2-yl)methyl)-3-phenyl-4,5-dihydroisoxazole (3h). Subsequent standard work-up on silica gel and flash column chromatography with (3:1 v / v) petroleum ether / ethyl acetate eluent, Rf= 0.4 in 3:1 v / v petroleum ether / ethyl acetate) gave compound 3h as a pale yellow oil (18.8 mg, 67%). 1 H NMR (500 MHz, CDC13) δ 8.40 (d, J = 5.0 Hz, 1H), 7.65 - 7.63 (m, 2H), 7.41 - 7.38 (m, 3H), 7.20 (s, 1H), 6.98 (d, J = 4.8 Hz, 1H), 4.58 (dd, J = 9.7, 3.5 Hz, 1H), 3.08 (ddd, J = 17.6, 14.1, 6.6 Hz, 2H), 2.34 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H); 13 C{ 1 H} NMR (126 MHz, CDC13) δ 165.2, 157.7, 149.0, 147.6, 129.6, 129.5, 128.5, 127.3, 125.0, 122.7, 90.0, 51.2, 37.0, 24.0, 21.0, 19.7; IR (ATR) v max 3057, 2968, 2926, 1606, 1463, 906, 767, 696 cm –1 ; HRMS (ESI) Calcd for C 18 H 21 N2O: [M+H] + = 281.1648. Found: 281.1643.

[0062] Example 9

[0063] In a 10 mL reaction tube, oxime (18.9 mg, 0.1 mmol), N-methoxy pyridinium salt (68.3 mg, 0.25 mmol), manganese acetate dihydrate (32.2 mg, 0.12 mmol) and photo-catalyst bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bipyridine]iridium di(hexafluorophosphate) (2.0 mg, 2 mol%) were added. The reaction was protected with nitrogen and 1 mL of dichloromethane was added. The reaction was irradiated with blue light (wavelength 456 nm, light intensity 10 watt) for 16 h with magnetic stirring. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (3 x 25 mL), the combined organic phase was washed with saturated brine (1 x 30 mL), then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent, petroleum ether: ethyl acetate = 2: 1) to give pyridine substituted isoxazole molecule 3i (22.2 mg) with a total yield of 65%.

[0064] 4,4-Dimethyl-3-phenyl-5-((4-phenylpyridin-2-yl)methyl)-4,5-dihydroisoxazole (3i). Standard work-up on silica gel and flash column chromatography with (2:1 v / v) petroleum ether / ethyl acetate eluent, Rf= 0.3 in 2:1 v / v petroleum ether / ethyl acetate) gave compound 3i (22.2 mg, 65%) as a pale yellow oil. 1 H NMR (500 MHz, CDC13) δ 8.59 (d, J = 5.2 Hz, 1H), 7.67 - 7.65 (m, 4H), 7.60 (d, J = 0.6 Hz, 1H), 7.46 (td, J = 7.2, 1.3 Hz, 2H), 7.42 - 7.37 (m, 5H), 4.66 (dd, J = 9.8, 3.4 Hz, 1H), 3.19 (ddd, J = 17.5, 14.1, 6.6 Hz, 2H), 1.40 (s, 3H), 1.37 (s, 3H); 13 C{ 1 H} NMR (126 MHz, CDC13) δ 165.1, 158.4, 149.5, 148.8, 138.0, 129.5, 129.3, 128.9, 128.8, 128.4, 127.2, 127.0, 122.0, 119.6, 89.8, 51.1, 37.1, 23.9, 19.6; IR (ATR) v^max 3057, 2967, 2928, 1597, 1545, 1464, 894, 761, 693 cm –1 ; HRMS (ESI) Calcd for C23 H 23 N2O:[M+H] + = 343.1805. Found: 343.1789.

[0065] Example 10

[0066] In a 10 mL reaction tube, oxime (18.9 mg, 0.1 mmol), N-methoxy pyridinium salt (68.3 mg, 0.25 mmol), manganese acetate dihydrate (32.2 mg, 0.12 mmol) and photocatalyst bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bipyridine]iridium dihexafluorophosphate (2.0 mg, 2 mol%) were added. The reaction was protected with nitrogen and 1 mL of organic solvent dichloromethane was added. The reaction was irradiated under blue light (wavelength 456 nm, light intensity 10 watt) with magnetic stirring for 16 hours. After the reaction was completed, the reaction was extracted with ethyl acetate (3 x 25 mL), the combined organic phase was washed with saturated brine (1 x 30 mL), then dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the concentrated crude was purified by silica gel column chromatography (eluent, petroleum ether: ethyl acetate = 2: 1) to obtain pyridine-substituted isoxazole molecule 3j (21.5 mg) (C2:C4 = 1.2:1), with a total yield of 63%.

[0067] 4,4-Dimethyl-3-phenyl-5-((6-phenylpyridin-2-yl)methyl)-4,5-dihydroisoxazole (3j) (major) (C2:C4 = 1.2:1). Standard work-up and flash column chromatography on silica gel with (2:1 v / v) petroleum ether / ethyl acetate eluent, Rf = 0.8 in 3:1 v / v petroleum ether / ethyl acetate) gave compound 3j (major) as a pale yellow oil (11.6 mg, 34%). 1 H NMR (300 MHz, CDC13) δ 8.03 - 7.99 (m, 2H), 7.75 - 7.69 (m, 1H), 7.68 - 7.64 (m, 2H), 7.60 (dd, J = 7.9, 1.0 Hz, 1H), 7.50 - 7.45 (m, 2H), 7.43 - 7.40 (m, 4H), 7.32 (dd, J = 7.6, 1.0 Hz, 1H), 4.76 (dd, J = 8.7, 4.6 Hz, 1H), 3.32 - 3.17 (m, 2H), 1.40 (s, 3H), 1.38 (s, 3H); 13 C{ 1H} NMR (75 MHz, CDC13) δ 165.5, 158.0, 157.1, 139.7, 137.3, 129.8, 129.7, 129.0, 128.8, 128.7, 127.6, 127.1, 122.5, 118.7, 90.2, 51.4, 37.4, 24.2, 20.0; IR (ATR) vmax2925, 1572, 1448, 899, 759, 694 cm –1 ; HRMS (ESI) Calcd for C 23 H 23 N2O: [M + H] + = 343.1805. Found: 343.1815.

[0068] 4,4-Dimethyl-3-phenyl-5-((2-phenylpyridin-4-yl)methyl)-4,5-dihydroisoxazole (3j) (minor) (C2:C4 = 1.2:1). Subsequent standard work-up on silica gel and flash column chromatography eluting with (2:1 v / v) petroleum ether / ethyl acetate, Rf= 0.6 in 3:1 v / v petroleum ether / ethyl acetate) afforded compound 3j (minor) as a pale yellow oil (9.9 mg, 29%). 1 H NMR (300 MHz, CDC13) δ 8.64 (dd, J = 5.0, 0.8 Hz, 1H), 8.02 - 7.99 (m, 2H), 7.73 (s, 1H), 7.67 - 7.64 (m, 2H), 7.48 - 7.45 (m, 2H), 7.44 - 7.39 (m, 4H), 7.24 (dd, J = 5.2, 1.8 Hz, 1H), 4.39 (dd, J = 9.9, 3.2 Hz, 1H), 3.13 (dd, J = 14.4, 9.9 Hz, 1H), 2.92 (dd, J = 14.5, 3.2 Hz, 1H), 1.40 (s, 3H), 1.37 (s, 3H); 13 C{ 1 H} NMR (75 MHz, CDC13) δ 165.4, 157.9, 149.9, 147.9, 139.5, 130.0, 129.3, 129.1, 128.8, 128.8, 127.5, 127.2, 123.1, 121.7, 90.3, 51.6, 34.3, 24.2, 19.9; IR (ATR) vmax2924, 1602, 1445, 894, 767, 695 cm –1 ; HRMS (ESI) Calcd for C 23 H 23 N2O: [M + H] += 343.1805. Found: 343.1810.

[0069] Example 11

[0070] In a 10 mL reaction tube, oxime (18.9 mg, 0.1 mmol), N-methoxy pyridinium salt (56.3 mg, 0.25 mmol), manganese acetate dihydrate (32.2 mg, 0.12 mmol) and photo-catalyst bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bipyridine]iridium di(hexafluorophosphate) (2.0 mg, 2 mol%) were added. The reaction was protected with nitrogen and 1 mL of dichloromethane was added. The reaction was irradiated with blue light (wavelength 456 nm, light intensity 10 watt) for 16 hours with magnetic stirring. After the reaction was completed, the reaction was extracted with ethyl acetate (3 x 25 mL), the combined organic phase was washed with saturated brine (1 x 30 mL), then dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the concentrated crude was purified by silica gel column chromatography (eluent, petroleum ether: ethyl acetate = 2: 1) to obtain pyridine-substituted isoxazole molecule 3k (14.7 mg) with a total yield of 50%.

[0071] 5-((2,6-Dimethylpyridin-4-yl)methyl)-4,4-dimethyl-3-phenyl-4,5-dihydroisoxazole (3k). Standard work-up on silica gel and flash column chromatography with (2:1 v / v) petroleum ether / ethyl acetate eluent, Rf= 0.2 in 2:1 v / v petroleum ether / ethyl acetate) gave compound 3k as a pale yellow oil (14.7 mg, 50%). 1 H NMR (300 MHz, CDC13) δ 7.67 - 7.62 (m, 2H), 7.44 - 7.39 (m, 3H), 6.98 (s, 2H), 4.31 (dd, J = 10.0, 3.1 Hz, 1H), 2.97 (dd, J = 14.4, 10.0 Hz, 1H), 2.77 (dd, J = 14.4, 3.2 Hz, 1H), 2.54 (s, 6H), 1.37 (s, 3H), 1.33 (s, 3H); 13 C{ 1 H} NMR (75 MHz, CDC13) δ 165.4, 157.8, 148.1, 130.0, 129.4, 128.8, 127.5, 121.4, 90.3, 51.5, 33.9, 29.8, 24.3, 24.1, 19.8; IR (ATR) v max 2929, 1613, 1569, 1463, 906, 767, 695 cm –1 ; HRMS (ESI) Calcd for C 19 H 23N₂O:[M+H] + =295.1805.Found:295.1800.

[0072] The activities of the compounds obtained from the reactions in Examples 1-11 above are shown in Table 1.

[0073]

[0074]

[0075] Example 12

[0076] Compound 3a obtained in Example 1 was prepared in concentration gradients (0, 1, 5, 10, 50, and 200 μM). The effects of compound 3a on the viability of breast cancer cells (MCF7), liver cancer cells (HepG2), and colon cancer cell line (Caco2) were determined using the MTT assay. The cytotoxicity of these compounds was studied using the Cell Counting Kit-8 (CCK-8) assay. The specific steps were as follows: Tumor cells were seeded in 96-well plates (3000 cells / well) and cultured overnight, then incubated with the compounds at concentrations of 0, 1, 5, 10, 50, and 200 μM for 48 hours. Subsequently, 20 μL of CCK-8 solution (Beyotime, Shanghai, China) was added to each well and incubated for 4 hours. The absorbance of each sample was measured at 450 nm using a microplate reader (Tecan Infinite M1000 Pro). The relative cell viability of each sample was normalized using DMSO control. The IC50 of the compounds on tumor cells was calculated based on cell viability. 50 Value. (Cell viability % = OD of sample treatment group) 570 / Mean OD of blank control group 570 (x100%).

[0077] Depend on Figures 1-3 It can be seen that after treating cancer cells with compound 3a for 48 hours, it exhibited good inhibitory activity against the proliferation of MCF7 and HepG2 cells, with an IC50 value of [missing information]. 50 The values ​​were 28.96±1.99 μM and 56.13±1.74 μM. However, within the 200 μM range, compound 3a had no effect on Caco2 cell viability, and Caco2 cells remained above 90% after 48 hours of treatment.

[0078] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0079] It should be noted that, for the foregoing method embodiments, for the sake of simple description, they are all expressed as a series of action combinations, but those skilled in the art should know that the present application is not limited by the action sequence described, because according to the present application, certain steps can be performed in other sequences or simultaneously. Secondly, those skilled in the art should know that the embodiments described in the specification all belong to preferred embodiments, and the actions and modules involved are not necessarily necessary for the present application.

[0080] In the above embodiments, the description of each embodiment has its own focus, and the parts not described in detail in a certain embodiment can be referred to the relevant description of other embodiments.

[0081] The above embodiments are only used to illustrate the technical solutions of the present application, but not limit it; although the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that: it can still modify the technical solutions recorded in the foregoing embodiments, or make equivalent replacement for part of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application.

[0082] The above-described embodiments only express several implementation manners of the present application, and the description is more specific and detailed, but it should not be understood as a limitation on the patent application scope. It should be noted that, for those skilled in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are all within the protection scope of the present application. Therefore, the protection scope of the patent of the present application should be subject to the appended claims.

Claims

1. A compound, characterized in that, Having the structure as shown in the following formula I: wherein, wherein R 1 , R 2 is C1-4alkyl or H, R 3 is any one of phenyl, H, CN-, halomethyl, Cl, F, Br, C1-4alkyl; R 4 is any one of C1-4alkyl, phenyl, H.

2. The compound of claim 1, wherein wherein R 1 , R 2 is methyl or H, R 3 is any one of phenyl, H, CN-, CF3, Cl, methyl; R 4 is any one of methyl, phenyl, H.

3. The compound of claim 2, wherein The compound of formula I is selected from: 4,4-dimethyl-3-phenyl-5-(pyridine-2-methyl)-4,5-dihydroisoxazole, 4,4-dimethyl-3-phenyl-5-(pyridine-4-methyl)-4,5-dihydroisoxazole, 4,4-dimethyl-3-phenyl-5-(4-(trifluoromethyl)pyridine-2-methyl)-4,5-dihydroisoxazole, 5-(4-chloropyridine-2-methyl)-4,4-dimethyl-3-phenyl-4,5-dihydroisoxazole, 4,4-dimethyl-5-(4-methylpyridine-2-methyl)-3-phenyl-4,5-dihydroisoxazole, 4,4-dimethyl-3-phenyl-5-(4-phenylpyridine-2-methyl)-4,5-dihydroisoxazole, 4,4-dimethyl-3-phenyl-5-(6-phenylpyridine-2-methyl)-4,5-dihydroisoxazole, 4,4-dimethyl-3-phenyl-5-(2-phenylpy-4-methyl)-4,5-dihydroisoxazole.

4. Process for the synthesis of the compounds of formula I according to any one of claims 1 to 3, characterized in that, The method comprises the following steps: using an oxime and an N-methoxypyridinium salt as raw materials, and using visible light to catalyze the synthesis of the compound of formula I, and the synthesis process is as follows: wherein, wherein R 1 , R 2 is C1-4alkyl or H, R 3 is any one of phenyl, H, CN-, halomethyl, Cl, F, Br, C1-4alkyl; R 4 is any one of C1-4alkyl, phenyl, H; The synthesis method is as follows: The oxime, the N-methoxypyridinium salt, manganese acetate dihydrate, and a photocatalyst are mixed, an organic solvent is added in an inert gas environment, blue light is irradiated, and magnetic stirring is performed until the reaction is completed. After the reaction, the solution is extracted with ethyl acetate, the combined organic phase is washed with saturated brine, then dried with anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the concentrated crude product is separated and purified by silica gel column chromatography to obtain the compound of formula I; the photocatalyst is bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bipyridine]iridium di(hexafluorophosphate) salt; and the organic solvent includes any one of dichloromethane, acetonitrile, and 1,2-dichloroethane.

5. The method of synthesis of a compound of Formula I according to claim 4, wherein, The wavelength of the blue light is 440 nm or 456 nm, the light intensity is 10 watts, and the irradiation time is 10-16 hours.

6. Use of the compound of formula I according to claims 1-3 for the preparation of a medicament for the treatment of liver cancer, breast cancer or colon cancer.

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