Artemisinin C-16 aromatic amine derivative as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medicine and chemical industry, and discloses an artemisinin C-16 aromatic amine derivative and a preparation method and application thereof, the structural general formula of the artemisinin C-16 aromatic amine derivative is as shown in the formula (1): imgabs0 #, r1 is one of 4-(tert-butyl) benzenesulfonyl, 4-chlorobenzenesulfonyl, 4-fluorobenzenesulfonyl, 4-(trifluoromethyl) benzenesulfonyl, cyclopropyl sulfonyl, cyclopropane formyl, 4-methyl benzoyl, isoquinoline-5-sulfonyl, 4-hydroxybenzenesulfonyl and 6-chloronicotinoyl, and R2 is one of 4-(tert-butyl) benzenesulfonyl, 4-chlorobenzenesulfonyl, 4-fluorobenzenesulfonyl, 4-(trifluoromethyl) benzenesulfonyl, cyclopropyl sulfonyl, cyclopropane formyl, 4-methyl benzoyl, isoquinoline-5-sulfonyl, 4- And n is 1 or 2. According to the artemisinin C-16 site aromatic amine derivative disclosed by the invention, a specific aromatic amide group is introduced to a C-16 site, so that a novel derivative is prepared. The artemisinin C-16 aromatic amine derivative disclosed by the invention has antitumor activity, and a new strategy is provided for chemical research and development of novel artemisinin derivatives and cancer treatment.

Description

Technical Field

[0001] This application relates to the technical field of pharmaceutical chemistry, and mainly relates to an artemisinin C-16 aromatic amine derivative, its preparation method and application. Background Art

[0002] Artemisinin (ART) is a sesquiterpene lactone compound with a peroxide group isolated from Artemisia annua L. in 1971, and has very good antimalarial activity. At present, in the research of artemisinin derivatives, scientists mainly focus on the structural optimization at the C-10 and C-9 positions, aiming to improve the physicochemical properties and druggability of artemisinin, so that artemisinin derivatives can be applied to antimalarial, antiviral, anti-inflammatory, anti-tumor and immunomodulation, etc. However, there are few reports on the structural optimization at the C-16 position, and there is also a promising development prospect in the anti-tumor direction.

[0003] Therefore, the existing technology still needs to be improved and developed. Summary of the Invention

[0004] In view of the above deficiencies of the existing technology, the purpose of this application is to provide an artemisinin C-16 aromatic amine derivative, its preparation method and application, aiming to provide a new type of artemisinin derivative and provide a new strategy for the chemical research and development of artemisinin derivatives and cancer treatment.

[0005] The technical solution of this application is as follows:

[0006] An artemisinin C-16 aromatic amine derivative, wherein its structural general formula is shown as formula (1):

[0007]

[0008] Wherein, R1 is one of 4-(tert-butyl)benzenesulfonyl, 4-chlorobenzenesulfonyl, 4-fluorobenzenesulfonyl, 4-(trifluoromethyl)benzenesulfonyl, cyclopropanesulfonyl, cyclopropanecarbonyl, 4-methylbenzoyl, isoquinoline-5-sulfonyl, 4-hydroxybenzenesulfonyl, 6-chloronicotinoyl;

[0009] n is 1 or 2.

[0010] The artemisinin C-16 aromatic amine derivative of this application is prepared by introducing a specific aromatic amide group at the C-16 position to obtain a new derivative. The artemisinin C-16 aromatic amine derivatives of this application all have anti-tumor activity, providing a new strategy for the chemical research and development of new artemisinin derivatives and cancer treatment.

[0011] The artemisinin C-16 aromatic amine derivative described above, wherein the structural general formula of the artemisinin C-16 aromatic amine derivative is shown as formula (2):

[0012]

[0013] The artemisinin C-16 aromatic amine derivative described above, wherein the artemisinin C-16 aromatic amine derivative is one of the following compounds 6a-6j:

[0014]

[0015]

[0016] A preparation method of the artemisinin C-16 aromatic amine derivative as described above, which includes the following steps:

[0017] S1: Using compound 0 as the starting material, through a reduction reaction in a hydrogen / palladium-carbon / zinc halide / EA system to obtain compound 1; wherein, the compound 0 is 4-nitrophenethyl bromide or 4-nitropropyl bromide;

[0018] S2: Protecting the compound 1 with Boc anhydride to obtain compound 2;

[0019] S3: Performing a radical addition reaction on the compound 2 and the compound 3 in an AIBN / Bu3SnH system to obtain compound 4 and another configurational compound; wherein, the compound 3 is artemisylene;

[0020] Refluxing the other configurational compound in a THF / DBU system to obtain the compound 4;

[0021] S4: Removing Boc from the compound 4 under acidic conditions to obtain compound 5;

[0022] S5: Performing a substitution reaction on the compound 5 and an acyl chloride under basic conditions to synthesize the artemisinin C-16 aromatic amine derivative.

[0023] The preparation method of the artemisinin C-16 aromatic amine derivative, wherein step S1 specifically includes the following steps:

[0024] Adding the compound 0 into a container, adding the palladium-carbon, the zinc halide, and the EA, performing hydrogen replacement 3 times under stirring and normal pressure, heating to 45±5°C under hydrogen protection for reaction for 72 h, detecting by TLC that the compound 0 disappears, and there is a solid precipitated in the reaction system; cooling down, filtering, washing the filter cake with EA, collecting the filter cake, pulping with MeOH for 3 h and then filtering, collecting the filtrate, concentrating the filtrate to dryness to obtain the compound 1;

[0025] Step S2 specifically includes the following steps:

[0026] Add the compound 1 and the solvent into a container, add TEA, dropwise add Boc anhydride under stirring, react at 20±5 °C for 10 h, detect by TLC until the compound 1 disappears, add water to quench, extract with EA, combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, and filter; evaporate the solvent under reduced pressure, after the crude product is subjected to flash column chromatography, slurry with PE for 3 h and filter to obtain the compound 2;

[0027] Step S3 specifically includes the following steps:

[0028] Dissolve the compound 3, the compound 2 and the AIBN in m-xylene, reflux and react for 1 h under nitrogen protection; then dropwise add the m-xylene solution of Bu3SnH, after dropping, reflux and react overnight at 85±5 °C, spin-dry the reaction solution to obtain a pale yellow crude product, dissolve the pale yellow crude product in EA, add saturated KF solution, stir and react at room temperature for 12 h, filter the solid, add water to the filtrate and extract with ethyl acetate, combine the ethyl acetate layers, dry over anhydrous sodium sulfate, and after evaporating the solvent, purify the residue by column chromatography to obtain the compound 4 and the other configurational compound;

[0029] Add the other configurational compound into the THF, add the DBU under stirring, heat the system to reflux for 18 h, detect by TLC to judge the conversion of the compound 4, concentrate to dryness, add water and extract with EA, separate the layers, dry, and purify by silica gel column chromatography to obtain the compound 4;

[0030] Step S4 specifically includes the following steps:

[0031] Dissolve the compound 4 in EA, dropwise add the ethyl acetate solution of hydrogen chloride to the reaction system, stir and react at room temperature for 6 h, after detecting by TLC that the compound 4 disappears, add water and ethyl acetate to extract the reaction solution, take the aqueous phase and neutralize it with saturated K2CO3, then extract with EA, combine the organic layers, wash once with saturated brine, dry the organic layer over anhydrous sodium sulfate, and after evaporating the solvent, obtain the compound 5;

[0032] Step S5 specifically includes the following steps:

[0033] Dissolve the compound 5 and a weak base in dichloromethane, add the acyl chloride to the reaction system, react at 25±5 °C, after detecting by TLC that the compound 5 has completely reacted, purify by column chromatography to obtain the artemisinin C-16 aromatic amine derivative.

[0034] The preparation method of the artemisinin C-16 aromatic amine derivative, wherein, in step S1, the zinc halide is zinc bromide;

[0035] In step S2, the solvent is selected from methanol or tetrahydrofuran;

[0036] In step S3, in the m-xylene solution of Bu3SnH, the volume ratio of Bu3SnH to the m-xylene solution is 1:1;

[0037] In step S5, the acyl chloride is one of 4-(tert-butyl)benzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-(trifluoromethyl)benzenesulfonyl chloride, cyclopropanesulfonyl chloride, cyclopropanecarbonyl chloride, 4-methylbenzoyl chloride, isoquinoline-5-sulfonyl chloride, 4-hydroxybenzenesulfonyl chloride, 6-chloronicotinoyl chloride;

[0038] In step S5, the weak base is one of pyridine, triethylamine, DIPEA.

[0039] The method for preparing the artemisinin C-16 aromatic amine derivative, wherein, in step S1, the equivalent ratio among palladium carbon, zinc halide, and EA is 0.16:1.3:23.5 - 25.0; the equivalent ratio between compound 0 and the zinc halide is 1.0:1.3;

[0040] In step S2, the equivalent ratio between compound 1 and Boc anhydride is 1.0:1.2 - 1.5; the equivalent ratio between compound 1 and TEA is 1.0:1.5 - 1.7;

[0041] In step S3, the equivalent ratio between AIBN and Bu3SnH is 0.3:1.5, the equivalent ratio among compound 2, compound 3, and AIBN is 1.15:1.0:0.3; the equivalent ratio between the other configuration compound and DBU is 1:2.0;

[0042] In step S5, the equivalent ratio among compound 5, the acyl chloride, and the weak base is 1.0:1.2 - 1.5:1.5 - 2.0.

[0043] The method for preparing the artemisinin C-16 aromatic amine derivative, wherein, in step S1, when leaching the filter cake with EA, the EA for leaching the filter cake is recovered;

[0044] In step S4, when adding water and ethyl acetate to extract the reaction solution, the ethyl acetate phase is recovered. For the recovered ethyl acetate phase, it is neutralized with saturated K2CO3, then extracted with EA, concentrated to dryness, and purified by column chromatography to obtain compound 5.

[0045] An application of the artemisinin C-16 aromatic amine derivative as described above, wherein the artemisinin C-16 aromatic amine derivative is used for preparing an anti-tumor drug.

[0046] Application of artemisinin C-16 aromatic amine derivatives, wherein the anti-tumor drug is one of anti-hepatocellular carcinoma drugs, anti-lung cancer drugs, anti-gastric cancer drugs, and anti-colorectal cancer drugs.

[0047] Beneficial effects: The artemisinin C-16 aromatic amine derivatives of the present application are prepared by introducing specific aromatic amide groups at the C-16 position to obtain novel derivatives. The artemisinin C-16 aromatic amine derivatives of the present application all have anti-tumor activity, providing a new strategy for the chemical research and development of novel artemisinin derivatives and cancer treatment. Description of the Drawings

[0048] Figure 1 1H NMR spectrum of compound 2 in Example 1 of the present application 1 1H NMR spectrum.

[0049] Figure 2 1H NMR spectrum of compound 6a in Example 1 of the present application 1 1H NMR spectrum.

[0050] Figure 3 1H NMR spectrum of compound 6b in Example 1 of the present application 1 1H NMR spectrum.

[0051] Figure 4 1H NMR spectrum of compound 6c in Example 1 of the present application 1 1H NMR spectrum.

[0052] Figure 5 1H NMR spectrum of compound 6d in Example 1 of the present application 1 1H NMR spectrum.

[0053] Figure 6 1H NMR spectrum of compound 6e in Example 1 of the present application 1 1H NMR spectrum.

[0054] Figure 7 1H NMR spectrum of compound 6f in Example 1 of the present application 1 1H NMR spectrum.

[0055] Figure 8 1H NMR spectrum of compound 6g in Example 1 of the present application 1 1H NMR spectrum.

[0056] Figure 9 1H NMR spectrum of compound 6h in Example 1 of the present application 1 1H NMR spectrum.

[0057] Figure 10 1H NMR spectrum of compound 6i in Example 1 of the present application 1 1H NMR spectrum.

[0058] Figure 11For the compound 6j in Example 1 of this application 1 HNMR spectrum. Detailed implementation mode

[0059] This application provides an artemisinin C-16 aromatic amine derivative, its preparation method and application. To make the purpose, technical solution and effect of this application clearer and more definite, the following further details this application. It should be understood that the specific embodiments described herein are only used to explain this application and are not used to limit this application.

[0060] Artemisinin derivatives have a complex structure and a special structure with an endoperoxide bridge in the ring. In the prior art, the modification of artemisinin derivatives mainly focuses on the lactone ring or the endoperoxide bridge structure. Previous studies mainly focused on structural optimization and derivation at the C-9 and C-10 positions, and less on derivation at the C-16 position to enrich its compound library and conduct necessary anti-tumor activity evaluations. There is insufficient research on the diversity design of aromatic amide docking at the C-16 position and its structure-activity relationship. Therefore, it is very important to carry out the design, synthesis and anti-tumor application research of novel artemisinin C-16 derivatives. In addition, artemisinin itself has problems such as poor water solubility, short half-life, insufficient targeting, and tumor cell drug resistance. Aromatic amide-based drugs can regulate the drug activity and pharmacokinetic properties of compounds. Connecting aromatic amines to artemisinin can prepare artemisinin derivatives with better solubility and stability, thereby improving their pharmacokinetic properties.

[0061] This application provides an artemisinin C-16 aromatic amine derivative. By introducing a specific aromatic amide group at the C-16 position, novel derivatives are prepared. Through experimental results, it is found that the artemisinin C-16 aromatic amine derivatives of this application all have anti-tumor activity, providing a new strategy for the chemical research and development of novel artemisinin derivatives and cancer treatment.

[0062] Specifically, the artemisinin C-16 aromatic amine derivative of this application has a general structural formula as shown in formula (1):

[0063]

[0064] Among them, R1 can be one of 4-(tert-butyl)benzenesulfonyl, 4-chlorobenzenesulfonyl, 4-fluorobenzenesulfonyl, 4-(trifluoromethyl)benzenesulfonyl, cyclopropanesulfonyl, cyclopropanecarbonyl, 4-methylbenzoyl, isoquinoline-5-sulfonyl, 4-hydroxybenzenesulfonyl, 6-chloronicotinoyl, etc.;

[0065] n can be 1 or 2.

[0066] Preferably, the artemisinin C-16 aromatic amine derivative of this application has a general structural formula as shown in formula (2):

[0067]

[0068] More preferably, the artemisinin C-16 aromatic amine derivative of the present application is one of the following compounds 6a-6j:

[0069]

[0070]

[0071] Furthermore, the present application also provides a preparation method for the artemisinin C-16 aromatic amine derivative, and its synthetic route is as follows:

[0072]

[0073] Specifically, the preparation method for the artemisinin C-16 aromatic amine derivative of the present application includes the following steps:

[0074] S1: Using compound 0 as the starting material, through a reduction reaction in a hydrogen / Pd-C / zinc halide / EA (ethyl acetate) system to obtain compound 1.

[0075] In step S1, compound 0 is n can be 1 or 2. Specifically, compound 0 can be 4-nitrophenethyl bromide or 4-nitropropyl bromide

[0077] The loading amount of palladium in Pd-C can be 0.08 wt.

[0078] The zinc halide can be zinc bromide.

[0079] In step S1, the equivalent ratio among Pd-C, zinc halide, and EA can be 0.16:1.3:23.5-25.0.

[0080] In step S1, the equivalent ratio between compound 0 and zinc halide can be 1.0:1.3.

[0081] In step S1, when carrying out the reaction, hydrogen replacement is carried out under normal pressure, and the reaction is carried out under hydrogen protection. Carrying out hydrogen replacement under normal pressure is convenient for operation and does not require the use of a pressure reactor for hydrogenation reaction.

[0082] In step S1, the reaction temperature is 45±5 °C, preferably 44±4 °C. This reaction temperature is optimized. If the reaction is carried out under low temperature conditions (T < 40 °C), the reaction process is slow, and the lower the temperature, the less the reaction proceeds; if the reaction is carried out at a higher temperature (T > 55 °C), the reaction by-products increase and azo compounds are easily formed. Therefore, in the solution of the present application, the optimal temperature for step S1 is 40-48 °C.

[0083] Specifically, step S1 includes the following steps:

[0084] Add the raw material compound 0 into a container, add Pd / C, zinc halide, and EA, conduct hydrogen displacement 3 times under stirring and normal pressure, protect with hydrogen, heat to 45 ± 5 °C and react for 72 h, detect by TLC until the raw materials disappear, and a solid precipitates in the reaction system; cool down, filter, wash the filter cake with EA, collect the filter cake, slurry it with MeOH (methanol) for 3 h and then filter, collect the filtrate, concentrate the filtrate to dryness to obtain a light yellow solid, i.e., compound 1.

[0085] Preferably, when washing the filter cake with EA, the EA for washing the filter cake can be recovered, concentrated to dryness, and the obtained solid can be used to obtain more compound 1.

[0086] S2: Compound 1 is protected with Boc anhydride to obtain compound 2.

[0087] In step S2, the solvent can be selected from methanol or tetrahydrofuran. In the examples of this application, the solvent used is methanol, and tetrahydrofuran can also be used as an alternative.

[0088] In step S2, the equivalent ratio between compound 1 and Boc anhydride ((Boc)2O) can be 1.0:1.2 - 1.5.

[0089] In step S2, a catalyst needs to be added. The catalyst can be TEA (triethylamine), and the equivalent ratio between compound 1 and the catalyst can be 1.0:1.5 - 1.7.

[0090] In step S2, the reaction temperature can be 20 ± 5 °C.

[0091] During the R & D process, the inventors also tried to use TsCl (p-toluenesulfonic acid) and TrtCl (triphenylchloromethane) for protection. However, a method for quickly and simply purifying the product could not be found for the time being. Therefore, in the solution of this application, it is preferably to use Boc anhydride for protection. Compound 2 obtained by protecting with Boc anhydride can obtain a single and clean product through flash column chromatography and slurrying with pure petroleum ether.

[0092] Specifically, step S2 includes the following steps:

[0093] Add compound 1 and the solvent into a container, add TEA (triethylamine), slowly dropwise add (Boc)2O (di-tert-butyl dicarbonate) under stirring, react at 20 ± 5 °C for 10 h, detect by TLC until the raw material compound 1 disappears, add water to quench, extract with EA, combine the organic phases, wash the organic phases with saturated brine, dry with anhydrous sodium sulfate, and filter; evaporate the solvent under reduced pressure, and after the crude product is processed by flash column chromatography, slurry it with PE (petroleum ether) for 3 h and filter to obtain compound 2.

[0094] In step S2, during flash column chromatography, a silica gel column was used, and petroleum ether:ethyl acetate = 10:1 (volume ratio) was used as the eluent.

[0095] S3: Compounds 2 and 3 were subjected to a radical addition reaction through an AIBN (azobisisobutyronitrile) / Bu3SnH (tributyltin hydride) system to obtain compound 4 and another configurational compound;

[0096] The other configurational compound was refluxed through a THF (tetrahydrofuran) / DBU (1,8-diazabicycloundec-7-ene) system to obtain compound 4.

[0097] In step S3, compound 3 was artemisylene

[0098] In step S3, the equivalent ratio between AIBN and Bu3SnH could be 0.3:1.5, and the equivalent ratio between compound 2, compound 3, and AIBN could be 1.15:1.0:0.3.

[0099] In step S3, the equivalent ratio between the other configurational compound and DBU could be 1:2.0.

[0100] Specifically, step S3 includes the following steps:

[0101] Compound 3, compound 2, and AIBN were dissolved in m-xylene, and refluxed under nitrogen protection for 1 h; then a solution of tributyltin hydride in m-xylene (the volume ratio of tributyltin hydride to m-xylene could be 1:1) was slowly added dropwise. After the addition, the mixture was refluxed at 85 ± 5 °C overnight. The reaction solution was rotary evaporated to obtain a pale yellow crude product. The crude product was dissolved in EA, saturated KF (potassium fluoride) solution was added, and the mixture was stirred at room temperature for 12 h. The solid was filtered, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by column chromatography to obtain compound 4 and another configurational compound;

[0102] The other configurational compound was added to THF, DBU was added under stirring, the system was heated to reflux for 18 h, and TLC was used to detect and judge the conversion of compound 4. The mixture was concentrated to dryness, water and EA were added for extraction and liquid separation, dried, and purified and separated by silica gel column chromatography to obtain compound 4.

[0103] In step S3, during the two column chromatography purifications, a silica gel column was used in both cases, and petroleum ether:ethyl acetate = 5:1 (volume ratio) was used as the eluent.

[0104] S4: Under acidic conditions, compound 4 was deprotected to remove Boc to obtain compound 5.

[0105] In step S4, the acid used can be one of hydrochloric acid, p-toluenesulfonic acid, trifluoroacetic acid, oxalyl chloride, etc.

[0106] Specifically, step S4 includes the following steps:

[0107] Compound 4 is dissolved in EA, and HCl / EA (ethyl acetate solution of hydrogen chloride) is added dropwise to the reaction system. The reaction is stirred at room temperature for 6 h. After TLC detection shows the disappearance of compound 4, water and ethyl acetate are added to extract the reaction solution. The ethyl acetate phase is recovered, the aqueous phase is neutralized with saturated K2CO3 (potassium carbonate), and then extracted with EA. The organic layers are combined, washed once with saturated brine, the organic layer is dried with anhydrous sodium sulfate, and the solvent is evaporated to obtain compound 5;

[0108] For the recovered ethyl acetate phase, it can be neutralized with saturated K2CO3 (potassium carbonate), then extracted with EA, concentrated to dryness, and purified by column chromatography to obtain compound 5. In this way, more products can be recovered as much as possible.

[0109] In step S4, during column chromatography purification, a silica gel chromatography column is used, and petroleum ether:ethyl acetate = 3:1 (volume ratio) is used as the eluent.

[0110] S5: Compound 5 undergoes a substitution reaction with an acyl chloride under basic conditions to synthesize compound 6, which is the artemisinin C-16 aromatic amine derivative of the present application.

[0111] In step S5, the base used in the substitution reaction is a weak base, and one of pyridine, triethylamine, DIPEA (N,N-diisopropylethylamine), etc. can be selected.

[0112] In step S5, the acyl chloride can be one of 4-(tert-butyl)benzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-(trifluoromethyl)benzenesulfonyl chloride, cyclopropanesulfonyl chloride, cyclopropanecarbonyl chloride, 4-methylbenzoyl chloride, isoquinoline-5-sulfonyl chloride, 4-hydroxybenzenesulfonyl chloride, 6-chloronicotinoyl chloride.

[0113] In step S5, the equivalent ratio among compound 5, acyl chloride, and weak base can be 1.0:1.2 - 1.5:1.5 - 2.0.

[0114] In step S5, the reaction temperature is 25 ± 10 °C, preferably 25 ± 5 °C.

[0115] Specifically, step S5 includes the following steps:

[0116] Compound 5 and the weak base are dissolved in dichloromethane, the acyl chloride is added to the reaction system, and the reaction is carried out at 25 ± 5 °C. After TLC detection shows that compound 5 has completely reacted, it is purified by column chromatography to obtain compound 6.

[0117] In step S5, during column chromatography purification, a silica gel chromatography column was used, silica gel column chromatography was adopted, and petroleum ether:ethyl acetate = 1:1 (volume ratio) was used as the eluent.

[0118] In the embodiment solution of the present application, the CCK-8 cell activity test method was adopted to evaluate the anti-tumor activity of the artemisinin C-16 aromatic amine derivative of the present application. Through the experimental results, it was found that the artemisinin C-16 aromatic amine derivatives of the present application all have anti-tumor activity. Therefore, in the solution of the present application, the application of the artemisinin C-16 aromatic amine derivative of the present application is also provided, and the artemisinin C-16 aromatic amine derivative is used to prepare anti-tumor drugs. Further, the anti-tumor drug can be one of anti-hepatocarcinoma drugs, anti-lung cancer drugs, anti-gastric cancer drugs, anti-colorectal cancer drugs, etc.

[0119] The following further illustrates the present application through specific examples.

[0120] Example 1

[0121] In this example, compound 6a-5j (i.e., artemisinin C-16 aromatic amine derivative) was synthesized. The specific synthesis route is as follows:

[0122]

[0123] Synthesis of compound 1 and compound 2:

[0124] Weigh the raw material 4-nitrophenethyl bromide (20 g, 86.93 mmol) and add it to a three-necked flask. Then add Pd / C (1.6 g, 0.08 wt), zinc bromide (25.45 g, 113 mmol), and EA (200 ml). Conduct hydrogen displacement three times under stirring and normal pressure, protect with hydrogen, heat to 50 °C and react for 72 h. Detect by TLC that the raw material disappears and a solid precipitates in the reaction system. Cool down, filter, wash the filter cake with EA, collect the filter cake, slurry it with MeOH (200 mL) for 3 h and then filter, collect the filtrate, concentrate the filtrate to dryness, and obtain 8.9 g of a light yellow solid, getting the reduction product compound 1 (the yield of this step is 68.73%). Directly carry out Boc protection. Add MeOH (60 mL) to the reaction flask, add TEA (6.79 g, 1.5 eq), slowly dropwise add (Boc)2O (11.7 g, 1.2 eq) under stirring, react at 20 ± 5 °C for 10 h. Detect by TLC that compound 1 disappears, add water to quench, extract with EA (extract three times, 50 ml each time), combine the organic phases, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and filter; evaporate the solvent under reduced pressure. After subjecting the crude product to flash column chromatography (silica gel chromatography column, petroleum ether:ethyl acetate = 10:1, volume ratio), slurry it with PE (20 mL) for 3 h and filter to obtain the target product compound 2 (tert-butyl(4-(2-bromoethyl)phenyl)carbamate), and the overall yield of the two steps is 53.95%.

[0125] Compound 2 was subjected to nuclear magnetic resonance analysis, and its 1 1H NMR spectrum is as Figure 1 shown, 1 and the 1H-NMR data are as follows:

[0126] 1 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 6.9 Hz, 2H), 7.15 (d, J = 6.9 Hz, 2H), 3.54 (t, J = 6.6 Hz, 2H), 3.14 (d, J = 6.9 Hz, 2H), 1.54 (s, 9H).

[0127] Synthesis of compound 4:

[0128] Compound 3 (2.04 g, 7.3 mmol), compound 2 (2.5 g, 8.4 mmol) and AIBN (360 mg, 2.2 mmol) were dissolved in m-xylene (25 mL), and the reaction was refluxed for 1 h under nitrogen protection. Then, a solution of tributyltin hydride (3.2 g, 10.9 mmol) in m-xylene (the volume ratio of tributyltin hydride to m-xylene was 1:1) was slowly added dropwise. After the addition, the reaction was refluxed overnight at 85 ± 5 °C. The reaction solution was rotary evaporated to obtain a pale yellow crude product. The crude product was dissolved in 30 mL of EA, 20 mL of saturated KF solution was added, and the reaction was stirred at room temperature for 12 h. The solid was filtered, the filtrate was added with water and extracted with ethyl acetate. The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by column chromatography (silica gel chromatography column, petroleum ether: ethyl acetate = 5:1, volume ratio) to obtain 837.2 mg (1.67 mmol) of compound 4, with a yield of 22.96%, and another 551 mg (1.10 mmol) of the compound with the other configuration was obtained, with a yield of 15.1%.

[0129] Another compound with the other configuration (551 mg, 1.10 mmol) was taken, THF (15 mL) was added, and DBU (334.87 mg, 2.19 mmol) was added under stirring. The reaction system was heated to reflux for 18 h. TLC detection was used to judge the conversion of compound 4. It was concentrated to dryness, water and EA were added for extraction and liquid separation, dried, and purified by silica gel column chromatography (silica gel chromatography column, petroleum ether: ethyl acetate = 5:1, volume ratio) to obtain compound 4 (46.84 mg), with a recovery rate of 8.5%.

[0130] Synthesis of compound 5:

[0131] Compound 4 (1.255 g, 2.5 mmol) was dissolved in EA (10 mL), and HCl / EA (2 M, 20 ml) was added dropwise to the reaction system. The reaction was stirred at room temperature for 6 h. After TLC detection showed the disappearance of compound 4, water and ethyl acetate were added to extract the reaction solution. The ethyl acetate phase was recovered, the aqueous phase was neutralized with saturated K2CO3, and extracted with EA (extracted three times, 10 ml each time). The organic layers were combined, washed once with saturated brine, the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated to obtain the target compound 5 (657 mg, 1.64 mmol); for the recovered ethyl acetate phase, it could be neutralized with saturated K2CO3 (potassium carbonate), then extracted with EA, concentrated to dryness, and purified by column chromatography (silica gel chromatography column, petroleum ether: ethyl acetate = 3:1, volume ratio) to recover the target compound 5 (330 mg, 0.83 mmol). A total of 987 mg (2.46 mmol) of compound 5 was obtained in this step, with a yield of 98.25%.

[0132] Synthesis of compound 6a:

[0133] Compound 5 (15 mg, 0.037 mmol) and pyridine (4.43 mg, 0.056 mmol) were dissolved in dichloromethane, and 4-(tert-butyl)benzenesulfonyl chloride (0.045 mmol) was added to the reaction system. The reaction was carried out at 25 ± 5 °C. After the reaction of compound 5 was detected to be complete by TLC, the target compound 6a (4-(tert-butyl)-N-(4-(3-((3R,5aS,8aR,9S,12R,12aR)-3,6-dimethyl-10-oxodecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-9-yl)propyl)phenyl)benzenesulfonamide) was purified by column chromatography (silica gel chromatography column, petroleum ether:ethyl acetate = 1:1, volume ratio) to obtain a yellow solid with a yield of 50.14%.

[0134] Nuclear magnetic resonance analysis was performed on compound 6a, and its 1 1H NMR spectrum is as Figure 2 shown, 1 and the 1H-NMR data are as follows:

[0135] 1 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 7.04 - 6.94 (m, 2H), 5.86 (s, 1H), 3.22 (dd, J = 13.2, 6.0 Hz, 1H), 2.69 - 2.50 (m, 2H), 2.42 (dd, J = 24.8, 13.6 Hz, 1H), 2.03 (d, J = 12.6 Hz, 2H), 1.79 - 1.70 (m, 4H), 1.62 (s, 2H), 1.41 - 1.37 (m, 2H), 1.32 (s, 9H), 1.28 (s, 3H), 1.08 (d, J = 11.8 Hz, 3H), 1.01 (d, J = 5.5 Hz, 3H).

[0136] The preparation process of compound 6b in this example:

[0137] The preparation process is basically the same as that of 6a, except that 4-chlorobenzenesulfonyl chloride is used for R1;

[0138] Compound 6b (4-chloro-N-(4-(3-((3R,5aS,8aR,9S,12R,12aR)-3,6-dimethyl-10-oxodecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-9-yl)propyl)phenyl)benzenesulfonamide) was prepared as a yellow oil with a yield of 51.16%.

[0139] Compound 6b was subjected to nuclear magnetic resonance analysis, and its 1 1H NMR spectrum is as shown in Figure 3 the following, 1 and the 1H-NMR data are as follows:

[0140] 1 1H NMR (400 MHz, DMSO) δ 10.19 (d, J = 38.6 Hz, 1H), 7.71 (dd, J = 8.9, 2.1 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 6.09 (s, 1H), 3.03 - 2.90 (m, 1H), 2.44 (dd, J = 14.0, 7.8 Hz, 1H), 2.32 - 2.19 (m, 1H), 2.04 (d, J = 13.4 Hz, 1H), 1.97 - 1.86 (m, 1H), 1.84 - 1.72 (m, 2H), 1.68 - 1.59 (m, 1H), 1.53 (dd, J = 15.7, 8.7 Hz, 5H), 1.40 -

[0141] 1.37 (m, 1H), 1.35 (s, 3H), 1.22 (d, J = 5.2 Hz, 1H), 1.12 - 0.96 (m, 2H), 0.89 - 0.86 (m, 3H).

[0142] The preparation process of compound 6c in this example is as follows:

[0143] The preparation process is basically the same as that of 6a, except that 4-fluorobenzenesulfonyl chloride is used for R1;

[0144] Compound 6c (N-(4-(3-((3R,5aS,8aR,9S,12R,12aR)-3,6-dimethyl-10-oxodecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-9-yl)propyl)phenyl)-4-(trifluoromethyl)benzenesulfonamide) was prepared as a yellow oil in 79.04% yield.

[0145] Compound 6c was subjected to nuclear magnetic resonance analysis, and its 1 1H NMR spectrum is as shown in Figure 4 the following, 1 and the 1H-NMR data are as follows:

[0146] 1 1H NMR (400 MHz, CDCl3) δ 7.80 - 7.73 (m, 2H), 7.16 - 7.06 (m, 4H), 6.98 (d, J = 7.8 Hz, 2H), 5.86 (s, 1H), 3.22 (dd, J = 12.6, 6.0 Hz, 1H), 2.59 (ddt, J = 21.3, 14.0, 7.1 Hz, 2H), 2.44 (t, J = 12.6 Hz, 1H), 2.11 - 1.99 (m, 3H), 1.84 - 1.67 (m, 5H), 1.58 (d, J = 33.0 Hz, 3H), 1.46 (s, 3H), 1.29 (d, J = 9.5 Hz, 3H), 1.02 (d, J = 5.4 Hz, 3H).

[0147] The preparation process of compound 6d in this example is as follows:

[0148] The preparation process is basically the same as that of 6a, except that 4-(trifluoromethyl)benzenesulfonyl chloride is used for R1;

[0149] Compound 6d (N-(4-(3-((3R,5aS,8aR,9S,12R,12aR)-3,6-dimethyl-10-oxodecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-9-yl)propyl)phenyl)-4-fluorobenzenesulfonamide) was prepared as a yellow oil in 61.02% yield.

[0150] Compound 6d was subjected to nuclear magnetic resonance analysis, and its 1 1H NMR spectrum is as shown in Figure 5 the following, 1The H-NMR data are as follows:

[0151] 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.2 Hz, 2H), 7.72 (d, J = 8.1 Hz, 2H), 7.08 (t, J = 9.4 Hz, 2H), 7.00 (dd, J = 8.4, 2.0 Hz, 2H), 5.72 (d, J = 22.3 Hz, 1H), 2.98 (d, J = 6.4 Hz, 1H), 2.67 - 2.52 (m, 2H), 2.04 (ddd, J = 9.8, 9.4, 4.0 Hz, 2H), 1.96 - 1.88 (m, 1H), 1.82 - 1.71 (m, 4H), 1.64 (s, 2H), 1.54 (s, 2H), 1.46 (s, 2H), 1.28 (t, J = 7.0 Hz, 3H), 1.09 (d, J = 6.2 Hz, 1H), 1.01 (d, J = 5.7 Hz, 1H), 0.99 - 0.90 (m, 3H).

[0152] The preparation process of compound 6e in this example:

[0153] The preparation process is basically the same as that of 6a, except that cyclopropylsulfonyl chloride is used for R1;

[0154] Compound 6e (N-(4-(3-((3R,5aS,8aR,9S,12R,12aR)-3,6-dimethyl-10-oxodecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-9-yl)propyl)phenyl)cyclopropanesulfonamide) was prepared, which is a white solid with a yield of 61.58%.

[0155] Compound 6e was analyzed by nuclear magnetic resonance, and its 1 1H NMR spectrum is as Figure 6 shown, 1 The H-NMR data are as follows:

[0156] 11H NMR (400 MHz, CDCl3) δ 7.18 (q, J = 8.4 Hz, 4H), 5.86 (s, 1H), 3.23 (dt, J = 8.6, 5.7 Hz, 1H), 2.74 - 2.55 (m, 2H), 2.53 - 2.37 (m, 2H), 2.12 - 1.97 (m, 3H), 1.86 - 1.70 (m, 4H), 1.69 - 1.57 (m, 2H), 1.46 (s, 3H), 1.41 (dd, J = 10.0, 4.7 Hz, 2H), 1.38 - 1.34 (m, 1H), 1.31 - 1.25 (m, 1H), 1.19 - 1.13 (m, 2H), 1.07 (d, J = 7.3 Hz, 1H), 1.01 (d, J = 5.8 Hz, 3H).

[0157] Preparation process of compound 6f in this example:

[0158] The preparation process is basically the same as that of 6a, with the only difference being that cyclopropanecarbonyl chloride is used for R1;

[0159] Compound 6f (N-(4-(3-((3R,5aS,8aR,9S,12R,12aR)-3,6-dimethyl-10-oxodecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-9-yl)propyl)phenyl)cyclopropanecarboxamide) was prepared, as a yellow solid, with a yield of 85.45%.

[0160] For nuclear magnetic resonance analysis of compound 6f, its 1 1H NMR spectrum is as Figure 7 shown, 1 and the 1H-NMR data are as follows:

[0161] 11H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 7.9 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 5.84 (s, 1H), 3.22 (dt, J = 8.6, 5.7 Hz, 1H), 2.69 - 2.60 (m, 1H), 2.55 (dd, J = 14.2, 6.8 Hz, 1H), 2.42 (td, J = 14.5, 3.7 Hz, 1H), 2.08 - 1.96 (m, 3H), 1.82 - 1.67 (m, 4H), 1.63 - 1.52 (m, 2H), 1.44 (s, 3H), 1.40 - 1.37 (m, 1H), 1.36 - 1.32 (m, 1H), 1.28 (d, J = 10.5 Hz, 1H), 1.05 (dd, J = 7.0, 3.0 Hz, 3H), 0.99 (d, J = 5.7 Hz, 3H), 0.83 - 0.77 (m, 2H).

[0162] Preparation process of compound 6g in this example:

[0163] The preparation process is basically the same as that of 6a, with the only difference being that 4-methylbenzoyl chloride is used for R1;

[0164] Compound 6g (N-(4-(3-((3R,5aS,8aR,9S,12R,12aR)-3,6-dimethyl-10-oxodecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-9-yl)propyl)phenyl)-4-methylbenzamide) was prepared, as a white solid, with a yield of 86.92%.

[0165] For nuclear magnetic resonance analysis of compound 6g, its 1 1H NMR spectrum is as Figure 8 shown, 1 The 1H-NMR data are as follows:

[0166] 1 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.2 Hz, 2H), 5.82 (s, 1H), 3.21 (dt, J = 8.5, 5.7 Hz, 1H), 2.73 - 2.61 (m, 1H), 2.61 - 2.52 (m, 1H), 2.49 - 2.34 (m, 4H), 2.03 (ddd, J = 18.3, 12.9, 5.6 Hz, 3H), 1.84 - 1.66 (m, 4H), 1.66 -

[0167] 1.53 (m, 1H), 1.44 (s, 3H), 1.38 (dd, J = 13.6, 9.0 Hz, 3H), 1.34 - 1.24 (m, 1H), 0.99 (d, J = 5.2 Hz, 3H).

[0168] The preparation process of compound 6h in this example:

[0169] The preparation process is basically the same as that of 6a, except that R1 is isoquinoline-5-sulfonyl chloride;

[0170] Compound 6h (N-(4-(3-((3R,5aS,8aR,9S,12R,12aR)-3,6-dimethyl-10-oxodecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-9-yl)propyl)phenyl)isoquinoline-5-sulfonamide) was prepared, which is a yellow oil with a yield of 60.10%.

[0171] Compound 6h was analyzed by nuclear magnetic resonance, and its 1 1H NMR spectrum is as Figure 9 shown, 1 The 1H-NMR data are as follows:

[0172] 1 1H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 8.63 (d, J = 6.1 Hz, 1H), 8.53 (d, J = 6.1 Hz, 1H), 8.36 (t, J = 11.5 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.67 - 7.58 (m, 1H), 7.03 - 6.82 (m, 4H), 5.86 (d, J = 15.4 Hz, 1H), 3.17 (dt, J = 8.4, 5.8 Hz, 1H), 2.48 (qdd, J = 22.5, 11.4, 5.1 Hz, 3H), 1.99 (ddt, J = 15.8, 10.4, 4.1 Hz, 3H), 1.81 - 1.60 (m, 5H), 1.53 - 1.49 (m, 1H), 1.42 (d, J = 8.6 Hz, 3H), 1.38 (d, J = 6.2 Hz, 1H), 1.34 - 1.20 (m, 5H), 1.02 - 0.95 (m, 3H).

[0173] The preparation process of compound 6i in this example:

[0174] The preparation process is basically the same as that of 6a, except that 4-hydroxybenzenesulfonyl chloride is used for R1;

[0175] Compound 6i (N-(4-(3-((3R,5aS,8aR,9S,12R,12aR)-3,6-dimethyl-10-oxodecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-9-yl)propyl)phenyl)-4-hydroxybenzenesulfonamide) was prepared as a white solid in a yield of 43.98%.

[0176] Compound 6i was subjected to nuclear magnetic resonance analysis, and its 1 1H NMR spectrum is as Figure 10 shown, 1 and the 1H-NMR data are as follows:

[0177] 1 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.20 (d, J = 7.4 Hz, 1H), 8.09 (s, 1H), 7.55 (d, J = 5.8 Hz, 2H), 7.47 (d, J = 7.7 Hz, 1H), 7.19 (d, J = 6.9 Hz, 2H), 5.85 (s, 1H), 2.77 - 2.55 (m, 2H), 2.44 (t, J = 13.2 Hz, 1H), 2.07 (d, J = 10.6 Hz, 4H), 1.77 (d, J = 10.9 Hz, 4H), 1.65 (s, 2H), 1.46 (s, 5H), 1.29 (d, J = 7.9 Hz, 2H), 1.10 - 0.99 (m, 5H).

[0178] The preparation process of compound 6j in this example:

[0179] The preparation process is basically the same as that of 6a, except that 6-chloronicotinoyl chloride is used for R1;

[0180] Compound 6j (6-chloro-N-(4-(3-((3R,5aS,8aR,9S,12R,12aR)-3,6-dimethyl-10-oxodecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-9-yl)propyl)phenyl)nicotinamide) was prepared as a white solid in a yield of 49.51%.

[0181] Compound 6j was subjected to nuclear magnetic resonance analysis, and its 1The HNMR spectrum is as follows Figure 11 as shown 1 The H-NMR data are as follows:

[0182] 1 H NMR(400MHz,CDCl3)δ8.89(d,J=1.3Hz,1H),8.19(dd,J=8.2,2.0Hz,1H),7.55(d,J=8.1Hz,2H),7.41(t,J=12.2Hz,1H),7.14(t,J=11.8Hz,2H),5.84(s,1H),3.22(dt,J=11.5,5.9Hz,1H),2.72-2.53(m,2H),2.50-2.37(m,1H),2.14-1.89(m,3H),1.87-1.68(m,4H),1.69-1.53(m,1H),1.52-1.45(m,1H),1.44(s,3H),1.39(s,1H),1.35(dd,J=12.4,4.9Hz,1H),1.28(d,J=11.3Hz,1H),1.00(d,J=5.7Hz,3H).

[0183] The CCK8 method was used to evaluate the activity of the prepared compounds 6a-6j:

[0184] The CCK8 method was used to evaluate the anti-tumor activities of compounds 6a-5j against five human cancer cell lines, A549, HepG2, RKO, MKN45, and MDA-MB-231.

[0185] The specific experimental steps include:

[0186] Cell seeding: One type of cancer cell was seeded in each well, and the number of cancer cells seeded in each well was 5000. Cell administration: Five concentrations were set for each compound, namely 0.39 μM, 1.56 μM, 6.25 μM, 25 μM, and 100 μM, and five replicates were set for each concentration. After administration, the culture time was 48 h.

[0187] Addition of CCK-8 reagent and determination of absorbance value. The OD value was detected using a microplate reader, the cell survival rate was calculated, and the IC50 value (half inhibitory concentration) was obtained by drawing graphs using GraphPad Prism 8 and Origin software.

[0188] The results are shown in Table 1. It can be seen that except for compounds 6b and 6f, other compounds all have obvious inhibitory effects on the growth of the five human cancer cell lines.

[0189] Table 1 IC50 values of compounds 6a-16j against five human cancer cell lines, A549, HepG2, RKO, MKN45, and MDA-MB-231

[0190]

[0191] In this embodiment, the artemisinin C-16 aromatic amine derivative prepared in this embodiment was also compared with artemisinin, artemisene, and the corresponding positive drugs (Gefitinib, Sorafenib (SOR), 5-Fluorouracil (5-FU), Docetaxel (DTX) as control drugs). The results are shown in Table 1 above. When evaluating the tumor activity by simply using artemisene and artemisinin, the effect is not good. However, it can be directly seen that the artemisinin C-16 aromatic amine derivative prepared in this embodiment has relatively high anti-tumor activity.

[0192] The IC50 values of compound 6a against three human cancer cells, HepG2, RKO, and MKN45, are 3.28 ± 0.02 μM, 3.53 ± 0.53 μM, and 7.47 ± 1.12 μM respectively, showing obvious inhibitory effects.

[0193] The IC50 value of compound 6b against MKN45 human cancer cells is 12.82 ± 3.18 μM, showing a slight inhibitory effect.

[0194] The IC50 values of compounds 6c and 6d against RKO human cancer cells are 5.74 ± 3.48 μM and 6.90 ± 1.10 μM respectively, showing obvious inhibitory effects.

[0195] The IC50 value of compound 6e against HepG2 human cancer cells is 7.66 ± 4.68 μM, showing an obvious inhibitory effect, and no obvious inhibitory effect on the other 4 types of human cancer cells.

[0196] The inhibitory level of compound 6f against five types of human cancer cells is not high.

[0197] Compound 6g has no obvious inhibitory effect on the MDA-MB-231 cell line, but shows strong inhibitory effects on the other 4 types of human cancer cells.

[0198] The IC50 values of compound 6h against A549 and MKN45 are 6.28 ± 0.54 μM and 8.46 ± 1.49 μM respectively, showing strong inhibitory effects.

[0199] The IC50 value of compound 6i against A549 is 13.22 ± 5.73 μM, showing an inhibitory effect, and no obvious inhibitory effect on other cancer cells.

[0200] The IC50 values of compound 6j against three kinds of cells, A549, HepG2 and RKO, are 12.57 ± 0.20 μM, 26.32 ± 7.42 μM and 23.44 ± 18.72 μM respectively, showing a slightly inhibitory effect.

[0201] It should be understood that the applications of the present application are not limited to the above examples. For those of ordinary skill in the art, improvements or transformations can be made according to the above description, and all such improvements and transformations should fall within the protection scope of the present application.

Claims

1. An artemisinin C-16 aromatic amine derivative, characterized in that, The general structural formula thereof is shown in Formula (1): Among them, R1 is one of 4-(tert-butyl)benzenesulfonyl, 4-chlorobenzenesulfonyl, 4-fluorobenzenesulfonyl, 4-(trifluoromethyl)benzenesulfonyl, cyclopropanesulfonyl, cyclopropanecarbonyl, 4-methylbenzoyl, isoquinoline-5-sulfonyl, 4-hydroxybenzenesulfonyl, 6-chloronicotinoyl; n is 1 or 2.

2. The artemisinin C-16 aromatic amine derivative according to claim 1, wherein The general structural formula of the artemisinin C-16 aromatic amine derivative is shown in Formula (2):

3. The artemisinin C-16 aromatic amine derivative according to claim 1, characterized in that, The artemisinin C-16 aromatic amine derivative is one of the following compounds 6a-6j:

4. A method for preparing an artemisinin C-16 aromatic amine derivative according to any one of claims 1-3, characterized in that, It includes the following steps: S1: Using compound 0 as the starting material, through a reduction reaction in a hydrogen / palladium carbon / zinc halide / EA system to obtain compound 1; among them, compound 0 is 4-nitrophenethyl bromide or 4-nitropropyl bromide; S2: Protecting compound 1 with Boc anhydride to obtain compound 2; S3: Performing a radical addition reaction on compound 2 and compound 3 in an AIBN / Bu3SnH system to obtain compound 4 and another configurational compound; among them, compound 3 is artemene; Refluxing the other configurational compound in a THF / DBU system to obtain compound 4; S4: Removing Boc from compound 4 under acidic conditions to obtain compound 5; S5: Performing a substitution reaction on compound 5 and acyl chloride under basic conditions to synthesize the artemisinin C-16 aromatic amine derivative.

5. The preparation method of the artemisinin C-16 aromatic amine derivative according to claim 4, characterized in that, Step S1 specifically includes the following steps: Adding compound 0 into a container, adding the palladium carbon, the zinc halide, and the EA, performing hydrogen replacement 3 times under stirring and normal pressure, under the protection of hydrogen, heating to 45±5°C and reacting for 72 h, detecting the disappearance of compound 0 by TLC, and there is a solid precipitated in the reaction system; cooling down, filtering, washing the filter cake with EA, collecting the filter cake, slurrying with MeOH for 3 h and then filtering, collecting the filtrate, concentrating the filtrate to dryness, to obtain compound 1; Step S2 specifically includes the following steps: Adding compound 1 and a solvent into a container, adding TEA, dropwise adding Boc anhydride under stirring, reacting at 20±5°C for 10 h, detecting the disappearance of compound 1 by TLC, adding water to quench, extracting with EA, combining the organic phases, washing the organic phase with saturated brine, drying with anhydrous sodium sulfate, filtering; evaporating the solvent under reduced pressure, subjecting the crude product to flash column chromatography, and slurrying with PE for 3 h and then filtering, to obtain compound 2; Step S3 specifically includes the following steps: Dissolving compound 3, compound 2, and AIBN in m-xylene, refluxing and reacting for 1 h under nitrogen protection; then dropwise adding the m-xylene solution of Bu3SnH, after dropping, refluxing and reacting overnight at 85±5°C, rotary evaporating the reaction solution to obtain a pale yellow crude product, dissolving the pale yellow crude product in EA, adding saturated KF solution, stirring and reacting at room temperature for 12 h, filtering the solid, adding water to the filtrate and extracting with ethyl acetate, combining the ethyl acetate layers, drying with anhydrous sodium sulfate, evaporating the solvent, and purifying the residue by column chromatography to obtain compound 4 and the other configurational compound; Add the other configurational compound to the THF, add the DBU under stirring, heat the system to reflux for 18 h, judge by TLC detection that the compound 4 is converted, concentrate to dryness, add water and EA for extraction and liquid separation, dry, and purify and separate by silica gel column chromatography to obtain the compound 4; Step S4 specifically includes the following steps: Dissolve the compound 4 in EA, add a solution of hydrogen chloride in ethyl acetate dropwise to the reaction system, stir at room temperature for 6 h, after TLC detection shows that the compound 4 has disappeared, add water and ethyl acetate to extract the reaction solution, take the aqueous phase and neutralize it with saturated K2CO3, then extract with EA, combine the organic layers, wash once with saturated brine, dry the organic layer with anhydrous sodium sulfate, and remove the solvent to obtain the compound 5; Step S5 specifically includes the following steps: Dissolve the compound 5 and a weak base in dichloromethane, add the acyl chloride to the reaction system, react at 25 ± 5 °C, after TLC detection shows that the compound 5 has completely reacted, purify by column chromatography to obtain the artemisinin C-16 aromatic amine derivative.

6. The method for preparing the artemisinin C-16 aromatic amine derivative according to claim 5, wherein in step S1, the zinc halide is zinc bromide; in step S2, the solvent is selected from methanol or tetrahydrofuran; in step S3, in the m-xylene solution of Bu3SnH, the volume ratio of Bu3SnH to the m-xylene solution is 1:1; in step S5, the acyl chloride is one of 4-(tert-butyl)benzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-(trifluoromethyl)benzenesulfonyl chloride, cyclopropanesulfonyl chloride, cyclopropanecarbonyl chloride, 4-methylbenzoyl chloride, isoquinoline-5-sulfonyl chloride, 4-hydroxybenzenesulfonyl chloride, 6-chloronicotinoyl chloride; in step S5, the weak base is one of pyridine, triethylamine, DIPEA; 7. The preparation method of the artemisinin C-16 aromatic amine derivative according to claim 5, characterized in that, in step S1, the equivalent ratio among the palladium carbon, zinc halide, and EA is 0.16:1.3:23.5 - 25.0; the equivalent ratio between the compound 0 and the zinc halide is 1.0:1.3; in step S2, the equivalent ratio between the compound 1 and the Boc anhydride is 1.0:1.2 - 1.5; the equivalent ratio between the compound 1 and the TEA is 1.0:1.5 - 1.7; in step S3, the equivalent ratio between the AIBN and the Bu3SnH is 0.3:1.5, the equivalent ratio among the compound 2, the compound 3, and the AIBN is 1.15:1.0:0.3; the equivalent ratio between the other configurational compound and the DBU is 1:2.0; in step S5, the equivalent ratio among the compound 5, the acyl chloride, and the weak base is 1.0:1.2 - 1.5:1.5 - 2.0; 8. The preparation method of the artemisinin C-16 aromatic amine derivative according to claim 5, characterized in that, in step S1, when washing the filter cake with EA, recycle the EA used for washing the filter cake; In step S4, during the step of adding water and ethyl acetate to extract the reaction solution, the ethyl acetate phase is recovered. For the recovered ethyl acetate phase, it is neutralized with saturated K2CO3, then extracted with EA, concentrated to dryness, and purified by column chromatography to obtain the compound 5.

9. Use of an artemisinin C-16 aromatic amine derivative according to any one of claims 1-3, characterized in that, The artemisinin C-16 aromatic amine derivative is used for preparing an anti-tumor drug.

10. Use of the artemisinin C-16 aromatic amine derivative according to claim 9, characterized in that, The anti-tumor drug is one of an anti-hepatocarcinoma drug, an anti-lung cancer drug, an anti-gastric cancer drug, and an anti-colorectal cancer drug.

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