Artemisinin C-16 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-bit derivative and a preparation method and application thereof, the structural general formula of the artemisinin C-16-bit derivative is as shown in formula (1): # imgabs0 #, R1 is one of 4-(tert-butyl) benzenesulfonyl, 4-chlorobenzenesulfonyl, 4-fluorobenzenesulfonyl, 4-(trifluoromethyl) benzenesulfonyl, 4-methyl benzoyl and cyclopropyl formyl; and n is 1 or 2. According to the artemisinin C-16 site derivative disclosed by the invention, a specific aryl ester group is introduced to the C-16 site, so that the molecular polarity and the pharmacokinetic property are optimized, and the anti-tumor activity is improved. The artemisinin C-16-bit derivative disclosed by the invention provides a new strategy 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 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, scientists' structural optimization of artemisinin derivatives mainly focuses on 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 immunomodulatory fields. At present, there are few reports on structural optimization at the C-16 position, and there is also a prospect for exploration in the anti-tumor direction. Therefore, it is very important to carry out the design, synthesis and anti-tumor application research of novel artemisinin derivatives at the C-16 position.

[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 derivative, its preparation method and application. This artemisinin C-16 derivative is an aromatic ester structure derivative, aiming to provide a new class of artemisinin derivatives and provide new strategies 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 derivative, wherein its general structural formula is shown in formula (1):

[0007]

[0008] Wherein, R1 is one of 4-(tert-butyl)benzenesulfonyl, 4-chlorobenzenesulfonyl, 4-fluorobenzenesulfonyl, 4-(trifluoromethyl)benzenesulfonyl, 4-methylbenzoyl, cyclopropylcarbonyl;

[0009] n is 1 or 2.

[0010] The artemisinin C-16 derivative of this application, this artemisinin C-16 derivative is an aromatic ester structure derivative. By introducing a specific aromatic ester group at the C-16 position, the molecular polarity and pharmacokinetic properties are optimized, and the anti-tumor activity is enhanced.

[0011] The artemisinin C-16 derivative described above, wherein its general structural formula is shown in formula (2):

[0012]

[0013] The artemisinin C-16 derivative, wherein the artemisinin C-16 derivative is one of the following compounds:

[0014]

[0015] A method for preparing the artemisinin C-16 derivative as described above, which includes the following steps:

[0016] S1: Using compound 0 as the starting material, through the TIPSCl / imidazole / DMF system, reacting at 5±5 °C to obtain compound 1; wherein, the compound 0 is p-hydroxyphenethyl bromide or p-hydroxyphenylpropyl bromide;

[0017] S2: Using AIBN and Bu3SnH to perform a radical addition reaction on the compound 1 and compound 2 to obtain compound 3; wherein, the compound 2 is artemene;

[0018] S3: Removing the protecting group TIPS from the compound 3 under the action of TBAF to obtain compound 4;

[0019] S4: Performing a substitution reaction on the compound 4 and an acyl chloride to obtain the artemisinin C-16 derivative; wherein, the acyl chloride is one of 4-(tert-butyl)benzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-(trifluoromethyl)benzenesulfonyl chloride, 4-methylbenzoyl chloride or cyclopropylcarbonyl chloride.

[0020] The method for preparing the artemisinin C-16 derivative, wherein, in step S1, the equivalent ratio among the TIPSCl, the imidazole, and the DMF is 1.1:1.5:11, and the equivalent ratio between the compound 0 and the TIPSCl is 1:1.1;

[0021] In step S2, the equivalent ratio among the compound 2, the AIBN, and the Bu3SnH is 1.0:0.3:1.2 - 1.5, and the equivalent ratio between the compound 2 and the compound 1 is 1:1.1 - 1.2;

[0022] In step S3, the mass ratio between the compound 3 and the TBAF is 1:0.8 - 1.2;

[0023] In step S4, a weak base needs to be added in the substitution reaction, and the weak base is one of pyridine, Et3N, and DIPEA;

[0024] In step S4, the molar ratio among the compound 4, the acyl chloride, and the weak base is 1:1.8 - 2.2:1.8 - 2.2.

[0025] The preparation method of the artemisinin C-16 derivative, wherein, in step S2, the reaction temperature is 85 ± 5 °C;

[0026] In step S3, the reaction temperature is room temperature;

[0027] In step S4, the reaction temperature is 25 ± 10 °C.

[0028] The preparation method of the artemisinin C-16 derivative, wherein step S1 specifically includes the following steps:

[0029] Dissolve the compound 0 and the imidazole in the DMF, cool and control the temperature in an ice bath between 5 ± 5 °C, dropwise add the TIPSCl, and after the addition is complete, raise the temperature to room temperature and react for 10 h;

[0030] After TLC detects that the raw materials have completely reacted, add water and ethyl acetate to extract the reaction solution, combine the organic layers, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the residue by column chromatography to obtain the compound 1;

[0031] Step S2 specifically includes the following steps:

[0032] Dissolve the compound 2, the compound 1 and the AIBN in anhydrous toluene, reflux and react at 85 ± 5 °C under nitrogen protection for 1 h;

[0033] Dropwise add the toluene solution of Bu3SnH, and after the addition is complete, reflux and react overnight. Spin-dry the reaction solution to obtain a pale yellow crude product. Dissolve the crude product in EA, add a 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 with anhydrous sodium sulfate, evaporate the solvent, and purify the residue by column chromatography to obtain the compound 3 and another configurational compound;

[0034] Place the other configurational compound in a THF solution of DBU and reflux for 18 h. After concentration to dryness, add water and EA for extraction, dry with anhydrous sodium sulfate, and purify by column chromatography to obtain the compound 3;

[0035] Step S3 specifically includes the following steps:

[0036] Dissolve the compound 3 in anhydrous THF, dropwise add the TBAF to the reaction system under nitrogen protection, stir and react at room temperature for 3 h. After TLC detects that the compound 3 has completely reacted, add water and ethyl acetate to extract the reaction solution, combine the organic layers, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the residue by column chromatography to obtain the compound 4;

[0037] Step S4 specifically includes the following steps:

[0038] Dissolve the compound 4 and the weak base in CH2Cl2, add the acyl chloride to the reaction system, and after detecting the complete reaction of the compound 4 by TLC, obtain the artemisinin C-16 derivative.

[0039] The method for preparing the artemisinin C-16 derivative, wherein the method for preparing the artemisinin C-16 derivative further comprises the following steps:

[0040] S5: Purify the artemisinin C-16 derivative with a thick preparative plate;

[0041] The purification process uses petroleum ether: ethyl acetate = 1:1 as the developing agent, stir with DCM for 3 h after scraping, filter, and concentrate to dryness.

[0042] An application of the artemisinin C-16 derivative as described above, wherein the artemisinin C-16 derivative is used to prepare an anti-tumor drug.

[0043] The application of the artemisinin C-16 derivative, wherein the anti-tumor drug is one of an anti-hepatocellular carcinoma drug, an anti-lung cancer drug, an anti-gastric cancer drug, an anti-colorectal cancer drug, and an anti-breast cancer drug.

[0044] Beneficial effects: The artemisinin C-16 derivative of the present application optimizes the molecular polarity and pharmacokinetic properties by introducing a specific aryl ester group at the C-16 position, and enhances the anti-tumor activity. The artemisinin C-16 derivative of the present application provides a new strategy for the chemical research and development of novel artemisinin derivatives and cancer treatment. Description of the Drawings

[0045] Figure 1 For the compound 1 in Example 1 of the present application 1 1H NMR spectrum.

[0046] Figure 2 For the compound 4 in Example 1 of the present application 1 1H NMR spectrum.

[0047] Figure 3 For the compound 5a in Example 1 of the present application 1 1HNMR spectrum.

[0048] Figure 4 For the compound 5b in Example 1 of the present application 1 1H NMR spectrum.

[0049] Figure 5 For the compound 5c in Example 1 of the present application 1 1HNMR spectrum.

[0050] Figure 6For the compound 5d in Example 1 of the present application 1 1H NMR spectrum.

[0051] Figure 7 For the compound 5e in Example 1 of the present application 1 1H NMR spectrum.

[0052] Figure 8 For the compound 5f in Example 1 of the present application 1 1H NMR spectrum. Detailed implementation manners

[0053] The present application provides an artemisinin C-16 derivative, its preparation method and application. To make the purpose, technical solution and effect of the present application clearer and more definite, the present application is further described in detail below. It should be understood that the specific embodiments described herein are only used to explain the present application and are not used to limit the present application.

[0054] 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, but the diversity design of the aryl ester substituents and the study of their structure-activity relationship are insufficient. In addition, traditional artemisinin derivatives have problems such as poor water solubility, insufficient targeting, and tumor cell drug resistance. Previous studies mainly focused on the structural optimization and derivation at the C-9 and C-10 positions, and less on the optimization and derivation at the C-16 position to enrich its compound library and conduct necessary anti-tumor activity evaluations.

[0055] The present application proposes an artemisinin C-16 derivative, which optimizes the molecular polarity and pharmacokinetic properties and enhances the anti-tumor activity by introducing a specific aryl ester group at the C-16 position.

[0056] Specifically, the artemisinin C-16 derivative of the present application has a general structural formula as shown in formula (1):

[0057]

[0058] Among them, R1 can be one of 4-(tert-butyl)benzenesulfonyl, 4-chlorobenzenesulfonyl, 4-fluorobenzenesulfonyl, 4-(trifluoromethyl)benzenesulfonyl, 4-methylbenzoyl, and cyclopropylcarbonyl;

[0059] n can be 1 or 2.

[0060] Preferably, the artemisinin C-16 derivative of the present application has a general structural formula as shown in formula (2):

[0061]

[0062] More preferably, the artemisinin C-16 derivative of the present application is one of the following compounds:

[0063]

[0064] Furthermore, the present application also provides a preparation method for the artemisinin C-16 derivative, and its synthetic route is as follows:

[0065]

[0066] Specifically, the preparation method for the artemisinin C-16 derivative includes the following steps:

[0067] S1: Using compound 0 as the starting material, through the TIPSCl (triisopropylchlorosilane) / imidazole / DMF (N,N-dimethylformamide) system, react at 5 ± 5 °C to obtain compound 1.

[0068] Among them, compound 0 is n can be 1 or 2. Compound 0 can be p-hydroxyphenethyl bromide or p-hydroxyphenylpropyl bromide

[0069]

[0070] In this step, the obtained compound 1 is n can be 1 or 2.

[0071] In the TIPSCl / imidazole / DMF system, the equivalent ratio among TIPSCl, imidazole, and DMF is preferably 1.1:1.5:11. Using this ratio can avoid excessive use of TIPSCl and reduce costs.

[0072] The equivalent ratio between compound 0 and TIPSCl is preferably 1:1.1.

[0073] In step S1, the reaction temperature is 5 ± 5 °C, preferably 5 ± 3 °C. In this way, the reaction can be controlled within a controllable range within this temperature range, and side products can be avoided due to excessive temperature.

[0074] Specifically, step S1 includes the following steps:

[0075] Dissolve compound 0 and imidazole in DMF, cool in an ice bath and control the temperature between 5 ± 5 °C, slowly dropwise add TIPSCl, and after the addition is complete, raise the temperature to room temperature and react for 10 h;

[0076] After TLC detects that the raw materials have completely reacted, add water and ethyl acetate to extract the reaction solution, combine the organic layers, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the residue by column chromatography to obtain compound 1.

[0077] In step S1, during column chromatography purification, silica gel column chromatography is used, and petroleum ether:ethyl acetate = 10:1 (volume ratio) is used as the eluent.

[0078] In step S1, during TLC detection, a thin layer plate is used, and PE (petroleum ether):EA (ethyl acetate) = 8:1 (volume ratio) is used as the eluent.

[0079] S2: Compound 3 is obtained by subjecting compound 1 and compound 2 to a radical addition reaction using AIBN (azobisisobutyronitrile) and Bu3SnH (tributyltin hydride).

[0080] Among them, compound 2 is artemene

[0081] Among them, the equivalent ratio among compound 2, AIBN, and Bu3SnH is 1.0:0.3:1.2 - 1.5, and the equivalent ratio between compound 2 and compound 1 is 1:1.1 - 1.2.

[0082] In step S2, the reaction temperature is 85 ± 5 °C, preferably 82 ± 2 °C.

[0083] Specifically, step S2 includes the following steps:

[0084] Dissolve compound 2, compound 1, and AIBN in anhydrous toluene, reflux and react for 1 h at 85 ± 5 °C under nitrogen protection; then slowly dropwise add a toluene solution of tributyltin hydride, and after the addition, reflux and react overnight. Rotate to dry the reaction solution to obtain a pale yellow crude product. The crude product is dissolved in EA (ethyl acetate), add a saturated KF (potassium fluoride) 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 with anhydrous sodium sulfate, evaporate the solvent, and purify the residue by column chromatography to obtain compound 3 and another configurational compound;

[0085] Place the other configurational compound in a THF (tetrahydrofuran) solution of DBU (1,8 - diazabicycloundec - 7 - ene) and reflux for 18 h. After concentration to dryness, add water and EA for extraction, dry with anhydrous sodium sulfate, and purify by column chromatography to obtain compound 3.

[0086] In step S2, the toluene solution of tributyltin hydride is prepared by diluting tributyltin hydride with anhydrous toluene, and the volume ratio between anhydrous toluene and tributyltin hydride can be 1:1.

[0087] In step S2, the equivalent ratio between compound 2 and DBU is 1:2. In the THF solution of DBU, the amount of THF used is sufficient for stirring.

[0088] In step S2, silica gel column chromatography is used for column chromatography purification, and petroleum ether:ethyl acetate = 10:1 to 5:1 (volume ratio) is used as the eluent.

[0089] S3: Compound 3 removes the protecting group TIPS under the action of TBAF (tetrabutylammonium fluoride) to obtain compound 4.

[0090] In step S3, the mass ratio between compound 3 and TBAF can be 1:0.8 to 1.2.

[0091] In step S3, the reaction temperature can be room temperature. Room temperature refers to between 20°C and 25°C.

[0092] Specifically, step S3 includes the following steps:

[0093] Dissolve compound 3 in anhydrous THF, add TBAF dropwise to the reaction system under the protection of nitrogen, stir at room temperature for 3 h. After TLC detects that compound 3 has completely reacted, add water and ethyl acetate to extract the reaction solution, combine the organic layers, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the residue by column chromatography to obtain compound 4.

[0094] In step S3, when monitoring by TLC, use PE:EA = 3:1 (volume ratio) as the eluent, under UV 254nm , iodine fuming for color development, ninhydrin for color development, Rf 化合物3 = 0.60, Rf 化合物4 = 0.20.

[0095] In step S3, silica gel column chromatography is used for column chromatography purification, and petroleum ether:ethyl acetate = 10:1 to 5:1 (volume ratio) is used as the eluent.

[0096] S4: Compound 4 undergoes a substitution reaction with an acyl chloride to synthesize compound 5, which is the artemisinin C-16 derivative of the present application.

[0097] In step S4, a weak base needs to be added in the substitution reaction, and the weak base can be selected from one of pyridine, Et3N (triethylamine), DIPEA (N,N-diisopropylethylamine), etc.

[0098] The acyl chloride can be one of 4-(tert-butyl)benzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-(trifluoromethyl)benzenesulfonyl chloride, 4-methylbenzoyl chloride, or cyclopropylcarbonyl chloride.

[0099] The molar ratio among compound 4, the acyl chloride, and the weak base can be 1:1.8 to 2.2:1.8 to 2.2.

[0100] In step S4, the reaction temperature can be 25 ± 10°C, preferably 25 ± 5°C.

[0101] Specifically, step S4 includes the following steps:

[0102] Dissolve compound 4 and a weak base in CH2Cl2, add the acyl chloride to the reaction system, and after TLC detects that compound 4 has completely reacted, compound 5, i.e., the artemisinin C-16 derivative of the present application, is obtained.

[0103] S5: Purify with a thick preparative plate.

[0104] In step S5, the process of purifying with a thick preparative plate is to develop in a developing tank with petroleum ether: ethyl acetate = 1:1 as the developing agent, stir with DCM for 3 h after scraping, filter, and concentrate to dryness to obtain the target compound.

[0105] In the embodiment solution of the present application, the CCK-8 cell activity test method is adopted to evaluate the anti-tumor activity of the artemisinin C-16 derivative of the present application. It is found through experimental results that the artemisinin C-16 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 derivative of the present application is also provided, and the artemisinin C-16 derivative is used to prepare an anti-tumor drug. Further, the anti-tumor drug can be one of an anti-hepatocellular carcinoma drug, an anti-lung cancer drug, an anti-gastric cancer drug, an anti-colorectal cancer drug, an anti-breast cancer drug, etc.

[0106] The following further illustrates the present application through specific examples.

[0107] Example 1

[0108] In this example, compounds 5a - 5f are synthesized, and the specific synthetic route is as follows:

[0109]

[0110] Among them, R1 is 4-(tert-butyl)benzenesulfonyl, 4-chlorobenzenesulfonyl, 4-fluorobenzenesulfonyl, 4-(trifluoromethyl)benzenesulfonyl, 4-methylbenzoyl, or cyclopropylcarbonyl.

[0111] Specifically, the preparation process of the artemisinin C-16 derivative 5a in this example is as follows:

[0112] Synthesis of compound 1:

[0113] Dissolve p - hydroxy phenethyl bromide (1.0 eq, 0.14 moL) and imidazole (1.5 eq, 14.37 g, 0.21 moL) in DMF (11.0 eq, 4.28 V, 1.56 moL), cool in an ice bath and control the temperature not higher than 5 ± 5 °C, slowly add dropwise TIPSCl (1.1 eq, 33 mL, 29.73 g, 0.154 moL), and after the addition, raise the temperature to room temperature and react for 10 h. After the raw materials are completely reacted by TLC detection (PE: EA = 8:1, thin layer plate), add water and ethyl acetate to extract the reaction solution, combine the organic layers, dry over anhydrous sodium sulfate, evaporate the solvent, and purify the residue by column chromatography (silica gel column, petroleum ether: ethyl acetate = 10:1) to obtain 45.49 g (127.3 mmol) of compound 1, with a yield of 91.4%.

[0114] Perform nuclear magnetic resonance analysis on compound 1, and its 1 1H NMR spectrum is as Figure 1 shown, 1 and the 1H - NMR data are as follows:

[0115] 1 1H NMR (400 MHz, CDCl3) δ 0.97 - 1.13 (m, 18H), 1.21 - 1.23 (m, 3H), 3.06 - 3.10 (t, J = 8.0, 2H), 3.50 - 3.53 (t, J = 8.0, 2H), 6.81 - 6.83 (m, 2H), 6.83 - 7.03 (m, 2H).

[0116] Synthesis of compound 3:

[0117] Dissolve compound 2 (1 eq, 2.92 g), compound 1 (4.47 g) and AIBN (0.3 eq, 0.51 g) in anhydrous toluene (180 mL), reflux and react for 1 h at 85 ± 5 °C under nitrogen protection. Then slowly add dropwise a toluene solution of tributyltin hydride (1.39 eq, 4.22 g) (anhydrous toluene: tributyltin hydride = 1:1), and after the addition, reflux and react overnight. Spin - dry the reaction solution to obtain a pale - yellow crude product. Dissolve the crude product in 150 mL of EA, add 50 mL of 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, evaporate the solvent, and purify the residue by column chromatography (silica gel column, petroleum ether: ethyl acetate = 10:1) to obtain 1.24 g (2.23 mmol) of compound 3, with a yield of 21.35%, and another isomer of 850.75 mg, with a yield of 14.62%.

[0118] Another configuration (850.75 mg) was refluxed in a THF solution of DBU (2 eq, 4.22 g) for 18 h. After concentration to dryness, water and EA were added for extraction, dried over anhydrous sodium sulfate, and purified by column chromatography (silica gel column, petroleum ether: ethyl acetate = 10:1) to obtain 59.6 mg of compound 3 with a yield of 7%.

[0119] Synthesis of compound 4:

[0120] Compound 3 (1.3 g) was dissolved in anhydrous THF (10 mL), and TBAF (70% aqueous solution, 1.30 g) was added dropwise to the reaction system under nitrogen protection. The reaction was stirred at room temperature for 3 h and monitored by TLC (TLC method: PE:EA = 3:1, UV 254nm , iodine fuming for color development, ninhydrin color development, Rf 化合物3 = 0.60, Rf 化合物4 = 0.20) until compound 3 disappeared. Water and ethyl acetate were added to extract the reaction solution. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography (silica gel column, petroleum ether: ethyl acetate = 10:1) to obtain 0.93 g (2.30 mmol) of compound 4 with a yield of 99.1%.

[0121] Compound 4 was analyzed by nuclear magnetic resonance, and its 1 1H NMR spectrum is as Figure 2 shown, 1 The 1H-NMR data are as follows:

[0122] 1 1H NMR (400 MHz, CDCl3) δ 7.06 (d, J = 7.5 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H), 5.92 (s, 1H), 2.62 (dt, J = 33.4, 7.2 Hz, 3H), 2.40 (t, J = 13.0 Hz, 1H), 2.22 - 2.03 (m, 4H), 1.96 (s, 1H), 1.71 (d, J = 12.8 Hz, 6H), 1.47 (s, 5H), 1.28 (s, 2H), 1.19 (d, J = 6.6 Hz, 1H), 1.13 (d, J = 7.3 Hz, 2H), 1.01 (s, 3H).

[0123] Synthesis of compound 5a:

[0124] Compound 4 (50 mg, 0.128 mmol) and Et3N (26 mg, 0.258 mmol) were dissolved in CH2Cl2, and 4-(tert-butyl)benzenesulfonyl chloride (0.258 mmol) was added to the reaction system. After TLC detected that the reaction of Compound 4 was complete, it was purified by a thick preparative plate, developed in a developing tank with petroleum ether:ethyl acetate = 1:1 as the developing agent, scraped, stirred with DCM (dichloromethane) for 3 h, filtered, and concentrated to dryness to obtain Compound 5a (4-(3-((3R,5aS,6S,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-(tert-butyl)benzenesulfonate), a white solid, with a yield of 33.58%.

[0125] Nuclear magnetic resonance analysis was performed on Compound 5a, and its 1 1H NMR spectrum was as Figure 3 shown, 1 and the 1H-NMR data were as follows:

[0126] 1 1H NMR (400 MHz, CDCl3) δ 7.79 - 7.73 (m, 2H), 7.57 - 7.52 (m, 2H), 7.10 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 5.92 (s, 1H), 2.68 - 2.54 (m, 2H), 2.44 - 2.31 (m, 1H), 2.20 - 2.02 (m, 3H), 2.02 - 1.92 (m, 1H), 1.83 - 1.76 (m, 1H), 1.74 - 1.64 (m, 5H), 1.57 - 1.51 (m, 1H), 1.49 (dd, J = 8.3, 3.3 Hz, 1H), 1.46 (s, 3H), 1.44 (d, J = 3.8 Hz, 1H), 1.40 (dd, J = 7.5, 3.3 Hz, 1H), 1.37 (s, 9H), 1.14 (dd, J = 22.8, 11.7 Hz, 1H), 1.00 (d, J = 5.8 Hz, 3H).

[0127] The preparation process of artemisinin C-16 derivative 5b in this example:

[0128] The preparation process was basically the same as that of 5a, with the only difference being that R1 was 4-chlorobenzenesulfonyl chloride;

[0129] Compound 5b (4-(3-((3R,5aS,6S,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-chlorobenzenesulfonate) was purified using a thick preparative plate to obtain a white solid with a yield of 17.36%.

[0130] Compound 5b was subjected to nuclear magnetic resonance analysis, and its 1 1H NMR spectrum is as Figure 4 shown, 1 and the 1H-NMR data are as follows:

[0131] 1 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 6.89 (d, J = 8.2 Hz, 2H), 5.92 (s, 1H), 2.61 (t, J = 7.0 Hz, 2H), 2.38 (dd, J = 18.7, 8.7 Hz, 1H), 2.15 - 2.03 (m, 3H), 2.01 - 1.89 (m, 1H), 1.74 (t, J = 14.7 Hz, 6H), 1.47 (s, 4H), 1.27 (s, 1H), 1.20 - 1.07 (m, 1H), 1.01 (d, J = 5.3 Hz, 3H).

[0132] The preparation process of artemisinin C-16 derivative 5c in this example:

[0133] The preparation process is basically the same as that of 5a, except that 4-fluorobenzenesulfonyl chloride is used for R1;

[0134] Compound 5c (4-(3-((3R,5aS,6S,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-fluorobenzenesulfonate) was purified using a thick preparative plate to obtain a white solid with a yield of 37.04%.

[0135] Compound 5c was subjected to nuclear magnetic resonance analysis, and its 1 1H NMR spectrum is as Figure 5 shown, 1 and the 1H-NMR data are as follows:

[0136] 1 1H NMR (400 MHz, CDCl3) δ 7.90 - 7.80 (m, 2H), 7.22 (t, J = 8.5 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 5.92 (s, 1H), 2.61 (t, J = 7.2 Hz, 2H), 2.38 (dd, J = 18.4, 9.1 Hz, 1H), 2.15 - 2.03 (m, 3H), 2.02 -

[0137] 1.93 (m, 1H), 1.86 - 1.59 (m, 7H), 1.51 (d, J = 3.4 Hz, 1H), 1.46 (s, 4H), 1.14 (dd, J = 22.7, 11.6 Hz, 1H), 1.01 (d, J = 5.6 Hz, 3H).

[0138] Preparation process of artemisinin C-16 derivative 5d in this example:

[0139] The preparation process is basically the same as that of 5a, with the only difference being that R1 is 4-(trifluoromethyl)benzenesulfonyl chloride;

[0140] Purified with a thick preparative plate to obtain compound 5d (4-(3-((3R,5aS,6S,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)benzenesulfonate), a white solid, with a yield of 15.4%.

[0141] Perform nuclear magnetic resonance analysis on compound 5d, and its 1 1H NMR spectrum is as Figure 6 shown, 1 The 1H-NMR data are as follows:

[0142] 11H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.9 Hz, 2H), 7.82 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 7.6 Hz, 2H), 6.90 (d, J = 7.5 Hz, 2H), 5.89 (d, J = 23.2 Hz, 1H), 2.62 (t, J = 6.7 Hz, 2H), 2.35 (dt, J = 16.5, 10.4 Hz, 1H), 2.12 (dd, J = 32.1, 21.6 Hz, 3H), 1.84 - 1.65 (m, 6H), 1.57 - 1.34 (m, 7H), 1.27 (d, J = 6.7 Hz, 1H), 1.11 (dd, J = 26.7, 15.6 Hz, 1H), 1.01 (d, J = 4.1 Hz, 3H).

[0143] The preparation process of artemisinin C-16 derivative 5e in this example:

[0144] The preparation process is basically the same as that of 5a, except that cyclopropylcarbonyl chloride is used for R1;

[0145] Purified with a thick preparative plate to obtain compound 5e (4-(3-((3R,5aS,6S,8aR,9S,12R,12aR)-3,6-dimethyl-10-oxodecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-9-yl)propyl)phenyl cyclopropanecarboxylate), colorless transparent oil, yield 32.73%.

[0146] Perform nuclear magnetic resonance analysis on compound 5e, and its 1 1H NMR spectrum is as Figure 7 shown, 1 The 1H-NMR data are as follows:

[0147] 11H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 5.92 (s, 1H), 2.63 (tq, J = 13.9, 6.8 Hz, 2H), 2.49 - 2.33 (m, 1H), 2.24 - 2.03 (m, 3H), 1.97 (dt, J = 22.8, 9.4 Hz, 1H), 1.84 (ddd, J = 13.7, 8.7, 4.6 Hz, 2H), 1.79 - 1.62 (m, 6H), 1.51 (dd, J = 10.7, 5.2 Hz, 1H), 1.47 (s, 3H), 1.43 (d, J = 2.8 Hz, 1H), 1.17 (dt, J = 7.9, 4.1 Hz, 2H), 1.14 - 1.06 (m, 1H), 1.03 (dd, J = 6.4, 3.2 Hz, 1H), 1.00 (d, J = 5.6 Hz, 3H).

[0148] The preparation process of artemisinin C-16 derivative 5f in this example:

[0149] The preparation process is basically the same as that of 5a, except that 4-methylbenzoyl chloride is used for R1;

[0150] The compound 5f (4-(3-((3R,5aS,6S,8aR,9S,12R,12aR)-3,6-dimethyl-10-oxodecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-9-yl)propyl)phenyl cyclopropanecarboxylate) was purified by thick preparative plate to obtain a colorless transparent oil, with a yield of 19.22%.

[0151] Nuclear magnetic resonance analysis was performed on compound 5f, and its 1 1H NMR spectrum is as Figure 8 shown, 1 The 1H-NMR data are as follows:

[0152] 11H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 5.92 (s, 1H), 2.63 (tq, J = 13.9, 6.8 Hz, 2H), 2.49 - 2.33 (m, 1H), 2.24 - 2.03 (m, 3H), 1.97 (dt, J = 22.8, 9.4 Hz, 1H), 1.84 (ddd, J = 13.7, 8.7, 4.6 Hz, 2H), 1.79 - 1.62 (m, 6H), 1.51 (dd, J = 10.7, 5.2 Hz, 1H), 1.47 (s, 3H), 1.43 (d, J = 2.8 Hz, 1H), 1.17 (dt, J = 7.9, 4.1 Hz, 2H), 1.14 - 1.06 (m, 1H), 1.03 (dd, J = 6.4, 3.2 Hz, 1H), 1.00 (d, J = 5.6 Hz, 3H).

[0153] The CCK8 method was used to evaluate the activity of the prepared compounds 5a - 5f:

[0154] The CCK8 method was adopted to evaluate the anti-tumor activities of compounds 5a - 5f against six human cancer cell lines, namely A549, HepG2, RKO, MKN45, MCF7, and MDA-MB-231.

[0155] The specific experimental steps are as follows:

[0156] 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 replicate wells were set for each concentration. After administration, the culture time was 48 h.

[0157] Addition of CCK-8 reagent and determination of absorbance value. The OD value was detected using a microplate reader, and then the cell survival rate was calculated. GraphPad Prism 8 and Origin software were used to draw graphs and obtain the IC50 value (half maximal inhibitory concentration).

[0158] The results are shown in Table 1. It can be seen that compounds 5a - 5c have obvious inhibitory effects on the growth of six human cancer cell lines, compound 5d has obvious inhibitory effects on three human cancer cells, namely HepG2, MKN45, and MCF7, and compound 5f has obvious inhibitory effects on five human cancer cells, namely A549, RKO, MKN45, MCF7, and MDA-MB-231.

[0159] Table 1 IC50 values of compounds 5a - 5f against six human cancer cell lines of A549, HepG2, RKO, MKN45, MCF7, and MDA-MB-231

[0160]

[0161]

[0162] In this embodiment, the artemisinin C-16 derivative prepared in this embodiment was also compared with artemisinin, artemisinene, and their respective positive drugs (using Gefitinib, Sorafenib (SOR), 5-Fluorouracil (5-FU), and Docetaxel (DTX) as control drugs). The results are shown in Table 1. The evaluation of tumor activity by simply using artemisinene and artemisinin showed poor effects. However, the artemisinin C-16 derivative prepared in this embodiment can be intuitively seen to have a relatively high anti-tumor activity.

[0163] It should be understood that the application of this application is 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 this application.

Claims

1. An artemisinin C-16 derivative, characterized in that, Its structural general formula is shown in Formula (1): Among them, R1 is one of 4-(tert-butyl)benzenesulfonyl, 4-chlorobenzenesulfonyl, 4-fluorobenzenesulfonyl, 4-(trifluoromethyl)benzenesulfonyl, 4-methylbenzoyl, cyclopropylcarbonyl; n is 1 or 2.

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

3. The artemisinin C-16 derivative according to claim 1, wherein The artemisinin C-16 derivative is one of the following compounds:

4. A method for preparing an artemisinin C-16 derivative as described in any one of claims 1-3, characterized in that, It includes the following steps: S1: Using compound 0 as the starting material, through the TIPSCl / imidazole / DMF system, reacting at 5±5°C to obtain compound 1; among them, the compound 0 is p-hydroxyphenethyl bromide or p-hydroxyphenylpropyl bromide; S2: Using AIBN and Bu3SnH to perform a radical addition reaction on the compound 1 and the compound 2 to obtain compound 3; among them, the compound 2 is artemisylene; S3: Removing the protecting group TIPS from the compound 3 under the action of TBAF to obtain compound 4; S4: The compound 4 undergoes a substitution reaction with an acyl chloride to obtain the artemisinin C-16 derivative; among them, the acyl chloride is one of 4-(tert-butyl)benzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-(trifluoromethyl)benzenesulfonyl chloride, 4-methylbenzoyl chloride or cyclopropylcarbonyl chloride.

5. The preparation method of the artemisinin C-16 derivative according to claim 4, wherein In step S1, the equivalent ratio among the TIPSCl, the imidazole, and the DMF is 1.1:1.5:11, and the equivalent ratio between the compound 0 and the TIPSCl is 1:1.1; In step S2, the equivalent ratio among the compound 2, the AIBN, and the Bu3SnH is 1.0:0.3:1.2 - 1.5, and the equivalent ratio between the compound 2 and the compound 1 is 1:1.1 - 1.2; In step S3, the mass ratio between the compound 3 and the TBAF is 1:0.8 - 1.2; In step S4, a weak base needs to be added in the substitution reaction, and the weak base is one of pyridine, Et3N, DIPEA; In step S4, the molar ratio among the compound 4, the acyl chloride, and the weak base is 1:1.8 - 2.2:1.8 - 2.

2.

6. The preparation method of the artemisinin C-16 derivative according to claim 4, characterized in that, In step S2, the reaction temperature is 85±5°C; In step S3, the reaction temperature is room temperature; In step S4, the reaction temperature is 25±10°C.

7. The preparation method of the artemisinin C-16 derivative according to claim 4, characterized in that, Step S1 specifically includes the following steps: Dissolve the compound 0 and the imidazole in the DMF, cool in an ice bath to control the temperature between 5±5°C, dropwise add the TIPSCl, and after the addition is complete, raise the temperature to room temperature and react for 10 h; After TLC detects that the raw materials have completely reacted, add water and ethyl acetate to extract the reaction solution, combine the organic layers, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the residue by column chromatography to obtain the compound 1; Step S2 specifically includes the following steps: Dissolve the compound 2, the compound 1, and the AIBN in anhydrous toluene, reflux and react at 85±5°C under nitrogen protection for 1 h; Add the toluene solution of Bu3SnH dropwise. After the addition is complete, reflux the reaction mixture overnight. Rotate the reaction solution to dryness to obtain a pale yellow crude product. Dissolve the crude product in EA, add saturated KF solution, stir the reaction 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 with anhydrous sodium sulfate, evaporate the solvent, and purify the residue by column chromatography to obtain the compound 3 and another compound with a different configuration; Reflux the compound with a different configuration in a THF solution of DBU for 18 h. After concentration to dryness, add water and EA for extraction, dry with anhydrous sodium sulfate, and purify by column chromatography to obtain the compound 3; Step S3 specifically includes the following steps: Dissolve the compound 3 in anhydrous THF. Add TBAF dropwise to the reaction system under the protection of nitrogen. Stir the reaction at room temperature for 3 h. After TLC detects that the compound 3 has completely reacted, add water and ethyl acetate to extract the reaction solution. Combine the organic layers, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the residue by column chromatography to obtain the compound 4; Step S4 specifically includes the following steps: Dissolve the compound 4 and a weak base in CH2Cl2. Add the acyl chloride to the reaction system. After TLC detects that the compound 4 has completely reacted, obtain the artemisinin C-16 derivative.

8. The preparation method of the artemisinin C-16 derivative according to claim 4, wherein The preparation method of the artemisinin C-16 derivative also includes the following steps: S5: Purify the artemisinin C-16 derivative with a thick preparative plate; The purification process uses petroleum ether:ethyl acetate = 1:1 as the developing agent. After scraping the plate, stir with DCM for 3 h, filter, and concentrate to dryness.

9. Use of an artemisinin C-16 derivative as described in any one of claims 1-3, characterized in that, Use the artemisinin C-16 derivative to prepare an anti-tumor drug.

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

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