Chiral amino alcohol modified artemisinin derivative as well as preparation method and application thereof

Abstract

The invention discloses a chiral amino alcohol modified artemisinin derivative as well as a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. According to the present invention, the alkali is adopted as the catalyst, the esterification reaction of the artesunate and the chiral amino alcohol is achieved for the first time, a series of the brand new derivatives simultaneously containing the artemisinin structure unit and the chiral amino alcohol structure unit are constructed, the synthesis path of the artemisinin derivative is expanded, and the research blank in the field is filled. The preparation method is novel, simple to operate, free of complex equipment, mild in reaction condition, high in reaction rate and high in yield, provides a new candidate compound for developing efficient and low-toxicity antitumor drugs, and has important clinical application value and market prospect.

Description

Technical Field

[0001] This application belongs to the field of medicinal chemistry technology, and in particular relates to a chiral amino alcohol modified artemisinin derivative, its preparation method and application. Background Technology

[0002] Artemisinin (ART) is a class of sesquiterpene trioxane antimalarial drugs extracted from Artemisia annua, with the molecular formula C2. 15 H 22 O5. ART possesses high oxidative activity, capable of damaging cell membrane structures, chromosomes, and proteins, and halting nutrient supply, ultimately killing the malaria parasite. ART has also demonstrated potent and broad-spectrum anticancer properties in a range of cell lines and animal models, including pro-apoptosis, anti-proliferation, anti-angiogenesis, anti-tumor metastasis, and regulation of the tumor microenvironment. Furthermore, ART exhibits fewer side effects on normal cells and demonstrates the ability to overcome multidrug resistance. This supports the hypothesis that ART has the potential to be developed as an effective anticancer therapy. Currently, this anticancer effect is believed to be related to the peroxidation bridge structure of its sesquiterpene lactones. Its semi-synthetic derivatives, such as artemether (AM), dihydroartemisinin (DHA), artesunate (AS), and artesunate, have been developed. These derivatives can be obtained through chemical synthesis and recombinant DNA technology. These derivatives are more water-soluble and have higher activity than ART. DHA has been shown to have antitumor effects in breast, glioma, lung, ovarian, pancreatic, and renal cell carcinoma cell lines, and its potential as an anticancer drug has been well demonstrated in in vivo and in vitro studies. In addition to its antimalarial activity, ARTs also exhibit potent cytotoxicity against many human tumor cell lines. Due to their low cost, high activity, and low toxicity, ARTs hold promise as new anti-colorectal cancer drugs.

[0003] Recent studies have shown that artemisinin and its derivatives possess broad-spectrum antitumor activities, such as activity against liver cancer, breast cancer, ovarian cancer cells, leukemia, lung cancer, and pancreatic cancer. Artesunate (ART), an artemisinin derivative extracted from the Asteraceae plant Artemisia annua, is widely used clinically as an antimalarial drug. ART not only treats malaria but also effectively inhibits the growth of solid tumors. It exerts its antitumor effect by inducing tumor cell apoptosis and inhibiting tumor cell proliferation, showing promising application prospects. Artesunate can also inhibit the proliferation, invasion, and metastasis of colorectal cancer cells, induce apoptosis, and promote reactive oxygen species generation, exerting its anti-colorectal cancer effect through multiple targets.

[0004] Chiral amino alcohols, due to their suitable coordinating atoms and the ability to increase the basicity of the central metal atom and regulate its electronic properties, allow for convenient control of coordination number and stereochemistry, improving the rigidity of complexes. Therefore, they can catalyze and induce various types of asymmetric organic reactions, making them a very important and efficient class of asymmetric synthetic catalysts when combined with metals, attracting widespread attention. In recent years, chiral amino alcohols have become important chiral intermediates; for example, threonine, alanine, and phenylalanine have been widely used in chiral drugs such as peptides and quinolones. Therefore, research on the preparation of chiral amino alcohols has significant practical value. The role of chiral amino alcohols in medicinal chemistry and organic chemistry is also becoming increasingly important. In medicinal chemistry, many drugs for treating various diseases possess amino alcohol structures. In the treatment of human respiratory and cardiovascular diseases, arylethanolamines and aryloxypropanolamines have shown good efficacy and are important research directions in drug development.

[0005] However, the esterification reaction of artesunate with chiral amino alcohols has not been reported in existing technologies, and the types of reactions involved by artesunate are limited, resulting in insufficient structural diversity of the products, which restricts its further application in drug development. Therefore, developing a novel, efficient, and atom-economical synthetic method to construct artesunate derivatives containing both artemisinin and chiral amino alcohol structural units is of significant scientific and practical value. Summary of the Invention

[0006] To overcome the aforementioned deficiencies in the prior art, this application provides a chiral amino alcohol-modified artemisinin derivative, its preparation method, and its application. The chiral amino alcohol-modified artemisinin derivative is obtained by esterification of artesunate with a series of amino alcohols having chiral centers. This preparation method has advantages such as simple operation, mild reaction, fast reaction rate, and high yield, and has good application potential in the field of anti-tumor drugs.

[0007] To achieve the above-mentioned objectives, this application provides the following technical solution: On the one hand, this application provides a chiral amino alcohol-modified artemisinin derivative, the structure of which is shown in general formula I: ; Wherein, R is a substituent corresponding to the chiral amino alcohol, and the chiral amino alcohol is selected from any one of L-phenylglycine, L-methionine, L-tryptophanine, L-pyroskinine, L-phenylalanine, L-threonine, L-valine, L-leucine, L-isoleucine, and L-prolyl. The configurations of each chiral center in Formula I are: 3R, 5aS, 6R, 8aS, 9R, 12R, 12aR.

[0008] Optionally, the structure of the artemisinin derivative is selected from any one of Formulas II to XI: ; ; .

[0009] Secondly, this application provides a method for preparing a chiral amino alcohol-modified artemisinin derivative, comprising the following steps: Under anhydrous and oxygen-free conditions, a solvent, artesunate, chiral amino alcohol, and catalyst are mixed and reacted to obtain the chiral amino alcohol-modified artemisinin derivative.

[0010] Optionally, the anhydrous and oxygen-free conditions are achieved by drying the reaction vessel for 2-10 minutes and then introducing nitrogen for protection.

[0011] Optionally, the molar ratio of artesunate to chiral amino alcohol is 1~1.5:1~1.5.

[0012] Optionally, the molar ratio of artesunate to chiral amino alcohol is 1:1.5.

[0013] Optionally, the amount of the catalyst used is 20 to 200 mol of 1 equivalent molar amount of artesunate.

[0014] Optionally, the amount of the catalyst used is 100 mol of 1 equivalent molar amount of artesunate.

[0015] Optionally, the ratio of the solvent to artesunate is 0.5~2mL:100mg.

[0016] Optionally, the ratio of the solvent to artesunate is 1 mL: 100 mg.

[0017] Optionally, the chiral amino alcohol is selected from any one of L-phenylglycine, L-methionine, L-tryptophanine, L-pyroskinine, L-phenylalanine, L-threonine, L-valine, L-leucine, L-isoleucine, and L-proline.

[0018] Optionally, the solvent is selected from any one of dichloromethane, trichloromethane, 1,2-dichloroethane, bromoethane, benzene, acetonitrile, tetrahydrofuran, anhydrous ethanol, N,N-dimethylformamide, ethyl acetate, and 1,4-dioxane.

[0019] Optionally, the catalyst is selected from any one of 4-dimethylaminopyridine, triethylenediamine, triethylamine, pyridine, imidazole, N,N'-dicyclohexylcarbodiimide, and sodium bicarbonate.

[0020] Optionally, when the catalyst is not N,N'-dicyclohexylcarbodiimide, the step of adding an N,N'-dicyclohexylcarbodiimide solution is further included before the reaction; The preparation steps of the N,N'-dicyclohexylcarbodiimide solution are as follows: dissolve 20~100mg of N,N'-dicyclohexylcarbodiimide in 0.8~1.2mL of solvent.

[0021] Optionally, the preparation step of the N,N'-dicyclohexylcarbodiimide solution is as follows: dissolve 64 mg of N,N'-dicyclohexylcarbodiimide in 1 mL of solvent.

[0022] Optionally, the reaction temperature is 0~40℃.

[0023] Optionally, the reaction temperature is 25°C.

[0024] Optionally, the reaction time is 6 to 24 hours.

[0025] Optionally, the reaction time is 12 hours.

[0026] Optionally, the reaction is carried out under stirring conditions; The stirring speed is 500~1500 rpm.

[0027] Optionally, the stirring speed is 1000 rpm.

[0028] Thirdly, this application provides the application of the chiral amino alcohol-modified artemisinin derivatives described above, or the chiral amino alcohol-modified artemisinin derivatives prepared by the above preparation method, in the preparation of antitumor drugs.

[0029] Compared with the prior art, this application has the following advantages: (1) This application utilizes base as a catalyst to realize the esterification reaction of artesunate and chiral amino alcohol for the first time, constructing a series of novel derivatives containing both artemisinin structural units and chiral amino alcohol structural units, expanding the synthetic route of artemisinin derivatives and filling the research gap in this field.

[0030] (2) The preparation method of this application has significant advantages: the reaction is novel and simple to operate, and no complex equipment is required; the reaction conditions are mild (25°C, conventional pressure) and the energy consumption is low; the reaction rate is fast (completed in 12 hours) and the yield is high (up to 68%); the atom economy is good and the byproducts are few, which is in line with the concept of green chemistry.

[0031] (3) The target derivative of this application has both the antitumor activity of artemisinin and the drug activity potential of chiral amino alcohols, providing new candidate compounds for the development of highly effective and low-toxicity antitumor drugs, and has important clinical application value and market prospects. Attached Figure Description

[0032] To more clearly illustrate the technical solutions of the embodiments of this application, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of this application and should not be regarded as a limitation of the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0033] Figure 1 These are images of the actual products prepared according to Examples 1-10 of this application. Detailed Implementation

[0034] The present application is further illustrated below with reference to specific embodiments. The following descriptions are merely a few embodiments of the present application and are not intended to limit the present application in any way. Although the present application discloses preferred embodiments as follows, they are not intended to limit the present application. Any modifications or variations made by those skilled in the art without departing from the scope of the technical solution of the present application using the disclosed technical content are equivalent to equivalent implementation cases and all fall within the scope of the technical solution.

[0035] Unless otherwise specified, the raw materials used in the embodiments of this application are all purchased commercially and used directly without any special treatment.

[0036] Unless otherwise specified, the analytical methods in the embodiments all adopt conventional instrument or equipment settings and conventional analytical methods.

[0037] The sources of raw materials used in the following examples and comparative examples are shown in Table 1.

[0038] Table 1 Sources of raw materials used in this application ;

[0039] Example 1 Preparation of L-phenylglycine-modified artemisinin derivatives 1-3a: ; Take a 50 mL round-bottom flask and treat it in an anhydrous and oxygen-free environment (heat the 50 mL round-bottom flask with a torch for 2 min, and then purge with nitrogen). Take 1 mL of dichloromethane (DCM) and put it into a reaction tube. Add artesunate (100 mg, 0.26 mmol), L-phenylglycine (53 mg, 0.39 mmol), and 4-dimethylaminopyridine (DMAP) (31.8 mg, 0.36 mmol) sequentially into the reaction tube and stir for 10 min. Dissolve N,N'-dicyclohexylcarbodiimide (DCC) (64 mg) in 1 mL of dichloromethane (DCM) and transfer it to the previous reaction tube. Stir at 25 °C for 12 h to obtain a white solid product, which is the L-phenylglycine-modified artemisinin derivative 1-3a. Figure 1 (a) was used to determine its yield, which was 68%.

[0040] The 1H NMR spectrum of L-phenylglycine-modified artemisinin derivative 1-3a ((R)-2-amino-2-phenylethyl ((3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)succinat(1-3a)) 1 H NMR, carbon spectrum ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below: 1H NMR (400 MHz, Acetone-d6)δ7.52 (d, J = 8.1 Hz, 1H), 7.38 (d, J =7.1 Hz, 1H), 7.30 (t, J = 7.5 Hz, 2H), 7.23 (d, J = 7.2 Hz, 1H), 5.71 (d, J =9.7 Hz, 1H), 5.61 (s, 1H), 5.51 (s, 1H), 5.03 (p, J = 5.7 Hz, 1H), 3.78–3.73(m, 2H), 2.76–2.56 (m, 4H), 2.43 (ddt, J = 12.7, 7.0, 3.5 Hz, 1H), 2.29 (td,J = 13.9, 4.0 Hz, 1H), 2.03–1.99 (m, 1H), 1.89 (ddt, J = 13.8, 6.9, 3.5 Hz,1H), 1.80–1.69 (m, 2H), 1.64–1.54 (m, 1H), 1.53–1.38 (m, 3H), 1.30 (s, 4H), 1.23 (dt, J = 11.4, 5.8 Hz, 1H), 1.10–1.00 (m, 1H), 0.95 (d, J = 6.4 Hz, 3H), 0.82 (d, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, Acetone- d 6) δ 171.29, 170.57, 141.08, 128.12,127.02, 126.83, 103.78, 91.94, 91.18, 79.94, 65.52, 55.55, 51.69, 45.26,36.76, 36.12, 34.09, 31.85, 30.06, 28.78, 28.59, 28.40, 25.15, 24.54, 21.53,19.65, 11.46. HRMS (ESI): m / zCalcd.For C 27 H 37 NO8 ([M+Na)) - ): 526.2412. Example 2

[0041] Preparation of L-methionine-modified artemisinin derivatives 1-3b: ; Take a 50 mL round-bottom flask and treat it in an anhydrous and oxygen-free environment (heat the 50 mL round-bottom flask with a torch for 2 min, and then purge with nitrogen). Take 1 mL of dichloromethane (DCM) and put it into a reaction tube. Add artesunate (100 mg, 0.26 mmol), L-methionine (52.73 mg, 0.39 mmol), and 4-dimethylaminopyridine (DMAP) (31.8 mg, 0.36 mmol) sequentially to the reaction tube and stir for 10 min. Dissolve N,N'-dicyclohexylcarbodiimide (DCC) (64 mg) in 1 mL of dichloromethane (DCM) and transfer it to the previous reaction tube. Stir at 25 °C for 12 h to obtain a white solid product, which is the L-methionine-modified artemisinin derivative 1-3b. Figure 1 (b) was used to determine its yield, which was 45%.

[0042] The 1H NMR spectrum of L-methionine-modified artemisinin derivative 1-3b ((S)-2-amino-4-methylpentyl((3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl) succinate(1-3b)) 1 H NMR, carbon spectrum ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below: 1 H NMR (400 MHz, Acetone-d6) δ 5.80 (dt, J = 6.4, 1.5 Hz, 1H), 5.35(d, J = 3.6 Hz, 1H), 4.01 (qd, J = 12.3, 3.8 Hz, 2H), 3.56 (dd, J = 7.1, 6.2Hz, 1H), 3.46 (dd, J = 7.1, 6.4 Hz, 1H), 3.32 – 3.24 (m, 1H), 2.76 – 2.64 (m,4H), 2.30 – 2.15 (m, 3H), 2.11 – 2.01 (m, 1H), 1.92 – 1.82 (m, 1H), 1.74 –1.67 (m, 1H), 1.66 – 1.57 (m, 4H), 1.55 – 1.49 (m, 1H), 1.45 (d,J = 7.1 Hz,1H), 1.42 (s, 3H), 1.40 (d, J = 7.2 Hz, 1H), 1.19 (dddd, J = 12.1, 7.9, 6.9,4.9 Hz, 1H), 1.07 (dtd, J = 12.3, 10.3, 7.3 Hz, 1H), 0.95 (dd, J = 7.8, 1.5Hz, 3H), 0.90 (dd, J = 7.1, 5.2 Hz, 9H). 13 C NMR (101 MHz, CDCl3) δ 172.91, 172.43, 138.82, 129.08, 129.08,128.75,128.75, 126.95, 104.30, 99.73, 91.17, 81.68, 67.27, 53.24, 49.34,43.88, 40.17, 37.16, 36.77, 36.03, 32.85, 29.65, 29.45, 24.91, 23.86, 23.63,20.34, 13.08. HRMS (ESI): m / zCalcd.For C 28 H 39 NO8 ([M+Na)) - ): 540.2512. Example 3

[0043] Preparation of L-tryptophanol-modified artemisinin derivatives 1-3c: ; Take a 50 mL round-bottom flask and treat it in an anhydrous and oxygen-free environment (heat the 50 mL round-bottom flask with a torch for 2 min, and then purge with nitrogen). Take 1 mL of dichloromethane (DCM) and put it into a reaction tube. Add artesunate (100 mg, 0.26 mmol), L-tryptophanol (74.2 mg, 0.39 mmol), and 4-dimethylaminopyridine (DMAP) (31.8 mg, 0.36 mmol) sequentially to the reaction tube and stir for 10 min. Dissolve N,N'-dicyclohexylcarbodiimide (DCC) (64 mg) in 1 mL of dichloromethane (DCM) and transfer it to the previous reaction tube. Stir at 25 °C for 12 h to obtain a white solid product, which is the L-tryptophanol-modified artemisinin derivative 1-3c. Figure 1(c) was used to determine its yield, which was 51%.

[0044] The 1H NMR spectrum of L-tryptophan-modified artemisinin derivative 1-3c ((S)-2-amino-3-methylbutyl ((3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)succinate(1-3c)) 1 H NMR, carbon spectrum ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below: 1 H NMR (400 MHz, Acetone-d6) δ 5.80 (dq, J = 5.9, 1.6 Hz, 1H), 5.35(d, J = 3.6 Hz, 1H), 4.05 (qd, J = 12.3, 4.8 Hz, 2H), 3.24 (d, J = 7.3 Hz, 2H), 2.93 (tdt, J = 7.3, 6.6, 4.9 Hz, 1H), 2.70 (d, J = 6.4 Hz, 1H), 2.68 –2.65 (m, 3H), 2.30 – 2.15 (m, 3H), 2.11 – 2.01 (m, 1H), 1.92 – 1.82 (m, 1H),1.79 (dq, J = 12.3, 6.2 Hz, 1H), 1.70 (dtd, J = 8.5, 7.1, 4.2 Hz, 1H), 1.66 –1.52 (m, 4H), 1.42 (s, 3H), 1.19 (dddd, J = 12.1, 7.9, 6.9, 4.9 Hz, 1H), 1.07(dtd, J = 12.3, 10.3, 7.3 Hz, 1H), 0.95 (dd, J = 7.7, 1.5 Hz, 3H), 0.93 (d, J = 6.1 Hz, 6H), 0.90 (d, J= 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 172.91, 172.44, 104.30, 99.73, 91.17,81.68, 67.02, 57.40, 49.34, 43.88, 37.16, 36.77, 36.03, 32.85, 31.59, 29.65,29.45, 24.91, 23.86, 23.63, 20.34, 19.09, 19.09,13.08. HRMS (ESI): m / zCalcd.For C 24 H 39 NO8 ([M+Na)) - ): 492.1436. Example 4

[0045] Preparation of L-pyroglutamyl alcohol-modified artemisinin derivatives 1-3d: ; Take a 50 mL round-bottom flask and treat it in an anhydrous and oxygen-free environment (heat the 50 mL round-bottom flask with a torch for 2 min, and then purge with nitrogen). Take 1 mL of dichloromethane (DCM) and put it into a reaction tube. Add artesunate (100 mg, 0.26 mmol), L-pyroglutamyl (44.9 mg, 0.39 mmol), and 4-dimethylaminopyridine (DMAP) (31.8 mg, 0.36 mmol) sequentially to the reaction tube and stir for 10 min. Dissolve N,N'-dicyclohexylcarbodiimide (DCC) (64 mg) in 1 mL of dichloromethane (DCM) and transfer it to the previous reaction tube. Stir at 25 °C for 12 h to obtain a white solid product, which is the L-pyroglutamyl modified artemisinin derivative 1-3d. Figure 1 The yield was measured to be 55% (d in the figure).

[0046] The 1H NMR spectrum of L-pyroglutamyl alcohol-modified artemisinin derivative 1-3d (((R)-5-oxopyrrolidin-2-yl)methyl((3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)succinate(1-3d)) 1 H NMR, carbon spectrum ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below: 1 1H NMR (400 MHz, Acetone-d6) δ 7.13 (d, J J = 7.0 Hz, 1H), 5.80 (dt, J J= 6.4, 1.5 Hz, 1H), 5.35 (d, J J = 3.6 Hz, 1H), 4.11 (d, J J = 4.3 Hz, 2H), 3.85(ddtd, J J = 6.9, 5.2, 4.3, 3.3 Hz, 1H), 2.74 – 2.64 (m, 4H), 2.34 (ddd, J J=11.2, 6.9, 5.3 Hz, 2H), 2.26 – 2.17 (m, 3H), 2.10 – 1.99 (m, 2H), 1.91 – 1.82(m, 2H), 1.74 – 1.67 (m, 1H), 1.66 – 1.57 (m, 3H), 1.56 – 1.49 (m, 1H), 1.42(s, 3H), 1.19 (dddd, J J = 12.1, 7.9, 6.9, 4.9 Hz, 1H), 1.07 (dtd, J J = 12.3,10.3, 7.3 Hz, 1H), 0.95 (dd, J J = 7.8, 1.5 Hz, 3H), 0.90 (d, J J = 7.1 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 177.90, 172.91, 171.40, 104.30, 99.73,91.17, 81.68, 67.22, 51.98, 49.34, 43.88, 37.16, 36.77, 36.03, 32.85, 30.34,29.66, 29.45, 25.66, 24.91, 23.86, 23.63, 20.34, 13.08. HRMS (ESI):m / zCalcd.For C 24 H 35 NO9 ([M+Na] - ): 504.2432. Example 5

[0047] Preparation of L-phenylalanine-modified artemisinin derivatives 1-3e: ; Take a 50 mL round-bottom flask and treat it in an anhydrous and oxygen-free environment (heat the flask with a torch for 2 min, then purge with nitrogen). Place 1 mL of dichloromethane (DCM) into a reaction tube, and sequentially add artesunate (100 mg, 0.26 mmol), L-phenylalanine (58.6 mg, 0.39 mmol), and 4-dimethylaminopyridine (DMAP) (31.8 mg, 0.36 mmol) to the reaction tube. Stir for 10 min. Dissolve N,N'-dicyclohexylcarbodiimide (DCC) (64 mg) in 1 mL of dichloromethane (DCM) and transfer to the previous reaction tube. Stir at 25 °C for 12 h to obtain a white solid product, which is the L-phenylalanine-modified artemisinin derivative 1-3e (…). Figure 1 (e) was used to determine its yield, which was 52%.

[0048] The 1H NMR spectrum of L-phenylalanine-modified artemisinin derivative 1-3e ((R)-2-amino-3-phenylpropyl ((3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)succinate(1-3e)) 1 H NMR, carbon spectrum ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below: 1 H NMR (400 MHz, Acetone-d6) δ 5.80 (dt, J = 6.4, 1.5 Hz, 1H), 5.35(d, J = 3.6 Hz, 1H), 4.01 (qd, J = 12.3, 3.8 Hz, 2H), 3.56 (dd, J = 7.1, 6.2Hz, 1H), 3.46 (dd, J= 7.1, 6.4 Hz, 1H), 3.32 – 3.24 (m, 1H), 2.76 – 2.64 (m,4H), 2.30 – 2.15 (m, 3H), 2.11 – 2.01 (m, 1H), 1.92 – 1.82 (m, 1H), 1.74 –1.67 (m, 1H), 1.66 – 1.57 (m, 4H), 1.55 – 1.49 (m, 1H), 1.45 (d, J = 7.1 Hz,1H), 1.42 (s, 3H), 1.40 (d, J = 7.2 Hz, 1H), 1.19 (dddd, J = 12.1, 7.9, 6.9,4.9 Hz, 1H), 1.07 (dtd, J = 12.3, 10.3, 7.3 Hz, 1H), 0.95 (dd, J = 7.8, 1.5Hz, 3H), 0.90 (dd, J = 7.1, 5.2 Hz, 9H). 13 C NMR (101 MHz, CDCl3) δ 172.91, 172.43, 138.82, 129.08, 129.08,128.75,128.75, 126.95, 104.30, 99.73, 91.17, 81.68, 67.27, 53.24, 49.34,43.88, 40.17, 37.16, 36.77, 36.03, 32.85, 29.65, 29.45, 24.91, 23.86, 23.63,20.34, 13.08. HRMS (ESI): m / zCalcd.For C 28 H 39 NO8 ([M+Na)) - ): 540.2512. Example 6

[0049] Preparation of L-threonol-modified artemisinin derivatives 1-3f: ; Take a 50 mL round-bottom flask and treat it in an anhydrous and oxygen-free environment (heat the 50 mL round-bottom flask with a torch for 2 min, and then purge with nitrogen). Take 1 mL of dichloromethane (DCM) and put it into a reaction tube. Add artesunate (100 mg, 0.26 mmol), L-threonine (41 mg, 0.39 mmol), and 4-dimethylaminopyridine (DMAP) (31.8 mg, 0.36 mmol) sequentially into the reaction tube and stir for 10 min. Dissolve N,N'-dicyclohexylcarbodiimide (DCC) (64 mg) in 1 mL of dichloromethane (DCM) and transfer it to the previous reaction tube. Stir at 25 °C for 12 h to obtain a white solid product, which is the L-threonine-modified artemisinin derivative 1-3f. Figure 1 The yield was measured to be 47% (f in the figure).

[0050] L-threonol-modified artemisinin derivative 1-3f ((2S,3S)-2-amino-3-hydroxybutyl The proton NMR spectrum of ((3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)succinate(1-3f)) 1 H NMR, carbon spectrum ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below: 1 H NMR (400 MHz, Acetone-d6) δ 5.80 (dq, J = 6.5, 1.5 Hz, 1H), 5.35(d, J = 3.6 Hz, 1H), 4.16 – 4.03 (m, 2H), 3.64 (pd, J = 5.8, 4.5 Hz, 1H), 3.33 – 3.23 (m, 2H), 3.11 (tdt, J = 7.1, 5.9, 4.7 Hz, 1H), 2.91 (t, J= 7.1Hz, 1H), 2.74 – 2.69 (m, 1H), 2.69 – 2.65 (m, 3H), 2.30 – 2.15 (m, 3H), 2.11– 2.01 (m, 1H), 1.92 – 1.82 (m, 1H), 1.74 – 1.67 (m, 1H), 1.66 – 1.60 (m,2H), 1.60 – 1.51 (m, 2H), 1.42 (s, 3H), 1.19 (d, J = 5.8 Hz, 4H), 1.07 (dtd, J = 12.3, 10.3, 7.3 Hz, 1H), 0.95 (dd, J = 7.8, 1.5 Hz, 3H), 0.90 (d, J = 7.1Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 172.91, 172.44, 104.30, 99.73, 91.17,81.68, 69.08, 64.99, 55.69, 49.34, 43.88, 37.16, 36.77, 36.03, 32.85, 29.66,29.45, 24.91, 23.86, 23.63, 20.34, 20.16, 13.08. HRMS (ESI): m / zCalcd.For C 23 H 37 NO9 ([M+Na)) - ): 494.1632. Example 7

[0051] Preparation of 1-3g of L-valine-modified artemisinin derivatives: ; Take a 50 mL round-bottom flask and treat it in an anhydrous and oxygen-free environment (heat the 50 mL round-bottom flask with a torch for 2 min, and then purge with nitrogen). Take 1 mL of dichloromethane (DCM) and put it into a reaction tube. Add artesunate (100 mg, 0.26 mmol), L-valine (40.2 mg, 0.39 mmol), and 4-dimethylaminopyridine (DMAP) (31.8 mg, 0.36 mmol) sequentially into the reaction tube and stir for 10 min. Dissolve N,N'-dicyclohexylcarbodiimide (DCC) (64 mg) in 1 mL of dichloromethane (DCM) and transfer it to the previous reaction tube. Stir at 25 °C for 12 h to obtain a white solid product, which is 1-3 g of L-valine-modified artemisinin derivative. Figure 1 The yield of g was measured to be 48%.

[0052] L-valine-modified artemisinin derivative 1-3g ((S)-2-amino-3-methylbutyl The proton NMR spectrum of ((3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)succinate(1-3g)) 1 H NMR, carbon spectrum ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below: 1 H NMR (400 MHz, Acetone-d6) δ 5.80 (dq, J = 5.9, 1.6 Hz, 1H), 5.35(d, J = 3.6 Hz, 1H), 4.05 (qd, J = 12.3, 4.8 Hz, 2H), 3.24 (d, J = 7.3 Hz, 2H), 2.93 (tdt, J = 7.3, 6.6, 4.9 Hz, 1H), 2.70 (d, J = 6.4 Hz, 1H), 2.68 –2.65 (m, 3H), 2.30 – 2.15 (m, 3H), 2.11 – 2.01 (m, 1H), 1.92 – 1.82 (m, 1H),1.79 (dq, J = 12.3, 6.2 Hz, 1H), 1.70 (dtd, J= 8.5, 7.1, 4.2 Hz, 1H), 1.66 –1.52 (m, 4H), 1.42 (s, 3H), 1.19 (dddd, J = 12.1, 7.9, 6.9, 4.9 Hz, 1H), 1.07(dtd, J = 12.3, 10.3, 7.3 Hz, 1H), 0.95 (dd, J = 7.7, 1.5 Hz, 3H), 0.93 (d, J = 6.1 Hz, 6H), 0.90 (d, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 172.91, 172.44, 104.30, 99.73, 91.17,81.68, 67.02, 57.40, 49.34, 43.88, 37.16, 36.77, 36.03, 32.85, 31.59, 29.65,29.45, 24.91, 23.86, 23.63, 20.34, 19.09, 19.09,13.08. HRMS (ESI): m / zCalcd.For C 24 H 39 NO8 ([M+Na)) - ): 492.1436. Example 8

[0053] Preparation of L-leucine-modified artemisinin derivatives in 1-3 hours: ; Take a 50 mL round-bottom flask and treat it in an anhydrous and oxygen-free environment (heat the 50 mL round-bottom flask with a torch for 2 min, and then purge with nitrogen). Take 1 mL of dichloromethane (DCM) and put it into a reaction tube. Add artesunate (100 mg, 0.26 mmol), L-leucine (45.7 mg, 0.39 mmol), and 4-dimethylaminopyridine (DMAP) (31.8 mg, 0.36 mmol) sequentially into the reaction tube and stir for 10 min. Dissolve N,N'-dicyclohexylcarbodiimide (DCC) (64 mg) in 1 mL of dichloromethane (DCM) and transfer it to the previous reaction tube. Stir at 25 °C for 12 h to obtain a white solid product, which is the L-leucine-modified artemisinin derivative 1-3 h ( Figure 1 The yield was measured to be 54% (h in the sample).

[0054] L-Leucine-modified artemisinin derivative 1-3h ((S)-2-amino-4-methylpentyl((3R, 5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2] The nuclear magnetic resonance hydrogen spectrum of dioxepino[4,3-i]isochromen-10-yl)succinate(1-3h)) 1 HNMR, carbon spectroscopy ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below: 1 H NMR (400 MHz, Acetone-d6) δ 7.31 – 7.16 (m, 5H), 5.80 (dt, J =6.5, 1.5 Hz, 1H), 5.35 (d, J = 3.6 Hz, 1H), 4.13 – 4.02 (m, 2H), 3.44 (pt, J = 6.7, 4.4 Hz, 1H), 2.89 (ddt, J = 14.6, 6.6, 1.1 Hz, 1H), 2.78 – 2.74 (m,1H), 2.73 – 2.70 (m, 1H), 2.71 – 2.64 (m, 3H), 2.49 (t, J = 7.1 Hz, 1H), 2.37(t, J = 7.1 Hz, 1H), 2.30 – 2.15 (m, 3H), 2.10 – 2.02 (m, 1H), 1.91 – 1.83(m, 1H), 1.74 – 1.67 (m, 1H), 1.66 – 1.50 (m, 5H), 1.42 (s, 2H), 1.22 – 1.16(m, 1H), 1.07 (dtd, J = 12.3, 10.3, 7.3 Hz, 1H), 0.95 (dd, J = 7.8, 1.5 Hz, 3H), 0.90 (d, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 172.91, 172.43, 104.30, 99.73, 91.17,81.68, 69.51, 49.34, 49.29, 43.88, 42.68, 37.16, 36.77, 36.03, 32.85, 29.65,29.45, 25.46, 24.91, 23.86, 23.63, 22.81, 22.81,20.34, 13.08. HRMS (ESI): m / zCalcd.For C 25 H 41 NO8 ([M+Na)) - ): 506.1412. Example 9

[0055] Preparation of L-isoleucine-modified artemisinin derivatives 1-3i: ; Take a 50 mL round-bottom flask and treat it in an anhydrous and oxygen-free environment (heat the 50 mL round-bottom flask with a torch for 2 min, and then purge with nitrogen). Take 1 mL of dichloromethane (DCM) and put it into a reaction tube. Add artesunate (100 mg, 0.26 mmol), L-isolenic acid (45.7 mg, 0.39 mmol), and 4-dimethylaminopyridine (DMAP) (31.8 mg, 0.36 mmol) sequentially into the reaction tube and stir for 10 min. Dissolve N,N'-dicyclohexylcarbodiimide (DCC) (64 mg) in 1 mL of dichloromethane (DCM) and transfer it to the previous reaction tube. Stir at 25 °C for 12 h to obtain a white solid product, which is the L-isolenic acid-modified artemisinin derivative 1-3i. Figure 1 The yield of i was measured to be 61%.

[0056] L-Isoleucine-modified artemisinin derivative 1-3i ((2S,3S)-2-amino-3-methylpentyl((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro) The proton NMR spectrum of -12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)succinate(1-3i)) 1 H NMR, carbon spectrum ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below: 1H NMR (400 MHz, Acetone-d6) δ 5.80 (dd, J = 6.4, 1.5 Hz, 1H), 5.35(d, J = 3.6 Hz, 1H), 4.09 – 3.98 (m, 2H), 3.15 (d, J = 6.6 Hz, 2H), 3.06 –2.96 (m, 1H), 2.73 – 2.69 (m, 1H), 2.68 – 2.65 (m, 3H), 2.27 – 2.18 (m, 3H),2.11 – 2.01 (m, 1H), 1.92 – 1.82 (m, 1H), 1.74 – 1.67 (m, 1H), 1.66 – 1.50 (m, 5H), 1.42 (s, 3H), 1.38 – 1.34 (m, 2H), 1.19 (dddd, J = 12.1, 7.9, 6.9,4.9 Hz, 1H), 1.07 (dtd, J = 12.3, 10.3, 7.3 Hz, 1H), 0.95 (dd, J = 8.0, 6.5Hz, 6H), 0.90 (d, J = 7.1 Hz, 3H), 0.85 (t, J = 7.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 172.91, 172.44, 104.30, 99.73, 91.17,81.68, 66.87, 56.14, 49.34, 43.88, 38.39, 37.16, 36.77, 36.03, 32.85, 29.65,29.45, 25.78, 24.91, 23.86, 23.63, 20.34, 15.49, 13.08, 11.52. HRMS (ESI): m / zCalcd.For C 25 H 41 NO8([M+Na)) - ): 506.1342. Example 10

[0057] Preparation of L-prolyl-modified artemisinin derivatives 1-3j: ; Take a 50 mL round-bottom flask and treat it in an anhydrous and oxygen-free environment (heat the 50 mL round-bottom flask with a torch for 2 min, and then purge with nitrogen). Take 1 mL of dichloromethane (DCM) and put it into a reaction tube. Add artesunate (100 mg, 0.26 mmol), L-prolyl (39.4 mg, 0.39 mmol), and 4-dimethylaminopyridine (DMAP) (31.8 mg, 0.36 mmol) sequentially into the reaction tube and stir for 10 min. Dissolve N,N'-dicyclohexylcarbodiimide (DCC) (64 mg) in 1 mL of dichloromethane (DCM) and transfer it to the previous reaction tube. Stir at 25 °C for 12 h to obtain a white solid product, which is the L-prolyl-modified artemisinin derivative 1-3j. Figure 1 (j) was used to measure its yield, which was 62%.

[0058] L-prolyl-modified artemisinin derivative 1-3j(((R)-pyrrolidin-2-yl)methyl((3R, The 1H NMR spectrum of (5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)succinate(1-3j)) 1 HNMR, carbon spectroscopy ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below: 1 H NMR (400 MHz, Acetone-d6) δ 5.80 (dd, J = 6.4, 1.5 Hz, 1H), 5.35(d, J = 3.6 Hz, 1H), 4.06 (t, J = 4.3 Hz, 2H), 3.51 – 3.46 (m, 1H), 3.20 (dt, J= 6.0, 2.4 Hz, 1H), 3.03 – 2.97 (m, 1H), 2.88 – 2.83 (m, 1H), 2.74 – 2.65(m, 4H), 2.27 – 2.18 (m, 3H), 2.10 – 2.02 (m, 1H), 1.91 – 1.83 (m, 1H), 1.80 – 1.70 (m, 4H), 1.64 – 1.51 (m, 5H), 1.42 (s, 3H), 1.19 (dddd, J = 12.1, 7.9,6.9, 4.9 Hz, 1H), 1.07 (dtd, J = 12.3, 10.3, 7.3 Hz, 1H), 0.95 (dd, J = 7.8, 1.6 Hz, 3H), 0.90 (d, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 172.91, 171.40, 104.30, 99.73, 91.17,81.68, 67.84, 58.25, 49.34, 45.91, 43.88, 37.16, 36.77, 36.03, 32.85, 29.65,29.45, 29.27, 24.91, 24.13, 23.86, 23.63, 20.34, 13.08. HRMS (ESI): m / zCalcd.For C 24 H 37 NO8 ([M+Na)) - ): 490.2136. Experimental Example 1

[0059] The effects of different catalysts (Catalyst, abbreviated as Cat) on the reaction of this application were investigated: ; The results are shown in Table 2.

[0060] Table 2 Effect of different catalysts ; ; Note: All the above reactions were carried out under the following conditions: artesunate (100 mg, 0.26 mmol), L-phenylglycine (53 mg, 0.39 mmol), at 25 °C, were mixed with a catalyst (100 mol%) and a solvent dichloromethane (DCM) (1 ml). DCC solution (64 mg N,N'-dicyclohexylcarbodiimide dissolved in 1 mL of solvent) was added before the reaction, and the reaction time was 12 h; NR indicates no reaction occurred; Trace indicates that only trace amounts of the target product were detected in the reaction, and the amount generated was extremely small and almost negligible.

[0061] Table 2 shows that different catalysts have different effects on the reaction. The yields of the catalysts 4-dimethylaminopyridine, triethylenediamine, triethylamine, pyridine, imidazole, N,N'-dicyclohexylcarbodiimide, and sodium bicarbonate are significantly better than those of sodium hydroxide, potassium hydroxide, N,N'-carbonyldiimidazole, and DBU, especially the highest yield when using 4-dimethylaminopyridine. Experiment Example 2

[0062] The effects of different reaction solvents on the reactions in this application were investigated. ; The results are shown in Table 3.

[0063] Table 3 Effect of different reaction solvents ; ; Note: All the above reactions were carried out under the following conditions: artesunate (100 mg, 0.26 mmol), L-phenylglycine (53 mg, 0.39 mmol), at 25 °C, were mixed with the catalyst 4-dimethylaminopyridine (DMAP) (100 mol%) and different solvents (1 ml). DCC solution (64 mg N,N'-dicyclohexylcarbodiimide dissolved in 1 mL of solvent) was added before the reaction. The reaction time was 12 h. NR indicates no reaction occurred. Trace indicates that only trace amounts of the target product were detected in the reaction, and the amount generated was extremely small and almost negligible.

[0064] As shown in Table 3, not all reaction solvents can facilitate the reaction, and different solvents have different effects on the reaction. The yields achieved using the solvents described in this application—dichloromethane, trichloromethane, 1,2-dichloroethane, bromoethane, benzene, acetonitrile, tetrahydrofuran, anhydrous ethanol, N,N-dimethylformamide, ethyl acetate, and 1,4-dioxane—are significantly better than those achieved using dimethyl sulfoxide or petroleum ether, with the highest yield obtained using dichloromethane.

[0065] Experimental Example 3 The effect of different reaction temperatures (T) on the reaction of this application was investigated: ; The results are shown in Table 4.

[0066] Table 4 Effect of different reaction temperatures ; ; Note: All the above reactions were carried out under the following conditions: artesunate (100 mg, 0.26 mmol), L-phenylglycine (53 mg, 0.39 mmol), were mixed with the catalyst 4-dimethylaminopyridine (DMAP) (100 mol%) and the solvent dichloromethane (DCM) (1 ml) at 25 °C. DCC solution (64 mg N,N'-dicyclohexylcarbodiimide dissolved in 1 mL of solvent) was added before the reaction and the reaction time was 12 h.

[0067] As shown in Table 4, the reaction temperature range of 0~40℃ can be used to promote the reaction of this application and obtain artemisinin derivatives, especially the highest yield at 25℃.

[0068] Experiment Example 4 Investigating the effects of different material ratios and catalyst loading on the reaction of this application: ; The results are shown in Table 5.

[0069] Table 5. Effect of different material ratios on catalyst loading ; Note: The above reaction conditions are as follows: artesunate and L-phenylglycine are mixed with catalyst 4-dimethylaminopyridine (DMAP) (with different loadings) and solvent dichloromethane (DCM) (1 mL) at 25 °C according to the above molar ratio. DCC solution (64 mg N,N'-dicyclohexylcarbodiimide dissolved in 1 mL solvent) is added before the reaction.

[0070] As shown in Table 5, the material ratio range (molar ratio of artesunate to chiral amino alcohol of 1:1 to 1.5) and catalyst loading range (catalyst amount of 20 to 200 mol% of the molar amount of artesunate) of this application can promote the reaction of this application and obtain artemisinin derivatives. In particular, the highest yield is obtained under the conditions of molar ratio of artesunate to chiral amino alcohol of 1:1.5 and catalyst loading of 100 mol%.

[0071] The above description is merely a few embodiments of this application and is not intended to limit this application in any way. Although this application discloses preferred embodiments as described above, it is not intended to limit this application. Any changes or modifications made by those skilled in the art without departing from the scope of the technical solution of this application using the disclosed technical content are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A chiral amino alcohol-modified artemisinin derivative, characterized in that, The structure of the chiral amino alcohol-modified artemisinin derivative is shown in general formula I: ； Wherein, R is a substituent corresponding to the chiral amino alcohol, and the chiral amino alcohol is selected from any one of L-phenylglycine, L-methionine, L-tryptophanine, L-pyroskinine, L-phenylalanine, L-threonine, L-valine, L-leucine, L-isoleucine, and L-prolyl. The configurations of each chiral center in Formula I are: 3R, 5aS, 6R, 8aS, 9R, 12R, 12aR.

2. The chiral amino alcohol-modified artemisinin derivative according to claim 1, characterized in that, The structure of the chiral amino alcohol-modified artemisinin derivative is selected from any one of Formulas II to XI: ； ； ； 。 3. The method for preparing a chiral amino alcohol-modified artemisinin derivative according to claim 1 or 2, characterized in that, Includes the following steps: Under anhydrous and oxygen-free conditions, a solvent, artesunate, chiral amino alcohol, and catalyst are mixed and reacted to obtain the chiral amino alcohol-modified artemisinin derivative.

4. The method for preparing a chiral amino alcohol-modified artemisinin derivative according to claim 3, characterized in that, The anhydrous and oxygen-free conditions are achieved by drying the reaction vessel for 2-10 minutes and then introducing nitrogen gas for protection.

5. The method for preparing a chiral amino alcohol-modified artemisinin derivative according to claim 3, characterized in that, The molar ratio of artesunate to chiral amino alcohol is 1~1.5:1~1.5; Preferably, the molar ratio of artesunate to chiral amino alcohol is 1:1.5; Preferably, the amount of catalyst used is 20-200 mol% of the molar amount of 1 equivalent of artesunate. Preferably, the amount of catalyst used is 100 mol% of the molar amount of artesunate (equivalent to 1 mol%). Preferably, the ratio of the solvent to artesunate is 0.5~2mL:100mg; Preferably, the ratio of the solvent to artesunate is 1 mL: 100 mg.

6. The method for preparing a chiral amino alcohol-modified artemisinin derivative according to claim 3, characterized in that, The chiral amino alcohol is selected from any one of L-phenylglycine, L-methionine, L-tryptophan, L-pyroskinin, L-phenylalanine, L-threonine, L-valine, L-leucine, L-isoleucine, and L-prolyl.

7. The method for preparing a chiral amino alcohol-modified artemisinin derivative according to claim 3, characterized in that, The solvent is selected from any one of dichloromethane, trichloromethane, 1,2-dichloroethane, bromoethane, benzene, acetonitrile, tetrahydrofuran, anhydrous ethanol, N,N-dimethylformamide, ethyl acetate, and 1,4-dioxane; Preferably, the catalyst is selected from any one of 4-dimethylaminopyridine, triethylenediamine, triethylamine, pyridine, imidazole, N,N'-dicyclohexylcarbodiimide, and sodium bicarbonate.

8. The method for preparing a chiral amino alcohol-modified artemisinin derivative according to claim 7, characterized in that, When the catalyst is not N,N'-dicyclohexylcarbodiimide, the step of adding an N,N'-dicyclohexylcarbodiimide solution is included before the reaction. The preparation steps of the N,N'-dicyclohexylcarbodiimide solution are as follows: dissolve 20~100mg of N,N'-dicyclohexylcarbodiimide in 0.8~1.2mL of solvent; Preferably, the preparation step of the N,N'-dicyclohexylcarbodiimide solution is as follows: dissolve 64 mg of N,N'-dicyclohexylcarbodiimide in 1 mL of solvent.

9. The method for preparing a chiral amino alcohol-modified artemisinin derivative according to claim 3, characterized in that, The reaction temperature is 0~40℃; Preferably, the reaction temperature is 25°C; Preferably, the reaction time is 6-24 hours; Preferably, the reaction time is 12 hours; Preferably, the reaction is carried out under stirring conditions; The stirring speed is 500~1500 rpm; Preferably, the stirring speed is 1000 rpm.

10. The use of the chiral amino alcohol-modified artemisinin derivative according to claim 1 or 2, or the chiral amino alcohol-modified artemisinin derivative prepared by the preparation method according to any one of claims 3 to 9, in the preparation of antitumor drugs.

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