Artesunate chiral amino alcohol amide derivative, and preparation method and application thereof

Abstract

The application discloses an artemether chiral amino alcohol amide derivative, a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. A series of amide compounds containing an artemisinin unit are constructed by reacting artemether with different chiral amino alcohols. The reaction is an atom-economic reaction. The preparation method has the advantages of simple operation, mild reaction, fast reaction rate, high yield and the like.

Description

Technical Field

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

[0002] Artemisinin is a hemiterpene lactone compound isolated from Artemisia annua. It has a unique peroxy-bridge structure and its molecular formula is C1. 15 H 22 O5. Since its discovery in the 1970s, artemisinin has attracted much attention due to its potent antimalarial activity. Its derivatives, such as dihydroartemisinin, artemether, and artesunate, the latter two of which have become first-line antimalarial drugs in clinical practice. Among them, artesunate not only retains antimalarial activity but also exhibits significant anticancer activity.

[0003] 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 stereoconfiguration, thus improving the rigidity of complexes. Consequently, they can catalyze and induce various types of asymmetric organic reactions, making them a crucial and highly efficient class of asymmetric synthetic catalysts when combined with metals, attracting widespread attention. In medicinal chemistry, chiral amide structures based on chiral amino alcohols can enhance the stereospecific binding ability of drug molecules to targets such as enzymes and receptors, thereby improving pharmacological activities such as antitumor and antimalarial activity. Chiral amides are important intermediates in the formation of many drug molecules, natural products, and bioactive molecules.

[0004] To fully utilize the antitumor activity of artesunate and combine it with the structural characteristics of chiral amino alcohols, the two can be molecularly spliced ​​to obtain compounds with superior antitumor activity. However, systematic research on derivatives formed by artesunate and chiral amino alcohols linked by amide bonds (i.e., artesunate chiral amino alcohol amide derivatives) is still insufficient. The effects of reaction conditions (such as catalyst type, solvent type, temperature, and other key factors) on product yield in their synthetic routes lack systematic optimization, and suitable process parameters have not yet been determined, thus limiting the further research and application of this type of compound in the field of antitumor therapy.

[0005] Therefore, how to provide an artesunate chiral amino alcohol amide derivative with superior antitumor activity and establish an efficient and controllable preparation method has become a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0006] To overcome the aforementioned deficiencies in the prior art, this application provides an artesunate chiral amino alcohol amide derivative, its preparation method, and its application.

[0007] To achieve the above-mentioned objectives, this application provides the following technical solution:

[0008] On the one hand, this application provides an artesunate chiral amino alcohol amide derivative, the structure of which is shown in general formula I:

[0009]

[0010] Ⅰ;

[0011] 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-phenylalanine, L-threonine, L-valine, L-leucine, L-isoleucine, L-proline, D-phenylglycine, D-valine, D-phenylalanine, and D-leucine.

[0012] The configurations of the chiral centers in Formula I are: 3R, 5aS, 6R, 8aS, 9R, 10S, 12R, 12aR.

[0013] Optionally, the structure of the artesunate chiral amino alcohol amide derivative is selected from any one of Formulas II to XIV:

[0014]

[0015] II; III;

[0016]

[0017] IV; V;

[0018]

[0019] VI; VII;

[0020]

[0021] VIII; IX;

[0022]

[0023] X; XI;

[0024]

[0025] XII; XIII;

[0026]

[0027] XIV.

[0028] Secondly, this application provides a method for preparing the above-mentioned artesunate chiral amino alcohol amide derivative, comprising the following steps:

[0029] Artesunate, chiral amino alcohol, catalyst, and solvent were mixed and reacted under anhydrous and oxygen-free conditions to obtain the artesunate chiral amino alcohol amide derivative.

[0030] Optionally, the anhydrous and oxygen-free conditions are achieved by drying the reaction vessel for 2-10 minutes and then introducing nitrogen for protection.

[0031] Optionally, the molar ratio of artesunate to chiral amino alcohol is 1~1.5:1~1.5.

[0032] Preferably, the molar ratio of artesunate to chiral amino alcohol is 1:1.5.

[0033] Optionally, the amount of the catalyst used is 20 to 200 mol of 1 equivalent molar amount of artesunate.

[0034] Preferably, the amount of catalyst used is 150 mol of 1 equivalent molar amount of artesunate.

[0035] Optionally, the ratio of the solvent to artesunate is 0.5~2mL:100mg.

[0036] Preferably, the ratio of the solvent to artesunate is 1 mL: 100 mg.

[0037] Optionally, the chiral amino alcohol is selected from any one of L-phenylglycine, L-methionine, L-tryptophanine, L-phenylalanine, L-threonine, L-valine, L-leucine, L-isoleucine, L-proline, D-phenylglycine, D-valine, D-phenylalanine, and D-leucine.

[0038] Optionally, the solvent is selected from any one of dichloromethane, chloroform, bromoethane, benzene, tetrahydrofuran, acetonitrile, anhydrous ethanol, N,N-dimethylformamide, ethyl acetate, and 1,4-dioxane.

[0039] Preferably, the catalyst is selected from any one of 4-dimethylaminopyridine, triethylamine, imidazole, pyridine, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, potassium carbonate, and N,N-carbonyldiimidazole.

[0040] Optionally, a step of adding a dehydrating agent is included before the reaction;

[0041] The dehydrating agent includes 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride;

[0042] The molar ratio of the dehydrating agent to artesunate is 1:1.5.

[0043] Optionally, the reaction temperature is 0~60℃.

[0044] Preferably, the reaction temperature is 25°C.

[0045] Optionally, the reaction time is 12-24 hours.

[0046] Thirdly, this application provides the application of the above-mentioned artesunate chiral amino alcohol amide derivative, or the artesunate chiral amino alcohol amide derivative prepared by the above preparation method, in the preparation of antitumor drugs.

[0047] Compared with the prior art, this application has the following advantages:

[0048] (1) This application constructs a series of artemisinin derivatives that simultaneously possess artemisinin structural units and amino alcohol structural units by reacting artesunate with different chiral amino alcohols.

[0049] (2) This application provides a new method for constructing amide compounds containing artemisinin units. This method has the advantages of simple operation, mild reaction, fast reaction rate and high yield.

[0050] (3) This application carried out substrate expansion under optimal reaction conditions, and connected the carboxyl group on artesunate to different chiral amino alcohols, and constructed a series of artesunate derivatives containing both artesunate structural units and chiral amino alcohols in a maximum yield of 78%. Detailed Implementation

[0051] 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.

[0052] Unless otherwise specified, the raw materials used in the embodiments of this application are all purchased commercially and used directly without any special treatment.

[0053] Unless otherwise specified, the analytical methods in the embodiments all adopt conventional instrument or equipment settings and conventional analytical methods.

[0054] The sources of raw materials used in the following examples and comparative examples are shown in Table 1.

[0055] Table 1 Source of Raw Materials

[0056]

[0057] All reactions were carried out under anhydrous, oxygen-free, and nitrogen-protected conditions. The products were purified by silica gel column chromatography using a dichloromethane-methanol system as the eluent. Thin-layer chromatography (TLC) was used to detect the entire reaction process. The colorimetric reagent was a laboratory-made anisaldehyde colorimetric reagent (prepared by mixing 13 mL anisaldehyde, 478 mL ethanol, 5 mL glacial acetic acid, and 18 mL concentrated sulfuric acid). Example 1

[0058] Preparation of artesunate chiral aminoolamide derivative 3aa:

[0059]

[0060] Synthesis of artesunate and L-phenylglycine: A clean, dry reaction tube was used. Under anhydrous and anaerobic conditions, L-phenylglycine (50.5 mg), (150 mol%) DMAP (4-dimethylaminopyridine) (47.7 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (74.8 mg, 0.39 mmol) (dehydrating agent), and 1.2 mL of ultra-dry DMF (N,N-dimethylformamide) were added for dissolution. After stirring at 25°C for five minutes, artesunate (100 mg) was added. (mg), reacted overnight, and after the reaction was completed, 0.5M hydrochloric acid solution was added to the reaction system to adjust the pH to 6-7, then ethyl acetate was added for dilution and extraction, and the organic phase was retained. The organic phase was extracted three times with water and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and then separated by silica gel column chromatography (eluent ratio of dichloromethane / methanol = 90 / 1, 80 / 1, 70 / 1, 60 / 1, 50 / 1) to obtain the target product with a yield of 78%.

[0061] 3aa's 1H NMR spectrum ( 1 H NMR, carbon spectrum ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below:

[0062] (3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl4-(((R)-2-hydroxy-1-phenylethyl)amino)-4-oxobutanoate(3aa)White solid.

[0063] 1H NMR (400 MHz, Acetone-d6) δ 7.57 – 7.16 (m, 6H), 5.71 (d, J = 9.8Hz, 1H), 5.51 (s, 1H), 5.02 (dt, J = 8.0, 5.9 Hz, 1H), 3.98 (t, J = 5.9 Hz,1H), 3.81 – 3.67 (m, 2H), 2.72 – 2.58 (m, 4H), 2.43 (ddd, J = 9.7, 7.1, 4.1Hz, 1H), 2.29 (td, J = 14.0, 4.0 Hz, 1H), 1.93 – 1.86 (m, 1H), 1.73 (ddt, J =13.7, 10.1, 3.3 Hz, 2H), 1.62 – 1.55 (m, 1H), 1.50 – 1.42 (m, 2H), 1.30 (s,5H), 1.23 (dt, J = 11.5, 5.8 Hz, 1H), 1.03 (dd, J = 12.4, 3.1 Hz, 1H), 0.96(d, J = 6.4 Hz, 3H), 0.83 (s, 3H).

[0064] 13 C NMR (101 MHz, Acetone-d6) δ 172.14, 171.44, 141.92, 128.97,128.97, 127.88, 127.69, 127.69, 104.64, 92.80, 92.03, 80.79, 66.37, 56.40,52.54, 46.12, 37.61, 36.98, 34.95, 32.70, 30.92, 30.42, 26.01, 25.40, 22.39,20.52, 12.32.

[0065] HRMS (ESI): m / zCalcd.For C 27 H 37 NO8([M+Na)) + ): 526.2412, found: 526.2413. Example 2

[0066] Preparation of artesunate chiral aminoolamide derivative 3ab:

[0067]

[0068] Synthesis of artesunate and L-methionine: A clean and dry reaction tube was used. Under anhydrous and anaerobic conditions, L-methionine (51.7 mg), (150 mol%) DMAP (47.7 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (74.8 mg, 0.39 mmol), and ultra-dry DMF (1.4 mL) were added sequentially for dissolution. After stirring at 25 °C for five minutes, artesunate (100 mg) was added and the reaction was allowed to proceed overnight. After the reaction was completed, 0.5 M hydrochloric acid solution was added to the reaction system to bring the pH to 6-7. Ethyl acetate was then added for dilution and extraction. The organic phase was retained and extracted three times with water. The organic phase was dried with anhydrous sodium sulfate and the solvent was removed by rotary evaporation under reduced pressure. The product was then separated by silica gel column chromatography (eluent ratio of dichloromethane / methanol = 90 / 1, 80 / 1, 70 / 1, 60 / 1, 50 / 1) to obtain the target product with a yield of 47%.

[0069] 3ab's proton NMR spectrum ( 1 H NMR, carbon spectrum ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below:

[0070] (3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i ]isochromen-10-yl4-(((R)-1-hydroxy-4-(methylthio)butan-2-yl)amino)-4-oxobutanoate(3ab)White solid.

[0071] 1H NMR (400 MHz, Acetone-d6) δ 6.78 (d, J = 8.5 Hz, 1H), 5.80 – 5.73 (m, 1H), 5.34 (dd, J = 3.4, 2.5 Hz, 1H), 3.77 – 3.68 (m, 1H), 3.59 – 3.50 (m,3H), 2.63 – 2.41 (m, 6H), 2.29 – 2.17 (m, 3H), 2.11 – 2.01 (m, 4H), 1.92 –1.82 (m, 1H), 1.76 – 1.53 (m, 7H), 1.56 – 1.47 (m, 1H), 1.42 (s, 3H), 1.07(dtd, J = 12.3, 10.3, 7.3 Hz, 1H), 0.98 – 0.90 (m, 3H), 0.90 (d, J = 7.1 Hz, 3H).

[0072] 13 C NMR (101 MHz, Acetone-d6) δ 173.85, 172.84, 104.30, 97.94, 89.55,81.68, 64.67, 51.34, 49.31, 41.87, 36.77, 35.79, 34.60, 32.85, 31.96, 31.89,31.61, 31.19, 26.96, 24.91, 23.70, 20.34, 15.29, 12.53.

[0073] HRMS (ESI): m / zCalcd.For C 24 H 39 NO8S ([M+Na)) + ): 524.2289, found:524.2299. Example 3

[0074] Preparation of artesunate chiral aminoolamide derivative 3ac:

[0075]

[0076] Synthesis of artesunate and L-tryptophan: A clean and dry reaction tube was taken, and L-tryptophan (49.5 mg), (150 mol%) DMAP (47.7 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (74.8 mg, 0.39 mmol), and ultra-dry DMF (1.9 mL) were added sequentially under anhydrous and oxygen-free conditions. After stirring at 25 °C for five minutes, artesunate (100 mg) was added, and the reaction was allowed to proceed overnight. After the reaction was completed, 0.5 M hydrochloric acid solution was added to the reaction system to bring the pH to 6-7. Ethyl acetate was then added for dilution and extraction. The organic phase was retained and extracted three times with water. The organic phase was dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The product was then separated by silica gel column chromatography (eluent ratio of dichloromethane / methanol = 90 / 1, 80 / 1, 70 / 1, 60 / 1, 50 / 1) to obtain the target product with a yield of 55%.

[0077] 3ac nuclear magnetic resonance hydrogen spectrum ( 1 H NMR, carbon spectrum ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below:

[0078] (3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]i sochromen-10-yl4-(((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)amino)-4-oxobutanoate(3ac)White solid.

[0079] 1H NMR (400 MHz, Acetone-d6) δ 9.24 (d, J = 6.8 Hz, 1H), 7.68 (dd, J= 7.5, 1.1 Hz, 1H), 7.35 (dd, J = 7.7, 1.6 Hz, 1H), 7.15 (td, J = 7.6, 1.1Hz, 1H), 7.14 – 7.05 (m, 2H), 7.02 (d, J = 9.0 Hz, 1H), 5.80 – 5.74 (m, 1H),5.34 (dd, J = 3.4, 2.5 Hz, 1H), 3.93 (dddd, J = 11.4, 9.0, 6.8, 4.7 Hz, 1H),3.63 (t, J = 5.3 Hz, 1H), 3.52 – 3.38 (m, 2H), 2.99 (dd, J = 14.7, 6.8 Hz,1H), 2.84 (dd, J = 14.7, 6.9 Hz, 1H), 2.63 – 2.54 (m, 2H), 2.57 – 2.41 (m,2H), 2.29 – 2.23 (m, 0H), 2.24 (s, 1H), 2.26 – 2.17 (m, 2H), 2.11 – 2.01 (m,1H), 1.92 – 1.82 (m, 1H), 1.76 – 1.47 (m, 6H), 1.42 (s, 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), 0.98 –0.90 (m, 3H), 0.90 (d, J = 7.1 Hz, 3H).

[0080] 13 C NMR (101 MHz, Acetone-d6) δ 173.70, 172.84, 136.52, 128.16,123.86, 121.91, 119.86, 118.85, 111.92, 111.69, 104.30, 97.94, 89.55, 81.68,64.22, 52.65, 49.31, 41.87, 36.77, 35.79, 34.60, 32.85, 31.89, 31.61, 27.92,26.96, 24.91, 23.70, 20.34, 12.53.

[0081] HRMS (ESI): m / zCalcd.For C 30 H 40 N₂O₈([M+Na)) + ): 579.2677, found: 579.2667. Example 4

[0082] Preparation of artesunate chiral aminoolamide derivative 3ad:

[0083]

[0084] Synthesis of artesunate and L-phenylalanine: A clean and dry reaction tube was taken, and L-phenylalanine (53.9 mg), (150 mol%) DMAP (47.7 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (74.8 mg, 0.39 mmol), and ultra-dry DMF (2 mL) were added sequentially under anhydrous and oxygen-free conditions. After stirring at 25 °C for five minutes, artesunate (100 mg) was added, and the reaction was allowed to proceed overnight. After the reaction was completed, 0.5 M hydrochloric acid solution was added to the reaction system to bring the pH to 6-7, and then ethyl acetate was added for dilution and extraction. The organic phase was retained and extracted three times with water. The organic phase was dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The product was then separated by silica gel column chromatography (eluent ratio of dichloromethane / methanol = 90 / 1, 80 / 1, 70 / 1, 60 / 1, 50 / 1) to obtain the target product with a yield of 68%.

[0085] 3ad nuclear magnetic resonance hydrogen spectrum ( 1 H NMR, carbon spectrum ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below:

[0086] (3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4, 3-i]isochromen-10-yl4-(((R)-1-hydroxy-3-phenylpropan-2-yl)amino)-4-oxobutanoate(3ad)White solid.

[0087] 11H NMR (400 MHz, Acetone-d6) δ 7.33 – 7.12 (m, 5H), 7.04 (d, J = 8.2Hz, 1H), 5.71 (d, J = 9.8 Hz, 1H), 5.51 (s, 1H), 4.07 (dq, J = 7.5, 3.7, 2.5Hz, 1H), 3.93 (t, J = 5.6 Hz, 1H), 3.50 (d, J = 5.1 Hz, 2H), 2.91 (dd, J =13.6, 6.8 Hz, 1H), 2.76 (s, 1H), 2.61 (dt, J = 6.5, 2.9 Hz, 2H), 2.51 – 2.45(m, 2H), 2.44 – 2.39 (m, 1H), 2.28 (td, J = 14.0, 4.0 Hz, 1H), 1.89 (ddd, J =10.1, 6.6, 3.4 Hz, 1H), 1.74 (ddd, J = 19.5, 12.5, 3.3 Hz, 2H), 1.62 – 1.41(m, 5H), 1.29 (s, 3H), 1.25 – 1.19 (m, 1H), 1.09 – 1.01 (m, 1H), 0.95 (d, J =6.4 Hz, 3H), 0.84 (d, J = 7.2 Hz, 3H).

[0088] 13 13C NMR (101 MHz, Acetone-d6) δ 173.70, 172.84, 138.53, 129.01,129.01, 128.97, 127.28, 127.28, 104.30, 97.94, 89.55, 81.68, 63.89, 53.69,49.31, 41.87, 37.35, 36.77, 35.79, 34.60, 32.85, 31.89, 31.61, 26.96, 24.91,23.70, 20.34, 12.53.

[0089] HRMS (ESI):m / zCalcd.For C 28 H 39 NO8([M+HCOO] - ): 562.2659, found:562.2658. Example 5

[0090] Preparation of artesunate chiral aminoolamide derivative 3ae:

[0091]

[0092] Synthesis of artesunate and L-threonine: A clean and dry reaction tube was taken, and L-threonine (41.0 mg), (150 mol%) DMAP (47.7 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (74.8 mg, 0.39 mmol), and ultra-dry DMF (1.6 mL) were added sequentially under anhydrous and anaerobic conditions. After stirring at 25 °C for five minutes, artesunate (100 mg) was added, and the reaction was allowed to proceed overnight. After the reaction was completed, 0.5 M hydrochloric acid solution was added to the reaction system to bring the pH to 6-7. Ethyl acetate was then added for dilution and extraction. The organic phase was retained and extracted three times with water. The organic phase was dried with anhydrous sodium sulfate and the solvent was removed by rotary evaporation under reduced pressure. The product was then separated by silica gel column chromatography (eluent ratio of dichloromethane / methanol = 90 / 1, 80 / 1, 70 / 1, 60 / 1, 50 / 1) to obtain the target product with a yield of 61%.

[0093] 3ae 1H NMR spectrum ( 1 H NMR, carbon spectrum ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below:

[0094] (3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4 ,3-i]isochromen-10-yl4-(((2R,3R)-1,3-dihydroxybutan-2-yl)amino)-4-oxobutanoate(3ae)White solid.

[0095] 1H NMR (400 MHz, Acetone-d6) δ 7.12 – 7.04 (m, 1H), 5.80 – 5.73 (m,1H), 5.34 (dd, J = 3.4, 2.4 Hz, 1H), 4.03 (dddd, J = 9.2, 6.3, 3.7, 1.5 Hz,2H), 3.88 – 3.80 (m, 1H), 3.71 – 3.63 (m, 1H), 3.64 (d, J = 4.4 Hz, 1H), 3.43(t, J = 5.1 Hz, 1H), 2.64 – 2.51 (m, 3H), 2.46 – 2.36 (m, 1H), 2.29 – 2.17(m, 3H), 2.11 – 2.01 (m, 1H), 1.92 – 1.82 (m, 1H), 1.76 – 1.47 (m, 5H), 1.42(s, 3H), 1.24 – 1.14 (m, 4H), 1.07 (dtd, J = 12.3, 10.3, 7.3 Hz, 1H), 0.98 –0.88 (m, 6H).

[0096] 13 C NMR (101 MHz, Acetone-d6) δ 174.14, 172.84, 104.30, 97.94, 89.55,81.68, 66.72, 61.04, 56.69, 49.31, 41.87, 36.77, 35.79, 34.60, 32.85, 31.91,31.61, 26.96, 24.91, 23.70, 20.34, 19.82, 12.53.

[0097] HRMS (ESI): m / zCalcd.For C 23 H 37 NO9([M+Na)) + ): 494.2361, found: 494.2369. Example 6

[0098] Preparation of artesunate chiral aminoolamide derivative 3af:

[0099]

[0100] Synthesis of artesunate and L-valine: A clean, dry reaction tube was used. Under anhydrous and anaerobic conditions, L-valine (40.2 mg), (150 mol%) DMAP (47.7 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (74.8 mg, 0.39 mmol), and ultra-dry DMF (0.8 mL) were added sequentially for dissolution. After stirring at 25 °C for five minutes, artesunate (100 mg) was added, and the reaction was allowed to proceed overnight. After the reaction was complete, 0.5 M hydrochloric acid solution was added to the reaction system until the pH reached 6-7. Ethyl acetate was then added for dilution and extraction. The organic phase was retained and extracted three times with water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure using a rotary evaporator. Separation was then performed by silica gel column chromatography (eluent ratios of dichloromethane / methanol = 90 / 1, 80 / 1, 70 / 1, 60 / 1, 50 / 1) to obtain the target product in 62% yield.

[0101] 3af nuclear magnetic resonance hydrogen spectrum ( 1 H NMR, carbon spectrum ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below:

[0102] (3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl4-(((R)-1-hydroxy-3-methylbutan-2-yl)amino)-4-oxobutanoate(3af)White solid.

[0103] 1H NMR (400 MHz, Chloroform-d) δ 7.26 (s, 1H), 5.94 (d, J = 8.3 Hz,1H), 5.76 (d, J = 9.8 Hz, 1H), 5.43 (s, 1H), 3.74 – 3.61 (m, 3H), 2.78 (dd, J= 6.5, 2.3 Hz, 2H), 2.54 (d, J = 6.5 Hz, 3H), 2.42 – 2.33 (m, 1H), 2.03 (ddd,J = 14.6, 4.9, 3.0 Hz, 1H), 1.88 (ddd, J = 13.7, 8.7, 4.9 Hz, 2H), 1.77 (dd,J = 13.3, 3.7 Hz, 1H), 1.74 – 1.69 (m, 1H), 1.65 – 1.58 (m, 1H), 1.48 (dd, J= 4.9, 2.5 Hz, 1H), 1.43 (s, 3H), 1.36 (dd, J = 13.5, 3.3 Hz, 1H), 1.31 –1.24 (m, 2H), 1.02 (d, J = 3.2 Hz, 1H), 0.97 – 0.91 (m, 9H), 0.84 (d, J = 7.1Hz, 3H).

[0104] 13 C NMR (101 MHz, Chloroform-d) δ 174.09, 172.84, 104.30, 97.94,89.55, 81.68, 63.08, 57.93, 49.31, 41.87, 36.77, 35.79, 34.60, 32.85, 31.91,31.61, 30.58, 26.96, 24.91, 23.70, 20.34, 18.52, 18.52, 12.53.

[0105] HRMS (ESI): m / zCalcd.For C 24 H 39 NO8([M+Na)) + ): 492.2568, found: 492.2576. Example 7

[0106] Preparation of 3ag of artesunate chiral aminoolamide derivative:

[0107]

[0108] Synthesis of artesunate and L-leucine: A clean and dry reaction tube was taken, and L-leucine (41.0 mg), (150 mol%) DMAP (47.7 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (74.8 mg, 0.39 mmol), and ultra-dry DMF (1.3 mL) were added sequentially under anhydrous and oxygen-free conditions. After stirring at 25 °C for five minutes, artesunate (100 mg) was added, and the reaction was allowed to proceed overnight. After the reaction was completed, 0.5 M hydrochloric acid solution was added to the reaction system to bring the pH to 6-7, and then ethyl acetate was added for dilution and extraction. The organic phase was retained and extracted three times with water. The organic phase was dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The product was then separated by silica gel column chromatography (eluent ratio of dichloromethane / methanol = 90 / 1, 80 / 1, 70 / 1, 60 / 1, 50 / 1) to obtain the target product with a yield of 65%.

[0109] 3ag of proton nuclear magnetic resonance spectrum (NMR spectrum) 1 H NMR, carbon spectrum ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below:

[0110] (3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-4-oxobutanoate(3ag)White solid.

[0111] 1H NMR (400 MHz, Chloroform-d) δ 7.26 (s, 1H), 5.77 (d, J = 9.9 Hz,2H), 5.43 (s, 1H), 4.08 – 3.97 (m, 1H), 3.68 (dd, J = 11.0, 3.3 Hz, 1H), 3.51(dd, J = 11.0, 5.4 Hz, 1H), 2.78 (d, J = 3.9 Hz, 2H), 2.52 (d, J = 6.5 Hz,3H), 2.42 – 2.31 (m, 1H), 2.21 (s, 1H), 2.08 – 2.00 (m, 1H), 1.94 – 1.84 (m,1H), 1.82 – 1.68 (m, 2H), 1.61 (dt, J = 8.7, 5.4 Hz, 2H), 1.53 – 1.45 (m,1H), 1.43 (s, 3H), 1.37 (s, 1H), 1.34 (dd, J = 5.5, 3.0 Hz, 1H), 1.31 – 1.29(m, 1H), 1.27 (d, J = 6.1 Hz, 1H), 1.02 (d, J = 3.4 Hz, 1H), 0.97 – 0.89 (m,9H), 0.85 (d, J = 7.1 Hz, 3H).

[0112] 13 C NMR (101 MHz, Chloroform-d) δ 173.88, 172.84, 104.30, 97.94,89.55, 81.68, 65.54, 49.31, 48.79, 41.87, 36.77, 35.79, 34.88, 34.60, 32.85,31.89, 31.61, 26.96, 24.91, 24.83, 23.70, 22.31, 22.31, 20.34, 12.53.

[0113] HRMS (ESI): m / zCalcd. For C 25 H 41 NO8([M+Na)) + ): 506.2724, found: 506.2737. Example 8

[0114] Preparation of artesunate chiral aminoolamide derivative 3ah:

[0115]

[0116] Synthesis of artesunate and L-isolenic acid: A clean and dry reaction tube was taken, and L-isolenic acid (46.0 mg), (150 mol%) DMAP (47.7 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (74.8 mg, 0.39 mmol), and ultra-dry DMF (1.7 mL) were added sequentially under anhydrous and oxygen-free conditions. After stirring at 25 °C for five minutes, artesunate (100 mg) was added, and the reaction was allowed to proceed overnight. After the reaction was completed, 0.5 M hydrochloric acid solution was added to the reaction system to bring the pH to 6-7. Ethyl acetate was then added for dilution and extraction. The organic phase was retained and extracted three times with water. The organic phase was dried with anhydrous sodium sulfate and the solvent was removed by rotary evaporation under reduced pressure. The product was then separated by silica gel column chromatography (eluent ratio of dichloromethane / methanol = 90 / 1, 80 / 1, 70 / 1, 60 / 1, 50 / 1) to obtain the target product with a yield of 70%.

[0117] 3ah 1H NMR spectrum ( 1 H NMR, carbon spectrum ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below:

[0118] (3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3- i]isochromen-10-yl4-(((2R,3S)-1-hydroxy-3-methylpentan-2-yl)amino)-4-oxobutanoate(3ah)White solid.

[0119] 1H NMR (400 MHz, Chloroform-d) δ 6.65 (d, J = 8.6 Hz, 1H), 5.77 (ddd,J = 6.2, 4.7, 2.5 Hz, 1H), 5.34 (dd, J = 3.4, 2.5 Hz, 1H), 3.62 – 3.52 (m,2H), 3.44 (ddt, J = 8.7, 7.7, 4.4 Hz, 1H), 3.30 (t, J = 5.4 Hz, 1H), 2.63 –2.53 (m, 3H), 2.55 – 2.43 (m, 1H), 2.29 – 2.17 (m, 3H), 2.11 – 2.01 (m, 1H),1.92 – 1.82 (m, 1H), 1.81 – 1.47 (m, 7H), 1.42 (s, 2H), 1.39 – 1.29 (m, 2H), 1.19 (dddd, J = 12.1, 7.9, 6.9, 4.9 Hz, 1H), 1.07 (dtd, J = 12.3, 10.2, 7.3Hz, 1H), 0.98 – 0.83 (m, 12H).

[0120] 13 C NMR (101 MHz, Chloroform-d) δ 174.04, 172.84, 104.30, 97.94,89.55, 81.68, 63.67, 56.69, 49.31, 41.87, 36.77, 36.38, 35.79, 34.60, 32.85,31.91, 31.61, 26.96, 26.42, 24.91, 23.70, 20.34, 15.49, 12.53, 11.64.

[0121] HRMS (ESI): m / zCalcd.For C 25 H 41 NO8([M+Na)) + ): 506.2724, found: 506.2728. Example 9

[0122] Preparation of artesunate chiral aminoolamide derivative 3ai:

[0123]

[0124] Synthesis of artesunate and L-prolyl: A clean and dry reaction tube was taken, and L-prolyl (39.4 mg), (150 mol%) DMAP (47.7 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (74.8 mg, 0.39 mmol), and ultra-dry DM (0.5 mL) F were added sequentially under anhydrous and oxygen-free conditions. After stirring at 25 °C for five minutes, artesunate (100 mg) was added, and the reaction was allowed to proceed overnight. After the reaction was completed, 0.5 M hydrochloric acid solution was added to the reaction system to bring the pH to 6-7, and then ethyl acetate was added for dilution and extraction. The organic phase was retained and extracted three times with water. The organic phase was dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The product was then separated by silica gel column chromatography (eluent ratio of dichloromethane / methanol = 90 / 1, 80 / 1, 70 / 1, 60 / 1, 50 / 1) to obtain the target product with a yield of 78%.

[0125] 3ai's proton nuclear magnetic resonance spectrum ( 1 H NMR, carbon spectrum ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below:

[0126] (3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl4-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)-4-oxobutanoate(3ai)White solid.

[0127] 1H NMR (400 MHz, Chloroform-d) δ 5.80 – 5.73 (m, 1H), 5.34 (dd, J =3.4, 2.5 Hz, 1H), 3.91 (qd, J = 6.0, 5.5, 4.3 Hz, 1H), 3.65 – 3.43 (m, 5H),2.63 (d, J = 4.0 Hz, 1H), 2.61 (d, J = 2.4 Hz, 1H), 2.62 – 2.50 (m, 2H), 2.29– 2.17 (m, 3H), 2.11 – 2.01 (m, 1H), 1.92 – 1.47 (m, 10H), 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), 0.98 – 0.88 (m, 6H).

[0128] 13 C NMR (101 MHz, Chloroform-d) δ 172.82, 171.71, 104.30, 97.94,89.55, 81.68, 65.64, 61.69, 49.31, 46.52, 41.87, 36.77, 35.79, 34.60, 32.85,31.34, 31.02, 28.36, 26.96, 24.91, 24.21, 23.70, 20.34, 12.53.

[0129] HRMS (ESI): m / zCalcd.For C 24 H 37 NO8([M+Na)) + ): 490.2411, found: 490.2413. Example 10

[0130] Preparation of artesunate chiral aminoolamide derivative 3aj:

[0131]

[0132] Synthesis of artesunate and D-phenylglycine: A clean and dry reaction tube was used. Under anhydrous and anaerobic conditions, D-phenylglycine (53.5 mg), (150 mol%) DMAP (47.7 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (74.8 mg, 0.39 mmol), and ultra-dry DMF (1.4 mL) were added sequentially for dissolution. After stirring at 25 °C for five minutes, artesunate (100 mg) was added, and the reaction was allowed to proceed overnight. After the reaction was completed, 0.5 M hydrochloric acid solution was added to the reaction system to bring the pH to 6-7. Ethyl acetate was then added for dilution and extraction. The organic phase was retained and extracted three times with water. The organic phase was dried with anhydrous sodium sulfate and the solvent was removed by rotary evaporation under reduced pressure. The product was then separated by silica gel column chromatography (eluent ratio of dichloromethane / methanol = 90 / 1, 80 / 1, 70 / 1, 60 / 1, 50 / 1) to obtain the target product with a yield of 70%.

[0133] 3aj's proton NMR spectrum ( 1 H NMR, carbon spectrum ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below:

[0134] (3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl4-(((S)-2-hydroxy-1-phenylethyl)amino)-4-oxobutanoate(3aj)White solid.

[0135] 1H NMR (400 MHz, Acetone-d6) δ 7.61 – 7.12 (m, 6H), 5.71 (d, J = 9.8Hz, 1H), 5.51 (s, 1H), 5.03 (dt, J = 8.1, 5.9 Hz, 1H), 3.98 (t, J = 5.9 Hz,1H), 3.81 – 3.68 (m, 2H), 2.72 – 2.57 (m, 4H), 2.41 (ddd, J = 9.8, 7.1, 4.1Hz, 1H), 2.34 – 2.22 (m, 1H), 2.01 (dd, J = 5.0, 3.2 Hz, 1H), 1.88 (ddd, J =13.7, 6.7, 3.4 Hz, 1H), 1.73 (ddd, J = 17.1, 13.1, 3.3 Hz, 2H), 1.61 – 1.55(m, 1H), 1.52 – 1.39 (m, 3H), 1.29 (s, 3H), 1.27 – 1.19 (m, 1H), 1.09 – 1.00(m, 1H), 0.95 (d, J = 6.4 Hz, 3H), 0.79 (d, J = 7.1 Hz, 3H).

[0136] 13 C NMR (101 MHz, Chloroform-d) δ 172.84, 172.64, 139.72, 128.98,128.98, 128.17, 126.63, 126.63, 104.30, 97.94, 89.55, 81.68, 65.94, 56.47,49.31, 41.87, 36.77, 35.79, 34.60, 32.85, 31.90, 31.61, 26.96, 24.91, 23.70,20.34, 12.53.

[0137] HRMS (ESI): m / zCalcd.For C 28 H 39 NO8([M+Na)) + ): 540.2568, found: 540.2577. Example 11

[0138] Preparation of artesunate chiral amino alcohol amide derivative 3ak:

[0139]

[0140] Synthesis of artesunate and D-valine: A clean and dry reaction tube was used. Under anhydrous and anaerobic conditions, D-valine (40.2 mg), (150 mol%) DMAP (47.7 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (74.8 mg, 0.39 mmol), and ultra-dry DMF (1.1 mL) were added sequentially for dissolution. After stirring at 25 °C for five minutes, artesunate (100 mg) was added and the reaction was allowed to proceed overnight. After the reaction was completed, 0.5 M hydrochloric acid solution was added to the reaction system to bring the pH to 6-7. Ethyl acetate was then added for dilution and extraction. The organic phase was retained and extracted three times with water. The organic phase was dried with anhydrous sodium sulfate and the solvent was removed by rotary evaporation under reduced pressure. The product was then separated by silica gel column chromatography (eluent ratio of dichloromethane / methanol = 90 / 1, 80 / 1, 70 / 1, 60 / 1, 50 / 1) to obtain the target product with a yield of 61%.

[0141] 3ak's proton NMR spectrum ( 1 H NMR, carbon spectrum ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below:

[0142] (3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]d-ioxepino[4,3-i]isochromen-10-yl4-(((S)-1-hydroxy-3-methylbutan-2-yl)amino)-4-oxob-utanoate

[0143] 1H NMR (400 MHz, Acetone-d6) δ 6.92 (d, J = 8.9 Hz, 1H), 5.72 (d, J =9.7 Hz, 1H), 5.51 (s, 1H), 3.77 – 3.67 (m, 1H), 3.56 (d, J = 2.2 Hz, 2H),2.90 (s, 1H), 2.66 (t, J = 6.5 Hz, 2H), 2.54 (t, J = 6.5 Hz, 2H), 2.43 (ddd,J = 9.7, 7.1, 4.2 Hz, 1H), 2.33 – 2.24 (m, 1H), 2.01 (dd, J = 5.0, 3.1 Hz,1H), 1.96 – 1.85 (m, 2H), 1.79 – 1.69 (m, 2H), 1.63 – 1.55 (m, 1H), 1.54 –1.39 (m, 3H), 1.30 (s, 3H), 1.24 (dt, J = 11.4, 5.7 Hz, 1H), 1.03 (dd, J =12.5, 3.3 Hz, 1H), 0.98 – 0.93 (m, 5H), 0.92 – 0.89 (m, 4H), 0.84 (d, J = 7.2Hz, 3H).

[0144] 13 C NMR (101 MHz, Acetone-d6) δ 172.19, 171.81, 104.63, 92.77, 92.03,80.79, 63.24, 57.40, 52.53, 46.10, 37.60, 36.97, 34.94, 32.72, 30.96, 30.42,26.00, 25.39, 22.38, 20.51, 19.98, 18.83, 12.35.

[0145] HRMS (ESI): m / zCalcd.For C 24 H 39 NO8([M+Na)) + ): 492.2568, found: 492.2576. Example 12

[0146] Preparation of artesunate chiral aminoolamide derivative 3al:

[0147]

[0148] Synthesis of artesunate and D-phenylalanine: A clean and dry reaction tube was used. Under anhydrous and anaerobic conditions, D-phenylalanine (58.9 mg), (150 mol%) DMAP (47.7 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (74.8 mg, 0.39 mmol), and ultra-dry DMF (1.2 mL) were added sequentially for dissolution. After stirring at 25 °C for five minutes, artesunate (100 mg) was added and the reaction was allowed to proceed overnight. After the reaction was completed, 0.5 M hydrochloric acid solution was added to the reaction system to bring the pH to 6-7. Ethyl acetate was then added for dilution and extraction. The organic phase was retained and extracted three times with water. The organic phase was dried with anhydrous sodium sulfate and the solvent was removed by rotary evaporation under reduced pressure. The product was then separated by silica gel column chromatography (eluent ratio of dichloromethane / methanol = 90 / 1, 80 / 1, 70 / 1, 60 / 1, 50 / 1) to obtain the target product with a yield of 69%.

[0149] 3al's proton nuclear magnetic resonance spectrum ( 1 H NMR, carbon spectrum ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below:

[0150] (3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]d-ioxepi no[4,3-i]isochromen-10-yl4-(((S)-1-hydroxy-3-phenylpropan-2-yl)amino)-4-oxobu-tanoate

[0151] 11H NMR (400 MHz, Acetone-d6) δ 7.32 – 7.14 (m, 5H), 7.07 (d, J = 8.3Hz, 1H), 5.71 (d, J = 9.8 Hz, 1H), 5.51 (s, 1H), 4.08 (ddt, J = 12.2, 7.3,3.7 Hz, 1H), 3.96 (t, J = 5.6 Hz, 1H), 3.51 (t, J = 5.4 Hz, 2H), 2.79 (dd, J= 13.6, 7.4 Hz, 1H), 2.61 (dt, J = 15.8, 6.9 Hz, 2H), 2.55 – 2.39 (m, 4H),2.33 – 2.23 (m, 1H), 2.01 (dd, J = 5.0, 3.0 Hz, 1H), 1.88 (ddd, J = 13.7,6.8, 3.4 Hz, 1H), 1.73 (ddt, J = 16.4, 13.1, 3.4 Hz, 2H), 1.62 – 1.54 (m,1H), 1.52 – 1.38 (m, 3H), 1.30 (s, 3H), 1.25 (dd, J = 11.4, 6.6 Hz, 1H), 1.10– 1.00 (m, 1H), 0.95 (d, J = 6.4 Hz, 3H), 0.83 (d, J = 7.2 Hz, 3H).

[0152] 13 13C NMR (101 MHz, Acetone-d6) δ 173.70, 172.84, 138.53, 129.01,128.97, 127.28, 104.30, 97.94, 89.55, 81.68, 63.89, 53.69, 49.31, 41.87,37.35, 36.77, 35.79, 34.60, 32.85, 31.89, 31.61, 26.96, 24.91, 23.70, 20.34,12.53.

[0153] HRMS (ESI):m / zCalcd. For C 28 1H 39 NO8([M+Na] + ): 540.2568, found: 540.2577. Example 13

[0154] Preparation of artesunate chiral aminoolamide derivative 3am:

[0155]

[0156] Synthesis of artesunate and D-leucine: A clean and dry reaction tube was taken, and D-leucine (46.0 mg), (150 mol%) DMAP (47.7 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (74.8 mg, 0.39 mmol), and ultra-dry DMF (1 mL) were added sequentially under anhydrous and oxygen-free conditions. After stirring at 25 °C for five minutes, artesunate (100 mg) was added, and the reaction was allowed to proceed overnight. After the reaction was completed, 0.5 M hydrochloric acid solution was added to the reaction system to bring the pH to 6-7, and then ethyl acetate was added for dilution and extraction. The organic phase was retained and extracted three times with water. The organic phase was dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The product was then separated by silica gel column chromatography (eluent ratio of dichloromethane / methanol = 90 / 1, 80 / 1, 70 / 1, 60 / 1, 50 / 1) to obtain the target product with a yield of 58%.

[0157] 3am nuclear magnetic resonance hydrogen spectrum ( 1 H NMR, carbon spectrum ( 13 The C10 NMR and high-resolution mass spectrometry (HRMS) data are shown below:

[0158] (3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]d-ioxepino[4,3-i]isochromen-10-yl4-(((S)-1-hydroxy-4-methylpentan-2-yl)amino)-4-oxob-utanoate

[0159] 1H NMR (400 MHz, Acetone-d6) δ 6.71 (d, J = 8.4 Hz, 1H), 5.80 – 5.74(m, 1H), 5.34 (dd, J = 3.4, 2.4 Hz, 1H), 3.73 (dtt, J = 8.4, 7.3, 4.2 Hz,1H), 3.61 (t, J = 5.2 Hz, 1H), 3.57 – 3.43 (m, 2H), 2.65 – 2.54 (m, 2H), 2.51(ddd, J = 15.7, 10.3, 8.0 Hz, 1H), 2.44 – 2.34 (m, 1H), 2.29 – 2.17 (m, 3H), 2.11 – 2.01 (m, 1H), 1.92 – 1.82 (m, 1H), 1.76 – 1.36 (m, 8H), 1.19 (dddd, J= 12.1, 7.9, 6.9, 4.9 Hz, 1H), 1.07 (dtd, J = 12.3, 10.2, 7.3 Hz, 1H), 0.98 –0.91 (m, 3H), 0.93 – 0.88 (m, 9H).

[0160] 13 C NMR (101 MHz, Acetone-d6) δ 173.88, 172.84, 104.30, 97.94, 89.55,81.68, 65.54, 49.31, 48.79, 41.87, 36.77, 35.79, 34.88, 34.60, 32.85, 31.89,31.61, 26.96, 24.91, 24.83, 23.70, 22.31, 20.34, 12.53.

[0161] HRMS (ESI): m / zCalcd.For C 25 H 41 NO8([M+Na)) + ): 506.2728, found: 506.2724.

[0162] Experimental Example 1

[0163] The effects of different catalysts (Catalyst, abbreviated as Cat) on the reaction of this application were investigated:

[0164]

[0165] The results are shown in Table 2.

[0166] Table 2 Effect of different catalysts

[0167]

[0168] As shown in Table 2, different catalysts have different effects on the reaction. The highest yield was achieved when using the catalyst 4-dimethylaminopyridine described in this application.

[0169] Experiment Example 2

[0170] The effects of different reaction solvents on the reactions in this application were investigated.

[0171]

[0172] The results are shown in Table 3.

[0173] Table 3 Effect of different reaction solvents

[0174]

[0175] As shown in Table 3, not all reaction solvents can facilitate the reaction; different solvents have different effects on the reaction. The highest yield was achieved when N,N-dimethylformamide from this application was used.

[0176] Experimental Example 3

[0177] The effect of different reaction temperatures (T) on the reaction of this application was investigated:

[0178]

[0179] The results are shown in Table 4.

[0180] Table 4 Effect of different reaction temperatures

[0181]

[0182] As shown in Table 4, the reaction temperature range of 0~60℃ can be used to promote the reaction of this application and obtain artesunate chiral amino alcohol amide derivatives, especially the highest yield at 25℃.

[0183] Experiment Example 4

[0184] Investigating the effects of different material ratios and catalyst loading on the reaction of this application:

[0185]

[0186] The results are shown in Table 5.

[0187] Table 5. Effect of different material ratios on catalyst loading

[0188]

[0189] As shown in Table 5, the material ratio range (molar ratio of artesunate to L-phenylglycine of 1~1.5:1~1.5) and catalyst loading range (catalyst amount of 20~200 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 150 mol%.

[0190] 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 aminoolamide derivative of artesunate, characterized in that, The structure of the artesunate chiral amino alcohol amide derivative is shown in general formula I: 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-phenylalanine, L-threonine, L-valine, L-leucine, L-isoleucine, L-proline, D-phenylglycine, D-valine, D-phenylalanine, and D-leucine. The configurations of the chiral centers in Formula I are: 3R, 5aS, 6R, 8aS, 9R, 10S, 12R, 12aR.

2. The artesunate chiral amino alcohol amide derivative according to claim 1, characterized in that, The structure of the artesunate chiral amino alcohol amide derivative is selected from any one of Formulas II to XIV: 。 3. A method for preparing an artesunate chiral amino alcohol amide derivative as described in claim 1 or 2, characterized in that, Includes the following steps: Artesunate, chiral amino alcohol, catalyst, and solvent were mixed and reacted under anhydrous and oxygen-free conditions to obtain the artesunate chiral amino alcohol amide derivative.

4. The method for preparing an artesunate chiral amino alcohol amide 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 for protection.

5. The method for preparing an artesunate chiral amino alcohol amide 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 150 mol% of the molar amount of artesunate (equivalent to 1). 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 an artesunate chiral amino alcohol amide derivative according to claim 3, characterized in that, The chiral amino alcohol is selected from any one of L-phenylglycine, L-methionine, L-tryptophanine, L-phenylalanine, L-threonine, L-valine, L-leucine, L-isoleucine, L-proline, D-phenylglycine, D-valine, D-phenylalanine, and D-leucine.

7. The method for preparing an artesunate chiral amino alcohol amide derivative according to claim 3, characterized in that, The solvent is selected from any one of dichloromethane, chloroform, bromoethane, benzene, tetrahydrofuran, acetonitrile, anhydrous ethanol, N,N-dimethylformamide, ethyl acetate, and 1,4-dioxane; Preferably, the catalyst is selected from any one of 4-dimethylaminopyridine, triethylamine, imidazole, pyridine, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, potassium carbonate, and N,N-carbonyldiimidazole.

8. The method for preparing an artesunate chiral amino alcohol amide derivative according to claim 3, characterized in that, Prior to the reaction, a dehydrating agent is also added; The dehydrating agent includes 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; The molar ratio of the dehydrating agent to artesunate is 1:1.

5.

9. The method for preparing an artesunate chiral amino alcohol amide derivative according to claim 3, characterized in that, The reaction temperature is 0~60℃; Preferably, the reaction temperature is 25°C; Preferably, the reaction time is 12-24 hours.

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

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