Dihydroartemisinin water-soluble derivative and preparation method thereof

Abstract

The invention provides a dihydroartemisinin water-soluble derivative and a preparation method thereof, and belongs to the field of chemical synthesis. The stachyose is functional tetraoligosaccharide composed of two alpha-galactose, one alpha-glucose and one beta-fructosyl, has good stability, is very easy to dissolve in water, and is insoluble in organic solvents such as ethanol and the like; and the stachyose, as a functional oligosaccharide, has the effects of improving gastrointestinal health, protecting the liver, improving the immunity of the organism, delaying senescence, reducing blood fat and blood pressure, resisting tumors and the like, so that the stachyose can effectively stimulate the growth of bifidobacteria and other beneficial bacteria in intestinal tracts. Based on the fact, stachyose is selected to modify the structure of dihydroartemisinin, so that the water solubility, the stability and the bioavailability of dihydroartemisinin are remarkably improved on the basis of keeping the original activity, and absorption of intestinal tracts and preparation of oral medicines are facilitated.

Description

Technical Field

[0001] The invention relates to the field of chemical synthesis, and in particular to a water-soluble dihydroartemisinin derivative and a preparation method thereof. Background Art

[0002] Dihydroartemisinin is a derivative and active metabolite of artemisinin. Its antimalarial effect is several times that of artemisinin. In addition, it also has the effects of regulating immunity, anti-inflammatory, anti-schistosomiasis, antiviral, antibacterial, anti-fibrosis and anti-tumor. Dihydroartemisinin has a unique chemical structure of "peroxide bridge" and lactone ring. It is this structure that makes it occupy a place in this field of antimalarial drugs, but it also causes it to be easily decomposed by light and heat, has the characteristics of poor stability, is not easy to preserve, and makes it difficult to carry out industrial production, which greatly reduces its clinical application. In addition, dihydroartemisinin also has the characteristics of poor water solubility, rapid metabolism in the human blood circulation, and low bioavailability, which leads to patients increasing the time of using the drug. After taking the drug for a long time, they will develop a certain dependence on it. In order to avoid these shortcomings, it is necessary to improve its stability, water solubility and enhance its bioavailability. Summary of the invention

[0003] The purpose of the present invention is to provide a water-soluble derivative of dihydroartemisinin and a preparation method thereof. The water-soluble derivative of dihydroartemisinin of the present invention has excellent stability, water solubility and bioavailability.

[0004] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0005] The present invention provides a water-soluble dihydroartemisinin derivative having a structural formula shown in Formula I:

[0006]

[0007] The present invention also provides a method for preparing the water-soluble derivative of dihydroartemisinin described in the above technical solution, comprising the following steps:

[0008] Mixing stachyose, succinic anhydride, a polar organic solvent and a catalyst and performing an addition reaction to generate a compound having a structure shown in Formula II to obtain an addition reactant;

[0009]

[0010] The addition reactant is mixed with dihydroartemisinin to carry out an esterification reaction to obtain a water-soluble derivative of dihydroartemisinin.

[0011] Preferably, the molar ratio of stachyose to succinic anhydride is 1:1-4.

[0012] Preferably, the polar organic solvent includes one or more of dimethyl sulfoxide, ethyl acetate and acetone.

[0013] Preferably, the catalyst comprises 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine.

[0014] Preferably, the molar ratio of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to succinic anhydride is 1 to 2:1;

[0015] The molar ratio of the 4-dimethylaminopyridine to succinic anhydride is 1-2:1.

[0016] Preferably, the temperature of the addition reaction is 25-40° C. and the time is 12-24 hours.

[0017] Preferably, the molar ratio of dihydroartemisinin to stachyose is 1 to 4:1.

[0018] Preferably, the esterification reaction is carried out at a temperature of 25 to 40° C. and for a time of 12 to 24 hours.

[0019] Preferably, after the esterification reaction, the process further comprises:

[0020] The product obtained by the esterification reaction is mixed with a monohydric alcohol solvent for recrystallization to obtain a crude dihydroartemisinin water-soluble derivative;

[0021] The crude dihydroartemisinin water-soluble derivative is washed, dispersed in water, and then freeze-dried to obtain a pure dihydroartemisinin water-soluble derivative.

[0022] The present invention provides a water-soluble dihydroartemisinin derivative having a structural formula shown in Formula I:

[0023]

[0024] Stachyose is a functional oligotetrasaccharide composed of two α-galactoses, one α-glucose and one β-fructose group. It has good stability, is easily soluble in water, and is insoluble in organic solvents such as ethanol. As a functional oligosaccharide, stachyose has the effects of improving gastrointestinal health, protecting the liver, improving body immunity, delaying aging, lowering blood lipids and blood pressure, and anti-tumor, because it can effectively stimulate the growth of bifidobacteria and other beneficial bacteria in the intestine. The present invention selects stachyose to modify the structure of dihydroartemisinin, and on the basis of maintaining the original activity, the water solubility, stability and bioavailability of dihydroartemisinin are significantly improved, which is beneficial to intestinal absorption and the preparation of oral medicines.

[0025] The process of modifying dihydroartemisinin with stachyose has the advantages of simple operation, short preparation cycle, simple process, low cost, easy expansion and easy industrialization; and the equipment required for the process of the present invention is simple and inexpensive, and does not require a very high preparation cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 A process diagram of synthesizing a water-soluble derivative of dihydroartemisinin according to an embodiment of the present invention;

[0027] Figure 2 It is the infrared spectrum detection diagram of dihydroartemisinin, stachyose and water-soluble derivatives of dihydroartemisinin;

[0028] Figure 3 This is a nuclear magnetic resonance hydrogen spectrum detection diagram of dihydroartemisinin;

[0029] Figure 4 This is the nuclear magnetic resonance hydrogen spectrum detection diagram of stachyose;

[0030] Figure 5 This is a nuclear magnetic resonance hydrogen spectrum detection diagram of a water-soluble derivative of dihydroartemisinin;

[0031] Figure 6 X-ray detection images of dihydroartemisinin, physical mixture, stachyose and water-soluble derivatives of dihydroartemisinin;

[0032] Figure 7 The scanning electron micrographs of stachyose, dihydroartemisinin and water-soluble derivatives of dihydroartemisinin are shown;

[0033] Figure 8 The figure is the experimental result of saturated solubility of dihydroartemisinin and dihydroartemisinin water-soluble derivatives in deionized water, artificial gastric juice and artificial intestinal juice;

[0034] Fig. 9 The graph is the result of the stability experiment of dihydroartemisinin and dihydroartemisinin water-soluble derivatives at 4°C, 25°C and 37°C for 24 hours;

[0035] Fig.10 is the dissolution curve of dihydroartemisinin and its water-soluble derivatives in artificial gastric juice;

[0036] Fig.11 is the dissolution curve of dihydroartemisinin and its water-soluble derivatives in artificial intestinal fluid;

[0037] Fig.12 This is a blood concentration-time curve of dihydroartemisinin and its water-soluble derivatives. DETAILED DESCRIPTION

[0038] The present invention provides a water-soluble dihydroartemisinin derivative having a structural formula shown in Formula I:

[0039]

[0040] The present invention also provides a method for preparing the water-soluble derivative of dihydroartemisinin described in the above technical solution, comprising the following steps:

[0041] Mixing stachyose, succinic anhydride, a polar organic solvent and a catalyst and performing an addition reaction to generate a compound having a structure shown in Formula II to obtain an addition reactant;

[0042]

[0043] The addition reactant is mixed with dihydroartemisinin to carry out an esterification reaction to obtain a water-soluble derivative of dihydroartemisinin.

[0044] In the present invention, unless otherwise specified, the raw materials used are commercially available products well known in the art.

[0045] The invention mixes stachyose, succinic anhydride, a polar organic solvent and a catalyst, and then performs an addition reaction to generate a compound having a structure shown in Formula II, thereby obtaining an addition reactant.

[0046] In the present invention, the molar ratio of stachyose to succinic anhydride is preferably 1:1-4, more preferably 1:2-3.

[0047] In the present invention, the ratio of the amount of stachyose to the volume of the polar organic solvent is preferably 1 mol: 10-40 mL, more preferably 1 mol: 15-35 mL, further preferably 1 mol: 20-25 mL; the polar organic solvent preferably includes one or more of dimethyl sulfoxide, ethyl acetate and acetone.

[0048] In the present invention, the catalyst preferably includes 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine; the molar ratio of the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to succinic anhydride is preferably 1 to 2:1, more preferably 0.5 to 1.5:1; the molar ratio of the 4-dimethylaminopyridine to succinic anhydride is preferably 1 to 2:1, more preferably 0.5 to 1.5:1.

[0049] In the present invention, the temperature of the addition reaction is preferably 25 to 40° C., more preferably 30 to 35° C.; the time is preferably 12 to 24 h, more preferably 15 to 20 h, and further preferably 16 to 18 h.

[0050] After obtaining the addition reactant, the present invention mixes the addition reactant with dihydroartemisinin for esterification reaction to obtain a water-soluble derivative of dihydroartemisinin.

[0051] In the present invention, the molar ratio of dihydroartemisinin to stachyose is preferably 1 to 4:1, more preferably 2 to 3:1.

[0052] In the present invention, the temperature of the esterification reaction is preferably 25 to 40° C., more preferably 30 to 35° C.; the time is preferably 12 to 24 h, more preferably 15 to 20 h, and further preferably 16 to 18 h.

[0053] After the esterification reaction, the present invention preferably further comprises:

[0054] The product obtained by the esterification reaction is mixed with a monohydric alcohol solvent for recrystallization to obtain a crude dihydroartemisinin water-soluble derivative;

[0055] The crude dihydroartemisinin water-soluble derivative is washed, dispersed in water and then freeze-dried to obtain the dihydroartemisinin water-soluble derivative.

[0056] In the present invention, the monohydric alcohol solvent preferably includes ethanol. The washing detergent is preferably ethanol.

[0057] The present invention has no particular limitation on the number of washing times, as long as the unreacted raw materials are sufficiently removed.

[0058] The water-soluble derivatives of dihydroartemisinin and the preparation method thereof provided by the present invention are described in detail below in conjunction with the examples, but they should not be construed as limiting the scope of protection of the present invention.

[0059] The process diagram of the present invention for synthesizing the water-soluble derivatives of dihydroartemisinin is as follows: Figure 1 shown.

[0060] Example 1

[0061] Stachyose and succinic anhydride are added to dimethyl sulfoxide (the ratio of the amount of stachyose to the volume of dimethyl sulfoxide is 1 mol: 20 mL) in a molar ratio of 1:1, stirred until dissolved, and a catalyst is added to the resulting solution (the catalyst is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine, and the molar ratio of the catalyst to succinic anhydride is 1:1), and the reaction is carried out at 40°C for 24 hours; then dihydroartemisinin is added to the resulting reaction system (the molar ratio of dihydroartemisinin to stachyose is 1:1) and an esterification reaction is carried out at 40°C for 24 hours; after the esterification reaction is completed, ethanol is added to the reaction system, and the synthetic product is separated by anti-solvent recrystallization. The product is washed with ethanol several times and then dispersed in water. After freeze-drying, a water-soluble derivative of dihydroartemisinin is obtained.

[0062] Infrared spectroscopy was performed on dihydroartemisinin (a), stachyose (b) and water-soluble (c) derivatives of dihydroartemisinin. The results are as follows: Figure 2 shown.

[0063] Depend on Figure 2 It can be seen that the water-soluble derivative of dihydroartemisinin has a peak at 1730 cm-1 in the infrared spectrum. -1 and 1150cm -1 There are stretching vibration peaks of C=O bond and CO bond in the ester bond, indicating that ester bonds are formed in the synthetic compound, proving the successful synthesis of the derivative.

[0064] The results of nuclear magnetic resonance hydrogen spectrum detection of dihydroartemisinin, stachyose and dihydroartemisinin water-soluble derivatives are as follows Figures 3 to 5 shown.

[0065] Depend on Figures 3 to 5 It can be seen that the nuclear resonance magnetic hydrogen spectrum of the water-soluble derivative of dihydroartemisinin contains characteristic peaks of dihydroartemisinin and stachyose, which further illustrates the successful synthesis of the derivative.

[0066] X-ray detection was performed on dihydroartemisinin (a), physical mixture (b), stachyose (c) and dihydroartemisinin water-soluble derivative (d). The results are as follows Figure 6 The physical combination is: a physical mixture of dihydroartemisinin and stachyose.

[0067] Depend on Figure 6 It can be seen that the connection between dihydroartemisinin and stachyose causes dihydroartemisinin to transform from a crystalline form to an amorphous form, that is, the water-soluble derivative of dihydroartemisinin is in an amorphous form.

[0068] The results of scanning electron microscopy analysis of stachyose, dihydroartemisinin and dihydroartemisinin water-soluble derivatives are as follows: Figure 7 shown. Figure 7 a in the middle is the SEM image of stachyose at a resolution of 10 μm; Figure 7 b is the SEM image of stachyose at a resolution of 1 μm; Figure 7 Middle c is the SEM image of dihydroartemisinin at a resolution of 10 μm; Figure 7 Middle d is the SEM image of dihydroartemisinin at a resolution of 1 μm; Figure 7 Middle e is the SEM image of the water-soluble derivative of dihydroartemisinin at a resolution of 10 μm; Figure 7 Image f in the middle is the SEM image of the water-soluble derivative of dihydroartemisinin at a resolution of 1 μm.

[0069] Depend on Figure 7It can be seen that stachyose is spherical with a cavity and a rough surface, dihydroartemisinin is needle-shaped, and the water-soluble derivative of dihydroartemisinin is a flake with textures. This further shows that chemical synthesis has changed the morphology of dihydroartemisinin.

[0070] Saturation solubility experiment

[0071] (1) Preparation of artificial gastric juice (pH = 1.2)

[0072] Prepare according to the method of "Chinese Pharmacopoeia": weigh 10g of pepsin and add it to a 1L volumetric flask, then use a pipette to absorb 3.84mL of 36% hydrochloric acid, add 800mL of water, shake well, and add water to make up to 1L.

[0073] (2) Preparation of artificial intestinal fluid (pH = 6.8)

[0074] Prepare according to the method of "Chinese Pharmacopoeia": weigh 6.8g of potassium dihydrogen phosphate, add 300mL of water to dissolve, and adjust the pH value to 6.8 with 0.1mol / L sodium hydroxide solution; weigh 10g of pancreatic enzyme, add 500mL of water to dissolve, mix the two liquids and add to a 1L volumetric flask, shake well, and dilute to 1L with water.

[0075] Excessive amounts of dihydroartemisinin original drug (denoted as DHA) and dihydroartemisinin water-soluble derivatives (denoted as sDHA) were weighed, dissolved in 5 mL of water, artificial gastric juice and artificial intestinal juice, placed in a constant temperature water bath, magnetically stirred at 37 ° C for 24 h, and then centrifuged at 10000 r / min for 10 min to take the supernatant, and 10 μL of the sample was taken for HPLC detection. The test was repeated three times, and the average value was taken as the final result of the test. The saturated solubility test results of dihydroartemisinin and dihydroartemisinin water-soluble derivatives in deionized water, artificial gastric juice and artificial intestinal juice are shown in Figure 2. Figure 8 shown.

[0076] Depend on Figure 8 It can be seen that dihydroartemisinin original drug is a compound that is poorly soluble in water. Its saturated solubility in deionized water, artificial gastric juice and artificial intestinal juice is approximately 0.085±0.012mg / mL, 0.64±0.042mg / mL and 0.16±0.023mg / mL, respectively. These data show that the solubility of dihydroartemisinin original drug in different media is significantly different, with the highest solubility in artificial gastric juice and the lowest solubility in deionized water. This difference may be related to factors such as the pH value and ionic strength of the medium.

[0077] In contrast, the solubility of water-soluble derivatives of dihydroartemisinin in these same solvents is significantly higher than that of the original dihydroartemisinin. The saturated solubility of water-soluble derivatives of dihydroartemisinin in deionized water, artificial gastric fluid, and artificial intestinal fluid is approximately 4.68±0.36mg / mL, 13.74±1.07mg / mL, and 10.62±0.78mg / mL, respectively, which is approximately 55 times, 86 times, and 66 times that of the original dihydroartemisinin. This result shows that the water-soluble derivatives of dihydroartemisinin have significantly improved water solubility compared to the original dihydroartemisinin.

[0078] Stability test

[0079] Take 6 portions of 200mL deionized water (n=3, i.e., 3 parallel experiments), add 10mg of dihydroartemisinin original drug and dihydroartemisinin water-soluble derivatives (containing 10mg dihydroartemisinin) to each portion of deionized water, and place them in a 37℃ water bath, a 4℃ refrigerator, and a 25℃ environment, respectively. The speed of the water bath is adjusted to 100rpm / min. Sampling was performed at fixed time points (5min, 10min, 15min, 30min, 1h, 1.5h, 2h, 4h, 6h, 8h, 12h, 24h, 48h, and 72h), 1mL each time, and then 1mL of deionized water was added to the cup. The sample solution was filtered with an organic filter membrane, and 10μL was taken for HPLC detection. Repeat three times, and the average value was taken as the final result of the test. The stability test results of dihydroartemisinin and dihydroartemisinin water-soluble derivatives at 4℃, 25℃, and 37℃ for 24h are as follows Fig. 9 shown.

[0080] Depend on Fig. 9 It can be seen that under 4°C conditions, dihydroartemisinin and its water-soluble derivatives are relatively stable within 72 hours, and the decomposition rate of dihydroartemisinin and its water-soluble derivatives in the solution does not exceed 2%; at room temperature 25°C, the degradation rate of dihydroartemisinin water-soluble derivatives is about 13% within 72 hours, and the degradation rate of the original drug dihydroartemisinin is about 25%; at 37°C conditions, the degradation rate of dihydroartemisinin water-soluble derivatives is about 16% within 72 hours, and the degradation rate of dihydroartemisinin original drug is about 27%; the decomposition rate of dihydroartemisinin water-soluble derivatives and dihydroartemisinin is positively correlated with temperature. As the temperature increases, the decomposition rate of dihydroartemisinin water-soluble derivatives and dihydroartemisinin increases.

[0081] Release rate experiment

[0082] Take 4 portions of the above 200mL artificial gastric juice and artificial intestinal juice and put them into beakers respectively, accurately weigh 10mg of dihydroartemisinin and water-soluble derivative of dihydroartemisinin (containing 10mg of dihydroartemisinin) and dissolve them in 10mL of deionized water, and then pour them into dialysis bags with a molecular weight of 1000 (after boiling in deionized water for 30min), and then put the dialysis bags into artificial gastric juice and artificial intestinal juice respectively. Put all 8 beakers into a constant temperature water bath at 37°C, with a speed of 50rpm / min, and take out 1mL of dissolution solution at 12 time points (5min, 10min, 15min, 30min, 1h, 1.5h, 2h, 4h, 6h, 8h, 12h and 24h), and add 1mL of blank artificial intestinal juice or artificial gastric juice to each system at each point. The sample was filtered through a filter membrane and the content of dihydroartemisinin was detected by HPLC. Three parallel experiments were performed and the average value of the test results was taken. Figures 10-11 As shown. Among them, Fig.10 is the dissolution curve of dihydroartemisinin and its water-soluble derivatives in artificial gastric juice; Fig.11 The dissolution curves of dihydroartemisinin and dihydroartemisinin water-soluble derivatives in artificial intestinal fluid are shown in Figure 1. The cumulative release percentage (%) is given by the following formula:

[0083]

[0084] Where D is the cumulative release percentage (%), C n represents the concentration of dihydroartemisinin in the sample obtained at the nth time point, V n represents the sample volume (mL) obtained at the nth time point, and M represents the total dosage of dihydroartemisinin.

[0085] Depend on Figures 10-11 It can be seen that the cumulative release of dihydroartemisinin in artificial gastric juice is 52.12%, while that of dihydroartemisinin water-soluble derivatives is 33.75%. This shows that the release rate of dihydroartemisinin water-soluble derivatives is slower, which may be due to the fact that dihydroartemisinin is wrapped in the inner core by micelles. This structure may not be easy to decompose in gastric juice, thus slowing down the release rate of dihydroartemisinin. In artificial intestinal fluid, the cumulative release of dihydroartemisinin reached 71.24%, while that of dihydroartemisinin water-soluble derivatives was 35.72%. This further proves the sustained-release characteristics of dihydroartemisinin water-soluble derivatives, and shows that in the intestinal fluid environment, the release rate of dihydroartemisinin is faster than that of dihydroartemisinin water-soluble derivatives.

[0086] Absorption test

[0087] 1. Experimental Animals

[0088] Sprague-Dawley (SD) rats, male, 180-200g, 6-8 weeks old, were provided by the Experimental Animal Center of the Second Affiliated Hospital of Harbin Medical University. All animals were raised in a specific sterile environment. The animal was kept at a temperature of (20±2)℃, a humidity of 50%-60%, and a light and dark cycle of 12h each day for 1 week. All animal experiments were conducted in strict accordance with the "Regulations on the Administration of Experimental Animals in Heilongjiang Province".

[0089] 2. Preparation of relevant solutions

[0090] (1) 10 mg / mL heparin sodium: Weigh 0.1 g of heparin sodium and dissolve it in 10 mL of normal saline. Dissolve it by ultrasonication. Heparin sodium can prevent blood from coagulating rapidly and facilitates the separation and collection of plasma.

[0091] (2) Place 0.1 mL of the prepared 10 mg / mL heparin sodium aqueous solution into several 1.5 mL centrifuge tubes for sampling.

[0092] (3) Preparation of drugs: Dissolve dihydroartemisinin and a water-soluble derivative of dihydroartemisinin in physiological saline to obtain a dihydroartemisinin solution and a water-soluble derivative of dihydroartemisinin solution, respectively.

[0093] 3. Test steps

[0094] Six male rats with an average weight of 180-200 g were selected and fasted for one night before the experiment, with free access to water. The six rats were randomly divided into two groups (n=3), and the dihydroartemisinin solution and the dihydroartemisinin water-soluble derivative solution were gavaged at a dose of 50 mg / kg (calculated according to the original drug) to the rats. Blood (600-800 μL) was collected from the eyes of the rats (after being stunned with ether) at 13 time points after administration (5min, 10min, 15min, 30min, 1h, 1.5h, 2h, 4h, 6h, 8h, 12h, 24h and 48h). After the blood sample was centrifuged at 3000×g for 10min, the supernatant (plasma) was transferred to a new 1.5mL centrifuge tube and stored at -20°C for later use.

[0095] Sample processing: 200 μL of plasma sample was precisely pipetted for each sample, 1 mL of methanol was added, vortexed for 5 min (to remove protein), and ultrasonicated for 30 min. The sample was blown dry with nitrogen, and 100 μL of methanol was added to re-dissolve the residue, and vortexed again for 3 min, and ultrasonicated for 10 min. The sample was centrifuged at 10000 r / min for 10 min, and the supernatant was taken. The content of dihydroartemisinin was detected by HPLC. The blood drug concentration-time curve is shown in Fig.12 shown.

[0096] Depend on Fig.12It can be seen that after oral administration, dihydroartemisinin and dihydroartemisinin water-soluble derivatives enter the digestive tract and enter the blood after being absorbed in the small intestine. max (1.24 mg / L) and AUC (0-t) (9.73 mg / L·h) are both greater than the C max (0.68mg / L) and AUC (0-t) (4.28 mg / L·h), indicating that the water-soluble derivatives of dihydroartemisinin significantly improved the absorption of the original drug dihydroartemisinin in rats.

[0097] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A water-soluble derivative of dihydroartemisinin, characterized in that: It has the structural formula shown in Formula I:

2. The method for preparing the water-soluble derivative of dihydroartemisinin according to claim 1, characterized in that: The following steps are involved: Mixing stachyose, succinic anhydride, a polar organic solvent and a catalyst and performing an addition reaction to generate a compound having a structure shown in Formula II to obtain an addition reactant; The addition reactant is mixed with dihydroartemisinin to carry out an esterification reaction to obtain a water-soluble derivative of dihydroartemisinin.

3. The preparation method according to claim 2, characterized in that: The molar ratio of stachyose to succinic anhydride is 1:1-4.

4. The preparation method according to claim 2, characterized in that: The polar organic solvent includes one or more of dimethyl sulfoxide, ethyl acetate and acetone.

5. The preparation method according to claim 2, characterized in that: The catalyst includes 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine.

6. The preparation method according to claim 5, characterized in that: The molar ratio of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to succinic anhydride is 1 to 2:1; The molar ratio of the 4-dimethylaminopyridine to succinic anhydride is 1-2:

1.

7. The preparation method according to claim 2, characterized in that: The temperature of the addition reaction is 25-40° C. and the time is 12-24 hours.

8. The preparation method according to claim 2, characterized in that: The molar ratio of dihydroartemisinin to stachyose is 1 to 4:

1.

9. The preparation method according to claim 2, characterized in that: The temperature of the esterification reaction is 25-40° C. and the time is 12-24 hours.

10. The preparation method according to claim 2, characterized in that: After the esterification reaction, the method further comprises: The product obtained by the esterification reaction is mixed with a monohydric alcohol solvent for recrystallization to obtain a crude dihydroartemisinin water-soluble derivative; The crude dihydroartemisinin water-soluble derivative is washed, dispersed in water, and then freeze-dried to obtain a pure dihydroartemisinin water-soluble derivative.

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