Preparation method of beta-artemether

Abstract

The invention discloses a preparation method of beta-artemether, which comprises the following steps: (1) cooling methanol, adding acyl chloride, and stirring at a controlled temperature to obtain a reaction solution; (2) adding trimethyl orthoacetate and dihydroartemisinin into the reaction solution, and stirring at a controlled temperature to obtain an artemisinin suspension; (3) adding water into the artemisinin suspension and stirring at a controlled temperature to obtain a crude artemether solution; and (4) filtering and drying the artemether crude product solution to obtain a dry product. The method disclosed by the invention is high in yield, high in purity, low in cost and capable of improving industrial production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry or organic chemistry, and a method for preparing beta-artemether using dihydroartemisinin as a raw material. Background Art

[0002] Malaria, an infectious disease caused by Plasmodium infection, has long had a significant impact on global health. Malaria is mainly transmitted through the bites of female Anopheles mosquitoes infected with Plasmodium. It is widely prevalent in tropical and subtropical regions such as Asia, Africa and Latin America. Its main symptoms include periodic fever, severe chills, headache and vomiting, and in severe cases it may even lead to anemia, jaundice, cerebral malaria, and even death. Malaria not only seriously threatens personal health, but also has a significant impact on economic development due to its high cost of treatment and prevention.

[0003] The discovery and application of β-artemisinin has become an important milestone in the search for an effective treatment for malaria. β-artemisinin, as a type of artemisinin drug, produces free radicals in the body through its unique peroxide bridge structure, effectively destroying the internal structure of malarial parasites, thereby effectively killing these parasites. Compared with other artemisinin derivatives, β-artemisinin has significant advantages in pharmacological properties. Its longer half-life and better bioavailability mean that it can maintain effective concentrations in the body for a longer time, reducing the frequency of dosing, thereby improving patient compliance and convenience of treatment.

[0004] Patent CN104557965A provides a process for preparing artemether from artemisinin. This process uses ethanol as a solvent, adds dihydroartemisinin, cools down and adds trimethyl acetate and methanesulfonic acid, and needs to adjust the pH value to about 0.5. It has high requirements for operation and needs to measure the pH value continuously. After the addition, the temperature needs to be raised and the reaction time takes three hours. The yield of the obtained product is about 96% and the purity is about 99.3%. However, the process provided by us only needs to add a specified amount of thionyl chloride (or other acyl chloride), which is easy to operate, does not require heating during the process, and has a fast reaction time (within 1 hour). The yield of the obtained product is about 95%, and the purity can reach more than 99.8%, which is convenient for industrial production. Summary of the invention

[0005] The purpose of the present invention is to provide a method for preparing β-artemether, which effectively improves the yield and quality through an etherification method and also simplifies the operation.

[0006] In order to achieve the above objectives, the present invention adopts the following technical solutions:

[0007] A method for preparing β-artemether by using dihydroartemisinin as a raw material and an etherification method comprises the following steps:

[0008] Step (1) Add methanol to a reaction vessel, start stirring and cool to 0-10°C, then slowly drop acyl chloride, stir for 15 minutes after the dropwise addition is complete, and control the temperature at 0-10°C.

[0009] Step (2) adding trimethyl orthoacetate and dihydroartemisinin to the solution of step (1), stirring for 1 hour, and controlling the temperature at 0-10°C.

[0010] Step (3) slowly drop water into the solution of step (2), stir for 1 hour after the dropwise addition is complete, and control the temperature at 0-10°C.

[0011] Step (4) Filter the solution of step (3) to obtain a crude wet product of β-artemisinin, and dry it to obtain a dry product with a molar yield of 90-95%, a purity of not less than 99.5%, and a single impurity of less than 0.3%.

[0012] To further elaborate, the range of cooling and temperature control can also be 0~20℃.

[0013] To further illustrate, in step (1), the volume-to-mass ratio of the methanol is 5-8 V / W.

[0014] To further explain, in step (1), the stirring time may also be in the range of 10 to 20 minutes.

[0015] To further illustrate, in step (1), the acyl chloride is selected from thionyl chloride, oxalyl chloride or propionyl chloride, and has a molar mass of 0.017-0.17 mol.

[0016] To further illustrate, in step (2), the volume-to-mass ratio of trimethyl orthoacetate is 1-1.5 V / W.

[0017] To further illustrate, in step (2), the molar mass of the dihydroartemisinin is 0.35 mol.

[0018] To further illustrate, in step (3), the volume-to-mass ratio of water is 6-12 V / W.

[0019] To further illustrate, in step (4), the drying is vacuum drying at 45-50°C.

[0020] Experiments have shown that the preparation method of the present invention increases the product conversion rate from 60-70% of the existing process to 90-95%, and the overall conversion rate is increased by 30%. The product quality is increased from more than 98% of the existing process to and stabilized at more than 99.5%. At the same time, the generation ratio of α-artemisinin is reduced, thereby reducing production costs. DETAILED DESCRIPTION

[0021] The specific embodiments of the present invention are explained by the following experiments.

[0022] The technical or scientific terms mentioned in the present invention have the meanings commonly understood by those skilled in the art.

[0023] In order to enable those skilled in the art to fully understand the technical information disclosed in this aspect, the embodiments will be presented in categories below with accompanying explanations.

[0024] Example 1

[0025] Add 500 ml of methanol to a 1000 ml four-necked flask, start stirring, cool to 0-10°C, slowly drop 2 g of thionyl chloride (0.017 mol), control the temperature at 0-10°C, stir for 15 minutes, add 100 ml of trimethyl orthoacetate (0.95 W / W) and 100 g of dihydroartemisinin, stir at 0-10°C for 1 hour, central control sampling point plate (ethyl acetate: n-hexane = 1:4, iodine fumigation color development), after the central control is qualified, transfer the feed liquid to a 2000 ml four-necked bottle, control the temperature at 0-10°C, slowly drop 1200 ml of drinking water, complete the addition, stir at 0-10°C for 1 hour; filter to obtain a crude wet product of artemether, vacuum dry, dry at 45-50°C, and obtain 94.5-99.8 g of a dry product with a yield of 90-95%, a purity of about 99.8%, and a single impurity of less than 0.2%.

[0026] Comparative Example 1

[0027] Add 100 ml of methanol and 400 ml of dichloromethane to a 1000 ml four-necked flask, add 100 g (0.352 mol) of dihydroartemisinin, stir for 5-15 minutes, slowly pour in 2 g (0.02 mol) of perchloric acid, after the addition is complete, heat to 30-35 °C, stir at 30-35 °C for 3 hours, and control the sampling point plate (ethyl acetate: n-hexane = 1:4, iodine fumigation for color development). After the control is qualified, slowly add 12 g of sodium bicarbonate to the reaction bottle and adjust the pH value to 7-8; transfer the feed solution to a 1000 ml single-necked bottle and control the temperature at 40-5 0℃, vacuum above 0.07MPa, desolventize until almost no liquid flows out, then stop desolventizing; add 600ml of methanol to the single-necked bottle to dissolve the feed liquid, transfer the feed liquid into a 2000ml four-necked bottle, heat to 40-50℃, stir for 5-15 minutes, cool to 30-35℃, control the temperature at 30-35℃, add 1200ml of drinking water dropwise, and after the addition is complete, cool to 0-5℃, and stir for 1h; filter to obtain a crude wet product of artemether, dry to obtain 63.0-73.5g of a dry product, with a yield of 60-70%, a purity of about 99.0%, and a single impurity of less than 0.5%.

[0028] Comparative Example 2

[0029] Add 500 ml of methanol into a 1000 ml four-necked flask, start stirring, cool to 20-30 °C, slowly add 2 g of thionyl chloride, control the temperature at 20-30 °C, stir for 15 minutes, add 100 ml of trimethyl orthoacetate and 100 g of dihydroartemisinin, stir at 20-30 °C for 1 hour, central control sampling point plate (ethyl acetate: n-hexane = 1:4, iodine fumigation color), after the central control is qualified, transfer the feed liquid into a 2000 ml four-necked bottle, control the temperature at 0-10 °C, slowly add 1200 ml of drinking water, complete the addition, stir at 0-10 °C for 1 hour, filter, and obtain a crude wet product of artemether, dry it, and obtain 92.8 g of a dry product with a yield of 88.4%, a purity of about 99.4%, and a single impurity of less than 0.2%.

[0030] Comparative Example 3

[0031] Add 500 ml of methanol to a 1000 ml four-necked flask, start stirring, cool to 0-10°C, slowly add 20 g of thionyl chloride, control the temperature at 0-10°C, stir for 15 minutes, add 100 ml of trimethyl orthoacetate and 100 g of dihydroartemisinin, stir at 20-30°C for 1 hour, and use the central control sampling point plate (ethyl acetate: n-hexane = 1:4, iodine fumigation for color development). After the central control is qualified, transfer the feed liquid to a 2000 ml four-necked bottle, add 0.3 g of sodium bicarbonate, and adjust the pH value to 7-8; then control the temperature at 0-10°C, slowly add 1200 ml of drinking water, complete the addition, stir at 0-10°C for 1 hour, filter, and obtain a crude wet product of artemether. Dry to obtain 93.8 g of a dry product with a yield of 89.3%, a purity of about 99.2%, and a single impurity of less than 0.3%.

[0032] Comparative Example 4

[0033] Add 100 ml of methanol and 400 ml of dichloromethane to a 1000 ml four-necked flask, add 100 g of dihydroartemisinin, stir for 5-15 minutes, slowly pour in 200 g of sulfuric acid, raise the temperature to 30-35 °C after the addition is complete, stir at 30-35 °C for 3 hours, and use the central control sampling point plate (ethyl acetate: n-hexane = 1:4, iodine fumigation for color development). After the central control is qualified, slowly add 120 g of sodium bicarbonate to the reaction bottle and adjust the pH value to 7-8; transfer the feed liquid to a 1000 ml single-necked bottle, control the temperature to 40-50 °C, vacuum above 0.07 MPa, reduce the pressure to desolventize until there is basically no liquid outflow, and stop desolventizing. Add 600 ml of methanol to the single-necked bottle to dissolve the feed liquid, transfer the feed liquid to a 2000 ml four-necked bottle, heat to 40-50 ° C, stir for 5-15 minutes, cool to 30-35 ° C, control the temperature at 30-35 ° C, add 1200 ml of drinking water, cool to 0-5 ° C after the addition is complete, stir for 1 hour, filter to obtain the crude wet product of artemether, dry to obtain 59.6 g of dry product, with a yield of 56.8%, a purity of 97.1%, and a single impurity of less than 1.0%.

[0034] Comparative Example 5

[0035] Add 500 ml of methanol into a 1000 ml four-necked flask, start stirring, cool to 0-10°C, slowly add 2 g of oxalyl chloride, control the temperature at 0-10°C, stir for 15 minutes, add 100 ml of trimethyl orthoacetate and 100 g of dihydroartemisinin, stir at 0-10°C for 1 hour, and use the central control sampling point plate (ethyl acetate: n-hexane = 1:4, iodine fumigation for color development). After the central control is qualified, transfer the feed liquid into a 2000 ml four-necked bottle, control the temperature at 0-10°C, slowly add 1200 ml of drinking water, complete the addition, stir at 0-10°C for 1 hour, filter, and obtain a crude wet product of artemether. Dry to obtain 94.8 g of a dry product with a yield of 93.1%, a purity of about 99.4%, and a single impurity of less than 0.3%.

[0036] It can be seen from the above examples that the new process of the present invention adopted in Example 1 has obvious improvements in yield and quality, and the operation is also simplified.

[0037] Etherification Reagent Example 1

[0038] Add 500 ml of methanol to a 1000 ml four-necked flask, start stirring, cool to 0~10℃, slowly add 2 g of thionyl chloride (0.017 mol), control the temperature at 0~10℃, stir for 15 minutes, add 100 ml of trimethyl orthoacetate (0.5~1.5 W / W) and 100 g of dihydroartemisinin, stir at 0~10℃ for 1 hour, central control sampling point plate (ethyl acetate: n-hexane = 1:4, iodine fumigation color), after the central control is qualified, transfer the feed liquid to a 2000 ml four-necked bottle, control the temperature at 0~10℃, slowly add 1200 ml of drinking water, complete the addition, stir at 0~10℃ for 1 hour, filter, obtain crude wet product of artemether, vacuum dry, dry at 45~50℃, obtain 94.5~99.8 g of dry product, yield 90~95%, purity about 99.8%, single impurity less than 0.2%.

[0039] Etherification reagent comparative example 1

[0040] Add 500ml of methanol to a 1000ml four-necked flask, start stirring, cool to 0~10℃, slowly add 2g of acetyl chloride (0.025mol), control the temperature at 0~10℃, stir for 15 minutes, add 100ml of trimethyl orthoacetate (1V / W) and 100g of dihydroartemisinin (0.352mol), stir at 20~30℃ for 1 hour, central control sampling point plate (ethyl acetate: n-hexane = 1:4, iodine fumigation color), after the central control is qualified, transfer the feed liquid to a 2000ml four-necked bottle, add 0.3g of sodium bicarbonate, and adjust the pH value to 7~8; then control the temperature at 0~10℃, slowly add 1200ml of drinking water, complete the addition, stir at 0~10℃ for 1 hour, filter, and obtain a crude wet product of artemether, dry it, and obtain 96.8g of dry product, with a yield of 92.2%, a purity of about 99.6%, and a single impurity of less than 0.2%.

[0041] Etherification reagent comparative example 2

[0042] Add 500ml of methanol to a 1000ml four-necked flask, start stirring, cool to -10~0℃, slowly add 10g of hydrochloric acid (0.082mol), control the temperature at -10~0℃, stir for 15 minutes, add 100ml of trimethyl orthoacetate (0.9W / W) and 100g of dihydroartemisinin (0.352mol), stir at -10~0℃ for 1 hour, central control sampling point plate (ethyl acetate: n-hexane = 1:4, iodine fumigation color), after the central control is qualified, transfer the feed liquid to a 2000ml four-necked bottle, control the temperature at -10~0℃, slowly add 1200ml of drinking water, complete the addition, stir at -10~0℃ for 1 hour, filter, and obtain a crude wet product of artemether, vacuum dry, and dry at 45~50℃ to obtain 93.9g of dry product, with a yield of 89.4%, a purity of about 99.1%, and a single impurity of less than 0.3%.

[0043] Etherification reagent comparative example 3

[0044] Add 500 ml of methanol to a 1000 ml four-necked flask, start stirring, cool to 0-10°C, slowly add 5 g of propionyl chloride, control the temperature at 0-10°C, stir for 15 minutes, add 100 ml of trimethyl orthoacetate and 100 g of dihydroartemisinin, stir at 0-10°C for 1 hour, and use the central control sampling point plate (ethyl acetate: n-hexane = 1:4, iodine fumigation for color development). After the central control is qualified, transfer the feed liquid to a 2000 ml four-necked bottle, control the temperature at 0-10°C, slowly add 1200 ml of drinking water, complete the addition, stir at 0-10°C for 1 hour, filter, and obtain a crude wet product of artemether. Dry to obtain 95.1 g of a dry product with a yield of 90.6%, a purity of about 99.1%, and a single impurity of less than 0.3%.

[0045] Etherification reagent comparative example 4

[0046] Add 500 ml of methanol to a 1000 ml four-necked flask, start stirring, cool to 0-10°C, slowly add 3 g of trifluoroacetic acid (0.026), control the temperature at 0-10°C, stir for 15 minutes, add 100 ml of trimethyl orthoacetate (1 V / W) and 100 g of dihydroartemisinin (0.352 mol), stir at 0-10°C for 1 hour, central control sampling point plate (ethyl acetate: n-hexane = 1:4, iodine fumigation color development), central control failed (residue of about 50%), delay time did not change, transfer the feed liquid to a 2000 ml four-necked bottle, control the temperature at 0-10°C, slowly add 1200 ml of drinking water, complete the addition, stir at 0-10°C for 1 hour, filter, and obtain a crude wet product of artemether, dry it, and obtain 93.1 g of a dry product with a yield of 88.6%, a purity of about 69.1%, and 30.1% of the raw material residue.

[0047] Etherification reagent comparative example 5

[0048] Add 500 ml of methanol into a 1000 ml four-necked flask, start stirring, cool to 0-10°C, slowly add 3 g of concentrated sulfuric acid (0.032), control the temperature at 0-10°C, stir for 15 minutes, add 100 ml of trimethyl orthoacetate (1 V / W) and 100 g of dihydroartemisinin (0.352 mol), stir at 0-10°C for 1 hour, control the sampling point plate (ethyl acetate: n-hexane = 1:4, iodine fumigation for color development), the central control is qualified, transfer the feed liquid into a 2000 ml four-necked bottle, control the temperature at 0-10°C, slowly add 1200 ml of drinking water, control the addition, stir at 0-10°C for 1 hour, filter, and obtain a crude wet product of artemether, dry it, and obtain 83.6 g of a dry product with a yield of 79.6%, a purity of about 95.8%, and a single impurity of 2.1%.

[0049] From the above examples, it can be seen that the reaction effects of thionyl chloride, hydrochloric acid, acetyl chloride and propionyl chloride are better, while sulfuric acid causes more degradation, and the reaction conversion rate of trifluoroacetic acid is lower. From the perspective of reducing costs, thionyl chloride is finally used as the etherification reagent.

[0050] Temperature Example 1

[0051] Add 500ml of methanol to a 1000ml four-necked flask, start stirring, cool to 0~10℃, slowly drop 2g of thionyl chloride (0.017mol), control the temperature at 0~10℃ (0~20℃), after the addition is complete, stir for 15 minutes (10~20 minutes), add 100ml of trimethyl orthoacetate (0.5~1.5W / W) and 100g of dihydroartemisinin, stir at 0~10℃ for 1 hour, and control the sampling point plate (ethyl acetate: n-hexane = 1:4, iodine fumigation for color development). After the central control is qualified, transfer the feed liquid into a 2000ml four-necked bottle, control the temperature at 0~10℃, slowly add 1200ml of drinking water, and after the addition is completed, stir at 0~10℃ for 1 hour, filter, and obtain the crude wet product of artemether. Dry it in vacuum and dry it at 45~50℃ to obtain 94.5~99.8g of dry product, with a yield of 90~95%, a purity of about 99.8%, and a single impurity of less than 0.2%.

[0052] Temperature Comparison Example 1

[0053] Add 500ml of methanol to a 1000ml four-necked flask, start stirring, cool to -10~0℃, slowly drop 2g of thionyl chloride (0.017mol), control the temperature at -10~0℃, after the addition is complete, stir for 15 minutes (10~20 minutes), add 100ml of trimethyl orthoacetate (0.9W / W) and 100g of dihydroartemisinin (0.352mol), stir at -10~0℃ for 1 hour, and take Sample plate (ethyl acetate: n-hexane = 1:4, iodine fumigation for color development), after the central control is qualified, the feed liquid is transferred to a 2000ml four-necked bottle, the temperature is controlled at -10~0℃, 1200ml of drinking water is slowly added, after the addition is completed, stir at -10~0℃ for 1 hour, filter, and obtain the crude wet product of artemether, vacuum dry, and dry at 45~50℃ to obtain 92.9g of dry product, with a yield of 88.5%, a purity of about 99.5%, and a single impurity of less than 0.2%.

[0054] Temperature Comparison Example 2

[0055] Add 500ml of methanol to a 1000ml four-necked flask, start stirring, control the temperature at 30~40℃, slowly drop 20g of thionyl chloride, control the temperature at 30~40℃, stir for 15 minutes, add 100ml of trimethyl orthoacetate and 100g of dihydroartemisinin, stir at 30~40℃ for 1 hour, central control sampling point plate (ethyl acetate: n-hexane = 1:4, iodine fumigation color), after the central control is qualified, transfer the feed liquid to a 2000ml four-necked bottle, add 0.3g of sodium bicarbonate, and adjust the pH value to 7~8. Then control the temperature at 30~40℃, slowly drop 1200ml of drinking water, complete the dropwise addition, cool to 0~10℃ and stir for 1 hour, filter, obtain the crude wet product of artemether, dry it, and obtain 83.8g of dry product, with a yield of 79.2%, a purity of about 98.2%, and a single impurity of less than 0.5%.

[0056] From the above examples, it can be seen that when the reaction is carried out in the temperature range of -10~0°C and 30~40°C, the yield and quality of the process are poor, so the yield and quality of the temperature range of 0~10°C adopted in the present invention are better.

[0057] Sulfonyl chloride equivalent Example 1

[0058] Add 500 ml of methanol to a 1000 ml four-necked flask, start stirring, cool to 0-10°C, slowly add 2 g of thionyl chloride (0.017 mol), control the temperature at 0-10°C, stir for 15 minutes, add 100 ml of trimethyl orthoacetate (1 V / W) and 100 g of dihydroartemisinin (0.352 mol), stir at 0-10°C for 1 hour, central control sampling point plate (ethyl acetate: n-hexane = 1:4, iodine fumigation color), after the central control is qualified (below 1%), transfer the feed liquid to a 2000 ml four-necked bottle, control the temperature at 0-10°C, slowly add 1200 ml of drinking water, complete the addition, stir at 0-10°C for 1 hour, filter, obtain crude wet artemether, vacuum dry, dry at 45-50°C, obtain 94.5-99.8 g of dry product, with a yield of 90-95%, a purity of about 99.8%, and a single impurity of less than 0.2%.

[0059] Sulfonyl chloride equivalent comparative example 1

[0060] Add 500 ml of methanol into a 1000 ml four-necked flask, start stirring, cool to 0-10°C, slowly drop 1 g of thionyl chloride (0.008 mol), control the temperature at 0-10°C, stir for 15 minutes, add 100 ml of trimethyl orthoacetate (1 V / W) and 100 g of dihydroartemisinin (0.352 mol), stir at 0-10°C for 1 hour, control the temperature, and the raw material residue is about 5-10%. Transfer the feed liquid into a 2000 ml four-necked flask, control the temperature at 0-10°C, slowly drop 1200 ml of drinking water, complete the addition, stir at 0-10°C for 1 hour, filter, and obtain a crude wet product of artemether. Dry in vacuum and dry at 45-50°C to obtain 88.2 g of a dry product with a yield of 84.0%, a purity of about 99.1%, and a single impurity of less than 0.5%.

[0061] Sulfonyl chloride equivalent comparative example 2

[0062] Add 500 ml of methanol into a 1000 ml four-necked flask, start stirring, cool to 0-10°C, slowly add 10 g of thionyl chloride (0.084 mol), control the temperature at 0-10°C, stir for 15 minutes, add 100 ml of trimethyl orthoacetate (1 V / W) and 100 g of dihydroartemisinin (0.352 mol), stir at 0-10°C for 1 hour, and transfer the feed liquid into a 2000 ml four-necked flask, control the temperature at 0-10°C, slowly add 1200 ml of drinking water, complete the addition, stir at 0-10°C for 1 hour, filter, and obtain a crude wet product of artemether, vacuum dry, and dry at 45-50°C to obtain 91.2 g of a dry product with a yield of 86.9%, a purity of about 98.6%, and a single impurity of less than 0.5%.

[0063] It can be seen from the above examples that when the thionyl chloride equivalent adopts the ratio disclosed in the present invention, the yield and quality of the process are better.

[0064] The above embodiments of the present invention are only used for detailed description and demonstration of the technical solution of the present invention, and are not to be regarded as limiting the patent scope of the present invention. Any non-substantial adjustments or modifications are within the protection scope of the technical solution of the present invention.

Claims

1. A method for preparing β-artemether, characterized in that: The process of preparing β-artemether by etherification method using dihydroartemisinin as raw material includes the following steps: Step (1) adding methanol into a reaction vessel, stirring and cooling to 0-10°C, then slowly adding the acyl chloride dropwise, stirring for 15 minutes after the addition is complete, and controlling the temperature at 0-10°C; Step (2) adding trimethyl orthoacetate and dihydroartemisinin to the solution of step (1), stirring for 1 hour, and controlling the temperature at 0-10°C; Step (3) slowly adding water to the solution of step (2), stirring for 1 hour after the addition is complete, and controlling the temperature at 0-10°C; Step (4) Filter the solution of step (3) to obtain a crude wet product of β-artemisinin, and dry it to obtain a dry product with a molar yield of 90-95%, a purity of not less than 99.5%, and a single impurity of less than 0.3%.

2. The preparation method according to claim 1, characterized in that: The range of cooling and temperature control can also be 0~20℃.

3. The preparation method according to claim 1, characterized in that: The volume-to-mass ratio of methanol in step (1) is 5-8 V / W.

4. The preparation method according to claim 1, characterized in that: The stirring time of step (1) may also be in the range of 10 to 20 minutes.

5. The preparation method according to claim 1, characterized in that: The acyl chloride in step (1) is selected from thionyl chloride, oxalyl chloride or propionyl chloride, and has a molar mass of 0.017-0.17 mol.

6. The preparation method according to claim 1, characterized in that: The volume-to-mass ratio of trimethyl orthoacetate in step (2) is 1-1.5 V / W.

7. The preparation method according to claim 1, characterized in that: The molar mass of dihydroartemisinin in step (2) is 0.35 mol.

8. The preparation method according to claim 1, characterized in that: The volume-to-mass ratio of water in step (3) is 6-12 V / W.

9. The preparation method according to claim 1, characterized in that: The drying in step (4) is vacuum drying at 45-50°C.