WO2021052225A1 - Chemical semi-synthesis method for artemisinin - Google Patents

Abstract

Disclosed is a chemical semi-synthesis method for artemisinin (VI), the method comprising the specific steps of: (1) reacting dihydroartemisinic acid (I) with oxalyl chloride (II) to produce dihydroartemisinyl chloride (III); (2) reacting the dihydroartemisinyl chloride (III) with the dihydroartemisinic acid (I) to produce dihydroartemisinic anhydride (IV) via an acylation reaction; and (3) subjecting the dihydroartemisinic anhydride (IV) to a photo-oxidation reaction and an oxidative rearrangement reaction using a microchannel reactor to prepare the target product, artemisinin (VI). Compared with the prior art, the method has the advantages of high product yield and good product purity, stable process, mild reaction conditions, easy industrial production, etc.

Description

A chemical semi-synthetic method of artemisinin Technical field

The invention relates to the field of bioengineering pharmacy, in particular to a chemical semi-synthetic method of artemisinin.

Background technique

Artemisinin is a sesquiterpene lactone drug with peroxide groups extracted from the stems and leaves of the compound inflorescence plant Artemisia annua. It was discovered by Chinese pharmacist Tu Youyou in 1971. The molecular formula of artemisinin is C ₁₅ H ₂₂ O ₅ , and its chemical structure is shown in the following formula (VI):

Artemisinin is the most effective anti-malarial drug after pyrimidine, chloroquine, and primaquine, especially for cerebral malaria and anti-quinoline malaria. It has the characteristics of quick-acting and low toxicity. It was once called by the World Health Organization as a drug "The only effective malaria treatment drug in the world". According to statistics, the world's annual sales of artemisinin and its derivatives are as high as US$1.5 billion. In recent years, artemisinin has also shown attractive prospects in the treatment of other diseases such as anti-schistosomiasis, regulating or inhibiting the immune function of body fluids, increasing the conversion rate of lymphocytes, and choleretic, expectorant, antitussive, and asthma. . Therefore, the market prospect of artemisinin is very broad.

At present, artemisinin can be obtained through three methods. One is to extract from the plant Artemisia annua. This method is susceptible to the influence of climate and region, and the yield is unstable, which causes the market price of artemisinin to fluctuate greatly; The second method is obtained through chemical total synthesis. The chemical reaction conditions are relatively harsh, the reaction method is complicated, and high-risk and high-toxic reagents are used. Therefore, the method is extremely difficult to industrialize and the cost is high; the third method is to use microorganisms first Artemisinic acid is obtained by fermentation, and artemisinin is obtained by chemical synthesis of artemisinic acid. This method has the advantages of high yield, stable production, low production cost, and green process. The preparation of artemisinin by this method has been It is widely accepted. In 2013, the WHO also approved the artemisinin produced by this process for clinical use.

Since the discovery of artemisinin, there have been many reports on the semi-synthesis of artemisinin from artemisinic acid. M. Jung et al. reported (Tetrahedron Letters, 20, 5973 (1989)) that artemisinic acid was reduced to obtain artemisinol, and then artemisinol was auto-oxidized to produce cyclic enyl ether, and then triphenyl phosphite was used. -Ozone compound treatment to obtain decarburized artemisinin, but the process is complicated and the yield is only 4%. Wu Yulin also reported (J. Chem. Soc, Chem. Commun., 727, 1990) the process of synthesizing artemisinin from artemisinic acid, in which artemisinin is synthesized from artemisinic acid, and the reaction temperature is -70℃～-78 ℃, the reaction conditions are harsh, and the yield is relatively low, which is not suitable for industrial production.

Patent WO2009088404 discloses a method for preparing artemisinin by introducing peroxy bonds with dihydroartemisinic acid as a starting material, sodium molybdate as a catalyst, and hydrogen peroxide as an oxidant. The product obtained by this method has poor selectivity. And there are many by-products, and the final total yield of artemisinin is low, and there is still a certain distance from industrial application.

Patent ZL201280042681.7 discloses a method and device for synthesizing artemisinin from dihydroartemisinic acid. Because it irradiates the tube, the mixing effect is uneven, the flux is small, and the efficiency of daily artemisinin production is low, and a large amount of artemisinin production is required for amplification. Pipes require a lot of space and are not easy to industrialize production.

Patent ZL201310615102.X discloses a method and equipment for preparing artemisinin on a large scale. The reactor is a chromatography column with a sand core, a glass tube is embedded in the middle of the chromatography column, and a reaction system is set between the chromatography column and the glass tube. , The glass tube is equipped with a light source, the reactor has no mixing device, the reaction light is uneven, the temperature is uneven, and the reaction temperature is harsh from -20°C to -50°C, and the reaction time is slow.

In summary, the existing artemisinin preparation methods have disadvantages such as poor synthesis selectivity, low yield, harsh reaction conditions, and difficulty in scale-up production. Therefore, it is necessary to develop a chemical semi-synthetic process of artemisinin with high production efficiency, high finished product yield and purity, low cost, mild reaction conditions, and industrialization.

Summary of the invention

The present invention provides a chemical semi-synthetic method of artemisinin (VI). The method of the present invention has simple operation, high product yield, good purity, low cost, mild reaction conditions, stable process and easy industrial production. The method includes the following steps:

(1) Dihydroartemisinic acid (I) reacts with oxalyl chloride (II) to produce dihydroartemisinyl chloride (III);

(2) Dihydroartemisinic acid (III) and dihydroartemisinic acid (I) undergo an acylation reaction to generate dihydroartemisinic anhydride (IV);

(3) In a microchannel reactor, dihydroartemisinic anhydride (IV) and oxygen undergo a photooxidation reaction under the action of a photocatalyst to obtain the peroxyalcohol (V) of dihydroartemisinic anhydride; Peroxyalcohol (V) and oxygen undergo an oxidative rearrangement reaction under the action of an acid catalyst to obtain artemisinin (VI).

In a preferred embodiment, the reaction temperature in the step (1) is -10°C to 40°C, preferably 0°C to 30°C, more preferably 10°C to 20°C.

In a preferred embodiment, the reaction solvent used in the step (1) is one or a mixture of dichloromethane, tetrahydrofuran, toluene, and hexane.

In a preferred embodiment, the catalyst a used in the step (1) is at least one of N,N-dimethylformamide, tetramethylurea and 1,3 dimethylimidazolinone.

In a preferred embodiment, the molar ratio of dihydroartemisinic acid (I) to catalyst a in the step (1) is 1:0.001 to 1.

In a preferred embodiment, the molar ratio of dihydroartemisinic acid (I) to oxalyl chloride (II) in the step (1) is 1:1.01-2.

In a preferred embodiment, the reaction temperature in the step (2) is -10°C to 20°C, preferably -5°C to 0°C.

In a preferred embodiment, the reaction solvent used in the step (2) is one or more of dichloromethane, tetrahydrofuran, toluene, and hexane.

In a preferred embodiment, the catalyst b used in the step (2) is an acid binding agent, preferably at least one of triethylamine, pyridine, and potassium carbonate.

In a preferred embodiment, in the step (2), the molar ratio of dihydroartemisinyl chloride (III) to dihydroartemisinic acid (I) is 1:1.01 to 1.2.

In a preferred embodiment, the organic solvent used in the photooxidation reaction in the step (3) is one or more of dichloromethane, toluene, acetonitrile, cyclohexane, and n-heptane.

In a preferred embodiment, the mass-volume ratio of dihydroartemisinic anhydride (IV) to the organic solvent in the step (3) is 1:2-20 (unit is g/mL), preferably 1:4-6.

In a preferred embodiment, the photocatalyst in the step (3) is tetraphenylporphyrin or a derivative thereof.

In a preferred embodiment, the molar ratio of the dihydroartemisinic anhydride (IV) to the photocatalyst is 1:0.001 to 1, preferably 1:0.002 to 0.01.

In a preferred embodiment, the acid catalyst in the step (3) is a protic acid and or a Lewis acid, preferably trifluoroacetic acid.

In a preferred embodiment, the molar ratio of dihydroartemisinic anhydride (IV) to the acid catalyst in the step (3) is 1:0.3-2, preferably 1:0.5.

In a preferred embodiment, the light source used in the photooxidation reaction in the step (3) is an LED light source.

In a preferred embodiment, the wavelength of the light source is 365-660 nm, preferably 385 nm or 405 nm, more preferably 385 nm.

In a preferred embodiment, the reaction temperature of the photooxidation reaction in the step (3) is -10°C to 20°C, preferably -5°C to 5°C, more preferably 0°C.

In a preferred embodiment, the reaction temperature of the oxidative rearrangement reaction in the step (3) is 5°C-60°C, preferably 20°C.

In a preferred embodiment, the residence time of the photooxidation reaction in the step (3) is 2.9 min to 10.2 min, preferably 4 min to 5.5 min; the residence time of the oxidation rearrangement reaction in the step (3) is 1.7 min ~5.7min.

In a preferred embodiment, the flow rate of oxygen in the microchannel reactor in the step (3) is 120 ml/min to 300 ml/min, preferably 160 ml/min to 240 ml/min.

In a preferred embodiment, the photooxidation reaction and the oxidation rearrangement reaction in the step (3) are continuous reactions, and the pressure of the photooxidation reaction and the oxidation rearrangement reaction are both 0.5-1.7 MPa.

In a preferred embodiment, the microchannel reactor includes a temperature controller 1, a glass microchannel module 2, a silicon carbide microchannel module 3, a light source 4, an oxygen source 5, feed pumps 7 and 8, and a back pressure valve 9; Among them,

The temperature controller 1 is a temperature controller with dual temperature zones;

The glass microchannel module 2 is made of glass material, is a thin plate square, and has a mixing device with a heart-shaped structure inside;

The silicon carbide microchannel module 3 is made of silicon carbide, is a thin plate square, and has a mixing device with a heart-shaped structure inside;

The feed pumps 7 and 8 are pumps that can withstand high pressure, preferably KP-22 or Hanbang;

The back pressure valve 9 has a back pressure adjustment function.

In a preferred embodiment, the step 3) also includes further crystallization and purification of the prepared artemisinin, and the crystallization solvent used is one of methanol, ethanol, isopropanol, acetone, methanol and water, ethanol and water Or several, preferably ethanol.

The process of converting dihydroartemisinic anhydride into artemisinin of the present invention is carried out in a microchannel reactor as follows: A) singlet oxygen photochemically induces oxidation of dihydroartemisinic anhydride; B) using trifluoroacetic acid Hydrolysis and Hock cracking; C) The oxidation reaction with triplet oxygen produces artemisinin.

The continuous type described in the present invention means that the mixed solution containing dihydroartemisinic anhydride flows continuously from the inlet to the outlet of the raw material of the microchannel reactor, and can react continuously, at least in the photooxidation reaction. Artemisinic anhydride is a peroxyalcohol that can be continuously converted to dihydroartemisinic anhydride. Under the condition that the raw material flow rate, oxygen flow rate, trifluoroacetic acid flow rate and other related parameters are set, the reaction can be continuously transformed, and the outlet of the microchannel reactor can continuously produce products. But it does not mean that the two oxidation reactions occurring in the microchannel reactor cannot be stopped. The reaction is stopped when the light source is adjusted and the oxygen is exhausted.

The photooxidation reaction and the oxidation rearrangement reaction carried out in the microchannel reactor of the present invention need to be carried out under pressure. When the pure oxygen in the oxygen tank is input, it can promote the advancement of the material liquid in the microchannel reactor, and give a continuous reaction. Provide a certain amount of motivation. In addition, the microchannel reactor equipment itself also has a back pressure valve (pressurization device). Pressure is extremely important for the efficiency of the photooxidation reaction, and it greatly affects the conversion efficiency of dihydroartemisinic anhydride.

The artemisinin prepared according to the method of the present invention has high yield, good purity, and the purity can be as high as 99.5%. In addition, the annual throughput of a microchannel reactor using the method of the present invention is 3.5 tons per year. Up to 42 tons/year (calculated as 300 days a year), high throughput, high conversion rate, good reaction liquid mixing effect, stable process, and can be used for mass production.

Compared with the prior art, the present invention has the following beneficial effects:

1. The artemisinin product prepared by the process of the present invention has high yield and good purity, and the purity can reach 99.5%.

2. The microchannel reactor used in the process of the present invention has high flux, high conversion rate, good reaction liquid mixing effect, safe and stable process, and can be used for mass production. At the same time, the photooxidation reaction and the oxidation rearrangement reaction in the microchannel reaction of the present invention have a short reaction time, and the microchannel reactor of the present invention can simultaneously perform the photooxidation reaction and the oxidation rearrangement reaction, further shortening the reaction time.

3. Compared with the reaction temperature of the microchannel disclosed in the prior art as low as -50°C, the reaction conditions of the present invention are mild.

4. The starting material of the present invention is dihydroartemisinic anhydride. Compared with dihydroartemisinic acid, the carboxylic acid is protected and the side reaction of decarboxylation is inhibited. Dihydroartemisinic anhydride can increase the solubility in organic solvents. , So that the solution is more uniform, so that the light transmission is also more uniform, which is conducive to the photo-oxidation reaction.

Description of the drawings

Figure 1 is a schematic diagram of the structure of the microchannel reactor of the present invention.

detailed description

The technical solutions in the embodiments of the present invention will be described clearly and completely below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative work shall fall within the protection scope of the present invention.

The reagents and solvents used in the present invention are not particularly limited, and commercially available conventional solvents can be used. It should be emphasized that the meaning or protection scope of the numerical value or numerical endpoint involved in the technical solution of the present invention is not limited to the number itself. Those skilled in the art can understand that they include those that have been widely used in the art. Acceptable allowable error ranges, such as experimental errors, measurement errors, statistical errors and random errors, etc., and these error ranges are all included in the scope of the present invention.

The purity of the artemisinin involved in the present invention is detected by high performance liquid chromatography (HPLC). The instrument and chromatographic conditions are as follows: the model of the liquid chromatograph is Agilent 1100series, and the chromatographic column is CAPCELL PAK C18 TYPE MGII, 4.6mm ×250mm, 5μm; mobile phase is acetonitrile: water=50:50(V:V); flow rate is 1ml/min; UV detection wavelength is 210nm; sample volume is 20μL. Purity refers to the percentage of the chromatographic peak area of the target in the HPLC spectrum to the total peak area. For example, the purity of artemisinin refers to the percentage of the peak area of artemisinin in the HPLC spectrum of the sample.

Dihydroartemisinic acid can be commercially available or synthesized. The dihydroartemisinic acid used in this example is prepared from artemisinic acid through a reduction reaction.

Examples of reaction equipment

1, the microchannel reactor of the present invention includes a temperature controller with dual temperature zone control 1, five glass microchannel modules 2, three silicon carbide microchannel modules 3, a light source 4, an oxygen source 5, and a gas flow Count 6, two feed pumps 7 and 8, a back pressure valve 9, two batching tanks 10 and 11, and a receiving tank 12. Among them: the light source 4 irradiates both sides of each glass microchannel module 2 at the same time, which increases the light transmittance of light, as shown by the arrow in Fig. 1; the glass microchannel module 2 is made of glass material and has a thin plate square shape inside. The mixing device with a heart-shaped structure increases the mixing effect of the reaction; the silicon carbide microchannel module 3 is made of silicon carbide and is a thin plate square with a mixing device with a heart-shaped structure inside, which increases the mixing effect of the reaction; temperature controller 1 The connected cooling liquid closely adheres to the glass microchannel module 2 and the silicon carbide microchannel module 3, which enhances the heat exchange efficiency of the reaction.

The temperature controller 1 has a cooling or heating function;

The glass microchannel module 2 and the silicon carbide microchannel module 3 are respectively connected to the temperature controller 1 in the dual temperature zone;

The reaction liquid flows continuously in the glass microchannel module 2 and the silicon carbide microchannel module 3;

The light source 4 is an LED light source;

The oxygen source 5 is oxygen;

The gas flow meter 6 is used to adjust the gas flow rate;

The feed pump 7 is used to feed the photo-oxidation reaction and provide continuous flow force;

The feed pump 8 is used to feed the oxidation rearrangement reaction and provide power;

The back pressure valve 9 is used to adjust the pressure;

The batching tank 10 is used to store dihydroartemisinic anhydride solution, and the batching tank 11 is used to store acid catalysts, such as trifluoroacetic acid;

The receiving tank 12 is used to receive the reaction liquid.

Preparation Example Preparation of dihydroartemisinic acid

Add 3000ml absolute ethanol and 2000ml (35.02mol) 85% hydrazine hydrate to 1000g (4.2675mol) artemisinic acid, add 1800ml (17.6294mol) 30% hydrogen peroxide dropwise at -10℃, the reaction is over after 4H, and 6N is added dropwise The hydrochloric acid aqueous solution to pH=1 to obtain 996.6 g (4.2170 mol) of dihydroartemisinic acid, with a yield of 98.74%.

Example 1: Preparation of artemisinin

Add 50g (0.2116mol) of dihydroartemisinic acid prepared in the preparation example to 250ml of dichloromethane, add 2.5ml (0.03247mol) of N,N-dimethylformamide, and add 21.67ml( 0.2543mol) oxalyl chloride. After 1 hour, the reaction was completed. After the reaction solution was concentrated to dryness, 53.2g (0.2094mol) of dihydroartemisinyl chloride was obtained. Then 250ml of dichloromethane and 20ml of triethylamine were added. Hydroartemisinic acid 50g (0.2116mol), after 2 hours, the reaction was completed, concentrated to obtain dihydroartemisinic anhydride 94.11g (0.2073mol), the yield was 97.97%.

94.11 g (0.2073 mol) of dihydroartemisinic anhydride and 0.3 g of tetraphenylporphyrin (0.00049 mol) were added to 560 ml of dichloromethane to dissolve the solution to obtain a liquid. Set the temperature of the glass microchannel module 2 connected to the thermostat 1 to -5℃, and the temperature of the silicon carbide microchannel module 3 connected to the thermostat 1 to 5℃, turn on the light source 4, set the wavelength to 405nm, and turn on the oxygen source 5. Set the oxygen flow rate to 240ml/min, use oxygen to adjust the back pressure valve 9 to 1.6MPa, and use the feed pump 7 to drive the above-mentioned liquid into the glass microchannel module 2 at a flow rate of 14ml/min, the residence time is 2.9 minutes After the photooxidation reaction is completed, the reaction solution is obtained. The reaction solution enters the silicon carbide microchannel module 3, the feed pump 8 is turned on, and trifluoroacetic acid is injected at a flow rate of 0.3ml/min to carry out the oxidation rearrangement reaction. The residence time is 1.7min. The crude artemisinin solution is 590ml, and the oxygen source 5, light source 4, feed pumps 7 and 8, and temperature controller 1 are turned off after receiving.

Add 80ml of saturated sodium bicarbonate aqueous solution to the crude artemisinin solution, separate the layers, discard the aqueous layer, and concentrate the organic phase to dryness under reduced pressure at 30°C. Add 500ml 90% ethanol aqueous solution to crystallize to obtain artemisinin (VI) 85g (0.3011mol), the yield is 72.62% (calculated by dihydroartemisinic anhydride), the purity of the compound of formula VI is 99.5% by HPLC detection, and the total yield is 71.14% (calculated by dihydroartemisinic acid).

Example 2: Preparation of artemisinin

Add 50g (0.2116mol) of dihydroartemisinic acid prepared in the preparation example to 250ml of dichloromethane, add 2.5ml (0.03247mol) of N,N-dimethylformamide, and add 21.67ml( 0.2543mol) oxalyl chloride. After 1 hour, the reaction is complete. After the reaction solution is concentrated to dryness, 52.8g (0.2079mol) of dihydroartemisinyl chloride is obtained. Then 250ml of dichloromethane and 20ml of triethylamine are added, and the temperature is controlled at -5°C. Dihydroartemisinic acid 50g (0.2116mol), the reaction was completed after 2 hours, concentrated to obtain dihydroartemisinic anhydride 93.1g (0.2051mol), the yield was 96.93%.

93.1 g (0.2051 mol) of dihydroartemisinic anhydride and 1.3 g of tetraphenylporphyrin (0.002117 mol) were added to 370 ml of toluene to dissolve to obtain a liquid. Set the temperature of the glass microchannel module 2 connected to the thermostat 1 to 0℃, and the temperature of the silicon carbide microchannel module 3 connected to the thermostat 1 to 20℃, turn on the light source 4, set the wavelength to 385nm, and turn on the oxygen source 5. , Set the oxygen flow rate to 200ml/min, use oxygen to adjust the back pressure valve 9 to 1MPa, and use the feed pump 7 to drive the above-mentioned liquid into the glass microchannel module 2 at a flow rate of 9ml/min. After a residence time of 4.6 minutes, After the photooxidation reaction is completed, the reaction solution is obtained. The reaction solution enters the silicon carbide reactor module 3, the feed pump 8 is turned on, and trifluoroacetic acid is injected at a flow rate of 0.3ml/min to carry out the oxidation rearrangement reaction. 400ml of crude artemisinin solution. After receiving, turn off the oxygen source 5, light source 4, feed pumps 7 and 8, temperature controller 1.

Add 80ml of saturated sodium bicarbonate solution to the crude artemisinin solution, separate the layers, discard the aqueous layer, and concentrate the organic phase to dryness under reduced pressure at 50°C. Add 500ml 90% ethanol aqueous solution to crystallize to obtain artemisinin (VI) 88g (0.3117mol), the yield is 75.99% (calculated based on dihydroartemisinic anhydride). Detected by HPLC, the purity of the compound of formula VI is 99.4%, and the total yield is 73.65% (calculated based on dihydroartemisinic acid).

Example 3: Preparation of artemisinin

Add 50g (0.2116mol) of dihydroartemisinic acid prepared in the preparation example to 250ml of dichloromethane, add 2.5ml (0.03247mol) of N,N-dimethylformamide, and add 21.67ml( 0.2543mol) oxalyl chloride. After 1 hour, the reaction was completed. After the reaction solution was concentrated to dryness, 52.8g (0.2079mol) of dihydroartemisinyl chloride was obtained. Then 250ml of dichloromethane and 20ml of triethylamine were added. Hydroartemisinic acid 50g (0.2116mol), the reaction was completed after 2 hours, concentrated to obtain dihydroartemisinic anhydride 92.8g (0.2041mol), the yield was 96.60%.

Add 92.8 g (0.2041 mol) of dihydroartemisinic anhydride and 0.3 g of tetraphenylporphyrin (0.00049 mol) to 500 ml of toluene to obtain a liquid. Set the temperature of the glass microchannel module 2 connected to the thermostat 1 to -5℃, and the temperature of the silicon carbide microchannel module 3 connected to the thermostat 1 to 50℃, turn on the light source 4, set the wavelength to 405nm, and turn on the oxygen source 5. Set the oxygen flow rate to 200ml/min, use oxygen to adjust the back pressure valve 9 to 0.6MPa, and use the feed pump 7 to inject the above-mentioned material into the glass microchannel module 2 at a flow rate of 4.2ml/min, with a residence time of 9.8 Minutes later, the photooxidation reaction is completed to obtain the reaction solution, the reaction solution enters the silicon carbide microchannel module 3, the feed pump 8 is turned on, and trifluoroacetic acid is injected at a flow rate of 0.2ml/min to carry out the oxidation rearrangement reaction. The residence time is 5.7min. Obtain 520ml of the crude artemisinin solution. After receiving, turn off the oxygen source 5, light source 4, feed pumps 7 and 8, and temperature controller 1.

Add 80ml of saturated aqueous sodium bicarbonate solution to the crude artemisinin solution, separate the layers, discard the aqueous layer, and concentrate the organic phase to dryness under reduced pressure at 30°C. Add 400ml of ethanol to crystallize to obtain 86g (0.3046mol) of artemisinin (VI) The yield is 74.62% (calculated by dihydroartemisinic anhydride), the purity of the compound of formula VI is 99.3% by HPLC detection, and the total yield is 72.08% (calculated by dihydroartemisinic acid).

Claims (9)

1. A chemical semi-synthetic method of artemisinin (VI), which is characterized in that it comprises the following steps:

   (1) Dihydroartemisinic acid (I) reacts with oxalyl chloride (II) to produce dihydroartemisinyl chloride (III);

   

   (2) Dihydroartemisinic acid (III) and dihydroartemisinic acid (I) undergo an acylation reaction to generate dihydroartemisinic anhydride (IV);

   

   (3) In a microchannel reactor, dihydroartemisinic anhydride (IV) and oxygen undergo a photooxidation reaction under the action of a photocatalyst to obtain the peroxyalcohol (V) of dihydroartemisinic anhydride; Peroxyalcohol (V) and oxygen undergo an oxidative rearrangement reaction under the action of an acid catalyst to obtain artemisinin (VI).

   
2. The method according to claim 1, wherein the organic solvent used in the photooxidation reaction in the step (3) is one or more of dichloromethane, toluene, acetonitrile, cyclohexane, and n-heptane The mass-volume ratio of the dihydroartemisinic anhydride (IV) to the organic solvent is 1:2-20 (unit is g/mL), preferably 1:4-6.
3. The method according to claim 1 or 2, wherein the photocatalyst in the step (3) is tetraphenylporphyrin or a derivative thereof, and the molar ratio of dihydroartemisinic anhydride (IV) to the photocatalyst is 1: 0.001 to 1, preferably 1: 0.002 to 0.01; the acid catalyst is a protic acid and or a Lewis acid, preferably trifluoroacetic acid.
4. The method according to any one of claims 1 to 3, wherein the light source used in the photooxidation reaction in the step (3) is an LED light source, and the wavelength of the light source is 365-660nm, preferably 385nm or 405nm, It is more preferably 385 nm.
5. The method according to any one of claims 1 to 4, wherein the reaction temperature of the photooxidation reaction in the step (3) is -10°C to 20°C, preferably -5°C to 5°C, more preferably The reaction temperature of the oxidative rearrangement reaction in the step (3) is 5°C to 60°C, preferably 20°C; the residence time of the photooxidation reaction in the step (3) is 2.9 min to 10.2 min, preferably 4min～5.5min; the residence time of the oxidation rearrangement reaction in the step (3) is 1.7min～5.7min.
6. The method according to any one of claims 1-5, wherein the flow rate of oxygen in the microchannel reactor in the step (3) is 120ml/min～300ml/min, preferably 160ml/min～240ml/min .
7. The method according to any one of claims 1-6, wherein the photooxidation reaction and the oxidation rearrangement reaction in the step (3) are continuous reactions, and the pressure of the photooxidation reaction and the oxidation rearrangement reaction are both 0.5 -1.7MPa.
8. The method according to any one of claims 1-7, wherein the microchannel reactor comprises a temperature controller 1, a glass microchannel module 2, a silicon carbide microchannel module 3, a light source 4, and an oxygen source 5. , Feed pumps 7 and 8, back pressure valve 9; among them,

   The temperature controller 1 is a temperature controller with dual temperature zones;

   The glass microchannel module 2 is made of glass material, is a thin plate square, and has a mixing device with a heart-shaped structure inside;

   The silicon carbide microchannel module 3 is made of silicon carbide, is a thin plate square, and has a mixing device with a heart-shaped structure inside;

   The feed pumps 7 and 8 are pumps that can withstand high pressure, preferably KP-22 or Hanbang pumps;

   The back pressure valve 9 has a back pressure adjustment function.
9. The method according to any one of claims 1-8, wherein the step 3) further comprises further crystallization and purification of the prepared artemisinin, and the crystallization solvent used is methanol, ethanol, isopropanol, acetone One or more of, methanol and water, ethanol and water, preferably ethanol.

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