CN110590802B - Chemical semi-synthesis method of artemisinin - Google Patents
Chemical semi-synthesis method of artemisinin Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
The invention provides a chemical semisynthesis method of artemisinin (VI), which comprises the following specific steps: (1) reacting dihydroartemisinic acid (I) with oxalyl chloride (II) to generate dihydroartemisinic chloride (III); (2) performing acylation reaction on the dihydroartemisinic acid chloride (III) and the dihydroartemisinic acid (I) to generate dihydroartemisinic anhydride (IV); (3) and (3) performing photooxidation reaction and oxidation rearrangement reaction on the dihydroarteannuic anhydride (IV) by using a microchannel reactor to obtain a target product artemisinin (VI). Compared with the prior art, the method has the advantages of high product yield, good purity, stable process, mild reaction conditions, easy industrial production and the like.
Description
Technical Field
The invention relates to the field of bioengineering pharmacy, in particular to a chemical semisynthesis method of artemisinin.
Background
Artemisinin is sesquiterpene lactone medicine with peroxy group extracted from stem and leaf of Artemisia annua L.of composite inflorescence, and is discovered in 1971 by U-yo of Chinese pharmacy. The molecular formula of the artemisinin is C15H22O5The chemical structure is shown as the following formula (VI):
artemisinin is the most effective antimalarial specific drug after acetamiprid, chloroquine and primaquine, particularly has the characteristics of quick response and low toxicity for cerebral malaria and quinoline malaria, and has been called as the 'only effective malaria treatment drug in the world' by the world health organization. Statistics show that artemisinin and its derivatives are sold worldwide in the number of $ 15 billion per year. In recent years, artemisinin has shown attractive prospects in the treatment of other diseases such as schistosomiasis resistance, regulation or inhibition of the immune function of body fluid, improvement of the conversion rate of lymphocytes, cholagogue, phlegm elimination, cough relief, asthma relief and the like. Therefore, the artemisinin has very wide market prospect.
At present, artemisinin can be obtained by three methods, one method is obtained by extracting from a plant, namely artemisia apiacea, the method is easily influenced by climate and region, and the yield is unstable, so that the market price fluctuation of artemisinin is large; the second method is obtained by chemical total synthesis, the chemical reaction conditions are harsh, the reaction method is complex, and high-risk and high-toxicity reagents are used, so that the method has great industrialization difficulty and high cost; the third method is to obtain arteannuin by microbial fermentation, and then obtain artemisinin by chemical synthesis of arteannuin, and the method has the advantages of high yield, stable production, low production cost, green and environment-friendly process and the like, and the preparation of artemisinin by the method is widely accepted, and the WHO in 2013 also approves the clinical application of artemisinin produced by the process.
From the discovery of artemisinin to date, numerous reports of chemical semisynthesis of artemisinin from artemisinic acid have been described in the literature. M. Jung et al reported (Tetrahedron Letters, 20, 5973(1989)) that arteannuic acid was subjected to reduction treatment to obtain arteannuin, followed by auto-oxidation of arteannuin to obtain cyclic enol ether, and further treatment with triphenyl phosphite-ozone compound to obtain decarburized artemisinin, but this process was complicated and the yield was only 4%. WuYulin also reports (J.chem.Soc, chem.Commun., 727, 1990) a process for synthesizing artemisinin from artemisinic acid, wherein the artemisinin is synthesized from artemisinic acid at the reaction temperature of-70 ℃ to-78 ℃, the reaction conditions are harsh, the yield is relatively low, and the process is not suitable for industrial production.
Patent WO2009088404 discloses a method for preparing artemisinin by introducing a peroxy bond, wherein dihydroartemisinic acid is used as a starting material, sodium molybdate is used as a catalyst, hydrogen peroxide is used as an oxidizing agent, the method has the advantages of poor product selectivity, more byproducts, lower total yield of final artemisinin and certain distance from industrial application.
Patent ZL201280042681.7 discloses a method and apparatus for synthesizing artemisinin from dihydroartemisinic acid, because of its illumination to the pipe, the mixing effect is not uniform, the flux is small, the daily production of artemisinin is inefficient, the enlargement needs a large number of pipes, needs a very large space, and is not easy for industrialized production.
Patent ZL201310615102.X discloses a method and equipment for preparing artemisinin on a large scale, wherein a reactor is a chromatographic column with a sand core, a glass tube is embedded in the middle of the chromatographic column, a reaction system is arranged between the chromatographic column and the glass tube, a light source is arranged in the glass tube, the reactor is free of a mixing device, the reaction illumination is uneven, the temperature is uneven, the reaction temperature is rigor between-20 ℃ and-50 ℃, and the reaction time is slow.
Comprehensively, the existing artemisinin preparation method has the defects of poor synthesis selectivity, low yield, harsh reaction conditions, difficult amplification production and the like. Therefore, it is necessary to develop a chemical semi-synthesis process of artemisinin with high production efficiency, high yield and purity of the finished product, low cost, mild reaction conditions and industrialization.
Disclosure of Invention
The invention provides a chemical semisynthesis method of artemisinin (VI), which has the advantages of simple operation, high product yield, good purity, low cost, mild reaction conditions, stable process and easy industrial production, and comprises the following steps:
(1) reacting dihydroartemisinic acid (I) with oxalyl chloride (II) to generate dihydroartemisinic chloride (III);
(2) performing acylation reaction on the dihydroartemisinic acid chloride (III) and the dihydroartemisinic acid (I) to generate dihydroartemisinic anhydride (IV);
(3) in a microchannel reactor, carrying out photooxidation reaction on dihydro arteannuic anhydride (IV) and oxygen under the action of a photocatalyst to obtain peroxyalcohol (V) of the dihydro arteannuic anhydride; oxidizing and rearranging the peroxyl (V) of the dihydroarteannuic anhydride and oxygen under the action of an acid catalyst to obtain the artemisinin (VI).
In a preferred embodiment, the reaction temperature in step (1) is from-10 ℃ to 40 ℃, preferably from 0 ℃ to 30 ℃, more preferably from 10 ℃ to 20 ℃.
In a preferred embodiment, the reaction solvent used in 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-dimethylimidazolidinone.
In a preferred embodiment, the molar ratio of dihydroartemisinic acid (I) to catalyst a in step (1) is 1: 0.001 to 1.
In a preferred embodiment, the molar ratio of dihydroartemisinic acid (I) to oxalyl chloride (II) in step (1) is 1: 1.01-2.
In a preferred embodiment, the reaction temperature of said step (2) is from-10 ℃ to 20 ℃, preferably from-5 ℃ to 0 ℃.
In a preferred embodiment, the reaction solvent used in 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, the molar ratio of the dihydroartemisinic chloride (III) to the dihydroartemisinic acid (I) in step (2) is 1: 1.01-1.2.
In a preferred embodiment, the organic solvent used in the photooxidation reaction in step (3) is one or more of dichloromethane, toluene, acetonitrile, cyclohexane and n-heptane.
In a preferred embodiment, the mass-to-volume ratio of the dihydroarteannuic anhydride (IV) to the organic solvent in step (3) is 1: 2 to 20 (unit is g/mL), preferably 1: 4 to 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 dihydroarteannuic anhydride (IV) to photocatalyst is 1: 0.001 to 1, preferably 1: 0.002 to 0.01.
In a preferred embodiment, the acid catalyst in step (3) is a protic acid and or a lewis acid, preferably trifluoroacetic acid.
In a preferred embodiment, the mole ratio of dihydroarteannuic anhydride (IV) to acid catalyst in step (3) is 1: 0.3 to 2, preferably 1: 0.5.
in a preferred embodiment, the light source used for the photooxidation reaction in the step (3) is an LED light source.
In a preferred embodiment, the light source has a wavelength of 365 to 660nm, preferably 385nm or 405nm, more preferably 385 nm.
In a preferred embodiment, the reaction temperature of the photooxidation reaction in the step (3) is from-10 ℃ to 20 ℃, preferably from-5 ℃ to 5 ℃, and more preferably 0 ℃.
In a preferred embodiment, the reaction temperature of the oxidative rearrangement reaction in the step (3) is 5 ℃ to 60 ℃, preferably 20 ℃.
In a preferred embodiment, the residence time of the photooxidation reaction in the step (3) is 2.9min to 10.2min, preferably 4min to 5.5 min; the retention time of the oxidation rearrangement reaction in the step (3) is 1.7 min-5.7 min.
In a preferred embodiment, the flow rate of oxygen in the microchannel reactor in step (3) is 120ml/min to 300ml/min, preferably 160ml/min to 240 ml/min.
In a preferred embodiment, the photo-oxidation reaction and the oxidation rearrangement reaction in the step (3) are continuous reactions, and the photo-oxidation reaction and the oxidation rearrangement reaction are both at 0.5-1.7 MPa.
In a preferred embodiment, the microchannel reactor comprises 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; wherein the content of the first and second substances,
the temperature controller 1 is a temperature controller of a dual-temperature zone;
the glass micro-channel module 2 is made of glass materials, is in a thin plate square shape, and is internally provided with a mixing device with a heart-shaped structure;
the silicon carbide micro-channel module 3 is made of silicon carbide materials, is a thin-plate square and is internally provided with a mixing device with a heart-shaped structure;
the feeding pumps 7 and 8 are pumps capable of bearing high pressure, and KP-22 or Hanbang is preferred;
the back pressure valve 9 has a back pressure regulating function.
In a preferred embodiment, the step 3) further comprises further crystallizing and purifying the obtained artemisinin, and the used crystallization solvent is one or more of methanol, ethanol, isopropanol, acetone, methanol and water, ethanol and water, preferably ethanol.
The process of converting the dihydroarteannuic anhydride into the artemisinin is carried out in a microchannel reactor as follows: A) the singlet oxygen photochemistry induces and oxidizes the dihydroarteannuic anhydride; B) carrying out hydrolysis and Hock cracking by using trifluoroacetic acid; C) oxidizing with triplet oxygen to produce artemisinin.
The continuous type of the invention refers to that the mixed solution containing the dihydroarteannuic anhydride continuously flows from the inlet to the outlet of the raw material of the microchannel reactor and can continuously react, and at least in the photooxidation reaction, the dihydroarteannuic anhydride is peroxyalcohol which can be continuously converted into the dihydroarteannuic anhydride. Under the condition that relevant parameters such as raw material flow, oxygen flow, trifluoroacetic acid flow and the like are set, the reaction can be continuously converted, and products can be continuously generated at the outlet of the microchannel reactor. When the two oxidation reactions which are generated in the microchannel reactor are not allowed to stop, the reaction is stopped when the light source is adjusted, the oxygen is used up and the like.
The photooxidation reaction and the oxidation rearrangement reaction carried out in the microchannel reactor need to be carried out under pressure, and when pure oxygen in an oxygen tank is input, the propulsion of feed liquid in the microchannel reactor can be promoted, so that certain power is provided for the continuously carried out reaction. In addition, the microchannel reactor device is also provided with a back pressure valve (pressurizing device), and the pressure is very important for the efficiency of the photo-oxidation reaction, thereby greatly influencing the conversion efficiency of the dihydroarteannuic anhydride.
The artemisinin prepared by the method has high yield and good purity, the purity can reach 99.5 percent, in addition, the method uses a microchannel reactor, the annual flux pilot scale is 3.5 tons/year, the production type can reach 42 tons/year (calculated by 300 days in one year), the flux is high, the conversion rate is high, the reaction liquid mixing effect is good, the process is stable, and the method can be used for batch production.
Compared with the prior art, the invention has the following beneficial effects:
1. the artemisinin finished product prepared by the process has high yield and good purity, and the purity can reach 99.5%.
2. The microchannel reactor used in the process has the advantages of high flux, high conversion rate, good reaction liquid mixing effect, safe and stable process and can be used for batch production. Meanwhile, the reaction time of the photo-oxidation reaction and the oxidation rearrangement reaction in the microchannel reactor is short, and the microchannel reactor can simultaneously carry out the photo-oxidation reaction and the oxidation rearrangement reaction, thereby further shortening the reaction time.
3. Compared with the microchannel reaction temperature disclosed by the prior art, the reaction temperature is as low as-50 ℃, and the reaction condition of the invention is mild.
4. The starting material of the invention is dihydroarteannuic anhydride, compared with dihydroarteannuic acid, carboxylic acid is protected, decarboxylation side reaction is inhibited, and the dihydroarteannuic anhydride can increase solubility in an organic solvent, so that the solution is more uniform, the light transmission is more uniform, and the photo-oxidation reaction is facilitated.
Drawings
FIG. 1 is a schematic view of a microchannel reactor according to the present invention.
Detailed Description
The technical solution in the embodiments of the present invention will be clearly and completely described below. It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without making any creative effort, shall fall within the protection scope of the present invention.
The reagent and solvent used in the present invention are not particularly limited, and commercially available conventional solvents can be used. It should be emphasized that any reference to a numerical value or any numerical end point in the claims is not to be limited to the numerical value itself, and those skilled in the art will appreciate that they include all the acceptable error ranges that are well accepted in the art, such as experimental error, measurement error, statistical error, random error, etc., and that such error ranges are included in the scope of the invention.
The purity of the artemisinin related in the invention is detected by High Performance Liquid Chromatography (HPLC), and the instruments and chromatographic conditions are as follows: the liquid chromatograph model is Agilent 1100series, and the chromatographic column is CAPCELL PAK C18 TYPE MGII, 4.6mm × 250mm, 5 μm; the mobile phase is acetonitrile: 50 parts of water: 50(V: V); the flow rate is 1 ml/min; the ultraviolet detection wavelength is 210 nm; the amount of sample was 20. mu.L. Purity refers to the percentage of the total peak area of the chromatographic peak area of the target in the HPLC profile. For example, artemisinin purity refers to the percentage of the peak area of artemisinin in the HPLC profile of a sample.
Dihydroartemisinic acid may be commercially available or may be synthesized, and the dihydroartemisinic acid used in this example is prepared from artemisinic acid by reduction.
Example of reaction apparatus
Referring to fig. 1, the microchannel reactor of the present invention comprises a temperature controller 1 controlled by a dual temperature zone, five glass microchannel modules 2, three silicon carbide microchannel modules 3, a light source 4, an oxygen source 5, a gas flow meter 6, two feed pumps 7 and 8, a back pressure valve 9, two dosing tanks 10 and 11, and a receiving tank 12. Wherein: the light sources 4 irradiate on both sides of each glass microchannel module 2 simultaneously, increasing the light transmittance, as shown by the arrows in fig. 1; the glass micro-channel module 2 is made of glass materials, is thin-plate square, and is internally provided with a mixing device with a heart-shaped structure, so that the mixing effect of the reaction is improved; the silicon carbide micro-channel module 3 is made of silicon carbide materials, is a thin square and internally provided with a mixing device with a heart-shaped structure, and increases the mixing effect of the reaction; the cooling liquid connected with the temperature controller 1 is tightly attached to the glass micro-channel module 2 and the silicon carbide micro-channel module 3, so that the heat exchange efficiency of the reaction is enhanced.
The temperature controller 1 has a cooling or heating function;
the glass micro-channel module 2 and the silicon carbide micro-channel module 3 are respectively connected with a temperature controller 1 of a dual-temperature zone;
the reaction liquid continuously flows in the glass micro-channel module 2 and the silicon carbide micro-channel module 3;
the light source 4 is an LED light source;
the oxygen source 5 is oxygen;
the gas flow meter 6 is used for adjusting the gas flow rate;
the feeding pump 7 is used for feeding the photo-oxidation reaction and providing continuous flow force;
the feeding pump 8 is used for feeding and providing power for the oxidation rearrangement reaction;
the backpressure valve 9 is used for adjusting pressure;
the batching tank 10 is used for storing the dihydroarteannuic anhydride solution, and the batching tank 11 is used for storing an acid catalyst, such as trifluoroacetic acid;
the receiving tank 12 is for receiving the reaction liquid.
Preparation example preparation of dihydroartemisinic acid
Adding 3000ml of absolute ethyl alcohol and 2000ml (35.02mol) of 85% hydrazine hydrate into 1000g (4.2675mol) of artemisinic acid, controlling the temperature to be 10 ℃ below zero, dropwise adding 1800ml (17.6294mol) of 30% hydrogen peroxide, finishing the reaction after 4H, and dropwise adding 6N hydrochloric acid aqueous solution until the pH value is 1 to obtain 996.6g (4.2170mol) of dihydroartemisinic acid, wherein the yield is 98.74%.
Example 1 preparation of artemisinin
Adding 50g (0.2116mol) of dihydroartemisinic acid prepared in the preparation example into 250ml of dichloromethane, adding 2.5ml (0.03247mol) of N, N-dimethylformamide, dropwise adding 21.67ml (0.2543mol) of oxalyl chloride at 10 ℃, completing the reaction after 1 hour, concentrating the reaction liquid to dryness to obtain 53.2g (0.2094mol) of dihydroartemisinic acid chloride, adding 250ml of dichloromethane and 20ml of triethylamine, adding 50g (0.2116mol) of dihydroartemisinic acid at the temperature of 0 ℃, completing the reaction after 2 hours, concentrating to obtain 94.11g (0.2073mol) of dihydroartemisinic anhydride, and obtaining 97.97 percent.
94.11g (0.2073mol) of dihydroarteannuic anhydride and 0.3g of tetraphenylporphyrin (0.00049mol) are added with 560ml of dichloromethane to be dissolved and clear to obtain feed liquid. Setting the temperature of a glass micro-channel module 2 connected in a temperature controller 1 to be-5 ℃, the temperature of a silicon carbide micro-channel module 3 connected in the temperature controller 1 to be 5 ℃, turning on a light source 4, setting the wavelength to be 405nm, turning on an oxygen source 5, setting the flow rate of oxygen to be 240ml/min, adjusting a back pressure valve by using oxygen to be 9-1.6 MPa, pumping the feed liquid into the glass micro-channel module 2 at the flow rate of 14ml/min by using a feed pump 7, staying for 2.9 minutes, finishing the photo-oxidation reaction to obtain a reaction liquid, enabling the reaction liquid to enter the silicon carbide micro-channel module 3, turning on a feed pump 8, pumping trifluoroacetic acid at the flow rate of 0.3ml/min, performing oxidation rearrangement reaction, staying for 1.7 minutes to obtain 590ml of an artemisinin crude product solution, and turning off the oxygen source 5, the light source 4, the feed pumps 7 and 8 and the temperature controller.
Adding 80ml saturated sodium bicarbonate water solution into the crude artemisinin solution, layering, discarding water layer, concentrating organic phase at 30 deg.C under reduced pressure to dryness, adding 500ml 90% ethanol water solution, crystallizing to obtain 85g (0.3011mol) of artemisinin (VI), with yield of 72.62% (calculated as dihydroarteannuic anhydride), and HPLC detecting to obtain the compound of formula VI with purity of 99.5% and total yield of 71.14% (calculated as dihydroarteannuic acid).
Example 2: preparation of artemisinin
Adding 50g (0.2116mol) of dihydroartemisinic acid prepared in the preparation example into 250ml of dichloromethane, adding 2.5ml (0.03247mol) of N, N-dimethylformamide, dropwise adding 21.67ml (0.2543mol) of oxalyl chloride at 10 ℃, completing the reaction after 1 hour, concentrating the reaction liquid to be dry to obtain 52.8g (0.2079mol) of dihydroartemisinic acid chloride, adding 250ml of dichloromethane and 20ml of triethylamine, adding 50g (0.2116mol) of dihydroartemisinic acid at the temperature of-5 ℃, completing the reaction after 2 hours, concentrating to obtain 93.1g (0.2051mol) of dihydroartemisinic anhydride, and obtaining the yield of 96.93%.
93.1g (0.2051mol) of dihydroarteannuic anhydride and 1.3g of tetraphenylporphyrin (0.002117mol) are added with 370ml of toluene to be dissolved and clear to obtain feed liquid. Setting the temperature of a glass micro-channel module 2 connected in a temperature controller 1 to be 0 ℃, the temperature of a silicon carbide micro-channel module 3 connected in the temperature controller 1 to be 20 ℃, turning on a light source 4, setting the wavelength to be 385nm, turning on an oxygen source 5, setting the flow rate of oxygen to be 200ml/min, adjusting a back pressure valve by using oxygen to be 9-1 MPa, pumping the feed liquid into the glass micro-channel module 2 at the flow rate of 9ml/min by using a feed pump 7, after the retention time is 4.6 minutes, finishing the photo-oxidation reaction to obtain a reaction liquid, feeding the reaction liquid into a silicon carbide reactor module 3, turning on a feed pump 8, pumping trifluoroacetic acid at the flow rate of 0.3ml/min, carrying out oxidation rearrangement reaction, obtaining 400ml of an artemisinin crude product solution after the retention time is 2.7 minutes, and turning off the oxygen source 5, the light source 4, the feed pumps 7 and 8 and the.
Adding 80ml saturated sodium bicarbonate solution into crude artemisinin solution, layering, discarding water layer, concentrating organic phase at 50 deg.C under reduced pressure to dryness, adding 500ml 90% ethanol water solution, and crystallizing to obtain 88g (0.3117mol) of artemisinin (VI) with yield of 75.99% (calculated as dihydroartemisinin anhydride). The compound of formula VI was 99.4% pure by HPLC and the overall yield was 73.65% (calculated as dihydroartemisinic acid).
Example 3: preparation of artemisinin
Adding 50g (0.2116mol) of dihydroartemisinic acid prepared in the preparation example into 250ml of dichloromethane, adding 2.5ml (0.03247mol) of N, N-dimethylformamide, dropwise adding 21.67ml (0.2543mol) of oxalyl chloride at 10 ℃, completing the reaction after 1 hour, concentrating the reaction liquid to dryness to obtain 52.8g (0.2079mol) of dihydroartemisinic acid chloride, adding 250ml of dichloromethane and 20ml of triethylamine, adding 50g (0.2116mol) of dihydroartemisinic acid at the temperature of 0 ℃, completing the reaction after 2 hours, concentrating to obtain 92.8g (0.2041mol) of dihydroartemisinic anhydride, and obtaining yield of 96.60%.
92.8g (0.2041mol) of dihydroarteannuic anhydride and 0.3g of tetraphenylporphyrin (0.00049mol) are added with 500ml of toluene to be dissolved and clear to obtain feed liquid. Setting the temperature of a glass micro-channel module 2 connected in a temperature controller 1 to be-5 ℃, the temperature of a silicon carbide micro-channel module 3 connected in the temperature controller 1 to be 50 ℃, turning on a light source 4, setting the wavelength to be 405nm, turning on an oxygen source 5, setting the flow rate of oxygen to be 200ml/min, adjusting a back pressure valve by using oxygen to be 9-0.6 MPa, pumping the feed liquid into the glass micro-channel module 2 at the flow rate of 4.2ml/min by using a feed pump 7, obtaining reaction liquid after the photooxidation reaction is finished after the residence time is 9.8 minutes, feeding the reaction liquid into the silicon carbide micro-channel module 3, turning on a feed pump 8, pumping trifluoroacetic acid at the flow rate of 0.2ml/min, performing the oxidation rearrangement reaction, obtaining 520ml of artemisinin crude product solution after the residence time is 5.7 minutes, and turning off the oxygen source 5, the light source 4, the feed pumps 7 and 8 and the.
Adding 80ml saturated sodium bicarbonate water solution into the crude artemisinin solution, layering, discarding water layer, concentrating organic phase at 30 deg.C under reduced pressure to dry, adding 400ml ethanol for crystallization to obtain 86g (0.3046mol) of artemisinin (VI), with yield 74.62% (calculated as dihydroarteannuic anhydride), and HPLC detecting to obtain compound of formula VI with purity of 99.3% and total yield 72.08% (calculated as dihydroarteannuic acid).
Claims (17)
1. A chemical semi-synthesis method of artemisinin (VI), which is characterized by comprising the following steps:
(1) reacting dihydroartemisinic acid (I) with oxalyl chloride (II) to generate dihydroartemisinic chloride (III);
(2) performing acylation reaction on the dihydroartemisinic acid chloride (III) and the dihydroartemisinic acid (I) to generate dihydroartemisinic anhydride (IV);
(3) in a microchannel reactor, carrying out photooxidation reaction on dihydro arteannuic anhydride (IV) and oxygen under the action of a photocatalyst to obtain peroxyalcohol (V) of the dihydro arteannuic anhydride; carrying out oxidation rearrangement reaction on peroxyalcohol (V) of dihydro arteannuic anhydride and oxygen under the action of an acid catalyst to obtain artemisinin (VI);
the microchannel reactor comprises 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); wherein the content of the first and second substances,
the temperature controller (1) is a temperature controller of a dual-temperature zone;
the glass micro-channel module (2) is made of glass materials, is in a sheet square shape, and is internally provided with a mixing device with a heart-shaped structure;
the silicon carbide micro-channel module (3) is made of a silicon carbide material, is in a sheet square shape, and is internally provided with a mixing device with a heart-shaped structure;
the feeding pumps (7) and (8) are pumps capable of bearing high pressure;
the back pressure valve (9) has a back pressure regulating function,
the reaction temperature of the oxidation rearrangement reaction in the step (3) is 5-60 ℃,
the retention time of the oxidation rearrangement reaction in the step (3) is 1.7 min-5.7 min.
2. The method of claim 1, wherein the feed pump is a KP-22 or hanbon pump.
3. The method as claimed in claim 1, wherein the organic solvent used in the photooxidation reaction in step (3) is one or more of dichloromethane, toluene, acetonitrile, cyclohexane and n-heptane, and the mass-to-volume ratio of the dihydroarteannuic anhydride (IV) to the organic solvent is 1: 2-20, unit is g/mL.
4. The method as claimed in claim 3, wherein the mass volume ratio of the dihydroarteannuic anhydride (IV) to the organic solvent is 1: 4-6, unit is g/mL.
5. The method as claimed in claim 1, wherein the photocatalyst in the step (3) is tetraphenylporphyrin, and the molar ratio of dihydroarteannuic anhydride (IV) to the photocatalyst is 1: 0.001 to 1; the acid catalyst is a protonic acid and/or a Lewis acid.
6. The method as claimed in claim 5, wherein in the step (3), the molar ratio of the dihydroarteannuic anhydride (IV) to the photocatalyst is 1: 0.002 to 0.01; the acid catalyst is trifluoroacetic acid.
7. The method as claimed in claim 1, 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 365-660 nm.
8. The method according to claim 7, wherein the light source used for the photooxidation reaction in the step (3) has a wavelength of 385nm or 405 nm.
9. The method according to claim 8, wherein the light source used for the photooxidation reaction in step (3) has a wavelength of 385 nm.
10. The method according to claim 1, wherein the reaction temperature of the photooxidation reaction in the step (3) is-10 ℃ to 20 ℃; the residence time of the photooxidation reaction in the step (3) is 2.9 min-10.2 min.
11. The method according to claim 10, wherein the reaction temperature of the photooxidation reaction in the step (3) is-5 ℃ to 5 ℃; the reaction temperature of the oxidation rearrangement reaction in the step (3) is 20 ℃; the residence time of the photooxidation reaction in the step (3) is 4min to 5.5 min.
12. The method as claimed in claim 11, wherein the reaction temperature of the photo-oxidation reaction in the step (3) is 0 ℃.
13. The method of claim 1, wherein the flow rate of the oxygen in the microchannel reactor in step (3) is 120ml/min to 300 ml/min.
14. The method of claim 13, wherein the flow rate of oxygen in step (3) in the microchannel reactor is 160ml/min to 240 ml/min.
15. The method according to claim 1, wherein the photo-oxidation reaction and the oxidative rearrangement reaction of step (3) are continuous reactions, and the photo-oxidation reaction and the oxidative rearrangement reaction are both at a pressure of 0.5 to 1.7 MPa.
16. The method according to any one of claims 1 to 15, wherein the step (3) further comprises further crystallization purification of the obtained artemisinin, and the crystallization solvent is one or more of methanol, ethanol, isopropanol, acetone, methanol and water, ethanol and water.
17. The process according to claim 16, wherein the crystallization solvent used in step (3) is ethanol.
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