Preparation method of artemisinene

Abstract

The invention belongs to the technical field of preparation of artemisinin, and discloses a preparation method of artemisinin, which comprises the following steps: reacting diisopropylamine with n-butyllithium in anhydrous THF (tetrahydrofuran) to generate strong base lithium diisopropylamide and obtain a strong base lithium diisopropylamide solution; step 2, then adding a mixed solution of artemisinin and THF into the strong base lithium diisopropylamide solution; the strong base lithium diisopropylamide is used as a strong base to capture specific acidic hydrogen in artemisinin molecules to form an enol salt intermediate; benzene sulfonyl chloride is added to react with hydroxyl of the enol salt intermediate to generate sulfonate; taking a sulfonate group as a good leaving group, carrying out beta-elimination under an alkaline condition to form a double bond, reacting to obtain an artemisinin solution, and purifying the artemisinin solution to obtain a pure product artemisinin; according to the method, benzenesulfonyl chloride and artemisinin which are low in price and easy to obtain are used as main raw materials, the artemisinin is synthesized through a one-pot method, and the method is simple in process, environmentally friendly, high in yield and suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of artemisinin preparation technology, and in particular to a method for preparing artemisinin. Background Technology

[0002] Artemisinin is an oxidative metabolite of artemisinin, and its content in Artemisia annua is extremely low (natural abundance <0.01%), therefore, artemisinin has not been widely used. Artemisinin can act as a chemical activator of Nrf2, activating the body's antioxidant defense system, eliminating free radicals produced by metabolism, and promoting the metabolism of ingested toxic environmental substances such as carcinogens. This can inhibit aging and prevent environmental pollution-induced tissue damage and cancer development. Artemisinin can also prevent the progression of various chronic diseases such as diabetes, cardiovascular disease, neurodegenerative diseases, and chronic lung and kidney diseases.

[0003] Artemisinin can be synthesized chemically. Existing technologies report methods for preparing artemisinin from artemisinin as a starting material through a four-step chemical reaction, but these methods involve many steps and have low yields. Another method uses artemisinin and phenyl selenide as the main raw materials to synthesize artemisinin, but phenyl selenide is expensive and highly toxic, making it unsuitable for pharmaceutical and food production. Furthermore, artemisinin is difficult to react completely during the reaction, leading to complex subsequent separation and purification processes. A third method uses artemisinin and phenyl diselenyl ether as the main raw materials, but phenyl diselenyl ether is expensive and highly toxic, and the reaction yield is low, making separation and purification difficult, also unsuitable for pharmaceutical and food production. A one-pot synthesis of artemisinin from artemisinin and p-toluenesulfinyl chloride is possible, but p-toluenesulfinyl chloride is extremely unstable and needs to be prepared and used immediately. This method is complex, environmentally unfriendly, and results in incomplete conversion of artemisinin, making subsequent separation and purification complex and unsuitable for industrial production. Summary of the Invention

[0004] To overcome the technical defects of the existing technology, the present invention provides a method for preparing artemisinin, which uses inexpensive and readily available benzenesulfonyl chloride and artemisinin as the main raw materials to synthesize artemisinin in a one-pot process. The process is simple, environmentally friendly, and has a high yield, making it suitable for industrial production.

[0005] The technical solution adopted in this invention is: a method for preparing artemisinin, comprising the following steps,

[0006] Step 1: React diisopropylamine and n-butyllithium in anhydrous THF to generate a strong base diisopropylaminolithium, thus obtaining a strong base diisopropylaminolithium solution.

[0007] Step 2: Then, add a mixture of artemisinin and THF to the strong base diisopropylaminolithium solution; the strong base diisopropylaminolithium acts as a strong base to remove specific acidic hydrogen from the artemisinin molecule, forming an enol salt intermediate.

[0008] Step 3: Add benzenesulfonyl chloride to react with the hydroxyl group of the enol salt intermediate to generate a sulfonate ester; the sulfonate ester group, as a good leaving group, undergoes β-elimination under alkaline conditions to form a double bond, and the reaction yields artemisinin solution.

[0009] Step 4: Purify the artemisinin solution to obtain pure artemisinin.

[0010] Preferably, the molar ratio of diisopropylamine, n-butyllithium, artemisinin, and benzenesulfonyl chloride is (1.0-3.0):(1.0-3.0):1.0:(1.2-3.0).

[0011] Preferably, the benzenesulfonyl chloride is one of benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, p-methoxybenzenesulfonyl chloride, p-chlorobenzenesulfonyl chloride, and p-(isopropyl)benzenesulfonyl chloride.

[0012] Preferably, the method for purifying the artemisinin solution to obtain pure artemisinin in step 4 is as follows: the artemisinin solution is introduced into a saturated ammonium chloride solution, stirred for 10-30 minutes, and extracted with ethyl acetate. The ethyl acetate phases are combined and washed successively with saturated sodium bicarbonate solution, water, and saturated brine. The mixture is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and a pale yellow solid is obtained. Finally, the solid is recrystallized from dichloromethane / petroleum ether to obtain a white needle-like solid.

[0013] Preferably, the reaction temperature of diisopropylamine and n-butyllithium in anhydrous THF in step 1 is -20°C to -40°C.

[0014] Preferably, the reaction temperature between the strong base diisopropylaminolithium solution and artemisinin in step 2 is -70 to -80°C.

[0015] Preferably, after adding benzenesulfonyl chloride and reacting with the hydroxyl group of the enol salt intermediate to generate a sulfonate ester, the temperature is raised to 0-10°C and the reaction continues for 1-3 hours.

[0016] The beneficial effects of this invention are as follows: By setting a specific preparation method, the process is as follows: Diisopropylamine and n-butyllithium are reacted in anhydrous THF to generate a strong base, diisopropylaminolithium, and a strong base diisopropylaminolithium solution is obtained; Step 2: Artemisinin and THF are then added to the strong base diisopropylaminolithium solution; the strong base diisopropylaminolithium, as a strong base, abstracts a specific acidic hydrogen from the artemisinin molecule to form an enol salt intermediate; benzenesulfonyl chloride is added to react with the hydroxyl group of the enol salt intermediate to generate a sulfonate ester; the sulfonate ester group, as a good leaving group, undergoes β-elimination under alkaline conditions to form a double bond, and the reaction yields an artemisinin solution; the artemisinin solution is purified to obtain pure artemisinin; artemisinin is synthesized in a one-pot process using inexpensive and readily available benzenesulfonyl chloride and artemisinin as the main raw materials. The process is simple, environmentally friendly, and has a high yield, making it suitable for industrial production. Attached Figure Description

[0017] One or more embodiments are illustrated by way of example with reference numerals in the accompanying drawings. These illustrations do not constitute a limitation on the embodiments. Elements with the same reference numerals in the drawings are denoted as similar elements. Unless otherwise stated, the figures in the drawings are not to be limited by scale.

[0018] Figure 1 This is a schematic diagram of the preparation process of the present invention;

[0019] Figure 2 The mass spectrum of artemisinin of the present invention is shown below;

[0020] Figure 3 This is the carbon NMR spectrum of artemisinin according to the present invention. Detailed Implementation

[0021] To make the objectives, technical solutions, and advantages of this invention clearer, the various embodiments of this invention will be described in detail below with reference to the accompanying drawings. However, those skilled in the art will understand that many technical details have been provided in the various embodiments of this invention to facilitate a better understanding of this application. However, the technical solutions claimed in the claims of this application can be implemented even without these technical details and with various variations and modifications based on the following embodiments.

[0022] like Figure 1-3 As shown in Example 1, this example provides a method for preparing artemisinin, including the following steps:

[0023] Step 1: React diisopropylamine and n-butyllithium in anhydrous THF to generate a strong base diisopropylaminolithium, thus obtaining a strong base diisopropylaminolithium solution.

[0024] Step 2: Then, add a mixture of artemisinin and THF to the strong base diisopropylaminolithium solution; the strong base diisopropylaminolithium acts as a strong base to remove specific acidic hydrogen from the artemisinin molecule, forming an enol salt intermediate.

[0025] Step 3: Add benzenesulfonyl chloride to react with the hydroxyl group of the enol salt intermediate to generate a sulfonate ester; the sulfonate ester group, as a good leaving group, undergoes β-elimination under alkaline conditions to form a double bond, and the reaction yields artemisinin solution.

[0026] Step 4: Purify the artemisinin solution to obtain pure artemisinin.

[0027] The reaction equation is shown below.

[0028]

[0029] This invention employs a specific preparation method, the process of which is as follows: Diisopropylamine and n-butyllithium are reacted in anhydrous THF to generate a strong base, diisopropylaminolithium, yielding a strong base diisopropylaminolithium solution; Step 2: A mixture of artemisinin and THF is then added to the strong base diisopropylaminolithium solution; the strong base diisopropylaminolithium, acting as a strong base, abstracts a specific acidic hydrogen from the artemisinin molecule, forming an enol salt intermediate; benzenesulfonyl chloride is added to react with the hydroxyl group of the enol salt intermediate to generate a sulfonate ester; the sulfonate ester group, acting as a good leaving group, undergoes β-elimination under alkaline conditions to form a double bond, resulting in an artemisinin solution; the artemisinin solution is then purified to obtain pure artemisinin; artemisinin is synthesized in a one-pot process using inexpensive and readily available benzenesulfonyl chloride and artemisinin as the main raw materials. This process is simple, environmentally friendly, and has a high yield, making it suitable for industrial production.

[0030] The molar ratio of diisopropylamine, n-butyllithium, artemisinin, and benzenesulfonyl chloride is (1.0-3.0):(1.0-3.0):1.0:(1.2-3.0). The benzenesulfonyl chloride is one of benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, p-methoxybenzenesulfonyl chloride, p-chlorobenzenesulfonyl chloride, and p-(isopropyl)benzenesulfonyl chloride.

[0031] The molar ratio of diisopropylamine, n-butyllithium, artemisinin, and p-toluenesulfonyl chloride may be 1.2-2.0:(1.2-2.0):1.0:(1.5-2.0); the benzenesulfonyl chloride is preferably benzenesulfonyl chloride, p-toluenesulfonyl chloride, or p-methoxybenzenesulfonyl chloride. Specific choices can be made at the discretion of the user.

[0032] The method for purifying artemisinin solution to obtain pure artemisinin in step 4 is as follows: the artemisinin solution is introduced into a saturated ammonium chloride solution, stirred for 10-30 minutes, and extracted with ethyl acetate. The ethyl acetate phases are combined and washed successively with saturated sodium bicarbonate solution, water, and saturated brine. The solution is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and a pale yellow solid is obtained. Finally, the solid is recrystallized from dichloromethane / petroleum ether to obtain a white needle-like solid.

[0033] In step 1, the reaction temperature of diisopropylamine and n-butyllithium in anhydrous THF is -20℃ to -40℃. This suppresses side reactions, improves selectivity, and reduces reagent decomposition: n-butyllithium (n-BuLi) readily undergoes side reactions (such as ring-opening or polymerization) with THF at higher temperatures; low temperatures slow down these processes and avoid reagent waste. It also prevents the self-reaction of the strong base diisopropylaminolithium (LDA): the generated strong base diisopropylaminolithium (LDA) may undergo self-decomposition or further reaction with the solvent at high temperatures; low temperatures suppress such side reactions.

[0034] Controlling reaction rate and exothermic risks: Exothermic reaction management: The reaction between DIPA and n-BuLi is exothermic. Low-temperature environments (such as below -20℃) can slow down the reaction rate and prevent local overheating that could lead to runaway or explosion risks. Uniform mixing: The moderate diffusion rate of reagents at low temperatures helps maintain the homogeneity of the reaction system and avoids excessively high local concentrations that could trigger violent reactions. Maintaining solvent performance and reagent stability: Low-temperature adaptability of THF: THF remains liquid at -40℃ (freezing point approximately -108℃), ensuring that the solvent effectively dissolves the reagent and participates in the coordination stabilization of LDA. Stability of lithium reagents: Low temperatures delay the oxidation or hydrolysis of n-butyllithium, improving reaction efficiency, optimizing LDA formation and activity, and coordination stabilization: The oxygen atoms of THF coordinate more effectively with lithium ions at low temperatures, stabilizing the LDA structure, enhancing its basic activity, and facilitating subsequent deprotonation steps.

[0035] In step 2, the reaction temperature between the strong base diisopropylaminolithium solution and artemisinin is -70 to -80°C. This improves deprotonation selectivity. Since artemisinin molecules may contain multiple acidic hydrogens (such as protons near the hydroxyl group or lactone ring), the extremely low temperature environment significantly slows the reaction rate, allowing LDA to preferentially abstract target acidic hydrogens (such as α-H at specific sites). This avoids excessive deprotonation or damage to other sensitive groups (such as peroxy bridge structures), thereby improving the purity of the product (such as artemisininene) and inhibiting artemisinin decomposition.

[0036] Artemisinin is heat-sensitive; high temperatures can lead to side reactions such as the breaking of its peroxide bridge or the opening of its lactone ring. Low temperatures below -70°C can maximize the structural stability of artemisinin, prevent raw material degradation, control the activity of strong bases and side reactions, and reduce the aggressiveness of LDA: although LDA is extremely basic, low temperatures can limit its side reactions with THF solvents or other reagents (such as THF ring-opening and lithium reagent polymerization). It also reduces the elimination of byproducts: if the reaction involves sulfonate intermediates (such as artemisinin-OTs), low temperatures can inhibit premature β-elimination or rearrangement, ensuring that the elimination step proceeds as expected.

[0037] After adding benzenesulfonyl chloride and reacting with the hydroxyl group of the enol salt intermediate to generate sulfonate, the temperature is raised to 0-10℃ and the reaction continues for 1-3 hours, thus promoting the complete sulfonation reaction.

[0038] Increase reaction rate: The reaction rate of sulfonyl chloride with enol salt is slow at low temperature (e.g. -78℃). Heating to above 0℃ can accelerate nucleophilic substitution and ensure more complete formation of sulfonate esters (e.g., artemisinin-OTs).

[0039] Reduce intermediate residues: Extending the reaction time (1–3 hours) helps consume unreacted benzenesulfonyl chloride or unconverted enolate, avoiding interference from impurities in subsequent steps. Preheating is also necessary for subsequent elimination reactions.

[0040] Activation elimination step: Sulfonate groups (-OTs) are good leaving groups. Heating to 0–10℃ can provide activation energy for subsequent β-elimination (to generate the double bond of artemisinin), making the elimination reaction more efficient.

[0041] Equilibrium reaction system: Gentle heating can avoid runaway caused by violent exothermic reactions, while maintaining the fluidity of the system and ensuring uniform mixing of reagents.

[0042] Suppressing side reactions and avoiding low-temperature crystallization: Solvents such as THF may induce crystallization of reactants or intermediates at extremely low temperatures. Heating to above 0°C can maintain a homogeneous solution. Controlling the hydrolysis of sulfonyl chloride: If too much benzenesulfonyl chloride remains, it may slowly hydrolyze to produce benzenesulfonic acid. Increasing the temperature and controlling the reaction time can reduce such byproducts.

[0043] Example 2: A method for preparing artemisinin, the specific process is as follows: Anhydrous THF (50 mL) and diisopropylamine (10.12 g, 100 mmol) were added to a 250 mL round-bottom flask. The reaction mixture was cooled to -20 °C, and 2.4 M n-butyllithium (30 mL, 72 mmol) was added dropwise. After the addition was complete, the reaction mixture was cooled to -80 °C, and a mixture of artemisinin (16.9 g, 60 mmol) and THF (60 mL) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed for 1 hour. Then, a pre-prepared mixture of p-toluenesulfonyl chloride (17.2 g, 90 mmol) and THF (40 mL) was added dropwise. After the addition was complete, the reaction was allowed to proceed for 1 hour. Then, the temperature was raised to 0 °C, and the reaction was continued for 2 hours. The reaction was stopped, and the reaction mixture was introduced into a saturated ammonium chloride solution (300 mL). The mixture was stirred for 10 minutes, extracted with ethyl acetate (250 mL × 3), and the combined ethyl acetate phases were washed successively with saturated sodium bicarbonate solution, water, and saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a pale yellow solid. Recrystallization from dichloromethane / petroleum ether (1:10) yielded 14.3 g of needle-like crystals, with a yield of 85%. Melting point: 161-162 °C.

[0044] Example 3: A method for preparing artemisinin, the specific process is as follows: Anhydrous THF (50 mL) and diisopropylamine (10.12 g, 100 mmol) were added to a 250 mL round-bottom flask. The reaction mixture was cooled to -40 °C, and 2.4 M n-butyllithium (30 mL, 72 mmol) was added dropwise. After the addition was complete, the reaction mixture was cooled to -80 °C, and a mixture of artemisinin (16.9 g, 60 mmol) and THF (60 mL) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed for 1 hour. Then, a pre-prepared mixture of p-toluenesulfonyl chloride (19.1 g, 100 mmol) and THF (40 mL) was added dropwise. After the addition was complete, the reaction was allowed to proceed for 1 hour. The temperature was then raised to 0 °C, and the reaction was continued for another hour. The reaction was stopped, and the reaction mixture was introduced into a saturated ammonium chloride solution (300 mL). The mixture was stirred for 10 minutes, extracted with ethyl acetate (250 mL × 3), and the combined ethyl acetate phases were washed successively with saturated sodium bicarbonate solution, water, and saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a pale yellow solid. Recrystallization from dichloromethane / petroleum ether (1:10) yielded 14.78 g of needle-like crystals, with a yield of 88%.

[0045] Example 4: A method for preparing artemisinin, the specific process is as follows: Anhydrous THF (50 mL) and diisopropylamine (8.1 g, 80 mmol) were added to a 250 mL round-bottom flask. The reaction mixture was cooled to -40 °C, and 2.4 M n-butyllithium (30 mL, 72 mmol) was added dropwise. After the addition was complete, the reaction mixture was cooled to -70 °C, and a mixture of artemisinin (16.9 g, 60 mmol) and THF (60 mL) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed for 1 hour. Then, a pre-prepared mixture of p-toluenesulfonyl chloride (22.9 g, 120 mmol) and THF (40 mL) was added dropwise. After the addition was complete, the reaction was allowed to proceed for 1 hour. The temperature was then raised to 0 °C, and the reaction was continued for 2 hours. The reaction was stopped, and the reaction mixture was introduced into a saturated ammonium chloride solution (300 mL). The mixture was stirred for 10 minutes, extracted with ethyl acetate (250 mL × 3), and the combined ethyl acetate phases were washed successively with saturated sodium bicarbonate solution, water, and saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a pale yellow solid. Recrystallization from dichloromethane / petroleum ether (1:10) yielded 13.44 g of needle-like crystals, with a yield of 80%.

[0046] Example 5: A method for preparing artemisinin, the specific process is as follows: Anhydrous THF (50 mL) and diisopropylamine (12.14 g, 120 mmol) were added to a 250 mL round-bottom flask. The reaction mixture was cooled to -40 °C, and 2.4 M n-butyllithium (50 mL, 120 mmol) was added dropwise. After the addition was complete, the reaction mixture was cooled to -70 °C, and a mixture of artemisinin (16.9 g, 60 mmol) and THF (60 mL) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed for 1 hour. Then, a pre-prepared mixture of p-toluenesulfonyl chloride (22.9 g, 120 mmol) and THF (40 mL) was added dropwise. After the addition was complete, the reaction was allowed to proceed for 1 hour. Then, the temperature was raised to 0 °C, and the reaction was continued for 2 hours. The reaction was stopped, and the reaction mixture was introduced into a saturated ammonium chloride solution (300 mL). The mixture was stirred for 10 minutes, extracted with ethyl acetate (250 mL × 3), and the combined ethyl acetate phases were washed successively with saturated sodium bicarbonate solution, water, and saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a pale yellow solid. Recrystallization from dichloromethane / petroleum ether (1:10) yielded 13.78 g of needle-like crystals, with a yield of 82%.

[0047] Example 6: A method for preparing artemisinin, the specific process is as follows: Anhydrous THF (50 mL) and diisopropylamine (6.07 g, 72 mmol) were added to a 250 mL round-bottom flask. The reaction mixture was cooled to -40 °C, and 2.4 M n-butyllithium (30 mL, 72 mmol) was added dropwise. After the addition was complete, the reaction mixture was cooled to -80 °C, and a mixture of artemisinin (16.9 g, 60 mmol) and THF (60 mL) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed for 1 hour. Then, a pre-prepared mixture of p-toluenesulfonyl chloride (22.9 g, 120 mmol) and THF (40 mL) was added dropwise. After the addition was complete, the reaction was allowed to proceed for 1 hour. Then, the temperature was raised to 0 °C, and the reaction was continued for 2 hours. The reaction was stopped, and the reaction mixture was introduced into a saturated ammonium chloride solution (300 mL). The mixture was stirred for 10 minutes, extracted with ethyl acetate (250 mL × 3), and the combined ethyl acetate phases were washed successively with saturated sodium bicarbonate solution, water, and saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a pale yellow solid. Recrystallization from dichloromethane / petroleum ether (1:10) yielded 13.10 g of needle-like crystals, with a yield of 78%.

[0048] Example 6: A method for preparing artemisinin, the specific process is as follows: Anhydrous THF (50 mL) and diisopropylamine (6.07 g, 72 mmol) were added to a 250 mL round-bottom flask. The reaction mixture was cooled to -20 °C, and 2.4 M n-butyllithium (30 mL, 72 mmol) was added dropwise. After the addition was complete, the reaction mixture was cooled to -80 °C, and a mixture of artemisinin (16.9 g, 60 mmol) and THF (60 mL) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed for 1 hour. Then, a pre-prepared mixture of p-methoxybenzenesulfonyl chloride (24.7 g, 120 mmol) and THF (40 mL) was added dropwise. After the addition was complete, the reaction was allowed to proceed for 1 hour. Then, the temperature was raised to 0 °C, and the reaction was continued for 2 hours. The reaction was stopped, and the reaction mixture was introduced into a saturated ammonium chloride solution (300 mL). The mixture was stirred for 10 minutes, extracted with ethyl acetate (250 mL × 3), and the combined ethyl acetate phases were washed successively with saturated sodium bicarbonate solution, water, and saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a pale yellow solid. Recrystallization from dichloromethane / petroleum ether (1:10) yielded 14.4 g of needle-like crystals, with a yield of 86%.

[0049] Example 7: A method for preparing artemisinin, the specific process is as follows: Anhydrous THF (50 mL) and diisopropylamine (6.07 g, 72 mmol) are added to a 250 mL round-bottom flask. The reaction mixture is cooled to -20 °C, and 2.4 M n-butyllithium (30 mL, 72 mmol) is added dropwise. After the addition is complete, the reaction mixture is cooled to -80 °C, and a mixture of artemisinin (16.9 g, 60 mmol) and THF (60 mL) is slowly added dropwise. After the addition is complete, the reaction is allowed to proceed for 1 hour. Then, a pre-prepared mixture of p-methoxybenzenesulfonyl chloride (24.7 g, 120 mmol) and THF (40 mL) is added dropwise. After the addition is complete, the reaction is allowed to proceed for 1 hour. Then, the temperature is raised to 0 °C, and the reaction continues for 2 hours. The reaction was stopped, and the reaction mixture was introduced into a saturated ammonium chloride solution (300 mL). The mixture was stirred for 10 minutes, extracted with ethyl acetate (250 mL × 3), and the combined ethyl acetate phases were washed successively with saturated sodium bicarbonate solution, water, and saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a pale yellow solid. Recrystallization from dichloromethane / petroleum ether (1:10) yielded 14.4 g of needle-like crystals, with a yield of 86%.

[0050] As can be seen from Examples 1-7, the artemisinin preparation method provided by this invention achieves an artemisinin yield of over 80%. This invention uses inexpensive and readily available benzenesulfonyl chloride and artemisinin as the main raw materials to synthesize artemisinin in a one-pot process. The process is simple, environmentally friendly, and has a high yield, making it suitable for industrial production.

[0051] Those skilled in the art will understand that the above embodiments are specific examples of implementing the present invention, and in practical applications, various changes in form and detail may be made without departing from the spirit and scope of the present invention.

Claims

1. A method for preparing artemisinin, characterized in that: Includes the following steps, Step 1: React diisopropylamine and n-butyllithium in anhydrous THF to generate a strong base diisopropylaminolithium, thus obtaining a strong base diisopropylaminolithium solution. Step 2: Then, add a mixture of artemisinin and THF to the strong base diisopropylaminolithium solution; the strong base diisopropylaminolithium acts as a strong base to remove specific acidic hydrogen from the artemisinin molecule, forming an enol salt intermediate. Step 3: Add benzenesulfonyl chloride to react with the hydroxyl group of the enol salt intermediate to generate sulfonate; the sulfonate group is a good leaving group, and under alkaline conditions, it undergoes β-elimination to form a double bond, and the reaction yields artemisinin solution; Step 4: Purify the artemisinin solution to obtain pure artemisinin.

2. The method for preparing artemisinin according to claim 1, characterized in that: The molar ratio of diisopropylamine, n-butyllithium, artemisinin, and benzenesulfonyl chloride is (1.0-3.0):(1.0-3.0):1.0:(1.2-3.0).

3. The method for preparing artemisinin according to claim 1, characterized in that: The benzenesulfonyl chloride is one of benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, p-methoxybenzenesulfonyl chloride, p-chlorobenzenesulfonyl chloride, and p-(isopropyl)benzenesulfonyl chloride.

4. The method for preparing artemisinin according to claim 1, characterized in that: The method for purifying artemisinin solution to obtain pure artemisinin in step 4 is as follows: the artemisinin solution is introduced into a saturated ammonium chloride solution, stirred for 10-30 minutes, and extracted with ethyl acetate. The ethyl acetate phases are combined and washed successively with saturated sodium bicarbonate solution, water, and saturated brine. The solution is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and a pale yellow solid is obtained. Finally, the solid is recrystallized from dichloromethane / petroleum ether to obtain a white needle-like solid.

5. The method for preparing artemisinin according to claim 1, characterized in that: The reaction temperature of diisopropylamine and n-butyllithium in anhydrous THF in step 1 is -20℃ to -40℃.

6. The method for preparing artemisinin according to claim 1, characterized in that: The reaction temperature between the strong base diisopropylaminolithium solution and artemisinin in step 2 is -70 to -80°C.

7. The method for preparing artemisinin according to claim 1, characterized in that, After adding benzenesulfonyl chloride and reacting with the hydroxyl group of the enol salt intermediate to form a sulfonate ester, the temperature is raised to 0-10℃ and the reaction continues for 1-3 hours.

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