Preparation method of beta-artemether
By optimizing the β-artemethyl ether preparation process, using specific reducing agents and etherification reagent ratios to control temperature and reaction time, the problem of low yield of the etherification step is solved, the total yield and product purity are improved, the production cost is reduced, and the efficient optimization of the process is achieved.
Patent Information
- Application Number
- CN202411680136.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-22
- Publication Date
- 2025-02-25
AI Technical Summary
In the existing β-artemisother preparation process, the yield of the etherification step is low, resulting in excessive total yield and product cost and lack of competitiveness.
By optimizing the process flow, specific reduction agent and etherification reagent ratio are adopted, and the temperature and reaction time are controlled to improve the yield of etherification reaction. The specific steps include adding a reducing agent in batches under 0 to 10°C, then adding etherification reagent and drinking water dropwise to control the stirring time, and ensuring that β-artemite ether is filtered and dried after the reaction is completed.
The etherification yield and total yield of β-artemisomethyl ether are significantly improved, and the product purity reaches more than 99.5%, reducing production costs, and improving process efficiency and product quality.
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic chemistry or medicinal chemistry, and in particular relates to a method for preparing beta-artemether. Background Art
[0002] Malaria is the most common and harmful mosquito-borne infectious disease in the world today, especially falciparum malaria, which still threatens the health of hundreds of millions of residents in tropical and subtropical countries.
[0003] Artemether is a derivative of artemisinin. In addition to the advantages of artemisinin such as rapid effect and low toxicity, it is also more soluble in oil than artemisinin, which is particularly beneficial for the preparation of preparations. Artemether has two isomers, α-artemether and β-artemether. The one with antimalarial activity is mainly β-artemether, while the α configuration has no antimalarial effect.
[0004] The production process of artemether uses artemisinin as the starting material, and obtains the intermediate dihydroartemisinin through a one-pot reduction reaction, then adds an etherification agent to obtain the crude artemether through an etherification reaction, and finally purifies artemether. The reduction reaction yield is stable at about 90%, the refining yield is about 92%, and the etherification step yield is about 60%, and the total yield is about 50%. The etherification process lowers the total yield mainly through the etherification process.
[0005] Since the yield of the existing etherification step for preparing artemether is about 60% and the total yield is about 50%, the material cost of the preparation is too high and it is not competitive in China, so it is necessary to further optimize the process to improve the yield and reduce the cost. Summary of the invention
[0006] In view of the deficiencies in the prior art, the present invention provides a method for preparing β-artemether. Through the preparation method, the average yield of etherification is about 90%, the total yield is about 85%, and the purity of the crude product is about 99.5%, which greatly improves the yield and reduces the preparation cost.
[0007] In order to achieve the above object, the technical solution of the present invention is:
[0008] A preparation method of β-artemisinin comprises the following steps: adding methanol and artemisinin into a container, cooling the temperature to -8 to 5°C, adding a reducing agent in three batches, stirring and reacting for 1 to 3 hours after the reducing agent is added, obtaining dihydroartemisinin, and controlling the temperature at 0 to 10°C if the intermediate control is qualified. Then, adding an etherification agent dropwise into the dihydroartemisinin, stirring for 5 minutes, adding trimethyl orthoacetate, keeping the temperature at 0 to 10°C, stirring for 1 to 2 hours, and controlling the temperature at 0 to 10°C if the intermediate control is qualified. Then, adding drinking water dropwise, keeping the temperature at 0 to 10°C, stirring for 1 to 2 hours, filtering to obtain a crude wet product of artemisinin, and drying to obtain β-artemisinin.
[0009] As another preferred scheme, the preparation method adopts a one-pot method, including the following operations: adding methanol to a container, starting stirring, cooling to 0-10°C, slowly dripping an etherification reagent, controlling the temperature at 0-10°C, stirring for 15 minutes after the addition is completed, adding trimethyl orthoacetate and dihydroartemisinin, stirring at 0-10°C for 1 hour, after the central control is qualified, transferring the feed liquid to another container, controlling the temperature at 0-10°C, slowly dripping drinking water, stirring at 0-10°C for 1 hour, filtering to obtain a crude wet product of artemisinin, and drying to obtain β-artemisinin.
[0010] Preferably, the reducing agent is sodium borohydride.
[0011] Preferably, the molar ratio of the reducing agent to artemisinin is 1:1 to 2:1.
[0012] Preferably, the etherification agent is any one of thionyl chloride, acetyl chloride and propionyl chloride.
[0013] Preferably, the molar ratio of dihydroartemisinin to the etherification agent and trimethyl orthoacetate is 1:(0.02-0.5):(2.0-2.5).
[0014] Technical effects and advantages of the present invention:
[0015] By adopting the β-artemisinin synthesis method of the present application, compared with the original production process, the yield of the β-artemisinin synthesis process is greatly enhanced, and the quality of the product is also ensured. Specifically, the conversion rate of the product is increased from the original 40-50% to 80-90%, and the overall conversion rate of the product is increased by nearly 30%; the quality of the product is higher than before, the original purity reached more than 98%, and now it is basically above 99.5%, which ensures the quality of the product; the generation ratio of α-artemisinin is reduced, and the production cost is reduced. DETAILED DESCRIPTION
[0016] The following examples are given to further illustrate the present invention in detail.
[0017] Embodiment 1 (one-step method)
[0018] The experiment was carried out using thionyl chloride as the etherification reagent:
[0019] Add 900 ml methanol and 50 g artemisinin into a 2000 ml four-necked flask, start stirring, cool to -2°C, add 10 g (3 g, 3 g, 4 g) of sodium borohydride in three portions, after the addition is completed and the central control is qualified, slowly add 62.5 g thionyl chloride dropwise, add 125 g trimethyl orthoacetate, control the temperature at 4°C, after the addition is completed, stir at 6°C for 1 hour, and take a central control sampling point plate (ethyl acetate: n-hexane = 1:4, iodine fumigation for color development). After the central control is qualified, transfer the feed liquid into a 3000 ml four-necked flask, control the temperature at 5°C, slowly add 1800 ml drinking water dropwise, after the addition is completed, stir at 8°C for 1 hour, filter, and obtain a crude wet product of artemether, dry at 45-50°C to obtain 46.3 g of a dry product, with a yield of 89.8%, a purity of about 99.3%, and a single impurity of less than 0.2%.
[0020] Embodiment 2 (one-step method)
[0021] The experiment was carried out using propionyl chloride as the etherification reagent:
[0022] Add 900 ml methanol and 50 g artemisinin into a 2000 ml four-necked flask, start stirring, cool to 1°C, add 20 g (7 g, 7 g, 6 g) sodium borohydride in three portions, after the addition is complete and the central control is qualified, slowly add 48.8 g propionyl chloride, add 125 g trimethyl orthoacetate, control the temperature at 3°C, stir for 2 hours, and use the central control sampling point plate (ethyl acetate: n-hexane = 1:4, iodine fumigation for color development). After the central control is qualified, transfer the feed liquid into a 3000 ml four-necked flask, control the temperature at 6°C, slowly add 1200 saturated salt water drops, after the addition is complete, stir at 9°C for 50 minutes, filter, and obtain a crude wet product of artemether, dry it, and obtain 47.5 g of a dry product with a yield of 90.1%, a purity of about 99.4%, and a single impurity of less than 0.2%.
[0023] Embodiment 3 (one-step method)
[0024] The experiment was carried out using acetyl chloride as the etherification reagent:
[0025] Add 900 ml methanol and 50 g artemisinin into a 2000 ml four-necked flask, start stirring, cool to -3°C, add 10 g (3 g, 3 g, 4 g) of sodium borohydride in three times, add 42.5 g acetyl chloride slowly, add 125 g trimethyl orthoacetate, control the temperature at 2°C, add dropwise, stir at 4°C for 1 hour, control the sampling point plate (ethyl acetate: n-hexane = 1:4, iodine fumigation for color development), after the control is qualified, transfer the feed liquid into a 3000 ml four-necked flask, control the temperature at 7°C, slowly add dropwise 1800 ml drinking water, add dropwise, stir at 10°C for 1 hour, filter, and obtain a crude wet product of artemether, dry it, and obtain 46.3 g of a dry product with a yield of 90.8%, a purity of about 99.5%, and a single impurity of less than 0.2%.
[0026] Comparative Example 1 (one-step method)
[0027] The experiment was carried out using hydrochloric acid as the etherification reagent:
[0028] Add 160 ml methanol and 20 g artemisinin into a 1000 ml four-necked bottle, cool to 5°C, add 4 g (1.5 g, 1.5 g, 1 g) sodium borohydride (0.106 mol) in 3 portions, after adding, control the temperature and stir to react for 1 to 3 hours, if the intermediate control is qualified, control the temperature at 10°C, drop 26 g hydrochloric acid (0.21 mol), after adding, stir for 5 minutes, add 50 g trimethyl orthoacetate, keep warm at 6°C and stir for 1.2 hours, if the intermediate control is qualified, extend the time has no effect, control the temperature at 7°C, add 320 ml drinking water, after adding, keep warm and stir for 1 hour, filter to obtain crude wet artemether, dry in vacuum, and dry at 45 to 50°C to obtain 17.9 g, with a yield of 84.9% and a purity of 98.5%.
[0029] Comparative Example 2 (one-step method)
[0030] The experiment was carried out using acetic acid as the etherification reagent:
[0031] Add 160 ml of methanol into a 1000 ml four-necked flask, cool to 1°C, add 4 g (1.5 g, 1.5 g, 1 g) of sodium borohydride (0.106 mol) in three portions, after the addition is completed, control the temperature and stir to react for 3 hours, if the intermediate control is qualified, control the temperature to 8°C, add 13 g of acetic acid (0.21 mol), after the addition is completed, stir for 5 minutes, add 50 g of trimethyl orthoacetate, keep warm at 8°C and stir for 1 hour, if the intermediate control is unqualified (most of the raw materials remain), control the temperature to 0-10°C, add 320 ml of drinking water, after the addition is completed, keep warm and stir for 1 hour, filter to obtain crude wet artemether, dry in vacuum, and dry at 45-50°C to obtain 92.9 g, with a yield of 84.9% and a purity of 48.5%.
[0032] Comparative Example 3 (one-step method)
[0033] The experiment was carried out using trifluoroacetic acid as the etherification reagent:
[0034] Add 160 ml methanol and 20 g artemisinin into a 1000 ml four-necked bottle, cool to 3°C, add 4 g (1.5 g, 1.5 g, 1 g) sodium borohydride (0.106 mol) in 3 portions, after the addition is completed, control the temperature and stir to react for 2 h. If the intermediate control is qualified, control the temperature to 5°C, drop 24 g trifluoroacetic acid (0.21 mol), after the addition is completed, stir for 5 minutes, add 50 g trimethyl orthoacetate, keep warm at 7°C and stir for 1.5 h. If the intermediate control is unqualified (the raw materials are basically unreacted), control the temperature to 7°C, add 320 ml drinking water, after the addition is completed, keep warm and stir for 1 h, filter to obtain crude wet artemether, dry in vacuum, and dry at 45-50°C to obtain 92.9 g, with a yield of 84.9% and a purity of 18.5%.
[0035] Comparative Example 4 (one-step method)
[0036] The experiment was carried out using perchloric acid as the etherification reagent:
[0037] Add 160 ml of methanol into a 1000 ml four-necked flask, cool to -1°C, add 4 g (1.5 g, 1.5 g, 1 g) of sodium borohydride (0.106 mol) in three portions, after the addition is completed, control the temperature and stir to react for 2 hours. If the intermediate control is qualified, control the temperature to 6°C, add 13 g of perchloric acid (0.21 mol) dropwise, after the addition is completed, stir for 5 minutes, add 50 g of trimethyl orthoacetate, keep the temperature at 6°C and stir for 1 hour, if the intermediate control is qualified, control the temperature to 8°C, add 320 ml of drinking water dropwise, after the addition is completed, keep the temperature and stir for 1 hour, filter to obtain crude wet product of artemether, vacuum dry, and dry at 45-50°C to obtain 92.9 g, with a yield of 84.9%, a purity of 97.5%, and a single impurity of not less than 0.5%.
[0038] From the results of the experiments of Examples 1-3 and Comparative Examples 1-4, it can be seen that the reaction effects of thionyl chloride, acetyl chloride and propionyl chloride are better, the degradation rate is higher when sulfuric acid is used, and the conversion rate of acetic acid, trifluoroacetic acid and perchloric acid is low.
[0039] Temperature Examination Example 1
[0040] The temperature for preparing β-artemether was controlled at 0-10°C for the experiment:
[0041] Add 160 ml methanol and 20 g artemisinin into a 1000 ml four-necked bottle, cool to -8-5°C, add 4 g (1.5 g, 1.5 g, 1 g) sodium borohydride (0.106 mol) in three portions, add 17 g acetyl chloride (0.21 mol) dropwise, stir for 5 minutes, add 50 g trimethyl orthoacetate, keep warm at 0-10°C and stir for 2 h, the central control is qualified, control the temperature at 0-10°C, add 320 ml drinking water dropwise, keep warm and stir for 1 h, filter to obtain crude wet artemether, vacuum dry, and dry at 45-50°C to obtain 19.2 g, with a yield of 90.8%, a purity of 99.6%, and a single impurity of less than 0.2%.
[0042] Temperature test comparison example 1
[0043] The temperature for preparing β-artemether was controlled at 10-20°C for the experiment:
[0044] Add 160 ml of methanol and 20 g of artemisinin into a 1000 ml four-necked bottle, cool to -8 to 5°C, add 4 g (1.5 g, 1.5 g, 1 g) of sodium borohydride (0.106 mol) in three portions, and after the addition is complete, add 17 g of acetyl chloride (0.21 mol) dropwise, stir for 5 minutes, add 50 g of trimethyl orthoacetate, keep warm at 10 to 20°C and stir for 1.2 h, the central control is qualified, control the temperature at 10 to 20°C, add 320 ml of drinking water dropwise, keep warm and stir for 1 h, filter to obtain crude wet artemether, vacuum dry, and dry at 45 to 50°C to obtain 18.7 g, with a yield of 88.8%, a purity of 99.4%, and a single impurity of less than 0.3%.
[0045] Temperature Test Comparative Example 2
[0046] The temperature for preparing β-artemether was controlled at 20-30°C for the experiment:
[0047] Add 160 ml of methanol and 20 g of artemisinin into a 1000 ml four-necked bottle, cool to -8-5°C, add 4 g (1.5 g, 1.5 g, 1 g) of sodium borohydride (0.106 mol) in three portions, add 17 g of acetyl chloride (0.21 mol) dropwise, stir for 5 minutes after the addition is complete, add 50 g of trimethyl orthoacetate), keep warm at 20-30°C and stir for 1 hour, control the temperature at 20-30°C if qualified, add 320 ml of drinking water dropwise, keep warm and stir for 1 hour, filter to obtain crude wet artemether, vacuum dry, and dry at 45-50°C to obtain 16.2 g, with a yield of 76.8%, a purity of 98.2%, and a single impurity of less than 1%.
[0048] It can be seen from the above-mentioned temperature test example 1 and temperature test comparative examples 1 and 2 that as the temperature increases, the product quality and yield deteriorate. Therefore, the yield and quality of 0 to 10° C. specified in the process of this application are better.
[0049] There is another preferred embodiment of the present application, which is to prepare β-artemisinin by a one-pot method:
[0050] Add 500 ml of methanol into a four-necked flask, start stirring, cool to 0-10°C, slowly add 2 g (0.017-0.17 mol) of thionyl chloride (catalyst), control the temperature at 0-10°C, stir for 15 minutes, add 100 ml of trimethyl orthoacetate and 0.35 mol (100 g) of dihydroartemisinin, stir at 0-10°C for 1 hour, control the sampling point plate (ethyl acetate: n-hexane = 1:4, iodine fumigation for color development), after the control is qualified, transfer the feed liquid into another four-necked flask, control the temperature at 0-10°C, slowly add 1200 ml of drinking water, control the addition, stir at 0-10°C for 1 hour, filter to obtain a crude wet product of artemether, dry to obtain a dry product with a molar yield of 95%, a purity of about 99.5%, and a single impurity of less than 0.3%.
[0051] The present application optimizes the process so that the average yield of etherification is about 90%, the total yield is about 85%, and the purity of the crude product is about 99.5%.
[0052] The above is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, which all belong to the protection scope of the present invention.
Claims
1. A method for preparing β-artemether, characterized in that: Add methanol and artemisinin into a container, cool to -8-5°C, add reducing agent in 3 batches, after the reducing agent is added, stir and react for 1-3h to obtain dihydroartemisinin, pass the intermediate control, control the temperature at 0-10°C, add etherification agent dropwise to dihydroartemisinin, stir for 5 minutes, add trimethyl orthoacetate, keep warm at 0-10°C, stir for 1-2h, pass the intermediate control, control the temperature at 0-10°C, add drinking water dropwise, keep warm and stir for 1h, filter to obtain crude wet artemisinin, dry to obtain β-artemisinin.
2. The method for preparing β-artemether according to claim 1, characterized in that: The preparation method adopts a one-pot method, including the following operations: adding methanol to a container, starting stirring, cooling to 0-10°C, slowly dripping an etherification reagent, controlling the temperature at 0-10°C, stirring for 15 minutes after the dripping is completed, adding trimethyl orthoacetate and dihydroartemisinin, stirring at 0-10°C for 1 hour, after the central control is qualified, transferring the feed liquid to another container, controlling the temperature at 0-10°C, slowly dripping drinking water, stirring at 0-10°C for 1 hour, filtering to obtain a crude wet product of artemether, and drying to obtain β-artemether.
3. The method for preparing β-artemether according to claim 1, characterized in that: The reducing agent is sodium borohydride.
4. The method for preparing β-artemether according to claim 3, characterized in that: The molar ratio of the reducing agent to artemisinin is 1:1 to 2:
1.
5. A method for preparing β-artemether according to claim 1 or 2, characterized in that: The etherification agent is selected from any one of thionyl chloride, acetyl chloride and propionyl chloride.
6. A method for preparing β-artemether according to claim 1 or 2, characterized in that: The molar ratio of the dihydroartemisinin to the etherification agent and trimethyl orthoacetate is 1:(0.02-0.5):(2.0-2.5).