CN110938080A - Preparation method of artesunate - Google Patents
Preparation method of artesunate Download PDFInfo
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- CN110938080A CN110938080A CN201910752539.5A CN201910752539A CN110938080A CN 110938080 A CN110938080 A CN 110938080A CN 201910752539 A CN201910752539 A CN 201910752539A CN 110938080 A CN110938080 A CN 110938080A
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- China
- Prior art keywords
- artesunate
- methanol solution
- dihydroartemisinin
- preparation
- esterification reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960004991 artesunate Drugs 0.000 title claims abstract description 62
- FIHJKUPKCHIPAT-AHIGJZGOSA-N artesunate Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@@H](OC(=O)CCC(O)=O)[C@@H]4C FIHJKUPKCHIPAT-AHIGJZGOSA-N 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 99
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 45
- 229960002521 artenimol Drugs 0.000 claims abstract description 26
- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 claims abstract description 26
- 229930016266 dihydroartemisinin Natural products 0.000 claims abstract description 26
- 239000007787 solid Substances 0.000 claims abstract description 24
- 238000005886 esterification reaction Methods 0.000 claims abstract description 22
- 239000000126 substance Substances 0.000 claims abstract description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000012043 crude product Substances 0.000 claims abstract description 19
- 229960001701 chloroform Drugs 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 16
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229940014800 succinic anhydride Drugs 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 238000007670 refining Methods 0.000 claims abstract description 12
- 239000000243 solution Substances 0.000 claims description 39
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 229960000583 acetic acid Drugs 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 8
- 239000012362 glacial acetic acid Substances 0.000 claims description 8
- 239000012047 saturated solution Substances 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229940086542 triethylamine Drugs 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 abstract description 7
- 230000008025 crystallization Effects 0.000 abstract description 7
- 239000007858 starting material Substances 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 24
- 238000001914 filtration Methods 0.000 description 11
- 238000001514 detection method Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 238000005265 energy consumption Methods 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 230000008014 freezing Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000009461 vacuum packaging Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 241000606646 Anaplasma Species 0.000 description 1
- 241000224016 Plasmodium Species 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/20—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention relates to the field of organic drug synthesis, and in particular relates to a preparation method of artesunate. The invention provides a preparation method of artesunate, which comprises the following steps: (1) taking trichloromethane as a solvent, and carrying out esterification reaction on dihydroartemisinin and succinic anhydride under the action of triethylamine to obtain a solid substance; (2) crystallizing the solid substance by adopting a methanol solution to obtain an artesunate crude product; (3) and refining the artesunate crude product to obtain the artesunate. The method takes dihydroartemisinin as a starting material, takes trichloromethane as a solvent, and generates esterification reaction with succinic anhydride under the action of triethylamine, and obtains the artesunate with the purity of more than 99.5 percent through crystallization and refining processes, wherein the yield is 140 percent, and compared with the traditional process, the yield of the artesunate is obviously improved.
Description
Technical Field
The invention relates to the field of organic drug synthesis, and in particular relates to a preparation method of artesunate.
Background
The artesunate is a compound synthesized by using dihydroartemisia apiacea as a raw material, and the molecular formula is C19H28O8White crystal with melting point of 1290-1400 ℃, no odor and bitter taste; it is easily soluble in chloroform, soluble in acetone, slightly soluble in methanol or ethanol, and hardly soluble in water. The artesunate has stronger killing effect on plasmodium anaplasma, can quickly control malaria attack, and has the defects of low yield, complex process and high energy consumption in the prior synthesis method of the artesunate.
Disclosure of Invention
The invention aims to provide a preparation method of artesunate, which is simple and easy to operate, improves the yield and reduces the production cost.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of artesunate, which comprises the following steps:
(1) taking trichloromethane as a solvent, and carrying out esterification reaction on dihydroartemisinin and succinic anhydride under the action of triethylamine to obtain a solid substance;
(2) crystallizing the solid substance by adopting a methanol solution to obtain an artesunate crude product;
(3) and refining the artesunate crude product to obtain the artesunate.
Preferably, the mass ratio of the dihydroartemisinin to the succinic anhydride is (1-2): (0.5 to 1.0).
Preferably, the dosage ratio of the dihydroartemisinin to the trichloromethane to the triethylamine is (1-2) kg: (10-20) L: (0.5-0.8) L.
Preferably, the temperature of the esterification reaction is 20-35 ℃ and the time is 3-18 min.
Preferably, after the esterification reaction is finished, the pH value of the system obtained by the esterification reaction is adjusted to 7 by using glacial acetic acid, and then the system is concentrated to remove the solvent to obtain a solid substance.
Preferably, the concentration is carried out under the condition of a water bath, and the temperature of the water bath is 40-90 ℃.
Preferably, the mass concentration of the methanol solution in the step (2) is 20%; the dosage ratio of the methanol solution to the dihydroartemisinin is 2L: 1 kg.
Preferably, the specific method for refining the artesunate crude product in the step (3) is as follows: adopting hot methanol solution to heat and dissolve the artesunate crude product into saturated solution, cooling and recrystallizing; the temperature of the hot methanol solution is 65 ℃, and the mass concentration of the hot methanol solution is 80%.
Preferably, the dosage ratio of the hot methanol solution to the dihydroartemisinin is (1.8-2) L: 1 kg.
Preferably, the method further comprises, after the completion of the refining: drying the refined crystal to obtain artesunate; the drying temperature is 55 ℃ and the drying time is 2 h.
The invention provides a preparation method of artesunate, which comprises the following steps: (1) taking trichloromethane as a solvent, and carrying out esterification reaction on dihydroartemisinin and succinic anhydride under the action of triethylamine to obtain a solid substance; (2) crystallizing the solid substance by adopting a methanol solution to obtain an artesunate crude product; (3) and refining the artesunate crude product to obtain the artesunate. The method takes dihydroartemisinin as a starting material, takes trichloromethane as a solvent, and generates esterification reaction with succinic anhydride under the action of triethylamine, and obtains the artesunate with the purity of more than 99.5 percent through crystallization and refining processes, wherein the yield is 140 percent, and compared with the traditional process, the yield of the artesunate is obviously improved. In addition, the preparation process provided by the invention is simple and easy to operate, has low energy consumption, reduces the production cost, and has industrial significance progress.
Detailed Description
The invention provides a preparation method of artesunate, which comprises the following steps:
(1) taking trichloromethane as a solvent, and carrying out esterification reaction on dihydroartemisinin and succinic anhydride under the action of triethylamine to obtain a solid substance;
(2) crystallizing the solid substance by adopting a methanol solution to obtain an artesunate crude product;
(3) and refining the artesunate crude product to obtain the artesunate.
In the present invention, unless otherwise specified, all the starting materials for the preparation are commercially available products well known in the art.
The invention takes trichloromethane as a solvent, and dihydroartemisinin and succinic anhydride carry out esterification reaction under the action of triethylamine to obtain a solid substance. In the invention, the mass ratio of the dihydroartemisinin to the succinic anhydride is preferably (1-2): (0.5 to 1.0), more preferably 1: 0.7; the preferable dosage ratio of the dihydroartemisinin, the trichloromethane and the triethylamine is (1-2) kg: (10-20) L: (0.5 to 0.8) L, more preferably 1 kg: 14L: 0.5L.
In the present invention, the addition sequence of each raw material is preferably that succinic anhydride, dihydroartemisinin and triethylamine are added in sequence to chloroform. In the present invention, the esterification reaction is preferably carried out under a stirring condition, and the stirring speed is preferably 30 to 2000rpm, and more preferably 10 to 1000 rpm.
In the invention, the temperature of the esterification reaction is preferably 20-35 ℃, and more preferably 27 ℃; the method preferably adopts thin-layer chromatography to monitor the reaction process, and the esterification reaction time is preferably 3-18 min, and more preferably 8 min. The preparation method provided by the invention has the advantages of mild reaction conditions, short reaction time, improved production efficiency and energy consumption saving.
After the esterification reaction is finished, the pH value of a system obtained by the esterification reaction is preferably adjusted to 7 by adopting glacial acetic acid, and then the solid matter is obtained by concentrating and removing the solvent. In the invention, the dosage ratio of the glacial acetic acid to the dihydroartemisinin is preferably (0.5-0.8) L: 1 kg. The pH value of the glacial acetic acid adjusting system is adopted to quickly neutralize the reaction liquid and terminate the chemical reaction.
In the invention, the concentration is preferably carried out under the condition of a water bath, and the temperature of the water bath is preferably 40-90 ℃, and more preferably 55 ℃.
After a solid substance is obtained, the solid substance is crystallized by adopting a methanol solution to obtain a crude artesunate product. In the present invention, the mass concentration of the methanol solution is preferably 20%; the dosage ratio of the methanol solution to the dihydroartemisinin is preferably 2L: 1 kg. In the invention, the artesunate is easy to crystallize in methanol, and a crystal form with better form can be obtained. In the present invention, the specific process of the crystallization is preferably: adding methanol solution into the solid matter, cooling, crystallizing, centrifuging and filtering to obtain crude artesunate. In the invention, the cooling crystallization temperature is preferably-10-30 ℃, and more preferably-8-20 ℃. In the invention, the yield of the artesunate crude product is preferably 120-165%.
After the artesunate crude product is obtained, the artesunate crude product is refined to obtain the artesunate. In the invention, the refining method comprises the following specific steps: and (3) adopting a hot methanol solution to heat and dissolve the artesunate crude product into a saturated solution, cooling and recrystallizing, and carrying out centrifugal filtration to obtain the artesunate. In the invention, the temperature of the hot methanol solution is preferably 65 ℃, and the mass concentration of the hot methanol solution is preferably 80%; the dosage ratio of the hot methanol solution to the dihydroartemisinin is preferably (1.8-2) L: 1 kg. In the invention, the solid substance obtained by centrifugal filtration is preferably subjected to high performance liquid detection, and after the detection is qualified, a subsequent drying process is carried out.
The present invention further comprises, after the completion of the refining: drying the crystal obtained by centrifugal filtration to obtain the artesunate. In the present invention, the drying is preferably performed by vacuum drying; the drying temperature is preferably 55 ℃ and the drying time is preferably 2 h.
The artesunate prepared by the preparation process has the purity of over 99.5 percent and the yield of 140 percent. In the invention, the calculation formula of the yield is as follows: (the mass of artesunate/the mass of dihydroartemisinin). times.100%.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Sequentially adding 14L of trichloromethane, 0.7kg of succinic anhydride, 1kg of dihydroartemisinin and 500mL of triethylamine into a reaction tank, stirring at the stirring speed of 450rpm, and carrying out esterification reaction at the reaction temperature of 27 ℃ for 8 min; when the thin-layer chromatography detection reaction is thorough, adjusting the pH value of a system to be 7 by using 500mL of glacial acetic acid, stopping the reaction, and filtering the system obtained after the reaction to obtain a reaction solution;
concentrating the obtained reaction solution in a water bath at 55 ℃ until no solvent exists, and obtaining a solid substance;
adding 2L of 20% methanol solution into the solid substance, freezing and crystallizing at 20 deg.C, and centrifuging to obtain artesunate crude product;
adding 1.8L of 80% methanol solution at 65 deg.C into crude artesunate, heating to dissolve the crude artesunate into saturated solution, cooling at 20 deg.C for crystallization, centrifuging, filtering, and performing high performance liquid detection;
and (3) drying the qualified product in vacuum at 55 ℃ for 2h to obtain 1.22kg of artesunate, vacuum packaging, filling a label, and preserving at low temperature.
Example 2
Sequentially adding 70L of trichloromethane, 3.5kg of succinic anhydride, 5kg of dihydroartemisinin and 1500mL of triethylamine into a reaction tank, stirring at the stirring speed of 400rpm, and carrying out esterification reaction at the reaction temperature of 27 ℃ for 8 min; when the thin-layer chromatography detection reaction is thorough, adopting 1500mL glacial acetic acid to adjust the pH value of a system to be 7, stopping the reaction, and filtering the system obtained after the reaction to obtain a reaction solution;
concentrating the obtained reaction solution in a water bath at 55 ℃ until no solvent exists, and obtaining a solid substance;
adding 10L of 20% methanol solution into the solid substance, freezing and crystallizing at 20 deg.C, and centrifuging to obtain artesunate crude product;
adding 10L of 80% methanol solution at 65 deg.C into crude artesunate, heating to dissolve the crude artesunate into saturated solution, cooling at 20 deg.C for crystallization, centrifuging, filtering, and performing high performance liquid detection;
and (3) drying the qualified product in vacuum at 55 ℃ for 2h to obtain 6.21kg of artesunate, vacuum packaging, filling a label, and preserving at low temperature.
Example 3
Sequentially adding 140L of trichloromethane, 7kg of succinic anhydride, 10kg of dihydroartemisinin and 3000mL of triethylamine into a reaction tank, stirring at the stirring speed of 400rpm, and carrying out esterification reaction at the reaction temperature of 27 ℃ for 8 min; when the thin-layer chromatography detection reaction is thorough, adopting 3000mL glacial acetic acid to adjust the pH value of a system to be 7, stopping the reaction, and filtering the system obtained after the reaction to obtain a reaction solution;
concentrating the obtained reaction solution in a water bath at 55 ℃ until no solvent exists, and obtaining a solid substance;
adding 20L of 20% methanol solution into the solid matter, freezing and crystallizing at 20 deg.C, and centrifuging and filtering to obtain crude artesunate;
adding 20L of 80% methanol solution at 65 deg.C into crude artesunate, heating to dissolve the crude artesunate into saturated solution, cooling at 20 deg.C for crystallization, centrifuging, filtering, and performing high performance liquid detection;
and (3) drying the qualified product in vacuum at 55 ℃ for 2h to obtain 6.21kg of artesunate, vacuum packaging, filling a label, and preserving at low temperature.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. The preparation method of artesunate is characterized by comprising the following steps:
(1) taking trichloromethane as a solvent, and carrying out esterification reaction on dihydroartemisinin and succinic anhydride under the action of triethylamine to obtain a solid substance;
(2) crystallizing the solid substance by adopting a methanol solution to obtain an artesunate crude product;
(3) and refining the artesunate crude product to obtain the artesunate.
2. The preparation method according to claim 1, wherein the mass ratio of the dihydroartemisinin to the succinic anhydride is (1-2): (0.5 to 1.0).
3. The preparation method according to claim 1, wherein the dosage ratio of dihydroartemisinin, chloroform and triethylamine is (1-2) kg: (10-20) L: (0.5-0.8) L.
4. The method according to claim 1, wherein the esterification reaction is carried out at a temperature of 20 to 35 ℃ for 3 to 18 min.
5. The method according to claim 1, wherein after the completion of the esterification reaction, the pH of the system obtained by the esterification reaction is adjusted to 7 with glacial acetic acid, and then the solution is concentrated to remove the solvent to obtain a solid substance.
6. The method according to claim 5, wherein the concentration is carried out under a water bath condition, and the temperature of the water bath is 40 to 90 ℃.
7. The production method according to claim 1, wherein the methanol solution in the step (2) has a mass concentration of 20%; the dosage ratio of the methanol solution to the dihydroartemisinin is 2L: 1 kg.
8. The preparation method according to claim 1, wherein the step (3) of refining the crude artesunate is as follows: adopting hot methanol solution to heat and dissolve the artesunate crude product into saturated solution, cooling and recrystallizing; the temperature of the hot methanol solution is 65 ℃, and the mass concentration of the hot methanol solution is 80%.
9. The method according to claim 8, wherein the ratio of the amount of the hot methanol solution to the amount of the dihydroartemisinin is (1.8-2) L: 1 kg.
10. The production method according to claim 1 or 8, further comprising, after the completion of the purification: drying the refined crystal to obtain artesunate; the drying temperature is 55 ℃ and the drying time is 2 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910752539.5A CN110938080A (en) | 2019-08-15 | 2019-08-15 | Preparation method of artesunate |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910752539.5A CN110938080A (en) | 2019-08-15 | 2019-08-15 | Preparation method of artesunate |
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| CN110938080A true CN110938080A (en) | 2020-03-31 |
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| CN201910752539.5A Pending CN110938080A (en) | 2019-08-15 | 2019-08-15 | Preparation method of artesunate |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102304137A (en) * | 2010-08-09 | 2012-01-04 | 恩施济源药业科技开发有限公司 | Method for producing artesunate |
| EP2929881A1 (en) * | 2014-04-11 | 2015-10-14 | CeMM - Forschungszentrum für Molekulare Medizin GmbH | Medical use of artemisinin compounds and gephyrin agonists |
| CN106565738A (en) * | 2015-10-11 | 2017-04-19 | 吴珊 | Method for producing artesunate |
-
2019
- 2019-08-15 CN CN201910752539.5A patent/CN110938080A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102304137A (en) * | 2010-08-09 | 2012-01-04 | 恩施济源药业科技开发有限公司 | Method for producing artesunate |
| EP2929881A1 (en) * | 2014-04-11 | 2015-10-14 | CeMM - Forschungszentrum für Molekulare Medizin GmbH | Medical use of artemisinin compounds and gephyrin agonists |
| CN106565738A (en) * | 2015-10-11 | 2017-04-19 | 吴珊 | Method for producing artesunate |
Non-Patent Citations (1)
| Title |
|---|
| 路娟 等: "青蒿素类衍生物结构修饰研究进展", 《中医药信息》 * |
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