CN110903298A - Preparation method of dihydroartemisinin - Google Patents
Preparation method of dihydroartemisinin Download PDFInfo
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- CN110903298A CN110903298A CN201910752509.4A CN201910752509A CN110903298A CN 110903298 A CN110903298 A CN 110903298A CN 201910752509 A CN201910752509 A CN 201910752509A CN 110903298 A CN110903298 A CN 110903298A
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- C07—ORGANIC CHEMISTRY
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- 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
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Abstract
The invention relates to the technical field of organic drug synthesis, in particular to a preparation method of dihydroartemisinin. According to the invention, sodium borohydride is used as a strong reducing agent to rapidly and effectively reduce artemisinin, and a suspension chemical reaction system is established by increasing the stirring speed in the mixing process, so that the reduction reaction is rapidly radiated, the reduction reaction speed is accelerated, the generation of byproducts is effectively inhibited, and the product yield and purity are improved; in addition, the preparation method provided by the invention is simple and convenient, saves a large amount of solvent, electricity and heat, shortens the production period and reduces the production cost. The embodiment shows that the yield of the dihydroartemisinin can reach 110% by adopting the preparation method provided by the invention, and compared with the traditional preparation process, the yield is obviously improved, and the preparation method is suitable for large-scale production.
Description
Technical Field
The invention relates to the technical field of organic drug synthesis, in particular to a preparation method of dihydroartemisinin.
Background
Dihydroartemisinin is an artemisinin derivative with a molecular formula of C15H24O5Molecular weight 284.35, and is generally used for symptom control of various types of malaria, especially for treating chloroquine-type malaria with high curative effect; the chemical name is (3R,5aS,6R,8aS,9R,12S,12aR) -octahydro-3, 6, 9-trimethyl-3, 12-oxo-12H-pyrido [4, 3-j)]1, 2-benzodiazepine 10(3H) alcohol. Dihydroartemisinin is white needle crystal, has no odor, bitter taste, is easily soluble in chloroform, is soluble in propanol, is slightly soluble in methanol or ethanol, and is almost insoluble in water; the melting point is 145-150 ℃, and the materials are decomposed simultaneously during melting. The synthesis of dihydroartemisinin by artemisinin at home and abroad has more researches, but the yield of most of the dihydroartemisinin is about 90 percent and the yield is lower.
Disclosure of Invention
The invention aims to provide a preparation method of dihydroartemisinin, which is simple and convenient to operate and can obviously improve the yield and purity of dihydroartemisinin.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of dihydroartemisinin, which comprises the following steps:
performing first mixing on artemisinin and a methanol solution to obtain an artemisinin solution;
carrying out second mixing on the artemisinin solution and sodium borohydride, and carrying out reduction reaction to obtain dihydroartemisinin;
the first mixing is carried out under the condition of stirring, and the stirring speed of the first mixing is 100 r/min;
the second mixing is carried out under stirring conditions, and the stirring speed of the second mixing is 600 r/min.
Preferably, the mass concentration of the methanol solution is 20-99%, and the dosage ratio of the artemisinin to the methanol solution is (1-2.5) kg: 10L.
Preferably, the temperature of the first mixing is-18 to 5 ℃.
Preferably, the mass ratio of the sodium borohydride to the artemisinin is (0.3-0.35): 1.
Preferably, the temperature of the reduction reaction is-18-5 ℃ and the time is 1 h.
Preferably, after the reduction reaction is finished, the pH value of the system is adjusted to be neutral by adopting acetic acid.
Preferably, after the reduction reaction is finished, the method further comprises a crystallization and washing process which are sequentially carried out.
Preferably, the specific method of crystallization is: stirring the system obtained by the reduction reaction for 10min at a stirring speed of 50r/min, standing for 30min, and centrifuging and filtering.
Preferably, the specific method of washing is: washing the crystal obtained in the crystallization process by using a methanol solution.
Preferably, after the washing, the method further comprises: drying the purified crystal obtained by washing to obtain dihydroartemisinin; the drying temperature is 55 ℃ and the drying time is 3 h.
The invention provides a preparation method of dihydroartemisinin, which comprises the following steps: performing first mixing on artemisinin and a methanol solution to obtain an artemisinin solution; carrying out second mixing on the artemisinin solution and sodium borohydride, and carrying out reduction reaction to obtain dihydroartemisinin; the first mixing is carried out under the condition of stirring, and the stirring speed of the first mixing is 100 r/min; the second mixing is carried out under stirring conditions, and the stirring speed of the second mixing is 600 r/min. According to the invention, sodium borohydride is used as a strong reducing agent to rapidly and effectively reduce artemisinin, and a suspension chemical reaction system is established by increasing the stirring speed in the mixing process, so that the reduction reaction is rapidly radiated, the reduction reaction speed is accelerated, the generation of byproducts is effectively inhibited, and the product yield and purity are improved; in addition, the preparation method provided by the invention is simple and convenient, saves a large amount of solvent, electricity and heat, shortens the production period and reduces the production cost. The embodiment shows that the yield of the dihydroartemisinin can reach 110% by adopting the preparation method provided by the invention, and compared with the traditional preparation process, the yield is obviously improved, and the preparation method is suitable for large-scale production.
Detailed Description
The invention provides a preparation method of dihydroartemisinin, which comprises the following steps:
performing first mixing on artemisinin and a methanol solution to obtain an artemisinin solution;
carrying out second mixing on the artemisinin solution and sodium borohydride, and carrying out reduction reaction to obtain dihydroartemisinin;
the first mixing is carried out under the condition of stirring, and the stirring speed of the first mixing is 100 r/min;
the second mixing is carried out under stirring conditions, and the stirring speed of the second mixing is 600 r/min.
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 mixes artemisinin with methanol solution for the first time to obtain artemisinin solution. In the present invention, the purity of the artemisinin is preferably above 90%; the mass concentration of the methanol solution is preferably 20-99%, and more preferably 60-90%; the dosage ratio of the artemisinin to the methanol solution is preferably (1-2.5) kg: 10L, more preferably (1-1.5) kg: 10L.
In the invention, the first mixing is carried out under stirring conditions, and the stirring speed of the first mixing is 100 r/min; the temperature of the first mixing is preferably-18 to 5 ℃. In a specific embodiment of the present invention, artemisinin is added to the methanol solution rapidly, preferably at a stirring rate of 100 r/min. In the present invention, the artemisinin is preferably added at a rate of 1 to 20 kg/min.
After the artemisinin solution is obtained, the artemisinin solution and sodium borohydride are mixed for the second time to carry out reduction reaction, and dihydroartemisinin is obtained. In the present invention, the purity of the sodium borohydride is preferably 99%; the mass ratio of the sodium borohydride to the artemisinin is preferably (0.3-0.35) to 1, more preferably (0.31-0.35): 1.
in the invention, the second mixing is carried out under the stirring condition, and the stirring speed of the second mixing is 600 r/min; the temperature of the reduction reaction is preferably-18-5 ℃, the reaction process is preferably monitored by adopting thin-layer chromatography, ethyl acetate and petroleum ether with the volume ratio of 4:1 are particularly preferably used as developing agents, 5% concentrated sulfuric acid vanillin is used for developing color, the reaction progress degree is judged by adopting the thin-layer chromatography, and the time of the reduction reaction is preferably 1 h.
In the present invention, after the reduction reaction is completed, the pH value of the acetic acid adjustment system is preferably adjusted to be neutral, and more preferably adjusted to be 7. In the invention, the mass concentration of the acetic acid is preferably 50-100%. In the specific embodiment of the invention, acetic acid is preferably added into the system obtained by the reduction reaction in three times, the pH value of the system is controlled to be 7, and the dosage ratio of the first added acetic acid, the second added acetic acid and the third added acetic acid to artemisinin is preferably (1-3) L:1L:20L:10 kg. The pH value of the system is preferably adjusted by adopting acetic acid at the stirring speed of 200 r/min.
The invention also preferably comprises crystallization and washing processes which are carried out in sequence after the pH value of the system is adjusted to be neutral. In the present invention, the specific method of crystallization is preferably: stirring the system obtained by the reduction reaction for 10min at a stirring speed of 50r/min, standing for 30min, and centrifuging and filtering. In the invention, the temperature of the crystallization is preferably-18 to 5 ℃.
In the present invention, the specific method of washing is preferably: washing the crystal obtained in the crystallization process by using a methanol solution. In the invention, the mass concentration of the methanol solution is preferably 10-100%; the dosage ratio of the methanol solution to the artemisinin is preferably 5L: 1 kg. In the present invention, the washing is preferably carried out under stirring conditions, the stirring speed is preferably 200r/min, and the stirring time is preferably 20 min. According to the invention, the system obtained by washing is preferably filtered and washed repeatedly for three times to obtain purified crystals. In the invention, the washing temperature is preferably-18-5 ℃.
According to the invention, after the washing is finished, the purified crystals obtained by washing are preferably dried to obtain dihydroartemisinin. In the present invention, the drying is preferably performed by vacuum drying; the drying temperature is preferably 55 ℃ and the drying time is preferably 3 h.
The purity of the dihydroartemisinin prepared by the preparation process is as high as 99.6 percent, and the yield is as high as 110 percent. In the invention, the calculation formula of the yield is as follows: (mass of dihydroartemisinin/mass of artemisinin). 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
Starting a refrigerating unit, stopping the refrigerating unit after the temperature is reduced to-15 ℃, starting a refrigerating switch, a temperature control switch and a stirring switch of a reactor, pouring 10L of methanol solution (with the mass concentration of 60%) into the reactor, adjusting the stirring speed to be 100r/min, and quickly adding 1kg of artemisinin;
adjusting the stirring speed to 600r/min, adding 0.35kg of sodium borohydride when the temperature is 1 ℃, carrying out reduction reaction for 1.5h, developing the color by using ethyl acetate/petroleum ether (the volume ratio is 4/1) and 5% concentrated sulfuric acid vanillin, and judging whether the reaction is finished or not through thin-layer chromatography;
when the reduction reaction reaches the end point, reducing the stirring speed to 200r/min, adding 500mL of acetic acid in 3 times, and when the temperature is lowered to 0 ℃, determining the end point by using a pH test paper to ensure that the pH value of the system is 7;
stirring at a stirring speed of 50r/min for 10min, standing for 30min, vacuum filtering, and performing concentrated mother liquor treatment;
putting the obtained crystal into a stainless steel container, adding 5L of 20% methanol solution for washing, stirring at 0 deg.C and 200r/min for 20min, standing for 20min, filtering the crystal, repeating for three times, filtering, and concentrating mother liquor;
detecting the purified crystal obtained by washing by a high performance liquid chromatography to obtain the purity of 99.1%; vacuum drying at 55 deg.C for 2 hr, sealing, and vacuum packaging to obtain 1.1kg dihydroartemisinin with purity of 98.8%, and storing at 25 deg.C.
Example 2
Starting a refrigerating unit, stopping the refrigerating unit after the temperature is reduced to-15 ℃, starting a refrigerating switch, a temperature control switch and a stirring switch of a reactor, pouring 100L of methanol solution (with the mass concentration of 60%) into the reactor, adjusting the stirring speed to be 100r/min, and quickly adding 10kg of artemisinin;
adjusting the stirring speed to 600r/min, adding 3.1kg of sodium borohydride when the temperature is 1 ℃, carrying out reduction reaction for 1.8h, developing the color by using ethyl acetate/petroleum ether (the volume ratio is 4/1) and 5% concentrated sulfuric acid vanillin, and judging whether the reaction is finished or not through TCL;
when the reduction reaction reaches the end point, reducing the stirring speed to 200r/min, adding 5000mL of acetic acid in total for 3 times, and when the temperature is lowered to 0 ℃, determining the end point by using pH test paper to ensure that the pH value of the system is 7;
stirring at a stirring speed of 50r/min for 15min, standing for 40min, vacuum filtering, and performing concentrated mother liquor treatment;
putting the obtained crystal into a stainless steel container, adding 50L of 20% methanol solution for washing, stirring at 0 deg.C and 200r/min for 20min, standing for 30min, filtering the crystal, repeating for three times, filtering, and concentrating mother liquor;
detecting the purified crystal obtained by washing by a high performance liquid chromatography, wherein the purity is 98.8%; vacuum drying at 55 deg.C for 2 hr, sealing, and vacuum packaging to obtain 9.7kg dihydroartemisinin with purity of 98.5%, and storing at 25 deg.C.
Example 3
Starting a refrigerating unit, stopping the refrigerating unit after the temperature is reduced to-17 ℃, starting a refrigerating switch, a temperature control switch and a stirring switch of a reactor, pouring 100L of methanol solution (with the mass concentration of 60%) into the reactor, adjusting the stirring speed to be 100r/min, and quickly adding 15kg of artemisinin;
adjusting the stirring speed to 600r/min, adding 4.5kg of sodium borohydride when the temperature is 1 ℃, carrying out reduction reaction for 2.0h, developing the color by using ethyl acetate/petroleum ether (the volume ratio is 4/1) and 5% concentrated sulfuric acid vanillin, and judging whether the reaction is finished or not through TCL;
when the reduction reaction reaches the end point, the stirring speed is reduced to 200r/min, the total 7400mL of acetic acid is added in 3 times, when the temperature is lowered to 0 ℃, the end point is determined by a pH test paper, and the pH value of the system is 7;
stirring at a stirring speed of 50r/min for 20min, standing for 30min, vacuum filtering, and performing concentrated mother liquor treatment;
putting the obtained crystal into a stainless steel container, adding 75L of 20% methanol solution for washing, stirring at 0 deg.C and 150r/min for 20min, standing for 20min, filtering the crystal, repeating for three times, filtering, and concentrating mother liquor;
detecting the purified crystal obtained by washing by a high performance liquid chromatography, wherein the purity is 98.3%; vacuum drying at 55 deg.C for 2 hr, sealing, and vacuum packaging to obtain 14.7kg dihydroartemisinin with purity of 98.2%, and storing at 25 deg.C.
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. A preparation method of dihydroartemisinin is characterized by comprising the following steps:
performing first mixing on artemisinin and a methanol solution to obtain an artemisinin solution;
carrying out second mixing on the artemisinin solution and sodium borohydride, and carrying out reduction reaction to obtain dihydroartemisinin;
the first mixing is carried out under the condition of stirring, and the stirring speed of the first mixing is 100 r/min;
the second mixing is carried out under stirring conditions, and the stirring speed of the second mixing is 600 r/min.
2. The preparation method according to claim 1, wherein the mass concentration of the methanol solution is 20-99%, and the dosage ratio of the artemisinin to the methanol solution is (1-2.5) kg: 10L.
3. The method according to claim 1 or 2, wherein the temperature of the first mixing is-18 to 5 ℃.
4. The preparation method according to claim 1, wherein the mass ratio of the sodium borohydride to the artemisinin is (0.3-0.35): 1.
5. The preparation method according to claim 1 or 4, wherein the temperature of the reduction reaction is-18 to 5 ℃ and the time is 1 hour.
6. The method according to claim 1, wherein the pH value of the system is adjusted to be neutral by acetic acid after the reduction reaction is completed.
7. The method according to claim 1, further comprising a crystallization and a washing process performed in sequence after the reduction reaction is completed.
8. The preparation method according to claim 7, wherein the specific method of crystallization is as follows: stirring the system obtained by the reduction reaction for 10min at a stirring speed of 50r/min, standing for 30min, and centrifuging and filtering.
9. The method for preparing the compound of claim 7 or 8, wherein the specific method for washing is as follows: washing the crystal obtained in the crystallization process by using a methanol solution.
10. The method according to claim 7, further comprising, after the washing: drying the purified crystal obtained by washing to obtain dihydroartemisinin; the drying temperature is 55 ℃ and the drying time is 3 h.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114426552A (en) * | 2021-10-22 | 2022-05-03 | 河南天源药物研究有限公司 | Stable artemisinin preparation method |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102304135A (en) * | 2010-07-10 | 2012-01-04 | 恩施济源药业科技开发有限公司 | Method for producing dihydroartemisinin |
| CN102350293A (en) * | 2011-09-02 | 2012-02-15 | 江苏斯威森生物医药工程研究中心有限公司 | Special reaction kettle for preparing dihydroartemisinin by hydroboration reduction |
| WO2012042536A2 (en) * | 2010-09-27 | 2012-04-05 | Sequent Scientific Limited | A process for preparation of ether derivatives of dihdroartemisinin |
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- 2019-08-15 CN CN201910752509.4A patent/CN110903298A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102304135A (en) * | 2010-07-10 | 2012-01-04 | 恩施济源药业科技开发有限公司 | Method for producing dihydroartemisinin |
| WO2012042536A2 (en) * | 2010-09-27 | 2012-04-05 | Sequent Scientific Limited | A process for preparation of ether derivatives of dihdroartemisinin |
| CN102350293A (en) * | 2011-09-02 | 2012-02-15 | 江苏斯威森生物医药工程研究中心有限公司 | Special reaction kettle for preparing dihydroartemisinin by hydroboration reduction |
Non-Patent Citations (1)
| Title |
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| LAI-KING SY ET AL.: "Synthesis of 6,7-dehydroartemisinic acid", 《J.CHEM.SOC.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114426552A (en) * | 2021-10-22 | 2022-05-03 | 河南天源药物研究有限公司 | Stable artemisinin preparation method |
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Application publication date: 20200324 |