CN107793429A - A kind of preparation method of qinghaosu - Google Patents
A kind of preparation method of qinghaosu Download PDFInfo
- Publication number
- CN107793429A CN107793429A CN201610767931.3A CN201610767931A CN107793429A CN 107793429 A CN107793429 A CN 107793429A CN 201610767931 A CN201610767931 A CN 201610767931A CN 107793429 A CN107793429 A CN 107793429A
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- CN
- China
- Prior art keywords
- qinghaosu
- acid
- preparation
- dihydroartemisinic acid
- dihydroartemisinic
- Prior art date
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- 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
Abstract
The invention discloses a kind of preparation method of qinghaosu, using Arteannuic acid as initiation material, dihydroartemisinic acid is obtained under hydrogen/metallic catalyst effect, then, dihydroartemisinic acid is in the presence of sodium molybdate by hydrogen peroxide oxidation into peroxidating dihydroartemisinic acid, finally acted under trifluoromethanesulfonic acid copper catalysis with oxygen, you can obtain target product qinghaosu in high yield.Compared with prior art, the invention has the advantages that：Agents useful for same is cheap and easily-available, and synthetic route is short, and reaction selectivity is high, and preparation process is environmentally friendly, and operation and post processing are simple, and total recovery is high, is adapted to industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of qinghaosu, belongs to organic drug synthesis field.
Background technology
Qinghaosu (Artemisinin), that is extracted from Chinese medicine artemisia annua has the sesquiterpene lactone anti-malarial of peroxy-radical
Class medicine is Chinese first found by internationally recognized natural drug.The antimalarial mechanism of qinghaosu and other antimalarials are not
Together, its main function is pellicle-mitochondrial function by disturbing plasmodium, and non-interference folic acid metabolism, so as to cause worm
Body structure is all disintegrated.In addition, using qinghaosu as raw material, can also synthesize its a variety of derivative, as dihydroartemisinine, Artemether,
Artesunate etc..These artemisinin-based drug toxicity are low, resist cruel property strong, are approved as treating encephalic malaria in world wide by WTO
With the choice drug of pernicious malaria.
Patent US4992561 introduces peroxide bridge using dihydroartemisinic acid as raw material using photochemical method.Due to photochemical
The limitation of itself is learned, it is such as cumbersome, it should not mass produce, therefore industrialized production difficult to realize.Document
(Tetrahedron, 1986,42,819-828) report with (R)-(+)-vanillic aldehyde be raw material come the method for synthetic artemisinin,
Grown yet with synthetic route, total recovery is low, and Atom economy is poor.In addition peroxide is introduced and using photochemical method
Key, it is difficult to realize industrialized production.Other are such as Mitchell A.Avery (J.Am.Chem.Soc., 1992.114.974-979)
Report is Material synthesis qinghaosu using pulegone, and its synthetic route is longer, yield is low.Simultaneously peroxide is introduced using ozone
Key, operating difficulties, security is poor, and industrial prospect is not high.If realize peroxide bridge using traditional chemical synthesis process
Introduce, it is not only workable, also it is very likely to test industrialized production.Document (J.Am.Chem.Soc., 1964,86,
3880, J.Am.Chem.Soc., 1968,90,975) it is reported in the presence of certain catalyst, singlet is produced using oxygen
Oxygen, and then the introducing of peroxide bridge can also be realized instead of photochemical method.
The content of the invention
The defects of purpose of the present invention is exactly to overcome prior art to exist and a kind of rational technology, simple to operate is provided
And the preparation method for the antimalarial class drug artemisinin that cost is cheap and total recovery is high.
The purpose of the present invention can be achieved through the following technical solutions：
A kind of preparation method of qinghaosu, it is characterised in that comprise the following steps：
Step 1), Arteannuic acid is dissolved in organic solvent, acted on by hydrogen/metallic catalyst, reduced and dihydro green grass or young crops is made
Artemisic acid；
Step 2), dihydroartemisinic acid in organic solvent, using sodium molybdate as catalyst, hydrogen peroxide as oxidant,
Peroxide dihydroartemisinic acid is made in oxidation；
Step 3), peroxide dihydroartemisinic acid are passed through oxygen under copper trifluoromethanesulfcomposite effect, reset and obtain qinghaosu.
Further, in step 1), the metallic catalyst is palladium carbon, Raney Ni, platinum oxide, wherein, metal catalytic
Agent dosage is the 0.01-0.1 of Arteannuic acid weight, and Hydrogen Vapor Pressure 1-10bar, reaction temperature is -50 DEG C of room temperature.
Further, the organic solvent selection dichloromethane, chloroform, acetone, methanol, ethanol, propyl alcohol, isopropanol, third
One kind or its mixing in ketone, ethyl acetate, tetrahydrofuran, dioxane, acetonitrile, DMF, DMSO.
Further, in step 2), the mole dosage of the sodium molybdate is 1-5 times of Arteannuic acid, hydrogen peroxide mole
Dosage is 2-10 times of Arteannuic acid.
Further, in step 2), the oxidation reaction is carried out under the conditions of -10-0 DEG C.
Further, in step 3), the rearrangement reaction is carried out under 0 DEG C-room temperature condition, and copper trifluoromethanesulfcomposite rubs
Your dosage is 1-10 times of dihydroartemisinic acid.
The synthetic route of the present invention is as follows：
Beneficial effects of the present invention：Step 1), obtained with accessory substance in qinghaosu extraction process or by fermentation process
Arteannuic acid is initiation material, and cost is low, and stereoselectivity is good, and product purity is high, and reaction yield is high, is easy to mass produce；Step
Rapid 2) hydrogen peroxide is green as oxidant, and post processing is simple, and reaction condition is gentle, and yield is high, beneficial to industrial metaplasia
Production；Step 3), reaction use cheap reagent, and mild condition is simple to operate, and yield is high.On the whole, preparation road of the present invention
Line yield is high, and reaction condition is gentle, green, and cost is cheap, is especially suitable for industrialized production.
Embodiment
The invention discloses a kind of preparation method of qinghaosu, those skilled in the art can use for reference present disclosure, suitably
Modified technique parameter is realized.It is important to note that all similar replacements and change are for a person skilled in the art
It will be apparent that they are considered as being included in the present invention, and related personnel can substantially not depart from present invention, spirit
Content described herein is modified or suitably changed with combining with the basis of scope, to realize and using the technology of the present invention.
In the present invention, unless otherwise stated, Science and Technology noun used herein has art technology
The implication that personnel are generally understood that.
In order that those skilled in the art more fully understands technical scheme, with reference to specific embodiment pair
The present invention is described in further detail.
Embodiment 1：
100g (0.43mol) Arteannuic acid is dissolved in 800mL chloroforms, at ambient temperature, Hydrogen Vapor Pressure 1bar, 1.5g palladium
Carbon overnight, diatomite filtering, chloroform, is recovered under reduced pressure solvent, obtains solid product dihydroartemisinic acid as catalyst, reaction
99g (0.42mol), yield 98%.
100g (0.42mol) dihydroartemisinic acid is dissolved in 500mL acetone, using 105g (0.44mol) sodium molybdates as urging
Agent, under the conditions of -10 DEG C, 30% hydrogen peroxide is slowly added dropwise as oxidant 150mL (about 1.32mol), reacts 24 hours, mistake
Filter, 200mL dichloromethane extract three times, organic phase anhydrous sodium sulfate drying.
Above-mentioned reaction solution is taken, is cooled to 0 DEG C, adds 200g (0.55mol) copper trifluoromethanesulfcomposite, is passed through oxygen, monitoring is anti-
Process is answered, question response terminates, and filtering, dichloromethane rinses, and solvent is recovered under reduced pressure, gained solid is recrystallized through methanol-water, produced
Qinghaosu 75g (0.27mol), yield 63%.
Embodiment 2：
100g (0.43mol) Arteannuic acid is dissolved in 1000mL tetrahydrofurans, at ambient temperature, Hydrogen Vapor Pressure 2bar,
5.5g Raney Nis overnight, diatomite filtering, ethyl acetate washing, are recovered under reduced pressure solvent, obtain solid product as catalyst, reaction
Dihydroartemisinic acid 96g (0.41mol), yield 95%.
100g (0.42mol) dihydroartemisinic acid is dissolved in 500mL isopropanols, using 105g (0.44mol) sodium molybdates as
Catalyst, under the conditions of -10 DEG C, 30% hydrogen peroxide is slowly added dropwise as oxidant 150mL (about 1.32mol), reacts 24 hours,
Filtering, 200mL dichloromethane extract three times, organic phase anhydrous sodium sulfate drying.
Above-mentioned reaction solution is taken, is cooled to 0 DEG C, adds 180g (0.50mol) copper trifluoromethanesulfcomposite, is passed through oxygen, monitoring is anti-
Process is answered, question response terminates, and filtering, dichloromethane rinses, and solvent is recovered under reduced pressure, gained solid is recrystallized through methanol-water, produced
Qinghaosu 69g (0.24mol), yield 57%.
Embodiment 3：
100g (0.43mol) Arteannuic acid is dissolved in 800mL propyl alcohol, under the conditions of 40 DEG C, Hydrogen Vapor Pressure 2bar, 1.5g palladium
Carbon overnight, diatomite filtering, chloroform, is recovered under reduced pressure solvent, obtains solid product dihydroartemisinic acid as catalyst, reaction
98g (0.41mol), yield 96%.
100g (0.42mol) dihydroartemisinic acid is dissolved in 600mL acetonitriles, using 125g (0.52mol) sodium molybdates as urging
Agent, under the conditions of 0 DEG C, 30% hydrogen peroxide is slowly added dropwise as oxidant 150mL (about 1.32mol), reacts 24 hours, mistake
Filter, 200mL dichloromethane extract three times, organic phase anhydrous sodium sulfate drying.
Take above-mentioned reaction solution, at room temperature, add 200g (0.55mol) copper trifluoromethanesulfcomposite, be passed through oxygen, monitoring react into
Journey, question response terminate, and filtering, dichloromethane rinses, and solvent is recovered under reduced pressure, gained solid recrystallizes through methanol-water, produces sweet wormwood
Plain 77g (0.27mol), yield 65%.
Claims (6)
1. a kind of preparation method of qinghaosu, it is characterised in that comprise the following steps：
Step 1), Arteannuic acid is dissolved in organic solvent, acted on by hydrogen/metallic catalyst, reduced and dihydroartemisinic acid is made；
Step 2), in organic solvent, using sodium molybdate as catalyst, hydrogen peroxide is as oxidant, oxidation for dihydroartemisinic acid
Peroxide dihydroartemisinic acid is made；
Step 3), peroxide dihydroartemisinic acid are passed through oxygen under copper trifluoromethanesulfcomposite effect, reset and obtain qinghaosu.
A kind of 2. preparation method of qinghaosu according to claim 1, it is characterised in that：In step 1), the metal catalytic
Agent is palladium carbon, Raney Ni, platinum oxide, wherein, amount of metal catalyst is the 0.01-0.1, Hydrogen Vapor Pressure 1- of Arteannuic acid weight
10bar, reaction temperature are -50 DEG C of room temperature.
A kind of 3. preparation method of qinghaosu according to claim 1, it is characterised in that：The organic solvent selects dichloromethane
Alkane, chloroform, acetone, methanol, ethanol, propyl alcohol, isopropanol, acetone, ethyl acetate, tetrahydrofuran, dioxane, acetonitrile, DMF,
One kind or its mixing in DMSO.
A kind of 4. preparation method of qinghaosu according to claim 1, it is characterised in that：In step 2), the sodium molybdate
Mole dosage is 1-5 times of dihydroartemisinic acid, and hydrogen peroxide mole dosage is 2-10 times of Arteannuic acid.
A kind of 5. preparation method of qinghaosu according to claim 1, it is characterised in that：In step 2), the oxidation reaction
Carried out under the conditions of -10-0 DEG C.
A kind of 6. preparation method of qinghaosu according to claim 1, it is characterised in that：In step 3), the rearrangement reaction
Carried out under 0 DEG C-room temperature condition, the mole dosage of copper trifluoromethanesulfcomposite is 1-10 times of dihydroartemisinic acid.
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| CN201610767931.3A CN107793429A (en) | 2016-08-30 | 2016-08-30 | A kind of preparation method of qinghaosu |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103087074A (en) * | 2012-12-14 | 2013-05-08 | 湖南科源生物制品有限公司 | Method of semi-synthesizing artemisinin |
| CN103172645A (en) * | 2012-06-05 | 2013-06-26 | 上海交通大学 | High-efficiency synthesis method of artemisinin |
-
2016
- 2016-08-30 CN CN201610767931.3A patent/CN107793429A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103172645A (en) * | 2012-06-05 | 2013-06-26 | 上海交通大学 | High-efficiency synthesis method of artemisinin |
| CN103087074A (en) * | 2012-12-14 | 2013-05-08 | 湖南科源生物制品有限公司 | Method of semi-synthesizing artemisinin |
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