CN107793428A - A kind of preparation method of Artemether - Google Patents
A kind of preparation method of Artemether Download PDFInfo
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- CN107793428A CN107793428A CN201610767719.7A CN201610767719A CN107793428A CN 107793428 A CN107793428 A CN 107793428A CN 201610767719 A CN201610767719 A CN 201610767719A CN 107793428 A CN107793428 A CN 107793428A
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- China
- Prior art keywords
- artemether
- added dropwise
- preparation
- methanol
- qinghaosu
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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 Artemether, mainly includes three steps：Step 1), the hydrogenation of qinghaosu；Step 2), the etherificate of dihydroartemisinine；Step 3), purifying crude.By above three step, Artemether fine work can be made, and β Artemethers content is high.The method of the invention features simple and practical process, reaction raw materials utilization rate is high, and product purity is high, is advantageous to industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of Artemether, belongs to pharmaceutical chemistry synthesis field.
Background technology
Malaria, it is commonly called as suffering from malaria, beats Lao Zhang, is a kind of acute parasitic infection global as caused by plasmodium, leads to
Malarial mosquito propagation is crossed, unique symptom is that intermittence is felt cold heating.In world wide, the case that clinical symptoms are presented is annual just 300,000,000
To between 500,000,000, every year because suffering from the dead number of malaria between one to three million, wherein most is children.Children, pregnant woman,
The new chum of traveller and various regions is poor to local popular plasmodium immunity, therefore is aguish people at highest risk.Malaria
Main Prevalent district is the northern torrid areas in central africa, South Asia, Southeast Asia and South America, among these again with the epidemic situation in Africa
Most very.
Artemether (English name Artemether), also known as first hydrogen reduction qinghaosu or Artemtherin, odorless, taste is micro-
Hardship, acetone or chloroform are highly soluble in, it is readily soluble in ethanol or ethyl acetate, water is practically insoluble in, fusing point is 86~90 DEG C.Hao Jia
Ether is the specific drug of the various critical malaria patients for the treatment of and rescue cerebral malaria patients by Chinese independent research, has drug effect
Hurry up, good effect, it is less toxic, easy to use, antimalarial active is high, with chloroquine without cross-resistance the advantages that, and because it is molten in oil
Xie Du is more than qinghaosu, and beneficial to preparation, it is preferred antimalarial that the World Health Organization (WHO) is recommended to turn into, and is included in base by WHO
This drug core catalogue.
Artemether is divided into two epimers of α-Artemether and β-Artemether, and has mainly β-wormwood artemisia of antimalarial active
Methyl ether, therefore carried out for the study on the synthesis of Artemether primarily directed to β-Artemether.The molecule of α-Artemether and β-Artemether
Structural formula difference is as follows：
The method of early stage synthesis β-Artemether has：At room temperature by dihydroartemisinine (also known as dihydroartemisinine) and methanol three
It is fluorinated under the catalysis of borate ether and carries out etherification reaction, reaction is separated after terminating with column chromatography, obtains β-Artemether crude product, is received
Rate it is relatively low (referring to《The synthesis of artemisinin derivative》, Li Ying etc., Science Bulletin, 1979,24 (14), 667-9), and operate multiple
It is miscellaneous, unsuitable and industrialized production.
Patent CN200910038509.4 provides one kind " using qinghaosu as primary industry stereospecific synthesis of beta-artemether "
In dichloromethane alkaline aqueous solution system, using sodium borohydride as reducing agent, tert-butoxy Al catalysts, it is blue or green that reduction obtains double hydrogen
Artemisin, aqueous phase is separated, add the catalyst that methanol and niter cake, aluminum perchlorate, nickelous perchlorate etc. react as methyl-etherified, wormwood artemisia
Methyl ether gross production rate is up to 93.5%, but in obtained product β-Artemether content it is still not high.
The content of the invention
It is an object of the invention to provide a kind of preparation method of β-Artemether, the preparation method is effectively inhibited in reaction
The generation of isomers α-Artemether, post processing is simple, and purity is high, and prepared β-Artemether crude product can reach through recrystallization
More than 99.8% purity, overcome the deficiency for preparing β-Artemether at present.
To realize object above, the present invention adopts the following technical scheme that：
A kind of preparation method of Artemether, is comprised the steps of：
Step 1), qinghaosu is dissolved in methanol, is cooled to -10~0 DEG C, under stirring, be slowly added to 2~4 equivalent boron hydrogen
Change potassium or sodium borohydride, monitor reaction process, question response terminates, is warmed to room temperature naturally, and saturated ammonium chloride solution is added dropwise and is neutralized to
Neutrality, dichloromethane extraction, anhydrous sodium sulfate drying；
Wherein, preferably the dosage of methanol is 5~20 times of qinghaosu weight, and the monitoring reaction process is supervised by TLC
Survey, reaction temperature is -2~0 DEG C；
Step 2), the organic solution that step 1) obtains is cooled to -10~0 DEG C, adds trimethyl orthoformate, stirring 10~
30min, the diethyl ether solution of BFEE is added dropwise, is added dropwise, continue reaction 1~2 hour, be warmed to room temperature naturally, monitor
Reaction process, question response terminate, and saturated sodium bicarbonate solution, regulation system to neutrality, liquid separation, aqueous phase dichloromethane is slowly added dropwise
Alkane extracts, and merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, obtains solid；
Wherein, preferred qinghaosu: trimethyl orthoformate: BFEE mol ratio is 1: 0.5~1: 0.1~0.5, institute
The diethyl ether solution for stating BFEE is the diethyl ether solution of the BFEE of concentration 30%, and etherification temperature is -4~-2 DEG C；
Step 3), solid obtained by step 2) is dissolved in methanol, adds proper amount of active carbon, backflow is decolourized, filtering, is dripped in filtrate
Add pure water, be cooled to -10~0 DEG C of crystallization, filter, wash, dry, produce Artemether；
Wherein, preferably gained solid masses (g): methanol volume (mL): pure water volume (mL) ratio be 1: 2~4: 4~8,
It is highly preferred that gained solid masses (g): methanol volume (mL): pure water volume (mL) ratio is 1: 3: 6.
Beneficial effects of the present invention are：The present invention can efficiently realize the hydrogenation of qinghaosu by step 1)；Pass through step
The rapid etherificate that 2) can further realize to qinghaosu；It can be realized in step 3) and obtained crude product Artemether is purified,
Obtain Artemether fine work.Said process can farthest realize the conversion of qinghaosu, and simple to operate, technological process is short, obtains
Product β-the Artemether obtained is up to more than 99.8%, and production cost significantly reduces, and is advantageous to industrialized production.
Embodiment
The invention discloses a kind of preparation method of β-Artemether, those skilled in the art can use for reference present disclosure, fit
When 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 is 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, essence
Content described herein is modified or suitably changed with combining on the basis of god and scope, to realize and using skill of the present invention
Art.
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 (0.35mol) qinghaosu is dissolved in 1L methanol, -2 DEG C, under stirring is cooled to, is slowly added to 40g
(1.1mol) sodium borohydride, TLC monitoring reaction process, question response terminate, are warmed to room temperature naturally, be added dropwise in saturated ammonium chloride solution
With to neutrality, 200mL dichloromethane extracts three times, washing, anhydrous sodium sulfate drying；
Above-mentioned organic solution is cooled to -2 DEG C, adds 22g (0.21mol) trimethyl orthoformate, stirs 30min, is added dropwise
The diethyl ether solution 35mL (about 0.07mol) of 30% BFEE, is added dropwise, and continues reaction 1 hour, rises to room naturally
Temperature, reaction process is monitored, question response terminates, and saturated sodium bicarbonate solution, regulation system to neutrality, liquid separation, aqueous phase is slowly added dropwise
It is extracted twice with 50mL dichloromethane, merges organic phase, 50mL saturated common salt water washings, anhydrous sodium sulfate drying, be removed under reduced pressure
Solvent, obtain solid；
Gained solid is dissolved in 250mL methanol, adds 8g activated carbons, and backflow is decolourized, filtering, and 500mL pure water is added dropwise in filtrate,
- 10 DEG C of crystallizations are cooled to, are filtered, are washed, dries, produces Artemether.
Embodiment 2：
100g (0.35mol) qinghaosu is dissolved in 1L methanol, -2 DEG C, under stirring is cooled to, is slowly added to 45g
(0.83mol) potassium borohydride, TLC monitoring reaction process, question response terminate, are warmed to room temperature naturally, and saturated ammonium chloride solution is added dropwise
Neutrality is neutralized to, 200mL dichloromethane extracts three times, washing, anhydrous sodium sulfate drying；
Above-mentioned organic solution is cooled to -2 DEG C, adds 21g (0.20mol) trimethyl orthoformate, stirs 30min, is added dropwise
The diethyl ether solution 35mL (about 0.07mol) of 30% BFEE, is added dropwise, and continues reaction 1 hour, rises to room naturally
Temperature, reaction process is monitored, question response terminates, and saturated sodium bicarbonate solution, regulation system to neutrality, liquid separation, aqueous phase is slowly added dropwise
It is extracted twice with 50mL dichloromethane, merges organic phase, 50mL saturated common salt water washings, anhydrous sodium sulfate drying, be removed under reduced pressure
Solvent, obtain solid；
Gained solid is dissolved in 250mL methanol, adds 9g activated carbons, and backflow is decolourized, filtering, and 500mL pure water is added dropwise in filtrate,
- 5 DEG C of crystallizations are cooled to, are filtered, are washed, dries, produces Artemether.
Embodiment 3：
100g (0.35mol) qinghaosu is dissolved in 1L methanol, 0 DEG C, under stirring is cooled to, is slowly added to 45g
(1.2mol) sodium borohydride, TLC monitoring reaction process, question response terminate, are warmed to room temperature naturally, be added dropwise in saturated ammonium chloride solution
With to neutrality, 200mL dichloromethane extracts three times, washing, anhydrous sodium sulfate drying；
Above-mentioned organic solution is cooled to -2 DEG C, adds 22g (0.21mol) trimethyl orthoformate, stirs 30min, is added dropwise
The diethyl ether solution 40mL (about 0.08mol) of 30% BFEE, is added dropwise, and continues reaction 1 hour, rises to room naturally
Temperature, reaction process is monitored, question response terminates, and saturated sodium bicarbonate solution, regulation system to neutrality, liquid separation, aqueous phase is slowly added dropwise
It is extracted twice with 50mL dichloromethane, merges organic phase, 50mL saturated common salt water washings, anhydrous sodium sulfate drying, be removed under reduced pressure
Solvent, obtain solid；
Gained solid is dissolved in 250mL methanol, adds 8g activated carbons, and backflow is decolourized, filtering, and 500mL pure water is added dropwise in filtrate,
- 10 DEG C of crystallizations are cooled to, are filtered, are washed, dries, produces Artemether.
Claims (5)
1. a kind of preparation method of Artemether, it is characterised in that comprise the following steps：
Step 1), qinghaosu is dissolved in methanol, is cooled to -10~0 DEG C, under stirring, be slowly added to 2~4 equivalent potassium borohydrides
Or sodium borohydride, reaction process is monitored, question response terminates, is warmed to room temperature naturally, and saturated ammonium chloride solution is added dropwise and is neutralized to neutrality,
Dichloromethane extracts, anhydrous sodium sulfate drying；
Step 2), the organic solution that step 1) obtains is cooled to -10~0 DEG C, adds trimethyl orthoformate, stirring 10~
30min, the diethyl ether solution of BFEE is added dropwise, is added dropwise, continue reaction 1~2 hour, be warmed to room temperature naturally, monitor
Reaction process, question response terminate, and saturated sodium bicarbonate solution, regulation system to neutrality, liquid separation, aqueous phase dichloromethane is slowly added dropwise
Alkane extracts, and merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, obtains solid；
Step 3), solid obtained by step 2) is dissolved in methanol, adds proper amount of active carbon, backflow is decolourized, filtering, is added dropwise in filtrate pure
Water, -10~0 DEG C of crystallization is cooled to, filtered, washed, dried, produce Artemether.
A kind of 2. preparation method of Artemether according to claim 1, it is characterised in that：In step 1), the dosage of methanol
For 5~20 times of qinghaosu weight, the monitoring reaction process is monitored by TLC, and reaction temperature is -2~0 DEG C.
A kind of 3. preparation method of Artemether according to claim 1, it is characterised in that：Qinghaosu: trimethyl orthoformate:
BFEE mol ratio is 1: 0.5~1: 0.1~0.5, and the diethyl ether solution of the BFEE is concentration 30% 3
The diethyl ether solution of borate ether is fluorinated, etherification temperature is -4~-2 DEG C.
A kind of 4. preparation method of Artemether according to claim 1, it is characterised in that in step 3), gained solid masses
(g): methanol volume (mL): pure water volume (mL) ratio is 1: 2~4: 4~8.
A kind of 5. preparation method of Artemether according to claim 4, it is characterised in that gained solid masses (g): methanol
Volume (mL): pure water volume (mL) ratio is 1: 3: 6.
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| CN201610767719.7A CN107793428A (en) | 2016-08-30 | 2016-08-30 | A kind of preparation method of Artemether |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112358488A (en) * | 2020-11-05 | 2021-02-12 | 张家港威胜生物医药有限公司 | Preparation method of beta-artemether |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102731523A (en) * | 2012-07-10 | 2012-10-17 | 刘志强 | Preparation method of beta-artemether |
| CN104725395A (en) * | 2013-12-20 | 2015-06-24 | 上海迪赛诺化学制药有限公司 | Technology for preparing beta-artemether |
| CN103180325B (en) * | 2011-09-20 | 2015-09-23 | 上海迪赛诺药业有限公司 | Prepare the method for β-Artemether |
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2016
- 2016-08-30 CN CN201610767719.7A patent/CN107793428A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103180325B (en) * | 2011-09-20 | 2015-09-23 | 上海迪赛诺药业有限公司 | Prepare the method for β-Artemether |
| CN102731523A (en) * | 2012-07-10 | 2012-10-17 | 刘志强 | Preparation method of beta-artemether |
| CN104725395A (en) * | 2013-12-20 | 2015-06-24 | 上海迪赛诺化学制药有限公司 | Technology for preparing beta-artemether |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112358488A (en) * | 2020-11-05 | 2021-02-12 | 张家港威胜生物医药有限公司 | Preparation method of beta-artemether |
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