CN108727168A - A kind of alpha-ararin synthesis technology - Google Patents
A kind of alpha-ararin synthesis technology Download PDFInfo
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- CN108727168A CN108727168A CN201810897731.9A CN201810897731A CN108727168A CN 108727168 A CN108727168 A CN 108727168A CN 201810897731 A CN201810897731 A CN 201810897731A CN 108727168 A CN108727168 A CN 108727168A
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- ararin
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- XAZKFISIRYLAEE-UHFFFAOYSA-N CC1CC(C)CC1 Chemical compound CC1CC(C)CC1 XAZKFISIRYLAEE-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
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Abstract
The invention belongs to pharmaceutical technology fields, and in particular to a kind of alpha-ararin synthesis technology.For the present invention in the dehydration elimination reaction stage of alpha-ararin synthesis technology, it is dehydrating agent to select propionic andydride, anhydrous propionic acid or propionic acid and propionic andydride mixed solution, and the molal weight ratio of 2,4,5- trimethoxy phenylpropanols and dehydrating agent is 1：(0.1-20), using anhydrous sodium propionate or anhydrous potassium propionate as dehydration catalyst, the molal weight ratio of 2,4,5- trimethoxy phenylpropanols and catalyst is 1：(0.1-2).Present invention process can significantly improve the yield of alpha-ararin, inhibit the impurity such as generation and the asarone polymer of β-asarone to generate, reduce cost, be suitble to the industrialized production of alpha-ararin.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of alpha-ararin synthesis technology.
Background technology
Alpha-ararin has very strong pharmacological activity, has cough-relieving, eliminating the phlegm, relievings asthma, is calm, spasmolysis and anticonvulsant action.
Also there is different degrees of inhibiting effect to the growth of Diplococcus pneumopniae, Staphylococcus aureus and Escherichia coli.Asarone is the country
Unique traditional Chinese medicine monomer synthesizes anti-inflammatory expelling phlegm and arresting coughing antiasthmatic, and effect more relieving cough and asthma than pure Chinese medicinal preparation becomes apparent from, with chemistry
The Western medicine preparation of synthesis becomes apparent from compared to therapeutic effect, and bronchorelaxing activity is stronger, and eliminating the phlegm, antiasthmatic effect are more preferable.Asarone
Injection is widely used to clinic, and has preferable clinical efficacy, You Duojia Asarone Injectins manufacturer of the current country,
Market demand is larger, and huge commercial value is contained on its body, so there is this product considerable economic benefit and society to imitate
Benefit.
In the synthetic route reported, a small amount of its cis-trans-isomer β-asarum is often accompanied by the alpha-ararin of synthesis
Brain, structure is similar to alpha-ararin, but β-asarone has very strong toxicity.According to the requirement of Chinese Pharmacopoeia, in synthesis
The content of alpha-ararin weight β-asarone should be less than 1%.Both isomers of asarone need to isolate and purify ability through complicated
Alpha-ararin is obtained, yield is not high, expensive, the problem of existing simultaneously using poisonous and hazardous organic solvent.
Progress dehydration is needed to obtain final product in the synthetic route of alpha-ararin, existing literature is mainly by following
Several dehydrating agents：
1) it is dehydrating agent with copper sulphate, dehydration obtains positive and negative two kinds of isomers, and stereoselectivity is higher, needs strictly anhydrous
Operation.
2) using benzene as solvent, p-methyl benzenesulfonic acid or m-toluene sulfonic acid are that dehydrating agent carries out reaction dehydration, products therefrom cooling
Afterwards, water, saturated sodium bicarbonate water washing, dry concentration is used to obtain alpha-ararin and β-asarone, total recovery 93%, warp successively
Detach to obtain final products alpha-ararin.
3) phosphorus trichloride or Al are used2O3,AlCl3Reaction dehydration is carried out for dehydrating agent and obtains positive and negative two kinds of isomers, through separation
Obtain alpha-ararin.
4) with 20% sulfuric acid be dehydrating agent carry out reaction dehydration obtain positive and negative two kinds of isomers, be isolated to α-asarum
Brain.
5) with to methyl this sulfonic acid-toluene, SOCl2(adding or be not added with pyridine), triphenyl phasphine-carbon tetrachloride, Al2O3Or trichlorine
Change phosphorus and obtain positive and negative two kinds of isomers, when separation encounters many difficulties.
Above various dewaterings, what is obtained is all the positive and negative two kinds of isomers of asarone, and stereoselectivity is relatively low, it is more difficult to
Separation, and β-asarone has larger toxicity, needs just become alpha-ararin by series reaction.
Invention content
In view of the problems of the existing technology, the present invention provides a kind of alpha-ararin synthesis technology, by dehydration
The selection of dehydrating agent is optimized, dehydrating agent selects the mixed solution of propionic andydride or propionic acid, propionic acid and propionic andydride, keeps α-thin
Pungent brain yield greatly improves, and is suitble to industrialized production.
The alpha-ararin synthesis technology of the present invention is that raw material prepares 2,4 by acylation reaction with 1,2,4- trimethoxy-benzene,
5- trimethoxy propiophenones；2,4,5- trimethoxy propiophenones obtain 2,4,5- trimethoxy phenylpropanols by reduction is counter；
It follows the steps below：
(1) under nitrogen protection, solvent and dehydrating agent are added into 2,4,5- trimethoxy phenylpropanols, or dehydration is added
Agent is simultaneously using dehydrating agent as solvent, and the dehydrating agent is propionic andydride, propionic acid, propionic acid and propionic andydride mixed solution, with anhydrous third
Sour sodium or potassium propionate are dehydration catalyst, and reaction temperature is ± 2 DEG C of (120~168), and TLC monitors the extent of reaction, until 1,2,4-
The reaction was complete for trimethoxy phenylpropanol, obtains reaction solution；
(2) when the dehydrating agent is propionic andydride, postcooling that the reaction was complete is transferred to constant pressure to 100 DEG C, by reaction solution
In dropping funel, be slowly added dropwise into the inorganic alkali solution added with appropriate organic solvent configured, wherein propionic andydride with it is inorganic
The molar ratio of alkali is 0.9:1.05, mechanical agitation is added dropwise 2 hours, detects the pH value of reaction solution, until acid anhydrides by completely in
Between being 7.0~7.5 with, pH value, the organic solution containing asarone is obtained；
When the dehydrating agent is propionic acid or propionic andydride and propionic acid mixed liquor, control temperature subtracts in 85 DEG C after the reaction was complete
Pressure distillation, until not going out liquid until, is down to room temperature, and appropriate organic solvent is added and suitable quantity of water stirring is layered, by reaction solution liquid separation,
Retain organic phase；Water phase is extracted 2 times with organic solvent, is ensured that water phase is remained without asarone, is merged organic phase, with unsaturated carbonate hydrogen
Sodium solution washes twice, and detects the pH value of reaction solution, until between pH value is about 7.0~7.2, obtain the crude product containing asarone has
Machine solution；
(3) organic phase is concentrated under reduced pressure, decrease temperature crystalline, filters, obtains white powdery solids, it is dry, obtain α-asarum
Brain crude product, yield are 72%~92%, 94.0% or more purity；
(4) alpha-ararin crude product is refined, obtains alpha-ararin fine work, refine yield be 75~80%, purity and
99.5% or more mass content.
Wherein, the dehydrating agent propionic acid and propionic andydride proportioning are arbitrary proportioning.
The molal weight ratio of the 2,4,5- trimethoxies phenylpropanol and dehydrating agent is 1：(0.1~20).
The molal weight ratio of the 2,4,5- trimethoxies phenylpropanol and catalyst is 1：(0.1~2).
The inorganic alkali solution is sodium hydroxide, potassium hydroxide, sodium carbonate/potassium or sodium bicarbonate/potassium solution, preferably
Sodium carbonate.
It is described it is refined be in three-necked flask, under condensing reflux, by alpha-ararin crude product and absolute alcohol or volume fraction
60%~95% alcohol solution obtains alpha-ararin fine work, and the absolute alcohol is methanol, ethyl alcohol, propyl alcohol, isopropanol or fourth
Alcohol, preferred alcohol.
The reaction system of the step (1) is molten with benzene,toluene,xylene, alkanes, aromatic hydrocarbons or ethers organic inert
Agent is solvent；It is preferably using dehydrating agent as solvent.
Reaction temperature in the step (1) is 120-170 DEG C, and preferable temperature is 135-145 DEG C, peak optimization reaction temperature
It is 140 ± 2 DEG C.
Organic solvent used in step (2) is water-insoluble solvent alkane, aromatic hydrocarbons or ether solvent；Wherein alkane is preferred
N-hexane and hexamethylene, the preferred petroleum ether of ethers, the preferred toluene of aromatic hydrocarbons.
There is a small amount of propionic acid to remain in the alpha-ararin fine work.
Compared with prior art, the features of the present invention and advantageous effect are：The receipts of α-asarone can significantly be improved
Rate inhibits the impurity such as generation and the asarone polymer of β-asarone to generate, reduces synthesis material cost, be more suitable for α-
The industrialized production of asarone.
By being optimized to the selection of dehydrating agent in dehydration, the special reaction for being dehydrated into alkene：
Dehydrating agent selects propionic andydride or propionic acid or the third acid anhydride and propionic acid mixture, dehydration catalyst be anhydrous sodium propionate or
Potassium propionate makes alpha-ararin yield greatly improve, and is suitble to industrialized production.
Specific implementation mode
In conjunction with embodiment, the present invention is further described.
Embodiment 1
The alpha-ararin synthesis technology of the present embodiment is that raw material prepares 2 by acylation reaction with 1,2,4- trimethoxy-benzene,
4,5- trimethoxy propiophenones；2,4,5- trimethoxy propiophenones obtain 2,4,5- trimethoxy phenylpropanols by reduction is counter；
It follows the steps below：
Under nitrogen protection, 4.48g potassium propionates are put into the flask of 250ml, and 104g propionic andydrides and propionic acid mixed liquor is added
Wherein propionic andydride 24g, propionic acid 80g are warming up to reflux, and 2,4,5- trimethoxy phenylpropanol 18.08g of reduzate, reflux point is added
Liquid reacts one hour, and control temperature is evaporated under reduced pressure at 85 DEG C, stops distillation until not going out liquid, is down to 45 DEG C of addition 100ml
N-hexane and the stirring layering of 50ml water；By reaction solution liquid separation, retain n-hexane phase；Water phase is stripped 2 times with n-hexane, ensures water phase
No asarone residual, merges n-hexane, is washed twice with the sodium bicarbonate solution of saturation, detect the pH value of reaction solution, until pH
Between value about 7.0~7.2.
Hexane solution is reduced to (asarone theoretical yield at 40 ± 2 DEG C：N-hexane=1:1.5) under state, stop dense
Contracting is transferred to stirring and crystallizing in there-necked flask while hot, stirs 6 hours, is filtered under diminished pressure, and obtains white powdery solids, and decompression is dry
It is dry, asarone crude product 15g is obtained, asarone 12.5g, yield 75%, purity and mass content 99.5% are refining to obtain.
Embodiment 2
The alpha-ararin synthesis technology of the present embodiment is that raw material prepares 2 by acylation reaction with 1,2,4- trimethoxy-benzene,
4,5- trimethoxy propiophenones；2,4,5- trimethoxy propiophenones obtain 2,4,5- trimethoxy phenylpropanols by reduction is counter；
It follows the steps below：
Under nitrogen protection, 4.48g potassium propionates are put into the flask of 250ml, and 104g propionic andydrides and propionic acid mixed liquor is added,
Wherein propionic andydride 30g, propionic acid 74g are warming up to reflux, and 2,4,5- trimethoxy phenylpropanol 18.08g of reduzate, reflux point is added
Liquid reacts one hour, and control temperature is evaporated under reduced pressure at 85 DEG C, stops distillation until not going out liquid, is down to 45 DEG C of addition 100ml
N-hexane and the stirring layering of 50ml water；By reaction solution liquid separation, retain n-hexane phase；Water phase is stripped 2 times with n-hexane, ensures water phase
No asarone residual, merges n-hexane, is washed twice with the sodium bicarbonate solution of saturation, detect the pH value of reaction solution, until pH
Between value about 7.0~7.2.
Hexane solution is reduced to (asarone theoretical yield at 40 ± 2 DEG C：N-hexane=1:1.5) under state, stop dense
Contracting is transferred to stirring and crystallizing in there-necked flask while hot, stirs 6 hours, is filtered under diminished pressure, and obtains white powdery solids, and decompression is dry
It is dry, asarone crude product 15g is obtained, asarone 12.5g, yield 75%, purity and mass content 99.5% are refining to obtain.
The explanation of above example is only intended to facilitate the understanding of the method and its core concept of the invention.It should be pointed out that pair
For those skilled in the art, without departing from the principle of the present invention, the present invention can also be carried out
Some improvements and modifications, these improvement and modification are also fallen within the protection scope of the claims of the present invention.
Claims (9)
1. alpha-ararin synthesis technology, with 2,4,5- trimethoxy phenylpropanols for raw material, dehydration obtains alpha-ararin, special
Sign is to follow the steps below：
(1) under nitrogen protection, addition solvent and dehydrating agent into 2,4,5- trimethoxy phenylpropanols, or addition dehydrating agent are same
When using dehydrating agent as solvent, the dehydrating agent is propionic andydride, propionic acid, propionic acid and propionic andydride mixed solution, with anhydrous sodium propionate
Or potassium propionate is dehydration catalyst, reaction temperature is ± 2 DEG C of (120~168), and TLC monitors the extent of reaction, until 1,2,4- front threes
The reaction was complete for oxygen phenylpropanol, obtains reaction solution；
(2) when the dehydrating agent is propionic andydride, postcooling that the reaction was complete is transferred to constant pressure addition to 100 DEG C, by reaction solution
It in funnel, is slowly added dropwise into the inorganic alkali solution added with organic solvent configured, wherein mole of propionic andydride and inorganic base
Than being 0.9:1.05, mechanical agitation is added dropwise 2 hours, detects the pH value of reaction solution, until acid anhydrides is fully neutralized, pH value is
Between 7.0~7.5, the organic solution containing asarone is obtained；
When the dehydrating agent is propionic acid or propionic andydride and propionic acid mixed liquor, control temperature is steamed in 85 DEG C of decompressions after the reaction was complete
It evaporates, until not going out liquid, is down to room temperature, appropriate organic solvent is added and suitable quantity of water stirring layering retains reaction solution liquid separation
Organic phase；Water phase is extracted 2 times with organic solvent, ensures that water phase is remained without asarone, merges organic phase, molten with saturated sodium bicarbonate
Liquid washes twice, and detects the pH value of reaction solution, until between pH value is about 7.0~7.2, obtains the organic molten of the crude product containing asarone
Liquid；
(3) organic phase is concentrated under reduced pressure, decrease temperature crystalline, filters, obtains white powdery solids, it is dry, it is thick to obtain alpha-ararin
Product, yield are 72%~92%, 94.0% or more purity；
(4) alpha-ararin crude product is refined, obtains alpha-ararin fine work, it is 75~80% to refine yield, purity and quality
99.5% or more content.
2. a kind of alpha-ararin synthesis technology according to claim 1, it is characterised in that described 2,4,5- trimethoxies
The mass ratio of phenylpropanol and dehydrating agent is 1：(0.1~20).
3. a kind of alpha-ararin synthesis technology according to claim 1, it is characterised in that described 2,4,5- trimethoxies
The molal weight of phenylpropanol and catalyst ratio is 1：(0.1~2).
4. a kind of alpha-ararin synthesis technology according to claim 1, it is characterised in that the inorganic alkali solution is hydrogen
Sodium oxide molybdena, potassium hydroxide, sodium carbonate/potassium or sodium bicarbonate/potassium solution, preferred sodium carbonate.
5. a kind of alpha-ararin synthesis technology according to claim 1, it is characterised in that it is described it is refined be to be burnt at three mouthfuls
In bottle, under condensing reflux, it is thin that the alcohol solution of alpha-ararin crude product and absolute alcohol or volume fraction 60%~95% is obtained into α-
Pungent brain fine work, the absolute alcohol are methanol, ethyl alcohol, propyl alcohol, isopropanol or butanol, preferred alcohol.
6. a kind of alpha-ararin synthesis technology according to claim 1, it is characterised in that the reactant of the step (1)
With benzene, toluene, dimethylbenzene, alkanes, aromatic hydrocarbons or ethers organic inert solvent are solvent for system；It is preferably molten with dehydrating agent
Agent.
7. a kind of alpha-ararin synthesis technology according to claim 1, it is characterised in that the reaction temperature in step (1) is
120-170 DEG C, preferable temperature is 135-145 DEG C, and peak optimization reaction temperature is 140 ± 2 DEG C.
8. a kind of alpha-ararin synthesis technology according to claim 1, it is characterised in that organic molten used in step (2)
Agent is water-insoluble solvent alkane, aromatic hydrocarbons or ether solvent；The wherein preferred n-hexane of alkane and hexamethylene, the preferred oil of ethers
Ether, the preferred toluene of aromatic hydrocarbons.
9. a kind of alpha-ararin synthesis technology according to claim 1, it is characterised in that in the alpha-ararin fine work
There is a small amount of propionic acid to remain.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110128248A (en) * | 2019-06-12 | 2019-08-16 | 承德石油高等专科学校 | It is a kind of green simplicity prepare alpha-ararin technique |
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|---|---|---|---|---|
| CN1511817A (en) * | 2002-12-30 | 2004-07-14 | 刘博纯 | Process for producing alpha-asarone raw material |
| CN101195562A (en) * | 2007-12-11 | 2008-06-11 | 广西中医学院 | Novel method for synthesizing alpha-asarone |
| CN101492351A (en) * | 2008-01-25 | 2009-07-29 | 亚邦化工集团有限公司 | Process for producing asarin |
| CN101891604A (en) * | 2010-05-11 | 2010-11-24 | 广西中医学院 | Method for synthesizing 2,4,5-trimethoxyethylphenylketone intermediate of alpha-asarin |
| CN102199077A (en) * | 2011-04-08 | 2011-09-28 | 陆超 | Method for producing (E)-2,4,5-trimethoxy-1-propenylbenzene |
-
2018
- 2018-08-08 CN CN201810897731.9A patent/CN108727168A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1511817A (en) * | 2002-12-30 | 2004-07-14 | 刘博纯 | Process for producing alpha-asarone raw material |
| CN101195562A (en) * | 2007-12-11 | 2008-06-11 | 广西中医学院 | Novel method for synthesizing alpha-asarone |
| CN101492351A (en) * | 2008-01-25 | 2009-07-29 | 亚邦化工集团有限公司 | Process for producing asarin |
| CN101891604A (en) * | 2010-05-11 | 2010-11-24 | 广西中医学院 | Method for synthesizing 2,4,5-trimethoxyethylphenylketone intermediate of alpha-asarin |
| CN102199077A (en) * | 2011-04-08 | 2011-09-28 | 陆超 | Method for producing (E)-2,4,5-trimethoxy-1-propenylbenzene |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110128248A (en) * | 2019-06-12 | 2019-08-16 | 承德石油高等专科学校 | It is a kind of green simplicity prepare alpha-ararin technique |
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