CN108358911A - A kind of method of magnetic induced Crystallization Separation hyoscine - Google Patents
A kind of method of magnetic induced Crystallization Separation hyoscine Download PDFInfo
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- CN108358911A CN108358911A CN201810354627.5A CN201810354627A CN108358911A CN 108358911 A CN108358911 A CN 108358911A CN 201810354627 A CN201810354627 A CN 201810354627A CN 108358911 A CN108358911 A CN 108358911A
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- hyoscine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of methods of magnetic induced Crystallization Separation hyoscine, first to hyoscine crude extract acid adding at salt, then scopolamine salt crystallization is made to be precipitated by induced by magnetic field effect, the impurity being filtered to remove in hyoscine crude product, one step obtains the scopolamine salt of high-purity, because hyoscine is unstable, general salifie form stores and transports for a long time.Compared with traditional method for crystallising, the present invention makes scopolamine salt accelerate nucleus formation, crystallization precipitation by magnetic induced, shortens crystallization time, improves the rate of recovery and purity of hyoscine.This method obtains the hyoscine of high-purity by one step of magnetic induced crystallization, reduces the use of organic solvent, simplifies the purifying process of substance, suitable industrialization large-scale production easy to operate.
Description
Technical field
The present invention relates to Separation of Natural Products technical field, specially a kind of side of magnetic induced Crystallization Separation hyoscine
Method.
Background technology
Hyoscine (Scopolamine) is a kind of tropane type alkaloid, be primarily present in plant of Solanaceae belladonna class and
It is main alkaloid in datura flower, Scopolia and henbane seed in datura class.1892, E. Schmidts were first from Anisodus luridus
In it is isolated.Clinically, the drug effect of hyoscine is based primarily upon the effect of its Antimuscarinic.As muscarine retarding agent, east
Hyoscyamine competes M-ChR, interrupts parasympathetic domination.Hyoscine has higher lipophilicity, therefore regardless of which kind of
Administration route, easily by blood-brain barrier, Central nervous system generates stronger effect.Compared with atropine, mydriasis and
Inhibit glandular secretion effect stronger, there is excitation to respiratory center, but have apparent inhibiting effect to cerebral cortex.With Liang
Henbane alkali is compared, and hyoscine has the characteristics that adverse reaction is few, strong drug action.Clinically, it is dynamic to be mainly used for analgesia, anesthesia, anti-blooming
Disease, treatment parkinsonism, improvement microcirculation, detoxification and addiction-removing, treatment pesticide poisoning etc., the market demand is very huge.With pharmacology
Progress of research, application range are gradually expanded.Safety is naturally mainly industrially extracted by chemical synthesis and natural extraction
Higher, but extraction difficulty is also big, and price is high.
Traditional hyoscine is purified, is usually obtained after crude extract further according to hyoscine by solvent extraction
The properties such as alkalinity, solubility, functional group are detached.According to the difference of mass transfer characteristics between phase border, mainly there are extraction, extraction, knot
The unit operations such as brilliant, absorption.It is industrial at present that sterling is mainly prepared by column chromatography, but there is low separation efficiency, energy consumptions
Greatly, easy racemization loses optical activity, toxic solvent remains the drawbacks such as exceeded.
Magnetization technology is a kind of technology that substance is carried out to magnetic field processing, which has application to every field.Magnetization point
From being the difference for utilizing element or component magnetic susceptibility, substance is subjected to magnetic field processing by external magnetic field, is divided to reach to strengthen
A kind of technology from process.With the appearance of high-intensity magnetic field, HGMS technology, the application of magnetic separation technique is from separation
Ferromagnetism bulky grain develops to removal weak magnetic and diamagnetic fine particle, is developed to from the magnetic separation with nonmagnetic elements
Separation between diamagnetic fluid homogeneous mixture component.As clean, energy-efficient emerging technology, magnetization separation would indicate that tempting
Foreground.
Magnetic field processing can have an impact solution crystallization kinetics, with the variation of magnetization condition, can significantly change
Metacrystal karyogenesis rate and crystal growth rate.Raw material with phase transformation trend, phase transition process shifts to an earlier date when by magnetic fields
Occur, crystallite of a large amount of disperses in fluid can be formed under magnetic fields.Under suitable conditions, it is analysed by nucleus of crystallite
Go out crystal.Magnetization technology is applied to hyoscine separation field, hyoscine is carried out by the method for magnetic induced crystallization
Crystallization Separation shortens crystallization time, improves the purity and the rate of recovery of hyoscine, and the present invention is suitable for the big rule of industry
Mould produces, therefore the present invention has very vast market prospect.
Invention content
The present invention is directed to deficiency of the prior art, it is desirable to provide a kind of magnetic induced Crystallization Separation hyoscine
Method.The product purity that the method for the present invention obtains is high, and production efficiency is big, is suitable for industrialized production.
Compared with traditional method for crystallising, the present invention makes scopolamine salt accelerate nucleus formation, crystallization by magnetic induced
It is precipitated, shortens crystallization time, improve the rate of recovery and purity of hyoscine.
The method of the magnetic induced Crystallization Separation hyoscine of the present invention, first to hyoscine extract acid adding at salt, so
It is precipitated scopolamine salt crystallization under induced by magnetic field effect afterwards, obtains the scopolamine salt of high-purity.Because of hyoscine shakiness
Fixed, general salifie form stores and transports for a long time.
The method of the magnetic induced Crystallization Separation hyoscine of the present invention, includes the following steps：
Step 1：Hyoscine is at salt
Hyoscine extract is dissolved in recrystallisation solvent, acid is then added, is uniformly mixing to obtain the salt of hyoscine
Solution；
Step 2：Magnetic induced crystallization
The salting liquid of hyoscine is kept at a certain temperature, being subsequently placed in magnetic field and carrying out magnetic induced crystallization；It is logical
Temperature and magnetic field intensity are overregulated, the growth of crystal is controlled.
Step 3：The separation of crystal
Step 2 gained mixed liquor filters, and washing removes plane of crystal impurity, and vacuum drying removes the remaining water of plane of crystal
Point and solvent, you can obtain scopolamine salt.
In step 1, the content of hyoscine is 80-85% in hyoscine extract.
In step 1, the recrystallisation solvent is in methanol, ethyl alcohol, isopropanol, n-butanol, ethyl acetate, acetone, water
One or more of mixed solvents.
In step 1, the acid includes hydrobromic acid or hydrochloric acid etc..
In step 2, the magnetic field includes transverse magnetic field, axial magnetic field, rotating excitation field and cusp fields etc..Form magnetic field
Device includes the magnetic field device that the magnetic field etc. being made of electromagnetic field, permanent magnet forms.
In step 2, the salting liquid of the hyoscine is supersaturated solution, and controls the concentration of solution in metastable region.
In step 2, specific temperature is 15-20 DEG C, magnetic field intensity ranging from 380-420mT.
In step 3, washing solvent for use is the solvents small to Crystal solubility and easily removing such as ethyl alcohol, acetone.
In the method, when in the magnetic field that the supersaturated solution containing scopolamine salt is put into certain magnetic field intensity
When, magnetic field has an impact solution crystallization kinetics, with the variation of magnetization condition, can significantly change nucleus generating rate
And crystal growth rate.Simultaneously using the difference of scopolamine salt and the magnetic susceptibility of other components, it can reach and strengthen east Liang
The separation of henbane alkali salt and impurity.The supersaturated solution of hyoscine has phase transformation trend, phase transition process when by magnetic fields
Occur in advance, crystallite of a large amount of disperses in fluid can be formed under magnetic fields.Under suitable conditions, using crystallite as nucleus
And it precipitates crystal.
In the method, when externally-applied magnetic field, due to the effect of induced by magnetic field " dipole-dipole force ", keep scopolamine salt intermolecular
The chance being bonded together mutually is collided to increase, thus nucleation rate is accelerated, to accelerate crystallization.And magnetic field is certain
Continuously distributed vector field in area of space has certain direction.When externally-applied magnetic field, electrically charged hyoscine molecules of salt
It moves in magnetic field, is enriched with to one end, increase the degree of supersaturation of solution, accelerate nucleation rate, to accelerate to finish
It is brilliant.
In the method, magnetic field makes the movement of hyoscine molecule have certain orientation, orientation along Movement in Magnetic Field direction
Guiding hyoscine molecular crystalline keeps the arrangement of crystal more regular to change crystal form.Simultaneously because of scopolamine salt and other groups
The difference of the magnetic susceptibility divided, enhances the separation of scopolamine salt and impurity, keeps the impurity that crystal is carried secretly less.Because crystal is arranged
Arrange more regular, the impurity more uncomplicated laundering removing of plane of crystal.So through crystal purity higher obtained by induced by magnetic field.
The present invention has the beneficial effect that：
So that scopolamine salt crystallization is precipitated using magnetic induced method in the present invention, it is made to be detached with impurity in solution
Purification.Hyoscine is directly precipitated at salt, compared with traditional column chromatography, crystallization, extraction etc., avoids organic solvent and largely uses
Pollution and toxic extractant such as chloroform human body is damaged.Product purity prepared by this method has up to 99% or more
There are higher product yield and product recovery rate.
The scopolamine salt that the present invention obtains is easier to preserve, and is not easy to lose bioactivity.Hyoscine is converted by salt
Patent medicine, single step reaction.Because a step at salting out, avoid repeatedly crystallize or couple other purification process obtain it is high-purity
Product, therefore the production time is substantially reduced, production efficiency is improved, the purifying process of substance is simplified, is suitable for the big rule of industrialization
Mould produces.
Specific implementation mode
To make the technical means, the creative features, the aims and the efficiencies achieved by the present invention be easy to understand, with reference to
Specific embodiment is further analyzed explanation to technical solution of the present invention.
Embodiment 1：
The method of magnetic induced Crystallization Separation hyoscine is as follows in the present embodiment：
1, hyoscine is at salt
It is 83% hyoscine crude product to take 125mg purity, is dissolved with 500 μ l absolute ethyl alcohols, and ultrasound makes Anisodus luridus alkali soluble
Solution, is then added the hydrobromic acid of 150 μ L 40wt%, is placed in magnetic stirring apparatus and stirs 5min, make hyoscine at salt, obtain
Scopolamine hydrobromide salting liquid.
2, magnetic induced crystallization
Scopolamine hydrobromide salting liquid is maintained at 20 DEG C, is subsequently placed in the magnetic field of 400mT and carries out magnetic induced knot
It is brilliant；Water temperature is measured in real time with temperature sensor, is maintained water temperature between 18~22 DEG C, and 15min starts nucleus occur, keeps temperature
Constant with magnetic field intensity, placing 2h makes crystal be precipitated completely.
3, the separation of crystal
Step 2 gained mixed liquor filters, and washing crystal with 0 DEG C of absolute ethyl alcohol of 1ml, to remove plane of crystal three times remaining miscellaneous
Matter is dried in vacuo at 40 DEG C and removes the remaining moisture of plane of crystal and solvent for 24 hours, obtains 108mg scopolamine hydrobromides.
Take a certain amount of crystal methanol：Water (40:60) it tests and analyzes, calculates in injection high performance liquid chromatograph after dissolving
The purity of scopolamine hydrobromide is 99.89%, the rate of recovery 71.96.
Remarks：
The rate of recovery is calculated by following formula：
Liquid-phase condition：Eclipse PlusC18 chromatographic columns (4.6mm × 250mm, 5 μm)；35 DEG C of column temperature；Detection wavelength
215nm；Flow velocity 1ml/min；20 μ L of sample size；
Mobile phase：Methanol-water (sodium acetate containing 0.02mol/L, 0.02% triethylamine), volume ratio=40/60.
Embodiment 2：
The method of magnetic induced Crystallization Separation hyoscine is as follows in the present embodiment：
1, hyoscine is at salt
It is 83% hyoscine crude product to take 46mg purity, is dissolved with 1ml isopropanols, and ultrasound makes hyoscine dissolve, so
The hydrobromic acid of 50 μ L 40wt% is added afterwards, is placed in magnetic stirring apparatus and stirs 5min, make hyoscine at salt, obtain hydrobromic acid
Hyoscine salting liquid.
2, magnetic induced crystallization
Scopolamine hydrobromide salting liquid is maintained at 15 DEG C, is subsequently placed in the magnetic field of 400mT and carries out magnetic induced knot
It is brilliant；Water temperature is measured in real time with temperature sensor, is maintained water temperature between 13-17 DEG C, and 15min starts nucleus occur, keeps temperature
Constant with magnetic field intensity, placing 2h makes crystal be precipitated completely.
3, the separation of crystal
Step 2 gained mixed liquor filters, and washing crystal with 0 DEG C of absolute ethyl alcohol of 1ml, to remove plane of crystal three times remaining miscellaneous
Matter is dried in vacuo at 40 DEG C and removes the remaining moisture of plane of crystal and solvent for 24 hours, obtains 43.3mg scopolamine hydrobromides.
It is tested and analyzed using high performance liquid chromatograph, the purity for calculating scopolamine hydrobromide is 99.42%, the rate of recovery
It is 78.02.
Claims (9)
1. a kind of method of magnetic induced Crystallization Separation hyoscine, it is characterised in that：First to hyoscine extract acid adding
At salt, then it is precipitated scopolamine salt crystallization under induced by magnetic field effect, obtains the scopolamine salt of high-purity.
2. according to the method described in claim 1, it is characterized by comprising following steps：
Step 1：Hyoscine is at salt
Hyoscine extract is dissolved in recrystallisation solvent, acid is then added, is uniformly mixing to obtain the salting liquid of hyoscine；
Step 2：Magnetic induced crystallization
The salting liquid of hyoscine is kept at a certain temperature, being subsequently placed in magnetic field and carrying out magnetic induced crystallization；Pass through tune
Temperature and magnetic field intensity are saved, the growth of crystal is controlled；
Step 3：The separation of crystal
Step 2 gained mixed liquor filter, washing remove plane of crystal impurity, vacuum drying remove the remaining moisture of plane of crystal and
Solvent, you can obtain scopolamine salt.
3. according to the method described in claim 2, it is characterized in that：
In step 1, the content of hyoscine is 80-85% in hyoscine extract.
4. according to the method described in claim 2, it is characterized in that：
In step 1, the one kind of the recrystallisation solvent in methanol, ethyl alcohol, isopropanol, n-butanol, ethyl acetate, acetone, water
Or several mixed solvent.
5. according to the method described in claim 2, it is characterized in that：
In step 1, the acid includes hydrobromic acid or hydrochloric acid etc..
6. according to the method described in claim 2, it is characterized in that：
In step 2, the magnetic field includes transverse magnetic field, axial magnetic field, rotating excitation field and cusp fields etc..
7. according to the method described in claim 2, it is characterized in that：
In step 2, the salting liquid of the hyoscine is supersaturated solution, and controls the concentration of solution in metastable region.
8. according to the method described in claim 2, it is characterized in that：
In step 2, specific temperature is 15-20 DEG C, magnetic field intensity ranging from 380-420mT.
9. according to the method described in claim 2, it is characterized in that：
In step 3, washing solvent for use is ethyl alcohol or acetone.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112694435A (en) * | 2020-04-13 | 2021-04-23 | 中南林业科技大学 | Method for extracting gynura procumbens alkaloid with high antibacterial activity |
| CN116731007A (en) * | 2023-08-16 | 2023-09-12 | 成都第一制药有限公司 | Preparation method of scopolamine hydrobromide |
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2018
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| CN1682723A (en) * | 2005-02-25 | 2005-10-19 | 丁国华 | Scopolamine hydrobromide dry powder inhalant for nose and preparing method |
| CN103172604A (en) * | 2011-12-22 | 2013-06-26 | 北大方正集团有限公司 | Lovastatin purification method combining auxiliary magnetic crystallization |
| WO2013098390A1 (en) * | 2011-12-30 | 2013-07-04 | Ucb Pharma Gmbh | Transdermal therapeutic system with a low tendency to spontaneously crystallize |
| CN107325145A (en) * | 2017-07-24 | 2017-11-07 | 合肥工业大学 | Electromagnetically induced phytosterol crystallization purifications |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112694435A (en) * | 2020-04-13 | 2021-04-23 | 中南林业科技大学 | Method for extracting gynura procumbens alkaloid with high antibacterial activity |
| CN116731007A (en) * | 2023-08-16 | 2023-09-12 | 成都第一制药有限公司 | Preparation method of scopolamine hydrobromide |
| CN116731007B (en) * | 2023-08-16 | 2023-10-24 | 成都第一制药有限公司 | Preparation method of scopolamine hydrobromide |
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Application publication date: 20180803 |