CN1587260A - Process for preparing high purity huperzine A - Google Patents
Process for preparing high purity huperzine A Download PDFInfo
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- CN1587260A CN1587260A CN 200410052688 CN200410052688A CN1587260A CN 1587260 A CN1587260 A CN 1587260A CN 200410052688 CN200410052688 CN 200410052688 CN 200410052688 A CN200410052688 A CN 200410052688A CN 1587260 A CN1587260 A CN 1587260A
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Abstract
The present invention relates to high speed countercurrent chromatographic process of separating high purity huperzine A from huperzine containing plant huperzine serrate. During the preparation, the solvent system comprising upper solid phase and lower flowing phase is prepared with normal alkane, fatty alcohol and water in the volume ratio of 1-5 to 0.1-2 to 1-5. At the temperature of 20-30 deg.c and after the column is filled with fixed phase, the system unit is rotated in 600-1000 rpm and the flowing phase is pumped into the column in the flow rate of 0.5-4 ml/min. After the system is balanced, sample is led in via the sample valve and monitor is used to monitor the target component. The fraction is concentrated, evaporated and crystallized to obtain huperzine A. The present invention is suitable for preparing huperzine A in various types of high speed countercurrent chromatograph, and has great separated amount, high recovery rate and simple operation.
Description
Technical field
The present invention relates to adopt high-speed countercurrent chromatography (HSCCC) from the plants of Huperzia Herba Lycopodii serrati, to prepare the preparation method of the method, particularly a kind of high-purity huperzine A of natural alkaloid.
Background technology
Along with the aging of social population, the senile dementia sickness rate rises relatively, and the dementia morbidity of over-65s is 5%～10% at present, and still among increasing.According to statistics, the world today has more than 5,000 ten thousand the elderlys to suffer from various degree senile dementia.China more than 60 years old population expect 2010 and will account for 15.7% of total population, the dementia problem is the inevitable problem that we faced equally.Therefore the active drug of seeking the treatment senile dementia disease has been subjected to the great attention of various countries, becomes the task of top priority.In the senile dementia 50%～60% be Alzheimer (Alzheimer ' s Disease, AD), it be a kind of be the primary grey matter encephalopathic of principal feature with memory loss and cognition dysfunction.Clinical manifestation is a progressive dementia, and its cause of disease is still indeterminate, and hypothesis has multiple, as neurotransmitter defective, inflammation, radical damage, amyloid, neurotoxicity, hormonoprivia, apoptosis etc.The purpose of treatment AD is to improve cognition dysfunction, improves patient's viability.The seventies, research mainly concentrates on the relation of vagusstoff and AD; Mainly be the influence of research anticholinesterase to AD the eighties; The nineties, research not only has acetyl choline receptor agonists, has also comprised oestrogenic hormon, antiphlogistic drug, has influenced the medicine of Radical Metabolism and the medicine of inhibition amyloid beta deposition.Up to the present, the clinical treatment of AD remains a global problem that remains to be broken through but for various reasons.In recent years, Chinese scholars is being done a large amount of fundamental researchs and clinical application research aspect the natural drug effective constituent treatment senile dementia using, because cholinergic system and people's study, memory function is closely-related in the brain.The early stage brain cholinergic system of discovering patient AD has been subjected to infringement, causes the decline of cynapse position acetyl choline content, thereby patient's study, memory capability exerted an influence.Therefore, at the acetyl choline content that improves in patient's AD brain, promote the medicine of cholinergic nerve function to arise at the historic moment.The research of this class medicine now concentrates on anticholinesterase and muscarine M1 receptor stimulant.Selagine (huperzine A) is a kind of new alkaloid that is separated to from plants of Huperzia Herba Lycopodii serrati Huperzia serrata (Thunb.) Tre v. in recent years for the potent acetylcholinesterase of reversibility (AChE) inhibitor of China's initiative.The clinical study of carrying out at present shows that it is better than tacrine (tacrine) in cholinergic synapses to the restraining effect of AChE.Animal ethology studies show that selagine can improve the learning and memory ability of animal, and therapeutic index is higher than tacrine, Physostigmine and lycoremine.In the double blind trial in clinical 8 weeks by a definite date, oral 0.2mg/d, has 58% patient significantly to improve all tested memories, cognition and capacity parameter P＜0.05 at every day 2 times, and serious reaction do not occur, so selagine is the medicine of a kind of rising treatment AD.To senile dementia, simple dysmnesia and myasthenia gravis treatment have significant curative effect, and duration of efficacy is long, and no serious adverse reaction is the most effective medicine of domestic and international above-mentioned illness, is paid close attention to deeply, domestic approved listing.Be listed in one of inhibitor of s-generation Pseudocholinesterase in the world.
The structural formula of selagine is as follows:
Chemical name be (5R, 9R, 11E)-5-amino-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is (b) pyridine-2 (1H) ketone also
(Hup A) is extremely low at the occurring in nature amount for selagine, and contains a large amount of impurity, has a large amount of researchists exploring so far both at home and abroad and seeks ideal separation way.Once the someone utilized methods such as solvent extraction, silica gel column chromatography to separate, though can obtain few products, eventually because of time-consuming, yield is low and be difficult to large-scale production.And the synthetic product are difficult to obtain the ideal curative effect.The adverse current chromatogram method for separating and preparing can reach the purity height, and yield is high and be better than traditional separation methods such as column chromatography.High-speed countercurrent chromatography (High-SpeedCountercurrent Chromatography, HSCCC) be that a kind of successive that grew up in nearly 30 years need not the efficient of any solid support, liquid liquid distribution chromatography isolation technique fast, its principle is the centrifugal force that utilizes borded pile to produce when planetary motion, immiscible two-phase is constantly mixed, keep a phase (solid phase) wherein simultaneously, utilize constant flow pump to import another phase (moving phase) continuously, the solute that enters borded pile with moving phase distributes between two-phase repeatedly, press the order of partition ratio, quilt is wash-out successively.The elder generation that allocation proportion is big in moving phase is by wash-out, otherwise, solid mutually in big back of allocation proportion by wash-out.The variety of issue that it has avoided solid state adhesion body or carrier to bring---sample is adsorbed easily, loss and sex change, when other liquid chromatography technology amount of being prepared is separated, its allocative efficiency can obviously reduce, solvent-oil ratio is big, HSCCC guarantees higher peak type resolution, fractional dose is big, sample is lossless, the rate of recovery is high, isolating environment relaxes, and saves solvent.High-speed counter-current chromatograph can directly advance a large amount of crude extract samples or synthetic mixture, separating resulting can reach quite high purity, even can directly connect instruments such as mass spectrograph, be widely used in the preparation separation and the purifying of field chemical substances such as biology, medicine, environmental protection.Therefore, HSCCC has easy and simple to handle, and the theoretical rate of recovery is 100%, favorable reproducibility and separation efficiency height, the characteristics that fractional dose is bigger.
Summary of the invention
The technical problem to be solved in the present invention is the defective that overcomes traditional isolation technique, adopts high-speed countercurrent chromatography (HSCCC), and a kind of preparation method of high-purity huperzine A is provided.This method has rate of recovery height,
Big and the advantages of simple operation of fractional dose.
Technical scheme of the present invention comprises the steps:
Adopt the high speed adverse current chromatogram preparation method, it comprises that preparation constitutes the solid phase, the solvent system of moving phase: be filled with the counter current chromatograph pillar with stationary phase earlier, regulate engine speed, moving phase is pumped in the post; After treating that whole system is set up running balance, by the sampling valve sample introduction; According to monitor uv-spectrogram receiving target composition.At first select the two combined of a solvent system, solvent system is made of three components, the A component can be selected from normal paraffins such as normal heptane, normal hexane, Skellysolve A, the B component can be selected from Fatty Alcohol(C12-C14 and C12-C18) and aliphatic ketones such as methyl alcohol, ethanol, propyl carbinol, acetone, the C component is a water, preferentially selects normal hexane-propyl carbinol-aqueous systems.
According to solubility constant, do not destroying under the system equilibrated situation, regulate A, B, C, the volume ratio of three components is followed successively by: 1-5: 0.1-2: 1-5.For example 2: 1: 2; 5: 1: 4; 20: 8: 20 etc.; Being stationary phase mutually on the above-mentioned system, is moving phase down mutually.And obtain the pure product of huperzine through flash liberation, purity is more than 99%.
Experiment condition is fit to temperature 20-30 ℃, and in the said temperature scope, when temperature was higher, appearance time slightly shifted to an earlier date, and separation efficiency changes little, and peak shape is not had much influences.
Engine speed and flow velocity need be controlled within the specific limits, by volume solvent system are placed separating funnel, shake up standing demix.Behind the ready to balance certain hour, upper and lower phase is separated, adopt the TBE-300A high-speed counter-current chromatograph, this type column volume is 300ml, and the sample introduction circle is 20ml, is furnished with AKTA Prime pump, monitor and registering instrument.Before the sample introduction, earlier be filled with whole pillar with stationary phase, the adjustment engine speed is 600-1000rpm, with the flow velocity of 0.5-4mL/min moving phase is pumped in the post.
Since the unstable of selagine, the target component that separates and collect, and the concentrated evaporate to dryness of horse back cut carries out crystallization and obtains monomer.
The inventive method has adopted the high speed adverse current chromatogram isolation technique, be a kind of successive need not any solid support efficiently, liquid liquid distribution chromatography isolation technique fast, it has overcome solid state adhesion body or carrier irreversible adsorption, loss and sex change, make separated object rate of recovery height, theory reaches 100%, and the present invention is actual to be reached more than 95%.Because adopt preferred solvent system, the processing condition of control experiment condition temperature, adjustment engine speed and flow velocity can high efficiencyly be separated, and obtain high-purity huperzine A monomer (reaching more than 99%) again.The inventive method is fit to separate the highly purified selagine monomer of preparation from the different content selagine crude product of various technology approach preparations.The counter current chromatograph that is used in various models separates preparation selagine monomer, can directly advance slightly get sample in a large number product or synthetic mixture, separating resulting can reach quite high purity, guarantee higher peak type resolution, fractional dose is big, the rate of recovery is high, isolating environment relaxes, save solvent, easy and simple to handle.
Embodiment
Embodiment 1
Choose normal hexane-propyl carbinol-aqueous systems separation and purification selagine on half preparation type counter current chromatograph.By 5: 1: 5 volume ratios above-mentioned solvent composition is disposed in the separating funnel earlier, shakes up the back standing demix.Ready to balance after for some time separates upper and lower phase.Adopt half preparation type counter current chromatograph, be furnished with the tetrafluoroethylene post, 20ml sampling valve, column volume are 200ml, AKTAPrime pump, detector and registering instrument.Taking by weighing 200mg selagine study is dissolved in the 20ml stationary phase stand-by.Before the sample introduction, earlier be filled with whole pillar with stationary phase, the adjustment engine speed is 950rpm, with the flow velocity of 3.0ml/min moving phase is pumped in the post; After treating that whole system is set up running balance, by the sampling valve sample introduction; Then according to the detector uv-spectrogram, the receiving target composition.Obtain the selagine fraction, carry out crystallization behind the concentrated evaporate to dryness, its HPLC purity reaches about 99%.
Embodiment 2
Choose normal hexane-methanol-water system separation and purification selagine on half preparation type counter current chromatograph.Experiment condition is fit to 25 ℃ of temperature, by 2: 1: 4 volume ratios above-mentioned solvent composition is disposed in the separating funnel earlier, shakes up the back standing demix.Ready to balance after for some time separates upper and lower phase.Adopt half preparation type counter current chromatograph, be furnished with the tetrafluoroethylene post, 20ml sampling valve, column volume are 200ml, AKTAPrime pump, detector and registering instrument.Taking by weighing 150mg selagine study is dissolved in the 20ml stationary phase stand-by.Before the sample introduction, earlier be filled with whole pillar with stationary phase, the adjustment engine speed is 750rpm, with the flow velocity of 4.0ml/min moving phase is pumped in the post; After treating that whole system is set up running balance, by the sampling valve sample introduction; Then according to the detector uv-spectrogram, the receiving target composition.Obtain the selagine fraction, carry out crystallization behind the concentrated evaporate to dryness, its HPLC purity reaches about 99%.
Embodiment 3
Choose normal hexane-ethanol-water system separation and purification selagine on half preparation type counter current chromatograph.Experiment condition is fit to 30 ℃ of temperature, by 2: 1: 4 volume ratios above-mentioned solvent composition is disposed in the separating funnel earlier, shakes up the back standing demix.Ready to balance after for some time separates upper and lower phase.Adopt half preparation type counter current chromatograph, be furnished with the tetrafluoroethylene post, 20ml sampling valve, column volume are 200ml, AKTA Prime pump, detector and registering instrument.Taking by weighing 150mg selagine study is dissolved in the 20ml stationary phase stand-by.Before the sample introduction, earlier be filled with whole pillar with stationary phase, the adjustment engine speed is 750rpm, with the flow velocity of 4.0ml/min moving phase is pumped in the post; After treating that whole system is set up running balance, by the sampling valve sample introduction; Then according to the detector uv-spectrogram, the receiving target composition.Obtain the selagine fraction, carry out crystallization behind the concentrated evaporate to dryness, its HPLC purity reaches about 99%.
Embodiment 4
Choose normal heptane-acetone-water system separation and purification selagine on half preparation type counter current chromatograph.Experiment condition is fit to 22 ℃ of temperature, by 4: 1: 3 volume ratios above-mentioned solvent composition is disposed in the separating funnel earlier, shakes up the back standing demix.Ready to balance after for some time separates upper and lower phase.Adopt half preparation type counter current chromatograph, be furnished with the tetrafluoroethylene post, 20ml sampling valve, column volume are 200ml, AKTA Prime pump, detector and registering instrument.Taking by weighing 150mg selagine study is dissolved in the 20ml stationary phase stand-by.Before the sample introduction, earlier be filled with whole pillar with stationary phase, the adjustment engine speed is 650rpm, with the flow velocity of 3.0ml/min moving phase is pumped in the post; After treating that whole system is set up running balance, by the sampling valve sample introduction; Then according to the detector uv-spectrogram, the receiving target composition.Obtain the selagine fraction, carry out crystallization behind the concentrated evaporate to dryness, its HPLC purity reaches about 99%.
Embodiment 5
Choose Skellysolve A-methanol-water system separation and purification selagine on half preparation type counter current chromatograph.Experiment condition is fit to 20 ℃ of temperature, by 2: 1: 1 volume ratios above-mentioned solvent composition is disposed in the separating funnel earlier, shakes up the back standing demix.Ready to balance after for some time separates upper and lower phase.Adopt half preparation type counter current chromatograph, be furnished with the tetrafluoroethylene post, 20ml sampling valve, column volume are 200ml, AKTAPrime pump, detector and registering instrument.Taking by weighing 180mg selagine study is dissolved in the 20ml stationary phase stand-by.Before the sample introduction, earlier be filled with whole pillar with stationary phase, the adjustment engine speed is 1000rpm, with the flow velocity of 3.0ml/min moving phase is pumped in the post; After treating that whole system is set up running balance, by the sampling valve sample introduction; Then according to the detector uv-spectrogram, the receiving target composition.Obtain the selagine fraction, carry out crystallization behind the concentrated evaporate to dryness, its HPLC purity reaches about 99%.
Claims (9)
1. the preparation method of a high-purity huperzine A, it comprises that preparation constitutes the solid phase, the solvent system of moving phase: be filled with the counter current chromatograph pillar with stationary phase earlier, regulate engine speed, moving phase is pumped in the post; After treating that whole system is set up running balance, by the sampling valve sample introduction; According to uv-spectrogram monitor receiving target composition, it is characterized in that: described solvent system is made up of normal paraffin and Fatty Alcohol(C12-C14 and C12-C18) or aliphatic ketone and water, and the volume ratio of three components is followed successively by 1-5: 0.1-2: 1-5, on be the solid phase mutually, is moving phase mutually down.
2. the preparation method of a kind of high-purity huperzine A according to claim 1, it is characterized in that: described normal paraffin is normal heptane, normal hexane or Skellysolve A, and described Fatty Alcohol(C12-C14 and C12-C18) is methyl alcohol, ethanol or propyl carbinol, and described aliphatic ketone is an acetone.
3. the preparation method of a high-purity huperzine A, it comprises that preparation constitutes the solid phase, the solvent system of moving phase: be filled with the counter current chromatograph pillar with stationary phase earlier, regulate engine speed, moving phase is pumped in the post; After treating that whole system is set up running balance, by the sampling valve sample introduction; According to monitor receiving target composition, it is characterized in that: the experiment condition temperature is 20-30 ℃.
4. the preparation method of a kind of high-purity huperzine A according to claim 3, it is characterized in that: described engine speed is just transferring 600-1000rpm to, and the flow velocity that described moving phase pumps in the post is 0.5-4mL/min.
5. according to the preparation method of claim 2 or 3 or 4 described a kind of high-purity huperzine As, it is characterized in that: described normal paraffin is a normal hexane, described Fatty Alcohol(C12-C14 and C12-C18) is a propyl carbinol, in normal hexane-n-butanol-water system, the volume ratio of three components is followed successively by: described volume ratio 5: 1: 5, engine speed is just changeing 950rpm, and the flow velocity that moving phase pumps in the post is 3ml/min.
6. according to the preparation method of claim 1 or 4 described a kind of high-purity huperzine As, it is characterized in that: described solvent system is normal heptane-acetone-water, the consumption volume ratio was followed successively by 4: 1: 3, described engine speed is just changeing 650rpm, and the flow velocity that described moving phase pumps in the post is 3ml/min.
7. according to the preparation method of claim 2 or 4 described a kind of high-purity huperzine As, it is characterized in that: described normal paraffin is a Skellysolve A, and described Fatty Alcohol(C12-C14 and C12-C18) is a methyl alcohol, and in Skellysolve A-methanol-water system, the consumption volume ratio was followed successively by 2: 1: 1.
8. according to the preparation method of claim 2 or 3 described a kind of high-purity huperzine As, it is characterized in that: described normal paraffin is normal hexane-alcohol-water, described Fatty Alcohol(C12-C14 and C12-C18) is an ethanol, in normal hexane-ethanol-water system, the consumption volume ratio was followed successively by 2: 1: 4, described engine speed is just changeing 750rpm, and the flow velocity that described moving phase pumps in the post is 4ml/min.
9. according to the preparation method of the described a kind of high-purity huperzine A of arbitrary claim in the claim 1 to 4, it is characterized in that: described normal paraffin is a normal hexane, described Fatty Alcohol(C12-C14 and C12-C18) is a methyl alcohol, in normal hexane-methanol-water system, the consumption volume ratio was followed successively by 2: 1: 4, and described experiment condition temperature is 25 ℃.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104016918A (en) * | 2012-03-22 | 2014-09-03 | 中国科学院上海药物研究所 | Huperzine A polymorphism body, preparation method thereof, pharmaceutical composition comprising polymorphism body and application thereof |
| CN105085523A (en) * | 2015-09-02 | 2015-11-25 | 中南大学 | Method for separating and preparing high-purity huperzine C through HSCCC (high-speed countercurrent chromatography) |
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2004
- 2004-07-09 CN CN 200410052688 patent/CN1264822C/en active Active
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104016918A (en) * | 2012-03-22 | 2014-09-03 | 中国科学院上海药物研究所 | Huperzine A polymorphism body, preparation method thereof, pharmaceutical composition comprising polymorphism body and application thereof |
| CN104016918B (en) * | 2012-03-22 | 2016-04-13 | 中国科学院上海药物研究所 | Huperzine A polymorph, its preparation method, comprise the medical composition and its use of described polymorphs body |
| CN105085523A (en) * | 2015-09-02 | 2015-11-25 | 中南大学 | Method for separating and preparing high-purity huperzine C through HSCCC (high-speed countercurrent chromatography) |
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| CN1264822C (en) | 2006-07-19 |
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