CN102060958A - Method for preparing fudosteine molecularly imprinted polymer - Google Patents
Method for preparing fudosteine molecularly imprinted polymer Download PDFInfo
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- CN102060958A CN102060958A CN 201010540492 CN201010540492A CN102060958A CN 102060958 A CN102060958 A CN 102060958A CN 201010540492 CN201010540492 CN 201010540492 CN 201010540492 A CN201010540492 A CN 201010540492A CN 102060958 A CN102060958 A CN 102060958A
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Abstract
The invention provides a method for preparing fudosteine molecularly imprinted polymer and belongs to the technical field of chemical engineering. The method comprises: dissolving fudosteine serving as template molecules, methacrylic acid serving as functional monomer and an ethylene glycol dimethacrylate serving as a cross-linking agent according to a molar ratio of 1:3-4:10, wherein a pore forming agent is mixed liquid of methanol and methylbenzene in a ratio of 1:1-3; adding azodiisobutyronitrile (AIBN) serving as an initiator; performing polymerization at 50 to 60 DEG C for 10 to 20 hours; milling the product, extracting with methanol-acetic acid solution for several times to remove template molecules, and drying at 60 DEG C and under vacuum to obtain fudosteine molecularly imprinted polymer. The fudosteine polymer prepared by the method can be used for detecting fudosteine residue in the environment or medicaments and the enrichment of trace amount of fudosteine, has the advantages of high speed, high flexibility, high accuracy, high yield, high repeatability and high sensitivity, and has a high application value and a bright market prospect.
Description
Technical field
The present invention relates to a kind of preparation method of Fudosteine molecularly imprinted polymer, belong to field of new.
Background technology
Fudosteine is a kind of novel cysteine derivative.Develop jointly by Japanese SS drugmaker and Welfide.2000, a kind of oral preparation composition that contains Fudosteine obtained patent of invention in Japan.Calendar year 2001, as a kind of new drug that is mainly used in treatment bronchitis and respiratory tract hyperemia, Fudosteine is sold in Japanese Initial Public Offering.At present, Fudosteine is got permission to recommend to use in Australia.2003, a kind of new oral preparation composition that contains Fudosteine obtained patent of invention in China.But because Fudosteine is difficult for degraded in vivo, the metabolism time is longer, and is residual if the improper use meeting causes, thereby people, animal, environment are caused damage or pollution.In the safety evaluation research in 52 weeks, the investigator has observed the long term toxicity of Fudosteine.Experimental result shows, continue to give toxicity dose (100,300,900mgkg-1), 300, water uptake appears in the male laboratory animal of 900mgkg-1 dosage group to be increased, kidney weight appears in 900mgk-1 dosage group laboratory animal to be increased, hydrouria, in the urine Na+ concentration rising etc. unusual, above untoward reaction all can be alleviated in 4 decubations in week or be recovered.In the safety evaluation research in 26 weeks, the investigator has observed the long term toxicity of Fudosteine.Experimental result shows that (100,250,625mgkg-1), it is unusual that part clinical examination value appears in 625mgkg-1 dosage group laboratory animal, and these untoward reactions all can be alleviated or be recovered to continue to give toxicity dose in 4 decubations in week.
At present, the molecular imprinting that detects in the residual method of Fudosteine is a kind of based on chemical polymerization thing technology of preparing on the molecular recognition basis, because of its inside has and molecules of interest complementary space structure and group, and has " memory " function, so can be special have an effect with template molecule, and can be, thereby reach the effect of purifying and enrichment molecules of interest by corresponding mode wash-out.Because molecularly imprinted polymer is to adopt the chemical process synthetic, have the advantage of severe environment such as opposing soda acid, reusable, so use more and more widely.
Summary of the invention
In order to overcome deficiency of the prior art, the preparation method that a kind of Fudosteine molecularly imprinted polymer is provided of the present invention, thereby this polymkeric substance can optionally be realized concentrating Fudosteine in conjunction with Fudosteine, purify, remove impurity effect in the medicine simultaneously, improve the sensitivity of existing detection method.The imprinted polymer of this molecule can be used for the stationary phase of Solid-Phase Extraction, is directly used in separation and enrichment to Fudosteine, also can be developed to the stratographic filler simultaneously, is used for the detection of trace Fudosteine.
The present invention is achieved through the following technical solutions, and the steps include:
(1) be Fudosteine with template molecule, function monomer methacrylic acid (MAA) and linking agent ethylene glycol dimethacrylate (EGDMA), press template molecule: function monomer: linking agent mol ratio=1: 2～8: 20, mixed dissolution is in pore-creating agent, the composition of pore-creating agent is the mixing solutions of methyl alcohol and toluene, and ratio is 1: 1.4.When template molecule is 0.5mol, the time, the volume of pore-creating agent is 2.5～5mL, adds initiator Diisopropyl azodicarboxylate (AIBN);
(2) feed nitrogen 5～10min, under nitrogen protection reaction flask is sealed, 50～60 ℃ of water bath heat preservation reaction 24～48h grind the synthetic polymkeric substance, remove trickle particle;
(3) further remove template molecule by soxhlet extraction 12～24h, extraction agent consist of methyl alcohol, the acetic acid mixed solution, ratio is 9: 1～7: 3, continues then with pure methanol extraction removal molecular acid;
(4) after extraction finishes, 60 ℃ of vacuum-dryings of removing the polymkeric substance of template molecule are spent the night to weight, obtain the molecularly imprinted polymer of Fudosteine.
The imprinted polymer surface tool vesicular structure of described preparation, mean pore size is 4.5nm.
The optimum process condition that wherein prepares the Fudosteine imprinted polymer is: be Fudosteine with template molecule in above-mentioned steps (1) and step (2), function monomer methacrylic acid (MAA) and linking agent ethylene glycol dimethacrylate (EGDMA), press template molecule: function monomer: linking agent mol ratio=1: 2～8: 20, mixed dissolution is to the mixing solutions 2.5～5mL of methyl alcohol and toluene, add initiator Diisopropyl azodicarboxylate (AIBN), the sealing back is in 55 ℃ of following polyreaction 14h.Described soxhlet extraction condition is methyl alcohol, acetic acid mixing solutions.Ratio be 9: 1～7: 3 the extraction more than three times, each 8～12 h use pure methanol extraction 1～2 time at last, remove remaining acetic acid.
Advantage of the present invention is: the molecularly imprinted polymer surface of preparation has porous surface structure, and Fudosteine is had specific adsorption.The maximal absorptive capacity that records this polymkeric substance by experiment is that every gram polymkeric substance adsorbs 20.19 milligrams of Fudosteine in theory.The Fudosteine molecularly imprinted polymer of preparation can be used as the filler of Solid-Phase Extraction, effective decontamination substrate, the efficiently concentrating Fudosteine, in conjunction with existing detection method (as HPLC etc.), significantly improve residual detection sensitivity of Fudosteine and detection efficiency, it has bigger application value.
Description of drawings
The invention will be further described below in conjunction with drawings and Examples.
Fig. 1 is the Fudosteine molecularly imprinted polymer sem photograph that embodiment 1 makes.
Fig. 2 is the Fudosteine molecularly imprinted polymer transmission electron microscope picture that embodiment 1 makes.
Embodiment
Below embodiments of the invention are elaborated: present embodiment is being to implement under the prerequisite with the technical solution of the present invention, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
Embodiment 1
With Fudosteine 0.5mmol, MAA1mmol, EGDMA10mmol mixes, and pours methyl alcohol into, and among the toluene mixture liquid 2.5ml, the two ratio is 1: 1.4, and room temperature adds initiator A IBN20mg after static half an hour.
Above mixed solution is inserted in the reaction flask ultrasonic degas 10min.With the system after the degassing, logical nitrogen deoxygenation 5min.Under nitrogen protection, seal rapidly.55 ℃ of water bath heat preservation reaction 14h.Obtain reaction product.
After reaction finishes, the molecularly imprinted polymer for preparing is ground, by the sample sifter sub-sieve.After acetone sedimentation three times, the polymkeric substance that drying obtains, the particle diameter of polymkeric substance is between 30-60um.By soxhlet extraction 12h, remove template molecule.The reagent of extraction is 180mL methyl alcohol, wherein contains acetic acid 10%.With the residual acetic acid of methanol-eluted fractions.60 ℃ of vacuum-dryings of molecularly imprinted polymer of removing template molecule are spent the night, obtain the Fudosteine molecularly imprinted polymer.Gained Fudosteine molecularly imprinted polymer sem photograph is seen Fig. 1.Polymer surfaces is vesicular structure, and the aperture is analyzed the pore size distribution that records polymkeric substance and relatively concentrated on the 4.5nm place.The used condition of present embodiment is the top condition of preparation Fudosteine molecularly imprinted polymer.
Embodiment 2
With Fudosteine 0.5mmol, MAA2mmol, EGDMA10mmol mixes, and pours pore-creating agent methyl alcohol into, and among the toluene mixture liquid 2.5mL, the two ratio is 1: 1.4, behind the static 1h of room temperature, adds initiator A IBN20mg.Above mixed solution is inserted in the reaction flask ultrasonic degas 5min.With the system after the degassing, logical nitrogen deoxygenation 5min.Under nitrogen protection, seal rapidly.60 ℃ of water bath heat preservation reaction 24h.
After reaction finishes, the molecularly imprinted polymer for preparing is ground, with standard sieve sub-sieve sample.Polymkeric substance is by after the acetone sedimentation 3 times, the polymkeric substance that drying obtains.20h removes template molecule by Soxhlet extracting extraction.The reagent of extraction is 180mL methyl alcohol, wherein contains acetic acid 20%.Methanol-eluted fractions 1-2 time of residual acetic acid.To remove 60 ℃ of vacuum-dryings of molecularly imprinted polymer of template molecule at last and spend the night, obtain the Fudosteine molecularly imprinted polymer.The surface of resulting polymkeric substance presents vesicular structure, and its pore size distribution is more concentrated, and gained Fudosteine molecularly imprinted polymer transmission electron microscope picture is seen Fig. 2.
Embodiment 3
With Fudosteine 0.5mmol, MAA 4mol, EGDMA 10mmol mixes, and pours among methyl alcohol, the toluene mixture liquid 2.5mL, and the ratio of the two is 1: 1.4, behind the static 1h of room temperature, adds initiator A IBN 20mg.Above mixed solution is inserted in the reaction flask ultrasonic degas 10min.With the system after the degassing, logical nitrogen deoxygenation 10min.Under protection of nitrogen gas, seal rapidly.55 ℃ of waters insulation reaction 20h.
After reaction finishes, the molecularly imprinted polymer for preparing is ground, by the sample sifter sub-sieve.After acetone sedimentation 3 times, the polymkeric substance that drying obtains.Method extraction 36h by cable-styled extraction removes template molecule.The reagent of extraction is 180ml methyl alcohol, wherein contains acetic acid 30%.To remove 60 ℃ of dried overnight of molecularly imprinted polymer of template molecule at last, obtain the Fudosteine molecularly imprinted polymer.The electron microscopic observation result proves that this polymkeric substance is a kind of material with vesicular structure.
Embodiment 4
With Fudosteine 0.5mmol, MAA 2mol, EGDMA 10mmol mixes, and pours methyl alcohol into, and among the toluene mixture liquid 2.5ml, the ratio of the two is 2: 3, behind the static 1h of room temperature, adds initiator A IBN20mg.
Above mixed solution is inserted in the reaction flask ultrasonic vibration degassing 10min.With the system after the degassing, logical nitrogen deoxygenation 10min.Under protection of nitrogen gas, seal rapidly.60 ℃ of waters insulation reaction 24h.
After reaction finishes, the molecularly imprinted polymer for preparing is ground, by the sample sifter sub-sieve.Behind acetone precipitation 3 times, the polymkeric substance that drying obtains.Remove template molecule by the method for cable-styled extraction at last.The reagent of extraction is the methyl alcohol of 180mL, wherein contains acetic acid 30%, and the time of extraction is 20h.To remove 60 ℃ of vacuum-dryings of molecularly imprinted polymer of template molecule at last and spend the night, obtain the Fudosteine molecularly imprinted polymer.
Embodiment 5
With Fudosteine 0.5mmol, MAA 2mol, EGDMA 10mmol mixes, and pours methyl alcohol into, and among the toluene mixture liquid 5mL, the ratio of the two is 1: 1.4, behind the static 1h of room temperature, adds initiator A IBN 20mg.
Above mixed solution is inserted in the reaction flask ultrasonic vibration degassing 10min.With the system after the degassing, logical nitrogen deoxygenation 10min.Under protection of nitrogen gas, seal rapidly.55 ℃ of insulation reaction 12h.
After reaction finishes, the molecularly imprinted polymer for preparing is ground, by the sample sifter sub-sieve.Behind acetone precipitation 3 times, the polymkeric substance that drying obtains.Remove template molecule by the method for cable-styled extraction at last.The reagent of extraction is the methyl alcohol of 180mL, wherein contains acetic acid 10%, and the extraction time is 15h.Use the residual acetic acid of methanol-eluted fractions at last.The 60 ℃ of vacuum-dryings of molecularly imprinted polymer that obtain are spent the night.The porous surface of resulting polymkeric substance, and aperture homogeneous have practical significance.
Claims (6)
1. the preparation method of a Fudosteine molecularly imprinted polymer is characterized in that comprising the steps:
(1) be Fudosteine with template molecule, function monomer methacrylic acid and linking agent ethylene glycol dimethacrylate, press template molecule: function monomer: linking agent mol ratio=1: 3-4: 10, mixed dissolution adds initiator A IBN (Diisopropyl azodicarboxylate) in pore-creating agent;
(2) under nitrogen protection reaction flask is sealed, 50-60 ℃ of water bath heat preservation reaction 10-20h obtains reaction product;
(3) the synthetic polymkeric substance is ground after, by soxhlet extraction, further remove template molecule, continue then with pure methanol extraction removal molecular acid;
(4) after extraction finishes, place 60 ℃ of vacuum-dryings to weight in polymkeric substance, obtain the molecularly imprinted polymer of Fudosteine at last.
2. the preparation method of Fudosteine molecularly imprinted polymer according to claim 1 is characterized in that, when template molecule was 0.5mol, the volume of pore-creating agent was 2.5-5ml.
3. according to the preparation method of claim 1 or 2 described Fudosteine molecularly imprinted polymers, it is characterized in that the composition of described pore-creating agent is the mixing solutions of methyl alcohol and toluene, ratio is 1: 1.4.
4. the preparation method of Fudosteine molecularly imprinted polymer according to claim 1 is characterized in that, described soxhlet extraction, and its condition is: extraction is more than three times, and each 8-12h uses pure methanol extraction 1-2 time at last, removes remaining acetic acid.
5. the preparation method of Fudosteine molecularly imprinted polymer according to claim 1 is characterized in that, described soxhlet extraction extraction agent consist of methyl alcohol, the acetic acid mixed solution, the two ratio is 10: 1 to 6: 3.
6. the preparation method of Fudosteine molecularly imprinted polymer according to claim 1 is characterized in that, the imprinted polymer of described preparation, and surperficial tool vesicular structure, mean pore size is about 4.5nm.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102432753A (en) * | 2011-09-02 | 2012-05-02 | 陕西科技大学 | Preparation method of epothilone B molecularly imprinted polymer |
| CN102585281A (en) * | 2011-12-31 | 2012-07-18 | 浙江工业大学 | Fluorescent ion imprinted sensor and application thereof in methyl mercury ion detection |
| CN109096434A (en) * | 2018-08-07 | 2018-12-28 | 昆明理工大学 | A kind of triazole type molecular blotting polymer microsphere and its preparation method and application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1840524A (en) * | 2005-03-31 | 2006-10-04 | 北京德众万全医药科技有限公司 | Process for preparing fudosteine |
| WO2007040188A1 (en) * | 2005-10-03 | 2007-04-12 | Sankyo Company, Limited | Medicinal composition for inhibiting the excessive formation of goblet cells |
| JP2007197423A (en) * | 2005-12-27 | 2007-08-09 | Daiichi Sankyo Healthcare Co Ltd | Pharmaceutical composition containing fudosteine and anticholinergic agent |
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2010
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1840524A (en) * | 2005-03-31 | 2006-10-04 | 北京德众万全医药科技有限公司 | Process for preparing fudosteine |
| WO2007040188A1 (en) * | 2005-10-03 | 2007-04-12 | Sankyo Company, Limited | Medicinal composition for inhibiting the excessive formation of goblet cells |
| JP2007197423A (en) * | 2005-12-27 | 2007-08-09 | Daiichi Sankyo Healthcare Co Ltd | Pharmaceutical composition containing fudosteine and anticholinergic agent |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102432753A (en) * | 2011-09-02 | 2012-05-02 | 陕西科技大学 | Preparation method of epothilone B molecularly imprinted polymer |
| CN102585281A (en) * | 2011-12-31 | 2012-07-18 | 浙江工业大学 | Fluorescent ion imprinted sensor and application thereof in methyl mercury ion detection |
| CN102585281B (en) * | 2011-12-31 | 2013-11-06 | 浙江工业大学 | Fluorescent ion imprinted sensor and application thereof in methyl mercury ion detection |
| CN109096434A (en) * | 2018-08-07 | 2018-12-28 | 昆明理工大学 | A kind of triazole type molecular blotting polymer microsphere and its preparation method and application |
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