CN103881016B - A kind of porous resin as synthesis in solid state carrier - Google Patents
A kind of porous resin as synthesis in solid state carrier Download PDFInfo
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Abstract
It is crosslinked polypropylene nitrile or cross-linked poly methyl acrylonitrile, the porous resin particle that function base is hydroxyl or amino and preparation method thereof the invention provides a kind of skeleton.This resinoid is that suspension free-radical combined polymerization is carried out in the presence of pore-foaming agent by acrylonitrile or methacrylonitrile, the crosslinking agent containing 2 or the double bond of more than 2, the function monomer containing alkenyl, obtain porous polymeric resins, resulting porous polymeric resins react by functionalizing again, obtain the porous resin containing functional base hydroxyl or amino.The resin may be used as the carrier of the synthesis in solid state of polypeptide or the synthesis in solid state of nucleotides.
Description
【Technical field】
The present invention relates to a kind of porous poly- crosslink propylene nitrile resin containing hydroxyl or amino, this resinoid be used for polypeptide or
The carrier of the synthesis in solid state of nucleic acid.
【Technical background】
Since Merrifield has invented solid-phase peptide synthesis (R.B.Merrifield,
J.Am.Chem.Soc., 1963,85,2149), solid phase synthesis process has obtained extensively should in terms of Peptide systhesis and nucleic acid synthesis
With.The advantage of solid phase synthesis process includes：Make reaction complete with excessive reaction reagent；The product often walked, which is all fixed on, not to be dissolved in
On the solid phase carrier of any solvent, therefore the separation of the small organic agents such as required product and other excess reagents, catalyst can lead to
Cross simple filtering and realize；In all operations step before cracking, solid phase carrier is in same container all the time, is not appointed
What mechanical loss；Easily realize automation.
The performance of solid phase carrier in solid phase synthesis process is successfully to realize one of key factor of synthesis in solid state.It is solid at present
Most widely used carrier is low cross linked polystyrene gel resin in phase Peptide systhesis, and its advantage is that low cross linked polystyrene coagulates
Gum resin has very high swellbility in the solvent such as dichloro hexane, dimethylformamide that Solid phase peptide synthssis is commonly used, and reacts
Reagent is easily diffused into reaction site, makes the complete of reaction progress.After it has the disadvantage that low cross linked polystyrene gel resin is swelled
Bad mechanical strength, it is broken after very multistep reaction, washing；Substantial amounts of organic solvent is used in reaction and washing process,
The efficiency of reactor is not only reduced, also increase synthesizes cost and causes environmental pollution；It is not suitable for continuous column type reactor solid phase to close
Into carrier.Also useful porous resin is as the report of Solid phase peptide synthssis carrier, and porous resin is typically all with higher friendship
Connection degree, its advantage is the high mechanical strength of porous resin, and swellbility in a solvent is small, using molten in reaction and washing process
Dosage is small, it is adaptable to which post method is synthesized.But it is reported in the literature using polystyrene or poly- (methyl) acrylate as skeleton macropore
The purity for the polypeptide that resin is synthesized as the carrier of Peptide systhesis is often relatively low.The carrier for nucleic acid synthesis in solid state is many earliest
Hole glass carrier, porous glass matrix has the easy functionalizing in surface, in a solvent non-swelling advantage.But porous glass matrix
Have the shortcomings that load capacity is relatively low.Develop high crosslinking, expanded polystyrene or poly- (methyl) acrylic resin later to make
The carrier synthesized for nucleic acid, its advantage is that load capacity is high, but the purity of the nucleic acid of synthesis is relatively low.
With the huge progress that polypeptide and nucleic acid drug are studied in recent years, increasing polypeptide and nucleic acid drug, which are realized, to be faced
Bed application.And can synthesis polypeptide and nucleic acid are the necessary bars that polypeptide and nucleic acid drug realize clinical practice on a large scale, at low cost
One of part, therefore exploitation combined coefficient is high, cost is low polypeptide and the carrier of nucleic acid synthesis in solid state have great importance.
【The content of the invention】
The purpose of the present invention is as polypeptide and nucleic acid for expanded polystyrene or poly- (methyl) acrylic resin
Synthesis in solid state carrier present in shortcoming, invented a class using crosslinked polypropylene nitrile or cross-linked poly methyl acrylonitrile be basic
Skeleton, contain the macroreticular resin of hydroxyl or amino as polypeptide and the carrier of the synthesis in solid state of nucleic acid, the resinoid is used for polypeptide
With the carrier of the synthesis in solid state of nucleic acid, synthesized polypeptide and the purity of nucleic acid are high, and the synthesis cost of resin is low.The resinoid
The polymer backbone of nitrile group-containing and the chemical structural formula of function base are as follows：
(R=H or CH3, R '=H, G=OH)
Or (R=H or CH3, R '=H or CH3, G=CONH (CH2)nNH2, wherein n=2~18)
To achieve these goals, the technical solution adopted by the present invention is：Acrylonitrile or methacrylonitrile, contain 2 or 2
Crosslinking agent, the function monomer containing alkenyl of double bond more than individual carry out suspension free-radical combined polymerization in the presence of pore-foaming agent, obtain
To porous polymeric resins, resulting porous polymeric resins react by functionalizing, obtain containing functional base hydroxyl again
Or the porous resin of amino.
The above-mentioned crosslinking agent containing 2 or the double bond of more than 2 includes but is not limited to divinylbenzene, dimethacrylate
Glycol ester, itaconic acid allyl ester, cyanuric acid triallyl ester, cyamelide triallyl ester etc., make in combined polymerization
With the crosslinking agent of one or more double bonds for containing 2 or more than 2.The described function monomer containing alkenyl includes：In order in tree
It is vinyl acetate that the function monomer used in hydroxyl is introduced in fat, is third to introduce the function monomer used in amino in resin
Olefin(e) acid ester or methacrylate.Because last functionalizing makes ester group occur the part of alcohol in aminolysis, ester group finally because of amine
Solve and depart from resin, so the structure of alcohol has no particular limits in acrylate used or methacrylate, preferably third
E pioic acid methyl ester, ethyl acrylate, methyl methacrylate and EMA.Described pore-foaming agent is anti-to be not involved in polymerization
Should, water-soluble less organic solvent, include but is not limited to：Aromatic hydrocarbon such as benzene, toluene, ethylbenzene etc.；Aliphatic hydrocarbon is as contained 6 to 12
The straight or branched alkane (such as hexane, heptane, octane, dodecane) of individual carbon；Halogenated hydrocarbons such as chloroform, dichloroethanes, four chloroethenes
Alkane, chlorobenzene etc.；Containing esters more than 4 carbon such as ethyl acetate, butyl acetate etc.；Alcohol such as the straight or branched fat containing 4 to 12 carbon
Fat alcohol (such as butanol, hexanol, octanol, 2-Ethylhexyl Alcohol, cyclohexanol).Pore-foaming agent can be above-mentioned organic solvent one kind or
It is several.
Specific implementation method is, by acrylonitrile or methacrylonitrile, function monomer, crosslinking agent, pore-foaming agent and initiator group
Into oil phase in certain stirring low suspension in the aqueous phase containing certain density salt and dispersion stabilizer, in certain temperature
The lower polymerization regular hour, one is obtained after can obtain porous resin, screening after the pore-foaming agent in resulting resin is removed
Surely there is the resin of certain particle size range.Resulting porous resin reacts by functionalizing again, obtains containing hydroxyl or ammonia
The porous resin of base.Polymerization temperature is 50~95 DEG C, and polymerization time is 1~24 hour.
In above-mentioned suspension polymerisation, (polymerisable monomer includes propylene in polymerisable monomer for acrylonitrile or methacrylonitrile
Nitrile or methacrylonitrile, function monomer and crosslinking agent) in content be 50~95%, function monomer containing in polymerisable monomer
Measure as 0.5%~30%, content of the crosslinking agent in polymerisable monomer is 5~50%, the ratio of pore-foaming agent and polymerisable monomer
For 0.3/1~2/1.Above-mentioned content or ratio are all by weight.
Above-mentioned suspension polymerisation can use any oil-soluble radical initiator, the example bag of the polymerization initiator
Include peroxide, such as benzoyl peroxide, lauroyl peroxide, stearoyl, two tertiary hexyl peroxide, two tertiary fourths
Base peroxide etc., or azo-compound, such as azodiisobutyronitrile, AMBN, ABVN.Consumption
For the 0.2~2% of polymerisable monomer amount.
In the present invention, dispersion stabilizer is not particularly limited, and can use arbitrary dispersion stabilizer, as long as it is outstanding
There is stably dispersing in floating polymerization.The example of dispersion stabilizer includes hydrophily protecting colloid agent, such as polyethylene
Alcohol, polyacrylic acid, gelatin, starch and carboxy methyl cellulose.Consumption of the dispersion stabilizer in aqueous phase is 0.1~2%.Aqueous phase
The effect of middle salt is to reduce solubility of each component in aqueous phase in oil phase, can be described with conventional any water miscible salt
The example of salt include sodium chloride, potassium chloride, ammonium chloride, calcium chloride, sodium sulphate, potassium sulfate, ammonium sulfate etc., salt is in aqueous phase
Consumption is 0~30%.
Gained resin is washed with water after the completion of polymerization, will be caused after resin is dried by the method for eluting or extracting in resin
Hole agent is removed, and can use any low boiling point organic solvent as elution or extractant, elution or extractant includes methanol, second
Alcohol, acetone, tetrahydrofuran, acetonitrile etc..
In order to introduce hydroxyl or amino, it is anti-that the resin obtained above comprising function monomer carries out further function keyization
Should.Resin containing polyvinyl acetate makes its ester group occur the aminolysis of ester and resin is introduced hydroxyl work(with primary amine or secondary amine reaction
Energy base, reaction equation is as follows.Used amine has no particular limits, as long as used amine can make poly- second contained in resin
The ester bond aminolysis of vinyl acetate, preferably primary amine, such as ethylenediamine, propylamine, butylamine.
Resin containing polyacrylate or methyl polyacrylate reacts with the excessive compound containing 2 primary amine groups, obtains
To the resin containing amino, reaction equation is as follows.Compound containing 2 primary amine groups be two ends be respectively provided with amino containing 2~18 carbon
Saturated hydrocarbon chains diamines, preferably ethylenediamine, butanediamine, hexamethylene diamine, octamethylenediamine, decamethylene diamine, dodecamethylene diamine, hexadecane two
Amine and octadecamethylene diamine.
R=H or CH3, R '=CH3Or C2H5, n=2~18
【Embodiment】
Below by embodiment, the invention will be further described, it will be appreciated that present disclosure is not limited to reality
Apply the scope of example.
Embodiment 1
1.5g polyvinyl alcohol is dissolved in 300mL distilled water and (can suitably heated to accelerate dissolving), then by 15g sodium chloride
It is dissolved in wherein, obtained aqueous phase is added in the 500mL there-necked flasks equipped with reflux condensing tube, mechanical agitator and thermometer.
Prepare in addition different comprising 10.75g acrylonitrile, 2.5g vinyl acetates, 3.75g divinylbenzenes (content is 79.6%), 3g trimerizations
Cyanic acid triallyl ester, 30g toluene and 0.15g azodiisobutyronitriles have oil phase, oil phase are added in above-mentioned there-necked flask,
Stirring is started, the size for the oil droplet that oil phase is formed in aqueous phase is adjusted by adjusting mixing speed, 60 DEG C are to slowly warm up to instead
Answer 1 hour, then raise temperature and react 6 hours to 70 DEG C, 80 DEG C are finally warming up to again and is reacted 2 hours.After reaction terminates, with big
The hot wash resin of amount, is placed in apparatus,Soxhlet's after drying naturally, with ethanol extract 12 hours, obtain crosslink propylene nitrile-
Vinyl acetate copolymer resin.Sieve the resin of 100~200 mesh.
The above-mentioned crosslink propylene nitrile-vinyl acetate copolymer resins of 5g are suspended in 30mL ethylenediamines, under agitation
It is heated to 30 DEG C to react 6 hours, resin is then washed with deionized for several times, untill cleaning solution is in neutrality.Gained resin
Vacuum drying, obtains the resin of hydroxyl.
The measure of hydroxy radical content：It is condensed by resin and excess Fmoc- glycine (Fmoc-Gly), then removes Fmoc and protect
Base, the amount for the Fmoc that colorimetric method for determining is removed are protected, it is 527 μm of ol/g that conversion, which obtains the hydroxy radical content of resin,.
Hydroxy radical content determine specific method be：~0.2g resins are accurately weighed, 5mLN, dinethylformamide is suspended in
(DMF) in, 0.2g Fmoc- glycine, 0.15g N, N '-DIC (DIC) and 0.05g 4- are then added
Dimethylamino naphthyridine (DMAP), at room temperature stir 2 hours, wash with DMF resin for several times up to cleaning solution at 301nm without suction
Receive.Then gained resin is suspended in the DMF solution of 20% piperidines, be stirred at room temperature 1 hour, filtered, collected filtrate, use DMF
Wash resin for several times and collect the filtrate after washing, collected all filtrates are merged and constant volume, determined after appropriate dilution
Its absorbance at 301nm.Similar Fmoc elimination reactions are made by the Fmoc- glycine of serial concentration known and suction is determined
Light value, makes standard curve.
Embodiment 2
Method same as Example 1 obtains crosslinked methacrylic nitrile-vinyl acetate copolymer resin, with embodiment 1
In unlike：Oil phase contains 11g methacrylonitriles, 2g vinyl acetates, 7g divinylbenzenes (content is 55.3%), 30g 1,
2- dichloroethanes and 0.25g azodiisobutyronitriles.
The above-mentioned crosslink propylene nitrile-methyl acrylate copolymer resins of 5g are suspended in 30mL ethylenediamines, under agitation
It is heated to 60 DEG C to react 8 hours, resin is then washed with deionized for several times, untill cleaning solution is in neutrality.Gained resin
Vacuum drying, obtains the resin of hydroxyl, determine hydroxy radical content is 419 μm of ol/g.
Embodiment 3
Method same as Example 1 is obtained in crosslink propylene nitrile-methyl acrylate copolymer resin, with embodiment 1 not
Be：Contain 3g gelatin in aqueous phase as dispersion stabilizer and 60g sodium chloride, oil phase contains 19g acrylonitrile, 1.5g acrylic acid
Methyl esters, 4.5g divinylbenzenes (content is 55.3%), 25g cyclohexanol and 0.25g azodiisobutyronitriles.
The above-mentioned crosslink propylene nitrile-methyl acrylate copolymer resins of 5g are suspended in 30mL ethylenediamines, under agitation
It is heated to 60 DEG C to react 8 hours, resin is then washed with deionized for several times, untill cleaning solution is in neutrality.Gained resin
Vacuum drying, obtains the resin containing amino.
The measure of amino content：It is condensed by resin and excess Fmoc- glycine, then removes Fmoc protection groups, colorimetric
Method determines removed Fmoc amount, and it is 510 μm of ol/g that conversion, which obtains the amino content of resin,.The assay method of amino content is same
The assay method of hydroxy radical content in embodiment 1.
Embodiment 4
Method same as Example 2 obtains cross-linked poly methyl acrylonitrile resin, unlike embodiment 2：Oil phase
Contain 16g methacrylonitriles, 2g methyl acrylates, 4.5g divinylbenzenes (content is 55.3%), 2.5g melamines containing oil phase
Sour triallyl ester, 15g toluene, 10g normal octanes and 0.25g benzoyl peroxides, polymerization temperature are 80 DEG C, and polymerization time is 12
Hour.
The above-mentioned crosslinked methacrylic nitrile-methyl acrylate copolymer resins of 5g are suspended in 30mL ethylenediamines, stirred
Mix down be heated to 60 DEG C react 8 hours, resin is then washed with deionized for several times, until cleaning solution in neutrality untill.Gained
Resin vacuum is dried, and obtains the resin containing amino, and amino content is 484 μm of ol/g.
Embodiment 5
The resin of the hydroxyl obtained in embodiment 1 is bonded for synthesis polypeptide with RinkAmide.In 25mL round bottom
The resin of the hydroxyl obtained in 1g embodiments 1 is suspended in 10mLDMF in flask, 0.75g RinkAmide is then added and connects
Agent (structural formula is as follows), 0.25mLDIC, 0.005g DMAP are met, is reacted 4 hours under slow magnetic agitation.Reaction terminates
Afterwards, wash resin for several times with methanol, dichloromethane and DMF successively, obtain the resin containing Rink Amide bridging agents.
Rink Amide bridging agents
Embodiment 6
With in the resin alternate embodiment 5 containing amino obtained in embodiment 4 it is used obtained in embodiment 1 contain hydroxyl
The resin of base, other operations are same as Example 5, obtain the resin of Rink Amide bridging agents.
Embodiment 7
Polypeptide A CP (65-74) synthesis：The resin obtained in embodiment 5 is put into the round-bottomed flask that volume is 25mL,
Add and reacted 0.5 hour under the DMF solution that 10mL contains 20% piperidines, slow magnetic agitation, slough Fmoc blocking groups.Reaction
After end, resin is washed for several times with methanol, dichloromethane and DMF successively, you can enter the circulation of peptide reaction.
Above-mentioned resin is put into the round-bottomed flask that volume is 25mL, adds 0.45g Fmoc- glycine (Fmoc-
Gly), 0.25mL DIC, 0.40g 1- hydroxy benzo triazoles (HOBt), 0.005g DMAP and 10mL DMF, and in room
Temperature is reacted 1 hour under slow magnetic agitation.Then a small amount of resin is taken in teat glass, ethanol is washed three times, add several drops
5% ninhydrin solution, boiling water bath 3min, resin nondiscolouring then illustrates that reaction is complete, otherwise continues to react.After reaction completely, according to
It is secondary to wash resin for several times with a small amount of methanol, dichloromethane and DMF, that is, obtain Fmoc-Gly-Rink resins.
Repeated the above steps with different Fmoc- amino acid, finally obtain the resin for being connected with polypeptide：Fmoc-Val-Gln
(Trt)-Ala-Ala-Ile-Asp (otBu)-Tyr (tBu)-Ile-Asn (Trt)-Gly-Rink resins.
The resin of the above-mentioned connecting peptides of 0.5g is put into the round-bottomed flask that volume is 25mL, three are slowly added dropwise in ice bath
The mixed solution 10mL of fluoroacetic acid/thioanisole/water (95: 2.5: 2.5, volume ratio).After reaction 2 hours, ice bath is removed, normal
Temperature is lower to be continued to react 2 hours.Suction filtration, resin is washed with trifluoroacetic acid three times, and filtrate revolving is removed into most trifluoroacetic acid,
The ice ether of 8-10 times of volume is added, refrigerator overnight is put into.Centrifugation, removes ether, and vacuum drying obtains thick peptide.Utilize
HPLC can isolate and purify required polypeptide, and finally in thick peptide ACP (65-74) purity be 81.3%.
Embodiment 8
With used in embodiment 5 in the resin alternate embodiment 7 of the RinkAmide bridging agents obtained in embodiment 6
The resin of the Rink Amide bridging agents of acquisition, other operations are same as Example 7, obtain ACP (65-74) polypeptide, its purity
For 80.6%.The resin of Rink Amide bridging agents.
Embodiment 9
The resin containing amino that 1g embodiments 3 are obtained is suspended in 10mL acetonitriles, then add 0.2g DMT-dT-3 '-
O- succinic acid, 0.2g DIC and 0.05g DMAP, react 12 hours at room temperature.After gained resin is washed for several times with acetonitrile, hang
Float in acetonitrile solutions of the 10mL containing 10% acetic anhydride, 0.5%DMAP and 2% diisopropyl ethyl amine, 4 are stirred at room temperature small
When, gained resin is washed for several times with acetonitrile, obtains loading DMT-dT resin.By using spectrophotometry trichloroacetic acid
The amount for the resin-carried DMT-dT that the DMT taken off is obtained is 184 μm of ol/g.
With above-mentioned load DMT-dT resin oligomerization is synthesized on the DNA synthesizers of Applied Biosystems 3400
Nucleotides dT13, synthesis scale is 100 μm of ol.Gained resin concentrated ammonia liquor is handled 12 hours at 55 DEG C to be made under nucleosides acid cleavage
Come, the purity of gained nucleotides is 91.6%.
Embodiment 10
With in the resin alternate embodiment 9 of the hydroxyl obtained in embodiment 2 it is used obtained in embodiment 3 contain ammonia
The resin of base, other operations are same as Example 9, obtain oligonucleotide dT13Purity be 91.0%.
Claims (8)
1. a kind of porous resin is used as the purposes of Solid phase peptide synthssis and solid phase oligonucleotide synthetic vectors, it is characterised in that：
The porous resin is the porous resin of a kind of crosslinked polypropylene nitrile containing hydroxyl or amino or cross-linked poly methyl acrylonitrile, should
The polymer backbone for the nitrile group-containing that porous resin is included and the structure of function base hydroxyl or amino can be represented by the formula：
R=H or CH3, R '=H, G=OH
Or R=H or CH3, R '=H or CH3, G=CONH (CH2)nNH2, wherein n=2~18.
2. porous resin according to claim 1 is used as the use of Solid phase peptide synthssis and solid phase oligonucleotide synthetic vectors
On the way, it is characterised in that：The preparation method of the porous resin includes acrylonitrile or methacrylonitrile, contains two or more
The crosslinking agent of double bond and function monomer containing alkenyl carry out suspension free-radical combined polymerization in the presence of pore-foaming agent, obtain porous poly-
Polymer resin, resulting porous polymeric resins react by functionalizing again, obtain containing functional base hydroxyl or amino
Porous resin.
3. porous resin according to claim 2 is used as the use of Solid phase peptide synthssis and solid phase oligonucleotide synthetic vectors
On the way, it is characterised in that：Described two or two or more double bond crosslinking agent includes divinylbenzene, ethylene glycol dimethacrylate
One or more combination in ester, itaconic acid allyl ester, cyanuric acid triallyl ester, cyamelide triallyl ester.
4. porous resin according to claim 2 is used as the use of Solid phase peptide synthssis and solid phase oligonucleotide synthetic vectors
On the way, it is characterised in that：The function monomer containing alkenyl includes vinyl acetate, acrylate and methacrylate.
5. porous resin according to claim 2 is used as the use of Solid phase peptide synthssis and solid phase oligonucleotide synthetic vectors
On the way, it is characterised in that：The pore-foaming agent include aromatic hydrocarbon, aliphatic hydrocarbon, halogenated hydrocarbons, containing esters more than 4 carbon, containing 4-12 carbon
One or more combination in straight or branched fatty alcohol.
6. porous resin according to claim 5 is used as the use of Solid phase peptide synthssis and solid phase oligonucleotide synthetic vectors
On the way, it is characterised in that：The aromatic hydrocarbon includes benzene, toluene, ethylbenzene；The aliphatic hydrocarbon includes hexane, heptane, octane, dodecane；
The halogenated hydrocarbons includes chloroform, dichloroethanes, tetrachloroethanes, chlorobenzene；The ester contained more than 4 carbon includes ethyl acetate, second
Acid butyl ester；The straight or branched fatty alcohol containing 4-12 carbon includes butanol, hexanol, octanol, 2-Ethylhexyl Alcohol.
7. porous resin according to claim 2 is used as the use of Solid phase peptide synthssis and solid phase oligonucleotide synthetic vectors
On the way, it is characterised in that：In the suspension free-radical combined polymerization, the content of acrylonitrile or methacrylonitrile in polymerisable monomer is
50%~95%, content of the function monomer in polymerisable monomer is 0.5%~30%, crosslinking agent containing in polymerisable monomer
Measure as 5%~50%, the percentage sum of polymerisable monomer is 100%, the ratio of pore-foaming agent and polymerisable monomer for 0.3/1~
2/1, above-mentioned content or ratio are all by weight.
8. porous resin according to claim 4 is used as the use of Solid phase peptide synthssis and solid phase oligonucleotide synthetic vectors
On the way, it is characterised in that：The functionalizing of the porous polymeric resins reacts：Resin containing polyvinyl acetate and primary amine or
Secondary amine reaction makes its ester group occur the aminolysis of ester and resin is introduced hydroxyl functional base；Containing polyacrylate or polymethylacrylic acid
The resin of ester reacts with the excessive compound containing two primary amine groups, obtains the resin containing amino.
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| CN107417853A (en) * | 2017-09-14 | 2017-12-01 | 湖南理工学院 | A kind of preparation method of porous polypropylene nitrile |
| CN114539458B (en) * | 2020-11-26 | 2023-07-25 | 西安蓝晓科技新材料股份有限公司 | Porous resin applied to solid phase synthesis and preparation method thereof |
| CN114539459B (en) * | 2020-11-26 | 2023-07-25 | 西安蓝晓科技新材料股份有限公司 | Solid phase synthesis carrier and preparation method and application thereof |
| CN113262769B (en) * | 2021-05-28 | 2022-08-09 | 江南大学 | Polyhydroxy amphoteric resin and application thereof in adsorption separation of succinic acid |
| CN113527757B (en) * | 2021-07-26 | 2022-11-04 | 江南大学 | Nitrogen-containing heterocyclic ring amphoteric resin and application thereof in adsorption separation of small molecular organic acid |
| CN113845587B (en) * | 2021-12-01 | 2022-02-18 | 浙江湃肽生物有限公司南京分公司 | Synthetic method of bivalirudin |
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| CN1670050A (en) * | 2005-02-28 | 2005-09-21 | 天津南开和成科技有限公司 | Crosslinked polystyrene gel and use thereof |
| CN102212177A (en) * | 2011-04-07 | 2011-10-12 | 天津南开和成科技有限公司 | Porous resin with surface hydrophily |
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| JP4932377B2 (en) * | 2006-08-08 | 2012-05-16 | 日東電工株式会社 | Carrier for solid phase synthesis and method for producing the same |
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| CN1088486A (en) * | 1992-12-19 | 1994-06-29 | 南开大学 | Weak acidic cation exchanging resin producing process |
| CN1082945A (en) * | 1993-05-27 | 1994-03-02 | 南开大学高分子化学研究所 | Weak-acid cation-exchange resin |
| CN1670050A (en) * | 2005-02-28 | 2005-09-21 | 天津南开和成科技有限公司 | Crosslinked polystyrene gel and use thereof |
| CN102212177A (en) * | 2011-04-07 | 2011-10-12 | 天津南开和成科技有限公司 | Porous resin with surface hydrophily |
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