CN1434284A - Spectrum identifying resin microball capable of self-coding - Google Patents
Spectrum identifying resin microball capable of self-coding Download PDFInfo
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- CN1434284A CN1434284A CN 03118696 CN03118696A CN1434284A CN 1434284 A CN1434284 A CN 1434284A CN 03118696 CN03118696 CN 03118696 CN 03118696 A CN03118696 A CN 03118696A CN 1434284 A CN1434284 A CN 1434284A
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Abstract
The invention discloses a self-coding spectrum identifying resin micro-ball, mainly composed of the basic monomer, the copolymerization monomer for character coding and the active group copolymerizatino monomer. The basic monomer is phenethylene or its alkyl substituted homologen, the copolymerization monomer is at least a kind of phenethylene homologen different from the basic monomer, and the weight percentage of the basic monomer is higher than that of each copolymerization monomer. It makes the character coding on the infrared and Raman absorption spectrum of the different chemical components of the solid-phase carrier resin micro-ball, which integrates the coding process into the chemical synthetizatino of the solid-phase carrier.
Description
Technical field
The invention belongs to biological chemistry and combinatorial chemistry technique field, but be specifically related to a kind of own coding spectrum identification resin microsphere.This resin microsphere utilizes himself polymerization single polymerization monomer to have the characteristic of different infrared and Raman spectrum fingerprint peakses, adopts the different monomers copolymerization, obtains resin microsphere and all has unique infrared and raman signatures absorption spectrum.Convert thereof into discernible bar code again, be used for the rapid screening identification of microballoon.
Background technology
Since sixties Merrifield proposes the solid-phase polypeptide synthetic method, be that the solid phase synthesis of carrier has caused a revolution with its distinctive advantage with the polymkeric substance in chemistry.Formed this completely new concept of combinatorial chemistry to late nineteen eighties.Contemporaneity, synchronously multiple synthesizing, (Simultaneous multiplesynthesis SMS) also developed rapidly in the synthetic field of solid-phase peptide, and (peptide library is during solid-phase polypeptide PL) is synthetic successfully to apply to the peptide storehouse.Can synthesize tens even up to ten million kinds of peptides and peptide analogues simultaneously with the SMS method, quicken the speed and the scale of chemosynthesis greatly.On this basis.People have produced interest to the synthetic method of a large amount of compounds of different nature, and can screen according to possible physiologically active and other activity these compounds.In combinatorial chemistry, worked out certain methods, in these methods, people sequentially add the part of each different unit as chemosynthesis, preparing all or most of possible compounds, the different choice that these compounds may exist in synthetic consecutive steps and obtaining.For this a large amount of combinational chemistries that synthesize the storehouses product, must need the method that is fit to measure these compounds, can measure the structure and the composition of so a large amount of compounds that synthesize by these methods people.For this reason, demand to combinatorial chemistry coding has been proposed.
Coding method commonly used has two kinds, and the one, in the physical code of solid-phase matrix being carried out detecting identification, as marking at resin microsphere with laser, but this method is with high costs; Another kind of method then is by in building-up process carrier being carried out chemical labeling, thereby obtain unique definite, the detectable chemical labeling relevant with process, this method need be carried out a series of parallel labeled reactant in synthetic reaction, thereby has increased the complicacy of reaction greatly.(, in the reaction mechanism mechanism of reaction, come label coding in conjunction with producing feature with different compound group by trityl as human trityls such as the Mikhal S.Shchepinov thing that serves as a mark.See Tetrahedron, Vol.56 (2000), 2713-2724)
Summary of the invention
But the object of the present invention is to provide a kind of own coding spectrum identification resin microsphere, this resin microsphere need not to carry out expensive micro-physical markings and complicated chemical parallel reactor mark, this resin microsphere self has different infrared and Raman absorption spectrums, can be used for feature coding, and be applicable to various types of resins.
For achieving the above object, but a kind of own coding spectrum identification resin microsphere, it is characterized in that: this resin microsphere mainly is made up of basic monomer, the comonomer that is used for feature coding and reactive group comonomer, described basic monomer is the homolog that alkyl replaces on styrene or the cinnamic phenyl ring, comonomer is at least a and is different from the styrene homolog of basic monomer that the mass percent of basic monomer is higher than the mass percent of each comonomer.
Above-mentioned reactive group comonomer is a 1-chloro-4-methyl-benzene, to carry out the combinatorial chemistry solid phase reaction on styrene resin.Equally can be by going up of p-poly-phenyl vinyl carried out chemical modification or modification to chloromethyl, can obtain different derivative type styrene solid phase synthesis resin (as the WangShi resin etc.).
At present, the resin that can be used for the combinatorial chemistry solid phase synthesis on laboratory and the market has 3 classes substantially: the 1.Merryfield resene; 2. polyglycol connects skill cross-linked styrene resene; 3. be with trityl polystyrene resin class.The present invention carries out feature coding by the infrared and Raman absorption spectrum to the different chemical component of solid phase carrier resin microsphere own, cataloged procedure is integrated in the chemosynthesis of solid phase carrier itself, all applicable to all resins, and need not to carry out expensive micro-physical markings and complicated chemical parallel reactor mark.More advantageously, the resin microsphere of this coded markings can synthesize in a large number, becomes a kind of standardized commercial chemistry reagent, and does not bring any influence to reacting itself, can satisfy the foundation and the screening of heterogeneity, the different combinatorial chemical libraries that require.It mainly is that adding in resin is synthetic of passing through has outside the Different Red comonomer with the Raman spectrum fingerprint that resin microsphere is encoded.
Description of drawings
Fig. 1 is styrene and homolog thereof;
Fig. 2 is the coding resin microsphere under the optical microscope;
Fig. 3 is the coding resin microsphere under the electron microscope;
Fig. 4 is the infrared absorption spectrum 1 of coding resin microsphere;
Fig. 5 is the infrared absorption spectrum 2 of coding resin microsphere;
Fig. 6 is the infrared absorption spectrum 3 of coding resin microsphere;
Fig. 7 is the bar coding of coding resin;
Fig. 8 is the synthetic screening of the coding of six peptides.
Embodiment
The coding resin (Merrifield resinoid) that with styrene is basic monomer below is example, and the present invention is further detailed explanation.
With styrene or the homolog that replaces with alkyl on the cinnamic phenyl ring is the basic monomer of resin, and at least a in addition different styrene homolog comonomer promptly has the styrene homolog (see figure 1) of all kinds of substituted radicals on the phenyl ring.
Because co-monomer content is lower than at 20% o'clock, under present technical conditions, it is infrared and raman signatures spectrum is all not obvious.Therefore, its minimum component concentration is decided by the instrument and the means that detect.Under existing detection means, each phenyl ring substituted phenylethylene homolog of participating in cross-linked polymeric accounts for being advisable more than 20% of cross-linked styrene monomer total amount.
Every kind of content as the styrene homolog of comonomer accounts for more than 20% of gross mass of polymerization reactant (promptly all participate in the component of polyreaction), but all is lower than the mass percent of basic monomer, also contains the 1-chloro-4-methyl-benzene of 5-20% in addition.By adding different styrene homology comonomers and changing its array mode, obtain a class and have the outer and styrene resin microballoon raman signatures absorption spectrum, that can be used for the combinatorial chemistry solid phase synthesis of Different Red.Though can obtain covering the styrene resin microballoon of whole micron and nanometer scale diameter with common resins synthetic methods such as suspension polymerization, dispersin polymerization, bulk polymerization and emulsion polymerizations, but infrared and detection minimum resolution Raman spectrometer only is 5 microns both at home and abroad at present, abroad the infrared spectrum detection limit to single resin microsphere is 50 microns, and solid phase synthesis resin size commonly used at present is many at the 80-200 micron.Therefore, has the particle size distribution range of coding resin microsphere of relative using value at present only between the 50-500 micron.But, along with the progress of detection technique and combinatorial chemistry synthetic technology, its effective range will be widened thereupon.
Styrene is the 100-500 micron order resin microsphere (Merrifield resinoid) of basic monomer, has added several styrene homologs and styrene monomer therein and has carried out crosslinking copolymerization, and suspension polymerization obtains, and it is as follows that it specifically reacts synthesis step:
1, proportion of raw materials and pre-service:
Proportion of raw materials is as shown in the table:
| Styrene (%) | ????40 | ????50 | ????45 | ????60 | |
| The styrene homolog | To t-butyl styrene (%) | ????20 | ????20 | ????/ | ????25 |
| P-methylstyrene (%) | ????25 | ????/ | ????25 | ????/ | |
| Between methyl styrene (%) | ????/ | ????20 | ????20 | ????/ | |
| Reactive group | P-chloromethyl styrene (%) | ????10 | ????5 | ????15 | ????10 |
| Initiating agent: benzoyl peroxide (%) | ????2 | ????1 | ????2 | ????1 | |
| Spreading agent: polyvinylpyrrolidone (%) | ????2 | ????2 | ????2 | ????2 | |
| Crosslinking chemical: to vinylstyrene (%) | ????1 | ????2 | ????1 | ????2 | |
All polymer raws all need process pre-service purifying before reaction, and styrene and homolog thereof at first will be removed the polymerization inhibitor that adds in commercially available reagent.Get 20 gram styrene and add the 10%NaOH washing of 3-5 times of volume, standing demix behind the thermal agitation, the separating funnel layer that anhydrates.With the deionized water wash twice of 3-5 times of volume of styrene, be neutral until pH value again, gained styrene carries out the decompression distillation purifying again.The styrene homolog that contains halogen group then needs directly to cross alum clay post decompression distillation purifying and removes polymerization inhibitor.
2, suspension polymerization:
Mixed raw material is added in the polymer reactor that contains 200 ml deionized water (as 500 milliliters of four-hole boiling flasks); the inflated with nitrogen protection; progressively be warmed up to 80 ℃; continue to stir with 300-400 rev/min of speed; successive reaction 24 hours; when stopping to stir, oil reservoir disappears, and it is reaction end that all microballoons all are deposited in reactor bottom.Be warming up to 95 ℃ of slakings 1 hour, pour out filtration, collect microballoon, 0.1 atmospheric pressure vacuum drying is 24 hours under room temperature.
3, resin aftertreatment:
The gained resin microsphere needs classification to sieve, and with the extracting 24 hours that respectively circulates of absolute ethyl alcohol and deionized water, 0.1 atmospheric pressure vacuum drying at room temperature obtains finished product (seeing Fig. 2 and Fig. 3) after 24 hours again.
4, the coding resin coding and build the storehouse:
The resin microsphere of different coding carries out infrared respectively and Raman spectrum detects, and obtains different characteristic light spectrogram (seeing Fig. 4-6).Carry out the checking of duplicate detection outside Different Red and on the Raman spectrometer by a kind of resin of encoding multiple batches of, variable concentrations, confirm the universality of its characteristic spectrum, eliminate the influence factor of building-up process and testing conditions, read in its characteristic light spectrogram with software, make visual code conversion and obtain the bar coding (see figure 7), and it is built in the standard database.
Embodiment 2
With the p-methylstyrene is the preparation of the 50-100 micron coding microball of basic monomer:
1, raw material proportioning:
| P-methylstyrene (%) | ????45 | ????45 | ????50 | ????55 | |
| The styrene homolog | To t-butyl styrene (%) | ????20 | ????20 | ????/ | ????25 |
| O-methyl styrene (%) | ????25 | ????/ | ????25 | ????/ | |
| Between methyl styrene (%) | ????/ | ????20 | ????20 | ????/ | |
| Reactive group | P-chloromethyl styrene (%) | ????5 | ????10 | ????10 | ????15 |
| Initiating agent: potassium persulfate (%) | ????0.5 | ????0.5 | ????0.5 | ????0.5 | |
| Spreading agent: polyvinylpyrrolidone (%) | ????3.5 | ????3.5 | ????3.5 | ????3.5 | |
| Crosslinking chemical: to vinylstyrene (%) | ????1 | ????1 | ????1 | ????1 | |
2, suspension polymerization
Mixed raw material (5-10 gram) is added in the polymer reactor that contains the 200-250 ml deionized water (as 500 milliliters of four-hole boiling flasks); the inflated with nitrogen protection; progressively be warmed up to 60 ℃; continue to stir with 300-350 rev/min of speed; successive reaction 30 hours, all to be deposited in reactor bottom be reaction end to all microballoons when stopping to stir.Be warming up to 95 ℃ of slakings 1 hour, pour out filtration, collect microballoon, 0.1 atmospheric pressure vacuum drying is 24 hours under room temperature.
3, resin aftertreatment
4, the coding resin coding and build the storehouse
(3,4 steps are all with embodiment 1)
Embodiment 3
With styrene is the preparation of the 1-20 micron coding microball of basic monomer
1, raw material proportioning:
| Styrene (%) | ????35 | ????35 | ????35 | ????50 | |
| The styrene homolog | To t-butyl styrene (%) | ????20 | ????20 | ????/ | ????25 |
| O-methyl styrene (%) | ????20 | ????/ | ????20 | ????/ | |
| Between methyl styrene (%) | ????/ | ????20 | ????20 | ????/ | |
| Reactive group | P-chloromethyl styrene (%) | ????10 | ????10 | ????10 | ????10 |
| Initiating agent: azoisobutyronitrile (%) | ????2 | ????2 | ????2 | ????2 | |
| Spreading agent: polyvinylpyrrolidone (%) | ????12 | ????11 | ????12 | ????11 | |
| Crosslinking chemical: to vinylstyrene (%) | ????1 | ????2 | ????1 | ????2 | |
2, dispersin polymerization:
Mixed material (10-15 gram) is poured in 200 milliliters of conical flasks with 30 milliliters of methyl cellosolves and 20 milliliters of absolute ethyl alcohols, and fully vibration is up to getting colourless solution.Simultaneously in 250 milliliters of there-necked flasks, feed nitrogen in advance after 30 minutes, mixed liquor is poured into, stir, warming-in-water to 75 ℃, sustained response 10-12 hour with 250-300 rev/min of rotating speed.After reaction is finished, remove water-bath, continue stirring and be cooled to room temperature, get white emulsion.
3, resin aftertreatment:
Resinous emulsion is respectively washed 2-3 time with equal-volume deionized water, acetone, ethanol respectively, and washing back high speed centrifugation under supercentrifuge removes the supernatant layer.Ultrasonic Separation resin microsphere in absolute ethyl alcohol, high speed centrifugation removes supernatant, repeats 5-6 time.Equal-volume deionization washing 3 times, high speed centrifugation removes the supernatant layer.
4, the coding resin coding and build the storehouse
Owing to limited by the instrumental resolution of infrared spectrometer, 1-20 submicron resin microballoon can only carry out the coding and the database work of Raman spectrum, and concrete steps are with embodiment 1.
Embodiment 4
With styrene is the preparation of the 10 nanometers-10 micron coding microball of basic monomer:
1, raw material proportioning:
| Styrene (%) | ????65 | ????85 |
| The styrene homolog | To t-butyl styrene (%) | ????20 | ????/ |
| Reactive group | P-chloromethyl styrene (%) | ????10 | ????10 |
| Initiating agent: ammonium persulfate (%) | ????3 | ????3 | |
| Crosslinking chemical: to vinylstyrene (%) | ????2 | ????2 | |
2, emulsion polymerization
Mixed raw material (5 gram) is added in the polymer reactor that contains 120 ml deionized water and 80 milliliters of acetone (as 500 milliliters of four-hole boiling flasks); the inflated with nitrogen protection progressively is warmed up to 75-85 ℃, continues to stir with 250-350 rev/min of speed; successive reaction 30 hours obtains emulsion.
3, resin aftertreatment:
Resinous emulsion is respectively washed 2-3 time with equal-volume deionized water, acetone, ethanol respectively, and washing back high speed centrifugation under supercentrifuge removes the supernatant layer.Obtain resin suspending liquid at last and wash 2 times with the deionized water bubble, each 24 hours, high speed centrifugation removed supernatant.
4, the coding resin coding and build the storehouse
Because infrared and instrument resolution Raman spectrometer all is not enough to the single resin microsphere of nanoscale size is carried out spectral detection, this work can't be carried out at present.But along with the continuous upgrading and the performance boost of optical detecting instrument, nano level coding resin microsphere will have its application corresponding in future and be worth and bigger application.
We are that example shows the encode purposes of resin microsphere of the present invention with the coding solid phase synthesis in the full storehouse of six peptides and screening.
As shown in Figure 8, the first step, we are corresponding one by one with 20 kinds of L-amino acid and 20 kinds of coding resin microspheres, solid phase synthesis, the corresponding a kind of coding resin (N of a seed amino acid
1-N
20); Then, 20 kinds of microballoons are mixed, add at random that with mixed point-score (spit-mix) four amino acid generate pentapeptide again; All microballoons are divided into 20 groups, numbering (M
1-M
20), every group connects a seed amino acid, obtains 20 group of six peptide word bank; Screen through fluorescently-labeled target thing molecule, obtain the highest microballoon of fluorescence intensity, according to its place group #, can learn the amino acid kind B of position, end on this microballoon, detect through infrared and Raman spectrum again, obtain the coding of this microballoon, according to initial one-to-one relationship, can learn the kind A (annotate, the A here, B, C, D, E, F are code name, rather than amino acid whose letter commonly used is called for short) of first amino acids on this microballoon.
Second step, known to the target molecule activity on the basis of the first and last amino acids sequence (A and B) of the highest six peptides, earlier all 20 kinds of coding microballs are all connected amino acid A, more corresponding one by one different amino acid, the coding (N of connecing of various coding microballs when second amino acid
1-N
20); Mix all microballoons, mix point-score and generate tetrapeptide; Be divided into 20 groups, numbering (M
1-M
20), every group connects a seed amino acid and obtains 20 pentapeptide word banks, and last every group all connects amino acid B and becomes six peptide AXXXXB (X represents unknown amino acid); Screen once more with the fluorescence labeling target molecule, in like manner can draw second and the 5th amino acids C, D of active six peptides.
The 3rd step, with all connecting two amino acid AC on 20 kinds of coding microballs earlier, when connecing the 3rd amino acid, corresponding one by one different amino acid, the coding (N of connecing of various coding microballs
1-N
20); Mix microballoon, be divided into 20 groups, numbering (M
1-M
20), respectively connect a seed amino acid and generate the tetrapeptide word bank; And then respectively connect amino acid D and B, generate six peptide ACXXDB; The fluorescence labeling target molecule screens for the third time, draws the 3rd and the 4th amino acids E, F of active six peptides, thereby can know that to six the highest peptide sequences of target molecule activity are ACEFDB.
After having adopted coding resin screening method, can two amino acid sequences of one-time positioning, be doubled compared with the efficient of scanning localization method by turn of routine, the workload of synthesis peptide library also alleviates greatly (from 6.4 * 10 of the full storehouse of six peptides
7Filter out target six peptides in individual six peptides and only need synthesize 60 word banks, will synthesize 120 word banks) and scan rule by turn.And need not to carry out other any labeled reactant, the solid phase synthesis process is had no effect.This method also can be applied among other combinatorial chemistry solid phase synthesis, is applicable to the screening of all kinds of combinatorial chemical libraries.
Claims (3)
- But 1, a kind of own coding spectrum identification resin microsphere, it is characterized in that: this resin microsphere mainly is made up of basic monomer, the comonomer that is used for feature coding and reactive group comonomer, described basic monomer is the homolog that alkyl replaces on styrene or the cinnamic phenyl ring, comonomer is at least a and is different from the styrene homolog of basic monomer that the mass percent of basic monomer should be higher than the mass percent of each comonomer in the resin.
- But 2, own coding spectrum identification resin microsphere according to claim 1, it is characterized in that: described reactive group comonomer is a 1-chloro-4-methyl-benzene, to carry out the combinatorial chemistry solid phase reaction on styrene resin.Can carry out chemical modification or modification to chloromethyl by going up of p-poly-phenyl vinyl equally, can obtain different derivative type styrene solid phase synthesis resins, the mass percent of 1-chloro-4-methyl-benzene is 5-20%.
- But 3, own coding spectrum according to claim 1 and 2 identification resin microsphere is characterized in that: each is used for the mass percent of comonomer of feature coding greater than 20%.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1317560C (en) * | 2005-10-19 | 2007-05-23 | 华中科技大学 | Method for increasing coding stability of quantum point coding microball |
| CN1317675C (en) * | 2005-03-24 | 2007-05-23 | 华中科技大学 | Method for coding and identifying resin microsphere by infrared spectrum |
| CN100340853C (en) * | 2004-03-04 | 2007-10-03 | 华中科技大学 | Method for raising correctness of resin microspheric spectrum coding |
| CN100427925C (en) * | 2006-02-20 | 2008-10-22 | 扬州大学 | Method for determining styrene micro-emulsion polymerization conversion rate by ultraviolet spectrometry |
| CN101543755B (en) * | 2009-04-01 | 2011-07-27 | 中国科学院苏州纳米技术与纳米仿生研究所 | Preparation method of encoding microspheres |
| CN103186803A (en) * | 2013-03-19 | 2013-07-03 | 南京大学 | Raman-spectrum-based nanometer bar code smart label and identification method thereof |
-
2003
- 2003-02-26 CN CN 03118696 patent/CN1434284A/en not_active Withdrawn
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100340853C (en) * | 2004-03-04 | 2007-10-03 | 华中科技大学 | Method for raising correctness of resin microspheric spectrum coding |
| CN1317675C (en) * | 2005-03-24 | 2007-05-23 | 华中科技大学 | Method for coding and identifying resin microsphere by infrared spectrum |
| CN1317560C (en) * | 2005-10-19 | 2007-05-23 | 华中科技大学 | Method for increasing coding stability of quantum point coding microball |
| CN100427925C (en) * | 2006-02-20 | 2008-10-22 | 扬州大学 | Method for determining styrene micro-emulsion polymerization conversion rate by ultraviolet spectrometry |
| CN101543755B (en) * | 2009-04-01 | 2011-07-27 | 中国科学院苏州纳米技术与纳米仿生研究所 | Preparation method of encoding microspheres |
| CN103186803A (en) * | 2013-03-19 | 2013-07-03 | 南京大学 | Raman-spectrum-based nanometer bar code smart label and identification method thereof |
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