CN105504159A - Bonded chiral amino alcohol polymer and preparation method and application thereof - Google Patents
Bonded chiral amino alcohol polymer and preparation method and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/52—Amides or imides
- C08F220/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
- C08F220/58—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing oxygen in addition to the carbonamido oxygen, e.g. N-methylolacrylamide, N-(meth)acryloylmorpholine
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- C07—ORGANIC CHEMISTRY
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F230/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal
- C08F230/04—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal containing a metal
- C08F230/08—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal containing a metal containing silicon
Abstract
The invention discloses a bonded chiral amino alcohol polymer and a preparation method and application thereof. The bonded chiral amino alcohol polymer is composed of chiral amino acid derivative monomers on modified silica gel by virtue of amide group bonding. The preparation method comprises the following steps: taking L-amino acid as a raw material, and sequentially performing methyl esterification and phenylmagnesium bromide addition; introducing double bonds through acryloyl chloride, thereby obtaining a chiral monomer; polymerizing the chiral monomer and modified silica gel introduced with double bonds through free radicals, thereby obtaining the product. The process is simple in method, wide in raw material source and low in cost and is beneficial to industrial production; and moreover, the bonded chiral amino alcohol polymer has organic solvent resistance and high chiral resolution performance, can serve as a novel HPLC chiral stationary phase material applied to chiral compound identification or resolution and overcomes the defect that the existing chiral resolution material is limited by mobile phase.
Description
Technical field
The present invention relates to a kind of chirr polymer material for chiral separation and its preparation method and application, be specifically related to a kind of bonded chiral amino alcohol polymeric material containing L-amino acid (L-Leu, L-phenylglycine, L-Phe) group, belong to functional high polymer material field.
Background technology
In recent years, the share that chiral drug occupies pharmaceutical market is increasing, general containing one or more chiral centre in this kind of drug molecular structure, exists with the form of enantiomer.Chirality plays important role in daily life, biological chemistry and pharmaceutical industry.In the organism lived, a pair enantiomorph usually shows different drug effects, toxicological characteristics.Generally believe now, sometimes the pharmacological action of two enantiomorphs is added, but more situation is that a kind of enantiomorph has activity (active isomer), and another kind does not have activity or activity very low (low activity isomer), even there is the drug effect of larger toxicity or two kinds of enantiomorphs completely contrary.Therefore in order to improve the security of mankind's chiral drug, studying new chiral separation technology, developing the essential domain that new chiral separation material has become world today's new drug development.
At present, nearly more than 100 kinds of chiral recognition materials obtain commercialization, and the chiral material obtained by polymerization has been widely used in the identification of chirality enantiomer.Different according to source, polymer chiral recognition material can be divided into four classes: the first kind is polymkeric substance and their derivative of nature existence; Equations of The Second Kind utilizes chiral monomer artificial-synthetic copolymer; 3rd class manually synthesizes singlehanded spiral macromolecular compound by method of asymmetric synthesis; Last class is the molecularly imprinted polymer that monomer becomes with template polymerization.For bonding on the substrate surface small molecules, increase chiral polymer recognizer and be easier at the amount ratio of stromal surface.Therefore the polymer materials synthesized has higher sample supporting capacity, and chirr polymer polymkeric substance (except protein molecule) seems to be best suited for the parting material prepared.Because polymer chiral recognition material has abundant chemical structure, is convenient to the chemically modified of chiral recognition, has the possibility obtaining high chiral recognition performance, so the synthesis of chirr polymer polymkeric substance has magnetism.
In recent years, optical active polymer due to its have unique molecular recognition, asymmetry catalysis characteristic, Optical resolution Racemic body function cause and pay close attention to widely.The polymerization of chiral monomer is used to one of common method of synthesis of optically active polymkeric substance.About the optical active polymer of synthesis has had a lot as the report of the sorbent material of Chromatographic resolution racemic modification, successfully split a lot of racemic modification with the polymkeric substance of natural existence or synthesis as the optical activity sorbent material of column chromatography.This base polymer major part is all synthesized by two kinds of methods below.First method is incorporated into by optical activity group on the inactive polymer support of optics (polystyrene, poly acryloyl chloride etc.) or insoluble matrix; Second method is the free radicals copolymerization reaction of the optically active monomer linking agent corresponding to some.
In pharmaceutical industry, pendant moiety is widely used in the chiral separation of medicine as chiral stationary phase with the chiral polymer of chiral amino acid.Amino acid and derivative thereof not only have stability of characteristics, the cheapness that is easy to get and be easy to the advantages such as preparation, and such compound structure diversity, hydrogen bond, π-differing molecular intermolecular forces such as π-electron effect and hydrophobic interaction can be formed with substrate molecule, be conducive to identifying with the material that this compounds synthesizes for chiral source multiple substrate molecule/splitting, thus make such chiral material have certain versatility.Naturally occurring amino acid is L-amino acid mostly, has important effect, particularly L-Leu in pharmacy and field of food.L-Leu is a kind of indispensable amino acid in organism.L-Leu makes it have very strong hydrophobicity due to its tertiary-butyl structure, and plays an important role in formation α-helixstructure and peptide and protein stability.
There is the amino acid whose optically active monomer of L-to be carried out the report of synthesis of chiral polymkeric substance by Raolical polymerizable in structure, just exist a long time ago.That carry out the earliest studying is (the document 1.BlaschkeG.ChemBer such as Blaschke in 1974,1974,107 (1): 237-252.) synthesized the polyacrylamide with optical activity side base, this polymkeric substance shows very high chiral recognition to amygdalic acid.
Optical active polymer chiral enantiomer preparation be separated in show huge advantage, there is boundless application prospect.At present, many commercial Chiral Separation of Amino Acid Derivatives stationary phase adopt the method for physics coating to be fixed on chromatography matrix by amino acid derivative, can cause the problem that chiral selector runs off like this, mobile phase composition is subject to larger restriction in actual applications.This shortcoming, result also in the limitation of the low-down even insoluble enantiomorph of some solubleness in chiral separation.Adopt the method for chemical bonding chiral selector can be made up the loss of chiral selector in stromal surface by chemical bonding, but rarely have report.(the document 2.OkamotoY such as Okamoto, SuzukiK, OhtaK, HatadaK, YukiH.JAmChemSoc, 1979,101 (16): 4763-4765.) under the condition of chiral catalyst, synthesized at the complex compound formed using n-Butyl Lithium and (-)-Tocosamine (Sp) vinylic polymers-polymethyl triphenyl phosphate methyl esters (PTrMA) that first optical activity only come from main chain spirane structure by asymmetric anionic polymerisation, be successfully applied to HPLC chiral stationary phase, a lot of enantiomorphs is separated.But the ester bond of polymethacrylate easily splits in methanol solvate, especially in acid condition, this makes it be difficult to studied or long its polymkeric substance of use.
Therefore, increasing people pays close attention to the chiral separation ability of this base polymer and derivative thereof, is badly in need of finding out a kind of technology splitting effective, that selectivity is high, cost is low, applied widely fractionation enantiomorph.
Summary of the invention
Be subject to as existing during chiral stationary phase the defect that moving phase limits, chiral selector easily runs off and bonding rate is low for existing commercialization chiral separation material, the object of the invention is to be to provide one to have efficient chiral separation ability, and organic solvent resistance is good, the novel key mould assembly chiral amino alkoxide polymer chiral separation macromolecular material that chiral selector can be avoided to run off.
Another object of the present invention is to provide a kind of method that cheaper starting materials, technique are simple, low cost prepares above-mentioned bonded chiral amino alcohol polymkeric substance chiral separation macromolecular material.
A further object of the invention is the application providing a kind of above-mentioned bonded chiral amino alcohol polymkeric substance, this chiral amino alcohol polymer application is in the fractionation of chipal compounds, method is simple, identify/split superior performance, resolution solvent selectivity is extensive, in chiral separation field, have a wide range of applications potentiality.
In order to realize above-mentioned technical purpose, the invention provides a kind of bonded chiral amino alcohol polymkeric substance, this bonded chiral amino alcohol polymkeric substance has formula 1 structural unit:
Wherein,
R is ethyl, phenyl or aminomethyl phenyl;
for silica-gel carrier.
Bonded chiral amino alcohol polymkeric substance repeated structural unit number of the present invention is between 2 ~ 5.
Bonded chiral amino alcohol polymkeric substance of the present invention introduces L-Chiral Separation of Amino Acid Derivatives group by amide group bonding in modified silica-gel matrix, and amide group has the characteristic of good organic solvent-resistant, and chiral radicals can not be run off by organic solvent dissolution; The L-amino acid derivative group simultaneously introduced, can form the diastereomer molecule of different stability with chipal compounds, by Intermolecular Forces if hydrogen bond, space steric effect are with π – π interaction force etc., make chipal compounds reach the object of fractionation.Bonded chiral amino alcohol polymkeric substance of the present invention, by changing the bonded amount of L-Chiral Separation of Amino Acid Derivatives group on silica matrix surface, and then the interaction such as identification, absorption between adjustment chiral separation material and separated material, thus realize the chiral separation function of such material.
Present invention also offers a kind of method preparing described bonded chiral amino alcohol polymkeric substance, the method comprises the following steps:
(1) formula 2 structure L-amino acid and methyl alcohol carry out condensation reaction under thionyl chloride effect, production 3 structure L-amino acid methyl ester hydrochloride, and described L-amino acid methyl ester hydrochloride and phenyl-magnesium-bromide carry out addition reaction, obtain formula 4 structure chiral amino alcohol; Gained chiral amino alcohol and acrylate chloride carry out esterification, obtain formula 5 structure chiral monomer;
(2) carry out linked reaction by excessive γ-methacryloxypropyl trimethoxy silane and silica-gel carrier, obtain γ-methacrylic ester silica derivative thing;
(3) by (1) gained chiral monomer and (2) gained methacrylic ester silica derivative thing under radical polymerization initiator and linking agent existence condition, initiated polymerization, to obtain final product;
Wherein, R is ethyl, phenyl or aminomethyl phenyl.
The key of preparation method of the present invention is by designing suitable chiral monomer and modified silica-gel, and both obtain bonded chiral amino alcohol polymkeric substance by radical polymerization.Containing L-Chiral Separation of Amino Acid Derivatives group and the acryl with free radical reaction activity in the chiral monomer molecular structure of the present invention's design; L-aminoalcohol derivative chiral radicals gives material chiral recognition/fractionation performance, and C=C double bond is then convenient to chiral monomer and other monomer containing C=C double bond carries out free radicals copolymerization reaction.And modified silica-gel is by γ-methacryloxypropyl trimethoxy silane and silica gel coupling, silica gel is introduced double bond, free radical reaction can be carried out with chiral monomer.The bonded chiral amino alcohol polymkeric substance of design and synthesis, has molecular structure stabilized, solvent-proof advantage, and it washes with water and re-use to middle performance, make chiral separation have persistence, weather resistance after 5 ~ 10% acetic acid wash-outs.
Preferred scheme, condensation reaction is in ice water bath environment, is added drop-wise to by thionyl chloride in the amino acid whose methanol solution of L-, and ensures that thionyl chloride drips in 30min, then reacts 24 ~ 40h under being placed in room temperature.
Preferred scheme, the mol ratio of L-amino acid and thionyl chloride is 1:1.5 ~ 5.
More preferably scheme, L-amino acid is L-Leu, L-phenylglycine or L-Phe.
Preferred scheme, addition reaction reacts 15 ~ 24h under temperature is the condition of 25 ~ 35 DEG C.
Preferred scheme, the mol ratio of L-amino acid methyl ester hydrochloride and phenyl-magnesium-bromide is 1:10 ~ 30.
Preferred scheme, esterification is under protective atmosphere, under 25 ~ 30 DEG C of temperature condition, react 10 ~ 24h.
Preferred scheme, acrylate chloride is excessive relative to chiral amino alcohol.
Preferred scheme, linked reaction is under nitrogen protection, under 70 ~ 90 DEG C of temperature condition, react 8 ~ 16h.
Preferred scheme, polyreaction reacts 20 ~ 24h under temperature is 80 ~ 100 DEG C of conditions.
Preferred scheme, the mass ratio of chiral monomer and γ-methacrylic ester silica derivative thing is 1:4 ~ 5.
Preferred scheme, the mol ratio of chiral monomer and linking agent is 9 ~ 10:1.
Preferred scheme, the mol ratio of chiral monomer and initiator is 90 ~ 100:1.
Preferred scheme, initiator is Diisopropyl azodicarboxylate.
Preferred scheme, linking agent is ethylene glycol dimethacrylate.
Present invention also offers the application of described bonded chiral amino alcohol polymkeric substance, by bonded chiral amino alcohol polymer application in chipal compounds identification or fractionation.
Bonded chiral amino alcohol polymkeric substance of the present invention contains L-Chiral Separation of Amino Acid Derivatives group due to its molecular structure side chain, and have very strong chiral recognition, chiral medicine has certain separating power; In addition, bonded chiral amino alcohol polymkeric substance has organic solvent-resistant, constitutionally stable characteristic, makes the selection of resolution solvent have more handiness.
Preferred scheme, the mol ratio of bonded chiral amino alcohol polymkeric substance and chiral racemate is 2 ~ 1:1.
Technical scheme of the present invention utilizes L-amino acid to make chiral source, bidentate L-amino acid derivative is obtained through esterification, grignard reaction, introduce double bond again and obtain novel amidation chiral monomer, then, the surface of this type of optically active monomer and modified is carried out Raolical polymerizable with the modified silica-gel of double bond and is obtained chiral separation material; Its synthetic route and target product structural formula as follows:
The present invention is comprised by free-radical polymerized bonded chiral amino alcohol polymer process of preparing:
1, the preparation of chiral monomer: methyl alcohol adds in round-bottomed flask, adds a certain amount of L-amino acid and is suspended in anhydrous methanol, under ice-water bath cooling conditions (temperature controls below 0 DEG C), by excessive SOC1
2be added drop-wise in anhydrous methanol suspension liquid, wherein L-amino acid and sulfur oxychloride mol ratio are 1:1.5 ~ 5, drip off in 30min, are then transferred to stirred at ambient temperature reaction 24 ~ 40h; Revolve desolventizing, add a certain amount of methyl alcohol and be spin-dried for solvent again and eliminate the hydrogenchloride of generation and excessive sulfur oxychloride, drying obtains white needle-like crystals L-amino acid methyl ester hydrochloride;
Anhydrous tetrahydro furan and a certain amount of magnesium chips add in three-necked bottle, reflux cooling, slowly drip bromobenzene and anhydrous tetrahydro furan mixing solutions, the mol ratio of bromobenzene and magnesium chips is 1:1 ~ 2, adds iodine initiation reaction, stirring and refluxing 20 ~ 40min, after reacting completely, the cooling of gained Grignard reagent is for subsequent use;
Under condition of ice bath, in above-mentioned Grignard reagent, add L-amino acid methyl ester hydrochloride in batches, under 25 ~ 35 DEG C of conditions, after stirring reaction 15 ~ 24h, under 0 ~ 5 DEG C of ice-water bath cooling, slowly saturated ammonium chloride solution is dripped in reaction solution, reaction solution ethyl acetate and water extracting and demixing, organic phase anhydrous sodium sulfate drying spends the night, revolve desolventizing, obtain white solid bidentate chiral amino acid derivative through column chromatography (sherwood oil: ethyl acetate (volume ratio)=20:1); Get after this product dissolves in anhydrous tetrahydro furan, add triethylamine, slowly drip acrylate chloride in ice bath downhill reaction liquid, bidentate chiral amino alcohol, triethylamine and acrylate chloride mol ratio are 1:1.5 ~ 2:1 ~ 2; Finish, reaction system is transferred to stirred at ambient temperature reaction and spends the night; Revolve desolventizing, add a certain amount of water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying spends the night, and revolves desolventizing, room temperature in vacuo dried overnight, obtains light yellow chiral monomer N-acryloyl L-amino acid-amino alcohol;
2, spherical silica gel (activating) is suspended in dry toluene, add excessive γ-methacryloxypropyl trimethoxy silane, under nitrogen protection, under 70 ~ 90 DEG C of temperature condition, react 8 ~ 16h, obtain γ-methacrylic ester silica derivative thing (γ-MAPS);
3, the preparation of bonded chiral amino alcohol polymeric material: γ-MAPS is suspended in dry toluene, monomer in molar ratio: linking agent EDMA: initiator A IBN=90 ~ 100:9 ~ 10:1 takes medicine and is dissolved in dry toluene, add the initiator A IBN of 1 ~ 2% of the amount of monomeric substance, logical nitrogen, add the linking agent EDMA of 9 ~ 10% of the amount of monomeric substance again, logical nitrogen, then under 80 ~ 100 DEG C of conditions, 20 ~ 24h is reacted, the bonded chiral amino alcohol polymkeric substance crude product of gained uses acetone successively, methanol wash several or immersion, namely bonded chiral amino alcohol polymkeric substance is obtained.
Hinge structure, the Advantageous Effects that technical scheme of the present invention is brought:
(1) in bonded chiral amino alcohol polymkeric substance of the present invention, L-Chiral Separation of Amino Acid Derivatives group is bonded on matrix resin by amide group, this type of material has fine physicochemical stability, particularly there is the characteristic of organic solvent-resistant, the problem that chiral radicals in organic solvent runs off can be avoided, there is solvent selectivity widely, for chiral drug resolution has widened solvent range of choice, make up now commercial chiral separation material and be subject to the deficiency of solvent selectional restriction; And there is efficient chiral separation ability, overcome the defect that existing chiral separation material splits weak effect.
(2) bonded chiral amino alcohol Macroscopic single crystal raw material of the present invention is cheap and easy to get, and preparation method is easy and simple to handle, quick, can realize suitability for industrialized production.
(3) bonded chiral amino alcohol polymkeric substance of the present invention is used for the method for chipal compounds identification or fractionation simply, identifies/split superior performance, and resolution solvent selectivity is extensive, in chiral separation field, have a wide range of applications potentiality.
Accompanying drawing explanation
The bonded chiral amino alcohol polymeric material selectivity absorption R/S-α-phenylethylamine uv-absorbing spectrogram that [Fig. 1] is prepared for the embodiment of the present invention 1;
The bonded chiral amino alcohol polymeric material selectivity absorption D/L-amygdalic acid uv-absorbing spectrogram that [Fig. 2] is prepared for the embodiment of the present invention 1;
[Fig. 3] is the thermogravimetric curve figure of embodiment 1 γ-MAPS, bonded chiral amino alcohol polymkeric substance.
The bonded chiral amino alcohol polymeric material selectivity absorption R/S-α-phenylethylamine uv-absorbing spectrogram that [Fig. 4] is prepared for the embodiment of the present invention 2;
The bonded chiral amino alcohol polymeric material selectivity absorption D/L-amygdalic acid uv-absorbing spectrogram that [Fig. 5] is prepared for the embodiment of the present invention 2;
[Fig. 6] is the thermogravimetric curve figure of embodiment 2 γ-MAPS, bonded chiral amino alcohol polymkeric substance.
Embodiment
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way the protection domain of claim.
Embodiment 1
The preparation of chiral monomer: 485mL is dry, and methyl alcohol adds in 1000mL round-bottomed flask, and 30g (0.2287mo1) L-Leu is suspended in anhydrous methanol, under ice-water bath cooling conditions, by excessive SOC1
2(80mL, 1.102mo1) is added drop-wise in anhydrous methanol suspension liquid, drips off in 30min, is then transferred to stirred at ambient temperature reaction 40h.Revolve desolventizing, add a certain amount of methyl alcohol and be spin-dried for solvent again and eliminate the hydrogenchloride of generation and excessive sulfur oxychloride, obtain white needles L-Leu methyl ester hydrochloride.At 30 DEG C, anhydrous tetrahydro furan 200mL is added in 1000mL three-necked bottle, magnesium chips (26.02g, 1.0842mol), load onto prolong and the dropping funnel that 114mL bromobenzene and 50mL tetrahydrofuran (THF) are housed, before non-mechanical stirring, the anhydrous tetrahydrofuran solution of 2mL bromobenzene (0.06mo1) is instilled in reaction system lentamente, then a small amount of iodine initiation reaction is added, color until iodine is about to slowly drip the tetrahydrofuran solution remaining bromobenzene in dropping funnel after disappearance i.e. reaction causes, control to drip speed, suitable cooling, micro-the boiling of reacting balance is carried out, drip off in 30min, the color of reaction solution gradually from light to dark, heating in water bath to 47.5 DEG C backflow 45min, grignard reaction is made to carry out completely, be chilled to room temperature for subsequent use.Then with the Grignard reagent of ice-water bath cooling preparation, under ice-water bath cooling, add L-Leu methyl ester hydrochloride (5g in batches, 0.0275mo1), 20g (0.11mol) L-Leu methyl ester hydrochloride is added in 10min, deicing water-bath, is warming up to 35 DEG C and continues reaction 15h by reaction system.React complete, under ice-water bath cooling, slowly saturated ammonium chloride solution is dripped in reaction solution, reaction is violent, reaction solution ethyl acetate and water extracting and demixing, organic phase anhydrous sodium sulfate drying spends the night, and revolves desolventizing, obtains white solid bidentate chiral amino acid derivative with appropriate sherwood oil recrystallization.58mL anhydrous tetrahydro furan is added in the mono-neck bottle of 100mL, 6.25mL (44.9mmol) triethylamine, 10g (37.2mmol) bidentate chiral amino alcohol, then reaction system is placed in the bath of constant temperature low temperature stirring reaction, under 0 DEG C of condition, in reaction soln, slowly drip excessive acrylate chloride (6mL, 73.8mmol), drip off in 30min, then reaction system is transferred to stirred at ambient temperature reaction and spends the night.Revolve desolventizing, add a certain amount of water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying spends the night, revolve desolventizing, room temperature in vacuo dried overnight, obtain light yellow solid N-acryloyl-L-Leu-amino alcohol 11.2g, yield 93.3%, Rf=0.76 (petrol ether/ethyl acetate=1:1); M.p224 ~ 226 DEG C;
1hNMR (CDCl
3, 400MH
z) δ: 0.88 ~ 1.03 [dd, 6H, (CH
3)
2cH], 1.26 ~ 1.29 [m, 1H, (CH
3)
2cH], 1.52 ~ 1.64 [m, 2H, (CH
3)
2cHCH
2], 5.18 ~ 5.23 (m, 1H, NHCH), 5.84 ~ 5.91 (m, 1H, CH
2=CH), 6.03 ~ 6.23 (dd, 2H, CH
2=CH), 7.15 ~ 7.35 (m, 10H, ArH), 7.54 ~ 7.56 (d, 1H, NHCH); IR (KBr) ν: 3441,3282,3091,2949,2860,1655,1613,1565,1489,1450,1370cm
-1.
The preparation of methacrylic ester silica derivative thing: 20.6435g spherical silica gel (activating) is suspended in the 250mL three-necked bottle of 150mL dry toluene, in nitrogen, in reaction system, add 20mL (84.15mmol) γ-methacryloxypropyl trimethoxy silane, reaction mixture is 80 DEG C of reaction 12h under drying nitrogen.Reaction mixture is filtered, then 100mL acetone (4 × 25mL) is used successively, 100mL methyl alcohol (4 × 25mL), 100mL ethanol (4 × 25mL), 50mL methylene dichloride (5 × 10mL) washing for several times, room temperature in vacuo dried overnight, obtains white solid powder γ-MAPS23.8015g, bonded amount 15.3wt%; EA analyzes: 2.33% (C), 0.00% (N), 0.44% (H); TG analyzes, and weightless 12.09%, the following accompanying drawing 3 of thermogravimetric curve illustrates.
Chiral monomer is utilized to prepare bonded chiral amino alcohol polymeric material: in 250mL three-necked bottle, 3.4886g γ-MAPS is suspended in 60mL dry toluene.Pass into nitrogen, 0.1mLEDMA, 0.7140g (2.211mmol) monomer and 22mg (0.134mmol) AIBN add in above-mentioned suspension under nitrogen protection, 80 DEG C of reaction 4h, backflow 8h, be cooled to room temperature, reaction mixture is filtered, then 50mL acetone (5 × 10mL) is used successively, 50mL methyl alcohol (5 × 10mL), 50mLEtOH (5 × 10mL) washs for several times, dried in vacuo overnight, obtains bonded chiral amino alcohol polymkeric substance 3.7070g, bonded amount 6.2wt%; EA analyzes: 4.38% (C), 0.26% (N), 0.53% (H); TG analyzes, and weightless 18.91%, the following accompanying drawing 3 of thermogravimetric curve illustrates.
Fig. 3 is the thermogravimetric curve figure of γ-MAPS, bonded chiral amino alcohol polymkeric substance: in a nitrogen environment, flow velocity 60mL/min, analyser output pressure 0.05Mpa, temperature 20 ~ 600 DEG C, the temperature rise rate of instrument is 20 DEG C/min to test condition.Temperature range is in 450 DEG C to 530 DEG C intervals, (a) is weightless, and obviously rate of weight loss reaches 12.09%, and after showing reaction, success is grafting double bond on silica gel, for next step carries out monomer-grafted laying the foundation.As can be seen from the weight-loss curve of (b), weightlessness is divided into three phases.First be that room temperature has less weightlessness to 300 DEG C, be classified as moisture and micromolecularly lose, therefore, below 300 DEG C, the structure of (a) is very stable, can be used in chiral separation experiment; Subordinate phase 300 ~ 500 DEG C, rate of weight loss is comparatively large, the polymkeric substance chain break mainly on bonded silica gel, causes most of polymeric constituent to lose and the weightlessness that produces; Be finally temperature range 500 ~ 620 DEG C, have weightlessness a little, the remaining residual organic substances being bonded to Silica Surface should be classified as and constantly lose and cause.Result shows, monomer on the successful bonding of γ-MAPS (a), can split material to carry out selective adsorption separation performance research to racemic modification as bonded chiral.
Embodiment 2
The preparation of chiral monomer: under ice-water bath cooling, by excessive SOC1
2(0.225mo1) be added drop-wise in the methyl alcohol suspension liquid of 150mLL-leucine (0.075mo1), drip off in 30min, be then transferred to stirring at room temperature reaction 24h.Revolve desolventizing, add a certain amount of methyl alcohol and be spin-dried for the hydrogenchloride that solvent eliminates generation again, obtain white needles L-Leu methyl ester hydrochloride 13.3g.At 30 DEG C, anhydrous diethyl ether 50mL is added in 100mL three-necked flask, magnesium chips (0.06mol), load onto prolong, dropping funnel, the diethyl ether solution of 2mL bromobenzene (0.06mo1) is first dripped in reaction system, add iodine initiation reaction, the diethyl ether solution of remaining bromobenzene is slowly dripped after the color disappearance i.e. reaction of iodine causes, maintain micro-the boiling of reacting balance to carry out, drip off in 15min, heating in water bath backflow 30min, grignard reaction is made to carry out completely, be chilled to room temperature for subsequent use. the Grignard reagent ice-water bath of preparation is cooled, add L-Leu methyl ester hydrochloride (15mmo1) in batches, after adding in 5min, reaction system is warming up to 30 DEG C and continues to drip saturated ammonium chloride solution in reaction 24h. ice-water bath cooling downhill reaction system, reaction is violent, reaction solution ethyl acetate and water extracting and demixing, organic phase anhydrous sodium sulfate drying spends the night, revolve desolventizing, white solid bidentate chiral amino acid derivative 1.7g is obtained with appropriate sherwood oil recrystallization.5.8mL anhydrous tetrahydro furan is added in the mono-neck bottle of 50mL, 0.625mL (4.49mmol) triethylamine, 1.0g (3.72mmol) bidentate chiral amino alcohol, then reaction system is placed in the bath of constant temperature low temperature stirring reaction, under 0 DEG C of condition, in reaction soln, slowly drip excessive acrylate chloride (0.6mL, 7.38mmol), drip off in 30min, then reaction system is transferred to stirred at ambient temperature reaction and spends the night.Revolve desolventizing, add a certain amount of water and extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying spends the night, revolve desolventizing, room temperature in vacuo dried overnight, obtain light yellow solid N-acryloyl-L-Leu-amino alcohol 1.12g, yield 93%, Rf=0.78 (petrol ether/ethyl acetate=1:1); M.p225 ~ 226 DEG C;
1described in HNMR, IR data consistent with Example 1. the preparation of methacrylic ester silica derivative thing: 10.3218g spherical silica gel (activating) is suspended in the 250mL three-necked bottle of 80mL dry toluene, in nitrogen, in reaction system, add 10mL (42.08mmol) γ-methacryloxypropyl trimethoxy silane, reaction mixture is 80 DEG C of reaction 12h under drying nitrogen.Reaction mixture is filtered, then 100mL acetone (4 × 25mL) is used successively, 100mL methyl alcohol (4 × 25mL), 100mL ethanol (4 × 25mL), 50mL methylene dichloride (5 × 10mL) washing for several times, room temperature in vacuo dried overnight, obtains white solid powder γ-MAPS11.90g, bonded amount 15.3wt%; EA analyzes: 2.33% (C), 0.00% (N), 0.44% (H); TG analyzes, and weightless 12.09%, the following accompanying drawing 6 of thermogravimetric curve illustrates.
Chiral monomer is utilized to prepare bonded chiral amino alcohol polymeric material: in 250mL three-necked bottle, 3.4886g γ-MAPS is suspended in 60mL dry toluene.Pass into nitrogen, 0.1mLEDMA, 0.7140g (2.211mmol) monomer and 22mg (0.134mmol) AIBN add in above-mentioned suspension under nitrogen protection, 100 DEG C of reaction 24h, be cooled to room temperature, reaction mixture is filtered, then 50mL acetone (5 × 10mL) is used successively, 50mL methyl alcohol (5 × 10mL), 50mLEtOH (5 × 10mL) washs for several times, dried in vacuo overnight, obtain bonded chiral amino alcohol polymkeric substance (c) 3.9605g, bonded amount 13.5wt%; EA analyzes: 7.25% (C), 0.51% (N), 1.03% (H); TG analyzes, and weightless 29.1%, the following accompanying drawing 6 of thermogravimetric curve illustrates.
Fig. 6 is the thermogravimetric curve figure of γ-MAPS, bonded chiral amino alcohol polymkeric substance (c): test condition in a nitrogen environment, flow velocity 60mL/min, analyser output pressure 0.05Mpa, temperature 20 ~ 600 DEG C, the temperature rise rate of instrument is 20 DEG C/min.Temperature range is in 450 DEG C to 530 DEG C intervals, (a) is weightless, and obviously rate of weight loss reaches 12.09%, and after showing reaction, success is grafting double bond on silica gel, for next step carries out monomer-grafted laying the foundation.As can be seen from the weight-loss curve of (c), weightlessness is divided into three phases.First be that room temperature has less weightlessness to 200 DEG C, be classified as moisture and micromolecularly lose, therefore, below 200 DEG C, the structure of (c) is very stable, can be used in chiral separation experiment; Subordinate phase 200 ~ 550 DEG C, rate of weight loss is comparatively large, the polymkeric substance chain break mainly on bonded silica gel, causes most of polymeric constituent to lose and the weightlessness that produces; Be finally temperature range 550 ~ 620 DEG C, have weightlessness a little, the remaining residual organic substances being bonded to Silica Surface should be classified as and constantly lose and cause.Result shows, monomer on the successful bonding of γ-MAPS (a), can split material to carry out selective adsorption separation performance research to racemic modification as bonded chiral.
The solubility property test of bonded chiral amino alcohol polymeric material of the present invention: this material does not dissolve in normal hexane/Virahol, methyl alcohol, ethanol, methylene dichloride, tetrahydrofuran (THF), chloroform, acetone, acetic acid, sherwood oil, acetone equal solvent.
The present invention also provides a kind of application to be Selective recognition absorption bonded chiral amino alcohol polymkeric substance being used for chipal compounds as fractionation material.Be that 2 ~ 1:1 feeds intake according to the mol ratio of chiral material and racemic modification, take chiral material in reaction flask, add L-type or the D type single enantiomer solution of 40mL1mg/mL, reaction system room temperature slowly stirs, then in not pipetting supernatant liquor exactly in the same time, survey its absorbancy, according to calibration curve determination concentration.Chiral material at different time to the adsorptive capacity Qt of L-type or D type single enantiomer according to formula Q
t=(C
0-C
t) V/m calculating, in formula, Q
tfor the adsorptive capacity (mg/g) of t chiral material; C
0for the starting point concentration (mg/mL) of L-type or D type single enantiomer; C
tfor the concentration (mg/mL) of t L or D type single enantiomer; V is liquor capacity (mL); M is chiral material quality (g).
1, bonded chiral amino alcohol polymkeric substance chirr polymer materials adsorption selectivity of the present invention: take chiral material 0.1g in reaction flask, add R-or the S-α-phenylethylamine enantiomorph solution of 40mL1mg/mL, reaction system room temperature slowly stirs, then in accurately not pipetting supernatant liquor in the same time, survey its absorbancy, calculate adsorptive capacity according to formula, make R/S-α-phenylethylamine ultraviolet absorption spectrum Fig. 1,4.Result shows, chiral material of the present invention shows different adsorptive poweies to R/S-α-phenylethylamine, and be more prone to absorption R-α-phenylethylamine, before absorption, the adsorptive power of 6h material increases gradually, reaches adsorption equilibrium to 8h.
2, bonded chiral amino alcohol polymeric materials adsorption selectivity of the present invention: take chiral material 0.1g in reaction flask, add L-or the D-mandelic acid enantiomer solution of 40mL1mg/mL, reaction system room temperature slowly stirs, then in not pipetting supernatant liquor exactly in the same time, survey its absorbancy, calculate adsorptive capacity according to formula, make D/L-amygdalic acid ultraviolet absorption spectrum Fig. 2,5.Result shows, chiral material of the present invention shows different adsorptive poweies to D/L-amygdalic acid, and be more prone to absorption D-amygdalic acid, before absorption, the adsorptive power of 6h material increases gradually, reaches adsorption equilibrium to 8h.
Claims (10)
1. a bonded chiral amino alcohol polymkeric substance, is characterized in that: have formula 1 structural unit:
Wherein,
R is ethyl, phenyl or aminomethyl phenyl;
for silica-gel carrier.
2. prepare the method for bonded chiral amino alcohol polymkeric substance according to claim 1, it is characterized in that: comprise the following steps:
(1) formula 2 structure L-amino acid and methyl alcohol carry out condensation reaction under thionyl chloride effect, production 3 structure L-amino acid methyl ester hydrochloride, and described L-amino acid methyl ester hydrochloride and phenyl-magnesium-bromide carry out addition reaction, obtain formula 4 structure chiral amino alcohol; Gained chiral amino alcohol and acrylate chloride carry out esterification, obtain formula 5 structure chiral monomer;
(2) carry out linked reaction by excessive γ-methacryloxypropyl trimethoxy silane and silica-gel carrier, obtain γ-methacrylic ester silica derivative thing;
(3) by (1) gained chiral monomer and (2) gained methacrylic ester silica derivative thing, under radical polymerization initiator and linking agent existence condition, initiated polymerization, to obtain final product;
Wherein, R is ethyl, phenyl or aminomethyl phenyl.
3. the method preparing bonded chiral amino alcohol polymkeric substance according to claim 2, is characterized in that:
Described condensation reaction is in ice water bath environment, is added drop-wise to by thionyl chloride in the amino acid whose methanol solution of L-, and ensures that thionyl chloride drips in 30min, then reacts 24 ~ 40h under being placed in room temperature;
Described L-amino acid and the mol ratio of thionyl chloride are 1:1.5 ~ 5.
4. the method preparing bonded chiral amino alcohol polymkeric substance according to claim 3, is characterized in that:
Described L-amino acid is L-Leu, L-phenylglycine or L-Phe.
5. the method preparing bonded chiral amino alcohol polymkeric substance according to claim 2, is characterized in that:
Described addition reaction reacts 15 ~ 24h under temperature is the condition of 25 ~ 35 DEG C;
Described L-amino acid methyl ester hydrochloride and the mol ratio of phenyl-magnesium-bromide are 1:10 ~ 30.
6. the method preparing bonded chiral amino alcohol polymkeric substance according to claim 2, is characterized in that:
Described esterification is under protective atmosphere, under 25 ~ 30 DEG C of temperature condition, react 10 ~ 24h;
Described acrylate chloride is excessive relative to chiral amino alcohol.
7. the method preparing bonded chiral amino alcohol polymkeric substance according to claim 2, is characterized in that:
Described linked reaction is under nitrogen protection, under 70 ~ 90 DEG C of temperature condition, react 8 ~ 16h.
8. the method preparing bonded chiral amino alcohol polymkeric substance according to claim 2, is characterized in that:
Described polyreaction reacts 20 ~ 24h under temperature is 80 ~ 100 DEG C of conditions;
The mass ratio of described chiral monomer and γ-methacrylic ester silica derivative thing is 1:4 ~ 5;
Described chiral monomer and the mol ratio of linking agent are 9 ~ 10:1;
Described chiral monomer and the mol ratio of initiator are 90 ~ 100:1;
Described initiator is Diisopropyl azodicarboxylate;
Described linking agent is ethylene glycol dimethacrylate.
9. the application of bonded chiral amino alcohol polymkeric substance according to claim 1, is characterized in that: be applied to chipal compounds identification or fractionation.
10. the application of bonded chiral amino alcohol polymkeric substance according to claim 9, is characterized in that: the mol ratio of bonded chiral amino alcohol polymkeric substance and chiral racemate is 2 ~ 1:1.
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| CN113441122A (en) * | 2020-03-24 | 2021-09-28 | 中国科学院大连化学物理研究所 | Chiral stationary phase of spiral polymer functionalized silica gel microsphere, preparation and application |
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| CN107880220A (en) * | 2017-11-02 | 2018-04-06 | 上海纳米技术及应用国家工程研究中心有限公司 | Synthetic method of polymerizing chiral amino acid ligand and products thereof and application |
| CN107880220B (en) * | 2017-11-02 | 2020-03-27 | 上海纳米技术及应用国家工程研究中心有限公司 | Synthetic method of polymerized chiral amino acid ligand, product and application thereof |
| CN113441122A (en) * | 2020-03-24 | 2021-09-28 | 中国科学院大连化学物理研究所 | Chiral stationary phase of spiral polymer functionalized silica gel microsphere, preparation and application |
| CN113441122B (en) * | 2020-03-24 | 2022-08-09 | 中国科学院大连化学物理研究所 | Chiral stationary phase of spiral polymer functionalized silica gel microsphere, preparation and application |
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