CN102649049B - 2,3-two-O- MOM methoxymethyl-6-O-benzyl-Beta-cyclodextrin gas chromatograph-mass spectrometer chiral stationary phase and preparation method thereof - Google Patents
2,3-two-O- MOM methoxymethyl-6-O-benzyl-Beta-cyclodextrin gas chromatograph-mass spectrometer chiral stationary phase and preparation method thereof Download PDFInfo
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- CN102649049B CN102649049B CN201110042903.2A CN201110042903A CN102649049B CN 102649049 B CN102649049 B CN 102649049B CN 201110042903 A CN201110042903 A CN 201110042903A CN 102649049 B CN102649049 B CN 102649049B
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Abstract
The invention relates to capillary gas chromatograph-mass spectrometer chiral stationary phase 2,3-two-O- MOM methoxymethyl-6-O-benzyl-Beta-cyclodextrin and a preparation method thereof. The chiral stationary phase is characterized in that MOM methoxymethyl is introduced to 2-place and 3-place of Beta-cyclodextrin molecules, and then benzyl is introduced to 6-place of Beta-cyclodextrin molecules, so as to obtain novel Beta-cyclodextrin derivatives. The novel Beta-cyclodextrin derivatives produced by the method are suitable to serve as the chiral stationary phase of capillary gas chromatograph-mass spectrometer and have a certain degree of chiral recognition capability and thus can successfully separate enantiomers of certain chiral compounds.
Description
Technical field
The present invention relates to 2,3-, bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin chiral stationary phase and preparation method thereof, belong to gas-chromatography enantiomer separation field.
Background technology
Chirality is one of the mankind's natural essential attribute of depending on for existence, and large biological molecule all has chirality feature as protein, polysaccharide, nucleic acid etc.Research discovery, has the medicine of chiral centre and the enantiomter chirality of agricultural chemicals often exists significant difference at the aspect such as biologically active, metabolic process.Therefore, obtain optically pure medicine and become the study hotspot in corresponding field.Study the each single optical siomerism body structure of chiral drug and active relation, measure in racemic modification the effectively ratio of body and invalid body, and in environment and biotransformation, effective body is monitored, all require Chiral pesticide to carry out compartment analysis.This alanysis testing is generally especially to realize with the direct separation on chromatogram chiral stationary phase by chromatogram means, and wherein Chiral GC Stationary Phase method is quick, sensitive with it, separating property is good, quantitatively accurately, with an organic solvent etc. advantage does not cause people's concern.
It is to use chiral stationary phase that capillary gas chromatography directly carries out chiral separation, and effect power by two enantiomters and chiral stationary phase is different causes different retention times, thereby is separated.Chiral stationary phase mainly comprises several classes such as chiral amino acid derivative, chiral metal complex, cyclodextrine derivatives.At present, in gas chromatography chiral Separation Research, with fastest developing speed, most widely used chiral stationary phase is various types of cyclodextrine derivatives.This class chiral stationary phase generally obtains by replacing various group at different the position of substitution of cyclodextrin molecular, and cyclodextrins chiral is fixing is divided into several classes such as alpha-cyclodextrin derivative, beta-cyclodextrin derivative, gamma-cyclodextrin derivative according to D-glucopyranose unit number difference contained in cyclodextrin molecular.Wherein the general structure of the most widely used beta-cyclodextrin derivative is as follows:
Wherein, R
1, R
2, R
3can be identical substituting group, can be also different substituting groups.
This class chiral stationary phase is current use amount maximum, the fixing phase of capillary gas chromatography chiral that a most widely used class is important.But, along with the appearance of increasing synthesising racemation mixture, these chiral stationary phases are also not all suitable for separating different types of racemic mixture, therefore, in the urgent need to developing the new chiral stationary phase with high separating property, can split a greater variety of racemic mixtures.
Research is found to replace different groups, its Chiral Separation Ability difference on cyclodextrin molecular.Of the present invention is to introduce methoxyl methyl in 2-position and the 3-position of beta-schardinger dextrin-molecule, introduce benzyl in 6-position, and the novel beta-cyclodextrin derivative obtaining, as the fixing phase of capillary gas chromatography chiral, for Chiral Separation, there is no at present report both at home and abroad.
Summary of the invention
Provided by the invention 2,3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin, is suitable as the fixing phase of capillary gas chromatography chiral, can separate the chipal compounds of various structures.
Described in the invention 2,3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin chiral stationary phase refers in the 2-position of beta-schardinger dextrin-molecule and 3-position introduces methoxyl methyl, and benzyl is introduced in 6-position, and the novel beta-cyclodextrin derivative making.The present invention includes described take beta-schardinger dextrin-as initiation material 2, the preparation of 3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin, and using describedly 2,3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin does the fixing enantiomer that splits mutually of capillary gas chromatography chiral.
Described in the invention 2,3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin capillary gas chromatography chiral is fixing has following structure mutually:
Wherein R
1for methoxyl methyl, there is following structure:
R
2for benzyl, there is following structure:
The present invention also provides a kind of above-mentioned 2, the preparation method of 3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin chiral stationary phase, it is characterized in that: first take dimethyl sulfoxide (DMSO) as solvent, under alkali condition, by cylite and β-CD reaction, hydrogen in substituted cyclodextrin molecule on the hydroxyl of 6-position, has synthesized 6-O-benzyl-β-CD.Then under the existence of diisopropylethylamine, 6-O-benzyl-β-CD and chloromethyl ether react in anhydrous methylene chloride, have replaced the hydrogen on the hydroxyl of 2,3-position, and have made 2,3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin.
Of the present invention 2, in the preparation method of the fixing phase of 3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin capillary gas chromatography chiral, comprise the following steps:
Beta-schardinger dextrin-molecule is reacted with cylite and make 6-O-benzyl group-beta-cyclodextrin;
6-O-benzyl group-beta-cyclodextrin is reacted with chloromethyl ether and makes 2,3-, bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin.
The present invention make 2,3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin, as the fixing phase of capillary gas chromatography chiral.Evaluate by capillary gas chromatography, result shows that prepared novel chiral is fixing and has mutually certain chiral Recognition ability, can separate multiple chipal compounds.Meanwhile, prepared novel chiral is fixing has good stability mutually, has the potentiality that are applied to daily Pharmaceutical Analysis and quality of production control.
Accompanying drawing explanation:
Fig. 1: cis-dichlor chrysanthemic acid methyl esters is at chiral stationary phase 2, the fractionation on 3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin, 100 ℃ of column temperatures
Fig. 2: trans-dichlor chrysanthemic acid methyl esters is at chiral stationary phase 2, the fractionation on 3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin, 100 ℃ of column temperatures.
Fig. 3: cis-chrysanthemumic acid methyl esters is at chiral stationary phase 2, the fractionation on 3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin, 100 ℃ of column temperatures.
Fig. 4: trans-chrysanthemumic acid methyl esters is at chiral stationary phase 2, the fractionation on 3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin, 100 ℃ of column temperatures.
Fig. 5: cis-chrysanthemumic acid ethyl ester is at chiral stationary phase 2, the fractionation on 3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin, 80 ℃ of column temperatures.
Fig. 6: trans-chrysanthemumic acid ethyl ester is at chiral stationary phase 2, the fractionation on 3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin, 80 ℃ of column temperatures.
Fig. 7: cis-time chrysanthemumic acid methyl esters is at chiral stationary phase 2, the fractionation on 3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin, 80 ℃ of column temperatures.
The specific embodiment: below by example, the present invention is specifically addressed, but is not limited to this.
The preparation of example 1:6-O-benzyl group-beta-cyclodextrin.
3g beta-schardinger dextrin-is dissolved in 60mL dimethyl sulfoxide (DMSO), adds 1.2g NaOH, after stirring at room temperature 30min, be warming up to 70 ℃ of reaction 2h, be then cooled to room temperature, drip 3.3mL cylite, after stirring at room temperature 12h, be warming up to 60 ℃ of reaction 8h.After completion of the reaction mixed liquor is poured into water, chloroform extraction three times, then uses the hydrochloric acid solution of 0.5mol/L successively, and saturated sodium bicarbonate and sodium chloride solution are washed till neutrality.Anhydrous sodium sulfate drying, rotary evaporation removes desolventizing and obtains crude product.
Example 2:2, the preparation of 3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin
0.5g 6-O-benzyl-β-CD is dissolved in 20mL anhydrous methylene chloride, adds 3.8mL diisopropylethylamine.At 5 ℃, drip 1.5mL chloromethyl ether, temperature rising reflux reaction 24h.React complete mixed liquor is poured into water, chloroform extraction three times, then uses the hydrochloric acid solution of 0.5mol/L successively, and saturated sodium bicarbonate and sodium chloride solution are washed till neutrality.Anhydrous sodium sulfate drying, rotary evaporation removes desolventizing and obtains crude product.Obtain product (column chromatography eluant, eluent is: benzinum: ethyl acetate=1: 1, v/v) through column chromatography purifying.
IR(cm
-1)：2931，1454，1362，1267，1209，1149，1032，737，701
1HNMR(600MHz，CDCl
3)：7.44-7.28(-CH
2-Ph-
H)，5.28(H1)，5.04(-C
H 2-Ph)，3.96(H
5)，4.71-4.56(CH
3-O-C
H 2O-)，3.84-3.70(H
3，H
4，H
6)，3.27-3.24(C
H 3-O-CH
2O-)，2.63(H
2)；?
13CNMR(600MHz，CDCl
3)：138.34-128.29(-CH
2-
Ph)，99.35(C
1)，99.21-96.71(-O
CH
2OCH
3)，77.37(C
2)，76.93(-
CH
2-Ph)，73.02(C
3，C
4)，71.10(C
5)，71.01(C
6)，56.18-55.26(-OCH
2O
CH
3)
Example 3:2,3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin is as the evaluation of the fixing phase of capillary gas chromatography chiral
Employing capillary gas chromatography is evaluated.By prepared 2,3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin, as chiral stationary phase, after being dissolved in respectively in carrene, adopts traditional static method, fixing phase wall is applied to the quartz capillary column wall with sodium chloride roughening, preparation chiral capillary gas chromatography chiral column.Evaluation result is in Table and figure.
Table 1 prepared 2, the result of 3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin chiral stationary phase part enantiomer sample.
Carrier gas high-purity N
2(99.99%); Vaporizer temperature: 250 ℃; Flame ionization ditector temperature: 250 ℃; Split ratio 30: 1.
Claims (1)
1. fix 2 of phase for capillary gas chromatography chiral for one kind, the preparation method of 3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin, is characterized in that, preparation process is as follows:
(1) preparation of 6-O-benzyl group-beta-cyclodextrin:
3g beta-schardinger dextrin-is dissolved in 60mL dimethyl sulfoxide (DMSO), adds 1.2g NaOH, after stirring at room temperature 30min, be warming up to 70 ℃ of reaction 2h, be then cooled to room temperature, drip 3.3mL cylite, after stirring at room temperature 12h, be warming up to 60 ℃ of reaction 8h; After completion of the reaction mixed liquor is poured into water, chloroform extraction three times, then uses the hydrochloric acid solution of 0.5mol/L successively, and saturated sodium bicarbonate and sodium chloride solution are washed till neutrality, anhydrous sodium sulfate drying, and rotary evaporation obtains crude product except desolventizing;
The preparation of (2) 2,3-, bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrins:
0.5g6-O-benzyl group-beta-cyclodextrin is dissolved in 20mL anhydrous methylene chloride, adds 3.8mL diisopropylethylamine, drip 1.5mL chloromethyl ether at 5 ℃, temperature rising reflux reaction 24h; Reacting complete is poured into water mixed liquor, chloroform extraction three times, then use successively the hydrochloric acid solution of 0.5mol/L, saturated sodium bicarbonate and sodium chloride solution are washed till neutrality, anhydrous sodium sulfate drying, and rotary evaporation removes desolventizing and obtains crude product, obtain product 2 through column chromatography purifying, 3-bis--O-methoxyl methyl-6-O-benzyl group-beta-cyclodextrin, wherein column chromatography eluant, eluent is: benzinum: ethyl acetate=1: 1, in v/v.
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