CN1660887A - Chemical bonded chirality fixed phase and preparing method - Google Patents
Chemical bonded chirality fixed phase and preparing method Download PDFInfo
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- CN1660887A CN1660887A CN 200410021198 CN200410021198A CN1660887A CN 1660887 A CN1660887 A CN 1660887A CN 200410021198 CN200410021198 CN 200410021198 CN 200410021198 A CN200410021198 A CN 200410021198A CN 1660887 A CN1660887 A CN 1660887A
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Abstract
A chemically linked chiral stationary phase used as the filler of efficient liquid-phase chromatography features that the glucopeptide-type macrocyclic antibiotic (demethylvacocin) is used as chiral selective agent, which is chemically linked to carrier. It has high chiral recognition power and stability.
Description
Technical field:
The present invention relates to use the chiral selector of a kind of novel macrocyclic antibiotic-Norvancomycin as the chemically bonded chiral stationary phase, be exactly specifically Norvancomycin to be bonded on the carrier surface, make and be suitable for the chiral separation chromatograph packing material by the method for chemical bonding.
Background technology:
Chirality is one of the mankind's natural essential attribute of depending on for existence, and biomacromolecule such as protein, polysaccharide, nucleic acid etc. have chirality entirely.Have optically active chiral material and extensively be formed in the bodies of aminal and plant, the solid of this biological three-dimensional selection and optical rotatory substance is synthetic, is the distinctive instinct of biosystem.For improving the activity of medicine, reduce toxic side effect in drug research, the mechanism of action, toxicity and the metabolism of further investigation medicine and drug manufacture, quality control all require to provide accurately, micro-, chiral determination method and optical purity medicine fast.
Solve stereochemistry problem, separating optical isomeric body with liquid phase chromatography,, cost quick and convenient owing to having not advantages of higher is subjected to extensive attention.At present, chiral chromatography still is in developmental stage, but has isolated tens classes, up to ten thousand kinds of chiral compound enantiomers, nearly head and shoulders above 100 years isolating 7000 kinds left and right sides chipal compounds.And have the development of the chiral stationary phase (CSP) of dissimilar chiral centres or chiral recognition ability, and be the field, forward position of chiral chromatography development, also be the key and the core of chiral chromatography development.
The development of CSP starts from the seventies later stage, undergoes an unusual development rapidly.A large amount of various types of CSP (as Pirkle type CSP, protein type CSP, cyclodextrin type CSP, Mierocrystalline cellulose and glycan CSP, chiral crown ether and charge transfer type CSP etc.) succeed in developing in succession, and have carried out the research of the relevant chiral recognition mechanism of action.The CSP of part type has obtained using widely in the chiral separation field as commodity selling.
Macrocyclic antibiotic class chiral stationary phase is the novel chiral stationary phase of a class, by people such as Armstrong synthetic first and use in 1994.Because this type of chiral stationary phase has very high chiral recognition ability and good stability, so at subsequently this section in the period, relevant research is more and more, has become the new research focus in chiral separation field.At present, macrocyclic antibiotic class material as the liquid chromatography chiral selector mainly contains vancomycin (vancomycin), trip wall rhzomorph (teicoplanin), Spontycine (ristocetin), because domestic still do not have this series products, so its market value is very expensive.
Norvancomycin is isolated a kind of antimicrobial substance from ten thousand-No. 23 fermented liquids of actinomycetes, it and vancomycin difference structurally is proved, its hydrochloride is put into production by North China Pharmaceutical Factory as commodity and is used for clinical [Ling Dakui, Zhou Yu, Chen Su. the structure of homemade " vancomycin " main component is differentiated. Acta Pharmaceutica Sinica, 1986,21 (3): 208].And be used for chromatographic separation as chiral selector, still there is not report at present both at home and abroad.
Summary of the invention:
The object of the present invention is to provide a kind of novel chemically bonded chiral stationary phase, can the chiral drug or the amino acid derivative of multiple structure type be separated, simultaneously, prepared stationary phase has good stability, is suitable as high performance liquid phase separation chromatograph packing material.
The invention provides a kind of chemically bonded chiral stationary phase, be suitable as high performance liquid phase separation chromatograph packing material, it is characterized in that this chiral stationary phase be with glycopeptide class macrocyclic antibiotic-Norvancomycin and derivative thereof as chiral selector, the method by chemical bonding is bonded to it on carrier to be made.
In the chemically bonded chiral stationary phase of the present invention, Norvancomycin and derivative thereof are meant Norvancomycin itself, and the phenyl isocyanate of phenyl isocyanate, replacement derive products therefrom, remove that Norvancomycin aglycone after the sugar unit etc. is derived as parent by Norvancomycin and other all materials of coming.
In the chemically bonded chiral stationary phase of the present invention, the used spacerarm of chemical bonding is meant (3-isocyanate group propyl group) triethoxyl silane, 1, the silylating reagent that chemical bondings such as 6-vulcabond hexane are used.
In the chemically bonded chiral stationary phase of the present invention, carrier is meant silica gel and other chromatographic grade filler.
In the chemically bonded chiral stationary phase of the present invention, silica gel comprises chromatographic grade sphere and amorphous silica gel.
The present invention also provides a kind of preparation method of above-mentioned chemically bonded chiral stationary phase, it is characterized in that with glycopeptide class macrocyclic antibiotic-Norvancomycin and derivative thereof as chiral selector, and the method by chemical bonding is bonded to it on carrier.
Among the preparation method of chemically bonded chiral stationary phase of the present invention, Norvancomycin and derivative thereof are meant Norvancomycin itself, and the phenyl isocyanate of phenyl isocyanate, replacement derive products therefrom, remove that Norvancomycin aglycone after the sugar unit etc. is derived as parent by Norvancomycin and other all materials of coming.
Among the preparation method of chemically bonded chiral stationary phase of the present invention, the used spacerarm of chemical bonding is meant (3-isocyanate group propyl group) triethoxyl silane, 1, the silylating reagent that chemical bondings such as 6-vulcabond hexane are used.
Among the preparation method of chemically bonded chiral stationary phase of the present invention, carrier is meant silica gel and other chromatographic grade filler.
Among the preparation method of chemically bonded chiral stationary phase of the present invention, silica gel comprises chromatographic grade sphere and amorphous silica gel.
The present invention adopts homemade norvancomycin hydrochloride first, and the method by chemical bonding after it is handled is bonded on the carrier, has made to be suitable for the high performance liquid phase chromatograph packing material.By the evaluation under different chromatogram modes, the result shows that institute's synthetic stationary phase has chiral recognition ability very widely, can separate the chiral drug or the amino acid derivative of multiple structure types such as neutral aromatic compound, acidic cpd, beta-Blocking agent.Simultaneously, prepared stationary phase has good stability, has the potentiality that are applied to daily pharmaceutical analysis and quality of production control.
Description of drawings:
Fig. 1 is the fractionation spectrogram of warfarin (Warfarin) chiral drug on the Norvancomycin chiral column;
Fig. 2 is the fractionation spectrogram of st-yrax (Benzoin) chiral drug on the Norvancomycin chiral column;
Fig. 3 is the fractionation spectrogram of st-yrax homologue (Benzoin analog) chiral drug on the Norvancomycin chiral column;
Fig. 4 is the fractionation spectrogram of Hydrex (Bendroflumethiazide) chiral drug on the Norvancomycin chiral column;
Fig. 5 is the fractionation spectrogram of praziquantel (Praziquantel) chiral drug on the Norvancomycin chiral column;
Fig. 6 is the fractionation spectrogram of indapamide (Indapamide) chiral drug on the Norvancomycin chiral column;
Fig. 7 is the fractionation spectrogram of hydroxyzine (Hydroxyzine) chiral drug on the Norvancomycin chiral column;
Fig. 8 is the fractionation spectrogram of verapamil (Verapamil) chiral drug on the Norvancomycin chiral column;
The separation spectrogram of Fig. 9 5-hydroxyl Propafenone (5-Hydroprafenone) beta-blocker class medicine on derivatize Norvancomycin bonded chiral stationary phase;
The separation spectrogram of Figure 10 Proprasylyte (Propranolol) beta-blocker class medicine on derivatize Norvancomycin bonded chiral stationary phase;
The separation spectrogram of Figure 11 terbutaline (Terbutaline) beta-blocker class medicine on derivatize Norvancomycin bonded chiral stationary phase;
The separation spectrogram of Figure 12 H-56/28 (Alprenolol) beta-blocker class medicine on derivatize Norvancomycin bonded chiral stationary phase;
The separation spectrogram of Figure 13 Zomitriptan (Zomitriptan) beta-blocker class medicine on derivatize Norvancomycin bonded chiral stationary phase;
The separation spectrogram of Fig. 14 thunder Lip river piperazine (Ranolazine) beta-blocker class medicines on derivatize Norvancomycin bonded chiral stationary phase;
The separation spectrogram of Figure 15 metoprolol (Metoprolol) beta-blocker class medicine on derivatize Norvancomycin bonded chiral stationary phase;
The separation spectrogram of Figure 16 atenolol USP 23 (Atenolol) beta-blocker class medicine on derivatize Norvancomycin bonded chiral stationary phase.
Embodiment:
Below by example the present invention is specifically addressed, but is not limited thereto.
Embodiment 1. is synthetic and the separating neutrality and alkaline drug of the Norvancomycin bonded chiral stationary phase of spacerarm with (3-isocyanate group propyl group) triethoxyl silane
(1) antibiotic pre-treatment
Get norvancomycin hydrochloride 1.0g, be dissolved in suitable quantity of water after, regulate the pH value to weakly alkaline with 1M NaOH, low temperature is placed down and is spent the night, filter, with cold water washing several times after, 60 ℃ of vacuum-drying 4～6h.
(2) the bonded chiral stationary phase is synthetic
Get the exsiccant Norvancomycin and place the 250mL three-necked round bottom flask; add the 100mL dry pyridine; stir 5min, be added dropwise to (3-isocyanate group propyl group) triethoxyl silane then, the following 70 ℃ of reaction 1h of nitrogen protection; after being chilled to room temperature; the silicon ball that adding activated through acid treatment in 70 ℃ of stirring reaction 8～12h, filters under the nitrogen protection; use pyridine, methyl alcohol, water, washing with acetone successively for several times, 60～80 ℃ of vacuum-dryings are spent the night.
(3) evaluation of bonded stationary phase
The employing high performance liquid chromatography is estimated, and chromatographic column is 200mm * 4.6mm, stainless steel column, and dress column pressure 70Mpa, homogenate is acetone-trichloromethane, displacing liquid is an ethanol.Moving phase is that methyl alcohol-TEAA damping fluid (2% triethylamine+2% acetate, pH is regulated by triethylamine or acetate)=35/65 is formed, and flow velocity is 0.8mL/min, detects wavelength 254nm.Sample concentration is 1mg/mL, and sampling volume is 2 μ L.Evaluation result sees Table 1 and Fig. 1～8.
Embodiment 2. is the Norvancomycin bonded chiral stationary phase of deriving synthetic of spacerarm and to the separation of beta-blocker class medicine with (3-isocyanate group propyl group) triethoxyl silane
(1) preparation of derivatize Norvancomycin bonding phase
After the preparation method of employing example 1 makes Norvancomycin bonded chiral stationary phase; products therefrom is placed the 250mL three-necked round bottom flask; add the 100mL dry pyridine; stir; and then adding excessive phenyl isocyanate, 110～120 ℃ of stirring reaction 2h under the nitrogen protection filter; use pyridine, methyl alcohol, water, washing with acetone successively for several times, 60～80 ℃ of vacuum-dryings are spent the night.
(2) example 1 is seen in the filling of stationary phase
(3) evaluation of bonded stationary phase
The Norvancomycin and the Norvancomycin bonding separating polar organic phase to beta-Blocking agent under the polarity organic pattern of deriving are made up of the acetonitrile and the methyl alcohol of different ratios, the organic acid (acetate) and the organic bases (ammoniacal liquor that add different ratios, diethylamine and triethylamine), sample dissolve with methanol (1mg/mL), sample size is 2 μ L, repetitive operation is three times under the same experimental conditions, and the detection wavelength is 254nm.Evaluation result sees Table 2 and Fig. 9～16.
Embodiment 3. is with 1, and 6-vulcabond hexane is Norvancomycin bonded chiral stationary phase synthetic of spacerarm and to the separation of drug enantiomer
(1) aminopropylization of silica gel
The acid-treated spherical silica gel of learning from else's experience places the 250mL three-necked round bottom flask, adds aminopropyl triethoxysilane and dry toluene then, under the nitrogen protection in 110～120 ℃ of stirring reaction 12h.With product, filter, use toluene, methyl alcohol, water, acetonitrile, water, washing with acetone successively, 60～80 ℃ of vacuum-dryings are spent the night.
(2) bonding of chiral selector
Get the aminopropyl silica gel that makes of step and place the 250mL three-necked round bottom flask, add dry toluene, be added dropwise to 1,6-vulcabond hexane, 70～80 ℃ of reaction 2h after stirring 5min.Be chilled to the room temperature after-filtration, use toluene wash 2～3 times, be transferred in the three-necked round bottom flask; and then add the pyridine that Norvancomycin (treating processes is seen example 1) and molecular sieve drying are crossed; under the nitrogen protection in 70～80 ℃ of stirring reaction 12h, be cooled to room temperature after, filter; use pyridine successively; water, methyl alcohol, acetonitrile; water, washing with acetone, 60～80 ℃ of vacuum-dryings are spent the night.
(3) example 1 is seen in the filling of stationary phase, evaluation the results are shown in Table 3.
The Norvancomycin chiral stationary phase is to the result of chiral drug resolution under table 1 different pH condition
| Compound | ????pH＝4.0 | ????pH＝5.5 | ????pH＝7.0 | ||||||
| Styrax (Benzoin) styrax similar (Benzoin analog) neodicoumarin (Warfarin bendroflumethiazide (Bendrofl iazide) praziquantel (Praziqua indapamide (Indapami hydroxyzine (Hydroxyzi Verapamil (Verapami | k 1’ 0.467 0.645 0.986 0.944 1.487 1.195 6.154 6.800 | ?α ??1.313 ?1.102 ?2.431 ?1.313 ?1.186 ?1.279 ?1.064 ?1.186 | ?Rs ?1.470 ?0.939 ?4.070 ?1.618 ?1.492 ?1.535 ?0.896 ?1.420 | ?k 1’ ??0.460 ?0.634 ?1.034 ?1.010 ?1.339 ?1.200 ?4.636 ?5.323 | ??α ????1.317 ??1.114 ??1.000 ??1.320 ??1.339 ??1.239 ??1.037 ??1.172 | ??Rs ??1.515 ??0.966 ??0 ??1.532 ??1.305 ??1.265 ??- ??1.388 | ??k 1’ ????0.444 ??0.583 ??0.352 ??1.092 ??1.267 ??1.236 ??4.149 ??6.539 | ??α ????1.322 ??1.118 ??1.940 ??1.324 ??1.219 ??1.241 ??1 ??1.141 | ?Rs ?1.496 ?0.948 ?1.810 ?1.462 ?1.428 ?1.412 ?0 ?1.412 |
Moving phase: methyl alcohol/TEAA buffering (35/65, V/V); Flow velocity: 0.8mL/min; Detect wavelength: 254nm
The separating resulting of table 2 beta-blocker class medicine on derivatize Norvancomycin bonded chiral stationary phase
| Compound C ompounds | Retention factors k 1’ | Separation factor alpha | Resolution Rs |
| 5-Hydroprafenone (5-Hydroprafenone Propranolol (Propranolol) Terbutaline (Terbutaline) alprenolol (Alprenolol) Zomitriptan (Zomitriptan) Ranolazine (Ranolazine) metoprolol (Metoprolol) atenolol (Atenolol) | ????5.260 ????5.622 ????6.698 ????4.381 ????11.36 ????3.532 ????4.126 ????2.524 | ????1.078 ????1.114 ????1.096 ????1.105 ????1.239 ????1.106 ????1.120 ????1.250 | ????1.152 ????1.549 ????1.432 ????1.456 ????2.600 ????1.000 ????1.171 ????1.160 |
Moving phase: thunder Lip river piperazine (Ranolazine) and Zomitriptan (Zomitriptan), methyl alcohol-acetate-triethylamine=100: 0.4: 0.2; Other sample, acetonitrile-methyl alcohol-acetate-triethylamine=60: 40: 0.4: 0.2; Flow velocity 1.0mL/min;
Detect wavelength: 254nm
Table 3 is with 1, and 6-vulcabond hexane is the separation knot of the Norvancomycin bonded chiral stationary phase of spacerarm to the part medicine
Really
| Compound C ompound | Retention factors k 1’ | Separation factor alpha | Resolution Rs |
| St-yrax a(Benzoin) indapamide a(Indapamide) grey hair order a(Warfarin) atenolol USP 23 b(Atenolol) Proprasylyte b(Propranolol) Zomitriptan b(Zomitriptan) 5-hydroxyl Propafenone b(5-Hydroprafenone) metoprolol b(Metoprolol) H-56/28 b(Alprenolol) | ????0.268 ????2.226 ????17.478 ????10.06 ????5.177 ????6.990 ????4.829 ????3.333 ????3.429 | ??2.534 ??1.149 ??1.401 ??2.105 ??1.821 ??1.096 ??1.043 ??1.090 ??1.108 | ????1.522 ????0.232 ????1.020 ????0.301 ????0.872 ????0.230 ????0.333 ????0.342 ????0.542 |
aMoving phase: methyl alcohol/TEAA buffering (60/40, V/V); Flow velocity: 0.8mL/min; Detect wavelength: 254nm
bMoving phase: acetonitrile-methyl alcohol-acetate-triethylamine=80: 20: 0.4: 0.2; Flow velocity 1.0mL/min; Detect wavelength: 254nm
Claims (10)
1, a kind of chemically bonded chiral stationary phase, be suitable as high performance liquid phase separation chromatograph packing material, it is characterized in that this chiral stationary phase be with glycopeptide class macrocyclic antibiotic-Norvancomycin and derivative thereof as chiral selector, the method by chemical bonding is bonded to it on carrier to be made.
2, according to the described chemically bonded chiral stationary phase of claim 1, it is characterized in that: described Norvancomycin and derivative thereof are meant Norvancomycin itself, and the phenyl isocyanate of phenyl isocyanate, replacement derive products therefrom, remove that Norvancomycin aglycone after the sugar unit etc. is derived as parent by Norvancomycin and other all materials of coming.
3, according to the described chemically bonded chiral stationary phase of claim 1, it is characterized in that: the used spacerarm of described chemical bonding is meant (3-isocyanate group propyl group) triethoxyl silane, 1, the silylating reagent that chemical bondings such as 6-vulcabond hexane are used.
4, according to the described chemically bonded chiral stationary phase of claim 1, it is characterized in that: described carrier is meant silica gel and other chromatographic grade filler.
5, according to the described chemically bonded chiral stationary phase of claim 4, it is characterized in that: described silica gel comprises chromatographic grade sphere and amorphous silica gel.
6, the preparation method of the described chemically bonded chiral stationary phase of a kind of claim 1 is characterized in that with glycopeptide class macrocyclic antibiotic-Norvancomycin and derivative thereof as chiral selector, and the method by chemical bonding is bonded to it on carrier.
7, according to the preparation method of the described chemically bonded chiral stationary phase of claim 6, it is characterized in that: described Norvancomycin and derivative thereof are meant Norvancomycin itself, and the phenyl isocyanate of phenyl isocyanate, replacement derive products therefrom, remove that Norvancomycin aglycone after the sugar unit etc. is derived as parent by Norvancomycin and other all materials of coming.
8, according to the preparation method of the described chemically bonded chiral stationary phase of claim 6, it is characterized in that: the used spacerarm of described chemical bonding is meant (3-isocyanate group propyl group) triethoxyl silane, 1, the silylating reagent that chemical bondings such as 6-vulcabond hexane are used.
9, according to the preparation method of the described chemically bonded chiral stationary phase of claim 6, it is characterized in that: described carrier is meant silica gel and other chromatographic grade filler.
10, according to the preparation method of the described chemically bonded chiral stationary phase of claim 9, it is characterized in that: described silica gel comprises chromatographic grade sphere and amorphous silica gel.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109569026A (en) * | 2018-01-11 | 2019-04-05 | 南开大学 | It prepares the chromatographic stationary phases that porous framework material is matrix and is used for chiral separation |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109569026A (en) * | 2018-01-11 | 2019-04-05 | 南开大学 | It prepares the chromatographic stationary phases that porous framework material is matrix and is used for chiral separation |
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