CN102039060B - Chiral separation chromatographic column - Google Patents
Chiral separation chromatographic column Download PDFInfo
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- CN102039060B CN102039060B CN2010105352225A CN201010535222A CN102039060B CN 102039060 B CN102039060 B CN 102039060B CN 2010105352225 A CN2010105352225 A CN 2010105352225A CN 201010535222 A CN201010535222 A CN 201010535222A CN 102039060 B CN102039060 B CN 102039060B
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- amino acid
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Abstract
The invention relates to a chiral separation chromatographic column, wherein the stationary phase of the chromatographic column adopts the compounds with the following general formula: carrier-(CH2)m-NHCO-chiral amino acid group-NH-(CH2)n-NH-chiral amino acid group-CONH-(CH2)o-carrier, wherein m is 2-12, n is 2-12, o is 2-12; the carrier is silica gel; and the chiral amino acid group is a chiral amino acid residue without H on amino and OH on carboxyl. The stationary phase obtained in the invention has stable property in organic solvent. The chiral separation chromatographic column has higher efficiency in the separation of the chiral compounds.
Description
Technical field
The present invention relates to a kind of chiral separation chromatography post, particularly a kind of chromatographic column of separating enantiomter belongs to the chipal compounds separation technology field.
Background technology
Stereoisomer is meant the molecule that the atom in the molecule differs from one another at spatial orientation, and wherein one type is enantiomter, and so-called enantiomter is a pair of molecule of mirror image each other each other.The particular arrangement that characterizes the atom of particular stereoisomer is called its optics conformation, specifically representes by known sequence rule, for example+,-(also using D, L) or (R or S).
Although just atom differs from one another at spatial orientation, the practical function of stereo-isomerism is very important.For example the physiology of chemical compound lot and pharmaceutically active have received the strong influence of its included specific conformation.Therefore, chemical compound lot only just is widely used when using with given stereoisomer form.
Object and its mirror image can not superimposed phenomenon be called chirality.Carbon atom is when forming organic molecule, and 4 atoms or group can form three-dimensional space structure through 4 covalent bonds, because atom that links to each other or group are different; It can form two kinds of molecular structures; Such with the outer object of mirror between them as if in the mirror, look corresponding each other, but their three-D space structure rotates in any case and can not overlap; Just as left hand and right hand that kind, so claim that these two kinds of molecules are chiral molecules.
Chirality is one of the mankind's natural essential attribute of depending on for existence.Chemical process in the biological phenomena is all carried out in highly asymmetric environment.Large biological molecule such as protein, polysaccharide, nucleic acid etc. all have chirality, and they cause chiral environment in vivo.Except that unexpected protein such as bacterium all are made up of left-handed L-amino acid; Sugar in polysaccharide and the nucleic acid then is the D-form of dextrorotation; Related material in the metabolism of body and regulation process like the acceptor of enzyme and cell surface, generally also all has chirality, and they cause chiral environment in vivo.Exactly because this stereochemical chirality characteristic makes the life system usually to medicine, a pair of enantiomter (optical isomer) in pesticide or the taste and smell compound shows different biological respinses.
After chiral drug gets in the organism, its pharmacological action many with it and body in chirality between the target molecule mate relevant with molecule distinguishability.Therefore contain the medicine of chirality, different enantiomters demonstrates different pharmacological actions and toxic and side effect.The enantiomter of having found a lot of chipal compounds has different physiologically actives; For example: the D-amphetamine is a kind of highly effective central nervous excitation agent; And its isomers does not almost have drug effect, and the biologically active of the L-ratios of the isomers D-isomers of general naphthalene Nore is high 100 times.Two kinds of enantiomers of some chiral drug have diverse pharmacological action, are bronchodilators like the S isomers of Tretoquinol, and the R isomers then has the pharmacological action that suppresses platelet aggregation.Some enantiomer also can cause toxic and side effect; A catastrophic example is the use of thalidomide (thalidomide, Thalidomide), and it is used as calmness and hypnotic as far back as nineteen sixty; Be used to treat gravidic bad reaction; But found afterwards that conceived early stage women took this medicine and can cause the fetus severe deformities, and this medicine is stopped using.Found that only R-(+) enantiomer Thalidomide had calmness and soporific function in 1979.And S-(-) enantiomer has teratogenesis to fetus, and this enantiomer is to calm or sleep peacefully unimportant.Therefore, if take (R)-(+) enantiomter separately, just can not produce teratogenesis, this medicine perhaps also possibly continue to use.
At present, contain one or more asymmetric centers in the nearly prescription medicine molecule more than 60%, and the overwhelming majority in this type chiral drug is in market sale with racemic form.Owing to will obtain very difficulty of two kinds of optically pure enantiomers, enantiomer of drugs pharmacologically active difference is not through research fully.In these medicines; Enantiomer a kind of maybe to patient maybe be useless or even harmful; In order accurately to understand drug effect and safe medication, FDA (Food and Drug Adminstration) (FDA) proposes new rules, must set forth clear to the physiological action of different isomerization body when requiring to declare chiral drug.
At present, obtain the chipal compounds of single enantiomer usually by following three kinds of methods: 1, chiral source synthetic method; 2, asymmetric syntheses method; 3, racemic modification Split Method.The racemic modification Split Method can specifically be divided into (1), chemical resolution method again; (2), enzyme or microbial method, (3), chromatogram Split Method.The chromatogram Split Method comprises high performance liquid chromatography, gas chromatography, thin-layered chromatography, supercritical chromatography, capillary electrophoresis and adverse current chromatogram-centrifugal partition chromatograph method.In these chromatographys, high performance liquid chromatography can not make the solute configuration change because of high temperature and lose biologically active, and the storage capacity is high, has the experiment of developing into great potential that preparation separates with the commercial scale enantiomer.The liquid chromatography chiral resolution can be divided into following three types according to its principle: 1, chiral derivation method; 2, chirality flowing phase method; 3, chiral stationary phase method.
Summary of the invention
The present invention provides a kind of chiral separation chromatography post.
For achieving the above object, the technical scheme that the present invention adopts is: a kind of chiral separation chromatography post, and the fixing of said chromatographic column is the compound that meets following general formula mutually:
Carrier-(CH
2)
m-NHCO-chiral amino acid groups-NH-(CH
2)
n-NH-chiral amino acid groups-CONH-(CH
2)
o-carrier;
Wherein, m=2～12; N=2～12; O=2～12; Said carrier is a silica gel; Said chiral amino acid groups is that the amino in the chiral amino acid loses H, carboxyl loses the group that is left behind the OH.
Related content in the technique scheme is explained as follows:
1, in the such scheme, said chiral amino acid is an a-amino acid, and alpha-carbon atom is an asymmetric carbon atom.
2, in the such scheme, said amino acid is the L-isoleucine.
Operation principle of the present invention is: the present invention is exactly the chiral chromatographic column that utilizes the chiral stationary phase method, and it is different and reach chiral separation to form the energy difference XOR stability of temporary transient diastereomer complex based on the sample and the fixing chiral selector of phase surface.
Because the technique scheme utilization, the present invention compared with prior art has advantage and effect:
1, the fixedly stable in properties in organic solvent that obtains of the present invention therefore can relative broad range ground selection flowing phase condition.Treat the resolution of racemic compound for some, when the present invention attempts to be used as flowing phase and splits, also can realize separating effectively.
2, chirality selector of the present invention and analyte have formed between attractive hydrogen bond or they and the analyte and have had attractive polar interaction.In addition, the steric interaction between analyte and chirality selector also is important.
The specific embodiment
Below in conjunction with embodiment the present invention is further described:
Embodiment one: a kind of chiral separation chromatography post
One, the preparation of chiral separation chromatography post
The first step: under the ice-water bath; The NaOH that in the three-necked bottle of the 2.0L that fills the 1.0L deionized water, adds 60g, stirring and dissolving adds the L-IleCOOH (L-isoleucine) of 196.5g again; After stirring complete dissolving; Drip the benzyloxy acyl chloride (carbobenzoxy chloride) of 255.8g and the 100ml deionized water solution (60gNaOH being dissolved in the deionized water of 100ml) of 60gNaOH simultaneously, after dropwising, stirring at room 12 hours.Ether with 500ml washs water at twice, and the aqueous phase under ice-water bath after the washing stirs fast and slowly adds concentrated hydrochloric acid down; It is acid regulating pH value, and static layering in ice-water bath is divided oil-yielding stratum; Water is used anhydrous Na with the ethyl acetate gradation extraction of 500ml after the merging organic facies
2SO
4Drying, elimination sodium sulphate, rotary evaporation is removed ethyl acetate, adds the CCl of 500ml then while hot
4, dissolving, wait cooling after, join in the benzinum of 1.0L of ice-water bath cooling, behind the standing demix, remove top supernatant liquid, following solid is used vacuum drying.
Second step: take by weighing the product that the 26.0g first step obtains and be placed in the three-necked bottle, add the ethyl acetate heated and stirred dissolving of 250ml.Ice bath adds the DCC (Dicyclohexylcarbodiimide, dicyclohexylcarbodiimide) of 23.0g down, stirs 1 hour; The back adds the triethylamine of 2.0ml; 12 diamines that take by weighing 10.0g are dissolved in the 200ml chloroform, slowly join then in the mixed liquor, and ice bath stirred 2 hours.Stirred 1.5 hours under the room temperature then, 45 ℃ were stirred 48 hours down, and 60 ℃ were stirred 3 hours down.Add 2.0ml acetic acid, stirred 1 hour.Heat filtering, crystallisation by cooling, suction filtration.Filtrating boils off partial solvent and concentrates in water-bath, crystallisation by cooling.Suction filtration.Filtrating boils off solvent, crystallisation by cooling again again in water-bath.Suction filtration.Dissolve all crystal that obtain with normal propyl alcohol cooling recrystallization, suction filtration.
The 3rd step: add 10.0g second in the three-necked bottle of 250ml and go on foot the crystal that makes, heating for dissolving is separated out after the cooling, adds a small amount of Pd/C (catalyst) with the ethanol dilution, in bottle, leads to N
2Gas is driven the air in the bottle away, feeds H instead
2Solid/liquid/gas reactions, if any separating out, heating for dissolving when not separating out after the cooling, stops reaction, and suction filtration is removed Pd/C twice, after filtrating concentrating done, adds THF (oxolane) dissolving, pours into then in the benzinum of frozen water cooling, separates out white precipitate, suction filtration.
The 4th step: the condition at logical nitrogen adds the product that the 3rd step of 2.0g makes in reaction bulb, add the oxolane that 100ml removed water then, and heating for dissolving is not separated out behind the cool to room temperature.From dropping funel, slowly drip 2.6g3-isocyano group propyl-triethoxysilicane with the oxolane dilution.Reaction is at room temperature spent the night, at nitrogen protection elimination solution.
The 5th step (1), get the 2.5g silica-gel sphere, add round-bottomed flask, add an amount of concentrated hydrochloric acid again, reflux 2 hours.The hydro-oxidation sodium solution is lowered the temperature in right amount with neutralizing acid then.
(2), filter, the washing solid is to pH=7.
(3), with proper amount of acetone flushing solid 3 times, with ether flushing solid 2～3 times, drain afterwards then.
(4), get 200mg monomer sample (the 4th step obtain sample) and in single neck bottle, add treated silica-gel sphere, add an amount of toluene again, on single neck bottle, connect water knockout drum, connect spherical condensation tube on the water knockout drum, reflux divides water about 12 hours.
(5), filter, use acetone afterwards, ether washes solid successively.
(6), drain solid.With the standard slurry packing resulting chiral stationary phase is packed in 3mm * 250mmHPLC post.
The structural formula of the fixedly phase that two, obtains is shown below:
Three, the application of chiral separation chromatography post
The 3mm that use makes * 250mmHPLC post, with efficient liquid phase process separation of racemic compound amphetamine, separative efficiency reaches 99%.
The foregoing description only is explanation technical conceive of the present invention and characteristics, and its purpose is to let the personage who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalences that spirit is done according to the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (3)
1. chiral separation chromatography post is characterized in that: said chromatographic column fixing mutually for meeting the compound of following general formula:
Carrier-(CH
2)
m-NHCO-chiral amino acid groups-NH-(CH
2)
n-NH-chiral amino acid groups-CONH-(CH
2)
o-carrier;
Wherein, m=2～12; N=2～12; O=2～12; Said carrier is a silica gel; Said chiral amino acid groups is that the amino in the chiral amino acid loses H, carboxyl loses the group that is left behind the OH.
2. chiral separation chromatography post according to claim 1 is characterized in that: said chiral amino acid is an a-amino acid, and alpha-carbon atom is an asymmetric carbon atom.
3. chiral separation chromatography post according to claim 2 is characterized in that: said chiral amino acid is the L-isoleucine.
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| CN2010105352225A CN102039060B (en) | 2010-11-09 | 2010-11-09 | Chiral separation chromatographic column |
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|---|---|---|---|
| CN2010105352225A CN102039060B (en) | 2010-11-09 | 2010-11-09 | Chiral separation chromatographic column |
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| CN102039060B true CN102039060B (en) | 2012-05-02 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102389783A (en) * | 2011-10-19 | 2012-03-28 | 苏州苏凯路化学科技有限公司 | Chiral chromatographic column and preparation method thereof |
| WO2023123194A1 (en) * | 2021-12-30 | 2023-07-06 | 浙江海正药业股份有限公司 | Analysis method for detecting chiral isomer impurities in methoprene |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1538171A (en) * | 2003-04-18 | 2004-10-20 | 中国科学院大连化学物理研究所 | Preparation method of chiral ligand exchange chromatographic stationary phase |
| CN1664576A (en) * | 2005-03-30 | 2005-09-07 | 中国科学院成都有机化学有限公司 | Stationary phase for chiral ligand exchange chromatography and method for making same |
| CN101121119A (en) * | 2007-07-06 | 2008-02-13 | 浙江大学 | Chemically bonded chiral stationary phase and its preparation method |
-
2010
- 2010-11-09 CN CN2010105352225A patent/CN102039060B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1538171A (en) * | 2003-04-18 | 2004-10-20 | 中国科学院大连化学物理研究所 | Preparation method of chiral ligand exchange chromatographic stationary phase |
| CN1664576A (en) * | 2005-03-30 | 2005-09-07 | 中国科学院成都有机化学有限公司 | Stationary phase for chiral ligand exchange chromatography and method for making same |
| CN101121119A (en) * | 2007-07-06 | 2008-02-13 | 浙江大学 | Chemically bonded chiral stationary phase and its preparation method |
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Address after: Chang Xu Road Jinchang District of Suzhou City, Jiangsu province 215008 No. 483 Investment Industrial Park 9 Building 102 room Applicant after: Suzhou Furis Biotech Co., Ltd. Address before: Chang Xu Road Jinchang District of Suzhou City, Jiangsu province 215008 No. 483 Investment Industrial Park 9 Building 102 room Applicant before: Suzhou Qingan Biotech Co., Ltd. |
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