CN102001904A - Novel chiral separation method - Google Patents
Novel chiral separation method Download PDFInfo
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- CN102001904A CN102001904A CN2009100441022A CN200910044102A CN102001904A CN 102001904 A CN102001904 A CN 102001904A CN 2009100441022 A CN2009100441022 A CN 2009100441022A CN 200910044102 A CN200910044102 A CN 200910044102A CN 102001904 A CN102001904 A CN 102001904A
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Abstract
提供了一种新的手性萃取分离方法，用于分离芳香酸类药物对映体，构建了一种新的双相(O/W)识别手性萃取分离芳香酸类药物对映体萃取体系。在分别研究疏水性D/L-酒石酸衍生物和水溶性β-环糊精衍生物萃取剂的单相识别手性萃取性能及其规律的基础上，在水相和有机相中分别加入两个具有相反手性识别方向的选择性最高的萃取剂构成双相(O/W)识别手性萃取体系。通过研究萃取剂浓度、对映体浓度、温度、pH、溶剂等因素对分配系数和分离因子的影响，获得最佳萃取参数和基本规律。为芳香酸类药物对映体分离应用提供理论依据和技术参数。Provided a new chiral extraction and separation method for the separation of aromatic acid drug enantiomers, and constructed a new two-phase (O/W) recognition chiral extraction separation of aromatic acid drug enantiomer extraction system . On the basis of studying the single-phase recognition chiral extraction properties and rules of hydrophobic D/L-tartaric acid derivatives and water-soluble β-cyclodextrin derivatives extractants, two The most selective extractants with opposite chiral recognition directions constitute a two-phase (O/W) chiral recognition extraction system. By studying the influence of extraction agent concentration, enantiomer concentration, temperature, pH, solvent and other factors on distribution coefficient and separation factor, the optimal extraction parameters and basic rules are obtained. Provide theoretical basis and technical parameters for the application of enantiomer separation of aromatic acid drugs.
Description
Technical field
The present invention relates to a kind of separation method of chemical field, be specifically related to a kind of new chiral separation method.
Background technology
The research of chiral drug is one of popular topic of current academia.Because the pharmacological action of chiral drug is to realize by chirality coupling strict between drug enantiomer molecule and the intravital macromole; On pharmacology, the chiral drug of taking single enantiomer can reduce dosage and metabolism burden, improves the amplitude of dosage and widens purposes, to pharmacokinetics and dosage better control can be arranged; For pharmacy corporation, produce the single enantiomer chiral drug and can save resource, reduce trash discharge, reduce pollution to environment; In the commercially available medicine, except that natural drugs such as some hormones, microbiotic mainly existed with the single enantiomer form, other synthetic drugs then great majority was racemic modifications, and this brings some serious problems obviously can for treatment of diseases or otherwise application.
At present, the preparation method of single enantiomer chiral drug mainly can be divided into three major types: chiral source synthesis method, asymmetric synthesis method and racemic modification Split Method.The chiral source synthesis method will synthesize diversified target product and can run into very big difficulty, and the synthetic route step is various because the kind of natural chiral material is limited, makes the product cost very high.The chemistry asymmetric synthesis method chirality unit of will diving exactly is converted into the chirality unit, makes the stereoisomerism product that produces inequality, and the reaction of high rotary light yield is still limited in this method; Though biological asymmetric synthesis has very high selectivity, reaction medium is generally rare aqueous buffer solution, and the reaction conditions gentleness requires height, slow, the product separation difficulty of reaction to substrate, thereby also be subjected to certain restriction on using; And in the pharmacological testing stage, it is high and very consuming time to develop a method of asymmetric synthesis cost.The racemic modification Split Method is a kind of important method that obtains the single enantiomer chiral drug.According to statistics, at present nearly 65% non-natural chiral drug is that fractionation by racemic modification or intermediate product obtains.As seen the preparation Separation Research of chiral drug enantiomorph seems very necessary.
Split at drug enantiomer, crystallization process, biological Split Method, chromatography, kinetic resolution method, liquid-film method, solid embrane method, supercritical fluid extraction, chiral solvent extraction process etc. have now been developed, but still there are many deficiencies in these methods, are difficult to practical application.Chiral solvent extraction is a kind of important chiral separation method, because its separation system has certain rules, and the scope of application widens greatly than other separation method, is subjected to numerous investigators' great attention in recent years.What chiral solvent extraction was different with traditional extraction is: except that racemic modification to be split, two liquid phases that contact with each other have a chirality extraction agent that contains opticity mutually at least.In the extraction process, the chirality extraction agent relies on polarization, induce and multiple Intermolecular Forces or coordinate bond and enantiomorph formation diastereomer such as hydrogen bond, and these two diastereomers have different chemistry and physical property, have certain free energy difference.The chiral solvent extraction relies on the free energy difference-Δ (Δ G) of two diastereomers that racemic modification is separated just.Based on as long as-Δ (Δ G) is greater than 0, promptly separation factor under abundant progression, can realize both high purity separation greater than 1.Particularly chiral solvent extraction and hollow fibre membrane extraction technique being combined is used for the fractionation of racemic modification, it have separation efficiency height, throughput greatly, good separating effect, rate of recovery height, reagent consumption is few, equipment is simple, production process easily is automated and characteristics such as serialization.Therefore, the chiral solvent extraction has very wide application prospect.
The key that influences the conventional chiral solvent extracting and separating factor is the stereoselectivity of extraction agent.At present, the extraction agent of chiral solvent extraction employing mainly contains following three kinds: (1) tartaric acid derivatives extraction agent; (2) amino acid derivative extraction agent; (3) new and effective synthetic extraction agent.The extraction system of above-mentioned three kinds of extraction agents still is difficult to large-scale industrial application.With the tartaric acid derivatives is the extraction system of extraction agent, because separation factor is too little, causes hollow fiber module facility investment increase and operational difficulty in the industrial application.Be the enantiomorph that the extraction system of extraction agent only is fit to formation complex compounds such as separation energy and cupric ion with the amino acid derivative, the scope of application is little; Because extraction agent solubleness in organic phase is little, cause the separation capacity of extraction system little simultaneously.Though new and effective synthetic extraction agent extraction system separation factor is bigger, because the extraction agent price is very expensive, its industrial application is restricted.
Therefore, the new chiral solvent abstraction technique with prospects for commercial application becomes the important research direction of chiral separation.This new chiral solvent abstraction technique requires extraction agent cheap on the one hand, requires extraction system extracting and separating enantiomorph need obtain bigger separation factor on the other hand.
Summary of the invention
This project has proposed a kind of new chiral separation technology at the deficiency of conventional chiral solvent extraction---the biphase identification chiral extraction.The extraction of two-phase (O/W) identification chirality is innovated on the single-phase identification chirality extraction process basis of (only adding the chirality extraction agent in organic phase), in water and organic phase, add two kinds of chirality extraction agents respectively enantiomorph is extracted fractionation, to improve separation factor with opposite chiral recognition ability.With fragrant acids drug enantiomer serves as to split object, adopt hydrophobicity D/L-tartaric acid derivatives and water-soluble beta-cyclodextrin derivative, by two-phase identification fragrant acids drug enantiomer is extracted fractionation research, obtained a kind of new chiral separation method, for the preparation separation of fragrant acids drug enantiomer provides theoretical foundation and technical parameter.
For realizing this purpose, (((Me-β-CD) is an aqueous phase chirality extraction agent for HE-β-CD) and methyl beta-cyclodextrin for HP-β-CD), hydroxyethyl beta-cyclodextrin with the commodity hydroxypropyl in technical scheme in the present invention, with D-and L-tartrate and a series of alcohol etc. is that raw material synthetic D/L-tartrate is an organic phase chirality extraction agent, fragrant acids drug enantiomer is extracted split research.Concrete scheme is as follows:
The present invention is the synthesizing hydrophobic D/L-tartrate fatty ester and the aromatic ester chirality extraction agent of chirality extraction agent at first.Under the alcoholic acid esterification reaction conditions of routine, be parent compound with cheap D/L-tartrate, have a tartrate chirality extraction agent of different nature with the Fatty Alcohol(C12-C14 and C12-C18) of different carbon numbers and aromatic alcohol are synthetic.
By investigating the extraction ability of single-phase identification chirality extraction system extraction agent, based on k to enantiomorph
RAnd k
SSize obtains extraction agent and preferentially discerns direction; Based on the α maximum principle, determine the highest extraction agent of selectivity simultaneously; Select for use the highest extraction agent of the opposite selectivity of identification direction as the extraction agent in water and the organic phase respectively, make up two-phase (O/W) identification chirality extraction system.
The present invention has investigated factors such as pH value of solution value, solvent, concentration and temperature to the k of two-phase (O/W) identification chirality extracting and separating fragrance acids drug enantiomer and influence and the rule thereof of α, based on the α maximum principle, determine best two-phase (O/W) identification chirality extraction parameter.
The extraction ability of the single-phase extraction system extraction agent of analysis-by-synthesis, two-phase (O/W) are discerned influence factor and rule, molecular recognition mechanism and the extraction agent structure of chirality extraction, obtain the relation of structure and performance, find out its dependency and rule.On this basis, obtain two-phase (O/W) identification chirality extraction basic law.
Extraction experiments: select a kind of fragrant acids medicine racemic modification to be dissolved in the buffered soln that contains beta-cyclodextrin derivative, be made into the racemic modification aqueous solution of this medicine; D-or L-tartrate isobutyl ester are dissolved in organic solvent and are made into certain density organic phase.Get 3mL water and organic phase solution respectively and place test tube, reach the extraction partition equilibrium in 5 ℃, this drug level of water is analyzed by HPLC and is recorded; Because volume change is very little before and after the extraction, can ignore, the organic phase drug level adopts minusing to try to achieve.
Wherein the recognition capability of an enantiomorph is greater than the recognition capability to another enantiomorph to medicine for the beta-cyclodextrin derivative of two-phase (O/W) identification chirality extraction system aqueous phase, and the D-tartrate in the organic phase is just in time opposite to the identification situation of this drug enantiomer.The concentration of extraction agent is bigger to the influence of k and α, and along with the increase of aqueous pH values, partition ratio and separation factor significantly reduce.The separating power of two-phase (O/W) identification chirality extraction is bigger than the separating power of single-phase identification chirality extraction.
Description of drawings
Fig. 1 is biphase identification chiral extraction synoptic diagram of the present invention;
Fig. 2 is two-phase of the present invention (O/W) identification chirality abstraction technique route map.
Embodiment 1:
α-Cyclo hexyl mandelic acid (CHMA) racemic modification is dissolved in the 0.1mol.L that contains beta-cyclodextrin derivative
-1NaH
2PO
4/ H
3PO
4Buffered soln is made into 1mmol.L
-1The CHMA racemic modification aqueous solution; D-or L-tartrate isobutyl ester are dissolved in 1, and the 2-ethylene dichloride is made into certain density organic phase.Get 3mL water and organic phase solution respectively and place test tube, reach the extraction partition equilibrium in 5 ℃, water CHMA concentration is analyzed by HPLC and is recorded; Because volume change is very little before and after the extraction, can ignore, organic phase C HMA concentration adopts minusing to try to achieve.
The result shows, the extraction of two-phase (O/W) identification chirality has very strong chiral separation ability, hydroxypropyl, hydroxyethyl beta-cyclodextrin, methyl beta-cyclodextrin all to the recognition capability of S-α-Cyclo hexyl mandelic acid enantiomorph greater than recognition capability, wherein with the recognition capability maximum of hydroxypropyl to R-α-Cyclo hexyl mandelic acid enantiomorph; And the recognition capability of D-tartrate isobutyl ester is just opposite; In hydroxypropyl and D-tartrate isobutyl ester extraction system, after α-Cyclo hexyl mandelic acid racemic modification single extraction separates, aqueous phase S-enantiomorph e.e.% reaches 27.6%, the partition ratio of R and S enantiomorph (kR and kS) is respectively 2.44 and 0.98, and separation factor (α) reaches 2.49.Partition ratio increases and increases along with D-tartrate isobutyl ester concentration.And the variation tendency of separation factor is parabola rule, is 2: 1 o'clock at ester concentration with the cyclodextrin concentration ratio, reaches maximum value.k
RAnd k
SSignificantly reduce along with the increase of hydroxypropyl concentration; Same α is to occur maximum value at 2: 1 o'clock at the concentration of ester and hydroxypropyl concentration ratio, along with concentration continues increase and α reduces.PH distributes the influence of behavior very big to α-CHMA enantiomorph, k
R, k
SAll raise along with pH and significantly reduction with α, extraction system generally maintains slightly acidic.Two-phase (O/W) identification has stronger chirality extracting and separating ability to α-Cyclo hexyl mandelic acid racemic modification.
Embodiment 2:
Research Naproxen Base (NAP) is in 1,2 ethylene dichloride organic phase of D (L)-tartrate isobutyl ester and the distribution behavior in the hydroxypropyl water extraction system; Investigate of the influence of factors such as tartrate configuration and concentration, hydroxypropyl concentration, aqueous pH values to extraction ability.The Naproxen Base racemic modification is dissolved in the 0.1molL that contains hydroxypropyl
-1NaH
2PO
4/ H
3PO
4In the buffered soln, be made into 0.2gL
-1The racemic modification aqueous solution; D-or L-tartrate are dissolved in and are made into certain density organic phase in 1,2 ethylene dichloride.Get 3mL water and organic phase solution respectively and place test tube, reach the extraction partition equilibrium in 5 ℃, water intaking is carried out HPLC mutually and is analyzed, because volume change is very little before and after the extraction, can ignore, and organic phase NAP concentration adopts minusing to try to achieve.
The result shows, greater than the recognition capability to R-Naproxen Base enantiomorph, and the recognition capability of L-tartrate isobutyl ester is just opposite to the recognition capability of S-Naproxen Base enantiomorph for hydroxypropyl.In hydroxypropyl and L-tartrate isobutyl ester extraction system, Naproxen Base racemic modification single extraction separates the partition ratio (k of back R and S enantiomorph
RAnd k
S) being respectively 8.92 and 5.41, separation factor (α) reaches 1.65.Partition ratio is along with L-tartrate isobutyl ester concentration increases.And the variation tendency of separation factor is parabola rule, is 2: 1 o'clock at ester concentration with the cyclodextrin concentration ratio, reaches maximum value.k
RAnd k
SSignificantly reduce along with the increase of hydroxypropyl concentration; Same α is to occur maximum value at 2: 1 o'clock at the concentration of ester and hydroxypropyl concentration ratio, along with concentration continues increase and α reduces.PH distributes the influence of behavior very big to the NAP enantiomorph, k
R, k
SAll raise with α and significantly reduce, the best when taking all factors into consideration extraction system and maintaining pH=2.5 along with pH.Temperature distributes the influence of behavior very big to the Naproxen Base enantiomorph, k
R, k
SAll raise and significantly reduction with α along with temperature.In scope of experiment, k
RAlways greater than k
S, promptly α is greater than 1.In the time of 5 ℃, effect of extracting is best.Two-phase (O/W) identification has stronger chirality extracting and separating ability to the Naproxen Base racemic modification.
Embodiment 3:
Zopiclone (ZPC) racemic modification is dissolved in the 0.1molL that contains beta-cyclodextrin derivative
-1NaH
2PO
4/ H
3PO
4Buffered soln is made into 0.2gL
-1The ZPC aqueous solution; D-or L-tartrate are dissolved in 1, and the 2-ethylene dichloride is made into certain density organic phase.Get 3mL water and organic phase solution respectively and place test tube, reach the extraction partition equilibrium in 5 ℃, water ZPC concentration is analyzed by HPLC and is recorded; Because volume change is very little before and after the extraction, can ignore, organic phase ZPC concentration adopts minusing to try to achieve.
The result shows, in the extraction Zopiclone system beta-cyclodextrin derivative all to the recognition capability of R type enantiomorph greater than recognition capability to S type enantiomorph, the tartrate recognition capability is opposite.Water adopts hydroxy propyl-Beta-CD to make extraction agent, when organic phase adopts L-tartrate isobutyl ester to make extraction agent, and the fractionation best results of O/W two-phase extraction system, R-is with after the S-ZPC single extraction separates, aqueous phase k
RAnd k
SBe respectively 2.2 and 1.6, α is 1.37.(hydroxy propyl-Beta-CD) two-phase extraction the resolution of zopiclone enantiomorph splits effective than single-phase (water contains extraction agent HP-β-CD, and α is 1.20) extraction O (L-tartrate isobutyl ester)/W.The concentration of extraction agent is bigger to the influence of partition ratio k and separation factor alpha, and the organic extractant phase agent is 2: 1 with the concentration optimum chemical dosage ratio of water extraction agent; Along with the increase of water pH, partition ratio and separation factor significantly reduce.PH distributes the influence of behavior very big to the ZPC enantiomorph, k
R, k
SAll raise and raise along with pH, but thereby separation factor raise along with pH and significantly reduce, extraction system remains on weakly alkaline the best.Temperature distributes the influence of behavior very big to the Zopiclone enantiomorph, k
R, k
SAll raise and significantly reduction with α along with temperature.In scope of experiment, k
RAlways greater than k
S, promptly α is greater than 1.In the time of 5 ℃, effect of extracting is best.Two-phase (O/W) identification has stronger chirality extracting and separating ability to the Zopiclone racemic modification.
Claims (7)
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| CN116986962A (en) * | 2023-08-01 | 2023-11-03 | 华东理工大学 | Method for biphase identification extraction resolution of ofloxacin chiral drug |
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| CN104557521A (en) * | 2013-10-28 | 2015-04-29 | 湖南理工学院 | Method for separating naproxen enantiomers by adopting centrifugal extractor and carrying out multi-stage counter current extraction |
| CN116986962A (en) * | 2023-08-01 | 2023-11-03 | 华东理工大学 | Method for biphase identification extraction resolution of ofloxacin chiral drug |
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