WO2022068634A1 - 一种用于氟比洛芬分子手性结构分析的试剂及其方法 - Google Patents

一种用于氟比洛芬分子手性结构分析的试剂及其方法 Download PDF

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WO2022068634A1
WO2022068634A1 PCT/CN2021/119482 CN2021119482W WO2022068634A1 WO 2022068634 A1 WO2022068634 A1 WO 2022068634A1 CN 2021119482 W CN2021119482 W CN 2021119482W WO 2022068634 A1 WO2022068634 A1 WO 2022068634A1
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flurbiprofen
ion
cyclodextrin
ions
calcium
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French (fr)
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方向
戴新华
江游
彭涛
徐福兴
吴芳玲
古连城
余绍宁
丁传凡
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中国计量科学研究院
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
    • G01N27/622—Ion mobility spectrometry
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/38—Diluting, dispersing or mixing samples
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode

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  • the invention relates to the technical field of analysis and detection, in particular to a reagent and a method for analyzing the molecular chiral structure of flurbiprofen.
  • Drugs are one of the basic weapons for centuries to overcome diseases. Among the more than 2,000 commonly used drug molecules, nearly half of them are chiral drugs. Research and practice have shown that different chiral drug molecules often have different clinical effects, such as For chiral drugs of the same molecular composition, one enantiomer is effective and the other is ineffective or less effective; sometimes one enantiomer is therapeutic and the other is toxic to the body ; Also, different enantiomer molecules exhibit completely different therapeutic effects, etc. Therefore, whether in drug development or drug production process, analysis and understanding of various chiral enantiomers in chiral drugs Whether or how much has significant value.
  • Flurbiprofen (flurbiprofen) is a chiral drug with two enantiomers. It is currently a common drug used in clinical treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, etc. Its chemical name is ( ⁇ )-2-(2-Fluoro-4-biphenyl)-propionic acid.
  • flurbiprofen is readily soluble in methanol, ethanol, acetone or ether, soluble in acetonitrile, and practically insoluble in water. It has a melting point of 110-112°C (lit.) and a boiling point of 376°C.
  • the molecular formula of flurbiprofen is C 15 H 13 FO 2 , the molecular weight is 244.27, and its molecular structure is shown in Figure 1 .
  • Flurbiprofen is one of the most commonly used drugs. It is mainly used for rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, etc. It can also be used for soft tissue diseases (such as sprains and strains) and mild to moderate pain (such as dysmenorrhea and postoperative pain, toothache, etc.) symptomatic treatment. Its anti-inflammatory and analgesic effects are 250 times and 50 times that of aspirin, respectively, stronger than ibuprofen, and less toxic. .
  • a common analytical method for chiral drug molecules is to first separate molecules containing two or more chiral structures, that is, chiral drug resolution.
  • Commonly used separation methods are: chiral high performance liquid chromatography, chiral capillary electrophoresis, chiral gas chromatography, chiral thin layer chromatography, circular dichroism, nuclear magnetic resonance and supercritical fluid chromatography. Then, perform structural analysis on the separated molecular system containing only a single chiral structure to obtain its chiral properties, that is, it belongs to left-handed or right-handed.
  • Another method for analyzing the structure of chiral molecules is the so-called derivatization, that is, using chiral molecules with different structures and other molecules, such as different reactivity or reaction processes of chiral reagents, to produce different product molecules, and then Different reaction products were analyzed to obtain the structure and content information of the original chiral molecules.
  • the existing methods for analyzing the structure of chiral molecules must first separate or derivatize the chiral molecules before they can be analyzed.
  • Mass spectrometry is the most commonly used molecular or atomic mass analysis technology. It can quickly analyze the mass-to-charge ratio or mass information of different atoms or molecules, but for chiral molecules with exactly the same mass-to-charge ratio and molecular mass Powerless.
  • the ion mobility spectrometry technique can analyze molecules with different structures, such as isomers. Its working principle and process are: firstly generate ions of the sample to be analyzed, and then introduce these ions into the ion mobility spectrum. Mobility spectroscopy was performed under low vacuum conditions. In the ion mobility spectrum, the sample ions do directional motion under the action of the electric field, and continuously collide with the inactive working gases in the mobility spectrum, such as nitrogen, argon, etc.
  • the object of the present invention is to overcome the defects of the prior art, and provide a reagent and a method for analyzing the chiral structure of flurbiprofen molecules.
  • the technical solution for realizing the object of the present invention is: a reagent for analyzing the chiral structure of flurbiprofen molecule, the reagent comprises flurbiprofen molecule mixed with solvent, cyclodextrin and monovalent or divalent metal ionic compound, the cyclodextrin is one of gamma cyclodextrin and beta cyclodextrin, and the compound containing monovalent or divalent metal ion is a compound containing monovalent lithium ion, containing divalent calcium An ionic compound.
  • the concentration of the solvent flurbiprofen molecule is 10 -12 to 1 mol/liter
  • the concentration of the gamma cyclodextrin is 10 -12 to 1 mol/liter
  • the beta The concentration of the cyclodextrin is 10 -12 to 1 mol/liter
  • the concentration of the compound containing divalent calcium ions is 10 -12 to 1 mol/liter
  • the concentration of the compound containing monovalent lithium ions is 10 - 12 to 1 mole/liter.
  • the flurbiprofen molecule described in the above technical solution has two chiral structures of R-type and S-type.
  • the compound containing divalent calcium ions described in the above technical solution is one of salts containing calcium ions, alkalis containing calcium ions, and complexes containing calcium ions; the compound containing monovalent lithium ions is lithium ions.
  • the gamma cyclodextrin further includes derivatives of gamma cyclodextrin; and the beta cyclodextrin also includes derivatives of beta cyclodextrin.
  • the solvent described in the above technical solution is one or more of water, methanol, ethanol, and acetic acid.
  • a method for analyzing the molecular chiral structure of flurbiprofen comprising the following steps:
  • the mixture of described flurbiprofen-gamma cyclodextrin-calcium ion is a liquid state or a solid state that needs to be prepared from a liquid state according to experimental analysis.
  • the mixture of flurbiprofen-gamma cyclodextrin-lithium ion is liquid or solid prepared from liquid according to experimental analysis.
  • the mixture of flurbiprofen-beta cyclodextrin-calcium ion is liquid or solid prepared from liquid according to experimental analysis.
  • the ion source is one of an electrospray ionization ion source, a laser-assisted desorption ionization ion source, and a desorption electrospray ionization ion source;
  • the present invention has following positive effect:
  • the present invention provides a chiral analysis reagent and method for a common drug-flurbiprofen molecule. It includes: firstly prepare a solution of flurbiprofen chiral molecule samples, cyclodextrins, and compounds containing metal ions, and then use ion generating devices, such as electrospray ionization ion sources to prepare complex ions, and finally use ions that can be measured.
  • the ion mobility spectrometry instrument device of the collision cross section measures the ion mobility spectrum of the complex ions containing flurbiprofen molecules with different chirality, and the chiral structure of the flurbiprofen molecules contained in the sample can be obtained.
  • the method provided by the present invention can also obtain information on their relative contents.
  • the method for analyzing the chiral structure of the flurbiprofen molecule provided by the present invention is simple, and it is not necessary to perform pre-chiral separation or derivatization of the flurbiprofen chiral molecule, and the chemical samples used in it are easy to obtain. , cheap, non-toxic and harmless. Compared with the commonly used methods, it has many advantages.
  • Figure 1 is a schematic diagram of two chiral molecular structures of flurbiprofen molecule.
  • Figure 2 is a schematic diagram of the molecular structure of cyclodextrin.
  • Figure 3 shows the ion mobility spectrum test results of the complex ions generated by flurbiprofen molecules, ⁇ -cyclodextrin molecules and calcium ions.
  • the upper part is the mixture of R-type and S-type flurbiprofen and ⁇ -cyclodextrin
  • the lower part is the ion mobility spectrum of the complex ion generated by S-type flurbiprofen molecule and calcium ion;
  • Figure 4 shows the ion mobility spectrum test results of the complex ions generated by flurbiprofen chiral molecules, cyclodextrin and lithium ions, the upper part is the mixture of R and S-type flurbiprofen chiral molecules and three lithium ions
  • the lower part is the ion mobility spectrum of the complex ion generated by S-type flurbiprofen and ⁇ -CD and three lithium ions (3Li + );
  • Figure 5 shows the ion mobility spectrum test results of the complex ions generated by flurbiprofen chiral molecules, ⁇ -cyclodextrin and calcium ions: the upper part is the mixture of R and S-type flurbiprofen chiral molecules with ⁇ CD and The ion mobility spectrum of complex ions generated by Ca ions, the lower part is the ion mobility spectrum of complex ions generated by S-type flurbiprofen, ⁇ CD and Ca ions.
  • the experimental device used in the present invention is a commercial ion mobility spectrometry-mass spectrometry instrument.
  • the TIMS-TOFMS instrument produced by Bruke Company analyzes the chiral structure of the flurbiprofen molecule.
  • the experimental results are shown in Figures 3, 4 and 4. 5 shown. It is clear from the experimental results that flurbiprofen molecules with different chiral structures can be easily distinguished.
  • the used compound containing calcium ions can be salts containing calcium ions, such as: CaCl 2 , Ca(NO 3 ) 2 , CaSO 4 calcium halide (except F), calcium nitrate, calcium chlorate, perchloric acid Calcium, calcium bicarbonate, calcium dihydrogen phosphate, calcium gluconate, calcium hydrogen phosphate, calcium lactate, etc., it can also be an alkali containing calcium ions, such as Ca(OH) 2 , or a complex containing ions, etc. Compounds that can give Ca 2+ in aqueous solutions.
  • the compound containing lithium ions can be salts containing lithium ions, such as: LiCl, LiNO 3 , Li 2 SO 4 lithium halides (except F), etc., or can be alkalis containing lithium ions, such as LiOH It may be a compound that can give Li in an aqueous solution, such as a Li ion-containing complex.
  • the ion source can be an electrospray ionization ion source (Electrospray Ionization, ESI), or a laser-assisted desorption ionization (Matrix Assist Laser Desorption Ionization, MALDI) ion source, or can desorb electrospray ionization ions
  • ESI Electrospray Ionization
  • MALDI laser-assisted desorption ionization
  • the source (Desorption Electrospray Ionization, DESI) can also be other types of ion sources, which are not limited here.
  • the ion source can be one kind of ion source, or can be any combination of a variety of different ion sources, so that multiple ion sources can simultaneously analyze multiple samples of the same type or different samples, and achieve high-pass Highly sensitive detection.
  • the TIMS-TOFMS instrument produced by Bruke was used to test the chiral structure of the flurbiprofen molecule.
  • ESI electrospray ionization
  • the solution can be calculated according to the ion mobility spectrum intensity corresponding to a certain chiral C 15 H 13 FO 2 molecule
  • the content of such chiral flurbiprofen molecules contained in the chiral flurbiprofen molecule can be quantitatively analyzed.
  • a solution of suitable concentration can be prepared according to needs, that is, the concentration of calcium chloride (CaCl 2 ), ⁇ -cyclodextrin ( ⁇ CD) and flurbiprofen molecules in the solution can be determined according to the needs of the experiment.
  • concentration of each compound in the mixed solution may be the same or different.
  • the type and relative content of the solvent used in the solution can be prepared according to the needs, that is, it can be a mixture of acetonitrile and methanol, or a mixture of water, acetonitrile and methanol, or water, methanol, ethanol, Mixing of any two or more reagents in common reagents such as acetonitrile, propionitrile, formic acid, acetone, etc., and the ratio of each reagent in the mixed solution is not limited, which is determined according to experimental needs.
  • LiCl lithium chloride
  • ⁇ CD ⁇ -cyclodextrin
  • flurbiprofen molecule C 15 H 13 FO 2
  • methanol acetonitrile mixed solution
  • the TIMS-TOFMS instrument produced by Bruke was used to test the chiral structure of the flurbiprofen molecule.
  • the specific experimental process was as follows: The electrospray ionization (ESI) ion source of the TIMS-TOFMS instrument was used to generate sample ions, and the ESI was analyzed by mass spectrometry. various ionic products are produced.
  • ESI electrospray ionization
  • the solution can be calculated according to the ion mobility spectrum intensity corresponding to a certain chiral C 15 H 13 FO 2 molecule
  • the content of such chiral flurbiprofen molecules contained in the chiral flurbiprofen molecule can be quantitatively analyzed.
  • a solution of suitable concentration can be prepared according to needs, that is, the concentration of lithium chloride (LiCl), ⁇ -cyclodextrin ( ⁇ CD) and flurbiprofen molecules in the solution can be determined according to the experimental needs.
  • concentration of each compound in the mixed solution may be the same or different.
  • the type and relative content of the solvent used in the solution can be prepared according to the needs, that is, it can be a mixture of acetonitrile and methanol, or a mixture of water, acetonitrile and methanol, or water, methanol, ethanol, Mixing of any two or more reagents in common reagents such as acetonitrile, propionitrile, formic acid, acetone, etc., and the ratio of each reagent in the mixed solution is not limited, which is determined according to experimental needs.
  • the TIMS-TOFMS instrument produced by Bruke was used to test the chiral structure of the flurbiprofen molecule.
  • ESI electrospray ionization
  • the solution can be calculated according to the ion mobility spectrum intensity corresponding to a certain chiral C 15 H 13 FO 2 molecule
  • the content of such chiral flurbiprofen molecules contained in the chiral flurbiprofen molecule can be quantitatively analyzed.
  • a solution of suitable concentration can be prepared according to needs, that is, the concentration of calcium chloride (CaCl 2 ), ⁇ -cyclodextrin ( ⁇ CD) and flurbiprofen molecules in the solution can be determined according to the experimental needs.
  • concentration of each compound in the mixed solution may be the same or different.
  • the type and relative content of the solvent used in the solution can be prepared according to the needs, that is, it can be a mixture of acetonitrile and methanol, or a mixture of water, acetonitrile and methanol, or water, methanol, ethanol, Mixing of any two or more reagents in common reagents such as acetonitrile, propionitrile, formic acid, acetone, etc., and the ratio of each reagent in the mixed solution is not limited, which is determined according to experimental needs.

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Abstract

一种用于常见药物-氟比洛芬(Flurbiprofen)分子的手性结构分析试剂和方法。包括：首先将氟比洛芬手性分子样品、环糊精、含有金属离子的化合物配制成溶液，然后再利用离子产生装置，如电喷雾电离离子源制备复合物离子，最后利用可以测量离子碰撞截面的离子迁移谱仪器装置测量含有不同手性氟比洛芬分子的复合物离子的离子迁移谱，即可获得样品中所含有的氟比洛芬分子的手性结构。

Description

一种用于氟比洛芬分子手性结构分析的试剂及其方法 技术领域
本发明涉及分析检测技术领域，具体涉及一种用于氟比洛芬分子手性结构分析的试剂及其方法。
背景技术
药物是人类战胜疾病的基本武器之一，在目前常用的2000多种药物分子中，其中有近一半为手性药物，研究和实践表明，不同的手性药物分子往往具有不同的临床效果，如对具有同一种分子组成的手性药物，其一种对映体有效，另外一种无效或效果较小；有时一种对映体有治疗效果，而另外一种对映体则对身体有毒性；还有，不同的对映体分子表现出完全不同的治疗效果等等，因此，不论在药物研发中，还是在药物生产过程中，分析和了解手性药物中各种手性对映体的有无或多少具有重要的价值。
氟比洛芬(flurbiprofen)是一种具有二种对映体的手性药物，目前临床上用于治疗类风湿关节炎、骨关节炎、强直性脊柱炎等的常见药物，它的化学名为(±)-2-(2-氟-4-联苯基)-丙酸。中文别名：氟联苯丙酸；氟布洛芬；2-(2-氟-4-联苯)丙酸；氟苯布洛芬；苯氟布洛芬；英文名称：flurbiprofen；英文别名：Flurbiprofen；Cebutid；ANSAID；ANSIDE；2-(2-Fluorobiphenyl-4-yl)propionic Acid；
它的一些基本化学性质为，氟比洛芬在甲醇、乙醇、丙酮或***中易溶，在乙腈中溶解，在水中几乎不溶。它的熔点为110-112℃(lit.)，沸点为376℃。
氟比洛芬的分子式为C 15H 13FO 2，分子量为244.27，其分子结构如图1所示。
氟比洛芬是目前最常用的药物之一，临床上主要适用于类风湿关节炎、骨关节炎、强直性脊柱炎等，也可用于软组织病(如扭伤及劳损)以及轻中 度疼痛(如痛经和手术后疼痛、牙痛等)的对症治疗。它的抗炎作用和镇痛作用分别为阿司匹林的250倍和50倍，比布洛芬强，且毒性更低，是目前已知的丙酸类非甾体抗炎药中作用最强的一种。
目前有关手性药物分子的常用分析方法为，首先对含有二种或多种手性结构的分子进行分离，即手性药物拆分。常用的分离方法有：手性高效液相色谱法，手性毛细管电泳法，手性气相色谱法，手性薄层色谱法，圆二色谱法、核磁共振法和超临界流体色谱法等。然后再对被拆分的只含有单一手性结构的分子体系进行结构分析，获得其手性性质，即属于左旋或右旋。另外一种进行手性分子结构分析的方法即所谓的衍生化，即利用具有不同结构的手性分子与其它分子，如手性试剂的不同反应活性或反应过程，产生不同的产物分子，然后再对不同的反应产物进行分析，获得原来手性分子的结构和含量信息。总之，现有的手性分子结构分析方法都必须先对手性分子进行分离或衍生化，然后才能进行分析。
质谱分析技术是目前最常用的一种分子或原子质量分析技术，它可以快速地分析出不同原子或分子的质荷比或质量信息，但对于质荷比和分子质量完全相同的手性分子完全无能为力。离子迁移谱技术可以对具有不同结构的分子，如同分异构体进行分析，它的工作原理和过程为，首先产生待分析样品的离子，然后将这些离子引入到离子迁移谱中，一般的离子迁移谱工作在低真空条件下。在离子迁移谱中，样品离子在电场作用下做定向运动，并与迁移谱中的非活泼工作气体，如氮气，氩气等发生不断的碰撞。不同的离子由于其不同的碰撞截面而不同的迁移率而被分离。所以根据获得的被分离的离子迁移谱可以得到离子或分子结构的信息。但由于目前的离子迁移谱的分辨能力都较低，对于分子结构差别较小，或分子本身就很小，如有机小分子，小分子药物等，离子迁移谱技术仍然无法分析它们的结构差别，特别是不同的手性结构差异，如氟比洛芬分子的手性结构分析。
发明内容
本发明的目的是克服现有技术的缺陷，提供一种用于氟比洛芬分子手 性结构分析的试剂及其方法。
实现本发明目的的技术方案是：一种用于氟比洛芬分子手性结构分析的试剂，所述试剂包括混合有溶剂的氟比洛芬分子、环糊精和含有一价或二价金属离子的化合物，所述环糊精为伽马环糊精、贝塔环糊精中的一种，所述含有一价或二价金属离子的化合物为含有一价锂离子的化合物、含有二价钙离子的化合物中的一种。
上述技术方案所述试剂中，所述溶剂氟比洛芬分子的浓度为10 -12～1摩尔/升，所述伽马环糊精的浓度为10 -12～1摩尔/升，所述贝塔环糊精的浓度为10 -12～1摩尔/升，所述含有二价钙离子的化合物的浓度为10 -12～1摩尔/升，所述含有一价锂离子的化合物的浓度为10 -12～1摩尔/升。
上述技术方案所述氟比洛芬分子具有R-型和S-型二种手性结构。
上述技术方案所述含有二价钙离子的化合物为含钙离子的盐、含钙离子的碱、含钙离子的络合物中的一种；所述含有一价锂离子的化合物为含锂离子的盐、含锂离子的碱、含锂离子的络合物中的一种。
上述技术方案所述伽马环糊精还包括伽马环糊精的衍生物；所述贝塔环糊精还包括贝塔环糊精的衍生物。
上述技术方案所述溶剂为水、甲醇、乙醇、乙酸中的一种或多种。
一种用于氟比洛芬分子手性结构分析的方法，具有以下步骤：
S1，将需要进行手性结构分析的氟比洛芬分子、伽马环糊精和含有二价钙离子化合物添加溶剂后配制成氟比洛芬-伽马环糊精-钙离子的混合物；
S2，将氟比洛芬-伽马环糊精-钙离子的混合物使用离子源产生氟比洛芬-伽马环糊精-钙离子的一价正离子，即(C 15H 13FO 2-γCD-Ca 2+-H +) +，质荷比为M/e＝1524Th；
S3，测量氟比洛芬-伽马环糊精-钙离子的一价正离子的离子碰撞截面，或使用离子迁移谱的实验装置测量氟比洛芬-伽马环糊精-钙离子的一价正离子的离子迁移谱，即可获得氟比洛芬分子的手性结构信息；
S2中，所述氟比洛芬-伽马环糊精-钙离子的混合物为液态或为根据实 验分析需要从液态制备的固态。
另一种用于氟比洛芬分子手性结构分析的方法，具有以下步骤：
S1，将需要进行手性结构分析的氟比洛芬分子、伽马环糊精和含有一价锂离子化合物添加溶剂后配制成氟比洛芬-伽马环糊精-锂离子的混合物；
S2，将氟比洛芬-伽马环糊精-锂离子的混合物使用离子源产生氟比洛芬-伽马环糊精-锂离子的二价正离子，即(C 15H 13FO 2-γCD-3Li +-H +) 2+，质荷比为M/e＝781Th；
S3，测量氟比洛芬-伽马环糊精-锂离子的二价正离子的离子碰撞截面，或使用离子迁移谱的实验装置测量氟比洛芬-伽马环糊精-锂离子的二价正离子的离子迁移谱，即可获得氟比洛芬分子的手性结构信息；
S2中，所述氟比洛芬-伽马环糊精-锂离子的混合物为液态或为根据实验分析需要从液态制备的固态。
另一种用于氟比洛芬分子手性结构分析的方法，具有以下步骤：
S1，将需要进行手性结构分析的氟比洛芬分子、贝塔环糊精和含有二价钙离子化合物添加溶剂后配制成氟比洛芬-贝塔环糊精-钙离子的混合物；
S2，将氟比洛芬-贝塔环糊精-钙离子的混合物使用离子源产生氟比洛芬-贝塔环糊精-钙离子的一价正离子，即(C 15H 13FO 2-βCD-Ca 2+-H +) +，质荷比为M/e＝1419Th；
S3，测量氟比洛芬-贝塔环糊精-钙离子的一价正离子的离子碰撞截面，或使用离子迁移谱的实验装置测量氟比洛芬-贝塔环糊精-钙离子的一价正离子的离子迁移谱，即可获得氟比洛芬分子的手性结构信息；
S2中，所述氟比洛芬-贝塔环糊精-钙离子的混合物为液态或为根据实验分析需要从液态制备的固态。
上述技术方案S1中，所述离子源为电喷雾电离离子源、激光辅助脱附电离离子源和解吸电喷雾电离离子源中的一种；S3中，所述实验装置为离子迁移谱、包含离子迁移谱的复合型实验装置中的一种。
采用上述技术方案后，本发明具有以下积极的效果：
本发明给出了一种用于常见药物-氟比洛芬(Flurbiprofen)分子的手性分析试剂和方法。包括：首先将氟比洛芬手性分子样品、环糊精、含有金属离子的化合物配制成溶液，然后再利用离子产生装置，如电喷雾电离离子源制备的复合物离子，最后利用可以测量离子碰撞截面的离子迁移谱仪器装置测量含有不同手性氟比洛芬分子的的复合物离子的离子迁移谱，即可获得样品中所含有的氟比洛芬分子的手性结构。更进一步，若样品中同时含有左旋和右旋的氟比洛芬分子，本发明给出的方法还可获得它们相对含量的信息。
很显然，本发明所给出的氟比洛芬分子的手性结构分析方法简单，无需对氟比洛芬手性分子进行预先的手性拆分或衍生化，其所用的化学样品很容易获得，价格便宜，无毒无害。相比与目前常用的方法具有很多优点。
附图说明
为了使本发明的内容更容易被清楚地理解，下面根据具体实施例并结合附图，对本发明作进一步详细的说明，其中
图1为氟比洛芬分子二种手性分子结构示意图。
图2为环糊精分子结构示意图。
图3为氟比洛芬分子与γ-环糊精分子和钙离子所生成的复合物离子的离子迁移谱测试结果，上半部分为R型和S型氟比洛芬混合物与γ-环糊精分子和钙离子所生成的复合物离子的离子迁移谱，下半部分为S型氟比洛芬分子和钙离子所生成的复合物离子的离子迁移谱；
图4为氟比洛芬手性分子与环糊精和锂离子所生成的复合物离子的离子迁移谱测试结果，上半部分为R和S型氟比洛芬手性分子混合物和三个锂离子(3Li +)生成的复合物离子的离子迁移谱，下半部分为S型氟比洛芬与β-CD和三个锂离子(3Li +)生成的复合物离子的离子迁移谱；
图5为氟比洛芬手性分子与β环糊精和钙离子所生成的复合物离子的离子迁移谱测试结果：上半部分为R和S型氟比洛芬手性分子混合物与βCD和Ca离子生成的复合物离子的离子迁移谱，下半部分为S型氟比洛芬 与βCD和Ca离子生成的复合物离子的离子迁移谱。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。通常在此处附图中描述和示出的本发明实施例的组件可以以各种不同的配置来布置和设计。
本发明使用的实验装置为商用的离子迁移谱-质谱联用仪器，由Bruke公司生产的TIMS-TOFMS仪器分析了氟比洛芬分子的手性结构，其实验结果如图3、图4、图5所示。从实验结果可以很清楚地看到，具有不同手性结构的氟比洛芬分子可以被很容易地区分开。
本发明中，所用的含钙离子的化合物可以是含钙离子的盐，如：CaCl 2、Ca(NO 3) 2、CaSO 4卤化钙(F除外)、硝酸钙、氯酸钙、高氯酸钙、碳酸氢钙、磷酸二氢钙，萄糖酸钙、磷酸氢钙、乳酸钙等，也可以是含钙离子的碱，如Ca(OH) 2,也可以是含离子的络合物等在含水溶液中可以给出Ca 2+的化合物。
本发明中，所用的含锂离子的化合物可以是含锂离子的盐，如：LiCl、LiNO 3、Li 2SO 4卤化锂(F除外)等等，也可以是含锂离子的碱，如LiOH也可以是含Li离子的络合物等在含水溶液中可以给出Li的化合物。
本发明中，所述离子源，可以是电喷雾电离离子源(Electrospray Ionization,ESI)，也可以是激光辅助脱附电离(Matrix Assistant Laser Desorption Ionization,MALDI)离子源，也可以解吸电喷雾电离离子源(Desorption Electrospray Ionization,DESI),也可以是其它类型的离子源，在此不多做限制。
本发明中，所述离子源，可以是一种离子源，也可以是多种不同离子源的任意排列组合，实现多个离子源对多个同类样品或者对不同样品进行同时分析，实现高通量高灵敏检测。
实施例1
首先，分别称取适量的氯化钙(CaCl 2)，γ-环糊精(γCD)样品，利用甲醇/水(CH 3OH:H 2O＝1：1)或乙腈/水的混合溶液(CH 3CN:H 2O＝1：1)溶液分别配制成浓度为10毫摩尔/每升(10mmol/L)的氯化钙(CaCl 2)，β-环糊精的母液；称取适量的氟比洛芬分子，利用甲醇：乙腈混合溶液(CH 3OH:CH 3CN＝1：1)配制成浓度为10毫摩尔/每升(10mmol/L)的氟比洛芬的母液，然后各取氯化钙(CaCl 2)，γ-环糊精和氟比洛芬的母液100μL溶液到样品管中，最后，加入甲醇：水(1：1)溶液并稀释到10 -4至10 -6mol/L。然后利用Bruke生产的TIMS-TOFMS仪器分别进行测试氟比洛芬分子的手性结构，其具体实验过程为，利用TIMS-TOFMS仪器的电喷雾电离(ESI)离子源产生样品离子，并质谱分析ESI所产生的各种离子产物。然后进一步利用此仪器分析(C 15H 13FO 2-γCD-Ca 2+-H +) +离子(m/e＝1524Th)的离子迁移谱(如图3所示)，由于(R-C 15H 13FO 2-γCD-Ca 2+-H +) +和(S-C 15H 13FO 2-γCD-Ca 2+-H +) +离子具有不同的碰撞截面，因此具有不同的离子迁移率(如图3所示)，通过对比分析，我们获得被分析C 15H 13FO 2分子的手性结构，即它是R-型还是S-型。同时由于所获得的质谱信号强度和离子迁移谱信号强度都与溶液中样品的浓度有关，因此，根据对应于某种手性C 15H 13FO 2分子的离子迁移谱强度，即可推算出溶液中所含此种手性氟比洛芬分子的含量，即实现定量分析。
在实验过程中，可以根据需要配制适合浓度的溶液，即溶液中氯化钙(CaCl 2)，γ-环糊精(γCD)和氟比洛芬分子的浓度可以根据实验需要而决定。此外，每种化合物在混合溶液中的浓度可以相同，也可以不同。
在实验过程中，可以根据需要配制溶液所用的溶剂种类和相对含量，即可以是乙腈和甲醇的混合，也可以是水与乙腈，甲醇三种试剂的混合，也可以是水，甲醇，乙醇，乙腈，丙腈，甲酸，丙酮等常用试剂中任何二种或多种试剂的混合，且各种试剂在混合溶液中的比例不受限制，根据实验需要决定。
实施例2
首先，分别称取适量的氯化锂(LiCl)，γ-环糊精(γCD)样品和氟比洛芬分子(C 15H 13FO 2)样品，利用甲醇/水(CH 3OH:H 2O＝1:1)或乙腈/水的混合溶液(CH 3CN:H 2O＝1：1)溶液分别配制成浓度为10毫摩尔/每升(10mmol/L)的氯化锂(LiCl)，β-环糊精的母液；称取适量的氟比洛芬分子，利用甲醇：乙腈混合溶液(CH 3OH:CH 3CN＝1:1)配制成浓度为10毫摩尔/每升(10mmol/L)的氟比洛芬的母液，然后各取氯化锂(LiCl)，γ-环糊精和氟比洛芬的母液100μL溶液到样品管中，最后，加入甲醇：水(1:1)溶液并稀释到10 -4至10 -6mol/L。然后利用Bruke生产的TIMS-TOFMS仪器分别进行测试氟比洛芬分子的手性结构，其具体实验过程为，利用TIMS-TOFMS仪器的电喷雾电离(ESI)离子源产生样品离子，并质谱分析ESI所产生的各种离子产物。然后进一步利用此仪器分析(C 15H 13FO 2-γCD-3Li +-H +) 2+离子(m/e＝781Th)的离子迁移谱(如图3所示)，由于(R-C 15H 13FO 2-γCD-3Li +-H +) 2+和(S-C 15H 13FO 2-γCD-3Li +-H +) 2+离子具有不同的碰撞截面，因此具有不同的离子迁移率(如图3所示)，通过对比分析，我们获得被分析C 15H 13FO 2分子的手性结构，即它是R-型还是S-型。同时由于所获得的质谱信号强度和离子迁移谱信号强度都与溶液中样品的浓度有关，因此，根据对应于某种手性C 15H 13FO 2分子的离子迁移谱强度，即可推算出溶液中所含此种手性氟比洛芬分子的含量，即实现定量分析。
在实验过程中，可以根据需要配制适合浓度的溶液，即溶液中氯化锂(LiCl)，γ-环糊精(γCD)和氟比洛芬分子的浓度可以根据实验需要而决定。此外，每种化合物在混合溶液中的浓度可以相同，也可以不同。
在实验过程中，可以根据需要配制溶液所用的溶剂种类和相对含量，即可以是乙腈和甲醇的混合，也可以是水与乙腈，甲醇三种试剂的混合，也可以是水，甲醇，乙醇，乙腈，丙腈，甲酸，丙酮等常用试剂中任何二种或多种试剂的混合，且各种试剂在混合溶液中的比例不受限制，根据实验需要决定。
实施例3
首先，分别称取适量的氯化钙(CaCl 2)，β-环糊精(βCD)样品，利用甲醇/水(CH 3OH:H 2O＝1:1)或乙腈/水的混合溶液(CH 3CN:H 2O＝1:1)溶液分别配制成浓度为10毫摩尔/每升(10mmol/L)的氯化钙(CaCl 2)，β-环糊精的母液，称取适量的氟比洛芬分子，利用甲醇：乙腈混合溶液(CH 3OH:CH 3CN＝1:1)配制成浓度为10毫摩尔/每升(10mmol/L)的氟比洛芬的母液，然后各取氯化钙(CaCl 2)，β-环糊精和氟比洛芬的母液100μL溶液到样品管中，最后，加入甲醇：水(1：1)溶液并稀释到10 -4至10 -6mol/L。然后利用Bruke生产的TIMS-TOFMS仪器分别进行测试氟比洛芬分子的手性结构，其具体实验过程为，利用TIMS-TOFMS仪器的电喷雾电离(ESI)离子源产生样品离子，并质谱分析ESI所产生的各种离子产物。然后进一步利用此仪器分析(C 15H 13FO 2-βCD-Ca 2+-H +) +离子(m/e＝1419th)的离子迁移谱(如图3所示)，由于(R-C 15H 13FO 2-βCD-Ca 2+-H +) +和(S-C 15H 13FO 2-βCD-Ca 2+-H +) +离子具有不同的碰撞截面，因此具有不同的离子迁移率(如图3所示)，通过对比分析，我们获得被分析C 15H 13FO 2分子的手性结构，即它是R-型还是S-型。同时由于所获得的质谱信号强度和离子迁移谱信号强度都与溶液中样品的浓度有关，因此，根据对应于某种手性C 15H 13FO 2分子的离子迁移谱强度，即可推算出溶液中所含此种手性氟比洛芬分子的含量，即实现定量分析。
在实验过程中，可以根据需要配制适合浓度的溶液，即溶液中氯化钙(CaCl 2)，β-环糊精(βCD)和氟比洛芬分子的浓度可以根据实验需要而决定。此外，每种化合物在混合溶液中的浓度可以相同，也可以不同。
在实验过程中，可以根据需要配制溶液所用的溶剂种类和相对含量，即可以是乙腈和甲醇的混合，也可以是水与乙腈，甲醇三种试剂的混合，也可以是水，甲醇，乙醇，乙腈，丙腈，甲酸，丙酮等常用试剂中任何二种或多种试剂的混合，且各种试剂在混合溶液中的比例不受限制，根据实验需要决定。
以上所述的具体实施例，对本发明的目的、技术方案和有益效果进行了进一步详细说明，所应理解的是，以上所述仅为本发明的具体实施例而 已，并不用于限制本发明，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种用于氟比洛芬分子手性结构分析的试剂，其特征在于：所述试剂包括混合有溶剂的氟比洛芬分子、环糊精和含有一价或二价金属离子的化合物，所述环糊精为伽马环糊精、贝塔环糊精中的一种，所述含有一价或二价金属离子的化合物为含有一价锂离子的化合物、含有二价钙离子的化合物中的一种。
  2. 根据权利要求1所述的一种用于氟比洛芬分子手性结构分析的试剂，其特征在于：所述试剂中，所述溶剂氟比洛芬分子的浓度为10 -12～1摩尔/升，所述伽马环糊精的浓度为10 -12～1摩尔/升，所述贝塔环糊精的浓度为10 -12～1摩尔/升，所述含有二价钙离子的化合物的浓度为10 -12～1摩尔/升，所述含有一价锂离子的化合物的浓度为10 -12～1摩尔/升。
  3. 根据权利要求1所述的一种用于氟比洛芬分子手性结构分析的试剂，其特征在于：所述氟比洛芬分子具有R-型和S-型二种手性结构。
  4. 根据权利要求1所述的一种用于氟比洛芬分子手性结构分析的试剂，其特征在于：所述含有二价钙离子的化合物为含钙离子的盐、含钙离子的碱、含钙离子的络合物中的一种；所述含有一价锂离子的化合物为含锂离子的盐、含锂离子的碱、含锂离子的络合物中的一种。
  5. 根据权利要求1所述的一种用于氟比洛芬分子手性结构分析的试剂，其特征在于：所述伽马环糊精还包括伽马环糊精的衍生物；所述贝塔环糊精还包括贝塔环糊精的衍生物。
  6. 根据权利要求1所述的一种用于氟比洛芬分子手性结构分析的试剂，其特征在于：所述溶剂为水、甲醇、乙醇、乙酸中的一种或多种。
  7. 一种用于氟比洛芬分子手性结构分析的方法，其特征在于，具有以下步骤：
    S1，将需要进行手性结构分析的氟比洛芬分子、伽马环糊精和含有二价钙离子化合物添加溶剂后配制成氟比洛芬-伽马环糊精-钙离子的混合物；
    S2，将氟比洛芬-伽马环糊精-钙离子的混合物使用离子源产生氟比洛芬-伽马环糊精-钙离子的一价正离子，即(C 15H 13FO 2-γCD-Ca 2+-H +) +，质荷比为M/e＝1524Th；
    S3，测量氟比洛芬-伽马环糊精-钙离子的一价正离子的离子碰撞截面，或使用离子迁移谱的实验装置测量氟比洛芬-伽马环糊精-钙离子的一价正离子的离子迁移谱，即可获得氟比洛芬分子的手性结构信息；
    S2中，所述氟比洛芬-伽马环糊精-钙离子的混合物为液态或为根据实验分析需要从液态制备的固态。
  8. 一种用于氟比洛芬分子手性结构分析的方法，其特征在于，具有以下步骤：
    S1，将需要进行手性结构分析的氟比洛芬分子、伽马环糊精和含有一价锂离子化合物添加溶剂后配制成氟比洛芬-伽马环糊精-锂离子的混合物；
    S2，将氟比洛芬-伽马环糊精-锂离子的混合物使用离子源产生氟比洛芬-伽马环糊精-锂离子的二价正离子，即(C 15H 13FO 2-γCD-3Li +-H +) 2+，质荷比为M/e＝781Th；
    S3，测量氟比洛芬-伽马环糊精-锂离子的二价正离子的离子碰撞截面，或使用离子迁移谱的实验装置测量氟比洛芬-伽马环糊精-锂离子的二价正离子的离子迁移谱，即可获得氟比洛芬分子的手性结构信息；
    S2中，所述氟比洛芬-伽马环糊精-锂离子的混合物为液态或为根据实验分析需要从液态制备的固态。
  9. 一种用于氟比洛芬分子手性结构分析的方法，其特征在于，具有以下步骤：
    S1，将需要进行手性结构分析的氟比洛芬分子、贝塔环糊精和含有二价钙离子化合物添加溶剂后配制成氟比洛芬-贝塔环糊精-钙离子的混合物；
    S2，将氟比洛芬-贝塔环糊精-钙离子的混合物使用离子源产生氟比洛芬-贝塔环糊精-钙离子的一价正离子，即(C 15H 13FO 2-βCD-Ca 2+-H +) +，质荷比 为M/e＝1419Th；
    S3，测量氟比洛芬-贝塔环糊精-钙离子的一价正离子的离子碰撞截面，或使用离子迁移谱的实验装置测量氟比洛芬-贝塔环糊精-钙离子的一价正离子的离子迁移谱，即可获得氟比洛芬分子的手性结构信息；
    S2中，所述氟比洛芬-贝塔环糊精-钙离子的混合物为液态或为根据实验分析需要从液态制备的固态。
  10. 根据权利要求7至9任一所述的一种用于氟比洛芬分子手性结构分析的方法，其特征在于：S1中，所述离子源为电喷雾电离离子源、激光辅助脱附电离离子源和解吸电喷雾电离离子源中的一种；S3中，所述实验装置为离子迁移谱、包含离子迁移谱的复合型实验装置中的一种。
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