Capillary Gas Chromatography Chiral Separation Column Based on Chiral Metal-Organic Macrocyclic Materials

Abstract

The present invention belongs to the field of chromatographic technology, and discloses a capillary gas chromatography chiral separation column based on a chiral metal-organic macrocyclic material. First, a chiral metal-organic macrocyclic material [ZnCl2L]2 was synthesized, dissolved in dichloromethane to form a solution as the stationary phase, and a gas chromatography separation column was prepared by the static column preparation method. The prepared chromatographic column exhibits excellent chiral separation performance for various types of chiral compounds including alcohols, esters, halogenated hydrocarbons, epoxides, organic carboxylic acids, amino acid derivatives, etc. The chromatographic column of the present invention is applied to the gas chromatography separation of chiral compounds, showing good separation ability and stability during the separation process, and the preparation of the stationary phase is simple and inexpensive. The research and development of chiral metal macrocycles as gas chromatography chiral stationary phases have good research significance and application prospects.

Description

Technical Field

[0001] The present invention belongs to the technical field of gas chromatography chiral separation, and relates to a gas chromatography capillary separation column, in particular to a gas chromatography chiral separation column suitable for resolving chiral compounds and using a chiral metal-organic macrocycle as a stationary phase. Background Art

[0002] Chirality refers to the phenomenon that a certain molecule or structure cannot coincide with its mirror image. Chiral molecules are ubiquitous in life. For example, most amino acids, sugars, proteins, nucleic acids, polypeptides, etc. in the human body are chiral compounds and play an important role in the metabolic process in living organisms. The enantiomers of chiral molecules have the same molecular formula and groups, but they may show huge differences in biological activities. Chiral phenomena exist in many natural products and drug molecules. Although the chemical compositions of drug enantiomers are the same, their spatial three-dimensional structures are different, which will cause different biological activities in living organisms, and these differences will affect the pharmacological activities and drug metabolisms of drugs. For chiral drugs, usually only one enantiomer exhibits good drug efficacy, and the other enantiomer may have no drug efficacy or even have side effects. In addition to the pharmaceutical industry, the demand for single enantiomer substances in the agrochemical, perfume, and food additive industries is also constantly expanding. Therefore, chiral resolution technology is crucial for the development of the entire chiral drug and human life and health. Chromatography is one of the commonly used methods for the separation and analysis of chiral substances. Gas chromatography has the characteristics of fast analysis speed and high sensitivity, and is especially suitable for the separation and analysis of volatile components. The selection of the stationary phase is of great significance for gas chromatography separation, especially in the separation of chiral compounds by gas chromatography. At present, most of the commonly used chiral stationary phases for gas chromatography are relatively complex in the synthesis process, the prepared chromatographic columns are also relatively expensive, and the analysis time is relatively long. For some chiral compounds, the resolution effect cannot be achieved. Therefore, it is of great significance to study new chiral stationary phases for gas chromatography with simple synthesis, low price, high chiral selectivity, and good repeatability.

[0003] Metal-organic macrocycles are coordination compounds with a cyclic structure formed by the self-assembly of organic ligands and central metal ions through coordination bonds. Metal-organic macrocycles have a well-defined molecular cavity structure, and metal-organic macrocycle materials with predictable shapes and sizes can be designed and prepared. So far, a large number of metal-organic macrocycles with different geometric configurations (such as triangles, squares, rectangles, rhombuses, pentagons, hexagons, etc.) have been successfully synthesized. In addition, efforts have been made to introduce functional groups with different functions into metal-organic macrocycles by different methods to obtain the required functions and applications. Metal-organic macrocycles have a cavity structure of a certain size, which allows guest molecules to enter the cavity, and have good host-guest chemical properties. They can achieve multi-site recognition of substrate molecules through hydrogen bonding, electrostatic interaction, confinement effect, etc. Therefore, they have a wide range of applications in drug delivery, sensing, catalysis, and molecular recognition. However, there has been no research report on the use of chiral metal-organic macrocycles for chiral separation in gas chromatography. Aiming at the deficiencies of current gas chromatography columns, for the first time, a chiral metal-organic macrocycle is used as a stationary phase to prepare a gas chromatography chiral separation column, which can resolve various types of chiral compounds with good separation effect, low cost, and relatively easy synthesis of the stationary phase material. Therefore, the research on chiral metal-organic macrocycle materials for gas chromatography chiral stationary phase is of great significance. Summary of the Invention

[0004] The object of the present invention is to solve the problems existing in the current gas chromatography columns. A chiral metal-organic macrocycle material is used as a gas chromatography chiral stationary phase, and the stationary phase is coated on the inner wall of a capillary tube pre-roughened by a sodium hydroxide solution through a static coating method to prepare a capillary gas chromatography column, and the chromatographic column is used to resolve chiral compounds. Various types of chiral compounds such as alcohols, esters, halogenated hydrocarbons, epoxides, organic carboxylic acids, and amino acid derivatives can be well resolved on this chromatographic column. A comparison is made with the existing commercial β-DEX 120 capillary chiral column, showing excellent chiral separation performance and separation advantages. The chromatographic column of the present invention has the advantages of good separation effect, fast analysis speed, good stability, low cost, and easy synthesis of the stationary phase.

[0005] To achieve the above object, the technical solutions adopted are as follows:

[0006] (1) Synthesis of chiral metal-organic macrocycle material: S-2-pyrrolidinemethanol reacts with isonicotinyl chloride to synthesize methyl S-(1-isonicotinylpyrrolidin-2-yl)isonicotinate (ligand L), and ligand L undergoes a coordination reaction with ZnCl2 in a molar ratio of 1:1, and the chiral metal-organic macrocycle material [ZnCl2L]2 used in the present invention is synthesized through [2+2] self-assembly.

[0007] (2) Roughening treatment of the inner wall of the capillary: To better coat the chiral metal-organic macrocyclic material on the inner wall of the quartz capillary, the inner wall of the quartz capillary was roughened with NaOH solution.

[0008] (3) Preparation of the chiral metal-organic macrocyclic gas chromatography capillary column: The chiral metal-organic macrocyclic material prepared in step (1) was dissolved in a volatile organic solvent (such as dichloromethane) to prepare a solution with a certain concentration as the stationary phase. This solution was filled into the capillary column roughened in step (2) by the static coating method, and the solvent in the column was volatilized to obtain the chiral metal-organic macrocyclic gas chromatography chiral column of the present invention.

[0009] (4) Application of the chiral column to the separation of chiral compounds: The prepared gas chromatography chiral column was connected to a gas chromatograph, and nitrogen was used as the carrier gas. Under suitable separation conditions, the separation of various types of chiral compounds such as alcohols, esters, halogenated hydrocarbons, epoxides, organic carboxylic acids, and amino acid derivatives was achieved.

[0010] The present invention has the following advantages:

[0011] 1. The gas chromatography column of the present invention can separate various types of chiral compounds (such as alcohols, esters, halogenated hydrocarbons, epoxides, organic carboxylic acids, amino acid derivatives, etc.) in gas chromatography analysis, showing excellent chiral separation performance;

[0012] 2. Compared with the existing commercial cyclodextrin derivative β-DEX 120 gas chromatography chiral column, the gas chromatography column of the present invention has significant chiral separation advantages for some chiral compounds;

[0013] 3. The chiral metal-organic macrocyclic chiral separation column used in the present invention has good separation reproducibility and stability, and the synthesis raw materials of the chiral stationary phase are inexpensive and the synthesis method is simple, which is conducive to popularization and use. Description of the Drawings

[0014] Figure 1 It is a schematic diagram of the synthesis of the chiral metal-organic macrocyclic material used in the present invention;

[0015] Figure 2 It is a thermogravimetric analysis diagram of the chiral metal-organic macrocyclic material used in the present invention;

[0016] Figure 3 It is a scanning electron microscope image of the inner wall and cross-section of the chromatographic column of the present invention;

[0017] Figure 4 It is a separation chromatogram of some chiral compounds by the chromatographic column of the present invention;

[0018] Figure 5It is a comparison chart of the chiral resolution effects of some chiral compounds using the chromatographic column of the present invention and the existing commercial β-DEX 120 (30 m × 0.25 mm i.d. × 0.25 μm film, Supelco Inc., USA) capillary chiral gas chromatographic column. Detailed implementation mode

[0019] The present invention will be further described in detail below in conjunction with the drawings and embodiments. However, the drawings and embodiments do not limit the technical solution of the present invention. All transformations made based on the teachings of the present invention fall within the protection scope of the present invention.

[0020] Example 1

[0021] (1) Synthesis of chiral metal-organic macrocyclic material:

[0022] Synthesis of ligand L: Dissolve 1.0 g (9.9 mmol) of S-2-pyrrolidinemethanol in 25 mL of dichloromethane. Under the conditions of 0 °C and nitrogen protection, add N,N-diisopropylethylamine (49.4 mmol, 8.6 mL), stir for 5 minutes, then under the condition of 0 °C, add isonicotinyl chloride hydrochloride solution (29.65 mmol, 5.28 g), continue to stir for 10 minutes, and then slowly heat the obtained mixture to room temperature and stir for 24 hours. After the reaction is completed, add a saturated solution of sodium bicarbonate (20 mL) to stop the reaction. After liquid separation, the aqueous layer is extracted 3 times with 20 mL of dichloromethane. The organic layer is washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a pale yellow product, which is ligand L.

[0023] Synthesis of chiral metal-organic macrocyclic material: Weigh 62.3 mg (0.2 mmol) of ligand L in a 50 mL round-bottom flask at room temperature, add 20 mL of tetrahydrofuran and ultrasonically dissolve for 5 minutes for standby. Separately, weigh 27 mg (0.2 mmol) of zinc chloride in a 25 mL beaker, add 20 mL of acetone and ultrasonically dissolve for 5 minutes. Then slowly drop the solution in the beaker into the ligand L solution in the round-bottom flask. After standing for several days, colorless crystals form on the inner wall of the round-bottom flask to obtain the chiral metal-organic macrocyclic material ([ZnCl2L]2).

[0024] (2) Pretreatment of quartz capillary column: Take a quartz capillary column with a length of 15 m and an inner diameter of 0.25 mm. Under nitrogen pressure, pump 1 mol / L NaOH solution into the capillary column and keep it for 2 hours, then rinse with ultrapure water and 0.1 mol / L hydrochloric acid for 1 hour respectively, and finally rinse with ultrapure water until the eluate is neutral; Connect one end of the capillary column to the injection port of the gas chromatograph and perform drying treatment at 120 °C to obtain a standby capillary column with a rough inner wall.

[0025] (3) Preparation of chiral metal-organic macrocyclic chromatographic column: Prepare a dichloromethane solution of chiral metal-organic macrocyclic material ([ZnCl2L]2) at a concentration of 3.0 mg / mL. Using the static column preparation method, fill this solution into the capillary column that has been roughened in step (2). After the solution fills the capillary column, seal one end of the capillary column and connect the other end to a vacuum pump. At the same time, place the capillary in a water bath at 36 °C to evaporate the dichloromethane solvent in the capillary. When the solvent is completely evaporated, the chiral metal-organic macrocyclic material is uniformly deposited on the inner wall of the capillary column, thus obtaining the chromatographic column of the present invention.

[0026] Example 2

[0027] Use the chiral metal-organic macrocyclic chromatographic column obtained in Example 1 to test its chiral separation effect on chiral compounds. The chromatograms of the separation are shown in Figure 4 , and the optimized chromatographic conditions and separation data results are shown in Table 1. Other chromatographic conditions: High-purity nitrogen is used as the carrier gas, the inlet temperature is 300 °C, the detector temperature is 300 °C, and the split ratio is 50:1.

[0028] From Figure 4 and Table 1, it can be seen that: The chromatographic column of the present invention has good chiral separation effects on many different types of chiral compounds, including alcohols, esters, halogenated hydrocarbons, epoxides, organic carboxylic acids, amino acid derivatives, etc.

[0029] Table 1 Chromatographic conditions and data results for the separation of some chiral compounds by the chromatographic column of the present invention

[0030]

[0031] v is the flow rate of the carrier gas (N2) in the capillary, a represents acetic anhydride derivative, b represents isopropyl trifluoroacetate derivative.

[0032] Example 3

[0033] Use the chiral metal-organic macrocyclic chromatographic column obtained in Example 1 and the existing commercial β-DEX 120 chromatographic column to conduct separation studies on some chiral compounds (such as proline derivatives, 2-iodobutane, epibromohydrin, 3-butyn-2-ol derivatives, 1,2-butanediol diacetate, 1,3-butanediol diacetate, 1-phenylpropanol acetate, threonine derivatives), and compare their chiral separation effects. The comparative separation effects are shown in Table 2, and the comparative chromatograms are as shown in Figure 5 shown.

[0034] Table 2 Comparative analysis data for the separation of some chiral compounds by the chromatographic column of the present invention and the commercial β-DEX 120 chromatographic column

[0035]

[0036] a represents isopropyl trifluoroacetate derivatives b represents acetic anhydride derivatives, - indicates not being split.

[0037] From Table 2 and Figure 5 it can be seen that: proline derivatives, 2-iodobutane, epibromohydrin, 3-butyn-2-ol derivatives were not resolved on the existing commercial β-DEX 120 capillary column, while the chromatographic column of the present invention can resolve the above chiral compounds well. In addition, the resolution effects of 1,2-butylene glycol diacetate, 1,3-butylene glycol diacetate, 1-phenylpropanol acetate, and threonine derivatives on the chromatographic column of the present invention are significantly better than those on the commercial β-DEX 120 capillary column, demonstrating the excellent chiral resolution performance of the chromatographic column of the present invention.

Claims

1. A capillary gas chromatography chiral separation column based on chiral metal-organic macrocyclic materials, characterized in that: This column uses the chiral metal-organic macrocycle [ZnCl2L]2 as the chiral stationary phase, which is applied to the resolution of chiral compounds and has excellent chiral resolution effect; The specific preparation method is as follows: Synthesis of chiral metal-organic macrocycle [ZnCl2L]2: ① Synthesis of ligand L: Using the reaction monomers with the molar ratio of S-2-pyrrolidinemethanol to isonicotinyl chloride hydrochloride being 1:3, N,N-diisopropylethylamine as the catalyst, dichloromethane as the solvent, stirring and reacting at room temperature for 24 hours, washing the organic layer with brine, drying with anhydrous sodium sulfate, filtering, and concentrating under vacuum to obtain the pale yellow product ligand L; ② Synthesis of chiral metal-organic macrocycle material: Conducting a coordination reaction between an equimolar amount of ligand L and ZnCl2, with the solvent being a mixed solution of equal volume of tetrahydrofuran and acetone. After several days, chiral metal-organic macrocycle [ZnCl2L]2 crystals can be obtained on the inner wall of the reaction vessel; Preparation of chiral metal-organic macrocycle gas chromatography separation column: Preparing a dichloromethane solution of chiral metal-organic macrocycle material [ZnCl2L]2 with a concentration of 3.0 mg / mL, removing bubbles by ultrasonic treatment, and then filling this solution into a capillary column with the inner wall roughened. The gas chromatography separation column of the present invention is prepared by the static column preparation method.

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