A fluorine-containing reagent for preparing and identifying and quantitatively analyzing pharmaceutical and bioactive molecules

Abstract

The present application provides a fluorine-containing probe which can be used for identifying and quantitatively analyzing drugs and other small organic molecules. Specifically, the present application provides a fluorine-containing probe complex and a preparation method thereof, wherein the complex has a structure shown in formula II. When the reagent is used for analyzing a sample, the sample does not need to have ultraviolet absorption or crystallinity, and a large number of different chemical substances can be quickly distinguished and detected by using nuclear magnetic resonance fluorine spectrum technology. The method can also be used for qualitative and quantitative analysis of drugs, and simultaneously determining the contents of multiple species in a complex system.

Description

Technical Field

[0001] This invention belongs to the field of analytical chemistry. Specifically, this invention provides a fluorine-containing reagent for the preparation of identification and quantitative analysis of drugs and bioactive molecules. Background Technology

[0002] The quality assurance of pharmaceuticals is crucial for safe, effective, and rational drug use; therefore, implementing quality testing and tracking throughout the drug research, development, production, and use processes is essential. Similarly, the detection, quality analysis, and determination of harmful substances in food, pharmaceuticals, and cosmetics—substances containing bioactive molecules—are also of great significance because people encounter them in daily life. Therefore, developing rapid, reliable, widely applicable, and qualitative / quantitative analytical techniques for pharmaceuticals and other small organic molecules has significant research value and application prospects.

[0003] Currently, gas chromatography, liquid chromatography, ultraviolet spectroscopy, and mass spectrometry are fundamental technologies in the field of drug analysis. These methods typically require sample purification and have certain requirements regarding the properties of the sample itself, such as ultraviolet absorption. Furthermore, the selection of chromatographic separation conditions is time-consuming, making it difficult to use for rapid differentiation and detection of large numbers of samples. Ultraviolet spectroscopy is easily affected by impurities and is generally difficult to apply to the qualitative and quantitative analysis of analytes. While mass spectrometry has high sensitivity and can provide molecular mass information, structural and content information of analytes is often lost during detection. The need for complex sample pretreatment processes, susceptibility to interference, slow detection speed, and narrow applicability limit the scope of these methods. In contrast, nuclear magnetic resonance spectroscopy is a non-separation-based testing method. Because its detection relies solely on low-energy radio frequency radiation, it is non-destructive and can acquire a wide range of information (such as relaxation time, chemical shift, and signal intensity), and is currently widely used in fields such as biological mechanism research and disease diagnosis. Nuclear magnetic resonance fluorine spectroscopy has the advantages of fast detection speed, high detection sensitivity, simple spectral analysis, and quantitative analysis. Therefore, applying nuclear magnetic resonance fluorine spectroscopy to the detection of drugs and other small organic molecules may make up for the shortcomings of previous analytical detection methods. Summary of the Invention

[0004] The purpose of this invention is to provide a probe molecule that can be used to rapidly distinguish and detect drugs and other small organic molecules, applicable to the qualitative and quantitative analysis of analytes. The invention also includes methods for synthesizing the probe molecule and its precursor molecules.

[0005] In a first aspect, this invention provides a method for preparing and synthesizing fluorine-containing NMR probes. Using this method, aluminum complexes with unique complex cavities can be synthesized, and the fluorine-containing groups are located close to the analyte, enabling effective identification of drug molecules and small organic molecules containing different functional groups and structures.

[0006] In a second aspect, the present invention provides a method for distinguishing and identifying drug molecules. Different drug molecules, upon complexing with a fluorine-containing probe, will generate nuclear magnetic resonance fluorine spectrum signals with specific chemical shifts, thereby enabling qualitative analysis of drug molecules and differentiation between different drug molecules.

[0007] In a third aspect, the present invention provides a method for determining the content of drug molecules and other small organic molecules. Because the ratio of complexation has a linear relationship with concentration, a reference substance with a known concentration can be used as a standard to determine the content of a specific drug component in a sample.

[0008] In a first aspect, the present invention provides a fluorine-containing probe complex having the structure shown in Formula II: In the formula, R 1 R 2 R 3 R 4 Each group is independently selected from the group consisting of: hydrogen atom, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5-20 membered heteroaryl; wherein the heteroaryl skeleton has 1-8 heteroatoms selected from N, O or S; wherein the substitution refers to one or more hydrogen atoms on the group being substituted by a substituent selected from the group consisting of: halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy; And R 1 and R 2 At least one of them is a fluorine-containing group; L is a molecule selected from the following group: C1-C6 chain or cyclic alcohols, C1-C6 chain or cyclic ethers, C1-C6 chain or cyclic amides, C1-C6 chain or cyclic sulfoxides, C1-C6 chain or cyclic sulfones, C1-C6 chain or cyclic aldehydes, C1-C6 chain or cyclic ketones, C1-C6 chain or cyclic carboxylic acids; C1-C6 chain or cyclic amines; C5-C10 nitrogen-containing heterocycles; M is a metal selected from the following group: aluminum, gallium, indium; Unless otherwise specified, the substitution refers to the substitution of one or more hydrogen atoms on the group by a substituent selected from the group consisting of: halogens, C1-C4 alkyl groups, and C1-C4 haloalkyl groups.

[0009] In another preferred embodiment, R 1 R 2 R 3 R 4Each of the following groups is independently selected from the group consisting of: halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy.

[0010] In another preferred embodiment, the R 1 and R 2 At least one of them is a group selected from the group consisting of: fluorine atom, trifluoromethyl, trifluoromethoxy, nonafluorotert-butoxy, or a group selected from the group consisting of: C6 to C20 aryl, 5 to 20 heteroaryl, substituted by fluorine atom, trifluoromethyl, trifluoromethoxy, or nonafluorotert-butoxy.

[0011] In another preferred embodiment, the complex has the structure shown in Formula I: .

[0012] In another preferred embodiment, the compound of formula II is prepared by the following method: By adding other small molecules L that can coordinate with the metal, and replacing the tetrahydrofuran molecule with L through ligand exchange, a complex with the structure of formula II is obtained.

[0013] In another preferred embodiment, the complex has a structure selected from the group consisting of: A second aspect of the invention provides a ligand having the structure shown in Formula III: In the formula, R 1 R 2 R 3 R 4 Each group is independently selected from the group consisting of: hydrogen atom, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5-20 membered heteroaryl; wherein the heteroaryl skeleton has 1-8 heteroatoms selected from N, O or S; wherein the substitution refers to one or more hydrogen atoms on the group being substituted by a substituent selected from the group consisting of: halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy; And R 1 and R 2 At least one of them is a fluorine-containing group; Unless otherwise specified, the substitution refers to the substitution of one or more hydrogen atoms on the group by a substituent selected from the group consisting of: halogens, C1-C4 alkyl groups, and C1-C4 haloalkyl groups.

[0014] In another preferred embodiment, the ligand has a structure selected from the group consisting of: .

[0015] A third aspect of the present invention provides a method for distinguishing and identifying small organic molecules, the method comprising the steps of: (1) In an inert solvent, the organic small molecule to be tested is mixed with the complex of formula I as described in the first aspect of the present invention or the complex of formula II as described in the second aspect of the present invention to obtain a second complex; (2) The second complex is subjected to... 19 fluorine spectrum signal was obtained by fluorine NMR detection; (3) The organic small molecules to be tested are determined by the fluorine spectrum signal obtained in step (2).

[0016] A fourth aspect of the present invention provides a method for determining and quantitatively analyzing drug content, the method comprising the steps of: (1) In an inert solvent, a detection solution is obtained by mixing the drug to be tested with a complex of formula II as described in the first aspect of the present invention and an analyte of known concentration; (2) The detection solution is subjected to... 19 fluorine spectrum signal was obtained by fluorine NMR detection; (3) The concentration of the drug to be tested is determined by integral analysis using the fluorine spectrum signal obtained in step (2).

[0017] In another preferred embodiment, the organic small molecule to be tested contains structural fragments selected from the group consisting of: hydroxyl, amino, amide, carboxyl, sulfoxide, ester, ether, nitroxy, amino, oxazoline ring, aromatic group (including aromatic or heteroaromatic ring), alkene bond, and alkyne bond.

[0018] In another preferred embodiment, the inert solvent is an organic solvent, preferably selected from the group consisting of chloroform, dichloromethane, toluene, n-hexane, benzene, petroleum ether, carbon tetrachloride, acetonitrile, ethyl acetate, or other solvents.

[0019] In another preferred embodiment, the solvent may be a deuterated solvent or a non-deuterated solvent.

[0020] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0021] Figure 1This is a schematic diagram illustrating the use of the probe molecule of this application for identification and detection. Different analytes, after complexing with the fluorine-containing probe molecule, will generate a fluorine spectrum signal at a specific chemical shift. This chemical shift does not change with concentration, thereby enabling the distinguishable identification of drug molecules.

[0022] Figure 2 This is a graph showing the effect of probe molecule 1-a on the detection of different drugs individually.

[0023] Figure 3 This is a graph showing the effect of probe molecule 1-b on the detection of different drugs individually.

[0024] Figure 4 This is a graph showing the effect of probe molecule 1-c on the detection of different drugs individually.

[0025] Figure 5 This is a graph showing the effect of probe molecule 1-d on the detection of different drugs individually.

[0026] Figure 6 This is a graph showing the effect of probe molecule 1-e on the detection of different drugs individually.

[0027] Figure 7 The graph shows the effect of probe molecules 1-f on the detection of different drugs individually.

[0028] Figure 8 This is a graph showing the effect of probe molecule 1-g on the detection of different drugs individually.

[0029] Figure 9 This is a graph showing the effect of probe molecule 1-h on the detection of different drugs individually.

[0030] Figure 10 This is a graph showing the effect of probe molecule 1-h on the detection of different analytes individually.

[0031] Figure 11 This is a graph showing the effect of probe molecule 1-h on the detection of different analytes individually. Figure 12 The diagram shows the effect of probe molecule 1-a in simultaneously distinguishing and detecting multiple drugs.

[0032] Figure 13 The diagram shows the effect of probe molecule 1-b in simultaneously distinguishing and detecting multiple drugs.

[0033] Figure 14 The diagram shows the effect of probe molecule 1-c in simultaneously distinguishing and detecting multiple drugs.

[0034] Figure 15 The diagram shows the effect of probe molecule 1-a in simultaneously distinguishing and detecting multiple drugs.

[0035] Figure 16Comparative graphs showing the detection effects of probe molecule 1-a, probe molecule 1-b, and probe molecule 1-c on the same complex system.

[0036] Figure 17 This is a diagram showing the effect of probe molecule 1-a on the quantitative analysis of the drug.

[0037] Figure 18 This study aims to determine the purity of commercially available peppermint oil and peppermint ice using probe molecule 1-a.

[0038] Figure 19 The diagram shows the calculation process of the linear relationship between the integral ratio and the content.

[0039] Figure 20 This is a schematic diagram of the structure of compound I. Detailed Implementation

[0040] Through long-term and in-depth research, the inventors have prepared a reagent capable of distinguishing and identifying drugs and other small organic molecules. The reagent is mixed with the analyte for analysis. 19 fluorine NMR spectroscopy can effectively differentiate and identify drugs. By analyzing the chemical shifts in the fluorine spectrum, drugs containing functional groups such as hydroxyl, amide, carboxylic acid, sulfoxide, cyclic ether, and ester can be quickly and conveniently identified. Furthermore, by analyzing the integral of the fluorine spectrum, the content of drugs such as alcohols, amides, carboxylic acids, sulfoxides, cyclic ethers, and esters can be determined within a certain error range. Moreover, the reaction conditions for preparing this reagent are mild and the cost is low, making it very suitable for industrial, large-scale production.

[0041] the term As used herein, the term “C1-C10 alkyl” refers to a straight-chain or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

[0042] The term "C6-C30 aryl" refers to an aryl group having 6 to 20 carbon atoms, including monocyclic or polycyclic aryl groups, such as phenyl, naphthyl, or similar groups.

[0043] The term "5-20 heteroaryl" refers to a heteroaryl group having 5 to 20 ring atoms (with 1 to 8 heteroatoms selected from N, O or S on the skeleton), such as pyrrole, pyridyl, furanyl, or similar groups.

[0044] Unless otherwise specified, in this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxy, halogen, hydroxyl, carboxyl (-COOH), C1-C10 aldehyde, C2-C10 acyl, C2-C10 ester, amino, and phenyl; wherein the phenyl includes unsubstituted phenyl or substituted phenyl having 1-3 substituents selected from: halogen, C1-C10 alkyl, cyano, OH, nitro, C3-C10 cycloalkyl, C1-C10 alkoxy, and amino.

[0045] Fluorine-containing probes and their synthesis methods This invention designs and synthesizes a series of fluorine-containing probe molecules. When these probe molecules complex with analytes of different structures, they generate different fluorine spectrum signals, thereby enabling the differentiated detection of drug molecules. This method can rapidly differentiate and detect a large number of different chemical substances containing functional groups such as hydroxyl, amide, carboxylic acid, sulfoxide, cyclic ether, and ester without sample preparation or requiring the sample to have UV absorption or fluorescence. The method can also be used for the rapid determination of drug molecule structures and the simultaneous detection of multiple different drug molecules in complex systems. Due to these advantages, this method has wide applications in drug identification, quality control, content determination, and impurity detection.

[0046] The fluorine-containing detection probe molecule of the present invention has the structure shown in Formula II: In the formula, R 1 R 2 R 3 R 4 Each group is independently selected from the group consisting of: hydrogen atom, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5-20 membered heteroaryl; wherein the heteroaryl skeleton has 1-8 heteroatoms selected from N, O or S; wherein the substitution refers to one or more hydrogen atoms on the group being substituted by a substituent selected from the group consisting of: halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy; And R 1 and R 2 At least one of them is a fluorine-containing group; L is a molecule selected from the following group: C1-C6 chain or cyclic alcohols, C1-C6 chain or cyclic ethers, C1-C6 chain or cyclic amides, C1-C6 chain or cyclic sulfoxides, C1-C6 chain or cyclic sulfones, C1-C6 chain or cyclic aldehydes, C1-C6 chain or cyclic ketones, C1-C6 chain or cyclic carboxylic acids; C1-C6 chain or cyclic amines; C5-C10 nitrogen-containing heterocycles; M is a metal selected from the following group: aluminum, gallium, indium; Unless otherwise specified, the substitution refers to the substitution of one or more hydrogen atoms on the group by a substituent selected from the group consisting of: halogens, C1-C4 alkyl groups, and C1-C4 haloalkyl groups.

[0047] When the fluorine-containing NMR probe molecule of the present invention complexes with different drugs or bioactive molecules and other analytes, it will generate specific fluorine spectrum signals with different chemical shifts, thereby enabling the differentiation and identification of analytes.

[0048] The fluorine-containing probe molecule of the present invention can be synthesized via the following design route: Route 1: Route 2: Route 3: Specifically, the fluorine-containing probe molecule has the structure shown in Formula I: In the formula, R 1 R 2 R 3 R 4 The group is selected from the group consisting of: hydrogen atoms, substituted or unsubstituted C1-C4 alkyl groups, substituted or unsubstituted C1-C4 alkoxy groups, substituted or unsubstituted C6-C20 aryl groups, and substituted or unsubstituted 5-20 heteroaryl groups; wherein the heteroaryl skeleton has 1-8 heteroatoms selected from N, O, or S; wherein the substitution refers to one or more hydrogen atoms on the group being substituted by substituents selected from the group consisting of: halogens and C1-C4 haloalkyl groups; Among them, R 1 and R 2 At least one of them is a fluorine-containing group, such as a fluorine atom, trifluoromethyl, trifluoromethoxy, nonafluorotert-butoxy, or a group selected from the group substituted by a fluorine atom, trifluoromethyl, trifluoromethoxy, or nonafluorotert-butoxy: aryl groups of C6 to C20, or heteroaryl groups of 5 to 20 members.

[0049] M is a metal selected from the following group: aluminum, gallium, indium.

[0050] Unless otherwise specified, the substitution refers to the substitution of one or more hydrogen atoms on the group by a substituent selected from the group consisting of: halogens, C1-C4 alkyl groups, and C1-C4 haloalkyl groups.

[0051] For complex I, other small molecules L that can coordinate with aluminum are added, and the tetrahydrofuran molecule is replaced with L through ligand exchange, thereby obtaining a complex with the structure of formula II. L is a molecule selected from the following group: C1-C6 chain or cyclic alcohols, C1-C6 chain or cyclic ethers, C1-C6 chain or cyclic amides, C1-C6 chain or cyclic sulfoxides, C1-C6 chain or cyclic sulfones, C1-C6 chain or cyclic aldehydes, C1-C6 chain or cyclic ketones, C1-C6 chain or cyclic carboxylic acids, C1-C6 chain or cyclic amines; and C5-C10 nitrogen-containing heterocycles.

[0052] It should be understood that Formula I of the present invention can be used Figure 20 The different forms of expression shown, when used Figure 20 Both forms of writing are intended to refer to compounds of formula I.

[0053] A method for distinguishing and identifying drugs and other small organic molecules The quality of medicines directly affects their safety and efficacy, and is related to the health and safety of users. Only by effectively controlling and supervising drug quality can we ensure that drug quality is stable and uniform, meets medication requirements, and guarantees safe, effective, and rational drug use. Therefore, the ability to quickly and conveniently distinguish and identify drugs and other small organic molecules has extremely important application value.

[0054] The principle of drug differentiation and identification in this invention is as follows: The fluorine-containing probe provided by this invention is an optically pure aluminum complex with an active coordination site. One of its small molecule ligands (such as tetrahydrofuran) can dynamically exchange with the drug. When the drug coordinates with this reagent, it induces a fluorine signal with a specific chemical shift. Therefore, different drugs can be differentiated and identified based on the different signals generated by the chemical shifts. A schematic diagram of the detection principle is shown below. Figure 1 As shown.

[0055] This invention provides a rapid and convenient method for distinguishing and identifying pharmaceuticals, the method comprising: (1) In an inert solvent, the drug to be tested is mixed with the complex of formula I as described in the first aspect of the present invention in a certain proportion to obtain a second complex; (2) The second complex is subjected to... 19 F NMR was used to obtain the fluorine spectrum signal; (3) Determine the structure of the drug to be tested by the fluorine spectrum signal obtained in step (2).

[0056] pass 19 Data obtained from F NMR testing allows for the differentiation and identification of drugs simply by analyzing chemical shift values.

[0057] In another preferred embodiment, the solvent described above is an organic solvent, preferably selected from the group consisting of chloroform, dichloromethane, toluene, n-hexane, benzene, petroleum ether, carbon tetrachloride, acetonitrile, ethyl acetate, or deuterated solvents thereof.

[0058] The pharmaceutical products can be a wide variety of chemical substances with functional groups such as hydroxyl, amino, amide, nitrogen-containing heterocycle, carboxylic acid, sulfoxide, cyclic ether and ester.

[0059] In the above method, there is no limitation on the mixing ratio of fluorine-containing reagent and drug, but it is preferably 0.1~100:1 (drug: fluorine-containing reagent).

[0060] In the above method, the NMR test temperature is -78 to -80°C. o C.

[0061] This detection method does not require samples to have UV absorption or crystallinity, and can rapidly distinguish and detect a large number of different chemical substances containing functional groups such as hydroxyl, amino, amide, nitrogen-containing heterocycles, carboxylic acids, sulfoxides, cyclic ethers, and esters. This method can also be applied to the qualitative and quantitative analysis of pharmaceuticals, as well as the simultaneous determination of multiple species in complex systems.

[0062] A method for determining drug content The principle of the fluorine-containing probe for drug content determination in this invention is as follows: The fluorine-containing probe provided by this invention can complex with drugs. Because the ratio of complexation strength between the probe and analytes with different structures is fixed, and fluorine signals with different chemical shifts are generated after complexation, an analyte with a known concentration is selected as a reference, and the integral ratio between the analyte and the analyte to be tested can be analyzed to determine the ratio between the drugs, thereby calculating the drug content.

[0063] Specifically, the present invention provides a rapid and convenient method for determining drug content, the method comprising: (1) In an inert solvent, a fluorine-containing probe of Formula I as described in the first aspect of the present invention is mixed with the drug to be tested and an analyte of known concentration to obtain an NMR analysis sample; (2) Perform NMR analysis on the sample. 19 F NMR was used to obtain the fluorine spectrum signal; (3) The peaks of the fluorine spectrum obtained in step (2) are analyzed and the content of the drug to be tested can be determined by integral analysis.

[0064] In another preferred embodiment, the solvent described above is an organic solvent, preferably selected from the group consisting of chloroform, dichloromethane, toluene, n-hexane, benzene, petroleum ether, carbon tetrachloride, acetonitrile, ethyl acetate, or deuterated solvents thereof.

[0065] The drug can be a large number of different organic compounds with functional groups such as alcohols, amines, amides, nitrogen-containing heterocycles, carboxylic acids, sulfoxides, cyclic ethers, and esters.

[0066] In the above methods, there are no restrictions on the mixing ratio of fluorine-containing reagents and drugs.

[0067] In the above method, the NMR test temperature is -78 to -80°C. o C.

[0068] The main advantages of this invention are: (1) The reagent of the present invention can identify drugs efficiently and quickly, and the analysis data is simple.

[0069] (2) The reagents of the present invention are simple to prepare and easy to obtain.

[0070] (3) The method of the present invention can be widely applied to the identification and synthesis of various compounds, and has great application value in the fields of drug design and synthesis, pesticide preparation, compound analysis, and reaction mechanism research.

[0071] (4) The present invention does not require the ultraviolet absorption properties and crystallinity of the test sample.

[0072] (5) The method of the present invention can simultaneously distinguish and detect multiple drug analytes without separation and chemical derivatization.

[0073] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0074] Synthesis steps Synthesis of benzyl-protected salicylaldehyde 1.0 equivalent of salicylaldehyde 1 and 1.1 equivalent of benzyl bromide were added to a reaction flask, dissolved in acetonitrile, followed by the addition of 1.0 equivalent of cesium carbonate solid. The mixture was refluxed at 120°C for 2 hours. The reaction solution was evaporated to dryness, neutralized with 2 N hydrochloric acid, and then separated after the addition of dichloromethane. The organic phase was evaporated to dryness and purified by column chromatography to give the corresponding benzyl-protected product 2. 17.91 g, 98% yield, pale yellow solid. 1 H NMR (400 MHz, Chloroform- d ) δ 10.26 (s, 1H), 8.07 (dd, J= 7.8,1.8 Hz, 1H), 7.96 – 7.87 (m, 1H), 7.52 – 7.32 (m, 6H), 5.10 (s, 2H). 19 F NMR (400 MHz, Chloroform- d ) δ -60.54. 3.20 g of solid NaOH was added to 150 mL of a mixed solvent of water and acetonitrile. Then, 3.74 g of 4-methyl-2-bromophenol 3 was added. The mixture was cooled to 5°C, and 6.51 g of heptafluoroisopropane iodoforme was added. After stirring for 1 min, 3.70 g of solid NaHCO3 was added. After stirring for 10 min, 7.66 g of solid Na2S2O4 was added. After stirring for 2 h, the reaction was carefully quenched with 3 N hydrochloric acid. The aqueous phase was extracted three times with ethyl acetate, and the organic phase was washed once with saturated sodium chloride solution. The organic phase was dried with anhydrous sodium sulfate, evaporated to dryness, and column chromatography to give 4.85 g of the product (68% yield), as a white solid. 1 H NMR (400 MHz, Chloroform- d ) δ 7.48 (d, J = 2.1 Hz, 1H), 7.32 (s, 1H), 5.91 (s, 1H), 2.33 (s, 3H). 19 F NMR (400 MHz, Chloroform- d ) δ -74.31 (d, J = 5.3 Hz). 6.35 g of starting material 4 and 3.36 g of benzyl bromide were added to a reaction flask, dissolved in 50 mL of acetonitrile, followed by the addition of 6.42 g of solid cesium carbonate. The mixture was refluxed at 120°C for 1 hour. The reaction solution was evaporated to dryness, neutralized with 2 N hydrochloric acid, and then separated after the addition of dichloromethane. The organic phase was evaporated to dryness and purified by column chromatography to give 5 and 6.71 g of white solid product (84% yield). 1 H NMR (400 MHz, Chloroform- d ) δ 7.64 (s, 1H), 7.57 (d, J = 7.4 Hz, 2H), 7.48-7.32 (m, 4H), 5.05 (s, 2H), 2.39 (s, 3H). 19 F NMR (400 MHz, Chloroform- d) δ -74.19 (d, J =6.2 Hz). 6.18 g of raw material 5 was weighed into a reaction flask, and after purging with nitrogen three times, anhydrous diethyl ether was added to dissolve it. The mixture was cooled to -78°C, and 8.1 mL of n-butyllithium solution (2.5 M in Hexane) was slowly added. The mixture was allowed to return to room temperature and maintained for half an hour. The mixture was then cooled to -78°C again, and 2.1 mL of DMF was added. The mixture was heated to -30°C, and 10 mL of concentrated hydrochloric acid was added to quench the reaction. Water was added to form two phases, and the mixture was separated. The aqueous phase was washed with ethyl acetate, and the combined organic phases were washed once with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. After rotary evaporation, the solution was purified by column chromatography to give 4.80 g of white solid product 6, in 90% yield. 1 H NMR (400 MHz, Chloroform- d ) δ 10.21 (d, J = 1.4 Hz, 1H), 7.85 (s, 1H), 7.62 (s,1H), 7.47 – 7.36 (m, 5H), 5.02 (s, 2H), 2.44 (s, 3H). 19 F NMR (376 MHz, Chloroform- d ) δ -74.37 (d, J = 6.2 Hz). Synthesis of benzylamine or its hydrochloride The corresponding aldehyde (1.0 equiv.) and tert-butylsulfinamide (1.1 equiv.) were weighed into a reaction flask, anhydrous THF was added, followed by tetraethyl titanate (1.1 equiv.). The mixture was stirred at 60°C for 6 hours, and the reaction was quenched with saturated sodium chloride. After stirring for 1 minute, ethyl acetate was added to dilute the mixture. The reaction solution was filtered through diatomaceous earth, and the aqueous phase was separated. The organic phase was evaporated to dryness and dissolved in methanol. Then, 1.5 equivalents of sodium borohydride were added, and the mixture was sonicated for 10 minutes. The reaction was then quenched with concentrated hydrochloric acid. All liquids were evaporated to dryness, and the residue was dissolved in ethyl acetate and saturated sodium carbonate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness before being passed through a column to obtain the product. 2.68 g, 81% yield, colorless oily liquid. 1 H NMR (400 MHz, DMSO- d 6) δ 7.51 (d, J =7.4 Hz, 2H), 7.43 (q,J = 7.7 Hz, 3H), 7.36 (d, J = 7.1 Hz, 1H), 7.20 (d, J =7.8 Hz, 1H), 7.06 (t, J = 7.7 Hz, 1H), 4.93 (s, 2H), 3.80 (s, 2H), 1.36 (s, 9H). 454 mg, 75% yield, yellow oily liquid. 1 H NMR (400 MHz, Acetonitrile- d 3) δ 7.75 (s, 1H), 7.64 (d, J = 7.5 Hz, 2H), 7.61 – 7.56 (m, 2H), 7.54 (d, J = 7.0 Hz,1H), 7.45 (s, 1H), 5.08 (s, 2H), 4.04 (s, 2H), 2.53 (s, 3H). 19 F NMR (400 MHz, Acetonitrile- d 3) δ -75.06 (d, J = 6.1 Hz). Benzyl-protected tertiary amines Route 1 Benzyl-protected salicylaldehyde (4.0 equiv.), ammonium acetate (1.0 equiv.), and sodium triacetylborohydride (6.0 equiv.) were dissolved in anhydrous THF and heated at 60 °C. o The mixture was stirred for 3 hours at temperature C. The reaction mixture was then cooled to room temperature, quenched by slow addition of a saturated NaHCO3 solution, and then extracted with ethyl acetate. The combined organic phases were extracted once with saturated NaCl, dried over anhydrous Na2SO4, and the target product was obtained by column chromatography. 2.66 g, 73% yield, white solid. 1 H NMR (400 MHz, Chloroform- d ) δ 7.44 (d, J =7.7 Hz, 3H), 7.33 – 7.26 (m, 15H), 7.15 (d, J= 8.3 Hz, 3H), 7.02 (t, J = 8.0Hz, 3H), 4.87 (s, 6H), 3.46 (s, 6H). 19 F NMR (400 MHz, Chloroform- d ) δ -57.49. 1.19 g, 29% yield, colorless oily liquid. 1 H NMR (400 MHz, Chloroform- d ) δ 7.88 (d, J = 7.7 Hz, 3H), 7.58 (d, J = 7.7 Hz, 3H), 7.38 (d, J = 16.6 Hz, 15H), 7.23(d, J = 7.8 Hz, 3H), 4.83 (s, 6H), 3.70 (s, 6H). 19 F NMR (400 MHz, Chloroform- d ) δ -60.35. 1.30 g, 39% yield, colorless oily liquid. 1 H NMR (400 MHz, Chloroform- d ) δ 7.42 –7.28 (m, 18H), 7.06 – 6.95 (m, 6H), 5.03 (d, J = 2.5 Hz, 6H), 3.52 (d, J =2.9 Hz, 6H). 19 F NMR (400 MHz, Chloroform- d ) δ -129.98 (dt, J = 10.5, 5.0 Hz). 1.26 g, 73% yield, oily liquid. 1 H NMR (400 MHz, Chloroform- d ) δ 7.63 (d, J=3.8 Hz, 3H), 7.43 – 7.30 (m, 18H), 4.78 (d, J = 2.9 Hz, 6H), 3.71 (d, J = 3.3Hz, 6H), 2.42 (d, J = 2.5 Hz, 9H). 19 F NMR (400 MHz, Chloroform- d ) δ -74.28(d, J = 6.3 Hz). Route 2 The corresponding salicylaldehyde (1.0 equiv.) and benzylamine (4.0 equiv.), ammonium acetate (1.0 equiv.) and sodium triacetylborohydride (6.0 equiv.) were dissolved in anhydrous THF and heated at 60 °C. o The mixture was stirred at C for 3 hours. The reaction mixture was then cooled to room temperature, and a saturated NaHCO3 solution (100 mL) was slowly added. The mixture was then extracted with ethyl acetate (100 × 3 mL). The combined organic phases were extracted once with saturated NaCl, dried over anhydrous Na2SO4, and the product was obtained by column chromatography. 1.27 g, 79% yield, colorless oily liquid. 1 H NMR (400 MHz, Chloroform- d ) δ 7.45 –7.32 (m, 15H), 7.22 (dd, J = 12.3, 7.8 Hz, 6H), 7.09 (t, J = 7.9 Hz, 3H), 5.06 (s, 6H), 3.78 (s, 6H), 1.66 (s, 18H). 19 F NMR (400 MHz, Chloroform- d ) δ -57.49. 1.49 g, 36% yield, colorless oily liquid. 1 H NMR (400 MHz, Chloroform- d ) δ 7.58 (d, J = 7.4 Hz, 1H), 7.50 (d, J= 7.6 Hz, 2H), 7.40 (d, J = 7.1 Hz, 2H), 7.34 (d, J = 7.2 Hz, 3H), 7.24 (s, 10H), 7.14 (d, J = 8.0 Hz, 3H), 7.03 (t, J = 7.8Hz, 3H), 4.85 (s, 4H), 4.76 (s, 2H), 3.62 (s, 2H), 3.50 (s, 4H), 1.39 (d, J =3.7 Hz, 9H). 19 F NMR (400 MHz, Chloroform- d ) δ -57.49. 677 mg, 56% yield, colorless oily liquid. 1 H NMR (400 MHz, Chloroform- d ) δ 7.57 (s, 2H), 7.28 (d, J = 2.5 Hz, 11H), 7.22 (s, 7H), 7.16 (d, J = 8.4 Hz, 1H), 7.02(t, J = 8.2 Hz, 1H), 4.85 (s, 2H), 4.66 (s, 4H), 3.56 (s, 4H), 3.48 (s, 2H), 2.32 (s, 6H). 19 F NMR (400 MHz, Chloroform- d ) δ -57.51(s, 3F), -74.30 (d, J =6.3 Hz) (s, 12F). 708 mg, 40% yield, colorless oily liquid. 1 H NMR (500 MHz, Chloroform- d ) δ 7.65 (d, J = 2.2 Hz, 1H), 7.46 (dd, J = 7.8, 1.6 Hz, 2H), 7.41 – 7.34 (m, 5H), 7.31(dt, J= 10.0, 3.8 Hz, 11H), 7.25 (s, 1H), 7.21 (dt, J = 8.2, 1.6 Hz, 2H), 7.08 (t, J = 8.0 Hz, 2H), 4.92 (s, 4H), 4.74 (s, 2H), 3.63 (s, 2H), 3.53 (s, 4H), 2.36 (s, 3H). 19 F NMR (400 MHz, Chloroform- d ) δ -57.49(s, 6F), -74.29 (d,J = 6.2 Hz) (s, 6F). Benzyl-protected tertiary amines undergo debenzylation protection A benzyl-protected tertiary amine (1.0 equiv.) and palladium hydroxide / carbon (10% on carbon, 0.2 equiv.) were dissolved in ethyl acetate or acetone and stirred for 3 hours under a hydrogen balloon atmosphere (2 atm). The solid was filtered through diatomaceous earth, the solvent was removed by rotary evaporation of the filtrate, and the residue was subjected to column chromatography to obtain the product. 1.23 g, 65% yield, white solid. 1 H NMR (400 MHz, Chloroform- d ) δ 7.11 (dd, J = 13.4, 8.5 Hz, 6H), 6.88 (br, 3H), 6.81 (t, J = 7.9 Hz, 3H), 3.78 (s, 6H). 19 F NMR (600 MHz, Chloroform- d ) δ -57.97. 473 mg, 74% yield, light brown solid. 1 H NMR (400 MHz, Chloroform- d ) δ 7.40 (d, J = 7.8 Hz, 3H), 7.30 (d, J = 7.4 Hz, 3H), 6.90 (t, J = 7.7 Hz, 6H), 3.80 (s, 6H). 19F NMR (400 MHz, Chloroform- d ) δ -60.79. 208 mg, 74% yield, pink solid. 1 H NMR (400 MHz, Chloroform- d ) δ 7.03 (s,3H), 7.00 – 6.90 (m, 6H), 6.75 (td, J = 8.0, 5.1 Hz, 3H), 3.78 (s, 6H). 19 FNMR (400 MHz, Chloroform- d ) δ -139.60 (dd, J = 10.8, 5.3 Hz). 300 mg, 80% yield, white solid. 1 H NMR (400 MHz, Chloroform- d ) δ 7.19 (s, 3H), 7.07 (d, J = 2.3 Hz, 3H), 3.69 (s, 6H), 2.27 (s, J = 2.0 Hz, 9H). 19 F NMR (400 MHz, Chloroform- d ) δ -74.65. 534 mg, 79% yield, pale yellow solid. 1 H NMR (400 MHz, Chloroform- d ) δ 7.17 (dd, J = 15.3, 8.1 Hz, 3H), 7.01 (t, J = 7.1 Hz, 1H), 6.95 (d, J = 7.4 Hz, 2H), 6.84 (t, J = 7.9 Hz, 1H), 6.75 (t, J = 7.6 Hz, 2H), 3.69 (s, 6H), 1.37 (s, 18H). 19F NMR (400 MHz, Chloroform- d ) δ -57.99. 559 mg, 69% yield, oily liquid. 1 H NMR (400 MHz, Chloroform- d ) δ 7.21 – 7.08(m, 5H), 6.92 (d, J = 7.3 Hz, 1H), 6.83 (t, J = 8.0 Hz, 2H), 6.74 (dt, J =7.7, 3.9 Hz, 1H), 3.74 (d, J = 4.0 Hz, 6H), 1.39 (d, J = 2.4 Hz, 9H). 19 F NMR (400 MHz, Chloroform- d ) δ -57.99. 415 mg, 82% yield, white solid. 1 H NMR (400 MHz, Chloroform- d ) δ 7.21 – 7.08(m, 5H), 7.02 – 6.98 (m, 1H), 6.84 (t, J = 8.0 Hz, 2H), 6.35 (s, 3H), 3.75(d, J = 9.3 Hz, 6H), 2.26 (s, 3H). 19 F NMR (400 MHz, Chloroform- d ) δ -58.05(s), -74.33 (d, J = 5.3 Hz). 19 F NMR (400 MHz, Chloroform- d ) δ -58.05(s, 6F), -74.33 (d, J = 5.3 Hz) (s, 6F). 299 mg, 68% yield, yellow solid. 1H NMR (400 MHz, Chloroform- d ) δ 7.20 – 7.13(m, 3H), 7.09 – 7.04 (m, 3H), 6.85 (t, J = 8.0 Hz, 1H), 3.72 (s, 6H), 2.27 (s, 6H). 19 F NMR (400 MHz, Chloroform- d ) δ -58.16(s, 3F), -74.49 (d, J = 5.4Hz) (s, 12F). Preparation of aluminum complex probes A tertiary amine containing three phenolic hydroxyl groups (1.0 equiv.) was weighed into a reaction flask. After purging with nitrogen three times, a solution of anhydrous THF was added. Then, trimethylaluminum (1.0 M heptane solution, 1.1 equiv.) was slowly added dropwise to the reaction solution. The reaction system was stirred at room temperature for 2 hours. The solvent was removed by vacuum to obtain a white solid product, which was then transferred in a glove box. 1.26 g, 88% yield, white solid. 1 H NMR (400 MHz, Chloroform- d ) δ 7.15 (d, J =8.1 Hz, 3H), 6.92 (d, J = 7.6 Hz, 3H), 6.68 (t, J = 7.8 Hz, 3H), 4.51 (s,4H), 4.25 (br, 3H), 2.99 (br, 3H), 2.19 – 2.08 (m, 4H). 19 F NMR (400 MHz, Chloroform) -d ) δ -58.07. 303 mg, 95% yield, white powder. 1 H NMR (400 MHz, Chloroform- d ) δ 7.47 (d, J =7.8 Hz, 3H), 7.14 (d, J = 7.4 Hz, 3H), 6.75 (t, J= 7.3 Hz, 3H), 4.48 (s, 4H), 4.23 (d, J = 13.7 Hz, 3H), 2.99 (d, J = 13.9 Hz, 3H), 2.20 – 2.07 (m,4H). 19 F NMR (400 MHz, Chloroform- d ) δ -62.16. 242 mg, 94% yield, white powder solid. 1 H NMR (400 MHz, Chloroform- d ) δ 6.98 (t, J = 9.5 Hz, 3H), 6.73 (d, J = 7.6 Hz, 3H), 6.61 (td, J = 7.9, 4.6 Hz, 3H), 4.57 (d, J = 6.4 Hz, 4H), 4.07 (s, 3H), 3.01 (s, 3H), 2.20 – 2.15 (m, 4H). 19 FNMR (400 MHz, Chloroform- d ) δ -136.88 (dd, J = 10.6, 4.6 Hz). 397 mg, 83% yield, white solid. 1 H NMR (400 MHz, Chloroform- d ) δ 7.23 (d, J =7.9 Hz, 2H), 7.12 (d, J = 8.2 Hz, 1H), 6.86 (dd, J = 13.8, 7.3 Hz, 3H), 6.66(dt, J = 10.9, 7.6 Hz, 3H), 4.60 (m, 4H), 4.20 (m, 3H), 3.09 – 2.70 (m, 3H), 2.14 (s, 4H), 1.41 (s, 18H). 19 F NMR (400 MHz, Chloroform-d ) δ -57.95. 473 mg, 97% yield, white solid. 1 H NMR (400 MHz, Chloroform- d ) δ 7.22 (s, 1H), 7.14 (d, J = 8.1 Hz, 2H), 6.88 (dd, J = 22.3, 7.4 Hz, 3H), 6.73 – 6.61(m, 3H), 4.59 (d, J = 20.0 Hz, 4H), 4.21 (s, 3H), 2.92 (s, 3H), 2.16 (s, 4H), 1.40 (s, 9H). 19 F NMR (400 MHz, Chloroform- d ) δ -58.03 (d, J = 23.0 Hz). 163 mg, 69% yield, white solid. 1 H NMR (400 MHz, Chloroform- d ) δ 7.22 (s, 1H), 7.13 (d, J = 8.1 Hz, 2H), 6.98 – 6.79 (m, 3H), 6.65 (t, J = 7.8 Hz, 2H), 4.48 (d, J = 27.2 Hz, 4H), 4.15 (q, J = 12.5, 11.4 Hz, 3H), 2.92 (q, J =14.5, 12.7 Hz, 3H), 2.23 (s, 3H), 2.09 (d, J = 6.2 Hz, 4H). 19 F NMR (376 MHz, Chloroform- d ) δ -58.19 (s, 3F), -73.36 (s, 3F), -74.73 (br, 3F). 249 mg, 89% yield, white solid.1 H NMR (400 MHz, Chloroform- d ) δ 7.25 – 7.02(m, 3H), 6.88 (d, J = 16.9 Hz, 3H), 6.66 (q, J = 8.0, 7.0 Hz, 1H), 4.43 (d, J = 31.4 Hz, 4H), 4.29 – 4.01 (m, 3H), 3.08 – 2.75 (m, 3H), 2.23 (s, 6H), 2.08 (s, 4H). 19 F NMR (376 MHz, Chloroform- d ) δ -58.20 (s, 3F), -72.97 – -74.67 (m, 12F). 156 mg, 80% yield, white solid. 1 H NMR (400 MHz, Chloroform- d ) δ 7.26 (s,2H), 7.16 (s, 1H), 6.91 (d, J = 20.2 Hz, 3H), 4.37 (s, 3H), 4.12 (d, J = 12.7Hz, 4H), 2.90 (dd, J = 43.6, 14.4 Hz, 4H), 2.25 (d, J = 9.8 Hz, 9H), 2.04 (s, 3H). 19 F NMR (400 MHz, Chloroform- d ) δ -73.89 (d, J = 226.9 Hz). Preparation of gallium-indium complex probes The corresponding tertiary amine (30 mg, 1.0 equiv.), gallium trichloride (9.9 mg, 1.1 equiv.), and pyridine (13.3 mg, 3.3 equiv.) were dissolved in anhydrous THF (10 mL) and stirred at room temperature. The reaction mixture was evaporated to dryness, washed once with n-hexane, dried under vacuum, and then deuterated chloroform was added. The mixture was filtered through a membrane and dried under vacuum to give the product. 30 mg, 80% yield, pale yellow solid.1 HNMR (400 MHz, Chloroform-d) δ 9.32 (d, J = 5.6 Hz, 2H), 8.02 (t, J = 7.7 Hz,1H), 7.59 (t, J = 6.8 Hz, 2H), 7.14 (d, J = 8.1 Hz, 3H), 6.94 (d, J = 7.7 Hz, 3H), 6.67 (t, J = 7.8 Hz, 3H), 2.85 (s, 6H). 19 F NMR (376 MHz, Chloroform-d) δ-58.05. The corresponding tertiary amine (30 mg, 1.0 equiv.), indium trichloride (12.4 mg, 1.1 equiv.), and pyridine (13.3 mg, 3.3 equiv.) were dissolved in anhydrous THF (10 mL) and stirred at room temperature. The reaction mixture was evaporated to dryness, washed once with n-hexane, dried under vacuum, and then deuterated chloroform was added. The mixture was filtered through a membrane filter and dried under vacuum to give the product. 32 mg, 79% yield, pale yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ 8.93 (s, 2H), 7.86 (t, J = 7.2 Hz, 1H), 7.45(s, 2H), 7.10 (dd, J = 12.7, 8.1 Hz, 6H), 6.80 (t, J = 7.9 Hz, 3H), 3.82 (s,6H). 19 F NMR (376 MHz, Chloroform-d) δ -57.98. Test Example 1: Effect diagram of probe molecules distinguishing and identifying drugs 1 mg of probe molecule Ia and 1-2 mg of analyte were dissolved in 0.5 mL of CDCl3, and their fluorine spectra were measured. The results are as follows: Figure 2 As shown. Figure 2 The results demonstrate the ability of probe molecules to distinguish and recognize different drugs. It can be seen that rapid analysis and detection of drug analytes can be achieved without sample preparation, and without requiring the sample to possess UV absorption or fluorescence. When analytes with different structures complex with the probe, specific fluorine spectrum signals are generated, each signal corresponding to a drug with a specific structure. The detection process for other probe molecules of different drugs is the same.

[0075] The superimposed spectrum of the fluorine spectrum signals of probe molecule Ib and the analyte in deuterated chloroform is shown in the figure below. Figure 3 As shown.

[0076] The superimposed spectrum of the fluorine spectrum signals of probe molecule Ic and the analyte in deuterated chloroform is shown in the figure below. Figure 4 As shown.

[0077] The superimposed spectrum of the probe molecule Id and the analyte in deuterated chloroform is shown in the following figure. Figure 5 As shown.

[0078] The superimposed spectrum of the fluorine spectrum signals of the probe molecule Ie and the analyte in deuterated chloroform is shown in the figure below. Figure 6 As shown.

[0079] The superimposed spectrum of the fluorine spectrum signals of the probe molecule If and the analyte in deuterated chloroform is shown in the figure below. Figure 7 As shown.

[0080] The superimposed spectrum of the fluorine spectrum signals of the probe molecule Ig and the analyte in deuterated chloroform is shown in the figure below. Figure 8 As shown.

[0081] The superimposed spectrum of the fluorine spectrum signals of probe molecule Ih and the analyte in deuterated chloroform is shown in the figure below. Figure 9 As shown.

[0082] The superimposed spectrum of the fluorine spectrum signals of probe molecule Ii and the analyte in deuterated chloroform is shown in the figure below. Figure 10 As shown.

[0083] The superimposed spectrum of the fluorine spectrum signals of probe molecule Ij and the analyte in deuterated chloroform is shown in the figure below. Figure 11 As shown.

[0084] The fluorine spectrum results of probe molecule Ib and the analyte in deuterated chloroform are as follows: Figure 12 As shown.

[0085] The fluorine spectrum results of probe molecule Ic and the analyte in deuterated chloroform are as follows: Figure 13 As shown.

[0086] The fluorine spectrum results of probe molecule Id and analyte in deuterated chloroform are as follows: Figure 14 As shown.

[0087] in Figure 12-14 This indicates that the probe molecules can be used to detect a wide variety of chemical substances, including alcohols, amides, carboxylic acids, sulfoxides, cyclic ethers, and esters.

[0088] Test Example 2: Graph illustrating the effect of probe molecules simultaneously distinguishing and detecting multiple drugs. 1 mg of probe molecule Ia was dissolved in 0.5–2.0 mg of analyte in 0.5 mL of CDCl3, and its fluorine spectrum was measured. The test results are as follows: Figure 15 As shown in the figure, the results indicate that when Ia is complexed with different drugs, it produces fluorine spectrum signals with specific chemical shifts. Figure 15 This indicates that probe molecules can simultaneously distinguish and detect multiple different drugs in complex systems.

[0089] The same complex system was detected using probe molecules 1-a, 1-b, and 1-c, respectively. The test results are as follows: Figure 16 . Figure 16 This indicates that the differentiation effect varies with different substituents, but all methods can effectively distinguish different test compounds.

[0090] Test Example 3: Quantitative Detection of Unknown Analytes Prepare a bottle of deuterated chloroform and dry it using molecular sieves. Weigh 12.5 mg of probe 1-a into a 5 ml glass bottle, and use a syringe to dispense 3.68 ml of dried deuterated chloroform to prepare a 5 mM / L solution. Weigh 52.7 mg of ibuprofen standard into a 5 ml glass bottle, and use a syringe to dispense 1.28 ml of dried deuterated chloroform to prepare a 200 mM / L solution. Weigh 46.7 mg of (R)-(+)-4-isopropyl-2-oxazolinone into a 5 ml glass bottle, and use a syringe to dispense 1.81 ml of dried deuterated chloroform to prepare a 200 mM / L solution. In an NMR tube, use a pipette to add 400 ml of probe solution (1 e.q.), 100 ml of amide solution (10 e.q.), and 20 ml of ibuprofen solution (2 e.q.) to prepare an ibuprofen:amide equivalent ratio of 1:5. Similarly, the volume of the added amide solution remains constant, while the volume of the ibuprofen solution is changed to 40 ml (4e.q.) to prepare a solution with an equivalence ratio of 2:5; the volume of the added ibuprofen solution is changed to 60 ml (6e.q.) to prepare a solution with an equivalence ratio of 3:5; the volume of the added ibuprofen solution is changed to 80 ml (8e.q.) to prepare a solution with an equivalence ratio of 4:5; and the volume of the added ibuprofen solution is changed to 100 ml (10e.q.) to prepare a solution with an equivalence ratio of 1:1. The NMR spectra are phase and baseline corrected, and the integral area ratio of ibuprofen to amide is obtained. Using the equivalence ratio as x and the integral area ratio as y, a linear fit is performed, yielding y = 0.6578x, R0. 2 = 0.9998. This function is the standard curve.

[0091] The results are as follows Figure 17 As shown, from Figure 17 As can be seen, after fixing the concentration of the known analyte, the integral ratio of the unknown analyte has a good linear relationship with the content, so it can be used for the rapid determination of drug content.

[0092] Based on the above results, diethylnicotinamide can be used as an internal standard to determine the menthol content in peppermint ice and peppermint oil purchased directly from the market. Figure 18The results showed that the tested peppermint ice contained 94% menthol, and the tested peppermint oil contained 68% menthol.

[0093] The specific calculation process of the linear relationship between the integral ratio and the content, and the relative error of this method are as follows: Figure 19 As shown.

[0094] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A fluorine-containing probe complex, characterized in that, The complex has the structure shown in Formula II: In the formula, R 1 R 2 R 3 R 4 Each group is independently selected from the group consisting of: hydrogen atom, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5-20 membered heteroaryl; wherein the heteroaryl skeleton has 1-8 heteroatoms selected from N, O or S; wherein the substitution refers to one or more hydrogen atoms on the group being substituted by a substituent selected from the group consisting of: halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy; And R 1 and R 2 At least one of them is a group selected from the group consisting of: fluorine atom, trifluoromethyl, trifluoromethoxy, nonafluorotert-butoxy, or a group selected from the group consisting of: C6 to C20 aryl, 5 to 20 heteroaryl, substituted by fluorine atom, trifluoromethyl, trifluoromethoxy, or nonafluorotert-butoxy. L is a molecule selected from the following group: C1-C6 chain or cyclic alcohols, C1-C6 chain or cyclic ethers, C1-C6 chain or cyclic amides, C1-C6 chain or cyclic sulfoxides, C1-C6 chain or cyclic sulfones, C1-C6 chain or cyclic aldehydes, C1-C6 chain or cyclic ketones, C1-C6 chain or cyclic carboxylic acids; C1-C6 chain amines; C5-C10 nitrogen-containing heterocycles; M is a metal selected from the following group: aluminum, gallium, indium.

2. The complex as described in claim 1, characterized in that, R 1 R 2 R 3 R 4 Each of the following groups is independently selected from the group consisting of: halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy.

3. The complex as described in claim 1, characterized in that, The complex has the structure shown in Formula I: 。 4. The complex as described in claim 1, characterized in that, The complexes have structures selected from the group consisting of: 。 5. A ligand, characterized in that, The ligand has the structure shown in Formula III: In the formula, R 1 R 2 R 3 R 4 Each group is independently selected from the group consisting of: hydrogen atom, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5-20 membered heteroaryl; wherein the heteroaryl skeleton has 1-8 heteroatoms selected from N, O or S; wherein the substitution refers to one or more hydrogen atoms on the group being substituted by a substituent selected from the group consisting of: halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy; And R 1 and R 2 At least one of them is a group selected from the group consisting of: fluorine atom, trifluoromethyl, trifluoromethoxy, nonafluorotert-butoxy, or a group selected from the group consisting of: C6 to C20 aryl, 5 to 20 heteroaryl, substituted by fluorine atom, trifluoromethyl, trifluoromethoxy, or nonafluorotert-butoxy. The substitution refers to the substitution of one or more hydrogen atoms on the group by a substituent selected from the group consisting of: halogens, C1-C4 alkyl groups, and C1-C4 haloalkyl groups; Furthermore, the ligands described do not have the structure shown in the following formula: 。 6. The ligand as described in claim 5, characterized in that, The ligands have structures selected from the group consisting of: 。 7. A method for distinguishing and identifying small organic molecules, characterized in that, The method includes the following steps: (1) In an inert solvent, the complex as described in any one of claims 1-3 is mixed with the small organic molecule to be tested to obtain a second complex; (2) The second complex is subjected to... 19 fluorine spectrum signal was obtained by fluorine NMR detection; (3) The organic small molecules to be tested are determined by the fluorine spectrum signal obtained in step (2).

8. A method for determining and quantitatively analyzing the content of a drug, characterized in that, The method includes the following steps: (1) In an inert solvent, the drug to be tested and an analyte of known concentration are mixed with the complex as described in any one of claims 1-3 to obtain a detection solution; (2) The detection solution is subjected to... 19 fluorine spectrum signal was obtained by fluorine NMR detection; (3) The concentration of the drug to be tested is determined by integral analysis using the fluorine spectrum signal obtained in step (2).

9. The method as described in claim 7 or 8, characterized in that, The tested organic small molecule or the tested drug contains structural fragments selected from the group consisting of: hydroxyl, amino, amide, carboxyl, sulfoxide, ester, ether, nitroxy, amino, oxazoline ring, aromatic group, alkene bond, and alkyne bond.

10. The method as described in claim 7 or 8, characterized in that, The inert solvent is an organic solvent.

11. The method as described in claim 7 or 8, characterized in that, The inert solvent is selected from the group consisting of: chloroform, dichloromethane, toluene, n-hexane, benzene, petroleum ether, carbon tetrachloride, acetonitrile, and ethyl acetate.

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