A boron ester furan derivative compound and its preparation method and application

Abstract

The present invention provides a boron ester furan derivative compound and its preparation method and application, belonging to the field of small molecule optical sensing technology. The present invention reacts after mixing 5-aldehyde furan-3-boric acid pinacol ester, compound a and solvent to obtain a boron ester furan derivative compound, wherein compound a is 2,2-dimethyl-1,3-dioxazolidine-4,6-diketone [malonic acid ring (sub) isopropyl ester], 3-trifluoromethylisoxazole-5 (4H)-ketone, 1,3-dimethylbarbituric acid or 1,2-diphenyl-3,5-pyrrolidone. The furan ring in the boron ester furan derivative compound prepared by the present invention can undergo nucleophilic reaction with the amino group in the drug to generate a linear structure derivative with a characteristic color and a triene group, and the solution color changes from colorless or light yellow to reddish brown, and the ultraviolet absorption spectrum changes significantly. This rapid sensing mode gives it huge development potential in terms of the distinction and sensitive detection of drugs and their analogs.

Description

Technical Field

[0001] The present invention relates to the technical field of small molecule optical sensing, and in particular to a boron ester furan derivative compound, a preparation method and application thereof. Background Art

[0002] Drug-related issues such as drug production, trafficking, and abuse pose a serious threat to social stability, public safety, and public health, and have attracted increasing attention from all sectors of society. Establishing sensitive, rapid, and reliable detection methods, as well as developing technologies and equipment capable of mobile detection and rapid screening, are of vital practical significance for drug investigation and the fight against drug crime. Currently, the main technologies used worldwide for concealed drug detection include chemical colorimetry, colloidal gold, gas chromatography-mass spectrometry (GC / MS), ion mobility spectrometry (IMS), surface-enhanced Raman spectroscopy (SERS), and specialized drug-sniffing dogs. Each of these technologies has its own advantages and disadvantages. For example, chemical colorimetry allows for rapid qualitative analysis, but is susceptible to subjective color perception and cannot detect trace amounts of drugs with similar chemical structures. Colloidal gold detection kits, while convenient and fast, are prone to false positives. GC / MS coupled methods offer high sensitivity but require complex and time-consuming sample pretreatment, expensive, large-scale equipment, and specialized personnel.

[0003] Compared with other methods, spectroscopy offers advantages such as high sensitivity, fast response, and the ability to collect a wide range of parameters, demonstrating its significant advantages in sensing detection. Therefore, there is an urgent need to develop a boron ester furan derivative with a rapid sensing mode, as well as its preparation and application. Summary of the Invention

[0004] The purpose of the present invention is to provide a boron ester furan derivative compound and its preparation method and application, so as to solve the technical problems of low sensitivity and slow response speed of drug detection in the prior art.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The present invention provides a boron ester furan derivative compound, the boron ester furan derivative compound has a structural formula as shown in Formula I:

[0007]

[0008] Where R is

[0009] The present invention provides a method for preparing a boron ester furan derivative compound, comprising the following steps: mixing 5-formylfuran-3-boronic acid pinacol ester, compound A and a solvent, and reacting the mixture to obtain the boron ester furan derivative compound;

[0010] The compound a is 2,2-dimethyl-1,3-dioxazolidine-4,6-dione [cycloisopropylmalonate], 3-trifluoromethylisoxazol-5(4H)-one, 1,3-dimethylbarbituric acid or 1,2-diphenyl-3,5-pyrrolidone.

[0011] Preferably, the molar volume ratio of the 5-formylfuran-3-boronic acid pinacol ester, compound a and solvent is 0.4-2.8 mmol: 0.4-3.8 mmol: 10-20 mL.

[0012] Preferably, the solvent is ethanol or dichloromethane.

[0013] Preferably, the reaction temperature is 20-65° C., and the reaction time is 6-14 h.

[0014] Preferably, the preparation method of 3-trifluoromethylisoxazol-5(4H)-one is: dissolving hydroxylamine sulfate, ethyl trifluoroacetoacetate and potassium carbonate in ethanol and performing a reflux reaction to obtain 3-trifluoromethylisoxazol-5(4H)-one.

[0015] Preferably, the molar volume ratio of the hydroxylamine sulfate, ethyl trifluoroacetoacetate, potassium carbonate and ethanol is 13-15 mmol: 14-16 mmol: 26-28 mmol: 40-60 mL.

[0016] Preferably, the temperature of the reflux reaction is 60-70° C., and the time of the reflux reaction is 3-4 h.

[0017] The present invention provides an application of a boron ester furan derivative compound in drug detection.

[0018] Beneficial effects of the present invention:

[0019] (1) The present invention successfully prepared four boron ester furan derivative compounds with a yield of more than 50%.

[0020] (2) The furan ring in the boron ester furan derivative compound prepared by the present invention can undergo a nucleophilic reaction with the amino group in the drug to produce a linear structure derivative with a characteristic color and a triene group. The solution color changes from colorless or light yellow to reddish brown, and the ultraviolet absorption spectrum changes significantly. This rapid sensing mode has great development potential in the differentiation and sensitive detection of drugs and their simulants.

[0021] (3) Compared with reference compounds containing only furan groups, the boron ester furan derivatives provided by the present invention have increased electron-donating capacity of the donor, enhancing the conjugation effect of the linear structure product with triene groups. The product color undergoes a significant red shift, the color change is more pronounced, the corresponding maximum absorption wavelength also undergoes a red shift, and the molar absorptivity increases. As the molecular structure is continuously optimized, the wavelength range of the responsive spectrum continues to expand, and the response sensitivity continues to increase.

[0022] (4) When the MEF, TFF, BAF and PYF compounds of the present invention are used to detect drugs and their simulants, the drugs are methamphetamine and amphetamine and their structurally similar simulants, and they have the advantages of rapidity, high efficiency, high sensitivity and good selectivity. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the H NMR spectrum of the MEF compound prepared in Example 1;

[0024] Figure 2 This is the H NMR spectrum of the TFF compound prepared in Example 2;

[0025] Figure 3 is a graph showing the UV-visible response of the MEF compound prepared in Example 1 to different concentrations of methamphetamine mimetics;

[0026] Figure 4 is a linear relationship diagram of the MEF compound prepared in Example 1 to different concentrations of methamphetamine mimetics based on UV-visible absorption spectra;

[0027] Figure 5 Graph showing the UV-visible response of the TFF compound prepared in Example 2 to different concentrations of methamphetamine simulants;

[0028] Figure 6 The figure is a linear relationship diagram of the TFF compound prepared in Example 2 to different concentrations of methamphetamine simulants based on UV-visible absorption spectra;

[0029] Figure 7 1 is a bar graph showing the selectivity of the MEF compound prepared in Example 1 and the TFF compound prepared in Example 2 for different types of drug simulants, wherein the numbers on the abscissa represent different types of drug simulants, 1 is 2,3,3-trimethylindole; 2 is 5-methyldihydropyrimidine-2,4(1H,3H)-dione; 3 is 3-methylindole; 4 is 4-acetaminophenethyl ether; 5 is 2-(2-oxopyrrolidin-1-yl)acetamide; 6 is an amphetamine simulant; 7 is a methamphetamine simulant;

[0030] Figure 8This is a principal component analysis PCA diagram of the sensor selectivity of the MEF compound prepared in Example 1 for different types of drug simulants. The interfering substances in the figure refer to 2,3,3-trimethylindole, 5-methyldihydropyrimidine-2,4(1H,3H)-dione, 3-methylindole, 4-acetaminophenethyl ether, and 2-(2-oxopyrrolidin-1-yl)acetamide;

[0031] Figure 9 This is a principal component analysis PCA diagram of the sensing selectivity of the TFF compound prepared in Example 2 for different types of drug simulants. The interfering substances in the figure refer to 2,3,3-trimethylindole, 5-methyldihydropyrimidine-2,4(1H,3H)-dione, 3-methylindole, 4-acetaminophenethyl ether, and 2-(2-oxopyrrolidin-1-yl)acetamide. DETAILED DESCRIPTION

[0032] The present invention provides a boron ester furan derivative compound, the boron ester furan derivative compound has a structural formula as shown in Formula I:

[0033]

[0034] Where R is

[0035] When R is When R is When R is When R is When, it is referred to as PYF compound.

[0036] The present invention provides a method for preparing a boron ester furan derivative compound, comprising the following steps: mixing 5-formylfuran-3-boronic acid pinacol ester, compound A and a solvent, and reacting the mixture to obtain the boron ester furan derivative compound;

[0037] The compound a is 2,2-dimethyl-1,3-dioxazolidine-4,6-dione [cycloisopropylmalonate], 3-trifluoromethylisoxazol-5(4H)-one, 1,3-dimethylbarbituric acid or 1,2-diphenyl-3,5-pyrrolidone.

[0038] In the present invention, the molar volume ratio of the 5-formyl furan-3-boronic acid pinacol ester, compound a and solvent is 0.4-2.8 mmol: 0.4-3.8 mmol: 10-20 mL, wherein the compound a is 2,2-dimethyl-1,3-dioxazolidine-4,6-dione [malonic acid cycloisopropyl ester], 5-formyl furan-3-boronic acid pinacol ester, 2,2-dimethyl-1,3-dioxazolidine-4,6-dione [propyl cycloisopropyl ester], The molar volume ratio of the dicarboxylic acid cycloisopropyl ester] and the solvent is preferably 1.7-1.9 mmol: 1.8-1.9 mmol: 14-16 mL, and more preferably 1.8 mmol: 1.9 mmol: 15 mL; when the compound a is 3-trifluoromethylisoxazol-5(4H)-one, the molar volume ratio of 5-formylfuran-3-boronic acid pinacol ester, 3-trifluoromethylisoxazol-5(4H)-one and the solvent is preferably 2.6-2. 8mmol:3.6~3.8mmol:18~20mL, more preferably 2.7mmol:3.7mmol:20mL; when the compound a is 1,3-dimethylbarbituric acid, the molar volume ratio of 5-formylfuran-3-boronic acid pinacol ester, 1,3-dimethylbarbituric acid and the solvent is preferably 0.7~0.9mmol:0.7~0.9mmol:14~16mL, more preferably 0.75~0.85mmol:0.75~0.85mmol:15mL; when the compound a is 1,2-diphenyl-3,5-pyrrolidone, the molar volume ratio of 5-formylfuran-3-boronic acid pinacol ester, 1,2-diphenyl-3,5-pyrrolidone and the solvent is preferably 0.4~0.45mmol:0.4~0.45mmol:10~12mL, more preferably 0.41mmol:0.43mmol:10mL.

[0039] In the present invention, the solvent is ethanol or dichloromethane, preferably ethanol.

[0040] In the present invention, the reaction temperature is 20-65°C, and the reaction time is 6-14h. When compound a is 2,2-dimethyl-1,3-dioxazolidine-4,6-dione [cycloisopropyl malonate], the reaction temperature is preferably 60-65°C, more preferably 65°C, and the reaction time is preferably 6-7h, more preferably 6.5h. When compound a is 3-trifluoromethylisoxazol-5(4H)-one, 1,3-dimethylbarbituric acid or 1,2-diphenyl-3,5-pyrrolidone, the reaction temperature is preferably 20-30°C, more preferably 25°C. When 3-trifluoromethylisoxazol-5(4H)-one participates in the reaction, the reaction time is preferably 14h, when 1,3-dimethylbarbituric acid participates in the reaction, the reaction time is preferably 6h, and when 1,2-diphenyl-3,5-pyrrolidone participates in the reaction, the reaction time is 10h.

[0041] In the present invention, the preparation method of 3-trifluoromethylisoxazol-5(4H)-one is as follows: hydroxylamine sulfate, ethyl trifluoroacetoacetate and potassium carbonate are dissolved in ethanol and subjected to reflux reaction to obtain 3-trifluoromethylisoxazol-5(4H)-one.

[0042] In the present invention, the molar volume ratio of hydroxylamine sulfate, ethyl trifluoroacetoacetate, potassium carbonate and ethanol is 13-15 mmol: 14-16 mmol: 26-28 mmol: 40-60 mL, preferably 14 mmol: 15 mmol: 27 mmol: 45-55 mL.

[0043] In the present invention, the reflux reaction temperature is 60-70°C, preferably 65-68°C, more preferably 65°C; the reflux reaction time is 3-4h, preferably 3.2-3.8h, more preferably 3.5h.

[0044] The present invention provides an application of a boron ester furan derivative compound in drug detection.

[0045] The colorless or pale yellow boron ester furan derivative compounds of the present invention all contain cyclic furan rings, which are easily nucleophilic with drug compounds containing active nitrogen atoms to produce linear triene structure derivatives with characteristic colors that are stable in polar solvents. The triene groups in the linear structure derivative molecules undergo π-π* transitions in the solvent, have strong absorption and color development, and exhibit a specific color. Furthermore, compared with reference compounds containing only furan groups, the electron donating capacity of the donor is increased, which enhances the conjugation effect of the linear structure product containing triene groups, resulting in a significant red shift in the color of the product, a more obvious color change, a corresponding red shift in the maximum absorption wavelength, and an increase in the molar absorptivity. As the molecular structure is continuously optimized, the wavelength range of the responsive spectrum continues to expand, and the response sensitivity continues to increase.

[0046] The technical solutions provided by the present invention are described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0047] Example 1

[0048] 1.8 mmol of 5-formylfuran-3-boronic acid pinacol ester and 1.9 mmol of 2,2-dimethyl-1,3-dioxazolidine-4,6-dione [malonic acid cycloisopropyl ester] were added to 15 mL of ethanol and reacted at 65° C. for 6.5 hours. The resulting reaction mixture was cooled to room temperature and filtered under vacuum to obtain a white solid (0.9 mmol, yield 52%), the structural formula of which is Referred to as MEF compound.

[0049] Example 2

[0050] 14mmol of hydroxylamine sulfate, 15mmol of ethyl trifluoroacetoacetate and 27mmol of potassium carbonate were dissolved in 50mL of ethanol and refluxed at 65°C for 3.5 hours. Cooled to room temperature, the solvent was removed by rotary evaporation to obtain a yellow solid, which was then dissolved in 10mL of sodium hydroxide solution (concentration of 4mol / L) and stirred for 10 minutes. Adjust its pH to 2 with hydrochloric acid, extract 3 times with dichloromethane, collect the organic phase and dry it with anhydrous magnesium sulfate, and remove the solvent by rotary evaporation to obtain yellow oily trifluoromethylisoxazole-5(4H)-one. 3.7mmol of trifluoromethylisoxazole-5(4H)-one was redissolved in 20mL of dichloromethane and 2.7mmol of 5-formylfuran-3-boronic acid pinacol ester was added, and the reaction was carried out at 25°C for 14 hours. The reaction solution was rotary evaporated until a small amount of solvent remained, water was added and solid was precipitated, and yellow solid (1.8mmol, yield 66%) was obtained by suction filtration, the structural formula of which is Referred to as TFF compound.

[0051] Example 3

[0052] 0.77 mmol of 5-formylfuran-3-boronic acid pinacol ester and 0.79 mmol of 1,3-dimethylbarbituric acid were added to 15 mL of ethanol, stirred at 25 ° C for 6 hours, and then filtered under vacuum to obtain a white solid (0.58 mmol, yield 75%), whose structural formula is Referred to as BAF compound.

[0053] Example 4

[0054] 0.41 mmol of 5-formylfuran-3-boronic acid pinacol ester and 0.43 mmol of 1,2-diphenyl-3,5-pyrrolidone were added to 10 mL of ethanol, stirred at 25 ° C for 10 hours, and then filtered under vacuum to obtain a white solid (0.22 mmol, yield 53%), whose structural formula is Referred to as PYF compound.

[0055] Application testing:

[0056] The MEF, TFF, BAF and PYF compounds prepared in Examples 1 to 4 were dissolved in acetonitrile to a concentration of 2.0×10 -5 ~3.0×10 -5 mol / L analytical solution. The specific detection method is: add unknown test substances to the MEF, TFF, BAF, and PYF compound analysis solutions. If the unknown test substances contain methamphetamine or amphetamine or similar structural analogs, the solution color will quickly change from colorless or light yellow to reddish brown, and the maximum UV-visible absorption wavelength will red-shift.

[0057] The maximum absorption wavelength of the MEF compound in acetonitrile is at 357 nm, the maximum absorption wavelength of the TFF compound in acetonitrile is at 394 nm, the maximum absorption wavelength of the BAF compound in acetonitrile is at 366 nm, and the maximum absorption wavelength of the PYF compound is at 371 nm.

[0058] The MEF compound prepared in Example 1 and the TFF compound prepared in Example 2 were prepared to a concentration of 2.5×10 -5 mol / L analytical solution, and then added methamphetamine simulants into the analytical solution respectively, and carried out UV-visible absorption spectrum test. The results are shown in Figure 3 、 Figure 4 、 Figure 5 and Figure 6 .from Figure 3 and Figure 4 It can be seen that as the concentration of methamphetamine analogues increases from 5.0 μg / mL to 40.0 μg / mL, the absorbance of MEF compound at 525 nm gradually increases, and the analogue concentration and absorbance maintain a good linear relationship, R 2 is 0.988. Figure 5 and Figure 6 It can be seen that the absorbance of the TFF compound at 393 nm decreases as the concentration of the methamphetamine simulant increases from 1.25 μg / mL to 8.75 μg / mL. At the same time, a new absorption peak is generated at 529 nm. The absorbance increases with the increase of the simulant concentration, and an isosbestic point appears at 445 nm. The simulant concentration and absorbance maintain a good linear relationship, R2 It is 0.976.

[0059] The MEF compound prepared in Example 1 and the TFF compound prepared in Example 2 were added to different types of drug simulants at a concentration of 0.1 mg / mL, respectively. Figure 7 It can be seen that the enhancement efficiency of methamphetamine and amphetamine simulants is greater than 50%, while the enhancement efficiency of other types of drugs is less than 5%. Figure 8 and Figure 9 It can be seen that the MEF compound prepared in Example 1 and the TFF compound prepared in Example 2 have good discrimination ability for methamphetamine and amphetamine, and can be clearly distinguished from other types of drugs.

[0060] As can be seen from the above examples, the present invention provides a boron ester furan derivative compound and its preparation method and application. The present invention mixes 5-formyl furan-3-boronic acid pinacol ester, compound a and a solvent and reacts them to obtain a boron ester furan derivative compound, wherein compound a is 2,2-dimethyl-1,3-dioxazolidine-4,6-dione [malonic acid cycloisopropyl ester], trifluoromethylisoxazol-5(4H)-one, 1,3-dimethylbarbituric acid or 1,2-diphenyl-3,5-pyrrolidone. The furan ring in the boron ester furan derivative compound prepared by the present invention can undergo a nucleophilic reaction with the amino group in the drug to generate a linear structure derivative with a characteristic color and a triene group. The solution color changes from colorless or light yellow to reddish brown, and the ultraviolet absorption spectrum changes significantly. This rapid sensing mode makes it have great development potential in the distinction and sensitive detection of drugs and their analogs.

[0061] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A boron ester furan derivative compound, characterized in that The boron ester furan derivative compound is selected from one of the following structures:

2. The method for preparing the boron ester furan derivative compound according to claim 1, wherein The following steps are involved: 5-formylfuran-3-boronic acid pinacol ester, compound a and a solvent are mixed and reacted to obtain a boron ester furan derivative compound; The compound a is 2,2-dimethyl-1,3-dioxazolidine-4,6-dione [cycloisopropylmalonate] or 3-trifluoromethylisoxazol-5(4H)-one.

3. The preparation method according to claim 2, characterized in that The molar volume ratio of the 5-formylfuran-3-boronic acid pinacol ester, compound a and solvent is 0.4-2.8 mmol: 0.4-3.8 mmol: 10-20 mL.

4. The preparation method according to claim 2 or 3, characterized in that The solvent is ethanol or dichloromethane.

5. The preparation method according to claim 4, characterized in that The reaction temperature is 20-65° C., and the reaction time is 6-14 hours.

6. The preparation method according to claim 2, 3 or 5, characterized in that: The preparation method of 3-trifluoromethylisoxazol-5(4H)-one is as follows: hydroxylamine sulfate, ethyl trifluoroacetoacetate and potassium carbonate are dissolved in ethanol and subjected to reflux reaction to obtain 3-trifluoromethylisoxazol-5(4H)-one.

7. The preparation method according to claim 6, characterized in that The molar volume ratio of the hydroxylamine sulfate, ethyl trifluoroacetoacetate, potassium carbonate and ethanol is 13-15 mmol: 14-16 mmol: 26-28 mmol: 40-60 mL.

8. The preparation method according to claim 7, characterized in that The temperature of the reflux reaction is 60-70° C., and the time of the reflux reaction is 3-4 hours.

9. Use of the boron ester furan derivative compound according to claim 1 in the detection of methamphetamine or amphetamine.

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