阅读说明：本技术 1,3,4,5-四取代吡唑衍生物及其制备方法 (1,3,4, 5-tetra-substituted pyrazole derivative and preparation method thereof ) 是由 王利民 王�琦 姚峰 杨阳 唐智聪 杨彭 钟懿 巩宇 田禾 韩建伟 于 2021-09-27 设计创作，主要内容包括：本发明涉及1,3,4,5-四取代的吡唑衍生物。所述吡唑衍生物为式I所示化合物。本发明提供的吡唑衍生物具有AIE效应,且溶液荧光最大发射光谱会随不良溶剂的增加发生“红移”。式I中,R-(1),R-(2)和R-(4)分别独立选自苯基或取代苯基中一种；R-(3)为多环芳基。(The present invention relates to 1,3,4, 5-tetrasubstituted pyrazole derivatives. The pyrazole derivative is a compound shown in a formula I. The pyrazole derivative provided by the invention has an AIE effect, and the maximum fluorescence emission spectrum of a solution can generate red shift along with the increase of poor solvents. In the formula I, R 1 ，R 2 And R 4 Each is independently selected from one of phenyl or substituted phenyl; r 3 Is a polycyclic aromatic group.)

1. A 1,3,4, 5-tetrasubstituted pyrazole derivative, which is a compound of formula I:

in the formula I, R₁，R₂And R₄Each is independently selected from one of phenyl or substituted phenyl; r₃Is a polycyclic aromatic radical;

wherein, the substituent of the substituted phenyl is selected from one or more than two of the following groups:

C₁～C₃alkyl of (C)₁～C₃Alkoxy or halogen of (a).

2. Pyrazole derivatives according to claim 1, wherein R is₁，R₂And R₄Are all phenyl groups.

3. Pyrazole derivatives according to claim 1 or 2, wherein R is₃Is pyrene ring group.

4. A process for the preparation of a pyrazole derivative according to any of claims 1 to 3, comprising the steps of:

(1) a step of preparing a compound shown as a formula III by taking a compound shown as a formula II as an initial raw material and reacting the compound shown as the formula II with methyl carbazate;

(2) a step of preparing a compound shown in a formula V by reacting a compound shown in a formula III with a compound shown in a formula IV;

(3) a step of halogenating the compound shown in the formula V at the 4-position to obtain a compound shown in the formula VI; and the combination of (a) and (b),

(4) a compound of formula VI with R₃-B(OH)₂Reacting to obtain a target object;

wherein X is Cl, Br or I, Y is Br or trifluoromethylsulfonate, R₁～R₄Is as defined in any one of claims 1 to 3.

5. The method of claim 4, wherein the main steps of step (1) are: reacting a compound shown as a formula II with methyl carbazate in a reaction solvent at 60-120 ℃ for 6-12 hours in the presence of a catalyst, cooling to room temperature, removing the reaction solvent, and purifying to obtain a compound shown as a formula III;

wherein the catalyst is a rare earth trifluoromethanesulfonate.

6. The method of claim 5, wherein the catalyst is ytterbium triflate.

7. The method of claim 4, wherein the main steps of step (2) are: and (3) placing the compound shown in the formula III and the compound shown in the formula IV in a mixture consisting of ammonia water and dichloroethane, stirring for 6-12 hours at room temperature, extracting the obtained reaction mixture by using dichloromethane, drying the obtained organic phase by using anhydrous sodium sulfate, and concentrating and purifying the filtrate to obtain the compound shown in the formula V.

8. The method of claim 4, wherein the main steps of step (3) are: and (3) placing the compound shown in the formula V, a halogenating agent and halohydrocarbon in a reactor, stirring for 6-12 hours at the temperature of 20-80 ℃, and purifying the obtained crude product to obtain the compound shown in the formula VI.

9. The method of claim 8, wherein the halogenating agent is N-bromosuccinimide.

10. The method of claim 4, wherein the main steps of step (4) are: a compound of formula VI, R₃-B(OH)₂And Pd (PPh)₃)₄Placing the mixture into a mixture composed of sodium carbonate aqueous solution, ethanol and toluene, stirring the mixture for 12 to 24 hours at the temperature of between 100 and 120 ℃ in the presence of inert gas, extracting the obtained reaction mixture by using dichloromethane, drying an obtained organic phase by using anhydrous sodium sulfate, and concentrating and purifying a filtrate to obtain the targetA compound (I) is provided.

Technical Field

The invention relates to a pyrazole (pyrazole) derivative and a preparation method thereof; in particular to a 1,3,4, 5-tetra-substituted pyrazole derivative and a preparation method thereof.

Background

Pyrazole and derivatives thereof are a very important five-membered heterocyclic compound, and are widely applied to biological systems (anti-inflammatory, antipyretic, antimicrobial, antiviral, antidepressant, pesticide and the like) and optical sensors (cosmetic colorants, fluorescent whitening agents, ultraviolet stabilizers and photoinduced electron transfer systems).

Muller group et al reported the synthesis of a series of 1,3,4, 5-tetrasubstituted pyrazole derivatives by Sonogashira coupling, cycloaddition condensation, bromination and Suzuki coupling in one pot (org. Lett., Vol.13, No.8, 2082-one-pot 2085, 2011); the perunicellathan group disclosed the synthesis of 1,3,4, 5-tetrasubstituted pyrazole derivatives and explored the effect of their Aggregation Induced Emission (AIE) effect on the luminescence properties (chem.

Hitherto, 1,3,4, 5-tetrasubstituted pyrazole derivatives have been reported to be obtained by substituting pyrazole with different monocyclic rings (aromatic or heteroaromatic groups, or substituted aromatic or heteroaromatic groups). No 1,3,4, 5-tetrasubstituted pyrazole derivatives containing polyaryl groups, in particular those containing a polyaryl group in the 4-position, have been reported.

Disclosure of Invention

The inventor designs and synthesizes a class of 1,3,4, 5-tetra-substituted pyrazole derivatives containing polyaryl ring groups, wherein the pyrazole derivatives have AIE effect, and the solution fluorescence maximum emission spectrum of some compounds can generate red shift along with the increase of poor solvent. The application field of the compound can be expanded (such as detecting the content of a poor solvent and the like).

One object of the present invention is to disclose a 1,3,4, 5-tetrasubstituted pyrazole derivative having a novel structure.

The 1,3,4, 5-tetra-substituted pyrazole derivative disclosed by the invention is a compound shown as a formula I:

in the formula I, R₁，R₂And R₄Each is independently selected from one of phenyl or substituted phenyl; r₃Is polycyclic aryl or ethynyl substituted with polycyclic aryl;

wherein, the substituent of the substituted phenyl is selected from one or more than two (including two) of the following groups:

C₁～C₃alkyl of (C)₁～C₃Alkoxy, or halogen (F, Cl, Br or I).

The invention also aims to provide a method for preparing the 1,3,4, 5-tetrasubstituted pyrazole derivative (the compound shown in the formula I).

The method comprises the following steps:

(1) taking a compound shown as a formula II as a starting material, and reacting the compound shown as the formula II with methyl carbazate (NH)₂NHCOOCH₃) Reacting to prepare a compound shown in a formula III;

(2) a step of reacting the compound of formula III with diaryl iodonium salt (compound of formula IV) to prepare a compound of formula V;

(3) a step of halogenating the compound shown in the formula V at the 4-position to obtain a compound shown in the formula VI; and the combination of (a) and (b),

(4) a compound of formula VI with R₃-B(OH)₂OrReacting to obtain a target compound (a compound shown in a formula I);

wherein X is Cl, Br or I, Y is Br or trifluoromethylsulfonate (TfO), and the compound shown in formula II is a known compound and the synthesis thereof is shown in Org.Biomol.chem., 2019, 17, 4225-4229).

Drawings

FIG. 1 is a diagram showing an ultraviolet absorption spectrum of a tetrahydrofuran solution of a compound represented by the formula Ia;

FIG. 2 is a fluorescence emission spectrum of a compound represented by formula Ia in a mixed solution of tetrahydrofuran and different water contents;

FIG. 3 shows the UV absorption spectrum of a tetrahydrofuran solution of a compound of formula Ib;

FIG. 4 shows fluorescence emission spectra of compounds of formula Ib in mixed solutions of tetrahydrofuran and different water contents.

Detailed Description

In a preferred embodiment of the present invention, R₁，R₂And R₄Are all phenyl groups.

In another preferred embodiment of the present invention, R₃Is pyrene cyclic groupWherein the curve mark is a substitution position.

In another preferred embodiment of the present invention, the process for preparing the compound of formula I comprises the steps of:

(1) reacting a compound represented by formula II with methyl carbazate (NH) in the presence of a catalyst₂NHCOOCH₃) Reacting in a reaction solvent at 60-120 ℃ for 6-12 hours, cooling to room temperature, removing the reaction solvent and purifying to obtain a compound shown in a formula III;

wherein the catalyst is a rare earth trifluoromethanesulfonate (such as ytterbium trifluoromethanesulfonate).

(2) Placing the compound shown in the formula III and diaryl iodonium salt (the compound shown in the formula IV) in a mixture consisting of ammonia water and dichloroethane, stirring for 6-12 hours at room temperature (15-35 ℃, the same applies below), extracting the obtained reaction mixture by using dichloromethane, drying the obtained organic phase by using anhydrous sodium sulfate, and concentrating and purifying the filtrate to obtain the compound shown in the formula V;

(3) placing a compound shown as a formula V, a halogenating reagent (such as N-bromosuccinimide (NBS) and the like) and halogenated hydrocarbon (reaction medium, such as methyl chloride and the like) in a reactor, stirring for 6-12 hours at the temperature of 20-80 ℃, and purifying the obtained crude product to obtain a compound shown as a formula VI; and the combination of (a) and (b),

(4) a compound of formula VI, R₃-B(OH)₂And Pd (PPh)₃)₄Placed in Na₂CO₃Stirring a mixture consisting of an aqueous solution, ethanol and toluene at the temperature of between 100 and 120 ℃ for 12 to 24 hours in the presence of inert gas (such as argon), extracting the obtained reaction mixture by using dichloromethane, drying an obtained organic phase by using anhydrous sodium sulfate, and concentrating and purifying a filtrate to obtain a target substance; or the like, or, alternatively,

the compound shown in the formula VI is reacted with a solvent,copper iodide and Pd (PPh)₃)₂Cl₂Placing the mixture into a mixture of 2-aminoethanol aqueous solution and Tetrahydrofuran (THF), stirring the mixture for at least 12 hours at a temperature of between 60 and 80 ℃ in the presence of inert gas (such as argon and the like), extracting the obtained reaction mixture by using dichloromethane, drying an obtained organic phase by using anhydrous sodium sulfate, and concentrating and purifying the filtrate to obtain the target compound.

The invention is further illustrated by the following examples, which are intended only for a better understanding of the contents of the invention. The examples given therefore do not limit the scope of protection of the invention.

Example 1

(1) Preparation of a Compound of formula IIIa:

(1) in the presence of ytterbium trifluoromethanesulfonateA compound of formula IIa with methyl carbazate (NH)₂NHCOOCH₃) Reacting in acetonitrile (reaction solvent) at 60-120 ℃ for 6-12 hours, cooling to room temperature, removing the reaction solvent, and performing silica gel column chromatography (eluent: petroleum ether/ethyl acetate 100/20(v/v)) gave a white solid (compound of formula IIIa) in 93% yield;

wherein, the compound shown as the formula IIa and NH₂NHCOOCH₃In a molar ratio of 1: (1.5-5.0).

(2) Preparation of a Compound of formula Va:

placing the compound shown in the formula IIIa and the compound shown in the formula IVa in a mixture consisting of ammonia water and dichloroethane, stirring for 6-12 hours at room temperature, extracting the obtained reaction mixture with dichloromethane, drying the obtained organic phase with anhydrous sodium sulfate, concentrating the filtrate, and performing silica gel column chromatography (eluent: petroleum ether/ethyl acetate-100/4 (v/v)) to obtain a solid, namely the compound shown in the formula Va, wherein the yield is 82%;

wherein the molar ratio of the compound shown in the formula IIIa to the compound shown in the formula IVa is 1: (1.5-2.0).

(3) Preparation of a Compound of formula VIa:

placing a compound shown as a formula Va, NBS (brominating reagent) and dichloromethane in a reactor, stirring for 6-12 hours at the temperature of 20-80 ℃, removing the solvent, and carrying out silica gel column chromatography (eluent: petroleum ether/ethyl acetate-100/4 (v/v)) on a residue to obtain a solid, namely the compound shown as a formula VIa;

(4) preparation of a Compound of formula Ia:

a compound of formula VIa (1.2g, 3.2mmol, 1.0 equivalent), a compound of formula A (2.36g, 9.60mmol, 3.0 equivalent), Pd (PPh)₃)₄(370mg, 0.32mmol), and supported on Na₂CO₃A mixture of an aqueous solution (2.0M, 8mL), ethanol (16mL) and toluene (32mL) was placed in a reactor, stirred for 24 hours at 110 ℃ in the presence of argon, the resulting reaction solution was extracted with dichloromethane, the organic phase obtained by the extraction was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate 100/4(v/v)) to give a yellow solid (the compound represented by formula Ia) in m.p.103 ℃ to 105 ℃ with a yield of 45%.

¹H NMR(400MHz,DMSO-d₆)δ8.34-8.15(m，5H)，8.09-7.91(m，4H)，7.48-7.35(m，5H)，7.34-7.27(m，2H)，7.14-6.97(m，8H)；

¹³C NMR(150MHz,DMSO-d₆)δ149.8，142.8，132.9，130.8，130.4，129.9，129.8，129.7，129.6，129.1，128.4，128.3，128.2，127.8，127.7，127.6，127.5，127.4，126.8，126.5，125.5，125.3，125.1，124.9，124.0，123.8，118.6；

IR(ATR)(3319，1735，1596，1493，1446，1364，1241，1173，1068，966，845，696)cm^-1；

HRMS (EI-TOF) calcd for (theoretical value) C₃₇H₂₄N₂[M]⁺496.1939; found (experimental value) 496.1942.

Example 2

Preparation of a Compound of formula Ib:

a compound represented by the formula VIa (1.2g, 3.2mmol, 1.0 equivalent), a compound represented by the formula B (681.8mg, 4.48mmol, 1.4 equivalents), copper iodide (53.3mg, 0.28mmol), Pd (PPh)₃)₂Cl₂(98.3mg, 0.14mmol), and a mixture of 2-aminoethanol in water (16mL)) And THF (32mL) was placed in a reactor, stirred for 24 hours at 80 ℃ in the presence of argon, the resulting reaction solution was extracted with dichloromethane, the organic phase obtained by the extraction was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate 100/4(v/v)) gave a yellow solid (compound of formula Ib) m.p.161-163 ℃ in 26% yield.

¹H NMR(400MHz，DMSO-d₆)δ8.26-8.19(m，2H)，8.03(s，1H)，7.94(dd，J＝8.8，5.3Hz，3H)，7.62-7.53(m，4H)，7.51-7.37(m，12H)；

¹³C NMR(150MHz,DMSO-d₆)δ151.0，146.1，139.1，132.6，132.3，132.0，130.4，129.5，129.3，129.2，128.8，128.7，128.6，128.5，128.4，128.3，127.8，127.7，127.6，127.0，126.9，126.7，125.4，119.9，101.2，93.5，82.8；

IR(ATR)(2919，2851，1592，1493，1189，1078，816，712)cm^-1；

HRMS(EI-TOF)calcd for C₃₃H₂₂N₂[M]⁺m/z＝446.1783；found 446.1787。

Example 3

Stock solutions of the compound of formula Ia (abbreviated as "Compound Ia") were prepared at a concentration of 100. mu. mol/L,

the specific operation steps are as follows: weighing 1.24mg of the compound Ia in a 25mL volumetric flask, adding 25mL of THF for dilution to the scale, thus obtaining 100 mu mol/L of the stock solution of the compound Ia, storing the stock solution in a refrigerator at 4 ℃ and keeping the stock solution for the experiment.

Taking 1mL of 100 mu mol/L stock solution of the compound Ia into a 10mL sample bottle, and adding 9mL of pure THF to obtain 10 mu mol/L solution of the compound Ia with the water content of 0%;

taking 1mL of 100 mu mol/L stock solution of the compound Ia into a 10mL sample bottle, and adding 8mL of pure THF and 1mL of pure water to obtain 10 mu mol/L solution of the compound Ia with the water content of 10%;

taking 1mL of 100 mu mol/L stock solution of the compound Ia into a 10mL sample bottle, and adding 7mL of pure THF and 2mL of pure water to obtain 10 mu mol/L solution of the compound Ia with the water content of 20%;

taking 1mL of 100 mu mol/L stock solution of the compound Ia into a 10mL sample bottle, and adding 6mL of pure THF and 3mL of pure water to obtain 10 mu mol/L solution of the compound Ia with the water content of 30%;

taking 1mL of 100 mu mol/L stock solution of the compound Ia into a 10mL sample bottle, and adding 5mL of pure THF and 4mL of pure water to obtain 10 mu mol/L solution of the compound Ia with the water content of 40%;

taking 1mL of 100 mu mol/L stock solution of the compound Ia into a 10mL sample bottle, and adding 4mL of pure THF and 5mL of pure water to obtain 10 mu mol/L solution of the compound Ia with the water content of 50%;

taking 1mL of 100 mu mol/L stock solution of the compound Ia into a 10mL sample bottle, and adding 3mL of pure THF and 6mL of pure water to obtain 10 mu mol/L solution of the compound Ia with the water content of 60%;

1mL of a stock solution of 100. mu. mol/L of compound Ia was taken in a 10mL sample bottle, and 2mL of pure THF and 7% pure water were added to obtain 10ol/L of a solution of compound Ia with a water content of 70%.

Taking 1mL of 100 mu mol/L stock solution of the compound Ia into a 10mL sample bottle, and adding 1mL of pure THF and 8mL of pure water to obtain 10 mu mol/L solution of the compound Ia with the water content of 80%;

1mL of a stock solution of 100. mu. mol/L of Compound Ia was taken in a 10mL sample bottle, and 9mL of pure water was added to obtain a 10. mu. mol/L solution of Compound Ia with a water content of 90%.

2mL of the above compound Ia solution having a concentration of 10. mu. mol/L and a water content of 0% was placed in a quartz cuvette, and the ultraviolet absorption intensity of the compound Ia solution was measured using an ultraviolet-visible spectrophotometer, and the results were recorded as shown in FIG. 1. The results show that compound Ia has different intensities of UV absorption at wavelengths around 240nm and 350nm, with the highest UV absorption at wavelength around 240nm and the relatively lower UV absorption at wavelength around 350 nm.

By measuring the fluorescence excitation spectrum of the compound Ia solution, the optimum excitation wavelength was determined at 348nm, and the fluorescence intensity of the compound Ia solution was measured at this wavelength, and the results were recorded as shown in FIG. 2.

As can be seen from FIG. 2, Compound Ia has a strong fluorescence emission peak around 380 nm. And the fluorescence intensity gradually increases as the water content in the solution increases. The fluorescence intensity reached a maximum when the water content was increased to 70%, indicating that the compound had AIE behavior, whereas a large decrease in fluorescence intensity was found when the water content was increased to 80% to 90%, which may result in fluorescence quenching due to the molecules in solution starting to aggregate to form precipitates with increasing water content in solution, and in a "red shift" of the emission spectrum of the solution with the change from homogeneous to emulsion.

Example 4

The ultraviolet absorption spectrum and the fluorescence emission spectrum (excitation wavelength: 320nm) of the compound represented by the formula Ib (abbreviated as "Compound Ib") were measured by the test method of example 3, and the results are shown in FIG. 3 and FIG. 4, respectively.

As can be seen from FIG. 4, Compound Ib has a strong fluorescence emission peak around 380 nm. And the fluorescence intensity gradually increases as the water content in the solution increases. The fluorescence intensity reached a maximum when the water content was increased to 40%, whereas it was found that the fluorescence intensity decreased significantly when the water content was increased to 80% to 90%, which may result in fluorescence quenching due to the molecules in the solution beginning to aggregate to form precipitates as the water content in the solution increased. Unlike compound Ia, however, the fluorescence emission spectrum of compound Ib only changes strongly and weakly with the increase of water content, and no "red shift" phenomenon is observed.