CN111518103B - Pyrazolo 1,3,5-triazine compound and preparation method thereof - Google Patents
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Abstract
The invention provides a pyrazolo 1,3,5-triazine compound and a preparation method thereof, and relates to the technical field of organic intermediates. The pyrazolo 1,3,5-triazine compound provided by the invention has a structure shown in formula I, is a 1,3,5-triazine compound with a novel structure, expands the variety of the 1,3,5-triazine compound, and can be applied to biological medicines and pesticides. The invention also provides a preparation method of the pyrazolo 1,3,5-triazine compound, which comprises the steps of mixing the aminopyrazole compound, the isothiocyanate compound, tetramethylguanidine and a polar organic solvent to obtain a mixed solution; the mixed solution is subjected to a light tandem cyclization reaction under the conditions of illumination and temperature of 20-80 ℃ and without a catalyst to obtain the pyrazolo 1,3,5-triazine compound.
Description
Technical Field
The invention relates to the technical field of organic intermediates, in particular to a pyrazolo 1,3,5-triazine compound and a preparation method thereof.
Background
The 1,3,5-triazine compounds are important nitrogen-containing heterocyclic compounds, have good biological activity and are widely applied to natural products and pharmaceutical chemistry. Compounds having 1,3,5-triazine structural units have a variety of physiological activities, such as antitumor, antitubercular, antiviral, antibacterial, antimalarial and as enzyme inhibitors; in addition, it can be used for preparing organic metal materials, liquid crystals, molecular probes and fluorescent whitening agents. Based on this, the application of 1,3,5-triazine compounds has attracted people's attention.
In recent years, researchers at home and abroad are always dedicated to the construction of 1,3,5-triazine compounds, such as Abhishek R.Tiwari and the like, benzyl alcohol and benzamidine hydrochloride with different substituents are added, nickel sulfide is used as a catalyst, cesium carbonate is used as alkali, DMSO is used as a solvent, the reaction is carried out for 16 hours at the temperature of 100 ℃, finally, the 1,3,5-triazine compounds with different substituents are obtained through cyclization reaction, the whole reaction process needs higher temperature (100 ℃), and additives such as alkali, NIS catalyst and the like, and the conditions are harsh and difficult to control. (see Abhishek R.Tiwari, NIS-Catalyzed Oxidative cycling of alcohols with amines: A Simple and Efficient, Transition-Metal Free Method for The Synthesis of 1,3,5-triazines.Org.biomol. chem.2015,13(45),10973-10976), The specific reaction scheme is as follows:
disclosure of Invention
In view of the above, the present invention aims to provide pyrazolo 1,3,5-triazine compounds and a preparation method thereof. The invention constructs a novel 1,3,5-triazine compound, and the preparation process of the 1,2, 4-triazole compound does not need a catalyst, has mild conditions and is easy to control.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a pyrazolo 1,3,5-triazine compound which has a structure shown in a formula I:
in the formula I, R1Is hydrogen, alkyl, halogen or phenyl; r2Is phenyl, benzyl, naphthyl, benzoyl, alkyl or the likeSubstituted phenyl, methoxy substituted phenyl, halogen substituted phenyl, trifluoromethyl substituted phenyl, p-nitro substituted phenyl, p-nitrile substituted phenyl, alkyl, cyclohexyl or ethyl formate.
Preferably, said R is1And R2The middle alkyl is independently alkyl with 1-5 carbon atoms;
preferably, said R is2In the formula (I), the alkyl-substituted phenyl group is p-ethylphenyl or 2,4, 6-trimethylphenyl, the methoxy-substituted phenyl group is p-methoxyphenyl, 2, 4-dimethoxyphenyl or 3,4, 5-trimethoxyphenyl, the halogen-substituted phenyl group is fluorine-substituted phenyl, chlorine-substituted phenyl or bromine-substituted phenyl, and the trifluoromethyl-substituted phenyl group is p-trifluoromethylphenyl, o-trifluoromethylphenyl or 3, 5-bis (trifluoromethyl) phenyl.
The invention provides a preparation method of pyrazolo 1,3,5-triazine compounds, which comprises the following steps:
mixing an amino pyrazole compound, an isothiocyanate compound, tetramethylguanidine and a polar organic solvent to obtain a mixed solution; carrying out a light tandem cyclization reaction on the mixed solution under the conditions of illumination and temperature of 20-80 ℃ and without a catalyst to obtain the pyrazolo 1,3,5-triazine compound;
the amino pyrazole compound has a structure shown in a formula II; the structural formula of the isothiocyanate compound is R2N＝C＝S。
Preferably, the molar ratio of the amino pyrazole compound, the isothiocyanate compound and the tetramethylguanidine is (3-4): 1: (2.9-3.1).
Preferably, the polar organic solvent is one or more of dimethyl sulfoxide, N-dimethylformamide, toluene, ethanol, acetonitrile and dichloromethane.
Preferably, the ratio of the volume of the polar organic solvent to the amount of the substance of the aminopyrazole-based compound is 1L: 0.1 to 0.3 mol.
Preferably, the wavelength of the light source of the illumination is 200-1000 nm.
Preferably, the temperature of the optical tandem cyclization reaction is 40-60 ℃.
Preferably, the time of the tandem cyclization reaction is 1-48 h.
The invention provides a pyrazolo 1,3,5-triazine compound which has a structure shown in a formula I, is a 1,3,5-triazine compound with a novel structure, and widens the variety of the 1,3,5-triazine compound. The pyrazolo 1,3,5-triazine compound provided by the invention has the characteristics of potential antibacterial, anti-inflammatory, anticancer, antivirus and insect-resistant properties, and can be applied to biological medicines and pesticides.
The invention provides a preparation method of pyrazolo 1,3,5-triazine compounds, which comprises the steps of mixing an aminopyrazole compound, an isothiocyanate compound, tetramethylguanidine and a polar organic solvent to obtain a mixed solution; and carrying out a light tandem cyclization reaction on the mixed solution under the conditions of illumination and temperature of 20-80 ℃ and without a catalyst to obtain the pyrazolo 1,3,5-triazine compound. Under the conditions of illumination and 20-80 ℃, the aminopyrazole compound, the isothiocyanate compound and the tetramethylguanidine react to form an electron donor and acceptor compound, the raw materials cannot absorb visible light, but the compound can absorb light, so that the raw materials are activated, the reaction of the raw materials is promoted, the pyrazolo 1,3,5 triazine compound can be prepared without a catalyst, the reaction conditions are mild, the steps are simple, and the control is easy.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a product obtained in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of the product obtained in example 1 of the present invention;
FIG. 3 is a NMR chart of a product obtained in example 2 of the present invention;
FIG. 4 is a nuclear magnetic resonance carbon spectrum of the product obtained in example 2 of the present invention;
FIG. 5 is a NMR chart of a product obtained in example 3 of the present invention;
FIG. 6 is the NMR spectrum of the product obtained in example 3 of the present invention;
FIG. 7 is a NMR chart of a product obtained in example 4 of the present invention;
FIG. 8 is the NMR spectrum of the product obtained in example 4 of the present invention;
FIG. 9 is a NMR chart of a product obtained in example 5 of the present invention;
FIG. 10 is the NMR spectrum of the product obtained in example 5 of the present invention;
FIG. 11 is a NMR chart of a product obtained in example 6 of the present invention;
FIG. 12 is a NMR spectrum of a product obtained in example 6 of the present invention;
FIG. 13 is a NMR chart of the product obtained in example 7 of the present invention;
FIG. 14 is a NMR spectrum of a product obtained in example 7 of the present invention;
FIG. 15 is a NMR chart of a product obtained in example 8 of the present invention;
FIG. 16 is a NMR spectrum of a product obtained in example 8 of the present invention;
FIG. 17 is a NMR chart of a product obtained in example 9 of the present invention;
FIG. 18 is a NMR spectrum of a product obtained in example 9 of the present invention;
FIG. 19 is a NMR spectrum of a product obtained in example 10 of the present invention;
FIG. 20 is a NMR spectrum of a product obtained in example 10 of the present invention;
FIG. 21 is a NMR chart of a product obtained in example 11 of the present invention;
FIG. 22 is a NMR spectrum of a product obtained in example 11 of the present invention;
FIG. 23 is a NMR chart of a product obtained in example 12 of the present invention;
FIG. 24 is a NMR spectrum of a product obtained in example 12 of the present invention;
FIG. 25 is a NMR chart of a product obtained in example 13 of the present invention;
FIG. 26 is a NMR spectrum of a product obtained in example 13 of the present invention;
FIG. 27 is a NMR chart of a product obtained in example 14 of the present invention;
FIG. 28 is the NMR spectrum of the product obtained in example 14 of the present invention.
Detailed Description
The invention provides a pyrazolo 1,3,5-triazine compound which has a structure shown in a formula I:
in the formula I, R1Is hydrogen, alkyl, halogen or phenyl; r2Is phenyl, benzyl, naphthyl, benzoyl, alkyl substituted phenyl, methoxy substituted phenyl, halogen substituted phenyl, trifluoromethyl substituted phenyl, p-nitro substituted phenyl, p-nitrile substituted phenyl, alkyl, cyclohexyl or ethyl formate.
In the present invention, said R1Is hydrogen radical, alkyl, halogen or phenyl. In the invention, the alkyl is preferably an alkyl with 1-5 carbon atoms, and is further preferably methyl, ethyl, tert-butyl or dimethyl; the halogen is preferably fluorine, chlorine or bromine, and more preferably bromine.
In the present invention, said R2Is phenyl, benzyl, naphthyl, benzoyl, alkyl substituted phenyl, methoxy substituted phenyl, halogen substituted phenyl, trifluoromethyl substituted phenyl, p-nitro substituted phenyl, p-nitrile substituted phenyl, alkyl, cyclohexyl or ethyl formate. In the present invention, the alkyl-substituted phenyl group is preferably a p-ethylphenyl group or a 2,4, 6-trimethylphenyl group; the methoxy-substituted phenyl is preferably p-methoxyphenyl, 2, 4-dimethoxyphenyl or 3,4, 5-trimethoxyphenyl; the halogen substituted phenyl is fluorine substituted phenyl, chlorine substituted phenyl or bromine substituted phenyl, and is further preferably p-fluorophenyl, p-bromophenyl, o-chlorophenyl, m-chlorophenyl or 2, 4-difluorophenyl; the trifluoromethyl substituted phenyl is p-trifluoromethylPhenyl, o-trifluoromethylphenyl or 3, 5-bis (trifluoromethyl) phenyl; the alkyl group is preferably an alkyl group having 1 to 5 carbon atoms, and more preferably a methyl group or an n-butyl group.
In the specific embodiment of the invention, the specific structure of the pyrazolo 1,3,5-triazine compound is as follows:
the pyrazolo 1,3,5-triazine compound provided by the invention is a 1,3,5-triazine compound with a novel structure, and the variety of the 1,3,5-triazine compound is expanded. The pyrazolo 1,3,5-triazine compound provided by the invention has the characteristics of potential antibacterial, anti-inflammatory, anticancer, antivirus and insect-resistant properties, and can be applied to biological medicines and pesticides.
The invention provides a preparation method of pyrazolo 1,3,5-triazine compounds, which comprises the following steps:
mixing an amino pyrazole compound, an isothiocyanate compound, tetramethylguanidine and a polar organic solvent to obtain a mixed solution; carrying out a light tandem cyclization reaction on the mixed solution under the conditions of illumination and temperature of 20-80 ℃ and without a catalyst to obtain the pyrazolo 1,3,5-triazine compound;
the amino pyrazole compound has a structure shown in a formula II; the structural formula of the isothiocyanate compound is R2N＝C＝S。
The preparation method comprises the steps of mixing an amino pyrazole compound, an isothiocyanate compound, tetramethylguanidine and a polar organic solvent to obtain a mixed solution. In the invention, the amino pyrazole compound has a structure shown in formula II, and R in the structure shown in formula II1And R in the structure shown in the formula I1Keeping the same is not described herein. In a specific embodiment of the invention, the amino pyrazole compound is specifically 3-amino-5-methylpyrazole, 3, 4-dimethyl-5-aminopyrazole, 3-amino-5-ethylpyrazole, 3-amino-5-tert-butylpyrazole, 3-amino-4-bromopyrazole, 3-amino-5-phenylpyrazole.
In the invention, the structural formula of the isothiocyanate compound is R2N ═ C ═ S, and R in the structural formula of the isothiocyanate compound2And R in the structure shown in the formula I2Keeping the same is not described herein. In a specific embodiment of the present invention, the isothiocyanate-based compound is specifically phenyl isothiocyanate, phenyl p-fluoroisothiocyanate, phenyl p-methoxyisothiocyanate, phenyl p-ethylisothiocyanate, phenyl 2, 4-dimethoxyisothiocyanate, benzyl isothiocyanate, methyl isothiocyanate, or phenyl 2,4, 6-trimethylisothiocyanate.
In the invention, the molar ratio of the amino pyrazole compound, the isothiocyanate compound and the tetramethylguanidine is preferably (3-4): 1: (2.9-3.1), and more preferably 3:1: 3.
In the invention, the polar organic solvent is preferably one or more of dimethyl sulfoxide, N-dimethylformamide, toluene, ethanol, acetonitrile and dichloromethane; the ratio of the volume of the polar organic solvent to the amount of the substance of the aminopyrazole-based compound is preferably 1L: 0.1 to 0.3 mol.
The invention has no special requirements on the sources of the aminopyrazole compound, the isothiocyanate compound, the tetramethylguanidine and the polar organic solvent, and can adopt corresponding commercial products which are well known by the technical personnel in the field. The method for mixing the components has no special requirement, and the raw material components are uniformly mixed by adopting a method well known by the technical personnel in the field.
After a mixed solution is obtained, the mixed solution is subjected to light tandem cyclization reaction under the conditions of illumination and the temperature of 20-80 ℃ to obtain the pyrazolo 1,3,5-triazine compound. In the invention, the wavelength of the light source for illumination is preferably 200-1000 nm, more preferably 300-800 nm, and even more preferably 400-465 nm. The present invention does not require the light source in particular, and can provide any light source having the above-mentioned wavelength. In the invention, the temperature of the optical tandem cyclization reaction is preferably 40-60 ℃; the time of the tandem cyclization reaction is preferably 1-48 h, and more preferably 6-24 h. In the present invention, the tandem cyclization reaction is preferably carried out under stirring conditions, and the stirring speed in the present invention is not particularly required.
After the phototandem cyclization reaction, the present invention preferably performs a purification treatment on the obtained phototandem cyclization reaction liquid. In the present invention, the purification treatment is preferably column chromatography. In the invention, the eluent of the column chromatography is preferably a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate in the mixed solvent is preferably 1-30: 1, more preferably 5 to 20: 1, more preferably 5: 1. the present invention does not require any particular method for carrying out column chromatography, and may be carried out in a manner known to those skilled in the art. According to the invention, petroleum ether and ethyl acetate are used as eluent, and the mixed solution after cyclization reaction is subjected to column chromatography purification treatment, so that the pyrazolo 1,3,5-triazine compound with higher purity can be obtained. In the present invention, the purity of the pyrazolo 1,3,5-triazine compound is preferably 98.5 to 99.9%, and more preferably 99 to 99.9%.
The invention provides a preparation method of pyrazolo 1,3,5-triazine compounds, which is characterized in that under the conditions of illumination and temperature of 20-80 ℃, amino pyrazole compounds, isothiocyanate compounds and tetramethylguanidine react to form an electron donor and acceptor compound, so that the reaction can be accelerated, the pyrazolo 1,3,5-triazine compounds can be prepared without a catalyst, and the preparation method is mild in reaction conditions, simple in steps and easy to control; in addition, the preparation method of the pyrazolo 1,3,5-triazine compound provided by the invention has good adaptability to raw materials, and can be used for preparing pyrazolo 1,3,5-triazine compounds with different substituents.
The pyrazolo 1,3,5-triazines and methods of preparation thereof provided by the present invention are described in detail below with reference to the examples, but they should not be construed as limiting the scope of the present invention.
Example 1
A pyrazolo 1,3,5-triazine compound has a structure shown in a formula I- (1):
the preparation method comprises the following steps: adding 0.3mmol of 3-amino-5-methylpyrazole, 0.1mmol of phenyl isothiocyanate, 0.3mmol of tetramethylguanidine, 0.5mL of acetonitrile and 0.5mL of DMF into a reaction tube, mixing, and stirring the mixed solution for reaction at 60 ℃ for 12h under the irradiation of a light source of 465 nm; after the reaction is finished, separating and purifying by chromatography, wherein the volume ratio of petroleum ether to ethyl acetate in column chromatography eluent is 5: 1, obtaining the purified target product 20.4mg, the yield is 76%, and the purity is 99.9%.
The structure of the obtained product is characterized, wherein a nuclear magnetic resonance hydrogen spectrogram and a nuclear magnetic resonance carbon spectrogram are respectively shown in fig. 1 and fig. 2, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3,ppm)：δ7.61-7.59(d,J＝8Hz,2H),7.31-7.28(t,J＝8Hz,2H),7.19(s,1H),7.02-6.98(t,J＝8Hz,1H),5.79(s,1H),3.54(s,6H),2.34(s,3H).
13C NMR(100MHz,CDCl3,ppm)：δ154.9,154.8,153.7,150.2,139.7,128.8,122.3,119.4,91.6,40.2,14.7.
MS(EI,70eV)：m/z(％)＝268,253,212,199,92.
according to the data and the spectrogram analysis, the obtained product conforms to the structure of the pyrazolo 1,3,5-triazine compound shown in the formula I- (1).
Example 2
A pyrazolo 1,3,5-triazine compound has a structure shown in a formula I- (2):
the preparation method comprises the following steps: adding 0.3mmol of 3, 4-dimethyl-5-aminopyrazole, 0.1mmol of phenyl isothiocyanate, 0.3mmol of tetramethylguanidine, 0.5mL of acetonitrile and 0.5mL of DMF into a reaction tube, mixing, and stirring the mixed solution for reaction for 48h at 20 ℃ under the irradiation of a light source of 465 nm; after the reaction is finished, carrying out chromatographic separation and purification, wherein the volume ratio of petroleum ether to ethyl acetate in column chromatography eluent is 5: 1, obtaining 16.9mg of a purified target product, wherein the yield is 60 percent, and the purity is 99.9 percent.
The structure of the obtained product is characterized, the nuclear magnetic resonance hydrogen spectrogram and the nuclear magnetic resonance carbon spectrogram are respectively shown in fig. 3 and 4, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3,ppm)：δ7.68-7.64(m,2H),7.33-7.29(m,2H),7.02-6.98(m,2H),3.54(s,6H),2.30(s,3H),2.09(s,3H).
13C NMR(100MHz,CDCl3,ppm)：δ154.2,154.1,150.2,150.2,140.0,128.8,122.0,118.9,99.5,40.1,12.8,6.8.
MS(EI,70eV)：m/z(％)＝282,228,214,161,118.
according to the data and the spectrogram analysis, the obtained product conforms to the structure of the pyrazolo 1,3,5-triazine compound shown as the formula I- (2).
Example 3
A pyrazolo 1,3,5-triazine compound has a structure shown in a formula I- (3):
the preparation method comprises the following steps: adding 0.3mmol of 3-amino-5-ethylpyrazole, 0.1mmol of phenyl isothiocyanate, 0.3mmol of tetramethylguanidine, 0.5mL of acetonitrile and 0.5mL of DMF into a reaction tube, mixing, and stirring the mixed solution for reaction at 70 ℃ for 15h under the irradiation of a 365nm light source; after the reaction is finished, carrying out chromatographic separation and purification, wherein the volume ratio of petroleum ether to ethyl acetate in column chromatography eluent is 5: 1, obtaining the purified target product of 18.0mg, 64 percent of yield and 99.9 percent of purity.
The structure of the obtained product is characterized, the nuclear magnetic resonance hydrogen spectrogram and the nuclear magnetic resonance carbon spectrogram are respectively shown in fig. 5 and 6, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3,ppm)：δ7.65-7.63(m,3H),7.35-7.31(m,2H),7.05-7.01(m,1H),5.86(s,1H),3.58(s,6H),2.77-2.71(q,J＝8Hz,2H),1.34-1.30(t,J＝8H,3H).
13C NMR(100MHz,CDCl3,ppm)：δ160.5,154.9,153.6,150.3,139.8,128.8,122.2,119.4,90.1,40.2,22.4,13.2.
MS(EI,70eV)：m/z(％)＝282,241,228,174,132.
according to the data and the spectrogram analysis, the obtained product conforms to the structure of the pyrazolo 1,3,5-triazine compound shown as the formula I- (3).
Example 4
A pyrazolo 1,3,5-triazine compound has a structure shown in a formula I- (4):
the preparation method comprises the following steps: adding 0.3mmol of 3-amino-5-tert-butylpyrazole, 0.1mmol of phenyl isothiocyanate, 0.3mmol of tetramethylguanidine, 0.5mL of acetonitrile and 0.5mL of DMF into a reaction tube, mixing, and stirring the mixed solution for reaction at 80 ℃ for 1h under the irradiation of a 365nm light source; after the reaction is finished, carrying out chromatographic separation and purification, wherein the volume ratio of petroleum ether to ethyl acetate in column chromatography eluent is 5: 1, obtaining 20.8mg of the purified target product, wherein the yield is 67 percent, and the purity is 99.9 percent.
The structure of the obtained product is characterized, the nuclear magnetic resonance hydrogen spectrogram and the nuclear magnetic resonance carbon spectrogram are respectively shown in fig. 7 and 8, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3,ppm)：δ7.62-7.60(t,J＝8Hz,3H),7.31-7.27(q,J＝8Hz,2H),7.23(s,1H),5.88(s,1H),3.56(s,6H),1.34(s,9H).
13C NMR(100MHz,CDCl3,ppm)：δ167.3,154.8,153.3,150.3,139.8,128.8,122.1,119.4,88.4,40.3,32.8,30.1.
MS(EI,70eV)：m/z(％)＝310,295,253,225,185.
according to the data and the spectrogram analysis, the obtained product conforms to the structure of the pyrazolo 1,3,5-triazine compound shown as the formula I- (4).
Example 5
A pyrazolo 1,3,5-triazine compound has a structure shown in a formula I- (5):
the preparation method comprises the following steps: adding 0.1mmol of 3-amino-4-bromopyrazole, 0.1mmol of phenyl isothiocyanate, 0.3mmol of tetramethylguanidine, 0.5mL of acetonitrile and 0.5mL of DMF into a reaction tube, mixing, and stirring the mixed solution for reaction at 80 ℃ for 6 hours under the irradiation of a light source with the wavelength of 415 nm; after the reaction is finished, carrying out chromatographic separation and purification, wherein the volume ratio of petroleum ether to ethyl acetate in column chromatography eluent is 5: 1, obtaining the purified target product 24.2mg, the yield is 73%, and the purity is 99.9%.
The structure of the obtained product is characterized, the nuclear magnetic resonance hydrogen spectrogram and the nuclear magnetic resonance carbon spectrogram are respectively shown in fig. 9 and fig. 10, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3,ppm)：δ7.76(s,1H),7.64-7.62(d,J＝8Hz,2H)，7.34-7.31(t,J＝8Hz,2H),7.10(s,1H),7.06-7.00(t,J＝8Hz,1H)，3.56(s,6H).
13C NMR(100MHz,CDCl3,ppm)：δ155.4,150.2,149.9,144.5,139.3,128.9,122.7,119.4,40.6.
MS(EI,70eV)：m/z(％)＝332,294,196,132,118.
according to the data and the spectrogram analysis, the obtained product conforms to the structure of the pyrazolo 1,3,5-triazine compound shown as the formula I- (5).
Example 6
A pyrazolo 1,3,5-triazine compound has a structure shown in a formula I- (6):
the preparation method comprises the following steps: adding 0.3mmol of 3-amino-5-phenylpyrazole, 0.1mmol of phenyl isothiocyanate, 0.3mmol of tetramethylguanidine, 0.5mL of acetonitrile and 0.5mL of DMF into a reaction tube, mixing, and stirring the mixed solution for reaction at 30 ℃ for 12 hours under the irradiation of a light source of 465 nm; after the reaction is finished, carrying out chromatographic separation and purification, wherein the volume ratio of petroleum ether to ethyl acetate in column chromatography eluent is 5: 1, obtaining 21.1mg of a purified target product, wherein the yield is 64 percent and the purity is 99.9 percent.
The structure of the obtained product is characterized, the nuclear magnetic resonance hydrogen spectrogram and the nuclear magnetic resonance carbon spectrogram are respectively shown in fig. 11 and 12, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3,ppm)：δ7.90(s,2H),7.63-7.61(d,J＝8Hz,2H),7.44-7.29(m,5H),7.03-7.00(t,J＝8Hz,1H),6.30-6.29(d,J＝4Hz,1H),3.58(s,6H).
13C NMR(100MHz,CDCl3,ppm)：δ155.6,155.0,154.0,150.2,139.6,133.0,128.9,128.8,128.6,126.4,122.4,119.5,88.7,40.5.
MS(EI,70eV)：m/z(％)＝330,278,253,200,132.
according to the data and the spectrogram analysis, the obtained product conforms to the structure of the pyrazolo 1,3,5-triazine compound shown as the formula I- (6).
Example 7
A pyrazolo 1,3,5-triazine compound has a structure shown in a formula I- (7):
the preparation method comprises the following steps: adding 0.3mmol of 3-aminopyrazole, 0.1mmol of phenyl isothiocyanate, 0.3mmol of tetramethylguanidine, 0.5mL of acetonitrile and 0.5mL of DMF into a reaction tube, mixing, and stirring at 60 ℃ for reaction for 48h under the irradiation of a light source with the wavelength of 425 nm; after the reaction is finished, carrying out chromatographic separation and purification, wherein the volume ratio of petroleum ether to ethyl acetate in column chromatography eluent is 5: 1, obtaining 21.3mg of a purified target product, wherein the yield is 84 percent, and the purity is 99.9 percent.
The structure of the obtained product is characterized, the nuclear magnetic resonance hydrogen spectrogram and the nuclear magnetic resonance carbon spectrogram are respectively shown in fig. 13 and 14, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3,ppm)：δ7.79(s,1H),7.62-7.60(d,J＝8Hz,2H),7.32-7.29(t,J＝8Hz,3H),7.03-7.00(t,J＝8Hz,1H),5.98(d,1H),3.56(s,6H).
13C NMR(100MHz,CDCl3,ppm)：δ＝154.9,153.3,150.6,144.9,139.6,128.9,122.5,119.5,91.6,40.4.
MS(EI,70eV)：m/z(％)＝254,212,156,132,104.
according to the data and the spectrogram analysis, the obtained product conforms to the structure of the pyrazolo 1,3,5-triazine compound shown as the formula I- (7).
Example 8
A pyrazolo 1,3,5-triazine compound has a structure shown in a formula I- (8):
the preparation method comprises the following steps: adding 0.1mmol of 3-aminopyrazole, 0.1mmol of p-fluoroisosulfocyanate, 0.3mmol of tetramethylguanidine, 0.5mL of acetonitrile and 0.5mL of DMF into a reaction tube, mixing, and stirring and reacting at 60 ℃ for 12h under the irradiation of a light source with the wavelength of 465 nm; after the reaction is finished, carrying out chromatographic separation and purification, wherein the volume ratio of petroleum ether to ethyl acetate in column chromatography eluent is 5: 1, obtaining the purified target product 19.6mg, the yield is 72 percent, and the purity is 99.9 percent.
The structure of the obtained product is characterized, the nuclear magnetic resonance hydrogen spectrogram and the nuclear magnetic resonance carbon spectrogram are respectively shown in fig. 15 and 16, and the structural characterization data are as follows:
1HNMR(400MHz,CDCl3,ppm)：7.79-7.78(d,J＝4.0Hz,1H),7.57-7.52(m,2H),7.17(s,1H),7.03-6.98(m,2H),5.96(d,1H),3.56(s,6H).
13C NMR(100MHz,CDCl3,ppm)：δ158.5(d,J＝24Hz),155.0,153.2,150.5,144.9,135.6,121.4(d,J＝7Hz),115.3(d,J＝2Hz),100.0,91.5,40.4.
MS(EI,70eV)：m/z(％)＝272,228,203,190,136.
according to the data and the spectrogram analysis, the obtained product conforms to the structure of the pyrazolo 1,3,5-triazine compound shown as the formula I- (8).
Example 9
A pyrazolo 1,3,5-triazine compound has a structure shown in a formula I- (9):
the preparation method comprises the following steps: adding 0.3mmol of 3-aminopyrazole, 0.1mmol of p-methoxy phenyl isothiocyanate, 0.3mmol of tetramethylguanidine, 0.5mL of acetonitrile and 0.5mL of DMF into a reaction tube, mixing, and stirring the mixed solution under the irradiation of a 1000nm light source at 60 ℃ for reaction for 12 h; after the reaction is finished, carrying out chromatographic separation and purification, wherein the volume ratio of petroleum ether to ethyl acetate in column chromatography eluent is 5: 1, obtaining 20.1mg of the purified target product, wherein the yield is 71 percent and the purity is 99.9 percent.
The structure of the obtained product is characterized, the nuclear magnetic resonance hydrogen spectrogram and the nuclear magnetic resonance carbon spectrogram are respectively shown in fig. 17 and fig. 18, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3,ppm)：δ7.78-7.76(t,J＝8Hz,1H),7.50-7.46(m,2H),7.32(s,1H),6.87-6.84(q,J＝4Hz,2H),5.93-5.92(d,J＝4Hz,1H),3.78(s,3H),3.53(s,6H).
13C NMR(100MHz,CDCl3,ppm)：δ155.4,155.3,153.4,150.4,144.8,132.7,121.9,114.0,91.2,55.5,40.3.
MS(EI,70eV)：m/z(％)＝284,269,199,188,148.
according to the data and the spectrogram analysis, the obtained product conforms to the structure of the pyrazolo 1,3,5-triazine compound shown as the formula I- (9).
Example 10
A pyrazolo 1,3,5-triazine compound has a structure shown in a formula I- (10):
the preparation method comprises the following steps: adding 0.3mmol of 3-aminopyrazole, 0.1mmol of p-ethyl phenyl isothiocyanate, 0.3mmol of tetramethylguanidine, 0.5mL of acetonitrile and 0.5mL of DMF into a reaction tube, mixing, and stirring at 60 ℃ for reacting for 18h under the irradiation of a light source with the wavelength of 465 nm; after the reaction is finished, carrying out chromatographic separation and purification, wherein the volume ratio of petroleum ether to ethyl acetate in column chromatography eluent is 5: 1, obtaining the purified target product 19.7mg, the yield is 70%, and the purity is 99.9%.
The structure of the obtained product is characterized, the nuclear magnetic resonance hydrogen spectrogram and the nuclear magnetic resonance carbon spectrogram are respectively shown in fig. 19 and fig. 20, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3,ppm)δ7.79-7.78(d,J＝4.0Hz,1H),7.52-7.50(d,J＝8Hz,2H),7.16-7.14(d,J＝8Hz,2H),6.99(s,1H),5.98-5.97(d,J＝4Hz,1H),3.56(s,6H),2.64-2.59(q,J＝8Hz,2H),1.25-1.21(q,J＝8Hz,3H).
13C NMR(100MHz,CDCl3,ppm)δ155.0,153.3,150.5,144.9,138.6,137.1,128.2,119.8,91.4,40.4,28.3,15.8.
Ms(EI):m/z＝282,267,238,213,197.
according to the data and the spectrogram analysis, the obtained product conforms to the structure of the pyrazolo 1,3,5-triazine compound shown as the formula I- (10).
Example 11
A pyrazolo 1,3,5-triazine compound has a structure shown in a formula I- (11):
the preparation method comprises the following steps: adding 0.3mmol of 3-aminopyrazole, 0.1mmol of 2, 4-dimethoxy phenyl isothiocyanate, 0.3mmol of tetramethylguanidine, 0.5mL of acetonitrile and 0.5mL of DMF into a reaction tube, mixing, and stirring the mixed solution for reaction at 50 ℃ for 6h under the irradiation of a 200nm light source; after the reaction is finished, carrying out chromatographic separation and purification, wherein the volume ratio of petroleum ether to ethyl acetate in column chromatography eluent is 5: 1, obtaining the purified target product 22.0mg, the yield is 70 percent, and the purity is 99.9 percent.
The structure of the obtained product is characterized, the nuclear magnetic resonance hydrogen spectrogram and the nuclear magnetic resonance carbon spectrogram are respectively shown in fig. 21 and 22, and the structural characterization data are shown as follows:
1H NMR(400MHz,CDCl3,ppm)δ8.33-8.31(d,J＝8Hz,1H),7.78-7.77(d,J＝4Hz,1H),7.21(s,1H),6.53-6.50(q,J＝12Hz,2H),5.98-5.97(d,J＝4Hz,1H),3.87(s,3H),3.80(s,3H),3.57(s,6H).
13C NMR(100MHz,CDCl3,ppm)δ155.3,154.9,153.3,150.4,149.4,144.8,122.7,120.1,103.7,98.7,91.3,55.7,55.6,40.4.
Ms(EI):m/z＝314,283,268,229,207.
according to the data and the spectrogram analysis, the obtained product conforms to the structure of the pyrazolo 1,3,5-triazine compound shown as the formula I- (11).
Example 12
A pyrazolo 1,3,5-triazine compound has a structure shown in a formula I- (12):
the preparation method comprises the following steps: adding 0.2mmol of 3-aminopyrazole, 0.1mmol of methyl isothiocyanate, 0.3mmol of tetramethylguanidine, 0.5mL of acetonitrile and 0.5mL of DMF into a reaction tube, mixing, and stirring the mixed solution at 60 ℃ for reaction for 12h under the irradiation of a light source with the wavelength of 425 nm; after the reaction is finished, carrying out chromatographic separation and purification, wherein the volume ratio of petroleum ether to ethyl acetate in column chromatography eluent is 5: 1, obtaining 13.1mg of a purified target product, wherein the yield is 68 percent, and the purity is 99.9 percent.
The structure of the obtained product is characterized, the nuclear magnetic resonance hydrogen spectrogram and the nuclear magnetic resonance carbon spectrogram are respectively shown in fig. 23 and 24, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3,ppm)δ7.69(d,J＝2Hz,1H),5.86(s,1H),3.46(s,6H),2.94-2.93(d,J＝4Hz,3H).
13C NMR(100MHz,CDCl3,ppm)δ158.2,153.9,150.3,144.6,88.0,40.1,28.3.
Ms(EI):m/z＝192,163,123,82,57.
according to the data and the spectrogram analysis, the obtained product conforms to the structure of the pyrazolo 1,3,5-triazine compound shown as the formula I- (12).
Example 13
A pyrazolo 1,3,5-triazine compound has a structure shown in a formula I- (13):
the preparation method comprises the following steps: adding 0.3mmol of 3-aminopyrazole, 0.1mmol of benzyl isothiocyanate, 0.3mmol of tetramethylguanidine, 0.5mL of acetonitrile and 0.5mL of DMF into a reaction tube, mixing, and stirring at 60 ℃ for reaction for 12h under the irradiation of a light source of 465 nm; after the reaction is finished, carrying out chromatographic separation and purification, wherein the volume ratio of petroleum ether to ethyl acetate in column chromatography eluent is 5: 1, obtaining 16.1mg of a purified target product, wherein the yield is 60 percent, and the purity is 99.9 percent.
The structure of the obtained product is characterized, the nuclear magnetic resonance hydrogen spectrogram and the nuclear magnetic resonance carbon spectrogram are respectively shown in fig. 25 and 26, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3,ppm)δ7.74(s,1H),7.36-7.31(q,J＝12Hz,4H),5.88(s,1H),5.33(s,1H),4.63-4.61(d,J＝8Hz,2H),3.49(s,6H).
13C NMR(100MHz,CDCl3,ppm)δ157.5,152.4,150.5,143.7,139.4,128.6,127.6,127.2,90.8,47.4,41.3.
Ms(EI):m/z＝268,224,197,163,134,106.
according to the data and the spectrogram analysis, the obtained product conforms to the structure of the pyrazolo 1,3,5-triazine compound shown as the formula I- (13).
Example 14
A pyrazolo 1,3,5-triazine compound has a structure shown in a formula I- (14):
the preparation method comprises the following steps: adding 0.3mmol of 3-aminopyrazole, 0.1mmol of 2,4, 6-trimethyl phenyl isothiocyanate, 0.3mmol of tetramethylguanidine, 0.5mL of acetonitrile and 0.5mL of DMF into a reaction tube, mixing, and stirring for reaction at 60 ℃ for 12h under the irradiation of a light source of 465 nm; after the reaction is finished, carrying out chromatographic separation and purification, wherein the volume ratio of petroleum ether to ethyl acetate in column chromatography eluent is 5: 1, obtaining the purified target product of 18.4mg, the yield is 62 percent, and the purity is 99.9 percent.
The structure of the obtained product is characterized, the nuclear magnetic resonance hydrogen spectrogram and the nuclear magnetic resonance carbon spectrogram are respectively shown in fig. 27 and 28, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3,ppm)δ7.70(d,J＝2Hz,1H),6.90(s,2H),5.78(s,1H),3.44(s,6H),2.28(s,3H),2.23(s,6H).
13C NMR(100MHz,CDCl3,ppm)δ156.8,154.0,150.6,144.7,136.0,133.2,128.7,93.2,40.1,21.0,10.0.
Ms(EI):m/z＝296,281,252,226,213.
according to the data and the spectrogram analysis, the obtained product conforms to the structure of the pyrazolo 1,3,5-triazine compound shown as the formula I- (14).
According to the characterization results of the examples 1 to 14, the invention provides a series of pyrazolo 1,3,5-triazine compounds; the preparation method provided by the invention provides the required energy for the raw materials by utilizing the irradiation and heating of light, can obtain the target product without adding a catalyst, and has mild reaction conditions and easy control; in addition, the preparation method provided by the invention has the advantages that the raw materials are easy to obtain, and the raw material cost is reduced; and the prepared pyrazolo 1,3,5-triazine compound has higher purity, so the preparation method provided by the invention has higher market popularization value.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (2)
1. The preparation method of the pyrazolo 1,3,5-triazine compound is characterized by comprising the following steps:
mixing an amino pyrazole compound, an isothiocyanate compound, tetramethylguanidine and a polar organic solvent to obtain a mixed solution; carrying out a light tandem cyclization reaction on the mixed solution under the conditions of illumination and temperature of 20-80 ℃ and without a catalyst to obtain a pyrazolo 1,3,5-triazine compound;
the pyrazolo 1,3,5-triazine compound has a structure shown in formula I:
in the formula I, R1Is hydrogen, alkyl, halogen or phenyl; r2Is phenyl, benzyl, naphthyl, benzoyl, alkyl substituted phenyl, methoxy substituted phenyl, halogen substituted phenyl, trifluoromethyl substituted phenyl, p-nitro substituted phenyl, p-nitrile substituted phenyl, alkyl, cyclohexyl or ethyl formate;
the R is1And R2The middle alkyl is independently alkyl with 1-5 carbon atoms;
the R is2Wherein the alkyl-substituted phenyl group is p-ethylphenyl or 2,4, 6-trimethylphenyl, the methoxy-substituted phenyl group is p-methoxyphenyl, 2, 4-dimethoxyphenyl or 3,4, 5-trimethoxyphenyl, the halogen-substituted phenyl group is fluoro-substituted phenyl, chloro-substituted phenyl or bromo-substituted phenyl, and the trifluoromethyl-substituted phenyl group is p-trifluoromethylphenyl, o-trifluoromethylphenyl or 3, 5-bis (trifluoromethyl) phenyl;
the amino pyrazole compound has a structure shown in a formula II; the structural formula of the isothiocyanate compound is R2N=C=S；
the molar ratio of the amino pyrazole compound, the isothiocyanate compound and the tetramethylguanidine is (3-4): 1: (2.9-3.1);
the polar organic solvent is one or more of dimethyl sulfoxide, N-dimethylformamide, toluene, ethanol, acetonitrile and dichloromethane; the ratio of the volume of the polar organic solvent to the amount of the substance of the aminopyrazole-based compound is 1L: 0.1-0.3 mol;
the wavelength of the light source for illumination is 200-1000 nm;
the time of the optical tandem cyclization reaction is 1-48 h.
2. The method according to claim 1, wherein the temperature of the phototandem cyclization reaction is 40 to 60 ℃.
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| WO2014189830A1 (en) * | 2013-05-20 | 2014-11-27 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Calcium channel agonists |
| CN107089983A (en) * | 2017-03-22 | 2017-08-25 | 浙江工业大学 | Imidazo s-triazine compound and its preparation method and application |
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