CN112480004B - 5-trifluoromethyl substituted pyrazole derivative and synthesis method and application thereof - Google Patents
5-trifluoromethyl substituted pyrazole derivative and synthesis method and application thereof Download PDFInfo
- Publication number
- CN112480004B CN112480004B CN202011215965.4A CN202011215965A CN112480004B CN 112480004 B CN112480004 B CN 112480004B CN 202011215965 A CN202011215965 A CN 202011215965A CN 112480004 B CN112480004 B CN 112480004B
- Authority
- CN
- China
- Prior art keywords
- substituted pyrazole
- reaction
- column chromatography
- pyrazole derivative
- hydrazone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a 5-trifluoromethyl substituted pyrazole derivative and a synthesis method and application thereof, belonging to the technical field of substituted pyrazole derivatives. The synthesis method comprises the following steps; adding chloroaldehyde hydrazone, 2-bromo-3, 3, 3-trifluoropropene, alkali and an organic solvent into a reactor, stirring for reaction, and carrying out aftertreatment on a reaction product to obtain the 5-trifluoromethyl substituted pyrazole derivative. The synthesis method of the invention does not use a catalyst, and the used raw materials are nontoxic, cheap and easy to obtain; the reaction has good adaptability to functional groups, wide adaptability to substrates, high product yield and good regioselectivity. The synthesis method of the invention has the advantages of simple and safe operation, mild reaction conditions, insensitivity to water and air, and good industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of substituted pyrazole derivatives, and particularly relates to a 5-trifluoromethyl substituted pyrazole derivative and a synthesis method thereof.
Background
5-trifluoromethylpyrazole derivatives play an important role in the pharmaceutical and agrochemical industries and are present in many drug molecules, agrochemical molecules and natural products. For example, compound I is a sEH inhibitor, which plays a major role in regulating vascular homeostasis, and is useful as a drug for regulating blood pressure (Ho, Yin, L.; Chuk, C.Man.; St. phane, De, Lombaert, bioorganic & Medicinal Chemistry Letters 2010,20, 6379). The compound II can regulate the calcium ion balance of a human body and is used as a medicament for treating diseases caused by calcium homeostasis disorder (Beatrice, Riva.; Alessia, Griglio.; Tracey, Pirali.J.Med.chem.2018,61,9756). Compound III has effect in modulating sphingosine-1-phosphate receptor, and can be used as an immunosuppressant (Machinaga, Nobuo.; Yoshiino, Toshiharu.; Suzuki, Takashi. JP Patent 2009114108[ P ] 2009-5-28.). Therefore, the development of a novel method for efficiently synthesizing 5-trifluoromethyl-substituted pyrazole derivatives is a very important subject in the pharmaceutical and chemical fields.
Conventional methods for the synthesis of trifluoromethyl-substituted pyrazole derivatives are generally obtained by the cyclocondensation of hydrazine with 1, 3-diketones or α, β -unsaturated carbonyl compounds (Fustero, S.; Sanchez-Rosello, M.; Barrio, P.; Sim on-Fuentes, A.Chem.Rev.2011,111, 6984). However, this method results in the formation of two isomeric mixtures of 3-and 5-substituents on the pyrazole ring, which, due to the small difference in polarity, are difficult to separate and purify to give a single 5-trifluoromethyl-substituted pyrazole derivative. Methods for the preparation of trifluoromethyl-substituted pyrazole derivatives by addition of alkynes have also been developed in recent years (Robert, s.foster; Harald, Jakobi; Joseph, p.a.org.lett.2012,14,4858). The method needs to be carried out at the temperature of more than 140 ℃ for more than 48 hours, the reaction conditions are harsh, and two 5-trifluoromethyl substituted pyrazole isomers are generated at the same time. In short, most of the prior art has the disadvantages of low yield, poor regioselectivity, harsh conditions, dangerous operation, need of adding a catalyst or a ligand and the like. Therefore, the development of a method for efficiently synthesizing trifluoromethyl-substituted pyrazole derivatives is still a challenging research topic at present.
Disclosure of Invention
In order to solve the disadvantages and shortcomings of the prior art, the invention primarily aims to provide a synthesis method of 5-trifluoromethyl substituted pyrazole derivatives.
The invention also aims to provide a 5-trifluoromethyl substituted pyrazole derivative synthesized by the method and application thereof.
The purpose of the invention is realized by the following technical scheme.
A method for synthesizing 5-trifluoromethyl substituted pyrazole derivatives comprises the following steps;
adding chloroaldehyde hydrazone, 2-bromo-3, 3, 3-trifluoropropene, alkali and an organic solvent into a reactor, stirring for reaction, and carrying out post-treatment on a reaction product to obtain the 5-trifluoromethyl substituted pyrazole derivative.
Preferably, the chloroaldehyde hydrazone has the general formula
The reaction formula of the synthesis method is as follows:
wherein R is 1 Is phenyl, p-fluorophenyl, naphthyl, p-methylphenyl, p-chlorophenyl, o-chlorophenyl, p-methoxyphenyl, m-cyanophenyl, p-bromophenyl, p-iodophenyl, thienyl, ethylformate, methylformate, methyl, ethyl, butyl, cyclohexyl or tert-butyl; r 2 Is phenyl, p-methylphenyl, p-bromophenyl, p-chlorophenyl, p-fluorophenyl, p-cyanophenyl or methyl.
Preferably, the base is selected from at least one of DABCO (1, 4-diazabicyclo [2.2.2] octane), triethylamine, triethylenediamine, cesium carbonate and potassium carbonate.
Preferably, the organic solvent is selected from at least one of toluene, tetrahydrofuran and xylene.
Preferably, the molar ratio of the chloroaldehyde hydrazone to the 2-bromo-3, 3, 3-trifluoropropene is 1:1-1: 3.
Preferably, the molar ratio of the added base to the chloroaldehyde hydrazone is 1:1-4: 1.
Preferably, the dosage relation of the chloroaldehyde hydrazone and the organic solvent is 0.05-0.2 mmol/mL.
Preferably, the post-treatment refers to adding ethyl acetate and water to extract a reaction solution after the reaction is finished, evaporating an organic layer under reduced pressure to remove a solvent to obtain a crude product, and purifying by column chromatography to obtain the 5-trifluoromethyl substituted pyrazole derivative; the column chromatography purification refers to column chromatography purification of mixed solvent eluent of petroleum ether and ethyl acetate in a volume ratio of (10-100): 1.
Preferably, the solvent is xylene; the alkali is triethylene diamine; the molar ratio of the chloroaldehyde hydrazone to the 2-bromo-3, 3, 3-trifluoropropene is 1: 2; the molar ratio of the added amount of the alkali to the chloroaldehyde hydrazone is 3: 1; the dosage relation of the chloral hydrazone and the organic solvent is 0.1 mmol/mL; the reaction time was 24 h.
Preferably, the reaction is carried out under an air or oxygen atmosphere.
A 5-trifluoromethyl substituted pyrazole derivative synthesized by the synthesis method of any one of the above methods, wherein the structural general formula of the 5-trifluoromethyl substituted pyrazole derivative is as follows:
wherein R is 1 Is p-fluorophenyl, naphthyl, p-methylphenyl, p-chlorophenyl, o-chlorophenyl, p-methoxyphenyl, m-cyanophenyl, p-bromophenyl, p-iodophenyl, thienyl, ethyl formate, methyl formate, ethyl, butyl, cyclohexyl or tert-butyl; r 2 Is p-methylphenyl, p-bromophenyl, p-chlorophenyl, p-fluorophenyl, p-cyanophenyl or methyl.
The 5-trifluoromethyl substituted pyrazole derivative is applied to preparation of pesticides and medicines.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) the synthesis method does not use a catalyst, and the used raw materials are nontoxic, cheap and easy to obtain; the reaction has good adaptability to functional groups, wide adaptability to substrates, high product yield and specific regioselectivity;
(2) the synthetic method provided by the invention is simple and safe to operate, mild in reaction conditions, insensitive to water and air, and good in industrial application prospect.
Drawings
FIG. 1 is a hydrogen diagram of 5-trifluoromethyl-substituted pyrazole derivative obtained in examples 1 to 10;
FIG. 2 is a carbon spectrum of a 5-trifluoromethyl-substituted pyrazole derivative obtained in examples 1 to 10;
FIG. 3 is a fluorine spectrum of a 5-trifluoromethyl-substituted pyrazole derivative obtained in examples 1 to 10.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the present invention is not limited thereto.
Example 1
The synthesis method of the 5-trifluoromethyl substituted pyrazole derivative provided by the embodiment comprises the following specific synthesis steps:
adding 1mmol of chlorobenzaldehyde phenylhydrazone, 10 ml of xylene, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and 3 mmol of cesium carbonate into a 50 ml reaction bottle in sequence, stirring and reacting at room temperature for 24 hours, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary evaporating to remove a solvent, and separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether serving as a column chromatography eluent is used to obtain the product with the yield of 72%.
Example 2
The synthesis method of the 5-trifluoromethyl substituted pyrazole derivative provided by the embodiment comprises the following specific synthesis steps:
adding 1mmol of chlorobenzaldehyde phenylhydrazone, 10 ml of xylene, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and 3 mmol of potassium carbonate into a 50 ml reaction bottle in sequence, stirring at room temperature for 24 hours, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary evaporating to remove a solvent, and separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether serving as eluent of the column chromatography is used, and the yield of the product is 69%.
Example 3
The synthesis method of the 5-trifluoromethyl substituted pyrazole derivative provided by the embodiment comprises the following specific synthesis steps:
adding 1mmol of chlorobenzaldehyde phenylhydrazone, 10 ml of xylene, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and 3 mmol of triethylamine into a 50 ml reaction bottle in sequence, stirring and reacting at room temperature for 24 hours, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and carrying out rotary evaporation to remove a solvent, and carrying out column chromatography separation and purification to obtain a target product, wherein the used column chromatography eluent petroleum ether is used to obtain the product with the yield of 90%.
Example 4
The synthesis method of the 5-trifluoromethyl substituted pyrazole derivative provided by the embodiment comprises the following specific synthesis steps:
adding 1mmol of chlorobenzaldehyde phenylhydrazone, 10 ml of tetrahydrofuran, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and 3 mmol of DABCO into a 50 ml reaction bottle in sequence, stirring and reacting for 24 hours at room temperature, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, separating and purifying by column chromatography to obtain a target product, wherein petroleum ether is used as eluent of the column chromatography, and the yield of the product is 70%.
Example 5
The synthesis method of the 5-trifluoromethyl substituted pyrazole derivative provided by the embodiment comprises the following specific synthesis steps:
adding 1mmol of chlorobenzaldehyde phenylhydrazone, 10 ml of toluene, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and 3 mmol of DABCO into a 50 ml reaction bottle in sequence, stirring and reacting for 24 hours at room temperature, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, separating and purifying by column chromatography to obtain a target product, wherein petroleum ether is used as eluent of the column chromatography, and the yield of the product is 93%.
Example 6
The synthesis method of the 5-trifluoromethyl substituted pyrazole derivative provided by the embodiment comprises the following specific synthesis steps:
adding 1mmol of chlorobenzaldehyde phenylhydrazone, 10 ml of xylene, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and 3 mmol of DABCO into a 50 ml reaction bottle in sequence, stirring and reacting for 24 hours at room temperature, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, separating and purifying by column chromatography to obtain a target product, wherein petroleum ether is used as eluent of the column chromatography, and the yield of the product is 98%.
Example 7
The synthesis method of the 5-trifluoromethyl substituted pyrazole derivative provided by the embodiment comprises the following specific synthesis steps:
adding 1mmol of chlorobenzaldehyde phenylhydrazone, 10 ml of xylene, 1mmol of 2-bromo-3, 3, 3-trifluoropropene and 3 mmol of DABCO into a 50 ml reaction bottle in sequence, stirring and reacting for 24 hours at room temperature, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and distilling to remove a solvent, separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is petroleum ether, and the yield of the product is 50%.
Example 8
The synthesis method of the 5-trifluoromethyl substituted pyrazole derivative provided by the embodiment comprises the following specific synthesis steps:
adding 1mmol of chlorobenzaldehyde phenylhydrazone, 10 ml of xylene, 3 mmol of 2-bromo-3, 3, 3-trifluoropropene and 3 mmol of DABCO into a 50 ml reaction bottle in sequence, stirring and reacting for 24 hours at room temperature, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, separating and purifying by column chromatography to obtain a target product, wherein petroleum ether is used as eluent of the column chromatography, and the yield of the product is 88%.
Example 9
The synthesis method of the 5-trifluoromethyl substituted pyrazole derivative provided by the embodiment comprises the following specific synthesis steps:
adding 1mmol of chlorobenzaldehyde phenylhydrazone, 10 ml of xylene, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and 1mmol of DABCO into a 50 ml reaction bottle in sequence, stirring and reacting for 24 hours at room temperature, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, separating and purifying by column chromatography to obtain a target product, wherein petroleum ether is used as eluent of the column chromatography, and the yield of the product is 44%.
Example 10
The synthesis method of the 5-trifluoromethyl substituted pyrazole derivative provided by the embodiment comprises the following specific synthesis steps:
adding 1mmol of chlorobenzaldehyde phenylhydrazone, 10 ml of xylene, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and 4 mmol of DABCO into a 50 ml reaction bottle in sequence, stirring and reacting for 24 hours at room temperature, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether serving as a column chromatography eluent is used to obtain the product with the yield of 90%.
The hydrogen, carbon and fluorine spectra of the products obtained in examples 1-10 above are shown in FIGS. 1, 2 and 3, respectively. The structural characterization data is as follows:
1 H NMR(500MHz,CDCl 3 )δ7.84–7.86(m,2H),7.53–7.55(m,2H),7.45–7.50(m,3H),7.40–7.43(m,2H),7.33–7.37(m,1H),7.09(s,1H).
13 C NMR(125MHz,CDCl 3 ):151.7,139.3,134.0(q, 2 J F-C ＝39.0Hz),131.9,129.4,129.2,128.9,128.8,126.0,125.8,119.9(q, 1 J F-C ＝267.5Hz),106.2(q, 3 J F-C ＝2.6Hz)；
19 F NMR(400MHz,CDCl 3 ):δ＝-57.6(s,3F)；
IR(KBr):3061,1593,1444,1292,1148,691；
HRMS(ESI,m/z):[M+H] + Calcd.for C 16 H 11 F 3 N 2 +H,289.0948；found,289.0940.
from the above data, it is concluded that the structure of the product obtained in this example is shown in the following formula:
example 11
The synthesis method of the 5-trifluoromethyl substituted pyrazole derivative provided by the embodiment comprises the following specific synthesis steps:
1mmol of chloro-p-bromophenylaldehyde phenylhydrazone, 10 ml of xylene, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and 3 mmol of DABCO are sequentially added into a 50 ml reaction bottle, stirring is stopped after stirring reaction is carried out for 24 hours at room temperature, ethyl acetate and water are added to extract a reaction solution, a solvent is removed by reduced pressure rotary evaporation, column chromatography separation and purification are carried out to obtain a target product, and petroleum ether is used as eluent of the column chromatography, so that the yield of the product is 71%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.75(d,J＝8.4Hz,2H),7.57–7.60(m,4H),7.50–7.54(m,3H),7.09(s,1H)；
13 C NMR(100MHz,CDCl 3 )δ150.6,139.1,134.0(q, 2 J F-C ＝39.1Hz),132.0,130.8,129.4,129.2,127.4,125.7,122.8,119.7(q, 1 J F-C ＝267.6Hz),106.1(q, 3 J F-C ＝2.5Hz)；
19 F NMR(376MHz,CDCl 3 )δ-57.5(s,3F)；
IR(KBr):3065,1589,1440,1147,820cm -1 ；
HRMS(ESI,m/z):[M+H] + Calcd.for C 16 H 10 BrF 3 N 2 +H,367.0052；found,367.0049.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
example 12
The synthesis method of the 5-trifluoromethyl substituted pyrazole derivative provided by the embodiment comprises the following specific synthesis steps:
adding 1mmol of chloro-p-iodobenzaldehyde phenylhydrazone, 10 ml of xylene, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and 3 mmol of DABCO into a 50 ml reaction bottle in sequence, stirring and reacting for 24 hours at room temperature, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether serving as a column chromatography eluent is used to obtain the product with the yield of 75%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.75(d,J＝8.4Hz,2H),7.58(d,J＝8.0Hz,2H),7.48–7.55(m,5H),7.07(s,1H)；
13 C NMR(100MHz,CDCl 3 )δ150.7,139.2,134.2(q, 2 J F-C ＝39.2Hz),131.4,129.5,129.3,127.6,125.8,119.7(q, 1 J F-C ＝267.8Hz),106.1,94.5；
19 F NMR(376MHz,CDCl 3 )δ-57.6(s,3F)；
IR(KBr):3061,1588,1442,1145,813cm -1 ；
HRMS(ESI,m/z):[M+H] + Calcd.for C 16 H 10 F 3 IN 2 +H,414.9914；found,414.9906.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
example 13
The synthesis method of the 5-trifluoromethyl substituted pyrazole derivative provided by the embodiment comprises the following specific synthesis steps:
adding 1mmol of chloro-p-cyanobenzaldehyde phenylhydrazone, 10 ml of xylene, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and 3 mmol of DABCO into a 50 ml reaction bottle in sequence, stirring and reacting for 24 hours at room temperature, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, separating and purifying by column chromatography to obtain a target product, wherein petroleum ether is used as eluent of the column chromatography, and the yield of the product is 67%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.95(d,J＝8.4Hz,2H),7.70(d,J＝8.4Hz,2H),7.50–7.56(m,5H),7.16(s,1H)；
13 C NMR(100MHz,CDCl 3 )δ149.7,138.9,136.1,134.5(q, 2 J F-C ＝39.3Hz),132.7,129.8,129.3,126.3,125.7,119.6(q, 1 J F-C ＝267.7Hz),118.8,112.1,106.6(q, 3 J F-C ＝2.6Hz)；
19 F NMR(376MHz,CDCl 3 )δ-57.7(s,3F)；
IR(KBr):3065,2223,1598,1442,1113,825cm -1 ；
HRMS(ESI,m/z):[M+H] + Calcd.for C 17 H 10 F 3 N 3 +H,314.0900；found,314.0893.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
example 14
The synthesis method of the 5-trifluoromethyl-substituted pyrazole derivative provided by the embodiment comprises the following specific synthesis steps:
adding 1mmol of chloro 3-cyanobenzaldehyde phenylhydrazone, 10 ml of xylene, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and 3 mmol of DABCO into a 50 ml reaction bottle in sequence, stirring and reacting for 24 hours at room temperature, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether serving as a column chromatography eluent is used to obtain the product yield of 83%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.17(s,1H),8.07(d,J＝8.0Hz,1H),7.63(d,J＝8.0Hz,1H),7.51–7.55(m,5H),7.13(s,1H)；
13 C NMR(100MHz,CDCl 3 )δ149.4,138.9,134.5(q, 2 J F-C ＝39.5Hz),133.1,132.0,130.0,129.8,129.7,129.4,129.3,125.7,119.6(q, 1 J F-C ＝267.5Hz),118.6,113.2,106.6(q, 3 J F-C ＝1.8Hz)；
19 F NMR(376MHz,CDCl 3 )δ-57.7(s,3F)；
IR(KBr):3058,1534,1424,1082,690cm -1 ；
HRMS(ESI,m/z):[M+H] + Calcd.for C 17 H 10 F 3 N 3 +H,314.0900；found,314.0892.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
example 15
The synthesis method of the 5-trifluoromethyl substituted pyrazole derivative provided by the embodiment comprises the following specific synthesis steps:
adding 1mmol of chloro-2-thiophenecarboxaldehyde phenylhydrazone, 10 ml of xylene, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and 3 mmol of DABCO into a 50 ml reaction bottle in sequence, stirring and reacting for 24 hours at room temperature, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent petroleum ether is used to obtain the product yield of 84%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.50–7.58(m,5H),7.45(d,J＝3.6Hz,1H),7.32(d,J＝5.2Hz,1H),7.11(t,J＝4.4Hz,1H),7.03(s,1H)；
13 C NMR(100MHz,CDCl 3 )δ147.1,139.0,134.7,133.9(q, 2 J F-C ＝39.3Hz),129.5,129.2,127.7,125.8,125.8,125.0,119.8(q, 1 J F-C ＝267.8Hz),106.1(q, 3 J F-C ＝1.9Hz)；
19 F NMR(376MHz,CDCl 3 )δ-57.6(s,3F)；
IR(KBr):3079,1590,1487,1144,699cm -1 ；
HRMS(ESI,m/z):[M+H] + Calcd.for C 14 H 9 F 3 N 2 S+H,295.0511；found,295.0507.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
example 16
The synthesis method of the 5-trifluoromethyl substituted pyrazole derivative provided by the embodiment comprises the following specific synthesis steps:
adding 1mmol of chlorobenzaldehyde p-chlorobenzohydrazone, 10 ml of dimethylbenzene, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and 3 mmol of DABCO into a 50 ml reaction bottle in sequence, stirring and reacting for 24 hours at room temperature, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether serving as a column chromatography eluent is used to obtain the product yield of 80%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.82–7.85(m,2H),7.34–7.51(m,7H),7.10(s,1H)；
13 C NMR(100MHz,CDCl 3 )δ152.7,137.8,135.4,134.0(q, 2 J F-C ＝39.0Hz),131.6,129.5,129.0,127.0,126.0,119.8(q, 1 J F-C ＝267.5Hz),106.6；
19 F NMR(376MHz,CDCl 3 )δ-57.6(s,3F)；
IR(KBr):3063,1502,1443,1289,1145,830cm -1 ；
HRMS(ESI,m/z):[M+H] + Calcd.for C 16 H 10 ClF 3 N 2 +H,323.0557；found,323.0552.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
example 17
The synthesis method of the 5-trifluoromethyl substituted pyrazole derivative provided by the embodiment comprises the following specific synthesis steps:
adding 1mmol of chlorobenzaldehyde-p-cyanobenzhydrazone, 10 ml of xylene, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and 3 mmol of DABCO into a 50 ml reaction bottle in sequence, stirring and reacting for 24 hours at room temperature, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether serving as a column chromatography eluent is used to obtain the product with the yield of 56%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.85–7.87(m,2H),7.81(d,J＝8.4Hz,2H),7.73(d,J＝8.4Hz,2H),7.39–7.48(m,3H),7.18(s,1H)；
13 C NMR(100MHz,CDCl 3 )δ152.8,142.6,133.9(q, 2 J F-C ＝39.4Hz),133.3,131.2,129.3,129.0,126.0,125.7(q, 3 J F-C ＝1.7Hz),119.8(q, 1 J F-C ＝267.6Hz),117.9,112.9,107.8；
19 F NMR(376MHz,CDCl 3 )δ-57.2(s,3F)；
IR(KBr):3163,1589,1450,1229,1113,759cm -1 ；
HRMS(ESI,m/z):[M+H] + Calcd.for C 17 H 10 F 3 N 3 +H,314.0090；found,314.0892.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
example 18
The synthesis method of the 5-trifluoromethyl substituted pyrazole derivative provided by the embodiment comprises the following specific synthesis steps:
adding 1mmol of chloro-o-chlorobenzaldehyde phenylhydrazone, 10 ml of xylene, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and 3 mmol of DABCO into a 50 ml reaction bottle in sequence, stirring and reacting for 24 hours at room temperature, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether serving as a column chromatography eluent is used to obtain the product yield of 82%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.87–7.90(m,1H),7.46–7.58(m,6H),7.36(s,1H),7.29–7.33(m,2H)；
13 C NMR(100MHz,CDCl 3 )δ149.4,139.2,133.2(q, 2 J F-C ＝38.9Hz),132.5,130.8,130.8,130.6,129.8,129.5,129.3,127.2,125.8,119.9(q, 1 J F-C ＝267.5Hz),110.1；
19 F NMR(376MHz,CDCl 3 )δ-57.5(s,3F)；
IR(KBr):3060,1590,1434,1116,761cm -1 ；
HRMS(ESI,m/z):[M+H] + Calcd.for C 16 H 10 ClF 3 N 2 +H,323.0558；found,323.0553.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
example 19
The synthesis method of the 5-trifluoromethyl substituted pyrazole derivative provided by the embodiment comprises the following specific synthesis steps:
in a 50 ml reaction flask, 0.8 mmol of trichloroisocyanuric acid and 2.4 mmol of dimethyl sulfide were sequentially added to 1mmol of cyclohexylcarboxaldehydrazone and 8 ml of dichloromethane at 0 ℃, and the reaction system was transferred to room temperature and stirred for reaction for 12 hours. And (3) after the reaction is finished, carrying out reduced pressure rotary evaporation to remove the solvent, directly and sequentially adding 10 ml of dimethylbenzene, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and 3 mmol of DABCO into the obtained crude product, stirring and reacting at room temperature for 24 hours, stopping stirring, adding ethyl acetate and water to extract the reaction solution, carrying out reduced pressure rotary evaporation to remove the solvent, carrying out column chromatography separation and purification to obtain the target product, wherein the used column chromatography eluent petroleum ether is used, and the product yield is 60%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.39–7.49(m,5H),6.61(s,1H),2.70–2.77(m,1H),2.02–2.07(m,2H),1.70–1.85(m,3H),1.28–1.52(m,5H)；
13 C NMR(100MHz,CDCl 3 )δ158.5,139.5,132.7(q, 2 J F-C ＝38.6Hz),129.1,129.0,125.7,120.1(q, 1 J F-C ＝267.3Hz),106.2,37.5,33.1,26.3,26.1；
19 F NMR(376MHz,CDCl 3 )δ-57.4(s,3F)；
IR(KBr):3064,2928,1462,1289,1145,771cm -1 ；
HRMS(ESI,m/z):[M+H] + Calcd.for C 16 H 17 F 3 N 2 +H,295.1417；found,295.1413.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
example 20
Adding 1mmol of chlorobenzaldehyde phenylhydrazone, 10 ml of xylene, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and 3 mmol of cesium carbonate into a 50 ml reaction bottle in sequence, stirring and reacting for 24 hours at different temperatures in Table 1, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-distilling to remove a solvent, separating and purifying by column chromatography to obtain a target product, and using column chromatography eluent petroleum ether.
TABLE 1 influence of reaction temperature on the Synthesis of 5-trifluoromethyl-substituted pyrazole derivatives
As is clear from Table 1, the reaction temperature is preferably room temperature.
Example 21
Adding 1mmol of chlorobenzaldehyde phenylhydrazone, 10 ml of different solvents shown in table 2, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and 3 mmol of cesium carbonate into a 50 ml reaction bottle in sequence, stirring and reacting for 24 hours at room temperature, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-distilling to remove the solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used eluent of the column chromatography is petroleum ether.
TABLE 2 influence of solvent type on the Synthesis of 5-trifluoromethyl-substituted pyrazole derivatives
As can be seen from Table 2, the solvent type is preferably xylene.
Example 22
1mmol of chlorobenzaldehyde phenylhydrazone, xylene with different dosage in table 3, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and 3 mmol of cesium carbonate are sequentially added into a 50 ml reaction bottle, stirring is stopped after stirring reaction is carried out for 24 hours at room temperature, ethyl acetate and water are added to extract a reaction solution, a solvent is removed by reduced pressure rotary evaporation, and then column chromatography separation and purification are carried out to obtain a target product, and petroleum ether is used as eluent of the column chromatography.
TABLE 3 influence of solvent dosage on the Synthesis of 5-trifluoromethyl-substituted pyrazole derivatives
As can be seen from Table 3, the amount of the solvent used is preferably 10 mL, i.e., the concentration of chlorobenzaldehyde phenylhydrazone is 0.1 mmol/mL.
Example 23
Adding 1mmol of chlorobenzaldehyde phenylhydrazone, 10 ml of dimethylbenzene, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and 3 mmol of different types of alkali in a table 4 into a 50 ml reaction bottle in sequence, stirring and reacting for 24 hours at room temperature, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-distilling to remove a solvent, and separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether is used as eluent of the column chromatography.
TABLE 4 influence of base type on the Synthesis of 5-trifluoromethyl-substituted pyrazole derivatives
As is clear from Table 4, the type of base is preferably triethylenediamine.
Example 24
1mmol of chlorobenzaldehyde phenylhydrazone, 10 ml of xylene, 2mmol of 2-bromo-3, 3, 3-trifluoropropene and triethylene diamine with different dosages in the table 5 are sequentially added into a 50 ml reaction bottle, stirring is stopped after stirring reaction is carried out for 24 hours at room temperature, ethyl acetate and water are added to extract a reaction solution, a solvent is removed by reduced pressure rotary evaporation, and the target product is obtained by column chromatography separation and purification, and the used column chromatography eluent petroleum ether is used.
TABLE 5 influence of the amount of base used on the synthesis of 5-trifluoromethyl-substituted pyrazole derivatives
As can be seen from table 5, the molar ratio of base to chlorobenzaldehyde phenylhydrazone is preferably 3: 1.
the above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (5)
1. A method for synthesizing 5-trifluoromethyl substituted pyrazole derivatives is characterized by comprising the following steps;
adding chloroaldehyde hydrazone, 2-bromo-3, 3, 3-trifluoropropene, alkali and an organic solvent into a reactor, stirring for reaction, and carrying out aftertreatment on a reaction product to obtain a 5-trifluoromethyl substituted pyrazole derivative;
the general formula of the chloroaldehyde hydrazone is
Wherein R is 1 Is phenyl, p-fluorophenyl, naphthyl, p-methylphenyl, p-chlorophenyl, o-chlorophenyl, p-methoxyphenyl, m-cyanophenyl, p-bromophenyl, p-iodophenyl, thienyl, methyl, ethyl, butyl, cyclohexyl or tert-butyl; r is 2 Is phenyl, p-methylphenyl, p-bromophenyl, p-chlorophenyl, p-fluorophenyl, p-cyanophenyl or methyl;
the alkali is selected from at least one of triethylamine and triethylene diamine;
the organic solvent is at least one selected from toluene and xylene;
the temperature of the reaction was room temperature.
2. The method for synthesizing 5-trifluoromethyl substituted pyrazole derivative according to claim 1, wherein the molar ratio of the chloroaldohydrazone to the 2-bromo-3, 3, 3-trifluoropropene is 1:1 to 1: 3.
3. The method for synthesizing 5-trifluoromethyl substituted pyrazole derivative according to claim 1, wherein the molar ratio of the base to the chloroaldehyde hydrazone is 1:1-4: 1; the dosage relation of the chloral hydrazone and the organic solvent is 0.05-0.2 mmol/mL.
4. The method for synthesizing 5-trifluoromethyl substituted pyrazole derivative according to claim 1, wherein the post-treatment comprises adding ethyl acetate and water to extract the reaction solution after the reaction is finished, evaporating the organic layer under reduced pressure to remove the solvent to obtain a crude product, and purifying by column chromatography to obtain the 5-trifluoromethyl substituted pyrazole derivative; the column chromatography purification refers to column chromatography purification of mixed solvent eluent of petroleum ether and ethyl acetate in a volume ratio of (10-100): 1.
5. The method for synthesizing 5-trifluoromethyl-substituted pyrazole derivatives according to claim 1, wherein the solvent is xylene; the alkali is triethylene diamine; the molar ratio of the chloroaldehyde hydrazone to the 2-bromo-3, 3, 3-trifluoropropene is 1: 2; the molar ratio of the added amount of the alkali to the chloroaldehyde hydrazone is 3: 1; the dosage relation of the chloral hydrazone and the organic solvent is 0.1 mmol/mL; the reaction time was 24 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011215965.4A CN112480004B (en) | 2020-11-04 | 2020-11-04 | 5-trifluoromethyl substituted pyrazole derivative and synthesis method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011215965.4A CN112480004B (en) | 2020-11-04 | 2020-11-04 | 5-trifluoromethyl substituted pyrazole derivative and synthesis method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112480004A CN112480004A (en) | 2021-03-12 |
| CN112480004B true CN112480004B (en) | 2022-08-12 |
Family
ID=74928184
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011215965.4A Active CN112480004B (en) | 2020-11-04 | 2020-11-04 | 5-trifluoromethyl substituted pyrazole derivative and synthesis method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112480004B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114805208A (en) * | 2022-05-05 | 2022-07-29 | 台州学院 | 4-trifluoromethyl-4, 5-dihydropyrazole derivative and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120046301A1 (en) * | 2010-08-20 | 2012-02-23 | Gruenenthal Gmbh | Substituted Cyclic Carboxamide and Urea Derivatives as Ligands of the Vanilloid Receptor |
| CN110590667A (en) * | 2019-09-20 | 2019-12-20 | 华南理工大学 | 3-trifluoromethyl substituted pyrazole derivative and synthesis method and application thereof |
-
2020
- 2020-11-04 CN CN202011215965.4A patent/CN112480004B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120046301A1 (en) * | 2010-08-20 | 2012-02-23 | Gruenenthal Gmbh | Substituted Cyclic Carboxamide and Urea Derivatives as Ligands of the Vanilloid Receptor |
| CN110590667A (en) * | 2019-09-20 | 2019-12-20 | 华南理工大学 | 3-trifluoromethyl substituted pyrazole derivative and synthesis method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112480004A (en) | 2021-03-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Gu et al. | Synthesis of chiral γ-aminophosphonates through the organocatalytic hydrophosphonylation of azadienes with phosphites | |
| CN108409747B (en) | Synthetic method of 2-aminoquinoline dihydrofuran compound | |
| CN108299423B (en) | Synthesis method of dihydropyrrolo-2-aminoquinoline compound | |
| CN108033922B (en) | Preparation method of 3-acyl quinoxalinone derivative | |
| CN112010817A (en) | Method for preparing tetrazine compound and application thereof | |
| CN112480004B (en) | 5-trifluoromethyl substituted pyrazole derivative and synthesis method and application thereof | |
| CN102977017B (en) | Method for catalytically preparing 6(5H)-phenanthridine ketone by copper component | |
| Yuan et al. | Reaction of aldimines and difluoroenoxysilane, an unexpected protocol for the synthesis of 2, 2-difluoro-3-hydroxy-1-ones | |
| Ram et al. | A facile access to the synthesis of functionalised unsymmetrical biaryls from 2 H-pyran-2-ones through carbanion induced C–C bond formation | |
| Gutmann et al. | Continuous-flow difluoromethylation with chlorodifluoromethane under biphasic conditions | |
| Kumar et al. | Mn-mediated oxidative radical cyclization of 2-(azidomethyl) phenyl isocyanides with carbazate: Access to quinazoline-2-carboxylates | |
| CN106045914A (en) | Method for synthesizing tri-substituted imidazole compounds | |
| Reddy et al. | An efficient catalyst-free one-pot synthesis of primary amides from the aldehydes of the Baylis–Hillman reaction | |
| CN106892826A (en) | A kind of preparation method and application of amine and imines N-methyl | |
| Ballini et al. | Nitroalkanes and dimethyl maleate as source of 3-alkyl succinic anhydrides and (E)-3-alkylidene succinic anhydrides | |
| CN111362795B (en) | Preparation method of substituted butyrate derivatives | |
| CN103435610A (en) | Preparation method of imidazo-[1,2-a] pyridine compound | |
| CN112574108A (en) | Preparation method of polysubstituted benzo [ b ] aza compound | |
| CN113636968B (en) | Synthetic method of 3-acyl pyrrole compound | |
| CN104860864B (en) | The synthetic method of the alkynyl azole compounds of 2 carbonyl 5 | |
| CN110028521B (en) | 11-aryl-1, 4-benzoxazinoimidazoline compounds and preparation method and application thereof | |
| CN109053736A (en) | A kind of preparation method of pyrrolo- [1,2- α] indoles -3- 01 derivatives | |
| CN113735873B (en) | Method for preparing Artemisinin G | |
| CN114957174B (en) | Alkyl substituted alpha-methylene-gamma-butyrolactone derivative and synthesis method thereof | |
| CN108558750B (en) | Process for synthesizing 3-nitroquinoline derivative by solvent-free method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |