CN108863936A - A kind of pyrazoles N- alkylation - Google Patents
A kind of pyrazoles N- alkylation Download PDFInfo
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- CN108863936A CN108863936A CN201810688273.8A CN201810688273A CN108863936A CN 108863936 A CN108863936 A CN 108863936A CN 201810688273 A CN201810688273 A CN 201810688273A CN 108863936 A CN108863936 A CN 108863936A
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- 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
- C07D231/14—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/16—Halogen atoms or nitro radicals
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- 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
- 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
- C07D231/14—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Abstract
A kind of pyrazoles N- alkylation is reacted in solvent with pyrazoles or its derivative and halogenated alkyl hydrocarbon in the presence of quaternary ammonium salt catalyst and acid binding agent, obtains N- alkyl substituted pyrazolecarboxylic.Operation of the present invention is simple, it is at low cost, do not need anhydrous and oxygen-free environment, can not heat, yield is higher, is easy to amplify industrialized production.
Description
Technical field
The present invention relates to a kind of pyrazoles N- alkylations.
Background technique
The alkylated pyrazole derivatives of N- are in Insecticiding-miticiding [referring to Song Hongjian, Liu Yuxiu, Wangqing County people, N- alkyl pyrazole -5-
The progress of benzamide type insecticidal/acaricidal agent, Chinese science:Chemistry [J] 2016,46 (11):1143-1154;], sterilization
（Referring to Ting-Ting Yao, Dou-Xin Xiao, Zhong-Shan Li, Jing-Li Cheng, Shao-Wei
Fang, Yong-Jun Du, Jin-Hao Zhao, Xiao-Wu Dong, and Guo-Nian Zhu Design,
Synthesis, and Fungicidal Evaluation of Novel Pyrazole-furan and Pyrazole-
pyrrole Carboxamide as Succinate Dehydrogenase Inhibitors J. Agric. Food
Chem. 2017, 65, 5397−5403;）, it is antiviral [referring to Haiyong Jia, Fuxiang Bai, Na Liu,
Xiaohong Liang, Peng Zhan, Chunhong Ma, Xuemei Jiang, Xinyong Liu Design,
synthesis and evaluation of pyrazole derivatives as nonnucleoside hepatitis B
virus inhibitors European Journal of Medicinal Chemistry 123 (2016) 202-210;]
, it is antitumor [referring to Jeffrey C. Bryan Srdan Verstovsek Overcoming treatment
challenges in myelofibrosis and polycythemia vera: the role of ruxolitinib
Cancer Chemother Pharmacol (2016) 77:1125–1142;] etc. fields be widely used, at present it is most of
The N- alkylation of pyrazoles generallys use cyclization method, the disadvantage is that the preparation of other diazanyl substituents is not easy in addition to methyl hydrazine, lacks work
Available materials in industry [referring to S R Singh, D Kumar, H Batra et al. Can.J.Chem., 2000,78 (
8), 1109-1120.
6. and R Alan, Katritzky, M Y Wang et al. J.Org.Chem., 2001,66 (20): 6787-
6791.].The second is highly basic method, as sodium ethoxide pulls out proton method [referring to Jones R G., Mann M J and Mclanghlin
K C. J.org.Chem. 1954, 19:1428.], reaction needs water-less environment, limits its application.The third is 4- diformazan
Aminopyridine catalysis method is [referring to Elguero J, Jaramillo C, and Pardo C. Synthesis. 1997:
563.], defect is to need to use the pyridine of foul smelling to make solvent, and application range is narrow, can only be to some specific active
Halogenated alkane is effective.The fourth is that common phase transfer catalyst method [referring to e.g. Hartshorne C M. and Steel P J.
Aust.J.Chem. 1995, 48:1587.], but need to use high poison and carcinogenic benzene makees solvent, it is high with relative price
Tetrabutylammonium hydroxide makees catalyst, and the heating reflux reaction time is more than 18 hours.
New development in recent years gone out microwave irradiation [referring to Almena, I., Diez-Barra, E., de la Hoz,
A., Ruiz, J., and Sanchez-Migallon, A., J.Heterocycl. chem. 1998, 35:1263],
The disadvantage is that reaction is not easy to amplify, and yield is relatively low, does not meet Atom economy requirement.
Summary of the invention
The technical problem to be solved by the present invention is to, overcome the deficiencies of the prior art and provide it is a kind of it is easy to operate, at low cost,
Do not need anhydrous and oxygen-free environment, can not heat, yield is higher, is easy to amplify the pyrazoles N- alkylation of industrialized production.
The technical solution used to solve the technical problems of the present invention is that
A kind of pyrazoles N- alkylation, with pyrazoles or its derivative and halogenated alkyl hydrocarbon in quaternary ammonium salt catalyst and acid binding agent
In the presence of, it is reacted in solvent, obtains N- alkyl substituted pyrazolecarboxylic.
Corresponding reaction equation is as follows：
R1 represents any substituent group on pyrazole ring；X represents halogen atom chlorine, bromine or iodine, and R2 is alkyl.
In the present invention,Indicate pyrazoles or its derivative（As 3- substituted pyrazolecarboxylic, 4- substituted pyrazolecarboxylic, 5- take
For pyrazoles）At least one of.
Halogenated alkyl hydrocarbon participates in reaction, is 1 ︰ 1 with the ratio between the amount of substance of pyrazoles or its derivative；If halogenated alkyl
The low boiling point of hydrocarbon, it is volatile, it can excessive addition（Comprehensively consider cost of material）.
Solvent is dimethyl sulfoxide（DMSO）.Solvent usage is preferably that 50- is added in every 1 mole pyrazole or its derivative
200ml solvent.The dosage of solvent on result influence and it is little.
Quaternary ammonium salt catalyst is tetrabutylammonium hydroxide, tetrabutylammonium bromide, tetrabutyl iodate amine, 4-butyl ammonium hydrogen sulfate
At least one of, quaternary ammonium salt catalyst plays the role of phase transfer catalysis (PTC) in the reaction, and quaternary ammonium salt catalyst dosage is with pyrazoles
Perhaps usage amount is the 0.001- for being equivalent to the amount of substance of pyrazoles or its derivative on the basis of the amount of the substance of its derivative
10 times（It is preferred that 0.05-0.1 times）.
It when the dosage of catalyst is more than or equal to 0.001 times, can react, and when the dosage increase of catalyst, instead
It answers speed to accelerate, but when the dosage of catalyst is greater than 0.1 times, is further added by its dosage, reaction speed increase is not obvious, this
When, the dosage increase of catalyst can't significantly accelerate reaction speed, only will cause the waste of catalyst material.
Acid binding agent is at least one of sodium hydroxide, potassium hydroxide, and the amount with pyrazoles or the substance of its derivative is
Benchmark, acid binding agent dosage are 1-10 times of amount for being equivalent to the substance of pyrazoles or its derivative.
Reaction temperature is 0-200 DEG C（It is preferred that room temperature）.Reaction time is to be stirred overnight after the aqueous solution for dripping acid binding agent.
It is preferred that using following steps：
By pyrazoles or its derivative, halogenated alkyl hydrocarbon, quaternary ammonium salt catalyst, it is dissolved in dimethyl sulfoxide（DMSO）In, dropwise addition is tied up
The aqueous solution of sour agent after being added dropwise, is stirred overnight, and adds water quenched dilution；Extraction（It is preferred that being extracted with methylene chloride or ethyl acetate
It takes）, dry, concentration, vacuum distillation, or adjust pH be 2-3 be precipitated to get.
Using the present invention, product yield can achieve 85% or more.
The principle of the invention is as follows：
R1 represents any substituent group on pyrazole ring, and M represents the metallic atoms such as sodium, the potassium being added, Q+Indicate quaternary ammonium salt cationic, X-
It indicates and the anion of quaternary ammonium salt pairing, R indicates any alkyl.
The principle of the present invention：Pyrazoles or its derivative form pyrazoles salt under the action of highly basic first, then in step
（1）In, exposed larger pyrazole anion is easy the product by compatibility preferably larger quaternary ammonium salt cationic pairing, after pairing
Then via approach（2）Into organic phase, inorganic salts are formed simultaneously, in organic phase, exposed pyrazole anion reactivity
It increases, such as step（3）Nucleophilic substitution occurs for shown and halogenated hydrocarbons, forms N- alkyl substituted pyrazolecarboxylic, while generating and initially urging
Agent quaternary ammonium salt, quaternary ammonium salt is via approach（4）Into water phase.
Operation of the present invention is simple, it is at low cost, do not need anhydrous and oxygen-free environment, can not heat, yield is higher, is easy to amplify
Industrialized production.
Detailed description of the invention
Fig. 1 is the nuclear magnetic resonance map of the 1 bromo- 1H- pyrazoles of products obtained therefrom 1- ethyl -4- of the embodiment of the present invention；
Fig. 2 is the nuclear magnetic resonance map of 2 products obtained therefrom 1- isopropyl -1H- pyrazoles of the embodiment of the present invention；
Fig. 3 is the nuclear magnetic resonance map of the 3 bromo- 1H- pyrazoles of products obtained therefrom 1- benzyl -4- of the embodiment of the present invention；
Fig. 4 is the nuclear magnetic resonance map of 4 products obtained therefrom 1- ethyl -3- methyl-1 H- pyrazoles -5- carboxylic acid of the embodiment of the present invention；
Fig. 5 is the nuclear magnetic resonance map of 4 products obtained therefrom 1- ethyl -5- methyl-1 H- pyrazoles -3- carboxylic acid of the embodiment of the present invention；
Fig. 6 is the nuclear magnetic resonance map of 8 products obtained therefrom 1- benzyl -3- nitro -1H- pyrazoles of the embodiment of the present invention；
Fig. 7 is the nuclear magnetic resonance map of the bromo- 1- allyl -1H- pyrazoles of 9 products obtained therefrom 4- of the embodiment of the present invention；
Fig. 8 is the nuclear magnetic resonance map of the embodiment of the present invention 10 the bromo- 1- of products obtained therefrom 4- (2- methoxy ethyl) -1H- pyrazoles；
Fig. 9 is the 11 bromo- 1- of products obtained therefrom 4- of the embodiment of the present invention（2- fluoro ethyl）The nuclear magnetic resonance map of -1H- pyrazoles；
Figure 10 is 12 products obtained therefrom 2- of the embodiment of the present invention（The bromo- 1H- pyrazoles of 4-）The nuclear magnetic resonance figures of-N, N- dimethyl amine
Spectrum.
Specific embodiment
Below in conjunction with specific embodiment, invention is further described in detail.
Embodiment 1
The synthesis of the bromo- 1H- pyrazoles of 1- ethyl -4-
At room temperature, by 4- bromine pyrazoles（15.6 grams, 0.1mol）, iodoethane (10.9 grams, 0.1mol), tetrabutylammonium iodide（3.7
Gram, 0.01mol）, it is dissolved in 5 milliliters of dimethyl sulfoxides（DMSO）In, sodium hydroxide solution is added dropwise, and [sodium hydroxide solution is：By 4.4
Gram（0.11mol）Sodium hydroxide is dissolved in solution obtained in 5 milliliters of water], exothermic heat of reaction after being added dropwise, was stirred at room temperature
Night adds water quenched dilution, is extracted with dichloromethane, dry, is concentrated, and vacuum distillation obtains the bromo- 1H- pyrazoles product of 1- ethyl -4-
16.8 grams, yield 96.0%.
Fig. 1 is the nuclear magnetic resonance map of the bromo- 1H- pyrazoles of the present embodiment products obtained therefrom 1- ethyl -4-；
1 H-NMR ( 500 MHz, CDCl3 ) δ: 7.45（1H,s）, 7.42（1H,s）, 4.15（2H,q,d=7.5Hz）,
1.47（2H,t,d=7.5Hz）.
Embodiment 2
The synthesis of 1- isopropyl -1H- pyrazoles
At room temperature, by pyrazoles（6.8 grams, 0.1mol）, bromo propane (12.3 grams, 0.1mol), tetrabutylammonium bromide（3.2
Gram, 0.01mol）, it is dissolved in 5 milliliters of dimethyl sulfoxides（DMSO）In, sodium hydroxide solution is added dropwise, and [sodium hydroxide solution is：By 8.8
Gram（0.22mol）Sodium hydroxide is dissolved in solution obtained in 10 milliliters of water], exothermic heat of reaction after being added dropwise, was stirred at room temperature
Night adds water quenched dilution, is extracted with dichloromethane, dry, is evaporated under reduced pressure after concentration, obtains 9.7 grams of product, yield 88.2%.
Fig. 2 is the nuclear magnetic resonance map of 2 products obtained therefrom 1- isopropyl -1H- pyrazoles of the embodiment of the present invention；
1 H-NMR ( 500 MHz, CDCl3 ) δ: 7.5（1H,d,d=2Hz）, 7.41（1H,d,d=2Hz）, 6.23（1H,t,
d=2Hz）,4.51（1H,m）,1.51（3H,s）, 1.50（3H,s）.
Embodiment 3
The synthesis of the bromo- 1H- pyrazoles of 1- benzyl -4-
At room temperature, by 4- bromine pyrazoles（14.7 grams, 0.1mol）, benzyl chloride (17.1 grams, 0.1mol), tetrabutylammonium hydroxide
（1.3 grams, 0.005mol）, it is dissolved in 10 milliliters of dimethyl sulfoxides（DMSO）In, potassium hydroxide solution [potassium hydroxide solution is added dropwise
For：By 11.2 grams（0.20mol）Potassium hydroxide is dissolved in solution obtained in 5 milliliters of water], exothermic heat of reaction, after being added dropwise, room
Temperature is stirred overnight, and is added water quenched dilution, is extracted with ethyl acetate, dry, is evaporated under reduced pressure after concentrated product, is obtained 20.5 grams of product,
Yield 86.5%.
Fig. 3 is the nuclear magnetic resonance map of the bromo- 1H- pyrazoles of the present embodiment products obtained therefrom 1- benzyl -4-；
1 H-NMR ( 500 MHz, CDCl3 ) δ: 7.49（1H,s）, 7.38-7.32（4H,m）, 7.23-7.21（2H,m）,
5.26（2H,s）.
Embodiment 4
The synthesis of 1- ethyl -3- methyl-1 H- pyrazoles -5- carboxylic acid and 1- ethyl -5- methyl-1 H- pyrazoles -3- carboxylic acid
At room temperature, by 5- methylpyrazole -3- methyl formate（14 grams, 0.1mol）, bromoethane (10.9 grams, 0.1mol), the tetrabutyl
Ammonium hydrogen sulfate（2.7 grams, 0.008mol）, it is dissolved in 10 milliliters of dimethyl sulfoxides（DMSO）In, potassium hydroxide solution [hydroxide is added dropwise
Potassium solution is：By 22.4 grams（0.40mol）Potassium hydroxide is dissolved in solution obtained in 20 milliliters of water], exothermic heat of reaction drips
Finish, be stirred overnight at room temperature, add water quenched dilution, it is 1- ethyl -3- first through nuclear magnetic resonance test that adjusting pH, which is 2 precipitation white solids,
The mixture of base pyrazoles -5- formic acid and 1- ethyl -5- methylpyrazole -3- formic acid, ratio 1:1, product gross weight 14.6 after drying
Gram, yield 94.8%.
Fig. 4 is the nuclear magnetic resonance map of the present embodiment products obtained therefrom 1- ethyl -3- methyl-1 H- pyrazoles -5- carboxylic acid；
Fig. 5 is the nuclear magnetic resonance map of the present embodiment products obtained therefrom 1- ethyl -5- methyl-1 H- pyrazoles -3- carboxylic acid.
Its nuclear magnetic resonance data is after being isolated and purified test：1- ethyl -3- methyl-1 H- pyrazoles -5- carboxylic acid1 H-NMR
( 500 MHz, DMSO-d6 ) δ: 10.85（1H,brs）, 6.74（1H,s）, 4.59（2H,q）,2.32（3H,s）,1.44
（3H,t）；1- ethyl -5- methyl-1 H- pyrazoles -3- carboxylic acid1 H-NMR ( 500 MHz, DMSO-d6 ) δ: 12.45（1H,
brs）, 6.45（1H,s）, 4.09（2H,q）,2.27（3H,s）,1.30（3H,t）.
Embodiment 5
The synthesis of the bromo- 1H- pyrazoles of 1- ethyl -4-
At room temperature, by 4- bromine pyrazoles（15.6 grams, 0.1mol）, iodoethane (10.9 grams, 0.1mol), tetrabutylammonium iodide（3.7
Gram, 0.0001mol）, it is dissolved in 5 milliliters of dimethyl sulfoxides（DMSO）In, sodium hydroxide solution is added dropwise, and [sodium hydroxide solution is：It will
4.4 gram（0.11mol）Sodium hydroxide is dissolved in solution obtained in 5 milliliters of water], exothermic heat of reaction after being added dropwise, is stirred at room temperature
Overnight, add water quenched dilution, be extracted with dichloromethane, it is dry, it is concentrated, vacuum distillation obtains the bromo- 1H- pyrazoles product of 1- ethyl -4-
15.0 grams, yield 85.7%.
Embodiment 6
The synthesis of the bromo- 1H- pyrazoles of 1- ethyl -4-
At room temperature, by 4- bromine pyrazoles（15.6 grams, 0.1mol）, iodoethane (10.9 grams, 0.1mol), tetrabutylammonium iodide（3.7
Gram, 0.001mol）, it is dissolved in 5 milliliters of dimethyl sulfoxides（DMSO）In, sodium hydroxide solution is added dropwise, and [sodium hydroxide solution is：It will
4.4 gram（0.11mol）Sodium hydroxide is dissolved in solution obtained in 5 milliliters of water], exothermic heat of reaction after being added dropwise, is stirred at room temperature
Overnight, add water quenched dilution, be extracted with dichloromethane, it is dry, it is concentrated, vacuum distillation obtains the bromo- 1H- pyrazoles product of 1- ethyl -4-
15.2 grams, yield 86.8%.
Embodiment 7
The synthesis of the bromo- 1H- pyrazoles of 1- ethyl -4-
At room temperature, by 4- bromine pyrazoles（15.6 grams, 0.1mol）, iodoethane (10.9 grams, 0.1mol), tetrabutylammonium iodide（3.7
Gram, 1mol）, it is dissolved in 5 milliliters of dimethyl sulfoxides（DMSO）In, sodium hydroxide solution is added dropwise, and [sodium hydroxide solution is：By 40 grams
（1mol）Sodium hydroxide is dissolved in solution obtained in 5 milliliters of water], exothermic heat of reaction after being added dropwise, is stirred overnight at room temperature, adds
Water quenched dilution, is extracted with dichloromethane, dry, is concentrated, and vacuum distillation obtains 16.2 grams of the bromo- 1H- pyrazoles product of 1- ethyl -4-,
Yield 92.6%.
Embodiment 8
The synthesis of 1- benzyl -3- nitro -1H- pyrazoles
At room temperature, by 3- nitropyrazole（11.3 grams, 0.1mol）, cylite (17.1 grams, 0.1mol), tetrabutylammonium bromide
（1.6 grams, 0.005mol）, it is dissolved in 10 milliliters of dimethyl sulfoxides（DMSO）In, sodium hydroxide solution [sodium hydroxide solution is added dropwise
For：By 8.8 grams（0.22mol）Sodium hydroxide is dissolved in solution obtained in 10 milliliters of water], exothermic heat of reaction, after being added dropwise, room
Temperature is stirred overnight, and is added water quenched dilution, is extracted with dichloromethane, dry, to half-dried plus petroleum ether recrystallization after concentration, obtains product
18.3 grams, yield 90%.
Fig. 6 is the nuclear magnetic resonance map of the present embodiment products obtained therefrom 1- benzyl -3- nitro -1H- pyrazoles；
1 H-NMR ( 500 MHz, CDCl3 ) δ: 7.41（4H,m）, 7.29（2H,m）, 6.90（1H,d,d=3.5Hz）,
5.37（2H,s）.
Embodiment 9
The synthesis of the bromo- 1- allyl -1H- pyrazoles of 4-
At room temperature, by 4- bromine pyrazoles（14.7 grams, 0.1mol）, 3- bromopropene (12.1 grams, 0.1mol), tetrabutylammonium bromide
（0.97 gram, 0.003mol）, it is dissolved in 6 milliliters of dimethyl sulfoxides（DMSO）In, sodium hydroxide solution [sodium hydroxide solution is added dropwise
For：By 8.8 grams（0.22mol）Sodium hydroxide is dissolved in solution obtained in 8 milliliters of water], exothermic heat of reaction, after being added dropwise, room
Temperature is stirred overnight, and is added water quenched dilution, is extracted with dichloromethane, dry, is evaporated under reduced pressure after concentration, is obtained 16.5 grams of product, yield
88%。
Fig. 7 is the nuclear magnetic resonance map of the bromo- 1- allyl -1H- pyrazoles of the present embodiment products obtained therefrom 4-；
1 H-NMR ( 500 MHz, CDCl3 ) δ: 7.47（4H,s）, 7.42（2H,m）, 6.60（1H,m）,5.27（2H,
m）,4.71(1H,m).
Embodiment 10
The synthesis of the bromo- 1- of 4- (2- methoxy ethyl) -1H- pyrazoles
At room temperature, by 4- bromine pyrazoles（14.7 grams, 0.1mol）, 2- bromo-ethyl-methyl ether (13.9 grams, 0.1mol), tetrabutyl bromine
Change ammonium（2.6 grams, 0.008mol）, it is dissolved in 8 milliliters of dimethyl sulfoxides（DMSO）In, sodium hydroxide solution is added dropwise, and [sodium hydroxide is molten
Liquid is：By 8.8 grams（0.22mol）Sodium hydroxide is dissolved in solution obtained in 20 milliliters of water], exothermic heat of reaction, after being added dropwise,
It is stirred overnight at room temperature, adds water quenched dilution, be extracted with dichloromethane, it is dry, it is evaporated under reduced pressure after concentration, obtains 19.1 grams of product, received
Rate 93%.
Fig. 8 is the nuclear magnetic resonance map of the bromo- 1- of the present embodiment products obtained therefrom 4- (2- methoxy ethyl) -1H- pyrazoles；
1 H-NMR ( 500 MHz, CDCl3 ) δ: 7.50（4H,s）, 7.46（2H,m）, 6.60（1H,m）,4.26（2H,t,
J=7.5Hz）,3.71(1H,t,J=6.5Hz),3.34(1H,s).
Embodiment 11
The bromo- 1- of 4-（2- fluoro ethyl）The synthesis of -1H- pyrazoles
At room temperature, by 4- bromine pyrazoles（14.7 grams, 0.1mol）, the bromo- 2- fluoroethane of 1- (12.7 grams, 0.1mol), tetrabutyl bromine
Change ammonium（3.2 grams, 0.01mol）, it is dissolved in 10 milliliters of dimethyl sulfoxides（DMSO）In, sodium hydroxide solution is added dropwise, and [sodium hydroxide is molten
Liquid is：By 17.6 grams（0.44mol）Sodium hydroxide is dissolved in solution obtained in 20 milliliters of water], exothermic heat of reaction is added dropwise
Afterwards, it is stirred overnight at room temperature, adds water quenched dilution, be extracted with dichloromethane, it is dry, it is evaporated under reduced pressure after concentration, obtains 16.6 grams of product,
Yield 86%.
Fig. 9 is the bromo- 1- of the present embodiment products obtained therefrom 4-（2- fluoro ethyl）The nuclear magnetic resonance map of -1H- pyrazoles；
1 H-NMR ( 500 MHz, CDCl3 ) δ: 7.50（2H,br）, 4.72（2H,d,J=8.5Hz）,4.36(2H,m).
Embodiment 12
2-（The bromo- 1H- pyrazoles of 4-）The synthesis of-N, N- dimethyl amine
At room temperature, by 4- bromine pyrazoles（14.7 grams, 0.1mol）, the bromo- N of 2-, N- dimethyl amine (15.2 grams, 0.1mol), four
Butylammonium bromide（3.2 grams, 0.02mol）, it is dissolved in 20 milliliters of dimethyl sulfoxides（DMSO）In, sodium hydroxide solution [hydrogen-oxygen is added dropwise
Changing sodium solution is：By 17.6 grams（0.44mol）Sodium hydroxide is dissolved in solution obtained in 40 milliliters of water], exothermic heat of reaction is added dropwise
After, it is stirred overnight at room temperature, adds water quenched dilution, be extracted with dichloromethane, it is dry, it is evaporated under reduced pressure after concentration, obtains product
19.0 grams, yield 87%.
Figure 10 is the present embodiment products obtained therefrom 2-（The bromo- 1H- pyrazoles of 4-）The nuclear magnetic resonance map of-N, N- dimethyl amine；
1 H-NMR ( 500 MHz, CDCl3 ) δ: 7.51（1H,s）, 7.45（1H,s）,4.18（2H,t,J=8Hz）,2.72
(2H, t, J=8Hz), 2.26（1H,s）.
Claims (10)
1. a kind of pyrazoles N- alkylation, which is characterized in that with pyrazoles or its derivative and halogenated alkyl hydrocarbon in quaternary ammonium salt
It in the presence of catalyst and acid binding agent, is reacted in solvent, obtains N- alkyl substituted pyrazolecarboxylic.
2. pyrazoles N- alkylation according to claim 1, which is characterized in that use following steps：
By pyrazoles or its derivative, halogenated alkyl hydrocarbon, quaternary ammonium salt catalyst, it is dissolved in dimethyl sulfoxide, acid binding agent is added dropwise
Aqueous solution after being added dropwise, is stirred overnight, and adds water quenched dilution；Extraction, dry, concentration, vacuum distillation, or adjusting pH is 2-3
Be precipitated to get.
3. pyrazoles N- alkylation according to claim 1 or 2, which is characterized in that halogenated alkyl hydrocarbon participates in reaction,
It is 1 ︰ 1 with the ratio between the amount of substance of pyrazoles or its derivative.
4. pyrazoles N- alkylation according to claim 1 or 2, which is characterized in that solvent is dimethyl sulfoxide；Solvent
Dosage is that 50-200ml solvent is added in every 1 mole pyrazole or its derivative.
5. pyrazoles N- alkylation according to claim 1 or 2, which is characterized in that quaternary ammonium salt catalyst is the tetrabutyl
At least one of ammonium hydroxide, tetrabutylammonium bromide, tetrabutyl iodate amine, 4-butyl ammonium hydrogen sulfate.
6. pyrazoles N- alkylation according to claim 1 or 2, which is characterized in that quaternary ammonium salt catalyst usage amount is
It is equivalent to 0.001-10 times of the amount of pyrazoles or the substance of its derivative.
7. pyrazoles N- alkylation according to claim 1 or 2, which is characterized in that quaternary ammonium salt catalyst usage amount is
It is equivalent to 0.05-0.1 times of the amount of pyrazoles or the substance of its derivative.
8. pyrazoles N- alkylation according to claim 1 or 2, which is characterized in that acid binding agent is sodium hydroxide, hydrogen-oxygen
Change at least one of potassium, on the basis of the amount of pyrazoles or the substance of its derivative, acid binding agent dosage be equivalent to pyrazoles or
1-10 times of the amount of the substance of its derivative of person.
9. pyrazoles N- alkylation according to claim 1 or 2, which is characterized in that reaction temperature is 0-200 DEG C.
10. pyrazoles N- alkylation according to claim 1 or 2, which is characterized in that the reaction time is to drip to tie up acid
It is stirred overnight after the aqueous solution of agent.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114105876A (en) * | 2021-12-08 | 2022-03-01 | 沈阳科创化学品有限公司 | Method for preparing pyrazoxyfen-ethyl intermediate |
| CN114181237A (en) * | 2021-12-01 | 2022-03-15 | 上海凌凯医药科技有限公司 | Synthesis method of 1-isopropylpyrazole-5-boronic acid pinacol ester |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114181237A (en) * | 2021-12-01 | 2022-03-15 | 上海凌凯医药科技有限公司 | Synthesis method of 1-isopropylpyrazole-5-boronic acid pinacol ester |
| CN114181237B (en) * | 2021-12-01 | 2024-02-23 | 上海凌凯医药科技有限公司 | Synthesis method of 1-isopropyl pyrazole-5-boric acid pinacol ester |
| CN114105876A (en) * | 2021-12-08 | 2022-03-01 | 沈阳科创化学品有限公司 | Method for preparing pyrazoxyfen-ethyl intermediate |
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