CN102766095B - Preparation method of electron-deficient group-containing multi-substituted pyrazole derivative - Google Patents

Preparation method of electron-deficient group-containing multi-substituted pyrazole derivative Download PDF

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CN102766095B
CN102766095B CN201210230698.7A CN201210230698A CN102766095B CN 102766095 B CN102766095 B CN 102766095B CN 201210230698 A CN201210230698 A CN 201210230698A CN 102766095 B CN102766095 B CN 102766095B
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phenyl
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ketone
tolylene
electron deficiency
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CN102766095A (en
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张俊良
于秀招
李文博
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East China Normal University
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Abstract

The invention relates to a preparation method of an electron-deficient group-containing multi-substituted pyrazole derivative. The preparation method comprises the following steps of: dissolving electron-deficient conjugated enyne, hydrazine and alkali in an organic solvent, and enabling the mixture to react in a range of room temperature to 40 DEG C, removing the solvent and obtaining a crude product; and obtaining the electron-deficient group-containing multi-substituted pyrazole derivative shown in a formula (I) or formula (II) by column chromatography. The preparation method has the advantages of simple and easy obtaining of raw materials, simplicity and safety in operation, high atom economy, high yield and high selectivity. The aldehyde ketone and other functional groups containing multi-substituted pyrazole derivative with a single isomer can be conveniently and effectively obtained by one step, various compound skeletons are provided, and the method has important significance on synthesis of the substituted pyrazole compound.

Description

A kind of preparation method of the multi-substituted pyrazol analog derivative containing electron deficiency group
Technical field
The present invention relates to a kind of preparation method of the pyrazole derivatives containing electron deficiency groups such as aldehyde ketones, be specifically related to a kind of preparation method of the multi-substituted pyrazol analog derivative containing electron deficiency group, belong to new synthetic method field.
Background technology
Through studying for many years, the synthetic method of a series of pyrazole derivatives is mutually supplemented and is improved (Heterocycles1991,32,1745., Chem.Rev., 2011,111,6984., R.Kinjo, B.Donnadieu, G.Bertrand, Angew.Chem., Int.Ed.2011,50,5560).The comparatively generalized synthesis of usual multi-substituted pyrazol analog derivative mostly by 1,3-diketone or its etc. when body and the condensation of hydrazine class, or to be obtained by the diazonium compounds of 1,3-dipole or imines nitrile and undersaturated alkene or alkynes.But these several class methods are due in regioselectivity, and the defect that the aspects such as the activity of nitrogenous substrate or dangerous and explosive exist greatly limit their application.Method with carbonyl (especially aldehyde radical and ketone carbonyl) on synthesizing pyrazole ring is but difficult to be realized by these several class methods.
Recently, synthesis has the substituted pyrazolecarboxylic of ketone carbonyl to occur novel method, the method is with amine, ketone and nitrile are substrate, by neutralized verdigris and air be oxygenant efficient selective obtain polysubstituted pyrazole compound (Angew.Chem., Int.Ed.2010,49,, and the universality of substrate is also better, can obtain the polyfunctional compound required for great majority 7790).But first generate imines by the condensation of amine and ketone because the method is still the same with the method for forefathers, and then be obtained by reacting final product pyrazoles with nitrile, so for the limited compatibility of functional group, during compound only containing two carbonyl in substrate, a carbonyl could be retained in pyrazole product.Also have a weak point to be exactly that it needs hot conditions and oxygenant consumption too large, although adopt air as co-oxidants, the consumption of neutralized verdigris reaches more than three times of equivalents, and this greatly limit its range of application further.So the novel method needing to develop a kind of simple efficient, carbonyl class substrate compatibility is to improve the synthesis of this compounds.
Summary of the invention
For the compatible not enough defect of group that existing preparation method exists, the invention provides the compatible various carbonyl of easy synthesis, cyano group, the novel method of the pyrazole derivative compound of the groups such as amide group.Synthetic method of the present invention can compatible aldehyde radical, and carbonyl, the groups such as acid amides are the features that other synthetic methods do not have.And the inventive method is simple to operate, raw material is easy to get, and meets the Green Chemistry requirement of Atom economy, has very important significance to the synthesis of pyrazole compound, the screening of novel type compound activity and research.
The object of the invention is open a kind of raw material cheap and easy to get, safety simple to operate, high-level efficiency obtains the synthetic method of the polysubstituted pyrazole derivatives of electron deficiency, with electron deficiency conjugated enynes, hydrazine is raw material, alkali (comprising mineral alkali and organic bases) is catalyzer, and catalyzed reaction optionally obtains comprising aldehyde radical, ketone carbonyl, ester group, cyano group, amide group, ketone acid ester group, the multi-substituted pyrazol of the electron deficiency groups such as sulfuryl and and the derivative of ring structure.And such pyrazole compound method containing functional groups such as aldehyde ketones adopts additive method of the prior art not easily to synthesize.
The present invention proposes a kind of preparation method of the multi-substituted pyrazol analog derivative containing electron deficiency group, electron deficiency conjugated enynes, hydrazine, alkali are dissolved in organic solvent, fully react under room temperature to 40 DEG C temperature range, obtain thick product after removing solvent, then obtain such as formula the multi-substituted pyrazol analog derivative containing electron deficiency group shown in (I) or formula (II) after column chromatography:
Wherein, described electron deficiency conjugated enynes is as shown in following chemical formula (III-A) or (III-B):
Described preparation method is by shown in following reaction formula (1) or reaction formula (2):
Reaction formula (1)
Reaction formula (2)
Wherein,
EWG is electron deficiency group, comprises ester group, ketone group, aldehyde radical, amide group, ketone acid ester group, cyano group or sulfuryl; EWG is including, but not limited to these electron deficiency groups aforementioned;
R is hydrogen; Aryl or heteroaryl: phenyl, adjacent, the substituted-phenyl of contraposition, thiophene, furans, pyrroles, the heteroaryls such as pyridine; Alkyl: methyl, ethyl, the alkyl such as the tertiary butyl; Acyl group, alkylsulfonyl, amide group, aldehyde radical, ester group, ketone carbonyl, cyano group, sulfuryl, ketone acid ester group etc.; R is including, but not limited to above-mentioned substituting group;
R 1for aryl or heteroaryl: phenyl, adjacent, p-nitrophenyl, adjacent, to fluorophenyl, adjacent, to bromophenyl, to, the substituted-phenyl such as Chloro-O-Phenyl, thiophene, pyrroles, the heteroaryls such as pyridine; Alkyl: methyl, ethyl, the alkyl such as normal-butyl; Acyl group, alkylsulfonyl, amide group, aldehyde radical, ester group, ketone carbonyl, cyano group, sulfuryl, the electron deficiency groups such as ketone acid ester group; R 1including, but not limited to above-mentioned substituting group;
R 2for aryl: phenyl, adjacent, p-methoxyphenyl, adjacent, to bromophenyl, adjacent, the substituted-phenyl such as rubigan, thiophene, pyrroles, the heteroaryls such as pyridine; Alkyl: methyl, ethyl, normal-butyl, cyclopropane base, 1-cyclohexenyl and etc. alkyl, acyl group, alkylsulfonyl, amide group, aldehyde radical, ester group, ketone carbonyl, cyano group, sulfuryl, the electron deficiency groups such as ketone acid ester group; Also can directly replace by hydrogen; R 2including, but not limited to above-mentioned substituting group;
X is carbon, nitrogen, oxygen;
n=1~6。
EWG, R, R 1, R 2, X is including, but not limited to above-mentioned group or compound.Such as, EWG comprises ester group, ketone group, aldehyde radical, amide group, ketone acid ester group, cyano group, sulfuryl, phosphoric acid ester, the electron deficiency groups such as carboxylic acid.R is hydrogen; Aryl or heteroaryl: phenyl, adjacent, the substituted-phenyl of contraposition, thiophene, furans, pyrroles, the heteroaryls such as pyridine; Alkyl: methyl, ethyl, the alkyl such as the tertiary butyl; Acyl group, alkylsulfonyl, amide group, aldehyde radical, ester group, ketone carbonyl, cyano group, sulfuryl, ketone acid ester group, carboxylic acid, phosphoric acid ester etc.; R is including, but not limited to above-mentioned substituting group.R 1for aryl or heteroaryl: phenyl, adjacent, p-nitrophenyl, adjacent, to fluorophenyl, adjacent, to bromophenyl, to, the substituted-phenyl such as Chloro-O-Phenyl, thiophene, pyrroles, the heteroaryls such as pyridine; Alkyl: methyl, ethyl, the alkyl such as normal-butyl; Acyl group, alkylsulfonyl, amide group, aldehyde radical, ester group, ketone carbonyl, cyano group, sulfuryl, ketone acid ester group, the electron deficiency groups such as carboxylic acid.R 1including, but not limited to above-mentioned substituting group.R 2for aryl: phenyl, adjacent, p-methoxyphenyl, adjacent, to bromophenyl, adjacent, the substituted-phenyl such as rubigan, thiophene, pyrroles, the heteroaryls such as pyridine; Alkyl: methyl, ethyl, normal-butyl, cyclopropane base, 1-cyclohexenyl and etc. alkyl, acyl group, alkylsulfonyl, amide group, aldehyde radical, ester group, ketone carbonyl, cyano group, sulfuryl, ketone acid ester group, carboxylic acid, the electron deficiency groups such as phosphoric acid ester; Also can directly replace by hydrogen; R 2including, but not limited to above-mentioned substituting group.X is carbon, nitrogen, oxygen.
Wherein, described electron deficiency conjugated enynes is 1, the 3-conjugated enynes compounds that aryl, heteroaryl or alkyl replace.
Wherein, electron deficiency conjugated enynes shown in described chemical formula (III-A) comprises 2-α-tolylene-4-phenyl-3-butynoic acid methyl esters, 2-(4-methoxybenzylidene)-4-phenyl-3-butynoic acid methyl esters, 2-(4-fluorobenzylidene)-4-phenyl-3-butynoic acid methyl esters, 2-α-tolylene-4-(4-p-methoxy-phenyl)-3-butynoic acid methyl esters, 2-α-tolylene-4-(1-naphthyl)-3-butynoic acid methyl esters, 2-α-tolylene-3-methyl 2-octynoate, 2-α-tolylene-4-cyclopropane base-3-butynoic acid methyl esters, 2-(4-methoxybenzylidene)-4-(4-p-methoxy-phenyl)-3-butynoic acid methyl esters, 2-(4-methoxybenzylidene)-4-(1-naphthyl)-3-butynoic acid methyl esters, 3-α-tolylene-5-phenyl-4-pentyne-2-ketone, 3-(4-methoxybenzylidene)-5-phenyl-4-pentyne-2-ketone, 3-(4-cyano group α-tolylene)-5-phenyl-4-pentyne-2-ketone, 3-α-tolylene-5-(1-naphthyl)-4-pentyne-2-ketone, 3-α-tolylene-5-(4-p-methoxy-phenyl)-4-pentyne-2-ketone, 3-α-tolylene-5-(4-nitrophenyl)-4-pentyne-2-ketone, 3-α-tolylene-5-(4-fluorophenyl)-4-pentyne-2-ketone, 3-α-tolylene-5-(1-cyclohexenyl)-4-pentyne-2-ketone, 2-α-tolylene-1, 4-phenylbenzene-3-butine-1-ketone, 2-α-tolylene-1-(4-chloro-phenyl-)-4-phenyl-3-butine-1-ketone, 6-phenyl-3-(phenylacetylene base)-3, 5-hexadiene-2-ketone, 3-α-tolylene-2-oxo-5-phenyl-4-pentynoic acid methyl esters, 3-α-tolylene-2-oxo-5-(4-tolyl)-4-pentynoic acid methyl esters, 2-α-tolylene-4-phenyl-3-butine nitrile, 2-α-tolylene-4-phenyl-3-tetrolic aldehyde, 3-(2-α-tolylene-4-phenyl-3-butine ketone group) oxazole-2-ketone etc., but be not limited to above-mentioned eneyne.
Wherein, electron deficiency conjugated enynes shown in described chemical formula (III-B) comprises 2-phenylacetylene base-2-tetrahydrobenzene 1-ketone, 2-phenylacetylene base-2-cyclopentenes 1-ketone, 3-phenylacetylene base-3-alkene-2-furanone, 3-phenylacetylene base-3-alkene-2-pyrrolidone, 2-phenylacetylene base-2-suberene 1-ketone etc., but be not limited to above-mentioned eneyne.
Wherein, described hydrazine is hydrazine hydrate, alkyl hydrazine, p-toluene sulfonyl hydrazide, phenylhydrazine, the aryl of replacement or heteroaryl hydrazine.Described hydrazine is including, but not limited to above-mentioned substituting group.
Wherein, described organic solvent is DMF, N,N-dimethylacetamide, methyl-sulphoxide or acetonitrile.Described organic solvent is including, but not limited to above-mentioned organic solvent.
Wherein, described alkali is triethylamine, Tetramethyl Ethylene Diamine (TMEDA), triethylene diamine (DABCO), 1,8-diazabicyclo [5,4,0]-ten one carbon-7-alkene (DBU), sodium-acetate or salt of wormwood etc.Described alkali is including, but not limited to above-mentioned alkali.
Wherein, the mol ratio of described electron deficiency conjugated enynes, hydrazine, alkali is electron deficiency conjugated enynes: hydrazine: alkali=1.0:1.2-1.5:0.05-0.2.Preferably, electron deficiency conjugated enynes: hydrazine: alkali=1.0:1.2:0.2.
Wherein, the add-on of described organic solvent is 10 ~ 15ml/mmol electron deficiency conjugated enynes.
Wherein, the mode of described removal solvent is for after first extracting by ether or ethyl acetate, dry and revolve to boil off and desolventize, or directly revolves to boil off and desolventize.
Wherein, described column chromatography adopts volume ratio to be ethyl acetate: the solution of sherwood oil=1:8 ~ 1:5 carries out.
Innovation of the present invention one of improves, and is that preparation method of the present invention carries out under specific temperature of reaction, e.g., carries out at room temperature to 40 DEG C temperature.Preferably, carry out at 23 DEG C of-40 DEG C of temperature.
In the present invention, " electron deficiency group " refers to the former molecular functional group with electron deficiency, such as ester group, ketone group, aldehyde radical, amide group, ketone acid ester group, cyano group, sulfuryl etc.
Each raw material in the present invention, organic solvent, alkali, hydrazines etc. all can be buied and directly use in market, such as, organic solvent (N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, methyl-sulphoxide, acetonitrile), alkali (triethylamine, Tetramethyl Ethylene Diamine (TMEDA), triethylene diamine (DABCO), 1, 8-diazabicyclo [5, 4, 0]-ten one carbon-7-alkene (DBU), sodium-acetate, salt of wormwood) and hydrazine (hydrazine hydrate, p-toluene sulfonyl hydrazide, phenylhydrazine, methyl hydrazine and Tertiary butyl hydrazine hydrochloride), the raw material electron deficiency unsaturated olefin (also can obtain product with corresponding aldehyde and ketone condensation) of the bromide precursor of preparation coupling, tetra-triphenylphosphine palladium (Pd (the PPh of coupling 3) 4), cuprous iodide, diisopropyl is pacified, bromine, sodium hydride, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, ether etc.
For realizing the object of the invention, innovation of the present invention one of improves, be with electron deficiency conjugated enynes compound and hydrazine class compound under the catalysis of conventional base (can be organic bases and mineral alkali), single pyrazole compound can be synthesized in directive property ground, namely can synthesize to feasible region selectivity controllable the multi-substituted pyrazol analog derivative of individual isomer.
The present invention adopts two component reaction one steps acquisitions to comprise various electron deficiency substituent target product multi-substituted pyrazol compound, comprises, ketone group class I A be shown below and I B, ester group class I C, aldehyde radical class I D, keto ester class I E, amides I F, cyano group class I G, sulfuryl class I H, and and ring like structure formula II A, II B, the multi-substituted pyrazol compounds of II C, II D.
R can be hydrogen; Aryl or heteroaryl: phenyl, adjacent, the substituted-phenyl of contraposition, thiophene, furans, pyrroles, the heteroaryls such as pyridine; Alkyl: methyl, ethyl, the alkyl such as the tertiary butyl; Acyl group, alkylsulfonyl, amide group, aldehyde radical, ester group, ketone carbonyl, cyano group, sulfuryl, ketone acid ester group, carboxylic acid, phosphoric acid ester etc.; R is including, but not limited to above-mentioned substituting group.
R 1for aryl or heteroaryl: phenyl, adjacent, p-nitrophenyl, adjacent, to fluorophenyl, adjacent, to bromophenyl, to, the substituted-phenyl such as Chloro-O-Phenyl, thiophene, pyrroles, the heteroaryls such as pyridine; Alkyl: methyl, ethyl, the alkyl such as normal-butyl; Acyl group, alkylsulfonyl, amide group, aldehyde radical, ester group, ketone carbonyl, cyano group, sulfuryl, ketone acid ester group, the electron deficiency groups such as carboxylic acid; R 1including, but not limited to above-mentioned substituting group.
R 2for aryl: phenyl, adjacent, p-methoxyphenyl, adjacent, to bromophenyl, adjacent, the substituted-phenyl such as rubigan, thiophene, pyrroles, the heteroaryls such as pyridine; Alkyl: methyl, ethyl, normal-butyl, cyclopropane base, 1-cyclohexenyl and etc. alkyl, acyl group, alkylsulfonyl, amide group, aldehyde radical, ester group, ketone carbonyl, cyano group, sulfuryl, ketone acid ester group, carboxylic acid, the electron deficiency groups such as phosphoric acid ester; Also can directly replace by hydrogen; R 2including, but not limited to above-mentioned substituting group.
R 3for aryl: phenyl, adjacent, rubigan, adjacent, the aryl such as p-methoxyphenyl, alkyl: methyl, ethyl, allyl group, the alkyl such as the tertiary butyl; R 3including, but not limited to above-mentioned substituting group.
Preparation method of the present invention is as follows: first take electron deficiency conjugated enynes, hydrazine, alkali by certain mol proportion, such as: electron deficiency conjugated enynes: hydrazine: alkali=1.0:1.2:0.2.By electron deficiency conjugated enynes, hydrazine, catalyzer alkali, adds in reaction flask, adds organic solvent, such as, adds 10-15ml organic solvent in every mmol group with imine moiety.Then react under room temperature reaction condition, or react at 40 DEG C, monitor reaction by tlc silica gel plate (TLC) in whipping process and carry out degree, the reaction times is about 1-24 hour, obtains thick product after reaction terminates rear removal solvent.When being high boiling N,N-dimethylacetamide according to solvent, then first being undertaken extracting rear drying by ether or ethyl acetate and revolve to boil off and desolventize; Be low boiling point solvent acetonitrile according to solvent, then can directly revolve to boil off and desolventize.Then, thick product is carried out column chromatography, obtain the pyrazole derivatives sterling with multi-substituent.Such as, be ethyl acetate by volume ratio: the solution of sherwood oil=1:8 ~ 1:5 carries out column chromatography.
In the present invention, high boiling solvent refers to the solvent being greater than 100 DEG C, and by not easily removing under the mode of common distillation.Low boiling point solvent refers to that temperature is lower than the solvent of 100 DEG C, and is easy to removing by the method for distillation.
In the present invention; above-mentioned electron deficiency conjugated enynes IIIA and IIIB is the bromide V(that obtains after alpha-brominated (or iodo) of the unsaturated olefin replaced by corresponding aldehyde, ketone, ester, nitrile etc. or iodide VII) with end alkynes VI by Sonogashira linked reaction react prepare (refer to J.Am.Chem.Soc.2004; 126,11164; Tetrahedron 1998,54,135; J.Am.Chem.Soc.2001,123,9472).
Chemical formula (III-A), prepares by following reaction formula:
Chemical formula (III-B), prepares by following reaction formula:
Preparation method of the present invention is with electron deficiency conjugated enynes, hydrazine is raw material, alkali (comprising mineral alkali and organic bases) is catalyzer, catalyzed reaction optionally obtains comprising aldehyde radical, ketone carbonyl, ester group, cyano group, amide group, ketone acid ester group, the multi-substituted pyrazol of the electron deficiency groups such as sulfuryl and and the derivative of ring structure.Advantage of the present invention comprises: the raw material that the inventive method adopts is simple and easy to get, and cost is inexpensive, safety simple to operate.Synthetic method route of the present invention is simple, a step establishing target product.There is Atom economy, high yield, the advantages such as highly selective, meet the requirement of Green Chemistry.Prior art not easily synthesizes the pyrazole compound containing functional groups such as aldehyde ketones, and energy simple and fast of the present invention effectively a step directly synthesize the multi-substituted pyrazol derivative replaced containing the functional group such as aldehyde ketone of individual isomer, multifarious compound scaffold is provided, not only significant to the synthesis of substituted pyrazolecarboxylic compounds, and to the synthesis screening of new drug and pharmaceutical technology, there is extremely important meaning.
Embodiment
In conjunction with following specific embodiment, the present invention is described in further detail.Implement process of the present invention, condition, reagent, experimental technique etc., except the following content mentioned specially, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.
Embodiment 1
Take 3-α-tolylene-5-phenyl-4-pentyne-2-ketone (0.20mmol, 49.2mg), tertiary butyl nitrile hydrochloride (0.24mmol, 29.9mg), they are all added in little reaction tubes by salt of wormwood (0.28mmol, 38.6mg), at room temperature add 2.0ml N,N-dimethylacetamide.Room temperature (23 DEG C) stirs after 1.2 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then is separated to obtain white solid pyrazole derivatives straight product IA-1 by column chromatography (eluent: sherwood oil: ethyl acetate=1:8).Yield 97%(64.4mg).m.p.:127~128℃。
1H NMR(400MHz,CDCl 3):δ=7.55(d,J=7.2Hz,2H),7.45~7.37(m,3H),7.26(t,J=7.2Hz,2H),7.17(t,J=7.2Hz,1H),7.04(d,J=7.2Hz,2H),4.59(s,2H),2.01(s,3H),1.60(s,9H). 13C NMR(100MHz,CDCl 3):δ=196.54,149.96,143.07,138.34,134.29,129.28,128.38,128.32,128.23,127.59,126.08,121.83,61.62,31.84,30.96,30.52ppm;MS(70eV):m/z(%):332(M +,94.70),261(100).HRMS calcd for C 22H 24N 2O:332.1889,found:332.1890。
Embodiment 2
Take 3-(4-methoxybenzylidene)-5-phenyl-4-pentyne-2-ketone (0.20mmol, 55.2mg), tertiary butyl nitrile hydrochloride (0.24mmol, 29.9mg), they are all added in little reaction tubes by salt of wormwood (0.28mmol, 38.6mg), at room temperature add 2.0ml N,N-dimethylacetamide.Continue stirring at room temperature after 4 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains yellow solid pyrazole derivatives straight product IA-2 by column chromatography (eluent: sherwood oil: ethyl acetate=1:8) separation.Yield 85%(62.0mg).m.p.:105~106℃。
1H NMR(400MHz,CDCl 3):δ=7.47(d,J=8.4Hz,2H),7.26(t,J=7.2Hz,2H),7.17(t,J=7.2Hz,1H),7.04(d,J=7.2Hz,2H),6.97(d,J=8.4Hz,2H),4.58(s,2H),3.84(s,3H),2.03(s,3H),1.59(s,9H). 13C NMR(100MHz,CDCl 3):δ=196.61,159.74,149.77,143.01,138.41,130.48,128.37,127.60,126.68,126.06,121.71,113.81,61.52,55.24,31.87,30.88,30.53ppm.MS(70eV):m/z(%):363(M +,17.50),215(100).HRMS calcd for C 23H 26N 2O 2:362.1994,found:362.1995.。
Embodiment 3
Take 3-(4-cyano group α-tolylene)-5-phenyl-4-pentyne-2-ketone (0.20mmol, 54.2mg), tertiary butyl nitrile hydrochloride (0.24mmol, 29.9mg), they are all added in little reaction tubes by salt of wormwood (0.28mmol, 38.6mg), at room temperature add 2.0ml N,N-dimethylacetamide.Continue stirring at room temperature after 1 hour, analyse silica-gel plate (TLC) monitoring by thin layer and react complete, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains white solid pyrazole derivatives straight product IA-3 by column chromatography (eluent: sherwood oil: ethyl acetate=1:8) separation.Yield 90%(64.3mg).m.p.:161~162℃。
1H NMR(400MHz,CDCl 3):δ=7.73(d,J=8.4Hz,2H),7.69(d,J=8.4Hz,2H),7.28(t,J=7.2Hz,2H),7.20(t,J=7.2Hz,1H),7.03(d,J=7.2Hz,2H),4.56(s,2H),2.05(s,3H),1.61(s,9H). 13C NMR(100MHz,CDCl 3):δ=196.03,147.63,143.38,138.81,137.88,132.11,129.75,128.54,127.58,126.37,122.28,118.69,111.81,62.16,31.81,31.09,30.50ppm.MS(70eV):m/z(%):357(M +,76.31),301(100).HRMS calcd for C 23H 23N 3O:357.1841,found:357.1842.。
Embodiment 4
Take 3-α-tolylene-5-(4-p-methoxy-phenyl)-4-pentyne-2-ketone (0.20mmol, 55.2mg), tertiary butyl nitrile hydrochloride (0.24mmol, 29.9mg), they are all added in little reaction tubes by salt of wormwood (0.28mmol, 38.6mg), at room temperature add 2.0ml N,N-dimethylacetamide.Continue stirring at room temperature after 4 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains colorless solid pyrazole derivatives straight product IA-4 by column chromatography (eluent: sherwood oil: ethyl acetate=1:8) separation.Yield 88%(64.0mg).m.p.:119~120℃。
1H NMR(400MHz,CDCl 3):δ=7.55(d,J=6.8Hz,2H),7.47~7.35(m,3H),6.97(d,J=8.4Hz,2H),6.82(d,J=8.4Hz,2H),4.52(s,2H),3.77(s,3H),2.03(s,3H),1.61(s,9H). 13CNMR(100MHz,CDCl 3):δ=196.61,157.91,149.93,143.51,134.32,130.34,129.27,128.58,128.33,128.23,121.76,113.84,61.63,55.13,31.02,31.00,30.55ppm.MS(70eV):m/z(%):362(M +,100).HRMS calcd for C 23H 26N 2O 2:362.1994,found:362.1993.。
Embodiment 5
Take 3-α-tolylene-5-(4-fluorophenyl)-4-pentyne-2-ketone (0.20mmol, 52.8mg), tertiary butyl nitrile hydrochloride (0.24mmol, 29.9mg), they are all added in little reaction tubes by salt of wormwood (0.28mmol, 38.6mg), at room temperature add 2.0ml N,N-dimethylacetamide.Continue stirring at room temperature after 1.5 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains yellow solid pyrazole derivatives straight product IA-5 by column chromatography (eluent: sherwood oil: ethyl acetate=1:8) separation.Yield 91%(64.2mg).m.p.:131~132℃。
1H NMR(400MHz,CDCl 3):δ=7.54(d,J=6.4Hz,2H),7.47~7.35(m,3H),7.04~6.92(m,4H),4.54(s,2H),2.01(s,3H),1.60(s,9H). 13C NMR(100MHz,CDCl 3):δ=196.43,161.31(d,J C-F=243Hz),150.11,143.05,134.21,133.98(d,J C-F=3.9Hz),7.54(d,J=6.4Hz,2H),7.47~7.35(m,3H),7.04~6.92(m,4H),4.54(s,2H),2.01(s,3H),1.60(s,9H). 13C NMR(100MHz,CDCl 3):δ=196.43,161.31(d,J C-F=243Hz),150.11,143.05,134.21,133.98(d,J C-F=3.9Hz),129.31,129.05,128.98,128.33(d,J C-F=3.8Hz),121.73,115.20(d,J C-F=21Hz),61.66,31.21,30.92,30.53ppm.MS(70eV):m/z(%):350(M +,87.64),279(100).HRMS calcd forC 22H 23N 2OF:350.1794,found:350.1792.。
Embodiment 6
Take 3-α-tolylene-5-(4-nitrophenyl)-4-pentyne-2-ketone (0.20mmol, 58.2mg), tertiary butyl nitrile hydrochloride (0.24mmol, 29.9mg), they are all added in little reaction tubes by salt of wormwood (0.28mmol, 38.6mg), at room temperature add 2.0ml N,N-dimethylacetamide.Continue stirring at room temperature after 1.2 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains Tan solid pyrazole derivatives straight product IA-6 by column chromatography (eluent: sherwood oil: ethyl acetate=1:8) separation.Yield 84%(63.2mg).m.p.:105~106℃。
1H NMR(400MHz,CDCl 3):δ=8.16(d,J=8.8Hz,2H),7.54(dd,J=8.8,1.2Hz,2H)7.50~7.40(m,3H),7.24(d,J=8.8Hz,2H),4.68(s,2H),2.02(s,3H),1.62(s,9H). 13C NMR(100MHz,CDCl 3):δ=196.16,150.55,146.55,146.33,141.82,134.06,129.47,128.57,128.45,123.75,121.79,61.82,32.39,30.84,30.64ppm.MS(70eV):m/z(%):377(M +,79.24),304(100).HRMScalcd for C 22H 23N 3O 3:377.1739,found:377.1740.。
Embodiment 7
Take 3-α-tolylene-4-pentyne-2-ketone (0.20mmol, 34.0mg), tertiary butyl nitrile hydrochloride (0.24mmol, 29.9mg), salt of wormwood (0.28mmol, 38.6mg), they are all added in little reaction tubes, at room temperature add 2.0ml N,N-dimethylacetamide.Continue stirring at room temperature after 1.2 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains colourless liquid pyrazole derivatives straight product IA-7 by column chromatography (eluent: sherwood oil: ethyl acetate=1:15) separation.Yield 90%(46.2mg).
1H NMR(400MHz,CDCl 3):δ=7.63~7.57(m,3H),7.32(d,J=7.2Hz,2H),2.99(s,3H),2.02(s,3H),1.59(s,9H). 13C NMR(100MHz,CDCl 3):δ=196.38,151.00,149.25,132.13,129.22,128.55,127.84,107.87,61.85,30.93,30.50,29.26ppm.MS(70eV):m/z(%):256(M +,100).HRMS calcd for C 16H 20N 2O:256.1576,found:256.1580.。
Embodiment 8
Take 2-α-tolylene-1,4-phenylbenzene-3-butine-1-ketone (0.20mmol, 61.6mg), tertiary butyl nitrile hydrochloride (0.24mmol, 29.9mg), salt of wormwood (0.28mmol, 38.6mg), they are all added in little reaction tubes, at room temperature adds 2.0mlN, N-N,N-DIMETHYLACETAMIDE.Continue stirring at room temperature after 1.5 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains yellow solid pyrazole derivatives straight product IA-8 by column chromatography (eluent: sherwood oil: ethyl acetate=1:8) separation.Yield 93%(73.0mg).m.p.:161~162℃。
1H NMR(400MHz,CDCl 3):δ=7.62(d,J=7.2Hz,2H),7.39~7.35(m,2H),7.28(t,J=7.2Hz,1H),7.22~7.08(m,8H),7.05(d,J=7.2Hz,2H),4.49(s,2H),1.64(s,9H). 13C NMR(100MHz,CDCl 3):δ=193.25,149.02,143.29,138.42,138.37,133.07,132.25,129.70,128.50,128.41,127.87,127.83,127.79,127.36,126.20,120.14,61.79,31.68,30.55ppm.MS(70eV):m/z(%):394(M +,56.07),337(100).HRMS calcd for C 27H 26N 2O:394.2045,found:394.2048.。
Embodiment 9
Take 3-α-tolylene-5-phenyl-4-pentyne-2-ketone (0.20mmol, 49.2mg), hydrazine hydrate (0.24mmol, 14.0mg), salt of wormwood (0.04mmol, 5.5mg), they are all added in little reaction tubes, at room temperature add 2.0ml acetonitrile.Being warming up to 40 DEG C stirs after 5.5 hours, complete by tlc silica gel plate (TLC) monitoring reaction, revolve to boil off to desolventize in 40 DEG C and to obtain thick product, then obtain white solid pyrazole derivatives straight product IA-9 by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 80%(44.4mg).m.p.:99~100℃。
1H NMR(400MHz,CDCl 3):δ=7.38(brs,5H),7.26~7.16(m,5H),4.16(s,2H),2.00(s,3H). 13C NMR(100MHz,CDCl 3):δ=195.15,150.72,149.95,137.57,131.91,129.30,129.17,128.98,128.55,128.52,126.62,118.39,32.92,30.45ppm.MS(70eV):m/z(%):276(M +,100),276(100).HRMS calcd for C 18H 16N 2O:276.1263,found:276.1265.。
Embodiment 10
Take 3-(4-cyano group α-tolylene)-5-phenyl-4-pentyne-2-ketone (0.20mmol, 54.2mg), hydrazine hydrate (0.24mmol, 14.0mg), salt of wormwood (0.04mmol, 5.5mg), they are all added in little reaction tubes, at room temperature add 2.0ml acetonitrile.Being warming up to 40 DEG C stirs after 4 hours, complete by tlc silica gel plate (TLC) monitoring reaction, revolve to boil off to desolventize in 40 DEG C and to obtain thick product, then obtain yellow liquid pyrazole derivatives straight product IA-10 by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 78%(47.0mg).
7.67(d,J=8.4Hz,2H),7.58(d,J=8.4Hz,2H),7.34~7.22(m,3H),7.22~7.20(m,2H),4.24(s,2H),2.11(s,3H). 13C NMR(100MHz,CDCl 3):δ=194.52,150.95,147.87,137.73,136.15,132.06,129.98,128.94,128.83,127.22,118.60,118.34,112.46,32.48,30.67ppm.MS(70eV):m/z(%):301(M +,100),301(100).HRMS calcd for C 19H 15N 3O:301.1215,found:301.1215.。
Embodiment 11
Take 3-α-tolylene-5-(4-nitrophenyl)-4-pentyne-2-ketone (0.20mmol, 58.2mg), hydrazine hydrate (0.24mmol, 14.0mg), salt of wormwood (0.04mmol, 5.5mg), they are all added in little reaction tubes, at room temperature add 2.0ml acetonitrile.Being warming up to 40 DEG C stirs after 4 hours, complete by tlc silica gel plate (TLC) monitoring reaction, revolve to boil off to desolventize in 40 DEG C and to obtain thick product, then obtain yellow solid pyrazole derivatives straight product IA-11 by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 73%(46.8mg).m.p.:171~172℃。
1H NMR(400MHz,CDCl 3):δ=8.10(d,J=8.8Hz,2H),7.49~7.41(m,7H),4.27(s,2H),1.98(s,3H). 13C NMR(100MHz,CDCl 3):δ=194.54,146.51,146.44，129.99,129.75,129.43,129.30,128.89,125.45,123.77,123.50,118.51,33.47,30.24ppm.MS(70eV):m/z(%):321(M +,93.58).77(100).HRMS calcd for C 18H 15N 3O 3:321.1113,found:321.1113.。
Embodiment 12
Take 3-α-tolylene-5-(1-cyclohexenyl)-4-pentyne-2-ketone (0.20mmol, 56.0mg), hydrazine hydrate (0.24mmol, 14.0mg), they are all added in little reaction tubes by salt of wormwood (0.04mmol, 5.5mg), at room temperature add 2.0ml N,N-dimethylacetamide.Being warming up to 40 DEG C stirs after 3 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off to desolventize in 20 DEG C and to be obtained thick product, then obtains yellow liquid pyrazole derivatives straight product IA-12 by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 76%(42.5mg).
1H NMR(400MHz,CDCl 3):δ=7.46~7.38(m,5H),5.43(brs,1H),3.49(s,2H),2.06(s,3H),1.96~1.88(m,4H),1.60~1.49(m,4H). 13C NMR(100MHz,CDCl 3):δ=195.49,147.98,133.98,132.69,129.26,128.86,128.39,128.27,124.38,118.75,34.42,30.54,28.41,25.12,22.70,22.05ppm.MS(70eV):m/z(%):280(M +,35.54),265(100).HRMS calcd for C 18H 20N 2O:280.1576,found:280.1579.。
Embodiment 13
Take 2-α-tolylene-Isosorbide-5-Nitrae-phenylbenzene-3-butine-1-ketone (0.20mmol, 61.6mg), hydrazine hydrate (0.24mmol, 14.0mg), salt of wormwood (0.04mmol, 5.5mg), they are all added in little reaction tubes, at room temperature add 2.0ml N,N-dimethylacetamide.Rising to 40 DEG C stirs after 4 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains colourless liquid pyrazole derivatives straight product IA-13 by column chromatography (eluent: sherwood oil: ethyl acetate=1:6) separation.Yield 78%(53.0mg).
1H NMR(400MHz,CDCl 3):δ=7.55(d,J=7.2Hz,2H),7.31(t,J=7.2Hz,1H),7.25~7.03(m,12H),4.07(s,2H). 13C NMR(100MHz,CDCl 3):δ=192.63,150.00,138.40,137.69,132.32,130.68,129.48,128.82,128.54,128.47,128.34,128.14,127.89,126.57,116.74,32.32ppmMS(70eV):m/z(%):338(M +,100).HRMS calcd for C 23H 18N 2O:338.1419,found:338.1417.。
Embodiment 14
Take 2-α-tolylene-1-(4-chloro-phenyl-)-4-phenyl-3-butine-1-ketone (0.20mmol, 68.6mg), hydrazine hydrate (0.24mmol, 14.0mg), they are all added in little reaction tubes by salt of wormwood (0.04mmol, 5.5mg), at room temperature add 2.0mlN, N-N,N-DIMETHYLACETAMIDE.Rising to 40 DEG C stirs after 4 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains yellow liquid pyrazole derivatives straight product IA-14 by column chromatography (eluent: sherwood oil: ethyl acetate=1:8) separation.Yield 84%(62.6mg).
1H NMR(400MHz,CDCl 3):δ=7.45(dd,J=6.8,2.0Hz,2H),7.24~7.05(m,12H),4.04(s,2H). 13C NMR(100MHz,CDCl 3):δ=191.21,149.86,138.61,137.54,136.66,130.81,130.45,129.06,128.74,128.55,128.46,128.29,128.15,127.84,126.63,116.37,32.24ppm.MS(70eV):m/z(%):372(M +,100).HRMS calcd for C 23H 17N 2OCl:372.1029,found:372.1030.。
Embodiment 15
Take 3-α-tolylene-5-phenyl-4-pentyne-2-ketone (0.20mmol, 49.2mg), acetonitrile (0.24mmol, 11.0mg), salt of wormwood (0.04mmol, 5.5mg), they are all added in little reaction tubes, at room temperature add 2.0ml N,N-dimethylacetamide.Being warming up to 40 DEG C stirs after 3.5 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains yellow solid pyrazole derivatives straight product IA-15 and IA-15 ' by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 86%(50.0mg) (isomer proportion IA-15:IA-15 '=4.9:1).Fusing point: 109 ~ 110 DEG C.
1H NMR(400MHz,CDCl 3):δ=[7.54~7.48(m,3H)];[7.48~7.38(m,2H)];[7.36~7.18(m,4H)];[7.18~7.10(m,1H)];[4.40(s,0.33H),4.31(s,1.67H)];[3.74(s,0.49H),3.59(s,2.51H)];[2.08(s,0.49H)];1.82(s,2.51H)]. 13C NMR(100MHz,CDCl 3):δ=(195.60,193.62),(152.70,152.31),(146.18,144.81),(139.60,136.67),(133.83,130.47),(129.76,129.66),(129.29,129.05),(128.99,128.71),(128.53,128.37),(128.21,128.10),(126.65,125.93),119.46,(36.86,36.47),(33.82,30.45),(30.74,30.05)ppm.MS(70eV):m/z(%):290(M +,100).HRMS calcd forC 19H 18N 2O:290.1419,found:290.1418.。
Embodiment 16
Take 3-α-tolylene-5-phenyl-4-pentyne-2-ketone (0.20mmol, 49.2mg), benzonitrile (0.24mmol, 26.0mg), salt of wormwood (0.04mmol, 5.5mg), they are all added in little reaction tubes, at room temperature add 2.0ml N,N-dimethylacetamide.Being warming up to 40 DEG C stirs after 9 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains yellow liquid pyrazole derivatives straight product IA-16 and IA-16 ' by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 90%(63.4mg) (isomer proportion IA-16:IA-16 ' >10:1).
1H NMR(400MHz,CDCl 3):δ=[7.59(dd,J=8.0,2.0Hz,2H)];[7.48~7.36(m,6H)];[7.34~7.30(m,2H)];[7.27~7.14(m,3H)];[6.99(d,J=6.8Hz,2H)];[4.38(s,0.18H),4.35(s,1.84H)],[2.13(s,2.73H),1.87(s,0.27H)]. 13C NMR(100MHz,CDCl 3):δ=195.80,153.20,145.38,(139.36,138.49),137.60,(133.47,130.30),(129.49,129.37),(129.15,129.10),128.97,(128.69,128.65),128.40,128.38,(128.12,127.69),(126.39,126.15),125.99,120.50,(33.83,30.98),(30.86,30.36)ppm.MS(70eV):m/z(%):352(M +,100).HRMS calcd for C 24H 20N 2O:352.1576,found:352.1576.。
Embodiment 17
Take 3-α-tolylene-5-phenyl-4-pentyne-2-ketone (0.20mmol, 49.2mg), to Methyl benzenesulfonyl hydrazine (0.24mmol, 44.6mg), salt of wormwood (0.04mmol, 5.5mg), they are all added in little reaction tubes, at room temperature add 2.0ml acetonitrile.Being warming up to 40 DEG C stirs after 5.5 hours, complete by tlc silica gel plate (TLC) monitoring reaction, revolve to boil off to desolventize in 40 DEG C and to obtain thick product, then by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) be separated obtain white solid pyrazole derivatives straight product with IA-9(data and structure the same manner as in Example 9).Yield 72%(39.7mg).mp.:99~100℃。
Embodiment 18
Take 6-phenyl-3-(phenylacetylene base)-3,5-hexadiene-2-ketone (0.20mmol, 54.8mg), hydrazine hydrate (0.24mmol, 14.0mg), salt of wormwood (0.04mmol, 5.5mg), they are all added in little reaction tubes, at room temperature add 2.0ml acetonitrile.Being warming up to 40 DEG C stirs after 6 hours, complete by tlc silica gel plate (TLC) monitoring reaction, revolve to boil off to desolventize in 40 DEG C and to obtain thick product, then obtain yellow solid pyrazole derivatives straight product IB by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 53%(32.0mg).m.p.:160~161℃。
1H NMR(400MHz,CDCl 3):δ=7.42(d,J=16.8Hz,1H),7.39~7.34(m,2H),7.32~7.25(m,3H),7.24~7.08(m,6H),4.20(s,2H),2.39(s,3H). 13C NMR(100MHz,CDCl 3):δ=194.09,137.46,135.97,133.85,133.18,128.72,128.65,128.60,128.44,128.37,126.94,126.70,117.95,116.73,33.83,30.95ppm.MS(70eV):m/z(%):302(M +,100).HRMS calcd forC 20H 18N 2O:302.1419,found:302.1421.。
Embodiment 19
Take 2-α-tolylene-4-phenyl-3-butynoic acid methyl esters (0.20mmol, 52.4mg), hydrazine hydrate (0.24mmol, 14.0mg), salt of wormwood (0.04mmol, 5.5mg), they are all added in little reaction tubes, at room temperature add 2.0ml N,N-dimethylacetamide.Rising to 40 DEG C stirs after 22 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains white solid pyrazole derivatives straight product IC-1 by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 95%(55.4mg).m.p.:119~120℃。
1H NMR(400MHz,CDCl 3):δ=9.58(brs,1H),7.48~7.44(m,2H),7.34~7.27(m,3H),7.24~7.13(m,5H),4.13(s,2H),3.65(s,3H). 13C NMR(100MHz,CDCl 3):δ=164.19,150.97,137.85,130.96,129.13,128.79,128.70,128.46,127.90,126.48,108.26,50.89,32.94ppm.MS(70eV):m/z(%):292(M +,51.01),260(100).HRMS calcd for C 18H 16N 2O 2:292.1212,found:292.1212.。
Embodiment 20
Take 2-(4-methoxybenzylidene)-4-phenyl-3-butynoic acid methyl esters (0.20mmol, 58.4mg), hydrazine hydrate (0.24mmol, 14.0mg), they are all added in little reaction tubes by salt of wormwood (0.04mmol, 5.5mg), at room temperature add 2.0mlN, N-N,N-DIMETHYLACETAMIDE.Rising to 40 DEG C stirs after 10.5 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains yellow liquid pyrazole derivatives straight product IC-2 by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 95%(61.2mg).
1H NMR(400MHz,CDCl 3):δ=7.41(d,J=8.8Hz,2H),7.25~7.20(m,2H),7.19~7.15(m,3H),6.81(d,J=8.8Hz,2H),4.14(s,2H),3.78(s,3H),3.67(s,3H). 13C NMR(100MHz,CDCl 3):δ=164.28,160.02,151.11,138.13,130.42,128.72,128.40,126.38,123.00,113.36,107.92,55.14,50.85,33.21ppm.MS(70eV):m/z(%):322(M +,80.30),290(100).HRMS calcdfor C 19H 18N 2O 3:322.1317,found:322.1318.。
Embodiment 21
Take 2-(4-fluorobenzylidene)-4-phenyl-3-butynoic acid methyl esters (0.20mmol, 56.0mg), hydrazine hydrate (0.24mmol, 14.0mg), they are all added in little reaction tubes by salt of wormwood (0.04mmol, 5.5mg), at room temperature add 2.0ml N,N-dimethylacetamide.Rising to 40 DEG C stirs after 10.5 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains yellow liquid pyrazole derivatives straight product IC-3 by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 93%(57.5mg).
1H NMR(400MHz,CDCl 3):δ=7.46~7.42(m,2H),7.26~7.15(m,3H),7.14(d,J=8.8Hz,2H),6.97(t,J=8.8Hz,2H),4.14(s,2H),3.67(s,3H). 13C NMR(100MHz,CDCl 3):δ=164.07,163.01(d,J C-F=246Hz),150.89,150.40,,137.43,131.07,130.99(d,J C-F=7.7Hz),128.67,128.59,127.33,126.68,114.89(d,J C-F=21Hz),108.30,50.98,32.83ppm.MS(70eV):m/z(%):310(M +,52.13),278(100).HRMS calcd for C 18H 15N 2O 2F:310.1118,found:310.1117.。
Embodiment 22
Take 2-α-tolylene-4-(4-p-methoxy-phenyl)-3-butynoic acid methyl esters (0.20mmol, 58.4mg), hydrazine hydrate (0.24mmol, 14.0mg), they are all added in little reaction tubes by salt of wormwood (0.04mmol, 5.5mg), at room temperature add 2.0mlN, N-N,N-DIMETHYLACETAMIDE.Rising to 40 DEG C stirs after 10 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains colourless liquid pyrazole derivatives straight product IC-4 by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 75%(48.0mg).
1H NMR(400MHz,CDCl 3):δ=7.52~7.49(m,2H),7.40~7.31(m,3H),7.11(d,J=8.8Hz,2H),6.99(d,J=8.8Hz,2H),4.12(s,2H),3.74(s,3H),3.70(s,3H). 13C NMR(100MHz,CDCl 3):δ=164.24,158.23,153.05,150.70,131.20,130.09,129.79,129.12,128.74,127.90,113.93,108.07,55.14,50.91,32.12ppm.MS(70eV):m/z(%):322(M +,52.93),290(100).HRMScalcd for C 19H 18N 2O 3:322.1317,found:322.1316.。
Embodiment 23
Take 2-α-tolylene-4-(1-naphthyl)-3-butynoic acid methyl esters (0.20mmol, 62.8mg), hydrazine hydrate (0.24mmol, 14.0mg), salt of wormwood (0.04mmol, 5.5mg), they are all added in little reaction tubes, at room temperature add 2.0ml N,N-dimethylacetamide.Rising to 40 DEG C stirs after 10 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains white solid pyrazole derivatives straight product IC-5 by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 94%(63.4mg).m.p.:146~147℃。
1H NMR(400MHz,CDCl 3):δ=7.96~7.92(m,1H),7.86~7.81(m,1H),7.74(d,J=8.8Hz,1H),7.55~7.45(m,4H),7.36~7.29(m,4H),7.25(d,J=8.8Hz,1H),4.65(s,2H),3.69(s,3H). 13C NMR(100MHz,CDCl 3):δ=164.40,151.68,150.21,133.87,133.25,133.19,131.85,129.14,128.74,127.90,127.82,127.14,126.40,125.85,125.55,123.82,108.23,51.06,30.63.ppm.MS(70eV):m/z(%):342(M +,30.53),310(100).HRMS calcd for C 22H 18N 2O 2:342.1368,found:342.1367.。
Embodiment 24
Take 2-α-tolylene-3-methyl 2-octynoate (0.20mmol, 48.4mg), hydrazine hydrate (0.24mmol, 14.0mg), salt of wormwood (0.04mmol, 5.5mg), they are all added in little reaction tubes, at room temperature add 2.0ml N,N-dimethylacetamide.Rising to 40 DEG C stirs after 11.5 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains yellow liquid pyrazole derivatives straight product IC-6 by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 55%(30.0mg).
1H NMR(400MHz,CDCl 3):δ=7.56~7.53(m,2H),7.42~7.36(m,3H),3.71(s,3H),2.78(t,J=8.0Hz,2H),1.64~1.54(m,2H),1.34~1.24(m,4H),0.88(t,J=7.2Hz,3H). 13CNMR(100MHz,CDCl 3):δ=164.43,159.63,152.34,131.77,129.19,128.65,127.91,50.91,31.55,28.55,26.71,22.33,13.94ppm.MS(70eV):m/z(%):272(M +,33.21),216(100).HRMS calcd forC 16H 20N 2O 2:272.1525,found:272.1526.。
Embodiment 25
Take 2-α-tolylene-4-cyclopropane base-3-butynoic acid methyl esters (0.20mmol, 45.4mg), hydrazine hydrate (0.24mmol, 14.0mg), salt of wormwood (0.04mmol, 5.5mg), they are all added in little reaction tubes, at room temperature add 2.0ml N,N-dimethylacetamide.Rising to 40 DEG C stirs after 11 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains yellow liquid pyrazole derivatives straight product IC-7 by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 78%(40.0mg).
1H NMR(400MHz,CDCl 3):δ=7.58~7.54(m,2H),7.38(t,J=3.2Hz,3H),3.71(s,3H),2.76(d,J=7.6Hz,2H),1.08~0.96(m,1H),0.51~0.45(m,2H),0.19~0.14(m,2H). 13CNMR(100MHz,CDCl 3):δ=164.47,152.38,151.00,132.13,129.22,128.55,127.84,107.87,50.92,31.32,9.06,4.57ppm.MS(70eV):m/z(%):256(M +,47.20),77(100).HRMS calcd forC 15H 16N 2O 2:256.1212,found:256.1213.。
Embodiment 26
Take 2-α-tolylene-4-phenyl-3-tetrolic aldehyde (0.20mmol, 46.4mg), hydrazine hydrate (0.24mmol, 14.0mg), salt of wormwood (0.04mmol, 5.5mg), they are all added in little reaction tubes, at room temperature add 2.0ml N,N-dimethylacetamide.Rising to 40 DEG C stirs after 3.5 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains yellow solid pyrazole derivatives straight product ID by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 58%(30.4mg).mp.:86~87℃。
1H NMR(400MHz,CDCl 3):δ=9.95(s,1H),7.52(d,J=7.2Hz,2H),7.45~7.39(m,3H),7.30~7.20(m,5H),4.28(s,2H). 13C NMR(100MHz,CDCl 3):δ=186.23,150.84,137.01,129.60,129.41,129.01,128.91,128.89,128.71,126.89,126.61,116.37,32.72ppm.MS(70eV):m/z(%):262(M +,36.53),84(100).HRMS calcd for C 17H 14N 2O:262.1106,found:262.1107.。
Embodiment 27
Take 3-α-tolylene-2-oxo-5-phenyl-4-pentynoic acid methyl esters (0.20mmol, 58.0mg), hydrazine hydrate (0.24mmol, 14.0mg), they are all added in little reaction tubes by salt of wormwood (0.04mmol, 5.5mg), at room temperature add 2.0ml N,N-dimethylacetamide.Rising to 40 DEG C stirs after 4 hours, complete by tlc silica gel plate (TLC) monitoring reaction, revolve to boil off to desolventize in 40 DEG C and to obtain thick product, then obtain yellow liquid pyrazole derivatives straight product IE-1 by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 61%(39.2mg).
1H NMR(400MHz,CDCl 3):δ=7.42~7.30(m,5H),7.28~7.17(m,5H),4.18(s,2H),3.23(s,3H). 13C NMR(100MHz,CDCl 3):δ=182.10,163.74,152.45,136.51,130.29,129.43,129.02,128.78,128.68,128.53,128.35,126.91,113.47,51.97,32.75ppm.MS(70eV):m/z(%):320(M +,2.19),261(100).HRMS calcd for C 19H 16N 2O 3:320.1161,found:320.1164.。
Embodiment 28
Take 3-α-tolylene-2-oxo-5-(4-tolyl)-4-pentynoic acid methyl esters (0.20mmol, 60.8mg), hydrazine hydrate (0.24mmol, 14.0mg), they are all added in little reaction tubes by salt of wormwood (0.04mmol, 5.5mg), at room temperature add 2.0mlN, N-N,N-DIMETHYLACETAMIDE.Rising to 40 DEG C stirs after 2 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains yellow liquid pyrazole derivatives straight product IE-2 by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 75%(50.0mg).
1H NMR(400MHz,CDCl 3):δ=7.43~7.28(m,5H),7.10(d,J=8.0Hz,2H),7.05(d,J=8.0Hz,2H),4.13(s,2H),3.23(s,3H),2.28(s,3H). 13C NMR(100MHz,CDCl 3):δ=182.10,163.76,152.60,151.32,136.51,133.87,133.36,130.49,129.37,128.89,128.76,128.50,113.34,51.95,32.28,20.96ppm.MS(70eV):m/z(%):334(M +,2.61),275(100).HRMS calcd forC 20H 18N 2O 3:334.1317,found:334.1315.。
Embodiment 29
Take 3-(2-α-tolylene-4-phenyl-3-butine ketone group) oxazole-2-ketone (0.20mmol, 49.2mg), hydrazine hydrate (0.24mmol, 14.0mg), they are all added in little reaction tubes by salt of wormwood (0.04mmol, 5.5mg), at room temperature add 2.0mlN, N-N,N-DIMETHYLACETAMIDE.Rising to 40 DEG C stirs after 12 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains yellow solid pyrazole derivatives straight product IG by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 19%(13.0mg).m.p.:70~71℃。
1H NMR(400MHz,CDCl 3):δ=7.46~7.42(m,2H),7.36~7.20(m,8H),4.09(s,2H),4.07(t,J=7.6Hz,2H),3.79(t,J=7.6Hz,2H). 13C NMR(100MHz,CDCl 3):δ=164.46,151.85,137.26,128.92,128.85,128.62,128.52,127.64,126.78,111.13,61.73,42.95,32.36ppm.MS(70eV):m/z(%):347(M +,11.49),260(100).HRMS calcd for C 20H 17N 3O 3:347.1270,found:347.1270.。
Embodiment 30
Take 2-α-tolylene-4-phenyl-3-butine nitrile (0.20mmol, 45.8mg), hydrazine hydrate (0.24mmol, 14.0mg), salt of wormwood (0.04mmol, 5.5mg), they are all added in little reaction tubes, at room temperature add 2.0ml N,N-dimethylacetamide.Rising to 40 DEG C stirs after 3.5 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains yellow solid pyrazole derivatives straight product IG-1 by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 97%(50.0mg).m.p.:127~128℃。
1H NMR(400MHz,CDCl 3):δ=11.66(brs,1H),7.74(t,J=4.0Hz,2H),7.43~7.38(m,3H),7.30~7.20(m,5H),4.02(s,2H). 13C NMR(100MHz,CDCl 3):δ=144.25,135.98,130.02,129.14,128.92,128.75,128.46,128.34,128.28,126.47,114.54,88.91,32.34ppm.MS(70eV):m/z(%):259(M +,100).HRMS calcd for C 17H 13N 3:259.1109,found:259.1110.。
Embodiment 31
Take 4-cyano group-5-phenyl-4-pentynoic acid methyl esters (0.20mmol, 42.1mg), hydrazine hydrate (0.24mmol, 14.0mg), salt of wormwood (0.04mmol, 5.5mg), they are all added in little reaction tubes, at room temperature add 2.0ml N,N-dimethylacetamide.Rising to 40 DEG C stirs after 3.5 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains yellow solid pyrazole derivatives straight product IG-2 by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 92%(44.0mg).m.p.:148~149℃。
1H NMR(400MHz,CDCl 3):δ=11.60(bs,1H),7.74(d,J=4.0Hz,2H),7.30~7.20(m,3H),4.02(s,2H),3.24(s,3H). 13C NMR(100MHz,CDCl 3):δ=167.42,135.98,130.02,129.14,128.92,128.28,126.47,114.54,88.91,52.04,32.34ppm.MS(70eV):m/z(%):259(M +,100).HRMS calcd for C 17H 13N 3:259.1109,found:259.1110.。
Embodiment 31
Take 2-phenylacetylene base-2-cyclopentenes 1-ketone (0.20mmol, 36.4mg), tertiary butyl nitrile hydrochloride (0.24mmol, 29.9mg), salt of wormwood (0.28mmol, 38.6mg), they are all added in little reaction tubes, at room temperature add 2.0ml N,N-dimethylacetamide.Continue stirring at room temperature after 2 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains colourless liquid pyrazole derivatives straight product IIA by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 70%(37.5mg).
1H NMR(400MHz,CDCl 3):δ=7.25(t,J=7.6Hz,2H),7.15(t,J=7.2Hz,1H),7.02(d,J=7.2Hz,2H),4.65(s,2H),2.87(t,J=6.4Hz,2H),2.13(t,J=6.4Hz,2H),1.54(s,9H). 13CNMR(100MHz,CDCl 3):δ=196.22,153.26,141.90,138.01,128.34,127.31,126.10,117.71,61.33,39.42,31.96,30.31,24.56ppm.MS(70eV):m/z(%):268(M +,46.22),226(100).HRMScalcd for C 17H 20N 2O:268.1576,found:268.1570.。
Embodiment 32
Take 3-phenylacetylene base-3-alkene-2-furanone (0.20mmol, 36.8mg), tertiary butyl nitrile hydrochloride (0.24mmol, 29.9mg), salt of wormwood (0.28mmol, 38.6mg), they are all added in little reaction tubes, at room temperature add 2.0ml N,N-dimethylacetamide.Continue stirring at room temperature after 2 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains colourless liquid pyrazole derivatives straight product IIB by column chromatography (eluent: sherwood oil: ethyl acetate=1:8) separation.Yield 78%(42.1mg).
1H NMR(400MHz,CDCl 3):δ=7.25(t,J=7.6Hz,2H),7.17(t,J=7.2Hz,1H),7.02(d,J=7.2Hz,2H),5.47(s,2H),4.68(s,2H),1.58(s,9H). 13C NMR(100MHz,CDCl 3):δ=167.29,153.94,141.91,137.87,128.50,127.69,126.25,117.91,68.46,61.43,31.98,23.27ppm.MS(70eV):m/z(%):270(M +,22.19),91(100).HRMS calcd for C 16H 18N 2O 2:270.1368,found:270.1370.。
Embodiment 33
Take 3-phenylacetylene base-3-alkene-2-pyrrolidone (0.20mmol, 36.6mg), tertiary butyl nitrile hydrochloride (0.24mmol, 29.9mg), salt of wormwood (0.28mmol, 38.6mg), they are all added in little reaction tubes, at room temperature add 2.0ml N,N-dimethylacetamide.Continue stirring at room temperature after 2 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains colourless liquid pyrazole derivatives straight product IIC by column chromatography (eluent: sherwood oil: ethyl acetate=1:3) separation.Yield 80%(43.1mg).
1H NMR(400MHz,CDCl 3):δ=7.24(t,J=7.6Hz,2H),7.16(t,J=7.2Hz,1H),7.03(d,J=7.2Hz,2H),6.70(bs,1H),4.66(s,2H),4.57(s,2H),1.57(s,9H). 13C NMR(100MHz,CDCl 3):δ=170.45,154.94,141.98,137.97,128.77,127.85,126.45,117.99,61.63,48.68,31.96,23.25ppm.MS(70eV):m/z(%):269(M +,31.31),91(100).HRMS calcd for C 16H 19N 3O:269.1528,found:269.1520.。
Embodiment 34
Take 2-phenylacetylene base-2-tetrahydrobenzene 1-ketone (0.20mmol, 39.6mg), tertiary butyl nitrile hydrochloride (0.24mmol, 29.9mg), salt of wormwood (0.28mmol, 38.6mg), they are all added in little reaction tubes, at room temperature add 2.0ml N,N-dimethylacetamide.Continue stirring at room temperature after 2 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains white solid pyrazole derivatives straight product IID-1 by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 75%(42.2mg).m.p.:118~119℃。
1H NMR(400MHz,CDCl 3):δ=7.24(t,J=7.6Hz,2H),7.16(t,J=7.2Hz,1H),7.00(d,J=7.2Hz,2H),4.67(s,2H),2.85(t,J=6.4Hz,2H),2.47(t,J=6.4Hz,2H),2.17~2.08(m,2H),1.54(s,9H). 13C NMR(100MHz,CDCl 3):δ=195.28,154.15,142.42,137.79,128.45,127.61,126.16,117.81,61.43,39.52,31.98,30.41,23.76,23.26ppm.MS(70eV):m/z(%):282(M +,57.22),226(100).HRMS calcd for CxH 22N 2O:282.1732,found:282.1730.。
Embodiment 35
Take 2-phenylacetylene base-2-suberene 1-ketone (0.20mmol, 42.0mg), tertiary butyl nitrile hydrochloride (0.24mmol, 29.9mg), salt of wormwood (0.28mmol, 38.6mg), they are all added in little reaction tubes, at room temperature add 2.0ml N,N-dimethylacetamide.Continue stirring at room temperature after 2 hours, complete by tlc silica gel plate (TLC) monitoring reaction, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized, then obtains colourless liquid pyrazole derivatives straight product IID-2 by column chromatography (eluent: sherwood oil: ethyl acetate=1:5) separation.Yield 66%(39.2mg).
1H NMR(400MHz,CDCl 3):δ=7.25(t,J=7.6Hz,2H),7.17(t,J=7.2Hz,1H),7.01(d,J=7.2Hz,2H),4.68(s,2H),2.84(t,J=6.4Hz,2H),2.46(t,J=6.4Hz,2H),2.10~1.88(m,4H),1.55(s,9H). 13C NMR(100MHz,CDCl 3):δ=195.37,154.11,142.40,137.77,128.42,127.51,126.13,117.79,61.42,39.50,31.96,30.40,23.75,23.25,21.20ppm.MS(70eV):m/z(%):296(M +,67.45),238(100).HRMS calcd for C 19H 24N 2O:296.1889,found:296.1883.。
Protection content of the present invention is not limited to above embodiment.Under the spirit and scope not deviating from inventive concept, the change that those skilled in the art can expect and advantage are all included in the present invention, and are protection domain with appending claims.

Claims (12)

1. the preparation method containing the multi-substituted pyrazol analog derivative of electron deficiency group, it is characterized in that, electron deficiency conjugated enynes, hydrazine, alkali are dissolved in organic solvent, fully react under room temperature to 40 DEG C temperature range, remove solvent, obtain thick product, through column chromatography, obtain such as formula the multi-substituted pyrazol analog derivative containing electron deficiency group shown in (I) or formula (II):
Wherein, described electron deficiency conjugated enynes is as shown in following formula (III-A) or (III-B):
Described preparation method is by shown in following reaction formula (1) or reaction formula (2):
Wherein,
EWG is electron deficiency group, is selected from ester group, alkyl-C (O)-and, aldehyde radical, amide group, cyano group, carboxyl;
R is selected from hydrogen, phenyl or substituted-phenyl, heteroaryl, alkyl, acyl group, amide group, ester group, cyano group, carboxyl;
R 1be selected from hydrogen, phenyl, substituted-phenyl, heteroaryl, alkyl, acyl group, amide group, ester group, cyano group, carboxyl;
R 2be selected from hydrogen, phenyl, substituted aryl, heteroaryl, alkyl, acyl group, amide group, ester group, cyano group, carboxyl;
X is carbon, nitrogen, oxygen;
n＝1～6。
2. as claimed in claim 1 containing the preparation method of the multi-substituted pyrazol analog derivative of electron deficiency group, wherein,
EWG is selected from phosphate-based;
R is selected from aldehyde radical, phosphate-based, alkylsulfonyl;
R 1be selected from aldehyde radical, alkylsulfonyl;
R 2be selected from aldehyde radical, phosphate-based, alkylsulfonyl.
3. the preparation method containing the multi-substituted pyrazol analog derivative of electron deficiency group, it is characterized in that, electron deficiency conjugated enynes, hydrazine, alkali are dissolved in organic solvent, fully react under room temperature to 40 DEG C temperature range, remove solvent, obtain thick product, through column chromatography, obtain such as formula the multi-substituted pyrazol analog derivative containing electron deficiency group shown in (I) or formula (II):
Wherein, described electron deficiency conjugated enynes is as shown in following formula (III-A) or (III-B):
Described preparation method is by shown in following reaction formula (1) or reaction formula (2):
Wherein, electron deficiency conjugated enynes shown in described chemical formula (III-A) is selected from 2-α-tolylene-4-phenyl-3-butynoic acid methyl esters, 2-(4-methoxybenzylidene)-4-phenyl-3-butynoic acid methyl esters, 2-(4-fluorobenzylidene)-4-phenyl-3-butynoic acid methyl esters, 2-α-tolylene-4-(4-p-methoxy-phenyl)-3-butynoic acid methyl esters, 2-α-tolylene-4-(1-naphthyl)-3-butynoic acid methyl esters, 2-α-tolylene-3-methyl 2-octynoate, 2-α-tolylene-4-cyclopropane base-3-butynoic acid methyl esters, 2-(4-methoxybenzylidene)-4-(4-p-methoxy-phenyl)-3-butynoic acid methyl esters, 2-(4-methoxybenzylidene)-4-(1-naphthyl)-3-butynoic acid methyl esters, 3-α-tolylene-5-phenyl-4-pentyne-2-ketone, 3-(4-methoxybenzylidene)-5-phenyl-4-pentyne-2-ketone, 3-(4-cyano group α-tolylene)-5-phenyl-4-pentyne-2-ketone, 3-α-tolylene-5-(1-naphthyl)-4-pentyne-2-ketone, 3-α-tolylene-5-(4-p-methoxy-phenyl)-4-pentyne-2-ketone, 3-α-tolylene-5-(4-nitrophenyl)-4-pentyne-2-ketone, 3-α-tolylene-5-(4-fluorophenyl)-4-pentyne-2-ketone, 3-α-tolylene-5-(1-cyclohexenyl)-4-pentyne-2-ketone, 2-α-tolylene-1, 4-phenylbenzene-3-butine-1-ketone, 2-α-tolylene-1-(4-chloro-phenyl-)-4-phenyl-3-butine-1-ketone, 6-phenyl-3-(phenylacetylene base)-3, 5-hexadiene-2-ketone, 3-α-tolylene-2-oxo-5-phenyl-4-pentynoic acid methyl esters, 3-α-tolylene-2-oxo-5-(4-tolyl)-4-pentynoic acid methyl esters, 2-α-tolylene-4-phenyl-3-butine nitrile, 2-α-tolylene-4-phenyl-3-tetrolic aldehyde, 3-(2-α-tolylene-4-phenyl-3-butine ketone group) oxazole-2-ketone,
Electron deficiency conjugated enynes shown in described chemical formula (III-B) is selected from 2-phenylacetylene base-2-tetrahydrobenzene 1-ketone, 2-phenylacetylene base-2-cyclopentenes 1-ketone, 3-phenylacetylene base-3-alkene-2-furanone, 3-phenylacetylene base-3-alkene-2-pyrrolidone, 2-phenylacetylene base-2-suberene 1-ketone.
4., as claimed in claim 1 containing the preparation method of the multi-substituted pyrazol analog derivative of electron deficiency group, it is characterized in that, described hydrazine is alkyl hydrazine, p-toluene sulfonyl hydrazide, phenylhydrazine, the phenyl hydrazine of replacement or heteroaryl hydrazine.
5., as claimed in claim 1 containing the preparation method of the multi-substituted pyrazol analog derivative of electron deficiency group, it is characterized in that, described organic solvent is DMF, N,N-dimethylacetamide, methyl-sulphoxide or acetonitrile.
6., as claimed in claim 1 containing the preparation method of the multi-substituted pyrazol analog derivative of electron deficiency group, it is characterized in that, described alkali is triethylamine, Tetramethyl Ethylene Diamine, triethylene diamine, 1,8-diazabicyclo [5,4,0]-ten one carbon-7-alkene, sodium-acetate or salt of wormwood.
7., as claimed in claim 1 containing the preparation method of the multi-substituted pyrazol analog derivative of electron deficiency group, it is characterized in that, the mol ratio of described electron deficiency conjugated enynes, hydrazine, alkali is electron deficiency conjugated enynes: hydrazine: alkali=1.0:1.2-1.5:0.05-0.2.
8., as claimed in claim 1 containing the preparation method of the multi-substituted pyrazol analog derivative of electron deficiency group, it is characterized in that, the add-on of described organic solvent is electron deficiency conjugated enynes described in 10 ~ 15ml/mmol.
9. as claimed in claim 1 containing the preparation method of the multi-substituted pyrazol analog derivative of electron deficiency group, it is characterized in that, the mode of described removal solvent is for after first extracting by ether or ethyl acetate, dry and revolve to boil off to desolventize or directly revolve to boil off and desolventize.
10. as claimed in claim 1 containing the preparation method of the multi-substituted pyrazol analog derivative of electron deficiency group, it is characterized in that, described column chromatography adopts volume ratio to be ethyl acetate: the solution of sherwood oil=1:8 ~ 1:5 carries out.
11. 1 kinds of preparation methods containing the multi-substituted pyrazol analog derivative of electron deficiency group, it is characterized in that, by 0.20mmol 56.0mg3-α-tolylene-5-(1-cyclohexenyl)-4-pentyne-2-ketone, 0.24mmol 14.0mg hydrazine hydrate, 0.04mmol 5.5mg salt of wormwood, all add in little reaction tubes, at room temperature add 2.0ml N,N-dimethylacetamide; Being warming up to 40 DEG C stirs after 3 hours, monitored by tlc silica gel plate TLC and react complete, add the extracted with diethyl ether of 4mL water and 10mL, aqueous phase uses the extracted with diethyl ether twice of 10mL again, merges organic phase, after saturated common salt water washing 2-3 time, add anhydrous sodium sulfate drying, filter, filtrate is revolved to boil off in 20 DEG C and is desolventized to obtain thick product, then by eluent: sherwood oil: ethyl acetate=1:5 column chromatography for separation obtains 42.5mg yellow liquid pyrazole derivatives straight product IA-12; Yield 76%
12. 1 kinds of preparation methods containing the multi-substituted pyrazol analog derivative of electron deficiency group, it is characterized in that, by 0.20mmol 54.8mg6-phenyl-3-(phenylacetylene base)-3,5-hexadiene-2-ketone, 0.24mmol 14.0mg hydrazine hydrate, 0.04mmol 5.5mg salt of wormwood, all adds in little reaction tubes, at room temperature adds 2.0ml acetonitrile; Being warming up to 40 DEG C stirs after 6 hours, monitored by tlc silica gel plate TLC and react complete, revolve to boil off in 40 DEG C and desolventize to obtain thick product, then by eluent: sherwood oil: ethyl acetate=1:5 column chromatography for separation obtains 32.0mg yellow solid pyrazole derivatives straight product IB; Yield 53%, m.p.:160 ~ 161 DEG C
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