CN113968819A - Synthesis method of polysubstituted pyrazole compound - Google Patents
Synthesis method of polysubstituted pyrazole compound Download PDFInfo
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- -1 polysubstituted pyrazole compound Chemical class 0.000 title claims abstract description 41
- 238000001308 synthesis method Methods 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 7
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 238000007670 refining Methods 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000002904 solvent Substances 0.000 abstract description 15
- 238000012986 modification Methods 0.000 abstract description 4
- 230000004048 modification Effects 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 125000003172 aldehyde group Chemical group 0.000 abstract description 3
- 239000003513 alkali Substances 0.000 abstract description 3
- 230000004071 biological effect Effects 0.000 abstract description 3
- 125000000524 functional group Chemical group 0.000 abstract description 3
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 48
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 6
- 239000011347 resin Substances 0.000 description 6
- 229920005989 resin Polymers 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 229940117916 cinnamic aldehyde Drugs 0.000 description 5
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 150000007857 hydrazones Chemical class 0.000 description 4
- 150000003217 pyrazoles Chemical class 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- AXRVRVKZFJPHBH-UHFFFAOYSA-N 1,3,4-triphenylpyrazole Chemical compound C1=C(C=2C=CC=CC=2)C(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AXRVRVKZFJPHBH-UHFFFAOYSA-N 0.000 description 2
- NWPWGORXCFKYJH-UHFFFAOYSA-N 1,3,5-triphenylpyrazole-4-carbaldehyde Chemical compound O=CC=1C(C=2C=CC=CC=2)=NN(C=2C=CC=CC=2)C=1C1=CC=CC=C1 NWPWGORXCFKYJH-UHFFFAOYSA-N 0.000 description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 2
- AXCXHFKZHDEKTP-NSCUHMNNSA-N 4-methoxycinnamaldehyde Chemical compound COC1=CC=C(\C=C\C=O)C=C1 AXCXHFKZHDEKTP-NSCUHMNNSA-N 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- HONRSHHPFBMLBT-OWOJBTEDSA-N (e)-3-(4-chlorophenyl)prop-2-enal Chemical compound ClC1=CC=C(\C=C\C=O)C=C1 HONRSHHPFBMLBT-OWOJBTEDSA-N 0.000 description 1
- XYRAWLRFGKLUMW-UHFFFAOYSA-N 3-(4-bromophenyl)prop-2-enal Chemical compound BrC1=CC=C(C=CC=O)C=C1 XYRAWLRFGKLUMW-UHFFFAOYSA-N 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- AXCXHFKZHDEKTP-UHFFFAOYSA-N para-methoxycinnamaldehyde Natural products COC1=CC=C(C=CC=O)C=C1 AXCXHFKZHDEKTP-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
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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
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of a polysubstituted pyrazole compound, belongs to the technical field of organic synthesis, and solves the problems of long route, atom uneconomic property, environment unfriendly property and complex operation of the skeleton of the compound in the synthesis process. The invention discloses a synthesis method of a polysubstituted pyrazole compound, which comprises the step of reacting a compound shown in a formula I with a compound shown in a formula II under an alkaline condition to generate a compound shown in a formula III and a compound shown in a formula IV. The method takes cheap and easily-obtained commodities as raw materials, and can simultaneously construct 1,3, 4-trisubstituted and 1,3,4, 5-tetrasubstituted multi-substituted pyrazole compounds only by normal-temperature reaction under the action of very cheap alkali catalysis and environmentally-friendly solvents. For the synthesized product 1,3,4, 5-tetra-substituted pyrazole compound, the 4-position aldehyde group can be subjected to structural modification, so that a target functional group is introduced to have different biological activities.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a polysubstituted pyrazole compound.
Background
Pyrazole is an important five-membered nitrogen-containing heterocyclic compound, widely exists in a plurality of natural products, bioactive molecules and drug molecules, and is an important organic synthesis intermediate.
In the prior art, the preparation methods of the polysubstituted pyrazole compounds mainly comprise two methods: one is prepared by utilizing a knorr pyrazole synthesis method, and the other is to carry out structural modification on pyrazole compounds through electrophilic or nucleophilic substitution reaction. For the former, the reaction catalyst is concentrated acid and the reaction temperature requirement is high, which has great conflict on the production safety and the green development. In the latter case, due to the unique steric structure and electronic effect of the pyrazole ring, it is difficult to introduce a target group at a specific site, thereby limiting its wide application in production.
Hydrazone is used as a good reagent and is widely applied to organic synthesis to construct various cyclic compounds, hydrazone can lose protons under the action of alkali, structure interconversion is carried out, then Michael addition is carried out on the hydrazone and olefine aldehyde to obtain an intermediate, and intramolecular cyclization is carried out to obtain a multi-substituted pyrazole compound. However, in the prior art, hydrazone is adopted as an initial raw material, only one pyrazole compound can be synthesized, and the problems of long synthetic route, atom uneconomic property, environment unfriendliness and complex operation exist.
Therefore, the method for synthesizing the multi-substituted pyrazole compound is provided, can synthesize more than one pyrazole compound at the same time, has simple operation, low cost and environmental friendliness, and is a problem to be solved by the technical people in the field.
Disclosure of Invention
The invention aims to provide a method for synthesizing a polysubstituted pyrazole compound, which takes a cheap and easily-obtained commodity as a raw material, and can simultaneously construct a 1,3, 4-trisubstituted pyrazole compound and a 1,3,4, 5-tetrasubstituted pyrazole compound only by normal-temperature reaction under the action of very cheap alkali catalysis and environmentally-friendly solvents; solves the problems of long route, atom uneconomic, environment unfriendly, complex operation and the like in the synthesis process of the compound skeleton.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention discloses a method for synthesizing a polysubstituted pyrazole compound, which comprises the following steps of reacting a compound shown in a formula I with a compound shown in a formula II under an alkaline condition to generate a compound shown in a formula III and a compound shown in a formula IV, wherein the reaction formulas are as follows:
(ii) a Wherein R is1Selected from substituted or unsubstituted phenyl, naphthyl, indenyl, furyl, pyrimidinyl, indolyl, thiazolyl, or thienyl;
R2selected from substituted or unsubstituted phenyl, naphthyl, indenyl, furyl, pyrimidinyl, indolyl, thiazolyl, or thienyl;
R3selected from substituted or unsubstituted phenyl, naphthyl, indenyl, furyl, pyrimidinyl, indolyl, thiazolyl or thienyl.
The method can be used for simultaneously synthesizing two pyrazole compounds, namely 1,3, 4-trisubstituted pyrazole compounds and 1,3,4, 5-tetrasubstituted pyrazole compounds. For the synthesized product 1,3,4, 5-tetra-substituted pyrazole compound, the 4-position aldehyde group can be subjected to structural modification, so that a target functional group is introduced to have different biological activities.
In some embodiments of the invention, R1The substituent of (A) is selected from halogen or methoxy; preferably, at least one selected from chlorine, fluorine, bromine and methoxy; more preferably, R1Are not in the same position.
In some embodiments of the invention, R2The substituents being selected from halogen-element, methyl or methoxy; preferably, at least one selected from chlorine, fluorine, methyl and methoxy; more preferably, R2Are not in the same position.
In some embodiments of the invention, R3The substituent of (A) is selected from halogen or methoxy; preferably, at least one selected from chlorine, bromine and methoxy; more preferably, R3The substituent(s) is para-substituted.
In some embodiments of the invention, the organic solvent is selected from at least one of tetrahydrofuran, ethyl acetate, acetonitrile, dichloromethane, ethanol; ethanol is preferred.
In some embodiments of the invention, the base is selected from Et3N、Cs2CO3、K2CO3Any one of DBU and DIPEA; preferably K2CO3。
In some embodiments of the invention, the mass ratio of the compound of formula I, the compound of formula II, and the base is 1:1.2:0.5 to 1:1.2: 2.5; preferably 1:1.2: 2.5.
In some embodiments of the present invention, the reaction temperature is 10 to 40 ℃, preferably room temperature.
In some embodiments of the present invention, the method further comprises a refining step, preferably, the refining step comprises column chromatography and recrystallization.
The room temperature is 10-30 ℃.
Compared with the prior art, the invention has the following beneficial effects:
the invention has scientific design, ingenious conception, simple method and simple and convenient operation. The method can synthesize the pyrazole compound containing various substituents, has fewer byproducts and is easy to purify. The method can simultaneously synthesize two pyrazole compounds, namely 1,3, 4-trisubstituted pyrazole compound and 1,3,4, 5-tetrasubstituted pyrazole compound, solves the problem that only one pyrazole compound can be synthesized in the known production method, and increases the application range of the method.
For the synthesized product 1,3,4, 5-tetra-substituted pyrazole compound, the 4-position aldehyde group can be subjected to structural modification, so that a target functional group is introduced to have different biological activities.
The raw materials are cheap and easy to obtain, the reaction cost is effectively reduced, the solvent is non-toxic and harmless, a metal catalyst is not needed, and the environment is protected; the reaction condition is simple, the target compound can be obtained at high yield in the air at normal temperature without heating or inert gas protection, a new route selection is provided for the synthesis of the molecules containing the skeleton active molecules, and the method has good industrial application prospect.
Drawings
FIG. 1 is a hydrogen spectrum of the compound of formula III-6 obtained in example 7;
FIG. 2 is a carbon spectrum of the compound of formula III-6 obtained in example 7;
FIG. 3 is a hydrogen spectrum of the compound of formula IV-6 obtained in example 7;
FIG. 4 is a carbon spectrum of the compound of formula IV-6 obtained in example 7;
FIG. 5 is a mass spectrum of the compound of formula III-6 obtained in example 7;
FIG. 6 is a mass spectrum of the compound of formula IV-6 obtained in example 7.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Example 1
This example prepared 1,3, 4-triphenyl-1H-pyrazole, a compound of formula III-1, and 1,3, 5-triphenyl-1H-pyrazole-4-carbaldehyde, a compound of formula IV-1, using N-phenylbenzohydrazone acid chloride, a compound of formula I-1, and cinnamaldehyde, a compound of formula II-1, as standard substrates, according to the following reaction schemes:
the specific operation is as follows: a10 mL reaction tube and a magnetic stirrer were preliminarily setDrying, then 100mg of N-phenylbenzohydrazone acid chloride (0.435mmol) and 150.2mg of K were added to the reaction tube, respectively2CO3(1.087mmol), then adding 2.2mL of ethanol solvent, finally adding 69.00mg of cinnamaldehyde (0.522mmol), placing the whole reaction at normal temperature for reaction, monitoring the whole reaction process by TLC, concentrating the solvent after the reaction is finished, carrying out column chromatography separation on the obtained crude product by using a mixed solution (30/1, v/v) of petroleum ether and ethyl acetate as an eluent and using 300-mesh 400-mesh silica gel as separation resin to obtain 1,3, 4-triphenyl-1H-pyrazole (59.18mg, light yellow oily) and 1,3, 5-triphenyl-1H-pyrazole-4-formaldehyde (74.64mg, yellow solid), wherein the yield of the compound shown in the formula III-1 is 45.99 percent, and the yield of the compound shown in the formula IV-1 is 53.00 percent.
A compound of formula III-1:1H NMR(600MHz,CDCl3)δ8.02(s,1H),7.82–7.78(m,2H),7.64–7.57(m,2H),7.50–7.45(m,2H),7.38–7.31(m,7H),7.31–7.27(m,2H).13C NMR(151MHz,CDCl3)δ150.26,139.70,132.89,132.63,129.25,128.48,128.32,128.24,128.11,127.70,126.73,126.44,126.25,122.71,118.74.HRMS-ESI(m/z):[M+H]+calcd for C21H17N2 297.1392；found,297.1385.
a compound of formula IV-1:1H NMR(600MHz,CDCl3)δ9.87(s,1H),7.97–7.92(m,2H),7.50–7.39(m,6H),7.37–7.34(m,2H),7.34–7.28(m,5H).13C NMR(151MHz,CDCl3)δ185.66,153.84,149.15,138.73,131.52,130.63,129.84,129.27,129.17,129.03,128.65,128.36,128.27,127.72,125.39,118.73.HRMS-ESI(m/z):[M+H]+calcd for C22H17N2O 325.1341；found,325.1333.
example 2
In this example, the reaction conditions for synthesizing the base-catalyzed polysubstituted pyrazole compound were studied using N-phenylbenzohydrazone acid chloride of formula I-1 and cinnamaldehyde of formula II-1 as standard substrates, and the reaction formula is:
the reaction conditions and results are shown in table 1:
TABLE 1
In table 1, "equiv" represents an equivalent; the temperature "rt" is room temperature; a is 2.5 equivalents of DDQ added into a reaction system; b is anhydrous and anaerobic condition.
Example 3
This example discloses the preparation of (4-bromophenyl) -1, 3-diphenyl-1H-pyrazole, the compound of formula III-2, and 5- (4-bromophenyl) -3- (cyclohexa-1, 3-dien-1-yl) -1-phenyl-1H-pyrazole-4-carbaldehyde, the compound of formula IV-2:
a10 mL reaction tube and a magnetic stirrer were previously dried, and then 100mg of N-phenylbenzohydrazone acid chloride (0.435mmol) and 150.2mg of K were added to the reaction tube, respectively2CO3(1.087mmol), then adding 2.2mL of ethanol solvent, finally adding 110.17mg of p-bromocinnamaldehyde (0.522mmol), placing the whole reaction at normal temperature for reaction, monitoring the whole reaction process by TLC, concentrating the solvent after the reaction is finished, and performing column chromatography on the obtained crude product by using a mixed solution of petroleum ether and ethyl acetate (30/1, v/v) as an eluent and using 300-membered 400-mesh silica gel as separation resin to obtain (4-bromophenyl) -1, 3-diphenyl-1H-pyrazole (47.4mg, light yellow oily) and 5- (4-bromophenyl) -3- (cyclohexa-1, 3-diene-1-yl) -1-phenyl-1H-pyrazole-4-formaldehyde (75.7mg, yellow solid), wherein the yield is as follows: 29.15% for the formula III-2 and 43.51% for the formula IV-2.
A compound of formula III-2:1H NMR(600MHz,CDCl3)δ8.01(s,1H),7.81–7.77(m,2H),7.60–7.54(m,2H),7.51–7.44(m,4H),7.38–7.33(m,3H),7.33–7.29(m,1H),7.24–7.19(m,2H).13C NMR(151MHz,CDCl3)δ149.11,138.46,131.46,130.48,130.37,128.89,128.17,127.12,126.78,125.31,125.24,120.39,119.60,117.68.HRMS-ESI(m/z):[M+H]+calcd for C21H16BrN2 375.0497；found,375.0489.
a compound of formula IV-2:1H NMR(600MHz,CDCl3)δ9.90(s,1H),7.90–7.86(m,2H),7.55–7.52(m,2H),7.51–7.44(m,3H),7.38–7.34(m,3H),7.32–7.28(m,2H),7.25–7.22(m,2H).13C NMR(151MHz,CDCl3)δ185.49,154.56,146.93,138.47,132.14,131.89,131.23,129.30,129.23,128.56,128.51,126.69,125.47,124.50,118.62.HRMS-ESI(m/z):[M+Na]+calcd for C22H15BrN2NaO 425.0265；found,425.0258.
example 4
This example discloses the preparation of 1, 4-diphenyl-3- (thiophen-2-yl) -1H-pyrazole, a compound of formula III-3, and 1, 5-diphenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carbaldehyde, a compound of formula IV-3:
a10 mL reaction tube and a magnetic stirrer were pre-dried, and then 100mg of N-phenylthiophene-2-carbohydrazone acid chloride (0.42mmol) and 145.18mg of K were added to the reaction tube, respectively2CO3(1.05mmol), then adding 2.1mL of ethanol solvent, finally adding 66.61mg of cinnamaldehyde (0.504mmol), placing the whole reaction at normal temperature for reaction, monitoring the whole reaction process by TLC, concentrating the solvent after the reaction is finished, and performing column chromatography on the obtained crude product by using a mixed solution of petroleum ether and ethyl acetate (30/1, v/v) as an eluent and using 300-mesh 400-mesh silica gel as separation resin to obtain 1, 4-diphenyl-3- (thiophene-2-yl) -1H-pyrazole (21.7mg, orange solid) and 1, 5-diphenyl-3- (thiophene-2-yl) -1H-pyrazole-4-formaldehyde (56.2mg, tan oil), wherein the yield: 16.96% for formula III-3 and 40.43% for formula IV-3.
A compound of formula III-3:1H NMR(600MHz,CDCl3)δ7.95(s,1H),7.80–7.75(m,2H),7.52–7.43(m,4H),7.43–7.38(m,2H),7.38–7.34(m,1H),7.33–7.28(m,1H),7.27–7.24(m,1H),7.08(dd,J＝3.6,1.2Hz,1H),6.95(dd,J＝5.1,3.6Hz,1H).13C NMR(151MHz,CDCl3)δ145.21,139.72,135.29,132.48,129.49,129.29,128.57,127.49,127.27,126.96,126.56,125.98,125.31,122.71,118.96.HRMS-ESI(m/z):[M+H]+calcd for C19H15N2S 303.0956；found,303.0949.
a compound of formula IV-3:1H NMR(600MHz,CDCl3)δ9.83(s,1H),8.29(dd,J＝3.7,1.2Hz,1H),7.48–7.44(m,1H),7.44–7.38(m,3H),7.35–7.30(m,5H),7.29(dt,J＝7.1,2.2Hz,2H),7.15(dd,J＝5.1,3.7Hz,1H).13C NMR(151MHz,CDCl3)δ185.27,150.34,147.37,138.44,133.82,130.63,130.01,129.70,129.05,128.81,128.35,127.70,127.43,127.06,125.34,118.35.HRMS-ESI(m/z):[M+H]+calcd for C20H15N2OS 331.0905；found,331.0897.
example 5
This example discloses the preparation of 1- (4-methoxyphenyl) -3- (naphthalen-2-yl) -4-phenyl-1H-pyrazole, a compound of formula III-4, and 1- (4-methoxyphenyl) -3- (naphthalen-2-yl) -5-phenyl-1H-pyrazole-4-carbaldehyde, a compound of formula IV-4:
a10 mL reaction tube and a magnetic stirrer were pre-dried, and then 100mg of N- (4-methoxyphenyl) -2-naphthylhydrazone acid chloride (0.323mmol) and 111.46mg of K were added to the reaction tube, respectively2CO3(0.806mmol), 2.1mL of ethanol solvent was added, 51.23mg of cinnamaldehyde (0.39mmol) was added, the whole reaction was allowed to react at room temperature, TLC monitored the progress of the reaction, and after completion of the reaction, concentrating the solvent, eluting the crude product with petroleum ether and ethyl acetate mixture (30/1, v/v), column chromatography was carried out using 300-mesh 400-mesh silica gel as a separation resin to give 1- (4-methoxyphenyl) -3- (naphthalen-2-yl) -4-phenyl-1H-pyrazole (46.7mg, yellow oil) and 1- (4-methoxyphenyl) -3- (naphthalen-2-yl) -5-phenyl-1H-pyrazole-4-carbaldehyde (63.9mg, red solid), yield: 38.50% for formula III-4 and 49.15% for formula IV-4.
Formula III-4:1H NMR(600MHz,CDCl3)δ8.12–8.09(m,1H),7.97(s,1H),7.87–7.81(m,1H),7.81–7.75(m,2H),7.77–7.71(m,2H),7.69(dd,J＝8.5,1.7Hz,1H),7.49–7.42(m,2H),7.40–7.35(m,2H),7.35–7.27(m,3H),7.05–6.99(m,2H),3.87(s,3H).13C NMR(151MHz,CDCl3)δ158.35,149.93,133.76,133.41,132.97,132.95,130.77,128.73,128.58,128.35,127.80,127.66,127.33,126.97,126.94,126.58,126.01,125.99,122.77,120.80,114.60,55.63.HRMS-ESI(m/z):[M+H]+calcd for C26H21N2O 377.1654；found,377.1648.
formula IV-4:1H NMR(600MHz,CDCl3)δ9.91(s,1H),8.52(d,J＝1.7Hz,1H),8.06(dd,J＝8.5,1.8Hz,1H),7.98–7.91(m,2H),7.89–7.82(m,1H),7.54–7.48(m,2H),7.46–7.38(m,3H),7.37–7.32(m,2H),7.31–7.21(m,2H),6.85–6.78(m,2H),3.77(s,3H).13C NMR(151MHz,CDCl3)δ184.10,157.73,151.85,147.77,132.04,131.62,130.15,129.06,128.17,127.42,127.28,127.10,127.03,126.28,126.14,126.11,125.17,125.10,124.97,124.61,117.07,112.60,53.90.HRMS-ESI(m/z):[M+H]+calcd for C27H21N2O2 405.1603；found,405.1600.
example 6
This example discloses the preparation of 4- (4-chlorophenyl) -3- (3-fluorophenyl) -1-mesityl-1H-pyrazole, a compound of formula III-5, and 5- (4-chlorophenyl) -3- (3-fluorophenyl) -1-mesityl-1H-pyrazole-4-carbaldehyde, a compound of formula IV-5:
a10 mL reaction tube and a magnetic stirrer were pre-dried, and then 100mg of 3-fluoro-N-mesitylphenylhydrazone acid chloride (0.344mmol) and 118.74mg of K were added to the reaction tube, respectively2CO3(0.859mmol), adding 1.7mL of ethanol solvent, finally adding 68.78mg of p-chlorocinnamaldehyde (0.413mmol), reacting at normal temperature, monitoring the whole reaction process by TLC, concentrating the solvent after the reaction is finished, taking petroleum ether and ethyl acetate mixed solution (30/1, v/v) as an eluent, and separating by using 300-mesh 400-mesh silica gelColumn chromatography on resin gave 4- (4-chlorophenyl) -3- (3-fluorophenyl) -1-mesitylene-1H-pyrazole (35.00mg, yellow oil) and 5- (4-chlorophenyl) -3- (3-fluorophenyl) -1-mesitylene-1H-pyrazole-4-carbaldehyde (95.7mg, yellow solid) in: 26.12% for the formula III-5 and 66.64% for the formula IV-5.
A compound of formula III-5:1H NMR(600MHz,CDCl3)δ7.52(s,1H),7.35–7.26(m,7H),7.03–6.97(m,3H),2.34(s,3H),2.11(s,6H).13C NMR(151MHz,CDCl3)δ161.99(d,J＝245.1Hz),147.22(d,J＝2.4Hz),138.39,135.67,134.86,134.57(d,J＝8.1Hz),132.01,130.56,130.53,129.20,129.02(d,J＝8.4Hz),128.17,128.02,123.26(d,J＝2.8Hz),119.26,114.41(d,J＝22.5Hz),113.84(d,J＝21.0Hz),20.34,16.69.HRMS-ESI(m/z):[M+H]+calcd for C24H21ClFN2 391.1377；found,391.1373.
a compound of formula IV-5:1H NMR(600MHz,CDCl3)δ9.92(s,1H),7.75(dt,J＝7.7,1.2Hz,1H),7.72–7.67(m,1H),7.44(td,J＝8.0,5.8Hz,1H),7.34–7.29(m,2H),7.24–7.18(m,2H),7.17–7.11(m,1H),6.89(s,2H),2.29(s,3H),1.98(s,6H).13C NMR(151MHz,CDCl3)δ185.22,162.70(d,J＝245.7Hz),152.99(d,J＝2.7Hz),149.23,139.87,136.25,135.36,134.03,133.62(d,J＝8.4Hz),131.12,129.87(d,J＝8.3Hz),129.28,128.82,125.55,125.05(d,J＝2.9Hz),117.28,116.22(d,J＝22.6Hz),116.08(d,J＝20.7Hz),21.15,17.78.HRMS-ESI(m/z):[M+H]+calcd for C25H21ClFN2O 419.1326；found,419.1321.
example 7
This example discloses the preparation of 3- (3-chlorophenyl) -1, 4-bis (4-methoxyphenyl) -1H-pyrazole, a compound of formula III-6, and 3- (3-chlorophenyl) -1, 5-bis (4-methoxyphenyl) -1H-pyrazole-4-carbaldehyde, a compound of formula IV-6:
a10 mL reaction tube and a magnetic stirrer were previously dried, and then 1 was added to the reaction tube, respectively00mg 3-chloro-N- (4-methoxyphenyl) benzohydrazone acid chloride (0.340mmol) and 117.53mg K2CO3(0.850mmol), then adding 1.7mL of ethanol solvent, finally adding 66.18mg of p-methoxycinnamaldehyde (0.41mmol), placing the whole reaction at normal temperature for reaction, monitoring the whole reaction process by TLC, concentrating the solvent after the reaction is finished, and performing column chromatography separation on the obtained crude product by using a mixed solution of petroleum ether and ethyl acetate (30/1, v/v) as an eluent and using 300-membered 400-mesh silica gel as a separation resin to obtain the preparation of 3- (3-chlorophenyl) -1, 4-bis (4-methoxyphenyl) -1H-pyrazole (38.80mg, light yellow oil) and 3- (3-chlorophenyl) -1, 5-bis (4-methoxyphenyl) -1H-pyrazole-4-formaldehyde (74.30mg, red solid), wherein the yield is as follows: 29.24% for formula III-6 and 52.25% for formula IV-6;
a compound of formula III-6:1H NMR(600MHz,CDCl3)δ7.86(d,J＝1.5Hz,1H),7.71–7.65(m,3H),7.40(dq,J＝7.6,1.5Hz,1H),7.33–7.16(m,4H),6.99(dd,J＝8.9,1.6Hz,2H),6.89(dd,J＝8.6,1.7Hz,2H),3.86(d,J＝1.4Hz,3H),3.84(d,J＝1.5Hz,3H).13C NMR(151MHz,CDCl3)δ158.82,158.37,148.39,135.21,134.24,133.62,129.87,129.48,128.20,127.74,126.73,126.49,124.87,122.35,120.67,114.58,114.09,55.62,55.31.HRMS-ESI(m/z):[M+H]+calcd for C23H20ClN2O2391.1213；found,391.1205.
a compound of formula IV-6:1H NMR(600MHz,CDCl3)δ9.82(s,1H),7.98(dt,J＝1.7,1.1Hz,1H),7.88(pd,J＝4.5,1.6Hz,1H),7.43–7.37(m,2H),7.28–7.23(m,2H),7.25–7.19(m,2H),6.95–6.89(m,2H),6.88–6.82(m,2H),3.84(s,3H),3.80(s,3H).13C NMR(151MHz,CDCl3)δ185.53,160.69,159.32,151.87,149.69,134.19,133.51,132.05,131.73,129.50,129.09,129.07,127.52,126.70,119.38,118.28,114.24,114.19,55.53,55.37.HRMS-ESI(m/z):[M+Na]+calcd for C24H19ClN2NaO3441.0982；found,441.0980.
the embodiments described above are some, but not all embodiments of the invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Claims (9)
1. A method for synthesizing a polysubstituted pyrazole compound is characterized in that a compound shown in a formula I and a compound shown in a formula II react under an alkaline condition to generate a compound shown in a formula III and a compound shown in a formula IV, wherein the reaction formula is as follows:
R2selected from substituted or unsubstituted phenyl, naphthyl, indenyl, furyl, pyrimidinyl, indolyl, thiazolyl, or thienyl;
R3selected from substituted or unsubstituted phenyl, naphthyl, indenyl, furyl, pyrimidinyl, indolyl, thiazolyl or thienyl.
2. The method of synthesis of claim 1, wherein R is1The substituent of (A) is selected from halogen or methoxy; preferably, at least one selected from chlorine, fluorine, bromine and methoxy; more preferably, R1Are not in the same position.
3. The method of synthesis of claim 1, wherein R is2The substituent of (A) is selected from halogen, methyl or methoxy; preferably, at least one selected from chlorine, fluorine, methyl and methoxy; more preferably, R2Are not in the same position.
4. The method of synthesis of claim 1, wherein R is3The substituent of (A) is selected from halogen or methoxy; preferably, at least one selected from chlorine, bromine and methoxy; more preferably, R3The substituent(s) is para-substituted.
5. The synthesis method according to any one of claims 1 to 4, wherein the organic solvent is at least one selected from tetrahydrofuran, ethyl acetate, acetonitrile, dichloromethane and ethanol; ethanol is preferred.
6. The method of any one of claims 1 to 4, wherein the base is selected from Et3N、Cs2CO3、K2CO3Any one of DBU and DIPEA; preferably K2CO3。
7. The synthesis method according to any one of claims 1 to 4, wherein the mass ratio of the compound of formula I, the compound of formula II and the base is 1:1.2:0.5-1:1.2: 2.5; preferably 1:1.2: 2.5.
8. The synthesis method according to any one of claims 1 to 4, characterized in that the reaction temperature is 10 to 40 ℃, preferably room temperature.
9. The synthesis method according to claim 1, further comprising a refining step, preferably the refining step comprises column chromatography and recrystallization.
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