CN113968819B - Synthesis method of polysubstituted pyrazole compound - Google Patents
Synthesis method of polysubstituted pyrazole compound Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 9
- -1 polysubstituted pyrazole compound Chemical class 0.000 title abstract description 37
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 21
- 150000003217 pyrazoles Chemical class 0.000 claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 4
- 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 abstract description 4
- 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
- 238000004440 column chromatography Methods 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 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
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 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
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 239000002585 base Substances 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
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 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
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000007670 refining Methods 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 15
- 238000012986 modification Methods 0.000 abstract description 4
- 230000004048 modification Effects 0.000 abstract description 4
- 230000004071 biological effect Effects 0.000 abstract description 3
- 125000000524 functional group Chemical group 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000011347 resin Substances 0.000 description 6
- 229920005989 resin Polymers 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 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
- 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
- 239000000203 mixture Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- 150000007857 hydrazones Chemical class 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 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
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940125904 compound 1 Drugs 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
- 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
- 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 1
- 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 1
- 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 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
- 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
- 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
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012544 monitoring process Methods 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
- 239000007858 starting material Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
Abstract
The invention discloses a polysubstituted pyrazoleThe synthesis method of the compound belongs to the technical field of organic synthesis, and solves the problems of long route, uneconomical atom, unfriendly environment and complex operation of the compound skeleton in the synthesis process. The invention discloses a synthesis method of polysubstituted pyrazole compounds, wherein a compound of formula I and a compound of formula II react under alkaline conditions to generate a compound of formula III and a compound of formula IV. The method takes cheap and easily available commodity as raw material, and can simultaneously construct the 1,3, 4-trisubstituted and 1,3,4, 5-tetrasubstituted polysubstituted pyrazole compounds by only normal temperature reaction under the action of very cheap alkali catalysis and environmentally harmless solvents. For the synthesized product 1,3,4, 5-tetra-substituted pyrazole compound, the 4-aldehyde group can be subjected to structural modification, so that target functional groups are 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 polysubstituted pyrazole compounds mainly comprise two methods: one is prepared by knorr pyrazole synthesis, 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 a concentrated acid and the reaction temperature is required to be high, which has a great conflict with the production safety and green development. In the latter case, the reaction is difficult to introduce a target group at a specific site due to the unique steric structure and electronic effect of the pyrazole ring, thus limiting its wide application in production.
Hydrazone is taken as a good reagent and is widely applied to organic synthesis to construct various ring compounds, the hydrazone can lose proton under the action of alkali to carry out structural interconversion, then Michael addition is carried out on the hydrazone and olefine aldehyde to obtain an intermediate, and then intramolecular cyclization is carried out to obtain the polysubstituted pyrazole compound. However, in the prior art, hydrazone is used as a starting material to synthesize only one pyrazole compound, and the problems of long synthetic route, uneconomical atom, unfriendly environment and complex operation exist.
Therefore, the synthesis method of the polysubstituted pyrazole compound can synthesize more than one pyrazole compound at the same time, is simple to operate, low in cost and environment-friendly, and becomes a problem to be solved urgently by those skilled in the art.
Disclosure of Invention
The invention aims to provide a synthesis method of a polysubstituted pyrazole compound, which takes cheap and easily available commodity as a raw material, and can simultaneously construct the 1,3, 4-trisubstituted and 1,3,4, 5-tetrasubstituted polysubstituted pyrazole compound by only normal-temperature reaction under the action of very cheap alkali catalysis and environment-friendly solvents; solves the problems of long route, uneconomical atom, unfriendly environment, complex operation and the like of the compound skeleton in the synthesis process.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the invention discloses a synthesis method of polysubstituted pyrazole compounds, wherein a compound in a formula I and a compound in a formula II react under an alkaline condition to generate a compound in a formula III and a compound in a formula IV, and the reaction formula is as follows:
the method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 1 Selected from substituted or unsubstituted phenyl, naphthyl, indenyl, furyl, pyrimidinyl, indolyl, thiazolyl or thienyl;
R 2 selected from substituted or unsubstituted phenyl, naphthyl, indenyl, furyl, pyrimidinyl, indolyl, thiazolyl or thienyl;
R 3 selected from the group consisting of substituted or unsubstituted phenyl, naphthyl, indenyl, furyl, pyrimidinyl, indolyl, thiazolyl, or thienyl.
The method can simultaneously synthesize two pyrazole compounds of 1,3, 4-trisubstituted and 1,3,4, 5-tetrasubstituted pyrazoles. For the synthesized product 1,3,4, 5-tetra-substituted pyrazole compound, the 4-aldehyde group can be subjected to structural modification, so that target functional groups are introduced to have different biological activities.
In some embodiments of the invention, R 1 Is selected from halogen or methoxy; preferably, at least one selected from chlorine, fluorine, bromine, methoxy; more preferably, R 1 Is different from the substituent of the (B).
In some embodiments of the invention, R 2 Is selected from halogen, methyl or methoxy; preferably, at least one selected from chlorine, fluorine, methyl, methoxy; more preferably, R 2 Is different from the substituent of the (B).
In some embodiments of the invention, R 3 Is selected from halogen or methoxy; preferably, at least one selected from chlorine, bromine and methoxy; more preferably, R 3 The substituent of (a) is para-position substitution.
In some embodiments of the present 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 Et 3 N、Cs 2 CO 3 、K 2 CO 3 Any one of DBU and DIPEA; preferably K 2 CO 3 。
In some embodiments of the present invention, 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.
In some embodiments of the invention, the reaction temperature is from 10 to 40 ℃, preferably room temperature.
In some embodiments of the invention, a refining step is further included, preferably comprising column chromatography, recrystallization.
The room temperature of the invention 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 convenient operation. The method can synthesize pyrazole compounds containing various substituents, has fewer byproducts and is easy to purify. The method can synthesize two pyrazole compounds of 1,3, 4-trisubstituted and 1,3,4, 5-tetrasubstituted pyrazole at the same time, solves the limit 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-aldehyde group can be subjected to structural modification, so that target functional groups are introduced to have different biological activities.
The raw materials are cheap and easy to obtain, the reaction cost is effectively reduced, and the solvent is nontoxic and harmless, does not need a metal catalyst, and is environment-friendly; the reaction condition is simple, the target compound can be obtained in high yield in normal temperature air without heating or inert gas protection, a new route selection is provided for synthesizing active molecules containing the skeleton, and the method has good industrial application prospect.
Drawings
FIG. 1 is a hydrogen spectrum of the compound of formula III-6 prepared in example 7;
FIG. 2 is a carbon spectrum of the compound of formula III-6 prepared in example 7;
FIG. 3 is a hydrogen spectrum of the compound of formula IV-6 prepared in example 7;
FIG. 4 is a graph showing the 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 prepared 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 more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1
In the embodiment, the compound of formula I-1N-phenylbenzohydrazone acyl chloride and the compound of formula II-1 cinnamaldehyde are used as standard substrates to prepare the compound of formula III-1, 3, 4-triphenyl-1H-pyrazole and the compound of formula IV-1, 3, 5-triphenyl-1H-pyrazole-4-formaldehyde, wherein the reaction formula is as follows:
the specific operation is as follows: 10mL of the reaction tube and the magnetic stirrer were dried in advance, and 100mg of N-phenylbenzohydrazone acyl chloride (0.435 mmol) and 150.2mg of K were then added to the reaction tube, respectively 2 CO 3 (1.087 mmol), then adding 2.2mL of ethanol solvent, finally adding 69.00mg of cinnamaldehyde (0.522 mmol), reacting at normal temperature, monitoring the whole reaction progress by TLC, concentrating the solvent after the reaction is finished, and separating the obtained crude product by column chromatography with petroleum ether and ethyl acetate mixed solution (30/1, v/v) as eluent and 300-400 meshes of silica gel as separating resin to obtain 1,3, 4-triphenyl-1H-pyrazole (59.18 mg, light yellow oily) and 1,3, 5-triphenyl-1H-pyrazole-4-formaldehyde (74.64 mg, yellow solid), wherein the yield of the compound of the formula III-1 is 45.99%, and the yield of the compound of the formula IV-1 is 53.00%.
A compound of formula iii-1: 1 H NMR(600MHz,CDCl 3 )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). 13 C NMR(151MHz,CDCl 3 )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 C 21 H 17 N 2 297.1392；found,297.1385.
a compound of formula iv-1: 1 H NMR(600MHz,CDCl 3 )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). 13 C NMR(151MHz,CDCl 3 )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 C 22 H 17 N 2 O 325.1341；found,325.1333.
example 2
In the embodiment, the reaction conditions of the synthesis of the base-catalyzed polysubstituted pyrazole compound are researched by taking N-phenylbenzohydrazone acyl chloride of the formula I-1 and cinnamaldehyde of the formula II-1 as standard substrates, wherein the reaction formula is as follows:
the reaction conditions and results are shown in Table 1:
TABLE 1
In table 1, "equiv" represents equivalent; the temperature "rt" is room temperature; a is that 2.5 equivalents of DDQ is added into a reaction system; b is anhydrous and anaerobic condition.
Example 3
This example discloses the preparation of the compound of formula III-2 (4-bromophenyl) -1, 3-diphenyl-1H-pyrazole and the compound of formula IV-2 5- (4-bromophenyl) -3- (cyclohex-1, 3-dien-1-yl) -1-phenyl-1H-pyrazole-4-carbaldehyde:
10mL reaction tube and magnetThe stirred mixture was dried in advance, and then 100 mgN-phenylbenzohydrazone acid chloride (0.435 mmol) and 150.2mg K were added to the reaction tube, respectively 2 CO 3 (1.087 mmol), 2.2mL of ethanol solvent was added, 110.17mg of p-bromocinnamaldehyde (0.522 mmol) was added, the whole reaction was allowed to react at room temperature, TLC was used to monitor the whole reaction progress, after the completion of the reaction, the solvent was concentrated, and the obtained crude product was separated by column chromatography using a mixture of petroleum ether and ethyl acetate (30/1, v/v) as an eluent and 300-400 mesh silica gel as a separation resin to give (4-bromophenyl) -1, 3-diphenyl-1H-pyrazole (47.4 mg, pale yellow oil) and 5- (4-bromophenyl) -3- (cyclohex-1, 3-dien-1-yl) -1-phenyl-1H-pyrazole-4-carbaldehyde (75.7 mg, yellow solid), yield: formula III-2 is 29.15% and formula IV-2 is 43.51%.
A compound of formula iii-2: 1 H NMR(600MHz,CDCl 3 )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). 13 C NMR(151MHz,CDCl 3 )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 C 21 H 16 BrN 2 375.0497；found,375.0489.
a compound of formula iv-2: 1 H NMR(600MHz,CDCl 3 )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). 13 C NMR(151MHz,CDCl 3 )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 C 22 H 15 BrN 2 NaO 425.0265；found,425.0258.
example 4
This example discloses the preparation of the compound 1, 4-diphenyl-3- (thiophen-2-yl) -1H-pyrazole of formula III-3 and the compound 1, 5-diphenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carbaldehyde of formula IV-3:
10mL of the reaction tube and the magnetic stirrer were dried in advance, and 100mg of N-phenylthiophene-2-carbazone chloride (0.42 mmol) and 145.18mg of K were added to the reaction tube, respectively 2 CO 3 (1.05 mmol), then 2.1mL of ethanol solvent was added, finally 66.61mg of cinnamaldehyde (0.504 mmol) was added, the whole reaction was allowed to react at normal temperature, TLC was used to monitor the whole reaction progress, after the reaction was completed, the solvent was concentrated, and the obtained crude product was separated by column chromatography using a mixture of petroleum ether and ethyl acetate (30/1, v/v) as an eluent and 300-400 mesh silica gel as a separation resin to obtain 1, 4-diphenyl-3- (thiophen-2-yl) -1H-pyrazole (21.7 mg, orange solid) and 1, 5-diphenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carbaldehyde (56.2 mg, tan) as yields: formula III-3 is 16.96% and formula IV-3 is 40.43%.
A compound of formula iii-3: 1 H NMR(600MHz,CDCl 3 )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). 13 C NMR(151MHz,CDCl 3 )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 C 19 H 15 N 2 S 303.0956；found,303.0949.
a compound of formula iv-3: 1 H NMR(600MHz,CDCl 3 )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). 13 C NMR(151MHz,CDCl 3 )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 C 20 H 15 N 2 OS 331.0905；found,331.0897.
example 5
This example discloses the preparation of the compound 1- (4-methoxyphenyl) -3- (naphthalen-2-yl) -4-phenyl-1H-pyrazole of formula iii-4 and the compound 1- (4-methoxyphenyl) -3- (naphthalen-2-yl) -5-phenyl-1H-pyrazole-4-carbaldehyde of formula iv-4:
10mL of the reaction tube and the magnetic stirrer were dried in advance, and then 100mg of N- (4-methoxyphenyl) -2-naphthylhydrazone chloride (0.323 mmol) and 111.46mg of K were added to the reaction tube, respectively 2 CO 3 (0.806 mmol) and then 2.1mL of ethanol solvent were added, and finally 51.23mg of cinnamaldehyde (0.39 mmol) was added, the whole reaction was allowed to react at room temperature, TLC was monitored for the progress of the whole reaction, after the completion of the reaction, the solvent was concentrated, and the obtained crude product was separated by column chromatography using a mixture of petroleum ether and ethyl acetate (30/1, v/v) as an eluent and 300-400 mesh silica gel as a separation resin to give 1- (4-methoxyphenyl) -3- (naphthalen-2-yl) -4-phenyl-1H-pyrazole (46.7 mg, yellow oil) and 1- (4-methoxyphenyl) -3- (naphthalen-2-yl) -5-phenyl-1H-pyrazole-4-carbaldehyde (63.9 mg, red solid), yield: formula III-4 is 38.50% and formula IV-4 is 49.15%.
Formula III-4: 1 H NMR(600MHz,CDCl 3 )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). 13 C NMR(151MHz,CDCl 3 )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 C 26 H 21 N 2 O 377.1654；found,377.1648.
formula IV-4: 1 H NMR(600MHz,CDCl 3 )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). 13 C NMR(151MHz,CDCl 3 )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 C 27 H 21 N 2 O 2 405.1603；found,405.1600.
example 6
This example discloses the preparation of the compound 4- (4-chlorophenyl) -3- (3-fluorophenyl) -1-mesityl-1H-pyrazole of formula III-5 and the compound 5- (4-chlorophenyl) -3- (3-fluorophenyl) -1-mesityl-1H-pyrazole-4-carbaldehyde of formula IV-5:
10mL of the reaction tube and the magnetic stirrer were dried in advance, and 100mg of 3-fluoro-N-mesityl benzohydrazone chloride (0.344 mmol) and 118.74mg of K were then added to the reaction tube, respectively 2 CO 3 (0.859 mmol), 1.7mL of ethanol solvent was added, 68.78mg of p-chlorocinnamaldehyde (0.413 mmol) was added, the whole reaction was allowed to react at normal temperature, TLC was used to monitor the whole reaction progress, after the completion of the reaction, the solvent was concentrated, and the obtained crude product was separated by column chromatography using a mixture of petroleum ether and ethyl acetate (30/1, v/v) as an eluent and 300-400 mesh silica gel as a separation resin to obtain 4- (4-chlorophenyl) -3- (3-fluorophenyl) -1-mesityl-1H-pyrazole (35.00 mg, yellow oily) and 5- (4-chlorophenyl) -3- (3-fluorophenyl) -1-mesityl-1H-pyrazole-4-carbaldehyde (95.7 mg, yellow solid), yield: formula III-5 is 26.12% and formula IV-5 is 66.64%.
A compound of formula iii-5: 1 H NMR(600MHz,CDCl 3 )δ7.52(s,1H),7.35–7.26(m,7H),7.03–6.97(m,3H),2.34(s,3H),2.11(s,6H). 13 C NMR(151MHz,CDCl 3 )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 C 24 H 21 ClFN 2 391.1377；found,391.1373.
a compound of formula iv-5: 1 H NMR(600MHz,CDCl 3 )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). 13 C NMR(151MHz,CDCl 3 )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 C 25 H 21 ClFN 2 O 419.1326；found,419.1321.
example 7
This example discloses the preparation of the compound 3- (3-chlorophenyl) -1, 4-bis (4-methoxyphenyl) -1H-pyrazole of formula III-6 and the compound 3- (3-chlorophenyl) -1, 5-bis (4-methoxyphenyl) -1H-pyrazole-4-carbaldehyde of formula IV-6:
10mL of the reaction tube and the magnetic stirrer were dried in advance, and 100mg of 3-chloro-N- (4-methoxyphenyl) benzohydrazone chloride (0.340 mmol) and 117.53mg of K were then added to the reaction tube, respectively 2 CO 3 (0.850 mmol) and then 1.7mL of ethanol solvent were added, and finally 66.18mg of p-methoxycinnamaldehyde (0.41 mmol) was added, the whole reaction was allowed to react at normal temperature, TLC was monitored for the whole reaction progress, after the reaction was completed, the solvent was concentrated, and the obtained crude product was separated by column chromatography using a mixture of petroleum ether and ethyl acetate (30/1, v/v) as an eluent and 300-400 mesh silica gel as a separation resin to obtain 3- (3-chlorophenyl) -1, 4-bis (4-methoxyphenyl) -1H-pyrazole (38.80 mg, pale yellow oil) and 3- (3-chlorophenyl) -1, 5-bis (4-methoxyphenyl) -1H-pyrazole-4-carbaldehyde (74.30 mg, red solid) as preparation, yield: formula III-6 is 29.24%, formula IV-6 is 52.25%;
a compound of formula iii-6: 1 H NMR(600MHz,CDCl 3 )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). 13 C NMR(151MHz,CDCl 3 )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 C 23 H 20 ClN 2 O 2 391.1213；found,391.1205.
a compound of formula iv-6: 1 H NMR(600MHz,CDCl 3 )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). 13 C NMR(151MHz,CDCl 3 )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 C 24 H 19 ClN 2 NaO 3 441.0982；found,441.0980.
the embodiments described above are some, but not all embodiments of the invention. The detailed description of the embodiments of the 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 made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Claims (12)
1. A synthesis method of polysubstituted pyrazole compounds is characterized in that a compound of formula I reacts with a compound of formula II in an organic solvent under alkaline conditions to generate a compound of formula III and a compound of formula IV, wherein the reaction formula is as follows:
wherein R is 1 Selected from substituted or unsubstituted phenyl, naphthyl, indenyl, furyl, pyrimidinyl, indolyl, thiazolyl or thienyl; r is R 1 Is selected from halogen or methoxy;
R 2 selected from substituted or unsubstituted phenyl, naphthyl, indenyl, furyl, pyrimidinyl, indolyl, thiazolyl or thienyl; r is R 2 Is selected from halogen, methyl or methoxy;
R 3 selected from substituted or unsubstituted phenyl, naphthyl, indenyl, furyl, pyrimidinyl, indolyl, thiazolyl or thienyl; r is R 3 Is selected from halogen or methoxy;
the molar ratio of the compound of the formula I to the compound of the formula II to the alkali is 1:1.2:1.0-1:1.2:2.5;
the base is selected from Et 3 N、K 2 CO 3 Any one of DIPEA;
the reaction temperature is 10-40 ℃.
2. The method of claim 1, wherein R 1 The substituent of (2) is at least one selected from chlorine, fluorine, bromine and methoxy.
3. The method of claim 1, wherein R 2 The substituent of (2) is at least one selected from chlorine, fluorine, methyl and methoxy.
4. The method of claim 1, wherein R 3 The substituent of (2) is at least one selected from chlorine, bromine and methoxy.
5. The method of claim 4, wherein R 3 The substituent of (a) is para-position substitution.
6. The method according to any one of claims 1 to 5, wherein the organic solvent is at least one selected from tetrahydrofuran, ethyl acetate, acetonitrile, dichloromethane, and ethanol.
7. The method of claim 6, wherein the organic solvent is ethanol.
8. The method according to any one of claims 1 to 5, wherein the base is K 2 CO 3 。
9. The method of any one of claims 1-5, wherein the molar ratio of the compound of formula I, the compound of formula II, and the base is 1:1.2:2.5.
10. The method of any one of claims 1 to 5, wherein the reaction temperature is room temperature.
11. The method of synthesis according to claim 1, further comprising a refining step.
12. The synthetic method of claim 11 wherein the refining step comprises column chromatography, recrystallization.
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