CN117820323A - Synthesis method of pyrazolone spiro-dihydropyrrole derivative - Google Patents
Synthesis method of pyrazolone spiro-dihydropyrrole derivative Download PDFInfo
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- CN117820323A CN117820323A CN202311750009.XA CN202311750009A CN117820323A CN 117820323 A CN117820323 A CN 117820323A CN 202311750009 A CN202311750009 A CN 202311750009A CN 117820323 A CN117820323 A CN 117820323A
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- pyrazolone
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- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical compound O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 238000001308 synthesis method Methods 0.000 title claims abstract description 9
- -1 butynedioic acid diester Chemical class 0.000 claims abstract description 80
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 239000007800 oxidant agent Substances 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 7
- 230000001590 oxidative effect Effects 0.000 claims abstract description 7
- 238000005406 washing Methods 0.000 claims abstract description 5
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000010438 heat treatment Methods 0.000 claims abstract description 3
- 239000012299 nitrogen atmosphere Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 66
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 38
- 239000003208 petroleum Substances 0.000 claims description 19
- 238000010189 synthetic method Methods 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical group [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 238000013375 chromatographic separation Methods 0.000 claims description 4
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical group CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 2
- 238000006452 multicomponent reaction Methods 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 2
- 235000011152 sodium sulphate Nutrition 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 34
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 238000000926 separation method Methods 0.000 abstract description 4
- 238000010523 cascade reaction Methods 0.000 abstract description 2
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 238000011403 purification operation Methods 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract description 2
- 150000001412 amines Chemical class 0.000 abstract 1
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- 238000004587 chromatography analysis Methods 0.000 abstract 1
- 238000001816 cooling Methods 0.000 abstract 1
- 238000002156 mixing Methods 0.000 abstract 1
- 239000002904 solvent Substances 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 108
- 238000001228 spectrum Methods 0.000 description 64
- 238000002360 preparation method Methods 0.000 description 48
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 47
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 47
- 229910052799 carbon Inorganic materials 0.000 description 47
- 239000001257 hydrogen Substances 0.000 description 47
- 229910052739 hydrogen Inorganic materials 0.000 description 47
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 30
- 238000012512 characterization method Methods 0.000 description 23
- 239000007858 starting material Substances 0.000 description 19
- 239000003480 eluent Substances 0.000 description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 125000003003 spiro group Chemical group 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000006845 Michael addition reaction Methods 0.000 description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000007806 chemical reaction intermediate Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- STRNXFOUBFLVIN-UHFFFAOYSA-N diethyl but-2-ynedioate Chemical compound CCOC(=O)C#CC(=O)OCC STRNXFOUBFLVIN-UHFFFAOYSA-N 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- QVSVMNXRLWSNGS-UHFFFAOYSA-N (3-fluorophenyl)methanamine Chemical compound NCC1=CC=CC(F)=C1 QVSVMNXRLWSNGS-UHFFFAOYSA-N 0.000 description 1
- YMVFJGSXZNNUDW-UHFFFAOYSA-N (4-chlorophenyl)methanamine Chemical compound NCC1=CC=C(Cl)C=C1 YMVFJGSXZNNUDW-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 1
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 description 1
- DEVLNUKFUVCZDW-UHFFFAOYSA-N 4-[(4-bromophenyl)methylidene]-5-methyl-2-phenylpyrazol-3-one Chemical compound CC1=NN(C=2C=CC=CC=2)C(=O)C1=CC1=CC=C(Br)C=C1 DEVLNUKFUVCZDW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- VHILMKFSCRWWIJ-UHFFFAOYSA-N dimethyl acetylenedicarboxylate Chemical compound COC(=O)C#CC(=O)OC VHILMKFSCRWWIJ-UHFFFAOYSA-N 0.000 description 1
- FBCRUXRGQFLOMC-UHFFFAOYSA-N ditert-butyl but-2-ynedioate Chemical compound CC(C)(C)OC(=O)C#CC(=O)OC(C)(C)C FBCRUXRGQFLOMC-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of organic synthesis, in particular to a synthesis method of pyrazolone spiro-dihydropyrrole derivatives. The method comprises the following steps: mixing alpha, beta-unsaturated pyrazolone I, amine II, butynedioic acid diester III, N-iodinated succinimide (NIS) and an oxidant, adding a solvent, and heating to react under nitrogen atmosphere; after the reaction is finished, cooling to room temperature, washing, extracting, drying and concentrating the reaction liquid under reduced pressure, and separating by chromatography to obtain the pyrazolone spiro dihydropyrrole derivative IV. The raw materials used in the invention are conventional, cheap and easily available, and the accelerator N-iodinated succinimide is cheap, safe and nontoxic; the reaction efficiency is improved by utilizing a one-pot multi-component domino reaction strategy, and the separation and purification operation is reduced; good reaction selectivity, less side reaction and high product yield.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthesis method of pyrazolone spiro-dihydropyrrole derivatives.
Background
Spiro structures are a class of active frameworks in ubiquitous natural products and drugs, particularly nitrogen-containing spiro compounds, which have been demonstrated to possess a broad range of biological activities, such as antitumor, antidiabetic, antibacterial, antitubercular, antiinflammatory, etc., with great potential in the biomedical field, and in addition, many unnatural synthetic pyrazolone spiro derivatives are also used in large numbers in the dye, agrochemical, analytical and pharmaceutical industries. Pyrazolone spiro dihydropyrrole as a very important member of the pyrazolone spiro family also has a broad spectrum of biological activity.
In view of this, intensive studies have been conducted on the synthesis of pyrazolone spiro dihydropyrrole derivatives or analogs thereof into pyrazolone spiro nitrogen-containing heterocyclic backbones, and synthetic methods developed so far mainly include noble metal-catalyzed and organocatalyzed pyrazolone-based serial cycloaddition reactions.
Although these methods all allow the synthesis of a wide variety of pyrazolone spiro nitrogen-containing heterocyclic derivatives, there are disadvantages such as: the method is characterized in that the method mainly involves special or complex raw materials, reaction intermediates or precursors need to be synthesized in advance, and a catalyst which is expensive, complex in structure, toxic and not easy to obtain is used, the reaction conditions are harsh, long reaction time is needed, and the separation and purification of the products are complicated.
The inventors have filed an invention patent for a method for synthesizing a pyrrole derivative (application number CN 202210778315.3) and a method for synthesizing an imidazole derivative (application number CN202210679449. X), respectively, and then tried to prepare a pyrazolone spiro dihydropyrrole derivative by a Michael addition reaction, and have studied and tested continuously, and finally studied the method for synthesizing a pyrazolone spiro dihydropyrrole derivative according to the present invention.
Disclosure of Invention
The invention aims to provide a synthesis method of pyrazolone spiro-dihydropyrrole derivatives, which can effectively solve the problems of difficult or expensive raw material synthesis, expensive or toxic catalyst, reaction requirement for synthesizing reaction intermediates or precursors in advance, harsh reaction conditions, complicated product separation, low yield and the like in the existing synthesis method of the pyrazolone spiro-dihydropyrrole derivatives.
The technical scheme for solving the problems is as follows:
a synthesis method of pyrazolone spiro-dihydropyrrole derivatives is characterized in that: and (3) carrying out multicomponent reaction on the compounds shown in the formulas I, II and III according to a certain proportion in the presence of an organic solvent, an accelerator and an oxidant, and purifying to obtain the pyrazolone spiro dihydropyrrole derivative shown in the formula IV.
The reaction general formula of the invention is:
wherein R is 1 Is any one of phenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethylphenyl, p-nitrophenyl, m-chlorophenyl, m-bromophenyl, naphthyl, 3, 4-dimethylphenyl and 3, 4-dichlorophenyl; r is R 2 Is any one of methyl, ethyl and phenyl; r is R 3 Is any one of phenyl, p-tolyl, p-fluorophenyl, p-chlorophenyl and m-tolyl; r is R 4 Is n-propyl, n-butyl, n-hexyl, benzyl, p-methoxybenzyl, p-chlorobenzyl, m-fluorobenzyl, phenethyl; r is R 5 Is any one of methyl, ethyl and tert-butyl.
Preferably, the accelerator is N-iodinated succinimide, and the organic solvent is dichloroethane, toluene or chlorobenzene.
Preferably, the ratio of the amounts of the compound shown in the formula I, the compound shown in the formula II, the compound shown in the formula III, the accelerator and the oxidant is 1:1.5-1.8:1.5-1.8:2.0-2.5.
Preferably, the reaction condition is heating reaction under nitrogen atmosphere, the reaction temperature is 80-110 ℃, and the reaction time is 2-4 h.
Preferably, the oxidant is one or two of sodium sulfate and potassium persulfate.
Preferably, the volume of the organic solvent is 10-15 times of the total mass of the raw materials.
Preferably, the purification steps are washing, extraction, drying, concentration under reduced pressure and chromatographic separation.
Preferably, the solution used in the washing step is an aqueous solution of sodium thiosulfate; the extractant adopted in the extraction step is ethyl acetate; the drying step is drying using anhydrous sodium sulfate.
Preferably, the chromatographic conditions of the chromatographic separation step are: the silica gel column with 200-300 meshes is prepared from a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:5-10.
The reaction mechanism of the invention is as follows: when R is 1 Is phenyl, R 2 Is methyl, R 3 Is phenyl, R 4 Is benzyl, R 5 In the case of ethyl, firstly, the beta-enamine ester A generated in situ by benzylamine II and diethyl butynedioate III reacts with the alpha, beta-unsaturated pyrazolone I added subsequently to form an intermediate B, and then the intermediate B and NIS are subjected to a Michael addition reaction by Na 2 S 2 O 8 I formed by oxidation 2 And (3) reacting to obtain an iodo intermediate C, forming a spiro intermediate D through intramolecular nucleophilic substitution, and removing protons to obtain a final pyrazolone spiro dihydropyrrole product IV. The reaction mechanism is illustrated as follows:
by adopting the technology, compared with the prior art, the invention has the beneficial effects that: the raw materials adopted by the invention are conventional, cheap and easily available, and are suitable for substrates substituted by various functional groups; the adopted accelerator NIS is a cheap, safe and nontoxic reagent; the domino reaction strategy of multiple components in one pot is utilized to reduce separation and purification operations, greatly improve reaction efficiency and reduce cost; the method has the advantages of good reaction selectivity, less side reaction and high product yield, and effectively solves the comprehensive problems of the method in the background technology.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of IV-1;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of IV-1;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of IV-2;
FIG. 4 is a nuclear magnetic resonance carbon spectrum of IV-2;
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of IV-3;
FIG. 6 is a nuclear magnetic resonance carbon spectrum of IV-3;
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of IV-4;
FIG. 8 is a nuclear magnetic resonance carbon spectrum of IV-4;
FIG. 9 is a nuclear magnetic resonance hydrogen spectrum of IV-5;
FIG. 10 is a nuclear magnetic resonance carbon spectrum of IV-5;
FIG. 11 is a nuclear magnetic resonance hydrogen spectrum of IV-6;
FIG. 12 is a nuclear magnetic resonance carbon spectrum of IV-6;
FIG. 13 is a nuclear magnetic resonance hydrogen spectrum of IV-7;
FIG. 14 is a nuclear magnetic resonance carbon spectrum of IV-7;
FIG. 15 is a nuclear magnetic resonance hydrogen spectrum of IV-8;
FIG. 16 is a nuclear magnetic resonance carbon spectrum of IV-8;
FIG. 17 is a nuclear magnetic resonance hydrogen spectrum of IV-9;
FIG. 18 is a nuclear magnetic resonance carbon spectrum of IV-9;
FIG. 19 is a nuclear magnetic resonance hydrogen spectrum of IV-10;
FIG. 20 is a nuclear magnetic resonance carbon spectrum of IV-10;
FIG. 21 is a nuclear magnetic resonance hydrogen spectrum of IV-11;
FIG. 22 is a nuclear magnetic resonance carbon spectrum of IV-11;
FIG. 23 is a nuclear magnetic resonance hydrogen spectrum of IV-12;
FIG. 24 is a nuclear magnetic resonance carbon spectrum of IV-12;
FIG. 25 is a nuclear magnetic resonance hydrogen spectrum of IV-13;
FIG. 26 is a nuclear magnetic resonance carbon spectrum of IV-13;
FIG. 27 is a nuclear magnetic resonance hydrogen spectrum of IV-14;
FIG. 28 is a nuclear magnetic resonance carbon spectrum of IV-14;
FIG. 29 is a nuclear magnetic resonance hydrogen spectrum of IV-15;
FIG. 30 is a nuclear magnetic resonance carbon spectrum of IV-15;
FIG. 31 is a nuclear magnetic resonance hydrogen spectrum of IV-16;
FIG. 32 is a nuclear magnetic resonance carbon spectrum of IV-16;
FIG. 33 is a nuclear magnetic resonance hydrogen spectrum of IV-17;
FIG. 34 is a nuclear magnetic resonance carbon spectrum of IV-17;
FIG. 35 is a nuclear magnetic resonance hydrogen spectrum of IV-18;
FIG. 36 is a nuclear magnetic resonance carbon spectrum of IV-18;
FIG. 37 is a nuclear magnetic resonance hydrogen spectrum of IV-19;
FIG. 38 is a nuclear magnetic resonance carbon spectrum of IV-19;
FIG. 39 is a nuclear magnetic resonance hydrogen spectrum of IV-20;
FIG. 40 is a nuclear magnetic resonance carbon spectrum of IV-20;
FIG. 41 is a nuclear magnetic resonance hydrogen spectrum of IV-21;
FIG. 42 is a nuclear magnetic resonance carbon spectrum of IV-21;
FIG. 43 is a nuclear magnetic resonance hydrogen spectrum of IV-22;
FIG. 44 is a nuclear magnetic resonance carbon spectrum of IV-22;
FIG. 45 is a nuclear magnetic resonance hydrogen spectrum of IV-23;
FIG. 46 is a nuclear magnetic resonance carbon spectrum of IV-23;
FIG. 47 is a nuclear magnetic resonance hydrogen spectrum of IV-24;
FIG. 48 is a nuclear magnetic resonance carbon spectrum of IV-24
FIG. 49 is a single crystal diffraction pattern of IV-24.
Detailed Description
The present invention will be specifically described with reference to examples below in order to make the objects and advantages of the present invention more apparent. It should be understood that the following text is intended to describe only one or more specific embodiments of the invention and does not limit the scope of the invention strictly as claimed.
Example 1:
taking as an example the preparation of diethyl 1-benzyl-6-methyl-9-oxo-4, 8-diphenyl-1, 7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-1) of the formula:
the preparation method comprises the following steps: reaction to 25mL4-Phenylmethylene-3-methyl-1-phenyl-1H-pyrazol-5 (4H) -one I (131.2 mg,0.5 mmol), NIS (168.7 mg,0.75 mmol), na were added to the tube 2 S 2 O 8 (238.1 mg,1.0 mmol) and then nitrogen gas, after which a mixture of benzylamine II (80.4 mg,0.75 mmol), diethyl butynedioate III (127.6 mg,0.75 mmol) and 1, 2-dichloroethane (5 mL) was added with a needle tube, after which the reaction tube was moved into an oil bath at 80℃and stirred for 2 hours, and nitrogen gas was continuously introduced during the reaction. After the reaction was completed, the reaction solution was washed with 10mL of a saturated aqueous sodium thiosulfate solution until the iodine color was completely removed, extracted three times with 20mL of ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate and filtered, and then a certain amount of silica gel was added to the organic layers, which was concentrated to powder by rotary evaporation under reduced pressure. Then column chromatography purification with ethyl acetate/petroleum ether (v/v=1:6) eluent gave product IV-1 in 92% yield.
Spectroscopic characterization data for IV-1: 1 H NMR(500MHz,CDCl 3 )δ(ppm)7.70(d,J＝8.1Hz,2H),7.39(t,J＝7.7Hz,2H),7.26–7.18(m,8H),7.11(d,J＝6.8Hz,2H),4.98(s,1H),4.33–4.21(m,2H),4.22(d,J＝14.9Hz,1H),4.13–3.96(m,2H),4.05(d,J＝14.9Hz,1H),1.34(s,3H),1.29(t,J＝7.2Hz,3H),1.04(t,J＝7.1Hz,3H)； 13 CNMR(125MHz,CDCl 3 )δ(ppm)171.2,163.6,162.5,158.4,153.4,137.5,135.8,134.5,129.2(2C),129.0(2C),128.64(2C),128.62,128.57(2C),128.2(2C),128.1,125.6,119.0(2C),102.2,80.8,62.8,59.9,57.0,50.9,15.2,14.2,14.0；HRMS(ESI-TOF)calcd for C 32 H 31 N 3 O 5 [M+H] + 538.2342,found 538.2337.
the nuclear magnetic resonance hydrogen spectrum of IV-1 is shown in figure 1, and the nuclear magnetic resonance carbon spectrum is shown in figure 2.
Example 2:
the procedure was as in example 1, except for the following technical scheme: k for oxidizing agent 2 S 2 O 8 Instead of Na 2 S 2 O 8 The product IV-1 was obtained in a yield of 81%.
Example 3:
the procedure was as in example 1, except for the following technical scheme: the reaction temperature was increased from 80℃to 100℃to give the product IV-1 in 74% yield.
Example 4:
taking as an example the preparation of diethyl 1-benzyl-4- (4-chlorophenyl) -6-methyl-9-oxo-8-phenyl-1, 7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-2) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: starting material I was 4- (4-chlorobenzenemethylene) -3-methyl-1-phenyl-1H-pyrazol-5 (4H) -one (148.4 mg,0.5 mmol) and the eluent ethyl acetate/petroleum ether (v/v=1:5) gave product IV-2 in 80% yield.
Spectroscopic characterization data for IV-2: 1 H NMR(600MHz,CDCl 3 )δ(ppm)7.68(d,J＝7.9Hz,2H),7.39(t,J＝7.7Hz,2H),7.27–7.18(m,8H),7.05(d,J＝7.9Hz,2H),4.95(s,1H),4.32–4.20(m,3H),4.11–3.98(m,3H),1.41(s,3H),1.30(t,J＝7.0Hz,3H),1.07(t,J＝6.9Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ(ppm)171.0,163.4,162.4,157.9,153.7,137.5,134.6,134.4,134.0,129.6(2C),129.3(2C),129.0(2C),128.9(2C),128.7,128.6(2C),125.7,119.0(2C),101.7,80.7,62.8,60.0,56.6,51.0,15.4,14.3,14.0；HRMS(ESI-TOF)calcd for C 32 H 31 ClN 3 O 5 [M+H] + 572.1952,found 572.1963.
the nuclear magnetic resonance hydrogen spectrum of IV-2 is shown in figure 3, and the nuclear magnetic resonance carbon spectrum is shown in figure 4.
Example 5:
taking as an example the preparation of diethyl 1-benzyl-4- (4-bromophenyl) -6-methyl-9-oxo-8-phenyl-1, 7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-3) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: starting material I was 4- (4-bromobenzylidene) -3-methyl-1-phenyl-1H-pyrazol-5 (4H) -one (170.6 mg,0.5 mmol) and the eluent ethyl acetate/petroleum ether (v/v=1:5) gave product IV-3 in 90% yield.
Spectroscopic characterization data for IV-3: 1 H NMR(600MHz,CDCl 3 )δ(ppm)7.68(d,J＝7.6Hz,2H),7.44–7.33(m,4H),7.26–7.18(m,6H),6.99(d,J＝7.3Hz,2H),4.93(s,1H),4.33–4.20(m,3H),4.11–3.98(m,3H),1.42(s,3H),1.30(t,J＝6.8Hz,3H),1.07(t,J＝6.8Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ(ppm)171.0,163.4,162.3,157.8,153.7,137.5,135.1,134.3,131.8(2C),129.9(2C),129.3(2C),129.0(2C),128.7,128.6(2C),125.7,122.1,119.0(2C),101.6,80.6,62.8,60.0,56.6,51.0,15.4,14.3,14.0；HRMS(ESI-TOF)calcd for C 32 H 31 BrN 3 O 5 [M+H] + 616.1447,found 616.1443.
IV-3 has a nuclear magnetic resonance hydrogen spectrum shown in FIG. 5 and a nuclear magnetic resonance carbon spectrum shown in FIG. 6.
Example 6:
take as an example the preparation of diethyl 1-benzyl-6-methyl-9-oxo-8-phenyl-4- (4- (trifluoromethyl) phenyl) -1,7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-4) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: starting material I was 4- (4- (trifluoromethyl) benzylidene) -3-methyl-1-phenyl-1H-pyrazol-5 (4H) -one (165.2 mg,0.5 mmol) and the eluent ethyl acetate/petroleum ether (v/v=1:5) to give product IV-4 in 91% yield.
Spectroscopic characterization data for IV-4: 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.68(d,J＝8.2Hz,2H),7.53(d,J＝8.0Hz,2H),7.39(t,J＝8.0Hz,2H),7.27–7.19(m,8H),5.03(s,1H),4.35–4.21(m,2H),4.25(d,J＝15.0Hz,1H),4.14–3.97(m,2H),4.04(d,J＝15.0Hz,1H),1.40(s,3H),1.31(t,J＝7.1Hz,3H),1.07(t,J＝7.1Hz,3H)； 13 CNMR(100MHz,CDCl 3 )δ(ppm)170.8,163.3,162.3,157.6,153.8,140.0,137.4,134.2,130.4(q,J＝32.6Hz),129.2(2C),129.0(2C),128.8,128.67(2C),128.66(2C),125.8,125.5(q,J＝9.7Hz,2C),124.0(q,J＝272.2Hz),118.9(2C),101.1,80.6,62.9,60.1,56.7,50.9,15.3,14.2,14.0；HRMS(ESI-TOF)calcd for C 33 H 31 F 3 N 3 O 5 [M+H] + 606.2216,found 606.2223.
IV-4 nuclear magnetic resonance hydrogen spectrum is shown in figure 7, and nuclear magnetic resonance carbon spectrum is shown in figure 8.
Example 7:
taking as an example the preparation of diethyl 1-benzyl-6-methyl-4- (4-nitrophenyl) -9-oxo-8-phenyl-1, 7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-5) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: starting material I was 4- (4-nitrobenzenemethylene) -3-methyl-1-phenyl-1H-pyrazol-5 (4H) -one (153.7 mg,0.5 mmol) and the eluent ethyl acetate/petroleum ether (v/v=1:5) gave product IV-5 in 86% yield.
Spectroscopic characterization data for IV-5: 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.12(d,J＝8.7Hz,2H),7.66(d,J＝7.9Hz,2H),7.39(t,J＝7.9Hz,2H),7.30(d,J＝8.5Hz,2H),7.26–7.17(m,6H),5.07(s,1H),4.37–4.23(m,2H),4.28(d,J＝14.9Hz,1H),4.14–3.98(m,2H),4.04(d,J＝14.9Hz,1H),1.47(s,3H),1.32(t,J＝7.2Hz,3H),1.08(t,J＝7.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm)170.5,163.1,162.0,157.0,154.0,147.6,143.2,137.2,133.9,129.20(2C),129.18(2C),129.0(2C),128.8,128.6(2C),125.8,123.7(2C),118.8(2C),100.4,80.4,62.9,60.1,56.7,50.9,15.3,14.2,13.9；HRMS(ESI-TOF)calcd for C 32 H 31 N 4 O 7 [M+H] + 583.2193,found583.2187.
the hydrogen nuclear magnetic resonance spectrum of IV-5 is shown in FIG. 9, and the carbon nuclear magnetic resonance spectrum is shown in FIG. 10.
Example 8:
taking as an example the preparation of diethyl 1-benzyl-4- (3-chlorophenyl) -6-methyl-9-oxo-8-phenyl-1, 7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-6) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: starting material I was 4- (3-chlorobenzenemethylene) -3-methyl-1-phenyl-1H-pyrazol-5 (4H) -one (148.4 mg,0.5 mmol) to give product IV-6 in 83% yield.
Spectroscopic characterization data for IV-6: 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.67(d,J＝7.8Hz,2H),7.39(t,J＝7.7Hz,2H),7.25–7.16(m,8H),7.12(s,1H),6.98(d,J＝7.4Hz,1H),4.94(s,1H),4.35–4.20(m,2H),4.24(d,J＝14.5Hz,1H),4.16–3.95(m,2H),4.03(d,J＝14.5Hz,1H),1.43(s,3H),1.30(t,J＝7.2Hz,3H),1.07(t,J＝7.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm)170.9,163.4,162.3,157.8,153.8,138.0,137.4,134.6,134.2,129.9,129.3(2C),129.0(2C),128.7,128.6(2C),128.4,128.3,126.4,125.8,119.1(2C),101.3,80.6,62.9,60.0,56.6,50.9,15.4,14.3,14.0；HRMS(ESI-TOF)calcd for C 32 H 31 ClN 3 O 5 [M+H] + 572.1952,found 572.1965.
the hydrogen nuclear magnetic resonance spectrum of IV-6 is shown in FIG. 11, and the carbon nuclear magnetic resonance spectrum is shown in FIG. 12.
Example 9:
take as an example the preparation of diethyl 1-benzyl-4- (3-bromophenyl) -6-methyl-9-oxo-8-phenyl-1, 7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-7) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: starting material I was 4- (3-bromobenzylidene) -3-methyl-1-phenyl-1H-pyrazol-5 (4H) -one (170.6 mg,0.5 mmol) and the eluent ethyl acetate/petroleum ether (v/v=1:5) gave product IV-7 in 90% yield.
Spectroscopic characterization data for IV-7: 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.67(d,J＝7.9Hz,2H),7.41–7.35(t,J＝7.4Hz,3H),7.28–7.18(m,7H),7.11(t,J＝7.8Hz,1H),7.02(d,J＝7.7Hz,1H),4.94(s,1H),4.35–4.20(m,2H),4.25(d,J＝15.2Hz,1H),4.17–3.94(m,2H),4.03(d,J＝15.2Hz,1H),1.44(s,3H),1.30(t,J＝7.2Hz,3H),1.06(t,J＝7.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm)170.7,163.2,162.1,157.6,153.7,138.1,137.2,134.1,131.2,131.1,130.1,129.1(2C),128.9(2C),128.6,128.5(2C),126.7,125.6,122.6,119.0(2C),101.0,80.5,62.7,59.9,56.5,50.8,15.2,14.2,13.8；HRMS(ESI-TOF)calcd for C 32 H 31 BrN 3 O 5 [M+H] + 616.1447,found 616.1434.
IV-7 is shown in FIG. 13, and IV-7 is shown in FIG. 14.
Example 10:
taking as an example the preparation of diethyl 1-benzyl-4- (3, 4-dimethylphenyl) -6-methyl-9-oxo-8-phenyl-1, 7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-8) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: starting material I was 4- (3, 4-dimethyl) benzylidene) -3-methyl-1-phenyl-1H-pyrazol-5 (4H) -one (145.2 mg,0.5 mmol) gave product IV-8 in 80% yield.
Spectroscopic characterization data for IV-8: 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.69(d,J＝8.2Hz,2H),7.37(t,J＝7.9Hz,2H),7.27–7.16(m,6H),6.99(d,J＝7.6Hz,1H),6.86–6.80(m,2H),4.93(s,1H),4.32–4.18(m,2H),4.23(d,J＝14.4Hz,1H),4.14–3.96(m,2H),4.02(d,J＝14.4Hz,1H),2.18(s,3H),2.13(s,3H),1.39(s,3H),1.28(t,J＝7.2Hz,3H),1.07(t,J＝7.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm)171.3,163.6,162.5,158.4,153.0,137.5,136.6,136.2,134.5,132.9,129.7,129.2,129.1(2C),128.8(2C),128.4(3C),125.45,125.40,119.0(2C),102.3,80.9,62.6,59.7,56.8,50.8,19.7,19.5,15.3,14.2,13.9；HRMS(ESI-TOF)calcd for C 34 H 36 N 3 O 5 [M+H] + 566.2655,found 566.2655.
the hydrogen nuclear magnetic resonance spectrum of IV-8 is shown in FIG. 15, and the carbon nuclear magnetic resonance spectrum is shown in FIG. 16.
Example 11:
taking as an example the preparation of diethyl 1-benzyl-4- (3, 4-dichlorophenyl) -6-methyl-9-oxo-8-phenyl-1, 7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-9) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: raw material I was 4- (3, 4-dichlorobenzylidene) -3-methyl-1-phenyl-1H-pyrazol-5 (4H) -one (165.6 mg,0.5 mmol) and the eluent ethyl acetate/petroleum ether (v/v=1:5) to give product IV-9 in 88% yield.
Spectroscopic characterization data for IV-9: 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.65(d,J＝7.9Hz,2H),7.38(t,J＝7.9Hz,2H),7.33(d,J＝8.2Hz,1H),7.25–7.18(m,7H),6.94(dd,J＝8.3,1.8Hz,1H),4.92(s,1H),4.36–4.21(m,2H),4.26(d,J＝14.7Hz,1H),4.17–4.08(m,1H),4.02(d,J＝14.7Hz,1H),4.05–3.96(m,1H),1.49(s,3H),1.30(t,J＝7.1Hz,3H),1.09(t,J＝7.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm)170.7,163.2,162.1,157.3,153.9,137.2,136.1,134.0,132.7,132.2,130.5,130.1,129.2(2C),128.9(2C),128.7,128.6(2C),127.5,125.8,119.0(2C),100.7,80.4,62.9,60.0,56.2,50.9,15.4,14.2,13.9；HRMS(ESI-TOF)calcd for C 32 H 30 Cl 2 N 3 O 5 [M+H] + 606.1563,found 606.1561.
the hydrogen nuclear magnetic resonance spectrum of IV-9 is shown in FIG. 17, and the carbon nuclear magnetic resonance spectrum is shown in FIG. 18.
Example 12:
taking as an example the preparation of diethyl 1-benzyl-6-methyl-4- (naphthalen-2-yl) -9-oxo-8-phenyl-1, 7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-10) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: starting material I was 4- (naphthalen-1-ylmethylene) -3-methyl-1-phenyl-1H-pyrazol-5 (4H) -one (156.2 mg,0.5 mmol) and the eluent ethyl acetate/petroleum ether (v/v=1:8) gave product IV-10 in 85% yield.
Spectroscopic characterization data for IV-10: 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.79–7.67(m,5H),7.57(s,1H),7.45–7.41(m,2H),7.38(t,J＝7.9Hz,2H),7.27–7.17(m,7H),5.17(s,1H),4.37–4.22(m,2H),4.27(d,J＝15.3Hz,1H),4.06(d,J＝15.3Hz,1H),4.12–3.94(m,2H),1.33(s,3H),1.31(t,J＝7.2Hz,3H),0.99(t,J＝7.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm)171.2,163.6,162.5,158.1,153.6,137.5,134.4,133.3,133.1,133.0,129.2(2C),128.9(2C),128.6,128.5(2C),128.3,128.0,127.7,127.1,126.3,126.2,126.0,125.6,119.0(2C),102.0,80.8,62.7,59.8,57.2,50.9,15.3,14.2,13.9；HRMS(ESI-TOF)calcd for C 36 H 34 N 3 O 5 [M+H] + 588.2498,found 588.2494.
the hydrogen nuclear magnetic resonance spectrum of IV-10 is shown in FIG. 19, and the carbon nuclear magnetic resonance spectrum is shown in FIG. 20.
Example 13:
taking as an example the preparation of diethyl 1-benzyl-6-ethyl-9-oxo-4, 8-diphenyl-1, 7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-11) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: starting material I was 4-benzylidene-3-ethyl-1-phenyl-1H-pyrazol-5 (4H) -one (138.2 mg,0.5 mmol) and the eluent was ethyl acetate/petroleum ether (v/v=1:7), giving product IV-11 in 80% yield.
Spectroscopic characterization data for IV-11: 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.74(d,J＝8.1Hz,2H),7.38(t,J＝7.9Hz,2H),7.27–7.17(m,9H),7.12–7.06(m,2H),5.02(s,1H),4.23(d,J＝15.2Hz,1H),4.30–4.15(m,2H),4.13–3.94(m,2H),4.00(d,J＝15.2Hz,1H),1.97–1.86(m,1H),1.64–1.53(m,1H),1.26(t,J＝7.2Hz,3H),1.04(t,J＝7.1Hz,3H),0.68(t,J＝7.3Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm)171.4,163.5,162.4,162.2,153.4,137.7,135.8,134.6,129.0(2C),128.8(2C),128.51(2C),128.48(2C),128.4,128.1(2C),127.9,125.4,119.0(2C),101.8,81.1,62.6,59.7,57.1,50.8,22.8,14.1,13.8,8.5；HRMS(ESI-TOF)calcd for C 33 H 34 N 3 O 5 [M+H] + 552.2498,found 552.2505.
the hydrogen nuclear magnetic resonance spectrum of IV-11 is shown in FIG. 21, and the carbon nuclear magnetic resonance spectrum is shown in FIG. 22.
Example 14:
taking as an example the preparation of diethyl 1-benzyl-6-methyl-9-oxo-4-phenyl-8- (p-toluene) -1,7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-12) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: starting material I was 4-benzylidene-3-methyl-1- (4-tolyl) -1H-pyrazol-5 (4H) -one (138.2 mg,0.5 mmol) gave product IV-12 in 89% yield.
Spectroscopic characterization data for IV-12: 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.58(d,J＝8.5Hz,2H),7.27–7.16(m,10H),7.13–7.08(m,2H),4.98(s,1H),4.33–4.18(m,2H),4.21(d,J＝14.6Hz,1H),4.04(d,J＝14.6Hz,1H),4.12–3.94(m,2H),2.34(s,3H),1.33(s,3H),1.28(t,J＝7.2Hz,3H),1.03(t,J＝7.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm)170.9,163.5,162.4,158.1,153.4,135.8,135.2,135.0,134.4,129.4(2C),129.1(2C),128.50(3C),128.46(2C),128.1(2C),128.0,118.9(2C),102.1,80.7,62.6,59.7,56.9,50.8,21.0,15.1,14.1,13.9；HRMS(ESI-TOF)calcd for C 33 H 34 N 3 O 5 [M+H] + 552.2498,found 552.2494.
the nuclear magnetic resonance hydrogen spectrum of IV-12 is shown in FIG. 23, and the nuclear magnetic resonance carbon spectrum is shown in FIG. 24.
Example 15:
take the preparation of ethyl 1-benzyl-8- (4-fluorophenyl) -6-methyl-9-oxo-4-phenyl-2- (propoxy) -1,7, 8-triazaspiro [4.4] non-2, 6-diene-3-carboxylate (IV-13) of the following formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: starting material I was 4-benzylidene-3-methyl-1- (4-fluorophenyl) -1H-pyrazol-5 (4H) -one (140.2 mg,0.5 mmol) gave product IV-13 in 95% yield.
Spectroscopic characterization data for IV-13: 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.69–7.62(m,2H),7.28–7.17(m,8H),7.13–7.02(m,4H),4.97(s,1H),4.35–4.20(m,2H),4.23(d,J＝14.8Hz,1H),4.13–3.95(m,2H),4.03(d,J＝14.8Hz,1H),1.35(s,3H),1.31(t,J＝7.1Hz,3H),1.04(t,J＝7.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm)171.0,163.4,162.4,160.1(d,J＝245.1Hz),158.4,153.3,135.8,134.3,133.6(d,J＝2.8Hz),129.2(2C),128.6(3C),128.5(2C),128.1(3C),120.6(d,J＝8.0Hz,2C),115.6(d,J＝22.6Hz,2C),102.1,80.6,62.7,59.8,57.0,50.9,15.2,14.1,13.9；HRMS(ESI-TOF)calcd for C 32 H 31 FN 3 O 5 [M+H] + 556.2248,found 556.2249.
the hydrogen nuclear magnetic resonance spectrum of IV-13 is shown in FIG. 25, and the carbon nuclear magnetic resonance spectrum is shown in FIG. 26.
Example 16:
taking as an example the preparation of diethyl 1-benzyl-8- (4-chlorophenyl) -6-methyl-9-oxo-4-phenyl-1, 7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-14) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: starting material I was 4-benzylidene-3-methyl-1- (4-chlorophenyl) -1H-pyrazol-5 (4H) -one (148.4 mg,0.5 mmol) to give product IV-14 in 93% yield.
Spectroscopic characterization data for IV-14: 1 H NMR(600MHz,CDCl 3 )δ(ppm)7.66(d,J＝8.7Hz,2H),7.33(d,J＝8.7Hz,2H),7.26–7.16(m,8H),7.11–7.06(m,2H),4.95(s,1H),4.34–4.25(m,2H),4.23(d,J＝14.9Hz,1H),4.12–3.96(m,2H),4.03(d,J＝14.9Hz,1H),1.35(s,3H),1.31(t,J＝7.1Hz,3H),1.04(t,J＝7.0Hz,3H)； 13 CNMR(150MHz,CDCl 3 )δ(ppm)171.2,163.5,162.4,158.6,153.4,136.2,135.9,134.4,130.6,129.3(2C),129.0(2C),128.7(3C),128.6(2C),128.2(3C),120.0(2C),102.4,80.7,62.8,59.9,57.2,51.0,15.3,14.2,14.0；HRMS(ESI-TOF)calcd for C 32 H 31 ClN 3 O 5 [M+H] + 572.1952,found 572.1947.
the hydrogen nuclear magnetic resonance spectrum of IV-14 is shown in FIG. 27, and the carbon nuclear magnetic resonance spectrum is shown in FIG. 28.
Example 17:
taking as an example the preparation of diethyl 1-benzyl-6-methyl-9-oxo-4-phenyl-8- (m-tolyl) -1,7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-15) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: starting material I was 4-benzylidene-3-methyl-1- (3-tolyl) -1H-pyrazol-5 (4H) -one (138.2 mg,0.5 mmol) gave product IV-15 in 82% yield.
Spectroscopic characterization data for IV-15: 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.55–7.49(m,2H),7.28–7.19(m,9H),7.14–7.08(m,2H),7.01(d,J＝7.6Hz,1H),4.98(s,1H),4.33–4.18(m,2H),4.20(d,J＝14.9Hz,1H),4.05(d,J＝14.9Hz,1H),4.12–3.94(m,2H),2.37(s,3H),1.32(s,3H),1.28(t,J＝7.1Hz,3H),1.04(t,J＝7.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm)171.0,163.4,162.4,158.1,153.4,138.7,137.4,135.8,134.4,129.1(2C),128.7,128.5(2C),128.4(3C),128.1(2C),128.0,126.3,119.4,116.0,102.1,80.7,62.6,59.7,56.8,50.7,21.5,15.1,14.1,13.8；HRMS(ESI-TOF)calcd for C 33 H 34 N 3 O 5 [M+H] + 552.2498,found 552.2502.
IV-15 nuclear magnetic resonance hydrogen spectrum is shown in figure 29, and nuclear magnetic resonance carbon spectrum is shown in figure 30.
Example 18:
take as an example the preparation of diethyl 1- (4-methoxybenzyl) -6-methyl-9-oxo-4, 8-diphenyl-1, 7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-16) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: starting material II was 4-methoxybenzylamine (102.9 mg,0.75 mmol) and the eluent was ethyl acetate/petroleum ether (v/v=1:5) to give product IV-16 in 81% yield.
Spectroscopic characterization data for IV-16: 1 H NMR(500MHz,CDCl 3 )δ(ppm)7.69(d,J＝7.9Hz,2H),7.38(t,J＝8.0Hz,2H),7.25–7.18(m,4H),7.13–7.08(m,4H),6.68(d,J＝8.6Hz,2H),4.95(s,1H),4.39–4.29(m,2H),4.20(d,J＝14.6Hz,1H),4.12–4.05(m,1H),4.03–3.95(m,1H),3.99(d,J＝14.6Hz,1H),3.68(s,3H),1.35(t,J＝7.2Hz,3H),1.34(s,3H),1.04(t,J＝7.1Hz,3H)； 13 C NMR(125MHz,CDCl 3 )δ(ppm)171.3,163.6,162.6,159.9,158.3,153.6,137.6,135.9,130.8(2C),128.9(2C),128.6(2C),128.2(2C),128.1,126.1,125.4,118.9(2C),113.9(2C),101.8,80.4,62.8,59.8,57.0,55.3,50.4,15.3,14.2,14.0；HRMS(ESI-TOF)calcd for C 33 H 34 N 3 O 6 [M+H] + 568.2448,found 568.2453.
the hydrogen nuclear magnetic resonance spectrum of IV-16 is shown in FIG. 31, and the carbon nuclear magnetic resonance spectrum is shown in FIG. 32.
Example 19:
take as an example the preparation of diethyl 1- (4-chlorobenzyl) -6-methyl-9-oxo-4, 8-diphenyl-1, 7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-17) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: starting material II was 4-chlorobenzylamine (106.2 mg,0.75 mmol) and the eluent ethyl acetate/petroleum ether (v/v=1:5) to give product IV-17 in 93% yield.
Spectroscopic characterization data for IV-17: 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.69(d,J＝8.0Hz,2H),7.39(t,J＝7.9Hz,2H),7.26–7.16(m,8H),7.12–7.07(m,2H),4.98(s,1H),4.34–4.21(m,2H),4.21(d,J＝15.1Hz,1H),4.13–3.94(m,2H),3.96(d,J＝15.1Hz,1H),1.39(s,3H),1.31(t,J＝7.2Hz,3H),1.04(t,J＝7.1Hz,3H)； 13 CNMR(100MHz,CDCl 3 )δ(ppm)171.1,163.4,162.4,158.0,152.9,137.4,135.6,134.5,133.0,130.5(2C),129.0(2C),128.7(2C),128.6(2C),128.12,128.07(2C),125.6,118.8(2C),102.5,80.7,62.8,59.9,56.9,50.1,15.2,14.2,13.9；HRMS(ESI-TOF)calcd for C 32 H 31 ClN 3 O 5 [M+H] + 572.1952,found 572.1950.
IV-17 nuclear magnetic resonance hydrogen spectrum is shown in figure 33, and nuclear magnetic resonance carbon spectrum is shown in figure 34.
Example 20:
take as an example the preparation of diethyl 1- (3-fluorobenzyl) -6-methyl-9-oxo-4, 8-diphenyl-1, 7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-18) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: starting material II was 3-fluorobenzylamine (93.9 mg,0.75 mmol) to give product IV-18 in 84% yield.
Spectroscopic characterization data for IV-18: 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.73(d,J＝8.1Hz,2H),7.39(t,J＝7.9Hz,2H),7.28–7.09(m,7H),7.05–6.98(m,2H),6.92(t,J＝8.3Hz,1H),5.00(s,1H),4.34–4.20(m,2H),4.20(d,J＝15.2Hz,1H),4.13–3.95(m,2H),4.01(d,J＝15.2Hz,1H),1.38(s,3H),1.29(t,J＝7.1Hz,3H),1.04(t,J＝7.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm)171.1,163.4,162.7(d,J＝247.3Hz),162.3,158.1,152.9,137.4,137.3(d,J＝7.0Hz),135.7,130.1(d,J＝8.1Hz),129.0(2C),128.6(2C),128.14,128.10(2C),125.6,124.6(d,J＝2.8Hz),118.8(2C),115.9(d,J＝22.0Hz),115.5(d,J＝21.1Hz),102.8,80.8,62.8,59.9,56.9,50.2,15.2,14.2,13.9；HRMS(ESI-TOF)calcd for C 32 H 31 FN 3 O 5 [M+H] + 556.2248,found 556.2243.
IV-18 nuclear magnetic resonance hydrogen spectrum is shown in figure 35, and nuclear magnetic resonance carbon spectrum is shown in figure 36.
Example 21:
taking as an example the preparation of diethyl 1-propyl-6-methyl-9-oxo-4, 8-diphenyl-1, 7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-19) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: starting material II was propylamine (59.1 mg,1.0 mmol) and the eluent was ethyl acetate/petroleum ether (v/v=1:8) to give product IV-19 in 90% yield.
Spectroscopic characterization data for IV-19: 1 H NMR(500MHz,CDCl 3 )δ(ppm)7.87(d,J＝8.0Hz,2H),7.43(t,J＝7.8Hz,2H),7.29–7.21(m,4H),7.15–7.08(m,2H),4.96(s,1H),4.53–4.40(m,2H),4.14–4.04(m,1H),4.03–3.94(m,1H),3.09–2.98(m,1H),2.81–2.70(m,1H),1.56(s,3H),1.50–1.39(m,5H),1.04(t,J＝7.1Hz,3H),0.81(t,J＝7.3Hz,3H)； 13 C NMR(125MHz,CDCl 3 )δ(ppm)171.9,163.6,162.5,158.7,154.0,137.7,135.9,129.1(2C),128.6(2C),128.2(2C),128.1,125.6,118.9(2C),100.8,81.1,62.7,59.7,57.1,48.8,23.0,15.3,14.2,14.1,11.3；HRMS(ESI-TOF)calcd for C 28 H 32 N 3 O 5 [M+H] + 490.2342,found490.2350.
the hydrogen nuclear magnetic resonance spectrum of IV-19 is shown in FIG. 37, and the carbon nuclear magnetic resonance spectrum is shown in FIG. 38.
Example 22:
taking as an example the preparation of diethyl 1-butyl-6-methyl-9-oxo-4, 8-diphenyl-1, 7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-20) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: raw material II was n-butylamine (73.1 mg,1.0 mmol) and ethyl acetate/petroleum ether (v/v=1:8) as eluent, giving product IV-20 in 88% yield.
Spectroscopic characterization data for IV-20: 1 H NMR(500MHz,CDCl 3 )δ(ppm)7.87(d,J＝7.9Hz,2H),7.43(t,J＝7.9Hz,2H),7.27–7.21(m,4H),7.14–7.09(m,2H),4.96(s,1H),4.52–4.41(m,2H),4.12–4.05(m,1H),4.02–3.95(m,1H),3.12–3.04(m,1H),2.82–2.74(m,1H),1.57(s,3H),1.44(t,J＝7.2Hz,3H),1.46–1.37(m,2H),1.29–1.16(m,2H),1.04(t,J＝7.1Hz,3H),0.81(t,J＝7.3Hz,3H)； 13 C NMR(125MHz,CDCl 3 )δ(ppm)171.9,163.6,162.5,158.7,154.0,137.7,135.9,129.1(2C),128.6(2C),128.1(2C),128.0,125.6,118.9(2C),100.8,81.1,62.7,59.7,57.1,46.8,31.6,19.9,15.3,14.2,14.1,13.6；HRMS(ESI-TOF)calcd for C 29 H 34 N 3 O 5 [M+H] + 504.2498,found 504.2496.
the hydrogen nuclear magnetic resonance spectrum of IV-20 is shown in FIG. 39, and the carbon nuclear magnetic resonance spectrum is shown in FIG. 40.
Example 23:
taking as an example the preparation of diethyl 1-hexyl-6-methyl-9-oxo-4, 8-diphenyl-1, 7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-21) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: raw material II was n-hexylamine (101.2 mg,1.0 mmol) and ethyl acetate/petroleum ether (v/v=1:8) as eluent to give product IV-21 in 87% yield.
Spectroscopic characterization data for IV-21: 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.87(d,J＝8.2Hz,2H),7.42(t,J＝7.8Hz,2H),7.29–7.20(m,4H),7.15–7.08(m,2H),4.96(s,1H),4.52–4.40(m,2H),4.13–3.94(m,2H),3.12–3.03(m,1H),2.82–2.73(m,1H),1.57(s,3H),1.44(t,J＝7.1Hz,3H),1.47–1.37(m,2H),1.29–1.11(m,6H),1.04(t,J＝7.1Hz,3H),0.81(t,J＝6.9Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm)171.9,163.6,162.5,158.7,153.9,137.7,135.9,129.0(2C),128.5(2C),128.1(2C),128.0,125.6,118.8(2C),100.7,81.1,62.7,59.7,57.0,47.0,31.2,29.5,26.3,22.4,15.2,14.2,14.1,13.9；HRMS(ESI-TOF)calcd for C 31 H 38 N 3 O 5 [M+H] + 532.2811,found532.2804.
the hydrogen nuclear magnetic resonance spectrum of IV-21 is shown in FIG. 41, and the carbon nuclear magnetic resonance spectrum is shown in FIG. 42.
Example 24:
taking as an example the preparation of diethyl 1-phenethyl-6-methyl-9-oxo-4, 8-diphenyl-1, 7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-22) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: starting material II was 2-phenylethylamine (90.9 mg,0.75 mmol) and the eluent was ethyl acetate/petroleum ether (v/v=1:7) to give product IV-22 in 85% yield.
Spectral structure of IV-22Characterization data: 1 H NMR(500MHz,CDCl 3 )δ(ppm)7.89(d,J＝8.0Hz,2H),7.43(t,J＝7.9Hz,2H),7.28–7.19(m,6H),7.19–7.10(m,3H),7.04(d,J＝7.3Hz,2H),4.97(s,1H),4.51–4.40(m,2H),4.12–3.96(m,2H),3.28–3.21(m,1H),3.05–2.98(m,1H),2.84–2.72(m,2H),1.44(t,J＝7.2Hz,3H),1.42(s,3H),1.05(t,J＝7.1Hz,3H)； 13 C NMR(125MHz,CDCl 3 )δ(ppm)171.8,163.5,162.5,158.7,153.2,137.63,137.62,135.9,129.1(2C),128.74(2C),128.73(2C),128.6(2C),128.13(2C),128.10,126.8,125.7,118.9(2C),101.8,81.2,62.9,59.8,56.9,48.7,36.3,15.0,14.2,14.1；HRMS(ESI-TOF)calcd for C 33 H 34 N 3 O 5 [M+H] + 552.2498,found 552.2508.
the hydrogen nuclear magnetic resonance spectrum of IV-22 is shown in FIG. 43, and the carbon nuclear magnetic resonance spectrum is shown in FIG. 44.
Example 25:
taking as an example the preparation of dimethyl 1-benzyl-6-methyl-9-oxo-4, 8-diphenyl-1, 7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-23) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: raw material III is dimethyl butynedioate (106.6 mg,0.75 mmol), and the eluent is ethyl acetate/petroleum ether (v/v=1:7), to obtain product IV-23 with a yield of 88%.
Spectroscopic characterization data for IV-23: 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.71(d,J＝7.9Hz,2H),7.38(t,J＝7.9Hz,2H),7.27–7.17(m,9H),7.12–7.07(m,2H),4.95(s,1H),4.18(d,J＝14.8Hz,1H),4.06(d,J＝14.8Hz,1H),3.82(s,3H),3.55(s,3H),1.27(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm)170.9,164.0,162.8,158.2,153.7,137.5,135.8,134.2,129.2(2C),128.9(2C),128.7(2C),128.6,128.5(2C),128.2,128.1(2C),125.5,118.8(2C),102.2,80.7,56.6,53.2,51.2,50.9,15.1；HRMS(ESI-TOF)calcd for C 30 H 28 N 3 O 5 [M+H] + 510.2029,found510.2044.
the hydrogen nuclear magnetic resonance spectrum of IV-23 is shown in FIG. 45, and the carbon nuclear magnetic resonance spectrum is shown in FIG. 46.
Example 26:
taking as an example the preparation of di-tert-butyl 1-benzyl-6-methyl-9-oxo-4, 8-diphenyl-1, 7, 8-triazaspiro [4.4] non-2, 6-diene-2, 3-dicarboxylate (IV-24) of the formula:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: starting material III was di-tert-butyl butynedioate (169.7 mg,0.75 mmol) and the eluent ethyl acetate/petroleum ether (v/v=1:10) gave product IV-24 in 62% yield.
Spectroscopic characterization data for IV-24: 1 H NMR(500MHz,CDCl 3 )δ(ppm)7.65(d,J＝8.1Hz,2H),7.37(t,J＝7.8Hz,2H),7.28–7.17(m,9H),7.12–7.07(m,2H),4.96(s,1H),4.36(d,J＝15.2Hz,1H),3.99(d,J＝15.2Hz,1H),1.50(s,9H),1.45(s,3H),1.19(s,9H)； 13 C NMR(125MHz,CDCl 3 )δ(ppm)171.6,163.1,161.4,158.7,152.8,137.6,136.5,135.2,129.0(2C),128.9(2C),128.5(2C),128.39,128.36(2C),128.3(2C),127.8,125.5,119.1(2C),103.8,84.4,80.9,79.8,58.0,50.5,28.0(3C),27.9(3C),15.3；HRMS(ESI-TOF)calcd for C 36 H 40 N 3 O 5 [M+H] + 594.2968,found 594.2980.
the hydrogen nuclear magnetic resonance spectrum of IV-24 is shown in FIG. 47, and the carbon nuclear magnetic resonance spectrum is shown in FIG. 48.
The single crystal diffraction pattern of the product IV-24 is shown in FIG. 49, and the structure is further confirmed by single crystal diffraction analysis as represented by the product IV-24, and the carbonyl group in the pyrazolone skeleton and the phenyl group in the dihydropyrrole skeleton are in trans (hetero-side) in the product structure.
While the embodiments of the present invention have been described in detail with reference to the drawings, the present invention is not limited to the above embodiments, and it will be apparent to those skilled in the art that various equivalent changes and substitutions can be made therein without departing from the principles of the present invention, and such equivalent changes and substitutions should also be considered to be within the scope of the present invention.
Claims (9)
1. A synthesis method of pyrazolone spiro-dihydropyrrole derivatives is characterized in that: under the condition of the existence of an accelerator, an organic solvent and an oxidant, carrying out multicomponent reaction on the compounds shown in the formula I, the formula II and the formula III according to a preset proportion, and purifying to obtain the pyrazolone spiro dihydropyrrole derivative shown in the formula IV:
wherein R is 1 Is any one of phenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethylphenyl, p-nitrophenyl, m-chlorophenyl, m-bromophenyl, naphthyl, 3, 4-dimethylphenyl and 3, 4-dichlorophenyl; r is R 2 Is any one of methyl, ethyl and phenyl; r is R 3 Is any one of phenyl, p-tolyl, p-fluorophenyl, p-chlorophenyl and m-tolyl; r is R 4 Is n-propyl, n-butyl, n-hexyl, benzyl, p-methoxybenzyl, p-chlorobenzyl, m-fluorobenzyl, phenethyl; r is R 5 Is any one of methyl, ethyl and tert-butyl.
2. The synthetic method of pyrazolone spiro dihydropyrrole derivatives according to claim 1, wherein the synthetic method comprises the steps of: the accelerator is N-iodinated succinimide, and the organic solvent is dichloroethane.
3. The synthesis method of pyrazolone spiro dihydropyrrole derivatives according to claim 1 or 2, characterized in that: the ratio of the amounts of the compound shown in the formula I, the compound shown in the formula II, the compound shown in the formula III, the accelerator and the oxidant is 1:1.5-1.8:1.5-1.8:2.0-2.5.
4. The synthetic method of pyrazolone spiro dihydropyrrole derivatives according to claim 1, wherein the synthetic method comprises the steps of: the reaction condition is heating reaction under nitrogen atmosphere, the reaction temperature is 80-110 ℃, and the reaction time is 2-4 h.
5. The synthetic method of pyrazolone spiro dihydropyrrole derivatives according to claim 1, wherein the synthetic method comprises the steps of: the oxidant is sodium sulfate and/or potassium persulfate.
6. The synthetic method of pyrazolone spiro dihydropyrrole derivatives according to claim 1, wherein the synthetic method comprises the steps of: the volume of the organic solvent is 10-15 times of the total mass of the raw materials.
7. The synthetic method of pyrazolone spiro dihydropyrrole derivatives according to claim 1, wherein the synthetic method comprises the steps of: the purification steps comprise washing, extraction, drying, reduced pressure concentration and chromatographic separation.
8. The synthetic method of pyrazolone spiro dihydropyrrole derivatives according to claim 7, wherein: the solution adopted in the washing step is sodium thiosulfate aqueous solution; the extracting agent adopted in the extracting step is ethyl acetate; and the drying step adopts anhydrous sodium sulfate for drying.
9. The synthetic method of pyrazolone spiro dihydropyrrole derivatives according to claim 7 or 8, characterized in that: the chromatographic conditions of the chromatographic separation step are as follows: the silica gel column with 200-300 meshes is prepared from a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:5-10.
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