CN117820230A - Synthesis method of pyrazolone spiro pentene - Google Patents
Synthesis method of pyrazolone spiro pentene Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 10
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical compound O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 title abstract description 11
- YGSMGHRVKGFZPG-UHFFFAOYSA-N spiro[2.2]pent-1-ene Chemical compound C1CC11C=C1 YGSMGHRVKGFZPG-UHFFFAOYSA-N 0.000 title abstract description 6
- -1 pyrazolone spiro-pentene derivative Chemical class 0.000 claims abstract description 61
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 238000001035 drying Methods 0.000 claims abstract description 7
- 238000000926 separation method Methods 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 230000035484 reaction time Effects 0.000 claims abstract description 4
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims abstract 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- 238000000034 method Methods 0.000 claims description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
- 239000003208 petroleum Substances 0.000 claims description 14
- 230000002194 synthesizing effect Effects 0.000 claims description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- 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
- 238000004440 column chromatography Methods 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000013375 chromatographic separation Methods 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000006452 multicomponent reaction Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 3
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract description 2
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- 238000004587 chromatography analysis Methods 0.000 abstract 1
- 238000001816 cooling Methods 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 238000002156 mixing Methods 0.000 abstract 1
- 230000001988 toxicity Effects 0.000 abstract 1
- 231100000419 toxicity Toxicity 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 80
- 238000001228 spectrum Methods 0.000 description 55
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 28
- 229910052799 carbon Inorganic materials 0.000 description 28
- 229910052739 hydrogen Inorganic materials 0.000 description 28
- 239000001257 hydrogen Substances 0.000 description 28
- 238000002360 preparation method Methods 0.000 description 28
- 238000012512 characterization method Methods 0.000 description 14
- 239000003480 eluent Substances 0.000 description 12
- 239000007858 starting material Substances 0.000 description 11
- 230000003595 spectral effect Effects 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 6
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical group IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 5
- 239000013078 crystal Substances 0.000 description 3
- 238000006845 Michael addition reaction Methods 0.000 description 2
- 239000007806 chemical reaction intermediate Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000002243 precursor 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
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical group C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- ZWJMMDQHGRHUCZ-UHFFFAOYSA-N 4-benzylidene-5-methyl-2-phenylpyrazol-3-one Chemical compound CC1=NN(C=2C=CC=CC=2)C(=O)C1=CC1=CC=CC=C1 ZWJMMDQHGRHUCZ-UHFFFAOYSA-N 0.000 description 1
- XBBJQEYIOGWMNL-UHFFFAOYSA-N 5-methyl-4-[(4-methylphenyl)methylidene]-2-phenylpyrazol-3-one Chemical compound CC1=NN(C=2C=CC=CC=2)C(=O)C1=CC1=CC=C(C)C=C1 XBBJQEYIOGWMNL-UHFFFAOYSA-N 0.000 description 1
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 238000004458 analytical method Methods 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
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000004071 biological effect Effects 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
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- RWPJUWHLVMMSQO-UHFFFAOYSA-N ethyl 3-(benzylamino)but-2-enoate Chemical compound CCOC(=O)C=C(C)NCC1=CC=CC=C1 RWPJUWHLVMMSQO-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to the technical field of organic synthesis, in particular to a synthesis method of pyrazolone spiro pentene, which comprises the following steps: mixing alpha, beta-unsaturated pyrazolone I, beta-enamine ester II, N-iodinated succinimide (NIS) and alkali, adding a solvent, and heating for reaction; after the reaction is finished, cooling to room temperature, extracting, drying and concentrating the reaction liquid under reduced pressure, and separating by chromatography to obtain the pyrazolone spiro-pentene derivative III. The raw materials used in the invention are conventional, cheap and easily available, the accelerator N-iodinated succinimide is cheap, safe and nontoxic, the reaction time is short, the reaction selectivity is good, the side reaction is less, and the product yield is high; can effectively solve the problems of difficult or expensive raw material synthesis, high catalyst toxicity, harsh reaction conditions, poor selectivity, complex product separation, low yield and the like of the existing synthesis method of pyrazolone spiro pentene derivatives or analogues thereof.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthesis method of pyrazolone cyclopentene.
Background
Pyrazolone spiropentene or a nitrogen-containing spiro compound of a similar skeleton thereof has been demonstrated to have a wide range of biological activities, such as antitumor, antidiabetic, antibacterial, antitubercular, antiinflammatory, phosphodiesterase inhibitor and the like, which has great potential in the biomedical field, and furthermore, many unnatural synthetic pyrazolone spirocyclic derivatives are also used in a large number of applications in dyes, agrochemicals, analysis and pharmaceutical industries.
In view of this, intensive studies have been conducted on the synthesis of pyrazolone spiro nitrogen-containing heterocyclic skeleton of pyrazolone spiro pentene derivative or analogue thereof, and the synthesis methods developed so far mainly include noble metal-catalyzed and organically-catalyzed pyrazolone-based serial cycloaddition reaction.
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 pyrazolone spiro pentene according to the present invention.
Disclosure of Invention
The invention aims to provide a synthesis method of pyrazolone cyclopentene, 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 pyrazolone cyclopentene.
The technical scheme for solving the problems is as follows:
a synthesis method of pyrazolone spiro pentene derivative is characterized in that: and (3) carrying out multicomponent reaction on the chemical shown in the formula I and the chemical shown in the formula II according to a certain proportion in the presence of an accelerator, an organic solvent and alkali, and purifying to obtain the pyrazolone spiro pentene derivative III shown in the formula III.
The reaction general formula of the invention is:
wherein R is 1 Is any one of phenyl, p-tolyl and p-trifluoromethylphenyl; r is R 2 Is any one of methyl, ethyl and phenyl; r is R 3 Is any one of phenyl, p-tolyl and p-fluorophenyl; r is R 4 Is any one of isopropyl, butyl, benzyl, p-methoxybenzyl, p-chlorobenzyl and o-chlorobenzyl; r is R 5 Is any one of methyl, ethyl and isobutyl.
Preferably, the accelerator is N-iodosuccinimide.
Preferably, the alkali is one or more of dipotassium hydrogen phosphate, potassium carbonate and sodium carbonate, and the solvent is one or two of dimethyl sulfoxide and methanol.
Preferably, the ratio of the amounts of the chemical of formula I, the chemical of formula II, the promoter and the base is: 1:1.5-1.8:1-1.2:1-1.2.
Preferably, the volume of the solvent is 10-15 times of the total mass of the raw materials.
Preferably, the reaction temperature is 70-120 ℃ and the reaction time is 1-3 h.
Preferably, the purification steps are extraction, drying, concentration under reduced pressure and column chromatography separation.
Preferably, the extraction agent adopted in the extraction step is ethyl acetate; the drying step is drying using anhydrous magnesium sulfate.
Preferably, the chromatographic conditions of the column 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 When ethyl is adopted, firstly, the alpha, beta-unsaturated pyrazolone I and beta-enamine ester II undergo Michael addition reaction to form an adduct intermediate A, then the intermediate A and NIS react to obtain an iodinated intermediate B, the intermediate B loses protons under the action of alkali to form a carbanion intermediate C, and the intermediate C loses iodine anions to form a final pyrazolone spiropentene product III through intramolecular nucleophilic substitution reaction. 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 separation and purification operation is simple and convenient, the reaction efficiency is greatly improved, and the cost is reduced; 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 III-1;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of III-1;
FIG. 3 is a single crystal diffraction diagram of III-1;
FIG. 4 is a nuclear magnetic resonance hydrogen spectrum of III-2;
FIG. 5 is a nuclear magnetic resonance carbon spectrum of III-2;
FIG. 6 is a nuclear magnetic resonance hydrogen spectrum of III-3;
FIG. 7 is a nuclear magnetic resonance carbon spectrum of III-3;
FIG. 8 is a nuclear magnetic resonance hydrogen spectrum of III-4;
FIG. 9 is a nuclear magnetic resonance carbon spectrum of III-4;
FIG. 10 is a hydrogen nuclear magnetic resonance spectrum of III-5;
FIG. 11 is a nuclear magnetic resonance carbon spectrum of III-5;
FIG. 12 is a nuclear magnetic resonance hydrogen spectrum of III-6;
FIG. 13 is a nuclear magnetic resonance carbon spectrum of III-6;
FIG. 14 is a nuclear magnetic resonance hydrogen spectrum of III-7;
FIG. 15 is a nuclear magnetic resonance carbon spectrum of III-7;
FIG. 16 is a nuclear magnetic resonance hydrogen spectrum of III-8;
FIG. 17 is a nuclear magnetic resonance carbon spectrum of III-8;
FIG. 18 is a nuclear magnetic resonance hydrogen spectrum of III-9;
FIG. 19 is a nuclear magnetic resonance carbon spectrum of III-9;
FIG. 20 is a nuclear magnetic resonance hydrogen spectrum of III-10;
FIG. 21 is a nuclear magnetic resonance carbon spectrum of III-10;
FIG. 22 is a nuclear magnetic resonance hydrogen spectrum of III-11;
FIG. 23 is a nuclear magnetic resonance carbon spectrum of III-11;
FIG. 24 is a nuclear magnetic resonance hydrogen spectrum of III-12;
FIG. 25 is a nuclear magnetic resonance carbon spectrum of III-12;
FIG. 26 is a nuclear magnetic resonance hydrogen spectrum of III-13;
FIG. 27 is a nuclear magnetic resonance carbon spectrum of III-13;
FIG. 28 is a nuclear magnetic resonance hydrogen spectrum of III-14;
FIG. 29 is a nuclear magnetic resonance carbon spectrum of III-14.
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 ethyl 8- (benzylamino) -1-methyl-4-oxo-3, 6-diphenyl-2, 3-diazaspiro [4.4] non-1, 7-diene-7-carboxylate (III-1) of the formula:
the preparation method comprises the following steps: to a 25mL reaction tube was added 4-benzylidene-3-methyl-1-phenyl-1H-pyrazol-5 (4H) -one I (262.0 mg,1.0 mmol), 3- (benzylamino) but-2-enoic acid ethyl ester (329.0 mg,1.5 mmol), NIS (225.0 mg,1.0 mmol), K 2 HPO 4 (174.3 mg,1.0 mmol) and dimethyl sulfoxide (8 mL) were stirred at 80℃for 1 hour, after the completion of the reaction, the organic layers were combined, dried over anhydrous magnesium sulfate and filtered, and a certain amount of silica gel was added to the organic layers, followed by concentration to powder by rotary evaporation under reduced pressure. Column chromatography purification was then performed with an eluent of ethyl acetate/petroleum ether (v/v=1:6) to give the product III-1 in 90% yield.
Spectral structure characterization data for III-1: 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.13(s,1H),7.51(d,J＝8.8Hz,2H),7.37(t,J＝7.3Hz,2H),7.34-7.14(m,8H),7.07(t,J＝7.4Hz,3H),4.51(dd,J＝15.8,6.7Hz,1H),4.44(dd,J＝15.8,6.7Hz,1H),4.32(s,1H),4.08-3.98(m,1H),3.97-3.87(m,1H),3.15(d,J＝17.2Hz,1H),2.63(d,J＝17.2Hz,1H),2.09(s,3H),0.92(t,J＝7.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm)172.7,167.5,163.1,161.9,139.4,138.6,137.8,129.1(2C),128.7(2C),128.0(2C),127.9(2C),127.8,127.3,126.8(2C),124.8,118.9(2C),94.5,59.8,58.9,55.9,48.5,36.3,14.3,13.8；HRMS(ESI-TOF)calcd for C 30 H 30 N 3 O 3 [M+H] + 480.2287,found480.2263.
the nuclear magnetic resonance hydrogen spectrum of III-1 is shown in figure 1, and the nuclear magnetic resonance carbon spectrum is shown in figure 2.
FIG. 3 is a single crystal diffraction pattern of the product III-1, and the structure was further confirmed by single crystal diffraction analysis, as represented by the product III-1, with the carbonyl group in the pyrazolone skeleton and the phenyl group in the dihydropyrrole skeleton in cis (on the same side) in the product structure.
Example 2:
the procedure was as in example 1, except for the following technical scheme: k for alkali 2 CO 3 Instead of K 2 HPO 4 The product III-1 was obtained in 78% yield.
Example 3:
except for the following technical schemeExample 1 is the same: na for alkali 2 CO 3 Instead of K 2 HPO 4 The product III-1 was obtained in 62% yield.
Example 4:
the procedure was as in example 1, except for the following technical scheme: the solvent was replaced with methanol to give the product III-1 in 68% yield.
Example 5:
the procedure was as in example 1, except for the following technical scheme: the reaction temperature was 100℃to give the product III-1 in 82% yield.
Example 6:
the procedure was as in example 1, except for the following technical scheme: the reaction temperature was 120℃to give the product III-1 in 65% yield.
Example 7:
taking as an example the preparation of ethyl 8- (benzylamino) -1-methyl-4-oxo-3-phenyl-6- (p-tolyl) -2, 3-diazaspiro [4.4] non-1, 7-diene-7-carboxylate (III-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-methylbenzylidene) -3-methyl-1-phenyl-1H-pyrazol-5 (4H) -one (276.3 mg,1.0 mmol) to give product III-2 in 88% yield.
Spectroscopic characterization data for III-2: 1 HNMR(600MHz,CDCl 3 )δ(ppm)8.11(s,1H),7.54(d,J＝7.9Hz,2H),7.38(t,J＝7.6Hz,2H),7.33-7.24(m,5H),7.08(t,J＝7.3Hz,1H),7.02(d,J＝7.5Hz,2H),6.94(s,2H),4.51(dd,J＝15.8,6.6Hz,1H),4.45(dd,J＝15.8,6.6Hz,1H),4.28(s,1H),4.06-3.91(m,2H),3.15(d,J＝17.3Hz,1H),2.62(d,J＝17.3Hz,1H),2.28(s,3H),2.07(s,3H),0.96(t,J＝7.0Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ(ppm)172.7,167.6,163.2,161.8,138.7,138.0,136.7,136.3,129.1(2C),128.7(2C),128.7(2C),127.9(2C),127.9,126.8(2C),124.8,119.0(2C),95.0,59.9,59.0,55.6,48.5,36.4,21.3,14.4,13.9；HRMS(ESI-TOF)calcd for C 31 H 32 N 3 O 3 [M+H] + 494.2444,found494.2452.
the nuclear magnetic resonance hydrogen spectrum of III-2 is shown in figure 4, and the nuclear magnetic resonance carbon spectrum is shown in figure 5.
Example 8:
taking as an example the preparation of ethyl 8- (benzylamino) -1-methyl-4-oxo-3-phenyl-6- (4- (trifluoromethyl) phenyl) -2, 3-diazaspiro [4.4] non-1, 7-diene-7-carboxylate (III-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-trifluoromethyl-benzylidene) -3-methyl-1-phenyl-1H-pyrazol-5 (4H) -one (330.3 mg,1.0 mmol) and the eluent ethyl acetate/petroleum ether (v/v=1:7) gave product III-3 in 91% yield.
Spectroscopic characterization data for III-3: 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.15(s,1H),7.47(t,J＝7.2Hz,4H),7.38(t,J＝7.3Hz,2H),7.33-7.23(m,5H),7.18(d,J＝7.2Hz,2H),7.09(t,J＝7.4Hz,1H),4.52(dd,J＝15.8,6.6Hz,1H),4.41(dd,J＝15.8,6.6Hz,1H),4.35(s,1H),4.08-3.85(m,2H),3.15(d,J＝17.3Hz,1H),2.68(d,J＝17.3Hz,1H),2.10(s,3H),0.91(t,J＝7.1Hz,3H)； 13 CNMR(100MHz,CDCl 3 )δ(ppm)172.4,167.2,162.7,162.1,143.7,138.4,137.6,129.4(q,J＝32.3Hz),129.1(2C),128.8(2C),128.5(2C),127.9,126.8(2C),125.1,124.9(q,J＝3.7Hz,2C),124.4(q,J＝272.0Hz),118.9(2C),94.0,59.5,59.1,55.4,48.5,36.5,14.2,13.8；HRMS(ESI-TOF)calcd for C 31 H 29 F 3 N 3 O 3 [M+H] + 548.2161,found 548.2155.
the nuclear magnetic resonance hydrogen spectrum of III-3 is shown in figure 6, and the nuclear magnetic resonance carbon spectrum is shown in figure 7.
Example 9:
taking as an example the preparation of ethyl 8- (benzylamino) -1-ethyl-4-oxo-3, 6-diphenyl-2, 3-diazaspiro [4.4] non-1, 7-diene-7-carboxylate (III-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-benzylidene-3-ethyl-1-phenyl-1H-pyrazol-5 (4H) -one (276.3 mg,1.0 mmol) and the eluent was ethyl acetate/petroleum ether (v/v=1:5) to give product III-4 in 92% yield.
Spectroscopic characterization data for III-4: 1 H NMR(600MHz,CDCl 3 )δ(ppm)8.13(s,1H),7.55(d,J＝7.7Hz,2H),7.38(t,J＝7.3Hz,2H),7.34-7.15(m,8H),7.11-6.97(m,3H),4.51(dd,J＝15.8,6.5Hz,1H),4.45(dd,J＝15.8,6.5Hz,1H),4.31(s,1H),4.07-3.99(m,1H),3.95-3.88(m,1H),3.16(d,J＝17.3Hz,1H),2.66(d,J＝17.3Hz,1H),2.61-2.52(m,1H),2.30-2.21(m,1H),1.56(s,1H),1.28(t,J＝7.3Hz,3H),0.93(t,J＝7.0Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ(ppm)172.9,167.6,166.9,162.1,139.6,138.6,138.1,129.1(2C),128.7(2C),128.1(2C),127.9,127.9(2C),127.3,126.9(2C),124.7,118.9(2C),94.8,59.9,59.0,56.2,48.6,36.6,21.2,14.3,9.6；HRMS(ESI-TOF)calcd for C 31 H 32 N 3 O 3 [M+H] + 494.2444,,found 494.2447.
the nuclear magnetic resonance hydrogen spectrum of III-4 is shown in figure 8, and the nuclear magnetic resonance carbon spectrum is shown in figure 9.
Example 10:
taking as an example the preparation of ethyl 8- (benzylamino) -4-oxo-1, 3, 6-triphenyl-2, 3-diazaspiro [4.4] non-1, 7-diene-7-carboxylate (III-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-benzylidene-3-phenyl-1H-pyrazol-5 (4H) -one (324.4 mg,1.0 mmol) and the eluent was ethyl acetate/petroleum ether (v/v=1:8), giving product III-5 in 95% yield.
Spectroscopic characterization data for III-5: 1 HNMR(400MHz,CDCl 3 )δ(ppm)8.23(s,1H),7.92-7.85(m,2H),7.60-7.40(m,4H),7.40-7.29(m,6H),7.29-7.20(m,4H),7.20-7.03(m,4H),4.91(s,1H),4.52(dd,J＝15.7,6.3Hz,1H),4.45(dd,J＝15.7,6.3Hz,1H),4.14-4.02(m,1H),3.90-3.78(m,1H),3.32(d,J＝17.7Hz,1H),3.17(d,J＝17.7Hz,1H),0.83(t,J＝7.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm)174.7,167.8,162.4,160.3,139.6,138.4,137.2,130.6,129.8,129.3(2C),129.0(2C),128.7(2C),128.0(2C),127.8,127.6(2C),127.1,126.9(2C),126.2(2C),125.3,119.7(2C),93.8,59.0,58.9,57.9,48.4,38.9,14.1；HRMS(ESI-TOF)calcd for C 35 H 32 N 3 O 3 [M+H] + 542.2444,found 542.2439.
the nuclear magnetic resonance hydrogen spectrum of III-5 is shown in figure 10, and the nuclear magnetic resonance carbon spectrum is shown in figure 11.
Example 11:
taking as an example the preparation of ethyl 8- (benzylamino) -1-methyl-4-oxo-6-phenyl-3- (p-tolyl) -2, 3-diazaspiro [4.4] non-1, 7-diene-7-carboxylate (III-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-benzylidene-3-methyl-1- (4-tolyl) -1H-pyrazol-5 (4H) -one (276.3 mg,1.0 mmol) and the eluent was ethyl acetate/petroleum ether (v/v=1:7) to give product III-6 in 89% yield.
Spectroscopic characterization data for III-6: 1 H NMR(600MHz,CDCl 3 )δ(ppm)8.13(s,1H),7.38(d,J＝7.9Hz,4H),7.34-7.28(m,3H),7.27-7.16(m,3H),7.06(d,J＝7.7Hz,4H),4.52(dd,J＝15.7,6.1Hz,1H),4.46(dd,J＝15.7,6.1Hz,1H),4.31(s,1H),4.07-3.99(m,1H),3.97-3.89(m,1H),3.16(d,J＝17.3Hz,1H),2.64(d,J＝17.3Hz,1H),2.28(s,3H),2.09(s,3H),0.93(t,J＝6.8Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ(ppm)172.6,167.6,162.9,162.0,139.5,138.6,135.5,134.5,129.3,129.3,129.1,129.1,128.1(2C),127.9(2C),127.9,127.3,126.9,126.8,119.0,119.0,94.7,59.8,59.0,55.9,48.5,36.4,21.0,14.3,13.8；HRMS(ESI-TOF)calcd for C 31 H 32 N 3 O 3 [M+H] + 494.2444,found 494.2456.
the nuclear magnetic resonance hydrogen spectrum of III-6 is shown in figure 12, and the nuclear magnetic resonance carbon spectrum is shown in figure 13.
Example 12:
taking as an example the preparation of ethyl 8- (benzylamino) -3- (4-fluorophenyl) -1-methyl-4-oxo-6-phenyl-2, 3-diazabicyclo [4.4] non-1, 7-diene-7-carboxylate (III-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-benzylidene-3-methyl-1- (4-fluorophenyl) -1H-pyrazol-5 (4H) -one (280.3 mg,1.0 mmol) and the eluent was ethyl acetate/petroleum ether (v/v=1:7) to give product III-7 in 91% yield.
Spectroscopic characterization data for III-7: 1 H NMR(600MHz,CDCl 3 )δ(ppm)8.13(s,1H),7.45(dd,J＝8.6,4.9Hz,2H),7.38(t,J＝7.7Hz,2H),7.35-7.27(m,3H),7.25-7.15(m,3H),7.06(s,2H),6.94(t,J＝8.5Hz,2H),4.52(dd,J＝15.8,6.5Hz,1H),4.46(dd,J＝15.8,6.5Hz,1H),4.31(s,1H),4.07-4.00(m,1H),3.96-3.89(m,1H),3.15(d,J＝17.3Hz,1H),2.65(d,J＝17.3Hz,1H),2.09(s,3H),0.92(t,J＝7.0Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ(ppm)172.7,167.5,163.2,161.9,159.8(d,J＝244.1Hz),139.4,138.6,134.0(d,J＝2.7Hz),129.1(2C),128.0(2C),127.9(2C),127.9,127.4,126.8(2C),120.7(d,J＝7.5Hz,2C),115.4(d,J＝22.6Hz,2C),94.6,59.8,59.0,56.0,48.5,36.3,14.3,13.8；HRMS(ESI-TOF)calcd for C 30 H 29 FN 3 O 3 [M+H] + 498.2193,found 498.2204.
the nuclear magnetic resonance hydrogen spectrum of III-7 is shown in figure 14, and the nuclear magnetic resonance carbon spectrum is shown in figure 15.
Example 13:
taking the preparation of ethyl 8- (isopropylamino) -1-methyl-4-oxo-3, 6-diphenyl-2, 3-diazaspiro [4.4] non-1-, 7-diene-7-carboxylate (III-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 II was 3- (isopropylamino) -2-methacrylic acid ethyl ester (256.8 mg,1.5 mmol) and the eluent was ethyl acetate/petroleum ether (v/v=1:9) to give product III-8 in 94% yield.
Spectral structure characterization data for III-8: 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.64(d,J＝10.1Hz,1H),7.53(d,J＝8.0Hz,2H),7.27(t,J＝7.9Hz,2H),7.24-7.13(m,3H),7.12-7.00(m,3H),4.31(s,1H),4.05-3.96(m,1H),3.95-3.85(m,1H),3.67-3.55(m,1H),3.18(d,J＝17.0Hz,1H),2.72(d,J＝17.0Hz,1H),2.21(s,3H),1.32(d,J＝6.4Hz,3H),1.28(d,J＝6.4Hz,3H),0.91(t,J＝7.0Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm)172.8,167.6,163.0,161.0,139.5,137.8,128.7(2C),128.0(2C),127.8(2C),127.2,124.8,118.9(2C),92.9,60.0,58.7,55.6,46.7,36.1,24.7,24.4,14.3,14.0；HRMS(ESI-TOF)calcd for C 26 H 30 N 3 O 3 [M+H] + 432.2287,found432.2275.
the nuclear magnetic resonance hydrogen spectrum of III-8 is shown in figure 16, and the nuclear magnetic resonance carbon spectrum is shown in figure 17.
Example 14:
taking as an example the preparation of ethyl 8- ((4-methoxybenzyl) amino) -1-methyl-4-oxo-3, 6-diphenyl-2, 3-diazaspiro [4.4] non-1, 7-diene-7-carboxylate (III-9) 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- (4-methoxybenzylamino) -2-methacrylic acid ethyl ester (374.0 mg,1.5 mmol) and the eluent was ethyl acetate/petroleum ether (v/v=1:5) to give product III-9 in 87% yield.
Spectral structure characterization data for III-9: 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.06(s,1H),7.51(d,J＝8.2Hz,2H),7.32-7.12(m,7H),7.07(t,J＝7.5Hz,3H),6.90(d,J＝8.6Hz,2H),4.43(dd,J＝15.4,6.3Hz,1H),4.37(dd,J＝15.4,6.3Hz,1H),4.31(s,1H),4.08-3.97(m,1H),3.96-3.85(m,1H),3.79(s,3H),3.15(d,J＝17.2Hz,1H),2.65(d,J＝17.2Hz,1H),2.10(s,3H),0.92(t,J＝7.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm)172.7,167.5,163.1,161.9,159.2,139.4,137.8,130.5,128.7(2C),128.1(2C),128.0(2C),127.9(2C),127.2,124.8,118.9(2C),114.4(2C),94.3,59.8,58.9,55.8,55.4,48.0,36.3,14.2,13.9；HRMS(ESI-TOF)calcd for C 31 H 32 N 3 O 4 [M+H] + 510.2393,found 510.2408.
the nuclear magnetic resonance hydrogen spectrum of III-9 is shown in figure 18, and the nuclear magnetic resonance carbon spectrum is shown in figure 19.
Example 15:
taking as an example the preparation of ethyl 8- ((4-chlorobenzyl) amino) -1-methyl-4-oxo-3, 6-diphenyl-2, 3-diazaspiro [4.4] non-1, 7-diene-7-carboxylate (III-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 II was 3- (4-chlorobenzylamino) -2-methacrylic acid ethyl ester (380.6 mg,1.5 mmol) and the eluent ethyl acetate/petroleum ether (v/v=1:5) to give product III-10 in 86% yield.
Spectral structure characterization data for III-10: 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.10(s,1H),7.49(d,J＝8.2Hz,2H),7.35(d,J＝8.4Hz,2H),7.30-7.13(m,7H),7.12-6.98(m,3H),4.47(dd,J＝16.0,6.5Hz,1H),4.41(dd,J＝16.0,6.5Hz,1H),4.33(s,1H),4.09-3.98(m,1H),3.97-3.86(m,1H),3.12(d,J＝17.2Hz,1H),2.61(d,J＝17.2Hz,1H),2.11(s,3H),0.92(t,J＝7.0Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm)172.7,167.5,162.8,161.6,139.2,137.7,137.1,133.6,129.2(2C),128.7(2C),128.1(2C),128.0(2C),127.9(2C),127.3,124.9,119.0(2C),94.9,59.8,59.0,55.8,47.8,36.2,14.2,13.9；HRMS(ESI-TOF)calcd for C 30 H 29 ClN 3 O 3 [M+H] + 514.1897,found514.1894.
the nuclear magnetic resonance hydrogen spectrum of III-10 is shown in figure 20, and the nuclear magnetic resonance carbon spectrum is shown in figure 21.
Example 16:
taking as an example the preparation of ethyl 8- ((2-chlorobenzyl) amino) -1-methyl-4-oxo-3, 6-diphenyl-2, 3-diazaspiro [4.4] non-1, 7-diene-7-carboxylate (III-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 II was 3- (2-chlorobenzylamino) -2-methacrylic acid ethyl ester (380.6 mg,1.5 mmol) and the eluent ethyl acetate/petroleum ether (v/v=1:5) to give product III-11 in 89% yield.
Spectral structure characterization data for III-11: 1 H NMR(600MHz,CDCl 3 )δ(ppm)8.12(s,1H),7.50(d,J＝7.9Hz,2H),7.42(d,J＝7.6Hz,1H),7.40(d,J＝7.9Hz,1H),7.32(t,J＝7.2Hz,1H),7.29–7.17(m,6H),7.11–7.01(m,3H),4.59(dd,J＝16.3,7.1Hz,1H),4.54(dd,J＝16.3,6.4Hz,1H),4.33(s,1H),4.07–4.01(m,1H),3.96–3.90(m,1H),3.19(d,J＝17.3Hz,1H),2.70(d,J＝17.3Hz,1H),2.14(s,3H),0.93(t,J＝7.1Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ(ppm)172.7,167.6,162.9,161.6,139.3,137.9,136.1,133.1,130.0,129.3,128.8(2C),128.5,128.1(2C),128.0(2C),127.5,127.3,124.9,119.0(2C),95.0,59.8,59.1,56.0,46.5,36.3,14.3,13.9；HRMS(ESI-TOF)calcd for C 30 H 29 35 ClN 3 O 3 [M+H] + 514.1897,found 514.1894.
the nuclear magnetic resonance hydrogen spectrum of III-11 is shown in figure 22, and the nuclear magnetic resonance carbon spectrum is shown in figure 23.
Example 17:
taking as an example the preparation of 8- (benzylamino) -1-methyl-4-oxo-3, 6-diphenyl-2, 3-diazaspiro [4.4] non-1, 7-diene-7-carboxylic acid methyl ester of the formula (III-12:
the preparation method comprises the following steps: the procedure was as in example 1, except for the following technical scheme: raw material II was methyl 3-benzylamino-2-methacrylate (307.8 mg,1.5 mmol) to give product III-12 in 88% yield.
Spectral structure characterization data for III-12: 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.17(s,1H),7.52(d,J＝7.8Hz,2H),7.40–7.34(m,2H),7.32–7.17(m,8H),7.10–7.00(m,3H),4.50(dd,J＝15.8,6.4Hz,1H),4.44(dd,J＝15.8,6.8Hz,1H),4.32(s,1H),3.50(s,3H),3.14(d,J＝17.3Hz,1H),2.60(d,J＝17.3Hz,1H),2.07(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm)172.5,167.9,163.1,162.3,139.3,138.5,137.8,129.1(2C),128.7(2C),128.0(2C),127.9(2C),127.8,127.4,126.8(2C),124.8,118.8(2C),94.0,59.8,55.7,50.6,48.4,36.2,13.8；HRMS(ESI-TOF)calcd for C 29 H 28 N 3 O 3 [M+H] + 466.2131,found466.2145.
the nuclear magnetic resonance hydrogen spectrum of III-12 is shown in figure 24, and the nuclear magnetic resonance carbon spectrum is shown in figure 25.
Example 18:
taking as an example the preparation of isobutyl 8- (benzylamino) -1-methyl-4-oxo-3, 6-diphenyl-2, 3-diazaspiro [4.4] non-1, 7-diene-7-carboxylate (III-13) 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 3-benzylamino-2-methacrylic acid tert-butyl ester (371.0 mg,1.5 mmol) and the eluent was ethyl acetate/petroleum ether (v/v=1:10) to give product III-13 in 89% yield.
Spectral Structure characterization number of III-13According to the following: 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.16(s,1H),7.53–7.48(m,2H),7.41–7.35(m,2H),7.34–7.15(m,8H),7.14–6.97(m,3H),4.53(dd,J＝15.8,6.4Hz,1H),4.46(dd,J＝15.8,6.8Hz,1H),4.32(s,1H),3.85(dd,J＝10.5,6.5Hz,1H),3.60(dd,J＝10.5,6.0Hz,1H),3.18(d,J＝17.2Hz,1H),2.64(d,J＝17.2Hz,1H),2.09(s,3H),1.62–1.52(m,1H),0.53(dd,J＝6.7,2.7Hz,6H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm)172.7,167.7,163.2,162.0,139.4,138.6,137.8,129.1(2C),128.8(2C),128.0(4C),127.9,127.4,126.8(2C),124.8,118.9(2C),94.6,69.2,59.7,56.0,48.5,36.3,27.8,18.8(2C),13.9；HRMS(ESI-TOF)calcd for C 32 H 34 N 3 O 3 [M+H] + 508.2600,found 508.2592.
the nuclear magnetic resonance hydrogen spectrum of III-13 is shown in figure 26, and the nuclear magnetic resonance carbon spectrum is shown in figure 27.
Example 19:
taking as an example the preparation of ethyl 8- (butylamino) -1-methyl-4-oxo-3, 6-diphenyl-2, 3-diazaspiro [4.4] non-1, 7-diene-7-carboxylate (III-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 II was 3-butylamino-2-methyl ethyl acrylate (278.0 mg,1.5 mmol) and the eluent was ethyl acetate/petroleum ether (v/v=1:10) to give product III-14 in 96% yield.
Spectral structure characterization data for III-14: 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.72(s,1H),7.55–7.50(m,2H),7.30–7.15(m,5H),7.12–7.00(m,3H),4.32(s,1H),4.06–3.97(m,1H),3.95–3.86(m,1H),3.32–3.22(m,2H),3.16(d,J＝17.1Hz,1H),2.71(d,J＝17.Hz,1H),2.21(s,3H),1.66–1.58(m,2H),1.49–1.39(m,2H),0.97(t,J＝7.3Hz,3H),0.92(t,J＝7.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm)172.9,167.7,163.1,162.1,139.6,137.8,128.8(2C),128.0(2C),127.9(2C),127.2,124.8,119.0(2C),92.9,59.9,58.8,55.8,44.7,36.3,33.2,20.1,14.3,14.0,13.9；HRMS(ESI-TOF)calcd for C 27 H 32 N 3 O 3 [M+H] + 446.2444,found 446.2450.
the nuclear magnetic resonance hydrogen spectrum of III-14 is shown in FIG. 28, and the nuclear magnetic resonance carbon spectrum is shown in FIG. 29.
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 pentene derivative is characterized in that: under the condition of the existence of an accelerator, an organic solvent and alkali, carrying out multicomponent reaction on the chemical compounds shown in the formula I and the formula II according to a preset proportion, and purifying to obtain a pyrazolone spiro pentene derivative III shown in the formula III;
wherein R is 1 Is any one of phenyl, p-tolyl and p-trifluoromethylphenyl; r is R 2 Is any one of methyl, ethyl and phenyl; r is R 3 Is any one of phenyl, p-tolyl and p-fluorophenyl; r is R 4 Is any one of isopropyl, butyl, benzyl, p-methoxybenzyl, p-chlorobenzyl and o-chlorobenzyl; r is R 5 Is any one of methyl, ethyl and isobutyl.
2. The method for synthesizing pyrazolone cyclopentene derivatives according to claim 1, wherein: the accelerator is N-iodinated succinimide.
3. The method for synthesizing pyrazolone cyclopentene derivatives according to claim 1, wherein: the alkali is one or more of dipotassium hydrogen phosphate, potassium carbonate and sodium carbonate, and the solvent is one or two of dimethyl sulfoxide and methanol.
4. The method for synthesizing pyrazolone cyclopentene derivatives according to claim 1, wherein: the ratio of the amounts of the chemical shown in the formula I, the chemical shown in the formula II, the accelerator and the alkali is as follows: 1:1.5-1.8:1-1.2:1-1.2.
5. A method for synthesizing pyrazolone spiropentene derivatives according to claim 1 or 3, wherein: the volume of the solvent is 10-15 times of the total mass of the raw materials.
6. The method for synthesizing pyrazolone cyclopentene derivatives according to claim 1, wherein: the reaction temperature is 70-120 ℃ and the reaction time is 1-3 h.
7. The method for synthesizing pyrazolone cyclopentene derivatives according to claim 1, wherein: the purification steps comprise extraction, drying, reduced pressure concentration and column chromatography separation.
8. The method for synthesizing pyrazolone cyclopentene derivatives according to claim 7, wherein: the extracting agent adopted in the extracting step is ethyl acetate; the drying step is drying using anhydrous magnesium sulfate.
9. The synthetic method of pyrazolone spiropentene derivative according to claim 7 or 8, wherein: the chromatographic conditions of the column 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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