Synthesis method of 3-pyrazolidone and seven-membered nitrogen heterocyclic ring derivative

Abstract

The invention discloses a synthesis method of 3-pyrazolidone and seven-membered nitrogen heterocyclic ring derivatives, and belongs to the field of organic synthesis. According to the method, isatin-derived alpha-trifluoromethacrylate is taken as a raw material, and reacts with hydrazine or o-phenylenediamine in an organic solvent, so that two different types of nitrogen-containing heterocyclic compounds, namely 3-pyrazolidone and seven-membered nitrogen-containing heterocyclic compounds, can be obtained. The method does not need any catalyst, the reaction is green, simple, convenient and efficient, the substrate is good in universality, and a new thought is provided for synthesis of the heterocyclic compound.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a synthesis method of 3-pyrazolidinone (also referred to as 3-pyrazolidinone compound) and seven-membered nitrogen-containing heterocyclic derivative (also referred to as seven-membered nitrogen-containing heterocyclic compound). BACKGROUND

[0002] Nitrogen-containing heterocyclic compounds are the core pharmacophore of many natural products and active pharmaceutical ingredients, among which 3-pyrazolidinone and seven-membered nitrogen-containing heterocyclic structure drugs occupy a unique position as a valuable source of therapeutic agents in medicinal chemistry. For example, the neuroprotective agent edaravone, the anti-inflammatory drug antipyrine, and the kinase inhibitor lead compound palosuran, etc.

[0003] Currently, the traditional synthesis strategy of 3-pyrazolidinone compounds is mainly through hydrazination-cyclization of α,β-unsaturated carbonyl compounds catalyzed by acid or base, such as the catalytic system of Lewis acid magnesium perchlorate and chiral ligand catalyzing the asymmetric conjugate addition reaction of monosubstituted hydrazine to α,β-unsaturated imide ([1] J Am Chem Soc, 2007, 129, 4522-4523), organic base triethylamine catalyzing the reaction of N1-substituted benzotriazole and phenylhydrazine to generate 3-pyrazolidinone derivatives ([2] Tetrahedron Lett, 2019, 60, 1202-1205), etc. The synthesis method of seven-membered nitrogen-containing heterocyclic compounds is mainly ring addition reaction or ring expansion reaction of cyclic compounds, such as [5+2] cycloaddition of transition metal rhodium catalyzed by cyclopropylimine and dimethyl acetylenedicarboxylate to synthesize dihydroazacycloalkane compounds ([3] J Am Chem Soc, 2002, 124, 15154-15155), silver-catalyzed [5+2] cycloaddition reaction of γ-amino ketone and alkyne to synthesize azepine derivatives ([4] Angew Chem Int Ed, 2013, 52, 10805-10808), and skeleton reconstruction of 3-alkylidene pyrrolidine and azlactone or butenolide catalyzed by palladium to expand the ring to seven-membered azepine derivatives ([5] ACS Catal, 2021, 11, 1774-1779). Although the above methods can synthesize corresponding nitrogen-containing heterocyclic compounds, there are still defects such as poor atom economy, expensive catalyst price, and limited substrate range, and it is still a challenging task to develop a catalytic system that can control the regioselectivity and stereoselectivity and directly and effectively perform ring formation reaction to construct multifunctional heterocyclic rings.

[0004] Therefore, the prior art still needs to be improved and developed. SUMMARY

[0005] In view of the above deficiencies of the prior art, the purpose of the present application is to provide a synthesis method of 3-pyrazolidinone compounds and seven-membered nitrogen-containing heterocyclic compounds, aiming to solve the problems of poor atom economy, expensive catalyst and limited substrate range existing in the traditional synthesis strategy of 3-pyrazolidinone and seven-membered nitrogen-containing heterocyclic compounds.

[0006] The alpha-trifluoromethyl-substituted isatin derivative is a very attractive Michael addition reaction acceptor, and it is a high-efficiency and convenient heterocyclic synthesis method to react it as an initial raw material with a nucleophile, open ring, and then construct a heterocyclic skeleton compound through intramolecular cyclization, for example, the following technologies are available: [6] Angew Chem Int Ed, 2017, 56, 338-342. [7] Adv Synth Catal, 2018, 360, 917-924. [8] Org Lett, 2019, 21, 9584-9588. [9] Org Chem Front, 2020, 7, 1679-1684.

[10] Org Lett, 2022, 24, 4058-4063. As can be seen, in recent years, great progress has been made in the research on ring-forming reactions based on the cleavage of the C-N amide bond of indolinone, and relevant successful cases have been reported. The 3-alkylidene indolinone derivative is an excellent Michael addition acceptor, which is often used to react with a nucleophile, cut off the C-N amide bond at the N1 and C2 positions of the indole, and then synthesize many different types of heterocyclic compounds through intramolecular cyclization. The skeletons synthesized by this strategy include but are not limited to dihydrocoumarin, pyrrolo dihydrocoumarin, 2-pyrrolidone, spirooxindole gamma-lactone, furan[2,3-B]benzofuranone.

[0007] Therefore, the present application provides a synthesis method of 3-pyrazolidinone compounds and seven-membered nitrogen-containing heterocyclic compounds based on the cleavage of the C-N amide bond of indolinone derivatives and lactamization.

[0008] To achieve the above-mentioned purpose, the present application provides the following technical solutions:

[0009] A synthesis method of 3-pyrazolidinone compounds based on the cleavage of the C-N amide bond of indolinone derivatives, comprising the following steps:

[0010] At room temperature, the compound shown in formula I (also referred to as the alpha-trifluoromethyl methacrylate derived from isatin) reacts with the compound shown in formula II in an organic solvent to obtain two 3-pyrazolidinone compounds shown in formula III and formula IV, which are non-diastereoisomers of each other. Adding a base (such as cesium carbonate) and stirring for a certain period of time will cause the intermediate 3-pyrazolidinone compound shown in formula III to be converted into the final product 3-pyrazolidinone compound shown in formula IV;

[0011] The specific reaction formula is as follows:

[0012]

[0013] Wherein, R 1 is selected from any one of hydrogen, fluorine, chlorine, bromine, methyl, methoxy, phenyl, R 2 is selected from any one of hydrogen, ethoxycarbonyl, methoxycarbonyl, R 3 is selected from any one of fluorine, chlorine, trifluoromethyl, trifluoroethyl, EWG is selected from any one of tert-butyloxycarbonyl, methoxycarbonyl, benzyloxycarbonyl, acetyl;

[0014] In the compound shown in formula II, phenylhydrazine can be replaced by naphthylhydrazine or hydrazine hydrate.

[0015] The method uses isatin-derived alpha-trifluoromethyl acrylate as a raw material, and reacts with hydrazine in an organic solvent, so that 3-pyrazolidinone compounds can be obtained. The method does not require any catalyst, the reaction is green, simple, efficient, and the substrate has good universality, thereby providing a new idea for the synthesis of heterocyclic compounds.

[0016] In some embodiments of the present application, the compound shown in formula I is selected from any one of the following compounds:

[0017]

[0018] In some embodiments of the present application, the compound shown in formula II is selected from any one of the following compounds:

[0019]

[0020] In some embodiments of the present application, the 3-pyrazolidinone compound shown in formula III is selected from any one of the following compounds:

[0021]

[0022] In some embodiments of the present application, the 3-pyrazolidinone compound shown in formula IV is selected from any one of the following compounds:

[0023]

[0024] In some embodiments of the present application, the molar ratio of the compound shown in formula I to the compound shown in formula II is 1:1.5-1:2, such as 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, and preferably 1:2.

[0025] In some embodiments of the present application, the amount of the base (such as cesium carbonate) added after the compound of formula I is consumed in the reaction is 10-200 mol%, such as 10 mol%, 30 mol%, 50 mol%, 70 mol%, 100 mol%, 150 mol%, 200 mol%, etc.

[0026] In some embodiments of the present application, the base is at least one of cesium carbonate, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, and preferably is cesium carbonate.

[0027] In some embodiments of the present application, the organic solvent for the reaction is any one of ethyl acetate, dichloromethane, methanol, ethanol, toluene, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, acetonitrile, and preferably is acetonitrile.

[0028] A method for synthesizing a seven-membered nitrogen-containing heterocyclic compound based on cleavage of an indolinone derivative C-N amide bond, comprising the following steps:

[0029] The compound of formula I reacts with the compound of formula V in an organic solvent at a temperature of 20-60°C (such as 60°C) to obtain a seven-membered nitrogen-containing heterocyclic compound of formula VI;

[0030] The specific reaction formula is as follows:

[0031]

[0032] wherein, R 1 is any one selected from hydrogen, fluorine, chlorine, bromine, methyl, methoxy, R 2 is any one selected from hydrogen and ethoxycarbonyl, and R 1 The substitution position is at any one or two of C4, C5, C6, and C7.

[0033] In some embodiments of the present application, the compound of formula I is any one selected from the following compounds:

[0034]

[0035]

[0036] In some embodiments of the present application, the seven-membered nitrogen-containing heterocyclic compound of formula VI is any one selected from the following compounds:

[0037]

[0038] In some embodiments of the present application, the molar ratio of the compound of formula I to the compound of formula V is 1:1.5-1:2, and preferably is 1:2.

[0039] In some embodiments of the present application, the organic solvent for the reaction is any one of ethyl acetate, dichloromethane, methanol, ethanol, toluene, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, acetonitrile, preferably toluene.

[0040] In some embodiments of the present application, the organic solvent is added with molecular sieves before the reaction, which mainly function to absorb moisture in the reaction system and improve reactivity. The amount of the molecular sieves added per milliliter of the organic solvent is 10-100 mg (e.g., 50 mg).

[0041] In some embodiments of the present application, the reaction temperature is 25-120°C, preferably 60°C.

[0042] The present application aims to develop a synthesis method of 3-pyrazolone compounds and seven-membered nitrogen-containing heterocyclic compounds by a strategy of cleaving open ring based on C-N amide bond of indolinone derivatives and then performing ring closure. The new method for synthesizing 3-pyrazolone compounds and seven-membered nitrogen-containing heterocyclic compounds has the advantages of simple operation, fast reaction rate, high reaction yield, good substrate universality, and no need to add any catalyst. BRIEF DESCRIPTION OF DRAWINGS

[0043] Figure 1 The molecular structure of the optional indolinone substrate in Example 2 is shown in the schematic diagram, and the molecular structure of the product after reaction of the corresponding substrate and the separation yield of the product are also shown;

[0044] Figure 2 The molecular structure of the optional phenylhydrazine substrate in Example 2 is shown in the schematic diagram, and the molecular structure of the product after reaction of the corresponding substrate and the separation yield of the product are also shown;

[0045] Figure 3 The molecular structure of the optional indolinone substrate in Example 5 is shown in the schematic diagram, and the molecular structure of the product after reaction of the corresponding substrate and the separation yield of the product are also shown;

[0046] Figure 4 The molecular structure of the optional phenylhydrazine substrate in Example 5 is shown in the schematic diagram, and the molecular structure of the product after reaction of the corresponding substrate and the separation yield of the product are also shown;

[0047] Figure 5 The molecular structure of the optional indolinone substrate in Example 8 is shown in the schematic diagram, and the molecular structure of the product after reaction of the corresponding substrate and the separation yield of the product are also shown. DETAILED DESCRIPTION

[0048] ​The application will be further described in the following with specific examples, and the application is not limited to the following examples.

[0049] Example 1

[0050]

[0051] In a dry round bottom flask equipped with a stir bar, weighed isatin-derived a-trifluoromethyl methacrylate I-1 (38.5 mg, 0.1 mmol) was added to dry acetonitrile solvent (1 mL), followed by the addition of phenylhydrazine II-1 (19.6 μΐ, 0.2 mmol), stirred at room temperature, thin layer chromatography to track the reaction, after the consumption of the raw material I-1, the reaction solution was evaporated under reduced pressure to remove the solvent, the crude product was purified by column chromatography (mobile phase was petroleum ether: ethyl acetate = 20: 1 to 5: 1, volume ratio), to obtain yellow oil intermediate III-1 (32 mg, yield 66%). 1 H NMR (500 MHz, Chloroform-d) δ 7.89 (d, J = 8.1 Hz, 2H), 7.60 (s, 1H), 7.42 (t, J = 8.0 Hz, 2H), 7.34 (t, J = 6.9 Hz, 1H), 7.22 (t, J = 7.5 Hz, 2H), 7.17-7.13 (m, 1H), 6.78 (s, 1H), 5.97 (s, 1H), 4.90 (s, 1H), 4.57 (dq, J = 10.7, 7.1 Hz, 1H), 4.46 (dq, J = 10.7, 7.2 Hz, 1H), 1.48 (s, 9H), 1.42 (t, J = 7.2 Hz, 3H). 13 CNMR (126 MHz, Chloroform-d) δ 167.19, 165.94, 153.31, 137.57, 137.45, 131.57, 129.39, 129.03, 125.65, 125.18, 122.71 (q, J = 284.7 Hz), 119.08, 80.76, 69.73 (q, J = 29.0 Hz), 65.15, 50.88, 28.28, 13.91. 19 FNMR (471 MHz, CDCl3) δ -71.01.

[0052] Example 2 Selection of substrates and corresponding products

[0053] 1, with the indolone compound as shown in Figure 1 as the reaction substrate, under the same reaction conditions as in Example 1, isatin-derived a-trifluoromethyl methacrylate

[0054] I-1 to I-10 (0.1 mmol) were added in anhydrous acetonitrile solvent (1 mL) respectively, then phenylhydrazine II-1 (19.6 μl, 0.2 mmol) was added, stirred at room temperature, TLC was used to track the reaction, after the raw material I was consumed, the solvent was removed by reduced pressure, the crude product was purified by column chromatography (the mobile phase was petroleum ether: ethyl acetate = 20:1 to 5:1, volume ratio), to obtain 3-pyrazolidone intermediates III-1 to III-10. Figure 1 The yield shown in the above table is the isolated yield.

[0055]

[0056] 2, the phenylhydrazine compound as shown in Figure 2 is used as the reaction substrate, and the reaction is carried out under the same reaction conditions as in Example 1. Indigo-derived α-trifluoromethyl methacrylate I-1 (0.1 mmol) is added in anhydrous acetonitrile solvent (1 mL), then phenylhydrazine II-1 to II-3 (19.6 μl, 0.2 mmol) is added respectively, stirred at room temperature, TLC is used to track the reaction, after the raw material I-1 is consumed, the solvent is removed by reduced pressure, the crude product is purified by column chromatography (the mobile phase is petroleum ether: ethyl acetate = 20:1 to 5:1, volume ratio), to obtain 3-pyrazolidone intermediates III-11 to III-13. Figure 2 The yield shown in the above table is the isolated yield.

[0057]

[0058] Example 3

[0059]

[0060] In a dry round-bottom flask equipped with a stirrer, indigo-derived α-trifluoromethyl methacrylate I-1 (38.5 mg, 0.1 mmol) was weighed and added in anhydrous acetonitrile solvent (1 mL), then phenylhydrazine II-1 (19.6 μl, 0.2 mmol) was added, stirred at room temperature, TLC was used to track the reaction, after the raw material I-1 was consumed, cesium carbonate (50 mg) was added to the reaction solution, stirred for 0.5 hours, to make the intermediate III-1 completely converted into IV-1, the solvent was removed by reduced pressure, the crude product was purified by column chromatography (the mobile phase was petroleum ether: ethyl acetate = 20:1 to 5:1, volume ratio), to obtain the final product IV-1 (47 mg, yield 95%) as a light yellow solid. 1H NMR (400 MHz, Chloroform-d) δ 7.84 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 7.9 Hz, 1H), 7.36 (t, J = 7.9 Hz, 2H), 7.27 (t, J = 7.2 Hz, 1H), 7.16 (t, J = 7.3 Hz, 1H), 7.05 (dt, J = 16.5, 7.8 Hz, 2H), 6.51 (s, 1H), 6.00 (s, 1H), 4.49 (s, 1H), 3.94 (dt, J = 14.4, 7.1 Hz, 1H), 3.77 - 3.70 (m, 1H), 1.46 (s, 9H), 0.93 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, CDC13) δ 166.79, 164.15, 153.15, 137.45, 136.98, 129.68, 129.01, 127.73, 125.83, 125.37, 125.26, 124.81, 123.77 (q, J = 271.7 Hz), 119.44, 80.82, 70.41 (q, J = 29.3 Hz), 64.38, 47.82, 28.28, 13.20. 19 F NMR (376 MHz, CDC13) δ -77.16; HRMS (ESI) C 24 H 26 N3O5F3 (M + Na) + Theoretical calculation: 516.1717, Actual value: 516.1719.

[0061] Optimization and selection of reaction conditions in Example 4

[0062] Under the same reaction conditions as in Example 3, changing different solvents has a significant effect on the reaction rate and product yield. Table 1 shows the effect of using different reaction solvents on the reaction rate and product yield.

[0063] Table 1, selection of solvents in the reaction and the effect of the output

[0064]

[0065]

[0066] Example 5 selection of substrates and corresponding products

[0067] 1, using indolone compounds as shown in Figure 3 Example 3 under the same reaction conditions, indigo-derived α-trifluoromethyl methacrylate

[0068] I-1 to I-12 (0.1 mmol) were added in anhydrous acetonitrile (1 mL) respectively, then phenylhydrazine II-1 (19.6 μl, 0.2 mmol) was added, stirred at room temperature, TLC was used to track the reaction, after the starting material I was consumed, cesium carbonate (50 mg) was added to the reaction solution, stirred for 0.5 hour, to make the intermediate III completely converted to IV, the solvent was removed by reduced pressure evaporation, the crude product was purified by column chromatography (the mobile phase was petroleum ether: ethyl acetate = 20:1 to 5:1, volume ratio), to obtain 3-pyrazolidone final product IV-1 to IV-12. Figure 3 The yield shown in the table is the isolated yield.

[0069]

[0070] 2, the phenylhydrazine compound as shown in Figure 4 the reaction conditions were the same as in Example 3, indigo derived α-trifluoromethyl methacrylate I-1 (0.1 mmol) was added in anhydrous acetonitrile (1 mL), then phenylhydrazine II-1 to II-5 (19.6 μl, 0.2 mmol) was added respectively, stirred at room temperature, TLC was used to track the reaction, after the starting material I-1 was consumed, cesium carbonate (50 mg) was added to the reaction solution, stirred for 0.5 hour, to make the intermediate III completely converted to IV, the solvent was removed by reduced pressure evaporation, the crude product was purified by column chromatography (the mobile phase was petroleum ether: ethyl acetate = 20:1 to 5:1, volume ratio), to obtain 3-pyrazolidone final product IV-13 to IV-17. Figure 4 The yield shown in the table is the isolated yield.

[0071]

[0072] Example 6

[0073]

[0074] In a dry round bottom flask equipped with a stirrer, indigo derived α-trifluoromethyl methacrylate I-1 (38.5 mg, 0.1 mmol) was weighed and added in toluene (1 mL), then 1,2-phenylenediamine V (21.6 mg, 0.2 mmol) was added, finally molecular sieves (50 mg) were added, stirred at 60 °C oil bath heating, TLC was used to track the reaction, after the starting material I-1 was consumed, the solvent was removed by reduced pressure evaporation, the crude product was purified by column chromatography (the mobile phase was petroleum ether: ethyl acetate = 20:1 to 5:1, volume ratio), to obtain white solid product VI-1 (36 mg, yield 68%). 1H NMR (400 MHz, Chloroform-d) δ 9.10 (s, 1H), 8.36 (s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.23 - 7.19 (m, 1H), 7.11 (t, J = 7.9 Hz, 1H), 7.01 - 6.92 (m, 2H), 6.75 (dt, J = 9.7, 5.0 Hz, 3H), 5.52 (s, 1H), 5.05 (s, 1H), 3.94 (qd, J = 7.1, 2.2 Hz, 2H), 1.47 (d, J = 2.2 Hz, 9H), 0.80 (td, J = 7.2, 2.1 Hz, 3H). 13 C NMR (101 MHz, CDC13) δ 169.64, 166.07, 153.59, 138.03, 133.48, 128.61, 126.43, 125.55, 124.43, 124.26, 124.12, 123.59 (q, J = 292.9 Hz) 122.31, 121.71, 120.87, 119.74, 80.29, 67.94 (q, J = 27.2 Hz), 64.39, 46.88, 28.36, 12.99. 19 F NMR (376 MHz, CDC13) δ -73.97. HRMS (ESI) C 24 H 26 N3O5F3 (M + Na) + Theoretical calculation: 516.1717, Actual value: 516.1716.

[0075] Optimization and selection of reaction conditions of Example 7

[0076] Using different reaction solvents, changing reaction temperature, adding additives under the same reaction conditions as Example 6 The effect of molecular sieves on the reaction rate and product yield is shown in Table 2, which is the effect of using different reaction solvents, changing reaction temperature, adding additives Molecular sieves on the reaction rate and product.

[0077] Table 2, selection of different solvents, temperature in the reaction and output effect

[0078]

[0079]

[0080] As shown in Table 2: because the reaction is more difficult at room temperature, the reaction is first carried out in different solvents under the condition of oil bath heating and reflux, after determining that toluene is the optimal solvent, the effect of different temperatures on the reaction is explored, and finally it is confirmed that under the condition of 60℃, the reaction time is 8h, and Ⅵ-1(31mg, yield 60%) is obtained.

[0081] Under the same reaction conditions as No. 12 in Table 2, an additive is added Molecular sieve (50mg), the reaction time is shortened to 7h, and Ⅵ-1(36mg, yield 68%) is obtained.

[0082] Selection of substrates and corresponding products in Example 8

[0083] 1, the indole ketone compound as shown in Figure 5 is reacted under the same reaction conditions as Example 6, and indigo-derived α-trifluoromethyl methacrylate I-1, I-2, I-4, I-5, I-6, I-9, I-10, I-12, I-13, I-14(0.1mmol) is added to toluene solvent(1mL), then 1,2-phenylenediamine V(21.6mg, 0.2mmol) is added, and finally molecular sieve (50mg) is added, stirred under oil bath heating at 60℃, thin layer chromatography is used to track the reaction, after the raw material I is consumed, the reaction solution is evaporated under reduced pressure to remove the solvent, and the crude product is purified by column chromatography (the mobile phase is petroleum ether: ethyl acetate = 20:1 to 5:1, volume ratio) to obtain seven-membered nitrogen-containing heterocyclic product Ⅵ-1-Ⅵ-10. Figure 5 The yield shown in the above-mentioned examples is the isolated yield.

[0084]

[0085] The above-mentioned examples only express several implementation methods of the present application, which are described in detail, but it cannot be understood as limiting the scope of the patent. It should be pointed out that for ordinary skilled in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are within the scope of protection of the present application.

Claims

1. A method for synthesizing 3-pyrazolidinone compounds based on cleavage of C-N amide bond of indolinone derivatives, characterized in that, The method comprises the following steps: The compound of formula I is reacted with the compound of formula II in an organic solvent at room temperature to obtain the 3-pyrazolidinone compound of formula III; Alternatively, the compound of formula I is reacted with the compound of formula II in an organic solvent at room temperature to obtain the 3-pyrazolidinone compound of formula III, and then a base is added and stirred to convert the 3-pyrazolidinone compound of formula III into the 3-pyrazolidinone compound of formula IV; The specific reaction formula is as follows: Among them, R 1 Selected from any one of hydrogen, fluorine, chlorine, bromine, methyl, methoxy, and phenyl, R 2 Selected from any one of hydrogen, ethoxycarbonyl, and methoxycarbonyl, R 3 It is selected from any one of fluorine, chlorine, trifluoromethyl, and trifluoroethyl, and EWG is selected from any one of tert-butoxycarbonyl, methoxycarbonyl, benzyloxycarbonyl, and acetyl.

2. The method for synthesizing 3-pyrazolidineone compounds based on the CN-amide bond cleavage of indoleone derivatives as described in claim 1, characterized in that, The phenylhydrazine in the compound of formula II is replaced by naphthalene hydrazine or hydrazine hydrate.

3. The method for synthesizing 3-pyrazolidineone compounds based on CN-amide bond cleavage of indoleone derivatives as described in claim 1, characterized in that, The organic solvent is any one of ethyl acetate, dichloromethane, methanol, ethanol, toluene, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether or acetonitrile; The molar ratio of the compound of formula I to the compound of formula II is 1:1.5-1:2; After the compound of formula I is consumed in the reaction, the amount of the added base is 10-200 mol %; The base is at least one of cesium carbonate, potassium carbonate, sodium carbonate, triethylamine or diisopropylethylamine.

4. The method for synthesizing 3-pyrazolidineone compounds based on the CN-amide bond cleavage of indoleone derivatives as described in claim 1, characterized in that, The compound of formula I is any one of the following compounds:

5. The method for synthesizing 3-pyrazolidineone compounds based on the CN-amide bond cleavage of indoleone derivatives as described in claim 1, characterized in that, The compound of formula II is any one of the following compounds:

6. The method for synthesizing 3-pyrazolidineone compounds based on CN-amide bond cleavage of indole ketone derivatives as described in claim 1, characterized in that, The 3-pyrazolidinone compound of formula III is any one of the following compounds:

7. The method for synthesizing 3-pyrazolidineone compounds based on CN-amide bond cleavage of indoleone derivatives as described in claim 1, characterized in that, The 3-pyrazolidinone compound of formula IV is any one of the following compounds:

8. A method for synthesizing a seven-membered nitrogen-containing heterocyclic compound based on cleavage of a C-N amide bond of an indolinone derivative, characterized by, The method comprises the following steps: The compound of formula I is reacted with the compound of formula V in an organic solvent at a temperature of 20-60 DEG C to obtain the seven-membered nitrogen-containing heterocyclic compound of formula VI; The specific reaction formula is as follows: wherein R is selected from any one of hydrogen, fluorine, chlorine, bromine, methyl, methoxy, R 1 is selected from any one of hydrogen, fluorine, chlorine, bromine, methyl, methoxy, R 2 is selected from any one of hydrogen, fluorine, chlorine, bromine, methyl, methoxy, R 9. The method for synthesizing seven-membered nitrogen-containing heterocyclic compounds based on the cleavage of the CN amide bond of indole ketone derivatives as described in claim 8, characterized in that, The organic solvent is any one of ethyl acetate, dichloromethane, methanol, ethanol, toluene, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether or acetonitrile; The molar ratio of the compound of formula I to the compound of formula V is 1:1.5-1:2; Also included is the addition of molecular sieves, wherein the amount of molecular sieves added per milliliter of organic solvent is between 10 and 100 mg. molecular sieves, wherein the amount of molecular sieves added per milliliter of organic solvent is between 10 and 100 mg. The reaction temperature is 25-120 DEG C; The compound of formula I is any one of the following compounds:

10. The method for synthesizing seven-membered nitrogen-containing heterocyclic compounds based on the CN-amide bond cleavage of indole ketone derivatives as described in claim 8, characterized in that, The seven-membered nitrogen-containing heterocyclic compound of formula VI is any one of the following compounds:

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