Five-membered double-spiro indoline derivative as well as preparation method and application thereof

Abstract

The invention discloses a five-membered double-spiro indoline derivative as well as a preparation method and application thereof. The structural formula of the five-membered double-spiro indoline derivative is shown as a formula (III); wherein R1 is selected from hydrogen, alkyl or halogen; r2 is selected from hydrogen, alkyl, allyl, benzyl or benzoyl; r3 is selected from phenyl, naphthyl, biphenyl, thienyl, furyl, alkyl phenyl, halogen phenyl, alkoxy phenyl, nitrophenyl or trifluoromethyl phenyl; r4 is selected from alkyl phenyl, halogen phenyl or nitrophenyl. According to the five-membered double-spiro indoline derivative, high-atom-economy and high-yield synthesis is achieved through a one-step method, the synthesis route is simplified, the production cost is reduced, and the influence on the environment is reduced due to the green chemical characteristic of the five-membered double-spiro indoline derivative. The five-membered double-spiro indoline derivative is found to have mildew-proof and antibacterial effects.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and in particular to a five-membered bispirocyclic indoline derivative and a preparation method and application thereof. Background Art

[0002] Mycotoxins pose a serious threat to human and animal health. Of the approximately 400 mycotoxins discovered so far, 30 are associated with various diseases that have serious effects on human and animal health. Mycotoxins are generally produced by pathogenic fungi. Studies have found that spiroindoline compounds have certain antifungal activity, especially against Aspergillus (Aspergillus niger, Aspergillus flavus), Candida albicans and Alternaria. Spiroindoline compounds usually inhibit fungal growth by interfering with the synthesis of fungal cell walls or cell membranes, or through other mechanisms. The above-mentioned fungi are commonly found in buildings, soil, and places involved in human daily life. The structures of spiroindoline derivatives that have been proven to have antifungal activity are shown below:

[0003]

[0004] There are many reports on the synthesis of the above compounds, but the existing methods generally require multiple additives, rely on expensive metal catalysts, and have difficulty in controlling the stereoconfiguration of the products. They perform poorly in terms of the economy of synthetic steps and atom economy. In the preparation of spirocyclic indoline derivatives, it is crucial to improve the synthesis efficiency, while also ensuring that the operation is simple, safe, economical and environmentally friendly to comply with the "green organic synthesis concept".

[0005] Therefore, it is very attractive to develop a method that can efficiently and accurately synthesize spiroindoline derivatives under mild conditions from simple and easily accessible raw materials. In addition, the use of simple thermal reaction synthetic routes that do not rely on expensive metal catalysts is also of great value for the preparation of spiroindoline derivatives with antifungal activity. Summary of the invention

[0006] In view of the above technical difficulties, the present invention aims to propose a five-membered bispiro indoline derivative, and introduces its preparation process and application field. This derivative can be constructed in a one-step reaction using simple raw materials, and the operation process is simple and easy. The desired five-membered bispiro indoline derivative can be efficiently synthesized by simply adjusting the type of solvent, temperature and reaction time in the reaction. This method provides a new way to efficiently and environmentally friendly construct a five-membered bispiro indoline skeleton. In addition, the derivative also exhibits antifungal activity.

[0007] The first object of the present invention is to disclose a five-membered bispirocyclic indoline derivative, the structural formula of which is shown in formula (III):

[0008]

[0009] Among them, R 1 is selected from hydrogen, alkyl or halogen;

[0010] R 2 is selected from hydrogen, alkyl, allyl, benzyl or benzoyl;

[0011] R 3 is selected from phenyl, naphthyl, biphenyl, thienyl, furanyl, alkylphenyl, halogenphenyl, alkoxyphenyl, nitrophenyl or trifluoromethylphenyl;

[0012] R 4 Selected from alkylphenyl, halogenphenyl or nitrophenyl.

[0013] In a preferred technical solution of the present invention, R 3 is selected from substituted or unsubstituted phenyl, naphthyl, biphenyl, thienyl or furyl; wherein the substituents on the substituted phenyl are independently selected from one or more of hydrogen, alkyl, alkoxy, halogen, nitro and trifluoromethyl.

[0014] In a preferred technical solution of the present invention, R 1 is selected from substituted phenyl, wherein the substituent on the substituted phenyl is selected from hydrogen, methyl, chlorine or bromine.

[0015] Preferably, R 2 Select hydrogen, methyl, allyl, benzyl or benzoyl.

[0016] Preferably, R 3 is selected from substituted or unsubstituted phenyl, naphthyl, biphenyl, thienyl or furanyl, wherein the substituents on the substituted phenyl are selected from hydrogen, methyl, methoxy, trifluoromethyl, nitro, fluorine, chlorine, bromine or iodine.

[0017] Preferably, R 4 is selected from substituted or unsubstituted phenyl, wherein the substituent on the substituted phenyl is selected from methyl, nitro or chlorine.

[0018] Preferably, the structural formula of the five-membered bispirocyclic indoline derivative is as shown in one of Formula III:

[0019]

[0020] In the above structural formula, Ph represents phenyl, Allyl represents p-allyl, Bn represents benzyl, Bz represents benzoyl, and 2-NaPh represents naphthyl.

[0021] The second object of the present invention is to disclose a method for preparing the above-mentioned five-membered bispirocyclic indoline derivative, comprising the following steps:

[0022] The compounds represented by formula (I) and formula (II) are reacted in an organic solvent, and after the reaction is completed, a five-membered bispirocyclic indoline derivative represented by formula (III) is obtained. The reaction scheme is as follows:

[0023]

[0024] Among them, R 1 , R 2 , R 3 and R 4 As described above.

[0025] Furthermore, the molar ratio of the compounds represented by formula (I) to formula (II) is (1.5-1.0):1.0.

[0026] Preferably, the compound represented by formula (I) is preferably selected from tryptamine isocyanide (1), 5-methyl tryptamine isocyanide (2), 5-chloro tryptamine isocyanide (3), 5-bromo tryptamine isocyanide (4), 6-bromo tryptamine isocyanide (5), N-methyl tryptamine isocyanide (6), N-allyl tryptamine isocyanide (7), N-benzyl tryptamine isocyanide (8), and N-benzoyl tryptamine isocyanide (9).

[0027] The specific structural formula of the compound represented by formula (I) corresponding to the above numbers is as follows:

[0028]

[0029] Preferably, the compound represented by formula (II) is preferably selected from unsaturated pyrazolone (10), 2-methyl unsaturated pyrazolone (11), 3-methyl unsaturated pyrazolone (12), 3-nitro unsaturated pyrazolone (13), 4-fluoro unsaturated pyrazolone (14), 4-chloro unsaturated pyrazolone (15), 4-bromo unsaturated pyrazolone (16), 4-iodo unsaturated pyrazolone (17), 4-nitro unsaturated pyrazolone (18), 4-trifluoromethyl unsaturated pyrazolone (19), 9), 4-methyl unsaturated pyrazolone (20), 4-methoxy unsaturated pyrazolone (21), naphthyl unsaturated pyrazolone (22), biphenyl unsaturated pyrazolone (23), thienyl unsaturated pyrazolone (24), furyl unsaturated pyrazolone (25), N-2-chlorophenyl unsaturated pyrazolone (26), N-4-chlorophenyl unsaturated pyrazolone (27), N-4-nitrophenyl unsaturated pyrazolone (28), N-4-methyl unsaturated pyrazolone (29).

[0030] The specific structural formula of the compound represented by formula (II) corresponding to the above numbers is as follows:

[0031]

[0033] Furthermore, the organic solvent is selected from one or more of methanol, ethanol, 1,4-dioxane, toluene, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, methyl tert-butyl ether, ethylene glycol dimethyl ether, hexafluoroisopropanol and tetrahydrofuran.

[0034] Specifically, tetrahydrofuran is selected as the organic solvent in the above reaction.

[0035] Furthermore, the reaction is carried out in an air atmosphere.

[0036] Furthermore, the reaction time is 2-12 hours.

[0037] Furthermore, the reaction temperature is 70-110°C.

[0038] Preferably, the reaction time is 4 h.

[0039] For a specific example, taking the reaction in which the raw materials are tryptamine isonitrile and unsaturated pyrazolone and the organic solvent is tetrahydrofuran as an example, the five-membered bispirocyclic indoline derivative represented by formula (III) of the present invention is prepared in the following reaction principle:

[0040]

[0041] Tryptamine isocyanide (1) nucleophilically attacks the double bond of unsaturated pyrazolone (10) to undergo Michael addition reaction to generate intermediate A, followed by ring closure at C3 of tryptamine isocyanide indole to generate intermediate B, and intermediate B undergoes double bond displacement to obtain intermediate C, which then undergoes cyclization reaction with tryptamine isocyanide indole C2 to finally obtain product III1.

[0042] The third object of the present invention is to disclose the use of five-membered bispirocyclic indoline derivatives in antifungal activity.

[0043] Compared with the prior art, the technical solution of the present invention has at least one or more of the following advantages:

[0044] The present invention uses tryptamine isonitrile and unsaturated pyrazolone compounds as starting materials to develop a preparation method for a five-membered bispiro indoline derivative. Compared with the conventional technology, the present invention proposes an efficient synthesis route with simplified steps, high atomic utilization and convenient post-processing. The target compound is efficiently synthesized by optimizing reaction conditions such as solvent type, reaction temperature and time, and exhibits advantages such as high atomic economy, excellent yield and wide substrate range, thus providing a simple and effective synthesis scheme for the five-membered bispiro indoline skeleton.

[0045] The invention provides a series of preparation methods of five-membered bispirocyclic indoline derivatives. The five-membered bispirocyclic indoline derivatives have potential antifungal activity.

[0046] The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention and implement it according to the contents of the specification, the following is a detailed description of the preferred embodiments of the present invention. DETAILED DESCRIPTION

[0047] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention.

[0048] The following examples of the present invention provide a method for preparing a five-membered bispirocyclic indoline derivative represented by one of the above formulae (III1) to (III28). The numbers in the following raw materials correspond to the numbers in the above.

[0049] Example 1: Synthesis of the compound shown in (III1)

[0050] Weigh 0.1 mmol of tryptamine isonitrile (the compound corresponding to number (1), 0.0170 g), 0.1 mmol of unsaturated pyrazolone (the compound corresponding to number (10), 0.0262 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0373 g of the reaction product.

[0051] The above reaction products were characterized and the results were as follows:

[0052] 1 H NMR(400MHz,DMSO-d6)δ7.94(d,J=7.6Hz,2H),7.50–7.43(m,2H),7.27–7.20(m,2H), 7.13(t,J=7.6Hz,2H),7.08–7.03(m,1H),6.98(d,J=3.6Hz,1H),6.91(t,J=7.2Hz,1H ),6.81(d,J=7.2Hz,2H),6.70–6.64(m,1H),6.61–6.52(m,2H),4.33(s,1H),4.08–3. 98(m,1H),3.90–3.80(m,1H),2.20–2.09(m,1H),1.89–1.81(m,1H),1.28(s,3H)ppm.

[0053] According to the characterization data, the obtained reaction product is pure (purity>95%); the product yield is 86%.

[0054] Example 2: Synthesis of the compound shown in (III2)

[0055] Weigh 0.1 mmol of 5-methyltryptamine isocyanate (the compound corresponding to number (2), 0.0184 g), 0.1 mmol of unsaturated pyrazolone (the compound corresponding to number (10), 0.0262 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0241 g of the reaction product.

[0056] The above reaction products were characterized and the results were as follows:

[0057] 1 H NMR (400MHz, DMSO-d6) δ7.93(d,J=8.0Hz,2H),7.46(t,J=7.6Hz,2H),7.21(t,J=7.2H z,1H),7.16–7.05(m,3H),6.97(d,J=3.6Hz,1H),6.94–6,85(m,2H),6.80(d,J=8.0Hz ,2H),6.47(d,J=7.6Hz,1H),6.33(d,J=2.4Hz,1H),4.31(s,1H),4.09–3.99(m,1H),3 .91–3.81(m,1H),2.23(s,3H),2.19–2.08(m,1H),1.89–1.80(m,1H),1.28(s,3H)ppm.

[0058] According to the characterization data, the obtained reaction product is a pure product (purity>95%); the product yield is 54%.

[0059] Example 3: Synthesis of the compound shown in (III3)

[0060] Weigh 0.1 mmol of 5-chlorotryptamine isonitrile (the compound corresponding to number (3), 0.0204 g), 0.1 mmol of unsaturated pyrazolone (the compound corresponding to number (10), 0.0262 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was subjected to vacuum evaporation and column chromatography separation (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0300 g of the reaction product.

[0061] The above reaction products were characterized and the results were as follows:

[0062] 1 H NMR(400MHz,DMSO-d6)δ7.93(d,J=8.0Hz,2H),7.47(t,J=8.0Hz,2H),7.26– 7.18(m,2H),7.17–7.08(m,3H),7.00(d,J=3.6Hz,1H),6.94(t,J=7.2Hz,1H ),6.81–6.77(m,3H),6.56(d,J=8.0Hz,1H),4.36(s,1H),4.07–3.96(m,1H) ,3.91–3.81(m,1H),2.20–2.08(m,1H),1.94–1.86(m,1H),1.35(s,3H)ppm.

[0063] According to the characterization data, the obtained reaction product is a pure product (purity>95%); the product yield is 64%.

[0064] Example 4: Synthesis of the compound shown in (III4)

[0065] Weigh 0.1 mmol of 5-bromotryptamine isonitrile (the compound corresponding to number (4), 0.0247 g), 0.1 mmol of unsaturated pyrazolone (the compound corresponding to number (10), 0.0262 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0348 g of the reaction product.

[0066] The above reaction products were characterized and the results were as follows:

[0067] 1H NMR(400MHz, DMSO-d6)δ7.93(d,J=7.6Hz,2H),7.49–7.44(m,2H),7.30(d,J=2.0 Hz,1H),7.25–7.20(m,2H),7.14–7.11(m,2H),7.00(d,J=3.6Hz,1H),6.93(d,J= 7.6Hz,1H),6.85–6.80(m,3H),6.53(d,J=8.0Hz,1H),4.35(s,1H),4.06–3.95(m ,1H),3.91–3.81(m,1H),2.20–2.09(m,1H),1.94–1.87(m,1H),1.36(s,3H)ppm.

[0068] According to the characterization data, the obtained reaction product is pure (purity>95%); the product yield is 68%.

[0069] Example 5: Synthesis of the compound shown in (III5)

[0070] Weigh 0.1 mmol of 6-bromotryptamine isonitrile (the compound corresponding to number (5), 0.0247 g), 0.1 mmol of unsaturated pyrazolone (the compound corresponding to number (10), 0.0262 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0337 g of the reaction product.

[0071] The above reaction products were characterized and the results were as follows:

[0072] 1 H NMR (400MHz, DMSO-d6) δ7.94(d,J=8.0Hz,2H),7.47(t,J=7.6Hz,2H),7.22(t,J=7.2Hz,1H),7.19–7.09(m,3H),7.00(d,J=3.6Hz,1H),6.96–6.87( m,2H),6.86–6.76(m,3H),6.71(s,1H),4.36(s,1H),4.07–3.94(m,1H),3 .91–3.80(m,1H),2.21–2.07(m,1H),1.92–1.81(m,1H),1.38(s,3H)ppm.

[0073] According to the characterization data, the obtained reaction product is pure (purity>95%); the product yield is 66%.

[0074] Example 6: Synthesis of the compound shown in (III6)

[0075] Weigh 0.1 mmol of N-methyltryptamine isocyanate (the compound corresponding to number (6), 0.0184 g), 0.1 mmol of unsaturated pyrazolone (the compound corresponding to number (10), 0.0262 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0277 g of the reaction product.

[0076] The above reaction products were characterized and the results were as follows:

[0077] 1 H NMR(400MHz,DMSO-d6)δ7.89(d,J=8.0Hz,2H),7.48(t,J=7.6Hz,2H),7.29–7.22(m,2 H),7.19–7.10(m,3H),7.03(d,J=3.6Hz,1H),6.92(t,J=7.2Hz,1H),6.78(d,J=7.6Hz ,2H),6.69(t,J=7.2Hz,1H),6.45(d,J=8.0Hz,1H),4.41(s,1H),4.08–3.97(m,1H),3 .91–3.82(m,1H),2.79(s,3H),2.21–2.11(m,1H),1.90–1.81(m,1H),1.25(s,3H)ppm.

[0078] According to the characterization data, the obtained reaction product is pure (purity>95%); the product yield is 62%.

[0079] Example 7: Synthesis of the compound shown in (III7)

[0080] Weigh 0.1 mmol of N-allyltryptamine isocyanate (compound corresponding to number (7), 0.0210 g), 0.1 mmol of unsaturated pyrazolone (compound corresponding to number (10), 0.0262 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0298 g of the reaction product.

[0081] The above reaction products were characterized and the results were as follows:

[0082] 1 H NMR(400MHz, DMSO-d6)δ7.89(d,J=8.0Hz,2H),7.48(t,J=7.6Hz,2H),7.31–7.21(m,2H),7.18 –7.09(m,3H),7.03(s,1H),6.92(t,J=7.2Hz,1H),6.79(d,J=8.0Hz,2H),6.72(t,J=7.6Hz,1H) ,6.59(d,J=7.6Hz,1H),5.80–5.62(m,1H),5.06–4.92(m,2H),4.38(s,1H),4.15–3.94(m,2H) ,3.91–3.77(m,1H),3.60–3.47(m,1H),2.20–2.06(m,1H),1.93–1.80(m,1H),1.30(s,3H)ppm.

[0083] According to the characterization data, the obtained reaction product is a pure product (purity>95%); the product yield is 63%.

[0084] Example 8: Synthesis of the compound shown in (III8)

[0085] Weigh 0.1 mmol of N-benzyltryptamine isocyanate (the compound corresponding to number (8), 0.0260 g), 0.1 mmol of unsaturated pyrazolone (the compound corresponding to number (10), 0.0262 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was subjected to vacuum evaporation and column chromatography separation (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0352 g of the reaction product.

[0086] The above reaction products were characterized and the results were as follows:

[0087] 1H NMR(400MHz,DMSO-d6)δ7.86(d,J=8.4Hz,2H),7.48(d,J=7.6Hz,2H),7.31–7.27(m,2H),7.2 2–7.18(m,4H),7.15–7.08(m,5H),7.04(d,J=3.6Hz,1H),6.92(t,J=7.2Hz,1H),6.78(d,J=8. 0Hz,1H),6.73(d,J=7.2Hz,1H),6.59(d,J=8.0Hz,1H),4.65(d,J=15.6Hz,1H),4.37(s,1H), 4.10–3.97(m,2H),3.91–3.79(m,1H),2.12–2.02(m,1H),1.92–1.84(m,1H),1.34(s,3H)ppm.

[0088] According to the characterization data, the obtained reaction product is pure (purity>95%); the product yield is 67%.

[0089] Example 9: Synthesis of the compound shown in (III10)

[0090] Weigh 0.1 mmol of tryptamine isonitrile (the compound corresponding to number (1), 0.0170 g), 0.1 mmol of 2-methyl unsaturated pyrazolone (the compound corresponding to number (11), 0.0276 g) and 30 mg of Molecular sieves were placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0323 g of the reaction product.

[0091] The above reaction products were characterized and the results were as follows:

[0092] 1H NMR (400MHz, DMSO-d6) δ7.84(d,J=8.4Hz,2H),7.41(t,J=7.6Hz,2H),7.26(d,J=7.6Hz ,1H),7.19–7.04(m,3H),6.98(dt,J=7.2,2.0Hz,1H),6.92–6.83(m,2H),6.68(t,J=7.2 Hz,1H),6.55(d,J=7.6Hz,1H),6.49(s,1H),5.93(d,J=4.0Hz,1H),4.44(s,1H),3.98– 3.86(m,1H),3.82–3.71(m,1H),2.27–2.14(m,4H),1.95–1.86(m,1H),1.41(s,3H)ppm.

[0093] According to the characterization data, the obtained reaction product is pure (purity>95%); the product yield is 72%.

[0094] Example 10: Synthesis of the compound shown in (III11)

[0095] Weigh 0.1 mmol of tryptamine isonitrile (the compound corresponding to number (1), 0.0170 g), 0.1 mmol of 3-methyl unsaturated pyrazolone (the compound corresponding to number (12), 0.0276 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0265 g of the reaction product.

[0096] The above reaction products were characterized and the results were as follows:

[0097] 1 H NMR (400MHz, DMSO-d6) δ7.91(d,J=8.0Hz,2H),7.47(t,J=8.0Hz,2H),7.29–7.19(m,2H),7.06(t,J=7.6Hz,1H),7.02–6.91(m,2H),6.76–6 .64(m,3H),6.59–6.49(m,3H),4.32(s,1H),4.09–3.98(m,1H),3.92–3.81(m,1H),2.19–2.07(m,4H),1.91–1.81(m,1H),1.27(s,3H)ppm.

[0098] According to the characterization data, the obtained reaction product is pure (purity>95%); the product yield is 59%.

[0099] Example 11: Synthesis of the compound shown in (III12)

[0100] Weigh 0.1 mmol of tryptamine isonitrile (the compound corresponding to number (1), 0.0170 g), 0.1 mmol of 3-nitro unsaturated pyrazolone (the compound corresponding to number (13), 0.0307 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0364 g of the reaction product.

[0101] The above reaction products were characterized and the results were as follows:

[0102] 1 H NMR(400MHz,DMSO-d6)δ7.92(d,J=8.0Hz,2H),7.73(dd,J=8.0,2.4Hz,1H),7 .54(d,J=3.6Hz,1H),7.51–7.39(m,4H),7.35–7.21(m,3H),7.08(t,J=7.6Hz ,1H),6.74–6.64(m,2H)6.59(d,J=7.6Hz,1H),4.38(s,1H),4.18–4.05(m,1H ),3.97–3.86(m,1H),2.26–2.13(m,1H),1.95–1.84(m,1H),1.28(s,3H)ppm.

[0103] According to the characterization data, the obtained reaction product is pure (purity>95%); the product yield is 76%.

[0104] Example 12: Synthesis of the compound shown in (III13)

[0105] Weigh 0.1 mmol of tryptamine isonitrile (the compound corresponding to number (1), 0.0170 g), 0.1 mmol of 4-fluorounsaturated pyrazolone (the compound corresponding to number (14), 0.0280 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0330 g of the reaction product.

[0106] The above reaction products were characterized and the results were as follows:

[0107] 1 H NMR (400MHz, DMSO-d6) δ7.92(d,J=8.0Hz,2H),7.51–7.39(m,4H),7.27–7.19(m,2H),7.12(d,J=3.6Hz,1H),7.06(t,J=7.6Hz,1H),6.67(t, J=7.6Hz,1H),6.63–6.50(m,4H),4.32(s,1H),4.11–3.98(m,1H),3.92–3.83(m,1H),2.21–2.09(m,1H),1.91–1.79(m,1H),1.26(s,3H)ppm.

[0108] According to the characterization data, the obtained reaction product is a pure product (purity>95%); the product yield is 73%.

[0109] Example 13: Synthesis of the compound shown in (III14)

[0110] Weigh 0.1 mmol of tryptamine isonitrile (the compound corresponding to number (1), 0.0170 g), 0.1 mmol of 4-chlorounsaturated pyrazolone (the compound corresponding to number (15), 0.0296 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0328 g of the reaction product.

[0111] The above reaction products were characterized and the results were as follows:

[0112] 1H NMR (400MHz, DMSO-d6) δ7.92(d,J=8.0Hz,2H),7.46(t,J=7.6Hz,2H),7.29–7.15(m,4H),7.14–7.03(m,2H),6.79(d,J=8.4Hz,2H),6.67(t, J=7.6Hz,1H),6.63–6.52(m,2H),4.33(s,1H),4.10–3.98(m,1H),3.93–3.82(m,1H),2.23–2.09(m,1H),1.91–1.79(m,1H),1.27(s,3H)ppm.

[0113] According to the characterization data, the obtained reaction product is a pure product (purity>95%); the product yield is 70%.

[0114] Example 14: Synthesis of the compound shown in (III15)

[0115] Weigh 0.1 mmol of tryptamine isonitrile (the compound corresponding to number (1), 0.0170 g), 0.1 mmol of 4-bromounsaturated pyrazolone (the compound corresponding to number (16), 0.0340 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0343 g of the reaction product.

[0116] The above reaction products were characterized and the results were as follows:

[0117] 1 H NMR(400MHz, DMSO-d6)δ7.92(d,J=8.0Hz,2H),7.46(t,J=7.6Hz,2H),7.35–7.20(m,4H),7.16–7.01(m,2H),6.77–6.64(m,3H) ,6.62–6.50(m,2H),4.32(s,1H),4.12–3.99(m,1H),3.94–3.81(m,1H),2.23–2.09(m,1H),1.90–1.78(m,1H),1.26(s,3H)ppm.

[0118] According to the characterization data, the obtained reaction product is pure (purity>95%); the product yield is 67%.

[0119] Example 15: Synthesis of the compound shown in (III16)

[0120] Weigh 0.1 mmol of tryptamine isonitrile (the compound corresponding to number (1), 0.0170 g), 0.1 mmol of 4-iodo unsaturated pyrazolone (the compound corresponding to number (17), 0.0388 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0387 g of the reaction product.

[0121] The above reaction products were characterized and the results were as follows:

[0122] 1 H NMR (400MHz, DMSO-d6) δ7.92(d,J=8.0Hz,2H),7.50–7.40(m,4H),7.26–7.19(m,2H),7.12(d,J=3.6Hz,1H),7.06(t,J=7.6Hz,1H),6.67(t, J=7.2Hz,1H),6.63–6.48(m,4H),4.32(s,1H),4.11–3.99(m,1H),3.93–3.82(m,1H),2.22–2.08(m,1H),1.90–1.80(m,1H),1.26(s,3H)ppm.

[0123] According to the characterization data, the obtained reaction product is pure (purity>95%); the product yield is 69%.

[0124] Example 16: Synthesis of the compound shown in (III17)

[0125] Weigh 0.1 mmol of tryptamine isonitrile (the compound corresponding to number (1), 0.0170 g), 0.1 mmol of 4-nitro unsaturated pyrazolone (the compound corresponding to number (18), 0.0307 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0374 g of the reaction product.

[0126] The above reaction products were characterized and the results were as follows:

[0127] 1 H NMR (400MHz, DMSO-d6) δ8.08–7.88(m,5H),7.48(t,J=7.6Hz,2H),7.31–7.19(m,2H),7.09(t,J=7.6Hz,1H),6.87(d,J=8.4Hz,2H),6.75–6. 65(m,2H),6.60(d,J=8.0Hz,1H),4.37(s,1H),4.26–4.10(m,1H),4.03–3.90(m,1H),2.30–2.16(m,1H),1.95–1.83(m,1H),1.25(s,3H)ppm.

[0128] According to the characterization data, the obtained reaction product is a pure product (purity>95%); the product yield is 78%.

[0129] Example 17: Synthesis of the compound shown in (III18)

[0130] Weigh 0.1 mmol of tryptamine isonitrile (the compound corresponding to number (1), 0.0170 g), 0.1 mmol of 4-trifluoromethyl unsaturated pyrazolone (the compound corresponding to number (19), 0.0330 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0426 g of the reaction product.

[0131] The above reaction products were characterized and the results were as follows:

[0132] 1 H NMR (400MHz, DMSO-d6) δ7.93(d,J=8.0Hz,2H),7.52–7.41(m,5H),7.29–7.19(m,2H),7.07(t,J=7.6Hz,1H),6.92(d,J=8.0Hz,2H),6.73–6. 61(m,2H),6.58(d,J=8.0Hz,1H),4.35(s,1H),4.17–4.05(m,1H),3.99–3.86(m,1H),2.24–2.12(m,1H),1.93–1.82(m,1H),1.26(s,3H)ppm.

[0133] According to the characterization data, the obtained reaction product is pure (purity>95%); the product yield is 85%.

[0134] Example 18: Synthesis of the compound shown in (III19)

[0135] Weigh 0.1 mmol of tryptamine isonitrile (the compound corresponding to number (1), 0.0170 g), 0.1 mmol of 4-methyl unsaturated pyrazolone (the compound corresponding to number (20), 0.0276 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0229 g of the reaction product.

[0136] The above reaction products were characterized and the results were as follows:

[0137] 1 H NMR (400MHz, DMSO-d6) δ7.93(d,J=8.0Hz,2H),7.46(t,J=7.6Hz,2H),7.28–7.17(m,2H),7.05(t,J=7.6Hz,1H),6.94(d,J=8.0Hz,2H),6.81(d,J=3.6Hz ,1H),6.76–6.63(m,3H),6.59–6.48(m,2H),4.32(s,1H),4.07–3.94(m,1H) ,3.90–3.80(m,1H),2.21–2.07(m,4H),1.89–1.78(m,1H),1.27(s,3H)ppm.

[0138] According to the characterization data, the obtained reaction product is pure (purity>95%); the product yield is 51%.

[0139] Example 19: Synthesis of the compound shown in (III20)

[0140] Weigh 0.1 mmol of tryptamine isonitrile (the compound corresponding to number (1), 0.0170 g), 0.1 mmol of 4-methoxy unsaturated pyrazolone (the compound corresponding to number (21), 0.0292 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0199 g of the reaction product.

[0141] The above reaction products were characterized and the results were as follows:

[0142] 1 H NMR(400MHz, DMSO-d6)δ7.93(d,J=7.2Hz,2H),7.51–7.42(m,2H),7.27–7.19(m,2H),7.05(td,J=7.6,1.2Hz,1H),6.79–6.70(m,4H),6.70–6.63( m,2H),6.58–6.51(m,2H),4.31(s,1H),4.04–3.94(m,1H),3.87–3.79(m, 1H),3.63(s,3H),2.18–2.07(m,1H),1.88–1.80(m,1H),1.28(s,3H)ppm.

[0143] According to the characterization data, the obtained reaction product is a pure product (purity>95%); the product yield is 43%.

[0144] Example 20: Synthesis of the compound shown in (III21)

[0145] Weigh 0.1 mmol of tryptamine isonitrile (the compound corresponding to number (1), 0.0170 g), 0.1 mmol of naphthyl unsaturated pyrazolone (the compound corresponding to number (22), 0.0312 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0377 g of the reaction product.

[0146] The above reaction products were characterized and the results were as follows:

[0147] 1H NMR(400MHz, DMSO-d6)δ7.95(d,J=8.0Hz,1H),7.90–7.81(m,3H),7.68(d,J=8.0Hz,1H),7.52–7.38(m,5H),7.27–7.09(m,4H),6.78(t,J=7.2Hz,1H) ,6.66–6.54(m,2H),5.83(d,J=4.1Hz,1H),4.55(s,1H),3.98–3.87(m,1H) ,3.75–3.66(m,1H),2.34–2.21(m,1H),1.99–1.92(m,1H),1.38(s,3H)ppm.

[0148] According to the characterization data, the obtained reaction product is a pure product (purity>95%); the product yield is 78%.

[0149] Example 21: Synthesis of the compound shown in (III22)

[0150] Weigh 0.1 mmol of tryptamine isonitrile (the compound corresponding to number (1), 0.0170 g), 0.1 mmol of biphenyl unsaturated pyrazolone (the compound corresponding to number (23), 0.0338 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0412 g of the reaction product.

[0151] The above reaction products were characterized and the results were as follows:

[0152] 1 H NMR(400MHz, DMSO-d6)δ8.72(s,1H),7.18(d,J=7.6Hz,1H),7.21–7.14(m,1H),7.05–6.94(m,4H),6.84(t,J=7.6Hz,1H),6.67–6.55(m,3H),6.5 1(d,J=7.6Hz,1H),6.40(d,J=7.6Hz,1H),6.22(s,1H),4.28–4.16(m,1H ),4.13(s,1H),3.98–3.87(m,1H),2.46–2.32(m,1H),1.94–1.83(m,1H).

[0153] According to the characterization data, the obtained reaction product is a pure product (purity>95%); the product yield is 81%.

[0154] Example 22: Synthesis of the compound shown in (III25)

[0155] Weigh 0.1 mmol of tryptamine isonitrile (the compound corresponding to number (1), 0.0170 g), 0.1 mmol of N-2-chlorophenyl unsaturated pyrazolone (the compound corresponding to number (26), 0.0296 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0304 g of the reaction product.

[0156] The above reaction products were characterized and the results were as follows:

[0157] 1 H NMR(400MHz, DMSO-d6)δ7.69–7.58(m,2H),7.55–7.45(m,2H),7.27–7.16(m,3H),7.06(t,J=7.6Hz,1H),7.02–6.90(m,4H)6.72–6. 60(m,2H),6.57(s,1H),4.32(s,1H),4.09–3.97(m,1H),3.91–3.81(m,1H),2.19–2.07(m,1H),1.90–1.80(m,1H),1.23(s,3H)ppm.

[0158] According to the characterization data, the obtained reaction product is pure (purity>95%); the product yield is 65%.

[0159] Example 23: Synthesis of the compound shown in (III26)

[0160] Weigh 0.1 mmol of tryptamine isonitrile (the compound corresponding to number (1), 0.0170 g), 0.1 mmol of N-4-chlorophenyl unsaturated pyrazolone (the compound corresponding to number (27), 0.0296 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0346 g of the reaction product.

[0161] The above reaction products were characterized and the results were as follows:

[0162] 1 H NMR (400MHz, DMSO-d6) δ7.97(d,J=8.8Hz,2H),7.53(d,J=8.8Hz,2H),7.25(d,J=7.2Hz,1 H),7.13(t,J=7.6Hz,2H),7.06(td,J=7.6,1.2Hz,1H),7.00(d,J=3.6Hz,1H),6.91(t,J=7 .2Hz,1H),6.82–6.76(m,2H),6.67(t,J=7.2Hz,1H),6.60–6.53(m,2H),4.33(s,1H),4.0 9–3.98(m,1H),3.91–3.82(m,1H),2.20–2.09(m,1H),1.90–1.81(m,1H),1.27(s,3H)ppm.

[0163] According to the characterization data, the obtained reaction product is pure (purity>95%); the product yield is 74%.

[0164] Example 24: Synthesis of the compound shown in (III27)

[0165] Weigh 0.1 mmol of tryptamine isonitrile (the compound corresponding to number (1), 0.0170 g), 0.1 mmol of N-4-nitrophenyl unsaturated pyrazolone (the compound corresponding to number (28), 0.0307 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was subjected to vacuum evaporation and column chromatography separation (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0383 g of the reaction product.

[0166] The above reaction products were characterized and the results were as follows:

[0167] 1H NMR (400MHz, DMSO-d6) δ8.38(d,J=8.8Hz,2H),8.23(d,J=8.8Hz,2H),7.27(d,J= 7.2Hz,1H),7.18–7.04(m,4H),6.92(t,J=7.2Hz,1H),6.79(d,J=8.0Hz,2H),6.6 9(t,J=7.2Hz,1H),6.63(s,1H),6.57(d,J=8.0Hz,1H),4.37(s,1H),4.12–3.99( m,1H),3.94–3.82(m,1H),2.24–2.10(m,1H),1.93–1.80(m,1H),1.31(s,3H)ppm.

[0168] According to the characterization data, the obtained reaction product is a pure product (purity>95%); the product yield is 80%.

[0169] Example 25: Synthesis of the compound shown in (III28)

[0170] Weigh 0.1 mmol of tryptamine isonitrile (the compound corresponding to number (1), 0.0170 g), 0.1 mmol of N-4-methyl unsaturated pyrazolone (the compound corresponding to number (29), 0.0276 g) and 30 mg of The molecular sieve was placed in an 8 mL sample bottle, 1 mL of anhydrous tetrahydrofuran was added as solvent, and the reaction was stirred at 90°C for 4 hours. After the reaction was completed, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase was 200-300 mesh silica gel powder, the mobile phase was ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) was 1:6) to obtain 0.0296 g of the reaction product.

[0171] The above reaction products were characterized and the results were as follows:

[0172] 1 H NMR(400MHz, DMSO-d6)δ7.80(d,J=8.4Hz,2H),7.30–7.22(m,3H),7.12(t,J=7. 6Hz,2H),7.05(td,J=7.6,1.2Hz,1H),6.98–6.88(m,2H),6.82–6.77(m,2H),6. 67(t,J=7.2Hz,1H),6.59–6.53(m,2H),4.31(s,1H),4.08–3.96(m,1H),3.91–3 .82(m,1H),2.32(s,3H),2.19–2.08(m,1H),1.90–1.81(m,1H),1.26(s,3H)ppm.

[0173] According to the characterization data, the obtained reaction product is pure (purity>95%); the product yield is 66%.

[0174] Example 26: Biological Activity Test

[0175] The specific mechanism of antifungal activity usually requires in vitro testing (such as minimum inhibitory concentration (MIC) determination), and further studies are needed to confirm its efficacy and safety.

[0176] The present invention selected 10 compounds prepared in the above examples and conducted cytotoxicity tests on fungi. The results are shown in Table 1, which show that the compounds represented by formula III4, III7, III8, III13, III16, III18, and III21 exhibit broad-spectrum antifungal activity (MIC values ​​are similar to Fluconazole); the compounds represented by formula III12, III20, and III25 have certain antifungal activity.

[0177] Table 1. Test results of antifungal activity (MIC, μg / mL) of different compounds

[0178]

[0179] The above results show that the five-membered bispirocyclic indoline derivatives synthesized in the present invention have antifungal activity.

[0180] Obviously, the above embodiments are merely examples for clear description and are not limitations of the implementation methods.

[0181] Although the above disclosure discusses some of the invention embodiments currently considered useful through various examples, it should be understood that such details are for illustrative purposes only, and the appended claims are not limited to the disclosed embodiments. On the contrary, the claims are intended to cover all modifications and equivalent combinations that are consistent with the essence and scope of the embodiments of the present application.

[0182] Similarly, it should be noted that in order to simplify the description of the disclosure of this application and thus facilitate the understanding of one or more embodiments of the invention, in the foregoing description of the embodiments of this application, multiple features are sometimes combined into one embodiment or its description. However, this disclosure method does not mean that the features required by the object of this application are more than the features mentioned in the claims.

[0183] In some embodiments, numbers describing the number of components and attributes are used. It should be understood that such numbers used in the description of the embodiments are modified by the modifiers "about", "approximately" or "substantially" in some examples. Unless otherwise specified, "about", "approximately" or "substantially" indicate that the numbers are allowed to vary by ±. Accordingly, in some embodiments, the numerical parameters used in the specification and claims are approximate values, which may vary according to the required features of individual embodiments.

[0184] Finally, it should be understood that the embodiments described in this application are only used to illustrate the principles of the embodiments of the present application. Other variations may also fall within the scope of the present application. Therefore, as an example and not a limitation, the alternative configurations of the embodiments of the present application may be considered to be consistent with the teachings of the present application. Accordingly, the embodiments of the present application are not limited to the embodiments explicitly introduced and described in the present application.

Claims

1. A rapid preparation method of a five-membered bispirocyclic indoline derivative, characterized in that: The following steps are involved: The compounds represented by formula (I) and formula (II) are reacted in an organic solvent to obtain a five-membered bispirocyclic indoline derivative represented by formula (III); Among them, R 1 is selected from hydrogen, alkyl or halogen; R 2 is selected from hydrogen, alkyl, allyl, benzyl or benzoyl; R 3 is selected from phenyl, naphthyl, biphenyl, thienyl, furanyl, alkylphenyl, halogenphenyl, alkoxyphenyl, nitrophenyl or trifluoromethylphenyl; R 4 Selected from alkylphenyl, halogenphenyl or nitrophenyl.

2. The preparation method according to claim 1, characterized in that: The molar ratio of the compounds represented by formula (I) and formula (II) is (1.5-1.0):1.

0.

3. The preparation method according to claim 1, characterized in that: The organic solvent is selected from one or more of methanol, ethanol, 1,4-dioxane, toluene, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, methyl tert-butyl ether, ethylene glycol dimethyl ether, hexafluoroisopropanol and tetrahydrofuran.

4. The rapid preparation method according to claim 1, characterized in that: The reaction is carried out under air atmosphere.

5. The rapid preparation method according to claim 1, characterized in that: The reaction temperature is 70-110° C., and the reaction time is 2 h-12 h.

6. The rapid preparation method according to claim 1, characterized in that: The compound represented by formula (I) is selected from tryptamine isocyanide, 5-methyltryptamine isocyanide, 5-chlorotryptamine isocyanide, 5-bromotryptamine isocyanide, 6-bromotryptamine isocyanide, N-methyltryptamine isocyanide, N-allyltryptamine isocyanide, N-benzyltryptamine isocyanide or N-benzoyltryptamine isocyanide.

7. The rapid preparation method according to claim 1 or 6, characterized in that: The compound represented by formula (II) is selected from unsaturated pyrazolone, 2-methyl unsaturated pyrazolone, 3-methyl unsaturated pyrazolone, 3-nitro unsaturated pyrazolone, 4-fluoro unsaturated pyrazolone, 4-chloro unsaturated pyrazolone, 4-bromo unsaturated pyrazolone, 4-iodo unsaturated pyrazolone, 4-nitro unsaturated pyrazolone, 4-trifluoromethyl unsaturated pyrazolone, 4-methyl unsaturated pyrazolone, 4-methoxy unsaturated pyrazolone, naphthyl unsaturated pyrazolone, biphenyl unsaturated pyrazolone, thienyl unsaturated pyrazolone, furyl unsaturated pyrazolone, N-2-chlorophenyl unsaturated pyrazolone, N-4-chlorophenyl unsaturated pyrazolone, N-4-nitrophenyl unsaturated pyrazolone or N-4-methyl unsaturated pyrazolone.

8. The rapid preparation method according to claim 7, characterized in that: The five-membered bispirocyclic indoline derivatives of formula (III) include compounds numbered III1-III28.

9. A five-membered bispirocyclic indoline derivative prepared by the preparation method according to any one of claims 1 to 8, characterized in that: The structural formula of the five-membered bispirocyclic indoline derivative is: Among them, R 1 is selected from hydrogen, alkyl or halogen; R 2 is selected from hydrogen, alkyl, allyl, benzyl or benzoyl; R 3 is selected from phenyl, naphthyl, biphenyl, thienyl, furanyl, alkylphenyl, halogenphenyl, alkoxyphenyl, nitrophenyl or trifluoromethylphenyl; R 4 Selected from alkylphenyl, halogenphenyl or nitrophenyl.

10. Use of the five-membered bispirocyclic indoline derivative prepared by the preparation method according to any one of claims 1 to 8 in antifungal activity.

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