Spiro structure-based pyrrole-indolone heterocyclic derivative as well as preparation method and application thereof

Abstract

The invention discloses a spiro-structure-based pyrrole-indolone heterocyclic derivative and a preparation method and application thereof.The spiro-structure-based pyrrole-indolone heterocyclic derivative is prepared through the steps that a cyclic imine ylide derivative (shown in the formula 1) and a 2-alkenyl indole derivative (shown in the formula 2) serve as starting raw materials and react for 6-24 h under the combined action of a catalyst, alkali and a solvent, and the spiro-structure-based pyrrole-indolone heterocyclic derivative is obtained. The pyrrole-indolone heterocyclic derivative based on the spiro structure is synthesized in one step; the preparation method has the advantages of few reaction steps, simple operation, easily available raw materials and high yield; the synthesis strategy opens up a new strategy for constructing the compound, and the stereochemical control characteristic of the product is obviously superior to that of a traditional method. The reaction system shows good tolerance to various substrate substituents (including electron donating / electron withdrawing groups), the steps of intermediate separation and purification are effectively avoided through a one-pot process, the synthesis efficiency is remarkably improved, and large-scale production feasibility is achieved.

Description

Technical Field

[0001] The invention relates to the field of chemical synthesis, and in particular to spirocyclic structure-based pyrrole-indolone heterocyclic derivatives and preparation methods and applications thereof. Background Art

[0002] As the core skeleton of many natural products and active pharmaceutical molecules, the pyrroloindolone structural unit (also known as the pyrroloindolone skeleton) has significant application value in the field of medicinal chemistry. This heterocyclic system not only exists in many natural alkaloids, but its unique spatial configuration also gives the compound special biological activity characteristics, showing important potential in the development of anti-tumor, central nervous system regulation and antimicrobial drugs. At the same time, spirocyclic compounds, as another type of pharmacophore with three-dimensional characteristics, also occupy a key position in drug molecule design and functional material development due to their rigid structure and special configuration of the quaternary carbon center. However, the stereoselective construction of the quaternary carbon center has always been a technical difficulty in the field of synthetic chemistry.

[0003] The synthesis methods reported in the existing literature mainly focus on constructing a single planar structure of the pyrroloindolone skeleton. The literature One-Pot Organocatalytic Asymmetric Synthesis of 1H-Pyrrolo[1,2a]indol-3(2H)-ones via a Michael-Hemiaminalization-Oxidation Sequence. Synlett, 2011(4), 469-472 reports an organic catalytic asymmetric synthesis strategy that achieves the preparation of the target product through a Michael-hemiamination-oxidation cascade reaction. It is worth noting that this method not only relies on high-cost chiral amine catalysts, but also requires the use of PCC oxidants with cumbersome post-processing to complete the final transformation. The literature Chemo- and Regioselective Synthesis of Functionalized 1H-imidazo[1,5-a]indol-3(2H)-ones via a Redox-Neutral Rhodium(III)-Catalyzed [4+1] Annulation between Indoles and Alkynes. Advanced Synthesis & Catalysis , 2021, 363, 18, 4380-4389 adopted a rhodium(III)-catalyzed [4+1] cyclization strategy. Although it achieved regioselective synthesis under redox neutral conditions, the use of noble metal catalysts and harsh reaction conditions significantly limited its scope of application.

[0004] It is worth noting that, although the above methods have made progress in the construction of planar structures, there has been no literature report on the synthesis of a three-dimensional skeleton combining pyrroloindolone with a spirocyclic system. The development of an efficient synthesis method for this molecular system with both types of advantageous structures will break through the technical bottleneck of the existing quaternary carbon center construction and provide a key material basis for the discovery of new drug lead compounds and the creation of functional materials. Therefore, the development of a general synthetic strategy for the one-step construction of a spirocyclic pyrroloindolone skeleton has important scientific research value and practical application prospects. Summary of the invention

[0005] In view of the above technical problems, the present invention proposes a pyrrole-indolone heterocyclic derivative based on a spirocyclic structure and a preparation method and use thereof. This synthetic strategy is guided by environmental friendliness and atom economy, and has the characteristics of a simple reaction system, convenient operation, mild conditions, high degree of commercialization of raw materials, controllable costs, excellent yield and good selectivity. Compared with the prior art, this method significantly improves the synthesis efficiency and practicality by simplifying the reaction process and avoiding the use of precious metal catalysts and strong oxidants. Its modular design is more conducive to the rapid construction of a derivative library, opening up a new path for the large-scale preparation of such compounds.

[0006] In order to achieve the above-mentioned invention object, the present invention adopts the following technical scheme: A pyrrole-indolone heterocyclic derivative based on a spirocyclic structure, the general structural formula of which is shown in Formula 3: , Among them, R 1 , R 2 , R 3 Each is independently selected from one of hydrogen atoms, alkoxy groups, alkyl groups or halogen atoms; the electron withdrawing group EWG is selected from one of nitro groups, carbonyl groups or ester groups. The above-mentioned pyrrole-indolone heterocyclic derivative based on the spirocyclic structure has a general structural formula of one of the following structures: .

[0007] The above-mentioned spirocyclic structure-based pyrrole-indolone heterocyclic derivative is synthesized by the following method: a cyclic imine ylide derivative of the structure shown in Formula 1 and a 2-alkenyl indole derivative of the structure shown in Formula 2 are used as reaction substrates, and reacted for 6 to 24 hours (the temperature can be from room temperature to reflux temperature, without special limitation) under the joint action of a catalyst, a base and a solvent. After the reaction is completed, the product is purified to obtain a spirocyclic structure-based pyrrole-indolone heterocyclic derivative shown in Formula 3. The general synthesis route is shown in the following formula: ; Among them, R 1 , R 2 , R 3Each is independently selected from one of a hydrogen atom, an alkyl group, an alkoxy group, and a halogen atom; and the electron withdrawing group EWG is selected from one of a nitro group, a carbonyl group, and an ester group.

[0008] Furthermore, the catalyst is a transition metal complex and / or a phase transfer catalyst.

[0009] Furthermore, the phase transfer catalyst includes conventional phase transfer catalytic materials such as quaternary ammonium salts, quaternary phosphonium salts, crown ether compounds, etc., including chiral quaternary ammonium salts or chiral quaternary phosphonium salts that can serve as stereoselective control components.

[0010] Furthermore, the transition metal complex is selected from at least one of divalent copper salts (such as CuCl2, CuBr2, CuI2, Cu(OTf)2, Cu(OAc)2), monovalent copper salts (such as CuCl, CuBr, CuI), trivalent iron salts (such as FeCl3), divalent iron salts (such as FeBr2, FeCl2), divalent nickel salts (such as NiCl2, NiBr2) and divalent cobalt salts (such as CoCl2, CoBr2, Co(OAc)2).

[0011] Furthermore, the base is selected from one of potassium carbonate, potassium bicarbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, cesium hydroxide, potassium phosphate trihydrate, anhydrous potassium phosphate, and potassium phosphate heptahydrate.

[0012] Furthermore, the solvent is selected from at least one of benzene, toluene, ether, tetrahydrofuran, n-hexane, petroleum ether, chloroform, ethyl acetate, dichloromethane and acetonitrile.

[0013] Furthermore, the amount of the cyclic imine ylide derivative shown in Formula 1 and the 2-alkenyl indole derivative shown in Formula 2 is controlled in the range of 1-3:1-2; the amount of the catalyst used is 0.01-0.5 equivalents of the molar number of the cyclic imine ylide derivative; and the amount of the base added is 1.0-5.0 equivalents of the molar number of the cyclic imine ylide derivative.

[0014] Based on a general inventive concept, the present invention also provides a pyrrole-indolone heterocyclic derivative or a stereoisomer thereof based on a spirocyclic structure.

[0015] The above compounds can be used as anti-inflammatory or anti-cancer compounds, and experimental results show that they have certain anti-inflammatory and anti-cancer activities.

[0016] Mechanism like Figure 1As shown, the cyclic imine ylide derivative (substrate A) is deprotonated to generate the active intermediate 1 under the synergistic effect of the catalyst and the alkaline environment. The intermediate carries out a nucleophilic attack on the olefinic bond region of the 2-alkenyl indole derivative (substrate B) to form intermediate 2; then a second deprotonation is carried out under alkaline conditions to produce intermediate 3. Finally, the nitrogen-terminal anion of intermediate 3 carries out intramolecular cyclization on the ester group, accompanied by the elimination of the methoxy group, completing the stereoselective construction of the spirocyclic product.

[0017] The beneficial effects of the present invention are embodied in: (1) Process innovation: Using cyclic imine ylide derivatives (Formula 1) and 2-vinyl indole derivatives (Formula 2) as starting materials, the spirocyclic pyrroloindolone skeleton can be efficiently constructed within 6-24 hours in a single reaction vessel through the regulation of the catalytic system: the operation process is simple (single-step reaction), and the raw materials have a high degree of commercialization; it avoids the use of precious metal catalysts and complies with the principles of green chemistry; the reaction yield is excellent and the atom economy is significant.

[0018] (2) Substrate tolerance: The catalytic system exhibits excellent compatibility with substrate substituents. Alkyl, alkoxy and halogen substituents on the aromatic ring can all stably participate in the reaction. The one-pot strategy avoids the intermediate purification step in the multi-step synthesis, significantly improving the synthesis efficiency.

[0019] (3) Industrial potential: The target product has clear crystal structure characteristics and a novel spirocyclic topological configuration. The reaction system is less sensitive to air / moisture, is easy to post-process, and is feasible for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 It is a reaction mechanism diagram of the preparation method of the present invention; Figure 2 is the H NMR spectrum of the target compound in Example 2; Figure 3 is the NMR carbon spectrum of the target compound in Example 2; Figure 4 is the H NMR spectrum of the target compound of Example 26; Figure 5 is the NMR carbon spectrum of the target compound in Example 26; Figure 6 Figure 2 shows the cellular NO content for the anti-inflammatory activity test; Figure 7 Figure 2 shows the cell viability of the cells tested for anti-inflammatory activity; Figure 8 Cell viability graph for anticancer activity test. DETAILED DESCRIPTION

[0021] In order to clarify the technical features and implementation advantages of the present invention, the following is described in detail in conjunction with the accompanying drawings and typical embodiments. The following embodiments are only used to illustrate the technical route of the present invention and do not constitute a limitation on the scope of the claims. Those skilled in the art, without departing from the core principles of the present invention, are subject to the protection scope of the present invention for equivalent replacements of reaction parameters, operating procedures or reagents. Unless otherwise specified, the embodiments adopt conventional technical means in the art, and the reagents involved are all commercially available analytical grade.

[0022] Example 1-25 Preparation of spirocyclic pyrrole-indolone heterocyclic derivatives In a 25 mL reaction bottle, add cyclic imine ylide derivatives (substrate A, 0.1-0.3 mmol), indole olefin derivatives (substrate B, 0.1-0.2 mmol), catalyst system (0.01-0.5 equivalents, based on substrate A) and base (1.0-5.0 equivalents, based on substrate A) in sequence, then add 10 mL of solvent, control the molar ratio of catalyst to substrate A to 0.01-0.5, and stir the reaction system at room temperature (25°C) to reflux temperature for 6-24 hours. After the reaction is completed, the solvent is removed by vacuum distillation, and the obtained crude product is separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate gradient system) to obtain a high-purity target compound. Its general synthetic route is shown as follows: After the reaction, post-treatment is performed to separate the product, and the yield of the product is calculated by weighing. The catalyst, base and solvent are shown in Table 1 below.

[0023] Table 1 Catalyst, base, solvent, time, temperature and product yield of Examples 1-25

[0024] The product of Example 2 is used as a typical analysis object, and its nuclear magnetic resonance hydrogen spectrum (¹H NMR, such as Figure 2 ) and nuclear magnetic carbon spectra (¹³C NMR, such as Figure 33H), 7.26 (td, J = 7.2, 1.5 Hz, 2H), 7.19 (d, J = 7.2 Hz, 1H),6.22 (d, J = 0.6 Hz, 1H), 4.10 (ddd, J = 9.5, 4.5, 1.3 Hz, 2H), 4.71 (d, J = 0.6, 1.6 Hz, 2H), 4.69 (ddd, J = 12.4, 4.7, 1.6 Hz, 2H), 4.93 (ddd, J = 12.4, 4.7, 1.6 Hz, 2H), 4.51 (ddd, J = 12.4, 4.7, 1.6 Hz, 2H), 4.65 (ddd, J = 12.4, 4.7, 1.6 Hz, 2H), 4.84 (ddd, J = 12.4, 4.7, 1.6 Hz, 2H), 4.85 (ddd, J = 12.4, 4.7, 1.6 Hz, 2H), 4.91 (d 1H), 3.49 (d, J =16.4 Hz, 1H), 3.28 (dd, J = 17.2, 9.6 Hz, 1H), 3.17 (dd, J = 17.2, 4.7 Hz,1H), 3.07 (d, J = 16.5 Hz, 1H), 2.48 (s, 3H). 13C NMR (100 MHz, CDCl3) δ196.57, 172.18, 165.55, 143.72, 136.33, 135.11, 133.56, 133.45, 131.72,130.80, 129.15, 128.67, 127.94, 127.84, 127.77, 126.07, 124.32, 123.76,120.85, 114.11, 102.33, 71.55, 40.92, 40.57, 29.72, 23.35. HRMS (ESI) m / zcalcd for C 28 H 22 N2O2[M+H]+ = 419.1760, found = 419.1766. Figure 2 The H NMR spectrum and Figure 3 The carbon spectrum shown confirms that the structural formula of the above-mentioned target product is completely consistent with the designed structure.

[0025] Embodiment 26 To a 25 mL reaction bottle, 0.12 mmol of cyclic imine ylide derivative, 0.12 mmol of indole olefin derivative, 0.01 mmol of catalyst (tetrabutylammonium bromide), 0.2 mmol of base (cesium carbonate) and 10 mL of solvent (ethanol) were added in sequence. The reaction was carried out at room temperature for 12 h, and the reaction was directly post-processed for column chromatography separation. The reaction formula is as follows: ; After the reaction, post-treatment, separation of products, weighing and calculation of product yield, the reaction product characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 7.4 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.57(d, J = 7.4 Hz, 1H), 7.44 (dd, J = 6.7, 1.6 Hz, 1H), 7.37 (dd, J = 7.5, 1.2Hz, 1H), 7.32 (dd, J = 7.5, 1.2 Hz, 1H), 7.30 – 7.23 (m, 3H), 7.21 (d, J =8.2 Hz, 3H), 6.21 (s, 1H), 4.08 (dd, J = 9.8, 4.5 Hz, 1H), 3.48 (d, J = 16.4Hz, 1H), 3.25 (dd, J = 17.0, 9.8 Hz, 1H), 3.13 (dd, J = 17.0, 4.6 Hz, 1H),3.06 (d, J = 16.5 Hz, 1H), 2.48 (s, 3H), 2.39 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 196.24, 172.21, 165.50, 144.34, 143.81, 135.13, 133.92, 133.63,131.69, 130.79, 129.34, 129.15, HRMS (ESI) m / z calcd for C 29 H 24 N2O2 [M+H]+ = 433.1916, found = 433.1918. Combined with H NMR spectrum (such as Figure 4 As shown), carbon spectrum (as Figure 5 As shown), it is known that the above-mentioned target product structure is correct. Embodiment 27

[0026] To a 25 mL reaction bottle, 0.12 mmol of cyclic imine ylide derivative, 0.15 mmol of indole olefin derivative, 0.01 mmol of catalyst (tetrabutylammonium bromide), 0.2 mmol of base (cesium carbonate) and 10 mL of solvent (ethanol) were added in sequence. The reaction was carried out at room temperature for 12 h, and the reaction was directly post-processed for column chromatography separation. The reaction formula is as follows: ;

[0027] After the reaction, post-treatment, separation of products, weighing and calculation of product yield, the reaction product characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 7.4 Hz, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.53(d, J = 7.2 Hz, 1H), 7.44 (dd, J = 6.7, 1.6 Hz, 1H), 7.37 (dd, J = 7.5, 1.2Hz, 1H), 7.32 (dd, J = 7.5, 1.2 Hz, 1H), 7.30 – 7.23 (m, 3H), 7.21 (d, J=8.2 Hz, 3H), 6.21 (s, 1H), 4.08 (dd, J = 9.8, 4.5 Hz, 1H), 3.48 (d, J = 16.4Hz, 1H), 3.25 (dd, J = 17.0, 9.8 Hz, 1H), 3.13 (dd, J = 17.0, 4.6 Hz, 1H),3.06 (d, J = 16.5 Hz, 1H), 2.48 (s, 3H), 2.39 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 196.20, 172.22, 165.30, 144.34, 143.81, 135.13, 133.92, 133.63,131.69, 130.79, 129.34, 129.10, HRMS (ESI) m / z calcd for C 29 H 24 N2O2 [M+H]+ = 433.1916, found = 433.1918. It can be seen that the above target product structure is correct.

[0028] Embodiment 28 To a 25 mL reaction bottle, 0.12 mmol of cyclic imine ylide derivative, 0.1 mmol of 4-chloro-substituted indole olefin derivative, 0.01 mmol of catalyst (tetrabutylammonium bromide), 0.2 mmol of base (cesium carbonate) and 10 mL of solvent (ethanol) were added in sequence. The reaction was carried out at room temperature for 12 h, and the reaction was directly post-processed for column chromatography separation. The reaction formula is as follows: ; The product characterization data are as follows: 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 7.2 Hz, 1H),7.73 (d, J = 7.2 Hz, 2H), 7.43 (dd, J= 14.2, 7.2 Hz, 2H), 7.56–7.32 (m, 2H), 7.37–7.31 (m, 2H), 7.26 (td, J = 7.2, 1.5 Hz, 2H), 7.19 (d, J = 7.2 Hz, 1H),6.22 (d, J = 0.6 Hz, 1H), 4.10 (ddd, J = 9.5, 4.5, 1.3 Hz, 1H), 3.49 (d, J =16.4 Hz, 1H), 3.28 (dd, J = 17.2, 9.6 Hz, 1H), 3.17 (dd, J = 17.2, 4.7 Hz, 1H), 3.07 (d, J = 16.5 Hz, 1H), 2.48 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ196.67, 172.30, 165.22, 143.42, 136.33, 135.31, 133.56, 132.45, 131.70,130.81, 129.15, 128.57, HRMS (ESI) m / zcalcd for C 28 H 21 ClN2O2 [M+H]+ = 453.1370, found = 453.1365. It can be seen that the above target product structure is correct.

[0029] Example 29 Biological Activity Test The compounds obtained from the above examples are selected as follows: ; Compound A, compound B and compound C were used as representative compounds for drug activity tests, and the results are as follows. (1) Anti-inflammatory activity test

[0030] RAW264.7 cells were seeded in 96-well plates, 5×10 4 / well, cultured overnight, pretreated with the above drugs for 1 h, and treated with LPS for 24 h.

[0031] The NO production was detected by Griess method. 100 μL supernatant + 100 μL Griess A / B reagent was incubated at room temperature for 10 min and the OD was detected. 540 , calculate the NO content based on the NaNO2 standard curve, the result is as follows Figure 6 As shown; Add CCK8 reagent, 10 μL / well, incubate at 37°C in the dark for 4 h, and measure OD 450 , calculate the cell survival rate, the results are as follows Figure 7 shown.

[0032] Figure 6 The results showed that compounds A (200 μM), B (200 μM), and C (200 μM) could inhibit NO production to a certain extent, indicating that they had certain anti-inflammatory activity. Figure 7 The results showed that compounds A (25 μM), B (12.5 μM), and C (12.5 μM) had certain anti-inflammatory activity against LPS-induced RAW264.7 cells. (2) Anticancer activity test

[0033] A549 (B16F10) cells were seeded in 96-well plates, 2x10 4 / well, overnight culture, drug treatment for 24 h; add CCK8 reagent, 10 μL / well, incubate at 37℃ in the dark for 4 h, and detect OD 450 , calculate the cell survival rate, the results are as follows Figure 8 As shown: Figure 8 The results showed that compound A (25 μM), compound B (200 μM), and compound C (200 μM) had certain anticancer activity against B16F10 melanoma cells.

Claims

1. A pyrrole-indolone heterocyclic derivative based on a spirocyclic structure, characterized in that: Its general structure is shown in Formula 3: ， Among them, R 1 , R 2 , R 3 Each is independently selected from one of hydrogen atom, alkoxy group, alkyl group or halogen atom; the electron withdrawing group EWG is selected from one of nitro group, carbonyl group or ester group.

2. The pyrrole-indolone heterocyclic derivative based on the spirocyclic structure according to claim 1, characterized in that: The general structural formula of the pyrrole-indolone heterocyclic derivative based on the spirocyclic structure is one of the following structures: 。 3. The method for preparing the spirocyclic pyrrole-indolone heterocyclic derivative according to claim 1 or 2, characterized in that: The method comprises the following steps: using a cyclic imine ylide derivative having a structure shown in Formula 1 and a 2-alkenyl indole derivative having a structure shown in Formula 2 as reaction substrates, reacting for 6-24 hours under the combined action of a catalyst, a base and a solvent, and purifying the product after the reaction to obtain a pyrrole-indolone heterocyclic derivative based on a spirocyclic structure shown in Formula 3. The general synthetic route thereof is shown in the following formula: ； Among them, R 1 , R 2 , R 3 Each is independently selected from one of a hydrogen atom, an alkyl group, an alkoxy group, and a halogen atom; and the electron withdrawing group EWG is selected from one of a nitro group, a carbonyl group, and an ester group.

4. The preparation method according to claim 3, characterized in that: The catalyst is a transition metal complex and / or a phase transfer catalyst.

5. The preparation method according to claim 4, characterized in that: The transition metal complex is at least one of monovalent copper salt, divalent copper salt, divalent iron salt, trivalent iron salt, divalent cobalt salt and divalent nickel salt; the phase transfer catalyst is at least one of quaternary ammonium salts, crown ether compounds or quaternary phosphonium salts.

6. The preparation method according to claim 3, characterized in that: The base is selected from one of potassium carbonate, potassium bicarbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, cesium hydroxide, potassium phosphate trihydrate, anhydrous potassium phosphate, and potassium phosphate heptahydrate.

7. The preparation method according to claim 3, characterized in that: The solvent is selected from at least one of benzene, toluene, ether, tetrahydrofuran, n-hexane, petroleum ether, chloroform, ethyl acetate, dichloromethane and acetonitrile.

8. The preparation method according to claim 3, characterized in that: The amount of the cyclic imine ylide derivative shown in formula 1 and the 2-alkenyl indole derivative shown in formula 2 is controlled in the range of 1-3:1-2; the amount of the catalyst used is 0.01-0.5 equivalents of the molar number of the cyclic imine ylide derivative; and the amount of the base added is 1.0-5.0 equivalents of the molar number of the cyclic imine ylide derivative.

9. A stereoisomer of a pyrrole-indolone heterocyclic derivative based on a spiro structure as claimed in claim 1 or 2 or a pyrrole-indolone heterocyclic derivative based on a spiro structure obtained by the preparation method according to any one of claims 3 to 8.

10. Use of the spirocyclic pyrrole-indolone heterocyclic derivative according to claim 1 or 2 or the spirocyclic pyrrole-indolone heterocyclic derivative obtained by the preparation method according to any one of claims 3 to 8 in anti-inflammatory compounds or anti-cancer compounds.

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