A method for preparing pyrrolopyridine derivatives by reacting a conjugated diene functionalized isonitrile with a methine isonitrile

Abstract

The application discloses a method for preparing pyrrolopyridine derivatives by reacting conjugated diene functionalized isonitrile and methine isonitrile, and belongs to the technical field of organic synthesis. The conjugated diene functionalized isonitrile and the methine isonitrile are used as reaction substrates, silver carbonate is used as a catalyst, and the reaction is carried out in an organic solvent to obtain 1H-pyrrolo[2,3-c]pyridine derivatives; the structural formula of the 1H-pyrrolo[2,3-c]pyridine derivatives is shown in the description. The application uses two types of isonitrile compounds, and the 1H-pyrrolo[2,3-c]pyridine derivatives can be prepared at normal temperature and pressure without isolating water or oxygen. The reaction condition is mild, the operation is simple, the raw materials and reagents are simple and easy to obtain, the practicability is high, and the method is suitable for synthesizing various 1H-pyrrolo[2,3-c]pyridine derivatives.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for preparing pyrrolopyridine derivatives by reacting conjugated diene-functionalized isonitriles with methylene isonitriles. Background Technology

[0002] 1H-pyrrolo[2,3-c]pyridine is a nucleus structure with various biological activities, including antitumor and antidiabetic effects. 1H-pyrrolo[2,3-c]pyridine derivatives have attracted widespread attention from researchers in fields such as chemistry, medicine, and bioengineering due to their unique structural characteristics and good biological activities. For example, in 2012, GANSER et al. synthesized 1H-pyrrolo[2,3-c]pyridine derivatives that showed high inhibitory activity against leukemia cells, vascular endothelial cells, and colon cancer cells. Journal of Medicinal Chemistry, 2012 , 55, 9531-9540. In 2013, Professor Liu Jingping's research group synthesized a 1H-pyrrolo[2,3-c]pyridine derivative that showed high inhibitory activity against cervical cancer cells, colorectal adenocarcinoma cells, gastric cancer cells, and lung cancer cells. Journal of Medicinal Chemistry, 2013 , 56, 8008- 8018. In 2017, Professor Hu Youhong's research group synthesized a 1H-pyrrolo[2,3-c]pyridine derivative that showed high activity against fibroblast growth factor receptor (FGFR1) and human acute myeloid leukemia cells. European Journal of Medicinal Chemistry 2017 , 126, 122- 132. Furthermore, in 2020, Professor Liu Changliang's research group synthesized a 1H-pyrrolo[2,3-c]pyridine derivative that exhibited high activity against human in situ pancreatic cancer cells (BxPC3 cells). Bioorganic Chemistry 2020 , 99, 103817-103832. Therefore, research on the synthetic methodologies of 1H-pyrrolo[2,3-c]pyridine derivatives has maintained a vigorous development.

[0003] Currently available efficient synthetic methods for 1H-pyrrolo[2,3-c]pyridine derivatives are very limited, such as the Ullmann cross-coupling method, the dehydrogenation cross-coupling method, and the catalytic cyclization method. However, these methods require stringent experimental conditions or the action of transition metal catalysts, and also present certain technical difficulties in operation. Paul A. Wender et al. synthesized fully substituted 2,3-dihydropyrrole compounds through a silver-catalyzed [3+2] cyclization reaction. This method involves a [3+2] cycloaddition reaction between aziridine and non-activated alkyne under Lewis acid catalysis to form the pyrrole core. Although this method can more easily achieve polysubstituted 2,3-dihydropyrrole, it produces diastereomers, and the structure of 2,3-dihydropyrrole is not the same as that of 1H-pyrrolo[2,3-c]pyridine, thus the preparation principle is also different. Malononitrile is a commonly used raw material in the preparation of 1H-pyrrolo[2,3-c]pyridine derivatives, but there are no reports on the preparation of 1H-pyrrolo[2,3-c]pyridine derivatives using only isonitrile compounds. If 1H-pyrrolo[2,3-c]pyridine derivatives could be prepared using only isonitrile compounds, it would provide an efficient and green new synthetic method for the synthesis of 1H-pyrrolo[2,3-c]pyridine derivatives. Summary of the Invention

[0004] To address the aforementioned limitations of existing technologies, the present invention aims to provide a method for preparing pyrrolopyridine derivatives by reacting conjugated diene-functionalized isonitriles with methylene isonitriles. This invention uses conjugated diene-functionalized isonitriles and methylene isonitriles as reaction substrates and silver carbonate as a catalyst. The reaction proceeds in an organic solvent without the need for the isolation of water or oxygen to obtain 1H-pyrrolo[2,3-c]pyridine derivatives. The preparation method of this invention features mild reaction conditions, simple operation, readily available raw materials and reagents, and strong practicality, making it suitable for synthesizing various 1H-pyrrolo[2,3-c]pyridine derivatives.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] In a first aspect, the present invention provides a method for preparing pyrrolopyridine derivatives by reacting conjugated diene-functionalized isonitriles with methylene isonitriles, the method comprising:

[0007] Using conjugated diene-functionalized isonitriles and methylene isonitriles as reaction substrates and silver carbonate as a catalyst, 1H-pyrrolo[2,3-c]pyridine derivatives were obtained by reacting them in an organic solvent.

[0008] Preferably, the conjugated diene-functionalized isonitrile is selected from ethyl(2Z,4E)-2-isocyano-5-phenylpentane-2,4-dienoate, ethyl(2Z,4E)-2-isocyano-5-(4-methoxyphenyl)pentane-2,4-dienoate, ethyl(2Z,4E)-2-isocyano-5-(p-methoxyphenyl)pentane-2,4-dienoate, ethyl(2Z,4E)-2-isocyano-5-(4-fluorophenyl)pentane-2,4-dienoate, ethyl(2Z,4E)-2-isocyano-5-(4-chlorophenyl)pentane-2,4-dienoate, ethyl(2Z,4E)-2-isocyano-5-(4-bromophenyl)pentane-2,4-dienoate, ethyl(2Z,4E) -2-Isocyano-5-(3-chlorophenyl)pent-2,4-dienoate, ethyl (2Z,4E)-2-isocyano-5-(2-methoxyphenyl)pent-2,4-dienoate, ethyl (2Z,4E)-2-cyano-5-(p-methoxyphenyl)pent-2,4-dienoate, ethyl (2Z,4E)-2-isocyano-5-(2-naphthyl)pent-2,4-dienoate, ethyl (2Z,4E)-2-isocyano-5-(3-thienyl)pent-2,4-dienoate, ethyl (2Z,4E)-2-isocyano-5-(2-furanyl)pent-2,4-dienoate, 1-cyano-4-phenylbut-1,3-dien-1-yl-sulfonyl-4-methylbenzene.

[0009] Preferably, the methylene isonitrile is selected from 1-isocyano-2-ethylsulfonyl-4-toluene, 1-isocyano-2-phenylethylsulfonyl-4-toluene, (1-isocyano-2-(4-methoxyphenyl)ethyl)sulfonyl-4-toluene, 1-fluoro-4-(2-isocyano-2-toluenesulfonylethyl)benzene, 1-bromo-4-(2-isocyano-2-toluenesulfonylethyl)benzene, ethyl-4-(2-isocyano-2-toluenesulfonylethyl)benzoic acid, 1-(2-isocyano-2-toluenesulfonylethyl)2-toluene, 1-(2-isocyano-2-toluenesulfonylethyl)3-toluene, 1-bromo-(2-isocyano-2-toluenesulfonylethyl)benzene, and 4-bromo-(3-isocyano-2-toluenesulfonylethyl)benzene.

[0010] Preferably, the molar ratio of the conjugated diene functionalized isonitrile, methylene isonitrile and silver carbonate is 1.5 : 1 : 0.3.

[0011] Preferably, the organic solvent is selected from tetrahydrofuran, acetonitrile, ethanol, deionized water, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether.

[0012] More preferably, the organic solvent is ethanol.

[0013] Preferably, the reaction temperature is 0~100℃ and the reaction time is 1~48h.

[0014] More preferably, the reaction temperature is 25°C and the reaction time is 2 hours.

[0015] In a second aspect, the present invention provides a 1H-pyrrolo[2,3-c]pyridine derivative obtained by the above method, wherein the structural formula of the 1H-pyrrolo[2,3-c]pyridine derivative is:

[0016] ;

[0017] Among them, R 1 Selected from alkyl, aryl, or heteroaryl groups; R 2 Selected from aryl or alkyl; R 3 Selected from aryl or alkyl groups.

[0018] Preferably, the R 1 Selected from the C1-C20 straight-chain or branched alkyl, aryl, and heteroaryl groups; the R 2 Selected from methyl ester, ethyl ester, tert-butyl ester, 4-trifluoromethylphenyl, p-toluyl, or 3-pyridyl; R 3 It is selected from ethyl, isopropyl, 4-tolyl, benzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-ethyl ester benzyl, 4-fluorobenzyl, 4-bromobenzyl, 2-methylbenzyl, 2-bromobenzyl, 3-methylbenzyl or 3-bromobenzyl.

[0019] Preferably, the 1H-pyrrolo[2,3-c]pyridine derivative is a compound having the following structural formula:

[0020] .

[0021] The beneficial effects of this invention are:

[0022] This invention uses conjugated diene-functionalized isonitriles and methylene isonitriles as reaction substrates and silver carbonate as a catalyst to react in an organic solvent to obtain 1H-pyrrolo[2,3-c]pyridine derivatives without the need for the isolation of water or oxygen. This invention utilizes the cross-heterocyclization reaction of conjugated diene-functionalized isonitriles and methylene isonitriles to generate 1H-pyrrolo[2,3-c]pyridine derivatives. The preparation method is mild, simple to operate, and uses readily available raw materials and reagents, making it highly practical and applicable to the synthesis of various 1H-pyrrolo[2,3-c]pyridine derivatives. Attached Figure Description

[0023] Figure 1 : The 1H NMR spectrum of the 1H-pyrrolo[2,3-c]pyridine derivative 3a prepared in Example 1;

[0024] Figure 2 : Carbon NMR spectrum of 1H-pyrrolo[2,3-c]pyridine derivative 3a prepared in Example 1;

[0025] Figure 3 : The 1H NMR spectrum of the 1H-pyrrolo[2,3-c]pyridine derivative 3c prepared in Example 2;

[0026] Figure 4 : Carbon NMR spectrum of 3c of 1H-pyrrolo[2,3-c]pyridine derivative prepared in Example 2;

[0027] Figure 5 3d 1H-pyrrolo[2,3-c]pyridine derivative prepared in Example 3;

[0028] Figure 6 : Carbon NMR spectrum of the 1H-pyrrolo[2,3-c]pyridine derivative prepared in Example 3 at 3d;

[0029] Figure 7 : The 1H NMR spectrum of the 1H-pyrrolo[2,3-c]pyridine derivative 3e prepared in Example 4;

[0030] Figure 8 : Carbon NMR spectrum of 3e of 1H-pyrrolo[2,3-c]pyridine derivative prepared in Example 4;

[0031] Figure 9 : Schematic diagram of the synthesis principle of this invention. Detailed Implementation

[0032] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of this application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains.

[0033] As introduced in the background section, there are currently very limited efficient synthetic methods for 1H-pyrrolo[2,3-c]pyridine derivatives, such as the Ullmann cross-coupling method, the dehydrogenation cross-coupling method, and the catalytic cyclization method. However, these methods require relatively stringent experimental conditions or the action of transition metal catalysts, and also present certain technical difficulties in operation.

[0034] Based on this, the object of the present invention is to provide a method for preparing pyrrolopyridine derivatives by reacting conjugated diene-functionalized isonitriles with methylene isonitriles. In the reaction substrate of the present invention, the conjugated diene-functionalized isonitrile is an isonitrile with two double bonds attached to the benzene ring and containing electron-withdrawing groups (e.g., ethyl ester group, p-toluenesulfonyl group). Due to their unique reactivity, isonitriles have proven to be a versatile synthetic building block in many transformations; however, the synthesis of 1H-pyrrolo[2,3-c]pyridine derivatives by the cross-heterocyclization reaction of isonitriles has not been achieved due to the difficulty in inhibiting homodimerization, homopolymerization, heteropolymerization, and polymerization. Therefore, based on readily available conjugated diene-functionalized isonitriles, a new method is provided for the de novo synthesis of several important bioactive core-1H-pyrrolo[2,3-c]pyridine derivatives through the chemoselective heterodimerization of conjugated diene-functionalized isonitriles with methylene isonitriles. Conjugated diene-functionalized isonitriles undergo chemoselective heterodimerization with methylene isonitriles under stable catalytic conditions. Following intermolecular affinity addition or [3+2] cycloaddition, and then the removal of silver ions and deprotection groups, the important synthon 1H-pyrrolo[2,3-c]pyridine is finally obtained.

[0035] The synthesis route is shown below:

[0036] .

[0037] The reaction principle is as follows: Figure 9 As shown, a conjugated diene-functionalized isonitrile undergoes a 1,6-addition reaction with a methylene isonitrile to give intermediate I. Subsequently, a silver ion leaves, and this intermediate undergoes intramolecular nucleophilic addition to generate intermediate II. Next, another silver ion leaves to generate intermediate III. Finally, the departure of the sulfonyl group yields a 1H-pyrrolo[2,3-c]pyridine derivative.

[0038] To enable those skilled in the art to better understand the technical solution of this application, the technical solution of this application will be described in detail below with reference to specific embodiments.

[0039] Note: In the examples, Ts represents p-toluenesulfonyl, COOEt or EtO2C represents ethyl ester, and Me represents methyl.

[0040] The test materials used in the embodiments of this invention are all conventional test materials in the art and can be purchased through commercial channels.

[0041] Example 1: Preparation of 1H-pyrrolo[2,3-c]pyridine derivative 3a

[0042] The synthetic route for 3a is as follows:

[0043] .

[0044] The specific preparation method is as follows:

[0045] (1) Preparation of ethyl(2Z,4E)-2-isocyano-5-phenylpentane-2,4-dienoate:

[0046] First, 11 mmol of cinnamaldehyde and 20 mL of acetonitrile solvent were mixed in a 50 mL round-bottom flask. Then, 10 mmol of ethyl isocyanate and 3 mmol of silver carbonate catalyst were added sequentially. The reaction system was kept at a constant temperature of 25±3℃ and stirred under closed conditions for 2 hours. The reaction progress was monitored by thin-layer chromatography until the starting material was completely converted. Next, 10 mL of 10 wt% acetic acid aqueous solution was slowly added dropwise to the reaction mixture until the system became clear. The mixture was then allowed to stand for 60 min to achieve phase separation. The pH of the aqueous phase was adjusted to neutral using saturated sodium bicarbonate solution, and the mixture was extracted three times with 20 mL of dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography, and 0.196 g of the target formamide derivative was finally obtained, with a yield of 87%.

[0047] A 50 mL three-necked reaction flask was pre-dried. 10 mmol of formamide derivative and 40 mmol of triethylamine were added. The system was cooled to 0 °C in an ice-salt bath and stirred continuously for 30 min. 15 mmol of freshly distilled phosphorus oxychloride was added dropwise to the reaction system using a constant-pressure dropping funnel. The reaction was continued at this low temperature with stirring for another 30 min. After the reaction was confirmed to be complete by thin-layer chromatography, the reaction solution was carefully transferred to a pre-cooled ice-salt aqueous solution for quenching. Extraction was repeated three times with 20 mL of diethyl ether. The combined organic phases were washed and dehydrated with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, and the final separation yielded yellow crystals, which were ethyl(2Z,4E)-2-isocyano-5-phenylpentane-2,4-dienoic acid ester, with a yield of 80%.

[0048] (2) Preparation of 1-isocyano-2-ethylsulfonyl-4-toluene: p-Toluenesulfonylmethylisocyanate (10 mmol, 1.95 g), 4-methylbenzaldehyde (10 mmol, 1.18 mL), triethylenediamine (DABCO) catalyst (112 mg, 10% of the molar amount of the reactants), and water (20 mL) were added to a 50 mL round-bottom flask. The reaction system was stirred at a constant temperature of 25 ± 3 °C for three hours. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was complete, the mixture was solidified in the round-bottom flask, filtered, washed with cold water to remove the catalyst, and dried to obtain 1-isocyano-2-ethylsulfonyl-4-toluene.

[0049] (3) Ethyl(2Z,4E)-2-isocyano-5-phenylpentane-2,4-dienoate (1a, 68.18 mg, 0.3 mmol), 1-isocyano-2-ethylsulfonyl-4-toluene (2a, 59.88 mg, 0.2 mmol), silver carbonate (16.5 mg, 0.06 mmol), and ethanol solvent (2 mL) were added sequentially to a 15 mL pressure-resistant tube. A stir bar was added, the pressure-resistant tube stopper was tightened, and the tube was placed in a metal module preheated to 25°C for heating and stirring for two hours. After the reaction 2a disappeared as detected by TLC, the reaction system was separated and concentrated by column chromatography to obtain a light yellow solid 3a (46.37 mg, 83%). Its 1H NMR spectrum and 1C NMR spectrum are shown below. Figure 1 and Figure 2 .

[0050] Spectral analysis data: 1 H NMR (400 MHz, CDCl3): δ 9.42 (s, 1H), 8.61 (s, 1H), 8.48 (s, 1H), 7.53-7.48 (m, 4H), 7.39-7.36 (m, 1H), 7.07 (t, J = 8.4 Hz, 4H), 4.41(q, J = 7.2 Hz, 2H), 4.26 (s, 2H), 2.28 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 166.5, 139.7, 138.0, 136.7, 134.3, 133.9, 133.3, 132.6,129.6, 129.4, 128.8, 128.6, 126.9, 117.1, 116.1, 61.3, 32.3, 20.9, 14.4; HRMS(ESI) m / z: [M+H] + calcd for C 17 H 15 N2O2 + 280.1206; found 280.1210.

[0051] Example 2: Preparation of 1H-pyrrolo[2,3-c]pyridine derivative 3c

[0052] The synthesis route for 3C is as follows:

[0053] .

[0054] The specific preparation method is as follows:

[0055] (1) Preparation of ethyl(2Z,4E)-2-isocyano-5-(4-methoxyphenyl)pentane-2,4-dienoate: p-methylcinnamaldehyde (1.61 g, 11 mmol) and CH3CN (20 mL) were added to a 50 mL round-bottom flask, followed by ethyl isocyanate (1.09 mL, 10 mmol) and Ag2CO3 (0.83 g, 3 mmol). The mixture was stirred for 2 hours at room temperature. After the substrate was completely converted by TLC, acetic acid aqueous solution (10 mL, 10 wt%) was added to the reaction solution until the solution was no longer turbid. After 1 h, saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate volume ratio = 8 / 1) to give formamide compound (2.47 g, 90%).

[0056] In a 50 mL round-bottom flask, formamide compound (2.75 g, 10 mmol) and triethylamine (5.54 mL, 40 mmol) were added and stirred at 0 °C for half an hour. Then, POCl3 (1.39 mL, 15 mmol) was slowly added dropwise to the reaction mixture using a constant-pressure low-pressure funnel. The mixture was stirred at low temperature for another half hour. After the starting material was consumed by TLC, the reaction was quenched with ice-cold brine. The organic phase was extracted with diethyl ether (20 mL × 3), washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, volume ratio = 30 / 1) to obtain a yellow solid, which was ethyl(2Z,4E)-2-isocyano-5-(4-methoxyphenyl)pentane-2,4-dienoate (2.21 g, 86%).

[0057] (2) The preparation of 1-isocyano-2-ethylsulfonyl-4-toluene is the same as step (2) in Example 1.

[0058] (3) Ethyl(2Z,4E)-2-isocyano-5-(4-methoxyphenyl)pentane-2,4-dienoate (1c, 77.18 mg, 0.3 mmol), 1-isocyano-2-ethylsulfonyl-4-toluene (2a, 59.88 mg, 0.2 mmol), silver carbonate (16.5 mg, 0.06 mmol), and ethanol solvent (2 mL) were added sequentially to a 15 mL pressure-resistant tube. A stir bar was added, the pressure-resistant tube stopcock was tightened, and the tube was placed in a metal module preheated to 25°C for heating and stirring for two hours. After the reaction 2a disappeared as detected by TLC, the reaction system was separated and concentrated by column chromatography to obtain a light yellow solid 3c (70.48 mg, 88%). Its 1H NMR spectrum and 1C NMR spectrum are shown below. Figure 3 and Figure 4 .

[0059] Spectral analysis data: 1 H NMR (400 MHz, CDCl3): δ 11.68 (s, 1H), 9.21 (s, 1H), 8.42 (s, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.6 Hz, 2H), 7.06 (t, J = 7.6Hz, 4H), 4.47 (q, J = 7.2 Hz, 2H), 4.28 (s, 2H), 3.89 (s, 3H), 2.26 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 163.5, 159.0, 136.6, 134.2,134.1, 132.9, 130.7, 129.5, 128.6, 124.5, 117.2, 117.1, 114.4, 62.3, 55.3,32.5, 20.9, 14.3; HRMS (ESI) m / z: [M+H] + calcd for C 25 H 25 N2O3 + 401.1860; found401.1865.

[0060] Example 3: Preparation of 1H-pyrrolo[2,3-c]pyridine derivative 3d

[0061] The 3D compositing process is as follows:

[0062] .

[0063] The specific preparation method is as follows:

[0064] (1) Preparation of ethyl (2Z,4E)-2-isocyano-5-(4-chlorophenyl)pentane-2,4-dienoate: 4-chlorocinnamaldehyde (1.83 g, 11 mmol) and CH3CN (20 mL) were added to a 50 mL round-bottom flask, followed by ethyl isocyanate (1.09 mL, 10 mmol) and Ag2CO3 (0.83 g, 3 mmol). The mixture was stirred for 2 h at room temperature. After the substrate was completely converted as monitored by TLC, acetic acid aqueous solution (10 mL, 10 wt%) was added to the reaction solution until the solution was no longer turbid. After 1 h, saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate volume ratio = 8 / 1) to give formamide compound (2.46 g, 88%).

[0065] Formamide compound (2.79 g, 10 mmol) and triethylamine (5.54 mL, 40 mmol) were added to a 50 mL round-bottom flask and stirred at 0 °C for half an hour. Then, POCl3 (1.39 mL, 15 mmol) was slowly added dropwise to the reaction system using a constant-pressure low-pressure funnel. The mixture was stirred at low temperature for another half hour. After the starting material was consumed by TLC, the reaction was quenched with ice-cold brine. The organic phase was extracted with diethyl ether (20 mL × 3), washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, volume ratio = 30 / 1) to obtain a yellow solid, which was ethyl(2Z,4E)-2-isocyano-5-(4-chlorophenyl)pentane-2,4-dienoate (2.33 g, 89%).

[0066] (2) The preparation of 1-isocyano-2-ethylsulfonyl-4-toluene is the same as step (2) in Example 1.

[0067] (3) Ethyl(2Z,4E)-2-isocyano-5-(4-chlorophenyl)pentane-2,4-dienoate (1d, 78.51 mg, 0.3 mmol), 1-isocyano-2-ethylsulfonyl-4-toluene (2a, 59.88 mg, 0.2 mmol), silver carbonate (16.5 mg, 0.06 mmol), and ethanol solvent (2 mL) were added sequentially to a 15 mL pressure-resistant tube. A stir bar was added, the pressure-resistant tube stopcock was tightened, and the tube was placed in a metal module preheated to 25°C for heating and stirring for two hours. After the reaction 2a disappeared as detected by TLC, the reaction system was separated and concentrated by column chromatography to obtain a light yellow solid 3d (72.07 mg, 89%). Its 1H NMR spectrum and 1C NMR spectrum are shown below. Figure 5 and Figure 6 .

[0068] Spectral analysis data: 1 H NMR (400 MHz, CDCl3): δ 8.76 (s, 1H), 8.44 (s, 2H), 7.47(q, J = 8.0 4H), 7.17 (d, J = 7.6 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 4.47 (q, J =7.2, 2H), 4.23 (s, 2H), 2.35 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H); 13 C NMR (100MHz, CDCl3): δ 162.7, 144.2, 138.2, 137.0, 135.9, 133.3, 132.3, 129.9, 129.3,128.7, 128.4, 127.6, 127.3, 122.9, 121.1, 117.2, 60.7, 32.6, 21.6, 21.0,14.1; HRMS (ESI) m / z: [M+H] + calcd for C 24 H 22 ClN2O2 + 405.1364; found 405.1366.

[0069] Example 4: Preparation of 1H-pyrrolo[2,3-c]pyridine derivative 3e

[0070] The synthesis route for 3e is as follows:

[0071] .

[0072] The specific preparation method is as follows:

[0073] (1) Preparation of 1-cyano-4-phenylbut-1,3-dien-1-yl-sulfonyl-4-methylbenzene: Cinnamaldehyde (1.25 mL, 11 mmol) and CH3CN (20 mL) were added to a 50 mL round-bottom flask, followed by p-toluenesulfonylmethylisocyanate (1.95 g, 10 mmol) and Ag2CO3 (0.83 g, 3 mmol). The mixture was stirred at room temperature for 2 hours. After the substrate was completely converted as monitored by TLC, an aqueous acetic acid solution (10 mL, 10 wt%) was added to the reaction solution until the solution was no longer turbid. After 1 h, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, volume ratio = 8 / 1) to give a formamide compound (2.95 g, 90%).

[0074] Formamide compound (3.27 g, 10 mmol) and triethylamine (5.54 mL, 40 mmol) were added to a 50 mL round-bottom flask, and the mixture was stirred at 0 °C for half an hour. Then, POCl3 (1.39 mL, 15 mmol) was slowly added dropwise to the reaction system using a constant-pressure low-pressure funnel. The mixture was stirred at low temperature for another half hour. After the starting material was consumed by TLC, the reaction was quenched with ice-cold brine. The organic phase was extracted with diethyl ether (20 mL × 3), washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, volume ratio = 30 / 1) to give a yellow solid, which was 1-cyano-4-phenylbut-1,3-dien-1-yl-sulfonyl-4-methylbenzene (3.50 g, 89%).

[0075] (2) The preparation of 1-isocyano-2-ethylsulfonyl-4-toluene is the same as step (2) in Example 1.

[0076] (3) 1-Cyano-4-phenylbut-1,3-dien-1-yl-sulfonyl-4-methylbenzene (1e, 92.81 mg, 0.3 mmol), 1-isocyano-2-ethylsulfonyl-4-toluene (2a, 59.88 mg, 0.2 mmol), silver carbonate (16.5 mg, 0.06 mmol), and ethanol solvent (2 mL) were added sequentially to a 15 mL pressure-resistant tube. A stir bar was added, the pressure-resistant tube stopcock was tightened, and the tube was placed in a metal module preheated to 25°C for heating and stirring for two hours. After the disappearance of reactant 2a was detected by TLC, the reaction system was separated and concentrated by column chromatography to obtain a light yellow solid 3e (76.93 mg, 85%). Its 1H NMR spectrum and 1C NMR spectrum are shown below. Figure 7 and Figure 8 .

[0077] Spectral analysis data: 1 H NMR (400 MHz, CDCl3): δ 9.14 (s, 1H), 8.52 (s, 1H), 8.48 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.53-7.48 (m, 4H), 7.43-7.38 (m, 1H), 7.20(d, J = 8.0 Hz, 2H), 7.04 (q, J = 8.0 Hz, 4H), 4.24 (s, 2H), 2.33 (s, 3H), 2.26 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 148.1, 143.8, 140.8, 137.5, 136.7, 134.1,134.0, 133.1, 132.6, 132.5, 128.6, 129.5, 129.3, 129.0, 128.6, 128.3, 128.2,127.2, 116.6, 114.3, 32.2, 29.6, 21.5, 20.9; HRMS (ESI) m / z: [M+H] + calcd forC 28 H 25 N2O2S + 453.161; found 453.1636.

[0078] The above description is merely a preferred embodiment of this application and is not intended to limit this application. Various modifications and variations can be made to this application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. A method for preparing pyrrolopyridine derivatives by reacting conjugated diene-functionalized isonitriles with methylene isonitriles, characterized in that, The method is as follows: Using conjugated diene-functionalized isonitriles and methylene isonitriles as reaction substrates and silver carbonate as a catalyst, 1H-pyrrolo[2,3-c]pyridine derivatives were obtained by reacting them in an organic solvent. The molar ratio of the conjugated diene-functionalized isonitrile, methylene isonitrile, and silver carbonate is 1.5 : 1 : 0.3; the organic solvent is selected from tetrahydrofuran, acetonitrile, ethanol, deionized water, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether; the reaction temperature is 25°C, and the reaction time is 2 hours. The conjugated diene-functionalized isonitrile is selected from compounds having the following structural formula: , , or The methyleneisocyanate is a compound having the following structural formula: ; The structural formula of the 1H-pyrrolo[2,3-c]pyridine derivative is: , , or .

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