Synthetic method and application of pyrrolo [2, 1-a] isoquinoline compound

Abstract

The invention belongs to the field of organic chemistry, and particularly relates to a synthetic method and application of a pyrrolo [2, 1-a] isoquinoline compound. According to the synthesis scheme, no catalyst needs to be added, acetonitrile serves as a solvent, the N-(2-formylphenyl)-3-phenyl propyne amide compound and the 1, 2, 3, 4-tetrahydroisoquinoline compound are added into a reaction flask, and the pyrrolo [2, 3, 4] isoquinoline compound is synthesized through the synergistic effect of an aldehyde amine condensation reaction and an intramolecular cyclization reaction. The invention discloses efficient construction of a molecular skeleton of a 1, 1-a] isoquinoline compound. The scheme has multiple advantages of simplified reaction process, mild and easily-controlled reaction conditions, accordance with a green synthesis concept, excellent reaction efficiency and the like. A biological activity test result shows that part of the obtained compounds show good biological activity. The synthesis method provides important technical support for research and development of novel pyrrolo [2, 1-a] isoquinoline heterocyclic skeleton drugs in China, and has significant application value.

Description

Technical Field

[0001] This invention relates to the field of organic chemistry, specifically to a method for synthesizing pyrrolo[2,1-a]isoquinoline and its application. Background Technology

[0002] Pyrrolo[2,1-a]isoquinoline compounds, as an important class of heterocyclic skeletons, are widely found in natural products and bioactive drug molecules. Formed by the fusion of a pyrrole ring and an isoquinoline ring, their unique molecular structure endows them with excellent biopharmacological activities, serving as a key bridge connecting natural product research and innovative drug development. The bioactivity of pyrrolo[2,1-a]isoquinoline derivatives covers multiple key therapeutic areas such as antitumor, antiviral, and antibacterial activity, providing clear directions for drug development. In antitumor therapy, spirotinic acid D blocks tumor cell DNA replication by inhibiting topoisomerase I activity, while reversing tumor multidrug resistance, and exhibits IC50 inhibitory activity against the proliferation of lung cancer, breast cancer, and other cell lines. 50 Values ​​can reach the micromolar level, effectively solving a key problem of drug resistance in some clinical chemotherapy drugs. In the antiviral field, some spirochete derivatives have been shown to target HIV-1 integrase, inhibiting the integration of the viral genome into host cells, providing a novel target for AIDS treatment. Natural products like ammosamides exhibit potent antibacterial activity, with minimum inhibitory concentrations (MICs) against pathogenic bacteria such as Staphylococcus aureus superior to traditional antibiotics, and are less likely to induce drug resistance. Furthermore, the bioactivity of these compounds in areas such as neuroprotection and anti-inflammation is being gradually explored, laying a solid foundation for the development of drugs with multiple indications.

[0003] In recent years, numerous scientists have reported the synthesis of pyrrolo[2,1-a]isoquinoline compounds. For example, Professor Wang Meixiang's group at Tsinghua University (Angewandte Chemie-International Edition, 2016, 55, 3799-3803) reported an intramolecular enantioselective addition reaction catalyzed by a copper trifluoromethanesulfonate / chiral pyridine bisoxazoline complex, which can generate a variety of tetrahydropyrrolo[2,1-a]isoquinoline-3(2H)-one derivatives in good to excellent yields, all of which are single diastereomers. Professor Huang Xueliang's group at the Chinese Academy of Sciences (ACS Catalysis, 2019, 9, 3, 2610-2617) developed a gold-catalyzed conjugated diacetylamide tandem reaction. This method allows for the atom-economical preparation of a series of sulfone-containing pyrrolo[2,1-a]isoquinoline compounds, which possess the core structural unit of spirochetin alkaloids. Density functional theory (DFT) calculations indicate the presence of a continuous 1,2-migration process of the sulfone group in the reaction, which is crucial for pyrrole ring formation. The Lei Aiwen research group (ACS Catalysis, 2020, 10, 12, 6676-6681) developed a manganese-catalyzed electrochemical radical tandem cyclization reaction, using electrical energy as the primary energy input to drive the reaction, ultimately synthesizing a series of benzo[4,5]imidazo[2,1-a]isoquinoline-6(5H)-one derivatives without the addition of an external oxidant. Aleksandr Savateev and colleagues (Nature Communications, 2019, 10, 945) reported a photocatalytic reaction between tetrahydroisoquinoline and chalcone, which generates 1,3-disubstituted-5,6-dihydropyrrolo[2,1-a]isoquinoline.

[0004] Currently, various general methods for synthesizing pyrrolo[2,1-a]isoquinoline derivatives have been developed through intermolecular multicomponent reactions or intramolecular cyclization reactions. However, existing synthetic methods generally suffer from limitations such as the need for pre-activation of reaction components, complex processes, or harsh reaction conditions, and often rely on expensive transition metals, photocatalysts, and complex raw materials, causing many problems for practical applications. Therefore, under the guidance of green chemistry principles, developing direct and efficient synthetic strategies for pyrrolo[2,1-a]isoquinoline compounds is of great significance for the development of drugs with independent intellectual property rights. Summary of the Invention

[0005] The purpose of this invention is to provide a novel synthetic method and application for pyrrolo[2,1-a]isoquinoline compounds. This synthetic scheme does not use any catalyst and has multiple advantages, including a simplified reaction process, mild and easily controllable reaction conditions, alignment with green synthesis principles, and excellent reaction efficiency. Furthermore, bioactivity tests have yielded novel pyrrolo[2,1-a]isoquinoline compound molecular skeletons with good pharmaceutical activity.

[0006] The objective of this invention is achieved through the following technical solution:

[0007] A novel synthetic method for pyrrolo[2,1-a]isoquinoline compounds having the following structures:

[0008]

[0009] Where R 1 R represents hydrogen or halogen. 2 R represents hydrogen, methoxy, or halogen. 3 It indicates hydrogen or methyl.

[0010] The novel preparation method (synthetic reaction formula) of the pyrrolo[2,1-a]isoquinoline compound is as follows:

[0011]

[0012] Step 1: First, prepare N-(2-formylphenyl)-3-phenylpropyneamide compounds: Add 2-arylpropynic acid compounds and (2-aminophenyl)methanol compounds to CH2Cl2 solvent; cool to 0 °C, and slowly add a CH2Cl2 solution of N,N-dicyclohexylcarbodiimide (DCC). After the addition is complete, slowly raise the temperature, stir the reaction system overnight at room temperature, and then filter and concentrate. Add the concentrated solid to a CH2Cl2 solution of pyridinium chlorochromate (PCC), stir at room temperature for 1-4 hours, filter, concentrate, and purify by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio of 15:1-10:1) to obtain N-(2-formylphenyl)-3-phenylpropyneamide compounds.

[0013] Step 2 (combination reaction): The N-(2-formylphenyl)-3-phenylpropynamide compound, 1,2,3,4-tetrahydroisoquinoline compound synthesized in Step 1 and acetonitrile were added to a reaction flask to react; after the reaction was completed, the reaction solution was successively cooled to room temperature, extracted with ethyl acetate, dried with anhydrous sodium sulfate, and then concentrated and purified by column chromatography to obtain the pyrrolo[2,1-a]isoquinoline compound.

[0014] The molar ratio of the N-(2-formylphenyl)-3-phenylpropyneamide compound and the 1,2,3,4-tetrahydroisoquinoline compound is 1:1 to 1:3, preferably 1:2; the reaction ratio of N-(2-formylphenyl)-3-phenylpropyneamide to the acetonitrile is 0.2 mmol / mL to 0.4 mmol / mL, preferably 0.2 mmol / mL.

[0015] The N-(2-formylphenyl)-3-phenylpropyne amides are N-(2-formylphenyl)-3-phenylpropyne amide, N-(2-formylphenyl)-3-(4-methoxyphenyl)propyne amide, N-(2-formylphenyl)-3-(4-chlorophenyl)propyne amide, N-(4-bromo-2-formylphenyl)-3-phenylpropyne amide, and N-(4-fluoro-2-formylphenyl)-3-phenylpropyne amide.

[0016] The 1,2,3,4-tetrahydroisoquinoline compounds are 1,2,3,4-tetrahydroisoquinoline and 7-methyl-1,2,3,4-tetrahydroisoquinoline.

[0017] The blending reaction (i.e., step two) is carried out by stirring at a temperature of 60-80 ℃ for 1-12 h.

[0018] Furthermore, the blending reaction was carried out with stirring at 70 °C for 8 h.

[0019] In step two, the eluent for column chromatography purification of the reaction solution is a mixture of petroleum ether and ethyl acetate, with a volume ratio of petroleum ether to ethyl acetate of 4:1.

[0020] The advantages of this invention lie in providing a novel method for synthesizing pyrrolo[2,1-a]isoquinoline compounds. This method involves reacting N-(2-formylphenyl)-3-phenylpropynamide compounds and 1,2,3,4-tetrahydroisoquinoline compounds in a reaction flask without the addition of any catalyst, using acetonitrile as a solvent. This synthetic scheme achieves efficient construction of the molecular skeleton of pyrrolo[2,1-a]isoquinoline compounds through the synergistic effect of aldehyde-amine condensation and intramolecular cyclization reactions. The raw materials used in this synthetic method are all commercially available chemical products, making them inexpensive and readily available. Furthermore, the novel synthetic scheme involved in this invention presents mild reaction conditions, high yields, and is environmentally friendly. In addition, the in vitro growth inhibitory activity of some compounds against three cancer cell lines—PC-9 (human lung adenocarcinoma), EC109 (human esophageal cancer), and MCF-7 (human breast cancer)—was assessed using the MTT assay. Detailed Implementation

[0021] The present invention will be further described below with reference to examples:

[0022] The structural formula of the pyrrolo[2,1-a]isoquinoline compound of the present invention is as follows:

[0023]

[0024] Where R 1 R represents hydrogen or halogen. 2 R represents hydrogen, methoxy, or halogen. 3 It indicates hydrogen or methyl.

[0025] The preparation method is as follows: N-(2-formylphenyl)-3-phenylpropyneamide, 1,2,3,4-tetrahydroisoquinoline, and acetonitrile are added to a reaction flask and reacted. The molar ratio of N-(2-formylphenyl)-3-phenylpropyneamide to 1,2,3,4-tetrahydroisoquinoline is 1:2, and the reaction ratio of N-(2-formylphenyl)-3-phenylpropyneamide to acetonitrile is 0.2 mmol / mL. The reaction is carried out at 70 °C with stirring for 8 h. After the reaction is complete, the reaction solution is cooled, extracted with ethyl acetate, dried with anhydrous sodium sulfate, and purified by column chromatography to obtain the pyrrolo[2,1-a]isoquinoline compound. The eluent for the column chromatography purification in the above reaction is a mixture of petroleum ether and ethyl acetate, with a volume ratio of petroleum ether to ethyl acetate of 4:1.

[0026] In addition, the in vitro growth inhibitory activity of some compounds against three cancer cell lines—PC-9 (human lung adenocarcinoma), EC109 (human esophageal cancer), and MCF-7 (human breast cancer)—was evaluated by MTT assay.

[0027] Example 1

[0028] Step 1: Add 2-phenylpropynic acid (4 mmol) and (2-aminophenyl)methanol (4 mmol) to 20 mL of CH2Cl2; cool to 0 °C, and slowly add a CH2Cl2 (10 mL) solution of N,N-dicyclohexylcarbodiimide (DCC) (4 mmol) after the addition is complete. After the addition is complete, slowly raise the temperature, stir the reaction system at room temperature overnight, filter and concentrate. Add the concentrated solid to a CH2Cl2 (30 mL) solution of pyridinium chlorochromate (PCC) (6-8 mmol), stir at room temperature for 1-4 hours, filter, concentrate and purify by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio of 15:1-10:1) to obtain N-(2-formylphenyl)-3-phenylpropynamide.

[0029] Step 2: The N-(2-formylphenyl)-3-phenylpropynamide (0.2 mmol), 1,2,3,4-tetrahydroisoquinoline (0.4 mmol), and acetonitrile (1 mL) synthesized in Step 1 were added to a reaction flask and reacted. The mixture was stirred at 70°C for 8 h in the presence of air. After the reaction was completed, the reaction system was cooled to room temperature. After extraction with ethyl acetate and drying with anhydrous sodium sulfate, the product was purified by concentrated silica gel column chromatography (petroleum ether to ethyl acetate volume ratio of 4:1) to obtain 1-phenyl-2,3-quinolinone and pyrrolo[2,1-a]isoquinoline. The reaction yield was 89%, and its structural formula is as follows:

[0030]

[0031] The spectral data for 1-phenyl-2,3-quinolinone and pyrrolo[2,1-a]isoquinoline are as follows:

[0032] Column chromatography eluent (petroleum ether: ethyl acetate = 4:1), yellow solid, melting point 217-219°C. o C.

[0033] 1 H NMR (500 MHz, DMSO-d6) δ 9.00 (s, 1H), 7.43 (d, J = 7.0 Hz, 1H), 7.39 – 7.37 (m, 2H), 7.31 – 7.27 (m, 3H), 7.04 – 6.92 (m, 4H), 6.75 (t, J =7.5 Hz, 1H), 6.31 (d, J = 7.5 Hz, 1H), 6.22 (d, J = 8.0 Hz, 1H), 5.75 (d, J =6.5 Hz, 1H), 5.30 (d, J = 6.5 Hz, 1H), 3.49 – 3.45 (m, 1H), 3.40 – 3.33 (m,1H), 3.12 – 3.06 (m, 1H), 2.45 (d, J = 15.5 Hz, 1H);

[0034] 13 C NMR (126 MHz, DMSO-d6) δ 162.9, 152.5, 135.9, 135.5, 134.5, 133.7,130.1, 129.0, 128.6, 128.5, 127.9, 127.6, 126.7, 126.4, 125.9, 125.5, 124.7,123.3, 115.6, 72.7, 66.9, 48.4, 24.4;

[0035] IR (KBr) 2917, 1642, 1587, 1484, 1419, 1355, 1247, 1073, 1045, 871,741, 693 cm -1 ;

[0036] HRMS for C 25 H 21 N2O + (M+H) + Calculated value: 365.16484, measured value: 365.15486.

[0037] Example 2

[0038] Step 1: Add 2-phenylpropynic acid (4 mmol) and (2-aminophenyl)methanol (4 mmol) to 20 mL of CH2Cl2; cool to 0 °C, and slowly add a CH2Cl2 (10 mL) solution of N,N-dicyclohexylcarbodiimide (DCC) (4 mmol) after the addition is complete. After the addition is complete, slowly raise the temperature, stir the reaction system at room temperature overnight, filter and concentrate. Add the concentrated solid to a CH2Cl2 (30 mL) solution of pyridinium chlorochromate (PCC) (6-8 mmol), stir at room temperature for 1-4 hours, filter, concentrate and purify by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio of 15:1-10:1) to obtain N-(2-formylphenyl)-3-phenylpropynamide.

[0039] Step 2: The N-(2-formylphenyl)-3-phenylpropynamide (0.2 mmol), 7-methyl-1,2,3,4-tetrahydroisoquinoline (0.4 mmol), and acetonitrile (1 mL) synthesized in Step 1 were added to a reaction flask and reacted. The mixture was stirred at 70 °C for 8 h in the presence of air. After the reaction was completed, the reaction system was cooled to room temperature. After extraction with ethyl acetate and drying with anhydrous sodium sulfate, the product was purified by concentrated silica gel column chromatography (petroleum ether to ethyl acetate volume ratio of 4:1) to obtain 9-methyl-1-phenyl-2,3-quinolinone and pyrrolo[2,1-a]isoquinoline. The reaction yield was 87%, and its structural formula is as follows:

[0040]

[0041] The spectral data for 9-methyl-1-phenyl-2,3-quinolinone and pyrrolo[2,1-a]isoquinoline are as follows:

[0042] Column chromatography eluent (petroleum ether: ethyl acetate = 4:1), yellow solid, melting point 139-141°C. o C.

[0043] 1 H NMR (500 MHz, CDCl3) δ 9.03 (s, 1H), 7.43 (d, J = 7.0 Hz, 1H), 7.36 (d, J = 7.0 Hz, 2H), 7.31 – 7.27 (m, 3H), 6.97 – 6.90 (m, 3H), 6.80 (d, J =7.5 Hz, 1H), 6.22 (d, J = 7.5 Hz, 1H), 6.08 (s, 1H), 5.69 (d, J = 6.0 Hz, 1H), 5.29 (d, J = 6.5 Hz, 1H), 3.46 (d, J = 13.5 Hz, 1H), 3.35 (t, J = 7.0Hz, 1H), 3.07 – 3.00 (m, 1H), 2.41 (d, J = 16.0 Hz, 1H), 1.88 (s, 3H);

[0044] 13 C NMR (126 MHz, CDCl3) δ 162.9, 152.6, 135.6, 135.2, 134.1, 133.9,132.6, 130.1, 128.7, 128.5, 128.4, 127.9, 127.5, 127.5, 127.2, 125.4, 124.7,123.2, 115.7, 72.8, 66.9, 48.5, 24.0, 21.0;

[0045] IR (KBr) 2920, 1648, 1592, 1481, 1363, 1248, 1046, 746, 688 cm -1 ;

[0046] HRMS for C 26 H 23 N2O + (M+H) + Calculated value: 379.18049, measured value: 379.18094.

[0047] Example 3

[0048] Step 1: Add 3-(4-methoxyphenyl)propynic acid (4 mmol) and (2-aminophenyl)methanol (4 mmol) to 20 mL of CH2Cl2; cool to 0 °C, and slowly add a CH2Cl2 (10 mL) solution of N,N-dicyclohexylcarbodiimide (DCC) (4 mmol) after the addition is complete. After the addition is complete, slowly raise the temperature, stir the reaction system overnight at room temperature, filter and concentrate. Add the concentrated solid to a CH2Cl2 (30 mL) solution of pyridinium chlorochromate (PCC) (6-8 mmol), stir at room temperature for 1-4 hours, filter, concentrate and purify by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio of 15:1-10:1) to obtain N-(2-formylphenyl)-3-(4-methoxyphenyl)propynamide.

[0049] Step 2: The N-(2-formylphenyl)-3-(4-methoxyphenyl)propynamide (0.2 mmol), 1,2,3,4-tetrahydroisoquinoline (0.4 mmol), and acetonitrile (1 mL) synthesized in Step 1 were added to a reaction flask and reacted. The mixture was stirred at 70 °C for 8 h in the presence of air. After the reaction was completed, the reaction system was cooled to room temperature. After extraction with ethyl acetate and drying with anhydrous sodium sulfate, the product was purified by concentrated silica gel column chromatography (petroleum ether to ethyl acetate volume ratio of 4:1) to obtain 1-(4-methoxy)-phenyl-2,3-quinolinone and pyrrolo[2,1-a]isoquinoline. The reaction yield was 85%, and its structural formula is as follows:

[0050]

[0051] The spectral data of 1-(4-methoxy)-phenyl-2,3-quinolinone and pyrrolo[2,1-a]isoquinoline are as follows:

[0052] Column chromatography eluent (petroleum ether: ethyl acetate = 4:1), yellow solid, melting point 194-196°C. o C.

[0053] 1H NMR (500 MHz, DMSO-d6) δ 10.1 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 7.0 Hz, 1H), 7.16 (t, J = 7.0 Hz, 1H), 7.12 (d, J = 7.0 Hz, 1H),7.06 – 7.01 (m, 2H), 6.93 – 6.88 (m, 3H), 6.83 (t, J = 7.0 Hz, 1H), 6.43 (d,J = 7.5 Hz, 1H), 5.86 (d, J = 5.5 Hz, 1H), 5.40 (d, J = 5.5 Hz, 1H), 3.78 (s, 3H), 3.46 (d, J = 13.0 Hz, 1H), 3.27 (t, J = 12.0 Hz, 1H), 3.14 (t, J = 12.5Hz, 1H), 2.50 – 2.46 (m, 1H);

[0054] 13 C NMR (126 MHz, DMSO-d6) δ 161.4, 159.4, 149.9, 136.3, 136.2, 135.2,131.7, 128.8, 128.6, 127.4, 126.1, 126.0, 125.9, 125.5, 124.9, 122.4, 115.1,112.8, 71.1, 66.5, 55.1, 47.8, 23.9;

[0055] IR (KBr) 2920, 2851, 1663, 1645, 1508, 1452, 1359, 1240, 1174, 1031,831, 741, 692 cm -1 ;

[0056] HRMS for C 26 H 23 N2O2 + (M+H) + Calculated value: 395.17540, measured value: 395.17538.

[0057] Example 4

[0058] Step 1: Add 3-(4-chlorophenyl)propynic acid (4 mmol) and (2-aminophenyl)methanol (4 mmol) to 20 mL of CH2Cl2; cool to 0 °C, and slowly add a CH2Cl2 (10 mL) solution of N,N-dicyclohexylcarbodiimide (DCC) (4 mmol) after the addition is complete. After the addition is complete, slowly raise the temperature, stir the reaction system at room temperature overnight, filter and concentrate. Add the concentrated solid to a CH2Cl2 (30 mL) solution of pyridinium chlorochromate (PCC) (6-8 mmol), stir at room temperature for 1-4 hours, filter, concentrate and purify by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio of 15:1-10:1) to obtain 3-(4-chlorophenyl)-N-(2-formylphenyl)propynamide.

[0059] Step 2: The 3-(4-chlorophenyl)-N-(2-formylphenyl)propynamide (0.2 mmol), 1,2,3,4-tetrahydroisoquinoline (0.4 mmol), and acetonitrile (1 mL) synthesized in Step 1 were added to a reaction flask and reacted. The mixture was stirred at 70 °C for 8 h in the presence of air. After the reaction was completed, the reaction system was cooled to room temperature. After extraction with ethyl acetate and drying with anhydrous sodium sulfate, the product was purified by concentrated silica gel column chromatography (petroleum ether to ethyl acetate volume ratio of 4:1) to obtain 1-(4-chloro)-phenyl-2,3-quinolinone and pyrrolo[2,1-a]isoquinoline. The reaction yield was 82%, and its structural formula is as follows:

[0060]

[0061] The spectral data for 1-(4-chloro)-phenyl-2,3-quinolinone and pyrrolo[2,1-a]isoquinoline are as follows:

[0062] Column chromatography eluent (petroleum ether: ethyl acetate = 4:1), yellow solid, melting point 220-222°C. o C.

[0063] 1H NMR (500 MHz, DMSO-d6) δ 10.2 (s, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 7.5 Hz, 1H), 7.44 – 7.41 (m, 2H), 7.18 (t, J = 7.5 Hz, 1H), 7.13(d, J = 7.5 Hz, 1H), 7.08 – 7.03 (m, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.86 (t,J = 7.5 Hz, 1H), 6.38 (d, J = 8.5 Hz, 1H), 5.89 (d, J = 6.5 Hz, 1H), 5.46 (d,J = 6.5 Hz, 1H), 3.49 – 3.46 (m, 1H), 3.24 (d, J = 11.5 Hz, 1H), 3.17 – 3.12(m, 1H), 2.48 (d, J = 16.0 Hz, 1H);

[0064] 13 C NMR (126 MHz, DMSO-d6) δ 161.1, 148.6, 136.3, 136.1, 134.5, 133.2,132.4, 131.9, 129.0, 128.4, 127.5, 127.5, 126.9, 126.1, 126.1, 125.5, 124.9,122.5, 115.2, 71.4, 66.7, 47.9, 23.9;

[0065] IR (KBr) 2916, 1668, 1592, 1421, 1353, 1246, 1085, 838, 743 cm -1 ;

[0066] HRMS for C 25 H 20 ClN2O + (M+H) + Calculated value: 399.12587, measured value: 399.12595.

[0067] Example 5

[0068] Step 1: Add 2-phenylpropynic acid (4 mmol) and (2-amino-5-bromophenyl)methanol (4 mmol) to 20 mL of CH2Cl2; cool to 0 °C, and slowly add a CH2Cl2 (10 mL) solution of N,N-dicyclohexylcarbodiimide (DCC) (4 mmol) after the addition is complete. After the addition is complete, slowly raise the temperature, stir the reaction system at room temperature overnight, filter and concentrate. Add the concentrated solid to a CH2Cl2 (30 mL) solution of pyridinium chlorochromate (PCC) (6-8 mmol), stir at room temperature for 1-4 hours, filter, concentrate and purify by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio of 15:1-10:1) to obtain N-(4-bromo-2-formylphenyl)-3-phenylpropynamide.

[0069] Step 2: The N-(4-bromo-2-formylphenyl)-3-phenylpropynamide (0.2 mmol), 1,2,3,4-tetrahydroisoquinoline (0.4 mmol), and acetonitrile (1 mL) synthesized in Step 1 were added to a reaction flask and reacted. The mixture was stirred at 70 °C for 8 h in the presence of air. After the reaction was completed, the reaction system was cooled to room temperature. After extraction with ethyl acetate and drying with anhydrous sodium sulfate, the product was purified by concentrated silica gel column chromatography (petroleum ether to ethyl acetate volume ratio of 4:1) to obtain 1-phenyl-2,3-(6-bromoquinoline) pyrrolo[2,1-a]isoquinoline. The reaction yield was 73%, and its structural formula is as follows:

[0070]

[0071] The spectral data for 1-phenyl-2,3-(6-bromo)quinolinone and pyrrolo[2,1-a]isoquinoline are as follows:

[0072] Column chromatography eluent (petroleum ether: ethyl acetate = 4:1), yellow solid, melting point 270-272°C. o C.

[0073] 1H NMR (500 MHz, DMSO-d6) δ 10.3 (s, 1H), 10.3 (s, 1H), 7.55 – 7.52(m, 3H), 7.39 – 7.34 (m, 4H), 7.12 (d, J = 7.5 Hz, 1H), 7.04 (t, J = 7.5 Hz,1H), 6.86 (d, J = 8.0 Hz, 1H), 6.79 (t, J = 7.5 Hz, 1H), 6.33 (d, J = 8.0 Hz,1H), 5.88 (d, J = 6.0 Hz, 1H), 5.46 (d, J = 6.5 Hz, 1H), 3.46 – 3.43 (m, 1H),3.22 (t, J = 7.5 Hz, 1H), 3.15 – 3.09 (m, 1H), 2.47 (d, J = 15.5 Hz, 1H);

[0074] 13 C NMR (126 MHz, DMSO-d6) δ 161.0, 150.6, 136.3, 135.6, 134.4, 133.3,131.2, 130.2, 130.0, 128.9, 128.7, 127.5, 127.4, 126.1, 126.1, 125.4, 125.1,117.3, 114.2, 71.6, 66.7, 47.9, 24.0;

[0075] IR (KBr) 2922, 2846, 1662, 1600, 1466, 1359, 1267, 1069, 813, 743,692 cm -1 ;

[0076] HRMS for C 25 H 20 BrN2O + (M+H) + Calculated value: 443.07535, measured value: 443.07559.

[0077] Example 6

[0078] Step 1: Add 2-phenylpropynic acid (4 mmol) and (2-amino-5-fluorophenyl)methanol (4 mmol) to 20 mL of CH2Cl2; cool to 0 °C, and slowly add a CH2Cl2 (10 mL) solution of N,N-dicyclohexylcarbodiimide (DCC) (4 mmol) after the addition is complete. After the addition is complete, slowly raise the temperature, stir the reaction system at room temperature overnight, filter and concentrate. Add the concentrated solid to a CH2Cl2 (30 mL) solution of pyridinium chlorochromate (PCC) (6-8 mmol), stir at room temperature for 1-4 hours, filter, concentrate and purify by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio of 15:1-10:1) to obtain N-(4-fluoro-2-formylphenyl)-3-phenylpropynamide.

[0079] Step 2: The N-(4-fluoro-2-formylphenyl)-3-phenylpropynamide (0.2 mmol), 1,2,3,4-tetrahydroisoquinoline (0.4 mmol), and acetonitrile (1 mL) synthesized in Step 1 were added to a reaction flask and reacted. The mixture was stirred at 70 °C for 8 h in the presence of air. After the reaction was completed, the reaction system was cooled to room temperature. After extraction with ethyl acetate and drying with anhydrous sodium sulfate, the product was purified by concentrated silica gel column chromatography (petroleum ether to ethyl acetate volume ratio of 4:1) to obtain 1-phenyl-2,3-(6-fluoro)quinolinone and pyrrolo[2,1-a]isoquinoline. The yield was 84%, and its structural formula is as follows:

[0080]

[0081] The spectral data of 1-phenyl-2,3-(6-fluoro)quinolinone and pyrrolo[2,1-a]isoquinoline are as follows:

[0082] Column chromatography eluent (petroleum ether: ethyl acetate = 4:1), yellow solid, melting point 217-219°C. o C.

[0083] 1H NMR (500 MHz, DMSO-d6) δ 10.2 (s, 1H), 7.57 – 7.55 (m, 2H), 7.37 –7.35 (m, 3H), 7.25 (dd, J = 9.0, 2.5 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 7.06– 7.02 (m, 2H), 6.95 – 6.92 (m, 1H), 6.80 (t, J = 7.5 Hz, 1H), 6.34 (d, J =8.0 Hz, 1H), 5.89 (d, J = 6.5 Hz, 1H), 5.45 (d, J = 6.5 Hz, 1H), 3.48 – 3.45(m, 1H), 3.26 – 3.20 (m, 1H), 3.17 – 3.10 (m, 1H), 2.48 (d, J = 15.5 Hz, 1H);

[0084] 13 C NMR (126 MHz, DMSO-d6) δ 160.9, 158.1 (d, J C-F = 239.4 Hz), 150.4,136.2, 134.5, 133.4, 132.6 (d, J C-F = 1.3 Hz), 130.8 (d, J C-F = 6.3 Hz), 130.0,128.9, 128.6, 127.4, 126.1, 125.4, 125.3, 116.5 (d, J C-F = 8.8 Hz), 114.0 (d,J C-F = 22.7 Hz), 111.8 (d, J C-F = 23.9 Hz), 71.6, 66.8, 47.7, 23.9;

[0085] 19 F NMR (470 MHz, DMSO-d6): δ -120.6

[0086] IR (KBr) 2898, 1646, 1512, 1487, 1382, 1246, 1048, 811, 739, 694 cm -1 ;

[0087] HRMS for C 25 H20 FN2O + (M+H) + Calculated value: 383.15542, measured value: 383.15533.

[0088] Test example:

[0089] The compounds obtained above were selected for activity assay.

[0090] Experimental materials:

[0091] 1. Human cancer cell lines: all purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences.

[0092] 2. Test drug: Dissolved in DMSO and prepared to an initial concentration of 10000 μg / mL for later use.

[0093] 3. 0.9% physiological saline: 250 mL; 2.25 g, Zhengzhou Yonghe Pharmaceutical Co., Ltd.

[0094] Test method:

[0095] Cells were routinely seeded in complete culture medium and cultured at 37 °C with 5% CO2 and saturated humidity for expansion. After digestion with 0.25% trypsin, the cells were diluted with culture medium to a concentration of 1 × 10⁻⁶ cells / mL. 5 Cell suspension (trypan blue staining, viable cell count >95%) was used for experiments. Negative control wells, positive control wells, and wells with different concentrations of the test sample were prepared in 96-well sterile culture plates. The concentrations were set at 64, 32, 16, 8, 4, 2, 1, and 0.5 μg / mL, with three replicates for each concentration. The prepared cell suspension was seeded into 96-well sterile culture plates and cultured for 24 h. Different concentrations of the compound were then added. An equal volume of culture medium was added to the negative control wells, and the plates were incubated. After 72 h of culture, 20 μL of MTT was added to each well, and the plates were incubated for another 4 h. After centrifugation, the supernatant was discarded. 150 μL of DMSO was added to each well, and the plates were shaken to completely dissolve the purple-blue formazan crystals. The OD value of each well was measured using a microplate reader, and the IC50 was calculated using SPSS software. 50 .

[0096] Test results

[0097] The anticancer activity evaluation data of the above compounds against three human cancer cells are as follows (IC50). 50 ):

[0098] compound Human lung adenocarcinoma cells (PC-9) (μM) Human esophageal cancer cells (EC109) (μM) Human breast cancer cells (MCF-7) (μM) 1 43.03±1.62 34.78±1.54 >50 2 >50 48.36±1.67 22.43±1.34 3 >50 12.62±1.09 26.41±1.42 4 27.38±1.44 5.74±0.76 16.45±1.21 5 25.47±1.42 10.31±1.02 15.27±1.19 6 12.30±1.07 8.29±0.91 10.22±0.99

[0099] The results showed that ① the synthesized new compound 6 had a significant inhibitory effect on the proliferation of human lung adenocarcinoma cells (PC-9) and human breast cancer cells (MCF-7); ② the synthesized new compounds 4 and 6 had a significant inhibitory effect on the proliferation of human esophageal cancer cells (EC109).

Claims

1. A method for synthesizing a pyrrolo[2,1-a]isoquinoline compound, characterized in that: The compound has the following structure: Where R 1 R represents hydrogen or halogen. 2 R represents hydrogen, methoxy, or halogen. 3 The compound, which represents hydrogen or methyl, is synthesized by the following method: N-(2-formylphenyl)-3-phenylpropyneamide, 1,2,3,4-tetrahydroisoquinoline, and acetonitrile are added to a reaction flask and reacted; after the reaction is completed, the reaction solution is successively cooled to room temperature, extracted with ethyl acetate, dried with anhydrous sodium sulfate, and purified by column chromatography to obtain the pyrrolo[2,1-a]isoquinoline compound.

2. The synthesis method according to claim 1, characterized in that, N-(2-formylphenyl)-3-phenylpropyne amides include N-(2-formylphenyl)-3-phenylpropyne amide, N-(2-formylphenyl)-3-(4-methoxyphenyl)propyne amide, N-(2-formylphenyl)-3-(4-chlorophenyl)propyne amide, N-(4-bromo-2-formylphenyl)-3-phenylpropyne amide, and N-(4-fluoro-2-formylphenyl)-3-phenylpropyne amide.

3. The synthesis method according to claim 1, characterized in that, The 1,2,3,4-tetrahydroisoquinoline compounds are 1,2,3,4-tetrahydroisoquinoline and 7-methyl-1,2,3,4-tetrahydroisoquinoline.

4. The synthesis method according to claim 1, 2, or 3, characterized in that, The molar ratio of N-(2-formylphenyl)-3-phenylpropyneamide compounds to 1,2,3,4-tetrahydroisoquinoline compounds is 1:1 to 1:3, preferably 1:2; the reaction ratio of N-(2-formylphenyl)-3-phenylpropyneamide to the acetonitrile is 0.2 mmol / mL to 0.4 mmol / mL, preferably 0.2 mmol / mL.

5. The synthesis method according to claim 1, characterized in that, The reaction takes place at a temperature of 60-80°C. o Stirring the reaction at C for 1-12 hours, preferably 70 h. o C reaction for 8 hours.

6. The synthesis method according to claim 1, characterized in that, The eluent used for column chromatography purification was a mixture of petroleum ether and ethyl acetate, with a volume ratio of 4:

1.

7. An application of a pyrrolo[2,1-a]isoquinoline compound synthesized by the method described in claim 1, characterized in that, Biological evaluation of its in vitro antiproliferative activity showed that this pyrrolo[2,1-a]isoquinoline compound effectively inhibited the proliferation of human lung adenocarcinoma cells (PC-9), human esophageal cancer cells (EC109), and human breast cancer cells (MCF-7), and had a significant inhibitory effect.

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