Preparation method of pyridino-isoquinoline-2-ketone derivative

Abstract

The invention discloses a preparation method of a pyridino-isoquinoline-2-ketone derivative, which comprises the following steps: under the protection of nitrogen, putting 1-aryl-3, 3-difluorocyclohexene, brominated N-(2-phenyl-2-oxo) ethyl isoquinolinium, alkali and a solvent into a reactor, reacting at 60 DEG C for a period of time, and then adding tert-butyl hydroperoxide to continue reacting; and after the reaction is finished, reducing pressure to remove the solvent, and carrying out column chromatography separation to obtain a pure product of the pyridino isoquinoline-2-ketone derivative. Initial raw materials are cheap, easy to obtain and wide in source, and products are complex and diversified in structure. The process flow is simple, and operation is simple and safe. Double bonds conjugated with two carbonyl groups in the target product can be further subjected to functionalization reaction, so that the target product can be conveniently subjected to diversified structural modification.

Description

Technical Field

[0001] The invention relates to the technical field of organic compound synthesis, and in particular to a method for preparing a pyridoisoquinoline-2-one derivative. Background Art

[0002] Condensed ring compounds containing pyridone and isoquinoline structural units are an important class of nitrogen-containing heterocyclic compounds. For example, isoquinolinopyridone compounds can be used to treat Huntington's disease (Chemical Science, 2022, 13, 10765-10772). Therefore, the development of simple and efficient methods to synthesize such compounds is of great significance for the development and research of new drugs.

[0003] The preparation methods of pyridoisoquinoline reported in the literature mainly include

[0004]

[0005] The starting materials used in this method are complex in structure, expensive, difficult to obtain, and the diversity of target products is insufficient. The reaction temperature greatly exceeds the boiling point of the solvent, and there are great safety risks in the operation process. Summary of the invention

[0006] In order to overcome the above-mentioned deficiencies in the prior art, the present invention aims to provide a method for preparing a pyridoisoquinoline-2-one derivative.

[0007] To achieve the above-mentioned purpose and other related purposes, the technical scheme provided by the present invention is: a method for preparing a pyridoisoquinolin-2-one derivative, comprising the following steps: 1) placing 1-aryl-3,3-difluorocyclohexene, N-(2-phenyl-2-oxo)ethylisoquinolinium bromide, a base and a solvent in a reactor under nitrogen protection, and reacting at 60° C.; 2) adding tert-butyl hydroperoxide to continue the reaction; 3) after the reaction is completed, removing the solvent under reduced pressure, and separating by column chromatography to obtain a pure pyridoisoquinolin-2-one derivative.

[0008] The preferred technical solution is: the base is potassium carbonate or cesium carbonate.

[0009] The preferred technical solution is: the solvent is acetonitrile, ethanol or ethyl acetate.

[0010] The preferred technical solution is: the 1-aryl-3,3-difluorocyclohexene is selected from one of 1-phenyl-3,3-difluorocyclohexene, 1-(4-methylphenyl)-3,3-difluorocyclohexene or 1-(4-chlorophenyl)-3,3-difluorocyclohexene.

[0011] The preferred technical solution is: the molar ratio of the 1-aryl-3,3-difluorocyclohexene, N-(2-phenyl-2-oxo)ethylisoquinolinium bromide, base and tert-butyl hydroperoxide is 1.0:1.0-1.5:1.0-3.0:4.0-8.0.

[0012] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0013] 1) The starting materials are cheap and readily available, with a wide range of sources, and the product structures are complex and diverse;

[0014] 2) The process is simple, easy and safe to operate;

[0015] 3) The double bonds conjugated with two carbonyl groups in the target product can be further functionalized to facilitate diversified structural modifications of the target product, improve the solubility of the molecule, increase the bioavailability of the molecule, reduce toxic side effects, and provide reaction sites for chemical modification. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Attached Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 1.

[0017] Attached Figure 2 The hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 2 is shown in FIG.

[0018] Attached Figure 3 The hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 3 is shown in FIG.

[0019] Attached Figure 4 The hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 4 is shown in FIG.

[0020] Attached Figure 5 This is a schematic diagram comparing the growth inhibition rates of the products obtained in Example 4 on human non-small cell lung cancer cells A549. DETAILED DESCRIPTION

[0021] The following is a description of the implementation of the present invention by means of specific embodiments. Those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification.

[0022] Example embodiments will now be described more fully with reference to the accompanying drawings. However, example embodiments can be implemented in a variety of forms and should not be construed as being limited to the examples set forth herein; on the contrary, these embodiments are provided so that the present invention will be more comprehensive and complete, and the concept of the example embodiments will be fully conveyed to those skilled in the art. The described features, structures, or characteristics may be combined in one or more embodiments in any suitable manner. In the following description, many specific details are provided to provide a full understanding of the embodiments of the present invention. However, those skilled in the art will appreciate that the technical solutions of the present invention may be practiced while omitting one or more of the specific details, or other methods, components, devices, steps, etc. may be adopted. In other cases, known technical solutions are not shown or described in detail to avoid obscuring various aspects of the present invention.

[0023] Example 1: A method for preparing a pyridoisoquinolin-2-one derivative I, which specifically comprises the following steps:

[0024] Step 1): under nitrogen protection, add 1-phenyl-3,3-difluorocyclohexene (0.15 mmol), N-(2-phenyl-2-oxo)ethylisoquinolinium bromide (0.18 mmol), cesium carbonate (0.30 mmol) and 1.5 mL of acetonitrile into a reaction tube, and react at 60° C. for 18 hours;

[0025] Step 2): add tert-butyl hydroperoxide (0.75 mmol) and continue the reaction for 18 hours;

[0026] Step 3): After the reaction is completed, the obtained mixture is decompressed to remove the solvent, and the pure product 1-phenyl-4-benzoyl-2H-pyrido[2,1-a]isoquinolin-2-one is separated by column chromatography. The structural formula is as follows:

[0027]

[0028] Yield: 68%; light yellow solid; Figure 1As shown, its H NMR spectrum is (CDCl3, 400MHz) δ8.05 (d, J = 7.8 Hz, 2H), 7.75 (t, J = 7.4 Hz, 1H), 7.58 (t, J = 7.4 Hz, 2H), 7.45 (dd, J = 10.5, 5.0 Hz, 5H), 7.38 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 7.5 Hz, 2H), 7.10 (dd, J = 9.5, 4.7 Hz, 1H), 6.92 (s, 1H), 6.7 3 (d, J = 7.6 Hz, 1H). C NMR (CDCl3, 101 MHz) δ 190.1, 174.9, 143.1, 141.9, 135.5 (d, J = 13.3 Hz), 135.0, 133.8, 132.1, 131.4, 130.7 (d, J = 18.6 Hz), 129.6, 129.3, 127.2, 126.4, 126.0, 125.3, 120.8, 113.2. High resolution mass spectrometry (ESI) calcd for C 26 H 17 ClNO2 + [M+H] + 410.0948, found 410.0936.

[0029] Example 2: A method for preparing a pyridoisoquinolin-2-one derivative II, which specifically comprises the following steps:

[0030] Step 1) Under nitrogen protection, 1-(4-methylphenyl)-3,3-difluorocyclohexene (0.15 mmol), N-(2-phenyl-2-oxo)ethylisoquinolinium bromide (0.18 mmol), cesium carbonate (0.30 mmol) and 1.5 mL of acetonitrile were added to a reaction tube and reacted at 60° C. for 18 hours;

[0031] Step 2) tert-butyl hydroperoxide (0.75 mmol) was added and the reaction was continued for 18 hours;

[0032] Step 3) After the reaction is completed, the obtained mixture is decompressed to remove the solvent, and separated by column chromatography to obtain pure 1-(4-methylphenyl)-4-benzoyl-2H-pyrido[2,1-a]isoquinolin-2-one, the structural formula of which is as follows:

[0033]

[0034] Yield: 67%; light yellow solid; Figure 2The H NMR spectrum shown is (CDCl3, 400MHz) δ8.05 (d, J = 7.8Hz, 2H), 7.73 (t, J = 7.5Hz, 1H), 7.57 (t, J = 7.7Hz, 2H), 7.47-7.33 (m, 5H), 7.31-7.23 (m, 2H), 7.10 (d, J = 7.4Hz, 1H), 7.03 (td, J = 8.4, 4.1Hz, 1H), 6.90 (s, 1H), 6.69 (d, J = 7.6Hz, 1H), 2.21 (s, 3H). Spectrum (CDCl3, 101MHz) δ190.4, 175.0, 143.3, 141.5, 137.3 (d, J = 18.5Hz), 135.4, 135.1, 131.0 (d, J = 8.4Hz), 130.6 (d, J = 2.6Hz), 129.8, 129.3 (d, J = 2.5Hz), 128.3, 127.6, 127.2, 126.4 (d, J = 19.9Hz), 125.9, 120.7, 113.0, 19.7. High resolution mass spectrometry (ESI) calcd for C 27 H 20 NO2 + [M+H] + 390.1494, found 390.1485.

[0035] Example 3: A method for preparing a pyridoisoquinolin-2-one derivative III, which specifically comprises the following steps:

[0036] Step 1) Under nitrogen protection, 1-(4-chlorophenyl)-3,3-difluorocyclohexene (0.15 mmol), N-(2-phenyl-2-oxo)ethylisoquinolinium bromide (0.18 mmol), cesium carbonate (0.30 mmol) and 1.5 mL of acetonitrile were added to the reaction tube and reacted at 60° C. for 18 hours.

[0037] Step 2) tert-butyl hydroperoxide (0.75 mmol) was added and the reaction was continued for 18 hours;

[0038] Step 3) After the reaction is completed, the resulting mixture is decompressed to remove the solvent, and separated by column chromatography to obtain pure 1-(4-chlorophenyl)-4-benzoyl-2H-pyrido[2,1-a]isoquinolin-2-one, the structural formula of which is as follows:

[0039]

[0040] Yield: 62%; light yellow solid; Figure 3As shown, its H NMR spectrum is (CDCl3, 400MHz) δ8.05 (d, J = 7.8 Hz, 2H), 7.75 (t, J = 7.4 Hz, 1H), 7.58 (t, J = 7.4 Hz, 2H), 7.45 (dd, J = 10.5, 5.0 Hz, 5H), 7.38 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 7.5 Hz, 2H), 7.10 (dd, J = 9.5, 4.7 Hz, 1H), 6.92 (s, 1H), 6.7 3 (d, J = 7.6 Hz, 1H). C NMR (CDCl3, 101 MHz) δ 190.1, 174.9, 143.1, 141.9, 135.5 (d, J = 13.3 Hz), 135.0, 133.8, 132.1, 131.4, 130.7 (d, J = 18.6 Hz), 129.6, 129.3, 127.2, 126.4, 126.0, 125.3, 120.8, 113.2. High resolution mass spectrometry (ESI) calcd for C 26 H 17 ClNO2 + [M+H] + 410.0948, found 410.0936.

[0041] Example 4: A method for preparing a pyridoisoquinolin-2-one derivative IV, which specifically comprises the following steps:

[0042] Step 1) Under nitrogen protection, 1-(2-chlorophenyl)-3,3-difluorocyclohexene (0.15 mmol), N-(2-phenyl-2-oxo)ethylisoquinolinium bromide (0.18 mmol), cesium carbonate (0.30 mmol) and 1.5 mL of acetonitrile were added to the reaction tube and reacted at 60°C for 18 hours.

[0043] Step 2) tert-butyl hydroperoxide (0.75 mmol) was added and the reaction was continued for 18 hours;

[0044] Step 3) After the reaction is completed, the resulting mixture is decompressed to remove the solvent, and separated by column chromatography to obtain pure 1-(2-chlorophenyl)-4-benzoyl-2H-pyrido[2,1-a]isoquinolin-2-one, the structural formula of which is as follows:

[0045]

[0046] Yield: 60%; light yellow solid; Figure 4As shown, its hydrogen nuclear magnetic resonance spectrum is (CDCl3, 400MHz) δ8.04 (d, J = 7.9Hz, 2H), 7.72 (t, J = 7.4Hz, 1H), 7.56 (t, J = 7.1Hz, 3H), 7.49-7.36 (m, 5H), 7.30 (dd, J = 11.1, 6.4Hz, 2H), 7.13-7.03 (m, 1H), 6.90 (s, 1H), 6.72 (d, J = 7.6Hz, 1H). Carbon nuclear magnetic resonance spectrum (C DCl3,101MHz)δ190.2,174.5,143.4,142.2,136.7,135.4,135.0,134.6,132.0,131.1,130.8,130.5(d,J=19.5Hz),129.5,129.3,128.9,127.9,127.7,126.6,126.2,125.9,125.5,120.9,113.1. High resolution mass spectrometry (ESI)calcd for C 26 H 17 ClNO2 + [M+H] + 410.0948, found410.0938. The preparation method of the pyridoisoquinoline-2-one derivative IV has cheap and readily available starting materials, with a wide range of sources, and the product structures are complex and diverse; the process flow is simple, the operation is simple and safe, and the double bonds conjugated with two carbonyl groups in the target product can be further functionalized, which is convenient for diversified structural modification of the target product, and the prepared product has a good inhibitory effect on tumor cell growth activity.

[0047] The CCK8 method was used to determine the growth inhibition ability of the product 1-(2-chlorophenyl)-4-benzoyl-2H-pyrido[2,1-a]isoquinolin-2-one prepared in Example 4 on human non-small cell lung cancer cells A549. 1-(2-chlorophenyl)-4-benzoyl-2H-pyrido[2,1-a]isoquinolin-2-one was diluted to three concentrations of 12.5, 25.0, and 50.0 μmol / L in RPMI-1640 cell culture medium. After 72 hours of action, its cytotoxicity to A549 was determined respectively. The results are as follows Figure 5 As shown, when the concentration is 12.5 μmol / L, the cell inhibition rate is 42.06%; when the concentration is 25.0 μmol / L, the cell inhibition rate is 55.82%; and when the concentration is 50.0 μmol / L, the cell inhibition rate is 88.71%. The above research results show that the product prepared by the present invention has good activity in inhibiting the growth of tumor cells, which has important guiding significance and application prospects for the discovery of new and efficient anti-tumor drugs.

[0048] The above embodiments are merely illustrative of the principles and effects of the present invention, and are not intended to limit the present invention. Anyone familiar with the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by a person of ordinary skill in the art without departing from the spirit and technical concept disclosed by the present invention shall still be covered by the claims of the present invention.

Claims

1. A method for preparing a pyridoisoquinolin-2-one derivative, characterized in that: It includes the following steps: 1) Under nitrogen protection, 1-aryl-3,3-difluorocyclohexene, N-(2-phenyl-2-oxo)ethylisoquinolinium bromide, a base and a solvent are placed in a reactor and reacted at 60° C.; 2) adding tert-butyl hydroperoxide to continue the reaction; 3) After the reaction is completed, the solvent is removed under reduced pressure and separated by column chromatography to obtain a pure pyridoisoquinolin-2-one derivative.

2. The method for preparing a pyridoisoquinolin-2-one derivative according to claim 1, characterized in that: The base is potassium carbonate or cesium carbonate.

3. The method for preparing a pyridoisoquinolin-2-one derivative according to claim 1, characterized in that: The solvent is acetonitrile, ethanol or ethyl acetate.

4. The method for preparing a pyridoisoquinolin-2-one derivative according to claim 1, characterized in that: The 1-aryl-3,3-difluorocyclohexene is selected from one of 1-phenyl-3,3-difluorocyclohexene, 1-(4-methylphenyl)-3,3-difluorocyclohexene and 1-(4-chlorophenyl)-3,3-difluorocyclohexene.

5. The method for preparing a pyridoisoquinolin-2-one derivative according to claim 1, characterized in that: The molar ratio of the 1-aryl-3,3-difluorocyclohexene, N-(2-phenyl-2-oxo)ethylisoquinolinium bromide, base and tert-butyl hydroperoxide is 1.0: 1.0-1.5: 1.0-3.0: 4.0-8.0.

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