2-fluoropyridino-isoquinoline derivative as well as preparation method and application thereof

Abstract

The invention discloses a novel compound 2-fluoropyridino-isoquinoline derivative as well as a preparation method and application thereof. The structural formula of the novel compound 2-fluoropyridino-isoquinoline derivative is as follows: # imgabs0 #, wherein Ar1 is phenyl, Ar2 is 3-chlorphenyl or Ar1 is 4-fluorophenyl, and Ar2 is phenyl; the preparation method comprises the following steps: reacting 1-aryl-3, 3-difluorocyclohexene, brominated N-(2-aryl-2-oxo) ethyl isoquinolinium, alkali and a solvent under the protection of nitrogen at the temperature of 60 DEG C; and after the reaction is finished, reducing pressure to remove the solvent, and performing column chromatography separation to obtain a pure product of the 2-fluoropyridinoisoquinoline derivative. The 2-fluoropyridinoisoquinoline derivative disclosed by the invention has better activity of inhibiting the growth of tumor cells, and has important guiding significance and application prospects for finding novel and efficient antitumor drugs.

Description

Technical Field

[0001] The invention relates to a novel compound 2-fluoropyridoisoquinoline derivative and a preparation method and application thereof. Background Art

[0002] Pyridoisoquinoline compounds are an important class of organic compounds. For example, such compounds can be used as inhibitors of tubulin polymerization and have anticancer activity [Journal of Heterocyclic Chemistry (2013), 50 (S1), E48-E54]. However, fluorinated pyridoisoquinoline compounds are rarely reported in the literature, and there are no reports on 2-fluoropyridoisoquinoline derivatives formed by the tandem cyclization of 1-aryl-3,3-difluorocyclohexene and N-(2-phenyl-2-oxo)ethylisoquinolinium bromide and their biological activities. Summary of the invention

[0003] To solve the above problems, the present invention provides a 2-fluoropyridoisoquinoline derivative having a simple preparation method, a wide source of raw materials, and complex and diverse product structures, and a preparation method of the derivative.

[0004] The technical solution of the present invention is: the structural formula of the novel compound 2-fluoropyridoisoquinoline derivative is as follows: Among them, Ar 1 Phenyl, Ar 2 is 3-chlorophenyl or Ar 1 is 4-fluorophenyl, Ar 2 It is phenyl.

[0005] The present invention also discloses a method for preparing the novel compound 2-fluoropyridoisoquinoline derivative, which specifically comprises the following steps: Step 1) reacting 1-aryl-3,3-difluorocyclohexene, N-(2-aryl-2-oxo)ethylisoquinolinium bromide (1-2 equivalents), a base (1-3 equivalents) and a solvent at 60° C. under nitrogen protection;

[0006] Step 2) After the reaction is completed, the solvent is removed under reduced pressure and separated by column chromatography to obtain a pure 2-fluoropyridoisoquinoline derivative; wherein the 2-fluoropyridoisoquinoline derivative has the structural formula

[0007]

[0008] The application of the above-mentioned 2-fluoropyridoisoquinoline derivatives in inhibiting the growth of tumor cells is tested by the CCK8 method.

[0009] Preferably, the solvent is acetonitrile, ethanol or ethyl acetate.

[0010] The patent of the present invention also discloses the application of a novel compound 2-fluoropyridoisoquinoline derivative, which is used for inhibiting the growth activity of tumor cells.

[0011] The above technical scheme has the following beneficial effects: 1. The raw material sources are wide and the product structures are complex and diverse; 2. The synthesis steps are simple and the reaction chemical selectivity is high; 3. The 2-fluoropyridoisoquinoline derivatives synthesized by the present invention have good activity in inhibiting tumor cell growth. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 The target compound of Example 1 of the present invention 1 H NMR spectrum.

[0013] Figure 2 The target compound of Example 1 of the present invention 13 C NMR spectrum.

[0014] Figure 3 The target compound of Example 1 of the present invention 19 F NMR spectrum.

[0015] Figure 4 The target compound of Example 2 of the present invention 1 H NMR spectrum.

[0016] Figure 5 The target compound of Example 2 of the present invention 13 C NMR spectrum.

[0017] Figure 6 The target compound of Example 2 of the present invention 19 F NMR spectrum.

[0018] Figure 7 This is a schematic diagram comparing the growth inhibition rates of the target compounds of Example 1 of the present invention on human non-small cell lung cancer cells A549.

[0019] Figure 8 This is a schematic diagram comparing the growth inhibition rates of the target compounds of Example 1 of the present invention on human non-small cell lung cancer cells A549. DETAILED DESCRIPTION

[0020] 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.

[0021] 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.

[0022] The present invention is further described in detail below in conjunction with embodiments.

[0023] The present invention discloses a 2-fluoropyridoisoquinoline derivative, the structural formula of which is as follows: Among them, Ar 1 Phenyl, Ar 2 is 3-chlorophenyl or Ar 1 is 4-fluorophenyl, Ar 2 The preparation methods of several embodiments of the derivatives are described below.

[0024] Example 1: Preparation method of 1-(4-fluorophenyl)-2-fluoro-4-benzoyl-11bH-pyrido[2,1-a]isoquinoline.

[0025] Under nitrogen protection, 1-phenyl-3,3-difluorocyclohexene (0.15 mmol), N-(2-(4-tert-butylphenyl)-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 the mixture was reacted at 60° C. for 18 hours. After the reaction, the solvent was removed from the obtained mixture under reduced pressure, and the mixture was separated by column chromatography to obtain pure 1-(4-fluorophenyl)-2-fluoro-4-benzoyl-11bH-pyrido[2,1-a]isoquinoline, the structural formula of which is as follows:

[0026]

[0027] Yield: 87%; red oil; Figures 1 to 3As shown, its hydrogen nuclear magnetic resonance spectrum (CDCl3, 400MHz): δ7.75 (d, J=7.5Hz, 2H), 7.52 (t, J=7.5Hz, 1H), 7.44-7.34 (m, 4H), 7.15 (t, J=7.5Hz, 1H), 7.05 (d, J=7.3Hz, 1H), 6.98 (dd, J=16.1, 7.5Hz, 4H), 6.80 (d, J=7.6Hz, 1H), 6.14 (d, J=7.3Hz, 1H), 5.84 (d, J=5.4Hz, 1H), 5.44 (d, J=9.1Hz, 1H). Carbon NMR (CDCl3, 101 MHz) δ 189.9 (d, J = 1.5 Hz), 163.1, 160.6, 154.4, 151.84, 140.6 (d, J = 9.8 Hz), 136.5, 133.5, 131.4, 129.8, 129.5 (d, J = 20.1 Hz), 129.3 (d, J = 7.6 Hz), 128.5, 127 .9 (d, J = 19.7 Hz), 126.1, 125.6, 123.0, 115.6, 115.4, 111.8, 106.5 (d, J = 9.5 Hz), 104.5, 104.1, 61.3 (d, J = 4.4 Hz). NMR fluorine spectrum (CDCl3, 376 MHz) δ -113.00, -118.60. High resolution mass spectrometry (ESI) calcd for C 26 H 18 F2NO + [M+H] + 398.1356, found 398.1347.

[0028] Example 2: Preparation method of 1-phenyl-2-fluoro-4-(3-chlorophenyl)formyl-11bH-pyrido[2,1-a]isoquinoline.

[0029] Step 1) Under nitrogen protection, 1-(4-fluorophenyl)-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;

[0030] Step 2) After the reaction is completed, the resulting mixture is decompressed to remove the solvent, and separated by column chromatography to obtain pure 1-phenyl-2-fluoro-4-(3-chlorophenyl)formyl-11bH-pyrido[2,1-a]isoquinoline, the structural formula of which is as follows:

[0031]

[0032] Yield: 86%; red solid; Figures 4 to 6 As shown, its H NMR spectrum (CDCl3, 400 MHz): δ7.81 (s, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.58 (t, J = 7.9 Hz, 3H), 7.36 (dt, J = 14.3, 7.4 Hz, 4H), 7.25 (t, J = 7.4 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.08 (t, J = 5.6 Hz, 2H), 6.95 (d, J = 7.6 Hz, 1H), 6.28 (d, J = 7.2 Hz, 1H), 6.00 (d, J = 5.4 Hz, 1H), 5.53 (d, J = 8.9 Hz, 1H). C NMR spectrum (CDCl3, 101MHz) δ188.5 (d, J = 1.5Hz), 154.3, 151.7, 140.0 (d, J = 9.7Hz), 138.2, 134.7, 133.6-133.2 (m), 131.32, 129.9-129.3 (m), 128.6, 128.3, 128.0-127.6 (m), 127.5 (d, J = 6.8Hz), 126.2, 125.6, 122.9, 112.5, 108.3 (d, J = 9.6Hz), 105.2, 104.9, 61.3 (d, J = 4.5Hz). F NMR spectrum (CDCl3, 376MHz) δ-118.14. High resolution mass spectrometry (ESI) calcd for C 26 H 17 FClNO + [M+H] + 414.1061, found 414.1053.

[0033] The preparation method has a wide range of raw material sources, and the product structures are complex and diverse; the synthesis steps are simple, and the reaction chemical selectivity is high. The 2-fluoropyridoisoquinoline derivative synthesized by the present invention has good activity in inhibiting tumor cell growth.

[0034] Experimental Example 1: The CCK8 method was used to determine the growth inhibitory ability of the product 1-(4-fluorophenyl)-2-fluoro-4-benzoyl-11bH-pyrido[2,1-a]isoquinoline prepared in Example 1 on human non-small cell lung cancer cells A549. 1-(4-fluorophenyl)-2-fluoro-4-benzoyl-11bH-pyrido[2,1-a]isoquinoline 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. The results are as follows Figure 7As shown, when the concentration was 12.5 μmol / L, the cell inhibition rate was 28.67%; when the concentration was 25.0 μmol / L, the cell inhibition rate was 53.41%; and when the concentration was 50.0 μmol / L, the cell inhibition rate was 84.96%.

[0035] Experimental Example 2: The CCK8 method was used to determine the growth inhibition ability of the product 1-phenyl-2-fluoro-4-(3-chlorophenyl)formyl-11bH-pyrido[2,1-a]isoquinoline prepared in Example 2 on human non-small cell lung cancer cells A549. 1-phenyl-2-fluoro-4-(3-chlorophenyl)formyl-11bH-pyrido[2,1-a]isoquinoline 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 8 As shown, when the concentration is 12.5μmol / L, the cell inhibition rate is 44.03%; when the concentration is 25.0μmol / L, the cell inhibition rate is 54.19%; and when the concentration is 50.0μmol / L, the cell inhibition rate is 73.81%. 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.

[0036] 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 2-fluoropyridoisoquinoline derivative, characterized in that: Its structural formula is as follows: Among them, Ar 1 Phenyl, Ar 2 is 3-chlorophenyl or Ar 1 is 4-fluorophenyl, Ar 2 It is phenyl.

2. The method for preparing a 2-fluoropyridoisoquinoline derivative according to claim 1, characterized in that: It includes the following steps: Step 1) reacting 1-aryl-3,3-difluorocyclohexene, N-(2-aryl-2-oxo)ethylisoquinolinium bromide (1-2 equivalents), a base (1-3 equivalents) and a solvent at 60° C. under nitrogen protection; Step 2) After the reaction is completed, the solvent is removed under reduced pressure and separated by column chromatography to obtain a pure 2-fluoropyridoisoquinoline derivative; wherein the 2-fluoropyridoisoquinoline derivative has the structural formula 3. The method for preparing the novel compound 2-fluoropyridoisoquinoline derivative according to claim 2, characterized in that: The solvent is acetonitrile, ethanol or ethyl acetate.

4. The use of the novel compound 2-fluoropyridoisoquinoline derivative as claimed in claim 1, characterized in that: It is used to inhibit tumor cell growth activity.

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