1-fluorobenzimidazopyridine derivative as well as preparation method and application thereof

Abstract

The invention discloses a 1-fluorobenzimidazopyridine derivative as well as a preparation method and application thereof. The structural formula of the 1-fluorobenzimidazopyridine derivative is as follows: # imgabs0 #, wherein Ar1 is phenyl, Ar2 is 4-bromophenyl or Ar1 is 3-chlorphenyl, and Ar2 is phenyl. The preparation method comprises the following steps: reacting 2-(2-benzimidazolyl)-3-aryl propionitrile, 1-aryl-3-trifluoromethyl-3-butene-1-alkyne, alkali and a solvent at a certain temperature, removing the solvent under reduced pressure after the reaction is finished, and performing column chromatography separation to obtain a pure product of the 1-fluorobenzimidazopyridine derivative. The 1-fluorobenzimidazopyridine 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 anti-tumor drugs.

Description

Technical Field

[0001] The present invention relates to a novel compound 1-fluorobenzimidazopyridine derivative and its preparation method and application. Background Art

[0002] Benzimidazopyridine compounds have important physiological and pharmacological activities. For example, such compounds have the activity of inhibiting the growth of tumor cells (Eur. J. Med. Chem. 2010, 45, 2405). However, fluorinated benzimidazopyridine compounds are rarely reported in the literature, and the research on 1-fluorobenzimidazopyridine derivatives formed by the tandem cyclization of 2-(2-benzimidazolyl)-3-arylpropanenitrile and 1-aryl-3-trifluoromethyl-3-buten-1-yne and their biological activities has not been reported. Summary of the Invention

[0003] To solve the above problems, the present invention provides a 1-fluorobenzimidazopyridine derivative with a simple preparation method, mild reaction conditions, and complex and diverse product structures, and a preparation method of this derivative.

[0004] The technical solution of the present invention is: The structural formula of the novel compound 1-fluorobenzimidazopyridine derivative is as follows:

[0005]

[0006] Wherein Ar 1 is phenyl, Ar 2 is 4-bromophenyl, or Ar 1 is 3-chlorophenyl, Ar 2 is phenyl.

[0007] The present invention also discloses a preparation method of this 1-fluorobenzimidazopyridine derivative, which specifically includes the following steps: Step 1) React 2-(2-benzimidazolyl)-3-arylpropanenitrile, 1-aryl-3-trifluoromethyl-3-buten-1-yne (1-2 equivalents), a base (1-3 equivalents) and a solvent;

[0008] Step 2) After the reaction is completed, remove the solvent under reduced pressure and separate by column chromatography to obtain a pure product of the 1-fluorobenzimidazopyridine derivative; wherein the structural formula of the 1-fluorobenzimidazopyridine derivative is

[0009]

[0010] Wherein Ar 1 is phenyl, Ar 2 is 4-bromophenyl, or Ar 1 is 3-chlorophenyl, Ar 2 is phenyl.

[0011] The application of the above-mentioned 1-fluorobenzimidazo[1,2-a]pyridine derivatives in inhibiting the growth activity of tumor cells was tested by the CCK8 method.

[0012] Preferably, the solvent is 1,4-dioxane, tetrahydrofuran or ethyl acetate.

[0013] Preferably, the reaction temperature is 20-40 °C.

[0014] Preferably, the base is potassium carbonate or cesium carbonate.

[0015] Preferably, the structural formula of the 1-fluorobenzimidazo[1,2-a]pyridine derivative is:

[0016]

[0017] The present invention also discloses the application of the novel compound 1-fluorobenzimidazo[1,2-a]pyridine derivative, which is used to inhibit the growth activity of tumor cells.

[0018] The above technical solutions have the following beneficial effects: 1. The reaction conditions are mild, and the product structures are complex and diverse; 2. The synthesis steps are simple, and the reaction has high chemoselectivity; 3. The 1-fluorobenzimidazo[1,2-a]pyridine derivatives synthesized by the present invention have good inhibitory activity against the growth of tumor cells. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 is the 1 H NMR spectrum of the target compound in Example 1 of the present invention.

[0020] Figure 2 is the 13 C NMR spectrum of the target compound in Example 1 of the present invention.

[0021] Figure 3 is the 19 F NMR spectrum of the target compound in Example 1 of the present invention.

[0022] Figure 4 is the 1 H NMR spectrum of the target compound in Example 2 of the present invention.

[0023] Figure 5 is the 13 C NMR spectrum of the target compound in Example 2 of the present invention.

[0024] Figure 6 is the 19 F NMR spectrum of the target compound in Example 2 of the present invention.

[0025] Figure 7Schematic diagram of the growth inhibition rate of the target compound in Example 1 of the present invention against human colon cancer cell line HT-29.

[0026] Figure 8 Schematic diagram of the growth inhibition rate of the target compound in Example 2 of the present invention against human colon cancer cell line HT-29. Detailed implementation manners

[0027] The following specific embodiments illustrate the implementation manners of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification.

[0028] Now, example embodiments will be described more fully with reference to the accompanying drawings. However, the example embodiments can be implemented in various forms and should not be construed as limited to the examples set forth herein; rather, these embodiments are provided so that this invention will be more complete and comprehensive, and will fully convey the concept of the example embodiments to those skilled in the art. The described features, structures, or characteristics can be combined in any suitable manner in one or more embodiments. In the following description, numerous specific details are provided to give a thorough understanding of the embodiments of the present invention. However, those skilled in the art will realize that the technical solutions of the present invention can be practiced without one or more of the specific details, or other methods, components, devices, steps, etc. can be used. In other cases, well-known technical solutions are not shown or described in detail to avoid obscuring various aspects of the present invention.

[0029] The present invention will be further described in detail below with reference to the embodiments.

[0030] The present invention discloses a 1-fluorobenzimidazo[1,2-a]pyridine derivative, and its structural formula is as follows:

[0031]

[0032] Wherein Ar 1 is phenyl, Ar 2 is 4-bromophenyl, or Ar 1 is 3-chlorophenyl, Ar 2 is phenyl.

[0033] The preparation methods of multiple embodiments of the derivative will be described below.

[0034] Example 1

[0035] A preparation method of 1-fluoro-4-benzyl-4-cyano-2-(4-bromophenylethynyl)-3,4-dihydropyrido[1,2-a]benzimidazole specifically includes the following steps:

[0036] Step 1): Add 2-(2-benzimidazolyl)-3-phenylpropionitrile (0.25 mmol), 1-(4-bromophenyl)-3-trifluoromethyl-3-buten-1-yne (0.30 mmol), cesium carbonate (0.50 mmol) and 2.5 mL of 1,4-dioxane into a reaction tube, and react at 25 °C for 18 hours;

[0037] Step 2): After the reaction is completed, remove the solvent under reduced pressure from the obtained mixture, and separate it by column chromatography to obtain the pure product 1-fluoro-4-benzyl-4-cyano-2-(4-bromophenylethynyl)-3,4-dihydropyrido[1,2-a]benzimidazole, and the structural formula is as follows:

[0038]

[0039] Yield: 77%; light yellow solid; as Figures 1 to 3 shown, its 1H NMR (CDCl3, 400 MHz): δ 7.92 (d, J = 6.6 Hz, 1H), 7.76 (d, J = 5.7 Hz, 1H), 7.55 (d, J = 7.7 Hz, 2H), 7.51 - 7.36 (m, 9H), 3.78 (d, J = 13.8 Hz, 1H), 3.37 (d, J = 13.9 Hz, 1H), 3.03 (dd, J = 15.9, 5.0 Hz, 1H), 2.91 (dd, J = 15.9, 4.9 Hz, 1H). 13C NMR (CDCl3, 101 MHz) δ 151.5, 148.8, 146.8, 142.3, 132.9 (d, J = 5.5 Hz), 131.8, 130.9 - 130.5 (m), 128.9, 128.4, 125.8, 124.8, 123.2, 121.4, 121.2, 118.0, 112.5 (d, J = 7.7 Hz), 95.8 (d, J = 6.2 Hz), 81.5, 79.8 (d, J = 12.1 Hz), 41.2, 39.3, 33.9. 19F NMR (CDCl3, 376 MHz) δ -105.80. High resolution mass spectrum (ESI) calcd for C 27 H 18 BrFN3 + [M+H] + 482.0668, found 482.0658.

[0040] Example 2

[0041] A preparation method of 1-fluoro-4-(3-chlorophenyl)methyl-4-cyano-2-(phenylethynyl)-3,4-dihydropyrido[1,2-a]benzimidazole, which specifically comprises the following steps:

[0042] Step 1): Add 2-(2-benzimidazolyl)-3-(3-chlorophenyl)propionitrile (0.25 mmol), 1-phenyl-3-trifluoromethyl-3-buten-1-yne (0.30 mmol), cesium carbonate (0.50 mmol) and 2.5 mL of 1,4-dioxane into a reaction tube, and react at 25 °C for 18 hours;

[0043] Step 2): After the reaction is completed, remove the solvent under reduced pressure from the obtained mixture, and separate by column chromatography to obtain the pure product 1-fluoro-4-(3-chlorophenyl)methyl-4-cyano-2-(phenylethynyl)-3,4-dihydropyrido[1,2-a]benzimidazole, and the structural formula is as follows:

[0044]

[0045] Yield: 65%; light yellow solid; as Figures 4 to 6 shown, its 1H NMR (CDCl3, 400 MHz): δ 7.92 (d, J = 6.8 Hz, 1H), 7.81 - 7.73 (m, 1H), 7.58 (d, J = 3.0 Hz, 2H), 7.45 (tdd, J = 23.0, 15.2, 7.6 Hz, 9H), 3.71 (d, J = 13.8 Hz, 1H), 3.35 (d, J = 13.9 Hz, 1H), 3.07 (dd, J = 15.9, 4.7 Hz, 1H), 2.90 (dd, J = 15.9, 4.8 Hz, 1H). 13C NMR (CDCl3, 101 MHz) δ 151.3, 148.6, 146.5, 142.3, 134.8 (d, J = 12.6 Hz), 131.6, 130.9 - 130.6 (m), 130.2, 129.0, 128.8 - 128.4 (m), 125.9, 124.8, 122.3, 121.1, 117.8, 112.5 (d, J = 7.7 Hz), 97.3 (d, J = 6.2 Hz), 80.20 - 79.77 (m), 40.7, 39.2, 34.0. 19F NMR (CDCl3, 376 MHz) δ -106.24. High resolution mass spectrum (ESI) calcd for C 27 H 18 ClFN3 + [M + H] + 438.1173, found 438.1165.

[0046] Preparing 1-fluorobenzimidazolopyridine derivatives by the above method has the advantages of mild reaction conditions, complex and diverse product structures; simple synthesis steps, high reaction chemoselectivity, etc.

[0047] The 1-fluorobenzimidazopyridine derivatives synthesized by the present invention have good activity in inhibiting the growth of tumor cells. In order to further prove their application effects, the following test examples were used for testing.

[0048] Test Example 1:

[0049] The growth inhibitory ability of the product 1-fluoro-4-benzyl-4-cyano-2-(4-bromophenylethynyl)-3,4-dihydropyrido[1,2-a]benzimidazole prepared in Example 1 on human colon cancer cells HT-29 was determined by the CCK8 method. 1-Fluoro-4-benzyl-4-cyano-2-(4-bromophenylethynyl)-3,4-dihydropyrido[1,2-a]benzimidazole was diluted with dimethyl sulfoxide into three concentrations of 100, 500 μg / L. After acting for 24 h, its cytotoxicity to HT-29 was measured respectively. The results are as Figure 7 shown. When the concentration was 100 μg / L, the cell inhibition rate was 43.30 ± 5.53%; when the concentration was 500 μg / L, the cell inhibition rate was 60.12 ± 10.04%.

[0050] Test Example 2:

[0051] The growth inhibitory ability of the product 1-fluoro-4-(3-chlorophenyl)methyl-4-cyano-2-(phenylethynyl)-3,4-dihydropyrido[1,2-a]benzimidazole prepared in Example 2 on human colon cancer cells HT-29 was determined by the CCK8 method. 1-Fluoro-4-(3-chlorophenyl)methyl-4-cyano-2-(phenylethynyl)-3,4-dihydropyrido[1,2-a]benzimidazole was diluted with dimethyl sulfoxide into three concentrations of 10, 100, 500 μg / L. After acting for 24 h, its cytotoxicity to HT-29 was measured respectively. The results are as Figure 8 shown. When the concentration was 10 μg / L, the cell inhibition rate was 12.91 ± 3.79%; when the concentration was 100 μg / L, the cell inhibition rate was 24.32 ± 3.36%; when the concentration was 500 μg / L, the cell inhibition rate was 43.17 ± 8.74%. The above research results show that the products prepared by the present invention have good activity in inhibiting the growth of tumor cells, which has important guiding significance and application prospects for the discovery of new and highly effective anti-tumor drugs.

[0052] The above embodiments merely illustrate the principles and effects of the present invention, rather than limiting the present invention. Any person familiar with this technology can modify or change the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or changes completed by those with ordinary knowledge in the technical field without departing from the spirit and technical idea disclosed by the present invention should still be covered by the claims of the present invention.

Claims

1. A 1-fluorobenzimidazolinpyridine derivative, characterized in that: Its structural formula is as follows: Among them, Ar 1 Phenyl, Ar 2 is 4-bromophenyl, or Ar 1 is 3-chlorophenyl, Ar 2 It is phenyl.

2. A method for preparing the 1-fluorobenzimidazolopyridine derivative according to claim 1, characterized in that: It includes the following steps: Step 1) reacting 2-(2-benzimidazolyl)-3-arylpropionitrile, 1-aryl-3-trifluoromethyl-3-butene-1-yne (1-2 equivalents), a base (1-3 equivalents) and a solvent; Step 2) After the reaction is completed, the solvent is removed under reduced pressure and separated by column chromatography to obtain a pure 1-fluorobenzimidazolopyridine derivative; wherein the 1-fluorobenzimidazolopyridine derivative has the structural formula: Among them, Ar 1 Phenyl, Ar 2 is 4-bromophenyl, or Ar 1 is 3-chlorophenyl, Ar 2 It is phenyl.

3. The method for preparing a 1-fluorobenzimidazolopyridine derivative according to claim 2, characterized in that: The solvent is 1,4-dioxane, tetrahydrofuran or ethyl acetate.

4. The method for preparing a 1-fluorobenzimidazolopyridine derivative according to claim 2, characterized in that: The reaction temperature is 20-40°C.

5. 1-Fluorobenzoic acid according to claim 2 A method for preparing an imidazopyridine derivative, characterized in that: It is characterized in that The alkali is potassium carbonate or cesium carbonate.

6. The method for preparing a 1-fluorobenzimidazolopyridine derivative according to claim 2, characterized in that: The structural formula of the 1-fluorobenzimidazolopyridine derivative is:

7. A use of the 1-fluorobenzimidazolopyridine derivative according to claim 1, characterized in that: It is used to inhibit tumor cell growth activity.

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