A 1-fluorobenzimidazopyridine derivative, a preparation method and application thereof

Abstract

This invention discloses a 1-fluorobenzimidazolidine derivative, its preparation method, and its application. Its structural formula is as follows: [Insert structural formula here]. 1 It is a phenyl group, Ar 2 It is 4-bromophenyl or Ar 1 It is 3-chlorophenyl, Ar 2 The compound is phenyl. It is produced by reacting 2-(2-benzimidazolyl)-3-arylpropionitrile, 1-aryl-3-trifluoromethyl-3-buten-1-yne, a base, and a solvent under specific temperature conditions. After the reaction, the solvent is removed under reduced pressure, and the product is purified by column chromatography to obtain the pure 1-fluorobenzimidazolidine derivative. The 1-fluorobenzimidazolidine derivative of this invention exhibits good inhibitory activity against tumor cell growth, and has important guiding significance and application prospects for the discovery of novel and highly effective antitumor drugs.

Description

Technical Field

[0001] This invention relates to a novel compound, 1-fluorobenzimidazole-pyridine derivative, its preparation method, and its application. Background Technology

[0002] Benzimidazolidine compounds possess important physiological and pharmacological activities. For example, these compounds exhibit inhibitory activity against tumor cell growth (Eur. J. Med. Chem. 2010, 45, 2405). However, fluorinated benzimidazolidine compounds are rarely reported in the literature, and studies on the biological activities of 1-fluorobenzimidazolidine derivatives formed by the tandem cyclization of 2-(2-benzimidazolyl)-3-arylpropionitrile and 1-aryl-3-trifluoromethyl-3-buten-1-yne are even less reported. Summary of the Invention

[0003] To address the aforementioned problems, this invention provides a simple preparation method, mild reaction conditions, and a variety of complex product structures for 1-fluorobenzimidazolidine derivatives, as well as a method for preparing such derivatives.

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

[0005]

[0006] Among them, Ar 1 For phenyl, Ar 2 It is 4-bromophenyl, or Ar 1 3-Chlorophenyl, Ar 2 It is a phenyl group.

[0007] This invention patent also discloses a method for preparing the 1-fluorobenzimidazolidine derivative, specifically including the following steps: Step 1) reacting 2-(2-benzimidazolyl)-3-arylpropionitrile, 1-aryl-3-trifluoromethyl-3-buten-1-yne (1-2 equivalents), base (1-3 equivalents) and solvent;

[0008] After the reaction in step 2) was completed, the solvent was removed under reduced pressure, and the product was separated by column chromatography to obtain the pure 1-fluorobenzimidazolidine derivative; wherein the structural formula of the 1-fluorobenzimidazolidine derivative is as follows:

[0009]

[0010] Among them, Ar 1 For phenyl, Ar 2 It is 4-bromophenyl, or Ar 1 It is 3-chlorophenyl, Ar 2 It is a phenyl group.

[0011] The application of the above-mentioned 1-fluorobenzimidazolidine derivatives in inhibiting tumor cell growth was tested using the CCK8 method.

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

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

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

[0015] Preferably, the 1-fluorobenzimidazolidine derivative has the following structural formula:

[0016]

[0017] This invention patent also discloses the application of a novel compound, 1-fluorobenzimidazolidine derivative, for inhibiting tumor cell growth activity.

[0018] The above technical solution has the following beneficial effects: 1. The reaction conditions are mild and the product structure is complex and diverse; 2. The synthesis steps are simple and the reaction chemical selectivity is high; 3. The 1-fluorobenzimidazolidine derivative synthesized in this invention has good inhibitory activity on tumor cell growth. Attached Figure Description

[0019] Figure 1 The target compound of Example 1 of this invention 1 H NMR spectrum.

[0020] Figure 2 The target compound of Example 1 of this invention 13 C10 NMR spectrum.

[0021] Figure 3 The target compound of Example 1 of this invention 19 F NMR spectrum.

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

[0023] Figure 5 The target compound of Example 2 of the present invention 13 C10 NMR spectrum.

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

[0025] Figure 7This is a schematic diagram showing the comparison of the growth inhibition rate of the target compound in Example 1 of the present invention against human colon cancer cells HT-29.

[0026] Figure 8 This is a schematic diagram showing the comparison of the growth inhibition rate of the target compound against human colon cancer cells HT-29 in Example 2 of the present invention. Detailed Implementation

[0027] The following specific embodiments illustrate the implementation 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] Exemplary embodiments will now be described more fully with reference to the accompanying drawings. However, these exemplary embodiments can be implemented in many forms and should not be construed as limited to the examples set forth herein; rather, these embodiments are provided to make the invention more comprehensive and complete, and to fully convey the concept of the exemplary 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 full understanding of embodiments of the invention. However, those skilled in the art will recognize that the technical solutions of the invention may be practiced with one or more of these specific details omitted, or other methods, components, apparatus, steps, etc., may be employed. In other instances, well-known technical solutions are not shown or described in detail to avoid obscuring various aspects of the invention.

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

[0030] This invention patent discloses a 1-fluorobenzimidazolidine derivative, the structural formula of which is as follows:

[0031]

[0032] Among them, Ar 1 For phenyl, Ar 2 It is 4-bromophenyl, or Ar 1 It is 3-chlorophenyl, Ar 2 It is a phenyl group.

[0033] The preparation methods of several embodiments of this derivative are described below.

[0034] Example 1

[0035] A method for preparing 1-fluoro-4-benzylmethyl-4-cyano-2-(4-bromophenylethynyl)-3,4-dihydropyrido[1,2-a]benzimidazole, specifically comprising the following steps:

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

[0037] Step 2): After the reaction was completed, the solvent was removed from the resulting mixture under reduced pressure, and the product was separated by column chromatography to obtain pure 1-fluoro-4-benzylmethyl-4-cyano-2-(4-bromophenylethynyl)-3,4-dihydropyridino[1,2-a]benzimidazole, with the following structural formula:

[0038]

[0039] Yield: 77%; pale yellow solid; as Figures 1 to 3 As shown, its 1H NMR spectrum (CDCl3, 400MHz) is as follows: δ 7.92 (d, J = 6.6Hz, 1H), 7.76 (d, J = 5.7Hz, 1H), 7.55 (d, J = 7.7Hz, 2H), 7.51-7.36 (m, 9H), 3.78 (d, J = 13.8Hz, 1H), 3.37 (d, J = 13.9Hz, 1H), 3.03 (dd, J = 15.9, 5.0Hz, 1H), 2.91 (dd, J = 15.9, 4.9Hz, 1H). Carbon NMR spectrum (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. Fluorine NMR spectrum (CDCl3, 376 MHz): δ -105.80. High-resolution mass spectrometry (ESI) calcd for C 27 H 18 BrFN3 + [M+H] + 482.0668, found 482.0658.

[0040] Example 2

[0041] A method for preparing 1-fluoro-4-(3-chlorophenyl)methyl-4-cyano-2-(phenylethynyl)-3,4-dihydropyrido[1,2-a]benzimidazole, specifically comprising the following steps:

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

[0043] Step 2): After the reaction was completed, the resulting mixture was subjected to reduced pressure to remove the solvent, and column chromatography was used to separate the pure product 1-fluoro-4-(3-chlorophenyl)methyl-4-cyano-2-(phenylethynyl)-3,4-dihydropyridino[1,2-a]benzimidazole, with the following structural formula:

[0044]

[0045] Yield: 65%; pale yellow solid; as Figures 4 to 6 As shown, its 1H NMR spectrum (CDCl3, 400MHz) is as follows: 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). Carbon NMR spectrum (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. Fluorine NMR spectrum (CDCl3, 376 MHz): δ -106.24. High-resolution mass spectrometry (ESI) calcd for C 27 H 18 ClFN3 + [M+H] + 438.1173, found 438.1165.

[0046] The method described above has the advantages of mild reaction conditions, complex and diverse product structures, simple synthetic steps, and high chemical selectivity.

[0047] The 1-fluorobenzimidazolidine derivative synthesized in this invention has good inhibitory activity against tumor cell growth. To further demonstrate its application effect, the following experimental examples were conducted.

[0048] Experimental Example 1:

[0049] The inhibitory effect of 1-fluoro-4-benzyl-4-cyano-2-(4-bromophenylethynyl)-3,4-dihydropyrido[1,2-a]benzimidazole, the product prepared in Example 1, on the growth of human colon cancer cells HT-29 was determined using the CCK8 assay. 1-fluoro-4-benzyl-4-cyano-2-(4-bromophenylethynyl)-3,4-dihydropyrido[1,2-a]benzimidazole was diluted with dimethyl sulfoxide to three concentrations of 100 and 500 μg / L, and after 24 h of treatment, its cytotoxicity against HT-29 cells was measured. The results are as follows: Figure 7 As shown, the cell inhibition rate was 43.30±5.53% at a concentration of 100 μg / L and 60.12±10.04% at a concentration of 500 μg / L.

[0050] Experimental Example 2:

[0051] The inhibitory effect of 1-fluoro-4-(3-chlorophenyl)methyl-4-cyano-2-(phenylethynyl)-3,4-dihydropyrido[1,2-a]benzimidazole, the product prepared in Example 2, on the growth of human colon cancer cells HT-29 was determined using the CCK8 assay. 1-fluoro-4-(3-chlorophenyl)methyl-4-cyano-2-(phenylethynyl)-3,4-dihydropyrido[1,2-a]benzimidazole was diluted with dimethyl sulfoxide to three concentrations of 10, 100, and 500 μg / L. After treatment for 24 h, its cytotoxicity against HT-29 cells was measured. The results are as follows: Figure 8 As shown, the cell inhibition rate was 12.91±3.79% at a concentration of 10 μg / L, 24.32±3.36% at a concentration of 100 μg / L, and 43.17±8.74% at a concentration of 500 μg / L. These results indicate that the product prepared in this invention exhibits good activity in inhibiting tumor cell growth, which has significant guiding significance and application prospects for the discovery of novel and highly effective anti-tumor drugs.

[0052] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. Any person skilled in the art can 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 those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.

Claims

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

2. A method for preparing the 1-fluorobenzimidazolidine derivative of claim 1, characterized in that, It includes the following steps: Step 1) 2-(2-benzimidazolyl)-3-phenylpropionitrile, 1-2 equivalents of 1-(4-bromophenyl)-3-trifluoromethyl-3-buten-1-yne, 1-3 equivalents of cesium carbonate and 1,4-dioxane solvent are reacted; Step 2) After the reaction is complete, the solvent is removed under reduced pressure, and the product is obtained by column chromatography as a pure 1-fluorobenzimidazolidine derivative; wherein the structural formula of the 1-fluorobenzimidazolidine derivative is: 。 3. A method for preparing the 1-fluorobenzimidazolidine derivative of claim 1, characterized in that, It includes the following steps: Step 1) 2-(2-benzimidazolyl)-3-(3-chlorophenyl)propionitrile, 1-2 equivalents of 1-phenyl-3-trifluoromethyl-3-buten-1-yne, 1-3 equivalents of cesium carbonate and 1,4-dioxane solvent are reacted; Step 2) After the reaction is complete, the solvent is removed under reduced pressure, and the product is obtained by column chromatography as a pure 1-fluorobenzimidazolidine derivative; wherein the structural formula of the 1-fluorobenzimidazolidine derivative is: 。 4. The method for preparing the 1-fluorobenzimidazolidine derivative according to claim 2, characterized in that, The reaction temperature is 20-40°C. o C.

5. The application of the 1-fluorobenzimidazolidine derivative of claim 1 in the preparation of a drug, characterized in that: The drug is used to inhibit the growth activity of tumor cells.

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