A process for the preparation of a benzimidazole derivative

Abstract

This invention discloses a method for preparing a benzimidazole derivative, the synthetic route of which is as follows: wherein, R 1 H, C1-C4 alkyl, C1-C4 alkoxy, halogen, or trifluoromethyl; R 2 The phenyl group can be H, C1-C4 alkyl, benzyl, furanyl, thiophene, pyridyl, quinolinyl, or substituted or unsubstituted, wherein the substituent on the phenyl group is selected from C1-C4 alkyl, C1-C4 alkoxy, or halogen. The raw materials of this invention are inexpensive and readily available, the reaction conditions are mild, the operation is simple, the product yield is high, the reaction time is short, the substrate applicability is broad, the reaction specificity is strong, and the obtained product can serve as a potential drug molecule unit.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and specifically relates to a method for preparing a benzimidazole derivative. Background Technology

[0002] Benzimidazole compounds are a class of benzo[a]heterocyclic compounds containing two nitrogen atoms. They are important intermediates in organic synthesis and key structural segments in many chemical and pharmaceutical raw material compounds. Many benzimidazole compounds possess significant biological activities, such as anti-AIDS, anticancer, anti-inflammatory, antibacterial, antioxidant, antihypertensive, and anticoagulant effects (Goodwin, KD; Lewis, MA; Tanious, FA; Tidwell, RR; David Wilson, W.; Georgiadis, MM; Long, EC J Am. Chem. Soc. 2006, 128, 7846.), and have important medicinal value. Meanwhile, benzimidazole compounds can also be used as corrosion inhibitors (Zhang, J.; Zhao, W.-M.; Guo, W.-Y.; Wang, Y.; Li, Z.-P. Acta Phys.-Chim. Sin. 2008, 24, 1239.), transition metal ligands (Isele, K.; Franz, P.; Ambrus, C.; Bernardinelli, G.; Decurtins, S.; Williams, AFINorg. Chem. 2005, 44, 3896.), and to mimic the bioactivity of natural superoxide dismutase (SOD) (Zhang, J.; Zhao, W.-M.; Guo, W.-Y.; Wang, Y.; Li, Z.-P. Acta Phys.-Chim. Sin. 2008, 24, 1239.), transition metal ligands (Isele, K.; Franz, P.; Ambrus, C.; Bernardinelli, G.; Decurtins, S.; Williams, AFINorg. Chem. 2005, 44, 3896.), and to mimic the bioactivity of natural superoxide dismutase (SOD) (Zhang, J.; Zhao, W.-M.; Guo, W.-Y.; Wang, Y.; Li, Z.-P. Acta Phys.-Chim. Sin. 2008, 24, 1239.). Phys.-Chim.Sin. 2008, 24, 1239.), surfactants (Raban, M.; Chang, H.; Craine, L. J.O.R.G. Chem. 1985, 50, 2205.), novel epoxy resin curing agents (Raban, M.; Chang, H.; Craine, L. J.O.R.G. Chem. 1985, 50, 2205.), and chemiluminescence (Raban, M.; Chang, H.; Craine, L. J.O.R.G. Chem. 1985, 50, 2205.), in the fields of...

[0003] In the existing technology, the traditional synthesis methods for benzimidazole compounds are mainly divided into two types:

[0004] One method involves reacting o-phenylenediamine and its derivatives with carboxylic acid compounds under the action of strong acids such as hydrochloric acid or polyphosphoric acid. This method typically requires high reaction temperatures or long reaction times, and the yield is not ideal, while also placing high demands on equipment.

[0005] Another method involves the cyclization of o-phenylenediamine and its derivatives with aldehydes under the action of an oxidizing agent. This reaction process is relatively simple, but it produces many byproducts that are difficult to separate. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for preparing benzimidazole derivatives.

[0007] The technical solution of the present invention is as follows:

[0008] A method for preparing a benzimidazole derivative, the synthetic route of which is as follows:

[0009]

[0010] Among them, R 1 It can be H, C1-C4 alkyl, C1-C4 alkoxy, halogen, or trifluoromethyl.

[0011] R 2 The phenyl group is H, C1=C4 alkyl, benzyl, furanyl, thiophene, pyridyl, quinolinyl, substituted or unsubstituted, wherein the substituent on the phenyl group is selected from C1-C4 alkyl, C1-C4 alkoxy or halogen.

[0012] Specifically, the reaction involves reacting aromatic diamine compounds and aldehyde compounds in an organic solvent at 25-30°C for 0.8-1.2 h under the action of a catalyst and a blue light source. After the reaction, the benzimidazole derivative is obtained through post-treatment. The catalyst is Cs2AgBiCl6 nanomaterial, Cs2AgBiBr6 nanomaterial, or Cs2AgBiI6 nanomaterial.

[0013] In a preferred embodiment of the invention, the R 1 It can be H, methyl, methoxy, fluorine, chlorine, or trifluoromethyl.

[0014] In a preferred embodiment of the invention, the R 2 It is a methyl, ethyl, n-propyl, isopropyl, cyclopropyl, benzyl, furanyl, thiophene, pyridyl or substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is at least one of methyl, isopropyl, tert-butyl, methoxy, trifluoromethyl, fluorine, chlorine, bromine and iodine.

[0015] In a preferred embodiment of the present invention, the benzimidazole derivative is one of the following:

[0016]

[0017] In a preferred embodiment of the present invention, the organic solvent is methanol, ethanol, toluene, dichloromethane, ethyl acetate, isopropanol, cyclohexane, chloroform, or dimethyl sulfoxide.

[0018] More preferably, the organic solvent is toluene.

[0019] In a preferred embodiment of the present invention, the catalyst is Cs2AgBiBr6 nanomaterial.

[0020] In a preferred embodiment of the present invention, the wavelength of the blue light is 440-460nm.

[0021] In a preferred embodiment of the present invention, the molar ratio of the aromatic diamine compound, the aldehyde compound and the catalyst is 0.8-1.2:1.2-1.3:0.0001.

[0022] More preferably, the molar ratio of the aromatic diamine compound, the aldehyde compound, and the catalyst is 1:1.25:0.0001.

[0023] The beneficial effects of this invention are: the raw materials are inexpensive and readily available, the reaction conditions are mild, the operation is simple, the product yield is high, the reaction time is short, the substrate has a wide range of applicability, the reaction is highly specific, and the obtained product can be used as a potential drug molecule unit. Detailed Implementation

[0024] The technical solution of the present invention will be further explained and described below through specific embodiments.

[0025] Example 1 Preparation of 2-Phenylenibimidazole

[0026]

[0027] A 0.01 mmol / L toluene solution of Cs₂AgBiBr₆ nanomaterials was prepared. 2.0 mL of this solution was added to a 10 mL quartz reaction tube, followed by the addition of 0.2 mmol of o-phenylenediamine and 0.25 mmol of benzaldehyde. The reaction was stirred at 25 °C for 1.0 h under blue light (445 nm, 10 W) irradiation, and then stopped. The reaction solution was diluted with dichloromethane, extracted three times with water, dried over anhydrous Na₂SO₄, filtered, and separated by column chromatography to obtain 38.0 mg of the target product, with a yield of 98%. The NMR characterization of the target product is as follows: 1 H NMR (400MHz, DMSO-d6) δ12.93 (s, 1H), 8.20 (d, J=7.3Hz, 2H), 7.74-7.45 (m, 5H), 7.27-7.15 (m, 2H). 13C NMR (100MHz, DMSO-d6) δ151.7, 144.3, 135.4, 130.6, 130.3, 126.9, 123.0, 122.1, 119.3, 111.8.

[0028] Example 2 Preparation of 2-o-methylphenylbenzimidazole

[0029]

[0030] A 0.01 mmol / L toluene solution of Cs₂AgBiBr₆ nanomaterials was prepared. 2.0 mL of this solution was added to a 10 mL quartz reaction tube, followed by the addition of 0.2 mmol of o-phenylenediamine and 0.25 mmol of 2-methylbenzaldehyde. The reaction was stirred at 25 °C for 1.0 h under blue light (445 nm, 10 W) irradiation, and then stopped. The reaction solution was diluted with dichloromethane, extracted three times with water, dried over anhydrous Na₂SO₄, filtered, and separated by column chromatography to obtain 40.0 mg of the target product, with a yield of 96%. The NMR characterization of the target product is as follows: 1 H NMR (400MHz, Methanol-d4) δ7.63 (m, 7.67-7.56, Hz, 3H), 7.44-7.24 (m, 5H), 2.51 (s, 3H). 13 C NMR (100MHz, Methanol-d4) δ 152.6, 138.4, 137.1, 130.7, 130.1, 129.6, 129.5, 125.7, 122.3, 114.5, 19.2.

[0031] Example 3 Preparation of 2-m-methylphenylbenzimidazole

[0032]

[0033] A 0.01 mmol / L toluene solution of Cs₂AgBiBr₆ nanomaterials was prepared. 2.0 mL of this solution was added to a 10 mL quartz reaction tube, followed by the addition of 0.2 mmol of o-phenylenediamine and 0.25 mmol of 3-methylbenzaldehyde. The reaction was stirred at 25 °C for 1.0 h under blue light (445 nm, 10 W) irradiation, and then stopped. The reaction solution was diluted with dichloromethane, extracted three times with water, dried over anhydrous Na₂SO₄, filtered, and separated by column chromatography to obtain 39.1 mg of the target product, with a yield of 94%. The NMR characterization of the target product is as follows: 1H NMR (400MHz, Methanol-d4) δ7.93-7.82(m, 2H), 7.62-7.55(m, 2H), 7.41-7.32(m, 1H), 7.31-7.17(m, 3H), 2.40(s, 3H). 13 C NMR (100MHz, Methanol-d4) δ 152.1, 138.7, 138.6, 130.6, 129.4, 128.6, 126.9, 123.5, 122.5, 114.4, 20.1.

[0034] Example 4 Preparation of 2-p-methylphenylbenzimidazole

[0035]

[0036] A 0.01 mmol / L toluene solution of Cs₂AgBiBr₆ nanomaterials was prepared. 2.0 mL of this solution was added to a 10 mL quartz reaction tube, followed by the addition of 0.2 mmol of o-phenylenediamine and 0.25 mmol of 4-methylbenzaldehyde. The reaction was stirred at 25 °C for 1.0 h under blue light (445 nm, 10 W) irradiation, and then stopped. The reaction solution was diluted with dichloromethane, extracted three times with water, dried over anhydrous Na₂SO₄, filtered, and separated by column chromatography to obtain 41.2 mg of the target product, with a yield of 99%. The NMR characterization of the target product is as follows: 1 H NMR (400MHz, DMSO-d6) δ12.86 (s, 1H), 8.14-8.02 (m, 3H), 7.72-7.47 (m, 2H), 7.41-7.30 (m, 2H), 7.20 (s, 1H), 2.38 (s, 3H). 13 C NMR (100MHz, DMSO-d6) δ151.8, 144.3, 140.0, 135.4, 130.0, 127.9, 126.8, 122.8, 122.0, 119.2, 111.6, 21.4.

[0037] Example 5 Preparation of 2-p-fluorophenylbenzimidazole

[0038]

[0039] A 0.01 mmol / L toluene solution of Cs₂AgBiBr₆ nanomaterials was prepared. 2.0 mL of this solution was added to a 10 mL quartz reaction tube, followed by the addition of 0.2 mmol of o-phenylenediamine and 0.25 mmol of 4-fluorobenzaldehyde. The reaction was stirred at 25 °C for 1.0 h under blue light (445 nm, 10 W) irradiation, and then stopped. The reaction solution was diluted with dichloromethane, extracted three times with water, dried over anhydrous Na₂SO₄, filtered, and separated by column chromatography to obtain 39.9 mg of the target product, with a yield of 94%. The NMR characterization of the target product is as follows: 1 H NMR (400MHz, DMSO-d6) δ12.96 (s, 1H), 8.24 (dt, J=8.6, 4.6Hz, 2H), 7.75-7.49 (m, 2H), 7.46-7.34 (m, 2H), 7.21 (s, 2H). 13 C NMR (100MHz, DMSO) δ164.7, 162.3, 150.9, 144.2, 135.5, 129.2 (d, J C-F =28.3Hz), 127.3 (d, J) C-F =2.8Hz), 122.6 (d, J) C-F =83.6Hz), 119.3, 116.5 (d, J C-F =28.6Hz), 111.8. 19 F NMR (376MHz, DMSO-d6) δ-111.1.

[0040] Example 6 Preparation of 2-p-chlorophenylbenzimidazole

[0041]

[0042] A 0.01 mmol / L toluene solution of Cs₂AgBiBr₆ nanomaterials was prepared. 2.0 mL of this solution was added to a 10 mL quartz reaction tube, followed by the addition of 0.2 mmol of o-phenylenediamine and 0.25 mmol of 4-chlorobenzaldehyde. The reaction was stirred at 25 °C for 1.0 h under blue light (445 nm, 10 W) irradiation, and then stopped. The reaction solution was diluted with dichloromethane, extracted three times with water, dried over anhydrous Na₂SO₄, filtered, and separated by column chromatography to obtain 36.9 mg of the target product, with a yield of 81%. The NMR characterization of the target product is as follows: 1 H NMR (400MHz, DMSO-d6) δ13.02 (s, 1H), 8.27-8.14 (m, 2H), 7.76-7.48 (m, 4H), 7.22 (s, 2H). 13C NMR (100MHz, DMSO-d6) δ150.6, 144.2, 135.5, 134.9, 129.5, 128.6, 123.3, 122.3, 119.4, 111.9.

[0043] Example 7 Preparation of 2-p-bromophenylbenzimidazole

[0044]

[0045] A 0.01 mmol / L toluene solution of Cs₂AgBiBr₆ nanomaterials was prepared. 2.0 mL of this solution was added to a 10 mL quartz reaction tube, followed by the addition of 0.2 mmol of o-phenylenediamine and 0.25 mmol of 4-bromobenzaldehyde. The reaction was stirred at 25 °C for 1.0 h under blue light (445 nm, 10 W) irradiation, and then stopped. The reaction solution was diluted with dichloromethane, extracted three times with water, dried over anhydrous Na₂SO₄, filtered, and separated by column chromatography to obtain 51.7 mg of the target product, with a yield of 95%. The NMR characterization of the target product is as follows: 1 H NMR (400MHz, DMSO-d6) δ13.02 (s, 1H), 8.17-8.08 (m, 2H), 7.81-7.74 (m, 2H), 7.72-7.50 (m, 2H), 7.22 (s, 2H). 13 C NMR (100MHz, DMSO-d6) δ150.6, 144.2, 135.5, 134.9, 129.5, 128.6, 123.3, 122.3, 119.4, 111.9.

[0046] Example 8 Preparation of 2-p-iodophenylbenzimidazole

[0047]

[0048] A 0.01 mmol / L toluene solution of Cs₂AgBiBr₆ nanomaterials was prepared. 2.0 mL of this solution was added to a 10 mL quartz reaction tube, followed by the addition of 0.2 mmol of o-phenylenediamine and 0.25 mmol of 4-iodobenzaldehyde. The reaction was stirred at 25 °C for 1.0 h under blue light (445 nm, 10 W) irradiation, and then stopped. The reaction solution was diluted with dichloromethane, extracted three times with water, dried over anhydrous Na₂SO₄, filtered, and separated by column chromatography to obtain 49.2 mg of the target product, with a yield of 77%. The NMR characterization of the target product is as follows: 1H NMR (400MHz, DMSO-d6) δ13.01 (s, 1H), 8.04-7.90 (m, 4H), 7.75-7.50 (m, 2H), 7.30-7.15 (m, 2H). 13 C NMR (100MHz, DMSO-d6) δ150.9, 144.2, 138.3, 135.5, 130.1, 128.8, 123.3, 122.3, 119.4, 111.9, 97.2.

[0049] Example 9 Preparation of 2-(4-isopropylphenyl)-benzimidazole

[0050]

[0051] A 0.01 mmol / L toluene solution of Cs₂AgBiBr₆ nanomaterials was prepared. 2.0 mL of this solution was added to a 10 mL quartz reaction tube, followed by the addition of 0.2 mmol of o-phenylenediamine and 0.25 mmol of 4-isopropylbenzaldehyde. The reaction was stirred at 25 °C for 1.0 h under blue light (445 nm, 10 W) irradiation, and then stopped. The reaction solution was diluted with dichloromethane, extracted three times with water, dried over anhydrous Na₂SO₄, filtered, and separated by column chromatography to obtain 43.9 mg of the target product, with a yield of 93%. The NMR characterization of the target product is as follows: 1 H NMR (400MHz, DMSO-d6) δ12.89 (s, 1H), 8.20-8.08 (m, 2H), 7.60 (s, 2H), 7.45 -7.37(m, 2H), 7.24-7.15(m, 2H), 3.01-2.86(m, 1H), 1.23(d, J=3.2Hz, 6H). 13 C NMR (100MHz, DMSO-d6) δ151.8, 150.8, 129.9, 128.3, 127.3, 127.0, 126.9, 122.4, 33.8, 24.1.

[0052] Example 10 Preparation of 2-(4-tert-butylphenyl)-benzimidazole

[0053]

[0054] A 0.01 mmol / L toluene solution of Cs₂AgBiBr₆ nanomaterials was prepared. 2.0 mL of this solution was added to a 10 mL quartz reaction tube, followed by the addition of 0.2 mmol of o-phenylenediamine and 0.25 mmol of 4-tert-butylbenzaldehyde. The reaction was stirred at 25 °C for 1.0 h under blue light (445 nm, 10 W) irradiation, and then stopped. The reaction solution was diluted with dichloromethane, extracted three times with water, dried over anhydrous Na₂SO₄, filtered, and separated by column chromatography to obtain 48.0 mg of the target product, with a yield of 96%. The NMR characterization of the target product is as follows: 1 H NMR (400MHz, DMSO-d6) δ12.88 (s, 1H), 8.18-8.09 (m, 2H), 7.73-7.46 (m, 4H), 7.27-7.13 (m, 2H), 1.32 (s, 9H). 13 C NMR (100MHz, DMSO) δ153.0, 151.8, 129.7, 127.9, 126.7, 126.2, 125.8, 122.5, 35.0, 31.4.

[0055] The above description is merely a preferred embodiment of the present invention, and therefore should not be construed as limiting the scope of the present invention. All equivalent changes and modifications made in accordance with the scope of the patent and the contents of the specification should still fall within the scope of the present invention.

Claims

1. A method for preparing a benzimidazole derivative, characterized in that: The benzimidazole derivative is one of the following: , , , , , , , , , ; Its synthetic route is as follows: ， wherein R 1 is H, R 2 is substituted or unsubstituted phenyl, the substituents on the phenyl being selected from the group consisting of methyl, fluorine, chlorine, bromine, iodine, isopropyl or tert-butyl, The preparation method specifically includes: reacting aromatic diamine compounds and aldehyde compounds in toluene at 25-30℃ for 0.8-1.2 h under the action of Cs2AgBiBr6 nanomaterials as catalysts and a blue light source, with the molar ratio of aromatic diamine compounds, aldehyde compounds and Cs2AgBiBr6 nanomaterials being 0.8-1.2: 1.2-1.3: 0.0001. After the reaction is completed, the benzimidazole derivative is obtained through post-treatment.

2. The preparation method according to claim 1, characterized in that: The wavelength of the blue light is 440-460nm.

3. The preparation method according to claim 1, characterized in that: The molar ratio of the aromatic diamine compound, the aldehyde compound, and the catalyst is 1:1.25:0.0001.

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