Method for preparing imidazopyridine compounds by using Cu-W2C / AC to catalyze lignin and β-O-4 model compounds

Abstract

The present invention relates to a method for preparing imidazopyridine compounds by using Cu-W2C / AC to catalyze lignin and model compounds, specifically a new method for one-step catalytic conversion of lignin β-O-4 model compounds or lignin raw materials into imidazopyridine heterocyclic chemicals by using Cu-W2C / AC as a catalyst, N,N-dimethylformamide as a reaction solvent, and amino pyridine compounds and isocyanide compounds as nitrogen sources. The present invention uses renewable biomass resources as raw materials, which are cheap and widely available; inorganic acids and bases are not required during the reaction process; the reaction conditions are mild, the yield of the target product is high, and the catalyst can be recycled, providing a new route for preparing high-value-added imidazopyridine heterocyclic chemicals from lignin.

Description

Technical Field

[0001] The present invention relates to the field of high-value utilization of biomass, and particularly to a method for synthesizing imidazopyridine compounds by catalytic reaction of a Cu-W2C / AC catalyst with a lignin β-O-4 model compound or lignin raw material and aminopyridine. Background Art

[0002] Among nitrogen-containing compounds, imidazole heterocyclic compounds exhibit a wide range of pharmacological and biological activities such as antiviral, antibacterial, bactericidal, and anti-inflammatory activities, and play an increasingly important role in medicinal chemistry and organic chemistry. Among them, the importance of the imidazopyridine scaffold in the field of drug research and development has been widely recognized, and many commercial drugs featuring this scaffold have been developed (Green Chem. 2014, 16, 1168). For example, an anxiolytic drug (alpidem), a hypnotic drug (zolpidem), an anti-ulcer drug (zolimidine), a sedative drug (sulpiride and nikopirdine), and an optically active drug (GSK812397), which is expected to be used for the treatment of HIV infection.

[0003] The synthesis of imidazopyridine compounds by green, mild, and simple methods is currently a research hotspot. At the same time, reducing or eliminating the use and generation of harmful substances is the goal of green chemistry. Imidazo[1,2-a]pyridine compounds are a class of nitrogen-bridged heterocyclic compounds that have received extensive attention due to their interesting biological activities (Mini-Rev Med Chem. 2007, 7, 888). Imidazo[1,a]pyridine has been shown to have a wide range of biological activities, and conditions such as the treatment of gastric diseases, heart diseases, migraines (Bioorg Med Chem 2009, 17, 368), viral diseases, HIV-1 inhibitors, and activities against colon cancer cell lines HT-29 and Caco-2 (Eur J Med Chem 2011, 46, 4573) have been studied. The common route for preparing imidazo[1,2-a]pyridine is the condensation reaction of o-aminopyridine, aldehyde, and isocyanide in the presence of a catalyst (Russ. Rev. 2011, 79, 787). However, some of these condensation processes have disadvantages such as high catalyst cost, large dosage, long time, difficult detection, and harsh reaction conditions. Some other methods use various catalysts such as scandium trifluoride and stannous chloride dihydrate, as well as acidic catalysts such as sulfuric acid silicate, p-toluenesulfonic acid, ionic liquids, and solid-phase synthesis. Although all these methods are beneficial, they have the following disadvantages: long reaction time, low product yield, use of toxic solvents, difficult procedure inspection, and harsh reaction conditions (Letters in Organic Chemistry, 2012, 9, 198-201).

[0004] Biomass is the only renewable organic carbon resource on Earth. Producing chemical products from biomass resources has become a viable way to alleviate the energy crisis. Among them, lignin, as an important component of biomass, is the only renewable aromatic compound resource in nature (Chem. Rev. 2015, 115, 11559 - 11624). However, its chemical properties are very stable and it has an amorphous state, making it difficult to depolymerize. It often exists as a by-product in the wood hydrolysis industry and the paper industry and cannot be fully utilized. Therefore, developing a directional catalytic approach to depolymerize lignin to prepare high-value aromatic compounds has the dual significance of effectively utilizing renewable resources and reducing environmental pollution. Using lignin as a green raw material to prepare ketones and aldehydes, and then preparing drug intermediates with high utilization value through synthetic reactions with nitrogen-containing compounds has important theoretical and practical significance for the rational development and utilization of lignin resources. Summary of the Invention

[0005] Based on the above background technology, the purpose of the present invention is to provide a method for catalyzing lignin with aminopyridine and isocyanide compounds to prepare imidazopyridine compounds. A new method for catalytically converting lignin model compounds and lignin raw materials into imidazopyridine compounds.

[0006] To achieve the above purpose, the technical solution adopted by the present invention is:

[0007] A method for preparing imidazopyridine compounds, characterized in that lignin β-O-4 model compounds or lignin raw materials are used as substrates, Cu-W2C / AC is used as a catalyst, DMF (N,N-dimethylformamide) is used as a reaction solvent, aminopyridine compounds and isocyanide compounds are used as nitrogen sources, and imidazopyridine nitrogen-containing aromatic compounds are prepared by reacting at 50 - 200 °C for 2 - 20 h.

[0008] The Cu-W2C / AC catalyst is a supported catalyst, and Cu and W2C are supported on AC; the loading amount of Cu is 0.5 - 5 wt%; the loading amount of W2C is 1 - 8 wt%.

[0009] The loading amount of Cu is 1.5 wt% Pd; the loading amount of W is 4 wt%.

[0010] The reaction temperature is 130 - 200 °C; the reaction time is 12 - 20 h.

[0011] The mass ratio of the substrate to the catalyst is 2:1 - 5:1, the molar ratio of the aminopyridine compound to the substrate is 3:1 - 8:1, and the molar ratio of the isocyanide compound to the substrate is 3:1 - 8:1.

[0012] The mass ratio of the substrate to the catalyst is 3:1.

[0013] The molar ratio of the aminopyridine compound to the substrate is 5:1.

[0014] The molar ratio of the isocyanide compound to the substrate is 5:1.

[0015] The lignin model compound is one or more of phenoxyethylbenzene, 2-(2-methoxyphenoxy)-1-phenylethanol, 2-phenoxy-1-phenylethanol, and 1-(4-methoxyphenyl)-2-phenoxyethanol.

[0016] The lignin raw material is one or more of organic lignin, calcium lignosulfonate, alkali lignin, groundwood lignin, enzymatically hydrolyzed lignin, and steam-exploded lignin.

[0017] The imidazopyridine compounds are one or more of N-cyclohexyl-2-phenylimidazo[1,2-a]pyridin-3-amine, N-(tert-butyl)-2-phenylimidazo[1,2-a]pyridin-3-amine, N-cyclohexyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridin-3-amine, N-cyclohexyl-2-(2,4-dichlorophenyl)imidazo[1,2-a]pyridin-3-amine, and N-cyclohexyl-2-(furan-2-yl)imidazo[1,2-a]pyridin-3-amine.

[0018] The aminopyridine compound is 2-aminopyridine or 2-amino-6-methylpyridine.

[0019] The isocyanide compound is isocyanocyclohexane or tert-butyl isocyanide.

[0020] The method provided by the present invention uses Cu-W2C / AC as a catalyst, DMF as a solvent, and aminopyridine compounds and isocyanide compounds as nitrogen sources to perform an ammoniation reaction on lignin model compound dimers or lignin raw materials to prepare nitrogen-containing imidazopyridine compounds. This method has mild reaction conditions, a high yield of imidazopyridine compounds, and the catalyst can be reused, thereby reducing the reaction cost.

[0021] Beneficial effects

[0022] (1) The catalyst used in the present invention has a very long service life and still maintains high activity after being recycled multiple times, greatly reducing the catalytic cost.

[0023] (2) The substrate used in the present invention is a renewable raw material, the raw material is cheap and widely available, the catalyst dosage is small and cheap, the atom economy is high, and the product yield is high.

[0024] (3) The reaction conditions of the present invention are mild, and no external acid is required for the reaction.

[0025] The present invention provides an effective and highly valuable approach for preparing imidazopyridine compounds by the reaction of Cu-W2C / AC with lignin, which is a way to prepare nitrogen-containing chemicals with high added value. Detailed implementation manners

[0026] The present invention will be illustrated by specific examples below. However, the protection scope of the present invention is not limited to these examples. The addition amount of the solvent is not limited, and those skilled in the art can make adjustments according to the actual situation. For 50 mg of the substrate in the present invention, the addition amount of the solvent is 1 - 5 ml, preferably 2 ml.

[0027] The catalyst Cu-W2C / AC described in the examples was synthesized according to the literature (ChemSusChem. 2016, 9, 3220–3229); the lignin model compounds 2-(2-methoxyphenoxy)-1-phenylethanol, 2-phenoxy-1-phenylethanol, and 1-(4-methoxyphenyl)-2-phenoxyethanol were synthesized according to the literature (J. Am. Chem. S℃. 2010, 132, 12554); the organic lignin, lignosulfonate, alkali lignin, groundwood lignin, enzymatic hydrolysis lignin, and steam-exploded lignin were synthesized according to the literature (Material 2013, 6, 359).

[0028] Example 1

[0029] Add 50 mg of the lignin model compound 2-(2-methoxyphenoxy)-1-phenylethanol, 18 mg of the catalyst Cu-W2C / AC (3 wt% Cu, 5 wt% W), 15 mg of 2-aminopyridine, 80 μl of cyclohexyl isocyanate, and 2 ml of water into a 50-ml glass tube. Add a magnetic stir bar and heat to 160 °C, and react for 15 hours. After the reaction is completed, cool to room temperature, filter, and the organic phase is subjected to chromatographic analysis. The conversion rate is 99.9%, the yield of guaiacol is 98.7%, and the yield of N-cyclohexyl-2-phenylimidazo[1,2-a]pyridin-3-amine is 88.5%.

[0030] Examples 2 - 6

[0031] Other process conditions and experimental procedures are the same as those in Example 1, but different reaction temperatures are used. The results are shown in Table 1.

[0032] Table 1. Experimental results of the catalytic conversion of lignin model compounds by Cu-W2C / AC at different reaction temperatures

[0033]

[0034] As can be seen from Table 1, the reaction temperature has a certain effect on the yield of the product. When the temperature is 130 - 200 °C, the yield of the product N-cyclohexyl-2-phenylimidazo[1,2-a]pyridin-3-amine is 75.4 - 88.5%, and the yield of the product guaiacol can reach 93.5 - 98.7%.

[0035] Examples 7 - 11

[0036] Other process conditions and experimental procedures are the same as those in Example 1, but different reaction times are used. The results are shown in Table 2

[0037] Table 2 Experimental results of catalytic conversion of lignin model compounds by Cu-W2C / AC under different reaction times

[0038]

[0039]

[0040] As shown in Table 2, with the extension of the reaction time, the yields of N-cyclohexyl-2-phenylimidazo[1,2-a]pyridin-3-amine and guaiacol increase, and the conversion rate also increases. When the reaction time is 15 - 20 h, the yield of the product N-cyclohexyl-2-phenylimidazo[1,2-a]pyridin-3-amine is 88.5 - 92.8%, and the yield of the product guaiacol can reach 98.7 - 99.5%.

[0041] Examples 12 - 14

[0042] Other process conditions and experimental procedures are the same as those in Example 1. In the used catalyst, the Cu loading is different. The results are shown in Table 3

[0043] Table 3. Experimental results of catalytic conversion of lignin model compounds by Cu-W2C / AC under different Cu loadings.

[0044]

[0045] Examples 15 - 18

[0046] Other process conditions and experimental procedures are the same as those in Example 1. In the used catalyst, the W loading is different. The results are shown in Table 3

[0047] Table 3. Experimental results of catalytic conversion of lignin model compounds by Cu-W2C / AC under different W loadings.

[0048]

[0049] Example 19

[0050] Other process conditions and experimental procedures are the same as in Example 1, but using W2C / AC (5 wt% W) as the catalyst, the conversion rate is 49.3%, the yield of the product N-cyclohexyl-2-phenylimidazo[1,2-a]pyridin-3-amine is 0%, and the yield of guaiacol is 48.3%.

[0051] Example 20

[0052] Other process conditions and experimental procedures are the same as in Example 1, but using Cu / AC (3 wt%) as the catalyst, the conversion rate is 12.8%, the yield of the product N-cyclohexyl-2-phenylimidazo[1,2-a]pyridin-3-amine is 5.7%, and the yield of guaiacol is 9.6%.

[0053] Example 21

[0054] Other process conditions and experimental procedures are the same as in Example 1, but using 1-(4-methoxyphenyl)-2-phenoxyethanol as the substrate, the conversion rate is 93.5%, the yield of the product N-cyclohexyl-2-phenylimidazo[1,2-a]pyridin-3-amine is 79.4%, and the yield of phenol is 86.7%.

[0055] Examples 22 - 26

[0056] Other process conditions and experimental procedures are the same as in Example 1, using different lignin raw materials, and the results are shown in Table 5.

[0057] Table 5. Experimental results of catalytic conversion of lignin raw materials by Cu-W2C / AC

[0058] Project Lignin Total Yield of Nitrogen-Containing Imidazole Heterocycles (%) Example 22 Organic Lignin 25.3 Example 23 Calcium Lignosulfonate 23.6 Example 24 Alkali Lignin 28.4 Example 25 Groundwood Lignin 28.2 Example 26 Explosion-Pulverized Lignin 19.5

[0059] Examples 27 - 38

[0060] To investigate the recycling of the catalyst, the specific operation is as follows: Add 50 mg of the lignin model compound 2-(2-methoxyphenoxy)-1-phenylethanol, 20 mg of the catalyst Cu-W2C / AC (3 wt% Cu, 5 wt% W), 12 mg of 2-aminopyridine, 80 μL of cyclohexyl isocyanate, and 2 mL of water into a 50 mL glass tube, heat to 160 °C, and react for 15 hours. After the reaction, cool to room temperature, filter, and the obtained organic phase supernatant is subjected to chromatographic analysis; the solid is retained, and then add 50 mg of the lignin model compound 2-(2-methoxyphenoxy)-1-phenylethanol into the reaction tube, 2 mg of 2-aminopyridine, 80 μL of cyclohexyl isocyanate, and 2 mL of water, heat to 160 °C, and react for 15 hours. The post-treatment method is the same as above.

[0061] Table 6. Recycling results of catalytic conversion of lignin model compounds by Cu-W2C / AC

[0062]

[0063]

[0064] As shown in Table 6, Cu-W2C / AC can be recycled 10 times with unchanged reactivity.

[0065] Comparative Examples 1-12

[0066] Other process conditions and experimental procedures were the same as in Example 1, but different catalysts were used. The comparison results are shown in Table 7. The catalysts described in the comparative examples were synthesized by changing the metal active components and supports according to the synthesis method in the literature (ChemSusChem. 2016, 9, 3220–3229).

[0067] Table 7. Experimental results of catalytic conversion of different lignin model compounds under different catalyst conditions

[0068]

[0069]

Claims

1. A method for preparing imidazopyridine compounds, characterized in that, Using a lignin β-O-4 model compound as a substrate, Cu-W2C / AC as a catalyst, DMF as a reaction solvent, and amino pyridine compounds and isocyanide compounds as nitrogen sources, an imidazole pyridine-based nitrogen-containing aromatic compound is prepared by reacting at 130 - 200 °C for 12 - 20 h; The lignin model compound is one or two of 2-(2-methoxyphenoxy)-1-phenylethanol and 2-phenoxy-1-phenylethanol; The amino pyridine compound is o-aminopyridine or 2-amino-6-methylpyridine; the isocyanide compound is isocyanocyclohexane or tert-butyl isocyanide; The Cu-W2C / AC catalyst is a supported catalyst, and Cu and W2C are supported on the AC.

2. The method according to claim 1, wherein The mass ratio of the substrate to the catalyst is 2:1 - 5:1, the molar ratio of the amino pyridine compound to the substrate is 3:1 - 8:1, and the molar ratio of the isocyanide compound to the substrate is 3:1 - 8:

1.

3. The method according to claim 2, wherein The mass ratio of the substrate to the catalyst is 3:1; the molar ratio of the amino pyridine compound to the substrate is 5:1; the molar ratio of the isocyanide compound to the substrate is 5:

1.

4. The method according to claim 1, wherein The imidazole pyridine compound is one or two of N-cyclohexyl-2-phenylimidazo[1,2-a]pyridin-3-amine and N-(tert-butyl)-2-phenylimidazo[1,2-a]pyridin-3-amine.

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