Method for preparing imidazopyridine compounds from lignin and model compounds using a Pd / C two-component system

Abstract

The application discloses a method for preparing imidazole pyridine compounds from lignin and model compounds by using a Pd / C two-component system as a catalyst, and in particular relates to a new method for one-step catalytic conversion of lignin beta-O-4 model compounds or lignin raw materials into imidazole pyridine heterocyclic chemicals by using Pd / C as a catalyst, using elemental iodine as an additive, using a mixture of an organic solvent and water as a reaction solvent, and using an amino pyridine compound as a nitrogen source. The application uses renewable biomass as raw materials, the raw materials are cheap and widely available, inorganic acids and bases are not needed in the reaction process, the reaction conditions are mild, the yield of the target product is high, and the catalyst can be recycled, so that a new route is provided for preparing high-value-added imidazole pyridine heterocyclic chemicals from lignin.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of high-value utilization of biomass, and particularly relates to a method for preparing imidazole pyridine compounds from lignin and model compounds in a Pd / C two-component system. BACKGROUND

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

[0003] Synthesizing imidazole pyridine compounds by a green, mild and simple method is a current 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]pyridines are a class of nitrogen-bridged heterocyclic compounds, which have attracted extensive attention due to their interesting biological activities (Mini-Rev Med Chem. 2007, 7, 888). Imidazo[1, a]pyridines have been proven to have a wide range of biological activities, and conditions such as treatment of gastric diseases, heart diseases, migraine (Bioorg Med Chem 2009, 17, 368), viral diseases, HIV-1 inhibitors, and activity against colon cancer cell lines HT-29 and Caco-2 (Eur J Med Chem 2011, 46, 4573) have been studied. A common route for preparing imidazo[1,2-a]pyridines is the condensation reaction of o-aminopyridines, aldehydes and isocyanides in the presence of a catalyst (Russ. Rev. 2011, 79, 787). However, some of these condensation processes have the disadvantages of high catalyst cost, large amount of catalyst, long time, difficult detection, harsh reaction conditions, etc. Other methods use various catalysts such as scandium triflate and tin chloride dihydrate, as well as acidic catalysts such as sulfuric acid, silicic acid, 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 process inspection and harsh reaction conditions (Letters in Organic Chemistry, 2012, 9, 198-201).

[0004] Biomass is the only renewable organic carbon resource on earth. It is a feasible way to alleviate energy crisis to produce chemical products from biomass resources. Lignin, as an important component of biomass, is the only renewable aromatic compound resource in nature (Chem. Rev. 2015, 115, 11559-11624). However, it is difficult to depolymerize due to its stable chemical properties and amorphous state, and it is often used as a byproduct of wood hydrolysis industry and paper industry, which cannot be fully utilized. Therefore, developing a directed catalytic approach to depolymerize lignin to prepare high value-added aromatic compounds has dual significance of effective utilization of renewable resources and reduction of environmental pollution. It has important theoretical and practical significance to use lignin as a green raw material to prepare ketone and aldehyde compounds, and then through synthetic reactions with nitrogen-containing compounds to prepare drug intermediates with high utilization value for the rational development and utilization of lignin resources. SUMMARY

[0005] In order to solve the above problems, the purpose of the present application is to provide a method for catalytically preparing imidazole pyridine compounds from lignin, amino pyridine and isocyan compounds. A new method for catalytically converting lignin model compounds and lignin raw materials into imidazole pyridine compounds is provided.

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

[0007] A method for preparing imidazole pyridine compounds from lignin and model compounds catalyzed by Pd / C two-component system, characterized in that lignin β-O-4 model compound or lignin raw material is used as a substrate, Pd / C is used as a catalyst, elemental iodine is used as an additive, toluene is used as a reaction solvent, and amino pyridine compound is used as a nitrogen source, and imidazole pyridine nitrogen-containing aromatic compounds are prepared at 50-250℃ for 1-20h.

[0008] Further, in the above technical solution, the Pd / C catalyst is a supported catalyst, and the Pd is supported on activated carbon; the loading amount of Pd is 0.1-10wt%.

[0009] Further, in the above technical solution, the loading amount of Pd is 5wt% Pd.

[0010] Further, in the above technical solution, the reaction temperature is 130-200℃; the reaction time is 12-20h; and the volume ratio of organic solvent to water is 1:1-5:1.

[0011] Further, in the above technical solution, the molar ratio of the substrate to the catalyst is 2:1-100:1, the molar ratio of the additive to the substrate is 2:1-6:1, and the molar ratio of the amino pyridine compound to the substrate is 3:1-8:1.

[0012] Further, in the above technical solution, the molar ratio of the substrate to the catalyst is 10:1.

[0013] Further, in the above technical solution, the molar ratio of the auxiliary agent to the substrate is 3:1

[0014] Further, in the above technical solution, the molar ratio of the amino pyridine compound to the substrate is 8:1.

[0015] Further, in the above technical solution, the organic solvent is one or more of toluene, xylene, ethyl acetate, ethanol, dimethyl sulfoxide, tetrahydrofuran, N,N-dimethylformamide, dichloromethane, chlorobenzene, n-hexane, and cyclohexane.

[0016] Further, in the above technical solution, 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.

[0017] Further, in the above technical solution, the lignin raw material is one or more of organic lignin, calcium lignosulfonate, alkali lignin, groundwood lignin, enzymatic hydrolysis lignin, and steam explosion lignin.

[0018] Further, in the above technical solution, the imidazole pyridine compound is one or more of 2-phenylimidazo[1,2-a]pyridine, 2-(4-methoxyphenyl)imidazo[1,2-a]pyridine, 2-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyridine, 8-methyl-2-phenylimidazo[1,2-a]pyridine, 8-methoxy-2-phenylimidazo[1,2-a]pyridine, 7-methyl-2-phenylimidazo[1,2-a]pyridine, 7-methoxy-2-phenylimidazo[1,2-a]pyridine, 6-methyl-2-phenylimidazo[1,2-a]pyridine, 5-methyl-2-phenylimidazo[1,2-a]pyridine, 6-chloro-2-phenylimidazo[1,2-a]pyridine, and 4-(imidazo[1,2-a]pyridin-2-yl)phenol.

[0019] Further, in the above technical solution, the amino pyridine compound is one or more of o-amino pyridine, 3-methyl-2-amino pyridine, 3-methoxy-2-amino pyridine, 4-methyl-2-amino pyridine, 4-methoxy-2-amino pyridine, 5-methyl-2-amino pyridine, 2-amino-5-chloro pyridine, and 6-methyl-2-amino pyridine. The method provided by the application provides a method for preparing imidazole pyridine compounds from lignin and a β-O-4 model compound by using a Pd / C-I2 two-component catalytic system. The lignin β-O-4 model compound or lignin raw material is catalytically converted into an imidazole pyridine heterocyclic compound in one step by using Pd / C as a catalyst, using elemental iodine as an additive, using toluene as a reaction solvent, and using an amino pyridine compound as a nitrogen source, so that efficient conversion of biomass into aromatic heterocyclic compounds is realized. The method has mild reaction conditions, high yield of imidazole pyridine compounds, and reusable catalysts.

[0020] Advantages of the application

[0021] (1) The catalyst used in the application has a very high service life, and remains highly active after multiple cycles, greatly reducing the cost of catalysis.

[0022] (2) The substrate used in the application is a renewable raw material, which is inexpensive and widely available. The catalyst is used in small amounts and is inexpensive, and the atom economy is high, resulting in high product yield.

[0023] (3) The reaction conditions of the application are mild, and no external acid is required. A new catalytic system is formed for efficient conversion of renewable lignin resources into nitrogen-containing heterocyclic compounds. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 2-phenyl imidazo[1,2-a]pyridine 1 H NMR spectrum;

[0025] Figure 2 2-phenyl imidazo[1,2-a]pyridine 13 C NMR spectrum. DETAILED DESCRIPTION

[0026] The application will be described in detail below with specific examples, but the scope of protection of the application is not limited to these examples. The amount of solvent added is not limited, and those skilled in the art can adjust it according to the actual situation. The application uses 50 mg of lignin β-O-4 model compound or lignin raw material as the substrate, and the amount of solvent added is 1-5 ml, preferably 2 ml.

[0027] The catalysts described in the examples were prepared as follows: carbon powder was first impregnated with aqueous solutions of palladium chloride at different concentrations, left at room temperature for 12 h, then dried in an oven at 120 °C for 12 h, and finally reduced at 300 °C under a N2 / H2(95:5 v / v) mixed gas stream (80 cc / min) for 3 h, with a heating rate of 2 °C / min. This resulted in Pd / C catalysts with different loadings. The lignin model compound 2-(2-methoxyphenoxy)

[0028] -1-phenylethanol, 2-phenoxy-1-phenylethanol, 1-(4-methoxyphenyl)-2-phenoxyethanol were synthesized according to the literature (J. Am. Chem. S. 2010, 132, 12554); the organolignin, lignosulfonate, alkali lignin, milled wood lignin, enzymatic hydrolysis lignin, steam exploded lignin were synthesized according to the literature (Material 2013, 6, 359).

[0029] Example 1

[0030] A mixture of 50 mg of the lignin model compound 2-phenoxy-1-phenylethanol, 20 mg of the catalyst Pd / C (5 wt% Pd), 50 mg of I2, 80 mg of o-aminopyridine, 1.5 mL of toluene and 0.5 mL of water was added to a 50 mL glass tube, a magnetic stirrer was added and the temperature was raised to 180 °C, and the reaction was carried out for 18 h. After the reaction was completed, the temperature was lowered to room temperature, and the organic phase was filtered and subjected to chromatographic analysis. The conversion was 99.9%, the yield of phenol was 98.7%, and the yield of 2-phenylimidazo[1,2-a]pyridine was 89.5%. The product was separated by column chromatography: after the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, and the wet sample was loaded and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the developing agent. The pure product obtained by separation was a white solid, which was dried and weighed to calculate the separation yield of 2-phenylimidazo[1,2-a]pyridine, which was 87.3%. The structure of the product was determined by 1 H NMR spectrum, 13 C NMR spectrum (see Figure 1 、 Figure 2 )

[0031]

[0032] 1 H NMR spectrum: 1H NMR (CDC13, 400 MHz) δ (ppm) 8.10 (d, 1H, J = 6.8 Hz), 7.95 (d, 2H, J = 7.6 Hz), 7.85 (s, 1H), 7.64 (d, 1H, J = 8.8 Hz), 7.43 (t, 2H, J = 7.6 Hz), 7.33 (t, 1H, J = 7.6 Hz), 7.17 (t, 1H, J = 8.0 Hz), 6.77 (t, 1H, J = 6.8 Hz).

[0033] 2-phenylimidazo[l,2-a]pyridine 13 C NMR spectrum:

[0034] 13 C NMR (CDC13, 100 MHz) δ (ppm) 145.8, 145.5, 133.5, 129.9, 128.7, 128.4, 128.0, 126.0, 125.6, 124.8, 117.4, 112.5, 108.1.

[0035] Examples 2-7

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

[0037] Table 1. Experimental results of Pd / C catalytic conversion of lignin model compound 2-phenoxy-1-phenylethanol at different reaction temperatures

[0038]

[0039] As shown in Table 1, the reaction temperature has a certain effect on the yield of the product. When the temperature is 160-200°C, the yield of the product 2-phenylimidazo[l,2-a]pyridine is 83.2-89.5%, and the yield of the product phenol can reach 95.5-98.7%.

[0040] Examples 8-13

[0041] Other process conditions and experimental procedures are the same as Example 1, but different reaction times are used, and the results are shown in Table 2.

[0042] Table 2. Experimental results of Pd / C catalytic conversion of lignin model compound 2-phenoxy-1-phenylethanol at different reaction times

[0043]

[0044]

[0045] As shown in Table 2, with the extension of reaction time, the yield of 2-phenyl imidazo[1,2-a]pyridine and the conversion rate of phenol also increased. When the reaction time was 15-20 h, the yield of 2-phenyl imidazo[1,2-a]pyridine was 85.5-89.5%, and the yield of phenol was 94.7-98.7%.

[0046] Examples 14-16

[0047] Other process conditions and experimental procedures were the same as in Example 1, and the catalysts used were different in Pd loading. The results are shown in Table 3.

[0048] Table 3. Experimental results of Pd / C catalytic conversion of lignin model compound 2-phenoxy-1-phenylethanol under different Pd loadings.

[0049]

[0050] Examples 17-21

[0051] Other process conditions and experimental procedures were the same as in Example 1, and the organic solvents used were different. The results are shown in Table 4.

[0052] Table 4. Experimental results of Pd / C catalytic conversion of lignin model compound 2-phenoxy-1-phenylethanol under different organic solvents.

[0053]

[0054] Examples 21-25

[0055] Other process conditions and experimental procedures were the same as in Example 1, and the volume ratios of organic solvent to water used were different. The results are shown in Table 5.

[0056] Table 5. Experimental results of Pd / C catalytic conversion of lignin model compound 2-phenoxy-1-phenylethanol under different organic solvents.

[0057]

[0058] Comparative Example 26

[0059] Other process conditions and experimental procedures were the same as in Example 1, but Pd / C (5 wt% Pd) was used as the catalyst without the aid of elemental iodine. The conversion rate was 39.3%, the yield of 2-phenyl imidazo[1,2-a]pyridine was 4.1%, and the yield of phenol was 30.3%.

[0060] Comparative Example 27

[0061] Other process conditions and experimental procedures were the same as in Example 1, but using elemental iodine as catalyst, conversion was 0%, product 2-phenyl imidazo[l,2-a]pyridine yield was 0%, phenol yield was 0%.

[0062] Example 28

[0063] Other process conditions and experimental procedures were the same as in Example 1, but using 2-phenoxy-l-phenylethanol as substrate, conversion was 95.5%, product 2-phenyl imidazo[l,2-a]pyridine yield was 31.4%, guaiacol yield was 85.7%.

[0064] Examples 29-33

[0065] Other process conditions and experimental procedures were the same as in Example 1, but using different lignin raw materials, results were shown in Table 6.

[0066] Table 6. Experimental results of Pd / C catalytic conversion of lignin raw materials

[0067]

[0068]

[0069] Examples 34-42

[0070] Catalyst recycling was investigated, the specific operation was: 50 mg of lignin model compound 2-phenoxy-l-phenylethanol, 20 mg of catalyst Pd / C (5wt% Pd), 80 mg of o-aminopyridine, 1.5 ml of toluene and 0.5 ml of water mixed solvent were added into a 50 ml glass tube, heated to 180°C, and reacted for 18 hours. After the reaction was completed, it was cooled to room temperature, filtered, and the organic supernatant was obtained and subjected to chromatographic analysis; the solid was retained and 50 mg of lignin model compound 2-phenoxy-l-phenylethanol was continuously added to the reaction tube, 80 mg of o-aminopyridine, 1.5 ml of toluene and 0.5 ml of water mixed solvent, heated to 180°C, reacted for 18 hours, and the post-treatment method was the same as above.

[0071] Table 7. Results of Pd / C catalytic conversion of lignin model compound 2-phenoxy-l-phenylethanol recycling

[0072]

[0073] As shown in Table 7, Pd / C can be recycled for 10 times, and the reaction activity remains unchanged

[0074] Comparative Examples 1-12

[0075] Other process conditions and experimental procedures were the same as in Example 1, but using different main catalysts, and the comparative results were shown in Table 8.

[0076] Table 8. Experimental results of different procatalysts participating in catalytic conversion of 2-phenoxy-1-phenylethanol

[0077]

[0078]

[0079] The catalysts described in the comparative examples were prepared according to the synthesis method of the literature (ChemSusChem. 2016, 9, 3220-3229) by using different metal active components and different supports.

Claims

1. A method for preparing imidazolium-pyridine compounds from lignin and model compounds using a Pd / C two-component system, characterized in that, Using lignin β-O-4 model compounds as substrates, Pd / C as catalysts, elemental iodine as an auxiliary agent, a mixture of organic solvents and water as reaction solvents, and aminopyridine compounds as nitrogen sources, imidazole pyridine nitrogen-containing aromatic compounds were prepared by reacting at 50–250 °C for 1–20 h. The Pd is loaded onto activated carbon; the loading amount of Pd is 0.1-20 wt%. The imidazopyridine compound is 2-phenylimidazo[1,2-a]pyridine; The aminopyridine compound is o-aminopyridine; The lignin β-O-4 model compound is 2-phenoxy-1-phenylethanol.

2. The method according to claim 1, characterized in that, The reaction temperature is 130-200℃; the reaction time is 12-20h; and the volume ratio of organic solvent to water is 1:1-5:

1.

3. The method according to claim 1, characterized in that, The molar ratio of the substrate to the catalyst is 2:1-100:1, the molar ratio of the auxiliary iodine to the substrate is 2:1-6:1, and the molar ratio of the aminopyridine compound to the substrate is 3:1-8:

1.

4. The method according to claim 1, characterized in that, The molar ratio of the substrate to the catalyst is 10:1; the molar ratio of the auxiliary iodine to the substrate is 3:1; the molar ratio of the aminopyridine compound to the substrate is 8:1; the Pd / C catalyst is a supported catalyst, wherein the Pd is supported on activated carbon; and the loading amount of Pd is 5 wt% Pd.

5. The method according to claim 1, characterized in that, The organic solvent is one or more of toluene, xylene, ethyl acetate, ethanol, dimethyl sulfoxide, tetrahydrofuran, N,N-dimethylformamide, dichloromethane, chlorobenzene, n-hexane, and cyclohexane.

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