Method for catalytic synthesis of phenoxy acetic acid ester derivatives from lignite residue

Abstract

This invention discloses a method for the catalytic synthesis of phenoxyacetic acid ester derivatives from lignite residue. The method uses phenolic and aryl diazonium ester compounds as raw materials, and the reaction is catalyzed by lignite residue catalyst. The catalyst used is lignite residue, which is widely available, inexpensive, and readily available. The reaction conditions are mild, and the yield is good, with a maximum separation yield of 86%. This method can achieve gram-scale reactions and has industrialization potential. Furthermore, the prepared compounds exhibit anti-inflammatory activity.

Description

Technical Field

[0001] This invention belongs to the field of organic chemistry, specifically relating to a method for the catalytic synthesis of phenoxyacetic acid ester derivatives from lignite residue. Background Technology

[0002] Lignite residue is the main residual material after lignite refining. It is rich in various metal ions and has a large content (Hydrometallurgy, 2017, 168: 141; Fuel, 2017, 203: 214). However, its post-processing has always been a difficult problem for environmental organizations at home and abroad (J. Anal. Appl. Pyrol., 2019, 139: 40; Energy,2022, 240: 122796). Currently, common treatment methods include using it as fertilizer (Sci. Total Environ., 2021,773: 145631; Coke. Chem., 2021, 64: 31; J. Air. Waste Manage., 2021, 71:1175), animal bedding (Waste Manage., 2021, 136: 113), adsorbent (Mine Water Environ.,2019, 38: 24), or degrading agent (J. Environ. Chem. Eng., 2021, 9: 104784; Chem. Eng. J.,2025, 521: 166275). If it could be used as an organic synthesis catalyst, it would not only alleviate the difficulty of treating lignite residue but also provide a new approach to catalyst selection in organic synthesis reactions, achieving the reuse of waste resources and aligning with the principles of green chemistry and environmental protection.

[0003] CO bonds exist in various types of organic compounds and are one of the important chemical bonds constituting various substances. They have always been a research hotspot in the field of organic synthesis both domestically and internationally (J. Am. Chem. Soc., 2023, 145: 17527). Currently reported methods for constructing CO bonds usually require expensive transition metal catalysts or complex ligands (Chem., 2024, 10:1897; ACS Catal., 2025, 15: 3636). Therefore, we attempt to develop a simple and efficient method for constructing CO bonds. Diazo compounds (R1R2C=N2) are a class of highly reactive reaction intermediates that can participate in various reactions to construct CX (X=O, N, C, S, P, Si, B, etc.) bonds (Chem. Soc. Rev., 2016, 45: 506, Nature Rev.Chem., 2019, 3: 347). In particular, they can form CO bonds with phenolic compounds through OH insertion reactions (GreenChem., 2020, 22: 1594). Based on this, we propose to utilize metal ions in lignite residues to induce aryl diazo ester compounds to construct CO bonds through metal carbene OH insertion reactions, thereby obtaining phenoxyacetic acid ester derivative drugs or drug skeletons in a one-step reaction, thus completing this invention. Summary of the Invention

[0004] This invention provides a method for the catalytic synthesis of phenoxyacetic acid ester derivatives from lignite residue. The method uses phenolic and aryl diazonium ester compounds as raw materials and lignite residue as a catalyst. Under heating conditions and in an air atmosphere, the CO bond is constructed through an OH insertion reaction, resulting in the one-step formation of phenoxyacetic acid ester derivatives.

[0005] In some embodiments, a method for the catalytic synthesis of phenoxyacetic acid ester derivatives from lignite residue according to the present invention comprises using phenolic and aryl diazonium ester compounds as raw materials and synthesizing them using lignite residue catalyst.

[0006] In some embodiments, as described in claim 3, the phenoxyacetic ester derivative has the structure shown in Formula 3, and its reaction formula is as follows:

[0007] In the formula, R 1 Selected from one or more of hydrogen, alkyl (preferably C1-C4 alkyl), alkoxy, acyl, halogen, and trifluoromethyl. R 2 Selected from alkyl, allyl, and phenyl, R 3It is selected from one or more of hydrogen, alkyl (preferably C1-C4 alkyl), alkoxy, acyl, nitro, aldehyde, halogen and trifluoromethyl.

[0008] In some implementation schemes, preferably, R 1 Selected from one or more of hydrogen and halogens, R 2 Selected from methyl and ethyl, R 3 It is selected from one or more of hydrogen, methyl, ethyl, propyl, methoxy, carboxyl, nitro, aldehyde, halogen and trifluoromethyl.

[0009] In some embodiments, the halogen in the method of the present invention described above is F, Cl, Br or I, more preferably Cl or Br.

[0010] In one specific embodiment, the method of the present invention described above includes the following steps: S1. Dissolve the aryl diazonium ester compound of Formula 1 and the phenolic compound of Formula 2 in a solvent; S2. Add the catalyst lignite residue, react at room temperature first, then heat to 60-90°C. o C continues to react; S3. The reaction products were separated by silica gel column chromatography to obtain the target product with the structure shown in Formula 3.

[0011] In some embodiments, in the method of the present invention described above, the heating temperature in step S2 is 75°C.

[0012] Terminology: Lignite Residue refers to the solid waste remaining after the main extractable chemical components (such as lignite wax, humic acid, coal tar, etc.) are removed during the mining, processing, or combustion of lignite (brown coal).

[0013] In another aspect, the present invention also provides a compound with the structure shown in Formula 3 or a pharmaceutical salt thereof.

[0014] In the formula, R 1 R 2 and R 3 The definition is the same as the definition mentioned above.

[0015] In some preferred embodiments, the phenoxyacetic acid ester derivative compounds of the present invention or their pharmaceutical salts are selected from the following compounds or their pharmaceutical salts.

[0016] .

[0017] The present invention also provides a pharmaceutical composition comprising a compound or pharmaceutical salt of the structure shown in Formula 3 and pharmaceutical excipients.

[0018] The present invention also provides the use of the compound or pharmaceutical salt of Formula 3 in the preparation of an anti-inflammatory drug.

[0019] Preferably, the compound or pharmaceutical salt represented by Formula 3 is selected from any of the compounds represented by Formulas 3a-3l or their pharmaceutical salts.

[0020] Compared with existing methods for synthesizing phenoxyacetic acid ester derivatives, the synthesis method of this invention avoids the use of additional transition metal catalysts and complex ligands, and selects widely available lignite residue as the catalyst, resulting in low cost and environmental friendliness. The reaction raw materials are readily available, the conditions are mild, and the yield is good (up to 80% separation yield, and the product separation yield can still reach 60% after the catalyst is reused three times). It can achieve gram-scale reactions and has industrialization prospects. At the same time, it realizes the reuse of waste resources, which is in line with the principles of green environmental protection and green chemistry.

[0021] Meanwhile, the compounds prepared by the method of the present invention have anti-inflammatory activity and have the potential to be used as drugs for treating inflammatory diseases.

[0022] The beneficial effects of this invention are as follows: 1. The catalyst used in the method of this invention is a lignite residue (Zhaotong, Yunnan), which does not require the introduction of other transition metals or complex ligands; the raw materials are readily available, the reaction conditions are mild, the yield is good, and it can achieve gram-scale reaction, which has industrialization prospects.

[0023] 2. This invention uses lignite residue as a catalyst, which not only alleviates the problem of difficult lignite residue treatment, but also provides a new approach to the selection of catalysts in organic synthesis reactions, realizing the recycling of waste resources and conforming to the principles of green chemistry and environmental protection. Detailed Implementation

[0024] The following embodiments are provided to describe the present invention in more detail. However, these embodiments are provided only to help further understand the present invention and are not intended to limit the present invention. Those skilled in the art should understand that equivalent substitutions or corresponding improvements made to the content of the present invention still fall within the protection scope of the present invention.

[0025] Example 1: Preparation of compound 3a

[0026] 0.5 mmol of methyl p-chlorophenyldiazoacetate and 0.7 mmol of p-nitrophenol were weighed sequentially into a clean, dry 25 mL Schlenk reaction tube. Under air atmosphere, 5 mL of acetonitrile was added, and the mixture was stirred at room temperature for 5 minutes. Then, 150 mg of lignite residue (from Zhaotong, Yunnan) catalyst was added, and the mixture was reacted at room temperature for 1 hour, followed by heating to 75 °C and continuing the reaction for 8 hours. After the reaction was confirmed to be complete by TLC, the reaction was stopped, filtered, and the filter cake was washed with dichloromethane until colorless. The filtrate was concentrated under reduced pressure to remove volatile components, and then separated by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, to obtain a white solid phenoxyacetic acid derivative 3a (138 mg), with a yield of 86%, mp: 138-143 °C.

[0027] The target product was confirmed by nuclear magnetic resonance spectroscopy: Methyl 2-(4-chlorophenyl)-2-(4-nitrophenoxy) acetate (3a): Whitesolid, mp: 138-143℃; 86% yield; 1 H NMR (400 MHz, CDCl3) δ (ppm) 8.21 – 8.15 (m, 2H), 7.50 (d, J = 8.5Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.02 – 6.94 (m, 2H), 5.69 (s, 1H), 3.75 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ (ppm) 168.65, 161.51, 142.19, 135.38,132.39, 129.09, 128.22, 125.78, 115.15, 77.81, 77.16, 76.84, 76.52, 52.88.

[0028] To demonstrate the rationality and superiority of this invention, the catalytic efficiencies of acid catalysts, base catalysts, metal catalysts, and sludge catalysts were compared under the same reaction conditions. Furthermore, the reusability efficiency of lignite residue catalysts and the catalytic efficiencies of lignite residue catalysts from different origins were also compared.

[0029] Comparative Example 1: Preparation using acid as a catalyst 0.5 mmol of methyl p-chlorophenyldiazoacetate and 0.7 mmol of p-nitrophenol were weighed sequentially into a clean, dry 25 mL Schlenk reaction tube. Under air atmosphere, 5 mL of acetonitrile was added, and the mixture was stirred at room temperature for 5 minutes. Then, 25 µL of trifluoromethanesulfonic acid catalyst was added, and the reaction was allowed to proceed at room temperature for 1 hour, followed by heating to 75 °C and continuing the reaction for another 8 hours. After the reaction was complete as determined by S3 and TLC, the reaction was stopped. The mixture was concentrated under reduced pressure to remove volatile components, and then separated by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, to obtain a white solid phenoxyacetic acid derivative 3a (132 mg), with a yield of 82%.

[0030] Comparative Example 2: Preparation using alkali as a catalyst 0.5 mmol of methyl p-chlorophenyldiazoacetate and 0.7 mmol of p-nitrophenol were weighed sequentially into a clean, dry 25 mL Schlenk reaction tube. Under air atmosphere, 5 mL of acetonitrile was added, and the mixture was stirred at room temperature for 5 minutes. Then, 25 µL of triethylamine catalyst was added, and the reaction was allowed to proceed at room temperature for 1 hour, followed by heating to 75 °C and continuing the reaction for another 8 hours. After TLC analysis confirmed the reaction was complete, the reaction was stopped, and the mixture was concentrated under reduced pressure to remove volatile components. Separation was then performed by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, yielding a white solid phenoxyacetic acid derivative 3a (56 mg), with a yield of 35%.

[0031] Comparative Example 3: Preparation using a metal catalyst 0.5 mmol of methyl p-chlorophenyldiazoacetate and 0.7 mmol of p-nitrophenol were weighed sequentially into a dry, clean 25 mL Schlenk reaction tube. Under air atmosphere, 5 mL of acetonitrile was added, and the mixture was stirred at room temperature for 5 minutes. After adding 150 mg of ferric chloride catalyst, the reaction was first carried out at room temperature for 1 hour, and then heated to 75 °C for another 8 hours. After the reaction was confirmed to be complete by TLC, the reaction was stopped, filtered, and the filter cake was washed with dichloromethane until colorless. The filtrate was concentrated under reduced pressure to remove volatile components, and separated by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, to obtain a white solid phenoxyacetic acid derivative 3a (100 mg), with a yield of 62%.

[0032] Comparative Example 4 uses sludge catalyst ( Green Chem ., 2020, 22 Preparation of 1594) 0.5 mmol of methyl p-chlorophenyldiazoacetate and 0.7 mmol of p-nitrophenol were weighed sequentially into a clean, dry 25 mL Schlenk reaction tube. Under air atmosphere, 5 mL of acetonitrile was added, and the mixture was stirred at room temperature for 5 minutes. Then, 150 mg of sludge catalyst was added, and the mixture was reacted at room temperature for 1 hour, followed by heating to 75 °C and continuing the reaction for 8 hours. After TLC detection showed complete reaction of the starting materials, the reaction was stopped, filtered, and the filter cake was washed with dichloromethane until colorless. The filtrate was concentrated under reduced pressure to remove volatile components, and separated by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, to obtain a white solid phenoxyacetic acid derivative 3a (120 mg), with a yield of 75%.

[0033] Example 1-1 First Reuse of Catalyst The lignite residue catalyst was reused. The catalyst was the filter cake after the reaction in Example 1, which was the lignite residue catalyst after one use, and was used for the first time in the reuse experiment.

[0034] 0.5 mmol of methyl p-chlorophenyldiazoacetate and 0.7 mmol of p-nitrophenol were weighed sequentially into a clean, dry 25 mL Schlenk reaction tube. Under air atmosphere, 5 mL of acetonitrile was added, and the mixture was stirred at room temperature for 5 minutes. Then, 150 mg of previously used lignite residue catalyst was added, and the mixture was reacted at room temperature for 1 hour, followed by heating to 75 °C and continuing the reaction for 8 hours. After TLC analysis to confirm complete reaction of the starting materials, the reaction was stopped, filtered, and the filter cake was washed with dichloromethane until colorless. The filtrate was concentrated under reduced pressure to remove volatile components, and then separated by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, to obtain a white solid phenoxyacetic acid derivative 3a (122 mg), with a yield of 76%.

[0035] Example 1-2 Catalyst reused for the second time Second reuse experiment of catalyst: Example 1-1 The lignite residue catalyst after use was used was reused for the second time in an experiment.

[0036] 0.5 mmol of methyl p-chlorophenyldiazoacetate and 0.7 mmol of p-nitrophenol were weighed sequentially into a clean, dry 25 mL Schlenk reaction tube. Under air atmosphere, 5 mL of acetonitrile was added, and the mixture was stirred at room temperature for 5 minutes. Then, 150 mg of lignite residue catalyst from Comparative Example 5 was added, and the mixture was reacted at room temperature for 1 hour, followed by heating to 75 °C and continuing the reaction for 8 hours. After TLC detection showed complete reaction of the starting materials, the reaction was stopped, filtered, and the filter cake was washed with dichloromethane until colorless. The filtrate was concentrated under reduced pressure to remove volatile components, and separated by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, to obtain a white solid phenoxyacetic acid derivative 3a (109 mg), with a yield of 68%.

[0037] Examples 1-3: Third reuse of catalyst Third reuse experiment of catalyst: The lignite residue catalyst used in Examples 1-2 was subjected to a third reuse experiment.

[0038] 0.5 mmol of methyl p-chlorophenyldiazoacetate and 0.7 mmol of p-nitrophenol were weighed sequentially into a clean, dry Schlenk reaction tube with a capacity of 25 mL. Under air atmosphere, 5 mL of acetonitrile was added, and the mixture was stirred at room temperature for 5 minutes. Then, 150 mg of lignite residue catalyst from Comparative Example 5 was added, and the mixture was reacted at room temperature for 1 hour, followed by heating to 75 °C and continuing the reaction for 8 hours. After TLC detection showed complete reaction of the starting materials, the reaction was stopped, filtered, and the filter cake was washed with dichloromethane until colorless. The filtrate was concentrated under reduced pressure to remove volatile components, and separated by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, to obtain a white solid phenoxyacetic acid derivative 3a (98 mg), with a yield of 61%.

[0039] Examples 1-4: Catalyst lignite residue sourced from Yimin, Inner Mongolia 0.5 mmol of methyl p-chlorophenyldiazoacetate and 0.7 mmol of p-nitrophenol were weighed sequentially into a clean, dry 25 mL Schlenk reaction tube. Under air atmosphere, 5 mL of acetonitrile was added, and the mixture was stirred at room temperature for 5 minutes. Then, 150 mg of lignite residue (Inner Mongolia Yimin) catalyst was added, and the reaction was carried out at room temperature for 1 hour, followed by heating to 75 °C and continuing the reaction for 8 hours. After the reaction was confirmed to be complete by TLC, the reaction was stopped, filtered, and the filter cake was washed with dichloromethane until colorless. The filtrate was concentrated under reduced pressure to remove volatile components, and then separated by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, to obtain a white solid phenoxyacetic acid derivative 3a (135 mg), with a yield of 84%.

[0040] Examples 1-5: Catalyst lignite residue sourced from Hegang, Heilongjiang Province. 0.5 mmol of methyl p-chlorophenyldiazoacetate and 0.7 mmol of p-nitrophenol were weighed into a clean, dry 25 mL Schlenk reaction tube. Under air atmosphere, 5 mL of acetonitrile was added and the mixture was stirred at room temperature for 5 minutes. 150 mg of lignite residue (Hegang, Heilongjiang) catalyst was added, and the mixture was reacted at room temperature for 1 hour, then heated to 75 °C and reacted for another 8 hours. After the reaction was confirmed to be complete by TLC, the reaction was stopped, filtered, and the filter cake was washed with dichloromethane until colorless. The filtrate was concentrated under reduced pressure to remove volatile components, and the product was separated by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, to obtain a white solid phenoxyacetic acid derivative 3a (136 mg), with a yield of 85%.

[0041] Through comparative examples 1-4, we found that under the same reaction conditions, the catalytic efficiency of lignite residue catalyst (86%) was better than that of acid (82%) / base (35%) catalyst, metal catalyst (62%) and sludge catalyst (75%), highlighting the rationality of choosing lignite residue catalyst in this invention.

[0042] The results of the repeated utilization experiments of lignite residue catalyst in Examples 1-1 to 1-3 (product yield of repeated lignite residue: 76% for the first time, 68% for the second time, and 61% for the third time) highlight the practicality of lignite residue catalyst and the superiority of the lignite residue catalyst selected in this invention. The results of Examples 1-4 to 1-5 show that the catalytic efficiency of lignite residue catalysts from different origins is not significantly different (catalytic yield of lignite residue from different origins: 86% in Zhaotong, Yunnan; 84% in Yimin, Inner Mongolia; and 85% in Hegang, Heilongjiang), revealing the universality of lignite residue catalyst. In summary, the above experimental results demonstrate the rationality, practicality, and superiority of the lignite residue catalyst selected in this invention.

[0043] Example 2 Preparation of compound 3b

[0044] 0.5 mmol of ethyl phenyldiazoate and 0.7 mmol of p-trifluoromethylphenol were weighed sequentially into a clean, dry 25 mL Schlenk reaction tube. Under air atmosphere, 5 mL of acetonitrile was added, and the mixture was stirred at room temperature for 5 minutes. Then, 150 mg of lignite residue catalyst was added, and the mixture was reacted at room temperature for 1 hour, followed by heating to 75 °C and continuing the reaction for 8 hours. After TLC detection showed complete reaction of the starting materials, the reaction was stopped, filtered, and the filter cake was washed with dichloromethane until colorless. The filtrate was concentrated under reduced pressure to remove volatile components, and separated by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, to obtain a colorless, transparent, viscous phenoxyacetic acid derivative 3b (122 mg), with a yield of 75%.

[0045] The target product was confirmed by nuclear magnetic resonance spectroscopy: Ethyl 2-phenyl-2-(4-(trifluoromethyl) phenoxy) acetate (3b):Colorless oil; 75% yield; 1 H NMR (400 MHz, CDCl3) δ 7.58 (dd, J = 7.6, 1.3 Hz, 2H), 7.54 (d, J =8.6 Hz, 2H), 7.46–7.36 (m, 3H), 7.02 (d, J = 8.6 Hz, 2H), 5.67 (s, 1H), 4.30–4.14 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 169.40,159.78, 134.88, 129.36, 129.03, 128.41, 127.19, 127.14, 127.10, 124.37 (q, J =271.3 Hz), 124.04 (q, J = 32.8 Hz), 120.33, 115.50, 78.71, 62.03, 14.13.

[0046] Example 3 Preparation of compound 3c

[0047] 0.5 mmol of ethyl phenyldiazoate and 0.7 mmol of p-chlorophenol were weighed sequentially into a dry, clean 25 mL Schlenk reaction tube. Under air atmosphere, 5 mL of acetonitrile was added, and the mixture was stirred at room temperature for 5 minutes. After adding 150 mg of lignite residue catalyst, the reaction was first carried out at room temperature for 1 hour, and then heated to 75 °C for another 8 hours. After the reaction was confirmed to be complete by TLC, the reaction was stopped, filtered, and the filter cake was washed with dichloromethane until colorless. The filtrate was concentrated under reduced pressure to remove volatile components, and separated by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, to obtain a colorless, transparent, viscous phenoxyacetic acid derivative 3c (110 mg), with a yield of 76%.

[0048] The target product was confirmed by nuclear magnetic resonance spectroscopy: Ethyl 2-(4-chlorophenoxy)-2-phenylacetate (3c): Colorless oil; 76%yield; 1 H NMR (400 MHz, CDCl3) δ 7.56 (dd, J = 7.6, 1.4 Hz, 2H), 7.44 – 7.34(m, 3H), 7.25 – 7.19 (m, 2H), 6.92 – 6.85 (m, 2H), 5.57 (s, 1H), 4.27 – 4.12(m, 2H), 1.21 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 169.70,155.98, 135.19, 129.59, 129.22, 128.96, 127.17, 126.88, 116.97, 79.04, 61.90,14.15.

[0049] Example 4: Preparation of compound 3d

[0050] 0.5 mmol of ethyl phenyldiazoate and 0.7 mmol of p-bromophenol were weighed sequentially into a clean, dry 25 mL Schlenk reaction tube. Under air atmosphere, 5 mL of acetonitrile was added, and the mixture was stirred at room temperature for 5 minutes. Then, 150 mg of lignite residue catalyst was added, and the reaction was carried out at room temperature for 1 hour, followed by heating to 75 °C and continuing the reaction for another 8 hours. After TLC analysis to confirm complete reaction of the starting materials, the reaction was stopped, filtered, and the filter cake was washed with dichloromethane until colorless. The filtrate was concentrated under reduced pressure to remove volatile components, and then separated by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, to obtain a colorless, transparent, viscous phenoxyacetic acid ester derivative 3d (122 mg), with a yield of 73%.

[0051] The target product was confirmed by nuclear magnetic resonance spectroscopy: Ethyl 2-(4-bromophenoxy)-2-phenylacetate (3d): Colorless oil; 73%yield; 1 H NMR (400 MHz, CDCl3) δ 7.58 (dd, J= 7.6, 1.6 Hz, 2H), 7.43 – 7.36(m, 5H), 6.93 – 6.80 (m, 2H), 5.59 (s, 1H), 4.30 – 4.14 (m, 2H), 1.22 (t, J =7.1 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 169.66, 156.50, 135.16, 132.54,129.24, 128.97, 127.18, 117.46, 114.25, 78.96, 61.93, 14.17.

[0052] Example 5 Preparation of compound 3e

[0053] 0.5 mmol of ethyl phenyldiazoate and 0.7 mmol of p-methylphenol were weighed sequentially into a clean, dry 25 mL Schlenk reaction tube. Under air atmosphere, 5 mL of acetonitrile was added, and the mixture was stirred at room temperature for 5 minutes. Then, 150 mg of lignite residue catalyst was added, and the reaction was carried out at room temperature for 1 hour, followed by heating to 75 °C and continuing the reaction for 8 hours. After TLC detection showed complete reaction of the starting materials, the reaction was stopped, filtered, and the filter cake was washed with dichloromethane until colorless. The filtrate was concentrated under reduced pressure to remove volatile components, and separated by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, to obtain a colorless oily phenoxyacetic acid derivative 3e (colorless oil, 86 mg), with a yield of 64%.

[0054] The target product was confirmed by nuclear magnetic resonance spectroscopy: Ethyl 2-phenyl-2-(p-tolyloxy) acetate (3e): Colorless oil; 64% yield; 1 H NMR (400 MHz, CDCl3) δ 7.62 – 7.55 (m, 2H), 7.42 – 7.33 (m, 3H),7.07 (d, J = 8.3 Hz, 2H), 6.90 – 6.83 (m, 2H), 5.59 (s, 1H), 4.28 – 4.12 (m,2H), 2.27 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.21,155.37, 135.81, 131.21, 130.11, 128.97, 128.85, 127.19, 115.54, 79.02, 61.69,20.63, 14.17.

[0055] Example 6 Preparation of compound 3f

[0056] 0.5 mmol of ethyl phenyldiazoate and 0.7 mmol of p-formaldehyde phenol were weighed sequentially into a clean, dry 25 mL Schlenk reaction tube. Under air atmosphere, 5 mL of acetonitrile was added, and the mixture was stirred at room temperature for 5 minutes. Then, 150 mg of lignite residue catalyst was added, and the reaction was carried out at room temperature for 1 hour, followed by heating to 75 °C and continuing the reaction for 8 hours. After TLC detection showed complete reaction of the starting materials, the reaction was stopped, filtered, and the filter cake was washed with dichloromethane until colorless. The filtrate was concentrated under reduced pressure to remove volatile components, and separated by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, to obtain a colorless, transparent, viscous phenoxyacetic acid derivative 3f (colorless oil, 87 mg), with a yield of 61%.

[0057] The target product was confirmed by nuclear magnetic resonance spectroscopy: Ethyl 2-(4-formylphenoxy)-2-phenylacetate (3f): Colorless oil; 61%yield; 1 H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 7.89 – 7.78 (m, 2H), 7.58 (dd, J = 7.6, 1.5 Hz, 2H), 7.45 – 7.37 (m, 3H), 7.06 (d, J = 8.7 Hz, 2H), 5.71 (s,1H), 4.28 – 4.15 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3)δ 190.88, 169.23, 162.24, 134.69, 132.12, 130.83, 129.44, 129.07, 127.21,115.73, 78.70, 62.11, 14.15.

[0058] Example 7 Preparation of 3g of compound

[0059] 0.5 mmol of ethyl phenyldiazoate and 0.7 mmol of m-methylphenol were weighed sequentially into a clean, dry 25 mL Schlenk reaction tube. Under air atmosphere, 5 mL of acetonitrile was added, and the mixture was stirred at room temperature for 5 minutes. Then, 150 mg of lignite residue catalyst was added, and the reaction was carried out at room temperature for 1 hour, followed by heating to 75 °C and continuing the reaction for 8 hours. After TLC detection showed complete reaction of the starting materials, the reaction was stopped, filtered, and the filter cake was washed with dichloromethane until colorless. The filtrate was concentrated under reduced pressure to remove volatile components, and separated by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, to obtain 3 g of a colorless, transparent, viscous phenoxyacetic acid ester derivative (colorless oil, 86 mg), with a yield of 64%.

[0060] The target product was confirmed by nuclear magnetic resonance spectroscopy: Ethyl 2-phenyl-2-(m-tolyloxy) acetate (3g): Colorless oil; 64% yield; 1 H NMR (400 MHz, CDCl3) δ 7.62 – 7.57 (m, 2H), 7.44 – 7.34 (m, 3H),7.16 (t, J = 7.8 Hz, 1H), 6.87 – 6.72 (m, 3H), 5.63 (s, 1H), 4.29 – 4.13 (m,2H), 2.32 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ170.17, 157.47, 139.77, 135.71, 129.36, 128.99, 128.85, 127.17, 122.73,116.56, 112.19, 78.67, 61.71, 21.63, 14.16.

[0061] Example 8: Preparation of compound 3h

[0062] 0.5 mmol of ethyl phenyldiazoate and 0.7 mmol of o-methylphenol were weighed sequentially into a dry, clean 25 mL Schlenk reaction tube. Under air atmosphere, 5 mL of acetonitrile was added, and the mixture was stirred at room temperature for 5 minutes. After adding 150 mg of lignite residue catalyst, the reaction was first carried out at room temperature for 1 hour, and then heated to 75 °C for another 8 hours. After the reaction was confirmed to be complete by TLC, the reaction was stopped, filtered, and the filter cake was washed with dichloromethane until colorless. The filtrate was concentrated under reduced pressure to remove volatile components, and separated by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, to obtain a colorless, transparent, viscous phenoxyacetic acid ester derivative 3h (colorless oil, 82 mg), with a yield of 61%.

[0063] The target product was confirmed by nuclear magnetic resonance spectroscopy: Ethyl 2-phenyl-2-(o-tolyloxy) acetate (3h): Colorless oil; 61% yield; 1 H NMR (400 MHz, CDCl3) δ 7.65 – 7.59 (m, 2H), 7.44 – 7.35 (m, 3H), 7.18 (dd, J = 7.3, 0.7 Hz, 1H), 7.14 – 7.06 (m, 1H), 6.94 – 6.87 (m, 1H), 6.76(d, J = 8.1 Hz, 1H), 5.65 (s, 1H), 4.25 – 4.10 (m, 2H), 2.38 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 170.25, 155.70, 136.02, 131.17, 128.91, 128.80, 127.86, 127.03, 126.78.

[0064] Example 9 Preparation of compound 3i

[0065] 0.5 mmol of ethyl phenyldiazoate and 0.7 mmol of 2-bromo-4-trifluoromethylphenol were weighed sequentially into a clean, dry Schlenk reaction tube with a capacity of 25 mL. Under air atmosphere, 5 mL of acetonitrile was added, and the mixture was stirred at room temperature for 5 minutes. Then, 150 mg of lignite residue catalyst was added, and the mixture was reacted at room temperature for 1 hour, followed by heating to 75 °C and continuing the reaction for 8 hours. After the reaction was confirmed to be complete by TLC, the reaction was stopped, filtered, and the filter cake was washed with dichloromethane until colorless. The filtrate was concentrated under reduced pressure to remove volatile components, and separated by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, to obtain a white solid phenoxyacetic acid derivative 3i (145 mg), with a yield of 75% and mp: 70-74 °C.

[0066] The target product was confirmed by nuclear magnetic resonance spectroscopy: Ethyl 2-(2-bromo-4-(trifluoromethyl) phenoxy)-2-phenylacetate (3i):White solid, mp: 70-74℃.; 75% yield; 1 H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 1.6 Hz, 1H), 7.69 – 7.61 (m,2H), 7.51 – 7.37 (m, 4H), 6.87 (d, J = 8.6 Hz, 1H), 5.72 (s, 1H), 4.26 – 4.13(m, 2H), 1.20 (t, J = 7.1 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 168.83,156.43, 134.40, 131.14 (q, J = 7.4, 3.7 Hz), 129.43, 129.03, 127.06, 125.86(q, J = 3.8 Hz), 125.18 (q, J = 33.4 Hz), 123.45 (q, J = 271.9 Hz), 113.69, 113.30, 79.45, 62.17, 14.11.

[0067] Example 10: Gram-scale Scale-up Reaction

[0068] 5 mmol of methyl p-chlorophenyldiazoacetate (1.05 g) and 7 mmol of p-nitrophenol (0.97 g) were weighed into a clean, dry 250 mL Schlenk reaction tube. Under air atmosphere, 50 mL of acetonitrile was added, and the mixture was stirred at room temperature for 10 minutes. Then, 150 mg of lignite residue catalyst was added, and the mixture was reacted at room temperature for 1 hour, followed by heating to 75 °C and continuing the reaction for another 10 hours. After TLC detection showed complete reaction of the starting materials, the reaction was stopped, filtered, and the filter cake was washed with dichloromethane until colorless. The filtrate was concentrated under reduced pressure to remove volatile components, and separated by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, to obtain a white solid phenoxyacetic acid derivative 3a (1.3 g), with a yield of 80% and mp: 138-143 °C.

[0069] The target product was confirmed by nuclear magnetic resonance spectroscopy: Methyl 2-(4-chlorophenyl)-2-(4-nitrophenoxy) acetate (3a): Whitesolid, mp: 138-143℃; 80% yield; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.21 – 8.15 (m, 2H), 7.50 (d, J = 8.5Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.02 – 6.94 (m, 2H), 5.69 (s, 1H), 3.75(s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 168.65, 161.51, 142.19, 135.38,132.39, 129.09, 128.22, 125.78, 115.15, 77.81, 77.16, 76.84, 76.52, 52.88.

[0070] To highlight the practicality of this invention, the reaction method was applied to the natural anti-inflammatory drug salicylic acid (o-hydroxybenzoic acid). By reacting with different aryl diazonium ester compounds, a series of salicylic acid OH insertion products were obtained, realizing the derivatization of salicylic acid. At the same time, some salicylic acid OH insertion products were selected for anti-inflammatory experiments. It was found that the anti-inflammatory activity of most salicylic acid OH insertion products was better than that of salicylic acid itself, and a few were even better than the positive control.

[0071] Example 11 Preparation of compound 3j (OH insertion reaction of natural anti-inflammatory drug salicylic acid)

[0072] 0.5 mmol of ethyl phenyldiazoate and 0.7 mmol of salicylic acid were weighed sequentially into a clean, dry 25 mL Schlenk reaction tube. Under air atmosphere, 5 mL of acetonitrile was added, and the mixture was stirred at room temperature for 5 minutes. Then, 150 mg of lignite residue catalyst was added, and the reaction was carried out at room temperature for 1 hour, followed by heating to 75 °C and continuing the reaction for 8 hours. After TLC detection showed complete reaction of the starting materials, the reaction was stopped, filtered, and the filter cake was washed with dichloromethane until colorless. The filtrate was concentrated under reduced pressure to remove volatile components, and separated by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, to obtain a white solid phenoxyacetic acid derivative 3j (123 mg), with a yield of 82%.

[0073] The target product was confirmed by nuclear magnetic resonance spectroscopy: 2-(2-ethoxy-2-oxo-1-phenylethoxy) benzoic acid (3j): Colorless oil; 82% yield; 1 H NMR (400 MHz, CDCl3) δ 10.42 (s, 1H), 7.97 (dd, J = 8.0, 1.6 Hz,1H), 7.60 – 7.52 (m, 2H), 7.49 – 7.39 (m, 4H), 6.98 (d, J = 8.4 Hz, 1H), 6.92– 6.86 (m, 1H), 6.12 (s, 1H), 4.28 – 4.14 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 169.42, 168.45, 161.96, 136.40, 133.63, 130.45,129.60, 129.06, 127.76, 119.50, 117.78, 111.91, 75.28, 62.11, 14.14.

[0074] Example 12 Preparation of compound 3k (OH insertion reaction of natural anti-inflammatory drug salicylic acid)

[0075] 0.5 mmol of ethyl p-chlorophenyldiazoate and 0.7 mmol of salicylic acid were weighed sequentially into a clean, dry 25 mL Schlenk reaction tube. Under air atmosphere, 5 mL of acetonitrile was added, and the mixture was stirred at room temperature for 5 minutes. Then, 150 mg of lignite residue catalyst was added, and the mixture was reacted at room temperature for 1 hour, followed by heating to 75 °C and continuing the reaction for 8 hours. After TLC detection showed complete reaction of the starting materials, the reaction was stopped. The mixture was filtered, and the filter cake was washed with dichloromethane until colorless. The filtrate was concentrated under reduced pressure to remove volatile components, and then separated by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, to obtain a white solid phenoxyacetic acid derivative 3k (140 mg), with a yield of 84%.

[0076] The target product was confirmed by nuclear magnetic resonance spectroscopy: 2-(1-(4-Chlorophenyl)-2-ethoxy-2-oxoethoxy) benzoic acid (3k):Colorless oil; 84% yield; 1 H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 7.96 (dd, J = 8.0, 1.5 Hz,1H), 7.59 – 7.53 (m, 2H), 7.48 – 7.38 (m, 4H), 6.91 (t, J = 7.5 Hz, 1H), 6.11(s, 1H), 4.25 – 4.16 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 169.47, 168.41, 162.06, 136.45, 135.14, 132.26, 130.31, 129.43,129.18, 119.62, 117.83, 111.79, 74.62, 62.34, 14.15.

[0077] Example 13 Preparation of compound 3l (OH insertion reaction of natural anti-inflammatory drug salicylic acid)

[0078] 0.5 mmol of ethyl p-methylphenyldiazoate and 0.7 mmol of salicylic acid were weighed into a clean, dry 25 mL Schlenk reaction tube. Under air atmosphere, 5 mL of acetonitrile was added, and the mixture was stirred at room temperature for 5 minutes. Then, 150 mg of lignite residue catalyst was added, and the mixture was reacted at room temperature for 1 hour, followed by heating to 75 °C and continuing the reaction for 8 hours. After TLC detection showed complete reaction of the starting materials, the reaction was stopped, filtered, and the filter cake was washed with dichloromethane until colorless. The filtrate was concentrated under reduced pressure to remove volatile components, and separated by silica gel column chromatography using petroleum ether (60-90 °C) / ethyl acetate, v / v = 10:1, to obtain 3 l (123 mg) of a white solid phenoxyacetic acid derivative, with a yield of 78%.

[0079] The target product was confirmed by nuclear magnetic resonance spectroscopy: 2-(2-Ethoxy-2-oxo-1-(p-tolyl) ethoxy) benzoic acid (3l): Colorlessoil; 78% yield; 1 H NMR (400 MHz, CDCl3) δ 10.43 (s, 1H), 7.98 (dd, J = 8.0, 1.7 Hz, 1H),7.52 – 7.46 (m, 1H), 7.46 – 7.35 (m, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.01– 6.92(m, 2H), 6.12 (s, 1H), 4.33 – 4.17 (m, 2H), 2.41 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 169.6, 168.8, 162.1, 139.8, 136.6, 130.71,130.54, 129.73, 127.9, 119.57, 117.74, 112.08, 75.24, 62.07, 21.43, 14.16.

[0080] Example 14 Evaluation of anti-inflammatory activity In vitro anti-inflammatory activity studies (see Green Chem., 2020, 22: 1594) Experimental principle (inhibition of nitric oxide synthase): When the body's immune cells are stimulated by inflammatory mediators, they produce a large amount of inducible nitric oxide synthase, which promotes NO production; NO then reacts with Grignard reagent to convert into nitrite (NO2). - The nitrite content was measured at 570 nm using an enzyme-linked immunosorbent assay (ELISA) reader, and the NO generation inhibition rate was calculated. NO generation inhibition rate (%) = (OD0.05 of the non-drug treatment group) 570 nm -Sample group OD 570 nm ) / Non-drug treatment group OD 570 nm ×100%, the NO generation inhibition rate is the most direct indicator for evaluating the anti-inflammatory activity of compounded drugs. It should be noted that MTS (MTS is a novel MTT analog, full name 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethylthiazol-2-yl)-5 ... Thoxyphenyl)-2-(4-sulfopheny)-2H-tetrazolium is a yellow dye. Succinate dehydrogenase in the mitochondria of living cells can metabolize and reduce MTS, generating soluble formazan. The formazan content can be measured using a microplate reader at 490 nm. Under normal circumstances, the amount of formazan produced is directly proportional to the number of viable cells; therefore, the number of viable cells can be estimated from the optical density (OD) value. Cell viability is assessed using a method that eliminates the toxic effects of the compound on cells.

[0081] Experimental Methods: Mouse RAW264.7 mononuclear macrophages were induced to produce inducible nitric oxide synthase (iNOS) using LPS lipopolysaccharide. Then, 50 μM concentrations of the natural anti-inflammatory drug salicylic acid, synthesized salicylic acid OH inserts (3j, 3k, 3l), and the positive control drug L-NMMA were added for testing. Finally, the inhibition rate of NO production by the tested compounds was calculated using the Griess method and compared with the positive control drug L-NMMA to evaluate the anti-inflammatory activity of the tested salicylic acid OH inserts, further confirming the practicality of this synthetic method. Detailed experimental results are shown in Table 1. Table 1. Inhibition rate of compounds against NO

[0082] Conclusion: Based on the actual reference " Green Chem.,The experimental method described in "2020, 22: 1594" was used for preliminary in vitro anti-inflammatory activity screening. As shown in Table 1, taking the inflammatory target nitric oxide synthase as an example, preliminary anti-inflammatory activity screening revealed that at a concentration of 50 μM, the tested compounds showed no cytotoxicity and all exhibited certain anti-inflammatory activity. Among them, the anti-inflammatory activities of salicylic acid OH insertion products 3k and 3l were superior to those of the natural anti-inflammatory drug salicylic acid. The anti-inflammatory effect of product 3k was even superior to that of the positive control L-NMMA, indicating that this method may provide an effective strategy for the derivatization of natural phenolic products, further highlighting the practicality of this invention.

[0083] In summary, the product yields obtained by the above embodiments and comparative examples using other acid or base catalysts, metal catalysts, or sludge catalysts under the same reaction conditions are all lower than those obtained by the lignite residue catalyst used in this application. This invention uses lignite residue as a catalyst, which is widely available, inexpensive, and readily available; the reaction conditions are mild, and the yield is good (the highest separation yield can reach 86%), enabling gram-scale reactions and possessing industrialization potential. Simultaneously, it achieves the recycling of waste resources (the product separation yield can still reach over 60% after the lignite residue catalyst is reused three times), and to some extent alleviates the problem of difficult lignite residue treatment, aligning with the principles of green environmental protection and green chemistry.

[0084] Finally, it should be noted that the above preferred embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail through the above preferred embodiments, those skilled in the art should understand that various changes can be made to it in form and detail without departing from the scope defined by the claims of the present invention.

Claims

1. A method for catalytic synthesis of phenoxyacetic acid ester derivatives from lignite residue, characterized in that: It is synthesized from phenolic and aryl diazonium ester compounds using lignite residue as a catalyst.

2. The method of claim 1, wherein the phenoxyacetic ester derivative has the structure shown in Formula 3, and its reaction formula is as follows: In the formula, R 1 Selected from one or more of hydrogen, alkyl (methyl, ethyl), alkoxy, acyl, halogen, and trifluoromethyl. R 2 Selected from alkyl, allyl, and phenyl, R 3 It is selected from one or more of hydrogen, alkyl (methyl, ethyl), alkoxy, acyl, nitro, aldehyde, halogen and trifluoromethyl.

3. The method as described in claim 2, R 1 Selected from one or more of hydrogen and halogens, R 2 Selected from methyl and ethyl, R 3 It is selected from one or more of hydrogen, methyl, ethyl, propyl, methoxy, carboxyl, nitro, aldehyde, halogen and trifluoromethyl.

4. The method according to claim 2 or 3, wherein the halogen is F, Cl, Br or I.

5. The method as described in claim 1 or 2, comprising the following steps: S1. Dissolve the aryl diazonium ester compound of Formula 1 and the phenolic compound of Formula 2 in a solvent; S2. Add the catalyst lignite residue, react at room temperature for a period of time, then heat to 60-90℃ to continue the reaction; S3. The reaction products were separated by silica gel column chromatography to obtain the target product with the structure shown in Formula 3.

6. The method as described in claim 5, wherein in step S2, the heating temperature is 75°C.

7. A compound with the structure shown in Formula 3 or a pharmaceutical salt thereof, In the formula, R 1 R 2 and R 3 The definition is the same as that in claim 2 or 3.

8. The compound of claim 7 or a pharmaceutical salt thereof, selected from the following compounds or pharmaceutical salts thereof, 。 9. A pharmaceutical composition comprising the compound of claim 7 or 8 or a pharmaceutical salt and a pharmaceutical excipient.

10. Use of the compound or pharmaceutical salt of claim 7 or 8 in the preparation of an anti-inflammatory medicament.

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