Method for catalytically synthesizing secondary amine acetate derivatives by using lignite residues

Abstract

The invention discloses a method for catalytically synthesizing a secondary amine acetate derivative by using lignite residues, which comprises the following steps: taking an amine (primary amine) compound and an aryl diazo ester compound as raw materials to react for preparation, and taking the lignite residues as a catalyst. The catalyst lignite residue adopted by the method is wide in source, low in cost and easy to obtain, the reaction condition is mild, the yield is good, gram-scale reaction can be achieved, and the method has industrialization prospects. The lignite residues are high in catalytic activity and can be recycled, recycling of waste resources is achieved, the problem that the lignite residues are difficult to treat is solved, and the method conforms to the sustainable development concepts of environmental protection and green chemistry.

Description

Technical Field

[0001] This invention belongs to the field of organic synthetic chemistry, specifically relating to a method for catalytic synthesis of secondary amine acetate derivatives using lignite residue. Background Technology

[0002] Lignite residue is the main residual material after lignite refining, rich in various metal ions and present in large quantities. Hydrometallurgy , 2017, 168 : 141; Fuel , 2017, 203 : 214), but its post-treatment has always been a difficult problem for environmental organizations both at home and abroad. J. Anal. Appl. Pyrol ., 2019, 139 : 40; Energy , 2022, 240 : 122796). Currently, the most common treatment method is to use 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 degradation agent ( J. Environ. Chem. Eng ., 2021, 9 : 104784; Chem. Eng. J ., 2025, 521 (e.g., 166275). If it can be used as an organic synthesis catalyst, it can not only alleviate the problem of difficult treatment of lignite residue, but also provide a new idea for the selection of catalysts in organic synthesis reactions, realize the reuse of waste resources, and conform to the tenets of green chemistry and green environmental protection.

[0003] Secondary amine acetate derivatives are a class of widely used organic substances found in various drugs, natural products, or bioactive preparations and their skeletal structures. ACC. Chem. Res ., 2013, 46 : 236; J. Am. Chem. Soc ,2013, 135 : 18798; Ind. Eng. Chem. Res ., 2020, 59 The construction of the CN bond, a key step in its preparation, has always been a research hotspot in the field of organic synthesis both domestically and internationally. Angew. Chem., Int. Ed ., 2017,56 :4156; Adv. Synth. Catal ., 2019, 362 : 1106). Currently reported CN-bond construction methods often require expensive transition metal catalysts, complex ligands or other toxic reagents, and harsh reaction conditions ( Science , 2019, 366 :990; Nat. Commun ., 2022, 13 (7649); Therefore, the inventors attempted to develop a new, simple, and efficient method for constructing CN bonds. Diazo compounds (R 1 R 2 C=N2) is a class of highly reactive reaction intermediates that can participate in various reactions and construct CX (X=N, O, C, S, P, Si, B, etc.) bonds. Chem. Soc. Rev ., 2016, 45 506, Nature Rev. Chem ., 2019, 3 : 347); Among them, amine (primary amine) compounds can achieve CN bond construction through NH insertion reaction ( Angew. Chem., Int. Ed ., 2017, 56 : 4156; Science , 2019, 366 Based on this, the inventors intend to use only the metal ions in lignite residue to attempt to induce primary amines and aryl diazonium esters to construct CN bonds through metal carbene NH insertion reaction, thereby obtaining secondary amine acetate derivatives and their drug skeletons in one step, thus completing the present invention. Summary of the Invention

[0004] The present invention aims to provide a method for synthesizing secondary amine acetate derivatives using lignite residue as a catalyst, and the use of lignite residue as a catalyst. This method uses amines (primary amines) and aryl diazonium esters as raw materials, and lignite residue as a catalyst. Under heating conditions, CN bonds are constructed through an NH insertion reaction, resulting in a one-step reaction that generates secondary amine acetate derivatives and their skeletal structures.

[0005] To achieve the objectives of this invention, the following implementation scheme is provided.

[0006] In one embodiment, a method for catalytically synthesizing secondary amine acetate derivatives using lignite residue is provided, wherein the method uses amine compounds and aryl diazonium ester compounds as raw materials and lignite residue as a catalyst.

[0007] Furthermore, the amine compounds are primary amine compounds.

[0008] Furthermore, the reaction formula of the method of the present invention described above is as follows:

[0009] In the formula, R 1 It is one or more of hydrogen, C1-C6 alkyl, methoxy, acyl, halogen and trifluoromethyl; R 2 It can be alkyl, allyl, isopropyl, benzyl, or phenyl; R 3 It is one or more of hydrogen, C1-C6 alkyl, methoxy, acyl, nitro, aldehyde, ester, halogen, and trifluoromethyl. Preferably, R 1 It is one or more of hydrogen, F, Cl, Br, and I; R 2 It is methyl, ethyl, propyl, or butyl; R 3 It is one or more of hydrogen, methyl, ethyl, carboxyl, Cl, Br, I and trifluoromethyl.

[0010] In some embodiments, a method for catalytic synthesis of secondary amine acetate derivatives using lignite residue includes the following steps: S1. Dissolve amine compounds and aryl diazonium ester compounds in a solvent; S2. Add the catalyst lignite residue, react at room temperature first, then heat to 60-90℃ to continue the reaction; S3. After the reaction is complete, remove the volatile components and separate them by silica gel column chromatography to obtain secondary amine acetate derivatives.

[0011] Furthermore, in the method of the present invention described above, the molar mass to weight (g) ratio of the aryl diazonium ester compound to the catalyst lignite residue is 1:300-4000.

[0012] Preferably, in the method of the present invention described above, the solvent in step S1 is acetonitrile.

[0013] Furthermore, in the method of the present invention described above, in step S2, after adding the catalyst lignite residue, the reaction is first carried out at room temperature for 1 hour, and then the reaction is continued at 80°C for 10-12 hours.

[0014] In another embodiment, the present invention also provides the use of lignite residue as a catalyst in the preparation of secondary amine acetate derivatives, using primary amine compounds and aryl diazonium ester compounds as raw materials and lignite residue as a catalyst.

[0015] In yet another embodiment, a secondary amine acetate derivative is selected from the following compounds: , , , and .

[0016] In one specific embodiment, a method for catalytic synthesis of secondary amine acetate derivatives using lignite residue according to the present invention includes the following steps: S1. Using aniline and ethyl phenyldiazoate as raw materials, acetonitrile is added and stirred; S2. After adding lignite residue catalyst, react at room temperature for 1 hour, then heat to 80°C and continue the reaction for 12 hours. S3. After removing volatile components, the secondary amine acetate derivatives are separated by silica gel column chromatography to obtain white / brown solids or colorless transparent viscous substances.

[0017] Further, in step S1, the amount of aniline is 0.5 mmol, the amount of ethyl phenyldiazoate is 0.8 mmol, the amount of solvent acetonitrile is 5 mL, the stirring time at room temperature after the addition of acetonitrile is 20 minutes, and the amount of lignite residue catalyst in step S2 is 200 mg.

[0018] The beneficial effects of this invention are as follows: 1. The catalyst used in this invention is lignite residue, 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, thus having industrialization prospects.

[0019] 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.

[0020] 3. Compared with the currently reported methods for synthesizing secondary amine acetate derivatives, this invention avoids the use of additional transition metal catalysts and complex ligands, and selects lignite residue, which is widely available, as a catalyst. This not only makes it low-cost and environmentally friendly, but also has high catalytic activity and can be repeatedly recycled. The yield is good (the highest separation yield can reach 88%, and the product separation yield can still reach 60% after the catalyst is reused three times). Detailed Implementation

[0021] To further understand the present invention, the following detailed description is provided with reference to embodiments, but this does not limit the scope of the invention in any way. All raw materials and reagents used in the embodiments are commercially available products, and the yield of the synthesized compound is calculated using the formula: actual reaction yield / theoretical reaction yield × 100%.

[0022] Example 1: Preparation of compound 3a

[0023] S1. Weigh 0.5 mmol of ethyl phenyldiazoate and 0.8 mmol of aniline into a dry, clean Schlenk reaction tube with a capacity of 25 mL, add 5 mL of acetonitrile, and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue (produced in Zhaotong, Yunnan) as catalyst, react at room temperature for 1 hour, then heat to 80°C and continue the reaction for 12 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and separate by silica gel column chromatography using eluent (petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1) to obtain a colorless, transparent, viscous secondary amine acetate derivative 3a (108 mg), with a yield of 85%.

[0024] 1 H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 7.1 Hz, 2H), 7.41–7.30 (m, 3H), 7.20–7.11 (m, 2H), 6.73 (t, J = 7.3 Hz, 1H), 6.63–6.56 (m, 2H), 5.11 (d, J =5.3 Hz, 1H), 5.02 (s, 1H), 4.32–4.08 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H). 13 C{ 1 H}NMR (100 MHz, CDCl3) δ 171.91, 146.08, 137.81, 129.31, 128.90, 128.30,127.29, 118.10, 113.48, 61.90, 60.86, 14.12.

[0025] To demonstrate the rationality and superiority of this invention, the catalytic efficiency of acid catalysts, alkali catalysts, metal catalysts and sludge catalysts were compared under the same reaction conditions. The reuse efficiency of lignite residue catalysts and the catalytic efficiency of lignite residue catalysts from different origins were also studied.

[0026] Comparative Example 1: Acid Catalyst Experiment Referring to the method in Example 1, the lignite residue catalyst was replaced with the acid catalyst trifluoromethanesulfonic acid.

[0027] S1. Weigh 0.5 mmol of ethyl phenyldiazoate and 0.8 mmol of aniline into a dry, clean Schlenk reaction tube with a capacity of 25 mL, add 5 mL of acetonitrile, and stir at room temperature for 20 minutes. S2. After adding 25 µL of trifluoromethanesulfonic acid catalyst, react at room temperature for 1 hour, then heat to 80°C and continue the reaction for 12 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and separate by silica gel column chromatography using petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1) to obtain a colorless, transparent, viscous secondary amine acetate derivative 3a. The target product obtained was 80 mg, with a yield of 63%.

[0028] Comparative Example 2: Alkali Catalyst Experiment Referring to the method in Example 1, the lignite residue catalyst was replaced with the alkaline catalyst triethylamine.

[0029] S1. Weigh 0.5 mmol of ethyl phenyldiazoate and 0.8 mmol of aniline into a dry, clean Schlenk reaction tube with a capacity of 25 mL, add 5 mL of acetonitrile, and stir at room temperature for 20 minutes. S2. After adding 25µL of triethylamine catalyst, react at room temperature for 1 hour, then heat to 80℃ and continue the reaction for 12 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and separate by silica gel column chromatography using petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1, to obtain a colorless, transparent, viscous secondary amine acetate derivative 3a. The target product obtained was 41 mg, with a yield of 32%.

[0030] Comparative Example 3: Metal Catalyst Experiment Referring to the method of Example 1, the lignite residue catalyst was replaced with a metal catalyst, copper chloride.

[0031] S1. Weigh 0.5 mmol of ethyl phenyldiazoate and 0.8 mmol of aniline into a dry, clean Schlenk reaction tube with a capacity of 25 mL, add 5 mL of acetonitrile, and stir at room temperature for 20 minutes. S2. After adding 200 mg of copper chloride catalyst, react at room temperature for 1 hour, then heat to 80°C and continue the reaction for 12 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and perform silica gel column chromatography separation using eluent (petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1) to obtain a colorless, transparent, viscous secondary amine acetate derivative 3a.

[0032] In this embodiment, the target product obtained was 96 mg, with a yield of 75%.

[0033] Comparative Example 4: Sludge Catalyst Experiment See sludge catalyst Green Chem 2020 22 : 1594; Ind. Eng. Chem. Res 2020 59 :4854, Referenced.

[0034] S1. Weigh 0.5 mmol of ethyl phenyldiazoate and 0.8 mmol of aniline into a dry, clean Schlenk reaction tube with a capacity of 25 mL, add 5 mL of acetonitrile, and stir at room temperature for 20 minutes. S2. After adding 200mg of sludge catalyst, react at room temperature for 1 hour, then heat to 80℃ and continue the reaction for 12 hours.

[0035] S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and separate by silica gel column chromatography using petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1, to obtain a colorless, transparent, viscous secondary amine acetate derivative 3a. The target product obtained was 84 mg, with a yield of 66%.

[0036] Example 1.1 Experiment on the reuse of lignite residue This embodiment is the first reuse experiment of lignite residue catalyst. Referring to Example 1, the lignite residue catalyst recovered after the reaction in Example 1 was used for the first reuse experiment.

[0037] S1. Weigh 0.5 mmol of ethyl phenyldiazoate and 0.8 mmol of aniline into a dry, clean Schlenk reaction tube with a capacity of 25 mL, add 5 mL of acetonitrile, and stir at room temperature for 20 minutes. S2. Add 200 mg of lignite residue catalyst recovered in Example 1, react at room temperature for 1 h, then heat to 80 °C and continue the reaction for 12 h. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and perform silica gel column chromatography using petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1 as eluent to obtain a colorless, transparent, viscous secondary amine acetate derivative 3a. The yield of the target product was 100 mg, with a yield of 78%.

[0038] Example 1.2 Experiment on the Reuse of Lignite Residue This embodiment is a second reuse experiment of lignite residue catalyst. Referring to Example 1, the lignite residue catalyst recovered after the reaction in Example 1.1 was used for the second reuse experiment.

[0039] S1. Weigh 0.5 mmol of ethyl phenyldiazoate and 0.8 mmol of aniline into a dry, clean Schlenk reaction tube with a capacity of 25 mL, add 5 mL of acetonitrile, and stir at room temperature for 20 minutes. S2. Add 200 mg of lignite residue catalyst recovered in Example 1.1, react at room temperature for 1 h, then heat to 80 °C and continue the reaction for 12 h; S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and separate by silica gel column chromatography using petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1) to obtain a colorless, transparent, viscous secondary amine acetate derivative 3a. The target product obtained was 91 mg, with a yield of 71%.

[0040] Example 1.3 Experiment on the Reuse of Lignite Residue This embodiment is the third reuse experiment of lignite residue catalyst. Referring to Example 1, the lignite residue catalyst recovered after the reaction in Example 1.2 was used for the third reuse experiment.

[0041] S1. Weigh 0.5 mmol of ethyl phenyldiazoate and 0.8 mmol of aniline into a dry, clean Schlenk reaction tube with a capacity of 25 mL, add 5 mL of acetonitrile, and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue catalyst from Comparative Example 5, react at room temperature for 1 hour, then heat to 80°C and continue the reaction for 12 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and separate by silica gel column chromatography using petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1) to obtain a colorless, transparent, viscous secondary amine acetate derivative 3a. The target product obtained was 80 mg, with a yield of 63%.

[0042] Example 1.4 Catalytic activity experiment of lignite residues from different origins (Yimin, Inner Mongolia) This experiment follows the method of Example 1, but replaces the lignite residue catalyst from Zhaotong, Yunnan with lignite residue catalyst from Yimin, Inner Mongolia.

[0043] S1. Weigh 0.5 mmol of ethyl phenyldiazoate and 0.8 mmol of aniline into a dry, clean Schlenk reaction tube with a capacity of 25 mL, add 5 mL of acetonitrile, and stir at room temperature for 20 minutes. S2. After adding 200mg of lignite residue (Inner Mongolia Yimin) catalyst, react at room temperature for 1 hour, then heat to 80℃ and continue the reaction for 12 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and perform silica gel column chromatography using petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1 as eluent to obtain a colorless, transparent, viscous secondary amine acetate derivative 3a. The target product obtained was 102 mg, with a yield of 80%.

[0044] Example 1.5 Catalytic activity experiment of lignite residues from different origins (Hegang, Heilongjiang) This experiment follows the method of Example 1, but replaces the lignite residue catalyst from Zhaotong, Yunnan with lignite residue catalyst from Hegang, Heilongjiang.

[0045] S1. Weigh 0.5 mmol of ethyl phenyldiazoate and 0.8 mmol of aniline into a dry, clean Schlenk reaction tube with a capacity of 25 mL, add 5 mL of acetonitrile, and stir at room temperature for 10 minutes. S2. After adding 200 mg of lignite residue (Hegang, Heilongjiang) catalyst, react at room temperature for 1 h, then heat to 80 °C and continue the reaction for 12 h. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and separate by silica gel column chromatography using petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1, to obtain a colorless, transparent, viscous secondary amine acetate derivative 3a. The target product obtained was 106 mg, with a yield of 83%.

[0046] The results of Comparative Examples 1-4 show that, under the same reaction conditions, the catalytic efficiency of the lignite residue catalyst (85%) is superior to that of the acid (63%) and alkali (32%) catalysts, the metal catalyst (75%), and the sludge catalyst (66%), highlighting the rationality and superiority of the present invention in selecting lignite residue as a catalyst.

[0047] The experimental results of Examples 1.1-1.3 show that the repeated use of lignite residue catalyst (product yield of repeated use of lignite residue: 78% in the first time, 71% in the second time, and 63% in the third time) proves the practicality, high activity and superiority of lignite residue catalyst in repeated use.

[0048] The experimental results of Examples 1.4-1.5 show that the catalytic efficiency of lignite residue catalysts from different origins is not significantly different (85% in Zhaotong, Yunnan; 80% in Yimin, Inner Mongolia; and 83% in Hegang, Heilongjiang), indicating that lignite residue catalysts have a wide range of sources and their catalytic activity is universal.

[0049] The lignite residue used in the following examples is sourced from Zhaotong, Yunnan.

[0050] Example 2 Preparation of compound 3b

[0051] S1. Weigh 0.5 mmol of ethyl phenyldiazoate and 0.8 mmol of p-trifluoromethylaniline into a dry, clean Schlenk reaction tube with a capacity of 25 mL, add 5 mL of acetonitrile, and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue catalyst, react at room temperature for 1 hour, then heat to 80°C and continue the reaction for 12 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and separate by silica gel column chromatography using petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1, to obtain a white solid secondary amine acetate derivative 3b. The target product obtained was 142 mg, with a yield of 88%.

[0052] 1 H NMR (400 MHz, CDCl3) δ 7.53 (d,J = 7.1 Hz, 2H), 7.41–7.32 (m, 5H), 6.62–6.57 (m, 2H), 5.37 (d, J = 5.4 Hz, 1H), 5.05 (s, 1H), 4.32–4.09 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 171.78, 147.4, 137.99,129.65, 128.74, 127.83, 126.28 (q, J = 3.9 Hz), 124.78 (q, J = 271.2 Hz), 120.37(q, J = 32.8 Hz), 113.57, 62.93, 61.12, 14.13.

[0053] Example 3 Preparation of compound 3c

[0054] S1. Weigh 0.5 mmol of ethyl phenyldiazoate and 0.8 mmol of p-chloroaniline into a dry, clean Schlenk reaction tube with a capacity of 25 mL, add 5 mL of acetonitrile, and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue catalyst, react at room temperature for 1 hour, then heat to 80°C and continue the reaction for 12 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and separate by silica gel column chromatography using petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1, to obtain a white solid secondary amine acetate derivative 3c. The target product obtained was 124 mg, with a yield of 86%.

[0055] 1 H NMR (400 MHz, CDCl3) δ 7.58 (dd, J = 7.6, 1.4 Hz, 2H), 7.43–7.31 (m,3H), 7.28–7.21 (m, 2H), 6.49 (d, J = 8.6 Hz, 2H), 5.42 (d, J= 5.3 Hz, 1H), 5.12(s, 1H), 4.30–4.13 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 171.09, 147.23, 136.57, 129.72, 129.46, 128.75, 127.62, 125.47, 115.83, 62.75, 61.39, 14.15.

[0056] Example 4: Preparation of Compound 3d

[0057] S1. Weigh 0.5 mmol of ethyl phenyldiazoate and 0.8 mmol of p-bromoaniline into a dry, clean Schlenk reaction tube with a capacity of 25 mL, add 5 mL of acetonitrile, and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue catalyst, react at room temperature for 1 hour, then heat to 80°C and continue the reaction for 12 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and separate by silica gel column chromatography using petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1, to obtain a brown solid secondary amine acetate derivative 3d. The target product obtained was 137 mg, with a yield of 82%.

[0058] 1 H NMR (400 MHz, CDCl3) δ 7.56 (dd, J = 7.6, 1.6 Hz, 2H), 7.42–7.30 (m,3H), 7.29–7.21 (m, 2H), 6.51 (d, J = 8.6 Hz, 2H), 5.41 (d, J = 5.3 Hz, 1H), 5.13(s, 1H), 4.32–4.15 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H). 13 C{ 1H} NMR (100 MHz, CDCl3) δ 171.87, 147.57, 137.52, 129.83, 129.35, 128.65, 127.54, 125.49, 115.83, 62.65, 61.44, 14.17.

[0059] Example 5 Preparation of compound 3e

[0060] S1. Weigh 0.5 mmol of ethyl phenyldiazoate and 0.8 mmol of p-methylaniline into a dry, clean Schlenk reaction tube with a capacity of 25 mL, add 5 mL of acetonitrile, and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue catalyst, react at room temperature for 1 hour, then heat to 80°C and continue the reaction for 12 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and separate by silica gel column chromatography using petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1, to obtain a white solid secondary amine acetate derivative 3e. The target product obtained was 103 mg, with a yield of 79%.

[0061] 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), 5.49 (d, J = 5.3 Hz, 1H), 5.18 (s,1H), 4.29–4.15 (m, 2H), 2.26 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H). 13 C NMR (100MHz, CDCl3) δ 171.21, 152.73, 134.85, 131.14, 130.21, 129.07, 128.75, 127.39,116.23, 67.32, 62.34, 20.73, 14.15.

[0062] Example 6 Preparation of compound 3f

[0063] S1. Weigh 0.5 mmol of ethyl phenyldiazoate and 0.8 mmol of p-methoxyaniline into a dry, clean Schlenk reaction tube with a capacity of 25 mL, add 5 mL of acetonitrile, and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue catalyst, react at room temperature for 1 hour, then heat to 80°C and continue the reaction for 12 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and separate by silica gel column chromatography using petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1, to obtain a white solid secondary amine acetate derivative 3f. The target product obtained was 107 mg, with a yield of 75%.

[0064] 1 H NMR (400 MHz, CDCl3) δ 7.59–7.51 (m, 2H), 7.45–7.34 (m, 3H), 7.09(d, J = 8.3 Hz, 2H), 6.91 –6.83 (m, 2H), 5.47 (d, J = 5.3 Hz, 1H), 5.16 (s,1H), 4.27–4.18 (m, 2H), 3.82 (s, 3H), 2.27 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 171.47, 152.53, 134.85, 131.14, 130.21, 129.07,128.75, 127.39, 116.23, 69.32, 65.34, 50.73, 14.13.

[0065] Example 7: Preparation of 3g of compound

[0066] S1. Weigh 0.5 mmol of ethyl phenyldiazoate and 0.8 mmol of o-methylaniline into a dry, clean Schlenk reaction tube with a capacity of 25 mL, add 5 mL of acetonitrile, and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue catalyst, react at room temperature for 1 hour, then heat to 80°C and continue the reaction for 12 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and separate by silica gel column chromatography using petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1, to obtain 3g of a brown solid secondary amine acetate derivative. The yield of the target product was 100mg, with a yield of 74%.

[0067] 1 H NMR (400 MHz, CDCl3) δ 7.61–7.56 (m, 2H), 7.43–7.35 (m, 3H), 7.18–7.06 (m, 2H), 6.73 (td, J = 7.4, 0.7 Hz, 1H), 6.42 (d, J = 7.9 Hz, 1H), 5.21 (s,1H), 5.03 (s, 1H), 4.27–4.13 (m, 2H), 2.34 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 171.08, 148.87, 135.92, 129.35, 128.72, 128.56, 128.43, 116.30, 113.08, 69.67, 61.71, 19.27, 14.14.

[0068] Example 8: Preparation of compound 3h

[0069] S1. Weigh 0.5 mmol of methyl phenyldiazoacetate and 0.8 mmol of p-trifluoromethylaniline into a dry, clean Schlenk reaction tube with a capacity of 25 mL, add 5 mL of acetonitrile, and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue catalyst, react at room temperature for 1 hour, then heat to 80°C and continue the reaction for 12 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and separate by silica gel column chromatography using petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1, to obtain a white solid secondary amine acetate derivative for 3 hours. The target product obtained was 133 mg, with a yield of 86%.

[0070] 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.6 Hz, 2H), 7.44–7.29 (m, 5H), 6.57 (d, J = 8.5 Hz, 2H), 5.41 (s, 1H), 5.13 (s, 1H), 3.78 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 171.78, 148.34, 136.78, 129.24, 128.65, 127.18, 126.74 (d, J = 3.7 Hz), 124.95 (q, J = 270.5 Hz), 112.57, 61.33, 52.97.

[0071] Example 9: Preparation of Compound 3i

[0072] S1. Weigh 0.5 mmol of p-chlorophenyldiazoacetic acid methyl ester and 0.8 mmol of p-trifluoromethylaniline into a dry, clean Schlenk reaction tube with a capacity of 25 mL, add 5 mL of acetonitrile, and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue catalyst, react at room temperature for 1 hour, then heat to 80°C and continue the reaction for 12 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and separate by silica gel column chromatography using petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1, to obtain a white solid secondary amine acetate derivative 3i. The target product obtained was 139 mg, with a yield of 81%.

[0073] 1 H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.5 Hz, 2H), 7.37 (dd, J = 8.5, 3.5Hz, 4H), 6.52 (d, J = 8.5 Hz, 2H), 5.38 (d, J = 5.1 Hz, 1H), 5.09 (d, J = 5.3 Hz, 1H), 3.78 (s, 3H);13 C{ 1 H} NMR (100 MHz, CDCl3) δ 171.47, 148.13, 135.35,134.67, 129.34, 128.52, 126.28 (q, J = 7.5 Hz), 124.87 (q, J =270.3 Hz), 120.09(q, J = 64.4 Hz), 112.76, 59.34, 53.42.

[0074] Example 10 Preparation of compound 3j

[0075] S1. Weigh 0.5 mmol of o-chlorophenyl diazonoacetate and 0.8 mmol of p-trifluoromethylaniline into a dry, clean Schlenk reaction tube with a capacity of 25 mL, add 5 mL of acetonitrile, and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue catalyst, react at room temperature for 1 hour, then heat to 80°C and continue the reaction for 12 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and separate by silica gel column chromatography using petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1, to obtain a white solid secondary amine acetate derivative 3j. The target product obtained was 134 mg, with a yield of 78%.

[0076] 1 H NMR (400 MHz, CDCl3) δ 7.48–7.37 (m, 2H), 7.35 (d, J = 8.6 Hz, 2H), 7.24 (dt, J = 3.3, 2.9 Hz, 2H), 6.54 (d, J = 8.6, Hz, 2H), 5.63 (d, J = 5.6 Hz, 1H), 5.45 (d, J = 5.4 Hz, 1H), 3.76 (s, 3H); 13 C{ 1H} NMR (100 MHz, CDCl3) δ171.48, 148.07, 135.12, 134.35, 130.51, 129.89, 128.24, 127.83, 126.82 (q, J =3.7 Hz), 126.23 (q, J = 270.5 Hz), 120.01 (q, J = 65.4 Hz), 112.81, 57.47, 53.65.

[0077] Examples 9-10 show that the product yields differed only slightly depending on the position of the same substituent (81% for para position and 78% for ortho position), indicating that the steric hindrance effect of the reaction system is not significant.

[0078] Example 11 Preparation of compound 3k

[0079] S1. Weigh 0.5 mmol benzyl phenyldiazoacetate and 0.8 mmol p-trifluoromethylaniline into a dry, clean Schlenk reaction tube with a capacity of 25 mL, add 5 mL of acetonitrile, and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue catalyst, react at room temperature for 1 hour, then heat to 80°C and continue the reaction for 12 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and separate by silica gel column chromatography using petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1, to obtain a white solid secondary amine acetate derivative 3k. The target product obtained was 154 mg, with a yield of 80%.

[0080] 1 H NMR (400 MHz, CDCl3) δ 7.53–7.45 (m, 2H), 7.42–7.29 (m, 8H), 7.24–7.15 (m, 2H), 6.57 (d, J = 8.5 Hz, 2H), 5.36 (d, J = 5.7 Hz, 1H), 5.24 (d, J = 12.3Hz, 1H), 5.14 (d, J = 12.3 Hz, 2H); 13 C{ 1H} NMR (100 MHz, CDCl3) δ 170.95,147.23, 135.62, 135.94, 128.97, 128.34 (d, J = 5.4 Hz), 128.67, 128.35, 127.51,126.43 (q, J = 7.6, 3.8 Hz), 124.87 (q, J = 270.3 Hz), 120.04 (q, J = 65.3, 32.6Hz), 112.59, 67.48, 61.03.

[0081] Example 12 Preparation of Compound 3l

[0082] S1. Weigh 0.5 mmol of methyl phenyldiazoacetate and 0.8 mmol of 3-aminopyridine into a dry, clean Schlenk reaction tube with a capacity of 25 mL, add 5 mL of acetonitrile, and stir at room temperature for 20 minutes. S2. After adding 200 mg of lignite residue catalyst, react at room temperature for 1 hour, then heat to 80°C and continue the reaction for 12 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and separate by silica gel column chromatography using petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1, to obtain 3l of a white solid secondary amine acetate derivative. The target product obtained was 73mg, with a yield of 60%.

[0083] 1 H NMR (400MHz, CDCl3) δ 8.09 (d, J = 5.8 Hz, 1H), 7.51 (d, J = 6.9 Hz,2H), 7.41–7.32 (m, 4H), 6.65–6.54 (m, 1H), 6.42 (d, J = 8.4 Hz, 1H), 5.57 (d, J =6.8 Hz, 1H), 5.37 (d, J = 6.3 Hz, 1H), 3.75 (s, 3H); 13 C{ 1H} NMR (100 MHz, CDCl3)δ 171.84, 156.27, 147.96, 137.12, 137.04, 128.83, 128.15, 127.27, 113.69,108.13, 58.56, 52.63.

[0084] Example 13 Gram-scale scale-up test A scale-up experiment was conducted using the preparation method of Example 2.

[0085] S1. Weigh 6 mmol of ethyl phenyldiazoate (1.14 g) and 9.6 mmol of p-trifluoromethylaniline (1.55 g) into a dry, clean Schlenk reaction tube with a capacity of 250 mL, add 60 mL of acetonitrile, and stir at room temperature for 40 minutes. S2. After adding 2.4g of lignite residue catalyst, react at room temperature for 1 hour, then heat to 80℃ and continue the reaction for 14 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and separate by silica gel column chromatography using petroleum ether (60-90℃) / ethyl acetate, v / v = 8:1, to obtain a white solid secondary amine acetate derivative 3b. The yield of the target product was 1.57 g, with a yield of 81%.

[0086] The successful execution of Example 13 (gram-scale scale-up reaction) demonstrates that the method of the present invention is easy to scale up and has industrialization potential.

[0087] In summary, compared with Comparative Examples 1-4 which used other acid or base catalysts, metal catalysts, or sludge catalysts, Examples 1-14, using lignite residue as a catalyst, showed a significant advantage in product yield under the same reaction conditions. This invention uses lignite residue as a catalyst, which is widely available, inexpensive, and readily accessible; the reaction conditions are mild, the yield is good (the highest separation yield can reach 88%), and it is easy to achieve gram-scale scale-up, possessing industrialization potential. It provides an effective strategy for the synthesis of secondary amine acetate derivatives and their drug skeletons. 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 lignite residue disposal difficulties, aligning with the principles of green environmental protection and green chemistry.

[0088] Finally, it should be noted that the above preferred embodiments are merely preferred technical solutions and not limitations. Although the present invention has been described in detail through the above preferred embodiments, those skilled in the art should understand that various changes or modifications can be made to it in form and detail, and such changes or modifications are within the scope of the claims of the present invention without departing from the spirit of the present invention.

Claims

1. A method for catalytic synthesis of secondary amine acetate derivatives using lignite residue, wherein the method uses amine compounds and aryl diazonium ester compounds as raw materials, characterized in that: Lignite residue was used as a catalyst.

2. The method according to claim 1, wherein the amine compound is a primary amine compound.

3. The method as described in claim 1, wherein the reaction formula is as follows: In the formula, R 1 It is one or more of hydrogen, C1-C6 alkyl, methoxy, acyl, halogen and trifluoromethyl; R 2 It can be alkyl, allyl, isopropyl, benzyl, or phenyl; R 3 It is one or more of hydrogen, C1-C6 alkyl, methoxy, acyl, nitro, aldehyde, ester, halogen, and trifluoromethyl.

4. The method as described in claim 3, R 1 It is one or more of hydrogen, F, Cl, Br, and I; R 2 It can be methyl, ethyl, propyl, butyl, or benzyl; R 3 It is one or more of hydrogen, methyl, ethyl, carboxyl, Cl, Br, I and trifluoromethyl.

5. The method of claim 1, comprising the following steps: S1. Dissolve amine compounds and aryl diazonium ester compounds in a solvent; S2. Add the catalyst lignite residue, react at room temperature first, then heat to 60-90℃ to continue the reaction; S3. After the reaction is complete, remove the volatile components and separate them by silica gel column chromatography to obtain secondary amine acetate derivatives.

6. The method according to claim 5, wherein the molar mass to weight (g) ratio of the aryl diazonium ester compound to the catalyst lignite residue is 1:300-4000.

7. The method of claim 5, wherein the solvent in step S1 is acetonitrile.

8. In the method of claim 5, in step S2, after adding the catalyst lignite residue, the reaction is first carried out at room temperature for 1 hour, and then the reaction is continued at 80°C for 10-12 hours.

9. The use of lignite residue as a catalyst in the preparation of secondary amine acetate derivatives, characterized in that, The raw materials are amine compounds and aryl diazonium esters, and the catalyst is lignite residue.

10. A secondary amine acetate derivative, selected from the following compounds: 、 、 、 and .

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