Method for preparing alpha-hydroxy ester compound by utilizing lignite residue catalysis

Abstract

The invention discloses a method for preparing an alpha-hydroxyl ester compound by utilizing lignite residue catalysis, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: S1, mixing water and an aryl diazo ester compound, then adding acetonitrile in an air atmosphere, and stirring; s2, adding lignite residues as a catalyst to catalyze a reaction, reacting at room temperature for 1 h, heating to 80 DEG C, and continuously reacting for 8-10 h; s3, stopping the reaction when the reaction is detected to be complete by TLC; and S4, filtering the reaction liquid, washing a filter cake with dichloromethane until the filter cake is colorless, carrying out reduced pressure concentration on the filtrate to remove volatile components, and carrying out silica gel column chromatography separation to obtain the alpha-hydroxyl ester compound. According to the method, the lignite residues are used as the catalyst which is wide in source, low in cost and easy to obtain, and other transition metals or complex ligands do not need to be additionally introduced in the reaction; the reaction conditions are mild, the yield is good, gram-scale reaction can be realized, and the method has industrial prospects; meanwhile, waste resources can be recycled, and the development themes of green chemistry and green environmental protection are met.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing α-hydroxy ester compounds using lignite residue as a catalyst. 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 often 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.

[0004] D-diazo compounds (R 1 R 2C=N2) is 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, NatureRev. Chem., 2019, 3: 347); among them, CO bonds can be constructed through OH insertion reaction with water (GreenChem., 2020, 22: 1594). Based on this, it is proposed to utilize metal ions in lignite residues to induce aryl diazonium esters to construct CO bonds with water through metal carbene OH insertion reaction, thereby obtaining α-hydroxy ester drugs or drug skeletons in a one-step reaction. Summary of the Invention

[0005] In view of this, the purpose of the present invention is to provide a method for preparing α-hydroxy ester compounds by catalysis using lignite residue.

[0006] To achieve the above objectives, the present invention provides the following technical solution: This invention provides the application of lignite residue as a catalyst for the generation of α-hydroxy ester compounds.

[0007] Furthermore, it also includes a method for synthesizing α-hydroxy ester compounds, the method comprising the following steps: S1. Mix water and aryl diazonium ester compounds, and then add acetonitrile under air atmosphere and stir. S2. Add lignite residue as a catalyst to catalyze the reaction. First, react at room temperature for 1 hour, then raise the temperature to 80℃ and continue the reaction for 8-10 hours. S3, the reaction is stopped when the TLC detection shows that the reaction is complete; S4. Filter the reaction liquid, wash the filter cake with dichloromethane until colorless, remove the volatile components from the filtrate under reduced pressure, and then separate by silica gel column chromatography to obtain α-hydroxy ester compounds.

[0008] Furthermore, the aryl diazonium ester compound is any one of ethyl p-chlorophenyldiazoacetate, ethyl p-bromophenyldiazoacetate, ethyl phenyldiazoacetate, and benzyl phenyldiazoacetate.

[0009] Further, in step S1, the volume ratio of water to aryldiazo ester compound is 8:5; the amount of lignite residue used is 150-200 mg.

[0010] Furthermore, in step S1, the stirring time after the acetonitrile is added is 5-10 minutes.

[0011] Furthermore, the entire reaction process is carried out in an air atmosphere, without the need for nitrogen or other inert gas protection.

[0012] Further, in step S4, the eluent used in the silica gel column chromatography separation is composed of petroleum ether and ethyl acetate in a volume ratio of 10:1, and the boiling point of the petroleum ether is 60-90℃.

[0013] Furthermore, the synthetic route is shown in the following reaction equation: .

[0014] Furthermore, in the reaction formula, R 1 It is one or more of hydrogen, methyl, ethyl, methoxy, acyl, halogen, and trifluoromethyl, wherein the halogen is F, Cl, Br, or I; R 2 It is one or more of methyl, ethyl, allyl, phenyl or alkyl.

[0015] The beneficial effects of this invention are as follows: 1. The method of the present invention uses lignite residue as a catalyst, which is widely available, inexpensive and readily available. The reaction does not require the introduction of other transition metals or complex ligands. Moreover, the reaction conditions of the present invention are mild and the yield is good, which can realize gram-scale reaction and has industrialization prospects.

[0016] 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.

[0017] Other advantages, objectives, and features of the invention will be set forth in the following description and will be apparent to those skilled in the art in some respects, or may be learned by practice of the invention. The objectives and other advantages of the invention can be realized and obtained through the following description. Attached Figure Description

[0018] To make the purpose, technical solution, and beneficial effects of the invention clearer, the following figures are provided for illustration: Figure 1 The α-hydroxy ester compound prepared in Example 1 of this invention 1 H NMR spectrum; Figure 2 The α-hydroxy ester compound prepared in Example 1 of this invention 13 C NMR spectrum. Detailed Implementation

[0019] like Figures 1-2 As shown, the present invention provides a method for preparing α-hydroxy ester compounds using lignite residue as a catalyst.

[0020] Example 1 (using lignite residue from Zhaotong, Yunnan as a catalyst) S1. Weigh 0.5 mmol of ethyl p-chlorophenyldiazoate and 0.8 mmol of water into a clean, dry Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 10 min. S2. Add 200 mg of lignite residue as a catalyst, react at room temperature for 1 h, and then raise the temperature to 80℃ and continue the reaction for 10 h. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reaction solution, 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 with eluent (petroleum ether (75℃) / ethyl acetate, v / v = 10∶1) to obtain a white solid α-hydroxy ester compound (3a).

[0021] In this embodiment, the target product obtained was 86 mg, with a yield of 80%.

[0022] The target product was confirmed by nuclear magnetic resonance spectroscopy as follows: Ethyl 2-(4-chlorophenyl)-2-hydroxyacetate (3a): White solid, 80% yield; 1 H NMR (400 MHz, CDCl3) δ 7.40 – 7.28 (m, 4H), 5.12 (d, J = 5.4Hz, 1H), 4.31 – 4.10 (m, 2H), 3.75 – 3.63 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 173.35, 136.97, 134.30, 128.77, 127.98, 72.28,62.50, 14.08. Example 2 S1. Weigh 0.5 mmol of ethyl p-bromophenyldiazoate and 0.8 mmol of water into a clean, dry Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under an air atmosphere and stir at room temperature for 10 min. S2. Add 150 mg of lignite residue catalyst, react at room temperature for 1 hour, then heat to 80°C and continue the reaction for 10 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reaction solution, 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 (75℃) / ethyl acetate, v / v = 10∶1) to obtain a white solid α-hydroxy ester compound (3b).

[0023] In this embodiment, the target product obtained was 98 mg, with a yield of 76%.

[0024] The target product was confirmed by nuclear magnetic resonance spectroscopy: Ethyl 2-(4-bromophenyl)-2-hydroxyacetate (3b): White solid, 65% yield; 1 H NMR (400 MHz, CDCl3) δ 7.51 – 7.43 (m, 2H), 7.33 – 7.27(m, 2H), 5.10 (d, J = 5.4 Hz, 1H), 4.30 – 4.09 (m, 2H), 3.79 – 3.69 (m, 1H), 1.20 (t, J = 7.1 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 173.22, 137.47, 131.69,128.28, 122.44, 72.31, 62.48, 14.06. Example 3 S1. Weigh 0.5 mmol of ethyl phenyldiazoate and 0.8 mmol of water into a clean, dry Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 10 min. S2. Add 200 mg of lignite residue catalyst, react at room temperature for 1 h, then heat to 80℃ and continue the reaction for 10 h; S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reaction solution, 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 (75℃) / ethyl acetate, v / v = 10∶1) to obtain a white solid α-hydroxy ester compound (3c).

[0025] In this embodiment, the target product obtained was 68 mg, with a yield of 75%.

[0026] The target product was confirmed by nuclear magnetic resonance spectroscopy: Ethyl 2-hydroxy-2-phenylacetate (3c):Colorless oil;75% yield; 1 H NMR (400 MHz, CDCl3) δ 7.46 – 7.40 (m, 2H), 7.40 – 7.29 (m, 3H), 5.16 (d, J = 5.8 Hz, 1H), 4.31 – 4.11 (m, 2H), 3.57 (d, J = 5.8 Hz, 1H), 1.22 (t, J = 7.1 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 173.78, 138.53, 128.66, 128.49,126.63, 72.99, 62.33, 14.12. Example 4 S1. Weigh 0.5 mmol benzyl phenyldiazoacetate and 0.8 mmol water into a clean, dry Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 10 min. S2. Add 200 mg of lignite residue catalyst, react at room temperature for 1 h, then heat to 80 °C and continue the reaction for 10 h; S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reaction solution, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and separate it by silica gel column chromatography using eluent (petroleum ether (75℃) / ethyl acetate, v / v = 10∶1) to obtain a white solid α-hydroxy ester compound (3d).

[0027] In this embodiment, the target product obtained was 82 mg, with a yield of 68%.

[0028] Benzyl phenyldiazoacetate has a large molecular weight of 242.09 (82 / 242.09x0.5=68%), and the product quantity is also large, so the yield is low.

[0029] The target product was confirmed by nuclear magnetic resonance spectroscopy: Benzyl 2-hydroxy-2-phenylacetate (3d): White solid, 68% yield; 1 H NMR (400 MHz, CDCl3) δ 7.47 – 7.41(m, 2H), 7.38 – 7.31 (m,6H), 7.25 – 7.17 (m, 2H), 5.25 (dd, J = 9.1, 3.2 Hz, 2H), 5.15 (d, J = 12.4 Hz, 1H), 3.67 (d, J = 5.8 Hz, 1H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 173.53, 138.27,135.08, 128.64, 128.61, 128.54, 128.48, 128.00, 126.67, 73.06,67.65. Example 5 S1. Weigh 0.5 mmol of ethyl p-methoxyphenyl diazoate and 0.8 mmol of water into a clean, dry Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 10 min. S2. Add 200 mg of lignite residue catalyst, react at room temperature for 1 h, then heat to 80°C. o C continued to react for 10 hours; S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reaction solution, 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 (75℃) / ethyl acetate, v / v = 10∶1) to obtain α-hydroxy ester compound (3e).

[0030] In this comparative example, the target product was 68 mg, with a yield of 65%.

[0031] The target product was confirmed by nuclear magnetic resonance spectroscopy: Ethyl 2-hydroxy-2-(4-methoxyphenyl) acetate (3e):White solid; 65% yield; 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.36 (m, 2H), 7.07 –6.85 (m, 2H), 5.18 (d, J = 4.8 Hz, 1H), 4.30 – 4.09 (m, 2H), 3.82 (s, 3H), 3.43(d, J = 5.5 Hz, 1H), 1.20 (t, J = 7.1 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) 173.43,158.81, 132.43, 128.87, 115.10, 73.53, 62.27, 54.94, 14.18. Example 6 S1. Weigh 0.5 mmol of ethyl p-methylphenyldiazoate and 0.8 mmol of water into a clean, dry Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 10 min. S2. Add 200 mg of lignite residue catalyst, react at room temperature for 1 h, then heat to 80 °C and continue the reaction for 10 h; S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reaction solution, wash the filter cake with dichloromethane until colorless, concentrate the filtrate under reduced pressure to remove volatile components, and separate it by silica gel column chromatography using eluent (petroleum ether (75℃) / ethyl acetate, v / v = 10∶1) to obtain a white solid α-hydroxy ester compound (3f).

[0032] In this comparative example, the target product was 59 mg, with a yield of 61%.

[0033] The target product was confirmed by nuclear magnetic resonance spectroscopy: Ethyl 2-hydroxy-2-( p -tolyl) acetate (3f):White solid;61% yield; 1 H NMR (400 MHz, CDCl3) δ 7.44 – 7.37 (m, 2H), 7.08 – 6.75 (m, 2H), 5.17 (d, J = 4.9 Hz, 1H), 4.32– 4.11 (m, 2H), 3.45 (d, J= 5.5 Hz, 1H), 2.26 (s,3H), 1.20 (t, J = 7.1 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) 173.52, 138.21,135.43, 129.05, 127.85, 72.63, 61.97, 21.81, 14.15. Examples 1-6 were used to examine the applicability of different aryl diazonium ester compounds, i.e., to investigate the suitability of the reaction method. At the same time, a series of different α-hydroxy ester compounds can be prepared, providing more options for the synthesis of such drugs or drug skeletons.

[0034] Comparing Examples 1-6, it was found that the yields of α-hydroxy ester compounds obtained using aryl diazonium esters not within the scope of this invention were relatively low, such as ethyl methoxydiazophenylacetate and ethyl p-methylphenyldiazoacetate. The relatively low yield of ethyl p-methoxyphenyldiazoacetate is due to the significant electronic effects of the reaction system. Electron-withdrawing groups (Cl, Br) favor the reaction process in this system, resulting in relatively high yields; while methoxy and methyl groups are electron-donating groups, which are unfavorable to the reaction process in this system, resulting in relatively low yields.

[0035] Example 7 (using Example 1 as an example, performing a gram-scale reaction) S1. Weigh 5 mmol of ethyl p-chlorophenyldiazoate (1.12 g) and 8 mmol of water (0.14 g) into a clean, dry Schlenk reaction tube with a capacity of 250 mL. Add 50 mL of acetonitrile under an air atmosphere and stir at room temperature for 20 min. S2. Add 2000 mg of lignite residue catalyst, react at room temperature for 2 h, then heat to 80°C. o C continued to react for 12 hours; S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reaction solution, 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 with eluent (petroleum ether (75℃) / ethyl acetate, v / v = 10∶1) to obtain a white solid α-hydroxy ester compound (3a).

[0036] In this embodiment, the target product obtained was 0.82 g, with a yield of 77%.

[0037] The target product was confirmed by nuclear magnetic resonance spectroscopy: Ethyl 2-(4-chlorophenyl)-2-hydroxyacetate (3a): White solid, 80% yield; 1 H NMR (400 MHz, CDCl3) δ 7.40 – 7.28 (m, 4H), 5.12 (d, J = 5.4Hz, 1H), 4.31 – 4.10 (m, 2H), 3.75 – 3.63 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 173.35, 136.97, 134.30, 128.77, 127.98, 72.28,62.50, 14.08. Example 8 (using lignite residue from Yimin, Inner Mongolia) S1. Weigh 0.5 mmol of ethyl p-chlorophenyldiazoate and 0.8 mmol of water into a clean, dry Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 10 min. S2. Add 150 mg of lignite residue as a catalyst, react at room temperature for 1 h, then heat to 80°C. o C continues to react for 10 hours; S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reaction solution, 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 with eluent (petroleum ether (75℃) / ethyl acetate, v / v = 10∶1) to obtain a white solid α-hydroxy ester compound (3a).

[0038] In this embodiment, the target product obtained was 82 mg, with a yield of 77%.

[0039] Example 9 (using lignite residue from Hegang, Heilongjiang) S1. Weigh 0.5 mmol of ethyl p-chlorophenyldiazoate and 0.8 mmol of water into a clean, dry Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 10 min. S2. Add 150 mg of lignite residue as a catalyst, react at room temperature for 1 h, then heat to 80°C. o C continues to react for 10 hours; S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reaction solution, 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 (75℃) / ethyl acetate, v / v = 10∶1) to obtain a white solid α-hydroxy ester compound.

[0040] In this embodiment, the target product obtained was 85 mg, with a yield of 79%.

[0041] Examples 8-9 show that the catalytic efficiency of lignite residue catalysts from different origins (80% in Zhaotong, Yunnan; 77% in Yimin, Inner Mongolia; and 79% in Hegang, Heilongjiang) is not significantly different, revealing that lignite residue catalysts have universal applicability.

[0042] This invention uses water and aryl diazonium esters as raw materials and lignite residue as a catalyst. Under heating conditions and in an air atmosphere, CO bonds are constructed through an OH insertion reaction, generating α-hydroxy esters in one step. This provides an effective strategy for the synthesis of α-hydroxy ester drugs or drug skeletons.

[0043] Compared with currently reported methods for synthesizing α-hydroxy esters, 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 (the highest separation yield can reach 80%, and the product separation yield can still reach 50% after the catalyst is reused three times), enabling gram-scale reactions and showing promise for industrialization. At the same time, it realizes the reuse of waste resources, alleviating the problem of difficult lignite residue treatment to a certain extent, which is in line with the principles of green environmental protection and green chemistry.

[0044] To demonstrate the rationality and superiority of the present invention, the applicant compared the catalytic efficiency of acid catalysts, base catalysts, metal catalysts and sludge catalysts under the same reaction conditions (Comparative Examples 1-4), and also compared the reuse efficiency of lignite residue catalysts (Comparative Examples 5-7).

[0045] Comparative Example 1 (using an acid catalyst) S1. Weigh 0.5 mmol of ethyl p-chlorophenyldiazoate and 0.8 mmol of water into a clean, dry Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 10 min. S2. After adding 25 µL of trifluoromethanesulfonic acid as a catalyst, the reaction was carried out at room temperature for 1 hour, and then heated to 80 °C to continue the reaction for 10 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reaction solution, 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 with eluent (petroleum ether (75℃) / ethyl acetate, v / v = 10∶1) to obtain a white solid α-hydroxy ester compound (3a).

[0046] In this comparative example, the target product was 72 mg, with a yield of 68%.

[0047] Comparative Example 2 (using an alkaline catalyst) S1. Weigh 0.5 mmol of ethyl p-chlorophenyldiazoate and 0.8 mmol of water into a clean, dry Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 10 min. S2. After adding 25 µL of triethylamine as a catalyst, the reaction was carried out at room temperature for 1 hour, and then heated to 80°C to continue the reaction for 10 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reaction solution, 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 (75℃) / ethyl acetate, v / v = 10∶1) to obtain a white solid α-hydroxy ester compound.

[0048] In this comparative example, the target product was 44 mg, with a yield of 41%.

[0049] Comparative Example 3 (using a metal catalyst) S1. Weigh 0.5 mmol of ethyl p-chlorophenyldiazoate and 0.8 mmol of water into a clean, dry Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 10 min. S2. After adding 150 mg of ferric chloride as a catalyst, the reaction was carried out at room temperature for 1 h, and then heated to 80 °C to continue the reaction for 10 h. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reaction solution, 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 (75℃) / ethyl acetate, v / v = 10∶1) to obtain a white solid α-hydroxy ester compound.

[0050] In this comparative example, the target product was 63 mg, with a yield of 59%.

[0051] Comparative Example 4 (using sludge catalyst) Green Chem2020 22 : 1594) S1. Weigh 0.5 mmol of ethyl p-chlorophenyldiazoate and 0.8 mmol of water into a clean, dry Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 10 min. S2. After adding 150 mg of sludge as a catalyst, react at room temperature for 1 h, then heat to 80℃ and continue the reaction for 10 h. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reaction solution, 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 (75℃) / ethyl acetate, v / v = 10∶1) to obtain a white solid α-hydroxy ester compound.

[0052] In this comparative example, the target product was 56 mg, with a yield of 52%.

[0053] By comparing Comparative Examples 1-4, it was found that under the same reaction conditions, the catalytic efficiency of lignite residue catalyst (80%) was better than that of acid (75%) / base (41%) catalyst, metal catalyst (59%) and sludge catalyst (52%), highlighting the rationality of selecting lignite residue as catalyst in this invention.

[0054] Comparative Example 5 (First reuse experiment of lignite residue catalyst: Referring to Example 1, a five-fold scale-up experiment was first conducted. After the reaction was completed, the mixture was filtered, and the filter cake, i.e. the lignite residue catalyst after one use, was used for the first reuse experiment.) S1. Weigh 0.5 mmol of ethyl p-chlorophenyldiazoate and 0.8 mmol of water into a clean, dry Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 10 min. S2. After adding 150 mg of lignite residue that had been used once in Example 1 as a catalyst, the mixture was reacted at room temperature for 1 hour, and then heated to 80°C to continue the reaction for 10 hours. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reaction solution and wash the filter cake with dichloromethane until it is colorless (keep the filter cake for later use as a catalyst in the repeated experiments). Concentrate the filtrate under reduced pressure to remove volatile components and separate it by silica gel column chromatography using petroleum ether (75℃) / ethyl acetate, v / v = 10:1) to obtain a white solid α-hydroxy ester compound.

[0055] In this comparative example, the target product was 79 mg, with a yield of 74%.

[0056] Comparative Example 6 (Second reuse experiment of catalyst: referring to Example 1, first a three-fold scale-up experiment of Comparative Example 5 was carried out, and then the lignite residue catalyst used in Comparative Example 5 was used for a second reuse experiment) S1. Weigh 0.5 mmol of ethyl p-chlorophenyldiazoate and 0.8 mmol of water into a clean, dry Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 10 min. S2. Add 150 mg of lignite residue used in Comparative Example 5 as a catalyst, react at room temperature for 1 h, and then heat to 80℃ to continue the reaction for 10 h. S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reaction solution and wash the filter cake with dichloromethane until it is colorless (keep the filter cake for later use as a catalyst in the repeated experiments). Concentrate the filtrate under reduced pressure to remove volatile components and separate it by silica gel column chromatography using petroleum ether (75℃) / ethyl acetate, v / v = 10:1) to obtain a white solid α-hydroxy ester compound.

[0057] In this comparative example, the target product was 70 mg, with a yield of 65%.

[0058] Comparative Example 7 (Third Reuse Experiment of Catalyst: Referring to Example 1, a double-scale experiment of Comparative Example 6 was first conducted, and then the lignite residue catalyst used in Comparative Example 6 was used for a third reuse experiment.) S1. Weigh 0.5 mmol of ethyl p-chlorophenyldiazoate and 0.8 mmol of water into a clean, dry Schlenk reaction tube with a capacity of 25 mL. Add 5 mL of acetonitrile under air atmosphere and stir at room temperature for 10 min. S2. After adding 150 mg of lignite residue catalyst from Comparative Example 6, react at room temperature for 1 h, then heat to 80°C. o C continued to react for 10 hours; S3, TLC detection showed that the reaction of the raw materials was complete, and the reaction was stopped. S4. Filter the reaction solution, 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 (75℃) / ethyl acetate, v / v = 10∶1) to obtain a white solid α-hydroxy ester compound.

[0059] In this comparative example, the target product was 59 mg, with a yield of 55%.

[0060] The comparative experiments of lignite residue catalyst reuse in Examples 5-7 (product yield of lignite residue reuse: 74% in the first time, 65% in the second time, and 55% in the third time) highlight the practicality of lignite residue catalyst and the superiority of selecting lignite residue as catalyst in this invention.

[0061] In summary, the verification results of this invention show that, under the same reaction conditions, the product yields obtained by Comparative Examples 1-4 using other acid or base catalysts, metal catalysts or sludge catalysts are all lower than the product yields obtained by the lignite residue catalyst used in this application.

[0062] 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 80%), enabling gram-scale reactions and showing promise for industrialization. Simultaneously, it achieves the recycling of waste resources (the lignite residue catalyst can be reused three times, and the product separation yield can still reach over 50%), and alleviates the difficulty of lignite residue disposal to some extent, aligning with the principles of green environmental protection and green chemistry. Furthermore, this invention provides a new approach to catalyst selection in organic synthesis and an effective method for the synthesis of α-hydroxy ester drugs or drug skeletons.

[0063] 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. Application of lignite residue as a catalyst for the generation of α-hydroxy ester compounds.

2. The application according to claim 1 further includes a method for synthesizing α-hydroxy ester compounds, characterized in that: The synthesis method includes the following steps: S1. Mix water and aryl diazonium ester compounds, and then add acetonitrile under air atmosphere and stir. S2. Add lignite residue as a catalyst to catalyze the reaction. First, react at room temperature for 1 hour, then raise the temperature to 80℃ and continue the reaction for 8-10 hours. S3, the reaction is stopped when the TLC detection shows that the reaction is complete; S4. Filter the reaction liquid, wash the filter cake with dichloromethane until colorless, remove the volatile components from the filtrate under reduced pressure, and then separate by silica gel column chromatography to obtain α-hydroxy ester compounds.

3. The method for synthesizing an α-hydroxy ester compound according to claim 2, characterized in that: The aryl diazonium ester compound is any one of ethyl p-chlorophenyldiazoacetate, ethyl p-bromophenyldiazoacetate, ethyl phenyldiazoacetate, and phenyldiazoacetic acid benzyl ester.

4. The method for synthesizing an α-hydroxy ester compound according to claim 3, characterized in that: In step S1, the volume ratio of water to aryl diazonium ester compound is 8:5; the amount of lignite residue used is 150-200 mg.

5. The method for synthesizing an α-hydroxy ester compound according to claim 4, characterized in that: In step S1, the stirring time after the acetonitrile is added is 5-10 minutes.

6. The method for synthesizing an α-hydroxy ester compound according to claim 5, characterized in that: The entire reaction process is carried out in an air atmosphere, without the need for nitrogen or other inert gas protection.

7. The method for synthesizing an α-hydroxy ester compound according to claim 6, characterized in that: In step S4, the eluent used in the silica gel column chromatography separation is composed of petroleum ether and ethyl acetate in a volume ratio of 10:1, and the boiling point of the petroleum ether is 60-90℃.

8. The method for synthesizing an α-hydroxy ester compound according to claim 2, characterized in that: The synthetic route is shown in the following reaction equation: 。 9. The method for synthesizing an α-hydroxy ester compound according to claim 8, characterized in that: In the reaction formula, R 1 It is one or more of hydrogen, methyl, ethyl, methoxy, acyl, halogen, and trifluoromethyl, wherein the halogen is F, Cl, Br, or I; R 2 It is one or more of methyl, ethyl, allyl, phenyl or alkyl.

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