A method for preparing 3,5-dihydroxytoluene
Using ethyl acetoacetate and acetaldehyde as raw materials, 3,5-dihydroxytoluene was successfully prepared under normal pressure via Knoevenagel condensation, Michael addition, and Claisen condensation reactions, combined with catalytic dehydrogenation. This solved the problems of harsh reaction conditions and high equipment requirements in existing technologies, and achieved high-yield and low-cost industrial production.
Patent Information
- Application Number
- CN202610505798.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-04-16
- Publication Date
- 2026-05-26
AI Technical Summary
Existing methods for preparing 3,5-dihydroxytoluene suffer from problems such as harsh reaction conditions, high equipment requirements, and significant safety and environmental concerns, and also have high industrialization costs.
Using ethyl acetoacetate and acetaldehyde as raw materials, 3-ethoxycarbonyl-3-penten-2-one was generated by Knoevenagel condensation reaction, followed by Michael addition and intramolecular Claisen condensation reaction to obtain 5-methylcyclohexane-1,3-dione, and finally 3,5-dihydroxytoluene was prepared by catalytic dehydrogenation reaction.
This method enables the preparation of 3,5-dihydroxytoluene under normal pressure and mild conditions, avoiding the need for high-pressure hydrogenation equipment, reducing energy consumption and safety risks, simplifying the operation process, and improving the yield and industrial application prospects.
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Figure CN122079747A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of fine chemical intermediate synthesis technology, and relates to a method for preparing 3,5-dihydroxytoluene. Background Technology
[0002] 3,5-Dihydroxytoluene (5-methyl-1,3-benzenediol), also known as orcinol, with the molecular formula C7H8O2, is an important fine chemical intermediate. In the pharmaceutical industry, it is a key intermediate for the synthesis of anti-inflammatory drugs, resveratrol, and coumarin, among other active molecules. In analytical chemistry, 3,5-dihydroxytoluene can be used as a colorimetric reagent for the colorimetric determination of serum sialic acid and surface sugars in cotton fibers. In materials science, the synthesis and performance research of biodegradable polyesters based on 3,5-dihydroxytoluene have also attracted widespread attention.
[0003] Currently, there are two main industrial methods for preparing 3,5-dihydroxytoluene: Route 1: Synthesizing p-toluidine from p-toluidine via a multi-step reaction involving nitration, diazotization, catalytic hydrogenation, and hydrolysis, or via a multi-step reaction involving sulfonation, diazotization, hydrolysis, and acidification. This route is complex, involves diazotization, and presents safety risks and environmental challenges.
[0004] Route 2: Using methyl 3,5-dihydroxybenzoate as a raw material, selective hydrogenation and decarboxylation are carried out via CuO-ZnO or Cu-Zn-Al catalysts, achieving a yield of up to 87%. Although this method yields a high yield, it requires high temperature (200℃) and high pressure (8~9 MPa) conditions, placing high demands on equipment, complicating catalyst preparation, and resulting in high industrialization costs.
[0005] In addition, there are literature reports on a method for preparing phenol from m-toluenesulfonic acid through sulfonation, alkali fusion and other steps. However, this process requires alkali fusion reaction at a high temperature of 300~400℃, which consumes a lot of energy and generates a large amount of sulfur-containing wastewater.
[0006] To address the shortcomings of existing technologies, developing a method for preparing 3,5-dihydroxytoluene that uses inexpensive and readily available raw materials, operates under mild conditions, is simple to operate, and is suitable for industrial production has significant economic value and practical implications. Summary of the Invention
[0007] The purpose of this invention is to provide a method for preparing 3,5-dihydroxytoluene, so as to overcome the problems of harsh reaction conditions, high equipment requirements, and great pressure on safety and environmental protection in the prior art.
[0008] The technical solution of this invention: A method for preparing 3,5-dihydroxytoluene includes the following steps: (1) Preparation of 3-ethoxycarbonyl-3-penten-2-one: 3-ethoxycarbonyl-3-penten-2-one was generated by Knoevenagel condensation reaction using ethyl acetoacetate and acetaldehyde as raw materials; (2) Preparation of 5-methylcyclohexane-1,3-dione: 3-ethoxycarbonyl-3-penten-2-one obtained in step (1) was reacted with dimethyl malonate under alkaline conditions by Michael addition and intramolecular Claisen condensation reaction, followed by hydrolysis and decarboxylation to obtain 5-methylcyclohexane-1,3-dione. (3) Preparation of 3,5-dihydroxytoluene: 3,5-dihydroxytoluene was obtained by catalytic dehydrogenation of the 5-methylcyclohexane-1,3-dione obtained in step (2).
[0009] Further, the molar ratio of ethyl acetoacetate and acetaldehyde in step (1) is 1:1 to 1:1.5, preferably 1:1.1.
[0010] Further, the ethyl acetoacetate mentioned in step (1) is replaced with methyl acetoacetate, propyl acetoacetate, or butyl acetoacetate.
[0011] Furthermore, the Knoevenagel condensation reaction described in step (1) is carried out in an organic solvent, which is one or more of dichloromethane, acetonitrile, tetrahydrofuran, methanol, and ethanol, preferably tetrahydrofuran.
[0012] Furthermore, the Knoevenagel condensation reaction described in step (1) requires the addition of a catalyst, which is pyridine or piperidine, and the molar ratio of the catalyst to acetaldehyde is 0.01:1 to 0.3:1, preferably 0.1:1.
[0013] Furthermore, the temperature of the Knoevenagel condensation reaction in step (1) is -10~30℃, and the reaction time is 2~10 hours.
[0014] Further, the alkaline condition in step (2) uses sodium methoxide and / or sodium ethoxide as the base; the molar ratio of the base to 3-ethoxycarbonyl-3-penten-2-one is 0.5:1 to 2:1, preferably 1:1 to 1.1:1.
[0015] Further, in step (2), the molar ratio of dimethyl malonate to 3-ethoxycarbonyl-3-penten-2-one is 0.5:1 to 2:1, preferably 1:1 to 1.1:1.
[0016] Furthermore, the solvent used in step (2) Michael addition and intramolecular Claisen condensation reaction is selected from one or more of tetrahydrofuran, methanol, and ethanol, with methanol being preferred.
[0017] Furthermore, the temperature of the Michael addition and intramolecular Claisen condensation reaction in step (2) is 10~60℃, preferably 50~60℃; the reaction time is 2~16 hours.
[0018] Furthermore, the hydrolysis conditions described in step (2) are acidic or alkaline conditions, and the acid used is one or more of hydrochloric acid, sulfuric acid, and phosphoric acid, and the alkali used is sodium hydroxide and / or potassium hydroxide.
[0019] Furthermore, the decarboxylation conditions described in step (2) are acidic conditions, and the acid used is selected from one or more of hydrochloric acid, sulfuric acid, and phosphoric acid.
[0020] Furthermore, the reaction in step (3) is carried out in an organic solvent, which is selected from one or more of toluene and xylene, preferably xylene.
[0021] Further, the catalyst used in the catalytic dehydrogenation reaction in step (3) is palladium on carbon, wherein the palladium content is 3 wt%, 5 wt% or 10 wt%; the molar ratio of the palladium content in the catalyst to 5-methylcyclohexane-1,3-dione is 0.01:1 to 0.5:1, preferably 0.05:1 to 0.1:1.
[0022] Furthermore, the temperature of the catalytic dehydrogenation reaction in step (3) is 80~150℃, preferably 120~140℃. The reaction time is 2~20 hours.
[0023] The beneficial effects of this invention are: (1) Raw material advantages: This invention uses bulk chemical raw materials such as ethyl acetoacetate, acetaldehyde, and dimethyl malonate as starting materials, which are inexpensive and have a stable supply, avoiding the use of toxic raw materials such as p-toluidine or expensive fine chemicals such as methyl 3,5-dihydroxybenzoate.
[0024] (2) Mild reaction conditions: The entire synthesis route is carried out under normal pressure and -10℃~150℃ conditions. No special equipment such as high-pressure hydrogenation is required. The equipment requirements are low, the safety is high, and the energy consumption is low.
[0025] (3) Simple operation: Each step of the reaction is a classic organic reaction, the process is mature and stable, there are few side reactions, and the intermediates are easy to separate and purify. In particular, the Michael addition and intramolecular Claisen condensation in step (2) can be completed in one pot, which simplifies the operation process.
[0026] (4) High yield: The total yield of the method of the present invention can reach more than 64%, which has good economic benefits and industrial application prospects.
[0027] (5) Environmental advantages: The method of the present invention does not use diazotization reaction, thus avoiding the generation of amine-containing wastewater and reducing the discharge of waste gas, wastewater, and solid waste. Attached Figure Description
[0028] Figure 1 It is the 5-methyl-1,3-cyclohexanedione in Example 1. 1 H NMR spectrum.
[0029] Figure 2 It is the 3,5-dihydroxytoluene in Example 1. 1 H NMR spectrum. Detailed Implementation
[0030] The specific embodiments of the present invention will be further described below with reference to the accompanying drawings and technical solutions.
[0031] Example 1: Step 1: Synthesis of 3-ethoxycarbonyl-3-penten-2-one; Ethyl acetoacetate (6.51 g, 50 mmol, 1.0 equiv.), tetrahydrofuran (13.02 g), and piperidine (0.43 g, 5 mmol, 0.1 equiv.) were added to a 50 mL reaction vessel. The mixture was cooled to 0–10 °C, and acetaldehyde (2.20 g, 50 mmol, 1.0 equiv.) was added dropwise. The mixture was stirred and kept at this temperature for 4 hours. The solvent was removed by vacuum distillation to obtain crude 3-ethoxycarbonyl-3-penten-2-one (7.9 g). This was used directly in the next reaction step.
[0032] Step 2: Synthesis of 5-methylcyclohexane-1,3-dione; Sodium methoxide (2.70 g, 50 mmol, 1.0 equiv.) and methanol (15.30 g) were added to a 100 mL reaction vessel. Dimethyl malonate (6.61 g, 50 mmol, 1.0 equiv.) was added, followed by the dropwise addition of crude 3-ethoxycarbonyl-3-penten-2-one (7.9 g) obtained in the first step. The mixture was slowly heated to 50–60 °C and maintained at this temperature for 2 hours. The methanol was removed by vacuum distillation to 60 °C. Water (50 g) and sodium hydroxide (8 g) were added, and the mixture was heated to 60–70 °C and maintained at this temperature for 4 hours. Then, 36% hydrochloric acid (25 g) was added, and the mixture was maintained at 60–70 °C for 3 hours. The mixture was cooled to room temperature, filtered, and dried to obtain 5-methylcyclohexane-1,3-dione (5.3 g, 84%), a white solid. 11H NMR (400 MHz, CDCl3): Major isomer (enol form) d 10.86 (br s, 1H), 5.48 (s,1H), 2.76-2.34 (m, 4H), 2.28-2.09 (m, 1H), 1.10 (d, J = 6.4 Hz, 3H); minor isomer (keto form) d 3.39 (s, 2H), 1.12 (d, J = 6.8 Hz, 3H), the remaining signal overlaps with the enol form. The integration ratio (enol form: keto form) is approximately 64:36.
[0033] Step 3: Synthesis of 3,5-dihydroxytoluene; 5-Methylcyclohexane-1,3-dione (0.63 g, 5 mmol, 1.0 equiv.), 5% palladium on carbon (0.53 g, 0.25 mmol Pd, 0.05 equiv.), and xylene (10 mL) were added to a 50 mL reaction vessel. The temperature was raised to 130–140 °C, and the reaction was maintained at this temperature for 8 hours. The reaction solution was filtered to remove the catalyst and evaporated to dryness. The residue was purified by silica gel column chromatography to give 3,5-dihydroxytoluene (0.46 g, 74%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6): d 9.03 (br s, 2H), 6.01 (s,1H), 6.01 (s, 2H), 2.11 (s, 3H). Example 2: Step 1: Synthesis of 3-ethoxycarbonyl-3-penten-2-one; Ethyl acetoacetate (6.51 g, 50 mmol, 1.0 equiv.), tetrahydrofuran (13.02 g), and piperidine (0.21 g, 2.5 mmol, 0.05 equiv.) were added to a 50 mL reaction vessel. The mixture was cooled to 10–20 °C, and acetaldehyde (2.20 g, 50 mmol, 1.0 equiv.) was added dropwise. The mixture was stirred and kept at this temperature for 8 hours. The solvent was removed by vacuum distillation to obtain crude 3-ethoxycarbonyl-3-penten-2-one (7.7 g). This crude product was used directly in the next reaction step.
[0034] Step 2: Synthesis of 5-methylcyclohexane-1,3-dione; Sodium methoxide (2.70 g, 50 mmol, 1.0 equiv.) and methanol (15.30 g) were added to a 100 mL reaction vessel. Dimethyl malonate (6.61 g, 50 mmol, 1.0 equiv.) was added, followed by the dropwise addition of crude 3-ethoxycarbonyl-3-penten-2-one (7.7 g) obtained in the first step. The mixture was slowly heated to 30–40 °C and maintained at this temperature for 8 hours. The methanol was removed by vacuum distillation to 60 °C. Water (50 g) and 36% hydrochloric acid (25 g) were added, and the reaction was maintained at 60–70 °C for 10 hours. The mixture was cooled to room temperature, filtered, and purified by silica gel column chromatography to obtain 5-methylcyclohexane-1,3-dione (4.6 g, 73%) as a white solid. 1 1H NMR (400 MHz, CDCl3): Major isomer (enol form) d 10.86 (br s, 1H), 5.48 (s, 1H), 2.76-2.34 (m, 4H), 2.28-2.09(m, 1H), 1.10 (d, J = 6.4 Hz, 3H); minor isomer (keto form) d 3.39 (s, 2H), 1.12 (d, J = 6.8Hz, 3H), the remaining signals overlap with the enol form. The integration ratio (enol form: keto form) is approximately 64:36.
[0035] Step 3: Synthesis of 3,5-dihydroxytoluene; 5-Methylcyclohexane-1,3-dione (0.63 g, 5 mmol, 1.0 equiv.), 10% palladium on carbon (0.27 g, 0.25 mmol Pd, 0.05 equiv.), and xylene (10 mL) were added to a 50 mL reaction vessel. The mixture was heated to 130–140 °C and reacted for 8 hours. The reaction solution was filtered to remove the catalyst and evaporated to dryness. The residue was purified by silica gel column chromatography to give 3,5-dihydroxytoluene (0.47 g, 76%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6): d 9.03 (br s, 2H), 6.01 (s,1H), 6.01 (s, 2H), 2.11 (s, 3H). Example 3: Step 1: Synthesis of 3-ethoxycarbonyl-3-penten-2-one; Ethyl acetoacetate (13.01 g, 0.1 mol, 1.0 equiv.), tetrahydrofuran (26.02 g), and piperidine (0.85 g, 0.01 mol, 0.1 equiv.) were added to a 100 mL reaction vessel. The mixture was cooled to 0–10 °C, and acetaldehyde (4.85 g, 0.11 mol, 1.1 equiv.) was added dropwise. The mixture was stirred and kept at this temperature for 4 hours. The solvent was removed by vacuum distillation to obtain crude 3-ethoxycarbonyl-3-penten-2-one (16.0 g). This crude product was used directly in the next reaction.
[0036] Step 2: Synthesis of 5-methylcyclohexane-1,3-dione; Sodium methoxide (5.40 g, 0.1 mol, 1.0 equiv.) and methanol (48.60 g) were added to a 250 mL reactor. Dimethyl malonate (13.21 g, 0.1 mol, 1.0 equiv.) was added, followed by the dropwise addition of crude 3-ethoxycarbonyl-3-penten-2-one (16.0 g) obtained in the first step. The mixture was slowly heated to 50–60 °C and maintained at this temperature for 2 hours. The methanol was removed by vacuum distillation to 60 °C. Water (100 g) and sodium hydroxide (16 g) were added, and the mixture was heated to 60–70 °C and maintained at this temperature for 4 hours. Then, 36% hydrochloric acid (50 g) was added, and the mixture was maintained at 60–70 °C for 3 hours. The mixture was cooled to room temperature and filtered to obtain 5-methylcyclohexane-1,3-dione (11.0 g, 87%), a white solid. 1 1H NMR (400 MHz, CDCl3): Major isomer (enol form) d 10.86 (br s, 1H), 5.48 (s,1H), 2.76-2.34 (m, 4H), 2.28-2.09 (m, 1H), 1.10 (d, J = 6.4 Hz, 3H); minor isomer (keto form) d 3.39 (s, 2H), 1.12 (d, J = 6.8 Hz, 3H), the remaining signal overlaps with the enol form. The integration ratio (enol form: keto form) is approximately 64:36.
[0037] Step 3: Synthesis of 3,5-dihydroxytoluene; 5-Methylcyclohexane-1,3-dione (6.31 g, 50 mmol, 1.0 equiv.), 5% palladium on carbon (5.32 g, 2.5 mmol Pd, 0.05 equiv.), and xylene (100 mL) were added to a 250 mL reaction vessel. The temperature was raised to 130–140 °C, and the reaction was maintained at this temperature for 10 hours. The reaction solution was filtered to remove the catalyst and evaporated to dryness. The residue was purified by silica gel column chromatography to give 3,5-dihydroxytoluene (4.60 g, 74%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6): d 9.03 (br s, 2H), 6.01 (s, 1H), 6.01 (s, 2H), 2.11 (s, 3H). Example 4: Example 4 is the same as Example 3 except for the third step.
[0038] Step 3: Synthesis of 3,5-dihydroxytoluene 5-Methylcyclohexane-1,3-dione (0.63 g, 5 mmol, 1.0 equiv.), 5% palladium on carbon (0.53 g, 0.25 mmol Pd, 0.05 equiv.), and toluene (10 mL) were added to a 50 mL reaction vessel. The mixture was heated to 90–110 °C and reacted for 16 hours. The reaction solution was filtered to remove the catalyst and evaporated to dryness. The residue was purified by silica gel column chromatography to give 3,5-dihydroxytoluene (0.42 g, 68%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6): d 9.03 (br s, 2H), 6.01 (s,1H), 6.01 (s, 2H), 2.11 (s, 3H). Example 5: Step 1: Synthesis of 3-ethoxycarbonyl-3-penten-2-one; Ethyl acetoacetate (6.51 g, 50 mmol, 1.0 equiv.), tetrahydrofuran (13.02 g), and pyridine (0.40 g, 5 mmol, 0.1 equiv.) were added to a 50 mL reaction vessel. The mixture was cooled to 0–10 °C, and acetaldehyde (2.20 g, 50 mmol, 1.0 equiv.) was added dropwise. The mixture was stirred and kept at this temperature for 4 hours. The solvent was removed by vacuum distillation to obtain crude 3-ethoxycarbonyl-3-penten-2-one (7.8 g). This was used directly in the next reaction step.
[0039] Step 2: Synthesis of 5-methylcyclohexane-1,3-dione; Sodium methoxide (2.70 g, 50 mmol, 1.0 equiv.) and methanol (15.30 g) were added to a 100 mL reaction vessel. Dimethyl malonate (6.61 g, 50 mmol, 1.0 equiv.) was added, followed by the dropwise addition of crude 3-ethoxycarbonyl-3-penten-2-one (7.8 g) obtained in the first step. The mixture was slowly heated to 40–50 °C and maintained at this temperature for 6 hours. The methanol was removed by vacuum distillation to 60 °C. Water (50 g) and potassium hydroxide (11.2 g) were added, and the mixture was heated to 60–70 °C and maintained at this temperature for 4 hours. Sulfuric acid (24 g) was then added, and the mixture was maintained at 60–70 °C for 3 hours. The mixture was cooled to room temperature, filtered, and dried to obtain 5-methylcyclohexane-1,3-dione (5.2 g, 83%), a white solid. 1 1H NMR (400 MHz, CDCl3): Major isomer (enol form) d 10.86 (br s, 1H), 5.48 (s,1H), 2.76-2.34 (m, 4H), 2.28-2.09 (m, 1H), 1.10 (d, J = 6.4 Hz, 3H); minor isomer (keto form) d 3.39 (s, 2H), 1.12 (d, J = 6.8 Hz, 3H), the remaining signal overlaps with the enol form. The integration ratio (enol form: keto form) is approximately 64:36.
[0040] The third step is the same as in Example 1.
[0041] Example 6: Step 1: Synthesis of 3-ethoxycarbonyl-3-penten-2-one; Ethyl acetoacetate (6.51 g, 50 mmol, 1.0 equiv.), dichloromethane (13.02 g), and piperidine (0.43 g, 5 mmol, 0.1 equiv.) were added to a 50 mL reaction vessel. The mixture was cooled to 0–10 °C, and acetaldehyde (2.20 g, 50 mmol, 1.0 equiv.) was added dropwise. The mixture was stirred and kept at this temperature for 4 hours. The solvent was removed by vacuum distillation to obtain crude 3-ethoxycarbonyl-3-penten-2-one (7.6 g). This crude product was used directly in the next reaction step.
[0042] Step 2: Synthesis of 5-methylcyclohexane-1,3-dione; Sodium methoxide (2.70 g, 50 mmol, 1.0 equiv.) and methanol (24.30 g) were added to a 100 mL reaction vessel. Dimethyl malonate (6.61 g, 50 mmol, 1.0 equiv.) was added, followed by the addition of crude 3-ethoxycarbonyl-3-penten-2-one (7.6 g) obtained in the first step. The mixture was slowly heated to 50–60 °C and maintained at this temperature for 2 hours. The methanol was removed by vacuum distillation to 60 °C. Water (50 g) and sodium hydroxide (8 g) were added, and the mixture was heated to 60–70 °C and maintained at this temperature for 4 hours. Then, 36% hydrochloric acid (25 g) was added, and the mixture was maintained at 60–70 °C for 3 hours. The mixture was cooled to room temperature, filtered, and purified by silica gel column chromatography to obtain 5-methylcyclohexane-1,3-dione (4.5 g, 71%) as a white solid. 1 1H NMR (400 MHz, CDCl3): Major isomer (enol form) d 10.86 (br s,1H), 5.48 (s, 1H), 2.76-2.34 (m, 4H), 2.28-2.09 (m, 1H), 1.10 (d, J = 6.4 Hz, 3H); minor isomer (keto form) d 3.39 (s, 2H), 1.12 (d, J = 6.8 Hz, 3H), the remaining signal overlaps with the enol form. The integration ratio (enol form: keto form) is approximately 64:36.
[0043] The third step is the same as in Example 1.
[0044] Example 7: Example 7 is the same as Example 1 except for the second step.
[0045] Step 2: Synthesis of 5-methylcyclohexane-1,3-dione Sodium ethoxide (3.40 g, 50 mmol, 1.0 equiv.) and ethanol (19.27 g) were added to a 100 mL reaction vessel. Dimethyl malonate (6.61 g, 50 mmol, 1.0 equiv.) was added, followed by the addition of crude 3-ethoxycarbonyl-3-penten-2-one (7.9 g) obtained in the first step. The mixture was slowly heated to 50–60 °C and maintained at this temperature for 2 hours. Methanol was removed by vacuum distillation to 60 °C. Water (50 g) and sodium hydroxide (8 g) were added, and the mixture was heated to 60–70 °C and maintained at this temperature for 4 hours. Then, 36% hydrochloric acid (25 g) was added, and the mixture was maintained at 60–70 °C for 3 hours. The mixture was cooled to room temperature, filtered, and purified by silica gel column chromatography to obtain 5-methylcyclohexane-1,3-dione (4.2 g, 67%) as a white solid. 1 1H NMR (400 MHz, CDCl3): Major isomer (enol form) d 10.86 (br s,1H), 5.48 (s, 1H), 2.76-2.34 (m, 4H), 2.28-2.09 (m, 1H), 1.10 (d, J = 6.4 Hz, 3H); minor isomer (keto form) d 3.39 (s, 2H), 1.12 (d, J = 6.8 Hz, 3H), the remaining signal overlaps with the enol form. The integration ratio (enol form: keto form) is approximately 64:36.
[0046] Example 8: Step 1: Synthesis of 3-ethoxycarbonyl-3-penten-2-one; Ethyl acetoacetate (6.51 g, 50 mmol, 1.0 equiv.), tetrahydrofuran (13.02 g), and piperidine (0.43 g, 5 mmol, 0.1 equiv.) were added to a 50 mL reaction vessel. The mixture was cooled to -10 to 0 °C, and acetaldehyde (2.42 g, 55 mmol, 1.1 equiv.) was added dropwise. The mixture was stirred and kept at this temperature for 4 hours. The solvent was removed by vacuum distillation to obtain crude 3-ethoxycarbonyl-3-penten-2-one (8.0 g). This crude product was used directly in the next reaction step.
[0047] Step 2: Synthesis of 5-methylcyclohexane-1,3-dione; Sodium methoxide (2.70 g, 50 mmol, 1.0 equiv.) and methanol (15.30 g) were added to a 100 mL reaction vessel. Dimethyl malonate (6.61 g, 50 mmol, 1.0 equiv.) was added, followed by the addition of crude 3-ethoxycarbonyl-3-penten-2-one (8.0 g) obtained in the first step. The mixture was kept at 10–20 °C for 16 hours. The methanol was removed by vacuum distillation to 60 °C. Water (50 g) and sodium hydroxide (8 g) were added, and the mixture was heated to 60–70 °C and reacted for 4 hours. Then, 36% hydrochloric acid (25 g) was added, and the mixture was kept at 60–70 °C for 3 hours. The mixture was cooled to room temperature, filtered, and purified by silica gel column chromatography to obtain 5-methylcyclohexane-1,3-dione (4.3 g, 68%) as a white solid. 1 1H NMR (400 MHz, CDCl3): Major isomer (enol form) d 10.86 (br s, 1H), 5.48 (s,1H), 2.76-2.34 (m, 4H), 2.28-2.09 (m, 1H), 1.10 (d, J = 6.4 Hz, 3H); minor isomer (keto form) d 3.39 (s, 2H), 1.12 (d, J = 6.8 Hz, 3H), the remaining signal overlaps with the enol form. The integration ratio (enol form: keto form) is approximately 64:36.
[0048] Step 3: Synthesis of 3,5-dihydroxytoluene; 5-Methylcyclohexane-1,3-dione (0.63 g, 5 mmol, 1.0 equiv.), 3% palladium on carbon (1.78 g, 0.5 mmol Pd, 0.1 equiv.), and xylene (10 mL) were added to a 50 mL reaction vessel. The mixture was heated to 130–140 °C and reacted for 8 hours. The reaction solution was filtered to remove the catalyst and evaporated to dryness. The residue was purified by silica gel column chromatography to give 3,5-dihydroxytoluene (0.41 g, 66%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6): d 9.03 (br s, 2H), 6.01 (s,1H), 6.01 (s, 2H), 2.11 (s, 3H). The methods described in this invention are illustrative only through preferred embodiments. Those skilled in the art, based on their understanding of the content, spirit, and scope of this invention, can reasonably adjust, combine, or improve the relevant process parameters to practically apply the technology of this invention. The specific embodiments in the specification are for detailed explanation but do not constitute a limitation of this invention. Any obvious substitutions or modifications made based on the principles of this invention, as well as improvements and modifications obtained without departing from the spirit of this invention, should fall within the protection scope of the claims of this invention.
Claims
1. A method for preparing 3,5-dihydroxytoluene, characterized in that, Includes the following steps: (1) Preparation of 3-ethoxycarbonyl-3-penten-2-one: 3-ethoxycarbonyl-3-penten-2-one was generated by Knoevenagel condensation reaction using ethyl acetoacetate and acetaldehyde as raw materials; (2) Preparation of 5-methylcyclohexane-1,3-dione: 3-ethoxycarbonyl-3-penten-2-one obtained in step (1) was reacted with dimethyl malonate under alkaline conditions by Michael addition and intramolecular Claisen condensation reaction, followed by hydrolysis and decarboxylation to obtain 5-methylcyclohexane-1,3-dione. (3) Preparation of 3,5-dihydroxytoluene: 3,5-dihydroxytoluene was obtained by catalytic dehydrogenation of the 5-methylcyclohexane-1,3-dione obtained in step (2).
2. The method for preparing 3,5-dihydroxytoluene according to claim 1, characterized in that, In step (1) The molar ratio of ethyl acetoacetate to acetaldehyde is 1:1 to 1:1.5; The ethyl acetoacetate is replaced with methyl acetoacetate, propyl acetoacetate, or butyl acetoacetate. The Knoevenagel condensation reaction is carried out in an organic solvent, which is one or a mixture of two or more of dichloromethane, acetonitrile, tetrahydrofuran, methanol, and ethanol. The Knoevenagel condensation reaction requires the addition of a catalyst, which is pyridine or piperidine, and the molar ratio of the catalyst to acetaldehyde is 0.01:1 to 0.3:
1. The Knoevenagel condensation reaction is carried out at a temperature of -10 to 30°C for 2 to 10 hours.
3. The method for preparing 3,5-dihydroxytoluene according to claim 1, characterized in that, In step (2) The alkaline conditions used are sodium methoxide and / or sodium ethoxide; the molar ratio of the base to 3-ethoxycarbonyl-3-penten-2-one is 0.5:1 to 2:
1. The molar ratio of dimethyl malonate to 3-ethoxycarbonyl-3-penten-2-one is 0.5:1 to 2:1; The solvents used in Michael addition and intramolecular Claisen condensation reactions are selected from one or more of tetrahydrofuran, methanol, and ethanol; The Michael addition and intramolecular Claisen condensation reactions are carried out at temperatures of 10–60 °C and for 2–16 hours. The hydrolysis conditions used are acidic or alkaline, and the acid used is one or more of hydrochloric acid, sulfuric acid, and phosphoric acid, and the base used is sodium hydroxide and / or potassium hydroxide. The decarboxylation conditions used are acidic conditions, and the acid used is selected from one or more of hydrochloric acid, sulfuric acid, and phosphoric acid.
4. The method for preparing 3,5-dihydroxytoluene according to claim 1, characterized in that, In step (3) The reaction is carried out in an organic solvent, wherein the organic solvent is selected from one or more of toluene and xylene; The catalyst used in the catalytic dehydrogenation reaction is palladium on carbon, wherein the palladium content is 3 wt%, 5 wt%, or 10 wt%; the molar ratio of palladium content in the catalyst to 5-methylcyclohexane-1,3-dione is 0.01:1 to 0.5:
1. The catalytic dehydrogenation reaction is carried out at a temperature of 80-150°C for 2-20 hours.