Synthesis method of 2, 3-dimethyl-1, 4-dihydronaphthalene-1, 4-diketone
Through the combined reaction of menadione, concentrated sulfuric acid, ferrous sulfate and tert-butyl hydroperoxide, the high cost problem of methylation and alkylation of quinone compounds was solved, and a high-yield synthesis was achieved, which is suitable for large-scale production.
Patent Information
- Application Number
- CN202510851011.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-24
- Publication Date
- 2025-09-09
AI Technical Summary
Existing methylation and alkylation methods for quinone compounds are costly and complex to operate, making large-scale production difficult.
Menadione, concentrated sulfuric acid, ferrous sulfate and tert-butyl hydroperoxide are reacted in methylcyclohexane solvent, methylation is carried out through a free radical mechanism, and the reaction conditions are controlled to improve the yield.
The high-yield synthesis of quinone compounds is achieved, which is suitable for gram to kilogram production, reduces production costs, and is suitable for commercial applications.
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Figure CN120607438A_ABST
Abstract
Description
Technical Field
[0001] The present application relates to the technical field of organic synthesis, and more specifically, to a method for synthesizing 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione. Background Art
[0002] Quinones are the core building blocks of many natural products and drugs. Due to their unique structure and electron transport properties, quinones are widely used as drugs, oxidants, dyes, ligands, and intermediates in organic synthesis. Methylated and alkyl-substituted quinones exhibit good biological activities, such as plumbagin and thymolquinone, which have anticancer properties, parvaquone, which is used in the treatment of malaria, vitamins K1 and K3, which have excellent coagulation properties, and coenzyme Q. 10 Studies have shown that small changes in the structure of quinones can significantly affect the potency of their biological activity, so developing synthetic methods for diverse quinone compound libraries will help evaluate structure-activity relationships.
[0003] Currently, the methylation and alkylation of quinones are usually achieved by the classic Minisci reaction or silver-mediated carboxylic acid alkylation method, but the reagents used are expensive, the operation is difficult, and large-scale production is not possible. Summary of the Invention
[0004] In order to reduce the production cost of methylation and alkylation of quinones, the present application provides a method for synthesizing 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione.
[0005] A method for synthesizing 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione comprises the following steps: Menadione, concentrated sulfuric acid, ferrous sulfate and an organic solvent are mixed to obtain a mixed solution; tert-butyl hydroperoxide is added to the mixed solution at 80-120° C. under a nitrogen atmosphere, and the mixture is stirred for reaction for 1-15 hours to obtain a reaction solution; and the reaction solution is post-treated to obtain 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione.
[0006] By adopting the above technical solution, since menadione (vitamin K3) relies on the oxidation of concentrated sulfuric acid, ferrous sulfate participates in the synergistic application, and tert-butyl hydroperoxide participates in its methylation modification through a free radical mechanism, a better methylation effect is obtained and the target product is successfully synthesized.
[0007] Preferably, the organic solvent is methylcyclohexane, 1,4-dioxane, acetonitrile, tetrahydrofuran or toluene.
[0008] By adopting the above technical solution, in the synthesis method of the present application, methylcyclohexane is the best solvent. The main reason is that methylcyclohexane provides an aprotic solvent, which is more likely to promote free radical reactions under reflux. Other solvents such as 1,4-dioxane, tetrahydrofuran, toluene, etc. have relatively poor reaction yields.
[0009] Preferably, the feeding ratio of the menadione and the organic solvent is 1 g: (5-10) mL.
[0010] By adopting the above technical solution, menadione and the organic solvent are fed into the reaction according to the above feeding ratio, the reaction effect is better, the post-treatment is more convenient, the purification is simple, and the yield is higher.
[0011] Preferably, the molar ratio of the menadione, concentrated sulfuric acid, ferrous sulfate and tert-butyl hydroperoxide is 1:(1-3):(0.01-0.03):(2-5).
[0012] Preferably, the purity of the concentrated sulfuric acid is 50%, and the molar ratio of the menadione to the concentrated sulfuric acid is 1:(2-3).
[0013] During the synthesis process, the concentration and equivalents of the acid were screened. When 2 equivalents of concentrated sulfuric acid were added, a black solid solid formed at the bottom of the reaction solution, the reaction solution was uneven, and the reaction yield decreased slightly. By adopting the above technical solution, the concentration of concentrated sulfuric acid was changed to 50%, and the yield increased to 66%. When the concentration was increased to 3 equivalents, the target product was obtained with a yield of 75%. It is speculated that the increase in equivalents may be more conducive to protonation in the subsequent reaction, promoting the reaction.
[0014] Preferably, the organic solvent is methylcyclohexane; the feed ratio of the menadione and methylcyclohexane is 1 g:7 mL; the purity of the concentrated sulfuric acid is 50%, and the molar ratio of the menadione and concentrated sulfuric acid is 1:3.
[0015] By adopting the above technical solution, the above raw materials are fed into the reaction according to the above feeding ratio, the post-processing is more convenient, the yield of the obtained 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione is higher, and it is more suitable for large-scale production.
[0016] Preferably, the post-treatment of the reaction solution comprises the following steps: The reaction solution was cooled to room temperature, solid precipitated, and filtered. The solid was dissolved with an organic solvent, washed with water and saturated brine in sequence, and the organic phase was collected; the organic phase was dried and concentrated, and then slurried with petroleum ether, filtered, and the slurried solid was collected; the slurried solid was purified to obtain 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione.
[0017] Preferably, during the column chromatography purification, the eluent is composed of a mixture of petroleum ether and ethyl acetate.
[0018] In summary, this application has the following beneficial effects: The methylation synthesis method of the present application uses inexpensive menadione as a starting material and inexpensive and easily purchased reagents such as tert-butyl hydroperoxide and concentrated sulfuric acid as auxiliary agents to produce high-yield methylated quinone. The synthesis process can be carried out smoothly from the gram level to the hundred-gram level, as well as the kilogram level. Currently, there are no kilogram-level reports of this process worldwide, and it has important commercial application value. BRIEF DESCRIPTION OF THE DRAWINGS
[0019] Figure 1 It is Page 1 in the GCMS chart of 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione in Example 9 of the present application; Figure 2 It is Page 2 in the GCMS chart of 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione in Example 9 of the present application; Figure 3 This is the HNMR chart of 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione in Example 9 of the present application. DETAILED DESCRIPTION
[0020] The present application is further described in detail below with reference to the accompanying drawings and examples. Example
[0021] Example 1 A method for synthesizing 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione, the synthetic route of which is as follows: The synthesis method of the above-mentioned 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione comprises the following steps: S1: In a 50 mL three-necked flask, methylcyclohexane (35 mL), menadione (5 g, 29.039 mmol), 98% concentrated sulfuric acid (1.55 mL, 15.805 mmol), and ferrous sulfate (0.13 g, 0.856 mmol) were added. The mixture was refluxed at 80°C and the nitrogen atmosphere was replaced three times to obtain a mixed solution. S2: tert-Butyl hydroperoxide (7.48 g, 58.100 mmol) was slowly added to the mixed solution at 80°C under nitrogen atmosphere using a constant pressure dropping funnel, and the mixture was stirred for 1 h to obtain a reaction solution; S3: The reaction solution was cooled to room temperature. A large amount of solid precipitated, which was collected by filtration. The solid was dissolved in ethyl acetate (200 mL), washed three times with water (500 mL*3) and saturated brine (500 mL*3). The organic phase was collected and concentrated under reduced pressure to obtain a crude product (4.5 g). The crude product (4.5 g) was slurried with petroleum ether (18 mL) for 3 to 6 h (the ratio of crude product to petroleum ether was 1:4, and the slurrying time in this application was 3 h), filtered, and the solid was collected for rapid elution (decolorization) by column chromatography to obtain a yellow solid (3 g, 16 mmol, yield 55%).
[0022] When the solid is rapidly eluted (decolorized) by column chromatography for gradient elution, the volume fraction and time of the mobile phase are shown in the following table. Time (min) Petroleum ether (%) Ethyl acetate (%) 10 95 5 10 93 7 20 90 10 30 85 15
[0023] After testing, the yellow solid was found to be 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione.
[0024] Example 2 A method for synthesizing 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione is provided, which differs from Example 1 in that 50 mL of 1,4-dioxane is used instead of methylcyclohexane.
[0025] Example 3 A method for synthesizing 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione is different from that of Example 1 in that 50 mL of acetonitrile is used instead of methylcyclohexane.
[0026] Example 4 A method for synthesizing 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione is different from that of Example 1 in that 50 mL of tetrahydrofuran is used instead of methylcyclohexane.
[0027] Example 5 A method for synthesizing 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione, which is different from Example 1 in that the volume of methylcyclohexane is 25 mL.
[0028] Example 6 A method for synthesizing 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione is different from that of Example 5 in that the amount of 98% concentrated sulfuric acid added is 58.079 mmol.
[0029] Example 7 A method for synthesizing 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione is different from that of Example 5 in that the purity of 98% concentrated sulfuric acid is 50% and the amount of the added substance is 15.805 mmol.
[0030] Example 8 A method for synthesizing 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione is different from that of Example 5 in that the purity of 98% concentrated sulfuric acid is 50% and the amount of the added substance is 87.118 mmol.
[0031] Example 9 A method for synthesizing 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione, the synthetic route of which is as follows: The synthesis method of the above-mentioned 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione comprises the following steps: S1: In a 5000 mL three-necked flask, methylcyclohexane (1400 mL), menadione (200 g, 1161.555 mmol), 98% concentrated sulfuric acid (683.48 g, 3484.665 mmol), and ferrous sulfate (2.65 g, 17.423 mmol) were added, and the mixture was refluxed at 80°C and replaced with nitrogen three times to obtain a mixed solution; S2: tert-Butyl hydroperoxide (299.08 g, 2323.110 mmol) was slowly added to the mixed solution at 80°C under nitrogen atmosphere using a constant pressure dropping funnel, and the mixture was stirred for 1 h to obtain a reaction solution; S3: The reaction solution was cooled to room temperature, and a large amount of solid precipitated. The solid was filtered and collected; the solid was dissolved in ethyl acetate (2 L), washed three times with water (500 mL*3) and saturated brine (500 mL*3), and the organic phase was collected and concentrated under reduced pressure to obtain a crude product (200 g); The crude product (200 g) was slurried with petroleum ether (800 mL) for 6 h, filtered, and the solid was collected and subjected to rapid elution (decolorization) by column chromatography to obtain a yellow solid (162.22 g, 871.166 mmol, 75%).
[0032] When the solid is rapidly eluted (decolorized) by column chromatography for gradient elution, the volume fraction and time of the mobile phase are shown in the following table. Time (min) Petroleum ether (%) Ethyl acetate (%) 10 95 5 10 93 7 20 90 10 30 85 15
[0033] Reference Figures 1 to 3 After testing, the yellow solid was found to be 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione.
[0034] The feed ratios of the raw materials and the yields of the products in Examples 1 to 9 are shown in the table below.
[0035] By analyzing the data in the above table, it can be seen that compared with Examples 1 and 5, the yield of 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione synthesized in Examples 2 to 4 is significantly reduced, and the yield of Example 1 is higher than that of Example 5. This shows that in the synthesis method of the present application, when methylcyclohexane is selected as the organic solvent and the feed ratio of menadione and methylcyclohexane is controlled to be 1g:7mL, the yield of 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione can be increased and the cost can be reduced. The reason for this may be that when 1,4-dioxane, acetonitrile or tetrahydrofuran is used as the solvent, the starting material menadione is not completely reacted and has an Rf value close to that of the product, making it difficult to separate and purify, so the yield of the product is low.
[0036] Compared with Example 5, the yield of Example 6 is lower. During the reaction process of Example 6, it was found that when 2 equivalents of concentrated sulfuric acid were added, black solidified solid appeared at the bottom of the reaction flask, and the reaction solution was uneven, so the reaction yield was slightly reduced.
[0037] Compared with Example 5, the yields of Examples 7 and 8 increased significantly, especially the highest yield in Example 8. This shows that in the synthesis method of the present application, when the purity of concentrated sulfuric acid is 50% and the molar ratio of menadione to concentrated sulfuric acid is 1: (2-3), the yield of the product can be increased, especially when the molar ratio of menadione to concentrated sulfuric acid is 1: 3, the product yield is the highest. The reason for this may be that the increase in equivalents is more conducive to the protonation of the subsequent reaction and promotes the reaction.
[0038] At the same time, it can be seen from Examples 8 and 9 that the synthesis method of the present application can be carried out smoothly from the gram level to the hundred-gram level, as well as the kilogram level, and the product yield of the kilogram-level synthesis method is as high as 75%.
[0039] Finally, we placed the reaction in air and the reaction yield also decreased, which shows that the presence of nitrogen atmosphere is very important in the synthesis method of this application.
[0040] Comparative Example Comparative Example 1 A method for synthesizing 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione, the synthetic route of which is as follows: The synthesis method of the above-mentioned 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione comprises the following steps: S1 Preparation of Intermediate 1: Reaction condition 1: Menadione (2 g, 11 mmol) was dissolved in toluene (30 mL), and NBS (2.5 g, 14 mmol) was added. The mixture was stirred at room temperature for 6 h to obtain a reaction solution. The reaction solution was detected by spot plate and LCMS. No intermediate 2 was found, indicating the reaction failed, and the next step was not performed.
[0041] Reaction condition 2: Menadione (2 g, 11 mmol) was dissolved in toluene (30 mL), and NBS (2.5 g, 14 mmol) was added. The mixture was heated to 60°C and stirred for 6 h to obtain a reaction solution. The reaction solution was detected by spot plate and LCMS. No intermediate 2 was found, indicating the reaction failed, and the next step was not performed.
[0042] Reaction condition 3: Menadione (2 g, 11 mmol) was dissolved in toluene (30 mL), and NBS (2.5 g, 14 mmol) was added. The mixture was heated to 110°C and stirred for 6 h to obtain a reaction solution. The reaction solution was detected by spot plate and LCMS. No intermediate 2 was found, indicating the reaction failed, and the next step was not performed.
[0043] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make non-creative modifications to the present embodiment as needed, but as long as they are within the scope of the claims of the present application, they are protected by the patent law.
Claims
1. A method for synthesizing 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione, characterized in that: The following steps are involved: Menadione, concentrated sulfuric acid, ferrous sulfate and an organic solvent are mixed to obtain a mixed solution; tert-butyl hydroperoxide is added to the mixed solution at 80-120° C. under a nitrogen atmosphere, and the mixture is stirred for reaction for 1-15 hours to obtain a reaction solution; and the reaction solution is post-treated to obtain 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione.
2. The method for synthesizing 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione according to claim 1, wherein The organic solvent is methylcyclohexane, 1,4-dioxane, acetonitrile, tetrahydrofuran or toluene.
3. The method for synthesizing 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione according to claim 2, characterized in that: The feeding ratio of the menadione and the organic solvent is 1 g: (5-10) mL.
4. The method for synthesizing 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione according to claim 1, wherein The molar ratio of the menadione, concentrated sulfuric acid, ferrous sulfate and tert-butyl hydroperoxide is 1:(1-3):(0.01-0.03):(2-5).
5. The method for synthesizing 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione according to claim 4, wherein: The purity of the concentrated sulfuric acid is 50%, and the molar ratio of the menadione to the concentrated sulfuric acid is 1:(2-3).
6. The method for synthesizing 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione according to claims 3 and 5, characterized in that: The organic solvent is methylcyclohexane; the feed ratio of the menadione and methylcyclohexane is 1 g:7 mL; the purity of the concentrated sulfuric acid is 50%, and the molar ratio of the menadione and concentrated sulfuric acid is 1:
3.
7. The method for synthesizing 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione according to claim 1, characterized in that: The post-treatment of the reaction solution comprises the following steps: The reaction solution was cooled to room temperature, solid precipitated, and filtered. The solid was dissolved with an organic solvent, washed with water and saturated brine in sequence, and the organic phase was collected; the organic phase was dried and concentrated, and then slurried with petroleum ether, filtered, and the slurried solid was collected; the slurried solid was purified to obtain 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione.
8. The method for synthesizing 2,3-dimethyl-1,4-dihydronaphthalene-1,4-dione according to claim 7, characterized in that: During the column chromatography purification, the eluent is composed of a mixture of petroleum ether and ethyl acetate.