A method for synthesizing and recycling 4-(3-ester oxopropyl) methyl benzoate

Abstract

The application discloses a synthesis and raw material recycling method of 4-(3-ester oxopropyl) methyl benzoate, and belongs to the field of organic synthesis. The application takes nipagin methyl ester and methyl acrylate as raw materials, and obtains 4-(3-ester oxopropyl) methyl benzoate product through a Michael addition reaction and post-treatment under the action of a catalyst. Under preferred conditions, the one-way product yield is close to 60%, the raw material recycling rate is close to 90%, and the comprehensive yield calculated based on nipagin methyl ester is greater than 90%. The synthesis method is simple to operate, only needs simple operations such as reduced pressure distillation, dissolution, precipitation and filtration, and does not need high energy consumption and complicated operations such as rectification and recrystallization. Meanwhile, the raw material recycling rate of the route is high, the pressure of three waste treatment is reduced, and the environment is friendly.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing methyl 4-(3-esteroxypropyl)benzoate and recovering raw materials. Background Technology

[0002] Methyl 4-(3-esteroxypropyl)benzoate is a white crystalline solid and a key intermediate in the synthesis of 4-(3-acylhydrazideoxypropyl)benzoylhydrazide curing agents. It plays a significant role in organic synthesis, and its structural formula is as follows:

[0003]

[0004] Patent EP0100633A2 discloses a method for synthesizing methyl 4-(3-esteropropyl)benzoate, which involves using methylparaben (20g) and methyl acrylate (56.4g) as raw materials, and 0.4g of sodium acrylate as a catalyst in a Michael addition reaction at 100–110°C for 5 hours. The subsequent processing involves extraction with diethyl ether, repeated washing with alkali and water, and evaporation to remove the solvent, yielding 15.5g of product. This patent only achieves a single-pass conversion, with a product yield of only 49.5%, and does not achieve the recycling of the two raw materials, thus exhibiting significant deficiencies in the separation and purification of the product and raw materials.

[0005] Separation and purification of the target product and raw materials are crucial for industrial production. The extraction method used in patent EP0100633A2 extracts a large number of components, making it difficult to guarantee product purity. Furthermore, subsequent vacuum distillation does not achieve separation of the acrylate raw material. Besides extraction, potential methods for separating the product from the raw material in the reaction solution after Michael addition include column chromatography, distillation or rectification, and recrystallization.

[0006] For column chromatography, references such as J. Org. Chem. 2019, 84, 860-868; Bioorgan. Med. Chem. 2009, 17, 1911–1917; Angew. Chem. Inter. Ed. 2013, 52, 9266–9270; Aust. J. Chem. 2008, 61, 122–130; and Chem. Commun. 2018, 54, 4437–4440 have all used column chromatography for the separation and purification of Michael addition products and starting materials. While it effectively separates and purifies the products and starting materials, the amount of purified product is very small, between 5 mg and 100 g. This is suitable for small-scale experimental applications, but in industrial production, the reaction solution volume is very large, leading to increased industrial production costs. Furthermore, the separation process of column chromatography is complex and time-consuming, making it difficult to scale up industrially.

[0007] Distillation or rectification methods are suitable for separating liquid mixtures with large differences in boiling points. While this invention can easily separate methyl acrylate, both methylparaben and the product methyl 4-(3-esteroxopropyl)benzoate are solids at room temperature. Distillation requires maintaining high temperatures, resulting in significant energy consumption. Lowering the temperature can cause methyl 4-(3-esteroxopropyl)benzoate to solidify, leading to blockages in the distillation equipment. This method is not economically viable, has high equipment requirements, and is therefore costly, making it unsuitable for the industrialization of this product.

[0008] Recrystallization primarily relies on the difference in solubility of products with different structures in solvents to achieve separation. However, in the Michael addition reaction, the solubility difference between the starting material methylparaben and the product methyl 4-(3-esteroxopropyl)benzoate in common organic solvents is not significant. Furthermore, the conversion rates of reactants in the Michael addition reaction are typically between 40-65%, meaning neither methylparaben nor methyl 4-(3-esteroxopropyl)benzoate can dominate in the mixture. High recovery rates in recrystallization are only achievable when one of the substances is present in small quantities. Therefore, recrystallization is not suitable.

[0009] The main components of the Michael addition reaction solution in this invention are methyl acrylate and methylparaben, and methyl 4-(3-esteroxopropyl)benzoate. Common separation methods such as extraction, column chromatography, distillation or rectification, and recrystallization are insufficient to separate and purify the raw materials and products, making them suitable for large-scale industrial applications.

[0010] Therefore, the present invention requires an efficient method for the synthesis and purification of methyl 4-(3-esteroxypropyl)benzoate, which can yield a product with high yield and high purity. Summary of the Invention

[0011] To address the aforementioned issues, this invention proposes a method for the synthesis and raw material recovery of methyl 4-(3-esteroxypropyl)benzoate. This method is simple to operate, environmentally friendly, and significantly improves the overall product yield (>90%).

[0012] A method for synthesizing methyl 4-(3-esteroxopropyl)benzoate and recovering raw materials involves mixing methylparaben, methyl acrylate, and a catalyst, and then conducting a Michael addition reaction under nitrogen protection to obtain a reaction solution; the catalyst is sodium methoxide. The specific reaction formula is as follows:

[0013]

[0014] Furthermore, the molar ratio of the raw material methylparaben to the catalyst is 1:0.1 to 0.2.

[0015] Furthermore, the molar volume ratio of methylparaben to methyl acrylate is 1 mol: 400-600 mL.

[0016] Furthermore, the reaction temperature is the reflux temperature, and the reaction time is 8–12 hours.

[0017] Furthermore, the reaction solution after the reaction is complete also includes the following post-treatment:

[0018] (1) After adding an organic small molecule acid to the reaction solution, the methyl acrylate raw material was recovered by vacuum distillation. Then, methanol was added to the remaining white gelatinous solid and vacuum distillation was performed. This process was repeated twice to obtain a white solid.

[0019] (2) The obtained white solid was dissolved in methanol and added dropwise to an ice-water solution along with the prepared sodium hydroxide solution. The mixture was filtered, and filter cake A and filtrate A were collected. After drying filter cake A, the pure product methyl 4-(3-esteroxypropyl)benzoate was obtained.

[0020] (3) After acidifying filtrate A, methanol is recovered by distillation. Then, the pH of the solution is adjusted to weakly alkaline. Filter cake B is collected and dried to recover the raw material methylparaben.

[0021] Furthermore, in step (1), the organic small molecule acid is acrylic acid, and the molar ratio of its addition to sodium methoxide during the reaction is 1:1 to 1.25:1.

[0022] Furthermore, in step (2), the mass ratio of methanol added to the mass of the resulting white solid is 5:1 to 20:1. The mass-to-volume ratio of ice water added to methanol added is 2:1 to 6:1. The molar ratio of sodium hydroxide added to the theoretically remaining methylparaben is 1.1:1 to 1.25:1. During the dropwise addition, the pH of the ice water is maintained between 9 and 11, and the ice water bath temperature is 0 to 10°C.

[0023] Furthermore, in step (3), the acidifying agent is hydrochloric acid, and the pH after acidification is 3-6. The alkalizing agent is sodium hydroxide, and the pH after alkalization is 7.5-8.0.

[0024] The beneficial effects of this invention are:

[0025] 1. With the action of a catalyst, the single-pass yield can reach 60%. The raw materials methyl acrylate and methylparaben can be recovered with a high recovery rate. The post-processing operation is simple and feasible, without the need for energy-intensive and cumbersome operations such as distillation and recrystallization. The overall yield based on methylparaben is greater than 90%.

[0026] 2. The raw materials used in this invention, methylparaben, methyl acrylate, and sodium methoxide, are all common chemicals. Methyl acrylate serves as both a solvent and a reactant. The catalyst used is used in small quantities, and all raw materials can be purchased in large quantities on the market, resulting in low cost. Attached Figure Description

[0027] Figure 1 Flowchart of the Michael Addition reaction for the preparation of dimethyl ester products;

[0028] Figure 2 The reaction mixture prepared in Example 1 1 H NMR spectrum;

[0029] Figure 3 Methyl 4-(3-esteroxypropyl)benzoate prepared in Example 1 1 H NMR spectrum;

[0030] Figure 4 Methyl 4-(3-esteroxypropyl)benzoate prepared in Example 1 13 C NMR spectrum;

[0031] Figure 5 The reaction mixture prepared in Example 2 1 H NMR spectrum;

[0032] Figure 6 Example 1: Recovered methyl acrylate 1 H NMR spectrum;

[0033] Figure 7 Example 1: Recovery of methylparaben 1 H NMR spectrum. Detailed Implementation

[0034] The embodiments of the present invention will now be described in detail with reference to examples.

[0035] Example 1:

[0036] In a 1000 mL round-bottom flask, methylparaben (1 mol, 152.20 g), sodium methoxide (0.1 mol, 5.40 g), and methyl acrylate (500 mL) were added sequentially. After three cycles of vacuuming and N2 purging, the mixture was refluxed under nitrogen protection for 12 h. After cooling to room temperature, a reaction mixture containing crude methyl 4-(3-esteropropyl)benzoate was obtained.

[0037] Acrylic acid (0.1 mol, 7.21 g) was added to the resulting reaction solution, followed by vacuum distillation to recover the raw material methyl acrylate (401 mL, methyl acrylate recovery rate: 90%). Then, 100 mL of methanol was added to the remaining white gelatinous solid, and the mixture was rotary evaporated to obtain a white solid. This operation was repeated twice. The obtained white solid was dissolved in 1200 mL of methanol. 17.61 g of sodium hydroxide was used to prepare a 400 mL sodium hydroxide solution. The sodium hydroxide solution and the dissolved mixture were then added dropwise to ice water (1200 g ice + 1200 g water). During the addition, the pH of the ice water was maintained between 9 and 11, and the ice water bath was maintained at approximately 4°C. After the addition was complete, the mixture was stirred for 5 min and then filtered to obtain filter cake A. After drying, pure product methyl 4-(3-esteroxypropyl)benzoate (142.94 g, single-pass yield 60%) was obtained. The pH of filtrate A was adjusted to 4.6 by adding hydrochloric acid. After distillation to recover methanol, the pH was adjusted to 7.5 by adding sodium hydroxide solution. The filter cake B was then collected by filtration and dried to obtain methylparaben (51.75 g). The methylparaben recovery rate was 85%. After deducting the recovered methylparaben, the overall yield was 91%.

[0038] Example 2:

[0039] In a 1000 mL round-bottom flask, methylparaben (1 mol, 152.20 g), 4-dimethylaminopyridine (0.1 mol, 12.22 g), and methyl acrylate (500 mL) were added sequentially. After three cycles of vacuuming and N2 purging, the mixture was refluxed under nitrogen protection for 12 h. After cooling to room temperature, a reaction mixture containing crude methyl 4-(3-esteropropyl)benzoate was obtained.

[0040] The resulting Michael addition reaction solution was prepared from methylparaben (1 mol, 152.20 g) and methyl acrylate (500 mL). Acrylic acid (0.1 mol, 7.21 g) was added to the resulting reaction solution, followed by vacuum distillation to recover the raw material methyl acrylate (412 mL, methyl acrylate recovery rate: 91%). Then, 100 mL of methanol was added to the remaining white gelatinous solid, and the mixture was rotary evaporated to obtain a white solid. This operation was repeated twice. The white solid was dissolved in 1200 mL of methanol, and 18.48 g of sodium hydroxide was used to prepare a 400 mL sodium hydroxide solution. The sodium hydroxide solution and the dissolved mixture were then added dropwise to ice water (1200 g ice + 1200 g water). During the addition, the pH of the ice water was maintained between 9 and 11, and the ice water bath was maintained at approximately 5°C. After stirring for 5 minutes, the mixture was filtered to obtain filter cake A. After drying, pure methyl 4-(3-esteropropyl)benzoate (121.36 g, single-pass yield 51%) was obtained. The pH of the filtrate was adjusted to 4.5 by adding hydrochloric acid, and then to 7.6 by adding sodium hydroxide solution. After filtration, filter cake B was collected and air-dried to obtain recovered methylparaben (64.88 g). The methylparaben recovery rate was 87%, and the overall yield after deducting the recovered methylparaben was 89%.

[0041] Example 3:

[0042] In a 1000 mL round-bottom flask, methylparaben (1 mol, 152.20 g), sodium methoxide (0.2 mol, 10.80 g), and methyl acrylate (500 mL) were added sequentially. After three cycles of vacuuming and N2 purging, the mixture was refluxed under nitrogen protection for 12 h. After cooling to room temperature, a reaction mixture containing crude methyl 4-(3-esteropropyl)benzoate was obtained.

[0043] Acrylic acid (0.2 mol, 14.42 g) was added to the resulting reaction solution, followed by vacuum distillation to recover the raw material methyl acrylate (398 mL, methyl acrylate recovery rate: 89%). Then, 100 mL of methanol was added to the remaining white gelatinous solid, and the mixture was rotary evaporated to obtain a white solid. This operation was repeated twice. The white solid was dissolved in 1200 mL of methanol, and 19.40 g of sodium hydroxide was used to prepare a 400 mL sodium hydroxide solution. The sodium hydroxide solution and the dissolved mixture were then added dropwise to ice water (1200 g ice + 1200 g water). During the addition, the pH of the ice water was maintained between 9 and 11, and the ice water bath was maintained at approximately 5°C. After stirring for 5 min, the mixture was filtered to obtain filter cake A. After drying, pure product methyl 4-(3-esteroxypropyl)benzoate (144.98 g, single-pass yield 61%) was obtained. The pH of the filtrate was adjusted to 4.5 by adding hydrochloric acid, and then to 7.5 by adding sodium hydroxide solution. After filtration, filter cake B was collected and air-dried to obtain methylparaben (50.22g). The recovery rate of methylparaben was 85%, and the overall yield after deducting the recovered methylparaben was 91%.

[0044] In summary, the present invention provides a method for synthesizing methyl 4-(3-esteropropyl)benzoate and recovering raw materials. The single-pass yield of the obtained methyl 4-(3-esteropropyl)benzoate can reach 60%, and both methylparaben and methyl acrylate can be recovered. After deducting the recovered methylparaben, the overall yield is greater than 90%. This process has a short route, low raw material cost, high recycling rate, simple operation, and can be mass-produced, making it suitable for industrialization.

[0045] Finally, the above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. For those skilled in the art, the present invention can have various modifications and variations. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for synthesizing methyl 4-(3-esteroxypropyl)benzoate and recovering raw materials, characterized in that, The raw materials methylparaben and methyl acrylate were mixed with a catalyst and subjected to a Michael addition reaction under nitrogen protection to obtain a reaction solution; the catalyst was sodium methoxide or 4-dimethylaminopyridine; the reaction solution after the reaction was completed was treated as follows: (1) After adding an organic small molecule acid to the reaction solution, the methyl acrylate raw material was recovered by vacuum distillation. Then, methanol was added to the remaining white gelatinous solid and vacuum distillation was performed. This process was repeated twice to obtain a white solid. (2) Dissolve the obtained white solid in methanol, and add it dropwise into an ice water solution along with the prepared sodium hydroxide solution. Filter the solution and collect filter cake A and filtrate A. After drying filter cake A, collect the pure product methyl 4-(3-esteroxypropyl)benzoate. (3) After acidifying filtrate A, methanol is recovered by distillation. Then, the pH of the solution is adjusted to weakly alkaline. Filter cake B is collected and dried to recover the raw material methylparaben.

2. The method for synthesizing and recovering raw materials of methyl 4-(3-esteroxypropyl)benzoate according to claim 1, characterized in that, The molar ratio of the raw material methylparaben to the catalyst is 1:0.1 to 0.

2.

3. The method for synthesizing and recovering raw materials of methyl 4-(3-esteroxypropyl)benzoate according to claim 1, characterized in that, The molar volume ratio of methylparaben to methyl acrylate is 1 mol: 400-600 mL.

4. The method for synthesizing and recovering raw materials of methyl 4-(3-esteroxypropyl)benzoate according to claim 1, characterized in that, The reaction temperature is the reflux temperature, and the reaction time is 8–12 hours.

5. The method for synthesizing and recovering raw materials of methyl 4-(3-esteroxypropyl)benzoate according to claim 1, characterized in that, In step (1), the organic small molecule acid is acrylic acid, and the molar ratio of the amount of acrylic acid fed to the amount of sodium methoxide during the reaction is 1 to 1.25:

1.

6. The method for synthesizing and recovering raw materials of methyl 4-(3-esteroxypropyl)benzoate according to claim 1, characterized in that, In step (2), the volume ratio of methanol added to the volume of the resulting white solid is 5-15 mL:1 g; the mass ratio of ice water added to methanol added is 2-6 g:1 mL; the molar ratio of sodium hydroxide added to the theoretical remaining methylparaben is 1.1-1.25:1; the pH of the ice water is maintained between 9 and 11 during the dropwise addition process, and the temperature of the ice water bath is 0-10℃.

7. The method for synthesizing and recovering raw materials of methyl 4-(3-esteroxypropyl)benzoate according to claim 1, characterized in that, In step (3), the acidifying agent is hydrochloric acid, and the pH after acidification is 3-6; the alkalizing agent is NaOH, and the pH after alkalization is 7.5-8.0.

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