Synthesis and raw material recovery method of 4-(3-ester oxopropyl) methyl benzoate

Abstract

The invention discloses a synthesis and raw material recovery method of 4-(3-ester oxopropyl) methyl benzoate, and belongs to the field of organic synthesis. According to the invention, methylparaben and methyl acrylate are used as raw materials, and under the action of a catalyst, a Michael addition reaction and post-treatment are carried out to obtain a 4-(3-ester oxopropyl) methyl benzoate product. Under preferable conditions, the one-way product yield is close to 60%, the raw material recycling rate is close to 90%, and the comprehensive yield in terms of methylparaben is greater than 90%. The synthesis method is simple to operate, only needs simple operations such as reduced pressure distillation, dissolution, precipitation and filtration, does not need high-energy-consumption tedious operations such as rectification and recrystallization, is high in raw material recycling rate, relieves the treatment pressure of three wastes, and is environment-friendly.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of methyl 4-(3-esteroxypropyl)benzoate and a raw material recovery method. Background Art

[0002] Methyl 4-(3-esteroxypropyl)benzoate is a white crystalline solid. It is a key intermediate for the synthesis of 4-(3-hydrazideoxypropyl)benzoylhydrazide curing agent and has great significance in organic synthesis. Its structural formula is as follows:

[0003]

[0004] Patent EP0100633A2 discloses a method for synthesizing methyl 4-(3-esteroxypropyl)benzoate, which uses methyl paraben (20 g) and methyl acrylate (56.4 g) as raw materials, 0.4 g sodium acrylate as catalyst to carry out Michael addition reaction, and reacts at 100-110° C. for 5 h. The subsequent treatment process is to extract with ether, repeatedly wash with alkali solution and water, and then evaporate the solvent to obtain 15.5 g of product. This patent only realizes a one-way conversion, and the yield of the product is only 49.5%. The recycling of the two raw materials is not realized, so there are huge defects in the separation and purification of the product and the raw materials.

[0005] Separation and purification of target products and raw materials is the key to industrial production. The extraction method adopted by patent EP0100633A2 can extract many components, making it difficult to ensure product purity, and the subsequent vacuum distillation does not achieve separation of acrylate raw materials. In addition to the extraction method, potential methods for separating the product and raw materials in the reaction liquid after Michael addition include column chromatography, distillation or rectification, recrystallization, etc.

[0006] Regarding column chromatography, 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; Chem.Commun.2018,54,4437–4440 and other literatures all applied column chromatography to the separation and purification of Michael addition products and raw materials, which effectively separated and purified the products and raw materials. However, the dosage of the separated and purified products was very small, between 5mg–100g, which was suitable for the experimental stage of small doses, but the dosage of the reaction solution was very large in industrial production, which increased the cost of industrial production and the separation process of column chromatography was complicated and time-consuming. In actual production, it is difficult to industrialize.

[0007] For distillation or rectification, it is suitable for the separation of liquid mixtures with large boiling point differences. For the present invention, methyl acrylate can be easily separated, but methyl paraben and the product 4-(3-ester group oxypropyl) methyl benzoate are both solid at room temperature. The use of distillation requires maintaining a relatively high temperature, which results in a relatively large energy loss. The temperature reduction can cause 4-(3-ester group oxypropyl) methyl benzoate to solidify and cause the distillation equipment to be blocked. The method has poor economic applicability, has relatively high requirements on equipment, and therefore has a relatively high cost, and is also not suitable for the industrialization of this product.

[0008] For the recrystallization method, it mainly relies on the difference in solubility of products with different structures in solvents to achieve the purpose of separation, but the solubility difference between the raw material methylparaben and the product 4-(3-ester group oxypropyl) benzoic acid methyl ester in common organic solvents is not large. Moreover, for the Michael addition reaction, the conversion rate of its reactants is between 40-65%, resulting in that neither methylparaben nor the product 4-(3-ester group oxypropyl) benzoic acid methyl ester can dominate in the mixture. And the recrystallization method can only obtain a high recovery rate when one of the substances is in small amounts. Therefore, the recrystallization method is not applicable.

[0009] The Michael addition reaction liquid of the present invention mainly contains raw materials methyl acrylate, methyl paraben and product 4-(3-esteroxypropyl) methyl benzoate. Common separation methods such as extraction, column chromatography, distillation or rectification, recrystallization, etc. are not sufficient to separate and purify the raw materials and products and are suitable for large-scale industrialization.

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

[0011] In order to solve the above problems, the present invention provides a method for synthesizing methyl 4-(3-esteroxypropyl)benzoate and recovering raw materials. The method is simple to operate, environmentally friendly, and the comprehensive yield of the product is significantly improved (>90%).

[0012] A method for synthesizing methyl 4-(3-esteroxypropyl)benzoate and recovering raw materials, wherein the raw materials methyl paraben and methyl acrylate are mixed with a catalyst, and a Michael addition reaction is carried out under nitrogen protection to obtain a reaction liquid; the catalyst is sodium methoxide. The specific reaction formula is as follows:

[0013]

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

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

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

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

[0018] (1) adding an organic small molecule acid to the reaction solution and then distilling under reduced pressure to recover the methyl acrylate raw material, then adding methanol to the remaining white colloidal solid and distilling under reduced pressure, repeating the process twice to obtain a white solid.

[0019] (2) The obtained white solid was dissolved in methanol, and dripped into an ice-water solution together with the prepared sodium hydroxide solution, filtered, and filter cake A and filtrate A were collected. The filter cake A was dried and collected to obtain the pure product methyl 4-(3-esteroxypropyl)benzoate.

[0020] (3) Acidifying the filtrate A and distilling to recover methanol, then adjusting the solution pH to weak alkalinity, collecting the filter cake B by filtration and drying it to recover the raw material methylparaben.

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

[0022] Furthermore, in the step (2), the mass ratio of the added methanol to the obtained white solid is 5:1 to 20:1. The mass volume ratio of the added ice water to the added methanol is 2:1 to 6:1. The molar ratio of the added sodium hydroxide to the theoretical 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 to 6. The alkalizing agent is sodium hydroxide, and the pH after alkalization is 7.5 to 8.0.

[0024] Beneficial effects of the present invention:

[0025] 1. Under the action of the catalyst, the single-pass yield can reach 60%, the raw materials methyl acrylate and methyl paraben can be recovered with a high recovery rate, the post-processing operation is simple and feasible, and no high-energy-consuming and cumbersome operations such as distillation and recrystallization are required. The comprehensive yield of methyl paraben is greater than 90%.

[0026] 2. The raw materials used in the present invention, methyl paraben, methyl acrylate, and sodium methoxide, are all common chemicals, among which methyl acrylate is both a solvent and a reactant; the amount of the catalyst used is small, and all raw materials can be purchased in large quantities on the market, with low cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 Technical flow chart for the preparation of dimethyl ester product by Michael Addition reaction;

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

[0029] Figure 3 Example 1 Preparation of 4-(3-ester oxypropyl) benzoic acid methyl ester 1 H NMR spectrum;

[0030] Figure 4 Example 1 Preparation of 4-(3-ester oxypropyl) benzoic acid methyl ester 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 Recovered methyl paraben 1 H NMR spectrum. DETAILED DESCRIPTION

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

[0035] Embodiment 1:

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

[0037] Acrylic acid (0.1 mol, 7.21 g) was added to the obtained reaction solution, and then the reaction solution was distilled under reduced pressure to recover the raw material methyl acrylate (401 mL, methyl acrylate recovery rate: 90%). 100 mL of methanol was added to the remaining white colloidal solid, and a white solid was obtained after rotary evaporation. The operation was repeated twice. 1200 mL of methanol was added to the obtained white solid to dissolve, 17.61 g of sodium hydroxide was taken to prepare 400 mL of sodium hydroxide solution, and then the sodium hydroxide solution and the dissolved mixed solution were dripped into ice water (1200 g of ice + 1200 g of water). During the dripping process, the pH of the ice water was maintained between 9 and 11, and the ice water bath was maintained at about 4°C. After the dripping was completed and stirred for 5 min, the filter cake A was obtained by filtration. After drying, the pure product 4-(3-ester oxypropyl) benzoic acid methyl ester (142.94 g, single-pass yield 60%) was obtained. The filtrate A was adjusted to pH=4.6 by dripping hydrochloric acid, and after distillation to recover methanol, the pH was adjusted to pH=7.5 by dripping sodium hydroxide solution, and the filter cake B was collected by filtration and dried to obtain the recovered raw material methyl paraben (51.75g), and the recovery rate of methyl paraben was 85%. After deducting the recovered methyl paraben, the comprehensive yield was 91%.

[0038] Embodiment 2:

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

[0040] The obtained Michael addition reaction liquid is prepared from methyl paraben (1 mol, 152.20 g) and methyl acrylate (500 mL). Acrylic acid (0.1 mol, 7.21 g) is added to the obtained reaction liquid, and then the raw material methyl acrylate (412 mL, methyl acrylate recovery rate: 91%) is recovered. 100 mL of methanol is added to the remaining white colloidal solid, and a white solid is obtained after rotary evaporation. This operation is repeated twice. After 1200 mL of methanol is added to the obtained white solid to dissolve, 18.48 g of sodium hydroxide is taken to prepare 400 mL of sodium hydroxide solution, and then the sodium hydroxide solution and the dissolved mixed solution are dripped into ice water (1200 g ice + 1200 g water). During the dripping process, the pH of the ice water is maintained between 9 and 11, and the ice water bath is maintained at about 5°C. After stirring for 5 minutes, filter to obtain filter cake A. After drying, the pure product 4-(3-esteroxypropyl)benzoic acid methyl ester (121.36 g, one-way yield 51%) was obtained. The filtrate was adjusted to pH=4.5 by dripping hydrochloric acid, and then adjusted to pH=7.6 by dripping sodium hydroxide solution, and then the filter cake B was collected by filtration and air-dried to obtain the recovered raw material methyl paraben (64.88 g), the recovery rate of methyl paraben: 87%, and the comprehensive yield after deducting the recovered methyl paraben was 89%.

[0041] Embodiment 3:

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

[0043] Acrylic acid (0.2 mol, 14.42 g) was added to the obtained reaction solution and then distilled under reduced pressure to recover raw material methyl acrylate (398 mL, methyl acrylate recovery rate: 89%). 100 mL of methanol was added to the remaining white colloidal solid, and a white solid was obtained after rotary evaporation. This operation was repeated twice. After 1200 mL of methanol was added to the obtained white solid to dissolve, 19.40 g of sodium hydroxide was taken to prepare 400 mL of sodium hydroxide solution, and then the sodium hydroxide solution and the dissolved mixed solution were dripped into ice water (1200 g of ice + 1200 g of water). During the dropping process, the pH of the ice water was maintained between 9 and 11, and the ice-water bath was maintained at about 5 ° C. After stirring for 5 min, filter cake A was obtained. After drying, pure product 4-(3-ester oxypropyl) benzoic acid methyl ester (144.98 g, single-pass yield 61%) was obtained. The filtrate was adjusted to pH=4.5 by dropping hydrochloric acid, and then adjusted to pH=7.5 by dropping sodium hydroxide solution. The filter cake B was collected by filtration and air-dried to obtain the recovered raw material methyl paraben (50.22 g). The recovery rate of methyl paraben was 85%, and the comprehensive yield after deducting the recovered methyl paraben was 91%.

[0044] In summary, the present invention provides a method for synthesizing methyl 4-(3-ester oxypropyl)benzoate and recovering raw materials, wherein the single-pass yield of the prepared methyl 4-(3-ester oxypropyl)benzoate can reach 60%, the raw materials methyl paraben and methyl acrylate can be recovered, and the comprehensive yield after deducting the recovered methyl paraben is greater than 90%. The process route is short, the raw material cost is low and the recovery rate is high, the operation is simple, and mass production is possible, which is suitable for industrialization.

[0045] Finally, the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope 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 methyl paraben and methyl acrylate are mixed with a catalyst, and a Michael addition reaction is carried out under nitrogen protection to obtain a reaction liquid; the catalyst is sodium methoxide or 4-dimethylaminopyridine.

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 methyl paraben to the catalyst is 1:0.1-0.

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 the raw materials methyl paraben and 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 reflux temperature, and the reaction time is 8 to 12 hours.

5. The method for synthesizing and recovering raw materials of methyl 4-(3-esteroxypropyl)benzoate according to claim 1, characterized in that: The reaction solution after the reaction is completed also includes the following post-treatment: (1) adding an organic small molecule acid to the reaction solution and then distilling under reduced pressure to recover the methyl acrylate raw material, then adding methanol to the remaining white colloidal solid and distilling under reduced pressure, repeating the process twice to obtain a white solid. (2) The obtained white solid was dissolved in methanol, and dripped into an ice-water solution together with the prepared sodium hydroxide solution, filtered, and filter cake A and filtrate A were collected. The filter cake A was dried and collected to obtain the pure product methyl 4-(3-esteroxypropyl)benzoate. (3) Acidifying the filtrate A and distilling to recover methanol, then adjusting the solution pH to weak alkalinity, collecting the filter cake B by filtration and drying it to recover the raw material methylparaben.

6. The post-treatment of the reaction solution according to claim 5, characterized in that: In the step (1), the organic small molecule acid is acrylic acid, and the molar ratio of the amount of acrylic acid added to the amount of sodium methoxide during the reaction is 1:1 to 1.25:

1.

7. The post-treatment of the reaction solution according to claim 5, characterized in that: In the step (2), the volume mass ratio of the added methanol to the volume mass of the obtained white solid is 5mL:1g-15mL:1g. The mass volume ratio of the added ice water to the added methanol is 2g:1mL-6g:1mL. The molar ratio of the added sodium hydroxide to the theoretical remaining methylparaben is 1.1:1-1.25:

1. During the dropwise addition, the pH of the ice water is maintained between 9 and 11, and the ice water bath temperature is 0-10°C.

8. The post-treatment of the reaction solution according to claim 5, characterized in that: In the 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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