Preparation method of high-purity ferulic acid

Abstract

The invention provides a preparation method of high-purity ferulic acid, which comprises the following steps: adding vanillin, propylene glycol and piperidine into a reaction solvent, heating to 80-100 DEG C, carrying out heating reaction for 10-20 hours, adding water, cooling, crystallizing by cooling, filtering, washing and drying to obtain the high-purity ferulic acid, the molar ratio of the vanillin to the malonic acid to the piperidine is 1: (1.2 to 2.8): (0.05 to 0.30). According to the method, vanillin and malonic acid are used as raw materials, and high-purity ferulic acid is obtained in a piperidine / 1, 4-dioxane system. The process provided by the invention is simple to operate, low in requirements on production equipment, high in yield and purity, low in production cost and suitable for industrial mass production.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical product preparation, and in particular to a method for preparing high-purity ferulic acid. Background Art

[0002] Ferulic acid, chemically known as 4-hydroxy-3-methoxycinnamic acid, has antiplatelet aggregation, inhibits platelet serotonin release, inhibits platelet thromboxane A2 (TXA2) production, enhances prostaglandin activity, provides analgesia, and relieves vasospasm. It is widely used in pharmaceuticals, cosmetics, and food additives. Ferulic acid is primarily derived from natural products and chemically synthesized. Chemically synthesized ferulic acid offers significant cost advantages, and most ferulic acid currently available on the market is obtained through chemical synthesis.

[0003] Chinese patent CN105622394A discloses a microwave synthesis process for ferulic acid. Vanillin is mixed with ammonium acetate in a malonic acid liquid, heated by radiation using a microwave reactor, and then subjected to circulating reflux heating, cooling, crystallization, and recrystallization to obtain ferulic acid. This method has a short reaction time and can be operated continuously, but it has certain requirements for equipment, requiring the use of a microwave reactor, and further recrystallization is required for post-processing to obtain a high-purity product, resulting in a relatively cumbersome process.

[0004] Chinese invention patent CN102701957A discloses a method for synthesizing trans-ferulic acid using vanillin and malonic acid as raw materials, an organic amine as a catalyst, and solvent water separation. This method requires only a single reaction step and is simple to operate. However, this process requires a water separator to continuously separate water during the reaction, and post-processing requires a recrystallization of the product to obtain a high-purity product, making production control difficult. Summary of the Invention

[0005] In view of this, the present invention aims to provide a method for preparing high-purity ferulic acid using vanillin and malonic acid as raw materials, piperidine as a catalyst, and 1,4-dioxane as a solvent. This method is simple, requires minimal equipment, and provides high yield and purity of ferulic acid, making it suitable for large-scale production. The synthetic route is as follows:

[0006]

[0007] The technical solution of the present invention is achieved as follows:

[0008] A method for preparing high-purity ferulic acid comprises the following steps: adding vanillin, propylene glycol and piperidine to a reaction solvent, heating to 80-100° C. for a heating reaction for 10-20 hours, adding water for cooling, cooling for crystallization, filtering, washing and drying to obtain the high-purity ferulic acid;

[0009] The molar ratio of the vanillin, malonic acid and piperidine is 1:1.2-2.8:0.05-0.30.

[0010] In a further embodiment, the molar ratio of the vanillin, malonic acid and piperidine is 1:1.4-2.5:0.15-0.30.

[0011] A further solution is to heat the reaction to 80°C for 15-20h;

[0012] Or heat to 90-100°C and carry out heating reaction for 10-20h.

[0013] A further solution is to heat the reaction to 80°C for 16-18h;

[0014] Or heat to 90-100°C and heat the reaction for 12-18 hours.

[0015] A further solution is that the mass volume ratio of the vanillin and the reaction solvent is 1g:2-8mL, and the reaction solvent is 1,4-dioxane.

[0016] A further solution is that the mass volume ratio of the vanillin and water is 1g:3-8mL.

[0017] A further solution is that the crystallization temperature is 0-15°C and the crystallization time is 2-6h.

[0018] A further solution is to use water for the washing, and the mass volume ratio of the vanillin to the washing water is 1g:0.5-2mL.

[0019] A further solution is that the drying temperature is 40-70°C.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] The invention uses vanillin and malonic acid as raw materials, and heats and reacts them in a piperidine / 1,4-dioxane system to generate high-purity ferulic acid. The product yield can be as high as 93%, the purity is above 99.5%, and the residue on ignition is within 0.1%.

[0022] The production process of high-purity ferulic acid provided by the present invention has simple equipment requirements and can be completed in a normal pressure reactor without the need for a microwave reaction or a water separator. The process is simple, and after the reaction is completed, a high-purity product can be precipitated by adding water without the need for further purification. The ferulic acid has a high yield and purity, low production cost, and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The chromatogram of ferulic acid prepared in Example 1 of the present invention;

[0024] Figure 2 The chromatogram of ferulic acid prepared in Example 2 of the present invention;

[0025] Figure 3 The chromatogram is of ferulic acid prepared in Example 3 of the present invention;

[0026] Figure 4 The chromatogram of ferulic acid prepared in Example 4 of the present invention;

[0027] Figure 5 The chromatogram of ferulic acid prepared in Example 5 of the present invention;

[0028] Figure 6 This is a chromatogram of ferulic acid prepared in Comparative Example 1 of the present invention;

[0029] Figure 7 This is a chromatogram of ferulic acid prepared in Comparative Example 2 of the present invention;

[0030] Figure 8 The chromatogram is of ferulic acid prepared in Comparative Example 3 of the present invention. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0032] Unless otherwise specified, the experimental methods used in the examples of the present invention are all conventional methods.

[0033] Unless otherwise specified, the materials, reagents, etc. used in the examples of the present invention can be obtained from commercial sources.

[0034] The related substances detection method of ferulic acid of the present invention is determined by high performance liquid chromatography (Appendix VD of Part II of the Chinese Pharmacopoeia 2010 edition), and the detection conditions are as follows:

[0035] Octadecylsilane bonded silica gel was used as the filler (Waters ACQUITY UPLC HSS T3, 150 mm × 2.1 mm, 1.8 μm); the mobile phase A was methanol-water-acetic acid (20:79:1.5, v / v / v), and methanol was used as the mobile phase B, eluting according to the gradient shown in Table 1 below; the detection wavelength was 275 nm; the flow rate was 1.0 mL / min; and the injection volume was 10 μL.

[0036] Table 1 Gradient elution table

[0037]

[0038] Example 1

[0039] Weigh 100.00g of vanillin and 164.40g of malonic acid, add 12mL of piperidine and 400mL of 1,4-dioxane, heat to 80°C, and maintain for 18 hours. Add 500mL of water, cool to 10°C, maintain for 2 hours, filter, wash the filter cake with 100mL of water, and dry it in a vacuum at 50°C to obtain 108.50g of product, with a yield of 85% and a purity of 99.71%.

[0040] Example 2

[0041] Weigh 100.00g of vanillin and 131.52g of malonic acid, add 12mL of piperidine and 300mL of 1,4-dioxane, heat to 90°C, and maintain for 12 hours. Add 500mL of water, cool to 5°C, maintain for 2 hours, filter, wash the filter cake with 100mL of water, and dry it in a vacuum at 60°C to obtain 118.3g of product, with a yield of 93% and a purity of 99.86%.

[0042] Example 3

[0043] Weigh 100.00g of vanillin and 98.64g of malonic acid, add 18mL of piperidine and 500mL of 1,4-dioxane, heat to 90°C, and maintain for 18 hours. Add 500mL of water, cool to 15°C, maintain for 2 hours, filter, wash the filter cake with 50mL of water, and dry it in a vacuum at 70°C to obtain 100.3g of product, with a yield of 79% and a purity of 99.56%.

[0044] Example 4

[0045] Weigh 100.00g of vanillin and 164.40g of malonic acid, add 15mL of piperidine and 200mL of 1,4-dioxane, heat to 90°C, and maintain for 12 hours. Add 500mL of water, cool to 10°C, maintain for 3 hours, filter, wash the filter cake with 200mL of water, and dry it in a vacuum at 50°C to obtain 113.3g of product, with a yield of 89% and a purity of 99.81%.

[0046] Example 5

[0047] Weigh 100.00g of vanillin and 131.52g of malonic acid, add 15mL of piperidine and 800mL of 1,4-dioxane, heat to 100°C, and maintain for 12 hours. Add 800mL of water, cool to 0°C, and maintain for 4 hours. Filter, wash the filter cake with 100mL of water, and dry it in a vacuum at 60°C to obtain 103.50g of product, with a yield of 81% and a purity of 99.50%.

[0048] Comparative Example 1

[0049] The difference from Example 1 is that the reaction time is 12 h, and the specific steps are as follows:

[0050] Weigh 100.00g of vanillin and 164.40g of malonic acid, add 12mL of piperidine and 400mL of 1,4-dioxane, heat to 80°C, and maintain for 12 hours. Add 500mL of water, cool to 10°C, maintain for 2 hours, filter, wash the filter cake with 100mL of water, and dry it in a vacuum at 50°C to obtain 96.62g of product, with a yield of 76.7% and a purity of 98.87%.

[0051] Comparative Example 2

[0052] The difference from Example 2 is that the reaction temperature is 70° C., and the specific steps are as follows:

[0053] Weigh 100.00g of vanillin and 131.52g of malonic acid, add 12mL of piperidine and 300mL of 1,4-dioxane, heat to 70°C, and maintain for 12 hours. Add 500mL of water, cool to 5°C, maintain for 2 hours, filter, wash the filter cake with 100mL of water, and dry it in a vacuum at 60°C to obtain 50.38g of product, with a yield of 40% and a purity of 96.78%.

[0054] Comparative Example 3

[0055] The difference from Example 3 is that the base used is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The specific steps are as follows:

[0056] Weigh 100.00 g of vanillin and 98.64 g of malonic acid, add 18 mL of DBU and 500 mL of 1,4-dioxane, heat to 90°C, and maintain for 18 hours. Add 500 mL of water, cool to 15°C, maintain for 2 hours, filter, wash the filter cake with 50 mL of water, and dry it in a vacuum at 70°C to obtain 52.96 g of product, with a yield of 41.5% and a purity of 97.82%.

[0057] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications are also considered to be within the scope of protection of the present invention.

Claims

1. A method for preparing high-purity ferulic acid, characterized in that, The method comprises the following steps: adding vanillin, propylene glycol and piperidine to a reaction solvent, heating to 80-100° C. for heating reaction for 10-20 hours, adding water for cooling, cooling for crystallization, filtering, washing and drying to obtain the high-purity ferulic acid; The molar ratio of the vanillin, malonic acid and piperidine is 1:1.2-2.8:0.05-0.

30.

2. A method for preparing high-purity ferulic acid according to claim 1, characterized in that, The molar ratio of the vanillin, malonic acid and piperidine is 1:1.4-2.5:0.15-0.

30.

3. A method for preparing high-purity ferulic acid according to claim 1, characterized in that, Heat to 80°C and carry out heating reaction for 15-20h; Or heat to 90-100°C and carry out heating reaction for 10-20h.

4. The method for preparing high-purity ferulic acid according to claim 3, wherein Heat to 80°C and carry out heating reaction for 16-18h; Or heat to 90-100°C and heat the reaction for 12-18 hours.

5. The method for preparing high-purity ferulic acid according to claim 1, wherein The mass volume ratio of the vanillin and the reaction solvent is 1 g:2-8 mL, and the reaction solvent is 1,4-dioxane.

6. The method for preparing high-purity ferulic acid according to claim 1, wherein The mass volume ratio of the vanillin and water is 1g:3-8mL.

7. The method for preparing high-purity ferulic acid according to claim 1, wherein The crystallization temperature is 0-15° C., and the crystallization time is 2-6 hours.

8. The method for preparing high-purity ferulic acid according to claim 1, wherein Water is used for the washing, and the mass volume ratio of the vanillin to the washing water is 1 g: 0.5-2 mL.

9. The method for preparing high-purity ferulic acid according to claim 1, wherein The drying temperature is 40-70°C.

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