Method for preparing methyl caffeate

Abstract

The invention discloses a method for preparing methyl caffeate, and belongs to the technical field of natural product preparation. The method comprises the following steps: (1) adding an alcohol solvent into isochlorogenic acid, adding alkali to adjust the pH value to be alkaline, and reacting to obtain a reaction solution; (2) adjusting the pH value of the reaction liquid to be acidic, continuously reacting, and then filtering to obtain filtrate; (3) carrying out evaporative crystallization on the filtrate, and concentrating until the solid content is 40-50%; and (4) adding water to adjust the solid content, carrying out solvent-out crystallization, filtering, and washing to obtain the methyl caffeate. Methyl caffeate is efficiently obtained through transesterification, the reaction continues after acid adjustment, and the product yield is increased. According to the dissolvability difference between the product and flavone, phospholipid and quinic acid, methyl caffeate is promoted to be separated out through evaporative crystallization, the yield of the methyl caffeate is increased through solventing-out crystallization, and the content of the obtained methyl caffeate is 98% or above; the method has the advantages of simple process, easy operation, high product purity and the like, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of natural product preparation, and particularly relates to a method for preparing caffeic acid methyl ester. Background Art

[0002] Caffeic acid methyl ester has antibacterial, antioxidant and anti-tumor pharmacological activities, so it is widely used in food, cosmetics, health care products and pharmaceutical industries. In addition, it is also used as an organic synthesis intermediate for the synthesis of chicoric acid, caffeic acid propyl ester and caffeic acid phenethyl ester.

[0003] The content of caffeic acid methyl ester in plants is low, so the plant extraction method is difficult to prepare caffeic acid methyl ester and the yield is low. The existing chemical synthesis method of caffeic acid methyl ester has a complex reaction route, and requires many types of reaction raw materials, most of which are pure compounds.

[0004] Most chemical synthesis methods use caffeic acid and methanol as raw materials, and react under acidic conditions to obtain caffeic acid methyl ester. Shin et al. used sulfuric acid catalysis to catalyze the esterification of caffeic acid and methanol to synthesize caffeic acid methyl ester, and the yield reached 71.0% after 10 hours of reaction. The invention patent CN101585770A discloses a method of synthesizing caffeic acid methyl ester by catalyzing the reaction of caffeic acid and methanol under microwave conditions with concentrated sulfuric acid, and the reaction time was 4 minutes, and the yield was 94%. There are also literature reports that p-toluenesulfonic acid was used to catalyze the synthesis of caffeic acid methyl ester with caffeic acid and methanol. After 4 hours of reaction, the product yield was 84.0%. However, the traditional acid catalysis method has the disadvantages of long reaction time, excessive by-products, strong corrosion of the catalyst to the equipment, complex product separation process, and easy volatilization of gases that pollute the environment.

[0005] Therefore, it is urgent to find a method for synthesizing caffeic acid methyl ester that can solve the above-mentioned technical defects under mild conditions. Summary of the invention

[0006] In order to solve the above technical problems, the present invention provides a method for preparing caffeic acid methyl ester, using isochlorogenic acid with a content of more than 20% as a raw material (the main impurities are water-soluble flavonoid glycosides, phospholipids, etc.), using an ester exchange method to convert isochlorogenic acid into caffeic acid methyl ester and quinic acid, and developing a simple and efficient purification method based on the characteristics of the raw materials. The specific technical scheme is: A method for preparing caffeic acid methyl ester comprises the following steps: (1) adding an alcohol solvent to isochlorogenic acid, and adding a base to adjust the pH value to alkaline, reacting to obtain a reaction solution; (2) adjusting the pH value of the reaction solution to acidic, continuing the reaction, and then filtering to obtain a filtrate; (3) Evaporating and crystallizing the filtrate to concentrate it to a solid content of 40-50%; (4) adding water to adjust the solid content to perform dissolution and crystallization, filtering and washing to obtain caffeic acid methyl ester.

[0007] Furthermore, in step (1), the content of isochlorogenic acid is ≥20wt%; and the alcohol solvent is 50% to 80% methanol.

[0008] Furthermore, in step (1), the mass volume ratio of isochlorogenic acid to alcohol solvent is 1:1 to 1:5.

[0009] Furthermore, in step (1), the base is one or more of sodium hydroxide, potassium hydroxide, and calcium hydroxide, and the pH value is 8 to 12.

[0010] Furthermore, in step (1), the reaction temperature is 25-70° C., and the reaction time is 10 min-12 h.

[0011] Furthermore, in step (2), the pH value of the reaction solution is adjusted to 2-7 using one or more of hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid.

[0012] Furthermore, in step (2), the pH value of the reaction solution is adjusted to 2-3.

[0013] Furthermore, in step (4), water is added to adjust the solid content to 15-20% for dissolution and crystallization.

[0014] Furthermore, in step (4), the mass content of caffeic acid methyl ester is ≥98%.

[0015] The present invention uses alkali as a catalyst to make the isochlorogenic acid react completely to obtain caffeic acid methyl ester. After the reaction is completed, acid is added to terminate the reaction in time to avoid further hydrolysis. Since the raw material contains a small amount of caffeic acid, and the hydrolysis of caffeic acid methyl ester will also generate caffeic acid, the caffeic acid in the system after acid addition can react with methanol to generate caffeic acid methyl ester, which is beneficial to improve the product yield.

[0016] During the evaporation and crystallization process, the methanol content gradually decreases, and caffeic acid methyl ester begins to precipitate gradually. Controlling a certain solid content is beneficial to removing impurities and reducing product losses. Adding water afterwards can reduce the solubility of caffeic acid methyl ester in the system, control a certain solid content, increase the yield of caffeic acid methyl ester, and ensure product purity.

[0017] The beneficial effect produced by adopting the above technical scheme is that: the present invention efficiently obtains caffeic acid methyl ester through ester exchange reaction, continues the reaction after acid adjustment, and improves the product yield. According to the difference in solubility between the product and flavonoids, phospholipids, and quinic acid, evaporation crystallization is used to promote the precipitation of caffeic acid methyl ester. Dissolution crystallization is used to improve the yield of caffeic acid methyl ester, and the obtained caffeic acid methyl ester content is more than 98%, and the yield is not less than 70%. The present invention has the advantages of simple process, easy operation, high product purity, etc., and is suitable for large-scale industrial production. DETAILED DESCRIPTION Example 1

[0018] This embodiment provides a method for preparing caffeic acid methyl ester, the steps of which are as follows: Add 200g of 50% isochlorogenic acid to a three-necked flask, add 32% liquid alkali, add 400mL80% methanol, and adjust the pH to 10.5. React at 60°C for 20min. Add 60% sulfuric acid to the reaction solution, adjust the pH to 2.5, continue the reaction for 12h, filter the sodium sulfate, evaporate the filtrate for crystallization, and concentrate to a solid content of 50%. Add water, adjust the solid content to 15%, let stand for crystallization, filter, use 200mL of water each time, wash 3 times, and dry to obtain caffeic acid methyl ester. After testing, the yield of caffeic acid methyl ester was 89% and the content was 98.5%. Example 2

[0019] This embodiment provides a method for preparing caffeic acid methyl ester, the steps of which are as follows: Add 200g of 20% isochlorogenic acid to a three-necked flask, add 32% liquid alkali, add 400mL70% methanol, and adjust the pH to 11. React at 70°C for 10min. Add 60% sulfuric acid to the reaction solution, adjust the pH to 2.5, continue the reaction for 12h, filter the sodium sulfate, evaporate the filtrate for crystallization, and concentrate to a solid content of 50%. Add water, adjust the solid content to 16%, let stand for crystallization, filter, use 200mL of water each time, wash 3 times, and dry to obtain caffeic acid methyl ester. After testing, the yield of caffeic acid methyl ester was 87% and the content was 98.5%. Example 3

[0020] This embodiment provides a method for preparing caffeic acid methyl ester, the steps of which are as follows: Add 200g of 50% isochlorogenic acid to a three-necked flask, add 32% liquid alkali, add 400mL 50% methanol, and adjust the pH to 12. React at 25°C for 12h. Add 60% sulfuric acid to the reaction solution, adjust the pH to 2.5, continue to react for 12h, filter the sodium sulfate, evaporate the filtrate for crystallization, and concentrate to a solid content of 50%. Add water, adjust the solid content to 16.4%, let stand for crystallization, filter, use 200mL of water each time, wash 3 times, and dry to obtain caffeic acid methyl ester. After testing, the yield of caffeic acid methyl ester was 80% and the content was 98.3%. Example 4

[0021] This embodiment provides a method for preparing caffeic acid methyl ester, the steps of which are as follows: Add 200g of 50% isochlorogenic acid to a three-necked flask, add 30% liquid alkali, add 400mL 80% methanol, and adjust the pH to 8. React at 58°C for 12h. Add 60% sulfuric acid to the reaction solution, adjust the pH to 2.5, continue to react for 12h, filter the sodium sulfate, evaporate the filtrate for crystallization, and concentrate to a solid content of 50%. Add water, adjust the solid content to 15%, let stand for crystallization, filter, use 200mL of water each time, wash 3 times, and dry to obtain caffeic acid methyl ester. After testing, the yield of caffeic acid methyl ester was 88% and the content was 98.4%. Example 5

[0022] This embodiment provides a method for preparing caffeic acid methyl ester, the steps of which are as follows: Add 200g of 50% isochlorogenic acid to a three-necked flask, add potassium hydroxide, add 200mL75% methanol, and adjust the pH to 11. React at 63℃ for 20min. Add 60% sulfuric acid to the reaction solution, adjust the pH to 2.5, continue the reaction for 12h, filter potassium sulfate, evaporate the filtrate for crystallization, and concentrate to a solid content of 40%. Add water, adjust the solid content to 20%, let stand for crystallization, filter, use 200mL of water each time, wash 3 times, and dry to obtain caffeic acid methyl ester. After testing, the yield of caffeic acid methyl ester was 81% and the content was 98.3%. Example 6

[0023] This embodiment provides a method for preparing caffeic acid methyl ester, the steps of which are as follows: Add 200g of 50% isochlorogenic acid to a three-necked flask, add 32% liquid alkali, add 1000mL 80% methanol, and adjust the pH to 10. React at 60°C for 20min. Add 60% sulfuric acid to the reaction solution, adjust the pH to 3, continue the reaction for 12h, filter the sodium sulfate, evaporate the filtrate for crystallization, and concentrate to a solid content of 45%. Add water, adjust the solid content to 20%, let stand for crystallization, filter, use 200mL of water each time, wash 3 times, and dry to obtain caffeic acid methyl ester. After testing, the yield of caffeic acid methyl ester was 83% and the content was 98.4%. Example 7

[0024] This embodiment provides a method for preparing caffeic acid methyl ester, the steps of which are as follows: Add 200g of 50% isochlorogenic acid to a three-necked flask, add 32% liquid alkali, add 600mL80% methanol, and adjust the pH to 11. React at 60℃ for 30min. Add concentrated hydrochloric acid to the reaction solution, adjust the pH to 2.5, continue the reaction for 12h, filter the sodium chloride, evaporate the filtrate for crystallization, and concentrate to a solid content of 48%. Add water, adjust the solid content to 15%, let stand for crystallization, filter, use 200mL of water each time, wash 3 times, and dry to obtain caffeic acid methyl ester. After testing, the yield of caffeic acid methyl ester was 78% and the content was 98.3%. Example 8

[0025] This embodiment provides a method for preparing caffeic acid methyl ester, the steps of which are as follows: Add 200g of 50% isochlorogenic acid to a three-necked flask, add 32% liquid alkali, add 400mL77% methanol, and adjust the pH to 11. React at 60℃ for 20min. Add concentrated hydrochloric acid to the reaction solution, adjust the pH to 7, continue the reaction for 12h, filter the sodium chloride, evaporate the filtrate for crystallization, and concentrate to a solid content of 50%. Add water, adjust the solid content to 15%, let stand for crystallization, filter, use 200mL of water each time, wash 3 times, and dry to obtain caffeic acid methyl ester. After testing, the yield of caffeic acid methyl ester was 72% and the content was 98.3%.

[0026] Comparative Example 1

[0027] This comparative example provides a method for preparing caffeic acid methyl ester, which differs from the method in Example 1 only in that: evaporation and crystallization are performed to a solid content of 35%. The results show that caffeic acid methyl ester is obtained with a content of 98.2% and a yield of only 61%.

[0028] Comparative Example 2

[0029] This comparative example provides a method for preparing caffeic acid methyl ester, which differs from the method in Example 1 only in that: evaporation and crystallization are performed to a solid content of 65%. The results show that caffeic acid methyl ester is obtained with a content of 85.2% and a yield of only 81%.

[0030] Comparative Example 3

[0031] This comparative example provides a method for preparing caffeic acid methyl ester, which differs from the method in Example 1 only in that water is added to adjust the solid content to 30%. The results show that caffeic acid methyl ester is obtained with a content of 98.1% and a yield of only 63%.

[0032] Comparative Example 4

[0033] This comparative example provides a method for preparing caffeic acid methyl ester, the steps of which are as follows: Add 200g of 50% isochlorogenic acid to a three-necked flask, add 32% liquid alkali, add 400mL 80% methanol, and adjust the pH to 13. React at 60°C for 20min. Add 60% sulfuric acid to the reaction solution, adjust the pH to 2.5, continue the reaction for 12h, filter the sodium sulfate, evaporate the filtrate for crystallization, and concentrate to a solid content of 50%. Add water, adjust the solid content to 15%, let stand for crystallization, filter, use 200mL of water each time, wash 3 times, and dry to obtain caffeic acid methyl ester. After testing, the yield of caffeic acid methyl ester was 64% and the content was 98.5%.

[0034] It can be seen from the embodiment and comparative examples 1 and 2 that the present invention promotes the precipitation of caffeic acid methyl ester by controlling the solid content in the evaporation and crystallization process, thereby ensuring the content and yield of the caffeic acid methyl ester product.

[0035] It can be seen from the embodiment and comparative examples 3 and 4 that the present invention improves the yield of caffeic acid methyl ester product by regulating the solid content in the dissolution and crystallization process and the appropriate pH value of the transesterification reaction.

[0036] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing caffeic acid methyl ester, characterized in that: The following steps are involved: (1) adding an alcohol solvent to isochlorogenic acid, and adding a base to adjust the pH value to alkaline, reacting to obtain a reaction solution; (2) adjusting the pH value of the reaction solution to acidic, continuing the reaction, and then filtering to obtain a filtrate; (3) Evaporating and crystallizing the filtrate to concentrate it to a solid content of 40-50%; (4) adding water to adjust the solid content to perform dissolution and crystallization, filtering and washing to obtain caffeic acid methyl ester.

2. The method for preparing caffeic acid methyl ester according to claim 1, characterized in that In step (1), the content of isochlorogenic acid is ≥20wt%; and the alcohol solvent is methanol with a content of 50% to 80%.

3. The method for preparing caffeic acid methyl ester according to claim 2, characterized in that In step (1), the mass volume ratio of isochlorogenic acid to alcohol solvent is 1:1 to 1:

5.

4. The method for preparing caffeic acid methyl ester according to claim 3, characterized in that: In step (1), the alkali is one or more of sodium hydroxide, potassium hydroxide, and calcium hydroxide, and the pH value is 8 to 12.

5. The method for preparing caffeic acid methyl ester according to claim 4, characterized in that: In step (1), the reaction temperature is 25-70° C. and the reaction time is 10 min-12 h.

6. The method for preparing caffeic acid methyl ester according to claim 1, characterized in that: In step (2), the pH value of the reaction solution is adjusted to 2-7 using one or more of hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid.

7. The method for preparing caffeic acid methyl ester according to claim 6, characterized in that: In step (2), the pH value of the reaction solution is adjusted to 2-3.

8. The method for preparing caffeic acid methyl ester according to claim 1, characterized in that In step (4), water is added to adjust the solid content to 15-20% for dissolution and crystallization.

9. The method for preparing caffeic acid methyl ester according to any one of claims 1 to 8, characterized in that: In step (4), the mass content of caffeic acid methyl ester is ≥98%.