A method for producing vitamin A palmitate

Abstract

The present invention provides a method for producing vitamin A palmitate. The method comprises the following steps: mixing a vitamin A alcohol solution and palmitic acid, and then introducing the mixture into a bubble column reactor filled with a catalyst for esterification reaction. A protective gas is introduced from the bottom of the bubble column reactor, and vitamin A palmitate is obtained after the reaction. The protective gas is discharged from the top of the bubble column reactor. A sieve plate is arranged below the interior of the bubble column reactor. The method of the present invention uses a bubble column reactor for the reaction, realizes the separation of the catalyst from the reaction liquid through the sieve plate, the catalyst does not need to be taken out, and has a high reuse rate, and can realize continuous multi-batch production. Dehydration during the reaction process is achieved through gas bubbling, while the reaction rate and conversion rate are improved, so that the conversion rate is ≥99%. At the same time, the production efficiency is also improved, and it has a good application prospect.

Description

Technical Field

[0001] The present invention belongs to the technical field of compound preparation, and particularly relates to a method for producing vitamin A palmitate. Background Art

[0002] Vitamin A has five major physiological functions: maintaining vision, maintaining the integrity of epithelial cell structure, promoting growth and development, enhancing immunity, and antioxidation. However, vitamin A is extremely unstable and is easily destroyed under conditions such as high temperature, air, oxides, acidic substances, and ultraviolet light. Therefore, it is converted into derivatives with the same function and more stable properties for use. Among them, vitamin A palmitate is more stable than other derivatives and has been widely used in cosmetics, drugs, feeds, etc.

[0003] At present, the production of vitamin A palmitate mainly includes chemical synthesis and enzymatic synthesis. The chemical method often produces some toxic substances and by-products, and requires high temperature and high pressure, with high requirements for equipment and energy consumption. The enzymatic method avoids these problems, and has mild reaction conditions, high catalytic efficiency, and inherent specificity, so it has good development prospects.

[0004] JP62248495 discloses a method for enzymatic synthesis of VA palmitate. The reaction is carried out at a temperature of 30 °C for 12 h, and the yield is only 80%. The enzymatic method must be carried out at a lower concentration, with low production capacity. The reaction product contains lipase, which makes subsequent separation difficult, has no cost advantage, and affects product quality.

[0005] CN112921064A discloses a preparation method for immobilized enzyme-catalyzed synthesis of vitamin A palmitate, including: adding palmitic acid, immobilized lipase, and a non-polar solvent to the vitamin A alcohol solution in an inert environment for an esterification reaction, removing the water generated by esterification to separate the water generated by the esterification reaction from the organic solvent to obtain an esterification solution; and desolvating, crystallizing, and filtering the esterification solution to obtain high-purity vitamin A palmitate, with a conversion rate of up to 99%, and the lipase can be reused multiple times. However, this method requires filtration and drying for each batch, with cumbersome steps and low production efficiency.

[0006] CN112724059A discloses a method for preparing vitamin A palmitate. This method uses metal cyanide to modify alkali metal sulfide to obtain a solid base catalyst for vitamin A palmitate, and fills it in a fixed-bed reactor, using VA acetate and palmitic acid as raw materials to achieve the preparation of vitamin A palmitate.

[0007] Currently, the preparation of vitamin A palmitate mostly uses batch reactors, and some also use fixed-bed reactors. When using a batch reactor to prepare vitamin A palmitate, the raw materials and the immobilized enzyme catalyst are put into the reactor. After stirring and mixing for a certain period of time, the product is taken out. The catalyst in the reaction solution is recovered by filtration and drying and then reused. However, the strong shear force during stirring is likely to break the immobilized enzyme, causing the enzyme to fall off the carrier, denature and inactivate, reducing the service life of the enzyme. When using a fixed-bed reactor to prepare vitamin A palmitate, the immobilized catalyst is orderly and evenly filled in the reactor bed layer. The reaction raw materials flow through the catalyst bed layer in a plug flow pattern to carry out the reaction. The water generated by the reaction will continuously accumulate in the fixed-bed reactor. The esterification reaction is a reversible reaction. As the water accumulates, the reaction rate of the esterification reaction decreases, and at the same time, the esterification product is hydrolyzed, resulting in a decrease in the conversion rate. Moreover, excessive water will be adsorbed into the immobilized enzyme, reducing the enzyme activity.

[0008] In summary, how to provide a method for producing vitamin A palmitate that can ensure the service life of the catalyst, achieve efficient dehydration, and improve the conversion rate has become an urgent problem to be solved. Summary of the Invention

[0009] Aiming at the problems existing in the prior art, the purpose of the present invention is to provide a method for producing vitamin A palmitate. The method improves the structure of a bubble column reactor and uses it to produce vitamin A palmitate, which can directly separate the catalyst from the reaction solution, and has the advantages of high reaction rate, high conversion rate, and high catalyst utilization rate.

[0010] To achieve this purpose, the present invention adopts the following technical solutions:

[0011] In the first aspect, the present invention provides a method for producing vitamin A palmitate, which includes the following steps:

[0012] Mix the vitamin A alcohol solution and palmitic acid and then introduce them into a bubble column reactor filled with a catalyst for an esterification reaction. Introduce a protective gas from the bottom of the bubble column reactor. After the reaction, vitamin A palmitate is obtained, and the protective gas is discharged from the top of the bubble column reactor;

[0013] A sieve plate is arranged below the interior of the bubble column reactor.

[0014] In the present invention, on the one hand, for the existing bubble column reactor, a sieve plate is arranged below its interior, and the catalyst is loaded above the sieve plate. During the reaction process, the filtration separation of the catalyst and the reaction liquid can be directly achieved, and the catalyst does not need to be taken out, with simple operation, avoiding the subsequent cumbersome steps such as filtration, drying, and recycling. Compared with the existing intermittent reaction kettle, it can effectively reduce the crushing effect of mechanical stirring on the catalyst and greatly improve the service life of the catalyst. On the other hand, the introduction of the protective gas can promote the uniform mixing of the catalyst and the reaction liquid, and at the same time achieve dehydration during the reaction process, making the esterification reaction proceed in the forward direction and improving the reaction rate and conversion rate.

[0015] The following are the preferred technical solutions of the present invention, but not the limitations of the technical solutions provided by the present invention. Through the following technical solutions, the technical purposes and beneficial effects of the present invention can be better achieved.

[0016] As a preferred technical solution of the present invention, the concentration of the vitamin A alcohol solution is 200 - 500 g / L, such as 200 g / L, 250 g / L, 300 g / L, 350 g / L, 400 g / L, 450 g / L or 500 g / L, etc., but not limited to the listed values. Other unlisted values within this numerical range are equally applicable, and preferably 300 - 400 g / L.

[0017] As a preferred technical solution of the present invention, the loading amount of the catalyst is 0.5 - 8% of the hourly feeding mass of vitamin A alcohol in the vitamin A alcohol solution, such as 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7% or 8%, etc., but not limited to the listed values. Other unlisted values within this numerical range are equally applicable, and preferably 2 - 6%.

[0018] As a preferred technical solution of the present invention, the mass ratio of vitamin A alcohol in the vitamin A alcohol solution to the catalyst is 1:(0.05 - 0.3), such as 1:0.05, 1:0.1, 1:0.15, 1:0.2, 1:0.25 or 1:0.3, etc., but not limited to the listed values. Other unlisted values within this numerical range are equally applicable, and preferably 1:(0.1 - 0.15).

[0019] As a preferred technical solution of the present invention, the catalyst includes lipase.

[0020] As a preferred technical solution of the present invention, the retinol solution and palmitic acid are mixed to form a raw material liquid, and the flow rate ratio of the raw material liquid to the protective gas introduced is 1 g:(0.0375 - 0.6) L, such as 1 g:0.0375 L, 1 g:0.05 L, 1 g:0.1 L, 1 g:0.2 L, 1 g:0.3 L, 1 g:0.4 L, 1 g:0.5 L or 1 g:0.6 L, etc., but not limited to the listed values. Other unlisted values within this numerical range are equally applicable, and preferably 1 g:(0.075 - 0.3) L.

[0021] In the present invention, the balanced ratio of the amount of the raw material liquid to the protective gas introduced is crucial for the reaction effect. If the amount of the protective gas introduced is too large, the backmixing degree in the reactor increases, the reaction rate slows down, and within the same residence time, the reaction conversion rate decreases; if the amount of the protective gas introduced is too small, although the backmixing degree in the reactor decreases, but at the same time the ability of nitrogen stripping water is reduced, the water content in the reaction liquid increases, and the esterification reaction is a reversible reaction, thus resulting in a decrease in the reaction conversion rate. The specific amounts of the raw material liquid and the protective gas introduced can be reasonably calculated by those skilled in the art according to the effective volume of the reactor.

[0022] As a preferred technical solution of the present invention, the operating pressure of the bubble reactor is 50 - 130 kPaA, such as 50 kPaA, 60 kPaA, 70 kPaA, 80 kPaA, 90 kPaA, 100 kPaA, 110 kPaA or 130 kPaA, etc., but not limited to the listed values. Other unlisted values within this numerical range are equally applicable, and preferably 80 - 105 kPaA.

[0023] As a preferred technical solution of the present invention, the operating temperature of the bubble reactor is 20 - 60 °C, such as 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, 45 °C, 50 °C, 55 °C or 60 °C, etc., but not limited to the listed values. Other unlisted values within this numerical range are equally applicable, and preferably 30 - 45 °C. As a preferred technical solution of the present invention, the time of the esterification reaction is 1 - 8 hours, such as 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours or 8 hours, etc., but not limited to the listed values. Other unlisted values within this numerical range are equally applicable, and preferably 2 - 4 hours.

[0024] As a preferred technical solution of the present invention, the esterification reaction liquid obtained from the bubble column reactor is crystallized to obtain vitamin A palmitate.

[0025] Preferably, the crystallizing agent used for the crystallization includes organic alcohol.

[0026] Preferably, the organic alcohol includes any one or a combination of at least two of methanol, ethanol, isopropanol, n-butanol or glycerol. Typical but non-limiting examples of the combination are: a combination of methanol and ethanol, a combination of ethanol and isopropanol, a combination of isopropanol, n-butanol and glycerol, etc. Methanol is preferred.

[0027] Preferably, the mass ratio of the crystallizing agent to the esterification reaction solution is (1-10):1, such as 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 10:1, etc., but is not limited to the listed values. Other unlisted values within this numerical range are equally applicable. (2-5):1 is preferred.

[0028] Preferably, the crystallization temperature is -10 to 10 °C, such as -10 °C, -5 °C, 0 °C, 2 °C, 4 °C, 6 °C, 8 °C or 10 °C, etc., but is not limited to the listed values. Other unlisted values within this numerical range are equally applicable. -2 to 5 °C is preferred.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] (1) In the method of the present invention, the esterification reaction is carried out in a bubble column reactor. Compared with a batch reactor, the crushing effect of mechanical stirring on the catalyst can be effectively reduced, and the service life of the enzyme can be greatly improved.

[0031] (2) Through the setting of the sieve plate in the method of the present invention, the catalyst does not drain out with the reaction solution during the reaction process and remains in the reactor all the time, avoiding cumbersome steps such as subsequent filtration, drying and recycling.

[0032] (3) In the method of the present invention, the esterification reaction is carried out using a bubble column reactor, which is beneficial to reducing backmixing and improving the reaction rate compared with a kettle reactor.

[0033] (4) When bubbling with a protective gas in the method of the present invention, it can promote the uniform mixing of the catalyst and the reaction solution, and at the same time can achieve dehydration during the reaction process, making the esterification reaction proceed in the forward direction, improving the reaction rate, conversion rate and yield. The conversion rate can reach more than 93.7%, and the yield can reach more than 93.4%. By further controlling the reaction conditions, the conversion rate can reach more than 99.2%, and the yield can reach more than 98.9%. Detailed Embodiments

[0034] To better illustrate the present invention and facilitate understanding of its technical solutions, the present invention will be further described in detail below. However, the following embodiments are only simple examples of the present invention and do not represent or limit the scope of the patent protection of the present invention. The scope of protection of the present invention is subject to the claims.

[0035] In the following examples and comparative examples of the present invention, unless otherwise specified, the raw materials used in the examples or comparative examples are all obtained from commercial channels. Among them, vitamin A acetate was purchased from Zhejiang Medicine Co., Ltd., palmitic acid was purchased from Aladdin, and the catalyst was Novozyme 435 lipase purchased from Novozymes.

[0036] In addition, in a specific embodiment, the present invention provides a method for preparing a vitamin A alcohol solution, and the preparation method includes:

[0037] The air in the three-necked flask was replaced with nitrogen. 100 g of vitamin A acetate was weighed and placed in the flask, and 200 g of methanol was weighed and placed in the three-necked flask, followed by stirring at a stirring speed of 200 rpm. At room temperature, 27 g of a 50 wt% NaOH solution was added for hydrolysis reaction for 1 h. After the reaction, 120 g of n-hexane was added to the reaction system for extraction, and the mixture was washed with water until neutral. The organic phase was taken and detected by HPLC method. The hydrolysis conversion rate was 100%, and the concentration of the vitamin A alcohol solution was measured to be 330 g / L. This vitamin A alcohol solution was used as the raw material source for the following examples and comparative examples.

[0038] The following are typical but non-limiting examples of the present invention:

[0039] Example 1:

[0040] This example provides a method for producing vitamin A palmitate. The preparation method uses a bubble column reactor with a diameter of 8 cm and a height of 80 cm. A porous sieve plate with a pore diameter of Φ0.5 mm is provided at the lower part inside, and a jacket is provided outside. Circulating water is introduced into the jacket to maintain the temperature of the whole system constant.

[0041] The method includes the following steps:

[0042] Weigh 2400 g of the esterification reaction solution prepared by the kettle reactor and add it as the bottom liquid into the bubble column reactor; weigh the catalyst and load it into the bubble column reactor, and the loaded catalyst mass is 4% of the hourly feed mass of vitamin A alcohol.

[0043] Nitrogen is introduced from the bottom of the bubble reactor at a flow rate of 2 L / min. The nitrogen is dispersed through the sieve plate to make the catalyst as evenly distributed as possible in the reaction solution under the bubbling state;

[0044] The vitamin A alcohol solution and palmitic acid are mixed in a mass ratio of 2.7:1 to form a raw material liquid, which is fed into the top feed port of the bubble reactor at a flow rate of 13.3 g / min, and the reaction pressure is controlled at atmospheric pressure and the temperature is 30 °C;

[0045] In the above esterification reaction, the residence time of the reaction was controlled to be 3 h. After the bottom liquid was completely replaced, a sample was taken from the discharge port at the bottom of the bubble reactor to test the reaction. The reaction conversion rate was measured to be 99.7%, and the yield was 99.5%. After continuous operation for 3 days, a sample was taken to test the reaction. The reaction conversion rate was measured to be 99.7%, the yield was 99.5%, and the water content was 0.31 wt%. After continuous operation for 5 days, a sample was taken to test the reaction. The reaction conversion rate was measured to be 99.2%, and the yield was 98.9%.

[0046] Example 2:

[0047] This example provides a method for producing vitamin A palmitate. The preparation method refers to the preparation method in Example 1, with the only difference being that the flow rate of nitrogen is 4 L / min.

[0048] In the above esterification reaction, the residence time of the reaction was controlled to be 3 h. A sample was taken from the discharge port at the bottom of the bubble reactor to test the reaction. The reaction conversion rate was measured to be 99.4%, and the yield was 99.2%. After continuous operation for 3 days, a sample was taken to test the reaction. The reaction conversion rate was measured to be 99.2%, the yield was 98.9%, and the water content was 0.29 wt%.

[0049] Example 3:

[0050] This example provides a method for producing vitamin A palmitate. The preparation method refers to the preparation method in Example 1, with the only difference being that the flow rate of nitrogen is 1 L / min.

[0051] In the above esterification reaction, the residence time of the reaction was controlled to be 3 h. A sample was taken from the discharge port at the bottom of the bubble reactor to test the reaction. The reaction conversion rate was measured to be 99.3%, and the yield was 99%. After continuous operation for 3 days, a sample was taken to test the reaction. The reaction conversion rate was measured to be 99.2%, the yield was 98.9%, and the water content was 0.89 wt%.

[0052] Example 4:

[0053] This example provides a method for producing vitamin A palmitate. The preparation method refers to the preparation method in Example 1, with the only difference being that the flow rate ratio of the raw material liquid to the nitrogen introduced is the same as that in Example 1. The flow rate of the raw material liquid was reduced to 10 g / min, and the flow rate of nitrogen was 1.5 L / min, ensuring that the mass of the loaded catalyst was 4% of the hourly feed mass of vitamin A alcohol.

[0054] In the above esterification reaction, the residence time of the reaction was controlled to be 4 h. A sample was taken from the discharge port at the bottom of the bubble reactor to test the reaction. The reaction conversion rate was measured to be 99.9%, and the yield was 99.7%.

[0055] Example 5:

[0056] This example provides a method for producing vitamin A palmitate. The preparation method refers to the preparation method in Example 1, with the only difference being that the flow rate of nitrogen is 8 L / min.

[0057] After running for 3 hours, a sample was taken from the discharge port at the bottom of the bubble reactor to test the reaction conditions. The reaction conversion rate was measured to be 93.7%, the yield was 93.4%, and the moisture content was 0.15 wt%.

[0058] Example 6:

[0059] This example provides a method for producing vitamin A palmitate. The preparation method refers to the preparation method in Example 1, with the only difference being that the flow rate of nitrogen is 0.5 L / min.

[0060] After running for 3 hours, a sample was taken from the discharge port at the bottom of the bubble reactor to test the reaction conditions. The reaction conversion rate was measured to be 94.6%, the yield was 94.2%, and the moisture content was 1.3 wt%.

[0061] Comparative Example 1:

[0062] This comparative example provides a method for producing vitamin A palmitate. The method uses a batch autoclave reactor, and the method includes:

[0063] The air in the batch autoclave reactor was replaced with nitrogen. 1740 g of vitamin A alcohol solution and 660 g of palmitic acid were weighed and placed in the batch autoclave reactor for stirring at a stirring speed of 200 rpm. 80 g of catalyst was weighed and added to the batch autoclave reactor, and at the same time, 500 g of anhydrous sodium sulfate was added for water removal. The operating pressure was controlled at atmospheric pressure, and the operating temperature was 30 °C.

[0064] After continuously stirring and reacting for 3 hours, a sample was taken for analysis. The reaction conversion rate was measured to be 93.6%, and the yield was 93.4%; after reacting for 5 hours, a sample was taken for analysis. The reaction conversion rate was measured to be 96.9%, and the yield was 96.2%; after reacting for 7 hours, a sample was taken for analysis. The reaction conversion rate was measured to be 97%, and the yield was 96.3%; limited by the water removal ability of anhydrous sodium sulfate, the conversion rate of the esterification reaction was only about 97%. The reaction time of the batch reactor was determined to be 5 hours.

[0065] After the 5-hour reaction was completed, the reaction solution was filtered through two layers of sieves with Φ3 mm and Φ0.5 mm respectively to obtain sodium sulfate solid and catalyst solid. The obtained catalyst was dried and reused. Referring to the above operation steps, the catalyst was recycled 6 times, with each reaction lasting 5 hours. The sampling analysis results are shown in Table 1.

[0066] Table 1

[0067]

[0068]

[0069] Analysis of Examples 1-3 shows that when the method of the present invention is continuously operated for three days, the processing capacity is equivalent to that of producing 24 batches using a batch reactor. The conversion rate remains above 99.2%, and the yield remains above 98.9%. In Comparative Example 1, after 6 recycles, the conversion rate and yield decreased to about 91%, proving that the method provided by the present invention has the technical effects of improving the conversion rate, yield, and reaction rate.

[0070] Furthermore, analysis of Example 1 and Example 4 shows that the reaction conversion rate of Example 4 is higher than that of Example 1. The reason is that with the same reaction volume, the feed flow rate of Example 4 decreases and the residence time increases, further improving the reaction conversion rate. The reaction conversion rate of Example 2 is lower than that of Example 1 because the nitrogen flow rate increases, the degree of backmixing in the reactor increases, and the reaction rate slows down. With the same residence time, the reaction conversion rate decreases, which is further confirmed by Example 5. The reaction conversion rate of Example 3 is lower than that of Example 1 because the nitrogen flow rate decreases. Although the degree of backmixing in the reactor decreases, the ability to strip water by nitrogen also decreases, and the water content in the reaction liquid increases. Since the esterification reaction is a reversible reaction, the reaction conversion rate decreases, which is further confirmed by Example 6.

[0071] Analysis of Example 1 and Comparative Example 1 shows that compared with the transesterification reaction using a bubble column reactor in the present invention, when using a batch reactor, the required reaction time increases from 3 hours to 5 hours, and the conversion rate decreases from 99.7% (Example 1) to 96.9% (Comparative Example 1), resulting in a significant reduction in production efficiency. In addition, a water remover needs to be added to the reaction system additionally, increasing the post-treatment steps. At the same time, when using the bubble column reactor proposed by the present invention for the esterification reaction, after continuous reaction for 5 days, the reaction conversion rate is still as high as 99.2%, equivalent to 40 batches of batch reactions. When using a batch reactor for the esterification reaction, after the catalyst is recycled 5 times, the reaction conversion rate < 93%. This is because the strong shear force of stirring easily breaks the immobilized enzyme, causing the enzyme to fall off the carrier, denature and inactivate, significantly reducing the service life of the enzyme.

[0072] From the above examples and comparative examples, it can be seen that the method for producing vitamin A palmitate of the present invention realizes the separation of the catalyst and the reaction liquid by setting a sieve plate in the bubble column reactor, so that the catalyst does not need to be taken out, the operation is simple, the reuse rate of the catalyst is improved, and continuous multi-batch production can be realized; dehydration during the reaction process is further realized by bubbling with a protective gas, improving the reaction rate and conversion rate. Using the method of the present invention can ensure a high reaction conversion rate (≥99%) even during long-term operation, and at the same time has higher production efficiency.

[0073] The present invention illustrates the detailed method of the present invention through the above embodiments, but the present invention is not limited to the above detailed method, that is, it does not mean that the present invention must rely on the above detailed method to be implemented. Those skilled in the art should understand that any improvement to the present invention, equivalent substitution of the operations of the present invention, addition of auxiliary operations, selection of specific modes, etc. all fall within the protection scope and the disclosure scope of the present invention.

Claims

1. A method for producing vitamin A palmitate, characterized in that, The method includes the following steps: Mix the vitamin A alcohol solution and palmitic acid, then introduce them into a bubble column reactor filled with a catalyst for esterification reaction. Introduce a protective gas from the bottom of the bubble column reactor. The esterification reaction liquid obtained from the bubble column reactor is crystallized to obtain vitamin A palmitate, and the protective gas is discharged from the top of the bubble column reactor; The method realizes dehydration during the reaction process to make the esterification reaction proceed in the forward direction; A sieve plate is arranged below the interior of the bubble column reactor; After the vitamin A alcohol solution and palmitic acid are mixed, a raw material liquid is formed. The flow rate ratio of the raw material liquid to the introduced protective gas is 1 g:(0.075 - 0.3) L; The crystallizing agent used for crystallization includes organic alcohol; The mass ratio of the crystallizing agent to the esterification reaction liquid is (1 - 10):1; The catalyst is lipase.

2. The method according to claim 1, wherein The concentration of the vitamin A alcohol solution is 200 - 500 g / L.

3. The method according to claim 2, characterized in that The concentration of the vitamin A alcohol solution is 300 - 400 g / L.

4. The method according to claim 1, wherein The molar ratio of vitamin A alcohol to palmitic acid in the vitamin A alcohol solution is 1:(0.8 - 1.6).

5. The method according to claim 4, wherein The molar ratio of vitamin A alcohol to palmitic acid in the vitamin A alcohol solution is 1:(1 - 1.2).

6. The method according to claim 1, wherein The loading amount of the catalyst is 0.5 - 8% of the hourly feeding mass of vitamin A alcohol in the vitamin A alcohol solution.

7. The method according to claim 6, wherein The loading amount of the catalyst is 2 - 6% of the hourly feeding mass of vitamin A alcohol in the vitamin A alcohol solution.

8. The method according to claim 1, wherein The operating pressure of the bubble reactor is 50 - 130 kPaA.

9. The method according to claim 8, wherein The operating pressure of the bubble reactor is 80 - 105 kPaA.

10. The method according to claim 1, wherein The operating temperature of the bubble reactor is 20 - 60 °C.

11. The method according to claim 10, wherein The operating temperature of the bubble reactor is 30 - 45 °C.

12. The method according to claim 1, wherein The time of the esterification reaction is 1 - 8 hours.

13. The method according to claim 12, wherein The time of the esterification reaction is 2 - 4 hours.

14. The method according to claim 1, characterized in that, The organic alcohol includes any one or a combination of at least two of methanol, ethanol, isopropanol, n-butanol or glycerol.

15. The method according to claim 14, wherein The organic alcohol is methanol.

16. The method according to claim 1, wherein The mass ratio of the crystallizing agent to the esterification reaction liquid is (2 - 5):

1.

17. The method according to claim 1, wherein The temperature of the crystallization is -10 - 10 °C.

18. The method according to claim 17, wherein The temperature of the crystallization is -2 - 5 °C.

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