A method for preparing 3-ethoxy-4-hydroxymandelic acid at low temperature

Abstract

The present invention relates to the technical field of ethyl vanillin intermediate production, and discloses a method for preparing 3-ethoxy-4-hydroxymandelic acid at low temperature, comprising S1 preparing a sodium glyoxylate solution, S2 preparing a sodium ethyl guaiacol solution, and S3 a reaction stage, wherein the sodium ethyl guaiacol solution is prepared from an ethyl guaiacol solution and a sodium hydroxide solution; the reaction stage is to simultaneously drop a sodium glyoxylate solution and a sodium hydroxide solution into the sodium ethyl guaiacol solution to form a mixed solution, and then heat and stir the reaction after a low-temperature reaction, so as to obtain 3-ethoxy-4-hydroxymandelic acid. In this scheme, the reaction stage adopts a method of first reacting at a low temperature and then heating and stirring the reaction, which effectively improves the reaction selectivity during the reaction, thereby improving the yield of the product 3-ethoxy-4-hydroxymandelic acid.

Description

Technical Field

[0001] The invention relates to the technical field of ethyl vanillin intermediate production, and in particular to a method for preparing 3-ethoxy-4-hydroxymandelic acid at low temperature. Background Art

[0002] 3-Ethoxy-4-hydroxymandelic acid is an important intermediate for the synthesis of ethyl vanillin (chemical name: 3-ethoxy-4-hydroxybenzaldehyde). Ethyl vanillin is a broad-spectrum fragrance with a wide range of uses, such as as a fragrance raw material, flavoring agent or fixative in the food, daily chemical and tobacco industries, with beverages, candies, cakes, biscuits, bread and roasted nuts being the most commonly used.

[0003] At present, the glyoxylic acid method is mainly used to synthesize 3-ethoxy-4-hydroxymandelic acid. The specific steps are: under alkaline conditions, guaiacol and glyoxylic acid undergo a condensation reaction to produce 3-methoxy-4-hydroxymandelic acid with a yield of 70-75%. This method has the advantages of simple process route and easy operation, but the existing method has the disadvantages of long reaction time, many by-products, and low product yield.

[0004] In order to solve the above problems, the prior art CN102190580A discloses a method for preparing 3-ethoxy-4-hydroxymandelic acid, an intermediate of ethyl vanillin synthesis, which is prepared by condensation reaction of glyoxylic acid and 2-ethoxyphenol in an alkaline solution under nitrogen protection, and the raw materials are mixed at 30°C and then kept at 30-60°C for 6 hours to make the raw material conversion rate 88-90%. However, the prior art only calculates the raw material conversion rate, and some by-products are generated during the reaction, so that the raw material conversion rate is not equal to the product yield (specifically, the product yield is less than the substrate conversion rate); the substrate conversion rate in the prior art is low (only 88-90%), which shows that the product yield is low, so that more raw materials are discharged with wastewater in the form of by-products, which significantly increases the production and wastewater treatment costs.

[0005] In summary, developing a method for preparing 3-ethoxy-4-hydroxymandelic acid with low reaction temperature, high substrate selectivity, few by-products and high product yield can not only effectively make up for the shortcomings of existing 3-ethoxy-4-hydroxymandelic acid production, but also reduce the waste of raw materials in the production process, which is of great significance to the expanded production and rapid supply of 3-ethoxy-4-hydroxymandelic acid for wide application. Summary of the invention

[0006] The present invention aims to provide a method for preparing 3-ethoxy-4-hydroxymandelic acid at low temperature, so as to solve the technical problem of low product yield in the existing method for preparing 3-ethoxy-4-hydroxymandelic acid.

[0007] To achieve the above object, the present invention adopts the following technical scheme: a method for preparing 3-ethoxy-4-hydroxymandelic acid at low temperature, comprising S1 preparing a sodium glyoxylate solution, S2 preparing a sodium ethyl guaiacol solution and S3 a reaction stage, wherein the sodium ethyl guaiacol solution is prepared from an ethyl guaiacol solution and a sodium hydroxide solution; the reaction stage comprises simultaneously dropping a sodium glyoxylate solution and a sodium hydroxide solution into the sodium ethyl guaiacol solution to form a mixed solution, reacting at low temperature and then heating and stirring to react, thereby obtaining 3-ethoxy-4-hydroxymandelic acid.

[0008] The principles and advantages of this solution are:

[0009] 1. Compared with the prior art in which the reaction temperature is always high and the product yield is low, the reaction stage in this scheme adopts a method of first low-temperature reaction and then heating and stirring reaction, which effectively improves the reaction selectivity S (S=product yield / substrate conversion rate) during the reaction process, thereby improving the yield of the product 3-ethoxy-4-hydroxymandelic acid. The applicant found in the experiment that the yield of 3-ethoxy-4-hydroxymandelic acid produced by this scheme is higher than 95%, and the reaction selectivity is higher than 96%, thereby significantly improving the production effect of 3-ethoxy-4-hydroxymandelic acid and facilitating the full utilization of raw materials.

[0010] 2. Compared with the limited product yield in the prior art, this solution can not only improve the reaction selectivity and significantly reduce the generation of by-products, but also improve the product yield by controlling the low-temperature reaction of the mixed solution and then heating and stirring the reaction. The applicant found through experiments that by first reacting at low temperature for a period of time, the reaction is effectively facilitated to proceed in the direction of synthesizing 3-ethoxy-4-hydroxymandelic acid, which not only significantly reduces the synthesis of by-products in the production process, but also greatly improves the product yield (product yield is greater than 95%), effectively improves the purity of the product (product purity is greater than 99%), and improves the production efficiency of the product; at the same time, because the amount of by-product synthesis in this solution is reduced, the utilization efficiency of raw materials is significantly improved, and the amount of raw material waste is reduced.

[0011] 3. Compared with the prior art which uses guaiacol as a raw material for producing 3-methoxy-4-hydroxymandelic acid and needs nitrogen protection to generate a relatively stable sodium guaiacol solution, this scheme selects ethyl guaiacol as a raw material, so that when preparing the sodium guaiacol solution in this scheme, a relatively stable sodium guaiacol solution can be generated without nitrogen protection, which effectively reduces the requirements for reaction conditions and effectively reduces production costs.

[0012] Preferably, in S3, the low-temperature reaction is carried out at 5 to 20° C. for 13 to 18 hours.

[0013] Beneficial effects: In this scheme, the sodium ethyl guaiacol solution and the sodium glyoxylate solution react at low temperature in an alkaline environment (sodium hydroxide solution), which can reduce the occurrence of side reactions, thereby improving the product yield and the utilization rate of ethyl guaiacol; and the applicant has found through research that the temperature of the low-temperature reaction can be selected in the range of 5 to 20°C, however, when reacting at lower or higher temperature conditions, the selectivity of the substrate reaction will decrease, which is manifested as a decrease in the product yield. Specifically, when the temperature below 2°C is selected for the reaction, the product yield is 82.4-89.5%; when the temperature above 20°C is selected for the reaction, the product yield is 91.3-93.6%.

[0014] Preferably, in S3, the temperature-raising stirring reaction is carried out at a temperature of 35 to 60° C. and a stirring speed of 300 to 400 rpm for 1 to 3 hours.

[0015] Beneficial effects: This solution reduces the reaction selectivity of by-products during low-temperature reactions and then increases the reaction temperature. At this time, increasing the reaction temperature can effectively increase the reaction rate and accelerate the reaction process. The applicant found through experiments that if the reaction is continued at a temperature of 5 to 20°C, the reaction time needs to be extended to 24 hours to achieve the product yield of 3 hours of temperature-raising reaction, which will significantly reduce the reaction efficiency. The applicant also found that when the temperature of the temperature-raising reaction exceeds 60°C, regardless of the reaction time, the yield of 3-ethoxy-4-hydroxymandelic acid produced by the reaction will be significantly reduced (specifically, the yield is 91.3-93.6%), thereby reducing the production effect.

[0016] Preferably, in S3, the molar ratio of sodium ethyl guaiacol, sodium glyoxylate and sodium hydroxide in the mixed solution is 1-1.3:1-1.3:10-13.

[0017] Beneficial effects: This solution effectively improves the utilization rate of raw materials by adding an appropriate amount of reaction raw materials and maintaining the reaction environment under the regulation of sodium hydroxide, thereby avoiding waste of raw materials.

[0018] Preferably, in S1, the preparation process of the sodium glyoxylate solution is to dropwise add 10wt% sodium hydroxide solution into a 50wt% glyoxylic acid solution at -5 to 10°C until the pH value of the solution is 4 to 6, and react to obtain the sodium glyoxylate solution.

[0019] Beneficial effects: This scheme reduces the reaction temperature of glyoxylic acid and sodium hydroxide, thereby effectively avoiding the disproportionation reaction of glyoxylic acid under high temperature conditions, which results in the generation of a large number of reaction by-products. This scheme can produce a sodium glyoxylate solution in a temperature range of -10 to 20°C, and can also effectively broaden the temperature range of the reaction, thereby reducing the restriction of the ambient temperature on the reaction.

[0020] Preferably, in S2, the preparation process of the sodium ethyl guaiacol solution is to dropwise add 10 wt % sodium hydroxide solution into the ethyl guaiacol solution at 10 to 25° C. until the solution pH is 10 to 12, and react to obtain the sodium ethyl guaiacol solution.

[0021] Beneficial effects: This solution reduces the reaction temperature of ethyl guaiacol and sodium hydroxide, effectively preventing ethyl guaiacol from agglomerating and precipitating under high temperature conditions in a strong alkaline environment, thereby failing to generate a stable sodium guaiacol solution, thereby affecting subsequent reactions. In particular, when the reaction produces a sodium glyoxylate solution within a temperature range of -5 to 10°C, the temperature range of the reaction can be effectively broadened, reducing the limitation of the ambient temperature on the reaction.

[0022] Preferably, in S1, S2 and S3, the dropping speed of the sodium hydroxide solution is 7-12 ml / min.

[0023] Beneficial effects: the reaction raw materials ethyl guaiacol and glyoxylic acid in the scheme are easy to react in a strong alkaline environment, resulting in a decrease in the efficiency of producing 3-ethoxy-4-hydroxymandelic acid by the reaction of the two, thereby reducing the yield of 3-ethoxy-4-hydroxymandelic acid; the scheme reduces the dripping speed of sodium hydroxide so that the local pH of the reaction solution is always within a relatively suitable range, thereby avoiding the excessively fast dripping speed of sodium hydroxide resulting in a strong alkaline environment in the solution, thereby causing the glyoxylic acid in S1 to undergo a disproportionation reaction, the ethyl guaiacol in S2 to agglomerate and precipitate when encountering a strong base, resulting in a raw material solution without normal formation of the reaction, and the reaction selectivity of the by-product in S3 to increase, thereby reducing the yield of the product 3-ethoxy-4-hydroxymandelic acid. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is a graph showing the change in glyoxylic acid conversion rate obtained at different sodium glyoxylate preparation temperatures in Experimental Example 1 of the present invention.

[0025] Figure 2 This is a graph showing the change in the yield of guaiacol obtained at different mass volume ratios of sodium glyoxylate: sodium ethyl lignin in Experimental Example 2 of the present invention.

[0026] Figure 3 This is a graph showing the yield of 3-ethoxy-4-hydroxymandelic acid obtained at different sodium hydroxide drop rates in Experimental Example 3 of the present invention.

[0027] Figure 4 This is a graph showing the yield of 3-ethoxy-4-hydroxymandelic acid obtained at different low temperature reaction temperatures in Experimental Example 4 of the present invention. DETAILED DESCRIPTION

[0028] The following is further described in detail through specific implementation methods, but the implementation methods of the present invention are not limited thereto. Unless otherwise specified, the technical means used in the following examples are conventional means well known to those skilled in the art; the experimental methods used are all conventional methods; the materials, reagents, etc. used can all be obtained from commercial channels. Taking Example 1 as an example, the method for preparing 3-ethoxy-4-hydroxymandelic acid at low temperature in this scheme is described.

[0029] Example 1

[0030] A method for preparing 3-ethoxy-4-hydroxymandelic acid at low temperature, comprising using ethyl guaiacol and glyoxylic acid as raw materials and adjusting the reaction pH value with sodium hydroxide solution, specifically comprising the following steps:

[0031] S1: prepare a sodium glyoxylate solution, add a 10wt% sodium hydroxide solution to a 50wt% glyoxylic acid solution at -5 to 10°C at a rate of 7 to 12 ml / min until the pH of the solution is 4 to 6, and react to obtain a sodium glyoxylate solution with a concentration of 10.6wt%, which is set aside.

[0032] This solution reduces the reaction temperature of glyoxylic acid and sodium hydroxide, thereby effectively avoiding the disproportionation reaction of glyoxylic acid under high temperature conditions, which results in the generation of a large number of reaction by-products. This solution can react to produce a sodium glyoxylate solution within a temperature range of -5 to 10°C, and can also effectively broaden the temperature range of the reaction, thereby reducing the restriction of the ambient temperature on the reaction.

[0033] S2: Prepare a sodium ethyl guaiacol solution, add a 10 wt % sodium hydroxide solution dropwise to a 11.8 wt % ethyl guaiacol solution at a temperature of 10 to 25° C. at a rate of 7 to 12 ml / min until the pH value of the solution is 10 to 12, and react to obtain a sodium ethyl guaiacol solution with a concentration of 10 wt %, which is then used for later use.

[0034] This solution reduces the reaction temperature of ethyl guaiacol and sodium hydroxide, effectively preventing ethyl guaiacol from agglomerating and precipitating under high temperature conditions in a strong alkaline environment, thereby failing to generate a stable sodium guaiacol solution, thereby affecting subsequent reactions. In particular, when the reaction produces a sodium glyoxylate solution within a temperature range of -5 to 10°C, the temperature range of the reaction can be effectively widened, reducing the limitation of the ambient temperature on the reaction.

[0035] S3: Reaction stage, the sodium glyoxylate solution prepared in S1 and 10wt% sodium hydroxide solution are simultaneously added dropwise to the sodium ethyl guaiacol solution prepared in S2 to form a mixed solution, until the mass / molar ratio of sodium ethyl guaiacol, sodium glyoxylate and sodium hydroxide in the mixed solution is 1-1.3:1-1.3:10-13, and the mixture is reacted at a low temperature of 5-20°C for 13-18h, then heated to 35-60°C, and stirred at a speed of 350rpm for 1-3h to obtain 3-ethoxy-4-hydroxymandelic acid.

[0036] The difference between Examples 2 to 6 and Example 1 is that Examples 2-18 demonstrate the low-temperature preparation of 3-ethoxy-4-hydroxymandelic acid under different conditions, and the difference between Comparative Examples 1 to 11 and the examples is that Comparative Examples 1 to 9 demonstrate the low-temperature preparation of 3-ethoxy-4-hydroxymandelic acid under conditions outside the scope of protection of the present scheme; the differences between the conditions for the low-temperature preparation of 3-ethoxy-4-hydroxymandelic acid in Examples 2 to 6 and Comparative Examples 1 to 9 and Example 1 are shown in Table 1.

[0037] Table 1 Differences in the conditions for preparing 3-ethoxy-4-hydroxymandelic acid at low temperature in Examples 1 to 6 and Comparative Examples 1 to 9

[0038]

[0039] Table 2 Results of low temperature preparation of 3-ethoxy-4-hydroxymandelic acid in Examples 1 to 18 and Comparative Examples 1 to 11

[0040]

[0041] Experimental data show that when the molar ratio of sodium ethyl guaiacol, sodium glyoxylate, and sodium hydroxide and other reaction conditions remain unchanged, changing the mixing temperature of sodium glyoxylate solution and sodium ethyl guaiacol solution (S3 low-temperature reaction temperature) will affect the reaction selectivity. As can be seen from the comparison of the product yields in Example 2 and Comparative Example 7, the mixing temperature of sodium glyoxylate solution and sodium ethyl guaiacol solution significantly affects the yield of subsequent products. Specifically, when the S3 low-temperature reaction temperature is higher than 20°C, the product yield in Comparative Example 7 is 6.9% less than that in Example 2. The reason for this is that due to the high temperature, the reaction is aggravated in the direction of generating by-products, resulting in a decrease in the yield of the main product.

[0042] The subsequent temperature increase reaction (S3 temperature increase reaction temperature) effectively increases the reaction rate and accelerates the reaction process. However, too high a reaction temperature reduces the product yield. For example, when the temperature of the temperature increase reaction exceeds 60°C (the temperature of the S3 temperature increase reaction in Comparative Example 3 is 70°C), regardless of the reaction time, the yield of 3-ethoxy-4-hydroxymandelic acid produced by the reaction will be significantly reduced (specifically, the yield is 91.3-93.6%), thereby reducing the production effect.

[0043] In addition, by comparing the examples with comparative examples 1-2, it can be seen that too high or too low reaction temperature of glyoxylic acid and sodium hydroxide (S1 reaction temperature) will lead to an increase in by-products in the sodium glyoxylate solution, thereby significantly reducing the conversion rate of sodium glyoxylate.

[0044] Finally, the comparison of the product yields in Example 1 and Comparative Examples 8-9 shows that the dripping speed of the sodium hydroxide solution also significantly affects the product yield. Specifically, in Comparative Example 8, the sodium hydroxide dripping speed is too fast, so that the local solution pH in the reaction solution rises too fast, so that the sodium glyoxylate undergoes a disproportionation reaction, resulting in an increase in the conversion process of sodium glyoxylate, but the yield of its ortho-condensation byproducts also increases accordingly, and the yield of the product 3-ethoxy-4-hydroxymandelic acid decreases instead; in Comparative Example 9, the sodium hydroxide dripping speed is too slow, so that the local solution pH in the reaction solution rises too slowly, so that the entire reaction process slows down, and the conversion rate and product yield of the two substrates are reduced; and from the comparison of Examples 1-6, it can be seen that the dripping speed of sodium hydroxide is within the range of 7-12ml / min, which can effectively avoid the decrease in product yield caused by the local pH in the reaction solution being too high; and after continuing to slow down the dripping speed of sodium hydroxide to be lower than the minimum sodium hydroxide dripping speed, its product yield has no obvious upward trend. Therefore, it can be determined that adding sodium hydroxide within the sodium hydroxide dropping speed range protected by this scheme can effectively improve the product yield of the scheme, thereby improving the production efficiency of the scheme.

[0045] In addition, by testing the purity of 3-ethoxy-4-hydroxymandelic acid prepared by this scheme, it was found that when 3-ethoxy-4-hydroxymandelic acid was prepared using the preparation process of 3-ethoxy-4-hydroxymandelic acid in this scheme, the purity of 3-ethoxy-4-hydroxymandelic acid obtained under reaction conditions within or outside the protection scope of this scheme was high, and as high as 99.8%, which was significantly higher than the purity of 3-ethoxy-4-hydroxymandelic acid products purchased on the market (purity of 99.0%), indicating that the quality of the 3-ethoxy-4-hydroxymandelic acid product prepared by this scheme is significantly better than the market standard.

[0046] Experimental Example 1: Effect of different preparation temperatures on glyoxylic acid conversion rate

[0047] On the basis of Example 1, the sodium glyoxylate reaction temperature (S1 reaction temperature) was set to -10°C, -5°C, 0°C, 5°C, 10°C, and 15°C in sequence, and the low temperature reaction time in S3 was 13h, and the heating reaction time in S3 was 1h; the remaining steps were carried out in the same manner as in Example 1 to produce sodium glyoxylate and determine the glyoxylic acid conversion rate. The results are shown in Tables 3 and Figure 1 .

[0048] Table 3 Glyoxylic acid conversion rate obtained at different sodium glyoxylate preparation temperatures

[0049]

[0050] Experimental data show that this scheme can significantly improve the glyoxylic acid conversion rate by controlling the preparation temperature of sodium glyoxylate, and as the preparation temperature decreases or increases, the sodium glyoxylate conversion rate shows a trend of first decreasing, then increasing, and then decreasing. Taking into account the yield and production cost of 3-ethoxy-4-hydroxymandelic acid, a preparation temperature of -5~10°C is selected to produce sodium glyoxylate, which can obtain a higher glyoxylic acid conversion rate.

[0051] Experimental Example 2: Effect of different mass volume ratios of sodium glyoxylate: sodium ethyl lignin on the yield of 3-ethoxy-4-hydroxymandelic acid

[0052] On the basis of Example 1, sodium glyoxylate: sodium ethyl lignin in a mass volume ratio of 1:0.5, 1:1, 1:1.1, 1:1.2, 1:1.25, 1:1.3, and 1:1.35 were added to the reactor in sequence, and the low temperature reaction time in S3 was 13 hours, and the heating reaction time in S3 was 1 hour; the remaining steps were produced in the manner of Example 1 and the yield of 3-ethoxy-4-hydroxymandelic acid was determined. The results are shown in Tables 4 and Figure 2 .

[0053] Table 4 Guaiacol yields at different mass volume ratios of sodium glyoxylate: sodium ethyl lignin

[0054]

[0055] Experimental data show that in this scheme, as the mass-volume ratio of sodium glyoxylate: sodium ethyl lignin added to the reactor increases (i.e., as the relative mass of sodium ethyl lignin increases), the yield of 3-ethoxy-4-hydroxymandelic acid shows an overall trend of first increasing and then decreasing. Taking into account the yield and production cost of 3-ethoxy-4-hydroxymandelic acid, a mass-volume ratio of sodium glyoxylate: sodium ethyl lignin of 1:1.5 is selected to produce 3-ethoxy-4-hydroxymandelic acid, which can obtain a higher yield of 3-ethoxy-4-hydroxymandelic acid.

[0056] Experimental Example 3: Effect of different sodium hydroxide dripping rates on the yield of 3-ethoxy-4-hydroxymandelic acid

[0057] On the basis of Example 1, sodium hydroxide was added at a drip rate of 7.0 ml / min, 9.5 ml / min, 12.0 ml / min, 15.5 ml / min, and 20.0 ml / min, and the low temperature reaction time in S3 was 13 h, and the temperature increase reaction time in S3 was 1 h; the remaining steps were produced in the same manner as in Example 1 and the yield of 3-ethoxy-4-hydroxymandelic acid was determined. The results are shown in Tables 5 and Figure 3 .

[0058] Table 5 Yield of 3-ethoxy-4-hydroxymandelic acid obtained at different sodium hydroxide drop rates

[0059]

[0060] Experimental data show that, in this scheme, as the dripping rate of sodium hydroxide into the three-necked flask increases, the yield of 3-ethoxy-4-hydroxymandelic acid shows a trend of first increasing and then decreasing. Although a higher yield of 3-ethoxy-4-hydroxymandelic acid can be obtained by dripping sodium hydroxide in the dripping rate range of 7.0-12.9 ml / min, 3-ethoxy-4-hydroxymandelic acid has the highest yield when the dripping rate is 9.5 ml / min. In summary, selecting a sodium hydroxide dripping rate of 9.5 / min to produce 3-ethoxy-4-hydroxymandelic acid can obtain a higher yield of 3-ethoxy-4-hydroxymandelic acid.

[0061] Experimental Example 4: Effect of different S3 low temperature reaction temperatures on the yield of 3-ethoxy-4-hydroxymandelic acid

[0062] On the basis of Example 1, the low temperature reaction temperature of S3 was set to 0°C, 5°C, 10°C, 15°C, 20°C, 25°C and 35°C in sequence, and the low temperature reaction time in S3 was 13h, and the heating reaction time in S3 was 1h; the remaining steps were carried out in the same manner as in Example 1 to produce 3-ethoxy-4-hydroxymandelic acid and determine the yield of 3-ethoxy-4-hydroxymandelic acid. The results are shown in Tables 6 and Figure 4 .

[0063] Table 6 Yield of 3-ethoxy-4-hydroxymandelic acid obtained at different low temperature reaction temperatures

[0064]

[0065] Experimental data show that this scheme can significantly improve the glyoxylic acid conversion rate by controlling the reaction temperature when sodium glyoxylate and sodium ethyl lignin are mixed, and as the reaction temperature decreases or increases, the yield of 3-ethoxy-4-hydroxymandelic acid shows a trend of first increasing and then decreasing. Considering the yield and production cost of 3-ethoxy-4-hydroxymandelic acid, a higher glyoxylic acid conversion rate can be obtained by selecting a preparation temperature of 0~20℃ to produce sodium glyoxylate.

[0066] The above is only an embodiment of the present invention, and the common knowledge such as the known specific technical solutions and / or characteristics in the solution is not described in detail here. It should be pointed out that for those skilled in the art, without departing from the technical solution of the present invention, several modifications and improvements can be made, which should also be regarded as the protection scope of the present invention, and these will not affect the effect of the implementation of the present invention and the practicality of the patent. The scope of protection required by this application shall be based on the content of its claims, and the specific implementation methods and other records in the specification can be used to interpret the content of the claims.

Claims

1. A method for preparing 3-ethoxy-4-hydroxymandelic acid at low temperature, characterized in that: The method comprises S1 preparing a sodium glyoxylate solution, S2 preparing a sodium ethyl guaiacol solution and S3 a reaction stage, wherein the sodium ethyl guaiacol solution is prepared from an ethyl guaiacol solution and a sodium hydroxide solution; the reaction stage comprises simultaneously dropping a sodium glyoxylate solution and a sodium hydroxide solution into the sodium ethyl guaiacol solution to form a mixed solution, reacting at a low temperature and then heating and stirring to react, thereby obtaining 3-ethoxy-4-hydroxymandelic acid; In S1, the preparation process of the sodium glyoxylate solution is to dropwise add 10 wt % sodium hydroxide solution into a 50 wt % glyoxylic acid solution at -5 to 10° C. until the pH value of the solution is 4 to 6, and react to obtain the sodium glyoxylate solution; In S2, the preparation process of the sodium ethyl guaiacol solution is to dropwise add a 10 wt % sodium hydroxide solution into a 10-25° C. ethyl guaiacol solution until the solution pH is 10-12, and react to obtain the sodium ethyl guaiacol solution; In S3, the mass volume ratio of the sodium ethyl guaiacol, sodium glyoxylate and sodium hydroxide is 1-1.3:1-1.3:10-13; the low temperature reaction is carried out at 5-20°C for 13-18h, and the heating stirring reaction is carried out at 35-60°C and a stirring speed of 300-400rpm for 1-3h; In S1, S2 and S3, the dropping speed of the sodium hydroxide solution is 7-12 ml / min.

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