A synthesis process of veratraldehyde

Abstract

The present application relates to the technical fields of organic chemical synthesis, and particularly to a synthesis process of veratraldehyde, which comprises the following steps: taking phosphorus oxychloride, N-methylformanilide and o-dimethyl ether as raw materials, mixing the phosphorus oxychloride and part of the N-methylformanilide to prepare a Vilsmeier reagent, dissolving the o-dimethyl ether in the remaining N-methylformanilide, adding the Vilsmeier reagent dropwise into the mixture, and then performing a heat preservation reaction, and finally hydrolyzing and extracting the reaction solution to obtain the veratraldehyde. The present application solves the technical problems of low yield and long preparation time of the veratraldehyde in the prior art.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic chemical synthesis, and particularly relates to a synthesis process of veratraldehyde. BACKGROUND

[0002] Veratraldehyde, also known as methyl vanillin, has a chemical name of 3,4-dimethoxybenzaldehyde, is an important synthetic perfume, and can be used as a food and cosmetic additive. Meanwhile, veratraldehyde is an intermediate of a plurality of medical products, including antiallergic drug tranilast, antihypertensive drug prazosin and tetrahydropalmatine for treating arthritis.

[0003] At present, veratraldehyde is mainly synthesized by a Vilsmeier-Haack reaction. Specifically, N-methylformanilide reacts with phosphorus oxychloride to generate a strong electrophilic Vilsmeier intermediate, then o-dimethyl ether performs an electrophilic substitution reaction, and after hydrolysis, veratraldehyde can be obtained, with a yield of about 80%. The method is suitable for industrial production due to mild reaction conditions.

[0004] For example, a Chinese patent with a publication number of CN101648854B discloses a catalytic synthesis method of veratraldehyde. N-methylformanilide and a catalyst are added dropwise into o-dimethyl ether and phosphorus oxychloride, the dropping speed of N-methylformanilide and the reaction ratio of raw materials are controlled, and finally the yield of veratraldehyde can reach 89%. However, the prior art still has the following problems: 1. The prior art improves the product yield, but there is still a large gap from the high-level production preparation. 2. The hydrolysis reaction time in the prior art is as long as 8 hours, which leads to a long overall preparation time of the product, and is not suitable for industrial production. 3. The prior art needs to use a catalyst, which increases the production cost and the cost of subsequent treatment and recovery of waste liquid.

[0005] Therefore, it is of great significance to develop a preparation method of veratraldehyde with high product yield, short reaction time, low pollution and low energy consumption, so as to make up for the deficiencies of the existing production method and process of veratraldehyde, and rapidly supply the expanded production and wide application of veratraldehyde. SUMMARY

[0006] The present application aims to provide a synthesis process of veratraldehyde, so as to solve the technical problems of low yield and long preparation time of veratraldehyde in the existing synthesis process of veratraldehyde.

[0007] In order to achieve the above object, the present application adopts the following technical scheme: a synthesis process of veratraldehyde, characterized in that: taking phosphorus oxychloride, N-methylformanilide and o-dimethyl ether as raw materials, first, the phosphorus oxychloride and part of the N-methylformanilide are mixed to prepare a Vilsmeier reagent, then the o-dimethyl ether is dissolved in the remaining N-methylformanilide and added dropwise into the Vilsmeier reagent for reaction, and finally the reaction solution is hydrolyzed and extracted to obtain the veratraldehyde.

[0008] The principle and advantages of the present application are as follows:

[0009] Compared with the raw material adding sequence in the prior art, in the present application, part of the N-methylformanilide is mixed with the phosphorus oxychloride in advance to prepare the Vilsmeier reagent, then the o-dimethyl ether is dissolved in the remaining N-methylformanilide, and finally the reaction substrate is added dropwise into the Vilsmeier reagent, so that the phosphorus oxychloride can always be in an excess state relative to the reaction substrate o-dimethyl ether, and the o-dimethyl ether and the Vilsmeier reagent can better interact with each other during the reaction process, thereby enhancing the reaction activity. The original required reaction holding time is shortened from 8 hours to 3 hours, and in most experimental cases, the reaction can be completed in 1-2 hours of reaction holding, thereby effectively reducing the reaction holding time during the reaction process and making the process more suitable for industrial production.

[0010] Meanwhile, compared with the prior art, the present application can better maintain the interaction and reaction efficiency of the reactants. Therefore, the present application can effectively improve the selectivity of the reaction and the conversion rate of the substrate, so that the yield of the prepared veratraldehyde can reach about 99%.

[0011] Preferably, as an improvement, the synthesis method comprises the following steps:

[0012] S1: preparing the Vilsmeier reagent, adding the phosphorus oxychloride into a reactor, then adding the N-methylformanilide dropwise into the reactor while keeping the reaction temperature constant, and continuing to keep the constant temperature and stirring after the addition of the N-methylformanilide is completed to prepare the Vilsmeier reagent;

[0013] S2: reaction stage, dissolving the o-dimethyl ether in the N-methylformanilide to prepare a mixed solution, then adding the mixed solution dropwise into the reactor, and keeping the reaction after the addition is completed;

[0014] S3: hydrolysis and extraction, transferring the reactants in S2 into a hydrolysis and extraction reactor, adding the toluene into the hydrolysis and extraction reactor and stirring, then adding water dropwise into the hydrolysis and extraction reactor for extraction, hydrolyzing and extracting for 1-3 hours after the water addition is completed, and then standing to separate the mixed solution into layers;

[0015] S4 post-processing: the layered organic phase and aqueous phase extraction separation, and the aqueous phase is extracted and separated twice. The extracted organic phase and separated organic phase are combined and subjected to atmospheric distillation, and then subjected to vacuum distillation; the extracted aqueous phase is adjusted to recover N-methylaniline, and the recovered aqueous phase is returned to S3 hydrolysis for reuse; N-methylaniline is reacted with formic acid to regenerate N-methylformanilide for reuse.

[0016] Preferably, as an improvement, the total molar ratio of the o-dioxane, N-methylformanilide and phosphorus oxychloride is 1:0.7-1.2:0.9-1.2.

[0017] In the present application, the Vilsmeier reagent is reduced from 2 times excess to 1.2 times excess or less, which not only effectively improves the selectivity of the reaction, improves the utilization efficiency of raw materials, reduces the energy consumption generated during the recovery of raw materials, but also reduces the waste of nitrogen and phosphorus elements in the synthesis.

[0018] Preferably, as an improvement, the reaction temperature in S1 is controlled to be 30-60°C, and the stirring time is 0-1 hour.

[0019] In the present application, the reaction temperature and stirring need to be controlled during the preparation of Vilsmeier, which can ensure that phosphorus oxychloride and N-methylformanilide can fully react.

[0020] Preferably, as an improvement, the molar ratio of o-dioxane to N-methylformanilide in the mixed solution in S2 is 1:0.3-0.6.

[0021] In the present application, pre-mixing o-dioxane with part of N-methylformanilide can greatly reduce the reaction time. If the amount of N-methylformanilide added in this step is small, the reaction rate will be reduced; if the amount is large, the reaction selectivity will be reduced, and the yield and purity of the target product will be reduced.

[0022] Preferably, as an improvement, the reaction temperature in S2 is controlled to be 40-80°C, and the holding reaction time is 0.5-3 hours.

[0023] In the present application, the holding reaction time is greatly shortened compared to the prior art. Short holding time will result in incomplete reaction, and long holding time will reduce the selectivity of the reaction, and reduce the yield and purity of the target product.

[0024] Preferably, as an improvement, the volume ratio of toluene to water in S3 is 1-2:1.

[0025] In the present application, using toluene and water to hydrolyze and extract can improve the purity of veratraldehyde.

[0026] Preferably, as an improvement, the water dropping speed in S3 is 5-12 ml / min, and the extraction temperature is 30-60°C.

[0027] In the present application, controlling the water dropping speed is to control the extraction speed, which can ensure the extraction speed is appropriate and improve the purity of the extracted product.

[0028] Preferably, as an improvement, the secondary extraction liquid in S4 is toluene.

[0029] In the present application, using methanol for extraction can improve the purity of the prepared veratraldehyde.

[0030] Preferably, as an improvement, the pH of the aqueous solution after adjusting the alkali in S4 is 8-12.

[0031] In the present application, adjusting the alkali in the aqueous phase facilitates the recovery of N-methylaniline in the aqueous phase, and the recovered N-methylaniline can be used to react to generate the raw material N-methylformanilide of the present application after reacting with formic acid. BRIEF DESCRIPTION OF DRAWINGS

[0032] Figure 1 The reaction schematic diagram of the synthesis process of veratraldehyde according to the present application;

[0033] Figure 2 The high performance liquid chromatogram comparison diagram of Example 1 and Comparative Example 1 of the present application (the upper diagram is Comparative Example 1, and the lower diagram is Example 1);

[0034] Figure 3 The experimental result line graph of Experimental Example 1;

[0035] Figure 4 The experimental result line graph of Experimental Example 2. DETAILED DESCRIPTION

[0036] The following will be further described in detail through specific embodiments:

[0037] Example 1

[0038] A synthesis process of veratraldehyde, using o-dimethyl ether, N-methylformanilide and phosphorus oxychloride as raw materials, wherein the molar ratio of the total amount of the three raw materials is 1:1:1. Specifically, first, all the phosphorus oxychloride is mixed with 60% N-methylformanilide to prepare Vilsmeier reagent, and then all the o-dimethyl ether is mixed with the remaining 40% N-methylformanilide and then added dropwise into the Vilsmeier reagent for reaction and heat preservation for 1.5 hours. Finally, the above reaction solution is hydrolyzed and extracted to obtain veratraldehyde. Specifically, the process includes the following steps:

[0039] S1 Preparation of Vilsmeier reagent: add phosphorus oxychloride into the reactor, then drop N-methyl formanilide into it and keep the reaction temperature constant, after the drop of N-methyl formanilide is completed, continue to keep constant temperature stirring to prepare Vilsmeier reagent;

[0040] Specifically, 0.25 mol of phosphorus oxychloride is added into the reaction container equipped with a stirring rod, a condenser and a thermometer, then N-methyl formanilide is dropped into it, and the total drop amount of N-methyl formanilide is 0.15 mol. The temperature of the solution in the reaction container is controlled and kept at 50°C during the drop process, after the drop is completed, the reaction is kept at 50°C for 0.5 hours, and then the material is transferred to the hydrolysis and extraction reactor.

[0041] S2 Reaction stage: dissolve o-dichlorodimethyl ether in N-methyl formanilide to prepare a mixed solution, then drop the mixed solution into the reactor, and keep the reaction after the drop is completed;

[0042] Specifically, 0.25 mol of o-dichlorodimethyl ether is dissolved in 0.1 mol of N-methyl formanilide solution, after stirring and dissolving completely, the mixed solution is dropped into the Vilsmeier reagent in S1, the temperature of the solution in the reaction container is controlled and kept at 60°C during the drop process, after the drop is completed, the reaction is kept for 1.5 hours.

[0043] S3 Hydrolysis and extraction: transfer the reactants in S2 to the hydrolysis and extraction reactor, add toluene into the hydrolysis and extraction reactor and stir, then drop water into the hydrolysis and extraction reactor for extraction, after the drop of water is completed, hydrolysis and extraction is carried out for 1-3 hours, then stand still to make the mixed solution stratify;

[0044] Specifically, after the reaction in S2 is completed, the reactants are transferred to the hydrolysis and extraction reactor, 150 ml of toluene is added into the hydrolysis and extraction reactor and stirred uniformly, 10 ml / min of secondary water is dropped into the hydrolysis and extraction reactor, and the total drop amount of secondary water is 100 ml. The temperature of the solution in the hydrolysis and extraction reactor is kept at 60°C during the drop process, after the drop of water is completed, hydrolysis is carried out for 2 hours at the temperature of 60°C, then stand still for 1 hour to stratify.

[0045] S4 Post-treatment: separate the stratified organic phase and the aqueous phase, and carry out secondary extraction and separation on the aqueous phase. The extracted organic phase and the separated organic phase are combined and subjected to atmospheric distillation, then subjected to reduced pressure distillation; the aqueous phase after extraction is adjusted to be alkaline to recover N-methyl aniline, the recovered aqueous phase is returned to S3 for reuse; N-methyl aniline is reacted with formic acid to generate N-methyl formanilide again for reuse.

[0046] Specifically, after the static stratification, the stratified water phase and organic phase are separated. The separated water phase is re-added into toluene for secondary extraction and separation, and the separated organic phase is mixed with the stratified organic phase and then poured into a distillation flask for atmospheric distillation for 2 hours. The remaining organic phase is subjected to vacuum distillation. The unreacted o-dimethyl ether is received in sequence during the vacuum distillation, and then the veratraldehyde product is received. Subsequently, the yield of the veratraldehyde product is calculated and the purity is detected.

[0047] The solution concentration is adjusted to pH 8 by adding a base to the water phase after the secondary extraction, and then N-methylaniline is recovered by separation. The separated water can be used for continuous use in the S3 hydrolysis reaction. The recovered N-methylaniline can generate N-methylformanilide by a simple reaction with formic acid, and the N-methylformanilide can be continuously used in S1 and S2.

[0048] Example 2

[0049] The difference between this example and Example 1 is that the reaction time is 3 hours in S2.

[0050] Example 3

[0051] The difference between this example and Example 1 is that the reaction time is 0.5 hours in S2.

[0052] Example 4

[0053] The difference between this example and Example 1 is that the total molar ratio of o-dimethyl ether, N-methylformanilide and phosphorus oxychloride is 1:0.7:0.9.

[0054] Example 5

[0055] The difference between this example and Example 1 is that the total molar ratio of o-dimethyl ether, N-methylformanilide and phosphorus oxychloride is 1:1.2:1.2.

[0056] Comparative Example 1

[0057] The difference between this example and Example 1 is that the order of adding raw materials is different. In this comparative example, o-dimethyl ether and phosphorus oxychloride are mixed first, and then N-methylformanilide is added dropwise. The specific reaction steps are as follows:

[0058] 1) 0.25 mol of o-dimethyl ether and 0.25 mol of phosphorus oxychloride are added to a reaction vessel equipped with a stirrer, a condenser tube and a thermometer, and then 0.25 mol of N-methylformanilide is added dropwise. The temperature of the solution in the reaction vessel is controlled and maintained at 50°C during the dropwise addition. After the dropwise addition is completed, the reaction is kept at 50°C for 1.5 hours, and then the material is transferred to a hydrolysis extraction reactor.

[0059] 2) Add 150 ml of toluene to the hydrolysis extraction reactor and stir evenly. Add secondary water to the hydrolysis extraction reactor at a rate of 10 ml / min, and the total amount of secondary water added is 100 ml. Keep the solution temperature in the hydrolysis extraction reactor at 60°C during the dropwise addition process. After the water is added, hydrolyze at 60°C for 2 hours, and then stand for 1 hour to separate the layers.

[0060] 3) After standing and separating the layers, separate the water phase and the organic phase after separation. The separated water phase is re-added to toluene for secondary extraction and separation. The separated organic phase is mixed with the separated organic phase and then poured into a distillation flask for atmospheric distillation for 2 hours. The remaining organic phase is subjected to vacuum distillation. Unreacted o-dimethyl ether is received in sequence during the vacuum distillation process, and the veratraldehyde product is then received. The yield and purity of the veratraldehyde product are then calculated and detected.

[0061] Comparative Example 2

[0062] The difference between this comparative example and Example 1 is that the o-dimethyl ether is not pre-mixed with the N-methylformanilide. The specific reaction steps are as follows:

[0063] 1) Add 0.25 mol of phosphorus oxychloride to a reaction vessel equipped with a stirrer, condenser, and thermometer, and then add N-methylformanilide dropwise. The total amount of N-methylformanilide added is 0.25 mol. Control and maintain the solution temperature in the reaction vessel at 50°C during the dropwise addition process. After the dropwise addition is complete, maintain the reaction at 50°C for 0.5 hours, and then transfer the material to a hydrolysis extraction reactor.

[0064] 2) Add 0.25 mol of o-dimethyl ether dropwise to the Vilsmeier reagent in S1. Control the solution temperature in the reaction vessel to be 60°C during the dropwise addition process. After the dropwise addition is complete, maintain the reaction at 60°C for 1.5 hours.

[0065] 3) Add 150 ml of toluene to the hydrolysis extraction reactor and stir evenly. Add secondary water to the hydrolysis extraction reactor at a rate of 10 ml / min, and the total amount of secondary water added is 100 ml. Keep the solution temperature in the hydrolysis extraction reactor at 60°C during the dropwise addition process. After the water is added, hydrolyze at 60°C for 2 hours, and then stand for 1 hour to separate the layers.

[0066] 4) After the static stratification, the water phase and the organic phase after stratification were separated. The separated water phase was re-added into toluene for secondary extraction and separation. The separated organic phase was mixed with the stratified organic phase and poured into a distillation flask for atmospheric distillation for 2 hours. The remaining organic phase after atmospheric distillation was subjected to vacuum distillation. The unreacted o-dimethyl ether was received in sequence during the vacuum distillation, and then the veratraldehyde product was received. Subsequently, the yield calculation and purity detection were performed on the veratraldehyde product. The veratraldehyde yield was 93.1%, the o-dimethyl ether conversion rate was 93.7%, the veratraldehyde selectivity was 99.5%, and the purity was 99.6%.

[0067] Comparative Example 3

[0068] The difference between the present comparative example and Example 1 is that the addition ratio of raw materials is different. Specifically, in the present comparative example, the total molar ratio of o-dimethyl ether, N-methylformanilide and phosphorus oxychloride is 1:2:1.2. The process steps are as follows:

[0069] S1 Preparation of Vilsmeier reagent: add phosphorus oxychloride into the reactor, then drop N-methylformanilide into it while keeping the reaction temperature constant. After the drop of N-methylformanilide is completed, continue to keep constant temperature stirring to prepare Vilsmeier reagent;

[0070] Specifically, 0.25 mol of phosphorus oxychloride was added into a reaction vessel equipped with a stirring rod, condenser tube and thermometer, and then N-methylformanilide was dropped into it. The total drop amount of N-methylformanilide was 0.5 mol. The temperature of the solution in the reaction vessel was controlled and kept at 50°C during the drop process. After the drop was completed, the solution was kept at 50°C for 0.5 hours, and then transferred to the hydrolysis extraction reactor.

[0071] S2 Reaction stage: dissolve o-dimethyl ether in N-methylformanilide to prepare a mixed solution, then drop the mixed solution into the reactor, and keep constant temperature after the drop is completed;

[0072] Specifically, 0.25 mol of o-dimethyl ether was dissolved in 0.1 mol of N-methylformanilide solution, and the mixed solution was dropped into the Vilsmeier reagent in S1 after complete stirring and dissolution. The temperature of the solution in the reaction vessel was controlled and kept at 60°C during the drop process. After the drop was completed, the solution was kept at constant temperature for 1.5 hours.

[0073] S3 Hydrolysis extraction: transfer the reactants in S2 to the hydrolysis extraction reactor, add toluene into the hydrolysis extraction reactor and stir, then drop water into the hydrolysis extraction reactor for extraction. After the drop of water was completed, the hydrolysis extraction was carried out for 1-3 hours, and then the mixed solution was allowed to stratify;

[0074] Specifically, after the reaction of S2 is completed, the reactants are transferred to a hydrolysis extraction reactor, 150 ml of toluene is added to the hydrolysis extraction reactor and stirred uniformly. Secondary water is added to the hydrolysis extraction reactor at a rate of 10 ml / min, and the total amount of secondary water added is 100 ml. During the addition process, the temperature of the solution in the hydrolysis extraction reactor is maintained at 60°C. After the water addition is completed, the solution is hydrolyzed at 60°C for 2 hours, and then allowed to stand for 1 hour to separate into layers.

[0075] S4 post-treatment: the separated organic phase and aqueous phase are extracted and separated, and the aqueous phase is subjected to secondary extraction and separation. The extracted organic phase and the separated organic phase are combined and subjected to atmospheric distillation, followed by vacuum distillation; the extracted aqueous phase is adjusted to recover N-methylaniline, the recovered aqueous phase is returned to S3 hydrolysis for reuse; N-methylaniline is reacted with formic acid to regenerate N-methylformanilide for reuse.

[0076] Specifically, after standing and separating into layers, the separated aqueous phase and organic phase are separated. The separated aqueous phase is re-added with toluene for secondary extraction and separation. The separated organic phase is combined with the separated organic phase and then poured into a distillation flask for atmospheric distillation for 2 hours. The remaining organic phase is subjected to vacuum distillation. During the vacuum distillation process, unreacted o-dimethyl ether is received first, followed by the reception of veratraldehyde product.

[0077] Comparative Example 4

[0078] The difference between this comparative example and Example 1 is that the addition ratio of raw materials is different. Specifically, in this comparative example, the total molar ratio of o-dimethyl ether, N-methylformanilide and phosphorus oxychloride is 1:0.5:0.6. The process steps are as follows:

[0079] S1 Preparation of Vilsmeier reagent: add phosphorus oxychloride to the reactor, then add N-methylformanilide dropwise and maintain the reaction temperature constant. After the addition of N-methylformanilide is completed, continue to maintain constant temperature stirring to prepare the Vilsmeier reagent;

[0080] Specifically, 0.15 mol of phosphorus oxychloride is added to a reaction vessel equipped with a stirring rod, condenser tube and thermometer, and then N-methylformanilide is added dropwise. The total amount of N-methylformanilide added is 0.065 mol. During the addition process, the temperature of the solution in the reaction vessel is controlled and maintained at 50°C. After the addition is completed, the solution is maintained at 50°C for 0.5 hours, and then transferred to a hydrolysis extraction reactor.

[0081] S2 reaction stage: dissolve o-dimethyl ether in N-methylformanilide to prepare a mixed solution, then add the mixed solution dropwise to the reactor, and maintain the reaction after the addition is completed;

[0082] Specifically, 0.25 mol of o-dimethyl ether is dissolved in a solution of 0.06 mol of N-methyl formanilide, after stirring until complete dissolution, the mixed solution is added dropwise into the Vilsmeier reagent in S1, and the temperature of the solution in the reaction vessel is controlled at 60°C during the dropwise addition. After the dropwise addition is completed, the reaction is incubated for 1.5 h.

[0083] S3 hydrolysis extraction: the reactants in S2 are transferred to a hydrolysis extraction reactor, toluene is added to the hydrolysis extraction reactor and stirred, then water is added dropwise to the hydrolysis extraction reactor for extraction, after the water addition is completed, the hydrolysis extraction is carried out for 1-3 hours, and then the mixed solution is allowed to stand to separate into layers;

[0084] Specifically, after the reaction in S2 is completed, the reactants are transferred to a hydrolysis extraction reactor, 150 ml of toluene is added to the hydrolysis extraction reactor and stirred uniformly. Secondary water is added dropwise to the hydrolysis extraction reactor at a rate of 10 ml / min, and the total amount of secondary water added is 100 ml. The temperature of the solution in the hydrolysis extraction reactor is maintained at 60°C during the dropwise addition, and after the water addition is completed, the hydrolysis is carried out at a temperature of 60°C for 2 hours, and then the mixed solution is allowed to stand for 1 hour to separate into layers.

[0085] S4 post-treatment: the separated organic phase and aqueous phase are extracted and separated, and the aqueous phase is subjected to secondary extraction and separation. The extracted organic phase and the separated organic phase are combined and subjected to atmospheric distillation, and then subjected to reduced pressure distillation; the extracted aqueous phase is adjusted to recover N-methylaniline, the recovered aqueous phase is returned to S3 for reuse; N-methylaniline is reacted with formic acid to regenerate N-methyl formanilide for reuse.

[0086] Specifically, after standing and separating into layers, the separated aqueous phase and organic phase are separated. The separated aqueous phase is re-added with toluene for secondary extraction and separation, the separated organic phase is combined with the separated organic phase and then poured into a distillation flask for atmospheric distillation for 2 hours. The remaining organic phase is subjected to reduced pressure distillation. Unreacted o-dimethyl ether is received first, and then veratraldehyde product is received during the reduced pressure distillation.

[0087] Comparative Example 5

[0088] The difference between this example and Example 1 is that the incubation reaction time in S2 is 6 hours.

[0089] The experimental data of the above experimental examples and comparisons are recorded in Table 1 below. Among them, the total molar ratio represents the molar ratio of the total amount of o-dimethyl ether, N-methyl formanilide and phosphorus oxychloride added; the S2 molar ratio represents the molar ratio of the amount of o-dimethyl ether and N-methyl formanilide added in step S2; the incubation time represents the incubation reaction time in step S2; the yield represents the yield of veratraldehyde; the conversion rate represents the reaction conversion rate of o-dimethyl ether; and the selectivity represents the reaction selectivity of veratraldehyde.

[0090] Table 1: Experimental conditions and results for the experimental examples and comparative examples.

[0091]

[0092] Analysis of experimental results:

[0093] Using the technical solution of this invention, the yield of veratral can reach over 95%, and the purity is higher than 99.5%. The quality and yield of the produced product are significantly improved compared to existing technologies. Furthermore, from the attached... Figure 2 The HPLC results show that there are basically no extra impurity peaks, indicating that there are basically no side reactions during the synthesis process, and the conversion rate and selectivity of the raw materials are very high.

[0094] Comparative Example 1, using a one-pot preparation method, showed a significant decrease in both the yield and purity of the product. (See attached...) Figure 2 The HPLC results showed numerous impurity peaks, indicating that the preparation method in Comparative Example 1 involved significant side reactions during the reaction, resulting in the formation of many impurities. Therefore, although the conversion rate of the raw materials was high, the selectivity of the reaction was very poor.

[0095] Comparative Example 2 used a stepwise addition of raw materials, but the o-phenylenedimethyl ether was not pre-dissolved in N-methylformamide. Under the same reaction time, the yield of veratral was significantly lower than in the Example 2. Analysis of other data shows that the selectivity and product purity were both high, but the conversion rate was low, indicating that the reaction was not complete. Therefore, it can be shown that the technical solution of this invention can effectively improve the reaction rate and reduce the reaction completion time. Detailed analysis can be found in Experimental Example 2.

[0096] In Comparative Example 3, the amount of Vilsmeier reagent was increased. The experimental results show that increasing the amount of Vilsmeier reagent actually led to a decrease in the selectivity of the reaction. Even with a high conversion rate of dimethyl ether, the yield and purity of the product both decreased significantly, indicating the presence of significant side reactions.

[0097] In Comparative Example 4, the amount of Vilsmeier reagent was reduced. The experimental results show that reducing the amount of Vilsmeier reagent led to incomplete reaction.

[0098] In Comparative Example 5, the heat preservation reaction time was extended. The experimental results show that extending the heat preservation reaction time leads to a decrease in the selectivity of the reaction. Even with a high conversion rate of raw materials, the yield and purity of the target product are both low, indicating that extending the reaction time is not conducive to the progress of the reaction.

[0099] Experimental Example 1: Effect of the molar ratio of o-phenylenedimethyl ether to N-methylformamide in S2 on the reaction conversion and yield

[0100] This experiment aims to verify the effect of the premixing ratio of o-phenylene ether to N-methylformamide in S2 on the synthesis process of veratral. The specific experimental results are attached. Figure 3 As shown in the figure. Analysis of the results shows that when phthalic acid is not pre-dissolved in N-methylformamide in the second step (i.e., Comparative Example 2), the yield of veratral is 93.1%, and the conversion rate of phthalic acid is 93.7%. When phthalic acid and N-methylformamide are pre-mixed in step S2, both the yield of veratral and the conversion rate of phthalic acid begin to increase. This is because this addition method ensures better association and interaction between phthalic acid and the Vilsmeier reagent, improving the selectivity of the reaction.

[0101] However, pre-mixing more than half of the total N-methylformaniline with phthalic acid resulted in a relative decrease in the yield of veratral and the conversion of phthalic acid, particularly a faster decrease in the conversion of phthalic acid. This indicates that reducing the amount of Vilsmeier reagent cannot guarantee that phosphorus oxychloride will always be in excess relative to the substrate phthalic acid during the reaction, thus reducing the selectivity of the reaction.

[0102] Experimental Example 2: Effect of Incubation Time on Reaction Conversion and Yield

[0103] This experiment aims to verify that the addition method in step S2 can shorten the incubation reaction time. The experimental method is the same as Comparative Example 2. Analysis of the results from Comparative Example 2 shows that without pre-dissolving phthalic ether in N-methylformamide, the reaction is incomplete under the same reaction time (1.5 h). Therefore, the reaction time was extended, and the experimental results are shown in the appendix. Figure 4 As shown in the figure. Experimental verification showed that when the incubation reaction time in S2 of Comparative Example 2 was extended to 5 hours, the reaction result achieved the same effect as in Example 1. Therefore, Experiment 2 effectively demonstrates that the technical solution of the present invention can effectively accelerate the reaction rate and reduce the reaction time.

[0104] The above descriptions are merely embodiments of the present invention, and common knowledge such as specific technical solutions and / or characteristics are not described in detail here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the technical solutions of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the implementation of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

Claims

1. A process for synthesizing veratral, characterized in that: Using phosphorus oxychloride, N-methylformamide and phthalic acid as raw materials, phosphorus oxychloride and part of N-methylformamide were first mixed and reacted to prepare Vilsmeier reagent. Then, phthalic acid was dissolved in the remaining N-methylformamide and added dropwise to Vilsmeier reagent and the reaction was kept at a constant temperature. Finally, the above reaction solution was hydrolyzed and extracted to obtain veratral. The total molar ratio of the phthalic acid dimethyl ether, N-methylformamide and phosphorus oxychloride is 1:0.7-1.2:0.9-1.2; The synthesis process includes the following steps: S1 Preparation of Vilsmeier reagent: Add phosphorus oxychloride to the reactor, then add N-methylformamide dropwise while keeping the reaction temperature constant. After the N-methylformamide is completely added, continue stirring at a constant temperature to prepare Vilsmeier reagent. The reaction temperature is 30–60°C, and the stirring time is 0–1 hour; S2 reaction stage: Dissolve phthalic acid in N-methylformamide to prepare a mixed solution, then add the mixed solution dropwise to Vilsmeier reagent, and keep the reaction at the temperature after the addition is complete; The molar ratio of o-phenylenediamine to N-methylformamide in the mixed solution is 1:0.3-0.6; the reaction temperature is 40-80℃, and the reaction time is 0.5-3 hours. S3 hydrolysis extraction: Transfer the reactants in S2 to the hydrolysis extraction reactor, add toluene to the hydrolysis extraction reactor and stir, then add water dropwise to the hydrolysis extraction reactor for extraction. After the water dropwise addition is complete, hydrolyze and extract for 1 to 3 hours, and then let stand to allow the mixed solution to separate into layers. S4 post-processing: The layered organic and aqueous phases are extracted and separated, and the aqueous phase is further extracted and separated; the extracted organic phase and the separated organic phase are combined into an atmospheric distillation apparatus for atmospheric distillation, and then subjected to vacuum distillation; the extracted aqueous phase is adjusted with alkali to recover N-methylaniline, and the recovered aqueous phase is returned to S3 for hydrolysis and reuse; N-methylaniline reacts with formic acid to generate N-methylformylaniline for reuse.

2. The synthesis process of veratral according to claim 1, characterized in that: The volume ratio of toluene to water in S3 is 1 to 2:

1.

3. The synthesis process of veratral according to claim 2, characterized in that: In S3, the water droplet rate is 5–12 ml / min, and the extraction temperature is 30–60 °C.

4. The synthesis process of veratral according to claim 3, characterized in that: The secondary extract in S4 is toluene.

5. The synthesis process of veratral according to claim 4, characterized in that: The pH of the aqueous phase solution in S4 after alkali adjustment is 8-12.

Images