Synthetic method of vanillin and derivatives thereof, product and application thereof

Abstract

The invention relates to the field of chemical synthesis, in particular to a synthetic method and application of vanillin and derivatives thereof. The synthesis method comprises the following synthesis steps: S1, bromination: reacting p-hydroxybenzaldehyde with a brominating agent to obtain a mixture of 3-bromo-4-hydroxybenzaldehyde and 3, 5-dibromo-4-hydroxybenzaldehyde; s2, separation and purification: taking the mixture of the 3-bromo-4-hydroxybenzaldehyde and the 3, 5-dibromo-4-hydroxybenzaldehyde, sequentially carrying out recrystallization and melt crystallization, and separating the 3-bromo-4-hydroxybenzaldehyde and the 3, 5-dibromo-4-hydroxybenzaldehyde; s3, etherification: taking 3-bromo-4-hydroxybenzaldehyde to react with sodium methoxide or sodium ethoxide, so as to obtain an etherified product. According to the method disclosed by the invention, high-purity 3-bromo-4-hydroxybenzaldehyde and 3, 5-dibromo-4-hydroxybenzaldehyde are obtained through recrystallization coupled with melt crystallization separation; the whole process is free of material loss, safe and environment-friendly.

Description

Technical Field

[0001] The invention relates to the field of chemical synthesis, and in particular to a synthesis method of vanillin and its derivatives and applications thereof. Background Art

[0002] Vanillin, also known as vanillin, has a chemical name of 3-methoxy-4-hydroxybenzaldehyde, a molecular formula of C8H8O3, a molecular weight of 152.15, and a melting point of 81°C-83°C. Vanillin was first extracted from vanilla beans, an orchid plant. It has the aroma of vanilla beans and a strong milky aroma, and can play a role in flavor enhancement and fixation. It is widely used in cosmetics, tobacco, cakes, candies, and baked food industries. It is one of the world's largest synthetic flavors, and the industrial production of vanillin has a history of more than 100 years. The current main production process is a semi-synthetic route using guaiacol as raw material, which has problems such as low yield and high pollution.

[0003] Ethyl vanillin, also known as 3-ethoxy-4-hydroxybenzaldehyde, has the molecular formula C9H 10 O3, molecular weight 166.147, melting point 77℃-78℃. As an upgraded variety of vanillin, ethyl vanillin has the same fragrance as vanillin, and its fragrance is 3-4 times that of vanillin. It has become one of the most important spices in the world. Ethyl vanillin can be used as a flavor enhancer and fixative, and is widely used in food, chemical, pharmaceutical, cosmetics, detergents and other fields. Since it cannot be obtained through natural synthesis methods, it can only be obtained through artificial synthesis. The production of ethyl vanillin has certain limitations. At present, the main companies producing ethyl vanillin include Rhodia in France, Shiono Spice Company in Japan, and Borregaard Company in Norway. Domestic technology has not yet been able to stably and mass-produce ethyl vanillin.

[0004] The intermediate of vanillin synthesized from p-hydroxybenzaldehyde is 3-bromo-4-hydroxybenzaldehyde. Since both sides of the hydroxyl groups of p-hydroxybenzaldehyde have the same reactivity, after it reacts with bromine to generate 3-bromo-4-hydroxybenzaldehyde, the hydrogen next to the hydroxyl group will still be replaced to generate the impurity 3,5-dibromo-4-hydroxybenzaldehyde. These two substances have similar structures and properties and have similar solubility in most solvents. Therefore, it is difficult to separate the impurities from the system. Obtaining high-purity 3-bromo-4-hydroxybenzaldehyde is the biggest difficulty in synthesizing vanillin from p-hydroxybenzaldehyde.

[0005] Chinese patent CN102249875A discloses a method for synthesizing vanillin, in which water recrystallization is used when separating the bromide, and the crystals are 3-bromo-4-hydroxybenzaldehyde after hot filtration and cooling. However, the solubility of 3-bromo-4-hydroxybenzaldehyde in boiling water is 3.16g / 100mL, and the solubility of 3,5-dibromo-4-hydroxybenzaldehyde in boiling water is 0.26g / 100mL, and at a temperature below 40°C, both bromides are almost insoluble in water. Therefore, the mixture can be initially separated by boiling water, but the impurity 3,5-dibromo-4-hydroxybenzaldehyde still exists in the separated product. Therefore, other purification methods need to be further adopted to obtain high-purity 3-bromo-4-hydroxybenzaldehyde.

[0006] Chinese patent CN113968779A discloses a method for separating lignin-based p-hydroxybenzaldehyde, vanillin, and syringaldehyde, which has a cumbersome process, a large solvent ratio, a long reaction time, and extremely high cost, and cannot be scaled up for mass production. Chinese patent CN108863747A discloses a method for synthesizing vanillin, which uses p-hydroxybenzaldehyde as a raw material, first brominating, and then etherifying to obtain a product. In order to obtain a pure product, it adopts controlled dibromo substitution production, uses bromine chloride as a bromine source, and uses a photosensitive catalyst to catalyze the reaction. The reaction process requires an ultraviolet light source, and the reaction is complex, which has high requirements for equipment.

[0007] Chinese patent CN110606801A discloses a method for continuously preparing vanillin and syringaldehyde. The method uses p-hydroxybenzaldehyde as a raw material, and uses a mixed solvent of methanol and chloroform to react with bromine at 0-5°C to obtain a mixture of 3-bromo-4-hydroxybenzaldehyde and 3,5-dibromo-4-hydroxybenzaldehyde; the mixture is not purified, but directly reacts with sodium methoxide (sodium ethoxide) in a mixed solvent of methanol and DMF, and the catalyst is copper oxide. After the reaction, the mixture of vanillin and syringaldehyde is separated and extracted. The total solvent ratio used in the bromide synthesis process is extremely large, about 20 times (w / v), which is not conducive to environmentally friendly production; the patent describes that pure vanillin and syringaldehyde can be obtained by refining and separating using the commonly known technology in the field, but in fact, the boiling point and melting point of vanillin and syringaldehyde are very different, and because of their similar structures, their solubility in various solvents is similar, making it difficult to separate them using conventional separation methods.

[0008] Chinese patent CN107954844A discloses a method for synthesizing vanillin from p-hydroxybenzaldehyde, wherein the bromination step uses DMF as a solvent, dissolves p-hydroxybenzaldehyde and then drips bromine to react, then neutralizes the generated byproduct hydrogen bromide, extracts with ethyl acetate and then adds n-hexane for crystallization. In this method, DMF is an alkaline solvent and may react with the byproduct hydrogen bromide, which is very dangerous; and the byproduct hydrogen bromide produces more saline wastewater through neutralization, and DMF and wastewater are difficult to separate and recycle. Its methoxylation step is to react with methanol under the catalysis of an equal amount of sodium methoxide, and the phenolic hydroxyl group of 3-bromo-4-hydroxybenzaldehyde is acidic and will react with the strongly alkaline sodium methoxide, affecting the product yield.

[0009] In summary, the existing technologies have not solved the technical problem of the difficulty in separating 3-bromo-4-hydroxybenzaldehyde and 3,5-dibromo-4-hydroxybenzaldehyde, and are still unable to achieve the synthesis and mass production of high-purity vanillin and its derivatives. Summary of the invention

[0010] The present invention provides a method for synthesizing vanillin and its derivatives. The method uses p-hydroxybenzaldehyde as a raw material, reacts under the action of a brominating agent to obtain a mixture of bromides 3-bromo-4-hydroxybenzaldehyde and 3,5-dibromo-4-hydroxybenzaldehyde, and effectively separates the two bromides by recrystallization coupled with melt crystallization separation to obtain high-purity 3-bromo-4-hydroxybenzaldehyde and 3,5-dibromo-4-hydroxybenzaldehyde. 3-bromo-4-hydroxybenzaldehyde is reacted with sodium ethoxide to obtain ethyl vanillin; sodium ethoxide is replaced with sodium methoxide to synthesize vanillin; 3,5-dibromo-4-hydroxybenzaldehyde is reacted with sodium methoxide to obtain syringaldehyde.

[0011] The vanillin and its derivatives involved in the present invention include 3-methoxy-4-hydroxybenzaldehyde (i.e. vanillin), 3-ethoxy-4-hydroxybenzaldehyde (i.e. ethyl vanillin), 3-bromo-4-hydroxybenzaldehyde and 3,5-dibromo-4-hydroxybenzaldehyde.

[0012] The first aspect of the present invention provides a method for synthesizing vanillin and its derivatives, the synthesis steps comprising:

[0013] S1. Bromination: taking p-hydroxybenzaldehyde and reacting with a brominating agent to obtain a mixture of 3-bromo-4-hydroxybenzaldehyde and 3,5-dibromo-4-hydroxybenzaldehyde;

[0014] S2. Separation and purification: taking the mixture of 3-bromo-4-hydroxybenzaldehyde and 3,5-dibromo-4-hydroxybenzaldehyde, sequentially subjecting the mixture to preliminary purification by recrystallization and melt crystallization to separate 3-bromo-4-hydroxybenzaldehyde and 3,5-dibromo-4-hydroxybenzaldehyde;

[0015] S3. Etherification: Take 3-bromo-4-hydroxybenzaldehyde and react it with sodium methoxide or sodium ethoxide to obtain vanillin or ethyl vanillin.

[0016] When the reactant in step S3 is sodium methoxide, the etherification product is vanillin; when the reactant in step S3 is sodium ethoxide, the etherification product is ethyl vanillin.

[0017] In some preferred embodiments, the bromination comprises the following steps:

[0018] S1-1. The p-hydroxybenzaldehyde is mixed with an organic solvent A and a co-solvent to dissolve the p-hydroxybenzaldehyde;

[0019] S1-2. Control the temperature at -10 to 10 ° C, add the brominating agent dropwise to the solution in step S1-1, and react for 2-4h after the addition is completed;

[0020] S1-3. Distill under reduced pressure to obtain a mixture of 3-bromo-4-hydroxybenzaldehyde and 3,5-dibromo-4-hydroxybenzaldehyde.

[0021] The reaction equation for the bromination step is as follows:

[0022]

[0023] The organic solvent A can be listed as one or more combinations of benzene, toluene, xylene, cyclohexane, chlorobenzene, dichlorobenzene, methanol, ethanol, isopropanol, ether, propylene oxide, ethyl acetate, acetonitrile, and dichloromethane; preferably dichloromethane (CH2Cl2).

[0024] The co-solvent can be one or more of methanol, ethanol, dimethyl sulfoxide, and ethyl acetate, preferably methanol (CH3OH).

[0025] In some preferred embodiments, based on the mass of p-hydroxybenzaldehyde, the volume addition amount of the organic solvent A is 3-5 times the mass of p-hydroxybenzaldehyde; more preferably 4-4.5 times (mL / g).

[0026] In some preferred embodiments, based on the mass of p-hydroxybenzaldehyde, the volumetric addition amount of the co-solvent is 0.5-1.5 times, more preferably 0.8-0.9 times (mL / g) the mass of p-hydroxybenzaldehyde.

[0027] The brominating agent may be exemplified by bromine, sodium bromide, potassium bromide, copper bromide, hydrogen bromide, ethyl bromide, bromobenzene, preferably bromine (Br2).

[0028] In some preferred embodiments, based on the molar amount of p-hydroxybenzaldehyde, the molar amount of the brominating agent added is more than 1 times, more preferably 1-1.5 times, that of p-hydroxybenzaldehyde.

[0029] In some preferred embodiments, the brominating agent is controlled to drip within 10-150 min, which can be listed as 10 min, 20 min, 30 min, 40 min, 50 min, 60 min, 70 min, 80 min, 90 min, 100 min, 110 min, 120 min, 130 min, 140 min, and 150 min.

[0030] In some preferred embodiments, the temperature control range in the step S1-2 is 0-10°C; more preferably, the temperature control range in the step S1-2 is 5°C.

[0031] In some preferred embodiments, the separation and purification comprises the following steps:

[0032] S2-1. Take the mixture of 3-bromo-4-hydroxybenzaldehyde and 3,5-dibromo-4-hydroxybenzaldehyde, add 20-30 times water, and heat to boiling;

[0033] S2-2. Filter the boiling material while hot to separate the filter residue and the filtrate; dry the filter residue to obtain an insoluble product; the content of 3,5-dibromo-4-hydroxybenzaldehyde in the insoluble product is more than 99%.

[0034] S2-3. The filtrate collected in step S2-2 was cooled to below 40 ° C and filtered again. The filter residue was the recrystallized product, and the filtrate (ie, water) was reused; the content of 3-bromo-4-hydroxybenzaldehyde in the obtained recrystallized product was 90wt% or more;

[0035] S2-4. The recrystallized product is completely melted, and then subjected to sequential cooling crystallization, separation of the mother liquor, heating for sweating, separation of the sweating liquid, and collection of the solid to obtain the primary crystallized product.

[0036] In some preferred embodiments, the S2-4 step specifically includes: transferring the recrystallized product to a crystallizer, melting the recrystallized product at 130-150°C under a nitrogen atmosphere, rapidly cooling to 120-122°C after complete melting, then cooling and crystallizing at a rate of (0.2-1)°C / 20min, crystals begin to appear when the temperature is lowered to 118°C, and the mother liquor is separated when the temperature is further lowered to 113±2°C; then heating and sweating at a rate of (0.2-1)°C / 20min, heating to 125-130°C to end sweating, separating the sweating liquid, and collecting the solid as the primary crystallization product; the content of 3-bromo-4-hydroxybenzaldehyde in the obtained primary crystallization product is 97.0% or more.

[0037] In some preferred embodiments, the separation and purification stage further comprises the steps of:

[0038] S2-5. Take the primary crystal product obtained in step S2-4 and perform secondary melt crystallization, and collect the secondary crystal product. Through multi-stage melt crystallization, a crystal product with a 3-bromo-4-hydroxybenzaldehyde content of more than 99.5 wt% can be collected.

[0039] More preferably, the step S2-5 specifically includes:

[0040] Under a nitrogen atmosphere, the primary crystal product is melted at 130-150° C., and after complete melting, the temperature is reduced and crystallized at a cooling rate of 1° C. / min. When the temperature is reduced to the point where crystals begin to appear, the temperature is maintained for crystallization for 2-4 hours, and the mother liquor is separated; then, the temperature is increased at a rate of (0.2-1)° C. / 20 min to sweat, and the temperature is increased to 125-132° C. to stop sweating, and the sweating liquid is separated to obtain a secondary crystal product; the content of 3-bromo-4-hydroxybenzaldehyde in the secondary crystal product is more than 99.5wt%.

[0041] In some preferred embodiments, the etherification step comprises: mixing the secondary crystal product with sodium methoxide or sodium ethoxide, reacting in the presence of a catalyst and an organic solvent B until the content of 3-bromo-4-hydroxybenzaldehyde is less than 1wt%; distilling to remove the solvent, adding water to dissolve, filtering to remove the catalyst, taking the filtrate to adjust the pH to 2-3, continuously stirring and cooling to below 15°C, filtering to collect the filter residue, and drying to obtain the etherification product.

[0042] The reaction equation of the etherification stage is as follows (taking sodium ethoxide as the reactant and synthesizing ethyl vanillin as an example):

[0043]

[0044] In some preferred embodiments, based on the mass of 3-bromo-4-hydroxybenzaldehyde (derived from the secondary crystallization product), the volume addition amount of the organic solvent B is 1-5 times (mL / g) of the mass of the secondary crystallization product.

[0045] In some preferred embodiments, based on the molar amount of 3-bromo-4-hydroxybenzaldehyde (derived from the secondary crystallization product), the molar amount of sodium methoxide added is 1-3 times the mass of the secondary crystallization product.

[0046] In some preferred embodiments, based on the molar amount of 3-bromo-4-hydroxybenzaldehyde (derived from the secondary crystallization product), the molar amount of sodium ethoxide added is 1-3 times that of the secondary crystallization product.

[0047] In some preferred embodiments, the catalyst is added in an amount of 0.05-5 wt % of the mass of the secondary crystallization product, more preferably 0.1-2 wt %.

[0048] In some preferred embodiments, the reaction temperature in the etherification step is 75-90°C; more preferably 78-85°C, which can be 78°C, 79°C, 80°C, 81°C, 82°C, 83°C, 84°C, 85°C; most preferably 80°C.

[0049] The second aspect of the present invention provides a product obtained by the synthesis method as described above, when the reactant in step S3 is sodium methoxide, the content of vanillin in the etherification product is more than 99.5wt%; when the reactant in step S3 is sodium ethoxide, the content of ethyl vanillin in the etherification product is more than 99.5wt%.

[0050] In the process of synthesizing vanillin / ethyl vanillin, it is difficult to completely separate the intermediate 3-bromo-4-hydroxybenzaldehyde and the impurity 3,5-dibromo-4-hydroxybenzaldehyde due to their similar structures, similar properties, and similar solubility in most solvents, which directly results in low purity of 3-bromo-4-hydroxybenzaldehyde, and low content of further synthesized vanillin / ethyl vanillin, and it is difficult to improve the synthesis efficiency. The prior art has not proposed an effective separation method (the inventor conducted experiments based on the patent disclosure, and after repeated verification, it was actually impossible to achieve efficient separation of 3-bromo-4-hydroxybenzaldehyde and 3,5-dibromo-4-hydroxybenzaldehyde, see Table 1-3 data for details). Experimental research found that recrystallization has limited separation effect on the two bromides. Although melt crystallization can improve the separation effect, only when the content of the target substance in the raw material reaches a certain level can a better crystallization result be obtained. The present invention combines the two separation and purification methods of recrystallization and melt crystallization, which greatly improves the separation effect of the two bromides; and the solubility of the two bromides in cold water is negligible, so there is no need to consider recycling raw materials in water; all materials in the entire separation and purification process can be recycled without material loss, which greatly improves product quality and production efficiency and has extremely high practicality.

[0051] The third aspect of the present invention provides an application of the above-mentioned synthesis method, wherein the synthesis method is applied to prepare syringaldehyde, and the preparation steps include:

[0052] The insoluble product of step S2 is mixed with sodium methoxide, and reacted in the presence of a catalyst and an organic solvent C until the content of 3,5-dibromo-4-hydroxybenzaldehyde is less than 1wt%; the solvent is removed by distillation, water is added to dissolve, the catalyst is removed by filtration, the filtrate is adjusted to pH 2-3, the mixture is continuously stirred and cooled to below 15°C, the filter residue is collected by filtration, and the syringaldehyde product is obtained by drying.

[0053] Preferably, the content of syringaldehyde in the obtained syringaldehyde product is above 99 wt%.

[0054] In some preferred embodiments, the amount of reactants and reaction conditions for preparing syringaldehyde are similar to those for the etherification reaction, the main difference being that the reactant is replaced with 3,5-dibromo-4-hydroxybenzaldehyde.

[0055] In some preferred embodiments, the organic solvent B and the organic solvent C are independently selected from benzene, toluene, xylene, cyclohexane, chlorobenzene, dichlorobenzene, methanol, ethanol, isopropanol, ether, propylene oxide, ethyl acetate, acetonitrile, dimethyl sulfoxide, dimethylformamide, etc., preferably dimethylformamide (DMF).

[0056] In some preferred embodiments, the catalyst is a cuprous halide, which may be cuprous chloride, cuprous iodide, cuprous bromide, and more preferably cuprous iodide (CuI).

[0057] Beneficial effects:

[0058] The present invention provides a synthesis method of vanillin and its derivatives and application thereof, which have the following advantages:

[0059] (1) The present invention solves the problem of poor separation of 3-bromo-4-hydroxybenzaldehyde and 3,5-dibromo-4-hydroxybenzaldehyde in the process of synthesizing vanillin and its derivatives through a synthesis process of bromination-separation and purification-etherification, and can produce high-purity 3-bromo-4-hydroxybenzaldehyde and 3,5-dibromo-4-hydroxybenzaldehyde, further improving the product quality of vanillin / ethyl vanillin.

[0060] (2) The present invention couples recrystallization and melt crystallization to avoid the loss of the target substance caused by dissolving in water; no material loss occurs during the entire separation and purification process, and the collected intermediate products can be recycled and reused, thereby improving production efficiency.

[0061] (3) The present invention adopts a secondary melt crystallization process to further increase the content of 3-bromo-4-hydroxybenzaldehyde in the crystallized product; the intermediate is purified to synthesize vanillin / ethyl vanillin, thereby avoiding the complex purification of the product after direct synthesis, and the operation process is simple and easy, and the product quality is high.

[0062] (4) High-purity 3,5-dibromo-4-hydroxybenzaldehyde can be obtained in the purification process of the present invention, and high-purity syringaldehyde can be obtained by reacting it with sodium methoxide; the application scope is further broadened.

[0063] (5) The overall process of the present invention is environmentally friendly, produces almost no three wastes, is environmentally friendly, and is conducive to mass production. DETAILED DESCRIPTION

[0064] Note: Unless otherwise specified, the solvents of the solutions involved in the present invention are all water; and the raw materials used are all commercially available.

[0065] Example 1

[0066] This embodiment provides a method for synthesizing vanillin and a product thereof, wherein the synthesis steps include:

[0067] S1. Bromination:

[0068] 2240g of p-hydroxybenzaldehyde, 10L of dichloromethane and 2L of anhydrous methanol were added into a reaction kettle, the temperature was lowered to 5°C under stirring, 3520g of bromine was added dropwise, and the dropping was controlled to be completed within 60min, and then the reaction was continued for 3h. During the reaction, a micro-flow was used to remove hydrogen bromide gas, which was absorbed and recovered with water. After the reaction was completed, the solvent was recovered by vacuum distillation, and a crude product was obtained by complete evaporation. The mass of the obtained crude product was 4246.3g, and it was determined that it contained 85.4wt% of 3-bromo-4-hydroxybenzaldehyde and 14.6wt% of 3,5-dibromo-4-hydroxybenzaldehyde.

[0069] S2.Separation and purification:

[0070] S2-1. Take 4000g of the crude product and add it to the reactor, add 108L of water and heat to boiling under stirring;

[0071] S2-2. The boiling material was filtered while hot, and the residue was dried to obtain an insoluble product. The mass of the insoluble product was 302g, wherein the content of 3,5-dibromo-4-hydroxybenzaldehyde was 99.6wt%;

[0072] S2-3. The filtrate was stirred continuously and slowly cooled to 35°C, filtered, and the filter residue was dried to obtain a recrystallized product; the mass of the obtained recrystallized product was 3678g, of which the content of 3-bromo-4-hydroxybenzaldehyde was 92.2%.

[0073] S2-4. Primary crystallization: 3600 g of the recrystallized product was placed in a crystallizer, and the recrystallized product was melted at 140 ° C in a nitrogen atmosphere. After the melting was complete, the temperature was cooled at a rate of 0.5 ° C / 20 min. Crystallization began to occur when the temperature dropped to 118 ° C. The temperature was slowly cooled to 114 ° C to separate the mother liquor; then the temperature was raised at a rate of 0.5 ° C / 20 min to sweat. When the temperature was raised to 127 ° C, the sweating was completed, and the sweating liquid was separated to obtain the primary crystal product;

[0074] The mother liquor and sweat liquid produced during the primary crystallization process totaled 1182 g, of which the content of 3-bromo-4-hydroxybenzaldehyde was 83.3 wt %, and the content of 3,5-dibromo-4-hydroxybenzaldehyde was 16.7 wt %; the mass of the primary crystallization product was 2399 g, of which the content of 3-bromo-4-hydroxybenzaldehyde was 97.1 wt %, and the content of 3,5-dibromo-4-hydroxybenzaldehyde was 2.9 wt %.

[0075] S2-5. Secondary crystallization: 2300 g of the primary crystal product was taken, and the primary crystal product was melted at 140 ° C in a nitrogen atmosphere. After the melting was complete, the temperature was lowered at a rate of 0.5 ° C / 20 min. Crystallization began to occur when the temperature dropped to 122 ° C. The crystallization was maintained at this temperature for 3 hours, and the mother liquor was separated; then the temperature was raised at a rate of 0.5 ° C / 20 min to sweat. When the temperature was raised to 130 ° C, no sweating liquid was produced, and sweating stopped; the sweating liquid was separated to obtain the secondary crystal product;

[0076] The mother liquor and sweat liquid produced during the secondary crystallization process totaled 834 g, of which the content of 3-bromo-4-hydroxybenzaldehyde was 91.9 wt %, and the content of 3,5-dibromo-4-hydroxybenzaldehyde was 8.1 wt %; the mass of the secondary crystallization product was 1454 g, of which the content of 3-bromo-4-hydroxybenzaldehyde was 99.9 wt %, and the content of 3,5-dibromo-4-hydroxybenzaldehyde was 0.1 wt %.

[0077] S3. Etherification:

[0078] 100.5 g of the secondary crystallization product, 400 mL of DMF, 59.4 g of sodium methoxide, and 1.0 g of cuprous iodide were added to a reactor in sequence, and the temperature was raised to 80° C. under a nitrogen atmosphere for reaction for 3 h. No 3-bromo-4-hydroxybenzaldehyde was detected in the sample; DMF was distilled off, and then 400 mL of water was added. The mixture was stirred and dissolved at 80° C., filtered, and the residue was dried and recycled. The pH of the filtrate was adjusted to 2.5±0.5 with concentrated hydrochloric acid, and the mixture was continuously stirred and cooled to precipitate crystals. A large amount of crystals precipitated at 26° C. The mixture was further cooled to 10° C., filtered, and the residue was collected and dried to obtain an etherified product (light yellow crystalline powder); the mass of the obtained etherified product was 69.5 g, and the content of vanillin was 99.8 wt %.

[0079] Example 2

[0080] This embodiment provides a method for synthesizing vanillin and a product thereof, wherein the synthesis steps include:

[0081] S1. Bromination:

[0082] 244 g of p-hydroxybenzaldehyde, 1000 mL of dichloromethane and 200 mL of anhydrous methanol were added into a reaction kettle, and the temperature was lowered to 5° C. under stirring, and 352 g of bromine was added dropwise, and the dropping was controlled to be completed within 60 minutes, and then the reaction was carried out for 3 hours. During the reaction, a micro-gas flow was used to remove hydrogen bromide gas, which was absorbed and recovered with water; after the reaction was completed, the solvent was recovered by vacuum distillation, and a crude product was obtained by complete evaporation; the mass of the obtained crude product was 423.9 g, and it was determined that it contained 86.1 wt % of 3-bromo-4-hydroxybenzaldehyde and 13.9 wt % of 3,5-dibromo-4-hydroxybenzaldehyde.

[0083] Steps S2 and S3 are the same as those in Example 1.

[0084] Example 3

[0085] This embodiment provides a method for synthesizing vanillin and a product thereof, wherein the synthesis steps include:

[0086] S1. Bromination:

[0087] 244 g of p-hydroxybenzaldehyde, 1200 mL of dichloromethane and anhydrous methanol (the anhydrous methanol comes from the recovered solvent in Example 2) were added to a reactor, the temperature was lowered to 5° C. under stirring, 352 g of bromine was added dropwise, and the dripping was controlled to be completed within 60 min, and then the reaction was carried out for 3 h. During the reaction, a micro-gas flow was used to remove hydrogen bromide gas, which was absorbed and recovered with water; after the reaction was completed, the solvent was recovered by vacuum distillation, and a crude product was obtained after complete evaporation; the mass of the obtained crude product was 422.7 g, and it was determined that it contained 86.3 wt % of 3-bromo-4-hydroxybenzaldehyde and 13.7 wt % of 3,5-dibromo-4-hydroxybenzaldehyde.

[0088] S2.Separation and purification:

[0089] S2-1. Take 200g of the crude product and add it to the reactor, add 5400mL of water and heat to boiling under stirring;

[0090] S2-2. The boiling material was filtered while hot, and the residue was dried to obtain an insoluble product. The mass of the insoluble product was 12.1 g, wherein the content of 3,5-dibromo-4-hydroxybenzaldehyde was 99.7 wt %;

[0091] S2-3. The filtrate was stirred continuously and slowly cooled to 35°C, filtered, and the residue was dried to obtain a recrystallized product; the mass of the obtained recrystallized product was 185.0 g, wherein the content of 3-bromo-4-hydroxybenzaldehyde was 92.1 wt%.

[0092] S2-4. Primary crystallization: 180 g of the recrystallized product was placed in a crystallizer, and the recrystallized product was melted at 140 ° C in a nitrogen atmosphere. After the melting was complete, the temperature was slowly lowered at a rate of 0.5 ° C / 30 min. Crystallization began to occur when the temperature dropped to 118 ° C. The temperature was slowly lowered to 114 ° C to separate the mother liquor; then the temperature was raised at a rate of 0.5 ° C / 20 min to sweat. When the temperature was raised to 127 ° C, the sweating was completed, and the sweating liquid was separated to obtain the primary crystal product;

[0093] The mother liquor and sweat liquid produced during the primary crystallization process totaled 55.7 g, of which the content of 3-bromo-4-hydroxybenzaldehyde was 82.0 wt %, and the content of 3,5-dibromo-4-hydroxybenzaldehyde was 18.0 wt %; the mass of the primary crystallization product was 122.9 g, of which the content of 3-bromo-4-hydroxybenzaldehyde was 96.5 wt %, and the content of 3,5-dibromo-4-hydroxybenzaldehyde was 3.5 wt %.

[0094] S2-5. Secondary crystallization: 120 g of the primary crystal product was taken, and the primary crystal product was melted at 140 ° C in a nitrogen atmosphere. After the melting was complete, the temperature was lowered at a rate of 0.5 ° C / 20 min. Crystallization began to occur when the temperature dropped to 122 ° C. The crystallization was maintained at this temperature for 3 hours, and the mother liquor was separated; then the temperature was raised at a rate of 0.5 ° C / 20 min to sweat. When the temperature was raised to 129 ° C, no sweating liquid was produced, and sweating stopped; the sweating liquid was separated to obtain the secondary crystal product;

[0095] The mother liquor and sweat liquid produced during the secondary crystallization process totaled 44.3 g, of which the content of 3-bromo-4-hydroxybenzaldehyde was 90.7 wt %, and the content of 3,5-dibromo-4-hydroxybenzaldehyde was 9.3 wt %; the mass of the secondary crystallization product was 74.9 g, of which the content of 3-bromo-4-hydroxybenzaldehyde was 99.9 wt %, and the content of 3,5-dibromo-4-hydroxybenzaldehyde was 0.1 wt %.

[0096] S3. Etherification:

[0097] 50.0 g of secondary crystallization product, 200 mL of DMF, 29.8 g of sodium methoxide and 0.5 g of cuprous iodide were added to a reactor in sequence, and the temperature was raised to 80° C. under a nitrogen atmosphere for reaction for 3 h. The 3-bromo-4-hydroxybenzaldehyde content was detected to be 0.03 wt % by sampling. DMF was removed by distillation, and then 100 mL of water was added. The mixture was stirred and dissolved at 80° C., filtered, and the residue was dried and recycled. The pH of the filtrate was adjusted to 2.5±0.5 with concentrated hydrochloric acid, and the mixture was continuously stirred and cooled to precipitate crystals. A large amount of crystals precipitated at 29° C. The mixture was further cooled to 10° C., filtered, and the residue was collected and dried to obtain an etherified product (light yellow crystalline powder). The mass of the obtained etherified product was 35.9 g, and the content of vanillin was 99.8%.

[0098] Example 4

[0099] This embodiment provides a method for synthesizing ethyl vanillin. The specific implementation method is the same as that of Example 1, except that:

[0100] S3. Etherification:

[0101] 100.5 g of the secondary crystal product of Example 1, 400 mL of DMF, 75.0 g of sodium ethoxide, and 1.0 g of cuprous iodide were added to a reactor in sequence, and the temperature was raised to 80° C. under a nitrogen atmosphere for reaction for 3 h. The 3-bromo-4-hydroxybenzaldehyde content was detected to be 0.04 wt % by sampling. DMF was removed by distillation, and then 400 mL of water was added. The mixture was stirred and dissolved at 80° C., filtered, and the residue was dried and recycled. The pH of the filtrate was adjusted to 2.5±0.5 with concentrated hydrochloric acid, and the mixture was continuously stirred and cooled to precipitate crystals. A large amount of crystals precipitated at 34° C. The mixture was further cooled to 10° C., filtered, and the residue was collected and dried to obtain an etherified product (light yellow crystalline powder). The mass of the etherified product was 72.1 g, and the content of vanillin was 99.7 wt %.

[0102] Example 5

[0103] This example provides a method for synthesizing ethyl vanillin. The specific implementation method is the same as that of Example 1. The secondary crystallization product of Example 1 is taken and the S3 etherification operation is repeated to observe the repeatability of the results. Specifically:

[0104] S3. Etherification:

[0105] 100.5 g of the secondary crystal product of Example 1, 400 mL of DMF, 75.0 g of sodium ethoxide, and 1.0 g of cuprous iodide were added to a reactor in sequence, and the temperature was raised to 80° C. under a nitrogen atmosphere for reaction for 3 h. The 3-bromo-4-hydroxybenzaldehyde content was detected to be 0.01 wt % by sampling; DMF was removed by distillation, and then 400 mL of water was added. The mixture was stirred and dissolved at 80° C., filtered, and the residue was dried and recycled. The pH of the filtrate was adjusted to 2.5±0.5 with concentrated hydrochloric acid, and the mixture was continuously stirred and cooled to precipitate crystals. A large amount of crystals precipitated at 36° C. The mixture was further cooled to 10° C., filtered, and the residue was collected and dried to obtain an etherified product (light yellow crystalline powder); the mass of the etherified product was 73.6 g, and the content of vanillin was 99.6 wt %.

[0106] Example 6

[0107] The present embodiment provides a method for synthesizing syringaldehyde, and the synthesis steps include: adding 28 g of the insoluble product obtained in Example 1, 112 mL of DMF, 17.3 g of sodium methoxide, and 1.0 g of cuprous iodide to a reaction kettle in sequence, heating to 80° C. under a nitrogen atmosphere for reaction for 3 h, sampling and detecting that the content of 3-bromo-4-hydroxybenzaldehyde is 0.01 wt %; distilling to remove DMF, then adding 400 mL of water, stirring and dissolving at 80° C., filtering, drying the filter residue and recycling it for use, adjusting the pH of the filtrate to 2.5±0.5 with concentrated hydrochloric acid, continuously stirring and cooling to precipitate crystals, a large amount of crystals precipitate at 45° C., continuing to cool to 10° C., filtering, collecting the filter residue and drying to obtain a syringaldehyde product (brown crystalline powder); the mass of the obtained syringaldehyde product is 16.9 g, wherein the content of syringaldehyde is 99.8 wt %.

[0108] Example 8

[0109] The present embodiment provides a method for synthesizing syringaldehyde, and the synthesis steps include: adding 56 g of the insoluble product obtained in Example 1, 112 mL of DMF, 33.5 g of sodium methoxide, and 0.5 g of cuprous iodide to a reaction kettle in sequence, heating to 80° C. under a nitrogen atmosphere for reaction for 3 h, sampling and detecting that the content of 3-bromo-4-hydroxybenzaldehyde is 0.08 wt %; distilling to remove DMF, then adding 224 mL of water, stirring and dissolving at 80° C., filtering, drying the filter residue and recycling it for use, adjusting the pH of the filtrate to 2.5±0.5 with concentrated hydrochloric acid, continuously stirring and cooling to precipitate crystals, a large amount of crystals precipitate at 45° C., continuing to cool to 10° C., filtering, collecting the filter residue and drying to obtain a syringaldehyde product (brown crystalline powder); the mass of the obtained syringaldehyde product is 34.4 g, wherein the content of syringaldehyde is 99.7 wt %.

[0110] Performance Test Results

[0111] The products of the synthesis methods of Examples 1-8 were qualitatively and quantitatively analyzed by GB / T14457.3 flavor melting point determination method and GB / T11539-2008 flavor filling gas chromatography analysis general method, and the content of the analyte was further calculated; at the same time, the methods disclosed in Chinese patents CN102249875A, CN110606801A, and CN107954844A were used for comparison; the test results are shown in Tables 1-3.

[0112] Table 1. Product contents of the bromination stage

[0113]

[0114]

[0115] Table 2. Product content in the separation and purification stage

[0116]

[0117] Table 3. Product content of etherification stage

[0118]

[0119]

[0120] Note: Since the bromination step of CN107954844A could not be carried out normally, the raw materials of comparative examples ① and ② were sourced from Example 1 of this method.

[0121] It can be seen from the scheme data of Table 1-3 and Examples 1-6 that the present invention can effectively separate 3-bromo-4-hydroxybenzaldehyde and 3,5-dibromo-4-hydroxybenzaldehyde by coupling recrystallization and melt crystallization; further secondary melt crystallization can increase the content of 3-bromo-4-hydroxybenzaldehyde in the crystallized product to 99.90%. In addition, there is no material loss in the entire synthesis and purification process, and all can be recycled, which can greatly improve production efficiency while ensuring product quality.

Claims

1. A method for synthesizing vanillin and its derivatives, characterized in that: The synthesis steps include: S1. Bromination: taking p-hydroxybenzaldehyde and reacting with a brominating agent to obtain a mixture of 3-bromo-4-hydroxybenzaldehyde and 3,5-dibromo-4-hydroxybenzaldehyde; S2. Separation and purification: taking the mixture of 3-bromo-4-hydroxybenzaldehyde and 3,5-dibromo-4-hydroxybenzaldehyde, and sequentially subjecting it to recrystallization and melt crystallization to separate 3-bromo-4-hydroxybenzaldehyde and 3,5-dibromo-4-hydroxybenzaldehyde; S3. Etherification: react 3-bromo-4-hydroxybenzaldehyde with sodium methoxide or sodium ethoxide to obtain an etherified product; When the reactant in step S3 is sodium methoxide, the etherification product is vanillin; when the reactant in step S3 is sodium ethoxide, the etherification product is ethyl vanillin.

2. The method for synthesizing vanillin and its derivatives according to claim 1, characterized in that: The separation and purification comprises the following steps: S2-1. Take the mixture of 3-bromo-4-hydroxybenzaldehyde and 3,5-dibromo-4-hydroxybenzaldehyde, add 20-30 times water, and heat to boiling; S2-2. The boiling material is filtered while hot to separate the residue and the filtrate; the residue is dried to obtain an insoluble product; S2-3. The filtrate collected in step S2-2 is cooled to below 40 ° C and filtered again. The residue is the recrystallized product; S2-4. The recrystallized product is completely melted, and then subjected to sequential cooling crystallization, separation of the mother liquor, heating for sweating, separation of the sweating liquid, and collection of the solid to obtain the primary crystallized product.

3. The method for synthesizing vanillin and its derivatives according to claim 2, characterized in that: The S2-4 step specifically includes: transferring the recrystallized product to a crystallizer, melting the recrystallized product at 130-150°C under a nitrogen atmosphere, rapidly cooling the temperature to 120-122°C after complete melting, then cooling and crystallizing at a rate of (0.2-1)°C / 20min, and separating the mother liquor when the temperature is cooled to 113±2°C; then heating and sweating at a rate of (0.2-1)°C / 20min, heating to 125-130°C to end sweating, separating the sweating liquid, and collecting the solid as the primary crystallization product.

4. The method for synthesizing vanillin and its derivatives according to claim 2 or 3, characterized in that: The separation and purification further comprises the following steps: S2-5. Take the primary crystal product obtained in step S2-4 and perform secondary melt crystallization, and collect the secondary crystal product.

5. The method for synthesizing vanillin and its derivatives according to claim 4, characterized in that: The S2-5 step specifically comprises: melting the primary crystalline product at 130-150°C under a nitrogen atmosphere, cooling and crystallizing at a rate of (0.2-1)°C / 20min after complete melting, maintaining this temperature for crystallization for 2-4h when the temperature starts to appear, and separating the mother liquor; then heating and sweating at a rate of (0.2-1)°C / 20min, heating to 125-132°C to stop sweating, separating the sweating liquid, and collecting the solid to obtain the secondary crystalline product.

6. The method for synthesizing vanillin and its derivatives according to claim 3, characterized in that: The content of 3-bromo-4-hydroxybenzaldehyde in the primary crystal product is above 97.0 wt %.

7. The product of the method for synthesizing vanillin and its derivatives according to claim 5, characterized in that: The content of 3-bromo-4-hydroxybenzaldehyde in the secondary crystallization product is above 99.5 wt %.

8. The method for synthesizing vanillin and its derivatives according to claim 5, characterized in that: The etherification step comprises: mixing the secondary crystal product with sodium methoxide or sodium ethoxide, reacting in the presence of a catalyst and an organic solvent B until the content of 3-bromo-4-hydroxybenzaldehyde is less than 1wt%; removing the solvent by distillation, adding water to dissolve, filtering, adjusting the pH of the filtrate to 2-3, continuously stirring and cooling to below 15°C, filtering and collecting the filter residue, and drying to obtain the etherification product.

9. A product of the synthesis method according to claim 5, characterized in that When the reactant in step S3 is sodium methoxide, the content of vanillin in the etherification product is more than 99.5 wt %. When the reactant in step S3 is sodium ethoxide, the content of ethyl vanillin in the etherification product is more than 99.5 wt %.

10. An application of the synthesis method according to claim 2, characterized in that: The synthesis method is applied to prepare syringaldehyde, and the preparation steps include: The insoluble product of step S2 is mixed with sodium methoxide, and reacted in the presence of a catalyst and an organic solvent C until the content of 3,5-dibromo-4-hydroxybenzaldehyde is less than 1wt%; the solvent is removed by distillation, water is added to dissolve, and the mixture is filtered. The filtrate is adjusted to a pH of 2-3, the mixture is continuously stirred and cooled to below 15°C, the filter residue is collected by filtration, and the syringaldehyde product is obtained by drying.

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