A method for preparing vanillin

Abstract

The present invention discloses a method for preparing vanillin. Using 2-methoxy-6-tert-butyl-p-cresol as the starting material, a low molecular weight alcohol or carboxylic acid as the solvent, adding copper, cobalt, and manganese salts as a composite catalyst, heating and stirring to promote dissolution, introducing air or oxygen, and carrying out an oxidation reaction following the Baik-Ji-type mechanism at 50-150 °C. After the oxidation reaction is completed, a non-oxidizing strong acid is added, and the reverse alkylation reaction for removing the tert-butyl group is continued under heating conditions. The inorganic salt catalyst is filtered off, the solvent is evaporated, and recrystallization is carried out, and finally vanillin is directly prepared in a one-pot manner. The present invention has the advantages of simple operation, high reaction efficiency, good atom economy, environmental friendliness, etc., and can further reduce the production cost.

Description

Technical Field

[0001] The present invention belongs to the technical field of synthetic flavors and relates to a process for green and efficient preparation of vanillin. Technical Background

[0002] Vanillin is the synthetic flavor with the largest global production volume, the most widely used flavor variety in the fragrance industry, and also an important organic synthesis intermediate, and its market demand shows an increasing trend year by year. Currently, the processes adopted for vanillin production at home and abroad are mostly guaiacol-glyoxylic acid synthesis routes (Formula 1), but this process route has disadvantages such as multiple synthesis steps, high price of glyoxylic acid, use of a large amount of copper sulfate oxidant, and large sewage discharge, making it difficult to further reduce production costs.

[0003]

[0004] In order to overcome the disadvantages of the existing vanillin production processes, the applicant has proposed a synthesis method for vanillin based on p-cresol and bromine (Ji Yafei et al., A method for preparing vanillin and its analogs, Chinese invention patent authorization ZL200910045117.0), and the synthesis route is shown in Formula 2 below. However, due to the high price of bromine in recent years, the practical application of this route is limited.

[0005]

[0006] In view of this, there is an urgent need in the field of spice production for a process for preparing vanillin with low cost, high efficiency and greenness. Using relatively easily available raw materials as the source, eliminating the use of raw and auxiliary materials such as glyoxylic acid and a large amount of copper sulfate in the existing routes, and minimizing environmental pollution to the greatest extent to meet the production requirements of the industrial sector for vanillin. Summary of the Invention

[0007] Based on the above problems, the present invention aims to avoid the use of glyoxylic acid and a large amount of copper sulfate in the existing process technologies, and at the same time further reduce the separation link of reaction intermediates, so as to provide a high-efficiency, low-cost and green vanillin manufacturing process, which is more convenient for industrial production to meet the needs of the industrial sector.

[0008] The concept and principle of the present invention are as follows:

[0009] In previous scientific research on the preparation of p-hydroxybenzaldehyde compounds by the transition metal-catalyzed oxidation of cresol compounds, the inventors proposed an oxidation reaction pathway following the Baik-Ji-type mechanism (Green Chem. 2014, 16, 1248–1254; Green Chem. 2014, 16, 2807–2814; Tetrahedron Lett. 2014, 55, 1406–1411; Syn. Commun. 2014, 44, 1430–1440.). Through the Baik-Ji-type oxidation reaction pathway, other p-hydroxybenzyl derivatives can also be oxidized and derived (Eur. J. Org. Chem. 2015, 5334–5338; Res. Chem. Intermediat. 2015, 41, 7115–7124; Synlett 2015, 26, 2145–2150.). Based on these basic research results, the inventors proposed to use relatively inexpensive 2-methoxy-6-tert-butyl-p-cresol as the starting material, and in a low molecular weight alcohol or carboxylic acid solvent, first carry out an oxidation reaction following the Baik-Ji-type mechanism to obtain the intermediate 3-methoxy-5-tert-butyl-p-hydroxybenzaldehyde. Then, a non-oxidizing strong acid is added to carry out the reverse alkylation reaction for removing the tert-butyl group, and finally vanillin, an artificial synthetic fragrance, is obtained in a one-pot manner. The reaction equation is as shown in Equation 3 below:

[0010]

[0011] To achieve the above object, the technical solution adopted in the present invention is as follows:

[0012] The preparation method of vanillin provided by the present invention is as follows: In a low molecular weight alcohol or carboxylic acid solvent, the starting material 2-methoxy-6-tert-butyl-p-cresol and the composite catalysts copper salt, cobalt salt and manganese salt are added, heated and stirred to promote dissolution, air or oxygen is bubbled in, and an oxidation reaction following the Baik-Ji-type mechanism is first carried out at 50–150 °C. After the oxidation reaction is completed, a non-oxidizing strong acid is added, and the reverse alkylation reaction for removing the tert-butyl group is continued under heating conditions to obtain the crude vanillin. The reaction solution is cooled, the inorganic salt catalyst is filtered off, the solvent is evaporated, and recrystallized and refined, and finally vanillin is obtained in a one-pot manner.

[0013] Among them, (1) The Baik-Ji-type oxidation reaction mechanism experienced by 2-methoxy-6-tert-butyl-p-cresol is as shown in Equation 4. The temperature of the oxidation reaction is in the range of 50–150 °C, and the reaction time is 2.0–16.0 hours; preferably, the reaction temperature is 60–120 °C, and the reaction time is 4.0–10.0 hours.

[0014]

[0015] or

[0016]

[0017] (2) The copper salt, cobalt salt, and manganese salt in the composite catalyst can be inorganic acid salts or organic acid salts, and preferably acetate salts with better solubility under heating conditions. The molar ratio of the starting material 2-methoxy-6-tert-butyl-p-cresol to the copper salt, cobalt salt, and manganese salt in the composite catalyst is 1.0: 0.01 - 0.1 (copper salt): 0.001 - 0.05 (cobalt salt): 0.001 - 0.05 (manganese salt); preferably 1.0: 0.02 - 0.06 (copper acetate): 0.003 - 0.02 (cobalt acetate): 0.003 - 0.02 (manganese acetate).

[0018] (3) The molar ratio of the solvent to 2-methoxy-6-tert-butyl-p-cresol is 1.0 - 10.0:1, preferably 3.0 - 6.0:1.

[0019] Low molecular weight alcohols are usually active alcohols such as methanol, ethanol, ethylene glycol, ethylene glycol monomethyl ether, trifluoroethanol, difluoroethanol, fluoroethanol, trichloroethanol, dichloroethanol, chloroethanol, etc. It can be either a single solvent or a mixed solvent of them. It is preferred to use inexpensive methanol, ethylene glycol, and ethylene glycol monomethyl ether as solvents.

[0020] Low molecular weight organic carboxylic acids are usually active organic carboxylic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, difluoroacetic acid, fluoroacetic acid, trichloroacetic acid, dichloroacetic acid, chloroacetic acid, etc. It can be either a single solvent or a mixed solvent of them. It is preferred to use inexpensive formic acid, acetic acid, and chloroacetic acid as solvents.

[0021] (4) The reverse alkylation reaction for removing the tert-butyl group from the intermediate 3-methoxy-5-tert-butyl-p-hydroxybenzaldehyde needs to be carried out under the mediation of a non-oxidizing strong acid. Non-oxidizing strong acids are usually organic strong acids such as methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-nitrobenzenesulfonic acid, etc. It is preferred to use inexpensive methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. The molar ratio of the starting material 2-methoxy-6-tert-butyl-p-cresol to the non-oxidizing strong acid is 1.0: 0.01 - 0.5, and the preferred ratio is 1.0: 0.03 - 0.3.

[0022] (5) The reaction temperature for removing the tert-butyl group from the intermediate 3-methoxy-5-tert-butyl-p-hydroxybenzaldehyde is in the range of 40 - 160 °C, and the reaction time is 1.0 - 16.0 hours; preferably the reaction temperature is 60 - 130 °C, and the reaction time is 4.0 - 12.0 hours.

[0023] Based on the above preferred conditions, the preferred technical solution of the present invention is as follows:

[0024] In an ethylene glycol solvent, the starting material 2-methoxy-6-tert-butyl-p-cresol, the catalysts copper acetate, cobalt acetate, and manganese acetate are added. The mixture is heated and stirred to dissolve the raw materials, then the temperature is raised to 60 - 120°C, and oxygen is bubbled in. TLC is used for tracking until the spots of the raw materials completely disappear and the spot of the intermediate 3-methoxy-5-tert-butyl-p-hydroxybenzaldehyde is the largest, thus completing the oxidation reaction. Then methanesulfonic acid is added, and the reaction continues to be heated at 60 - 120°C for the reaction of removing the tert-butyl group. TLC is used for tracking until the spot of 3-methoxy-5-tert-butyl-p-hydroxybenzaldehyde disappears and the spot of the product vanillin is the largest, thus completing the reaction of removing the tert-butyl group. It is cooled to room temperature, the inorganic salt catalyst is filtered off, and the ethylene glycol solvent is removed by distillation under reduced pressure. Recrystallization is carried out with isopropanol, and finally the milky white product vanillin is obtained in a one-pot manner. The yield of vanillin based on the starting material 2-methoxy-6-tert-butyl-p-cresol can reach over 85%.

[0025] The present invention further protects the vanillin prepared according to the above method.

[0026] The beneficial technical effects of the present invention are as follows:

[0027] The starting material 2-methoxy-6-tert-butyl-p-cresol of the present invention can be derived from the by-products of the cresol industry, which is obtained by the tert-butylation, separation, and derivatization of mixed cresols, and the price is relatively low. The oxidation reaction adopts a green oxidation method, and the by-product is only water, which is non-toxic and harmless. In addition, the process design is reasonable, the reaction is efficient, and there is no need to separate the reaction intermediate. It is a vanillin manufacturing process with low cost, less pollution, and simple operation. Specific Embodiments

[0028] The following further elaborates on the present invention through examples, aiming to better understand the content of the present invention. The examples given do not limit the protection scope of the present invention: I. Specific Examples

[0030] Example 1

[0031] In a 250 mL three-necked flask, 100 mL of ethylene glycol, 19.4 g of 2-methoxy-6-tert-butyl-p-cresol (0.10 mol), 0.91 g of copper acetate (5 mmol), 0.18 g of cobalt acetate (1 mmol), and 0.17 g of manganese acetate (1 mmol) were successively added. The mixture was heated and stirred to dissolve the raw materials. The temperature was raised to 100 °C, and oxygen was bubbled in. The reaction was monitored by TLC. The oxidation reaction was completed after about 7 hours until the spots of the raw materials disappeared. The temperature was lowered to 60 °C, and 0.5 mL of methanesulfonic acid (8 mmol) was added dropwise. The reaction was continued at 60 °C for 5 hours and monitored by TLC until the spot of the intermediate 3-methoxy-5-tert-butyl-p-hydroxybenzaldehyde disappeared and the spot of the product vanillin was the largest, completing the reaction of removing the tert-butyl group. The mixture was cooled to room temperature, and the inorganic salt catalyst was filtered off. Ethylene glycol was removed by distillation under reduced pressure. Recrystallization was carried out with isopropanol, filtered, and the filter cake was dried to obtain 13.8 g of milky white vanillin, m.p. 82–83 °C, with a yield of 91%.

[0032] 1 H NMR(400MHz,CDCl 3 ,ppm):9.81(br s,1H),7.42–7.40(m,2H),7.03(br d,J=8.8Hz,1H),6.29(br s,1H),3.95(s,3H); 13 C NMR(100MHz,CDCl 3 ,ppm):191.1,151.8,147.2,129.8,127.6,114.5,108.9,56.1;HRMS(ESI):m / z[M–H + calcd.forC 8 H 7 O 3 151.0395,found 151.0410。

[0033] Example 2

[0034] In a 250 mL three-necked flask, 100 mL of ethylene glycol, 19.4 g of 2-methoxy-6-tert-butyl-p-cresol (0.10 mol), 0.91 g of copper acetate (5 mmol), 0.18 g of cobalt acetate (1 mmol), and 0.17 g of manganese acetate (1 mmol) were successively added. The mixture was heated and stirred to dissolve the raw materials. The temperature was raised to 100 °C, and air was bubbled in. The reaction was monitored by TLC. The reaction took about 10 hours until the spots of the raw materials disappeared, and the oxidation reaction was completed. The temperature was lowered to 60 °C, and 0.5 mL of methanesulfonic acid (8 mmol) was added dropwise. The reaction was continued by heating at 60 °C for 5 hours. The reaction was monitored by TLC until the spots of the intermediate 3-methoxy-5-tert-butyl-p-hydroxybenzaldehyde disappeared and the spot of the product vanillin was the largest, and the reaction of removing the tert-butyl group was completed. The mixture was cooled to room temperature, the inorganic salt catalyst was filtered off, and ethylene glycol was removed by distillation under reduced pressure. Recrystallization was carried out with isopropanol, filtered, and the filter cake was dried to obtain 13.5 g of milky white vanillin, m.p. 82–83 °C, and the yield was 89%.

[0035] Example 3

[0036] In a 250 mL three-necked flask, 100 mL of ethylene glycol monomethyl ether, 19.4 g of 2-methoxy-6-tert-butyl-p-cresol (0.10 mol), 0.91 g of copper acetate (5 mmol), 0.18 g of cobalt acetate (1 mmol), and 0.17 g of manganese acetate (1 mmol) were successively added. The mixture was heated and stirred to dissolve the raw materials. The temperature was raised to 100 °C, and oxygen was bubbled in. The reaction was monitored by TLC. The reaction took about 7 hours until the spots of the raw materials disappeared, and the oxidation reaction was completed. The temperature was lowered to 60 °C, and 0.5 mL of methanesulfonic acid (8 mmol) was added dropwise. The reaction was continued by heating at 60 °C for 5 hours. The reaction was monitored by TLC until the spots of the intermediate 3-methoxy-5-tert-butyl-p-hydroxybenzaldehyde disappeared and the spot of the product vanillin was the largest, and the reaction of removing the tert-butyl group was completed. The mixture was cooled to room temperature, the inorganic salt catalyst was filtered off, and ethylene glycol monomethyl ether was removed by distillation under reduced pressure. Recrystallization was carried out with isopropanol, filtered, and the filter cake was dried to obtain 13.7 g of milky white vanillin, m.p. 82–83 °C, and the yield was 90%.

[0037] Example 4

[0038] In a 250 mL three-necked flask, 100 mL of methanol, 19.4 g of 2-methoxy-6-tert-butyl-p-cresol (0.10 mol), 0.91 g of copper acetate (5 mmol), 0.18 g of cobalt acetate (1 mmol), and 0.17 g of manganese acetate (1 mmol) were successively added. The mixture was heated and stirred to dissolve the raw materials. The temperature was raised to 80 °C, and oxygen was bubbled in. The reaction was monitored by TLC and continued for about 12 hours until the spots of the raw materials disappeared, completing the oxidation reaction. The temperature was lowered to 60 °C, and 0.5 mL of methanesulfonic acid (8 mmol) was added dropwise. The reaction was continued by heating at 60 °C for 5 hours and monitored by TLC until the spots of the intermediate 3-methoxy-5-tert-butyl-p-hydroxybenzaldehyde disappeared and the spot of the product vanillin was the largest, completing the reaction for removing the tert-butyl group. The reaction mixture was cooled to room temperature, the inorganic salt catalyst was filtered off, and methanol was removed by distillation under reduced pressure. Recrystallization was carried out with isopropanol, followed by filtration and drying of the filter cake to obtain 13.1 g of milky white vanillin, with a melting point of 82–83 °C and a yield of 86%.

[0039] Example 5

[0040] In a 250 mL three-necked flask, 80 mL of methanol and 20 mL of ethylene glycol, 19.4 g of 2-methoxy-6-tert-butyl-p-cresol (0.10 mol), 0.91 g of copper acetate (5 mmol), 0.18 g of cobalt acetate (1 mmol), and 0.17 g of manganese acetate (1 mmol) were successively added. The mixture was heated and stirred to dissolve the raw materials. The temperature was raised to about 90 °C, and oxygen was bubbled in. The reaction was monitored by TLC and continued for about 8 hours until the spots of the raw materials disappeared, completing the oxidation reaction. The temperature was lowered to 60 °C, and 0.5 mL of methanesulfonic acid (8 mmol) was added dropwise. The reaction was continued by heating at 60 °C for 5 hours and monitored by TLC until the spots of the intermediate 3-methoxy-5-tert-butyl-p-hydroxybenzaldehyde disappeared and the spot of the product vanillin was the largest, completing the reaction for removing the tert-butyl group. The reaction mixture was cooled to room temperature, the inorganic salt catalyst was filtered off, and the mixed solvent was removed by distillation under reduced pressure. Recrystallization was carried out with isopropanol, followed by filtration and drying of the filter cake to obtain 13.8 g of milky white vanillin, with a melting point of 82–83 °C and a yield of 91%.

[0041] II. Comparison of the effects of different reaction conditions on the yield of vanillin

[0042] 1. Catalyst

[0043] The reaction procedure of Example 1 was followed, and only the type of catalyst was changed to determine the effect of different catalyst combinations on the yield of vanillin.

[0044] Table 1 Effect of different catalyst combinations on the yield of vanillin

[0045] Catalyst Vanillin yield Copper acetate (5 mmol) 83％ Cobalt acetate (5 mmol) 36％ Manganese acetate (5 mmol) 20％ Copper acetate (5 mmol), cobalt acetate (1 mmol) 86％ Copper acetate (5 mmol), manganese acetate (1 mmol) 85％ Copper acetate (5 mmol), cobalt acetate (5 mmol), manganese acetate (5 mmol) 91％ Copper acetate (5 mmol), cobalt acetate (1 mmol), manganese acetate (1 mmol) 91％

[0046] As can be seen from the data in Table 1, by changing the combination of catalysts, the highest yield of vanillin is still obtained with the catalyst combination used in Example 1. Therefore, in this application, the combination of copper salt, cobalt salt, and manganese salt is selected as the composite catalyst.

[0047] 2. Non-oxidizing strong acid

[0048] Operate according to the reaction procedure of Example 1, only change different types and their dosages, and measure their effects on the yield of vanillin.

[0049] Table 2 Effects of different non-oxidizing strong acids and dosages on the yield of vanillin

[0050] Dosage of non-oxidizing strong acid for the catalyst to remove tert-butyl Vanillin yield Methanesulfonic acid (12 mmol) 91％ Trifluoromethanesulfonic acid (6 mmol) 93％ Trifluoromethanesulfonic acid (12 mmol) 93％ Benzenesulfonic acid (6 mmol) 90％ Benzenesulfonic acid (15 mmol) 92％ p-Toluenesulfonic acid (6 mmol) 90％ p-Toluenesulfonic acid (15 mmol) 92％

[0051] As can be seen from the data in Table 2, by changing different non-oxidizing strong acids for removing tert-butyl catalysts and their dosages, relatively high yields of vanillin can be obtained. Considering that the catalyst dosage should not be too much or too little, the molar ratio of 2-methoxy-6-tert-butyl-p-cresol to non-oxidizing strong acid is selected to be 1.0:0.01 - 0.5, and the preferred ratio is 1.0:0.03 - 0.3.

[0052] 3. Solvent

[0053] Operate according to the reaction procedure of Example 1, only change the solvent to an active low-molecular-weight organic carboxylic acid, and measure the effects of different carboxylic acids on the yield of vanillin.

[0054] Table 3 Effects of different solvent combinations and dosages on the yield of vanillin

[0055] Organic carboxylic acid and its dosage Vanillin yield Formic acid (100 mL) 88％ Acetic acid (100 mL) 86％ Trifluoroacetic acid (100 mL) 92％ Monochloroacetic acid (100 mL) 91％ Acetic acid (80 mL), monochloroacetic acid (20 mL) 88％ Acetic acid (80 mL), formic acid (20 mL) 88％

[0056] As can be seen from the data in Table 3, when using an active low-molecular-weight organic carboxylic acid as the solvent, relatively good yields of vanillin can also be obtained. Considering the cost of carboxylic acids, it is preferred to use cheap formic acid, acetic acid, and chloroacetic acid as solvents.

[0057] The above are only preferred embodiments of the present invention, and do not impose any form of limitation on the present invention. Although the present invention has been disclosed in the above embodiments, it does not limit the scope of use of the present invention. Any person skilled in the art of this patent, without departing from the technical solution of the present invention, can make some changes or modifications using the technical content prompted above, which should be regarded as equivalent embodiments. All content that does not depart from the technical solution of the present invention, any simple modification, equivalent change, and modification made to the above embodiments based on the technical essence of the present invention still fall within the scope of the present invention's solution.

Claims

1. A method for preparing vanillin, characterized in that, in a low molecular weight alcohol or carboxylic acid solvent, starting material 2-methoxy-6-tert-butyl-p-cresol and a composite catalyst of copper salt, cobalt salt and manganese salt are added, heated and stirred to promote dissolution, air or oxygen is bubbled in, and an oxidation reaction following the Baik-Ji-type mechanism is carried out at 50-150 °C, and the raw material is converted into intermediate 3-methoxy-5-tert-butyl-p-hydroxybenzaldehyde; after the oxidation reaction is completed, a non-oxidizing strong acid is added, and the reverse alkylation reaction for removing the tert-butyl group is continued under heating conditions to obtain crude vanillin; after the reaction solution is cooled, the inorganic salt catalyst is filtered off, the solvent is removed by distillation under reduced pressure, and recrystallization is carried out for purification, and finally the artificial synthetic fragrance vanillin is prepared in a one-pot manner, wherein, the copper salt, cobalt salt and manganese salt are copper acetate, cobalt acetate and manganese acetate respectively.

2. The method for preparing vanillin according to claim 1, characterized in that: wherein, the molar ratio of 2-methoxy-6-tert-butyl-p-cresol to the copper salt, cobalt salt and manganese salt in the composite catalyst is 1.0:0.01-0.1:0.001-0.05:0.001-0.

05.

3. The method for preparing vanillin according to claim 1, characterized in that: wherein, the molar ratio of the solvent to 2-methoxy-6-tert-butyl-p-cresol is 1.0-10.0:1; the low molecular weight alcohol is selected from any one or more of methanol, ethanol, ethylene glycol, ethylene glycol monomethyl ether, trifluoroethanol, difluoroethanol, fluoroethanol, trichloroethanol, dichloroethanol, chloroethanol; the low molecular weight carboxylic acid is selected from any one or more of formic acid, acetic acid, propionic acid, trifluoroacetic acid, difluoroacetic acid, fluoroacetic acid, trichloroacetic acid, dichloroacetic acid, chloroacetic acid.

4. The method for preparing vanillin according to claim 1, characterized in that: wherein, the molar ratio of the solvent to 2-methoxy-6-tert-butyl-p-cresol is 3.0-6.0:1; the low molecular weight alcohol is selected from any one or more of methanol, ethylene glycol, ethylene glycol monomethyl ether; the low molecular weight carboxylic acid is selected from any one or more of formic acid, acetic acid, chloroacetic acid.

5. The method for preparing vanillin according to claim 1, characterized in that: wherein, the temperature for carrying out the Baik-Ji-type oxidation reaction of 2-methoxy-6-tert-butyl-p-cresol is 60-120 °C, and the reaction time is 4.0-10.0 hours.

6. The method for preparing vanillin according to claim 1, characterized in that: wherein, the non-oxidizing strong acid is selected from any one or more of methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-nitrobenzenesulfonic acid, and the molar ratio of 2-methoxy-6-tert-butyl-p-cresol to the non-oxidizing strong acid is 1.0:0.01-0.

5.

7. The method for preparing vanillin according to claim 1, characterized in that: wherein, the reaction temperature for removing the tert-butyl group from the intermediate 3-methoxy-5-tert-butyl-p-hydroxybenzaldehyde is in the range of 40-160 °C, and the reaction time is 1.0-16.0 hours.

8. The method for preparing vanillin according to claim 1, characterized in that: wherein, TLC was used for tracking during the reaction; After filtering out the inorganic salt catalyst from the reaction solution and distilling off the solvent under reduced pressure, recrystallization purification was carried out using isopropanol.

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