A method for preparing anisaldehyde from p-methoxybenzyl chloride

Abstract

This invention discloses a method for preparing anisaldehyde from p-methoxybenzyl chloride, comprising the following steps: oxidation of a p-methoxybenzyl chloride solution under a mixed atmosphere of inert gas and oxygen, catalyzed by an N-oxygen free radical compound, a metal salt, an oxidation regulator, and water; and post-treatment after the reaction to obtain the anisaldehyde. The metal salt is a water-soluble salt of copper, iron, or cerium; and the oxidation regulator is a bidentate organic ligand containing oxygen, nitrogen, and sulfur atoms. This method employs a special catalytic system, significantly improving the reaction yield and reducing costs.

Description

Technical Field

[0001] This invention relates to a process for synthesizing anisaldehyde, and more specifically, to a process for preparing anisaldehyde from p-methoxybenzyl chloride. Background Technology

[0002] Anisaldehyde, also known as p-methoxybenzaldehyde or 4-methoxybenzaldehyde, is a common food flavoring agent. It has a long-lasting hawthorn blossom aroma and is the main flavoring agent in hawthorn blossom fragrances. Anisaldehyde can also be used in floral fragrances such as lilac, orchid, sunflower, and acacia, as well as non-floral fragrances such as lavender, and in heavy woody fragrances such as sandalwood. In food, it is used to blend flavors and add sweetness. Furthermore, anisaldehyde is an excellent brightening agent for cyanide-free zinc plating (DE additive); it is also an important pharmaceutical intermediate used in the synthesis of the antimicrobial drug amoxicillin; and it is a key raw material for commonly used sunscreens such as avobenzone and OMC.

[0003] Stable nitric oxide radicals such as TEMPO act as oxidants, playing a crucial role in the conversion of low-oxidation-state organic compounds into high-oxidation-state organic compounds such as aldehydes and ketones. This is particularly true in the oxidation of primary alcohols to aldehydes, where over-oxidation is rare and the acid ratio is very low. In specific oxidation processes, TEMPO and its derivatives can function as equimolar oxidants, or as catalytic oxidants (referred to as primary oxidants) assisting equimolar oxidants (referred to as secondary oxidants), such as sodium hypochlorite, hydrogen peroxide, m-CPBA, iodobenzene acetate, periodic acid, and oxygen, to complete the corresponding oxidation processes. (See "Oxidation of Alcohols to Aldehydes and Ketones—A Guide to Current Common Practice," Gabriel Tojo, Marcos Fernándes, Chapter 5).

[0004] In the synthesis of anisaldehyde, methods using TEMPO as an oxidation catalyst can be divided into two main categories:

[0005] The first type uses p-methoxybenzyl alcohol as a raw material. For example, in 1984, Semmelhack et al. used CuCl, TEMPO, and oxygen to obtain anisaldehyde with a yield of up to 97% (J. Am. Chem. Soc., 1984, 106, 3374-3376); in 2014, Ullrich Jahn et al. used TEMPO, boron trifluoride ether, and tert-butyl nitrite to obtain anisaldehyde with a yield of up to 99% (Org. Lett., 2014, 16, 58-61).

[0006] The second category uses p-methoxybenzyl chloride as a raw material. For example, in 2010, Lu Ming et al. obtained anisaldehyde with a yield of 15% using TEMPO, potassium nitrite, and oxygen (Synthetic Communications, 2010, 40, 1106-1114); in 2013, Lu Ming et al. obtained anisaldehyde with a yield of 72% using TEMPO and hydrogen peroxide (Journal of Chemical Research, 2013, 37, 22-24).

[0007] Oxygen is a very green and inexpensive oxidant. Using oxygen as a secondary oxidant in oxidation reactions involving TEMPO is a very green method. This method is highly efficient in the conversion of p-methoxybenzyl alcohol to anisaldehyde, but when applied to the oxidation of p-methoxybenzyl chloride to anisaldehyde, it suffers from poor oxidation selectivity and low yield (only 15%). Summary of the Invention

[0008] To address the above problems, this invention provides a method for preparing anisaldehyde from p-methoxybenzyl chloride. This method employs a novel TEMPO catalytic system, which improves the reaction yield and achieves efficient conversion of p-methoxybenzyl chloride to anisaldehyde.

[0009] A method for preparing anisaldehyde from p-methoxybenzyl chloride includes the following steps:

[0010] Anisaldehyde was obtained by oxidizing a solution of methoxybenzyl chloride in a mixed atmosphere of inert gas and oxygen under the co-catalysis of TEMPO derivatives or functional group analogs, metal salts, oxidation regulators and water. After the reaction was completed, the solution was post-treated.

[0011] The metal salts mentioned are water-soluble salts of copper, iron, and cerium;

[0012] The oxidation regulator is a bidentate organic ligand containing oxygen, nitrogen, and sulfur atoms.

[0013] In this invention, by adding a bidentate organic ligand as an oxidation regulator, a complexation effect is generated with the metal ions, which enhances their catalytic cycle effect in the oxidation process. At the same time, due to the complexation effect of the regulator, the Lewis acidity of the metal ions is reduced, effectively inhibiting their catalytic activity in side reactions, thereby improving the overall yield of the oxidation reaction.

[0014] Further, the TEMPO derivative or functional group analogue includes one or two of the following: 2,2,6,6-tetramethylpiperidine oxide (TEMPO), 4-methoxy-2,2,6,6-tetramethylpiperidine oxide (4-OMe TEMPO), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (4-OH TEMPO), 4-acetoxy-2,2,6,6-tetramethylpiperidine oxide, 4-acetamino-2,2,6,6-tetramethylpiperidine oxide, N-hydroxyphthalimide (NHPI), 9-azabicyclo[3.3.1]nonane-N-oxy radical (ABNO), 4-amino-TEMPO, 2-azaadamantane-N-oxy (AZADO), 1-methyl-azaadamantane-N-oxy (1-Me-AZADO), and 4-benzoyloxy-TEMPO (BzO-TEMPO), preferably TEMPO, 4-OH TEMPO, and 4-OMe. TEMPO and ABNO.

[0015] The amount of the TEMPO derivative or functional group analog added is 0.3%-6% of the mass of the added p-methoxybenzyl chloride, preferably 0.5%-2.0%.

[0016] Further, the metal salt refers to a water-soluble salt or solution of metals such as copper, iron, and cerium. The metal salt includes one or two of the following: copper chloride, copper sulfate, copper acetate, copper nitrate, copper phosphate, copper acetylacetonate, ferric nitrate, ferric chloride, ferric sulfate, ferric phosphate, ferric acetylacetonate, ferric acetate, cerium nitrate, cerium ammonium nitrate, cerium sulfate, cerium chloride, cerium phosphate, cerium acetate, cerium isopropoxide, and cerium octanoate. Preferably, copper sulfate, ferric sulfate, ferric nitrate, and cerium nitrate are used alone or in combination.

[0017] The mass of the metal salt is 0.5%-12.0% of the mass of the p-methoxybenzyl chloride, preferably 1.0-5.0%.

[0018] Furthermore, the oxidation regulator refers to a specific type of bidentate organic ligand containing oxygen, nitrogen, and sulfur atoms, mainly divided into two categories: dicarboxylic acid ligands and thiourea ligands. These two types of ligands can be used alone or in combination. The dicarboxylic acid ligands are dicarboxylic acids with 15 or fewer carbon atoms, and their structural formula is as follows: Wherein, A is an alkylene group with 1 to 13 carbon atoms, including one or two of malonic acid, methylmalonic acid, dimethylmalonic acid, ethylmalonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, octanoic acid, azelaic acid, sebacic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, and tetradecanoic acid; the second type is a thiourea ligand with the structural formula […]. R1, R2, R3, and R4 are independently selected from H or C1-C4 alkyl groups, and R1, R2, R3, and R4 are not all H. Preferably, the N-position is replaced by 1-4 alkyl groups, and the alkyl groups are further C1-C4 alkyl groups, including one or two of tetramethylthiourea, N,N'-dimethylthiourea, methylthiourea, ethylthiourea, N,N'-diethylthiourea, and tetraethylthiourea. Methylmalonic acid, succinic acid, and tetramethylthiourea are preferably used alone or in combination.

[0019] The amount of the oxidation regulator added is 0.2%-10.0% of the mass of the p-methoxybenzyl chloride, preferably 1.0%-3.0%.

[0020] Furthermore, the water added is 40%-400% of the mass of p-methoxybenzyl chloride, preferably 80%-120%.

[0021] Furthermore, the solvent used in the solution of p-methoxybenzyl chloride is selected from benzene, toluene, chlorobenzene, o-dichlorobenzene, p-dichlorobenzene, m-dichlorobenzene, m-xylene, p-xylene, o-xylene, dichloromethane, chloroform, 1,2-dichloroethane, 1,1-dichloroethane, 1,2-dimethoxyethane, tetrahydrofuran, acetonitrile, 1,4-dioxane, isopropyl ether, methyl tert-butyl ether, fluorobenzene, cyclohexane, n-hexane, n-hexanol, etc., preferably chloroform, 1,2-dichloroethane, and toluene;

[0022] The mass ratio of solvent to benzyl chloride in the solution of p-methoxybenzyl chloride is 20:1-0.5:1, preferably 5:1-3:1.

[0023] Furthermore, the oxidation reaction temperature is 50℃-110℃, preferably 70℃-80℃.

[0024] Furthermore, the mixed atmosphere of the inert gas and oxygen is obtained in the following manner:

[0025] First, adjust the pressure of the inert gas to 1.0MPa-5.0MPa, preferably 2.0MPa-3.0MPa, and then introduce oxygen with a purity of 99.9% or higher, controlling the oxygen content of the system to 2%-6% (v / v), preferably 3%-5%.

[0026] Furthermore, after the reaction is complete, the post-processing procedure is as follows:

[0027] The temperature is lowered to 20℃-35℃, and then the reactants are discharged from the reactor. The reactants are then washed with water, extracted, desolventized, deweighed, and distilled to obtain the anisaldehyde. Furthermore, the distillation is vacuum distillation, with a pressure of 140-150 Pa and a distillation temperature of 123-125℃.

[0028] The specific process flow of this invention is as follows:

[0029] 1) A certain amount of p-methoxybenzyl chloride is dissolved in a specific amount of organic solvent and then added to a high-pressure reactor;

[0030] 2) Add a specific amount of TEMPO catalytic system to the reactor. The catalytic system includes: a first catalyst, a second catalyst, an oxidation regulator, and water. The order in which the four are added is not affected.

[0031] 3) Then, the reaction system is replaced with a nitrogen atmosphere, heated to a specific temperature, and the total pressure of the reaction system is adjusted to a certain level. Then, oxygen is introduced into the reaction system to control the oxygen content of the reaction system and keep it within a certain range.

[0032] 4) By monitoring the reaction progress in the gas phase, when the content of p-methoxybenzyl chloride in the system decreases to below 0.5% of the original value, the reaction endpoint can be considered reached. After that, the temperature is lowered to a certain level, and the reactants are discharged from the reactor.

[0033] The term "lowering to a certain temperature" refers to cooling the temperature to between 20℃ and 35℃, preferably between 25℃ and 30℃.

[0034] 5) The reactants are washed with water, extracted, dissolved, dehydrated, and distilled to obtain a qualified fragrance product—anesinaldehyde. The reaction formula is as follows:

[0035]

[0036] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0037] (1) The present invention uses a special catalytic system to carry out the reaction, and the yield of methoxybenzyl chloride to anisaldehyde is much higher than the level reported in the literature, with the highest yield reaching 92%.

[0038] (2) The reaction system of the present invention is in a non-reflux state and the oxidation environment is in an oxygen-deficient state, resulting in a high reaction safety factor. Detailed Implementation

[0039] The preferred embodiments of the present invention are described below. It should be understood that the preferred embodiments described herein are for illustration and explanation only and are not intended to limit the present invention.

[0040] The calculation method in this embodiment of the invention is as follows:

[0041] Reaction yield = [(mass of anisaldehyde produced / 136.15) / (mass of p-methoxybenzyl chloride consumed / 156.61)] * 100%

[0042] Example 1

[0043] 120.10 g of p-methoxybenzyl chloride was dissolved in 501.30 g of toluene, and then added to a high-pressure reactor. 1.81 g of 4-OMe TEMPO, 3.64 g of ferric nitrate, 1.50 g of tetramethylthiourea, and 13.11 g of water were added to the reactor. The reaction system was then purged with nitrogen, and the temperature was raised to 80°C. The total pressure of the reaction system was adjusted to 2.0 MPa using nitrogen, and oxygen was introduced into the reaction system, controlling the oxygen content in the gas phase space to approximately 4%. The reaction progress was monitored in the gas phase. After 12 hours of reaction, the p-methoxybenzyl chloride content in the system decreased to the set range. The temperature was then lowered to 25°C, and the reactants were discharged from the high-pressure reactor. The reactants were washed with water, extracted, desolventized, and deweighed to obtain crude anisaldehyde. The crude product was distilled, and the fraction collected at a pressure of 140-145 Pa and a temperature of 123-124 °C was used to obtain 91.23 g of anisaldehyde with a purity of 99.41%, with a yield of 86.86%.

[0044] NMR data of anisaldehyde:

[0045] 1 H-NMR (400MHz, CDCl3): δ9.78(s,1H),7.72-7.74(d,2H),6.89-6.90(d,2H),3.96(s,3H).

[0046] 13 C NMR (100MHz, CDCl3): δ190.8,164.6,132.5,129.9,114.7,55.5.

[0047] Example 2

[0048] 124.68 g of p-methoxybenzyl chloride was dissolved in 501.30 g of chloroform and then added to a high-pressure reactor. 1.75 g of 4-OMe TEMPO, 3.59 g of ferric nitrate, 1.64 g of tetramethylthiourea, and 12.95 g of water were added to the reactor. The reaction system was then purged with nitrogen, and the temperature was raised to 80°C. The total pressure of the reaction system was adjusted to 2.0 MPa with nitrogen, and oxygen was introduced into the reaction system, controlling the oxygen content in the gas phase space to approximately 4%. The reaction progress was monitored in the gas phase. After 8 hours of reaction, the p-methoxybenzyl chloride content in the system decreased to the set range. The temperature was then lowered to 25°C, and the reactants were discharged from the high-pressure reactor. The reactants were washed with water, extracted, desolventized, and deweighed to obtain crude anisaldehyde. The crude product was distilled, and the fraction collected at a pressure of 140-145 Pa and a temperature of 123-124 °C was used to obtain 98.15 g of anisaldehyde with a purity of 99.01%, with a yield of 89.65%.

[0049] Example 3

[0050] 122.62 g of p-methoxybenzyl chloride was dissolved in 505.33 g of 1,2-dichloroethane and then added to a high-pressure reactor. 1.54 g of 4-OMe TEMPO, 4.21 g of ferric nitrate, 3.04 g of tetramethylthiourea, and 12.62 g of water were added to the reactor. The reaction system was then purged with nitrogen, and the temperature was raised to 80°C. The total pressure of the reaction system was adjusted to 2.0 MPa using nitrogen, and oxygen was introduced into the reaction system, maintaining an oxygen content of approximately 4% in the gas phase. The reaction progress was monitored in the gas phase. After 7 hours of reaction, the p-methoxybenzyl chloride content in the system decreased to the set range. The temperature was then lowered to 25°C, and the reactants were discharged from the high-pressure reactor. The reactants were washed with water, extracted, dissolved, and weighed to obtain crude anisaldehyde. The crude product was distilled, and the fraction collected at a pressure of 150-155 Pa and a temperature of 124-125 °C was used to obtain 95.41 g of anisaldehyde with a purity of 99.12%, with a yield of 88.71%.

[0051] Example 4

[0052] 120.99 g of p-methoxybenzyl chloride was dissolved in 500.35 g of 1,2-dichloroethane and then added to a high-pressure reactor. 2.14 g of TEMPO, 4.71 g of ferric sulfate, 3.41 g of methylmalonic acid, and 12.88 g of water were added to the reactor. The reaction system was then purged with nitrogen, heated to 80 °C, and the total pressure was adjusted to 2.0 MPa with nitrogen. Oxygen was then introduced into the reaction system, maintaining an oxygen content of approximately 4% in the gas phase. The reaction progress was monitored in the gas phase. After 14 hours of reaction, the p-methoxybenzyl chloride content in the system decreased to the set range. The temperature was then lowered to 25 °C, and the reactants were discharged from the high-pressure reactor. The reactants were washed with water, extracted, desolventized, and deweighed to obtain crude anisaldehyde. The crude product was distilled, and the fraction collected at a pressure of 140-145 Pa and a temperature of 123-124 °C was used to obtain 89.01 g of anisaldehyde with a purity of 99.48%, with a yield of 84.18%.

[0053] Example 5

[0054] 115.71 g of p-methoxybenzyl chloride was dissolved in 381.12 g of chloroform and then added to a high-pressure reactor. 1.98 g of ABNO, 2.37 g of copper sulfate, 1.99 g of succinic acid, and 16.19 g of water were added to the reactor. The reaction system was then purged with nitrogen, heated to 75°C, and the total pressure was adjusted to 2.0 MPa with nitrogen. Oxygen was then introduced into the reaction system, controlling the oxygen content in the gas phase to 3-5%. The reaction progress was monitored in the gas phase. After 10 hours of reaction, the p-methoxybenzyl chloride content in the system decreased to the set range. The temperature was then lowered to 25°C, and the reactants were discharged from the high-pressure reactor. The reactants were washed with water, extracted, desolventized, and deweighed to obtain crude anisaldehyde. The crude product was distilled, and the fraction collected at a pressure of 142-147 Pa and a temperature of 123-124 °C was used to obtain 86.17 g of anisaldehyde with a purity of 99.51%, with a yield of 85.24%.

[0055] Example 6

[0056] 121.54 g of p-methoxybenzyl chloride was dissolved in 482.15 g of toluene, and then added to a high-pressure reactor. 1.75 g of ABNO, 2.98 g of cerium nitrate, 2.15 g of succinic acid, and 14.58 g of water were added to the reactor. The reaction system was then purged with nitrogen, heated to 80°C, and the total pressure was adjusted to 2.0 MPa with nitrogen. Oxygen was then introduced into the reaction system, controlling the oxygen content in the gas phase to approximately 4%. The reaction progress was monitored in the gas phase. After 13 hours of reaction, the p-methoxybenzyl chloride content in the system decreased to the set range. The temperature was then lowered to 25°C, and the reactants were discharged from the high-pressure reactor. The reactants were washed with water, extracted, desolventized, and deweighed to obtain crude anisaldehyde. The crude product was distilled, and the fraction collected at a pressure of 142-147 Pa and a temperature of 123-124 °C was used to obtain 79.12 g of anisaldehyde with a purity of 99.59%, with a yield of 74.57%.

[0057] Example 7

[0058] 124.21 g of p-methoxybenzyl chloride was dissolved in 502.41 g of chloroform, and then added to a high-pressure reactor. 1.51 g of 4-OMe TEMPO, 4.21 g of copper nitrate, 1.62 g of methylmalonic acid, 1.59 g of tetramethylthiourea, and 12.11 g of water were added to the reactor. The reaction system was then purged with nitrogen, heated to 80°C, and the total pressure was adjusted to 2.0 MPa with nitrogen. Oxygen was then introduced into the reaction system, controlling the oxygen content in the gas phase to approximately 4%. The reaction progress was monitored in the gas phase. After 7 hours of reaction, the p-methoxybenzyl chloride content in the system decreased to the set range. The temperature was then lowered to 25°C, and the reactants were discharged from the high-pressure reactor. The reactants were washed with water, extracted, desolventized, and deweighed to obtain crude anisaldehyde. The crude product was distilled, and the fraction collected at a pressure of 140-147 Pa and a temperature of 123-124 °C was used to obtain 99.02 g of anisaldehyde with a purity of 99.38%, with a yield of 91.13%.

[0059] Example 8

[0060] 121.95g of p-methoxybenzyl chloride was dissolved in 490.25g of chloroform, and then added to a high-pressure reactor. 1.68g of 4-OMe TEMPO, 5.62g of copper nitrate, 1.08g of succinic acid, 1.84g of tetramethylthiourea, and 13.24g of water were added to the reactor. The reaction system was then purged with nitrogen, heated to 80℃, and the total pressure was adjusted to 2.0MPa with nitrogen. Oxygen was then introduced into the reaction system, controlling the oxygen content in the gas phase space to approximately 4%. The reaction progress was monitored in the gas phase. After 8 hours of reaction, the p-methoxybenzyl chloride content in the system decreased to the set range. The temperature was then lowered to 25℃, and the reactants were discharged from the high-pressure reactor. The reactants were washed with water, extracted, desolventized, and deweighed to obtain crude anisaldehyde. The crude product was distilled, and the fraction collected at a pressure of 148-150 Pa and a temperature of 124-125 °C was used to obtain 90.29 g of anisaldehyde with a purity of 99.47%, with a yield of 84.71%.

[0061] Example 9

[0062] 119.51 g of p-methoxybenzyl chloride was dissolved in 475.49 g of chloroform, and then added to a high-pressure reactor. 1.79 g of 4-OMe TEMPO, 5.842 g of ferric nitrate, 1.10 g of succinic acid, 1.64 g of tetramethylthiourea, and 13.11 g of water were added to the reactor. The reaction system was then purged with nitrogen, heated to 80°C, and the total pressure was adjusted to 2.0 MPa with nitrogen. Oxygen was then introduced into the reaction system, maintaining an oxygen content of approximately 4% in the gas phase. The reaction progress was monitored in the gas phase. After 12 hours of reaction, the p-methoxybenzyl chloride content in the system decreased to the set range. The temperature was then lowered to 25°C, and the reactants were discharged from the high-pressure reactor. The reactants were washed with water, extracted, desolventized, and deweighed to obtain crude anisaldehyde. The crude product was distilled, and the fraction collected at a pressure of 140-146 Pa and a temperature of 123-124 °C was used to obtain 89.66 g of anisaldehyde with a purity of 99.42%, with a yield of 85.80%.

[0063] Example 10

[0064] 125.49 g of p-methoxybenzyl chloride was dissolved in 490.21 g of chloroform, and then added to a high-pressure reactor. 1.54 g of 4-OMe TEMPO, 4.34 g of ferric nitrate, 1.65 g of methylmalonic acid, 1.57 g of tetramethylthiourea, and 12.34 g of water were added to the reactor. The reaction system was then purged with nitrogen, heated to 80°C, and the total pressure was adjusted to 2.0 MPa with nitrogen. Oxygen was then introduced into the reaction system, controlling the oxygen content in the gas phase to approximately 4%. The reaction progress was monitored in the gas phase. After 9 hours of reaction, the p-methoxybenzyl chloride content in the system decreased to the set range. The temperature was then lowered to 25°C, and the reactants were discharged from the high-pressure reactor. The reactants were washed with water, extracted, desolventized, and deweighed to obtain crude anisaldehyde. The crude product was distilled, and the fraction collected at a pressure of 145-148 Pa and a temperature of 123-124 °C was used to obtain 98.54 g of anisaldehyde with a purity of 99.39%, with a yield of 89.77%.

[0065] Example 11

[0066] 123.95g of p-methoxybenzyl chloride was dissolved in 495.24g of chloroform, and then added to a high-pressure reactor. 1.61g of 4-OMe TEMPO, 4.45g of cerium nitrate, 1.73g of methylmalonic acid, 1.49g of tetramethylthiourea, and 11.99g of water were added to the reactor. The reaction system was then purged with nitrogen, heated to 80°C, and the total pressure was adjusted to 2.0MPa with nitrogen. Oxygen was then introduced into the reaction system, controlling the oxygen content in the gas phase to approximately 4%. The reaction progress was monitored in the gas phase. After 8 hours of reaction, the p-methoxybenzyl chloride content in the system decreased to the set range. The temperature was then lowered to 25°C, and the reactants were discharged from the high-pressure reactor. The reactants were washed with water, extracted, desolventized, and deweighed to obtain crude anisaldehyde. The crude product was distilled, and the fraction collected at a pressure of 150-155 Pa and a temperature of 124-125 °C was used to obtain 95.89 g of anisaldehyde with a purity of 99.19%, with a yield of 88.27%.

[0067] Example 12

[0068] 121.46 g of p-methoxybenzyl chloride was dissolved in 399.11 g of chloroform, and then added to a high-pressure reactor. 1.68 g of 4-OMe TEMPO, 4.59 g of copper nitrate, 1.81 g of methylmalonic acid, 1.39 g of tetramethylthiourea, and 12.58 g of water were added to the reactor. The reaction system was then purged with nitrogen, heated to 80°C, and the total pressure was adjusted to 2.0 MPa with nitrogen. Oxygen was then introduced into the reaction system, controlling the oxygen content in the gas phase to approximately 4%. The reaction progress was monitored in the gas phase. After 9 hours of reaction, the p-methoxybenzyl chloride content in the system decreased to the set range. The temperature was then lowered to 25°C, and the reactants were discharged from the high-pressure reactor. The reactants were washed with water, extracted, dissolved, and weighed to obtain crude anisaldehyde. The crude product was distilled, and the fraction collected at a pressure of 140-145 Pa and a temperature of 123-124 °C was used to obtain 93.49 g of anisaldehyde with a purity of 99.28%, with a yield of 87.90%.

[0069] Example 13

[0070] 119.22 g of p-methoxybenzyl chloride was dissolved in 504.82 g of toluene, and then added to a high-pressure reactor. 1.59 g of 4-OMe TEMPO, 4.71 g of copper nitrate, 1.77 g of methylmalonic acid, 1.52 g of tetramethylthiourea, and 13.68 g of water were added to the reactor. The reaction system was then purged with nitrogen, heated to 80 °C, and the total pressure was adjusted to 2.0 MPa with nitrogen. Oxygen was then introduced into the reaction system, controlling the oxygen content in the gas phase to approximately 4%. The reaction progress was monitored in the gas phase. After 10 hours of reaction, the p-methoxybenzyl chloride content in the system decreased to the set range. The temperature was then lowered to 25 °C, and the reactants were discharged from the high-pressure reactor. The reactants were washed with water, extracted, desolventized, and deweighed to obtain crude anisaldehyde. The crude product was distilled, and the fraction collected at a pressure of 142-148 Pa and a temperature of 123-124 °C was used to obtain 89.15 g of anisaldehyde with a purity of 99.50%, with a yield of 85.58%.

[0071] Example 14

[0072] 148.22 g of p-methoxybenzyl chloride was dissolved in 630.25 g of 1,2-dichloroethane, and then added to a high-pressure reactor. 2.01 g of 4-OMe TEMPO, 6.87 g of copper nitrate, 2.84 g of methylmalonic acid, 2.41 g of tetramethylthiourea, and 20.19 g of water were added to the reactor. The reaction system was then purged with nitrogen, heated to 80°C, and the total pressure was adjusted to 2.0 MPa with nitrogen. Oxygen was then introduced into the reaction system, maintaining an oxygen content of approximately 5% in the gas phase. The reaction progress was monitored in the gas phase. After 12 hours of reaction, the p-methoxybenzyl chloride content in the system decreased to the set range. The temperature was then lowered to 25°C, and the reactants were discharged from the high-pressure reactor. The reactants were washed with water, extracted, desolventized, and deweighed to obtain crude anisaldehyde. The crude product was distilled, and the fraction collected at a pressure of 144-147 Pa and a temperature of 123-124 °C was used to obtain 117.24 g of anisaldehyde with a purity of 99.52%, with a yield of 90.55%.

[0073] Example 15

[0074] 145.61 g of p-methoxybenzyl chloride was dissolved in 618.92 g of 1,2-dichloroethane, and then added to a high-pressure reactor. 2.41 g of 4-OH TEMPO, 7.05 g of copper nitrate, 3.11 g of methylmalonic acid, 2.39 g of tetramethylthiourea, and 21.85 g of water were added to the reactor. The reaction system was then purged with nitrogen, heated to 80°C, and the total pressure was adjusted to 2.0 MPa with nitrogen. Oxygen was then introduced into the reaction system, maintaining an oxygen content of approximately 3% in the gas phase. The reaction progress was monitored in the gas phase. After 11 hours of reaction, the p-methoxybenzyl chloride content in the system decreased to the set range. The temperature was then lowered to 25°C, and the reactants were discharged from the high-pressure reactor. The reactants were washed with water, extracted, desolventized, and deweighed to obtain crude anisaldehyde. The crude product was distilled, and the fraction collected at a pressure of 140-143 Pa and a temperature of 123-124 °C was used to obtain 113.98 g of anisaldehyde with a purity of 99.58%, with a yield of 89.66%.

[0075] Example 16: Effects of other oxidation regulators

[0076] This embodiment uses Example 7 as a baseline to examine the reaction effect of a single type of oxidation regulator. The molar amount of oxidation regulator added is the sum of the molar amounts of the two oxidation regulators in Example 7. Apart from this, all other material types and operations remain consistent, and the molar amounts of all materials added are within 0.5% of those in Example 7. Specific experimental data and results are shown in the table below:

[0077]

[0078]

[0079] Comparative Example 1: No Oxidation Regulator

[0080] 119.02 g of p-methoxybenzyl chloride was dissolved in 502.33 g of chloroform and then added to a high-pressure reactor. 1.57 g of 4-OMe TEMPO, 4.40 g of copper nitrate, and 12.57 g of water were added to the reactor. The reaction system was then purged with nitrogen, heated to 80°C, and the total pressure was adjusted to 2.0 MPa with nitrogen. Oxygen was then introduced into the reaction system, maintaining an oxygen content of approximately 4% in the gas phase. The reaction progress was monitored in the gas phase. After 8 hours of reaction, the p-methoxybenzyl chloride content in the system decreased to the set range. The temperature was then lowered to 25°C, and the reactants were discharged from the high-pressure reactor. The reactants were washed with water, extracted, desolventized, and deweighed to obtain crude anisaldehyde. The crude product was distilled, and the fraction collected at a pressure of 140-145 Pa and a temperature of 123-124 °C yielded 39.58 g of anisaldehyde with a purity of 98.12%, with a yield of 37.53%.

[0081] Finally, it should be noted that the above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing anisaldehyde from p-methoxybenzyl chloride, characterized in that, Includes the following steps: A solution of p-methoxybenzyl chloride was oxidized in a mixed atmosphere of inert gas and oxygen under the co-catalysis of N-oxygen free radical compound, metal salt, oxidation regulator and water. After the reaction was completed, anisaldehyde was obtained by post-treatment. The metal salt is a water-soluble salt of copper, iron, or cerium; the oxidation regulator is a bidentate organic ligand containing oxygen, nitrogen, and sulfur atoms. The N-oxygen free radical compound is one or more of the following: 2,2,6,6-tetramethylpiperidine oxide, 4-methoxy-2,2,6,6-tetramethylpiperidine oxide, 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide, 4-acetoxy-2,2,6,6-tetramethylpiperidine oxide, 4-acetamino-2,2,6,6-tetramethylpiperidine oxide, N-hydroxyphthalimide, 9-azabicyclo[3.3.1]nonane-N-oxy radical, 4-amino-TEMPO, 2-azaadamantane-N-oxy, 1-methyl-azaadamantane-N-oxy, and 4-benzoyloxy-TEMPO; The water-soluble salts of copper, iron, and cerium are one or more of the following: copper chloride, copper sulfate, copper acetate, copper nitrate, copper phosphate, copper acetylacetone, ferric nitrate, ferric chloride, ferric sulfate, ferric phosphate, ferric acetylacetone, ferric acetate, cerium nitrate, cerium ammonium nitrate, cerium sulfate, cerium chloride, cerium phosphate, cerium acetate, cerium isopropoxide, and cerium octoate. The bidentate organic ligand containing oxygen, nitrogen, and sulfur atoms is selected from one or more of dicarboxylic acid ligands or thiourea ligands; The structural formula of the dicarboxylic acid ligand is as follows: Where A is an alkylene group with 1 to 13 carbons; The structural formula of the thiourea ligand is as follows: R1, R2, R3 and R4 are independently selected from H or C1~C4 alkyl groups, and R1, R2, R3 and R4 are not all H at the same time.

2. The method for preparing anisaldehyde from p-methoxybenzyl chloride according to claim 1, characterized in that, The N-oxygen free radical compound is one or more of 2,2,6,6-tetramethylpiperidine oxide, 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide, 4-methoxy-2,2,6,6-tetramethylpiperidine oxide, and 9-azabicyclo[3.3.1]nonane-N-oxy radical; The amount of the N-oxygen free radical compound added is 0.3%-6% of the mass of the p-methoxybenzyl chloride.

3. The method for preparing anisaldehyde from p-methoxybenzyl chloride according to claim 2, characterized in that, The amount of the N-oxygen free radical compound added is 0.5%-2.0% of the mass of the p-methoxybenzyl chloride.

4. The method for preparing anisaldehyde from p-methoxybenzyl chloride according to claim 1, characterized in that, The metal salt is one or more of copper sulfate, ferric sulfate, ferric nitrate, and cerium nitrate; The mass of the metal salt is 0.5%-12.0% of the mass of the p-methoxybenzyl chloride.

5. The method for preparing anisaldehyde from p-methoxybenzyl chloride according to claim 4, characterized in that, The mass of the metal salt is 1.0-5.0% of the mass of the p-methoxybenzyl chloride.

6. The method for preparing anisaldehyde from p-methoxybenzyl chloride according to claim 1, characterized in that, The dicarboxylic acid ligands are one or two of the following: malonic acid, methylmalonic acid, dimethylmalonic acid, ethylmalonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, octanoic acid, azelaic acid, sebacic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, and tetradecanoic acid; the thiourea ligands are one or more of the following: tetramethylthiourea, N,N'-dimethylthiourea, methylthiourea, ethylthiourea, N,N'-diethylthiourea, and tetraethylthiourea. The amount of the oxidation regulator added is 0.2%-10.0% of the mass of the p-methoxybenzyl chloride.

7. The method for preparing anisaldehyde from p-methoxybenzyl chloride according to claim 6, characterized in that, The dicarboxylic acid ligand is one or more of methylmalonic acid, succinic acid, and tetramethylthiourea; The amount of the oxidation regulator added is 1.0%-3.0% of the mass of the p-methoxybenzyl chloride.

8. The method for preparing anisaldehyde from p-methoxybenzyl chloride according to claim 1, characterized in that, The mass of water added is 40%-400% of the mass of p-methoxybenzyl chloride.

9. The method for preparing anisaldehyde from p-methoxybenzyl chloride according to claim 1, characterized in that, The solvent used in the solution of p-methoxybenzyl chloride is selected from one or more of the following: benzene, toluene, chlorobenzene, o-dichlorobenzene, p-dichlorobenzene, m-dichlorobenzene, m-xylene, p-xylene, o-xylene, dichloromethane, trichloromethane, 1,2-dichloroethane, 1,1-dichloroethane, 1,2-dimethoxyethane, tetrahydrofuran, acetonitrile, 1,4-dioxane, isopropyl ether, methyl tert-butyl ether, fluorobenzene, cyclohexane, n-hexane, and n-hexanol. The mass ratio of solvent to benzyl chloride in the solution of p-methoxybenzyl chloride is 20:1 to 0.5:

1.

10. The method for preparing anisaldehyde from p-methoxybenzyl chloride according to claim 9, characterized in that, The solvent used in the solution of p-methoxybenzyl chloride is selected from chloroform, 1,2-dichloroethane or toluene; The mass ratio of solvent to benzyl chloride in the solution of p-methoxybenzyl chloride is 5:1 to 3:

1.

11. The method for preparing anisaldehyde from p-methoxybenzyl chloride according to claim 1, characterized in that, The oxidation reaction occurs at temperatures ranging from 50℃ to 110℃.

12. The method for preparing anisaldehyde from p-methoxybenzyl chloride according to claim 11, characterized in that, The oxidation reaction takes place at a temperature of 70℃-80℃.

13. The method for preparing anisaldehyde from p-methoxybenzyl chloride according to claim 1, characterized in that, The mixed atmosphere of inert gas and oxygen is obtained in the following manner: First, adjust the pressure of the inert gas to 1.0MPa-5.0MPa, then introduce oxygen with a purity of 99.9% or higher, and control the oxygen content of the system to 2%-6%.

14. The method for preparing anisaldehyde from p-methoxybenzyl chloride according to claim 1, characterized in that, After the reaction is complete, the post-processing procedure is as follows: The temperature is lowered to 20℃-35℃, and then the reactants are discharged from the reactor. After washing with water, extraction, solvent removal, weight removal and distillation, the anisaldehyde is obtained.

Images