Process for the preparation of benzaldehyde and derivatives thereof

Abstract

The present application relates to the field of organic chemical synthesis, and discloses a preparation method of benzaldehyde and derivatives thereof.A first solution containing a compound A with a structure of formula (I) and a first solvent is mixed with a second solution containing an oxidizing agent, a halogenating agent and a second solvent, and then the mixture is reacted; in formula (I), R1 is selected from an electron-withdrawing group, a phenyl group, an alkoxy group, an alkyl group, a hydroxyl group or a halogenated alkyl group; n is an integer of 0-5; R2 is selected from hydrogen, a phenyl group, an alkyl group or an alkoxy group; and R3 is halogen.The halogenating agent has a structure of formula (IV), wherein R4 is a C8-C20 alkyl group or a benzyl group; R5 is a C1-C5 alkyl group; and X is halogen.The method of the present application can obtain benzaldehyde and derivatives thereof with high yield.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, specifically to a method for preparing benzaldehyde and its derivatives. Background Technology

[0002] Benzaldehyde is an important organic intermediate that plays a vital role in the pharmaceutical, pesticide, new materials, and food industries. Currently, its industrial preparation methods mainly include organic electrosynthesis, toluene oxidation, toluene chlorination and hydrolysis, benzyl alcohol oxidation, and ester or carboxylic acid reduction. Organic electrosynthesis methods primarily include direct electrolytic oxidation, indirect electrolytic oxidation, reduction, and sacrificial anode methods. These methods require sophisticated equipment and are not yet mature enough for large-scale production.

[0003] Toluene oxidation mainly includes gas-phase oxidation, liquid-phase oxidation, and phase-transfer catalytic oxidation. The toluene oxidation process involves numerous side reactions, poor selectivity, low yield, high reaction cost, and significant environmental pollution. In my country, benzaldehyde production primarily relies on chlorination hydrolysis. Controlling the chlorination depth and hydrolysis conditions is crucial in this method. Acidic or alkaline hydrolysis of benzyl dichloride is performed in traditional batch reactors, which presents problems such as high wastewater volume, demanding equipment requirements, operational instability, and safety concerns.

[0004] In recent years, there have been some reports on the hydrolysis of benzyl dichloride to produce benzaldehyde, but these methods are characterized by high equipment requirements and complex processes. Benzyl alcohol can be oxidized to benzaldehyde under catalytic conditions. According to literature reports, the main oxidants are halogen-containing oxidants and some transition metal oxidants. Esters or carboxylic acids can be reduced to the corresponding aldehydes under reducing agent conditions. The literature frequently reports on the reduction of benzoic acid alcohol esters to benzaldehyde under reducing agent conditions. This method is simple, has a high product yield and good quality, and causes little environmental pollution. However, reducing agents are not readily available and are expensive, resulting in high production costs and making industrial-scale production difficult.

[0005] In my country, the main method for producing p-fluorobenzaldehyde is chlorination hydrolysis. This method uses readily available raw materials and has a simple process, but the utilization rate of the raw materials is low. These methods are limited in their development and application due to environmental pollution, high cost, operational difficulty, and low reaction yield. Summary of the Invention

[0006] The purpose of this invention is to overcome the problems of low raw material utilization, high operational difficulty, and low reaction yield in the preparation of benzaldehyde and its derivatives using existing technologies. This invention provides a method for preparing benzaldehyde and its derivatives. This method enables continuous operation and achieves high yields of the target products.

[0007] To achieve the above objectives, the present invention provides a method for preparing benzaldehyde and its derivatives, comprising a first solution containing compound A of formula (I) and a first solvent, and mixing and reacting it with a second solution containing an oxidant, a halogenated reagent, and a second solvent; Equation (Ⅰ), In formula (Ⅰ), R1 is selected from electron-withdrawing groups, phenyl, alkoxy, alkyl, hydroxy or haloalkyl; n is an integer from 0 to 5; R2 is selected from hydrogen, phenyl, alkyl or alkoxy; R3 is a halogen; The structure of the halogenated reagent is as shown in formula (IV). Formula (IV), In formula (IV), R4 is a C8-C20 alkyl or benzyl; R5 is a C1-C5 alkyl; and X is a halogen.

[0008] Through the above technical solution, the present invention has at least the following beneficial effects: This invention enables better miscibility of the reaction system under the action of specific halogenated reagents, promoting a stable and efficient reaction. It has advantages such as mild conditions, short reaction time, high raw material utilization, effective control of the reaction process, safety and stability, continuous operation and high production efficiency, and can also obtain high yields of benzaldehyde and its derivatives. Attached Figure Description

[0009] Figure 1 The reaction equation for the preparation of benzaldehyde and its derivatives in this invention is as follows; Figure 2 This is a flowchart of a method for preparing benzaldehyde and its derivatives in one embodiment of the present invention.

[0010] Explanation of reference numerals in the attached figures Detailed Implementation

[0011] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0012] This invention provides a method for preparing benzaldehyde and its derivatives, wherein a first solution containing compound A of formula (I) and a first solvent is mixed with a second solution containing an oxidant, a halogenated reagent, and a second solvent and reacted. Equation (Ⅰ), In formula (Ⅰ), R1 is selected from electron-withdrawing groups, phenyl, alkoxy, alkyl, hydroxy or haloalkyl; n is an integer from 0 to 5; R2 is selected from hydrogen, phenyl, alkyl or alkoxy; R3 is a halogen; The structure of the halogenated reagent is as shown in formula (IV). Formula (IV), In formula (IV), R4 is a C8-C20 alkyl or benzyl; R5 is a C1-C5 alkyl; and X is a halogen.

[0013] In this invention, the inventors discovered that the preparation method of this invention can prepare benzaldehyde-like substances, namely benzaldehyde and its derivatives. It is understood that when n is 0, there are no substituents on the benzene ring representing the structure of formula (Ⅰ); when n is 0 and R2 is hydrogen, compound A is benzyl halide, and the target product obtained is benzaldehyde. According to the preparation method of this invention, the specific group of R1, the number of R1 groups, and the specific group of R2 (i.e., the derivative of benzyl halide) can be selected as needed.

[0014] According to the present invention, it is understood that the reaction equations for the preparation of benzaldehyde and its derivatives in the present invention are as follows: Figure 1 As shown, those skilled in the art can select the specific groups of R1, R2, and R3 and the specific value of n according to the solution of the present invention based on the required product.

[0015] According to the present invention, in some embodiments, n is an integer from 0 to 3 (e.g., 0, 1, 2, or 3). Using the aforementioned embodiments, higher yields of benzaldehyde and its derivatives can be obtained.

[0016] According to the present invention, in some preferred embodiments, R1 is selected from electron-withdrawing groups, phenyl, C1-C5 alkoxy, C1-C8 alkyl, hydroxyl or C1-C5 haloalkyl.

[0017] According to the present invention, in some preferred embodiments, R1 is selected from electron-withdrawing groups, C1-C3 alkoxy groups, or C1-C3 alkyl groups. By employing the aforementioned embodiments, the influence of larger group values ​​on the yield of the target product can be avoided, resulting in higher yields of benzaldehyde and its derivatives. However, it is understood that the present invention does not limit the specific type of group of R1 as long as the objectives of the present invention are achieved.

[0018] According to the present invention, in some preferred embodiments, R1 is selected from halogens (e.g., fluorine, chlorine, bromine or iodine), nitro, cyano, carboxyl, aldehyde, C1-C3 alkoxy (e.g., methoxy, ethoxy or propoxy) or C1-C3 alkyl (e.g., methyl, ethyl or propyl).

[0019] According to some preferred embodiments of the present invention, R2 is selected from hydrogen, phenyl, C1-C8 alkyl or C1-C8 alkoxy.

[0020] According to the present invention, in some preferred embodiments, R2 is selected from hydrogen, phenyl, C1-C3 alkyl (e.g., methyl, ethyl, or propyl), or C1-C3 alkoxy (e.g., methoxy, ethoxy, or propoxy). Using the foregoing embodiments, not only can the desired benzaldehyde and its derivative products be obtained mildly and stably, but the utilization rate of raw materials and the yield of products are also higher. That is to understand, the present invention does not limit the specific type of group of R2 as long as the objectives of the present invention are achieved.

[0021] According to the present invention, in some preferred embodiments, R3 is selected from fluorine, chlorine, bromine, or iodine, preferably chlorine, bromine, or iodine, and more preferably bromine or iodine. In the aforementioned preferred embodiments, bromine or iodine is more readily removed, which accelerates the oxidation reaction rate, increases the mildness of the reaction, and also yields a higher yield of the target product.

[0022] According to the present invention, it is understood that R1 can be located at any one of the para, meta, or ortho positions of the benzene ring in the structure of formula (I), or at any two or three of the para, meta, or ortho positions of the benzene ring. The specific groups of R1 at each position can be the same or different, and can be selected according to specific needs. In some embodiments, when R1 is located at the para position of the benzene ring in the structure of formula (I), R1 is selected from halogen, nitro, cyano, carboxyl, aldehyde, C1-C3 alkoxy, or C1-C3 alkyl. Using the foregoing embodiments, a higher yield of the product can be obtained.

[0023] According to the present invention, in some embodiments, when R1 is located at the meta position of the benzene ring in the structure of formula (I), R1 is selected from halogen, nitro or cyano.

[0024] According to the present invention, in some embodiments, when R1 is located at the ortho position of the benzene ring in the structure of formula (I), R1 is selected from halogen, nitro or cyano.

[0025] According to the present invention, it is understood that, based on the technical solution of the present invention, those skilled in the art can select the appropriate number of R1s and their positions on the benzene ring, as well as the specific types of groups at each position, as needed, including but not limited to the above embodiments.

[0026] According to the present invention, the specific group of R4 is not particularly limited as long as the purpose of the present invention can be achieved. In some preferred embodiments, R4 is a C12-C18 alkyl or benzyl. By adopting the aforementioned embodiments, the yield of the target product benzaldehyde and its derivatives can be increased. The inventors speculate that the halogenated reagent of this structure is conducive to the reaction proceeding mildly and smoothly in the direction of the target product, increasing the internal forces of the system and increasing the yield of the target product.

[0027] According to the present invention, in some preferred embodiments, R4 is benzyl, and the halogenated reagent in the aforementioned embodiments is more conducive to the solubility of the reaction system, increasing the smooth progress of the hydrolysis and oxidation reactions of the system.

[0028] According to the present invention, in some embodiments, R5 is a C1-C2 alkyl group (e.g., methyl or ethyl). The aforementioned halogenated reagents can facilitate the transfer of the starting material in the solvent and increase the yield of the target product. According to the present invention, in some embodiments, X is selected from fluorine, chlorine, bromine, or iodine, preferably bromine or iodine. The inventors have found that by employing the aforementioned embodiments, the reaction time and temperature can be reduced, the reaction becomes milder, and the yield of the target product can be increased. The inventors speculate that the presence of halogens, especially bromine or iodine, can better increase the active sites of the system reaction, and in a microreactor, can increase the number of active ions, thus significantly accelerating the reaction rate.

[0029] According to the present invention, as long as the objective of the present invention can be achieved, the amount of material added to the reaction system can be adjusted as needed. In some embodiments, the molar ratio of compound A to the halogenated reagent is 1:(0.02-0.2), for example 1:0.02, 1:0.05, 1:0.1, 1:0.13, 1:0.15, or 1:0.2, preferably 1:(0.02-0.15), and more preferably 1:(0.02-0.1). Under the aforementioned molar ratios of compound A and the halogenated reagent, a high yield of the target product can be obtained.

[0030] According to the present invention, the concentration of compound A can be selected as needed. In some embodiments, the concentration of compound A in the first solution is 0.10-1.0 mol / L (e.g., 0.10 mol / L, 0.20 mol / L, 0.28 mol / L, 0.30 mol / L, 0.40 mol / L, 0.50 mol / L, 0.70 mol / L, or 1.0 mol / L), preferably 0.20-0.50 mol / L. Using the aforementioned embodiments, the utilization rate of raw materials can be increased and the yield of the target product can be improved.

[0031] According to the present invention, the concentration of the halogenating agent can be selected as needed. In some embodiments, the concentration of the halogenating agent in the second solution is 0.01-0.10 mol / L (e.g., 0.01 mol / L, 0.02 mol / L, 0.03 mol / L, 0.04 mol / L, 0.05 mol / L, 0.06 mol / L, 0.07 mol / L, 0.08 mol / L, or 0.10 mol / L), preferably 0.01-0.04 mol / L. By employing the aforementioned embodiments, the utilization rate of raw materials and the yield of the target product can be increased.

[0032] According to the present invention, the type of oxidant can be selected as needed to achieve the purpose of the invention. In some embodiments, the oxidant is selected from one or more of perchlorates (e.g., potassium perchlorate), permanganates (e.g., potassium permanganate), dichromates (e.g., sodium dichromate or potassium dichromate), hydrogen peroxide, sodium peroxide, and nitric acid, preferably hydrogen peroxide. Using hydrogen peroxide as the preferred oxidant not only has no environmental harm and good atom economy, which is beneficial for industrial production, but also increases the yield of the target product. The inventors speculate that hydrogen peroxide produces water in this reaction, which not only improves the solubility of the raw materials but also facilitates the synergistic effect between hydrogen peroxide and the halogenated reagent in the present invention to promote the oxidation reaction of the system, thereby increasing the utilization rate of the raw materials and the yield of the target product.

[0033] According to the present invention, the amount of oxidant is not particularly limited as long as the purpose of the invention can be achieved. In some embodiments, the molar ratio of compound A to oxidant is 1:(1-5), preferably 1:(2-3). In the prior art, in order to prevent over-oxidation of the oxidant, it is generally added slowly dropwise. This process is not easy to implement and control, and the yield of the raw materials is not high. In the present invention, the solution containing the oxidant is directly mixed with the solution containing the raw materials and reacted. Furthermore, under the aforementioned embodiment of oxidant dosage, the reaction can proceed gently while reducing the formation of other impurity products.

[0034] According to the present invention, as long as the purpose of the present invention can be achieved, the concentration of the oxidant in the second solution is 0.1-3 mol / L (preferably 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, 0.5 mol / L, 0.7 mol / L, 0.9 mol / L, 1.2 mol / L, 1.5 mol / L or 2 mol / L), preferably 0.5-2 mol / L.

[0035] According to the present invention, solvents that are favorable to the solubility of the reaction substrate can be selected as needed. In some embodiments, the first solvent and the second solvent each independently comprise 0-100% by volume of water, preferably 30-60% by volume of water. Using the aforementioned embodiments can increase the utilization rate of raw materials and the yield of the target product.

[0036] According to the present invention, in some preferred embodiments, the first solvent and the second solvent each independently comprise 30-60 vol% water, 40-70 vol% C1-C4 alcohol solvent and / or nitrile solvent; preferably, the first solvent and the second solvent each independently comprise 30-60 vol% water and 40-70 vol% C1-C4 alcohol solvent. Using the aforementioned embodiments, the halogenated reagent in the present invention, on the one hand, acts like a surfactant to promote the interaction and reaction of compound A, the oxidant, and the halogenated reagent in the solvent; on the other hand, it works synergistically with the oxidant to facilitate the deoxidation reaction of halogens on the raw material to generate aldehydes. Especially in the aforementioned reaction system containing water and C1-C4 alcohol solvents in the first and second solvents, it is more conducive to the solubility of the reaction substrate and can better promote the mild and stable progress of the reaction.

[0037] According to the present invention, in some embodiments, the C1-C4 alcohol solvent is selected from one or more of methanol, ethanol, propanol, isobutanol, and n-butanol, preferably methanol. Using the aforementioned embodiments can better promote the mild and stable progress of the reaction, increase the utilization rate of raw materials, and increase the yield of the target product.

[0038] According to the present invention, in some embodiments, the nitrile solvent is selected from one or more of acetonitrile, propionitrile, isopropionitrile, succinic anionyl nitrile, butyric anionyl nitrile, and adiponitrile, preferably acetonitrile. Using the foregoing embodiments can increase the utilization rate of raw materials and the yield of the target product.

[0039] According to some embodiments of the invention, the mixing and reaction are carried out in a microchannel reactor.

[0040] According to the present invention, the selection of the microchannel reactor is not limited as long as the purpose of the present invention can be achieved. Commonly used microchannel reactors in the art can be selected as needed. In some embodiments, the microchannel reactor includes a first feed pump for pumping in a first solution, a second feed pump for pumping in a second solution, a micromixer for mixing the first solution and the second solution, and a microreactor for reaction; wherein the first feed pump and the second feed pump are connected in parallel and connected in series with the micromixer through a connecting pipe; the micromixer and the microreactor are connected in series through a pipeline.

[0041] In this invention, the inventors discovered that in a microchannel reactor, using a first solution containing compound A of formula (Ⅰ) and a first solvent mixed with a second solution containing an oxidant, a halogenated reagent, and a second solvent can achieve mild reaction conditions, which are more conducive to industrial production. Furthermore, the utilization rate of raw materials is high, and high yields of benzaldehyde and its derivative products can be obtained. Furthermore, when R1 is an electron-withdrawing group, benzaldehyde derivatives exhibit higher yields. The inventors speculate that, on the one hand, the presence of electron-withdrawing groups reduces the electron cloud density on the aromatic ring, which is beneficial for the removal of X (halogen). On the other hand, this invention utilizes specific halogenated reagents and oxidants to react with compound A in solution within a microchannel reactor, resulting in a reaction system with good compatibility, allowing for better miscibility and facilitating the departure of X (halogen) and the nucleophilic reaction, thereby promoting better oxidation and increasing the yield of the target product. Moreover, when R1 is an electron-donating group such as phenyl, C1-C5 alkoxy, C1-C8 alkyl, hydroxyl, or halogenated C1-C5 alkyl, a higher yield of the product can also be achieved.

[0042] According to the present invention, the flow rates of the first solution and the second solution entering the microchannel reactor can be selected as needed, and their specific selection is not particularly limited. In some embodiments, the flow rates of the first solution and the second solution entering the microchannel reactor are each independently 0.05-0.30 mL / min (e.g., 0.05 mL / min, 0.10 mL / min, 0.15 mL / min, 0.20 mL / min, 0.25 mL / min, 0.30 mL / min).

[0043] In this invention, the inventors discovered that using a first solution containing compound A of formula (Ⅰ) and a first solvent, mixed and reacted with a second solution containing an oxidant, a halogenated reagent, and a second solvent in a microchannel reactor, not only offers advantages such as effective control of the reaction process, safety and stability, continuous operation, and high production efficiency, but also provides advantages such as mild conditions, short reaction time, high raw material utilization, and high yield of the target product. In some embodiments, the reaction temperature in the microchannel reactor is 0-50°C (e.g., 0°C, 10°C, 25°C, 30°C, 40°C, or 50°C), preferably 10-40°C.

[0044] According to the present invention, the residence time in the microchannel reactor can be selected as needed. In some embodiments, the residence time of the reaction in the microchannel reactor is 1-30 min (e.g., 1 min, 2 min, 3 min, 5 min, 7 min, 10 min, 12 min, 16 min, 20 min, 25 min, or 30 min). To illustrate the advantages of the present invention, a preferred embodiment of the present invention is described in the context of 5 min, but the present invention is not limited to this embodiment.

[0045] According to the present invention, in order to prevent the raw materials from corroding the micromixer microchannel reactor, polytetrafluoroethylene connecting pipes and pipelines can be selected as needed.

[0046] According to the present invention, the diameter of the connecting pipe is 0.1-5 mm and the length is 0.5-60 m. There are no specific limitations on its selection, and it will not be elaborated further in this invention.

[0047] According to the present invention, the diameter of the conduit between the micromixer and the microreactor is 0.5-5 mm, preferably 2-5 mm. There are no specific limitations on its selection, and it will not be elaborated upon further in this invention.

[0048] According to the present invention, in some embodiments, the micro mixer is of type T, type Y or inverted Y, preferably type Y.

[0049] According to the present invention, in some embodiments, the volume of the microreactor is 0.5-1.5 mL. In this invention, the volume of the microreactor is 1.00 mL as an example to illustrate the advantages of the present invention, but the present invention is not limited thereto.

[0050] According to the present invention, in order to obtain the target product, in some embodiments, a collection bottle is used to collect the reaction liquid that flows out after mixing and reaction in the microchannel reactor, which is diluted five times (by volume) with dichloromethane, washed with water, dried, filtered, separated by column chromatography, and distilled under reduced pressure to obtain the target product. The column chromatography was performed by eluting with a mixed solvent of ethyl acetate and petroleum ether (volume ratio of 1:10-1:30) to obtain the target product.

[0051] According to the present invention, in some embodiments, the preparation process of benzaldehyde and its derivatives is as follows: Figure 2As shown, compound A is dissolved in a first solvent to obtain a first solution, which is added to a first feed pump 1; the halogenated reagent and the oxidant are dissolved in a second solvent to obtain a second solution, which is added to a second feed pump 2. The first solution and the second solution are injected into a micro mixer 3 for mixing through the first feed pump 1 and the second feed pump 2, and then enter a microreactor 4 for reaction. After the reaction in the microreactor, the reaction liquid is collected in a collection bottle 5.

[0052] The present invention will be described in detail below through embodiments. In the following embodiments and comparative examples: (1) The reaction was carried out in the same microchannel reactor (where the mixer in the microchannel reactor is of type Y and the volume of the microreactor is 1.00 mL). (2) Purification of the reaction solution: Collect the reaction solution that flows out after mixing and reaction in the microchannel reactor, dilute it five times (by volume) with dichloromethane, wash it with water, dry it, filter it, and then perform column chromatography separation and vacuum distillation to obtain the target product. The column chromatography described herein is performed by eluting with a mobile phase of a mixed solvent of ethyl acetate / petroleum ether (volume ratio of 1:10-1:30) to obtain the target product; Table 1 shows the chemical structural formulas of the target products prepared in the examples and comparative examples; (3) After the reaction solution is tested by HPLC, the yield of the target product is calculated from the peak area ratio; Example 1-a Preparation of compound 3a like Figure 2 As shown, 1 mmol (126.59 mg) of benzyl chloride was dissolved in 2.5 mL of a methanol / water mixture (volume ratio 1:1) to obtain a first solution, which was added to the first feed pump 1. 5 mol% (11.51 mg) of benzyltrimethylammonium bromide and 2.5 mmol of hydrogen peroxide were dissolved in 2.5 mL of a methanol / water mixture (volume ratio 1:1) to obtain a second solution, which was added to the second feed pump 2. Both the first feed pump 1 and the second feed pump 2 injected the first and second solutions into a micromixer 3 at a flow rate of 0.2 mL / min, respectively. After mixing in the micromixer 3, the mixture entered a microreactor 4 for reaction, with a residence time of 5.0 min. The microreactor temperature was 25 °C. After the reaction in the microreactor, the reaction liquid was collected in a collection bottle 5. The product yield was 90% as calculated by HPLC. The target product (compound 3a) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3a are shown in Table 1. The results of obtaining 3a from the proton and carbon spectra are shown in Table 2.

[0053] Example 1-b Preparation of compound 3a like Figure 2 As shown, 1 mmol (126.59 mg) of benzyl chloride was dissolved in 2.5 mL of acetonitrile / water (volume ratio 1:1) to obtain a first solution, which was added to the first feed pump 1. 5 mol% (11.51 mg) of benzyltrimethylammonium bromide and 2.5 mmol of hydrogen peroxide were dissolved in 2.5 mL of acetonitrile / water (volume ratio 1:1) to obtain a second solution, which was added to the second feed pump 2. Both the first feed pump 1 and the second feed pump 2 injected the first and second solutions into the micromixer 3 at a flow rate of 0.2 mL / min, respectively. After mixing in the micromixer 3, the mixture entered the microreactor 4 for reaction, with a residence time of 5.0 min. The microreactor temperature was 25 °C. After the reaction in the microreactor, the reaction liquid was collected in a collection bottle 5. The product yield was 81% as calculated by HPLC. The target product (compound 3a) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3a are shown in Table 1. The results of obtaining 3a from the proton and carbon spectra are shown in Table 2.

[0054] Example 1-c Preparation of compound 3a like Figure 2 As shown, 1 mmol (126.59 mg) of benzyl chloride was dissolved in 2.5 mL of acetonitrile / water (volume ratio 1:1.5) to obtain a first solution, which was added to the first feed pump 1. 5 mol% (11.51 mg) of benzyltrimethylammonium bromide and 2.5 mmol of hydrogen peroxide were dissolved in 2.5 mL of methanol / water (volume ratio 1:1.5) to obtain a second solution, which was added to the second feed pump 2. Both the first feed pump 1 and the second feed pump 2 injected the first solution and the second solution into the micromixer 3 at a flow rate of 0.2 mL / min, respectively. After mixing in the micromixer 3, the mixture entered the microreactor 4 for reaction, with a reaction residence time of 5.0 min. The temperature of the microreactor was 25 °C. After the reaction in the microreactor, the reaction liquid was collected in a collection bottle 5.

[0055] The product yield was 83% as calculated by HPLC. The target product (compound 3a) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3a are shown in Table 1. The results of obtaining 3a from the proton and carbon spectra are shown in Table 2.

[0056] Example 1-d Preparation of compound 3a like Figure 2As shown, 1 mmol (126.59 mg) of benzyl chloride was dissolved in 2.5 mL of water to obtain a first solution, which was added to the first feed pump 1; 5 mol% (11.51 mg) of benzyltrimethylammonium bromide and 2.5 mmol of hydrogen peroxide were dissolved in 2.5 mL of water to obtain a second solution, which was added to the second feed pump 2; the first feed pump 1 and the second feed pump 2 respectively injected the first solution and the second solution into the micromixer 3 at a flow rate of 0.2 mL / min. After mixing in the micromixer 3, the mixture entered the microreactor 4 for reaction, with a reaction residence time of 5.0 min; the temperature of the microreactor was 25℃; after the reaction in the microreactor, the reaction liquid was collected in the collection bottle 5.

[0057] The product yield was 46% as calculated by HPLC. The target product (compound 3a) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3a are shown in Table 1. The results of obtaining 3a from the proton and carbon spectra are shown in Table 2.

[0058] Example 1-e The method according to Example 1-a differs in that: Replace 5 mol% (11.51 mg) of benzyltrimethylammonium bromide with 5 mol% (13.61 mg) of benzyltriethylammonium bromide.

[0059] The product yield was 85% as calculated by HPLC. The target product (compound 3a) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3a are shown in Table 1. The results of obtaining 3a from the proton and carbon spectra are shown in Table 2.

[0060] Example 1-f The method according to Example 1-a differs in that: Replace 5 mol% (11.51 mg) of benzyltrimethylammonium chloride with 5 mol% (9.28 mg) of benzyltrimethylammonium chloride.

[0061] The product yield was 70% as calculated by HPLC. After purification of the reaction solution, the target product (compound 3a) was obtained. The proton and carbon spectra of compound 3a are shown in Table 1; the results of obtaining 3a from the proton and carbon spectra are shown in Table 2.

[0062] Example 1-g The method according to Example 1-a differs in that: Replace 5 mol% (11.51 mg) of benzyltriethylammonium chloride with 5 mol% (11.39 mg) of benzyltrimethylammonium bromide.

[0063] The product yield was 71% as calculated by HPLC. The target product (compound 3a) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3a are shown in Table 1. The results of obtaining 3a from the proton and carbon spectra are shown in Table 2.

[0064] Example 1-h The method according to Example 1-a differs in that: Replace 5 mol% (11.51 mg) of benzyltrimethylammonium bromide with 5 mol% (15.42 mg) of dodecyltrimethylammonium bromide.

[0065] The product yield was calculated to be 59% using HPLC. The target product (compound 3a) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3a are shown in Table 1. The results of obtaining 3a from the proton and carbon spectra are shown in Table 2.

[0066] Example 1-i The method according to Example 1-a differs in that: Both the first feed pump 1 and the second feed pump 2 inject the first solution and the second solution into the micromixer 3 at a flow rate of 0.1 mL / min, respectively.

[0067] The product yield was calculated to be 69% by HPLC. The target product (compound 3a) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3a are shown in Table 1. The results of obtaining 3a from the proton and carbon spectra are shown in Table 2.

[0068] Example 1-j The method according to Example 1-a differs in that: The first feed pump 1 and the second feed pump 2 inject the first solution and the second solution into the micromixer 3 at a flow rate of 0.3 mL / min.

[0069] The product yield was 61% as calculated by HPLC. The target product (compound 3a) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3a are shown in Table 1. The results of obtaining 3a from the proton and carbon spectra are shown in Table 2.

[0070] Example 1-k The method according to Example 1-a differs in that: The temperature of the microreactor is 50℃.

[0071] The product yield was 68% as calculated by HPLC. The target product (compound 3a) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3a are shown in Table 1. The results of obtaining 3a from the proton and carbon spectra are shown in Table 2.

[0072] Example 1-1 The method according to Example 1-a differs in that: The temperature of the microreactor is 0℃.

[0073] The product yield was 51% as calculated by HPLC. The target product (compound 3a) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3a are shown in Table 1. The results of obtaining 3a from the proton and carbon spectra are shown in Table 2.

[0074] Example 1-m The method according to Example 1-a differs in that: The amount of hydrogen peroxide used was 2.0 mmol.

[0075] The product yield was 79% as calculated by HPLC. The target product (compound 3a) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3a are shown in Table 1. The results of obtaining 3a from the proton and carbon spectra are shown in Table 2.

[0076] Example 1-n The method according to Example 1-a differs in that: The amount of hydrogen peroxide added was 3.0 mmol.

[0077] The product yield was 85% as calculated by HPLC. The target product (compound 3a) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3a are shown in Table 1. The results of obtaining 3a from the proton and carbon spectra are shown in Table 2.

[0078] Example 1-o The method according to Example 1-a differs in that: Replace 2.5 mmol of hydrogen peroxide with 2.5 mmol of potassium permanganate; The product yield was calculated to be 52% using HPLC.

[0079] The target product (compound 3a) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3a are shown in Table 1. The results of obtaining 3a from the proton and carbon spectra are shown in Table 2.

[0080] Example 1-p The method according to Example 1-a differs in that: The amount of benzyltrimethylammonium bromide used was 10 mol% (23.02 mg).

[0081] The product yield was 83% as calculated by HPLC. The target product (compound 3a) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3a are shown in Table 1. The results of obtaining 3a from the proton and carbon spectra are shown in Table 2.

[0082] Example 1-q The method according to Example 1-a differs in that: The amount of benzyltrimethylammonium bromide added was 2 mol% (4.604 mg).

[0083] The product yield was calculated to be 57% using HPLC. The target product (compound 3a) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3a are shown in Table 1. The results of obtaining 3a from the proton and carbon spectra are shown in Table 2.

[0084] Example 1-r The method according to Example 1-a differs in that: Replace 1 mmol (126.59 mg) of benzyl chloride with 1 mmol (218.03 mg) of benzyl iodide.

[0085] The product yield was 85% as calculated by HPLC. The target product (compound 3a) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3a are shown in Table 1. The results of obtaining 3a from the proton and carbon spectra are shown in Table 2.

[0086] Example 2 Preparation of compound 3b The method according to Example 1-a differs in that: Replace 1 mmol (126.59 mg) of benzyl chloride with 1 mmol (161.029 mg) of p-chlorobenzyl chloride.

[0087] The product yield was 87% as calculated by HPLC. The target product (compound 3b) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3b are shown in Table 1. The results of obtaining 3b from the proton and carbon spectra are shown in Table 2.

[0088] Example 3 Preparation of compound 3c The method according to Example 1-a differs in that: Replace 1 mmol (126.59 mg) of benzyl chloride with 1 mmol (161.029 mg) of m-chlorobenzyl chloride.

[0089] The product yield was 83% as calculated by HPLC. After purification of the reaction solution, the target product (compound 3c) was obtained. The proton and carbon spectra of compound 3c are shown in Table 1. The results of obtaining 3c from the proton and carbon spectra are shown in Table 2.

[0090] Example 4 Preparation of compound 3d Replace 1 mmol (126.59 mg) of benzyl chloride with 1 mmol (161.029 mg) of o-chlorobenzyl chloride.

[0091] The product yield was 79% as calculated by HPLC. The target product (compound 3d) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3d are shown in Table 1. The results of 3d obtained by proton and carbon spectra are shown in Table 2.

[0092] Example 5 Preparation of compound 3e Replace 1 mmol (126.59 mg) of benzyl chloride with 1 mmol (205.48 mg) of p-bromobenzyl chloride.

[0093] The product yield was 85% as calculated by HPLC. After purification of the reaction solution, the target product (compound 3e) was obtained. The proton and carbon spectra of compound 3e are shown in Table 1. The results of obtaining 3e from the proton and carbon spectra are shown in Table 2.

[0094] Example 6 Preparation of compound 3f Replace 1 mmol (126.59 mg) of benzyl chloride with 1 mmol (144.57 mg) of parafluorobenzyl chloride.

[0095] The product yield was 89% as calculated by HPLC. The target product (compound 3f) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3f are shown in Table 1. The results of obtaining 3f from the proton and carbon spectra are shown in Table 2.

[0096] Example 7 Preparation of 3g of compound Replace 1 mmol (126.59 mg) of benzyl chloride with 1 mmol (171.58 mg) of p-nitrobenzyl chloride.

[0097] The product yield was 81% as calculated by HPLC. After purification of the reaction solution, the target product (compound 3g) was obtained. The proton and carbon spectra of compound 3g are shown in Table 1. The results of the proton and carbon spectra of 3g are shown in Table 2.

[0098] Example 8 Preparation of compound 3h Replace 1 mmol (126.59 mg) of benzyl chloride with 1 mmol (156.61 mg) of p-methoxybenzyl chloride.

[0099] The product yield was 72% as calculated by HPLC. After purification of the reaction solution, the target product (compound 3h) was obtained. The proton and carbon spectra of compound 3h are shown in Table 1. The results of 3h obtained by proton and carbon spectra are shown in Table 2.

[0100] Example 9 Preparation of compound 3i Replace 1 mmol (126.59 mg) of benzyl chloride with 1 mmol (140.61 mg) of p-methylbenzyl chloride.

[0101] The product yield was 89% as calculated by HPLC. The target product (compound 3i) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3i are shown in Table 1. The results of obtaining 3i from the proton and carbon spectra are shown in Table 2.

[0102] Example 10 Preparation of compound 3j Replace 1 mmol (126.59 mg) of benzyl chloride with 1 mmol (151.59 mg) of p-cyanobenzyl chloride.

[0103] The product yield was calculated to be 57% using HPLC. After purification of the reaction solution, the target product (compound 3j) was obtained. The proton and carbon spectra of compound 3j are shown in Table 1. The results of obtaining 3j from the proton and carbon spectra are shown in Table 2.

[0104] Example 11 Preparation of compound 3k Replace 1 mmol (126.59 mg) of benzyl chloride with 1 mmol (140.61 mg) of 1-chloro-1-phenylethane.

[0105] The product yield was 92% as calculated by HPLC. The target product (compound 3k) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3k are shown in Table 1. The results of 3k obtained by proton and carbon spectra are shown in Table 2.

[0106] Example 12 Preparation of compound 3l Replace 1 mmol (126.59 mg) of benzyl chloride with 1 mmol (202.68 mg) of diphenylchloromethane.

[0107] The product yield was 95% as calculated by HPLC. The target product (compound 3l) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3l are shown in Table 1. The results of obtaining 3l from the proton and carbon spectra are shown in Table 2.

[0108] Comparative Example 1-1 The method according to Example 1-a differs in that: Replace 5 mol% (11.51 mg) of benzyltrimethylammonium bromide with 5 mol% (5.14 mg) of sodium bromide; The product yield was 15% as calculated by HPLC. The target product (compound 3a) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3a are shown in Table 1. The results of obtaining 3a from the proton and carbon spectra are shown in Table 2.

[0109] Comparative Examples 1-2 The method according to Example 1-a differs in that: Replace 5 mol% (11.51 mg) of benzyltrimethylammonium bromide with a combination of 2.5 mol% (3.91 mg) of 2,2,6,6-tetramethylpiperidine oxide and 2.5 mol% (2.57 mg) of sodium bromide. The product yield was 24% as calculated by HPLC. The target product (compound 3a) was obtained after purification of the reaction solution. The proton and carbon spectra of compound 3a are shown in Table 1. The results of obtaining 3a from the proton and carbon spectra are shown in Table 2.

[0110] Table 1

[0111] Table 2

[0112] The results of the embodiments show that, compared with traditional halogenated reagents such as sodium bromide, the halogenated reagents with the specific structure of the embodiments of the present invention can better synergize with the raw materials, make the reaction system more miscible, and promote the stable and efficient reaction. At the same time, it can better achieve the advantages of mild conditions, short reaction time, high raw material utilization, effective control of the reaction process, safety and stability, continuous operation and high production efficiency in the microchannel reactor, and can obtain high yields of benzaldehyde and its derivatives.

[0113] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for preparing benzaldehyde and its derivatives, characterized in that, A first solution containing compound A of formula (Ⅰ) and a first solvent is mixed with a second solution containing an oxidizing agent, a halogenated reagent, and a second solvent and reacted. Equation (Ⅰ), In formula (Ⅰ), R1 is selected from halogen, nitro, cyano, carboxyl, aldehyde, C1-C3 alkoxy or C1-C3 alkyl; n is an integer from 0 to 3; R2 is selected from hydrogen, phenyl, C1-C3 alkyl or C1-C3 alkoxy; R3 is chlorine, bromine, or iodine; The structure of the halogenated reagent is shown in formula (IV). Formula (IV), In formula (IV), R4 is a C12-C18 alkyl or benzyl; R5 is a C1-C2 alkyl; and X is selected from fluorine, chlorine, bromine, or iodine. The molar ratio of compound A to the halogenated reagent is 1:(0.02-0.2). The molar ratio of compound A to oxidant is 1:(1-5). In the first solution, the concentration of compound A is 0.10-1.0 mol / L; In the second solution, the concentration of the halogenated reagent is 0.01-0.10 mol / L; The oxidant is selected from one or more of perchlorate, permanganate, dichromate, hydrogen peroxide, sodium peroxide, and nitric acid; The mixing and reaction are carried out in a microchannel reactor; the microchannel reactor includes a micromixer for mixing the first solution and the second solution, and the reaction temperature in the micromixer is 0-50°C.

2. The preparation method according to claim 1, wherein, When R1 is located at the para position of the benzene ring in the structure of formula (I), R1 is selected from halogen, nitro, cyano, carboxyl, aldehyde, C1-C3 alkoxy, or C1-C3 alkyl; and / or When R1 is located at the meta position of the benzene ring in the structure of formula (I), R1 is selected from halogen, nitro, or cyano; and / or When R1 is located in the ortho position of the benzene ring in the structure of formula (Ⅰ), R1 is selected from halogen, nitro or cyano.

3. The preparation method according to claim 1, wherein, R4 is benzyl; and / or X is bromine or iodine.

4. The preparation method according to claim 1, wherein, The molar ratio of compound A to the halogenated reagent is 1:(0.02-0.15). In the first solution, the concentration of compound A is 0.20-0.50 mol / L; and / or In the second solution, the concentration of the halogenated reagent is 0.01-0.04 mol / L.

5. The preparation method according to claim 1, wherein, The molar ratio of compound A to oxidant is 1:(2-3); In the second solution, the concentration of the oxidant is 0.1-3 mol / L.

6. The preparation method according to claim 5, wherein, In the second solution, the concentration of the oxidant is 0.5-2 mol / L.

7. The preparation method according to claim 1, wherein, The oxidant is hydrogen peroxide.

8. The preparation method according to claim 1, wherein, The first solvent and the second solvent each independently comprise 0-100% by volume of water.

9. The preparation method according to claim 8, wherein, The first solvent and the second solvent each independently comprise 30-60% by volume of water, 40%-70% by volume of C1-C4 alcohol solvents and / or nitrile solvents.

10. The preparation method according to claim 9, wherein, The C1-C4 alcohol solvents are selected from one or more of methanol, ethanol, propanol, isobutanol, and n-butanol; and / or The nitrile solvent is selected from one or more of acetonitrile, propionitrile, isopropionitrile, succinic anhydride, butyric anhydride, and adiponitrile.

11. The preparation method according to claim 10, wherein, The C1-C4 alcohol solvent is methanol; and / or The nitrile solvent is acetonitrile.

12. The preparation method according to claim 1, wherein, The microchannel reactor includes a first feed pump for pumping in a first solution, a second feed pump for pumping in a second solution, a micromixer for mixing the first and second solutions, and a microreactor for the reaction. The first and second feed pumps are connected in parallel and then connected in series with the micro mixer via connecting pipes; the micro mixer and the microreactor are connected in series via pipes.

13. The preparation method according to claim 12, wherein, The flow rates of the first and second solutions entering the microchannel reactor are each independently 0.05–0.30 mL / min; and / or In the micromixer, the residence time of the reaction is 1-30 min.

14. The preparation method according to claim 12, wherein, In the micro mixer, the reaction temperature is 10-40℃.

15. The preparation method according to claim 12, wherein, The micro mixer is of type T, type Y, or inverted Y; and / or The volume of the microreactor is 0.5-1.5 mL.

16. The preparation method according to claim 15, wherein, The micro mixer is a Y-type.

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