Method for continuous preparation of p-chlorobenzaldehyde

Abstract

This invention relates to the field of p-chlorobenzaldehyde preparation technology and discloses a method for the continuous preparation of p-chlorobenzaldehyde. The method includes: dissolving p-chlorobenzyl alcohol in a first solvent to obtain a homogeneous solution A; dissolving an oxidant, a catalyst accelerant, and a catalyst in a second solvent to obtain a homogeneous solution B; and pumping homogeneous solutions A and B into a microchannel reactor for reaction. The continuous preparation method for p-chlorobenzaldehyde provided by this invention uses p-chlorobenzyl alcohol as a raw material and combines it with a microchannel reactor for one-step continuous reaction to prepare p-chlorobenzaldehyde. This method can improve reaction efficiency, shorten reaction time, and simultaneously achieve low reaction temperature, high product yield, and virtually no hydrochloric acid wastewater generation.

Description

Technical Field

[0001] This invention relates to the field of p-chlorobenzaldehyde preparation technology, and more specifically to a method for the continuous preparation of p-chlorobenzaldehyde. Background Technology

[0002] p-Chlorobenzaldehyde is a widely used fine organic chemical intermediate with significant applications in pharmaceuticals, pesticides, and dyes. In pharmaceuticals, p-chlorobenzaldehyde can be synthesized into phenalool via condensation and cyclization with mercaptopropionic acid, and can also be used to synthesize the drug chlorophenylaminobenzoic acid. In pesticides, p-chlorobenzaldehyde is an important intermediate in the synthesis of plant growth regulators uniconazole and paclobutrazol, and the herbicide methylphenidate. In dyes, triphenylmethane-type acid dyes using p-chlorobenzaldehyde as an intermediate exhibit good brightness and high colorfastness, and are widely used in the wool and silk dyeing industries. Furthermore, p-chlorobenzaldehyde can also be used as an intermediate in textile auxiliaries, flame retardants, and photosensitive materials. In recent years, with the continuous development of downstream products of p-chlorobenzaldehyde, its demand has been increasing year by year.

[0003] There are many methods for synthesizing p-chlorobenzaldehyde, most of which use p-chlorotoluene as a raw material. These include chlorination-catalytic hydrolysis, manganese dioxide oxidation, air catalytic oxidation, and electrochemical oxidation. Another route uses p-nitrotoluene as a raw material. Among these routes using p-chlorotoluene, chlorination-catalytic hydrolysis suffers from drawbacks such as high equipment requirements, difficulty in controlling the degree of chlorination and oxidation, cumbersome production processes, large amounts of hydrolysis wastewater, long reaction times, and severe equipment corrosion. Similarly, manganese dioxide oxidation also suffers from difficulties in controlling the degree of oxidation, the tendency for over-oxidation to yield p-chlorobenzoic acid, and the presence of Mn. 2+ The wastewater treatment problem; air catalytic oxidation requires a highly efficient catalyst, and suffers from drawbacks such as difficult catalyst preparation, high reaction temperature, and low yield; electrochemical oxidation is still some distance from industrialization due to the high technical difficulty of electrolysis. In the synthetic route using p-nitrotoluene as a raw material, p-nitrotoluene is used as the starting material, with sodium sulfide (Na2S) as the... X Using a redox agent, a diazonium salt solution of p-aminobenzaldehyde is prepared, which is then subjected to a Sandmeier reaction to finally obtain p-chlorobenzaldehyde. This method is relatively complicated and produces a large amount of waste.

[0004] CN109651111A discloses a method for preparing p-chlorobenzaldehyde. This method uses p-chlorotoluene as a raw material and reacts it with chlorine gas in the presence of a catalyst to obtain a mixture of p-chlorobenzyl chloride and p-chlorobenzylidene dichloride. This mixture is then subjected to hydrolysis and air catalytic oxidation in the presence of a catalyst to obtain p-chlorobenzaldehyde. Although this method lowers the reaction temperature of the substitution reaction through the use of a catalyst and improves the yield of p-chlorobenzaldehyde by combining hydrolysis and air catalytic oxidation, the total reaction time exceeds 10 hours, and the production process is cumbersome. Summary of the Invention

[0005] The purpose of this invention is to overcome the problems of long reaction time, troublesome wastewater treatment, cumbersome operation and low product yield in the synthesis of p-chlorobenzaldehyde in the prior art. It provides a method for continuous preparation of p-chlorobenzaldehyde, which has the advantages of high reaction efficiency, short reaction time, low reaction temperature and high product yield and basically no hydrochloric acid wastewater generation.

[0006] To achieve the above objectives, the present invention provides a method for the continuous preparation of p-chlorobenzaldehyde, the method comprising:

[0007] (1) Dissolve p-chlorobenzyl alcohol in a first solvent to obtain a homogeneous solution A; dissolve the oxidant, catalyst promoter and catalyst in a second solvent to obtain a homogeneous solution B;

[0008] (2) Pump the homogeneous solution A and homogeneous solution B obtained in step (1) into the microchannel reaction device for reaction.

[0009] In existing technologies, the main method for producing p-chlorobenzaldehyde is the catalytic hydrolysis of p-chlorotoluene using p-chlorotoluene as a raw material. However, large-scale production still primarily relies on batch production in intermittent reactors, which suffers from problems such as high equipment requirements, difficulty in controlling the depth of chlorination and oxidation, cumbersome production processes, long reaction times, low product yields, and significant waste generation. Microchemical technology, on the other hand, is a green synthetic technology for preparing pesticide and pharmaceutical intermediates through process intensification. Micro-functional devices are the core of microchemical technology, and they can be categorized by function into micro-heat exchangers, micro-mixers, micro-dispersants, microreactors, and micro-detectors, among others. Microreactors, with their small size, large specific surface area, and ordered flow, possess unique properties in microchemical reactions, including: inherently safe reaction, rapid mixing of homogeneous and heterogeneous phases, efficient and rapid heat exchange, narrow temperature distribution, short residence time, narrow residence time distribution, precise process control, and no scale-up effect.

[0010] Based on this, the inventors of this invention creatively use p-chlorobenzyl alcohol as a raw material and combine it with a microchannel reaction device to prepare p-chlorobenzaldehyde in a one-step continuous reaction, which can improve reaction efficiency, shorten reaction time, and at the same time, the reaction temperature is low and the product yield is high, and there is basically no hydrochloric acid wastewater generated.

[0011] The method provided by the present invention, through the above technical solution, has the following advantages:

[0012] (1) Compared with the traditional batch production method, the method provided by the present invention uses a microchannel reaction device to realize the continuous production of p-chlorobenzaldehyde, which can shorten the reaction time from the traditional tens of hours to tens of minutes or even minutes. The reaction efficiency is high, the reaction conditions are mild, and the product yield is high, up to 86%.

[0013] (2) The method provided by the present invention uses p-chlorobenzyl alcohol, which is relatively inexpensive and readily available, as a starting material, and has high atom economy and good substrate universality.

[0014] (3) In a preferred embodiment, the method provided by the present invention uses hydrogen peroxide as an oxidant, and no expensive organic or metal catalysts need to be added during the reaction process. It is simple to operate and has low cost.

[0015] In summary, the method provided by this invention uses a microchannel reaction device to prepare p-chlorobenzaldehyde by reacting a homogeneous solution A containing p-chlorobenzyl alcohol with a homogeneous solution B containing an oxidant, a catalyst catalyst, and a catalyst in one continuous step. The reaction process is easy to control, has high safety, and the reaction conditions are mild, thus having better potential for industrial scale-up. Attached Figure Description

[0016] Figure 1 This is a schematic diagram of the reaction process according to a preferred embodiment of the present invention;

[0017] Figure 2 It is the p-chlorobenzaldehyde product obtained in Example 1. 1 H NMR spectrum;

[0018] Figure 3 It is the p-chlorobenzaldehyde product obtained in Example 1. 13 C NMR spectrum.

[0019] Explanation of reference numerals in the attached figures

[0020] 1. Homogeneous solution A 2. Homogeneous solution B 3. First syringe pump

[0021] 4. Second injection pump; 5. Micromixer; 6. Microchannel reactor

[0022] 7. Separation Unit Detailed Implementation

[0023] 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.

[0024] This invention provides a method for the continuous preparation of p-chlorobenzaldehyde, the method comprising:

[0025] (1) Dissolve p-chlorobenzyl alcohol in a first solvent to obtain a homogeneous solution A; dissolve the oxidant, catalyst promoter and catalyst in a second solvent to obtain a homogeneous solution B;

[0026] (2) Pump the homogeneous solution A and homogeneous solution B obtained in step (1) into the microchannel reaction device for reaction.

[0027] Existing methods for preparing p-chlorobenzaldehyde from p-chlorotoluene via substitution and hydrolysis include: 1. Replacing p-chlorotoluene with chlorine under ultraviolet light to synthesize p-chlorobenzyl chloride, which is then hydrolyzed to obtain p-chlorobenzaldehyde. This method yields a maximum of only 60% of p-chlorobenzaldehyde and has a long reaction time. 2. Replacing p-chlorotoluene with chlorine under ultraviolet light to synthesize p-chlorobenzyl dichloride, which is then purified and hydrolyzed to obtain p-chlorobenzaldehyde. This method has a high yield, but the purification process is costly, and the reaction time remains long. 3. Replacing p-chlorotoluene with chlorine under ultraviolet light to synthesize a mixture of p-chlorobenzyl chloride and p-chlorobenzyl dichloride, which is then hydrolyzed to obtain p-chlorobenzaldehyde. This method has a high yield, but also suffers from a long reaction time (total reaction time exceeds 10 hours). Furthermore, the substitution reaction between p-chlorotoluene and chlorine requires harsh conditions, typically necessitating temperatures above 120-140°C and exposure to light or ultraviolet light. Additionally, the methyl group of p-chlorotoluene has three hydrogen atoms that can be replaced by chlorine atoms, making it very difficult to control the extent of the substitution reaction under these conditions.

[0028] The method provided by this invention uses a microchannel reaction device to prepare p-chlorobenzaldehyde by reacting a homogeneous solution A containing p-chlorobenzyl alcohol with a homogeneous solution B containing an oxidant, a catalyst facilitator, and a catalyst in a one-step continuous reaction. Preferably, the method uses hydrogen peroxide as the oxidant. The specific reaction equations in the reaction process are shown below:

[0029]

[0030] The method provided by this invention has easy-to-control reaction process, improves reaction efficiency, shortens reaction time, and can achieve a high yield of p-chlorobenzaldehyde product at a relatively mild reaction temperature.

[0031] According to some embodiments of the present invention, preferably, in step (1), the concentration of p-chlorobenzyl alcohol in the homogeneous solution A is 0.05-0.5 mmol / mL, more preferably 0.2-0.4 mmol / mL. Limiting the concentration of p-chlorobenzyl alcohol in the homogeneous solution A to the above range is beneficial to improving the utilization rate of p-chlorobenzyl alcohol.

[0032] According to some embodiments of the present invention, preferably, in step (1), the concentration of the oxidant in the homogeneous solution B is 0.2-2 mmol / mL, more preferably 0.5-1 mmol / mL. Limiting the concentration of the oxidant in the homogeneous solution B to the above range is beneficial to improving the reaction selectivity.

[0033] According to some embodiments of the present invention, preferably, the molar mass ratio of the oxidant to p-chlorobenzyl alcohol is (1-5):1, more preferably (2-3):1, and even more preferably (2.5-3):1. Using the above preferred embodiments is beneficial for further improving the yield and selectivity of p-chlorobenzaldehyde products.

[0034] According to some embodiments of the present invention, the range of types of oxidants that can be selected is relatively wide; any oxidant capable of oxidizing the hydroxyl group of p-chlorobenzyl alcohol to an aldehyde group is within the scope of the present invention. Preferably, the oxidant is selected from at least one of hydrogen peroxide, peracetic acid, peroxypropionic acid, potassium permanganate, and potassium dichromate, with hydrogen peroxide being the most preferred; more preferably, the oxidant is provided in the form of hydrogen peroxide; even more preferably, the mass fraction of the hydrogen peroxide is 30%-100%, preferably 50%-100%. In the preferred case, providing the oxidant in the form of hydrogen peroxide simplifies the operation and reduces production costs. Furthermore, a mass fraction of hydrogen peroxide within the above-mentioned preferred range is beneficial for further improving the yield of p-chlorobenzaldehyde product.

[0035] According to some embodiments of the present invention, preferably, the catalyst accounts for 1%-10% of the mass fraction of p-chlorobenzyl alcohol, more preferably 2%-8%, and even more preferably 3%-4%. Using the above-described preferred embodiments is beneficial for increasing the catalytic rate of the reaction and further improving the yield of the p-chlorobenzaldehyde product.

[0036] According to some embodiments of the present invention, the range of types of catalyst promoters that can be selected is relatively wide; any catalyst promoter that can accelerate the catalytic action is within the scope of the present invention. Preferably, the catalyst promoter is selected from at least one of sodium bromide, potassium bromide, and magnesium bromide, preferably sodium bromide; more preferably, the sodium bromide is provided in the form of an aqueous solution; even more preferably, the mass fraction of the sodium bromide in the aqueous solution is 1%-10%, preferably 5%-10%. Using a catalyst promoter within the above preferred range is beneficial to improving the catalytic rate of the reaction.

[0037] According to some embodiments of the present invention, preferably, the catalyst accounts for 1%-20% of the mass fraction of p-chlorobenzyl alcohol, more preferably 1.5%-15%, and even more preferably 2%-6%. Using the above-described preferred embodiments is beneficial for accelerating the reaction rate and further improving the yield of the p-chlorobenzaldehyde product.

[0038] According to some embodiments of the present invention, the range of types of catalysts that can be selected is relatively wide, and any catalyst capable of providing acidity is within the scope of the present invention. Preferably, the catalyst is selected from at least one of sulfuric acid, hydrochloric acid, and phosphoric acid, preferably sulfuric acid; more preferably, the sulfuric acid is provided in the form of an aqueous solution; even more preferably, the mass fraction of the sulfuric acid in the aqueous solution is 1%-10%, preferably 1%-5%. Catalysts within the above preferred range are beneficial for accelerating the reaction rate.

[0039] According to some embodiments of the present invention, the types of the first solvent and the second solvent can be selected from a wide range, as long as they are miscible and capable of dissolving p-chlorobenzyl alcohol, the oxidant, the catalyst promoter, and the catalyst. Preferably, the first solvent and the second solvent are the same or different, each independently selected from at least one of acetonitrile, dimethyl sulfoxide (DMSO), dioxane, and N,N-dimethylformamide (DMF), more preferably at least one of dimethyl sulfoxide, dioxane, and N,N-dimethylformamide, more preferably dimethyl sulfoxide and / or dioxane, and even more preferably dioxane; more preferably, the first solvent and the second solvent are the same. Selecting the first solvent and the second solvent within the above preferred range is beneficial to improving the reaction efficiency and further increasing the yield of the p-chlorobenzaldehyde product.

[0040] According to some embodiments of the present invention, preferably, in step (2), the microchannel reaction device includes a micromixer and a microreactor (microchannel reactor). The microchannel reaction device can effectively increase the contact area between reactants, enhance their mass and heat transfer effects, improve the utilization rate of oxidant, and shorten the reaction time. The stability of the oxidant and the selectivity of the target product are also greatly improved.

[0041] According to some embodiments of the present invention, preferably, the reaction volume of the microreactor is 3-10 mL, more preferably 5-8 mL. Using the above-described preferred embodiments is beneficial for further improving the yield of p-chlorobenzaldehyde products.

[0042] According to some embodiments of the present invention, preferably, the inner diameter of the microreactor is 0.3-1 mm, more preferably 0.5-0.8 mm. Using the above-described preferred embodiments is beneficial for further improving the yield of p-chlorobenzaldehyde products.

[0043] According to some embodiments of the present invention, preferably, in step (2), the homogeneous solution A and homogeneous solution B obtained in step (1) are first pumped into the micro mixer for mixing, and then the resulting mixture is sent into the microreactor for reaction.

[0044] According to some embodiments of the present invention, preferably, the mixing is carried out at room temperature and pressure; the mixing time is 1-20 ms. Room temperature refers to 20-30°C, and room pressure refers to 1 standard atmosphere. All pressures mentioned in this invention are gauge pressures.

[0045] According to some embodiments of the present invention, preferably, the hydraulic radius of the micromixer is 5-50 micrometers.

[0046] According to some embodiments of the present invention, preferably, in step (2), the flow rates of homogeneous solution A and homogeneous solution B are the same or different, each independently being 0.1-0.5 mL / min, preferably 0.2-0.4 mL / min; more preferably, the flow rates of homogeneous solution A and homogeneous solution B are the same. Using the above preferred embodiments is beneficial for improving the reaction effect and further increasing the yield of p-chlorobenzaldehyde product.

[0047] According to some embodiments of the present invention, the flow rates of the homogeneous solution A and the homogeneous solution B can be regulated using conventional flow control / metering devices in the art, without any particular limitation. For example, metering pumps and / or syringe pumps can be used to regulate the flow rates of the homogeneous solution A and the homogeneous solution B.

[0048] According to some embodiments of the present invention, preferably, in step (2), the reaction conditions include: a reaction temperature of 50-90°C, preferably 60-80°C; and a reaction residence time of 5-30 min, preferably 10-25 min. The reaction conditions within the above-mentioned preferred ranges are beneficial for improving the reaction effect and further increasing the yield of p-chlorobenzaldehyde product.

[0049] According to some embodiments of the present invention, preferably, the method further includes a step of separating the product obtained in step (2). The separation can be performed with reference to existing techniques and is not particularly limited thereto. More preferably, the separation is column chromatography.

[0050] According to a particularly preferred embodiment of the present invention, the method for continuously preparing p-chlorobenzaldehyde includes the following steps:

[0051] (1-1) Dissolve p-chlorobenzyl alcohol in a first solvent to obtain a homogeneous solution A; dissolve the oxidant, catalyst promoter and catalyst in a second solvent to obtain a homogeneous solution B;

[0052] (2-1) Homogeneous solution A and homogeneous solution B obtained in step (1-1) are pumped into a microchannel reaction device to carry out the reaction.

[0053] Wherein, the first solvent and the second solvent are the same, both selected from at least one of acetonitrile, dimethyl sulfoxide, dioxane, and N,N-dimethylformamide, preferably at least one of dimethyl sulfoxide, dioxane, and N,N-dimethylformamide, more preferably dimethyl sulfoxide and / or dioxane, and even more preferably dioxane; the oxidant is hydrogen peroxide with a mass fraction of 30%-100%; the catalyst is sodium bromide; and the catalyst is an aqueous solution of sulfuric acid with a mass fraction of 1%-10%.

[0054] Figure 1 This is a schematic diagram of a reaction flow according to a preferred embodiment of the present invention, wherein the method includes:

[0055] (1-2) Dissolve p-chlorobenzyl alcohol in a first solvent to obtain a homogeneous solution A1; dissolve the oxidant, catalyst promoter and catalyst in a second solvent to obtain a homogeneous solution B2;

[0056] (2-2) Homogeneous solutions A1 and B2 are metered by the first injection pump 3 and the second injection pump 4, respectively, and then mixed in the micro mixer 5. They are then mixed in the microchannel reactor 6 for reaction. The product obtained from the reaction is then sent to the separation unit 7 for column chromatography separation to obtain the p-chlorobenzaldehyde product.

[0057] The present invention will be described in detail below through embodiments.

[0058] Unless otherwise specified, all raw materials used in the following embodiments are commercially available products.

[0059] The yield of p-chlorobenzaldehyde was determined by high-performance liquid chromatography with external standard (HPLC) to identify the p-chlorobenzaldehyde content in the reaction liquid. The calculation formula is: Yield of p-chlorobenzaldehyde = Molar mass of p-chlorobenzaldehyde produced ÷ Molar mass of p-chlorobenzyl alcohol added in the reaction × 100%.

[0060] Reaction residence time = reaction volume / total feed rate (where the total feed rate is the total flow rate of the first injection pump and the second injection pump).

[0061] The following embodiments are all in accordance with Figure 1 The reaction process shown is used to prepare p-chlorobenzaldehyde.

[0062] Example 1

[0063] 3 mmol (0.428 g) of p-chlorobenzyl alcohol was dissolved in 10 mL of dioxane to obtain homogeneous solution A. 50 wt% hydrogen peroxide (containing 7.5 mmol (0.255 g) of hydrogen peroxide), 5 wt% sodium bromide solution (containing 0.015 g of sodium bromide), and 1 wt% sulfuric acid solution (containing 0.01 g of sulfuric acid) were dissolved in 10 mL of dioxane to obtain homogeneous solution B. Homogeneous solutions A and B were metered by a first syringe pump and a second syringe pump, respectively, and then fed into a micromixer (hydraulic radius 20 μm). After rapid mixing at room temperature and pressure, the mixture was then fed into a microchannel reactor for reaction. The reaction solution was analyzed. The flow rates of both the first and second syringe pumps were 0.2 mL / min. The reaction volume of the microchannel reactor was V = 5 mL, the inner diameter was 0.5 mm, and the reactor temperature was 70 °C. After two cycles in the microchannel reactor, the reaction liquid was collected. The product yield was calculated to be 86% by HPLC. p-Chlorobenzaldehyde was obtained after column chromatography.

[0064] Figure 2 It is the product of p-chlorobenzaldehyde. 1 The 1H-NMR spectrum (400MHz, deuterated chloroform) shows δ 9.91 (s, 1H), 7.78–7.71 (m, 2H), and 7.46–7.41 (m, 2H), indicating that the p-chlorobenzaldehyde product contains five hydrogens. The singlet at chemical shift 9.91 represents the aldehyde hydrogen, while the remaining four hydrogens are arranged in two groups of two, corresponding to the four aromatic hydrogens after para-substitution on the benzene ring and matching the structure of p-chlorobenzaldehyde.

[0065] Figure 3 It is the product of p-chlorobenzaldehyde. 13 The C-NMR spectrum (101 MHz, deuterated chloroform) shows values ​​of δ189.85, 139.93, 133.70, 129.89, and 128.44, indicating that the p-chlorobenzaldehyde product contains five carbon atoms, with δ189.85 being the carbonyl carbon, matching the C-NMR spectrum of p-chlorobenzaldehyde. HRMS (TOF) m / z [M+H]+Calcd for C7H6ClO + The results 141.0107 found 141.0152, proving that the molecular weight of this substance is the same as that of p-chlorobenzaldehyde.

[0066] Example 2

[0067] 3 mmol of p-chlorobenzyl alcohol was dissolved in 10 mL of dioxane to obtain homogeneous solution A. 50 wt% hydrogen peroxide (containing 6 mmol (0.204 g) of hydrogen peroxide), 5 wt% sodium bromide solution (containing 0.015 g of sodium bromide), and 1 wt% sulfuric acid solution (containing 0.01 g of sulfuric acid) were dissolved in 10 mL of dioxane to obtain homogeneous solution B. Homogeneous solutions A and B were metered by a first syringe pump and a second syringe pump, respectively, and then fed into a micromixer (hydraulic radius 20 μm). After rapid mixing at room temperature and pressure, the mixture was then fed into a microchannel reactor for reaction. The reaction solution was analyzed. The flow rates of both the first and second syringe pumps were 0.2 mL / min. The reaction volume of the microchannel reactor was V = 5 mL, the inner diameter was 0.5 mm, and the reactor temperature was 70 °C. After two cycles in the microchannel reactor, the reaction liquid was collected. The product yield was calculated to be 81% by HPLC. p-Chlorobenzaldehyde was obtained after column chromatography.

[0068] Example 3

[0069] 3 mmol of p-chlorobenzyl alcohol was dissolved in 10 mL of dioxane to obtain homogeneous solution A. 50 wt% hydrogen peroxide (containing 9 mmol (0.306 g) of hydrogen peroxide), 5 wt% sodium bromide solution (containing 0.015 g of sodium bromide), and 1 wt% sulfuric acid solution (containing 0.01 g of sulfuric acid) were dissolved in 10 mL of dioxane to obtain homogeneous solution B. Homogeneous solutions A and B were metered by a first syringe pump and a second syringe pump, respectively, and then fed into a micromixer (hydraulic radius 20 μm). After rapid mixing at room temperature and pressure, the mixture was then fed into a microchannel reactor for reaction. The reaction solution was analyzed. The flow rates of both the first and second syringe pumps were 0.2 mL / min. The reaction volume of the microchannel reactor was V = 5 mL, the inner diameter was 0.5 mm, and the reactor temperature was 70 °C. After two cycles in the microchannel reactor, the reaction liquid was collected. The product yield was calculated to be 85% by HPLC. The product, p-chlorobenzaldehyde, was obtained after column chromatography.

[0070] Example 4

[0071] 3 mmol of p-chlorobenzyl alcohol was dissolved in 10 mL of dioxane to obtain homogeneous solution A. 50 wt% hydrogen peroxide (containing 7.5 mmol (0.255 g) of hydrogen peroxide), 10 wt% sodium bromide solution (containing 0.03 g of sodium bromide), and 1 wt% sulfuric acid solution (containing 0.01 g of sulfuric acid) were dissolved in 10 mL of dioxane to obtain homogeneous solution B. Homogeneous solutions A and B were metered by a first syringe pump and a second syringe pump, respectively, and then fed into a micromixer (hydraulic radius 20 μm). After rapid mixing at room temperature and pressure, the mixture was then fed into a microchannel reactor for reaction. The reaction solution was analyzed. The flow rates of both the first and second syringe pumps were 0.2 mL / min. The reaction volume of the microchannel reactor was V = 5 mL, the inner diameter was 0.5 mm, and the reactor temperature was 70 °C. After two cycles in the microchannel reactor, the reaction liquid was collected. The product yield was calculated to be 81% by HPLC. The product, p-chlorobenzaldehyde, was obtained after column chromatography.

[0072] Example 5

[0073] 3 mmol of p-chlorobenzyl alcohol was dissolved in 10 mL of dioxane to obtain homogeneous solution A. 50 wt% hydrogen peroxide (containing 7.5 mmol (0.255 g) of hydrogen peroxide), 5 wt% sodium bromide solution (containing 0.015 g of sodium bromide), and 5 wt% sulfuric acid solution (containing 0.05 g of sulfuric acid) were dissolved in 10 mL of dioxane to obtain homogeneous solution B. Homogeneous solutions A and B were metered by a first syringe pump and a second syringe pump, respectively, and then fed into a micromixer (hydraulic radius 20 μm). After rapid mixing at room temperature and pressure, the mixture was then fed into a microchannel reactor for reaction. The reaction solution was analyzed. The flow rates of both the first and second syringe pumps were 0.2 mL / min. The reaction volume of the microchannel reactor was V = 5 mL, the inner diameter was 0.5 mm, and the reactor temperature was 70 °C. After two cycles in the microchannel reactor, the reaction liquid was collected. The product yield was calculated to be 80% by HPLC. The product, p-chlorobenzaldehyde, was obtained after column chromatography.

[0074] Example 6

[0075] 3 mmol of p-chlorobenzyl alcohol was dissolved in 10 mL of acetonitrile to obtain homogeneous solution A. 50 wt% hydrogen peroxide (containing 7.5 mmol (0.255 g) of hydrogen peroxide), 5 wt% sodium bromide solution (containing 0.015 g of sodium bromide), and 1 wt% sulfuric acid solution (containing 0.01 g of sulfuric acid) were dissolved in 10 mL of acetonitrile to obtain homogeneous solution B. Homogeneous solutions A and B were metered by a first syringe pump and a second syringe pump, respectively, and then fed into a micromixer (hydraulic radius 20 μm) for rapid mixing before entering a microchannel reactor for reaction. The reaction solution was analyzed. The flow rates of both the first and second syringe pumps were 0.2 mL / min. The reaction volume of the microchannel reactor was V = 5 mL, the inner diameter was 0.5 mm, and the reactor temperature was 70 °C. After two cycles in the microchannel reactor, the reaction liquid was collected. The product yield was calculated to be 46% by HPLC. p-Chlorobenzaldehyde was obtained after column chromatography.

[0076] Example 7

[0077] 3 mmol of p-chlorobenzyl alcohol was dissolved in 10 mL of dimethyl sulfoxide (DMSO) to obtain homogeneous solution A. 50 wt% hydrogen peroxide (containing 7.5 mmol (0.255 g) of hydrogen peroxide), 5 wt% sodium bromide solution (containing 0.015 g of sodium bromide), and 1 wt% sulfuric acid solution (containing 0.01 g of sulfuric acid) were dissolved in 10 mL of DMSO to obtain homogeneous solution B. Homogeneous solutions A and B were metered by a first syringe pump and a second syringe pump, respectively, and then fed into a micromixer (hydraulic radius 20 μm). After rapid mixing at room temperature and pressure, the mixture was then fed into a microchannel reactor for reaction. The reaction solution was analyzed. The flow rates of both the first and second syringe pumps were 0.2 mL / min. The reaction volume of the microchannel reactor was V = 5 mL, the inner diameter was 0.5 mm, and the reactor temperature was 70 °C. After two cycles in the microchannel reactor, the reaction liquid was collected. The product yield was calculated to be 76% by HPLC. p-Chlorobenzaldehyde was obtained after column chromatography.

[0078] Example 8

[0079] 3 mmol of p-chlorobenzyl alcohol was dissolved in 10 mL of N,N-dimethylformamide (DMF) to obtain homogeneous solution A. 50 wt% hydrogen peroxide (containing 7.5 mmol (0.255 g) of hydrogen peroxide), 5 wt% sodium bromide solution (containing 0.015 g of sodium bromide), and 1 wt% sulfuric acid solution (containing 0.01 g of sulfuric acid) were dissolved in 10 mL of DMF to obtain homogeneous solution B. Homogeneous solutions A and B were metered by a first syringe pump and a second syringe pump, respectively, and then fed into a micromixer (hydraulic radius 20 μm). After rapid mixing at room temperature and pressure, the mixture was then fed into a microchannel reactor for reaction. The reaction solution was analyzed. The flow rates of both the first and second syringe pumps were 0.2 mL / min. The reaction volume of the microchannel reactor was V = 5 mL, the inner diameter was 0.5 mm, and the reactor temperature was 70 °C. After two cycles in the microchannel reactor, the reaction liquid was collected. The product yield was calculated to be 62% by HPLC. p-Chlorobenzaldehyde was obtained after column chromatography.

[0080] Example 9

[0081] 3 mmol of p-chlorobenzyl alcohol was dissolved in 10 mL of dioxane to obtain homogeneous solution A. 50 wt% hydrogen peroxide (containing 7.5 mmol (0.255 g) of hydrogen peroxide), 5 wt% sodium bromide solution (containing 0.015 g of sodium bromide), and 1 wt% sulfuric acid solution (containing 0.01 g of sulfuric acid) were dissolved in 10 mL of dioxane to obtain homogeneous solution B. Homogeneous solutions A and B were metered by a first syringe pump and a second syringe pump, respectively, and then fed into a micromixer (hydraulic radius 20 μm). After rapid mixing at room temperature and pressure, the mixture was then fed into a microchannel reactor for reaction. The reaction solution was analyzed. The flow rates of both the first and second syringe pumps were 0.1 mL / min. The reaction volume of the microchannel reactor was V = 5 mL, the inner diameter was 0.5 mm, and the reactor temperature was 70 °C. After two cycles in the microchannel reactor, the reaction liquid was collected. The product yield was calculated to be 76% by HPLC. p-Chlorobenzaldehyde was obtained after column chromatography.

[0082] Example 10

[0083] 3 mmol of p-chlorobenzyl alcohol was dissolved in 10 mL of dioxane to obtain homogeneous solution A. 50 wt% hydrogen peroxide (containing 7.5 mmol (0.255 g) of hydrogen peroxide), 5 wt% sodium bromide solution (containing 0.015 g of sodium bromide), and 1 wt% sulfuric acid solution (containing 0.01 g of sulfuric acid) were dissolved in 10 mL of dioxane to obtain homogeneous solution B. Homogeneous solutions A and B were metered by a first syringe pump and a second syringe pump, respectively, and then fed into a micromixer (hydraulic radius 20 μm). After rapid mixing at room temperature and pressure, the mixture was then fed into a microchannel reactor for reaction. The reaction solution was analyzed. The flow rates of both the first and second syringe pumps were 0.3 mL / min. The reaction volume of the microchannel reactor was V = 5 mL, the inner diameter was 0.5 mm, and the reactor temperature was 70 °C. After two cycles in the microchannel reactor, the reaction liquid was collected. The product yield was calculated to be 71% by HPLC. p-Chlorobenzaldehyde was obtained after column chromatography.

[0084] Example 11

[0085] 3 mmol of p-chlorobenzyl alcohol was dissolved in 10 mL of dioxane to obtain homogeneous solution A. 50 wt% hydrogen peroxide (containing 7.5 mmol (0.255 g) of hydrogen peroxide), 5 wt% sodium bromide solution (containing 0.015 g of sodium bromide), and 1 wt% sulfuric acid solution (containing 0.01 g of sulfuric acid) were dissolved in 10 mL of dioxane to obtain homogeneous solution B. Homogeneous solutions A and B were metered by a first syringe pump and a second syringe pump, respectively, and then fed into a micromixer (hydraulic radius 20 μm). After rapid mixing at room temperature and pressure, the mixture was then fed into a microchannel reactor for reaction. The reaction solution was analyzed. The flow rates of both the first and second syringe pumps were 0.2 mL / min. The reaction volume of the microchannel reactor was V = 5 mL, the inner diameter was 0.5 mm, and the reactor temperature was 50 °C. After two cycles in the microchannel reactor, the reaction liquid was collected. The product yield was calculated to be 51% by HPLC. p-Chlorobenzaldehyde was obtained after column chromatography.

[0086] Example 12

[0087] 3 mmol of p-chlorobenzyl alcohol was dissolved in 10 mL of dioxane to obtain homogeneous solution A. 50 wt% hydrogen peroxide (containing 7.5 mmol (0.255 g) of hydrogen peroxide), 5 wt% sodium bromide solution (containing 0.015 g of sodium bromide), and 1 wt% sulfuric acid solution (containing 0.01 g of sulfuric acid) were dissolved in 10 mL of dioxane to obtain homogeneous solution B. Homogeneous solutions A and B were metered by a first syringe pump and a second syringe pump, respectively, and then fed into a micromixer (hydraulic radius 20 μm). After rapid mixing at room temperature and pressure, the mixture was then fed into a microchannel reactor for reaction. The reaction solution was analyzed. The flow rates of both the first and second syringe pumps were 0.2 mL / min. The reaction volume of the microchannel reactor was V = 5 mL, the inner diameter was 0.5 mm, and the reactor temperature was 90 °C. After two cycles in the microchannel reactor, the reaction liquid was collected. The product yield was calculated to be 79% by HPLC. p-Chlorobenzaldehyde was obtained after column chromatography.

[0088] Example 13

[0089] 3 mmol of p-chlorobenzyl alcohol was dissolved in 10 mL of dioxane to obtain homogeneous solution A. 30 wt% hydrogen peroxide (containing 7.5 mmol (0.255 g) of hydrogen peroxide), 5 wt% sodium bromide solution (containing 0.015 g of sodium bromide), and 1 wt% sulfuric acid solution (containing 0.01 g of sulfuric acid) were dissolved in 10 mL of dioxane to obtain homogeneous solution B. Homogeneous solutions A and B were metered by a first syringe pump and a second syringe pump, respectively, and then fed into a micromixer (hydraulic radius 20 μm). After rapid mixing at room temperature and pressure, the mixture was then fed into a microchannel reactor for reaction. The reaction solution was analyzed. The flow rates of both the first and second syringe pumps were 0.2 mL / min. The reaction volume of the microchannel reactor was V = 5 mL, the inner diameter was 0.5 mm, and the reactor temperature was 70 °C. After two cycles in the microchannel reactor, the reaction liquid was collected. The product yield was calculated to be 75% by HPLC. p-Chlorobenzaldehyde was obtained after column chromatography.

[0090] Example 14

[0091] 3 mmol of p-chlorobenzyl alcohol was dissolved in 10 mL of dioxane to obtain homogeneous solution A. 100 wt% hydrogen peroxide (containing 7.5 mmol (0.255 g) of hydrogen peroxide), 5 wt% sodium bromide solution (containing 0.015 g of sodium bromide), and 1 wt% sulfuric acid solution (containing 0.01 g of sulfuric acid) were dissolved in 10 mL of dioxane to obtain homogeneous solution B. Homogeneous solutions A and B were metered by a first syringe pump and a second syringe pump, respectively, and then fed into a micromixer (hydraulic radius 20 μm). After rapid mixing at room temperature and pressure, the mixture was then fed into a microchannel reactor for reaction. The reaction solution was analyzed. The flow rates of both the first and second syringe pumps were 0.2 mL / min. The reaction volume of the microchannel reactor was V = 5 mL, the inner diameter was 0.5 mm, and the reactor temperature was 70 °C. After two cycles of reaction in the microchannel reactor, the reaction liquid was collected. The product yield was calculated to be 82% by HPLC. p-Chlorobenzaldehyde was obtained after column chromatography.

[0092] Example 15

[0093] 3 mmol of p-chlorobenzyl alcohol was dissolved in 10 mL of dioxane to obtain homogeneous solution A. 50 wt% hydrogen peroxide (containing 7.5 mmol (0.255 g) of hydrogen peroxide), 5 wt% sodium bromide solution (containing 0.015 g of sodium bromide), and 1 wt% sulfuric acid solution (containing 0.01 g of sulfuric acid) were dissolved in 10 mL of dioxane to obtain homogeneous solution B. Homogeneous solutions A and B were metered by a first syringe pump and a second syringe pump, respectively, and then fed into a micromixer (hydraulic radius 20 μm). After rapid mixing at room temperature and pressure, the mixture was then fed into a microchannel reactor for reaction. The reaction solution was analyzed. The flow rates of both the first and second syringe pumps were 0.2 mL / min. The reaction volume of the microchannel reactor was V = 5 mL, the inner diameter was 1 mm, and the reactor temperature was 70 °C. After two cycles in the microchannel reactor, the reaction liquid was collected. The product yield was calculated to be 76% by HPLC. p-Chlorobenzaldehyde was obtained after column chromatography.

[0094] Example 16

[0095] 3 mmol of p-chlorobenzyl alcohol was dissolved in 10 mL of dioxane to obtain homogeneous solution A. 50 wt% hydrogen peroxide (containing 7.5 mmol (0.255 g) of hydrogen peroxide), 5 wt% sodium bromide solution (containing 0.015 g of sodium bromide), and 1 wt% sulfuric acid solution (containing 0.01 g of sulfuric acid) were dissolved in 10 mL of dioxane to obtain homogeneous solution B. Homogeneous solutions A and B were metered by a first syringe pump and a second syringe pump, respectively, and then fed into a micromixer (hydraulic radius 20 μm). After rapid mixing at room temperature and pressure, the mixture was then fed into a microchannel reactor for reaction. The reaction solution was analyzed. The flow rates of both the first and second syringe pumps were 0.2 mL / min. The reaction volume of the microchannel reactor was V = 10 mL, the inner diameter was 0.5 mm, and the reactor temperature was 70 °C. After two cycles in the microchannel reactor, the reaction liquid was collected. The product yield was calculated to be 80% by HPLC. The product, p-chlorobenzaldehyde, was obtained after column chromatography.

[0096] The results above show that the method provided by this invention for the continuous preparation of p-chlorobenzaldehyde has high reaction efficiency, short reaction time, low reaction temperature, and high product yield.

[0097] Comparing the results of Examples 1-3, it can be seen that the yield of p-chlorobenzaldehyde product is higher when the molar mass ratio of oxidant to p-chlorobenzyl alcohol is within the preferred range.

[0098] Comparing the results of Example 1 and Example 4, it can be seen that the yield of p-chlorobenzaldehyde product is higher when the molar mass ratio of the catalyst to p-chlorobenzyl alcohol is within the preferred range.

[0099] Comparing the results of Example 1 and Example 5, it can be seen that the yield of p-chlorobenzaldehyde product is higher when the molar mass ratio of catalyst to p-chlorobenzyl alcohol is within the preferred range.

[0100] Comparing the results of Example 1 and Examples 6-8, it can be seen that the yield of p-chlorobenzaldehyde product obtained by using the first and second solvents within the preferred range is higher.

[0101] Comparing the results of Examples 1 and 9-10, it can be seen that the yield of p-chlorobenzaldehyde product is higher when the flow rates of homogeneous solution A and homogeneous solution B are within the preferred range.

[0102] Comparing the results of Example 1 and Examples 11-12, it can be seen that the yield of p-chlorobenzaldehyde product is higher when the reaction conditions and temperature are within the preferred range.

[0103] Comparing the results of Example 1 and Examples 13-14, it can be seen that when the oxidant is hydrogen peroxide, the yield of p-chlorobenzaldehyde product is higher when its mass fraction is within the preferred range.

[0104] Comparing the results of Example 1 and Examples 15-16, it can be seen that the reaction volume and / or inner diameter of the microreactor (microchannel reactor) within the preferred range yields higher yields of p-chlorobenzaldehyde.

[0105] 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 process for the continuous production of p-chlorobenzaldehyde, characterized in that, The method comprises: (1) dissolving p-chlorobenzyl alcohol in a first solvent to obtain a homogeneous solution A; dissolving an oxidizing agent, a catalytic aid and a catalyst in a second solvent to obtain a homogeneous solution B; (2) pumping the homogeneous solution A and the homogeneous solution B obtained in step (1) into a micro-channel reaction device for reaction; In step (2), the micro-channel reaction device comprises a micro-mixer and a micro-channel reactor. The catalyst is selected from at least one of sulfuric acid, hydrochloric acid and phosphoric acid. The oxidizing agent is selected from at least one of hydrogen peroxide, peroxyacetic acid, peroxypropionic acid, potassium permanganate and potassium dichromate.

2. The method of claim 1, wherein, In step (1), the concentration of the p-chlorobenzyl alcohol in the homogeneous solution A is 0.05-0.5 mmol / mL. And / or, the concentration of the oxidizing agent in the homogeneous solution B is 0.2-2 mmol / mL.

3. The method of claim 2, wherein, In step (1), the concentration of the p-chlorobenzyl alcohol in the homogeneous solution A is 0.2-0.4 mmol / mL.

4. The method of claim 2, wherein, The concentration of the oxidizing agent in the homogeneous solution B is 0.5-1 mmol / mL.

5. The method of claim 1, wherein, The molar mass ratio of the oxidizing agent to p-chlorobenzyl alcohol is (1-5):1; and / or The oxidizing agent is hydrogen peroxide.

6. The method of claim 5, wherein, The molar mass ratio of the oxidizing agent to p-chlorobenzyl alcohol is (2-3):

1.

7. The method of claim 6, wherein, The molar mass ratio of the oxidizing agent to p-chlorobenzyl alcohol is (2.5-3):

1.

8. The method of claim 5, wherein, The oxidizing agent is provided in the form of hydrogen peroxide.

9. The method of claim 8, wherein, The mass fraction of the hydrogen peroxide is 30%-100%.

10. The method of claim 9, wherein, The mass fraction of the hydrogen peroxide is 50%-100%.

11. The method of any of claims 1-9, wherein, In step (1), the mass fraction of the catalytic aid in p-chlorobenzyl alcohol is 1%-10%; and / or The catalytic aid is selected from at least one of sodium bromide, potassium bromide and magnesium bromide.

12. The method of claim 11, wherein, In step (1), the mass fraction of the catalytic aid in p-chlorobenzyl alcohol is 2%-8%.

13. The method of claim 12, wherein, In step (1), the mass fraction of the catalytic aid in p-chlorobenzyl alcohol is 3%-4%.

14. The method of claim 11, wherein, The catalytic aid is sodium bromide.

15. The method of claim 14, wherein, The sodium bromide is provided in the form of an aqueous solution.

16. The method of claim 15, wherein, The mass fraction of the sodium bromide in the aqueous solution is 1%-10%.

17. The method of claim 16, wherein, The mass fraction of the sodium bromide in the aqueous solution is 5%-10%.

18. The method of any one of claims 1-9, wherein, In step (1), the mass fraction of the catalyst in p-chlorobenzyl alcohol is 1%-20%; and / or The catalyst is sulfuric acid.

19. The method of claim 18, wherein, In step (1), the mass fraction of the catalyst in p-chlorobenzyl alcohol is 1.5%-15%.

20. The method of claim 19, wherein, In step (1), the mass fraction of the catalyst in p-chlorobenzyl alcohol is 2%-6%.

21. The method of claim 18, wherein, The sulfuric acid is provided in the form of an aqueous solution.

22. The method of claim 21, wherein, The mass fraction of the sulfuric acid in the aqueous solution is 1%-10%.

23. The method of claim 22, wherein, The mass fraction of the sulfuric acid in the aqueous solution is 1%-5%.

24. The method of any one of claims 1-9, wherein, In step (1), the first solvent and the second solvent are the same or different, and each is independently selected from at least one of acetonitrile, dimethyl sulfoxide, dioxane and N,N-dimethylformamide.

25. The method of claim 24, wherein, In step (1), the first solvent and the second solvent are the same or different, and each is independently at least one of dimethyl sulfoxide, dioxane and N,N-dimethylformamide.

26. The method of claim 25, wherein, In step (1), the first solvent and the second solvent are the same or different, and each is independently dimethyl sulfoxide and / or dioxane.

27. The method of claim 26, wherein, In step (1), the first solvent and the second solvent are the same or different, each independently is dioxane.

28. The method of claim 27, wherein, In step (1), the first solvent and the second solvent are the same.

29. The method of any one of claims 1-9, wherein, the reaction volume of the microreactor is 3-10 mL; and / or, the inner diameter of the microreactor is 0.3-1 mm.

30. The method of claim 29, wherein, the reaction volume of the microreactor is 5-8 mL.

31. The method of claim 29, wherein, the inner diameter of the microreactor is 0.5-0.8 mm.

32. The method of any one of claims 1-9, wherein, In step (2), the homogeneous solution A and the homogeneous solution B obtained in step (1) are pumped into the micro-mixer for mixing, and then the mixture is sent into the micro-channel reactor for reaction.

33. The method of claim 32, wherein, The mixing is carried out at normal temperature and pressure; the mixing time is 1-20 ms.

34. The method of claim 32, wherein, The hydrodynamic radius of the micro-mixer is 5-50 microns.

35. The method of any one of claims 1-9, wherein, In step (2), the flow rate of the homogeneous solution A and the homogeneous solution B is the same or different, each independently is 0.1-0.5 mL / min.

36. The method of claim 35, wherein, In step (2), the flow rate of the homogeneous solution A and the homogeneous solution B is the same or different, each independently is 0.2-0.4 mL / min.

37. The method of claim 36, wherein, In step (2), the flow rate of the homogeneous solution A and the homogeneous solution B is the same.

38. The method of any one of claims 1-9, wherein, In step (2), the reaction conditions include: the reaction temperature is 50-90℃; the reaction residence time is 5-30 min.

39. The method of claim 38, wherein, In step (2), the reaction conditions include: the reaction temperature is 60-80℃.

40. The method of claim 38, wherein, In step (2), the reaction conditions include: the reaction residence time is 10-25 min.

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