Green preparation method of (2-alkoxy ethyoxyl) acetaldehyde di-low-carbon alkanol

Abstract

The invention provides a preparation method of (2-alkoxy ethyoxyl) acetaldehyde di-low-carbon alkanol, which comprises the following steps: 1) carrying out aldolization on halogenated acetaldehyde and low-carbon alcohol in the presence of a solid acid catalyst to obtain halogenated acetaldehyde di-low-carbon alkanol; and 2) carrying out a Williamson etherification reaction on the halogenated acetaldehyde di-low carbon alkanol and ethylene glycol monoalkyl ether in the presence of an alkali metal hydroxide to prepare the (2-alkoxy ethyoxyl) acetaldehyde di-low carbon alkanol. The solid acid is used as the catalyst, the halogenated acetaldehyde and the low-carbon alcohol are used as raw materials, the halogenated acetaldehyde di-low-carbon alkanol is prepared through the one-pot method, the reaction is simple and easy to operate, the safety is high, and the catalyst can be used for circular reaction; the method comprises the following steps of: performing a Williamson etherification reaction with ethylene glycol monoalkyl ether and alkali metal hydroxide to prepare ethylene glycol diether which is a key intermediate of macrolide semi-synthetic antibiotics, and is wide in application.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a green preparation method of (2-alkoxyethoxy) acetaldehyde di-lower alkanol acetal. Background Art

[0002] In the field of contemporary medicinal chemistry research, macrolide semisynthetic antibiotics have become a hot topic of research and development due to their outstanding efficacy and wide clinical application. In particular, as a key intermediate in the synthesis of this drug, 2-chloroacetaldehyde dimethyl acetal plays an indispensable role in the preparation process. Acetal compounds are a class of organic compounds with unique chemical properties. Due to their unique chemical properties, they are usually used for carbonyl protection and exist as intermediates. In an acidic environment, the intermediate will be hydrolyzed into an aldehyde or hemiacetal form, and then condensed with components such as erythromycin to synthesize erythromycin derivatives with optimized pharmacokinetic properties and improved acid stability. These derivatives not only retain the broad-spectrum antibacterial ability of erythromycin, but also show a broader application prospect in clinical treatment due to their improved oral absorbability.

[0003] The acetal reaction is usually carried out under acidic conditions by catalyzing aldehyde compounds and alcohol compounds. The existing acetal synthesis process mainly uses homogeneous catalysts such as sulfuric acid, which has obvious disadvantages, such as high corrosion to equipment, difficulty in separation, blackening of color during reaction time, and inability to be recycled. With the continuous deterioration of the ecological environment and the continuous improvement of people's green environmental awareness, it is urgent to find a green and environmentally friendly preparation process for alcohol acetals.

[0004] At present, the synthesis of (2-alkoxyethoxy) acetaldehyde di-lower alkanol depends on sodium (Na) and sodium hydride (NaH) and other reaction reagents (Il In MV, Safinskaya YV, Polonnikov DA, et al. Chalcogen-and Halogen-Bond-Donating Cyanoborohydrides Provide Imine Hydrogenation [J]. The Journal of Organic Chemistry, 2024, 89 (5): 2916-2925). In addition, using strongly reducing Na and NaH as reaction reagents, because inevitable side reactions can cause the purity and yield of the final product to be unstable. The application aims to provide a new synthetic route, which can not only improve the yield and purity of the product, but also reduce environmental impact and reduce production costs, and there is no hydrogen release, and safety is greatly improved. Summary of the invention

[0005] In order to solve the above problems in the prior art, the present invention provides a method for preparing (2-alkoxyethoxy) acetaldehyde di-low-carbon alkanol acetal. Specifically, a solid acid is used as a catalyst, halogenated acetaldehyde, low-carbon alcohol and ethylene glycol monoalkyl ether are used as raw materials, and (2-alkoxyethoxy) acetaldehyde di-low-carbon alkanol acetal is finally prepared. The reaction process is simple and easy to operate, the catalyst can be recycled, the yield and purity are high, and the safety is high, which is suitable for popularization and application.

[0006] To achieve the above object, the present invention provides the following technical solutions:

[0007] The present invention provides a method for preparing (2-alkoxyethoxy) acetaldehyde di-lower alkanol acetal, comprising the following steps: 1) reacting halogenated acetaldehyde and low-carbon alcohol (C 1 -C 4 alcohol) in the presence of a solid acid catalyst to carry out an acetalization reaction to obtain a halogenated acetaldehyde di-lower alkanol;

[0008] In some feasible examples, in step 1), a water-carrying agent is further added to the reaction, and the water-carrying agent is selected from at least one of cyclohexane, toluene or petroleum ether, and the amount of the water-carrying agent is 10-60% of the mass of the raw materials in the corresponding reaction system, and can be 10-20%, 20-30%, 30-40%, 40-50% or 50-60%. Too much or too little amount of the water-carrying agent will have an adverse effect on the acetalization reaction. For example, insufficient amount will cause the water in the reaction system to be unable to be completely taken out, while excessive addition will reduce the concentration of reactants and the effective content of the catalyst, and at the same time reduce the reaction temperature, thereby affecting the reaction yield.

[0009] In some feasible examples, the low carbon alcohol is C 1 ~C 4 Alcohols, such as methanol, ethanol, propanol, isopropanol or butanol, etc.

[0010] In some feasible examples, the alkyl group in the ethylene glycol monoalkyl ether is C 1 ~C 6 Alkyl groups, such as ethylene glycol methyl ether, ethylene glycol ethyl ether, ethylene glycol propyl ether, ethylene glycol isopropyl ether, ethylene glycol butyl ether and ethylene glycol hexyl ether, etc.

[0011] In some feasible embodiments, the amount of the solid acid catalyst is 0.3-8% of the total mass of the halogenated acetaldehyde and the low-carbon alcohol, which can be optionally 0.3-1%, 1-2%, 2-3%, 3-4%, 4-5%, 5-6%, 6-7% or 7-8%, preferably 2-4%.

[0012] In some feasible examples, the acetal reaction of step 1) includes: 1-1) the acetal reaction system is pre-reacted at 45-55°C for 0.5-1h; 1-2) an azeotropic reaction is performed for 0.5-7h, and when no water is produced by the reaction, the reaction temperature is reduced to 20-40°C, the reaction is stopped, and the halogenated acetaldehyde di-lower alkanol is obtained by post-treatment. The post-treatment is specifically to filter and remove the solid acid catalyst, and remove the unreacted reactants and water-carrying agent. The azeotropic reaction temperature can be 55-65°C, 65-75°C, 75-85°C or 85-100°C. Optionally, the total reaction time is selected according to actual needs, for example, 1-3h, 3-5h or 5-8h.

[0013] In some feasible examples, the solid acid catalyst is selected from Lewis acid modified montmorillonite, SO 4 2- / M x O y At least one of a solid superacid, a metal oxide solid acid, a heteropolyacid solid acid, or a supported ionic liquid. Preferably, the Lewis acid-modified montmorillonite is AlCl 3 Modified montmorillonite (MMT-AlCl 3 ) or FeCl 3 Modified montmorillonite (MMT-FeCl 3 ) or a combination of the two or other necessary auxiliary components, and the specific combination ratio is adjusted according to the reagent requirements. 4 2- / M x O y The solid superacid is SO 4 2- / ZrO 2 or SO 4 2- / TiO 2 or a combination of the two or including other necessary auxiliary components, the heteropoly acid solid acid is HPW / ZrO 2 or HPW / TiO 2 or a combination of the two or other necessary auxiliary components, the metal oxide solid acid includes MoO 3 / ZrO 2 In some feasible examples, in step 1), the molar ratio of the halogenated acetaldehyde to the low-carbon alcohol is 1:(2-4), which can be 1:2 or 1:2.5 or 1:3 or 1:4.

[0014] 2) halogenated acetaldehyde dialkyl acetal and ethylene glycol monoalkyl ether (alkyl is C 1 -C 6 ) is subjected to Williamson etherification reaction in the presence of an alkali metal hydroxide to obtain (2-alkoxyethoxy)acetaldehyde di-lower alkanol acetal.

[0015] In some feasible examples, a water-carrying agent is further added to the reaction in step 2), and the etherification reaction includes:

[0016] 2-1) After the ethylene glycol monoalkyl ether and the alkali metal hydroxide are mixed, they react under the action of a quaternary ammonium salt phase transfer catalyst until no water is produced; the quaternary ammonium salt phase transfer catalyst can be selected as needed, such as tetramethylammonium chloride, tetrabutylammonium chloride, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride, etc. The amount of the catalyst is 5-20% by weight of the alkali metal hydroxide. It can be selected to be 5-8%, 8-12%, 12-16% or 16-20%.

[0017] 2-2) Adding halogenated acetaldehyde di-lower alkanol acetal to step 2-1), reacting, and then post-treating to obtain (2-alkoxyethoxy) acetaldehyde di-lower alkanol acetal.

[0018] Specifically, in step 2-1), the reaction temperature is 70-100°C, the temperature can be 70-80°C, 80-90°C, 90-100°C or 100-110°C; in step 2-2), the reaction temperature is 90-110°C, and the reaction time is 3-5h. The temperature can be 90-100°C or 100-110°C, and the reaction time can be 3-4h or 4-5h.

[0019] In some feasible examples, in step 2), a water-carrying agent is further added to the reaction, and the water-carrying agent is selected from at least one of cyclohexane, toluene or petroleum ether. The amount of the water-carrying agent is 10-60% of the total mass of the raw materials in the etherification reaction (the raw materials are halogenated acetaldehyde acetal di-lower alkanol and ethylene glycol monoalkyl ether). It can be selected as 10-20%, 20-30%, 30-40%, 40-50% or 50-60%. Too much or too little use of the water-carrying agent will have an adverse effect on the etherification reaction. For example, insufficient use will result in the inability to completely remove the water in the reaction system, while excessive addition will reduce the concentration of reactants and the effective content of the catalyst, thereby affecting the reaction yield.

[0020] In some feasible examples, the molar ratio of alkali metal hydroxide, ethylene glycol monoalkyl ether and halogenated acetaldehyde di-lower alkanol acetal is (1-1.5):(1-3):1. For example, (1-1.2):(1-3):1 or (1.2-1.5):(1-3):1.

[0021] In some feasible examples, the ethylene glycol monoalkyl ether is selected from one of ethylene glycol methyl ether, ethylene glycol ethyl ether, ethylene glycol propyl ether, ethylene glycol isopropyl ether, ethylene glycol butyl ether or ethylene glycol hexyl ether.

[0022] In some feasible examples, the halogenated acetaldehyde is 2-bromoacetaldehyde or 2-chloroacetaldehyde.

[0023] In some feasible examples, the alkali metal hydroxide is selected from at least one of sodium hydroxide, potassium hydroxide or lithium hydroxide.

[0024] As follows, halogenated acetaldehyde and methanol are used as examples for explanation, wherein X is a halogen atom, preferably Cl, the catalyst is a solid acid catalyst, MOH is an alkali metal hydroxide, benzyltriethylammonium chloride (XY-02) is a catalyst, and the specific reaction equation is as follows. To achieve the above-mentioned purpose and other related purposes, the present invention is achieved by the following technical solutions:

[0025]

[0026]

[0027] The present invention has the following technical effects including but not limited to:

[0028] The invention uses solid acid as a catalyst, halogenated aldehyde and alcohol reagents as raw materials, and prepares (2-alkoxyethoxy) acetaldehyde di-lower alkanol acetal through a one-pot method. The reaction is simple and easy to operate, and the safety is high. The catalyst can be circulated for reaction, and the invention is suitable for popularization and application. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The infrared spectra of the raw material methanol used in Example 1 and the 2-chloroacetaldehyde dimethyl acetal prepared in Example 1 are shown.

[0030] Figure 2 The raw material methanol of Example 1 and the 2-chloroacetaldehyde dimethyl acetal prepared in Example 1 1 H NMR spectra.

[0031] Figure 3 This is the infrared spectrum of the raw materials ethylene glycol methyl ether, 2-chloroacetaldehyde dimethyl acetal and the product (2-methoxyethoxy) acetaldehyde dimethyl acetal used in Example 1.

[0032] Figure 4 The raw materials ethylene glycol methyl ether, 2-chloroacetaldehyde dimethyl acetal and the product (2-methoxyethoxy) acetaldehyde dimethyl acetal used in Example 1 are 1 H NMR spectrum. DETAILED DESCRIPTION

[0033] The following describes the embodiments of the present invention through specific examples, and those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present invention.

[0034] In addition, for the numerical range in the present invention, it is understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or intermediate value in the range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0035] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0036] The catalyst HPW / ZrO used in the following examples is 2 、HPW / TiO 2 、SO 4 2- / ZrO 2 、SO 4 2- / TiO 2 and MoO 3 / ZrO 2 Methanol, ethylene glycol methyl ether, NaOH, chloroform, concentrated H 2 SO 4 (98wt%), and XY-02 (benzyltriethylammonium chloride) were purchased from Anhui Xinyuan Co., Ltd.; 40wt% 2-chloroacetaldehyde solution, aluminum chloride and ferric chloride hexahydrate were purchased from MacLean Co., Ltd. Other unspecified raw materials involved in the following examples and effect verification of the present invention are all commercially available products. Glass spring packing was used for the packing column.

[0037] Preparation example:

[0038] MMT-AlCl 3 and MMT-FeCl 3 The preparation method is:

[0039] 15 g of calcium-based bentonite was dispersed in 200 g of distilled water to obtain a calcium-based bentonite dispersion, which was then mixed with 2.0 g of hydrogen chloride, stirred at 25° C. for 4 h, aged at 25° C. for 8 h, filtered, dried at 100° C. for 12 h, and ground to obtain hydrogenated bentonite; 10 g of hydrogenated bentonite was dispersed in 200 g of distilled water to obtain a hydrogenated bentonite dispersion; 10.0 g of a 20 wt % ferric chloride aqueous solution was slowly added to the hydrogenated bentonite dispersion under rapid stirring, immersed at 50° C. for 1 h, aged at 25° C. for 12 h, and then filtered. The filter cake was washed with deionized water until neutral, dried at 100° C. for 12 h, and the dried product was ground and passed through a 200-mesh sieve to obtain a solid acid catalyst MMT-FeCl 3 .

[0040] 15g of calcium-based bentonite was dispersed in 200g of distilled water to obtain a calcium-based bentonite dispersion, which was then mixed with 1.0g of sodium chloride, stirred at 25°C for 4h, aged at 25°C for 8h, filtered, dried at 100°C for 12h, and ground to obtain sodium bentonite; 10g of sodium bentonite was dispersed in 200g of distilled water to obtain a sodium bentonite dispersion; 10.4g of a 20wt% aluminum chloride aqueous solution was slowly added to the sodium bentonite dispersion under rapid stirring, immersed at 50°C for 1h, aged at 25°C for 12h, and then filtered. The filter cake was washed with deionized water until neutral, dried at 100°C for 12h, and the dried product was ground and passed through a 200-mesh sieve to obtain a solid acid catalyst MMT-AlCl 3 .

[0041] Example 1

[0042] The preparation of (2-methoxyethoxy)acetaldehyde dimethyl acetal is as follows:

[0043] 1) 117 g of 40 wt% 2-chloroacetaldehyde aqueous solution, 67.2 g of methanol, 36.8 g of cyclohexane and the catalyst MMT-FeCl 3 6.6 g was added into a 500 mL four-necked flask equipped with a magnetic stirrer, a thermometer, a packing column, a water separator and a condenser, and the system was heated to 50 °C for pre-reaction for 1 h; then the temperature was raised to boiling, and the system temperature was gradually heated from 70 °C to 100 °C within 6 h. When the reaction system no longer separated water, the reaction was terminated and cooled to room temperature; the reaction solution was filtered to remove the catalyst MMT-FeCl 3 , the water-carrying cyclohexane and unreacted methanol were distilled off at normal pressure to obtain 59.2 g of the product 2-chloroacetaldehyde dimethyl acetal with a purity of 98.1% and a yield of 79.2%.

[0044] 2) 72.3g of ethylene glycol methyl ether, 26.6g of NaOH, 0.3945g of XY-02 and 19.78g of cyclohexane were added to a 500mL four-necked flask equipped with a magnetic stirrer, a thermometer, a packing column, a water separator and a condenser tube, and the temperature was raised to boiling. The system temperature was gradually heated from 70°C to 100°C within 3h, and the reaction system no longer separated water. Then 59.2g of 2-chloroacetaldehyde dimethyl acetal obtained in the first step was added dropwise, and the reaction temperature was controlled to 100-110°C. After reacting for 4h, the mixture was cooled to room temperature. The crude product was filtered, and the cyclohexane, ethylene glycol methyl ether and 2-chloroacetaldehyde dimethyl acetal in the crude product were recovered by atmospheric distillation to obtain 67.8g of the target product (2-methoxyethoxy) acetaldehyde dimethyl acetal, with a purity of 97.4% and a yield of 87.1%.

[0045] Figure 1 The raw material methanol used in this example is characterized by its hydroxyl-OH stretching vibration, which appears in the form of a broadband in the infrared spectrum with a wave number range of about 3200-3600 cm -1 , whose broad outline reflects the collective effect of intermolecular hydrogen bonding. -1 In the region, the -CH stretching vibration peak of the methyl group is clearly visible, while in the range of 1000-1300 cm -1 The stretching vibration peak of the carbonyl group between 1050 and 1150 cm further confirmed the structural characteristics of the alcohol group. For the spectrum of the product 2-chloroacetaldehyde dimethyl acetal, the disappearance of the stretching vibration of the hydroxyl group OH in the product suggests the elimination of the hydroxyl functional group during the synthesis reaction. -1 A new sharp absorption peak appears in the region, which is attributed to the stretching vibration of the -COC- ether bond. Its existence strongly indicates the progress of the acetal reaction and the formation of the product.

[0046] Figure 2 The raw material methanol adopted for the present embodiment shows the characteristic signal peak of hydroxyl proton at δ=3.05ppm place. However, in the product 2-chloroacetaldehyde dimethyl acetal nuclear magnetic spectrum, this hydroxyl signal peak disappears, and correspondingly new proton signal peaks appear at δ=3.5ppm and 4.51ppm place. These new peaks correspond to the methylene hydrogen at position 1 and the methylene hydrogen connected to chlorine atom in the 2-chloroacetaldehyde dimethyl acetal molecule respectively. The disappearance of this hydroxyl signal and the appearance of the methylene signal have proved the successful synthesis of 2-chloroacetaldehyde dimethyl acetal effectively.

[0047] Figure 3The raw materials ethylene glycol methyl ether and 2-chloroacetaldehyde dimethyl acetal and the product (2-methoxyethoxy) acetaldehyde dimethyl acetal used in this example were characterized by Fourier infrared. The characteristic of ethylene glycol methyl ether is its hydroxyl-OH stretching vibration, which appears in the form of a broadband in the infrared spectrum with a wave number range of about 3200-3600cm -1 , whose broad outline reflects the collective effect of intermolecular hydrogen bonding. The characteristic of 2-chloroacetaldehyde dimethyl acetal is its -C-Cl stretching vibration, which appears in the infrared spectrum as a broadband with a wave number range of 762cm -1 , the spectrum of (2-methoxyethoxy)acetaldehyde dimethyl acetal shows the disappearance of hydroxyl -OH and -C-Cl stretching vibrations in the product. In the spectrum of the product obtained by analysis, 1050~1110cm -1 The characteristic peak of -COC- ether bond appeared in the region. These results showed that ethylene glycol methyl ether, 2-chloroacetaldehyde formal and NaOH underwent successful etherification reaction.

[0048] Depend on Figure 4 The raw materials ethylene glycol methyl ether and 2-chloroacetaldehyde dimethyl acetal and the product (2-methoxyethoxy) acetaldehyde dimethyl acetal used in this embodiment are 1 H NMR characterization. At the chemical shift δ = 2.62 ppm, the raw material ethylene glycol methyl ether 1 The characteristic signal peak of hydroxyl proton is presented in the HNMR spectrum. However, in the product after the chemical reaction, the hydroxyl signal peak has disappeared, and a new triplet peak appears at δ=3.55ppm. In addition, the doublet peak of the raw material 2-chloroacetaldehyde dimethyl acetal at δ=3.51ppm no longer exists. This change is due to the fact that in the etherification reaction, 2-chloroacetaldehyde dimethyl acetal reacts with sodium alcohol to generate NaCl, which leads to the removal of chlorine atoms and the corresponding ethoxy peak is shown at the third position of the molecular structure of the product (2-methoxyethoxy) acetaldehyde dimethyl acetal. The disappearance of this hydroxyl signal and the appearance of the ethoxy peak prove the successful synthesis of 2-chloroacetaldehyde dimethyl acetal.

[0049] Example 2

[0050] The preparation of (2-methoxyethoxy)acetaldehyde dimethyl acetal is as follows:

[0051] 1) 117 g of 40 wt% 2-chloroacetaldehyde aqueous solution, 67.2 g of methanol, 36.8 g of cyclohexane and the catalyst MMT-AlCl 36.6 g was added into a 500 mL four-necked flask equipped with a magnetic stirrer, a thermometer, a packing column, a water separator and a condenser. Then, the system was heated to 50 °C for a pre-reaction for 1 h. Then, the temperature was raised to boiling, and the system temperature was gradually raised from 70 °C to 100 °C within 6 h. When the reaction system no longer separated water, the reaction was terminated and cooled to room temperature. The reaction solution was filtered to remove the catalyst MMT-AlCl 3 , the water-carrying cyclohexane and unreacted methanol were distilled off at normal pressure to obtain 56.6 g of product with a purity of 97.4% and a yield of 75.7%.

[0052] 2) 69.1g of ethylene glycol methyl ether, 23.6g of NaOH, 0.3771g of XY-02 and 37.0g of cyclohexane were added to a 500mL four-necked flask equipped with a magnetic stirrer, a thermometer, a packing column, a water separator and a condenser tube, and the temperature was raised to boiling. The system temperature was gradually heated from 70°C to 100°C within 4 hours. When the reaction system no longer separated water, 56.6g of 2-chloroacetaldehyde dimethyl acetal obtained in the first step was added dropwise, the reaction temperature was controlled to 100-110°C, and the reaction was cooled to room temperature after 5 hours. The crude product was filtered and the cyclohexane, ethylene glycol methyl ether and 2-chloroacetaldehyde dimethyl acetal in the crude product were recovered by atmospheric distillation to obtain 62.7g of the target product (2-methoxyethoxy) acetaldehyde dimethyl acetal, with a purity of 97.1% and a yield of 84.2%.

[0053] Example 3

[0054] The preparation of (2-propoxyethoxy)acetaldehyde dimethyl acetal is as follows:

[0055] 1) 117 g of 40 wt% 2-chloroacetaldehyde aqueous solution, 76.8 g of methanol, 85.0 g of cyclohexane and catalyst SO 4 2- / ZrO 2 7g was added into a 500mL four-necked flask equipped with a magnetic stirrer, a thermometer, a packing column, a water separator and a condenser, and the system was heated to 50°C for a pre-reaction of 0.5h; then the temperature was raised to boiling, and the system temperature was gradually raised from 70°C to 100°C within 6.5h. When the reaction system no longer separated water, the reaction was terminated and cooled to room temperature. The reaction solution was filtered to remove the catalyst SO 4 2- / ZrO 2 , the water-carrying cyclohexane and unreacted methanol were distilled off at normal pressure to obtain 45.5 g of product with a purity of 97.8% and a yield of 60.8%.

[0056] 2) 95.2 g of ethylene glycol propyl ether, 19 g of NaOH, 0.345 g of XY-02 and 51.0 g of cyclohexane were added to a 500 mL four-necked flask equipped with a magnetic stirrer, a thermometer, a packing column, a water separator and a condenser, and the temperature was raised to boiling. The system temperature was gradually heated from 70° C. to 100° C. within 5 h. When the reaction system no longer separated water, 45.5 g of 2-chloroacetaldehyde dimethyl acetal obtained in the first step was added dropwise, the reaction temperature was controlled at 100-110° C., and the reaction was cooled to room temperature after 3 h. The crude product was filtered to obtain a crude product, and the cyclohexane, ethylene glycol propyl ether and 2-chloroacetaldehyde dimethyl acetal in the crude product were recovered by atmospheric distillation to obtain 69.5 g of the target product (2-propoxyethoxy) acetaldehyde dimethyl acetal with a purity of 96.4% and a yield of 84.7%.

[0057] Example 4

[0058] The preparation of (2-methoxyethoxy)acetaldehyde dimethyl acetal is as follows:

[0059] 1) 117 g of 40 wt% 2-chloroacetaldehyde aqueous solution, 76.8 g of methanol, 60 g of cyclohexane and catalyst SO 4 2- / TiO 2 7g was added to a 500mL four-necked flask equipped with a magnetic stirrer, a thermometer, a packing column, a water separator and a condenser, and the system was heated to 50°C for a pre-reaction of 1.0h; then the temperature was raised to boiling, and the system temperature was gradually heated from 70°C to 100°C within 6.0h. When the reaction system no longer separated water, the reaction was terminated and cooled to room temperature. The reaction solution was filtered to remove the catalyst SO 4 2- / TiO 2 , distill off the water-carrying cyclohexane and unreacted methanol under normal pressure to obtain 48.1 g of product with a purity of 96.3% and a yield of 64.3%. 2)

[0060] 73.4 g of ethylene glycol methyl ether, 20.1 g of NaOH, 0.3645 g of XY-02 and 55 g of cyclohexane were added to a 500 mL four-necked flask equipped with a magnetic stirrer, a thermometer, a packing column, a water separator and a condenser, and the temperature was raised to boiling. The system temperature was gradually heated from 70° C. to 100° C. within 3 h. When the reaction system no longer separated water, 48.1 g of 2-chloroacetaldehyde dimethyl acetal obtained in the first step was added dropwise, the reaction temperature was controlled at 100-110° C., and the reaction was cooled to room temperature after 4 h. The crude product was filtered to obtain a crude product, and the cyclohexane, ethylene glycol methyl ether and 2-chloroacetaldehyde dimethyl acetal in the crude product were recovered by atmospheric distillation to obtain 54.6 g of the target product (2-methoxyethoxy) acetaldehyde dimethyl acetal with a purity of 95.7% and a yield of 86.3%.

[0061] Example 5

[0062] The preparation of (2-methoxyethoxy)acetaldehyde dimethyl acetal is as follows:

[0063] 1) 117 g of 40 wt% 2-chloroacetaldehyde aqueous solution, 67.2 g of methanol, 76 g of cyclohexane and catalyst HPW / TiO 2 6.6 g was added into a 500 mL four-necked flask equipped with a magnetic stirrer, a thermometer, a packing column, a water separator and a condenser, and the system was heated to 50 °C for a pre-reaction of 1.0 h; then the temperature was raised to boiling, and the system temperature was gradually heated from 70 °C to 100 °C within 5.0 h. When the reaction system no longer separated water, the reaction was terminated and cooled to room temperature; the reaction solution was filtered to remove the catalyst HPW / TiO 2 , the water-carrying cyclohexane and unreacted methanol were distilled off at normal pressure to obtain 43.3 g of product with a purity of 94.3% and a yield of 57.9%.

[0064] 2) 52.9 g of ethylene glycol methyl ether, 19.5 g of NaOH, 0.2886 g of XY-02 and 40 g of cyclohexane were added to a 500 mL four-necked flask equipped with a magnetic stirrer, a thermometer, a packing column, a water separator and a condenser, and the temperature was raised to boiling. The system temperature was gradually heated from 70° C. to 100° C. within 4 h. When the reaction system no longer separated water, 43.3 g of 2-chloroacetaldehyde dimethyl acetal obtained in the first step was added dropwise, the reaction temperature was controlled at 100-110° C., and the reaction was cooled to room temperature after 4 h. The crude product was filtered to obtain a crude product, and the cyclohexane, ethylene glycol methyl ether and 2-chloroacetaldehyde dimethyl acetal in the crude product were recovered by atmospheric distillation to obtain 48.2 g of the target product (2-methoxyethoxy) acetaldehyde dimethyl acetal with a purity of 92.7% and a yield of 84.6%.

[0065] Example 6

[0066] The preparation of (2-methoxyethoxy)acetaldehyde dimethyl acetal is as follows:

[0067] 1) 117 g of 40 wt% 2-chloroacetaldehyde aqueous solution, 67.2 g of methanol, 50 g of cyclohexane and catalyst HPW / ZrO 2 6.6 g was added into a 500 mL four-necked flask equipped with a magnetic stirrer, a thermometer, a packing column, a water separator and a condenser, and the system was heated to 50 °C for a pre-reaction of 1.0 h; then the temperature was raised to boiling, and the system temperature was gradually heated from 70 °C to 100 °C within 5.0 h. When the reaction system no longer separated water, the reaction was terminated and cooled to room temperature; the reaction solution was filtered to remove the catalyst HPW / ZrO 2 , the water-carrying cyclohexane and unreacted methanol were distilled off at normal pressure to obtain 43 g of product with a purity of 94.6% and a yield of 57.5%.

[0068] 2) 52.5 g of ethylene glycol methyl ether, 19.3 g of NaOH, 0.2865 g of XY-02 and 40 g of petroleum ether (bp 60-90° C.) were added to a 500 mL four-necked flask equipped with a magnetic stirrer, a thermometer, a packing column, a water separator and a condenser, and the temperature was raised to boiling. The system temperature was gradually heated from 70° C. to 100° C. within 5 h, and 43 g of 2-chloroacetaldehyde dimethyl acetal obtained in the first step was added dropwise. The reaction temperature was controlled at 100-110° C., and the reaction was cooled to room temperature after 4 h. The crude product was filtered to obtain a crude product, and the petroleum ether, ethylene glycol methyl ether and 2-chloroacetaldehyde dimethyl acetal in the crude product were recovered by atmospheric distillation to obtain 47.6 g of the target product (2-methoxyethoxy) acetaldehyde dimethyl acetal with a purity of 94.2% and a yield of 84.2%.

[0069] The above embodiments are merely illustrative of the principles and effects of the present invention, and are not intended to limit the present invention. Anyone familiar with the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by a person of ordinary skill in the art without departing from the spirit and technical concept disclosed by the present invention shall still be covered by the claims of the present invention.

Claims

1. A method for preparing (2-alkoxyethoxy)acetaldehyde di-lower alkanol acetal, comprising the following steps: 1) subjecting halogenated acetaldehyde and low-carbon alcohol to acetalization reaction in the presence of a solid acid catalyst to obtain halogenated acetaldehyde di-low-carbon alkanol acetal; 2) subjecting halogenated acetaldehyde di-lower alkanol acetal and ethylene glycol monoalkyl ether to Williamson etherification reaction in the presence of alkali metal hydroxide to obtain (2-alkoxyethoxy) acetaldehyde di-lower alkanol acetal.

2. The method for preparing (2-alkoxyethoxy)acetaldehyde di-lower alkanol acetal according to claim 1, characterized in that: A water-carrying agent is also added to the reaction in step 2), and the etherification reaction includes: 2-1) Ethylene glycol monoalkyl ether and alkali metal hydroxide are mixed and reacted under the action of a quaternary ammonium salt phase transfer catalyst until no water is produced during the reaction; 2-2) halogenated acetaldehyde di-lower alkanol acetal is added to step 2-1) to react, and then post-treated to obtain (2-alkoxyethoxy) acetaldehyde di-lower alkanol acetal.

3. The method for preparing (2-alkoxyethoxy)acetaldehyde di-lower alkanol acetal according to claim 1, characterized in that: In step 1), a water-carrying agent is also added during the reaction; And / or, the low-carbon alcohol is a C1-C4 alcohol; And / or, the alkyl group in the ethylene glycol monoalkyl ether is a C1-C6 alkyl group.

4. The method for preparing (2-alkoxyethoxy)acetaldehyde di-lower alkanol acetal according to claim 2 or 3, characterized in that: The water-carrying agent is selected from at least one of cyclohexane, toluene or petroleum ether; In step 1) or step 2), the amount of the water-carrying agent is 10 to 60% of the mass of the raw materials in the corresponding reaction system; And / or, the amount of the solid acid catalyst used is 0.3-8% of the total mass of the halogenated acetaldehyde and the low-carbon alcohol.

5. The method for preparing (2-alkoxyethoxy)acetaldehyde di-lower alkanol acetal according to claim 2, characterized in that: In step 1), the reaction temperature of the acetal reaction is 45 to 100° C., and the reaction time is 1 to 8 hours; And / or, in step 2-1), the reaction temperature is 70-100°C; in step 2-2), the reaction temperature is 90-110°C, and the reaction time is 3-5h.

6. The method for preparing (2-alkoxyethoxy)acetaldehyde di-lower alkanol acetal according to claim 5, characterized in that: The acetal reaction comprises: 1-1) pre-reacting the acetal reaction system at 45-55° C. for 0.5-1 h; 1-2) conducting an azeotropic reaction for 0.5-7 h, and when no water is produced during the reaction, lowering the reaction temperature to 20-40° C. to stop the reaction, and obtaining the halogenated acetaldehyde di-lower carbon alcohol through post-treatment.

7. The method for preparing (2-alkoxyethoxy)acetaldehyde di-lower alkanol acetal according to claim 1, characterized in that: The solid acid catalyst is selected from AlCl3 modified montmorillonite, FeCl3 modified montmorillonite, SO4 2- / M x O y At least one of a solid superacid, a heteropolyacid solid acid, a metal oxide solid acid or a supported ionic liquid.

8. The method for preparing (2-alkoxyethoxy)acetaldehyde di-lower alkanol acetal according to claim 1, characterized in that: In step 1), the molar ratio of halogenated acetaldehyde to low-carbon alcohol is 1:(2-4).

9. The method for preparing (2-alkoxyethoxy)acetaldehyde di-lower alkanol acetal according to claim 1, characterized in that: In step 2), the molar ratio of alkali metal hydroxide, ethylene glycol monoalkyl ether and halogenated acetaldehyde di-lower alkanol acetal is (1-1.5):(1-3):

1.

10. The method for preparing (2-alkoxyethoxy)acetaldehyde di-lower alkanol acetal according to claim 1, characterized in that: The low-carbon alcohol is selected from one of methanol, ethanol, isopropanol or butanol; And / or, the ethylene glycol monoalkyl ether is selected from one of ethylene glycol methyl ether, ethylene glycol ethyl ether, ethylene glycol propyl ether, ethylene glycol isopropyl ether, ethylene glycol butyl ether or ethylene glycol hexyl ether; And / or, the halogenated acetaldehyde is 2-bromoacetaldehyde or 2-chloroacetaldehyde; And / or, the alkali metal hydroxide is selected from at least one of sodium hydroxide, potassium hydroxide or lithium hydroxide.

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