Preparation method of 3-ethyoxyl salicylaldehyde

Abstract

The invention belongs to the technical field of intermediate synthesis, and particularly relates to a preparation method of 3-ethyoxyl salicylaldehyde. Comprising the following steps: subjecting o-ethoxyphenol, triethylamine and magnesium chloride to a substitution reaction so as to form a complex ITM1; paraformaldehyde is added into the complex ITM1 for an electrophilic reaction, and a complex ITM2 is formed; adding magnesium chloride and paraformaldehyde into the complex ITM2, promoting the electrophilic reaction to be complete, sequentially adding a quenching agent and an extracting agent after the reaction is finished, and carrying out vacuum concentration on an organic phase to obtain a 3-ethyoxyl salicylaldehyde crude product; and carrying out vacuum distillation and recrystallization on the 3-ethyoxyl salicylaldehyde crude product to obtain the 3-ethyoxyl salicylaldehyde. The preparation method of the 3-ethyoxyl salicylaldehyde is simple to operate, mild in reaction condition and simple in post-treatment, avoids a large amount of organic waste liquid and alkaline waste liquid, is green and environment-friendly in technological process, and is suitable for industrial production, and the obtained product is optimal in quality.

Description

Technical Field

[0001] The present invention belongs to the technical field of intermediate synthesis, and particularly relates to a preparation method of 3-ethoxysalicylaldehyde. Background Art

[0002] 3-Ethoxysalicylaldehyde, also known as 3-ethoxy-4-hydroxybenzaldehyde, is an organic compound. Its molecular formula is C9H 10 O3, and its structure contains an ethoxy group and a hydroxyl group. 3-Ethoxysalicylaldehyde has various uses in the chemical and pharmaceutical fields, including: (1) being used as an important intermediate in organic synthesis and can be used to synthesize other compounds; (2) serving as a structural unit of drug molecules and can be used to synthesize certain drugs; (3) during the organic synthesis process, it can be used to introduce ethoxy and hydroxyl pharmacodynamic functional groups.

[0003] At the same time, 3-ethoxysalicylaldehyde is also called o-ethylvanillin. Ethylvanillin has gradually become a substitute for vanillin because its taste and smell are about 3-4 times that of vanillin. 3-Ethoxysalicylaldehyde often appears as a by-product during the production process of ethylvanillin. Usually, during the separation and purification process of ethylvanillin, 3-ethoxysalicylaldehyde is discarded. In recent years, it has been found that 3-ethoxysalicylaldehyde has potential application prospects in optical utilization, biology, catalysis, corrosion inhibition, etc.

[0004] Currently, the main methods for synthesizing 3-ethoxysalicylaldehyde are as follows: (1)

[0006]

[0007] Using acetonitrile as a solvent, after reacting o-ethoxyphenol with triethylamine for a period of time, formaldehyde is added thereto, and the reaction is carried out in an inert atmosphere to generate the target product. (2)

[0009]

[0010] Using LiAlH4 as a reducing agent, the corresponding amide is reduced to the target product in an inert atmosphere. (3)

[0012]

[0013] Using o-ethoxyphenol and chloroform as reaction raw materials, the target product is generated under the action of a base.

[0014] In the above reaction paths, there are more or less some limiting factors, such as relatively harsh reaction conditions, low yield of the target product, low product purity, resulting in difficulty in separating and purifying the target compound. Summary of the Invention

[0015] The present invention provides a preparation method of 3-ethoxysalicylaldehyde. o-Ethoxyphenol forms a complex under the action of triethylamine and magnesium chloride, and paraformaldehyde is added to obtain the crude product of 3-ethoxysalicylaldehyde. After that, rectification and recrystallization are carried out for purification, and finally the pure product of 3-ethoxysalicylaldehyde is obtained. The operation is simple, the reaction conditions are mild, the post-treatment is simple, and a large amount of organic waste liquid and alkaline waste liquid are avoided. The process is green and environmentally friendly, the product quality is optimal, it is suitable for industrial production, and it has a very wide application prospect in the field of pharmaceutical and chemical industry.

[0016] The present invention solves the above technical problems through the following technical solutions.

[0017] The present invention provides a preparation method of 3-ethoxysalicylaldehyde, which comprises the following steps:

[0018] o-Ethoxyphenol SM, triethylamine and magnesium chloride undergo a substitution reaction under a reaction solvent to form a complex ITM1;

[0019] Paraformaldehyde is added to the complex ITM1 to undergo an electrophilic reaction to form a complex ITM2;

[0020] Magnesium chloride and paraformaldehyde are added to the complex ITM2 to promote the complete electrophilic reaction. After the reaction is completed, a quenching agent and an extracting agent are added in sequence, and the organic phase is concentrated under reduced pressure to obtain the crude product CP of 3-ethoxysalicylaldehyde;

[0021] The crude product of 3-ethoxysalicylaldehyde is subjected to vacuum rectification and recrystallization to obtain 3-ethoxysalicylaldehyde TM;

[0022] The reaction process is as follows:

[0023]

[0024] Furthermore, in the process of preparing the complex ITM1, the molar ratio of o-ethoxyphenol, triethylamine and magnesium chloride is 1:4.0 - 5.0:1.0 - 1.5.

[0025] Furthermore, in the process of preparing the complex ITM2, the molar ratio of o-ethoxyphenol and paraformaldehyde is 1:1.0 - 1.5.

[0026] Furthermore, in the process of preparing the crude product of 3-ethoxysalicylaldehyde, the molar ratio of o-ethoxyphenol, magnesium chloride and paraformaldehyde is 1:2.0 - 3.0:2.0 - 3.0.

[0027] Furthermore, in the process of preparing the complex ITM1, the substitution reaction temperature is 70°C - 90°C.

[0028] Furthermore, during the preparation of the complex ITM2, the temperature of the electrophilic reaction is 70°C - 90°C.

[0029] Furthermore, the mass-to-volume ratio of the o-ethoxyphenol to the reaction solvent is 1 g:10 ml, and the reaction solvent is acetonitrile.

[0030] Furthermore, during the preparation of the crude 3-ethoxysalicylaldehyde, the quenching agent is a 6 - 12 mol / L hydrochloric acid solution, and the extractant is ethyl acetate.

[0031] Furthermore, the mass-to-volume ratio of the o-ethoxyphenol to the extractant is 1 g:15 ml.

[0032] Furthermore, during the vacuum distillation, the crude 3-ethoxysalicylaldehyde is formulated into an ethanol aqueous solution with a concentration of 40 - 60%, and the residual ethyl acetate is removed by distillation at 70°C - 80°C, and then the temperature is raised to 150°C - 160°C for continuous distillation.

[0033] Furthermore, the recrystallization temperature is 70°C - 80°C, and the crystallization temperature is 35°C - 45°C.

[0034] The present invention has the following beneficial effects compared with the prior art:

[0035] 1. The preparation method of 3-ethoxysalicylaldehyde in the present invention is simple in operation, mild in reaction conditions, simple in post-treatment, and avoids a large amount of organic waste liquid and alkaline waste liquid. The process is green and environmentally friendly, the product quality is optimal, suitable for industrial production and popularization, and has a very wide application prospect in the field of pharmaceutical chemistry.

[0036] 2. The preparation method of 3-ethoxysalicylaldehyde in the present invention can stably obtain the target product with a purity of more than 99%. The product with a higher purity is obtained through simple steps, which is cheap, efficient, and has high economic benefits.

[0037] 3. The preparation method of 3-ethoxysalicylaldehyde in the present invention is a brand-new synthetic route and a brand-new post-treatment method, which has the advantages of controllable reaction, simple operation, low requirements for equipment, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 It is the high-performance liquid chromatography spectrum of the 3-ethoxysalicylaldehyde prepared in Example 1 of the present invention.

[0039] Figure 2 It is the high-performance liquid chromatography spectrum of the 3-ethoxysalicylaldehyde prepared in Example 2 of the present invention.

[0040] Figure 3 It is the nuclear magnetic spectrum of the 3-ethoxysalicylaldehyde prepared in Example 2 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0041] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0042] It should be noted that the professional terms used in the present invention are only for the purpose of describing specific embodiments, and are not intended to limit the protection scope of the present invention. Unless otherwise specifically stated, various raw materials, reagents, instruments and equipment used in the following embodiments of the present invention can be obtained through market purchase or prepared by existing methods.

[0043] The present invention provides a method for preparing 3-ethoxysalicylaldehyde, comprising the following steps:

[0044] S1. Substitution reaction occurs among o-ethoxyphenol SM, triethylamine and magnesium chloride in a system of solvent acetonitrile (ACN) to form complex ITM1. Since there is a temperature rise when o-ethoxyphenol, triethylamine and magnesium chloride are added to acetonitrile in sequence, the following method can be used to mix o-ethoxyphenol with triethylamine and magnesium chloride: First, add solvent acetonitrile to the reaction vessel, then add o-ethoxyphenol, then add triethylamine, and then add magnesium chloride to the reaction kettle at 30°C.

[0045] S2. An electrophilic reaction occurs by adding paraformaldehyde to complex ITM1 to form complex ITM2. Paraformaldehyde is solid formaldehyde with a high formaldehyde content, in the form of solid particles, which is convenient for storage and transportation and can become formaldehyde vapor at a relatively high temperature. By replacing formaldehyde with paraformaldehyde, the defects of large toxicity of formaldehyde and harm to the human body are overcome.

[0046] Complex ITM1 contains magnesium ions. The interaction between paraformaldehyde and magnesium ions in the complex enhances the positive charge of the carbonyl group in paraformaldehyde, thereby causing an electrophilic reaction to generate ITM2 ((2-ethoxyphenyl)benzylmagnesium oxychloride).

[0047] When paraformaldehyde is added to complex ITM1, the temperature of the complex will rise. In order to avoid the occurrence of other side reactions, paraformaldehyde is added to the complex in batches.

[0048] S3. Add magnesium chloride and paraformaldehyde to complex ITM2 to promote the completion of the electrophilic reaction. After the reaction is completed, a quenching agent and an extractant are added in sequence, and the organic phase is concentrated under reduced pressure to obtain the crude product CP of 3-ethoxysalicylaldehyde.

[0049] To maintain the reaction activity and ensure the completion of the reaction, magnesium chloride and paraformaldehyde are continuously added to complex ITM2; after the reaction is completed, a quenching agent such as hydrochloric acid solution is added to adjust the pH to pH≈2; the quenching reaction is to reduce the occurrence of by-products; then an extractant such as ethyl acetate is added, the organic phase and the aqueous phase are separated, and the organic phase is collected to obtain an ethyl acetate solution of 3-ethoxysalicylaldehyde.

[0050] S4. The crude 3-ethoxysalicylaldehyde is subjected to vacuum distillation and recrystallization to obtain 3-ethoxysalicylaldehyde TM;

[0051] The crude 3-ethoxysalicylaldehyde is subjected to vacuum distillation. The fore fraction (residual ethyl acetate) is removed by distillation at 70 °C - 80 °C, and the temperature is raised to 150 °C - 160 °C for continued distillation, and then transferred to another reaction kettle.

[0052] Ethanol solution is added to the reaction kettle for recrystallization. The recrystallization temperature is 70 °C - 80 °C, and the temperature for cooling and crystal precipitation is 35 °C - 45 °C. After filtration, pure 3-ethoxysalicylaldehyde (TM) is obtained.

[0053] The reaction process is as follows:

[0054]

[0055] During the reaction process, compound SM is o-ethoxyphenol, complex ITM1 is 2-ethoxyphenol magnesium chloride, complex ITM2 is (2-ethoxyphenyl) benzyl oxymagnesium chloride, and compound TM is 3-ethoxysalicylaldehyde.

[0056] The reaction mechanism of 3-ethoxysalicylaldehyde is as follows:

[0057]

[0058] In step step1, compound SM o-ethoxyphenol forms complex ITM1 under the action of triethylamine and magnesium chloride, and the complex contains magnesium ions; in step step2, paraformaldehyde acts on the magnesium ions in the complex, making the carbon positive charge of paraformaldehyde enhanced, and thus an electrophilic reaction occurs to generate complex ITM2; in step step3, magnesium chloride and paraformaldehyde are continuously added to promote the completion of the reaction, and then a quenching agent is added to quench the reaction to avoid the occurrence of side reactions. Then an extractant is added, the organic phase and the aqueous phase are separated, and the crude 3-ethoxysalicylaldehyde is in the organic phase. At this time, the organic phase is concentrated to obtain the crude 3-ethoxysalicylaldehyde in the liquid state; when the crude 3-ethoxysalicylaldehyde in the liquid state is obtained by concentrating the organic phase, in step4, the crude 3-ethoxysalicylaldehyde needs to be rectified, and the main fraction obtained is recrystallized with an ethanol aqueous solution to obtain high-purity pure 3-ethoxysalicylaldehyde.

[0059] The preparation method of 3-ethoxysalicylaldehyde in the present invention is simple in operation, mild in reaction conditions, simple in post-treatment, and avoids a large amount of organic waste liquid and alkaline waste liquid. The target product with a purity of over 99% can be stably obtained. A product with a relatively high purity is obtained through simple steps, which is inexpensive, efficient, and has high economic benefits. The process is green and environmentally friendly, the product quality is optimal, suitable for industrial production, and suitable for promotion, and has a very wide application prospect in the field of pharmaceutical chemistry. The preparation method of 3-ethoxysalicylaldehyde in the present invention is a brand-new synthesis route and a brand-new post-treatment method, with the advantages of controllable reaction, simple operation, low requirements for equipment, and being suitable for industrial production.

[0060] In a specific embodiment, during the preparation of complex ITM1, the molar ratio of o-ethoxyphenol, triethylamine, and magnesium chloride is 1:4.0 - 5.0:3.0 - 4.0. In the present invention, as a preferred technical solution of the present invention, the molar ratio of o-ethoxyphenol, triethylamine, and magnesium chloride can be any specific ratio between 1:4.0 - 5.0:1.0 - 1.5, such as 1:4:1.0, 1:5:1.5, or 1:5:1.0, etc., but is not limited to the listed values. Other unlisted values within the above numerical range are equally applicable and will not be elaborated one by one here.

[0061] In a specific embodiment, during the preparation of complex ITM1, the reaction solvent is acetonitrile, and the mass-volume ratio of compound SM to the reaction solvent is 1 g:10 ml.

[0062] In a specific embodiment, during the preparation of complex ITM2, the molar ratio of o-ethoxyphenol and paraformaldehyde is 1:1.0 - 1.5. In the present invention, as a preferred technical solution of the present invention, the molar ratio of o-ethoxyphenol and paraformaldehyde can be any specific ratio between 1:1.0 - 1.5, such as 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5, etc., but is not limited to the listed values. Other unlisted values within the above numerical range are equally applicable and will not be elaborated one by one here.

[0063] In a specific embodiment, during the preparation of the crude 3-ethoxysalicylaldehyde, the molar ratio of o-ethoxyphenol, magnesium chloride, and paraformaldehyde is 1:2.0 - 3.0:2.0 - 3.0. In the present invention, as a preferred technical solution of the present invention, the molar ratio of o-ethoxyphenol, magnesium chloride, and paraformaldehyde can be any specific ratio between 1:2.0 - 3.0:2.0 - 3.0, such as 1:3:3, 1:2:3, 1:3:2, or 1:2:2, etc., but is not limited to the listed values. Other unlisted values within the above numerical range are equally applicable and will not be elaborated one by one here.

[0064] In a specific embodiment, during the preparation of complex ITM1, the substitution reaction temperature is 70°C - 90°C, and the reaction time is 1.0 h. In the present invention, as a preferred technical solution of the present invention, the substitution reaction temperature can be any specific value between 70°C and 90°C, such as 70°C, 80°C, or 90°C, etc., but is not limited to the listed values. Other unlisted values within the above numerical range are equally applicable and will not be elaborated one by one here.

[0065] In a specific embodiment, during the preparation of complex ITM2, the electrophilic reaction temperature is 70°C - 90°C, and the reaction time is 1.0 h. In the present invention, as a preferred technical solution of the present invention, the substitution reaction temperature can be any specific value between 70°C and 90°C, such as 70°C, 80°C, or 90°C, etc., but is not limited to the listed values. Other unlisted values within the above numerical range are equally applicable and will not be elaborated one by one here.

[0066] In a specific embodiment, during the preparation of crude 3-ethoxysalicylaldehyde, the temperature for promoting the completion of the electrophilic reaction is 70°C - 90°C, and the reaction time is 1.0 - 2.0 h. In the present invention, as a preferred technical solution of the present invention, the temperature for promoting the completion of the electrophilic reaction can be any specific value between 70°C and 90°C, such as 70°C, 80°C, or 90°C, etc., and the reaction time can be any specific value between 1.0 - 2.0 h, such as 1 h, 1.5 h, or 2 h, etc., but is not limited to the listed values. Other unlisted values within the above numerical range are equally applicable and will not be elaborated one by one here.

[0067] In a specific embodiment, during the preparation of crude 3-ethoxysalicylaldehyde, the quenching agent is a 6 - 12 mol / L hydrochloric acid solution, and the extraction agent is ethyl acetate. In the present invention, as a preferred technical solution of the present invention, the quenching reaction is to reduce the occurrence of by-products. The quenching agent can be any specific value between 6 - 12 mol / L hydrochloric acid solution, such as 6 mol / L, 8 mol / L, 10 mol / L, or 12 mol / L, etc., but is not limited to the listed values. Other unlisted values within the above numerical range are equally applicable and will not be elaborated one by one here.

[0068] In a specific embodiment, the mass-volume ratio of the o-ethoxyphenol to the extraction agent is 1 g:15 ml. The role of the extraction agent is to separate the crude 3-ethoxysalicylaldehyde CP from the mixed solution to obtain an ethyl acetate solution of 3-ethoxysalicylaldehyde, and then the organic phase is concentrated under reduced pressure to obtain the crude 3-ethoxysalicylaldehyde.

[0069] In a specific embodiment, during the vacuum distillation process, the crude 3-ethoxysalicylaldehyde is formulated into an ethanol aqueous solution with a concentration of 40%-60%, and the residual ethyl acetate is removed by distillation at 70°C - 80°C, and then the temperature is raised to 150°C - 160°C for continuous distillation. In the present invention, as a preferred technical solution of the present invention, the temperature for distilling and removing the residual ethyl acetate can be any specific value between 70°C and 80°C, such as 70°C, 72°C, 74°C, 76°C, 78°C or 80°C, etc., and the temperature for raising the temperature and continuing distillation can be any specific value between 150°C and 160°C, such as 150°C, 152°C, 154°C, 156°C, 158°C or 160°C, etc., but it is not limited to the listed values, and other unlisted values within the above numerical range are equally applicable, and will not be elaborated one by one here.

[0070] The preparation method of 3-ethoxysalicylaldehyde provided by the present invention is a brand-new synthesis route and a brand-new post-treatment method, which has the advantages of controllable reaction, simple operation, low requirements for equipment, and is suitable for industrial production.

[0071] The following is further illustrated by specific examples.

[0072] Example 1

[0073] A preparation method of 3-ethoxysalicylaldehyde comprises the following steps:

[0074] S1. Add 500 mL of acetonitrile to a dry and clean reaction flask, add 50.00 g of o-ethoxyphenol (1.0 eq), start stirring, then add 146.47 g of triethylamine (4.0 eq), control the temperature below 30°C, and slowly add 34.45 g of magnesium chloride (1 eq). A large amount of solid precipitates, and the temperature is raised to 80°C to undergo a substitution reaction to form the complex ITM1;

[0075] S2. Add 32.60 g of paraformaldehyde (1 eq) to the complex ITM1, and carry out an electrophilic reaction at 80°C for 1 h to form the complex ITM2; the complex ITM1 contains magnesium ions, and the paraformaldehyde acts on the magnesium ions in the complex, making the carbonyl positive charge of the paraformaldehyde stronger, so as to undergo an electrophilic reaction to generate ITM2 ((2-ethoxyphenyl)benzyl oxymagnesium chloride); when adding paraformaldehyde to the complex ITM1, the temperature of the complex will rise. In order to avoid the occurrence of other side reactions, the paraformaldehyde is added to the complex in batches;

[0076] S3. Add 103.37 g of magnesium chloride (3 eq) and 97.79 g of paraformaldehyde (3 eq) to the complex ITM2, promote the electrophilic reaction at 80 °C for 2 h. After the reaction is completed, cool to room temperature, slowly add 30 g of water, and a large amount of solid dissolves. Adjust the pH to 2 with 6 mol / L hydrochloric acid. After quenching is completed, add 250 mL of ethyl acetate for extraction, stir for 0.5 h, let it stand for liquid separation, separate the liquid, and concentrate the organic phase under reduced pressure to obtain an oily substance, which is the crude product of 3-ethoxysalicylaldehyde;

[0077] S4. Subject the oily substance (crude product of 3-ethoxysalicylaldehyde) to vacuum distillation. The external temperature is about 120 °C, and the fraction temperature is about 80 °C. Remove the fore fraction, raise the temperature and continue distillation. The external temperature is 180 °C, and the fraction temperature is 100 °C. When the distillation is basically completed, continue to raise the temperature and no product is distilled out. Add anhydrous ethanol (150 g) and water (150 g) to the distilled product, raise the temperature to 80 °C until it dissolves clearly, and slowly cool to 45 °C. A large amount of light yellow solid precipitates. Filter to obtain a yellow needle-like solid product (40.77 g, HPLC purity 99.616%, yield 67.8%), which is 3-ethoxysalicylaldehyde. The high-performance liquid chromatogram is as Figure 1 shown.

[0078] Example 2

[0079] A preparation method of 3-ethoxysalicylaldehyde, comprising the following steps:

[0080] S1. Add 200 kg of acetonitrile to a dry and clean reaction flask, add 25 kg of o-ethoxyphenol (1.0 eq), start stirring, then add 73.24 g of triethylamine (4.0 eq), control the temperature below 30 °C, and slowly add 17.23 kg of magnesium chloride (1 eq). A large amount of solid precipitates, and the temperature is raised to 80 °C to carry out a substitution reaction to form the complex ITM1;

[0081] S2. Add 16.30 kg of paraformaldehyde (1 eq) to the complex ITM1, and carry out an electrophilic reaction at 80 °C for 1 h to form the complex ITM2; the complex ITM1 contains magnesium ions, and paraformaldehyde acts on the magnesium ions in the complex, making the carbonyl positive charge of paraformaldehyde stronger, thus an electrophilic reaction occurs to generate ITM2 ((2-ethoxyphenyl)benzyl oxymagnesium chloride); when paraformaldehyde is added to the complex ITM1, the temperature of the complex will increase. In order to avoid the occurrence of other side reactions, paraformaldehyde is added to the complex in batches;

[0082] S3. Add 34.45 kg of magnesium chloride (2 eq) and 32.60 kg of paraformaldehyde (2 eq) to the complex ITM2, promote the electrophilic reaction at 80 °C for 2 h. After the reaction is completed, cool it to room temperature, slowly add 150 kg of water, and a large amount of solid dissolves. Adjust the pH to 2 with 6 mol / L hydrochloric acid; after quenching, add 112.75 kg of ethyl acetate for extraction, stir for 0.5 h, let it stand for layer separation, separate the liquid, and concentrate the organic phase under reduced pressure to obtain an oily substance, which is the crude product of 3-ethoxysalicylaldehyde;

[0083] S4. Subject the oily substance (crude product of 3-ethoxysalicylaldehyde) to vacuum rectification. The external temperature is about 120 °C, and the fraction temperature is about 80 °C. Remove the fore fraction, raise the temperature and continue distillation. The external temperature is 180 °C, and the fraction temperature is 100 °C. When the distillation is basically completed, continue to raise the temperature and no product is distilled out. Add anhydrous ethanol (29.59 kg) and water (37.5 kg) to the distilled product, raise the temperature to 80 °C until it is dissolved clearly, and slowly cool it to 45 °C. A large amount of light yellow solid precipitates. Filter to obtain a yellow needle-like solid product (20.45 kg, HPLC purity 99.933%, yield 68%), which is 3-ethoxysalicylaldehyde. The high-performance liquid chromatogram is as Figure 2 shown; the nuclear magnetic spectrum is as Figure 3 shown, 1 HNMR(CDCl3,400MHz)δ: 11.059(s,1H,CHO), 9.919(d,1H,OH), 7.189~7.167(m,1H,PhH), 7.125~7.106(d,1H,PhH), 6.967~6.927(m,1H,PhH), 4.160~4.108(q,2H,CH2) 1.503~1.468(t,3H,CH3).

[0084] Example 3

[0085] A preparation method of 3-ethoxysalicylaldehyde, comprising the following steps:

[0086] S1. Add 500 mL of acetonitrile to a dry and clean reaction flask, add 50.00 g of o-ethoxyphenol (1.0 eq), start stirring, then add 146.47 g of triethylamine (4.0 eq), control the temperature below 30 °C, and slowly add 34.45 g of magnesium chloride (1 eq). A large amount of solid precipitates. Raise the temperature to 80 °C to undergo a substitution reaction to form the complex ITM1;

[0087] S2. Add 32.60 g of paraformaldehyde (1 eq) to the complex ITM1, and carry out an electrophilic reaction at 80 °C for 1 h to form the complex ITM2. The complex ITM1 contains magnesium ions. The paraformaldehyde reacts with the magnesium ions in the complex, enhancing the positive charge of the carbonyl group in the paraformaldehyde, thereby causing an electrophilic reaction to generate ITM2 ((2-ethoxyphenyl)benzylmagnesium oxychloride). When adding paraformaldehyde to the complex ITM1, the temperature of the complex will increase. To avoid the occurrence of other side reactions, the paraformaldehyde is added to the complex in batches.

[0088] S3. Add 68.91 g of magnesium chloride (2 eq) and 62.53 g of paraformaldehyde (2 eq) to the complex ITM2, promote the electrophilic reaction at 80 °C for 2 h. After the reaction is completed, cool to room temperature, slowly add 30 g of water, and a large amount of solid dissolves. Adjust the pH to 1 - 2 with 6 mol / L hydrochloric acid. After quenching, add 250 mL of ethyl acetate for extraction, stir for 0.5 h, let it stand for layer separation, separate the liquid, and concentrate the organic phase under reduced pressure to obtain an oily substance, which is the crude product of 3-ethoxysalicylaldehyde.

[0089] S4. Carry out vacuum distillation on the oily substance (crude product of 3-ethoxysalicylaldehyde). The external temperature is about 120 °C, and the distillate temperature is about 70 - 80 °C. Remove the fore-fraction, raise the temperature and continue distillation. The external temperature is 180 °C, and the distillate temperature is 100 °C. When the distillation is basically completed, continue to raise the temperature and no product is distilled out. Add anhydrous ethanol (150 g) and water (150 kg) to the distilled product, heat to 70 °C until it is clear, and slowly cool to 35 - 45 °C. A large amount of light yellow solid precipitates. Filter to obtain a yellow needle-like solid product, which is 3-ethoxysalicylaldehyde.

[0090] Example 4

[0091] A preparation method of 3-ethoxysalicylaldehyde, comprising the following steps:

[0092] S1. Add 500 mL of acetonitrile to a dry and clean reaction flask, add 50.00 g of o-ethoxyphenol (1.0 eq), start stirring, then add 183.09 g of triethylamine (5.0 eq), control the temperature below 30 °C, and slowly add 51.67 g of magnesium chloride (1.5 eq). A large amount of solid precipitates. Raise the temperature to 80 °C to carry out a substitution reaction to form the complex ITM1.

[0093] S2. Add 48.90 g of paraformaldehyde (1.5 eq) to the complex ITM1, and carry out an electrophilic reaction at 80 °C for 1 h to form the complex ITM2. The complex ITM1 contains magnesium ions. The paraformaldehyde acts on the magnesium ions in the complex, enhancing the positive charge of the carbonyl group in the paraformaldehyde, thereby causing an electrophilic reaction to generate ITM2 ((2-ethoxyphenyl)benzylmagnesium oxychloride). When adding paraformaldehyde to the complex ITM1, the temperature of the complex will increase. To avoid the occurrence of other side reactions, the paraformaldehyde is added to the complex in batches.

[0094] S3. Add 103.37 g of magnesium chloride (3 eq) and 97.79 g of paraformaldehyde (3 eq) to the complex ITM2, promote the electrophilic reaction at 80 °C for 2 h. After the reaction is completed, cool to room temperature, slowly add 30 g of water, a large amount of solid dissolves, and adjust the pH to 1 - 2 with 12 mol / L hydrochloric acid. After quenching, add 250 mL of ethyl acetate for extraction, stir for 0.5 h, let it stand for liquid separation, separate the liquid, and concentrate the organic phase under reduced pressure to obtain an oily substance, which is the crude product of 3-ethoxysalicylaldehyde.

[0095] S4. Carry out vacuum distillation on the oily substance (crude product of 3-ethoxysalicylaldehyde). The external temperature is about 120 °C, and the distillate temperature is about 70 - 80 °C. Remove the fore-fraction, raise the temperature and continue distillation. The external temperature is 180 °C, and the distillate temperature is 100 °C. When the distillation is basically completed, continue to raise the temperature and no product is distilled out. Add anhydrous ethanol (150 g) and water (150 kg) to the distilled product, heat up to 70 - 80 °C to dissolve clearly, and slowly cool down to 35 - 45 °C. A large amount of light yellow solid precipitates, and filter to obtain a yellow needle-like solid product, which is 3-ethoxysalicylaldehyde.

[0096] Comparative Example 1

[0097] A preparation method of 3-ethoxysalicylaldehyde, comprising the following steps:

[0098] S1. Add 200 kg of acetonitrile to a dry and clean reaction flask, add 25 kg of o-ethoxyphenol (1.0 eq), start stirring, then add 73.24 g of triethylamine (4.0 eq), control the temperature below 30 °C, and slowly add 17.23 kg of magnesium chloride (1 eq). A large amount of solid precipitates, raise the temperature to 80 °C, and carry out a substitution reaction to form the complex ITM1.

[0099] S2. Add 16.30 kg of paraformaldehyde (1 eq) to the complex ITM1, and carry out an electrophilic reaction at 80 °C for 1 h to form the complex ITM2. The complex ITM1 contains magnesium ions. The paraformaldehyde reacts with the magnesium ions in the complex, enhancing the positive charge of the carbonyl group in the paraformaldehyde, thus causing an electrophilic reaction to generate ITM2 ((2-ethoxyphenyl)benzylmagnesium chloride). When adding paraformaldehyde to the complex ITM1, the temperature of the complex will increase. To avoid the occurrence of other side reactions, the paraformaldehyde is added to the complex in batches.

[0100] S3. Add 51.68 kg of magnesium chloride (3 eq) and 48.90 kg of paraformaldehyde (3 eq) to the complex ITM2, promote the electrophilic reaction at 80 °C for 2 h. After the reaction is completed, cool to room temperature, slowly add 150 kg of water, a large amount of solid dissolves, and adjust the pH to 2 with 6 mol / L hydrochloric acid. After quenching, add 112.75 kg of ethyl acetate for extraction, stir for 0.5 h, let it stand for liquid separation, separate the liquid, and concentrate the organic phase under reduced pressure to obtain an oily substance, which is the crude product of 3-ethoxysalicylaldehyde.

[0101] S4. Dissolve 74 kg (or 100 L) of methyl tert-butyl ether in the oily substance (some inorganic salts will precipitate out), add 100 kg (or 100 L) of water to dissolve, separate the liquid, adjust the pH of the organic phase to 9 - 10 with ammonia water (about 22.75 kg consumed), a large amount of yellow solid precipitates, and filter.

[0102] S5. Add 74 kg (or 100 L) of methyl tert-butyl ether to the solid, adjust the pH to 1 - 2 with 6 mol / L hydrochloric acid (about 17.7 kg consumed), separate the liquid, take the organic phase, add 12.5 kg of anhydrous sodium sulfate and 12.5 kg of activated carbon, stir at room temperature for 0.5 - 1 h, filter by suction, concentrate, obtain an oily substance, cool down to precipitate, and obtain 3.76 kg of yellow solid, which is 3-ethoxysalicylaldehyde, with a yield of 12.5%.

[0103] In summary, the preparation method of 3-ethoxysalicylaldehyde in the present invention has the advantages of simple operation, mild reaction conditions, simple post-treatment, and avoids a large amount of organic waste liquid and alkaline waste liquid. It can stably obtain a target product with a purity of over 99%. A product with a higher purity is obtained through simple steps, which is cheap, efficient, has high economic benefits, the process is green and environmentally friendly, the product quality is optimal, suitable for industrial production and promotion, and has a very wide application prospect in the field of pharmaceutical and chemical industry. The preparation method of 3-ethoxysalicylaldehyde in the present invention is a brand-new synthetic route and a brand-new post-treatment method, with the advantages of controllable reaction, simple operation, low requirements for equipment, and suitable for industrial production.

[0104] It should be noted that when the present invention involves numerical ranges, it should be understood that both endpoints of each numerical range and any value between the two endpoints can be selected. Since the step methods adopted are the same as those in the embodiments, in order to avoid redundancy, the present invention describes the preferred embodiments. Although the preferred embodiments of the present invention have been described, those skilled in the art can make additional changes and modifications to these embodiments once they know the basic creative concept. Therefore, the appended claims are intended to be construed as including the preferred embodiments and all changes and modifications falling within the scope of the present invention.

[0105] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention is also intended to include these modifications and variations.

Claims

1. A preparation method of 3-ethoxysalicylaldehyde, characterized in that, It includes the following steps: Substitution reaction occurs between o-ethoxyphenol, triethylamine and magnesium chloride in a reaction solvent to form complex ITM1; paraformaldehyde is added to complex ITM1 to carry out an electrophilic reaction to form complex ITM2; magnesium chloride and paraformaldehyde are added to complex ITM2 to promote the completion of the electrophilic reaction, and 3-ethoxysalicylaldehyde is obtained after the reaction ends. The reaction process is as follows:

2. The preparation method of 3-ethoxysalicylaldehyde according to claim 1, wherein, During the preparation of complex ITM1, the molar ratio of o-ethoxyphenol, triethylamine and magnesium chloride is 1:4.0 - 5.0:1.0 - 1.

5.

3. The preparation method of 3-ethoxysalicylaldehyde according to claim 1, characterized in that, During the preparation of complex ITM2, the molar ratio of o-ethoxyphenol and paraformaldehyde is 1:1.0 - 1.

5.

4. The preparation method of 3-ethoxysalicylaldehyde according to claim 1, characterized in that, During the process of promoting the completion of the electrophilic reaction, the molar ratio of o-ethoxyphenol, magnesium chloride and paraformaldehyde is 1:2.0 - 3.0:2.0 - 3.

0.

5. The preparation method of 3-ethoxysalicylaldehyde according to claim 1, characterized in that, The mass-volume ratio of o-ethoxyphenol to the reaction solvent is 1g:10ml, and the reaction solvent is acetonitrile.

6. The preparation method of 3-ethoxysalicylaldehyde according to claim 1, wherein, During the preparation of complex ITM1, the substitution reaction temperature is 70°C - 90°C.

7. The preparation method of 3-ethoxysalicylaldehyde according to claim 1, characterized in that, During the preparation of complex ITM2, the temperature of the electrophilic reaction is 70°C - 90°C.

8. The preparation method of 3-ethoxysalicylaldehyde according to claim 1, characterized in that, After promoting the completion of the electrophilic reaction, a quenching agent and an extractant are added in sequence. The organic phase is concentrated under reduced pressure to obtain the crude product of 3-ethoxysalicylaldehyde. The crude product of 3-ethoxysalicylaldehyde is subjected to vacuum distillation and recrystallization to obtain 3-ethoxysalicylaldehyde.

9. The preparation method of 3-ethoxysalicylaldehyde according to claim 8, characterized in that, During the preparation of the crude product of 3-ethoxysalicylaldehyde, the quenching agent is a 6 - 12mol / L hydrochloric acid solution, the extractant is ethyl acetate, and the mass-volume ratio of o-ethoxyphenol to the extractant is 1g:15ml.

10. The preparation method of 3-ethoxysalicylaldehyde according to claim 8, characterized in that, During vacuum distillation, the crude product of 3-ethoxysalicylaldehyde is formulated into a 40 - 60% ethanol aqueous solution, and the residual ethyl acetate is removed by distillation at 70°C - 80°C, and then the temperature is raised to 150°C - 160°C for continuous distillation; the recrystallization temperature is 70°C - 80°C, and the crystallization temperature is 35°C - 45°C.

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