Process for the preparation of salicylonitrile

Abstract

This application discloses a method for preparing salicylate. The method for preparing salicylate provided in this application uses inexpensive and readily available raw and auxiliary materials, has simple reaction steps, mild reaction conditions, does not involve high-pressure, sulfonation, nitration or other high-level or high-pollution production processes, and does not contain flammable, explosive or toxic reactants. It has a high yield and is suitable for industrial preparation.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and particularly to a method for preparing salicylate. Background Technology

[0002] Salicylic nitrile is widely used in the pharmaceutical field for the synthesis of aspirin, acetaminophen, and other pharmaceuticals; in the pesticide field for the synthesis of various insecticides and herbicides; and it also plays an important role in the cosmetics industry. Currently, the main production process for salicylic nitrile is the salicylaldehyde dealdehyde method, such as the method described in Chinese patent CN112898180A, which involves reacting salicylaldehyde with hydroxylamine to form an aldoxime, followed by dehydration with acetic anhydride or thionyl chloride as a dehydrating agent to produce salicylic nitrile; or the salicylamide dehydration method, such as the method described in Chinese patent CN104610095B, ​​which uses salicylamide under phosgene conditions to produce salicylic nitrile. However, these methods are cumbersome and require the participation of toxic phosgene in the reaction, posing a high risk. Patent CN106083651A disclosed a method for synthesizing o-chlorobenzonitrile from the raw material o-chlorobenzonitrile under high temperature and high pressure conditions above 170°C. Although the steps are simple, the synthesis process uses flammable and explosive liquids, involves dangerous high-temperature and high-pressure reaction conditions, has a low industrial conversion rate, and is not suitable for large-scale promotion.

[0003] Therefore, there is an urgent need in this field to develop a simple, low-cost, and safe process for preparing salicylates. Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing salicylnitrile.

[0005] To solve the above-mentioned technical problems, the present invention provides a method for preparing salicylnitrile, the method comprising the following steps:

[0006] S1: Under a nitrogen atmosphere, o-chlorobenzonitrile and a strong base are reacted in an aprotic polar solvent to obtain an intermediate;

[0007] S2: Treat the intermediate with hydrochloric acid to obtain the salicylnitrile.

[0008] In some preferred embodiments, the aprotic polar solvent is selected from at least one of dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), hexamethylphosphoric triamine (HMPA), and 1,3-dimethyl-2-imidazolinone (DMI), and more preferably, the solvent is hexamethylphosphoric triamine and / or 1,3-dimethyl-2-imidazolinone.

[0009] In some preferred embodiments, the strong base is sodium methoxide or sodium ethoxide.

[0010] In some preferred embodiments, the mass ratio of o-chlorobenzonitrile to sodium methoxide is (120-140):(100-120); for example, 136:118.

[0011] In some preferred embodiments, in step S1, the o-chlorobenzonitrile and the sodium methoxide are mixed at ≤10°C and then heated to 60 to 80°C to carry out the reaction.

[0012] In some preferred embodiments, in step S1, the reaction time is not less than 3 minutes, preferably not less than 5 minutes, for example 5-10 minutes.

[0013] In some preferred embodiments, in step S1, the temperature of the reaction is not higher than 100°C, preferably not higher than 80°C, for example 30-80°C, and more preferably 60-80°C.

[0014] In some preferred embodiments, step S1 further includes the steps of cooling to 0-5°C and filtering to collect the filter residue to obtain the intermediate after the reaction is completed.

[0015] In some preferred embodiments, in step S2, the intermediate is treated with hydrochloric acid until the pH is 2-3, filtered, and the filter residue is dried to obtain the salicylnitrile.

[0016] In some preferred embodiments, in step S2, the intermediate is dissolved in water, and the aqueous solution of the intermediate is treated with hydrochloric acid until the pH is 2-3. The filter residue is then dried to obtain the salicylnitrile.

[0017] Compared with the prior art, the present invention has at least the following advantages:

[0018] (1) The preparation method of salicylnitrile provided by the present invention uses inexpensive and readily available raw and auxiliary materials, has simple reaction steps, mild reaction conditions, does not involve high-pressure, sulfonation, nitration and other high-level or high-pollution production processes, and has no flammable, explosive or toxic reactants. It has a high yield, with a process yield of more than 99%, obvious cost advantages, and is suitable for industrial preparation.

[0019] (2) The preparation method of salicylnitrile provided by the present invention is carried out in a continuous pipeline reactor, with a high safety factor, obvious advantages in scale-up production, and the use of solvents that can be recycled and produce less industrial wastewater.

[0020] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0021] Existing methods for preparing salicylnitrile involve high-temperature, high-pressure, sulfonation, and nitration processes, which are highly hazardous and polluting. These methods are complex, have low yields, and limited industrial application value. Through extensive and in-depth research, the inventors have developed a method for preparing salicylnitrile suitable for industrial production. This method is simple, avoids high-temperature and high-polluting steps, uses readily available and inexpensive raw materials, and achieves high industrial conversion rates, making it suitable for widespread application.

[0022] Preparation method of salicylic nitrile

[0023] This invention relates to a method for preparing salicylnitrile, comprising the steps of...

[0024] S1: Under a nitrogen atmosphere, o-chlorobenzonitrile and a strong base are reacted in an aprotic polar solvent to obtain an intermediate; and

[0025] S2: Treat the intermediate with hydrochloric acid to obtain the salicylnitrile.

[0026] In step S1 above, the aprotic polar solvent is selected from at least one of dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), hexamethylphosphoric triamine (HMPA), and 1,3-dimethyl-2-imidazolinone (DMI). In a more preferred embodiment, the solvent is hexamethylphosphoric triamine, 1,3-dimethyl-2-imidazolinone, or a mixture of both in a suitable proportion, where a suitable proportion is any proportion that allows for blending. The inventors have discovered that when o-chlorobenzonitrile and a strong base react in the solvent system described above, the reaction conditions can be milder and the yield higher compared to other commonly used solvents such as methanol or DMF. Conventional processes use solvents such as methanol under high temperature and high pressure conditions, resulting in harsh reaction conditions and low yields.

[0027] In this invention, a strong base refers to a base whose alkalinity is not lower than that of sodium hydroxide at the same molar concentration, such as sodium methoxide or sodium ethoxide. In a preferred embodiment of this invention, the strong base is sodium methoxide.

[0028] In a preferred embodiment of the present invention, the reaction between o-chlorobenzonitrile and sodium methoxide in step S1 is carried out at a temperature not exceeding 100°C, more preferably not exceeding 80°C; even more preferably at a temperature not lower than 30°C, and even more preferably not lower than 50°C, for example, 60-80°C. Excessively high reaction temperatures can lead to excessive energy consumption and increase the risk factor. In this invention, the solvent and reactants work synergistically to enable the reactants to react at a relatively low temperature and atmospheric pressure, achieving a reaction conversion rate of over 99%.

[0029] In a preferred embodiment of the present invention, the reaction time of step S1 is not less than 3 minutes, more preferably not less than 5 minutes, for example 5-10 minutes.

[0030] In a preferred embodiment of the present invention, o-chlorobenzonitrile and sodium methoxide are first mixed at ≤10°C, and then the temperature is raised to 60 to 80°C for reaction. Mixing the materials at a low temperature can reduce the decomposition of the reactants and improve the reaction yield.

[0031] In a preferred embodiment of the present invention, the mass ratio of o-chlorobenzonitrile to sodium methoxide is (120-140):(100-120); for example, 136:118. Within this feed ratio range, the reaction proceeds completely with minimal material waste.

[0032] In a preferred embodiment of the present invention, step S1 further includes the step of cooling to 0-5°C and filtering to collect the filter residue to obtain the intermediate after the reaction of o-chlorobenzonitrile and sodium methoxide is completed. After filtration, the filtrate and filter residue are separated. The filtrate does not contain flammable or explosive solvents and can be collected and recycled, thus improving material utilization.

[0033] In a preferred embodiment of the present invention, step S1 is followed by step S2, in which the intermediate is treated with hydrochloric acid to a pH of 2-3 (preferably, the filter residue collected in step S1 is dissolved in water, and then hydrochloric acid is added dropwise until the solution pH is 2-3), the filter residue is filtered, dried, and salicylnitrile is obtained.

[0034] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the present invention is further described below in conjunction with specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight. Unless otherwise specified, the experimental materials and reagents used in the following embodiments are commercially available.

[0035] Unless otherwise specified, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. It should be noted that the terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the exemplary embodiments of this application.

[0036] Unless otherwise specified, the term “or” means the term “and / or” and is used interchangeably with the term “and / or”.

[0037] As used herein, including the appended claims, unless the context clearly indicates otherwise, the singular forms of words such as “an,” “a,” and “the” include their respective plural referents.

[0038] In a preferred embodiment of the present invention, salicylnitrile is prepared with reference to the following reaction formula:

[0039]

[0040] Example 1: Preparation of salicylonitrile

[0041] Under nitrogen protection, 400 parts of hexamethylphosphoric triamine (HMPA) and 136 parts of o-chlorobenzonitrile were added to the mixing tank. 118 parts of sodium methoxide were added while maintaining the temperature inside the mixing tank at ≤10℃. After thorough mixing, the mixture was pumped into a pipeline reactor, with the jacket temperature controlled at 60-80℃. The material remained in the pipeline reactor for 5-10 minutes. Once the outlet temperature of the material was detected at 80-100℃, the material flowed into a collection tank. Feeding was stopped when the material reached 80% of its volume (it could be fed into a second collection tank). The mixture was then cooled to 0-5℃ and filtered under nitrogen protection. The filtrate was collected back into the mixing tank for recycling. The filter cake was collected. Twice the mass of water was added to the filter cake, and the pH was adjusted to 2-3 with hydrochloric acid. After filtration and drying, white crystalline salicylnitrile was obtained (yield 99.3%; HPLC: 99.6%).

[0042] Example 2: Preparation of salicylic nitrile

[0043] In this embodiment, the method for preparing salicylate is largely the same as in Example 1, except that a different solvent is used. Example 1 used hexamethylphosphoric triamine (HMPA), while this embodiment adds the same amount of 1,3-dimethyl-2-imidazolinone (DMI). The specific method is as follows:

[0044] Under nitrogen protection, 400 parts of 1,3-dimethyl-2-imidazolinone (DMI) and 136 parts of o-chlorobenzonitrile were added to the mixing tank. 118 parts of sodium methoxide were added while maintaining the temperature inside the mixing tank at ≤10℃. After thorough mixing, the mixture was pumped into a pipeline reactor, with the jacket temperature controlled at 60–80℃. The material remained in the pipeline reactor for 15–20 minutes. Once the outlet temperature of the material was detected at 80–100℃, the material flowed into a collection tank. Feeding was stopped when the material reached 80% of its volume (it could be fed into a second collection tank). The mixture was then cooled to 0–5℃ and filtered under nitrogen protection. The filtrate was collected back into the mixing tank for recycling. The filter cake was collected. Twice the mass of water was added to the filter cake, and the pH was adjusted to 2–3 with hydrochloric acid. The mixture was then filtered and dried to obtain white crystalline salicylnitrile (yield 99.1%; HPLC: 99.5%).

[0045] Example 3

[0046] In this comparative example, the method for preparing salicylate is largely the same as in Example 1, except that the solvent used is DMF. The specific method is as follows:

[0047] Under nitrogen protection, add 400 parts DMF and 136 parts o-chlorobenzonitrile to the mixing tank; control the temperature inside the mixing tank to ≤10℃ and add 118 parts sodium methoxide. After stirring evenly, press the mixture into the pipeline reactor while controlling the jacket temperature of the pipeline reactor to 60-80℃. The material stays in the pipeline reactor for 15-20 minutes. After the material temperature at the outlet of the pipeline reactor is detected to be 80-100℃, the material flows into the collection tank. After the material in the collection tank is collected to 80% of its volume, stop feeding (the material can be fed into a second collection tank). Cool the material to 0-5℃ and filter under nitrogen protection. Collect the filtrate in the mixing tank for recycling. Collect the filter cake. Add 2 times the mass of water to the filter cake, adjust the pH to 2-3 with hydrochloric acid, filter and dry to obtain white crystalline salicylnitrile (yield 89.6%; HPLC: 98.3%).

[0048] Comparative Example 1

[0049] In this comparative example, the method for preparing salicylate is largely the same as in Example 1, except that methanol is used instead of methanol. The specific method is as follows:

[0050] Under nitrogen protection, methanol (400 parts) and o-chlorobenzonitrile (136 parts) were added to the mixing tank. Sodium methoxide (118 parts) was added while maintaining the temperature inside the mixing tank at ≤10℃. After thorough mixing, the mixture was pumped into a pipeline reactor, with the jacket temperature controlled at 100-120℃. The material remained in the pipeline reactor for 15-20 minutes. Once the outlet temperature of the material was detected at 100-120℃, the material flowed into a collection tank. Feeding was stopped when the material reached 80% of its volume (it could be fed into a second collection tank). The mixture was then cooled to 0-5℃ and filtered under nitrogen protection. The filtrate was collected back into the mixing tank for recycling. The filter cake was collected. The filter cake was then mixed with twice its mass of water, and the pH was adjusted to 2-3 with hydrochloric acid. After filtration and drying, white crystalline salicylnitrile was obtained (yield 76.6%; HPLC: 89.1%).

[0051] Table 1 below shows the effect of the reaction solvent on the experimental yield.

[0052] Table 1

[0053] Group reaction solvent yield Example 1 HMPA 99.3％ Example 2 DMI 99.1％ Example 3 DMF 89.6％ Comparative Example 1 methanol 76.6％

[0054] Those skilled in the art will understand that the above embodiments are specific examples of implementing the present invention, and in practical applications, various changes in form and detail may be made without departing from the spirit and scope of the present invention.

Claims

1. A process for the preparation of salicylonitrile, characterized in that, The method includes the following steps: S1: In an inert atmosphere, o-chlorobenzonitrile and sodium methoxide are reacted in an aprotic polar solvent to obtain an intermediate; S2: Treat the intermediate with hydrochloric acid to obtain the salicylate; The aprotic polar solvent is hexamethylphosphoric triamine and / or 1,3-dimethyl-2-imidazolinone. The mass ratio of o-chlorobenzonitrile to sodium methoxide is (120-140):(100-120). In step S1, the o-chlorobenzonitrile and the sodium methoxide are mixed at ≤10°C, and then heated to 60 to 80°C for reaction, and the reaction time is not less than 3 minutes.

2. The method of claim 1, wherein, The mass ratio of o-chlorobenzonitrile to sodium methoxide is 136:

118.

3. The method of claim 1, wherein, After the reaction is completed, the process further includes the steps of cooling to 0-5°C and filtering to collect the filter residue to obtain the intermediate.

4. The method of claim 1, wherein, In step S2, the intermediate is treated with hydrochloric acid until the pH is 2-3, filtered, and the filter residue is dried to obtain the salicylonitrile.

5. The method of claim 1, wherein, In step S2, the intermediate is dissolved in water, and the aqueous solution of the intermediate is treated with hydrochloric acid until the pH is 2-3. The filter residue is then dried to obtain the salicylnitrile.

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