Separation method of 2-methylphenylacetic acid-alpha-ketoxime isomer
By using a mixed solvent and acidification treatment of n-butanol and water in a specific ratio, the problem of difficult separation of E configuration and Z configuration of 2-methylphenylacetic acid-α-ketoxime in the prior art is solved, and two types of them are realized The high-purity separation of the configuration provides high-purity raw materials to avoid the effects of pharmaceutical effects.
Patent Information
- Application Number
- CN202411184562.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-08-27
- Publication Date
- 2024-12-24
AI Technical Summary
It is difficult to directly separate the E configuration and Z configuration of 2-methylphenylacetic acid-α-ketoxime in the prior art, and it is impossible to effectively separate the two configurations when the Z configuration content is high after the reaction is completed.
A mixture of n-butanol and water in a specific ratio was used, and high-purity 2-methylphenylacetic acid-α-ketoxime Z configuration and E configuration were obtained by heating and acidification respectively, and the solubility difference of the disodium salt was used. Separation.
The purity of both configurations is greater than 97%, providing high-purity raw materials for subsequent synthesis of etherstrophlastine or oxistrophlastine, avoiding the mutual influence of drug efficacy.
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Figure CN119176765A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of pesticides, and in particular to a method for separating 2-methylphenylacetic acid-alpha-ketoxime isomers. Background Art
[0002] The compound 2-methylphenylacetic acid-α-ketoximate is an important intermediate for the synthesis of trifloxystrobin and kresoxim-methyl. The traditional synthesis method is to obtain the target product by cyanidation, alkaline hydrolysis and oximation of 2-methylbenzoyl chloride. The specific synthesis route is as follows: ; At present, the new process uses 2-methylbenzyl cyanide and nitrite as raw materials, and generates 2-methylphenylacetic acid-α-ketoxime by base catalysis. The specific synthesis route is as follows: ; The above two processes both generate E configuration and Z configuration after preparing the product, and the structure is shown below: ; Among them, the Z configuration accounts for about 80% and the E configuration accounts for about 20%. Therefore, the subsequently synthesized kresoxim-methyl or trifloxystrobin also has the E configuration and the Z configuration. Therefore, it is very necessary to control the content of the two configurations when preparing 2-methylphenylacetic acid-α-ketoxime.
[0003] In the existing process of controlling 2-methylphenylacetic acid-α-ketoxime, the content of the Z configuration is reduced by controlling the reaction parameters. However, the existing process has no way to directly separate the two configurations. At the same time, when the content of the Z configuration in the product after the reaction is still high, it is also impossible to directly separate the E configuration and the Z configuration by an effective method. These are all problems existing in the prior art. Summary of the invention
[0004] Aiming at the technical problem that the E configuration and the Z configuration in the 2-methylphenylacetic acid-α-ketoxime product are difficult to separate, the present invention provides a method for separating 2-methylphenylacetic acid-α-ketoxime isomers to solve the above problem. The present invention can separate the two by using a mixed solvent of n-butanol and water in a specific ratio, and the purity of the two configurations finally obtained is greater than 97%.
[0005] The technical solution of the present invention is as follows: A method for separating isomers of 2-methylphenylacetic acid-α-ketoxime, comprising taking 2-methylphenylacetic acid-α-ketoxime as a raw material, adding it to n-butanol, adding an aqueous solution of sodium hydroxide under stirring, and performing solid-liquid separation after sufficient reaction, wherein the solid is treated with acid to obtain 2-methylphenylacetic acid-α-ketoxime Z configuration; and the liquid is treated with acid to obtain 2-methylphenylacetic acid-α-ketoxime E configuration; The mass ratio of n-butanol to water is 1.1~2.5:1; the dosage is 1.2~1.8 ml / g based on the dosage of 2-methylphenylacetic acid-α-ketoxime.
[0006] Furthermore, after adding sodium hydroxide, the reaction system is heated to 90-95° C. By heating, the sodium salt of 2-methylphenylacetic acid-α-ketoxime E configuration can be better dissolved in the solvent.
[0007] Furthermore, the solid acidification treatment method is: dissolving the solid in toluene, cooling to below 5°C, slowly adding sulfuric acid to adjust the pH of the reaction system to 2-3, stirring sufficiently, filtering, washing with water until the filtrate is neutral, and drying to obtain 2-methylphenylacetic acid-α-ketoxime Z configuration.
[0008] Furthermore, the method for liquid acidification treatment is: concentrating the liquid to recover n-butanol, then cooling the reaction system to below 5°C, adding hydrochloric acid dropwise to adjust the pH of the reaction system to 2-3, stirring sufficiently, filtering, washing with water until the filtrate is neutral, and drying to obtain 2-methylphenylacetic acid-α-ketoxime E configuration.
[0009] A method for separating 2-methylphenylacetic acid-α-ketoxime isomers comprises the following steps: (1) Take 2-methylbenzeneacetonitrile and n-butyl nitrite, add n-butanol, mix well and cool the solution to below 5°C; (2) Dissolve sodium hydroxide in water; (3) dripping sodium hydroxide aqueous solution into the solution of step (1), controlling the reaction system to be less than 5°C, and keeping the temperature to react after the dripping is completed to obtain an alkaline hydrolysis reaction intermediate; (4) After the insulation is completed, the reaction system is heated to 95-100°C for reaction. The residual intermediate of the alkaline hydrolysis reaction is less than 1% during the insulation reaction, indicating the end of the reaction. The solid and liquid are separated to obtain solid and liquid. (5) Add toluene to the solid, cool to below 5°C, then add concentrated sulfuric acid dropwise to adjust the pH of the reaction system to 2-3, stir thoroughly, filter, wash with water until the filtrate is neutral, and dry to obtain 2-methylphenylacetic acid-α-ketoximine Z configuration; (6) The liquid is concentrated to recover n-butanol, and then the reaction system is cooled to below 5°C. Hydrochloric acid is added dropwise to adjust the pH of the reaction system to 2-3, and then stirred sufficiently, filtered, washed with water until the filtrate is neutral, and dried to obtain 2-methylphenylacetic acid-α-ketoximine E configuration.
[0010] In the solid and liquid separated in the above reaction step (4), the solid is the sodium salt of 2-methylphenylacetic acid-α-ketoxime in Z configuration; the main component in the liquid is the sodium salt of 2-methylphenylacetic acid-α-ketoxime in E configuration. The Z configuration and E configuration of 2-methylphenylacetic acid-α-ketoxime can be obtained respectively by simple post-treatment and acidification.
[0011] Furthermore, the molar ratio of the 2-methylbenzeneacetonitrile to n-butyl nitrite is 1:1.2-1.4.
[0012] Furthermore, based on the amount of 2-methylbenzeneacetonitrile fed, the amount of n-butanol used is 1-1.5 g / g; and the amount of water used is 0.61-0.91 g / g.
[0013] Furthermore, the molar ratio of the 2-methylbenzeneacetonitrile to the sodium hydroxide is 1:2.5-3.
[0014] The beneficial effects of the present invention are: (1) The present invention utilizes the difference in solubility of the disodium salt of 2-methylphenylacetic acid-α-ketoximine Z configuration and E configuration in a specific solvent and within a specific ratio range to separate the disodium salt of 2-methylphenylacetic acid-α-ketoximine Z configuration and E configuration; high-purity 2-methylphenylacetic acid-α-ketoximine Z configuration and E configuration can be obtained after a simple acidification treatment; the purity of the two configurations is above 97%, providing raw materials for preparing kresoxim-methyl and trifloxystrobin of specific configuration, thereby avoiding mutual influence of drug efficacy.
[0015] (2) The present invention uses a non-protonic solvent to treat the Z-configuration 2-methylphenylacetic acid-α-ketoxime, controls the system temperature and moisture, and avoids its transposition when the disodium salt of the Z-configuration 2-methylphenylacetic acid-α-ketoxime is acidified, thereby obtaining high-purity Z-configuration 2-methylphenylacetic acid-α-ketoxime. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, for ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.
[0017] Figure 1 It is the HPLC spectrum of 2-methylphenylacetic acid-α-ketoxime used in Example 1 of the present invention.
[0018] Figure 2 This is the HPLC spectrum of (Z)-2-methylphenylacetic acid-α-ketoxime prepared in Example 1 of the present invention.
[0019] Figure 3 This is the HPLC spectrum of (E)-2-methylphenylacetic acid-α-ketoxime prepared in Example 1 of the present invention.
[0020] Figure 4 It is the HPLC spectrum of 2-methylphenylacetic acid-α-ketoxime prepared in Comparative Example 1 of the present invention.
[0021] Figure 5It is the HPLC spectrum of (Z)-2-methylphenylacetic acid-α-ketoxime prepared in Comparative Example 2 of the present invention.
[0022] Figure 6 It is the HPLC spectrum of (E)-2-methylphenylacetic acid-α-ketoxime prepared in Comparative Example 2 of the present invention. DETAILED DESCRIPTION
[0023] In order to enable those skilled in the art to better understand the technical solutions in the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work should fall within the scope of protection of the present invention.
[0024] Example 1 A method for separating 2-methylphenylacetic acid-α-ketoxime isomers, the specific method is as follows: (1) Take 90g of 2-methylphenylacetic acid-α-ketoxime and test it. The content of Z configuration is 83.85% and the content of E configuration is 15.08%. The HPLC spectrum is shown in Figure 1 . Add 66.8g of n-butanol, add sodium hydroxide aqueous solution with stirring, including 23.2g of sodium hydroxide and 40.6g of water, and after the addition, heat to 90-95°C for reaction for 0.5h, cool to 55-60°C, and filter; rinse the filter cake with 25% water-containing n-butanol.
[0025] (2) Add 200 g of toluene to the filter cake, cool to below 5°C, slowly add concentrated sulfuric acid to adjust the pH of the reaction solution to 2-3, stir for 0.5 h, filter and wash with water until the filtrate is neutral, dry the filter cake to obtain 68.0 g, and the Z configuration content is 97.5% (area normalization method). The detection spectrum is detailed in Figure 2 .
[0026] (3) The filtrate was heated to 117°C to evaporate the solvent and recover n-butanol, then cooled to 5°C, 30% hydrochloric acid was added dropwise to adjust the pH to 2-3, stirred for 0.5 h, filtered, and washed with water until the filtrate was neutral. The filter cake was dried to obtain 17.0 g. The E configuration content was detected to be 98.2% (area normalization method). The detection spectrum is shown in Figure 3 .
[0027] Example 2 A method for separating 2-methylphenylacetic acid-α-ketoxime isomers, the specific method is as follows: (1) Mix 66.8 g of 2-methylbenzeneacetonitrile, 65.1 g of n-butyl nitrite and 100.3 g of n-butanol, and cool the solution to below 5°C; (2) Mix and dissolve 50.8 g of sodium hydroxide and 40.6 g of water to obtain an aqueous solution of sodium hydroxide; (3) Slowly drop an aqueous solution of sodium hydroxide into a mixture of 2-methylbenzeneacetonitrile and n-butyl nitrite, strictly controlling the temperature below 5°C. After the dropwise addition is completed, the mixture is kept warm for 8 hours to obtain an alkaline hydrolysis intermediate; (4) After the insulation is completed, the temperature is raised to 98-100°C for reaction. After the insulation reaction is completed for 6 hours, the residual intermediate of the alkaline hydrolysis reaction is detected to be 0.85%, and the reaction is completed; (5) Cool down to 55-60°C, filter while hot, and rinse the filter cake with n-butanol containing 25% water; (6) The filter cake was mixed with 185 g of toluene solvent, cooled to below 5 °C, and concentrated sulfuric acid was slowly added dropwise to adjust the pH to 2-3. The mixture was stirred for 0.5 h, filtered, and washed with water until the filtrate was neutral. The filter cake was dried to obtain 61.8 g of the product. The Z configuration content was found to be 97.3% (area normalization method).
[0028] (7) The filtrate obtained in step (5) was heated to 117°C for desolventizing and recovering n-butanol, then cooled to below 5°C, and 30% hydrochloric acid was added dropwise to adjust the pH to 2-3. After stirring for 0.5 h, the mixture was filtered and washed with water until the filtrate was neutral. The filter cake was dried to obtain 20.6 g of the E configuration content, which was found to be 98.1% (area normalization method).
[0029] Example 3 A method for separating 2-methylphenylacetic acid-α-ketoxime isomers, the specific method is as follows: (1) Mix 66.8 g of 2-methylbenzeneacetonitrile, 75.9 g of n-butyl nitrite and 80.2 g of n-butanol, and cool the solution to below 5°C; (2) Mix and dissolve 60.9 g of sodium hydroxide and 48.7 g of water to obtain an aqueous solution of sodium hydroxide; (3) Slowly drop an aqueous solution of sodium hydroxide into a mixture of 2-methylbenzeneacetonitrile and n-butyl nitrite, strictly controlling the temperature below 5°C. After the dropwise addition is completed, the mixture is kept warm for 8 hours to obtain an alkaline hydrolysis intermediate; (4) After the insulation is completed, the temperature is raised to 98-100°C for reaction. After the insulation reaction is completed for 6 hours, the residual intermediate of the alkaline hydrolysis reaction is detected to be 0.65%, and the reaction is completed; (5) Cool down to 55-60°C, filter while hot, and rinse the filter cake with n-butanol containing 25% water; (6) The filter cake was mixed with 213 g of toluene solvent, cooled to below 5 °C, and concentrated sulfuric acid was slowly added dropwise to adjust the pH to 2-3. The mixture was stirred for 0.5 h, filtered, and washed with water until the filtrate was neutral. The filter cake was dried to obtain 71.3 g of the product. The Z configuration content was found to be 97.8% (area normalization method).
[0030] (7) The filtrate obtained in step (5) was heated to 117°C for desolventizing and recovering n-butanol, then cooled to below 5°C, and 30% hydrochloric acid was added dropwise to adjust the pH to 2-3. After stirring for 0.5 h, the mixture was filtered and washed with water until the filtrate was neutral. The filter cake was dried to obtain 14.6 g of the obtained cake. The E configuration content was found to be 98.5% (area normalization method).
[0031] Example 4 A method for separating 2-methylphenylacetic acid-α-ketoxime isomers, the specific method is as follows: (1) Mix 66.8 g of 2-methylbenzeneacetonitrile, 70.5 g of n-butyl nitrite and 66.8 g of n-butanol, and cool the solution to below 5°C; (2) Mix and dissolve 54.8 g of sodium hydroxide and 43.9 g of water to obtain an aqueous solution of sodium hydroxide; (3) Slowly drop an aqueous solution of sodium hydroxide into the mixed solution of 2-methylbenzeneacetonitrile and n-butyl nitrite, strictly controlling the temperature below 5°C. After the dropwise addition is completed, the mixture is kept warm for 8 hours to obtain an alkaline hydrolysis intermediate; (4) After the insulation is completed, the temperature is raised to 98-100°C for reaction. After the insulation reaction is completed for 6 hours, the residual intermediate of the alkaline hydrolysis reaction is detected to be 0.75%, and the reaction is completed; (5) Cool down to 55-60°C, filter while hot, and rinse the filter cake with n-butanol containing 25% water; (6) The filter cake was mixed with 198 g of toluene solvent, cooled to below 5 °C, and concentrated sulfuric acid was slowly added dropwise to adjust the pH to 2-3. The mixture was stirred for 0.5 h, filtered, and washed with water until the filtrate was neutral. The filter cake was dried to obtain 66.3 g of the product. The Z configuration content was found to be 97.5% (area normalization method).
[0032] (7) The filtrate obtained in step (5) was heated to 117°C for desolventizing and recovering n-butanol, then cooled to below 5°C, and 30% hydrochloric acid was added dropwise to adjust the pH to 2-3. After stirring for 0.5 h, the mixture was filtered and washed with water until the filtrate was neutral. The filter cake was dried to obtain 18.7 g of the obtained cake. The content of E configuration was 98.0% (area normalization method).
[0033] Comparative Example 1 A method for preparing 2-methylphenylacetic acid-α-ketoxime, the specific method is as follows: (1) Mix 66.8 g of 2-methylbenzyl acetonitrile, 65.1 g of n-butyl nitrite and 100.3 g of n-butanol and cool to below 5°C; (2) Mix and dissolve 50.8 g of sodium hydroxide and 40.6 g of water to obtain an aqueous solution of sodium hydroxide; (3) Slowly drop an aqueous solution of sodium hydroxide into the mixed solution of 2-methylbenzeneacetonitrile and n-butyl nitrite, strictly controlling the temperature below 5°C. After the dropwise addition is completed, the mixture is kept warm for 8 hours to obtain an alkaline hydrolysis intermediate; (4) After the insulation is completed, the temperature is raised to 98-100°C for reaction. After the insulation reaction is completed for 6 hours, the residual intermediate of the alkaline hydrolysis reaction is detected to be 0.8%, indicating the end of the reaction; (5) The reaction solution was heated to 117°C to remove the n-butanol, then cooled to below 5°C, and 30% hydrochloric acid was added dropwise to adjust the pH to 2-3. After stirring for 0.5 h, the mixture was filtered and washed with water until neutral. The filter cake had a drying weight of 85 g. The Z configuration content was 5.78% (area normalization method) and the E configuration content was 82.88% (area normalization method).
[0034] Compared with Example 2, after the alkaline hydrolysis reaction of the comparative example is completed, the subsequent treatment is directly carried out without separation method. During the acidification process, most of the Z configuration is converted to the E configuration, but the conversion cannot be completed, and 5.78% of the Z configuration isomer remains. Under the detection conditions, 3.5min and 5min impurities are generated, accounting for about 4%, and the product quality is poor.
[0035] Comparative Example 2 A method for separating 2-methylphenylacetic acid-α-ketoxime isomers, the specific method is as follows: (1) Mix 66.8 g of 2-methylbenzyl acetonitrile, 65.1 g of n-butyl nitrite and 33.4 g of n-butanol and cool to below 5°C; (2) Mix and dissolve 50.8 g of sodium hydroxide and 76.1 g of water to obtain an aqueous solution of sodium hydroxide; (3) Slowly drop an aqueous solution of sodium hydroxide into a mixture of 2-methylbenzeneacetonitrile and n-butyl nitrite, strictly controlling the temperature below 5°C. After the dropwise addition is completed, the mixture is kept warm for 8 hours to obtain an alkaline hydrolysis intermediate; (4) After the insulation is completed, the temperature is raised to 98-100°C for reaction. After the insulation reaction is completed for 6 hours, the residual intermediate of the alkaline hydrolysis reaction is detected to be 0.92%, indicating the end of the reaction; (5) Cool down to 55-60°C, filter while hot, and rinse the filter cake with n-butanol containing 25% water; (6) The filter cake was mixed with 185 g of toluene solvent, cooled to below 5 °C, and concentrated sulfuric acid was slowly added dropwise to adjust the pH to 2-3. The mixture was stirred for 0.5 h, filtered, and washed with water until the filtrate was neutral. The filter cake was dried to obtain 60.3 g of the product. The Z configuration content was found to be 93.9% (area normalization method).
[0036] (7) The filtrate obtained in step (5) was heated to 117°C for desolventizing and recovering n-butanol, then cooled to below 5°C, and 30% hydrochloric acid was added dropwise to adjust the pH to 2-3. After stirring for 0.5 h, the mixture was filtered and washed with water until the filtrate was neutral. The filter cake was dried to obtain 21.6 g of the mixture. The E configuration content was found to be 90.8% (area normalization method).
[0037] It can be seen from this comparative example that the separation effect between Z-type and E-type is not good when the ratio of water to n-butanol is changed.
[0038] Although the present invention has been described in detail with reference to the accompanying drawings and in combination with the preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, a person of ordinary skill in the art may make various equivalent modifications or substitutions to the embodiments of the present invention, and these modifications or substitutions shall be within the scope of the present invention. Any person of ordinary skill in the art may easily think of changes or substitutions within the technical scope disclosed by the present invention, and these shall be within the scope of protection of the present invention.
Claims
1. A method for separating 2-methylphenylacetic acid-α-ketoximine isomers, characterized in that: 2-methylphenylacetic acid-α-ketoxime is used as a raw material, added to n-butanol, and an aqueous solution of sodium hydroxide is added under stirring. After sufficient reaction, the solid and liquid are separated, and the solid is treated with acid to obtain 2-methylphenylacetic acid-α-ketoxime Z configuration; the liquid is treated with acid to obtain 2-methylphenylacetic acid-α-ketoxime E configuration; The mass ratio of n-butanol to water is 1.1~2.5:1; the dosage is 1.2~1.8 ml / g based on the dosage of 2-methylphenylacetic acid-α-ketoxime.
2. The separation method according to claim 1, characterized in that After adding sodium hydroxide, heat the reaction system to 90-95°C.
3. The separation method according to claim 1, characterized in that The solid acidification treatment method is as follows: dissolving the solid in toluene, cooling to below 5°C, adding sulfuric acid dropwise to adjust the pH of the reaction system to 2-3, stirring sufficiently, filtering, washing with water until the filtrate is neutral, and drying to obtain 2-methylphenylacetic acid-α-ketoxime Z configuration.
4. The separation method according to claim 1, characterized in that The liquid acidification treatment method comprises: concentrating the liquid to recover n-butanol, then cooling the reaction system to below 5°C, adding hydrochloric acid dropwise to adjust the pH value of the reaction system to 2-3, stirring sufficiently, filtering, washing with water until the filtrate is neutral, and drying to obtain 2-methylphenylacetic acid-α-ketoxime E configuration.
5. A method for separating 2-methylphenylacetic acid-α-ketoximine isomers, characterized in that: The following steps are involved: (1) Take 2-methylbenzeneacetonitrile and n-butyl nitrite, add n-butanol, mix well and cool the solution to below 5°C; (2) Dissolve sodium hydroxide in water; (3) dripping sodium hydroxide aqueous solution into the solution of step (1), controlling the reaction system to be less than 5°C, and keeping the temperature to react after the dripping is completed to obtain an alkaline hydrolysis reaction intermediate; (4) After the insulation is completed, the reaction system is heated to 95-100°C for reaction. The residual intermediate of the alkaline hydrolysis reaction is less than 1% during the insulation reaction, indicating the end of the reaction. The solid and liquid are separated to obtain solid and liquid. (5) Add toluene to the solid, cool to below 5°C, then add concentrated sulfuric acid dropwise to adjust the pH of the reaction system to 2-3, stir thoroughly, filter, wash with water until the filtrate is neutral, and dry to obtain 2-methylphenylacetic acid-α-ketoximine Z configuration; (6) The liquid is concentrated to recover n-butanol, and then the reaction system is cooled to below 5°C. Hydrochloric acid is added dropwise to adjust the pH of the reaction system to 2-3, and then stirred sufficiently, filtered, washed with water until the filtrate is neutral, and dried to obtain 2-methylphenylacetic acid-α-ketoximine E configuration.
6. The separation method according to claim 5, characterized in that The molar ratio of the 2-methylbenzeneacetonitrile to n-butyl nitrite is 1:1.2-1.
4.
7. The separation method according to claim 5, characterized in that Calculated on the basis of the amount of 2-methylbenzeneacetonitrile fed, the amount of n-butanol used is 1-1.5 g / g; the amount of water used is 0.61-0.91 g / g.
8. The separation method according to claim 5, characterized in that The molar ratio of the 2-methylbenzeneacetonitrile to the sodium hydroxide is 1:2.5-3.