Continuous production method of (E) 2-hydroxyimino-[(2-o-methylphenyl)] acetic acid
Through the continuous production process and the three-stage reactor series reaction with optimized parameters, the problems of low production efficiency and unstable quality of (E) 2-hydroxyimine-[(2-o-methylphenyl)] acetic acid in the prior art were solved, and low-cost and efficient industrial production was achieved.
Patent Information
- Application Number
- CN202510624254.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-14
- Publication Date
- 2025-08-19
AI Technical Summary
In the prior art, the batch kettle reaction process for producing (E)2-hydroxyimine-[(2-o-methylphenyl)]acetic acid has problems of low efficiency, high cost and unstable product quality.
The continuous production method is adopted, and the acidification reaction is carried out in the acidification kettle after the continuous reaction in the three-stage reaction kettle. The process parameters such as temperature, time and material ratio are optimized, and the reaction is used with nitrite and alkali, and finally the product is obtained by centrifugation.
It achieves low-cost and efficient production, stable product quality, and is suitable for industrial production.
Smart Images
Figure CN120504611A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of industrialized production of organic synthesis, and more specifically to a continuous production method for efficiently synthesizing (E)2-hydroxyimino-[(2-o-methylphenyl)]acetic acid (oxime acid for short). Background Art
[0002] (E)2-Hydroxyimino-[(2-o-methylphenyl)]acetic acid (oxime acid) is an important raw material for the synthesis of (E)2-methoxyimino-[(2-o-methylphenyl)]acetic acid methyl ester, which is in turn an important raw material for the synthesis of trifloxystrobin and kresoxim-methyl. Trifloxystrobin, a highly effective, broad-spectrum, low-toxic, and environmentally friendly strobilurin fungicide developed by Syngenta and Bayer in Germany, has become a hot topic in fungicide research. Furthermore, (E)2-Hydroxyimino-[(2-o-methylphenyl)]acetic acid (oxime acid) is widely used in the pharmaceutical, pesticide, and chemical industries.
[0003] The current process for producing (E)-2-hydroxyimino-[(2-o-methylphenyl)]acetic acid in the industry is a batch-type reaction process. This process has problems such as the requirement for a large amount of solvent, low efficiency, high energy consumption, and unstable product quality. Therefore, the development of a green, economical, and efficient production process is of great practical significance. Summary of the Invention
[0004] In view of the problems existing in the prior art, the object of the present invention is to provide a continuous production method of (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid, which improves the yield, reduces the cost and reduces the pollution to the environment by optimizing the key control parameters of the process.
[0005] To solve the above problems, the present invention adopts the following technical solutions.
[0006] A continuous production method of (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid, comprising:
[0007]
[0008] The compound of formula I is o-methylphenylacetonitrile as a raw material, and a nitrite and a base are reacted in a certain proportion in three series reactors. The resulting reaction solution is then continuously flowed into an acidification reactor to add acid for acidification reaction, and then centrifuged and dried to obtain (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid;
[0009] Wherein, the R group of the nitrite is an alkyl group independently selected from tert-butyl, n-butyl, ethyl, n-propyl or isopropyl.
[0010] Furthermore, the R group of the nitrite is preferably tert-butyl, n-butyl and ethyl.
[0011] Furthermore, the three-stage reactor continuous reaction process is as follows: the compound shown in Formula I is pumped into the first reactor at a constant flow rate, and at the same time, nitrite and base are continuously fed into the first reactor at a constant flow rate, and the obtained reaction liquid overflows into the second reactor through the overflow port of the first reactor, and at the same time, nitrite and base are continuously fed into the second reactor at a constant flow rate to obtain a secondary reaction liquid, and the obtained secondary reaction liquid overflows into the third reactor through the overflow port of the second reactor to continue the reaction until completion.
[0012] Furthermore, the feed molar flow ratio of nitrite to o-methylphenylacetonitrile in the first reactor is 0.4-0.8:1; the feed molar flow ratio of nitrite to o-methylphenylacetonitrile in the second reactor is 0.2-0.7:1. Preferably, the feed molar flow ratio of nitrite to o-methylphenylacetonitrile in the first reactor is 0.5-0.8:1; the feed molar flow ratio of nitrite to o-methylphenylacetonitrile in the second reactor is 0.25-0.7:1.
[0013] Furthermore, the reaction temperature of the first reactor is 20-120° C., the reaction temperature of the second reactor is 40-140° C., and the reaction temperature of the third reactor is 50-150° C. Preferably, the reaction temperature of the first reactor is 20-80° C., the reaction temperature of the second reactor is 50-85° C., and the reaction temperature of the third reactor is 60-90° C.
[0014] Furthermore, the total residence time of the three-stage reactor continuous reaction is 6 to 20 hours. Preferably, the total residence time of the three-stage reactor continuous reaction is 10 to 12 hours.
[0015] Furthermore, the base is any one of the following bases or their aqueous solutions: potassium carbonate, sodium carbonate, sodium bicarbonate, sodium methoxide, ethanolamine, potassium hydroxide and sodium hydroxide.
[0016] Furthermore, the base is any one of the following bases or their aqueous solutions: potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide and sodium hydroxide.
[0017] Furthermore, the feed molar flow ratio of the alkali used in the first reactor to o-methylphenylacetonitrile is 0.5-5:1, and the feed molar flow ratio of the alkali used in the second reactor to o-methylphenylacetonitrile is 1-4:1; preferably, the feed molar flow ratio of the alkali used in the first reactor to o-methylphenylacetonitrile is 0.7-4.4:1; and the feed molar flow ratio of the alkali used in the second reactor to o-methylphenylacetonitrile is 1.2-3.3:1.
[0018] Furthermore, the acid is hydrochloric acid with a mass concentration of 30% or sulfuric acid with a mass concentration of 30%.
[0019] Furthermore, the temperature for the acidification reaction is 10 to 80° C. Preferably, the temperature for the acidification reaction is 50 to 70° C.
[0020] Furthermore, the residence time of the material in the reactor during the acidification reaction is 0.5 to 5 hours. Preferably, the residence time of the material in the reactor during the acidification reaction is 1 to 3 hours.
[0021] Compared with the prior art, the advantages of the present invention are:
[0022] 1. The synthesis method of the present invention has low reaction cost, high production efficiency, stable product quality, and is suitable for industrial production.
[0023] 2. The present invention uses a continuous synthesis process to enable the reactants to react continuously in the three-stage reactor and the acidification reactor, thereby synthesizing E-type oxime acid in a single step. BRIEF DESCRIPTION OF THE DRAWINGS
[0024] Figure 1 It is a schematic diagram of the process of the present invention.
[0025] Description of the numbers in the figure:
[0026] 01 first reactor, 02 second reactor, 03 third reactor, 04 acidification reactor, 05 bottom regulating valve, 06 centrifuge, 07 dryer. DETAILED DESCRIPTION
[0027] Example 1:
[0028] In this embodiment, the production process of (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid is as follows:
[0029] Three 1500L reactors were connected in series to form a three-stage continuous reactor unit. After turning on the stirring function of the first reactor 01, the temperature was raised to 80°C. The raw material pump and feed valve were opened, and 300L / h of o-methylphenylacetonitrile, 160L / h of tert-butyl nitrite, and 180L / h of ethanolamine were continuously pumped into the first reactor 01. The temperature in the first reactor 01 was controlled at 80°C to produce a primary reaction liquid. When the primary reaction liquid overflowed from the overflow port of the first reactor 01 into the second reactor 02, stirring was resumed. Simultaneously, 120L / h of tert-butyl nitrite and 150L / h of ethanolamine were continuously pumped into the second reactor 02. The reaction temperature in the second reactor 02 was controlled at 80°C to produce a secondary reaction liquid. Secondary reaction liquid overflows to the 3rd reactor 03 by the overflow port of the second reactor 02 and carries out slaking, and controlling the 3rd reactor 03 internal reaction temperature is 85 ℃ to reacting completely (sampling HPLC detects, o-methylbenzene acetonitrile purity<0.5% is considered as reaction end), obtains three-level reaction liquid.Open stirring when three-level reaction liquid overflows to 5000L acidifying still 04 by the overflow port of the 3rd reactor 03, and maintaining temperature in the acidifying still 04 is 65 ℃, and pumping into mass concentration is 30% hydrochloric acid 350L / h simultaneously, after continuing 3h, open bottom regulating valve 05, while keeping liquid level substantially unchanged in the acidifying still 04, discharging to centrifuge 06 is centrifugal, centrifuged solid is dried through drying machine 07, obtains (E) 2-hydroxyimino-[(2-o-methylphenyl)] acetic acid, according to HPLC quantitative analysis, content is 99.21%, and yield is 90.26%.
[0030] Example 2:
[0031] In this embodiment, the production process of (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid is as follows:
[0032] Three 1500L reactors were connected in series to create a three-stage continuous reactor system. After turning on the stirring function of the first reactor 01, the temperature was raised to 50°C. The raw material pump and feed valve were opened, and 300L / h of o-methylphenylacetonitrile, 160L / h of n-butyl nitrite, and 290kg / h of potassium carbonate powder were simultaneously and continuously pumped into the first reactor 01. The temperature in the first reactor 01 was controlled at 50°C to produce a primary reaction liquid. When the primary reaction liquid overflowed from the overflow port of the first reactor 01 into the second reactor 02, stirring was resumed. Simultaneously, 120L / h of n-butyl nitrite and 365kg / h of potassium carbonate powder were continuously pumped into the second reactor 02. The reaction temperature in the second reactor 02 was controlled at 60°C to produce a secondary reaction liquid. When the secondary reaction liquid overflows into the third reactor 03 through the overflow port of the second reactor 02, it is ripened and the reaction temperature in the third reactor 03 is controlled to be 70°C until the reaction is complete (sampling HPLC detection shows that the purity of o-methylphenylacetonitrile is less than 0.5% and is considered as the reaction end point), a tertiary reaction liquid is obtained. When the tertiary reaction liquid overflows into the 5000L acidifying reactor 04 through the overflow port of the third reactor 03, the stirring function of the acidifying reactor 04 is turned on, and 380L / h of hydrochloric acid is obtained by pumping in a mass concentration of 30%, and the reaction temperature is maintained at 65°C. After continuing for 2h, the bottom regulating valve 05 is opened. While keeping the liquid level in the acidifying reactor 04 substantially unchanged, the material is discharged into the centrifuge 06 for centrifugation. The centrifuged solid is dried by the dryer 07 to obtain (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid, which has a content of 99.27% and a yield of 96.61% according to HPLC quantitative analysis.
[0033] Example 3:
[0034] In this embodiment, the production process of (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid is as follows:
[0035] Three 1500L reactors were connected in series to create a three-stage continuous reactor system. After turning on the stirring function of the first reactor (01), the temperature was raised to 40°C. The raw material pump and feed valve were opened, and 300L / h of o-methylphenylacetonitrile, 160L / h of n-butyl nitrite, and 164kg / h of potassium hydroxide powder were continuously pumped into the first reactor (01). The temperature in the first reactor (01) was maintained at 40°C to produce a primary reaction liquid. When the primary reaction liquid overflowed through the overflow port of the first reactor (01) into the second reactor (02), stirring was resumed. Simultaneously, 120L / h of n-butyl nitrite and 215kg / h of potassium hydroxide powder were continuously pumped into the second reactor (02). The reaction temperature in the second reactor (02) was maintained at 80°C to produce a secondary reaction liquid. When the secondary reaction liquid overflowed into the third reactor, it was matured until the reaction was complete to produce a tertiary reaction liquid (a sample was taken for HPLC analysis; an o-methylphenylacetonitrile purity of <0.5% was considered the reaction endpoint). The reaction was then controlled at 80°C. When the tertiary reaction liquid overflowed into the 5000L acidifying kettle 04 through the overflow port of the second reactor 02, stirring was started and 450L / h of 30% hydrochloric acid was pumped in. At the same time, the temperature in the acidifying kettle 04 was maintained at 70°C for 5 hours. The bottom regulating valve 05 was opened and the material was discharged to centrifuge 06 while keeping the liquid level in the acidifying kettle 04 basically unchanged. The centrifuged solid was dried in dryer 07 to obtain (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid. According to HPLC quantitative analysis, the content was 99.27% and the yield was 97.58%.
[0036] Example 4:
[0037] In this embodiment, the production process of (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid is as follows:
[0038] Three 1500L reactors were connected in series to form a three-stage continuous reactor unit. After turning on the stirring function of the first reactor 01, the temperature was raised to 100°C. The raw material pump and feed valve were opened, and 300L / h of o-methylphenylacetonitrile, 140L / h of isopropyl nitrite, and 202kg / h of sodium hydroxide powder were continuously pumped into the first reactor 01. The temperature in the first reactor 01 was controlled at 100°C, and the reaction was carried out to obtain a primary reaction liquid. When the primary reaction liquid overflowed from the overflow port of the first reactor 01 into the second reactor 02 through the overflow port, stirring was resumed. At the same time, 120L / h of isopropyl nitrite and 224kg / h of sodium hydroxide powder were continuously pumped into the second reactor 02. The reaction temperature in the second reactor 02 was controlled at 90°C, and the reaction was carried out to obtain a secondary reaction liquid. When secondary reaction liquid overflows into the 3rd reactor 03 by the overflow port of the second reactor 02 and carries out slaking, and controlling the reaction temperature in the 3rd reactor 03 is 100 ℃ to reacting completely (sampling HPLC detects, o-methylbenzene acetonitrile purity<0.5% is regarded as reaction end), obtain tertiary reaction liquid.When tertiary reaction liquid overflows into the 5000L acidifying still by the overflow port of the 3rd reactor 03 and opens stirring, and pumping into mass concentration is 30% hydrochloric acid 472L / h, maintains temperature in the acidifying still 04 simultaneously in 70 ℃, after continuing 4h, open bottom regulating valve 05, while keeping the interior liquid level of the acidifying still 04 substantially unchanged, discharging to centrifuge 06 is centrifugal, and centrifuged solid is dried through drying machine 07, obtains (E) 2-hydroxyimino-[(2-o-methylphenyl)] acetic acid, according to HPLC quantitative analysis, content 99.17%, yield 93.21%.
[0039] Example 5:
[0040] In this embodiment, the production process of (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid is as follows:
[0041] Three 1500L reactors were connected in series to create a three-stage continuous reactor system. After turning on the stirring function of the first reactor (01), the temperature was raised to 40°C. The raw material pump and feed valve were opened, and 300L / h of o-methylphenylacetonitrile, 130L / h of ethyl nitrite, and 164kg / h of potassium hydroxide powder were continuously pumped into the first reactor (01). The temperature in the first reactor (01) was controlled at 40°C to produce a primary reaction liquid. When the primary reaction liquid overflowed from the overflow port of the first reactor (01) into the second reactor (02), stirring was resumed. Simultaneously, 128L / h of ethyl nitrite and 215kg / h of potassium hydroxide powder were continuously pumped into the second reactor (02). The reaction temperature in the second reactor (02) was controlled at 80°C to produce a secondary reaction liquid. When the secondary reaction liquid overflowed into the third reactor, it was matured until the reaction was complete to produce a tertiary reaction liquid (a sample was taken for HPLC analysis; an o-methylphenylacetonitrile purity of <0.5% was considered the reaction endpoint). The reaction was then controlled at 80°C. When the tertiary reaction liquid overflowed into the 5000L acidifying kettle 04 through the overflow port of the second reactor 02, stirring was started and 450L / h of 30% hydrochloric acid was pumped in. At the same time, the temperature in the acidifying kettle 04 was maintained at 70°C for 5 hours. The bottom regulating valve 05 was opened. While keeping the liquid level in the acidifying kettle 04 basically unchanged, the material was discharged to centrifuge 06 for centrifugation. The centrifuged solid was dried in dryer 07 to obtain (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid. According to HPLC quantitative analysis, the content was 99.32% and the yield was 95.12%.
[0042] Example 6:
[0043] Three 1500L reactors were connected in series to create a three-stage continuous reactor system. After turning on the stirring function of the first reactor (01), the temperature was raised to 40°C. The raw material pump and feed valve were opened, and 300L / h of o-methylphenylacetonitrile, 160L / h of n-butyl nitrite, and 1250L / h of a 25% aqueous sodium hydroxide solution were continuously pumped into the first reactor (01). The temperature in the first reactor (01) was maintained at 40°C to produce a primary reaction liquid. When the primary reaction liquid overflowed from the overflow port of the first reactor (01) into the second reactor (02), stirring was resumed. Simultaneously, 120L / h of n-butyl nitrite and 350L / h of a 25% aqueous sodium hydroxide solution were continuously pumped into the second reactor (02). The reaction temperature in the second reactor (02) was maintained at 80°C to produce a secondary reaction liquid. When secondary reaction liquid overflows to the 3rd reactor slaking to reacting completely and obtains tertiary reaction liquid (sampling HPLC detects, o-methylbenzene acetonitrile purity<0.5% is regarded as reaction end), controlled temperature 80 ℃ of reactions.Open stirring when tertiary reaction liquid overflows to 5000L acidifying still 04 by the overflow port of second reactor 02, and pumping into mass concentration is 30% sulfuric acid 550L / h, and maintaining temperature in the acidifying still 04 is 70 ℃ simultaneously, after continuing 5h.Open bottom regulating valve 05, under the situation that liquid level in the acidifying still 04 is basically unchanged, discharging to centrifuge 06 is centrifugal, and centrifuged solid is dried through drying machine 07, obtains (E) 2-hydroxyimino-[(2-o-methylphenyl)] acetic acid, according to HPLC quantitative analysis, content 99.41%, yield 94.22%.
Claims
1. A continuous production method of (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid, characterized in that: The method comprises: The compound shown in formula I is o-methylphenylacetonitrile as a raw material, and a nitrite and a base are reacted in a certain proportion in a three-stage series reactor. The resulting reaction solution is continuously flowed into an acidification reactor (04) to add acid for acidification reaction, and then centrifuged and dried to obtain (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid; Wherein, the R group of the nitrite is an alkyl group independently selected from tert-butyl, n-butyl, ethyl, n-propyl or isopropyl.
2. A continuous production method of (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid according to claim 1, characterized in that: The three-stage reactor continuous reaction process is as follows: the compound shown in Formula I is pumped into the first reactor (01) at a constant flow rate, and nitrite and base are continuously fed into the first reactor (01) at a constant flow rate, and the obtained reaction liquid overflows into the second reactor (02) through the overflow port of the first reactor (01), and nitrite and base are continuously fed into the second reactor (02) at a constant flow rate to obtain a secondary reaction liquid, and the obtained secondary reaction liquid overflows into the third reactor (03) through the overflow port of the second reactor (02) to continue the reaction until completion.
3. A continuous production method of (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid according to claim 2, characterized in that: The feed molar flow ratio of nitrite to o-methylphenylacetonitrile in the first reactor (01) is 0.4-0.8:1; the feed molar flow ratio of nitrite to o-methylphenylacetonitrile in the second reactor (02) is 0.2-0.7:
1.
4. The continuous production method of a (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid according to claim 2, characterized in that: The reaction temperature of the first reactor (01) is 20-120°C, the reaction temperature of the second reactor (02) is 40-140°C, and the reaction temperature of the third reactor (03) is 50-150°C.
5. The continuous production method of (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid according to claim 1, wherein: The total residence time of the three-stage reactor continuous reaction is 6 to 20 hours.
6. The continuous production method of (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid according to claim 2, characterized in that: The base is any one of the following bases or their aqueous solutions: potassium carbonate, sodium carbonate, sodium bicarbonate, sodium methoxide, ethanolamine, potassium hydroxide and sodium hydroxide.
7. The continuous production method of (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid according to claim 6, characterized in that: The alkali is any one of the following alkalis or their aqueous solutions: potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide and sodium hydroxide.
8. The continuous production method of (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid according to claim 2, characterized in that: The molar flow ratio of the alkali used in the first reaction kettle (01) to the feed of o-methylphenylacetonitrile is 0.5-5:1, and the molar flow ratio of the alkali used in the second reaction kettle (02) to the feed of o-methylphenylacetonitrile is 1-4:
1.
9. The continuous production method of (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid according to claim 1, characterized in that: The acid is hydrochloric acid with a mass concentration of 30% or sulfuric acid with a mass concentration of 30%.
10. The continuous production method of (E) 2-hydroxyimino-[(2-o-methylphenyl)]acetic acid according to claim 1, characterized in that: The reaction temperature of the acidification reaction is 10-80° C.; the residence time of the material in the acidification kettle (04) during the acidification reaction is 0.5-5 h.