CN110423205B - Synthesis process of 2,3,4, 5-tetrafluoro-N-methylbenzamide suitable for continuous production - Google Patents
Synthesis process of 2,3,4, 5-tetrafluoro-N-methylbenzamide suitable for continuous production Download PDFInfo
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Abstract
The invention belongs to the technical field of preparation of tetrafluorobenzamide, and particularly relates to a green synthesis process of 2,3,4, 5-tetrafluoro-N-methylbenzamide. The green synthesis process of the 2,3,4, 5-tetrafluoro-N-methylbenzamide comprises the following steps: the raw material 3,4,5, 6-tetrafluoro-N-methylphthalimide is subjected to decarboxylation reaction under the catalysis of inorganic base, wherein the inorganic base is potassium fluoride, potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate. The invention provides a green synthesis process of 2,3,4, 5-tetrafluoro-N-methylbenzamide suitable for continuous production of 2,3,4, 5-tetrafluorobenzoyl chloride, and the 2,3,4, 5-tetrafluoro-N-methylbenzamide prepared by the process has high purity and yield.
Description
Technical Field
The invention belongs to the technical field of tetrafluorobenzamide preparation, and particularly relates to a synthesis process of 2,3,4, 5-tetrafluoro-N-methylbenzamide suitable for continuous production.
Background
2,3,4, 5-tetrafluorobenzoyl chloride is an important medical intermediate in the synthesis process of third-generation fluoroquinolone broad-spectrum antibacterial drugs ofloxacin and levofloxacin.
In view of production cost and the like, 2,3,4, 5-tetrafluorobenzoyl chloride is prepared from phthalic anhydride and other substances as starting materials through multi-step reactions in actual production.
Through retrieval, the decarboxylation reaction involved in the preparation process of the 2,3,4, 5-tetrafluorobenzoyl chloride in the prior art is mainly prepared by decarboxylation of 3,4,5, 6-tetrafluorophthalic acid under the action of tertiary amine.
For example, Chinese patent CN102627553A discloses that 2,3,4, 5-tetrafluorobenzoic acid is prepared by decarboxylation of hydrolysate 3,4,5, 6-tetrafluorophthalic acid of 2,3,4, 5-tetrafluorophthalimide under the catalysis of tri-n-butylamine. The decarboxylation reaction route in the reaction route is as follows:
the decarboxylation reaction is to carry out decarboxylation reaction on the raw materials 3,4,5, 6-tetrafluorophthalic acid and tri-n-butylamine, after the reaction is finished, water is added, then alkali liquor is added, the tri-n-butylamine is separated out, the alkali liquor phase is neutralized by adding acid, and an extraction solvent is used for extracting materials; the conditions of the shuttle stripping reaction are as follows: the reaction temperature is 100 ℃ and 150 ℃, and the reaction time is 1-5 hours.
For another example, chinese patent CN102603521A discloses that 3,4,5, 6-tetrafluorophthalic acid is used as a raw material, decarboxylation is performed in an aromatic hydrocarbon solvent in the presence of a catalyst organic tertiary amine at 160 ℃ for 10-30 hours, after the reaction is completed, the reaction system is cooled to 20-30 ℃, filtration is performed, the filtrate is used for the next decarboxylation, an acyl chlorination reagent and an organic amide catalyst are directly added to the filtered 2,3,4, 5-tetrafluorobenzoic acid solid, the temperature is raised for reaction for 3-15 hours, after the acyl chlorination reaction is completed, a low-boiling-point substance is removed by evaporation from the reaction system, and the 2,3,4, 5-tetrafluorobenzoyl chloride finished product is obtained by rectification and reduced pressure. The organic amine is any one or more of tri-N-propylamine, tri-isopropylamine, diisopropylethylamine, tri-N-butylamine, N-methylmorpholine, N-dimethylpiperazine and N-methylpyrrolidine. The aromatic hydrocarbon solvent is one or more of toluene, xylene, trimethylbenzene and chlorobenzene.
However, the purity of the product in each step in the above reaction route is generally between 50-65%, and the product can be used in the subsequent reaction after purification and drying, and the industrial continuous production can not be carried out due to the change of the solvent system between each step. For this reason, the applicant has made an effort to develop a reaction route which is suitable for continuous production and has high product purity and yield in each step. Multiple tests show that the 2,3,4, 5-tetrafluoro-benzoic acid tetrafluoride is prepared by decarboxylation of 3,4,5, 6-tetrafluoro-N-methylphthalimide and then hydrolyzed to prepare the 2,3,4, 5-tetrafluoro-benzoic acid, which is suitable for continuous production of 2,3,4, 5-tetrafluorobenzoyl chloride.
Disclosure of Invention
In order to solve the above problems in the prior art, the present invention is directed to a method for preparing 2,3,4, 5-tetrafluoro-N-methyl-benzamide from 3,4,5, 6-tetrafluoro-N-methylphthalimide with high yield and purity, which facilitates continuous production.
In order to achieve the above object, the present invention provides the following technical solutions:
a green synthesis process of 2,3,4, 5-tetrafluoro-N-methylbenzamide comprises the following steps:
the raw material 3,4,5, 6-tetrafluoro-N-methylphthalimide is subjected to decarboxylation reaction under the catalysis of inorganic base, wherein the inorganic base is potassium fluoride, potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate.
Preferably, the solvent for the decarboxylation reaction is one of aprotic polar solvents, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide DMSO and sulfolane.
Further preferably, the solvent is dimethyl sulfoxide DMSO, and the volume mass ratio of the dimethyl sulfoxide DMSO to the raw material 3,4,5, 6-tetrafluoro-N-methylphthalimide is 2-10:1 mL/g.
Preferably, the H in dimethyl sulfoxide DMSO is2The content of O is 1-30%.
Preferably, the inorganic base is potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate.
Further preferred is potassium hydroxide or sodium hydroxide.
The alkali of the scheme is used as a catalyst, and the generated reaction by-products can be repeatedly used in the reaction process, so that the use amount of the alkali is reduced, the generation of solid waste is avoided, and green production is realized.
Preferably, the inorganic base is added in the form of an aqueous solution having a concentration of 1-20%. The concentration of the inorganic alkali liquor directly influences the purity and yield of the product. When the concentration of the alkali liquor is too low, the reaction time is long, even basically no reaction is carried out, and the production efficiency is low; when the concentration of the alkali liquor is too high, the concentration exceeds 20 percent, fluorine in the raw material 3,4,5, 6-tetrafluoro-N-methylphthalimide falls off to different degrees, byproducts are increased, and the yield is reduced.
Further preferably, the aqueous inorganic base solution is 5 to 10% potassium hydroxide.
Preferably, the decarboxylation reaction conditions are: the reaction temperature is 90-120 ℃, the pH value of the solution is 7-8, and the reaction time is 1-10 hours.
Further preferably, the decarboxylation reaction conditions are: the reaction temperature is 95-110 ℃, the pH value of the solution is 7-8, and the reaction time is 1-6 hours; still more preferably 1-4 hours.
Preferably, the depondensation reaction is carried out at the temperature of between 25 and 30 ℃ for 1 to 10 hours before the depondensation reaction is carried out at the temperature of between 90 and 120 ℃.
Further preferably, the polycondensation reaction is carried out at the temperature of between 25 and 30 ℃ for 1 to 5 hours before the deponderation reaction is carried out at the temperature of between 90 and 120 ℃; still more preferably 1-3 hours.
As a preferred embodiment, the green synthesis process of the 2,3,4, 5-tetrafluoro-N-methylbenzamide comprises the following steps: adding inorganic alkali liquor into the 3,4,5, 6-tetrafluoro-N-methylphthalimide solution, adjusting the pH of the solution to 7-8, carrying out decarboxylation reaction at 90-120 ℃, filtering after the reaction is finished, concentrating to remove the solvent, adding water for dilution, filtering, and drying to obtain a target product; the inorganic base is potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate.
Preferably, the residual solvent in the solvent removal by concentration is 0.8 to 1.5 times equivalent to the raw material of 3,4,5, 6-tetrafluoro-N-methylphthalimide; that is, if the amount of the starting material is 1g, the amount of the residual solution is 0.8 to 1.5 mL.
When the water is added for dilution, the amount of the added water is 2-10 times of the concentrated solution, namely about 1mL of residual solution, and 2-10mL of the added water is added.
Preferably, the conditions for concentrating the desolventizer are: the pressure is between 0.08 and 0MPa below zero, and the temperature is between 90 and 120 ℃.
Compared with the prior art, the green synthesis process of the 2,3,4, 5-tetrafluoro-N-methylbenzamide provided by the invention has the following beneficial effects:
(1) the invention provides a green synthesis process of 2,3,4, 5-tetrafluoro-N-methylbenzamide suitable for continuous production of 2,3,4, 5-tetrafluorobenzoyl chloride, and the 2,3,4, 5-tetrafluoro-N-methylbenzamide prepared by the process has high purity and yield.
(2) According to the preferred embodiment provided by the invention, potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate is used as the base to catalyze the decarboxylation reaction, and the generated reaction by-products can be repeatedly used in the reaction process, so that the use amount of the base is reduced, the generation of solid waste is avoided, and the green production is realized.
(3) In the traditional process, as the decarboxylation process is easy to generate side reaction for removing fluorine, a plurality of byproducts are generated; and because the target product and the by-product have close polarity and are difficult to separate, the purity of the product 2,3,4, 5-tetrafluoro-N-methylbenzamide is generally not more than 70 percent, and the product cannot be used for the continuous production of the 2,3,4, 5-tetrafluorobenzoyl chloride.
By adopting the synthesis process provided by the invention, the raw material 2,3,4, 5-tetrafluoro-N-methylphthalimide is not easy to generate defluorination reaction, and the purity and yield of the product can reach more than 90%. In the preparation process of the 2,3,4, 5-tetrafluorobenzoyl chloride, the benzoyl chloride can be directly used for the next reaction without purification. The purification step can be saved, and the operation steps for producing the 2,3,4, 5-tetrafluorobenzoyl chloride are simplified.
Detailed Description
In order to make the purpose and technical solution of the embodiments of the present invention clearer, the technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. In the embodiment of the invention, in continuous production, the filtered product can be directly used for the next hydrolysis reaction without drying.
Example 1
A green synthesis process of 2,3,4, 5-tetrafluoro-N-methylbenzamide comprises the following steps:
mixing and dissolving 3,4,5, 6-tetrafluoro-N-methylphthalimide and a solvent DMSO in a ratio of 1g to 10mL, dropwise adding a potassium hydroxide solution with the mass concentration of 5% at normal temperature, adjusting the pH value of the solution to 7, carrying out heat preservation reaction at 25-30 ℃ for 1 hour, then heating to 95 ℃, carrying out heat preservation reaction for 2 hours, finishing the reaction, filtering, concentrating the solvent to be 1 time of the amount of the raw material 3,4,5, 6-tetrafluoro-N-methylphthalimide under the conditions of the pressure of-0.08 MPa to 0MPa and the temperature of 100 ℃, adding water which is 2 times of the amount of the concentrated solution for dilution, cooling to about 40 ℃, filtering, and drying to obtain a target product pure 2,3,4, 5-tetrafluoro-N-methylbenzamide; the by-product obtained by filtration can be used for the next batch of reaction after the pH value is adjusted. In this example, the product 2,3,4, 5-tetrafluoro-N-methylbenzamide had a purity of 95% and a yield of 95%.
Example 2
A green synthesis process of 2,3,4, 5-tetrafluoro-N-methylbenzamide comprises the following steps:
mixing and dissolving 3,4,5, 6-tetrafluoro-N-methylphthalimide and a solvent DMSO in a ratio of 1g to 10mL, dropwise adding a potassium fluoride solution with the mass concentration of 5% at normal temperature, adjusting the pH value of the solution to 7, carrying out heat preservation reaction at 25-30 ℃ for 1 hour, then heating to 95 ℃, carrying out heat preservation reaction for 2 hours, finishing the reaction, filtering, concentrating the solvent to be 1 time of the amount of the raw material 3,4,5, 6-tetrafluoro-N-methylphthalimide under the conditions of the pressure of-0.08 MPa to 0MPa and the temperature of 100 ℃, adding water which is 2 times of the amount of the concentrated solution for dilution, cooling to about 40 ℃, filtering, and drying to obtain the target product pure 2,3,4, 5-tetrafluoro-N-methylbenzamide.
The product, 2,3,4, 5-tetrafluoro-N-methylbenzamide, was 70% pure by this example, and was 91% yield.
Example 3
A green synthesis process of 2,3,4, 5-tetrafluoro-N-methylbenzamide comprises the following steps:
mixing and dissolving 3,4,5, 6-tetrafluoro-N-methylphthalimide and a solvent DMSO in a ratio of 1g to 10mL, dropwise adding a potassium hydroxide solution with the mass concentration of 5% at normal temperature, adjusting the pH value of the solution to 7, carrying out heat preservation reaction at 25-30 ℃ for 1 hour, then heating to 135 ℃, carrying out heat preservation reaction for 2 hours, finishing the reaction, filtering, concentrating the solvent to be 1 time of the amount of the raw material 3,4,5, 6-tetrafluoro-N-methylphthalimide under the conditions of the pressure of-0.08 MPa to 0MPa and the temperature of 100 ℃, adding water which is 2 times of the amount of the concentrated solution for dilution, cooling to about 40 ℃, filtering, and drying to obtain a target product pure 2,3,4, 5-tetrafluoro-N-methylbenzamide; the by-product obtained by filtration can be used for the next batch of reaction after the pH value is adjusted.
The product, 2,3,4, 5-tetrafluoro-N-methylbenzamide, was 85% pure in 93% yield.
Example 4
A green synthesis process of 2,3,4, 5-tetrafluoro-N-methylbenzamide comprises the following steps:
mixing and dissolving 3,4,5, 6-tetrafluoro-N-methylphthalimide and a solvent DMSO in a ratio of 1g to 10mL, dropwise adding a potassium hydroxide solution with the mass concentration of 5% at normal temperature, adjusting the pH value of the solution to 7, heating to 95 ℃, preserving heat for reaction for 3 hours, finishing the reaction, filtering, concentrating the solvent to 1 time of the amount of the raw material 3,4,5, 6-tetrafluoro-N-methylphthalimide under the conditions of the pressure of-0.08 MPa to 0MPa and the temperature of 100 ℃, adding water of 2 times of the concentrated solution for dilution, cooling to about 40 ℃, filtering and drying to obtain a target product pure 2,3,4, 5-tetrafluoro-N-methylbenzamide; the by-product obtained by filtration can be used for the next batch of reaction after the pH value is adjusted.
The product, 2,3,4, 5-tetrafluoro-N-methylbenzamide, was 75% pure in 91% yield.
Example 5
A green synthesis process of 2,3,4, 5-tetrafluoro-N-methylbenzamide comprises the following steps:
mixing and dissolving 3,4,5, 6-tetrafluoro-N-methylphthalimide and a solvent DMSO in a ratio of 1g to 10mL, dropwise adding a potassium hydroxide aqueous solution with the mass concentration of 25% at normal temperature, adjusting the pH value of the solution to 7, carrying out heat preservation reaction at 25-30 ℃ for 1 hour, then heating to 95 ℃, carrying out heat preservation reaction for 2 hours, finishing the reaction, filtering, concentrating the solvent to be 1 time of the amount of the raw material 3,4,5, 6-tetrafluoro-N-methylphthalimide under the conditions of the pressure of-0.08 MPa to 0MPa and the temperature of 100 ℃, adding water which is 2 times of the amount of the concentrated solution for dilution, cooling to about 40 ℃, filtering, and drying to obtain a target product pure 2,3,4, 5-tetrafluoro-N-methylbenzamide; the by-product obtained by filtration can be used for the next batch of reaction after the pH value is adjusted.
The product, 2,3,4, 5-tetrafluoro-N-methylbenzamide, was 78% pure in 92% yield.
Example 6
A green synthesis process of 2,3,4, 5-tetrafluoro-N-methylbenzamide comprises the following steps:
mixing and dissolving 3,4,5, 6-tetrafluoro-N-methylphthalimide and a solvent N, N-dimethylformamide according to a ratio of 1g:10mL, dropwise adding a potassium hydroxide solution with the mass concentration of 25% at normal temperature, adjusting the pH value of the solution to 7, carrying out heat preservation reaction at 25-30 ℃ for 1 hour, then heating to 95 ℃, carrying out heat preservation reaction for 2 hours, finishing the reaction, filtering, concentrating the solvent to 1 time of the amount of 3,4,5, 6-tetrafluoro-N-methylphthalimide which is equivalent to the raw material under the conditions of the pressure of-0.08 MPa to 0MPa and the temperature of 100 ℃, adding water which is equivalent to 2 times of the amount of the concentrated solution for dilution, cooling to about 40 ℃, filtering and drying to obtain a target product of pure 2,3,4, 5-tetrafluoro-N-methylbenzamide; the by-product obtained by filtration can be used for the next batch of reaction after the pH value is adjusted.
The product, 2,3,4, 5-tetrafluoro-N-methylbenzamide, was 91% pure in 93% yield.
The above are merely embodiments of the present invention, which are described in detail and with particularity, and therefore should not be construed as limiting the scope of the invention. It should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the spirit of the present invention, and these changes and modifications are within the scope of the present invention.
Claims (1)
1. A synthetic process of 2,3,4, 5-tetrafluoro-N-methylbenzamide suitable for continuous production is characterized by comprising the following steps:
mixing and dissolving 3,4,5, 6-tetrafluoro-N-methylphthalimide and a solvent DMSO in a ratio of 1g to 10mL, dropwise adding a potassium hydroxide solution with the mass concentration of 5% at normal temperature, adjusting the pH value of the solution to 7, carrying out heat preservation reaction at 25-30 ℃ for 1 hour, then heating to 95 ℃, carrying out heat preservation reaction for 2 hours, finishing the reaction, filtering, concentrating the solvent to be 1 time of the amount of the raw material 3,4,5, 6-tetrafluoro-N-methylphthalimide under the conditions of the pressure of-0.08 MPa to 0MPa and the temperature of 100 ℃, adding water which is 2 times of the amount of the concentrated solution for dilution, cooling to about 40 ℃, filtering, and drying to obtain a target product pure 2,3,4, 5-tetrafluoro-N-methylbenzamide; the by-product obtained by filtration can be used for the next batch of reaction after the pH value is adjusted.
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Citations (4)
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|---|---|---|---|---|
| CN86106151A (en) * | 1985-09-09 | 1987-06-03 | 沃纳·兰伯特公司 | The improved method for preparing tetrafluorobenzoic aid |
| US5233082A (en) * | 1982-11-16 | 1993-08-03 | Occidental Chemical Corporation | Method of making 3-hydroxy-2,4,5-trifluorobenzoic acid |
| CN1201779A (en) * | 1998-07-09 | 1998-12-16 | 华东理工大学 | Preparation of 2,3,4,5-tetrafluorobenzoic acid |
| CN107188875A (en) * | 2016-03-15 | 2017-09-22 | 联化科技股份有限公司 | A kind of Preparation Method And Their Intermediate of substituted benzene phthalein compounds |
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2019
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Patent Citations (4)
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|---|---|---|---|---|
| US5233082A (en) * | 1982-11-16 | 1993-08-03 | Occidental Chemical Corporation | Method of making 3-hydroxy-2,4,5-trifluorobenzoic acid |
| CN86106151A (en) * | 1985-09-09 | 1987-06-03 | 沃纳·兰伯特公司 | The improved method for preparing tetrafluorobenzoic aid |
| CN1201779A (en) * | 1998-07-09 | 1998-12-16 | 华东理工大学 | Preparation of 2,3,4,5-tetrafluorobenzoic acid |
| CN107188875A (en) * | 2016-03-15 | 2017-09-22 | 联化科技股份有限公司 | A kind of Preparation Method And Their Intermediate of substituted benzene phthalein compounds |
Non-Patent Citations (1)
| Title |
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| Unmasking Amides: Ruthenium-Catalyzed Protodecarbonylation of N‑Substituted Phthalimide Derivatives;Yu-Chao Yuan等;《organic letters》;20171231(第19期);6404-6407 * |
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