CN111662172A - Process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid by one-pot method - Google Patents
Process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid by one-pot method Download PDFInfo
- Publication number
- CN111662172A CN111662172A CN202010449320.0A CN202010449320A CN111662172A CN 111662172 A CN111662172 A CN 111662172A CN 202010449320 A CN202010449320 A CN 202010449320A CN 111662172 A CN111662172 A CN 111662172A
- Authority
- CN
- China
- Prior art keywords
- trifluoro
- reaction
- methoxybenzoic acid
- preparing
- methyltetrafluorophthalimide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- B01J27/06—Halogens; Compounds thereof
- B01J27/138—Halogens; Compounds thereof with alkaline earth metals, magnesium, beryllium, zinc, cadmium or mercury
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
- C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
Abstract
The invention discloses a process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid by a one-pot method, which comprises the step of obtaining 4-hydroxy salt-3, 5, 6-trifluoro phthalate, and the step comprises the following steps: the 4-hydroxy salt-3, 5, 6-trifluoro phthalate is obtained by putting N-methyl tetrafluorophthalimide in an alkaline environment and carrying out hydrolytic defluorination and hydroxylation reaction by taking metal halide as a catalyst. The invention has low cost of raw materials and short process route, and the synthesis of the 4-hydroxy salt-3, 5, 6-trifluorophthalate only takes about 8-10 hours; the alkali consumption is reduced by more than 50 percent, side reactions are less or not generated at all, the total molar yield of the reaction can reach 85 percent, and the purity of the product can reach more than 99.8 percent.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid by a one-pot method.
Background
2,4, 5-Trifluoro-3-methoxybenzoic Acid (2,4, 5-trifluo-3-Methoxy Benzoic Acid) is a key intermediate for synthesizing new fluoroquinolone antibacterial drugs such as gatifloxacin (gatifloxacin), balofloxacin (balofloxacin), moxifloxacin (moxifioxicacin) and the like, and due to the irreplaceability of the intermediate, the synthesis process of the 2,4, 5-Trifluoro-3-methoxybenzoic Acid is improved in recent decades, and currently, the synthesis route suitable for industrial production mainly comprises the following steps:
in the first route, N-methyltetrafluorophthalimide is taken as a raw material (see U.S. patent publication No. US 05380926), and the method comprises the following steps (1) and (2):
(1)
(2)
and the second route is that tetrafluorophthalic acid is taken as a raw material (see the literature: Tianzhiming, Liu Ming, Guo Huiyuan. 2,4, 5-trifluoro-3-methoxybenzoic acid preparation [ J ] China medicine industry journal 20000.31 (12): 557-558):
the existing synthetic method of 2,4, 5-trifluoro-3-methoxybenzoic acid has the following defects: in the first route, N-methyltetrafluorophthalimide is subjected to hydrolytic defluorination in an alkaline aqueous solution, but after the hydrolytic defluorination, 2,4, 5-trifluoro-3-hydroxybenzoic acid needs to be separated out firstly, and then the subsequent reaction is carried out, and the subsequent reaction can not be carried out continuously in the same reaction vessel, so that the process route is longer; although the second route is a method for synthesizing 2,4, 5-trifluoro-3-methoxybenzoic acid by a one-pot method, the price of the tetrafluorophthalic acid is relatively high, and in the existing synthetic routes including the first route and the second route, a large amount of sodium hydroxide is required, so that the side reactions are more, and the purification of the target product is difficult.
Disclosure of Invention
The invention aims to provide a process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid by a one-pot method, the synthesis method can be continuously carried out in the same reaction vessel, the process route is short, the time consumption is short, the alkali consumption is small, the raw material cost is low, the side reaction is less or not generated at all, the yield is high, and the purity of the target product is high.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid by a one-pot method comprises the step of obtaining 4-hydroxy salt-3, 5, 6-trifluorophthalate, and is characterized in that the step of obtaining 4-hydroxy salt-3, 5, 6-trifluorophthalate comprises the following steps:
the 4-hydroxy salt-3, 5, 6-trifluoro phthalate is obtained by putting N-methyl tetrafluorophthalimide in an alkaline environment and carrying out hydrolytic defluorination and hydroxylation reaction by taking metal halide as a catalyst.
In the case of sodium hydroxide providing an alkaline environment, the reaction is shown in formula (I):
after synthesizing the 4-hydroxy salt-3, 5, 6-trifluoro phthalate, the 2,4, 5-trifluoro-3-methoxybenzoic acid can be further synthesized by adopting a conventional one-pot method.
In the synthesis process of the 2,4, 5-trifluoro-3-methoxybenzoic acid, N-methyltetrafluorophthalimide with low price is used as a raw material, the 2,4, 5-trifluoro-3-methoxybenzoic acid is synthesized in the same reaction vessel by a one-pot method, and an intermediate product does not need to be separated and purified in the synthesis process, so that the process route is short and the operation is convenient.
In the hydrolysis defluorination and hydroxylation reaction, the amido bond of the N-methyltetrafluorophthalimide is not directly broken, but an intermediate is firstly generated, and the intermediate is shown as a formula (IV):
the amide bonds of these two intermediates are further cleaved to form the 4-hydroxy salt 3,5, 6-trifluorophthalate, which results in a longer reaction time for this step.
Therefore, the metal halide is added as a catalyst in the hydrolysis defluorination and hydroxylation reactions, and can promote the amide bond to be broken, thereby greatly accelerating the reaction process. In addition, the addition of the catalyst can also greatly reduce the use amount of alkali (such as sodium hydroxide), avoid the phenomena that the reaction system cannot transfer materials due to excessive salt content or hydrolysis defluorination and hydroxylation reaction are incomplete because a large amount of salt (such as sodium chloride) is generated by acid-base reaction, improve the reaction conversion rate and facilitate industrial production.
Furthermore, after the catalyst is added, the using amount of alkali is greatly reduced, the reaction time is greatly shortened, and the occurrence of side reaction double hydroxylation (side reaction is shown as the formula (V)) can be avoided to a greater or lesser extent:
and the reduction or complete avoidance of side reactions can improve the purity of the target product, and avoid the trouble of purification and refining of the target product.
The 2,4, 5-trifluoro-3-methoxybenzoic acid prepared by the one-pot synthesis process has low raw material cost and short process route, and the synthesis of the 4-hydroxy salt-3, 5, 6-trifluorophthalate only takes about 8-10 hours and has short time consumption; the usage amount of alkali is reduced by more than 50%, side reactions are less or not generated at all, the total molar yield of the reaction can reach 85%, and the purity of the target product can reach more than 99.8%.
Preferably, the process for preparing the 2,4, 5-trifluoro-3-methoxybenzoic acid by the one-pot method sequentially comprises the following steps of:
(1) putting N-methyl tetrafluorophthalimide in an alkaline environment by taking metal halide as a catalyst, and obtaining 4-hydroxy salt-3, 5, 6-trifluoro phthalate through hydrolysis defluorination and hydroxylation reaction;
taking sodium hydroxide as an example of providing an alkaline environment, the reaction formula of step (1) is shown as formula (I):
(2) adding acid into the reaction system, and obtaining 2,4, 5-trifluoro-3-hydroxybenzoic acid through decarboxylation;
the reaction formula is shown as formula (II):
(3) under the alkaline condition, adding a methylating agent into a reaction system, and obtaining 2,4, 5-trifluoro-3-methoxybenzoate through methylation reaction; continuously adding acid, and obtaining the 2,4, 5-trifluoro-3-methoxybenzoic acid through acidification reaction.
Taking sodium hydroxide as an example to provide an alkaline environment, the reaction formula of step (3) is shown as formula (III):
in the process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid by the one-pot method, in the step (1), the molar ratio of N-methyltetrafluorophthalimide to the alkali is 1 (2-3).
Preferably, in the above one-pot process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid, the molar ratio of N-methyltetrafluorophthalimide to base in step (1) is 1: 3.1.
The base may be a base commonly used in the art, such as sodium hydroxide.
In the above one-pot process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid, in step (1), the metal halide is at least one of zinc chloride, aluminum trichloride or ferric trichloride.
Preferably, in the above one-pot process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid, in step (1), the metal halide is zinc chloride.
In the above one-pot process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid, in step (1), the molar ratio of the metal halide to the N-methyltetrafluorophthalimide is (7-10): 100.
Preferably, in the above process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid by the one-pot method, in the step (1), the molar ratio of the zinc chloride to the N-methyltetrafluorophthalimide is 8.5: 100.
Preferably, the implementation method of the step (1) comprises the following steps: adding N-methyltetrafluorophthalimide, alkali and a catalyst into a reaction kettle according to a preset molar ratio, heating to 90-110 ℃, and preserving heat for 8-10 h. After the reaction is finished, the temperature of the reaction system is reduced to below 35 ℃.
In the process for preparing the 2,4, 5-trifluoro-3-methoxybenzoic acid by the one-pot method, in the step (2), the molar ratio of the acid to the N-methyltetrafluorophthalimide is (3.5-4.5): 1.
Preferably, in the above one-pot process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid, the molar ratio of the acid to N-methyltetrafluorophthalimide in step (2) is 3.9: 1.
In the present invention, the methylation reaction is carried out by a conventional method.
Preferably, in the above one-pot process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid, in step (3), the methylating agent is dimethyl carbonate or dimethyl sulfate, and the molar ratio of the methylating agent to N-methyltetrafluorophthalimide is (2-3): 1.
More preferably, the methylating agent is dimethyl carbonate, and the molar ratio of the dimethyl carbonate to the N-methyltetrafluorophthalimide is 2.4: 1.
Compared with the prior art, the invention has the beneficial effects that:
(1) in the synthesis process of the 2,4, 5-trifluoro-3-methoxybenzoic acid, N-methyltetrafluorophthalimide with low price is used as a raw material, the 2,4, 5-trifluoro-3-methoxybenzoic acid is synthesized in the same reaction vessel by a one-pot method, and an intermediate product does not need to be separated and purified in the synthesis process, so that the process route is short and the operation is convenient.
(2) In the synthesis process of the 2,4, 5-trifluoro-3-methoxybenzoic acid, the metal halide is added as a catalyst in the hydrolysis defluorination and hydroxylation reactions, the metal halide can promote the breakage of amide bonds, the reaction process is greatly accelerated, the reaction process of the formula (I) only needs about 8 hours, and the consumed time is short.
(3) In the synthesis process of the 2,4, 5-trifluoro-3-methoxybenzoic acid, the addition of the catalyst greatly reduces the use amount of alkali (such as sodium hydroxide), the use amount of the alkali is reduced by more than 50 percent, the phenomena that a reaction system cannot transfer materials due to excessive salt content or hydrolysis defluorination and hydroxylation reaction are incomplete because a large amount of salt (such as sodium chloride) is generated by acid-base reaction are avoided, the reaction yield is improved, and the industrial production is facilitated.
(4) In the synthesis process of the 2,4, 5-trifluoro-3-methoxybenzoic acid, the addition of the catalyst can greatly reduce the alkali consumption and shorten the reaction time, and simultaneously can avoid the occurrence of side reaction double hydroxylation to a greater or lesser extent, and the reduction or complete avoidance of the side reaction can improve the purity of the target product, thereby avoiding the trouble of purification and refining of the target product; in the invention, the total molar yield of the reaction can reach 85%, and the purity of the target product can reach more than 99.8%.
Drawings
FIG. 1 is a process scheme of a process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid by a one-pot method according to the present invention;
FIG. 2 is a gas chromatography detection diagram of the end product of the process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid by the one-pot method.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to the accompanying drawings and the detailed description.
Example 1
The process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid by the one-pot method (the process route is shown in figure 1) of the embodiment sequentially comprises the following steps:
(1) putting N-methyl tetrafluorophthalimide in an alkaline environment by taking zinc chloride as a catalyst, and obtaining 4-hydroxy salt-3, 5, 6-trifluoro phthalate through hydrolysis defluorination and hydroxylation reaction;
concretely, 3000kg of water, 1000kg of N-methyltetrafluorophthalimide, 2000kg of 30% caustic soda liquid and 50kg of zinc chloride (the molar ratio of the N-methyltetrafluorophthalimide to the sodium hydroxide is 1:3.1, the molar ratio of the N-methyltetrafluorophthalimide to the zinc chloride is 100:8.5) are added into a reaction kettle, the temperature is raised to 100 ℃, the temperature is kept for 8 hours, and the temperature is lowered to below 35 ℃ after the reaction is finished;
the reaction formula is shown as formula (I):
(2) adding acid into the reaction system, and obtaining 2,4, 5-trifluoro-3-hydroxybenzoic acid through decarboxylation;
specifically, 35% concentrated hydrochloric acid is added into a reaction kettle, the pH of a reaction solution is adjusted to be neutral, and the decarboxylation reaction is carried out through reflux; after the reaction is finished, cooling to 55 ℃;
the reaction formula is shown as formula (II):
(3) under the alkaline condition, adding a methylating agent into a reaction system, and obtaining 2,4, 5-trifluoro-3-methoxybenzoate through methylation reaction; continuously adding acid, and obtaining 2,4, 5-trifluoro-3-methoxybenzoic acid through acidification reaction;
specifically, the pH value of the reaction solution is kept between 8 and 10 by using liquid alkali, 2000kg of dimethyl carbonate is dripped into the reaction kettle, the temperature is controlled to be between 55 and 60 ℃, the temperature is kept for 2 hours, and the temperature is reduced to be below 35 ℃ after the reaction is finished; 2000kg of 35% concentrated hydrochloric acid is added, and 818.86kg of 2,4, 5-trifluoro-3-methoxybenzoic acid is obtained through acidification reaction, wherein the total molar yield of the reaction is 85%.
The reaction formula is shown as formula (III):
the final product was subjected to gas chromatography and the results are shown in FIG. 2.
As shown in FIG. 2, the content of 2,4, 5-trifluoro-3-methoxybenzoic acid in the final product reached 99.8%.
Example 2
The embodiment of the invention relates to a process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid by a one-pot method, which sequentially comprises the following steps:
(1) putting N-methyl tetrafluorophthalimide in an alkaline environment by taking zinc chloride as a catalyst, and obtaining 4-hydroxy salt-3, 5, 6-trifluoro phthalate through hydrolysis defluorination and hydroxylation reaction;
concretely, 3000kg of water and 1000kg of N-methyltetrafluorophthalimide are added into a reaction kettle, and 30% of liquid caustic soda and zinc chloride are added, wherein the molar ratio of the N-methyltetrafluorophthalimide to the sodium hydroxide is 1:2, and the molar ratio of the N-methyltetrafluorophthalimide to the zinc chloride is 100: 10; heating to 100 ℃, preserving heat for 8 hours, cooling to below 35 ℃ after the reaction is finished (the content of N-methyltetrafluorophthalimide in a liquid phase detection reaction system is less than 1%);
(2) adding acid into the reaction system, and obtaining 2,4, 5-trifluoro-3-hydroxybenzoic acid through decarboxylation;
specifically, 35% concentrated hydrochloric acid is added into a reaction kettle, the pH of a reaction solution is adjusted to be neutral, and the decarboxylation reaction is carried out through reflux; after the reaction is finished (the content of the intermediate 2,4, 5-trifluoro-3-hydroxyphthalic acid is less than 1 percent through liquid phase detection), the temperature is reduced to 55 ℃;
(3) under the alkaline condition, adding a methylating agent into a reaction system, and obtaining 2,4, 5-trifluoro-3-methoxybenzoate through methylation reaction; continuously adding acid, and obtaining 2,4, 5-trifluoro-3-methoxybenzoic acid through acidification reaction;
specifically, the pH value of the reaction solution is kept between 8 and 10 by using liquid alkali, 2000kg of dimethyl carbonate is dripped into the reaction kettle, the temperature is controlled to be between 55 and 60 ℃, the temperature is kept for 2 hours, and the temperature is reduced to be below 35 ℃ after the reaction is finished (the content of the intermediate 2,4, 5-trifluoro-3-hydroxybenzoic acid is detected to be less than 1 percent by liquid phase); then 2000kg of 35% concentrated hydrochloric acid was added, and 816.86kg of 2,4, 5-trifluoro-3-methoxybenzoic acid was obtained by acidification reaction. The total molar yield was 84.8%; the content of the 2,4, 5-trifluoro-3-methoxybenzoic acid reaches 99.7 percent.
Example 3
The embodiment of the invention relates to a process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid by a one-pot method, which sequentially comprises the following steps:
(1) putting N-methyl tetrafluorophthalimide in an alkaline environment by taking zinc chloride as a catalyst, and obtaining 4-hydroxy salt-3, 5, 6-trifluoro phthalate through hydrolysis defluorination and hydroxylation reaction;
concretely, 3000kg of water and 1000kg of N-methyltetrafluorophthalimide are added into a reaction kettle, and then 30% liquid caustic soda and zinc chloride are added, wherein the molar ratio of the N-methyltetrafluorophthalimide to the sodium hydroxide is 1:3.5, and the molar ratio of the N-methyltetrafluorophthalimide to the zinc chloride is 100: 7; heating to 100 ℃, preserving heat for 9 hours, cooling to below 35 ℃ after the reaction is finished (the content of N-methyltetrafluorophthalimide in a liquid phase detection reaction system is less than 1%);
(2) adding acid into the reaction system, and obtaining 2,4, 5-trifluoro-3-hydroxybenzoic acid through decarboxylation;
specifically, 35% concentrated hydrochloric acid is added into a reaction kettle, the pH of a reaction solution is adjusted to be neutral, and the decarboxylation reaction is carried out through reflux; after the reaction is finished (the content of the intermediate 2,4, 5-trifluoro-3-hydroxyphthalic acid is less than 1 percent through liquid phase detection), the temperature is reduced to 55 ℃;
(3) under the alkaline condition, adding a methylating agent into a reaction system, and obtaining 2,4, 5-trifluoro-3-methoxybenzoate through methylation reaction; continuously adding acid, and obtaining 2,4, 5-trifluoro-3-methoxybenzoic acid through acidification reaction;
specifically, the pH value of the reaction solution is kept between 8 and 10 by using liquid alkali, 2000kg of dimethyl carbonate is dripped into the reaction kettle, the temperature is controlled to be between 55 and 60 ℃, the temperature is kept for 2 hours, and the temperature is reduced to be below 35 ℃ after the reaction is finished (the content of the intermediate 2,4, 5-trifluoro-3-hydroxybenzoic acid is detected to be less than 1 percent by liquid phase); then 2000kg of 35% concentrated hydrochloric acid was added, and 814.93kg of 2,4, 5-trifluoro-3-methoxybenzoic acid was obtained by acidification reaction. The total molar yield was 84.6%; the content of the 2,4, 5-trifluoro-3-methoxybenzoic acid reaches 99.7 percent.
Example 4
The embodiment of the invention relates to a process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid by a one-pot method, which sequentially comprises the following steps:
(1) putting N-methyltetrafluorophthalimide in an alkaline environment by taking aluminum trichloride as a catalyst, and obtaining 4-hydroxy salt-3, 5, 6-trifluorophthalate through hydrolysis defluorination and hydroxylation reaction;
concretely, 3000kg of water and 1000kg of N-methyltetrafluorophthalimide are added into a reaction kettle, and 30% of liquid caustic soda and aluminum trichloride are added, wherein the molar ratio of the N-methyltetrafluorophthalimide to the sodium hydroxide is 1:3.5, and the molar ratio of the N-methyltetrafluorophthalimide to the aluminum trichloride is 100: 10; heating to 100 ℃, preserving heat for 10 hours, cooling to below 35 ℃ after the reaction is finished (the content of N-methyltetrafluorophthalimide in a liquid phase detection reaction system is less than 1%);
(2) adding acid into the reaction system, and obtaining 2,4, 5-trifluoro-3-hydroxybenzoic acid through decarboxylation;
specifically, 35% concentrated hydrochloric acid is added into a reaction kettle, the pH of a reaction solution is adjusted to be neutral, and the decarboxylation reaction is carried out through reflux; after the reaction is finished (the content of the intermediate 2,4, 5-trifluoro-3-hydroxyphthalic acid is less than 1 percent through liquid phase detection), the temperature is reduced to 55 ℃;
(3) under the alkaline condition, adding a methylating agent into a reaction system, and obtaining 2,4, 5-trifluoro-3-methoxybenzoate through methylation reaction; continuously adding acid, and obtaining 2,4, 5-trifluoro-3-methoxybenzoic acid through acidification reaction;
specifically, the pH value of the reaction solution is kept between 8 and 10 by using liquid alkali, 2000kg of dimethyl carbonate is dripped into the reaction kettle, the temperature is controlled to be between 55 and 60 ℃, the temperature is kept for 2 hours, and the temperature is reduced to be below 35 ℃ after the reaction is finished (the content of the intermediate 2,4, 5-trifluoro-3-hydroxybenzoic acid is detected to be less than 1 percent by liquid phase); then 2000kg of 35% concentrated hydrochloric acid was added, and 793.74kg of 2,4, 5-trifluoro-3-methoxybenzoic acid was obtained by acidification reaction.
The total molar yield was 82.4%; the content of the 2,4, 5-trifluoro-3-methoxybenzoic acid reaches 99.6 percent.
Example 5
The embodiment of the invention relates to a process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid by a one-pot method, which sequentially comprises the following steps:
(1) putting N-methyltetrafluorophthalimide in an alkaline environment by taking ferric trichloride as a catalyst, and obtaining 4-hydroxy salt-3, 5, 6-trifluorophthalate through hydrolysis defluorination and hydroxylation reaction;
concretely, 3000kg of water and 1000kg of N-methyltetrafluorophthalimide are added into a reaction kettle, and 30% of liquid caustic soda and ferric trichloride are added, wherein the molar ratio of the N-methyltetrafluorophthalimide to the sodium hydroxide is 1:3.5, and the molar ratio of the N-methyltetrafluorophthalimide to the ferric trichloride is 100: 10; heating to 100 ℃, preserving heat for 10 hours, cooling to below 35 ℃ after the reaction is finished (the content of N-methyltetrafluorophthalimide in a liquid phase detection reaction system is less than 1%);
(2) adding acid into the reaction system, and obtaining 2,4, 5-trifluoro-3-hydroxybenzoic acid through decarboxylation;
specifically, 35% concentrated hydrochloric acid is added into a reaction kettle, the pH of a reaction solution is adjusted to be neutral, and the decarboxylation reaction is carried out through reflux; after the reaction is finished (the content of the intermediate 2,4, 5-trifluoro-3-hydroxyphthalic acid is less than 1 percent through liquid phase detection), the temperature is reduced to 55 ℃;
(3) under the alkaline condition, adding a methylating agent into a reaction system, and obtaining 2,4, 5-trifluoro-3-methoxybenzoate through methylation reaction; continuously adding acid, and obtaining 2,4, 5-trifluoro-3-methoxybenzoic acid through acidification reaction;
specifically, the pH value of the reaction solution is kept between 8 and 10 by using liquid alkali, 2000kg of dimethyl carbonate is dripped into the reaction kettle, the temperature is controlled to be between 55 and 60 ℃, the temperature is kept for 2 hours, and the temperature is reduced to be below 35 ℃ after the reaction is finished (the content of the intermediate 2,4, 5-trifluoro-3-hydroxybenzoic acid is detected to be less than 1 percent by liquid phase); then 2000kg of 35% concentrated hydrochloric acid was added, and 782.18kg of 2,4, 5-trifluoro-3-methoxybenzoic acid was obtained by acidification reaction. The total molar yield is 81.2%; the content of the 2,4, 5-trifluoro-3-methoxybenzoic acid reaches 99.6 percent.
Claims (10)
1. The process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid by a one-pot method comprises the step of obtaining 4-hydroxy salt-3, 5, 6-trifluorophthalate, and is characterized in that the step of obtaining 4-hydroxy salt-3, 5, 6-trifluorophthalate comprises the following steps:
the 4-hydroxy salt-3, 5, 6-trifluoro phthalate is obtained by putting N-methyl tetrafluorophthalimide in an alkaline environment and carrying out hydrolytic defluorination and hydroxylation reaction by taking metal halide as a catalyst.
2. The one-pot process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid according to claim 1, wherein the molar ratio of N-methyltetrafluorophthalimide to the base is 1 (2-3).
3. The one-pot process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid according to claim 2, wherein the molar ratio of N-methyltetrafluorophthalimide to base is 1: 3.1.
4. The one-pot process of claim 1, wherein the metal halide is at least one of zinc chloride, aluminum trichloride or ferric trichloride.
5. The one-pot process of claim 4 for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid, wherein the metal halide is zinc chloride.
6. The one-pot process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid according to any one of claims 1 to 5, wherein the molar ratio of the metal halide to N-methyltetrafluorophthalimide in step (1) is (7-10): 100.
7. The process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid according to claim 6, wherein in step (1), the N-methyltetrafluorophthalimide, the alkali and the metal halide are mixed uniformly according to a preset molar ratio, heated to 90-110 ℃, and kept warm for 8-10 h.
8. The one-pot process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid according to any one of claims 1 to 7, comprising the following steps in sequence:
(1) putting N-methyl tetrafluorophthalimide in an alkaline environment by taking metal halide as a catalyst, and obtaining 4-hydroxy salt-3, 5, 6-trifluoro phthalate through hydrolysis defluorination and hydroxylation reaction;
(2) adding acid into the reaction system, and obtaining 2,4, 5-trifluoro-3-hydroxybenzoic acid through decarboxylation;
(3) under the alkaline condition, adding a methylating agent into a reaction system, and obtaining 2,4, 5-trifluoro-3-methoxybenzoate through methylation reaction; continuously adding acid, and obtaining the 2,4, 5-trifluoro-3-methoxybenzoic acid through acidification reaction.
9. The one-pot process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid according to claim 8, wherein in step (2), the molar ratio of the acid to N-methyltetrafluorophthalimide is (3.5-4.5): 1.
10. The one-pot process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid according to claim 8, wherein in step (3), the methylating agent is dimethyl carbonate or dimethyl sulfate, and the molar ratio of the methylating agent to N-methyltetrafluorophthalimide is (2-3): 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010449320.0A CN111662172A (en) | 2020-05-25 | 2020-05-25 | Process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid by one-pot method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010449320.0A CN111662172A (en) | 2020-05-25 | 2020-05-25 | Process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid by one-pot method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111662172A true CN111662172A (en) | 2020-09-15 |
Family
ID=72384568
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010449320.0A Pending CN111662172A (en) | 2020-05-25 | 2020-05-25 | Process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid by one-pot method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111662172A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114736133A (en) * | 2022-04-14 | 2022-07-12 | 内蒙古源宏精细化工有限公司 | Preparation of 2,4, 5-trifluoro-3-methoxybenzoic acid |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5380926A (en) * | 1994-03-28 | 1995-01-10 | Occidental Chemical Corporation | Method of making 3-methoxy-2,4,5-trifluorobenzoic acid |
| CN103450013A (en) * | 2013-08-30 | 2013-12-18 | 岳阳亚王精细化工有限公司 | Industrial preparation method of 2,4,5-trifluoro-3-methoxybenzoyl chloride |
| CN110357816A (en) * | 2019-08-08 | 2019-10-22 | 内蒙古源宏精细化工有限公司 | A kind of synthetic method of gatifloxacin cyclized ester |
-
2020
- 2020-05-25 CN CN202010449320.0A patent/CN111662172A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5380926A (en) * | 1994-03-28 | 1995-01-10 | Occidental Chemical Corporation | Method of making 3-methoxy-2,4,5-trifluorobenzoic acid |
| CN103450013A (en) * | 2013-08-30 | 2013-12-18 | 岳阳亚王精细化工有限公司 | Industrial preparation method of 2,4,5-trifluoro-3-methoxybenzoyl chloride |
| CN110357816A (en) * | 2019-08-08 | 2019-10-22 | 内蒙古源宏精细化工有限公司 | A kind of synthetic method of gatifloxacin cyclized ester |
Non-Patent Citations (1)
| Title |
|---|
| 刘正超编著: "《染化药剂 下》", 31 July 1965, 中国财政经济出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114736133A (en) * | 2022-04-14 | 2022-07-12 | 内蒙古源宏精细化工有限公司 | Preparation of 2,4, 5-trifluoro-3-methoxybenzoic acid |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100503601C (en) | Process of preparing troipisetron | |
| CN107857741A (en) | The new technique for synthesizing of ainothiazoly loximate | |
| CN107513031A (en) | A kind of preparation method of 2- OXo-1-pyrrolidines chiral derivatives | |
| CN102675306A (en) | Preparing method of moxifloxacin or slat thereof | |
| CN111662172A (en) | Process for preparing 2,4, 5-trifluoro-3-methoxybenzoic acid by one-pot method | |
| CN111635307B (en) | 2,4,5-trifluoro-3-methoxybenzoyl chloride synthesis method | |
| CN112409201A (en) | Preparation method of 2-hydroxy-5- [2- (4- (trifluoromethylphenyl) ethylamino) ] benzoic acid | |
| CN109438214B (en) | Preparation method of high-purity 5-bromo-2, 4-difluorobenzoic acid | |
| CN104086466A (en) | Preparation method of 2-chloro-4-methylsulfonylbenzoic acid | |
| CN101693685A (en) | Method for preparing 4-hydroxylethylpyrrolidone-2-acetamide | |
| CN105566257A (en) | Industrial preparation method of acetyl tetrahydrofuran with high optical purity | |
| CN101506141A (en) | 2-(4-methoxycarbonylmethylphenoxymethyl)benzoic acid methyl ester and method for producing the same | |
| CN107936045A (en) | A kind of preparation method of high-purity Flurbiprofen known impurities | |
| CN102617486B (en) | Process for preparing 6-chlorine-1,3-dimethyl uracil | |
| CN103387577A (en) | Asymmetric synthesis method of sitagliptin base | |
| CN108250126B (en) | Preparation method of indole-3-formic acid | |
| CN106478422A (en) | A kind of preparation method of paranitrophenylacetic acid | |
| CN114736133B (en) | Preparation of 2,4, 5-trifluoro-3-methoxybenzoic acid | |
| CN107325078B (en) | Preparation method of cilostazol | |
| CN101823982A (en) | Method for preparing hydrazine ethyl acetate hydrochloride | |
| CN112094205A (en) | Method for preparing Fmoc-Ser (tBu) -OH | |
| CN103333145B (en) | Preparation method of 3-(alpha- methoxyl) methylene benzofuran-2(3H)-ketone | |
| KR100564072B1 (en) | Method for pressureless production of ?,?-dimethylphenylacetic acid from ?,?-dimethylbenzyl cyanide | |
| CN114716373B (en) | Preparation method of gatifloxacin cyclized ester | |
| CN115536610B (en) | Preparation method of vothixetine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |