CN115231996A - Synthetic method of 3-fluoro-4-methylbenzoic acid - Google Patents
Synthetic method of 3-fluoro-4-methylbenzoic acid Download PDFInfo
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- CN115231996A CN115231996A CN202110441133.2A CN202110441133A CN115231996A CN 115231996 A CN115231996 A CN 115231996A CN 202110441133 A CN202110441133 A CN 202110441133A CN 115231996 A CN115231996 A CN 115231996A
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- acid
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- methylbenzoic acid
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- 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
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/20—Diazonium compounds
Abstract
The invention relates to the technical field of benzoic acid, discloses a synthetic method of 3-fluoro-4-methylbenzoic acid, and solves the problems that in the prior art, the operation difficulty is high, the yield is low, the industrial production cannot be realized, and the like. The method comprises the following steps: step 1) taking 3-amino-4-methyl ethyl benzoate or 3-amino-4-methyl benzoate as a main raw material, adding a solvent for dissolving, dropwise adding acid after the dissolution is finished, dropwise adding a sodium nitrite solution after the cooling, and adding fluoboric acid or fluophosphoric acid after the reaction is finished to prepare diazonium salt; step 2) adding an inert solvent into the dehydrated diazonium salt obtained in the step 1), and slowly heating for pyrolysis; cooling to room temperature after pyrolysis, removing toluene, adding ethanol, and dropwise adding alkali for alkaline hydrolysis; after alkaline hydrolysis, dropwise adding acid to precipitate a product, and filtering and drying to obtain the 3-fluoro-4-methylbenzoic acid. The method has the advantages of simple operation, low cost, high yield, low pollution and suitability for industrial production.
Description
Technical Field
The invention relates to the technical field of benzoic acid, and particularly relates to a synthetic method of 3-fluoro-4-methylbenzoic acid.
Background
The current synthesis process of 3-fluoro-4-methylbenzoic acid usually takes 4-bromo-2-fluorotoluene as a raw material, and the synthesis process is prepared by a Grignard reaction and then a reaction with carbon dioxide, and from an industrial point of view, the reaction has the following defects:
1. the Grignard reaction must be carried out under anhydrous and anaerobic conditions, the process reaction conditions are harsh, and the reaction risk is high;
2. the Grignard reagent needs to directly react with carbon dioxide, and the control difficulty is high. The side reaction of Grignard reaction is more, the purity of the prepared product is not high, and the requirement of the medical intermediate is difficult to achieve.
In addition, 2-fluoro-p-xylene is used as a raw material in the other process, and the 3-fluoro-4-methylbenzoic acid is directly synthesized by catalytic oxidation, although the route is short, the defects of extremely high risk degree of oxidation reaction and poor product quality exist, and the industrialization is difficult to realize.
In view of the defects of the existing synthetic method of the 3-fluoro-4-methylbenzoic acid and the good pharmaceutical value and market prospect of the 3-fluoro-4-methylbenzoic acid, the synthetic method which is simple to operate and safe and is suitable for industrial large-scale production is found, and the method has great practical significance.
Disclosure of Invention
The invention aims to solve the technical problem of providing a synthetic method of 3-fluoro-4-methylbenzoic acid, which is simple to control, low in cost, high in yield, low in pollution and suitable for industrial production.
In order to solve the technical problems, the technical scheme of the invention is as follows: a synthetic method of 3-fluoro-4-methylbenzoic acid comprises the following steps:
step 1) diazonium salt preparation:
using 3-amino-4-methyl ethyl benzoate or 3-amino-4-methyl benzoate as a main raw material, adding a solvent for dissolution, dropwise adding acid after the dissolution is finished, dropwise adding a sodium nitrite solution after the cooling, and adding fluoboric acid or fluophosphoric acid after the reaction is finished to prepare diazonium salt of the fluoboric acid or the fluophosphoric acid; the diazonium salt is subjected to the next reaction after dehydration;
the diazonium salt has the following chemical formula:
step 2) preparation of 3-fluoro-4-methylbenzoic acid:
adding an inert solvent into the diazonium salt subjected to water removal in the step 1), slowly heating for pyrolysis, wherein the pyrolysis time is more than 1 h; cooling to room temperature after pyrolysis, and removing toluene under reduced pressure; adding ethanol after removing toluene, dropwise adding alkali, and carrying out alkaline hydrolysis under alkaline conditions, wherein the alkaline hydrolysis time is more than 1 h; after alkaline hydrolysis, dropwise adding acid to separate out a product, and filtering and drying to obtain 3-fluoro-4-methylbenzoic acid;
the chemical formula of the 3-fluoro-4-methylbenzoic acid is as follows:
as a preferred embodiment, the solvent in step 1) is one of water or tetrahydrofuran.
As a preferred embodiment, the acid in step 1) is one of sulfuric acid, hydrochloric acid, fluoroboric acid, formic acid, acetic acid and phosphoric acid.
As a preferred embodiment, the molar ratio of the added amount of the main raw material and the acid in the step 1) is 1:1-1.
In a preferred embodiment, the temperature after the cooling in step 1) is from-10 ℃ to 10 ℃.
In a preferred embodiment, the molar ratio of the added amount of the main raw material and the sodium nitrite solution in the step 1) is 1:1-1:5.
As a preferred embodiment, the inert solvent in step 2) is toluene or xylene.
As a preferred embodiment, the pyrolysis temperature in step 2) is 50 to 100 ℃.
In a preferred embodiment, the alkali in step 2) is one of sodium hydroxide, potassium hydroxide and lithium hydroxide.
As a preferred embodiment, the acid in step 2) is hydrochloric acid or dilute sulfuric acid.
By adopting the technical scheme, the obtained product has high purity and can be used as a medical intermediate. The reaction process is simple to control, the reaction temperature is low, high temperature and high pressure are not involved, and the safety coefficient is extremely high. Therefore, the method has the advantages of simple operation of the product, low cost, high yield and little pollution, and is suitable for industrial production.
Detailed Description
The following further describes the embodiments of the present invention. It should be noted that the description of the embodiments is provided to help understanding of the present invention, and is not intended to limit the present invention. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
Example 1
Step 1) preparation of diazonium salt:
1000ml three-necked flask, thermometer, 3-amino-4-methyl ethyl benzoate 50 g and THF200 ml, mechanically stirring for dissolution, cooling to below 10 deg.C in ice water bath, and adding 48% HBF 4 150ml, and the temperature is controlled to be not more than 25 ℃. After the dripping is finished, cooling to about 0 ℃, and dripping 80ml of 40 percent NaNO 2 Controlling the dropping speed of the solution to keep the reaction temperature between 0 and 5 ℃, and continuing stirring for 1 hour after the dropping is finished. The reaction solution is put into a refrigerator to be frozen for 1 to 2 hours, filtered and dried in vacuum at normal temperature to obtain 66.8 g with the yield of 86 percent.
Step 2) preparation of 3-fluoro-4-methylbenzoic acid:
a1000 ml three-neck flask is filled with a thermometer, 66.8 g of the diazonium salt and 600 ml of toluene are added, the temperature is raised to about 75 ℃ (the external oil temperature is 80-90 ℃) and the mixture is stirred and reacted until white solid basically disappears (about 2 hours), and then the temperature is raised to about 90 ℃ and the mixture is stirred and reacted for 1 hour. Cooled to room temperature, toluene was removed under reduced pressure, 250ml ethanol, 250ml water, 62 g KOH were added, and the mixture was refluxed for 1 hour. Cooled to room temperature, filtered, and washed with a small amount of ethanol/water (1:1). 75ml of concentrated hydrochloric acid was added to the filtrate with stirring to precipitate a solid (pH = 1-2), after stirring for 15 minutes, 250ml of water was added thereto and stirred for 5 minutes, the reaction solution was put into a refrigerator and frozen for half an hour, filtered, and pressed to dryness as much as possible, and washed 3 times with ice-ethanol/water (1:1) and pressed to dryness as much as possible each time. Oven drying at 50 ℃ overnight gave 23.3 g, 63% yield, 99.5% HPLC.
Example 2
Step 1) preparation of diazonium salt:
1000ml of three-mouth bottle is filled with a thermometer, 50 g of methyl 3-amino-4-methylbenzoate and 200 ml of THF are added, the mixture is mechanically stirred and dissolved, the mixture is cooled to below 10 ℃ in ice water bath, 150ml of 30% hydrochloric acid is dropwise added, and the temperature is controlled to be not higher than 25 ℃. Cooling to about 0 ℃ after the dripping is finished, and dripping 100ml of 40 percent NaNO 2 The solution is added dropwise at a rate such that the reaction temperature is maintained between 0 and 5 deg.C, after the addition is completed, stirring is continued for 1 hour to dissolve, and 48% of HBF is added dropwise 4 40ml. The reaction solution is filtered for 1 to 2 hours and dried in vacuum at normal temperature to obtain 70 g, and the yield is 87.1 percent.
Step 2) preparation of 3-fluoro-4-methylbenzoic acid:
a1000 ml three-neck flask is filled with a thermometer, 66 g of the diazonium salt and 600 ml of toluene are added, the temperature is raised to about 75 ℃ (the external oil temperature is 80-90 ℃), the mixture is stirred and reacted until white solid basically disappears (about 2 hours), and the temperature is raised to about 90 ℃ and the mixture is stirred and reacted for 1 hour. Cooled to room temperature, the toluene was removed under reduced pressure, 250ml of ethanol, 250ml of water and 50 g of NaOH were added, and the mixture was refluxed for 1 hour. Cooled to room temperature, filtered and washed with a small amount of ethanol/water (1:1). 65ml of concentrated hydrochloric acid was added to the filtrate with stirring to precipitate a solid (pH = 1-2) and after stirring for 15 minutes, 250ml of water was added and stirred for 5 minutes, and the reaction solution was frozen in a refrigerator for half an hour, filtered, and pressed to dryness, and washed 3 times with iced ethanol/water (1:1) and pressed to dryness as much as possible each time. Oven drying at 50 ℃ overnight gave 25.9 g, 67.3% yield, 99.4% HPLC.
Example 3
Step 1) diazonium salt preparation:
1000ml of three-mouth bottle is filled with a thermometer, 50 g of methyl 3-amino-4-methylbenzoate and 200 ml of water are added, the mixture is mechanically stirred and dissolved, the mixture is cooled to below 10 ℃ in ice water bath, 150ml of 40% sulfuric acid aqueous solution is dropwise added, and the temperature is controlled to be not higher than 25 ℃. After the dripping is finished, cooling to about 0 ℃, and dripping 100ml of 40 percent NaNO 2 The solution is added dropwise at a rate such that the reaction temperature is maintained between 0 and 5 deg.C, after the addition is completed, stirring is continued for 1 hour to dissolve, and 60% of HPF is added dropwise 6 40ml of reaction solution for 1 to 2 hours, filtering and vacuum drying at normal temperature to obtain 69 grams, and the yield is 85.8 percent.
Step 2) preparation of 3-fluoro-4-methylbenzoic acid:
a1000 ml three-neck flask is filled with a thermometer, 69 g of the diazonium salt and 600 ml of xylene are added, the temperature is raised to about 75 ℃ (the external oil temperature is 80-90 ℃) and the mixture is stirred and reacted until white solid basically disappears (about 2 hours), and then the temperature is raised to about 90 ℃ and the mixture is stirred and reacted for 1 hour. Cooled to room temperature, the toluene was removed under reduced pressure, 250ml of ethanol, 250ml of water and 50 g of NaOH were added, and the mixture was refluxed for 1 hour. Cooled to room temperature, filtered, and washed with a small amount of ethanol/water (1:1). 65ml of concentrated hydrochloric acid was added to the filtrate with stirring to precipitate a solid (pH = 1-2), 250ml of water was added after stirring for 15 minutes, and the mixture was stirred for 5 minutes, and the reaction mixture was frozen in a refrigerator for half an hour, filtered, and dried as much as possible, and washed 3 times with ice ethanol/water (1:1) with drying as much as possible. Oven drying at 50 ℃ overnight gave 27 g, 67.1% yield, HPLC 99.1%.
Example 4
Step 1) diazonium salt preparation:
1000ml of three-mouth bottle is filled with a thermometer, 50 g of 3-amino-4-methyl ethyl benzoate and 200 ml of water are added, the mixture is mechanically stirred and dissolved, the mixture is cooled to below 10 ℃ in ice water bath, 150ml of 50% phosphoric acid aqueous solution is dripped, and the temperature is controlled to be not more than 25 ℃. Cooling to about 0 ℃ after the dripping is finished, and dripping 80ml of 40 percent NaNO 2 The solution is added dropwise at a rate such that the reaction temperature is maintained between 0 and 5 ℃, after the addition is completed, stirring is continued for 1 hour, 60% of HPF is added dropwise 6 40ml of reaction solution is filtered for 1 to 2 hours, and 60 grams of reaction solution is obtained after filtration and vacuum drying at normal temperature, and the yield is 77.3 percent.
Step 2) preparation of 3-fluoro-4-methylbenzoic acid:
a1000 ml three-neck flask is filled with a thermometer, 60 g of the diazonium salt and 600 ml of xylene are added, the temperature is raised to about 75 ℃ (the external oil temperature is 80-90 ℃) and stirred to react until white solid basically disappears (about 2 hours), and then the temperature is raised to about 90 ℃ and stirred to react for 1 hour. Cooled to room temperature, toluene was removed under reduced pressure, 250ml ethanol, 250ml water, 62 g KOH were added, and the mixture was refluxed for 1 hour. Cooled to room temperature, filtered, and washed with a small amount of ethanol/water (1:1). 75ml of concentrated hydrochloric acid was added to the filtrate with stirring to precipitate a solid (reaction solution pH = 1-2), 250ml of water was added after stirring for 15 minutes, stirring was carried out for 5 minutes, the reaction solution was frozen in a refrigerator for half an hour, filtered, dried as much as possible, and washed 3 times with ice ethanol/water (1:1) with drying as much as possible. Oven drying at 50 ℃ overnight gave 21.5 g, 65% yield, HPLC 99.2%.
Example 5
Step 1) preparation of diazonium salt:
1000ml of three-mouth bottle is filled with a thermometer, 50 g of methyl 3-amino-4-methylbenzoate and 200 ml of THF are added, the mixture is mechanically stirred and dissolved, the mixture is cooled to below 10 ℃ in an ice water bath, 150ml of 40% formic acid aqueous solution is dropwise added, and the temperature is controlled to be not higher than 25 ℃. Cooling to about 0 ℃ after the dripping is finished, and dripping 100ml of 40 percent NaNO 2 The solution is added dropwise at a rate such that the reaction temperature is maintained between 0 and 5 deg.C, after the addition is completed, stirring is continued for 1 hour, and 48% of HBF is added dropwise 4 40ml. The reaction solution is filtered for 1-2 hours and dried in vacuum at normal temperature to obtain 58 g, and the yield is 72.2%.
Step 2) preparation of 3-fluoro-4-methylbenzoic acid:
a1000 ml three-neck flask is filled with a thermometer, 58 g of the diazonium salt and 600 ml of toluene are added, the temperature is raised to about 75 ℃ (the external oil temperature is 80-90 ℃) and stirred to react until white solid basically disappears (about 2 hours), and then the temperature is raised to about 90 ℃ and stirred to react for 1 hour. Cooled to room temperature, toluene was removed under reduced pressure, 250ml of ethanol, 250ml of water and 50 g of NaOH were added, and the mixture was refluxed for 1 hour. Cooled to room temperature, filtered, and washed with a small amount of ethanol/water (1:1). 65ml of concentrated hydrochloric acid was added to the filtrate with stirring to precipitate a solid (pH = 1-2) and after stirring for 15 minutes, 250ml of water was added and stirred for 5 minutes, and the reaction solution was frozen in a refrigerator for half an hour, filtered, and pressed to dryness, and washed 3 times with iced ethanol/water (1:1) and pressed to dryness as much as possible each time. Oven drying at 50 deg.C overnight gave 22.3 g, 65.9% yield, HPLC 99.4%.
The embodiments of the present invention have been described in detail above, but the present invention is not limited to the described embodiments. It will be apparent to those skilled in the art that various changes, modifications, substitutions and alterations can be made in the embodiments without departing from the principles and spirit of the invention, and these embodiments are still within the scope of the invention.
Claims (10)
1. A synthetic method of 3-fluoro-4-methylbenzoic acid is characterized by comprising the following steps:
step 1) diazonium salt preparation:
using 3-amino-4-methyl ethyl benzoate or 3-amino-4-methyl benzoate as a main raw material, adding a solvent for dissolution, dropwise adding acid after the dissolution is finished, dropwise adding a sodium nitrite solution after the cooling, and adding fluoboric acid or fluophosphoric acid after the reaction is finished to prepare diazonium salt of the fluoboric acid or the fluophosphoric acid; the diazonium salt is subjected to next reaction after being dehydrated;
the diazonium salt has the following chemical formula:
step 2) preparation of 3-fluoro-4-methylbenzoic acid:
adding an inert solvent into the diazonium salt subjected to water removal in the step 1), slowly heating for pyrolysis, wherein the pyrolysis time is more than 1 h; cooling to room temperature after pyrolysis, and removing toluene under reduced pressure; adding ethanol after removing toluene, dropwise adding alkali, and carrying out alkaline hydrolysis under alkaline conditions, wherein the alkaline hydrolysis time is more than 1 h; after alkaline hydrolysis, dropwise adding acid to separate out a product, and filtering and drying to obtain 3-fluoro-4-methylbenzoic acid;
the chemical formula of the 3-fluoro-4-methylbenzoic acid is as follows:
2. the method of synthesizing 3-fluoro-4-methylbenzoic acid according to claim 1, characterized in that: the solvent in the step 1) is one of water or tetrahydrofuran.
3. The method of synthesizing 3-fluoro-4-methylbenzoic acid according to claim 1, characterized in that: the acid in the step 1) is one of sulfuric acid, hydrochloric acid, fluoroboric acid, formic acid, acetic acid and phosphoric acid.
4. The method of synthesizing 3-fluoro-4-methylbenzoic acid according to claim 1, characterized in that: the addition molar ratio of the main raw material to the acid in the step 1) is 1:1-1.
5. The method of synthesizing 3-fluoro-4-methylbenzoic acid according to claim 1, characterized in that: the temperature after cooling in the step 1) is-10 ℃ to 10 ℃.
6. The method of synthesizing 3-fluoro-4-methylbenzoic acid according to claim 1, characterized in that: the molar ratio of the added amount of the main raw material to the sodium nitrite solution in the step 1) is 1:1-1:5.
7. The method of synthesizing 3-fluoro-4-methylbenzoic acid according to claim 1, characterized in that: the inert solvent in the step 2) is toluene or xylene.
8. The method of synthesizing 3-fluoro-4-methylbenzoic acid according to claim 1, characterized in that: the pyrolysis temperature in the step 2) is 50-100 ℃.
9. The method of synthesizing 3-fluoro-4-methylbenzoic acid according to claim 1, characterized in that: the alkali in the step 2) is one of sodium hydroxide, potassium hydroxide and lithium hydroxide.
10. The method of synthesizing 3-fluoro-4-methylbenzoic acid according to claim 1, characterized in that: the acid in the step 2) is hydrochloric acid or dilute sulfuric acid.
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Citations (5)
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|---|---|---|---|---|
| CN1398846A (en) * | 2002-08-28 | 2003-02-26 | 浙江工业大学 | Chemical synthesis process of 4-chloro-2-fluoro nitrobenzene |
| CN101367738A (en) * | 2008-10-14 | 2009-02-18 | 天津大学 | Preparation method of m-fluoroaniline |
| CN101838179A (en) * | 2010-04-26 | 2010-09-22 | 浙江秦燕化工有限公司 | New process for producing 2-chloro-6-halogenated methylbenzene |
| CN103298474A (en) * | 2010-11-10 | 2013-09-11 | 无限药品股份有限公司 | Heterocyclic compounds and uses thereof |
| CN112441907A (en) * | 2019-08-30 | 2021-03-05 | 山东有言环保科技有限公司 | Method for co-producing mono-substituted methyl benzoic acid and mono-substituted phthalic acid |
-
2021
- 2021-04-23 CN CN202110441133.2A patent/CN115231996A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1398846A (en) * | 2002-08-28 | 2003-02-26 | 浙江工业大学 | Chemical synthesis process of 4-chloro-2-fluoro nitrobenzene |
| CN101367738A (en) * | 2008-10-14 | 2009-02-18 | 天津大学 | Preparation method of m-fluoroaniline |
| CN101838179A (en) * | 2010-04-26 | 2010-09-22 | 浙江秦燕化工有限公司 | New process for producing 2-chloro-6-halogenated methylbenzene |
| CN103298474A (en) * | 2010-11-10 | 2013-09-11 | 无限药品股份有限公司 | Heterocyclic compounds and uses thereof |
| CN112441907A (en) * | 2019-08-30 | 2021-03-05 | 山东有言环保科技有限公司 | Method for co-producing mono-substituted methyl benzoic acid and mono-substituted phthalic acid |
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| 李文露: "含密胺基团的单/双偶氮苯凝胶因子的合成及其凝胶性能", 《中国优秀硕士学位论文全文数据库工程科技Ⅰ辑》, pages 014 - 690 * |
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