CN110903182A - Simple and environment-friendly chemical synthesis method of 4-fluoro-2-methylbenzoic acid - Google Patents
Simple and environment-friendly chemical synthesis method of 4-fluoro-2-methylbenzoic acid Download PDFInfo
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- CN110903182A CN110903182A CN201811071218.0A CN201811071218A CN110903182A CN 110903182 A CN110903182 A CN 110903182A CN 201811071218 A CN201811071218 A CN 201811071218A CN 110903182 A CN110903182 A CN 110903182A
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
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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
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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Abstract
The invention relates to a simple and environment-friendly chemical synthesis method of 4-fluoro-2-methylbenzoic acid. The synthesis method takes m-fluorotoluene and acetyl chloride as initial raw materials, generates a Friedel-crafts acylation reaction under the catalysis of anhydrous aluminum trichloride, then generates a haloform reaction with sodium hypochlorite, and obtains o-and p-isomers of 4-fluoro-2-methylbenzoic acid and 2-fluoro-4-methylbenzoic acid after hydrolysis. And separating isomers through recrystallization to obtain the target product 4-fluoro-2-methylbenzoic acid. The method has the advantages of mild reaction conditions, low cost, environmental protection and suitability for industrial production.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and relates to a simple and environment-friendly synthetic method of a compound 4-fluoro-2-methylbenzoic acid.
Background
4-fluoro-2-methylbenzoic acid is an important raw material (JP2012088575,2012.05.10) of an electronic chemical photoinitiator and is also a medicinal intermediate (WO2004050651,2004.06.17) with great development potential. At present, the following methods are mainly used for synthesizing 4-fluoro-2-methylbenzoic acid:
(1) johansson et al directly heat hydrolyze 4-fluoro-2-methylbenzonitrile under strongly basic conditions to give 4-fluoro-2-methylbenzoic acid (WO 2004110344, 2004.12.23). The method is simple, the yield is high, but the synthetic route of the raw material 4-fluoro-2-methylbenzonitrile is complex, and the cost is high.
(2) Brunck et al used 2-bromo-5-fluorotoluene as a starting material, reacted in Grignard reaction to give magnesium salt, and reacted with dry ice to give 4-fluoro-2-methylbenzoic acid (US6342504,2002.01.29). Rudolph et al use 2-bromo-5-fluorotoluene as the starting material, lithiate with butyllithium at low temperatures (-78 deg.C), and react with dry ice to produce 4-fluoro-2-methylbenzoic acid (WO2004050651,2004.06.15). The two methods have harsh reaction conditions, require anhydrous and anaerobic reaction, require ultralow temperature operation for lithiation reaction, and are not beneficial to industrial scale-up production. And the synthesis of the raw material 2-bromo-5-fluorotoluene is more complex and the cost is higher.
(3) Gohier et al, which use 4-fluorobenzoic acid as raw material, directly react with sec-butyl lithium or tert-butyl lithium to obtain lithium salt, and then react with methyl iodide to obtain 4-fluoro-2-methylbenzoic acid (Journal of organic chemistry, 70(4), 1501-1504; 2005). The reaction has harsh reaction conditions, more isomers, troublesome refining and purification and lower yield.
The above reaction routes are not suitable for industrial production, either the raw material preparation is complicated, the cost is high, or the reaction conditions are harsh, the yield is low. Therefore, it is necessary to develop a synthetic method which has lower raw material cost, mild reaction conditions, environmental protection and suitability for industrial production.
Disclosure of Invention
The invention aims to provide a method for synthesizing 4-fluoro-2-methylbenzoic acid. The method has the advantages of easily available raw materials, low cost and mild reaction conditions, and is suitable for industrial production. The specific reaction route is shown as formula (I):
for the above synthetic route, the specific steps are:
(1) m-fluorotoluene is used as an initial raw material and subjected to a friedel-crafts acylation reaction with acetyl chloride under the catalysis of Lewis acid to obtain isomers of o-ketone and p-ketone.
(2) Performing haloform reaction with hypohalite aqueous solution, and hydrolyzing to obtain o-isomer and p-isomer 4-fluoro-2-methylbenzoic acid and 2-fluoro-4-methylbenzoic acid.
(3) And recrystallizing and purifying to obtain the target product 4-fluoro-2-methylbenzoic acid.
In the above steps, m-fluorotoluene and acetyl chloride are used as starting materials in step (1), and may be subjected to a Friedel-crafts acylation reaction under the catalysis of Lewis acid, and the Lewis acid catalyst may be anhydrous aluminum trichloride, anhydrous zinc chloride, boron trifluoride, anhydrous ferric trichloride, anhydrous stannic chloride and the like, preferably anhydrous aluminum trichloride. The solvent can be selected from dichloromethane, 1, 2-dichloroethane, carbon disulfide, chlorobenzene, nitrobenzene, etc., preferably 1, 2-dichloroethane. The reaction temperature is-20 to 20 degrees, preferably-5 to 10 degrees. In step (2), the hypohalite can be selected from sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, sodium hypobromite, sodium hypoiodite and the like, and preferably sodium hypochlorite. In the step (3), toluene, benzene, ethyl acetate, chloroform and the like can be selected for recrystallization, and a mixed solvent can also be used.
The invention takes m-fluorotoluene and acetyl chloride as initial raw materials, and generates 4-fluoro-2-methylbenzoic acid under the catalysis of anhydrous aluminum trichloride for experiment to verify the reliability of the synthesis method. The protection contents of the present invention are not limited to the following embodiments.
The specific implementation case is as follows:
1.4-fluoro-2-methylacetophenone and its isomer synthesis:
110 g (1 mol) of m-fluorotoluene and 550 g of 1, 2-dichloroethane are sequentially added into a 2000ml four-mouth reaction bottle, the temperature is reduced to about 0 ℃ under the protection of nitrogen, 146.3 g (1.1 mol) of anhydrous aluminum trichloride is added, then 86.4 g (1.1 mol) of acetyl chloride is added dropwise, the temperature is controlled between-5 ℃ and 10 ℃, the reaction process is monitored by HPLC after the dropwise addition is finished, and the reaction is stopped when the m-fluorotoluene is less than 0.5 percent. The reaction solution was slowly poured into about 750 g of 5% cold hydrochloric acid water, stirred to dissolve completely, then left to stand for layering, the upper aqueous phase was removed, and the organic phase was washed once more with water. Analysis shows that the product 4-fluoro-2-methylacetophenone has a content of about 78% and an isomer content of about 21%. The organic phase was not further treated and was directly subjected to the next reaction.
2.4-fluoro-2-methylbenzoic acid and its isomer synthesis:
and (3) slowly adding about 850 g of sodium hypochlorite aqueous solution containing about 10% of available chlorine into the organic phase at room temperature, stirring for two hours, adjusting the pH value to 3-4 by using concentrated hydrochloric acid, standing for liquid separation, removing the aqueous phase, washing with water once, and distilling at normal pressure to remove the solvent to obtain about 150 g of crude product.
Refining of 4-fluoro-2-methylbenzoic acid:
adding 300 g of toluene and 70 g of ethyl acetate into the crude product obtained in the second step, heating to reflux, slowly cooling to 20 ℃ after dissolving, filtering and drying to obtain 98 g of a product, wherein the total yield is 63.6 percent, and the purity (HPLC) is about 98.5 percent.
Claims (8)
1. The simple and environment-friendly synthesis method of 4-fluoro-2-methylbenzoic acid is characterized by comprising the following steps:
(1) m-fluorotoluene and acetyl chloride are taken as initial raw materials, dissolved in a solvent, and subjected to a Friedel-crafts acylation reaction under the catalysis of Lewis acid to obtain two isomers of ortho-position and para-position;
(2) after reacting with hypohalite, hydrolyzing to obtain o-isomer and p-isomer 4-fluoro-2-methylbenzoic acid and 2-fluoro-4-methylbenzoic acid;
(3) and recrystallizing and purifying to obtain the target product 4-fluoro-2-methylbenzoic acid.
2. According to claim 1, in step (1), the Lewis acid catalyst can be selected from anhydrous aluminum trichloride, anhydrous zinc chloride, boron trifluoride, anhydrous ferric trichloride, anhydrous stannic tetrachloride and the like, and preferably anhydrous aluminum trichloride.
3. The process according to claim 1, wherein the molar ratio of m-fluorotoluene to acetyl chloride in step (1) is 1:1 to 1:5, preferably 1:1.1, and the molar ratio of m-fluorotoluene to anhydrous aluminum trichloride is 1:1 to 1:4, preferably 1: 1.1.
4. According to claim 1, the reaction solvent in step (1) can be selected from dichloromethane, 1, 2-dichloroethane, carbon disulfide, chlorobenzene, nitrobenzene, etc., preferably 1, 2-dichloroethane.
5. The process according to claim 1, wherein the reaction temperature in step (1) is-20 to 20 degrees, preferably-5 to 10 degrees.
6. According to claim 1, in step (2), the hypohalite can be selected from sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, sodium hypobromite, sodium hypoiodite, etc., preferably sodium hypochlorite.
7. According to claim 1, the hypohalite in step (2) can also be produced by reacting the corresponding halogen (chlorine, bromine, iodine) with the corresponding alkali solution in the production site, preferably bromine and sodium hydroxide aqueous solution.
8. According to claim 1, in the step (3), toluene, benzene, ethyl acetate, chloroform, etc. can be selected for recrystallization, or a mixed solvent can be used.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811071218.0A CN110903182A (en) | 2018-09-14 | 2018-09-14 | Simple and environment-friendly chemical synthesis method of 4-fluoro-2-methylbenzoic acid |
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| CN201811071218.0A CN110903182A (en) | 2018-09-14 | 2018-09-14 | Simple and environment-friendly chemical synthesis method of 4-fluoro-2-methylbenzoic acid |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112125790A (en) * | 2020-10-27 | 2020-12-25 | 埃法姆药物研发(宁夏)有限公司 | Synthesis method of 7-chloro-1-naphthaldehyde |
| CN116813508A (en) * | 2022-03-21 | 2023-09-29 | 湖南华腾医药有限公司 | Method for synthesizing 5-halogeno-2-methylbenzoic acid with high selectivity |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85107015A (en) * | 1985-09-19 | 1987-04-01 | 拜尔公司 | Preparation 2, the benzoic method of 4-two chloro-5-fluoro- |
| WO2003032912A2 (en) * | 2001-10-16 | 2003-04-24 | Hypnion, Inc. | Treatment of cns disorders using cns target modulators |
| CN1746147A (en) * | 2004-09-06 | 2006-03-15 | 大连绿源药业有限责任公司 | Preparation of 2,4,6-trichloromethane acid |
-
2018
- 2018-09-14 CN CN201811071218.0A patent/CN110903182A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85107015A (en) * | 1985-09-19 | 1987-04-01 | 拜尔公司 | Preparation 2, the benzoic method of 4-two chloro-5-fluoro- |
| WO2003032912A2 (en) * | 2001-10-16 | 2003-04-24 | Hypnion, Inc. | Treatment of cns disorders using cns target modulators |
| CN1746147A (en) * | 2004-09-06 | 2006-03-15 | 大连绿源药业有限责任公司 | Preparation of 2,4,6-trichloromethane acid |
Non-Patent Citations (1)
| Title |
|---|
| KRISHNA C. JOSHI, ET AL.: "Fluorine containing bioactive heterocycles. Part III: Synthesis of some new fluorine containing phenylglyoxals and 1,2,4-triazine derivatives", 《HETEROCYCLES》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112125790A (en) * | 2020-10-27 | 2020-12-25 | 埃法姆药物研发(宁夏)有限公司 | Synthesis method of 7-chloro-1-naphthaldehyde |
| CN116813508A (en) * | 2022-03-21 | 2023-09-29 | 湖南华腾医药有限公司 | Method for synthesizing 5-halogeno-2-methylbenzoic acid with high selectivity |
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