CN111662185A - Synthesis method of N-methyl o-fluoroaniline - Google Patents
Synthesis method of N-methyl o-fluoroaniline Download PDFInfo
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Abstract
The invention discloses a synthetic method of N-methyl o-fluoroaniline, which comprises the following steps: amidation reaction: taking o-fluoroaniline as a raw material, mixing the o-fluoroaniline with toluene and formic acid, heating to react, and dehydrating while reacting to obtain N- (2-fluorophenyl) formamide; methylation reaction: adding dimethyl carbonate and a catalyst into N- (2-fluorophenyl) formamide serving as a raw material, filling the mixture into a high-pressure kettle, and heating the mixture to perform methylation reaction to obtain N-methyl-N-formyl-2-fluoroaniline; and (3) hydrolysis reaction: taking N-methyl-N-formyl-2-fluoroaniline as a raw material, mixing the raw material with water and sulfuric acid, hydrolyzing, and carrying out post-treatment to obtain the N-methyl o-fluoroaniline. The method has the advantages of easily available raw materials, low raw material cost, mild reaction conditions, green and safe method, high total yield up to 90 percent and great industrial application prospect.
Description
Technical Field
The invention belongs to the field of preparation of pesticides and medical intermediates, and particularly relates to a synthesis method of N-methyl o-fluoroaniline.
Background
The N-methyl o-fluoroaniline belongs to fluorine-containing N-alkyl arylamine, is a very important organic raw material and fine chemical intermediate, and is widely applied to the fields of dye, plastics, medicine, pesticide and the like. With the continuous development of pesticides and medicines, the demand of N-methyl o-fluoroaniline is rapidly increasing, and the corresponding synthesis and development thereof are also receiving much attention.
Specifically, there are many synthetic methods for N-methyl o-fluoroaniline, which can be classified into the following ones according to the reaction route:
(1) the o-fluoroaniline is used as a raw material and is subjected to methylation reaction with dimethyl carbonate to prepare the compound. However, since dimethyl carbonate is a starting material which can be methylated relatively easily, a substantial portion (84%) of dimethyl-substituted N, N-dimethyl-o-fluoroaniline is formed, and the target product, N-methyl-o-fluoroaniline, is only 5%.
(2) The o-fluoroaniline is used as an initial raw material, tetrahydrofuran is used as a solvent, and the o-fluoroaniline and dimethyl sulfate are subjected to methylation reaction under the catalysis of n-butyl lithium to prepare the compound. The method needs to be carried out at a low temperature of-78 ℃, the conditions are harsh, dimethyl sulfate is a highly toxic product, and n-butyl lithium requires anhydrous and anaerobic conditions, so that the potential safety hazard is large.
(3) The o-fluoroaniline is used as an initial raw material, DMF is used as a solvent, and the o-fluoroaniline and iodomethane are subjected to methylation reaction under the catalytic action of sodium hydride to prepare the compound. The method uses sodium hydride, is unsafe, the methyl iodide is expensive, the cost of raw materials is high, and the industrial application is difficult.
(4) Chinese patent application CN107973721A discloses: the N-methyl o-fluoroaniline is prepared by taking o-fluoroaniline as a starting material, performing enamine reaction with paraformaldehyde and performing catalytic hydrogenation. The method has low total yield. The hydrogenation catalyst is a more expensive noble metal catalyst or a raney nickel catalyst which is easy to catch fire, and the residual hydrogen after the reaction has larger potential safety hazard.
(5) Chinese patent application CN109053486A discloses: the N-methyl o-fluoroaniline is prepared by diazotizing and aminolysis by taking o-fluoroaniline as a starting material. The method adopts diazotization, and belongs to a high-risk process. The used concentrated hydrochloric acid and methylamine aqueous solution belong to volatile substances, have strong corrosivity, have higher requirements on equipment and increase the tail gas treatment cost.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a synthesis method of N-methyl o-fluoroaniline, which has the advantages of easily available raw materials, lower raw material cost and mild reaction conditions, and dimethyl carbonate used in the methylation process belongs to an environment-friendly green raw material, thereby reducing the environmental burden.
The technical scheme adopted by the invention is as follows:
a synthetic method of N-methyl o-fluoroaniline comprises the following steps:
step (1), amidation reaction: taking o-fluoroaniline as a raw material, mixing the o-fluoroaniline with toluene and formic acid, heating to react, and dehydrating while reacting to obtain N- (2-fluorophenyl) formamide;
step (2), methylation reaction: adding dimethyl carbonate and a catalyst into N- (2-fluorophenyl) formamide serving as a raw material, filling the mixture into a high-pressure kettle, and heating the mixture to perform methylation reaction to obtain N-methyl-N-formyl-2-fluoroaniline;
and (3) hydrolysis reaction: taking N-methyl-N-formyl-2-fluoroaniline as a raw material, mixing the raw material with water and sulfuric acid, hydrolyzing, and carrying out post-treatment to obtain the N-methyl o-fluoroaniline.
In the step (1), the reaction of the raw materials is incomplete due to insufficient feeding amount of formic acid, the yield is low, and the molar ratio of the o-fluoroaniline to the formic acid is 1: 1.0-2.0, preferably 1: 1.3-1.5. The formic acid is 88% aqueous formic acid solution.
The toluene is used as a water-carrying agent in a system, the addition amount of the toluene is insufficient, incomplete dehydration is easily caused, byproducts are increased, the yield is low, and the mass ratio of the o-fluoroaniline to the toluene is 1: 3.0-5.0, preferably 1: 3.5-4.0.
The initial temperature of dehydration is 88 ℃, if the later dehydration temperature is too low, dehydration is not thorough, the product yield is low, the temperature is continuously increased to 105-110 ℃, heat preservation dehydration is carried out, and the total dehydration time is 6-8 hours.
And after the amidation reaction is finished, cooling the reaction liquid to 25-30 ℃, washing with water to remove redundant formic acid until the pH value is 6-7, layering, and removing toluene by organic phase vacuum evaporation to obtain the N- (2-fluorophenyl) formamide.
In the step (2), the catalyst is potassium carbonate or cesium carbonate. Since potassium carbonate can be directly removed by filtration after the methylation reaction is completed, and since cesium carbonate is dissolved in an organic solvent, post-treatment is inconvenient, the catalyst is preferably potassium carbonate. The insufficient feeding amount of the catalyst causes incomplete reaction of raw materials and prolongs the reaction time. The molar ratio of the catalyst to the N- (2-fluorophenyl) formamide is 3-10: 100, and preferably 5: 100.
Carbon dioxide is continuously discharged along with the reaction process, dimethyl carbonate is carried away, and incomplete reaction and low yield can be caused if the feeding amount of dimethyl carbonate is insufficient. The molar ratio of the N- (2-fluorophenyl) formamide to the dimethyl carbonate is 1: 3.0-5.0, and preferably 1: 4.0-4.5.
The temperature of the methylation reaction is 120-140 ℃, if the temperature is lower than 120 ℃, the reaction cannot be carried out, if the temperature is too high, the pressure is sharply increased, and potential safety hazards exist; the pressure of the methylation reaction is 0.4-0.6 MPa; the methylation reaction time is 3-5 h.
And after the methylation reaction is finished, cooling the reaction liquid to 25-30 ℃, filtering, and evaporating methanol and dimethyl carbonate to obtain the N-methyl-N-formyl-2-fluoroaniline.
In the step (3), if the feed amount of the sulfuric acid is too low, the content of the sulfuric acid (the concentration of the sulfuric acid diluted by water) in the reaction system is too low, the hydrolysis is incomplete, and if the content of the sulfuric acid is too high, the amount of impurities is increased. The N-methyl-N-formyl-2-fluoroaniline is reacted with sulfuric acid (as H)2SO4Calculated) is 1: 1.0-2.0, and the content of sulfuric acid is 10% -20%; preferably, the molar ratio of the N-methyl-N-formyl-2-fluoroaniline to the sulfuric acid is 1: 1.3-1.5, and the content of the sulfuric acid is 11.5% -15%.
The temperature of the hydrolysis reaction is 60-80 ℃, if the temperature is too low, the reaction is not thorough, and if the temperature is too high, the impurity amount is increased; the time of the hydrolysis reaction is 4-6 h.
The post-treatment comprises the following steps: and after the hydrolysis reaction is finished, cooling the reaction liquid to 25-30 ℃, dropwise adding a 10% sodium hydroxide solution to adjust the pH to 7-8, standing, layering, and collecting fractions at 85-90 ℃ (20mmHg) under negative pressure to obtain the N-methyl o-fluoroaniline.
Compared with the prior art, the invention has the following beneficial effects:
the method has the advantages of easily available raw materials, low raw material cost, mild reaction conditions, green and safe method, high total yield up to 90 percent and great industrial application prospect.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments.
Example 1
Amidation reaction:
putting 111g (1mol) of o-fluoroaniline, 400g of toluene and 78.5g of formic acid (the concentration is 88 percent and 1.5mol) into a reaction bottle, heating to 88 ℃, starting to dehydrate water at the moment, continuously heating to 105-110 ℃ under the condition of ensuring no material flushing, preserving heat and dehydrating, wherein the total dehydrating time is 6 hours; after the reaction is finished, cooling the reaction liquid to 30 ℃, adding water to wash the reaction liquid until the pH value is 6-7, layering, and evaporating toluene by organic phase decompression to obtain 136.6g of N- (2-fluorophenyl) formamide, wherein the purity of the liquid phase is 99% and the yield is 98.2%.
Methylation reaction:
139g (1mol) of N- (2-fluorophenyl) formamide, 360g (4mol) of dimethyl carbonate and 6.9g (0.05mol) of potassium carbonate are put into an autoclave (with a condenser), the temperature is raised to 130 ℃, the pressure is gradually increased to 0.6MPa, the autoclave is slowly emptied to keep the pressure stable at 0.4MPa to 0.6MPa, and the temperature is kept for 4 hours. After the reaction is finished, the reaction liquid is cooled to 30 ℃, potassium carbonate is removed by filtration, and methanol and dimethyl carbonate are evaporated to obtain 144g of N-methyl-N- (2-fluorophenyl) formamide, wherein the purity of the liquid phase is 98.6 percent, and the yield is 94.1 percent.
And (3) hydrolysis reaction:
830g of water was put into a reaction flask, 135g (1.35mol) of 98% sulfuric acid was added dropwise thereto, 153g (1mol) of N-methyl-N- (2-fluorophenyl) formamide was added thereto, the temperature was raised to 80 ℃ and the mixture was stirred and kept for 5 hours. After the reaction is finished, cooling the reaction liquid to 30 ℃, dropwise adding 10% sodium hydroxide until the pH value is 7-8, standing, layering, and collecting 85-90 ℃ (20mmHg) fractions under negative pressure to obtain 123.2g of N-methyl o-fluoroaniline, wherein the purity is 99.2% by gas phase measurement, and the molar yield is 98.4%.
Example 2
Amidation reaction:
putting 111g (1mol) of o-fluoroaniline, 400g of toluene and 68g of formic acid (the concentration is 88 percent and 1.3mol) into a reaction bottle, heating to 88 ℃, starting to dehydrate with water, continuously heating to 105-110 ℃, keeping the temperature and dehydrating, wherein the total dehydrating time is 6h, after the reaction is finished, cooling the reaction solution to 30 ℃, adding water and washing to the pH value of 6-7, layering, and distilling out the toluene by organic phase under reduced pressure to obtain 136.2g of N- (2-fluorophenyl) formamide, wherein the purity of the liquid phase is 99 percent and the yield is 97.9 percent.
Methylation reaction:
139g (1mol) of N- (2-fluorophenyl) formamide, 270g (3mol) of dimethyl carbonate and 6.9g (0.05mol) of potassium carbonate are put into an autoclave (with a condenser), the temperature is raised to 130 ℃, the pressure is gradually increased to 0.6MPa, the autoclave is slowly emptied to keep the pressure stable between 0.4MPa and 0.6MPa, and the temperature is kept for 4 hours. After the reaction is finished, the reaction liquid is cooled to 30 ℃, and is filtered, methanol and dimethyl carbonate are evaporated to obtain 142g of N-methyl-N- (2-fluorophenyl) formamide, the purity of the liquid phase is 97.8 percent, and the yield is 92.8 percent.
And (3) hydrolysis reaction:
830g of water was put into a reaction flask, 100g (1.00mol) of 98% sulfuric acid was added dropwise thereto, 153g (1mol) of N-methyl-N- (2-fluorophenyl) formamide was added, the temperature was raised to 80 ℃ and the mixture was stirred and kept warm for 5 hours. After the reaction is finished, cooling the reaction liquid to 30 ℃, dropwise adding 10% sodium hydroxide until the pH value is 7-8, standing, layering, and collecting fractions at 85-90 ℃ (20mmHg) under negative pressure to obtain 108.3g of N-methyl o-fluoroaniline, wherein the purity is 99.2% by gas phase measurement, and the molar yield is 86.5%.
Example 3
Amidation reaction
The same as in example 1.
Methylation reaction
The same as in example 1.
Hydrolysis reaction
830g of water was put into a reaction flask, 160g (1.6mol) of 98% sulfuric acid was added dropwise thereto, 153g (1mol) of N-methyl-N- (2-fluorophenyl) formamide was added thereto, the temperature was raised to 80 ℃ and the mixture was stirred and held for 5 hours. After the reaction is finished, cooling the reaction liquid to 30 ℃, dropwise adding 10% sodium hydroxide until the pH value is 7-8, standing, layering, and collecting 85-90 ℃ (20mmHg) fractions under negative pressure to obtain 115g of N-methyl o-fluoroaniline, wherein the purity is 99.2% in a gas phase test, and the molar yield is 91.9%.
Example 4
Amidation reaction
111g (1mol) of o-fluoroaniline, 400g of toluene and 104.6g of formic acid (the concentration is 88 percent and 2.0mol) are put into a reaction bottle, the temperature is raised to 88 ℃, water begins to be dehydrated, the temperature is continuously raised to 105-110 ℃, the temperature is kept for dehydration, and the total dehydration time is 6 hours. After the reaction is finished, cooling the reaction liquid to 30 ℃, adding water to wash the reaction liquid until the pH value is 6-7, layering, and evaporating toluene by organic phase under reduced pressure to obtain 136.3g of N- (2-fluorophenyl) formamide, wherein the purity of the obtained liquid phase is 99%, and the yield is 98.0%.
Methylation reaction
139g (1mol) of N- (2-fluorophenyl) formamide, 450g (5mol) of dimethyl carbonate and 6.9g (0.05mol) of potassium carbonate are put into an autoclave (with a condenser), the temperature is raised to 130 ℃, the pressure is gradually increased to 0.6MPa, the autoclave is slowly emptied to keep the pressure stable between 0.4MPa and 0.6MPa, and the temperature is kept for 4 hours. After the reaction is finished, the reaction liquid is cooled to 30 ℃, and is filtered, and the methanol and the dimethyl carbonate are evaporated to obtain 145.2g of N-methyl-N- (2-fluorophenyl) formamide, wherein the purity of the liquid phase is 98.9 percent, and the yield is 94.8 percent.
Hydrolysis reaction
1000g of water was put into a reaction flask, 135g of 98% sulfuric acid was added dropwise, 153g (1mol) of N-methyl-N- (2-fluorophenyl) formamide was added, the temperature was raised to 80 ℃ and the mixture was kept under stirring for 5 hours. After the reaction is finished, cooling the reaction liquid to 30 ℃, dropwise adding 10% sodium hydroxide until the pH value is 7-8, standing, layering, and collecting 85-90 ℃ (20mmHg) fractions under negative pressure to obtain 120.2g of N-methyl o-fluoroaniline, wherein the purity is 99.2% by gas phase measurement, and the molar yield is 96.04%.
Example 5
Amidation reaction
The same as in example 1.
Methylation reaction
139g (1mol) of N- (2-fluorophenyl) formamide, 360g (4mol) of dimethyl carbonate and 13.8g (0.1mol) of potassium carbonate are put into an autoclave (with a condenser), the temperature is raised to 130 ℃, the pressure is gradually increased to 0.6MPa, the autoclave is slowly emptied to keep the pressure stable at 0.4MPa to 0.6MPa, and the temperature is kept for 4 hours. After the reaction is finished, the reaction liquid is cooled to 30 ℃, and is filtered, methanol and dimethyl carbonate are evaporated, so that 146.1g of N-methyl-N- (2-fluorophenyl) formamide is obtained, the purity of the liquid phase is 98.9%, and the yield is 95.4%.
Comparative example 1
Amidation reaction:
111g (1mol) of o-fluoroaniline, 300g of toluene and 78.5g of formic acid (the concentration is 88 percent and 1.5mol) are put into a reaction bottle, the temperature is raised to 88 ℃, water begins to be dehydrated, the temperature is continuously raised to 105-110 ℃, the temperature is kept for dehydration, and the total dehydration time is 6 hours. After the reaction is finished, cooling the reaction liquid to 30 ℃, adding water to wash the reaction liquid until the pH value is 6-7, layering, and evaporating toluene by organic phase decompression to obtain 106.3g of N- (2-fluorophenyl) formamide, wherein the purity of the obtained liquid phase is 99% and the yield is 76.4%.
Comparative example 2
Methylation reaction:
139g (1mol) of N- (2-fluorophenyl) formamide and 360g (4mol) of dimethyl carbonate are put into an autoclave (with a condenser), the temperature is raised to 130 ℃, the pressure is gradually raised to 0.6MPa, the autoclave is slowly emptied to keep the pressure stable between 0.4MPa and 0.6MPa, and the temperature is kept for 4 hours without products.
Comparative example 3
Hydrolysis reaction
Putting 500g of water into a reaction bottle, dropwise adding 135g of 98% sulfuric acid, putting 153g (1mol) of N-methyl-N- (2-fluorophenyl) formamide, heating to 80 ℃, keeping the temperature for 5 hours under a stirring state, cooling to 30 ℃, dropwise adding 10% sodium hydroxide to a pH value of 7-8, standing, layering, and collecting fractions at 85-90 ℃ (20mmHg) under negative pressure to obtain 97.4g of N-methyl o-fluoroaniline, wherein the purity is 96.5% when the gas phase is detected, and the molar yield is 77.8%.
Claims (10)
1. A synthetic method of N-methyl o-fluoroaniline is characterized by comprising the following steps:
step (1), amidation reaction: taking o-fluoroaniline as a raw material, mixing the o-fluoroaniline with toluene and formic acid, heating to react, and dehydrating while reacting to obtain N- (2-fluorophenyl) formamide;
step (2), methylation reaction: adding dimethyl carbonate and a catalyst into N- (2-fluorophenyl) formamide serving as a raw material, filling the mixture into a high-pressure kettle, and heating the mixture to perform methylation reaction to obtain N-methyl-N-formyl-2-fluoroaniline;
and (3) hydrolysis reaction: taking N-methyl-N-formyl-2-fluoroaniline as a raw material, mixing the raw material with water and sulfuric acid, hydrolyzing, and carrying out post-treatment to obtain the N-methyl o-fluoroaniline.
2. The synthesis method of N-methyl o-fluoroaniline according to claim 1, characterized in that in step (1), the molar ratio of o-fluoroaniline to formic acid is 1: 1.0-2.0, preferably 1: 1.3-1.5; the mass ratio of the o-fluoroaniline to the toluene is 1: 3.0-5.0, and preferably 1: 3.5-4.0.
3. The synthesis method of N-methyl-o-fluoroaniline according to claim 1, characterized in that in step (1), the initial temperature of dehydration is 88 ℃, the temperature is continuously raised to 105-110 ℃, the temperature is kept for dehydration, and the total dehydration time is 6-8 h.
4. The method for synthesizing N-methyl-o-fluoroaniline according to claim 1, wherein in step (1), after the amidation reaction, the reaction solution is cooled to 25-30 ℃, washed with water to pH 6-7, layered, and subjected to organic phase vacuum distillation to remove toluene, thereby obtaining N- (2-fluorophenyl) formamide.
5. The method for synthesizing N-methyl-o-fluoroaniline according to claim 1, characterized in that in the step (2), the catalyst is potassium carbonate, cesium carbonate, preferably potassium carbonate; the molar ratio of the catalyst to the N- (2-fluorophenyl) formamide is 3-10: 100, and preferably 5: 100.
6. The method for synthesizing N-methyl-o-fluoroaniline according to claim 1, wherein in step (2), the molar ratio of the N- (2-fluorophenyl) formamide to the dimethyl carbonate is 1: 3.0-5.0, preferably 1: 4.0-4.5.
7. The method for synthesizing N-methyl-o-fluoroaniline according to claim 1, wherein in step (2), the methylation reaction temperature is 120-140 ℃ and the reaction pressure is 0.4-0.6 MPa.
8. The process for synthesizing N-methyl-o-fluoroaniline according to claim 1, wherein in step (3), H is used2SO4The molar ratio of the N-methyl-N-formyl-2-fluoroaniline to the sulfuric acid is 1: 1.0-2.0, and the content of the sulfuric acid is 10% -20%; preferably, the molar ratio of the N-methyl-N-formyl-2-fluoroaniline to the sulfuric acid is 1: 1.3-1.5, and the content of the sulfuric acid is 11.5% -15%.
9. The synthesis method of N-methyl-o-fluoroaniline according to claim 1, characterized in that in step (3), the temperature of the hydrolysis reaction is 60-80 ℃, and the time of the hydrolysis reaction is 4-6 h.
10. The process for the synthesis of N-methyl-o-fluoroaniline according to claim 1, characterized in that in step (3), the post-treatment is: and after the hydrolysis reaction is finished, cooling the reaction liquid to 25-30 ℃, dropwise adding a 10% sodium hydroxide solution to adjust the pH to 7-8, standing, layering, and collecting fractions at 85-90 ℃ (20mmHg) under negative pressure to obtain the N-methyl o-fluoroaniline.
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| CN113429297A (en) * | 2021-07-08 | 2021-09-24 | 江西汇和化工有限公司 | Method for synthesizing N-methyl o-fluoroaniline by one-pot method |
| CN115160151A (en) * | 2022-08-04 | 2022-10-11 | 合肥星宇化学有限责任公司 | Preparation method of N-alkyl-2-fluoroaniline |
| CN115197072A (en) * | 2022-07-12 | 2022-10-18 | 合肥星宇化学有限责任公司 | Preparation method of N-alkyl-2-fluoroaniline |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112374998A (en) * | 2020-12-04 | 2021-02-19 | 阜新睿光氟化学有限公司 | Preparation method of N-methyl o-fluoroaniline |
| CN113429297A (en) * | 2021-07-08 | 2021-09-24 | 江西汇和化工有限公司 | Method for synthesizing N-methyl o-fluoroaniline by one-pot method |
| CN115197072A (en) * | 2022-07-12 | 2022-10-18 | 合肥星宇化学有限责任公司 | Preparation method of N-alkyl-2-fluoroaniline |
| CN115197072B (en) * | 2022-07-12 | 2024-05-03 | 合肥星宇化学有限责任公司 | Preparation method of N-alkyl-2-fluoroaniline |
| CN115160151A (en) * | 2022-08-04 | 2022-10-11 | 合肥星宇化学有限责任公司 | Preparation method of N-alkyl-2-fluoroaniline |
| CN115160151B (en) * | 2022-08-04 | 2024-01-09 | 合肥星宇化学有限责任公司 | Preparation method of N-alkyl-2-fluoroaniline |
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