CN112374998A - Preparation method of N-methyl o-fluoroaniline - Google Patents
Preparation method of N-methyl o-fluoroaniline Download PDFInfo
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- CN112374998A CN112374998A CN202011416091.9A CN202011416091A CN112374998A CN 112374998 A CN112374998 A CN 112374998A CN 202011416091 A CN202011416091 A CN 202011416091A CN 112374998 A CN112374998 A CN 112374998A
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
Abstract
The invention discloses a preparation method of N-methyl o-fluoroaniline, belonging to the technical field of organic synthesis. Reacting o-fluoroaniline with formaldehyde in an organic solvent under an alkaline condition to obtain an intermediate N-methoxymethyl o-fluoroaniline; and reducing the intermediate N-methoxy methyl o-fluoroaniline in the presence of a catalyst to obtain the N-methyl o-fluoroaniline. The method has the advantages of easily obtained raw materials, simple process conditions and used equipment, no need of equipment replacement, capability of completing two-step reaction in one reaction kettle, total yield of over 85 percent, product content of over 99.5 percent and easiness in industrial production.
Description
Technical Field
The invention belongs to the field of organic synthesis of traditional Chinese medicine/pesticide intermediates, and particularly relates to a preparation method of N-methyl o-fluoroaniline.
Background
N-methyl o-fluoroaniline is an important intermediate widely applied to medicines and pesticides, such as herbicide metamifop, Chinese patent is due in 2019, production and popularization are necessarily more extensive, and demand is gradually increased.
However, the literature on the synthesis of N-methyl o-fluoroaniline does not report a lot, and the main reaction process route is as follows:
1) chinese patent CN1656085A adopts anhydrous formic acid and acetic anhydride to prepare mixed anhydride, then the mixed anhydride reacts with o-fluoroaniline to generate N-formyl o-fluoroaniline, and then the N-formyl o-fluoroaniline is reduced by tetrahydrofuran solution of borane to obtain N-methyl o-fluoroaniline. The borane solution used as the raw material in the route is dangerous, expensive and has no advantages in raw material cost.
2) Chinese patent CN107973721A adopts o-fluoroaniline and paraformaldehyde to prepare N-methylene o-fluoroaniline, and then the N-methyl o-fluoroaniline is obtained by hydrogenation reaction in the presence of a catalyst. In the route, the N-methylene o-fluoroaniline is not easy to prepare, and needs to be reduced by hydrogen in a high-pressure reaction kettle, and the requirement on equipment is high.
3) Chinese patent CN109053486A adopts o-fluoroaniline to prepare diazonium salt, and then the diazonium salt reacts with methylamine water solution to obtain N-methyl o-fluoroaniline. The process has the disadvantages that the amount of high-salinity wastewater generated by diazotization reaction is very large, the components are complex and difficult to treat, and the application in production is also influenced.
4) Chinese journal "chemical reagents" 2018, 40(7), P699: the description describes that after 88% formic acid is used for synthesizing N-formyl o-fluoroaniline, methyl methanesulfonate is used for methylation, and after hydrochloric acid acidolysis, formyl is removed to obtain the N-methyl o-fluoroaniline. The process has long reaction route, and the methylating agent methyl methanesulfonate is expensive, difficult to purchase and difficult to industrialize.
Disclosure of Invention
Aiming at the process defects, the invention has the characteristics that the used raw materials are easily available, the process conditions and the used equipment are simple, the two-step reaction can be completed in one reaction kettle without replacing the equipment, the total yield can reach more than 90 percent, the product content is more than 99.5 percent, and the industrial production is easy to realize.
The invention relates to a preparation method of N-methyl o-fluoroaniline, which comprises the following steps:
1) reacting o-fluoroaniline with formaldehyde in an organic solvent under an alkaline condition to obtain an intermediate N-methoxymethyl o-fluoroaniline;
2) and reducing the intermediate N-methoxy methyl o-fluoroaniline in the presence of a catalyst to obtain the N-methyl o-fluoroaniline.
The technical route is as follows:
further, in the technical scheme, the solvent in the step (1) is C1-C4 alkyl alcohol, and the mass ratio of the feeding mass to the o-fluoroaniline is 2-20: 1.
further, in the above technical solution, the base in step (1) is selected from potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, and the molar ratio of the base to the o-fluoroaniline is 1: 1 to 5.
Further, in the technical scheme, the formaldehyde in the step (1) is formaldehyde aqueous solution, paraformaldehyde or trioxymethylene, and the molar ratio of the formaldehyde to the o-fluoroaniline is 1-3: 1; the preferable molar ratio is 1.2-1.5: 1.
further, in the above technical scheme, the reducing agent in step (2) is hydrogen, sodium borohydride, potassium borohydride, ammonium formate, hydrazine hydrate, and the molar ratio of the reducing agent to o-fluoroaniline is 0.3-2: 1; the preferable molar ratio is 0.5-0.8: 1.
further, in the above technical scheme, the catalyst in step (2) is ferric chloride, aluminum trichloride, zinc chloride, B (C)6F5)3Nickel-aluminum alloy, palladium-carbon, platinum-carbon or Raney nickel, preferably zinc chloride, and the mass ratio of the catalyst to the o-fluoroaniline is 0.02-0.10: 1; the preferable mass ratio is 0.05: 1.
further, in the technical scheme, the reaction temperature in the step (1) is 0-60 ℃, the preferable temperature is 20-30 ℃, the reaction time is 3-16 hours, and the preferable reaction time is 3-5 hours.
Further, in the technical scheme, the reaction temperature in the step (2) is 25-65 ℃, the preferable temperature is 20-30 ℃, the reaction time is 1-6 hours, and the preferable reaction time is 2-3 hours.
Furthermore, in the above technical scheme, after the reaction in the step (1) is finished, the reaction in the step (2) is directly performed in the same reaction kettle without treatment.
Further, in the above technical scheme, the post-treatment in step (2) is that hydrochloric acid is added after the reaction is finished, the solvent is distilled off, and the N-methyl o-fluoroaniline is obtained by extractive distillation.
Advantageous effects of the invention
In the invention, the formed intermediate is not stable for R as methyl and ethyl, so the intermediate is ready to use, is easy to decompose at room temperature, can eliminate imine generation in the presence of common Lewis acid, and generates a product in the presence of a reducing agent such as sodium borohydride and the like.
When R is isopropyl or tert-butyl, the stability of the intermediate is increased, and a specific Lewis acid B (C) is required6F5)3Imine is formed in the presence of a catalyst, so that reduction is realized, the synthesis of the N-methyl o-fluoroaniline is completed by using a one-pot method, and the method has the advantages of simple conditions, few types of used raw materials, easiness in purchase, low energy consumption, high product yield and good quality, and is easy to realize industrial production.
Detailed Description
Example 1
Adding 33.3g of o-fluoroaniline and 250mL of methanol into a 500mL reaction bottle, starting stirring, adding 25g of solid sodium methoxide under the protection of nitrogen, keeping the temperature at 25-30 ℃, adding 13g of paraformaldehyde, and reacting for 5 hours at 25-30 ℃; 1.7g of anhydrous zinc chloride is added, 5.8g of sodium borohydride is added in batches, the addition is finished for about 1 hour, stirring is continued for 3 hours at the temperature, sampling is carried out, the content of the o-fluoroaniline is less than 1 percent, 50g of water is added, 100g of 30 percent hydrochloric acid is slowly dropped, most of methanol is evaporated, 20 percent sodium hydroxide aqueous solution is used for neutralizing until the pH value is more than 10, 150ml of dichloromethane is used for extraction for 3 times, organic phases are combined, dichloromethane is evaporated at normal pressure, then a product is evaporated at the top temperature of 78-80 ℃ in a rectifying tower under the vacuum of 15-20 mmHg, the product is colorless to light yellow liquid, 34.2g of N-methyl o-fluoroaniline is obtained, the content is 99.6 percent, and the yield is 91 percent.
Example 2
Adding 66.6g of o-fluoroaniline and 500mL of methanol into a 1000mL reaction bottle, starting stirring, adding 60g of solid sodium methoxide under the protection of nitrogen, keeping the temperature at 25-30 ℃, adding 30g of paraformaldehyde, and reacting for 5 hours at 25-30 ℃; adding 3.5g of anhydrous zinc chloride, adding 12.0g of sodium borohydride in batches, completing the addition for about 1 hour, continuing stirring for 5 hours at the temperature, sampling, adding 100g of water until the content of the o-fluoroaniline is less than 0.8%, slowly dropping 200g of 30% hydrochloric acid, distilling out most of methanol, neutralizing with 20% sodium hydroxide aqueous solution until the pH value is more than 10, adding 200mL of dichloromethane for extraction for 3 times, combining organic phases, distilling out dichloromethane at normal pressure, then adopting a rectifying tower to distill out a product at the top temperature of 79-81 ℃ under the vacuum of 15-20 mmHg to obtain colorless to light yellow liquid, and obtaining 69.8g of N-methyl o-fluoroaniline, the content of 99.5% and the yield of 93%.
Example 3
Putting 66.6g of o-fluoroaniline and 500mL of anhydrous ethanol into a 1000mL reaction bottle, starting stirring, adding 75.6g of solid sodium ethoxide under the protection of nitrogen, keeping the temperature of the reaction solution at 25-30 ℃, adding 30g of paraformaldehyde, reacting for 5 hours at 25-30 ℃, adding 4.0g of anhydrous ferric chloride, adding 12.0g of sodium borohydride in batches, completing the addition for about 1 hour, keeping the temperature, continuing the reaction for 6 hours, sampling, adding 100g of water, slowly dropping 200g of 30% hydrochloric acid, distilling out most of methanol, neutralizing with 20% sodium hydroxide aqueous solution until the pH value is more than 10, adding 200mL of dichloromethane for extraction for 3 times, combining organic phases, distilling out dichloromethane at normal pressure, then adopting a rectifying tower to distill products at the vacuum of 20-25 mmHg under the vacuum of the top temperature of 88-90 ℃, distilling out colorless to light yellow liquid to obtain 66.2g of N-methyl o-fluoroaniline, the content is 99.2 percent, and the yield is 88.2 percent.
Example 4
In 500mL33.3g of o-fluoroaniline and 300mL of tert-butanol were put into a reaction flask, stirring was started, 62.3g of potassium tert-butoxide was added under nitrogen protection, the temperature of the reaction solution was kept at 25 to 30 ℃, 15.0g of paraformaldehyde was added, the reaction solution was reacted at 25 to 30 ℃ for 5 hours, and 3.0g of 3.0g B (C) was added6F5)3Adding 6.0g of sodium borohydride in batches, finishing the adding within 0.5 hour, keeping the temperature and continuing to react for 6 hours, sampling, adding 60g of water, slowly dropping 100g of 30% hydrochloric acid, evaporating most of methanol, neutralizing with 20% sodium hydroxide aqueous solution until the pH value is more than 10, adding 200mL of dichloromethane for extraction for 3 times, combining organic phases, evaporating dichloromethane at normal pressure, then adopting a rectifying tower to evaporate a product at the top temperature of 79-81 ℃ under the vacuum of 15-20 mmHg to obtain colorless to light yellow liquid, and obtaining 66.8g of N-methyl o-fluoroaniline with the content of 99.1%, and the yield of 90%.
Example 5
In a 500mL reaction flask, 33.3g of o-fluoroaniline and 300mL of t-butanol were placed, stirring was turned on, 62.3g of potassium t-butoxide was added under nitrogen protection, the reaction mixture was allowed to warm to 25-30 ℃, 15.0g of paraformaldehyde was added, the mixture was reacted at 25-30 ℃ for 5 hours, and 1.2g of 5% Pd/C and 3.2g B (C)6F5)3Introducing hydrogen under normal pressure, continuing to react for 6 hours, sampling, adding 60g of water when the content of the o-fluoroaniline is less than 0.6%, slowly dropping 100g of 30% hydrochloric acid, distilling out most of methanol, neutralizing with 20% sodium hydroxide aqueous solution until the pH value is more than 10, adding 200mL of dichloromethane for extraction for 3 times, combining organic phases, distilling out dichloromethane under normal pressure, and then distilling out a product at the top temperature of 80-83 ℃ in a rectifying tower under the vacuum of 17-22 mmHg to obtain colorless to light yellow liquid, thus obtaining 65.3g of N-methyl o-fluoroaniline with the content of 99.0% and the yield of 88%.
The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (10)
1. The preparation method of the N-methyl o-fluoroaniline is characterized by comprising the following steps:
(1) reacting o-fluoroaniline with formaldehyde in an organic solvent under an alkaline condition to obtain an intermediate N-methoxymethyl o-fluoroaniline;
(2) and reducing the intermediate N-methoxy methyl o-fluoroaniline in the presence of a catalyst to obtain the N-methyl o-fluoroaniline.
2. The process for the preparation of N-methyl-o-fluoroaniline according to claim 1, characterized in that: the solvent in the step (1) is C1-C4 alkyl alcohol, and the mass ratio of the feeding mass to the o-fluoroaniline is 2-20: 1.
3. the process for the preparation of N-methyl-o-fluoroaniline according to claim 1, characterized in that: the alkali in the step (1) is selected from potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, and the molar ratio of the alkali to the o-fluoroaniline is 1: 1 to 5.
4. The process for the preparation of N-methyl-o-fluoroaniline according to claim 1, characterized in that: in the step (1), the formaldehyde is aqueous solution of formaldehyde, paraformaldehyde or trioxymethylene, and the molar ratio of the formaldehyde to the o-fluoroaniline is 1: 1 to 3.
5. The process for the preparation of N-methyl-o-fluoroaniline according to claim 1, characterized in that: the reducing agent in the step (2) is hydrogen, sodium borohydride, potassium borohydride, ammonium formate and hydrazine hydrate, and the molar ratio of the reducing agent to the o-fluoroaniline is 1: 0.3 to 2.
6. The process for the preparation of N-methyl-o-fluoroaniline according to claim 1, characterized in that: the catalyst in the step (2) is ferric chloride, aluminum trichloride, zinc chloride and B (C)6F5)3The catalyst is prepared from nickel-aluminum alloy, palladium-carbon, platinum-carbon or Raney nickel, wherein the mass ratio of the catalyst to o-fluoroaniline is 1: 0.02 to 0.10.
7. The process for the preparation of N-methyl-o-fluoroaniline according to claim 1, characterized in that: the reaction temperature in the step (1) is 0-60 ℃, and the reaction time is 3-16 hours.
8. The process for the preparation of N-methyl-o-fluoroaniline according to claim 1, characterized in that: the reaction temperature in the step (2) is 25-65 ℃, and the reaction time is 1-6 hours.
9. The process for the preparation of N-methyl-o-fluoroaniline according to claim 1, characterized in that: and (3) after the reaction in the step (1) is finished, directly carrying out the reaction in the step (2) in the same reaction kettle without treatment.
10. The process for the preparation of N-methyl-o-fluoroaniline according to claim 1, characterized in that: and (2) performing post-treatment, namely adding hydrochloric acid after the reaction is finished, evaporating the solvent, and performing extractive distillation to obtain the N-methyl o-fluoroaniline.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114230078A (en) * | 2021-12-21 | 2022-03-25 | 武汉瑞阳化工有限公司 | Comprehensive utilization method of acidic wastewater generated in 1-fluoronaphthalene production |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090176786A1 (en) * | 2005-10-20 | 2009-07-09 | Masato Konobe | Benzoylurea Compounds and Use Thereof |
| CN107973721A (en) * | 2017-11-23 | 2018-05-01 | 浙江林江化工股份有限公司 | A kind of synthetic method of N- methyl neighbour's fluoroaniline |
| CN111662185A (en) * | 2020-06-18 | 2020-09-15 | 江苏富鼎化学有限公司 | Synthesis method of N-methyl o-fluoroaniline |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090176786A1 (en) * | 2005-10-20 | 2009-07-09 | Masato Konobe | Benzoylurea Compounds and Use Thereof |
| CN107973721A (en) * | 2017-11-23 | 2018-05-01 | 浙江林江化工股份有限公司 | A kind of synthetic method of N- methyl neighbour's fluoroaniline |
| CN111662185A (en) * | 2020-06-18 | 2020-09-15 | 江苏富鼎化学有限公司 | Synthesis method of N-methyl o-fluoroaniline |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114230078A (en) * | 2021-12-21 | 2022-03-25 | 武汉瑞阳化工有限公司 | Comprehensive utilization method of acidic wastewater generated in 1-fluoronaphthalene production |
| CN114230078B (en) * | 2021-12-21 | 2023-09-22 | 武汉瑞阳化工有限公司 | Comprehensive utilization method of acid wastewater generated in production of 1-fluoronaphthalene |
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