CN115197072A - Preparation method of N-alkyl-2-fluoroaniline - Google Patents

Abstract

The invention provides a preparation method of N-alkyl-2-fluoroaniline, comprising: S1) in the presence of an acidic catalyst, heating and reacting o-fluoroaniline and trialkyl orthoformate to obtain an acylated intermediate product; S2) hydrolyzing the acylated intermediate product to obtain N-alkyl-2-fluoroaniline. Compared with the prior art, the present invention uses o-fluoroaniline as a raw material and trialkyl orthoformate as an acylating reagent, and prepares an acylated intermediate product through a substitution-rearrangement "one-pot method" under the action of a catalyst, Then N-alkyl-2-fluoroaniline is obtained by hydrolysis, the raw materials are cheap and easy to obtain, the process route is short, does not contain harsh reaction conditions, the operation is safe, the conversion rate is high, the organic solvent is used less, and the amount of three wastes can be effectively reduced. Good prospects for industrial application.

Description

A kind of preparation method of N-alkyl-2-fluoroaniline

technical field

The invention belongs to the technical field of organic synthesis, in particular to a preparation method of N-alkyl-2-fluoroaniline.

Background technique

N-methyl-2-fluoroaniline belongs to fluorine-containing N-alkylarylamines, which are an important class of organic raw materials and fine chemical intermediates, and are widely used in plastics, fuels, medicines, pesticides and other fields. With the continuous development of the dye and rubber industry, the dosage of pesticides and medicines has been increasing, and the market demand for N-methyl-2-fluoroaniline is huge, and its corresponding synthesis development has also attracted much attention.

The synthesis of N-methyl-2-fluoroaniline has more public reports, according to different reaction routes, the more mainstream synthetic methods at present have the following several:

1. Using o-fluoroaniline as the starting material, through condensation and dehydration with paraformaldehyde, the imine intermediate is obtained, and then the product is obtained by catalytic hydrogenation (or reduction with sodium borohydride). However, this method has many reaction steps, the required catalyst is expensive, and the cost is relatively high, and a large amount of formaldehyde-containing wastewater will be generated in the first step, which is difficult for industrial application.

2. Using o-fluoroaniline as raw material, firstly carry out acylation reaction with formylating reagent, and then react with methylating reagent (such as dimethyl carbonate) under alkali catalysis conditions to obtain intermediate with formyl protecting group , and finally the product is obtained by hydrochloric acid-methanol hydrolysis and deformylation. This method also requires three-step reactions, and the required dimethyl sulfate and formic acid have carcinogenic toxicity and strong acidity, and have great potential safety hazards, and a large amount of acid-containing wastewater will be generated in the first step.

3. Using o-fluoroaniline as raw material, first perform acylation reaction with formylation reagent, and then reduce the product by reducing agent (borane is generally required for acyl reduction). The borane used in the method is expensive, explosive, and has high safety risks; in addition, the two-step reaction will generate a large amount of acid-containing wastewater and waste gas respectively, which is unfavorable for industrial application.

4. Using o-fluoroaniline as raw material, it can be directly reacted with methylation reagents (such as methyl iodide, dimethyl sulfate, dimethyl carbonate, etc.) to prepare the product in one step. Most of the highly active methylating reagents required by this method have clear carcinogenic toxicity, and the products need to be separated by high-efficiency rectification with low yields.

SUMMARY OF THE INVENTION

In view of this, the technical problem to be solved by the present invention is to provide a preparation method of N-alkyl-2-fluoroaniline, which has a short technical route and a high conversion rate.

The invention provides a preparation method of N-alkyl-2-fluoroaniline, comprising:

S1) under the condition that acidic catalyst exists, o-fluoroaniline and trialkyl orthoformate are heated and reacted to obtain the intermediate product of acylation;

S2) hydrolyzing the acylated intermediate product to obtain N-alkyl-2-fluoroaniline.

Preferably, the trialkyl orthoformate is selected from trimethyl orthoformate.

Preferably, the acidic catalyst is selected from one or more of concentrated hydrochloric acid, acetic acid and concentrated sulfuric acid.

Preferably, the molar ratio of the o-fluoroaniline, the trialkyl orthoformate and the acidic catalyst is 1:(1-10):(0.02-0.1).

Preferably, the temperature of the heating reaction in the step S1) is 110°C to 180°C; the time of the heating reaction is 2 to 5 hours.

Preferably, the step S1) is specifically:

In the presence of an acidic catalyst, o-fluoroaniline and trialkyl orthoformate are heated to 110°C to 140°C to react, and the resulting alcohol is evaporated. After no liquid is evaporated, the temperature is raised to 150°C to 180°C to continue. The reaction yields an acylated intermediate.

Preferably, the reaction time is 0.5-3h; the continuous reaction time is 0.5-3h.

Preferably, the acylated intermediate product in the step S2) is hydrolyzed by heating under reflux in a mixed solution of methanol and hydrochloric acid.

Preferably, the mass concentration of the hydrochloric acid is 5%-15%; the hydrolysis time is 0.5-2h.

Preferably, after hydrolysis, the pH value of the reaction system is adjusted to be alkaline, and the organic phase is extracted with ether to obtain N-alkyl-2-fluoroaniline.

The invention provides a preparation method of N-alkyl-2-fluoroaniline, comprising: S1) in the presence of an acidic catalyst, heating and reacting o-fluoroaniline and trialkyl orthoformate to obtain an acylated intermediate product; S2) The acylated intermediate is hydrolyzed to obtain N-alkyl-2-fluoroaniline. Compared with the prior art, the present invention uses o-fluoroaniline as a raw material and trialkyl orthoformate as an acylating reagent, and prepares an acylated intermediate product through a substitution-rearrangement "one-pot method" under the action of a catalyst, Then, N-alkyl-2-fluoroaniline is obtained by hydrolysis. The raw materials are cheap and easy to obtain, the process route is short, no harsh reaction conditions are contained, the operation is safe, the conversion rate is high, and the organic solvent is used less, which can effectively reduce the amount of three wastes. Good prospects for industrial application.

Description of drawings

Fig. 1 is the hydrogen nuclear magnetic resonance spectrum of N-methyl-2-fluoroaniline obtained in Example 1 of the present invention.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

The invention provides a preparation method of N-alkyl-2-fluoroaniline, comprising: S1) in the presence of an acidic catalyst, heating and reacting o-fluoroaniline and trialkyl orthoformate to obtain an acylated intermediate product; S2) The acylated intermediate is hydrolyzed to obtain N-alkyl-2-fluoroaniline.

Wherein, in the present invention, there is no special restriction on the sources of all raw materials, and they can be commercially available.

In the present invention, the acidic catalyst is preferably one or more of concentrated hydrochloric acid, acetic acid and concentrated sulfuric acid; the trialkyl orthoformate is preferably trimethyl orthoformate. Taking the raw material trialkyl orthoformate as trimethyl orthoformate as an example, the general reaction formula is as follows:

In the presence of an acidic catalyst, the o-fluoroaniline and trialkyl orthoformate are heated and reacted; the molar ratio of the o-fluoroaniline, trialkyl orthoformate and the acidic catalyst is preferably 1: (1～10): (0.02-0.1); in the examples provided by the present invention, the molar ratios of the o-fluoroaniline, trialkyl orthoformate and acid catalyst are specifically 1:1.5:0.05, 1:1:0.1, 1:10 : 0.02 or 1: 2: 0.074; the temperature of the heating reaction is preferably 110℃～180℃; the time of the heating reaction is preferably 2～5h; in the present invention, this step is preferably as follows: in the presence of an acidic catalyst Under the same conditions, the o-fluoroaniline and trialkyl orthoformate are heated to 110 ℃～140 ℃ to react, and the generated alcohol is steamed out. The temperature is raised to 170°C to 180°C to continue the reaction; wherein, the reaction time is preferably 0.5 to 3h; in the embodiments provided by the present invention, the reaction time is specifically 0.5h, 3h, 1.5h or 1h; The time for continuing the reaction is 0.5-3h, more preferably 1-3h; in the embodiments provided by the present invention, the time for continuing the reaction is specifically 1.5h, 1h, 3h or 2h.

After the reaction, it is preferably cooled to room temperature and distilled under reduced pressure to obtain an acylated intermediate product.

The acylated intermediate product is hydrolyzed; in the present invention, the acylated intermediate product is preferably heated and refluxed in a mixed solution of methanol and hydrochloric acid for hydrolysis; the mass concentration of the hydrochloric acid is preferably 5% to 15%, more It is preferably 8% to 12%, and more preferably 10%; the volume ratio of methanol to hydrochloric acid is preferably 1:(1 to 10); in the embodiments provided by the present invention, the volume ratio of methanol to hydrochloric acid is specific is 1:10 or 1:1; the hydrolysis time is preferably 0.5-2h, more preferably 0.8-1.5h, and still more preferably 1h.

After the hydrolysis, it is preferable to adjust the pH value of the reaction system to be alkaline, more preferably after cooling first, remove methanol under reduced pressure, and then adjust the pH value of the reaction system to be basic; in the present invention, it is preferable to use an alkali metal hydroxide solution to adjust the reaction The pH value of the system is alkaline; the alkali metal hydroxide solution is preferably an aqueous sodium hydroxide solution and/or an aqueous potassium hydroxide solution; the mass concentration of the alkali metal hydroxide solution is preferably 5% to 20%, more It is preferably 8% to 15%, more preferably 10%; in the present invention, the pH value of the reaction system is preferably adjusted to 8 to 12, more preferably 10.

After adjusting the pH value of the reaction system to basic, the organic phase is preferably extracted with ether, dried, filtered and concentrated to obtain N-alkyl-2-fluoroaniline.

In the present invention, o-fluoroaniline is used as raw material, trialkyl orthoformate is used as acylating reagent, and acylated intermediate product is prepared by substitution-rearrangement "one-pot method" under the action of catalyst, and then N-alkane is obtained by hydrolysis Base-2-fluoroaniline has cheap and easy-to-obtain raw materials, short process route, no harsh reaction conditions, safe operation, high conversion rate, less use of organic solvents, can effectively reduce the amount of three wastes, and has good industrial application prospects.

In order to further illustrate the present invention, a preparation method of N-alkyl-2-fluoroaniline provided by the present invention will be described in detail below with reference to the examples.

The reagents used in the following examples are all commercially available.

Example 1

Mix o-fluoroaniline (0.135 mol), trimethyl orthoformate (0.2025 mol) and concentrated sulfuric acid (0.007 mol), stir and heat to 140 ° C, react for 0.5 h, and evaporate the generated methanol, when no liquid is evaporated. The temperature was raised to 170 °C, the reaction was continued for 1.5 h, cooled to room temperature, and then distilled under reduced pressure to obtain N-methyl-N-formyl-2-fluoroaniline.

The obtained N-methyl-N-formyl-2-fluoroaniline was dissolved in 50 ml of methanol, 500 ml of a 10% hydrochloric acid solution was added, and the mixture was heated and refluxed for 1 h for hydrolysis. After cooling, methanol was removed under reduced pressure, the pH value of the solution was adjusted to 10 with 10% sodium hydroxide solution, and the organic phase was extracted with ether, dried, filtered, and concentrated to obtain N-methyl-2-fluoroaniline, yield 93 %, purity >98%.

The N-methyl-2-fluoroaniline obtained in Example 1 was analyzed by nuclear magnetic resonance, and its hydrogen nuclear magnetic resonance spectrum was obtained as shown in Figure 1. The result ¹ HNMR (500 MHz, DMSO-d ₆ ): δ6.90 -7.10(m, 2H), 6.60-6.75(m, 2H), 3.93(s, 1H), 2.86(s, 3H).

Comparative Example 1:

Mix o-fluoroaniline (0.135mol), trimethyl orthoformate (0.2025mol) and concentrated sulfuric acid (0.007mol), stir and heat to 100°C, react for 0.5h, and evaporate the generated methanol, when no liquid is evaporated. The reaction was continued at 100° C. for 5 h, and then cooled to room temperature. No N-methyl-N-formyl-2-fluoroaniline was detected by TLC.

Example 2

Mix o-fluoroaniline (0.135mol), trimethyl orthoformate (0.135mol) and concentrated sulfuric acid (0.014mol), stir and heat to 110°C, react for 3h, and steam out the generated methanol, and heat up when no liquid is steamed out To 170 ° C, continue to react for 1.0 h, cooled to room temperature, and then distilled under reduced pressure to obtain N-methyl-N-formyl-2-fluoroaniline.

The obtained N-methyl-N-formyl-2-fluoroaniline was dissolved in 50 ml of methanol, 100 ml of a 10% hydrochloric acid solution was added, and the mixture was heated and refluxed for 1 h for hydrolysis. After cooling, methanol was removed under reduced pressure, the pH of the solution was adjusted to 10 with 10% sodium hydroxide solution, and the organic phase was extracted with ether, dried, filtered, and concentrated to obtain N-methyl-2-fluoroaniline with a yield of 87 %, purity >98%.

The N-methyl-2-fluoroaniline obtained in Example 2 was analyzed by nuclear magnetic resonance and the results were similar to those in Example 1, and it was confirmed that the obtained product was the target product.

Comparative Example 2

Mix o-fluoroaniline (0.135 mol) and trimethyl orthoformate (0.135 mol), stir and heat to 110 ° C, react for 3 h, and steam the generated methanol, when no liquid is evaporated, the temperature is raised to 170 ° C, and the reaction is continued for 1.0 h, cooled to room temperature, only a small amount of N-methyl-N-formyl-2-fluoroaniline was generated by TLC detection.

Example 3

Mix o-fluoroaniline (0.135mol), trimethyl orthoformate (1.35mol) and concentrated hydrochloric acid (0.003mol), stir and heat to 140°C, react for 1.5h, and evaporate the generated methanol, when no liquid is evaporated. The temperature was raised to 180 °C, the reaction was continued for 3 h, cooled to room temperature, and then distilled under reduced pressure to obtain N-methyl-N-formyl-2-fluoroaniline.

The obtained N-methyl-N-formyl-2-fluoroaniline was dissolved in 50 ml of methanol, 100 ml of a 10% hydrochloric acid solution was added, and the mixture was heated and refluxed for 1 h for hydrolysis. After cooling, methanol was removed under reduced pressure, the pH of the solution was adjusted to 10 with 10% sodium hydroxide solution, and the organic phase was extracted with ether, dried, filtered, and concentrated to obtain N-methyl-2-fluoroaniline, yield 91 %, purity >98%.

The N-methyl-2-fluoroaniline obtained in Example 3 was analyzed by nuclear magnetic resonance and the results were similar to those in Example 1, and it was confirmed that the obtained product was the target product.

Comparative Example 3

Mix o-fluoroaniline (0.135mol), trimethyl orthoformate (1.35mol) and concentrated hydrochloric acid (0.003mol), stir and heat to 140°C, react for 1.5h, and evaporate the generated methanol, when no liquid is evaporated. The temperature was raised to 180 °C, the reaction was continued for 3 h, cooled to room temperature, and then distilled under reduced pressure to obtain N-methyl-N-formyl-2-fluoroaniline.

The obtained N-methyl-N-formyl-2-fluoroaniline was added to 100 ml of a 10% hydrochloric acid solution, and heated under reflux for 1 h for hydrolysis. After cooling, the pH value of the solution was adjusted to 10 with 10% sodium hydroxide solution, and the organic phase was extracted with ether, dried, filtered and concentrated to obtain N-methyl-2-fluoroaniline, yield 55%, purity >98 %.

The N-methyl-2-fluoroaniline obtained in Comparative Example 3 was analyzed by nuclear magnetic resonance and the results were similar to those of Example 1, and it was confirmed that the target product was obtained, but the yield was low.

Example 4

Mix o-fluoroaniline (0.135 mol), trimethyl orthoformate (0.2025 mol) and acetic acid (0.007 mol), stir and heat to 140 ° C, react for 0.5 h, and evaporate the generated methanol, and heat up when no liquid is evaporated. At 170°C, the reaction was continued for 1.5 h, cooled to room temperature, and then distilled under reduced pressure to obtain N-methyl-N-formyl-2-fluoroaniline with a purity of >98%.

The obtained N-methyl-N-formyl-2-fluoroaniline was dissolved in 50 ml of methanol, 50 ml of a 10% hydrochloric acid solution was added, and the mixture was heated and refluxed for 1 h for hydrolysis. After cooling, methanol was removed under reduced pressure, the pH value of the solution was adjusted to 10 with 10% sodium hydroxide solution, and the organic phase was extracted with ether, dried, filtered, and concentrated to obtain N-methyl-2-fluoroaniline, yield 86 %, purity >98%.

The N-methyl-2-fluoroaniline obtained in Example 4 was analyzed by nuclear magnetic resonance and the results were similar to those in Example 1, and it was confirmed that the obtained product was the target product.

Example 5

Mix o-fluoroaniline (0.135 mol), trimethyl orthoformate (0.27 mol) and concentrated sulfuric acid (0.01 mol), stir and heat to 140 ° C, react for 1 h, and evaporate the generated methanol, and heat up when no liquid is evaporated. To 170 ° C, continue to react for 2 h, cooled to room temperature, and then distilled under reduced pressure to obtain N-methyl-N-formyl-2-fluoroaniline.

The obtained N-methyl-N-formyl-2-fluoroaniline was dissolved in 50 ml of methanol, 500 ml of a 10% hydrochloric acid solution was added, and the mixture was heated and refluxed for 1 h for hydrolysis. After cooling, methanol was removed under reduced pressure, the pH value of the solution was adjusted to 10 with 10% sodium hydroxide solution, and the organic phase was extracted with ether, dried, filtered, and concentrated to obtain N-methyl-2-fluoroaniline with a yield of 88 %, purity >98%.

The N-methyl-2-fluoroaniline obtained in Example 5 was analyzed by nuclear magnetic resonance and the results were similar to those in Example 1, and it was confirmed that the obtained product was the target product.

Claims (10)

1. A method for preparing N-alkyl-2-fluoroaniline, which is characterized by comprising the following steps:

s1) heating o-fluoroaniline and trialkyl orthoformate to react in the presence of an acid catalyst to obtain an acylated intermediate product;

s2) hydrolyzing the acylated intermediate product to obtain the N-alkyl-2-fluoroaniline.

2. The method according to claim 1, wherein the trialkyl orthoformate is selected from trimethyl orthoformate.

3. The method according to claim 1, wherein the acidic catalyst is one or more selected from concentrated hydrochloric acid, acetic acid and concentrated sulfuric acid.

4. The method according to claim 1, wherein the molar ratio of the o-fluoroaniline, the trialkyl orthoformate, and the acidic catalyst is from 1: (1-10): (0.02-0.1).

5. The preparation method according to claim 1, wherein the temperature of the heating reaction in the step S1) is 110 to 180 ℃; the heating reaction time is 2-5 h.

6. The preparation method according to claim 1, wherein the step S1) is specifically:

heating o-fluoroaniline and trialkyl orthoformate to 110-140 ℃ for reaction in the presence of an acid catalyst, evaporating generated alcohol, raising the temperature to 150-180 ℃ for continuous reaction after no liquid is evaporated, and obtaining an acylated intermediate product.

7. The preparation method according to claim 6, characterized in that the reaction time is 0.5 to 3 hours; the continuous reaction time is 0.5-3 h.

8. The method according to claim 1, wherein the acylated intermediate in step S2) is hydrolyzed by heating under reflux in a mixed solution of methanol and hydrochloric acid.

9. The preparation method according to claim 8, wherein the mass concentration of the hydrochloric acid is 5-15%; the hydrolysis time is 0.5-2 h.

10. The process according to claim 1, wherein after the hydrolysis, the pH of the reaction system is adjusted to be alkaline, and the organic phase is extracted with diethyl ether to obtain the N-alkyl-2-fluoroaniline.

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