CN115197072A - Preparation method of N-alkyl-2-fluoroaniline - Google Patents
Preparation method of N-alkyl-2-fluoroaniline Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000010438 heat treatment Methods 0.000 claims abstract description 38
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000013067 intermediate product Substances 0.000 claims abstract description 16
- 230000007062 hydrolysis Effects 0.000 claims abstract description 15
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 239000003377 acid catalyst Substances 0.000 claims abstract description 9
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 72
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 26
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical group COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 238000001704 evaporation Methods 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 11
- 230000035484 reaction time Effects 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 8
- 230000002378 acidificating effect Effects 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 239000002994 raw material Substances 0.000 abstract description 9
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 8
- 238000005917 acylation reaction Methods 0.000 abstract description 5
- 230000010933 acylation Effects 0.000 abstract description 3
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- LDVAIJZDACHGML-UHFFFAOYSA-N 2-fluoro-n-methylaniline Chemical compound CNC1=CC=CC=C1F LDVAIJZDACHGML-UHFFFAOYSA-N 0.000 description 17
- 238000001816 cooling Methods 0.000 description 15
- STNQTMAEQMBISR-UHFFFAOYSA-N n-(2-fluorophenyl)-n-methylformamide Chemical compound O=CN(C)C1=CC=CC=C1F STNQTMAEQMBISR-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 238000002156 mixing Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000004821 distillation Methods 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000002351 wastewater Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910000085 borane Inorganic materials 0.000 description 2
- 230000000711 cancerogenic effect Effects 0.000 description 2
- 231100000315 carcinogenic Toxicity 0.000 description 2
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 230000022244 formylation Effects 0.000 description 2
- 238000006170 formylation reaction Methods 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000001035 methylating effect Effects 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000005815 base catalysis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000000446 fuel Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012022 methylating agents Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
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Abstract
The invention provides a preparation method of N-alkyl-2-fluoroaniline, which comprises 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. Compared with the prior art, the invention takes the o-fluoroaniline as the raw material, takes the trialkyl orthoformate as the acylation reagent, prepares the acylated intermediate product by a substitution-rearrangement 'one-pot' method under the action of the catalyst, and then obtains the N-alkyl-2-fluoroaniline by hydrolysis.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of N-alkyl-2-fluoroaniline.
Background
The N-methyl-2-fluoroaniline belongs to fluorine-containing N-alkyl arylamine, is an important organic raw material and fine chemical intermediate, and is widely applied to the fields of plastics, fuels, medicines, pesticides and the like. With the continuous development of dye and rubber industries, the dosage of pesticides and medicines is continuously increased, the market demand of N-methyl-2-fluoroaniline is huge, and the corresponding synthesis and development of N-methyl-2-fluoroaniline are also concerned.
The synthesis of N-methyl-2-fluoroaniline has been reported in many publications, and according to different reaction routes, the currently mainstream synthesis methods include the following methods:
1. the o-fluoroaniline is used as a starting material, and is condensed with paraformaldehyde and dehydrated to obtain an imine intermediate, and then the imine intermediate is subjected to catalytic hydrogenation (or reduction by sodium borohydride) to obtain a product. However, the method has more reaction steps, expensive catalyst and higher cost, and can generate a large amount of formaldehyde-containing wastewater in the first step, so that the industrial application is difficult.
2. The o-fluoroaniline is used as raw material, firstly, it is undergone the process of acylation reaction with formylation reagent, then it is reacted with methylating reagent (for example dimethyl carbonate) under the condition of base catalysis to obtain intermediate with formyl protecting group, finally, it is hydrolyzed by hydrochloric acid-methanol to remove formyl group so as to obtain the invented product. The method also needs three steps of reaction, the needed dimethyl sulfate and formic acid have carcinogenic toxicity and strong acidity, the potential safety hazard is large, and a large amount of acid-containing wastewater can be generated in the first step.
3. The o-fluoroaniline is used as a raw material, and is firstly subjected to acylation reaction with a formylation reagent, and then is reduced by a reducing agent (borane is generally used for acyl reduction) to prepare the product. The borane used in the method is expensive, explosive and high in safety risk; in addition, the two-step reaction also produces a large amount of acid-containing wastewater and waste gas respectively, which is not beneficial to industrial application.
4. The o-fluoroaniline is used as a raw material and can directly react with a methylating agent (such as methyl iodide, dimethyl sulfate, dimethyl carbonate and the like) in one step to prepare a product. Most of the high-activity methylating reagents required by the method have definite carcinogenic toxicity, and the products need to be separated by high-efficiency rectification, so that the yield is low.
Disclosure of Invention
In view of this, the technical problem to be solved by the present invention is to provide a method for preparing N-alkyl-2-fluoroaniline, which has a short process route and a high conversion rate.
The invention provides a preparation method of N-alkyl-2-fluoroaniline, which comprises 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.
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 heating reaction temperature in the step S1) is 110-180 ℃; the heating reaction time is 2-5 h.
Preferably, 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.
Preferably, the reaction time is 0.5-3 h; the continuous reaction time is 0.5-3 h.
Preferably, the acylated intermediate product in 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 0.5-2 h.
Preferably, after 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.
The invention provides a preparation method of N-alkyl-2-fluoroaniline, which comprises the following steps: s1) in the presence of an acid catalyst, heating o-fluoroaniline and trialkyl orthoformate to react to obtain an acylated intermediate product; s2) hydrolyzing the acylated intermediate product to obtain the N-alkyl-2-fluoroaniline. Compared with the prior art, the invention takes the o-fluoroaniline as the raw material, takes the trialkyl orthoformate as the acylation reagent, prepares the acylated intermediate product by a substitution-rearrangement 'one-pot method' under the action of the catalyst, and then obtains the N-alkyl-2-fluoroaniline by hydrolysis.
Drawings
FIG. 1 is a NMR chart of N-methyl-2-fluoroaniline obtained in example 1 of the present invention.
Detailed Description
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, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides a preparation method of N-alkyl-2-fluoroaniline, which comprises 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.
In the present invention, the sources of all raw materials are not particularly limited, and they may be commercially available.
In the 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 trialkyl orthoformate as an example of the trimethyl orthoformate, the reaction formula is shown as follows:
in the presence of an acid catalyst, heating o-fluoroaniline and trialkyl orthoformate to react; the molar ratio of o-fluoroaniline, trialkyl orthoformate and acidic catalyst is preferably 1: (1-10): (0.02-0.1); in the embodiment provided by the invention, the molar ratio of the o-fluoroaniline, the trialkyl orthoformate and the acidic catalyst is 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 heating reaction time is preferably 2-5 h; in the present invention, this step is preferably embodied as follows: 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 more preferably raising the temperature to 170-180 ℃ for continuous reaction; wherein the reaction time is preferably 0.5-3 h; in the embodiment provided by the invention, the reaction time is specifically 0.5h, 3h, 1.5h or 1h; the continuous reaction time is 0.5 to 3 hours, and more preferably 1 to 3 hours; in the examples provided by the 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 give the acylated intermediate.
Hydrolyzing the acylated intermediate; in the present invention, it is preferable that the acylated intermediate is hydrolyzed by heating under reflux in a mixed solution of methanol and hydrochloric acid; the mass concentration of the hydrochloric acid is preferably 5-15%, more preferably 8-12%, and still more preferably 10%; the volume ratio of the methanol to the hydrochloric acid is preferably 1 (1-10); in the embodiment provided by the invention, the volume ratio of the methanol to the hydrochloric acid is specifically 1:10 or 1:1; the hydrolysis time is preferably 0.5 to 2 hours, more preferably 0.8 to 1.5 hours, and still more preferably 1 hour.
After the hydrolysis, the pH value of the reaction system is preferably adjusted to be alkaline, more preferably, after cooling, methanol is removed under reduced pressure, and then the pH value of the reaction system is adjusted to be alkaline; in the present invention, it is preferable to adjust the pH of the reaction system to alkaline with an alkali metal hydroxide solution; 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 preferably 8 to 15%, and still more preferably 10%; in the present invention, the pH of the reaction system is preferably adjusted to 8 to 12, more preferably 10.
After adjusting the pH of the reaction system to be alkaline, the organic phase is preferably extracted with diethyl ether, dried, filtered and concentrated to obtain the N-alkyl-2-fluoroaniline.
The invention takes o-fluoroaniline as raw material, takes trialkyl orthoformate as acylation reagent, prepares acylated intermediate product by substitution-rearrangement 'one-pot method' under the action of catalyst, and then obtains N-alkyl-2-fluoroaniline by hydrolysis, the raw material is cheap and easy to obtain, the process route is short, harsh reaction conditions are not contained, the operation is safe, the conversion rate is higher, less organic solvent is used, the amount of three wastes can be effectively reduced, and the invention has better industrial application prospect.
In order to further illustrate the present invention, the following examples are given to describe in detail the process for preparing N-alkyl-2-fluoroaniline according to the present invention.
The reagents used in the following examples are all commercially available.
Example 1
Mixing o-fluoroaniline (0.135 mol), trimethyl orthoformate (0.2025 mol) and concentrated sulfuric acid (0.007 mol), stirring and heating to 140 ℃, reacting for 0.5h, evaporating generated methanol, heating to 170 ℃ when no liquid is evaporated, continuing to react for 1.5h, cooling to room temperature, and then carrying out reduced pressure distillation to obtain the N-methyl-N-formyl-2-fluoroaniline.
The obtained N-methyl-N-formyl-2-fluoroaniline was dissolved in 50ml of methanol, 500ml of a 10% hydrochloric acid solution was added, and hydrolysis was carried out by heating under reflux for 1 hour. After cooling, the methanol was removed under reduced pressure, the pH of the solution was adjusted to 10 with 10% sodium hydroxide solution, the organic phase was extracted with diethyl ether, dried, filtered and concentrated to give N-methyl-2-fluoroaniline in 93% yield and 98% purity.
The N-methyl-2-fluoroaniline obtained in example 1 was analyzed by nuclear magnetic resonance, and the nuclear magnetic resonance hydrogen spectrum thereof was as shown in FIG. 1, with the results that 1 HNMR(500MHz,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:
mixing o-fluoroaniline (0.135 mol), trimethyl orthoformate (0.2025 mol) and concentrated sulfuric acid (0.007 mol), stirring and heating to 100 ℃, reacting for 0.5h, evaporating generated methanol, continuing to react for 5h at 100 ℃ when no liquid is evaporated, then cooling to room temperature, and detecting by TLC that no N-methyl-N-formyl-2-fluoroaniline is generated.
Example 2
Mixing o-fluoroaniline (0.135 mol), trimethyl orthoformate (0.135 mol) and concentrated sulfuric acid (0.014 mol), stirring and heating to 110 ℃, reacting for 3h, evaporating generated methanol, heating to 170 ℃ when no liquid is evaporated, continuing to react for 1.0h, cooling to room temperature, and then carrying out reduced pressure distillation to obtain N-methyl-N-formyl-2-fluoroaniline.
The obtained N-methyl-N-formyl-2-fluoroaniline was dissolved in 50ml of methanol, and 100ml of a 10% hydrochloric acid solution was added thereto, followed by heating and refluxing for 1 hour to conduct hydrolysis. After cooling, the methanol was removed under reduced pressure, the pH of the solution was adjusted to 10 with 10% sodium hydroxide solution, the organic phase was extracted with diethyl ether, dried, filtered and concentrated to give N-methyl-2-fluoroaniline in 87% yield and 98% purity.
The analysis of N-methyl-2-fluoroaniline obtained in example 2 by nuclear magnetic resonance was carried out in analogy to the results of example 1, and it was confirmed that the objective product was obtained.
Comparative example 2
Mixing o-fluoroaniline (0.135 mol) and trimethyl orthoformate (0.135 mol), stirring and heating to 110 ℃, reacting for 3h, evaporating generated methanol, heating to 170 ℃ when no liquid is evaporated, continuing to react for 1.0h, cooling to room temperature, and detecting by TLC that only a small amount of N-methyl-N-formyl-2-fluoroaniline is generated.
Example 3
Mixing o-fluoroaniline (0.135 mol), trimethyl orthoformate (1.35 mol) and concentrated hydrochloric acid (0.003 mol), stirring and heating to 140 ℃, reacting for 1.5h, evaporating generated methanol, heating to 180 ℃ when no liquid is evaporated, continuing to react for 3h, cooling to room temperature, and then carrying out reduced pressure distillation to obtain the N-methyl-N-formyl-2-fluoroaniline.
The obtained N-methyl-N-formyl-2-fluoroaniline was dissolved in 50ml of methanol, and 100ml of a 10% hydrochloric acid solution was added thereto, followed by heating and refluxing for 1 hour to conduct hydrolysis. After cooling, the methanol was removed under reduced pressure, the pH of the solution was adjusted to 10 with 10% sodium hydroxide solution, the organic phase was extracted with diethyl ether, dried, filtered and concentrated to give N-methyl-2-fluoroaniline in 91% yield and 98% purity.
The analysis of the N-methyl-2-fluoroaniline obtained in example 3 by nuclear magnetic resonance was carried out in analogy to the results of example 1, and it was confirmed that the objective product was obtained.
Comparative example 3
Mixing o-fluoroaniline (0.135 mol), trimethyl orthoformate (1.35 mol) and concentrated hydrochloric acid (0.003 mol), stirring and heating to 140 ℃, reacting for 1.5h, evaporating generated methanol, heating to 180 ℃ when no liquid is evaporated, continuing reacting for 3h, cooling to room temperature, and then carrying out reduced pressure distillation to obtain the N-methyl-N-formyl-2-fluoroaniline.
The resulting N-methyl-N-formyl-2-fluoroaniline was added to 100ml of a 10% hydrochloric acid solution, and the mixture was refluxed for 1 hour to conduct hydrolysis. After cooling, the pH value of the solution is adjusted to 10 by 10 percent sodium hydroxide solution, and then the organic phase is extracted by ether, dried, filtered and concentrated to obtain the N-methyl-2-fluoroaniline, the yield is 55 percent, and the purity is more than 98 percent.
Analysis of the N-methyl-2-fluoroaniline obtained in comparative example 3 by means of nuclear magnetic resonance was similar to the results of example 1, and it was confirmed that the objective product was obtained but the yield was low.
Example 4
Mixing o-fluoroaniline (0.135 mol), trimethyl orthoformate (0.2025 mol) and acetic acid (0.007 mol), stirring and heating to 140 ℃, reacting for 0.5h, evaporating generated methanol, heating to 170 ℃ when no liquid is evaporated, continuing to react for 1.5h, cooling to room temperature, and then carrying out reduced pressure distillation to obtain the N-methyl-N-formyl-2-fluoroaniline with the purity of more than 98%.
The resulting N-methyl-N-formyl-2-fluoroaniline was dissolved in 50ml of methanol, 50ml of a 10% hydrochloric acid solution was added, and hydrolysis was carried out by heating under reflux for 1 hour. After cooling, the methanol was removed under reduced pressure, the pH of the solution was adjusted to 10 with 10% sodium hydroxide solution, the organic phase was extracted with diethyl ether, dried, filtered and concentrated to give N-methyl-2-fluoroaniline in 86% yield and 98% purity.
The analysis of the N-methyl-2-fluoroaniline obtained in example 4 by nuclear magnetic resonance was carried out in analogy to the results of example 1, and it was confirmed that the objective product was obtained.
Example 5
Mixing o-fluoroaniline (0.135 mol), trimethyl orthoformate (0.27 mol) and concentrated sulfuric acid (0.01 mol), stirring and heating to 140 ℃, reacting for 1h, evaporating generated methanol, heating to 170 ℃ when no liquid is evaporated, continuing to react for 2h, cooling to room temperature, and then carrying out reduced pressure distillation to obtain the N-methyl-N-formyl-2-fluoroaniline.
The obtained N-methyl-N-formyl-2-fluoroaniline was dissolved in 50ml of methanol, 500ml of a 10% hydrochloric acid solution was added, and hydrolysis was carried out by heating under reflux for 1 hour. After cooling, the methanol was removed under reduced pressure, the pH of the solution was adjusted to 10 with 10% sodium hydroxide solution, the organic phase was extracted with diethyl ether, dried, filtered and concentrated to give N-methyl-2-fluoroaniline in 88% yield and purity >98%.
The analysis of N-methyl-2-fluoroaniline obtained in example 5 by means of nuclear magnetic resonance was carried out in analogy to the results of example 1, confirming that the desired product was obtained.
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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| CN202210814400.0A CN115197072B (en) | 2022-07-12 | 2022-07-12 | Preparation method of N-alkyl-2-fluoroaniline |
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| 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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| CN113620830A (en) * | 2021-09-26 | 2021-11-09 | 合肥星宇化学有限责任公司 | Synthesis method of metamifop intermediate |
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| 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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