A process for the preparation of N1,N2-dimethylbenzene-1,2-diamine

Abstract

The application discloses a preparation method of N1,N2-dimethyl benzene-1,2-diamine and belongs to the technical field of medical intermediate preparation. The method comprises the following steps: taking o-phenylenediamine as a raw material, reacting with ethyl formate, then adopting dimethyl sulfate to perform a nitrogen-methylation reaction, and finally removing a formyl group under the action of an acid to obtain N1,N2-dimethyl benzene-1,2-diamine. In the method, all raw materials can be conveniently purchased on the market, the process of each reaction is simple, there is no expensive catalyst, the yield is high, and the industrialized production is easy.

Description

A method for preparing N1,N2-dimethylphenyl-1,2-diamine Technical Field

[0001] This invention relates to a method for preparing N1,N2-dimethylbenzene-1,2-diamine, belonging to the field of pharmaceutical intermediate preparation technology. Background Technology

[0002] N1,N2-Dimethylphenyl-1,2-diamine (CAS No:3213-79-4) is an organic compound with multiple uses. It can be used as a synthetic intermediate for dyes, pharmaceuticals or pesticides, and can also participate in polymerization reactions or be used as a resin additive.

[0003] For this product, after reviewing existing literature, there are many reported synthesis methods. Several main synthesis routes are listed below.

[0004] Patents and literature [CN110845420A; WO2020104779A; Journal of the American Chemical Society, 2024, 146, 28832; Angewandte Chemie International Edition, 2012, 51, 13058; Journal of Organic Chemistry, 2005, 70, 9632] report the reaction of o-phenylenediamine with p-toluenesulfonyl chloride, followed by nitrogen-methylation with iodomethane, and finally removal of the p-toluenesulfonyl group to generate N1,N2-dimethylphenyl-1,2-diamine.

[0005] Patents and literature [Advanced Synthesis and Catalysis, 2012, 354, 847; Organic Letters, 2018, 20, 5985; Catalysis Science and Technology, 2024, 14, 1958] report the reaction of o-phenylenediamine as a raw material with methanol under the action of a noble metal catalyst and high temperature to produce N1,N2-dimethylphenyl-1,2-diamine, with a yield of 25-82%.

[0006] The literature [Journal of the American Chemical Society, 2008, 130, 2144] reports that o-phenylenediamine is used as a raw material and reacted with ethyl chloroformate, followed by reduction with lithium aluminum hydride to produce N1,N2-dimethylphenyl-1,2-diamine.

[0007] In view of the shortcomings in the aforementioned literature and patents, it is necessary to conduct in-depth research on the synthetic route of N1,N2-dimethylbenzene-1,2-diamine to provide a better, simpler, safer, more stable and economical process route that uses readily available raw materials to meet the growing market demand. Summary of the Invention

[0008] To address the aforementioned problems, this application provides a novel approach for synthesizing N1,N2-dimethylphenyl-1,2-diamine. The synthetic method employed in this application involves reacting o-phenylenediamine as a starting material with ethyl formate; followed by nitrogen-methylation; and finally, removal of the formyl group to obtain N1,N2-dimethylphenyl-1,2-diamine. This route is logically sound, comprising three steps, and provides a concise and effective new pathway for the preparation of N1,N2-dimethylphenyl-1,2-diamine.

[0009] This application discloses a method for preparing N1,N2-dimethylphenyl-1,2-diamine, which is achieved through the following technical solution, and the reaction equation is shown below:

[0010]

[0011] Includes the following steps:

[0012] A. Mix o-phenylenediamine and ethyl formate in a solvent and react under reflux to generate intermediate 1;

[0013] B. Mix intermediate 1, dimethyl sulfate and sodium hydroxide in a solvent and react under reflux to generate intermediate 2;

[0014] C. Intermediate 2 and Lewis acid are mixed in an alcohol solvent and reacted under reflux to generate N1,N2-dimethylphenyl-1,2-diamine.

[0015] As a further improvement to this application, in step A above, the solvent is selected from toluene, n-hexane, or n-heptane. To simplify the reaction operation, ethyl formate is directly used as the solvent for direct reflux reaction in this step. After the reaction is completed, intermediate 1 can be obtained by distillation.

[0016] As a further improvement of this application, in step A above, the molar ratio of o-phenylenediamine to ethyl formate is 1:2-6.

[0017] As a further improvement to this application, in step B above, the solvent is selected from acetonitrile, tetrahydrofuran, or acetone.

[0018] As a further improvement of this application, in step B above, the molar ratio of intermediate 1, dimethyl sulfate and sodium hydroxide is 1:2-2.5:2.5-3.5.

[0019] As a further improvement to this application, in step C above, the Lewis acid is selected from boron trifluoride ether, triphenylboron, or tri(pentafluorophenyl)boron.

[0020] As a further improvement of this application, in step C above, the alcohol solvent is selected from methanol, ethanol, isopropanol, ethylene glycol or 1,3-propanediol.

[0021] As a further improvement to this application, in step C above, the molar ratio of intermediate 2 to Lewis acid is 1:0.01-0.40. The optimal combination is the reaction of tris(pentafluorophenyl)boron with ethylene glycol or 1,3-propanediol, which effectively removes the two formyl groups.

[0022] The beneficial effects of this application lie in the following advantages of the preparation route of N1,N2-dimethylphenyl-1,2-diamine:

[0023] A. This application develops a simple and practical synthetic route that uses low-cost o-phenylenediamine as a raw material. The entire route does not use expensive catalysts or raw materials, has low production costs, is reasonably designed, and produces less waste.

[0024] B. This application uses ethyl formate to react directly with o-phenylenediamine, followed by methylation. Neither reaction requires a catalyst, resulting in high reaction yield, simple operation, and good economic benefits. Detailed Implementation

[0025] Although this application has been described in detail by way of preferred embodiments, it is not limited thereto. Various equivalent modifications or substitutions can be made to the embodiments of this application by those skilled in the art without departing from the spirit and substance of this application, and such modifications or substitutions should all be within the scope of this invention. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in this application should also be covered within the protection scope of this application. Therefore, the protection scope of this application should be determined by the scope of the claims.

[0026] Example 1

[0027]

[0028] Under nitrogen protection, o-phenylenediamine (10.8 g, 0.1 mol) and ethyl formate (39.0 g, 0.53 mol) were mixed in 100 mL of toluene and refluxed for 10 hours. After the reaction was complete as determined by TLC, the reaction solution was cooled to room temperature and concentrated. The crude product was slurried in n-hexane, filtered, and dried to yield 16.1 g of intermediate 1, with a yield of 98% and an HPLC purity of 99.2%. 1H NMR (400MHz, CDCl3): 8.21 (d, 2H), 7.63 (s, 2H), 7.21 (d, 2H), 6.46 (s, 2H) ppm.

[0029] Example 2

[0030]

[0031] Under nitrogen protection, 10.8 g (0.1 mol) of o-phenylenediamine and 150 mL of ethyl formate were mixed and reacted under reflux for 5 hours. After the reaction was complete as detected by TLC, the reaction solution was cooled to room temperature and concentrated, then slurried with n-hexane, filtered, and dried to yield 15.7 g of intermediate 1, with a yield of 96% and an HPLC purity of 99%.

[0032] Example 3

[0033]

[0034] Under nitrogen protection, intermediate 1 (16.4 g, 0.1 mol) and sodium hydroxide (12 g, 0.3 mol) were mixed in 100 mL of acetonitrile and stirred at room temperature for 30 min. Dimethyl sulfate (29 g, 0.23 mol) was added, and the mixture was then heated to reflux and reacted for 6 hours. The mixture was cooled to room temperature, extracted twice with dichloromethane, concentrated, and the crude product was purified by column chromatography using ethyl acetate / petroleum ether (v / v = 1 / 15-20) as the eluent to give 16.3 g of intermediate 2, with a yield of 85% and an HPLC resolution of 99.5%. 1 HNMR (400MHz, CDCl3): 8.70 (s, 2H), 7.61 (d, 2H), 7.39 (d, 2H), 3.22 (s, 6H) ppm.

[0035] Example 4

[0036]

[0037] Under nitrogen protection, intermediate 2 (19.2 g, 0.1 mol) and tris(pentafluorophenyl)boron (2.6 g, 0.005 mol) were mixed in 60 mL of ethylene glycol and 150 mL of toluene and reacted under reflux for 7 hours. After cooling to room temperature, excess reactants and solvents were concentrated. The pH was adjusted to 10-11 by adding 20% ​​ammonia. The mixture was extracted twice with 100 mL of dichloromethane, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and distilled to obtain 13.3 g of N1,N2-dimethylphenyl-1,2-diamine, with a yield of 98% and an HPLC purity of 99.3%. 1HNMR(400MHz, DMSO-d6):6.66-6.56(m,2H),6.49-6.40(m,2H),4.57(m,2H),2.75(d,6H)ppm.

[0038] Example 5

[0039]

[0040] Under nitrogen protection, intermediate 2 (19.2 g, 0.1 mol) and triphenylboron (3.5 g, 0.014 mol) were mixed in 60 mL of ethylene glycol and 150 mL of toluene and reacted overnight under reflux. After cooling to room temperature, excess reactants and solvent were concentrated. The pH was adjusted to 10-11 by adding 20% ​​ammonia. The mixture was extracted twice with 100 mL of dichloromethane. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and distilled to obtain 10.5 g of N1,N2-dimethylphenyl-1,2-diamine, with a yield of 77% and an HPLC purity of 98.9%.

[0041] The above description is merely a preferred embodiment of this application, but the scope of protection of this application is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in this application, based on the technical solution and inventive concept of this application, should be included within the scope of protection of this application.

Claims

1. A method for preparing N1,N2-dimethylphenyl-1,2-diamine, characterized in that, Includes the following steps: ； A. O-phenylenediamine and ethyl formate are mixed in a solvent and reacted under reflux to generate intermediate 1; B. Intermediate 1, dimethyl sulfate, and sodium hydroxide are mixed in a solvent and reacted under reflux to generate intermediate 2; the solvent is selected from acetonitrile, tetrahydrofuran, or acetone; the molar ratio of intermediate 1, dimethyl sulfate, and sodium hydroxide is 1:2-2.5:2.5-3.5; C. Intermediate 2 and a Lewis acid are mixed in an alcohol solvent and reacted under reflux to generate N1,N2-dimethylphenyl-1,2-diamine; the Lewis acid is tris(pentafluorophenyl)boron; the alcohol solvent is selected from ethylene glycol or 1,3-propanediol; the molar ratio of intermediate 2 to the Lewis acid is 1:0.01-0.

40.

2. The method for preparing N1,N2-dimethylphenyl-1,2-diamine according to claim 1, characterized in that: In step A, the solvent is selected from toluene, n-hexane, n-heptane, or ethyl formate.

3. The method for preparing N1,N2-dimethylphenyl-1,2-diamine according to claim 1, characterized in that: In step A, the molar ratio of o-phenylenediamine to ethyl formate is 1:2-6.

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