A preparation method of 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline

Abstract

The invention discloses a preparation method of 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline, wherein m-nitrobenzaldehyde, ethylenediamine and trimethylsilyl chloride are dissolved in an aprotic solvent, and the temperature is raised under nitrogen protection to react, and the temperature is lowered to room temperature after the reaction is completed, and water is added to precipitate a solid, and 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline is obtained after filtration. The reaction conditions of the invention are mild, the reaction time is short, the post-processing operation is simple, the reagents used are cheap and easy to obtain, the purity is high, the yield is high, the cost is low, and the invention is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and specifically relates to a method for preparing 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline. Background Art

[0002] Imidocarb, chemically known as N,N'-di[3-(4,5-dihydro-1H-imidazol-2-yl)phenyl]urea, was developed by Monbijoustrass of Switzerland. Its dihydrochloride or dipropionate is used to treat piroplasmosis. This veterinary drug has a broad spectrum, low toxicity, wide application range, long duration of action, and small dosage. It not only has a good therapeutic effect on livestock piroplasmosis, anaplasmosis, and eperythrozoonosis in pigs and dogs, but also has a good preventive effect. Its structural formula is as follows:

[0003]

[0004] With the widespread spread of piroplasmosis around the world, the demand for this type of drug is increasing. In the face of the urgent demand for this drug at home and abroad, exploring methods suitable for industrial production and finding economically reasonable process routes will have significant economic and social benefits in filling domestic gaps, promoting the development of the veterinary drug industry, and meeting domestic and foreign needs.

[0005] At present, the synthesis route of imidazole phenylurea uses m-nitrobenzonitrile as the starting material, and obtains the target compound (imidazole phenylurea) through three steps of cyclization, reduction, and condensation. The reaction equation is as follows:

[0006]

[0007] The preparation process of the imidazole phenylurea intermediate 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline requires the use of catalyst sulfur, but sulfur is a national controlled chemical and is not easy to purchase; at the same time, the reaction time is refluxed for up to 24 hours, and the raw material still remains 5%, resulting in low purity, low yield, large amount of solvent (10 times the amount) of the obtained 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline, and relatively cumbersome post-treatment (needs to cool and filter, and then distill under reduced pressure), which affects the subsequent yield, yield and purity of 2-(3-aminophenyl)-4,5-dihydro-1H-imidazoline. Therefore, a method suitable for industrial production of 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline is needed, which has mild reaction conditions, short reaction time, simple post-treatment operation, cheap and easy-to-obtain reagents, high purity, high yield, low cost, and is suitable for industrial production of 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline. Summary of the invention

[0008] In view of the above prior art, the purpose of the present invention is to provide a method for preparing 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline. The method has mild reaction conditions, short reaction time, simple post-treatment operation, cheap and readily available reagents, high purity, high yield, low cost, and is suitable for industrial production.

[0009] To achieve the above object, the present invention adopts the following technical solution:

[0010] The present invention provides a method for preparing 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline, which comprises:

[0011] Dissolve m-nitrobenzaldehyde, ethylenediamine and trimethylsilyl chloride in a non-protonic solvent, heat up under nitrogen protection to react, cool to room temperature after the reaction is completed, add water to precipitate solid, and filter to obtain 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline.

[0012] Preferably, the aprotic solvent is selected from dioxane, dimethyl sulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide.

[0013] Preferably, the aprotic solvent is N,N-dimethylformamide.

[0014] Preferably, the reaction temperature is 60-110° C., and the reaction time is 6-8 h.

[0015] More preferably, the reaction is carried out by heating the mixture to 60-89° C. for 3-5 hours, and then continuing to heat the mixture to 90-110° C. for 1-3 hours.

[0016] Preferably, the molar ratio of m-nitrobenzaldehyde to ethylenediamine is 1:(1-3).

[0017] Preferably, the molar ratio of m-nitrobenzaldehyde to ethylenediamine is 1:1.2.

[0018] Preferably, the volume ratio of the m-nitrobenzaldehyde to the aprotic solvent is 1:(1-5).

[0019] Preferably, the volume ratio of the m-nitrobenzaldehyde to the aprotic solvent is 1:2.

[0020] Preferably, the molar ratio of m-nitrobenzaldehyde to trimethylchlorosilane is 1:(0.05-5).

[0021] Preferably, the molar ratio of m-nitrobenzaldehyde to trimethylchlorosilane is 1:0.1.

[0022] Beneficial effects of the present invention:

[0023] (1) The present invention solves the problem that the imidazophenylurea intermediate 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline cannot be crystallized in common solvents (such as methanol, ethanol, etc.).

[0024] (2) The present invention solves the problems of long reaction time, large amount of solvent, catalyst being difficult to purchase, and low yield during the cyclization of 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline.

[0025] (3) The cyclization reaction conditions of the present invention are mild, the reaction time is short, the post-treatment operation is simple, the reagents used are cheap and readily available, the purity is high, the yield is high, the cost is low, the environmental pollution is small, and it is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 : is the product obtained in Example 1 in CD3OD 1 H-NMR spectrum.

[0027] Figure 2 : is the product obtained in Example 1 in CD3OD 13 C-NMR spectrum. DETAILED DESCRIPTION

[0028] It should be noted that the following detailed descriptions are illustrative and are intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present application belongs.

[0029] As described in the background technology, 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline is an intermediate for the production of imidazole phenyl urea, which is generally prepared by reaction with m-nitrobenzonitrile and ethylenediamine as raw materials, sulfur as a catalyst, and alcohols (methanol or ethanol) as solvents. However, sulfur is a state-controlled chemical and is not easy to purchase; at the same time, the reaction time is long, and the utilization rate of raw materials needs to be improved, resulting in low purity of the obtained 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline, low yield, large amount of solvent (10 times the amount), and complicated post-processing (needs to be cooled, filtered, and then distilled under reduced pressure).

[0030] Based on this, the present invention provides a method for preparing 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline. 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline is prepared using m-nitrobenzaldehyde and ethylenediamine as reaction raw materials, trimethylsilyl chloride as a catalyst, and N,N-dimethylformamide as a solvent. The preparation method has short reaction time, small amount of solvent, easy to obtain raw materials, mild reaction, easy precipitation of the product in aprotic solvents, and greatly improved yield and purity.

[0031] The reaction scheme of the present invention is as follows:

[0032]

[0033] In order to enable those skilled in the art to more clearly understand the technical solution of the present application, the technical solution of the present application will be described in detail below in conjunction with specific embodiments.

[0034] The test materials used in the examples of the present invention are all conventional test materials in the art and can be purchased through commercial channels.

[0035] Example 1

[0036] Dissolve 30.2g of m-nitrobenzaldehyde, 18g of ethylenediamine, and 2.2g of trimethylsilyl chloride in 90ml of N,N-dimethylformamide, pass nitrogen gas, stir and heat to 80℃, maintain the reaction for 4h, then heat to 100℃, continue the reaction for 2h, after the reaction is completed, cool the solution to 25℃; slowly add 270ml of water, slowly precipitate solid, continue stirring for 1h, filter, and dry to obtain 36.6g of yellow powdery solid, i.e. 2-(3-nitrophenyl)imidazoline, with a yield of 95.6% and a purity of 98.4%. The hydrogen and carbon spectra of the product are shown in Figure 1 and 2 .

[0037] Example 2

[0038] 30.2 g of m-nitrobenzaldehyde, 18 g of ethylenediamine, and 1.1 g of trimethylsilyl chloride were dissolved in 90 ml of N,N-dimethylformamide, and nitrogen was passed through. The temperature was raised to 80°C with stirring, and the reaction was maintained for 4 hours. The temperature was then raised to 100°C and the reaction was continued for 2 hours. After the reaction was completed, the solution was cooled to 25°C; 270 ml of water was slowly added dropwise, and a solid was slowly precipitated. The mixture was stirred for 1 hour, filtered, and dried to obtain 36.3 g of a yellow powdery solid, i.e., 2-(3-nitrophenyl)imidazoline, with a yield of 95.0% and a purity of 96.6%.

[0039] Example 3

[0040] 30.2 g of m-nitrobenzaldehyde, 14.4 g of ethylenediamine and 2.2 g of trimethylsilyl chloride were dissolved in 60 ml of N,N-dimethylformamide, and nitrogen was passed through. The temperature was raised to 80°C with stirring, and the reaction was maintained for 4 hours. The temperature was then raised to 100°C and the reaction was continued for 2 hours. After the reaction was completed, the solution was cooled to 25°C; 180 ml of water was slowly added dropwise to slowly precipitate a solid, and the stirring was continued for 1 hour. 37.2 g of a yellow powdery solid, i.e., 2-(3-nitrophenyl)imidazoline, was obtained by filtration with a yield of 97.4% and a purity of 98.1%.

[0041] Example 4

[0042] 30.2 g of m-nitrobenzaldehyde, 14.4 g of ethylenediamine and 2.2 g of trimethylsilyl chloride were dissolved in 60 ml of N,N-dimethylacetamide, and nitrogen was passed through. The temperature was raised to 70°C with stirring, and the reaction was maintained for 4 hours. The temperature was then raised to 110°C and the reaction was continued for 2 hours. After the reaction was completed, the solution was cooled to 25°C; 180 ml of water was slowly added dropwise to slowly precipitate a solid, and the stirring was continued for 1 hour. 36.8 g of a yellow powdery solid, i.e., 2-(3-nitrophenyl)imidazoline, was obtained by filtration, with a yield of 96.3% and a purity of 97.8%.

[0043] Comparative Example 1

[0044] Dissolve 29.6 g of m-nitrobenzonitrile, 14.4 g of ethylenediamine and 3.3 g of sulfur in 300 ml of methanol, stir and heat to reflux, and maintain reflux reaction for 24 hours; after the reaction is completed, cool the solution to 25°C; filter, distill the filtrate at atmospheric pressure, recover 210 ml of methanol, cool the mother liquor to 15°C to slowly precipitate solid, and continue stirring for 1 hour; filter to obtain 34.5 g of yellow powdery solid, i.e. 2-(3-nitrophenyl)imidazoline, with a yield of 90.3% and a purity of 91.3%.

[0045] Comparative Example 2

[0046] Dissolve 29.6 g of m-nitrobenzonitrile, 14.4 g of ethylenediamine and 3.3 g of sulfur in 300 ml of ethanol, stir and heat to reflux, and maintain reflux reaction for 21 hours; after the reaction is completed, cool the solution to 25°C, filter, distill the filtrate at atmospheric pressure, recover 200 ml of ethanol, cool the mother liquor to 15°C to slowly precipitate solid, and continue stirring for 1 hour; filter to obtain 34.2 g of yellow powdery solid, i.e. 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline, with a yield of 89.5% and a purity of 92.5%.

[0047] Test example

[0048] 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline prepared in Examples 1 to 4 and Comparative Examples 1 to 2 were respectively used to prepare 2-(3-aminophenyl)-4,5-dihydro-1H-imidazoline under the same conditions, and the yield and purity of 2-(3-aminophenyl)-4,5-dihydro-1H-imidazoline were compared. The results are shown in Table 1.

[0049] 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline The method for preparing 2-(3-aminophenyl)-4,5-dihydro-1H-imidazoline under the same conditions is as follows: 45g of 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline is added to 230ml of n-butanol, 3.8g of ferric chloride and 4.5g of activated carbon are added, the temperature is continued to rise to 75°C, 23g of 80% hydrazine hydrate solution is slowly added dropwise under stirring, the temperature is controlled at 75-85°C, and after the addition is completed, the temperature is maintained at 75-85°C for 2h; after the reaction is completed, the mother liquor is cooled to 5-10°C after hot filtration, stirring is continued for 1h, and a light yellow powdery solid is obtained by filtration, i.e., 2-(3-aminophenyl)-4,5-dihydro-1H-imidazoline.

[0050] Table 1

[0051] project Yield % purity% Example 1 90.7 98.5 Example 2 89.5 97.4 Example 3 92.3 98.3 Example 4 91.6 97.8 Comparative Example 1 81.7 93.3 Comparative Example 2 82.3 94.2

[0052] Comparative Examples 1 to 2 use a conventional method to prepare 2-(3-nitrophenyl)imidazoline. It can be seen from the comparison between Examples 1 to 4 and Comparative Examples 1 to 2 that the preparation time of the embodiments is generally 5 to 8 hours, while the preparation time of the comparative examples requires at least 21 hours. Therefore, the preparation time of 2-(3-nitrophenyl)imidazoline can be greatly shortened by using the preparation method of the present invention, and the yield is increased from 90.3% to 97.4%, the raw materials are fully converted into products, and the material conservation is met, and the purity is increased from 91.3% to 98.4%. It can be seen from Table 1 that the 2-(3-nitrophenyl)imidazoline prepared by the method of the present invention has a higher purity and a higher yield for the subsequent preparation of 2-(3-aminophenyl)-4,5-dihydro-1H-imidazoline.

[0053] The above description is only the preferred embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline, characterized in that: The preparation method is: Dissolve m-nitrobenzaldehyde, ethylenediamine and trimethylsilyl chloride in a non-protonic solvent, heat up under nitrogen protection to react, cool to room temperature after the reaction is completed, add water to precipitate solid, and filter to obtain 2-(3-nitrophenyl)-4,5-dihydro-1H-imidazoline.

2. The preparation method according to claim 1, characterized in that: The aprotic solvent is selected from dioxane, dimethyl sulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide.

3. The preparation method according to claim 2, characterized in that: The aprotic solvent is N,N-dimethylformamide.

4. The preparation method according to claim 1, characterized in that: The reaction temperature is 60-110° C., and the reaction time is 6-8 hours.

5. The preparation method according to claim 1, characterized in that: The molar ratio of the m-nitrobenzaldehyde to ethylenediamine is 1:(1-3).

6. The preparation method according to claim 5, characterized in that: The molar ratio of the m-nitrobenzaldehyde to ethylenediamine is 1:1.

2.

7. The preparation method according to claim 1, characterized in that: The volume ratio of the m-nitrobenzaldehyde to the aprotic solvent is 1:(1-5).

8. The preparation method according to claim 7, characterized in that: The volume ratio of the m-nitrobenzaldehyde to the aprotic solvent is 1:

2.

9. The preparation method according to claim 1, characterized in that: The molar ratio of the m-nitrobenzaldehyde to trimethylchlorosilane is 1:(0.05-5).

10. The preparation method according to claim 9, characterized in that: The molar ratio of the m-nitrobenzaldehyde to trimethylchlorosilane is 1:0.1.

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