CN114671810A - Preparation method of imidocarb - Google Patents

Preparation method of imidocarb Download PDF

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CN114671810A
CN114671810A CN202210274805.XA CN202210274805A CN114671810A CN 114671810 A CN114671810 A CN 114671810A CN 202210274805 A CN202210274805 A CN 202210274805A CN 114671810 A CN114671810 A CN 114671810A
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杜萧宇
杜军丽
冯巧巧
毋贺彤
王立生
杜仁财
关婵
黄建智
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Jinan Hongwan Biotechnology Co ltd
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Abstract

The invention discloses a preparation method of imidocarb, which comprises the following steps: dissolving m-nitroimidazoline, ferric trichloride and active carbon in n-butyl alcohol, heating and dropwise adding 80 wt% hydrazine hydrate, filtering at 75-80 ℃ after the reaction is finished, cooling the filtrate, slowly separating out solids, and filtering to obtain m-amino imidazoline; dissolving m-amino imidazoline, N' -carbonyl diimidazole and diisopropylethylamine in DMF, heating, slowly separating out solid, cooling, and filtering to obtain imidazole phenylurea. The preparation method of the m-nitroimidazoline comprises the following steps: dissolving m-nitrobenzaldehyde, ethylenediamine and trimethylchlorosilane in DMF, heating under the protection of nitrogen, cooling to room temperature after the reaction is finished, adding water to slowly separate out solids, and filtering to obtain the m-nitrobenzaldehyde. The invention avoids the problem of side reaction caused by excessive use of raw materials, and simultaneously, the preparation method has the advantages of low cost, high yield, low toxicity, cheap and easily-obtained reagents, recyclable solvent and suitability for industrial production.

Description

Preparation method of imidocarb
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of imidocarb.
Background
Imidazofenoxuron (imidacloprarb) is white or white-like powder, odorless, tasteless and insoluble in water, belongs to a derivative of diphenyl urea, is a novel antiprotozoal chemical drug special for animals, and is clinically used for treating the piriformis disease by using dihydrochloride or dipropionate of the imidacloprarb. The structural formula is as follows:
Figure BDA0003555424150000011
U.S. Pat. No. 3,3338917 describes a process for preparing imidocarb by reacting 2- (3-aminophenyl) imidazoline with phosgene; chinese patent CN1850805A describes a method for preparing imidazole phenylurea by using m-aminobenzonitrile as a raw material, firstly generating a structure of diphenyl urea with triphosgene, and then preparing imidazole phenylurea with ethylenediamine; chinese patents CN111574455A, CN106957265A, CN102924380A and CN103896843A describe a method of preparing imidazole phenylurea by using m-nitrobenzonitrile, m-nitrobenzoic acid or m-methyl nitrobenzoate as raw materials, first preparing m-nitroimidazoline with ethylenediamine, then reducing with zinc powder, iron powder or palladium carbon, and condensing the reduction product with urea, diphosgene or triphosgene.
The chemical reaction equation is as follows:
Figure BDA0003555424150000012
the preparation method of the imidazole phenylurea adopts zinc powder, iron powder and palladium/carbon for catalytic hydrogenation reduction. Iron powder reduction belongs to the national obsolete class, and reduced iron mud has great environmental pollution and is not suitable for industrial mass production; zinc powder and palladium/carbon catalysts are expensive, have strict requirements on equipment, use flammable gas hydrogen, and are not suitable for industrial production. Meanwhile, phosgene, diphosgene and triphosgene used in the condensation reaction have high toxicity, which brings inconvenience to transportation and use, the operation safety is low, and a large amount of hydrogen chloride gas generated in the reaction pollutes the atmosphere; although the urea is environment-friendly, the yield is lower due to the requirement of high temperature (160 ℃), the generated wastes are more, the pollution is heavy, the production period is long, the reaction yield is low, the energy consumption is high, and the industrial production difficulty is large. Therefore, a safe, pollution-free, short-period, high-yield and low-energy-consumption preparation method of imidocarb is needed.
Disclosure of Invention
In view of the prior art, the invention aims to provide a preparation method of imidocarb. The invention avoids the problem of side reaction caused by excessive use of raw materials by designing a reaction route and reselecting reagents participating in the reaction, and meanwhile, the preparation method has the advantages of low cost, high yield, low toxicity, cheap and easily-obtained reagents, recyclable solvents and suitability for industrial production.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of imidocarb, which comprises the following steps:
(1) dissolving m-nitroimidazoline, ferric trichloride and active carbon in n-butyl alcohol, heating and dropwise adding 80 wt% hydrazine hydrate, filtering at 75-80 ℃ after the reaction is finished, cooling the filtrate, slowly separating out solid, and filtering to obtain m-aminoimidazoline;
(2) dissolving the m-amino imidazoline obtained in the step (1), N' -carbonyl diimidazole and diisopropylethylamine in DMF, heating for reaction, slowly separating out solids, cooling to room temperature, stirring and filtering to obtain imidazole phenylurea.
Preferably, in the step (1), the preparation method of the m-nitroimidazoline is as follows: dissolving m-nitrobenzaldehyde, ethylenediamine and trimethylchlorosilane in DMF, heating under the protection of nitrogen, cooling to room temperature after the reaction is finished, adding water to slowly separate out solids, and filtering to obtain the m-nitrobenzaldehyde.
Preferably, the molar ratio of m-nitrobenzaldehyde to ethylenediamine to trimethylchlorosilane is 1 (1-3) to 0.05-5; the volume ratio of the m-nitrobenzaldehyde to the aprotic solvent is 1 (1-5).
Preferably, the reaction temperature is 60-110 ℃, and the reaction time is 6-8 h.
Preferably, in the step (1), the volume ratio of the m-nitroimidazoline to the n-butanol is 1 (1-10); the molar ratio of the m-nitroimidazoline to the ferric trichloride, the activated carbon and the 80 wt% hydrazine hydrate is 1 (0.05-0.5) to (1-5).
Preferably, in the step (1), the temperature is increased to 50-100 ℃; the reaction time is 2-4 h; cooling to 5-10 deg.C.
Preferably, in the step (2), the molar ratio of the m-amino imidazoline to the N, N' -carbonyl diimidazole and diisopropylethylamine is 1: (0.5-3.0): (0.5 to 3.0); the volume ratio of the m-amino imidazoline to the DMF is 1: (1-10).
Preferably, the temperature of the temperature rise is raised to 40-100 ℃, and the reaction time is 4-6 h; the stirring time is 1 h.
The synthetic route for preparing the imidazole phenylurea comprises the following steps:
Figure BDA0003555424150000031
the invention has the beneficial effects that:
(1) the invention solves the problem that the imidazole phenylurea intermediate meta-amino imidazoline cannot be crystallized in methanol and ethanol: the solubility of the m-amino imidazoline in methanol and ethanol is high, the solvent needs to be distilled under reduced pressure, the solubility in n-butyl alcohol is low, the reduced pressure distillation is not needed, and meanwhile, reaction byproducts can be removed; meanwhile, the problems of serious environmental pollution, high price of zinc powder and palladium/carbon catalysts, high risk coefficient and the like caused by the generation of a large amount of arylamine-containing iron mud and wastewater by iron powder when the m-nitroimidazoline is reduced into the m-aminoimidazoline are solved.
(2) The invention solves the problems of high toxicity and low operation safety caused by using phosgene, diphosgene and triphosgene as raw materials when m-amino imidazoline is used for preparing imidazole phenylurea in the prior art, and solves the problems of high temperature (160 ℃) and low yield caused by using urea as a raw material when m-amino imidazoline is used for preparing imidazole phenylurea in the prior art.
(3) The invention prepares the imidazole phenylurea by 80 wt% hydrazine hydrate and carbonyl condensing agent CDI (N, N-carbonyl diimidazole) which have stable chemical property, safe and convenient use and mild reaction condition. The reducing agent 80 wt% of hydrazine hydrate and the carbonyl condensing agent CDI selected by the invention are convenient to use and stable in chemical property, and the problem of side reaction caused by excessive use is avoided; meanwhile, the method has the advantages of low cost, high yield, low toxicity, cheap and easily-obtained reagents, capability of recycling the solvent and suitability for industrial production.
Drawings
FIG. 1: for the imidazophenylurea obtained in example 1 in D6In MSO1H-NMR spectrum.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
In order to make the technical solutions of the present application more clearly understood by those skilled in the art, the technical solutions of the present application will be described in detail below with reference to specific embodiments.
The test materials used in the examples of the present invention were all conventional in the art and commercially available.
Example 1
The preparation method of the imidazole phenylurea comprises the following steps:
(1) dissolving 30.2kg of m-nitrobenzaldehyde, 14.4kg of ethylenediamine and 2.2kg of trimethylchlorosilane in 60L N N-dimethylformamide, introducing nitrogen for protection, stirring and heating to 80 ℃, maintaining the reaction for 4 hours, then heating to 100 ℃, continuing the reaction for 2 hours, and cooling the solution to 25 ℃ after the reaction is finished; slowly dropping 180L of water, slowly separating out solid, continuously stirring for 1h, filtering, and drying to obtain 36.3kg of yellow powdery solid, namely m-nitroimidazoline, with the yield of 95.0% and the purity of 96.6%.
(2) Dissolving 34.4kg of m-nitroimidazoline prepared in the step (1) in 172L of n-butanol, adding 5.8kg of ferric trichloride and 3.4kg of activated carbon, heating to 75 ℃, slowly dropwise adding 17.5kg of 80 wt% hydrazine hydrate solution under a stirring state, controlling the temperature to be 80 ℃, and continuously maintaining the temperature of 80 ℃ for reaction for 2 hours after dropwise adding is finished; after the reaction is finished, directly filtering at 80 ℃, cooling the filtrate to 7 ℃, and continuously stirring for 1 h; the filtrate was filtered to obtain 23.9kg of a pale yellow powdery solid, i.e., m-aminoimidazoline, with a yield of 82.3% and a purity of 97.7%.
(3) And (3) dissolving 21.0kg of m-amino imidazoline prepared in the step (2), 11.4kg of CDI and 10.1kg of diisopropylethylamine in 63L of DMF (N, N-dimethylformamide), stirring and heating to 70 ℃, slowly separating out solids after clearing, reacting for 5 hours, cooling the solution to 10-15 ℃ after the reaction is finished, stirring and crystallizing for 1 hour, filtering and washing, and drying in vacuum at 60 ℃ to obtain 21.2kg of white solid imidazole phenylurea with the yield of 93.4%.
Through detection, the purity of the prepared imidazole phenylurea liquid phase is 99.2%, and the melting point is 350-.
Example 2
The synthesis as described in example 1, with the difference that in step (3):
dissolving the prepared 21.0kg of m-amino imidazoline, 13kg of CDI and 10.1kg of diisopropylethylamine in 63L of DMF, stirring and heating to 60 ℃, slowly separating out solids after dissolving, reacting for 6h, cooling the solution to 5-10 ℃ after the reaction is finished, stirring for 1h, filtering and washing, and drying in vacuum at 60 ℃ to obtain 21.6kg of white solid imidazole phenylurea with the yield of 95.2%.
Through detection, the purity of the prepared imidazole phenylurea liquid phase is 99.0%, and the melting point is 350-.
Example 3
The preparation process as described in example 1, with the difference that in step (3):
dissolving the prepared 21.0kg of m-amino imidazoline, 11.4kg of CDI and 10.1kg of diisopropylethylamine in 84L of DMF, stirring and heating to 80 ℃, slowly separating out solids from the solution, reacting for 4h, cooling the solution to 15-20 ℃ after the reaction is finished, stirring and crystallizing for 1h, filtering and washing, and drying in vacuum at 60 ℃ to obtain 20.7kg of white solid imidazole phenylurea with the yield of 91.2%.
Through detection, the purity of the prepared imidazole phenylurea liquid phase is 99.5%, and the melting point is 350-.
Example 4
The preparation process as described in example 1, with the difference that in step (2):
dissolving the prepared 34.4kg of m-nitroimidazoline in 174L of n-butanol, adding 3.0kg of ferric trichloride and 3.4kg of activated carbon, heating to 75 ℃, slowly dropwise adding 23g of 80 wt% hydrazine hydrate solution under a stirring state, controlling the temperature to be 75 ℃, and continuously maintaining the temperature of 75 ℃ for reaction for 2 hours after dropwise adding is finished; after the reaction is finished, directly filtering at 75 ℃, cooling the filtrate to 10 ℃, and continuously stirring for 1 h; the filtrate was filtered to obtain 24.2kg of a pale yellow powdery solid, i.e., m-aminoimidazoline, with a yield of 83.4% and a purity of 98.2%.
Example 5
The preparation process as described in example 1, with the difference that in step (2):
dissolving the prepared 34.4kg of m-nitroimidazoline in 174L of n-butanol, adding 3.0kg of ferric trichloride and 3.4kg of activated carbon, heating to 60 ℃, slowly dropwise adding 23g of 80 wt% hydrazine hydrate solution under a stirring state, controlling the temperature to be 70 ℃, and continuously maintaining the temperature of 70 ℃ for reaction for 2 hours after dropwise adding; after the reaction is finished, directly filtering at 70 ℃, cooling the filtrate to 10 ℃, and continuously stirring for 1 h; the filtrate was filtered to obtain 24.4kg of a pale yellow powdery solid, i.e., m-aminoimidazoline, with a yield of 84.3% and a purity of 96.3%.
Example 6
The preparation process as described in example 1, with the difference that in step (2):
dissolving the prepared 34.4kg of m-nitroimidazoline in 280 n-butanol, adding 3.0kg of ferric trichloride and 3.4kg of activated carbon, heating to 75 ℃, slowly dropwise adding 23g of 80 wt% hydrazine hydrate solution under a stirring state, controlling the temperature to be 85 ℃, and continuously maintaining the temperature of 85 ℃ for reaction for 2 hours after dropwise adding; after the reaction is finished, directly filtering at 85 ℃, cooling the filtrate to 10 ℃, and continuously stirring for 1 h; the filtrate was filtered to obtain 23.4kg of pale yellow powdery solid, i.e., m-amino imidazoline, with yield of 80.6% and purity of 98.7%.
Comparative example 1
The imidazophenylurea was prepared according to example 3 of a method for preparing imidazophenylurea disclosed in application No. 201410155713.5.
Dissolving 18.1g of methyl m-nitrobenzoate, 4.0g of ethylenediamine and 0.32g of sulfur in 181ml of methanol, refluxing for 3 hours at 65 ℃, then adding 2.0g of ethylenediamine, refluxing for 2 hours, evaporating most of solvent under reduced pressure, and filtering to obtain m-nitroimidazoline, wherein the molar yield is 96.4%.
And taking 17.2g of intermediate product m-nitroimidazoline, dissolving the intermediate product m-nitroimidazoline in 90ml of 50% methanol, adding 5mol/L hydrochloric acid to adjust the pH value to 3.5, adding 8.8g of zinc powder while stirring for four times at normal temperature for 2 hours, and continuing to stir for reaction for 2 hours after the addition is finished. After the reaction is finished, zinc chloride is removed by filtration, most of solvent is evaporated out by decompression, and m-amino imidazoline is prepared by crystallization with the molar yield of 92.0%.
Dissolving 13.0g of m-amino imidazoline in 65ml of tetrahydrofuran-water (1:6, V: V) solution, adjusting the pH value to 8 by using 0.1mol/l sodium hydroxide solution, adding 0.13mol of triphosgene at 35 ℃, reacting for 4 hours, performing suction filtration and drying to obtain the imidocarb, wherein the product is white powder, and the molar yield is 91.9%.
Comparative example 2
The imidazophenylurea was prepared according to the method of example in the method of preparation of imidazophenylurea hydrochloride disclosed in application No. 200810079399.1.
A. Preparation of m-nitroimidazoline
Adding 100ml of methanol, 8.0ml (0.12mol) of ethylenediamine, 14.8g (0.1mol) of m-nitrobenzonitrile and 1.6g (0.05mol) of sulfur into a 250ml reaction bottle, starting stirring, heating to reflux, starting timing, reacting for 20 hours, filtering out the sulfur while hot, concentrating the filtrate to 40ml, cooling, standing for crystallization for 2 hours, filtering, and drying the filter cake in vacuum at 60 ℃ for 8 hours to obtain 18.2g of light yellow powdery m-nitroimidazoline, wherein the melting point is 159-161 ℃, and the yield is 95.3%.
B. Preparation of meta-amino imidazolines
Adding 20g (0.36mol) of reduced iron powder, 1ml (0.01mol) of concentrated hydrochloric acid and 200ml of water into a 500ml reaction bottle, heating, refluxing and stirring for 10 minutes, cooling to 90 ℃, adding 19.1g (0.10mol) of m-nitroimidazoline prepared in the step A, heating, stirring, refluxing and reacting for 6 hours, filtering iron mud while hot, washing the iron mud with 20ml of multiplied by 2 hot water, combining washing liquid and filtrate, carrying out bath temperature of below 100 ℃, carrying out reduced pressure concentration to 80ml, cooling to below 5 ℃ in an ice bath, standing, crystallizing for 1 hour, filtering, washing a filter cake twice with cold water, and carrying out vacuum drying for 6 hours at 60 ℃ to obtain 12.9g of white or quasi-white crystalline m-aminoimidazoline, wherein the melting point is 139-143 ℃, and the yield is 80.1%.
C. Adding 20g (0.36mol) of reduced iron powder, 2ml (0.02mol) of concentrated hydrochloric acid and 200ml of water into a 500ml reaction bottle, heating, refluxing and stirring for 10 minutes, cooling to 90 ℃, adding 19.1g (0.10mol) of m-nitroimidazoline prepared in the step A, heating, stirring, refluxing and reacting for 6 hours, filtering out iron mud while hot, washing the iron mud with 20ml of hot water multiplied by 2, combining washing liquid and filtrate, carrying out bath temperature below 100 ℃, carrying out reduced pressure concentration to 80ml, carrying out ice bath cooling to below 5 ℃, standing, crystallizing for 1 hour, filtering, washing a filter cake twice with cold water, carrying out vacuum drying for 6 hours at 60 ℃, and obtaining 15.6g of white or quasi-white crystalline m-aminoimidazoline hydrochloride, wherein the melting point is 215-216 ℃, and the yield is 79.2%.
D. Adding 20g (0.36mol) of reduced iron powder, 3ml (0.03mol) of concentrated hydrochloric acid and 200ml of water into a 500ml reaction bottle, heating, refluxing and stirring for 10 minutes, cooling to 90 ℃, adding 19.1g (0.10mol) of m-nitroimidazoline prepared in the step A, heating, stirring, refluxing and reacting for 6 hours, filtering out iron mud while hot, washing the iron mud with 20ml of multiplied by 2 hot water, combining washing liquid and filtrate, carrying out bath temperature of below 100 ℃, carrying out reduced pressure concentration to 80ml, cooling to below 5 ℃ in ice bath, standing, crystallizing for 1 hour, filtering, washing a filter cake twice with cold water, carrying out vacuum drying for 6 hours at 60 ℃, and obtaining 18.4g of white or quasi-white crystalline m-aminoimidazoline dihydrochloride, wherein the melting point is more than 260 ℃, and the yield is 78.6%.
E. Preparation of imidocarb hydrochloride
And (3) adding 16.1g (0.10mol) of m-aminoimidazoline prepared in the step C, 3.0g (0.05mol) of urea, 20ml (0.24mol) of concentrated hydrochloric acid and 100ml of n-butyl alcohol into a 250ml reaction bottle, starting stirring, heating to 100 ℃, stirring for reaction for 2 hours, cooling to 0 ℃ in an ice bath, standing for crystallization for 2 hours, washing a filter cake with 25ml of multiplied by 2 absolute ethyl alcohol and 25ml of multiplied by 2 ethyl ether respectively, and drying in vacuum at 60 ℃ for 5 hours to obtain 18.1g of a white or off-white product, namely imidazole phenylurea hydrochloride, wherein the melting point is more than 350 ℃ (decomposition) yield is 85.9%.
F. Preparation of imidocarb hydrochloride
And (3) adding 19.7g (0.10mol) of the m-aminoimidazoline hydrochloride prepared in the step C, 3.0g (0.05mol) of urea, 20ml (0.24mol) of concentrated hydrochloric acid and 100ml of n-butyl alcohol into a 250ml reaction bottle, starting stirring, heating to 100 ℃, stirring for reaction for 2 hours, cooling to 0 ℃ in an ice bath, standing for crystallization for 2 hours, washing a filter cake with 25ml of multiplied by 2 absolute ethyl alcohol and 25ml of multiplied by 2 ethyl ether respectively, and drying in vacuum at 60 ℃ for 5 hours to obtain 18.1g of a white or off-white product, namely imidazole phenylurea hydrochloride, wherein the melting point is more than 350 ℃ (decomposition) yield is 85.9%.
G. Preparation of imidocarb hydrochloride
And (3) adding 23.4g (0.10mol) of m-aminoimidazoline prepared in the step C, 3.0g (0.05mol) of urea, 20ml (0.24mol) of concentrated hydrochloric acid and 100ml of n-butyl alcohol into a 250ml reaction bottle, starting stirring, heating to 100 ℃, stirring for reaction for 2 hours, cooling to 0 ℃ in an ice bath, standing for crystallization for 2 hours, washing a filter cake with 25ml of multiplied by 2 absolute ethyl alcohol and 25ml of multiplied by 2 ethyl ether respectively, and drying in vacuum at 60 ℃ for 5 hours to obtain 18.1g of a white or off-white product, namely imidazole phenylurea hydrochloride, wherein the melting point is more than 350 ℃ (decomposition) yield is 85.9%.
Comparative example 3
Imidazophenylurea was prepared according to the method of example 5 among the methods for preparing Imidazophenylurea dipropionate and its intermediate disclosed in application No. 202010411314.6
Adding 1L of water, 2- (3-nitrophenyl) imidazoline (120g, 0.63mol) into a 3L reaction bottle, carefully adding 8.4g of 10% wet palladium carbon, slowly heating and stirring until refluxing, slowly dropwise adding a water (240mL) solution of ammonium formate (119.7g, 1.89mol), keeping the temperature for reacting for 2h after about 0.5h is finished, filtering to obtain a light yellow clarified liquid, and directly feeding the filtrate to the next step.
And (3) sequentially adding the reaction liquid in the previous step, hydrochloric acid (134mL, 1.6mol) and urea (19.2g, 0.32mol) into a 2L three-opening reaction bottle, heating and stirring to reflux under the protection of nitrogen, preserving the temperature for reaction for 8h, cooling the reaction liquid to room temperature, adjusting the pH of the reaction liquid to 9-10 by using 2mol/L sodium hydroxide aqueous solution, precipitating a large amount of white solid, stirring for 0.5h at room temperature, filtering, washing a filter cake by a small amount of water, and drying by blowing the product to obtain the white-like solid imidazole phenylurea (88.5g, 80.7 percent yield in two steps).
Comparative example 4
Imidazophenylurea was prepared according to example 1 of the process for preparing Imidazophenylurea disclosed in application No. 201210454778.0
(1) Adding 121.0kg of m-nitrobenzoic acid and 344.9kg of thionyl chloride into a reaction kettle, mixing, stirring, heating to 80 ℃, refluxing for reaction for 4 hours, controlling the temperature to be 75 ℃, carrying out reduced pressure concentration to remove the thionyl chloride, and preparing 134.1kg of m-nitrobenzoyl chloride as a yellow solid with the molar yield of 99.8% at room temperature;
(2) 133.3kg of m-nitrobenzoyl chloride prepared in the step (1) is added into 600L of acetonitrile, then 8.0kg of phosphomolybdovanadophosphoric acid is added, 47.3kg of ethylenediamine is added under stirring, the temperature is raised to 80 ℃, reflux reaction is carried out for 2h, filtration is carried out, filtrate is taken, yellow-green 2- (3-nitrophenyl) imidazoline solid 126.5kg is prepared after vacuum concentration at 75 ℃, and the molar yield is 91.6%.
(3) Adding 124.4kg of 2- (3-nitrophenyl) imidazoline prepared in the step (2) into 600L of water, then adding 10.0kg of 5% palladium-carbon catalyst, carrying out reductive hydrogenation reaction for 4 hours under the conditions of temperature of 70 ℃, atmosphere of hydrogen and pressure of 0.4MPa, filtering, adjusting the pH of filtrate to 6.0 by using 6mol/L hydrochloric acid, cooling to-2 ℃, standing for crystallization for 1 hour, filtering, taking precipitate, and carrying out vacuum drying at 60 ℃ to obtain 120.5kg of white-like 2- (3-aminophenyl) imidazoline hydrochloride solid with the molar yield of 93.7%;
(4) and (4) adding 120.5kg of 2- (3-aminophenyl) imidazoline hydrochloride prepared in the step (3) into 700L N N-methylformamide, stirring and adding 33kg of urea, stirring and heating to 160 ℃, reacting for 5 hours, cooling to 3 ℃, standing and crystallizing for 1 hour, filtering and washing, and performing vacuum drying at 60 ℃ to obtain 89.5kg of imidazophenylurea white solid.
Through detection, the mp (melting point) of the prepared imidazole phenylurea is 350-352 ℃, the content is 99.3%, and the molar yield is 83.7%.
Statistics were made on the yield and purity of the intermediates or imidazophenylureas prepared in examples 1-3 and comparative examples 1-4, and the results are shown in table 1.
TABLE 1
Name of product Molar yield (%) Purity (%)
Example 1 Imidazophenylurea 93.4 99.2
Example 2 Imidazophenylurea 95.2 99.0
Example 3 Imidazolylphenylureas 91.2 99.5
Comparative example 1 Imidazolylphenylureas 91.9 98.1
Comparative example 2 Imidazole phenylurea hydrochloride 85.9 97.8
Comparative example 3 Imidazolylphenylureas 80.7 96.2
Comparative example 4 Imidazolylphenylureas 83.7 99.3
The imidazole phenylurea is obtained through three steps of reactions, the operation is simple, the solvent can be recycled, the three wastes are less, the environmental pollution is less, the purity is high, and the yield is high. The solvent used in the comparative example is not easy to recycle, the iron powder, the zinc powder, the triphosgene, the phosgene and the diphosgene have serious environmental pollution, and the used palladium/carbon catalyst has higher price: one kilogram is about ten-thousand yuan, while the cost of the catalyst used in the present application is about 100 yuan/kg, which is 1/1000 of the cost of the comparative example, so that the production cost is high by using the catalyst of the comparative example, such as palladium/carbon catalyst, although the purity and yield of the prepared meta-aminoimidazoline are high, the purity and yield of the meta-aminoimidazoline prepared by the method of the present application are also high, and the purity and yield of the imidophenylurea prepared by the method of the present application are higher than those of the comparative example. Meanwhile, triphosgene, phosgene and diphosgene used in the comparative example are used as condensing agents to obtain the product imidazole phenylurea dihydrochloride, and sodium hydroxide is needed for hydrolysis to obtain the target product, so that more waste water is caused, and the cost is higher.
Therefore, the method has the advantages of improving the purity and yield of the prepared imidazole phenylurea, along with low preparation cost, no pollutant generated in the preparation process, environmental friendliness and human body friendliness, and suitability for industrial production.
The above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims (8)

1. The preparation method of the imidocarb is characterized by comprising the following steps of:
(1) dissolving m-nitroimidazoline, ferric trichloride and active carbon in n-butyl alcohol, heating and dropwise adding 80 wt% hydrazine hydrate, filtering at 75-80 ℃ after the reaction is finished, cooling the filtrate, slowly separating out solid, and filtering to obtain m-aminoimidazoline;
(2) dissolving the m-amino imidazoline, N' -carbonyl diimidazole and diisopropylethylamine obtained in the step (1) in DMF, heating, slowly separating out solids, cooling to room temperature, and filtering to obtain imidazole phenylurea.
2. The method according to claim 1, wherein in the step (1), the m-nitroimidazoline is prepared by: dissolving m-nitrobenzaldehyde, ethylenediamine and trimethylchlorosilane in DMF, heating for reaction under the protection of nitrogen, cooling to room temperature after the reaction is finished, adding water to slowly separate out solids, and filtering to obtain the m-nitrobenzaldehyde.
3. The method according to claim 2, wherein the molar ratio of m-nitrobenzaldehyde, ethylenediamine and trimethylchlorosilane is 1 (1-3) to (0.05-5); the volume ratio of the m-nitrobenzaldehyde to the aprotic solvent is 1 (1-5).
4. The method according to claim 2, wherein the reaction temperature is 60-110 ℃ and the reaction time is 6-8 h.
5. The preparation method according to claim 1, wherein in the step (1), the volume ratio of the m-nitroimidazoline to the n-butanol is 1 (1-10); the mol ratio of the m-nitroimidazoline to the ferric trichloride, the activated carbon and the 80 wt% hydrazine hydrate is 1 (0.05-0.5) to (1-5).
6. The method according to claim 1, wherein in the step (1), the temperature of the temperature rise is increased to 50-100 ℃; the reaction time is 2-4 h; cooling to 5-10 deg.C.
7. The method according to claim 1, wherein in the step (2), the molar ratio of the m-aminoimidazoline to the N, N' -carbonyldiimidazole and diisopropylethylamine is 1: (0.5-3.0): (0.5 to 5.0); the volume ratio of the m-amino imidazoline to the DMF is 1: (1-10).
8. The preparation method according to claim 1, wherein in the step (2), the temperature of the temperature rise is raised to 40-100 ℃, and the reaction time is 4-6 h; the stirring time is 1 h.
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