CN114671810B - Preparation method of imidazole phenylurea - Google Patents

Preparation method of imidazole phenylurea Download PDF

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CN114671810B
CN114671810B CN202210274805.XA CN202210274805A CN114671810B CN 114671810 B CN114671810 B CN 114671810B CN 202210274805 A CN202210274805 A CN 202210274805A CN 114671810 B CN114671810 B CN 114671810B
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imidazole
phenylurea
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CN114671810A (en
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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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract

The invention discloses a preparation method of imidazole phenylurea, which comprises the following steps: dissolving m-nitroimidazoline, ferric trichloride and active carbon in n-butanol, heating, dropwise adding 80wt% of hydrazine hydrate, filtering at 75-80 ℃ after the reaction is finished, cooling filtrate, slowly separating out solids, and filtering to obtain m-amino imidazoline; m-amino imidazoline, N' -carbonyl diimidazole and diisopropylethylamine are dissolved in DMF, the temperature is raised, solids are slowly separated out, the temperature is lowered, and the imidazole phenylurea is obtained by filtering. The preparation method of the m-nitroimidazoline comprises the following steps: dissolving m-nitrobenzaldehyde, ethylenediamine and trimethylchlorosilane in DMF, heating under nitrogen protection, cooling to room temperature after the reaction, adding water to slowly precipitate solid, and filtering to obtain the final product. The invention avoids the problem of side reaction caused by excessive raw materials, and simultaneously has the advantages of low cost, high yield, low toxicity, low price and easy obtainment of the used reagent, recycling of the solvent and suitability for industrial production.

Description

Preparation method of imidazole phenylurea
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of imidazole phenylurea.
Background
The imidazole phenylurea (imidocarb) is white or white-like powder, is odorless and tasteless, is indissolvable in water, is chemically named as N, N' -di [3- (4, 5-dihydro-1H-imidazol-2-yl) phenyl ] urea, belongs to derivatives of the stilbene urea, is a novel anti-protozoal chemical medicine special for animals, and is generally used for treating piroxicam clinically by using dihydrochloride or dipropionate thereof. The structural formula is as follows:
U.S. Pat. No. 3,182,62 describes a process for the preparation of imidocarb by reacting 2- (3-aminophenyl) imidazoline with phosgene; chinese patent CN1850805a describes a method for preparing imidazole phenylurea from m-aminobenzonitrile as raw material, firstly with triphosgene to form diphenylurea, and then with ethylenediamine; chinese patents CN111574455A, CN106957265A, CN102924380a and CN103896843a describe a process for preparing imidazole phenylurea by condensing m-nitrobenzonitrile, m-nitrobenzoic acid or methyl m-nitrobenzoate with ethylenediamine to prepare m-nitroimidazoline, then reducing with zinc powder, iron powder or palladium carbon, and condensing the reduced product with urea, diphosgene or triphosgene.
The chemical reaction equation is as follows:
the preparation method of the imidazole phenylurea is used for catalytic hydrogenation reduction of zinc powder, iron powder and palladium/carbon. The iron powder reduction belongs to the national obsolete class, and the reduced iron mud has larger environmental pollution and is not suitable for industrialized 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, bring a plurality of inconveniences to transportation and use, have low operation safety, and generate a large amount of hydrogen chloride gas to pollute the atmosphere in the reaction; the urea is environment-friendly, but needs high temperature (160 ℃) and has low yield, and the produced waste is more, pollution is heavy, production period is long, reaction yield is low, energy consumption is high and industrial production difficulty is high. Therefore, there is a need for a safe, pollution-free, short-cycle, high-yield, low-energy-consumption process for the preparation of imidazole phenylurea.
Disclosure of Invention
Aiming at the prior art, the invention aims to provide a preparation method of the imidazole phenylurea. The invention avoids the problem of side reaction caused by excessive raw materials by designing the reaction route and reselecting the reagent participating in the reaction, and simultaneously has the advantages of low cost, high yield, low toxicity, low price and easy obtainment of the used reagent, recycling of the solvent and suitability for industrial production.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of imidazole phenylurea, which comprises the following steps:
(1) Dissolving m-nitroimidazoline, ferric trichloride and active carbon in n-butanol, heating, dropwise adding 80wt% of hydrazine hydrate, filtering at 75-80 ℃ after the reaction is finished, cooling filtrate, slowly separating out solids, and filtering to obtain m-amino imidazoline;
(2) Dissolving m-amino imidazoline obtained in the step (1), N' -carbonyl diimidazole and diisopropylethylamine in DMF, heating to react, slowly separating out solid, cooling to room temperature, stirring and filtering to obtain the imidazole phenylurea.
Preferably, in the step (1), the preparation method of the m-nitroimidazoline comprises the following steps: dissolving m-nitrobenzaldehyde, ethylenediamine and trimethylchlorosilane in DMF, heating under nitrogen protection, cooling to room temperature after the reaction, adding water to slowly precipitate solid, and filtering to obtain the final product.
Preferably, the molar ratio of the m-nitrobenzaldehyde, the ethylenediamine and the trimethylchlorosilane is 1 (1-3) (0.05-5); the volume ratio of the m-nitrobenzaldehyde to the aprotic solvent is 1 (1-5).
Preferably, the temperature of the reaction is 60-110 ℃, and the reaction time is 6-8h.
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 to the active carbon to the hydrazine hydrate of 80wt% is 1 (0.05-0.5) (1-5).
Preferably, in the step (1), the temperature of the heating is raised to 50-100 ℃; the reaction time is 2-4h; cooling to 5-10deg.C.
Preferably, in the step (2), the molar ratio of the m-amino imidazoline to the N, N' -carbonyl diimidazole to diisopropylethylamine is 1: (0.5-3.0): (0.5-3.0); the volume ratio of the m-amino imidazoline to DMF is 1: (1-10).
Preferably, the temperature of the heating is increased to 40-100 ℃, and the reaction time is 4-6h; the stirring time is 1h.
The synthetic route for preparing the imidazole phenylurea is as follows:
the invention has the beneficial effects that:
(1) The invention solves the problem that the m-amino imidazoline of the imidazole phenylurea intermediate cannot be crystallized in methanol and ethanol: m-amino imidazoline has high solubility in methanol and ethanol, needs reduced pressure distillation of solvent, has low solubility in n-butanol, does not need reduced pressure distillation, and can remove reaction byproducts; meanwhile, the problems of serious environmental pollution, high price of zinc powder and palladium/carbon catalyst, high risk coefficient and the like caused by that a large amount of iron mud and wastewater containing aromatic amine are generated by iron powder when the m-nitroimidazoline is reduced into m-amino imidazoline are solved.
(2) The invention solves the problems of high toxicity and low operation safety of phosgene, diphosgene and triphosgene which are used as raw materials when the m-amino imidazoline is used for preparing the imidazole phenylurea in the prior art, and the problems of high temperature (160 ℃) and low yield which are required when the urea is used as the raw material when the m-amino imidazoline is used for preparing the imidazole phenylurea in the prior art.
(3) The invention prepares the mizofenozide by 80wt% hydrazine hydrate (CDI (N, N-carbonyl diimidazole) which has stable chemical property, safe and convenient use and mild reaction condition. The reducing agent of 80wt% hydrazine hydrate and carbonyl condensing agent CDI selected by the invention has convenient use and stable chemical property, and avoids the problem of side reaction caused by excessive use; meanwhile, the method has the advantages of low cost, high yield, low toxicity, low price and easy obtainment of the used reagent, and recycling of the solvent, and is suitable for industrial production.
Drawings
Fig. 1: the imidazole phenylurea obtained in example 1 was found in D 6 In MSO 1 H-NMR spectrum.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the present application. 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 enable those skilled in the art to more clearly understand the technical solutions of the present application, 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 are all conventional in the art and are commercially available.
Example 1
The preparation process of imidazole phenylurea includes the following steps:
(1) 30.2kg of m-nitrobenzaldehyde, 14.4kg of ethylenediamine and 2.2kg of trimethylchlorosilane are dissolved in 60L of N, N-dimethylformamide, nitrogen is introduced for protection, stirring is carried out, the temperature is raised to 80 ℃, the reaction is maintained for 4 hours, then the temperature is raised to 100 ℃, the reaction is continued for 2 hours, and after the reaction is completed, the solution is cooled to 25 ℃; 180L of water is slowly added dropwise, solids are slowly separated out, stirring is continued for 1h, filtering and drying are carried out, and 36.3kg of yellow powdery solid, namely m-nitroimidazoline, is obtained, the yield is 95.0%, and the purity is 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 80wt% hydrazine hydrate solution under stirring, controlling the temperature at 80 ℃, and continuously maintaining the temperature at 80 ℃ for 2 hours after dropwise adding; after the reaction is finished, directly filtering at 80 ℃, cooling the filtrate to 7 ℃, and continuously stirring for 1h; the mixture 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) Dissolving 21.0kg of m-amino imidazoline, 11.4kg of CDI and 10.1kg of diisopropylethylamine prepared in the step (2) in 63L of DMF (N, N-dimethylformamide), stirring and heating to 70 ℃, slowly separating out solids after dissolving, 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 vacuum drying at 60 ℃ to obtain 21.2kg of white solid imidazole phenylurea with the yield of 93.4%.
Through detection, the purity of the liquid phase of the prepared imidazole phenylurea is 99.2%, and the melting point is 350-353 ℃.
Example 2
The synthetic method as described in example 1, differing 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 solid after dissolving, reacting for 6 hours, cooling the solution to 5-10 ℃ after the reaction is finished, stirring for 1 hour, filtering and washing, and vacuum drying at 60 ℃ to obtain 21.6kg of white solid imidazole phenylurea, wherein the yield is 95.2%.
Through detection, the purity of the liquid phase of the prepared imidazole phenylurea is 99.0%, and the melting point is 350-353 ℃.
Example 3
The preparation method as described in example 1, which is different from step (3):
dissolving 21.0kg of prepared m-amino imidazoline, 11.4kg of CDI and 10.1kg of diisopropylethylamine in 84L of DMF, stirring and heating to 80 ℃, slowly separating out solid after solution clearing, reacting for 4 hours, cooling the solution to 15-20 ℃ after the reaction is finished, stirring and crystallizing for 1 hour, filtering and washing, and vacuum drying at 60 ℃ to obtain 20.7kg of white solid imidazole phenylurea, wherein the yield is 91.2%.
Through detection, the purity of the liquid phase of the prepared imidazole phenylurea is 99.5%, and the melting point is 350-353 ℃.
Example 4
The preparation method as described in example 1, which is different from the step (2):
dissolving 34.4kg of the prepared m-nitroimidazoline in 174L of n-butanol, adding 3.0kg of ferric trichloride and 3.4kg of active carbon, heating to 75 ℃, slowly dropwise adding 23g of 80wt% hydrazine hydrate solution under stirring, controlling the temperature at 75 ℃, and continuously maintaining the temperature of 75 ℃ for reaction for 2 hours after the dropwise adding is completed; after the reaction is finished, directly filtering at 75 ℃, cooling the filtrate to 10 ℃, and continuously stirring for 1h; filtration gave 24.2kg of pale yellow powdery solid, i.e. m-aminoimidazoline, yield 83.4% and purity 98.2%.
Example 5
The preparation method as described in example 1, which is different from the step (2):
dissolving 34.4kg of the prepared m-nitroimidazoline in 174L of n-butanol, adding 3.0kg of ferric trichloride and 3.4kg of active carbon, heating to 60 ℃, slowly dropwise adding 23g of 80wt% hydrazine hydrate solution under stirring, controlling the temperature at 70 ℃, and continuously maintaining the temperature at 70 ℃ for reaction for 2 hours after the dropwise adding is completed; after the reaction is finished, directly filtering at 70 ℃, cooling the filtrate to 10 ℃, and continuously stirring for 1h; filtration gave 24.4kg of pale yellow powdery solid, i.e. m-aminoimidazoline, yield 84.3% and purity 96.3%.
Example 6
The preparation method as described in example 1, which is different from the step (2):
dissolving 34.4kg of the prepared m-nitroimidazoline in 280 n-butanol, adding 3.0kg of ferric trichloride and 3.4kg of active carbon, heating to 75 ℃, slowly dropwise adding 23g of 80wt% hydrazine hydrate solution under stirring, controlling the temperature at 85 ℃, and continuously maintaining the temperature of 85 ℃ for reaction for 2 hours after the dropwise adding is finished; after the reaction is finished, directly filtering at 85 ℃, cooling the filtrate to 10 ℃, and continuously stirring for 1h; the mixture was filtered to obtain 23.4kg of a pale yellow powdery solid, i.e., m-aminoimidazoline, with a yield of 80.6% and a purity of 98.7%.
Comparative example 1
The imidazole phenylurea was prepared according to the method of example 3 in the preparation method of imidazole phenylurea disclosed in application number 201410155713.5.
18.1g of m-nitrobenzoic acid methyl ester, 4.0g of ethylenediamine and 0.32g of sulfur are taken and dissolved in 181ml of methanol, reflux is carried out for 3 hours at 65 ℃, 2.0g of ethylenediamine is added and reflux is carried out for 2 hours, most solvent is distilled off under reduced pressure, and then m-nitroimidazoline is obtained after filtration, wherein the molar yield is 96.4%.
Then 17.2g of intermediate m-nitroimidazoline is taken and dissolved in 90ml of 50% methanol, 5mol/L hydrochloric acid is added to adjust the pH value to 3.5, 8.8g of zinc powder is added while stirring for four times in 2 hours at normal temperature, and the stirring reaction is continued for 2 hours after the addition. After the reaction, zinc chloride is removed by filtration, most solvent is distilled out under reduced pressure, and m-amino imidazoline prepared by crystallization has a molar yield of 92.0%.
13.0g of m-aminoimidazoline is taken and dissolved in 65ml of tetrahydrofuran-water (1:6, V: V) solution, the pH value is regulated to 8 by 0.1mol/l sodium hydroxide solution, 0.13mol of triphosgene is added at 35 ℃ for reaction for 4 hours, and after suction filtration and drying, the imidazole phenylurea is obtained, the product is white powder, and the molar yield is 91.9%.
Comparative example 2
The imidazole phenylurea was prepared according to the method of example in the preparation method of imidazole phenylurea hydrochloride disclosed in application No. 200810079399.1.
A. Preparation of m-nitroimidazolines
In a 250ml reaction bottle, adding 100ml methanol, 8.0ml (0.12 mol) ethylenediamine, 14.8g (0.1 mol) m-nitrobenzonitrile and 1.6g (0.05 mol) sulfur, stirring, heating to reflux, starting timing, reacting for 20 hours, filtering off sulfur while hot, concentrating the filtrate to 40ml, cooling, standing for crystallization for 2 hours, filtering, and vacuum drying the filter cake at 60 ℃ for 8 hours to obtain light yellow powdery m-nitroimidazoline with a melting point of 159-161 ℃ and a yield of 95.3 percent.
B. Preparation of meta-amino imidazolines
In a 500ml reaction bottle, 20g (0.36 mol) of reduced iron powder, 1ml (0.01 mol) of concentrated hydrochloric acid and 200ml of water are added, heating reflux and stirring are carried out for 10 minutes, cooling is carried out to 90 ℃, 19.1g (0.10 mol) of m-nitroimidazoline prepared in the step A is added, heating reflux reaction is carried out for 6 hours, iron mud is filtered out while hot, 20ml of x 2 hot water is used for washing iron mud, washing liquid and filtrate are combined, bath temperature is lower than 100 ℃, decompression concentration is carried out to 80ml, ice bath cooling is carried out to lower than 5 ℃, standing crystallization is carried out for 1 hour, filtration is carried out, filter cake is washed twice by cold water, vacuum drying is carried out at 60 ℃ for 6 hours, and white or quasi-white crystalline m-amino imidazoline is obtained, melting point is 139-143 ℃, and yield is 80.1%.
C. Adding 20g (0.36 mol) of reduced iron powder, 2ml (0.02 mol) 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 (0.10 mol) of m-nitroimidazoline prepared in the step A, heating, stirring and refluxing for reaction for 6 hours, filtering iron mud while hot, washing the iron mud with 20ml multiplied by 2 hot water, merging washing liquid and filtrate, concentrating to 80ml under reduced pressure at a bath temperature of 100 ℃, cooling to below 5 ℃ in an ice bath, standing and crystallizing for 1 hour, filtering, washing the filter cake twice with cold water, and drying in vacuum at 60 ℃ for 6 hours to obtain white or quasi-white crystalline m-amino imidazoline hydrochloride with a melting point of 215-216 ℃ and a yield of 79.2%.
D. In a 500ml reaction bottle, 20g (0.36 mol) of reduced iron powder, 3ml (0.03 mol) of concentrated hydrochloric acid and 200ml of water are added, heating reflux and stirring are carried out for 10 minutes, cooling is carried out to 90 ℃, 19.1g (0.10 mol) of m-nitroimidazoline prepared in the step A is added, heating reflux reaction is carried out for 6 hours while hot, iron mud is filtered out, 20ml of x 2 hot water is used for washing iron mud, washing liquid and filtrate are combined, bath temperature is lower than 100 ℃, decompression concentration is carried out to 80ml, ice bath cooling is carried out to lower than 5 ℃, standing crystallization is carried out for 1 hour, filtration is carried out, filter cake is washed twice by cold water, vacuum drying is carried out at 60 ℃ for 6 hours, and thus, 18.4g of white or quasi-white crystalline m-amino imidazoline dihydrochloride is obtained, the melting point is more than 260 ℃, and the yield is 78.6%.
E. Preparation of imidazole phenylurea hydrochloride
In a 250ml reaction bottle, 16.1g (0.10 mol) of m-amino imidazoline prepared in the step C, 3.0g (0.05 mol) of urea, 20ml (0.24 mol) of concentrated hydrochloric acid, 100ml of n-butyl alcohol, starting stirring, heating to 100 ℃, stirring for 2 hours, cooling to 0 ℃ by ice bath, standing for 2 hours, washing filter cakes respectively with 25ml of x 2 absolute ethyl alcohol and 25ml of x 2 diethyl ether, and vacuum drying at 60 ℃ for 5 hours to obtain 18.1g of white or quasi-white product imidazole phenylurea hydrochloride, wherein the melting point is more than 350 ℃ (decomposition) and the yield is 85.9%.
F. Preparation of imidazole phenylurea hydrochloride
In a 250ml reaction bottle, 19.7g (0.10 mol) of m-amino imidazoline hydrochloride prepared in the step C, 3.0g (0.05 mol) of urea, 20ml (0.24 mol) of concentrated hydrochloric acid, 100ml of n-butanol, stirring, heating to 100 ℃, stirring for 2 hours, cooling to 0 ℃ by an ice bath, standing for 2 hours, washing filter cakes by 25ml of x 2 absolute ethyl alcohol and 25ml of x 2 diethyl ether respectively, and drying in vacuum at 60 ℃ for 5 hours to obtain 18.1g of white or off-white product imidazole phenylurea hydrochloride, wherein the melting point is more than 350 ℃ (decomposition) and the yield is 85.9%.
G. Preparation of imidazole phenylurea hydrochloride
In a 250ml reaction bottle, 23.4g (0.10 mol) of m-amino imidazoline prepared in the step C, 3.0g (0.05 mol) of urea, 20ml (0.24 mol) of concentrated hydrochloric acid, 100ml of n-butyl alcohol, starting stirring, heating to 100 ℃, stirring for 2 hours, cooling to 0 ℃ by ice bath, standing for 2 hours, washing filter cakes respectively with 25ml of x 2 absolute ethyl alcohol and 25ml of x 2 diethyl ether, and vacuum drying at 60 ℃ for 5 hours to obtain 18.1g of white or quasi-white product imidazole phenylurea hydrochloride, wherein the melting point is more than 350 ℃ (decomposition) and the yield is 85.9%.
Comparative example 3
Imidazole phenylurea was prepared according to the method of example 5 in the preparation of imidazole phenylurea dipropionate and its intermediates as disclosed in application number 202010411314.6
1L of water, 2- (3-nitrophenyl) imidazoline (120 g,0.63 mol), 8.4g of 10% wet palladium carbon was carefully added into a 3L reaction flask, the mixture was slowly warmed and stirred until reflux, a solution of ammonium formate (119.7 g,1.89 mol) in water (240 mL) was slowly added dropwise, the reaction was carried out for about 0.5h after the dropwise addition, the reaction was carried out for 2h under heat insulation, and a pale yellow clear liquid was obtained by filtration, and the filtrate was directly fed to the next step.
Sequentially adding the reaction solution of the last step, hydrochloric acid (134 mL,1.6 mol) and urea (19.2 g,0.32 mol) into a 2L three-port reaction bottle, heating and stirring under nitrogen protection until reflux, carrying out heat preservation reaction for 8h, cooling the reaction solution to room temperature, regulating the pH value to 9-10 by using a 2mol/L sodium hydroxide aqueous solution, precipitating a large amount of white solid, stirring at room temperature for 0.5h, filtering, washing a filter cake with a small amount of water, and carrying out forced air drying on the product to obtain the white solid-like imidazole phenylurea (88.5 g, 80.7% in two steps).
Comparative example 4
The imidazole phenylurea was prepared according to the method of example 1 in the imidazole phenylurea preparation method disclosed in application number 201210454778.0
(1) 121.0kg of m-nitrobenzoic acid and 344.9kg of thionyl chloride are added into a reaction kettle, mixed and stirred, heated to 80 ℃, subjected to reflux reaction for 4 hours, decompressed and concentrated at the temperature of 75 ℃ to remove thionyl chloride, 134.1kg of m-nitrobenzoyl chloride is prepared at room temperature, and the molar yield of m-nitrobenzoyl chloride is 99.8%;
(2) Adding 133.3kg of m-nitrobenzoyl chloride prepared in the step (1) into 600L of acetonitrile, then adding 8.0kg of phosphomolybdic vanadium heteropolyacid, stirring, adding 47.3kg of ethylenediamine, stirring, heating to 80 ℃, carrying out reflux reaction for 2h, filtering, taking filtrate, and concentrating under reduced pressure at 75 ℃ to obtain 126.5kg of yellow-green 2- (3-nitrophenyl) imidazoline solid with a molar yield of 91.6%.
(3) 124.4kg of the 2- (3-nitrophenyl) imidazoline prepared in the step (2) is added into 600L of water, then 10.0kg of 5% palladium-carbon catalyst is added, the reduction hydrogenation reaction is carried out for 4 hours under the conditions of 70 ℃ temperature, 0.4MPa of atmosphere and hydrogen pressure, the filtrate is filtered, the pH value of the filtrate is regulated to be 6.0 by 6mol/L of hydrochloric acid, then the filtrate is cooled to-2 ℃ and is left to stand for crystallization for 1 hour, the filtrate is filtered, the precipitate is taken out, and the precipitate is dried in vacuum at 60 ℃ to prepare 120.5kg of off-white 2- (3-aminophenyl) imidazoline hydrochloride solid with 93.7 mol yield;
(4) 120.5kg of the 2- (3-aminophenyl) imidazoline hydrochloride prepared in the step (3) is added into 700L of N, N-methyl formamide, 33kg of urea is added in a stirring manner, the temperature is raised to 160 ℃, the reaction is carried out for 5 hours, the temperature is reduced to 3 ℃, standing and crystallization are carried out for 1 hour, filtration and washing are carried out, and 89.5kg of imidazole phenylurea white solid is obtained after vacuum drying at 60 ℃.
Through detection, the prepared imidazole phenylurea mp (melting point) is 350-352 ℃, the content is 99.3%, and the molar yield is 83.7%.
The yields and purities of the intermediates or imidazole phenylurea prepared in examples 1 to 3 and comparative examples 1 to 4 were counted, and the results obtained are shown in Table 1.
TABLE 1
Product name Molar yield (%) Purity (%)
Example 1 Imidazole phenylurea 93.4 99.2
Example 2 Imidazole phenylurea 95.2 99.0
Example 3 Imidazole phenylurea 91.2 99.5
Comparative example 1 Imidazole phenylurea 91.9 98.1
Comparative example 2 Imidazole phenylurea hydrochloride 85.9 97.8
Comparative example 3 Imidazole phenylurea 80.7 96.2
Comparative example 4 Imidazole phenylurea 83.7 99.3
The imidazole phenylurea is obtained through three-step reaction, the operation is simple, the solvent can be recycled, the three wastes are less, the environmental pollution is small, the purity is high, and the yield is high. The solvents used in the comparative examples are not easy to recycle, the environment pollution of iron powder, zinc powder, triphosgene, phosgene and diphosgene is serious, and the price of the used palladium/carbon catalyst is more expensive: the price of one kilogram is about hundreds of thousands yuan, and the cost of the catalyst used in the application is about 100 yuan/kilogram, which is 1/1000 of the cost of the comparative example, so the catalyst such as palladium/carbon catalyst used in the comparative example has higher purity and yield of the m-amino imidazoline, but the production cost is high, the purity and yield of the m-amino imidazoline prepared by the method are also high, and the purity and yield of the imidazole phenylurea prepared by the method are higher than those of the comparative example. Meanwhile, the triphosgene, phosgene and diphosgene used in the comparative example are taken as condensing agents to obtain products which are imidazole phenylurea dihydrochloride, and sodium hydroxide is also required to be used for hydrolysis to obtain target products, so that more waste water is generated, and the cost is higher.
Therefore, the purity and the yield of the imidazole phenylurea prepared by the method are improved, the preparation cost is low, no pollutant is generated in the preparation process, and the method is environment-friendly and human-friendly and is suitable for industrial production.
The foregoing description is only of the preferred embodiments of the present application and is not intended to limit the same, but rather, various modifications and variations may be made by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application should be included in the protection scope of the present application.

Claims (5)

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