CN103896843A - Preparation method of imidocarb - Google Patents
Preparation method of imidocarb Download PDFInfo
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- CN103896843A CN103896843A CN201410155713.5A CN201410155713A CN103896843A CN 103896843 A CN103896843 A CN 103896843A CN 201410155713 A CN201410155713 A CN 201410155713A CN 103896843 A CN103896843 A CN 103896843A
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- imidazophenylurea
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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
- C07D233/24—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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Abstract
The invention relates to a preparation method of imidocarb. The preparation method comprises the steps of dissolving methyl-m-nitrobenzoate into a solvent, enabling methyl-m-nitrobenzoate and ethylenediamine to be subjected to cyclization reaction at the temperature of 55-65 DEG C for 3-6h under the action of a catalyst, and separating to prepare m-nitroimidazoline; dissolving m-nitroimidazoline into a water solution of methanol, adding zinc powder under an acidic condition, after the addition is ended, carrying out reduction reaction for 1-2h while stirring at normal temperature, and separating and purifying to prepare m-aminoimidazoline; dissolving m-aminoimidazoline into a water solution of tetrahydrofuran, regulating the pH value to 7-10, adding triphosgene, reacting at the temperature of 10-40 DEG C for 2-6h, filtering and drying to obtain imidocarb. Methyl-m-nitrobenzoate is used as a starting raw material, and zinc powder is used as a reducing agent, so that the preparation method is mild in reaction condition, convenient in operation and relatively low in cost.
Description
Technical field
The present invention relates to a kind of preparation method of imidazophenylurea, belong to compou nd synthesis technical field.
Background technology
Imidazophenylurea is beast drug chemical, is anti-pyriform worm medicine hexichol ureas diamidine derivative, is a kind of important bioactive compound that has, generally common with dihydrochloride and dipropionate.They have the advantages such as wide spectrum, low toxicity, applied range, long action time, dosage be little, and the eperythrozoonosis of domestic animal piroplasmosis, anaplasmosis and pig dog etc. is not only had to good therapeutic action, also have good preventive effect.
US Patent No. 3338917 has been introduced a kind of with 2-(3-aminophenyl) tetrahydroglyoxaline and phosgene reaction prepare the synthesis mode of imidazophenylurea; Chinese patent CN1850805A has introduced a kind of taking m-aminophenyl formonitrile HCN as raw material, first forms sym-diphenylurea structure with triphosgene, then prepares the method for imidazoles urea with reacting ethylenediamine; Chinese patent CN101348465A has introduced a kind of taking m-nitro formonitrile HCN as raw material, first and reacting ethylenediamine make a nitroimidazole quinoline, then through iron powder reducing, reduzate and urea condensation, prepare the method for imidazophenylurea.The defect of aforesaid method is, imidazophenylurea preparation process is loaded down with trivial details, and waste is many, pollutes heavy.Production cycle is long, and reaction yield is low, and energy consumption is high, and suitability for industrialized production difficulty is large.
Summary of the invention
The preparation method who the object of the invention is to overcome prior art deficiency and provide a kind of imidazophenylurea, production cost reduces, and yield improves.Reaction conditions gentleness, easy to operate.Form the production process route of a low input, low cost, environmental protection.
The technical scheme that the present invention takes is:
A preparation method for imidazophenylurea, comprises that step is as follows:
(1) methyl-m-nitrobenzoate is dissolved in solvent, under catalyst action, at 55 DEG C-65 DEG C, ring-closure reaction occurs with quadrol, reaction times 3-6 hour, separates and makes a nitroimidazole quinoline;
(2) a nitroimidazole quinoline is dissolved in the aqueous solution of methyl alcohol, under acidic conditions, adds zinc powder, add under rear normal temperature and stir reduction reaction 1-2 hour, separating-purifying makes an aminooimidazole quinoline;
(3) will between aminooimidazole quinoline be dissolved in tetrahydrofuran (THF)-aqueous solution, regulate pH=7-10, add triphosgene, 10 DEG C-40 DEG C reaction 2-6 hour, filter, dry and obtain imidazophenylurea.
In above-mentioned preparation method, the mol ratio of step (1) methyl-m-nitrobenzoate and quadrol is 1:1-2, and the mol ratio of methyl-m-nitrobenzoate and catalyzer is 1:0.05-0.1.Described solvent is methyl alcohol, and add-on is 5-10 times of methyl-m-nitrobenzoate volume.Described catalyzer is sulphur.
Between described in step (2), the mol ratio of nitroimidazole quinoline and zinc powder is 1:1.2-1.5.The aqueous solution volumetric concentration of methyl alcohol is 50%, and consumption is a 5-10 of nitroimidazole quinoline volume times.Described acidic conditions pH=3.5-4.5.The described zinc powder mode that adds was preferably divided and is added for four times in 2 hours.
Between described in step (3), the mol ratio of aminooimidazole quinoline and triphosgene is 1:1-1.8.In described tetrahydrofuran (THF)-aqueous solution, tetrahydrofuran (THF) and water volume ratio=1:5-8, the volume of tetrahydrofuran (THF)-aqueous solution is a 4-6 of aminooimidazole quinoline volume times.
Reaction process of the present invention is as follows:
The production technique of imidazophenylurea of the present invention, with existing production technique comparison, has following advantage:
(1) using methyl-m-nitrobenzoate is starting raw material, current domestic many productions that have of methyl-m-nitrobenzoate, and low price, raw material is easy to get, methyl-m-nitrobenzoate and quadrol Cheng Huan, obtain 2-(3-nitrophenyl) and tetrahydroglyoxaline, yield 95%.
(2) 2-(3-nitrophenyl) imidazoline reduction makes reductive agent with zinc powder, reaction conditions gentleness, easy to operate, to be convenient to separate, produced simultaneously zinc chloride can be sold as industrial goods after recrystallization, has avoided pollution, and reaction yield reaches 90%, and cost is lower.
(3) our choice for use of condensation reaction uses mixed solvent, normal-temperature reaction, and mild condition, easy to operate, yield reaches 90%.
Brief description of the drawings
Fig. 1 is standard substance infared spectrum;
Fig. 2 is the embodiment of the present invention 1 product infared spectrum.
Embodiment
Further illustrate below in conjunction with embodiment.
Embodiment 1:
Get methyl-m-nitrobenzoate 18.1g, quadrol 6.0g, 0.16g sulphur is dissolved in 110ml methyl alcohol, at 65 DEG C, reflux 4 hours, decompression steam after most of solvent, filter between nitroimidazole quinoline, molar yield is 95.0%.
Get again nitroimidazole quinoline 17.2g between intermediate product, be dissolved in 90ml50% methyl alcohol, with 5mol/L salt acid for adjusting pH value to 4.0, in 2 hours at normal temperatures, divide and add while stirring 7.0g zinc powder four times, finish and continue stirring reaction 1 hour.After reaction finishes, remove by filter zinc chloride, decompression steams most of solvent, aminooimidazole quinoline between crystallization system, and molar yield is 91.3%.
Getting an aminooimidazole quinoline 13.0g is dissolved in 65ml tetrahydrofuran (THF)-water (1:5) solution again, by 0.1mol/L sodium hydroxide solution adjusting pH value to 8, at 20 DEG C, add 0.08mol triphosgene, react after 3 hours, suction filtration, dries, and obtains imidazophenylurea, product is white powder, and molar yield is 91.1%.
Embodiment 2:
Get methyl-m-nitrobenzoate 18.1g, quadrol 9.0g, 0.16g sulphur is dissolved in 110ml methyl alcohol, at 65 DEG C, reflux 5 hours, decompression steam after most of solvent, filter between nitroimidazole quinoline, molar yield is 95.1%.
Get again nitroimidazole quinoline 17.2g between intermediate product, be dissolved in 90ml50% methyl alcohol, with 5mol/L salt acid for adjusting pH value to 3.5, in 2 hours at normal temperatures, divide and add while stirring 8.0g zinc powder four times, finish and continue stirring reaction 2 hours.After reaction finishes, remove by filter zinc chloride, decompression steams most of solvent, aminooimidazole quinoline between crystallization system, and molar yield is 91.7%.
Get an aminooimidazole quinoline 13.0g and be dissolved in 65ml tetrahydrofuran (THF)-water (1:5, V:V) in solution, by 0.1mol/l sodium hydroxide solution adjusting pH value to 10, at 30 DEG C, add 0.08mol triphosgene, react after 3 hours suction filtration, dry, obtain imidazophenylurea, product is white powder, and molar yield is 90.2%.
Embodiment 3:
Get methyl-m-nitrobenzoate 18.1g, quadrol 4.0g, 0.32g sulphur is dissolved in 181ml methyl alcohol, refluxes after 3 hours at 65 DEG C, add again quadrol 2.0g to reflux 2 hours, decompression steam after most of solvent, filter between nitroimidazole quinoline, molar yield is 96.4%.
Get again nitroimidazole quinoline 17.2g between intermediate product, be dissolved in 90ml50% methyl alcohol, add 5mol/L salt acid for adjusting pH value to 3.5, in 2 hours at normal temperatures, divide and add while stirring 8.8g zinc powder four times, finish and continue stirring reaction 2 hours.After reaction finishes, remove by filter zinc chloride, decompression steams most of solvent, aminooimidazole quinoline between crystallization system, and molar yield is 92.0%.
Get an aminooimidazole quinoline 13.0g and be dissolved in 65ml tetrahydrofuran (THF)-water (1:6, V:V) in solution, by 0.1mol/l sodium hydroxide solution adjusting pH value to 8, at 35 DEG C, add 0.13mol triphosgene, react after 4 hours suction filtration, dry, obtain imidazophenylurea, product is white powder, and molar yield is 91.9%.
Embodiment 4:
Get methyl-m-nitrobenzoate 18.1g, quadrol 6.0g, 0.32g sulphur is dissolved in 181ml methyl alcohol, at 65 DEG C, reflux 6 hours, decompression steam after most of solvent, filter between nitroimidazole quinoline, molar yield is 94.8%.
Get again nitroimidazole quinoline 17.2g between intermediate product, be dissolved in 100ml50% methyl alcohol, add 5mol/L salt acid for adjusting pH value to 3.5, in 2 hours at normal temperatures, divide and add while stirring 9.0g zinc powder four times, finish and continue stirring reaction 1 hour.After reaction finishes, remove by filter zinc chloride, decompression steams most of solvent, aminooimidazole quinoline between crystallization system, and molar yield is 92.3%.
Get an aminooimidazole quinoline 13.0g and be dissolved in 78ml tetrahydrofuran (THF)-water (1:8, V:V) in solution, by 0.1mol/L sodium hydroxide solution adjusting pH value to 8, at 30 DEG C, add 0.12mol triphosgene, react after 3 hours suction filtration, dry, obtain imidazophenylurea, product is white powder, and molar yield is 91.1%.
Claims (9)
1. a preparation method for imidazophenylurea, is characterized in that, comprises that step is as follows:
(1) methyl-m-nitrobenzoate is dissolved in solvent, under catalyst action, at 55 DEG C-65 DEG C, ring-closure reaction occurs with quadrol, reaction times 3-6 hour, separates and makes a nitroimidazole quinoline;
(2) a nitroimidazole quinoline is dissolved in the aqueous solution of methyl alcohol, under acidic conditions, adds zinc powder, add under rear normal temperature and stir reduction reaction 1-2 hour, separating-purifying makes an aminooimidazole quinoline;
(3) will between aminooimidazole quinoline be dissolved in tetrahydrofuran (THF)-aqueous solution, regulate pH=7-10, add triphosgene, 10 DEG C-40 DEG C reaction 2-6 hour, filter, dry and obtain imidazophenylurea.
2. the preparation method of a kind of imidazophenylurea according to claim 1, is characterized in that, the mol ratio of step (1) methyl-m-nitrobenzoate and quadrol is 1:1-2, and the mol ratio of methyl-m-nitrobenzoate and catalyzer is 1:0.05-0.1.
3. the preparation method of a kind of imidazophenylurea according to claim 1 and 2, is characterized in that, the described catalyzer of step (1) is sulphur.
4. the preparation method of a kind of imidazophenylurea according to claim 1, is characterized in that, the described solvent of step (1) is methyl alcohol, and add-on is 5-10 times of methyl-m-nitrobenzoate volume.
5. the preparation method of a kind of imidazophenylurea according to claim 1, is characterized in that, described in step (2) between the mol ratio of nitroimidazole quinoline and zinc powder be 1:1.2-1.5.
6. the preparation method of a kind of imidazophenylurea according to claim 1, is characterized in that, in step (2), the aqueous solution volumetric concentration of methyl alcohol is 50%, and consumption is a 5-10 of nitroimidazole quinoline volume times.
7. the preparation method of a kind of imidazophenylurea according to claim 1, is characterized in that, the described zinc powder mode that adds was preferably divided and added for four times in 2 hours.
8. the preparation method of a kind of imidazophenylurea according to claim 1, is characterized in that, step (3) described between the mol ratio of aminooimidazole quinoline and triphosgene be 1:1-1.8.
9. the preparation method of a kind of imidazophenylurea according to claim 1, is characterized in that, in described tetrahydrofuran (THF)-aqueous solution, and tetrahydrofuran (THF) and water volume ratio=1:5-8, the volume of tetrahydrofuran (THF)-aqueous solution is a 4-6 of aminooimidazole quinoline volume times.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110256354A (en) * | 2019-07-26 | 2019-09-20 | 齐鲁动物保健品有限公司 | A kind of imidocard dipropionate impurity A and its impurity A preparation method |
| CN112521337A (en) * | 2020-12-15 | 2021-03-19 | 河北威远药业有限公司 | Preparation method of imidocarb dipropionate sterile bulk drug |
| CN114671810A (en) * | 2022-03-21 | 2022-06-28 | 济南鸿湾生物技术有限公司 | Preparation method of imidocarb |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3338917A (en) * | 1960-10-14 | 1967-08-29 | Wander Ag Dr A | Diimidazolinylcarbanilide |
| CN101348465A (en) * | 2008-09-17 | 2009-01-21 | 河北远征药业有限公司 | Preparation of imidazophenylurea hydrochloride |
| WO2010127081A1 (en) * | 2009-05-01 | 2010-11-04 | Wyeth Llc | Blood parasiticide |
| CN102924380A (en) * | 2012-11-13 | 2013-02-13 | 齐鲁动物保健品有限公司 | Preparation method of imidocarb |
-
2014
- 2014-04-17 CN CN201410155713.5A patent/CN103896843B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3338917A (en) * | 1960-10-14 | 1967-08-29 | Wander Ag Dr A | Diimidazolinylcarbanilide |
| CN101348465A (en) * | 2008-09-17 | 2009-01-21 | 河北远征药业有限公司 | Preparation of imidazophenylurea hydrochloride |
| WO2010127081A1 (en) * | 2009-05-01 | 2010-11-04 | Wyeth Llc | Blood parasiticide |
| CN102924380A (en) * | 2012-11-13 | 2013-02-13 | 齐鲁动物保健品有限公司 | Preparation method of imidocarb |
Non-Patent Citations (1)
| Title |
|---|
| 李光壁，等: "盐酸咪唑苯脲的合成", 《中国医药工业杂志》, vol. 39, no. 2, 29 February 2008 (2008-02-29), pages 88 - 89 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110256354A (en) * | 2019-07-26 | 2019-09-20 | 齐鲁动物保健品有限公司 | A kind of imidocard dipropionate impurity A and its impurity A preparation method |
| CN112521337A (en) * | 2020-12-15 | 2021-03-19 | 河北威远药业有限公司 | Preparation method of imidocarb dipropionate sterile bulk drug |
| CN112521337B (en) * | 2020-12-15 | 2022-08-05 | 河北威远药业有限公司 | Preparation method of imidocarb dipropionate sterile bulk drug |
| CN114671810A (en) * | 2022-03-21 | 2022-06-28 | 济南鸿湾生物技术有限公司 | Preparation method of imidocarb |
| CN114671810B (en) * | 2022-03-21 | 2024-03-22 | 济南鸿湾生物技术有限公司 | Preparation method of imidazole phenylurea |
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| CN103896843B (en) | 2016-02-24 |
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Denomination of invention: Preparation method of imidocarb Effective date of registration: 20200528 Granted publication date: 20160224 Pledgee: Jinan Chengdong sub branch of Qilu Bank Co., Ltd Pledgor: SHANDONG JIULONG FINE CHEMICAL Co.,Ltd. Registration number: Y2020370000089 |
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Date of cancellation: 20210520 Granted publication date: 20160224 Pledgee: Jinan Chengdong sub branch of Qilu Bank Co., Ltd Pledgor: SHANDONG JIULONG FINE CHEMICAL Co.,Ltd. Registration number: Y2020370000089 |