CN103224452B - 2-bromine-4,6-dichloroaniline preparation method - Google Patents
2-bromine-4,6-dichloroaniline preparation method Download PDFInfo
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- CN103224452B CN103224452B CN201210020618.5A CN201210020618A CN103224452B CN 103224452 B CN103224452 B CN 103224452B CN 201210020618 A CN201210020618 A CN 201210020618A CN 103224452 B CN103224452 B CN 103224452B
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Abstract
The invention relates to a preparation method for a medicine KCNQ potassium channel conditioning agent critical material 2-bromine-4,6-dichloroaniline. According to the invention, 2,4-dichloroaniline is taken as a raw materials, and is subjected to NBS (N-bromosuccinimide) bromination to obtain a target object, and the preparation method of the invention has the advantages of low preparation method and simple operation, and has industrial production value.
Description
Technical field
The present invention relates to a kind of preparation method of compound, particularly a kind of critical materials of medical KCNQ potassium ion channel modulators and the preparation method of bromo-4, the 6-dichlorphenamide bulk powders of 2-.
Background technology
Ionic channel is the protein controlling ion turnover cell, and they are extensively present on various cytolemma, have selective penetrated property.It is the basis of neural, muscle and other cell membranes in tissue excitement, is also the basis of bioelectric.The Kai Heguan of ionic channel makes neurocyte produce the nerve impulse relevant to electricity.Scientist knows, ionic channel is relevant to the various diseases such as epilepsy, parkinsonism, and is the only way which must be passed that toxin and many medicines work.
Potassium-channel is the class ionic channel that type is maximum up to now, and they are distributed in skeletal muscle, nerve widely.They not only participate in the adjustment of the many important physiological function of body, and also have vital role in some diseases.
Bromo-4, the 6-dichlorphenamide bulk powders of 2-are a kind of important pharmaceutical-chemical intermediate, are the critical materialses of preparation KCNQ potassium ion channel modulators.
Bromo-4, the 6-dichlorphenamide bulk powder KCNQ potassium ion channel modulators of 2-
Train at reference Xu Fu, Wang Qiming at chemical reagent, 8(6), 374-375, in 1986 report, with 2,4 dichloro aniline (formula III) for raw material, obtain target compound through NBS bromo, its reaction process is shown below:
Bromo-4, the 6-dichlorphenamide bulk powders of 2,4 dichloro aniline 2-
In the method, 2,4 dichloro aniline and N-bromo-succinimide (NBS) bromination reaction, obtain bromo-4, the 6-dichlorphenamide bulk powders of 2-.Then, reaction mass is poured into water, obtains bromo-4, the 6-dichlorphenamide bulk powder crude products of 2-, crude product is carried out recrystallization and obtains target product.The outstanding feature of this preparation method is that transformation efficiency is high, reaches 100%, avoids too much separating-purifying.Reaction employs the relatively high NBS of price and does bromide reagent, and the solvent DMF used due to reaction again reclaims difficulty, causes that cost is high, industrialization difficulty is large.
Contriver studies above-mentioned preparation method, finds the obvious shortcoming that this preparation method exists: (1) bromide reagent NBS price is high; (2) use a large amount of high boiling solvent, difficult solvent recovery in reaction, therefore whole process costs is high, does not have the value of industrial implementation.
Summary of the invention
The technical problem to be solved in the present invention is to provide the preparation method of bromo-4, the 6-dichlorphenamide bulk powders of a kind of 2-.This preparation method can overcome in existing method the problem that there is the high not easily industrial implementation of cost, is that a kind of production cost is low and simple to operate, has the preparation method that industrial production is worth.
The present invention prepares 2-bromo-4, be be raw material with 2,4 dichloro aniline in the method for 6-dichlorphenamide bulk powder, concrete technology comprises the following steps: add 2 in reaction flask, 4-dichlorphenamide bulk powder, reaction solvent, bromide reagent is added, insulation reaction 5 ~ 20h, to 2-bromo-4 at 10 ~ 50 DEG C, 6-dichlorphenamide bulk powder stops heating without during increase, continue to stir decrease temperature crystalline, filter and obtain structural formula I compound, yield 97.5 ~ 98.5%.
In above-mentioned preparation method, the bromide reagent adopted in bromination reaction is bromine, Hydrogen bromide-hydrogen peroxide, Hydrogen bromide-clorox, Hydrogen bromide-sodium bromate, preferred Hydrogen bromide-hydrogen peroxide; The solvent wherein reacted is water, methyl alcohol, ethanol, Virahol or propyl carbinol, preferably water.
The present inventor finds in research process, and adopt low-cost Hydrogen bromide-hydrogen peroxide to carry out bromination reaction, reaction conversion ratio also can reach the level that original text is offered: 100%.Reaction process water or alcohol do reaction solvent, reaction terminates, target product is directly separated out from reaction solvent, the target product of content more than 99% is obtained after suction filtration, mother liquor directly overlaps to be used in bromo-reaction, avoid in former technique the problem needing to process a large amount of DMF aqueous solution, decrease the crude product recrystallization operation in former technique, do not need distillating recovering solvent.Simultaneously, in former literature method, react with high boiling point DMF for solvent, react complete, mixture is poured into water, product is separated out in solid form from mixture, collected by suction, and mother liquor is the mixture of DMF and water and the undecomposed product that wherein contains, crude product recrystallization use acetic acid water or ethanol water mixed crystallization.Due to DMF and acetic acid, not only boiling point is high but also dissolve each other with water, is difficult to carry out efficient recovery to composition various in this part solution, directly causes pollution and the high energy consumption of significant loss, environment.And in method of the present invention, at Hydrogen bromide-hydrogen peroxide bromide reagent that reaction process uses price relatively cheap, high boiling solvent is not used in whole reaction simultaneously and last handling process, reaction mother liquor can directly overlap uses bromination reaction, not only make product ultimate yield higher, and avoid solvent recuperation, there is simple to operate, that cost is low feature.
Outstanding feature of the present invention is: (1) employs relatively cheap bromide reagent, does not use high boiling solvent in reaction process, and post-reaction treatment mother liquor directly overlaps to be used in reaction, and reaction yield is high, and cost is low, without the three wastes; (2) simple to operate, be easy to industrializing implementation.
Embodiment
The preparation of bromo-4, the 6-dichlorphenamide bulk powders of embodiment 1:2-
In 1000ml reaction flask, add 32.4g(0.2mol) 2,4 dichloro aniline, water 500ml, 48% Hydrogen bromide
33.8g (0.2mol), stirring heating, makes to remain on 10-50 DEG C and drips hydrogen peroxide, is incubated 10-50 DEG C of reaction 10h, stop reaction, stir cooling, solid is separated out, suction filtration, obtain pale solid powder, dry and obtain 47.0g, content: 99.7%, yield 97.8%.
The preparation of bromo-4, the 6-dichlorphenamide bulk powders of embodiment 2:2-
In 1000ml reaction flask, add 32.4g(0.2mol) 2,4 dichloro aniline, water 500ml, 48% Hydrogen bromide 33.8g (0.2mol), stirring heating, makes to remain on 10-50 DEG C and drips hydrogen peroxide, is incubated 10-50 DEG C of reaction 10h, stop reaction, stir cooling, solid is separated out, suction filtration, obtain pale solid powder, oven dry obtains 47.1g, content: 99.8%, yield 98.1%.
Claims (2)
1. preparing the method for bromo-4, the 6-dichlorphenamide bulk powders of 2-for one kind, it is characterized in that, is raw material with 2,4 dichloro aniline, through following steps:
In 1000ml reaction flask, add 32.4g 2,4 dichloro aniline, water 500ml, 48% Hydrogen bromide 33.8g, stirring heating, makes to remain on 10 ~ 50 DEG C and drips hydrogen peroxide, is incubated 10 ~ 50 DEG C of reaction 10h, stop reaction, stir cooling, solid is separated out, suction filtration, obtain pale solid powder, oven dry obtains 47.0g, content: 99.7%, yield 97.8%.
2. preparing the method for bromo-4, the 6-dichlorphenamide bulk powders of 2-for one kind, it is characterized in that, is raw material with 2,4 dichloro aniline, through following steps:
In 1000ml reaction flask, add 32.4g 2,4 dichloro aniline, water 500ml, 48% Hydrogen bromide 33.8g, stirring heating, makes to remain on 10 ~ 50 DEG C and drips hydrogen peroxide, is incubated 10 ~ 50 DEG C of reaction 10h, stop reaction, stir cooling, solid is separated out, suction filtration, obtain pale solid powder, oven dry obtains 47.1g, content: 99.8%, yield 98.1%.
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Citations (5)
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|---|---|---|---|---|
| DE3014972C2 (en) * | 1980-04-18 | 1984-11-22 | Chemische Fabrik Kalk GmbH, 5000 Köln | Process for the preparation of 2,4-dinitro-6-bromaniline |
| CN1136037A (en) * | 1996-03-01 | 1996-11-20 | 大连理工大学 | 2,6-dibromo-4-carboxysulfonateacyl aminobenzene and its synthesis |
| CN1357533A (en) * | 2001-07-23 | 2002-07-10 | 昆山双鹤药业有限责任公司 | Prepn. of 2,6-dibromo aniline |
| CN101492343A (en) * | 2008-12-30 | 2009-07-29 | 中钢集团鞍山热能研究院有限公司 | Process for producing 3,5-dimethyl bromobenzene |
| CN101928224A (en) * | 2009-06-18 | 2010-12-29 | 巨野金岭生物科技发展有限公司 | Method for preparing tribromoaniline by peroxide bromination method |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2001242468A1 (en) * | 2000-03-16 | 2001-09-24 | Basf Aktiengesellschaft | Method for producing 7-(pyrazole-3-yl) benzoxazoles |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3014972C2 (en) * | 1980-04-18 | 1984-11-22 | Chemische Fabrik Kalk GmbH, 5000 Köln | Process for the preparation of 2,4-dinitro-6-bromaniline |
| CN1136037A (en) * | 1996-03-01 | 1996-11-20 | 大连理工大学 | 2,6-dibromo-4-carboxysulfonateacyl aminobenzene and its synthesis |
| CN1357533A (en) * | 2001-07-23 | 2002-07-10 | 昆山双鹤药业有限责任公司 | Prepn. of 2,6-dibromo aniline |
| CN101492343A (en) * | 2008-12-30 | 2009-07-29 | 中钢集团鞍山热能研究院有限公司 | Process for producing 3,5-dimethyl bromobenzene |
| CN101928224A (en) * | 2009-06-18 | 2010-12-29 | 巨野金岭生物科技发展有限公司 | Method for preparing tribromoaniline by peroxide bromination method |
Non-Patent Citations (2)
| Title |
|---|
| 一种温和的、选择性的芳胺单溴化反应;徐福培等;《化学试剂》;19861231(第06期);第375页左栏第1段和第374页右栏产物（III）反应式 * |
| 一种温和的、选择性的芳胺单溴化反应;徐福培等;《化学试剂》;19861231;第8卷(第6期);第375页左栏第1段和第374页右栏产物（III）反应式 * |
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