CN103224452A - 2-bromine-4,6-dichloroaniline preparation method - Google Patents
2-bromine-4,6-dichloroaniline preparation method Download PDFInfo
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- CN103224452A CN103224452A CN2012100206185A CN201210020618A CN103224452A CN 103224452 A CN103224452 A CN 103224452A CN 2012100206185 A CN2012100206185 A CN 2012100206185A CN 201210020618 A CN201210020618 A CN 201210020618A CN 103224452 A CN103224452 A CN 103224452A
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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, a kind of critical materials of particularly medical KCNQ potassium ion channel modulators (formula I) is a 2-bromo-4, the preparation method of 6-dichlorphenamide bulk powder (formula II).
Background technology
Ionic channel is the protein of control ion turnover cell, and they extensively are present on the various cytolemma, have the selection perviousness.It is the basis of nerve, muscle and other cell membranes in tissue excitement, also is the basis of bioelectric.The Kai Heguan of ionic channel makes neurocyte produce the nerve impulse relevant with electricity.Scientist knows, multiple disease-relateds such as ionic channel and epilepsy, parkinsonism, and be the only way which must be passed that toxin and many medicines work.
Potassium-channel is the maximum class ionic channel of type up to now, and they are distributed in skeletal muscle, nerve widely.They not only participate in the adjusting of the many important physiological function of body, and also have vital role in some diseases.
Bromo-4, the 6-dichlorphenamide bulk powder, be a kind of important pharmaceutical-chemical intermediate, be the critical materials of preparation KCNQ potassium ion channel modulators.
Ⅰ Ⅱ
2-bromo-4,6-dichlorphenamide bulk powder KCNQ potassium ion channel modulators
At reference " chemical reagent ", 8 (6), 374-5; In 1986, be raw material with 2,4 dichloro aniline (formula III), obtain target compound through the NBS bromo, its reaction process is shown below:
Ⅲ Ⅰ
2,4 dichloro aniline 2-bromo-4, the 6-dichlorphenamide bulk powder
In this method, 2,4 dichloro aniline and N-bromo-succinimide (NBS) bromination reaction obtain 2-bromo-4, the 6-dichlorphenamide bulk powder.Then, reaction mass is poured in the water, obtained 2-bromo-4,6-dichlorphenamide bulk powder crude product carries out recrystallization with crude product and obtains target product.This preparation method's outstanding feature is the transformation efficiency height, has reached 100%, has avoided too much separation to purify.Reaction has used the higher relatively NBS of price to do bromide reagent, again because the solvent DMF that reaction is used reclaims difficulty, causes that cost is high, the industrialization difficulty is big.
The contriver studies above-mentioned preparation method, finds the significant disadvantages that this preparation method exists: (1) bromide reagent NBS price height; (2) use a large amount of high boiling solvents in the reaction, difficult solvent recovery, therefore whole technology cost height does not have the value of industrial implementation.
Summary of the invention
The technical problem to be solved in the present invention provides a kind of 2-bromo-4, the preparation method of 6-dichlorphenamide bulk powder.This preparation method can overcome in the existing method and exists the cost height to be difficult for the problem of industrial implementation, 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, and for being raw material with the 2,4 dichloro aniline, concrete technology may further comprise the steps in the method for 6-dichlorphenamide bulk powder:
Bromination reaction: add 2,4 dichloro aniline, reaction solvent in the reaction flask, 10～50 ℃ add bromide reagent down, insulation reaction 5～20h, to 2-bromo-4, the 6-dichlorphenamide bulk powder stops heating when not having increase, continue to stir decrease temperature crystalline, filter and obtain structural formula I compound, yield 97.5～98.5%.
Ⅱ Ⅰ
In above-mentioned preparation method, the bromide reagent that adopts in the bromination reaction is N-bromo-succinimide, liquid bromine, Hydrogen bromide-hydrogen peroxide, Hydrogen bromide-clorox, Hydrogen bromide-sodium bromate, preferred Hydrogen bromide-hydrogen peroxide; Wherein Fan Ying solvent is water, methyl alcohol, ethanol, Virahol or propyl carbinol, preferably water.
The inventor finds in research process, adopts low-cost Hydrogen bromide-hydrogen peroxide to carry out bromination reaction, and reaction conversion ratio also can reach the level of former document: 100%.Reaction process water or alcohol are done reaction solvent, reaction finishes, target product is directly separated out from reaction solvent, obtain the target product of content more than 99% behind the suction filtration, mother liquor directly cover is used in the bromo-reaction, avoid needing in the former technology to handle the problem of a large amount of DMF aqueous solution, reduced the crude product recrystallization operation in the former technology, do not needed distillating recovering solvent.Simultaneously, in former document method, reaction is a solvent with high boiling point DMF, reaction finishes, mixture is poured in the water, product with the solid form from mixture, separate out, suction filtration collects, and mother liquor is the mixture of DMF and water and the undecomposed product that wherein contains, crude product recrystallization use acetate water or ethanol water mixed crystallization.Because DMF and acetate not only boiling point are high but also dissolve each other with water, are difficult to various compositions in this part solution are carried out efficient recovery, directly cause the pollution and the high energy consumption of significant loss, environment.And in the method for the present invention, use the relatively cheap Hydrogen bromide-hydrogen peroxide bromide reagent of price in reaction process, do not use high boiling solvent in entire reaction and the last handling process simultaneously, reaction mother liquor can directly overlap uses bromination reaction, not only make the product ultimate yield higher, and avoided solvent recuperation, had characteristics simple to operate, that cost is low.
Outstanding feature of the present invention is: (1) has used relatively cheap bromide reagent, does not use high boiling solvent in the reaction process, and post-reaction treatment mother liquor directly cover is used in the reaction, the reaction yield height, and cost is low, the no three wastes; (2) simple to operate, be easy to industrializing implementation.
Embodiment
Embodiment 1:2-bromo-4, the preparation of 6-dichlorphenamide bulk powder
In the 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 ℃ of dropping hydrogen peroxide, is incubated 10-50 ℃ of reaction 10h, stop reaction, stir cooling, solid is separated out, suction filtration, obtain the pale solid powder, oven dry obtains 47.0g, content: 99.7%, and yield 97.8%.
Embodiment 2:2-bromo-4, the preparation of 6-dichlorphenamide bulk powder
In the 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 ℃ of dropping hydrogen peroxide, is incubated 10-50 ℃ of reaction 10h, stop reaction, stir cooling, solid is separated out, suction filtration, obtain the pale solid powder, oven dry obtains 47.1g, content: 99.8%, and yield 98.1%.
Claims (6)
1. one kind prepares 2-bromo-4, and the method for 6-dichlorphenamide bulk powder is characterized in that, is raw material with the 2,4 dichloro aniline, the process following steps:
Bromination reaction: add 2,4 dichloro aniline, reaction solvent in the reaction flask, 10～50 ℃ add bromide reagent down, insulation reaction 5～20h,, to 2-bromo-4, the 6-dichlorphenamide bulk powder stops heating when not having increase, continue to stir decrease temperature crystalline, filters and obtains structural formula I compound.
2. one kind is carried out the method that bromo prepares structural formula I compound with structural formula II compound, it is characterized in that: structural formula II compound, after bromide reagent mixes, 10～50 ℃ add reaction solvent down, insulation reaction 5～20h, when structural formula I compound has increase, do not stop heating, continue to stir decrease temperature crystalline, filter and obtain structural formula I compound.
3. preparation method according to claim 2, wherein bromide reagent is N-bromo-succinimide, liquid bromine, Hydrogen bromide-hydrogen peroxide, Hydrogen bromide-clorox, Hydrogen bromide-sodium bromate, preferred Hydrogen bromide-hydrogen peroxide.
4. method according to claim 2, wherein Fan Ying bromide reagent is Hydrogen bromide-hydrogen peroxide.
5. preparation method according to claim 2, wherein reaction solvent is water, methyl alcohol, ethanol, Virahol or propyl carbinol, preferably water.
6. method according to claim 2, wherein anti-solvent are water.
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| CN201210020618.5A CN103224452B (en) | 2012-01-30 | 2012-01-30 | 2-bromine-4,6-dichloroaniline preparation method |
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| CN201210020618.5A CN103224452B (en) | 2012-01-30 | 2012-01-30 | 2-bromine-4,6-dichloroaniline preparation method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020114813A1 (en) | 2018-12-04 | 2020-06-11 | Basf Se | Process for preparation of 5-bromo-1,3-dichloro-2-fluoro-benzene |
Citations (6)
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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 |
| US20030050477A1 (en) * | 2000-03-16 | 2003-03-13 | Cyrill Zagar | Method for producing 7-(pyrazole-3-yl) benzoxazoles |
| 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 |
-
2012
- 2012-01-30 CN CN201210020618.5A patent/CN103224452B/en active Active
Patent Citations (6)
| 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 |
| US20030050477A1 (en) * | 2000-03-16 | 2003-03-13 | Cyrill Zagar | Method for producing 7-(pyrazole-3-yl) benzoxazoles |
| 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 (1)
| Title |
|---|
| 徐福培等: "一种温和的、选择性的芳胺单溴化反应", 《化学试剂》, vol. 8, no. 06, 31 December 1986 (1986-12-31) * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020114813A1 (en) | 2018-12-04 | 2020-06-11 | Basf Se | Process for preparation of 5-bromo-1,3-dichloro-2-fluoro-benzene |
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