CN102260154A - Preparation method of pharmaceutical intermediate alpha-bromo-p-chloropropiophenone - Google Patents
Preparation method of pharmaceutical intermediate alpha-bromo-p-chloropropiophenone Download PDFInfo
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- CN102260154A CN102260154A CN2011101552284A CN201110155228A CN102260154A CN 102260154 A CN102260154 A CN 102260154A CN 2011101552284 A CN2011101552284 A CN 2011101552284A CN 201110155228 A CN201110155228 A CN 201110155228A CN 102260154 A CN102260154 A CN 102260154A
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Abstract
The invention discloses a preparation method of pharmaceutical intermediate alpha-bromo-p-chloropropiophenone. The alpha-bromo-p-chloropropiophenone is obtained by reacting raw materials of p-chloropropiophenone and liquid bromine in the presence of a catalyst. The preparation method disclosed by the invention, which is used for synthesizing the alpha-bromo-p-chloropropiophenone, has the advantages of simple separation and purification process, short reaction time, high product purity, product yield of more than 97%, less energy consumption, less environment pollution and low cost, and is a more ideal process for realizing industrial production.
Description
Technical field
The present invention relates to the alpha-brominated preparation method of a kind of medicine intermediate to chlorophenyl acetone.
Background technology
Rimonabant is a kind of novel diet pill, and alpha-brominated is the key intermediate of synthetic Rimonabant to chlorophenyl acetone, external few about the relevant report of this intermediate study on the synthesis at present, and domestic still do not have a report.Alpha-brominated is to be solvent with the Glacial acetic acid to the existing synthetic method of chlorophenyl acetone, chlorophenyl acetone and liquid bromine is reacted make under the condition of room temperature, and the purity of product is lower, wherein contains a large amount of isolating by products that is difficult to.Alpha-brominated molecular formula: C to chlorophenyl acetone
9H
8ClOBr, molecular weight: 247.5, molecular structural formula:
Physico-chemical property: outward appearance is the colourless crystallization solid, fusing point: 76-77 ℃.According to alpha-brominated structure to chlorophenyl acetone, synthetic method is improved, designed alpha-brominated synthesis route to chlorophenyl acetone, it is catalyzer that present method adopts metal halide, with to be that raw material is synthetic to chlorophenyl acetone alpha-brominatedly have good catalytic activity to chlorophenyl acetone, it is fast that this method has speed of response to the liquid bromine for this catalyzer, and the reaction times is short, reaction preference height, product yield and purity are all than higher.
Summary of the invention
The objective of the invention is in order to overcome above deficiency, a kind of product yield height, less energy consumption, environmental pollution is little, cost the is low alpha-brominated preparation method to chlorophenyl acetone of medicine intermediate are provided.
The present invention is achieved through the following technical solutions: the alpha-brominated preparation method to chlorophenyl acetone of a kind of medicine intermediate, be being main raw material to chlorophenyl acetone, liquid bromine, under the condition of solvent and catalyzer existence, carry out bromination reaction, reaction finishes the back distilling off solvent, surplus solution washes with water, adds refining solvent and dissolves, again cooling, crystallization is filtered to such an extent that purified is alpha-brominated to the chlorophenyl acetone product.
Further improvement of the present invention is: to chlorophenyl acetone, liquid bromine, solvent, catalyst consumption ratio be by mass: 1:0.45-1.25:0.9-2.1:0.01-0.15.
Further improvement of the present invention is: solvent is Glacial acetic acid or methylene dichloride or ether, is preferably methylene dichloride.
Further improvement of the present invention is: refining solvent is dehydrated alcohol or anhydrous methanol or benzene, is preferably dehydrated alcohol.
Further improvement of the present invention is: catalyzer is cupric bromide or aluminum trichloride (anhydrous) or alchlor or boron trifluoride or iron trichloride or ferric bromide, be preferably the mixture of cupric bromide and aluminum trichloride (anhydrous), the usage ratio of aluminum trichloride (anhydrous), cupric bromide is by mass: 1:0.05-0.2.
Further improvement of the present invention is: the temperature of bromination reaction is 5-20 ℃, and the time of bromination reaction is 1.5-5.5h.
The present invention compared with prior art has the following advantages: the present invention is synthetic alpha-brominated to chlorophenyl acetone, it is simple to separate purification process, reaction times is short, product purity is higher, product yield reaches more than 97%, less energy consumption, and environmental pollution is little, cost is low, is the comparatively ideal technology that realizes suitability for industrialized production.
Embodiment:
In order to deepen the understanding of the present invention, the invention will be further described below in conjunction with embodiment, and following examples only are used to explain the present invention, do not constitute the qualification to protection domain of the present invention.
The alpha-brominated preparation method of medicine intermediate to chlorophenyl acetone, be with to chlorophenyl acetone, the liquid bromine is a main raw material, the solvent of bromination reaction is Glacial acetic acid or methylene dichloride or ether, be preferably methylene dichloride, under the condition that catalyzer exists, carry out bromination reaction, catalyzer is cupric bromide or aluminum trichloride (anhydrous) or alchlor or boron trifluoride or iron trichloride or ferric bromide, be preferably the mixture of cupric bromide and aluminum trichloride (anhydrous), aluminum trichloride (anhydrous), the usage ratio of cupric bromide is by mass: 1:0.05-0.2, to chlorophenyl acetone, the liquid bromine, solvent, the catalyst consumption ratio is by mass: 1:0.45-1.25:0.9-2.1:0.01-0.15, the temperature of bromination reaction is 5-20 ℃, the time of bromination reaction is 1.5-5.5h, and reaction finishes the back distilling off solvent, and surplus solution washes with water, refining solvent is dehydrated alcohol or anhydrous methanol or benzene, be preferably dehydrated alcohol, add refining solvent and dissolve, again cooling, crystallization is filtered to such an extent that purified is alpha-brominated to the chlorophenyl acetone product.
Embodiment 1:
In the four-hole reaction flask of electric mixer, reflux exchanger and thermometer is housed, add the liquid bromine of 33.7g, the solvent of 50.0g, the catalyzer of 0.75g successively to chlorophenyl acetone, 16.8g, load onto reflux condensing tube, thermometer, start agitator, when temperature is controlled to be 15 ℃, pick up counting reaction times 2.5h.Reaction finishes the back distilling off solvent, and surplus solution washes with water, and add refining solvent and dissolve, cooling again, crystallization is filtered to such an extent that purified is alpha-brominated to the chlorophenyl acetone product, alpha-brominated the chlorophenyl acetone yield is reached 97.13%, and fusing point is 76-77 ℃.
Embodiment 2:
In the four-hole reaction flask of electric mixer, reflux exchanger and thermometer is housed, add the liquid bromine of 33.7g, the solvent of 50.0g, the catalyzer of 0.75g successively to chlorophenyl acetone, 19.2g, load onto reflux condensing tube, thermometer, start agitator, when temperature is controlled to be 15 ℃, pick up counting reaction times 2.5h.Reaction finishes the back distilling off solvent, and surplus solution washes with water, and add refining solvent and dissolve, cooling again, crystallization is filtered to such an extent that purified is alpha-brominated to the chlorophenyl acetone product, alpha-brominated the chlorophenyl acetone yield is reached 97.85%, and fusing point is 76-77 ℃.
Embodiment 3:
In the four-hole reaction flask of electric mixer, reflux exchanger and thermometer is housed, add the liquid bromine of 33.7g, the solvent of 50.0g, the catalyzer of 0.75g successively to chlorophenyl acetone, 26.9g, load onto reflux condensing tube, thermometer, start agitator, when temperature is controlled to be 15 ℃, pick up counting reaction times 2.5h.Reaction finishes the back distilling off solvent, and surplus solution washes with water, and add refining solvent and dissolve, cooling again, crystallization is filtered to such an extent that purified is alpha-brominated to the chlorophenyl acetone product, alpha-brominated the chlorophenyl acetone yield is reached 98.08%, and fusing point is 76-77 ℃.
Embodiment 4:
In the four-hole reaction flask of electric mixer, reflux exchanger and thermometer is housed, add the liquid bromine of 33.7g, the solvent of 50.0g, the catalyzer of 1.4g successively to chlorophenyl acetone, 16.8g, load onto reflux condensing tube, thermometer, start agitator, when temperature is controlled to be 15 ℃, pick up counting reaction times 2.5h.Reaction finishes the back distilling off solvent, and surplus solution washes with water, and add refining solvent and dissolve, cooling again, crystallization is filtered to such an extent that purified is alpha-brominated to the chlorophenyl acetone product, alpha-brominated the chlorophenyl acetone yield is reached 97.57%, and fusing point is 76-77 ℃.
Embodiment 5:
In the four-hole reaction flask of electric mixer, reflux exchanger and thermometer is housed, add the liquid bromine of 33.7g, the solvent of 50.0g, the catalyzer of 1.68g successively to chlorophenyl acetone, 17.2g, load onto reflux condensing tube, thermometer, start agitator, when temperature is controlled to be 15 ℃, pick up counting reaction times 2.5h.Reaction finishes the back distilling off solvent, and surplus solution washes with water, and add refining solvent and dissolve, cooling again, crystallization is filtered to such an extent that purified is alpha-brominated to the chlorophenyl acetone product, alpha-brominated the chlorophenyl acetone yield is reached 98.15%, and fusing point is 76-77 ℃.
The present invention is synthetic alpha-brominated to chlorophenyl acetone, and it is simple to separate purification process, and the reaction times is short, and product purity is higher, and product yield reaches more than 97%, less energy consumption, and environmental pollution is little, and cost is low, is the comparatively ideal technology that realizes suitability for industrialized production.
Claims (7)
1. alpha-brominated preparation method of medicine intermediate to chlorophenyl acetone, it is characterized in that: be being main raw material chlorophenyl acetone, liquid bromine, under the condition of solvent and catalyzer existence, carry out bromination reaction, reaction finishes the back distilling off solvent, surplus solution washes with water, adds refining solvent and dissolves, again cooling, crystallization is filtered to such an extent that purified is alpha-brominated to the chlorophenyl acetone product.
2. according to the alpha-brominated preparation method of the described medicine intermediate of claim 1, it is characterized in that: describedly be by mass: 1:0.45-1.25:0.9-2.1:0.01-0.15 chlorophenyl acetone, liquid bromine, solvent, catalyst consumption ratio to chlorophenyl acetone.
3. according to claim 1 or the alpha-brominated preparation method to chlorophenyl acetone of 2 described medicine intermediates, it is characterized in that: described solvent is Glacial acetic acid or methylene dichloride or ether.
4. according to the alpha-brominated preparation method to chlorophenyl acetone of each described medicine intermediate of claim 1-3, it is characterized in that: described refining solvent is dehydrated alcohol or anhydrous methanol or benzene.
5. according to the alpha-brominated preparation method to chlorophenyl acetone of each described medicine intermediate of claim 1-4, it is characterized in that: described catalyzer is cupric bromide or aluminum trichloride (anhydrous) or alchlor or boron trifluoride or iron trichloride or ferric bromide.
6. according to the alpha-brominated preparation method to chlorophenyl acetone of the described medicine intermediate of claim 1, it is characterized in that: the temperature of described bromination reaction is 5-20 ℃.
7. according to the alpha-brominated preparation method to chlorophenyl acetone of the described medicine intermediate of claim 1, it is characterized in that: the time of described bromination reaction is 1.5-5.5h.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103483173A (en) * | 2013-09-24 | 2014-01-01 | 河南海汇药物研究有限公司 | Preparation method for intermediate (namely 1-(4-benzyloxy-phenyl)-2-bromo-propan-1-one) for bazedoxifene acetate |
| CN110526808A (en) * | 2018-05-25 | 2019-12-03 | 河南仁华生物科技有限公司 | A kind of medicine intermediate and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1767529A1 (en) * | 2004-06-09 | 2007-03-28 | Sumitomo Chemical Company, Limited | Pyridazine compound and use thereof |
| CN101495458A (en) * | 2006-05-23 | 2009-07-29 | 拜耳医药保健股份公司 | Substituted arylimidazolone and triazolone as inhibitors of vasopressin receptors |
-
2011
- 2011-06-10 CN CN2011101552284A patent/CN102260154A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1767529A1 (en) * | 2004-06-09 | 2007-03-28 | Sumitomo Chemical Company, Limited | Pyridazine compound and use thereof |
| CN101495458A (en) * | 2006-05-23 | 2009-07-29 | 拜耳医药保健股份公司 | Substituted arylimidazolone and triazolone as inhibitors of vasopressin receptors |
Non-Patent Citations (2)
| Title |
|---|
| 《化学世界》 20031231 张竞等 溴素法alpha-溴代间氯苯丙酮合成研究 91-93 5 , 第2期 * |
| 张竞等: "溴素法α-溴代间氯苯丙酮合成研究", 《化学世界》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103483173A (en) * | 2013-09-24 | 2014-01-01 | 河南海汇药物研究有限公司 | Preparation method for intermediate (namely 1-(4-benzyloxy-phenyl)-2-bromo-propan-1-one) for bazedoxifene acetate |
| CN110526808A (en) * | 2018-05-25 | 2019-12-03 | 河南仁华生物科技有限公司 | A kind of medicine intermediate and preparation method thereof |
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Application publication date: 20111130 |