CN102643162B - A method for preparing 1-(2-chlorophenyl)-2-(4-fluorophenyl) propylene - Google Patents
A method for preparing 1-(2-chlorophenyl)-2-(4-fluorophenyl) propylene Download PDFInfo
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- CN102643162B CN102643162B CN201110041189.5A CN201110041189A CN102643162B CN 102643162 B CN102643162 B CN 102643162B CN 201110041189 A CN201110041189 A CN 201110041189A CN 102643162 B CN102643162 B CN 102643162B
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Abstract
The invention belongs to organic synthesis field, discloses a method for preparing 1-(2-chlorophenyl)-2-(4-fluorophenyl) propylene, comprises the following reaction steps that: (1). 2-chlorobenzylphosphodiester is prepared by the stirring reaction of 2-cyanobenzylchloride and sulphite under backflow state; (2). 1-(2- chlorophenyl)-2-(4- fluorophenyl) propylene is prepared by the reaction of 2-chlorobenzylphosphodiester and 4-fluoroacetophenone; wherein, the step 2 uses N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone, 1,4-dioxane or acetonitrile and other polar solvent as the catalyst and undergoes reaction under highly basic condition. The preparation method of the invention has advantages of simple operation, mild condition, adequate product quality and high yield, and is suitable for industrialization popularization and application.
Description
Technical field
The invention belongs to organic synthesis field, relate to the method that one is prepared 1-(2-chloro-phenyl-)-2-(4-fluorophenyl) propylene.
Background technology
Epoxiconazole (epoxiconazole; trade(brand)name Europe despot) be the wide-spectrum bactericide with preventive and therapeutic action of BASF Aktiengesellschaft's nineteen eighty-three exploitation; not only there is good protection, treat and roots out activity; but also there is interior suction and residual activity preferably; be widely used in cash crop, almost can prevent and treat all fungal diseases.
The production of epoxiconazole mainly adopts the synthetic method of US Patent No. 50812317A report, in the method reaction process, uses Grignard reagent, emits a large amount of hydrogen in reaction process, higher to the safety requirements in workshop.In Chinese patent application CN101513183A, disclose a kind of new synthetic route, 1-(2-chloro-phenyl-)-2-(4-fluorophenyl) propylene is an important intermediate in this synthetic route.But the product yield that in specification sheets, disclosed preparation method obtains and quality all can not be satisfactory.
Summary of the invention
In order to meet the needs of preparing epoxiconazole in suitability for industrialized production, the present invention is devoted to develop a kind of yield and purity is higher and the cost lower method of preparing 1-(2-chloro-phenyl-)-2-(4-fluorophenyl) propylene again.With crossing a large amount of intensive research, the present invention proposes the technical scheme of a kind of new preparation 1-(2-chloro-phenyl-)-2-(4-fluorophenyl) propylene.
Technical scheme of the present invention is as follows:
One is prepared the method for 1-(2-chloro-phenyl-)-2-(4-fluorophenyl) propylene, comprises following reactions steps: 1). and adjacent chlorobenzyl chloride and phosphorous acid ester stirring reaction under reflux state is prepared o-chlorobenzyl phosphonic acid diester; 2). o-chlorobenzyl phosphonic acid diester with fluoro acetophenone is reacted to preparation 1-(2-chloro-phenyl-)-2-(4-fluorophenyl) propylene.Reaction formula is as follows:
In formula: R represent methylidene or ethyl.
The 1st) phosphorous acid ester that step is reacted used is selected from trimethyl phosphite or triethyl-phosphite; The consumption of phosphorous acid ester with the 1-3 that mole counts adjacent chlorobenzyl chloride doubly.React complete, reclaim excessive phosphorous acid ester, obtain o-chlorobenzyl phosphonic acid diester; The judgement of reaction end: the adjacent chlorobenzyl chloride of sampling analysis reacts completely.Reclaim excessive phosphorous acid ester and conventionally adopt distillation mode, this is that those skilled in the art is known.
The 2nd) in step reaction process, contriver finds first, using polar solvent as catalyzer, carry out under strong alkaline condition, can obtain best reaction effect.The suitable mol ratio of the consumption of reacting middle catalyst and o-chlorobenzyl phosphonic acid diester is 1: 0.5-5.
By the screening to a large amount of polar solvents, applicant has determined preferably as the 2nd) catalyzer of step reaction is selected from N, dinethylformamide (DMF), N, N-N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO) (DMSO), N-Methyl pyrrolidone, Isosorbide-5-Nitrae-dioxane or acetonitrile.
The 2nd), in step reaction, the consumption of o-chlorobenzyl phosphonic acid diester to be mole to count to the 1-1.5 of fluoro acetophenone doubly, temperature of reaction 0-50 DEG C, and reaction times 2-24 hour, reaction solvent is selected from benzene, toluene or dimethylbenzene.React alkali used and be selected from the alkali metal hydroxides such as the basic metal alkoxyl group things such as sodium methylate, sodium ethylate, sodium tert-butoxide and sodium hydroxide, potassium hydroxide, alkali-metal add-on be 2-5 to the mol ratio of fluoro acetophenone: 1.Concrete operations are: by o-chlorobenzyl phosphonic acid diester with fluoro acetophenone is joined in reaction solvent, under strong alkaline condition, under the effect of catalyzer, carry out Wei Tixi-Huo Nan (Wittig-Horner) reaction.The judgement of reaction end: fluoro acetophenone is reacted completely.After reaction finishes, washing, precipitation, obtain target product 1-(o-chlorobenzyl)-2-(4-fluorophenyl)-1-propylene.
Further preferred catalyzer is selected from DMF, dimethyl sulfoxide (DMSO) or N-Methyl pyrrolidone.
Preparation method provided by the invention, easy and simple to handle, mild condition, suitability for industrialized is applied, and reacting raw materials used and reagent all has commercially availablely, and product yield and content all can reach more than 94%.
Preparation method of the present invention has following beneficial effect:
1. owing to adopting trialkyl phosphite to substitute the triphenyl phosphorus of reporting in prior art, can reduce raw materials cost, and alleviate the impact on environment;
2. the 2nd) add suitable catalyzer in step reaction, the reaction times is shortened more than 4 hours, improve equipment capacity;
High yield, obtain 1-(o-chlorobenzyl)-2-(4-fluorophenyl)-1-propylene in high quality, meet the needs of suitability for industrialized production epoxiconazole.
Embodiment
Following examples are used for further illustrating the present invention, but the present invention only limits to absolutely not this.
Embodiment 1
Adjacent chlorobenzyl chloride 161g (1mol), phosphonous acid triethyl 249g (1.5mol) add in the there-necked flask of 500ml, be warming up to backflow, and continue to reflux, temperature is raised to 170～180 DEG C, react (when the adjacent chlorobenzyl chloride of sampling analysis has reacted) decompression in 12 hours and slough excessive phosphonous acid triethyl, obtain o-chlorobenzyl diethyl phosphonate 255g, content 95%, yield 97%.
Embodiment 2
Adjacent chlorobenzyl chloride 161g (1mol), phosphonous acid trimethyl 186g (1.5mol) add in the there-necked flask of 500ml, be warming up to backflow, and continue to reflux, temperature is raised to 170～180 DEG C, react (when the adjacent chlorobenzyl chloride of sampling analysis has reacted) decompression in 12 hours and slough excessive phosphonous acid trimethyl, obtain o-chlorobenzyl dimethyl phosphonate 218g, content 95.5%, yield 97%.
Embodiment 3
Potassium hydroxide 218g (3.9mol), toluene 1000ml, DMF 95g add in 2000ml there-necked flask, (lower with) o-chlorobenzyl diethyl phosphonate 349 (1.33mol) that adds prepared by embodiment 1 under stirring and to fluoro acetophenone 180g (1.3mol, content 98%), in 20～30 DEG C of stirring reactions 12 hours, it is complete that gas-chromatography is followed the tracks of reaction, add 400ml water, stir layering.Organic layer underpressure distillation is sloughed after solvent, obtains 1-(o-chlorobenzyl)-2-(4-fluorophenyl)-1-propylene 305g, content 96%, yield 95%.
Embodiment 4
Sodium hydroxide 156g (3.9mol), toluene 1000ml, DMSO 95g add in the there-necked flask of 2000ml, under stirring, add o-chlorobenzyl dimethyl phosphonate 317 (1.33mol) and to fluoro acetophenone 180g (1.3mol, 98%), in 20～30 DEG C of stirring reactions 12 hours, it is complete that gas-chromatography is followed the tracks of reaction, add 400ml water to stir, layering.Organic layer underpressure distillation is sloughed after solvent, obtains 1-(o-chlorobenzyl)-2-(4-fluorophenyl)-1-propylene 304.4g, content 94.5%, yield 94.8%.
Embodiment 5
Potassium hydroxide 218g (3.9mol), toluene 1000ml, N-Methyl pyrrolidone 95g add in 2000ml there-necked flask, under stirring, add o-chlorobenzyl diethyl phosphonate 349 (1.33mol) and to fluoro acetophenone 180g (1.3mol, content 98%), in 20～30 DEG C of stirring reactions 12 hours, it is complete that gas-chromatography is followed the tracks of reaction, add 400ml water, stir layering.Organic layer underpressure distillation is sloughed after solvent, obtains 1-(o-chlorobenzyl)-2-(4-fluorophenyl)-1-propylene 304.5g, content 96.5%, yield 94.8%.
Embodiment 6
Potassium hydroxide 218g (3.9mol), benzene 1000ml, DMF 200g add in the there-necked flask of 2000ml, start to stir, add o-chlorobenzyl diethyl phosphonate 349 (1.33mol) and to fluoro acetophenone 180g (1.3mol, 98%), stirring reaction 12 hours at 20～30 DEG C of temperature, it is complete that gas-chromatography is followed the tracks of reaction, add 400ml water to stir, then layering, organic layer is sloughed solvent, obtain 1-(o-chlorobenzyl)-2-(4-fluorophenyl)-1-propylene 306g, content 96.0%, yield 95.3%.
Claims (1)
1. prepare the method for 1-(2-chloro-phenyl-)-2-(4-fluorophenyl) propylene for one kind, comprise following reactions steps: 1). adjacent chlorobenzyl chloride and phosphorous acid ester stirring reaction under reflux state is prepared o-chlorobenzyl phosphonic acid diester, 2). o-chlorobenzyl phosphonic acid diester with fluoro acetophenone is reacted to preparation 1-(2-chloro-phenyl-)-2-(4-fluorophenyl) propylene; It is characterized in that: the 2nd) step is reacted using polar solvent as catalyzer, under strong alkaline condition, carried out, and the mol ratio of the consumption of catalyzer and o-chlorobenzyl phosphonic acid diester is 1:0.5-5;
Described catalyzer is selected from DMF, dimethyl sulfoxide (DMSO), N-Methyl pyrrolidone;
The 1st) in step reaction, phosphorous acid ester used is selected from trimethyl phosphite or triethyl-phosphite; The consumption of phosphorous acid ester with the 1-3 that mole counts adjacent chlorobenzyl chloride doubly;
The 2nd) in step reaction the consumption of o-chlorobenzyl phosphonic acid diester mole to count to the 1-1.5 of fluoro acetophenone doubly, temperature of reaction 0-50 DEG C, reaction times 2-24 hour, reaction solvent is selected from benzene, toluene or dimethylbenzene;
The 2nd) alkali that step is reacted used is selected from sodium methylate, sodium ethylate, sodium tert-butoxide, sodium hydroxide or potassium hydroxide.
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| CN103145526B (en) * | 2012-11-29 | 2015-05-13 | 江苏长青农化股份有限公司 | Ultrasonic synthetic method of fungicide epoxiconazole intermediate 1- (2-chlorphenyl)-2-(4-fluorophenyl) propylene |
| CN112661599B (en) * | 2021-01-25 | 2022-10-04 | 浙江工业大学 | Synthesis method of (Z) -3-halogenated-2- (4-fluorophenyl) -1- (2-chlorphenyl) propylene |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1680404A (en) * | 2005-01-20 | 2005-10-12 | 申厚宝 | Production of o-chlorobenzyl dimethyl phosphonate |
| CN101513183A (en) * | 2008-02-18 | 2009-08-26 | 北京绿色农华植保科技有限责任公司 | Method for preparing stable epoxiconazole raw drug |
| WO2010089353A1 (en) * | 2009-02-05 | 2010-08-12 | Basf Se | Method for producing hydroxymethyl diphenyloxiranes and corresponding 1-azolylmethyl-1,2-diphenyloxiranes |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1680404A (en) * | 2005-01-20 | 2005-10-12 | 申厚宝 | Production of o-chlorobenzyl dimethyl phosphonate |
| CN101513183A (en) * | 2008-02-18 | 2009-08-26 | 北京绿色农华植保科技有限责任公司 | Method for preparing stable epoxiconazole raw drug |
| WO2010089353A1 (en) * | 2009-02-05 | 2010-08-12 | Basf Se | Method for producing hydroxymethyl diphenyloxiranes and corresponding 1-azolylmethyl-1,2-diphenyloxiranes |
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Effective date of registration: 20160128 Address after: 110021 Liaodong Road, Tiexi District, Liaoning, No. 8-1, No. Patentee after: SHENYANG SINOCHEM PESTICIDE CHEMICAL RESEARCH AND DEVELOPMENT CO., LTD. Address before: 100031 Beijing, Xicheng District, the door of the revitalization of the main street, No. 28 Patentee before: Sinochem Corporation Patentee before: Shenyang Research Institute of Chemical Industry |