CN101774946A - Method for preparing para methoxy phenyl acetonitrile - Google Patents
Method for preparing para methoxy phenyl acetonitrile Download PDFInfo
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- CN101774946A CN101774946A CN200910201165A CN200910201165A CN101774946A CN 101774946 A CN101774946 A CN 101774946A CN 200910201165 A CN200910201165 A CN 200910201165A CN 200910201165 A CN200910201165 A CN 200910201165A CN 101774946 A CN101774946 A CN 101774946A
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Abstract
The invention relates to a method for preparing para methoxy phenyl acetonitrile, which comprises the following steps: firstly adopting p-methoxybenzaldehyde as the raw material to generate anisyl alcohol under the action of a reducing agent; after drying the obtained reaction product, carrying out chlorination on the dried reaction product by thionyl chloride to obtain benzyl chloride; and carrying out cyanoethylation reaction on the obtained benzyl chloride under the alkaling conndition and under the action of a phase transfer catalyst to obtain the para methoxy phenyl acetonitrile, wherein the total yield of the para methoxy phenyl acetonitrile reaches over 85 percent.
Description
Technical field
The present invention relates to the pharmaceutical intermediate synthesis technical field, be specifically related to a kind of technical field by the synthetic nitrile of aldehydes.
Background technology
PARA METHOXY PHENYL ACETONITRILE is mainly used in synthetic medicine, and Chemicals such as agricultural chemicals are a kind of important organic intermediates.PARA METHOXY PHENYL ACETONITRILE synthetic has several different methods.Reported in literature has been arranged directly synthesized PARA METHOXY PHENYL ACETONITRILE with aubepine, Journal of the Chemical Society wherein, Perkin Transactions 1:Organic and Bio-OrganicChemistry (1972-1999), (11), 2635-40; 1984 have reported directly synthetic with triphenyl phosphorus, but the yield in the document is lower than 50%, Synthetic Communications, 10 (5), 399-403; 1980 have reported directly synthetic, but the yield that document is reported has only 70%.While document Tetrahedron Letters, 49 (45), 6475-6479; 2008 have also reported earlier and have reduced, carry out cyanation again, but its reduction is to make catalyzer with ruthenium element, earlier aubepine is carried out hydrogenating reduction, yield carries out nitrilation to base again 96%, yield is 82%, two step yields altogether have only 78.7%, but wherein use precious metal, but also need carry out reaction under high pressure.Huaxue Fanying Gongcheng Yu Gongyi, 21 (2), 181-185; 2005 have reported with methyl-phenoxide and have carried out direct chloromethylation earlier, carry out nitrilation again, carry out twice rectifying at last and obtain product.Yield has only 34.8%.This chloromethylation wherein has the adjacent by product to produce, and will lead to hydrogen chloride gas in the experiment.Though wanting cheaply with aubepine of raw material ratio, the operability and the yield of reaction all get more than the indirect method difference.
Summary of the invention
In view of the defective that present PARA METHOXY PHENYL ACETONITRILE synthetic method exists, the invention provides a kind of easy and simple to handle, cost is low, yield is high, reaction conditions is easy to realize and less to ecological environmental pollution, is convenient to the method for suitability for industrialized production PARA METHOXY PHENYL ACETONITRILE.
PARA METHOXY PHENYL ACETONITRILE preparation method of the present invention comprises the steps:
Step a aubepine with go back original reagent generation reduction reaction, common agents is used in this reaction, obtains corresponding alcohols;
The benzylalcohol that step b will obtain above reacts with thionyl chloride in solvent, obtains intermediate benzyl chlorine;
Step c under the phase-transfer catalyst effect, in alkaline condition reaction down, obtains the crude product of PARA METHOXY PHENYL ACETONITRILE with the intermediate benzyl chlorine that makes and sodium cyanide.
Above-mentioned reaction scheme is as follows:
Step a of the present invention obtains benzylalcohol going back under the original reagent effect reduction aubepine, and temperature of reaction is controlled to be made as 5～80 ℃, and the reaction times is 2～15 hours, after reacting completely, carries out the separatory extraction, obtains organic phase.The original reagent of going back that this reaction is adopted can be POTASSIUM BOROHYDRIDE, sodium borohydride, tetrahydrochysene lithium aluminium etc., and the solvent that this reaction is adopted can be methylene dichloride, ethylene dichloride, trichloromethane, tetracol phenixin etc. and other halogenated alkane class; The polysubstituted thing of the alkyl of benzene, toluene, ethylbenzene, dimethylbenzene, diethylbenzene and other benzene; In the ester class that ethyl formate, ethyl acetate, propyl acetate, butylacetate etc. are used always one or more.
Step b is the organic phase that will obtain above, be directly used in chlorination, temperature of reaction is controlled to be made as 5～80 ℃, and the reaction times is 2～15 hours, and the solvent that this reaction is adopted can be methylene dichloride, ethylene dichloride, trichloromethane, tetracol phenixin etc. and other halogenated alkane class; The polysubstituted thing of alkyl of benzene, toluene, ethylbenzene, dimethylbenzene, diethylbenzene etc. and other benzene; In the ester class that ethyl formate, ethyl acetate, propyl acetate, butylacetate etc. are used always one or more.
Step c is the organic phase that step b is obtained, and is directly used in cyanation, and this reaction is under the phase-transfer catalyst effect, and in alkaline condition reaction down, temperature of reaction is controlled at 40～90 ℃.Reaction times is 2～10h, obtains product.The solvent that this reaction is adopted is water, alcohol-water mixture etc.In Tetrabutyl amonium bromide, benzyltriethylammoinium chloride, tetrabutylammonium iodide, tetraethylammonium bromide and other quaternary ammonium salt of used phase-transfer catalyst one or more, used alkali can be one or more in the mineral alkalis such as sodium hydroxide, potassium hydroxide.
The present invention has got rid of and has used expensive ruthenium catalyst, got rid of logical hydrogen chloride gas, simultaneously, the crude product purity that obtains is higher, just can obtain pure product as long as once subtract to steam, and has exempted the method that adopts repeatedly rectifying and just can obtain pure product, make that operation is easy, work simplification, reduced cost, and the total recovery of reaction also improves greatly, and yield 85%～95% is higher than 72% yield of prior art.Be applicable to suitability for industrialized production.
Embodiment
Further elaborate preparation method of the present invention by following example.
Example 1: the preparation of PARA METHOXY PHENYL ACETONITRILE:
The preparation of step a p-methoxybenzyl alcohol:
Get 136g (1mol) aubepine and join the 500ml there-necked flask, controlled temperature is got 19g (0.35mol) POTASSIUM BOROHYDRIDE and is dissolved in the 50ml water at 10～40 ℃, and solution of potassium borohydride is added drop-wise to wherein, uses the TLC endpoint detection.Reaction is finished, and adds the 200ml methylene dichloride, and separatory, water layer are used the 100ml dichloromethane extraction once again, merges organic phase.Organic phase is directly put into the next step, GC＞99% after adding anhydrous sodium sulfate drying.
Step b: to the preparation of methoxyl group benzyl chloride:
Above-mentioned organic phase is joined in the there-necked flask of 1000ml, between 20～50 ℃ of the control reaction temperature, get thionyl chloride 131g (1.1mol) and drip the TLC endpoint detection.Reaction is finished, and adds water 200ml, and separatory is used the 100ml dichloromethane extraction, merges organic phase.Wash with water to neutrality.Directly put among the next step GC＞96% then.
Step c: the preparation of PARA METHOXY PHENYL ACETONITRILE:
Get the there-necked flask of 1000ml, add 30%NaCN212g (1.3mol), add 13gNaOH then to wherein, in reactor, add TBAB13g again and be stirred to molten, the organic phase that the step makes in the disposable then adding.Temperature control is in 50～80 ℃ of reactions down.The TLC endpoint detection.Reaction is finished, and is cooled to room temperature, adds 200ml methylene dichloride and 200ml water then, stirs 15min, separatory.Water layer 100ml dichloromethane extraction merges organic phase, is washed to neutrality.Drying is spin-dried for solvent, obtains the 147.7g red liquid, crude product GC 95.4%.Crude product subtracts steaming in 135 ℃ and obtains 127.9g colourless liquid product under 5～10mmHg.Total recovery 87%.GC?99％。
Example 2: the preparation of PARA METHOXY PHENYL ACETONITRILE:
The preparation of step a p-methoxybenzyl alcohol:
Get 136g (1mol) aubepine and join the 500ml there-necked flask, controlled temperature is got 19g (0.35mol) POTASSIUM BOROHYDRIDE and is joined wherein in batches at 10～40 ℃, the temperature of control reaction in the process that in batches adds.Add water 200ml then, continue reaction, the TLC endpoint detection.Add the 200ml methylene dichloride and carry out separatory, water layer is used the 100ml dichloromethane extraction once again, merges organic phase.Drying is spin-dried for solvent, obtains the 138g product, GC＞99%.
Step b: to the preparation of methoxyl group benzyl chloride:
Above-mentioned product is joined in the there-necked flask of 1000ml, add the dissolving of 400ml methylene dichloride, between 20～50 ℃ of the control reaction temperature, get thionyl chloride 131g (1.1mol) and be added drop-wise in the reaction flask, speed, TLC endpoint detection are dripped in control.Reaction is finished, and adds water 200ml, and separatory is used 100ml dichloromethane extraction water simultaneously, merges organic phase.Wash with water to neutrality, directly put among the next step GC＞97% then.
Step c: the preparation of PARA METHOXY PHENYL ACETONITRILE:
Get the there-necked flask of 1000ml, add 30%NaCN212g (1.3mol), add 13gNaOH then to wherein, in reactor, add TEAB 13g again and be stirred to molten, the organic phase that the step makes in the disposable then adding, temperature control is in 50～80 ℃ of reactions down.The TLC endpoint detection.Reaction is finished, and is cooled to room temperature, adds 200ml methylene dichloride and 200ml water then, stirs 15min, separatory.Water layer with the 100ml dichloromethane extraction once merges organic phase, and organic phase is washed to neutrality.Add anhydrous sodium sulfate drying, be spin-dried for solvent, obtain the 145.3g red liquid, crude product GC 94.8%.Crude product subtracts steaming in 135 ℃ and obtains 125.1g colourless liquid product under 5～10mmHg.Total recovery 85%.GC?99％。
Example 3: the preparation of PARA METHOXY PHENYL ACETONITRILE:
Step a: the preparation of p-methoxybenzyl alcohol:
Get 136g (1mol) aubepine and join the 500ml there-necked flask, controlled temperature is got 13.2g (0.35mol) sodium borohydride and is dissolved in the 50ml water at 10～40 ℃, and above-mentioned drips of solution is added to wherein, continues reaction, the TLC endpoint detection.Add the 200ml methylene dichloride and carry out separatory, water layer is used the 100ml dichloromethane extraction again, merges organic phase.Drying is spin-dried for solvent, obtains the 138g product, GC＞99%.
Step b: to the preparation of methoxyl group benzyl chloride:
Product of last step is joined in the there-necked flask of 1000ml, add the dissolving of 400ml methylene dichloride, between 20～50 ℃ of the control reaction temperature, get thionyl chloride 131g (1.1mol) and be added drop-wise in the reaction flask, speed, TLC endpoint detection are dripped in control.Add water 200ml and destroy, separatory is used the dichloromethane extraction of 100ml simultaneously, merges organic phase.Be washed till neutrality.Directly put among the next step GC＞96% then.
Step c: the preparation of PARA METHOXY PHENYL ACETONITRILE:
Get the there-necked flask of 1000ml, add 30%NaCN212g (1.3mol), add 13gKOH then to wherein, in reactor, add TBAB 13g again and be stirred to molten, the organic phase that the step makes in the disposable then adding.Temperature control is in 50～80 ℃ of reactions down.The TLC endpoint detection.Reaction is finished, and is cooled to room temperature, adds 200ml methylene dichloride and 200ml water then, stirring, separatory.Water layer 100ml dichloromethane extraction merges organic phase, is washed to neutrality.Drying is spin-dried for solvent, obtains the 149.5g red liquid, crude product GC 96.2%.Crude product subtracts steaming in 135 ℃ and obtains 132.3g colourless liquid product under 5～10mmHg.Total recovery 90%.GC?99％。
Example 4: the preparation of PARA METHOXY PHENYL ACETONITRILE:
Step a: the preparation of p-methoxybenzyl alcohol:
Get 136g (1mol) aubepine and join the 500ml there-necked flask, add the dissolving of 400ml methylene dichloride, controlled temperature is at 10～40 ℃, get 11.3g (0.3mol) sodium borohydride and join wherein in batches, add about 2～3h, add water 200ml then, continue reaction, the TLC endpoint detection.Add the 200ml methylene dichloride and carry out separatory, water layer is used the 100ml dichloromethane extraction again, merges organic phase.Add anhydrous sodium sulfate drying, be spin-dried for solvent, obtain the 138g product, GC＞99%.
Step b: to the preparation of methoxyl group benzyl chloride:
Product of last step is joined in the there-necked flask of 1000ml, between 20～30 ℃ of the control reaction temperature, get thionyl chloride 131g (1.1mol) and dropwise join in the reaction flask, speed is dripped in control.Add and continue reaction, TLC endpoint detection.Add water 200ml, separatory is used the dichloromethane extraction water of 100ml simultaneously, merges organic phase.Wash with water to neutrality.Directly put among the next step GC＞95% then.
Step c: the preparation of PARA METHOXY PHENYL ACETONITRILE:
Get the there-necked flask of 1000ml, get 30%NaCN212g (1.3mol) and join wherein, add 13gKOH then, in reactor, add TEAB 13g again and be stirred to molten, the organic phase that the step makes in the disposable then adding.Temperature control is in 50～80 ℃ of reactions down.The TLC endpoint detection.Reaction is finished, and reduces to room temperature, adds 200ml methylene dichloride and water then, stirs 15min, separatory.Water layer with the 100ml dichloromethane extraction once merges organic phase, is washed to neutrality.Add anhydrous sodium sulfate drying, be spin-dried for solvent, obtain the 145.4g red oil, crude product HPLC 95.3%.Crude product subtracts steaming in 135 ℃ and obtains 126.4g colourless liquid product under 5～10mmHg.Total recovery 86%.HPLC?99％。
Claims (9)
1. the preparation method of PARA METHOXY PHENYL ACETONITRILE, its structural formula is as follows:
It is characterized in that this method may further comprise the steps:
Step a aubepine and reductive agent react, and common agents is used in this reaction, obtains p-methoxybenzyl alcohol;
Step b obtains p-methoxybenzyl alcohol and reacts with thionyl chloride in solvent, obtains intermediate benzyl chlorine;
Step c reacting in the presence of the phase-transfer catalyst, obtains PARA METHOXY PHENYL ACETONITRILE with intermediate benzyl chlorine and sodium cyanide under alkaline condition.
2. the method for claim 1 is characterized in that, the original reagent of going back among the step a is POTASSIUM BOROHYDRIDE, sodium borohydride, tetrahydrochysene lithium aluminium, red aluminium.The mol ratio 0.25～0.5: 1 of the consumption of original reagent and aubepine also.
3. the method for claim 1 is characterized in that, the solvent among the step a can be methylene dichloride, ethylene dichloride, trichloromethane, tetracol phenixin etc. and other halogenated alkane class; The polysubstituted thing of the alkyl of benzene, toluene, ethylbenzene, dimethylbenzene, diethylbenzene and other benzene; In the ester class that ethyl formate, ethyl acetate, propyl acetate, butylacetate etc. are used always one or more.
4. the method for claim 1 is characterized in that, the temperature of reaction of step a is 5 ℃～80 ℃, and the reaction times is 2～15 hours.
5. the method for claim 1 is characterized in that, in the chlorination of step b, and methylene dichloride, ethylene dichloride, trichloromethane, tetracol phenixin etc. and other halogenated alkane class; The polysubstituted thing of the alkyl of benzene, toluene, ethylbenzene, dimethylbenzene, diethylbenzene and other benzene; In the ester class that ethyl formate, ethyl acetate, propyl acetate, butylacetate etc. are used always one or more.Temperature of reaction is 5 ℃～80 ℃.Reaction times is 2～15 hours.P-methoxybenzyl alcohol and thionyl chloride mol ratio are 1: 1～1.2.
6. the method for claim 1 is characterized in that, the cyanation of step c prepares PARA METHOXY PHENYL ACETONITRILE under the phase-transfer catalyst effect, and phase-transfer catalyst can be a quaternary ammonium salt-type phase transfer catalyst.
7. the method for claim 1, it is characterized in that, the phase-transfer catalyst that the cyanation of step c is used can be one or more of Tetrabutyl amonium bromide, benzyltriethylammoinium chloride, tetrabutylammonium iodide, tetraethylammonium bromide and other quaternary ammonium salt.Temperature of reaction is 40 ℃～90 ℃, and the reaction times is 2～10 hours.Phase-transfer catalyst and benzyl chlorine mass ratio are 0.01～0.2: 1.
8. the method for claim 1 is characterized in that, the used alkali of the cyanation of step c is mineral alkali, can be sodium hydroxide, potassium hydroxide etc.Mineral alkali and benzyl chlorine mass ratio are 0.01～0.2: 1.
9. the method for claim 1 is characterized in that, the nitrilation sodium that the cyanation of step c is used and the mol ratio of benzyl chlorine compound are 1～1.5: 1.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103936568A (en) * | 2014-05-04 | 2014-07-23 | 宿迁科思化学有限公司 | Method for preparing p-methoxybenzyl alcohol from p-methoxy toluene |
| CN104844448A (en) * | 2015-05-05 | 2015-08-19 | 厦门圣健达生物科技有限公司 | Synthetic method of Dl - salvianic acid |
| CN109265330A (en) * | 2018-10-25 | 2019-01-25 | 广州中大南沙科技创新产业园有限公司 | A kind of preparation method of 4-(4-hydroxyphenyl)-2-butanone |
-
2009
- 2009-12-15 CN CN200910201165A patent/CN101774946A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103936568A (en) * | 2014-05-04 | 2014-07-23 | 宿迁科思化学有限公司 | Method for preparing p-methoxybenzyl alcohol from p-methoxy toluene |
| CN103936568B (en) * | 2014-05-04 | 2016-01-13 | 宿迁科思化学有限公司 | A kind of method being prepared by methoxy toluene to p-methoxybenzyl alcohol |
| CN104844448A (en) * | 2015-05-05 | 2015-08-19 | 厦门圣健达生物科技有限公司 | Synthetic method of Dl - salvianic acid |
| CN109265330A (en) * | 2018-10-25 | 2019-01-25 | 广州中大南沙科技创新产业园有限公司 | A kind of preparation method of 4-(4-hydroxyphenyl)-2-butanone |
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Application publication date: 20100714 |