CN102584626A - Synthetic method of (ethoxymethylene)-malononitrile - Google Patents
Synthetic method of (ethoxymethylene)-malononitrile Download PDFInfo
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- CN102584626A CN102584626A CN2011104338600A CN201110433860A CN102584626A CN 102584626 A CN102584626 A CN 102584626A CN 2011104338600 A CN2011104338600 A CN 2011104338600A CN 201110433860 A CN201110433860 A CN 201110433860A CN 102584626 A CN102584626 A CN 102584626A
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Abstract
The invention relates to a synthetic method of (ethoxymethylene)-malononitril, which includes the following steps: (1) dropwise adding malononitrile into triethyl orthoformate in ice bath cooling condition, and adding catalyst anhydrous zinc chloride after dropwise adding for reaction for 2-4 hours, and (2) steaming and removing ethanol after the reaction is finished, cooling for dissolving out solids, and filtering and collecting the solids to obtain the (ethoxymethylene)-malononitrile. The synthetic method is easy to operate, high in yield, low in cost, environment-friendly, high in product crystallization purity, stable in quality and suitable for large-scale industrial production.
Description
Technical field
The present invention relates to the organic synthesis field, be specifically related to a kind of compound method of medicine intermediate Ethoxy methylene malononitrile 99.
Background technology
Ethoxy methylene malononitrile 99 (Ethoxymethylenemalononitrile), shown in I, Chinese another name: oxyethyl group dicyano ethene; Ethoxy methylene malononitrile; Ethoxy methylene malononitrile 99, oxyethyl group methene base propane dinitrile, (ethoxymethyl) thiazolinyl propane dinitrile.The CAS registration number is 123-06-8, molecular formula C
6H
6N
2O, molecular weight 122.1246.
Formula I
The Ethoxy methylene malononitrile 99 outward appearance is that white is to the off-white color crystalline powder; Water insoluble, be soluble in organic solvents such as ethanol, fusing point 65-67 ℃, 160 ℃ of boiling points (12mmHg).Can be used for industry, medicine intermediate, as be used for the synthetic of milrinone.
At present; Mostly the compound method of Ethoxy methylene malononitrile 99 is that propane dinitrile, triethyl orthoformate are in organic solvent and catalyzer existence condition refluxed reaction; Used organic solvent is generally the higher solvents of boiling point such as toluene; Therefore temperature of reaction is higher, thereby is prone to take place yield and the purity that side reaction influences title product.A kind of compound method (Liu Qiming, Su Yuyong, Chen Bangyin, Zhang Hanping of Ethoxy methylene malononitrile 99 are disclosed like Liu Qiming etc.Synthetic and the structure of phosphodiesterase inhibitor milrinone is identified.Central China University of Science and Technology's journal (medicine): pack in the reaction vessel propane dinitrile and toluene, add Zinc Chloride Anhydrous, drip triethyl orthoformate again; About 1h drips off, and back flow reaction changes reflux into water distilling apparatus then; Steam the ethanol that reaction generates, decompression steams toluene to doing then, after cold dark red solid; With hexanaphthene one ethyl alcohol recrystallization, about 79% (in the propane dinitrile) of yield.This method uses a large amount of toluene to make solvent, and cost is high, has increased difficulty of post-processing, and has been unfavorable for environmental protection; In addition, the refining employing mixed solvent of Ethoxy methylene malononitrile 99 is also inadvisable in present method, and cost increases, and the recovery of solvent is also comparatively difficult.
Summary of the invention
The consumption of organic solvent that existing synthetic Ethoxy methylene malononitrile 99 method exists is big, temperature of reaction is high in order to overcome, target product yield and the unfavorable defective of purity, the purpose of this invention is to provide a kind of compound method of Ethoxy methylene malononitrile 99.
Ethoxy methylene malononitrile 99 compound method provided by the invention may further comprise the steps:
(1) the ice bath cooling drips propane dinitrile down in triethyl orthoformate, adds the catalyzer Zinc Chloride Anhydrous after dropwising again, and 60～80 ℃ were reacted 2～4 hours down;
(2) reaction finishes the back steaming except that ethanol, and solid is separated out in cooling, and solid collected by filtration promptly gets.
Triethyl orthoformate in molar ratio: propane dinitrile=1.0～1.2: 1.
The add-on of said catalyzer Zinc Chloride Anhydrous is 0.5～1.5% of a propane dinitrile quality.
The time that drips propane dinitrile in the step (1) was controlled at 30～50 minutes.
Controlled temperature is at 15～25 ℃ in the process of the middle dropping of step (1) propane dinitrile.
The compound method of said Ethoxy methylene malononitrile 99 also comprises: step (2) is filtered the solid of collecting the back make with extra care through recrystallization.
The process of said recrystallization is: the Ethoxy methylene malononitrile 99 solid is added organic solvent dissolution, activated carbon decolorizing, freezing then crystallization, filtering separation crystal, 40～50 ℃ of following vacuum-drying 5～6 hours.
Preferably, said organic solvent is ethanol, propyl alcohol, acetone or ETHYLE ACETATE.More preferably, said organic solvent is an absolute ethyl alcohol, add-on and the bullion equivalent of treating recrystallization.
Said bleaching time is 30～50 minutes.
Ethoxy methylene malononitrile 99 compound method provided by the invention has the following advantages:
1, this reaction adopts triethyl orthoformate and propane dinitrile directly to react, and does not use reagent such as toluene to make solvent, has reduced pollution, has reduced cost, and has made aftertreatment simpler.And temperature of reaction obviously reduces, and can reduce the generation of side reaction, improved the purity of title product.
2, changed the order of addition(of ingredients) of existing method, propane dinitrile is added drop-wise in the triethyl orthoformate, rate of addition is more quick, has practiced thrift the whole reaction times, also can make the more complete of propane dinitrile reaction, has improved the yield of target product.
3, improved process for purification, directly adopted single solvent to carry out recrystallization, consumption is few, and is simple to operate, and product purity is high, and HPLC analyzes and shows and can reach more than 99.5%, and solvent can also recycle again, further practiced thrift cost.
In a word, method provided by the invention is simple to operate, yield is high, cost is low, environmental protection, product crystallization purity high, steady quality, is fit to large-scale industrial production.
Embodiment
Following examples are used to explain the present invention, but are not used for limiting scope of the present invention.
Embodiment 1
1) preparation of Ethoxy methylene malononitrile 99:
In the 5000ml there-necked flask, mounting temperature meter, prolong, mechanical stirring add triethyl orthoformate 2600g; Ice-water bath is cooled to about 20 ℃, is interrupted to drip propane dinitrile 1050g fast, does not have obvious heat release; Dropwise after 30 minutes; Add Zinc Chloride Anhydrous 10g then, heating in water bath to 70 ℃, stirring reaction 3h.Steam the ethanol that reaction generates after the reaction end, get dark red solid after the cooling, suction filtration behind the refrigeration crystallization gets Ethoxy methylene malononitrile 99 bullion (need not dry, directly descend one-step refining).
2) Ethoxy methylene malononitrile 99 is refining:
Above Ethoxy methylene malononitrile 99 bullion is added in the 5000ml there-necked flask mounting temperature meter, prolong, mechanical stirring.Add absolute ethyl alcohol 1700g, 60 ℃ of stirring in water bath dissolvings add the 30g gac, stir decolouring 30 minutes, filter, and filtrating is chilled to room temperature earlier, puts into the freezing crystallization 3h of refrigerator-freezer again, suction filtration, 50 ℃ of vacuum-drying 6 hours, finished product 1597g, yield 82%.HPLC measures content greater than 99.5%.
Embodiment 2
1) preparation of Ethoxy methylene malononitrile 99:
In the 5000ml there-necked flask, mounting temperature meter, prolong, mechanical stirring.Add triethyl orthoformate 2600g, ice-water bath is cooled to about 20 ℃, is interrupted to drip propane dinitrile 1100g fast, does not have obvious heat release, dropwises after 50 minutes, adds Zinc Chloride Anhydrous 10g then, heating in water bath to 70 ℃, stirring reaction 2.5h.Steam the ethanol that reaction generates after the reaction end, get dark red solid after the cooling, suction filtration behind the refrigeration crystallization gets Ethoxy methylene malononitrile 99 bullion (need not dry, directly descend one-step refining).
2) Ethoxy methylene malononitrile 99 is refining:
Above Ethoxy methylene malononitrile 99 bullion is added in the 5000ml there-necked flask mounting temperature meter, prolong, mechanical stirring.Add absolute ethyl alcohol 1750g, 60 ℃ of stirring in water bath dissolvings add the 30g gac, stir decolouring 40 minutes, filter, and filtrating is chilled to room temperature earlier, puts into the freezing crystallization 4h of refrigerator-freezer again, suction filtration, 50 ℃ of vacuum-drying 5 hours, finished product 1628g, yield 80%.HPLC measures content greater than 99.5%.
Embodiment 3
1) preparation of Ethoxy methylene malononitrile 99:
In the 5000ml there-necked flask, mounting temperature meter, prolong, mechanical stirring.Add triethyl orthoformate 2600g, ice-water bath is cooled to about 20 ℃, is interrupted to drip propane dinitrile 1160g fast, does not have obvious heat release, dropwises after 40 minutes, adds Zinc Chloride Anhydrous 11g then, heating in water bath to 70 ℃, stirring reaction 4h.Steam the ethanol that reaction generates after the reaction end, get dark red solid after the cooling, suction filtration behind the refrigeration crystallization gets Ethoxy methylene malononitrile 99 bullion (need not dry, directly descend one-step refining).
2) Ethoxy methylene malononitrile 99 is refining:
Above Ethoxy methylene malononitrile 99 bullion is added in the 5000ml there-necked flask mounting temperature meter, prolong, mechanical stirring.Add acetone 1800g, 60 ℃ of stirring in water bath dissolvings add the 30g gac, stir decolouring 50 minutes, filter, and filtrating is chilled to room temperature earlier, puts into the freezing crystallization 4h of refrigerator-freezer again, suction filtration, 50 ℃ of vacuum-drying 5.5 hours, finished product 1776g, yield 83%.HPLC measures content greater than 99.5%.
Though, the present invention has been done detailed description in the preceding text with general explanation and specific embodiments, on basis of the present invention, can to some modifications of do or improvement, this will be apparent to those skilled in the art.Therefore, these modifications or the improvement on the basis of not departing from spirit of the present invention, made all belong to the scope that requirement of the present invention is protected.
Claims (9)
1. the compound method of an Ethoxy methylene malononitrile 99 is characterized in that, may further comprise the steps:
(1) the ice bath cooling drips propane dinitrile down in triethyl orthoformate, adds the catalyzer Zinc Chloride Anhydrous after dropwising again, and 60～80 ℃ were reacted 2～4 hours down;
(2) reaction finishes the back steaming except that ethanol, and solid is separated out in cooling, and solid collected by filtration promptly gets.
2. compound method according to claim 1 is characterized in that, in molar ratio triethyl orthoformate: propane dinitrile=1.0～1.2: 1.
3. compound method according to claim 1 is characterized in that, the time that drips propane dinitrile in the step (1) was controlled at 30～50 minutes.
4. compound method according to claim 1 is characterized in that, controlled temperature is at 15～25 ℃ in the process of the middle dropping of step (1) propane dinitrile.
5. compound method according to claim 1 is characterized in that, the add-on of said catalyzer Zinc Chloride Anhydrous is 0.5～1.5% of a propane dinitrile quality.
6. according to each described compound method of claim 1-5, it is characterized in that said compound method also comprises: step (2) is filtered the solid of collecting the back make with extra care through recrystallization.
7. compound method according to claim 6 is characterized in that, the process of said recrystallization is: the Ethoxy methylene malononitrile 99 solid is added organic solvent dissolution; Activated carbon decolorizing; Freezing then crystallization, filtering separation crystal, 40～50 ℃ of following vacuum-drying 5～6 hours.
8. compound method according to claim 7 is characterized in that, said organic solvent is ethanol, propyl alcohol, acetone or ETHYLE ACETATE.
9. compound method according to claim 7 is characterized in that, said bleaching time is 30～50 minutes.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103333145A (en) * | 2013-07-22 | 2013-10-02 | 重庆紫光化工股份有限公司 | Preparation method of 3-(alpha- methoxyl) methylene benzofuran-2(3H)-ketone |
| CN103664695A (en) * | 2013-12-18 | 2014-03-26 | 南京易亨制药有限公司 | Preparation method and refining method of ethoxymethylenemalononitrile |
| CN106025278A (en) * | 2016-07-01 | 2016-10-12 | 东莞市凯欣电池材料有限公司 | High-voltage lithium ion battery |
| CN109180578A (en) * | 2018-10-19 | 2019-01-11 | 山东创新药物研发有限公司 | A kind of preparation method of bosutinib |
| CN111072518A (en) * | 2019-12-18 | 2020-04-28 | 凯莱英医药集团（天津）股份有限公司 | Continuous synthesis method of ethoxymethylene malononitrile |
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| CN102115474A (en) * | 2009-12-31 | 2011-07-06 | 北京师范大学 | New type18F-labeled pyrazolo [1,5-a] pyrimidines and their preparation and application |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103333145A (en) * | 2013-07-22 | 2013-10-02 | 重庆紫光化工股份有限公司 | Preparation method of 3-(alpha- methoxyl) methylene benzofuran-2(3H)-ketone |
| CN103664695A (en) * | 2013-12-18 | 2014-03-26 | 南京易亨制药有限公司 | Preparation method and refining method of ethoxymethylenemalononitrile |
| CN106025278A (en) * | 2016-07-01 | 2016-10-12 | 东莞市凯欣电池材料有限公司 | High-voltage lithium ion battery |
| CN106025278B (en) * | 2016-07-01 | 2018-09-14 | 东莞市凯欣电池材料有限公司 | A kind of high-voltage lithium ion batteries |
| CN109180578A (en) * | 2018-10-19 | 2019-01-11 | 山东创新药物研发有限公司 | A kind of preparation method of bosutinib |
| CN111072518A (en) * | 2019-12-18 | 2020-04-28 | 凯莱英医药集团（天津）股份有限公司 | Continuous synthesis method of ethoxymethylene malononitrile |
| CN111072518B (en) * | 2019-12-18 | 2022-11-29 | 凯莱英医药集团（天津）股份有限公司 | Continuous synthesis method of ethoxymethylene malononitrile |
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