CN101318901A - Novel synthesis process for dimethyl fumarate - Google Patents
Novel synthesis process for dimethyl fumarate Download PDFInfo
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- CN101318901A CN101318901A CNA2008101231794A CN200810123179A CN101318901A CN 101318901 A CN101318901 A CN 101318901A CN A2008101231794 A CNA2008101231794 A CN A2008101231794A CN 200810123179 A CN200810123179 A CN 200810123179A CN 101318901 A CN101318901 A CN 101318901A
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- dimethyl fumarate
- methyl alcohol
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- fumaric acid
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Abstract
The invention relates to a new process for synthesizing an antiseptic, namely dimethyl fumarate, wherein, two stages of esterification between a fumaric acid and methanol under the action of a catalyst are performed to generate the dimethyl fumarate; the catalyst is a cerous methylsulfonic acid. With application of the new process and the catalyst, the shortcomings of the prior art are overcome and production cost can be reduced effectively; and the new process has simple post-processing, less environmental pollution and good development and application prospect.
Description
Technical field
The invention belongs to technical field of synthesis of ester compounds in the organic chemistry, particularly relate to a kind of synthetic method of dimethyl fumarate.
Background technology
Dimethyl fumarate (Dimethyl fumarate) is called for short DMF, it is the current new food preservative of developing energetically both at home and abroad, have distinguishing features such as efficient, broad-spectrum antimicrobial, toxicity are low, cheap, mould is especially have special restraining effect to flavus, and Mlc is low, claims mould jinx again.DMF has sublimability, therefore also has contact sterilization and stifling germ-resistant dual function that general sanitas difficulty has.Because DMF changes normal meta-bolites fumaric acid into after advancing the human organism very soon, therefore safe to use, be widely used in the fresh-keeping etc. of the anticorrosion and vegetables of food, grain, feed etc. and fruit, more and more widely at present in the application of foodstuffs industry.Usage quantity was few when cause reached target effect, and cost is low, and compared with similar products, its market capacity is bigger, development prospect is more wide, was worth application and development energetically.
The operational path of synthetic DMF mainly contains two: the one, and be raw material with the maleic anhydride, under the esterifying catalyst effect, generate dimethyl maleate, obtain dimethyl fumarate through isomerization reaction again; The one, be raw material with the fumaric acid, with methyl alcohol under catalyst action, directly make dimethyl fumarate by esterification.
Many both at home and abroad at present employing second operational paths are that the direct esterification method is synthesized, and used catalyzer mostly is protonic acids such as sulfuric acid, and this technology has following shortcoming:
1. the production route is long, production cost is high
Bronsted acid catalysts such as sulfuric acid are serious to equipment corrosion, increased facility investment; The follow-up catalyzer of removing needs neutralization, washing step, and it is long to produce route; Under effect of sulfuric acid, poor selectivity, the side reaction of reaction are many, and the purity of product yield and product is low, the production cost height; Simultaneously, the discharging of a large amount of sour waters also can pollute environment.
2. many, the long reaction time of methanol usage
Because the boiling point of methyl alcohol is low and dissolve each other with water, adopt which kind of band aqua all can cause the methyl alcohol loss, so can't divide water in the reaction process, normally methyl alcohol is excessive to improve the way of yield.But the excessive influence to yield of methyl alcohol is not remarkable.Simultaneously, excessive methyl alcohol needs to reclaim, and has increased the aftertreatment burden.
In addition, in the prior art, catalyzer can also be solid acid, ion exchange resin, heteropolyacid, inorganic salt etc., though use these materials can overcome above-mentioned several problems to a certain extent as catalyzer, but shortcoming such as exist the Preparation of Catalyst difficulty, consumption is many, molar ratio of alcohol to acid is big, the catalyzer reusability is not good, therefore be necessary to propose novel process, method is in the past improved.
Summary of the invention
The objective of the invention is for overcoming above-mentioned the deficiencies in the prior art, a kind of production technique of improved dimethyl fumarate is provided, and the catalyst levels of this technology is few, reaction yield is high, the product purity height that synthesizes, catalyzer is reusable, and production cost is low, environmental pollution is little.
For solving above technical problem, the present invention takes following technical scheme:
A kind of new technology of synthesis of dimethyl fumarate, fumaric acid and methyl alcohol esterification take place under the effect of catalyzer generate described dimethyl fumarate, it is characterized in that: described catalyzer is the inferior cerium of methylsulphonic acid.
A kind of new technology of synthesis of dimethyl fumarate according to claim 1 is characterized in that: the add-on of the inferior cerium of described catalyzer methylsulphonic acid is 0.3～0.4% of fumaric acid and a methyl alcohol total mass.
A kind of new technology of synthesis of dimethyl fumarate according to claim 1 is characterized in that: described esterification is carried out under reflux temperature, and the reaction times is 7～10h.
A kind of new technology of synthesis of dimethyl fumarate according to claim 1 is characterized in that: when carrying out esterification, described methyl alcohol is excessive with respect to fumaric acid.
A kind of new technology of synthesis of dimethyl fumarate according to claim 4 is characterized in that: described methyl alcohol is 6.0～8.0: 1 with the amount of substance ratio of described fumaric acid.
According to the described a kind of new technology of synthesis of dimethyl fumarate of above-mentioned any claim, it is characterized in that: reaction divides two stages to carry out the fs, drop into the methyl alcohol of half amount earlier, after reacting completely, steam the first alcohol and water, drop into remaining methyl alcohol again, carry out the reaction of subordinate phase.Owing to take above technical scheme, the present invention compared with prior art has the following advantages and positively effect:
1. adopting the inferior cerium of methylsulphonic acid is catalyzer, compares with existing an acidic catalyst, and speed of response is approaching; But catalyst levels is few, and selectivity is good, and catalyzer is reusable after simple separation, has reduced raw materials cost.
2. compare with existing an acidic catalyst, the inferior cerium of methylsulphonic acid can etching apparatus, has saved facility investment; Removing catalyzer only needs simple filtration and need not operations such as neutralization, washing, has reduced sewage discharge, environmentally friendly.
.3. compare with the existing processes route, though the consumption of methyl alcohol does not reduce, yet not shortening of reaction times, the yield of product is improved.
Embodiment
In three mouthfuls of reaction flasks of the 500mL that reflux condensing tube is housed, add 116.0g (1.0mol) fumaric acid, 96.12g (3.0mol) methyl alcohol, the inferior cerium of 1.24g (0.0025mol) methylsulphonic acid successively, behind the about 3h of heating reflux reaction, steam the water that removes methyl alcohol and reaction generation, add 96.12g (3.0mol) methyl alcohol continuation heating reflux reaction 4h again in reaction flask, filtered while hot reclaims the inferior cerium of methylsulphonic acid (the inferior cerium of the methylsulphonic acid of recovery is reusable).Filtrate through wash, leave standstill, cooling, crystallization, suction filtration, dry white crystal shape dimethyl fumarate.Quality product 137.95g (yield is 95.8%), 102～104 ℃ of fusing points.
Reaction equation is:
Wherein, the above-mentioned inferior cerium of methylsulphonic acid can synthesize by the following method:
Take by weighing the 14.4g methylsulphonic acid, mix by 1: 1 volume ratio with water and to add in the flask, disposable adding 10.2g cerium dioxide is loaded onto reflux condensing tube and is fixed on the magnetic stirrer and heats, reflux conditions slowly drips the 150mL hydrogen peroxide down, behind the reaction 4-5h, filtered while hot is with twice of a small amount of distilled water wash filter residue, merging filtrate, evaporate to dryness, in vacuum drying oven 100 ℃ down behind the dry 3h, it is standby to put into moisture eliminator.The inferior cerium quality of gained methylsulphonic acid is 23.2g (yield is 93.5%).
Claims (6)
1. new technology of synthesis of dimethyl fumarate, fumaric acid and methyl alcohol esterification take place under the effect of catalyzer generates described dimethyl fumarate, it is characterized in that: described catalyzer is the inferior cerium of methylsulphonic acid.
2. a kind of new technology of synthesis of dimethyl fumarate according to claim 1 is characterized in that: the add-on of the inferior cerium of described catalyzer methylsulphonic acid is 0.3～0.4% of fumaric acid and a methyl alcohol total mass.
3. a kind of new technology of synthesis of dimethyl fumarate according to claim 1 is characterized in that: described esterification is carried out under reflux temperature, and the reaction times is 7～10h.
4. a kind of new technology of synthesis of dimethyl fumarate according to claim 1 is characterized in that: when carrying out esterification, described methyl alcohol is excessive with respect to fumaric acid.
5. a kind of new technology of synthesis of dimethyl fumarate according to claim 4 is characterized in that: described methyl alcohol is 6.0～8.0: 1 with the amount of substance ratio of described fumaric acid.
6. according to the described a kind of new technology of synthesis of dimethyl fumarate of above-mentioned any claim, it is characterized in that: reaction divides two stages to carry out, fs, drop into the methyl alcohol of half amount earlier, after reacting completely, steam the first alcohol and water, drop into remaining methyl alcohol again, carry out the reaction of subordinate phase.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101231794A CN101318901A (en) | 2008-06-17 | 2008-06-17 | Novel synthesis process for dimethyl fumarate |
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2008101231794A CN101318901A (en) | 2008-06-17 | 2008-06-17 | Novel synthesis process for dimethyl fumarate |
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103483194A (en) * | 2012-11-30 | 2014-01-01 | 杨寅柯 | 2-fuloro fumarate (formula I), and preparation method and application thereof |
| WO2014160633A1 (en) | 2013-03-24 | 2014-10-02 | Xenoport, Inc. | Pharmaceutical compositions of dimethyl fumarate |
| US8906420B2 (en) | 2009-01-09 | 2014-12-09 | Forward Pharma A/S | Pharmaceutical formulation comprising one or more fumaric acid esters in an erosion matrix |
| WO2014205392A1 (en) | 2013-06-21 | 2014-12-24 | Xenoport, Inc. | Cocrystals of dimethyl fumarate |
| WO2015042294A1 (en) | 2013-09-18 | 2015-03-26 | Xenoport, Inc. | Nanoparticle compositions of dimethyl fumarate |
| CN104483344A (en) * | 2015-01-07 | 2015-04-01 | 重庆民泰香料化工有限责任公司 | Fast judging method for DMF of mildew preventive |
| US9302977B2 (en) | 2013-06-07 | 2016-04-05 | Xenoport, Inc. | Method of making monomethyl fumarate |
| US9416096B2 (en) | 2013-09-06 | 2016-08-16 | Xenoport, Inc. | Crystalline forms of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, methods of synthesis and use |
| US9452972B2 (en) | 2008-08-19 | 2016-09-27 | Xenoport, Inc. | Methods of using prodrugs of methyl hydrogen fumarate and pharmaceutical compositions thereof |
| US9597292B2 (en) | 2012-08-22 | 2017-03-21 | Xenoport, Inc. | Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof |
| US9999672B2 (en) | 2014-03-24 | 2018-06-19 | Xenoport, Inc. | Pharmaceutical compositions of fumaric acid esters |
| US10945984B2 (en) | 2012-08-22 | 2021-03-16 | Arbor Pharmaceuticals, Llc | Methods of administering monomethyl fumarate and prodrugs thereof having reduced side effects |
| US11052062B2 (en) | 2004-10-08 | 2021-07-06 | Biogen Swiss Manufacturing Gmbh | Controlled release pharmaceutical compositions comprising a fumaric acid ester |
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2008
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| 王敏等: "《甲烷磺酸盐的合成及其对酯化反应的催化性能》", 《工业催化》 * |
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Cited By (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11229619B2 (en) | 2004-10-08 | 2022-01-25 | Biogen Swiss Manufacturing Gmbh | Controlled release pharmaceutical compositions comprising a fumaric acid ester |
| US11052062B2 (en) | 2004-10-08 | 2021-07-06 | Biogen Swiss Manufacturing Gmbh | Controlled release pharmaceutical compositions comprising a fumaric acid ester |
| US9452972B2 (en) | 2008-08-19 | 2016-09-27 | Xenoport, Inc. | Methods of using prodrugs of methyl hydrogen fumarate and pharmaceutical compositions thereof |
| US8906420B2 (en) | 2009-01-09 | 2014-12-09 | Forward Pharma A/S | Pharmaceutical formulation comprising one or more fumaric acid esters in an erosion matrix |
| US11173123B2 (en) | 2009-01-09 | 2021-11-16 | Biogen Swiss Manufacturing Gmbh | Pharmaceutical formulation comprising one or more fumaric acid esters in an erosion matrix |
| US10945984B2 (en) | 2012-08-22 | 2021-03-16 | Arbor Pharmaceuticals, Llc | Methods of administering monomethyl fumarate and prodrugs thereof having reduced side effects |
| US10940117B2 (en) | 2012-08-22 | 2021-03-09 | Arbor Pharmaceuticals, Llc | Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof |
| US10716760B2 (en) | 2012-08-22 | 2020-07-21 | Arbor Pharmaceuticals, Llc | Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof |
| US9597292B2 (en) | 2012-08-22 | 2017-03-21 | Xenoport, Inc. | Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof |
| CN103483194B (en) * | 2012-11-30 | 2016-03-09 | 杨寅柯 | A kind of 2-fluoro fumarate (structural formula I) and preparation method thereof and application |
| CN103483194A (en) * | 2012-11-30 | 2014-01-01 | 杨寅柯 | 2-fuloro fumarate (formula I), and preparation method and application thereof |
| US11938111B2 (en) | 2013-03-24 | 2024-03-26 | Arbor Pharmaceuticals, Llc | Pharmaceutical compositions of dimethyl fumarate |
| WO2014160633A1 (en) | 2013-03-24 | 2014-10-02 | Xenoport, Inc. | Pharmaceutical compositions of dimethyl fumarate |
| US10179118B2 (en) | 2013-03-24 | 2019-01-15 | Arbor Pharmaceuticals, Llc | Pharmaceutical compositions of dimethyl fumarate |
| US9302977B2 (en) | 2013-06-07 | 2016-04-05 | Xenoport, Inc. | Method of making monomethyl fumarate |
| US9421182B2 (en) | 2013-06-21 | 2016-08-23 | Xenoport, Inc. | Cocrystals of dimethyl fumarate |
| WO2014205392A1 (en) | 2013-06-21 | 2014-12-24 | Xenoport, Inc. | Cocrystals of dimethyl fumarate |
| US9682057B2 (en) | 2013-09-06 | 2017-06-20 | Xenoport, Inc. | Crystalline forms of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, methods of synthesis and use |
| US9416096B2 (en) | 2013-09-06 | 2016-08-16 | Xenoport, Inc. | Crystalline forms of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, methods of synthesis and use |
| WO2015042294A1 (en) | 2013-09-18 | 2015-03-26 | Xenoport, Inc. | Nanoparticle compositions of dimethyl fumarate |
| US11135296B2 (en) | 2014-03-24 | 2021-10-05 | Arbor Pharmaceuticals, Llc | Pharmaceutical compositions of fumaric acid esters |
| US9999672B2 (en) | 2014-03-24 | 2018-06-19 | Xenoport, Inc. | Pharmaceutical compositions of fumaric acid esters |
| CN104483344A (en) * | 2015-01-07 | 2015-04-01 | 重庆民泰香料化工有限责任公司 | Fast judging method for DMF of mildew preventive |
| CN104483344B (en) * | 2015-01-07 | 2017-05-10 | 重庆民泰香料化工有限责任公司 | Fast judging method for DMF of mildew preventive |
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