CN100537513C - Process for preparing monomethyl fumerate - Google Patents

Process for preparing monomethyl fumerate Download PDF

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CN100537513C
CN100537513C CNB2004100515790A CN200410051579A CN100537513C CN 100537513 C CN100537513 C CN 100537513C CN B2004100515790 A CNB2004100515790 A CN B2004100515790A CN 200410051579 A CN200410051579 A CN 200410051579A CN 100537513 C CN100537513 C CN 100537513C
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fumaric acid
methyl
tech grade
maleic anhydride
preparation technology
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CN1616400A (en
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李文佳
汪树清
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LI WENJIA WANG SHUQING
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LI WENJIA WANG SHUQING
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Abstract

The monomethyl fumerate preparing process features that maleic anhydride is first alcoholized and ring-opening esterified with methanol into monomethyl maleate; and monomethyl maleate is then positioning reacted in non-polar solvent with hydrogen halide as catalyst to produce monomethyl fumerate. The present invention has simple preparation process, short production period of 1-2 hr, high yield up to 85-90 % and high production efficiency.

Description

The preparation technology of FUMARIC ACID TECH GRADE mono-methyl
Technical field
The present invention relates to a kind of preparation technology of the high-efficiency broad spectrum antimildew disinfectant FUMARIC ACID TECH GRADE mono-methyl as grain, food and feed.
Technical background
The FUMARIC ACID TECH GRADE mono-methyl is monomethyl fumarate again, English name is: mono-methylfurmarate, be called for short MMF, and MMF can wide and practical suppress growing of mould in the environment, quenchable bacterium and yeast reach kind more than 30, wherein especially flavus are have had strong inhibitory effects.The germ resistance of MMF is not subjected to the influence of pH value simultaneously, and DMF compares with dimethyl fumarate, if will reach same anti-mold effect, then the consumption of MMF only is 3/5ths of a DMF consumption.In addition, the toxicity of MMF and pungency are well below DMF.Therefore MMF is the antimycotic antiseptic mothproofing agent of a kind of comparatively ideal grain, food and feed.
At present, the preparation method of MMF has following two kinds of approach: the one, and the fumaric acid method is a raw material with fumaric acid (FUMARIC ACID TECH GRADE, fumaric acid) promptly, at the vitriol oil or BF 3Catalysis is reacted with methyl alcohol down and is made.Another kind of approach is to be raw material with MALEIC ANHYDRIDE (be apple anhydride dehydration again, or maleic anhydride), and its route comprises two kinds again, and the step of two kinds of routes is distinguished as follows:
One, MALEIC ANHYDRIDE → maleic acid → FUMARIC ACID TECH GRADE → FUMARIC ACID TECH GRADE mono-methyl (being monomethyl fumarate).
Another route is MALEIC ANHYDRIDE → monomethyl cis-butenedioic acid → FUMARIC ACID TECH GRADE mono-methyl.
Fumaric acid exists few at nature, it is made through thiocarbamide catalysis by the toxilic acid aqueous solution, or from molasses fermented and make but most fumaric acid is transformed by MALEIC ANHYDRIDE.Therefore directly preparing its starting raw material of monomethyl fumarate by fumaric acid remains MALEIC ANHYDRIDE.
In existing monomethyl fumarate synthetic method, the production cycle is all longer.As the Zhong Guoqing of school district, Southwestern University Rongchang County, Ceng Renquan report [" fine chemistry industry " 2002.19 (6) 343-345] is made solvent with benzene, and hydrochloric acid-pyridine is done the composite catalyst following reaction times of effect and wanted 3h, yield 83%; And Chongqing spices chemical industry limited liability company is when synthetic monomethyl fumarate, the first step, and reaction will be used 1.5-5h; Second step was reflected under the solvent-free existence makes catalyzer with hydrochloric acid, then needs 20-60h, then needs 3-8h as make solvent with ethyl acetate, and yield is about 95%.
Summary of the invention
For addressing the above problem, the purpose of this invention is to provide a kind of preparation technology of FUMARIC ACID TECH GRADE mono-methyl, its reaction times is short, and yield is higher, and production efficiency improves greatly.
The object of the present invention is achieved like this: a kind of preparation technology of FUMARIC ACID TECH GRADE mono-methyl, it is characterized in that: be monomethyl cis-butenedioic acid with MALEIC ANHYDRIDE alcoholysis esterification by ring opening at first by methyl alcohol, make catalyzer with hydrogen halide then, monomethyl cis-butenedioic acid is reacted in non-polar solvent, and transposition generates the FUMARIC ACID TECH GRADE mono-methyl.
The preparation technology of FUMARIC ACID TECH GRADE mono-methyl of the present invention is simple, and is with short production cycle, only needs 1-2 hour can finish reaction, and yield is higher, can reach 85-90%, and production efficiency is greatly enhanced.
Embodiment
The present invention is to be raw material with the MALEIC ANHYDRIDE, is monomethyl cis-butenedioic acid through methyl alcohol alcoholysis esterification by ring opening, generates the technology of monomethyl fumarate again through transposition, and its reaction formula is as follows:
Figure C200410051579D00051
Analyze the structure of MALEIC ANHYDRIDE (I), two carbonyl groups are arranged in the molecule, so be easy in the presence of methyl alcohol, carry out the alcoholysis open loop and esterification, obtain monomethyl cis-butenedioic acid (II), this step reaction is very fast, and heat release, therefore only need add thermal booster reaction in the reaction and just can continue to carry out.For making the thorough esterification of MALEIC ANHYDRIDE, so adopt MALEIC ANHYDRIDE: the molar ratio of methyl alcohol=1: 1.05-1.1.Step 2. in, the mol ratio of MALEIC ANHYDRIDE and catalyzer is 1: 0.25-0.4, temperature of reaction is 80-95 ℃.In monomethyl cis-butenedioic acid (II) transposition is in the process of FUMARIC ACID TECH GRADE monoesters (III), because two keys can not rotate freely, therefore to show as at first be breaking and then forming carbon-to-carbon σ-key of carbon-to-carbon double bond to the reaction mechanism of transposition process, have only σ-key just can rotate, in the monomethyl cis-butenedioic acid molecule, be in hydroxy-acid group-COOH and carboxylic acid group's methyl esters group-COOCH of homonymy 3Owing to there is steric effect, in case two key breaks, these two groups rotate to be heteropleural by σ-key, are the process of FUMARIC ACID TECH GRADE monoesters thereby finished by the monomethyl cis-butenedioic acid transposition at once.Here, the breaking of carbon-to-carbon double bond is to realize by the addition of two keys and hydrogen halide rather than with the addition of halogenation hydracid, halogen hydracid also can react with two keys to a certain extent, but the water of halogen hydracid can hinder this reaction, so making the catalyzer the reaction time with concentrated hydrochloric acid can be very long, therefore adopts in the present invention and feed hydrogen chloride gas as catalyzer.Product FUMARIC ACID TECH GRADE mono-methyl is the more weak lipoid substance of polarity, when monomethyl cis-butenedioic acid is converted into the FUMARIC ACID TECH GRADE mono-methyl of transconfiguration, as use with the material of its structural similitude and make solvent, according to the similar person principle that mixes, product is separated out the crystallization required time from solvent necessarily longer, if make dispersion solvent with apolar substance, then product can be separated out from solvent with crystallized form very soon, therefore adopt apolar substance among the present invention, as sherwood oil, as the solvent of translocation reaction, can shorten the reaction times greatly.
With MALEIC ANHYDRIDE: the molar ratio of methyl alcohol=1: 1.05-1.1, methyl alcohol is monomethyl cis-butenedioic acid with MALEIC ANHYDRIDE alcoholysis esterification by ring opening, temperature of reaction is 45-90 ℃, and the time is 30-60min, then with sherwood oil as the reaction dispersion solvent, feed HCl, the mol ratio of MALEIC ANHYDRIDE and HCl is 1: 0.25-0.4, and the transposition of catalysis monomethyl cis-butenedioic acid is FUMARIC ACID TECH GRADE mono-methyl, i.e. monomethyl fumarate, temperature of reaction is 80-95 ℃, and the time is 30-60min.
Embodiment
With MALEIC ANHYDRIDE 98 grams (1mol), methyl alcohol 35.2 restrains under stirring and is heated to 50 ℃, and MALEIC ANHYDRIDE begins dissolving.Because this reaction is thermopositive reaction, therefore in reaction process, can stop heating, temperature can rise to 90 ℃.Pick up counting from 50 ℃, behind 30min, add sherwood oil 100ml, feed HCl, at 80-95 ℃ of following stirring reaction 0.5-1h, it is 1: 0.3 that the flow of control HCl makes the HCl mol ratio of MALEIC ANHYDRIDE and feeding, filter, dry FUMARIC ACID TECH GRADE mono-methyl crude product, crude product aqueous ethanolic solution recrystallization, filter, dry must the crystallization of white FUMARIC ACID TECH GRADE mono-methyl, fusing point 142-144 ℃, yield is 85-90%.

Claims (7)

1. the preparation technology of a FUMARIC ACID TECH GRADE mono-methyl is characterized in that may further comprise the steps: be monomethyl cis-butenedioic acid by methyl alcohol with MALEIC ANHYDRIDE alcoholysis esterification by ring opening 1.; 2. make catalyzer with hydrogen halide, monomethyl cis-butenedioic acid is reacted in non-polar solvent, transposition generates the FUMARIC ACID TECH GRADE mono-methyl.
2. the preparation technology of FUMARIC ACID TECH GRADE mono-methyl according to claim 1 is characterized in that: described step in 1. MALEIC ANHYDRIDE and the molar ratio of methyl alcohol be 1: 1.05-1.1.
3. the preparation technology of FUMARIC ACID TECH GRADE mono-methyl according to claim 1 is characterized in that: the temperature of reaction of 1. middle MALEIC ANHYDRIDE of described step and methyl alcohol is 45-90 ℃.
4. the preparation technology of FUMARIC ACID TECH GRADE mono-methyl according to claim 1 is characterized in that: the mol ratio of described MALEIC ANHYDRIDE and catalyzer is 1: 0.25-0.4.
5. the preparation technology of FUMARIC ACID TECH GRADE mono-methyl according to claim 1 is characterized in that: the catalyzer of described step in 2. is hydrogenchloride.
6. the preparation technology of FUMARIC ACID TECH GRADE mono-methyl according to claim 1 is characterized in that: the non-polar solvent of described step in 2. is sherwood oil.
7. the preparation technology of FUMARIC ACID TECH GRADE mono-methyl according to claim 1 is characterized in that: the temperature of reaction of described step in 2. is 80-95 ℃.
CNB2004100515790A 2004-09-23 2004-09-23 Process for preparing monomethyl fumerate Expired - Fee Related CN100537513C (en)

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Publication number Priority date Publication date Assignee Title
JP5670331B2 (en) 2008-08-19 2015-02-18 ゼノポート,インコーポレイティド Methyl hydrogen fumarate prodrug, pharmaceutical composition thereof and method of use
CN101880229A (en) * 2009-05-08 2010-11-10 广州中医药大学 (+)-monobornyl maleinate as well as preparation method and application thereof
CN101830801B (en) * 2010-05-17 2012-11-14 淮安苏瑞精细化工有限公司 Method for preparing monomethyl cis-butenedioic acid
CN101823962B (en) * 2010-05-17 2012-11-14 淮安苏瑞精细化工有限公司 Method for preparing dimethyl maleate
CA2882730C (en) 2012-08-22 2019-12-31 Xenoport, Inc. Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof
CA2882713A1 (en) 2012-08-22 2014-02-27 Xenoport, Inc. Methods of administering monomethyl fumarate and prodrugs thereof having reduced side effects
CN103044249A (en) * 2012-12-31 2013-04-17 广东石油化工学院 New method for compounding maleic diacid single low-carbon alcohol ester
WO2014160633A1 (en) 2013-03-24 2014-10-02 Xenoport, Inc. 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
EP3041467A1 (en) 2013-09-06 2016-07-13 XenoPort, Inc. Crystalline forms of (n,n-diethylcarbamoyl)methyl methyl (2e)but-2-ene-1,4-dioate, methods of synthesis and use
US9999672B2 (en) 2014-03-24 2018-06-19 Xenoport, Inc. Pharmaceutical compositions of fumaric acid esters
CN105906505B (en) * 2016-06-03 2018-06-12 陕西能源职业技术学院 A kind of process for preparing fumaric monoalkylester

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