CN104177473A - Synthesis method of neotame - Google Patents
Synthesis method of neotame Download PDFInfo
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- CN104177473A CN104177473A CN201410413292.1A CN201410413292A CN104177473A CN 104177473 A CN104177473 A CN 104177473A CN 201410413292 A CN201410413292 A CN 201410413292A CN 104177473 A CN104177473 A CN 104177473A
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Abstract
The invention relates to a synthesis method of neotame. The method comprises the following steps: (1) adding aspartame and 3,3-dimethyl-butyl aldehyde to an organic solvent in a vacuum state, reacting at the reaction temperature of 20-50 DEG C for 5-24 hours, carrying out concentration and separation at 0-50 DEG C after reaction is ended, concentrating to obtain white paste, adding deionized water to devitrify, thus obtaining a neotame intermediate imine in a centrifuging manner; (2) adding imine and an organic solvent to a hydrogenation reactor, introducing hydrogen until the pressure is 0.1-0.5MPa, adding a catalyst, reacting at the temperature of 35-40 DEG C for 5-30 hours, filtering and removing the catalyst, concentrating the filtrate and removing an organic solvent, and recrystallizing and purifying by water, methanol or ethanol, so as to obtain the neotame. According to the synthesis method, the defects in the prior art are overcome, high-purity imine is generated, the activity of the catalyst is reduced, the selectivity of the catalyst on the imine is increased, the service life of the catalyst is prolonged, the reaction impurity is reduced, and the product purity is improved.
Description
Technical field
The present invention relates to the synthetic method that a kind of knob is sweet.
Background technology
Knob is sweet is the derivative of aspartame, by two scholars invention of France the earliest, and in acquisition substance invention patent in 1993, calendar year 2001 is ratified to use in food in Australia and New Zealand the earliest, in July, 2002 U.S. FDA also official approval use, Ministry of Health of the People's Republic of China ratifies in April, 2003 that knob is sweet to be used in varieties of food items.
The mouthfeel that knob is sweet is pure, similar sucrose, sugariness is 7000～13000 times of sucrose, there is good stability, and heat is provided hardly, harmless to human-body safety, be the non-nutritive intense sweetener that a class performance is very excellent, be widely used in the processed foods such as milk-product, beverage, bread, chewing gum, jelly, preserved fruit, biscuit cake, ice-creams, jam and pickles, and in medicine, healthcare products and animal-feed.The sweet characteristic also with local flavor enhancing of knob, can effectively reduce the consumption of essence and citric acid in food, the compatibility that knob is sweet is splendid, not only can take use with the nutritional type sweeting agent that comprises sucrose and high fructose is mixed, also can the composite use with the intense sweetener of non-nutritive.The sweet fluctuation that can not cause blood sugar in body of knob, is not only applicable to children, pregnant woman and obesity, cardiovascular diseases and glycosuria patient, can also be applicable to use the phenylketonuria patient of aspartame.
In the sweet chemical synthesis process of knob; can be by take sodium cyanoborohydride as reductive agent; with 3,3-dimethyl butyraldehyde, aspartame is carried out to N-alkylation building-up reactions (referring to US Patent No. 5480668), due to expensive; synthetic stone produces and is difficult to separated impurity simultaneously; introduce the N of two alkyl, N-[bis-(3,3-dimethylbutyl)-L-α-aspartyl]-L-Phe methyl esters; synthetic cost is too high, is not suitable for industrial production.
Chinese patent CN101270092B discloses with formic acid, by aspartame and 3, 3-dimethyl butyraldehyde carries out N-alkylation building-up reactions, but react not thorough, also can produce and be difficult to separated impurity simultaneously, introduce the N of two alkyl, N-[bis-(3, 3-dimethylbutyl)-L-α-aspartyl]-L-Phe methyl esters, be not suitable for scale production, in US Patent No. 7288640, described with catalyzer, if platinum carbon or palladium carbon are by 3, the mixture of 3-dimethyl butyraldehyde precursor and aspartame carries out hydrogenation and carrys out synthesizing neotame, but yield is less than 60%, product purity is not high yet, only has 97% left and right, be not suitable for industrial production yet.In patent CN1784418A and CN101565451A, adopted the single catalyst of a series of platinum family elements such as palladium carbon and palladium black, the activity of element is higher, causes the phenyl ring overreaction in aspartame, makes to add in hydrogenation reaction excess hydrogen, form the sweet derivative of knob, cause impurity to increase.The iridium adopting in Chinese patent CN101775066B is catalyst based, although improved the selectivity to imines, imines is not carried out to separation, can produce side reaction equally, generates difficult separated impurity.
Summary of the invention
The object of this invention is to provide the synthetic method that a kind of knob is sweet, customer service deficiency of the prior art, generates high purity imines, reduce the activity of catalyzer, increased the selectivity of catalyzer to imines, the work-ing life of extending catalyst, reduce reaction impurities, improve product purity.
The sweet synthetic method of a kind of knob of the present invention, comprises the following steps:
(1), under vacuum state, aspartame and 3,3-dimethyl butyraldehyde are added in organic solvent, under 20-50 ℃ of temperature of reaction, react 5-24h, after reaction finishes, 0-50 ℃ of concentrating and separating, concentrate and obtain white paste, add deionized water crystallization, then through the centrifugal sweet intermediate imines of knob that obtains;
(2) imines and organic solvent are added to hydrogenation still, logical hydrogen to pressure is 0.1-0.5MPa, adds catalyzer, temperature is at 35-40 ℃, and reaction 5-30h, removes by filter catalyzer, the concentrated organic solvent of removing of filtrate, water, methyl alcohol or ethyl alcohol recrystallization are purified, and obtain knob sweet.
In step (1), the pressure of vacuum state is-0.8--0.96MPa.
In step (1), the mol ratio of aspartame and 3,3-dimethyl butyraldehyde is 1.05～1.1:1.
In step (1), heating mode is that water-bath is heated.
Heat preferably 30～45 ℃ of temperature of water-bath.
In step (1), recrystallization temperature is 0-20 ℃, and the time is 5-15h.
In step (2), catalyzer is palladium-ruthenium or palladium-nickel bimetal composite catalyzer; Wherein, palladium-ruthenium or palladium-nickel bimetal composite catalyzer are to account for the palladium-ruthenium of 5-15% of catalyzer total mass or palladium-nickelalloy to carry and be attached on gac, aluminum oxide, silicon-dioxide, diatomite, barium sulfate or calcium carbonate.Preferably palladium-ruthenium or palladium-nickel bimetal composite catalyzer account for the 5-10% of catalyzer total mass.Reduce the activity of catalyzer, by the selectivity of the catalyst based increase imines of iridium, overcome the feature that palladium or platinum are not high to the selectivity of imines, greatly improved the sweet purity of knob.
In palladium-ruthenium or palladium-nickelalloy, the massfraction of palladium is 70-90%, and the massfraction of ruthenium or nickel is 30-10%.
Organic solvent is one or both in methyl alcohol, ethanol, ethyl acetate or water.
The present invention obtains the sweet intermediate imines of highly purified knob, has reduced the N of two alkyl, N-[bis-(3,3-dimethylbutyl)-L-α-aspartyl] generation of-L-Phe methyl esters.
It is 99.9% (HPLC) that the present invention just can make the sweet purity of knob by crystallization, approaches 100%.
The present invention is divided into two-step reaction: the imines of first synthesis of high purity, then by catalyst synthesizing neotame, both improved the sweet synthetic purity of knob, and also reduced the synthetic difficulty of product, be applicable to the sweet production of large-scale knob.
Compared with prior art, the present invention has following beneficial effect:
The synthetic method that knob of the present invention is sweet, customer service deficiency of the prior art, generates high purity imines, has reduced the activity of catalyzer, increases the selectivity of catalyzer to imines, in the work-ing life of extending catalyst, reduces reaction impurities, improves product purity.
Embodiment
Below in conjunction with example, the invention will be further described.
Embodiment 1
After vacuum tank is evacuated down to-0.7MPa, add methyl alcohol 1200g, add aspartame 294g and 3,3-dimethyl butyraldehyde 100g, heating in water bath to 30 ℃, reaction times 13h, then concentrated at 40 ℃ of temperature, obtain white paste, add 1800g deionized water crystallization, recrystallization temperature is controlled at 15 ℃, time is 15h, the white solid thing obtaining is centrifugal, obtain 372 grams of white solids, the yield of imines is 98.9%;
The 372g imines of acquisition is added in hydrogenation still, add 1500g methyl alcohol, passing into hydrogen to pressure is 0.5MPa, adds 85g palladium-ruthenium/activated carbon catalyst, heating in water bath to 40 ℃, reaction 15h, remove by filter catalyzer, the concentrated methanol solution of removing of filtrate is sweet with the method acquisition knob of ethyl alcohol recrystallization, yield is greater than 90%, and purity is higher than 99% (HPLC).
Wherein, palladium-ruthenium/activated carbon catalyst is that palladium-ruthenium alloy of 5% of accounting for catalyzer total mass carries and is attached to gac; In palladium-ruthenium alloy, palladium accounts for 70% of alloy mass, and ruthenium accounts for 30% of alloy mass.
Embodiment 2
After vacuum tank is evacuated down to-0.96MPa, add ethanol 1500g, add aspartame 294g and 3,3-dimethyl butyraldehyde 100g, heating in water bath to 33 ℃, reaction times 24h, concentrating and separating at 40 ℃ of temperature, obtain white paste, add 1800g deionized water crystallization, recrystallization temperature is controlled at 20 ℃, time is 10h, the white solid thing obtaining is centrifugal, obtain 373.1 grams of white solids, the yield of imines is 99.2%;
The 373.1g imines of acquisition is added in hydrogenation still, add 1200g ethanol, passing into hydrogen to pressure is 0.3MPa, adds 30g palladium-ruthenium/aluminium oxide catalyst, heating in water bath to 35 ℃, reaction 5h, remove by filter catalyzer, concentrated ethanolic soln, it is sweet that the method for water recrystallization obtains knob, yield is greater than 90%, and purity is higher than 99% (HPLC).
Wherein, palladium-ruthenium/aluminium oxide catalyst is that palladium-ruthenium alloy of 10% of accounting for catalyzer total mass carries and is attached on aluminum oxide; In palladium-ruthenium alloy, palladium accounts for 80% of alloy mass, and ruthenium accounts for 20% of alloy mass.
Embodiment 3
After vacuum tank is evacuated down to-0.85MPa, add ethyl acetate 2500g, add aspartame 294g and 3,3-dimethyl butyraldehyde 100g, heating in water bath to 35 ℃, reaction times 24h, concentrating and separating at 35 ℃ of temperature, obtain white paste, add 1800g deionized water crystallization, recrystallization temperature is controlled at 5 ℃, time is 5h, the white solid thing obtaining is centrifugal, obtain 366.7 grams of white solids, the yield of imines is 97.5%;
The 366.7g imines of acquisition is added in hydrogenation still, add 1500g ethyl acetate, passing into hydrogen to pressure is 0.1MPa, adds 55g palladium-nickel/activated carbon catalyst, heating in water bath to 35 ℃, reaction 5h, remove by filter catalyzer, concentrated ethyl acetate solution is sweet with the method acquisition knob of ethyl alcohol recrystallization, yield is greater than 90%, and purity is higher than 99% (HPLC).
Wherein, palladium-nickel/activated carbon catalyst is that palladium-ruthenium alloy of 15% of accounting for catalyzer total mass carries and is attached to gac; In palladium-ruthenium alloy, palladium accounts for 90% of alloy mass, and nickel accounts for 10% of alloy mass.
Claims (9)
1. the sweet synthetic method of knob, is characterized in that, comprises the following steps:
(1), under vacuum state, aspartame and 3,3-dimethyl butyraldehyde are added in organic solvent, under 20-50 ℃ of temperature of reaction, react 5-24h, after reaction finishes, 0-50 ℃ of concentrating and separating, concentrate and obtain white paste, add deionized water crystallization, then through the centrifugal sweet intermediate imines of knob that obtains;
(2) imines and organic solvent are added to hydrogenation still, logical hydrogen to pressure is 0.1-0.5MPa, adds catalyzer, temperature is at 35-40 ℃, and reaction 5-30h, removes by filter catalyzer, the concentrated organic solvent of removing of filtrate, water, methyl alcohol or ethyl alcohol recrystallization are purified, and obtain knob sweet.
2. according to the sweet synthetic method of knob described in right 1, it is characterized in that, in step (1), the pressure of vacuum state is-0.8--0.96MPa.
3. according to the sweet synthetic method of knob described in right 1, it is characterized in that, in step (1), the mol ratio of aspartame and 3,3-dimethyl butyraldehyde is 1.05～1.1:1, and the mass ratio of aspartame, organic solvent and catalyzer is 1:3-10:0.1-0.3.
4. according to the sweet synthetic method of knob described in right 1, it is characterized in that, in step (1), heating mode is that water-bath is heated.
5. according to the sweet synthetic method of knob described in right 1, it is characterized in that, in step (1), recrystallization temperature is 0-20 ℃, and the crystallization time is 5-15h.
6. according to the sweet synthetic method of knob described in right 1, it is characterized in that, in step (2), catalyzer is palladium-ruthenium or palladium-nickel bimetal composite catalyzer.
7. according to the sweet synthetic method of knob described in right 6, it is characterized in that, palladium-ruthenium or palladium-nickel bimetal composite catalyzer are to account for the palladium-ruthenium of 5-15% of catalyzer total mass or palladium-nickelalloy to carry and be attached on gac, aluminum oxide, silicon-dioxide, diatomite, barium sulfate or calcium carbonate.
8. according to the sweet synthetic method of knob described in right 6, it is characterized in that, in palladium-ruthenium or palladium-nickelalloy, the massfraction of palladium is 70-90%, and the massfraction of ruthenium or nickel is 30-10%.
9. according to the sweet synthetic method of knob described in right 1, it is characterized in that, organic solvent is one or both in methyl alcohol, ethanol, ethyl acetate or water.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104693159A (en) * | 2015-02-17 | 2015-06-10 | 华东师范大学 | Method for preparing gamma-valerolactone by liquid-phase hydrogenation and catalyst used by same |
| CN105504006A (en) * | 2016-01-28 | 2016-04-20 | 柳玉荣 | Synthetic method for improving quality of neotame |
| CN105541965A (en) * | 2016-01-28 | 2016-05-04 | 柳玉荣 | Synthetic method for improving neotame yield |
| CN109467586A (en) * | 2018-12-15 | 2019-03-15 | 山东诚汇双达药业有限公司 | A kind of refining methd of neotame |
| CN111450857A (en) * | 2020-05-13 | 2020-07-28 | 江苏帕睿尼新材料科技有限公司 | Catalyst and preparation process of tert-butyl isothiocyanate |
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| CN1966518A (en) * | 2006-11-16 | 2007-05-23 | 暨南大学 | Synthetic methods for nutame |
| CN101775066A (en) * | 2010-01-29 | 2010-07-14 | 常茂生物化学工程股份有限公司 | Method for synthesizing neotame |
| CN103145796A (en) * | 2013-03-25 | 2013-06-12 | 重庆民泰香料化工有限责任公司 | Synthesis process of neotame |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104693159A (en) * | 2015-02-17 | 2015-06-10 | 华东师范大学 | Method for preparing gamma-valerolactone by liquid-phase hydrogenation and catalyst used by same |
| CN104693159B (en) * | 2015-02-17 | 2017-01-04 | 华东师范大学 | The method of gamma-valerolactone and the catalyst of use thereof are prepared in liquid-phase hydrogenatin |
| CN105504006A (en) * | 2016-01-28 | 2016-04-20 | 柳玉荣 | Synthetic method for improving quality of neotame |
| CN105541965A (en) * | 2016-01-28 | 2016-05-04 | 柳玉荣 | Synthetic method for improving neotame yield |
| CN105504006B (en) * | 2016-01-28 | 2019-01-04 | 柳玉荣 | A kind of synthetic method improving neotame quality |
| CN105541965B (en) * | 2016-01-28 | 2019-01-18 | 柳玉荣 | A kind of synthetic method improving neotame yield |
| CN109467586A (en) * | 2018-12-15 | 2019-03-15 | 山东诚汇双达药业有限公司 | A kind of refining methd of neotame |
| CN109467586B (en) * | 2018-12-15 | 2021-06-22 | 济南诚汇双达化工有限公司 | Neotame refining method |
| CN111450857A (en) * | 2020-05-13 | 2020-07-28 | 江苏帕睿尼新材料科技有限公司 | Catalyst and preparation process of tert-butyl isothiocyanate |
| CN111450857B (en) * | 2020-05-13 | 2023-06-13 | 江苏帕睿尼新材料科技有限公司 | Catalyst and preparation process of tert-butyl isothiocyanate |
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Denomination of invention: Synthesis method of neotame Effective date of registration: 20230420 Granted publication date: 20170811 Pledgee: Shandong Lijin Rural Commercial Bank Co.,Ltd. Pledgor: Shandong Benyue Biotechnology Co.,Ltd. Registration number: Y2023980038550 |
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