CN103333085B - Preparation and separation method of neotame intermediate imine - Google Patents
Preparation and separation method of neotame intermediate imine Download PDFInfo
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- CN103333085B CN103333085B CN201310290681.5A CN201310290681A CN103333085B CN 103333085 B CN103333085 B CN 103333085B CN 201310290681 A CN201310290681 A CN 201310290681A CN 103333085 B CN103333085 B CN 103333085B
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Abstract
The invention belongs to the technical field of chemical synthesis, and relates to a preparation and separation method of neotame intermediate imine. The preparation and separation method of the neotame intermediate imine comprises the following steps that S1, aspartame reacts with 3,3-dimethyl butyraldehyde in a solvent under nitrogen protection; the reaction time of a reaction solution under the condition of water bath insulation at 35-37 DEG C is 10-15h; and S2, an upper film of the reaction solution is filtered and condensed under the nitrogen protection; the filtering temperature is 28-35 DEG C; a concentrated solution obtained by separation is devitrified and filtered; a filter cake is washed by the solvent; and white solid, namely neotame intermediate imine is obtained. Neotame prepared by intermediate feed prepared and separated by the preparation and separation method of neotame intermediate imine can be directly devitrified from the reaction solution without crystallization or purification again, and a neotame product with the liquid phase purity greater than 99.5% is obtained.
Description
Technical field
The invention belongs to chemosynthesis technical field, relate to the preparative separation method of the sweet intermediate imine of a kind of knob.
Background technology
Knob is sweet is a kind of novel non-nutritive intense sweetener, its chemistry (N-[N-(3,3-dimethylbutyl)-L-A-aspartic acid]-L-Phe-1-methyl esters) by name, and be called for short NTM, structural formula is as follows:
。
Knob is sweet is the derivative of aspartame (APM), invented by two of France scholars the earliest, and obtained substance invention patent in 1993, ratify that knob is sweet to be used in food calendar year 2001 the earliest in Australia and New Zealand, the also official approval use of in July, 2002 U.S. FDA, 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, adds by need of production amount.Knob is sweet does not provide energy, has the pure sweet taste of similar sucrose, without any assorted taste.It is all very stable, especially relatively stable than aspartame in moisture food system under dry or neutral condition.
Knob is sweet has local flavor enhancing characteristic, effectively can reduce the usage quantity of essence and citric acid in food.The compound property that knob is sweet is splendid, not only can mixedly with the nutritive sweeteners comprising sucrose and high fructose syrup use, also can use composite with the intense sweetener of non-nutritive.Knob is sweet is not only applicable to comprise all groups of children, pregnant woman, lactating women and obesity, cardiovascular diseases and diabetic subject, is also applicable to the phenylketonuria patient that can not eat aspartame.Allow in China in the various sweeting agents used, knob is sweet is the one that each side advantage is maximum.Therefore, knob is sweet to be widely used in the processed foods such as beverage, chewing gum, milk-product, preserved fruit, jelly pudding, syrup, bread, biscuit cake, ice-creams, jam and pickles, and medicine, healthcare products, in animal-feed, with alternative sucrose and other sweeting agents.
The conventional synthesis path that knob is sweet is be that raw material reaction obtains (synthetic route that the knob recorded as patent CN101270092 is sweet) by 3,3-dimethyl butyraldehyde and aspartame.Its intermediate imine N-[N-(3, 3-dimethylbutylene)-L-α-aspartyl]-L-Phe 1-methyl esters a kind of never effective preparative separation method, all that to prepare knob sweet without separation direct hydrogenation, but without separation, discovery can cause side reaction under study for action, can to detect after the sweet main peak of knob that in Liquid Detection is separated retention time is about the sweet retention time of knob 5 times of places and has larger impurity peaks, by analysis for two molecules 3 have been gone up in the amino reaction in a part aspartame, 3-dimethyl, more difficult removal, sternly must have impact on the sweet quality of knob, purifying for aftertreatment causes larger difficulty, add aftertreatment cost, be unfavorable for producing purifying and cost control.
The chemical formula of the sweet intermediate imine of knob is:
.
Summary of the invention
In order to solve above-mentioned technical problem, the invention provides the preparative separation technology of the sweet intermediate imine of a kind of knob, thus realize the preparative separation to the sweet intermediate imine of knob, improve the sweet yield of knob and quality.
The present invention is realized by following technical scheme:
A preparative separation method for the sweet intermediate imine of knob, comprises the steps:
S1: under nitrogen protection, reacts in a solvent by aspartame and 3,3-dimethyl butyraldehyde, and 35 ~ 37 DEG C of condition lower reaction times of reaction solution water bath heat preservation are 10 ~ 15 hours;
S2: under nitrogen protection, concentrates membrane filtration on reaction solution, and filtration temperature is 28 ~ 35 DEG C, is separated the concentrated solution crystallization obtained, and filter, filter cake solvent wash, obtains white solid, is the sweet intermediate imine of knob.
In the preparative separation method of the sweet intermediate imine of above-mentioned knob, the solvent described in step S1 is the one in methyl alcohol or ethanol.
In the preparative separation method of the sweet intermediate imine of above-mentioned knob, the raw material aspartame added in step S1 and the mol ratio of 3,3-dimethyl butyraldehyde are 1:1.
In the preparative separation method of the sweet intermediate imine of above-mentioned knob, the film that in step S2, membrane filtration is used is hollow fiber ultrafiltration membrane 8060.
In the preparative separation method of the sweet intermediate imine of above-mentioned knob, in step S2, filtration temperature is 28 ~ 35 DEG C, and recrystallization temperature is-5 ~ 5 DEG C, and the crystallization time is 10 ~ 15 hours.
In the preparative separation method of the sweet intermediate imine of above-mentioned knob, in step S2, filtration temperature is 32 DEG C, and recrystallization temperature is 0 DEG C, and the crystallization time is 13 hours.
In the preparative separation method of the sweet intermediate imine of above-mentioned knob, in step S2, filter cake washing solvent is the one in methyl alcohol or ethanol.
Beneficial effect of the present invention is:
(1) the invention provides the preparative separation technology of the sweet intermediate imine of a kind of knob, thus realize the preparative separation to the sweet intermediate imine of knob, improve the sweet yield of knob and quality.
(2) the Intermediate Preparation knob adopting the preparative separation method of the sweet intermediate imine of knob of the present invention to prepare is sweet, can effectively avoid this side reaction, simplify post-processing operation and cost, can obtain the sweet product of knob of high-quality easily, saves the sweet production cost of knob.
(3) the preparative separation method of the sweet intermediate imine of knob of the present invention, does not need to react under the conditions such as high vacuum, high temperature, high pressure, operates more simple and safety.
(4) the preparative separation method of the sweet intermediate imine of knob of the present invention, without the need to using highly basic, strong acid, reaction conditions is gentle, and corrosion-free to conversion unit, environmental pollution is little.
(5) shown by contrast and experiment, sweet by the feed intake knob of preparation of the intermediate gone out with the preparative separation method preparative separation of the sweet intermediate imine of knob of the present invention, directly can obtain the sweet product of liquid phase purity > 99.5% knob from reaction solution crystallization without crystallization purifying again.
Embodiment
Below in conjunction with specific embodiment, the present invention is further described, so that those skilled in the art more understands the present invention, but does not therefore limit the present invention.
Embodiment 1
Dehydrated alcohol 1500 grams is added in 5L reaction flask, passes into nitrogen, stir, then add aspartame 294 grams, 3,3-diformazan butyraldehyde 100 grams, water-bath temperature control 37 DEG C, stirring reaction 15 hours, filter and remove a small amount of unreacted aspartame; By upper for filtrate film (hollow fiber ultrafiltration membrane 8060).Filtering and concentrating, filtration temperature is 35 DEG C, be separated the ethanol obtained and contain a small amount of 3, the solution recycling of 3-dimethyl butyraldehyde, the sweet intermediate imine concentrated solution of knob puts into 0 DEG C of refrigerator crystallization 12 hours, and filter, white solid 352 grams washed to obtain by a small amount of cold ethanol of filter cake, yield 93.6%, HPLC:> 98.5%
Embodiment 2
Anhydrous methanol 1800 grams is added in 5L reaction flask, passes into nitrogen, stir, then add aspartame 294 grams, 3,3-diformazan butyraldehyde 100 grams, water-bath temperature control 37 DEG C, stirring reaction 12 hours, filter and remove a small amount of unreacted aspartame; By upper for filtrate film (hollow fiber ultrafiltration membrane 8060).Filtering and concentrating, filtration temperature is 28 DEG C, be separated the methyl alcohol obtained and contain a small amount of 3, the solution recycling of 3-dimethyl butyraldehyde, the sweet intermediate imine concentrated solution of knob puts into 0 DEG C of refrigerator crystallization 15 hours, and filter, a small amount of cold methanol of filter cake washes to obtain white solid 355 grams, yield 94.4%, HPLC:> 99%
Embodiment 3
Dehydrated alcohol 1500 grams is added in 5L reaction flask, passes into nitrogen, stir, then add aspartame 294 grams, 3,3-diformazan butyraldehyde 100 grams, water-bath temperature control 36 DEG C, stirring reaction 12 hours, filter and remove a small amount of unreacted aspartame; By upper for filtrate film (hollow fiber ultrafiltration membrane 8060).Filtering and concentrating, filtration temperature is 30 DEG C, be separated the ethanol obtained and contain a small amount of 3, the solution recycling of 3-dimethyl butyraldehyde, the sweet intermediate imine concentrated solution of knob puts into 5 DEG C of refrigerator crystallizatioies 15 hours, and filter, white solid 362.5 grams washed to obtain by a small amount of cold ethanol of filter cake, yield 96.4%, HPLC:> 99%.
Embodiment 4: prepare the sweet embodiment of knob with the intermediate imine of preparative separation of the present invention.
Add 2000ml methyl alcohol in the little autoclave of 5L, and the intermediate imine 370 grams of gained of the present invention is added in the little autoclave of 5L, catalyzer 10% palladium 10 grams, carbon (wet basis), pass into hydrogen pressure to 0.8Mpa, temperature control 55 ~ 65 degree of reactions 4 hours, filtration catalizer, concentration and recovery methyl alcohol, adding 1500 grams in gained residue oily matter goes dried up, 10 DEG C of crystallizatioies 4 hours, filter, filtration cakes torrefaction obtains 374.1 grams of pure white crystalline solids, yield 96%, HPLC > 99.5%
Embodiment 5: directly prepare the sweet embodiment of knob without separation.
Add 2000ml methyl alcohol in the little autoclave of 5L, add aspartame 294 grams, 3,3-diformazan butyraldehyde 100 grams, catalyzer 10% palladium 10 grams, carbon (wet basis), passes into hydrogen pressure to 0.8Mpa, temperature control 55 ~ 65 degree of reactions 4 hours, filtration catalizer, concentration and recovery methyl alcohol, adding 1500 grams in gained residue oily matter goes dried up, 10 DEG C of crystallizatioies 4 hours, filter, filtration cakes torrefaction obtains 272.8 grams of pure white crystalline solids, yield 70%, HPLC:92.6%
Gained solid is added acetic acid ethyl dissolution complete, slowly drip sherwood oil to solution and become muddy, 10 DEG C of crystallizatioies 5 hours, filter, filter cake drying obtains white solid 218.2 grams, HPLC:98.5%, yield 80%.
Can find out from the data of example 4 and example 5: sweet through separation of intermediates imines gained knob: can more than 92%, more than HPLC:99.5% to be reached in aspartame total recovery, all recyclable recycling of all solvents; Sweet without separating obtained knob: in aspartame total recovery 56%, HPLC:98.5%, and crystallization purifying solvent is ethyl acetate and sherwood oil, because both boiling points are close, cannot Separation and Recovery recycling.
Claims (2)
1. a preparative separation method for the sweet intermediate imine of knob, is characterized in that, comprise the steps:
S1: under nitrogen protection, reacts in a solvent by aspartame and 3,3-dimethyl butyraldehyde, and 35 ~ 37 DEG C of condition lower reaction times of reaction solution water bath heat preservation are 10 ~ 15 hours;
S2: under nitrogen protection, concentrates membrane filtration on reaction solution, and filtration temperature is 28 ~ 35 DEG C, is separated the concentrated solution crystallization obtained, and filter, filter cake solvent wash, obtains white solid, is the sweet intermediate imine of knob;
Solvent described in step S1 is the one in methyl alcohol or ethanol;
The raw material aspartame added in step S1 and the mol ratio of 3,3-dimethyl butyraldehyde are 1:1;
The film that in step S2, membrane filtration is used is hollow fiber ultrafiltration membrane 8060;
In step S2, filtration temperature is 28 ~ 35 DEG C, and recrystallization temperature is-5 ~ 5 DEG C, and the crystallization time is 10 ~ 15 hours;
In step S2, filter cake washing solvent is the one in methyl alcohol or ethanol.
2. the preparative separation method of the sweet intermediate imine of knob according to claim 1, is characterized in that, in described step S2, filtration temperature is 32 DEG C, and recrystallization temperature is 0 DEG C, and the crystallization time is 13 hours.
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| CN108169342B (en) * | 2016-12-07 | 2020-12-25 | 内蒙古蒙牛乳业（集团）股份有限公司 | Method for detecting neotame content in milk-containing beverage |
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