CN112321676A - Salt forming method of neotame - Google Patents

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a salt forming method of neotame, namely a method for forming a salt by N- [ N- (3, 3-dimethylbutyl) -L-alpha-aspartyl ] -L-phenylalanine-1-methyl ester (neotame) and inorganic or organic acid. The method is characterized in that: heating and dissolving neotame in low molecular alcohol, adding acid to form salt, distilling to remove alcohol, and adding ethyl acetate to crystallize to obtain the product. The invention has the beneficial effects that the neotame salt refined product is obtained by salifying neotame and inorganic acid or organic acid, the yield is over 90%, and the liquid phase purity is over 99.7%. The high-quality neotame salt is more beneficial to improving the neotame stability and water solubility in production, thereby further improving and meeting the quality safety and application requirements of pharmaceutical auxiliary materials, food additives and feed additives.

Description

Salt forming method of neotame

Technical Field

The invention belongs to the technical field of chemical synthesis, and particularly relates to a salt forming method of neotame, which can increase the stability and water solubility of neotame N- [ N- (3, 3-dimethylbutyl) -L-alpha-aspartyl ] -L-phenylalanine-1-methyl ester.

Background

Chemical name of neotame: n- [ N- (3, 3-dimethylbutyl) -L-alpha-aspartyl ] -L-phenylalanine-1-methyl ester, which is a white crystalline powder containing about 4.5% of crystal water, is a functional sweetener. The structural formula of neotame is as follows:

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neotame has a pure sweet taste, is synergistic in sweetness, is very close to aspartame, and has no bitter taste and metallic taste which are often associated with other intense sweeteners. The sweetness is 7000-13000 times that of cane sugar and 30-60 times that of aspartame, the energy value is almost zero, and the sugar cane sugar-free sweetener is more favorable for special crowds such as children, pregnant women, lactating women, diabetics, phenylketonuria patients and the like.

Neotame is widely applied to medicine auxiliary materials, food additives and feed additives; the demand is increasing, and simultaneously, the requirement on the product quality is also increasing. Although neotame has certain stability at an instant high temperature, in practical application, a process of keeping the high temperature for a long time is often adopted, so that the neotame is easily decomposed. In addition, the neotame is easy to hydrolyze to generate N- [ N- (3, 3-dimethylbutyl) -L-alpha-aspartyl ] -L-phenylalanine which is an impurity after being placed in a humid environment for a long time. The neotame is unstable at a temperature of more than 40 ℃, and the storage temperature in a closed space in summer often exceeds 40 ℃, so that the stability of the neotame is improved, and the key problem to be solved urgently is solved. The inventor finds in practice that the stability of neotame can be improved after the neotame is salified, and the neotame is not easy to decompose to generate impurities even in a high-temperature environment.

Patents CN1784418A, CN 104045688A, CN 101565449A, CN 102167722A, CN 104177473A, CN 108676064A, CN 110467648A, CN101270092A, CN102863511A, US5510508, US6281380, US5480668, butyrol and the like, progress of research on synthesis of neotame and its intermediate 3, 3-dimethylbutyraldehyde, "chinese food additive" (2012, (stage 6), zhangjinfeng and the like, new process for synthesizing neotame, a new process for food research and development "(2011, (stage 4), yan-ri-an and the like, improvement of a synthetic method of neotame, a new process for synthesizing neo; the above documents only relate to a synthetic method of neotame, and no report and method relate to salt formation of neotame.

Disclosure of Invention

In order to solve the technical problems, the invention provides a salt forming method of neotame, and the method is used for obtaining the qualified neotame salt with the yield of more than 90% and the liquid phase purity of more than 99.7% through experiments and production amplification verification.

The invention is realized by the following technical scheme:

a salt forming method of neotame is characterized by comprising the following steps:

(1) putting low molecular alcohol into a reaction kettle, and adding neotame while stirring;

(2) heating the solution in the step (1) to raise the temperature, and dissolving;

(3) adding inorganic or organic acid into the solution obtained in the step (2) to form salt;

(4) distilling the solution obtained in the step (3) under reduced pressure to remove low molecular alcohol, adding ethyl acetate, uniformly stirring, introducing ice saline water, cooling and crystallizing, centrifuging after crystallization is finished, washing wet products with ethyl acetate, centrifuging again, collecting the wet products, and drying to obtain the high-purity neotame salt.

In the above salt formation method of neotame, the low molecular alcohol in step (1) is one or more of methanol, ethanol and isopropanol; the acid in the step (3) is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, tartaric acid and citric acid.

Preferably, in the above salt-forming method of neotame, the low molecular alcohol in step (1) is methanol; the acid in the step (3) is sulfuric acid.

In the above salt formation method of neotame, in the step (1), the weight ratio of neotame to low-molecular alcohol is 1: 1-5;

in the above salt formation method of neotame, in the step (1), the optimal weight ratio of neotame to methanol is 1: 2.

in the above salt-forming method of neotame, in the step (3), the reaction temperature of neotame and sulfuric acid in the solution is 20-40 ℃.

In the above salt-forming method of neotame, in the step (3), the molar ratio of neotame to acid is 1: 0.4-1.5.

In the above salt-forming method of neotame, in the step (4), neotame: the weight ratio of ethyl acetate is 1: 1-4.

In the above salt formation method of neotame, in the step (4), the temperature for cooling and crystallizing is-10-10 ℃.

The method for salifying neotame comprises the following steps:

(1) putting methanol into a reaction kettle, adding neotame while stirring to obtain a mixed solution, wherein the weight ratio of the methanol to the neotame is 2: 1;

(2) heating the solution in the step (1) to 30-40 ℃, and dissolving;

(3) adding concentrated sulfuric acid into the material in the step (2);

(4) and (3) carrying out reduced pressure concentration on the solution in the step (3), adding ethyl acetate with the weight 2 times that of the neotame, uniformly stirring, introducing ice saline, cooling to-10-10 ℃ for crystallization, centrifuging after crystallization is finished, washing wet products with ethyl acetate, centrifuging again, collecting the wet products, and drying to obtain the high-purity neotame salt.

In the present invention, all amounts and parts are by weight, and all raw materials and equipment are commercially available, unless otherwise specified.

Compared with the prior art, the invention has the advantages that:

(1) the salt forming method of neotame provided by the invention has the advantages that the product yield can reach more than 90%, and the product purity can reach more than 99.7%.

(2) The stability of the salt-formed neotame is enhanced, the decomposition speed of the salt-formed neotame is lower than that of a neotame raw material in a humid environment, and the salt-formed neotame raw material is more favorable for storing the neotame.

Drawings

FIG. 1 is a liquid phase diagram of neotame material used in the neotame example.

FIG. 2 is a liquid phase detection profile of neotame material used in the examples of neotame after heating at 60 ℃ for 2 hours.

FIG. 3 is a liquid phase detection spectrum of neotame sulfate prepared in example 1.

FIG. 4 is a liquid phase detection pattern of neotame hydrochloride prepared in example 1 after heating at 60 ℃ for 2 hours.

FIG. 5 is a liquid phase detection spectrum of Neotame citrate dihydrochloride prepared in example 2.

FIG. 6 is a liquid phase detection pattern of Neotame citrate dihydrochloride prepared in example 2 after heating at 60 ℃ for 2 hours.

Detailed Description

The present invention will be further described with reference to specific examples so that those skilled in the art may better understand the present invention, but the present invention is not limited thereto.

Neotame used in this application is made by this company.

Example 1

Putting 600kg of methanol into a 1500L reaction kettle, adding 300kg of neotame under stirring, heating to 30-40 ℃ for dissolving, slowly adding 37.5kg of concentrated sulfuric acid, slowly adding the concentrated sulfuric acid to prevent violent heat release, reacting at 30-40 ℃ for 1 hour after the adding, then distilling the methanol under reduced pressure to be viscous, adding 600kg of ethyl acetate, stirring for dispersing, introducing ice brine, cooling for crystallization, centrifuging when the temperature is reduced to 5-10 ℃, washing a solid material with 50kg of cold ethyl acetate, centrifuging again to obtain a wet product, drying under reduced pressure to obtain 313.8kg of a neotame sulfate dry product, wherein the yield is 97.0%.

Example 2

Placing 800kg of ethanol in a 1500L reaction kettle, adding 300kg of neotame under stirring, heating to 30-40 ℃ for dissolving, slowly adding 72.8kg of anhydrous citric acid, paying attention to slow addition to prevent a large amount of heat release, reacting for 2 hours at 30-40 ℃ after the addition, then distilling the ethanol under reduced pressure to be viscous, adding 900kg of ethyl acetate, stirring for dispersing, then cooling with ice saline, stirring for crystallization, centrifuging when the temperature is reduced to-5-0 ℃, washing a solid material with 50kg of cold ethyl acetate, centrifuging again to obtain a wet neotame citrate dihydrochloride, and drying under reduced pressure to obtain 323.6kg of a dry product with the yield of 90.1%.

Example 3

Putting 600kg of methanol into a 1500L reaction kettle, adding 300kg of neotame under stirring, heating to 30-40 ℃ for dissolving, adding 80kg of hydrochloric acid (with the concentration of 36.5%), slowly adding the hydrochloric acid to prevent a large amount of heat release, reacting at 30-40 ℃ for 1 hour after the addition is finished, then distilling the methanol under reduced pressure to be viscous, adding 600kg of ethyl acetate, stirring for dispersing, then introducing ice saline, cooling, stirring for crystallization, centrifuging when the temperature is reduced to 0-5 ℃, washing a solid material with 50kg of cold ethyl acetate, centrifuging again to obtain a wet neotame hydrochloride, drying the material under reduced pressure to obtain 301.1kg of a dry product, and obtaining the yield of 95.9%.

Because the neotame is unstable at a temperature of above 40 ℃, the purity of the neotame raw material, the prepared neotame sulfate and neotame citrate dihydrochloride before and after the comparison of the neotame raw material, the prepared neotame sulfate and neotame citrate dihydrochloride after the comparison of the neotame raw material and the prepared neotame sulfate and neotame citrate dihydrochloride after the comparison and the content of N- [ N- (3, 3-dimethylbutyl) -L-alpha-aspartyl ] -L-phenylalanine impurity (area normalization method) are measured, and the results are as follows:

	neotame raw material	Neotame sulfate	Neotame citrate dibasic salt
				Purity of liquid phase before heating	99.734%	99.791%	99.799%
Maximum single impurity before heating (%)	0.119%	0.124%	0.181%
				Purity of liquid phase after heating	96.500%	99.752%	99.755%
Maximum single impurity after heating	3.337%	0.181%	0.201%

From the results in the table, it can be seen that the neotame material is decomposed more under the test condition of heating at 60 ℃ for 2 hours, the impurity content of the neotame material after heating for about 0.787 minutes is increased to 3.337%, and the impurity content of the impurity A is increased from 0.119% before heating to 0.124% after heating.

The speed of decomposing the neotame into impurities in a high-temperature environment after the neotame is salified is slower than that of the neotame raw material, and the stability of the neotame can be improved by salifying the neotame.

Claims (9)

1. A salt forming method of neotame is characterized by comprising the following steps:

(1) putting low molecular alcohol into a reaction kettle, and adding neotame while stirring;

(2) heating the solution in the step (1) to raise the temperature, and dissolving;

(3) adding inorganic or organic acid into the solution obtained in the step (2) to form salt;

(4) distilling the solution obtained in the step (3) under reduced pressure to remove low molecular alcohol, adding ethyl acetate, uniformly stirring, introducing ice saline water, cooling and crystallizing, centrifuging after crystallization is finished, washing wet products with ethyl acetate, centrifuging again, collecting the wet products, and drying to obtain the high-purity neotame salt.

2. The method for salifying neotame according to claim 1, wherein the low molecular alcohol in step (1) is one or more of methanol, ethanol and isopropanol; the acid in the step (3) is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, citric acid, tartaric acid and the like.

3. The method for salifying neotame according to claim 2, wherein the low molecular alcohol in step (1) is methanol; the acid in the step (3) is sulfuric acid.

4. The method for salifying neotame according to claim 1, wherein in step (1), the weight ratio of neotame to low molecular alcohol is 1: 1-5;

the method for salifying neotame according to claim 4, wherein in step (1), the optimal weight ratio of neotame to methanol is 1: 2.

5. the method for salifying neotame according to claim 4, wherein in step (3), the reaction temperature of neotame and sulfuric acid in the solution is 20-40 ℃.

6. The method for salifying neotame according to claim 1, wherein in step (3), the molar ratio of neotame to acid is 1: 0.4-1.5.

7. The method for salifying neotame according to claim 1, wherein in step (4), the ratio of neotame: the weight ratio of ethyl acetate is 1: 1-4.

8. A process for salifying neotame as claimed in claim 1, wherein in step (4), the temperature for cooling and crystallization is in the range of-10 to 10 ℃.

9. A process for salifying neotame according to claim 1, comprising the steps of:

(1) putting methanol into a reaction kettle, adding neotame while stirring to obtain a mixed solution, wherein the weight ratio of the methanol to the neotame is 2: 1;

(2) heating the solution in the step (1) to 30-40 ℃, and dissolving;

(3) adding concentrated sulfuric acid into the material in the step (2);

(4) and (3) carrying out reduced pressure concentration on the solution in the step (3), adding ethyl acetate with the weight 2 times that of the neotame, uniformly stirring, introducing ice saline, cooling to-10-10 ℃ for crystallization, centrifuging after crystallization is finished, washing wet products with ethyl acetate, centrifuging again, collecting the wet products, and drying to obtain the high-purity neotame salt.

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