CN113956304B - Preparation method of N-acetylneuraminic acid - Google Patents
Preparation method of N-acetylneuraminic acid Download PDFInfo
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- CN113956304B CN113956304B CN202111138235.3A CN202111138235A CN113956304B CN 113956304 B CN113956304 B CN 113956304B CN 202111138235 A CN202111138235 A CN 202111138235A CN 113956304 B CN113956304 B CN 113956304B
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- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
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- C—CHEMISTRY; METALLURGY
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
The application provides a preparation method of N-acetylneuraminic acid. The preparation method comprises the following steps: after the sialic acid-containing solution was adsorbed and decolorized, N-acetylneuraminic acid was adsorbed using a strong base anion column. The preparation method of N-acetylneuraminic acid provided by the application can optimize the purity and yield of the prepared sialic acid product, the yield can reach more than 90%, and the whiteness of the product is also more than 90. The method provided by the application is simple to operate, low in cost, clean to produce and free from environmental pollution.
Description
Technical Field
The application relates to the technical field of separation and purification, in particular to a preparation method of N-acetylneuraminic acid.
Background
N-acetylneuraminic acid, also known as sialic acid, is a naturally occurring carbohydrate, which plays an important role in the normal development of brain function in children, and is widely used in milk powder or nutritional products during pregnancy or after pregnancy. Commercially available sialic acid is usually obtained by fermentation, hydrolysis or extraction, and how to obtain sialic acid with high yield and purity has been a hot spot of research.
Patent CN10567500c discloses a method for extracting polysialic acid from a fermentation broth of escherichia coli producing polysialic acid, which is characterized in that the method is adsorbed by a cation column and analyzed by chloroform, has high toxicity and is not suitable for industrial production. Patent CN102532208B discloses a method for continuously separating sialic acid, which adds a large amount of ethanol and ethyl acetate for mixed extraction, and cannot be recycled in the later period. Patent CN111386350a discloses a method for purifying sialic acid from fermentation broth, which gives crystals of low purity.
The applicant research team adopts the mode of conversion crystallization and crystal grading washing to extract and purify sialic acid, and obtains satisfactory effect on the purity improvement of sialic acid, but the yield and economic efficiency of the sialic acid cannot be well considered, industrial production cannot be well met, and a method with higher yield and crystal purity meeting the standard and realizing simplified process control cost is required to be developed.
Disclosure of Invention
The application aims to provide a preparation method of N-acetylneuraminic acid, which comprises the following steps:
after the sialic acid-containing solution was adsorbed and decolorized, N-acetylneuraminic acid was adsorbed using a strong base anion column.
In the prior art, the technology of ion exchange is common, but no matter what source of sialic acid is, the sialic acid is only subjected to the steps of deproteinization and/or degerming before ion exchange, and the purity and the yield of N-acetylneuraminic acid cannot be both achieved. Through a great deal of researches, the research team of the application discovers that the purity and the yield of the prepared sialic acid product can be optimized by carrying out adsorption decoloration treatment on the stock solution containing sialic acid before carrying out ion exchange adsorption on sialic acid. The ion exchange adsorption sialic acid is to adsorb N-acetylneuraminic acid by using a strong base anion column, and the ion exchange technology in the prior art is used for removing impurities, so that the beneficial effects of the application cannot be obtained. In the present application, the sialic acid-containing solution obtained by using the prior art can be used for the preparation (extraction) of N-acetylneuraminic acid by the method of the present application, for example, a sialic acid-containing solution obtained by hydrolysis or a sialic acid-containing solution obtained by fermentation. In the specific examples of the present application, the present application will be described in detail with respect to a sialic acid-containing solution (i.e., SA fermentation broth) obtained by fermentation, and the SA fermentation broth in examples and comparative examples may be the same, and the SA content thereof may be controlled unless otherwise specified.
In a preferred embodiment of the present application, the strong base anion column of the present application is a strong base anion resin, including but not limited to anion resins containing quaternary ammonium functionality. In order to further enhance the adsorption effect of SA, the water content of the strong base anion column of the present application is preferably 50 to 60%, the particle size is preferably 20 to 40 mesh, and the adsorption capacity is preferably 3 to 5mmol/g. In practice, it is preferable to select a commercially available anionic resin having a quaternary ammonium group function within the above-mentioned parameters, and in the examples of the present application, the present application is described in detail with respect to a commercially available anionic resin having a quaternary ammonium group function of WSD 260. Wherein, in the present application, the filler amount of the strong base anion resin is preferably: packing was performed at 20gSA per 100g of adsorbent. The SA content in the solution is usually detected before the decolored filler, the total SA of the material is calculated, and the filler amount of the strong base anion resin is calculated according to the required filler amount.
In a preferred embodiment of the present application, the method further comprises resolving SA (N-acetylneuraminic acid) adsorbed on a strong base anion column, collecting resolved solution, desalting, concentrating and drying. Preferably, sodium chloride aqueous solution is used for resolving N-acetylneuraminic acid obtained by adsorption on a strong base anion column, resolving liquid is collected, desalted, concentrated until the N-acetylneuraminic acid content is 80-100 g/L, and dried to obtain pure N-acetylneuraminic acid. Among them, the method commonly used in the present application can be used for desalting, and the conductivity of the desalted solution is preferably 50us or less. In the application, the analysis solution is preferably desalted by a nanofiltration membrane (preferably a nanofiltration membrane of 500 DA), the clear solution outlet is a salt-containing solution, and on-line detection of the conductivity can judge whether the salt in the SA solution is completely removed, and the conductivity of the clear solution outlet is required to be below 50 us/cm. In the application, the resolved strong base anion column can be regenerated by strong base solution (such as 3-5% sodium hydroxide solution), and is washed by pure water until the pH value is about 8-10, and the column can be reused continuously.
In the present application, the "drying" may use a drying method commonly used in the art, and preferred "drying" steps include: and (3) carrying out spray drying on the concentrated solution to obtain coarse crystals with the water content not higher than 10%, and carrying out secondary drying at 50-65 ℃ until the water content is not higher than 2%, thereby obtaining a pure product, namely the target product. Wherein the material temperature is kept between 50 and 65 ℃ in the spray drying process, and the secondary drying can be vacuum drying or microwave drying.
In a preferred embodiment of the application, the preparation process preferably comprises the step of reacting sialic acid-containing monomersAnd (3) after the solution is adsorbed and decolorized until the chromaticity value of the solution is not higher than 15 ℃, adsorbing N-acetylneuraminic acid by using a strong base anion column. Wherein the "adsorption bleaching" may be carried out by a method commonly used in the art, as long as the solution color value thereof is not higher than 15 °. Wherein, the steps of the adsorption decoloration can be as follows: and (3) performing adsorption decolorization by using an adsorption medium. The adsorption medium can be decolorized macroporous resin, activated carbon or attapulgite. In the present application, the decoloring is preferably performed using a decoloring macroporous resin, and the parameters of the decoloring macroporous resin are further preferably: the specific surface area is 480 to 600 square meters per gram, the pore size distribution is 8 to 9nm, and the pore volume is 1 to 3m 3 And/g, with 20-40 mesh granularity. The filler content of the decolorized macroporous resin is preferably 2-3 wt% of the material to be adsorbed. The decolored macroporous resin can be regenerated by using 3-5% sodium hydroxide solution after adsorption, and is continuously reused.
In a preferred embodiment of the application, the sialic acid containing solution is preferably a sialic acid solution of fermentative origin. Preferably from a fermentation broth containing sialic acid, by degerming and deproteinizing. Among them, the steps of degerming and deproteinizing may be those commonly used in the art, and in the present application, the step of "degerming" preferably includes: filtering with micro-hollow ceramic membrane under the filtering pressure of 0.2-0.4 Mpa, washing with clear water, and collecting clear liquid. Wherein the pore diameter of the micro-hollow ceramic membrane can be selected according to the requirement, and the 200nm micro-hollow ceramic membrane is used in the application.
The "deproteinizing" may be performed by centrifugation, sedimentation, filtration, silica gel adsorption, or the like, and in a specific embodiment of the present application, the deproteinizing may be performed by centrifugation, which may be the following steps: heating the clear liquid after degerming to 75 ℃, and centrifuging at the rotating speed of 4000-8000 r to obtain the clear liquid after degerming.
The preparation method of N-acetylneuraminic acid provided by the application can also be called an extraction method of N-acetylneuraminic acid, and the purity and yield of the prepared sialic acid product can be optimized by carrying out adsorption decoloration treatment on the stock solution containing sialic acid before carrying out ion exchange adsorption on sialic acid, the yield can reach more than 90%, the whiteness of the product is also more than 90%, and meanwhile, the main anion column in the method can be regenerated and recycled, so that the cost is reduced. The method provided by the application is simple to operate, can detect the content of the substances in the key steps on line or in real time, can effectively improve the separation efficiency, and simultaneously realizes the maximum utilization of the materials, and has the advantages of low cost, clean production and no environmental pollution.
Detailed Description
The following describes the embodiments of the present application in further detail with reference to examples. The following examples are illustrative of the application and are not intended to limit the scope of the application.
Example 1
The embodiment provides a preparation method of N-acetylneuraminic acid, which comprises the following steps:
1. taking SA fermentation liquor, wherein the SA content is 25g/L.
2. And (3) degerming: filtering with 200nm micro-hollow ceramic membrane with filtering pressure controlled at 0.3Mpa.
3. Collecting clear liquid: collecting the clear liquid obtained by filtration, and the target product is in the clear liquid.
4. Removing protein from the clear solution: the clear liquid was heated to 75 ℃ by a plate heat exchanger and passed through a centrifuge under the following conditions: rotating speed is 6000r, and continuously feeding and separating to obtain protein-removed clear liquid.
5. Decoloring and removing impurities: and (3) conveying the protein-removed clear liquid into macroporous resin special for decolorization to adsorb and remove impurities, and obtaining colorless clear liquid. Wherein the amount of the decolored resin filler is 3wt% of the total treatment material, and the chromaticity value of the decolored solution is monitored by an online colorimeter and is 15 degrees; wherein the specific surface area of the macroporous resin special for decolorization is 550 square meters per gram, the pore size distribution is 8nm, and the pore volume is 2.1m 3 And/g, particle size of 30 meshes.
6. Anion column adsorption: and (3) adsorbing N-acetylneuraminic acid in the decolorized solution by using a strong base type anion resin. Packing was performed at 20gSA per 100g of adsorbent. The strong base type anion resin is acrylic resin quaternary ammonium group (model WSD260, manufacturer: anhui tree chemical industry Co., ltd.) with water content of 50%, granularity of 20 meshes and adsorption capacity of 3.6mmol/g.
7. Analysis: analyzing the strong base anion column adsorbed with N-acetylneuraminic acid by using 0.2mol/l sodium chloride aqueous solution, and judging whether the analysis is complete or not by detecting the SA absorbance change in column liquid under analysis by an online preparation chromatograph.
8. Collecting an analysis solution: after the analysis is completed, collecting the analysis liquid.
9. Desalting by nanofiltration membranes: desalting the obtained analytical solution by a nanofiltration membrane of 500DA, and completing desalting when the conductivity of the clear liquid at the outlet is below 50 us/cm.
10. Concentrating: after the desalting is completed, the stock solution is continuously concentrated to the SA content of about 100g/L.
11. Predrying: and (3) carrying out spray drying on the obtained concentrated solution to obtain SA coarse crystals, and maintaining the material temperature at about 60 ℃.
12. And (3) secondary drying: further microwave drying is carried out, the drying temperature is 60 ℃, the microwave power is 400W, and the obtained N-acetylneuraminic acid (SA) crystal content is 98.8%, the yield is 90%, and the whiteness is 94.
Example 2
This example provides a process for the preparation of N-acetylneuraminic acid which is identical to the process of example 1, except that:
5. decoloring and removing impurities: adding active carbon into the deproteinized clear liquid for adsorption decolorization, and stopping decolorization when the chromaticity value of the decolorized solution is not higher than 15 ℃ by monitoring by an online colorimeter to obtain colorless clear liquid.
The N-acetylneuraminic acid (SA) crystal obtained in this example had a content of 98.4%, a yield of 91% and a whiteness of 92.
Example 3
This example provides a process for the preparation of N-acetylneuraminic acid which is identical to the process of example 1, except that:
5. decoloring and removing impurities: and (3) conveying the protein-removed clear liquid into macroporous resin special for decolorization to adsorb and remove impurities, and obtaining colorless clear liquid. Wherein the amount of the decolorized resin filler is 3wt% of the total treatment material, and the chromaticity value of the decolorized solution is monitored by an on-line colorimeter and is 20 degrees. Wherein the specific surface area of the macroporous resin special for decolorization is 550 square meters per gram, the pore size distribution is 8nm, and the pore volume isProduct 2.1m 3 And/g, particle size of 30 meshes.
The N-acetylneuraminic acid (SA) crystal obtained in this example had a content of 98.0%, a yield of 92% and a whiteness of 90.
Example 4
This example provides a process for the preparation of N-acetylneuraminic acid which is identical to the process of example 1, except that:
12. and (3) secondary drying: further vacuum drying at 60 ℃.
The N-acetylneuraminic acid (SA) crystal obtained in this example had a content of 98.1%, a yield of 90% and a whiteness of 92.
Comparative example 1
The comparative example provides a method for preparing N-acetylneuraminic acid, which comprises the following steps:
1. taking SA fermentation liquor, wherein the SA content is 25g/L.
2. And (3) degerming: filtering with 200nm micro-hollow ceramic membrane with filtering pressure controlled at 0.3Mpa.
3. Collecting clear liquid: collecting the clear liquid obtained by filtration, and the target product is in the clear liquid.
4. Removing protein from the clear solution: the clear liquid was heated to 75 ℃ by a plate heat exchanger and passed through a centrifuge under the following conditions: rotating speed is 6000r, and continuously feeding and separating to obtain protein-removed clear liquid.
5. Anion column adsorption: and (3) adsorbing N-acetylneuraminic acid in the decolorized solution by using a strong base type anion resin. Packing was performed at 20gSA per 100g of adsorbent. The strong base type anion resin is acrylic resin quaternary ammonium group (model WSD260, manufacturer: anhui tree chemical industry Co., ltd.) with water content of 50%, granularity of 20 meshes and adsorption capacity of 3.6mmol/g.
6. Analysis: analyzing the strong base anion column adsorbed with N-acetylneuraminic acid by using 0.2mol/l sodium chloride aqueous solution, and judging whether the analysis is complete or not by detecting the SA absorbance change in column liquid under analysis by an online preparation chromatograph.
7. Collecting an analysis solution: after the analysis is completed, collecting the analysis liquid.
8. Decoloring and removing impurities: will beAnd (3) conveying the resolved liquid into macroporous resin special for decolorization to adsorb and remove impurities, and obtaining colorless clear liquid. Wherein the amount of the decolored resin filler is 3wt% of the total treatment material, and the chromaticity value of the decolored solution is monitored by an online colorimeter and is 15 degrees; wherein the specific surface area of the macroporous resin special for decolorization is 550 square meters per gram, the pore size distribution is 8nm, and the pore volume is 2.1m 3 And/g, particle size of 30 meshes.
9. Desalting by nanofiltration membranes: desalting the obtained analytical solution by a nanofiltration membrane of 500DA, and completing desalting when the conductivity of the clear liquid at the outlet is below 50 us/cm.
10. Concentrating: after the desalting is completed, the stock solution is continuously concentrated to the SA content of about 100g/L.
11. Predrying: and (3) carrying out spray drying on the obtained concentrated solution to obtain SA coarse crystals, and maintaining the material temperature at about 60 ℃.
12. Vacuum drying: further vacuum drying at 60 deg.c to obtain crystal content of 97.3%, yield 83% and whiteness 95.
Comparative example 2
1. The SA fermentation broth in this comparative example was one having an SA content of 25g/L.
2. And (3) degerming: filtering with 200nm micro-hollow ceramic membrane with filtering pressure controlled at 0.3Mpa.
3. Collecting clear liquid: collecting the clear liquid obtained by filtration, and the target product is in the clear liquid.
4. Removing protein from the clear solution: the clear liquid was heated to 75 ℃ by a plate heat exchanger and passed through a centrifuge under the following conditions: rotating speed 6000r, continuously feeding and separating to obtain protein-removed clear liquid
5. Decoloring: adding activated carbon accounting for 4% of the mass of the deproteinized fermentation broth into the deproteinized fermentation broth, and performing adsorption decolorization for 0.5h at 30 ℃ to obtain decolorized fermentation broth;
6. inorganic salt is removed: slowly feeding the decolorized fermentation liquor into a D001 type cation exchange resin column, continuously exchanging, and removing inorganic salts such as calcium, magnesium and the like in the deproteinized fermentation liquor, which affect the purity of the product, so as to obtain a desalted fermentation liquor;
7. and (3) crystallization: concentrating the desalted fermentation liquid by reduced pressure evaporation to 200g/L, adding a mixed solvent of methanol and acetic acid (the mixing ratio of the methanol to the acetic acid is 1:4) with 3 times of volume into the concentrated liquid, cooling to 10 ℃, and crystallizing for 20 hours to obtain crystals;
8. washing and drying: washing the crystallized crystal by absolute ethyl alcohol, and then carrying out temperature programming vacuum drying and drying, wherein the vacuum drying method is that the vacuum drying is carried out for 3 hours at 75 ℃, then the temperature is increased to 85 ℃ and then the vacuum drying is carried out for 4 hours.
The obtained crystals had a content of 98.2%, a yield of 70% and a whiteness of 91.
Finally, the method of the present application is only a preferred embodiment and is not intended to limit the scope of the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.
Claims (3)
1. A method for preparing N-acetylneuraminic acid, which is characterized by comprising the following steps:
adsorbing and decolorizing the solution containing sialic acid, and adsorbing N-acetylneuraminic acid by using a strong base anion column after the solution containing sialic acid is adsorbed and decolorized to a value of not higher than 15 DEG; resolving the N-acetylneuraminic acid obtained by adsorption on the strong base anion column by using sodium chloride aqueous solution, collecting resolved liquid, desalting, concentrating until the N-acetylneuraminic acid content is 80-100 g/L, and drying to obtain the product;
the sialic acid-containing solution is prepared by degerming and deproteinizing sialic acid-containing fermentation liquor;
the strong base type anion column is strong base type anion resin, and the strong base type anion resin is anion resin containing quaternary ammonium group functional groups; the water content of the strong base anion column is 50-60%, the granularity is 20-40 meshes, and the adsorption capacity is 3-5 mmol/g;
the specific steps of the drying method comprise: spray drying the concentrated solution to obtain coarse crystals with water content not higher than 10%, and secondary drying at 50-65 ℃ to water content not higher than 2%;
the steps of adsorption decolorization are as follows: using an adsorption medium to carry out adsorption decolorization; the adsorption medium is decolorized macroporous resin or activated carbon;
the parameters of the decolored macroporous resin are as follows: the specific surface area is 480-600 square meters per gram, the pore size distribution is 8-9 nm, the pore volume is 1-3 m, and the granularity is 20-40 meshes; the filler amount of the decolored macroporous resin is 2-3 wt% of the material to be adsorbed.
2. The method according to claim 1, wherein the step of "degerming" comprises: filtering with ceramic membrane under the filtering pressure of 0.2-0.4 Mpa, and collecting the clear liquid.
3. The method according to claim 1 or 2, wherein the "deproteinizing" step is sedimentation deproteinization, filtration deproteinization, silica gel adsorption deproteinization or centrifugation deproteinization.
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