A purification and crystallization method of L-asparagine desalted feed solution

Abstract

The application belongs to the technical field of pharmaceutical chemistry, and discloses a purification and crystallization method of L-asparagine desalination feed liquid. The purification and crystallization method comprises the following steps: L-asparagine desalination feed liquid is subjected to cation exchange resin and anion exchange resin to obtain overflow liquid; the overflow liquid is filtered through a nanofiltration membrane; the feed liquid after nanofiltration membrane filtration is mixed with activated carbon for decolorization, and the filtered decolorized liquid is obtained; the decolorized liquid is crystallized and incubated, and the crude product is obtained after solid-liquid separation; the crude product is washed and vacuum dried to obtain L-asparagine finished product. The raw material of the application has a wide source and low cost, the crystallization method is simple, there is no intermediate and byproduct in the scheme, etc.; in addition, the purification and crystallization method has high finished product quality, the product crystal structure is uniform, the particle size is uniform, the overall process is clean and has no VOC emission, and the application is a high-efficiency and environmentally-friendly production method.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, and in particular to a method for purifying and crystallizing L-asparagine desalting solution. Background Technology

[0002] L-Asparagine is an important non-essential amino acid with wide applications in the pharmaceutical, food, and chemical industries. In the pharmaceutical field, L-asparagine is commonly used in the preparation of antihypertensive and diuretic drugs, and it also shows promise for tumor treatment due to its ability to relieve glutamine-induced apoptosis. In the food industry, it can undergo the Maillard reaction with reducing sugars, making it an important precursor for acrylamide formation in baked goods. With the continuous expansion of its applications, the market demand for high-purity L-asparagine is increasing.

[0003] Currently, there are three main methods for preparing L-asparagine: extraction, enzymatic synthesis, and chemical synthesis. Extraction involves separation from natural materials such as white lupin and sweet clover, but this method is heavily limited by raw material availability, and the process is complex and difficult to control stably. Enzymatic synthesis utilizes asparagine synthase to catalyze the amino transfer of ammonium ions or glutamine, offering significant advantages such as mild reaction conditions, environmental friendliness, and ease of control. However, enzymatic synthesis still faces a key technical bottleneck in practical applications—the residual substrate L-aspartic acid is difficult to control effectively. The conversion solution contains both L-asparagine and L-aspartic acid, which have similar physicochemical properties, making subsequent separation and purification challenging. Chemical synthesis mainly involves the amidation reaction of L-aspartic acid methyl ester hydrochloride with ammonia, offering mild conditions, simple operation, and a relatively mature process.

[0004] However, the chemical synthesis method contains residual inorganic salts and unconverted L-aspartic acid, among other impurities, in the feed solution. If these are not completely removed, they will directly affect the purity and yield of the crystallization process.

[0005] Therefore, developing a purification and crystallization method with high purification efficiency, good crystallization yield, and stable product quality, tailored to the characteristics of L-asparagine desalting solution, has become a pressing technical problem in this field. Summary of the Invention

[0006] The purpose of this invention is to provide a purification and crystallization method for L-asparagine desalting solution. This method is low in cost, simple in process, easy to operate, and produces high-quality finished products.

[0007] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a method for purifying and crystallizing L-asparagine desalting solution, comprising the following steps: S1. The L-asparagine desalination solution is passed sequentially through a cation exchange resin and an anion exchange resin to obtain the overflow solution; S2. Filter the overflow liquid through a nanofiltration membrane; S3. Mix the liquid filtered by nanofiltration membrane with activated carbon for decolorization treatment, and obtain a decolorized liquid after filtration. S4. The decolorizing solution is crystallized and grown into crystals. After solid-liquid separation, crude L-asparagine is obtained. S5. The crude L-asparagine is washed and vacuum dried to obtain the finished L-asparagine product.

[0008] Furthermore, in the purification and crystallization method, the concentration of L-asparagine in the L-asparagine desalting solution in step S1 is 5~55 g / L.

[0009] Furthermore, in the purification and crystallization method, the cation exchange resin in step S1 is a styrene-based cation exchange resin; The anion exchange resin mentioned in step S1 is an acrylic anion exchange resin; The rate of passage in step S1 is independently 0.25~2.5 BV / h.

[0010] Furthermore, in the purification and crystallization method, the styrene-based cation exchange resin is a 732-H type cation exchange resin; The acrylic anion exchange resin is a 315-OH type anion exchange resin.

[0011] Furthermore, in the purification and crystallization method, the molecular weight cutoff of the nanofiltration membrane in step S2 is ≤1000 Da.

[0012] Furthermore, in the purification and crystallization method, the mass of the activated carbon in step S3 is 1-2% of the mass of the feed solution after nanofiltration. The decolorization process in step S3 is carried out at a temperature of 55~85℃ for 15~60 minutes.

[0013] Furthermore, in the purification and crystallization method, step S4 specifically includes: concentrating the decolorizing solution at 25~85℃ until crystals precipitate, cooling to 25℃ for dispersion, then cooling to 15℃ for dispersion, and then cooling to 0~5℃ for crystallization.

[0014] Furthermore, in the purification and crystallization method, the mass concentration of L-asparagine is 5-15% when the concentration reaches crystal precipitation; The dispersion time at 25°C is 30~60 min; The dispersion time at 15℃ is 30~60 min; The crystallization time is 0.5~12h.

[0015] Furthermore, in the purification and crystallization method, the washing reagent in step S5 is water, and the mass ratio of the washing reagent to the crude L-asparagine is 0.1~2:1.

[0016] Furthermore, in the purification and crystallization method, the vacuum drying temperature in step S5 is 55~60℃, and the drying time is 4~16h.

[0017] As can be seen from the above technical solution, compared with the prior art, the present invention has the following beneficial effects: (1) The raw materials of this invention are widely available, inexpensive, and easy to obtain.

[0018] (2) The crystallization method of the present invention is simple and easy to operate.

[0019] (3) This invention has no intermediates, no by-products, etc., and the mother liquor can be recycled.

[0020] (4) The purification and crystallization method of the present invention has high product quality, uniform crystal structure, uniform particle size, and the whole process is clean and has no VOC emissions, which is a highly efficient and environmentally friendly production method. Detailed Implementation

[0021] This invention provides a method for purifying and crystallizing L-asparagine desalting solution, comprising the following steps: S1. The L-asparagine desalination solution is passed sequentially through a cation exchange resin and an anion exchange resin to obtain the overflow solution; S2. Filter the overflow liquid through a nanofiltration membrane; S3. Mix the liquid filtered by nanofiltration membrane with activated carbon for decolorization treatment, and obtain a decolorized liquid after filtration. S4. The decolorizing solution is crystallized and grown into crystals. After solid-liquid separation, crude L-asparagine is obtained. S5. The crude L-asparagine is washed and vacuum dried to obtain the finished L-asparagine product.

[0022] In this invention, the source of the L-asparagine desalination solution in step S1 is: chemically synthesized L-asparagine solution, which is obtained after electrodialysis desalination treatment.

[0023] In this invention, the concentration of L-asparagine in the L-asparagine desalination solution in step S1 is preferably 5~55 g / L, more preferably 40~55 g / L, and even more preferably 50 g / L.

[0024] In this invention, the cation exchange resin in step S1 is preferably a styrene-based cation exchange resin.

[0025] In this invention, the styrene-based cation exchange resin is preferably a 732-H type cation exchange resin.

[0026] In this invention, the anion exchange resin in step S1 is preferably an acrylic anion exchange resin.

[0027] In this invention, the acrylic anion exchange resin is preferably a 315-OH type anion exchange resin.

[0028] In this invention, the throughput rate in step S1 is preferably 0.25~2.5 BV / h, more preferably 0.5~1.5 BV / h, and even more preferably 1 BV / h.

[0029] In this invention, the molecular weight cutoff of the nanofiltration membrane in step S2 is preferably ≤1000Da, more preferably ≤500Da, and even more preferably ≤150Da.

[0030] In this invention, the mass of activated carbon in step S3 is preferably 1 to 2% of the mass of the feed liquid after nanofiltration membrane filtration, more preferably 1.2 to 1.8%, and even more preferably 1.5%.

[0031] In this invention, the temperature of the decolorization process in step S3 is preferably 55~85℃, more preferably 55~70℃, and even more preferably 60℃; the decolorization time is preferably 15~60min, more preferably 20~40min, and even more preferably 30min.

[0032] In this invention, the pore size of the filter membrane used for filtration in step S3 is preferably 0.1~0.22μm, more preferably 0.2~0.22μm, and even more preferably 0.22μm.

[0033] In this invention, step S4 specifically includes: concentrating the decolorizing solution at 25~85°C until crystals precipitate, cooling it to 25°C to disperse, then cooling it to 15°C to disperse, and then cooling it to 0~5°C to crystallize. The equipment for concentration preferably includes a reverse osmosis membrane or a vacuum concentration device; The concentration temperature is further preferably 55~85℃, more preferably 60℃; When the concentration is increased to the point of crystal precipitation, the mass concentration of L-asparagine is preferably 5-15%, more preferably 5-10%, and even more preferably 7%. The dispersion time at 25°C is preferably 30-60 min, more preferably 30-45 min, and even more preferably 30 min; The dispersion time at 15°C is preferably 30-60 min, more preferably 30-45 min, and even more preferably 30 min; The crystallization temperature is further preferably 1~3℃, more preferably 2℃; The crystallization time is preferably 0.5 to 12 hours, more preferably 3 to 9 hours, and even more preferably 6 hours.

[0034] In this invention, the solid-liquid separation method in step S4 is direct filtration with heat preservation.

[0035] In this invention, the washing reagent in step S5 is preferably water, and more preferably deionized water.

[0036] In this invention, the mass ratio of the washing reagent to the crude L-asparagine is preferably 0.1 to 2:1, more preferably 0.5 to 1.5:1, and even more preferably 1.1:1.

[0037] In this invention, the vacuum drying temperature in step S5 is preferably 55~60℃, more preferably 57~59℃, and even more preferably 58℃; the drying time is preferably 4~16h, more preferably 6~12h, and even more preferably 10h.

[0038] In the purification and crystallization method of this invention, unless otherwise specified, commercially available products well known in the art can be used for the raw materials; and unless otherwise specified, well-known solutions in the art can be used for other parameters and conditions.

[0039] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0040] In the examples, the manufacturer of the 732-H type cation exchange resin is Anhui Samsung Resin Technology Co., Ltd. The manufacturer of the 315-OH type anion exchange resin is Anhui Samsung Resin Technology Co., Ltd. The activated carbon is manufactured by Nanping Activated Carbon Co., Ltd.

[0041] Example 1

[0042] This embodiment provides a purification and crystallization method for L-asparagine desalting solution, including the following steps: S1. The L-asparagine solution after amidation reaction is desalted by electrodialysis to obtain an L-asparagine desalted solution containing 50 g / L of L-asparagine. The desalted solution is then passed sequentially through a 732-H type cation exchange resin and a 315-OH type anion exchange resin at rates of 1 BV / h and 1 BV / h, respectively, to obtain a flow solution. S2. Filter the overflow liquid through a nanofiltration membrane with a molecular weight cutoff of ≤150 Da; S3. Mix the feed solution filtered through the nanofiltration membrane with 1.5% activated carbon by weight of the feed solution, decolorize at 60℃ for 30 min, and filter through a 0.22μm filter membrane to obtain the decolorized solution. S4. Using a reverse osmosis membrane concentration device, the decolorizing solution is concentrated at 60℃ until crystals precipitate, at which point the mass concentration is 7.9%; the temperature is lowered to 25℃ and stirred for 30 min, then lowered to 15℃ and stirred for 30 min, then lowered to 5℃ and crystallized for 6 h, and after being kept at 5℃ and directly filtered, L-asparagine crude product is obtained. S5. The crude L-asparagine was washed with 1.1 times its mass of deionized water and dried under vacuum at 58°C for 10 hours to obtain the finished L-asparagine product. The molecular weight of L-asparagine is 132 g / mol. Based on the content, the total weight was 51.25 g, and the yield was 82.17%.

[0043] Example 2

[0044] This embodiment provides a purification and crystallization method for L-asparagine desalting solution, including the following steps: S1. The L-asparagine solution after amidation reaction is desalted by electrodialysis to obtain an L-asparagine desalted solution containing 50 g / L of L-asparagine. The desalted solution is then passed sequentially through a 732-H type cation exchange resin and a 315-OH type anion exchange resin at rates of 1 BV / h and 1 BV / h, respectively, to obtain a flow solution. S2. Filter the overflow liquid through a nanofiltration membrane with a molecular weight cutoff of ≤150 Da; S3. Mix the feed solution filtered through the nanofiltration membrane with 1.5% activated carbon by weight of the feed solution, decolorize at 60℃ for 30 min, and filter through a 0.22μm filter membrane to obtain the decolorized solution. S4. Using a reverse osmosis membrane concentration device, the decolorizing solution is concentrated at 60℃ until crystals precipitate, at which point the mass concentration is 7%; the temperature is lowered to 25℃ and stirred for 30 min, then lowered to 15℃ and stirred for 30 min, then lowered to 3℃ and crystallized for 6 h, and after being kept at 3℃, it is directly filtered to obtain crude L-asparagine. S5. The crude L-asparagine was washed with 1.1 times its mass of deionized water and dried under vacuum at 58°C for 10 hours to obtain the finished L-asparagine product. The molecular weight of L-asparagine was 132 g / mol. Based on the content, the total weight was 59.25 g, and the yield was 89.96%.

[0045] Example 3

[0046] This embodiment provides a purification and crystallization method for L-asparagine desalting solution, including the following steps: S1. The L-asparagine solution after amidation reaction is desalted by electrodialysis to obtain an L-asparagine desalted solution containing 50 g / L of L-asparagine. The desalted solution is then passed sequentially through a 732-H type cation exchange resin and a 315-OH type anion exchange resin at rates of 1 BV / h and 1 BV / h, respectively, to obtain a flow solution. S2. Filter the overflow liquid through a nanofiltration membrane with a molecular weight cutoff of ≤150 Da; S3. Mix the feed solution filtered through the nanofiltration membrane with 1.5% activated carbon by weight of the feed solution, decolorize at 60℃ for 30 min, and filter through a 0.22μm filter membrane to obtain the decolorized solution. S4. Using a reverse osmosis membrane concentration device, the decolorizing solution is concentrated at 60℃ until crystals precipitate, at which point the mass concentration is 7%; the temperature is lowered to 25℃ and stirred for 30 minutes, then lowered to 15℃ and stirred for 30 minutes, then lowered to 5℃ and crystallized for 6 hours. After being kept at 5℃, it is directly filtered to obtain crude L-asparagine. S5. The crude L-asparagine was washed with 1.1 times its mass of deionized water and dried under vacuum at 58°C for 10 hours to obtain the finished L-asparagine product. The molecular weight of L-asparagine is 132 g / mol. Based on the content, the total weight was 51.15 g, and the yield was 82.07%.

[0047] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for purifying and crystallizing L-asparagine desalting solution, characterized in that, Includes the following steps: S1. The L-asparagine desalination solution is passed sequentially through a cation exchange resin and an anion exchange resin to obtain the overflow solution; S2. Filter the overflow liquid through a nanofiltration membrane; S3. Mix the liquid filtered by nanofiltration membrane with activated carbon for decolorization treatment, and obtain a decolorized liquid after filtration. S4. The decolorizing solution is crystallized and grown into crystals. After solid-liquid separation, crude L-asparagine is obtained. S5. The crude L-asparagine is washed and vacuum dried to obtain the finished L-asparagine product.

2. The purification and crystallization method according to claim 1, characterized in that, In step S1, the concentration of L-asparagine in the L-asparagine desalination solution is 5~55 g / L.

3. The purification and crystallization method according to claim 1, characterized in that, The cation exchange resin mentioned in step S1 is a styrene-based cation exchange resin; The anion exchange resin mentioned in step S1 is an acrylic anion exchange resin; The rate of passage in step S1 is independently 0.25~2.5 BV / h.

4. The purification and crystallization method according to claim 3, characterized in that, The styrene-based cation exchange resin is a 732-H type cation exchange resin; The acrylic anion exchange resin is a 315-OH type anion exchange resin.

5. The purification and crystallization method according to claim 1, characterized in that, The molecular weight cutoff of the nanofiltration membrane described in step S2 is ≤1000 Da.

6. The purification and crystallization method according to claim 1, characterized in that, The mass of activated carbon in step S3 is 1-2% of the mass of the liquid after nanofiltration. The decolorization process in step S3 is carried out at a temperature of 55~85℃ for 15~60 minutes.

7. The purification and crystallization method according to claim 1, characterized in that, Step S4 specifically includes: concentrating the decolorizing solution at 25~85℃ until crystals precipitate, cooling it to 25℃ for dispersion, then cooling it to 15℃ for dispersion, and then cooling it to 0~5℃ for crystallization.

8. The purification and crystallization method according to claim 7, characterized in that, When the concentration reaches the point of crystal precipitation, the mass concentration of L-asparagine is 5-15%. The dispersion time at 25°C is 30~60 min; The dispersion time at 15℃ is 30~60 min; The crystallization time is 0.5~12h.

9. The purification and crystallization method according to claim 1, characterized in that, The washing reagent in step S5 is water, and the mass ratio of the washing reagent to the crude L-asparagine is 0.1~2:

1.

10. The purification and crystallization method according to claim 1, characterized in that, The vacuum drying temperature in step S5 is 55~60℃, and the drying time is 4~16h.