CN108084211B - Method for recovering cefalexin - Google Patents
Method for recovering cefalexin Download PDFInfo
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- CN108084211B CN108084211B CN201711391343.5A CN201711391343A CN108084211B CN 108084211 B CN108084211 B CN 108084211B CN 201711391343 A CN201711391343 A CN 201711391343A CN 108084211 B CN108084211 B CN 108084211B
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- cephalexin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
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Abstract
The invention relates to a recovery method of cefalexin, which takes phenols as complexing agents to enrich cefalexin in solution; separating cephalexin by taking an amine substance as a decomplexer. The invention uses phenols as complexing agent, realizes high-efficiency complexing enrichment of cefalexin in solution, and the complexing yield can reach 97%; the amine substance is used as the decomplexing agent, green separation of cephalexin is realized, the decomplexing yield can reach 99%, VOC pollution caused by volatilization of an organic solvent is eliminated from a process source, and the dosage of the decomplexing agent is greatly reduced. The method provided by the invention can realize the high-efficiency recovery of the cefalexin in the solution, and the total yield of the cefalexin is more than or equal to 90 percent. The amine substance decomplexing agent is recovered by a chemical method in the recovery process, the recovery yield of the decomplexing agent is more than or equal to 90 percent, the cyclic utilization of the decomplexing agent is realized, the energy consumption is reduced, and the method has good economic benefit and wide application prospect.
Description
Technical Field
The invention relates to the field of antibiotic recovery, and particularly relates to a method for recovering cephalexin.
Background
Cephalexin is a cephalosporin antibiotic widely applied clinically. Cefalexin is an amphoteric substance, and the solubility in an aqueous solution is greatly changed along with the pH. At the isoelectric point, the solubility of the cefalexin in the aqueous solution is the lowest, and the concentration can reach 12-15 g/L. Industrially, the cefalexin bulk drug is catalytically synthesized by a chemical method or an enzymatic method, and cefalexin in a synthetic reaction solution is subjected to isoelectric point crystallization to obtain a crystallization mother solution, wherein the crystallization mother solution contains about 12-15g/L of cefalexin. Cefalexin in the crystallization mother liquor needs to be recovered in time, otherwise economic loss is caused, the environment is polluted, and the danger of inducing drug-resistant bacteria and super bacteria exists.
CN105349608A discloses a method for recycling phenylglycine in cephalexin crystal mother liquor, which adopts lyase to crack cephalexin in the crystal mother liquor into 7-aminodesacetoxycephalosporanic acid (7-ADCA) and a byproduct phenylglycine, only recovers the phenylglycine, and does not recover the 7-ADCA. The method has poor economy, and the discharged wastewater contains 7-ADCA and has high COD content.
CN 104058537A discloses a method for treating wastewater from cefalexin enzymatic synthesis mother liquor, and the method adopts an electrodialysis integrated reverse osmosis system to recover inorganic salts in the mother liquor, but does not mention the recovery of cefalexin and other organic matters.
CN 106220646A discloses a method for recycling cefalexin mother liquor synthesized by an enzymatic method, wherein resin is adopted to adsorb acidified crystallization mother liquor, an analysis solution is obtained by operations such as water washing and ethanol water solution desorption, the pH value is adjusted, and cefalexin products are obtained by crystallization; and the residual filtrate is subjected to reduced pressure distillation to obtain recycled solvent ethanol. The process is simple to operate and low in cost, and can effectively recover cefalexin in the crystallization mother liquor, but a large amount of ethanol aqueous solution is used in the elution process, VOC pollution can be generated, the ethanol distillation recovery energy consumption is high, and a large amount of wastewater is generated by resin regeneration.
In the process research of recovering cephalexin by a resin adsorption method, different adsorption resins are screened to realize enrichment of cephalexin in a crystal liquid, 40% ethanol (pH 2.0) is adopted to effectively desorb the cephalexin adsorbed on a resin column, and a cephalexin product is obtained by isoelectric point crystallization (see ion exchange and adsorption, Neissan, Liu-Can, Lei-Nei, etc., 2012 and 28(5):463 and 468). The process uses a large amount of ethanol solution, and a large amount of acid and alkali solution is consumed in the pretreatment and regeneration processes of the resin, so that the environmental pollution is increased.
The conventional method for recovering cephalexin in crystallization mother liquor, which is disclosed by CN 106220646A, is to recover the residual cephalexin in the mother liquor by adopting β -naphthol as a complexing agent and dichloromethane as a decomplexing agent, wherein the process has low complexation yield (92%), about 8% of cephalexin is not complexed and remains in waste water, a large amount of low-boiling-point organic solvent dichloromethane is used in the decomplexing process to cause serious VOC pollution, and the dichloromethane is recovered by adopting a rectification process and needs a large amount of heat energy and a refrigerant.
As is clear from the above, there are many conventional methods for recovering cephalexin in an aqueous solution, but they generally have disadvantages such as low recovery rate, high energy consumption, serious pollution, and incomplete recovery, and therefore, it is necessary to develop a novel technique for recovering cephalexin in a solution.
Disclosure of Invention
In view of the problems in the prior art, the invention aims to provide a method for recovering cephalexin, which realizes efficient complexing enrichment of cephalexin in a solution and green separation of cephalexin, wherein the complexing yield can reach 97 percent, and the decomplexing yield can reach 99 percent; the cost is reduced, the VOC pollution is eliminated, the high-efficiency recovery of the cephalexin in the solution is finally realized, the total yield of the cephalexin is more than or equal to 90 percent, and the method has good economic benefit and application prospect.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a method for recovering cephalexin, which takes phenols as complexing agents to enrich cephalexin in a solution; separating cephalexin by taking an amine substance as a decomplexer.
According to the invention, the method comprises the following steps:
(1) adding a phenolic substance into the solution containing cefalexin, and performing solid-liquid separation after complete complexation to obtain a double-salt precipitate;
(2) adding water and amine substances into the complex salt precipitate obtained in the step (1) for decomplexing, adjusting the pH value to completely dissolve the complex salt precipitate, allowing cephalexin to enter a water phase, extracting phenolic substances to enter the amine substances, and separating the water phase from an organic phase;
(3) and (3) separating the cephalexin in the water phase obtained by separation in the step (2) to obtain a cephalexin product.
The solution containing cephalexin in step (1) of the present invention refers to a solution in which cephalexin is dissolved, and more particularly, an aqueous solution of cephalexin, and for example, it may be a crystallization mother liquor obtained by subjecting cephalexin in a synthesis reaction solution to isoelectric point crystallization, but is not limited thereto.
According to the invention, the phenolic substance is a phenolic compound and/or a phenolic derivative, preferably any one or a combination of at least two of 1-naphthol, 2-naphthol, 1, 2-dihydroxynaphthalene, 1, 3-dihydroxynaphthalene, 1, 4-dihydroxynaphthalene, 1, 5-dihydroxynaphthalene, 1, 6-dihydroxynaphthalene, 2, 3-dihydroxynaphthalene, 2, 7-dihydroxynaphthalene, 1,2, 3-pyrogallol, 1,2, 4-benzenetriol, 2,4, 6-benzenetriol, catechol, resorcinol, hydroquinone, o-aminophenol, m-aminophenol, p-aminophenol, methyl paraben, ethyl paraben, propyl paraben, methyl paraben, ethyl paraben, 2-phenylphenol or 4-phenylphenol; examples thereof include 1-naphthol, 2-naphthol, 1, 2-dihydroxynaphthalene, 1, 3-dihydroxynaphthalene, 1, 4-dihydroxynaphthalene, 1, 5-dihydroxynaphthalene, 1, 6-dihydroxynaphthalene, 2, 3-dihydroxynaphthalene, 2, 7-dihydroxynaphthalene, 1,2, 3-pyrogallol, 1,2, 4-benzenetriol, 2,4, 6-benzenetriol, any one of catechol, resorcinol, hydroquinone, o-aminophenol, m-aminophenol, p-aminophenol, methyl paraben, ethyl paraben, propyl paraben, methyl paraben, ethyl paraben, 2-phenylphenol or 4-phenylphenol, with a typical but non-limiting combination being: 1-naphthol and 2-naphthol; resorcinol and hydroquinone; methyl paraben, ethyl paraben and the like, are not exhaustive for the invention, limited in space and for the sake of brevity.
According to the invention, the amine substance is any one or combination of at least two of primary amine, secondary amine, tertiary amine and quaternary ammonium salt, preferably tri-N-octylamine, tri-isooctylamine, tri-N-nonylamine, tri-N-decylamine, tri-N-dodecylamine, tri (2-ethylhexyl) amine, di-N-octylamine, N235Or dodecyl dimethylamine, or a combination of at least two thereof; examples thereof include tri-N-octylamine, triisooctylamine, tri-N-nonylamine, tri-N-decylamine, tri-N-dodecylamine, tri (2-ethylhexyl) amine, di-N-octylamine, N235Or dodecyl dimethylamine; typical but non-limiting combinations are: tri-n-octylamine and tri-isooctylamine; tri-n-decylamine and tri-n-dodecylamine; tris (2-ethylhexyl) amine and di-n-octylamine; n is a radical of235And dodecyl dimethylamine, etc., are not exhaustive for the invention, but are included for brevity and clarity.
In order to eliminate VOC pollution caused by volatilization of an organic solvent from a process source, amine substances without VOC pollution are selected as a decomplexing agent for application, and the boiling point of the amine substances is more than or equal to 260 ℃.
According to the invention, the molar ratio between the phenolic substance in step (1) and cephalexin in the solution is (0.5-1.5):1, and may be, for example, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1 or 1.5:1, and the particular values between the above values, limited to space and for reasons of brevity, are not exhaustive.
According to the invention, the pH is adjusted in step (2) to a value of 0.2 to 1.3, which may be, for example, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2 or 1.3, and the values between these values are not exhaustive for reasons of brevity and simplicity.
According to the present invention, the pH in step (2) is adjusted by using an acid solution commonly used in the art, such as sulfuric acid, nitric acid, hydrochloric acid, acetic acid, etc., as long as the purpose of adjusting the pH to 0.2-1.3 is achieved.
Preferably, the volume ratio of the amine-like substance and water added to the precipitation of the double salt in step (2) is (0.1-2):1, and may be, for example, 0.1:1, 0.3:1, 0.5:1, 0.8:1, 1:1, 1.2:1, 1.5:1, 1.8:1 or 2:1, and the specific values therebetween are not exhaustive for reasons of space and simplicity.
According to the invention, the liquid-solid ratio of the amine-based substance added in step (2) and the precipitation of the double salt is (0.5-7):1, and may be, for example, 0.5:1, 0.8:1, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1 or 7:1, and the specific values between the above values are limited by space and for the sake of brevity and are not exhaustive.
The unit of the liquid-solid ratio is ml/g.
According to the invention, the pH value of the water phase obtained by separation in the step (2) is adjusted to 4.6-4.75 in the step (3), and crystallization is carried out at the isoelectric point of cephalexin to remove impurities (such as phenol and amine impurities) in the process, so as to obtain the cephalexin product.
According to the present invention, the pH of the aqueous phase in step (3) is adjusted by using an alkaline pH adjuster commonly used in the art, as long as the purpose of adjusting the pH is achieved, and the type of the pH adjuster is not particularly limited, and for example, the pH adjuster may be adjusted by using an aqueous ammonia solution, a sodium carbonate solution, a sodium hydroxide solution, or the like, but is not limited thereto.
For the purpose of recovering the decomplexing agent, an alkalizer is added into the organic phase obtained after separation in the step (2) for back extraction treatment, so that phenolic substances in the organic phase enter a water phase, and the organic phase obtained after two-phase separation is an amine substance and can be returned to the step (2) to be used as the decomplexing agent for recycling.
According to the invention, the alkalizer is any one or combination of at least two of sodium hydroxide solution, potassium hydroxide solution or lithium hydroxide solution; for example, the solution can be any one of sodium hydroxide solution, potassium hydroxide solution or lithium hydroxide solution, and the typical but non-limiting combination is sodium hydroxide solution and potassium hydroxide solution; sodium hydroxide and lithium hydroxide solutions; potassium hydroxide and lithium hydroxide solutions; sodium hydroxide solution, potassium hydroxide solution, and lithium hydroxide solution.
According to the invention, the molar ratio of the alkaline substance in the alkalizing agent added during the stripping treatment to the complexing agent (phenolic substance) in the organic phase is (1-3.5):1, and may be, for example, 1:1, 1.5:1, 2:1, 2.5:1, 3:1 or 3.5:1, and the specific values between the above values are not exhaustive and for the sake of brevity.
According to the invention, the volume ratio of the alkalizing agent to the organic phase during the stripping is (0.1-10):1, and may be, for example, 0.1:1, 0.5:1, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 10:1, and the specific values therebetween are not intended to be exhaustive for reasons of space and simplicity.
In the present invention, the temperature at which the reaction proceeds is not particularly limited as long as the reaction proceeds smoothly.
The invention adopts the means commonly used in the field to carry out solid-liquid separation, as long as the aim of separating solution and sediment, water phase and organic phase can be achieved, for example, the means of filtration, suction filtration, centrifugation, sedimentation and the like can be used, but the invention is not limited to the method and should be reasonably selected according to the experimental situation.
As a preferred technical scheme, the method for recovering cephalexin comprises the following steps:
(1) adding a phenolic substance into the solution containing the cefalexin, and performing solid-liquid separation after complete complexation to obtain a double-salt precipitate, wherein the molar ratio of the phenolic substance to the cefalexin in the solution is (0.5-1.5): 1; the phenolic substance is 1-naphthol, 2-naphthol, 1, 2-dihydroxynaphthalene, 1, 3-dihydroxynaphthalene, 1, 4-dihydroxynaphthalene, 1, 5-dihydroxynaphthalene, 1, 6-dihydroxynaphthalene, 2, 3-dihydroxynaphthalene, 2, 7-dihydroxynaphthalene, 1,2, 3-pyrogallol, 1,2, 4-benzenetriol, 2,4, 6-benzenetriol, any one or combination of at least two of catechol, resorcinol, hydroquinone, o-aminophenol, m-aminophenol, p-aminophenol, methyl paraben, ethyl paraben, propyl paraben, methyl paraben, ethyl paraben, 2-phenylphenol or 4-phenylphenol;
(2) adding water and amine substances into the complex salt precipitate obtained in the step (1), controlling the volume ratio of the amine substances to the water to be (0.1-2):1, and the liquid-solid ratio of the amine substances to the complex salt precipitate to be (0.5-7):1, performing decomplexation, adjusting the pH to be 0.2-1.3 to completely dissolve the cefalexin, introducing the cefalexin into a water phase, extracting the phenol substances into the amine substances, and separating the water phase from an organic phase; the amine substance is tri-N-octylamine, tri-iso-octylamine, tri-N-nonylamine, tri-N-decylamine, tri-N-dodecylamine, tri (2-ethylhexyl) amine, di-N-octylamine, N235Or dodecyl dimethylamine, or a combination of at least two thereof;
(3) adjusting the pH value of the water phase obtained after separation in the step (2) to 4.6-4.75, and crystallizing at the isoelectric point of cephalexin to obtain a cephalexin product;
(4) and (3) adding an alkalizer into the organic phase obtained after separation in the step (2), controlling the molar ratio of an alkaline substance in the alkalizer to a complexing agent in the organic phase to be (1-3.5):1, and the volume ratio of the alkalizer to the organic phase to be (0.1-10):1, carrying out back extraction treatment to enable phenolic substances in the organic phase to enter a water phase, and returning the organic phase obtained after two-phase separation to be an amine substance to be used as a decomplexing agent for recycling in the step (2).
The invention can independently carry out the operation of the step (1), namely only limited phenolic substances are used as complexing agents to complex the cephalexin without carrying out decomplexing operation, and the complexing yield of the cephalexin can reach 97 percent, thus having obvious advantages compared with the prior art.
Similarly, the invention can also independently carry out the operation of the step (2), namely, amine substances are used for decomplexing the complexed cefalexin (the complexing method is not limited to phenolic substances), the decomplexing yield can reach 99 percent, and the dosage of the decomplexing agent is greatly reduced. For the present invention, whether the phenolic substance defined in step (1) is used alone as a complexing agent for complexing cephalexin or the amine substance defined in step (2) is used for decomplexing, the significant progress is achieved over the prior art and the present invention falls within the protection scope.
Compared with the prior art, the invention at least has the following beneficial effects:
(1) the invention takes phenols such as 1-naphthol as complexing agent, realizes the high-efficiency complexing enrichment of cefalexin in the solution, and the complexing yield of cefalexin can reach 97%.
(2) According to the invention, the amine substance is used as the decomplexing agent, so that green separation of cefalexin is realized, the decomplexing yield can reach 99%, and compared with a dichloromethane decomplexing process adopted in the industry at present, the consumption of the decomplexing agent is reduced by more than 92%; amine substances without VOC pollution are selected, and VOC pollution caused by volatilization of organic solvents can be eliminated from a process source.
(3) The method provided by the invention can realize the high-efficiency recovery of the cefalexin in the solution, and the total yield of the cefalexin is more than or equal to 90 percent.
(4) The invention adopts a chemical method to recover the amine substance decomplexing agent, the recovery yield of the decomplexing agent is more than or equal to 90 percent, thereby realizing the cyclic utilization of the decomplexing agent and avoiding the high energy consumption of the distillation and rectification process.
Drawings
FIG. 1 is a process flow diagram provided by one embodiment of the present invention.
The present invention is described in further detail below. The following examples are merely illustrative of the present invention and do not represent or limit the scope of the claims, which are defined by the claims.
Detailed Description
The technical scheme of the invention is further explained by the specific implementation mode in combination with the attached drawings.
As shown in fig. 1, a process flow provided by one embodiment of the present invention may be: adding a phenol complexing agent into the solution containing cefalexin, and carrying out solid-liquid separation after complexing to obtain a double-salt precipitate; adding water and an amine substance into the obtained double-salt precipitate for decomplexing, adjusting the pH value by using an acidifying agent to completely dissolve the double-salt precipitate to obtain a two-phase system of a water phase and an organic phase, allowing cephalexin to enter the water phase, extracting a phenol substance to enter the amine substance, and separating the water phase from the organic phase; crystallizing the cephalexin in the water phase obtained by separation at an isoelectric point to obtain a cephalexin product; adding an alkalizer into the separated organic phase for back extraction to obtain an amine substance, and returning the amine substance to the previous step for recycling as a decomplexing agent.
To better illustrate the invention and to facilitate the understanding of the technical solutions thereof, typical but non-limiting examples of the invention are as follows:
the aqueous solution containing cephalexin used in the following examples had a cephalexin content of 13 g/L; the phenolic substances used are all dissolved in a solvent before addition to the solution of cephalexin water.
Example 1
(1) Dripping 0.828g of 1-naphthol into 200mL of cefalexin aqueous solution, complexing at room temperature, and after the reaction is finished, carrying out suction filtration and drying to obtain cefalexin double salt precipitate;
(2) adding 16mL of water and 3.2mL of tri-n-octylamine into the double salt precipitate obtained in the step (1), adjusting the pH value to 1.0 for decomplexation reaction, allowing cephalexin to enter a water phase, allowing 1-naphthol to enter tri-n-octylamine, and completely separating the water phase from an organic phase after centrifugal separation;
(3) adjusting the pH value of the water phase obtained by separation in the step (2) to 4.72, carrying out crystallization separation at the isoelectric point of cefalexin, and carrying out suction filtration, washing and vacuum drying after crystal precipitation to obtain a cefalexin product;
(4) and (3) adding a sodium hydroxide solution into the organic phase obtained by separation in the step (2), controlling the volume ratio of the sodium hydroxide solution to the organic phase to be 1:1 and the molar ratio of the sodium hydroxide to the 1-naphthol to be 2.5:1, carrying out back extraction, stirring, and carrying out centrifugal separation to obtain an organic phase of tri-n-octylamine.
The result shows that the complexation yield of the cefalexin reaches 97 percent, and the decomplexation yield reaches 99 percent; the total yield of cefalexin after crystallization is 94 percent, and the recovery rate of tri-n-octylamine is 90.6 percent.
Example 2
(1) Dripping 0.92g of 1, 6-dihydroxynaphthalene into 200mL of cefalexin aqueous solution, complexing at room temperature, and filtering and drying after the reaction is finished to obtain cefalexin double salt precipitate;
(2) adding 16mL of water and 8mL of tri-n-octylamine into the complex salt precipitate obtained in the step (1), adjusting the pH value to 0.2 for decomplexation reaction, allowing cephalexin to enter a water phase, allowing 1, 6-dihydroxynaphthalene to enter the tri-n-octylamine, and completely separating the water phase from an organic phase after centrifugal separation;
(3) adjusting the pH value of the water phase obtained by separation in the step (2) to 4.70, carrying out crystallization separation at the isoelectric point of cefalexin, and carrying out suction filtration, washing and vacuum drying after crystal precipitation to obtain a cefalexin product;
(4) and (3) adding a potassium hydroxide solution into the organic phase obtained by separation in the step (2), controlling the volume ratio of the potassium hydroxide solution to the organic phase to be 0.8:1 and the molar ratio of the potassium hydroxide to the 1, 6-dihydroxynaphthalene to be 2:1, carrying out back extraction, stirring, carrying out centrifugal separation to obtain an organic phase which is tri-n-octylamine, and returning the obtained tri-n-octylamine to the step (2) for recycling.
The results showed that the overall yield of cephalexin was 94% and the recovery of tri-n-octylamine was 90.3%.
Example 3
(1) Dripping 0.828g of 2-naphthol into 200mL of cefalexin aqueous solution, complexing at room temperature, and after the reaction is finished, carrying out suction filtration and drying to obtain cefalexin double salt precipitate;
(2) adding 16mL of water and 3.2mL of tri-n-octylamine into the double salt precipitate obtained in the step (1), adjusting the pH value to 1.3 for decomplexation reaction, allowing cephalexin to enter a water phase, allowing 2-naphthol to enter tri-n-octylamine, and completely separating the water phase from an organic phase after centrifugal separation;
(3) adjusting the pH value of the water phase obtained by separation in the step (2) to 4.68, carrying out crystallization separation at the isoelectric point of cefalexin, and carrying out suction filtration, washing and vacuum drying after crystal precipitation to obtain a cefalexin product;
the results showed that the overall yield of cephalexin was 90%.
Example 4
(1) Dripping 0.828g of 1-naphthol into 200mL of cefalexin aqueous solution, complexing at room temperature, and after the reaction is finished, carrying out suction filtration and drying to obtain cefalexin double salt precipitate;
(2) adding 16mL of water and 5mL of tri-n-decylamine into the complex salt precipitate obtained in the step (1), adjusting the pH value to 0.8 for decomplexation reaction, allowing cephalexin to enter a water phase and 1-naphthol to enter the tri-n-decylamine, and completely separating the water phase from an organic phase after centrifugal separation;
(3) adjusting the pH value of the water phase obtained by separation in the step (2) to 4.72, carrying out crystallization separation at the isoelectric point of cefalexin, and carrying out suction filtration, washing and vacuum drying after crystal precipitation to obtain a cefalexin product;
(4) and (3) adding a potassium hydroxide solution into the organic phase obtained by separation in the step (2), controlling the volume ratio of the potassium hydroxide solution to the organic phase to be 1:1 and the molar ratio of the potassium hydroxide to the 1-naphthol to be 3:1, carrying out back extraction, and carrying out centrifugal separation after stirring to obtain an organic phase of tri-n-decylamine.
The total yield of cefalexin was 94.5%, and the recovery of tri-n-decylamine was 90%.
Example 5
(1) Dripping 0.92g of 1, 6-dihydroxynaphthalene into 200mL of cefalexin aqueous solution, complexing at room temperature, and after the reaction is finished, carrying out suction filtration and drying to obtain cefalexin double salt precipitate;
(2) adding 16mL of water and 4mL of tri-n-decylamine into the complex salt precipitate obtained in the step (1), adjusting the pH value to 1.2 for decomplexation reaction, allowing cephalexin to enter a water phase, allowing 1, 6-dihydroxynaphthalene to enter the tri-n-decylamine, and completely separating the water phase from an organic phase after centrifugal separation;
(3) adjusting the pH value of the water phase obtained by separation in the step (2) to 4.72, carrying out crystallization separation at the isoelectric point of cefalexin, and carrying out suction filtration, washing and vacuum drying after crystal precipitation to obtain a cefalexin product;
(4) and (3) adding a sodium hydroxide solution into the organic phase obtained by separation in the step (2), controlling the volume ratio of the sodium hydroxide solution to the organic phase to be 1:2 and the molar ratio of the sodium hydroxide to the 1, 6-dihydroxynaphthalene to be 3.5:1, carrying out back extraction, stirring, carrying out centrifugal separation to obtain an organic phase which is tri-n-decylamine, and returning the obtained tri-n-decylamine to the step (2) for recycling.
The results showed that the overall yield of cephalexin was 94% and the recovery of tri-n-decylamine was 90.2%.
Example 6
(1) Dripping 0.828g of 2-naphthol into 200mL of cefalexin aqueous solution, complexing at room temperature, and after the reaction is finished, carrying out suction filtration and drying to obtain cefalexin double salt precipitate;
(2) adding 16mL of water and 16mL of tri-n-decylamine into the complex salt precipitate obtained in the step (1), adjusting the pH value to 1.3 for decomplexation reaction, allowing cephalexin to enter a water phase, allowing 2-naphthol to enter the tri-n-decylamine, and completely separating the water phase from an organic phase after centrifugal separation;
(3) and (3) adjusting the pH value of the water phase obtained by separation in the step (2) to 4.72, carrying out crystallization separation at the isoelectric point of cefalexin, and carrying out suction filtration, washing and vacuum drying after crystal precipitation to obtain a cefalexin product.
The results showed that the overall yield of cephalexin was 91.7%.
Example 7
(1) Dripping 0.414g of 1-naphthol into 100mL of cefalexin aqueous solution, complexing at room temperature, and after the reaction is finished, carrying out suction filtration to obtain wet cefalexin double salt precipitate;
(2) adding 8mL of water and 1.6mL of tri-n-octylamine into the double salt precipitate obtained in the step (1), adjusting the pH value to 1.1 for decomplexation reaction, allowing cephalexin to enter a water phase, allowing 1-naphthol to enter tri-n-octylamine, and completely separating the water phase from an organic phase after centrifugal separation;
(3) and (3) adjusting the pH value of the water phase obtained in the step (2) to 4.65, carrying out crystallization separation at the isoelectric point of cefalexin, and carrying out suction filtration, washing and vacuum drying after crystal precipitation to obtain a cefalexin product.
The results showed that the overall yield of cephalexin was 91%.
Example 8
(1) Dripping 0.46g of 1, 6-dihydroxynaphthalene into 100mL of cefalexin aqueous solution, complexing at room temperature, and after the reaction is finished, carrying out suction filtration to obtain wet cefalexin double salt precipitate;
(2) adding 8mL of water and 2.5mL of tri-n-decylamine into the complex salt precipitate obtained in the step (1), adjusting the pH value to 1.1 for decomplexation reaction, allowing cephalexin to enter a water phase, allowing 1, 6-dihydroxynaphthalene to enter the tri-n-decylamine, and completely separating the water phase from an organic phase after centrifugal separation;
(3) and (3) adjusting the pH value of the water phase obtained by separation in the step (2) to 4.72, carrying out crystallization separation at the isoelectric point of cefalexin, and carrying out suction filtration, washing and vacuum drying after crystal precipitation to obtain a cefalexin product.
The results showed that the overall yield of cephalexin was 90.8%.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.
Claims (12)
1. The method for recovering cephalexin is characterized in that a phenolic substance is used as a complexing agent to enrich cephalexin in a solution; separating cephalexin by taking an amine substance as a decomplexer; the method comprises the following steps:
(1) adding a phenolic substance into the solution containing cefalexin, and performing solid-liquid separation after complete complexation to obtain a double-salt precipitate;
(2) adding water and amine substances into the complex salt precipitate obtained in the step (1) for decomplexing, adjusting the pH value to completely dissolve the complex salt precipitate, allowing cephalexin to enter a water phase, extracting phenolic substances to enter the amine substances, and separating the water phase from an organic phase;
(3) separating the cephalexin in the water phase obtained by the separation in the step (2) to obtain a cephalexin product;
adding an alkalizer into the organic phase obtained after separation in the step (2) for back extraction treatment, so that phenolic substances in the organic phase enter a water phase, and returning the organic phase obtained after two-phase separation to the step (2) as an amine substance for recycling;
the amine substance is tri-N-octylamine, tri-iso-octylamine, tri-N-nonylamine, tri-N-decylamine, tri-N-dodecylamine, tri (2-ethylhexyl) amine, di-N-octylamine, N235Or dodecyl dimethylamine, or a combination of at least two thereof.
2. The method of claim 1, wherein the phenolic material is a phenolic compound and/or a phenolic derivative.
3. The method of claim 2, the phenolic substance is any one or a combination of at least two of 1-naphthol, 2-naphthol, 1, 2-dihydroxynaphthalene, 1, 3-dihydroxynaphthalene, 1, 4-dihydroxynaphthalene, 1, 5-dihydroxynaphthalene, 1, 6-dihydroxynaphthalene, 2, 3-dihydroxynaphthalene, 2, 7-dihydroxynaphthalene, 1,2, 3-pyrogallol, 1,2, 4-benzenetriol, 2,4, 6-benzenetriol, catechol, resorcinol, hydroquinone, o-aminophenol, m-aminophenol, p-aminophenol, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, methyl o-hydroxybenzoate, ethyl o-hydroxybenzoate, 2-phenylphenol or 4-phenylphenol.
4. The process according to claim 1, wherein the molar ratio of the phenolic substance to the cefalexin in the solution in step (1) is (0.5-1.5): 1.
5. The method of claim 1, wherein the pH is adjusted to 0.2 to 1.3 in step (2).
6. The method according to claim 1, wherein the volume ratio of the amine-based substance to water added to the precipitation of the double salt in the step (2) is (0.1-2): 1.
7. The method of claim 1, wherein the amine-based substance added in step (2) and the precipitation of the double salt have a liquid-solid ratio of (0.5-7) to 1.
8. The process according to claim 1, wherein the crystallization in step (3) is carried out by adjusting the pH of the aqueous phase obtained by separation in step (2) to a value of 4.6 to 4.75 at the isoelectric point of cephalexin to obtain cephalexin product.
9. The method of claim 1, wherein the alkalizing agent used is any one of or a combination of at least two of sodium hydroxide solution, potassium hydroxide solution or lithium hydroxide solution.
10. The method according to claim 1, wherein the molar ratio of the alkaline substance in the alkalizing agent added during the stripping treatment to the complexing agent in the organic phase is (1-3.5): 1.
11. The method of claim 10, wherein the volume ratio of the alkalizer to the organic phase during the stripping is (0.1-10): 1.
12. The method according to any one of claims 1 to 11, characterized in that it comprises the steps of:
(1) adding a phenolic substance into the solution containing the cefalexin, and performing solid-liquid separation after complete complexation to obtain a double-salt precipitate, wherein the molar ratio of the phenolic substance to the cefalexin in the solution is (0.5-1.5): 1; the phenolic substance is 1-naphthol, 2-naphthol, 1, 2-dihydroxynaphthalene, 1, 3-dihydroxynaphthalene, 1, 4-dihydroxynaphthalene, 1, 5-dihydroxynaphthalene, 1, 6-dihydroxynaphthalene, 2, 3-dihydroxynaphthalene, 2, 7-dihydroxynaphthalene, 1,2, 3-pyrogallol, 1,2, 4-benzenetriol, 2,4, 6-benzenetriol, any one or combination of at least two of catechol, resorcinol, hydroquinone, o-aminophenol, m-aminophenol, p-aminophenol, methyl paraben, ethyl paraben, propyl paraben, methyl paraben, ethyl paraben, 2-phenylphenol or 4-phenylphenol;
(2) adding water and amine substances into the complex salt precipitate obtained in the step (1), controlling the volume ratio of the amine substances to the water to be (0.1-2):1, and the liquid-solid ratio of the amine substances to the complex salt precipitate to be (0.5-7):1, performing decomplexation, adjusting the pH to be 0.2-1.3 to completely dissolve the cefalexin, introducing the cefalexin into a water phase, extracting the phenol substances into the amine substances, and separating the water phase from an organic phase; the amine substance is tri-N-octylamine, tri-iso-octylamine, tri-N-nonylamine, tri-N-decylamine, tri-N-dodecylamine, tri (2-ethylhexyl) amine, di-N-octylamine, N235Or dodecyl dimethylamine, or a combination of at least two thereof;
(3) adjusting the pH value of the water phase obtained after separation in the step (2) to 4.6-4.75, and crystallizing at the isoelectric point of cephalexin to obtain a cephalexin product;
(4) and (3) adding an alkalizer into the organic phase obtained after separation in the step (2), controlling the molar ratio of an alkaline substance in the alkalizer to a complexing agent in the organic phase to be (1-3.5):1, and the volume ratio of the alkalizer to the organic phase to be (0.1-10):1, carrying out back extraction treatment to enable phenolic substances in the organic phase to enter a water phase, and returning the organic phase obtained after two-phase separation to be an amine substance to be used as a decomplexing agent for recycling in the step (2).
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4003896A (en) * | 1974-12-17 | 1977-01-18 | Novo Industri A/S | Method of preparing a sparingly soluble complex of cephalexin |
| WO1993012250A1 (en) * | 1991-12-19 | 1993-06-24 | Novo Nordisk A/S | AN IMPROVED METHOD FOR THE PREPARATION OF CERTAIN β-LACTAM ANTIBIOTICS |
| CN1830982A (en) * | 2006-04-17 | 2006-09-13 | 苏州中联化学制药有限公司 | Method for recovery of cefaclor |
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2017
- 2017-12-21 CN CN201711391343.5A patent/CN108084211B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4003896A (en) * | 1974-12-17 | 1977-01-18 | Novo Industri A/S | Method of preparing a sparingly soluble complex of cephalexin |
| WO1993012250A1 (en) * | 1991-12-19 | 1993-06-24 | Novo Nordisk A/S | AN IMPROVED METHOD FOR THE PREPARATION OF CERTAIN β-LACTAM ANTIBIOTICS |
| CN1830982A (en) * | 2006-04-17 | 2006-09-13 | 苏州中联化学制药有限公司 | Method for recovery of cefaclor |
Non-Patent Citations (2)
| Title |
|---|
| C.G.P.H. Schroën et al..In situ product removal during enzymatic cephalexin synthesis by complexation.《ENZYME AND MICROBIAL TECHNOLOGY》.2002,第31卷264-273. * |
| Efficiency of cephalosporin complexation with aromatic compounds;Gerardus J. Kemperman et al.;《J. Chem. Soc., Perkin Trans. 》;20011231;第2卷;633-638 * |
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