CN113005168B - Preparation method of 6-aminopenicillanic acid - Google Patents
Preparation method of 6-aminopenicillanic acid Download PDFInfo
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- CN113005168B CN113005168B CN202110259291.6A CN202110259291A CN113005168B CN 113005168 B CN113005168 B CN 113005168B CN 202110259291 A CN202110259291 A CN 202110259291A CN 113005168 B CN113005168 B CN 113005168B
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P37/00—Preparation of compounds having a 4-thia-1-azabicyclo [3.2.0] heptane ring system, e.g. penicillin
- C12P37/06—Preparation of compounds having a 4-thia-1-azabicyclo [3.2.0] heptane ring system, e.g. penicillin by desacylation of the substituent in the 6 position
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- C07—ORGANIC CHEMISTRY
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- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/18—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/42—Compounds with a free primary amino radical attached in position 6
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Abstract
The invention discloses a preparation method of 6-aminopenicillanic acid, belonging to the technical field of biological fermentation, and the method comprises the steps of obtaining a treated penicillin fermentation liquor by utilizing a penicillin fermentation liquor through a pretreatment process; the pretreatment process comprises a wall breaking process, a releasing process, an extracting process and a separating process; the invention has the beneficial effects that: abandons the later stage of the existing 6-amino penicillanic acid preparation method, uses a large amount of organic solvents such as butyl acetate, n-butyl alcohol and the like, creatively carries out wall breaking treatment on penicillin thalli by using chitinase, removes the cell wall protoplast from trichloroacetic acid, and carries out denaturation removal on the binding protein which is combined with the penicillin in the protoplast to obtain the penicillin with the binding protein removed; the problem of lower penicillin content in the fermentation liquor is solved; the extraction process is creatively introduced, and the penicillin content in the fermentation liquor is further improved.
Description
The technical field is as follows:
the invention belongs to the technical field of biological fermentation, and particularly relates to a preparation method of 6-aminopenicillanic acid.
Background art:
6-aminopenicillanic acid (6-aminopenicillanic acid, 6-APA) is a white flaky crystal, is an important intermediate for synthesizing various semi-synthetic penicillins, and has wide application range. The chemical structure modification is carried out by taking the penicillin-resistant bacteria as a raw material, and side chains with different structures are connected, so that the novel semi-synthetic penicillin which is sensitive to penicillin-resistant bacteria and has wider antibacterial spectrum, such as ampicillin, amoxicillin, phenoxymethylpenicillin and other various semi-synthetic penicillins with wider antibacterial spectrum can be manufactured.
At present, the side chain of penicillin is industrially removed and the penicillin is cracked into 6-APA mainly by a microbial enzyme catalytic cracking method and a chemical cracking method. With the rapid development of bioengineering technology, 6-APA is produced by adopting immobilized enzyme or immobilized cells, so that the process is greatly simplified, the economic benefit is obvious, and the 6-APA with higher purity can be obtained. In recent years, enzymatic methods have become the mainstream of industrial production of 6-APA.
Chemical cracking method: the process route for chemical cracking for industrial production is: at very low temperature, the carboxyl group of penicillin is first converted into silicone ester to protect it, and the amide on side chain is then activated to form penicillin substituted imino ether derivative, which is then hydrolyzed to 6-APA under very mild condition.
Biological enzyme catalysis method: penicillin acylases are produced in nature by bacteria, actinomycetes, yeasts and higher fungi. With the development of modern biotechnology, progress is made in various fields of enzyme strain improvement, fermentation automation, enzyme large-scale, enzyme immobilization, reactor design, subsequent processes and the like, and the penicillin acylase is already mature for preparing 6 APA. The immobilized enzyme can be reused, is easy to separate from the reaction liquid, and can effectively prevent protein pollution, microbial pollution and the like to the product.
The national invention patent with the patent number of 201410208804.0 discloses a method for directly preparing 6-aminopenicillanic acid from penicillin fermentation broth, and provides a method for directly preparing 6-aminopenicillanic acid from penicillin fermentation broth, which avoids the use of organic solvents such as butyl acetate, n-butyl alcohol and the like, improves the yield of products, reduces the energy consumption in the preparation process, is a green and energy-saving 6-aminopenicillanic acid production method, but has lower yield.
There are many strains producing penicillin in nature, for example, penicillium chrysogenum (penicillium chrysogenum) is a natural strain producing penicillin with high yield, and the effective amount of penicillin in the penicillin fermentation liquor is about 100000u/mL according to the existing penicillin production process; however, there is a general problem in common, such as that penicillin in Penicillium chrysogenum exists in two forms, one in free form, which can be transferred to the fermentation broth through cell membranes and cell walls, i.e., 100000u/mL as the main source, and the other in bound form, which binds to the binding protein and cannot be transferred to the fermentation broth through cell membranes and cell walls;
however, this method causes the release of cell contents, which makes it difficult to separate the penicillin in a subsequent separation step, and the product contains a small amount of soluble protein, which affects the quality of the product.
The invention content is as follows:
in order to solve the problems and overcome the defects of the prior art, the invention provides a preparation method of 6-aminopenicillanic acid, which can effectively solve the problem of low effective dosage of penicillin.
The specific technical scheme for solving the technical problems comprises the following steps: the preparation method of 6-aminopenicillanic acid comprises the steps of obtaining treated penicillin fermentation liquor by utilizing penicillin fermentation liquor through a pretreatment process;
the penicillin fermentation liquor is obtained by fermenting penicillium chrysogenum (Penicillium chrysogenum), and the microbiological characteristics of the penicillium chrysogenum are as follows: the morphology of the single colony is: the bacterial colony is white and round, has a convex middle part and is fully covered with regular folds; the spores are white or off-white, and the spores are round under a microscope.
The pretreatment process comprises a wall breaking process, a releasing process, an extracting process and a separating process;
the wall breaking process is to add chitinase into the fermentation liquor with the penicillium to carry out wall breaking treatment to obtain a treatment liquid of the protoplast with the penicillium;
the releasing process comprises the steps of adding trichloroacetic acid into the treatment liquid, allowing the trichloroacetic acid to enter the protoplast, and performing denaturation and removal on the binding protein bound with the penicillin in the protoplast to obtain the penicillin without the binding protein;
in the extraction process, the temperature of the fermentation mixed liquor is raised to 55-60 ℃, and the penicillin for removing the binding protein is extracted from the cells subjected to wall breaking treatment;
the separation process is to remove protoplasts containing penicillium by ultrafiltration to obtain penicillin filtrate.
The penicillin concentration of the penicillin filtrate is 400000 and 500000 u/mL.
The molecular weight cut-off of the filter membrane in the ultrafiltration is 5000-15000 Da.
The reaction temperature of the wall breaking process is 35-45 ℃, and the addition amount of the trichloroacetic acid is 0.2-0.5 per mill of the mass of the treatment fluid.
The suspension mixed solution containing penicillin is a mixture of penicillin solution and penicillin thallus protoplast containing denatured protein in the content.
Adding penicillin acylase into the treated penicillin fermentation liquor to carry out a cracking reaction, and obtaining mixed liquor containing 6-aminopenicillanic acid and phenylacetic acid after the reaction is finished;
carrying out nanofiltration concentration on the mixed solution to obtain a concentrated mixed solution of 6-aminopenicillanic acid and phenylacetic acid;
decolorizing the concentrated mixed solution of 6-aminopenicillanic acid and phenylacetic acid, and adsorbing and separating the phenylacetic acid in the concentrated mixed solution by using resin to obtain an aqueous solution of 6-aminopenicillanic acid;
adjusting the pH value of the aqueous solution of 6-aminopenicillanic acid to the isoelectric point of 6-aminopenicillanic acid to obtain 6-aminopenicillanic acid crystals, filtering, washing and drying to obtain 6-aminopenicillanic acid.
The temperature of the cracking reaction is 22-28 ℃, the pH value of the fermentation liquor in the reaction process is 7.2-8.2, and the reaction time of the cracking reaction is 1-2 h.
The invention has the beneficial effects that:
the invention abandons the use of a large amount of organic solvents such as butyl acetate, n-butanol and the like in the later stage of the existing 6-aminopenicillanic acid preparation method, has complex and complicated process, removes mycelium and macromolecular impurities by a membrane filtration technology, and obtains a target product by an isoelectric point crystallization method, wherein the purity of the target product obtained by the method is not lower than 98.5 percent, and the yield is more than 89 percent;
the invention skillfully separates zymolyte from fungus thallus at the same time of the pretreatment process, provides a cleaner and single substrate environment, and then adds penicillin acylase, thereby reducing the influence of influencing factors of the substrate on the penicillin acylase and further improving the conversion efficiency of 6-amino penicillanic acid;
creatively breaking the walls of penicillin thalli by using chitinase, removing the cell wall protoplast by trichloroacetic acid, and performing denaturation removal on binding protein which is combined with penicillin in the protoplast to obtain the penicillin with the binding protein removed; the problem of lower penicillin content in the fermentation liquor is solved;
the extraction process is creatively introduced, and the penicillin content in the fermentation liquor is further improved.
The specific implementation mode is as follows:
in the description of the invention, specific details are given for the purpose of providing a thorough understanding of embodiments of the invention, but it will be appreciated by those skilled in the art that the invention may be practiced without limitation to these details. In other instances, well-known structures and functions have not been described or shown in detail to avoid obscuring the points of the embodiments of the invention. The specific meanings of the above terms in the present invention can be understood in specific cases to those skilled in the art.
The various biological materials described in the examples are obtained by way of experimental acquisition for the purposes of this disclosure and should not be construed as limiting the source of the biological material of the invention. In fact, the sources of the biological materials used are wide and any biological material that can be obtained without violating the law and ethics can be used instead as suggested in the examples.
The specific implementation mode of the invention is as follows:
the preparation method of 6-aminopenicillanic acid comprises the steps of obtaining treated penicillin fermentation liquor by utilizing penicillin fermentation liquor through a pretreatment process;
the penicillin fermentation liquor is obtained by fermenting penicillium chrysogenum (Penicillium chrysogenum) from Shandong Lu anti-medicine GmbH, and has the microbiological characteristics as follows: the morphology of the single colony is: the bacterial colony is white and round, has a convex middle part and is fully covered with regular folds; the spores are white or off-white, and the spores are round under a microscope.
The pretreatment process comprises a wall breaking process, a releasing process, an extracting process and a separating process;
the wall breaking process is to add chitinase into the fermentation liquor with the penicillium to carry out wall breaking treatment to obtain a treatment liquid of the protoplast with the penicillium;
the releasing process comprises the steps of adding trichloroacetic acid into the treatment liquid, allowing the trichloroacetic acid to enter the protoplast, and performing denaturation and removal on the binding protein bound with the penicillin in the protoplast to obtain the penicillin without the binding protein;
in the extraction process, the temperature of the fermentation mixed liquor is raised to 55-60 ℃, and the penicillin for removing the binding protein is extracted from the cells subjected to wall breaking treatment;
the separation process is to remove protoplasts containing penicillium by ultrafiltration to obtain penicillin filtrate.
The penicillin concentration of the penicillin filtrate is 400000 and 500000 u/mL.
The molecular weight cut-off of the filter membrane in the ultrafiltration is 5000-15000 Da.
The reaction temperature of the wall breaking process is 35-45 ℃, and the addition amount of the trichloroacetic acid is 0.2-0.5 per mill of the mass of the treatment fluid.
The suspension mixed solution containing penicillin is a mixture of penicillin solution and penicillin thallus protoplast containing denatured protein in the content.
Adding penicillin acylase into the treated penicillin fermentation liquor to carry out a cracking reaction, and obtaining mixed liquor containing 6-aminopenicillanic acid and phenylacetic acid after the reaction is finished;
carrying out nanofiltration concentration on the mixed solution to obtain a concentrated mixed solution of 6-aminopenicillanic acid and phenylacetic acid;
decolorizing the concentrated mixed solution of 6-aminopenicillanic acid and phenylacetic acid, and adsorbing and separating the phenylacetic acid in the concentrated mixed solution by using resin to obtain an aqueous solution of 6-aminopenicillanic acid;
adjusting the pH value of the aqueous solution of 6-aminopenicillanic acid to the isoelectric point of 6-aminopenicillanic acid to obtain 6-aminopenicillanic acid crystals, filtering, washing and drying to obtain 6-aminopenicillanic acid.
The temperature of the cracking reaction is 22-28 ℃, the pH value of the fermentation liquor in the reaction process is 7.2-8.2, and the reaction time of the cracking reaction is 1-2 h.
In order to more intuitively show the process advantages of the invention, the method disclosed by the invention is particularly used;
comparative example one: by way of reference, the method of the national invention patent 201410208804.0, a method for directly preparing 6-aminopenicillanic acid from penicillin fermentation broth, is adopted for comparison, and the strain is penicillium chrysogenum (Penicillium chrysogenum) from Shandong Lu anti-medicine GmbH;
the method comprises the steps of taking penicillin fermentation liquor without wall breaking, wherein the concentration of penicillin is 100000u/mL, and 1000mL of the penicillin fermentation liquor is placed in a stirring reactor with the temperature controlled at 28-30 ℃ for stirring; adding penicillinase for acylation when the temperature of the fermentation solution reaches 28-30 ℃, cracking, continuously dropwise adding 10% ammonia water in the cracking process, maintaining the pH value in the reactor at about 7.0, and finishing the reaction when the pH value in the reactor is kept unchanged within 20min after the ammonia water is stopped being added;
comparative example two: the preparation method is the same as the first comparative example except that: in the preparation process of the comparative example, a wall breaking machine is adopted for wall breaking treatment, the concentration of the penicillin is 400000 and 500000u/mL, and then penicillin is acylated by penicillin enzyme;
comparative example three: the preparation method is the same as the embodiment except that: in the preparation process of the comparative example, wall breaking treatment is adopted, the concentration of the penicillin is 400000 and 500000u/mL, penicillin is acylated by penicillin enzyme,
comparative example four: the preparation method is the same as the embodiment except that: the preparation method of the 6-aminopenicillanic acid does not adopt a wall breaking process,
comparative example five: the preparation method is the same as the embodiment except that: in the preparation method of 6-aminopenicillanic acid, trichloroacetic acid is not added into the treatment fluid for deproteinization;
comparative example six: the preparation method is the same as the embodiment except that: the preparation method of 6-aminopenicillanic acid does not adopt an extraction process;
and the content of the protein in the solution is determined according to a Coomassie brilliant blue G-250 color development method for detection, and the detection is carried out according to a detection method related to antibiotics in Chinese pharmacopoeia 2005, wherein the test data is as follows:
table 1: influence of different processes on different indexes
From the above data analysis, it can be seen that:
the invention and the comparative example compare to see that: the first comparative example is introduced by means of citation, because the wall breaking treatment is not carried out, although the subsequent extraction process is easier to carry out and the protein content in the product is lower, the penicillin binding protein in fungus bodies cannot be utilized by the method, so that the penicillin content in the fermentation liquor is lower to 100000-120000 u/mL; consequently, the yield of 6-aminopenicillanic acid after the subsequent enzymolysis process is low.
The invention and comparative example two and comparative example three compare: compared with the prior art, the content of penicillin is greatly improved because the fungal cell structure after wall breaking is damaged, the content and the penicillin bound to protein are transferred into the fermentation broth, but the penicillin bound to protein cannot perform site recognition and cleavage with penicillin acylase, so that the content of penicillin in the comparative example is not remarkably improved, and a large amount of intracellular protein is released into the fermentation broth due to the release of the cell content, so that the separation is not facilitated, and part of water-soluble protein is brought into a final product, so that the purity of the product is influenced;
particularly, when the pretreatment process is carried out, the zymolyte is separated from the fungus thallus in advance, a cleaner and single environment for a substrate is provided, and then the penicillin acylase is added, so that the influence of external influencing factors on the penicillin acylase is reduced;
comparative example four analysis showed that: because the cell wall is not treated, the trichloroacetic acid added subsequently can not enter the protoplast, and the penicillin in the protoplast can not be smoothly released out of the cell, so that the contents of the penicillin and the protein are both low;
the comparison between the invention and the fifth comparative example and the sixth comparative example shows that: both comparative example five and comparative example six, in which the cell wall was treated with chitinase, the content of penicillin in comparative example five was not significantly increased because no trichloroacetic acid was added through the release process, the binding protein bound to penicillin in protoplasts could not be separated from penicillin, and penicillin bound to the binding protein could not be freely diffused and transported through the cell membrane;
compared with the method disclosed by the invention, the efficiency is poor because the temperature of the fermentation mixed liquor in the extraction process is raised to 55-60 ℃, the penicillin removing the binding protein is extracted from the cell subjected to wall breaking treatment, and the content of the penicillin is further improved.
In summary, the following steps:
the invention abandons the use of a large amount of organic solvents such as butyl acetate, n-butanol and the like in the later stage of the existing 6-aminopenicillanic acid preparation method, has complex and complicated process, removes mycelium and macromolecular impurities by a membrane filtration technology, and obtains a target product by an isoelectric point crystallization method, wherein the purity of the target product obtained by the method is not lower than 98.5 percent, and the yield is more than 89 percent;
when the pretreatment process is carried out, the zymolyte is separated from the fungus thallus in advance, a cleaner and single substrate environment is provided, and then the penicillin acylase is added, so that the influence of influencing factors of the substrate on the penicillin acylase is reduced, and the conversion efficiency of the 6-aminopenicillanic acid is further improved;
creatively breaking the walls of penicillin thalli by using chitinase, removing the cell wall protoplast by trichloroacetic acid, and performing denaturation removal on binding protein which is combined with penicillin in the protoplast to obtain the penicillin with the binding protein removed; the problem of lower penicillin content in the fermentation liquor is solved;
the extraction process is creatively introduced, and the penicillin content in the fermentation liquor is further improved.
Claims (7)
1. A preparation method of 6-aminopenicillanic acid is characterized by comprising the following steps: obtaining a treated penicillin fermentation liquor by using a penicillin fermentation liquor through a pretreatment process;
(1) adding penicillin acylase into the treated penicillin fermentation liquor to carry out a cracking reaction, and obtaining mixed liquor containing 6-aminopenicillanic acid and phenylacetic acid after the reaction is finished;
(2) carrying out nanofiltration concentration on the mixed solution to obtain a concentrated mixed solution of 6-aminopenicillanic acid and phenylacetic acid;
(3) decolorizing the concentrated mixed solution of 6-aminopenicillanic acid and phenylacetic acid, and adsorbing and separating the phenylacetic acid in the concentrated mixed solution by using resin to obtain an aqueous solution of 6-aminopenicillanic acid;
(4) adjusting the pH value of the aqueous solution of 6-aminopenicillanic acid to the isoelectric point of 6-aminopenicillanic acid to obtain 6-aminopenicillanic acid crystal, filtering, washing and drying to obtain 6-aminopenicillanic acid,
the pretreatment process comprises a wall breaking process, a releasing process, an extracting process and a separating process;
the wall breaking process is to add chitinase into the fermentation liquor with the penicillium to carry out wall breaking treatment to obtain a treatment liquid of the protoplast with the penicillium;
the releasing process comprises the steps of adding trichloroacetic acid into the treatment liquid, allowing the trichloroacetic acid to enter the protoplast, and performing denaturation and removal on the binding protein bound with the penicillin in the protoplast to obtain the penicillin without the binding protein;
the extraction process raises the temperature of the fermentation mixed liquor to 55-60 ℃, and extracts the penicillin without the binding protein from the cells subjected to wall breaking treatment;
the separation process is to remove protoplasts containing penicillium by ultrafiltration to obtain penicillin filtrate.
2. The process according to claim 1, wherein the penicillin fermentation broth is obtained by fermentation of Penicillium chrysogenum.
3. The method according to claim 1, wherein the temperature of the cleavage reaction is 22-28 ℃, the pH of the fermentation broth during the reaction is 7.2-8.2, and the reaction time of the cleavage reaction is 1-2 hours.
4. The process according to claim 1, wherein the penicillin filtrate has a penicillin concentration of 400000 and 500000 u/mL.
5. The process for producing 6-aminopenicillanic acid according to claim 1, wherein the molecular weight cut-off of the filtration membrane in the ultrafiltration is 5000 to 15000 Da.
6. The method according to claim 1, wherein the reaction temperature of the wall-breaking step is 35-45 ℃, and the amount of trichloroacetic acid added is 0.2-0.5 ‰ of the mass of the treatment solution.
7. The process according to claim 1, wherein the suspension liquid containing penicillin is a mixture of a penicillin solution and penicillin protoplasts containing denatured proteins in their contents.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5500352A (en) * | 1993-03-24 | 1996-03-19 | Sepracor, Inc. | Membrane filtration process for 6-aminopenicillanic acid |
| CN104004002A (en) * | 2014-05-16 | 2014-08-27 | 河北天俱时生物科技有限公司 | Method using penicillin fermentation liquor for direct preparation of 6-aminopenicillanicacid |
| CN105567778A (en) * | 2016-03-02 | 2016-05-11 | 南京正亮医药科技有限公司 | Preparation method of 6-aminopenicillanic acid |
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- 2021-03-10 CN CN202110259291.6A patent/CN113005168B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5500352A (en) * | 1993-03-24 | 1996-03-19 | Sepracor, Inc. | Membrane filtration process for 6-aminopenicillanic acid |
| CN104004002A (en) * | 2014-05-16 | 2014-08-27 | 河北天俱时生物科技有限公司 | Method using penicillin fermentation liquor for direct preparation of 6-aminopenicillanicacid |
| CN105567778A (en) * | 2016-03-02 | 2016-05-11 | 南京正亮医药科技有限公司 | Preparation method of 6-aminopenicillanic acid |
Non-Patent Citations (1)
| Title |
|---|
| 超滤技术在6-APA直通工艺中的应用;高建军等;《中国抗生素杂志》;20081225(第12期);全文 * |
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