CN111378704A - Method for producing 4-AA intermediate by ketoreductase - Google Patents
Method for producing 4-AA intermediate by ketoreductase Download PDFInfo
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- CN111378704A CN111378704A CN202010210225.5A CN202010210225A CN111378704A CN 111378704 A CN111378704 A CN 111378704A CN 202010210225 A CN202010210225 A CN 202010210225A CN 111378704 A CN111378704 A CN 111378704A
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- 101001110310 Lentilactobacillus kefiri NADP-dependent (R)-specific alcohol dehydrogenase Proteins 0.000 title claims abstract description 22
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 64
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 33
- 102000004190 Enzymes Human genes 0.000 claims abstract description 27
- 108090000790 Enzymes Proteins 0.000 claims abstract description 27
- 239000012074 organic phase Substances 0.000 claims abstract description 20
- 239000000243 solution Substances 0.000 claims abstract description 20
- 239000002994 raw material Substances 0.000 claims abstract description 18
- 238000002425 crystallisation Methods 0.000 claims abstract description 14
- 230000008025 crystallization Effects 0.000 claims abstract description 14
- 238000000605 extraction Methods 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 11
- 210000003298 dental enamel Anatomy 0.000 claims abstract description 11
- 238000005406 washing Methods 0.000 claims abstract description 11
- 238000002156 mixing Methods 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 7
- 239000005515 coenzyme Substances 0.000 claims abstract description 6
- 239000008367 deionised water Substances 0.000 claims abstract description 6
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 6
- 239000007791 liquid phase Substances 0.000 claims abstract description 6
- 239000012266 salt solution Substances 0.000 claims abstract description 6
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 238000007599 discharging Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000012071 phase Substances 0.000 claims description 5
- 235000001674 Agaricus brunnescens Nutrition 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000000543 intermediate Substances 0.000 claims 5
- 238000005119 centrifugation Methods 0.000 claims 1
- 239000012141 concentrate Substances 0.000 claims 1
- 230000007613 environmental effect Effects 0.000 abstract description 7
- 238000001514 detection method Methods 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 3
- 239000007788 liquid Substances 0.000 abstract 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 10
- 239000004473 Threonine Substances 0.000 description 5
- 229960002898 threonine Drugs 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- OEYMQQDJCUHKQS-UHFFFAOYSA-N (4-oxoazetidin-2-yl) acetate Chemical compound CC(=O)OC1CC(=O)N1 OEYMQQDJCUHKQS-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 1
- 229960002182 imipenem Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 1
- 229960002260 meropenem Drugs 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
Abstract
The invention discloses a method for producing a 4-AA intermediate by ketoreductase, which comprises the following steps: s1, enzyme catalyzed: adding enzyme catalysis reaction raw materials into an enamel reaction kettle, wherein the reaction raw materials are in the following ratio: 15-25% of C3, 5-15% of ketoreductase, 5-10% of isopropanol, 0.01-0.05% of coenzyme and deionized water as a solvent, uniformly mixing after constant volume, stirring for reaction, and adding hydrochloric acid to adjust the pH value to 4.0-5.0 after the liquid phase detection C3 finishes the reaction, thereby terminating the reaction; s2, concentrating: after the reaction is finished, concentrating the reaction solution at the temperature of 40-50 ℃ until the reaction solution is completely dried; s3, extraction: adding ethyl acetate to extract the product; s4, concentration and crystallization: transferring the organic phase after extraction into a concentration crystallization kettle, adding saturated salt solution into the organic phase, washing, separating liquid, concentrating the organic phase, crystallizing after concentration, and centrifuging in a centrifuge to obtain a product; compared with the foreign enzyme method process, the method has the remarkable advantages of high conversion rate, simple preparation process, safety, environmental protection and the like, is more suitable for industrial scale production, and better accords with the current national safety and environmental protection policy.
Description
Technical Field
The invention relates to the technical field of chemical 4-AA, in particular to a method for producing a 4-AA intermediate by ketoreductase.
Background
4-AA is short for 4-acetoxy azetidinone, is a main raw material for producing all carbapenem antibiotics (namely penem antibiotics) bulk drugs, is used for synthesizing mother nucleus of penem antibiotics such as meropenem, imipenem and the like, and carbapenem is a novel antibiotic with a brand new chemical structure developed in the last 70 th century of the United states, is formed by structural modification of penicillin, and belongs to 'β lactam antibiotics' with penicillin and cephalosporin.
In the process of synthesizing 4-AA, chiral isomers are generated in the process of reducing ketone into alcohol, and the difficulty of catalytic reaction is to obtain products with fixed configuration. The enzymatic process for producing 4-AA at present is still in an experimental stage, and industrial scale production cannot be realized due to high cost. The ruthenium chiral catalyst with high cost is used by high sand companies in Japan, and other manufacturers in China generally adopt a process route starting from L-threonine, and the process has the characteristics that the raw materials are cheap, the cost is relatively low, but more dangerous wastes are generated, ozone, epoxide, azide and the like are used, the danger coefficient is high, the current environmental protection and safety policies are not met, and the process is gradually eliminated.
Disclosure of Invention
In order to overcome the above-mentioned disadvantages, it is an object of the present invention to provide a method for producing a 4-AA intermediate by a ketoreductase.
In order to achieve the purpose, the invention is implemented according to the following technical scheme:
a method of producing a 4-AA intermediate from a ketoreductase enzyme comprising the steps of:
s1, enzyme catalyzed: adding enzyme catalysis reaction raw materials into an enamel reaction kettle, wherein the reaction raw materials are in the following ratio: 15-25% of C3, 5-15% of ketoreductase, 5-10% of isopropanol, 0.01-0.05% of coenzyme and deionized water as a solvent, uniformly mixing after constant volume, stirring for reaction, and adding hydrochloric acid to adjust the pH value to 4.0-5.0 after the liquid phase detection C3 finishes the reaction, thereby terminating the reaction; the chemical structural formula of C3 is:
s2, concentrating: after the reaction is finished, concentrating the reaction solution at the temperature of 40-50 ℃ until the reaction solution is completely dried;
s3, extraction: adding ethyl acetate to extract a product, washing the lower layer of mushroom dregs with water, and discharging;
s4, concentration and crystallization: transferring the organic phase after extraction into a concentration crystallization kettle, adding saturated salt solution into the organic phase, washing, separating, draining the water phase, concentrating the organic phase, crystallizing after concentration, centrifuging in a centrifuge to obtain a product, and drying the product in a double cone for later use;
further, in the S1 enzyme catalysis reaction stage, the constant temperature environment of 35-40 ℃ is kept in the enamel reaction kettle, and the stirring reaction is carried out for 20-40 h;
further, in the S1 enzyme-catalyzed reaction stage, after constant volume and uniform mixing, regulating the pH value of the solution to 6.70-7.00;
further, in the S3 extraction stage, the amount of ethyl acetate added is 10-20 times of the amount of the S2 concentrated product;
further, in the S4 concentration and crystallization stage, the concentration of the organic phase is carried out at the temperature of 40-60 ℃.
Compared with the prior art, compared with the traditional 4-AA production process of L-threonine and the reduction process of a Japanese chiral catalyst, the method for producing the 4-AA intermediate by using the ketoreductase has the advantages of convenient raw material acquisition, low raw material cost, small toxic and side effects and simple processing and production process; compared with the foreign enzyme method process, the method has the remarkable advantages of high conversion rate, simple preparation process, low safety and environmental protection risks, low production cost and the like, is more suitable for industrial scale production, and better accords with the current national safety and environmental protection policy; the method for preparing 4-AA breaks through the technical bottleneck of enzyme method production of 4-AA, realizes large-scale industrialization, has the yield of more than 40 percent, solves the problems of low enzyme process yield, complex process and difficult industrialization, reduces the process ratio of three wastes to L-threonine by more than 50 percent, and fills the domestic similar technology introduction blank.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without creative efforts.
FIG. 1 is a flow chart of the present invention.
Detailed Description
The invention will be further described with reference to the drawings and specific embodiments, which are illustrative of the invention and are not to be construed as limiting the invention.
Example 1
A method of producing a 4-AA intermediate by a ketoreductase enzyme as shown in FIG. 1, comprising the steps of:
s1, enzyme catalyzed: adding enzyme catalysis reaction raw materials into an enamel reaction kettle, wherein the reaction raw materials are in the following ratio: 15% of C3, 5% of ketoreductase, 5% of isopropanol, 0.01% of coenzyme and deionized water as a solvent, uniformly mixing after constant volume, regulating the pH value of a solution to 6.70, keeping a constant temperature environment of 35 ℃ in an enamel reaction kettle, stirring for reaction for 20 hours, and adding hydrochloric acid to regulate the pH value to 4.0 to terminate the reaction after the liquid phase detection C3 is finished;
s2, concentrating: after the reaction is finished, concentrating the reaction solution at the temperature of 40-50 ℃ until the reaction solution is completely dried;
s3, extraction: adding ethyl acetate to extract the product, wherein the amount of the added ethyl acetate is 10 times of the amount of the S2 concentrated product, and discharging lower-layer mushroom dregs after washing;
s4, concentration and crystallization: transferring the organic phase after extraction into a concentration crystallization kettle, adding saturated salt solution into the organic phase, washing, separating, draining the water phase, concentrating the organic phase at 40-60 ℃, crystallizing after concentration, centrifuging in a centrifuge to obtain a product, and drying the product in a double cone for later use.
Example 2
A method of producing a 4-AA intermediate by a ketoreductase enzyme as shown in FIG. 1, comprising the steps of:
s1, enzyme catalyzed: adding enzyme catalysis reaction raw materials into an enamel reaction kettle, wherein the reaction raw materials are in the following ratio: 25% of C3, 15% of ketoreductase, 10% of isopropanol, 0.05% of coenzyme and deionized water as a solvent, uniformly mixing after constant volume, regulating the pH of a solution to 7.00, keeping a constant temperature environment of 35-40 ℃ in an enamel reaction kettle, stirring for reaction for 40 hours, and adding hydrochloric acid to regulate the pH to 5.0 to terminate the reaction after the liquid phase detection C3 is finished;
s2, concentrating: after the reaction is finished, concentrating the reaction solution at the temperature of 40-50 ℃ until the reaction solution is completely dried;
s3, extraction: adding ethyl acetate to extract the product, wherein the amount of the added ethyl acetate is 20 times of the amount of the S2 concentrated product, and discharging lower-layer mushroom dregs after washing;
s4, concentration and crystallization: transferring the organic phase after extraction into a concentration crystallization kettle, adding saturated salt solution into the organic phase, washing, separating, draining the water phase, concentrating the organic phase at 40-60 ℃, crystallizing after concentration, centrifuging in a centrifuge to obtain a product, and drying the product in a double cone for later use.
Example 3
A method of producing a 4-AA intermediate by a ketoreductase enzyme as shown in FIG. 1, comprising the steps of:
s1, enzyme catalyzed: adding enzyme catalysis reaction raw materials into an enamel reaction kettle, wherein the reaction raw materials are in the following ratio: 20% of C3, 10% of ketoreductase, 7% of isopropanol, 0.03% of coenzyme and deionized water as a solvent, uniformly mixing after constant volume, regulating the pH of a solution to 6.9, keeping a constant temperature environment of 35-40 ℃ in an enamel reaction kettle, stirring for reaction for 30 hours, and adding hydrochloric acid to regulate the pH to 4.5 after the reaction of liquid phase detection C3 is finished to terminate the reaction;
s2, concentrating: after the reaction is finished, concentrating the reaction solution at the temperature of 40-50 ℃ until the reaction solution is completely dried;
s3, extraction: adding ethyl acetate to extract the product, wherein the amount of the added ethyl acetate is 15 times of the amount of the S2 concentrated product, and discharging lower-layer bacterial residues after washing;
s4, concentration and crystallization: transferring the organic phase after extraction into a concentration crystallization kettle, adding saturated salt solution into the organic phase, washing, separating, draining the water phase, concentrating the organic phase at 40-60 ℃, crystallizing after concentration, centrifuging in a centrifuge to obtain a product, and drying the product in a double cone for later use.
Compared with the traditional process for producing the 4-AA intermediate by using the L-threonine and the Japanese chiral catalyst for reduction, the method for producing the 4-AA intermediate by using the ketoreductase has the advantages of convenient raw material acquisition, low raw material cost, small toxic or side effect and simple processing and production process; compared with the foreign enzyme method process, the method has the remarkable advantages of high conversion rate, simple preparation process, low safety and environmental protection risks, low production cost and the like, is more suitable for industrial scale production, and better accords with the current national safety and environmental protection policy; the method for preparing 4-AA breaks through the technical bottleneck of enzyme method production of 4-AA, realizes large-scale industrialization, has the yield of more than 40 percent, solves the problems of low enzyme process yield, complex process and difficult industrialization, reduces the process ratio of three wastes to L-threonine by more than 50 percent, and fills the domestic similar technology introduction blank.
The technical solution of the present invention is not limited to the limitations of the above specific embodiments, and all technical modifications made according to the technical solution of the present invention fall within the protection scope of the present invention.
Claims (5)
1. A method of producing a 4-AA intermediate from a ketoreductase enzyme comprising the steps of:
s1, enzyme catalyzed: adding enzyme catalysis reaction raw materials into an enamel reaction kettle, wherein the reaction raw materials are in the following ratio: 15% -25% of C3, 5% -15% of ketoreductase, 5% -10% of isopropanol, 0.01% -0.05% of coenzyme and deionized water as a solvent, uniformly mixing after constant volume, stirring for reaction, and adding hydrochloric acid to adjust the pH value to 4.0-5.0 after the reaction of C3 is detected by a liquid phase, so as to terminate the reaction, wherein the chemical structure of C3 is as follows:
s2, concentrating: after the reaction is finished, concentrating the reaction solution at the temperature of 40-50 ℃ until the reaction solution is completely dried;
s3, extraction: adding ethyl acetate to extract a product, washing the lower layer of mushroom dregs with water, and discharging;
s4, concentration and crystallization: transferring the organic phase after extraction into a concentration crystallization kettle, adding saturated salt solution into the organic phase, washing, separating, draining the water phase, concentrating the organic phase, crystallizing after concentration, putting into a centrifuge for centrifugation to obtain a product, and putting the product into a double cone for drying for later use.
2. The method for producing the 4-AA intermediate by the ketoreductase enzyme as claimed in claim 1, wherein in the S1 enzyme catalysis reaction stage, the enamel reaction kettle is kept in a constant temperature environment of 35 ℃ to 40 ℃ and stirred for reaction for 20 to 40 hours.
3. The method for producing a 4-AA intermediate by ketoreductase according to claim 2, wherein the pH of the solution is adjusted to 6.70-7.00 after constant volume mixing in the S1 enzyme-catalyzed reaction stage.
4. The ketoreductase process of claim 1 to produce 4-AA intermediates, wherein ethyl acetate is added in an amount 10-20 times the amount of S2 concentrate during the S3 extraction stage.
5. The method of ketoreductase production of 4-AA intermediate as claimed in claim 1, wherein the concentrating the organic phase is performed at 40 ℃ -60 ℃ in S4 concentrating crystallization stage.
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| CN202010210225.5A CN111378704A (en) | 2020-03-23 | 2020-03-23 | Method for producing 4-AA intermediate by ketoreductase |
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| CN202010210225.5A CN111378704A (en) | 2020-03-23 | 2020-03-23 | Method for producing 4-AA intermediate by ketoreductase |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113173947A (en) * | 2021-04-30 | 2021-07-27 | 焦作健康元生物制品有限公司 | Preparation method of 4AA |
| CN114634957A (en) * | 2020-12-15 | 2022-06-17 | 苏州引航生物科技有限公司 | Method for synthesizing 4AA intermediate through biocatalysis |
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| US20090162909A1 (en) * | 2007-10-01 | 2009-06-25 | Codexis, Inc. | Ketoreductase Polypeptides for the Production of Azetidinone |
| WO2014180085A1 (en) * | 2013-05-10 | 2014-11-13 | 苏州汉酶生物技术有限公司 | Biological preparation method for chiral n-protection peridol |
| CN105624125A (en) * | 2014-11-26 | 2016-06-01 | 南京博优康远生物医药科技有限公司 | Aldo-keto reductase and application thereof in synthesis of (2S,3R)-2-benzoylaminomethyl-3-hydroxybutyrate |
| CN107903228A (en) * | 2017-12-01 | 2018-04-13 | 焦作健康元生物制品有限公司 | A kind of high-purity mycophenolic acid production technology |
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2020
- 2020-03-23 CN CN202010210225.5A patent/CN111378704A/en active Pending
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114634957A (en) * | 2020-12-15 | 2022-06-17 | 苏州引航生物科技有限公司 | Method for synthesizing 4AA intermediate through biocatalysis |
| CN113173947A (en) * | 2021-04-30 | 2021-07-27 | 焦作健康元生物制品有限公司 | Preparation method of 4AA |
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Application publication date: 20200707 |
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