CN106337075A - Process for synthesizing cefodizime sodium through enzyme method - Google Patents
Process for synthesizing cefodizime sodium through enzyme method Download PDFInfo
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- CN106337075A CN106337075A CN201610718954.5A CN201610718954A CN106337075A CN 106337075 A CN106337075 A CN 106337075A CN 201610718954 A CN201610718954 A CN 201610718954A CN 106337075 A CN106337075 A CN 106337075A
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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
- C12P35/00—Preparation of compounds having a 5-thia-1-azabicyclo [4.2.0] octane ring system, e.g. cephalosporin
- C12P35/04—Preparation of compounds having a 5-thia-1-azabicyclo [4.2.0] octane ring system, e.g. cephalosporin by acylation of the substituent in the 7 position
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- 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
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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Abstract
The invention relates to the technical field of bulk drug synthesis, particularly to a process for synthesizing cefodizime sodium through an enzyme method. According to the present invention, an immobilized cefodizime synthetase is firstly used and TACA and a 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetic acid derivative are adopted as starting reactants to prepare the cefodizime sodium, such that the reaction process is complete, the reaction time is short, the yield of the reaction is increased, the quality of the cefodizime sodium is good, the purity is high, and the yield is high.
Description
Technical field
The present invention relates to a kind of synthesis technical field of crude drug, a kind of specifically enzymatic clarification Cefodizime Sodium
Technique.
Background technology
Cefodizime Sodium is a third generation cephalosporin with immune enhancing function, internal in animal model and people
Outer research in find Cefodizime Sodium can activating macrophage, improve the huge of it and bite activity.At present, Cefodizime Sodium is unique one
Individual existing wide spectrum strength antibacterial has the cephalosporins of immunoregulatory activity effect again, and clinically Cefodizime Sodium is mainly used in
This kind of patient such as respiratory tract infection, gonorrhoea infection, urinary tract infection, gynecological infection, postoperative infection, meningitiss is easily by various cause of diseases
Microbiological attack, thus cause infection.And cefodizime acid is the key intermediate of synthesis Cefodizime Sodium, by cefodizime acid
It is that a simple step becomes salt to Cefodizime Sodium, this makes Cefodizime Sodium accounting in the production process of whole Cefodizime Sodium
According to critical role.
Enzyme process is compared chemical method and is had obvious advantage in environmental protection and cost.Enzyme process prepares the technique phase of Cefodizime Sodium
Short to flow process, equipment and process is simple, the bringing into and produce less of impurity, no solvent and poisonous reagent in building-up process, former
Material cost reduces.
Content of the invention
For chemosynthesis Cefodizime Sodium complex process, the problems such as use a large amount of organic solvent, the invention provides one
Kind of immobilization Cefodizime synthesis enzymatic synthesiss cefodizime acid, so synthesize Cefodizime Sodium new technology.
Present disclosure is passed through by below scheme:
A kind of technique of enzymatic clarification Cefodizime Sodium, specifically comprises the following steps that
(1) by step immobilization Cefodizime acid enzyme, 7- amino -3- (5- carboxymethyl -4- methyl isophthalic acid, 3- thiazole -2- mercapto first
Base) cephalo -2- alkene -2- carboxylic acid (taca), ainothiazoly loximate derivant add to water stirring mixing, obtains mixed liquor；Control gained
Mixed liquor ph value scope be 6.5 ~ 7.5, control mixeding liquid temperature be 5 ~ 25 DEG C, react 60 ~ 180min, using hplc carry out with
Track detects, until taca residual concentration is≤1mg/ml, terminates reaction；
Described taca with the mol ratio of ainothiazoly loximate derivant for concentration in reaction system for 1/1.05 ~ 1.20, the taca is
300 ~ 600mmol/ml, concentration in reaction system for the immobilization Cefodizime acid enzyme is 10 ~ 40 u/ml；
Preferred reaction time is 100 ~ 120min, and the response time is too short, and conversion ratio is low, and reaction is not exclusively；But the response time is long,
Cefodizime acid starts to hydrolyze.This response time is the optimum response investigating out according to taca optimal conversion during enzyme catalysiss
Time.
(2) take the mixed liquor of step 1) gained, by screen cloth, isolate reactant liquor and immobilized enzyme；
Described screen cloth is 80 ~ 120 mesh, preferably 90 ~ 110 mesh；Sieve number is excessive, and immobilized enzyme is easy for revealing from screen cloth；
Mesh number is too small, and Cefodizime acid crude is just more difficult from screen cloth blowing；
(3) reactant liquor mass fraction be 15% hydrochloric acid solution molten clear to ph be certain value, washing, be dried, obtain final product product cephalo
Ground piperazine acid crude；
(4) cefodizime acid dissolving crude product is obtained solution a in mixed solvent, be dissolved in mixing with the isooctanol sodium of certain mass
Obtain solution b in solvent, solution b is slowly dropped in solution a, slowly stirs and go out crystalline substance to muddiness, then Deca toluene crystallize, growing the grain 1
Hour, sucking filtration, toluene washs, and is vacuum dried to obtain Cefodizime Sodium.
Ainothiazoly loximate derivant described in step (1) is ainothiazoly loximate methyl ester or Ethyl Methylaminothiazolyloximate.
The minimum residual concentration of taca described in step (1) is 0 ~ 0.5mg/ml.
Screen cloth described in step (2) is 80 ~ 120 mesh.
Ph value described in step (3) is 2.0 ~ 5.0.
Mixed solvent described in step (4) is the ethanol acetone mixed solvent of 1:1 for volume ratio, cephalo ground in solution a
Piperazine acid crude is 1:3 ~ 5(g:ml with the mass volume ratio of mixed solvent), the mass body of isooctanol sodium and mixed solvent in solution b
Long-pending ratio is 1:1 ~ 3(g:ml)；Isooctanol sodium described in step (4) and cefodizime acid crude product quality are than for 0.6 ~ 1:1；Step
(4) volume for crystallize toluene described in is 0.2 ~ 0.5 times of mixed solvent cumulative volume in solution a and b.
The Cefodizime acid crude purity more than 98.5% of described product, reacts molar yield more than 90%, final cephalo ground
The purity of piperazine sodium reaches more than 99%.
Cefodizime acid enzyme of the present invention is to carry in amino-epoxy type from immobilized penicillin amidase
On body, acylase immobilization process is prior art；Carrier is 1:3-8(g with the mass volume ratio of acylase fermentation enzyme liquid:
Ml)；In acylase fermentation enzyme liquid, acylase enzyme activity content is 1200-1400u/ml；
Not yet it is related to the relevant report of enzymatic clarification cefodizime acid in existing document, and existing chemical method synthesis Cefodizime
The highest yield of acid is suitable with the enzyme process yield of this paper, but its complex operation, and use multiple organic solvents.
The present invention puts into immobilized enzyme in aqueous phase, only needs mother solution and deionized water cleaning to be reusable after every secondary response.
Taca and ainothiazoly loximate derivant disposably add in proportion, are reacted.After having reacted, by screen cloth blowing.Whole synthesis
Process, process is simple, easy to operate, the response time is short, energy consumption is low, pollution is few.Products obtained therefrom quality is good, high income.Therefore, originally
Invention is a kind of efficient green production process.
With regard to the innovative point of the present invention, can be illustrated by following aspects:
(1) enzyme catalysiss process does not use organic solvent, and environmental protection, pollution-free, process is simple are easy to operate.
(2) the enzyme-catalyzed reaction time is short, and more preferably, yield is higher for reacted cefodizime acid product quality.
(3) and immobilized enzyme can reclaim reuse, reduce cost.In addition immobilized enzyme performance is more stable.
It is easier to separate after reaction.Additionally, being also convenient for transport, storage and automation mechanized operation.
(4) first cefodizime acid is prepared using immobilization Cefodizime acid enzyme in the present invention, and determines
, so that this course of reaction is complete, the response time is shorter for the PA ase optimal proportion carrier immobilized with amino-epoxy type,
Improve reaction yield, cefodizime acid better quality, purity is higher, and yield is higher.
Specific embodiment
The present invention illustrates the present invention by embodiment, but the invention is not limited in any way.
In all embodiments in the present invention, described Cefodizime acid enzyme is from immobilized penicillin amidase
On amino-epoxy type carrier, acylase immobilization process is prior art；Carrier and the quality volume of acylase fermentation enzyme liquid
Than for 1:3-8(g:ml)；In acylase fermentation enzyme liquid, acylase enzyme activity content is 1200-1400u/ml.
Embodiment one
In the reactor, the immobilization Cefodizime synzyme of 3900u is added to the deionized water of 130ml, open stirring.
Add the ainothiazoly loximate methyl ester of taca and 0.046mol of 0.04mol.Add sodium hydroxide, tune reaction ph value to 6.8.Keep anti-
Temperature is answered to be 18 ~ 20 DEG C.Reaction 90min.Reactant liquor is separated with immobilization Cefodizime synzyme.Products therefrom quality is divided
Number adjusts ph to 3.2 for 15% hydrochloric acid, filters, and washing is dried, obtains Cefodizime acid crude, cefodizime acid dissolving crude product is existed
100ml ethanol, in the mixed solvent of 100ml acetone, is dissolved in 25ml ethanol, 25ml acetone mixed solvent with isooctanol sodium 12g
In, it is slowly dropped in above-mentioned mixed solvent, slowly stir and go out crystalline substance to muddiness, Deca toluene 100ml, 10 DEG C of growing the grains 1 hour,
Sucking filtration, 20ml toluene washs, and is vacuum dried to obtain Cefodizime Sodium.
Embodiment two
In the reactor, the immobilization Cefodizime synzyme of 2600u is added to the deionized water of 130ml, open stirring.
Add the ainothiazoly loximate methyl ester of taca and 0.048mol of 0.04mol.Add sodium hydroxide, tune reaction ph value to 7.0.Keep anti-
Temperature is answered to be 13-15 DEG C.Reaction 140min.Reactant liquor is separated with immobilization Cefodizime synzyme.Products therefrom quality
Fraction is that 15% hydrochloric acid adjusts ph to 3.7, filters, washing, is dried, obtains Cefodizime acid crude.Cefodizime acid dissolving crude product is existed
80ml ethanol, in the mixed solvent of 80ml acetone, is dissolved in 30ml ethanol with isooctanol sodium 15g, in 30ml acetone mixed solvent,
It is slowly dropped in above-mentioned mixed solvent, slowly stir and go out crystalline substance to muddiness, Deca toluene 80ml, 10 DEG C of growing the grains 1 hour, take out
Filter, 20ml toluene washs, and is vacuum dried to obtain Cefodizime Sodium.
Embodiment three
In the reactor, the immobilization Cefodizime synzyme of 3000u is added to the deionized water of 130ml, open stirring.
Add the Ethyl Methylaminothiazolyloximate of taca and 0.044mol of 0.04mol.Add sodium hydroxide, tune reaction ph value to 7.1.Keep anti-
Temperature is answered to be 10-12 DEG C.Reaction 115min.Reactant liquor is separated with immobilization Cefodizime synzyme.Products therefrom quality
Fraction is that 15% hydrochloric acid adjusts ph to 2.9, filters, washing, is dried, obtains Cefodizime acid crude.Cefodizime acid dissolving crude product is existed
95ml ethanol, in the mixed solvent of 95ml acetone, is dissolved in 36ml ethanol with isooctanol sodium 18g, in 36ml acetone mixed solvent,
It is slowly dropped in above-mentioned mixed solvent, slowly stir and go out crystalline substance to muddiness, Deca toluene 100ml, 10 DEG C of growing the grains 1 hour, take out
Filter, 20ml toluene washs, and is vacuum dried to obtain Cefodizime Sodium.
Example IV
In the reactor, the immobilization Cefodizime synzyme of 3000u is added to the deionized water of 130ml, open stirring.
Add the Ethyl Methylaminothiazolyloximate of taca and 0.042mol of 0.04mol.Add sodium hydroxide, tune reaction ph value to 7.1.Keep anti-
Temperature is answered to be 18 ~ 20 DEG C.Reaction 120min.Reactant liquor is separated with immobilization Cefodizime synzyme.Products therefrom quality
Fraction is that 15% hydrochloric acid adjusts ph to 3.3, filters, washing, is dried, obtains Cefodizime acid crude.Cefodizime acid dissolving crude product is existed
130ml ethanol, in the mixed solvent of 130ml acetone, is dissolved in 60ml ethanol, 60ml acetone mixed solvent with isooctanol sodium 20g
In, it is slowly dropped in above-mentioned mixed solvent, slowly stir and go out crystalline substance to muddiness, Deca toluene 75ml, 10 DEG C of growing the grains 1 hour,
Sucking filtration, 20ml toluene washs, and is vacuum dried to obtain Cefodizime Sodium.
Embodiment five
In the reactor, the immobilization Cefodizime synzyme of 3000u is added to the deionized water of 130ml, open stirring.
Add the Ethyl Methylaminothiazolyloximate of taca and 0.048mol of 0.04mol.Add sodium hydroxide, tune reaction ph value to 6.9.Keep anti-
Temperature is answered to be 8 ~ 10 DEG C.Reaction 100min.Reactant liquor is separated with immobilization Cefodizime synzyme.Products therefrom quality is divided
Number adjusts ph to 4.0 for 15% hydrochloric acid, filters, and washing is dried, obtains Cefodizime acid crude.Cefodizime acid dissolving crude product is existed
105ml ethanol, in the mixed solvent of 105ml acetone, is dissolved in 33ml ethanol, 33ml acetone mixed solvent with isooctanol sodium 22g
In, it is slowly dropped in above-mentioned mixed solvent, slowly stir and go out crystalline substance to muddiness, Deca toluene 80ml, 10 DEG C of growing the grains 1 hour,
Sucking filtration, 20ml toluene washs, and is vacuum dried to obtain Cefodizime Sodium.
, performance test is carried out to the cefodizime acid of embodiment one ~ five gained, Cefodizime Sodium product
Testing result is as shown in the table:
Gained cefodizime acid crude product quality is high, need not refine the synthesis that can be directly used for Cefodizime Sodium.And be used for producing head
Spore ground piperazine sodium quality is also high.
Knowable to result above: present invention process is simple, and easy to operate, the response time is short, energy consumption is low, pollution is few.Gained
Good product quality, high income.Therefore, the present invention is a kind of efficient green production process.
Claims (5)
1. a kind of enzymatic clarification technique of Cefodizime Sodium is it is characterised in that specifically comprise the following steps that
(1) by immobilization Cefodizime synzyme, 7- amino -3- (5- carboxymethyl -4- methyl-1,3-thiazole -2- thiopurine methyltransferase) head
Spore -2- alkene -2- carboxylic acid (taca), ainothiazoly loximate derivant add to water stirring mixing, obtain mixed liquor；Control the mixing of gained
Liquid ph value scope be 6.5 ~ 7.5, control mixeding liquid temperature be 5 ~ 25 DEG C, react 60 ~ 180min, until taca residual concentration be≤
1mg/ml, terminates reaction；Described taca is 1/1.05 ~ 1.20 with the mol ratio of ainothiazoly loximate derivant, immobilization cephalo ground
Concentration in reaction system for the piperazine synzyme is 10 ~ 40 u/ml；
(2) take the mixed liquor of step 1) gained, by screen cloth, isolate reactant liquor and immobilized enzyme；
(3) reactant liquor Deca mass fraction be 15% hydrochloric acid solution to ph=2.0-5.0, filter, washing, be dried, obtain final product cephalo
Ground piperazine acid crude；
(4) cefodizime acid dissolving crude product is obtained solution a in mixed solvent, be dissolved in mixing with the isooctanol sodium of certain mass
Obtain solution b in solvent, solution b is slowly dropped in solution a, slowly stirs and go out crystalline substance to muddiness, then Deca toluene, growing the grain 1 hour,
Sucking filtration, toluene washs, and is vacuum dried to obtain Cefodizime Sodium.
2. enzymatic clarification Cefodizime Sodium as claimed in claim 1 technique it is characterised in that: institute in described step (1)
The ainothiazoly loximate derivant stated is ainothiazoly loximate methyl ester or Ethyl Methylaminothiazolyloximate.
3. enzymatic clarification Cefodizime Sodium as claimed in claim 1 technique it is characterised in that: institute in described step (1)
The minimum residual concentration of taca stated is 0～0.5mg/ml.
4. enzymatic clarification Cefodizime Sodium as claimed in claim 1 technique it is characterised in that: institute in described step (2)
The screen cloth stated is 80 ~ 120 mesh.
5. enzymatic clarification Cefodizime Sodium as claimed in claim 1 technique it is characterised in that: institute in described step (4)
The mixed solvent stated is the ethanol acetone mixed solvent of 1:1 for volume ratio, Cefodizime acid crude and mixed solvent in solution a
Mass volume ratio is 1:3 ~ 5(g:ml), in solution b, isooctanol sodium and the mass volume ratio of mixed solvent are 1:1 ~ 3(g:ml)；Step
Suddenly the isooctanol sodium described in (4) and cefodizime acid crude product quality are than for 0.6 ~ 1:1；Described in step (4) for crystallize
The volume of toluene is 0.2 ~ 0.5 times of mixed solvent cumulative volume in solution a and b.
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| CN201610718954.5A CN106337075A (en) | 2016-08-25 | 2016-08-25 | Process for synthesizing cefodizime sodium through enzyme method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109336904A (en) * | 2018-11-21 | 2019-02-15 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of Cefditoren pivoxil Cephalosporins |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5521308A (en) * | 1990-08-23 | 1996-05-28 | Hoechst Aktiengesellschaft | Process for the preparation of crystalline TACA |
| CN104928340A (en) * | 2015-06-08 | 2015-09-23 | 山东鲁抗立科药业有限公司 | Process for enzymatic synthesis of cefprozil |
-
2016
- 2016-08-25 CN CN201610718954.5A patent/CN106337075A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5521308A (en) * | 1990-08-23 | 1996-05-28 | Hoechst Aktiengesellschaft | Process for the preparation of crystalline TACA |
| CN104928340A (en) * | 2015-06-08 | 2015-09-23 | 山东鲁抗立科药业有限公司 | Process for enzymatic synthesis of cefprozil |
Non-Patent Citations (1)
| Title |
|---|
| 李爱军: "头孢地嗪钠合成工艺改进", 《中国抗生素杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109336904A (en) * | 2018-11-21 | 2019-02-15 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of Cefditoren pivoxil Cephalosporins |
| CN109336904B (en) * | 2018-11-21 | 2020-06-09 | 山东罗欣药业集团股份有限公司 | Preparation method of cefditoren pivoxil |
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