CN105622634A - Method for producing ceftizoxime acid - Google Patents
Method for producing ceftizoxime acid Download PDFInfo
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- CN105622634A CN105622634A CN201610122942.6A CN201610122942A CN105622634A CN 105622634 A CN105622634 A CN 105622634A CN 201610122942 A CN201610122942 A CN 201610122942A CN 105622634 A CN105622634 A CN 105622634A
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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
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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
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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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 provides a method for producing ceftizoxime acid. According to the method, dichloromethane, 7-ANCA and AE active ester serve as raw materials, reaction conditions are optimized, particularly the reaction temperature and crystal growing process steps are controlled, and the industrialized production method of the ceftizoxime acid is simple in preparation process, high in safety, high in purity and high in yield. The obtained finished product of the ceftizoxime acid reaches 99.3% and above, the yield reaches 93% and above, and compared with the prior art, the yield is obviously raised.
Description
Technical field
The present invention relates to technical field of medicine synthesis, particularly relate to the production method of a kind of ceftizoxime acid.
Background technology
Ceftizoxime sodium is by the Third generation Cephalosporins microbiotic of Fujisawa Pharmaceutical Co., Ltd of Japan exploitation, and in nineteen eighty-two first in Japan's listing, commodity are called Ceftizox. This product is as third generation cephalosporin microbiotic, and its mechanism of action is reach germicidal action by the biosynthesizing of anti-bacteria cell wall mucopeptide, has wide spectrum, enzyme efficient, resistance to, low poison and the feature by hemato encephalic barrier. The wide spectrum ��-lactamase (comprising penicillinase and cephalosporinase) that multiple gram positive organism and gram-negative bacteria produce is stablized. The enterobacteriaceae lactobacteriaceaes such as escherichia coli, Klebsiella Pneumoniae, Proteus mirabilis are had powerful anti-microbial effect, and the Rhodopseudomonass such as Pseudomonas aeruginosa and acinetobacter are poor to this product susceptibility. Hemophilus influenzae and neisseria gonorrhoeae are had good anti-microbial effect by ceftizoxime. To the effect of streptococcus aureus and staphylococcus epidermidis, relatively first, second cynnematin for poor in generation, and methicillin-resistant staphylococcus aureus and enterococcus spp are to this product resistance, and various suis is all extremely sensitive to this product. The anerobes such as dyspepsiacoccus, peptostreptococcus and part Bacteroides are many in responsive to this product, and clostridium difficile is to this product resistance. Meningitis and Simple gonorrhea caused by the lower respiratory infection caused by sensitive organism, urinary tract infections, abdominal cavity infection, pelvic infection, septicemia, skin soft-tissue infection, bone and the infection of joint, streptococcus pneumoniae or hemophilus influenzae it is used for the treatment of on clinical.
About the synthetic method of ceftizoxime sodium, meticulous having delivered with specialty chemicals magazine is entitled as " study on the synthesis of ceftizoxime sodium " one literary composition, and document report is salt forming agent taking sodium bicarbonate. But reaction times and quality product are had a significant impact by the consumption of anhydrous sodium carbonate, anhydrous sodium carbonate consumption increases, and the reaction times obviously shortens, but the ceftizoxime sodium content in product obviously declines, and the corresponding increase of foreign matter content, product colour is also obviously deteriorated; And products obtained therefrom easily comprises undissolved sodium bicarbonate, affects quality product. The article being entitled as " ceftizoxime sodium synthesising process research " delivered by Mountain Western Medicine S University's journal, literary composition is mentioned acid-soluble for ceftizoxime in water, drip and add triethylamine stirring and dissolving, after activated carbon decolorizing, drip the ethanolic soln adding Sodium isooctanoate, after regulating pH, dripping and add ethanol, analysis is brilliant, obtains ceftizoxime acid, there is ethanol in products obtained therefrom, it is not easy to dry.
US Patent No. 4427674 discloses two lines, one be taking 7-phenylacetyl amido-3-cynnematin-4 carboxylic acid to methoxybenzyl ester as raw material, through repeatedly sloughing blocking group, then ceftizoxime sodium obtained with salt forming agent. This route repeatedly sloughs protecting group, causes reactions steps long, adds schedule of operation and production cost. Another is so that 7-amino-nothing-3-head spore-4-formic acid is as raw material and cefotaxime acetic acid direct polycondensation, and then becomes salt, and this route side reaction is more, and products therefrom through column chromatography purification, need to be not suitable for suitability for industrialized production.
CN101348492A discloses a kind of method preparing high-purity ceftizoxime or its salt, and it comprises the steps: that the aqueous solution of ceftizoxime or its salt crude product is changed into ceftizoxime acid by (1) in acid condition; (2) ceftizoxime acid crude is obtained by organic solvent extraction (1); (3) using aluminum oxide as the filler of chromatography column, taking the mixed solution of hydrocarbon solvent and chlorinated solvents as eluent, step (2) gained ceftizoxime acid crude is carried out chromatographic separation, collect the flow point that ceftizoxime acid content is not less than 80%; (4) solvent in the ceftizoxime acid flow point of removing step (3) gained, then adds lower alkyl alcohol dissolution with solvents, adds alkali to precipitating out precipitation; (5) by the precipitation lower alkyl alcohol solvent recrystallization of step (4) gained, obtaining high-purity ceftizoxime or its salt, the method is comparatively complicated, and product rate is not high, and poor reproducibility, is not suitable for suitability for industrialized production.
Chinese patent CN201210041485.X discloses the preparation method of a kind of ceftizoxime sodium, comprising (1) 7-ANCA is raw material, with 2-(2-amino-4-thiazolyl)-2-methoxy imino-acetyl-benzothiazole thioesters (2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester) sour intermediate of obtained ceftizoxime with condensation under alkali existent condition in a solvent; (2) ceftizoxime acid intermediate ceftizoxime sodium obtained with the reaction of salt forming agent sodium hydroxide again. Disclosing a kind of preparation technology's relative ease in this patent, the preparation method of reaction conditions gentleness, can realize suitability for industrialized production to a certain extent, but, its receipts rate is only 80%-88%, and production cost is higher, raw material and finished product are wasted bigger, it is necessary to improve its reasonable receipts rate further.
Chinese patent CN200910304558.8 discloses the synthetic method of a kind of bulk drug ceftizoxime sodium, it prepares the method for ceftizoxime sodium fine work: in sterilisable chamber, the ceftizoxime sodium crude product of gained is dissolved in water, add gac again, stir, take out filter, filtrate filters, in filtrate, dehydrated alcohol is slowly added when stirring, finish, precipitate out precipitation, refrigeration analysis is brilliant, filter, use dehydrated alcohol drip washing, drain, filter cake drying under reduced pressure, obtain ceftizoxime sodium fine work, in the method, activated carbon consumption too much causes product rate on the low side, it is about 83%, in commercial process, receipts rate has greater room for improvement.
Chinese patent 201010570298.1 discloses a kind of method preparing ceftizoxime sodium, by slowly add crystallization solvent to crystal solution occur micro-muddy time, stop adding solvent, slow stirring supports brilliant 0.5 hour, then continue to add remaining solvent, stir again after adding and support brilliant 1 hour, obtain a kind of receipts rate 93% ~ 95%, the good ceftizoxime sodium product of crystallization degree, but this patented method is not announced the purity of the product obtained.
Summary of the invention
For the problems referred to above, the present invention provides the production method of a kind of ceftizoxime acid, obtains the ceftizoxime acid that a kind of purity is 99.3%, receipts rate is greater than 93%.
In order to realize the technical purpose of the present invention, the present invention adopts following technique means.
The production method of a kind of ceftizoxime acid, it is characterised in that comprise the steps:
(1) react: in the anhydrous reactor of cleaning, add methylene dichloride or ethylene dichloride, solvent one, mix rear cooling down to-10 DEG C, add 7-ANCA and MEAM successively, stir even backward feed liquid is slowly dripped and add alkali lye, after reacting 2 hours at-5 DEG C after dropwising, slowly temperature being risen to 0 ~ 5 DEG C and continue reaction 10 hours, when being less than 0.5% to 7-ANCA residual quantity, reaction terminates;
(2) separatory is extracted: after reaction terminates, the pure water adding 7-ANCA quality 8 ~ 15 times at 10 DEG C-15 DEG C is in step (1) reactor, vigorous stirring carries out first time extraction separatory after 30 minutes after, continue to add the pure water washing of 7-ANCA quality 4 ~ 8 times, carry out second time and extract separatory, obtain organic phase;
(3) wash: the aqueous phase after first time, second time extraction separatory is merged, and washs separatory after aqueous phase with methylene dichloride backwash, obtain organic phase;
(4) decolour: the organic phase mixing that will obtain in step (2) and step (3), regulates material liquid pH value to be 6.8 with diluted acid, then add EDTA-2Na and activated carbon decolorizing that mass ratio is 1:5 in feed liquid, be filtered to remove gac;
(5) crystalline substance is supported: the feed liquid obtained after filtering in step (4) adds solvent two, feed liquid is warming up to 20 DEG C ~ 30 DEG C, drip add dilute hydrochloric acid solution regulate material liquid pH be 4-5, stop dripping and add dilute hydrochloric acid, insulation continues slowly to drip after supporting brilliant 2 ~ 3h to add dilute hydrochloric acid solution to PH to 2.0-2.5, is cooled to 0 ~ 5 DEG C and supports brilliant 3h;
(6) washing is dry: feed liquid is filtered after terminating by foster crystalline substance, washing, vacuum-drying, obtains ceftizoxime acid finished product.
Preferably, in described step (1), solvent one is the one in methyl alcohol, ethanol, propyl alcohol or n-butyl alcohol.
Preferably, in described step (1), the mass ratio of methylene dichloride or ethylene dichloride, solvent one, 7-ANCA, MEAM and alkali lye is 10 ~ 15:1 ~ 1.5:1:2:0.1.
Preferred, in described step (1), the mass ratio of methylene dichloride or ethylene dichloride, solvent one, 7-ANCA, MEAM and alkali lye is 15:1.5:1:2:0.1.
Preferably, in described step (1), alkali lye is the one in triethylamine, diethylamine, dipropyl amine or Diisopropylamine.
Preferably, in described step (4) diluted acid to be massfraction be 6% ~ 10% rare sulfurous acid, phenol, one in sodium bisulfite or sodium bisulfate.
Preferably, in described step (4), the mass ratio of gac and 7-ANCA is 0.05 ~ 0.2:1.
Preferably, in described step (5), solvent two is the one in Virahol, methyl alcohol, ethanol, propyl alcohol, propyl carbinol or isopropylcarbinol.
Preferably, in described step (5), the mass ratio of solvent two and 7-ANCA is 3 ~ 10:1.
Preferably, in described step (5), dilute hydrochloric acid is volume ratio is the concentrated hydrochloric acid of 1:3 ~ 6 and the mixing solutions of pure water.
Preferably, in described step (6), vacuum-drying temperature is 30 DEG C ~ 50 DEG C, and the time is 2-6 hour.
The invention has the beneficial effects as follows: the production method of a kind of ceftizoxime acid provided by the invention, taking methylene dichloride, 7-ANCA and MEAM as raw material, by the optimization to reaction conditions, the particularly control of temperature of reaction and the control of foster brilliant processing step, obtain that a kind of preparation technology is simple, security height, purity height, the industrialized preparing process of the ceftizoxime acid that receipts rate is high, gained ceftizoxime acid finished product purity reaches more than 99.3%, molar yield reaches more than 93%, compared to prior art, in receipts rate, tool is significantly improved.
Embodiment
For a better understanding of the present invention, below in conjunction with embodiment, invention is described in detail.
Embodiment 1
A production method for ceftizoxime acid, adopts following steps:
(1) react: in the anhydrous 3000L reactor of cleaning, add methylene dichloride 1500kg, methyl alcohol 150kg, mix rear cooling down to-10 DEG C, add 7-ANCA100kg and MEAM 200kg successively, stir even backward feed liquid is slowly dripped and add triethylamine 10kg, after reacting 2 hours at-5 DEG C after dropwising, slowly temperature being risen to 0 ~ 5 DEG C and continue reaction 10 hours, when being less than 0.5% to 7-ANCA residual quantity, reaction terminates;
(2) separatory is extracted: after reaction terminates, the pure water adding 1300kg at 10 DEG C-15 DEG C is to, in step (1) reactor, vigorous stirring carries out first time extraction separatory after 30 minutes after, continuing to add the washing of reactor volume 600kg pure water, carry out second time and extract separatory, obtain organic phase;
(3) wash: the aqueous phase after first time, second time extraction separatory is merged, and washs separatory after aqueous phase with 400kg methylene dichloride backwash, obtain organic phase;
(4) decolouring: the organic phase mixing that will obtain in step (2) and step (3), the rare sulfurous acid being 6% with massfraction regulates material liquid pH value to be 6.8, then adds EDTA-2Na and the 10kg activated carbon decolorizing of 2kg in feed liquid, is filtered to remove gac;
(5) crystalline substance is supported: the feed liquid obtained after filtering in step (4) adds 400kg Virahol, feed liquid is warming up to 20 DEG C ~ 30 DEG C, dripping that to add concentrated hydrochloric acid and pure water volume ratio be the dilute hydrochloric acid solution adjustment material liquid pH of 1:4.5 is 5.0, stop dripping and add dilute hydrochloric acid, insulation continues slowly to drip after supporting brilliant 2 ~ 3h to add dilute hydrochloric acid solution to PH to 2.0-2.5, is cooled to 0 ~ 5 DEG C and supports brilliant 3h;
(6) washing is dry: feed liquid is filtered after terminating by foster crystalline substance, washing, vacuum-drying 3 hours at 40 DEG C, obtains ceftizoxime acid finished product, after testing product purity be greater than 99.3%, molar yield be 93%.
Embodiment 2
A production method for ceftizoxime acid, adopts following steps:
(1) react: in the anhydrous 3000L reactor of cleaning, add ethylene dichloride 1500kg, ethanol 150kg, mix rear cooling down to-10 DEG C, add 7-ANCA100kg and MEAM 200kg successively, stir in even backward feed liquid and slowly drip with Diisopropylamine 10kg, after reacting 2 hours at-5 DEG C after dropwising, slowly temperature being risen to 0 ~ 5 DEG C and continue reaction 10 hours, when being less than 0.5% to 7-ANCA residual quantity, reaction terminates;
(2) separatory is extracted: after reaction terminates, the pure water adding 1000kg at 10 DEG C-15 DEG C is to, in step (1) reactor, vigorous stirring carries out first time extraction separatory after 30 minutes after, continuing to add the washing of reactor volume 600kg pure water, carry out second time and extract separatory, obtain organic phase;
(3) wash: the aqueous phase after first time, second time extraction separatory is merged, and washs separatory after aqueous phase with 400kg ethylene dichloride backwash, obtain organic phase;
(4) decolouring: the organic phase mixing that will obtain in step (2) and step (3), the phenol solution being 6% with massfraction regulates material liquid pH value to be 6.8, then adds EDTA-2Na and the 10kg activated carbon decolorizing of 2kg in feed liquid, is filtered to remove gac;
(5) crystalline substance is supported: the feed liquid obtained after filtering in step (4) adds 600kg ethanol, feed liquid is warming up to 20 DEG C ~ 30 DEG C, dripping that to add concentrated hydrochloric acid and pure water volume ratio be the dilute hydrochloric acid solution adjustment material liquid pH of 1:5 is 4.0, stop dripping and add dilute hydrochloric acid, insulation continues slowly to drip after supporting brilliant 2 ~ 3h to add dilute hydrochloric acid solution to PH to 2.0-2.5, is cooled to 0 ~ 5 DEG C and supports brilliant 3h;
(6) washing is dry: feed liquid is filtered after terminating by foster crystalline substance, washing, vacuum-drying 3 hours at 40 DEG C, obtains ceftizoxime acid finished product, and product purity 99.6%, molar yield are 93.5% after testing.
Embodiment 3
A production method for ceftizoxime acid, adopts following steps:
(1) react: in the anhydrous 3000L reactor of cleaning, add methylene dichloride 1500kg, propyl alcohol 150kg, mix rear cooling down to-10 DEG C, add 7-ANCA100kg and MEAM 200kg successively, stir in even backward feed liquid and slowly drip with dipropyl amine 10kg, after reacting 2 hours at-5 DEG C after dropwising, slowly temperature being risen to 0 ~ 5 DEG C and continue reaction 10 hours, when being less than 0.5% to 7-ANCA residual quantity, reaction terminates;
(2) separatory is extracted: after reaction terminates, the pure water adding 1200kg at 10 DEG C-15 DEG C is to, in step (1) reactor, vigorous stirring carries out first time extraction separatory after 30 minutes after, continuing to add the washing of reactor volume 600kg pure water, carry out second time and extract separatory, obtain organic phase;
(3) wash: the aqueous phase after first time, second time extraction separatory is merged, and washs separatory after aqueous phase with 400kg methylene dichloride backwash, obtain organic phase;
(4) decolour: the organic phase mixing that will obtain in step (2) and step (3), the sodium bisulfate being 6% with massfraction regulates material liquid pH value to be 6.8, then in feed liquid, add EDTA-2Na and the 10kg activated carbon decolorizing of 2kg, it is filtered to remove gac;
(5) crystalline substance is supported: the feed liquid obtained after filtering in step (4) adds 400kg propyl carbinol, feed liquid is warming up to 20 DEG C ~ 30 DEG C, dripping that to add concentrated hydrochloric acid and pure water volume ratio be the dilute hydrochloric acid solution adjustment material liquid pH of 1:4 is 4.4, stop dripping and add dilute hydrochloric acid, insulation continues slowly to drip after supporting brilliant 2 ~ 3h to add dilute hydrochloric acid solution to PH to 2.0-2.5, is cooled to 0 ~ 5 DEG C and supports brilliant 3h;
(6) washing is dry: feed liquid is filtered after terminating by foster crystalline substance, washing, vacuum-drying 3 hours at 40 DEG C, obtains ceftizoxime acid finished product, and product purity 99.5%, molar yield are 93.3% after testing.
Embodiment 4
A production method for ceftizoxime acid, adopts following steps:
(1) react: in the anhydrous 3000L reactor of cleaning, add methylene dichloride 1000kg, n-butyl alcohol 150kg, mix rear cooling down to-10 DEG C, add 7-ANCA100kg and MEAM 200kg successively, stir even backward feed liquid is slowly dripped and add diethylamine 10kg, after reacting 2 hours at-5 DEG C after dropwising, slowly temperature being risen to 0 ~ 5 DEG C and continue reaction 10 hours, when being less than 0.5% to 7-ANCA residual quantity, reaction terminates;
(2) separatory is extracted: after reaction terminates, the pure water adding 800kg at 10 DEG C-15 DEG C is to, in step (1) reactor, vigorous stirring carries out first time extraction separatory after 30 minutes after, continuing to add the washing of reactor volume 800kg pure water, carry out second time and extract separatory, obtain organic phase;
(3) wash: the aqueous phase after first time, second time extraction separatory is merged, and washs separatory after aqueous phase with 400kg methylene dichloride backwash, obtain organic phase;
(4) decolour: the organic phase mixing that will obtain in step (2) and step (3), the sodium sulfite solution being 10% with massfraction regulates material liquid pH value to be 6.8, then in feed liquid, add EDTA-2Na and the 20kg activated carbon decolorizing of 4kg, it is filtered to remove gac;
(5) crystalline substance is supported: the feed liquid obtained after filtering in step (4) adds 1000kg methyl alcohol, feed liquid is warming up to 20 DEG C ~ 30 DEG C, dripping that to add concentrated hydrochloric acid and pure water volume ratio be the dilute hydrochloric acid solution adjustment material liquid pH of 1:6 is 4.8, stop dripping and add dilute hydrochloric acid, insulation continues slowly to drip after supporting brilliant 2 ~ 3h to add dilute hydrochloric acid solution to PH to 2.0-2.5, is cooled to 0 ~ 5 DEG C and supports brilliant 3h;
(6) washing is dry: feed liquid is filtered after terminating by foster crystalline substance, washing, vacuum-drying 2 hours at 50 DEG C, obtains ceftizoxime acid finished product, and product purity 99.8%, molar yield are 93.6% after testing.
Embodiment 5
A production method for ceftizoxime acid, adopts following steps:
(1) react: in the anhydrous 3000L reactor of cleaning, add ethylene dichloride 1200kg, methyl alcohol 100kg, mix rear cooling down to-10 DEG C, add 7-ANCA100kg and MEAM 200kg successively, stir even backward feed liquid is slowly dripped and add triethylamine 10kg, after reacting 2 hours at-5 DEG C after dropwising, slowly temperature being risen to 0 ~ 5 DEG C and continue reaction 10 hours, when being less than 0.5% to 7-ANCA residual quantity, reaction terminates;
(2) separatory is extracted: after reaction terminates, the pure water adding 1500kg at 10 DEG C-15 DEG C is to, in step (1) reactor, vigorous stirring carries out first time extraction separatory after 30 minutes after, continuing to add the washing of reactor volume 400kg pure water, carry out second time and extract separatory, obtain organic phase;
(3) wash: the aqueous phase after first time, second time extraction separatory is merged, and washs separatory after aqueous phase with 400kg methylene dichloride backwash, obtain organic phase;
(4) decolouring: the organic phase mixing that will obtain in step (2) and step (3), the rare sulfurous acid solution being 8% with massfraction regulates material liquid pH value to be 6.8, then adds EDTA-2Na and the 5kg activated carbon decolorizing of 1kg in feed liquid, is filtered to remove gac;
(5) crystalline substance is supported: the feed liquid obtained after filtering in step (4) adds 300kg isopropylcarbinol, feed liquid is warming up to 20 DEG C ~ 30 DEG C, dripping that to add concentrated hydrochloric acid and pure water volume ratio be the dilute hydrochloric acid solution adjustment material liquid pH of 1:3 is 4.6, stop dripping and add dilute hydrochloric acid, insulation continues slowly to drip after supporting brilliant 2 ~ 3h to add dilute hydrochloric acid solution to PH to 2.0-2.5, is cooled to 0 ~ 5 DEG C and supports brilliant 3h;
(6) washing is dry: feed liquid is filtered after terminating by foster crystalline substance, washing, vacuum-drying 6 hours at 30 DEG C, obtains ceftizoxime acid finished product, and product purity 99.7%, molar yield are 93.1% after testing.
More than show and describe the ultimate principle of the present invention, main feature and advantage. The technician of the industry is not it should be understood that above-described embodiment limits the present invention in any form, and all employings are equal to the technical scheme that the mode of replacement or equivalent transformation obtains, and all drop in protection scope of the present invention.
Claims (10)
1. the production method of a ceftizoxime acid, it is characterised in that comprise the steps:
(1) react: in the anhydrous reactor of cleaning, add methylene dichloride or ethylene dichloride, solvent one, mix rear cooling down to-10 DEG C, add 7-ANCA and MEAM successively, stir even backward feed liquid is slowly dripped and add alkali lye, after reacting 2 hours at-5 DEG C after dropwising, slowly temperature being risen to 0 ~ 5 DEG C and continue reaction 10 hours, when being less than 0.5% to 7-ANCA residual quantity, reaction terminates;
(2) separatory is extracted: after reaction terminates, the pure water adding 7-ANCA quality 8 ~ 15 times at 10 DEG C-15 DEG C is in step (1) reactor, vigorous stirring carries out first time extraction separatory after 30 minutes after, continue to add the pure water washing of 7-ANCA quality 4 ~ 8 times, carry out second time and extract separatory, obtain organic phase;
(3) wash: the aqueous phase after first time, second time extraction separatory is merged, and washs separatory after aqueous phase with methylene dichloride backwash, obtain organic phase;
(4) decolour: the organic phase mixing that will obtain in step (2) and step (3), regulates material liquid pH value to be 6.8 with diluted acid, then add EDTA-2Na and activated carbon decolorizing that mass ratio is 1:5 in feed liquid, be filtered to remove gac;
(5) crystalline substance is supported: the feed liquid obtained after filtering in step (4) adds solvent two, feed liquid is warming up to 20 DEG C ~ 30 DEG C, drip add dilute hydrochloric acid solution regulate material liquid pH be 4-5, stop dripping and add dilute hydrochloric acid, insulation continues slowly to drip after supporting brilliant 2 ~ 3h to add dilute hydrochloric acid solution to PH to 2.0-2.5, is cooled to 0 ~ 5 DEG C and supports brilliant 3h;
(6) washing is dry: feed liquid is filtered after terminating by foster crystalline substance, washing, vacuum-drying, obtains ceftizoxime acid finished product.
2. the production method of a kind of ceftizoxime acid according to claim 1, it is characterised in that: in described step (1), solvent one is the one in methyl alcohol, ethanol, propyl alcohol or n-butyl alcohol.
3. the production method of a kind of ceftizoxime acid according to claim 1, it is characterised in that: in described step (1), the mass ratio of methylene dichloride or ethylene dichloride, solvent one, 7-ANCA, MEAM and alkali lye is 10 ~ 15:1 ~ 1.5:1:2:0.1.
4. the production method of a kind of ceftizoxime acid according to claim 1, it is characterised in that: in described step (1), alkali lye is the one in triethylamine, diethylamine, dipropyl amine or Diisopropylamine.
5. the production method of a kind of ceftizoxime acid according to claim 1, it is characterised in that: in described step (4) diluted acid to be massfraction be 6 ~ 10% rare sulfurous acid, phenol, one in sodium bisulfite or sodium bisulfate.
6. the production method of a kind of ceftizoxime acid according to claim 1, it is characterised in that: in described step (4), the mass ratio of gac and 7-ANCA is 0.05 ~ 0.2:1.
7. the production method of a kind of ceftizoxime acid according to claim 1, it is characterised in that: in described step (5), solvent two is the one in Virahol, methyl alcohol, ethanol, propyl alcohol, propyl carbinol or isopropylcarbinol.
8. the production method of a kind of ceftizoxime acid according to claim 1, it is characterised in that: in described step (5), solvent two is 3 ~ 10:1 with the mass ratio of 7-ANCA.
9. the production method of a kind of ceftizoxime acid according to claim 1, it is characterised in that: in described step (5), dilute hydrochloric acid is volume ratio is the concentrated hydrochloric acid of 1:3 ~ 6 and the mixing solutions of pure water.
10. the production method of a kind of ceftizoxime acid according to claim 1, it is characterised in that: in described step (6), vacuum-drying temperature is 30 DEG C ~ 50 DEG C, and the time is 2-6 hour.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109503629A (en) * | 2018-12-29 | 2019-03-22 | 山东罗欣药业集团股份有限公司 | A kind of synthetic method of Ceftizoxime acid |
| CN109553626A (en) * | 2018-12-29 | 2019-04-02 | 山东罗欣药业集团股份有限公司 | A kind of refining methd of ceftizoxime sodium |
| CN112321607A (en) * | 2020-12-04 | 2021-02-05 | 苏州盛达药业有限公司 | Method for synthesizing ceftizoxime acid by one-pot method |
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| CN109503629A (en) * | 2018-12-29 | 2019-03-22 | 山东罗欣药业集团股份有限公司 | A kind of synthetic method of Ceftizoxime acid |
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| CN109503629B (en) * | 2018-12-29 | 2021-02-26 | 山东罗欣药业集团股份有限公司 | Synthesis method of ceftizoxime acid |
| CN112321607A (en) * | 2020-12-04 | 2021-02-05 | 苏州盛达药业有限公司 | Method for synthesizing ceftizoxime acid by one-pot method |
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