CN101016305B - Method of synthesizing cefixime - Google Patents
Method of synthesizing cefixime Download PDFInfo
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- CN101016305B CN101016305B CN200710073334A CN200710073334A CN101016305B CN 101016305 B CN101016305 B CN 101016305B CN 200710073334 A CN200710073334 A CN 200710073334A CN 200710073334 A CN200710073334 A CN 200710073334A CN 101016305 B CN101016305 B CN 101016305B
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Abstract
The invention discloses a synthesizing method of cefuroxime, which is characterized by the following: crystallizing cefuroxime intermediate MECEF; synthesizing cefuroxime through water-phased extractof MECEF without dissolving MECEF; saving cost to improve receiving rate effectively; shortening manufacturing period.
Description
Technical field
The invention belongs to the Cefixime Micronized technical field of chemical pharmacy industry, relate in particular to a kind of synthetic method of Cefixime Micronized.
Background technology
Cefixime Micronized is a third generation oral cephalosporin antibiotics, it has broad-spectrum antibacterial action to gram-positive microorganism and negative bacterium, particularly the intestinal bacteria in the influenza Pseudomonas in the gram-positive microorganism (as streptococcus pneumoniae, epidermis suis), streptococcus pneumoniae and the Gram-negative bacteria, Morakot Bordetella, gonococcus, proteus mirabilis, catarrh Pseudomonas etc. is demonstrated the germicidal action stronger than other oral cephalosporin.It has characteristics such as wide spectrum, efficient, anti-enzyme, low toxicity, is widely used clinically anti-infective oral pharmaceutical.
The technology status of existing synthetic Cefixime Micronized is as follows:
(1) one the band temperature of displaced air take into account in the retort of logical nitrogen device, add MICA (cefixime side chain), altax (dibenzothiazyl disulfide), triphenylphosphine, tetrahydrofuran (THF), logical nitrogen reaction back stream adds triethylamine, finish afterreaction, reaction is finished, and cooling adds AVNA (gram oxime parent nucleus), be 7-amino-3-vinyl cethalosporanic acid, purified water, holding temperature 15～20 degree reactions;
(2) the adding ethyl acetate is finished in reaction, with the pure water extraction that is lower than 5 ℃; Leave standstill 30 minutes separatory, organic phase is carried out mark, reclaims barrelling, and water adds ethyl acetate extraction, leaves standstill 30 minutes separatory, and organic phase is carried out mark, reclaims barrelling, and water adds ethyl acetate extraction, leaves standstill 30 minutes separatory, and organic phase reclaims; Water adds ethyl acetate extraction, leaves standstill 30 minutes separatory, and organic phase is carried out mark, reclaims barrelling; Water adds ethyl acetate extraction, leaves standstill 30 minutes separatory, and organic phase reclaims, and water adds EDTA (disodium ethylene diamine tetraacetate), vat powder (V-Brite B), gac, and decolouring is stirred in cooling;
(3) press filtration, filter cake washes with water, membrane filtration, merging filtrate and washing lotion, the H of dropping 10%
2SO
4Crystallization, to PH be 3.2; 5 ℃ stirring back blowing is centrifugal down, uses cold water washing, the dry MECEF (Cefixime Micronized methyl esters) that gets, and weight yield is 170～180%, moisture requirement is lower than 5%;
(4) in clean retort, add acetone, pure water is cooled to-5 ℃, adds MECEF, and stream adds 5% NaHCO
3Dissolving, controlled temperature is no more than 0 ℃, finishes, and is stirred well to dissolving fully; Open the chuck cooling water temperature to-7 ℃, stream adds 10%NaOH fast, finishes and keeps-3 ℃ of hydrolysis, detects to MECEF with HPLC (high performance liquid phase) to be lower than 0.3% o'clock stopped reaction; Stream adds 20% hydrochloric acid fast, and adjusting PH is 5.0, adds gac, stirs decolouring, and the filtering gac is pressed in another retort by filter membrane, after the frozen water washed twice, merges mother liquor and wash water; Open chuck hot water and heat up, 28 ℃ of crystallizations of controlled temperature, adjusting PH with 20% hydrochloric acid is 2.5, is cooled to below 5 ℃ under stirring at a slow speed, keeps stirring, blowing is centrifugal then, washing, vacuum-drying gets Cefixime Micronized, its weight yield 88～92%.
From the above: this technology has been used this solvent of acetone, reclaim this part to solvent and brought certain degree of difficulty, and MECEF crystallization, the mother liquor after centrifugal can take away partial material, influences yield; Secondly, this technology is long time of drying, and about 24 hours, and drying can cause degraded, influences quality; Moreover this its product yield of method synthetic Cefixime Micronized is on the low side, and the yield of MECEF has only 175% (weight yield), and the yield of gram oxime hydrolysis has only 88～92% (weight yields), and total recovery is 158% (weight yield).
Summary of the invention
The objective of the invention is to overcome the deficiency that above-mentioned prior art exists, a kind of synthetic method of Cefixime Micronized is provided, and it has adopted than inexpensive inorganic salt and has replaced acetone, and two-step reaction and be single step reaction, realize " technology for the treatment of different things alike ", solved the low and ropy problem of yield.
For addressing the above problem, the technical solution used in the present invention step is as follows:
(1) add 300～500L methyl chloride in a clean retort, 40～50kg MICA-active ester is dissolved into the clarification back and adds 25～30kg AVNA, pure water 100～150L, and 26～35L triethylamine, 10～15 ℃ of holding temperatures were reacted 3～6 hours;
(2) adding 560～680L ethyl acetate was finished in reaction, with pure water 300～400L extractions of 3～5 ℃ 10～20 minutes;
(3) leave standstill 30～60 minutes separatory, organic phase is carried out mark, reclaims barrelling; Water adds ethyl acetate 400～450L extraction 20～30 minutes after transferring PH to 6.0～9.0 with 36% acetate;
(4) leave standstill 30～60 minutes separatory, organic phase is carried out mark, reclaims barrelling; Water adds ethyl acetate 400～450L extraction 20～30 minutes, leaves standstill 30～60 minutes separatory, and organic phase reclaims;
(5) water adds EDTA (disodium ethylene diamine tetraacetate) 0.5～1kg, vat powder (V-Brite B) 0.5～1kg, and gac 10～12kg, decolouring 30～60 minutes is stirred in cooling;
(7) press filtration, filter cake water 300～340L washing, membrane filtration, merging filtrate and washing lotion;
(7) add the dissolving of 80～100kg an alkali metal salt, open the chuck cooling water temperature to-3～-5 ℃;
(8) stream adds 20%NaOH 72～80L fast, finishes and keeps-5～-10 ℃ of hydrolysis 10～15 minutes, detects to showing that MECEF is lower than 0.3% o'clock stopped reaction with HPLC (high performance liquid phase);
(9) stream adds 20% hydrochloric acid, 50～60L fast, and adjusting PH is 5.0～5.5, adds 6～8kg gac, stirs decolouring 30～60 minutes;
(10) filtering gac is pressed in another retort by millipore filtration, uses the frozen water washed twice, each 100～120L, and merging filtrate and washing lotion are opened chuck hot water and are heated up, 28～30 ℃ of crystallizations of controlled temperature, adjusting PH with 20% hydrochloric acid is 2.5～2.6;
(11) be cooled to 0～5 ℃ under the stirring at a slow speed, keep and stirred 1～2 hour, blowing is centrifugal, washing, and vacuum-drying gets Cefixime Micronized 52～63kg.
Methyl chloride is methylene dichloride or trichloromethane in the described step (1).
An alkali metal salt is NaCl, KCl, Na in the described step (7)
2SO
4Deng.
The aperture of millipore filtration is 0.25～0.45 micron in the described step (10).
Washing in the described step (11) is the pure water washed twice with 1～5 ℃ of 300～400L.
By the Cefixime Micronized of method for preparing, its total recovery is 200～210%.
Present method reaction process is as follows:
The present invention compared with prior art at first because the present invention's solvent of no use has saved this process of recovery to solvent, has so just saved expense, has reduced production cost, and yield has also improved; Second, for further improving the quality and the yield of product, the present invention does not crystallize out intermediate of cefixime MECEF, but directly by the synthetic Cefixime Micronized of the water extraction liquid of MECEF, so both saved dissolution process, also saved H intermediate of cefixime MECEF
2SO
4And NaHCO
3Use, also saved a large amount of time, for production brings great convenience, this method has also reduced the loss of material, has improved yield; The 3rd,, realize " technology for the treatment of different things alike " that shortened the production cycle widely, total recovery brings up to 200～210% to two-step reaction owing to being single step reaction also, content is brought up to more than 99%.
Embodiment
Below in conjunction with embodiment the present invention is done to describe further.
Embodiment 1
(1) in a clean retort, add the 300L methylene dichloride, 40kg MICA-active ester, molten clear back adds 25kg AVNA, pure water 100L, the 26L triethylamine, 10 ℃ of holding temperatures were reacted 5.5 hours;
(2) adding 560L ethyl acetate was finished in reaction, with 5 ℃ pure water 300L extractions 10 minutes;
(3) leave standstill 30 minutes separatory, organic phase is carried out mark, reclaims barrelling; Water adds ethyl acetate 400L extraction 20 minutes after transferring PH to 7.0 with 36% acetate;
(4) leave standstill 30 minutes separatory, organic phase is carried out mark, reclaims barrelling; Water adds ethyl acetate 400L extraction 20 minutes, leaves standstill 30 minutes separatory, and organic phase reclaims;
(5) water adds EDTA 0.5kg, vat powder 0.5kg, and gac 10kg, decolouring 30 minutes is stirred in cooling;
(6) press filtration, filter cake water 300L washing, membrane filtration, merging filtrate and washing lotion;
(7) add 80kg KCl dissolving, open the chuck cooling water temperature to-3 ℃;
(8) stream adds 20%NaOH 72L fast, finishes and keeps-5 ℃ of hydrolysis 10 minutes, detects to showing that MECEF is lower than 0.3% o'clock stopped reaction with HPLC;
(9) stream adds 20% hydrochloric acid 50L fast, and adjusting PH is 5.5, adds the 6kg gac, stirs decolouring 30 minutes;
(10) filtering gac is that 0.45 micron millipore filtration is pressed in another retort by the aperture, uses the frozen water washed twice, each 100L, and merging filtrate and washing lotion are opened chuck hot water and are heated up, 28 ℃ of crystallizations of controlled temperature, PH is 2.6 with the adjustment of 20% hydrochloric acid;
(11) be cooled to 0 ℃ under the stirring at a slow speed, keep and stirred 1 hour, blowing is centrifugal, and with 300L1 ℃ pure water washed twice, vacuum-drying gets Cefixime Micronized 52kg, and total recovery is 200%.
Embodiment 2
(1) in a clean retort, add the 400L trichloromethane, 50kg MICA-active ester, molten clear back adds 30kg AVNA, pure water 136.4L, the 32.8L triethylamine, 15 ℃ of holding temperatures were reacted 4 hours;
(2) adding 680L ethyl acetate was finished in reaction, with 3 ℃ pure water 400L extractions 20 minutes;
(3) leave standstill 60 minutes separatory, organic phase is carried out mark, reclaims barrelling; Water adds ethyl acetate 450L extraction 30 minutes after transferring PH to 6.2 with 36% acetate;
(4) leave standstill 60 minutes separatory, organic phase is carried out mark, reclaims barrelling; Water adds ethyl acetate 450L extraction 30 minutes, leaves standstill 60 minutes separatory, and organic phase reclaims;
(5) water adds EDTA 1kg, vat powder 1kg, and gac 12kg, decolouring 60 minutes is stirred in cooling;
(6) press filtration, filter cake water 340L washing, membrane filtration, merging filtrate and washing lotion;
(7) add 100kg NaCl dissolving, open the chuck cooling water temperature to-5 ℃;
(8) stream adds 20%NaOH 80L fast, finishes and keeps-10 ℃ of hydrolysis 15 minutes, detects to showing that MECEF is lower than 0.3% o'clock stopped reaction with HPLC;
(9) stream adds 20% hydrochloric acid 60L fast, and adjusting PH is 5.0, adds the 8kg gac, stirs decolouring 60 minutes;
(10) filtering gac is that 0.25 micron millipore filtration is pressed in another retort by the aperture, uses the frozen water washed twice, each 120L, and merging filtrate and washing lotion are opened chuck hot water and are heated up, 30 ℃ of crystallizations of controlled temperature, PH is 2.5 with the adjustment of 20% hydrochloric acid;
(11) be cooled to 5 ℃ under the stirring at a slow speed, keep and stirred 2 hours, blowing is centrifugal, uses 400L, 5 ℃ pure water washed twice, and vacuum-drying gets Cefixime Micronized 62.4kg, and total recovery is 208%.
Embodiment 3
(1) in a clean retort, add the 500L methylene dichloride, 45kg MICA-active ester, molten clear back adds 28kg AVNA, pure water 127L, the 30L triethylamine, 13 ℃ of holding temperatures were reacted 3 hours;
(2) adding 630L ethyl acetate was finished in reaction, with 4 ℃ pure water 370L extractions 15 minutes;
(3) leave standstill 50 minutes separatory, organic phase is carried out mark, reclaims barrelling; Water adds ethyl acetate 430L extraction 25 minutes after transferring PH to 8.5 with 36% acetate;
(4) leave standstill 50 minutes separatory, organic phase is carried out mark, reclaims barrelling; Water adds ethyl acetate 430L extraction 25 minutes, leaves standstill 50 minutes separatory, and organic phase reclaims;
(5) water adds EDTA 0.8kg, vat powder 0.8kg, and gac 11kg, decolouring 45 minutes is stirred in cooling;
(6) press filtration, filter cake water 320L washing, membrane filtration, merging filtrate and washing lotion;
(7) add 90kg Na
2SO
4Dissolving is opened the chuck cooling water temperature to-4 ℃;
(8) stream adds 20%NaOH 76L fast, finishes and keeps-8 ℃ of hydrolysis 13 minutes, detects to showing that MECEF is lower than 0.3% o'clock stopped reaction with HPLC;
(9) stream adds 20% hydrochloric acid 55L fast, and adjusting PH is 5.3, adds the 7kg gac, stirs decolouring 45 minutes;
(10) filtering gac is that 0.3 micron millipore filtration is pressed in another retort by the aperture, uses the frozen water washed twice, each 110L, and merging filtrate and washing lotion are opened chuck hot water and are heated up, 29 ℃ of crystallizations of controlled temperature, PH is 2.55 with the adjustment of 20% hydrochloric acid;
(11) be cooled to 3 ℃ under the stirring at a slow speed, keep and stirred 1.5 hours, blowing is centrifugal, and with the pure water washed twice of 3 ℃ of 350L, vacuum-drying gets Cefixime Micronized 56.8kg, and total recovery is 203%.
Claims (3)
1. the synthetic method of a Cefixime Micronized is characterized in that, step is as follows:
(1) in a clean retort, adds 300～500L methyl chloride, 40～50kg methyl cefixime side chain active ester, be dissolved into the clarification back and add 25～30kg7-amino-3-vinyl cethalosporanic acid, pure water 100～150L, 26～35L triethylamine, 10～15 ℃ of holding temperatures were reacted 3～6 hours;
(2) adding 560～680L ethyl acetate was finished in reaction, with pure water 300～400L extractions of 3～5 ℃ 10～20 minutes;
(3) leave standstill 30～60 minutes separatory, organic phase is carried out mark, reclaims barrelling; Water adds ethyl acetate 400～450L extraction 20～30 minutes after transferring PH to 6.0～9.0 with 36% acetate;
(4) leave standstill 30～60 minutes separatory, organic phase is carried out mark, reclaims barrelling; Water adds ethyl acetate 400～450L extraction 20～30 minutes, leaves standstill 30～60 minutes separatory, and organic phase reclaims;
(5) water adds disodium ethylene diamine tetraacetate 0.5～1kg, V-Brite B 0.5～1kg, and gac 10～12kg, decolouring 30～60 minutes is stirred in cooling;
(6) press filtration, filter cake water 300～340L washing, membrane filtration, merging filtrate and washing lotion;
(7) add the dissolving of 80～100kg an alkali metal salt, open the chuck cooling water temperature to-3～-5 ℃;
(8) stream adds 20%NaOH 72～80L fast, finishes and keeps-5～-10 ℃ of hydrolysis 10～15 minutes, detects to showing that cephalo gram hydroxyimino methyl is lower than 0.3% o'clock stopped reaction with HPLC;
(9) stream adds 20% hydrochloric acid, 50～60L fast, and adjusting PH is 5.0～5.5, adds 6～8kg gac, stirs decolouring 30～60 minutes;
(10) filtering gac is pressed in another retort by millipore filtration, uses the frozen water washed twice, each 100～120L, and merging filtrate and washing lotion are opened chuck hot water and are heated up, 28～30 ℃ of crystallizations of controlled temperature, adjusting PH with 20% hydrochloric acid is 2.5～2.6;
(11) stir at a slow speed down and be cooled to 0～5 ℃, keep stirring 1～2 hour, blowing is centrifugal, washing, vacuum-drying get Cefixime Micronized 52～63kg;
Methyl chloride is methylene dichloride or trichloromethane in the described step (1); An alkali metal salt is NaCl, KCl or Na in the described step (7)
2SO
4
2. the synthetic method of Cefixime Micronized according to claim 1 is characterized in that, the aperture of millipore filtration is 0.25～0.45 micron in the described step (10).
3. the synthetic method of Cefixime Micronized according to claim 1 is characterized in that, the washing in the described step (11) is the pure water washed twice with 1～5 ℃ of 300～400L.
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| CN200710073334A CN101016305B (en) | 2007-02-12 | 2007-02-12 | Method of synthesizing cefixime |
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| CN200710073334A CN101016305B (en) | 2007-02-12 | 2007-02-12 | Method of synthesizing cefixime |
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| CN101016305B true CN101016305B (en) | 2010-05-26 |
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Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102268018A (en) * | 2010-06-03 | 2011-12-07 | 广州白云山制药股份有限公司广州白云山化学制药厂 | Crystallization method of cefixime |
| CN101928292B (en) * | 2010-09-19 | 2013-03-13 | 苏州致君万庆药业有限公司 | Method for preparing cefuroxime acid |
| CN103467495A (en) * | 2013-09-29 | 2013-12-25 | 天津理工大学 | Method for preparing cefixime compound |
| CN103965217A (en) * | 2014-05-21 | 2014-08-06 | 广州白云山制药股份有限公司广州白云山化学制药厂 | Preparation method of 3-triazinylcyclo-7-(thiazolylcarboxylmethoxyimino)cephalosporanic acid |
| CN103965216A (en) * | 2014-05-21 | 2014-08-06 | 广州白云山制药股份有限公司广州白云山化学制药厂 | Manufacturing method of 7-(thiazolylcarboxylmethoxyimino)-3-triazinylcyclocephalosporin compound |
| CN104193765B (en) * | 2014-08-12 | 2016-08-17 | 浙江普洛得邦制药有限公司 | A kind of synthetic method of cefixime |
| CN112194650A (en) * | 2020-02-26 | 2021-01-08 | 南京国星生物技术研究院有限公司 | Omeprazole refining method |
| CN112300198B (en) * | 2020-11-26 | 2022-04-22 | 浙江普洛得邦制药有限公司 | Synthesis method of cefixime and cefixime ester |
| CN117924319A (en) * | 2023-12-22 | 2024-04-26 | 广药白云山化学制药(珠海)有限公司 | Method for removing cefixime polymer impurities and method for preparing cefixime |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040242557A1 (en) * | 2003-06-02 | 2004-12-02 | Ramesh Dandala | Process for preparing cefdinir |
| WO2006103686A1 (en) * | 2005-03-29 | 2006-10-05 | Hetero Drugs Limited | An improved process for the preparation of cefixime |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040242557A1 (en) * | 2003-06-02 | 2004-12-02 | Ramesh Dandala | Process for preparing cefdinir |
| WO2006103686A1 (en) * | 2005-03-29 | 2006-10-05 | Hetero Drugs Limited | An improved process for the preparation of cefixime |
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