CN103467491B - Method for preparing cephalosporin midbody penicillin sulfoxide - Google Patents
Method for preparing cephalosporin midbody penicillin sulfoxide Download PDFInfo
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- CN103467491B CN103467491B CN201310459281.2A CN201310459281A CN103467491B CN 103467491 B CN103467491 B CN 103467491B CN 201310459281 A CN201310459281 A CN 201310459281A CN 103467491 B CN103467491 B CN 103467491B
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Abstract
The invention relates to a method for preparing cephalosporin midbody penicillin sulfoxide. According to the method for preparing the cephalosporin midbody penicillin sulfoxide, treatment such as extraction, decoloration, concentration and column chromatography is conducted on a penicillin fermentation extracting solution, and then the treated penicillin fermentation extracting solution is used as an initial raw material for preparation of the cephalosporin midbody penicillin sulfoxide. By the adoption of the method for preparing the cephalosporin midbody penicillin sulfoxide, the production steps are simplified, the production efficiency is improved, the energy consumption is reduced, emission is reduced, and remarkable economic benefits and remarkable social benefits are obtained.
Description
Technical field
The invention belongs to bulk drug synthesis technical field, in particular to a kind of preparation method of cephalosporin intermediate penicillin sulfoxide.
Background technology
Penicillin sulfoxide is the intermediate of producing the crucial parent nucleus 7-ADCA of β-lactam antibitics, and 7-ADCA can be used to produce the β-lactam antibiticss such as Cephalexin Monohydrate Micro/Compacted, Cephradine, S 578, cefetamet pivoxil, these microbiotic, because of its definite clinical efficacy, still occupy the stable market share.
At present, commercially producing of penicillin sulfoxide is with penicillin Industrial Salt, and the xln of penicilline g potassium is prepared as starting raw material.Specifically penicillin Industrial Salt is mixed with to the aqueous solution, through Peracetic Acid oxidation, then under acidic conditions, crystallization obtains penicillin sulfoxide.Its reaction equation is as follows:
Penicillin sulfoxide obtains 7-ADCA through steps such as dehydration, esterification, ring expansion, enzymatic lysises again.
At present, what the production technique of penicillin Industrial Salt adopted is solvent crystallization, basic step is to obtain butyl ester phase with N-BUTYL ACETATE extractive fermentation liquid, then obtain mutually water with alkaline solution back extraction butyl ester, after water decolouring, add butanols azeotropic band elutriation to go out penicillin Industrial Salt, and then centrifugal, washing, dry.
Under existing process condition, penicillin Industrial Salt is extracting the yield of crystallisation process at 90-92%, penicillin Industrial Salt is 88-90% to the yield of penicillin sulfoxide, and so now technique is from penicillin fermentation extracting solution to being prepared into penicillin sulfoxide, and yield is 79.2-82.8%.
Because existing penicillin sulfoxide production technique all need to be using penicillin Industrial Salt xln as starting raw material, therefore it has not only increased production stage, reduce the yield of finished product, and increased using and reclaiming of solvent, be unfavorable for energy-saving and emission-reduction and reduce costs.
Summary of the invention
In view of the deficiencies in the prior art, the object of the present invention is to provide a kind of new penicillin sulfoxide preparation method.In the method, penicillin Industrial Salt is directly prepared penicillin sulfoxide without crystallization, thereby reduce penicillium crystallization, the production stage such as dry, reduced using and reclaiming of solvent, realized energy-saving and emission-reduction, improve product yield, the object such as reduce production costs.
In order to realize object of the present invention, contriver is studied and is explored by lot of experiments, has finally obtained following technical scheme:
A preparation method for cephalosporin intermediate penicillin sulfoxide, comprises the following steps:
A. at 0-20 DEG C, in penicillin fermentation extracting solution, add salts solution, control pH=6.0-8.0, preferably control pH=6.5-7.5, extraction, separates to obtain water;
B. by water decolouring, concentrating under reduced pressure, then by alumina column adsorption treatment, obtain penicillin Industrial Salt solution;
C. at 0-15 DEG C, penicillin Industrial Salt solution is oxidized through Peracetic Acid, then regulates pH=0.9-1.2 crystallization with diluted acid, filtration washing obtains penicillin sulfoxide.
Preferably, the preparation method of cephalosporin intermediate penicillin sulfoxide as above, wherein the extraction temperature in step a is 5-10 DEG C.
Preferably, the preparation method of cephalosporin intermediate penicillin sulfoxide as above, the N-BUTYL ACETATE extracting solution that wherein the penicillin fermentation extracting solution described in step a is penicillin fermentation liquid.
Preferably, the preparation method of cephalosporin intermediate penicillin sulfoxide as above, wherein the salts solution described in step a is the aqueous solution of carbonate or vitriol.
Further preferably, the preparation method of cephalosporin intermediate penicillin sulfoxide as above, wherein the salts solution described in step a is the aqueous solution of volatile salt, sodium carbonate, salt of wormwood, ammonium sulfate, sodium sulfate or potassium sulfate; Further preferred described salts solution is the aqueous solution of sodium carbonate, salt of wormwood again.
Preferably, the preparation method of cephalosporin intermediate penicillin sulfoxide as above, wherein in step a gained water, the concentration of penicillin salt is controlled at 150-300mg/ml.
Preferably, the preparation method of cephalosporin intermediate penicillin sulfoxide as above, the be wherein not less than-0.09Mpa of vacuum tightness of concentrating under reduced pressure in step b.
Preferably, the preparation method of cephalosporin intermediate penicillin sulfoxide as above, the filler that wherein in step b, alumina column uses is neutral or alkaline oxygenated aluminum particulate, and granularity is 100-160 order, and pillar internal diameter and Length Ratio are 1:10-20.
Preferably, the preparation method of cephalosporin intermediate penicillin sulfoxide as above, wherein the oxidizing reaction temperature in step c is 0-5 DEG C.
Preferably, the preparation method of cephalosporin intermediate penicillin sulfoxide as above, wherein in step c, diluted acid used is sulfuric acid, hydrochloric acid or Glacial acetic acid.
Compared with prior art, the penicillin sulfoxide preparation technology tool the present invention relates to has the following advantages and marked improvement: penicillin Industrial Salt need not crystallize out directly down prepares penicillin sulfoxide, reduce the process loss of penicillin Industrial Salt, made the production yield of penicillin sulfoxide improve 5-8%; Whole flow process of while does not re-use a large amount of butanols and carries out solvent crystal, need not consider the recovery of butanols yet, has reduced the drying step of penicillin Industrial Salt, has realized the object of energy-saving and emission-reduction.As can be seen here, the present invention has simplified production stage, has improved production yield, has reduced energy consumption, has reduced discharge, has obvious economic and social benefit.
Embodiment
Further illustrate preparation technology of the present invention below by embodiment.Embodiments of the invention are only used for illustrating the present invention, instead of limitation of the present invention, under design prerequisite of the present invention, preparation method's of the present invention simple modifications are all belonged to the scope of protection of present invention.Unless otherwise indicated, the per-cent the present invention relates to is mass percent.
Embodiment 1
A. get N-BUTYL ACETATE extracting solution (BA liquid) 1000ml tiring as the penicillin fermentation liquid of 9-12 ten thousand units/ml, temperature control is at 5-10 DEG C, and the wet chemical with 8% regulates pH=6.5-6.8, stirs extraction 30min, phase-splitting obtains benzylpenicillin potassium salt brine solution, controls benzylpenicillin potassium salt concn 225mg/ml.
B. add the gac of potassium salt of penicillin weight 3%, vacuumize be not less than-0.095Mpa, stir the de-ester 60min of decolouring, suction filtration.Filtrate mistake
the alumina column of 30mm × 300mm, selects the alkaline oxygenated Al filler of 100 order, collected post liquid, then wash pillar with deionized water in 30min, and washing lotion was incorporated to post liquid.
C. be cooled to 3 DEG C, the peracetic acid soln of dropping 30% is oxidized, and the amount of Peracetic Acid used is 1.10 times of penicillin mole number, and 30-60min adds.Then in 60-120min, be adjusted to pH=0.9-1.0 with 30% dilute sulphuric acid, filter, wash and to obtain penicillin sulfoxide.
In the present embodiment, be 88.2% from penicillin fermentation extracting solution to the yield that is prepared into penicillin sulfoxide.
Embodiment 2
Difference from Example 1 is that the salts solution that in step a, extraction is selected is aqueous sodium carbonate, and in step b, the filler of alumina column is selected 120 object alkali aluminas.The present embodiment is 86.6% from penicillin fermentation extracting solution to the yield that is prepared into penicillin sulfoxide.
Embodiment 3
A. get the BA liquid 1000ml tiring as 8-10 ten thousand units/ml, temperature control is at 5-10 DEG C, and the wet chemical with 5% regulates pH=7.0-7.2, stirs extraction 30min, and phase-splitting obtains benzylpenicillin potassium salt brine solution, controls benzylpenicillin potassium salt concn 220mg/ml.
B. add the gac of potassium salt of penicillin weight 3%, vacuumize be not less than-0.095Mpa, stir the de-ester 60min of decolouring, suction filtration.Filtrate mistake
the alumina column of 30mm × 450mm, selects 120 order neutral alumina fillers, collected post liquid, then wash pillar by appropriate amount of deionized water in 30min, and washing lotion was incorporated to post liquid.
C. be cooled to 5 DEG C, the peracetic acid soln of dropping 30% is oxidized, and the amount of Peracetic Acid used is 1.10 times of penicillin mole number, and 30-60min adds.Then in 60-120min, be adjusted to pH=0.9-1.0 with 20% dilute hydrochloric acid, filter, wash and to obtain penicillin sulfoxide.
In the present embodiment, be 86.2% from penicillin fermentation extracting solution to the yield that is prepared into penicillin sulfoxide.
Embodiment 4
Difference from Example 3 is that the filler of alumina column in step b selects 100 object neutral aluminas, and the Peracetic Acid concentration using in step c is 35%.The present embodiment is 87.5% from penicillin fermentation extracting solution to the yield that is prepared into penicillin sulfoxide.
Claims (1)
1. a preparation method for cephalosporin intermediate penicillin sulfoxide, is characterized in that comprising the following steps:
A. get the N-BUTYL ACETATE extracting solution 1000ml tiring as the penicillin fermentation liquid of 9-12 ten thousand units/ml, temperature control is at 5-10 DEG C, and the wet chemical with 8% regulates pH=6.5-6.8, stirs extraction 30min, phase-splitting obtains benzylpenicillin potassium salt brine solution, controls benzylpenicillin potassium salt concn 225mg/ml;
B. add the gac of potassium salt of penicillin weight 3%, vacuumize be not less than-0.095Mpa, stir the de-ester 60min of decolouring, suction filtration; Filtrate is crossed the alumina column of 30mm × 300mm, selects the alkaline oxygenated Al filler of 100 order, collected post liquid, then wash pillar with deionized water in 30min, and washing lotion was incorporated to post liquid;
C. be cooled to 3 DEG C, the peracetic acid soln of dropping 30% is oxidized, and the amount of Peracetic Acid used is 1.10 times of penicillin mole number, and 30-60min adds; Then in 60-120min, be adjusted to pH=0.9-1.0 with 30% dilute sulphuric acid, filter, wash and to obtain penicillin sulfoxide.
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Address after: 312400, No. 1000, Shengzhou Avenue, Shengzhou, Zhejiang, Shaoxing Patentee after: ZHEJIANG ANGLIKANG PHARMACEUTICAL Co.,Ltd. Patentee after: JIANGSU YUEXIN PHARMACEUTICAL Co.,Ltd. Address before: 312400, No. 1000, Shengzhou Avenue, Shengzhou, Zhejiang, Shaoxing Patentee before: ZHEJIANG ANGLIKANG PHARMACEUTICAL Co.,Ltd. Patentee before: JIANGSU YUEXIN PHARMACEUTICAL Co.,Ltd. |
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Denomination of invention: A preparation method for cephalosporin intermediate penicillin sulfoxide Effective date of registration: 20230601 Granted publication date: 20140827 Pledgee: Bank of Ningbo Co.,Ltd. Shaoxing Branch Pledgor: ZHEJIANG ANGLIKANG PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980042571 |