CN108610352B - Method for preparing mezlocillin sodium by solvent crystallization - Google Patents
Method for preparing mezlocillin sodium by solvent crystallization Download PDFInfo
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- CN108610352B CN108610352B CN201810603658.XA CN201810603658A CN108610352B CN 108610352 B CN108610352 B CN 108610352B CN 201810603658 A CN201810603658 A CN 201810603658A CN 108610352 B CN108610352 B CN 108610352B
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- mezlocillin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
- C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
- C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
- C07D499/68—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms with aromatic rings as additional substituents on the carbon chain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/14—Preparation of salts
- C07D499/16—Preparation of salts of alkali or alkaline earth metals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/18—Separation; Purification
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for preparing mezlocillin sodium by solvent crystallization, which comprises the following preparation steps: 1) mixing mezlocillin acid, acetone, water and sodium isooctanoate to obtain a mixed solution; 2) and heating the mixed solution, and mixing the heated mixed solution with acetone to obtain mezlocillin sodium. The invention solves the problem of mixed solvents by only using the same solvent in the whole process, and the obtained product mezlocillin sodium has the yield of 80-95%, the purity of 99.2-99.8% and the total impurities of 0.05-0.15%.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a method for preparing mezlocillin sodium by solvent crystallization.
Background
Mezlocillin sodium, which is one of the national basic drugs, belongs to the third-generation semi-synthetic penicillin antibacterial drugs, is an irreversible β -lactamase inhibitor, and has antibacterial effects on Escherichia coli, Proteus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter, Neisseria gonorrhoeae, Neisseria meningitidis, Streptococcus, Bacteroides and the like.
The preparation method of mezlocillin sodium for injection at present mainly comprises 3 methods of freeze drying method, solvent crystallization method and elution crystallization method. The solvent crystallization method is a crystallization process of dissolving a product in a suitable medium (generally an organic solvent), and then reducing the temperature or the amount of the solvent to make the product reach a supersaturated state in the solvent, thereby slowly precipitating the product. The method uses the compound solvent, and the distribution ratio of various solvent components has larger influence on the crystal crystallization process in the production process, and is not beneficial to solvent recovery.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for preparing mezlocillin sodium by solvent crystallization, wherein only one solvent is used in the whole process, which is beneficial to solvent recovery and solves the problem of mixed solvents.
In order to achieve the above object, the present invention provides the following technical solutions:
a method for preparing mezlocillin sodium by solvent crystallization comprises the following steps:
1) carrying out neutralization reaction on mezlocillin acid, acetone, water and sodium isooctanoate to obtain reaction liquid;
2) and (2) heating the reaction solution obtained in the step (1), and mixing the heated reaction solution with acetone to obtain mezlocillin sodium.
Preferably, the dosage ratio of mezlocillin acid, acetone, water and sodium isooctanoate in the step 1) is 1 kg: 3-8L: 0.1-1 kg: 0.2-0.5 kg.
Preferably, in the step 2), the ratio of the amount of the acetone to the amount of the mezlocillin in the step 1) is 3-9L: 1 kg.
Preferably, the temperature of the reaction solution after temperature rise is 10-40 ℃.
Preferably, the source of mezlocillin acid comprises mezlocillin acid meeting the quality standards of intermediates.
The beneficial technical effects are as follows: the invention provides a method for preparing mezlocillin sodium by solvent crystallization. And heating the reaction solution, and mixing the reaction solution with acetone to obtain mezlocillin sodium. Only the same solvent acetone is used in the whole process, and the solvent is recovered (acetone with high water content and unqualified content is rectified by a rectifying tower to obtain the acetone with low water content and high acetone content for production). The problem of mixing solvents is solved, and the yield of the obtained product mezlocillin sodium reaches 80-95%, the purity is 99.2-99.8%, and the total impurities are 0.05-0.15%.
Detailed Description
The invention provides a method for preparing mezlocillin sodium by solvent crystallization, which comprises the following steps:
1) carrying out neutralization reaction on mezlocillin acid, acetone, water and sodium isooctanoate to obtain reaction liquid;
2) heating the reaction solution obtained in the step 1), and mixing the reaction solution with acetone to obtain mezlocillin sodium.
The method comprises the following steps of carrying out neutralization reaction on mezlocillin acid, acetone, water and sodium isooctanoate to obtain a reaction solution;
in the invention, the dosage ratio of mezlocillin acid, acetone, water and sodium isooctanoate is 1 kg: 3-8L: 0.1-1 kg: 0.2-0.5kg, more preferably 1 kg: 5-7L: 0.3-0.7 kg: 0.2-0.5 kg.
In the present invention, the water is preferably purified water.
In the invention, preferably, mezlocillin is dissolved in acetone to form a mezlocillin acetone solution, then water is added for stirring, and sodium isooctanoate is added for neutralization reaction.
In the invention, the stirring speed is preferably 20-50 Hz, more preferably 45Hz, and the stirring time is preferably 30-50 min, more preferably 35-45 min.
In the present invention, it is preferable to dissolve mezlocillin in acetone to form a mezlocillin acetone solution, and then add water thereto. Adding sodium isooctanoate to produce mezlocillin sodium.
In the present invention, the reaction temperature of the neutralization reaction is preferably room temperature; the time for the neutralization reaction is preferably 30 to 120min, more preferably 60 min. In the present invention, the time for the neutralization reaction is calculated from the time when the sodium isooctanoate is completely dissolved.
In the invention, the source of the mezlocillin acid comprises mezlocillin acid meeting the quality standard of an intermediate.
After reaction liquid is obtained, the reaction liquid is heated and then mixed with acetone to obtain mezlocillin sodium.
In the invention, the mass ratio of the mezlocillin to the acetone is preferably 1 kg: 3-8L, and more preferably 1 kg: 7L.
In the invention, the temperature of the reaction liquid is preferably controlled to be 25-35 ℃, and more preferably to be 28-30 ℃.
In the invention, after the mezlocillin sodium is crystallized, the crystallized liquid is filtered, and the obtained solid is dried to obtain the finished product of mezlocillin sodium.
In the invention, the drying temperature is preferably 30-80 ℃, more preferably 50-70 ℃, and the drying time is preferably 1-6 hours, more preferably 2-4 hours.
In order to better understand the present invention, the following examples are further provided to illustrate the present invention, but the present invention is not limited to the following examples.
Example 1
Adding 134kg of mezlocillin acid, adding 670L acetone for dissolving, adding 134kg of purified water, stirring for half an hour, adding 40.2kg of sodium isooctanoate, controlling the temperature to be 25 ℃ after complete dissolution, adding 1200L acetone, stirring for half an hour, separating out mezlocillin sodium crystals, filtering, washing and drying to obtain a mezlocillin sodium product 131 kg. with the yield of 94%, the purity of 99.78% and the total impurities of 0.2%.
Example 2
Adding 134kg of mezlocillin acid, adding 402L acetone for dissolving, adding 67kg of purified water, stirring for half an hour, adding 46.9kg of sodium isooctanoate, controlling the temperature to be 27 ℃ after complete dissolution, adding 804L acetone, stirring for half an hour, separating out mezlocillin sodium crystals, filtering, washing and drying to obtain a mezlocillin sodium product 133.9 kg. with the yield of 96%, the purity of 99.82% and the total impurity of 0.2%.
Example 3
Adding 134kg of mezlocillin acid, adding 1072L of acetone for dissolving, adding 13.4kg of purified water, stirring for half an hour, adding 43.3kg of sodium isooctanoate, controlling the temperature at 30 ℃ after complete dissolution, adding 410L of acetone, stirring for half an hour, separating out mezlocillin sodium crystals, filtering, washing and drying to obtain a mezlocillin sodium product 129.4 kg., wherein the yield is 92.78%, the purity is 99.91 and the total impurities are 0.1%.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (1)
1. A method for preparing mezlocillin sodium by solvent crystallization comprises the following steps:
adding 134kg of mezlocillin acid, adding 670L acetone for dissolving, adding 134kg of purified water, stirring for half an hour, adding 40.2kg of sodium isooctanoate, controlling the temperature to be 25 ℃ after complete dissolution, adding 1200L acetone, stirring for half an hour, separating out mezlocillin sodium crystals, filtering, washing and drying to obtain 131kg of mezlocillin sodium product, wherein the product yield is 94%, the purity is 99.78% and the total impurities are 0.2%;
or, putting 134kg of mezlocillin acid, adding 402L acetone for dissolution, adding 67kg of purified water, stirring for half an hour, adding 46.9kg of sodium isooctanoate, controlling the temperature to be 27 ℃ after complete dissolution, adding 804L acetone, stirring for half an hour, separating out mezlocillin sodium crystals, filtering, washing and drying to obtain 133.9kg of a mezlocillin sodium product, wherein the product yield is 96%, the purity is 99.82%, and the total impurities are 0.2%;
or, adding 134kg of mezlocillin acid, adding 1072L acetone for dissolution, adding 13.4kg of purified water, stirring for half an hour, adding 43.3kg of sodium isooctanoate, controlling the temperature to be 30 ℃ after complete dissolution, adding 410L acetone, stirring for half an hour, separating out mezlocillin sodium crystals, filtering, washing and drying to obtain 129.4kg of mezlocillin sodium product, wherein the product yield is 92.78%, the purity is 99.91% and the total impurities are 0.1%.
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| CN201810603658.XA CN108610352B (en) | 2018-06-12 | 2018-06-12 | Method for preparing mezlocillin sodium by solvent crystallization |
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| CN201810603658.XA CN108610352B (en) | 2018-06-12 | 2018-06-12 | Method for preparing mezlocillin sodium by solvent crystallization |
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| CN108610352B true CN108610352B (en) | 2020-08-04 |
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| CN101570543B (en) * | 2009-06-04 | 2011-05-25 | 浙江工业大学 | Preparation method of mezlocillin sodium solvent crystal |
| CN101654457A (en) * | 2009-08-07 | 2010-02-24 | 菏泽睿鹰制药集团有限公司 | Method for synthesizing mezlocillin sodium through solvent method |
| CN102161666B (en) * | 2011-04-08 | 2012-02-08 | 苏州二叶制药有限公司 | Preparation method of mezlocillin sodium and mezlocillin sodium for injection |
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