CN105384755A - Refining method for improving purity of ampicillin sodium - Google Patents
Refining method for improving purity of ampicillin sodium Download PDFInfo
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- CN105384755A CN105384755A CN201510782703.9A CN201510782703A CN105384755A CN 105384755 A CN105384755 A CN 105384755A CN 201510782703 A CN201510782703 A CN 201510782703A CN 105384755 A CN105384755 A CN 105384755A
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- Prior art keywords
- ampicillin
- purification
- purity
- raising
- ketone
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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
-
- 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
-
- 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
Abstract
The invention discloses a refining method for improving the purity of ampicillin sodium, belonging to the technical field of medicine synthesis. The refining method is characterized by adding crude ampicillin sodium to purified water and a water-soluble organic solvent to be dissolved, then adding activated carbon and aluminium oxide to remove impurities, adding a crystallization reagent precooled to -10 to 25 DEG C under stirring to carry out crystallization and crystal growing and finally carrying out washing and drying, thus obtaining the high-purity ampicillin sodium white crystal. The refining method for improving the purity of ampicillin sodium has the beneficial effects that the obtained product has low dimer content and high purity, has the effects of reducing the adverse effect occurrence rates of clinical patients and improving the compliance of the patients and is beneficial to disease treatment; besides, the method is simple in process and mild in reaction conditions; the obtained product has good flowability and is easy to subpackage and industrially produce.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to a kind of process for purification improving ampicillin purity.
Background technology
Ampicillin, chemical name (2S, 5R, 6R)-3,3-dimethyl-6-[(R)-2-amino-2-phenylacetylamino]-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid sodium salt.
Ampicillin is a kind of wide spectrum semi-synthetic penicillins microbiotic, reaches sterilization effect by the synthesis of anti-bacteria cell walls, is white or off-white powder or crystallization, odorless or micro-smelly, mildly bitter flavor, have draw moist.To Hemolytic streptococcus, streptococcus pneumoniae with do not produce the stronger anti-microbial effect of penicillinase staphylococcus tool.
The synthetic method of ampicillin mainly contains solvent crystallization and lyophilization two kinds, all commercially has sale, and due to this product determined curative effect, application is comparatively extensive, is one of medicine welcome by doctor patient.Large quantifier elimination is verified, penicillins medicine is the class microbiotic than being easier to cause allergic reaction, it causes irritated principal element to be exactly the high molecular polymer class related substances such as the dipolymer that contains of the inside, and the content close association of anaphylactoid incidence and this High-molecular weight polymer impurity, and ampicillin all likely causes exceeding standard of the related substances such as high molecular polymer in the control of producing and the exception deposited in process, cause medicine defective or at borderline pass, use patient and will cause serious consequence, at present, this material of bibliographical information is not still had to reduce the recrystallization process of this dimer or high molecular polymer.
Summary of the invention
The object of this invention is to provide a kind of process for purification improving ampicillin purity, present method technique is simple, reaction conditions is gentle, be easy to suitability for industrialized production, products obtained therefrom dipolymer is low, and product purity is high, reduces the adverse reaction rate of clinical patient, improve the compliance of patient, be conducive to the treatment of disease.
To achieve these goals, the technical solution used in the present invention is:
The present invention improves the process for purification of ampicillin purity, comprises the following steps:
1) dissolve: purified water and water-miscible organic solvent are under agitation added in ampicillin crude product, is stirred to and dissolves completely, obtain solution A;
2) removal of impurities: add gac and aluminum oxide stirring in solution A, decolouring 20 ~ 60min, millipore filtration membrane filtration, imurity-removal, obtains liquor B;
3) crystallization: under agitation liquor B be added drop-wise in the crystalline reagents being chilled to-10 ~-25 DEG C in advance, control time for adding is 30 ~ 40min, dropwises rear insulation-15 ~-10 DEG C, growing the grain 2 ~ 3h;
4) aftertreatment: the intermediate product after above-mentioned crystallization is filtered, then with organic detergent, gained crystal is washed, vacuum-drying at 40 ~ 45 DEG C, obtain high purity ampicillin white crystals.
The weight ratio of ampicillin used and purified water, water-miscible organic solvent, gac, aluminum oxide, crystalline reagents, organic detergent is 1:(1.5 ~ 3.0): (0.5 ~ 1.5): (0.01 ~ 0.05): (0.03 ~ 0.07): (25 ~ 40): (5 ~ 10).
Described water-miscible organic solvent is the one in the alkyl ketone of C3 ~ C10, the alkyl alcohol of C1 ~ C4 or acetonitrile.
Described gac is 767 needle-use activated carbons.
Described aluminum oxide is gama-alumina.
Described crystalline reagents is the one in ketone or alcoholic solvent.
Described ketone is the alkyl ketone of C3 ~ C10, and described alcohols is the alkyl alcohol of C1 ~ C4.
Described organic detergent is one or both the combination in ketone or alcoholic solvent.
Described ketone is the alkyl ketone of C3 ~ C10, and described alcohols is the alkyl alcohol of C1 ~ C4.
The temperature of described organic detergent controls as-10 ~ 5 DEG C.
Beneficial effect of the present invention is: the present invention improves the process for purification of ampicillin purity, and products obtained therefrom dipolymer is low, and product purity is high, reduces the adverse reaction rate of clinical patient, improves the compliance of patient, is conducive to the treatment of disease; In addition the method technique is simple, and reaction conditions is gentle, and products obtained therefrom good fluidity, is easy to packing, is easy to suitability for industrialized production.
Embodiment
Be below the specific embodiment of the present invention, described embodiment is to further describe the present invention, instead of restriction the present invention.
Embodiment 1
The present invention improves the process for purification of ampicillin purity, comprises the following steps:
1) 200ml there-necked flask, adds acetonitrile 10ml, purified water 30ml, is cooled to 0 DEG C, adds crude product ampicillin 20g, be stirred to and dissolve completely, obtain solution A under stirring;
2) in solution A, add gama-alumina 1.0g, 767 needle-use activated carbon 0.5g, decolouring 20min, millipore filtration membrane filtration, obtains liquor B;
3) 1000ml four-hole bottle, adds dehydrated alcohol 600ml, is cooled to-10 DEG C, liquor B be slowly added drop-wise in the ethanol of stirring, and slowly have precipitation white crystals, 40min dropwises, and dropwises rear insulation-10 DEG C, stirs 3h growing the grain;
4) filter, with-10 DEG C of absolute ethanol washings, then use-10 DEG C of washing with acetones, 40 DEG C of vacuum-dryings, obtain ampicillin fine work 17g, purity 99.2%, dipolymer 0.03%, yield 85%.
Embodiment 2
The present invention improves the process for purification of ampicillin purity, comprises the following steps:
1) 200ml there-necked flask, adds acetonitrile 10ml, purified water 30ml, is cooled to 5 DEG C, adds crude product ampicillin 20g, be stirred to and dissolve completely, obtain solution A under stirring;
2) in solution A, add gama-alumina 1.0g, 767 needle-use activated carbon 0.5g, decolouring 60min, millipore filtration membrane filtration, obtains liquor B;
3) 1000ml four-hole bottle, adds dehydrated alcohol 600ml, is cooled to-15 DEG C, liquor B be slowly added drop-wise in the ethanol of stirring, and slowly have precipitation white crystals, 30min dropwises, and dropwises rear insulation-15 DEG C, stirs 2h growing the grain;
4) filter, with 5 DEG C of washing with acetones, 42 DEG C of vacuum-dryings, obtain ampicillin fine work 18g, purity 99.2%, dipolymer 0.02%, yield 90%.
Embodiment 3
The present invention improves the process for purification of ampicillin purity, comprises the following steps:
1) 200ml there-necked flask, adds acetonitrile 10ml, purified water 30ml, is cooled to 3 DEG C, adds crude product ampicillin 20g, be stirred to and dissolve completely, obtain solution A under stirring;
2) in solution A, add gama-alumina 1.0g, 767 needle-use activated carbon 0.5g, decolouring 40min, millipore filtration membrane filtration, obtains liquor B;
3) 1000ml four-hole bottle, adds dehydrated alcohol 500ml, is cooled to-12 DEG C, liquor B be slowly added drop-wise in the ethanol of stirring, and slowly have precipitation white crystals, 35min dropwises, and dropwises rear insulation-12 DEG C, stirs 3h growing the grain;
4) filter, with 0 DEG C of absolute ethanol washing, 41 DEG C of vacuum-dryings, obtain ampicillin fine work 18.4g, purity 99.3%, dipolymer 0.02%, yield 92%.
Embodiment 4
The present invention improves the process for purification of ampicillin purity, comprises the following steps:
1) 200ml there-necked flask, adds acetonitrile 10ml, purified water 60ml, is cooled to 3 DEG C, adds crude product ampicillin 20g, be stirred to and dissolve completely, obtain solution A under stirring;
2) in solution A, add gama-alumina 1.0g, 767 needle-use activated carbon 0.5g, decolouring 40min, millipore filtration membrane filtration, obtains liquor B;
3) 1000ml four-hole bottle, adds anhydrous propanone 800ml, is cooled to-12 DEG C, liquor B be slowly added drop-wise in the acetone of stirring, and slowly have precipitation white crystals, 35min dropwises, and dropwises rear insulation-12 DEG C, stirs 2h growing the grain;
4) filter, with 0 DEG C of anhydrous propanone washing, 42 DEG C of vacuum-dryings, obtain ampicillin fine work 18.4g, purity 99.1%, dipolymer 0.05%, yield 91%.
Embodiment 5
The present invention improves the process for purification of ampicillin purity, comprises the following steps:
1) 200ml there-necked flask, adds ethanol 10ml, purified water 30ml, is cooled to 3 DEG C, adds crude product ampicillin 20g, be stirred to and dissolve completely, obtain solution A under stirring;
2) in solution A, add gama-alumina 1.4g, 767 needle-use activated carbon 0.4g, decolouring 40min, millipore filtration membrane filtration, obtains liquor B;
3) 1000ml four-hole bottle, adds anhydrous propanone 500ml, is cooled to-12 DEG C, liquor B be slowly added drop-wise in the acetone of stirring, and slowly have precipitation white crystals, 35min dropwises, and dropwises rear insulation-12 DEG C, stirs 3h growing the grain;
4) filter, with 0 DEG C of anhydrous propanone washing, 40 DEG C of vacuum-dryings, obtain ampicillin fine work 18.0g, purity 99.2%, dipolymer 0.04%, yield 90%.
Claims (10)
1. improve a process for purification for ampicillin purity, it is characterized in that, comprise the following steps:
1) dissolve: purified water and water-miscible organic solvent are under agitation added in ampicillin crude product, is stirred to and dissolves completely, obtain solution A;
2) removal of impurities: add gac and aluminum oxide stirring in solution A, decolouring 20 ~ 60min, millipore filtration membrane filtration, imurity-removal, obtains liquor B;
3) crystallization: under agitation liquor B be added drop-wise in the crystalline reagents being chilled to-10 ~-25 DEG C in advance, control time for adding is 30 ~ 40min, dropwises rear insulation-15 ~-10 DEG C, growing the grain 2 ~ 3h;
4) aftertreatment: the intermediate product after above-mentioned crystallization is filtered, then with organic detergent, gained crystal is washed, vacuum-drying at 40 ~ 45 DEG C, obtain high purity ampicillin white crystals.
2. the process for purification of raising ampicillin purity according to claim 1, it is characterized in that, the weight ratio of ampicillin and purified water, water-miscible organic solvent, gac, aluminum oxide, crystalline reagents, organic detergent is 1:(1.5 ~ 3.0): (0.5 ~ 1.5): (0.01 ~ 0.05): (0.03 ~ 0.07): (25 ~ 40): (5 ~ 10).
3. the process for purification of raising ampicillin purity according to claim 1 and 2, is characterized in that, described water-miscible organic solvent is the one in the alkyl ketone of C3 ~ C10, the alkyl alcohol of C1 ~ C4 or acetonitrile.
4. the process for purification of raising ampicillin purity according to claim 1 and 2, is characterized in that, described gac is 767 needle-use activated carbons.
5. the process for purification of raising ampicillin purity according to claim 1 and 2, is characterized in that, described aluminum oxide is gama-alumina.
6. the process for purification of raising ampicillin purity according to claim 1 and 2, is characterized in that, described crystalline reagents is the one in ketone or alcoholic solvent.
7. the process for purification of raising ampicillin purity according to claim 6, is characterized in that, described ketone is the alkyl ketone of C3 ~ C10, and described alcohols is the alkyl alcohol of C1 ~ C4.
8. the process for purification of raising ampicillin purity according to claim 1 and 2, is characterized in that, described organic detergent is one or both the combination in ketone or alcoholic solvent.
9. the process for purification of raising ampicillin purity according to claim 8, is characterized in that, described ketone is the alkyl ketone of C3 ~ C10, and described alcohols is the alkyl alcohol of C1 ~ C4.
10. the process for purification of raising ampicillin purity according to claim 1 and 2, is characterized in that, the temperature of described organic detergent controls as-10 ~ 5 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201510782703.9A CN105384755A (en) | 2015-11-13 | 2015-11-13 | Refining method for improving purity of ampicillin sodium |
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| CN201510782703.9A CN105384755A (en) | 2015-11-13 | 2015-11-13 | Refining method for improving purity of ampicillin sodium |
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| CN105384755A true CN105384755A (en) | 2016-03-09 |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1666990A (en) * | 2004-03-12 | 2005-09-14 | 河北张药股份有限公司 | Process for preparing ampicillin sodium |
| CN101486717A (en) * | 2008-12-05 | 2009-07-22 | 华北制药股份有限公司 | Method for preparing ampicillin sodium |
| CN101723957A (en) * | 2008-10-24 | 2010-06-09 | 华北制药股份有限公司 | Method for preparing ampicillin sodium salt |
| CN103880863A (en) * | 2014-03-27 | 2014-06-25 | 哈药集团制药总厂 | Preparation method of ampicillin sodium |
| CN104151324A (en) * | 2014-09-03 | 2014-11-19 | 齐鲁天和惠世制药有限公司 | Method for preparing ampicillin sodium by menstruum crystallization method |
| CN104945418A (en) * | 2015-05-28 | 2015-09-30 | 浙江长典医药有限公司 | Children ampicillin sodium compound entity and pharmaceutical preparation thereof |
-
2015
- 2015-11-13 CN CN201510782703.9A patent/CN105384755A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1666990A (en) * | 2004-03-12 | 2005-09-14 | 河北张药股份有限公司 | Process for preparing ampicillin sodium |
| CN101723957A (en) * | 2008-10-24 | 2010-06-09 | 华北制药股份有限公司 | Method for preparing ampicillin sodium salt |
| CN101486717A (en) * | 2008-12-05 | 2009-07-22 | 华北制药股份有限公司 | Method for preparing ampicillin sodium |
| CN103880863A (en) * | 2014-03-27 | 2014-06-25 | 哈药集团制药总厂 | Preparation method of ampicillin sodium |
| CN104151324A (en) * | 2014-09-03 | 2014-11-19 | 齐鲁天和惠世制药有限公司 | Method for preparing ampicillin sodium by menstruum crystallization method |
| CN104945418A (en) * | 2015-05-28 | 2015-09-30 | 浙江长典医药有限公司 | Children ampicillin sodium compound entity and pharmaceutical preparation thereof |
Non-Patent Citations (2)
| Title |
|---|
| 李润妍，等: "氨苄西林钠溶析结晶的工艺研究", 《中国抗生素杂志》 * |
| 杨华伟: "氨苄西林钠溶媒结晶工艺研究", 《天津大学工程硕士学位论文》 * |
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Application publication date: 20160309 |