CN107383061A - The synthetic method of azlocillin sodium - Google Patents
The synthetic method of azlocillin sodium Download PDFInfo
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- CN107383061A CN107383061A CN201710656477.9A CN201710656477A CN107383061A CN 107383061 A CN107383061 A CN 107383061A CN 201710656477 A CN201710656477 A CN 201710656477A CN 107383061 A CN107383061 A CN 107383061A
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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 kind of synthetic method of azlocillin sodium, comprise the following steps：（1）Dissolution of raw material；（2）Condensation reaction；（3）Purified treatment；（4）Prepare finished product azlocillin acid；（5）Salt-forming reaction；（6）Filtration sterilization；（7）Freeze-drying.A kind of synthetic method of azlocillin sodium of the present invention, designed by rational synthesis technique, be effectively simplified building-up process, make reaction condition gentle, exploitativeness is high, its raw material is easy to get, and the controllability of synthesis technique is preferable, is easy to industrialized production, the azlocillin sodium yield of gained is high, purity is big, and the property of medicine is stable, wide market.
Description
Technical field
The present invention relates to antibiotics synthesis technical field, more particularly to a kind of synthesis side of azlocillin sodium
Method.
Background technology
Azlocillin sodium (Azlocillin sodium), also known as Azlocillin, entitled (2S, 5R, 6R) -3 of chemistry,
3- dimethyl -6- [(R) -2- (2- oxo -1- imidazolidine formamido group -2- phenylacetylaminos) -7- oxo -4- thias -
1- azabicyclos [3.2.0] heptane -2- formic acid sodium salts.
Molecular formula：C20H22N5NaO6S
Molecular weight：483.47
It is semi-synthetic uride penicillin, is initiated by Britain, successively obtains clinical answer in states such as Germany, Britain, the U.S. and Japan
With to gram positive bacteria and negative bacterium, especially there is good antibacterial action to pseudomonas aeruginosa.China was in 1996 1
The moon has issued New Drug Certificate and production licence to Zhejiang Zhejiang CONBA Pharmaceutical Co., Ltd, and has produced A Le by the said firm
Glad injection powder injection.
The preparation method of existing azlocillin sodium, the defects of process route is complicated, yield is low, cost is high be present, be unfavorable for
Industrialized production.
The content of the invention
The present invention solves the technical problem of provide a kind of synthetic method of azlocillin sodium.
In order to solve the above technical problems, one aspect of the present invention is：A kind of conjunction of azlocillin sodium is provided
Into method, comprise the following steps：
（1）Dissolution of raw material：At a certain temperature, a certain amount of acetone, purified water and the water of ampicillin three are added into retort
Acid, after stirring, constant temperature is added dropwise triethylamine and clarified completely to solution, is completely dissolved the water acid of ampicillin three；
（2）Condensation reaction：First to step（1）Settled solution in be slowly added to a certain amount of 1-Chlorocarbonyl-2-Imidazolidone,
The pH value of triethylamine regulation mixed solution is stirring evenly and then adding into, then low-temp reaction for a period of time, makes ampicillin and 1- chlorine
Condensation reaction occurs for formoxyl -2- imidazolidinones, generates azlocillin acid solution；
（3）Purified treatment：To step（2）In add a certain amount of medicinal carbon in obtained reaction solution, after stirring is decolourized, mistake
Filter decarburization, and carbon slag is multiple with purifying water washing, will filtering gained filtrate and cleaning solution mix after through filter filtration sterilization,
Azlocillin acid solution after being purified；
（4）Prepare finished product azlocillin acid：Under stirring, by step（3）In azlocillin acid after obtained purification it is molten
Hydrochloric acid is added in liquid, adjusts the pH value of mixed liquor to acidity, and continues stirring until azlocillin acid crystal and all separates out, vacuum
Filter, then wash crystal with acetone, vacuum drying obtains finished product azlocillin acid；
（5）Salt-forming reaction：By step（4）In obtained solid azlocillin be dissolved in purified water, under stirring, with a constant speed
Sodium hydroxide solution, and the pH value of implementing monitoring mixed solution is added dropwise in rate thereto, when solution becomes clarification, stops being added dropwise；
（6）Filtration sterilization：To step（5）In add a certain amount of medicinal carbon in obtained reaction solution, after stirring is decolourized, according to
Secondary to carry out filtration sterilization through decarburizing filter, accurate filter, sterilizing filter and nano-filtration membrane filter, what is be purified is molten
Liquid；
（7）Freeze-drying：By step（6）In obtained purified solution load in lyophilized plate, be first placed in the cold-trap of freeze dryer
Row pre-freeze, vacuum freeze-drying is then carried out, obtain finished product azlocillin sodium powder.
In a preferred embodiment of the present invention, the step（1）In, the temperature is 5~12 DEG C, the acetone, pure
Change water and the water of ampicillin three acid addition be：120~150ml：200~240ml：20~25g.
In a preferred embodiment of the present invention, the step（2）In, the 1-Chlorocarbonyl-2-Imidazolidone adds
It is step to enter quality（1）The 1/2 of the middle water acid quality of ampicillin three；The pH value is 7.5~10；The condition of the condensation reaction
For：3~5 DEG C of temperature, 3.5~4h of time.
In a preferred embodiment of the present invention, the step（3）In, the addition of the medicinal carbon is reaction solution
The 0.3~0.35% of quality.
In a preferred embodiment of the present invention, the step（3）In, the filter includes accurate filter and degerming
Filter, wherein, the filter core of the accurate filter is 0.25 μm of nylon filter core, and the sterilizing filter is 0.20 μm poly-
Ether sulfone filter core.
In a preferred embodiment of the present invention, the step（4）In, the mass concentration for adding hydrochloric acid for 10~
15%；The pH value is 1.8~2.5；The speed of the stirring is：First stirred with 150~200r/min speed to mixed solution
PH value be 4~5, then stirred using 100~120r/min speed to pH value as 1.8~2.5, then with 40~60r/min's
Speed is stirred to crystal and separated out completely.
In a preferred embodiment of the present invention, the step（5）In, the quality of the solid azlocillin and purified water
Than for 1:6~8；Relation between the concentration and drop rate and pH value of the sodium hydroxide solution is：PH value 3~3.5 it
Before, 3.5~4mol/L sodium hydroxide solution is added dropwise with 10~15 drops/min speed, pH value is before 5~5.5, with 8~12
2.5~3mol/L sodium hydroxide solution is added dropwise in drop/min speed, and pH value continues to increase to solution clarification stage, with 8~10
1.5mol/L sodium hydroxide solution is added dropwise in drop/min speed.
In a preferred embodiment of the present invention, the step（6）In, the addition of the medicinal carbon is reaction solution
The 0.2~0.3% of quality；The accurate filter, the filter core of sterilizing filter are respectively 0.25 μm of nylon filter core, 0.20 μm
Polyether sulfone filter core；The filter membrane thickness of the nano-filtration membrane filter is 10~50nm.
In a preferred embodiment of the present invention, the step（7）In, the process conditions of the pre-freeze are：Temperature -40
~-45 DEG C, 2.5~3h of time；The process conditions of the vacuum freeze-drying are：15~20Pa of vacuum, first at -35~-20 DEG C
Constant temperature freezes 2~3h, -20 DEG C~-5 DEG C 1~2h of heating, then constant temperature freezes 1~2h at -5~0 DEG C, 0~30 DEG C of heating 4~
5h, 30 DEG C of constant temperature 8~10h, 30~50 DEG C of heatings 2~3h, 50 DEG C of 15~20h of constant temperature.
The beneficial effects of the invention are as follows：A kind of synthetic method of azlocillin sodium of the present invention, passes through rational synthesis technique
Design, is effectively simplified building-up process, makes reaction condition gentle, and exploitativeness is high, and its raw material is easy to get, the controllability of synthesis technique
Preferably, it is easy to industrialized production, the azlocillin sodium yield of gained is high, and purity is big, and the property of medicine is stable, wide market.
Embodiment
Presently preferred embodiments of the present invention is described in detail below so that advantages and features of the invention can be easier to by
It will be appreciated by those skilled in the art that apparent clearly defined so as to be made to protection scope of the present invention.
The embodiment of the present invention includes：
Embodiment 1
（1）Dissolution of raw material：At 5 DEG C, 120ml acetone, 200ml purified waters and 20g ampicillins three is added into retort
Water acid, after stirring, constant temperature is added dropwise triethylamine and clarified completely to solution, is completely dissolved the water acid of ampicillin three；
（2）Condensation reaction：To step（1）Settled solution in be slowly added dropwise with 5ml/min speed and account for step（1）Middle ammonia benzyl west
The 1-Chlorocarbonyl-2-Imidazolidone of the water acid quality 1/2 of woods three, it is stirring evenly and then adding into the pH value of triethylamine regulation mixed solution
For 7.5~10, then in 3~5 DEG C of low-temp reaction 3.5h, ampicillin is set to be condensed with 1-Chlorocarbonyl-2-Imidazolidone
Reaction, generate azlocillin acid solution；
（3）Purified treatment：Stop stirring, to step（2）In add 0.3% medicine for accounting for reaction solution quality in obtained reaction solution
With activated carbon, cover charge door, open stirring, more than decolouring 60min filters decarburization, and by carbon slag with purifying water washing 3 times with
On, will filter gained filtrate and cleaning solution mix after squeeze into successively through delivery pump 0.25 μm of nylon filter core accurate filter and
The sterilizing filter filtration sterilization of 0.20 μm of polyether sulfone filter core, the azlocillin acid solution after being purified；
（4）Prepare finished product azlocillin acid：Under stirring, by step（3）In azlocillin acid after obtained purification it is molten
In liquid add mass concentration be 10% hydrochloric acid, first stirred using 150r/min speed to the pH value of mixed solution as 4, then with
It is 1.8 that 100r/min speed, which is stirred to pH value, then is stirred to crystal with 40r/min speed and separated out completely, is filtered by vacuum, so
Crystal to be washed with acetone afterwards, is 50 DEG C in temperature, vacuum is under 0.03~0.05MPa vacuum, is dried in vacuo more than 8h,
Obtain finished product azlocillin acid；
（5）Salt-forming reaction：It is 1 in mass ratio:6-8 ratio, by step（4）In obtained solid azlocillin be dissolved in 6-8 times
Purified water in, under stirring, sodium hydroxide solution, and the pH of implementing monitoring mixed solution are added dropwise with given pace thereto
Value, when solution becomes clarification, stop being added dropwise；
Wherein, the relation between the concentration and drop rate and pH value of the sodium hydroxide solution is：PH value before 3~3.5,
3.5~4mol/L sodium hydroxide solution is added dropwise with 10~15 drops/min speed, pH value before 5~5.5, with 8~12 drops/
2.5~3mol/L sodium hydroxide solution is added dropwise in min speed, and pH value continues to increase to solution clarification stage, with 8~10 drops/
1.5mol/L sodium hydroxide solution is added dropwise in min speed；
（6）Filtration sterilization：Stop stirring, charge door is opened, to step（5）In add in obtained reaction solution and account for reaction solution quality
0.2% medicinal carbon, after covering lid mouth, stirring is opened, more than decolouring 90min, stops stirring and decolourizes, delivery pump is opened and beats
Return valve is driven, is recycled in optic cup after feed clarification, filtrate pH value is measured by sampling in sample tap, meets step（5）Middle pH value mark
After standard, mixed liquor is squeezed into from reactor to the accurate mistake of decarburizing filter, 0.25 μm of nylon filter core successively by delivery pump
The nano-filtration membrane filter of filter, the sterilizing filter of 0.20 μm of polyether sulfone filter core and 10~50nm filter membrane thickness filtered out
Bacterium, compressed air is opened, the feed liquid remained in conveying system is pressed between input and output material crushing not with 0.10~0.14MPa pressure
The solution being purified in rust steel drum；
（7）Freeze-drying：Feed liquid is fitted into lyophilized plate, is then placed in the cold-trap of freeze dryer and is carried out in advance at -40 DEG C
Freeze 3h, vacuum freeze-drying then is carried out to it again, process conditions are：Under 15~20Pa vacuum, first constant temperature freezes at -35 DEG C
Dry 2h, -20~-5 DEG C of heating 1h, then constant temperature freezes 1h at -5 DEG C, 0~30 DEG C of heating 4h, 30 DEG C of constant temperature 8h, 30~50 DEG C rise
Warm 2h, 50 DEG C of constant temperature 15h；After lyophilized end, the sterilized whole broken machine of treated crushing crushes, and obtains finished product azlocillin sodium powder
End.
Embodiment 2
A kind of synthetic method of azlocillin sodium, comprises the following steps：
（1）Dissolution of raw material：At 12 DEG C, 150ml acetone, 240ml purified waters and 25g ampicillins three are added into retort
Water acid, after stirring, constant temperature is added dropwise triethylamine and clarified completely to solution, is completely dissolved the water acid of ampicillin three；
（2）Condensation reaction：To step（1）Settled solution in be slowly added dropwise with 8ml/min speed and account for step（1）Middle ammonia benzyl west
The 1-Chlorocarbonyl-2-Imidazolidone of the water acid quality 1/2 of woods three, it is stirring evenly and then adding into the pH value of triethylamine regulation mixed solution
For 7.5~10, then in 5 DEG C of low-temp reaction 3.5h, ampicillin is set with 1-Chlorocarbonyl-2-Imidazolidone condensation to occur anti-
Should, generate azlocillin acid solution；
（3）Purified treatment：Stop stirring, to step（2）In add 0.35% medicine for accounting for reaction solution quality in obtained reaction solution
With activated carbon, cover charge door, open stirring, more than decolouring 60min filters decarburization, and by carbon slag with purifying water washing 3 times with
On, will filter gained filtrate and cleaning solution mix after squeeze into successively through delivery pump 0.25 μm of nylon filter core accurate filter and
The sterilizing filter filtration sterilization of 0.20 μm of polyether sulfone filter core, the azlocillin acid solution after being purified；
（4）Prepare finished product azlocillin acid：Under stirring, by step（3）In azlocillin acid after obtained purification it is molten
In liquid add mass concentration be 15% hydrochloric acid, first stirred using 200r/min speed to the pH value of mixed solution as 5, then with
It is 2.5 that 120r/min speed, which is stirred to pH value, then is stirred to crystal with 40~60r/min speed and separated out completely, and vacuum is taken out
Filter, then washs crystal with acetone, is 50 DEG C in temperature, vacuum is under 0.03~0.05MPa vacuum, is dried in vacuo 8h
More than, obtain finished product azlocillin acid；
（5）Salt-forming reaction：It is 1 in mass ratio:6-8 ratio, by step（4）In obtained solid azlocillin be dissolved in 6-8 times
Purified water in, under stirring, sodium hydroxide solution, and the pH of implementing monitoring mixed solution are added dropwise with given pace thereto
Value, when solution becomes clarification, stop being added dropwise；
Wherein, the relation between the concentration and drop rate and pH value of the sodium hydroxide solution is：PH value before 3~3.5,
3.5~4mol/L sodium hydroxide solution is added dropwise with 10~15 drops/min speed, pH value before 5~5.5, with 8~12 drops/
2.5~3mol/L sodium hydroxide solution is added dropwise in min speed, and pH value continues to increase to solution clarification stage, with 8~10 drops/
1.5mol/L sodium hydroxide solution is added dropwise in min speed；
（6）Filtration sterilization：Stop stirring, charge door is opened, to step（5）In add in obtained reaction solution and account for reaction solution quality
0.3% medicinal carbon, after covering lid mouth, stirring is opened, more than decolouring 90min, stops stirring and decolourizes, delivery pump is opened and beats
Return valve is driven, is recycled in optic cup after feed clarification, filtrate pH value is measured by sampling in sample tap, meets step（5）Middle pH value mark
After standard, mixed liquor is squeezed into from reactor to the accurate mistake of decarburizing filter, 0.25 μm of nylon filter core successively by delivery pump
The nano-filtration membrane filter of filter, the sterilizing filter of 0.20 μm of polyether sulfone filter core and 10~50nm filter membrane thickness filtered out
Bacterium, compressed air is opened, the feed liquid remained in conveying system is pressed between input and output material crushing not with 0.10~0.14MPa pressure
The solution being purified in rust steel drum；
（7）Freeze-drying：Feed liquid is fitted into lyophilized plate, is then placed in the cold-trap of freeze dryer and is carried out in advance at -45 DEG C
Freeze 2.5h, vacuum freeze-drying then is carried out to it again, process conditions are：Under 15~20Pa vacuum, the first constant temperature at -20 DEG C
Lyophilized 3h, -20 DEG C~-5 DEG C heating 2h, then constant temperature freezes 2h at 0 DEG C, 0~30 DEG C of heating 5h, 30 DEG C of constant temperature 10h, 30~50
DEG C heating 3h, 50 DEG C of constant temperature 20h；After lyophilized end, the sterilized whole broken machine of treated crushing crushes, and obtains finished product azlocillin
Sodium powder end.
The azlocillin sodium that the above method obtains, after tested, its yield be 90.5~95.5%, product purity be up to 98% with
On.
Embodiments of the invention are the foregoing is only, are not intended to limit the scope of the invention, it is every to utilize this hair
The equivalent structure or equivalent flow conversion that bright description is made, or directly or indirectly it is used in other related technology necks
Domain, it is included within the scope of the present invention.
Claims (9)
1. a kind of synthetic method of azlocillin sodium, it is characterised in that comprise the following steps：
（1）Dissolution of raw material：At a certain temperature, a certain amount of acetone, purified water and the water of ampicillin three are added into retort
Acid, after stirring, constant temperature is added dropwise triethylamine and clarified completely to solution, is completely dissolved the water acid of ampicillin three；
（2）Condensation reaction：First to step（1）Settled solution in be slowly added to a certain amount of 1-Chlorocarbonyl-2-Imidazolidone,
The pH value of triethylamine regulation mixed solution is stirring evenly and then adding into, then low-temp reaction for a period of time, makes ampicillin and 1- chlorine
Condensation reaction occurs for formoxyl -2- imidazolidinones, generates azlocillin acid solution；
（3）Purified treatment：To step（2）In add a certain amount of medicinal carbon in obtained reaction solution, after stirring is decolourized, mistake
Filter decarburization, and carbon slag is multiple with purifying water washing, will filtering gained filtrate and cleaning solution mix after through filter filtration sterilization,
Azlocillin acid solution after being purified；
（4）Prepare finished product azlocillin acid：Under stirring, by step（3）In azlocillin acid after obtained purification it is molten
Hydrochloric acid is added in liquid, adjusts the pH value of mixed liquor to acidity, and continues stirring until azlocillin acid crystal and all separates out, vacuum
Filter, then wash crystal with acetone, vacuum drying obtains finished product azlocillin acid；
（5）Salt-forming reaction：By step（4）In obtained solid azlocillin be dissolved in purified water, under stirring, with a constant speed
Sodium hydroxide solution, and the pH value of implementing monitoring mixed solution is added dropwise in rate thereto, when solution becomes clarification, stops being added dropwise；
（6）Filtration sterilization：To step（5）In add a certain amount of medicinal carbon in obtained reaction solution, after stirring is decolourized, according to
Secondary to carry out filtration sterilization through decarburizing filter, accurate filter, sterilizing filter and nano-filtration membrane filter, what is be purified is molten
Liquid；
（7）Freeze-drying：By step（6）In obtained purified solution load in lyophilized plate, be first placed in the cold-trap of freeze dryer
Row pre-freeze, vacuum freeze-drying is then carried out, obtain finished product azlocillin sodium powder.
2. the synthetic method of azlocillin sodium according to claim 1, it is characterised in that the step（1）In, the temperature
Spend for 5~12 DEG C, the addition of the acetone, purified water and the water of ampicillin three acid is：120~150ml：200~240ml：
20~25g.
3. the synthetic method of azlocillin sodium according to claim 1, it is characterised in that the step（2）In, the 1-
The addition quality of chloroformyl -2- imidazolidinones is step（1）The 1/2 of the middle water acid quality of ampicillin three；The pH value is 7.5
~10；The condition of the condensation reaction is：3~5 DEG C of temperature, 3.5~4h of time.
4. the synthetic method of azlocillin sodium according to claim 1, it is characterised in that the step（3）In, the medicine
With 0.3~0.35% that the addition of activated carbon is reaction solution quality.
5. the synthetic method of azlocillin sodium according to claim 1, it is characterised in that the step（3）In, the mistake
Filter includes accurate filter and sterilizing filter, wherein, the filter core of the accurate filter is 0.25 μm of nylon filter core, institute
State the polyether sulfone filter core that sterilizing filter is 0.20 μm.
6. the synthetic method of azlocillin sodium according to claim 1, it is characterised in that the step（4）In, it is described to add
The mass concentration for entering hydrochloric acid is 10~15%；The pH value is 1.8~2.5；The speed of the stirring is：First with 150~200r/
It is 4~5 that min speed, which is stirred to the pH value of mixed solution, is then stirred using 100~120r/min speed to pH value as 1.8
~2.5, then stirred to crystal with 40~60r/min speed and separated out completely.
7. the synthetic method of azlocillin sodium according to claim 1, it is characterised in that the step（5）In, it is described solid
The mass ratio of body azlocillin and purified water is 1:6-8；Between the concentration and drop rate and pH value of the sodium hydroxide solution
Relation be：3.5~4mol/L sodium hydroxide solution is added dropwise with 10~15 drops/min speed before 3~3.5 for pH value,
2.5~3mol/L sodium hydroxide solution is added dropwise with 8~12 drops/min speed before 5~5.5 for pH value, and pH value continues to increase
Greatly to solution clarification stage, with 8~10 drops/min speed dropwise addition 1.5mol/L sodium hydroxide solution.
8. the synthetic method of azlocillin sodium according to claim 1, it is characterised in that the step（6）In, the medicine
With 0.2~0.3% that the addition of activated carbon is reaction solution quality；The accurate filter, the filter core of sterilizing filter are respectively
0.25 μm of nylon filter core, 0.20 μm of polyether sulfone filter core；The filter membrane thickness of the nano-filtration membrane filter is 10~50nm.
9. the synthetic method of azlocillin sodium according to claim 1, it is characterised in that the step（7）In, it is described pre-
The process conditions of jelly are：Temperature -40~-45 DEG C, 2.5~3h of time；The process conditions of the vacuum freeze-drying are：Vacuum 15~
20Pa, first constant temperature freezes 2~3h, -20 DEG C~-5 DEG C 1~2h of heating at -35~-20 DEG C, then constant temperature freezes at -5~0 DEG C
1~2h, 0~30 DEG C of heating 4~5h, 30 DEG C of constant temperature 8~10h, 30~50 DEG C of heatings 2~3h, 50 DEG C of 15~20h of constant temperature.
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| CN1704418A (en) * | 2004-06-02 | 2005-12-07 | 浙江金华康恩贝生物制药有限公司 | Process for preparing azlocillin sodium |
| CN102161665A (en) * | 2011-05-05 | 2011-08-24 | 苏州二叶制药有限公司 | Preparation method of azlocillin sodium and azlocillin sodium used for injection |
| CN102311450A (en) * | 2011-09-23 | 2012-01-11 | 江苏汉斯通药业有限公司 | Preparation method for Azlocillin sodium |
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2017
- 2017-08-03 CN CN201710656477.9A patent/CN107383061A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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