CN101486717A - Method for preparing ampicillin sodium - Google Patents
Method for preparing ampicillin sodium Download PDFInfo
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- CN101486717A CN101486717A CNA2008100799470A CN200810079947A CN101486717A CN 101486717 A CN101486717 A CN 101486717A CN A2008100799470 A CNA2008100799470 A CN A2008100799470A CN 200810079947 A CN200810079947 A CN 200810079947A CN 101486717 A CN101486717 A CN 101486717A
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- ampicillin
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Abstract
The invention discloses a preparation method of ampicillin sodium, which comprises the steps: (a) a 15%-50% sodium iso-octoate solution is prepared; (b) ampicillin amine slat is prepared: firstly, ampicillin is dissolved in an organic solvent to prepare an organic ampicillin solution which is then dehydrated till the moisture thereof is lower than 1% and then reacts with diisopropylamine; (c) the amine salt obtained from step (b) is pressed into a crystallizing tank and added with the sodium iso-octoate solution for two times, and after crystallization the growing of crystal is carried out; and (d) after the crystallization reaction is finished, separation, washing and menstruum recovering processes are carried out. The preparation method has simple processes and easy operation, is capable of further improving the quality of the finished ampicillin sodium products and being beneficial to the recovery of the menstruum in the technical system, and can effectively reduce the production costs simultaneously.
Description
Technical field
The present invention relates to the preparation method of compound, specifically a kind of preparation method of ampicillin sodium salt.
Background technology
The Ampicillin Trihydrate is semisynthetic penbritin, be that first is applied to clinical wide spectrum semi-synthetic penicillins medicine in the world, be mainly used in the infection such as gram-positive cocci, intestinal bacteria, Bacillus proteus, gas bacillus and hemophilus influenza of penicillin sensitivity, be used for the treatment that urinary system, respiratory system, biliary tract, enteron aisle etc. infect.The method of suitability for industrialized production ampicillin has three kinds at present: spray-drying process, freeze-drying and solvent crystallization.Wherein spray-drying process, freeze-drying be owing to need to use the highly basic agent, and need carry out under comparatively high temps, thus beta-lactam nucleus destroyed easily and degraded, quality index such as the content of resultant product, degradation material and look level all not the person of modern times anticipate.Solvent crystallization is with organic bases the Ampicillin Trihydrate to be dissolved in the organic solvent, adds the organic salt forming agent that contains sodium ion, makes it form replacement(metathesis)reaction, generates the ampicillin crystallization.Though solvent crystallization prepares its quality of ampicillin and is better than other two kinds of methods usually, it still has many improvements of demanding urgently.For example, adopt the clarity of its product of ampicillin of solvent crystallization preparation to stablize inadequately.Existing solvent crystallization adopts following two kinds of methods, i.e. methylene dichloride solvent crystallization and Virahol solvent crystallization usually.Find after deliberation, these two kinds of organic salt forming agents that method adopted are Sodium isooctanoate, and in the finished product remaining isocaprylic acid be cause product clarity instability and the unsteady major cause of quality product [Li Qiuyuan etc. crystallization process of ampicillin sodium. Chinese microbiotic magazine .2005.30 (1): 56].For further improving the final product quality that crystallization process prepares ampicillin, CN1666990 discloses a kind of preparation method of ampicillin, this method is at first dissolved in Sodium isooctanoate and is carried out purifying in the ritalin, Ampicillin Trihydrate three water acid is dissolved in the dehydrated alcohol, with two Isopropylamine reactions again.Behind the reaction solution purifying, the ritalin solution reaction of the Sodium isooctanoate of crossing with purifying again, reaction solution is crystallization in crystallizer, and the gained crystallisate is filtered, washs, is drying to obtain the ampicillin finished product.Though this method has improved the ampicillin final product quality to a certain extent, but still there is the weak point of following several respects in it: 1) because this method has been introduced the dehydrated alcohol (boiling point 78 ℃) close with the boiling point of ritalin (57 ℃ of boiling points) in system, thereby strengthened the difficulty that solvent reclaims, increased manufacturing cost and environmental protection pressure; 2) in crystallizing system,, cause that particle is thin, impurity is many, active constituent content is low because alcoholic acid influence causes crystallisate mostly to be unformed powder greatly; 3) the made crystal solution viscosity height of this method is so increased the difficulty of operations such as separation, washing, drying, whole grain.
Summary of the invention
Purpose of the present invention is exactly the preparation method that a kind of new ampicillin will be provided, this method is simple relatively, and is easy to operate, and it both can further improve the final product quality of ampicillin, be convenient to recycle the solvent in the process system again, also can effectively reduce manufacturing cost simultaneously.
The object of the present invention is achieved like this:
The inventive method may further comprise the steps:
(a) preparation liquid Sodium isooctanoate: according to 1: 0.8～1: 1.3 mol ratio, sodium hydroxide solution added in the isocaprylic acid react, reaction back dephlegmate branch is cooled to below 45 ℃, add organic solvent, be diluted to concentration and be 15%～50% Sodium isooctanoate solution for standby;
Organic solvent in this operation can be selected employed organic solvent in the general solvent crystallization for use, as methylene dichloride, propyl carbinol, Virahol, vinyl acetic monomer etc. or its mixture.
In order further to guarantee that made finished product has good crystal formation, this operation is being distilled when dewatering, and preferably the water content with Sodium isooctanoate solution is controlled at below 1.5%; PH preferably is controlled at 6.5～7.5 in the reaction process of sodium hydroxide solution and isocaprylic acid.
(b) preparation Ampicillin Trihydrate amine salt:, take by weighing Ampicillin Trihydrate and Diisopropylamine according to the mol ratio of 1:1.2～1:3.05; The Ampicillin Trihydrate is dissolved in the organic solvent, makes Ampicillin Trihydrate organic solution; With anhydrous magnesium sulfate Ampicillin Trihydrate organic solution is dewatered to moisture＜1%, again with Diisopropylamine reaction 30～60 minutes, degerming, filtration, filtrate (being the Ampicillin Trihydrate amine salt, hereinafter to be referred as amine salt) is standby;
B〉in the operation organic solvent can with a organic solvent in the operation is identical.
In order further to improve final product quality, at b〉filter cake in the operation preferably adopts the organic solvent repeated washing 1～2 time that contains Diisopropylamine, and filtrate is continued to employ.The organic solvent that contains Diisopropylamine, wherein the mass percent concentration of Diisopropylamine preferably is controlled at 5～25%.In said dehydration, temperature of reaction preferably is controlled at 3～12 ℃.
(c) with b〉prepared amine salt is pressed into crystallizer in the operation, adds a at twice〉prepared Sodium isooctanoate solution in the operation, add 40%～90% of Sodium isooctanoate solution total amount for the first time; Behind the crystallization, growing the grain 30～60 minutes adds residual content again, growing the grain 40～90 minutes;
(d) after crystallization reaction finishes, separate according to routine, washing and solvent reclaim.
Innovation part of the present invention shows the following aspects:
1, the inventive method adopts direct acid-base reaction to prepare the liquid Sodium isooctanoate, make the Sodium isooctanoate that contains alkaline solution participate in salt-forming reaction directly as organic salt forming agent, thereby not only simplified production process, reduced production cost, improved final product quality, the solvent of also having avoided existing method to be caused in purifying Sodium isooctanoate process simultaneously reclaims difficult problem.
2, the present invention adopts the secondary addition method to add Sodium isooctanoate, effectively controlled the generation of the unformed powder of ampicillin, improve and finish brilliant crystalline shape, strengthened the flowability of crystal powder, thereby reduced the difficulty of product in operations such as separation, washing, drying, also omitted whole grain operation simultaneously.
3, the prepared ampicillin finished product of the inventive method has steady quality, and degradation product is low, characteristics such as active constituent content height.
The beneficial effect of the inventive method has been waited until confirmation by following contrast experiment.
| Clarity | The look level | Content is (by the Ampicillin Trihydrate anhydride | Inhale iodine thing (%) | Granularity | (comparing with reference examples) reduces cost | |
| Embodiment 1 product | 0.25# | Yellowish green 1.5# | 94.2％ | 0.3 | 75%＜100 order of gross weight, mobile powder need not whole grain | 15％ |
| Embodiment 2 products | 0.25# | Yellowish green 1.5# | 91.5％ | 0.3 | 75%＜100 order of gross weight, mobile powder need not whole grain | 10％ |
| Embodiment 3 products | 0.25# | Yellowish green 1.5# | 93.1％ | 0.3 | 80%＜100 order of gross weight, mobile powder need not whole grain | 12％ |
| The reference examples product | 0.5# | Yellowish green 2# | 88.6％ | 1.8 | Hard cake needs whole grain | —— |
Annotate: the reference examples product is according to the described method manufacturing of the embodiment of the disclosed preparation ampicillin of CN1666990.
Product quality indicator is measured according to 2005 editions described methods of pharmacopeia.
2005 editions pharmacopeia are to the specification of quality of ampicillin: clarity≤1#, look level≤yellowish green 3#, content (by the Ampicillin Trihydrate anhydride) 〉=85.0%.
Specific implementation method
Embodiment 1
A) preparation of liquid Sodium isooctanoate: at first add the 250L purified water in the alkali batch tank, weighing 75kg sodium hydroxide adds, and is stirred to dissolving.By calculating isocaprylic acid add-on at 1: 1.1, in isocaprylic acid suction retort with the sodium hydroxide mol ratio.The sodium hydroxide solution stirring that configures is pushed down in the retort that is equipped with isocaprylic acid, and PH is controlled between 6.5～7.5, stirs 30 minutes.
Open the jacket steam valve, 85～100 ℃ of Heating temperatures, the vacuum gauge pressure＜-0.06MPa, decompression steams the about 250L of moisture content, add propyl carbinol 200L and azeotropic band water is carried out in heating in debris, endpoint detection is measured Sodium isooctanoate solution contained humidity＜1.25% o'clock, open cool brine to be cooled to≤35 ℃ the time, add about methylene dichloride 800L, being diluted to concentration is to be about 35% Sodium isooctanoate solution for standby.
B) preparation of Ampicillin Trihydrate amine salt: taking by weighing Ampicillin Trihydrate 100kg, is 1: 1.2 according to the mol ratio of Ampicillin Trihydrate and Diisopropylamine, takes by weighing Diisopropylamine; The Ampicillin Trihydrate is dissolved in the 1500L methylene dichloride, makes Ampicillin Trihydrate organic solution; Add anhydrous magnesium sulfate 45kg, temperature is controlled at 3～12 ℃, Ampicillin Trihydrate organic solution is dewatered to moisture＜1% (detect moisture this moment is 0.58%) back adding Diisopropylamine, stir, reacted 30～60 minutes, degerming, filtration, filter cake are with the organic solution repeated washing 1 time that contains 150L methylene dichloride, 7.5L Diisopropylamine, and merging filtrate (being amine salt) back is standby.
C) with b〉prepared amine salt is pressed into crystallizer in the operation, and frequency converter frequency transfers to 30Hz, and 80% of the liquid Sodium isooctanoate that a) operation is prepared adds in the crystallizer, stirs, and growing the grain added the Sodium isooctanoate of residual content after 40 minutes.Growing the grain is 40 minutes again, blowing.
D) after usefulness 120L methylene dichloride washs the wet crystal in crystallizer and the whizzer, dry.The brilliant drying that will wet obtains the ampicillin finished product.After mother liquor washed phase-splitting with purified water, heavy phase was beaten to recovery, and methylene dichloride is reclaimed in 43 ℃ of rectifying of control tower top temperature, reclaims moisture content of finished products 0.5%.The control tower top temperature reclaims propyl carbinol for 117 ℃.
Embodiment 2
A) preparation of liquid Sodium isooctanoate: at first add the 250L purified water in the alkali batch tank, weighing 75kg sodium hydroxide adds, and is stirred to dissolving.By calculating isocaprylic acid dosage at 1: 0.8, in isocaprylic acid suction retort with the sodium hydroxide mol ratio.The sodium hydroxide solution stirring that configures is pushed down in the retort that is equipped with isocaprylic acid, stirred 60 minutes.Open the jacket steam valve, decompression steams the big approximately 200L of moisture content, and azeotropic band water is carried out in adding isopropylcarbinol 300L and heating in debris, endpoint detection mensuration Sodium isooctanoate solution contained humidity＜1.25% o'clock, add isopropylcarbinol again, be diluted to concentration and be 50% Sodium isooctanoate solution for standby.
B) preparation of Ampicillin Trihydrate amine salt: taking by weighing Ampicillin Trihydrate 100kg, is 1: 2.5 according to the mol ratio of Ampicillin Trihydrate and Diisopropylamine, takes by weighing Diisopropylamine; The Ampicillin Trihydrate is dissolved in the 1200L isopropylcarbinol, makes Ampicillin Trihydrate organic solution; Add anhydrous magnesium sulfate 50kg, Ampicillin Trihydrate organic solution is dewatered to moisture＜1%, add Diisopropylamine, stir, reacted 30～60 minutes, degerming, filtration, filtrate (being amine salt) is standby.
C) with b〉prepared amine salt is pressed into crystallizer in the operation, and 40% of the liquid Sodium isooctanoate that a) operation is prepared adds in the crystallizer, stirs, and growing the grain added the Sodium isooctanoate of residual content after 60 minutes.Growing the grain is 90 minutes again, blowing.
D) after crystallization reaction finishes, separate according to routine, washing and solvent reclaim.
Embodiment 3
A) preparation of liquid Sodium isooctanoate: at first add the 250L purified water in the alkali batch tank, weighing 75kg sodium hydroxide adds, and is stirred to dissolving.By calculating isocaprylic acid dosage at 1: 1.3, in isocaprylic acid suction retort with the sodium hydroxide mol ratio.The sodium hydroxide solution stirring that configures is pushed down in the retort that is equipped with isocaprylic acid, stirred 60 minutes.Decompression steams the big approximately 250L of moisture content, be cooled to about 25 ℃ after, add methylene dichloride again, be diluted to concentration and be 15% Sodium isooctanoate solution for standby.
B) preparation of Ampicillin Trihydrate amine salt: taking by weighing Ampicillin Trihydrate 100kg, is 1: 3.0 according to the mol ratio of Ampicillin Trihydrate and Diisopropylamine, takes by weighing Diisopropylamine; The Ampicillin Trihydrate is dissolved in the 1000L methylene dichloride, makes Ampicillin Trihydrate organic solution; Add anhydrous magnesium sulfate 40kg, Ampicillin Trihydrate organic solution is dewatered to moisture＜1%, add Diisopropylamine, stir, reacted degerming, filtration 30～60 minutes, filter cake with the organic solution repeated washing 2 times that contains 100L propyl carbinol, 25L Diisopropylamine after, merging filtrate (being amine salt) is standby.
C) with b〉prepared amine salt is pressed into crystallizer in the operation, and 90% of the liquid Sodium isooctanoate that a) operation is prepared adds in the crystallizer, stirs, and growing the grain added the Sodium isooctanoate of residual content after 30 minutes.Growing the grain is 40 minutes again, blowing.
D) after crystallization reaction finishes, separate according to routine, washing and solvent reclaim.
The foregoing description only is used to further specify the inventive method, and it does not limit the present invention in any form.
Claims (6)
1, a kind of preparation method of ampicillin is characterized in that it may further comprise the steps:
(a) preparation liquid Sodium isooctanoate: according to 1: 0.8～1: 1.3 mol ratio, sodium hydroxide solution added in the isocaprylic acid react, reaction back dephlegmate branch is cooled to below 45 ℃, add organic solvent, be diluted to concentration and be 15%～50% Sodium isooctanoate solution for standby;
(b) preparation Ampicillin Trihydrate amine salt:, take by weighing Ampicillin Trihydrate and Diisopropylamine according to 1: 1.2～1: 3.05 mol ratio; The Ampicillin Trihydrate is dissolved in the organic solvent, makes Ampicillin Trihydrate organic solution; With anhydrous magnesium sulfate Ampicillin Trihydrate organic solution is dewatered to moisture＜1%, again with Diisopropylamine reaction 30～60 minutes, degerming, filtration, filtrate for later use;
(c) with b〉prepared amine salt is pressed into crystallizer in the operation, adds a at twice〉prepared Sodium isooctanoate solution in the operation, add 40%～90% of Sodium isooctanoate solution total amount for the first time, behind the crystallization, growing the grain 30～60 minutes adds residual content again, growing the grain 40～90 minutes;
(d) after crystallization reaction finishes, separate according to routine, washing and solvent reclaim.
2, the preparation method of ampicillin according to claim 1 is characterized in that a〉prepared its contained humidity of Sodium isooctanoate solution＜1.5% in the operation.
3, the preparation method of ampicillin according to claim 1 and 2 is characterized in that b〉said dehydration in the operation, temperature of reaction is controlled at 3～12 ℃.
4, the preparation method of ampicillin according to claim 1 and 2 is characterized in that a〉reaction process of sodium hydroxide solution and isocaprylic acid in the operation, PH is controlled at 6.5～7.5.
5, the preparation method of ampicillin according to claim 1 and 2 is characterized in that b〉filter cake in the operation adopts the organic solvent repeated washing 1～2 time that contains Diisopropylamine, and filtrate is continued to employ.
6, the preparation method of ampicillin according to claim 5 is characterized in that the said mass percent concentration that contains its Diisopropylamine of organic solvent of Diisopropylamine is 5～25%.
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| CNA2008100799470A CN101486717A (en) | 2008-12-05 | 2008-12-05 | Method for preparing ampicillin sodium |
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| WO2011158133A1 (en) * | 2010-06-16 | 2011-12-22 | Vardhman Chemtech Limited | Improved process for preparing amoxicillin sodium |
| CN102399234A (en) * | 2011-12-06 | 2012-04-04 | 苏州中联化学制药有限公司 | Preparation method of cefoxitin sodium |
| CN103467493A (en) * | 2013-10-16 | 2013-12-25 | 华北制药集团先泰药业有限公司 | Preparation method of anhydrous ampicillin |
| 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 |
| CN104644629A (en) * | 2015-01-27 | 2015-05-27 | 华北制药股份有限公司 | Ampicillin sodium sulbactam sodium preparation for injection and preparation method thereof |
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| CN105384755A (en) * | 2015-11-13 | 2016-03-09 | 山东鲁抗医药股份有限公司 | Refining method for improving purity of ampicillin sodium |
| CN115448930A (en) * | 2022-09-02 | 2022-12-09 | 国药集团威奇达药业有限公司 | Process for preparing ampicillin sodium |
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- 2008-12-05 CN CNA2008100799470A patent/CN101486717A/en active Pending
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| CN102971328A (en) * | 2010-06-16 | 2013-03-13 | 瓦尔德曼化学科技股份有限公司 | Improved process for preparing amoxicillin sodium |
| WO2011158133A1 (en) * | 2010-06-16 | 2011-12-22 | Vardhman Chemtech Limited | Improved process for preparing amoxicillin sodium |
| CN102399234A (en) * | 2011-12-06 | 2012-04-04 | 苏州中联化学制药有限公司 | Preparation method of cefoxitin sodium |
| CN103467493A (en) * | 2013-10-16 | 2013-12-25 | 华北制药集团先泰药业有限公司 | Preparation method of anhydrous ampicillin |
| CN103467493B (en) * | 2013-10-16 | 2016-01-20 | 华北制药集团先泰药业有限公司 | The preparation method of ampicillin anhydrous |
| CN103880863B (en) * | 2014-03-27 | 2015-10-28 | 哈药集团制药总厂 | A kind of preparation method of ampicillin |
| CN103880863A (en) * | 2014-03-27 | 2014-06-25 | 哈药集团制药总厂 | Preparation method of ampicillin sodium |
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| 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 |
| CN104644629A (en) * | 2015-01-27 | 2015-05-27 | 华北制药股份有限公司 | Ampicillin sodium sulbactam sodium preparation for injection and preparation method thereof |
| CN104961748A (en) * | 2015-05-22 | 2015-10-07 | 华北制药集团先泰药业有限公司 | Method for reducing residual quantity of dichloromethane in ampicillin |
| CN104961748B (en) * | 2015-05-22 | 2017-03-01 | 华北制药集团先泰药业有限公司 | A kind of method of residual dichloromethane level in reduction ampicillin |
| 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 |
| CN105384755A (en) * | 2015-11-13 | 2016-03-09 | 山东鲁抗医药股份有限公司 | Refining method for improving purity of ampicillin sodium |
| CN115448930A (en) * | 2022-09-02 | 2022-12-09 | 国药集团威奇达药业有限公司 | Process for preparing ampicillin sodium |
| CN115448930B (en) * | 2022-09-02 | 2024-10-01 | 国药集团威奇达药业有限公司 | Preparation method of ampicillin sodium |
| CN115850298A (en) * | 2022-11-29 | 2023-03-28 | 华北制药集团先泰药业有限公司 | Ampicillin sodium raw powder and preparation method thereof |
| WO2024113658A1 (en) * | 2022-11-29 | 2024-06-06 | 华北制药集团先泰药业有限公司 | Ampicillin sodium raw powder and preparation method therefor |
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Open date: 20090722 |