CN104151324A - Method for preparing ampicillin sodium by menstruum crystallization method - Google Patents
Method for preparing ampicillin sodium by menstruum crystallization method Download PDFInfo
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- CN104151324A CN104151324A CN201410446587.9A CN201410446587A CN104151324A CN 104151324 A CN104151324 A CN 104151324A CN 201410446587 A CN201410446587 A CN 201410446587A CN 104151324 A CN104151324 A CN 104151324A
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- ampicillin
- crystallization
- sodium
- dichloromethane
- methylene dichloride
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- 0 CC(C)(C1C(*)=O)SC(C2NCC(C(c3ccccc3)N)=O)N1C2=O Chemical compound CC(C)(C1C(*)=O)SC(C2NCC(C(c3ccccc3)N)=O)N1C2=O 0.000 description 1
- ZCYJCZZRELKUKO-UHFFFAOYSA-N CC(C)(C1C(O)=O)SC(C2NCC(C(c3ccccc3)N)=O)N1C2=O Chemical compound CC(C)(C1C(O)=O)SC(C2NCC(C(c3ccccc3)N)=O)N1C2=O ZCYJCZZRELKUKO-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
- C07D499/18—Separation; Purification
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for preparing ampicillin sodium by a menstruum crystallization method. The method comprises the following steps: firstly, dissolving sodium 2-ethylhexanoate into methanol, controlling the temperature to 15 DEG C, adding ampicillin acid into dichloromethane, and dripping diisopropylamine for a dissolution reaction; adding a sodium 2-ethylhexanoate solution into a crystallization tank, then adding a dichloromethane liquation agent in a flowing manner, and adding a seed crystal for growing crystals in a standing manner; then adding the dichloromethane liquation agent for crystallization; controlling the crystallization temperature to 20-25 DEG C; controlling the flowing acceleration of the liquation agent to 100 ml/h; after the crystallization reaction is completed, discharging materials, filtering the discharged materials, and drying the filtered materials to obtain the ampicillin sodium. According to the method, the methanol solvent, in which the ampicillin sodium is easy to dissolve, is selected for use, and then the dichloromethane solvent is used for dissolving out products, so that the crystallization speed of the product can be controlled; in addition, measures of adding the seed crystal for growing the crystal, controlling the dissolving temperature and the crystallization temperature, controlling the flowing acceleration of the liquation agent and the like are taken, so that the crystallization speed can be controlled, the crystal nucleus of the product are enlarged and uniform, the product purity is high, the dissolving residue is low, and the quality is stable.
Description
Technical field
The present invention relates to a kind of preparation method of ampicillin, belong to medical technical field.
Background technology
Ampicillin is first-generation wide spectrum semisynthetic penicillin, by Pfizer, in 1962, developed, and go on the market in nineteen sixty-five production, along with the development of synthetic technology, penicillin has developed into the s-generation, third generation semisynthetic penicillin now.As first-generation semisynthetic penicillin, ampicillin has wide spectrum, low toxicity, the feature such as efficient and cheap.Can be for intramuscularly or intravenous injection.Extensively in order to treat upper and lower respiratory tract infection due to sensitive bacterial, gastrointestinal tract infection, urinary tract infections, skin, soft tissue infection, meningitis, septicemia, endocarditis etc.
At present, the Ampicillin Trihydrate production method of sodium for suitability for industrialized production has three kinds: spray-drying process, freeze-drying and solvent crystallization.Due to the difference of production method, the activeconstituents of ampicillin is also not quite similar the suffered destruction of production process.According to not acid-and base-resisting of Ampicillin Trihydrate and hot feature, spray dry, cryochem are because needs are used highly basic agent sodium hydroxide, add and will under comparatively high temps, carry out, lactam nucleus is easily destroyed and is degraded, and the quality index such as the content of resulting product, degradation material and look level are poor than solvent crystallization obviously.
Solvent crystallization is with organic bases, Ampicillin Trihydrate acid to be dissolved in organic solvent, adds the organic salt forming agent that contains sodium ion, makes it carry out replacement(metathesis)reaction, generates ampicillin xln.Through update search, go out the patent documentation about Ampicillin Trihydrate sodium solvent crystal, its production process mainly contains two steps and forms, first be that the diisopropyl amine salt that generates Ampicillin Trihydrate is reacted in Ampicillin Trihydrate acid with Diisopropylamine, then in the solution obtaining, add salt forming agent reactive crystallization to obtain ampicillin (as shown in reaction equation 1).Crystalline product prepared by aforesaid method, easily there are some problems in product, as bigger than normal in dipolymer, and anaphylaxis easily occurs during clinical application; Isocaprylic acid is residual easily to exceed standard, and affects clarity and the stability of product; There is agglomeration phenomena in product; The inhomogeneous series of problems that waits of size-grade distribution, has a strong impact on the quality of product.
Patent application 201410117746.0 discloses a kind of preparation method of ampicillin, and in the method, ampicillin is crystallization at high temperature, and Tc has reached 50～60 ℃, has used high boiling point single solvent---Virahol.Through overtesting comparison, during high temperature crystallization, particularly temperature has surpassed 50 ℃, and in its product, the index of dipolymer rises highlyer, has reached 3% level.Patent 200410008807.6 discloses a kind of preparation method of ampicillin, and the method is used the three water acid of dissolve with ethanol Ampicillin Trihydrate, uses ritalin dissolution with solvents Sodium isooctanoate, low temperature crystallization at low temperature-2～2 ℃.The ampicillin quality of this invention preparation is better than like product.The method is due to low temperature, and crystallization is too quick, and isocaprylic acid and solvent are easily wrapped in crystal, causes isocaprylic acid and dissolvent residual higher, thereby affects the clarity of product.Patent application 200810079947.0 discloses a kind of preparation method of ampicillin, the method has been prepared Sodium isooctanoate liquid with isocaprylic acid and sodium hydroxide, in dichloromethane solvent, prepare the Diisopropylamine salts solution with the Ampicillin Trihydrate of anhydrous magnesium sulfate dehydration, then Sodium isooctanoate solution is poured into salify in the Diisopropylamine solution of Ampicillin Trihydrate.The shortcoming of the method is uncontrollable crystallization velocity equally, causes product crystallization fast, causes propyl carbinol parcel wherein, molten residual height, and powder is careful little, and size-grade distribution is uneven, is not easy to packing.And Ampicillin Trihydrate amine salt need to be used anhydrous magnesium sulfate processed, complex operation, solvent recuperation trouble.
Summary of the invention
The preparation method who the object of this invention is to provide a kind of ampicillin, the method can crystallization control speed, makes the isocaprylic acid of product residual low, and the large and homogeneous of product granularity, is easy to packing.Steady quality higher than 2010 editions standards of pharmacopoeia, solvent recuperation is simple.
Technical scheme of the present invention is: a kind of solvent crystallization is prepared the method for ampicillin, it is characterized in that,
(1) configuration of Sodium isooctanoate solution: Sodium isooctanoate is dissolved in methyl alcohol, by the sterile filtration of resulting Sodium isooctanoate solution, uses dichloromethane rinse pipeline, merge washing lotion and filtrate to the storage tank of crystallizing field;
(2) preparation of Ampicillin Trihydrate amine salt: by the recirculated water in chuck, control 15 ℃ of temperature, Ampicillin Trihydrate acid is added in methylene dichloride, drip Diisopropylamine and carry out solubilizing reaction; Reacted rear reaction solution sterile filtration to crystallizer, used washed with dichloromethane pipeline, washing lotion is also filtered to crystallizer;
(3) crystallization: Sodium isooctanoate solution is joined in crystallizer, then add 4.8-5.2 doubly to measure the methylene dichloride dissolved agent of (with respect to quantity of methyl alcohol, by volume) toward stream in crystallizer; Then add the standing growing the grain 10-30 minute of crystal seed; And then the methylene dichloride dissolved agent that adds 4.8-5.2 doubly to measure (with respect to quantity of methyl alcohol, by volume), stir 25-35 minute; The Tc that the present invention controls in whole crystallisation process is 20～25 ℃; The flow acceleration of controlling dissolved agent methylene dichloride is 100ml/h;
(4) crystallization reaction finishes rear blowing, filters, and uses washed with dichloromethane filter cake, and filtrate and washing lotion are recycled; Filter cake first dries up post-drying with nitrogen at 40 ℃, obtains ampicillin sodium salt.
Preferably, the methylene dichloride consumption of described step (2) be methanol usage (volume) 2.5-3 doubly.
Preferably, the consumption of described crystal seed is 0.1% of Ampicillin Trihydrate acid quality.
Preferably, the acid of described Ampicillin Trihydrate is 1:1.2-1.5 with the mol ratio of Diisopropylamine, and Ampicillin Trihydrate acid is 1:1.02-1.1 with the mol ratio of Sodium isooctanoate.
The invention has the beneficial effects as follows: select ampicillin is easy to the methanol solvate dissolving, and then add that dissolved agent---dichloromethane solvent is separated out product, so just can control the speed of product crystallization; In addition, add 0.1% crystal seed growing the grain, control solvent temperature at 15 ℃, the means such as 20～25 ℃ of Tcs, the flow acceleration of controlling dissolved agent are 100ml/h, can make crystallization velocity controlled, the nucleus of product becomes large and homogeneous, and the purity of product is high, molten residual low, steady quality.
(1) compare with patent application 201410117746.0, Tc of the present invention obviously reduces, and this patent is 50～60 ℃, the present invention is 15 ℃, due under hot conditions, product is easy to degraded, and in the present invention, the dipolymer index of product is obviously much lower compared with patent.The solvent of using in patent is Virahol, and recovery complexity, need to use distillation tower and the rate of recovery is low; It is crystallization solvent that the present invention adopts methylene dichloride, easily recycles;
(2) with Chinese patent CN200410008807.6 comparison, the preparation method of this patent is due to low temperature, and crystallization is too quick, and isocaprylic acid and solvent are easily wrapped in crystal, cause isocaprylic acid and dissolvent residual higher, thereby affect the clarity of product.The present invention, by the means such as flow acceleration of crystal seed growing the grain, crystallization control temperature, the agent of control dissolved, can make crystallization velocity controlled, the main granularity of product is increased, size-grade distribution homogeneous;
(3) with Chinese patent CN200810079947.0 comparison, the shortcoming of this patent is uncontrollable crystallization velocity equally, causes product crystallization fast, causes propyl carbinol parcel wherein, molten residual height, and size-grade distribution is uneven.And Ampicillin Trihydrate amine salt need to be used anhydrous magnesium sulfate processed, complex operation, solvent recuperation trouble.The present invention can crystallization control speed, and aftertreatment is simple.
Accompanying drawing explanation
Fig. 1 be the present invention and patent documentation 201410117746.0 (CN103880863A), CN200410008807.6 and CN200810079947.0 main size ratio.
Embodiment
Embodiment 1
(1) preparation of Sodium isooctanoate: the Sodium isooctanoate of 45 kilograms is dissolved in 90 liters of methyl alcohol, the sterile filtration of gained solution, to crystallizer, with 50 liters of dichloromethane rinse pipelines, is also filtered washing lotion in the storage tank of squeezing into crystallizing field, standby;
(2) preparation of Ampicillin Trihydrate amine salt: squeeze into 200 liters of methylene dichloride in material-compound tank, by chuck, be cooled to 15 ℃, add the three water acid of 100 kilograms of Ampicillin Trihydrates, then drip 45 liters of Diisopropylamines, Ampicillin Trihydrate acid is dissolved gradually and is become clear, by the sterile filtration of gained clear liquid to crystallizer, with 50 liters of washed with dichloromethane pipelines;
(3) Sodium isooctanoate solution is proceeded in crystallizer, stream adds the methylene dichloride of 450 liters; Then the ampicillin crystal seed that adds 0.1 kilogram, static growing the grain 30 minutes; Treat that feed liquid becomes muddy, nucleus increases after precipitation, opens and stirs, more slowly add 450 liters of methylene dichloride, after adding, stirs 30 minutes; The Tc that the present embodiment is controlled in whole crystallisation process is 20～25 ℃; The flow acceleration of controlling dissolved agent methylene dichloride is 100ml/h;
(4) be then discharged in three-in-one filter, with 100 liters of washed with dichloromethane filter cakes, at 40 ℃, nitrogen dries up oven dry.Obtain 76 kilograms of ampicillin sodium salts, molar yield 83%.
The patent documentation 201410117746.0,200810069947.0 of the product of embodiment 1 preparation and 20041000807.6 have substances content (dipolymer, single the unknown and other impurity) relatively in Table 1, main size ratio is shown in Fig. 1.From table 1 and Fig. 1, can find out: with respect to existing patent documentation, its its related substances reduces greatly, and granularity is large, is evenly distributed.
The comparative experimental example of table 1 the present invention and pertinent literature
Embodiment 2
(1) preparation of Sodium isooctanoate: the Sodium isooctanoate of 45 kilograms is dissolved in 90 liters of methyl alcohol, the sterile filtration of gained solution, to crystallizer, with 45 liters of dichloromethane rinse pipelines, is also filtered washing lotion in the storage tank of squeezing into crystallizing field, standby;
(2) preparation of Ampicillin Trihydrate amine salt: control temperature at 15 ℃, the three water acid of 100 kilograms of Ampicillin Trihydrates are joined in 220 liters of methylene dichloride, drip 45 liters of Diisopropylamines, Ampicillin Trihydrate acid is dissolved gradually and is become clear, by the sterile filtration of gained clear liquid to crystallizer, with 40 liters of washed with dichloromethane pipelines;
(3) Sodium isooctanoate solution is proceeded in crystallizer; Stream adds the methylene dichloride of 420 liters, then adds the ampicillin crystal seed of 0.1 kilogram, and static growing the grain 20 minutes treats that feed liquid becomes muddy, and nucleus increases after precipitation; Open and stir, more slowly add 480 liters of methylene dichloride; After adding, stir 35 minutes; The Tc that the present embodiment is controlled in whole crystallisation process is 20～25 ℃; The flow acceleration of controlling dissolved agent methylene dichloride is 100ml/h;
(4) be then discharged in three-in-one filter, with 100 liters of washed with dichloromethane filter cakes, at 40 ℃, nitrogen dries up oven dry.Obtain 76.5 kilograms of ampicillin sodium salts, molar yield 84%.
Claims (5)
1. solvent crystallization is prepared a method for ampicillin, it is characterized in that,
(1) configuration of Sodium isooctanoate solution: Sodium isooctanoate is dissolved in methyl alcohol, by the sterile filtration of resulting Sodium isooctanoate solution, uses dichloromethane rinse pipeline, merge washing lotion and filtrate to the storage tank of crystallizing field;
(2) preparation of Ampicillin Trihydrate amine salt: control 15 ℃ of temperature, Ampicillin Trihydrate acid is added in methylene dichloride, drip Diisopropylamine and carry out solubilizing reaction; Reacted rear reaction solution sterile filtration to crystallizer, used washed with dichloromethane pipeline, washing lotion is also filtered to crystallizer;
(3) crystallization: Sodium isooctanoate solution is joined in crystallizer, and the methylene dichloride dissolved agent that then adds 4.5-5.5 doubly to measure toward stream in crystallizer, then adds the standing growing the grain 10-30 minute of crystal seed; And then the methylene dichloride dissolved agent that adds 4.5-5.5 doubly to measure, stir 25-35 minute; The Tc of controlling in whole crystallisation process is 20～25 ℃; The flow acceleration of controlling dissolved agent methylene dichloride is 100ml/h; The consumption of described methylene dichloride dissolved agent is the volumeter with the methyl alcohol of step (1);
(4) crystallization reaction finishes rear blowing, filters, and uses washed with dichloromethane filter cake, and filtrate and washing lotion are recycled; Filter cake first dries up post-drying with nitrogen at 40 ℃, obtains ampicillin sodium salt.
2. a kind of solvent crystallization as claimed in claim 1 is prepared the method for ampicillin, it is characterized in that, the consumption of described crystal seed is 0.1% of Ampicillin Trihydrate acid quality.
3. a kind of solvent crystallization as claimed in claim 1 is prepared the method for ampicillin, it is characterized in that, the acid of described Ampicillin Trihydrate is 1:1.2-1.5 with the mol ratio of Diisopropylamine.
4. a kind of solvent crystallization as claimed in claim 1 is prepared the method for ampicillin, it is characterized in that, the acid of described Ampicillin Trihydrate is 1:1.02-1.1 with the mol ratio of Sodium isooctanoate.
5. the solvent crystallization as described in any one in claim 1-4 is prepared the method for ampicillin, it is characterized in that, the methylene dichloride consumption of described step (2) is 2.5-3 times of methyl alcohol volume.
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| CN201410446587.9A CN104151324B (en) | 2014-09-03 | 2014-09-03 | A kind of solvent crystallization prepares the method for ampicillin |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
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| CN1666990A (en) * | 2004-03-12 | 2005-09-14 | 河北张药股份有限公司 | Process for preparing ampicillin sodium |
| WO2007105253A2 (en) * | 2006-03-15 | 2007-09-20 | Carthesia S.A.S. Di Emanuela Migliavacca & C. | PREPARATION OF (1-OXA- OR l-THIA-)3- CEPHEM DERIVATIVES |
| CN101486717A (en) * | 2008-12-05 | 2009-07-22 | 华北制药股份有限公司 | Method for preparing ampicillin sodium |
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2014
- 2014-09-03 CN CN201410446587.9A patent/CN104151324B/en active Active
Patent Citations (3)
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| CN1666990A (en) * | 2004-03-12 | 2005-09-14 | 河北张药股份有限公司 | Process for preparing ampicillin sodium |
| WO2007105253A2 (en) * | 2006-03-15 | 2007-09-20 | Carthesia S.A.S. Di Emanuela Migliavacca & C. | PREPARATION OF (1-OXA- OR l-THIA-)3- CEPHEM DERIVATIVES |
| CN101486717A (en) * | 2008-12-05 | 2009-07-22 | 华北制药股份有限公司 | Method for preparing ampicillin sodium |
Non-Patent Citations (1)
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| 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》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
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| CN104151324B (en) | 2016-08-24 |
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Effective date of registration: 20200302 Address after: No. 10678, Wenliang Road, Dongjia street, Licheng District, Jinan City, Shandong Province Patentee after: Shandong Anxin Pharmaceutical Co., Ltd Address before: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Patentee before: QILU TIANHE PHARMACEUTICAL Co.,Ltd. |