CN101475578A - Flucloxacillin sodium compound and preparation thereof - Google Patents
Flucloxacillin sodium compound and preparation thereof Download PDFInfo
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- CN101475578A CN101475578A CNA2009100076283A CN200910007628A CN101475578A CN 101475578 A CN101475578 A CN 101475578A CN A2009100076283 A CNA2009100076283 A CN A2009100076283A CN 200910007628 A CN200910007628 A CN 200910007628A CN 101475578 A CN101475578 A CN 101475578A
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- flucloxacillin
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- dibenzyl ethylenediamine
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Abstract
The invention discloses a flucloxacillin sodium compound and a method for preparing the same. The method comprises that: firstly, N'N-dibenzylethylene diamine salt and flucloxacillin acid are mixed and reacted to form a salt; and secondly, high-purity flucloxacillin sodium is obtained through the displacement of a cation exchange resin. The invention adopts a purification method which is simple and easy to operate, thereby greatly improving the purity of the flucloxacillin sodium compound to a certain degree, removing a large amount of high molecular polymers, stabilizing the product quality of related preparations and ensuring the safety of clinic medication use.
Description
Technical field
The present invention relates to a kind of flucloxacillin sodium compound and preparation method thereof.
Background technology
Sodium flucloxacillin, chemistry is by name: (2S, 5R, 6R)-6-[[3-(2-chloro-6-fluorophenyl)-5-methyl isophthalic acid, 2-oxazole-4-formyl] amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid sodium salt, belong to the 4th Dai isoxazole penicillin, play powerful germicidal action by the biosynthesizing that suppresses the glutinous peptide of bacteria cell wall, antimicrobial spectrum is wide than penicillin, acidproof anti-enzyme has very strong sterilizing activity to penicillin resistance staphylococcus etc.The structural formula of Sodium flucloxacillin is:
The loaded British Pharmacopoeia of Sodium flucloxacillin version in 2000, the listing preparation has injection and oral preparations at present, domestic production producer is less, exists purity difference to cause the unsettled defective of quality mostly, and a large amount of high molecular polymers has had a strong impact on its clinical application safety.Isolate superpolymer, the purifying Sodium flucloxacillin can be prepared high-quality related preparations and pharmaceutical composition thereof.
Be difficult to separate with traditional solvent extraction method, by chromatogram purification, the lyophilize separation and purification, step is complicated and loaded down with trivial details.United States Patent (USP) 4737492 and European patent application EP 0399094 have been described other cynnematin antimicrobial double benzyl ethylenediamine salt.United States Patent (USP) 4737492 has been described cefadole double benzyl ethylenediamine salt used in the ophthalmia composition.European patent application EP 0399094 has been described improving one's methods of preparation Ro-13-9904.Its common feature is that medicine passes through and the double benzyl ethylenediamine salify, reaches the purpose of purifying, carries out ion exchange again, thereby obtains the corresponding salt of required medicine, but this process reduces the productive rate of product.
Summary of the invention
At the problems referred to above, the invention provides a kind of purification process of Sodium flucloxacillin, this purification process is simple to operation, does not influence the productive rate of product.
For solving the problems of the technologies described above, technical scheme provided by the present invention is: a kind of preparation method of flucloxacillin sodium compound, earlier N ' N-dibenzyl ethylenediamine salt and Flucloxacillin acid hybrid reaction are generated salt, and then obtain highly purified Sodium flucloxacillin with the Zeo-karb displacement.
The preparation of described Flucloxacillin N ' N-dibenzyl ethylenediamine salt: will need the Sodium flucloxacillin of purifying water-soluble, regulating the pH value is 2.0～8.0, add organic solvent then, add N ' N-dibenzyl ethylenediamine salt again, add-on is 0.5～4:1 with the molar equivalent ratio of Sodium flucloxacillin, mixes and stirs 3～5 hours, filters then, drying gets Flucloxacillin N ' N-dibenzyl ethylenediamine salt crystal.
Described Sodium flucloxacillin pH value of solution value is adjusted to 3.0～4.0.
The add-on of described N ' N-dibenzyl ethylenediamine salt is 2.2～2.5:1 with the molar equivalent ratio of Sodium flucloxacillin.
Described organic solvent is a methyl alcohol.
The preparation of described Flucloxacillin sodium salt:
(1) Flucloxacillin N ' N-dibenzyl ethylenediamine salt is suspended in ethanol, methyl alcohol or the water, wherein the volume ratio of the quality of salt and solvent is 1 kilogram: 5～30 liters;
(2) stir, add strong acid or storng-acid cation exchange resin, the ratio of weight and number of its add-on and Flucloxacillin N ' N-dibenzyl ethylenediamine salt is 1～10:1;
(3) 5～35 ℃ of dissolvings are complete, and the filtering resin drips the sodium salt that dissolves in organic solvent in filtrate, regulate pH value of filtrate and reach 5～6;
(4) at 5～15 ℃, stirred 2～5 hours, separate out product, drying gets the Flucloxacillin sodium salt.
The quality of described Flucloxacillin N ' N-dibenzyl ethylenediamine salt and the volume ratio of solvent are 1 kilogram: 10～20 liters.
The ratio of weight and number of the add-on of described strong acid or storng-acid cation exchange resin and Flucloxacillin N ' N-dibenzyl ethylenediamine salt is 1～3:1.
The described sodium salt that dissolves in organic solvent is a 2 ethyl hexanoic acid sodium, Sodium.alpha.-hydroxypropionate or sodium acetate or highly basic such as aqueous sodium hydroxide solution or sodium alkoxide.
The temperature of described step (4) is 5～10 ℃.
A kind of flucloxacillin sodium compound, this compound are to adopt earlier N ' N-dibenzyl ethylenediamine salt and Flucloxacillin acid hybrid reaction are generated salt, and then obtain with the Zeo-karb displacement.
The advantage that the present invention has: this purification process is simple to operation, has improved the purity of Sodium flucloxacillin to a certain extent greatly, has removed a large amount of high molecular polymers, has stablized the quality product of related preparations, has guaranteed clinical drug safety.
Embodiment:
The invention will be further described below in conjunction with specific embodiment, to help understanding content of the present invention.
Embodiment 1
The preparation of i, Flucloxacillin N ' N-dibenzyl ethylenediamine salt
951.7g is dissolved in 15L water with the 2mol Sodium flucloxacillin, with salt acid for adjusting pH value to 3.0, adds methyl alcohol 8.5L then, add 4.4mol N ' N-dibenzyl-ethylenediamin diacetate salt 1576.6g again, mixed stirring reaction 3 hours at 20～25 ℃, produce white solid, reaction mixture is cooled to 10～15 ℃, filter, white solid washes with water three times, uses methanol wash again three times, 30～35 ℃ of vacuum-dryings, get solid 1136.8g, productive rate 98.8%.The crystalline melting range is 192～198 ℃, first water, and obtaining fusing point with this salt of methanol wash again is 195～198 ℃ product, analyzes to show that crystal is a N ' N-dibenzyl-ethylenediamin: Flucloxacillin acid is 1; 1 mixture.
The preparation of ii, Flucloxacillin sodium salt
N ' N-dibenzyl ethylenediamine salt crystal 1100g is suspended in the 11L ethanol with the Flucloxacillin, in stirred suspension, add Amberlyst 15 resin 2200g, be stirred to Flucloxacillin N ' N-dibenzyl ethylenediamine salt dissolving and obtain a settled solution at 5～35 ℃, the filtering resin, the alcohol sodium solution of Dropwise 5 in filtrate～10 ℃, reach 5.5 to filtrate pH value, separate out the white solid precipitation, keep stirring 3 hours under 5～10 ℃ of temperature condition, filter, drying gets Flucloxacillin sodium salt 711.3g.
Embodiment 2
The preparation of i, Flucloxacillin N ' N-dibenzyl ethylenediamine salt
1427.4g is dissolved in 25L water with the 3mol Sodium flucloxacillin, with second acid for adjusting pH value to 4.0, adds acetone 9.5L then, add 1.5mol N ' N-dibenzyl-ethylenediamin diacetate salt 537.5g again, mixed stirring reaction 5 hours at 20～25 ℃, produce white solid, reaction mixture is cooled to 10～15 ℃, filter, white solid washes with water three times, uses washing with acetone again three times, 30～35 ℃ of vacuum-dryings, get solid 1536.8g, productive rate 99.1%.The crystalline melting range is 192～198 ℃, first water, and obtaining fusing point with this salt of washing with acetone again is 195～198 ℃ product, analyzes to show that crystal is a N ' N-dibenzyl-ethylenediamin: Flucloxacillin acid is the mixture of 1.2:1.
The preparation of ii, Flucloxacillin sodium salt
N ' N-dibenzyl ethylenediamine salt crystal 1200g is suspended in the 6L ethanol with the Flucloxacillin, in stirred suspension, add Duolite ES-280 resin 1200g, be stirred to Flucloxacillin N ' N-dibenzyl ethylenediamine salt dissolving and obtain a settled solution at 5～35 ℃, the filtering resin, in filtrate, drip 10～15 ℃ alcohol sodium solution, reach 6 to filtrate pH value, separate out the white solid precipitation, keep stirring 2 hours under 5～7 ℃ of temperature condition, filter, drying gets Flucloxacillin sodium salt 731.3g.
Embodiment 3
The preparation of i, Flucloxacillin N ' N-dibenzyl ethylenediamine salt
475.8g is dissolved in 5L water with the 1mol Sodium flucloxacillin, with salt acid for adjusting pH value to 4.0～5.0, adds acetonitrile 4.5L then, add 4mol N ' N-dibenzyl-ethylenediamin diacetate salt 1433g again, mixed stirring reaction 4 hours at 20～25 ℃, produce white solid, reaction mixture is cooled to 10～15 ℃, filter, white solid washes with water three times, again with acetonitrile washing three times, 30～35 ℃ of vacuum-dryings, get solid 566.8g, productive rate 98.7%.The crystalline melting range is 192～198 ℃, first water, and washing this salt with acetonitrile again, to obtain fusing point be 195～198 ℃ product, analyze to show that crystal is a N ' N-dibenzyl-ethylenediamin: Flucloxacillin acid is the mixture of 1:1.1.
The preparation of ii, Flucloxacillin sodium salt
N ' N-dibenzyl ethylenediamine salt crystal 5 00g is suspended in the 10L ethanol with the Flucloxacillin, in stirred suspension, adds Thermax T-63 resin 5000g, be stirred to Flucloxacillin N ' N-dibenzyl ethylenediamine salt dissolving and obtain a settled solution at 5～35 ℃, the filtering resin drips 10～15 ℃ alcohol sodium solution in filtrate, reach 6 to filtrate pH value, separate out the white solid precipitation, keep stirring 4 hours under 6～8 ℃ of temperature condition, filter, drying gets Flucloxacillin sodium salt 261.3g.
Embodiment 4
The preparation of i, Flucloxacillin N ' N-dibenzyl ethylenediamine salt
237.9g is dissolved in 2.5L water with the 0.5mol Sodium flucloxacillin, with sulphur acid for adjusting pH value to 6.0～7.0, add dimethyl sulfoxide (DMSO) then, dimethyl formamide, ethyl acetate or methyl ethyl ketone 2.5L, add 2mol N ' N-dibenzyl-ethylenediamin diacetate salt 714.8g again, mixed stirring reaction 5 hours at 20～25 ℃, produce white solid, reaction mixture is cooled to 10～15 ℃, filter, white solid washes with water three times, uses dimethyl sulfoxide (DMSO) again, dimethyl formamide, ethyl acetate or methyl ethyl ketone washing three times, 30～35 ℃ of vacuum-dryings, get solid 288.9g, productive rate 98.8%.The crystalline melting range is 192～198 ℃, elder generation's water, washing this salt with dimethyl sulfoxide (DMSO), dimethyl formamide, ethyl acetate or methyl ethyl ketone again, to obtain fusing point be 195～198 ℃ product, and analyze to show that crystal is a N ' N-dibenzyl-ethylenediamin: Flucloxacillin acid is the mixture of 1:1.2.
The preparation of ii, Flucloxacillin sodium salt
N ' N-dibenzyl ethylenediamine salt crystal 2 00g is suspended in the 6L ethanol with the Flucloxacillin, in stirred suspension, add Amberlite IR-120 resin 600g, be stirred to Flucloxacillin N ' N-dibenzyl ethylenediamine salt dissolving and obtain a settled solution at 5～35 ℃, the filtering resin, in filtrate, drip 10～15 ℃ alcohol sodium solution, reach 5.6 to filtrate pH value, separate out the white solid precipitation, keep stirring 5 hours under 9～10 ℃ of temperature condition, filter, drying gets Flucloxacillin sodium salt 106.3g.
Embodiment 5
The preparation of i, Flucloxacillin N ' N-dibenzyl ethylenediamine salt
713.7g is dissolved in 7.5L water with the 1.5mol Sodium flucloxacillin, with salt acid for adjusting pH value to 7.0～8.0, add ethanol then, Virahol, tetrahydrofuran (THF), toluene or methyl iso-butyl ketone (MIBK) 6.5L, add 3.0molN ' N-dibenzyl-ethylenediamin diacetate salt 1074.7g again, mixed stirring reaction 5 hours at 20～25 ℃, produce white solid, reaction mixture is cooled to 10～15 ℃, filter, white solid washes with water three times, uses ethanol again, Virahol, tetrahydrofuran (THF), toluene or methyl iso-butyl ketone (MIBK) washing three times, 30～35 ℃ of vacuum-dryings, get solid 748.9g, productive rate 98.9%.The crystalline melting range is 192～198 ℃, elder generation's water, washing this salt with ethanol, Virahol, tetrahydrofuran (THF), toluene or methyl iso-butyl ketone (MIBK) again, to obtain fusing point be 195～198 ℃ product, and analyze to show that crystal is a N ' N-dibenzyl-ethylenediamin: Flucloxacillin acid is the mixture of 1:1.
The preparation of ii, Flucloxacillin sodium salt
N ' N-dibenzyl ethylenediamine salt crystal 6 00g is suspended in the 15L ethanol with the Flucloxacillin, in stirred suspension, add Thermax T-54 resin 1800g, be stirred to Flucloxacillin N ' N-dibenzyl ethylenediamine salt dissolving and obtain a settled solution at 5～35 ℃, the filtering resin, in filtrate, drip 10～15 ℃ alcohol sodium solution, reach 5.6 to filtrate pH value, separate out the white solid precipitation, keep stirring 5 hours under 9～10 ℃ of temperature condition, filter, drying gets Flucloxacillin sodium salt 301.3g.
Embodiment 6
The preparation of i, Flucloxacillin N ' N-dibenzyl ethylenediamine salt
951.7g is dissolved in 15L water with the 2mol Sodium flucloxacillin, with salt acid for adjusting pH value to 3.0～4.0, adds methyl alcohol 8.5L then, add 5mol N ' N-dibenzyl-ethylenediamin diacetate salt 1791.6g again, mixed stirring reaction 5 hours at 20～25 ℃, produce white solid, reaction mixture is cooled to 10～15 ℃, filter, white solid washes with water three times, uses methanol wash again three times, 30～35 ℃ of vacuum-dryings, get solid 1136.8g, productive rate 98.8%.The crystalline melting range is 192～198 ℃, first water, and obtaining fusing point with this salt of methanol wash again is 195～198 ℃ product, analyzes to show that crystal is a N ' N-dibenzyl-ethylenediamin: Flucloxacillin acid is 1: 1 mixture.
The preparation of ii, Flucloxacillin sodium salt
N ' N-dibenzyl ethylenediamine salt crystal 1100g is suspended in the 22L ethanol with the Flucloxacillin, in stirred suspension, add Amberlyst15 resin 3300g, be stirred to Flucloxacillin N ' N-dibenzyl ethylenediamine salt dissolving and obtain a settled solution at 5～35 ℃, the filtering resin, the alcohol sodium solution of Dropwise 5 in filtrate～10 ℃, reach 5.5 to filtrate pH value, separate out the white solid precipitation, keep stirring 3 hours under 5～10 ℃ of temperature condition, filter, drying gets Flucloxacillin sodium salt 711.3g.
The above, it only is preferred embodiment of the present invention, be not that the present invention is done any pro forma restriction, though the present invention discloses as above with preferred embodiment, yet be not in order to limit the present invention, any those skilled in the art, in not breaking away from the technical solution of the present invention scope, when the technology contents that can utilize above-mentioned announcement is made a little change or is modified to the equivalent embodiment of equivalent variations, in every case be the content that does not break away from technical solution of the present invention, according to technical spirit of the present invention to any simple modification that above embodiment did, equivalent variations and modification all still belong in the scope of technical solution of the present invention.
Claims (10)
1, a kind of preparation method of flucloxacillin sodium compound is characterized in that: earlier N ' N-dibenzyl ethylenediamine salt and Flucloxacillin acid hybrid reaction are generated salt, and then obtain highly purified Sodium flucloxacillin with the Zeo-karb displacement.
2, the purification process of Sodium flucloxacillin according to claim 1, it is characterized in that: described generation salt is Flucloxacillin N ' N-dibenzyl ethylenediamine salt, its preparation process is as follows: will need the Sodium flucloxacillin of purifying water-soluble, regulating the pH value is 2.0～8.0, add organic solvent then, add N ' N-dibenzyl ethylenediamine salt again, add-on is 1～3:1 with the molar equivalent ratio of Sodium flucloxacillin, mix and stirred 3～5 hours, filter then, drying gets Flucloxacillin N ' N-dibenzyl ethylenediamine salt crystal.
3, the purification process of Sodium flucloxacillin according to claim 2 is characterized in that: described Sodium flucloxacillin pH value of solution value is adjusted to 3.0～4.0.
4, the purification process of Sodium flucloxacillin according to claim 2 is characterized in that: the add-on of described N ' N-dibenzyl ethylenediamine salt is 2.2～2.5:1 with the molar equivalent ratio of Sodium flucloxacillin.
5, the purification process of Sodium flucloxacillin according to claim 2 is characterized in that: described organic solvent is a methyl alcohol.
6, the purification process of Sodium flucloxacillin according to claim 1 is characterized in that: the preparation process of described high purity Sodium flucloxacillin is as follows:
(1) Flucloxacillin N ' N-dibenzyl ethylenediamine salt is suspended in ethanol, methyl alcohol or the water, wherein the volume ratio of the quality of salt and solvent is 1 kilogram: 5～30 liters;
(2) stir, add strong resin or storng-acid cation exchange resin, the ratio of weight and number of add-on and Flucloxacillin N ' N-dibenzyl ethylenediamine salt is 1～10:1;
(3) 5～35 ℃ of dissolvings are complete, and the filtering resin drips the sodium salt that dissolves in organic solvent in filtrate, regulate pH value of filtrate and reach 5～6;
(4) at 5～10 ℃, stirred 2～5 hours, separate out product, drying gets Sodium flucloxacillin.
7, the purification process of Sodium flucloxacillin according to claim 6 is characterized in that: the quality of described Flucloxacillin N ' N-dibenzyl ethylenediamine salt and the volume ratio of solvent are 1 kilogram: 10～20 liters.
8, the purification process of Sodium flucloxacillin according to claim 6 is characterized in that: the ratio of weight and number of the add-on of described strong acid or storng-acid cation exchange resin and Flucloxacillin N ' N-dibenzyl ethylenediamine salt is 1～3:1.
9, the purification process of Sodium flucloxacillin according to claim 6 is characterized in that: the described sodium salt that dissolves in organic solvent is 2 ethyl hexanoic acid sodium, Sodium.alpha.-hydroxypropionate, sodium acetate, highly basic or sodium alkoxide.
10, a kind of flucloxacillin sodium compound is characterized in that: this compound is to adopt earlier N ' N-dibenzyl ethylenediamine salt and Flucloxacillin acid hybrid reaction are generated salt, and then obtains with the Zeo-karb displacement.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102285998A (en) * | 2011-06-17 | 2011-12-21 | 桂林理工大学 | Preparation method of amorphous and three polymorphic substances of flucloxacillin sodium |
| CN102351882A (en) * | 2011-09-20 | 2012-02-15 | 海南美兰史克制药有限公司 | Flucloxacillin sodium compound and preparation method thereof |
| CN102964356A (en) * | 2012-12-25 | 2013-03-13 | 菏泽睿智科技开发有限公司 | Synthesis method of flucloxacillin sodium |
| CN103288852A (en) * | 2011-06-17 | 2013-09-11 | 桂林理工大学 | Preparation method of flucloxacillin sodium crystal form II |
| CN104402904A (en) * | 2014-11-04 | 2015-03-11 | 齐鲁天和惠世制药有限公司 | Preparation method for flucloxacillin sodium |
| CN109400630A (en) * | 2018-11-23 | 2019-03-01 | 浙江普洛得邦制药有限公司 | A kind of synthetic method of flucloxacillin sodium |
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2009
- 2009-02-12 CN CNA2009100076283A patent/CN101475578A/en active Pending
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| CN103288852B (en) * | 2011-06-17 | 2015-05-20 | 桂林理工大学 | Preparation method of flucloxacillin sodium crystal form II |
| CN102285998B (en) * | 2011-06-17 | 2013-12-18 | 桂林理工大学 | Preparation method of amorphous and three polymorphic substances of flucloxacillin sodium |
| CN103288851B (en) * | 2011-06-17 | 2016-04-06 | 桂林理工大学 | The preparation method of Sodium flucloxacillin crystal form II I |
| CN103288850A (en) * | 2011-06-17 | 2013-09-11 | 桂林理工大学 | Preparation method of flucloxacillin sodium amorphous crystal-form substance |
| CN103288852A (en) * | 2011-06-17 | 2013-09-11 | 桂林理工大学 | Preparation method of flucloxacillin sodium crystal form II |
| CN103288850B (en) * | 2011-06-17 | 2015-09-23 | 桂林理工大学 | The preparation method of the amorphous crystal formation thing of Sodium flucloxacillin |
| CN103288851A (en) * | 2011-06-17 | 2013-09-11 | 桂林理工大学 | Preparation method of flucloxacillin sodium crystal form III |
| CN102285998A (en) * | 2011-06-17 | 2011-12-21 | 桂林理工大学 | Preparation method of amorphous and three polymorphic substances of flucloxacillin sodium |
| CN102351882B (en) * | 2011-09-20 | 2012-09-05 | 海南美兰史克制药有限公司 | Flucloxacillin sodium compound and preparation method thereof |
| CN102351882A (en) * | 2011-09-20 | 2012-02-15 | 海南美兰史克制药有限公司 | Flucloxacillin sodium compound and preparation method thereof |
| CN102964356B (en) * | 2012-12-25 | 2015-06-17 | 菏泽睿智科技开发有限公司 | Synthesis method of flucloxacillin sodium |
| CN102964356A (en) * | 2012-12-25 | 2013-03-13 | 菏泽睿智科技开发有限公司 | Synthesis method of flucloxacillin sodium |
| CN104402904A (en) * | 2014-11-04 | 2015-03-11 | 齐鲁天和惠世制药有限公司 | Preparation method for flucloxacillin sodium |
| CN109400630A (en) * | 2018-11-23 | 2019-03-01 | 浙江普洛得邦制药有限公司 | A kind of synthetic method of flucloxacillin sodium |
| CN109400630B (en) * | 2018-11-23 | 2021-07-02 | 浙江普洛得邦制药有限公司 | Synthetic method of flucloxacillin sodium |
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