CN102532165A - Preparation method for cefathiamidine crystals - Google Patents
Preparation method for cefathiamidine crystals Download PDFInfo
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- CN102532165A CN102532165A CN2010105969297A CN201010596929A CN102532165A CN 102532165 A CN102532165 A CN 102532165A CN 2010105969297 A CN2010105969297 A CN 2010105969297A CN 201010596929 A CN201010596929 A CN 201010596929A CN 102532165 A CN102532165 A CN 102532165A
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- 0 C*(C)C1*(C)C1SC*C(C1SCC(*C(C)=O)C(C(O)=O)N11)C1=O Chemical compound C*(C)C1*(C)C1SC*C(C1SCC(*C(C)=O)C(C(O)=O)N11)C1=O 0.000 description 1
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Abstract
The invention relates to a preparation method for cefathiamidine crystals. By the method, according to a cefathiamidine impurity generation mechanism and in the process of preparing cefathiamidine, the water content of a solvent system is controlled, a stirring speed, feeding time and temperature are controlled in the crystallization process, and the source of possible impurities is cut off, so that the low-impurity and high-stability cefathiamidine crystals are obtained.
Description
Technical field:
The present invention relates to chemical pharmacy field, be specifically related to the preparation method of microbiotic crystalline cephem sulphur amidine.
Background technology:
Cefathiamidine is the unique cynnematin of development voluntarily of China.Gram-positive microorganism and part negative bacillus all there is good antibacterial activity, particularly to streptococcus aureus, staphylococcus epidermidis, streptococcus pneumoniae, faecalis gram-positive coccis such as (comprising Resistant strain).Be widely used in responsive microbial respiratory tract infection, wound and surgical infection, skin and soft tissue infection, urinary tract infections, otorhinolaryngology infection, endocarditis and septicemia.Use cefathiamidine aseptic crystallization powder clinically.
The chemistry of cefathiamidine is by name: (molecular formula is C for 6R, 7R)-3 amine salt in [(ethanoyl) methyl]-7-[a-(N, N '-diisopropylamidinateand sulfenyl)-kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-formic acid
19H
28N
4O
6S
2
Structural formula is:
The technology of preparing of existing cefathiamidine has two kinds; A kind of is solvent crystallization, sees that application number is 02115356.6,03136191.9 and 03142622.0 etc., through in the moisture polar solvent solution of cefathiamidine, add dissolve each other with polar solvent and with cefathiamidine slightly soluble or insoluble solvent to solution crystallization; Separate; Drying obtains crystalline cephem sulphur amidine; Another kind is a lyophilization, sees that application number is 03129662.9 and 03146824.1, is that water dissolves cefathiamidine, carries out lyophilize by freeze-dry process then, processes the cefathiamidine lyophilized injectable powder.
Cefathiamidine is relatively more responsive to temperature and moisture content, especially in aqueous solution state, be higher than in temperature+5 ℃ situation under, degraded produces degraded product easily, its main degraded product is for going acetyl cefathiamidine and cephalo ester amidine.
Mechanism of degradation is: in the aqueous solution, the C-3 position acetoxyl group hydrolysis of cefathiamidine generates the active less acetyl cefathiamidine that goes, and its mass spectrum is seen shown in Figure 1.
Because of the active carboxyl of the C-3 hydroxyl and the C-4 that remove the acetyl cefathiamidine is in the same sides of two keys between C-3 and C-4, therefore further dehydrating condensation forms the compound cephalo ester amidine of more stable lactonic ring structure, and its mass spectrum is seen shown in Figure 2.
The DeR formula is:
Therefore control moisture content through strict in the crystallization processes process, and the temperature of whole crystallisation process and stirring velocity, can reduce the generation of impurity, improve the stability of cefathiamidine.
The crystallization preparation method of the relevant cefathiamidine of prior art does not all relate to the generation of crystallization control process impurities, thereby improves the crystallization method of cefathiamidine stability.
Summary of the invention:
The preparation method who the purpose of this invention is to provide a kind of high-quality crystalline cephem sulphur amidine.
Technical scheme of the present invention is:
The preparation method of a kind of crystalline cephem sulphur amidine is characterized in that it comprises following steps:
1) with the cefathiamidine dissolving crude product in the solvent of solubilized cefathiamidine, preparation cefathiamidine crude product solution;
2) in the cefathiamidine crude product solution of step 1 gained, add siccative and gac, stir, filter, prepare anhydrous cefathiamidine solution;
3) in the cefathiamidine anhydrous solution of step 2 gained, add with anhydrous solution in solvent dissolve each other but with the insoluble anhydrous solvent crystallization of cefathiamidine;
4) growing the grain;
5) filter, washing obtains the crystallinity cefathiamidine after the drying.。
In preparation method of the present invention; The solvent of the described solubilized cefathiamidine of step 1 can be selected from binary, ternary or the polybasic mixture of the saturated lower alcohol of methyl alcohol or methyl alcohol and other, saturated lower ketones, saturated low-carbon carboxylate, and its add-on is clear for the cefathiamidine bullion is dissolved.
Unexpectedly, we find to select for use methyl alcohol can access more excellent effect.
The described siccative of step 2 is selected from one or more mixtures among molecular sieve, silica gel, SODIUM SULPHATE ANHYDROUS 99PCT, anhydrous calciumsulphate, anhydrous magnesium sulfate, Anhydrous potassium carbonate, barium oxide, the quicklime among the preparation method of the present invention.And its add-on is 0.1～2 times of cefathiamidine bullion quality.
The solvent with in the anhydrous solution described in the inventive method step 3 dissolves each other but is selected from no water saturation lower alcohol, saturated lower ketones, saturated low-carbon carboxylate or their binary, ternary or polybasic mixture with the insoluble anhydrous solvent of cefathiamidine.Its add-on is 10～50 milliliters based on per 1 gram cefathiamidine bullion.
In whole invention, described no water saturation lower alcohol can be absolute ethyl alcohol, Virahol, n-propyl alcohol, isopropylcarbinol, propyl carbinol; Described no water saturation lower aliphatic ketone is anhydrous propanone, methylethylketone, pentanone, diethyl ketone, mibk; Described no water saturation low-carbon carboxylate is anhydrous formic acid ethyl ester, propyl formate, ETHYLE ACETATE, propyl acetate, butylacetate.
Unexpectedly; We find that in the crystallization process of step 3 the strict control dropping time is 1-5 hour, and stirring velocity is 30～90 rev/mins; Tc is controlled at-5 ℃～+ 5 ℃ can be so that the cefathiamidine crystal better quality obtains gratifying effect.
In the growing the grain process of step 4, keeping mixing speed is 50～70 rev/mins, and temperature is-5 ℃～+ 5 ℃, and rearing crystal time is can obtain even more ideal cefathiamidine crystal in 1～4 hour.
Advantage of the present invention is the crystalline cephem sulphur amidine that gained crystalline cephem sulphur amidine quality is superior to prior art for preparing, and it is placed for a long time, and indexs such as color and luster, visible foreign matters, particulate matter, related substance are all more stable than the crystalline cephem sulphur amidine of prior art for preparing.
Description of drawings
Shown in Figure 1 for removing acetyl cefathiamidine mass spectrum.
Shown in Figure 2 is the compound cephalo ester amidine mass spectrum of lactonic ring structure.
Embodiment
Embodiment 1
Under 0 ℃, 20 gram cefathiamidine bullions are dissolved in 180 ml methanol solution clarification.Add 20 gram SODIUM SULPHATE ANHYDROUS 99PCTs and 2 gram gacs, stir dehydration, decolouring 30 minutes, the nitrogen press filtration.In the control stirring velocity is under 60～75 rev/mins, in filtrating, adds 600 milliliters of crystallizatioies of anhydrous propanone in about 2 hours.Continuation is at 0 ℃, and stirring velocity is under 55～65 rev/mins, and growing the grain filtered after 1 hour, with anhydrous propanone washing 3 times, each 40 milliliters.35～45 ℃ of vacuum-drying 28 hours obtains cefathiamidine 14.25g.
Embodiment 2
Under-2 ℃, 20 gram cefathiamidine bullions are dissolved in 180 milliliters of anhydrous methanols and the 150 milliliters of anhydrous isopropyl alcohols, the solution clarification adds 20 mol sieve and 2 gram gacs, stirs dehydration, decolours the nitrogen press filtration 20 minutes.In the control stirring velocity is under 60～75 rev/mins, about 4.5 interior hours 600 milliliters of crystallizatioies of adding anhydrous isopropyl alcohol in filtrating.Continuation is at-2 ℃, and stirring velocity is 55～65 rev/mins of following growing the grains after 2 hours, filter, and with anhydrous isopropyl alcohol washing 2 times, each 40 milliliters, again with anhydrous propanone washing 3 times, each 40 milliliters.35～45 ℃ of vacuum-drying 28 hours obtains cefathiamidine 15.13g.
Embodiment 3
Under 2 ℃, cefathiamidine bullion 20g is dissolved in 180 ml methanol, adds 5 gram Anhydrous potassium carbonate and 1.5g gacs, stir dehydration, decolouring 20 minutes, the solution clarification.After adding 100 milliliters of anhydrous ethyl acetates, the nitrogen press filtration.In the control stirring velocity is under 40～55 rev/mins, in filtrating, adds 600 milliliters of crystallizatioies of anhydrous ethyl acetate in about 1.5 hours.Continuation is at 2 ℃, and stirring velocity is under 55～65 rev/mins, and growing the grain with anhydrous ethyl acetate washing 2 times, each 40 milliliters, washs 3 times each 40 milliliters after 2 hours again with anhydrous propanone.35～45 ℃ of vacuum-drying 28 hours obtains cefathiamidine 15.45g.
Embodiment 4
Under 0 ℃, 20 gram cefathiamidine bullions are dissolved in 180 ml methanol solution clarification.Add 10 gram SODIUM SULPHATE ANHYDROUS 99PCTs and 1.5 gram gacs, stir dehydration, decolouring 30 minutes, the nitrogen press filtration.In the control stirring velocity is under 60～75 rev/mins, in filtrating, adds 600 milliliters of crystallizatioies of anhydrous propanone in about 2 hours.Continuation is at 0 ℃, and stirring velocity is under 55～65 rev/mins, and growing the grain filtered after 1 hour, with anhydrous propanone washing 3 times, each 40 milliliters.35～45 ℃ of vacuum-drying 28 hours obtains cefathiamidine 14.65g.
Under 0 ℃, 20 gram cefathiamidine bullions are dissolved in 180 ml methanol and 150 milliliters of anhydrous isopropyl alcohols, the 150 milliliters of absolute ethyl alcohols solution clarification.Add 20 gram SODIUM SULPHATE ANHYDROUS 99PCTs and 2 gram gacs, stir dehydration, decolouring 30 minutes, the nitrogen press filtration.In the control stirring velocity is under 50～65 rev/mins, in filtrating, adds 600 milliliters of crystallizatioies of anhydrous propanone in about 2 hours.Continuation is at 0 ℃, and stirring velocity is under 50～60 rev/mins, and growing the grain filtered after 3 hours, with anhydrous propanone washing 3 times, each 40 milliliters.35～45 ℃ of vacuum-drying 28 hours obtains cefathiamidine 13.50g.
Embodiment 6
It is following that the crystalline cephem sulphur amidine of gained crystalline cephem sulphur amidine of the present invention and prior art for preparing is cooked its test result of contrast stability test (60 ℃ were placed 10 days):
The stability test of two kinds of crystalline cephem sulphur of table 1 amidine
The result shows and utilizes preparation method of the present invention, and prepared crystalline cephem sulphur amidine is 60 ℃ of high temperature, places under 10 days the situation, and its solution color and luster is superior to the preparation method of prior art, and the content of its related substance is significantly less than art methods.
This shows, utilize the prepared crystalline cephem sulphur amidine of method of the present invention to have better stability.
The foregoing description is a preferred implementation of the present invention; But embodiment of the present invention is not restricted to the described embodiments; Other any do not deviate from change, the modification made under spirit of the present invention and the principle, substitutes, combination, simplify; All should be the equivalent replacement mode, be included within protection scope of the present invention.
Claims (9)
1. the preparation method of a crystalline cephem sulphur amidine is characterized in that it comprises following steps:
1) with the cefathiamidine dissolving crude product in the solvent of solubilized cefathiamidine, preparation cefathiamidine crude product solution;
2) in the cefathiamidine crude product solution of step 1 gained, add siccative and gac, stir, filter, prepare anhydrous cefathiamidine solution;
3) in the cefathiamidine anhydrous solution of step 2 gained, add with anhydrous solution in solvent dissolve each other but with the insoluble anhydrous solvent crystallization of cefathiamidine;
4) growing the grain;
5) filter, washing obtains the crystallinity cefathiamidine after the drying.
2. the preparation method of a kind of crystalline cephem sulphur amidine according to claim 1; The solvent that it is characterized in that the described solubilized cefathiamidine of step 1 is binary, ternary or the polybasic mixture of methyl alcohol or methyl alcohol and other saturated lower alcohol, saturated lower ketones, saturated low-carbon carboxylate, and it is clear for the cefathiamidine bullion is dissolved as going into amount.
3. the preparation method of a kind of crystalline cephem sulphur amidine according to claim 1, it is characterized in that step 3 described with anhydrous solution in solvent dissolve each other but with the insoluble anhydrous solvent of cefathiamidine be no water saturation lower alcohol, saturated lower ketones, saturated low-carbon carboxylate or their binary, ternary or polybasic mixture.
4. the preparation method of a kind of crystalline cephem sulphur amidine according to claim 4 is characterized in that the add-on of described no water saturation lower alcohol, saturated lower ketones, saturated low-carbon carboxylate or their binary, ternary or polybasic mixture is 10～50 milliliters based on per 1 gram cefathiamidine bullion.
5. the preparation method of a kind of crystalline cephem sulphur amidine according to claim 1 is characterized in that the control dropping time is 1～5 hour in the described crystallization process of step 3, and mixing speed is 30～90 rev/mins, and Tc is controlled at-5 ℃～+ 5 ℃.
6. the preparation method of a kind of crystalline cephem sulphur amidine according to claim 1 is characterized in that keeping mixing speed in the described growing the grain process of step 4 is 50～70 rev/mins, and temperature is-5 ℃～+ 5 ℃, growing the grain 1～4 hour.
7. according to the preparation method of claim 2,3 or 4 described a kind of crystalline cephem sulphur amidines, it is characterized in that described no water saturation lower alcohol is absolute ethyl alcohol, Virahol, n-propyl alcohol, isopropylcarbinol, propyl carbinol.
8. according to the preparation method of claim 2,3 or 4 described a kind of crystalline cephem sulphur amidines, it is characterized in that described no water saturation lower aliphatic ketone is anhydrous propanone, methylethylketone, pentanone, diethyl ketone, mibk.
9. according to the preparation method of claim 2,3 or 4 described a kind of crystalline cephem sulphur amidines, it is characterized in that described no water saturation low-carbon carboxylate is anhydrous formic acid ethyl ester, propyl formate, ETHYLE ACETATE, propyl acetate, butylacetate.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103556226A (en) * | 2013-10-23 | 2014-02-05 | 广州白云山制药股份有限公司广州白云山化学制药厂 | Cefathiamidine monocrystal |
| CN103833773A (en) * | 2013-12-20 | 2014-06-04 | 悦康药业集团有限公司 | Cefathiamidine compound |
| CN104628743A (en) * | 2014-12-31 | 2015-05-20 | 天津大学 | New crystal form of cefathiamidine compounds and crystallized preparation method thereof |
| CN105646534A (en) * | 2016-02-18 | 2016-06-08 | 海南灵康制药有限公司 | Novel-crystal-form cefathiamidine compound adopting crystal product molecular assembly and form optimization technology in particle process and preparation |
| CN106220647A (en) * | 2016-07-25 | 2016-12-14 | 海南汤臣史克生物科技有限公司 | A kind of cefathiamidine compound and preparation thereof and preparation method |
| CN108948048A (en) * | 2018-07-26 | 2018-12-07 | 华北制药河北华民药业有限责任公司 | A kind of refining methd of cefathiamidine |
| CN109734727A (en) * | 2019-01-30 | 2019-05-10 | 山东省分析测试中心 | A method of cefathiamidine crystal is prepared by controlling crystal seed crystal form |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103556226A (en) * | 2013-10-23 | 2014-02-05 | 广州白云山制药股份有限公司广州白云山化学制药厂 | Cefathiamidine monocrystal |
| CN103556226B (en) * | 2013-10-23 | 2016-08-24 | 广州白云山医药集团股份有限公司白云山化学制药厂 | Cefathiamidine monocrystal |
| CN103833773A (en) * | 2013-12-20 | 2014-06-04 | 悦康药业集团有限公司 | Cefathiamidine compound |
| CN103833773B (en) * | 2013-12-20 | 2016-01-27 | 悦康药业集团有限公司 | A kind of cefathiamidine compound |
| CN104628743A (en) * | 2014-12-31 | 2015-05-20 | 天津大学 | New crystal form of cefathiamidine compounds and crystallized preparation method thereof |
| CN105646534A (en) * | 2016-02-18 | 2016-06-08 | 海南灵康制药有限公司 | Novel-crystal-form cefathiamidine compound adopting crystal product molecular assembly and form optimization technology in particle process and preparation |
| CN106220647A (en) * | 2016-07-25 | 2016-12-14 | 海南汤臣史克生物科技有限公司 | A kind of cefathiamidine compound and preparation thereof and preparation method |
| CN108948048A (en) * | 2018-07-26 | 2018-12-07 | 华北制药河北华民药业有限责任公司 | A kind of refining methd of cefathiamidine |
| CN109734727A (en) * | 2019-01-30 | 2019-05-10 | 山东省分析测试中心 | A method of cefathiamidine crystal is prepared by controlling crystal seed crystal form |
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Application publication date: 20120704 |