CN101037444A - Method for synthesizing compound of cefpiramide sodium - Google Patents
Method for synthesizing compound of cefpiramide sodium Download PDFInfo
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- CN101037444A CN101037444A CN 200710051907 CN200710051907A CN101037444A CN 101037444 A CN101037444 A CN 101037444A CN 200710051907 CN200710051907 CN 200710051907 CN 200710051907 A CN200710051907 A CN 200710051907A CN 101037444 A CN101037444 A CN 101037444A
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- sodium
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- cefpiramide
- diethylamine
- triethylamine
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Abstract
The invention relates to a synthesis method of cefpiramide sodium, including reacting of cefpriamide free acid with triethylamine, diethylamine or diethylamine in the organic solvent in -10-40 deg c, then getting mixture after reaction, dripping 10-15wt% sodium sulfocyanate acetone solution, adjusting pH to 6-8, filtering, drying to obtain cefpiramide sodium. The synthesis cefpiramide sodium has an even polytype, a good color, a high purity, and a good product stability and a safe conservation.
Description
Technical field
The present invention relates to the synthetic method of compound of cefpiramide sodium.
Background technology
The chemistry of Wy-44635 is called (6R, 7R)-7-[(R)-2-(4-hydroxyl-6-methyl-3-pyridine carbonylamino)-2-(p-hydroxybenzene) kharophen]-3-[[(1-methyl isophthalic acid H-tetrazolium-5-yl) sulphur] methyl]-8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid sodium salt.Molecular formula: C
25H
23N
8NaO
7S
2Its structural formula is:
Wy-44635 has very strong anti-microbial activity to gram-positive microorganism, and the bacterium that comprises Gram-negative bacteria is also had broad spectrum antibiotic activity.Simultaneously, non-glucose fermentation gram negative bacilluses such as Pseudomonas aeruginosa there is very strong anti-microbial activity.It act as sterilization, and stable to various bacteriogenic β-Nei Xiananmeis.When being used for experimental infection (mouse), present good result of treatment.To penicillins, other cephalosporins or the drug-fast bacterium of aminoglycosides antibiotics, especially to the Pseudomonas aeruginosa sensitivity.
At present, the main products of Wy-44635 is a freeze-dried powder, because lyophilized powder is inhomogeneous, color and luster is relatively poor, purity is on the low side, the content height of related substance, product instability, be difficult for preserving, and needs special freeze-drier and production site, thereby production cost is higher.
The patent application of Chinese patent application numbers 200410027956.7 discloses a kind of preparation method of Wy-44635, and this method is dissolved Cefpiramide Acid with solvent, adds sodium transforming agent, separates out the Wy-44635 crystallization by adding organic solvent then.But separate out very soon owing to add in the organic solvent process Wy-44635 crystalline, crystallization is wayward, and crystal formation is inhomogeneous, and not only purity is low, influence the stability of product, and owing to the inhomogeneous meeting of crystal formation makes filtration time long.
Summary of the invention
The object of the present invention is to provide a kind of synthetic method of Wy-44635, this method synthetic cefpiramide sodium crystal is more even, and color and luster is good, purity is higher, product is stable and be easy to preservation.
Technical scheme provided by the invention is: the synthetic method of Wy-44635, Cefpiramide Acid and triethylamine, diethylamine or quadrol in organic solvent ,-10～40 ℃ of reactions, drip the acetone soln of the sodium salt of 10-15wt% in the mixture that after reaction is finished, obtains, adjust pH is to 6-8, and filtration, drying obtain Wy-44635; Described sodium salt is a weak acid strong alkali salt.
The preferred Sodium Thiocyanate 99 of above-mentioned sodium salt, Sodium isooctanoate, sodium-acetate or Sodium.alpha.-hydroxypropionate; With Sodium Thiocyanate 99 for better.
The above-mentioned organic solvent of stating is methyl alcohol, ethanol and/or acetonitrile.
The consumption mol ratio of above-mentioned Cefpiramide Acid and triethylamine, diethylamine or quadrol is 1: 1.1～1.3.
The consumption of above-mentioned Sodium Thiocyanate 99 is 1.8～2.5 times of Cefpiramide Acid molar weight.
The drop rate of the acetone soln of the Sodium Thiocyanate 99 of dropping 10-15wt% is the 0.03-0.8mL/ per second in the mixture that the present invention obtains after reaction is finished.
The present invention is owing to adopt technique scheme, prepare the cefpiramide acid ammonium salt by Cefpiramide Acid and triethylamine, diethylamine or reacting ethylenediamine, the acetone soln that drips weakly alkaline sodium salt again makes cefpiramide acid ammonium salt and sodium salt reaction, and the reaction product Wy-44635 is separated out while generating, obtain the uniform Wy-44635 product of crystal formation; And because the weakly alkaline of sodium salt, its reaction temperature and, can avoid partial over-alkali and destroy the structure of cefpiramide, guarantee degree of purity of production, and then improve the stability of product.In addition, earlier with Cefpiramide Acid and triethylamine, diethylamine or reacting ethylenediamine, product that obtains and weakly alkaline sodium salt can react under the condition of milder, make reaction more thorough, and guarantee the quality of final product.Synthetic cefpiramide sodium crystal of the present invention is more even, and color and luster is good, purity is higher, product is stable and be easy to preservation.
Embodiment
The embodiment that below provides will help to understand the present invention, but not limit content of the present invention.
Embodiment 1:
Get Cefpiramide Acid 50g, methyl alcohol 150mL, acetonitrile 75mL, triethylamine 10.5mL in 25 ℃ of mixing, add the 5g gac and stirred 30 minutes, filter.Drip the acetone soln (wherein containing Sodium Thiocyanate 99 12.5g) of the Sodium Thiocyanate 99 of 10wt% with the speed of 0.7L/ per second, drip the back and add 0.065g yellow soda ash adjust pH, stirred 15 minutes, filter (filtration velocity is fast), drying gets born of the same parents' amine sodium to the end, purity 99.7%, impurity summation 0.21%, stability: purity 99.5% after one month; MMT0.3.Purity 98.6% after three months, MMT0.35.
Embodiment 2:
Get Cefpiramide Acid 50g, methyl alcohol 150mL, acetonitrile 75mL, triethylamine 10.5mL in 25 ℃ of mixing, add the 5g gac and stirred 20 minutes, filter.Drip the acetone soln (wherein containing Sodium isooctanoate 25.5g) of the Sodium isooctanoate of 10wt% with the speed of 0.7L/ per second, drip the back and add 0.065g yellow soda ash adjust pH, stirred 15 minutes, filter (filtration velocity is fast), drying gets born of the same parents' amine sodium to the end, purity 98.2%, impurity summation 1.07%, stability: purity 96.6% after one month; Purity 94.3% after three months.
Embodiment 3:
Get Cefpiramide Acid 50g, methyl alcohol 150mL, acetonitrile 75mL, triethylamine 10.5mL in 25 ℃ of mixing, add the 5g gac and stirred 25 minutes, filter.Drip the acetone soln (wherein containing sodium-acetate 12.7g) of the sodium-acetate of 10wt% with the speed of 0.7L/ per second, drip the back and add 0.065g yellow soda ash adjust pH, stirred 15 minutes, filter (filtration velocity is fast), drying gets born of the same parents' amine sodium to the end, purity 96.4%, impurity summation 2.6%; Stability: purity 92.2% after one month, MMT0.6; Purity 90.8% after three months.MMT0.7。
Embodiment 4:
Get Cefpiramide Acid 50g, methyl alcohol 150mL, acetonitrile 75mL, triethylamine 10.5mL in 25 ℃ of mixing, add the 5g gac and stirred 40 minutes, filter.Drip the acetone soln (wherein containing Sodium.alpha.-hydroxypropionate 17.3g) of the Sodium.alpha.-hydroxypropionate of 10wt% with the speed of 0.7L/ per second, drip the back and add 0.065g yellow soda ash adjust pH, stirred 15 minutes, filter (filtration velocity is very fast), drying gets born of the same parents' amine sodium to the end, purity 99.5%, impurity summation 0.26%; Stability: purity 99.0% after one month, MMT0.25; Purity 98.1% after three months.MMT0.28。
Embodiment 5:
Get Cefpiramide Acid 50g, acetone 250mL, diethylamine 11mL in-10 ℃ of mixing, add the 5g gac and stirred 30 minutes, filter.Drip the acetone soln (wherein containing Sodium Thiocyanate 99 13g) of the Sodium Thiocyanate 99 of 15wt% with the speed of 0.4L/ per second, drip the back and add 0.065g yellow soda ash adjust pH, stirred 15 minutes, filter, drying gets born of the same parents' amine sodium to the end, purity 99.6%, impurity summation 0.23%, stability: purity 99.4% after one month; Purity 98.3% after three months.
Embodiment 6:
Get Cefpiramide Acid 50g, ethanol 200mL, quadrol 5.5mL in 35 ℃ of mixing, add the 5g gac and stirred 30 minutes, filter.Drip the acetone soln (wherein containing Sodium Thiocyanate 99 15.3g) of the Sodium Thiocyanate 99 of 13wt% with the speed of 0.05L/ per second, drip the back and add 0.065g yellow soda ash adjust pH, stirred 15 minutes, filter, drying gets born of the same parents' amine sodium to the end, purity 99.5%, impurity summation 0.26%, stability: purity 99.3% after one month; Purity 98.1% after three months.
Even by the foregoing description technical scheme synthetic of the present invention as can be known cefpiramide sodium crystal, the purity height, product color is good, stable and be easy to preserve.Especially adopt sulphur hydracid sodium more remarkable effect.
Embodiment 7:
The same terms adopts different sodium reagent amplification tests to prepare the quality synopsis of Wy-44635 down
| Sodium salt | Purity (%) | Impurity summation (%) | Stability (%) | Process time |
| Sulphur hydracid sodium | 99.7 | 0.20 | Purity after January: 99.4 | 20 hours |
| Purity after March: 98.7 | ||||
| Sodium isooctanoate | 98.1 | 1.08 | Purity after January: 96.6 | 18 hours |
| Purity after March: 94.2 | ||||
| Sodium-acetate | 96.5 | 2.6 | Purity after January: 92.3 | 21 hours |
| Purity after March: 90.7 | ||||
| Sodium.alpha.-hydroxypropionate | 99.4 | 0.25 | Purity after January: 98.9 | 33 hours |
| Purity after March: 98.0 |
Claims (7)
1. the synthetic method of Wy-44635, Cefpiramide Acid and triethylamine, diethylamine or quadrol in organic solvent ,-10～40 ℃ of reactions, drip the acetone soln of the sodium salt of 10-15wt% in the mixture that obtains after reaction is finished, adjust pH is to 6-8, and filtration, drying obtain Wy-44635; Described sodium salt is a weak acid strong alkali salt.
2. synthetic method according to claim 1 is characterized in that: described sodium salt is Sodium Thiocyanate 99, Sodium isooctanoate, sodium-acetate or Sodium.alpha.-hydroxypropionate.
3. synthetic method according to claim 1 is characterized in that: described sodium salt is a Sodium Thiocyanate 99.
4. according to claim 1 or 2 or 3 described synthetic methods, it is characterized in that: described organic solvent is methyl alcohol, ethanol, acetone and/or acetonitrile.
5. according to claim 1 or 2 or 3 described synthetic methods, it is characterized in that: the consumption mol ratio of Cefpiramide Acid and triethylamine, diethylamine or quadrol is 1: 0.9～1.3.
6. according to claim 1 or 2 or 3 described synthetic methods, it is characterized in that: the consumption of Sodium Thiocyanate 99 is 1.8～2.5 times of Cefpiramide Acid molar weight.
7. according to claim 1 or 2 or 3 described synthetic methods, it is characterized in that: the drop rate of the acetone soln of the Sodium Thiocyanate 99 of dropping 10-15wt% is the 0.03-0.8mL/ per second in the mixture that obtains after reaction is finished.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100519070A CN100480251C (en) | 2007-04-18 | 2007-04-18 | Method for synthesizing compound of cefpiramide sodium |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100519070A CN100480251C (en) | 2007-04-18 | 2007-04-18 | Method for synthesizing compound of cefpiramide sodium |
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| CN101037444A true CN101037444A (en) | 2007-09-19 |
| CN100480251C CN100480251C (en) | 2009-04-22 |
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| CNB2007100519070A Expired - Fee Related CN100480251C (en) | 2007-04-18 | 2007-04-18 | Method for synthesizing compound of cefpiramide sodium |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101838276A (en) * | 2010-05-17 | 2010-09-22 | 胡梨芳 | Cefpiramide sodium hydrate and preparation method and application thereof |
| CN102286002A (en) * | 2011-08-31 | 2011-12-21 | 山东罗欣药业股份有限公司 | Cefpiramide sodium powder injection composition and preparation method thereof |
| CN103319505A (en) * | 2013-06-07 | 2013-09-25 | 华北制药河北华民药业有限责任公司 | Method for crystallizing and producing cefpiramide sodium crystals |
| CN109369683A (en) * | 2018-11-01 | 2019-02-22 | 华北制药河北华民药业有限责任公司 | A kind of preparation method of CefPiramide Sodium |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1305877C (en) * | 2004-07-07 | 2007-03-21 | 广州白云山医药科技发展有限公司 | Process for preparing cefpiramide sodium |
-
2007
- 2007-04-18 CN CNB2007100519070A patent/CN100480251C/en not_active Expired - Fee Related
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101838276A (en) * | 2010-05-17 | 2010-09-22 | 胡梨芳 | Cefpiramide sodium hydrate and preparation method and application thereof |
| WO2011144021A1 (en) * | 2010-05-17 | 2011-11-24 | 胡梨芳 | Cefpiramide sodium hydrate, preparation method and uses thereof |
| CN101838276B (en) * | 2010-05-17 | 2012-10-10 | 胡梨芳 | Cefpiramide sodium hydrate and preparation method and application thereof |
| CN102286002A (en) * | 2011-08-31 | 2011-12-21 | 山东罗欣药业股份有限公司 | Cefpiramide sodium powder injection composition and preparation method thereof |
| CN102286002B (en) * | 2011-08-31 | 2013-07-03 | 山东罗欣药业股份有限公司 | Cefpiramide sodium powder injection composition and preparation method thereof |
| CN103319505A (en) * | 2013-06-07 | 2013-09-25 | 华北制药河北华民药业有限责任公司 | Method for crystallizing and producing cefpiramide sodium crystals |
| CN109369683A (en) * | 2018-11-01 | 2019-02-22 | 华北制药河北华民药业有限责任公司 | A kind of preparation method of CefPiramide Sodium |
| CN109369683B (en) * | 2018-11-01 | 2020-04-07 | 华北制药河北华民药业有限责任公司 | Preparation method of cefpiramide sodium |
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| CN100480251C (en) | 2009-04-22 |
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Denomination of invention: Method for synthesizing compound of cefpiramide sodium Effective date of registration: 20110201 Granted publication date: 20090422 Pledgee: Bank of Communications Ltd Wuhan East Lake New Technology Development Zone sub branch Pledgor: Tongyuan Pharmaceutical Ind Co., Ltd., Wuhan Registration number: 2011990000041 |
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Date of cancellation: 20180628 Granted publication date: 20090422 Pledgee: Bank of Communications Ltd Wuhan East Lake New Technology Development Zone sub branch Pledgor: Tongyuan Pharmaceutical Ind Co., Ltd., Wuhan Registration number: 2011990000041 |