CN1203075C - Prepn of cefotaxime - Google Patents
Prepn of cefotaxime Download PDFInfo
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- CN1203075C CN1203075C CN 02118226 CN02118226A CN1203075C CN 1203075 C CN1203075 C CN 1203075C CN 02118226 CN02118226 CN 02118226 CN 02118226 A CN02118226 A CN 02118226A CN 1203075 C CN1203075 C CN 1203075C
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Abstract
The present invention relates to an improved method for preparing ceftiofur sodium, which comprises: 7-amino-3-[(2-furancarbonyl)thiomethyl]cephalosporanic acid reacts with 2-(2-amino-4-thiazolyl)-2-cis-methoxyimine acetate-2-mercaptobenzothiazole thioester in an aqueous solution of proper organic solvents under the existence of any one kind of triethylamine, trimethylamine, N-ethyl piperidine, dimethylamino pyridine, 1, 4-dimethylpiperazine and pyridine, the aqueous solution obtained by reactions is treated by any one kind of salts of diphenylamine, N-tert-butyl-cyclohexylamine, diisopropylamine, procaine, dicyclohexylamine and N, N-diphenyl ethylenediamine to obtain precipitates, and the precipitates react with sodium acetate and 2-ethyl sodium caproate in proper solvents to obtain the ceftiofur sodium.
Description
The present invention be a kind of preparation (6R, 7R)-7-[2-(thiazolamine-4-yl)-(Z)-2-(methoxy imino) acetamido]-3-[(2-furans carbonyl) thiomethyl]-3-cephem-4-carboxylic acid sodium is the new method of ceftiofur sodium (I).
Patent WO87/01117 has set forth the method for preparing ceftiofur sodium (I) from ceftiofur hydrochloride (IV),
In addition, patent EP0180372 has set forth the method for preparing ceftiofur hydrochloride (IV) from the ceftiofur (III) of ceftiofur (II) or trityl as protecting group.That is to say that prior art is told us, ceftiofur sodium can prepare by ceftiofur hydrochloride from ceftiofur or trityl ceftiofur.We are surprised to find a kind of new preparation ceftiofur sodium now, and it is simple to have method, and yield is higher, the advantage that product purity is high.Therefore, purpose of the present invention just provides a kind of method that more effectively prepares ceftiofur sodium.
The present invention prepares ceftiofur sodium by following synthetic route
Reaction (1) is finished at-20 ℃ to 30 ℃, and preferable reaction temperature is-5 ℃ to 25 ℃, preferred especially 0 ℃ to 10 ℃.
Reaction (1) is carried out in a kind of appropriate organic solvent aqueous solution, organic solvent is tetrahydrofuran (THF), N,N-DIMETHYLACETAMIDE, dimethyl formamide, dioxane, glycol dimethyl ether or above-mentioned suitable mixed solvent, and preferred solvent is tetrahydrofuran (THF), N,N-DIMETHYLACETAMIDE or both mixed solvents.
Reaction (1) should be carried out in the presence of a kind of organic amine, and organic amine is Dimethylamino pyridine, Trimethylamine 99, pyridine, 1, the 4-lupetazin, and N-ethylpiperidine, triethylamine, preferred organic amine is a triethylamine.
The salt (V) that reaction generates is not separated from reaction solution, and directly uses N, and N-dibenzyl-ethylenediamin acetate is handled, and obtains purer salt (VI) quantitatively thereby can be actually.
N, the N-dibenzyl-ethylenediamin can be used dicyclohexyl amine, pentanoic, Diisopropylamine, N-tertiary butyl hexahydroaniline and procaine base substitute.
Salt (VI) appropriate organic solvent such as tetrahydrofuran (THF), ketone such as acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK), alcohol as methyl alcohol and ethanol in or in the above-mentioned aqueous solutions of organic solvent with sodium-acetate, 2 ethyl hexanoic acid sodium prepared in reaction ceftiofur sodium (I).
Whole inventive method prepares ceftiofur sodium (I) total efficiency and is stabilized in and is higher than 80.0%.
Therefore, the present invention relates to the i.e. (6R of a kind of preparation ceftiofur sodium, 7R)-7-[2-(thiazolamine-4-yl)-(Z)-2-(methoxy imino) acetamido]-3-[(2-furans carbonyl) thiomethyl]-method of 3-cephem-4-carboxylic acid sodium, it comprises 7-amino-3-[(2-furans carbonyl) thiomethyl] Cephalosporanic acid and 2-(2-amino-4 thiazolyl)-2-methoxy imino acetate-2-mercaptobenzothiazole thioesters be at organic solvent and triethylamine, dimethylamino pyridine, Trimethylamine 99, pyridine, 1, in the aqueous solution under any amine exists in 4-lupetazin and the N-ethylpiperidine,-20 ℃ to 30 ℃ reactions, and then use dicyclohexyl amine, pentanoic, Diisopropylamine, N-tertiary butyl hexahydroaniline, procaine base and N, the salt of any alkali is handled and is obtained precipitation in the N-dibenzyl-ethylenediamin, and this is deposited in organic solvent or reacts with sodium-acetate or 2 ethyl hexanoic acid sodium in aqueous solutions of organic solvent.
Be embodiments of the invention below, described embodiment just is used for illustrating the present invention, rather than limits the present invention.
Embodiment 1
(6R, 7R)-7-[2-(thiazolamine-4-yl)-(Z)-2-(methoxy imino) acetamido]-3-[(2-furans carbonyl) thiomethyl]-3-cephem-4-carboxylic acid N, the preparation of N-dibenzyl-ethylenediamin acetate
With the 30ml N,N-DIMETHYLACETAMIDE, the mixing solutions of 200ml tetrahydrofuran (THF) and 200ml water is cooled to 0-3 ℃, add 20g 7-amino-3-[(2-furans carbonyl) thiomethyl] Cephalosporanic acid and 23.16gAE active thioester, under the 0-3 ℃ of stirring 13.62ml triethylamine is added dropwise in the above-mentioned suspension, extremely transparent 0-3 ℃ of reaction.The 200ml ethyl acetate is added above-mentioned transparent liquid, stir evenly, leave standstill, tell water, stir adding 10.44gN down, N-dibenzyl-ethylenediamin acetate, add the 150ml methylene dichloride then, obtain precipitation, filter, drying obtains 43.0g 7-[2-(thiazolamine-4-yl)-(Z)-2-(methoxy imino) acetamido under the vacuum]-3-[(2-furans carbonyl) thiomethyl]-3-cephem-4-carboxylic acid N, N-dibenzyl-ethylenediamin acetate (yield 93.68%).
Embodiment 2
With 10g 7-[2-(thiazolamine-4-yl)-2-(methoxy imino) acetamido]-3-[(2-furans carbonyl) thiomethyl]-3-cephem-4-carboxylic acid N, N-dibenzyl-ethylenediamin acetate adds in the 60ml tetrahydrofuran (THF) and the 4.4ml aqueous solution, add 4.56g 2 ethyl hexanoic acid sodium then, stirred 15 minutes, add the 350ml tetrahydrofuran (THF), filter solids, use the 30ml washing with acetone again three times, the dry 5.67g ceftiofur sodium (HPLC purity is not less than 98.0%, yield 85.4%) that gets under vacuum.
Embodiment 3
With 20g ceftiofur N, N-dibenzyl-ethylenediamin acetate adds in the 100ml tetrahydrofuran (THF) and the 8.8ml aqueous solution, add in the 37ml tetrahydrofuran solution of 9.12g 2 ethyl hexanoic acid sodium, stirred 15 minutes, add the 680ml tetrahydrofuran (THF), filter solids, use the 60ml washing with acetone again three times, vacuum-drying gets 11.42g ceftiofur sodium (HPLC purity is not less than 98.0%, yield 86.0%).
Embodiment 4
With 10g ceftiofur N, N-dibenzyl-ethylenediamin acetate adds in the 100ml acetone and the 25ml aqueous solution, adds the 1.59g sodium-acetate, stirred 30 minutes, and added 230ml acetone, filter solids, with 30ml washing with acetone three times, vacuum-drying obtains the 5.84g ceftiofur sodium.HPLC purity is not less than 98.0%, yield 88.0%.
Embodiment 5
With 20g ceftiofur N, N-dibenzyl-ethylenediamin acetate adds in the 184ml acetone and the 46ml aqueous solution, add the 3.17g sodium-acetate and be dissolved in 4ml water and 16ml acetone mixed solution, stirred 30 minutes, add 460ml acetone, filter solids, with 60ml washing with acetone three times, obtain the 11.8g ceftiofur sodium.HPLC purity is not less than 98.0%, yield 88.9%.
Claims (7)
1. one kind prepares the i.e. (6R of ceftiofur sodium, 7R)-7-[2-(thiazolamine-4-yl)-(Z)-2-(methoxy imino) acetamido]-3-[(2-furans carbonyl) thiomethyl]-method of 3-cephem-4-carboxylic acid sodium, it comprises 7-amino-3-[(2-furans carbonyl) thiomethyl] Cephalosporanic acid and 2-(2-amino-4 thiazolyl)-2-methoxy imino acetate-2-mercaptobenzothiazole thioesters be at organic solvent and triethylamine, dimethylamino pyridine, Trimethylamine 99, pyridine, 1, in the aqueous solution under any amine exists in 4-lupetazin and the N-ethylpiperidine,-20 ℃ to 30 ℃ reactions, and then use dicyclohexyl amine, pentanoic, Diisopropylamine, N-tertiary butyl hexahydroaniline, procaine base and N, the salt of any alkali is handled and is obtained precipitation in the N-dibenzyl-ethylenediamin, and this is deposited in organic solvent or reacts with sodium-acetate or 2 ethyl hexanoic acid sodium in aqueous solutions of organic solvent.
2. the method for preparing ceftiofur sodium according to claim 1 is characterized in that 7-amino-3-[(2-furans carbonyl) thiomethyl] Cephalosporanic acid and 2-(2-amino-4-thiazolyl)-2-methoxy imino acetate 2-mercaptobenzothiazole dredge that said organic solvent is tetrahydrofuran (THF), N,N-DIMETHYLACETAMIDE, dimethyl formamide, dioxane, glycol dimethyl ether or above-mentioned suitable mixed solvent in the ester reaction.
3. the method for preparing ceftiofur sodium according to claim 2 is characterized in that said organic solvent is tetrahydrofuran (THF), N,N-DIMETHYLACETAMIDE or both mixed solvents.
4. the method for preparing ceftiofur sodium according to claim 1 is characterized in that 7-amino-3-[(2-furans carbonyl) thiomethyl] Cephalosporanic acid and 2-(2-amino-4-thiazolyl)-2-methoxy imino acetate 2-mercaptobenzothiazole thioesters be reflected in organic solvent and the triethylamine aqueous solution under existing and carry out.
5. the method for preparing ceftiofur sodium according to claim 1, it is characterized in that 7-amino-3-[(2-furans carbonyl) thiomethyl] Cephalosporanic acid and 2-(2-amino-4-thiazolyl)-2-methoxy imino acetate 2-mercaptobenzothiazole thioesters reaction back N, N-dibenzyl-ethylenediamin acetate is handled and is obtained precipitation.
6. the method for preparing ceftiofur sodium according to claim 1, it is characterized in that ceftiofur sodium is by 7-[2-(thiazolamine-4-base-2-(methoxy imino) acetamido)-3-[(2-furans carbonyl) thiomethyl]-3-cephem-4-carboxylic acid N, N-dibenzyl-ethylenediamin acetate is in aqueous solutions of organic solvent and sodium-acetate or 2 ethyl hexanoic acid sodium reaction and making.
7. the method for preparing ceftiofur sodium according to claim 1, it is characterized in that 7-amino-3-[(2-furans carbonyl) thiomethyl] Cephalosporanic acid and 2-(2-amino-4-thiazolyl)-2-methoxy imino acetate-2-mercaptobenzothiazole thioesters be in the aqueous solution of the mixed solvent of tetrahydrofuran (THF) and N,N-DIMETHYLACETAMIDE and triethylamine,-20 ℃ to 30 ℃ reactions, and then use N, N-dibenzyl-ethylenediamin acetate is handled and is obtained precipitation, and this is deposited in organic solvent or reacts with sodium-acetate or 2 ethyl hexanoic acid sodium in aqueous solutions of organic solvent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02118226 CN1203075C (en) | 2002-04-26 | 2002-04-26 | Prepn of cefotaxime |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02118226 CN1203075C (en) | 2002-04-26 | 2002-04-26 | Prepn of cefotaxime |
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| CN1453280A CN1453280A (en) | 2003-11-05 |
| CN1203075C true CN1203075C (en) | 2005-05-25 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN 02118226 Expired - Fee Related CN1203075C (en) | 2002-04-26 | 2002-04-26 | Prepn of cefotaxime |
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Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101245078B (en) * | 2007-03-19 | 2010-05-26 | 齐鲁动物保健品有限公司 | Benzathine salt of ceftiofur, preparation method and application thereof |
| CN101654458B (en) * | 2009-09-28 | 2012-01-04 | 洛阳普莱柯生物工程有限公司 | Preparation method of hydrochloric acid ceftiofur |
| CN102093391A (en) * | 2009-12-09 | 2011-06-15 | 上海华理生物医药有限公司 | New preparation method of ceftiofur sodium |
| CN101829063B (en) * | 2010-03-18 | 2012-01-25 | 青岛康地恩药业有限公司 | Lung targeting microsphere of veterinary ceftiofur hydrochloride and preparation method |
| CN102584855B (en) * | 2012-02-16 | 2014-06-25 | 青岛科技大学 | Improved method for preparing ceftiofur |
| CN111171051B (en) * | 2020-03-05 | 2021-09-10 | 山西阳和医药技术有限公司 | Preparation method of cefixime |
| CN115772179A (en) * | 2022-12-09 | 2023-03-10 | 山东鑫泉医药有限公司 | Recrystallization method of ceftiofur sodium |
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- 2002-04-26 CN CN 02118226 patent/CN1203075C/en not_active Expired - Fee Related
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