CN101245078A - Benzathine salt of ceftiofur, preparation method and application thereof - Google Patents
Benzathine salt of ceftiofur, preparation method and application thereof Download PDFInfo
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- CN101245078A CN101245078A CNA200710087836XA CN200710087836A CN101245078A CN 101245078 A CN101245078 A CN 101245078A CN A200710087836X A CNA200710087836X A CN A200710087836XA CN 200710087836 A CN200710087836 A CN 200710087836A CN 101245078 A CN101245078 A CN 101245078A
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Abstract
The invention relates to the double benzyl (or the substituted benzyl) ethylenediamine salt of Ceftiofur, the preparation method and the application in the preparation of ceftiofur sodium salt. The double benzyl (or the substituted benzyl) ethylenediamine salt of Ceftiofur is adopted for the preparation of ceftiofur sodium by the treatment of cation resin, the preparation process and the processing are simple, the purity of products is high and the technique is stable, thus being suitable for the industrial production.
Description
Technical field
The present invention relates to two benzyls (or substituted benzyl) ethylenediamine salt of ceftiofur, its preparation method and the application in the preparation of ceftiofur sodium salt thereof.
Background technology
Ceftiofur (ceftiofur, formula I), chemical name: (6R, 7R)-7-[2-(thiazolamine-4-yl)-(Z)-(methoxy imino) acetamido]-the 3-[(2-furyl carbonyl) thiomethyl]-3-cephem-4-carboxylic acid, be U.S. Pharmacia ﹠amp; The cephalosporins veterinary drug of Upjohn company exploitation is mainly used in the bacterial respiratory tract infection of treatment livestock etc.
The sodium-salt form ceftiofur sodium (formula II) of ceftiofur has good solubility in water, be easy to prepare injection preparation, is used widely.
Multiple Preparation of ceftiofur sodium method is disclosed in the document, for example, US4937330 discloses by ceftiofur hydrochloride (formula III) in basic resin and form the solution that contains ceftiofur, the method for preparing ceftiofur salt then with the metal exchange agent, but the ceftiofur hydrochloride synthesis yield is lower, and hydrochloric acid absorption does not thoroughly make and contains sodium-chlor in the product and influence quality product.
US6555679 discloses by ceftiofur hydrochloride and has prepared ceftiofur, then with the method for sodium exchanger prepared in reaction ceftiofur sodium, and the problem that this method exists the lower and ceftiofur of ceftiofur hydrochloride synthesis yield to be difficult to dry, stability is bad.
Patent disclosure such as US6555680, US6610845 directly form the method that triethylamine salt transfers sodium salt then in the synthetic ceftiofur process, but the triethylamine in the reaction, sodium-chlor etc. are difficult for effectively removing, and have influenced the purity of ceftiofur sodium.
US2005119244 and US2005119478 disclose the compound of following formula I V as preparing the ceftiofur useful as intermediates:
Chinese patent ZL94192110.7 discloses double benzyl ethylenediamine salt (formula V) of crystalline cefonicid and preparation method thereof, and the double benzyl ethylenediamine salt that has disclosed cefonicid has better stability and makes synthetic the purification be more prone to.
Chinese patent ZL02118226.4 discloses the Preparation of ceftiofur sodium method, and the salt (formula VI) with ceftiofur and the following structure of double benzyl ethylenediamine acetate reaction formation obtains ceftiofur sodium with sodium acetate or the direct salify of 2 ethyl hexanoic acid sodium then,
But this method exists the salt of formula VI to be difficult to dissolving, preparation ceftiofur sodium salify halfway defective in solvent, and the purity of product ceftiofur sodium and solvability do not reach medicinal requirements.
Summary of the invention
Variety of issue at the quality aspect of ceftiofur sodium preparation existence in the prior art, the inventor finds after deliberation, ceftiofur and two benzyl (or substituted benzyl) quadrol salifies obtain a kind of two benzyl (or substituted benzyl) ethylenediamine salts (formula VII) of ceftiofur of new texture, and then handle and can obtain the high purity ceftiofur sodium through Zeo-karb with the reaction of sodium exchanger by two benzyl (or substituted benzyl) ethylenediamine salts of ceftiofur, solve the purity and the solubility problem of ceftiofur sodium product, thereby finished the present invention.
More particularly, two benzyl (or substituted benzyl) the ethylenediamine salt solubleness in water and organic solvent of discoverable type VII ceftiofur of the present invention are less, and two benzyls (or substituted benzyl) quadrol can form, and two positive charges strengthen and the absorption of Zeo-karb, make that two benzyl (or substituted benzyl) quadrol absorption are more thorough, in ceftiofur and two benzyl (or substituted benzyl) quadrol salification process, keep slant acidity in addition, effectively avoided the degraded of ceftiofur, thereby guaranteed in preparation process, to form highly purified ceftiofur sodium with high yield.
Therefore, a first aspect of the present invention relates to two benzyl (or substituted benzyl) ethylenediamine salts of formula VII ceftiofur,
Wherein,
R1, R2, R3 are H, C1～C5 alkyl or substituted alkyl, halogen, nitro etc. independently of one another.Substituting group on the described substituted alkyl is selected from halogen and C1～C5 alkoxyl group.
As the useful intermediates of synthetic ceftiofur sodium, the advantage that two benzyl (or substituted benzyl) ethylenediamine salts of formula VII ceftiofur have the purity height, are easy to purify.
Another aspect of the present invention relates to the preparation method of two benzyl (or substituted benzyl) ethylenediamine salts of formula VII ceftiofur, and this method comprises that the appropriate form that makes ceftiofur reacts with formula VIII pair of benzyl (or substituted benzyl) quadrols or its salt,
Wherein,
R1, R2, R3 are H, C1～C5 alkyl or substituted alkyl, halogen, nitro etc. independently of one another.Substituting group on the described substituted alkyl is selected from halogen and C1～C5 alkoxyl group.
In above-mentioned preparation process, the appropriate form of described ceftiofur can be that not purified reaction solution also can be purified form, as metal-salt, ammonium salt, organic amine salt, inorganic acid salt or the organic acid salt of ceftiofur acid or ceftiofur.Two benzyls (or substituted benzyl) quadrol can be that the form of unhindered amina also can be the form of the salt of organic acid or mineral acid, as dihydrochloride or diacetin.
The reaction solvent that uses can be that water also can be the mixed solvent of water and organic solvent, described organic solvent comprises acetone, acetonitrile, dimethyl sulfoxide (DMSO), dimethyl formamide, methylene dichloride, ethyl acetate, methylethylketone, methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF) etc., preferred methylene dichloride or acetone.
During operation, need earlier with conventional organic acid or mineral acid or organic bases or mineral alkali, for example the pH value that will contain the solution of ceftiofur such as hydrochloric acid, acetate, sodium hydroxide, triethylamine, ammoniacal liquor is adjusted to 2～10, more preferably 4～8, add N then, the suitable salt of N '-two benzyls (or substituted benzyl) quadrol is as diacetin.With respect to 1 mole of ceftiofur, the add-on of two benzyls (or substituted benzyl) ethylenediamine salt is about 0.3 to 2 mole, and preferred about 0.5 to about 1 mole, more preferably from about 0.5 to about 0.8 mole.Keeping is enough to make two benzyl (or substituted benzyl) the ethylenediamine salt solids of ceftiofur to separate out the time completely, normally 1 to 6 hour, filters to isolate solid then.Analyze to show that two benzyl (or substituted benzyl) ethylenediamine salts of described ceftiofur be pair benzyl (or substituted benzyl) quadrols: the form of ceftiofur=1: 2 mol ratio.
Further aspect of the present invention relates to the application that two benzyl (or substituted benzyl) ethylenediamine salts of formula VII ceftiofur are used to prepare ceftiofur sodium.
The further aspect of the present invention relates to the method that is prepared highly purified ceftiofur sodium by two benzyl (or substituted benzyl) ethylenediamine salts of formula VII ceftiofur, this method is included in the solvent and handles two benzyl (or substituted benzyl) ethylenediamine salts of formula VII ceftiofur with Zeo-karb, the filtering resin, in filtrate, add the sodium exchanger then, obtain ceftiofur sodium.Can be referring to following preparation scheme:
Specifically, in solvent, handle two benzyl (or substituted benzyl) ethylenediamine salts of formula VII ceftiofur with Zeo-karb, for example, two benzyl (or substituted benzyl) ethylenediamine salts of formula VII ceftiofur can be suspended in tetrahydrofuran (THF), ethyl acetate, acetonitrile, acetone, ethanol, methyl alcohol, water and mixed solvent thereof, in the mixed solvent of preferred tetrahydrofuran (THF) and water, when stirring, add storng-acid cation exchange resin, stir down this mixture for several hour at 0～30 ℃, so that two benzyl (or substituted benzyl) the ethylenediamine salt dissolvings of ceftiofur, two benzyl (or substituted benzyl) quadrols are fallen in absorption, discharge ceftiofur acid, obtain a settled solution.Filter resin.If necessary, the filtrate processing of can decolouring.
Handle this free acid with the organic acid salt or the highly basic that dissolve in organic solvent then, promptly in filtrate, add the solution of sodium exchanger or dropping sodium exchanger.From solution, be settled out the ceftiofur sodium salt, keep temperature to be no more than 30 ℃ in this process, preferred 0～20 ℃, after the stirred for several hour, leach product.
According to the present invention, in the above-mentioned ceftiofur sodium preparation process ratio of two benzyl (or substituted benzyl) ethylenediamine salts of ceftiofur and solvent be about 1: 2 to about 1: 100w/vol, preferred 1: 3 to 1: 40w/vol.
The storng-acid cation exchange resin that adds can be selected from 001 * 7 storng-acid cation exchange resin, Amberlyst 15 and Amberlite IR-120 etc.The ratio of two benzyls (or substituted benzyl) ethylenediamine salt and described resin from about 1: 0.5 to about 1: 10w/w, preferred 1: 2 to 1: 5w/w.
The described sodium exchanger that dissolves in organic solvent is selected from 2 ethyl hexanoic acid sodium, and Sodium.alpha.-hydroxypropionate and sodium acetate, highly basic be selected from sodium hydroxide or sodium alkoxide, as sodium methylate etc., preferred 2 ethyl hexanoic acid sodium.
The ratio of two benzyl (or substituted benzyl) ethylenediamine salts of ceftiofur and sodium exchanger is 1: 0.5 to about 1: 3 mol ratio, preferred 1: 1 to about 1: 2 mol ratio.
Embodiment
Following examples will further specify the present invention, but not limit the present invention.
Embodiment 1: the preparation of ceftiofur double benzyl ethylenediamine salt
The 200ml methylene dichloride is cooled to 0～5 ℃, add 30.0g 7-amino-3-[(2-furans carbonyl) thiomethyl]-3-cephem-4-carboxylic acid, the 10ml anhydrous methanol, the 20ml triethylamine, drop into 33.0g 2-(thiazolamine-4-yl)-(Z)-(methoxy imino) acetate benzothiazole thioesters (AE active ester) then, 0～5 ℃ of reaction 8 hours.100ml water is added above-mentioned reaction solution, stir evenly, leave standstill, tell water; Add 100ml water again and stir evenly, leave standstill, tell water.Merge water, methylene dichloride 200ml extraction.Water is transferred PH to 6.0～8.0 with dilute hydrochloric acid, adds gac 1g decolorization filtering, and 100ml washes gac, merges water, adds the 100ml methylene dichloride, stirs.Other gets double benzyl ethylenediamine diacetin 20.0g, uses the 200ml water dissolution.Double benzyl ethylenediamine diacetin solution is added above-mentioned solution, promptly separate out ceftiofur double benzyl ethylenediamine salt, filter, washing, vacuum-drying get the double benzyl ethylenediamine salt (HPLC analyzes and shows that purity is greater than 97%) of 51g ceftiofur.
1HNMR analytical proof ceftiofur double benzyl ethylenediamine salt is two benzyl (or substituted benzyl) quadrols: the form of ceftiofur=1: 2 mol ratio.
1HNMR(DMSO-d
6，600MHz)δ9.56(d，1H)，8.04(d，1H)，7.45～7.20(m，8H)，6.76～6.73(m，1H)，5.69～5.66(m，1H)，5.05(d，1H)，4.21～3.95(dd，2H)，3.94(s，2H)，3.82(s，3H)，3.62～3.22(dd，2H)，2.95(s，2H).
Embodiment 2: the preparation of ceftiofur double benzyl ethylenediamine salt
Operation wherein contains ceftiofur and merges aqueous phase with adding 500ml acetone replacement 100ml methylene dichloride, and add 1000ml water with embodiment 1, gets the double benzyl ethylenediamine salt of 47g ceftiofur, and structure is identical with embodiment 1.
Embodiment 3: the preparation of ceftiofur double benzyl ethylenediamine salt
The 60g Ceftiofur Hydrochloride is suspended in the 400ml water, adds weak ammonia and regulate PH to 6.0～8.0, treat the solution clarification after, add gac 2g, stirred 30 minutes, filter, filtrate adds the 200ml methylene dichloride, stirring.Other gets double benzyl ethylenediamine diacetin 28g, uses the 300ml water dissolution.Double benzyl ethylenediamine diacetin solution is added above-mentioned solution, promptly separate out the double benzyl ethylenediamine salt of ceftiofur, stir, filter, washing, vacuum-drying gets the double benzyl ethylenediamine salt of 62g ceftiofur, and structure is identical with embodiment 1.
Embodiment 4: the preparation of ceftiofur double benzyl ethylenediamine salt
Operation wherein contains the ceftiofur water and adds 800ml acetone replacement 200ml methylene dichloride, and add 2000ml water with embodiment 3, gets the double benzyl ethylenediamine salt of 56g ceftiofur, and structure is identical with embodiment 1.
Embodiment 5: Preparation of ceftiofur sodium
The double benzyl ethylenediamine salt (27.2mmol) of the 35g ceftiofur of embodiment 1 preparation is suspended in the 250ml tetrahydrofuran (THF), add 25ml water, 150g 001 * 7 storng-acid cation exchange resin (Hydrogen), stir, reaction is to clarification, filter, with 100ml tetrahydrofuran (THF) washing resin, merge the tetrahydrofuran (THF) phase.The 3g gac is added above-mentioned solution, stirred 30 minutes, filter, the 250ml tetrahydrofuran (THF) is washed gac.Get 2 ethyl hexanoic acid sodium 10g, with the dissolving of 100ml tetrahydrofuran (THF).The 2 ethyl hexanoic acid sodium solution is stirred down the slowly above-mentioned ceftiofur solution of adding, keep temperature below 20 ℃, finish and continue to stir 5 hours, filter, tetrahydrofuran (THF) washing, vacuum-drying get 26.5g ceftiofur sodium salt (HPLC analyzes and shows purity greater than 99.0%, and yield is 89.3%).
Embodiment 6: Preparation of ceftiofur sodium
The double benzyl ethylenediamine salt (27.2mmol) of the 35g ceftiofur of embodiment 3 preparation is suspended in the 300ml acetone, adds 50ml water, 150g 001 * 7 storng-acid cation exchange resin (Hydrogen), stir, reaction is to clarification, filter, wash resin, merge the acetone phase with 100ml acetone.The 3g gac is added above-mentioned solution, stirred 30 minutes, filter, 100ml washing with acetone gac merges, and adds 500ml acetone, stirs.Get 2 ethyl hexanoic acid sodium 10g, use the 100ml acetone solution.The 2 ethyl hexanoic acid sodium solution is stirred down slowly adding ceftiofur solution, keep temperature below 20 ℃, finish and continue to stir 2 hours, filter, washing with acetone, vacuum-drying get 24g ceftiofur sodium salt (HPLC analyzes and shows purity greater than 99.0%, and yield is 80.9%).
Claims (10)
1. the compound of formula VII:
Wherein,
R1, R2, R3 are H, C1～C5 alkyl or substituted alkyl, halogen, nitro independently of one another, and the substituting group on the described substituted alkyl is selected from halogen and C1～C5 alkoxyl group.
2. the preparation method of the formula VII compound of claim 1, described method comprise makes ceftiofur and two benzyl (or substituted benzyl) quadrols of formula VIII or its reactant salt
Wherein,
R1, R2, R3 are respectively H, C1～C5 alkyl or substituted alkyl, halogen, nitro, and the substituting group on the described substituted alkyl is selected from halogen and C1～C5 alkoxyl group.
3. the method for claim 2, described ceftiofur is metal-salt, ammonium salt, organic amine salt, inorganic acid salt or the organic acid salt of ceftiofur acid or ceftiofur.
4. the method for claim 2, the pH value that it is characterized in that containing the solution of ceftiofur is adjusted to 2～10, add N then, N '-two benzyls (or substituted benzyl) quadrol or its salt, and with respect to 1 mole of ceftiofur, N, the add-on of N '-two benzyls (or substituted benzyl) quadrol or its salt is 0.3 to 2 mole.
5. the method for claim 4 is characterized in that described N, and the salt of N '-two benzyls (or substituted benzyl) quadrol is diacetin.
6. the method for preparing ceftiofur sodium comprises the compound of handling the formula VII that limits in the claim 1 with Zeo-karb, the filtering resin, and the solution that adds sodium exchanger or sodium exchanger subsequently in filtrate obtains the ceftiofur sodium precipitation.
7. the method for claim 6 is characterized in that described Zeo-karb is 001 * 7 storng-acid cation exchange resin.
8. claim 6 or 7 method is characterized in that reaction solvent is the mixed solvent of tetrahydrofuran (THF) and water.
9. claim 6 or 7 method is characterized in that described sodium exchanger is a 2 ethyl hexanoic acid sodium.
10. two benzyl (or substituted benzyl) ethylenediamine salts of formula VII ceftiofur that limit of claim 1 application that is used to prepare ceftiofur sodium.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101829063A (en) * | 2010-03-18 | 2010-09-15 | 青岛康地恩药业有限公司 | Lung targeting microsphere of veterinary ceftiofur hydrochloride and preparation method |
| CN102319219A (en) * | 2011-09-30 | 2012-01-18 | 四川金瑞克动物药业有限公司 | Chitosan nanoparticle preparation of ceftiofur sodium, and preparation method thereof |
| CN102885820A (en) * | 2011-07-20 | 2013-01-23 | 洛阳惠中兽药有限公司 | Medicinal composition containing ceftiofur bisbenzylethylenediamine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1203075C (en) * | 2002-04-26 | 2005-05-25 | 浙江海正药业股份有限公司 | Prepn of cefotaxime |
| US20050119244A1 (en) * | 2003-12-02 | 2005-06-02 | Acs Dobfar S.P.A. | Process for preparing cephalosporins with salified intermediate |
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2007
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101829063A (en) * | 2010-03-18 | 2010-09-15 | 青岛康地恩药业有限公司 | Lung targeting microsphere of veterinary ceftiofur hydrochloride and preparation method |
| CN102885820A (en) * | 2011-07-20 | 2013-01-23 | 洛阳惠中兽药有限公司 | Medicinal composition containing ceftiofur bisbenzylethylenediamine |
| CN102319219A (en) * | 2011-09-30 | 2012-01-18 | 四川金瑞克动物药业有限公司 | Chitosan nanoparticle preparation of ceftiofur sodium, and preparation method thereof |
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Effective date of registration: 20111026 Address after: 250100 Ji'nan Industrial Road, Shandong, No. 243 Co-patentee after: Qilu Synva Pharmaceutical Co., Ltd. Patentee after: Qilu Animal Health Products Co., Ltd. Address before: 250100 Ji'nan Industrial Road, Shandong, No. 243 Patentee before: Qilu Animal Health Products Co., Ltd. |