CN102234289B - Novel method for preparing ceftiofur intermediate - Google Patents
Novel method for preparing ceftiofur intermediate Download PDFInfo
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- CN102234289B CN102234289B CN201010180899.1A CN201010180899A CN102234289B CN 102234289 B CN102234289 B CN 102234289B CN 201010180899 A CN201010180899 A CN 201010180899A CN 102234289 B CN102234289 B CN 102234289B
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Abstract
The invention relates to a novel method for preparing a ceftiofur intermediate. The method comprises the steps of: dropwise adding furoyl chloride into an ethyl acetate solution containing sodium hydrosulphide, adding tap water after the reaction, and neutralizing and dehydrating to obtain an ethyl acetate solution containing furan-2-carbothiolic acid; adding 7-aminocephalosporanic acid and ethyl acetate into a reacting bottle, then adding propionic acid and the ethyl acetate solution containing the furan-2-carbothiolic acid, at last adding boron trifluoride ethyl acetate for reaction; performing acidolysis by using hydrochloric acid after the reaction, neutralizing by using dilute ammonia water in a water phase, and separating to obtain the ceftiofur intermediate, namely 7-amino-3-[2-(furylcarbonyl)sulfomethyl]-3-cephem-4-carboxylic acid, wherein the yield of the intermediate reaches 97%.
Description
Technical field
The present invention relates to the preparation method of drug chemical, specifically, is a kind of ceftiofur intermediates preparation.
Background technology
7-amino-3-[2-(furyl carbonyl) thiomethyl]-3-cephem-4-carboxylic acid is the key intermediate of producing ceftiofur sodium, ceftiofur sodium (ceftiofur sodium) is that PharmaciaUpjohn company is in the cephalosporins veterinary drug of the exploitation eighties in 20th century.Its mechanism of action is to act on the bacterium transpeptidase and block the synthetic of cell walls, presents germicidal action, is used for the treatment of and controls the bacillary enteron aisle of livestock and respiratory tract infection.It is synthetic mainly to be raw material with the 7-amino-cephalosporanic acid, 3 condensation reaction and 7 amidate action takes place make ceftiofur acid, makes ceftiofur hydrochloride with the concentrated hydrochloric acid reaction then, changes into sodium salt finally by ceftiofur hydrochloride.
US Patent No. 6476220 and US6800756 etc. have set forth 7-amino-3-[2-(furyl carbonyl) thiomethyl]-preparation method of 3-cephem-4-carboxylic acid.Basic way is that sodium sulphite is dissolved in the tap water, drips furoyl chloride, and it is extremely acid with hydrochloric acid or phosphoric acid adjust pH that reaction finishes the back, obtains containing the solution of furans-2-carbothiolic acid then with ethyl acetate extraction.7-amino-cephalosporanic acid is dissolved in the ethyl acetate, adds above-mentioned solution, feeds boron triflouride gas and reacts, and obtains intermediate at aqueous phase with hydrochloric acid or phosphoric acid neutralization then.
Chinese patent CN02826649.8 has also set forth 7-amino-3-[2-(furyl carbonyl) thiomethyl]-preparation method of 3-cephem-4-carboxylic acid, basic way is equal to US Patent No. 6476220 and US6800756 etc.Chinese patent CN01142350.1 has set forth the method for producing the ceftiofur intermediate with the complex compound of methylcarbonate and its boron trifluoride.
The yield of above-mentioned several method is all below 80%.
Summary of the invention
The purpose of this invention is to provide the new preparation method of a kind of ceftiofur intermediate.This preparation method's yield height, the intermediate preparation cost is low, and the purity height has the good commercial prospect.
In order to achieve the above object, the present invention is by the following technical solutions:
Furoyl chloride and Sodium sulfhydrate react in organic solvent, obtain furans-2-carbothiolic acid solution, in solvent, under catalyst action, react with 7-amino-cephalosporanic acid then, obtain ceftiofur intermediate 7-amino-3-[2-(furyl carbonyl) thiomethyl through acid-alkali treatment]-3-cephem-4-carboxylic acid.
Described organic solvent is ethyl acetate.
Described solvent is ethyl acetate and propionic acid.
Described catalyzer is boron trifluoride ethyl acetate complex compound.
Described soda acid is hydrochloric acid and ammoniacal liquor.
Described hydrochloric acid is 11% hydrochloric acid, and described alkali is 10% ammoniacal liquor.
The synthetic route of preparation ceftiofur intermediate of the present invention, as described below:
Ceftiofur intermediates preparation of the present invention more specifically, comprises following steps:
(1), the preparation of furans-2-carbothiolic acid
In the reaction vessel that agitator, thermometer and constant pressure funnel are housed, add Sodium sulfhydrate, ethyl acetate, drip furoyl chloride, dropwise room temperature reaction 1-2 hour.Add tap water, use in the hydrochloric acid and pH to 1-2, divide to fall water layer, organic layer adds no dried over sodium sulfate, filters, and obtains containing the ethyl acetate solution of furans-2-carbothiolic acid.
(2), 7-amino-3-[2-(furyl carbonyl) thiomethyl]-preparation of 3-cephem-4-carboxylic acid
In the reaction vessel that agitator, thermometer are housed, add ethyl acetate, propionic acid, 7-amino-cephalosporanic acid, add ethyl acetate solution and the boron trifluoride ethyl acetate that contains furans-2-carbothiolic acid then, be warming up to 40-50 ℃ of reaction 2 hours.After reaction finishes, the ice bath cooling adds hydrochloric acid and reacted 30 minutes, filter, filter cake is suspended in the distilled water, transfer pH at 3.3-3.5 with weak ammonia, filtering separation, 35-40 ℃ of drying obtains off-white color ceftiofur intermediate 7-amino-3-[2-(furyl carbonyl) thiomethyl]-3-cephem-4-carboxylic acid.
Ceftiofur intermediate 7-amino-3-[2-(furyl carbonyl) thiomethyl that the present invention's reaction obtains]-3-cephem-4-carboxylic acid, instrument detects by analysis, and is consistent with the standard diagram of this material that document is put down in writing.Whole inventive method prepares ceftiofur intermediate 7-amino-3-[2-(furyl carbonyl) thiomethyl]-to be stabilized in 97%, HPLC purity be 95% to the total recovery of 3-cephem-4-carboxylic acid.
The present invention has characteristics such as yield height, quality is good, cost is low, is particularly suitable for suitability for industrialized production.
Embodiment
Be embodiments of the invention below, described embodiment just is used for illustrating the present invention, and should not be considered to be limitation of the present invention.
Embodiment 1
The preparation of furans-2-carbothiolic acid
In the 20ml ethyl acetate, add 8.0gNaSH.Splash into the 13.6g furoyl chloride under the room temperature, dropwise the back and stir 1h.Reaction finishes, and adds the 30ml tap water, stirs after 10 minutes, is neutralized between the pH=0.5-1.0 with concentrated hydrochloric acid.Tell organic phase, add the anhydrous sodium sulfate drying after-filtration.Be directly used in next step reaction.
Embodiment 2
7-amino-3-[2-(furyl carbonyl) thiomethyl]-preparation of 3-cephem-4-carboxylic acid
Under the room temperature condition, in clean dry reaction flask, drop into ethyl acetate 20ml, the 1ml propionic acid is opened and is stirred, and drops into 7-ACA15g then, drops into the ethyl acetate solution of the furans-2-carbothiolic acid of above-mentioned preparation.Be warming up to 43-45 ℃, add 21ml boron trifluoride ethyl acetate.Keep 43-45 ℃ of reaction 2 hours.Be down to room temperature, add 0.1gEDTA-2Na and 0.1g Sodium Pyrosulfite.Beginning slowly drips 11% hydrochloric acid 15ml in the feed liquid in the ice bath, reacts filtration 1.0 hours.Above-mentioned filter cake is suspended in the 50ml tap water.It is 3.3-3.5 that ammoniacal liquor with 10% is adjusted the pH value.Stirring at room 1 hour.Filtering separation, tap water washing 3 times, use washing with acetone at last 3 times, obtain Powdered loose off-white color product, 35-40 ℃ of oven drying, obtain ceftiofur intermediate 7-amino-3-[2-(furyl carbonyl) thiomethyl]-3-cephem-4-carboxylic acid 18.3g, yield 97%, HPLC purity is 95%.
More than ceftiofur intermediates preparation provided by the present invention is described in detail, used specific case herein principle of the present invention and embodiment are set forth, the explanation of above embodiment just is used for helping to understand method of the present invention and core concept thereof; Simultaneously, for one of ordinary skill in the art, according to thought of the present invention, the part that all can change in specific embodiments and applications, in sum, this description should not be construed as limitation of the present invention.
Claims (1)
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| Application Number | Priority Date | Filing Date | Title |
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| CN201010180899.1A CN102234289B (en) | 2010-05-02 | 2010-05-02 | Novel method for preparing ceftiofur intermediate |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201010180899.1A CN102234289B (en) | 2010-05-02 | 2010-05-02 | Novel method for preparing ceftiofur intermediate |
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| CN102234289A CN102234289A (en) | 2011-11-09 |
| CN102234289B true CN102234289B (en) | 2013-07-10 |
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| CN201010180899.1A Expired - Fee Related CN102234289B (en) | 2010-05-02 | 2010-05-02 | Novel method for preparing ceftiofur intermediate |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804394A (en) * | 2014-01-24 | 2014-05-21 | 瑞普（天津）生物药业有限公司 | Preparation method of ceftiofur intermediate |
| CN104530085A (en) * | 2014-12-07 | 2015-04-22 | 河南领先科技药业有限公司 | New preparation method of ceftiofur sodium |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4937330A (en) * | 1985-08-12 | 1990-06-26 | The Upjohn Company | Conversion of cephalosporin hydrohalide salt to alkali metal salt |
| US20020065412A1 (en) * | 2000-11-27 | 2002-05-30 | Uthira Kumar | Cephalosporin compound and a process for its preparation |
| CN1424316A (en) * | 2001-12-11 | 2003-06-18 | 浙江海正药业股份有限公司 | Preparation of cephalosporin compound |
| WO2003059914A1 (en) * | 2002-01-15 | 2003-07-24 | Orchid Chemicals & Pharmaceuticals Limited | An improved synthesis of ceftiofur intermediate |
| WO2003093278A2 (en) * | 2002-05-03 | 2003-11-13 | Orchid Chemicals And Pharmaceuticals Limited | Process for the preparation of ceftiofur acid |
| CN1639169A (en) * | 2002-01-04 | 2005-07-13 | 奥齐德化学和制药有限公司 | An improved synthesis of ceftiofur intermediate |
-
2010
- 2010-05-02 CN CN201010180899.1A patent/CN102234289B/en not_active Expired - Fee Related
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4937330A (en) * | 1985-08-12 | 1990-06-26 | The Upjohn Company | Conversion of cephalosporin hydrohalide salt to alkali metal salt |
| US20020065412A1 (en) * | 2000-11-27 | 2002-05-30 | Uthira Kumar | Cephalosporin compound and a process for its preparation |
| CN1424316A (en) * | 2001-12-11 | 2003-06-18 | 浙江海正药业股份有限公司 | Preparation of cephalosporin compound |
| CN1639169A (en) * | 2002-01-04 | 2005-07-13 | 奥齐德化学和制药有限公司 | An improved synthesis of ceftiofur intermediate |
| WO2003059914A1 (en) * | 2002-01-15 | 2003-07-24 | Orchid Chemicals & Pharmaceuticals Limited | An improved synthesis of ceftiofur intermediate |
| WO2003093278A2 (en) * | 2002-05-03 | 2003-11-13 | Orchid Chemicals And Pharmaceuticals Limited | Process for the preparation of ceftiofur acid |
| US20030216567A1 (en) * | 2002-05-03 | 2003-11-20 | Orchid Chemicals And Pharmaceuticals Limited | New method for the preparation of ceftiofur sodium and its intermediates |
Non-Patent Citations (11)
| Title |
|---|
| 吴汝林等.头孢噻呋钠的合成工艺研究.《中国兽药杂志》.2007,第41卷(第2期),19-20. |
| 头孢噻呋的合成;朱阳等;《中国医药工业杂志》;20010620;第32卷(第6期);241-242 * |
| 头孢噻呋钠的制备;曾裕建等;《中国抗生素杂志》;20031230;第28卷(第11期);645-646 * |
| 头孢噻呋钠的合成工艺研究;吴汝林等;《中国兽药杂志》;20070220;第41卷(第2期);19-20 * |
| 实施例. |
| 曾裕建等.头孢噻呋钠的制备.《中国抗生素杂志》.2003,第28卷(第11期),645-646. |
| 朱阳等.头孢噻呋的合成.《中国医药工业杂志》.2001,第32卷(第6期),241-242. |
| 权利要求1-11 |
| 说明书第2页第5段 |
| 说明书第3页第5段 |
| 说明书第4页第2-3段. |
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