CN101613359B - Method for synthesizing cefuroxime sodium - Google Patents
Method for synthesizing cefuroxime sodium Download PDFInfo
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- CN101613359B CN101613359B CN2009101628676A CN200910162867A CN101613359B CN 101613359 B CN101613359 B CN 101613359B CN 2009101628676 A CN2009101628676 A CN 2009101628676A CN 200910162867 A CN200910162867 A CN 200910162867A CN 101613359 B CN101613359 B CN 101613359B
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Abstract
The invention relates to a method for synthesizing cefuroxime sodium, which comprises the following steps: 1, performing the N- acylation reaction of 3-deacetyl-7aminocephalosporanic acid and methoxyaminofuranyl ammonium salt which serve as raw materials and adjusting the pH value with hydrochloric acid to less than 7 in a mixed solvent phase to precipitate crystals to obtain 3-deoxyformyl cefuroxime acid; 2, performing the addition reaction of the 3-deoxyformyl cefuroxime acid and chlorosulfonyl isocyanate serving as a strong ammonia formylating agent in an organic solvent to obtain chlorosulfonyl cefuroxime acid, dehydrating the chlorosulfonyl cefuroxime acid to obtain the cefuroxime acid, decarburizing and concentrating the cefuroxime acid, crystallizing the cefuroxime acid in a solvent phase, and drying the crystals under vacuum to obtain a solid product of cefuroxime acid; and 3, dissolving the cefuroxime acid in alkaline solution, decarburizing the resulting product, crystallizing the resulting product in a mixed solvent phase, filtering crystals, and drying the crystals under vacuum to obtain the cefuroxime sodium.
Description
Technical field
The present invention relates to the medicine synthetic method, particularly a kind of new chemical synthesis process of antibiont medicine Cefuroxime sodium.
Technical background
Cephalosporins listing kind is from the first-generation to the existing kind more than 50 of four generations, cephalofruxin series belongs to second generation cephalosporin, has broad-spectrum antibacterial action, bacterium is produced the pharmaceutically-active lytic enzyme of destruction have high stability, thereby ensured good anti-microbial activity, few generation untoward reaction in clinical application, great majority are produced the pathogenic microbial infection of β-Nei Xiananmei remarkable curative effect.Cefuroxime sodium is that Britain Ge Lan element (Glaxo) company took the lead in developing listing in 1975; went on the market in the U.S. in 1988; after patent protection in 1996 expiration; be still the handsome person in the beta-lactam anti-infectives; its formulation has dry suspensoid, tablet, capsule, dispersible tablet and injection, and the present invention just provides a kind of production method of injection raw material.
The Cefuroxime sodium molecular structural formula is as follows:
Method for synthesizing cefuroxime sodium at present commonly used is:
Be raw material at first with 7-amino-cephalosporanic acid (7-ACA) and the amino furans ammonium acetate of methoxy (SMIA); earlier SMIA is made acyl chlorides at methylene dichloride; then carry out the N-acylation reaction with 7-ACA; and under the strong basicity environment, the ethanoyl hydrolysis of 3-position is fallen, separate out the MDCC crystallization at aqueous phase with hydrochloric acid at last.Then with MDCC and strong carbamylation reagent Sulfuryl chloride isocyanate (CSI); in tetrahydrofuran (THF), ethyl acetate, methylcarbonate equal solvent, carry out nucleophilic addition(Adn) and obtain the chlorosulfonylation cefuroxime acid; obtain cefuroxime acid after the capable again hydrolysis; at last directly obtain the Cefuroxime sodium crude product, again crude product refining is obtained the Cefuroxime sodium finished product with the crystallization of Sodium isooctanoate salify.
Above-mentioned processing method is used by domestic and international most of producers always, reached more stable production level, but in the first step under the highly basic condition hydrolysis meeting beta-lactam nucleus is produced very havoc effect, not only can reduce yield, also very big to the constant product quality influence, cause look level instability, content reduces, defectives such as production cost height.
Summary of the invention
Technical problem to be solved by this invention is, a kind of different Cefuroxime sodium preparation method is provided, and is raw material with 7-DACD, and final sodium salt is improved yield with mixed solvent crystalline route, reduces production costs the stability of improving the quality of products.
The present invention finishes the preparation of Cefuroxime sodium by following three steps:
Step 1, be raw material, carry out the N-acylation reaction earlier, transfer pH value to acid with hydrochloric acid at mixed solvent in mutually again, separate out crystallization, obtain 3-deoxidation formyl cefuroxime acid with the amino SMIA of 3-deacetylation-7 amino-cephalo-alkanoic acid and methoxy;
Step 2, in organic solvent, carry out addition reaction with 3-deoxidation formyl cefuroxime acid and chlorine sulphonyl isocyanide ester and obtain the chlorosulfonylation cefuroxime acid, obtain cefuroxime acid after the hydrolysis immediately, take off charcoal, concentrate the back in the crystallization of solvent phase, cefuroxime acid.
Step 3, cefuroxime acid is dissolved with weak lye, take off charcoal, adopt the mixed solvent crystallization, filter, obtain Cefuroxime sodium.
Preferable methods, step is as follows:
Step 1, be raw material, carry out the N-acylation reaction earlier, transfer pH value to 1-7 with hydrochloric acid at water and methylene dichloride mixed solvent in mutually again, separate out crystallization, obtain 3-deoxidation formyl cefuroxime acid with the amino SMIA of 3-deacetylation-7 amino-cephalo-alkanoic acid and methoxy;
Step 2,3-deoxidation formyl cefuroxime acid and chlorine sulphonyl isocyanide ester carry out addition reaction and obtain the chlorosulfonylation cefuroxime acid in tetrahydrofuran (THF); obtain cefuroxime acid after the hydrolysis immediately; take off charcoal, concentrate the back, get cefuroxime acid in the crystallization of methylene dichloride solvent phase.
Step 3, with cefuroxime acid with the dissolving of sodium bicarbonate alkali lye, take off charcoal, adopt dehydrated alcohol and the crystallization of acetone mixed solvent, filter, obtain Cefuroxime sodium.
Wherein,
Water in the step 1 and methylene dichloride mixed solvent are volume ratio 10: 1-1: 10, and transfer pH value to 1-4 with hydrochloric acid;
Sodium bicarbonate alkali lye in the step 3 is the sodium bicarbonate alkali lye of 1-50%, and dehydrated alcohol and acetone mixed solvent are volume ratio 10: 1-1: 10.
Preferably, wherein:
Water in the step 1 and methylene dichloride mixed solvent are volume ratio 5: 1-1: 5, and transfer pH value to 1-3 with hydrochloric acid;
Sodium bicarbonate alkali lye in the step 3 is the sodium bicarbonate alkali lye of 1-30%, and dehydrated alcohol and acetone mixed solvent are volume ratio 5: 1-1: 5.
Particularly preferred, wherein
Water in the step 1 and methylene dichloride mixed solvent are volume ratio 2: 1-1: 2, and transfer pH value to 1-2 with hydrochloric acid;
Sodium bicarbonate alkali lye in the step 3 is the sodium bicarbonate alkali lye of 1-10%, and dehydrated alcohol and acetone mixed solvent are volume ratio 2: 1-1: 2.
The present invention is most preferred to be embodiment 1.
The invention has the advantages that:
Simplify production stage, improve product yield (total recovery is more than 143%), stabilized product quality reduces production costs, as:
Step 1 is a raw material with 7-DACA and SMIA; 7-position N-acylation reaction in advance; at mixed phase (water: separate out crystallization MDCC with hydrochloric acid methylene dichloride); avoided is the highly basic hydrolysing step of starting raw material with 7-ACA; and employing mixed phase (water: hydrochloric acid crystallization process methylene dichloride); yield significantly improves, and yield can reach 150%.
Be to carry out in solvent phase (methylene dichloride) during step 2 cephalofruxin acid crystal, yield can reach 105%.
The crystallization method of step 3 Cefuroxime sodium be with this acid after soda solution dissolving, (dehydrated alcohol: crystallization acetone), yield can reach 91% to drip mixed solvent.
Embodiment
Below with embodiment the present invention is described, but do not limit the present invention.
Embodiment 1:
The preparation of MDCC (deammoniation formyl cefuroxime acid):
In 1000 milliliters of dry four-necked bottles, add methylene dichloride 220ml, PCI
535g stirred 1 hour soon, lowered the temperature-30 ℃, added DMA (N.N-N,N-DIMETHYLACETAMIDE) 48ml, SMIA 26g, and-10～-12 ℃, reacted 80 minutes, with the washing of 3 * 110mil purified water, it is mutually stand-by to tell methylene dichloride.
In another 250ml four-necked bottle, add the 132ml purified water, add 7-DACA 25.4g, 0～2 ℃, dissolution of sodium hydroxide with 15% is clarification extremely, in the solution after top methylene dichloride adding at twice mutually (last time poured into, the back the is inferior to splash into) dissolving, keep PH6.5-7.0, reacted 2 hours, and told water, add the extraction of 36ml purified water more once, merge water, when intensification reaches 5-10 ℃, add EDTA disodium 0.16g, Sodium Pyrosulfite 0.3g and 150ml methylene dichloride, regulate feed liquid PH 2.0 with 16% hydrochloric acid 52ml again, stir 30 fens after-filtration, 120ml washing 2 times, the 80ml methylene dichloride is taken out and is washed 2 times, 40 ℃ of vacuum-drying 18 hours is to moisture≤1.8%, get dry product 38.1g, purity 97%, yield 150%.
The preparation of cefuroxime acid:
In the 500ml four-necked bottle, add 108ml tetrahydrofuran (THF), MDCC36g, 20 ℃, stirred 10 fens, and added CSI 10.4ml rapidly, temperature control-40 ℃, reacted 40 fens, and added purified water 36ml, stirred soon 40 fens, after the hydrolysis, add 60ml solvent (tetrahydrofuran (THF): ethyl acetate, 1: 1), drip 18% sodium bicarbonate 190ml and make into PH6.5, add the 180ml ethyl acetate again and stirred soon 10 fens, drip 30% hydrochloric acid 14ml and make into PH2.0, stir 10, get the ester phase, add the 2.0g charcoal, stirred 15 fens, filter take off charcoal liquid after, carry out 30 ℃ when being evaporated to half volume, slowly drip dichloromethane 280ml finished in 90 minutes, 5 ℃ of stirring and crystallizing are after 60 minutes, filter, 50 ℃ of dryings 9 hours are to moisture≤1%, content 98%, yield 105%.
The preparation of Cefuroxime sodium:
Add 75ml water for injection in the 1000ml four-necked bottle, stir down, add the 27.5g cefuroxime acid, drip 10% soda solution 25ml to molten entirely, add the 0.5g gac, stirred 30 fens, filter carbon removal, stir and in taking off charcoal liquid, drip mixed solvent 500ml (dehydrated alcohol: acetone, 1: 1) down, behind the crystallization, 8-10 ℃, to stir 2 hours, filter is brilliant, 500ml acetone is washed crystalline substance, drains 45 ℃ of vacuum-drying 5 hours, get product 25.02g, moisture 3.0%, content 89.5%, yield 91.0%.
Embodiment 2:
Method is with embodiment 1,
Wherein water and methylene dichloride mixed solvent are volume ratio 100ml: 200ml, transfer pH value to 1 with hydrochloric acid; Sodium bicarbonate alkali lye is 1% sodium bicarbonate alkali lye, and dehydrated alcohol and acetone mixed solvent are volume ratio 2: 1.
Embodiment 3:
Method is with embodiment 1,
Wherein water and methylene dichloride mixed solvent are volume ratio 500ml: 100ml, transfer pH value to 2 with hydrochloric acid; Sodium bicarbonate alkali lye is 10% sodium bicarbonate alkali lye, and dehydrated alcohol and acetone mixed solvent are volume ratio 1: 2.
Embodiment 4:
Method is with embodiment 1,
Wherein water and methylene dichloride mixed solvent are volume ratio 100ml: 500ml, transfer pH value to 2 with hydrochloric acid; Sodium bicarbonate alkali lye is 5% sodium bicarbonate alkali lye, and dehydrated alcohol and acetone mixed solvent are volume ratio 5: 1.
Embodiment 5:
Method is with embodiment 1,
Wherein water and methylene dichloride mixed solvent are volume ratio 500ml: 100ml, transfer pH value to 1 with hydrochloric acid; Sodium bicarbonate alkali lye is 8% sodium bicarbonate alkali lye, and dehydrated alcohol and acetone mixed solvent are volume ratio 1: 5.
Claims (1)
1. the synthetic method of a Cefuroxime sodium is characterized in that, comprises the steps: the preparation of deammoniation formyl cefuroxime acid:
In 1000 milliliters of dry four-necked bottles, add methylene dichloride 220ml, PCl
535g stirred 1 hour soon, lowered the temperature-30 ℃, added N,N-dimethylacetamide 48ml, the amino furans ammonium acetate of methoxy 26g, and-10～-12 ℃, reacted 80 minutes, with the washing of 3 * 110ml purified water, it is mutually stand-by to tell methylene dichloride;
In another 250ml four-necked bottle, add the 132ml purified water, add 3-deacetylation-7 amino-cephalo-alkanoic acid 25.4g, 0～2 ℃, dissolution of sodium hydroxide with 15% is to clarification, in the solution after adding is dissolved at twice mutually with top methylene dichloride, keep pH6.5-7.0, reacted 2 hours, tell water, add the extraction of 36ml purified water more once, merge water, heat up when reaching 5-10 ℃, add disodium ethylene diamine tetraacetate 0.16g, Sodium Pyrosulfite 0.3g and 150ml methylene dichloride are regulated material liquid pH 2.0 with 16% hydrochloric acid 52ml again, stir 30 fens after-filtration, 120ml washing 2 times, the 80ml methylene dichloride is taken out and is washed 2 times, and 40 ℃ of vacuum-drying 18 hours is to moisture≤1.8%, dry product 38.1g, purity 97%, yield 150%; The preparation of cefuroxime acid:
In the 500ml four-necked bottle, add 108ml tetrahydrofuran (THF), deammoniation formyl cefuroxime acid 36g, 20 ℃, stirred 10 fens, and added Sulfuryl chloride isocyanate 10.4ml rapidly, temperature control-40 ℃, reacted 40 fens, and added purified water 36ml, stirred soon 40 fens, after the hydrolysis, add the 60ml tetrahydrofuran (THF): ethyl acetate, 1: 1 solvent, drip 18% sodium bicarbonate 190ml and make into pH6.5, add the 180ml ethyl acetate again and stirred soon 10 fens, drip 30% hydrochloric acid 14ml and make into pH2.0, stirred 10 fens, get the ester phase, add the 2.0g charcoal, stirred 15 fens, filter take off charcoal liquid after, carry out 30 ℃ when being evaporated to half volume, slowly drip dichloromethane 280ml finished in 90 minutes, 5 ℃ of stirring and crystallizing are after 60 minutes, filter, 50 ℃ of dryings 9 hours are to moisture≤1%, content 98%, yield 105%; The preparation of Cefuroxime sodium:
Add 75ml water for injection in the 1000ml four-necked bottle, stir down, add the 27.5g cefuroxime acid, drip 10% soda solution 25ml to molten entirely, add the 0.5g gac, stirred 30 fens, filter carbon removal, stir and in taking off charcoal liquid, drip dehydrated alcohol down: acetone, 1: 1 mixed solvent 500ml, behind the crystallization, 8-10 ℃, stirred 2 hours, filter is brilliant, and 500ml acetone is washed crystalline substance, drain, 45 ℃ of vacuum-drying 5 hours, product 25.02g, moisture 3.0%, content 89.5%, yield 91.0%.
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Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102134252B (en) * | 2010-01-27 | 2013-03-27 | 四平市精细化学品有限公司 | Preparation method of high-purity cefuroxime acid |
| CN101967156B (en) * | 2010-09-26 | 2012-07-18 | 石药集团中诺药业（石家庄）有限公司 | Method for recrystallizing cefuroxime sodium |
| CN102391291B (en) * | 2011-09-21 | 2014-06-04 | 河北九派制药有限公司 | Cefmetazole acid preparation method |
| CN102702231B (en) * | 2012-06-18 | 2014-10-29 | 山东大学 | Method for preparing 3-descarbamoyl-cefuroxime acid |
| CN103159784B (en) * | 2013-03-29 | 2015-09-09 | 山东罗欣药业集团股份有限公司 | A kind of cefuroxime lysine and preparation thereof |
| CN103145734B (en) * | 2013-03-29 | 2016-05-04 | 山东罗欣药业集团股份有限公司 | A kind of cefuroxime lysine and preparation thereof |
| CN103450223A (en) * | 2013-08-16 | 2013-12-18 | 广东立国制药有限公司 | Preparation method of descarbamoyl cefuroxime |
| CN104072519A (en) * | 2014-07-04 | 2014-10-01 | 刘力 | Cefuroxime sodium compound entity and application thereof |
| CN104774211A (en) * | 2015-04-27 | 2015-07-15 | 四川制药制剂有限公司 | Preparation technique of cefuroxime sodium for injection |
| CN105440055B (en) * | 2015-12-30 | 2017-11-07 | 广东金城金素制药有限公司 | A kind of former development quality cefuroxime acid and its pharmaceutical preparation |
| CN106478667A (en) * | 2016-08-31 | 2017-03-08 | 河北科技大学 | A kind of preparation technology of 3 descarbamoyl cefuroxime acid crystals |
| CN106565748B (en) * | 2016-09-30 | 2019-03-22 | 华北制药河北华民药业有限责任公司 | The preparation method of Cefuroxime Sodium and its preparation |
| CN107652306B (en) * | 2017-10-24 | 2021-02-09 | 北京红太阳药业有限公司 | Cefuroxime sodium crystal compound |
| CN109851627B (en) * | 2018-12-21 | 2022-04-12 | 广州白云山天心制药股份有限公司 | Preparation method of cefuroxime sodium crystal compound |
| CN112679525B (en) * | 2020-12-24 | 2022-09-30 | 齐鲁安替制药有限公司 | Preparation method of cefuroxime acid |
| CN115353524A (en) * | 2022-08-25 | 2022-11-18 | 浙江东盈药业有限公司 | Synthesis method of cefuroxime sodium |
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Inventor after: Ma Jie Inventor after: Zhao Yuxin Inventor after: Jing Shiyun Inventor after: Huang Yuhong Inventor after: Zou Guoli Inventor after: Hu Qiao Feng Inventor after: Yang Jianing Inventor after: Dai Chunyan Inventor after: Ding Zhiyu Inventor before: Ma Jie Inventor before: Zhao Yuxin Inventor before: Jing Shiyun Inventor before: Huang Yuhong Inventor before: Zou Guoli Inventor before: Hu Qiao Feng Inventor before: Yang Jianing Inventor before: Dai Chunyan Inventor before: Ding Zhiyu |
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Effective date of registration: 20221019 Address after: No. 68, Limin West 4th Street, Limin Development Zone, Harbin, Heilongjiang 150500 Patentee after: HARBIN PHARMACEUTICAL GROUP HOLDING Co.,Ltd. Patentee after: MEDSHINE DISCOVERY Inc. Address before: 150086 No. 109, Xuefu Road, Harbin, Heilongjiang Patentee before: MEDSHINE DISCOVERY Inc. |
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