CN100554271C - The synthetic method of antibiotics cefamandole nafate - Google Patents
The synthetic method of antibiotics cefamandole nafate Download PDFInfo
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- CN100554271C CN100554271C CNB2007100242833A CN200710024283A CN100554271C CN 100554271 C CN100554271 C CN 100554271C CN B2007100242833 A CNB2007100242833 A CN B2007100242833A CN 200710024283 A CN200710024283 A CN 200710024283A CN 100554271 C CN100554271 C CN 100554271C
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Abstract
The present invention relates to a kind of synthetic method of antibiotics cefamandole nafate; it adopts, and 7-amino-3-(1-methyl isophthalic acid H-tetrazole-5-yl)-thiomethyl-3-cephalo-4-carboxylic acid is a raw material; obtain the Sodium O-formylcefamole solid by silicon alkyl reaction, acylation reaction, hydrolysis reaction, decolouring, five steps of salt-forming reaction, what used silanizing agent adopted in the silicon alkyl reaction is the mixture of silicon amine alkane and alkyl halogen silanes.The present invention has compared with prior art that technological operation is simple, with low cost, product yield is high, the advantage of good product quality and suitable suitability for industrialized production.
Description
Technical field
The present invention relates to a kind of synthetic method of antibiotics cefamandole nafate, belong to the synthetic field of medicine.Sodium O-formylcefamole is mainly used in formulations such as preparation injection powder injection and oral preparations, uses wider clinically.
Background technology
Sodium O-formylcefamole belongs to second generation cephalosporin class microbiotic, its chemical name is 7-D-(2-methanoyl phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5 base) thiomethyl]-3-cephem-4-carboxylic acid sodium salt, this product is the second generation cephalosporin class microbiotic of being succeeded in developing by U.S. Lilly company at first.
Sodium O-formylcefamole is the prodrug of Cefamandole, and its anti-microbial activity only is 1/5 of a Cefamandole, and Sodium O-formylcefamole enters and is hydrolyzed to Cefamandole in the body rapidly, so both anti-microbial effects in vivo are basic identical.Cefamandole has stronger anti-microbial effect to most gram positive coccus.Its mechanism of action mainly is to combine with penicillin-binding protein (PBPs) on the bacterial cell membrane; make the transpeptidase acidylate; suppress in the bacterium synthetic every with cell walls; the intersection that influences the cell wall mucopeptide composition links; cell fission and growth are suppressed; ne ar is elongated, dissolving at last and dead.
Sodium O-formylcefamole is applicable to pulmonary infection, urinary tract infections, biliary tract infection, skin soft-tissue infection, bone and the infection of joint due to the sensitive bacterial and septicemia, abdominal cavity infection etc.
The synthetic method of Sodium O-formylcefamole, according to the document of having reported mainly is with 7-amino-cephalosporanic acid (7-ACA) or 7-amino-3-(1-methyl isophthalic acid H-tetrazole-5-yl)-thiomethyl-3-cephalo-4-carboxylic acid (7-ATCA) is a starting raw material, and method or chloride method by active ester synthesize.The method of active ester is introduced as United States Patent (USP) (US4351947); formyl mandelic acid and 1-methyl-5-sulfydryl-1; 2; 3; active ester is made in the reaction of 4-tetrazole; with 7-ACA or 7-amino-3-(1-methyl isophthalic acid H-tetrazole-5-yl)-thiomethyl-3-cephalo-4-carboxylic acid (7-ATCA) reaction, obtain Mandokef acid again, obtain Sodium O-formylcefamole through salt-forming reaction again.This method technology more complicated.Use toxicity and the bigger materials of supersensitivity such as DCC in the technology, need strict labor protection aborning, and synthetic total recovery is not high, is about 72%, quality product is also unstable.Introduced the synthetic Sodium O-formylcefamole of the method that adopts acyl chlorides in the European patent (EP0432297).7-ACA and 1-methyl-5-sulfydryl-1,2,3; the reaction of 4-tetrazole obtains 7-ATCA; 7-ATCA through the silylation protection, carries out acylation reaction with D-(-)-2-methanoyl-2-phenyl Acetyl Chloride 98Min. more again, separates to obtain Mandokef acid sodium solid after hydrolysis, decolouring, salt-forming reaction.In the method; produce the by product ammonia in the silicon alkyl reaction; need from the silicon alkyl reaction system, to drive away clean as far as possible; otherwise can have influence on the carrying out of acylation reaction; simultaneously; this method also adds the hydrogenchloride that extra Fu's acid agent neutralizes and produces again when acylation reaction; employed Fu's acid agent N; accelerine has carcinogenic toxicity; and need to isolate separately earlier Mandokef acid in the technology; increase operation steps, reduced yield, also therefore increased the manufacturing cost of this product.
Summary of the invention
The purpose of this invention is to provide a kind of operation simpler, be more suitable for that suitability for industrialized production, product yield are higher, the synthetic method of the synthetic method of the Sodium O-formylcefamole of better quality.
Technical scheme of the present invention is: a kind of synthetic method of antibiotics cefamandole nafate, and it adopts, and 7-amino-3-(1-methyl isophthalic acid H-tetrazole-5-yl)-thiomethyl-3-cephalo-4-carboxylic acid is a raw material, and comprises following five steps:
(1), silicon alkyl reaction: 7-amino-3-(1-methyl isophthalic acid H-tetrazole-5-yl)-thiomethyl-3-cephalo-4-carboxylic acid obtains the estersil of 7-amino-3-(1-methyl isophthalic acid H-tetrazole-5-yl)-thiomethyl-3-cephalo-4-carboxylic acid with the silanizing agent reaction under the condition that organic solvent exists, described silanizing agent is a silicon amine alkane;
(2), acylation reaction: step (1) gained reaction product and D-(-)-2-methanoyl-2-phenyl excess acetyl chloride;
(3), hydrolysis reaction: step (2) products therefrom hydrolysis obtains the Mandokef acid solution;
(4), decolouring: separating step (3) gained Mandokef acid solution, through the activated carbon decolorizing after-filtration, after gained concentrating filter liquor, crystallization, the filtration, dry gained crystal obtains Mandokef acid solid, and the Mandokef acid solid with gained is dissolved in the organic solvent again;
(5), salt-forming reaction: with step (4) gained solution and organic acid sodium salt reaction, reaction gained solution obtains the Sodium O-formylcefamole solid through crystallization, filtration after washing gained crystal and the drying;
Wherein: what the described silanizing agent in the step (1) adopted is the mixture of silicon amine alkane and alkyl halogen silanes.
Adopt technique scheme; silanizing agent is a mixture; except existing silicon amine alkane; also added alkyl halogen silanes; therefore in silylation protection process; the by product ammonia that silicon amine alkane produces can be by in the hydrogen halide that alkyl halogen silanes produced and form ammonium halide; so do not need to add extra acid or other means and drive away the by product ammonia of generation; when acylation reaction, do not need to add Fu's acid agent N yet; the hydrogenchloride that accelerine neutralizes and produced, direct and D-(-)-2-methanoyl-2-phenyl excess acetyl chloride of silicon alkyl reaction products therefrom.Therefore, need not use the N of carcinogenic toxicity, accelerine, can increase operation security, reduce pollution to environment.The mixed silanes agent of Shi Yonging and the single silanizing agent of use such as hexamethyldisilazane (HMDS) or N in addition, the two silica-based ethanamides of front three (BSA) of O-are compared, and cost is much lower.
Preferred 5: 8～8: 5 of the mol ratio of silicon amine alkane and alkyl halogen silanes, wherein said alkyl halogen silanes is trimethylchlorosilane, dimethyldichlorosilane(DMCS), Iodotrimethylsilane, bromotrimethylsilane, preferred trimethylchlorosilane or dimethyldichlorosilane(DMCS).
The organic solvent that uses in the step (1) is one or more the mixture in ethyl acetate, ethylene dichloride, methylene dichloride, propyl acetate, isopropyl acetate, butylacetate, acetone, methyl iso-butyl ketone (MIBK), the acetonitrile, ethyl acetate.
As a further improvement on the present invention, can in step (4), activated carbon decolorizing after-filtration gained filtrate vacuum concentration extremely be done, obtain weak yellow foam shape solid, add this weak yellow foam shape solid of organic solvent dissolution again, and decolour to wherein adding gac, filter and obtain the Mandokef acid solution, described organic solvent is one or more the mixture in acetone, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, methyl iso-butyl ketone (MIBK), methyl alcohol, ethanol, Virahol, the acetonitrile.Adopt aforesaid method, compare with existing method, on the one hand can continuous production, need not separate Cefamandole acid midway separately, simplified production process, improved the yield (improving about 5%) of product, can also prevent the degraded of Mandokef acid; Improve the quality of product.
In the methods of the invention, the employed solvent of each step reaction, preferably be easy to the mixed solvent of Separation and Recovery, preferred especially single component solvent, used organic solvent can obtain by the method for known rectifying reclaiming and recycling, and the quality product that obtains is better, and purity is higher, technology controlling and process is simpler, and cost is lower.
Organic acid sodium salt described in the step (5) is the salt that organic acid and sodium hydroxide form, can select sodium-acetate or Sodium isooctanoate for use in step (5) salt-forming reaction, these two kinds of organic acid sodium salts are higher than the solubleness in the organic solvent cheap and that use in above-mentioned step (4).
Generally speaking, the present invention have compared with prior art that technological operation is simple, with low cost, product yield is high, the advantage of good product quality and suitable suitability for industrialized production.
The Sodium O-formylcefamole synthetic route is as follows:
Embodiment
Come the present invention is set forth below in conjunction with specific embodiment.
Embodiment
In the four-hole reaction flask of 500ml, add the 300ml ethyl acetate, 30 gram 7-ATCA (0.092mol) are controlled at 20～25 ℃ with temperature, add 13.5ml HMDS (0.064mol), drip 8.2ml trimethylchlorosilane (0.064mol) in the time of stirring.Be warming up to 35～40 ℃ after dropwising and react, react and be cooled to 25～30 ℃ again after 3～4 hours, obtain the estersil solution of 7-ATCA.
In the estersil solution of above-mentioned 7-ATCA, drip 15.6ml D-(-)-2-methanoyl-2-phenyl Acetyl Chloride 98Min. (0.092mol), after dripping off in 30 minutes, temperature is remained on 25～30 ℃, restir reacted 1.5～2 hours, with HPLC detection reaction reach home (residual 7-ATCA concentration is lower than 1mg/ml in the reaction solution).
Add the reaction that is hydrolyzed of 200ml deionized water, stirred 20 minutes, remove water layer, the organic layer that contains Cefamandole acid usefulness 150ml saturated nacl aqueous solution again washs, and obtains the Cefamandole acid solution behind the branch vibration layer.
The Cefamandole acid solution that contains that obtains adds gac again and decolours, and filters, and gained filtrate vacuum concentration obtains weak yellow foam shape solid to doing (control material temperature is lower than 50 ℃).Treat that solid is cold slightly,, stir decolouring 30 minutes, filter again to wherein adding 250ml acetone and an amount of gac, and with 20ml washing with acetone charcoal layer.Collect filtrate and washing lotion at last, obtain the acetone soln of Mandokef acid.
In the four-hole reaction flask of another 250ml, add 28g Sodium isooctanoate and 100ml acetone, after the stirring and dissolving, again to wherein adding the 1g gac, temperature is controlled at 20～25 ℃ stirs decolouring 30 minutes down, remove by filter gac, with 10ml washing with acetone gac, last merging filtrate and washing lotion obtain the Sodium isooctanoate acetone soln.
The Sodium isooctanoate acetone soln was added drop-wise in 30～45 minutes in the Mandokef acid acetone soln, temperature is remained on 25～30 ℃, stirred 10 minutes, add 0.1g Sodium O-formylcefamole crystal seed, crystallization is 2～3 hours under stirring, and filters crystal, with washing with acetone gained crystal, and, obtain 43g Sodium O-formylcefamole solid, yield 92% 40 ℃ of following vacuum-dryings.
Claims (6)
1, a kind of synthetic method of antibiotics cefamandole nafate, it adopts, and 7-amino-3-(1-methyl isophthalic acid H-tetrazole-5-yl)-thiomethyl-3-cephalo-4-carboxylic acid is a raw material, and comprises following five steps:
(1), silicon alkyl reaction: 7-amino-3-(1-methyl isophthalic acid H-tetrazole-5-yl)-thiomethyl-3-cephalo-4-carboxylic acid obtains the estersil of 7-amino-3-(1-methyl isophthalic acid H-tetrazole-5-yl)-thiomethyl-3-cephalo-4-carboxylic acid with the silanizing agent reaction under the condition that organic solvent exists;
(2), acylation reaction: step (1) gained reaction product and D-(-)-2-methanoyl-2-phenyl excess acetyl chloride;
(3), hydrolysis reaction: step (2) products therefrom hydrolysis obtains the Mandokef acid solution;
(4), decolouring: separating step (3) gained Mandokef acid solution, through the activated carbon decolorizing after-filtration, after gained concentrating filter liquor, crystallization, the filtration, dry gained crystal obtains Mandokef acid solid, and the Mandokef acid solid with gained is dissolved in the organic solvent again;
(5), salt-forming reaction: with step (4) gained solution and organic acid sodium salt reaction, reaction gained solution obtains the Sodium O-formylcefamole solid through crystallization, filtration after washing gained crystal and the drying;
It is characterized in that: what the described silanizing agent in the step (1) adopted is the mixture of silicon amine alkane and alkyl halogen silanes, the mol ratio of silicon amine alkane and alkyl halogen silanes is 5: 8～8: 5, and described alkyl halogen silanes is selected from trimethylchlorosilane, dimethyldichlorosilane(DMCS), Iodotrimethylsilane or bromotrimethylsilane.
2, the synthetic method of antibiotics cefamandole nafate according to claim 1 is characterized in that: described alkyl halogen silanes is trimethylchlorosilane or dimethyldichlorosilane(DMCS).
3, the synthetic method of antibiotics cefamandole nafate according to claim 1 is characterized in that: the organic solvent that uses in the step (1) is one or more the mixture in ethyl acetate, methylene dichloride, ethylene dichloride, propyl acetate, isopropyl acetate, butylacetate, acetone, methyl iso-butyl ketone (MIBK), the acetonitrile.
4, the synthetic method of antibiotics cefamandole nafate according to claim 3 is characterized in that: the organic solvent that uses in the step (1) is ethyl acetate.
5, the synthetic method of antibiotics cefamandole nafate according to claim 1, it is characterized in that: in the step (4) activated carbon decolorizing after-filtration gained filtrate vacuum concentration is extremely done, obtain weak yellow foam shape solid, add this weak yellow foam shape solid of organic solvent dissolution again, and decolour to wherein adding gac, filter and obtain the Mandokef acid solution, described organic solvent is an acetone, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, methyl iso-butyl ketone (MIBK), methyl alcohol, ethanol, Virahol, the mixture of one or more in the acetonitrile.
6, the synthetic method of antibiotics cefamandole nafate according to claim 5 is characterized in that: the organic acid sodium salt described in the step (5) is sodium-acetate or Sodium isooctanoate.
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Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101279979B (en) * | 2008-06-03 | 2010-07-28 | 海南本创医药科技有限公司 | Separation and purification method of cefamandole nafate and preparation of cefathiamidine freeze-dried injectable powder |
| CN101880290B (en) * | 2010-06-28 | 2012-03-07 | 海南新中正制药有限公司 | Preparation method of cefamandole nafate |
| CN102250124B (en) * | 2011-05-20 | 2013-10-16 | 海南合瑞制药股份有限公司 | Synthesis method of cefbuperazone |
| CN102276629A (en) * | 2011-08-22 | 2011-12-14 | 苏州二叶制药有限公司 | Synthetic route for cefamandole nanfate |
| CN102766148B (en) * | 2012-08-06 | 2013-07-17 | 夏智红 | Cefamandole nafate compound and composite thereof |
| ES2721623T3 (en) * | 2012-10-19 | 2019-08-02 | Sandoz Ag | Novel procedure for the preparation of ceftaroline fosamil |
| CN103044453B (en) * | 2013-01-22 | 2014-07-30 | 湖北济生医药有限公司 | Cefamandole nafate compound and pharmaceutical composition thereof |
| CN104193767B (en) * | 2014-08-07 | 2016-07-06 | 杭州长典医药科技有限公司 | A kind of cefamandole nafate superfine powder preparation and preparation method thereof |
| CN105037392A (en) * | 2015-08-13 | 2015-11-11 | 青岛蓝盛洋医药生物科技有限责任公司 | Bactericidal medicine efamandole nafate compound and preparing method of bactericidal medicine efamandole nafate compound |
| CN105713012A (en) * | 2016-02-16 | 2016-06-29 | 顾伟 | Cefamandole nafate refining method |
| CN105646539B (en) * | 2016-03-16 | 2017-02-15 | 重庆福安药业集团庆余堂制药有限公司 | Cefotiam hydrochloride for reducing anaphylaxis and preparation thereof |
| CN106565750B (en) * | 2016-11-09 | 2018-09-11 | 哈药集团制药总厂 | A kind of synthetic method of dextrorotation Mandokef acid |
| CN109836438A (en) * | 2019-03-19 | 2019-06-04 | 河北科技大学 | The synthetic method of cefalexin impurity |
| CN110407857B (en) * | 2019-07-22 | 2020-11-03 | 山东罗欣药业集团股份有限公司 | Preparation process of cefathiamidine |
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Address after: 215212 No. 6 Jinzi Road, Lili Town, Wujiang District, Suzhou City, Jiangsu Province Patentee after: Suzhou Shengda Pharmaceutical Co., Ltd. Address before: 215212 No. 9 Jiaotong East Road, Lili Town, Wujiang City, Jiangsu Province Patentee before: China Union Chempharma (Suzhou) Co., Ltd. |