CN101475580A - Cefamandole nafate compounds and synthesizing method thereof - Google Patents
Cefamandole nafate compounds and synthesizing method thereof Download PDFInfo
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- CN101475580A CN101475580A CNA2009100008981A CN200910000898A CN101475580A CN 101475580 A CN101475580 A CN 101475580A CN A2009100008981 A CNA2009100008981 A CN A2009100008981A CN 200910000898 A CN200910000898 A CN 200910000898A CN 101475580 A CN101475580 A CN 101475580A
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Abstract
The invention relates to a cefamandole sodium compound and a method for synthesizing the same. The method comprises: carrying out hydroformylation of a formic acid and a D-(-)-mandelic acid in the presence of 4A molecular sieve; selecting a proper reaction solvent and amine for activation; reacting products obtained after activation with 7-amino-3-(1-methyl-1H-5-tetrazolyl)sulfidomethyl-3-cephem-4-carboxylic acid to obtain a cefamandole acid; and obtaining the cefamandole sodium after salification. Compared with the prior method, the method has the advantages of environmentally-friendly and safe technique, simple technical operation, mild condition, high product yield and the like and is more suitable for industrial production.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, be specifically related to the synthetic method of a kind of Mandokef acid and pharmaceutical salts, particularly Sodium O-formylcefamole.
The withered art of background
Sodium O-formylcefamole, chemical name are 7-D-(2-methanoyl phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5 base) thiomethyl]-3-cephem-4-carboxylic acid sodium salt, structural formula is as follows:
Sodium O-formylcefamole is a second generation cephalosporin class microbiotic, strong to the gram-negative bacteria effect, stronger, particularly the most effective to effects such as the positive Bacillus proteuss of clostridium, meningococcus, gonococcus, intestinal bacteria, pneumobacillus, hemophilus influenza and indoles that is sick of to hemophilus.Be mainly used in the various infection due to the sensitive organism clinically, as infection such as respiratory tract infection, biliary tract infection, pyelonephritis, urinary tract infections, peritonitis, septicemia and skin soft tissue, bone, joints.
The synthetic method of Sodium O-formylcefamole, existing a lot of documents and patent report, mostly adopting 7-amino-3-(1-methyl isophthalic acid H-tetrazolium-5-yl)-thiomethyl-3-cephalo-4-carboxylic acid (7-ATCA) and D-(-)-2-methanoyl-phenyl Acetyl Chloride 98Min. is the precursor intermediate, and method or chloride method by active ester synthesize.Described in the method for active ester such as the U.S. Pat 4351947; formyl mandelic acid and 1-methyl-5-sulfydryl-1; 2; 3; active ester is made in the reaction of 4-tetrazole; with 7-amino-cephalosporanic acid (7-ACA) or 7-amino-3-(1-methyl isophthalic acid H-tetrazolium-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 is used 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 50%, and quality product is also unstable.Introduced the synthetic Sodium O-formylcefamole of the method that adopts acyl chlorides in the European patent EP 0432297; 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-phenyl Acetyl Chloride 98Min. more again, separates obtaining the Sodium O-formylcefamole 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, and accelerine has carcinogenic toxicity.
Summary of the invention
The object of the present invention is to provide the synthetic method of a kind of Mandokef acid and pharmaceutical salts, particularly Sodium O-formylcefamole.The defective that it has overcome active ester method or chloride method existence makes to be reflected under the more gentle condition and takes place, for suitability for industrialized production is laid a good foundation.
The synthetic method of Mandokef acid provided by the invention or its pharmacy acceptable salt is characterized in that may further comprise the steps:
(1) formyl mandelic acid (D-(-)-2-methanoyl-toluylic acid) is synthetic
Formic acid and D-(-)-amygdalic acid react in the presence of the 4A molecular sieve and obtain D-(-)-2-methanoyl-toluylic acid;
(2) D-(-)-2-methanoyl-phenyllacetyl chloride is synthetic
D-(-)-2-methanoyl-toluylic acid, isopropyl chlorocarbonate, N-methyl piperidine react in organic solvent and obtain D-(-)-2-methanoyl-phenyllacetyl chloride;
(3) Mandokef acid or its pharmaceutical salts is synthetic
D-(-)-2-methanoyl-phenyllacetyl chloride and 7-amino-3-(1-methyl isophthalic acid H-tetrazolium-5-yl)-thiomethyl-3-cephalo-4-carboxylic acid (7-ATCA) reaction obtains Mandokef acid, if desired, Mandokef acid is formed Mandokef acid pharmacy acceptable salt.
Above-mentioned described Mandokef acid pharmacy acceptable salt is preferably Sodium O-formylcefamole, can be made by Mandokef acid and organic acid sodium salt reaction.Particularly, preferred Mandokef acid forms Sodium O-formylcefamole with organic acid sodium salt in Virahol and acetone soln; The volume ratio of preferred Virahol and acetone is (1-5): (1-5), more preferably the volume ratio of Virahol and acetone is 1:1.
Wherein, described organic acid sodium salt for example can be selected from sodium acetate, Sodium isooctanoate, Sodium propanecarboxylate, Sodium Benzoate, sodium bromate, is preferably sodium acetate.
As preferably, the above-mentioned described method of the present invention, wherein preferred described step (1) is for to add D-(-)-amygdalic acid and 4A molecular sieve in formic acid solution, reacting by heating, underpressure distillation, add toluene, remove by filter molecular sieve, use the distilled water wash organic phase, use the solid drier drying again, underpressure distillation obtains D-(-)-2-methanoyl-toluylic acid.
Wherein, described solid drier is not particularly limited, and for example can be selected from anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate, anhydrous calciumsulphate and activated alumina, is preferably anhydrous sodium sulphate.
Further, the present invention preferably, step (1) adds D-(-)-amygdalic acid and 4A molecular sieve in formic acid solution, be heated to 50-70 ℃ the reaction 2-5 hour, preferably, be heated to 60 ℃ the reaction 3 hours.
The above-mentioned described method of the present invention, wherein, step (2) and (3) can be carried out for one still process, and step (2) reaction product need not separated and directly carried out next step.For example, preferably, isopropyl chlorocarbonate is joined in the organic solvent solution of D-(-)-2-methanoyl-toluylic acid, add the N-methyl piperidine, stir, heating up makes solution becomes clear, and cooling again adds 7-amino-3-(1-methyl isophthalic acid H-tetrazolium-5-yl)-thiomethyl-3-cephalo-4-carboxylic acid, reaction adds entry, stirs, separatory gets organic phase, adds activated carbon decolorizing, filters, concentrate, add methylene dichloride and stir, separate out solid, filter, drying obtains Mandokef acid.
In the above-mentioned synthetic method, step (2) organic solvent, for example can be preferably ethyl acetate for one or more the mixture in ethyl acetate, methylene dichloride, ethylene dichloride, propyl acetate, isopropyl acetate, methyl acrylate, butylacetate, acetone, methyl iso-butyl ketone (MIBK), the acetonitrile.
In the above-mentioned synthetic method, preferred steps (2) and (3) are one still process, promptly add the N-methyl piperidine, stir, reactant is warmed up to 30 ℃, makes solution becomes clear, be cooled to 5 ℃ again, add 7-amino-3-(1-methyl isophthalic acid H-tetrazolium-5-yl)-thiomethyl-3-cephalo-4-carboxylic acid, kept this thermotonus 2 hours.
Above-mentioned described method, synthesizing of special preferably Sodium O-formylcefamole, Mandokef acid is dissolved in Virahol and the acetone soln, add the Virahol and the acetone soln of organic acid sodium salt, separate out crystallization, stir, filter, with Virahol and acetone soln washing leaching cake, drying, get Sodium O-formylcefamole.Especially the volume ratio of Virahol and acetone is 1:1.
With respect to existing prior art, the inventive method, the formylation of amygdalic acid is by adding the 4A molecular sieve in reaction system; can add fast response, and the usage quantity of formic acid significantly reduces, become present 5 times by 16 times of original amygdalic acid; reduced production cost, for industrialization is laid a good foundation.In the butt joint of two intermediates, use acyl chlorides and silylation to need very strong anhydrous condition, bigger to productive rate and product purity influence.The present invention is by selecting the activation of suitable reaction solvent and amine, improved reaction conditions, make to be reflected under the more gentle situation and take place, avoid the by product ammonia of silylation generation and driven away the acid that ammonia needs, also need not use Fu's acid agent N of carinogenicity, accelerine has increased security, has reduced the pollution to environment.In addition, the total recovery of the Sodium O-formylcefamole that is made by method of the present invention is generally about 80%, is higher than the yield of bibliographical information.
Embodiment
Further explain and describe content of the present invention by the following examples.But the embodiment that is provided should not be understood that protection domain of the present invention is construed as limiting.
Used 4A molecular sieve is available from global molecular sieve factory of Henan Province Nan Zhao among the present invention.
The Sodium O-formylcefamole of used product in contrast listing raw material is available from changing associating chemical pharmacy company limited among the present invention in the Suzhou, and lot number is 20070917.
Synthesizing of embodiment 1 formyl mandelic acid
D-(-)-amygdalic acids and the 50 gram 4A molecular sieves that in 98% the formic acid solution of 2500ml, add 500 grams, this mixture is heated to 60 ℃ of reactions 3 hours, unnecessary formic acid is removed in underpressure distillation, with adding the toluene of 3000ml in the residuum, remove by filter molecular sieve, with the distilled water wash organic phase of 2000ml, the organic phase anhydrous sodium sulfate drying, underpressure distillation obtains D-(-)-2-methanoyl-toluylic acid product 562 grams, yield 95%, mp:58-60 ℃.
Ultimate analysis C:70.5%, H:6.0%, O:23.5% (theoretical value C:70.6%, H:5.9%, O:23.5%)
Synthesizing of embodiment 2 Mandokef acid
Isopropyl chlorocarbonate with 400ml under the condition of room temperature joins in 3 liters of solution of the ethyl acetate that contains 500 gram D-(-)-2-methanoyl-toluylic acids, the N-methyl piperidine that adds 400ml stirs, and reactant is warmed up to 30 ℃, it is clear that reaction solution becomes, be cooled to 5 ℃, the 7-ATCA that adds 912 grams reacted 2 hours under this temperature, added the water of 1000ml, stir, separatory is removed water, adds activated carbon decolorizing in ethyl acetate layer, stirs half an hour, filter, filtrate is concentrated, obtain oily matter, add methylene dichloride (please replenish and add volume) and under 5 ℃ condition, stir, separate out solid, continue to stir 2 hours, product is fully separated out, filter, dry under 40 ℃ vacuum, obtain Mandokef acid 1264 grams, yield 93%, mp:129-131 ℃.
Ultimate analysis C:46.6%, H:3.6%, N:17.2%, O:19.4%, S:13.2% (theoretical value C:46.5%, H:3.7%, N:17.1%, O:19.6%, S:13.1%)
Synthesizing of embodiment 3 Sodium O-formylcefamoles
200 gram Mandokef acid are dissolved in 500ml Virahol and acetone (V:V=1:1) solution, slowly add the Virahol and acetone (V:V=1:1) the solution 500ml that contain 49 gram sodium acetates, the control flow velocity has crystallization to separate out after adding at per minute 20ml, stirs 2 hours, filtering product, with Virahol and acetone (V:V=1:1) washing leaching cake, product gets Sodium O-formylcefamole product 189 grams 40 ℃ of following vacuum-dryings, yield 91%, mp:191-193 ℃.
Ultimate analysis C:44.6%, H:3.3%, N:16.4%, O:18.6%, S:12.6%, Na:4.5% (theoretical value C:44.5%, H:3.4%, N:16.4%, O:18.7%, S:12.5%, Na:4.5%)
Embodiment 4 differentiates
Get the sample of embodiment 3 preparations, add water and make the solution that contains Cefamandole 20 μ g among every 1ml, measure according to spectrophotometry (two appendix IVA of Chinese Pharmacopoeia version in 2005), the result has maximum absorption at the wavelength place of 269nm.The result meets the ultraviolet spectrum characteristic of Sodium O-formylcefamole.
Embodiment 5 related substance inspections are according to high performance liquid chromatography.
Chromatographic condition and system suitability test octadecylsilane chemically bonded silica are weighting agent; With acetonitrile-10% triethylamine solution (with phosphorus acid for adjusting pH value to 2.5) is moving phase (20:80); The detection wavelength is 254nm.Number of theoretical plate calculates by the Sodium O-formylcefamole peak should be not less than 1500.
Detection method is got the sample of embodiment 3 preparations, adds water and makes the solution that every 1ml contains Cefamandole 0.5mg, as need testing solution; Get the listing Mandokef sodium raw materials of product in contrast, add water and make the solution that every 1ml contains Cefamandole 5 μ g, solution in contrast; Get above-mentioned need testing solution and contrast solution respectively, inject liquid chromatograph, the record color atlas is to 2 times of principal constituent peak retention time.The retention time of trial-product main peak is consistent with the retention time at reference substance peak as a result.
Test-results shows: embodiment 3 samples show that with high-performance liquid chromatogram determination it is consistent with the Sodium O-formylcefamole reference substance through differentiating.And the related substance of embodiment 3 samples is better than listing Mandokef sodium raw materials.The embodiment of the invention 3 makes the Sodium O-formylcefamole product.
According to the above embodiments the present invention has been made detailed description.It should be noted that above embodiment is just to illustrating the present invention.Under the prerequisite that does not depart from spirit of the present invention and essence, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be within protection scope of the present invention.
Claims (10)
1, the synthetic method of a kind of Mandokef acid or its pharmacy acceptable salt is characterized in that may further comprise the steps:
(1) formic acid and D-(-)-amygdalic acid react in the presence of the 4A molecular sieve and obtain D-(-)-2-methanoyl-toluylic acid;
(2) D-(-)-2-methanoyl-toluylic acid, isopropyl chlorocarbonate, N-methyl piperidine react in organic solvent and obtain D-(-)-2-methanoyl-phenyllacetyl chloride;
(3) D-(-)-2-methanoyl-phenyllacetyl chloride and 7-amino-3-(1-methyl isophthalic acid H-tetrazolium-5-yl)-thiomethyl-3-cephalo-4-carboxylic acid (7-ATCA) reaction obtains Mandokef acid, if desired, Mandokef acid is formed Mandokef acid pharmacy acceptable salt.
2, method according to claim 1 is characterized in that described Mandokef acid pharmacy acceptable salt is a Sodium O-formylcefamole, can be made by Mandokef acid and organic acid sodium salt reaction.
3, method according to claim 2 is characterized in that Mandokef acid forms Sodium O-formylcefamole with organic acid sodium salt in Virahol and acetone soln; The volume ratio of preferred Virahol and acetone is (1-5): (1-5), more preferably the volume ratio of Virahol and acetone is 1:1.
4, according to the described method of claim 2-3, wherein said organic acid sodium salt is selected from sodium acetate, Sodium isooctanoate, Sodium propanecarboxylate, Sodium Benzoate, sodium bromate, is preferably sodium acetate.
5, according to the described method of claim 1-4, it is characterized in that described step (1) is for adding D-(-)-amygdalic acid and 4A molecular sieve in formic acid solution, reacting by heating, underpressure distillation adds toluene, removes by filter molecular sieve, use the distilled water wash organic phase, use the solid drier drying again, underpressure distillation obtains D-(-)-2-methanoyl-toluylic acid.
6, method according to claim 5, wherein said solid drier is selected from anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate, anhydrous calciumsulphate and activated alumina, is preferably anhydrous sodium sulphate.
7, according to the described method of claim 5-6, it is characterized in that step (1) adds D-(-)-amygdalic acid and 4A molecular sieve in formic acid solution, be heated to 50-70 ℃ of reaction 2-5 hour, preferably, be heated to 60 ℃ of reactions 3 hours.
8, according to the described method of claim 1-7, it is characterized in that step (2) and (3) can carry out for one still process, step (2) reaction product need not separated and directly carried out next step.
9, method according to claim 8, it is characterized in that isopropyl chlorocarbonate is joined in the organic solvent solution of D-(-)-2-methanoyl-toluylic acid, add the N-methyl piperidine, intensification makes solution becomes clear, cooling again, add 7-amino-3-(1-methyl isophthalic acid H-tetrazolium-5-yl)-thiomethyl-3-cephalo-4-carboxylic acid reaction, obtain Mandokef acid.
10, according to the described method of claim 1-9, it is characterized in that the organic solvent described in the step (2) is one or more the mixture in ethyl acetate, methylene dichloride, ethylene dichloride, propyl acetate, isopropyl acetate, methyl acrylate, butylacetate, acetone, methyl iso-butyl ketone (MIBK), the acetonitrile, is preferably ethyl acetate.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101880290A (en) * | 2010-06-28 | 2010-11-10 | 海南新中正制药有限公司 | Preparation method of cefamandole nafate |
| CN101914106A (en) * | 2010-08-20 | 2010-12-15 | 湖北济生医药有限公司 | Cefamandole nafate hydrate and preparation method thereof |
| CN102372728A (en) * | 2011-11-28 | 2012-03-14 | 齐鲁安替制药有限公司 | Synthesizing method for cephalosporin compound |
| CN103044453A (en) * | 2013-01-22 | 2013-04-17 | 湖北济生医药有限公司 | Cefamandole nafate compound and pharmaceutical composition thereof |
| CN104193767A (en) * | 2014-08-07 | 2014-12-10 | 杭州长典医药科技有限公司 | Cefamandole nafate superfine powder preparation and preparation method thereof |
| CN106565750A (en) * | 2016-11-09 | 2017-04-19 | 哈药集团制药总厂 | Synthesis method for dextrorotation cefamandole nafate |
| CN113354534A (en) * | 2021-07-07 | 2021-09-07 | 江西科苑生物股份有限公司 | Preparation method of D- (-) -formyl mandelic acid chloride |
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2009
- 2009-01-21 CN CN2009100008981A patent/CN101475580B/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101880290A (en) * | 2010-06-28 | 2010-11-10 | 海南新中正制药有限公司 | Preparation method of cefamandole nafate |
| CN101914106A (en) * | 2010-08-20 | 2010-12-15 | 湖北济生医药有限公司 | Cefamandole nafate hydrate and preparation method thereof |
| CN102372728A (en) * | 2011-11-28 | 2012-03-14 | 齐鲁安替制药有限公司 | Synthesizing method for cephalosporin compound |
| CN103044453A (en) * | 2013-01-22 | 2013-04-17 | 湖北济生医药有限公司 | Cefamandole nafate compound and pharmaceutical composition thereof |
| 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 |
| CN104193767A (en) * | 2014-08-07 | 2014-12-10 | 杭州长典医药科技有限公司 | Cefamandole nafate superfine powder preparation and preparation method thereof |
| CN106565750A (en) * | 2016-11-09 | 2017-04-19 | 哈药集团制药总厂 | Synthesis method for dextrorotation cefamandole nafate |
| 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 |
| CN113354534A (en) * | 2021-07-07 | 2021-09-07 | 江西科苑生物股份有限公司 | Preparation method of D- (-) -formyl mandelic acid chloride |
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