A kind of preparation method of cefuroxime axetilTechnical field
The present invention relates to medical manufacture field, be specifically related to a kind of preparation method of cefuroxime axetil.
Background technology
Cefuroxime axetil, chemical name: (6R, 7R)-7-[2-furyl (methoxyimino) kharophen]-3-carbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid; General medicine name CefuroximeAxetil; Have another name called cefuroxime axetil; Molecular formula: C20h22n4o10s, molecular weight: 510.48, CA registration number: 64544-07-61, its molecular structural formula is as figure below:
Cefuroxime axetil (Cefuroximeaxetil, Ceftin) is the initiative of GlaxoSmithKline PLC company, within 1988, goes on the market first in the U.S., 1996 years Patent expiries.Cefuroxime axetil is s-generation oral cephalosporin, this medicine by force fat-soluble, and oral absorption is good.Cefuroxime axetil is the carboxylate of cephalofruxin, disengages cephalofruxin in vivo and play its anti-microbial activity after hydrolysis.The latter's has a broad antifungal spectrum, anti-microbial effect are strong, stablize lactamase.The anti-microbial activity of cefuroxime axetil is very low, be hydrolyzed rapidly by nonspecific esterase in intestinal mucosa and portal system after oral absorption 3-4 minute, discharge cephalofruxin and play its anti-microbial effect, therefore the antimicrobial spectrum of cefuroxime axetil is identical with anti-microbial activity and cephalofruxin.Be mainly used in that sensitive organism is caused light clinically, moderate respiratory infection, urogenital infections, skin soft-tissue infection and gonorrhoea etc., in order to improve curative effect, pharmacopoeial requirements cefuroxime axetil is amorphous products.Cefuroxime axetil be obtain crystallization product by cefuroxime acid through over-churning, hydrolysis, crystallization three step, more namely drying obtains amorphous products.
Current synthesis cefuroxime axetil mainly contains following several path: cefuroxime acid and paraldehyde and acetyl bromide are carried out addition substitution reaction, in reaction process, keep temperature of reaction system to be-15 DEG C, adding a large amount of salt of wormwood in reaction process regulates reaction solution pH value to carry out reaction controlling, after reaction terminates, adopt Virahol and normal hexane crystallization.
The shortcoming of this technique is:
First: paraldehyde is unstable, and oxidizable one-tenth carboxylic acid, is easily decomposed into acetaldehyde in acid condition;
Second: adopt salt of wormwood as catalysts, it easily absorbs water and is alkalescence thus causes katalysis to decline, and conversion rate of products is low, long reaction time, and produce impurity many, color is dark;
3rd: adopt Virahol and normal hexane crystallization, these two kinds of solvents exist azeotropism, be not easy separately, to bring difficulty to industrial production recovery.
In Chinese patent application CN1447812A by the amine salt of cephalofruxin and 1-bromoethylacetic ester under the katalysis of salt of wormwood in-3 ~ 0 DEG C of condition sustained reaction 5 hours, after ethyl acetate, hydrochloric acid, sodium chloride solut-ion washing, with the crystalline mixture of ethyl acetate, methyl alcohol and hexane, dry cefuroxime axetil.Though the method can obtain the higher product of purity, conversion rate of products is low, and the production cycle is long.
(the cefuroxime axetil Study of synthesis method [J] such as Zhang Junli, 2006,23(6): 328-329+363) take dimethyl formamide as solvent, cefuroxime acid is raw material, salt of wormwood makes catalyzer, below 0 DEG C, drip the reaction of 1-acetyl oxygen-1-monobromethane, and carry out crystallization with isopropyl ether or dimethylbenzene and synthesize cefuroxime axetil.Although the method shortens the production cycle, adopt salt of wormwood to make catalyzer, conversion rate of products is low, impurity is many, color is dark, and operational condition is harsh, and energy consumption is large, produces and not easily controls.
Summary of the invention
The object of the invention is to for the deficiencies in the prior art, a kind of synthetic method of cefuroxime axetil of high purity high conversion good stability is provided.
This object is achieved by following technical solution.This technical scheme, for be dissolved completely by cefuroxime acid with dimethyl formamide, drips 1-bromoethylacetic ester and selects cupric chloride to be that catalyzer carries out esterification; Ethyl acetate and sodium chloride solution is selected to be hydrolyzed to reaction solution, to extract; Add hexanaphthene after underpressure distillation and carry out crystallization, suction filtration, be drying to obtain cefuroxime axetil.
Concrete technology comprises the steps:
The first step: add cefuroxime acid while stirring to dissolving completely in dimethyl formamide, control lysate temperature is T1 is 0-10 DEG C, slow dropping 1-bromoethylacetic ester, complete, add copper chloride catalyst, solution temperature to be warming up to T2 be 15-35 DEG C of Keep agitation reaction t is 0.5-3 hour;
Second step: add ethyl acetate after gained reaction in mixed solution while stirring and be hydrolyzed reaction in the first step, complete, add sodium chloride solution and stir extraction, remove lower phase aqueous phase, get phase organic phase, add aqueous hydrochloric acid and extract;
Remove lower phase aqueous phase, obtain phase organic phase; By upper phase organic phase, temperature control less than 25 DEG C, underpressure distillation, removing cut;
3rd step: add hexanaphthene and carry out crystallization in the solution after second step underpressure distillation, and make its sufficient crystallising, suction filtration by continuing stirring after crystal solution cooling, be drying to obtain product cefuroxime axetil.
Wherein, the 10-15%(mass unit that described cefuroxime acid quality consumption numerically equals dimethyl formamide volumetric usage is g, and volume unit is mL), be preferably 13%.
Described 1-bromoethylacetic ester volumetric usage is 1.0-1.5 times of cefuroxime acid quality consumption, is preferably 1.2 times.
Described concentration of sodium chloride solution is 10%, and concentration of hydrochloric acid solution is 3%.
Described cupric chloride consumption is the 10-15% of cefuroxime acid consumption, is preferably 12.5%;
Described T1 is preferably 2-8 DEG C, more preferably 5 DEG C;
Described T2 is preferably 20-30 DEG C, more preferably 25 DEG C;
Described t is preferably 1.5h;
Described ethyl acetate volumetric usage is 8-12 times for cefuroxime axetil quality consumption, is preferably 10 times.
Described hydrochloric acid volumetric usage is 6-9 times of cefuroxime axetil quality consumption, is preferably 7.5 times.
Described hexanaphthene volumetric usage is 15-20 times of cefuroxime acid quality consumption, and be preferably 17.5 times, described mass unit is g, and described volume unit is ml.
Technical scheme of the present invention has the following advantages:
First: processing condition are gentle
This motion technological reaction temperature requirement is not harsh between 5-35 DEG C, easy to control, and existing technique then must be reacted under low temperature (-15 DEG C), and control ratio is more difficult, and energy consumption is also larger;
Second: adopt cupric chloride to make catalyzer
Cupric chloride is nontoxic, excellent catalytic effect, and the reaction times is short, and product catalytic conversion is high, and the catalyzer that existing technique uses is salt of wormwood, and its catalytic effect is poor, causes conversion rate of products not high, and reaction impurities is more;
3rd: adopt cyclohexane give to be product crystallization solvent
Cyclohexane give is product crystallization solvent, easy to recovery of applied, and existing technique uses Virahol, normal hexane crystallization, and this mixed solvent separation difficulty, is unfavorable for recovery.
4th: adopt 1-bromoethylacetic ester to replace paraldehyde and acetyl bromide
1-bromoethylacetic ester and cefuroxime acid one-step synthesis sintetics, shorten the production cycle, improve the quality of products.
Embodiment
Following content is in conjunction with concrete preferred implementation further description made for the present invention, can not assert that specific embodiment of the invention is confined to these explanations.For general technical staff of the technical field of the invention; without departing from the inventive concept of the premise; some simple deduction or replace can also be made; all should be considered as belonging to protection scope of the present invention; the present invention uses but the technology be not described and indexing section, is prior art.
embodiment 1
In reaction flask, add dimethyl formamide 150mL, add 15g cefuroxime acid under stirring, lysate, to clarification, is cooled to 0 DEG C by stirring and dissolving; Slow dropping 15mL1-bromoethylacetic ester; After 1-bromoethylacetic ester drips, add the copper chloride catalyst of 1.5g, solution temperature is warming up to 15 DEG C and continues stirring reaction 0.5 hour, reaction process adopts HPLC monitoring, controls cephalofruxin acid-respons residual≤1.0%;
React complete, add 120ml ethyl acetate and stir 15 minutes under stirring, complete, the sodium chloride solution adding 10% stirs extraction 20 minutes, stratification, and lower phase aqueous phase is removed and obtained phase organic phase and be transferred in reaction flask; In organic phase, again add the aqueous hydrochloric acid agitator treating 20 minutes of 90mL3%, stratification, lower phase aqueous phase is removed and is obtained phase organic phase and be transferred in another reaction flask;
Control in reaction flask warm below 25 DEG C, underpressure distillation, removing cut; Then add 225mL hexanaphthene to stream in reaction flask and carry out crystallization, and continue stirring 2 hours sufficient crystallisings after crystal solution is cooled to 0 DEG C, suction filtration, is drying to obtain product cefuroxime axetil.Products obtained therefrom yield is 95.2%, and gas chromatographic analysis product purity is 98.1%.
embodiment 2
In reaction flask, add dimethyl formamide 150mL, add 16.5g cefuroxime acid under stirring, lysate, to clarification, is cooled to 2 DEG C by stirring and dissolving; Slow dropping 15mL1-bromoethylacetic ester; After 1-bromoethylacetic ester drips, add the copper chloride catalyst of 1.7g, solution temperature is warming up to 20 DEG C and continues stirring reaction 1.0 hours, reaction process adopts HPLC monitoring, controls cephalofruxin acid-respons residual≤1.0%;
React complete, add 148.5ml ethyl acetate and stir 15 minutes under stirring, complete, the sodium chloride solution adding 10% stirs extraction 20 minutes, stratification, and lower phase aqueous phase is removed and obtained phase organic phase and be transferred in reaction flask; In organic phase, again add the aqueous hydrochloric acid agitator treating 20 minutes of 99mL3%, stratification, lower phase aqueous phase is removed and is obtained phase organic phase and be transferred in another reaction flask;
Control in reaction flask warm below 25 DEG C, underpressure distillation, removing cut; Then add 288.8mL hexanaphthene to stream in reaction flask and carry out crystallization, and continue stirring 2 hours sufficient crystallisings after crystal solution is cooled to 0 DEG C, suction filtration, is drying to obtain product cefuroxime axetil.Products obtained therefrom yield is 95.8%, and gas chromatographic analysis product purity is 98.8%.
embodiment 3
In reaction flask, add dimethyl formamide 150mL, add 18g cefuroxime acid under stirring, lysate, to clarification, is cooled to 5 DEG C by stirring and dissolving; Slow dropping 21.6mL1-bromoethylacetic ester; After 1-bromoethylacetic ester drips, add the copper chloride catalyst of 2.3g, solution temperature is warming up to 25 DEG C and continues stirring reaction 1.0 hours, reaction process adopts HPLC monitoring, controls cephalofruxin acid-respons residual≤1.0%;
React complete, add 180ml ethyl acetate and stir 15 minutes under stirring, complete, the sodium chloride solution adding 10% stirs extraction 20 minutes, stratification, and lower phase aqueous phase is removed and obtained phase organic phase and be transferred in reaction flask; In organic phase, again add the aqueous hydrochloric acid agitator treating 20 minutes of 135mL3%, stratification, lower phase aqueous phase is removed and is obtained phase organic phase and be transferred in another reaction flask;
Control in reaction flask warm below 25 DEG C, underpressure distillation, removing cut; Then add 315mL hexanaphthene to stream in reaction flask and carry out crystallization, and continue stirring 2 hours sufficient crystallisings after crystal solution is cooled to 0 DEG C, suction filtration, is drying to obtain product cefuroxime axetil.Products obtained therefrom yield is 96.4%, and gas chromatographic analysis product purity is 99.0%.
embodiment 4
In reaction flask, add dimethyl formamide 150mL, add 19.5g cefuroxime acid under stirring, lysate, to clarification, is cooled to 5 DEG C by stirring and dissolving; Slow dropping 23.4mL1-bromoethylacetic ester; After 1-bromoethylacetic ester drips, add the copper chloride catalyst of 2.5g, solution temperature is warming up to 25 DEG C and continues stirring reaction 1.5 hours, reaction process adopts HPLC monitoring, controls cephalofruxin acid-respons residual≤1.0%;
React complete, add 195ml ethyl acetate and stir 15 minutes under stirring, complete, the sodium chloride solution adding 10% stirs extraction 20 minutes, stratification, and lower phase aqueous phase is removed and obtained phase organic phase and be transferred in reaction flask; In organic phase, again add the aqueous hydrochloric acid agitator treating 20 minutes of 146.3mL3%, stratification, lower phase aqueous phase is removed and is obtained phase organic phase and be transferred in another reaction flask;
Control in reaction flask warm below 25 DEG C, underpressure distillation, removing cut; Then add 341.3mL hexanaphthene to stream in reaction flask and carry out crystallization, and continue stirring 2 hours sufficient crystallisings after crystal solution is cooled to 0 DEG C, suction filtration, is drying to obtain product cefuroxime axetil.Products obtained therefrom yield is 97.8%, and gas chromatographic analysis product purity is 99.2%.
embodiment 5
In reaction flask, add dimethyl formamide 150mL, add 21g cefuroxime acid under stirring, lysate, to clarification, is cooled to 8 DEG C by stirring and dissolving; Slow dropping 25.2mL1-bromoethylacetic ester; After 1-bromoethylacetic ester drips, add the copper chloride catalyst of 2.6g, solution temperature is warming up to 30 DEG C and continues stirring reaction 1.5 hours, reaction process adopts HPLC monitoring, controls cephalofruxin acid-respons residual≤1.0%;
React complete, add 210ml ethyl acetate and stir 15 minutes under stirring, complete, the sodium chloride solution adding 10% stirs extraction 20 minutes, stratification, and lower phase aqueous phase is removed and obtained phase organic phase and be transferred in reaction flask; In organic phase, again add the aqueous hydrochloric acid agitator treating 20 minutes of 157.5mL3%, stratification, lower phase aqueous phase is removed and is obtained phase organic phase and be transferred in another reaction flask;
Control in reaction flask warm below 25 DEG C, underpressure distillation, removing cut; Then add 367.5mL hexanaphthene to stream in reaction flask and carry out crystallization, and continue stirring 2 hours sufficient crystallisings after crystal solution is cooled to 0 DEG C, suction filtration, is drying to obtain product cefuroxime axetil.Products obtained therefrom yield is 98.2%, and gas chromatographic analysis product purity is 99.2%.
embodiment 6
In reaction flask, add dimethyl formamide 150mL, add 22.5g cefuroxime acid under stirring, lysate, to clarification, is cooled to 10 DEG C by stirring and dissolving; Slow dropping 33.7mL1-bromoethylacetic ester; After 1-bromoethylacetic ester drips, add the copper chloride catalyst of 3.3g, solution temperature is warming up to 35 DEG C and continues stirring reaction 0.5 hour, reaction process adopts HPLC monitoring, controls cephalofruxin acid-respons residual≤1.0%;
React complete, add 270ml ethyl acetate and stir 15 minutes under stirring, complete, the sodium chloride solution adding 10% stirs extraction 20 minutes, stratification, and lower phase aqueous phase is removed and obtained phase organic phase and be transferred in reaction flask; In organic phase, again add the aqueous hydrochloric acid agitator treating 20 minutes of 202.5mL3%, stratification, lower phase aqueous phase is removed and is obtained phase organic phase and be transferred in another reaction flask;
Control in reaction flask warm below 25 DEG C, underpressure distillation, removing cut; Then add 450mL hexanaphthene to stream in reaction flask and carry out crystallization, and continue stirring 2 hours sufficient crystallisings after crystal solution is cooled to 0 DEG C, suction filtration, is drying to obtain product cefuroxime axetil.Products obtained therefrom yield is 95.7%, and gas chromatographic analysis product purity is 98.9%.