CN103613604A - Method for preparing cefmenoxime sodium - Google Patents
Method for preparing cefmenoxime sodium Download PDFInfo
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- CN103613604A CN103613604A CN201310647452.4A CN201310647452A CN103613604A CN 103613604 A CN103613604 A CN 103613604A CN 201310647452 A CN201310647452 A CN 201310647452A CN 103613604 A CN103613604 A CN 103613604A
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- cefmenoxime
- sodium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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Abstract
The invention discloses a method for preparing cefmenoxime sodium. According to the method, by preparing the cefmenoxime of a sodium salt mode, the stability of the active ingredient, namely, the cefmenoxime, is improved, the cefmenoxime sodium disclosed by the invention can be directly dosed without being mixed, the costs of labor, power and auxiliary materials are lowered, and moreover the contamination rate is reduced.
Description
Technical field
The present invention relates to the synthetic field of medicine, specifically, relate to a kind of preparation method of cefmenoxime sodium.
Background technology
Cefmenoxime, English by name: Cefmenoxime, molecular formula is: C16H17N9O5S2, chemical name is: (6R, 7R)-7-[2-(2-amino-4-thiazolyl) (methoxyimino) kharophen]-3-[[1-methyl isophthalic acid H-tetrazolium-5-yl]]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid, belong to third generation cephalosporin, for the semisynthetic cephalosporins Broad spectrum antibiotics of the third generation, the biosynthesizing by anti-bacteria cell walls reaches germicidal action.In vitro tests shows, cefmenoxime all has effect to gram-positive microorganism and negative bacterium, it is because it is good and stable to β-lactamase to the permeability of epicyte that Gram-negative bacteria is had to strong anti-microbial effect, and to penicillin the organogenetic period of rat, rabbit and monkey medicine-feeding test result show, each administration group of rabbit all occurs that doe is dead or miscarries, but various animal is showed no teratogenesis.Rat General Reproductiv e Toxicity Assessment, perinatal period, reproductive toxicity test was showed no obvious abnormalities.Its avidity in conjunction with albumen (PBPs) 1A, 1B and 3 is strong, thereby cell wall mucopeptide is cross-linked to form and has stronger inhibition.Cefmenoxime is conventionally prepared into hydrochloride when medical, and its structural formula is:
Cefmenoxime Hemihydrochloride is by the semi-synthetic Broad spectrum antibiotics of the exploitation of Japanese Takede Chemical Industries Ltd, production, within 1996, enters Chinese market.It all has anti-microbial effect to Gram-negative and positive aerophil and anerobe.In Gram-negative bacteria, slightly stronger than cefotiam to the anti-microbial effect of intestinal bacteria, pneumobacillus, and be obviously better than the Kefzol of the first-generation, the anti-microbial effect of influenza being bitten to blood bacillus, Bacillus proteus, serratia marcesens, Citrobacter, enterobacter is also more intense, and Bacteroides is also had to very strong anti-microbial effect.In gram-positive microorganism, also stronger to micrococcus scarlatinae, pneumococcal anti-microbial effect.Peptococcus, Peptostreptococcus are also had to powerful anti-microbial effect.Stable to β-lactamase.Quiet notes 1g, blood medicine peak value 99.4ug/ml, intramuscular injection 0.5g, blood medicine peak value is 10.8ug/ml, serum T 1/2 is about 1 hour.Metabolism hardly in vivo, mainly through renal excretion.Binding rate of serum protein 85%.Good to bile transport, higher at the body fluid such as sputum, tonsilla, celiolymph, hydrothorax, peritoneal exudate, kidney, the bladder wall, uterus, uterine tube, ovary, pelvic cavity transudate, Cord blood, amniotic fluid and tissue distribution concentration, but transport seldom in milk.Be applicable to responsive microbial septicemia, meningitis, respiratory tract infection, pyothorax, liver and courage infection, peritonitis, urinary tract infection, genital system infection and burn and surgical wound infection etc.Since nineteen eighty-three listing, clinical application constantly expands, and sales volume rises year by year, and is written into state's latest edition pharmacopeia such as Japan and the United States.
Yet Cefmenoxime Hemihydrochloride is acid, must mix and could use with sterile sodium carbonate, cost is high, and step is many, and complicated operation has increased microbiological contamination and the probability of introducing visible foreign matters, and Cefmenoxime Hemihydrochloride contacts easily degraded with alkaline sodium carbonate.
Summary of the invention
In order to solve the defect existing in prior art, the invention provides a kind of preparation method of cefmenoxime sodium, by preparing the cefmenoxime of sodium-salt form, activeconstituents cefmenoxime stability is improved.
The preparation method who the present invention relates to a kind of cefmenoxime sodium, is achieved through the following technical solutions:
A preparation method for cefmenoxime sodium, comprises following processing step:
The 7-ATCA shown in formula (I) of take is raw material, under the condition of reaction solvent and basifier existence, carry out condensation reaction with MEAM, add water extraction, merge water, add ester phase solvent, use dilute hydrochloric acid to be adjusted to pH2.5～3.5, make cefmenoxime transfer to ester phase, ester divides mutually to the de-tank of charcoal, adds activated carbon decolorizing, through sterile filtration, enter in sterilisable chamber crystallizer, in filtrate, add aseptic Sodium isooctanoate or the sodium acetate soln in acetone or alcohol that be dissolved in, growing the grain, filtration, acetone or alcohol washing, vacuum-drying, obtain aseptic cefmenoxime sodium.
Described reaction solvent is any one or a few in methylene dichloride, ethyl acetate, methyl alcohol, ethanol, acetone.
Described basifier is any one or a few in pyridine, triethylamine, tetramethyl guanidine, sodium hydroxide.
Described ester phase solvent is any one in methylene dichloride, ethyl acetate, butylacetate.
Described growing the grain is 15～30 ℃ of growing the grains 30～60 minutes, is cooled to 5～15 ℃ of growing the grains 1～3 hour.
The cefmenoxime sodium that this preparation method obtains is with its sodium-salt form administration, without the directly administration of mixed powder, has reduced manually, the cost of power, auxiliary material, has reduced microbiological contamination probability, and finished product does not contact more stable with alkali.
The present invention adopts the method for anhydrous one-tenth sodium salt, utilize cefmenoxime acid to be dissolved in organic solvent, cefmenoxime sodium is insoluble to organic solvent, and needs the time because cefmenoxime becomes sodium salt, by controlling temperature, crystal is slowly grown up, thereby obtain the crystallization of the good cefmenoxime sodium of stability.Avoided because cefmenoxime sodium is soluble in water, be insoluble to acetone and other organic solvent, use solvent crystallization cause the supersaturation of cefmenoxime sodium, separate out too fast, be prone to water-in-oil or oil-in-water phenomenon, cause forming grume, thereby cause, cannot separate out cefmenoxime sodium.In addition, Sodium isooctanoate or sodium-acetate that the present invention uses are organic weak base, for dissolving in the salt forming agent of organic solvent, have overcome that the sodium carbonate of conventional use or sodium bicarbonate are only soluble in the aqueous phase and can not be for the defect of anhydrous salify.
Embodiment
By following examples, further describe the present invention, but should notice that scope of the present invention is not subject to any restriction of these embodiment.
Experimental example 1
In retort, add methylene dichloride 100L, methyl alcohol 10L, add 7-ATCA15kg, be cooled to 0 ℃ and add triethylamine 4.6kg, add MEAM 17.6kg, temperature control-5～10 ℃, react 6 hours, with 100L water and 50L water, respectively extract once, merge water, add ethyl acetate 200L, the hydrochloric acid that drips 3mol/L is adjusted to pH3.0 makes cefmenoxime transfer to ester phase, ester divides mutually to the de-tank of charcoal, add 0.1kg activated carbon decolorizing 15～30 minutes, through sterile filtration, enter in sterilisable chamber crystallizer, in alkali-prepared tank, add 100L acetone, add 8kg Sodium isooctanoate, stirring and dissolving, through sterile filtration, enter in sterilisable chamber crystallizer, separate out gradually, 15～30 ℃ of growing the grains 30～60 minutes, be cooled to 5～15 ℃ of growing the grains 1～3 hour, filter, 50L acetone is washed, 40 ℃ of vacuum-drying 16 hours, obtain aseptic cefmenoxime sodium 20.01kg, molar yield 82.09%, purity 99.3%.
Experimental example 2
In retort, add methylene dichloride 100L, methyl alcohol 10L, add 7-ATCA15kg, be cooled to 0 ℃ and add triethylamine 4.6kg, add MEAM 17.6kg, temperature control-5～10 ℃, react 6 hours, with 100L water and 50L water, respectively extract once, merge water, add ethyl acetate 200L, the hydrochloric acid that drips 3mol/L is adjusted to pH3.0 makes cefmenoxime transfer to ester phase, ester divides mutually to the de-tank of charcoal, add 0.1kg activated carbon decolorizing 15～30 minutes, through sterile filtration, enter in sterilisable chamber crystallizer, in alkali-prepared tank, add 100L acetone, add 4kg sodium-acetate, stirring and dissolving, through sterile filtration, enter in sterilisable chamber crystallizer, separate out gradually, 15～30 ℃ of growing the grains 30～60 minutes, be cooled to 5～15 ℃ of growing the grains 1～3 hour, filter, 50L acetone is washed, 40 ℃ of vacuum-drying 16 hours, obtain aseptic cefmenoxime sodium 19.89kg, molar yield 81.6%, purity 99.4%.
Embodiment 3
The aseptic cefmenoxime sodium that embodiments of the invention 2 are prepared grinds medicine with a day basis and under illumination, high temperature and super-humid conditions, places 10 days respectively, and at 0 day, 5 days and 10 days, measure respectively its clarity, color, its related substances and activeconstituents cefmenoxime content, the results are shown in Table 1.
Table 1 stability experiment
Table 1 data presentation, under illumination, high temperature and super-humid conditions, experimental example 2 is with former to grind medicine consistent in the clarity result of 0 day, 5 days and 10 days; When 5 days and 10 days, the product of embodiment 2 is more shallow than former color of grinding medicine; All to grind medicine low than former for its related substances of the product of embodiment 2 when 0 day, 5 days and 10 days, and related substance increases Zhang Sudu, and also to grind medicine slow than former; The product of experimental example 2 when 0 day, 5 days and 10 days cefmenoxime content all to grind medicine high than former, degradation speed and former to grind medicine basically identical.Obviously, the quality of the product of embodiment 2 and stability with former grind medicine compare substantially quite, even better.
Although illustrate and described exemplary embodiments more of the present invention, but those skilled in the art should know, without departing from the principles and spirit of the present invention, can make change to these exemplary embodiments, scope of the present invention is limited by claim and equivalent thereof.
Claims (5)
1. a preparation method for cefmenoxime sodium, said method comprising the steps of:
The 7-ATCA shown in formula (I) of take is raw material, under the condition of reaction solvent and basifier existence, carry out condensation reaction with MEAM, add water extraction, merge water, add ester phase solvent, use dilute hydrochloric acid to be adjusted to pH2.5～3.5, make cefmenoxime transfer to ester phase, ester divides mutually to the de-tank of charcoal, adds activated carbon decolorizing, through sterile filtration, enter in sterilisable chamber crystallizer, in filtrate, add aseptic Sodium isooctanoate or the sodium acetate soln in acetone or alcohol that be dissolved in, growing the grain, filtration, acetone or alcohol washing, vacuum-drying, obtain aseptic cefmenoxime sodium.
2. the preparation method of cefmenoxime sodium according to claim 1, is characterized in that: described reaction solvent is any one or a few in methylene dichloride, ethyl acetate, methyl alcohol, ethanol, acetone.
3. the preparation method of cefmenoxime sodium according to claim 1, is characterized in that: described basifier is any one or a few in pyridine, triethylamine, tetramethyl guanidine, sodium hydroxide.
4. the preparation method of cefmenoxime sodium according to claim 1, is characterized in that: described ester phase solvent is any one in methylene dichloride, ethyl acetate, butylacetate.
5. the preparation method of cefmenoxime sodium according to claim 1, is characterized in that: described growing the grain is 15～30 ℃ of growing the grains 30～60 minutes, is cooled to 5～15 ℃ of growing the grains 1～3 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201310647452.4A CN103613604A (en) | 2013-12-04 | 2013-12-04 | Method for preparing cefmenoxime sodium |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310647452.4A CN103613604A (en) | 2013-12-04 | 2013-12-04 | Method for preparing cefmenoxime sodium |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447799A (en) * | 2014-12-25 | 2015-03-25 | 广州白云山天心制药股份有限公司 | Method of preparing cefmenoxime E isomers |
| CN109096308A (en) * | 2017-06-20 | 2018-12-28 | 海南灵康制药有限公司 | 1/4 water cefmenoxime hydrochloride compound of one kind and its pharmaceutical composition |
-
2013
- 2013-12-04 CN CN201310647452.4A patent/CN103613604A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447799A (en) * | 2014-12-25 | 2015-03-25 | 广州白云山天心制药股份有限公司 | Method of preparing cefmenoxime E isomers |
| CN109096308A (en) * | 2017-06-20 | 2018-12-28 | 海南灵康制药有限公司 | 1/4 water cefmenoxime hydrochloride compound of one kind and its pharmaceutical composition |
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