CN101591347A - Cefixime acid type double salt compound and preparation method thereof - Google Patents
Cefixime acid type double salt compound and preparation method thereof Download PDFInfo
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- CN101591347A CN101591347A CNA2009100989573A CN200910098957A CN101591347A CN 101591347 A CN101591347 A CN 101591347A CN A2009100989573 A CNA2009100989573 A CN A2009100989573A CN 200910098957 A CN200910098957 A CN 200910098957A CN 101591347 A CN101591347 A CN 101591347A
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Abstract
The invention provides a kind of chemistry (6R by name, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(carboxymethoxyl imines) acetamido]-3-ethene-8-oxo-5-thia-1-azabicyclo [4, the acidic complex salt of 2,0] eight yuan-oct-2-ene-2-carboxylic acid.By Cefixime Micronized elder generation and sulfuric acid or phosphatase reaction, make Cefixime Micronized acid salt, react in polar solvent with MOR again, concentrate, use the weak polar solvent crystallization, filter, with solid drying, promptly get the Cefixime Micronized acidic complex salt.Preparation method of the present invention is reasonable in design, and technology is simple, and cost is low.By Cefixime Micronized acidic complex salt purity, the content height of the inventive method preparation, have characteristics such as good stability, difficult generation polymkeric substance.The medicine of preparation can overcome cephalosporin analog antibiotic easily to be produced polymkeric substance, can cause defective such as intensive anaphylaxis.
Description
Technical field
The invention belongs to the chemical pharmaceutical technical field, relate to cefixime acid type double salt compound and preparation method thereof.
Technical background
Cefixime Micronized (Cefixime (Cefspan)) chemistry (6R by name, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(carboxymethoxyl imines) acetamido]-3-ethene-8-oxo-5-thia-1-azabicyclo [4,2,0] eight yuan-oct-2-ene-2-carboxylic acid trihydrate, structural formula:
Pharmacological toxicology: Cefixime Micronized is a third generation oral cephalosporin.Cefixime Micronized all has anti-microbial effect more widely to gram-positive microorganism and Gram-negative bacteria, particularly the gonococcus in the streptococcus in the gram-positive microorganism, streptococcus pneumoniae, the Gram-negative bacteria, Bai Leihan Bordetella, intestinal bacteria, Serratia genus, the white Bordetella of Cray, proteus, hemophilus influenza etc. are had stronger antibacterial ability than other oral cephalosporin, its mode of action is sterilization.Because Cefixime Micronized is extremely stable to the β-Nei Xiananmei that various bacterium produced, thereby the bacterium that produces β-Nei Xiananmei also had excellent antimicrbial power.The mechanism of action of Cefixime Micronized mainly is stop bacteria cell wall synthetic.
Indication: broad-spectrum antibiotics.Effective to streptococcus, streptococcus pneumoniae, gonococcus, Bai Leihan Bordetella, intestinal bacteria, Serratia genus, klebsiella, proteus, the caused infection of hemophilus influenza disease.Be mainly used in treatment bronchitis, bronchiectasis concurrent infection, the secondary infection of chronic respiratory illness, pneumonia, pyelonephritis, urocystitis, gonococcal urethritis, cholecystitis, cholangitis, scarlet fever, otitis media, nasal sinusitis.
The Chinese patent publication number be CN1696134 patent disclosure prepare the method for Cefixime Micronized by perhalide, to obtain the high Cefixime Micronized of purity.
The Chinese patent publication number be CN1593423 patent disclosure a kind of Cefixime Micronized medicinal composition of injection, it is pressed 1～15: 1 weight proportion by active ingredient Cefixime Micronized and solubility promoter, thorough mixing is formulated under gnotobasis, and described solubility promoter is selected the inorganic or organic acid salt of basic aminoacids, basic metal or alkaline-earth metal for use.This patent introduction be a kind of pharmaceutical formulation.
The Chinese patent publication number is a kind of Cefixime Micronized sodium of the patent of CN1594322 medical compounds, and preparation after the sodium bicarbonate complete reaction of 1 mole Cefixime Micronized and 2 moles is got.
Currently available products further do not improve, and restricted the raising of the quality level of bulk drug, preparation.
Summary of the invention
The object of the invention is to provide a kind of quality height, good stability, Cefixime Micronized acidic complex salt that untoward reaction is few, has following general structure:
Wherein:
M is Na
+(sodium ion), K
+(potassium ion), NH4
+(ammonium ion), Cs
+A kind of in (cesium ion).
Y is SO4
2-(sulfate radical), HPO4
2-A kind of in (phosphoric acid one hydrogen root).
Compound chemistry of the present invention is called (6R, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(carboxymethoxyl imines) acetamido]-3-ethene-8-oxo-5-thia-1-azabicyclo [4,2,0] eight yuan-oct-2-ene-2-carboxylic acid acidic complex salt, as (6R, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(carboxymethoxyl imines) acetamido]-3-ethene-8-oxo-5-thia-1-azabicyclo [4,2,0] eight yuan-oct-2-ene-2-carboxylic acid sulfuric acid double salt and (6R, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(carboxymethoxyl imines) acetamido]-3-ethene-8-oxo-5-thia-1-azabicyclo [4,2,0] eight yuan-oct-2-ene-2-carboxylic acid salt of phosphoric acid.
Described compound is a kind of in the following structural formula:
The Cefixime Micronized sodium pyrosulfate
The Cefixime Micronized sal enixum
The Cefixime Micronized monoammonium sulfate
The Cefixime Micronized cesium hydrogen sulfate
The Cefixime Micronized SODIUM PHOSPHATE, MONOBASIC
The Cefixime Micronized potassium primary phosphate
The Cefixime Micronized primary ammonium phosphate
The Cefixime Micronized cesium dihydrogen phosphate
The preparation method one of Cefixime Micronized acidic complex salt of the present invention is: with Cefixime Micronized elder generation and H
2Cefixime Micronized acid salt is made in Y (sulfuric acid or phosphoric acid) reaction, and Cefixime Micronized acid salt and MOR react in polar solvent, concentrates, and at the weak polar solvent crystallization, filters, and with solid drying, promptly gets the Cefixime Micronized acidic complex salt.
Reaction formula is
Wherein M, Y are as mentioned above;
R is CH
3-, CH
3CH
2-, CH
3CH
2CH
2-, CH
3CH
2CH
2CH
2-, (CH
3)
2CH-, (CH
3)
3C-, CH
3CO-, CH
3CH
2CO-, CH
3CH
2CH
2A kind of among CO-or the H (being respectively methyl alcohol, ethanol, propyl alcohol, butanols, Virahol, butyl alcohol-tert, acetic acid, propionic acid, butyro-compound, oxyhydroxide or ammonia).
The preparation method two of Cefixime Micronized acidic complex salt of the present invention is: earlier with Cefixime Micronized and MOR compound, react completely after, make the Cefixime Micronized subsalt, again with Cefixime Micronized and H
2Y makes Cefixime Micronized acid salt after mixing, reacting completely, at last with the Cefixime Micronized subsalt with after Cefixime Micronized acid salt mixes in polar solvent, reacts completely, concentrate, add the weak polar solvent crystallization, filter, with solid drying, promptly get the Cefixime Micronized acidic complex salt.
Reaction formula is
Wherein M, Y, R are as mentioned above;
R '=M or H also are Na
+(sodium ion), K
+(potassium ion), NH4
+(ammonium ion), Cs
+(cesium ion or H
+A kind of in (hydrogen ion).
The preparation method three of Cefixime Micronized acidic complex salt of the present invention is: earlier with Cefixime Micronized and MOR compound, react completely after, make the Cefixime Micronized subsalt, Cefixime Micronized subsalt and H
2After Y mixes in polar solvent, reacts completely, concentrate, add the weak polar solvent crystallization, filter,, promptly get the Cefixime Micronized acidic complex salt solid drying.
Reaction formula is
Wherein M, Y, R, R ' are as mentioned above.
The preparation method four of Cefixime Micronized acidic complex salt of the present invention is: with Cefixime Micronized with after MHY mixes in polar solvent, reacts completely with 1: 1 mol ratio, concentrate, add the weak polar solvent crystallization, filter, with solid drying, promptly get the Cefixime Micronized acidic complex salt.
Reaction formula is
Wherein M and Y are as mentioned above.
Polar solvent described in the present invention is selected a kind of among ethanol, methyl alcohol, acetone, DMF or the DMSO for use.
The weak polar solvent that crystallization of the present invention is used is a kind of in ether, sherwood oil, normal hexane or the hexanaphthene.
Preparation method two described MHY select a kind of in monoammonium sulfate, sodium pyrosulfate, sal enixum, cesium hydrogen sulfate, primary ammonium phosphate, SODIUM PHOSPHATE, MONOBASIC, potassium primary phosphate or the cesium dihydrogen phosphate for use.
Contain in sodium, potassium, ammonium, the cesium element any in the cefixime acid type double salt compound molecular structure provided by the invention.
Cefixime Micronized acidic complex salt of the present invention adds pharmaceutical excipient, can be made into oral and preparations two kinds of approach of drug administration by injection.
Preparation method of the present invention is reasonable in design, and technology is simple, and cost is low.By Cefixime Micronized acidic complex salt purity, the content height of the inventive method preparation, have characteristics such as good stability, difficult generation polymkeric substance.The medicine of preparation can overcome cephalosporin analog antibiotic and easily produce polymkeric substance, and polymkeric substance can cause the intensive anaphylaxis in animal experiment, also often produce defectives such as serious adverse effects in the process of clinical application.
Embodiment
The present invention is further described in conjunction with the embodiments.Present invention is described for following examples, and these examples only are can not be interpreted as limitation of the scope of the invention for explanation.
Embodiment 1
In the 100ml reaction flask, add Cefixime Micronized 453mg, use the 50ml anhydrous alcohol solution, stir, add sulfuric acid 98mg, after reaction is finished, recovery concentrates, and obtains Cefixime Micronized vitriol 549mg, and Cefixime Micronized acid salt is again at the acetone mixing, add 54mg sodium methylate reaction 2 hours, concentrating under reduced pressure adds an amount of ether, separates out solid, filtration, with ether washing, drying, obtain white solid Cefixime Micronized sodium pyrosulfate double salt 554mg.
With Cefixime Micronized sodium pyrosulfate double salt (in Cefixime Micronized) 500g, 1000 or 500 of aseptic subpackaged one-tenth promptly get the Cefixime Micronized sodium pyrosulfate double salt powder pin of 0.1g and 500mg specification.
Embodiment 2
In the 100ml reaction flask, add Cefixime Micronized 453mg, with the dissolving of 50ml anhydrous methanol, stir, add phosphatase 79 8mg, after reaction is finished, recovery concentrates, and obtains Cefixime Micronized phosphoric acid salt 531mg, and Cefixime Micronized phosphoric acid salt is again at the acetone mixing, add 70mg potassium methylate reaction 2.5 hours, concentrating under reduced pressure adds an amount of sherwood oil, separates out solid, filtration, with petroleum ether, drying, obtain white solid Cefixime Micronized potassium primary phosphate double salt 523mg.
With Cefixime Micronized sodium pyrosulfate double salt (in Cefixime Micronized) 500g, aseptic subpackaged 500, promptly get 0.1g Cefixime Micronized sodium pyrosulfate double salt powder pin.
Embodiment 3
In the 100ml reaction flask, add Cefixime Micronized 453mg, with the dissolving of 50ml dry DMF, stir, add sulfuric acid 98mg, after reaction is finished, recovery concentrates, and obtains Cefixime Micronized vitriol 545mg, and Cefixime Micronized vitriol is again at the acetone mixing, add 77mg ammonium acetate reaction 1 hour, concentrating under reduced pressure adds an amount of DMSO, separates out solid, filtration, with normal hexane washing, drying, obtain white solid Cefixime Micronized monoammonium sulfate double salt 484mg.
Embodiment 4
In the 100ml reaction flask, add Cefixime Micronized 453mg, with the anhydrous DMSO dissolving of 50ml, stir, add phosphatase 79 8mg, after reaction is finished, recovery concentrates, and obtains Cefixime Micronized phosphoric acid salt 538mg, and Cefixime Micronized phosphoric acid salt is mixing in ethanol again, add 164mg methyl alcohol caesium reaction 2 hours, concentrating under reduced pressure adds an amount of hexanaphthene, separates out solid, filtration, with hexanaphthene washing, drying, obtain white solid Cefixime Micronized cesium dihydrogen phosphate double salt 620mg.
Embodiment 5
In the 100ml reaction flask, add Cefixime Micronized 453mg, use the 50ml anhydrous alcohol solution, stir, add sulfuric acid 98mg, after reaction is finished, recovery concentrates, and obtains Cefixime Micronized vitriol 542mg, and Cefixime Micronized acid salt is again at the acetone mixing, add 68mg sodium ethylate reaction 2 hours, concentrating under reduced pressure adds an amount of ether, separates out solid, filtration, with ether washing, drying, obtain white solid Cefixime Micronized sodium pyrosulfate double salt 521mg.
Embodiment 6
In the 100ml reaction flask, add Cefixime Micronized 453mg, with the dissolving of 50ml anhydrous methanol, stir, add phosphatase 79 8mg, after reaction is finished, recovery concentrates, and obtains Cefixime Micronized phosphoric acid salt 533mg, and Cefixime Micronized phosphoric acid salt is again at the acetone mixing, add 98mg potassium propylate reaction 2.5 hours, concentrating under reduced pressure adds an amount of sherwood oil, separates out solid, filtration, with petroleum ether, drying, obtain white solid Cefixime Micronized potassium primary phosphate double salt 502mg.
Embodiment 7
In the 100ml reaction flask, add Cefixime Micronized 453mg, with the dissolving of 50ml dry DMF, stir, add sulfuric acid 98mg, after reaction is finished, recovery concentrates, and obtains Cefixime Micronized vitriol 542mg, and Cefixime Micronized vitriol is again at the acetone mixing, add 92mg propionic acid ammonium reaction 3 hours, concentrating under reduced pressure adds an amount of normal hexane, separates out solid, filtration, with normal hexane washing, drying, obtain white solid Cefixime Micronized monoammonium sulfate double salt 467mg.
With Cefixime Micronized sodium pyrosulfate double salt (in Cefixime Micronized) 500g, 250 of aseptic subpackaged one-tenth promptly get the Cefixime Micronized sodium pyrosulfate double salt powder pin of 0.2g specification.
Embodiment 8
In the 100ml reaction flask, add Cefixime Micronized 453mg, with the anhydrous DMSO dissolving of 50ml, stir, add phosphatase 79 8mg, after reaction is finished, recovery concentrates, and obtains Cefixime Micronized phosphoric acid salt 534mg, and Cefixime Micronized phosphoric acid salt is mixing in ethanol again, add 192mg Virahol caesium, reaction finishes, concentrating under reduced pressure, add an amount of hexanaphthene, separate out solid, filtration,, obtain white solid Cefixime Micronized cesium dihydrogen phosphate double salt 591mg with hexanaphthene washing, drying
Embodiment 9
In the 100ml reaction flask, add Cefixime Micronized 453mg, separate with the 50ml anhydrous propanone, stir, add sulfuric acid 98mg, after reaction is finished, recovery concentrates, and obtains Cefixime Micronized vitriol 542mg, and Cefixime Micronized acid salt is again at the acetone mixing, add 94mg butyl alcohol-tert sodium, reaction finishes, concentrating under reduced pressure, add an amount of ether, separate out solid, filtration,, obtain white solid Cefixime Micronized sodium pyrosulfate double salt 419mg with ether washing, drying.
Embodiment 10
In the 100ml reaction flask, add Cefixime Micronized 453mg, use the 50ml anhydrous alcohol solution, stir, add phosphatase 79 8mg, after reaction is finished, recovery concentrates, and obtains Cefixime Micronized phosphoric acid salt 533mg, and Cefixime Micronized phosphoric acid salt is again at the acetone mixing, add the 95mg Potassium ethanoate, reaction finishes, concentrating under reduced pressure, add an amount of sherwood oil, separate out solid, filtration,, obtain white solid Cefixime Micronized potassium primary phosphate double salt 514mg with petroleum ether, drying.
Embodiment 11
In the 100ml reaction flask, add Cefixime Micronized 453mg, with the dissolving of 50ml anhydrous propanone, stir, add sulfuric acid 98mg, after reaction is finished, recovery concentrates, and obtains Cefixime Micronized vitriol 542mg, and Cefixime Micronized vitriol is again at the acetone mixing, add and go into 217mg butyric acid caesium, reaction is finished, concentrating under reduced pressure, add an amount of normal hexane, separate out solid, filtration,, obtain white solid Cefixime Micronized cesium hydrogen sulfate double salt 527mg with normal hexane washing, drying.
Embodiment 12
In the 100ml reaction flask, add Cefixime Micronized 453mg, use the 50ml anhydrous alcohol solution, stir, add sodium ethylate 68mg, after reaction is finished, recovery concentrates, and obtains Cefixime Micronized sodium 468mg, and gained Cefixime Micronized sodium is mixing in acetone again, add 543mg Cefixime Micronized vitriol reaction 2 hours, concentrating under reduced pressure adds an amount of ether, separates out solid, filtration, with ether washing, drying, obtain white solid Cefixime Micronized sodium pyrosulfate double salt 834mg.
Embodiment 13
In the 100ml reaction flask, add Cefixime Micronized 453mg, with the dissolving of 50ml anhydrous propanone, stir, add potassium methylate 70mg, after reaction is finished, recovery concentrates, and obtains Cefixime Micronized potassium 469mg, and gained Cefixime Micronized potassium is mixing in acetone again, add 526mg Cefixime Micronized vitriol, reaction finishes, concentrating under reduced pressure, add an amount of sherwood oil, separate out solid, filtration,, obtain white solid Cefixime Micronized sal enixum double salt 961mg with petroleum ether, drying.
Embodiment 14
In the 100ml reaction flask, add Cefixime Micronized 453mg, with the dissolving of 50ml dry DMF, stir, add ammonium acetate 78mg, after reaction finishes, reclaim to concentrate, obtain Cefixime Micronized ammonium 451mg, with above-mentioned Cefixime Micronized ammonium mixing in methyl alcohol again, add 529mg Cefixime Micronized phosphoric acid salt, reaction finishes, concentrating under reduced pressure, add an amount of normal hexane, separate out solid, filtration,, obtain white solid Cefixime Micronized primary ammonium phosphate double salt 784mg with a spot of normal hexane washing, drying.
Embodiment 15
In the 100ml reaction flask, add Cefixime Micronized 453mg, with the anhydrous DMSO dissolving of 50ml, stir, add propyl alcohol caesium 192mg, after reaction is finished, reclaim to concentrate, obtain Cefixime Micronized caesium 534mg, with gained Cefixime Micronized caesium mixing in DMSO again, add 503mg Cefixime Micronized phosphoric acid salt, after reaction finishes, concentrating under reduced pressure, add an amount of hexanaphthene, separate out solid, filtration,, obtain white solid Cefixime Micronized cesium dihydrogen phosphate double salt 877mg with a small amount of hexanaphthene washing, drying.
Embodiment 16
In the 100ml reaction flask, add Cefixime Micronized 453mg, use the 50ml anhydrous alcohol solution, stir, add sodium butylate 96mg, after reaction is finished, recovery concentrates, and obtains Cefixime Micronized sodium 452mg, and gained Cefixime Micronized sodium is mixing in acetone again, add 93mg sulfuric acid, after reaction finishes, concentrating under reduced pressure, add an amount of ether, separate out solid, filtration,, obtain white solid Cefixime Micronized sodium pyrosulfate double salt 461mg with ether washing, drying.
Embodiment 17
In the 100ml reaction flask, add Cefixime Micronized 453mg, with the dissolving of 50ml anhydrous propanone, stir, add potassium isopropoxide 98mg, after reaction is finished, recovery concentrates, and obtains Cefixime Micronized potassium 466mg, and gained Cefixime Micronized potassium is mixing in acetone again, add 93mg sulfuric acid, reaction finishes, concentrating under reduced pressure, add an amount of sherwood oil, separate out solid, filtration,, obtain white solid Cefixime Micronized sal enixum double salt 510mg with petroleum ether, drying.
Embodiment 18
In the 100ml reaction flask, add Cefixime Micronized 453mg, with the dissolving of 50ml dry DMF, stir, add propionic acid ammonium 92mg, after reaction finishes, reclaim to concentrate, obtain Cefixime Micronized ammonium 432mg, with above-mentioned Cefixime Micronized ammonium mixing in methyl alcohol again, add 90mg phosphoric acid, reaction finishes, concentrating under reduced pressure, add an amount of normal hexane, separate out solid, filtration,, obtain white solid Cefixime Micronized primary ammonium phosphate double salt 476mg with a spot of normal hexane washing, drying.
Embodiment 19
In the 100ml reaction flask, add Cefixime Micronized 453mg, with the dissolving of 50ml anhydrous methanol, stir, add butyl alcohol-tert caesium 206mg, after reaction is finished, reclaim to concentrate, obtain Cefixime Micronized caesium 543mg, with gained Cefixime Micronized caesium mixing in methyl alcohol again, add 91mg phosphoric acid, after reaction finishes, concentrating under reduced pressure, add an amount of hexanaphthene, separate out solid, filtration,, obtain white solid Cefixime Micronized cesium dihydrogen phosphate double salt 572mg with a small amount of hexanaphthene washing, drying.
Embodiment 20
In the 100ml reaction flask, add Cefixime Micronized 453mg, use the 50ml anhydrous alcohol solution, stir, add sodium hydroxide 40mg, after reaction is finished, recovery concentrates, and obtains Cefixime Micronized sodium 457mg, and gained Cefixime Micronized sodium is mixing in acetone again, add 94mg sulfuric acid, after reaction finishes, concentrating under reduced pressure, add an amount of ether, separate out solid, filtration,, obtain white solid Cefixime Micronized sodium pyrosulfate double salt 479mg with ether washing, drying.
Embodiment 21
In the 100ml reaction flask, add Cefixime Micronized 453mg, with the dissolving of 50ml anhydrous propanone, stir, add potassium hydroxide 56mg, after reaction is finished, recovery concentrates, and obtains Cefixime Micronized potassium 474mg, and gained Cefixime Micronized potassium is mixing in acetone again, add 95mg sulfuric acid, reaction finishes, concentrating under reduced pressure, add an amount of sherwood oil, separate out solid, filtration,, obtain white solid Cefixime Micronized sal enixum double salt 530mg with petroleum ether, drying.
Embodiment 22
In the 100ml reaction flask, add Cefixime Micronized 453mg, with the dissolving of 50ml dry DMF, stir, add ammonium hydroxide 35mg, after reaction finishes, reclaim to concentrate, obtain Cefixime Micronized ammonium 412mg, with above-mentioned Cefixime Micronized ammonium mixing in methyl alcohol again, add 86mg phosphoric acid, reaction finishes, concentrating under reduced pressure, add an amount of normal hexane, separate out solid, filtration,, obtain white solid Cefixime Micronized primary ammonium phosphate double salt 456mg with a spot of normal hexane washing, drying.
Embodiment 23
In the 100ml reaction flask, add Cefixime Micronized 453mg, with the dissolving of 50ml anhydrous methanol, stir, add cesium hydroxide 150mg, after reaction is finished, reclaim to concentrate, obtain Cefixime Micronized caesium 512mg, with gained Cefixime Micronized caesium mixing in methyl alcohol again, add 86mg phosphoric acid, after reaction finishes, concentrating under reduced pressure, add an amount of hexanaphthene, separate out solid, filtration,, obtain white solid Cefixime Micronized phosphoric acid ground dihydro caesium double salt 545mg with a small amount of hexanaphthene washing, drying.
Embodiment 24
In the 100ml reaction flask, add Cefixime Micronized 453mg, use the 50ml anhydrous alcohol solution, stir, add sodium hydroxide 40mg, after reaction is finished, recovery concentrates, and obtains Cefixime Micronized sodium 457mg, and gained Cefixime Micronized sodium is mixing in acetone again, add 94mg sulfuric acid, after reaction finishes, concentrating under reduced pressure, add an amount of ether, separate out solid, filtration,, obtain white solid Cefixime Micronized sodium pyrosulfate double salt 479mg with ether washing, drying.
Embodiment 25
In the 100ml reaction flask, add Cefixime Micronized 453mg, with the dissolving of 50ml anhydrous propanone, stir, add potassium hydroxide 56mg, after reaction is finished, recovery concentrates, and obtains Cefixime Micronized potassium 474mg, and gained Cefixime Micronized potassium is mixing in acetone again, add 95mg sulfuric acid, reaction finishes, concentrating under reduced pressure, add an amount of sherwood oil, separate out solid, filtration,, obtain white solid Cefixime Micronized sal enixum double salt 530mg with petroleum ether, drying.
The capsule prescription:
Cefixime Micronized sal enixum double salt (in Cefixime Micronized) 5%-70%
Thinner starch 20%-60%
Tackiness agent dextrin 2%-15%
Disintegrating agent Microcrystalline Cellulose 0.2%-10%
Magnesium stearate lubricant 0.1%-5%
Cefixime Micronized sal enixum double salt and above-mentioned mixing diluents is even, add the tackiness agent that dextrin is made, wet granulation, dry, whole grain, add an amount of disintegrating agent, lubricant, make capsule to contain every 50mg of Cefixime Micronized, 100mg, promptly get the Cefixime Micronized sal enixum double salt capsule of required specification.
Embodiment 26
In the 100ml reaction flask, add Cefixime Micronized 453mg, with the dissolving of 50ml dry DMF, stir, add ammonium hydroxide 35mg, after reaction finishes, reclaim to concentrate, obtain Cefixime Micronized ammonium 412mg, with above-mentioned Cefixime Micronized ammonium mixing in methyl alcohol again, add 86mg phosphoric acid, reaction finishes, concentrating under reduced pressure, add an amount of normal hexane, separate out solid, filtration,, obtain white solid Cefixime Micronized primary ammonium phosphate double salt 456mg with a spot of normal hexane washing, drying.
Embodiment 27
In the 100ml reaction flask, add Cefixime Micronized 453mg, with the dissolving of 50ml anhydrous methanol, stir, add cesium hydroxide 150mg, after reaction is finished, reclaim to concentrate, obtain Cefixime Micronized caesium 512mg, with gained Cefixime Micronized caesium mixing in methyl alcohol again, add 86mg phosphoric acid, after reaction finishes, concentrating under reduced pressure, add an amount of hexanaphthene, separate out solid, filtration,, obtain white solid Cefixime Micronized cesium dihydrogen phosphate double salt 531mg with a small amount of hexanaphthene washing, drying.
Embodiment 28
In the 100ml reaction flask, add Cefixime Micronized 453mg, use the 50ml anhydrous alcohol solution, stir, add sodium-acetate 82mg, after reaction is finished, recovery concentrates, and obtains Cefixime Micronized sodium 417mg, and gained Cefixime Micronized sodium is mixing in acetone again, add 86mg sulfuric acid, after reaction finishes, concentrating under reduced pressure, add an amount of ether, separate out solid, filtration,, obtain white solid Cefixime Micronized sodium pyrosulfate double salt 438mg with ether washing, drying.
Embodiment 29
In the 100ml reaction flask, add Cefixime Micronized 453mg, with the dissolving of 50ml anhydrous propanone, stir, add potassium propionate 114mg, after reaction is finished, recovery concentrates, and obtains Cefixime Micronized potassium 451mg, and gained Cefixime Micronized potassium is mixing in acetone again, add 90mg sulfuric acid, reaction finishes, concentrating under reduced pressure, add an amount of sherwood oil, separate out solid, filtration,, obtain white solid Cefixime Micronized sal enixum double salt 512mg with petroleum ether, drying.
Embodiment 30
In the 100ml reaction flask, add Cefixime Micronized 453mg, with the dissolving of 50ml anhydrous methanol, stir, add butyric acid caesium 221mg, after reaction is finished, reclaim to concentrate, obtain Cefixime Micronized caesium 532mg, with gained Cefixime Micronized caesium mixing in methyl alcohol again, add 89mg phosphoric acid, after reaction finishes, concentrating under reduced pressure, add an amount of hexanaphthene, separate out solid, filtration,, obtain white solid Cefixime Micronized cesium dihydrogen phosphate double salt 501mg with a small amount of hexanaphthene washing, drying.
Embodiment 31
In the 100ml reaction flask, add Cefixime Micronized 453mg, use the 50ml anhydrous alcohol solution, stir, add sodium pyrosulfate 120mg, after reaction was finished, recovery concentrated, and obtains white solid Cefixime Micronized sodium pyrosulfate double salt 540mg.
Embodiment 32
In the 100ml reaction flask, add Cefixime Micronized 453mg, use the dissolving of 50ml anhydrous propanone, stir, add sal enixum 136mg, after reaction was finished, recovery concentrated, and obtains white solid Cefixime Micronized sal enixum double salt 556mg.
Embodiment 33
In the 100ml reaction flask, add Cefixime Micronized 453mg, use the dissolving of 50ml anhydrous propanone, stir, add monoammonium sulfate 115mg, after reaction was finished, recovery concentrated, and obtains white solid Cefixime Micronized monoammonium sulfate double salt 556mg.
Embodiment 34
In the 100ml reaction flask, add Cefixime Micronized 453mg, use the dissolving of 50ml anhydrous propanone, stir, add cesium hydrogen sulfate 230mg, after reaction was finished, recovery concentrated, and obtains white solid Cefixime Micronized cesium hydrogen sulfate double salt 560mg.
Embodiment 35
In the 100ml reaction flask, add Cefixime Micronized 453mg, use the 50ml anhydrous alcohol solution, stir, add SODIUM PHOSPHATE, MONOBASIC 120mg, after reaction was finished, recovery concentrated, and obtains white solid Cefixime Micronized SODIUM PHOSPHATE, MONOBASIC double salt 532mg.
Tablet formulation:
Cefixime Micronized SODIUM PHOSPHATE, MONOBASIC double salt (in Cefixime Micronized) 5%-70%
Thinner lactose 20%-60%
Tackiness agent PVP 2%-15%
Disintegrating agent PVPP 0.2%-10%
Magnesium stearate lubricant 0.1%-5%
Cefixime Micronized SODIUM PHOSPHATE, MONOBASIC double salt and above-mentioned auxiliary material are mixed, and behind 80 mesh sieves, dry granulation adds the moderate lubrication agent, to contain every 50mg of Cefixime Micronized, 100mg compressing tablet, promptly gets the Cefixime Micronized SODIUM PHOSPHATE, MONOBASIC double salt sheet of required specification excessively.
Embodiment 36
In the 100ml reaction flask, add Cefixime Micronized 453mg, use the dissolving of 50ml anhydrous propanone, stir, add potassium primary phosphate 136mg, after reaction was finished, recovery concentrated, and obtains white solid Cefixime Micronized potassium primary phosphate double salt 569mg.
Embodiment 37
In the 100ml reaction flask, add Cefixime Micronized 453mg, use the dissolving of 50ml anhydrous propanone, stir, add primary ammonium phosphate 115mg, after reaction was finished, recovery concentrated, and obtains white solid Cefixime Micronized primary ammonium phosphate double salt 523mg.
Embodiment 38
In the 100ml reaction flask, add Cefixime Micronized 453mg, use the dissolving of 50ml anhydrous propanone, stir, add cesium dihydrogen phosphate 230mg, after reaction was finished, recovery concentrated, and obtains white solid Cefixime Micronized cesium dihydrogen phosphate double salt 547mg.
Embodiment 39
Compound of the present invention is measured content with PHLC, result such as table 1.Compound purity of the present invention is much improved, and total impurities is all below 0.8%.
Table 1
| Sequence number | Title | Content % | Purity % |
| 1 | The Cefixime Micronized sodium pyrosulfate | 99.14 | 99.23 |
| 2 | The Cefixime Micronized sal enixum | 98.89 | 99.58 |
| 3 | The Cefixime Micronized monoammonium sulfate | 99.32 | 99.47 |
| 4 | The Cefixime Micronized cesium hydrogen sulfate | 99.44 | 99.64 |
| 5 | The Cefixime Micronized sodium hydrogen phosphate | 99.39 | 99.54 |
| 6 | The Cefixime Micronized potassium hydrogen phosphate | 99.62 | 99.63 |
| 7 | The Cefixime Micronized ammonium hydrogen phosphate | 98.94 | 99.57 |
| 8 | Cefixime Micronized phosphoric acid hydrogen caesium | 99.04 | 99.75 |
Embodiment 40
Compound of the present invention is used in RH92%, 60 ℃ of placements of temperature were investigated test in one week, and with the Cefixime Micronized contrast, polymer content sees Table 2.Can remove polymkeric substance in the compound process of the present invention, and in rupture test, also be difficult for producing polymkeric substance.
Table 2
| Sequence number | Title | Test prepolymer % | Test post polymerization thing % |
| 1 | Cefixime Micronized | 0.026 | 0.676 |
| 2 | The Cefixime Micronized sodium pyrosulfate | Do not detect | 0.024 |
| 3 | The Cefixime Micronized sal enixum | Do not detect | 0.032 |
| 4 | The Cefixime Micronized monoammonium sulfate | Do not detect | 0.024 |
| 5 | The Cefixime Micronized cesium hydrogen sulfate | Do not detect | 0.041 |
| 6 | The Cefixime Micronized sodium hydrogen phosphate | Do not detect | 0.054 |
| 7 | The Cefixime Micronized potassium hydrogen phosphate | Do not detect | 0.012 |
| 8 | The Cefixime Micronized ammonium hydrogen phosphate | Do not detect | 0.023 |
| 9 | Cefixime Micronized phosphoric acid hydrogen caesium | Do not detect | 0.019 |
Claims (9)
1. Cefixime Micronized acidic complex salt has following general structure:
Wherein:
M is Na
+, K
+, NH4
+Or Cs
+In a kind of,
Y is SO4
2-Or HPO4
2-
2. a kind of Cefixime Micronized acidic complex salt according to claim 1 is characterized in that described compound is a kind of in the following structural formula:
The Cefixime Micronized sodium pyrosulfate
The Cefixime Micronized sal enixum
The Cefixime Micronized monoammonium sulfate
The Cefixime Micronized cesium hydrogen sulfate
The Cefixime Micronized SODIUM PHOSPHATE, MONOBASIC
The Cefixime Micronized potassium primary phosphate
The Cefixime Micronized primary ammonium phosphate
The Cefixime Micronized cesium dihydrogen phosphate
3. the preparation method of a kind of Cefixime Micronized acidic complex salt according to claim 1 and 2 is characterized in that realizing by following steps: with Cefixime Micronized elder generation and H
2Cefixime Micronized acid salt is made in the Y reaction, and Cefixime Micronized acid salt and MOR react in polar solvent, concentrates, and at the weak polar solvent crystallization, filters, and with solid drying, promptly gets the Cefixime Micronized acidic complex salt,
Reaction formula is
Wherein M, Y according to claim 1,
R is CH
3-, CH
3CH
2-, CH
3CH
2CH
2-, CH
3CH
2CH
2CH
2-, (CH
3)
2CH-, (CH
3)
3C-, CH
3CO-, CH
3CH
2CO-, CH
3CH
2CH
2A kind of among CO-or the H.
4. the preparation method of a kind of Cefixime Micronized acidic complex salt according to claim 1 and 2 is characterized in that realizing by following steps: earlier with Cefixime Micronized and MOR compound, make the Cefixime Micronized subsalt, again with Cefixime Micronized and H
2Y mixes, and makes Cefixime Micronized acid salt, and the Cefixime Micronized subsalt is mixed in polar solvent with Cefixime Micronized acid salt, concentrates, and adds the weak polar solvent crystallization, filters, and with solid drying, promptly gets the Cefixime Micronized acidic complex salt,
Reaction formula is
Wherein M, Y, according to claim 1, R be as described in the claim 3,
R '=M or H.
5. the preparation method of a kind of Cefixime Micronized acidic complex salt according to claim 1 and 2 is characterized in that realizing by following steps: earlier with Cefixime Micronized and MOR compound, make the Cefixime Micronized subsalt, Cefixime Micronized subsalt and H
2Y mixes in polar solvent, concentrates, and adds the weak polar solvent crystallization, filters, and with solid drying, promptly gets the Cefixime Micronized acidic complex salt,
Reaction formula is
Wherein M, Y, R, R ' are as described in the claim 4.
6. the preparation method of a kind of Cefixime Micronized acidic complex salt according to claim 1 and 2, it is characterized in that realizing: Cefixime Micronized is mixed in polar solvent with 1: 1 mol ratio with MHY by following steps, concentrate, add the weak polar solvent crystallization, filter, with solid drying, promptly get the Cefixime Micronized acidic complex salt
Reaction formula is
Wherein M and Y according to claim 1,
Described polar solvent is selected a kind of among ethanol, methyl alcohol, acetone, DMF or the DMSO for use.
7. according to the preparation method of the arbitrary described a kind of Cefixime Micronized acidic complex salt of claim 3-5, it is characterized in that: the weak polar solvent that crystallization is selected for use is a kind of in ether, sherwood oil, normal hexane or the hexanaphthene.
8. the preparation method of a kind of Cefixime Micronized acidic complex salt according to claim 4 is characterized in that: described MHY selects a kind of in monoammonium sulfate, sodium pyrosulfate, sal enixum, cesium hydrogen sulfate, primary ammonium phosphate, SODIUM PHOSPHATE, MONOBASIC, potassium primary phosphate or the cesium dihydrogen phosphate for use.
9. a kind of Cefixime Micronized acidic complex salt according to claim 1 and 2 is characterized in that described Cefixime Micronized acidic complex salt adds pharmaceutical excipient, makes oral preparations or injection formulations.
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|---|---|---|---|
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|---|---|---|---|
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102382125A (en) * | 2011-07-29 | 2012-03-21 | 成都市考恩斯科技有限责任公司 | Cefditoren water-soluble composite, preparation method and corresponding pharmaceutical preparation thereof |
| CN104004003A (en) * | 2013-02-22 | 2014-08-27 | 广州白云山制药股份有限公司广州白云山制药总厂 | Cefixime derivative and manufacturing method and purpose thereof |
-
2009
- 2009-05-25 CN CNA2009100989573A patent/CN101591347A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102382125A (en) * | 2011-07-29 | 2012-03-21 | 成都市考恩斯科技有限责任公司 | Cefditoren water-soluble composite, preparation method and corresponding pharmaceutical preparation thereof |
| CN102382125B (en) * | 2011-07-29 | 2014-04-09 | 成都市考恩斯科技有限责任公司 | Cefditoren water-soluble composite, preparation method and corresponding pharmaceutical preparation thereof |
| CN104004003A (en) * | 2013-02-22 | 2014-08-27 | 广州白云山制药股份有限公司广州白云山制药总厂 | Cefixime derivative and manufacturing method and purpose thereof |
| CN104004003B (en) * | 2013-02-22 | 2016-05-25 | 广州白云山医药集团股份有限公司白云山制药总厂 | Cefixime derivative and its production and use |
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