CN101633665A - Cephalosporin antibiotic acidic complex salt and preparation method thereof - Google Patents
Cephalosporin antibiotic acidic complex salt and preparation method thereof Download PDFInfo
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- CN101633665A CN101633665A CN200910101287A CN200910101287A CN101633665A CN 101633665 A CN101633665 A CN 101633665A CN 200910101287 A CN200910101287 A CN 200910101287A CN 200910101287 A CN200910101287 A CN 200910101287A CN 101633665 A CN101633665 A CN 101633665A
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Abstract
The invention provides a cephalosporin antibiotic acidic complex salt and a preparation method thereof. The method comprises the following steps: mixing cephalosporin antibiotic and acid in polar solvent and then preparing cephalosporin antibiotic acidic salt; adding salt to react; concentrating and then adding weak polar solvent to crystallize, filter and dry to obtain the cephalosporin antibiotic acidic complex salt. The cephalosporin antibiotic acidic complex salt prepared by the method has the advantages of high purity, favorable stability difficult generation of polymer and has the characteristics of high solubility and bioavailability, absorption increase, medicine effect improvement, and the like. The invention has reasonable preparation method, simple technology and favorable aqueous solution, can be made into injection, widens the clinic application range and provides the structural formula (I) of the cephalosporin antibiotic acidic complex salt.
Description
Technical field
The invention belongs to the chemical pharmaceutical technical field, relate to cephalosporin antibiotic acidic complex salt and preparation method thereof.
Technical background
His U.S. ester of spore, Tomiron 100, Cefpodoxime Proxetil, S-1108, Ceftibuten, cephalo Toro, S 578, Cephradine, Cefaclor, Cephalexin Monohydrate Micro/Compacted, Prozef, cefetamet Sulbactam ester, cephalofruxin Sulbactam ester, Cephradine Sulbactam ester, Cephalexin Monohydrate Micro/Compacted Sulbactam ester, S 578 Sulbactam ester, Cefaclor Sulbactam ester are cephalosporins, have different clinical demands and indication.
Disclosed bibliographical information these antibiotic structure and preparation methods, also the disclose various acid salt such as cephalosporin analog antibiotic and sulfuric acid that have generate sulfuric acid cephalosporin analog antibiotic, subsalt such as cephalosporin analog antibiotic and sodium hydroxide generation cephalosporin analog antibiotic sodium,
Currently available products has restricted the raising of the quality level of bulk drug and preparation existing certain deficiency aspect solvability, purity, the bioavailability.
Cephalosporin analog antibiotic produces polymkeric substance, and polymkeric substance can cause the intensive anaphylaxis in animal experiment, also often produce serious adverse effects in the process of clinical application.
Summary of the invention
The object of the invention is to provide a kind of quality height, good stability, solubleness is good, bioavailability is high cephalosporin antibiotic acidic complex salt.
Cephalosporin antibiotic acidic complex salt of the present invention has formula (I) general structure:
Wherein:
[A-NH
3]
+In A-NH
2For containing-NH
2Cephalosporin analog antibiotic, described cephalosporin analog antibiotic is selected a kind of in cefetamet pivoxil, Tomiron 100, Cefpodoxime Proxetil, S-1108, Ceftibuten, cephalo Toro, S 578, Cephradine, Cefaclor, Cephalexin Monohydrate Micro/Compacted, Prozef, cefetamet Sulbactam ester, cephalofruxin Sulbactam ester, Cephradine Sulbactam ester, Cephalexin Monohydrate Micro/Compacted Sulbactam ester, S 578 Sulbactam ester or the Cefaclor Sulbactam ester for use.
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).
Described cephalosporin antibiotic acidic complex salt comprises the cefetamet pivoxil acidic complex salt, the Tomiron 100 acidic complex salt, the Cefpodoxime Proxetil acidic complex salt, the S-1108 acidic complex salt, the Ceftibuten acidic complex salt, cephalo Toro acidic complex salt, the S 578 acidic complex salt, the Cephradine acidic complex salt, the Cefaclor acidic complex salt, the Cephalexin Monohydrate Micro/Compacted acidic complex salt, the Prozef acidic complex salt, cefetamet Sulbactam ester acidic complex salt, cephalofruxin Sulbactam ester acidic complex salt, Cephradine Sulbactam ester acidic complex salt, Cephalexin Monohydrate Micro/Compacted Sulbactam ester acidic complex salt, S 578 Sulbactam ester acidic complex salt, Cefaclor Sulbactam ester acidic complex salt, structural formula is as follows respectively:
The cefetamet pivoxil acidic complex salt
The Tomiron 100 acidic complex salt
The Cefpodoxime Proxetil acidic complex salt
The S-1108 acidic complex salt
The Ceftibuten acidic complex salt
Cephalo Toro acidic complex salt
The S 578 acidic complex salt
The Cephradine acidic complex salt
The Prozef acidic complex salt
The Cefaclor acidic complex salt
The Cephalexin Monohydrate Micro/Compacted acidic complex salt
Cefetamet Sulbactam ester acidic complex salt
Cephalofruxin Sulbactam ester acidic complex salt
Cephradine Sulbactam ester acidic complex salt
Cephalexin Monohydrate Micro/Compacted Sulbactam ester acidic complex salt
S 578 Sulbactam ester acidic complex salt
Cefaclor Sulbactam ester acidic complex salt
Y, M are as defined above in the formula.
The present invention also provides two kinds of preparation methods of described cephalosporin antibiotic acidic complex salt, and the preparation method of first kind of cephalosporin antibiotic acidic complex salt realizes by following steps: cephalosporin analog antibiotic and equimolar H
2Y makes cephalosporin antibiotic acidic salt after mixing in polar solvent, add and the equimolar MOR compound of cephalosporin analog antibiotic again, after reacting completely, concentrates, and adds the weak polar solvent crystallization, filters, and with solid drying, promptly gets cephalosporin antibiotic acidic complex salt.
Reaction formula is:
A-NH wherein
2, M and Y as defined 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-, the H.
The preparation method of second kind of cephalosporin antibiotic acidic complex salt realizes by following steps: with cephalosporin analog antibiotic with after the MHY compound mixes in polar solvent, reacts completely with 1: 1 mol ratio, concentrate, add the weak polar solvent crystallization, filter, with solid drying, promptly get cephalosporin antibiotic acidic complex salt.
Reaction formula is
A-NH wherein
2, M and Y as previously mentioned, the MHY described in the preparation method 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.
Polar solvent described in the preparation method is selected a kind of among ethanol, methyl alcohol, acetone, DMF or the DMSO for use.
Weak polar solvent described in the preparation method is a kind of in ether, sherwood oil, normal hexane or the hexanaphthene.
Preparation method of the present invention is reasonable, and technology is simple.Cephalosporin antibiotic acidic complex salt purity, content by the inventive method preparation have improved more than 1%, have good stability, the difficult characteristics that produce polymkeric substance.Described cephalosporin antibiotic acidic complex salt bioavailability height has increased absorption, has improved drug effect.
The cephalosporin antibiotic acidic complex salt purity of the present invention and the aqueous solution are good, can be made into into injection, increase clinical application range.
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 cefetamet pivoxil 511.57mg, use the 50ml anhydrous alcohol solution, stir, add sulfuric acid 98mg, after reaction is finished, recovery concentrates, and obtains cefetamet pivoxil vitriol 549mg, and cefetamet pivoxil 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 cefetamet pivoxil sodium pyrosulfate double salt 514mg.
Embodiment 2
In the 100ml reaction flask, add Tomiron 100 593.64mg, with the dissolving of 50ml anhydrous methanol, stir, add phosphatase 79 8mg, after reaction is finished, recovery concentrates, and obtains Tomiron 100 phosphoric acid salt 622mg, and Tomiron 100 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 Tomiron 100 potassium primary phosphate double salt 594mg.
Embodiment 3
In the 100ml reaction flask, add Cefpodoxime Proxetil 427.46mg, with the dissolving of 50ml dry DMF, stir, add sulfuric acid 98mg, after reaction is finished, recovery concentrates, and obtains Cefpodoxime Proxetil vitriol 473mg, and Cefpodoxime Proxetil 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 Cefpodoxime Proxetil monoammonium sulfate double salt 490mg.
Embodiment 4
In the 100ml reaction flask, add S-1108 567.64mg, with the anhydrous DMSO dissolving of 50ml, stir, add phosphatase 79 8mg, after reaction is finished, recovery concentrates, and obtains S-1108 phosphoric acid salt 599mg, and S-1108 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 S-1108 cesium dihydrogen phosphate double salt 657mg.
Embodiment 5
In the 100ml reaction flask, add Ceftibuten 410.42mg, use the 50ml anhydrous alcohol solution, stir, add sulfuric acid 98mg, after reaction is finished, recovery concentrates, and obtains Ceftibuten vitriol 457mg, and Ceftibuten 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 Ceftibuten sodium pyrosulfate double salt 431mg.
Embodiment 6
In the 100ml reaction flask, add cephalo Toro 712.65mg, with the dissolving of 50ml anhydrous methanol, stir, add phosphatase 79 8mg, after reaction is finished, recovery concentrates, and obtains cephalo Toro phosphoric acid salt 729mg, and cephalo Toro 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 cephalo Toro potassium primary phosphate double salt 690mg.
Embodiment 7
In the 100ml reaction flask, add S 578 363.39mg, with the dissolving of 50ml dry DMF, stir, add sulfuric acid 98mg, after reaction is finished, recovery concentrates, and obtains S 578 vitriol 415mg, and S 578 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 S 578 monoammonium sulfate double salt 429mg.
Embodiment 8
In the 100ml reaction flask, add Cephradine 349.4mg, with the anhydrous DMSO dissolving of 50ml, stir, add phosphatase 79 8mg, after reaction is finished, recovery concentrates, and obtains Cephradine phosphoric acid salt 403mg, and Cephradine 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 Cephradine cesium dihydrogen phosphate double salt 480mg with hexanaphthene washing, drying.
Embodiment 9
In the 100ml reaction flask, add Cefaclor 367.8mg, separate with the 50ml anhydrous propanone, stir, add sulfuric acid 98mg, after reaction is finished, recovery concentrates, and obtains Cefaclor vitriol 419mg, and Cefaclor 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 Cefaclor sodium pyrosulfate double salt 397mg with ether washing, drying.
Embodiment 10
In the 100ml reaction flask, add Cephalexin Monohydrate Micro/Compacted 347.39mg, use the 50ml anhydrous alcohol solution, stir, add phosphatase 79 8mg, after reaction is finished, recovery concentrates, and obtains Cephalexin Monohydrate Micro/Compacted phosphoric acid salt 400mg, and Cephalexin Monohydrate Micro/Compacted 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 Cephalexin Monohydrate Micro/Compacted potassium primary phosphate double salt 395mg with petroleum ether, drying.
Embodiment 11
In the 100ml reaction flask, add Prozef 389.43mg, with the dissolving of 50ml anhydrous propanone, stir, add sulfuric acid 98mg, after reaction is finished, recovery concentrates, and obtains Prozef vitriol 439mg, and Prozef 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 Prozef cesium hydrogen sulfate double salt 513mg with normal hexane washing, drying.
Embodiment 12
In the 100ml reaction flask, add cefetamet Sulbactam ester 642.68mg, with the dissolving of 50ml anhydrous propanone, stir, add sulfuric acid 98mg, after reaction is finished, recovery concentrates, and obtains cefetamet Sulbactam ester vitriol 666mg, and cefetamet Sulbactam ester vitriol is again at the acetone mixing, add and go into the 54mg sodium methylate, reaction is finished, concentrating under reduced pressure, add an amount of normal hexane, separate out solid, filtration,, obtain white solid cefetamet Sulbactam ester sodium pyrosulfate double salt 686mg with normal hexane washing, drying.
Embodiment 13
In the 100ml reaction flask, add cephalofruxin Sulbactam ester 669.64mg, with the dissolving of 50ml anhydrous propanone, stir, add sulfuric acid 98mg, after reaction is finished, recovery concentrates, and obtains cephalofruxin Sulbactam ester vitriol 691mg, and cephalofruxin Sulbactam ester vitriol is again at the acetone mixing, add and go into the 70mg potassium methylate, reaction is finished, concentrating under reduced pressure, add an amount of normal hexane, separate out solid, filtration,, obtain white solid cephalofruxin Sulbactam ester sal enixum double salt 724mg with normal hexane washing, drying.
Embodiment 14
In the 100ml reaction flask, add Cephradine Sulbactam ester 594.66mg, with the dissolving of 50ml anhydrous propanone, stir, add phosphatase 79 8mg, after reaction is finished, recovery concentrates, and obtains Cephradine Sulbactam ester vitriol 623mg, and Cephradine Sulbactam ester vitriol is again at the acetone mixing, add and go into the 77mg ammonium acetate, reaction is finished, concentrating under reduced pressure, add an amount of normal hexane, separate out solid, filtration,, obtain white solid Cephradine Sulbactam ester ammonium hydrogen phosphate double salt 638mg with normal hexane washing, drying.
Embodiment 15
In the 100ml reaction flask, add Cephalexin Monohydrate Micro/Compacted Sulbactam ester 592.64mg, with the dissolving of 50ml anhydrous propanone, stir, add phosphatase 79 8mg, after reaction is finished, recovery concentrates, and obtains Cephalexin Monohydrate Micro/Compacted Sulbactam ester vitriol 622mg, and Cephalexin Monohydrate Micro/Compacted Sulbactam ester vitriol is again at the acetone mixing, add and go into 164mg methyl alcohol caesium, reaction is finished, concentrating under reduced pressure, add an amount of normal hexane, separate out solid, filtration,, obtain white solid Cephalexin Monohydrate Micro/Compacted Sulbactam ester phosphoric acid hydrogen caesium double salt 738mg with normal hexane washing, drying.
Embodiment 16
In the 100ml reaction flask, add S 578 Sulbactam ester 608.64mg, dissolve with the 50ml anhydrous propanone, stir, add sulfuric acid 98mg, after reaction was finished, recovery concentrated, and obtains S 578 Sulbactam ester vitriol 636mg, S 578 Sulbactam ester vitriol is again at the acetone mixing, add and go into the 54mg sodium methylate, reaction is finished, concentrating under reduced pressure, add an amount of normal hexane, separate out solid, filtration,, obtain white solid S 578 Sulbactam ester sodium pyrosulfate double salt 655mg with normal hexane washing, drying.
Embodiment 17
In the 100ml reaction flask, add Cefaclor Sulbactam ester 613.06mg, with the dissolving of 50ml anhydrous propanone, stir, add sulfuric acid 98mg, after reaction is finished, recovery concentrates, and obtains Cefaclor Sulbactam ester vitriol 640mg, and Cefaclor Sulbactam ester vitriol is again at the acetone mixing, add and go into the 95mg Potassium ethanoate, reaction is finished, concentrating under reduced pressure, add an amount of normal hexane, separate out solid, filtration,, obtain white solid Cefaclor Sulbactam ester sal enixum double salt 673mg with normal hexane washing, drying.
Embodiment 18
In the 100ml reaction flask, add cefetamet pivoxil 511.57mg, use the 50ml anhydrous alcohol solution, stir, add sodium pyrosulfate 120mg, after reaction was finished, recovery concentrated, and obtains white solid cefetamet pivoxil sulphur
Sodium double salt 568mg.
Embodiment 19
In the 100ml reaction flask, add cefetamet pivoxil 511.57mg, use the dissolving of 50ml anhydrous propanone, stir, add sal enixum 136mg, after reaction was finished, recovery concentrated, and obtains white solid cefetamet pivoxil sal enixum double salt 583mg.
Embodiment 20
In the 100ml reaction flask, add Tomiron 100 593.64mg, use the 50ml anhydrous alcohol solution, stir, add sodium pyrosulfate 120mg, after reaction was finished, recovery concentrated, and obtains white solid Tomiron 100 sodium pyrosulfate double salt 642mg.
Embodiment 21
In the 100ml reaction flask, add Tomiron 100 593.64mg, use the dissolving of 50ml anhydrous propanone, stir, add monoammonium sulfate 115mg, after reaction was finished, recovery concentrated, and obtains white solid Tomiron 100 monoammonium sulfate double salt 638mg.
Embodiment 22
In the 100ml reaction flask, add Cefpodoxime Proxetil 427.46mg, use the 50ml anhydrous alcohol solution, stir, add sodium pyrosulfate 120mg, after reaction was finished, recovery concentrated, and obtains white solid Cefpodoxime Proxetil sodium pyrosulfate double salt 493mg.
Embodiment 23
In the 100ml reaction flask, add Cefpodoxime Proxetil 427.46mg, use the dissolving of 50ml anhydrous propanone, stir, add cesium hydrogen sulfate 230mg, after reaction was finished, recovery concentrated, and obtains white solid Cefpodoxime Proxetil cesium hydrogen sulfate double salt 592mg.
Embodiment 24
In the 100ml reaction flask, add S-1108 567.64mg, use the 50ml anhydrous alcohol solution, stir, add sodium pyrosulfate 120mg, after reaction was finished, recovery concentrated, and obtains white solid S-1108 sodium pyrosulfate double salt 688mg.
Embodiment 25
In the 100ml reaction flask, add Ceftibuten 410.42mg, use the 50ml anhydrous alcohol solution, stir, add sodium pyrosulfate 120mg, after reaction was finished, recovery concentrated, and obtains white solid Ceftibuten sodium pyrosulfate double salt 477mg.
Embodiment 26
In the 100ml reaction flask, add cephalo Toro 712.65mg, use the 50ml anhydrous alcohol solution, stir, add sodium pyrosulfate 120mg, after reaction was finished, recovery concentrated, and obtains white solid cephalo Toro sodium pyrosulfate double salt 749mg.
Embodiment 27
In the 100ml reaction flask, add S 578 363.39mg, use the 50ml anhydrous alcohol solution, stir, add sodium pyrosulfate 120mg, after reaction was finished, recovery concentrated, and obtains white solid S 578 sodium pyrosulfate double salt 435mg.
Embodiment 28
In the 100ml reaction flask, add Cephradine 349.4mg, use the 50ml anhydrous alcohol solution, stir, add sodium pyrosulfate 120mg, after reaction was finished, recovery concentrated, and obtains white solid Cephradine sodium pyrosulfate double salt 422mg.
Embodiment 29
In the 100ml reaction flask, add Cefaclor 367.8mg, use the 50ml anhydrous alcohol solution, stir, add sodium pyrosulfate 120mg, after reaction was finished, recovery concentrated, and obtains white solid Cefaclor sodium pyrosulfate double salt 439mg.
Embodiment 30
In the 100ml reaction flask, add Cephalexin Monohydrate Micro/Compacted 347.39mg, use the 50ml anhydrous alcohol solution, stir, add sodium pyrosulfate 120mg, after reaction was finished, recovery concentrated, and obtains white solid Cephalexin Monohydrate Micro/Compacted sodium pyrosulfate double salt 421mg.
Embodiment 31
In the 100ml reaction flask, add Prozef 389.43mg, use the 50ml anhydrous alcohol solution, stir, add sodium pyrosulfate 120mg, after reaction was finished, recovery concentrated, and obtains white solid Prozef sodium pyrosulfate double salt 458mg.
Embodiment 32
In the 100ml reaction flask, add cefetamet Sulbactam ester 642.68mg, use the 50ml anhydrous alcohol solution, stir, add sodium pyrosulfate 120mg, after reaction was finished, recovery concentrated, and obtains white solid cefetamet Sulbactam ester sodium pyrosulfate double salt 686mg.
Embodiment 33
In the 100ml reaction flask, add cephalofruxin Sulbactam ester 669.64mg, use the 50ml anhydrous alcohol solution, stir, add sodium pyrosulfate 120mg, after reaction was finished, recovery concentrated, and obtains white solid cephalofruxin Sulbactam ester sodium pyrosulfate double salt 711mg.
Embodiment 34
In the 100ml reaction flask, add Cephradine Sulbactam ester 594.66mg, use the 50ml anhydrous alcohol solution, stir, add sodium pyrosulfate 120mg, after reaction was finished, recovery concentrated, and obtains white solid Cephradine Sulbactam ester sodium pyrosulfate double salt 643mg.
Embodiment 35
In the 100ml reaction flask, add Cephalexin Monohydrate Micro/Compacted Sulbactam ester 592.64mg, use the 50ml anhydrous alcohol solution, stir, add sodium pyrosulfate 120mg, after reaction was finished, recovery concentrated, and obtains white solid Cephalexin Monohydrate Micro/Compacted Sulbactam ester sodium pyrosulfate double salt 641mg.
Embodiment 36
In the 100ml reaction flask, add S 578 Sulbactam ester 608.64mg, use the 50ml anhydrous alcohol solution, stir, add sodium pyrosulfate 120mg, after reaction was finished, recovery concentrated, and obtains white solid S 578 Sulbactam ester sodium pyrosulfate double salt 656mg.
Embodiment 37
In the 100ml reaction flask, add Cefaclor Sulbactam ester 613.06mg, use the 50ml anhydrous alcohol solution, stir, add sodium pyrosulfate 120mg, after reaction was finished, recovery concentrated, and obtains white solid Cefaclor Sulbactam ester sodium pyrosulfate double salt 660mg.
Embodiment 38
In the 100ml reaction flask, add cefetamet pivoxil 511.57mg, use the 50ml anhydrous alcohol solution, stir, add SODIUM PHOSPHATE, MONOBASIC 120mg, after reaction was finished, recovery concentrated, and obtains white solid cefetamet pivoxil SODIUM PHOSPHATE, MONOBASIC double salt 568mg.
Embodiment 39
In the 100ml reaction flask, add cefetamet pivoxil 511.57mg, use the dissolving of 50ml anhydrous propanone, stir, add potassium primary phosphate 136mg, after reaction was finished, recovery concentrated, and obtains white solid cefetamet pivoxil potassium primary phosphate double salt 583mg.
Embodiment 40
In the 100ml reaction flask, add Tomiron 100 593.64mg, use the 50ml anhydrous alcohol solution, stir, add SODIUM PHOSPHATE, MONOBASIC 120mg, after reaction was finished, recovery concentrated, and obtains white solid Tomiron 100 SODIUM PHOSPHATE, MONOBASIC double salt 642mg.
Embodiment 41
In the 100ml reaction flask, add Tomiron 100 593.64mg, use the dissolving of 50ml anhydrous propanone, stir, add primary ammonium phosphate 115mg, after reaction was finished, recovery concentrated, and obtains white solid Tomiron 100 primary ammonium phosphate double salt 638mg.
Embodiment 42
In the 100ml reaction flask, add Cefpodoxime Proxetil 427.46mg, use the 50ml anhydrous alcohol solution, stir, add SODIUM PHOSPHATE, MONOBASIC 120mg, after reaction was finished, recovery concentrated, and obtains white solid Cefpodoxime Proxetil SODIUM PHOSPHATE, MONOBASIC double salt 493mg.
Embodiment 43
In the 100ml reaction flask, add Cefpodoxime Proxetil 427.46mg, use the dissolving of 50ml anhydrous propanone, stir, add cesium dihydrogen phosphate 230mg, after reaction was finished, recovery concentrated, and obtains white solid Cefpodoxime Proxetil cesium dihydrogen phosphate double salt 592mg.
Embodiment 44
In the 100ml reaction flask, add S-1108 567.64mg, use the 50ml anhydrous alcohol solution, stir, add SODIUM PHOSPHATE, MONOBASIC 120mg, after reaction was finished, recovery concentrated, and obtains white solid S-1108 SODIUM PHOSPHATE, MONOBASIC double salt 619mg.
Embodiment 45
In the 100ml reaction flask, add S-1108 567.64mg, use the dissolving of 50ml anhydrous propanone, stir, add potassium primary phosphate 136mg, after reaction was finished, recovery concentrated, and obtains white solid S-1108 potassium primary phosphate double salt 633mg.
Embodiment 46
In the 100ml reaction flask, add Ceftibuten 410.42mg, use the 50ml anhydrous alcohol solution, stir, add SODIUM PHOSPHATE, MONOBASIC 120mg, after reaction was finished, recovery concentrated, and obtains white solid Ceftibuten SODIUM PHOSPHATE, MONOBASIC double salt 477mg.
Embodiment 47
In the 100ml reaction flask, add Ceftibuten 410.42mg, use the dissolving of 50ml anhydrous propanone, stir, add primary ammonium phosphate 115mg, after reaction was finished, recovery concentrated, and obtains white solid Ceftibuten primary ammonium phosphate double salt 473mg.
Embodiment 48
In the 100ml reaction flask, add cephalo Toro 712.65mg, use the 50ml anhydrous alcohol solution, stir, add SODIUM PHOSPHATE, MONOBASIC 120mg, after reaction was finished, recovery concentrated, and obtains white solid cephalo Toro SODIUM PHOSPHATE, MONOBASIC double salt 749mg.
Embodiment 49
In the 100ml reaction flask, add cephalo Toro 712.65mg, use the dissolving of 50ml anhydrous propanone, stir, add cesium dihydrogen phosphate 230mg, after reaction was finished, recovery concentrated, and obtains white solid cephalo Toro cesium dihydrogen phosphate double salt 848mg.
Embodiment 50
In the 100ml reaction flask, add S 578 363.39mg, use the 50ml anhydrous alcohol solution, stir, add SODIUM PHOSPHATE, MONOBASIC 120mg, after reaction was finished, recovery concentrated, and obtains white solid S 578 SODIUM PHOSPHATE, MONOBASIC double salt 435mg.
Embodiment 51
In the 100ml reaction flask, add S 578 363.39mg, use the dissolving of 50ml anhydrous propanone, stir, add potassium primary phosphate 136mg, after reaction was finished, recovery concentrated, and obtains white solid S 578 potassium primary phosphate double salt 449mg.
Embodiment 52
In the 100ml reaction flask, add Cephradine 349.4mg, use the 50ml anhydrous alcohol solution, stir, add SODIUM PHOSPHATE, MONOBASIC 120mg, after reaction was finished, recovery concentrated, and obtains white solid Cephradine SODIUM PHOSPHATE, MONOBASIC double salt 422mg.
Embodiment 53
In the 100ml reaction flask, add Cephradine 349.4mg, use the dissolving of 50ml anhydrous propanone, stir, add primary ammonium phosphate 115mg, after reaction was finished, recovery concentrated, and obtains white solid Cephradine potassium primary phosphate double salt 418mg.
Embodiment 54
In the 100ml reaction flask, add Cefaclor 367.8mg, use the 50ml anhydrous alcohol solution, stir, add SODIUM PHOSPHATE, MONOBASIC 120mg, after reaction was finished, recovery concentrated, and obtains white solid Cefaclor SODIUM PHOSPHATE, MONOBASIC double salt 488mg.
Embodiment 55
In the 100ml reaction flask, add Cefaclor 367.8mg, use the dissolving of 50ml anhydrous propanone, stir, add cesium dihydrogen phosphate 230mg, after reaction was finished, recovery concentrated, and obtains white solid Cefaclor potassium primary phosphate double salt 538mg.
Embodiment 56
In the 100ml reaction flask, add Cephalexin Monohydrate Micro/Compacted 347.39mg, use the 50ml anhydrous alcohol solution, stir, add SODIUM PHOSPHATE, MONOBASIC 120mg, after reaction was finished, recovery concentrated, and obtains white solid Cephalexin Monohydrate Micro/Compacted SODIUM PHOSPHATE, MONOBASIC double salt 421mg.
Embodiment 57
In the 100ml reaction flask, add Cephalexin Monohydrate Micro/Compacted 347.39mg, use the dissolving of 50ml anhydrous propanone, stir, add potassium primary phosphate 136mg, after reaction was finished, recovery concentrated, and obtains white solid Cephalexin Monohydrate Micro/Compacted potassium primary phosphate double salt 435mg.
Embodiment 58
In the 100ml reaction flask, add Prozef 389.43mg, use the 50ml anhydrous alcohol solution, stir, add SODIUM PHOSPHATE, MONOBASIC 120mg, after reaction was finished, recovery concentrated, and obtains white solid Prozef SODIUM PHOSPHATE, MONOBASIC double salt 458mg.
Embodiment 59
In the 100ml reaction flask, add Prozef 389.43mg, use the dissolving of 50ml anhydrous propanone, stir, add primary ammonium phosphate 115mg, after reaction was finished, recovery concentrated, and obtains white solid Prozef potassium primary phosphate double salt 454mg.
Embodiment 60
In the 100ml reaction flask, add cefetamet Sulbactam ester 642.68mg, use the 50ml anhydrous alcohol solution, stir, add SODIUM PHOSPHATE, MONOBASIC 120mg, after reaction was finished, recovery concentrated, and obtains white solid cefetamet Sulbactam ester SODIUM PHOSPHATE, MONOBASIC double salt 686mg.
Embodiment 61
In the 100ml reaction flask, add cephalofruxin Sulbactam ester 669.64mg, use the 50ml anhydrous alcohol solution, stir, add SODIUM PHOSPHATE, MONOBASIC 120mg, after reaction was finished, recovery concentrated, and obtains white solid cephalofruxin Sulbactam ester SODIUM PHOSPHATE, MONOBASIC double salt 711mg.
Embodiment 62
In the 100ml reaction flask, add Cephradine Sulbactam ester 594.66mg, use the 50ml anhydrous alcohol solution, stir, add SODIUM PHOSPHATE, MONOBASIC 120mg, after reaction was finished, recovery concentrated, and obtains white solid Cephradine Sulbactam ester SODIUM PHOSPHATE, MONOBASIC double salt 643mg.
Embodiment 63
In the 100ml reaction flask, add Cephalexin Monohydrate Micro/Compacted Sulbactam ester 592.64mg, use the 50ml anhydrous alcohol solution, stir, add SODIUM PHOSPHATE, MONOBASIC 120mg, after reaction was finished, recovery concentrated, and obtains white solid Cephalexin Monohydrate Micro/Compacted Sulbactam ester SODIUM PHOSPHATE, MONOBASIC double salt 641mg.
Embodiment 64
In the 100ml reaction flask, add S 578 Sulbactam ester 608.64mg, use the 50ml anhydrous alcohol solution, stir, add SODIUM PHOSPHATE, MONOBASIC 120mg, after reaction is finished, recovery concentrates, and obtains white solid S 578 Sulbactam ester SODIUM PHOSPHATE, MONOBASIC double salt 656mg.
Embodiment 65
In the 100ml reaction flask, add Cefaclor Sulbactam ester 613.06mg, use the 50ml anhydrous alcohol solution, stir, add SODIUM PHOSPHATE, MONOBASIC 120mg, after reaction was finished, recovery concentrated, and obtains white solid Cefaclor Sulbactam ester SODIUM PHOSPHATE, MONOBASIC double salt 660mg.
Embodiment 66
Compound cefetamet pivoxil sodium pyrosulfate of the present invention, Tomiron 100 sodium pyrosulfate, Cefpodoxime Proxetil sodium pyrosulfate, S-1108 sodium pyrosulfate, Ceftibuten sodium pyrosulfate, cephalo Toro sodium pyrosulfate, S 578 sodium pyrosulfate, Cephradine sodium pyrosulfate, Cefaclor sodium pyrosulfate, Cephalexin Monohydrate Micro/Compacted sodium pyrosulfate, Prozef sodium pyrosulfate are 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 cefetamet pivoxil sodium pyrosulfate | ??99.14 | ??99.23 |
| ??2 | The Tomiron 100 sodium pyrosulfate | ??98.89 | ??99.58 |
| ??3 | The Cefpodoxime Proxetil sodium pyrosulfate | ??99.32 | ??99.47 |
| ??4 | The S-1108 sodium pyrosulfate | ??99.44 | ??99.64 |
| ??5 | The Ceftibuten sodium pyrosulfate | ??99.39 | ??99.54 |
| ??6 | Cephalo Toro sodium pyrosulfate | ??99.62 | ??99.63 |
| ??7 | The S 578 sodium pyrosulfate | ??98.94 | ??99.57 |
| ??8 | The Cephradine sodium pyrosulfate | ??99.04 | ??99.75 |
| ??9 | The Cefaclor sodium pyrosulfate | ??98.67 | ??99.13 |
| ??10 | The Cephalexin Monohydrate Micro/Compacted sodium pyrosulfate | ??99.82 | ??99.56 |
| ??11 | The Prozef sodium pyrosulfate | ??99.54 | ??99.09 |
Embodiment 67
Compound of the present invention is used in RH92%, 60 ℃ of placements of temperature were investigated test in one week, and with the S 578 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 % |
| ??0 | S 578 | ??0.026 | ??0.159 |
| ??1 | The cefetamet pivoxil sodium pyrosulfate | Do not detect | ??0.076 |
| ??2 | The Tomiron 100 sodium pyrosulfate | Do not detect | Do not detect |
| ??3 | The Cefpodoxime Proxetil sodium pyrosulfate | Do not detect | ??0.032 |
| ??4 | The S-1108 sodium pyrosulfate | Do not detect | ??0.024 |
| ??5 | The Ceftibuten sodium pyrosulfate | Do not detect | Do not detect |
| ??6 | Cephalo Toro sodium pyrosulfate | Do not detect | Do not detect |
| ??7 | The S 578 sodium pyrosulfate | Do not detect | ??0.012 |
| ??8 | The Cephradine sodium pyrosulfate | Do not detect | ??0.023 |
| ??9 | The Cefaclor sodium pyrosulfate | Do not detect | Do not detect |
| ??10 | The Cephalexin Monohydrate Micro/Compacted sodium pyrosulfate | Do not detect | ??0.031 |
| ??11 | The Prozef sodium pyrosulfate | Do not detect | Do not detect |
Embodiment 68
Compound cefetamet pivoxil sodium pyrosulfate of the present invention, Tomiron 100 sodium pyrosulfate, Cefpodoxime Proxetil sodium pyrosulfate, S-1108 sodium pyrosulfate, Ceftibuten sodium pyrosulfate, cephalo Toro sodium pyrosulfate, S 578 sodium pyrosulfate, Cephradine sodium pyrosulfate, Cefaclor sodium pyrosulfate, Cephalexin Monohydrate Micro/Compacted sodium pyrosulfate, Prozef sodium pyrosulfate are contrast with the cynnematin of correspondence respectively, the rat oral gavage administration, measure Plasma Concentration, carry out animal organism availability absorption test.Result such as table 3.Compound bioavailability of the present invention is much improved.
Table 3
| Sequence number | The ratio of contrivance and corresponding bulk drug | Bioavailability ratio % |
| ??1 | Cefetamet pivoxil sodium pyrosulfate/cefetamet pivoxil | ??121.67 |
| ??2 | Tomiron 100 sodium pyrosulfate/Tomiron 100 | ??144.19 |
| ??3 | Cefpodoxime Proxetil sodium pyrosulfate/Cefpodoxime Proxetil | ??127.27 |
| ??4 | S-1108 sodium pyrosulfate/S-1108 | ??125.51 |
| ??5 | Ceftibuten sodium pyrosulfate/Ceftibuten | ??149.61 |
| ??6 | Cephalo Toro sodium pyrosulfate/cephalo Toro | ??143.72 |
| ??7 | S 578 sodium pyrosulfate/S 578 | ??120.03 |
| ??8 | Cephradine sodium pyrosulfate/Cephradine | ??128.28 |
| ??9 | Cefaclor sodium pyrosulfate/Cefaclor | ??143.55 |
| ??10 | Cephalexin Monohydrate Micro/Compacted sodium pyrosulfate/Cephalexin Monohydrate Micro/Compacted | ??147.11 |
| ??11 | Prozef sodium pyrosulfate/Prozef | ??154.64 |
Claims (5)
1. cephalosporin antibiotic acidic complex salt has following general structure:
Wherein:
[A-NH
3]
+In A-NH
2For containing-NH
2Cephalosporin analog antibiotic, described cephalosporin analog antibiotic is selected a kind of in cefetamet pivoxil, Tomiron 100, Cefpodoxime Proxetil, S-1108, Ceftibuten, cephalo Toro, S 578, Cephradine, Cefaclor, Cephalexin Monohydrate Micro/Compacted, Prozef, cefetamet Sulbactam ester, cephalofruxin Sulbactam ester, Cephradine Sulbactam ester, Cephalexin Monohydrate Micro/Compacted Sulbactam ester, S 578 Sulbactam ester or the Cefaclor Sulbactam ester for use;
M is Na
+(sodium ion), K
+(potassium ion), NH4
+(ammonium ion), Cs
+A kind of in (cesium ion);
Y is S04
2-(sulfate radical), HPO4
2-A kind of in (phosphoric acid one hydrogen root).
2. a kind of cephalosporin antibiotic acidic complex salt according to claim 1, it is characterized in that, described cephalosporin antibiotic acidic complex salt comprises the cefetamet pivoxil acidic complex salt, the Tomiron 100 acidic complex salt, the Cefpodoxime Proxetil acidic complex salt, the S-1108 acidic complex salt, the Ceftibuten acidic complex salt, cephalo Toro acidic complex salt, the S 578 acidic complex salt, the Cephradine acidic complex salt, the Cefaclor acidic complex salt, the Cephalexin Monohydrate Micro/Compacted acidic complex salt, the Prozef acidic complex salt, cefetamet Sulbactam ester acidic complex salt, cephalofruxin Sulbactam ester acidic complex salt, Cephradine Sulbactam ester acidic complex salt, Cephalexin Monohydrate Micro/Compacted Sulbactam ester acidic complex salt, S 578 Sulbactam ester acidic complex salt, Cefaclor Sulbactam ester acidic complex salt, structural formula is respectively:
The cefetamet pivoxil acidic complex salt
The Tomiron 100 acidic complex salt
The Cefpodoxime Proxetil acidic complex salt
The S-1108 acidic complex salt
The Ceftibuten acidic complex salt
Cephalo Toro acidic complex salt
The S 578 acidic complex salt
The Cephradine acidic complex salt
The Prozef acidic complex salt
The Cefaclor acidic complex salt
The Cephalexin Monohydrate Micro/Compacted acidic complex salt
Cefetamet Sulbactam ester acidic complex salt
Cephalofruxin Sulbactam ester acidic complex salt
Cephradine Sulbactam ester acidic complex salt
Cephalexin Monohydrate Micro/Compacted Sulbactam ester acidic complex salt
S 578 Sulbactam ester acidic complex salt
Cefaclor Sulbactam ester acidic complex salt
Y, M are according to claim 1 in the formula.
3. the preparation method of cephalosporin antibiotic acidic complex salt according to claim 1 is characterized in that, realizes by following steps: with cephalosporin analog antibiotic and equimolar H
2The Y compound is made cephalosporin antibiotic acidic salt after mixing in polar solvent, add and the equimolar MOR compound of cephalosporin analog antibiotic again, after reacting completely, concentrate, add the weak polar solvent crystallization, filter,, promptly get cephalosporin antibiotic acidic complex salt solid drying;
Reaction formula is:
A-NH wherein
2, M and Y such as claim 1 definition;
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 cephalosporin antibiotic acidic complex salt according to claim 1, it is characterized in that, realize by following steps: with cephalosporin analog antibiotic with after the MHY compound mixes in polar solvent, reacts completely with 1: 1 mol ratio, concentrate, add the weak polar solvent crystallization, filter,, promptly get cephalosporin antibiotic acidic complex salt solid drying;
Reaction formula is:
A-NH wherein
2, M and Y according to claim 1,
Described MHY compound is selected 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.
5. according to claim 3 or 4 described preparation methods, it is characterized in that described polar solvent is selected a kind of among ethanol, methyl alcohol, acetone, DMF or the DMSO for use; Described weak polar solvent is selected a kind of in ether, sherwood oil, normal hexane or the hexanaphthene for use.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102127094A (en) * | 2010-12-02 | 2011-07-20 | 海南美大制药有限公司 | Cefteram pivoxil compound and novel preparation method thereof |
| 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 |
-
2009
- 2009-07-27 CN CN200910101287A patent/CN101633665A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102127094A (en) * | 2010-12-02 | 2011-07-20 | 海南美大制药有限公司 | Cefteram pivoxil compound and novel preparation method thereof |
| CN102127094B (en) * | 2010-12-02 | 2012-11-21 | 海南美大制药有限公司 | Cefteram pivoxil compound and novel preparation method thereof |
| 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 |
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