CN102268019B - Cefadroxil compound and preparation method thereof - Google Patents
Cefadroxil compound and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a cefadroxil compound and a preparation method thereof. The preparation method comprises the following steps: 1) adding ethanol or ethyl ether into cefadroxil serving as a raw material, keeping the temperature below 30 DEG C, fiercely stirring, filtering, washing filter cake with ethanol or ethyl ether at a temperature of below 15 DEG C, drying under vacuum or in the air; 2) placing the filter cake in ammonia water, mildly stirring, keeping pH value below 9, obtaining ammonia water solution of cefadroxil, and filtering out precipitate; 3) slowly adding hydrochloric acid at concentration of 1 to 3 mol/L into the ammonia water solution of cefadroxil, keeping the temperature between 30 and 60 DEG C, keeping the final pH between 4.0 and 6.0, keeping the pH value for 30 minutes to 5 hours till crystals precipitate slowly, lowering the temperature to a minimum value of 10 DEG C, standing, crystallizing, filtering under vacuum, drying and thus obtaining refined cefadroxil; and 4) returning crystallization mother solution in which crystals precipitate to the step 3). When the method disclosed by the invention is used, the purity of the cefadroxil is increased, the content of related matters is lowered obviously, the quality of preparation product is improved, and the toxic and side effects are reduced.
Description
Technical field
The present invention relates to a kind of purifying cefadroxil benzyl compound and method for making thereof, belong to medical technical field.
Background technology
S 578 (Cefadroxil, CFD), chemical name is: (6R, 7R)-the 3-methyl-7-[(R)-2-amino-2-(4-hydroxy phenyl) kharophen]-8-oxygen-5-thia-1-dicyclo [4.2.0] oct-2-ene-2-formic acid monohydrate, molecular formula: C
16H
17N
3O
5SH
2O, molecular weight is: 381.41, structural formula is:
S 578 belongs to the semi-synthetic cynnematin of the first-generation, it is the semisynthetic cephalosporins medicine of U.S.'s Bristol Laboratories-Meyer company first-generation, be mainly used in treating the various infection of respiratory tract and urinary tract, produce germicidal action by suppressing synthesizing of bacteria cell wall.To the golden Portugal bacterium that produces penicillinase and do not produce penicillinase, the good anti-microbial effects of most of bacterial strain tool such as coagulase negative staphylococcus, streptococcus pneumoniae, A group Hemolytic streptococcus; Escherichia coli, Proteus mirabilis, Salmonella, Shigella, hemophilus influenzae and gonococcus also there is certain anti-microbial activity.
It is reported, the synthetic method of S 578 has the chloride method of US Patent No. 4254029 announcements in 1981, nineteen eighty-two the mixed anhydride method announced of US Patent No. 4358588, Nanjing pharmacy in 1985 reported the DCC method and nineteen eighty-three Chinese Journal of Pharmaceuticals reported enzyme process.The S 578 purity that aforesaid method makes is lower, and yield is not high yet.
The purity that how to improve S 578 is present problem demanding prompt solution, has important social benefit and economic benefit.
Summary of the invention
The inventor by comprising the process for purification of following treatment step, can increase substantially the purity of the cefadroxil benzyl compound of formula (I) structure through discovering with keen determination:
Step 1) adds ethanol or ether in the raw material S 578, and the control temperature is no more than 30 ℃, and vigorous stirring is filtered then, and filter cake is no more than 15 ℃ ethanol or ether with temperature and washs, and vacuum-drying or air dry;
Step 2), filter cake is put into ammoniacal liquor, mild stirring, control pH value is no more than 9, obtains the ammonia soln of S 578, then the throw out of separating out is filtered out;
Step 3), slowly adding concentration in the ammonia soln of S 578 is the hydrochloric acid of 1-3mol/L, temperature control is at 30-60 ℃, and final pH is controlled at 4.0-6.0, keeps 30 minutes to 5 hours, slowly there is crystal to separate out, progressively temperature is reduced to minimum 10 ℃ then, leaves standstill crystallization, suction filtration, vacuum-drying gets the S 578 elaboration.
Embodiment
Below by the method for purification step specific descriptions according to purifying S 578 of the present invention.
Step 1) adds ethanol or ether in the raw material S 578, and the control temperature is no more than 30 ℃, and vigorous stirring is filtered then, and filter cake is no more than 15 ℃ ethanol or ether with temperature and washs, and vacuum-drying or air dry.
Make with extra care and generally also contain the organic solvent of introducing in the preparation process, various raw material and intermediate product in the raw material S 578 of purifying, in the prior art as synthetic S 578, generally be to be starting raw material with the benzylpenicillin potassium, obtain 7-ADCA through oxidation, ring expansion, cracking, form with the condensation of side chain para hydroxybenzene glycosides propylhomoserin again.Except above-mentioned raw materials, in reaction and purification process, also use than raw materials such as multi-solvent, auxiliary agent and acylating agents, wherein, chloro-formic ester class, methylene dichloride, pivaloyl chloride etc. are all poisonous.And because the tetra-atomic ring tension force of beta-lactam material is big and the amido linkage facile hydrolysis, so by product, isomer and degradation product etc. are more, also generate the polymer class material when handling under comparatively high temps or depositing easily.
The inventor notices that these impurity materials are to cause the not high major cause of raw material S 578 purity, not only reduce active constituents of medicine content, and causes the color and luster of product to be deepened.Owing to do not take the specific aim purification process, these impurity are generally still mixed in together with raw material S 578 crude product.
The inventor finds that these organic property impurity solvability in organic solvent is bigger, and S 578 is almost insoluble in ethanol, chloroform or ether.According to the present invention, the processing through step 1) can separate these impurity and remove from the S 578 crude product.
Preferred embodiment a kind of according to the present invention, in raw material S 578 crude product, add ethanol or ether, most preferably add ethanol.The control temperature is no more than 30 ℃, preferably is no more than 25 ℃, more preferably no more than 20 ℃, and vigorous stirring in this process.
The inventor finds, if temperature is too high when adding ethanol or ether, then causes target compound to run off because of dissolving easily, if higher temperature, as be higher than 80 ℃, S 578 is because degraded and polyreaction can cause active constituents of medicine content to reduce, color and luster is strengthened, and polymeric impurities content raises.And temperature is more low, and S 578 does not more dissolve in organic solvent, removes but too low temperature also influences the dissolving of organic property impurity, therefore, adds solvent treatment temperature and should be not less than 5 ℃.
After above-mentioned processing, the solvent filter that is dissolved with impurity is fallen, filter cake is no more than 15 ℃ with temperature, preferably is no more than 12 ℃, and the S 578 insoluble solvent more preferably no more than 10 ℃ washs as ethanol or ether.
In the preferred embodiment of the present invention, the solvent of washing usefulness preferably with the used solvent phase of dissolving raw material S 578 crude product with.
In drying process, preferably adopt air to dry or normal temperature vacuum-drying mode is carried out drying.
Step 2), filter cake is put into ammoniacal liquor, mild stirring, control pH value is no more than 9, obtains the ammonia soln of S 578, then insoluble precipitate is filtered out.
Except S 578, generally also may contain inorganic nature material such as the trace catalyst of introducing in the preparation process, various salt and heavy metal and deposit the bacterial endotoxin that produces in the process in the filter cake that step 1) obtains.These materials generally are difficult to be dissolved in organic solvent such as ethanol or the ether, therefore are difficult to effectively remove in step 1).By adding ammoniacal liquor, pH raises gradually, exist the S 578 of amino and carboxyl to be easy to be dissolved in the alkaline aqueous solution, and part inorganic nature material can be separated out with subsalt form precipitation, by filtering, can effectively reduce this class impurity.
Preferred embodiment a kind of according to the present invention, adding concentration in the filter cake that obtains to step 1) is the ammoniacal liquor of 12-20%, treatment time was preferably 30 minutes-5 hours, more preferably 1-4 hour, most preferably 2-3 hour, reach weakly alkaline until the aqueous solution, preferred pH value is no more than 9, more preferably no more than 8.5, be most preferably not exceeding 8.For abundant mixing, in treating processes, stir, and the sedimentation and filtration of separating out is fallen.
Preferred embodiment a kind of according to the present invention, behind filtering-depositing, the aqueous solution is heated to 30-60 ℃, preferred 35-55 ℃, more preferably 40-50 ℃, can remove remaining ammonia composition in the aqueous solution on the one hand, also be conducive to follow-up crystallisation step on the other hand.
Step 3), slowly adding concentration in the ammonia soln of above-mentioned S 578 is the hydrochloric acid of 1-3mol/L, temperature control is at 30-60 ℃, and final pH is controlled at 4.0-6.0, keeps 30 minutes to 5 hours, slowly there is crystal to separate out, progressively temperature is reduced to minimum 10 ℃ then, leaves standstill crystallization, suction filtration, vacuum-drying gets S 578.
We discover, adopt S 578 to be dissolved in or to be suspended in to reflux in the common solvent and stir, and are difficult to crystallization well.And directly handle the purity that the S 578 crude product can not reach expection with optimum-poor solvent liberation method.
Surprisingly, through step 1) of the present invention and 2) handle after, by the choose reasonable concentration of hydrochloric acid and control suitable pH, reach iso-electric point after, S 578 can be separated out from water in crystallization, obtains the crystal of based on very high purity.Its reason may be step 1) of the present invention and 2) removed the impurity material that crystallization is had disadvantageous effect, improved the purity of crystalline mother solution, S 578 can be separated out by direct crystallization from water.
Preferred embodiment a kind of according to the present invention, slowly adding concentration in the ammonia soln of above-mentioned S 578 is 1-3mol/L, preferred 1.5-2.5mol/L, the more preferably hydrochloric acid of 1.8-2.0mol/L, temperature is controlled at 30-60 ℃, preferred 40-55 ℃, more preferably 45-50 ℃, final pH is controlled at 4.0-6.0, preferred 4.5-5.5, more preferably 4.8-5.2, kept 30 minutes to 5 hours, preferred 50 minutes to 3 hours, more preferably 1 hour to 2 hours, slowly there is crystal to separate out.
Progressively temperature is reduced to minimum 10 ℃ then, preferred minimum 12 ℃, more preferably minimum 15 ℃, leave standstill crystallization, suction filtration, vacuum-drying gets S 578.
Usually, temperature is fallen more lowly, just has more S 578 to separate out, but the inventor finds, if temperature is lower than 10 ℃, S 578 more with powder noncrystal separating out, and wrap up in assorted more multi-solvent or impurity material easily.
The optional S 578 crystal seed that drops in temperature-fall period.In temperature-fall period, when especially soon beginning crystallization, easily cause the degree of supersaturation height, add crystal seed and can effectively prevent too much tiny nucleus, suppress elementary nucleation, reduce coalescently, be conducive to crystal growth.
According to the preferred embodiment of the present invention, in crystallisation process, add organic solvent, as alcoholic solvent, as methyl alcohol, ethanol, Virahol; Acetone or ether have not only improved crystallization velocity, but also improve product yield.The addition of these solvents accounts for the 10-25% of crystalline mother solution volume, preferred 12-20%, most preferably 15-18%.
After placing 2-24 hour, crystallization is complete, carries out drying then, can adopt air to dry or dries.
Preferred embodiment a kind of according to the present invention, the S 578 aqueous solution is concentrated can be in step 2) in add in the heat extraction aqueous solution and carry out in the remaining ammonia composition, that is to say step 2) in when adding hydrothermal solution at last, removed remaining ammonia composition on the one hand.Also be beneficial on the other hand the S 578 aqueous solution is concentrated, need not lower the temperature and directly to carry out the crystallisation process of step 3).
Step 4), the optional crystalline mother solution that will separate out after the crystallization returns step 3).
Because this crystalline mother solution is that cooling preferred minimum 12 ℃, is more preferably separated out crystal or acquisition minimum 15 ℃ the time until minimum 10 ℃ in step 3), wherein contain a certain amount of undecomposed S 578, it is returned step 3), proceed crystallization, improved the yield of S 578 greatly.
The S 578 highly finished product of above-mentioned embodiment gained are measured according to high performance liquid chromatography (2005 editions two appendix VD of Chinese Pharmacopoeia), and the purity that is converted into S 578 is not less than 99.3%, generally is not less than 99.5%.Ignition residue is lower than 0.04%, and macromolecule impurity content major part is lower than 0.08%.Extremely low by particulate matter content in its prepared injection.
In view of the powder flowbility of S 578, intrinsic dissolution rate, Pickering and preparation operability huge to the influence of the performance of its activity and the preparation prepared, and the S 578 that purity is largely increased dissolution rate, the property prepared and stable aspect also corresponding obvious improvement.
Therefore, the S 578 refining according to the inventive method is fit to be mixed with antibacterial combination fully, and described pharmaceutical composition comprises according to the inventive method refining S 578 and pharmaceutically acceptable vehicle.
The present invention has fundamentally changed the lower present situation of domestic and international S 578 material purity; solved the difficult problem that rough S 578 and S 578 bulk drug face; improved because a series of clinical adverse of particulate matter or the more initiation of polymeric impurities composition; improved the quality of formulation products; reduced toxic side effect, that the inventive method also has is easy, be easy to control and the characteristics of suitability for industrialized production.
Further explain and describe content of the present invention by the following examples.But the embodiment that provides should not be understood that protection domain of the present invention is construed as limiting.
One, HPLC measures the purity of S 578:
Chromatographic condition and system suitability test are weighting agent with octadecylsilane chemically bonded silica; (with Glacial acetic acid adjust pH to 4.0)-methyl alcohol (90: 10) is moving phase with the 0.015mol/L sodium acetate soln; The detection wavelength is 230nm; S 578 should be not less than 2.0 with the retention time ratio at 7-aminodesacetoxycephalosporanic acid peak.
Assay method: it is an amount of to get this product, accurately claims surely, makes the solution that contains 0.3mg among every 1ml approximately with the moving phase dissolving, gets 10 μ l and injects liquid chromatograph, the record color atlas; Other gets the S 578 reference substance and measures with method in right amount.Go out C in the trial-product by external standard method with calculated by peak area
16H
17N
3O
5The content of S.
Two, the mensuration of polymer content:
Adopt the macromolecule impurity content in the Sephadex G-10 gel chromatography systems inspection mensuration S 578.
Embodiment 1
Get 10g S 578 crude product, the content that high performance liquid chromatography records S 578 is 94%, and gel chromatography systems measurement polymer content is 3%.Add ethanol in the raw material S 578, the control temperature is no more than 28 ℃, and vigorous stirring is filtered then, and filter cake washs with temperature 12-14 ℃ ethanol, and air dries.
It is 18% ammoniacal liquor that filter cake is put into concentration, and the treatment time is 2 hours, reaches weakly alkaline until the aqueous solution, and preferred pH value is no more than 8.5.In treating processes, stir, the sedimentation and filtration of separating out is fallen.The aqueous solution is heated to 40 ℃ then, removes remaining ammonia composition in the aqueous solution.
Slowly adding concentration in the ammonia soln of the S 578 that obtains is the hydrochloric acid of 2mol/L, and temperature is controlled at 40 ℃, and final pH is controlled 5.0, keeps 2 hours, slowly has crystal to separate out.Progressively temperature is reduced to 12-14 ℃ then, leaves standstill crystallization, suction filtration, vacuum-drying gets white S 578 9.3g.
The purity that high performance liquid chromatography records S 578 is 99.5%, gel chromatography macromolecule impurity content 0.07%, ignition residue 0.02%, heavy metal detect less than.Get highly finished product and add water and make the solution that contains 0.1g among every 1ml approximately, the solution clarification is colourless.
Embodiment 2
(Zhonglian Chemical Pharmaceutical Co., Ltd., Suzhou, lot number: 20100906), the purity that high performance liquid chromatography records S 578 is 96%, gel chromatography macromolecule impurity content 2.2% to get 10g S 578 bulk drug.Add ether in the raw material S 578, the control temperature is no more than 25 ℃, and vigorous stirring is filtered then, and filter cake washs vacuum-drying with temperature 10-13 ℃ ether.
It is 15% ammoniacal liquor that filter cake is put into concentration, and the treatment time is 3 hours, reaches weakly alkaline until the aqueous solution, and preferred pH value is no more than 9.In treating processes, stir, the sedimentation and filtration of separating out is fallen.The aqueous solution is heated to 45 ℃ then, removes remaining ammonia composition in the aqueous solution.
Slowly adding concentration in the ammonia soln of the S 578 that obtains is the hydrochloric acid of 1.8mol/L, and temperature is controlled at 50 ℃, and final pH is controlled 5.5, keeps 2 hours, adds ethanol in this process, and addition accounts for 15% of crystalline mother solution volume.Slowly cooling drops into the S 578 crystal seed in temperature-fall period, slowly have crystal to separate out, and progressively temperature is reduced to 10-13 ℃, leaves standstill crystallization, suction filtration, and vacuum-drying gets white S 578 9.5g.
The purity that high performance liquid chromatography records S 578 is 99.6%, gel chromatography macromolecule impurity content 0.06%, ignition residue 0.03%, heavy metal detect less than.Get highly finished product and add water and make the solution that contains 0.1g among every 1ml approximately, the solution clarification is colourless.
Embodiment 3
(Weiqida Pharmaceutical Ind Co., Ltd., lot number: 20080215), the purity that high performance liquid chromatography records S 578 is 92%, gel chromatography macromolecule impurity content 5% to get long S 578 bulk drug of 10g date manufactured.Add ethanol in the raw material S 578, the control temperature is no more than 20 ℃, and vigorous stirring is filtered then, and filter cake is no more than 12-15 ℃ ethanol with temperature and washs vacuum-drying.
It is 20% ammoniacal liquor that filter cake is put into concentration, and the treatment time is 4 hours, reaches weakly alkaline until the aqueous solution, and preferred pH value is no more than 8.In treating processes, stir, the sedimentation and filtration of separating out is fallen.The aqueous solution is heated to 50 ℃ then, removes remaining ammonia composition in the aqueous solution.
Slowly adding concentration in the ammonia soln of the S 578 that obtains is the hydrochloric acid of 3mol/L, and temperature is controlled at 45 ℃, and final pH is controlled 6.0, keeps 2 hours, adds Virahol in this process, and addition accounts for 10% of crystalline mother solution volume.Slowly cooling drops into the S 578 crystal seed in temperature-fall period, slowly have crystal to separate out, and progressively temperature is reduced to minimum 12 ℃, leaves standstill crystallization, and suction filtration returns crystalline mother solution in the crystallisation process, crystal vacuum-drying, final white S 578 9.1g.
The purity that high performance liquid chromatography records S 578 is 99.6%, gel chromatography macromolecule impurity content 0.05%, ignition residue 0.02%.Get highly finished product and add water and make the solution that contains 0.1g among every 1ml approximately, the solution clarification is colourless.
Embodiment 4
Get the expired S 578 bulk drug of 10g, the purity that high performance liquid chromatography records S 578 is 90%, gel chromatography macromolecule impurity content 5.7%.Add ether in the raw material S 578, the control temperature is no more than 18 ℃, and vigorous stirring is filtered then, and filter cake washs vacuum-drying with temperature 11-14 ℃ ethanol.
It is 16% ammoniacal liquor that filter cake is put into concentration, and the treatment time is 2 hours, reaches weakly alkaline until the aqueous solution, and preferred pH value is no more than 8.5.In treating processes, stir, the sedimentation and filtration of separating out is fallen.The aqueous solution is heated to 45 ℃ then, removes remaining ammonia composition in the aqueous solution.
Slowly adding concentration in the ammonia soln of the S 578 that obtains is the hydrochloric acid of 1.5mol/L, and temperature is controlled at 40 ℃, and final pH is controlled at 4.5-4.8, keeps 3 hours, adds acetone in this process, and addition accounts for 12% of crystalline mother solution volume.Slowly cooling drops into the S 578 crystal seed in temperature-fall period, slowly have crystal to separate out, and progressively temperature is reduced to 11-13 ℃, leaves standstill crystallization, and suction filtration returns crystalline mother solution in the crystallisation process, crystal vacuum-drying, final white S 578 8.9g.
The purity that high performance liquid chromatography records S 578 is 99.5%, gel chromatography macromolecule impurity content 0.06%, ignition residue 0.03%.Get highly finished product and add water and make the solution that contains 0.1g among every 1ml approximately, the solution clarification is colourless.
According to the above embodiments the present invention has been made detailed description.It should be noted that above embodiment is just to illustrating the present invention.Under the prerequisite that does not depart from spirit of the present invention and essence, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be within protection scope of the present invention.
Claims (9)
1. the method for making of the cefadroxil benzyl compound of a formula (I) structure is characterized in that this method comprises following treatment step:
Step 1) adds ethanol or ether in the raw material S 578, and the control temperature is no more than 30 ℃, and vigorous stirring is filtered then, and filter cake is no more than 15 ℃ ethanol or ether with temperature and washs, and vacuum-drying or air dry;
Step 2), filter cake is put into ammoniacal liquor, mild stirring, control pH value is no more than 9, obtains the ammonia soln of S 578, then the throw out of separating out is filtered out;
Step 3), slowly adding concentration in the ammonia soln of S 578 is the hydrochloric acid of 1-3mol/L, temperature control is at 30-60 ℃, and final pH is controlled at 4.0-6.0, keeps 30 minutes to 5 hours, slowly there is crystal to separate out, progressively temperature is reduced to minimum 10 ℃ then, leaves standstill crystallization, suction filtration, vacuum-drying gets the S 578 elaboration;
Step 4), the optional crystalline mother solution that will separate out after the crystallization returns step 3).
2. according to the method for making of the S 578 of claim 1, it is characterized in that in the step 1), as solvent, the control temperature is no more than 30 ℃, vigorous stirring in this process with ethanol.
3. according to the method for making of the S 578 of claim 1 or 2, it is characterized in that, in step 1), the filter cake that obtains is no more than 15 ℃ ethanol or ether with temperature washs; In drying process, the employing air dries or normal temperature vacuum-drying mode is carried out drying.
4. according to the method for making of the S 578 of claim 1, it is characterized in that, in step 2) in, adding concentration in the filter cake is the ammoniacal liquor of 12-20%, treatment time is 30 minutes-5 hours, reaches weakly alkaline until the aqueous solution, and the pH value is no more than 9, in treating processes, stir, and filter out the precipitation of separating out.
5. according to the method for making of the S 578 of claim 1, it is characterized in that, in step 2) in, behind filtering-depositing, the aqueous solution is heated to 30-60 ℃.
6. according to the method for making of the S 578 of claim 1, it is characterized in that, in step 3), to step 2) slowly to add concentration in the ammonia soln that obtains be the hydrochloric acid of 1-3mol/L, temperature control is at 30-60 ℃, and final pH is controlled at 4.0-6.0, keeps 30 minutes to 5 hours; Progressively temperature is reduced to minimum 10 ℃ then, leaves standstill crystallization, suction filtration, vacuum-drying gets S 578.
7. according to the method for making of the S 578 of claim 1, it is characterized in that, in step 3), the optional S 578 crystal seed that drops in temperature-fall period.
8. according to the method for making of the S 578 of claim 1, it is characterized in that in step 3), add organic solvent in crystallisation process, described organic solvent is alcoholic solvent methyl alcohol, ethanol or Virahol; Acetone or ether, the addition of these solvents accounts for the 10-25% of crystalline mother solution volume.
9. according to the method for making of the S 578 of claim 1, it is characterized in that in step 4), the mother liquor that obtains separate out crystal in the time of minimum 10 ℃ after of will lowering the temperature returns step 3) in step 3).
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| CN103360412B (en) * | 2013-06-08 | 2015-08-19 | 苏州中联化学制药有限公司 | A kind of synthetic method of S 578 |
| CN104130272A (en) * | 2014-08-05 | 2014-11-05 | 孙丽华 | Improvement method of cefalexin synthesis process |
| CN104447795B (en) * | 2014-11-28 | 2016-08-17 | 珠海金鸿药业股份有限公司 | A kind of cefadroxil benzyl compound and pharmaceutical composition thereof |
| CN105534937B (en) * | 2015-12-30 | 2019-12-03 | 石药集团欧意药业有限公司 | A kind of cefadroxil tablet and preparation method thereof |
| CN105640895B (en) * | 2016-01-15 | 2019-03-01 | 石药集团欧意药业有限公司 | A kind of cefadroxil granular preparation and preparation method thereof |
| CN106588953B (en) * | 2016-11-08 | 2018-11-27 | 山东罗欣药业集团恒欣药业有限公司 | A kind of anti-infectives cefadroxil crystal-form compound and combinations thereof |
| CN106588954B (en) * | 2016-11-08 | 2018-11-27 | 山东罗欣药业集团恒欣药业有限公司 | A kind of anti-infectives amoxycillin crystalline compounds and combinations thereof |
| CN108395444B (en) * | 2018-04-04 | 2020-06-12 | 梯尔希（南京）药物研发有限公司 | Preparation method of 3-ethyl cefadroxil |
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| IT1233863B (en) * | 1988-02-24 | 1992-04-21 | Opos Biochimica Srl | PROCEDURE FOR THE PREPARATION OF 7- (D (-) - ALPHA-AMINO-ALPHA- (P-HYDROXYPENYL) ACETAMIDE) -3-METHYL-3-CEFEM-4-CARBOXYL MONOHYDRATE |
| EP2024374A1 (en) * | 2006-05-19 | 2009-02-18 | DSMIP Assets B.V. | Process for the crystallisation of cefadroxil |
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