CN102276629A - Synthetic route for cefamandole nanfate - Google Patents
Synthetic route for cefamandole nanfate Download PDFInfo
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Abstract
The invention discloses a method for preparing cefamandole nanfate. A reaction route comprises the following steps of: reacting 7-amino-3-(1-methyl-1H-tetrazole-5-yl) sulfur methyl-3-cephalo-4-carboxylic acid (7-TMCA) serving as a raw material and active ester to obtain cefamandole, and performing salifying reaction of the obtained cefamandole to obtain the cefamandole nanfate. A reasonable process route is designed by studying influencing factors in the synthetic process for the cefamandole nanfate carefully, observing the yield under different reaction conditions and improving the conventional reaction condition. The problems of complex conventional process and low total synthetic yield, and the problem that substances with large toxicity and irritability such as dicyclohexyl carbodiimide (DCC) and the like are used are solved. The generated 'waste gas, waste water and industrial residues' (three wastes) mainly comprise organic waste water, ethyl acetate, ethanol, acetone and the like and can be recycled, so the influence on environment is small.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of improvement of synthetic route of Sodium O-formylcefamole.
Background technology
Sodium O-formylcefamole belongs to second generation cephalosporin class microbiotic, this product is the second generation cephalosporin class microbiotic of being succeeded in developing by U.S. Lilly company at first, site infection such as respiratory tract, genito-urinary system, skin and soft tissue, bone and the joint of clinical application due to the gram-negative bacteria of sensitivity, pharynx otorhinolaryngology and peritonitis, septicemia etc.Biliary tract and intestinal tract infections there is better curative effect.
At present the synthetic route of Sodium O-formylcefamole mainly contains following three kinds: with 7-amino-cephalosporanic acid (7-ACA) or 7-amino-3-(1-methyl isophthalic acid H-tetrazole-5-yl)-thiomethyl-3-cephalo-4-carboxylic acid (7-TMCA) is a starting raw material, method or chloride method by active ester synthesize.Route 1 is all synthetic with the method for active ester with route 2; use formyl mandelic acid and 1-methyl-5-sulfydryl-1; 2; 3; active ester is made in the reaction of 4-tetrazole; difference is that route 1 is the reaction of raw material and active ester with 7-ACA, and route 2 is that raw material and active ester are reacted with 7-TMCA, and the Mandokef acid that obtains makes Sodium O-formylcefamole through salt-forming reaction again.This method technology more complicated use toxicity and the bigger materials of supersensitivity such as DCC in the technology, and synthetic total recovery is not high, is about 70 %.Route 3 adopts the synthetic Sodium O-formylcefamole of the method for acyl chlorides; with 7-TMCA is raw material; through the silylation protection, carry out acylation reaction with D-(-)-2-methanoyl-2-phenyl Acetyl Chloride 98Min. again, after hydrolysis, decolouring, salt-forming reaction, separate obtaining the Sodium O-formylcefamole solid.
Owing to select methylene dichloride and methyl alcohol for use in the silicon alkyl reaction, the mixed solvent of acetonitrile etc. is difficult for reclaiming, and the hydrolysis rear decoloring then uses ethyl acetate as solvent, therefore can adopt single ethyl acetate to substitute, and makes technological operation simple, reduces cost.Silylation reagent is selected hexamethyldisilazane (HMDS) or N for use, and the two silica-based ethanamides of front three of O-(N, O-BSA).
Summary of the invention
Consider that from synthetic difficulty of product and aspects such as cost and operation the present invention finally adopts following synthetic route:
This route yield is higher, and cost is low, and starting raw material and reagent are easy to get, and toxicity is little; " three wastes " are handled simple, are fit to industrialization and generate.The present invention observes the earning rate under the differential responses condition by the influence factor in the Sodium O-formylcefamole synthesis technique is carried out careful research, improves existing reaction conditions, determines a more rational operational path.This technological reaction condition is gentle relatively, does not have violent reaction, does not also have hypertoxic raw material and reagent, and simple to operate, raw material is easy to get, and is with short production cycle.Product by this technology obtains through structural identification, can be consistent with data in literature.And this process products yield height always consumes lowly, makes the cost of product reduce, and very high economic benefit is arranged." three wastes " that produced are mainly organic waste water, and ethyl acetate, ethanol, acetone etc. can recovery set usefulness, and are minimum to environmental influence.Because this technology is not used hypertoxic raw material and reagent, therefore little to operator's actual bodily harm, carry out labour protection easily.
In the production technique of the present invention, with 7-TMCA is the reaction of raw material and active ester, the Mandokef acid that obtains makes Sodium O-formylcefamole through salt-forming reaction again, the principal character of reaction conditions is: when synthetic Mandokef is sour, in the time of-10～-5 ℃, drip formyl mandelic acid chloride, dropwise, be warming up to 0～5 ℃ of reaction, 7-TMCA: formyl mandelic acid chloride=1:1.2-1:1.5, employing is at 5 ℃ of water that add 15 ℃ down, add the EDTA of catalytic amount and the sodium sulfite reaction that is hydrolyzed partially, the ethanolic soln processing obtains Mandokef acid; When generating Sodium O-formylcefamole, Mandokef acid solution and Sodium isooctanoate solution are cooled to below 10 ℃, slowly add Sodium isooctanoate in the reaction solution again, the equivalence ratio of Sodium isooctanoate and starting raw material is got 1:1-1.2:1, adopts acetone: ethanol is that the mixing solutions of 2:1 is as this reaction solvent.
Two stages of generation synthetic and Sodium O-formylcefamole that the synthesis technique of Sodium O-formylcefamole are divided into Mandokef acid are studied, and particular content is as follows:
One, the influence factor of Mandokef acid synthesis technique
1, temperature of reaction, time are to the influence of acylation reaction
Because it is thermopositive reaction that formyl mandelic acid chloride and 7-TMCA form the reaction of acid amides, and the generation of HCl is arranged, if temperature is too high, the reaction times is long, the Mandokef acid degradation that easily causes generating becomes Cefamandole acid.Therefore formyl mandelic acid chloride is dissolved in ethyl acetate, slowly drops in the 7-TMCA estersil solution after the cooling, dropwise temperature reaction again, investigated temperature of reaction and reaction times two factors emphatically, the influence of temperature of reaction sees Table-1; The influence in reaction times sees Table-2.
The reaction conditions contrast of table-1 differing temps
3 groups of experiments are all carried out under identical reaction times condition.By 1,2 group experimental result as can be seen, when temperature of reaction was 10 ℃ of left and right sides, a large amount of Mandokef acid degradations was Cefamandole acid, and it is then better that temperature is controlled at 0～5 ℃ response situation; 2,3 groups experimental result explanation, when dripping formyl mandelic acid chloride, temperature remains on that the influence to reaction result is more or less the same below-5 ℃.Therefore, should go and the consideration of cost aspect, in the time of-10～-5 ℃, drip formyl mandelic acid chloride, dropwise, be warming up to 0～5 ℃ of reaction from convenient.
Under this selected temperature, the insulation reaction time that drips behind the formyl mandelic acid chloride also had been the contrast experiment to the influence of reaction result.
The reaction conditions contrast of-2 differential responses times of table
0 ℃ of reaction 1 h, be warming up to 5 ℃ of reactions down, material content was lower than 0.3 % when 0.5 h was found in the liquid phase monitoring, by last table result as can be seen, 3 groups of experiment products therefrom purity (content of Mandokef acid and Cefamandole acid) are more or less the same, react 0.5 h, 1 h and 2 h, a spot of degraded product (Cefamandole acid) is all only arranged, and each component content is approaching.Therefore, after guaranteeing to make reaction complete as far as possible under the less condition of reaction product degraded, selecting to drip formyl mandelic acid chloride, react 1 h, be warming up to 5 ℃ of reaction 1 h, the experiment of the deprotection base that is hydrolyzed then at 0 ℃.
2, the acylating reagent equivalent is selected the influence to reaction
Adopt formyl mandelic acid chloride to react, studied the equivalents of formyl mandelic acid chloride, it the results are shown in Table-3.
Table-3 formyl mandelic acid chloride usage quantitys are to the influence of yield
| Lot number | 7-TMCA: formyl mandelic acid chloride | Yield (%) |
| 1 | 1:1 | 67.4 |
| 2 | 1:1.2 | 81.8 |
| 3 | 1:1.5 | 81.3 |
From above-mentioned three groups of experiments as can be seen; as 7-TMCA: during formyl mandelic acid chloride=1:1; product yield is lower; and react 2 and 3 as can be seen from data; at 7-TMCA: during formyl mandelic acid chloride=1:1.2-1:1.5; the productive rate difference is little, and comprehensive yied and cost factor, the usage quantity of formyl mandelic acid chloride should be defined as 1.2 equivalents.
4, hydrolysis deprotection reaction
Hydrolysis deprotection base is a primitive reaction, adds the EDTA and the inclined to one side sodium sulfite of catalytic amount in reaction process, and experimental result sees Table-4.
Table-4 EDTA, the influence of sodium sulfite to reacting partially
Annotate: the equivalent of EDTA and inclined to one side sodium is respectively the equivalence ratio of EDTA and inclined to one side sodium and starting raw material 7-TMCA in the table
Above-mentioned experiment is carried out under identical reaction times condition, in the table result as can be seen, do not add EDTA and partially the intermediate that obtains of the experiment of sodium more easily degrade.2nd, 3 groups of experiments show, the influence that the consumption of EDTA and inclined to one side sodium increases reaction result is more or less the same.Therefore, adopt the water that add 15 ℃ down at 5 ℃, add the EDTA of catalytic amount and the sodium sulfite reaction that is hydrolyzed partially.Leave standstill branch vibration layer after half an hour, the washing of organic layer saturated sodium-chloride is after the ethyl acetate solution that anhydrous magnesium sulfate dewaters, activated carbon decolorizing obtains Mandokef acid.
5, handle the influence of solvent selection to intermediate
Under the above-mentioned reaction conditions that adopts, the ethyl acetate solution of gained Mandokef acid revolves to steam and obtains white solidliquid mixture, revolves after the adding different solvents stirring and dissolving to steam to the dried slightly sour solid of thickness Mandokef of white that obtains.Different solvents is handled influence is obtained and preserved to Mandokef acid solid, and ethanol and methylene dichloride have been done corresponding comparison, sees Table-5.
Table-5 different solvents are to the influence contrast of reaction
Steam to doing by more easily revolving after the methylene dichloride processing, it is less to degrade behind Mandokef acid solid 24 h that obtain; To steam difficulty bigger and revolve after the use Ethanol Treatment, contains small amount of ethanol in the Mandokef acid solid that obtains, and the content that is degraded into Cefamandole acid behind 24 h is bigger, influence the next step, reduction Sodium O-formylcefamole total recovery and product purity.But because down the step salt-forming reaction can be carried out in alcohol solvent, and ethanol is than the methylene dichloride environmental protection, cheaply be easy to get, and the acid of gained Mandokef can directly drop into the next step, has effectively reduced the degraded of intermediate, is more suitable for suitability for industrialized production.Ethanolic soln is handled the direct experimental result that drops into the next step of back gained Mandokef acid and is seen Table-6.Therefore, we select for use ethanol as solvent, revolve to obtain slightly thickness Mandokef acid solid of white after the steaming.
Table-6 intermediate ethanolic solns are handled and are directly dropped into the next step experimental result
Two, the influence factor in the synthesis technique of Sodium O-formylcefamole
1, temperature of reaction is to the influence of reaction
Mandokef acid and the synthetic Sodium O-formylcefamole of Sodium isooctanoate reaction, Sodium isooctanoate has exothermic phenomenon after adding the Mandokef acid solution, so we investigate the influence of reaction temperature of reaction, sees Table-7.
Table-7 temperature of reaction are to the influence of reaction
As seen from the above table, in reaction solution, add Sodium isooctanoate under the room temperature, easily cause the Sodium O-formylcefamole degraded that generates.Therefore Mandokef acid solution and Sodium isooctanoate solution are cooled to below 10 ℃, again Sodium isooctanoate are slowly added in the reaction solution.
2, the Sodium isooctanoate consumption is to the influence of reaction
Because the Mandokef acid that obtains of this reaction contains solvent, so we investigate the equivalence ratio of starting raw material 7-TMCA and Sodium isooctanoate, see Table-8.
Table-8 Sodium isooctanoate usage quantitys are to the influence of yield
As can be seen from the above table, when the equivalence ratio of Sodium isooctanoate and starting raw material was got 1:1-1.2:1, the total recovery of reaction was more or less the same, and the Sodium isooctanoate amount increases again, effect to total recovery does not promote has caused Sodium O-formylcefamole to be degraded to Cefamandole in a large number on the contrary; When the equivalence ratio of Sodium isooctanoate and starting raw material was got 0.8:1, though the Sodium O-formylcefamole purity that generates is qualified, yield reduced more.Therefore, the usage quantity of Sodium isooctanoate should be defined as 1 equivalent of starting raw material 7-TMCA.
3, solvent is selected the influence to reaction
The different solvent that adopts reacts, and the total recovery and the finished product purity of reaction are made comparisons.Because when low temperature, Sodium isooctanoate solubleness in acetone is lower, but solvability is better in ethanol, therefore respectively to using acetone and acetone: ethanol is investigated as the mixing solutions of 2:1, and it the results are shown in Table-9.
Table-9 different solvents are to the influence contrast of reaction
By last table result as can be seen; adopt acetone or acetone, alcohol mixeding liquid to make solvent; the yield and the finished product content of reaction are more or less the same; preceding step acidylate gained intermediate uses Ethanol Treatment, oven dry, but directly drop into this step salt-forming reaction; be mixed with ethanol in the intermediate; therefore and ethanol is more cheap and easy to get than acetone, considers from the cost aspect, adopts acetone: ethanol is that the mixing solutions of 2:1 is as this reaction solvent.
Description of drawings
Fig. 1, process flow sheet.
Specific embodiment
Synthesizing of Cefamandole acid
Raw material and charging capacity:
| Title | Molecular weight | Charging capacity (kg) | Mole number (mol) | Remarks |
| 7-TMCA | 328 | 23.1 | 70.4 | ? |
| N,O-BSA | 203.4 | 30.8 | 151.4 | 0.81-0.83 g/mL |
| Formyl mandelic acid chloride | 198.5 | 17.1 | 85.9 | 1.3 g/mL |
| Ethyl acetate | ? | 230L | ? | ? |
| Burnt sodium sulfite | 190.11 | 0.11 | 0.56 | ? |
| EDTA | 292.25 | 0.11 | 0.37 | ? |
| Anhydrous magnesium sulfate | 120.37 | 13.8 | ? | ? |
| Gac | ? | 2.3 | ? | ? |
| Ethanol | ? | 27L | ? | ? |
Operation:
Under the normal temperature, in reactor 1, add the 7-TMCA of 23.1kg successively, the 230L ethyl acetate, stir about 10 minutes is even to system; Stir down, in 30 min, in aforesaid reaction vessel 1, progressively add 30.8kg (0.81-0.83 g/mL) BSA; 26-30 ℃ of reaction 2.5-3 hours, system was clarified fully.Stir down, cool to-5 to-10 ℃; Slowly drip 17.1kg formyl mandelic acid chloride (being dissolved in the 25L ethyl acetate), controlled temperature is no more than-5 ℃ in the dropping process; After dropwising, be warmed up to 0 ℃ of reaction 1 hour, 5 ℃ were reacted 1 hour down, and whether monitoring system reacted and finish after 0 ℃ of reaction finished.
Under reaction finishes 5 ℃, in aforesaid reaction vessel 1, add about 15 ℃ deionized water 92L, EDTA 0.11kg, sodium 0.11k g partially; Stirred 30 minutes, and left standstill layering in 30 minutes; Water layer separates, and adds the 46L saturated nacl aqueous solution in the organic layer again, stirs 15 minutes, leaves standstill layering 30 minutes; The water layer branch falls; Merge organic layer.
In the organic layer of reactor 1, add the 13.8kg anhydrous magnesium sulfate, stir dehydration 60 minutes; Add the 2.3kg gac again, stir decolouring 30 minutes; Filter, with the filtrate press filtration to reactor 2; With 28L * 3 ethyl acetate washing reaction stills 1 and filter cake 3 times, combined ethyl acetate; At 25-32 ℃ of following concentrating under reduced pressure, obtain the pale yellow colored solid liquid mixture, the system thickness; In reaction solution, add 37L ethanol, make 25 ℃ of slow stirrings to be partly dissolved; 25-32 ℃ of following underpressure distillation obtains the faint yellow slightly about 31kg of sticky solid.It is 91.9 % that HPLC detects purity.
Synthesizing of Sodium O-formylcefamole
Raw material and charging capacity:
Operation:
In reactor 2, add the solution of 249L acetone (2:1); Open and stir, the formyl radical Mandokef acid that previous step is obtained is stirred to whole dissolvings; Add the 2.3kg gac, stir decolouring 1 hour;
Above-mentioned reaction solution suction filtration, filtrate are pressed in the sterilisable chamber reactor 3, and with 21L * 2 acetone (2:1) solution washing filter cake 2 times, filtrate merges; Be cooled to 8-10 ℃; Add the 11.7kg Sodium isooctanoate simultaneously and add in 34L acetone (2:1) solution in dissolution kettle, stirring and dissolving is cooled to below 10 ℃ to clarification; Sodium isooctanoate solution is pressed in the reactor 3,6.8L acetone (2:1) solution washing dissolution kettle, washing lotion adds in the reaction solution, and temperature is controlled at below 10 ℃; After adding finishes, slowly stir, be warming up to 22 ℃; After being warming up to 22 ℃, add crystal seed 46.2g, after the system muddiness, add 83L ethanol in 30 minutes; Slowly stirred growing the grain 1 hour; Be cooled to 10-15 ℃;
The reaction solution suction filtration; Use 42L acetone (2:1) solution washing filter cake; Use 55L washing with acetone filter cake; Filter cake vacuum-drying, temperature are no more than 38 ℃, are dried to sampling and survey moisture less than＜1.0%; Sample cooling back discharging, barrelling.The HPLC detection level is 90.2 %, total recovery 83.5 %.
Claims (9)
1. the technology of a synthetic Sodium O-formylcefamole, with 7-TMCA is the reaction of raw material and active ester, the Mandokef acid that obtains makes Sodium O-formylcefamole through salt-forming reaction again, principal character is: drip formyl mandelic acid chloride in the time of-10～-5 ℃, dropwise, be warming up to 0～5 ℃ of reaction, 7-TMCA: formyl mandelic acid chloride=1:1.2-1:1.5, employing is at 5 ℃ of water that add 15 ℃ down, add the EDTA of catalytic amount and the sodium sulfite reaction that is hydrolyzed partially, the ethanolic soln processing obtains Mandokef acid; Mandokef acid solution and Sodium isooctanoate solution are cooled to below 10 ℃, slowly add Sodium isooctanoate in the reaction solution again, the equivalence ratio of Sodium isooctanoate and starting raw material is got 1:1-1.2:1, adopts acetone: ethanol is that the mixing solutions of 2:1 is as this reaction solvent.
2. synthesis technique according to claim 1 drips behind the formyl mandelic acid chloride at 0 ℃ of reaction 1 h, is warming up to 5 ℃ of reaction 1 h, and deprotection base then is hydrolyzed.
3. synthesis technique according to claim 1,7-TMCA: formyl mandelic acid chloride=1:1.2.
4. synthesis technique according to claim 1, the usage quantity of Sodium isooctanoate should be defined as 1 equivalent of starting raw material 7-TMCA.
5. synthesis technique according to claim 1 prepares Mandokef acid, under the normal temperature, adds the 7-TMCA of 23.1kg successively in reactor 1, the 230L ethyl acetate, and stir about 10 minutes is even to system; Stir down, in 30 min, in aforesaid reaction vessel 1, progressively add 30.8kg (0.81-0.83 g/mL) BSA; 26-30 ℃ of reaction 2.5-3 hours, system was clarified fully.
6. stir down, cool to-5 to-10 ℃; Slowly drip 17.1kg formyl mandelic acid chloride (being dissolved in the 25L ethyl acetate), controlled temperature is no more than-5 ℃ in the dropping process; After dropwising, be warmed up to 0 ℃ of reaction 1 hour, 5 ℃ were reacted 1 hour down, and whether monitoring system reacted and finish after 0 ℃ of reaction finished.
7. under reaction finishes 5 ℃, in aforesaid reaction vessel 1, add about 15 ℃ deionized water 92L, EDTA 0.11kg, sodium 0.11k g partially; Stirred 30 minutes, and left standstill layering in 30 minutes; Water layer separates, and adds the 46L saturated nacl aqueous solution in the organic layer again, stirs 15 minutes, leaves standstill layering 30 minutes; The water layer branch falls; Merge organic layer.
8. in the organic layer of reactor 1, add the 13.8kg anhydrous magnesium sulfate, stir dehydration 60 minutes; Add the 2.3kg gac again, stir decolouring 30 minutes; Filter, with the filtrate press filtration to reactor 2; With 28L * 3 ethyl acetate washing reaction stills 1 and filter cake 3 times, combined ethyl acetate; At 25-32 ℃ of following concentrating under reduced pressure, obtain the pale yellow colored solid liquid mixture, the system thickness; In reaction solution, add 37L ethanol, make 25 ℃ of slow stirrings to be partly dissolved; 25-32 ℃ of following underpressure distillation obtains the faint yellow slightly about 31kg of sticky solid.
9. synthesis technique according to claim 1 prepares Sodium O-formylcefamole, adds the solution of 249L acetone (2:1) in reactor 2; Open and stir, the formyl radical Mandokef acid that previous step is obtained is stirred to whole dissolvings; Add the 2.3kg gac, stir decolouring 1 hour;
Above-mentioned reaction solution suction filtration, filtrate are pressed in the sterilisable chamber reactor 3, and with 21L * 2 acetone (2:1) solution washing filter cake 2 times, filtrate merges; Be cooled to 8-10 ℃; Add the 11.7kg Sodium isooctanoate simultaneously and add in 34L acetone (2:1) solution in dissolution kettle, stirring and dissolving is cooled to below 10 ℃ to clarification; Sodium isooctanoate solution is pressed in the reactor 3,6.8L acetone (2:1) solution washing dissolution kettle, washing lotion adds in the reaction solution, and temperature is controlled at below 10 ℃; After adding finishes, slowly stir, be warming up to 22 ℃; After being warming up to 22 ℃, add crystal seed 46.2g, after the system muddiness, add 83L ethanol in 30 minutes; Slowly stirred growing the grain 1 hour; Be cooled to 10-15 ℃;
The reaction solution suction filtration; Use 42L acetone (2:1) solution washing filter cake; Use 55L washing with acetone filter cake; Filter cake vacuum-drying, temperature are no more than 38 ℃, are dried to sampling and survey moisture less than＜1.0%; Sample cooling back discharging, barrelling.
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| WO2013057196A1 (en) * | 2011-10-20 | 2013-04-25 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Process for the preparation of cefamandole nafate |
| CN104193767A (en) * | 2014-08-07 | 2014-12-10 | 杭州长典医药科技有限公司 | Cefamandole nafate superfine powder preparation and preparation method thereof |
| CN104829631A (en) * | 2015-05-08 | 2015-08-12 | 天津大学 | New crystal form of cefamandole nafate and crystallization and preparation methods thereof |
| CN104844625A (en) * | 2015-05-08 | 2015-08-19 | 天津大学 | Cefamandole nafate new crystal form and crystallization preparing method thereof |
| CN104844626A (en) * | 2015-05-08 | 2015-08-19 | 天津大学 | Cefamandole nafate new crystal form and crystallization preparing method thereof |
| CN105037392A (en) * | 2015-08-13 | 2015-11-11 | 青岛蓝盛洋医药生物科技有限责任公司 | Bactericidal medicine efamandole nafate compound and preparing method of bactericidal medicine efamandole nafate compound |
| CN106565750A (en) * | 2016-11-09 | 2017-04-19 | 哈药集团制药总厂 | Synthesis method for dextrorotation cefamandole nafate |
| CN106565749A (en) * | 2016-09-30 | 2017-04-19 | 华北制药河北华民药业有限责任公司 | Method for improving quality of cemandil sodium by using three-dimensional column plate to purify solvent |
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| CN104193767A (en) * | 2014-08-07 | 2014-12-10 | 杭州长典医药科技有限公司 | Cefamandole nafate superfine powder preparation and preparation method thereof |
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| CN104844626A (en) * | 2015-05-08 | 2015-08-19 | 天津大学 | Cefamandole nafate new crystal form and crystallization preparing method thereof |
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| CN106565749A (en) * | 2016-09-30 | 2017-04-19 | 华北制药河北华民药业有限责任公司 | Method for improving quality of cemandil sodium by using three-dimensional column plate to purify solvent |
| CN106565750A (en) * | 2016-11-09 | 2017-04-19 | 哈药集团制药总厂 | Synthesis method for dextrorotation cefamandole nafate |
| CN106565750B (en) * | 2016-11-09 | 2018-09-11 | 哈药集团制药总厂 | A kind of synthetic method of dextrorotation Mandokef acid |
| CN110974832A (en) * | 2019-11-06 | 2020-04-10 | 华北制药河北华民药业有限责任公司 | Preparation method of cefamandole nafate for injection |
| CN110974832B (en) * | 2019-11-06 | 2021-03-02 | 华北制药河北华民药业有限责任公司 | Preparation method of cefamandole nafate for injection |
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