CN109651402A - A kind of preparation process of cefazedone sodium - Google Patents
A kind of preparation process of cefazedone sodium Download PDFInfo
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- CN109651402A CN109651402A CN201811638227.3A CN201811638227A CN109651402A CN 109651402 A CN109651402 A CN 109651402A CN 201811638227 A CN201811638227 A CN 201811638227A CN 109651402 A CN109651402 A CN 109651402A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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Abstract
The invention belongs to pharmaceutical technology fields, disclose a kind of preparation process of cefazedone sodium.With 3,5- dichloropyridine ketone acetic acid and pivaloyl chloride for Material synthesis mixed acid anhydride, then the intermediate reaction generated with 7-amino-cephalosporanic acid and mercapto tetrazole, through obtaining cefazedone sodium at salt.The present invention uses mixed solvent in 3- substitution, keeps reaction more steady soft, reduces the generation of by-product, mixed acid anhydride is used in acylation reaction, and activity is high, is conducive to 7- acylation reactions and carries out, gained cefazedone sodium yield and purity are higher.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of preparation process of cefazedone sodium.
Background technique
Cefazedone is in late 1970s, and by EMerck, Darmstadt development in laboratory development is first generation head
Spore bacteriums antibiotic.The chemical name of cefazedone sodium are as follows: (6R, 7R) -3- (5- methyl-1,3,4- thiadiazolyl group -2- mercaptos
Methyl) -7 (3,5- bis- chloro- 4- pyridone -1- acetyl group amido) -8- oxo -5- thia -1- azabicyclo [4.2.0] octyl- 2-
Alkene -2- carboxylic acid sodium salt, structural formula are as follows:
The synthetic method of cefazedone sodium is mainly the following
(1) direct synthesis technique.Patent CN101584671B with 7-amino-cephalosporanic acid (7-ACA) be raw material, with 3,5- bis-
Amidation process occurs for chloropyridine ketone acetic acid, and then with 2- sulfydryl -5- methyl-1,3,4- thiadiazoles (MMTD), which react, synthesizes head
Cefazedone sodium.Synthetic route is as follows:
The route uses expensive condensing agent DCC, while anhydrous condition being needed to react, and is not suitable for industrialized production.
In addition there is technology first to react with MMTD using 7-ACA, then synthesize cefazedone sodium, but carboxylic with 3,5- dichloropyridine ketone acetic acidreaction
Acid, which participates in competitive reaction, causes yield lower, and is easy to produce by-product.
Patent CN108084213A replaces 3,5- dichloropyridine ketone acetic acid with 3,5- dichloropyridine ketone ethyl acetate, solves
Carboxyl participates in the problem of competitive reaction, improves yield, but 3,5- dichloropyridine ketone ethyl acetate raw materials are not easy to obtain and price
Valuableness is not suitable for industrialized production.
Patent CN106967092A is to go acetoxyl group 7-ACA as raw material, first and 3,5- dichloropyridine ketone acetic acidreaction, then
Replaced with N-bromosuccinimide, finally react to obtain cefazedone sodium with MMTD, changing reaction, there are bromo-reactions
Selective problems, product purity cannot ensure.
(2) chloride method.CN104230958A is raw material using 3,5- dichloropyridine ketone acetic acid, and life is reacted with trichloro-acetic chloride
At mixed acid anhydride, is then reacted with 7-ACA and generate 7- (3,5- bis- chloro- 4- pyridone -1-2 acetamide)-cephemcarboxylic acid, finally
Cefazedone is synthesized with 5- methyl -2- sulfydryl -1,3,4- thiadiazoles.Synthetic route is as follows:
The route overcomes the deficiency of raw material sources in the prior art and reaction condition, but yield and purity are still undesirable.
(3) active ester method, patent CN105017285B, which is disclosed, a kind of uses 3,5- dichloropyridine ketone acetic acid and 5- methyl-
Then 2- sulfydryl -1,3,4- thiadiazoles synthesizing activity ester react the method for generating cefazedone sodium with 7-ACA.Synthetic route is such as
Shown in lower:
Patent CN105017286 reacts to obtain GTDE with MMTD using GCLE as raw material, then remove to methoxy-benzyl and
Phenylacetyl group obtains 7-TDA, and 7-TDA reacts to obtain cefazedone sodium with active ester.Active ester reactivity is high, but stability
Difference, not easy to maintain, reaction must be carried out continuously, and industrial process operation is difficult.
Summary of the invention:
In order to overcome the deficiencies in the prior art, the present invention provides a kind of preparation process of cefazedone sodium, and existing
There is technology to compare, the synthetic method raw material of cefazedone sodium provided by the invention is cheap and easy to get, reaction condition is mild, without special
Equipment is suitble to industrialized production, and products obtained therefrom yield and purity are higher.
The preparation process of cefazedone sodium provided by the invention, sequentially includes the following steps:
(1) MMTD and 7-ACA is added in dimethyl carbonate solvent, and another solvent is added, is slowly added to catalyst,
A kind of alkali adjusting PH is added dropwise in 20~30 DEG C of temperature control reactions after reaction, and cool down crystallization, obtains 7-TD A;
(2) compound 3,5- dichloropyridine ketone acetic acid and pivaloyl chloride generate mixed anhydride reaction under the effect of the catalyst
Liquid;
(3) it is added 7-TDA in three batches into mixed anhydride reaction liquid, every batch of with acid binding agent adjusts pH after adding, and addition is urged
Agent, temperature control -10~0 DEG C reaction are added sodium bicarbonate solution into salt after completion of the reaction, are warmed to room temperature extraction, acetone analysis is added
Crystalline substance obtains cefazedone sodium;
Reaction route is as follows:
Another solvent is one of citric acid, tartaric acid, 2- hydroxysuccinic acid, acetic acid, benzoic acid in step (1)
Or it is several, the molar ratio of the solvent and 7-ACA are 1~3:1;
In step (1) catalyst be boron trifluoride-carbonic acid dimethyl ester complex, boric carbonic acid dimethyl ester complex trifluoride with
The molar ratio of 7-ACA is 6~8:1;
Alkali used is one of concentrated ammonia liquor, triethylamine, sodium hydroxide in step (1), and adjusting pH value is 3.0~4.5;
Catalyst is N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N in step (2), in N- diisopropylethylamine
One kind;
Acid binding agent is one of concentrated ammonia liquor, triethylamine, sodium hydroxide in step (3), adjusts pH three times respectively to 6.0
~7.0,5.5~6.5,4.5-5.0;
Catalyst is one of 2,6- lutidines, 4-dimethylaminopyridine, N-methylcyclohexylamine in step (3).
A kind of preparation process of cefazedone sodium provided by the invention, obtain it is following the utility model has the advantages that
(1) in 7-TDA synthesis process, another solvent is added and dimethyl carbonate forms mixed solvent, on the one hand can adjust
The polarity of solution is saved, proton concentration is changed, increases the dissolubility of 7-ACA and MMTD, homogeneous reaction is formed, on the other hand, to anti-
Inhibiting effect appropriate should be played, keeps reaction more steady soft, reduces the generation of by-product, obtain product yield and purity
To raising;Use the boron trifluoride methylcarbonate of high concentration as catalyst, improves 3- substitution reaction activity, reduce
Reaction time.
(2) when preparing mixed acid anhydride using pivaloyl chloride and pyridone acetic acid, mixed acid anhydride activation energy is lower, and activity is high,
Be conducive to 7- acylation reactions to carry out, be able to suppress the side reaction of parent nucleus carboxyl, improve reaction purity.
(3) in cefazedone sodium synthesis process, 7-TDA is fed directly in the reaction solution of mixed acid anhydride, it is easy to operate;With
A kind of acid binding agent adjusts back PH three times, and (mixed acid anhydride is reacted with amino, generates an one's share of expenses for a joint undertaking carboxylic acid, and the carboxylic acid and acid binding agent of generation are anti-
Answer, generate carboxylate), with disposably adjust PH compared with, the acid binding agent in reaction system will not be accumulated, avoid mixed acid anhydride with
The passage of time gradually resolved into raw material and lose reactivity, accelerate reaction rate and be unlikely to keep reaction excessively acute
It is strong, keep reaction more thorough, reduces the generation of impurity, improve product yield and purity.
Specific embodiment
Below with reference to embodiment, the present invention will be further described, but does not therefore limit the contents of the present invention.
Embodiment 1
(1) dimethyl carbonate 60mL is added in 500mL there-necked flask, MMTD is added in citric acid 7.06g while stirring
7-ACA10.00g is added in 4.85g, is slowly added to boron trifluoride-carbonic acid dimethyl ester complex 34.82g, and 20~30 DEG C of temperature control anti-
It answers, HPLC monitoring reaction terminates after 1h, and sodium dithionite 1.28g is added, stirs 10min, goes to and isopropanol is added in water
80mL is slowly added dropwise concentrated ammonia liquor and adjusts pH to 3.0, controls 30~60min of time for adding, be cooled to 0~10 DEG C of crystallization 1h.It takes out
Filter, is dried in vacuo to obtain 7-TDA 11.60g, yield 91.7%, and HPLC detects purity 99.4%, largest single impurity 0.08%.
(2) methylene chloride 150mL is added in 500mL there-necked flask, 3,5- dichloropyridine ketone acetic acid 10.00g, cooling is added
To -10~0 DEG C, n,N-diisopropylethylamine 5.85g is slowly added dropwise, is slowly added to pivaloyl chloride 10.86g.Temperature control -10~0 DEG C
It reacts, HPLC monitoring reaction terminates after 30min, obtains mixed anhydride reaction liquid, and HPLC detects purity 99.7%.
(3) mixed anhydride reaction liquid obtained by step (2) is cooled to -5~5 DEG C, 7-TDA obtained by step (1) is added
4.00g is added triethylamine and adjusts pH to 6.0,7-TDA4.00g is added, and triethylamine is added and adjusts pH to 5.5,7-TDA is added
2.32g is added triethylamine and adjusts pH to 4.5, and 4-dimethylaminopyridine 0.37g, temperature control -10~0 DEG C reaction, rear HPLC is added
Monitoring reaction is completed, and 10% sodium bicarbonate solution is added and adjusts pH to 7.0~8.0, is warmed to room temperature and acetone 60mL crystallization is added
1h adds acetone 60mL crystallization 1h.It filters, vacuum drying, obtains cefazedone sodium 15.45g, yield 90.5%, HPLC detection
Purity 99.7%, largest single impurity 0.09%.
Embodiment 2
(1) dimethyl carbonate 60mL is added in 500mL there-necked flask, MMTD is added in 2- hydroxysuccinic acid 9.86g while stirring
7-ACA10.00g is added in 4.85g, is slowly added to boron trifluoride-carbonic acid dimethyl ester complex 40.62g, and 20~30 DEG C of temperature control anti-
It answers, HPLC monitoring reaction terminates after 1h, and sodium dithionite 1.28g is added, stirs 10min, goes to and n-butanol is added in water
80mL is slowly added dropwise triethylamine and adjusts pH to 4.5, controls 30~60min of time for adding, be cooled to 0~10 DEG C of crystallization 1h.It takes out
Filter, is dried in vacuo to obtain 7-TDA 11.65g, yield 92.1%, and HPLC detects purity 99.2%, largest single impurity 0.10%.
(2) methylene chloride 150mL is added in 500mL there-necked flask, 3,5- dichloropyridine ketone acetic acid 10.00g, cooling is added
To -10~0 DEG C, DMF 3.31g is slowly added dropwise, is slowly added to pivaloyl chloride 10.86g.Temperature control -10~0 DEG C is reacted, after 30min
HPLC monitoring reaction terminates, and obtains mixed anhydride reaction liquid, and HPLC detects purity 99.6%.
(3) mixed anhydride reaction liquid obtained by step (2) is cooled to -5~5 DEG C, 7- obtained by step (1) is added
TDA4.00g is added triethylamine and adjusts PH to 7.0,7-TDA4.00g is added, and triethylamine is added and adjusts pH to 6.5,7- is added
TDA 2.32g is added triethylamine and adjusts pH to 5.0, and 2,6- lutidines 0.32g is added, and temperature control -10~0 DEG C is reacted, after
HPLC monitoring reaction is completed, and 10% sodium bicarbonate solution is added and adjusts pH to 7.0~8.0, is warmed to room temperature and acetone 60mL analysis is added
Brilliant 1h adds acetone 60mL crystallization 1h.It filters, vacuum drying, obtains cefazedone sodium 15.64g, yield 91.6%, HPLC inspection
Survey purity 99.8%, largest single impurity 0.07%.
Embodiment 3
(1) dimethyl carbonate 60mL, acetic acid 6.62g are added in 500mL there-necked flask, MMTD 4.85g is added while stirring,
7-ACA10.00g is added, is slowly added to boron trifluoride-carbonic acid dimethyl ester complex 46.42g, 20~30 DEG C of temperature control are reacted, after 1h
HPLC monitoring reaction terminates, and sodium dithionite 1.28g is added, stirs 10min, goes to addition isopropanol 80mL in water, slowly
Sodium hydroxide is added and adjusts pH to 4.0, controls 30~60min of time for adding, is cooled to 0~10 DEG C of crystallization 1h.It filters, vacuum is dry
It is dry that 7-TDA 11.64g, yield 92.0%, HPLC detect purity 99.3%, largest single impurity 0.08%.
(2) methylene chloride 150mL is added in 500mL there-necked flask, 3,5- dichloropyridine ketone acetic acid 10.00g, cooling is added
To -10~0 DEG C, DMAC3.94g is slowly added dropwise, is slowly added to pivaloyl chloride 10.86g.Temperature control -10~0 DEG C is reacted, after 30min
HPLC monitoring reaction terminates, and obtains mixed anhydride reaction liquid, and HPLC detects purity 99.6%.
(3) mixed anhydride reaction liquid obtained by step (2) is cooled to -5~5 DEG C, 7- obtained by step (1) is added
TDA4.00g is added triethylamine and adjusts PH to 6.5,7-TDA4.00g is added, and triethylamine is added and adjusts pH to 6.0,7- is added
TDA2.32g is added triethylamine and adjusts pH to 4.8, and N-methylcyclohexylamine 0.34g, temperature control -10~0 DEG C reaction, rear HPLC is added
Monitoring reaction is completed, and 10% sodium bicarbonate solution is added and adjusts pH to 7.0~8.0, is warmed to room temperature and acetone 60mL crystallization is added
1h adds acetone 60mL crystallization 1h.It filters, vacuum drying, obtains cefazedone sodium 15.43g, yield 90.4%, HPLC detection
Purity 99.8%, largest single impurity 0.08%.
Embodiment 4
(1) dimethyl carbonate 60mL is added in 500mL there-necked flask, MMTD is added in citric acid 14.12g while stirring
7-ACA10.00g is added in 4.85g, is slowly added to boron trifluoride-carbonic acid dimethyl ester complex 34.82g, and 20~30 DEG C of temperature control anti-
It answers, HPLC monitoring reaction terminates after 1h, and sodium dithionite 1.28g is added, stirs 10min, goes to and isopropanol is added in water
80mL is slowly added dropwise concentrated ammonia liquor and adjusts pH to 3.5, controls 30~60min of time for adding, be cooled to 0~10 DEG C of crystallization 1h.It takes out
Filter, is dried in vacuo to obtain 7-TDA 11.70g, yield 92.5%, and HPLC detects purity 99.5%, largest single impurity 0.07%.
(2) methylene chloride 150mL is added in 500mL there-necked flask, 3,5- dichloropyridine ketone acetic acid 10.00g, cooling is added
To -10~0 DEG C, n,N-diisopropylethylamine 5.85g is slowly added dropwise, is slowly added to pivaloyl chloride 10.86g.Temperature control -10~0 DEG C
It reacts, HPLC monitoring reaction terminates after 30min, obtains mixed anhydride reaction liquid, and HPLC detects purity 99.5%.
(3) mixed anhydride reaction liquid obtained by step (2) is cooled to -5~5 DEG C, 7-TDA obtained by step (1) is added
4.00g is added triethylamine and adjusts PH to 6.5,7-TDA4.00g is added, and triethylamine is added and adjusts pH to 6.0,7- is added
TDA2.32g is added triethylamine and adjusts pH to 5.0, and DMAP0.37g, temperature control -10~0 DEG C reaction, rear HPLC monitoring reaction is added
It completes, 10% sodium bicarbonate solution is added and adjusts pH to 7.0~8.0, is warmed to room temperature and acetone 60mL crystallization 1h is added, add
Acetone 60mL crystallization 1h.It filters, vacuum drying, obtains cefazedone sodium 15.58g, yield 91.3%, HPLC detects purity
99.9%, largest single impurity 0.06%.
Comparative example 1
Dimethyl carbonate 60mL is added in 500mL there-necked flask, MMTD 4.85g is added while stirring, 7- is added
ACA10.00g is slowly added to boron trifluoride-carbonic acid dimethyl ester complex 34.82g, and 20~30 DEG C of temperature control are reacted, HPLC after 1h
Monitoring reaction terminates, and sodium dithionite 1.28g is added, and stirs 10min, goes to addition isopropanol 80mL in water, is slowly added dropwise
5% sodium hydroxide adjusts PH to 3.0, controls 30~60min of time for adding, is cooled to 0~10 DEG C of crystallization 1h.It filters, vacuum is dry
It is dry that 7-TDA9.23g, yield 73.0%, HPLC detect purity 97.5%, largest single impurity 0.43%.
Comparative example 2:
Dimethyl carbonate 60mL is added in 500mL there-necked flask, p-methyl benzenesulfonic acid 6.33g is added, MMTD is added while stirring
7-ACA10.00g is added in 4.85g, is slowly added to boron trifluoride-carbonic acid dimethyl ester complex 34.82g, and 20~30 DEG C of temperature control anti-
It answers, HPLC monitoring reaction terminates after 1h, and sodium dithionite 1.28g is added, stirs 10min, goes to and isopropanol is added in water
80mL is slowly added dropwise 5% sodium hydroxide and adjusts pH to 3.0, controls 30~60min of time for adding, be cooled to 0~10 DEG C of crystallization
1h.It filters, is dried in vacuo to obtain 7-TDA 9.51g, yield 75.2%, HPLC detects purity 97.9%, largest single impurity 0.51%.
Comparative example 3:
By 1 step of embodiment (1) and step (2) preparation 7-TDA and mixed anhydride reaction liquid.Mixed anhydride reaction liquid is dropped
7-TDA 10.32g is added to -5~5 DEG C in temperature, and triethylamine is added and adjusts PH to 5.0, and 2,6- lutidines 0.32g, control is added
- 10~0 DEG C of reaction of temperature, rear HPLC monitoring reaction are completed, 10% sodium bicarbonate solution are added and adjusts PH to 7.0~8.0, rises to room
Acetone 60mL crystallization 1h is added in temperature, adds acetone 60mL crystallization 1h.It filters, vacuum drying obtains cefazedone sodium 13.47g, receives
Rate 78.9%, HPLC detect purity 96.2%, largest single impurity 0.49%.
Comparative example 4:
By 1 step of embodiment (1) and step (2) preparation 7-TDA and mixed anhydride reaction liquid.Mixed anhydride reaction liquid is dropped
7-TDA 4.00g obtained by step (1) is added to -5~5 DEG C in temperature, and triethylamine is added and adjusts pH to 5.5,7-TDA4.00g is added,
Triethylamine is added and adjusts PH to 5.0,7-TDA 2.32g is added, triethylamine is added and adjusts PH to 4.0, DMAP 0.37g, control is added
- 10~0 DEG C of reaction of temperature, rear HPLC monitoring reaction are completed, 10% sodium bicarbonate solution are added and adjusts PH to 7.0~8.0, rises to room
Acetone 60mL crystallization 1h is added in temperature, adds acetone 60mL crystallization 1h.It filtering, vacuum drying obtains cefazedone sodium 15.00g,
Yield 87.9%, HPLC detect purity 99.1%, largest single impurity 0.16%.
Claims (10)
1. a kind of preparation process of cefazedone sodium, it is characterised in that the following steps are included:
(1) compound I and compound II is added in dimethyl carbonate solvent, and another solvent is added, catalyst is added, instead
A kind of alkali adjusting pH is added after answering, obtains compound III;
(2) compound IV and pivaloyl chloride generate compound V under the effect of the catalyst;
(3) compound III is added in three batches into the reaction solution of compound V, adjusts pH with acid binding agent after adding every time, addition is urged
Agent obtains cefazedone sodium at salt after reaction;
Reaction route is as follows:
2. the preparation process of cefazedone sodium according to claim 1, which is characterized in that is be added in step (1) is another
Kind solvent is one or more of citric acid, tartaric acid, 2- hydroxysuccinic acid, acetic acid, benzoic acid.
3. the preparation process of cefazedone sodium according to claim 1, which is characterized in that another kind used in step (1)
The molar ratio of solvent and compound I are 1~3:1.
4. the preparation process of cefazedone sodium according to claim 1, which is characterized in that catalyst is three in step (1)
The molar ratio of boron fluoride-carbonic acid dimethyl ester complex, boric carbonic acid dimethyl ester complex trifluoride and compound I are 6~8:1.
5. the preparation process of cefazedone sodium according to claim 1, which is characterized in that alkali used in step (1) is
One or more of concentrated ammonia liquor, triethylamine, sodium hydroxide.
6. the preparation process of cefazedone sodium according to claim 1, which is characterized in that adjust in step (1) pH to
3.0-4.5。
7. the preparation process of cefazedone sodium according to claim 1, which is characterized in that catalyst is N in step (2),
Dinethylformamide, DMAC N,N' dimethyl acetamide, N, one or more of N- diisopropylethylamine.
8. the preparation process of cefazedone sodium according to claim 1, which is characterized in that acid binding agent used in step (3)
For one or more of concentrated ammonia liquor, triethylamine, sodium hydroxide.
9. the preparation process of cefazedone sodium according to claim 1, which is characterized in that step adjusts back pH in (3) three times
Respectively to 6.0~7.0,5.5~6.5,4.5-5.0.
10. the preparation process of cefazedone sodium according to claim 1, which is characterized in that catalyst is 4- in step (3)
One or more of dimethylamino naphthyridine, 2,6- lutidines, N-methylcyclohexylamine, DIPEA.
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Cited By (2)
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CN110437256A (en) * | 2019-09-20 | 2019-11-12 | 山东罗欣药业集团恒欣药业有限公司 | A kind of synthesis technology of Cefazedone |
CN110563750A (en) * | 2019-09-20 | 2019-12-13 | 山东罗欣药业集团恒欣药业有限公司 | Synthesis method of cefazedone |
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CN108084213A (en) * | 2017-12-29 | 2018-05-29 | 山东裕欣药业有限公司 | A kind of preparation method of Cefazedone sodium compound |
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CN101584671A (en) * | 2009-07-17 | 2009-11-25 | 山东罗欣药业股份有限公司 | Cefazedone sodium medicament powder injection and method for synthesizing raw medicine of Cefazedone sodium |
CN102617606A (en) * | 2012-03-31 | 2012-08-01 | 哈药集团制药总厂 | Method for preparing ceftezole sodium compound |
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CN110437256A (en) * | 2019-09-20 | 2019-11-12 | 山东罗欣药业集团恒欣药业有限公司 | A kind of synthesis technology of Cefazedone |
CN110563750A (en) * | 2019-09-20 | 2019-12-13 | 山东罗欣药业集团恒欣药业有限公司 | Synthesis method of cefazedone |
CN110563750B (en) * | 2019-09-20 | 2022-08-23 | 山东罗欣药业集团恒欣药业有限公司 | Synthesis method of cefazedone |
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