CN1982315A - Synthesis of cefaclor - Google Patents
Synthesis of cefaclor Download PDFInfo
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- CN1982315A CN1982315A CN 200510111468 CN200510111468A CN1982315A CN 1982315 A CN1982315 A CN 1982315A CN 200510111468 CN200510111468 CN 200510111468 CN 200510111468 A CN200510111468 A CN 200510111468A CN 1982315 A CN1982315 A CN 1982315A
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Abstract
Production of cefaclor is carried out by reacting glycine salt with pinrine under action of catalyst to form mixed anhydride solution, acylation reacting with 7-ACCA and salt solution with nitrogenous organic base, hydrolyzing by acid, precipitating aqueous layer to obtain DMF or DMAC solvent, converting into cefaclor or de-coloring for aqueous layer, adjusting pH value to 4.0-5.2 by alkali solution and crystallizing to obtain cefaclor. It's cheap and efficient and can be reutilized.
Description
Technical field: the present invention relates to the synthetic method of medicine cefaclor, the synthetic method of particularly a kind of cefaclor hydrate (I).
Background technology: relative words are explained:
7-ACCA:7-amino-3-chloro Cephalosporanic acid
DMF:N, dinethylformamide
DMAC:N, the N-N,N-DIMETHYLACETAMIDE
The DMAP:4-dimethylamino pyridine
TMG:1,1,3,3 ,-tetramethyl guanidine
DBU:1,8-diazabicylo [4.2.0]-7-alkene
DBN:1,5-diazabicylo [3.2.0]-5-alkene
Cefaclor is a kind of semi-synthetic s-generation β-Nei Xiananleikangshengsu, for gram-positive microorganism stronger anti-microbial activity is arranged, and has efficient, wide spectrum, better chemical stability, is one of important drugs of present clinical treatment infectation of bacteria.
Since cefaclor successfully went on the market from nineteen seventies, as efficient, wide spectrum and good clinical safety, be subjected to people's high praise always, but because known synthetic method, technology difficulty is bigger, and step is long, yield is low, cost is high, causes the price of product expensive unusually, limited applying of cefaclor product, particularly in the large-scale clinical application of developing country.
7-amino-3-chloro Cephalosporanic acid (being called for short 7-ACCA) is a key intermediate of present the synthesis of cefaclor, because structure is comparatively complicated, has chiral centre, particularly introduced Cl for 3, complete synthesis relatively difficulty, be still at present and adopt semisynthetic method to obtain through the ring expansion transformation of penicillin Industrial Salt, development in science and technology and technical progress through three more than ten years, cefaclor parent nucleus---7-ACCA has successfully realized suitability for industrialized production, has also realized suitability for industrialized production from the 7-ACCA the synthesis of cefaclor.I and II seen in the chemical structural formula of cefaclor and 7-ACCA:
In Chinese Pharmacopoeia, medicinal cefaclor raw material is a monohydrate, can make capsule, tablet, granule, sustained release dosage etc., is particularly suitable for making the children preparation.
The cefaclor preparation method who introduces in laid-open U.S. Patents US3925372 is: 7-ACCA is through N, and the silica-based ethanamide of O-pair-front three is protected, and the mixed anhydride reactant that forms with phenylglycine Deng salt (methyl sodium salt) and methyl-chloroformate makes.In this patented method, the yield of cefaclor only 43%.
J.Med.Chem., 18:403, cefaclor is synthetic in 1975., and that uses 7-ACCA is starting raw material to the nitrobenzyl ester, needs at last to obtain cefaclor (I) product, total recovery about 50% by the hydrolysis of cefaclor ester.
In U.S. Pat 5608055, the synthesis technique of cefaclor is that employing 7-ACCA is a raw material, and the condensation of process acidylate, hydrolysis obtain the hydrochloride aqueous solution of cefaclor, adds DMF and make cefaclor DMF mixture in this solution.Cefaclor DMF mixture obtains the cefaclor bulk drug through conversion.Yield can reach 80%.
In the method for the synthesis of cefaclor of above bibliographical information, all exist yield on the low side, raw materials used (as N, O-is two-the silica-based ethanamide of front three etc.) cost height, acetonitrile equal solvent such as are difficult to reclaim, product color is relatively poor at shortcoming.
Summary of the invention: the method that the purpose of this invention is to provide the higher the synthesis of cefaclor of a kind of yield.It is on the low side to solve present cefaclor synthesis yield, and cost is higher, the quality problem of unstable.Technical solution of the present invention is: a kind of synthetic method of cefaclor is a starting raw material through two step the synthesis of cefaclor with 7-amino-3-chloro Cephalosporanic acid and phenylglycine Deng salt (ethyl sodium salt), and it is characterized in that: the cefaclor synthesis step is:
1-1, with phenylglycine Deng salt (ethyl sodium salt), pivaloyl chloride (trimethyl-acetyl chloride) be material dissolution in aprotic, polar type organic solvent, under the effect of pyridines catalyzer, react, obtain mixed acid anhydride solution (mix acid anhydride);
1-2,7-ACCA and nitrogenous organic base salify also are dissolved in the aprotic, polar type organic solvent, obtain the 7-ACCA lysate;
1-3,7-ACCA lysate and mixed acid anhydride carry out the acidylate condensation reaction under pyridines catalyzer condition, add the salify mineral acid hydrolysis, and phase-splitting obtains the cefaclor and the sour salifiable aqueous solution;
Add DMF or DMAC in 1-4, cefaclor and the sour salifiable aqueous solution, adding DMF or the DMAC solvate that makes cefaclor under the alkali condition;
The DMF of 1-5, cefaclor or DMAC solvate obtain cefaclor through conversion in water and moisture homogeneous phase organic solution.The yield of cefaclor DMF mixture reaches 90%, and total recovery can reach more than 82%.
The present invention can also adopt single stage method to obtain cefaclor, and promptly the cefaclor that obtains at step 1-3 and the sour salifiable aqueous solution is through activated carbon decolorizing, filtration, adjusting the pH value with alkali is 4.0～5.2 formation cefaclor crystal of hydrate, filter, washing is dry, promptly gets cefaclor monohydrate finished product.Tc is controlled at 5～50 ℃.
Synthetic route through cefaclor DMF solvate the synthesis of cefaclor is as follows:
Aprotic, polar type organic solvent is the mixed solvent of one or more solvents of methylene dichloride, ethylene dichloride, acetonitrile, tetrahydrofuran (THF), DMF, DMAC, toluene, ethyl acetate, butylacetate, isopropyl acetate etc., and preferred solvent is a methylene dichloride;
The pyridines catalyzer is pyridine, 2-picoline, 4-picoline, 2, a kind of in 4-lutidine, 4-dimethylamino pyridine and piperidines and the inorganic acid salt thereof; Preferred 4-dimethylamino pyridine (DMAP) or its hydrochloride, hydrobromate and the vitriol of using;
Nitrogenous organic base is a kind of among triethylamine, TMG, DBU, the DBN.Preferably TMG or DBU;
The salify mineral acid is meant: a kind of in hydrochloric acid, Hydrogen bromide or the sulfuric acid.
Used alkali is a kind of or its aqueous solution a kind of in triethylamine, sodium hydroxide, potassium hydroxide, ammoniacal liquor, yellow soda ash, sodium bicarbonate, salt of wormwood, the saleratus.
7-ACCA dissolved temperature of reaction is-50～30 ℃ among the step 1-1, preferred-10～10 ℃; Reaction times is 5～60 minutes, preferred 10～20 minutes.
The temperature of reaction of mixing acid anhydride among the step 1-2 is-60～10 ℃, preferred-30～-10 ℃; Reaction times is 5～120 minutes, preferred 30～60 minutes.
Acidylate setting-up point among the step 1-3 is-80～10 ℃, and the reaction times is 1～6 hour.
The add-on of DMF or DMAC is water liquid long-pending 0.5～10 times (volume ratio) among the step 1-4, and temperature of reaction is 0～50 ℃.
The invention has the beneficial effects as follows: the abundant and relative low price of the raw material sources that use, reaction process is easy to control, solvent for use can be used by recovery set, more shallow, the good fluidity of product color, quality stability is good (to see Table 1: cefaclor accelerated stability data sheet), only produce a spot of three wastes in the process of reproduction of the present invention, and be easy to handle, wherein by product trimethylacetic acid and used organic bases (as TMG, DBU, DBN etc.) all can be recycled.See Table 1: cefaclor accelerated stability data sheet.(40℃，RH75％)
| Lot number | The investigation time | The investigation project | |||
| Proterties | Related substance | Moisture (%) | Content (%) | ||
| 0411001 | 0 month | Off-white powder | Qualified | 4.96 | 99.37 |
| 1 month | Off-white powder | Qualified | 5.08 | 99.20 | |
| 2 months | Off-white powder | Qualified | 5.18 | 98.92 | |
| 3 months | Off-white powder | Qualified | 5.26 | 98.40 | |
| 6 months | Micro-yellow powder | Qualified | 5.19 | 98.39 | |
| 0411002 | 0 month | Off-white powder | Qualified | 5.09 | 99.68 |
| 1 month | Off-white powder | Qualified | 5.21 | 99.52 | |
| 2 months | Off-white powder | Qualified | 5.29 | 98.71 | |
| 3 months | Off-white powder | Qualified | 5.40 | 99.23 | |
| 6 months | Micro-yellow powder | Qualified | 5.47 | 98.57 | |
| 0411003 | 0 month | Off-white powder | Qualified | 4.26 | 99.53 |
| 1 month | Off-white powder | Qualified | 4.40 | 99.61 | |
| 2 months | Off-white powder | Qualified | 4.49 | 98.78 | |
| 3 months | Off-white powder | Qualified | 4.51 | 98.57 | |
| 6 months | Micro-yellow powder | Qualified | 4.69 | 98.46 | |
Following implementation method is that the present invention is carried out specific description, but content of the present invention is not limited to following implementation method.
Embodiment:
Embodiment one: the preparation of cefaclor DMF solvate:
In 1000ml four-hole reaction flask, add methylene dichloride 200ml, DMAC 100ml drops into phenylglycine Deng salt 78g, DMAP0.05g stirred 10 minutes, and liquid nitrogen cooling drips pivaloyl chloride 31.8g to-35/-30 ℃, stirring reaction 1 hour is cooled to-75/-65 ℃, must mix anhydride solution.Add methylene dichloride 250ml in another 500ml four-hole reaction flask, 7-ACCA50g (0.2136mol) is cooled to-10/-5 ℃, adds tetramethyl guanidine 36g, stirs 30 minutes, must the 7-ACCA lysate.The 7-ACCA lysate for preparing is added drop-wise in the mixed anhydride solution, and maintenance-50/-40 ℃ was carried out acylation reaction 4 hours, sampling detection reaction terminal point (HPLC), and when 7-ACCA content was less than 2mg/ml in the reaction solution, acylation reaction finished.In acidylate liquid, add 350g deionized water and 55g concentrated hydrochloric acid (36%w/w), stir hydrolysis 30 minutes, standing demix.Lower floor goes for the dichloromethane layer branch; The upper strata is a water layer, add DMF800ml, stir down and regulate pH6.5/7.0 with triethylamine, stirred 30 minutes, filter, washing with acetone gets the wet about 110g of product of cefaclor DMF solvate, 30 ℃ of vacuum-drying 3 hours, exsiccant cefaclor DMF solvate 95g (content 74%, K.F:0.5%).
The preparation of cefaclor monohydrate
The 300ml deionized water is cooled to below 10 ℃, and gradation drops into the about 95g of cefaclor DMF mixture, regulates pH0.5/0.8 with hydrochloric acid simultaneously and makes dissolving; Filter, the less water washing, merging filtrate and washing lotion keep 10/15 ℃, regulate pH4.5/5.0 with triethylamine.Stirred 30 minutes, and filtered, 100ml deionization hydration 200 washing with acetones get the about 78g of cefaclor wet product, and vacuum-drying gets the about 67.5g of cefaclor dry product.(content: 99.45%, K.F:5.0%)
Embodiment two: the preparation of cefaclor DMF solvate:
In 1000ml four-hole reaction flask, add methylene dichloride 200ml, DMF100ml drops into phenylglycine Deng salt 78g, 4-picoline 0.05g stirred 10 minutes, and liquid nitrogen cooling drips pivaloyl chloride 31.8g to-35/-30 ℃, stirring reaction 1 hour is cooled to-75/-65 ℃, must mix anhydride solution.
Below operation comes to the same thing with embodiment one.
Embodiment three: operation is with embodiment one, and the dissolving of 7-ACCA substitutes TMG with 44g degree DBU, and other operations are identical, and the result is identical with embodiment one.
Embodiment four: operation is with embodiment two, and the dissolving of 7-ACCA substitutes TMG with 44g degree DBU, and other operations are identical, and the result is identical with embodiment two.
Embodiment five: operates with embodiment one, and the toluene instead of methylene chloride, the result is identical with embodiment one.
Embodiment six: operates with embodiment two, and the toluene instead of methylene chloride, the result is identical with embodiment two.
Embodiment seven: in 1000ml four-hole reaction flask, add methylene dichloride 200ml, DMAC 100ml drops into phenylglycine Deng salt 78g, DMAP0.05g, stirred 10 minutes, liquid nitrogen cooling drips pivaloyl chloride 31.8g, stirring reaction 1 hour to-35/-30 ℃, be cooled to-75/-65 ℃, must mix anhydride solution.Add methylene dichloride 250ml in another 500ml four-hole reaction flask, 7-ACCA50g (0.2136mol) is cooled to-10/-5 ℃, adds tetramethyl guanidine 36g, stirs 30 minutes, must the 7-ACCA lysate.The 7-ACCA lysate for preparing is added drop-wise in the mixed anhydride solution, and maintenance-50/-40 ℃ was carried out acylation reaction 4 hours, sampling detection reaction terminal point (HPLC), and when 7-ACCA content was less than 2mg/ml in the reaction solution, acylation reaction finished.In acidylate liquid, add 350g deionized water and 55g concentrated hydrochloric acid, stir hydrolysis 30 minutes, standing demix.Lower floor goes for the dichloromethane layer branch.The upper strata is a water layer, adds the 2g gac, stirs 60 minutes, filters washing; Merging filtrate and water lotion stir down and regulate pH4.5/5.0 with triethylamine, stir 30 minutes, centrifugal, washing with acetone gets the about 80g of cefaclor wet product, 30～35 ℃ of vacuum-drying 8 hours, exsiccant cefaclor-hydrate 68g (content: 98.7%, K.F:5.2%).
Embodiment eight: in 1000ml four-hole reaction flask, add methylene dichloride 200ml, DMF100ml drops into phenylglycine Deng salt 78g, 4-picoline 0.05g, stirred 10 minutes, liquid nitrogen cooling drips pivaloyl chloride 31.8g, stirring reaction 1 hour to-35/-30 ℃, be cooled to-75/-65 ℃, must mix anhydride solution.Below operation comes to the same thing with embodiment seven.
Embodiment nine: operation is with embodiment seven, and the dissolving of 7-ACCA substitutes TMG with 44gDBU, and other operations are identical, and the result is identical with embodiment seven.
Embodiment ten: operation is with embodiment eight, and the dissolving of 7-ACCA substitutes TMG with 44g DBU, and other operations are identical, and the result is identical with embodiment eight.
Embodiment 11: operates with embodiment seven, and the toluene instead of methylene chloride, the result is identical with embodiment seven.
Embodiment 12: operates with embodiment eight, and the toluene instead of methylene chloride, the result is identical with embodiment eight.
Claims (18)
1, a kind of synthetic method of cefaclor is a starting raw material through two step the synthesis of cefaclor with 7-amino-3-chloro Cephalosporanic acid and phenylglycine Deng salt, and it is characterized in that: the cefaclor synthesis step is:
1-1, with phenylglycine Deng salt, pivaloyl chloride be material dissolution in aprotic, polar type organic solvent, under the effect of pyridines catalyzer, react, obtain mixed acid anhydride solution;
1-2,7-amino-3-chloro Cephalosporanic acid and nitrogenous organic base salify also are dissolved in the aprotic, polar type organic solvent, obtain 7-amino-3-chloro Cephalosporanic acid lysate;
1-3,7-amino-3-chloro Cephalosporanic acid lysate and mixed acid anhydride solution carry out the acidylate condensation reaction under pyridines catalyzer condition, add the salify mineral acid hydrolysis, and phase-splitting obtains the cefaclor and the sour salifiable aqueous solution;
Add N in 1-4, cefaclor and the sour salifiable aqueous solution, dinethylformamide or N,N-dimethylacetamide are adding the N that makes cefaclor under the alkali condition, dinethylformamide or N,N-dimethylacetamide solvate;
The N of 1-5, cefaclor, dinethylformamide or N,N-dimethylacetamide solvate obtain cefaclor through conversion in water and moisture homogeneous phase organic solution.
2, a kind of synthetic method of cefaclor is a starting raw material through two step the synthesis of cefaclor with 7-amino-3-chloro Cephalosporanic acid and phenylglycine Deng salt, and it is characterized in that: the cefaclor synthesis step is:
1-1, with phenylglycine Deng salt, pivaloyl chloride be material dissolution in aprotic, polar type organic solvent, under the effect of pyridines catalyzer, react, obtain mixed acid anhydride solution;
1-2,7-amino-3-chloro Cephalosporanic acid and nitrogenous organic base salify also are dissolved in the aprotic, polar type organic solvent, obtain 7-amino-3-chloro Cephalosporanic acid lysate;
1-3,7-amino-3-chloro Cephalosporanic acid lysate and mixed acid anhydride solution carry out the acidylate condensation reaction under pyridines catalyzer condition, add the salify mineral acid hydrolysis, and phase-splitting obtains the cefaclor and the sour salifiable aqueous solution;
The 1-4 cefaclor and the sour salifiable aqueous solution filter through activated carbon decolorizing, and adjusting the pH value with alkali is 4.0～5.2 formation cefaclor crystal of hydrate, filters, and washing is dry, promptly gets cefaclor monohydrate finished product.
3, the synthetic method of a kind of cefaclor according to claim 1 and 2, it is characterized in that, aprotic, polar type organic solvent is methylene dichloride, ethylene dichloride, acetonitrile, tetrahydrofuran (THF), N, the mixed solvent of one or more solvents of dinethylformamide, N,N-dimethylacetamide, toluene, ethyl acetate, butylacetate, isopropyl acetate etc.
4, the synthetic method of a kind of cefaclor according to claim 3 is characterized in that, aprotic, polar type organic solvent is a methylene dichloride.
5, the synthetic method of a kind of cefaclor according to claim 1 and 2 is characterized in that, the pyridines catalyzer is pyridine, 2-picoline, 4-picoline, 2, a kind of in 4-lutidine, 4-dimethylamino pyridine and piperidines and the inorganic acid salt thereof.
6, the synthetic method of a kind of cefaclor according to claim 5 is characterized in that, the pyridines catalyzer is a kind of in 4-dimethylamino pyridine or its hydrochloride, hydrobromate and the vitriol.
7, the synthetic method of a kind of cefaclor according to claim 1 and 2 is characterized in that, nitrogenous organic base is a triethylamine, 1,1,3,3,-tetramethyl guanidine, 1,8-diazabicylo [4.2.0]-7-alkene, 1, a kind of in 5-diazabicylo [3.2.0]-5-alkene.
8, the synthetic method of a kind of cefaclor according to claim 7 is characterized in that, nitrogenous organic base is 1,1,3,3 ,-tetramethyl guanidine or 1,8-diazabicylo [4.2.0]-7-alkene.
9, the synthetic method of a kind of cefaclor according to claim 1 and 2 is characterized in that, the salify mineral acid is meant: a kind of in hydrochloric acid, Hydrogen bromide or the sulfuric acid.
10, the synthetic method of a kind of cefaclor according to claim 1 and 2, it is characterized in that used alkali is a kind of or its aqueous solution a kind of in triethylamine, sodium hydroxide, potassium hydroxide, ammoniacal liquor, yellow soda ash, sodium bicarbonate, salt of wormwood, the saleratus.
11, the synthetic method of a kind of cefaclor according to claim 1 and 2 is characterized in that, 7-amino among the step 1-1-3-chloro Cephalosporanic acid dissolved temperature of reaction is-50～30 ℃, and the reaction times is 5～60 minutes.
12, the synthetic method of a kind of cefaclor according to claim 11 is characterized in that, 7-amino among the step 1-1-3-chloro Cephalosporanic acid dissolved temperature of reaction is-10～10 ℃, and the reaction times is 10～20 minutes.
13, the synthetic method of a kind of cefaclor according to claim 1 and 2 is characterized in that, the temperature of reaction of mixing acid anhydride among the step 1-2 is-60～10 ℃, and the reaction times is 5～120 minutes.
14, the synthetic method of a kind of cefaclor according to claim 13 is characterized in that, the temperature of reaction of mixing acid anhydride among the step 1-2 is-30～-10 ℃, and the reaction times is 30～60 minutes.
15, the synthetic method of a kind of cefaclor according to claim 1 and 2 is characterized in that, the acidylate setting-up point among the step 1-3 is-80～10 ℃, and the reaction times is 1～6 hour.
16, the synthetic method of a kind of cefaclor according to claim 1 is characterized in that, N among the step 1-4, and the add-on of dinethylformamide or N,N-dimethylacetamide is long-pending 0.5～10 times of water liquid, temperature of reaction is 0～50 ℃.
17, the synthetic method of a kind of cefaclor according to claim 2 is characterized in that, Tc is controlled at 5～50 ℃.
18, the synthetic method of a kind of cefaclor according to claim 2 is characterized in that, described drying is 30～45 ℃ of vacuum-dryings 8～10 hours.
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| CN 200510111468 CN1982315A (en) | 2005-12-14 | 2005-12-14 | Synthesis of cefaclor |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102796120A (en) * | 2012-08-24 | 2012-11-28 | 苏州中联化学制药有限公司 | Method for preparing cefaclor |
| CN104086573A (en) * | 2014-07-24 | 2014-10-08 | 孙巧玲 | One-pot preparation method of cefaclor |
| CN104230955A (en) * | 2013-06-17 | 2014-12-24 | 华北制药集团新药研究开发有限责任公司 | Preparation method of p-hydroxy penicillin V acid and salt thereof |
| CN104910190A (en) * | 2015-06-17 | 2015-09-16 | 华北制药河北华民药业有限责任公司 | Preparation method of cefotiam dihydrochloride |
| CN105085549A (en) * | 2015-09-01 | 2015-11-25 | 山东罗欣药业集团股份有限公司 | Cefaclor compound, medicine composition of cefaclor compound and bromhexine hydrochloride, and preparation of cefaclor compound |
| CN105769873A (en) * | 2016-03-17 | 2016-07-20 | 华北制药河北华民药业有限责任公司 | Cefaclor preparation and preparation method thereof |
| CN109266713A (en) * | 2018-11-12 | 2019-01-25 | 齐鲁安替制药有限公司 | A kind of preparation method suitable for industrial Cefaclor |
| CN109694381A (en) * | 2019-01-21 | 2019-04-30 | 天津大学 | A kind of cefaclor hydrate and preparation method thereof |
| CN109908079A (en) * | 2019-04-10 | 2019-06-21 | 中山市方剂中药科技有限公司 | A kind of Cefadole oral liquor solution and preparation method thereof |
| CN111057072A (en) * | 2019-12-16 | 2020-04-24 | 广州维奥康药业科技有限公司 | Cefaclor impurity removal method |
| CN111440197A (en) * | 2020-04-09 | 2020-07-24 | 辽宁美亚制药有限公司 | Preparation method of ceftriaxone sodium |
| CN112574233A (en) * | 2020-12-30 | 2021-03-30 | 苏州盛达药业有限公司 | Cefaclor bulk drug |
-
2005
- 2005-12-14 CN CN 200510111468 patent/CN1982315A/en active Pending
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102796120A (en) * | 2012-08-24 | 2012-11-28 | 苏州中联化学制药有限公司 | Method for preparing cefaclor |
| CN104230955A (en) * | 2013-06-17 | 2014-12-24 | 华北制药集团新药研究开发有限责任公司 | Preparation method of p-hydroxy penicillin V acid and salt thereof |
| CN104230955B (en) * | 2013-06-17 | 2016-06-22 | 华北制药集团新药研究开发有限责任公司 | A kind of preparation method to the acid of hydroxyl penicillin V and salt thereof |
| CN104086573A (en) * | 2014-07-24 | 2014-10-08 | 孙巧玲 | One-pot preparation method of cefaclor |
| CN104910190A (en) * | 2015-06-17 | 2015-09-16 | 华北制药河北华民药业有限责任公司 | Preparation method of cefotiam dihydrochloride |
| CN105085549A (en) * | 2015-09-01 | 2015-11-25 | 山东罗欣药业集团股份有限公司 | Cefaclor compound, medicine composition of cefaclor compound and bromhexine hydrochloride, and preparation of cefaclor compound |
| CN105769873A (en) * | 2016-03-17 | 2016-07-20 | 华北制药河北华民药业有限责任公司 | Cefaclor preparation and preparation method thereof |
| CN105769873B (en) * | 2016-03-17 | 2017-04-05 | 华北制药河北华民药业有限责任公司 | Cefaclor preparation and preparation method thereof |
| CN109266713A (en) * | 2018-11-12 | 2019-01-25 | 齐鲁安替制药有限公司 | A kind of preparation method suitable for industrial Cefaclor |
| CN109694381A (en) * | 2019-01-21 | 2019-04-30 | 天津大学 | A kind of cefaclor hydrate and preparation method thereof |
| CN109908079A (en) * | 2019-04-10 | 2019-06-21 | 中山市方剂中药科技有限公司 | A kind of Cefadole oral liquor solution and preparation method thereof |
| CN111057072A (en) * | 2019-12-16 | 2020-04-24 | 广州维奥康药业科技有限公司 | Cefaclor impurity removal method |
| CN111440197A (en) * | 2020-04-09 | 2020-07-24 | 辽宁美亚制药有限公司 | Preparation method of ceftriaxone sodium |
| CN112574233A (en) * | 2020-12-30 | 2021-03-30 | 苏州盛达药业有限公司 | Cefaclor bulk drug |
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