CN101210019A - Methoxy cephalosporin intermediate - Google Patents
Methoxy cephalosporin intermediate Download PDFInfo
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- CN101210019A CN101210019A CNA2006101715878A CN200610171587A CN101210019A CN 101210019 A CN101210019 A CN 101210019A CN A2006101715878 A CNA2006101715878 A CN A2006101715878A CN 200610171587 A CN200610171587 A CN 200610171587A CN 101210019 A CN101210019 A CN 101210019A
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention relates to a synthesis method of an intermediate of methoxyl cephalosporin. C3 site methyl halide of a cephems compound with C4,7 site being protected, instead of the ordinary 7-ACA, is used as a material, functionalized at C3 site, and then methoxylated at C7 site, finally de-protected, and the intermediate of methoxyl cephalosporin is prepared. The compound can be conveniently used in the synthesis of various methoxyl cephalosporin medicines. The invention has apparent advantages of clear synthesis route, less steps, less and inexpensive reagents, comparatively single solvent, convenience for recovery and recycling, low material cost and operation expenses.
Description
The art field
The present invention relates to beta-lactam, be specifically related to the preparation of the intermediate of synthetic cynnematin.
Background technology
Methoxy cephalosporin is meant that the cephamycin C (Cephamycin C) that streptomycete (Streptomyces lactamdurans) fermentation produces is parent nucleus through a semi-synthetic class that makes with the cephem, the C on beta-lactam nucleus
7There is the cynnematin of a trans methoxyl group position.The existence of methoxyl group stops the approaching of lactam nucleus and enzyme molecule, strengthen the stability of medicine to β-Nei Xiananmei, and improve activity to anerobe, and make this class microbiotic have the stronger enzyme performance of anti-the beta-lactam, some bacteriums that produce β-Nei Xiananmeis there is stronger anti-microbial effect.The anti-microbial property of methoxy cephalosporin is similar to cynnematin, presses the sorting technique of cephalo rhzomorph, and cefmetazole, cefoxitin belong to the s-generation, and cefotetan, cefminox belong to the third generation.(" chemical encyclopedia ", the 9th the volume, the 711st～742 page, Chemical Industry Press, nineteen ninety-five version)
The synthetic of methoxy cephalosporin can obtain by two kinds of methods.A kind of is chemical synthesis, and another kind is a microbial method, promptly so-called two enzyme process.At present because technology limitation mainly is to introduce 7 α-methoxyl group by chemical process on the cephem parent nucleus.From the synthetic method that document is reported, chemical process generally is to introduce 7 α-methoxyl group earlier on the various derivatives of 7-ACA, synthesizes the methoxy cephalosporin intermediate shown in the right formula (compound 1),
C in the formula
3Position Z is various functional groups, C
4The position is hydrogen or blocking group.Utilize compound 1 to synthesize the methoxy cephalosporin of various needs then.The method that the various derivatives of 7-ACA are introduced 7 α-methoxyl group it is reported: 1) nitrine intermediate: AgBF in methyl alcohol
4Under the condition that exists, methoxyl group nucleophilic attack 7-nitrine-7-bromo cephem obtains the intermediate of 7 α-methoxy cephalosporin; 2) unsettled penicillin acyl group imine intermediate: directly carry out directly obtaining 7 α-methoxyl group cephem by 6 α-methoxyl group penicillin by rearrangement reaction; 3) unsettled cynnematin acyl group imine intermediate: with excessive LiOCH
3And (CH
3)
3COCl obtains the methoxylation compound-80 ℃ of reactions; 4) earlier synthetic 7 α-thiomethyl cynnematin, the reaction of carrying out other again obtains 7 α-methoxy cephalosporin; 5) Ketenimine and intermediate thereof: obtain a Ketenimine intermediate by a novel elimination reaction, utilize the addition of stereospecificity to obtain 7 α-methoxy cephalosporin with very high yield again from 7 β-(alpha-halogen amido) cynnematin; 6) Quinoidal intermediate: be on the dimethylbenzene methyl ester of 7-ACA, to form Schiff alkali, in excessive methyl alcohol, use Schiff alkali to carry out oxidizing reaction again, obtain the intermediate of 7 α-methoxy cephalosporin; 7) sulfenyl imines (Sulfenimine) intermediate:, on the cephem parent nucleus, introduce 7 α-methoxyl group because therefore the sulfenyl chloride molecule utilizes this advantage usually as the protecting group of 7 bit aminos; 8) earlier with C
7The whole bag of tricks such as methoxyl group are introduced in the position halogenation then.
More than various synthetic methods all have good actual application to be worth for the synthetic of methoxy cephalosporin, but because this body structure of 7-ACA, i.e. C
4Position, C
7The position needs protection in reaction process, simultaneously C
3The reactive behavior of position is lower; this has all caused protecting, go to protect route long partially on the synthetic needs from 7-ACA to the methoxy cephalosporin, and the reaction more complicated needs some relatively more expensive reaction reagents; on cost and operability, need to improve energetically.
Comparing produces the 7-ACA that cephalosporin obtains through enzymatic cleavage again by fermentation, is raw material synthetic C with the penicillin salt of cheapness
4,7Position protection, C
3Position monochloromethyl cephalosporin intermediate (compound 2, structural formula are seen right diagram),
Compound 2
As GCLE (corresponding C
3Position X is a chlorine, C
4Position R1 is to methoxy-benzyl, C
7The position is a phenylacetyl), its C
3What connect on the position is chloromethyl, realizes the conversion of functional group easily.Can make C as lead compound
3The position contains the various cephalosporins medicines of two keys, thiomethyl, quaternary ammonium salt etc.Secondly, for producing methoxy cephalosporin, because the C of compound 2
4,7The existing protection in position, can avoid with 7-ACA is to protect on the needs that cause of raw material, go to protect the route complexity, needs some relatively reaction reagents of costliness, the more high a series of problems of cost.In addition, for China as penicillin production big country, exploitation is that starting raw material is produced all kinds of efficient cephalo parent nucleus with the penicillin salt, comprise compound 1 and 2, can digest superfluous penicillin product well, synthesize how novel cephalo product, this is for changing the situation that China's cephalo drug manufacture falls behind, improve the cephalo research level, have epochmaking strategic importance.
Summary of the invention
The inventor is studying on the cynnematin synthetic basis for many years, and imagination can be with C
4,7Position protection, C
3The compound 2 of position monochloromethyl be a raw material, makes full use of the constructional feature of compound 2, develops to synthesize the new brief synthetic route of cephalosporin intermediate compound 1, is exactly with compound 2 replacement 7-ACA.Synthetic route is that compound 2 is earlier through C
3Bit functionization is passed through C again
7The position methoxylation, protection obtained methoxy cephalosporin midbody compound 1 through the past at last.Concrete invention scheme is as follows:
1) be the synthetic cephalosporin intermediate compound 1 of starting raw material with compound 2, in the various substituting groups of compound 2, C
3The halogen atom of position monochloromethyl is chlorine, bromine and iodine, preferred chlorine atom.C
4Position R1 is the carboxylic acid protecting group; protecting group comprises methoxy-benzyl, trimethoxy benzyl; the chloro benzyl; to nitrobenzyl, adjacent nitrobenzyl, dinitrobenzene benzyl, diphenyl-methyl, two (p-methoxyphenyl) methyl, ethyl, propyl group, butyl, trifluoromethyl, three chloroethyls, benzyl, styroyl, trityl, preferred methoxy-benzyl and diphenyl-methyl.C
7Be alkyl and aromatic group, comprise benzyl, phenoxymethyl, chloro benzyl, nitrobenzyl, methoxy-benzyl, menaphthyl, chloro phenoxymethyl, preferred benzyl and phenoxymethyl.
2) be starting raw material with compound 2, through C
3The functionalization of position monochloromethyl obtains C
3The position contains the compound 3 of functional groups such as two keys, thiomethyl, quaternary ammonium salt,
R1 and R2 and last same in the formula, C
3The bit function group comprises: vinyl, propenyl, the 1-pyridylmethyl, 1-(4-formamido pyridine) methyl, 2-(1-Methylimidazole) thiomethyl, 2-(1,3, the 4-thiadiazoles) thiomethyl, 2-(5-methyl isophthalic acid, 3, the 4-thiadiazoles) thiomethyl, 2-(1,3,4, the 5-tetrazole) thiomethyl, 2-(1-methyl isophthalic acid, 3,4, the 5-tetrazole) thiomethyl, 2-[1-(2-N, N-dimethylaminoethyl) methyl isophthalic acid, 3,4, the 5-tetrazole] thiomethyl, 3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxygen-1,2, the 4-triazine)] thiomethyl, 3-(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2, the 4-triazine) thiomethyl, 1-(1-methyl isophthalic acid-pyrrolidyl) methyl, 2-[(5-carboxymethyl-4-methyl) thiazole] thiomethyl, 2-(dihydro-5H-pentamethylene is [b] pyridine also) methyl etc., preferred 2-(1-methyl isophthalic acid, 3,4, the 5-tetrazole) thiomethyl, 1-pyridylmethyl and 1-(1-methyl isophthalic acid-pyrrolidyl) methyl.
3) with compound 3 and excessive LiOCH
3And (CH
3)
3COCl is in reaction below-80 ℃, at the C of compound 2
7The position is directly introduced methoxyl group and is obtained obtaining as shown at right methoxylation compound 4,
C in the formula
3,4 and 7Group and compound 3 identical.LiOCH in the reaction process
3Consumption be 1.5～10 times of compound 3, preferred 2～4 times.(CH
3)
3The COCl consumption is 1.0～3 times of compound 3, preferred 1.1～2 times.Reaction solvent is one or more among methyl alcohol, tetrahydrofuran (THF), ethyl acetate, toluene, benzene, methylene dichloride, chloroform, tetracol phenixin, the DMF etc., particular methanol and tetrahydrofuran (THF).
4) protection obtained compound 1, C in the formula to methoxylation compound 4 through the past
3Position group and last same, C
4The position is because de-protected degree difference changes to some extent.If go protection fully, i.e. C
4 and 7The position is gone protection fully, and then R1 is hydrogen and sodium ion; If C only
7Protection, then C are removed in the position
4The position blocking group is constant and last same.C
4The position goes protection that acid system, phenol method and shortening method, C are arranged
7The position goes protection method that phosphorus pentachloride method and enzyme process are arranged, preferred C
4Position shortening method and C
7Position enzyme process integrated process.
The inventor makes full use of C studying for many years on the cynnematin synthetic basis
4,7Position protection, C
3The constructional feature of the compound 2 of position monochloromethyl, the synthetic route that exploitation makes new advances.Through the methoxy cephalosporin midbody compound 1 that this route obtains, can be used for the synthetic of various methoxy cephalosporins easily.Comparing commonly used is the route of raw material with 7-ACA, the present invention has tangible advantage, be that route is distinct, step is brief, required reagent type is few and cheap, the more single recovery set that helps of solvent ratio is used, even yield and 7-ACA route maintain an equal level, its raw materials cost and process cost also can reduce by 1/3rd to 1/2nd and not wait.
Below mode by concrete enforcement technical scheme of the present invention is described in further detail, be limitation of the present invention but should not be construed as.
Embodiment
Embodiment 1
7-phenylacetyl amido-3-vinyl-4-cephemcarboxylic acid is to methoxy benzyl ester
Add 7-phenylacetyl amido-3-chloromethyl-4-cephemcarboxylic acid to methoxy benzyl ester 10g, NaI 3g, triphenylphosphine 5.93g, acetone 60mL in five neck flasks, 20 ℃ are stirred 1h.Add methylene dichloride 60mL then, 37% formalin 17mL cools to 15 ℃.Keep this temperature, splash into 1mol/L sodium hydroxide solution 20mL.Drip Bi Jixu and stir 30min, this mixed solution is poured among the 0.1mol/L hydrochloric acid 60mL, stir 10min, tell organic phase.Water 60mL methylene dichloride extracting.Merge organic phase, use the 100mL water washing.25 ℃ of concentrating under reduced pressure organic phases steam partial solvent, mend and go into to be preheated to 30 ℃ methyl alcohol 150mL, add crystal seed, crystallization behind the 30min.Continue to concentrate, steam partial solvent once more, mend entry 30mL.Cool to 0～5 ℃.The 30min after-filtration is with 75% methanol solution that is chilled to 0 ℃ in advance.Room temperature vacuum-drying 12h, the 7-phenylacetyl amido-3-vinyl-4-cephemcarboxylic acid that obtains white powder be to methoxy benzyl ester, yield 85%.
Embodiment 2
7-benzene oxygen acetylaminohydroxyphenylarsonic acid 3-picolyl-4-Cephalosporanic acid benzhydryl ester
7-benzene oxygen acetylaminohydroxyphenylarsonic acid 3-iodomethyl-4-Cephalosporanic acid benzhydryl ester 10g is dissolved in the 80mL methylene dichloride, and temperature adjustment to 8～10 ℃ drip pyridine 4mL, 10min adds, and is warming up to 20～25 ℃ of reaction 2h, and reaction is finished, be cooled to 0～5 ℃, add isopropyl ether 100mL, stir 1h, suction filtration, filter cake is drained room temperature vacuum-drying 6h with isopropyl ether 20mL washing, get pale yellow powder 7-benzene oxygen acetylaminohydroxyphenylarsonic acid 3-picolyl-4-Cephalosporanic acid benzhydryl ester, yield 90%.
Embodiment 3
7-naphthalene acetamide base-7 α-methoxyl group-3-(1-methyl isophthalic acid, 3,4,5-tetrazole) thiomethyl-4-cephemcarboxylic acid is to the nitrobenzyl ester
In the 250mL there-necked flask, add the treated anhydrous methanol of 50mL; nitrogen protection; arrive below-80 degree with cooled with liquid nitrogen; add the 1.0g lithium methoxide, in addition with 5.9g7-naphthalene acetamide base-3-(1-methyl isophthalic acid, 3; 4; the 5-tetrazole) thiomethyl-4-cephemcarboxylic acid is dissolved in the 50mL anhydrous tetrahydro furan the nitrobenzyl ester, and fast speed is added dropwise to reaction system, and the guarantee system temperature is below-80 degree simultaneously.Add t-butyl hypochlorate 1.5mL behind the 5min.Stirred 30 minutes in-80 degree.The back adds trimethyl phosphite and glacial acetic acid.Be warmed up to room temperature, boil off solvent,, use saturated sodium-chloride continuously, sodium bicarbonate, saturated sodium-chloride washing with the methylene dichloride dissolving.Behind the anhydrous magnesium sulfate drying, solvent evaporated obtains 7-naphthalene acetamide base-7 α-methoxyl group-3-(1-methyl isophthalic acid, 3,4,5-tetrazole) thiomethyl-4-cephemcarboxylic acid of yellow powdery solid to the nitrobenzyl ester, yield 80%.
Embodiment 4
7-beta-amino-7 α-methoxyl group-3-(2-the propenyl)-4-cephemcarboxylic acid tert-butyl ester
With PCl
5Be dissolved in the 30mL methylene dichloride, cool to 0～-10 degree, drip pyridine while stirring, obtain lurid suspended mixture, slowly add 7-β-p-nitrophenyl acetylaminohydroxyphenylarsonic acid 7 α-methoxyl group-3-(2-allyl group)-4-cephemcarboxylic acid tert-butyl ester, about 10 minutes.Spend stirring reaction 1 hour 0～-10.After the liquid chromatography monitoring reaction, raw material consumption fully, cool to below-20 degree, with 1, the 2-propylene glycol is added dropwise to, and guarantees temperature below-20 degree, about 15 minutes.After be warmed up to-5～0 degree, stirring reaction 1 hour adds the water of 5 degree, stirs the back extraction.Water is used methylene dichloride (5mL) extraction again.Combining extraction liquid is with the water washing of 5 degree.Organic phase was handled 30 minutes at 5 degree with gac, filtered, and added Virahol and obtained the soup compound that compound is removed to protect in the C7 position, steamed partial solvent.Filter, use washed with isopropyl alcohol, drying under reduced pressure obtains 7-beta-amino-7 α-methoxyl group-3-(2-propenyl)-4-cephemcarboxylic acid tert-butyl ester, and yield is 80%.
Embodiment 5
7-beta-amino-7 α-methoxyl group-3-(1-methyl isophthalic acid-pyrrolidyl) methyl-4-cephemcarboxylic acid
60 milliliters of meta-cresols and 0.24 milliliter of vitriol oil as in 200 milliliters the four-hole boiling flask, are heated to 35 degree.Add 10 gram 7-β-p-nitrophenyl acetylaminohydroxyphenylarsonic acid 7 α-methoxyl group-3-(1-methyl isophthalic acid-pyrrolidyl) methyl-4-cephemcarboxylic acid benzhydryl esters.Temperature of reaction 30～40 degree, about 2～3 hours, monitoring reaction.After reaction finishes, add 200 milliliters of ethyl acetate, mixture is cooled to 5 degree.To the sodium bicarbonate aqueous solution of 65 milliliter 4% of mixture adding, product extraction water inlet phase.Organic phase is washed with 10 ml waters, merges water.Water washs with 300 milliliters ethyl acetate, and water is by the resin cation (R.C.) adsorption column.With 75 milliliters water washing adsorption column, solution behind the merging post in the reactor that contains the 4g acylase, reacts under the condition of 28 degree pH7.7～8.1, regulates the pH value with the ammoniacal liquor of 1N, and is constant substantially until pH.Cross the elimination enzyme, 100 milliliters of ethyl acetate washings, solution is cooled to below 5 degree, with 3M salt acid for adjusting pH value to 3.8.Slaking is 1 hour under the condition of 5 degree, filters the crystal thing that obtains.Successively with 20 milliliters of cold water and 20 milliliters of washing with acetone products, drying under reduced pressure obtains product, and yield is 85%.
Reference example 1
Synthesizing of Cefminox sodium salt
9.0g 7-beta-amino-7 α-methoxyl group-3-(1-methyl isophthalic acid, 3,4,5-tetrazole) thiomethyl-3-cephalo acid-obtusilic acid adds in the 100mL50% water-containing tetrahydrofuran, stirs and obtains suspension.Add the 5.1g triethylamine, the crystallization dissolving obtains clear solution.Add bromo Acetyl Chloride 98Min. 5.1g again, stirring reaction 2h under room temperature.With the neutralization of 5M hydrochloric acid, the pH value is 2.2, uses ethyl acetate extraction then, behind the washing and drying, obtains 7-Beta-bromo acetylaminohydroxyphenylarsonic acid 7 α-methoxyl group-3-(1-methyl isophthalic acid, 3,4,5-tetrazole) thiomethyl-3-cephalo acid-obtusilic acid after removing solvent under reduced pressure.
7-Beta-bromo acetylaminohydroxyphenylarsonic acid 7 α-methoxyl group-3-(1-methyl isophthalic acid, 3,4,5-tetrazole) thiomethyl-3-cephalo acid-obtusilic acid that above-mentioned reaction is obtained suspends in water, the pH value of solution value is adjusted to 7.0 makes its dissolving.The back adds the D-cysteine hydrochloride, and maintenance system pH is 7.0, reaction 2h.After reaction is finished, to 7-β-(2-D-amino-2-carboxyl) ethyl sulfur acetyl-7 α-methoxyl group-3-(1-methyl isophthalic acid, 3,4,5-tetrazole) thiomethyl-3-cephalo acid-obtusilic acid.Product is through handling on the Diaion HP-20 chromatographic column, and the product that obtains obtains Cefminox sodium salt at last through the sodium salt solution recrystallization.
Claims (6)
1. method for preparing the methoxy cephalosporin intermediate, the structure of described methoxy cephalosporin intermediate is as follows:
Compound 1
Z is a functional group in the formula, and R1 is hydrogen ion, sodium ion or carboxylic acid protective group, it is characterized in that: said method comprising the steps of: (1) is with C
4,7Position protection, C
3The cepham compound of position monochloromethyl is a raw material, with C
3Bit functionization; (2) with C
7The position methoxylation; (3) with C
4And C
7Protection is gone in the position, obtains the methoxy cephalosporin intermediate.
2. the method for preparing the methoxy cephalosporin intermediate according to claim 1 is characterized in that: reaction raw materials C
4,7Position protection, C
3The cepham compound concrete structure of position monochloromethyl is as follows:
Compound 2
X is chlorine, bromine and iodine in the formula, preferred chlorine atom;
R1 is the carboxylic acid protecting group, described protecting group is selected from methoxy-benzyl, trimethoxy benzyl, the chloro benzyl is to nitrobenzyl, adjacent nitrobenzyl, dinitrobenzene benzyl, diphenyl-methyl, two (p-methoxyphenyl) methyl, ethyl, propyl group, butyl, trifluoromethyl, three chloroethyls, benzyl, styroyl, trityl; Preferred methoxy-benzyl or diphenyl-methyl;
R
2Alkyl or aromatic group, as benzyl, phenoxymethyl, chloro benzyl, nitrobenzyl, methoxy-benzyl, menaphthyl or chloro phenoxymethyl, preferred benzyl or phenoxymethyl.
3. the method for preparing the methoxy cephalosporin intermediate according to claim 1 and 2, it is characterized in that: Z is selected from: vinyl, allyl group, the 1-pyridylmethyl, 1-(4-formamido pyridine) methyl, 2-(1-Methylimidazole) thiomethyl, 2-(1,3, the 4-thiadiazoles) thiomethyl, 2-(5-methyl isophthalic acid, 3, the 4-thiadiazoles) thiomethyl, 2-(1,3,4, the 5-tetrazole) thiomethyl, 2-(1-methyl isophthalic acid, 3,4, the 5-tetrazole) thiomethyl, 2-[1-(2-N, the N-dimethylaminoethyl) methyl isophthalic acid, 3,4, the 5-tetrazole] thiomethyl, 3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxygen-1,2, the 4-triazine)] thiomethyl, 3-(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2, the 4-triazine) thiomethyl, 1-(1-methyl isophthalic acid-pyrrolidyl) methyl, 2-[(5-carboxymethyl-4-methyl) thiazole] thiomethyl, 2-(dihydro-5H-pentamethylene is [b] pyridine also) methyl, preferred 2-(1-methyl isophthalic acid, 3,4, the 5-tetrazole) thiomethyl, 1-pyridylmethyl and 1-(1-methyl isophthalic acid-pyrrolidyl) methyl.
4. according to each described method for preparing the methoxy cephalosporin intermediate in the claim 1～3, it is characterized in that: step (2) is compound that step (1) is obtained and excessive LiOCH
3And (CH
3)
3COCl is in reaction below-80 ℃, at its C
7Methoxyl group is directly introduced in the α position.
5. according to each described method for preparing the methoxy cephalosporin intermediate in the claim 4, it is characterized in that: LiOCH
3Consumption be 1.5～10 times of the compound that obtains of step (1), preferred 2～4 times; (CH
3)
3The COCl consumption is 1.0～3 times of the compound that obtains of step (1), preferred 1.1～2 times.
6. according to the described method for preparing the methoxy cephalosporin intermediate of claim 1～5, it is characterized in that: C
4The de-protected method in position is selected from acid system, phenol method and shortening method, C
7The de-protected method in position is selected from phosphorus pentachloride method and enzyme process; Preferred C
4Position shortening method and C
7Position enzyme process integrated process.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006101715878A CN101210019A (en) | 2006-12-31 | 2006-12-31 | Methoxy cephalosporin intermediate |
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|---|---|---|---|
| CNA2006101715878A CN101210019A (en) | 2006-12-31 | 2006-12-31 | Methoxy cephalosporin intermediate |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101696214B (en) * | 2009-08-28 | 2011-02-02 | 海南美大制药有限公司 | Cefminox sodium compound of new route |
| CN102295655A (en) * | 2011-07-05 | 2011-12-28 | 山东睿鹰先锋制药有限公司 | Oxacephem antibiotic intermediate solvate and preparation method thereof |
| CN102321100A (en) * | 2011-07-08 | 2012-01-18 | 海南新中正制药有限公司 | Preparation method of cefminox sodium |
| CN102898440A (en) * | 2012-10-11 | 2013-01-30 | 南通康鑫药业有限公司 | Technology for preparing 7-phenylacetylamino-3-vinyl cephalosporanic acid p-methoxybenzyl ester |
| CN105924456A (en) * | 2016-06-17 | 2016-09-07 | 重庆福安药业集团庆余堂制药有限公司 | Cefminox sodium compound reducing adverse reactions and preparation thereof |
| CN109422767A (en) * | 2017-08-30 | 2019-03-05 | 重庆天地药业有限责任公司 | The synthetic method of methoxy cephalosporin intermediate, preparation method and cefminox sodium |
| CN110283869A (en) * | 2019-07-05 | 2019-09-27 | 国药集团威奇达药业有限公司 | The preparation method of 7-amino-cephalosporanic acid |
| CN113336775A (en) * | 2021-06-21 | 2021-09-03 | 湖北凌晟药业有限公司 | Synthesis method of cefotaxime intermediate |
-
2006
- 2006-12-31 CN CNA2006101715878A patent/CN101210019A/en active Pending
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101696214B (en) * | 2009-08-28 | 2011-02-02 | 海南美大制药有限公司 | Cefminox sodium compound of new route |
| CN102295655A (en) * | 2011-07-05 | 2011-12-28 | 山东睿鹰先锋制药有限公司 | Oxacephem antibiotic intermediate solvate and preparation method thereof |
| CN102295655B (en) * | 2011-07-05 | 2013-05-29 | 山东睿鹰先锋制药有限公司 | Oxacephem antibiotic intermediate solvate and preparation method thereof |
| CN102321100A (en) * | 2011-07-08 | 2012-01-18 | 海南新中正制药有限公司 | Preparation method of cefminox sodium |
| CN102898440A (en) * | 2012-10-11 | 2013-01-30 | 南通康鑫药业有限公司 | Technology for preparing 7-phenylacetylamino-3-vinyl cephalosporanic acid p-methoxybenzyl ester |
| CN105924456A (en) * | 2016-06-17 | 2016-09-07 | 重庆福安药业集团庆余堂制药有限公司 | Cefminox sodium compound reducing adverse reactions and preparation thereof |
| CN109422767A (en) * | 2017-08-30 | 2019-03-05 | 重庆天地药业有限责任公司 | The synthetic method of methoxy cephalosporin intermediate, preparation method and cefminox sodium |
| CN109422767B (en) * | 2017-08-30 | 2021-07-02 | 重庆天地药业有限责任公司 | Methoxycephalosporin intermediate, preparation method thereof and synthesis method of cefminox sodium |
| CN110283869A (en) * | 2019-07-05 | 2019-09-27 | 国药集团威奇达药业有限公司 | The preparation method of 7-amino-cephalosporanic acid |
| CN110283869B (en) * | 2019-07-05 | 2021-06-25 | 国药集团威奇达药业有限公司 | Preparation method of 7-aminocephalosporanic acid |
| CN113336775A (en) * | 2021-06-21 | 2021-09-03 | 湖北凌晟药业有限公司 | Synthesis method of cefotaxime intermediate |
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