CN102718779B - The synthetic method of ceftiaoxline sodium for injection and preparation method thereof, bulk drug ceftizoxime sodium - Google Patents
The synthetic method of ceftiaoxline sodium for injection and preparation method thereof, bulk drug ceftizoxime sodium Download PDFInfo
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Abstract
The invention provides the synthetic method of ceftiaoxline sodium for injection and preparation method thereof, bulk drug ceftizoxime sodium; Ceftiaoxline sodium for injection particle size range provided by the present invention is moderate, have that purity is high, the content of impurity is few, quality is more excellent more stable, the advantages such as clarity is better, can ensure that the packing efficiency in producing is high, content uniformity is little, and can ensure that again in clinical application, medicine dissolution rate is fast, solvability is good; Preparation method's technique of ceftiaoxline sodium for injection is simple, energy consumption is low, low for equipment requirements, with low cost, be suitable for large-scale industrial production and application, be with a wide range of applications; The synthetic method craft of bulk drug ceftizoxime sodium is simple, energy consumption is low, low for equipment requirements, with low cost, be suitable for large-scale industrial production and application.
Description
Technical field
The present invention relates to medical art, particularly relate to the synthetic method of ceftiaoxline sodium for injection and preparation method thereof, bulk drug ceftizoxime sodium.
Background technology
Ceftizoxime sodium, English by name: Ceftizoxime Sodium, chemical name is: and (6R, 7R)-7-[amino-4 – thiazolyls of (Z)-2-(2-)-2-methoxyimino acetamido] assorted two rings [4.2.0] oct-2-ene-2-carboxylic acid sodium salt of-8-oxo-5-thia-1-ammonia.
Molecular formula: C
13h
12n
5naO
5s
2
Molecular weight: 405.38
Structural formula is formula G:
Ceftizoxime sodium is the Third generation Cephalosporins microbiotic developed by Japanese Fujisawa Pharmaceutical Co., Ltd, and in nineteen eighty-two first in Japan's listing, commodity are called Ceftizox.This product embraces rhzomorph microbiotic as third generation head, and its mechanism of action is that the biosynthesizing of gluing skin by anti-bacteria cell walls reaches germicidal action, has wide spectrum, efficient, resistance to enzyme, low toxicity and the feature by hemato encephalic barrier.The wide spectrum β-lactamase (comprising penicillinase and cephalosporinase) that multiple gram positive organism and gram-negative bacteria produce is stablized.Have powerful anti-microbial effect to enterobacteriaceae lactobacteriaceaes such as escherichia coli, Klebsiella Pneumoniae, Proteus mirabilises, the Rhodopseudomonass such as Pseudomonas aeruginosa and acinetobacter poor to this product susceptibility.Ceftizoxime has good anti-microbial effect to hemophilus influenzae and neisseria gonorrhoeae.To the effect of streptococcus aureus and staphylococcus epidermidis comparatively first, first generation cephalosporin for poor, methicillin-resistant staphylococcus aureus and enterococcus spp are to this product resistance, and various suis is all extremely sensitive to this product.The anerobes such as dyspepsiacoccus, peptostreptococcus and part Bacteroides are many in responsive to this product, and clostridium difficile is to this product resistance.Be used for the treatment of meningitis and Simple gonorrhea caused by the lower respiratory infection caused by sensitive organism, urinary tract infections, abdominal cavity infection, pelvic infection, septicemia, skin soft-tissue infection, bone and the infection of joint, streptococcus pneumoniae or hemophilus influenzae clinically.
About the synthesis of bulk drug ceftizoxime sodium; 2 synthetic routes are disclosed in US Patent No. 4427674; article 1, be with 7-phenylacetylamino-3-cephalosporin-4-carboxyl acid to methoxybenzyl ester for raw material; the cis-methoxyimino of 2--2-(2-formamido group) thiazolyl acetic acid is introduced at C7 position side chain; slough the blocking group that side chain is introduced in C4 position afterwards; obtain ceftizoxime acid; ceftizoxime sodium is obtained again with salt forming agent; this route repeatedly sloughs blocking group; extend reactions steps, add schedule of operation and production cost.Article 2, be that this route side reaction is more, and products therefrom need through column chromatography purification with 7-amino-3-demethyl-3-Cephalosporanic acid (7-ANCA) for raw material and cefotaxime acetic acid direct polycondensation obtain ceftizoxime acid salify again.
Ceftizoxime sodium normally uses with the form of ceftiaoxline sodium for injection clinically.The mobility of grain diameter influence's drugs packaging of ceftiaoxline sodium for injection and the dissolution rate of medicine, in general, particle diameter is larger, and mobility is better, and namely drugs packaging efficiency improves, and content uniformity is little, but solvability reduces, and dissolution rate slows down; Otherwise particle diameter is less, mobility is poorer, and namely drugs packaging efficiency reduces, and content uniformity is large, but solvability improves, and dissolution rate is accelerated.Therefore, particle diameter is too large or too littlely all to have an impact to the packing of medicine and solvability.
Summary of the invention
For solving the problem, the first object of the present invention is to provide ceftiaoxline sodium for injection, after this ceftiaoxline sodium for injection dissolves, clarity is good, good stability in the aqueous solution, can ensure produce in packing efficiency high, content uniformity is little, can ensure that again in clinical application, medicine dissolution rate is fast, solvability is good.
The second object of the present invention is the preparation method providing ceftiaoxline sodium for injection, and the method packing effect packing effect is better, and solvability is good.
The third object of the present invention is the synthetic method providing a kind of bulk drug ceftizoxime sodium, and the method raw materials cost is lower, and synthesis technique difficulty is less, and reaction conditions is gentle, stable and reliable product quality.
The invention provides the synthetic method of bulk drug ceftizoxime sodium, comprise the following steps:
1) preparation is such as formula the compound t-butoxycarbonyl amino thiophene oxime acetic acid shown in B
Get such as formula the compound 2-(2-amino-4-thiophene oximido shown in A)-2-methoxyimino acetic acid; add in dioxane-water mixed solution; dissolve, triethylamine adjusts pH to alkalescence, adds tert-Butyl dicarbonate reaction in ice-water bath; salt acid for adjusting pH; separate out white solid, suction filtration, chloroform flush cake; drying under reduced pressure, obtained such as formula the compound t-butoxycarbonyl amino thiophene oxime acetic acid shown in B;
Formula A:
Formula B:
2) preparation is such as formula the compound t-butoxycarbonyl amino thiophene oxime diacetyl oxide shown in C
Get and slowly join in tetrahydrofuran (THF) such as formula the compound t-butoxycarbonyl amino thiophene oxime acetic acid shown in B, dissolving, take Vanadium Pentoxide in FLAKES as dewatering agent, at room temperature react, reaction is finished, and decompression steams tetrahydrofuran (THF), obtained such as formula the compound t-butoxycarbonyl amino thiophene oxime diacetyl oxide shown in C;
Formula C:
3) preparation is such as formula D amino thiophene oxime diacetyl oxide
Get the ethanolic soln back flow reaction 3 ~ 5h such as formula the amino thiophene oxime diacetyl oxide of the compound tert.-butoxy shown in C and hydrazine hydrate, filter, filtrate pressurization evaporate to dryness, obtained such as formula the amino thiophene oxime of the compound shown in D diacetyl oxide;
Formula D:
4) preparation is such as formula the compound ceftizoxime acid shown in F
Get and go first Cephalosporanic acid to be added in chloroform such as formula the compound 7-amino-3-shown in E, add triethylamine and regulate pH to alkalescence, add step 3) obtained such as formula the amino thiophene oxime of the compound shown in D diacetyl oxide, room temperature reaction 4 ~ 6h; Reaction is finished, and add water extraction, merges aqueous phase, adds gac, and room temperature is decoloured, and filters, adjusts pH value with hydrochloric acid, separates out faint yellow solid, suction filtration, and chloroform rinses, drying under reduced pressure, obtained such as formula the compound ceftizoxime acid shown in F;
Formula E:
Formula F:
5) preparation is such as formula the compound ceftizoxime sodium crude product shown in G
Get step 4) obtained soluble in water such as formula the compound ceftizoxime acid shown in F, stir, add triethylamine, stirring and dissolving, filters, gets organic layer, the solution of instillation Sodium isooctanoate and butanols, stirs, slowly drips butanols, stir, separate out off-white color solid, suction filtration, acetone rinsing, drying under reduced pressure, obtained such as formula the compound ceftizoxime sodium crude product shown in G;
Formula G:
6) preparation is such as formula the raw materials of compound medicine ceftizoxime sodium shown in G
In sterilisable chamber, get such as formula the compound ceftizoxime sodium crude product shown in G water-soluble, add gac, room temperature decolouring suction filtration, dehydrated alcohol is added, crystallization in filtrate, with acetone rinsing, suction filtration, filtrate is filtered, drying under reduced pressure, obtained such as formula the raw materials of compound medicine ceftizoxime sodium shown in G.
Formula G:
Preferably, in described step 1), pH to 9 ~ 10 adjusted by triethylamine, add tert-Butyl dicarbonate reaction 6 ~ 8h in ice-water bath.
Preferably, described step 2) at room temperature react 2 ~ 3.5h.
Preferably, in described step 4), add triethylamine and regulate pH to be 9 ~ 10, adjust pH value 1.5 ~ 2.5 with hydrochloric acid.
Preferably, in described step 5), add triethylamine, stirring and dissolving at 0 ~ 5 DEG C, filter, get organic layer, the solution of 0 ~ 5 DEG C of instillation Sodium isooctanoate and butanols, stirs 1 ~ 2h, slowly drips butanols, stirs 1 ~ 2h.
Preferably, in described step 1), dioxane-water mixed solution is dioxane: water=2:1, and hydrochloric acid adjusts pH to 4.5 ~ 5.5.
Preferably, in described step 6), recrystallization temperature is 0 ~ 5 DEG C, rinses 3 times, suction filtration with acetone 50ml, and filtrate uses 0.22um membrane filtration.
The invention provides the synthetic method of bulk drug ceftizoxime sodium, there is following beneficial effect:
1. gained bulk drug ceftizoxime sodium purity of the present invention is high, and its purity is not less than 99%;
2. purge process of the present invention is pollution-free, cost is low, and all solvents are all recyclable, is convenient to industrial continuous seepage;
3. the present invention eliminates more insoluble impurities in treating process, improves the solvability of ceftiaoxline sodium for injection in water, improves the stability of its aqueous solution simultaneously;
4. the bulk drug ceftizoxime sodium of the inventive method synthesis is superior in quality, overcome by the defect such as clarity difference and aqueous stability difference after the not high dissolving caused of bulk drug ceftizoxime sodium purity, the clarity after described ceftiaoxline sodium for injection dissolves and its aqueous stability improve a lot than current clinical ceftiaoxline sodium for injection used.
Present invention also offers ceftiaoxline sodium for injection and preparation method thereof.
The preparation method of ceftiaoxline sodium for injection comprises raw materials medicine ceftizoxime sodium and by bulk drug ceftizoxime sodium aseptic refining or aseptic refining with carry out aseptic subpackaged after pulverizing again, wherein, aseptic refining or aseptic refining and carry out aseptic subpackaged comprising the following steps again after pulverizing:
1) crush and screen: the aseptic bulk drug ceftizoxime sodium of synthesis is pulverized, sieved, obtains the bulk drug ceftizoxime sodium of particle diameter 23 ~ 75um;
2) aseptic subpackaged and moulding plug: in sterile workshop, the bulk drug ceftizoxime sodium of particle diameter 23 ~ 75um is loaded in sterile glass vials, cover aseptic plug;
3) roll lid: aluminium-plastic combined cover is pressed into step 2) aseptic plug on;
4) lamp inspection: the product that step 3) obtains imports lamp inspection machine into through travelling belt and carries out lamp inspection;
5) pack: the step 4) product be up to the standards sends into label sticking machine labeling, packaging through travelling belt.
The particle diameter of ceftiaoxline sodium for injection is 23 ~ 75um.
Ceftiaoxline sodium for injection provided by the invention and preparation method thereof, has following beneficial effect:
1. aseptic refining and crushing technology are applied in the bulk drug ceftizoxime sodium of chemicals and the preparation method of ceftiaoxline sodium for injection by the present invention, and the drugs packaging efficiency that can solve existing for regular injection ceftizoxime sodium is low, the defects such as solvability is bad; The ceftiaoxline sodium for injection obtained in the present invention obtains that purity is high, the content of impurity is low especially, more excellent more stable, the advantage such as clarity is better of quality, all good in product packing efficiency, content uniformity, Clinical practice dissolution rate index, mobility and solvability are all good, both ensure that production efficiency and quality product, facilitate Clinical practice again.
2. in the present invention, bulk drug ceftizoxime sodium is ground into particle diameter 23 ~ 75um, there is not electrostatic adhesion phenomenon, easy packing, and make mixed powder good uniformity, redissolve fast, and after redissolving, clarity is good, divide mobility in process of assembling better, without obvious content uniformity.
3. preparation method's technique of ceftiaoxline sodium for injection of the present invention is simple, energy consumption is low, low for equipment requirements, with low cost, be suitable for large-scale industrial production and application, be with a wide range of applications.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of bulk drug ceftizoxime sodium.
Embodiment
The following stated is the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications are also considered as protection scope of the present invention.
Embodiment one
The synthetic method of bulk drug ceftizoxime sodium, is characterized in that, the method comprises the following steps:
1) preparation is such as formula the compound t-butoxycarbonyl amino thiophene oxime acetic acid shown in B
By 100g such as formula the compound 2-(2-amino-4-thiophene oximido shown in A)-2-methoxyimino acetic acid (cefotaxime acetic acid) adds in dioxane-water mixed solution (dioxane: water is 2:1) 500ml; dissolve; pH to 9 adjusted by triethylamine; tert-Butyl dicarbonate 108g is added in ice-water bath; reaction 6h; hydrochloric acid adjusts pH to 4.5; separate out white solid; suction filtration; chloroform 50ml flush cake 2 times; drying under reduced pressure, obtained such as formula the compound t-butoxycarbonyl amino thiophene oxime acetic acid 138g shown in B, yield 92.2%;
Formula A:
Formula B:
2) preparation is such as formula the compound t-butoxycarbonyl amino thiophene oxime diacetyl oxide shown in C
148g is slowly joined in tetrahydrofuran (THF) 800ml such as formula the compound t-butoxycarbonyl amino thiophene oxime acetic acid shown in B, dissolves, be dewatering agent with Vanadium Pentoxide in FLAKES, at room temperature react 2h; Reaction is finished, and decompression steams tetrahydrofuran (THF), obtained such as formula the compound t-butoxycarbonyl amino thiophene oxime diacetyl oxide 132g shown in C, yield 91.9%;
Formula C:
3) preparation is such as formula the amino thiophene oxime of the compound shown in D diacetyl oxide
By the ethanolic soln back flow reaction 3h of 140g such as formula the amino thiophene oxime diacetyl oxide of the compound tert.-butoxy shown in C and hydrazine hydrate, filter, filtrate pressurization evaporate to dryness, obtain such as formula the amino thiophene oxime of the compound shown in D diacetyl oxide 82.4g, yield 89.5%;
Formula D:
4) preparation is such as formula the compound ceftizoxime acid shown in F
Getting 94g goes first Cephalosporanic acid to be added in 800ml chloroform such as formula the compound 7-amino-3-shown in E, adds triethylamine modulation alkaline pH 9, add that step 3) obtains such as formula the amino thiophene oxime of the compound shown in D diacetyl oxide, room temperature reaction 46h; After reaction terminates, the 500ml that adds water extracts 2 times, and merge aqueous phase, add gac 1g, room temperature is decoloured 20 minutes; filter, adjust pH value 1.5 with hydrochloric acid, separate out faint yellow solid, suction filtration; chloroform 50ml rinses 3 times, drying under reduced pressure, and obtain such as formula the compound ceftizoxime acid 151.4g shown in F, yield is 84.6%;
Formula E:
Formula F:
5) preparation is such as formula the compound ceftizoxime sodium crude product shown in G
What step 4) obtained is acid-soluble in 250ml water such as formula the compound ceftizoxime shown in F, stirs, adds triethylamine 500ml at 5 DEG C; stirring and dissolving, filters, gets organic layer; the solution of 5 DEG C of instillation Sodium isooctanoate 72g and butanols 200ml, stirs 1h, slowly drips butanols 1000ml; stir 1h, separate out off-white color solid, suction filtration; acetone 50ml rinses 3 times; drying under reduced pressure, obtain such as formula the compound ceftizoxime sodium crude product 168.1g shown in G, yield is 93%;
Formula G:
6) preparation is such as formula the raw materials of compound medicine ceftizoxime sodium shown in G
In sterilisable chamber, by such as formula the water-soluble 1000ml of compound ceftizoxime sodium crude product shown in G, add gac 2g, room temperature decolouring 1h, suction filtration, adds dehydrated alcohol 200ml in filtrate, 0 DEG C of crystallization 8h, with acetone 50ml drip washing 3 times, suction filtration, filtrate crosses 0.22um filter membrane, drying under reduced pressure, obtain such as formula the raw materials of compound medicine ceftizoxime sodium 153.4g shown in G, yield is 87.5%.
Formula G:
The preparation method of ceftiaoxline sodium for injection, is characterized in that, described ceftiaoxline sodium for injection is under aseptic environment condition, comprises the following steps:
1) crush and screen: the sterile bulk drug ceftizoxime sodium of synthesis is pulverized, sieves, obtain the bulk drug ceftizoxime sodium of particle diameter 75um;
2) aseptic subpackaged and moulding plug: in sterile workshop, the sterile bulk drug ceftizoxime sodium of particle diameter 75um is loaded in sterile glass vials, cover aseptic plug;
3) roll lid: aluminium-plastic combined cover is pressed into step 2) aseptic plug on;
4) lamp inspection: the product that step 3) obtains imports lamp inspection machine into through travelling belt and carries out lamp inspection;
5) pack: the step 4) product be up to the standards sends into label sticking machine labeling, packaging through travelling belt.
Embodiment two
The synthetic method of bulk drug ceftizoxime sodium, is characterized in that, the method comprises the following steps:
1) preparation is such as formula the compound t-butoxycarbonyl amino thiophene oxime acetic acid shown in B
By 100g such as formula the compound 2-(2-amino-4-thiophene oximido shown in A)-2-methoxyimino acetic acid (cefotaxime acetic acid) adds in dioxane-water mixed solution (dioxane: water is 2:1) 500ml; dissolve; pH to 10 adjusted by triethylamine; tert-Butyl dicarbonate 108g is added in ice-water bath; reaction 8h; hydrochloric acid adjusts pH to 5.5; separate out white solid; suction filtration; chloroform 50ml flush cake 2 times; drying under reduced pressure, obtained such as formula the compound t-butoxycarbonyl amino thiophene oxime acetic acid 148g shown in B, yield 98.9%;
Formula A:
Formula B:
2) preparation is such as formula the compound t-butoxycarbonyl amino thiophene oxime diacetyl oxide shown in C
148g is slowly joined in tetrahydrofuran (THF) 800ml such as formula the compound t-butoxycarbonyl amino thiophene oxime acetic acid shown in B, dissolves, be dewatering agent with Vanadium Pentoxide in FLAKES, at room temperature react 3.5h; Reaction is finished, and decompression steams tetrahydrofuran (THF), obtained such as formula the compound t-butoxycarbonyl amino thiophene oxime diacetyl oxide 140g shown in C, yield 97.5%;
Formula C:
3) preparation is such as formula the amino thiophene oxime of the compound shown in D diacetyl oxide
By the ethanolic soln back flow reaction 5h of 140g such as formula the amino thiophene oxime diacetyl oxide of the compound tert.-butoxy shown in C and hydrazine hydrate, filter, filtrate pressurization evaporate to dryness, obtain such as formula the amino thiophene oxime of the compound shown in D diacetyl oxide 90.3g, yield 98.1%;
Formula D:
4) preparation is such as formula the compound ceftizoxime acid shown in F
Getting 94g goes first Cephalosporanic acid to be added in 800ml chloroform such as formula the compound 7-amino-3-shown in E, adds triethylamine modulation alkaline pH 10, add that step 3) obtains such as formula the amino thiophene oxime of the compound shown in D diacetyl oxide, room temperature reaction 6h; After reaction terminates, the 500ml that adds water extracts 3 times, and merge aqueous phase, add gac 1g, room temperature is decoloured 40 minutes; filter, adjust pH value 2.5 with hydrochloric acid, separate out faint yellow solid, suction filtration; chloroform 50ml rinses 3 times, drying under reduced pressure, and obtain such as formula the compound ceftizoxime acid 165.8g shown in F, yield is 92.6%;
Formula E:
Formula F:
5) preparation is such as formula the compound ceftizoxime sodium crude product shown in G
What step 4) obtained is acid-soluble in 250ml water such as formula the compound ceftizoxime shown in F, stirs, adds triethylamine 500ml at 5 DEG C; stirring and dissolving, filters, gets organic layer; the solution of 5 DEG C of instillation Sodium isooctanoate 72g and butanols 200ml, stirs 2h, slowly drips butanols 1000ml; stir 2h, separate out off-white color solid, suction filtration; acetone 50ml rinses 3 times; drying under reduced pressure, obtain such as formula the compound ceftizoxime sodium crude product 175.3g shown in G, yield is 97%;
Formula G:
6) preparation is such as formula the raw materials of compound medicine ceftizoxime sodium shown in G
In sterilisable chamber, by such as formula the water-soluble 1000ml of compound ceftizoxime sodium crude product shown in G, add gac 2g, room temperature decolouring 1h, suction filtration, adds dehydrated alcohol 200ml in filtrate, 0 DEG C of crystallization 8h, with acetone 50ml drip washing 3 times, suction filtration, filtrate crosses 0.22um filter membrane, drying under reduced pressure, obtain such as formula the raw materials of compound medicine ceftizoxime sodium 157.5g shown in G, yield is 89.8%.
Formula G:
The preparation method of ceftiaoxline sodium for injection, is characterized in that, described ceftiaoxline sodium for injection is under aseptic environment condition, comprises the following steps:
1) crush and screen: the sterile bulk drug ceftizoxime sodium of synthesis is pulverized, sieves, obtain the bulk drug ceftizoxime sodium of particle diameter 48um;
2) aseptic subpackaged and moulding plug: in sterile workshop, the sterile bulk drug ceftizoxime sodium of particle diameter 48um is loaded in sterile glass vials, cover aseptic plug;
3) roll lid: aluminium-plastic combined cover is pressed into step 2) aseptic plug on;
4) lamp inspection: the product that step 3) obtains imports lamp inspection machine into through travelling belt and carries out lamp inspection;
5) pack: the step 4) product be up to the standards sends into label sticking machine labeling, packaging through travelling belt.
Embodiment three
The synthetic method of bulk drug ceftizoxime sodium, is characterized in that, the method comprises the following steps:
1) preparation is such as formula the compound t-butoxycarbonyl amino thiophene oxime acetic acid shown in B
By 100g such as formula the compound 2-(2-amino-4-thiophene oximido shown in A)-2-methoxyimino acetic acid (cefotaxime acetic acid) adds in dioxane-water mixed solution (dioxane: water is 2:1) 500ml; dissolve; pH to 10 adjusted by triethylamine; tert-Butyl dicarbonate 108g is added in ice-water bath; reaction 8h; hydrochloric acid adjusts pH to 5.5; separate out white solid; suction filtration; chloroform 50ml flush cake 2 times; drying under reduced pressure, obtained such as formula the compound t-butoxycarbonyl amino thiophene oxime acetic acid 148g shown in B, yield 98.9%;
Formula A:
Formula B:
2) preparation is such as formula the compound t-butoxycarbonyl amino thiophene oxime diacetyl oxide shown in C
148g is slowly joined in tetrahydrofuran (THF) 800ml such as formula the compound t-butoxycarbonyl amino thiophene oxime acetic acid shown in B, dissolves, be dewatering agent with Vanadium Pentoxide in FLAKES, at room temperature react 3.5h; Reaction is finished, and decompression steams tetrahydrofuran (THF), obtained such as formula the compound t-butoxycarbonyl amino thiophene oxime diacetyl oxide 140g shown in C, yield 97.5%;
Formula C:
3) preparation is such as formula the amino thiophene oxime of the compound shown in D diacetyl oxide
By the ethanolic soln back flow reaction 5h of 140g such as formula the amino thiophene oxime diacetyl oxide of the compound tert.-butoxy shown in C and hydrazine hydrate, filter, filtrate pressurization evaporate to dryness, obtain such as formula the amino thiophene oxime of the compound shown in D diacetyl oxide 90.3g, yield 98.1%;
Formula D:
4) preparation is such as formula the compound ceftizoxime acid shown in F
Getting 94g goes first Cephalosporanic acid to be added in 800ml chloroform such as formula the compound 7-amino-3-shown in E, adds triethylamine modulation alkaline pH 10, add that step 3) obtains such as formula the amino thiophene oxime of the compound shown in D diacetyl oxide, room temperature reaction 6h; After reaction terminates, the 500ml that adds water extracts 3 times, and merge aqueous phase, add gac 1g, room temperature is decoloured 40 minutes; filter, adjust pH value 2.5 with hydrochloric acid, separate out faint yellow solid, suction filtration; chloroform 50ml rinses 3 times, drying under reduced pressure, and obtain such as formula the compound ceftizoxime acid 165.8g shown in F, yield is 92.6%;
Formula E:
Formula F:
5) preparation is such as formula the compound ceftizoxime sodium crude product shown in G
What step 4) obtained is acid-soluble in 250ml water such as formula the compound ceftizoxime shown in F, stirs, adds triethylamine 500ml at 5 DEG C; stirring and dissolving, filters, gets organic layer; the solution of 5 DEG C of instillation Sodium isooctanoate 72g and butanols 200ml, stirs 2h, slowly drips butanols 1000ml; stir 2h, separate out off-white color solid, suction filtration; acetone 50ml rinses 3 times; drying under reduced pressure, obtain such as formula the compound ceftizoxime sodium crude product 175.3g shown in G, yield is 97%;
Formula G:
6) preparation is such as formula the raw materials of compound medicine ceftizoxime sodium shown in G
In sterilisable chamber, by such as formula the water-soluble 1000ml of compound ceftizoxime sodium crude product shown in G, add gac 2g, room temperature decolouring 1h, suction filtration, adds dehydrated alcohol 200ml in filtrate, 0 DEG C of crystallization 8h, with acetone 50ml drip washing 3 times, suction filtration, filtrate crosses 0.22um filter membrane, drying under reduced pressure, obtain such as formula the raw materials of compound medicine ceftizoxime sodium 157.5g shown in G, yield is 89.8%.
Formula G:
The preparation method of ceftiaoxline sodium for injection, is characterized in that, described ceftizoxime sodium composition sterile powder for injection is under aseptic environment condition, comprises the following steps:
1) crush and screen: the sterile bulk drug ceftizoxime sodium of synthesis is pulverized, sieves, obtain the bulk drug ceftizoxime sodium of particle diameter 38um;
2) aseptic subpackaged and moulding plug: in sterile workshop, the sterile bulk drug ceftizoxime sodium of particle diameter 38um is loaded in sterile glass vials, cover aseptic plug;
3) roll lid: aluminium-plastic combined cover is pressed into step 2) aseptic plug on;
4) lamp inspection: the product that step 3) obtains imports lamp inspection machine into through travelling belt and carries out lamp inspection;
5) pack: the step 4) product be up to the standards sends into label sticking machine labeling, packaging through travelling belt.
Embodiment four
The synthetic method of bulk drug ceftizoxime sodium, is characterized in that, the method comprises the following steps:
1) preparation is such as formula the compound t-butoxycarbonyl amino thiophene oxime acetic acid shown in B
By 100g such as formula the compound 2-(2-amino-4-thiophene oximido shown in A)-2-methoxyimino acetic acid (cefotaxime acetic acid) adds in dioxane-water mixed solution (dioxane: water is 2:1) 500ml; dissolve; pH to 10 adjusted by triethylamine; tert-Butyl dicarbonate 108g is added in ice-water bath; reaction 8h; hydrochloric acid adjusts pH to 5.5; separate out white solid; suction filtration; chloroform 50ml flush cake 2 times; drying under reduced pressure, obtained such as formula the compound t-butoxycarbonyl amino thiophene oxime acetic acid 148g shown in B, yield 98.9%;
Formula A:
Formula B:
2) preparation is such as formula the compound t-butoxycarbonyl amino thiophene oxime diacetyl oxide shown in C
148g is slowly joined in tetrahydrofuran (THF) 800ml such as formula the compound t-butoxycarbonyl amino thiophene oxime acetic acid shown in B, dissolves, be dewatering agent with Vanadium Pentoxide in FLAKES, at room temperature react 3.5h; Reaction is finished, and decompression steams tetrahydrofuran (THF), obtained such as formula the compound t-butoxycarbonyl amino thiophene oxime diacetyl oxide 140g shown in C, yield 97.5%;
Formula C:
3) preparation is such as formula the amino thiophene oxime of the compound shown in D diacetyl oxide
By the ethanolic soln back flow reaction 5h of 140g such as formula the amino thiophene oxime diacetyl oxide of the compound tert.-butoxy shown in C and hydrazine hydrate, filter, filtrate pressurization evaporate to dryness, obtain such as formula the amino thiophene oxime of the compound shown in D diacetyl oxide 90.3g, yield 98.1%;
Formula D:
4) preparation is such as formula the compound ceftizoxime acid shown in F
Getting 94g goes first Cephalosporanic acid to be added in 800ml chloroform such as formula the compound 7-amino-3-shown in E, adds triethylamine modulation alkaline pH 10, add that step 3) obtains such as formula the amino thiophene oxime of the compound shown in D diacetyl oxide, room temperature reaction 6h; After reaction terminates, the 500ml that adds water extracts 3 times, and merge aqueous phase, add gac 1g, room temperature is decoloured 40 minutes; filter, adjust pH value 2.5 with hydrochloric acid, separate out faint yellow solid, suction filtration; chloroform 50ml rinses 3 times, drying under reduced pressure, and obtain such as formula the compound ceftizoxime acid 165.8g shown in F, yield is 92.6%;
Formula E:
Formula F:
5) preparation is such as formula the compound ceftizoxime sodium crude product shown in G
What step 4) obtained is acid-soluble in 250ml water such as formula the compound ceftizoxime shown in F, stirs, adds triethylamine 500ml at 5 DEG C; stirring and dissolving, filters, gets organic layer; the solution of 5 DEG C of instillation Sodium isooctanoate 72g and butanols 200ml, stirs 2h, slowly drips butanols 1000ml; stir 2h, separate out off-white color solid, suction filtration; acetone 50ml rinses 3 times; drying under reduced pressure, obtain such as formula the compound ceftizoxime sodium crude product 175.3g shown in G, yield is 97%;
Formula G:
6) preparation is such as formula the raw materials of compound medicine ceftizoxime sodium shown in G
In sterilisable chamber, by such as formula the water-soluble 1000ml of compound ceftizoxime sodium crude product shown in G, add gac 2g, room temperature decolouring 1h, suction filtration, adds dehydrated alcohol 200ml in filtrate, 0 DEG C of crystallization 8h, with acetone 50ml drip washing 3 times, suction filtration, filtrate crosses 0.22um filter membrane, drying under reduced pressure,, obtain such as formula the raw materials of compound medicine ceftizoxime sodium 157.5g shown in G, yield is 89.8%.
Formula G:
The preparation method of ceftiaoxline sodium for injection, is characterized in that, described ceftizoxime sodium composition sterile powder for injection is under aseptic environment condition, comprises the following steps:
1) crush and screen: the sterile bulk drug ceftizoxime sodium of synthesis is pulverized, sieves, obtain the bulk drug ceftizoxime sodium of particle diameter 25um;
2) aseptic subpackaged and moulding plug: in sterile workshop, the sterile bulk drug ceftizoxime sodium of particle diameter 25um is loaded in sterile glass vials, cover aseptic plug;
3) roll lid: aluminium-plastic combined cover is pressed into step 2) aseptic plug on;
4) lamp inspection: the product that step 3) obtains imports lamp inspection machine into through travelling belt and carries out lamp inspection;
5) pack: the step 4) product be up to the standards sends into label sticking machine labeling, packaging through travelling belt.
Embodiment five
The synthetic method of bulk drug ceftizoxime sodium, is characterized in that, the method comprises the following steps:
1) preparation is such as formula the compound t-butoxycarbonyl amino thiophene oxime acetic acid shown in B
By 100g such as formula the compound 2-(2-amino-4-thiophene oximido shown in A)-2-methoxyimino acetic acid (cefotaxime acetic acid) adds in dioxane-water mixed solution (dioxane: water is 2:1) 500ml; dissolve; pH to 10 adjusted by triethylamine; tert-Butyl dicarbonate 108g is added in ice-water bath; reaction 8h; hydrochloric acid adjusts pH to 5.5; separate out white solid; suction filtration; chloroform 50ml flush cake 2 times; drying under reduced pressure, obtained such as formula the compound t-butoxycarbonyl amino thiophene oxime acetic acid 148g shown in B, yield 98.9%;
Formula A:
Formula B:
2) preparation is such as formula the compound t-butoxycarbonyl amino thiophene oxime diacetyl oxide shown in C
148g is slowly joined in tetrahydrofuran (THF) 800ml such as formula the compound t-butoxycarbonyl amino thiophene oxime acetic acid shown in B, dissolves, be dewatering agent with Vanadium Pentoxide in FLAKES, at room temperature react 3.5h; Reaction is finished, and decompression steams tetrahydrofuran (THF), obtained such as formula the compound t-butoxycarbonyl amino thiophene oxime diacetyl oxide 140g shown in C, yield 97.5%;
Formula C:
3) preparation is such as formula the amino thiophene oxime of the compound shown in D diacetyl oxide
By the ethanolic soln back flow reaction 5h of 140g such as formula the amino thiophene oxime diacetyl oxide of the compound tert.-butoxy shown in C and hydrazine hydrate, filter, filtrate pressurization evaporate to dryness, obtain such as formula the amino thiophene oxime of the compound shown in D diacetyl oxide 90.3g, yield 98.1%;
Formula D:
4) preparation is such as formula the compound ceftizoxime acid shown in F
Getting 94g goes first Cephalosporanic acid to be added in 800ml chloroform such as formula the compound 7-amino-3-shown in E, adds triethylamine modulation alkaline pH 10, add that step 3) obtains such as formula the amino thiophene oxime of the compound shown in D diacetyl oxide, room temperature reaction 6h; After reaction terminates, the 500ml that adds water extracts 3 times, and merge aqueous phase, add gac 1g, room temperature is decoloured 40 minutes; filter, adjust pH value 2.5 with hydrochloric acid, separate out faint yellow solid, suction filtration; chloroform 50ml rinses 3 times, drying under reduced pressure, and obtain such as formula the compound ceftizoxime acid 165.8g shown in F, yield is 92.6%;
Formula E:
Formula F:
5) preparation is such as formula the compound ceftizoxime sodium crude product shown in G
What step 4) obtained is acid-soluble in 250ml water such as formula the compound ceftizoxime shown in G, stirs, adds triethylamine 500ml at 5 DEG C; stirring and dissolving, filters, gets organic layer; the solution of 5 DEG C of instillation Sodium isooctanoate 72g and butanols 200ml, stirs 2h, slowly drips butanols 1000ml; stir 2h, separate out off-white color solid, suction filtration; acetone 50ml rinses 3 times; drying under reduced pressure, obtain such as formula the compound ceftizoxime sodium crude product 175.3g shown in G, yield is 97%;
Formula G:
6) preparation is such as formula the raw materials of compound medicine ceftizoxime sodium shown in G
In sterilisable chamber, by such as formula the water-soluble 1000ml of compound ceftizoxime sodium crude product shown in G, add gac 2g, room temperature decolouring 1h, suction filtration, adds dehydrated alcohol 200ml in filtrate, 0 DEG C of crystallization 8h, with acetone 50ml drip washing 3 times, suction filtration, filtrate crosses 0.22um filter membrane, drying under reduced pressure, obtain such as formula the raw materials of compound medicine ceftizoxime sodium 157.5g shown in G, yield is 89.8%.
Formula G:
The preparation method of ceftiaoxline sodium for injection, is characterized in that, described ceftizoxime sodium composition sterile powder for injection is under aseptic environment condition, comprises the following steps:
1) crush and screen: the sterile bulk drug ceftizoxime sodium of synthesis is pulverized, sieves, obtain the bulk drug ceftizoxime sodium of particle diameter 23um;
2) aseptic subpackaged and moulding plug: in sterile workshop, the sterile bulk drug ceftizoxime sodium of particle diameter 23um is loaded in sterile glass vials, cover aseptic plug;
3) roll lid: aluminium-plastic combined cover is pressed into step 2) aseptic plug on;
4) lamp inspection: the product that step 3) obtains imports lamp inspection machine into through travelling belt and carries out lamp inspection;
5) pack: the step 4) product be up to the standards sends into label sticking machine labeling, packaging through travelling belt.
effect example
In order to understand beneficial effect of the present invention better, with various test, essence of the present invention will be described below, but content of the present invention is not limited thereto.
One main research
1. optimum grain-diameter screening
Test objective: bulk drug ceftizoxime sodium is carried out pulverize, sieve, be divided into 5 size ranges, so that experiment investigation.
Research method: temperature 18 DEG C to 26 DEG C, in ten thousand grades of clean area production environments of humidity 45% to 65%, by aseptic bulk drug ceftizoxime sodium through pulverizing, sieving, assembling production lines packing ceftiaoxline sodium for injection 1000 bottles is respectively divided, every bottle of 1.5g at the IMA-400 type powder pin of Italian Yi Ma group.
Table 1 bulk drug ceftizoxime sodium 5 granularity group medicinal powder standards
2. slope of repose
Test objective: the slope of repose measuring powder, investigates the quality of powder flowbility.
Research method: the funnel getting 3 100ml is connected and is vertically fixed on 1cm At The Height on the graph paper of horizontal positioned, carefully composition medicinal powder is poured in the funnel of the superiors along funnel, until the composition medicinal powder particle cone tips that graph paper is formed touches flare opening below, replicate(determination) 5 times, average, calculate slope of repose α=arctg(H/R), H is the height of cone, and R is the radius of cone.
Table 2 slope of repose judgement criteria
| Degree (θ) | Judgement criteria |
| θ≤30 degree | Good fluidity |
| θ≤40 degree | The need for liquidity in production process can be met |
3. dissolution time test
Object: by the mensuration to dissolution time, judges the speed of dissolution rate.
Research method: operate routinely with syringe and inject 15ml water for injection, sodium chloride injection, 5% glucose injection respectively in the vial that ceftiaoxline sodium for injection is housed, dissolve, observe the degree that ceftiaoxline sodium for injection dissolves, calculate the time for the treatment of needed for solution clear, replicate(determination) 5 times, calculates the mean time of dissolving.
Table 3 dissolution time judgement criteria
| Dissolution time | Judgement criteria |
| >=2 minutes | Slower |
| 1 ~ 2 minute | Slightly slow |
| 30 ~ 60 seconds | Hurry up |
| ≤ 30 seconds | Comparatively fast |
4. drugs packaging efficiency
Test objective: investigate different range particle diameter to the impact of drugs packaging efficiency.
Research method: according to the sample packing speed of its packing Time Calculation per minute used ceftiaoxline sodium for injection.
Table 4 drugs packaging time and efficiency comparison
5. content uniformity
Test objective: to the bulk drug ceftizoxime sodium packing of different-grain diameter, investigates its impact on content uniformity.
Research method: content uniformity %=(W
1-W
2)/W
2× 100% wherein W
1for the actual weight loading amount of sample, W
2for the sign theoretical weight loading amount of medicine, and investigate the content uniformity situation of packing sample.
Table 5 medicine content uniformity compares
| Content uniformity | Judgement criteria |
| ±5% | Well |
| ±10% | Poor |
6. test of long duration:
Test objective: by simulation normal temperature condition, investigate the quality stability of ceftiaoxline sodium for injection.
Research method: be positioned over by the ceftiaoxline sodium for injection in the various embodiments described above in the climatic chamber of temperature 25 DEG C ± 2 DEG C, relative humidity 60% ± 10%, sampling in 0,3,6,12,18,24 month detects, investigates and the results are shown in Table 10.
Two results and analysis
1. slope of repose
Table 6 slope of repose measurement result
2. dissolution time
Table 7 dissolution time measurement result
3. content uniformity
Table 8 content uniformity measurement result
3. drugs packaging efficiency
Table 9 drugs packaging efficiency test result
As can be seen from above-mentioned table 6-9, although the sample packing speed of the above particle size range of 200 order is fast, content uniformity is little, but its dissolution time is all more than 2 minutes, dissolution time is all good relative to the mobility of the ceftiaoxline sodium for injection of particle diameter 23 ~ 75um, content uniformity, dissolution time aspect, both ensure that production efficiency and quality product, facilitate Clinical practice again.
4. test of long duration
The test of long duration of table 10 three batches of ceftiaoxline sodium for injection investigates result
Above-mentioned long-term test results shows, place 24 months in the climatic chamber of temperature 25 DEG C ± 2 DEG C, relative humidity 60% ± 10%, ceftiaoxline sodium for injection proterties, potential of hydrogen, clarity and color, moisture, related substances and assay result compared with 0 month without considerable change, the bulk drug ceftizoxime sodium that visible synthetic method in the present invention obtains is carried out aseptic refining and after pulverizing, is carried out the good stability of aseptic subpackaged obtained ceftiaoxline sodium for injection.
Claims (7)
1. the synthetic method of bulk drug ceftizoxime sodium, is characterized in that, the method comprises the following steps:
1) preparation is such as formula the compound t-butoxycarbonyl amino thiophene oxime acetic acid shown in B
Get such as formula compound 2-(2-amino-4-thiophene the oximido)-2-methoxyimino acetic acid shown in A, add in dioxane-water mixed solution, dissolve, triethylamine adjusts pH to alkalescence, adds tert-Butyl dicarbonate reaction in ice-water bath, salt acid for adjusting pH, separate out white solid, suction filtration, chloroform flush cake, drying under reduced pressure, obtained such as formula the compound t-butoxycarbonyl amino thiophene oxime acetic acid shown in B;
Formula A:
Formula B:
2) preparation is such as formula the compound t-butoxycarbonyl amino thiophene oxime diacetyl oxide shown in C
Get and slowly join in tetrahydrofuran (THF) such as formula the compound t-butoxycarbonyl amino thiophene oxime acetic acid shown in B, dissolving, take Vanadium Pentoxide in FLAKES as dewatering agent, at room temperature react, reaction is finished, and decompression steams tetrahydrofuran (THF), obtained such as formula the compound t-butoxycarbonyl amino thiophene oxime diacetyl oxide shown in C;
Formula C:
3) preparation is such as formula the amino thiophene oxime of the compound shown in D diacetyl oxide
Get the ethanolic soln back flow reaction 3 ~ 5h such as formula the amino thiophene oxime diacetyl oxide of the compound tert.-butoxy shown in C and hydrazine hydrate, filter, filtrate pressurization evaporate to dryness, obtained such as formula the amino thiophene oxime of the compound shown in D diacetyl oxide;
Formula D:
4) preparation is such as formula the compound ceftizoxime acid shown in F
Get and go first Cephalosporanic acid to be added in chloroform such as formula the compound 7-amino-3-shown in E, add triethylamine and regulate pH to 9 ~ 10, add step 3) obtained such as formula the amino thiophene oxime of the compound shown in D diacetyl oxide, room temperature reaction 4 ~ 6h; Reaction is finished, and add water extraction, merges aqueous phase, adds gac, and room temperature is decoloured, and filters, and with hydrochloric acid adjust pH 1.5 ~ 2.5, separate out faint yellow solid, suction filtration, chloroform rinses, drying under reduced pressure, obtained such as formula the compound ceftizoxime acid shown in F; Formula E:
Formula F:
5) preparation is such as formula the compound ceftizoxime sodium crude product shown in G
Get step 4) obtained soluble in water such as formula the compound ceftizoxime acid shown in F, stir, add triethylamine, stirring and dissolving, filters, gets organic layer, the solution of instillation Sodium isooctanoate and butanols, stirs, slowly drips butanols, stir, separate out off-white color solid, suction filtration, acetone rinsing, drying under reduced pressure, obtained such as formula the compound ceftizoxime sodium crude product shown in G;
Formula G:
6) preparation is such as formula the raw materials of compound medicine ceftizoxime sodium shown in G
In sterilisable chamber, get such as formula the compound ceftizoxime sodium crude product shown in G water-soluble, add gac, room temperature decolouring suction filtration, dehydrated alcohol is added, crystallization in filtrate, with acetone rinsing, suction filtration, filtrate is filtered, drying under reduced pressure, obtained such as formula the raw materials of compound medicine ceftizoxime sodium shown in G;
Formula G:
2. synthetic method according to claim 1, is characterized in that, described step 1) middle triethylamine tune pH to 9 ~ 10, add tert-Butyl dicarbonate reaction 6 ~ 8h in ice-water bath.
3. synthetic method according to claim 1, is characterized in that, described step 2) at room temperature react 2 ~ 3.5h.
4. synthetic method according to claim 1, is characterized in that, described step 5) in, add triethylamine at 0 ~ 5 DEG C, stirring and dissolving, filters, gets organic layer, the solution of 0 ~ 5 DEG C of instillation Sodium isooctanoate and butanols, stir 1 ~ 2h, slowly drip butanols, stir 1 ~ 2h.
5. synthetic method according to claim 1, is characterized in that, described step 1) in, dioxane-water mixed solution is dioxane: water=2:1, and hydrochloric acid adjusts pH to 4.5 ~ 5.5.
6. synthetic method according to claim 1, is characterized in that, described step 6) in, recrystallization temperature is 0 ~ 5 DEG C, rinses 3 times, suction filtration with acetone 50ml, and filtrate uses 0.22um membrane filtration.
7. the preparation method of ceftiaoxline sodium for injection, is characterized in that, described ceftiaoxline sodium for injection is under aseptic environment condition, comprises the following steps:
1) raw materials medicine ceftizoxime sodium: the synthetic method according to a claim as arbitrary in claim 1-6 prepares aseptic bulk drug ceftizoxime sodium;
2) crush and screen: the aseptic bulk drug ceftizoxime sodium of being synthesized by claim 1-7 is pulverized, screening, obtains the bulk drug ceftizoxime sodium of particle diameter 23 ~ 75um;
3) aseptic subpackaged and moulding plug: in sterile workshop, the bulk drug ceftizoxime sodium of particle diameter 23 ~ 75um is loaded in sterile glass vials, cover aseptic plug;
4) roll lid: aluminium-plastic combined cover is pressed into step 2) aseptic plug on;
5) lamp inspection: step 3) product that obtains imports lamp inspection machine into through travelling belt and carries out lamp inspection;
6) pack: the step 4 be up to the standards) product sends into label sticking machine labeling, packaging through travelling belt.
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| CN103524532B (en) * | 2013-10-31 | 2014-11-05 | 浙江亚太药业股份有限公司 | Ceftizoxime sodium compound crystal form, and preparing method and pharmaceutical preparation thereof |
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Address after: 518110, No. 16, Lan Qing Road, Guanlan new high tech Zone, Longhua New District, Guangdong, Shenzhen Patentee after: Sinopharm (Shenzhen) Pharmaceutical Co., Ltd. Address before: 518110 Guanlan high tech Industrial Park, Shenzhen, Guangdong, Baoan District Patentee before: Zhijun Pharmaceutical Co., Ltd., Shenzhen |
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