CN101229129A - Ceftezole sodium powder injection and synthesizing method thereof - Google Patents
Ceftezole sodium powder injection and synthesizing method thereof Download PDFInfo
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- CN101229129A CN101229129A CNA2008100011871A CN200810001187A CN101229129A CN 101229129 A CN101229129 A CN 101229129A CN A2008100011871 A CNA2008100011871 A CN A2008100011871A CN 200810001187 A CN200810001187 A CN 200810001187A CN 101229129 A CN101229129 A CN 101229129A
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Abstract
The invention which provides a ceftezole sodium powder injection and a synthesis method for the powder injection consists of more stable ceftezole sodium crystals; in the method, tetrazoleacetic acid, N, N'- dicyclohexylcarbodiimide and 7-amino cefgadoleic acid with the proportion of 1.4 to 1.7:1 to 1.3:1 make reactions in dimethyl sulfoxide; ceftezole is prepared by causing a react intermediate to react with thiadiazole thiol of 1.1 to 1.3 times; the ceftezole sodium is prepared in sodium bicarbonate water solution after acetone is re-crystallized. The method is easy in operation and has the total yield of 55.5 percent.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of cephalo medicine and synthetic method thereof, is a kind of cefobutazine sodium powder pin and synthetic method thereof in particular.
Background technology
Cefobutazine sodium (Ceftezole Sodium, molecular weight 462.47, molecular formula C
13H
11N
8NaO
4S
3), chemical name be (6R, 7R)-3-([(1,3,4-thiadiazoles-2-yl) sulfur] methyl)-7-((1H-tetrazolium-1-yl) acetylamino)-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid sodium salt.Its chemical structural formula is as follows:
This material be white to light yellow crystalline powder, odorless, have draw moist.
Cefobutazine sodium is a first generation injection cephalosporins, is semisynthetic cephalosporins derivatives, and its mechanism of action is by suppressing the synthetic antibacterial activity of bringing into play of bacteria cell wall.To gram positive bacteria, especially coccus, comprise the staphylococcus aureus, micrococcus scarlatinae, streptococcus pneumoniae, B group Hemolytic streptococcus, Streptococcus viridans, the staphylococcus epidermidis that produce penicillinase and do not produce penicillinase, and diphtheria corynebacterium, anthrax bacillus sensitivity all relatively.Some gram-negative bacteria is medium sensitivity, as escherichia coli, Klebsiella, Salmonella, Shigella, proteus mirabilis etc.Be used for secondary infection, pulmonary abscess, peritonitis, pyelonephritis, the cystitis of septicemia, pneumonia, bronchitis, bronchiectasis (during infection), chronic respiratory system diseases, the treatment of urethritis.Cefobutazine sodium is at first by the exploitation of Japanese rattan pool company, transfers Chugai in 1978 and goes on the market with trade name " Falomesin ".Simultaneously, the cefobutazine sodium of Hirst company also at first goes on the market in Japan with trade name " Celoslin ".This medicine is used later in thing China, breathed out medicine in 2002 and there are crude drug and preparation production in Xinfeng, Tianjin, and in recent years, the use amount annual rate of growth is 399%.
Its preparation at present is with 7-amino-cephemcarboxylic acid (7-ACA) be raw material, synthesize by series reaction, but all has some defectives,, employing reagent costliness low as complex steps, yield etc.
Amino substituent with 7-ACA among the JP56053684A is a raw material, generates thioether with the sulfydryl cefpimizole earlier, and then carries out the substitution reaction generation ceftezole of thioether alkyl with dimercaptothiodiazole.This method adds the reaction that the sulfydryl cefpimizole becomes thioether, has increased reactions steps, has improved production cost.
Patent application CN200610009611 discloses a kind of method for preparing the ceftezode three-position intermediate, and he reacts in a kind of solvent complex with dimercaptothiodiazole earlier with 7-ACA, and described solvent complex is the complex that acetonitrile, formic acid are equal to boron trifluoride.This method has been used the boron trifluoride of expensive high pollution, has improved production cost, has also strengthened the difficulty that the three wastes are handled.
Synthetic handbook (the version in 2002 of Zhu Baoquan chief editor's newly organized medicine, p377-379) reported a kind of ceftezole synthetic method in, this method is raw material with 7-ACA, under DCC catalysis, react earlier with tetrazoleacetic acid, generate 7 bit amino substituents, and then generate ceftezole with the dimercaptothiodiazole reaction.This method is fairly simple, but yield is very low, total recovery 18.3%
7-ACA Compound I ceftezole
All there is poor stability in the cefobutazine sodium aseptic powder injection of listing at present, and the unstability of temperature and light is become turbid as the Yin Wendu reason, can heat its clarification back is used.Preferably use immediately after the dissolving, preserve as need, for preventing precipitation, (below 15 ℃) are preserved in the cool, but must be in 72 hours shortcoming such as use.
" Acta Pharmaceutica Sinica " disclosed a kind of cefobutazine sodium method for crystallising among the p275-279 in 2002 37 (4), wherein mention the cefobutazine sodium that recrystallization obtains and be its monohydrate, and there are two kinds of crystal structures of I type and II type simultaneously, I type crystal water molecules is loose, under 35～117 ℃, lose, II type water molecules is tight, loses under 110～160 ℃.This article mentions simultaneously that wherein I type crystal proportion is high more, and its stability is good more.Wherein I type crystal but how controlled condition make and generate the research that awaits of single crystal form cefobutazine sodium.
In sum, there is poor stability in existing cefobutazine sodium aseptic powder injection, the shortcomings such as unstability of temperature and light.This clinical practice to this medicine has very big restricted.In addition, at present the preparation method yield of cefobutazine sodium is very low, and higher cost has caused costing an arm and a leg of this pharmaceutical preparation, has increased the weight of patient's financial burden, and it has used the strong chemical reagent of contaminative in synthetic, and is bigger to environment damage.In view of this, through the secular test of the inventor, the present invention is proposed.
Summary of the invention
One of the object of the invention is to provide a kind of cefobutazine sodium powder pin, and this powder needle set has the advantage of good stability.
Another purpose of the present invention is to provide a kind of synthetic method of cefobutazine sodium, and this method is simple, the yield height.
For achieving the above object, the technical scheme taked of the present invention is:
A kind of cefobutazine sodium powder pin, described cefobutazine sodium powder pin prepares as follows:
(1) dosing: the ceftezole crystal adds in the sodium bicarbonate aqueous solution, the stirring at room dissolving,
(2) decolouring: add activated carbon, stir decolouring, the titanium rod filters decarburization then, and filtrate is with 0.22 μ m filtering with microporous membrane,
(3) crystallization: stir the isopropyl alcohol and the alcohol mixed solution that in filtrate, add aseptic process down, solution is cooled to 10 ℃ with 30 ℃/hour earlier, be cooled to 0 ℃ with 120 ℃/hour again, kept mixing speed 100-160 rev/min stirring and crystallizing then 3 hours, and refiltered, with aseptic isopropyl alcohol and alcohol mixed solution washing leaching cake, 35 ℃ of drying under reduced pressure 4 hours, packing is jumped a queue, and rolls lid.
Shortcoming at cefobutazine sodium powder pin less stable in the prior art, the inventor is through groping, find the cefobutazine sodium ceftezole sodium crystal that recrystallization obtains in the mixed solution of isopropyl alcohol, second alcohol and water through the TGA analysis, confirm that major part is a better I type crystal of stability.Often various crystal formations were separated out simultaneously when the usual method recrystallization was freezing, the present invention is through overtesting, find to be cooled to 10 ℃ by 30 ℃/hour earlier, accelerate chilling rate again, make that more I type crystal is separated out rapidly originally, and II type crystal has little time owing to content is very little further to separate out, and promptly is cooled to 0 ℃ with 120 ℃/minute, can further improve I type crystalline content like this.Mixing speed when the present invention separates out by control again is 100-160 rev/min, finds again I type crystal is further abundant.Principle may influence intermolecular effect for certain mixing speed, and the I type is crystalline to be separated out thereby be beneficial to.Description of the present invention back has also been enumerated cefobutazine sodium powder pin of the present invention and has been thought confirmation with commercially available cefobutazine sodium powder pin stability contrast test data.
According to foregoing cefobutazine sodium powder pin,
Sodium bicarbonate aqueous solution described in step (1) dosing is that mole is prepared by the sodium bicarbonate of 1 times of amount of ceftezole and the injection pure water of 10.4 times of ceftezoles;
The activated carbon addition is 0.3% of a liquor capacity described in step (2) decolouring, and described stirring is 30 minutes;
Described in step (3) crystallization in the mixed solution isopropyl alcohol and ethanol volume ratio be 1: 1, stir addition down and be ceftezole 9.36 times, described mixing speed is 130 rev/mins.
The cefobutazine sodium that this preferred version obtains is analyzed through TGA, is almost pure I type crystal, and this scheme is a preferred version of the present invention.
A kind of synthetic method of cefobutazine sodium as previously mentioned, described synthetic method is:
(1) Compound I is synthetic: with tetrazoleacetic acid and N, N '-dicyclohexylcarbodiimide, be dissolved in the dimethyl sulfoxine, 7-amino-cephemcarboxylic acid, triethylamine and the ethyl acetate solution for preparing is added drop-wise in the reactant liquor, after reaction finished, reactant liquor added water treatment again, the organic solvent extraction of water layer except that chloroform, reuse acid for adjusting pH＜2, and then, merge organic layer with the organic solvent extraction except that chloroform, obtain Compound I after the processing
Wherein said tetrazoleacetic acid, N, N '-dicyclohexylcarbodiimide and 7-amino-cephemcarboxylic acid ratio are 1.4～1.7: 1～1.3: 1, three's ratio is 2.34: 1.55: 1 in the prior art at present, tetrazoleacetic acid is excessive serious, not only increased cost, unnecessary tetrazoleacetic acid can cause that also other side reactions take place, and among the present invention inventory has been carried out groping repeatedly, and find in three's ratio 1.4～1.7: 1～1.3: 1 scope is the most suitable;
Described reaction is-10～5 ℃ of reactions 1 hour, 0～10 ℃ was reacted 1 hour then, room temperature reaction is 2～4 hours again, react the long period under the often same temperature of reaction condition in the prior art, be generally more than 7 hours, the present invention has formulated the reaction temperature curve that is fit to more according to reaction principle, gradient increased temperature has shortened the response time;
By these improvement this step reaction yield is brought up to 72.8%.
(2) ceftezole is synthetic: the Compound I of step (1) gained is dissolved in 10% sodium bicarbonate aqueous solution, with this solution and 1,3, it is in 6.4 the phosphate buffer that 4-thiadiazoles-2-mercaptan adds pH, 60 ℃ of reactions 6 hours down, then with the extremely clarification of ether washing reaction liquid, water layer is transferred pH＜2.0 with 10% hydrochloric acid, and the reuse ethyl acetate extraction merges organic layer, obtain ceftezole after the processing
Described Compound I is with 1,3,4-thiadiazoles-2-mercaptan ratio is 1: 1.1～1.3, in the prior art 1,3,4-thiadiazoles-2-mercaptan large usage quantity, it is 1.1～1.3: 1 that the present invention is reduced to its consumption with the major ingredient ratio through overtesting, reduced the side reaction occurrence probability that seriously causes because of adjuvant is excessive, through improving, this step yield is increased to 86.8%;
(3) recrystallization: with step (2) gained ceftezole crude product acetone heating for dissolving, crystallize then, obtain the ceftezole crystal, because the preparation of sodium salt is comparatively harsh to condition, and the sodium salt recrystallization comparatively bothers, and the present invention carries out recrystallization earlier after obtaining the ceftezole crude product, carry out the preparation of sodium salt again, overcome above-mentioned difficulties.The present invention screens multiple solvent in recrystallization, has finally selected acetone, significantly improved product matter, and yield is up to 90.4%;
(4) cefobutazine sodium is synthetic: the ceftezole crystal that step (3) is obtained adds in the sodium bicarbonate aqueous solution, the stirring at room dissolving, add activated carbon, stir decolouring, the titanium rod filters decarburization then, filtrate is with 0.22 μ m filtering with microporous membrane, stir the isopropyl alcohol and the alcohol mixed solution that in filtrate, add aseptic process down, solution is cooled to 10 ℃ with 30 ℃/hour earlier, is cooled to 0 ℃ with 120 ℃/hour again, keeps mixing speed 100-160 rev/min stirring and crystallizing then 3 hours, refilter, with aseptic isopropyl alcohol and alcohol mixed solution washing leaching cake, 35 ℃ of drying under reduced pressure 4 hours, the ceftezole sodium crystal.
According to foregoing cefobutazine sodium synthetic method, in the described synthetic method:
Described 7-amino-cephemcarboxylic acid, triethylamine and ethyl acetate solution are added drop-wise to of step (1) is dropping under-10～5 ℃ in the reactant liquor, the dropping time is 1～2 hour;
Described reaction is-5～0 ℃ of reaction 1 hour, and 0～5 ℃ was reacted 1 hour then, and room temperature reaction is 3 hours again; Described tetrazoleacetic acid, N, N '-dicyclohexylcarbodiimide and 7-amino-cephemcarboxylic acid ratio are 1.5～1.6: 1～1.1: 1;
Described solvent except that chloroform is ethyl acetate, ether.
According to foregoing cefobutazine sodium synthetic method, in the described synthetic method: the described tetrazoleacetic acid of step (1), N, N '-dicyclohexylcarbodiimide and 7-amino-cephemcarboxylic acid ratio are 1.5: 1.06: 1; Described solvent except that chloroform is an ethyl acetate.
According to foregoing cefobutazine sodium synthetic method, in the described synthetic method, the described Compound I of step (2) is with 1,3, and 4-thiadiazoles-2-mercaptan ratio is 1: 1.2.
According to foregoing cefobutazine sodium synthetic method, in the described synthetic method: the described crystallize of step (3) is for placing the natural cooling crystallize 2 hours; Described acetone consumption is 6 times of ceftezole crude product.
According to foregoing cefobutazine sodium synthetic method, in the described synthetic method: the described sodium bicarbonate aqueous solution of step (4) is that mole is prepared by the sodium bicarbonate of 1 times of amount of ceftezole and the injection pure water of 10.4 times of ceftezoles;
Described activated carbon addition is 0.3% of a liquor capacity, and described stirring is 30 minutes;
Isopropyl alcohol and ethanol volume ratio are 1: 1 in the described mixed solution, and the following addition of stirring is 9.36 times of ceftezole, and described mixing speed is 130 rev/mins.
According to foregoing cefobutazine sodium synthetic method, it is specially:
(1) Compound I is synthetic: with tetrazoleacetic acid and N, N '-dicyclohexylcarbodiimide, be dissolved in the dimethyl sulfoxine, again with the 7-amino-cephemcarboxylic acid for preparing, triethylamine and ethyl acetate solution are in 1～2 hour, be added drop-wise in the reactant liquor under-10～5 ℃, drip and finish-10～5 ℃ of reactions 1 hour, 0～10 ℃ was reacted 1 hour then, room temperature reaction is 2～4 hours again, after reaction was finished, reactant liquor added water treatment, and water layer is with ethyl acetate or extracted with diethyl ether, reuse hydrochloric acid is regulated pH＜2, and then, merge organic layer with ethyl acetate or extracted with diethyl ether, obtain Compound I after the processing;
Compound I
(2) ceftezole is synthetic: the Compound I of step (1) gained is dissolved in 10% sodium bicarbonate aqueous solution, with this solution and 1,3, it is in 6.4 the phosphate buffer that 4-thiadiazoles-2-mercaptan adds pH, 60 ℃ of reactions 6 hours down, then with ether washing reaction liquid to clarification, water layer is transferred pH＜2.0 with 10% hydrochloric acid, the reuse ethyl acetate extraction merges organic layer, obtains ceftezole after the processing;
(3) recrystallization: step (2) gained ceftezole crude product with 6 times of acetone heating for dissolving, was placed the natural cooling crystallize 2 hours then, obtain the ceftezole crystal;
(4) the ceftezole crystal that step (3) is obtained adds in the sodium bicarbonate aqueous solution, the stirring at room dissolving, the activated carbon that adds liquor capacity 0.3%, stir decolouring in 30 minutes, the titanium rod filters decarburization then, filtrate is with 0.22 μ m filtering with microporous membrane, stir the isopropyl alcohol and the alcohol mixed solution that in filtrate, add aseptic process down, solution is cooled to 10 ℃ with 30 ℃/hour earlier, be cooled to 0 ℃ with 120 ℃/hour again, kept mixing speed 100-160 rev/min stirring and crystallizing then 3 hours, and filtered then, with aseptic isopropyl alcohol and alcohol mixed solution washing leaching cake, 35 ℃ of drying under reduced pressure 4 hours, obtain cefobutazine sodium, described sodium bicarbonate consumption is 1 times of ceftezole, and described concentration of aqueous solution is 1.8%.
According to foregoing cefobutazine sodium synthetic method, it more specifically is:
(1) Compound I is synthetic: with 1.5 parts of tetrazoleacetic acids and 1.06 parts of N, N '-dicyclohexylcarbodiimide, be dissolved in 25 times of dimethyl sulfoxines, to prepare again by 1 part of 7-amino-cephemcarboxylic acid, 3 parts of triethylamines and 15 times of ethyl acetate solutions are in 1.5 hours, be added drop-wise in the reactant liquor under-5～0 ℃, drip and finish-5～0 ℃ of reaction 1 hour, 0～5 ℃ was reacted 1 hour then, room temperature reaction is 3 hours again, after reaction was finished, reactant liquor added water treatment, and water layer is with ethyl acetate or extracted with diethyl ether, reuse hydrochloric acid is regulated pH＜2, and then, merge organic layer with ethyl acetate or extracted with diethyl ether, obtain Compound I after the processing;
(2) ceftezole is synthetic: the Compound I of step (1) gained is dissolved in 2.1 times of 10% sodium bicarbonate aqueous solution, with this solution and 1.2 times 1,3, it is in 6.4 the phosphate buffer that 4-thiadiazoles-2-mercaptan adds pH, 60 ℃ of reactions 6 hours down, then with ether washing reaction liquid to clarification, water layer is transferred pH＜2.0 with 10% hydrochloric acid, the reuse ethyl acetate extraction merges organic layer, obtains ceftezole after the processing;
(3) recrystallization: step (2) gained ceftezole crude product with 6 times of acetone heating for dissolving, was placed the natural cooling crystallize 2 hours then, obtain the ceftezole crystal;
(4) the ceftezole crystal that step (3) is obtained adds in the sodium bicarbonate aqueous solution, the stirring at room dissolving, the activated carbon that adds liquor capacity 0.3%, stir decolouring in 30 minutes, the titanium rod filters decarburization then, filtrate is with 0.22 μ m filtering with microporous membrane, stir 1: 1 the isopropyl alcohol and the alcohol mixed solution that in filtrate, add 9.36 times of amount aseptic process down, solution is cooled to 10 ℃ with 30 ℃/hour earlier, be cooled to 0 ℃ with 120 ℃/hour again, kept mixing speed 100-160 rev/min stirring and crystallizing then 3 hours, and filtered then, with aseptic isopropyl alcohol and alcohol mixed solution washing leaching cake, 35 ℃ of drying under reduced pressure 4 hours, obtain cefobutazine sodium, described sodium bicarbonate consumption is 1 times of ceftezole, and described concentration of aqueous solution is 1.8%.
The present invention is through repetition test, and final selected synthetic method has following advantage:
(1) product purity height, good stability.
(2) reaction yield height, total recovery is up to 55.5%.
(3) easy reaction is convenient to suitability for industrialized production.
(4) the reaction solvent that adopts is common agents, and the three wastes are handled easily.
Following table is reactions steps (1) reaction condition screening contrast:
| Scheme | Ingredient proportion * | Reaction temperature, time | Estimate | Sum up |
| 1 | 2.3∶1.4∶1 | 0～5 ℃ was reacted 5 hours | Yield is low, purity is low | Select 3 to be final technology |
| 2 | 1.5∶1.2∶1 | -5～0 ℃ of reaction 2h, room temperature reaction 3h | Yield increases | |
| 3 | 1.5∶1.06∶1 | -5～0 ℃ of reaction 1h, 0～5 ℃ of reaction 1h, room temperature reaction 3h | Yield is higher, purity is high |
* ingredient proportion is: 2-(1-H-1-tetrazolium) guanidine-acetic acid: N, N '-dicyclohexylcarbodiimide: 7-ACA
The specific embodiment
Synthesizing of embodiment 1:7-(1H-1-tetrazole radical) acetamide-Cephalosporanic acid (I)
With 1412g (11.03mol) tetrazoleacetic acid and 1609g (8.75mol) N, N '-dicyclohexylcarbodiimide (DCC), 50L dimethyl sulfoxide join in the 100L reactor, stir to make dissolving fully.With 2000g (7.35mol) 7-amino-Cephalosporanic acid, 2227g (22.05mol) triethylamine, 30L ethyl acetate mixed dissolution, be added dropwise to after the dissolving in the above tetrazoleacetic acid solution, control reaction temperature is between-5～0 ℃, and 1.5h adds.After dropwising, at-5～0 ℃ of reaction 1h, 0～5 ℃ of reaction 1h, room temperature reaction 3h.The elimination precipitate adds 70L water in filtrate, divide the water intaking layer.Water layer divides 2 washings with ethyl acetate 10L.Transfer pH＜2 with 10% hydrochloric acid, separate out a large amount of precipitations.Add the 45L ethyl acetate, at twice extraction.Combining extraction liquid with saturated nacl aqueous solution washing, adds a little anhydrous sodium sulfate dehydration drying, 40 ℃ be evaporated to dried, the crude product 2043g of chemical compound (III), yield: 72.8%.
Embodiment 2:7-(1H-1-tetrazole radical) acetylaminohydroxyphenylarsonic acid 3-[2-(1,3, the 4-thiadiazolyl group)] sulfidomethyl-3-cephem-4-carboxylic acid (ceftezole) synthetic
With 2043g (5.35mol) chemical compound (III) with an amount of 10%NaHCO
3Solution dissolving (about 4300ml), then with this solution and 755g (6.40mol) 1,3,4-thiadiazoles-2-mercaptan (IV) joins among the phosphate buffer 80L of pH value 6.4, is heated to 60 ℃, stirring reaction 6h.Wash to solution becomes with ether then and clarify.Water layer to pH＜2.0, is separated out a large amount of precipitations with 10% hcl acidifying.Divide 2 extractions with the 70L ethyl acetate, combining extraction liquid, with saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, crystallize, sucking filtration gets crude product 2028 grams.
Embodiment 3:7-(1H-1-tetrazole radical) acetylaminohydroxyphenylarsonic acid 3-[2-(1,3, the 4-thiadiazolyl group)] sulfidomethyl-3-cephem-4-carboxylic acid (ceftezole) refining
2028g ceftezole crude product is heated to 60 ℃ with 6 times of acetone, makes dissolving fully.Put cold analysis then brilliant 2 hours, sucking filtration, a little washing with alcohol, 40 ℃ of drying under reduced pressure 4 hours, 1834 gram products, yield: 94.8%.
Embodiment 4: the preparation of cefobutazine sodium (VI) aseptic powder
Used reactor, filter, apparatus are carried out aseptic process.1923g (4.37mol) ceftezole, 368g (4.37mol) sodium bicarbonate and 20L purified water are joined in the 50L reactor, and stirring at room makes dissolving fully, adds the 60g active carbon then, stirring and adsorbing 30 minutes.Titanium rod filtering decarbonization, 0.22 μ m microporous filter membrane double-filtration, be transferred in the 50L crystallizer in ten thousand grades of part hundred clean areas, to wherein adding 1: 1 isopropyl alcohol of aseptic process: dehydrated alcohol mixed liquor 18L, the limit edged stirs, solution is cooled to 10 ℃ with 30 ℃/hour earlier, be cooled to 0 ℃ with 120 ℃/hour again, kept 130 rev/mins of stirring and crystallizing of mixing speed then 3 hours, sucking filtration, aseptic washed with isopropyl alcohol, 35 ℃ of drying under reduced pressure 4 hours.Weigh: 1872 grams, yield: 92.7%.
Synthesizing of embodiment 5:7-(1H-1-tetrazole radical) acetamide-Cephalosporanic acid (I)
With 1317g (10.29mol) tetrazoleacetic acid and 1514g (7.35mol) N, N '-dicyclohexylcarbodiimide (DCC), 50L dimethyl sulfoxide join in the 100L reactor, stir to make dissolving fully.With 2000g (7.35mol) 7-amino-Cephalosporanic acid, 2227g (22.05mol) triethylamine, 30L ethyl acetate mixed dissolution, be added dropwise to after the dissolving in the above tetrazoleacetic acid solution, control reaction temperature is between-10～-5 ℃, and 1h adds.After dropwising, at-10 ℃ of reaction 1h, 0 ℃ of reaction 1h, room temperature reaction 4h.The elimination precipitate adds 70L water in filtrate, divide the water intaking layer.Water layer divides 2 washings with ethyl acetate 10L.Transfer pH＜2 with 10% hydrochloric acid, separate out a large amount of precipitations.Add the 45L ethyl acetate, at twice extraction.Combining extraction liquid with saturated nacl aqueous solution washing, adds a little anhydrous sodium sulfate dehydration drying, 40 ℃ be evaporated to dried, the crude product 2023g of chemical compound (III), yield: 72.1%.
Synthesizing of embodiment 6:7-(1H-1-tetrazole radical) acetamide-Cephalosporanic acid (I)
With 1600g (12.5mol) tetrazoleacetic acid and 1968g (9.55mol) N, N '-dicyclohexylcarbodiimide (DCC), 50L dimethyl sulfoxide join in the 100L reactor, stir to make dissolving fully.With 2000g (7.35mol) 7-amino-Cephalosporanic acid, 2227g (22.05mol) triethylamine, 30L ethyl acetate mixed dissolution, be added dropwise to after the dissolving in the above tetrazoleacetic acid solution, control reaction temperature is between 0～5 ℃, and 2h adds.After dropwising, at 5 ℃ of reaction 1h, 10 ℃ of reaction 1h, room temperature reaction 2h.The elimination precipitate adds 70L water in filtrate, divide the water intaking layer.Water layer divides 2 washings with ether 20L.Transfer pH＜2 with 10% hydrochloric acid, separate out a large amount of precipitations.Add the 60L ether, at twice extraction.Combining extraction liquid with saturated nacl aqueous solution washing, adds a little anhydrous sodium sulfate dehydration drying, 40 ℃ be evaporated to dried, the crude product 2034g of chemical compound (III), yield: 72.5%.
Embodiment 7:7-(1H-1-tetrazole radical) acetylaminohydroxyphenylarsonic acid 3-[2-(1,3, the 4-thiadiazolyl group)] sulfidomethyl-3-cephem-4-carboxylic acid (ceftezole) synthetic
With 2043g (5.35mol) chemical compound (III) with an amount of 10%NaHCO
3Solution dissolving (about 4300ml), then with this solution and 694g (5.88mol) 1,3,4-thiadiazoles-2-mercaptan (IV) joins among the phosphate buffer 80L of pH value 6.4, is heated to 60 ℃, stirring reaction 6h.Wash to solution becomes with ether then and clarify.Water layer to pH＜2.0, is separated out a large amount of precipitations with 10% hcl acidifying.Divide 2 extractions with the 70L ethyl acetate, combining extraction liquid, with saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, crystallize, sucking filtration gets crude product 2004 grams.
Embodiment 8:7-(1H-1-tetrazole radical) acetylaminohydroxyphenylarsonic acid 3-[2-(1,3, the 4-thiadiazolyl group)] sulfidomethyl-3-cephem-4-carboxylic acid (ceftezole) synthetic
With 2043g (5.35mol) chemical compound (III) with an amount of 10%NaHCO
3Solution dissolving (about 4300ml), then with this solution and 821g (6.95mol) 1,3,4-thiadiazoles-2-mercaptan (IV) joins among the phosphate buffer 80L of pH value 6.4, is heated to 60 ℃, stirring reaction 6h.Wash to solution becomes with ether then and clarify.Water layer to pH＜2.0, is separated out a large amount of precipitations with 10% hcl acidifying.Divide 2 extractions with the 70L ethyl acetate, combining extraction liquid, with saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, crystallize, sucking filtration gets crude product 2012 grams.
Embodiment 9:7-(1H-1-tetrazole radical) acetylaminohydroxyphenylarsonic acid 3-[2-(1,3, the 4-thiadiazolyl group)] sulfidomethyl-3-cephem-4-carboxylic acid (ceftezole) refining
2028g ceftezole crude product is heated to 50 ℃ with 6 times of acetone, makes dissolving fully.Put cold analysis then brilliant 2 hours, sucking filtration, a little washing with alcohol, 40 ℃ of drying under reduced pressure 4 hours, 1839 gram products, yield: 90.7%.
Embodiment 10: the preparation of cefobutazine sodium (VI) aseptic powder
Used reactor, filter, apparatus are carried out aseptic process.1000g (2.27mol) ceftezole, 191g (2.27mol) sodium bicarbonate and 10.4L purified water are joined in the 30L reactor, and stirring at room makes dissolving fully, adds the 31.2g active carbon then, stirring and adsorbing 30 minutes.Titanium rod filtering decarbonization, 0.22 μ m microporous filter membrane double-filtration, be transferred in the 50L crystallizer in ten thousand grades of part hundred clean areas, to wherein adding 1: 1 isopropyl alcohol of aseptic process: dehydrated alcohol mixed liquor 9.36L, the limit edged stirs, solution is cooled to 10 ℃ with 30 ℃/hour earlier, be cooled to 0 ℃ with 120 ℃/hour again, kept 100 rev/mins of stirring and crystallizing of mixing speed then 3 hours, sucking filtration, aseptic washed with isopropyl alcohol, 35 ℃ of drying under reduced pressure 4 hours.Weigh: 965 grams, yield: 91.9%.
Embodiment 11: the preparation of cefobutazine sodium (VI) aseptic powder
Used reactor, filter, apparatus are carried out aseptic process.2000g (4.54mol) ceftezole, 382g (4.54mol) sodium bicarbonate and 20.8L purified water are joined in the 50L reactor, and stirring at room makes dissolving fully, adds the 62.4g active carbon then, stirring and adsorbing 30 minutes.Titanium rod filtering decarbonization, 0.22 μ m microporous filter membrane double-filtration, be transferred in the 50L crystallizer in ten thousand grades of part hundred clean areas, to wherein adding 1: 1 isopropyl alcohol of aseptic process: dehydrated alcohol mixed liquor 18.72L, the limit edged stirs, solution is cooled to 10 ℃ with 30 ℃/hour earlier, be cooled to 0 ℃ with 120 ℃/hour again, kept 160 rev/mins of stirring and crystallizing of mixing speed then 3 hours, sucking filtration, aseptic washed with isopropyl alcohol, 35 ℃ of drying under reduced pressure 4 hours.Weigh: 1945 grams, yield: 92.6%.
The ceftezole sodium content height of the method for the invention preparation, steady quality now is listed below its quality research as the test example:
Test example 1: quality standard research
Raw material of the present invention and intermediate ground control of quality standard
Cefobutazine sodium aseptic powder of the present invention is that white is to little yellow crystalline powder, odorless.
Cefobutazine sodium aseptic powder of the present invention was placed 24 hours in 25 ℃, RH80% environment, draw moist all greater than 2%, have draw moist.
With the solubility test of cefobutazine sodium aseptic powder of the present invention in multiple solvent, the result shows that this product is easily molten in water, and slightly soluble in methanol is almost insoluble in ethanol and ether.
Measure the absorptance of cefobutazine sodium aseptic powder of the present invention in water, three batches of raw materials absorptance be respectively 287,290 and 291, all in absorptance 270～300 scopes of pharmacopeia regulation.
The specific optical rotation average out to-7.0 of cefobutazine sodium aseptic powder of the present invention in water °.
Differentiate cefobutazine sodium of the present invention, its aqueous solution has absorption maximum at the wavelength place of 272nm.
Test example 2: long term test data
(1) the accelerated test result shows: this product was placed 6 months under the condition of 40 ℃ ± 2 ℃ of temperature, humidity 75% ± 5%, and every index and 0 month, relatively related substance had rising slightly, and content slightly descends.Other indexs do not have significant change, meet to produce to use the quality standard draft.
(2) long term test shows: this product was placed 12 months under 25 ℃ ± 2 ℃, humidity 60% ± 10% condition, and related substance slightly raises, and content slightly descends, and all other indexs and 0 month relatively do not have significant change, illustrate that this product quality is more stable; According to measured every result, can fix tentatively effect duration is 2 years.This work is proceeded.
| Be subjected to test product (content %) | Accelerated test (content %) | Long term test (content %) | ||
| 6 months | 12 months | 12 months | 24 months | |
| The present invention (102.5) | 102.2 | 101.6 | 102.4 | 102.0 |
| Reference substance (102.3) | 100.4 | 96.7 | 101.4 | 99.5 |
Reference substance is commercially available cefobutazine sodium powder pin
Claims (8)
1. a cefobutazine sodium powder pin is characterized in that, described cefobutazine sodium powder pin prepares as follows:
(1) dosing: the ceftezole crystal adds in the sodium bicarbonate aqueous solution, the stirring at room dissolving,
(2) decolouring: add activated carbon, stir decolouring, the titanium rod filters decarburization then, and filtrate is with 0.22 μ m filtering with microporous membrane,
(3) crystallization: stir the isopropyl alcohol and the alcohol mixed solution that in filtrate, add aseptic process down, solution is cooled to 10 ℃ with 30 ℃/hour earlier, be cooled to 0 ℃ with 120 ℃/hour again, kept mixing speed 100-160 rev/min stirring and crystallizing then 3 hours, and refiltered, with aseptic isopropyl alcohol and alcohol mixed solution washing leaching cake, 35 ℃ of drying under reduced pressure 4 hours, packing is jumped a queue, and rolls lid.
2. cefobutazine sodium powder pin according to claim 1 is characterized in that,
Sodium bicarbonate aqueous solution described in step (1) dosing be mole be 1 times of amount of ceftezole sodium bicarbonate and
10.4 doubly the injection pure water of ceftezole is prepared;
The activated carbon addition is 0.3% of a liquor capacity described in step (2) decolouring, and described stirring is 30 minutes;
Described in step (3) crystallization in the mixed solution isopropyl alcohol and ethanol volume ratio be 1: 1, stir addition down and be ceftezole 9.36 times, described mixing speed is 130 rev/mins.
3. the synthetic method of the described cefobutazine sodium of claim 1 is characterized in that, described synthetic method is:
(1) Compound I is synthetic: with tetrazoleacetic acid and N, N '-dicyclohexylcarbodiimide, be dissolved in the dimethyl sulfoxine, 7-amino-cephemcarboxylic acid, triethylamine and the ethyl acetate solution for preparing is added drop-wise in the reactant liquor, after reaction finished, reactant liquor added water treatment again, the organic solvent extraction of water layer except that chloroform, reuse acid for adjusting pH＜2, and then, merge organic layer with the organic solvent extraction except that chloroform, obtain Compound I after the processing
Wherein said tetrazoleacetic acid, N, N '-dicyclohexylcarbodiimide and 7-amino-cephemcarboxylic acid ratio are 1.4～1.7: 1～1.3: 1,
Described reaction is-10～5 ℃ of reactions 1 hour, and 0～10 ℃ was reacted 1 hour then, and room temperature reaction is 2～4 hours again;
(2) ceftezole is synthetic: the Compound I of step (1) gained is dissolved in 10% sodium bicarbonate aqueous solution, with this solution and 1,3, it is in 6.4 the phosphate buffer that 4-thiadiazoles-2-mercaptan adds pH, 60 ℃ were reacted 6 hours down, and with the extremely clarification of ether washing reaction liquid, water layer is transferred pH＜2.0 with 10% hydrochloric acid then, the reuse ethyl acetate extraction, merge organic layer, obtain ceftezole after the processing, described Compound I is with 1,3,4-thiadiazoles-2-mercaptan ratio is 1: 1.1～1.3;
(3) recrystallization: with step (2) gained ceftezole crude product acetone heating for dissolving, crystallize obtains the ceftezole crystal then;
(4) cefobutazine sodium is synthetic: the ceftezole crystal that step (3) is obtained adds in the sodium bicarbonate aqueous solution, the stirring at room dissolving, add activated carbon, stir decolouring, the titanium rod filters decarburization then, filtrate is with 0.22 μ m filtering with microporous membrane, stir the isopropyl alcohol and the alcohol mixed solution that in filtrate, add aseptic process down, solution is cooled to 10 ℃ with 30 ℃/hour earlier, is cooled to 0 ℃ with 120 ℃/hour again, keeps mixing speed 100-160 rev/min stirring and crystallizing then 3 hours, refilter, with aseptic isopropyl alcohol and alcohol mixed solution washing leaching cake, 35 ℃ of drying under reduced pressure 4 hours, the ceftezole sodium crystal.
4. cefobutazine sodium synthetic method according to claim 3 is characterized in that, in the described synthetic method:
Described 7-amino-cephemcarboxylic acid, triethylamine and ethyl acetate solution are added drop-wise to of step (1) is dropping under-10～5 ℃ in the reactant liquor, the dropping time is 1～2 hour;
Described reaction is-5～0 ℃ of reaction 1 hour, and 0～5 ℃ was reacted 1 hour then, and room temperature reaction is 3 hours again;
Described tetrazoleacetic acid, N, N '-dicyclohexylcarbodiimide and 7-amino-cephemcarboxylic acid ratio are 1.5～1.6: 1～1.1: 1;
Described solvent except that chloroform is ethyl acetate, ether.
5. cefobutazine sodium synthetic method according to claim 4 is characterized in that, in the described synthetic method:
The described tetrazoleacetic acid of step (1), N, N '-dicyclohexylcarbodiimide and 7-amino-cephemcarboxylic acid ratio are 1.5: 1.06: 1; Described solvent except that chloroform is an ethyl acetate.
6. cefobutazine sodium synthetic method according to claim 3 is characterized in that, in the described synthetic method,
The described Compound I of step (2) is with 1,3, and 4-thiadiazoles-2-mercaptan ratio is 1: 1.2.
7. cefobutazine sodium synthetic method according to claim 3 is characterized in that, in the described synthetic method:
The described crystallize of step (3) is for placing the natural cooling crystallize 2 hours; Described acetone consumption is 6 times of ceftezole crude product.
8. cefobutazine sodium synthetic method according to claim 3 is characterized in that, in the described synthetic method:
The described sodium bicarbonate aqueous solution of step (4) is that mole is prepared by the sodium bicarbonate of 1 times of amount of ceftezole and the injection pure water of 10.4 times of ceftezoles;
Described activated carbon addition is 0.3% of a liquor capacity, and described stirring is 30 minutes;
Isopropyl alcohol and ethanol volume ratio are 1: 1 in the described mixed solution, and the following addition of stirring is 9.36 times of ceftezole, and described mixing speed is 130 rev/mins.
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