CN102532166A - Preparation method of refined ceftezole acid - Google Patents
Preparation method of refined ceftezole acid Download PDFInfo
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- CN102532166A CN102532166A CN201010606399XA CN201010606399A CN102532166A CN 102532166 A CN102532166 A CN 102532166A CN 201010606399X A CN201010606399X A CN 201010606399XA CN 201010606399 A CN201010606399 A CN 201010606399A CN 102532166 A CN102532166 A CN 102532166A
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- filter cake
- ceftezole
- refining
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- DZMVCVMFETWNIU-LDYMZIIASA-N ceftezole Chemical compound O=C([C@@H](NC(=O)CN1N=NN=C1)[C@H]1SC2)N1C(C(=O)O)=C2CSC1=NN=CS1 DZMVCVMFETWNIU-LDYMZIIASA-N 0.000 title claims abstract description 30
- 229960004366 ceftezole Drugs 0.000 title claims abstract description 30
- 239000002253 acid Substances 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 25
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 24
- 238000001914 filtration Methods 0.000 claims abstract description 17
- 238000001035 drying Methods 0.000 claims abstract description 16
- 239000000047 product Substances 0.000 claims abstract description 14
- 238000005406 washing Methods 0.000 claims abstract description 10
- 239000012043 crude product Substances 0.000 claims abstract description 5
- 239000013078 crystal Substances 0.000 claims abstract description 5
- 239000012065 filter cake Substances 0.000 claims description 21
- 238000002425 crystallisation Methods 0.000 claims description 18
- 230000008025 crystallization Effects 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
- 238000007670 refining Methods 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 238000005070 sampling Methods 0.000 claims description 12
- 239000008367 deionised water Substances 0.000 claims description 10
- 229910021641 deionized water Inorganic materials 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000011347 resin Substances 0.000 claims description 8
- 229920005989 resin Polymers 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 238000001514 detection method Methods 0.000 claims description 5
- 238000010298 pulverizing process Methods 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 238000007599 discharging Methods 0.000 claims description 4
- 239000004744 fabric Substances 0.000 claims description 4
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- 230000000384 rearing effect Effects 0.000 claims description 4
- 238000012216 screening Methods 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
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- 210000002421 cell wall Anatomy 0.000 description 3
- 238000005352 clarification Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- 101100313763 Arabidopsis thaliana TIM22-2 gene Proteins 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000003640 drug residue Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 208000013223 septicemia Diseases 0.000 description 2
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- 239000002904 solvent Substances 0.000 description 2
- 239000002594 sorbent Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 206010063409 Acarodermatitis Diseases 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
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- 206010016936 Folliculitis Diseases 0.000 description 1
- 206010061977 Genital infection female Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 201000008197 Laryngitis Diseases 0.000 description 1
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- 206010067268 Post procedural infection Diseases 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
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- 208000025865 Ulcer Diseases 0.000 description 1
- 206010000269 abscess Diseases 0.000 description 1
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical class [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229940000635 beta-alanine Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 1
- FLKYBGKDCCEQQM-WYUVZMMLSA-M cefazolin sodium Chemical compound [Na+].S1C(C)=NN=C1SCC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 FLKYBGKDCCEQQM-WYUVZMMLSA-M 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
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- 230000001684 chronic effect Effects 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 238000011026 diafiltration Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 206010025226 lymphangitis Diseases 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002468 redox effect Effects 0.000 description 1
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- 210000002345 respiratory system Anatomy 0.000 description 1
- 208000005687 scabies Diseases 0.000 description 1
- 230000035943 smell Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
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- 208000019206 urinary tract infection Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of refined ceftezole acid. The method comprises the following steps of: a, dissolving a crude product; b, decoloring, filtering and purifying; c, crystallizing and cultivating crystal; d, washing, detecting an HPLC (high performance liquid chromatography) value; and e, smashing and drying. According to the invention, the purity of ceftezole acid prepared by the method is high, the product is purified from 91.0% to 99.5%, and other quality indexes are higher than those of common ceftezole acid; and the method is simple in process flow and low in cost, and is suitable for large-scale popularization and application.
Description
Technical field
The invention belongs to resource and pharmaceutical chemistry technical field, be specifically related to a kind of preparation method of ceftezole acid.
Background technology
Ceftezole acid is used for synthetic FR-10123, and FR-10123 (ceftezole Sodium) is semi-synthetic cephalosporin analog antibiotic, is the substitute products of cefazolin cephazolin sodium; Molecular formula: C13H11N8NaO4S3 molecular weight: 462.5 chemical names: sodium (6R; 7R)-3-[(1,3,4-thiophene-azoles-2-yl)-thiomethyl]-8 oxos-7-[2-(1H)-for azoles base kharophen]-5-thia-1-azabicyclo [4; 2,0] suffering-2-carboxylate salt proterties: white, flaxen crystalline powder.Soluble in water, be insoluble in methyl alcohol, be dissolved in acetone hardly, ether, ethanol, chloroform or benzene.In cephalosporins medicine, it is the first-selected medicines of many in the world countries, also is that the expert uses one of maximum medicine.In antimicrobial spectrum, G+ bacterium and G-bacterium all there is the sterilizing power that extensively and by force has.In the G-bacterium, for intestinal bacteria, the anti-microbial effect of Bacillus proteus is especially powerful.It is fine in body fluid, tissue, to distribute after the administration, and it is excreted in the urine with the original shape medicine, and it is dense.Clinical effectiveness shows for urinary tract infections and septicemia good effect is arranged also.Renal toxicity is extremely low, also can use as one sees fit renal insufficiency patient person.Pharmacological action: through with the peptidoglycolipid that constitutes cell walls in pentapeptide combines, make the deactivation of Beta Alanine transpeptidase, thereby cause the termination of cell walls synthetic, the cell walls attenuation, break, by morphologic variation that causes bacterium and bacteriolysis.Clinical indication: 1. respiratory system infection (secondary infection of acute/chronic bronchitis, pneumonia, bronchiectasis, chronic respiratory tract disease etc.); 2. urinary system infection (nephropyelitis, ureteritis, urocystitis, urethritis etc.); 3. cholecystitis, cholangitis, peritonitis; 4. traumatic infection, septicemia, burn, scald; 5. the fester sexuality is dyed (folliculitis, paronychia, scabies, carbuncle, abscess, cellulitis, erysipelas, ulcer etc.); 6. deep pyogenic infection (lymphangitis, mazoitis etc.); 7. gynecological infection (trachelitis, endometritis, appendagitis, pelvic inflammatory disease, lochiopyra etc.); 8. Otorhinolaryngologic Department infects (otitis media, sinusitis paranasal sinusitis, pharyngitis, laryngitis, tonsillitis); 9. before the art, postoperative infection prevention.The technical process of existing preparation ceftezole acid is complicated, and production cost is high, and the purity of ceftezole acid is relatively poor.
Summary of the invention
The object of the invention is exactly relatively poor in order to solve the existing purity of existing ceftezole acid, and the technical problem that quality index is relatively poor proposes a kind of refining ceftezole acid preparation method; This method not only can prepare the ceftezole acid with higher degree, and its multinomial quality index all has raising in various degree; And this method technical process is simple, and cost is lower, is fit to large-scale promotion and application.
The present invention implements through following technical scheme:
A kind of refining ceftezole acid preparation method, this method may further comprise the steps:
A, dissolving crude product: in reaction kettle, add purity 91% acid of bullion ceftezole and deionized water, dripping alkali liquid in the reaction kettle, adjustment pH value is controlled pH=5.5-5.8, and holding temperature 10-12 ℃, and stirring;
B, decolouring, filtration, purifying: add the activated carbon decolorizing after-filtration, the resin column purifying of filtrating refilters the entering crystallization kettle;
C, crystallization, growing the grain: be cooled to 0-5 ℃, drip rare HC1 and carry out crystallization, adjustment pH value, control pH=1.5-2.0, crystallization time 2-4, the growing the grain of lowering the temperature, growing the grain temperature-1 is to-3 ℃, rearing crystal time 1-1.5 hour;
D, washing, detection HPLC value: above-mentioned brilliant liquid compound placed have the filter cloth whizzer and dry; Filter cake, sampling detects HPLC value, HPLC >=99.5% o'clock is treated the next procedure processing; Otherwise dry the back with the deionized water wash filter cake and detect the HPLC value, detect HPLC >=99.5% until sampling;
E, pulverizing, drying: will wash filter cake after drying and pulverize and be placed on vacuum drier and carry out vacuum-drying, holding temperature is no more than 40 ℃, vacuum tightness >=-0.090Mpa; 4-5 hour time of drying; Moisture is surveyed in sampling, if moisture＜3% stops dry discharging and gets finished product.
At the alkali lye described in the step a is the sodium hydrogencarbonate of concentration 8-10%.
At the gac described in the step b is aciculiform gac 767.
Resin column purifying excessively described in the step b is the alumina column purifying.
Detect HPLC >=99.5% o'clock in the filter cake described in steps d sampling, use the organic solvent washing filter cake again, dry the back and get into next procedure and handle, described organic solvent is a kind of in ethanol, methyl alcohol, the acetone.
Dry again behind the filter cake crushing screening described in the step e.
The present invention has adopted two kinds of methods in the physics method separating impurity, promptly 1. utilizes absorption principle to come separating impurity, adopts sorbent material that impurity in the product and color are adsorbed; 2. utilize the recrystallization method of liquid-solid equilibrium relationship in making with extra care.Utilize discoloring agent (sorbent material) that wherein impurity and color are adsorbed totally, through filtering clear filtrate.Described discoloring agent is a gac; Gac has flourishing pore structure and special surface property to be made it have extremely strong absorption property, redox property, electrical property usually to be applied in the water treatment; The present invention utilizes these performances of gac not only impurity such as water-fast arsenic salt, molysite, heavy metal to be had stronger adsorption function just; And, has removal effect preferably like materials such as colourity, odor smells to the organism that biological process and other method are difficult to remove; What dissolving alkali adopted is edible refining sodium bicarbonate, and product is not constituted secondary pollution and drug residue; The purified water that solvent adopts has been practiced thrift production cost and has been alleviated environmental protection treatment pressure; Conventional suction filtration has been abandoned in filtration, but adopts filter board and PP secondary filter cascade filtration, both filtration velocity has been carried soon 6 hours, has guaranteed filtering effect simultaneously again; Adopt reproducible aluminum oxide resin purification, both improved product gas purity, improved raw-material utilization ratio again, abandoned the HP20 macroporous resin adsorption selectivity of conventional employing and the shortcoming of reproducibility difference.
The present invention has the following advantages:
1, utilize the ceftezole acid purity of preparing method's preparation of the present invention higher, product purity is purified to 99.5% by 91.0%; Other quality index is all high than common ceftezole acid; Improved its value capable of using in pharmaceutical industries greatly.
What 2, dissolving alkali adopted is edible refining sodium bicarbonate, and product is not constituted secondary pollution and drug residue.
3, the purified water of solvent employing of the present invention has been practiced thrift production cost and has been alleviated environmental protection treatment pressure.
4, the present invention filters and has abandoned conventional suction filtration, but adopts filter board and PP secondary filter cascade filtration, both filtration velocity has been carried soon 6 hours, has guaranteed filtering effect simultaneously again.
5, the present invention adopts reproducible aluminum oxide resin purification, has both improved product gas purity, has improved raw-material utilization ratio again, has abandoned the HP20 macroporous resin adsorption selectivity of conventional employing and the shortcoming of reproducibility difference.
6, technological process of the present invention is simple, and preparation cost is lower, and required equipment is less; Be fit to large-scale promotion and application.
Embodiment:
Pass through embodiment below, and combine accompanying drawing, do further bright specifically technical scheme of the present invention.
Embodiment 1: a kind of refining ceftezole acid preparation method, and this method may further comprise the steps:
A, dissolving crude product: in the 500L enamel reaction still; Add purity 91% bullion ceftezole acid 90kg and 400L deionized water, in reaction kettle, drip the sodium hydrogencarbonate that concentration is 8-10% first quick and back slow, the sodium hydrogencarbonate add-on is a principle with the dissolving clarification; Adjustment pH value; Control pH=5.5-5.8, holding temperature 10-12 ℃, and stirred 30 minutes;
B, decolouring, filtration, purifying: add 3kg aciculiform gac 767 and stir decolouring 30mi n after-filtration, filtrating peroxo-aluminium column purification filters through plate filter, 0.20um secondary filter and gets into 2000L enamel crystallization kettle;
C, crystallization, growing the grain: be cooled to 0-5 ℃, slowly dripping concentration toward the enamel crystallization kettle is that rare HCl of 6% carries out crystallization, and adjustment pH value is controlled pH=1.5-2.0, crystallization 3 hours, and the growing the grain of lowering the temperature again, growing the grain temperature-1 is to-3 ℃, rearing crystal time 1 hour;
D, washing, detection HPLC value: above-mentioned brilliant liquid compound placed have the filter cloth whizzer and dry; Get filter cake; Sampling detects HPLC value, when HPLC >=99.5%, use washing with alcohol filter cake, drying entering next procedure then; Detect HPLC value again after when HPLC＜99.5%, drying with the deionized water wash filter cake, until sampling detection HPLC >=99.5%:
E, pulverizing, drying: will wash the about 80Kg of filter cake after drying and pulverize 40 mesh sieves and be placed on vacuum drier and carry out vacuum-drying; Holding temperature is no more than 40 ℃; Vacuum tightness >=-0.090Mpa, 4-5 hour time of drying, moisture is surveyed in sampling; If moisture＜3% stops dry discharging and gets the about 50kg of finished product.
Embodiment 2: a kind of refining ceftezole acid preparation method, and this method may further comprise the steps:
A, dissolving crude product: will prepare in advance: 10kgNaHCO3 and 100kg deionized water vacuum suction sodium hydrogencarbonate header tank are subsequent use, in the 500L enamel reaction still, add the 400L deionized water; Holding temperature 10-12 ℃, add purity 91% bullion ceftezole acid 90kg, catalyst A: 0.25Kg; Catalyst B: 0.25Kg stirs, and drips the NaHCO3 solution for preparing in advance first quick and back slow; Control pH=5.5-5.8, the NaHCO3 solution amount of adding is a principle with the dissolving clarification;
B, decolouring, filtration, purifying: stir 30 minutes to clarification; Add 3kg aciculiform gac 767, stir 30 minutes after-filtration of decolouring, with 50kg deionized water wash dissolution kettle wall charcoal layer; Merge in diafiltration liquid to the 1000L header tank after the alumina column of activation treatment in advance; Press dry with 600L damping fluid or purified water wash-out alumina column, merge, get into 2000L enamel crystallization kettle through plate filter, 0.20um secondary filter again by in destainer and elutriant to the 1000L collection still; Control pH=5.5～5.8, temperature 10-12 ℃;
C, crystallization, growing the grain: be cooled to 0-5 ℃, slowly dripping concentration toward the enamel crystallization kettle is that rare HCl of 7% carries out crystallization, and adjustment pH value is controlled pH=1.5-2.0, crystallization 3 hours, and the growing the grain of lowering the temperature again, growing the grain temperature-1 is to-3 ℃, rearing crystal time 1 hour;
D, washing, detection HPLC value: under the normal temperature above-mentioned brilliant liquid compound placed to have the filter cloth whizzer and dry, in time get centrifuge mother liquor, whether damaged to confirm the filter bag; Dry filter cake 15～30 minutes, mother liquor goes mother liquor holding tank pending, with drying 15 minutes behind the 200L deionized water wash filter cake; Get filter cake appearance and detect the HPLC value; When HPLC >=99.5%, dry 60 minutes again, with drying 30～60 minutes behind the 100L washing with alcohol filter cake, the ethanol washing lotion changes ethanol over to and reclaims the post then;
E, pulverizing, drying: the material in the whizzer is taken out, through pulverizing 40 mesh sieves, the about 80Kg of article that must wet, the vacuum article that will wet suck double cone dryer; Material maintains the progressively intensification after 1 hour of 20-25 ℃ of vacuum cold-draw in the dry awl, and holding temperature is no more than 40 ℃, vacuum tightness>=-0.090Mpa; Dry 4～5 hours, use the nitrogen vacuum pumping then, moisture is surveyed in sampling; If moisture＜3 stop drying, utilize the cold water circulation; Temperature of charge drops to normal temperature discharging barrelling in will boring, the about 50kg of finished product, finished product requirement HPLC>=99% is moisture≤3%.
Ceftezole acid quality of production standard:
| Test item | The internal control quality standard |
| Proterties | White is to pale yellow powder |
| Differentiate | Trial-product is answered consistent with the main peak RT of reference substance solution |
| Moisture content | ≤3.0％ |
| Residue on ignition | ≤0.2％ |
| Acidity | 2.0-4.5 |
| Uptake factor | 270-310 |
| Solution colour | <=Y1 or YG1 |
| Specific optical rotation | -5°--11° |
| Chromatographic purity | ≥99.5％ |
| Content (by anhydride) | ≥99.5％ |
Embodiment is just for the ease of understanding technical scheme of the present invention; Do not constitute restriction to protection domain of the present invention; Every interior any simple modification, equivalent variations and modification of perhaps according to technical spirit of the present invention above scheme being done that does not break away from technical scheme of the present invention all still belongs within the protection domain of the present invention.
Claims (7)
1. refining ceftezole acid preparation method, this method may further comprise the steps:
A, dissolving crude product: in reaction kettle, add purity 91% acid of bullion ceftezole and deionized water, dripping alkali liquid in the reaction kettle, adjustment pH value is controlled pH=5.5-5.8, and holding temperature 10-12 ℃, and stirring;
B, decolouring, filtration, purifying: add the activated carbon decolorizing after-filtration, the resin column purifying of filtrating refilters the entering crystallization kettle;
C, crystallization, growing the grain: be cooled to 0-5 ℃, drip rare HCl and carry out crystallization, adjustment pH value, control pH=1.5-2.0, crystallization time 2-4, the growing the grain of lowering the temperature, growing the grain temperature-1 is to-3 ℃, rearing crystal time 1-1.5 hour;
D, washing, detection HPLC value: above-mentioned brilliant liquid compound placed have the filter cloth whizzer and dry; Filter cake, sampling detects HPLC value, HPLC >=99.5% o'clock is treated the next procedure processing; Otherwise dry the back with the deionized water wash filter cake and detect the HPLC value, detect HPLC >=99.5% until sampling;
E, pulverizing, drying: will wash filter cake after drying and pulverize and be placed on vacuum drier and carry out vacuum-drying, holding temperature is no more than 40 ℃, vacuum tightness >=-0.090Mpa; 4-5 hour time of drying; Moisture is surveyed in sampling, if moisture＜3% stops dry discharging and gets finished product.
2. refining ceftezole acid preparation method according to claim 1, it is characterized in that: at the alkali lye described in the step a is the sodium hydrogencarbonate of concentration 8-10%.
3. refining ceftezole acid preparation method according to claim 1, it is characterized in that: at the gac described in the step b is aciculiform gac 767.
4. refining ceftezole acid preparation method according to claim 1, it is characterized in that: the resin column purifying excessively described in the step b is the alumina column purifying.
5. according to claim 1,2,3 or 4 described refining ceftezole acid preparing methods; It is characterized in that: detect HPLC >=99.5% o'clock in the filter cake described in steps d sampling; Use the organic solvent washing filter cake again; Dry the back and get into next procedure and handle, described organic solvent is a kind of in ethanol, methyl alcohol, the acetone.
6. according to claim 1,2,3 or 4 described refining ceftezole acid preparing methods, it is characterized in that: dry again behind the filter cake crushing screening described in the step e.
7. refining ceftezole acid preparation method according to claim 5 is characterized in that: dry again behind the filter cake crushing screening described in the step e.
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| CN103558169A (en) * | 2013-10-31 | 2014-02-05 | 天津德凯化工股份有限公司 | Method for detecting content of anthraquinone blue base |
| CN104610282A (en) * | 2015-02-14 | 2015-05-13 | 石药集团中诺药业（石家庄）有限公司 | Method for purifying cefazolin acid |
| CN108948048A (en) * | 2018-07-26 | 2018-12-07 | 华北制药河北华民药业有限责任公司 | A kind of refining methd of cefathiamidine |
| CN109535181A (en) * | 2018-11-21 | 2019-03-29 | 山东罗欣药业集团股份有限公司 | A kind of ceftezole acylating acid reaction process |
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