CN102219795B - Method for preparing ceftezole sodium - Google Patents
Method for preparing ceftezole sodium Download PDFInfo
- Publication number
- CN102219795B CN102219795B CN201110214204.1A CN201110214204A CN102219795B CN 102219795 B CN102219795 B CN 102219795B CN 201110214204 A CN201110214204 A CN 201110214204A CN 102219795 B CN102219795 B CN 102219795B
- Authority
- CN
- China
- Prior art keywords
- minutes
- add
- reactor
- acid
- ceftezole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 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 28
- 229960004366 ceftezole Drugs 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 title claims abstract description 16
- JUNAPQMUUHSYOV-UHFFFAOYSA-N 2-(2h-tetrazol-5-yl)acetic acid Chemical compound OC(=O)CC=1N=NNN=1 JUNAPQMUUHSYOV-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000008064 anhydrides Chemical class 0.000 claims abstract description 8
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 claims abstract description 7
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims abstract description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 239000011734 sodium Substances 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 20
- 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 claims description 17
- 229910052708 sodium Inorganic materials 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 16
- 230000015572 biosynthetic process Effects 0.000 claims description 16
- 238000003786 synthesis reaction Methods 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 150000008065 acid anhydrides Chemical class 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000001632 sodium acetate Substances 0.000 claims description 6
- 235000017281 sodium acetate Nutrition 0.000 claims description 6
- 150000004867 thiadiazoles Chemical class 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 4
- MEMUCXUKCBNISQ-UHFFFAOYSA-N acetonitrile;trifluoroborane Chemical compound CC#N.FB(F)F MEMUCXUKCBNISQ-UHFFFAOYSA-N 0.000 claims description 4
- 238000013019 agitation Methods 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000013078 crystal Substances 0.000 claims description 4
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 4
- 230000003068 static effect Effects 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 2
- 239000008367 deionised water Substances 0.000 claims description 2
- 229910021641 deionized water Inorganic materials 0.000 claims description 2
- 229960004756 ethanol Drugs 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract description 2
- 159000000000 sodium salts Chemical class 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract 4
- -1 1,3,4-thiadiazole-2-yl Chemical group 0.000 abstract 2
- HSHGZXNAXBPPDL-IOJJLOCKSA-N (6r)-3-(acetyloxymethyl)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C(N)[C@@H]12 HSHGZXNAXBPPDL-IOJJLOCKSA-N 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- 239000011593 sulfur Substances 0.000 abstract 1
- 229910052717 sulfur Inorganic materials 0.000 abstract 1
- 229960004249 sodium acetate Drugs 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 2
- OBZPELDGSNYFTD-UHFFFAOYSA-N NC(C1SCC(CSc2nnc[s]2)=C(C(O)=O)N11)C1=O Chemical compound NC(C1SCC(CSc2nnc[s]2)=C(C(O)=O)N11)C1=O OBZPELDGSNYFTD-UHFFFAOYSA-N 0.000 description 2
- 108010087702 Penicillinase Proteins 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 229950009506 penicillinase Drugs 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 241000193738 Bacillus anthracis Species 0.000 description 1
- HSHGZXNAXBPPDL-UHFFFAOYSA-N CC(OCC(CSC1C2N)=C(C(O)=O)N1C2=O)=O Chemical compound CC(OCC(CSC1C2N)=C(C(O)=O)N1C2=O)=O HSHGZXNAXBPPDL-UHFFFAOYSA-N 0.000 description 1
- FPVUWZFFEGYCGB-UHFFFAOYSA-N Cc1nnc(S)[s]1 Chemical compound Cc1nnc(S)[s]1 FPVUWZFFEGYCGB-UHFFFAOYSA-N 0.000 description 1
- 241001478240 Coccus Species 0.000 description 1
- 241000186216 Corynebacterium Species 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- DZMVCVMFETWNIU-UHFFFAOYSA-N OC(C1=C(CSc2nnc[s]2)CSC(C2NC(C[n]3nnnc3)=O)N1C2=O)=O Chemical compound OC(C1=C(CSc2nnc[s]2)CSC(C2NC(C[n]3nnnc3)=O)N1C2=O)=O DZMVCVMFETWNIU-UHFFFAOYSA-N 0.000 description 1
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000191963 Staphylococcus epidermidis Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 241001312524 Streptococcus viridans Species 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 206010013023 diphtheria Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- IXSZQYVWNJNRAL-UHFFFAOYSA-N etoxazole Chemical compound CCOC1=CC(C(C)(C)C)=CC=C1C1N=C(C=2C(=CC=CC=2F)F)OC1 IXSZQYVWNJNRAL-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
Abstract
The invention relates to a method for preparing ceftezole sodium, which comprises the following steps of: 1, synthesizing (6R,7R)-3-[[(1,3,4-thiadiazole-2-yl)sulfur]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]octa-2-alkene-2-carboxylic acid (TZT), namely reacting demethyl thiadiazole with 7-amino-3-acetoxy methyl-3-cephem-4-carboxylic acid (7-ACA) to obtain the TZT; 2, synthesizing anhydride, namely reacting tetrazole acetic acid with pivaloyl chloride to obtain the anhydride; 3, synthesizing ceftezole, namely reacting the TZT with the anhydride to obtain the ceftezole; and 4, synthesizing the ceftezole sodium, namely reacting the ceftezole with sodium salt to obtain the ceftezole sodium.
Description
Technical field
The present invention relates to a kind of preparation method of medical compounds, particularly a kind of new preparation method of antibacterials cefobutazine sodium.
Background technology
Cefobutazine sodium, English name: Ceftezole Sodium
Chemical name: (6R, 7R)-3-(((1,3,4-thiazol-2-yl) sulphur) methyl)-7-((1H-TETRAZOLE-1-base) kharophen)-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid sodium salt.Structural formula is:
Cefobutazine sodium is the cynnematin analog derivative with anti-microbial activity, and mechanism of action is that the synthesis of anti-bacteria cell walls plays its anti-microbial activity.To gram positive organism, especially coccus, comprise and produce penicillinase and do not produce the streptococcus aureus of penicillinase, micrococcus scarlatinae, streptococcus pneumoniae, B group Hemolytic streptococcus, Streptococcus viridans, staphylococcus epidermidis, and diphtheria corynebacterium, anthrax bacillus are all more responsive.Be medium sensitivity to some gram-negative bacteria, as intestinal bacteria, Klebsiella, Salmonella, Shigella, Proteus mirabilis etc.
Result of study shows: " ceftezole is oral can not by gastrointestinal absorption, intramuscularly 1g, Tmax >=25 minute, and Cmax is 43ug/ml, t1/2 is 1.5 hours.Intravenous injection 1g, after 15 minutes, Cmax is about 74ug/ml, and t1/2 is 0.41 hour.This product mainly at liver metabolism, dosage more than 80% by homaluria.”。
The existing method preparing cefobutazine sodium is a lot, and as Chinese patent: CN101735250A and CN101544659A, above method complex process, operational difficulty, yield is not high, contaminate environment.
The present invention improves prior art for this reason, finds a kind of preparation method of new cefobutazine sodium.
Summary of the invention:
The invention provides a kind of preparation method of new cefobutazine sodium, the method is through following steps:
Step 1, the synthesis of TZT
First thiadiazoles and 7-ACA is gone to be obtained by reacting TZT,
Step 2, the synthesis of acid anhydrides
acid anhydrides
Tetrazoleacetic acid and pivaloyl chloride are obtained by reacting acid anhydrides,
Step 3, the synthesis of ceftezole
TZT and anhydride reaction obtain ceftezole,
Step 4, the synthesis of cefobutazine sodium
Ceftezole and sodium salt are obtained by reacting cefobutazine sodium,
Technological process is as follows:
1, the synthesis of TZT
2, acid anhydrides preparation,
3, ceftezole acid synthesis
4, cefobutazine sodium synthesis
Preferably, method of the present invention is as follows:
Step 1, the synthesis of ceftezode three-position intermediate TZT
In reactor, add acetonitrile, boron trifluoride acetonitrile complex compound, add first thiadiazoles under agitation condition, 7-ACA, in 40 DEG C ± 5 DEG C reactions 60 minutes, water is joined in condensated liquid, stir 60 minutes, drip Na
2cO
3solution is to pH=3.5, and suction filtration, washs dry II.
Step 2, prepared by acid anhydrides
Methylene dichloride is added in reactor, add tetrazoleacetic acid, by cooled with liquid nitrogen to-10 DEG C, in 10 minutes, triethylamine is dripped under whipped state, be stirred to tetrazoleacetic acid all to dissolve, cool to-35 ± 5 DEG C, add pyridine and pivaloyl chloride, at-20 ± 2 DEG C of temperature react 50 minutes, be then cooled to-30 DEG C for subsequent use.
Step 3, ceftezole acid synthesis
In anhydride reaction still, add methylene dichloride, under whipped state, add II, then dripped triethylamine at 20-30 minute ,-20 ± 2 DEG C of reactions 90 minutes.Under stirring, water is added in reactor, keep temperature 25 ± 2 DEG C in tank, stir 15 minutes, static 15 minutes.Layering, aqueous phase adds activated carbon, stirs decolouring 30 minutes, filters and enters in reactor, adjust pH=2.0 ± 0.2, be cooled to 10 ± 2 DEG C with hydrochloric acid, by water and washing with alcohol, is separated to obtain ceftezole acid.
Step 4, cefobutazine sodium is synthesized
In reactor, add water, ceftezole is added in reactor, maintain the temperature at 25 ± 2 DEG C, drip sodium acetate soln, control ph, between 5.9 ± 0.2, makes solution clarify, and adds sodium bisulfite and EDTA, stir 30 minutes, drip dehydrated alcohol, temperature remains on 10 ± 2 DEG C, and time for adding controls at 150 minutes, filtration drying, obtains white crystal.
Compared to the prior art, the invention has the advantages that:
1, the present invention adopts " one kettle way " technique in the building-up process of ceftezole acid, can from the tetrazoleacetic acid be relatively simple and easy to for ceftezole acid, without the separation of intermediate, the baroque ceftezole acid of direct acquisition, technique has the advantages that yield is high, purity is high, cost is low.
2, use acid anhydrides technique, reaction conditions is gentle, and the cycle is short, and purity is high.
3, use sodium-acetate salify, reaction conditions is gentle, and total recovery is high, purity is high.
Cefobutazine sodium yield method of calculation=cefobutazine sodium/7-ACA.
4, whole process yield is high, and total recovery reaches 114%.
5, cost is low, use cheap equipment and raw material as: sodium-acetate and sodium carbonate are raw material.
Embodiment:
Further illustrate the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1
Step 1, the synthesis of ceftezode three-position intermediate TZT
In reactor, add acetonitrile 600ml, boron trifluoride acetonitrile complex compound 680g, add first thiadiazoles 80g, 7-ACA170g under agitation condition, in 40 DEG C ± 5 DEG C reactions 60 minutes, survey 7-ACA is residual was less than 1.0%.1000ml water is joined in condensated liquid, stirs 60 minutes, drip Na
2cO
3solution is to pH=3.5, and suction filtration, wash dry II, purity is greater than 98.5%, yield 104%.
Step 2, prepared by acid anhydrides
Methylene dichloride 500ml is added in reactor, add tetrazoleacetic acid 78.5g, by cooled with liquid nitrogen to-10 DEG C, in 10 minutes, triethylamine 120ml is dripped under whipped state, be stirred to tetrazoleacetic acid all to dissolve, cool to-35 ± 5 DEG C, add pyridine 5.4ml and pivaloyl chloride 71.5ml, at-20 ± 2 DEG C of temperature react 50 minutes, be then cooled to-30 DEG C for subsequent use.
Step 3, ceftezole acid synthesis
In anhydride reaction still, add methylene dichloride 2000ml, under whipped state, add II 174g, then dripped triethylamine 109ml at 20-30 minute ,-20 ± 2 DEG C of reactions 90 minutes.Under stirring, 1500ml water is added in reactor, keep temperature 25 ± 2 DEG C in tank, stir 15 minutes, static 15 minutes.Layering, aqueous phase adds activated carbon 20g and stirs decolouring 30 minutes, filtration enters in reactor, pH=2.0 ± 0.2 is dropped to the salt slow acid of 3mol/l, be cooled to 10 ± 2 DEG C, growing the grain 1 hour, wash with deionized water 2000ml and ethanol 400ml respectively, be separated to obtain ceftezole acid wet product 330g, wet product purity is greater than 98.5%.
Step 4, cefobutazine sodium is synthesized
In reactor, add water 500ml, ceftezole wet product 330g is added in reactor, maintain the temperature at 25 ± 2 DEG C, drip the sodium acetate soln of 4mol/l, control ph, between 5.9 ± 0.2, makes solution clarify, add sodium bisulfite 4.5g and EDTA4g, stir 30 minutes, drip dehydrated alcohol 5000ml, temperature remains on 10 ± 2 DEG C, time for adding controls at 150 minutes, growing the grain 60 minutes, filtration drying, obtain white crystal, purity more than 99%.Yield 109%.
Claims (2)
1. a preparation method for cefobutazine sodium, the method is through following steps:
Step 1, the synthesis of ceftezode three-position intermediate TZT
In reactor, add acetonitrile, boron trifluoride acetonitrile complex compound, add first thiadiazoles under agitation condition, 7-ACA, in 40 DEG C ± 5 DEG C reactions 60 minutes, water is joined in condensated liquid, stir 60 minutes, drip Na
2cO
3solution is to pH=3.5, and suction filtration, washs dry II,
Step 2, prepared by acid anhydrides
Methylene dichloride is added in reactor, add tetrazoleacetic acid, by cooled with liquid nitrogen to-10 DEG C, in 10 minutes, triethylamine is dripped under whipped state, be stirred to tetrazoleacetic acid all to dissolve, cool to-35 ± 5 DEG C, add pyridine and pivaloyl chloride, at-20 ± 2 DEG C of temperature react 50 minutes, be then cooled to-30 DEG C for subsequent use;
Step 3, ceftezole acid synthesis
In anhydride reaction still, add methylene dichloride, under whipped state, add II, then drip triethylamine at 20-30 minute,-20 ± 2 DEG C of reactions 90 minutes, under stirring, water is added in reactor, keep temperature 25 ± 2 DEG C in tank, stir 15 minutes, static 15 minutes, layering, aqueous phase adds activated carbon, stirs decolouring 30 minutes, filters and enters in reactor, pH=2.0 ± 0.2 is adjusted with hydrochloric acid, be cooled to 10 ± 2 DEG C, by water and washing with alcohol, be separated to obtain ceftezole acid;
Step 4, cefobutazine sodium is synthesized
In reactor, add water, ceftezole is added in reactor, maintain the temperature at 25 ± 2 DEG C, drip sodium acetate soln, control ph, between 5.9 ± 0.2, makes solution clarify, and adds sodium bisulfite and EDTA, stir 30 minutes, drip dehydrated alcohol, temperature remains on 10 ± 2 DEG C, and time for adding controls at 150 minutes, filtration drying, obtains white crystal;
Wherein, the chemical formula of described compound ii is as follows:
。
2. preparation method according to claim 1, is characterized in that, the method is through following steps:
Step 1, the synthesis of ceftezode three-position intermediate TZT
In reactor, add acetonitrile 600ml, boron trifluoride acetonitrile complex compound 680g, under agitation condition, add first thiadiazoles 80g, 7-ACA170g, in 40 DEG C ± 5 DEG C reactions 60 minutes, survey 7-ACA is residual was less than 1.0%, 1000ml water is joined in condensated liquid, stirs 60 minutes, drip Na
2cO
3solution to pH=3.5, suction filtration, wash dry II, purity is greater than 98.5%, yield 104%;
Step 2, prepared by acid anhydrides
Methylene dichloride 500ml is added in reactor, add tetrazoleacetic acid 78.5g, by cooled with liquid nitrogen to-10 DEG C, in 10 minutes, triethylamine 120ml is dripped under whipped state, be stirred to tetrazoleacetic acid all to dissolve, cool to-35 ± 5 DEG C, add pyridine 5.4ml and pivaloyl chloride 71.5ml, at-20 ± 2 DEG C of temperature react 50 minutes, be then cooled to-30 DEG C for subsequent use;
Step 3, ceftezole acid synthesis
Methylene dichloride 2000ml is added in anhydride reaction still, II 174g is added under whipped state, then triethylamine 109ml was dripped at 20-30 minute,-20 ± 2 DEG C of reactions 90 minutes, under stirring, 1500ml water is added in reactor, keep temperature 25 ± 2 DEG C in tank, stir 15 minutes, static 15 minutes, layering, aqueous phase adds activated carbon 20g and stirs decolouring 30 minutes, filtration enters in reactor, pH=2.0 ± 0.2 is dropped to the salt slow acid of 3mol/l, be cooled to 10 ± 2 DEG C, growing the grain 1 hour, wash with deionized water 2000ml and ethanol 400ml respectively, be separated to obtain ceftezole acid wet product 330g, wet product purity is greater than 98.5%,
Step 4, cefobutazine sodium is synthesized
In reactor, add water 500ml, ceftezole wet product 330g is added in reactor, maintain the temperature at 25 ± 2 DEG C, drip the sodium acetate soln of 4mol/l, control ph, between 5.9 ± 0.2, makes solution clarify, add sodium bisulfite 4.5g and EDTA4g, stir 30 minutes, drip dehydrated alcohol 5000ml, temperature remains on 10 ± 2 DEG C, and time for adding controls at 150 minutes, growing the grain 60 minutes, filtration drying, obtain white crystal, purity more than 99%, yield 109%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110214204.1A CN102219795B (en) | 2011-07-28 | 2011-07-28 | Method for preparing ceftezole sodium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110214204.1A CN102219795B (en) | 2011-07-28 | 2011-07-28 | Method for preparing ceftezole sodium |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102219795A CN102219795A (en) | 2011-10-19 |
| CN102219795B true CN102219795B (en) | 2014-12-24 |
Family
ID=44776523
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110214204.1A Active CN102219795B (en) | 2011-07-28 | 2011-07-28 | Method for preparing ceftezole sodium |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102219795B (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102432628A (en) * | 2011-11-15 | 2012-05-02 | 华北制药奥奇德药业有限公司 | Method for preparing cefonicid intermediate |
| CN102617606B (en) * | 2012-03-31 | 2014-04-16 | 哈药集团制药总厂 | Method for preparing ceftezole sodium compound |
| CN102977122A (en) * | 2012-10-08 | 2013-03-20 | 江苏德峰药业有限公司 | Ceftezole acid preparation method |
| CN104804018B (en) * | 2015-05-08 | 2017-07-21 | 沈阳三九药业有限公司 | A kind of preparation method of I types ceftezole sodium crystal |
| CN104910190B (en) * | 2015-06-17 | 2017-08-25 | 华北制药河北华民药业有限责任公司 | A kind of preparation method of Cefotiam Dihydrochloride |
| CN105131018B (en) * | 2015-09-23 | 2017-12-26 | 浙江华方药业股份有限公司 | A kind of preparation method of ceftezole acid |
| CN109160922A (en) * | 2017-07-20 | 2019-01-08 | 海南灵康制药有限公司 | A kind of 1/2 water Cefobutazine sodium compound |
| CN108129493A (en) * | 2018-02-07 | 2018-06-08 | 宁夏天心医药有限责任公司 | A kind of Cefobutazine sodium compound and its preparation |
| CN109336907B (en) * | 2018-11-21 | 2020-05-26 | 山东罗欣药业集团股份有限公司 | Preparation method of ceftezole sodium |
| CN109824697A (en) * | 2019-02-28 | 2019-05-31 | 广西科伦制药有限公司 | A kind of preparation method of ceftezole acid |
| CN110759932A (en) * | 2019-10-30 | 2020-02-07 | 广州牌牌生物科技有限公司 | Preparation method of cefazolin sodium impurity C |
| CN111440197A (en) * | 2020-04-09 | 2020-07-24 | 辽宁美亚制药有限公司 | Preparation method of ceftriaxone sodium |
| CN112174984A (en) * | 2020-10-27 | 2021-01-05 | 湖北凌晟药业有限公司 | Preparation method of ceftezole acid and sodium salt thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1803803A (en) * | 2006-01-10 | 2006-07-19 | 哈药集团制药总厂 | Process for preparing ceftezode three-position intermediate |
| CN101544659A (en) * | 2008-03-25 | 2009-09-30 | 北京申科联华科技有限公司 | Preparation method of ceftezole and midbody thereof |
| CN101544661B (en) * | 2009-05-12 | 2010-06-30 | 海南数尔药物研究有限公司 | Cefobutazine sodium compound and pharmaceutical composition made therefrom |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS557A (en) * | 1978-03-20 | 1980-01-05 | Banyu Pharmaceut Co Ltd | Production of ceftezole |
-
2011
- 2011-07-28 CN CN201110214204.1A patent/CN102219795B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1803803A (en) * | 2006-01-10 | 2006-07-19 | 哈药集团制药总厂 | Process for preparing ceftezode three-position intermediate |
| CN101544659A (en) * | 2008-03-25 | 2009-09-30 | 北京申科联华科技有限公司 | Preparation method of ceftezole and midbody thereof |
| CN101544661B (en) * | 2009-05-12 | 2010-06-30 | 海南数尔药物研究有限公司 | Cefobutazine sodium compound and pharmaceutical composition made therefrom |
Non-Patent Citations (1)
| Title |
|---|
| 头孢替唑钠合成路线图解;余江河等;《南阳师范学院学报》;20060930;第5卷(第9期);第52-54页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102219795A (en) | 2011-10-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102219795B (en) | Method for preparing ceftezole sodium | |
| CN102617606B (en) | Method for preparing ceftezole sodium compound | |
| CN100554271C (en) | The synthetic method of antibiotics cefamandole nafate | |
| CN102010426B (en) | Method for preparing ceftizoxime sodium | |
| CN101812076B (en) | Cefuroxime sodium and preparation method thereof | |
| CN102030762B (en) | Preparation method of cefprozil | |
| CN105541870A (en) | Preparation method of cefazolin sodium with previous research quality and medicine preparation of cefazolin sodium | |
| CN101229129A (en) | Ceftezole sodium powder injection and synthesizing method thereof | |
| CN105017286A (en) | Preparation method for cephalosporin anti-infective drug | |
| CN101921284A (en) | Preparation method of cefathiamidine | |
| CN101220040A (en) | Preparation of cefixime cephalosporin and fine purification method | |
| CN105669700A (en) | Cefuroxime sodium new crystal type compound and preparation adopting particle process crystal product molecular assembly and form optimizing technology | |
| CN102153566B (en) | Method for preparing cefdinir | |
| CN102516261A (en) | Preparation method of cefdinir | |
| CN102977122A (en) | Ceftezole acid preparation method | |
| CN101906109B (en) | Method for preparing cefuroxime sodium | |
| CN103319503A (en) | Preparation method of cefdinir | |
| CN107266473A (en) | A kind of synthetic method of cefotaxime | |
| CN104130272A (en) | Improvement method of cefalexin synthesis process | |
| CN108084213B (en) | Preparation method of cefazedone sodium compound | |
| CN101550146A (en) | Cefetamet pivoxil hydrochloride compound and preparation method thereof | |
| CN109232610B (en) | Refining method of cefonicid dibenzylethylenediamine salt | |
| CN108033971B (en) | Method for synthesizing cefcapene pivoxil hydrochloride | |
| CN106565748A (en) | Preparation method for cefuroxime sodium and preparation thereof | |
| CN108727411A (en) | A kind of preparation method of cefotiam hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent for invention or patent application | ||
| CB03 | Change of inventor or designer information |
Inventor after: Wang Xijun Inventor after: Wang Wei Inventor after: Yang Xinchun Inventor after: Tao Shuqing Inventor before: Wu Zhijun Inventor before: Wang Wei Inventor before: Yang Xinchun Inventor before: Tao Shuqing |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: INVENTOR; FROM: WU ZHIJUN WANG WEI YANG XINCHUN TAO SHUQING TO: WANG XIJUN WANG WEI YANG XINCHUN TAO SHUQING |
|
| C53 | Correction of patent for invention or patent application | ||
| CB03 | Change of inventor or designer information |
Inventor after: Xie Yingxin Inventor after: Wang Xijun Inventor after: Wang Wei Inventor before: Wang Xijun Inventor before: Wang Wei Inventor before: Yang Xinchun Inventor before: Tao Shuqing |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: INVENTOR; FROM: WANG XIJUN WANG WEI YANG XINCHUN TAO SHUQING TO: XIE YINGXIN WANG XIJUN WANG WEI |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20200616 Address after: No.7 Qunli Avenue, Daoli District, Harbin City, Heilongjiang Province Co-patentee after: Harbin Pharmaceutical Group Co.,Ltd. General Pharmaceutical Factory Patentee after: HARBIN PHARMACEUTICAL GROUP HOLDING Co.,Ltd. Address before: 150046, No. 109, Xuefu Road, Harbin, Heilongjiang Patentee before: Harbin Pharmaceutical Group Co.,Ltd. General Pharmaceutical Factory |
|
| TR01 | Transfer of patent right |