CN102010428A - Cefathiamidine compound and new preparation method thereof - Google Patents
Cefathiamidine compound and new preparation method thereof Download PDFInfo
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- 229950005040 cefathiamidine Drugs 0.000 title claims abstract description 44
- -1 Cefathiamidine compound Chemical class 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- JYXACOFERDBGGQ-RHSMWYFYSA-N cefathiamidine Chemical compound S1CC(COC(C)=O)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CSC(NC(C)C)=NC(C)C)[C@H]21 JYXACOFERDBGGQ-RHSMWYFYSA-N 0.000 claims description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 239000000706 filtrate Substances 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- 238000000746 purification Methods 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 11
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 10
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 10
- 229960004217 benzyl alcohol Drugs 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- 238000001291 vacuum drying Methods 0.000 claims description 10
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 9
- 229960000583 acetic acid Drugs 0.000 claims description 9
- 239000012043 crude product Substances 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 239000012362 glacial acetic acid Substances 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- 238000004821 distillation Methods 0.000 claims description 8
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 7
- 238000005261 decarburization Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- RUTXIHLAWFEWGM-UHFFFAOYSA-H iron(3+) sulfate Chemical group [Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O RUTXIHLAWFEWGM-UHFFFAOYSA-H 0.000 claims description 7
- 229910000360 iron(III) sulfate Inorganic materials 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 238000010521 absorption reaction Methods 0.000 claims description 3
- 239000003610 charcoal Substances 0.000 claims description 3
- 239000012535 impurity Substances 0.000 claims description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- 229910016508 CuCl22H2O Inorganic materials 0.000 claims description 2
- 229910016374 CuSO45H2O Inorganic materials 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical group [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- 239000001175 calcium sulphate Substances 0.000 claims description 2
- 235000011132 calcium sulphate Nutrition 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- 229960003280 cupric chloride Drugs 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 3
- 230000032050 esterification Effects 0.000 abstract description 3
- 238000005886 esterification reaction Methods 0.000 abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 239000007809 chemical reaction catalyst Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 241000295644 Staphylococcaceae Species 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 206010061695 Biliary tract infection Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- JYXACOFERDBGGQ-UHFFFAOYSA-N CC(C)N/C(/SCC(NC(C1SCC(COC(C)=O)=C(C(O)=O)N11)C1=O)=O)=N/C(C)C Chemical compound CC(C)N/C(/SCC(NC(C1SCC(COC(C)=O)=C(C(O)=O)N11)C1=O)=O)=N/C(C)C JYXACOFERDBGGQ-UHFFFAOYSA-N 0.000 description 1
- 0 CCC(*C(C1ICC(COC(C)=O)=C(C(C)O)*11)C1=O)=O Chemical compound CCC(*C(C1ICC(COC(C)=O)=C(C(C)O)*11)C1=O)=O 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 206010061977 Genital infection female Diseases 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 241001312524 Streptococcus viridans Species 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
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-N sodium;hydron;carbonate Chemical compound [Na+].OC(O)=O UIIMBOGNXHQVGW-UHFFFAOYSA-N 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 150000003952 β-lactams Chemical group 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a cefathiamidine compound and a new preparation method thereof. In the invention, the cefathiamidine compound with high purity is prepared by hydrolysis reaction and esterification, and the purity is more than 99.2%, the reaction step is simple, the yield is high, the cost is low, the quality of the preparation product is improved and the toxic or side effects are reduced; and strong acid salt is selected as the catalyst, the reaction time is short, the yield is high and cost is low, thus the strong acid slat is an ideal reaction catalyst.
Description
Technical field
The present invention relates to a kind of cefathiamidine compound and new preparation method thereof, belong to medical technical field.
Background technology
Cefathiamidine is by the β-Nei Xiananleikangshengsu of the common independent research of Shanghai Institute of Pharmaceutical Industry and Baiyunshan Pharmaceutics Stock-sharing Co., Ltd., Guangzhou City, belongs to first generation cephalosporin, for China's initiative is used for clinical.Antimicrobial spectrum is wider, stronger to gold-coloured staphylococci, Streptococcus viridans, pneumococcal effect, faecalis there is unique anti-microbial activity, is mainly used in infection such as respiratory tract infection due to gold-coloured staphylococci, streptococcus pneumoniae and the suis, biliary tract infection, urinary tract infections, gynecological infection, septicemia, pneumonia, meningitis.
Cefathiamidine (cefathiamidine), molecular formula: C
19H
28N
4O
6S
2, chemical being called (6R, 7R)-the 3-[(acetoxyl group) methyl]-7-[α-(N, N '-diisopropylamidinateand sulfenyl) kharophen]-8-oxo-5 thias-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid betaine, structural formula is:
Because cefathiamidine has the unique molecular structure of zwitter-ion inner salt, meet heat, meet light, meet moist lability, easily decompose variable color.Cefathiamidine uses bromoacetyl bromide in building-up process, if deal with improperly, and easy residual bromide anion in product.
In this external condensation reaction, solvent systems is selected bad, and impurity is difficult for removing, and causes content in crude product low easily, influences the clinical efficacy of medicine.At present the purification process to cefathiamidine has a lot, as with the cefathiamidine crude product with solvent treatment, through nucleogenesis, control the crystallization method of supersaturation concentration; Another kind of method commonly used is the method for transferring iso-electric point with acid, alkali, and the beta-lactam structure with acid, soda finishing method destructible cefathiamidine can cause product degradation as open loop, and product content reduces, and product stability is impacted; Adopt the dissolved method in addition in addition, this method needs a large amount of solvents, and cost is higher; The distillation crystallization process, shortcoming is the cost height, difficult operation, difficult quality guarantee.
Aspect cefathiamidine synthetic, though worked out other synthetic route, technology simple before do not improved the purity of cefathiamidine, yet so still need explore the novel method of cefathiamidine purifying.
Summary of the invention
The object of the present invention is to provide a kind of process for purification of cefathiamidine compound, obtain the cefathiamidine prosoma intermediate by hydrolysis reaction, by the charcoal absorption purifying, carry out esterification again and obtain highly purified cefathiamidine, reactions steps is simple, the productive rate height, cost is low, and product purity is greatly improved.
The technical scheme that the present invention solves comprises:
The invention provides the cefathiamidine compound shown in a kind of formula (I),
It is characterized in that carrying out purifying by the method that comprises the steps:
(1) the cefathiamidine crude product is dispersed in the water, adds alkaline catalysts, solid is separated out in heating after the reaction,
Make intermediate (II);
(2) intermediate (II) is dissolved in the organic solvent, adds the charcoal absorption removal of impurities, filter decarburization, get filtrate;
(3) add Glacial acetic acid in step (2) gained filtrate, add strong acid salt catalyzer and band aqua, reaction obtains cefathiamidine.
Above-mentioned described purification process is characterized in that described alkaline catalysts is selected from sodium hydroxide, potassium hydroxide, ammoniacal liquor, sodium bicarbonate, saleratus in the described step (1); Preferred described alkaline catalysts is a sodium hydroxide.
Above-mentioned described purification process, it is characterized in that in the described step (2), described organic solvent is selected from: methyl alcohol, ethanol, acetonitrile, the trimethyl carbinol, Virahol, trichloromethane, methylene dichloride, ether, sherwood oil, phenylcarbinol, N, in the dinethylformamide one or more are preferably phenylcarbinol.
Above-mentioned described purification process, it is characterized in that in the described step (3), in filtrate, add Glacial acetic acid and mix stirring, add strong acid salt catalyzer and band aqua again, stirring reaction, filtering is not tolerant, filtrate is used the solid drier drying again, organic solvent is removed in underpressure distillation, and vacuum-drying promptly gets highly purified cefathiamidine.
Wherein, described strong acid salt catalyzer is selected from ferric sulfate (Fe2 (SO4) 39H2O), iron(ic) chloride (FeCl36H2O), cupric chloride (CuCl22H2O), copper sulfate (CuSO45H2O), is preferably ferric sulfate (Fe2 (SO4) 39H2O).
Wherein, described band aqua is selected from hexanaphthene, sherwood oil, benzene, methylene dichloride, n-propyl alcohol, and preferred described band aqua is a hexanaphthene.
Wherein, described solid drier is selected from anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate, anhydrous calciumsulphate or activated alumina, is preferably activated alumina.
The above-mentioned described purification process of the present invention, the purity that it is characterized in that the cefathiamidine compound that obtains is greater than 99.2%.
As the present invention's one preferred embodiment, the purification step of described cefathiamidine compound comprises:
(1) the cefathiamidine crude product is dispersed in the water, adds 5% sodium hydroxide solution, be heated to 70-80 ℃ as catalyzer, stirring reaction 1-2 hour, separate out solid, to filter, drying gets intermediate (II);
(2) intermediate (II) is dissolved in the organic solvent, adds the gac of total liquid volume 0.2-0.5% (g/ml), be incubated 50-60 ℃ of whip attachment 30min, filter decarburization, get filtrate;
(3) in filtrate, add Glacial acetic acid and mix stirring, add strong acid salt again as catalyzer, cyclohexane give is the band aqua, 40-50 ℃ of stirring reaction 30-60min, filtering insolubles, filtrate are used the solid drier drying again, and organic solvent is removed in underpressure distillation, 50-60 ℃ of vacuum-drying promptly gets highly purified cefathiamidine.
The invention has the advantages that: make highly purified cefathiamidine compound by hydrolysis reaction and esterification, reactions steps is simple, the productive rate height, and cost is low, has improved quality product, has reduced toxic side effect.In addition, it is catalyzer that the present invention selects strong acid salt for use, and the reaction times is short, the yield height, and cost is low, is a kind of better catalysts.
Embodiment
Embodiment 1
The purifying of cefathiamidine
(1) 100g cefathiamidine crude product is dispersed in the 500ml water, adds 5% sodium hydroxide solution 20ml as catalyzer, be heated to 70 ℃, stirring reaction 2 hours is separated out solid, filters, and 50 ℃ of vacuum-dryings get the 81.47g intermediate, yield 92.6%;
(2) the 81.47g intermediate is dissolved in the 500ml phenylcarbinol, adds the gac of 0.5g, be incubated 80 ℃ of whip attachment 30min, filter decarburization, get filtrate;
(3) in filtrate, add the 15.8g Glacial acetic acid and mix stirring, add 3.5g ferric sulfate (Fe2 (SO4) 39H2O) again as catalyzer, the 20ml cyclohexane give is band aqua, 50 ℃ of stirring reaction 60min, filtering insolubles, filtrate is used the activated alumina drying again, phenylcarbinol is removed in underpressure distillation, and 60 ℃ of vacuum-dryings obtain highly purified cefathiamidine 90.8g, yield 90.8%, purity 99.92%.
Structural identification
1, ultimate analysis C19H28N4O6S2
Theoretical value: C:48.24%; H:5.92%; N:11.85%; O:20.31%; S:13.54%.
Measured value: C:48.44%; H:5.93%; N:11.82%; O:20.331%; S:13.50%
2, magnetic resonance spectroscopy is resolved
1H NMR (DMSO-d6) δ: 1.15[d, J=7Hz, 12H, CH (CH3) 2 * 2], 2.02 (s, 3H, OCOCH3), 3.34～3.55 (q, J=18Hz, 2H, C2-H), 3.95 (s, 2H, SCH2CO), 3.95 (m, 2H, CH * 2), 4.79～5.03 (q, the AB type, J=12Hz, 2H, C3-CH * 2), 5.05 (d, J=5Hz, 1H, C6-H), 5.59 (q, J1=5Hz, J2=7Hz, 1H, C7-H), 9.47 (d, J=7Hz, 1H, NH).
Embodiment 2
The purifying of cefathiamidine
(1) 100g cefathiamidine crude product is dispersed in the 500ml water, adds 10% sodium hydroxide solution 20ml as catalyzer, be heated to 70 ℃, stirring reaction 2 hours is separated out solid, filters, and 50 ℃ of vacuum-dryings get the 82.17g intermediate, yield 92.3%;
(2) the 82.17g intermediate is dissolved in the 500ml phenylcarbinol, adds the gac of 0.5g, be incubated 80 ℃ of whip attachment 30min, filter decarburization, get filtrate;
(3) in filtrate, add the 15.8g Glacial acetic acid and mix stirring, add 3.5g ferric sulfate (Fe2 (SO4) 39H2O) again as catalyzer, the 20ml cyclohexane give is band aqua, 50 ℃ of stirring reaction 60min, filtering insolubles, filtrate is used the activated alumina drying again, phenylcarbinol is removed in underpressure distillation, and 60 ℃ of vacuum-dryings obtain highly purified cefathiamidine 91.3g, yield 91.3%, purity 99.89%.
Embodiment 3
The purifying of cefathiamidine
(1) 100g cefathiamidine crude product is dispersed in the 500ml water, adds 10% sodium hydroxide solution 20ml as catalyzer, be heated to 75 ℃, stirring reaction 1.5 hours is separated out solid, filters, and 50 ℃ of vacuum-dryings get the 81.17g intermediate, yield 91.5%;
(2) the 81.17g intermediate is dissolved in the 500ml phenylcarbinol, adds the gac of 0.75g, be incubated 80 ℃ of whip attachment 30min, filter decarburization, get filtrate;
(3) in filtrate, add the 15.2g Glacial acetic acid and mix stirring, add 3.5g ferric sulfate (Fe2 (SO4) 39H2O) again as catalyzer, the 20ml cyclohexane give is band aqua, 50 ℃ of stirring reaction 60min, filtering insolubles, filtrate is used the activated alumina drying again, phenylcarbinol is removed in underpressure distillation, and 60 ℃ of vacuum-dryings obtain highly purified cefathiamidine 92.1g, yield 92.1%, purity 99.89%.
Claims (9)
1. the cefathiamidine compound shown in the formula (I),
It is characterized in that carrying out purifying by the method that comprises the steps:
(1) the cefathiamidine crude product is dispersed in the water, adds alkaline catalysts, solid is separated out in heating after the reaction, make intermediate (II);
(2) intermediate (II) is dissolved in the organic solvent, adds the charcoal absorption removal of impurities, filter decarburization, get filtrate;
(3) add Glacial acetic acid in step (2) gained filtrate, add strong acid salt catalyzer and band aqua, reaction obtains cefathiamidine.
2. purification process according to claim 1 is characterized in that described alkaline catalysts is selected from sodium hydroxide, potassium hydroxide, ammoniacal liquor, sodium bicarbonate, saleratus in the described step (1); Preferred described alkaline catalysts is a sodium hydroxide.
3. purification process according to claim 1, it is characterized in that in the described step (2), described organic solvent is selected from: methyl alcohol, ethanol, acetonitrile, the trimethyl carbinol, Virahol, trichloromethane, methylene dichloride, ether, sherwood oil, phenylcarbinol, N, in the dinethylformamide one or more are preferably phenylcarbinol.
4. purification process according to claim 1, it is characterized in that in the described step (3), in filtrate, add Glacial acetic acid and mix stirring, add strong acid salt catalyzer and band aqua again, stirring reaction, filtering is not tolerant, filtrate is used the solid drier drying again, organic solvent is removed in underpressure distillation, and vacuum-drying promptly gets highly purified cefathiamidine.
5. according to the described purification process of claim 1-4, it is characterized in that in the described step (3), described strong acid salt catalyzer is selected from ferric sulfate (Fe2 (SO4) 39H2O), iron(ic) chloride (FeCl36H2O), cupric chloride (CuCl22H2O), copper sulfate (CuSO45H2O), is preferably ferric sulfate (Fe2 (SO4) 39H2O).
6. according to the described purification process of claim 1-5, it is characterized in that in the described step (3), described band aqua is selected from hexanaphthene, sherwood oil, benzene, methylene dichloride, n-propyl alcohol, preferred described band aqua is a hexanaphthene.
7. according to the described purification process of claim 1-6, it is characterized in that described solid drier is selected from anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate, anhydrous calciumsulphate or activated alumina, is preferably activated alumina in the described step (3).
8. according to the described purification process of claim 1-7, it is characterized in that described step is:
(1) the cefathiamidine crude product is dispersed in the water, adds 5% sodium hydroxide solution, be heated to 70-80 ℃ as catalyzer, stirring reaction 1-2 hour, separate out solid, to filter, drying gets intermediate (II);
(2) intermediate (II) is dissolved in the organic solvent, adds the gac of total liquid volume 0.2-0.5% (g/ml), be incubated 50-60 ℃ of whip attachment 30min, filter decarburization, get filtrate;
(3) in filtrate, add Glacial acetic acid and mix stirring, add strong acid salt again as catalyzer, cyclohexane give is the band aqua, 40-50 ℃ of stirring reaction 30-60min, filtering insolubles, filtrate are used the solid drier drying again, and organic solvent is removed in underpressure distillation, 50-60 ℃ of vacuum-drying promptly gets highly purified cefathiamidine.
9. according to the described purification process of claim 1-8, the purity that it is characterized in that the cefathiamidine compound that obtains is greater than 99.2%.
Priority Applications (1)
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102863461A (en) * | 2011-07-08 | 2013-01-09 | 广州白云山制药股份有限公司广州白云山化学制药厂 | (6R, 7R)-3-hydroxymethyl-7-[alpha-(N, N'-diisopropylamidino thio)-acetamido]-8-oxo-5-thia-1-azabicycle [4, 2, 0]-oct-2-ene-2-carboxylic acid |
| CN105646534A (en) * | 2016-02-18 | 2016-06-08 | 海南灵康制药有限公司 | Novel-crystal-form cefathiamidine compound adopting crystal product molecular assembly and form optimization technology in particle process and preparation |
| 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 |
| CN115124552A (en) * | 2022-06-16 | 2022-09-30 | 国药集团威奇达药业有限公司 | Preparation method of deacetyl cefathiamidine |
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| CN1385434A (en) * | 2002-06-10 | 2002-12-18 | 广州白云山制药股份有限公司广州白云山化学制药厂 | Method for making cefathiamidine crystal |
| CN1431211A (en) * | 2003-01-28 | 2003-07-23 | 广州白云山制药股份有限公司 | Amine salt of cefathiamiding, its preparing method and application |
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| CN1431211A (en) * | 2003-01-28 | 2003-07-23 | 广州白云山制药股份有限公司 | Amine salt of cefathiamiding, its preparing method and application |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102863461A (en) * | 2011-07-08 | 2013-01-09 | 广州白云山制药股份有限公司广州白云山化学制药厂 | (6R, 7R)-3-hydroxymethyl-7-[alpha-(N, N'-diisopropylamidino thio)-acetamido]-8-oxo-5-thia-1-azabicycle [4, 2, 0]-oct-2-ene-2-carboxylic acid |
| CN105646534A (en) * | 2016-02-18 | 2016-06-08 | 海南灵康制药有限公司 | Novel-crystal-form cefathiamidine compound adopting crystal product molecular assembly and form optimization technology in particle process and preparation |
| 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 |
| CN115124552A (en) * | 2022-06-16 | 2022-09-30 | 国药集团威奇达药业有限公司 | Preparation method of deacetyl cefathiamidine |
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| CN102010428B (en) | 2012-02-15 |
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