CN101671349A - New method for preparing cefuroxime sodium compound - Google Patents
New method for preparing cefuroxime sodium compound Download PDFInfo
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- CN101671349A CN101671349A CN200910017764A CN200910017764A CN101671349A CN 101671349 A CN101671349 A CN 101671349A CN 200910017764 A CN200910017764 A CN 200910017764A CN 200910017764 A CN200910017764 A CN 200910017764A CN 101671349 A CN101671349 A CN 101671349A
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- URDOHUPGIOGTKV-JTBFTWTJSA-M Cefuroxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 URDOHUPGIOGTKV-JTBFTWTJSA-M 0.000 title claims abstract description 14
- 229960000534 cefuroxime sodium Drugs 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 50
- 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 16
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims abstract description 8
- 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 abstract description 7
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000011734 sodium Substances 0.000 claims abstract description 7
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 48
- 239000000243 solution Substances 0.000 claims description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 238000010189 synthetic method Methods 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 230000001105 regulatory effect Effects 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- 239000012044 organic layer Substances 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 150000003388 sodium compounds Chemical class 0.000 claims description 8
- 239000001117 sulphuric acid Substances 0.000 claims description 8
- 235000011149 sulphuric acid Nutrition 0.000 claims description 8
- QALUUCSIORXIHV-UHFFFAOYSA-N 3-methoxy-3H-furan-2-imine Chemical class COC1C(OC=C1)=N QALUUCSIORXIHV-UHFFFAOYSA-N 0.000 claims description 7
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- OEOIWYCWCDBOPA-UHFFFAOYSA-N 6-methyl-heptanoic acid Chemical compound CC(C)CCCCC(O)=O OEOIWYCWCDBOPA-UHFFFAOYSA-N 0.000 claims description 6
- 239000007790 solid phase Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-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
- 238000001816 cooling Methods 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 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
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 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
- 239000000843 powder Substances 0.000 claims description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 2
- 235000011152 sodium sulphate Nutrition 0.000 claims description 2
- -1 furylacetic acid ammonium salt Chemical class 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 abstract 1
- 108010013043 Acetylesterase Proteins 0.000 description 5
- 241001619326 Cephalosporium Species 0.000 description 5
- 102100036617 Monoacylglycerol lipase ABHD2 Human genes 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 241000235342 Saccharomycetes Species 0.000 description 4
- 238000000855 fermentation Methods 0.000 description 4
- 230000004151 fermentation Effects 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 229930186147 Cephalosporin Natural products 0.000 description 3
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 229960001668 cefuroxime Drugs 0.000 description 3
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 description 3
- 229940124587 cephalosporin Drugs 0.000 description 3
- OUSLHGWWWMRAIG-FBCAJUAOSA-N (6r,7r)-7-[[(2z)-2-(furan-2-yl)-2-methoxyiminoacetyl]amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound N([C@@H]1C(N2C(=C(CO)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 OUSLHGWWWMRAIG-FBCAJUAOSA-N 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 241000304886 Bacilli Species 0.000 description 1
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 description 1
- 241001478240 Coccus Species 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960003016 cefoxitin sodium Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
The invention relates to a new method for preparing a cefuroxime sodium compound. A target product is prepared by using triphosgene and triphenylphosphine oxide as catalysts, reacting 7-amino-cephalosporanic acid with (Z)-methoxyl imido furylacetic acid ammonium salt and sequentially adding chlorosulfonyl isocyanate and sodium iso-octoate for reaction. The cefuroxime sodium compound prepared by the method is greatly enhanced in purity and yield coefficient and has advantages of inexpensive using materials, simple synthesizing technology and equipment and easy production separation and purification.
Description
Technical field
The present invention relates to a kind of synthetic method of cephalosporin compound, be specifically related to a kind of synthetic method of cephalofruxin sodium compound of variation route, belong to chemosynthesis technical field.
Background technology
Cefuroxime sodium, its chemical name is: (6R, 7R)-7-[2-furyl (methoxyimino) kharophen]-3-carbamyl oxygen methyl-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-sodium formiate, molecular formula is C
16H
15N
4NaO
8S, molecular weight are 446.36, and structural formula is:
Be second generation cephalosporin class microbiotic, similar to first generation cephalosporin or slightly poor to the anti-microbial activity of gram positive coccus, but the beta lactamase quite stable that staphylococcus and gram negative bacilli are produced.At present, be mainly used in the caused various infection of sensitive organism clinically.
The synthetic method of Cefuroxime sodium is a starting raw material with Glaxo) or 7-ACA (7-amino-cephalosporanic acid) usually, synthesizes by polystep reaction, obtains Cefuroxime sodium.
Be the route of starting raw material with the Glaxo) wherein, the cefoxitin sodium waste is higher, and reactions steps is many, and the cost height does not almost have producer to adopt this route.
With 7-ACA is the method that starting raw material becomes present widespread use; at present; two class synthetic methods are arranged; the first kind is reacted with 7 bit aminos of (cis)-2-(2-furyl)-2-(methoxyimino) Acetyl Chloride 98Min. and 7-ACA earlier; use 3 ester groups of the cephalosporium acetylesterase selective hydrolysis 7-ACA of scarlet saccharomycetes to make fermentation generation again; make 3-deammoniation formyl radical cefuroxime acid; be called for short DCCF; 3 hydroxyls transforming DCCF again transform carboxamide oxygen methyl as and obtain cefuroxime acid; at present the cephalosporium acetylesterase that produces of scarlet saccharomycetes to make fermentation costs an arm and a leg and does not domesticly have an industrialization supplier, has limited the application of the first kind.Second class methods make key intermediate 3-deacetylation-7-amino-Cephalosporanic acid with 3 ester groups of the cephalosporium acetylesterase selective hydrolysis 7-ACA that 7-ACA produces by the scarlet saccharomycetes to make fermentation, obtain cefuroxime acid through two approach then.The common drawback of second class methods is that 7-ACA makes 7-DACA by the cephalosporium acetylesterase selective hydrolysis that the scarlet saccharomycetes to make fermentation produces, cephalosporium acetylesterase costs an arm and a leg, long reaction time, 7-ACA, 7-DACA in the aqueous solution in its molecular structure the easy hydrolysis of tetra-atomic ring lactam bond cause tetra-atomic ring open loop easier hydrolysis under 25 ℃, the enzymatic hydrolysis concentration of substrate is low to cause aftertreatment very difficult, product 7-DACA crystallization carefully causes filtering and dry difficulty is difficult to suitability for industrialized production, also having a shortcoming is exactly to generate a kind of and very approaching lactone of 7-DACA character, be difficult to separately cause finished product purity low.
Summary of the invention
The object of the present invention is to provide a kind of synthetic method of cephalofruxin sodium compound, solved the problem that above-mentioned prior art exists, simplified reaction greatly, be more suitable in large-scale industrial production, cost is low, and quality is higher.
The synthetic method of cephalofruxin sodium compound of the present invention, what two intermediate 7-amino-cephalosporanic acids and (Z)-methoxy imino furans acetate ammonium salt was at home and abroad studied is many, in order to improve the synthetic of cephalofruxin, we have improved butt joint technology, promptly adopt triphosgene and triphenylphosphinc oxide to obtain good effect as catalyzer.We find pleasantly surprisedly, compound purity and yield all improve a lot, and the raw material that uses is cheap, synthesis technique is simple, equipment is simple, the product separate easily is purified, and (Z)-and methoxy imino furans acetate ammonium salt and 7-ACA dock earlier and reduced side reaction.
Particularly, technical scheme provided by the invention is as follows:
A kind of synthetic method of cephalofruxin sodium compound, it comprises the steps:
(1) 7-amino-cephalosporanic acid is dissolved in the solvent, low temperature adds sodium hydroxide solution down, and adjusting pH is 11-13, stirring reaction, and adding the salt acid for adjusting pH value again is 10-11, gets solution (1);
(2) triphosgene, (Z)-methoxy imino furans acetate ammonium salt and triphenylphosphinc oxide are dissolved in the toluene, stirring reaction gets solution (2);
(3) with solution (2) and solution (1) hybrid reaction, regulating the pH value with sodium hydroxide solution and dilute sulphuric acid respectively is 1-2, gets organic layer, drying, and concentrating under reduced pressure gets product (A);
(4) product (A) is dissolved in the organic solvent, adds the chlorosulfonic acid isocyanate reaction, add Sodium isooctanoate again, stirring reaction gets Cefuroxime sodium.
Control reaction temperature is-10 ℃ to-20 ℃ in the above-mentioned described synthetic method, step (1), is preferably-13 ℃ to-15 ℃; Control reaction temperature is 0 ℃ to 10 ℃ in step (2)-(4), is preferably 2 ℃ to 8 ℃.
Solvent is the mixing solutions of first alcohol and water in the above-mentioned described synthetic method, step (1), and volume ratio is 1: 1.
Organic layer adopts the solid drier drying in the above-mentioned described synthetic method, step (3), and solid drier is selected from anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate, anhydrous calciumsulphate or activated alumina, is preferably anhydrous sodium sulphate.
Organic solvent is selected from acetonitrile, acetone, methylene dichloride, Virahol, methyl alcohol in the above-mentioned described synthetic method, step (4), is preferably acetonitrile.
Regulating pH with sodium hydroxide solution earlier in the above-mentioned described synthetic method, step (1) is 11-13, and adding the salt acid for adjusting pH value again is 10-11; Regulating pH with sodium hydroxide solution earlier in the step (3) is 9-10, adds dilute sulphuric acid adjusting pH value again and is 1-2.
As concrete preferred version of the present invention, the synthetic method of cephalofruxin sodium compound provided by the invention comprises the steps:
(1) 7-amino-cephalosporanic acid is dissolved in 1: 1 the solvent of methyl alcohol and water volume ratio, stir cooling, be cooled to-10 ℃ to-20 ℃, be preferably-13 ℃ to-15 ℃, the aqueous solution of the sodium hydroxide of Dropwise 5-15%, control reaction temperature is at-13 ℃ to-15 ℃, adjusting pH is 11.5-12.5, reacted 1-2 hour, and regulated pH=9.5 with the hydrochloric acid soln of 2mol/L then, get solution (1);
(2) triphosgene is dissolved in toluene, control reaction temperature is added drop-wise in the toluene solution of (Z)-methoxy imino furans acetate ammonium salt and triphenylphosphinc oxide at 2 ℃ to 8 ℃, stirring reaction 2-4 hour, gets solution (2);
(3) solution (2) is added drop-wise to hybrid reaction in the solution (1), sodium hydroxide solution with 5-15% in the reaction is regulated pH=9.5, control reaction temperature is at 2 ℃ to 8 ℃, after dripping, reaction 20-30min regulates pH=1 with dilute sulphuric acid then, layering, the organic layer anhydrous sodium sulfate drying, concentrating under reduced pressure gets solid phase prod (A);
(4) solid phase prod (A) is dissolved in the acetonitrile, control reaction temperature slowly is added dropwise to chlorosulfonic acid isocyanate at 2 ℃ to 8 ℃, stirring reaction 1-2 hour, the acetone soln that drips the 10-15% Sodium isooctanoate was then regulated pH=6.7, stirs, separate out solid, filter, get Cefuroxime sodium.
As preferably, above-mentioned described synthetic method, the mol ratio of 7-amino-cephalosporanic acid and (Z)-methoxy imino furans acetate ammonium salt is 1: 1.
Synthetic route is:
Embodiment
Further explain and describe content of the present invention by the following examples.But the embodiment that is provided should not be understood that protection domain of the present invention is construed as limiting.
Embodiment 1:
1, deacetylate-7-amino-cephalosporanic acid
272 gram 7-amino-cephalosporanic acids are dissolved in the mixing solutions of 1L methyl alcohol and 1L water, stir cooling, be cooled to-15 ℃, the aqueous solution of the sodium hydroxide of dropping 15%, control reaction temperature is at-13 ℃ to-15 ℃, and regulating pH is 12.5, reacts 2 hours, regulate pH=9.5 with the hydrochloric acid soln of 2mol/L then, get solution (1).
2,7-[2-(2-furyl)-2-(Z)-(methoxy imino) kharophen]-3-methylol-cephalo-3-alkene-4-carboxylic acid
600 gram triphosgene are dissolved in the 1L toluene, in the toluene of 2L of 5 ℃ of (Z)-methoxy imino furans acetate ammonium salts that are added drop-wise to 186 grams and 556 gram triphenylphosphinc oxides, be incubateds 5 ℃ of reactions 3 hours, get solution (2); Solution (2) is added drop-wise to hybrid reaction in the solution (1), sodium hydroxide solution with 15% in the reaction is regulated pH=9.5, control reaction temperature after dripping, is reacted 30min at 5 ℃, regulate pH=1 with dilute sulphuric acid then, layering, organic layer anhydrous sodium sulfate drying, concentrating under reduced pressure, get product (A) 354 grams, yield: 93%.
3, the target product Cefuroxime sodium is synthetic
(A) is dissolved in the acetonitrile with above-mentioned solid phase prod, stirring cools to 5 ℃, be controlled at the chlorosulfonic acid isocyanate that slowly drips 124ml under this temperature, insulation reaction 1.5 hours, the acetone soln that drips 15% Sodium isooctanoate is then regulated pH=6.7, stirs, separate out solid, filter, get Cefuroxime sodium 373 grams, yield 90%.
Embodiment 2:
1, deacetylate-7-amino-cephalosporanic acid
136 gram 7-amino-cephalosporanic acids are dissolved in the mixing solutions of 0.5L methyl alcohol and 0.5L water, stir cooling, be cooled to-13 ℃, the aqueous solution of the sodium hydroxide of Dropwise 5 %, control reaction temperature is at-13 ℃ to-15 ℃, and regulating pH is 11.5, reacts 1 hour, regulate pH=9.5 with the hydrochloric acid soln of 2mol/L then, get solution (1).
2,7-[2-(2-furyl)-2-(Z)-(methoxy imino) kharophen]-3-methylol-cephalo-3-alkene-4-carboxylic acid
300 gram triphosgene are dissolved in the 0.5L toluene, in the toluene of 1L of 8 ℃ of (Z)-methoxy imino furans acetate ammonium salts that are added drop-wise to 93 grams and 278 gram triphenylphosphinc oxides, be incubateds 8 ℃ of reactions 2 hours, get solution (2); Solution (2) is added drop-wise to hybrid reaction in the solution (1), sodium hydroxide solution with 5% in the reaction is regulated pH=10, control reaction temperature after dripping, is reacted 30min at 8 ℃, regulate pH=1.5 with dilute sulphuric acid then, layering, organic layer anhydrous sodium sulfate drying, concentrating under reduced pressure, get product (A) 179.8 grams, yield: 94.5%.
3, the target product Cefuroxime sodium is synthetic
(A) is dissolved in the acetonitrile with above-mentioned solid phase prod, stirring cools to 6 ℃, be controlled at the chlorosulfonic acid isocyanate that slowly drips 64ml under this temperature, insulation reaction 2 hours, the acetone soln that drips 10% Sodium isooctanoate is then regulated pH=6.7, stirs, separate out solid, filter, get Cefuroxime sodium 189.6 grams, yield 91.5%.
Claims (10)
1, a kind of cephalofruxin sodium compound of variation route, it comprises the steps:
(1) 7-amino-cephalosporanic acid is dissolved in the solvent, low temperature adds sodium hydroxide solution down and regulates the pH value, and stirring reaction adds the salt acid for adjusting pH value again, gets solution (1);
(2) triphosgene, (Z)-methoxy imino furans acetate ammonium salt and triphenylphosphinc oxide are dissolved in the toluene, stirring reaction gets solution (2);
(3) with solution (2) and solution (1) hybrid reaction, regulate the pH value with sodium hydroxide solution and dilute sulphuric acid respectively, get organic layer, drying, concentrating under reduced pressure gets product (A);
(4) product (A) is dissolved in the organic solvent, adds the chlorosulfonic acid isocyanate reaction, add Sodium isooctanoate again, stirring reaction gets Cefuroxime sodium.
2, synthetic method according to claim 1 is characterized in that control reaction temperature is-10 ℃ to-20 ℃ in the step (1); Control reaction temperature is 0 ℃ to 10 ℃ in step (2)-(4).
3, synthetic method according to claim 2 is characterized in that control reaction temperature is-13 ℃ to-15 ℃ in the step (1); Control reaction temperature is 2 ℃ to 8 ℃ in step (2)-(4).
4, synthetic method according to claim 1 is characterized in that solvent is the mixing solutions of first alcohol and water in the step (1), and its volume ratio is 1: 1.
5, synthetic method according to claim 1 is characterized in that organic layer adopts the solid drier drying in the step (3), and solid drier is selected from anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate, anhydrous calciumsulphate or activated alumina.
6, synthetic method according to claim 5 is characterized in that organic layer adopts the solid drier drying in the step (3), and solid drier is selected from anhydrous sodium sulphate.
7, synthetic method according to claim 1 is characterized in that organic solvent is selected from acetonitrile, acetone, methylene dichloride, Virahol or methyl alcohol in the step (4).
8, synthetic method according to claim 7 is characterized in that organic solvent is selected from acetonitrile in the step (4).
9, synthetic method according to claim 1 is characterized in that regulating pH with sodium hydroxide solution earlier in the step (1) is 11-13, and adding the salt acid for adjusting pH value again is 10-11; Regulating pH with sodium hydroxide solution earlier in the step (3) is 9-10, adds dilute sulphuric acid adjusting pH value again and is 1-2.
10, a kind of synthetic method of cephalofruxin sodium compound, it further comprises the steps:
(1) 7-amino-cephalosporanic acid is dissolved in 1: 1 the solvent of methyl alcohol and water volume ratio, stir cooling, be cooled to-10 ℃ to-20 ℃, the aqueous solution of the sodium hydroxide of Dropwise 5-15%, control reaction temperature is at-13 ℃ to-15 ℃, and adjusting pH is 11.5-12.5, reacts 1-2 hour, regulate pH=9.5 with the hydrochloric acid soln of 2mol/L then, get solution (1);
(2) triphosgene is dissolved in toluene, control reaction temperature is added drop-wise in the toluene solution of (Z)-methoxy imino furans acetate ammonium salt and triphenylphosphinc oxide at 0 ℃ to 10 ℃, stirring reaction 2-4 hour, gets solution (2);
(3) solution (2) is added drop-wise to hybrid reaction in the solution (1), sodium hydroxide solution with 5-15% in the reaction is regulated pH=9.5, control reaction temperature is at 2 ℃ to 8 ℃, after dripping, reaction 20-30min regulates pH=1 with dilute sulphuric acid then, layering, the organic layer anhydrous sodium sulfate drying, concentrating under reduced pressure gets solid phase prod (A);
(4) solid phase prod (A) is dissolved in the acetonitrile, control reaction temperature slowly is added dropwise to chlorosulfonic acid isocyanate at 2 ℃ to 8 ℃, stirring reaction 1-2 hour, the acetone soln that drips the 10-15% Sodium isooctanoate was then regulated pH=6.7, stirs, separate out solid, filter, get Cefuroxime sodium.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100177640A CN101671349B (en) | 2009-08-28 | 2009-08-28 | New method for preparing cefuroxime sodium compound |
Applications Claiming Priority (1)
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103450223A (en) * | 2013-08-16 | 2013-12-18 | 广东立国制药有限公司 | Preparation method of descarbamoyl cefuroxime |
| CN103717607A (en) * | 2012-09-12 | 2014-04-09 | 海南卫康制药(潜山)有限公司 | Cefuroxime sodium crystal compound and composition powder injection thereof |
| CN108440568A (en) * | 2018-04-11 | 2018-08-24 | 广东立国制药有限公司 | A kind of preparation method of descarbamoyl cefuroxime |
| CN109988183A (en) * | 2019-04-17 | 2019-07-09 | 广东立国制药有限公司 | A kind of environment-friendly preparation method of the intermediate of cefuroxime acid |
| CN112707919A (en) * | 2020-12-30 | 2021-04-27 | 山东金城昆仑药业有限公司 | Method for synthesizing 3-decarbamoyl cefuroxime acid by using graphene-supported copper catalyst |
| CN114292282A (en) * | 2021-12-09 | 2022-04-08 | 山东金特安全科技有限公司 | Method for synthesizing cefuroxime sodium based on continuous flow reaction technology |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100564382C (en) * | 2006-11-12 | 2009-12-02 | 西南合成制药股份有限公司 | The synthetic method of Cefuroxime sodium |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103717607A (en) * | 2012-09-12 | 2014-04-09 | 海南卫康制药(潜山)有限公司 | Cefuroxime sodium crystal compound and composition powder injection thereof |
| CN103450223A (en) * | 2013-08-16 | 2013-12-18 | 广东立国制药有限公司 | Preparation method of descarbamoyl cefuroxime |
| CN108440568A (en) * | 2018-04-11 | 2018-08-24 | 广东立国制药有限公司 | A kind of preparation method of descarbamoyl cefuroxime |
| CN109988183A (en) * | 2019-04-17 | 2019-07-09 | 广东立国制药有限公司 | A kind of environment-friendly preparation method of the intermediate of cefuroxime acid |
| CN112707919A (en) * | 2020-12-30 | 2021-04-27 | 山东金城昆仑药业有限公司 | Method for synthesizing 3-decarbamoyl cefuroxime acid by using graphene-supported copper catalyst |
| CN112707919B (en) * | 2020-12-30 | 2022-06-07 | 山东金城昆仑药业有限公司 | Method for synthesizing 3-decarbamoyl cefuroxime acid by using graphene-supported copper catalyst |
| CN114292282A (en) * | 2021-12-09 | 2022-04-08 | 山东金特安全科技有限公司 | Method for synthesizing cefuroxime sodium based on continuous flow reaction technology |
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| CN101671349B (en) | 2010-12-15 |
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