CN102816173B - Preparation method of cefodizime sodium - Google Patents
Preparation method of cefodizime sodium Download PDFInfo
- Publication number
- CN102816173B CN102816173B CN201210317362.4A CN201210317362A CN102816173B CN 102816173 B CN102816173 B CN 102816173B CN 201210317362 A CN201210317362 A CN 201210317362A CN 102816173 B CN102816173 B CN 102816173B
- Authority
- CN
- China
- Prior art keywords
- sodium
- compound
- acetone
- washing
- preparation
- 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
- 229960001958 cefodizime Drugs 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- XDZKBRJLTGRPSS-BGZQYGJUSA-N cefodizime Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(C)=C(CC(O)=O)S1 XDZKBRJLTGRPSS-BGZQYGJUSA-N 0.000 title abstract description 46
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 239000012046 mixed solvent Substances 0.000 claims abstract description 20
- 239000002994 raw material Substances 0.000 claims abstract description 18
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 64
- 150000001875 compounds Chemical class 0.000 claims description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 25
- 238000005406 washing Methods 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 15
- 238000000967 suction filtration Methods 0.000 claims description 14
- 238000001291 vacuum drying Methods 0.000 claims description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 10
- OEOIWYCWCDBOPA-UHFFFAOYSA-N 6-methyl-heptanoic acid Chemical compound CC(C)CCCCC(O)=O OEOIWYCWCDBOPA-UHFFFAOYSA-N 0.000 claims description 9
- 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 9
- 239000011734 sodium Substances 0.000 claims description 9
- 229910052708 sodium Inorganic materials 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 229960004249 sodium acetate Drugs 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 3
- 229910001509 metal bromide Inorganic materials 0.000 claims description 2
- 229910001511 metal iodide Inorganic materials 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- WBOBLQIRACJNPA-QQFCNTMUSA-L disodium;(6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[[5-(carboxylatomethyl)-4-methyl-1,3-thiazol-2-yl]sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].[Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)/C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(C)=C(CC([O-])=O)S1 WBOBLQIRACJNPA-QQFCNTMUSA-L 0.000 claims 2
- 239000000047 product Substances 0.000 abstract description 36
- KFCMZNUGNLCSJQ-NFBKMPQASA-N (4-methoxyphenyl)methyl (6r,7r)-3-(chloromethyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1=CC(OC)=CC=C1COC(=O)C1=C(CCl)CS[C@H]2N1C(=O)[C@H]2NC(=O)CC1=CC=CC=C1 KFCMZNUGNLCSJQ-NFBKMPQASA-N 0.000 abstract description 19
- 238000000034 method Methods 0.000 abstract description 15
- 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 abstract description 12
- 238000007086 side reaction Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 2
- 230000003247 decreasing effect Effects 0.000 abstract 1
- 239000012467 final product Substances 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 229960004756 ethanol Drugs 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- -1 5-carboxymethyl-4-methyl-2-thiazolyl Chemical group 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229930186147 Cephalosporin Natural products 0.000 description 4
- 229940124587 cephalosporin Drugs 0.000 description 4
- 150000001780 cephalosporins Chemical class 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 235000009518 sodium iodide Nutrition 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- NVIAYEIXYQCDAN-CLZZGJSISA-N 7beta-aminodeacetoxycephalosporanic acid Chemical compound S1CC(C)=C(C(O)=O)N2C(=O)[C@@H](N)[C@@H]12 NVIAYEIXYQCDAN-CLZZGJSISA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- WGJCBBASTRWVJL-UHFFFAOYSA-N 1,3-thiazolidine-2-thione Chemical compound SC1=NCCS1 WGJCBBASTRWVJL-UHFFFAOYSA-N 0.000 description 1
- ZPOLNCDBPYJDSE-UHFFFAOYSA-N 3-[4-[bis(2-chloroethyl)amino]phenyl]-2-formamidopropanoic acid Chemical compound O=CNC(C(=O)O)CC1=CC=C(N(CCCl)CCCl)C=C1 ZPOLNCDBPYJDSE-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- IYNDLOXRXUOGIU-LQDWTQKMSA-M benzylpenicillin potassium Chemical compound [K+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 IYNDLOXRXUOGIU-LQDWTQKMSA-M 0.000 description 1
- 229950005499 carbon tetrachloride Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- GPRBEKHLDVQUJE-VINNURBNSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-VINNURBNSA-N 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
The invention relates to a preparation method of cefodizime sodium. By the preparation method, GCLE substitutes for traditional 7-ACA (7-Aminocephalosporanic acid) as starting materials to synthesize the cefodizime sodium, and after decoloration, reaction liquor is not subjected to separation and purification but is directly dropwise added with salt-forming agents for reaction so that the cefodizime sodium is obtained. The preparation method is short in step and less in side reaction, solves the problem of high superpolymer content of a final product and enables the superpolymer content to be decreased from 1.0% to smaller than 0.1%, product purity is improved and is above 99.8%, and product yield is improved and is above 90% by the aid of the raw material ratio and mixed solvent. Additionally, the preparation method is shorter in process step, timesaving, simple in process, high in yield and product purity, low in cost, cheap and available in raw materials and suitable for industrial production.
Description
Technical field
The invention belongs to the synthetic field of chemicals, be specifically related to a kind of GCLE of take and prepare the method for Cefodizime Sodium as starting raw material.
Background technology
Cefodizime Sodium, have another name called Cefodizime, English name is Cefodizime Sodium, its chemical name is: (6R, 7R)-7-[(2-amino-4-thiazolyl)-(methoxyimino) acetamido]-3-[[(5-carboxymethyl-4-methyl-2-thiazolyl) sulphur] methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid disodium salt, molecular formula: C
20h
18n
6o
7s
4na
2, molecular weight: 628.64, structural formula is as shown in compound V:
Cefodizime Sodium belongs to third generation cephalosporin for injections class microbiotic, by German Hirst company, developed, be mainly used in treating acute bacterial infection disease, the diseases such as lower respiratory infection, urinary system infection have certain effect to improving human immunity regulating power simultaneously.
At present, prepare Cefodizime Sodium and be all with 7-ACA or take the subsequent products cefotaxime acid of 7-ACA as raw material in prior art, easily produce by product in reaction process, affect quality product, purity is not high; Adopting 7-ACA is that raw material is prepared Cefodizime Sodium and existed yield low, and quality is not good enough, and long reaction time, is unfavorable for continuity, large-scale industrial production.Therefore, research and development technique simple, high yield, high quality, and be suitable for the synthetic technology of large-scale industrial production, become the task of top priority.
Cefodizime Sodium is mainly by Cefodizime acid preparation, and important in preparation process is exactly the dissolving of Cefodizime acid.US Patent No. 5126445 discloses Cefodizime acid has been suspended in water, drips triethylamine and dissolves, and to dripping Sodium isooctanoate solution in settled solution, separates out Cefodizime Sodium, and products obtained therefrom color is darker, need to refine, and affects quality product and yield.US Patent No. 4590267 discloses dissolves Cefodizime Sodium with sodium bicarbonate, drip alcohol and separate out Cefodizime Sodium, with sodium bicarbonate, dissolves, and dissolution time is long, and easily comprises undissolved sodium bicarbonate in products obtained therefrom, affects quality product.Chinese patent CN101239985 discloses Cefodizime acid has been suspended in two-phase system, add Sodium isooctanoate to stir entirely molten, layering, water layer adds alcohol to separate out Cefodizime Sodium, and its two-phase system is selected from methylene dichloride/water, tetrachloromethane/water, toluene/water or ethyl acetate/water, in the method, use a large amount of organic solvents, and the rate of recovery is low, contaminate environment, cost is higher, operation steps is many and complicated, and product purity is lower.Chinese patent CN101723958B discloses Cefodizime acid has been suspended in ethanol, dropping triethylamine dissolves, decolouring, to the ethanolic soln crystallization that drips Sodium isooctanoate in settled solution, suction filtration, with dehydrated alcohol and washing with acetone, dry, obtain Cefodizime Sodium, in the method, use a large amount of ethanol, production cost is higher, and operation steps is many and complicated.
Summary of the invention
In the present invention, in order to narrate conveniently, by GCLE, i.e. GCLE, referred to as chemical compounds I; First thyroidan acetic acid is referred to as compound ii; (6R, 7R)-7-amido]-3-[[(5-carboxymethyl-4-methyl-2-thiazolyl) sulphur] methyl]-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-ene-2-formic acid is referred to as compound III; MEAM is referred to as compounds Ⅳ; Cefodizime Sodium is referred to as compound V.
For the deficiencies in the prior art part, the object of the present invention is to provide a kind of GCLE of take to replace traditional 7-ACA to prepare the method for Cefodizime Sodium as starting raw material, with the synthetic Cefodizime Sodium of GCLE two steps, solved the high problem of superpolymer content in prior art, this building-up reactions step is short, and side reaction is few, simple to operate, yield is high, and products obtained therefrom purity is high.
A preparation method for Cefodizime Sodium, employing chemical compounds I is starting raw material, concrete steps comprise:
(1) chemical compounds I and compound ii are suspended in the aqueous solution containing organic solvent, are heated to 50 ℃, stir to clarify, add catalyzer, the sodium hydrogen carbonate solution that is 8%-12% with massfraction or sodium carbonate solution are adjusted pH 5.0-5.5, reaction 1-2 hour, add after halogenated acid hydrolysis, then add activated carbon decolorizing, washing, the ammoniacal liquor that is 25%-28% with massfraction is adjusted pH 2.5-3.5, growing the grain, suction filtration, washing, vacuum-drying, obtains light yellow or off-white color crystalline powder, i.e. compound III;
(2) in mixed solvent, compound III and compounds Ⅳ are added to rear stirring, then drip organic bases reaction 1-2 hour, add activated carbon decolorizing, filter, washing, drip salt forming agent solution, slowly be stirred to muddiness and go out crystalline substance, growing the grain, suction filtration, washing, vacuum-drying, obtains white or off-white color compound V, i.e. Cefodizime Sodium.
Synthetic route is:
Wherein, the catalyzer described in step (1) is metal bromide or metal iodide, is preferably sodium iodide, and sodium iodide is participated in halogenating reaction ratio and is easier to, and consumption is little and reaction is thorough, and effect is better; Halogenated acid described in step (1) is trifluoroacetic acid.
In described step (1), the mass ratio of chemical compounds I and compound ii is 1:0.41-0.47, because chemical combination I is higher than compound ii cost, so this ratio range can guarantee expensive chemical compounds I, reacts completely; The mass ratio of chemical compounds I and catalyzer is 1:0.01-0.03, higher than this ratio range, reacts not thorough, residual height, and lower than this ratio range, the color of product is heavier, causes the waste of catalyzer simultaneously; The mass ratio of chemical compounds I and halogenated acid is 1:1.8-4.7, at this ratio range, can guarantee removing completely of 4 protecting group carboxyls in chemical compounds I, otherwise 4 protecting groups can not remove completely, increases the impurity in product, or causes the waste of raw material.
Organic solvent described in step (1) is acetone, and the described volume ratio containing acetone in the aqueous solution of organic solvent and water is 20:1-2, reacts more thorough in this proportional range, and yield is high, and the color of product is better simultaneously.
The mass ratio of the compound III described in step (2) and compounds Ⅳ is 1:1.37-1.71, higher than in this proportional range, causes the reaction of compound III not exclusively, and impurity raises; Lower than this, than row, cause the waste of compounds Ⅳ, aftertreatment is simultaneously also cumbersome.
Mixed solvent described in step (2) is the solvent of acetone or toluene and alcohol composition, and described alcohol is ethanol; Described mixed solvent is preferably the solvent of acetone and ethanol composition, and the volume ratio of acetone and ethanol is 1-3:1.The effect of mixed solvent is the solubleness that reduces Cefodizime Sodium, improves yield, and has good removal effect for the little impurity of polarity, has improved the purity of product.This proportional range is best solvent amount, and not only little to the solvability of generated sodium salt, yield is high, and the crystal formation of product is the bar-shaped crystal formation of rule, easily dry, easily packing.
Organic bases described in step (2) is a kind of of pyridine or triethylamine or diethylamine or TERTIARY BUTYL AMINE or aniline or morpholine, preferably triethylamine.The Main Function of described organic bases is the effect of dissolving and catalysis, still, from yield and the color of product, from alkalescence size, considers that the effect of triethylamine is gentleer.
Salt forming agent described in step (2) is a kind of in Sodium isooctanoate or sodium methylate or sodium-acetate, the mass ratio of compound III and salt forming agent is 1:0.15-0.95, described salt forming agent consumption is very few, salify is not thorough, affect product yield, salt forming agent consumption is excessive, and the residual height of organic acid, causes allergic phenomena.The preferred Sodium isooctanoate of wherein said salt forming agent, this is because the solvability of Sodium isooctanoate in organic solvent is larger, and the by product organic acid generating is also removed than being easier to.
In described step (1) and step (2), the temperature range of growing the grain process is 10 ℃-15 ℃, and rearing crystal time is 1 hour.
Salt forming agent solution in described step (2) is that salt forming agent is dissolved in to the solution forming in mixed solvent.Described step (2), in mixed solvent, adds rear stirring by compound III and compounds Ⅳ, then drips organic bases reaction 1-2 hour, adds activated carbon decolorizing, filters washing; Salt forming agent is dissolved in mixed solvent and is dripped, be slowly stirred to muddiness and go out crystalline substance, in order to separate out more polycrystal, drip again acetone or toluene, growing the grain, suction filtration, washing, vacuum-drying obtains white or off-white color compound V, i.e. Cefodizime Sodium.
GCLE, it is GCLE, continue 7-ACA, 7-ADCA(7-amino-3-desacetoxycephalosporanic acid) after another synthetic cephalosporins medicine parent nucleus, can replace 7-ACA for the preparation of cynnematin, its C-3 position is-CH
2cl, can, as lead compound, make C-3 position containing a series of cephalosporins medicines of two keys, thiomethyl, n-formyl sarcolysine base etc.Chlorine on its C-3 has increased reactive behavior, and C-4 position carboxyl, C-7 bit amino are protected, can reduce side reaction and occur while reacting in C-3 position, and products obtained therefrom purity is high, and appearance color is good.Take GCLE when parent nucleus is produced cynnematin, and product yield is higher, production technique is simpler, working condition milder, product cost are lower.GCLE be take cheap potassium penicillin G as starting raw material preparation, and product cost is low, and price is only 60% left and right of 7-ACA price.GCLE is by the development and production the earliest of Japanese Otsuka Kagaku K.K.; so far have the history of more than ten years; the synthetic production technology of recent year GCLE is very ripe; add the continuous expansion of domestic penicillin production capacity and the greater advantage of fermentation technique aspect; GCLE price significantly declines; not only in supply country, use at present, also a large amount of outlets, the synthetic cephalosporins medicine of GCLE demonstrates stronger quality and cost advantage.
Compared with prior art, its beneficial effect is in the present invention:
One, take GCLE and replace traditional 7-ACA as the synthetic Cefodizime Sodium of starting raw material, product yield is higher, production technique is simpler, working condition milder, product cost are lower.Due to chemical method, to prepare 7-ACA cost too high, be difficult to buy, and that enzyme process is prepared 7-ACA protein content is high, cause the finished product superpolymer content high, during medication, irritated probability is large, and the preparation method of Cefodizime Sodium of the present invention has solved the high problem of the finished product superpolymer content, and superpolymer content is reduced to below 0.1% from 1.0%, improved purity, purity is more than 99.8% simultaneously;
Two, in mixed solvent, compound III and compounds Ⅳ add organic alkali reaction and generate Cefodizime acid, add gac to decolour, reaction solution after decolouring, without purification procedures, is dissolved in salt forming agent in mixed solvent, directly drips salt forming agent solution reaction and generates Cefodizime Sodium, the use of described mixed solvent has reduced the solubleness of Cefodizime Sodium, improve yield, and had good removal effect for the impurity of little polarity, improved the purity of product; And synthetic intermediate Cefodizime acid needs, through crystallization, washing and drying process step, also to need again solubilizing agent to dissolve in reacting with salt forming agent in prior art.Step in the present invention (2) completes in mixed solvent, and the separating step in the middle of having saved, has shortened processing step, has saved the time; The use of the proportioning raw materials described in the present invention and mixed solvent, has improved yield, and product yield is reached more than 90%.
The preparation method of Cefodizime Sodium provided by the invention, step is short, side reaction is few, solved the high problem of the finished product superpolymer content, superpolymer content is reduced to below 0.1% from 1.0%, and has improved purity, product purity is more than 99.8%, described proportioning raw materials and the use of mixed solvent, improved yield, and product yield is reached more than 90%.The present invention has shortened processing step, has saved the time, and technique is simple, and yield is high, and cost is low, and product purity is high, and raw material is cheap and easy to get, is applicable to suitability for industrialized production.
Accompanying drawing explanation
Accompanying drawing 1 is the embodiment of the present invention 1 Cefodizime Sodium HPLC collection of illustrative plates;
Accompanying drawing 2 is the embodiment of the present invention 2 Cefodizime Sodium HPLC collection of illustrative plates;
Accompanying drawing 3 is the embodiment of the present invention 3 Cefodizime Sodium HPLC collection of illustrative plates;
Accompanying drawing 4 is the embodiment of the present invention 4 Cefodizime Sodium HPLC collection of illustrative plates.
Embodiment
Below in conjunction with embodiment, the present invention will be further described, and described is only several concrete forms of implementation of the present invention, for the person of ordinary skill of the art, can also make many distortion and improvement.All do not exceed the distortion described in claim or improve all should be considered as scope of the present invention.
embodiment 1
The preparation method of Cefodizime Sodium, employing chemical compounds I is starting raw material, concrete steps comprise:
(1) chemical compounds I (GCLE) 30g and compound ii 12.3g are added in the system that contains 200mL acetone and 20mL water, be heated to 50 ℃, stir to clarify, add sodium iodide 0.3g, with massfraction, be that 10% sodium carbonate solution tune pH is 5.0, react 2 hours, add after 100g trifluoroacetic acid hydrolysis, add gac 1.5g decolouring, adopt 10mL acetone and the washing of 1mL water mixed liquid, the ammoniacal liquor that is 25% with massfraction is adjusted pH to 3.0, 10 ℃ of growing the grains 1 hour, suction filtration, 100mL water and 100mL acetone wash respectively, vacuum-drying, obtain 22.1g compound III, yield is 92%, purity is 98.76%,
(2) compound III 20g and compounds Ⅳ 27.4g are added in the mixed solvent system that contains 100mL toluene and 100mL methyl alcohol, drip triethylamine 23mL, 5 ℃ of reaction 1.5hr, add 1g activated carbon decolorizing, filter, 5mL toluene and the washing of 5mL methyl alcohol mixed liquor, standby;
Sodium isooctanoate 19g is dissolved in the mixing solutions of 25mL toluene and 25mL methyl alcohol, slowly splash in above-mentioned standby reaction solution, be slowly stirred to muddiness and go out crystalline substance, drip toluene 100mL, 10 ℃ of growing the grains 1 hour, suction filtration, 50mL toluene wash, vacuum-drying, obtain 28.5g compound V, yield is 91%, and purity is 99.84%, and superpolymer content is 0.083%.
embodiment 2
The preparation method of Cefodizime Sodium, employing chemical compounds I is starting raw material, concrete steps comprise:
(1) chemical compounds I (GCLE) 30g and compound ii 13.2g are added in the system that contains 200mL acetone and 15mL water, be heated to 50 ℃, stir to clarify, add Sodium Bromide 0.7g, with massfraction, be that 8% sodium hydrogen carbonate solution regulates pH to 5.5, react 1 hour, add after 141g trifluoroacetic acid hydrolysis, add gac 1.5g decolouring, 10mL acetone and the washing of 0.75mL water mixed liquid, it is 3.5 that the ammoniacal liquor that is 28% with massfraction is adjusted pH, 12 ℃ of growing the grains 1 hour, suction filtration, 100mL water and 100mL acetone wash respectively, vacuum-drying, obtain 21.8g compound III, yield is 91%, purity is 98.62%,
(2) compound III 20g and compounds Ⅳ 34.2g are added in the mixed solvent system that contains 200mL toluene and 100mL ethanol, drip diethylamine 23mL, 10 ℃ of reaction 1.5hr, add 1g activated carbon decolorizing, filter, 10mL toluene and the washing of 5mL alcohol mixeding liquid, standby;
Sodium methylate 3g is dissolved in the mixing solutions of 50mL toluene and 25mL ethanol, slowly splash in above-mentioned standby reaction solution, be slowly stirred to muddiness and go out crystalline substance, drip toluene 100mL, 12 ℃ of growing the grains 1 hour, suction filtration, 50mL toluene wash, vacuum-drying, obtain 28.2g compound V, yield is 90%, and purity is 99.80%, and superpolymer content is 0.09%.
embodiment 3
The preparation method of Cefodizime Sodium, employing chemical compounds I is starting raw material, concrete steps comprise:
(1) chemical compounds I (GCLE) 30g and compound ii 14.1g are added in the system that contains 200mL acetone and 10mL water, be heated to 50 ℃, stir to clarify, add Potassium Bromide 0.9g, the sodium hydrogen carbonate solution that is 12% with massfraction regulates pH to 5.2, react 2 hours, add after trifluoroacetic acid 54g hydrolysis, add gac 1.5g decolouring, 10mL acetone and the washing of 1mL water mixed liquid, the ammoniacal liquor that is 26% with massfraction is adjusted pH to 3.5, 15 ℃ of growing the grains 1 hour, suction filtration, 100mL water and 100mL acetone wash respectively, vacuum-drying, obtain 21.5g compound III, yield is 90%, purity is 98.56%,
(2) compound III 20g and compounds Ⅳ 30g are added in the mixed solvent system that contains 100mL acetone and 100mL methyl alcohol, drip TERTIARY BUTYL AMINE 23mL, 6 ℃ of reaction 1.5hr, add 1g activated carbon decolorizing and filter, and 5mL acetone and the washing of 5mL methyl alcohol mixed liquor are standby;
Sodium-acetate 10g is dissolved in the mixing solutions of 25mL acetone and 25mL methyl alcohol, slowly splash in above-mentioned standby reaction solution, be slowly stirred to muddiness and go out crystalline substance, drip acetone 100mL, 15 ℃ of growing the grains 1 hour, suction filtration, 50mL washing with acetone, vacuum-drying, obtain 28.4g compound V, yield is 90.6%, and purity is 99.86%, and superpolymer content is 0.08%.
embodiment 4
The preparation method of Cefodizime Sodium, employing chemical compounds I is starting raw material, concrete steps comprise:
(1) chemical compounds I (GCLE) 30g and compound ii 13g are added in the system that contains 200mL acetone and 20mL water, be heated to 50 ℃, stir to clarify, add 0.7g potassiumiodide, the sodium hydrogen carbonate solution that is 9% with massfraction regulates pH to 5.3, react 2 hours, add after 100g trifluoroacetic acid hydrolysis, add gac 1.5g decolouring, 10mL acetone and the washing of 1mL water mixed liquid, the ammoniacal liquor that is 27% with massfraction is adjusted pH to 2.5, 13 ℃ of growing the grains 1 hour, suction filtration, 100mL water and 100mL acetone wash respectively, vacuum-drying, obtain 21.7g compound III, yield is 91.5%, purity is 98.60%,
(2) compound III 20g and compounds Ⅳ 30g are added in the mixed solvent system that contains 100mL acetone and 100mL ethanol, drip pyridine 23mL, 8 ℃ are reacted 1.5 hours, add 1g activated carbon decolorizing, filter, and 5mL acetone and 5mL washing with alcohol, standby;
Sodium isooctanoate 10g is dissolved in the mixing solutions of 25mL acetone and 25mL ethanol, slowly splash in above-mentioned standby reaction solution, be slowly stirred to muddiness and go out crystalline substance, drip acetone 100mL, 13 ℃ of growing the grains 1 hour, suction filtration, 50mL washing with acetone, vacuum-drying, obtain 28.2g compound V, yield is 90%, and purity is 99.82%, and superpolymer content is 0.09%.
According to embodiment 1-4, can find out, the preparation method of Cefodizime Sodium provided by the invention, step is short, side reaction is few, has solved the high problem of the finished product superpolymer content, and superpolymer content is below 0.1%, product purity is more than 99.8%, and product yield reaches more than 90%; The present invention has shortened processing step, has saved the time, and technique is simple, and yield is high, and cost is low, and product purity is high, and supplementary material is cheap and easy to get, is applicable to suitability for industrialized production.
Claims (1)
1. a preparation method for Cefodizime Sodium, is characterized in that: employing chemical compounds I is starting raw material, and concrete steps comprise:
(1) chemical compounds I and compound ii are suspended in the aqueous solution containing organic solvent, are heated to 50 ℃, stir to clarify, add catalyzer, the sodium hydrogen carbonate solution that is 8%-12% with massfraction or sodium carbonate solution are adjusted pH to 5.0-5.5, reaction 1-2 hour, add after halogenated acid hydrolysis, then add activated carbon decolorizing, washing, the ammoniacal liquor that is 25%-28% with massfraction is adjusted pH to 2.5-3.5, growing the grain, suction filtration, washing, vacuum-drying, obtains light yellow or off-white color crystalline powder, i.e. compound III;
(2) in mixed solvent, compound III and compounds Ⅳ are added to rear stirring, then drip organic bases reaction 1-2 hour, add activated carbon decolorizing, filter, washing, drip salt forming agent solution, slowly be stirred to muddiness and go out crystalline substance, growing the grain, suction filtration, washing, vacuum-drying, obtains white or off-white color compound V, i.e. Cefodizime Sodium;
Synthetic route is:
；
Catalyzer described in step (1) is metal bromide or metal iodide;
Halogenated acid described in step (1) is trifluoroacetic acid;
Chemical compounds I in described step (1): compound ii: catalyzer: the mass ratio of halogenated acid is 1:0.41-0.47:0.01-0.03:1.8-4.7;
Organic solvent described in step (1) is acetone, and the described volume ratio containing acetone in the aqueous solution of organic solvent and water is 20:1-2;
The mass ratio of the compound III described in step (2) and compounds Ⅳ is 1:1.37-1.71;
Mixed solvent described in step (2) is the solvent that acetone and ethanol form, and its volume ratio is 1-3:1;
Organic bases described in step (2) is a kind of of pyridine or triethylamine or diethylamine or TERTIARY BUTYL AMINE or aniline or morpholine;
Salt forming agent described in step (2) is Sodium isooctanoate or sodium methylate or sodium-acetate, and the mass ratio of compound III and salt forming agent is 1:0.15-0.95.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210317362.4A CN102816173B (en) | 2012-08-31 | 2012-08-31 | Preparation method of cefodizime sodium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210317362.4A CN102816173B (en) | 2012-08-31 | 2012-08-31 | Preparation method of cefodizime sodium |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102816173A CN102816173A (en) | 2012-12-12 |
| CN102816173B true CN102816173B (en) | 2014-08-13 |
Family
ID=47300659
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210317362.4A Active CN102816173B (en) | 2012-08-31 | 2012-08-31 | Preparation method of cefodizime sodium |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102816173B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101143870A (en) * | 2006-09-12 | 2008-03-19 | 黄振华 | Novel cephalosporin derivative |
| CN101239985A (en) * | 2008-03-12 | 2008-08-13 | 齐鲁安替制药有限公司 | Method for preparing cefodizime sodium |
-
2012
- 2012-08-31 CN CN201210317362.4A patent/CN102816173B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101143870A (en) * | 2006-09-12 | 2008-03-19 | 黄振华 | Novel cephalosporin derivative |
| CN101239985A (en) * | 2008-03-12 | 2008-08-13 | 齐鲁安替制药有限公司 | Method for preparing cefodizime sodium |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102816173A (en) | 2012-12-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101613359B (en) | Method for synthesizing cefuroxime sodium | |
| CN102372729B (en) | Novel method for synthesizing cefoperazone sodium compound | |
| CN105131017B (en) | A kind of preparation method of Method of cefcapene pivoxil hydrochloride | |
| CN101812076B (en) | Cefuroxime sodium and preparation method thereof | |
| CN102002060B (en) | Preparation method of cefozopran hydrochloride | |
| CN105399754B (en) | A kind of preparation method of Cefamandole Nafate | |
| CN101948476A (en) | Method for preparing cefotiam hexetil hydrochloride | |
| CN105017286A (en) | Preparation method for cephalosporin anti-infective drug | |
| CN107058447A (en) | A kind of method of enzymatic clarification cefadroxil | |
| CN109608476B (en) | Method for treating production waste liquid of cephalosporin antibiotics and production method | |
| CN104193765A (en) | Method for synthesizing cefixime | |
| CN103467496A (en) | Preparing method of 7-((thiazolyl hydroxyl imino group) acetamido)-3-methyl cephalosporanic acid and another purpose | |
| CN104447800A (en) | Synthesis technology of cefoxitin acid | |
| CN103319503A (en) | Preparation method of cefdinir | |
| CN101941982B (en) | Novel preparation method of pharmaceutical ceforanide | |
| CN110407857B (en) | Preparation process of cefathiamidine | |
| CN104277053A (en) | High purity cefodizime and preparation method for intermediate cefodizime acid | |
| US20070213313A1 (en) | Direct process for the production of an amino acid dihydrochloride | |
| CN102816173B (en) | Preparation method of cefodizime sodium | |
| CN104230956B (en) | A kind of preparation method of cefoxitin | |
| CN103044416A (en) | Synthetic method of Carumonam sodium | |
| CN102911186A (en) | Ceftizoxime sodium preparation and refining method | |
| CN103665000B (en) | A kind of preparation method of cynnematin and another purposes | |
| CN108299470B (en) | Preparation method of cefteram pivoxil | |
| CN105254650A (en) | Synthesis method of antibacterial drug cefoxitin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee | ||
| CP03 | Change of name, title or address |
Address after: 272073 Shandong city of Jining province high tech Zone Shixian Road No. 1688 Patentee after: AMICOGEN (CHINA) BIOPHARM CO.,LTD. Address before: 272000 Shandong city of Jining province high tech Zone East Ring Road Lukang International Industrial Park Patentee before: SHANDONG LUKANG RECORD PHARMACEUTICALS Co.,Ltd. |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A preparation method of cefodizime sodium Effective date of registration: 20200730 Granted publication date: 20140813 Pledgee: Jining City branch of the China Co truction Bank Corp. Pledgor: AMICOGEN (CHINA) BIOPHARM Co.,Ltd. Registration number: Y2020980004549 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20211115 Granted publication date: 20140813 Pledgee: Jining City branch of the China Co truction Bank Corp. Pledgor: AMICOGEN (CHINA) BIOPHARM CO.,LTD. Registration number: Y2020980004549 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A preparation method of cefdizime sodium Effective date of registration: 20211201 Granted publication date: 20140813 Pledgee: Jining City branch of the China Co truction Bank Corp. Pledgor: AMICOGEN (CHINA) BIOPHARM CO.,LTD. Registration number: Y2021980013624 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20221115 Granted publication date: 20140813 Pledgee: Jining City branch of the China Co truction Bank Corp. Pledgor: AMICOGEN (CHINA) BIOPHARM CO.,LTD. Registration number: Y2021980013624 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A preparation method of cefodizime sodium Effective date of registration: 20221117 Granted publication date: 20140813 Pledgee: Jining City branch of the China Co truction Bank Corp. Pledgor: AMICOGEN (CHINA) BIOPHARM CO.,LTD. Registration number: Y2022980022253 |