CN109942598A - A kind of preparation method of trans- cefuroxime derivative - Google Patents
A kind of preparation method of trans- cefuroxime derivative Download PDFInfo
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- CN109942598A CN109942598A CN201910307533.7A CN201910307533A CN109942598A CN 109942598 A CN109942598 A CN 109942598A CN 201910307533 A CN201910307533 A CN 201910307533A CN 109942598 A CN109942598 A CN 109942598A
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- Prior art keywords
- trans
- cefuroxime
- methoxyimino
- furans
- cis
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- JFPVXVDWJQMJEE-SWWZKJRFSA-N 55268-75-2 Chemical class 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-SWWZKJRFSA-N 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 48
- 229960001668 cefuroxime Drugs 0.000 claims abstract description 54
- 238000003756 stirring Methods 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 239000002904 solvent Substances 0.000 claims abstract description 23
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims abstract description 15
- 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 claims abstract description 14
- 239000002253 acid Substances 0.000 claims abstract description 11
- 150000001408 amides Chemical class 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 10
- -1 carbamyl cefuroxime Chemical compound 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 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 description 21
- 230000015572 biosynthetic process Effects 0.000 claims description 20
- 238000003786 synthesis reaction Methods 0.000 claims description 20
- 150000002148 esters Chemical class 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 239000002994 raw material Substances 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 10
- 229960002620 cefuroxime axetil Drugs 0.000 claims description 9
- 230000007062 hydrolysis Effects 0.000 claims description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 claims description 8
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 7
- GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 230000009466 transformation Effects 0.000 claims description 7
- 239000005695 Ammonium acetate Substances 0.000 claims description 6
- 229940043376 ammonium acetate Drugs 0.000 claims description 6
- 235000019257 ammonium acetate Nutrition 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- 150000001298 alcohols Chemical class 0.000 claims description 5
- 150000001299 aldehydes Chemical class 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 229940113088 dimethylacetamide Drugs 0.000 claims description 5
- 150000002170 ethers Chemical class 0.000 claims description 5
- 229930195733 hydrocarbon Natural products 0.000 claims description 5
- 150000002430 hydrocarbons Chemical class 0.000 claims description 5
- 150000002576 ketones Chemical class 0.000 claims description 5
- 150000002825 nitriles Chemical class 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 3
- 150000002240 furans Chemical class 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- NVIAYEIXYQCDAN-MHTLYPKNSA-N (6r,7s)-7-azaniumyl-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S1CC(C)=C(C([O-])=O)N2C(=O)[C@H]([NH3+])[C@@H]12 NVIAYEIXYQCDAN-MHTLYPKNSA-N 0.000 claims 2
- KJZZIFMBNAAUCX-UHFFFAOYSA-N 3H-furan-2-imine hydrochloride Chemical compound Cl.O1C(CC=C1)=N KJZZIFMBNAAUCX-UHFFFAOYSA-N 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 7
- 238000010189 synthetic method Methods 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
- 239000000243 solution Substances 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 239000012071 phase Substances 0.000 description 15
- 239000012535 impurity Substances 0.000 description 8
- 238000005191 phase separation Methods 0.000 description 8
- 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 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- KEJCWVGMRLCZQQ-YJBYXUATSA-N Cefuroxime axetil Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(=O)OC(C)OC(C)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 KEJCWVGMRLCZQQ-YJBYXUATSA-N 0.000 description 2
- 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 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229960000534 cefuroxime sodium Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 2
- 229910001867 inorganic solvent Inorganic materials 0.000 description 2
- 239000003049 inorganic solvent Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- HAIUIAZIUDPZIE-UHFFFAOYSA-N 3-bromobutanoic acid Chemical compound CC(Br)CC(O)=O HAIUIAZIUDPZIE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- NVIAYEIXYQCDAN-UHFFFAOYSA-N 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(C)=C(C(O)=O)N2C(=O)C(N)C12 NVIAYEIXYQCDAN-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- PDNNQADNLPRFPG-UHFFFAOYSA-N N.[O] Chemical compound N.[O] PDNNQADNLPRFPG-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- ZWNSXPIVYODLLM-PHZXCRFESA-N azane;(2z)-2-(furan-2-yl)-2-methoxyiminoacetic acid Chemical compound [NH4+].CO\N=C(/C([O-])=O)C1=CC=CO1 ZWNSXPIVYODLLM-PHZXCRFESA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
The present invention relates to a kind of preparation methods of trans- cefuroxime derivative, comprising: A, phosphorus pentachloride is dissolved in solvent, in the presence of amide reagent, cis- Syn-2-Methoxyimino-2-(2-Furyl)-Acetic Acid-Ammonia Salt is added, reaction obtains cis- methoxyimino furans chloride solution；B, solvent is added into cis- methoxyimino furans chloride solution, adds strong acid or highly basic, stir, cis- methoxyimino furans chloride solution is changed into trans- methoxyimino furans chloroacetic chloride.The preparation method of trans- cefuroxime derivative of the invention it is original prepare cis- methoxy imino furans chloroacetic chloride on the basis of, a kind of method of initiative is provided, by the way that appropriate solvent is added, in the presence of strong acid or highly basic, the conversion of cis-trans isomerism is carried out, so as to efficiently prepare the cefuroxime antiderivative of high-purity by synthetic method.
Description
Technical field
The present invention relates to field of pharmaceutical technology, and in particular to a kind of preparation method of trans- cefuroxime derivative.
Background technique
Cefuroxime Sodium (ester) is most representative product in second generation cephalo-type product.It is required with to Drug Administration
Continuous improvement, to drug in process of production there may be or the impurity of degradation be required to be studied accordingly, while Europe
Continent pharmacopeia EP9.0 also lists the structural formula of the corresponding trans- impurity of Cefuroxime Sodium and CEFUROXIME AXETIL.The preparation of impurity is always
It is the difficult point during drug research and development, the trans- impurity of cefuroxime generallys use the method for preparation liquid phase separation originally to obtain,
But since amount of the impurity in principal product is few, the method using preparation liquid phase is high with cost to prepare, and yield is very low
The shortcomings that, cause the price of trans- impurity very high, is unfavorable for furtheing investigate the impurity of bulk pharmaceutical chemicals.
Summary of the invention
The object of the present invention is to provide a kind of preparation methods of trans- cefuroxime derivative, solve cephalo in the prior art
The problem of trans- impurity preparation cost of cefuroxime is high, yield is low etc..
The technical proposal for solving the technical problem of the invention is: a kind of preparation side of trans- cefuroxime derivative
Method, comprising:
A, phosphorus pentachloride is dissolved in solvent, in the presence of amide reagent, cis- methoxyimino furans second is added
Sour ammonium, reaction obtain cis- methoxyimino furans chloride solution；
B, solvent is added into cis- methoxyimino furans chloride solution, adds strong acid or highly basic, stir, it is cis-
The transformation synthesis of methoxyimino furans chloride solution obtains trans- methoxyimino furans chloroacetic chloride.
In the preparation method of trans- cefuroxime derivative of the invention, in step, the amide reagent with it is described
The mass ratio of phosphorus pentachloride is 0.2~3:1；The mass ratio of the phosphorus pentachloride and the cis- Syn-2-Methoxyimino-2-(2-Furyl)-Acetic Acid-Ammonia Salt
It is 0.5~3:1.
In the preparation method of trans- cefuroxime derivative of the invention, in step A and B, solvent used includes
Alcohols, esters, hydro carbons, ketone, aldehydes, amine, ethers, nitrile organic solvent or water inorganic solvent；
In stepb, strong acid is added after solvent being added into cis- methoxyimino furans chloride solution, stirs, makes
PH≤1, cis- methoxyimino furans chloride solution transformation synthesis obtain trans- methoxyimino furans chloroacetic chloride；Or
In step B, highly basic is added after solvent is added into cis- methoxyimino furans chloride solution, stirs, makes pH >=13, it is cis-
The transformation synthesis of methoxyimino furans chloride solution obtains trans- methoxyimino furans chloroacetic chloride.
In the preparation method of trans- cefuroxime derivative of the invention, in step, the amide reagent is N, N-
Dimethylformamide or DMAC N,N' dimethyl acetamide.
In the preparation method of trans- cefuroxime derivative of the invention, in stepb, temperature when stirring 10~
90℃；The time of stirring is 2h-10h.
It after stepb further include step C: with step in the preparation method of trans- cefuroxime derivative of the invention
The trans- methoxyimino furans chloroacetic chloride obtained after rapid A and B reaction is raw material, is reacted with 7-ACA, synthesis obtains trans- acetyl
Cefuroxime solution, then trans- acetyl cefuroxime is obtained after crystallized and filtered；The wherein cis- methoxyimino in step A
The mass ratio of furans ammonium acetate and 7-ACA are 0.5~2:1.
It after stepb further include step D: with anti-in the preparation method of trans- cefuroxime derivative of the invention
Formula methoxy imino furans chloroacetic chloride is raw material, is reacted with 7-ACA, and synthesis obtains trans- acetyl cefuroxime solution, using strong
Obtained after basic hydrolysis, crystallization, filtering it is trans- remove carbamyl cefuroxime, the wherein cis- methoxyimino furans second in step A
The mass ratio of sour ammonium and 7-ACA are 0.5~2:1.
It further include step E after step D: with anti-in the preparation method of trans- cefuroxime derivative of the invention
It is raw material that formula, which removes carbamyl cefuroxime, is reacted with chlorosulphonyl isocyanate, and synthesis obtains trans- cefuroxime acid solution, then passes through
Cross extracting and washing, trans- cefuroxime acid obtained after decoloration, condensing crystallizing, filtering, wherein it is trans- go carbamyl cefuroxime with
The mass ratio of chlorosulphonyl isocyanate is 1~3:1.
It further include step F after step E: with anti-in the preparation method of trans- cefuroxime derivative of the invention
Formula cefuroxime acid is raw material, react with 1- bromoethylacetic ester, synthesizes and obtains trans- CEFUROXIME AXETIL, then through extraction, washing,
Trans- CEFUROXIME AXETIL is obtained after decoloration, condensing crystallizing, filtering, wherein the matter of trans- cefuroxime acid and 1- bromoethylacetic ester
Measuring ratio is 1~3:1.
It after stepb further include step G: with step in the preparation method of trans- cefuroxime derivative of the invention
The trans- methoxyimino furans chloroacetic chloride that rapid A and B reacts is that raw material and 7-ADCA react, and synthesis obtains trans- going first
Oxygen ammonia cefuroxime solution, then obtain after crystallized and filtered it is trans- remove methoxy ammonia cefuroxime, the wherein cis- first in step A
The mass ratio of oxyimino group furans ammonium acetate and 7-ADCA are 0.5~2:1.
The preparation method for implementing trans- cefuroxime derivative of the invention has the advantages that of the invention anti-
The preparation method of formula cefuroxime derivative it is original prepare cis- methoxy imino furans chloroacetic chloride on the basis of, provide one
The initiative method of kind carries out the conversion of cis-trans isomerism in the presence of strong acid or highly basic by the way that appropriate solvent is added, thus
The cefuroxime antiderivative of high-purity can be efficiently prepared by synthetic method.
Specific embodiment
Below with reference to embodiment, the preparation method of trans- cefuroxime derivative of the invention is described further:
The present invention relates to a kind of preparation methods of trans- cefuroxime derivative, comprising:
A, phosphorus pentachloride is dissolved in solvent, is cooled to -30~10 DEG C, in the presence of amide reagent, be added cis-
Syn-2-Methoxyimino-2-(2-Furyl)-Acetic Acid-Ammonia Salt (cis- SMIA ammonium salt, CAS registration number are 97148-39-5) controls -30~10 DEG C of stirring 60-
240min, reaction obtain cis- methoxyimino furans chloride solution (cis- SMIA solution of acid chloride)；Wherein, solvent include but
It is not limited to esters, alcohols, hydro carbons, ketone, aldehydes, amine, nitrile, ethers etc.；Amide reagent includes but is not limited to N, N- diformazan
Base formamide, DMAC N,N' dimethyl acetamide etc.；The mass ratio of phosphorus pentachloride and solvent is 1:2~12, i.e. 1:2 to 1:12, pentachloro-
The mass ratio for changing phosphorus and solvent is preferably 1:3~8；The mass ratio of amide reagent and phosphorus pentachloride is 0.2~3:1, i.e. 0.2:1 is extremely
3:1；The mass ratio of phosphorus pentachloride and cis- Syn-2-Methoxyimino-2-(2-Furyl)-Acetic Acid-Ammonia Salt is 0.5~3:1, i.e. 0.5:1 to 3:1.
B, solvent is added into cis- methoxyimino furans chloride solution (cis- SMIA solution), adds strong acid and stirs
Mixing makes pH≤1 or highly basic is added and stirs to make pH >=13, and cis- methoxyimino furans chloride solution (cis- SMIA solution) turns
Become synthesis and obtains trans- methoxyimino furans chloroacetic chloride (trans- SMIA acyl chlorides)；Wherein, toward cis- methoxyimino furans second
The solvent being added in solution of acid chloride includes but is not limited to that alcohols, esters, hydro carbons, ketone, amine, aldehydes, ethers, nitrile etc. are organic
The inorganic solvents such as solvent or water, such as common methanol, ethyl alcohol, acetone, acetonitrile, ether organic solvent；Wherein, highly basic includes nothing
Machine highly basic or organic alkali, inorganic strong alkali include but is not limited to sodium hydroxide, potassium hydroxide etc., and organic alkali includes but is not limited to
Sodium methoxide, butyl lithium etc..Wherein, strong acid includes inorganic acid or organic acid.Inorganic acid includes but is not limited to hydrochloric acid, sulphur
Acid, nitric acid, perchloric acid etc., organic acid include but is not limited to formic acid, trifluoroacetic acid etc..
The mass ratio of the solvent that is added in step B and the cis- Syn-2-Methoxyimino-2-(2-Furyl)-Acetic Acid-Ammonia Salt in step A is 0.01~
10:1, i.e. 0.01:1 are to 10:1.Preferably, the cis- methoxyimino furans acetic acid in solvent and step A being added in step B
The mass ratio of ammonium is 0.01~3:1.In addition, the mass ratio of strong acid or highly basic and cis- Syn-2-Methoxyimino-2-(2-Furyl)-Acetic Acid-Ammonia Salt is 0.01
~2:1.
In stepb, temperature when stirring is at 10~90 DEG C, and preferably 20~70 DEG C；The time of stirring is 2h-10h.
In one embodiment, can also include after stepb step C: by 7-ACA, (7-amino-cephalosporanic acid, CAS be stepped on
Mark is 957-68-6) Yu Shuizhong is mixed, the sodium hydroxide solution that 5%-30% concentration is added dissolves 7-ACA, and step A is added
With obtained trans- methoxyimino furans chloroacetic chloride (trans- SMIA acyl chlorides) after B reaction, 1- is stirred to react at -20~20 DEG C
5h, synthesis obtain trans- acetyl cefuroxime solution, are layered, and organic solvent mutually separates, and 5%-35% concentration is added in water phase
Hydrochloric acid solution, adjust pH to 1.0-3.0, then crystallized precipitation, be filtered, washed, dry after obtain trans- acetyl cefuroxime；
Wherein the mass ratio of the cis- Syn-2-Methoxyimino-2-(2-Furyl)-Acetic Acid-Ammonia Salt in step A and 7-ACA are 0.5~2:1.
It can also include after stepb step D in another embodiment: 7-ACA being mixed into Yu Shuizhong, 5%- is added
The sodium hydroxide solution of 30% concentration dissolves 7-ACA, and the trans- methoxyimino furans obtained after step A and B reaction is added
Chloroacetic chloride, -20~20 DEG C are stirred to react 1-5h, and synthesis obtains trans- acetyl cefuroxime solution, are layered, organic solvent phase point
From the sodium hydroxide solution of addition acetone and 15%-30% concentration in water phase controls -25 DEG C~-5 DEG C stirrings hydrolysis
The hydrochloric acid solution of 5%-35% concentration is added in 10min-60min after hydrolysis, adjust pH to 1.0-3.0, then crystallized analysis
Out, trans- carbamyl cefuroxime (trans- DCC) must be removed after being filtered, washed, drying, wherein the cis- methoxy imido in step A
The mass ratio of base furans ammonium acetate and 7-ACA are 0.5~2:1.
Further, further include step E after step D: going carbamyl cefuroxime (trans- DCC) for original with trans-
Material, is added ethyl acetate in trans- DCC, is cooled to -70 DEG C~-20 DEG C, add chlorosulphonyl isocyanate (CSI), maintain -
70 DEG C~-20 DEG C reaction 8min-50min are added water stirring hydrolysis 15min-180min, add sodium bicarbonate aqueous solution, adjust
Save pH to 1.0-3.0, layering, water phase discards, and ethyl acetate phase is concentrated in vacuo to crystal precipitation, be filtered, washed, dry after obtain
Trans- cefuroxime acid, wherein trans-, to remove the mass ratio of carbamyl cefuroxime and chlorosulphonyl isocyanate be 1~3:1.
It further, further include step F after step E: using trans- cefuroxime acid as raw material, with 1- bromoethyl acetic acid
Ester (BEA) reaction, synthesis obtain trans- CEFUROXIME AXETIL, then obtain after extraction, washing, decoloration, condensing crystallizing, filtering trans-
CEFUROXIME AXETIL (i.e. CEFUROXIME AXETIL E isomer), wherein the mass ratio of trans- cefuroxime acid and 1- bromoethylacetic ester is 1
~3:1.
It in another embodiment, after stepb further include step G: sub- with the trans- methoxy that step A and B react
Amino furan chloroacetic chloride is raw material and 7-ADCA (7-aminodesacetoxycephalosporanic acid, CAS registration number are 26395-99-3)
Reaction, synthesis obtain it is trans- remove methoxy ammonia cefuroxime solution, then obtain trans- removing methoxy ammonia cephalo furan after crystallized and filtered
Pungent, wherein the mass ratio of the cis- methoxy imino furans ammonium acetate and 7-ADCA in step A is 0.5~2:1.
Organic solvent mentioned herein include but is not limited to alcohols, esters, hydro carbons, ketone, amine, aldehydes, ethers,
The organic solvents such as nitrile.
Above-mentioned preparation method is referring to following reaction equations:
Step A reaction equation:
Step B reaction equation:
Step C reaction equation:
Step D reaction equation:
Step E reaction equation:
Step F reaction equation:
Step G reaction equation:
It is described in detail below by specific embodiment.
Embodiment 1
The preparation of trans- methoxy imino furans chloroacetic chloride: being added 180g ethyl acetate for 35g phosphorus pentachloride, mix, cooling
To 0~10 DEG C, 50g dimethyl acetamide is added, the cis- methoxy imino furans acetic acid ammonium salt of 30g is then added, controls 0~10 DEG C
Cis- methoxy imino furans chloroacetic chloride is prepared in stirring 150 minutes, and 16g acetone is added, it is molten to add 3.8g10% sulfuric acid
Liquid, 50 DEG C of control are stirred to react 6 hours, obtain trans- methoxy imino furans chloroacetic chloride, purity 96.3%.
Embodiment 2:
The preparation of trans- methoxy imino furans chloroacetic chloride: 35g phosphorus pentachloride is added in 230g methylene chloride, is stirred molten
Solution is cooled to -5~0 DEG C, and 40g dimethylformamide is added, and the cis- methoxy imino furans acetic acid ammonium salt of 25g, control is then added
- 5~-5 DEG C of system is stirred to react 130 minutes, and cis- methoxy imino furans chloroacetic chloride is prepared, and 10g ethyl alcohol is added, adds
5g15% sodium hydroxide solution, 60 DEG C of control are stirred to react 4 hours, obtain trans- methoxy imino furans chloroacetic chloride, purity
96.9%.
Embodiment 3:
The preparation of trans- methoxy imino furans chloroacetic chloride: 35g phosphorus pentachloride is added in 230g methylene chloride, is stirred molten
Solution is cooled to -30 DEG C, and 50g dimethyl acetamide is added, and the cis- methoxy imino furans acetic acid ammonium salt of 70g, control-is then added
30~-20 DEG C are stirred to react 130 minutes, and cis- methoxy imino furans chloroacetic chloride is prepared, and 11g acetonitrile is added, adds
5g15% sodium hydroxide solution, 90 DEG C of control are stirred to react 3 hours, obtain trans- methoxy imino furans chloroacetic chloride, purity
95.6%.
Embodiment 4:
The preparation of trans- methoxy imino furans chloroacetic chloride: 35g phosphorus pentachloride is added in 180g butyl acetate, is stirred molten
Solution, is cooled to -25 DEG C, and the cis- methoxy imino furans acetic acid ammonium salt of 11.67g is then added, and -25~-20 DEG C of control is stirred to react
130 minutes, cis- methoxy imino furans chloroacetic chloride is prepared, 8g methanol is added, adds 5g37% hydrochloric acid solution, controls 10 DEG C
It is stirred to react 10 hours, obtains trans- methoxy imino furans chloroacetic chloride, purity 96.1%.
Embodiment 5:
The preparation of trans- acetyl cefuroxime: 25g7-ACA is mixed in 100g water, and 25% sodium hydroxide solution, which is added, to be made
Then 7-ACA dissolution is added the trans- methoxy imino furans chloroacetic chloride that embodiment 1 is prepared, it is anti-to control -10~-5 DEG C of stirrings
It answers 5 hours, is layered, 30% hydrochloric acid solution is added into water phase for ethyl acetate phase separation, adjusts pH to 1.3, and crystallization is precipitated, mistake
Trans- acetyl cefuroxime about 36.8g, yield 147.0%, purity 96.5% are obtained after filter, washing, drying.
Embodiment 6:
The preparation of trans- acetyl cefuroxime: 60g7-ACA is mixed in 200g water, and 25% sodium hydroxide solution, which is added, to be made
Then 7-ACA dissolution is added the trans- methoxy imino furans chloroacetic chloride that embodiment 1 is prepared, it is anti-to control 10~15 DEG C of stirrings
It answers 2 hours, is layered, 30% hydrochloric acid solution is added into water phase for ethyl acetate phase separation, adjusts pH to 1.5, and crystallization is precipitated, mistake
Trans- acetyl cefuroxime about 40.2g, yield 145.0%, purity 96.2% are obtained after filter, washing, drying.
Embodiment 7:
The preparation of trans- acetyl cefuroxime: 15g7-ACA is mixed in 50g water, and 25% sodium hydroxide solution, which is added, makes 7-
ACA dissolution, is then added the trans- methoxy imino furans chloroacetic chloride that embodiment 1 is prepared, and 5~10 DEG C of control is stirred to react 4
Hour, 30% hydrochloric acid solution is added into water phase for layering, ethyl acetate phase separation, adjusts pH to 1.6, and crystallization is precipitated, filtering,
Trans- acetyl cefuroxime about 28.8g, yield 141.0%, purity 96.1% are obtained after washing, drying.
Embodiment 8:
The trans- preparation for removing carbamyl cefuroxime: 25g7-ACA is mixed in 100g water, and it is molten that 25% sodium hydroxide is added
Liquid dissolves 7-ACA, and the trans- methoxy imino furans chloroacetic chloride that embodiment 1 is prepared then is added, controls 5~10 DEG C of stirrings
The sodium hydroxide solution of acetone and 20ml25%, control-are added into water phase for reaction 4 hours, layering, ethyl acetate phase separation
12~-5 DEG C of stirrings hydrolyze 30 minutes, and 30% hydrochloric acid solution is added after hydrolysis, adjust pH to 1.7, and crystallization is precipitated, filtering,
Washing, it is dry after obtain trans- going carbamyl cefuroxime (trans- DCC) about 30.6g, yield 122.4%, purity 97.1%.
Embodiment 9:
The trans- preparation for removing carbamyl cefuroxime: 60g7-ACA is mixed in 200g water, and it is molten that 25% sodium hydroxide is added
Liquid dissolves 7-ACA, and the trans- methoxy imino furans chloroacetic chloride that embodiment 1 is prepared then is added, and 15~20 DEG C of control is stirred
Reaction 2 hours, layering are mixed, the sodium hydroxide solution of acetone and 25%, control -20 are added into water phase for ethyl acetate phase separation
~-18 DEG C of stirrings hydrolyze 50 minutes, and 30% hydrochloric acid solution is added after hydrolysis, adjust pH to 1.9, and crystallization is precipitated, filters, washes
Wash, dry after obtain trans- going carbamyl cefuroxime (trans- DCC) about 38.2g, yield 120.1%, purity 96.3%.
Embodiment 10:
The trans- preparation for removing carbamyl cefuroxime: 15g7-ACA is mixed in 50g water, and 25% sodium hydroxide solution is added
7-ACA is dissolved, the trans- methoxy imino furans chloroacetic chloride that embodiment 1 is prepared then is added, controls -10~0 DEG C of stirring
The sodium hydroxide solution of acetone and 25%, control -8~-5 are added into water phase for reaction 4 hours, layering, ethyl acetate phase separation
It DEG C stirring hydrolysis 20 minutes, is added 30% hydrochloric acid solution after hydrolysis, adjusts pH to 1.5, crystallization is precipitated, is filtered, washed, does
It obtains trans- going carbamyl cefuroxime (trans- DCC) about 26.9g, yield 121.3%, purity 97.2% after dry.
Embodiment 11:
The preparation of trans- cefuroxime acid: the trans- DCC of 35g is added in 180g ethyl acetate, is cooled to -50~-40 DEG C,
21.6g chlorosulphonyl isocyanate is added, the temperature is maintained to be stirred to react 40 minutes, water 100g is added, stirring hydrolyzes 30 minutes, then
The aqueous solution of sodium bicarbonate is added, adjusts pH to 1.8 or so, layering, water phase discards, and ethyl acetate phase is concentrated in vacuo to a large amount of crystalline substances
Body is precipitated, and is cooled to 5 DEG C, continues stirred crystallization 2 hours, be filtered, washed, dry after obtain trans- cefuroxime acid 29g, yield
82.9%, purity 97.7%.
Embodiment 12:
The preparation of trans- CEFUROXIME AXETIL: the trans- cefuroxime acid of 20g is added in 150ml dimethylformamide, cooling
To 10 DEG C, 8.8g1- bromoethylacetic ester is added, maintains 10 DEG C to react 180 minutes, 200g acetic acid fourth then is added in reaction solution
In the mixed solution of ester and 250g water, butyl acetate phase is washed with sodium-chloride water solution after stirring extraction, is concentrated in vacuo after filtering
To being precipitated compared with polycrystalline, 200g isopropyl ether is then added, crystallization 5 hours is sufficiently stirred in room temperature, be filtered, washed, dry after obtain
Trans- CEFUROXIME AXETIL 18.3g, yield 91.5%, purity 97.5%.
Embodiment 12:
The trans- preparation for removing methoxy ammonia cefuroxime: 25g7-ADCA is mixed in 100g water, and it is molten that 25% sodium hydroxide is added
Liquid dissolves 7-ADCA, and the trans- methoxy imino furans chloroacetic chloride that embodiment 1 is prepared then is added, and 10~15 DEG C of control is stirred
Reaction 3 hours, layering are mixed, 30% hydrochloric acid solution is added into water phase for ethyl acetate phase separation, adjusts pH to 2.5, crystallization analysis
Out, be filtered, washed, dry after obtain trans- going methoxy ammonia cefuroxime about 36.8g, yield 147.0%, purity 96.5%.
It should be understood that for those of ordinary skills, it can be modified or changed according to the above description,
Within all these improvement or transformation should all belong to the protection domain of appended claims of the present invention.
Claims (10)
1. a kind of preparation method of trans- cefuroxime derivative characterized by comprising
A, phosphorus pentachloride is dissolved in solvent, in the presence of amide reagent, cis- Syn-2-Methoxyimino-2-(2-Furyl)-Acetic Acid-Ammonia Salt is added,
Reaction obtains cis- methoxyimino furans chloride solution；
B, solvent is added into cis- methoxyimino furans chloride solution, adds strong acid or highly basic, stir, cis- methoxy
The transformation synthesis of imino furan chloride solution obtains trans- methoxyimino furans chloroacetic chloride.
2. the preparation method of trans- cefuroxime derivative according to claim 1, which is characterized in that in step, institute
The mass ratio for stating amide reagent and the phosphorus pentachloride is 0.2~3:1；The phosphorus pentachloride and the cis- methoxyimino furan
The mass ratio of ammonium acetate of muttering is 0.5~3:1.
3. the preparation method of trans- cefuroxime derivative according to claim 1, which is characterized in that in step A and B
In, solvent used includes the inorganic molten of alcohols, esters, hydro carbons, ketone, aldehydes, amine, ethers, nitrile organic solvent or water
Agent；
In stepb, into cis- methoxyimino furans chloride solution be added solvent after strong acid is added, stir, make pH≤
1, cis- methoxyimino furans chloride solution transformation synthesis obtains trans- methoxyimino furans chloroacetic chloride；Or in step
In B, highly basic is added after solvent is added into cis- methoxyimino furans chloride solution, stirs, makes pH >=13, cis- methoxy
The transformation synthesis of imino furan chloride solution obtains trans- methoxyimino furans chloroacetic chloride.
4. the preparation method of trans- cefuroxime derivative according to claim 1, which is characterized in that in step, institute
Stating amide reagent is N,N-dimethylformamide or DMAC N,N' dimethyl acetamide.
5. the preparation method of trans- cefuroxime derivative according to claim 1, which is characterized in that in stepb, stir
Temperature when mixing is at 10~90 DEG C；The time of stirring is 2h-10h.
6. the preparation method of trans- cefuroxime derivative according to claim 1, which is characterized in that after stepb
Further include step C: using the trans- methoxyimino furans chloroacetic chloride obtained after step A and B reaction as raw material, being reacted with 7-ACA,
Synthesis obtains trans- acetyl cefuroxime solution, then obtains trans- acetyl cefuroxime after crystallized and filtered；Wherein in step A
Cis- Syn-2-Methoxyimino-2-(2-Furyl)-Acetic Acid-Ammonia Salt and the mass ratio of 7-ACA be 0.5~2:1.
7. the preparation method of trans- cefuroxime derivative according to claim 1, which is characterized in that after stepb
Further include step D: using trans- methoxy imino furans chloroacetic chloride as raw material, being reacted with 7-ACA, synthesis obtains trans- acetyl cephalo furan
Pungent solution, using obtained after highly basic hydrolysis, crystallization, filtering it is trans- remove carbamyl cefuroxime, the wherein cis- first in step A
The mass ratio of oxyimino group furans ammonium acetate and 7-ACA are 0.5~2:1.
8. the preparation method of trans- cefuroxime derivative according to claim 7, which is characterized in that after step D
Further include step E: going carbamyl cefuroxime as raw material using trans-, reacted with chlorosulphonyl isocyanate, synthesis obtains trans- head
Spore cefuroxime acid solution obtains trans- cefuroxime acid using extracting and washing after decoloration, condensing crystallizing, filtering, wherein trans- go
The mass ratio of carbamyl cefuroxime and chlorosulphonyl isocyanate is 1~3:1.
9. the preparation method of trans- cefuroxime derivative according to claim 8, which is characterized in that after step E
Further include step F: using trans- cefuroxime acid as raw material, being reacted with 1- bromoethylacetic ester, synthesis obtains trans- cefuroxime
Ester, then trans- CEFUROXIME AXETIL is obtained after extraction, washing, decoloration, condensing crystallizing, filtering, wherein trans- cefuroxime acid with
The mass ratio of 1- bromoethylacetic ester is 1~3:1.
10. the preparation method of trans- cefuroxime derivative according to claim 1, which is characterized in that after stepb
Further include step G: being reacted using the trans- methoxyimino furans chloroacetic chloride that step A and B react as raw material and 7-ADCA,
Synthesis obtain it is trans- remove methoxy ammonia cefuroxime solution, then obtain after crystallized and filtered it is trans- remove methoxy ammonia cefuroxime, wherein
The mass ratio of cis- Syn-2-Methoxyimino-2-(2-Furyl)-Acetic Acid-Ammonia Salt and 7-ADCA in step A is 0.5~2:1.
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