CN85108996A - 氨基噻唑乙酸衍生物的制备方法 - Google Patents
氨基噻唑乙酸衍生物的制备方法 Download PDFInfo
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- CN85108996A CN85108996A CN85108996.8A CN85108996A CN85108996A CN 85108996 A CN85108996 A CN 85108996A CN 85108996 A CN85108996 A CN 85108996A CN 85108996 A CN85108996 A CN 85108996A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 239000002253 acid Substances 0.000 title description 4
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 title description 2
- 229950003476 aminothiazole Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 150000001335 aliphatic alkanes Chemical class 0.000 claims abstract description 5
- 150000001336 alkenes Chemical class 0.000 claims abstract description 5
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- 239000000243 solution Substances 0.000 description 22
- -1 4Be hydrogen Chemical class 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- 150000002430 hydrocarbons Chemical class 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229960003328 benzoyl peroxide Drugs 0.000 description 6
- 229930195733 hydrocarbon Natural products 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000012188 paraffin wax Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000001103 potassium chloride Substances 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 206010013786 Dry skin Diseases 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 150000001340 alkali metals Chemical group 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- IKWLIQXIPRUIDU-ZCFIWIBFSA-N (6r)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound OC(=O)C1=CCS[C@@H]2CC(=O)N12 IKWLIQXIPRUIDU-ZCFIWIBFSA-N 0.000 description 2
- 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
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- 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 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical class [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000002178 crystalline material Substances 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- QDHCHVWSKUMZDZ-UHFFFAOYSA-N ethyl dihydrogen phosphite Chemical compound CCOP(O)O QDHCHVWSKUMZDZ-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 125000000542 sulfonic acid group Chemical group 0.000 description 2
- 150000007970 thio esters Chemical class 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 150000003952 β-lactams Chemical class 0.000 description 2
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical class CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- 125000005999 2-bromoethyl group Chemical group 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- GZONHMGOJOQEEX-UHFFFAOYSA-N C=CC.[K] Chemical compound C=CC.[K] GZONHMGOJOQEEX-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- UCTLHLZWKJIXJI-LXIBVNSESA-N [(3s,8r,9s,10r,13s,14s)-17-chloro-16-formyl-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15-decahydro-1h-cyclopenta[a]phenanthren-3-yl] acetate Chemical compound C([C@@H]12)C[C@]3(C)C(Cl)=C(C=O)C[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)C)C1 UCTLHLZWKJIXJI-LXIBVNSESA-N 0.000 description 1
- MKUSAUJRCWWAMK-UHFFFAOYSA-N [K]CC=C Chemical compound [K]CC=C MKUSAUJRCWWAMK-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- SWEYNHYBJHPVJL-UHFFFAOYSA-N butanoic acid;sodium Chemical compound [Na].CCCC(O)=O SWEYNHYBJHPVJL-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- JUMYIBMBTDDLNG-OJERSXHUSA-N hydron;methyl (2r)-2-phenyl-2-[(2r)-piperidin-2-yl]acetate;chloride Chemical compound Cl.C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 JUMYIBMBTDDLNG-OJERSXHUSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- XRBCRPZXSCBRTK-UHFFFAOYSA-N phosphonous acid Chemical compound OPO XRBCRPZXSCBRTK-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- RKEWSXXUOLRFBX-UHFFFAOYSA-N pimavanserin Chemical compound C1=CC(OCC(C)C)=CC=C1CNC(=O)N(C1CCN(C)CC1)CC1=CC=C(F)C=C1 RKEWSXXUOLRFBX-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940099204 ritalin Drugs 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- 229940094989 trimethylsilane Drugs 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
具有下述通式的化合物的制备方法。
这里R1是低级烷烃基,低级烷酰基,低级烯烃基或是-CH2COOR2基团,或是-C(CH3)2COOR2基团,R2实际上是一种容易裂解的基团。
Description
本发明涉及制备具有下述通式的化合物的方法,
这里的M是一种碱金属原子。
这个方法包括具有下述通式的化合物
这里的R是低级烷烃,
同具有下述通式的化合物反应,
CH2=CH-CH2-OM+Ⅲ
这里M和上面提到的M意义相同。
反应是在无水条件下和在一种实际上由烯丙醇组成的溶剂中进行的。
本发明也涉及到制备下述通式化合物的方法,
这里R1是低级烷烃,低级烷酰基,低级烯烃或者是-CH2C2OOR2基团,或是-C(CH3)2COOR2基团。R2是一种很容易裂解的基团。这个方法包括依照本发明得到的通式Ⅰ的化合物同具有下述通式的化合物的反应
这里的X是一个可离解的基团,R1含义和上面的相同。以及应用这些方法制备具有灭菌活性的单-β-内酰胺,头孢菌素,青霉素的方法,在β-内酰胺环上的氨基基团可以被具有下述通式的基团所取代
这里R3是氢,低级烷烃,低级烯烃,或-CH2COOR4基团,或-C(CH3)2COOR4基团,R4是氢,或者是容易被氢离解的基团。
“低级”这一词指的是最多7个,最好是4个碳原子的根或化合物。“烷烃”一词指的是直链或支链的,被取代的碳氢化合物的根,如甲基,乙基和另一丁基。“烯烃”一词指的是直链或支链的不饱和碳氢化合物根,如丙烯基,2-丁烯基,3-丁烯基。“烷酰基”一词指的是直链或支链的脂肪酸的根,如乙酰基,丙酰基,和异丁酰基。
“容易裂解的基团”一词,优先指的是苯环被囟素,低级烷氧基,或硝基任意取代的苯基例如,苯,对-硝基苯,对-甲氧基苯,2,4或3,4-二甲氧基苯,对-氯苯,特-烷烃基团,如特-丁基,在2-位上被囟化的低级烷烃基团,如2,2,2-三氯代乙基,2-溴代乙基,2-碘代乙基,在2-位上被甲基硅烷化的低级烷烃,如2-三甲基硅烷乙基,用氢解容易除去的基团,特别优先考虑那些生理学条件下容易被除去的基团,特别是低级-烷酰氧基-低级烷基基团,如醋酸甲酯,三甲基乙酸甲酯,1-醋酸乙酯和1-三甲基乙酸乙酯基团,和低级烷氧基羧酸-低级烷基酯基团,如甲氧基甲酸甲酯,1-乙氧基甲酸乙酯和1-异丙氧基甲酸乙酯基团。
“离解基团”一词习惯上指的是能离解的基团,如磺酸基和囟原子。例如适合的磺酸基团是低级的烷基磺酸基团,如甲基磺酸基团和芳基磺酸基团,如对-苯甲磺酸基团。适合的囟原子是氯,溴,碘原子。
按照本发明通式Ⅱ的化合物同通式Ⅲ的烯丙醇碱金属盐的反应可以在很宽的温度范围内进行,例如在大约0℃到反应混合物沸腾温度范围内进行。然而,反应很容易在室温下完成。如果通式Ⅱ的化合物作为原料,最好使用相应的乙酯,这是一种从市场上可购买到的化合物。最好使用烯丙醇钾作为通式Ⅲ的原料。
通式Ⅲ的丙烯醇的碱金属盐可以用丙烯醇同碱金属,碱金属的氢化物,如氢化钠,碱金属的烷基化物,如正-丁基锂或碱金属的氢氧化物,如氢氧化钾,按照已知的方法反应而制备。
为了完成按照本发明用通式Ⅴ的化合物得到通式Ⅰ的化合物的反应,通式Ⅰ的化合物最好是悬浮或溶解在一种惰性的有机溶剂中,例如,适合的溶剂是碳氢化合物,如戊烷,己烷,环己烷,石油醚,苯,甲苯和二甲苯,醚类,如四氢呋喃,二噁烷,乙二醇二甲基醚,乙醚,特-基甲基醚,N,N-二甲基甲酰胺,丙酮,乙酸乙酯,乙腈和二甲基亚砜。反应可以在一个很宽的温度范围内完成,例如从大约0℃到反应混合物沸腾温度的范围内完成。如果通式Ⅴ的化合物作为原料,最好使用相应的囟化物。
如上所述,本发明的方法可用于制备具有抗微生物活性的单-β-内酰胺,头孢菌素和盘尼西林衍生物,β-内酰胺环上的氨基基团可被通式Q的基团所取代。通式Ⅳ的化合物属于一类已知的化合物,可以相似的方法将其转换为所需要的,具有抗微生物活性的单-β-内酰胺,透孢菌素,和盘尼西林。
实例1
a)33.7克(600毫克分子)的氢氧化钾溶解在200毫升的烯丙醇中,并向其中加入300毫升的甲苯,过滤稍许混浊的溶液,滤液在真空中,30℃下浓缩(除去水份)。油状的剩余物再次溶解在300毫升的甲苯中,溶液再次在真空中浓缩。得到的丙烯醇钾溶解在900毫升丙烯醇中,随后溶液用64.5克(300毫克分子)的乙基2-(2-氨基-4-噻唑基)-2-顺-羟基亚胺基乙酸酯处理,混合物在室温下搅拌2天,结晶出的物质在减压下抽滤出,依次用丙烯醇,醋酸乙酯和乙醚洗涤,并在40℃下真空干燥。得到熔点>250℃的烯丙基2-(2-氨基-4-噻唑基)-2-顺-羟基亚胺基-乙酸酯的钾盐。
b)76.2克(287.2毫克分子)的烯丙基2-(2-氨基-4-噻唑基)-2-顺-羟基亚胺基-乙酸酯的钾盐悬浮在1.4升的四氢呋喃中,悬浮液冷却到0℃并在搅拌下用20.4毫升(287.2毫克分子)的乙酰氯处理。一小时以后,混合物浓缩到很少的体积,并用3升乙酸乙酯处理。得到的溶液用水洗涤三次,水萃取液同1升的乙酸乙酯一起振摇。黑色的有机相用骨碳处理,用硫酸镁干燥,并在真空中挥发。剩余物溶解在1升的二氯甲烷中,过滤出不溶的物质,然后用2升的四氯化碳处理,并浓缩到很小的体积。在减压下过滤出结晶的物质,用四氯化碳和石油醚洗涤,并在40℃下真空干燥。得到熔点144-147℃的烯丙基2-(2-氨基-4-噻唑基)-2-顺-醋酸基亚胺基-醋酸酯。
c)54克(200毫克分子)的烯丙基2-(2-氨基-4-噻唑基)-2-顺-醋酸基亚胺基-醋酸酯在氮气下溶解在1.4升的乙腈中,溶液冷却到0℃,并依次用448毫克(2毫克分子)的醋酸钯(Ⅱ)和1.72毫升(10毫克分子)亚膦酸三乙酯处理。5分钟以后,将23,2毫升(220毫克分子)的N-甲基-四氢吡咯加入其中,混合物在氮气下,在0℃搅拌过夜,从而,2-(2-氨基-4-噻唑基)-2-顺-乙酸基亚胺基-乙酸的N-烯丙基-N-甲基四氢吡咯盐被结晶出。
d)接着向其中加入28毫升(248毫克分子)的N-甲基吗啉,30分钟以后,加入74克(220毫克分子)的2,2-二硫代-双苯并噻唑。在4小时之内,在0℃搅拌下,向其中滴加42毫升(245毫克分子)的亚磷酸三乙酯在200毫升乙腈中的溶液。接着混合物再搅拌30分钟。析出的结晶的物质在减压下过滤,首先用乙腈洗涤,然后用乙醚洗涤,并在30℃下真空干燥。得到熔点为170-172℃的2-(2-氨基-4-噻唑基)2-顺-乙酸基亚胺基-乙酸的2-苯并噻唑的硫酯。熔点:170-172℃。
e)29.6克(80毫克分子)的7-氨基-3-{[2.5-二氢-6-羟基-2-甲基-5-氧代-不对称-3-三吖嗪基)硫代]甲基}-3-头孢烯-4-羧酸悬浮在56毫升的N,N-二甲基甲酰胺中,悬浮液用24.8毫升(176毫克分子)的三乙基胺处理,混合物冷却到0℃,并向其中加入80毫升的水。向得到的澄清溶液中加入38克(100毫克分子)的固定的2-(2-氨基-4-噻唑基)-2-顺-乙酸基亚胺基-乙酸的2-苯并噻唑的硫酯,反应混合物在0℃搅拌3小时。过滤黑色的溶液,剩余物用每次用40毫升的N,N-二甲基甲酰胺洗二次。溶液冷却到0℃,用96毫升(192毫克分子)的2-乙基乙酸钠(在乙酸乙酯中)的2N溶液处理,1080毫升的丙酮在30分钟内,在0℃下加入其中,同时加以搅拌,在减压下过滤颗粒状的物质,先用比例为3∶2的丙酮和N,N-二甲基甲酰胺的混合物500毫升洗涤,然后再用500毫升的丙酮洗涤,室温下真空干燥,得到7-[2-(2-氨基-4-噻唑基)-2-顺-乙酸基亚胺基乙酰胺基]-3-{-[(2,5-二氢-6-羟基-2-甲基-5-氧代-不对称-3-三吖嗪基)-硫代]甲基}-3-头孢烯-4-羧酸的二钠盐,用HPLC(高效液相色谱)测定,强度96.6%。
f)48克(76.6毫克分子)的7-[2-(2-氨基-4-噻唑基)-2-顺-乙酸基亚胺基乙酰胺基]-3-{-[(2,5-二氢-6-羟基-2-甲基-5-氧代-不对称-3-三吖嗪基)-硫代]甲基}-3-头孢烯-4-羧酸的二钠盐溶解在一种冷却到25℃的520毫升的甲醇和400毫升的水溶液中。溶液的PH借助于1N的氢氧化钠调整到8,并且在整个反应延续时期内保持这个PH值。从而氢氧化钠的消耗量是非常的少。反应完成以后(反应的过程用HPLC检测),用1N的盐酸把PH值调整到7,黑色的溶液同10克的活性碳一起搅拌20分钟。随后过滤混合物,剩余物用52毫升的甲醇和40毫升水的混合物洗涤。在搅拌下用2.4升的乙醇处理,得到黄色的溶液,随后混合物冷却到0℃,在减压下滤出颗粒状的物质,先用350毫升乙醇和水的混合物(6∶1)洗涤,然后再用450毫升乙醇洗,接着在1600Pa下干燥,然后在高真空下室温干燥。得到347克(77.5%)的7-[2-(2-氨基-4-噻唑基)-2-顺-乙酸基亚胺基乙酰胺基]-3-{-[(2,5-二氢-6-羟基-2-甲基-5-氧代-不对称-3-三吖嗪基)-硫代]甲基}-3-头孢烯-4-羧酸的二钠盐,仅含有
5.9%乙醇和4.9%的水。
微量元素分析:[按照C17H14N8Na2O7S3(584.51)|5.9%乙醇|4.9%水计算]
计算值:C34.24;H3.48;N17.10
测定值:C33.79;H3.20;N17.24
实例2
a)4.30克的氢化钠(百分之99)在2℃下分批加入到200毫升的烯丙醇中。气体挥发净以后,40.0克的乙基2-(2-氨基-4-噻唑基)-2-顺-羟基亚胺基-乙酸酯一次加入,化合物在室温下搅拌2小时,随后立即在真空下蒸出40毫升的溶剂,剩余物在室温下搅拌过夜。滤出产物,用乙酸乙酯和特-丁基甲基醚洗涤,在高真空下干燥到恒量。得到烯丙基2-(2-氨基-4-噻唑基)-2-顺-羟基亚胺基-乙酸酯的钠盐。
b)62毫升的正-丁基锂(1.6M在己烷中)在-78℃下滴加到240毫升的烯丙醇中,混合物避免在室温下受热,在真空下除去100毫升溶剂。然后在21.5克的乙基2-(2-氨基-4-噻唑基)-2-顺-羟基亚胺基-乙酸酯加到其中,反应混合物搅拌过夜。滤出产物,用乙酸乙酯和特-丁基甲基醚洗涤,并在高真空下干燥到恒量。得到熔点>260℃的烯丙基2-(2-氨基-4-噻唑基)-2-顺-羟基亚胺基-乙酸酯。
c)在搅拌下将337克的氢氧化钾溶解在2升的烯丙醇中,溶液用3升的甲苯处理,混合物在真空下(2000Pa)挥发。混合物再次用3升的甲苯处理,并再次挥发。剩余物溶解在1升的烯丙醇中,随后溶液用645克的乙基2-(2-氨基-4-噻唑基)-2-顺-羟基亚胺基-乙酸酯处理,在室温下搅拌45小时。滤出产物,用1升的烯丙醇,8升的乙酸乙酯,和2.5升的特-丁基甲基醚洗涤,在高真空下,40℃干燥至恒量。得到烯丙基2-(2-氨基-4-噻唑基)-2-顺-羟基亚胺基-乙酸酯。
HNMR在(CD3)2SO中的光谱:每种情况下的讯号为:
9.20(S宽度);5.96(S,1H);6.3-5.0(m,3H);
4.66(d J=6.5Hz 2H)ppm。
实例3
4.60克的烯丙基2-(2-氨基-4-噻唑基)-2-顺-羟基亚胺基-乙酸酯溶解在20毫升无水N,N-二甲基甲酰胺中,随后溶液滴加3.4毫升新蒸馏过的烯丙基溴。接着温度升到50℃。15分钟以后混合物用饱和的氯化铵溶液处理,然后用乙酸乙酯萃取,合并有机相,用水和饱和的氯化钠溶液洗二次,并用硫酸镁干燥。挥发溶剂后得到的剩余物从特-丁基甲基醚中重结晶。得到熔点106-107℃的烯丙基2-(2-氨基-4-噻唑基)-2-顺-烯丙醇基亚胺基-乙酸酯。
实例4
a)82克(0.38克分子)的乙基2-(2-氨基-4-噻唑基)-2-顺-羟基亚胺基-乙酸酯加到360毫升含有0.5克分子的烯丙基钾的烯丙醇溶液中,在氩气下,悬浮液在室温下搅拌20小时,随后在减压下滤出颗粒状的物质,用乙酸乙酯和乙醚洗涤,在真空下(1600Pa)50℃干燥。得到烯丙基2-(2-氨基-4-噻唑基)-2-顺-羟基亚胺基-乙酸酯的钾盐。
b)大约39.5克的钾盐,在室温下悬浮在450毫升的无水丙酮中。悬浮液用5克的碘化钾和26.9克的氯代乙酸特-丁酯处理,随后混合物在氩气下回流4小时。然后混合物倾入750毫升乙酸乙酯和750毫升水中,充分地搅拌,分离成两相,水相用400毫升乙酸乙酯洗涤,合并乙酸乙酯,并用饱和的氯钠溶液洗涤。在硫酸钠上干燥,并挥发。剩余物从540毫升甲苯中重结晶,从而得到烯丙基2-(2-氨基-4-噻唑基)-2-顺-{[(特-丁氧基羰基)-甲氧基]亚胺基}-乙酸酯,熔点136-138℃。
c)21.5克的烯丙基2-(2-氨基-4-噻唑基)-2-顺-{[(特-丁氧基羰基)-甲氧基]亚胺基}-乙酸酯悬浮在150毫升无水乙腈中,然后在氩气下,同时加以搅拌,依次加入120毫克的乙酸钯(Ⅱ),0.5毫升的亚磷酸三乙基酯,和5.3毫升的N-甲基四氢吡咯,混合物在室温下搅拌大约1.5小时,随后,2-(2-氨基-4-噻唑基)-2-顺-{[(特-丁氧基羰基)-甲氧基]亚胺基}-乙酸的N-烯丙基,-N-甲基四氢吡咯盐被结晶出。悬浮液接着用6毫升N-甲基吗啉和20克二硫代-双-2-苯并噻唑处理,将混合物冷却到-5℃到0℃,然后将12毫升的亚磷酸三乙基酯(在30毫升的无水乙腈中)溶液,在2小时内滴加到其中。在滴完后1小时,将混合物冷却到-10℃,在减压下滤出结晶的硫酯,依次用35毫升的乙腈和35毫升的乙醚洗涤,在真空下(1600Pa)60℃干燥。得到2-(2-氨基-4-噻唑基)-2-顺-{[(特-丁氧基羰基)-甲氧基]亚胺基}-乙酸的2-苯并噻唑的硫酯,熔点142-144℃。
d)71.8克(0.13克分子)的(3S,4S)-3-氨基-4-氨基甲酸基-甲基-2-氧代-1-氮杂环丁二烯磺酸分散在1.5升二氯甲烷中,随后分散液一边搅拌,一边用45.6克(0.45克分子)的三乙基胺和148,6克(0.33克分子)的2-(2-氨基-4-噻唑基)-2-顺-{[(特-丁氧基羰基)-甲氧基]亚胺基}-乙酸的2-苯并噻唑硫酯处理。反应混合物在室温下搅拌5小时。加入1.5升的水,分离出水相,每次用250毫升二氯甲烷萃取二次,加入850毫升百分之37的盐酸酸化。在室温搅拌2小时以后,得到的悬浮液冷却到0℃,再继续搅拌0.5小时。滤出颗粒物,依次用1000毫升冷水,1000毫升甲醇和1000毫升乙醚洗涤,在真空中(1600Pa)40℃干燥12小时。得到(3S,4S)-3-{(Z)-2-(2-氨基-4-噻唑基)2-[(羟基-甲氧基)亚胺基]乙酰胺基}-4-氨基甲酸基甲基-2-氧代-1-氮杂环丁二烯磺酸,熔点:207℃。
实例5
11.66克的烯丙基2-(2-氨基-4-噻唑基)-2-顺-羟基亚胺基-乙酸酯在室温下悬浮在100毫升无水的四氢呋喃中。悬浮液用6.2毫升三甲基乙酰氯处理,混合物搅拌45分钟,把溶剂挥发掉,剩余物分布在乙酸乙酯和水之间。水相用乙酸乙酯萃取二次。合并有机相用饱和的碳酸氢盐溶液洗涤二次,每次都用水和饱和的氯化钠洗一次。在硫酸镁上干燥,并挥发。剩余物从特-丁基甲基醚中重结晶,得到烯丙基2-(2-氨基-4-噻唑基)-2-顺-三甲基乙酸基亚胺基乙酸酯,熔点:141-143℃。
Claims (6)
2、根据权利要求1的方法所述,其特征在于M是钾原子。
3、根据权利要求1或2的方法所述,其特征在于R是乙基。
5、根据权利要求4的方法所述,其特征在于X是囟素。
6、如上面文中所述的本发明。
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US (1) | US4888429A (zh) |
EP (1) | EP0185221B1 (zh) |
JP (1) | JPH0730057B2 (zh) |
KR (1) | KR930004194B1 (zh) |
CN (1) | CN1013675B (zh) |
AT (1) | ATE56963T1 (zh) |
AU (1) | AU581046B2 (zh) |
CA (1) | CA1263399A (zh) |
DE (1) | DE3579894D1 (zh) |
DK (1) | DK591185A (zh) |
HU (1) | HU195958B (zh) |
IL (1) | IL77329A (zh) |
NZ (1) | NZ214536A (zh) |
PH (1) | PH21127A (zh) |
ZA (1) | ZA859536B (zh) |
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CH674645A5 (zh) * | 1987-12-23 | 1990-06-29 | Lonza Ag | |
JPH0320265A (ja) * | 1989-02-10 | 1991-01-29 | Meiji Seika Kaisha Ltd | アミノチアゾール酢酸誘導体並びにその製造法 |
WO1992007840A1 (en) * | 1990-11-02 | 1992-05-14 | Taisho Pharmaceutical Co., Ltd. | Thiazole thioester derivative |
US7105659B2 (en) * | 2003-06-02 | 2006-09-12 | Aurobind - Pharma Ltd. | Process for preparing cefdinir |
US20110118462A1 (en) * | 2009-11-18 | 2011-05-19 | Guangzhou Baiyunshan Pharmaceutical Co., Ltd. Guangzhou Baiyunshan Pharmaceutical Factory | N-heterocyclic substituent-containing antibiotic, preparation and use thereof |
FI20096394A0 (fi) | 2009-12-23 | 2009-12-23 | Valtion Teknillinen | Tunkeutumisen havaitseminen viestintäverkoissa |
CN112830903A (zh) * | 2020-12-29 | 2021-05-25 | 山东金城柯瑞化学有限公司 | 头孢克肟侧链酸活性酯的制备方法 |
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EP0096296B1 (de) * | 1982-06-03 | 1987-07-29 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | 1-Sulfo-2-oxoazetidinderivate |
DE3377061D1 (en) * | 1982-06-03 | 1988-07-21 | Hoffmann La Roche | Process for the preparation of 1-sulfo-2-oxoazetidine derivatives |
NL8202342A (nl) * | 1982-06-10 | 1984-01-02 | Schulte & Lestraden Bv | Cel. |
IE55406B1 (en) * | 1982-08-07 | 1990-09-12 | Tanabe Seiyaku Co | Novel cephalosporin compounds and preparation thereof |
JPS59184186A (ja) * | 1983-04-01 | 1984-10-19 | Meiji Seika Kaisha Ltd | 新規セフエム化合物 |
US4652651A (en) * | 1983-05-31 | 1987-03-24 | Hoffmann-La Roche Inc. | Process for the manufacture of 1-sulpho-2-oxoazetidine carboxylic acid intermediates via catalytic ester cleavage |
-
1985
- 1985-11-12 CA CA000495059A patent/CA1263399A/en not_active Expired
- 1985-11-25 EP EP85114900A patent/EP0185221B1/de not_active Expired - Lifetime
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- 1985-11-25 DE DE8585114900T patent/DE3579894D1/de not_active Expired - Fee Related
- 1985-12-07 CN CN85108996A patent/CN1013675B/zh not_active Expired
- 1985-12-12 NZ NZ214536A patent/NZ214536A/xx unknown
- 1985-12-12 ZA ZA859536A patent/ZA859536B/xx unknown
- 1985-12-13 AU AU51194/85A patent/AU581046B2/en not_active Ceased
- 1985-12-13 IL IL77329A patent/IL77329A/xx unknown
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- 1985-12-18 DK DK591185A patent/DK591185A/da not_active Application Discontinuation
- 1985-12-18 JP JP60283148A patent/JPH0730057B2/ja not_active Expired - Lifetime
- 1985-12-19 KR KR1019850009583A patent/KR930004194B1/ko active IP Right Grant
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Publication number | Publication date |
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DK591185D0 (da) | 1985-12-18 |
HU195958B (en) | 1988-08-29 |
JPH0730057B2 (ja) | 1995-04-05 |
ZA859536B (en) | 1986-08-27 |
NZ214536A (en) | 1988-08-30 |
DE3579894D1 (de) | 1990-10-31 |
KR860004861A (ko) | 1986-07-14 |
AU5119485A (en) | 1986-06-26 |
EP0185221B1 (de) | 1990-09-26 |
AU581046B2 (en) | 1989-02-09 |
CN1013675B (zh) | 1991-08-28 |
DK591185A (da) | 1986-06-20 |
US4888429A (en) | 1989-12-19 |
EP0185221A2 (de) | 1986-06-25 |
HUT41015A (en) | 1987-03-30 |
IL77329A (en) | 1990-02-09 |
EP0185221A3 (en) | 1987-08-19 |
CA1263399A (en) | 1989-11-28 |
JPS61145170A (ja) | 1986-07-02 |
KR930004194B1 (ko) | 1993-05-21 |
PH21127A (en) | 1987-07-27 |
ATE56963T1 (de) | 1990-10-15 |
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