TW467915B - Process for the preparation of cefodizime - Google Patents
Process for the preparation of cefodizime Download PDFInfo
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- TW467915B TW467915B TW075102826A TW75102826A TW467915B TW 467915 B TW467915 B TW 467915B TW 075102826 A TW075102826 A TW 075102826A TW 75102826 A TW75102826 A TW 75102826A TW 467915 B TW467915 B TW 467915B
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- 238000000034 method Methods 0.000 title claims abstract description 24
- 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 claims abstract 4
- 229960001958 cefodizime Drugs 0.000 title claims abstract 4
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 125000006239 protecting group Chemical group 0.000 claims abstract description 8
- 239000000047 product Substances 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 7
- -1 fluorenyl Isobutyl ketone Chemical compound 0.000 claims description 7
- 125000001477 organic nitrogen group Chemical group 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- 229940072049 amyl acetate Drugs 0.000 claims description 2
- PGMYKACGEOXYJE-UHFFFAOYSA-N anhydrous amyl acetate Natural products CCCCCOC(C)=O PGMYKACGEOXYJE-UHFFFAOYSA-N 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- UIUXUFNYAYAMOE-UHFFFAOYSA-N methylsilane Chemical compound [SiH3]C UIUXUFNYAYAMOE-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- 238000006386 neutralization reaction Methods 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- NDVMCQUOSYOQMZ-UHFFFAOYSA-N 2,2-bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)C(C(N)=O)[Si](C)(C)C NDVMCQUOSYOQMZ-UHFFFAOYSA-N 0.000 claims 1
- 239000005046 Chlorosilane Substances 0.000 claims 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims 1
- 239000004202 carbamide Substances 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 claims 1
- 229960004126 codeine Drugs 0.000 claims 1
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 claims 1
- 230000002079 cooperative effect Effects 0.000 claims 1
- UBHZUDXTHNMNLD-UHFFFAOYSA-N dimethylsilane Chemical compound C[SiH2]C UBHZUDXTHNMNLD-UHFFFAOYSA-N 0.000 claims 1
- AJFDBNQQDYLMJN-UHFFFAOYSA-N n,n-diethylacetamide Chemical compound CCN(CC)C(C)=O AJFDBNQQDYLMJN-UHFFFAOYSA-N 0.000 claims 1
- 230000001681 protective effect Effects 0.000 claims 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 229910052902 vermiculite Inorganic materials 0.000 claims 1
- 235000019354 vermiculite Nutrition 0.000 claims 1
- 239000010455 vermiculite Substances 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 8
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical group CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 description 2
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Chemical compound NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 2
- PHBYJSOMJRZRIO-UHFFFAOYSA-N methylsilylurea Chemical compound C[SiH2]NC(=O)N PHBYJSOMJRZRIO-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 1
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- YOJMBZHCDWUXMF-UHFFFAOYSA-N 2,2-bis(trimethylsilyl)ethanamine Chemical compound C[Si](C)(C)C(CN)[Si](C)(C)C YOJMBZHCDWUXMF-UHFFFAOYSA-N 0.000 description 1
- HGUFODBRKLSHSI-UHFFFAOYSA-N 2,3,7,8-tetrachloro-dibenzo-p-dioxin Chemical compound O1C2=CC(Cl)=C(Cl)C=C2OC2=C1C=C(Cl)C(Cl)=C2 HGUFODBRKLSHSI-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- RGXJMLZFKIUGNH-UHFFFAOYSA-N 3-amino-3-iminopropanamide Chemical compound NC(=N)CC(N)=O RGXJMLZFKIUGNH-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- 240000002853 Nelumbo nucifera Species 0.000 description 1
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 1
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000009835 boiling Methods 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
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- VNJCDDZVNHPVNM-UHFFFAOYSA-N chloro(ethyl)silane Chemical compound CC[SiH2]Cl VNJCDDZVNHPVNM-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000003746 feather Anatomy 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229910052705 radium Inorganic materials 0.000 description 1
- HCWPIIXVSYCSAN-UHFFFAOYSA-N radium atom Chemical compound [Ra] HCWPIIXVSYCSAN-UHFFFAOYSA-N 0.000 description 1
- 229910052704 radon Inorganic materials 0.000 description 1
- SYUHGPGVQRZVTB-UHFFFAOYSA-N radon atom Chemical compound [Rn] SYUHGPGVQRZVTB-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Diaphragms For Electromechanical Transducers (AREA)
- Control Of El Displays (AREA)
- Analysing Materials By The Use Of Radiation (AREA)
Description
乓詳細說明： 下式之哂巩達嗪（hr Ξ21 )
(哂叽達嗪）
爲一種抗生素，其製法及®異抗生素活性業已知於文獻 。其可由將下式之ATS
C ATS ) 該ATS於羧基部扮經活化，與下式之TACS進行反應而製
—種特別合適之製備頭芽孢菌素之方法係描述於EP-A _23 45：3 。但，若使用該方法以製備哂吼達嗪，則除了 所需哂!％達嗓外有約5至15%副產物形成。雖然該副產 物之含量可經由各種連續的純化步驟而減低，然仍無法 將副產物自哂贶達嗪中完全除去。再者，這些純化步驗 C例如色層分析或再結晶）均是昂貴的，此乃甶於它們 皆是複雜的且貢質上會減低總產量。 —4 — ¥4(210X297公发) — 3-86-2000 4 6 7 9 15 因此曾經做過一些嘗試來改變反應參數以抑锢副產物 之形成，例如改變莫耳比，溫度，反溫時間，溶劑，鹼 (可添加或不添加），活化劑，或添加其它物質。然這 些嘗試却無一成功，如此證明，欲減低所稱副產物之形 成是不可能的。 >於對其它添加物之硏究中，本發明令人驚奇地發現經 由添加甲矽烷化劑於TACS中可實質上完全避免副產物之 形成。 本發明因此係關於下式之哂吼達嗪之製法
C哂晛達嗪）
其中 ⑻式II化合物（ATS N-j-C-COOA R.HN—N-OCH, i 5 其中\代表氫或氨基保護基且A代表氫原子或一當量 數之鹼金屬或鹼土金屬，銨或有機氮鹼，首先與式III 化合物 R— 其中R代表選擇取代烷基，芳基或芳烷基且Hal代表 鹵素原子，於有機溶劑中且，若適當，於鹼存在下進 行反膘， -5 - T4(210X297公发) 3-86-2000 4 6 7 9 15 ⑹式工化合物c TACS )
其中A之定義如前，與甲矽烷化劑於有機溶劑中且， 若適當，於鹼存在下進行反應，後 '⑹於⑻及(b)中所形成二產物於其反應溶液中進行反膘， 且除去任何存在於式工最終產物之保護基％。 除去代表氫或銨外，A亦可代表一當量敷之鹼金屬， 例如，鈉或鉀，驗土金屬，例如，#5或鎂，有機氮鹼， 例如，二乙基一，三甲基一，三乙基-，甲基—，丙基 —，N，N-二甲基乙醇一或乙醇胺。 適當之保護基％爲描述於頭芽孢菌素或胜肽化學上之 氨基保護基，如描述於EP-A-23 453 ，第3頁，43-63 行者。根.據本發明，最好使用\代表氣之化合物。由於 氨基之保護並非必須的，因此可免除二反腫步驟C保護 及除去），如此將導致產量之提高。 適當式III化合物爲文獻中所述適合與羧酸反應者· 例如甲烷磺醯氯或甲苯磺醯氯，可能有經活化羧酸基-CDOSC]2R 形成。由於這些化合物具有好的反應性且可容 易取得，化合物如對位-甲苯磺醯氯或苯基磺逦氯爲較 隹者。Hal代表氯之式III化合物亦爲較佳者。 式II及式III化合物之反膘可於無水有機溶劑如內酮 ，乙酸乙酯，四氫呋喃，乙腈，四氯化碳，二氯甲烷， —d — 甲4(210X297公釐）.~ ：
3-86-2000 甲苯，二噁線，異丙醚》N·甲基吡咯烷_或=甲基甲 醯胺中，但最好於二甲基乙醯胺中•在約-30及， ,最好是*10及-^ec間之溫度下，加以進行。 若使用游籬酸形式之式II化合物（A =氫），添加鹸 ，最好是有機氮鹼如三乙胺，N，N -二甲基苯胺，三 丁胺，N -甲基鵪啉，吡啶或皮考啉，或，例如碳酸鈉 ，碳酸鉀碳酸氬鈉，威碳酸氫鉀，尤其是三乙胺*是 有利的。若係使用前述鹽形成之一之式Π羧酸，則鹸之 添加可予免除。 進一步之反應係然後如下加以進行：將式Ϊ化合物（ TAGS )，於無水有機溶劑如二氯甲烷，工甲基乙醢胺， 甲基特• 丁基醚，甲基異** 丁基酬，乙酸丁酯或乙酸戊 基酯中，特别是於二氯甲烷或甲基特_ 丁基醚中，與約 s莫耳當量數之甲矽烷化劑，最好是與ε甲基氯甲矽糖 ，於約化學計量-以甲矽烷化劑爲基準-之有機氮鹸存 在下，特別是於3乙胺存在下，進行反應，然後將所得 產物與式η之羧酸（其業經與式m化合物反應而加以 活化）進行反應。 除了三甲基氯甲矽烷外，亦可使用其它甲矽烷化劑， · 例如，双·3甲基甲矽烷基乙醯胺，二氯=甲基甲矽烷 ，a氯甲基甲砂焼或N » ν’, ·双-s甲基甲矽燒基脲* 双-兰申基甲矽烷基乙醯胺爲其中較隹者、稍微趨過3 莫耳當量數之甲砂烷化劑對反臘並無不良影響。 —7 _ T 4(210X297^"*) " 裝 i
六刺 3*86-6000 467915 當使用双•三甲基甲矽烷基乙醜胺或N，N -双-三 .r甲基甲矽焼基脲時，逝不需要於甲较線化時添加鹸，此: f乃由於此時並役有氬氯酸（其赵須被束縛住）產生。 戎Ϊ化合物之甲硖烷化係於約20及25%閻之溫度下加 以進行。此溫度亦甩提升至，例如，約40°G C二氯甲烷 之沸_') V .經活化ATS最好與甲矽烷化TAGS如下地結合：將經 活化ATS溶液於約**S〇及〇eG，最好是-10及*12eG ， 間之溫度下Μ夠緩慢地加入於經甲矽烷化TAGS溶液中，. 以使反應所生熟可容易地移去，例如於K至2小時之期 簡內。 ^ 將反應混合物攪禅一短暫時間，然後以習知方忒加以 完成。例如，可將其傾入水中，其中PH値可經由添加， 例如*有機氮鹼，尤其是二乙胺，.而保持在約β·0« 。於分離相後，可以水（有乙酸鈉溶於其中）再次萃取 有機稆。自合併之水溶液相（若鑛要，其可以活性炭進 一步加以澄淸），可經調pH値至約2.8 C經添加無機酸 如硫酸）而將哂贱_嗪以游離酸沉澱出。 當所使用式rr羧酸帶有氨基保護基R0，在進行最後 < . 完成作用前必須以描述於文獻之方式除去該舞護基。. 於在稍高溫及眞空中乾燥後*可得非常純之哂呎達嗪 酸。 "'' " '. ； ：. 除了前述不可預期地使爾產物之含量下降至低於i % ' 装 订 線 六利.乘代律理 師人 甲 4(210x297公麓） 3-86-6000 以下外*須特別陳明的是於前述职WW03 453 之貢施例 a至a中須使用._?〇及簡之屎朧溫度於醯化，用 中。反之》根據本發明之反應，可以約40至之溫 度加以進抒而不致造成品質或產量之下降<»該項事贊對 工業生產哂睨達嗪是相當重要的，蓋其逢謂著較短的操 诈時間及較少的冷却鶬最。 _ 9 — Τ4(210χ 297^-¾) 3-86*6000 467915 實例1 步纗]： 將於取公斤=甲基乙釀胺中之17·8金斤（87,彳奠薄） ATS以8*95公斤（β8*β莫耳）3乙胺，於20至羽*^之溫 度下，轉變成銨P*且一面加以攪摔3〇分鐘： 將12·9公斤C βθ·〇奠耳）對位-甲苯礙醯氣，於30分 鐘內在ab*25eG下溶於13.2^斤二甲基乙_胺中，後使 溶液於*»1〇β〇至**14eG下在30分鐘內 ，..流入ATS之甚乙 銨鹽懸浮液中》並繼續再攪掸2,5小時。 步驟2 將23,9ί&斤（9?,0莫耳）TAGS懸浮於212公斤念氯甲 烷中；使19,7公斤（1β1·0莫耳）S乙基氯甲矽烷於go » 23β(3下流入，後於31#鐘內在SO » 41**G C =氯甲焼之 囘滩溫度）之溫度下將18.2公斤（《0·0莫耳）SZ*胺 加入。 當添加作用完成後*迅速地將溶液冷却至*15\;，後 於30分鏟內在*10至_12°G下將步驟1所得經活化AT3 溶液加入繼續攪掸5分鐘、，之後使反應混合物於e至 ία分鐘內流入一含W3升水及19·3公斤艺乙胺之混僉_ 中》pH値維持在β及7*5之間。於分離相後，再以 水（其中業溶有2*5公斤乙酸鈉·3Η^〇)萃取二氯甲麵姻 ，以1·2公斤活性炭及1·2公斤代卡利特矽藻土澄餘_ 併之水溶液相，後經添加18^强硫酸至PH値達 -10 -
k T 4(210 x 297公麓) 3*86-6000
4 6 / y Ί 5 鐳莲相中將哂矾達嗪以游離酸彤式沉澱出。於將産物過 濂出並於如100毫米莱柱下乾燥狻*可得30.S公斤 哂巩達嗪，經HPLG分析純度96_ 97 %。 實例2 步驟1與實例1所述之程序相同。 步驟3 ; 將23,7發斤C SS.O莫耳）TAGS懸浮於212公斤二氣甲 .烧中，後將36.0公’.斤（.177»0 _莫耳）双三毕基甲矽焼 基乙醯胺加入。於20 »25^；下攪拌30分鐘，蔣澄淸溶液 冷却.至._13eC ，後將於步驟1所得經活化ATS溶液於30 分鐘內萑31怕至-i/e下加入。於進行攪掸5分鐘後， 使反應混合物於5至10.分鐘內流入143升水中，並同時 以三乞胺使pH値維持在S.0及7,S之間β於分雛相後， 再次使用#斤水（含2.2公斤乙酸鈉' 萃取有機 2 相。以1ί2公斤活性炭及1,2金斤代卡利特矽藻土澄淸 合併之水溶液相*後經添加10%强硫酸至pH値達2』可 將產物沉澱出。於將產物過漉出並於40°G及彳00毫米汞 柱下加以乾燥後》可得30.0公斤游離酸形式:之哦晛達嗪 ，根據ΗΡϋ：分析純度爲97¾0 —IX _ 甲 4(210X297公釐） -裝· •線- 六乘隼r 3«8^60〇0
Claims (1)
- 5 Α8 j4 6cs/ b 1 5 D8 六、申請專利範圍 專利申請案第75102826號 ROC Patent Appln. Νο.75102826 修正之申請專利範圍中文本-附件（一） Amended Claims in Chinese - Enel.(I) (民國90年3月：έ日送呈) (Submitted on March ^ , 2001) 1. 一種製備下式°西D凡達B秦(cefodizime)之方法N CH. z ——Γ——-Ι·——------裝—— (請先閲讀背面之注意事項再填寫本頁) (°西机達嗪） 其中 ⑻式II化合物(ATS) .- Η—— Γ—\ • C-COOA R,HK—ίί-OCH^ -線._ 經濟部智慧財產局員工消費合作社印製 其中心代表氫或氨基保護基且A代表氫原子或一當 量數之驗金屬或驗土金屬，錢或有機氮臉，首先與 式ΠΙ化合物 R-S02-Hal 其中R代表經(CrC4-烷基)取代之苯基且Hal代表鹵 素原子_，於有機溶劑中且，若適當，於鹼存在下進 行尽應， -12 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 75102826B 6 4 5 1— 9 六、申請專利範圍 (b)式I化合物(TACS)經濟部智慧財產局員工消費合作社印製 其中A之定義如前，與曱石夕烧化.劑於有機溶劑中 且，若適當，於鹼存在下進行反應，後 c)於(a)及(b)中所形成二產物於其反應溶液中在-20°C至 0°C之溫度下進行反應，且除去任何存在於式I最終 產物之保護基心；其中該曱矽烷化劑為三曱基氯曱矽 烷，二氣二甲基甲矽烷，三氣甲基甲矽烷，雙-三甲 基甲矽烷基乙醯胺或Ν,Ν’-雙-三甲基曱矽烷基脲；-及 該有機氮鹼為三乙基胺，Ν，Ν-二甲基苯胺，三丁基 胺，Ν-甲基嗎啡，吡啶或曱吡啶》 · 2. 根據申請專利範圍第1項之方法，其中式ΠΙ化合物中 之R代表對-曱苯基且Hal代表氣。 3. 根據申請專利範圍第1項之方法，其中式II化合物 (ATS)中之R,及A代表氫。 4. 根據申請專利範圍第1至3項中任一項之方法，其中方 法步’(a)中所使用溶劑為丙酮，二甲基乙醯胺，乙酸 乙酯，四氫呋喃，乙腈，四氣化碳，二氯甲烧，甲苯， 二噁烷，異丙醚，正-曱基吡咯烷酮或二曱基曱醯胺。 5. 根據申請專利範圍第4項之方法，其中該溶劑為二甲基 乙醯胺。 -13 - (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 4 5 A8B8C8D8 六、申請專利範圍 6. 根據申請專利範圍第1項之方法，其中該甲矽烷化劑為 三甲基氣甲矽烷。 7. 根據申請專利範圍第1或6項之方法，其中使用3莫耳 當量數，以TACS為基準，之甲矽烷化劑。 8. 根據申請專利範圍第1至3項中任一項之方法，其中方 法步驟(b)中所用溶劑為二氣曱烷，二曱基乙醯胺，甲 基特-丁基醚，曱基異丁基酮，乙酸丁酯或乙酸戊酯。 9. 根據申請專利範圍第8項之方法，其中該溶劑為二氣甲 烷或曱基特-丁基醚。 10. 根據申請專利範圍第1至3項中任一項之方法，其中， 若適當，於個別方法步驟中所添加之鹼為三乙胺。 11. 根據申請專利範圍第1至3項中任一項之方法，其中方 法步驟(a)之反應係於-30及0°C間之溫度下加以進行。 12. 根據申請專利範圍第1至3項中任一項之方法，其中方 法步驟(b)之反應係於-20及Ot：間之溫度下加以進行。 — — — — — ·1111111 — — — — (請先W讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 -14 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 5 Α8 j4 6cs/ b 1 5 D8 六、申請專利範圍 專利申請案第75102826號 ROC Patent Appln. Νο.75102826 修正之申請專利範圍中文本-附件（一） Amended Claims in Chinese - Enel.(I) (民國90年3月：έ日送呈) (Submitted on March ^ , 2001) 1. 一種製備下式°西D凡達B秦(cefodizime)之方法N CH. z ——Γ——-Ι·——------裝—— (請先閲讀背面之注意事項再填寫本頁) (°西机達嗪） 其中 ⑻式II化合物(ATS) .- Η—— Γ—\ • C-COOA R,HK—ίί-OCH^ -線._ 經濟部智慧財產局員工消費合作社印製 其中心代表氫或氨基保護基且A代表氫原子或一當 量數之驗金屬或驗土金屬，錢或有機氮臉，首先與 式ΠΙ化合物 R-S02-Hal 其中R代表經(CrC4-烷基)取代之苯基且Hal代表鹵 素原子_，於有機溶劑中且，若適當，於鹼存在下進 行尽應， -12 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 75102826B
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| DE19853542644 DE3542644A1 (de) | 1985-12-03 | 1985-12-03 | Verfahren zur herstellung von cefodizim |
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| JP2578113B2 (ja) * | 1987-05-08 | 1997-02-05 | 株式会社東芝 | 高熱伝導性窒化アルミニウム焼結体の製造方法 |
| ES2006988A6 (es) * | 1988-06-20 | 1989-05-16 | Gema Sa | Procedimiento de preparar hidrocloruro cloruro-2-(2-aminotiazol-4-il)-2-metoxiiminoacetil-sulfito-dimetilformiminio y procedimiento de utilizacion del mismo para obtencion de amidas. |
| EP0377987A3 (en) * | 1988-12-27 | 1991-08-28 | Eli Lilly And Company | Acylation process for obtaining cephalosporin derivatives |
| DE4026630A1 (de) * | 1990-08-23 | 1992-02-27 | Hoechst Ag | Verfahren zur herstellung von kristalliner tacs |
| ES2143644T3 (es) * | 1994-08-02 | 2000-05-16 | Procter & Gamble | Procedimiento para elaborar compuestos antimicrobianos. |
| KR100239200B1 (ko) * | 1994-08-02 | 2000-03-02 | 데이비드 엠 모이어 | 퀴놀로닐 락탐 항생제의 제조 방법 및 신규 중간체 화합물 |
| EP0791596A1 (en) * | 1996-02-21 | 1997-08-27 | Lupin Laboratories Limited | Method for manufacture of cephalosporins and intermediates thereof |
| EP0791597B1 (en) * | 1996-02-21 | 2000-07-12 | Lupin Laboratories Limited | Method for manufacture of cephalosporins and intermediates thereof |
| CN108997378A (zh) * | 2018-07-25 | 2018-12-14 | 上海上药新亚药业有限公司 | 一种头孢地嗪酸的制备方法 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2714880A1 (de) * | 1977-04-02 | 1978-10-26 | Hoechst Ag | Cephemderivate und verfahren zu ihrer herstellung |
| FR2462439A1 (fr) * | 1979-07-26 | 1981-02-13 | Roussel Uclaf | Nouveau procede de preparation de produits derives de l'acide 7-/(2-aryl) 2-hydroxyimino acetamido/cephalosporanique |
| DE3145727A1 (de) * | 1981-11-19 | 1983-05-26 | Bayer Ag, 5090 Leverkusen | Zwischenprodukte, verfahren zu deren herstellung und verfahren zur herstellung von cephalosporinen |
| DE3316798A1 (de) * | 1983-05-07 | 1984-11-08 | Hoechst Ag, 6230 Frankfurt | Verfahren zur herstellung von cephemverbindungen |
| DE3316797A1 (de) * | 1983-05-07 | 1984-11-08 | Hoechst Ag, 6230 Frankfurt | Verfahren zur herstellung von cephemverbindungen |
| IT1180207B (it) * | 1984-07-30 | 1987-09-23 | Istituto Biochimico Italiano | Procedimento per la preparazione, con resa e purezza elevate, di antibiotici beta-lattamici |
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1985
- 1985-12-03 DE DE19853542644 patent/DE3542644A1/de not_active Withdrawn
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1986
- 1986-06-19 TW TW075102826A patent/TW467915B/zh not_active IP Right Cessation
- 1986-11-27 AT AT86116509T patent/ATE90682T1/de not_active IP Right Cessation
- 1986-11-27 DE DE8686116509T patent/DE3688587D1/de not_active Expired - Lifetime
- 1986-11-27 EP EP86116509A patent/EP0226093B1/de not_active Expired - Lifetime
- 1986-11-27 ES ES86116509T patent/ES2058056T3/es not_active Expired - Lifetime
- 1986-12-01 DD DD86296913A patent/DD252606A5/de unknown
- 1986-12-01 HU HU864969A patent/HU197912B/hu unknown
- 1986-12-01 MA MA21050A patent/MA20818A1/fr unknown
- 1986-12-01 CS CS868816A patent/CS259544B2/cs not_active IP Right Cessation
- 1986-12-01 IL IL80816A patent/IL80816A/xx not_active IP Right Cessation
- 1986-12-01 EG EG743/86A patent/EG17611A/xx active
- 1986-12-01 NZ NZ218452A patent/NZ218452A/xx unknown
- 1986-12-01 US US06/936,187 patent/US4868295A/en not_active Expired - Lifetime
- 1986-12-01 FI FI864886A patent/FI84829C/fi not_active IP Right Cessation
- 1986-12-02 AU AU66020/86A patent/AU585414B2/en not_active Expired
- 1986-12-02 PT PT83858A patent/PT83858B/pt unknown
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- 1986-12-02 IE IE316386A patent/IE60571B1/en not_active IP Right Cessation
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- 1986-12-02 DK DK579486A patent/DK164671C/da not_active IP Right Cessation
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- 1986-12-03 JP JP61288656A patent/JPH0686460B2/ja not_active Expired - Lifetime
- 1986-12-03 KR KR1019860010312A patent/KR940000240B1/ko not_active IP Right Cessation
- 1986-12-03 TN TNTNSN86154A patent/TNSN86154A1/fr unknown
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1995
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