JPH0251556B2 - - Google Patents
Info
- Publication number
- JPH0251556B2 JPH0251556B2 JP9132184A JP9132184A JPH0251556B2 JP H0251556 B2 JPH0251556 B2 JP H0251556B2 JP 9132184 A JP9132184 A JP 9132184A JP 9132184 A JP9132184 A JP 9132184A JP H0251556 B2 JPH0251556 B2 JP H0251556B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- acid
- compound
- distilled
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229930186147 Cephalosporin Natural products 0.000 claims description 3
- 229940124587 cephalosporin Drugs 0.000 claims description 3
- 150000001780 cephalosporins Chemical class 0.000 claims description 3
- 241000486679 Antitype Species 0.000 claims description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 33
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- 150000001875 compounds Chemical class 0.000 description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- -1 alkali metal salts Chemical class 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 125000006239 protecting group Chemical group 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000000862 absorption spectrum Methods 0.000 description 12
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 12
- 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 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- 239000010410 layer Substances 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 235000013736 caramel Nutrition 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000004475 Arginine Substances 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- YJLZLUSKICMKJX-UHFFFAOYSA-N chloroform;formic acid;propan-2-ol Chemical compound OC=O.CC(C)O.ClC(Cl)Cl YJLZLUSKICMKJX-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000003960 organic solvent 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
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- OBETXYAYXDNJHR-UHFFFAOYSA-N 2-Ethylhexanoic acid Chemical compound CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- QJCKSIBRMGEZBX-UHFFFAOYSA-N 2-[1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]oxyimino-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid Chemical compound CC(C)(C)OC(=O)C(C)ON=C(C(O)=O)C1=CSC(NC(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 QJCKSIBRMGEZBX-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 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
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- SHZIWNPUGXLXDT-UHFFFAOYSA-N caproic acid ethyl ester Natural products CCCCCC(=O)OCC SHZIWNPUGXLXDT-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- LIOIDYIXMHPGGB-UHFFFAOYSA-N chloroform;formic acid;methanol Chemical compound OC.OC=O.ClC(Cl)Cl LIOIDYIXMHPGGB-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- PBMIETCUUSQZCG-UHFFFAOYSA-N n'-cyclohexylmethanediimine Chemical compound N=C=NC1CCCCC1 PBMIETCUUSQZCG-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 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
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
[発明の技術分野]
本発明は下記一般式()で示される新規なセ
フアロスポリン誘導体及びその塩に関する。
[式中、R1はカルボキシ基又はカルバモイル基
で置換されていてもよい低級アルキル基を、R2
はカルボキシ基を、R3はカルバモイル基を意味
し、波線の結合はアンチ(anti)形又はシン
(syn)形の結合を表わす。以下同様]
[発明の具体的説明]
本明細書の一般式の基の定義において『低級』
なる語は炭素数1〜5個を有する直鎖又は分枝状
の炭素鎖を意味する。従つて、低級アルキル基と
しては具体的にはメチル基、エチル基、プロピル
基、イソプロピル基、ブチル基、イソブチル基、
tert−ブチル基、アミル基、イソペンチル基、1
−メチルブチル基、2−メチルブチル基、ネオペ
ンチル基等が挙げられる。
本発明は一般式()で示される化合物の薬理
学上許容される非毒性の塩類をも包含するもので
あり、かかる塩としてはナトリウム、カリウム等
のアルカリ金属、カルシウム、マグネシウム等の
アルカリ土類金属等の無機塩基との塩、アンモニ
ウム塩、トリメチルアミン、トリエチルアミン、
シクロヘキシルアミン、ジシクロヘキシルアミ
ン、ジエタノールアミン、アルギニン、リジン等
の有機塩基や塩基性アミン酸との塩、塩酸、硫
酸、リン酸等の鉱酸塩、酢酸、乳酸、酒石酸、フ
マール酸、マレイン酸、メタンスルホン酸、エタ
ンスルホン酸等の有機酸との塩が挙げられる。
本発明化合物()は、イミノエーテル型のオ
キシムや2−置換チアゾール基を有しており、こ
れらの化合物には幾何異性体や互変異性体が存在
する。本発明はこれらシン(syn)、アンチ
(anti)形の幾何異性体や相互の互変異性体の全
てを包含するものである。
[化合物の効果]
本発明によつて提供される上記一般式()で
示される化合物及びその塩は、セフアロスポリン
骨格の3位に置換イミノアルキリデンジチエタン
−2−イル基を有する点に化学構造上の特徴を有
する新規化合物であり、グラム陽性菌ならびにグ
ラム陰性菌殊に緑膿菌に対して優れた抗菌作用を
有し、抗菌剤として有用である。本発明化合物の
抗菌作用を
セフオタジシム(Ceftazidime)
と対比して次表に示す。
[Technical Field of the Invention] The present invention relates to a novel cephalosporin derivative represented by the following general formula () and a salt thereof. [In the formula, R 1 is a lower alkyl group which may be substituted with a carboxy group or a carbamoyl group, and R 2
represents a carboxy group, R 3 represents a carbamoyl group, and the wavy bond represents an anti-type or syn-type bond. The same applies hereinafter] [Specific description of the invention] In the definition of the group in the general formula of this specification, "lower"
The term refers to a straight or branched carbon chain having 1 to 5 carbon atoms. Therefore, specific examples of lower alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group,
tert-butyl group, amyl group, isopentyl group, 1
-methylbutyl group, 2-methylbutyl group, neopentyl group, etc. The present invention also includes pharmacologically acceptable non-toxic salts of the compound represented by the general formula (), and such salts include alkali metal salts such as sodium and potassium, alkaline earth salts such as calcium and magnesium, etc. Salts with inorganic bases such as metals, ammonium salts, trimethylamine, triethylamine,
Salts with organic bases and basic amino acids such as cyclohexylamine, dicyclohexylamine, diethanolamine, arginine, and lysine; mineral acid salts such as hydrochloric acid, sulfuric acid, and phosphoric acid; acetic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, and methanesulfone. Examples include salts with acids and organic acids such as ethanesulfonic acid. The compound of the present invention () has an iminoether type oxime or a 2-substituted thiazole group, and these compounds have geometric isomers and tautomers. The present invention includes all of these syn and anti geometric isomers and mutual tautomers. [Effect of the compound] The compound represented by the above general formula () and its salt provided by the present invention have a chemical structure in that it has a substituted iminoalkylidene dithietan-2-yl group at the 3-position of the cephalosporin skeleton. It is a novel compound with the following characteristics, and has excellent antibacterial activity against Gram-positive and Gram-negative bacteria, especially Pseudomonas aeruginosa, and is useful as an antibacterial agent. The antibacterial activity of the compound of the present invention The following table shows the comparison.
【表】
[化合物の製造]
本発明化合物は種々の方法により製造すること
ができる。代表的な方法を以下に例示する。
(式中、R4は保護基により保護されていてもよ
いアミノ基を、R5は保護基により保護されてい
てもよいカルボキシ基、又はカルバモイル基で置
換されていてもよい低級アルキル基を、R6は水
酸基を意味する。
本発明化合物は3位が置換イソチアゾール−5
−イルチオメチル基である対応するセフアロスポ
リン化合物を塩基で処理して転位させることによ
り製造される。
ここに、アミノ基の保護基としては当該ペプチ
ド化学の分野において通常用いられ、容易に除去
できる保護基を意味、具体的にはたとえば、ホル
ミル基、アセチル基、プロピオニル基、tert−ブ
トキシカルボニル基、メトキシアセチル基、メト
キシプロピオニル基、ベンジルオキシカルボニル
基、p−ニトロベンジルオキシカルボニル基等の
アシル基、ベンジル基、ベンズヒドリル基、トリ
チル基等のアラルキル基等が挙げられる。
また、カルボキシ基の保護基としては具体的に
はトリメチルシリル基、ベンズヒドリル基、β−
メチルスルホニルエチル基、フエナシル基、p−
メトキシベンジル基、tert−ブチル基、p−ニト
ロベンジル基など、緩和な条件下容易に脱離しう
る保護基が挙げられる。
この反応に用いられる塩基としては炭酸水素ナ
トリウム、炭酸カリウム、炭酸ナトリウム、トリ
エチルアミンなどの弱塩基性物質が挙げられる。
この反応は通常溶媒中で室温乃至冷却下で行な
われる。溶媒としては反応に関与しないものであ
れば特に制限はないが、好ましくは水又は水と混
和しうるメタノール、アセトン、テトラヒドロフ
ラン、ジメチルスルホキシド、ジメチルホルムア
ミドなどを単独または適宜混合して使用すること
ができる。
原料化合物として保護基のある化合物を用いる
場合は次いで保護基を除去する。
アミノ基の保護基の脱離は保護基として前述し
たトリチル基の如きアラルキル基やアシル基を用
いる場合には酸で処理することによつて容易に行
なうことができる。この際用いられる酸としては
ギ酸、トリフルオロ酢酸、塩酸等が好ましい。
また、カルボキシ基の保護基の除去はたとえば
ベンズヒドリル基、p−メトキシベンジル基等は
酸によつて、トリメチルシリル基は水と接触させ
ることによつて容易に行なうことができる。
なお、カルボキシ基及びアミノ基の保護基の脱
離は同時に行なうことも可能である。
一般式()で示される本発明化合物の塩はた
とえば上記製法において予じめ原料化合物を塩を
用いて製造することにより、あるいは上記製法に
より製造された遊離の化合物に当分野で慣用され
ている造塩反応を適用することにより製造するこ
とができる。
たとえば、2−エチルヘキサン酸アルカリのn
−ブタノール溶液を加え、次に溶解性の異なるエ
ーテル、酢酸エチル等の有機溶媒を加えることに
よりアルカリ金属塩を、ジシクロヘキシルアミ
ン、トリエチルアミン、シクロヘキシルアミン、
ジエタノールアミン、アルギニン、リジン等の有
機塩基や塩基性アミノ酸を当量ないし少過剰量加
え反応させることにより有機塩基や塩基性アミノ
酸との塩を、アンモニア水を加えることによりア
ンモニウム塩を製造できる。
本発明化合物()及びその塩の単離精製は常
法に従つて行なわれ、有機溶媒による抽出、結晶
化、カラムクロマトグラフイーによる分離精製が
用いられる。
[化合物の利用]
一般式()で示される化合物やその塩を主成
分として含有する抗菌剤は任意慣用の製薬用担体
や、賦形剤を用いて任意慣用の方法で調製され
る。投与は錠剤、丸剤、カプセル剤、顆粒剤等の
経口投与あるいは静注、筋注等の注射剤、坐剤等
の非経口投与のいずれの形態であつてもよい。投
与量は症状や投与対象者の年令、性別等を考慮し
て個々の場合に応じて適宜決定されるが、通常成
人1日当り250〜3000mgであり、これを1日2〜
4回に分けて投与する。
[実施例]
以下に実施例を掲記し、本発明を更に詳細に説
明する。なお、一般式()で示される原料化合
物はいずれも新規物質であり、原出願である特開
昭57−167992号に記載した方法により容易に入手
することができる。
参考例 1
(Z)−α−(1−tert−ブトキシカルボニル−
1−メチルエトキシイミノ)−α−(2−トリチル
アミノチアゾール−4−イル)酢酸3.87g
(0.0067モル)をジオキサン45mlに懸濁させて、
これに1−ヒドロキシベンゾトリアゾール914mg
(0.0067モル)、及びジシクロヘキシルカルボジイ
ミド1.42gを加え、室温で1時間反応させる。反
応終了後析出するジシクロヘキシル尿素を過し
て除き、活性エステルのジオキサン溶液を得る。
一方、7−アミノ−3−[(4−カルボキシ−3−
ヒドロキシイソチアゾール−5−イル)チオメチ
ル]−Δ3−セフエム−4−カルボン酸1.7g
(0.00437モル)をジメチルスルホキシド17mlに溶
解し氷水冷却下トリエチルアミン1.5mlを加える。
それに先の活性エステルジオキサン溶液を滴下す
る。滴下終了後室温にて3日間反応させる。反応
終了後減圧下にジオキサンを留去した残渣に水5
ml、炭酸水素ナトリウム水溶液5mlを加えて溶解
し酢酸エチル20ml、10mlで2回洗浄する。ついで
水層をメチルエチルケトン50mlを張つて2N塩酸
で酸性にする。不溶物を過して除き、メチルエ
チルケトン30ml、15mlで水層を再度抽出する。有
機層を集め、飽和食塩水で充分に洗い無水硫酸マ
グネシウムで乾燥した後、メチルエチルケトンを
減圧下留去してカラメル3.5gを得る。カラメル
をシリカゲルカラムクロマトグラフイーに付しク
ロロホルム−メタノール−ギ酸(容量比90:10:
2)で溶出し目的物を含むフラクシヨンを集め溶
媒を留去すれば(Z)−3−[4−(カルバモイル
カルボキシメチレン)−1,3−ジチエタン−2
−イル]−7−[α−(1−tert−ブトキシカルボ
ニル−1−メチルエトキシイミノ)−α−(2−ト
リチルアミノチアゾール−4−イル)アセタミ
ド]−Δ3−セフエム−4−カルボン酸640mgを得
る。
赤外線吸収スペクトル
νKBr naxcm-1;3360、2970、1780、1720、1665〜70、
1625、1490、1365、1140
核磁気共鳴スペクトル(d6−DMSO中)
δ(ppm);1.38(9H、s、tBu)
3.90(2H、s、2位CH2)
5.12(1H、d、6位CH)
5.64〜5.8(1H、7位CH)
5.70(1H、s、[Table] [Production of Compound] The compound of the present invention can be produced by various methods. Typical methods are illustrated below. (In the formula, R 4 is an amino group which may be protected by a protecting group, R 5 is a carboxy group which may be protected by a protecting group, or a lower alkyl group which may be substituted with a carbamoyl group, R 6 means a hydroxyl group. The compound of the present invention has a substituted isothiazole-5 at the 3-position.
It is produced by rearranging the corresponding cephalosporin compound, which is an -ylthiomethyl group, by treating it with a base. Here, the protecting group for the amino group means a protecting group that is commonly used in the field of peptide chemistry and can be easily removed, specifically, for example, a formyl group, an acetyl group, a propionyl group, a tert-butoxycarbonyl group, Examples include acyl groups such as a methoxyacetyl group, methoxypropionyl group, benzyloxycarbonyl group, and p-nitrobenzyloxycarbonyl group, and aralkyl groups such as a benzyl group, benzhydryl group, and trityl group. In addition, specific examples of protective groups for carboxyl groups include trimethylsilyl group, benzhydryl group, and β-
Methylsulfonylethyl group, phenacyl group, p-
Protective groups that can be easily removed under mild conditions include a methoxybenzyl group, a tert-butyl group, and a p-nitrobenzyl group. Examples of the base used in this reaction include weakly basic substances such as sodium hydrogen carbonate, potassium carbonate, sodium carbonate, and triethylamine. This reaction is usually carried out in a solvent at room temperature or under cooling. The solvent is not particularly limited as long as it does not participate in the reaction, but preferably water or water-miscible methanol, acetone, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, etc. can be used alone or in appropriate mixtures. . When a compound with a protecting group is used as a raw material compound, the protecting group is then removed. When an aralkyl group such as the above-mentioned trityl group or an acyl group is used as a protecting group, the removal of the protecting group for the amino group can be easily carried out by treatment with an acid. Preferred acids used in this case include formic acid, trifluoroacetic acid, and hydrochloric acid. Further, the protective group for a carboxyl group can be easily removed by contacting a benzhydryl group, a p-methoxybenzyl group, etc. with an acid, and a trimethylsilyl group by contacting it with water. Note that it is also possible to remove the protecting groups for the carboxyl group and the amino group at the same time. The salt of the compound of the present invention represented by the general formula () can be prepared, for example, by preparing the raw material compound in advance using a salt in the above-mentioned production method, or by adding a salt to the free compound produced by the above-mentioned production method, as is commonly used in the art. It can be produced by applying a salt-forming reaction. For example, n of alkali 2-ethylhexanoate
- By adding a butanol solution and then adding an organic solvent such as ether or ethyl acetate with different solubility, the alkali metal salt can be converted into dicyclohexylamine, triethylamine, cyclohexylamine,
Salts with organic bases or basic amino acids can be produced by adding an equivalent or a slight excess of an organic base such as diethanolamine, arginine, or lysine, or a basic amino acid, and ammonium salts can be produced by adding aqueous ammonia. Isolation and purification of the compound () of the present invention and its salts are carried out according to conventional methods, including extraction with organic solvents, crystallization, and separation and purification by column chromatography. [Usage of Compound] An antibacterial agent containing the compound represented by the general formula () or a salt thereof as a main component can be prepared by any conventional method using any conventional pharmaceutical carrier or excipient. Administration may be in the form of oral administration such as tablets, pills, capsules, or granules, or parenteral administration such as injections such as intravenous or intramuscular injection, or suppositories. The dosage is determined on a case-by-case basis, taking into consideration the symptoms, the age and gender of the recipient, but it is usually 250 to 3000 mg per day for adults, and this is 2 to 300 mg per day.
Administer in 4 divided doses. [Example] The present invention will be described in further detail by referring to Examples below. All of the raw material compounds represented by the general formula () are new substances and can be easily obtained by the method described in the original application, JP-A-57-167992. Reference example 1 (Z)-α-(1-tert-butoxycarbonyl-
3.87 g of 1-methylethoxyimino)-α-(2-tritylaminothiazol-4-yl)acetic acid
(0.0067 mol) was suspended in 45 ml of dioxane,
Add to this 914mg of 1-hydroxybenzotriazole
(0.0067 mol) and 1.42 g of dicyclohexylcarbodiimide were added, and the mixture was allowed to react at room temperature for 1 hour. After the reaction is completed, precipitated dicyclohexyl urea is removed by filtration to obtain a dioxane solution of the active ester.
On the other hand, 7-amino-3-[(4-carboxy-3-
1.7 g of hydroxyisothiazol-5-yl)thiomethyl]-Δ 3 -cephem-4-carboxylic acid
(0.00437 mol) is dissolved in 17 ml of dimethyl sulfoxide, and 1.5 ml of triethylamine is added while cooling with ice water.
The active ester dioxane solution was added dropwise thereto. After completion of the dropwise addition, the reaction was allowed to proceed for 3 days at room temperature. After the reaction was completed, dioxane was distilled off under reduced pressure, and 5% of water was added to the residue.
ml and 5 ml of aqueous sodium hydrogen carbonate solution to dissolve, and wash twice with 20 ml and 10 ml of ethyl acetate. Next, add 50 ml of methyl ethyl ketone to the aqueous layer and acidify with 2N hydrochloric acid. Insoluble matter was removed by filtration, and the aqueous layer was extracted again with 30 ml and 15 ml of methyl ethyl ketone. The organic layers were collected, thoroughly washed with saturated brine and dried over anhydrous magnesium sulfate, and then methyl ethyl ketone was distilled off under reduced pressure to obtain 3.5 g of caramel. The caramel was subjected to silica gel column chromatography using chloroform-methanol-formic acid (volume ratio 90:10:
2) Collect the fraction containing the target product and distill off the solvent to obtain (Z)-3-[4-(carbamoylcarboxymethylene)-1,3-dithiethane-2
-yl]-7-[α-(1-tert-butoxycarbonyl-1-methylethoxyimino)-α-(2-tritylaminothiazol-4-yl)acetamide]-Δ 3 -cephem-4-carboxylic acid 640 mg get. Infrared absorption spectrum ν KBr nax cm -1 ; 3360, 2970, 1780, 1720, 1665~70,
1625, 1490, 1365, 1140 Nuclear magnetic resonance spectra (in d 6 -DMSO) δ (ppm); 1.38 (9H, s, tBu) 3.90 (2H, s, 2nd position CH 2 ) 5.12 (1H, d, 6th position CH) 5.64-5.8 (1H, 7th CH) 5.70 (1H, s,
【式】) 6.66(1H、s、【formula】) 6.66 (1H, s,
【式】)
7.24〜7.28(15H、Cφ3)
8.72(1H、φ3 CHN−)
9.2〜9.36(1H、CONH)
実施例 1
トリフルオロ酢酸5mlを5℃に冷却し、それに
前記参考例1で得られた化合物640mgを添加する。
15〜17℃で60分間次いで氷冷下水2.5mlを加え10
〜15℃で60分間反応させる。反応終了後トリフル
オロ酢酸、水を減圧下に留去し得られた残渣にエ
タノール3mlを加え溶解し一部エタノールを減圧
下に留去してエーテル20mlで粉末化して過す
る。粉末をエーテルで充分洗つて乾燥して、(Z)
−7−[α−(2−アミノチアゾール−4−イル)
−α−(1−カルボキシ−1−メチルエトキシイ
ミノ)アセタミド]−3−[4−(カルバモイルカ
ルボキシメチレン)−1,3−ジチエタン−2−
イル]−Δ3−セフエム−4−カルボン酸308mgを
得る。
赤外線吸収スペクトル
νKBr naxcm-1;3400、1770、1620〜1680、1480、
1355、1260、1180〜85、1140
核磁気共鳴スペクトル(d6−DMSO中)
δ(ppm);1.46(6H、s、−CH3)
3.94(2H、2位CH2)
5.16(1H、d、6位CH)
5.71(1H、s、[Formula]) 7.24 to 7.28 (15H, Cφ 3 ) 8.72 (1H, φ 3 C H N-) 9.2 to 9.36 (1H, CONH) Example 1 5 ml of trifluoroacetic acid is cooled to 5°C, and 640 mg of the compound obtained in Reference Example 1 is added thereto.
Incubate at 15-17℃ for 60 minutes, then add 2.5ml of ice-cold water for 10 minutes.
Incubate for 60 min at ~15 °C. After the reaction is complete, trifluoroacetic acid and water are distilled off under reduced pressure, and 3 ml of ethanol is added to the resulting residue to dissolve it, a portion of the ethanol is distilled off under reduced pressure, and the mixture is powdered with 20 ml of ether and filtered. Wash the powder thoroughly with ether and dry it (Z)
-7-[α-(2-aminothiazol-4-yl)
-α-(1-carboxy-1-methylethoxyimino)acetamide]-3-[4-(carbamoylcarboxymethylene)-1,3-dithiethane-2-
308 mg of yl]-Δ 3 -cephem-4-carboxylic acid are obtained. Infrared absorption spectrum ν KBr nax cm -1 ; 3400, 1770, 1620-1680, 1480,
1355, 1260, 1180-85, 1140 Nuclear magnetic resonance spectrum ( d6 -DMSO) δ (ppm); 1.46 (6H, s, -CH3 ) 3.94 (2H, 2nd CH2 ) 5.16 (1H, d, 6th place CH) 5.71 (1H, s,
【式】) 5.88(1H、q、7位CH) 6.62(1H、s、【formula】) 5.88 (1H, q, 7th CH) 6.62 (1H, s,
【式】)
9.42(1H、d、CONH−)
参考例 2
(Z)−3−[(4−カルボキシ−3−ヒドロキ
シイソチアゾール−5−イル)チオメチル]−7
−[α−(メトキシイミノ)−α−(2−トリエチル
アミノチアゾール−4−イル)アセタミド]−Δ3
−セフエム−4−カルボン酸247mg(0.0003モル)
をジメチルスルホキシド1mlに溶かしジオキサン
3mlを加える。室温下トリエチルアミン117μ
を加え、3日間室温にて反応させる。反応液より
ジオキサンを減圧下に留去し得られた残留物に水
10mlを加え飽和炭酸水素ナトリウム水溶液0.5ml
を加えて溶解し、酢酸エチル20ml、10mlで順次洗
浄する。水層にメチルエチルケトン20mlを張つて
2N−塩酸で酸性にして抽出後更に水層をメチル
エチルケトン10mlで抽出する。メチルエチルケト
ン層を合せて最初水10ml次いで飽和食塩水10mlで
洗浄する。有機層を無水硫酸マグネシウムにて乾
燥後メチルエチルケトンを留去する。得られた残
留物をシリカゲルカラムクロマトグラフイーに付
しクロロホルム−イソプロパノール−ギ酸(容量
比90:10:2)で溶出し目的物を含むフラクシヨ
ンを集め溶媒を濃縮して(Z)−3−[4−(カル
バモイルカルボキシメチレン)−1,3−ジチエ
タン−2−イル]−7−[α−メトキシイミノ−α
−(2−トリチルアミノチアゾール−4−イル)
アセタミド]−Δ3−セフエム−4−カルボン酸36
mgを得る。
赤外線吸収スペクトル
νKBr naxcm-1;3350、2910、1775、1670、1620、
1490、1350〜1380、1260、1020
核磁気共鳴スペクトル(d6−DMSO中)
δ(ppm);3.80(3H、s、OCH3)
3.84(2H、s、2位CH2)
5.12(1H、d、6位CH)
5.71(1H、s、[Formula]) 9.42 (1H, d, CONH−) Reference example 2 (Z)-3-[(4-carboxy-3-hydroxyisothiazol-5-yl)thiomethyl]-7
-[α-(methoxyimino)-α-(2-triethylaminothiazol-4-yl)acetamide]-Δ 3
-Cefem-4-carboxylic acid 247 mg (0.0003 mol)
Dissolve in 1 ml of dimethyl sulfoxide and add 3 ml of dioxane. Triethylamine 117μ at room temperature
and react at room temperature for 3 days. Dioxane was distilled off from the reaction solution under reduced pressure, and water was added to the resulting residue.
Add 10ml and 0.5ml of saturated sodium bicarbonate aqueous solution.
Add and dissolve, and wash sequentially with 20 ml and 10 ml of ethyl acetate. Add 20ml of methyl ethyl ketone to the water layer.
After acidifying with 2N hydrochloric acid and extracting, the aqueous layer is further extracted with 10 ml of methyl ethyl ketone. The methyl ethyl ketone layers are combined and washed first with 10 ml of water and then with 10 ml of saturated saline. After drying the organic layer over anhydrous magnesium sulfate, methyl ethyl ketone was distilled off. [ 4-(Carbamoylcarboxymethylene)-1,3-dithietan-2-yl]-7-[α-methoxyimino-α
-(2-tritylaminothiazol-4-yl)
acetamide]-Δ 3 -cephem-4-carboxylic acid 36
Get mg. Infrared absorption spectrum ν KBr nax cm -1 ; 3350, 2910, 1775, 1670, 1620,
1490, 1350-1380, 1260, 1020 Nuclear magnetic resonance spectrum ( d6 -DMSO) δ (ppm); 3.80 (3H, s, OCH3 ) 3.84 (2H, s, 2nd CH2) 5.12 (1H, d , 6th place CH) 5.71 (1H, s,
【式】 5.66〜5.78(1H、q、7位CH) 6.72(1H、s、【formula】 5.66-5.78 (1H, q, 7th CH) 6.72 (1H, s,
【式】)
7.28(15H、s、Cφ3)
8.76(1H、s、NH)
9.58(1H、d、−NHCO−)
実施例 2
トリフルオロ酢酸3mlを氷水にて冷却し前記参
考例2で得られた化合物35mgを加える。溶解して
から水1.5mlを加えて、10〜15℃で60分間反応さ
せる。反応終了後、反応液より水、トリフルオロ
酢酸を留去してエタノール3mlを加え均一にとか
し一部分エタノールを留去して得られた溶液にエ
ーテル10mlを加え粉末化する。過後エーテルで
洗浄して23.3mgの(Z)−7−[α−2−アミノチ
アゾール−4−イル)−α−メトキシイミノアセ
タミド]−3−[4−カルバモイルカルボキシメチ
レン)−1,3−ジチエタン−2−イル)−Δ3−
セフエム−4−カルボン酸を得る。
赤外線吸収スペクトル
νKBr naxcm-1;3300、1870、1770、1660、1620、1480
〜1485、1360〜1380
核磁気共鳴スペクトル(d6−DMSO中)
δ(ppm);3.84(3H、s、OCH3)
5.15(1H、d、6位CH)
5.71(1H、s、[Formula]) 7.28 (15H, s, Cφ 3 ) 8.76 (1H, s, NH) 9.58 (1H, d, -NHCO-) Example 2 3 ml of trifluoroacetic acid was cooled with ice water, and 35 mg of the compound obtained in Reference Example 2 was added thereto. After dissolving, add 1.5ml of water and react at 10-15℃ for 60 minutes. After the reaction is complete, water and trifluoroacetic acid are distilled off from the reaction solution, 3 ml of ethanol is added and the mixture is stirred uniformly, and ethanol is partially distilled off. To the resulting solution, 10 ml of ether is added and powdered. After filtering and washing with ether, 23.3 mg of (Z)-7-[α-2-aminothiazol-4-yl)-α-methoxyiminoacetamide]-3-[4-carbamoylcarboxymethylene)-1,3 was obtained. -dithiethane-2-yl)-Δ 3 -
Cefem-4-carboxylic acid is obtained. Infrared absorption spectrum ν KBr nax cm -1 ; 3300, 1870, 1770, 1660, 1620, 1480
~1485, 1360~1380 Nuclear magnetic resonance spectrum ( d6 -DMSO) δ (ppm); 3.84 (3H, s, OCH3 ) 5.15 (1H, d, CH at 6th position) 5.71 (1H, s,
【式】) 5.76(1H、q、7位CH) 6.65(1H、s、【formula】) 5.76 (1H, q, 7th CH) 6.65 (1H, s,
【式】)
9.52(1H、d、−CONH−)
参考例 3
(Z)−3−[(4−カルボキシ−3−ヒドロキ
シイソチアゾール−5−イル)チオメチル]−7
[α−(1−tert−ブトキシカルボニル−1−メチ
ルプロポキシイミノ)−α−(2−トリチルアミノ
チアゾール−4−イル)アセタミド]−Δ3−セフ
エム−4−カルボン酸460mg(0.477ミリモル)を
ジメチルスルホキシド3mlに溶解しジオキサン10
mlを加える。室温下トリエチルアミン250μを
加え4日間室温にて反応させる。反応液よりジオ
キサンを減圧下に留去して得られた残留物を氷水
10mlに分散し、2N−塩酸5mlを加えメチルエチ
ルケトン20mlで2回抽出する。有機層を合せて最
初水5ml、次いで飽和食塩水10mlで洗浄する。メ
チルエチルケトン層を無水硫酸マグネシウムにて
乾燥後溶媒を留去して得たカラメルをシリカゲル
カラムクロマトグラフイーに付し、クロロホルム
−イソプロパノール−ギ酸(容量比90:10:2)
で溶出する。目的物を含むフラクシヨンを集め減
圧濃縮して(Z)−3−[4−(カルバモイルカル
ボキシメチレン)−1,3−ジチエタン−2−イ
ル]−7−[α−(1−tert−ブトキシカルボニル
−1−メチルプロポキシイミノ)−α−(2−トリ
チルアミノチアゾール−4−イル)アセタミド]
−Δ3−セフエム−4−カルボン酸245mgを得た。
赤外線吸収スペクトル
νKBr naxcm-1;3300〜3400、2970、1770、1670、
1620、1490、1365、1255、1140、700
核磁気共鳴スペクトル(d6−DMSO中)
δ(ppm);0.91(3H、t、CH3−)
1.40(9H、3H、s、tBu、CH3−)
1.90(2H、q、−CH2−)
3.98(2H、2位CH)
5.07(1H、d、6位CH)
5.90、5.94(1H、各々s、[Formula]) 9.52 (1H, d, -CONH-) Reference example 3 (Z)-3-[(4-carboxy-3-hydroxyisothiazol-5-yl)thiomethyl]-7
[α-(1-tert-butoxycarbonyl-1-methylpropoxyimino)-α-(2-tritylaminothiazol-4-yl)acetamide]-Δ 3 -cephem-4-carboxylic acid (460 mg (0.477 mmol)) was dissolved in dimethyl 10 dioxane dissolved in 3 ml of sulfoxide
Add ml. Add 250μ of triethylamine at room temperature and react at room temperature for 4 days. Dioxane was distilled off from the reaction solution under reduced pressure, and the resulting residue was poured into ice water.
Disperse in 10 ml, add 5 ml of 2N hydrochloric acid, and extract twice with 20 ml of methyl ethyl ketone. The organic layers are combined and washed first with 5 ml of water and then with 10 ml of saturated saline. After drying the methyl ethyl ketone layer over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting caramel was subjected to silica gel column chromatography and chloroform-isopropanol-formic acid (volume ratio 90:10:2)
It elutes with Fractions containing the target product were collected and concentrated under reduced pressure to give (Z)-3-[4-(carbamoylcarboxymethylene)-1,3-dithiethan-2-yl]-7-[α-(1-tert-butoxycarbonyl- 1-methylpropoxyimino)-α-(2-tritylaminothiazol-4-yl)acetamide]
245 mg of -Δ 3 -cephem-4-carboxylic acid was obtained. Infrared absorption spectrum ν KBr nax cm -1 ; 3300-3400, 2970, 1770, 1670,
1620, 1490, 1365, 1255, 1140, 700 Nuclear magnetic resonance spectra ( d6- in DMSO) δ (ppm); 0.91 (3H, t, CH3- ) 1.40 (9H, 3H, s, tBu, CH3- ) 1.90 (2H, q, -CH 2 -) 3.98 (2H, 2nd CH) 5.07 (1H, d, 6th CH) 5.90, 5.94 (1H, each s,
【式】) 5.8〜5.96(1H、7位CH) 6.68(1H、s、【formula】) 5.8-5.96 (1H, 7th place CH) 6.68 (1H, s,
【式】)
7.1〜7.4(15H、3φ)
8.50(1H、−NH〜−)
実施例 3
トリフルオロ酢酸9ml、アニソール1mlの混液
に上記参考例3で得られた化合物240mgを加え19
〜21℃で1時間反応させる。反応終了後減圧下に
トリフルオロ酢酸を留去して得たオイルをエーテ
ルで粉末化させる。取した粉末を再度トリフル
オロ酢酸7mlに溶かし20℃以下で水4mlを滴下す
る。滴下終了後19〜21℃で1時間反応させる。反
応終了後減圧トリフルオロ酢酸を留去して得た残
留物にエタノール10mlを加えて均一化し、エタノ
ールを一部留去したオイルにエチルエーテルを加
えて粉末化して
(Z)−7−[α−2−アミノチアゾール−4−
イル)−α−(1−カルボキシ−1−メチルプロポ
キシイミノ)アセタミド]−3−[4−(カルバモ
イルカルボキシメチレン)−1,3−ジチエタン
−2−イル)−Δ3−セフエム−4−カルボン酸
146mgを得た。
赤外線吸収スペクトル
νKBr naxcm-1;3300、2960、1765、1490、1370、
1260、1140、1000、800、720
核磁気共鳴スペクトル(d6−DMSO中)
δ(ppm);0.85(3H、t、CH3−)
1.38、1.40(3H、各々s、CH3−)
1.77(2H、q、−CH2−)
3.93(2H、2位CH2)
5.15(1H、d、6位CH)
5.72(1H、s、[Formula]) 7.1~7.4 (15H, 3φ) 8.50 (1H, -NH~-) Example 3 Add 240 mg of the compound obtained in Reference Example 3 above to a mixture of 9 ml of trifluoroacetic acid and 1 ml of anisole.
Incubate for 1 hour at ~21°C. After the reaction is complete, trifluoroacetic acid is distilled off under reduced pressure, and the resulting oil is pulverized with ether. The powder taken was dissolved again in 7 ml of trifluoroacetic acid, and 4 ml of water was added dropwise at 20°C or below. After the dropwise addition is completed, the reaction is allowed to proceed for 1 hour at 19-21°C. After the completion of the reaction, 10 ml of ethanol was added to the residue obtained by distilling off the trifluoroacetic acid under reduced pressure to homogenize it, and ethyl ether was added to the oil from which some of the ethanol had been distilled off to form a powder. (Z)-7-[α -2-aminothiazole-4-
yl)-α-(1-carboxy-1-methylpropoxyimino)acetamide]-3-[4-(carbamoylcarboxymethylene)-1,3-dithiethan-2-yl)-Δ 3 -cephem-4-carboxylic acid
Obtained 146mg. Infrared absorption spectrum ν KBr nax cm -1 ; 3300, 2960, 1765, 1490, 1370,
1260, 1140, 1000, 800, 720 Nuclear magnetic resonance spectrum (in d 6 -DMSO) δ (ppm); 0.85 (3H, t, CH 3 -) 1.38, 1.40 (3H, each s, CH 3 -) 1.77 ( 2H, q, -CH 2 -) 3.93 (2H, 2nd CH 2 ) 5.15 (1H, d, 6th CH) 5.72 (1H, s,
【式】) 5.88(1H、q、7位CH) 6.69(1H、s、【formula】) 5.88 (1H, q, 7th CH) 6.69 (1H, s,
【式】)
9.44(1H、d、−CONH−)
参考例 4
前記参考例と同様の方法で、(Z)−3−[4−
(カルバモイルカルボキシメチレン)−1,3−ジ
チエタン−2−イル]−7−[α−(1−tert−ブ
トキシカルボニルイソブチルオキシイミノ)−α
−(2−トリチルアミノチアゾール−4−イル)
アセタミド]−Δ3−セフエム−4−カルボン酸を
得た。
赤外線吸収スペクトル
νKBr naxcm-1;3350、2960、1780、1670、1490、
1360、1250、1150、1020、690
核磁気共鳴スペクトル(d6−DMSO中)
δ(ppm);0.94(6H、d、CH3−)
1.40(9H、s、t−Bu)
1.9〜2.2(1H、 ‐
−CH−
)
3.90(2H、q、2位CH2)
4.18(1H、d、 ‐
−CH−
)
5.14(1H、d、6位CH)
5.73(1H、s、[Formula]) 9.44 (1H, d, -CONH-) Reference example 4 (Z)-3-[4-
(carbamoylcarboxymethylene)-1,3-dithiethan-2-yl]-7-[α-(1-tert-butoxycarbonylisobutyloxyimino)-α
-(2-tritylaminothiazol-4-yl)
Acetamide]-Δ 3 -cephem-4-carboxylic acid was obtained. Infrared absorption spectrum ν KBr nax cm -1 ; 3350, 2960, 1780, 1670, 1490,
1360, 1250, 1150, 1020, 690 Nuclear magnetic resonance spectrum (in d6 -DMSO) δ (ppm); 0.94 (6H, d, CH3- ) 1.40 (9H, s, t-Bu) 1.9-2.2 (1H , - -CH- ) 3.90 (2H, q, 2nd position CH 2 ) 4.18 (1H, d, - -CH- ) 5.14 (1H, d, 6th position CH) 5.73 (1H, s,
【式】) 5.6〜5.86(1H、7位CH) 6.72(1H、【formula】) 5.6-5.86 (1H, 7th place CH) 6.72 (1H,
【式】)
7.1〜7.5(15H、3φ)
8.76(1H、−NH〜−)
9.3〜9.54(1H、−CONH〜−)
実施例 4
実施例3と同様にギ酸で保護基を除去して
(Z)−7−[α−(2−アミノチアゾール−4−イ
ル)−α−(1−カルボキシイソブチルオキシイミ
ノ)アセタミド]−3−[4−(カルバモイルカル
ボキシメチレン)−2−イル]−Δ3−セフエム−
4−カルボン酸を得た。
赤外線吸収スペクトル
νKBr naxcm-1;3100〜3400、2960、1770、1620、
1520、1380、1230〜1270、1020
核磁気共鳴スペクトル(d6−DMSO中)
δ(ppm);0.97(6H、d、CH3−)
1.9〜2.3(1H、m、 ‐
−CH−
)
3.93(2H、q、2位CH2)
4.22、4.28(1H、各々d、6位CH)
5.18(1H、d、6位CH)
5.66(1H、s、[Formula]) 7.1~7.5 (15H, 3φ) 8.76 (1H, -NH~-) 9.3~9.54 (1H, -CONH~-) Example 4 The protecting group was removed with formic acid in the same manner as in Example 3 to give (Z)-7-[α-(2-aminothiazol-4-yl)-α-(1-carboxyisobutyloxyimino)acetamide]-3-[ 4-(Carbamoylcarboxymethylene)-2-yl]-Δ 3 -Cefem-
4-carboxylic acid was obtained. Infrared absorption spectrum ν KBr nax cm -1 ; 3100-3400, 2960, 1770, 1620,
1520, 1380, 1230-1270, 1020 Nuclear magnetic resonance spectrum ( d6 -DMSO) δ (ppm); 0.97 (6H, d, CH3- ) 1.9-2.3 (1H, m, - -CH-) 3.93 ( 2H, q, 2nd place CH 2 ) 4.22, 4.28 (1H, respectively d, 6th place CH) 5.18 (1H, d, 6th place CH) 5.66 (1H, s,
【式】) 5.8〜5.98(1H、m、7位CH) 6.73、6.78(1H、各々s、【formula】) 5.8-5.98 (1H, m, 7th CH) 6.73, 6.78 (1H, each s,
【式】)
7.23(1H、−NH〜−)
9.38〜9.64(1H、−CONH〜−)
参考例 5
ジオキサン5mlに2−(1−tert−ブトキシカ
ルボニルエトキシイミノ)−2−(2−トリチルア
ミノチアゾール−4−イル)酢酸510mg(0.9ミリ
モル)、1−ヒドロキシベンゾトリアゾール124mg
(0.93ミリモル)及びシクロヘキシルカルボジイ
ミド190mg(0.92モル)を加えて室温にて1時間
反応させる。
反応終了後、析出するジシクロヘキシル尿素を
去して、活性エステルのジオキサン溶液を得
る。一方、7−アミノ−3−[(4−カルボキシ−
3−ヒドロキシイソチアゾール−5−イル)チオ
メチル]−Δ3−セフエム−4−カルボン酸500mg
をジメチルスルホキシド3mlに懸濁させ、20℃以
下でトリエチルアミン450μを加え溶解させる。
それに先の活性エステルジオキサン溶液を滴下す
る。滴下終了後室温にて3日間反応させたのち減
圧下にジオキサンを留留去した残渣に水45ml、飽
和炭酸水素ナトリウム5mlを加え溶かし酢酸エチ
ル50mlで2回洗浄する。次いで水層を2N−塩酸
10mlを加えメチルエチルケトン50mlで2回抽出
し、その間析出する不純物は過して除く。有機
層を集め水20mlで2回、飽和食塩水20mlで洗浄し
て、無水硫酸マグネシウムで乾燥した後、メチル
エチルケトンを減圧下留去してカラメルを得る。
カラメルをシリカゲルカラムクロマトグラフイー
に付し、クロロホルム−イソプロパノール−ギ酸
(容量比90:10:2)で溶出し目的物を含むフラ
クシヨンを集め溶媒を留去して(Z)−3−[4−
(カルバモイルカルボキシメチレン)−1,3−ジ
チエタン−2−イル]−7−[α−(1−tert−ブ
トキシカルボニルエトキシイミノ−α−(2−ト
リチルアミノチアゾール−4−イル)アセタミ
ド]−Δ3−セフエム−4−カルボン酸335mgを得
た。
赤外線吸収スペクトル
νKBr naxcm-1;3300〜3350、2960、1780、1720、
1675、1625、1490、1365、1250、695
核磁気共鳴スペクトル(d6−DMSO)
δ(ppm);1.28(3H、d、CH3−)
1.37(9H、s、t−Bu)
3.90(2H、s、2位CH2)
4.50(1H、q、 ‐
−CH−
)
5.12(1H、d、6位CH)
5.55(1H、d、d、7位CH)
5.72(1H、s、[Formula]) 7.23 (1H, -NH~-) 9.38~9.64 (1H, -CONH~-) Reference example 5 510 mg (0.9 mmol) of 2-(1-tert-butoxycarbonylethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid and 124 mg of 1-hydroxybenzotriazole in 5 ml of dioxane.
(0.93 mmol) and 190 mg (0.92 mol) of cyclohexylcarbodiimide are added and reacted at room temperature for 1 hour. After the reaction is completed, the precipitated dicyclohexyl urea is removed to obtain a dioxane solution of the active ester. On the other hand, 7-amino-3-[(4-carboxy-
3-hydroxyisothiazol-5-yl)thiomethyl]-Δ 3 -cephem-4-carboxylic acid 500 mg
Suspend in 3 ml of dimethyl sulfoxide and dissolve by adding 450 µ of triethylamine at 20°C or lower.
The active ester dioxane solution was added dropwise thereto. After completion of the dropwise addition, the reaction was allowed to proceed at room temperature for 3 days, and then dioxane was distilled off under reduced pressure. To the residue were added 45 ml of water and 5 ml of saturated sodium bicarbonate, and the mixture was dissolved and washed twice with 50 ml of ethyl acetate. Next, the aqueous layer was treated with 2N-hydrochloric acid.
Add 10 ml and extract twice with 50 ml of methyl ethyl ketone, removing impurities that precipitate during that time. The organic layer is collected, washed twice with 20 ml of water and 20 ml of saturated brine, dried over anhydrous magnesium sulfate, and then methyl ethyl ketone is distilled off under reduced pressure to obtain caramel.
The caramel was subjected to silica gel column chromatography, eluted with chloroform-isopropanol-formic acid (volume ratio 90:10:2), the fraction containing the target product was collected, and the solvent was distilled off to give (Z)-3-[4-
(Carbamoylcarboxymethylene)-1,3-dithietan-2-yl]-7-[α-(1-tert-butoxycarbonylethoxyimino-α-(2-tritylaminothiazol-4-yl)acetamide]-Δ 3 -Cefem-4-carboxylic acid (335 mg) was obtained. Infrared absorption spectrum ν KBr nax cm -1 ; 3300-3350, 2960, 1780, 1720,
1675, 1625, 1490, 1365, 1250, 695 Nuclear magnetic resonance spectrum (d 6 -DMSO) δ (ppm); 1.28 (3H, d, CH 3 -) 1.37 (9H, s, t-Bu) 3.90 (2H, s, 2nd position CH 2 ) 4.50 (1H, q, - -CH-) 5.12 (1H, d, 6th position CH) 5.55 (1H, d, d, 7th position CH) 5.72 (1H, s,
【式】) 6.72(1H、s、【formula】) 6.72 (1H, s,
【式】)
7.10〜7.40(15H、Cφ3)
8.78(1H、s、−NH〜−)
9.3〜9.5(1H、−CONH〜−)
実施例 5
実施例3と同様に参考例4で得られた化合物
330mgより保護基を除去して(Z)−7−[α−(2
−アミノチアゾール−4−イル)−α−(1−カル
ボキシエトキシイミノ)アセタミド]−3−[4−
カルバモイルカルボキシメチレン)−1,3−ジ
チエタン−2−イル]−Δ3−セフエム−4−カル
ボン酸230mgを得た。
赤外線吸収スペクトル
νKBr naxcm-1;3260〜3320、1765、1670、1620、
1485、1360〜1390、1250、1190、1030、795
核磁気共鳴スペクトル(d6−DMSO中)
δ(ppm);1.43(3H、d、CH3−)
3.94(2H、s、2位CH2)
4.62(1H、q、‐
−CH−
)
5.17(1H、d、6位CH)
5.73(1H、s、[Formula]) 7.10~7.40 (15H, Cφ3 ) 8.78 (1H, s, -NH~-) 9.3~9.5 (1H, -CONH~-) Example 5 Compound obtained in Reference Example 4 in the same manner as Example 3
The protecting group was removed from 330 mg to give (Z)-7-[α-(2
-aminothiazol-4-yl)-α-(1-carboxyethoxyimino)acetamide]-3-[4-
230 mg of carbamoylcarboxymethylene)-1,3-dithiethan-2-yl]-Δ 3 -cephem-4-carboxylic acid was obtained. Infrared absorption spectrum ν KBr nax cm -1 ; 3260-3320, 1765, 1670, 1620,
1485, 1360-1390, 1250, 1190, 1030, 795 Nuclear magnetic resonance spectrum ( d6 -DMSO) δ (ppm); 1.43 (3H, d, CH3- ) 3.94 (2H, s, 2nd position CH2 ) 4.62 (1H, q, - -CH-) 5.17 (1H, d, 6th position CH) 5.73 (1H, s,
【式】) 5.8〜6.0(1H、m、7位CH) 6.78(1H、s、【formula】) 5.8-6.0 (1H, m, 7th place CH) 6.78 (1H, s,
【式】)
9.46、9.51(1H、各々d、−CONH〜−)
参考例 6
前記参考例2と同様な方法で、(Z)−3−[4
−カルバモイルカルボキシメチレン)−1,3−
ジチエタン−2−イル]−7−[α−(1−tert−
ブトキシカルボニルプロポキシイミノ)−α−(2
−トリチルアミノチアゾール−4−イル)アセタ
ミド]−Δ3−セフエム−4−カルボン酸を得た。
赤外線吸収スペクトル
νKBr naxcm-1;3280〜3330、2960、1770、1670、
1620、1485、1360、1230、1150、995、690
核磁気共鳴スペクトル(d6−DMSO中)
δ(ppm);0.94(3H、t、CH3−)
1.38(9H、s、t−Bu)
1.76(2H、q、−CH2−)
3.91(2H、2位CH2)
4.34(1H、t、‐
−CH−
)
5.16(1H、d、6位CH)
5.74(1H、s、[Formula]) 9.46, 9.51 (1H, each d, -CONH~-) Reference example 6 (Z)-3-[4
-carbamoylcarboxymethylene)-1,3-
dithiethan-2-yl]-7-[α-(1-tert-
butoxycarbonylpropoxyimino)-α-(2
-tritylaminothiazol-4-yl)acetamide]-Δ 3 -cephem-4-carboxylic acid was obtained. Infrared absorption spectrum ν KBr nax cm -1 ; 3280-3330, 2960, 1770, 1670,
1620, 1485, 1360, 1230, 1150, 995, 690 Nuclear magnetic resonance spectrum (d 6 - in DMSO) δ (ppm); 0.94 (3H, t, CH 3 -) 1.38 (9H, s, t-Bu) 1.76 (2H, q, -CH 2 -) 3.91 (2H, 2nd CH 2 ) 4.34 (1H, t, - -CH-) 5.16 (1H, d, 6th CH) 5.74 (1H, s,
【式】) 5.70〜5.8(1H、7位CH) 6.72、6.77(1H、各々s、【formula】) 5.70-5.8 (1H, 7th place CH) 6.72, 6.77 (1H, each s,
【式】)
7.1〜7.5(15H、3φ)
8.80(1H、−NH〜−)
9.3〜9.5(1H、−CONH〜−)
実施例 6
実施例2と同様の方法で保護基を除去して、
(Z)−7−[α−(2−アミノチアゾール−4−イ
ル)−α−(1−カルボキシプロポキシイミノ)ア
セタミド]−3−[4−(カルバモイルカルボキシ
メチレン)−1,3−ジチエタン−2−イル]−
Δ3−セフエム−4−カルボン酸を得た。
赤外線吸収スペクトル
νKBr naxcm-1;3250〜3339、2950、1770、1620、
1480、1370、1250、1000
核磁気共鳴スペクトル(d6−DMSO中)
δ(ppm);0.98(3H、t、CH3−)
1.82(2H、q、−CH2−)
3.96(2H、2位CH2)
4.50(1H、−CH−)
5.18(1H、d、6位CH)
5.75(1H、s、[Formula]) 7.1~7.5 (15H, 3φ) 8.80 (1H, -NH~-) 9.3~9.5 (1H, -CONH~-) Example 6 The protecting group was removed in the same manner as in Example 2,
(Z)-7-[α-(2-aminothiazol-4-yl)-α-(1-carboxypropoxyimino)acetamide]-3-[4-(carbamoylcarboxymethylene)-1,3-dithiethane-2 -il]-
Δ 3 -Cefem-4-carboxylic acid was obtained. Infrared absorption spectrum ν KBr nax cm -1 ; 3250-3339, 2950, 1770, 1620,
1480, 1370, 1250, 1000 Nuclear magnetic resonance spectra (d 6 - in DMSO) δ (ppm); 0.98 (3H, t, CH 3 -) 1.82 (2H, q, -CH 2 -) 3.96 (2H, 2nd position CH 2 ) 4.50 (1H, -CH-) 5.18 (1H, d, 6th CH) 5.75 (1H, s,
【式】) 5.8〜6.0(1H、m、7位CH) 6.78〜6.82(1H、各々s、【formula】) 5.8-6.0 (1H, m, 7th place CH) 6.78~6.82 (1H, each s,
【式】) 9.40〜9.60(1H、−CONH〜−)【formula】) 9.40~9.60 (1H, -CONH~-)
Claims (1)
置換されていてもよい低級アルキル基を、R2は
カルボキシ基を、R3はカルバモイル基を意味し、
波線の結合はアンチ(anti)形又はシン(syn)
形の結合を表わす] で示される新規なセフアロスポリン誘導体又はそ
の塩。[Claims] 1. General formula [In the formula, R 1 represents a lower alkyl group which may be substituted with a carboxy group or a carbamoyl group, R 2 represents a carboxy group, and R 3 represents a carbamoyl group,
Bonds with wavy lines are anti-type or syn-type.
A novel cephalosporin derivative or a salt thereof represented by:
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9132184A JPS59225190A (en) | 1984-05-07 | 1984-05-07 | Novel cephalosporin derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9132184A JPS59225190A (en) | 1984-05-07 | 1984-05-07 | Novel cephalosporin derivative |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP56052408A Division JPS6011917B2 (en) | 1981-04-09 | 1981-04-09 | Novel cephalosporin compounds |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS59225190A JPS59225190A (en) | 1984-12-18 |
JPH0251556B2 true JPH0251556B2 (en) | 1990-11-07 |
Family
ID=14023189
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP9132184A Granted JPS59225190A (en) | 1984-05-07 | 1984-05-07 | Novel cephalosporin derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS59225190A (en) |
-
1984
- 1984-05-07 JP JP9132184A patent/JPS59225190A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS59225190A (en) | 1984-12-18 |
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