JPH0251555B2 - - Google Patents
Info
- Publication number
- JPH0251555B2 JPH0251555B2 JP58186601A JP18660183A JPH0251555B2 JP H0251555 B2 JPH0251555 B2 JP H0251555B2 JP 58186601 A JP58186601 A JP 58186601A JP 18660183 A JP18660183 A JP 18660183A JP H0251555 B2 JPH0251555 B2 JP H0251555B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- esters
- ester
- group
- acids
- 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 - Lifetime
Links
- -1 alkali metal salt Chemical class 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 15
- 229910052783 alkali metal Inorganic materials 0.000 claims description 9
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000002253 acid Substances 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000000243 solution Substances 0.000 description 14
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- 238000000034 method Methods 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 150000007513 acids Chemical class 0.000 description 9
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 150000008065 acid anhydrides Chemical class 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 159000000000 sodium salts Chemical class 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- VCVXTGHARNCYNB-UHFFFAOYSA-N 2-[2-amino-1-(1,3-thiazol-2-yl)ethylidene]propanedioic acid Chemical compound OC(=O)C(C(O)=O)=C(CN)C1=NC=CS1 VCVXTGHARNCYNB-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003463 adsorbent Substances 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 235000010755 mineral Nutrition 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
- 150000003460 sulfonic acids Chemical class 0.000 description 3
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N CD3OD Substances [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 206010041925 Staphylococcal infections Diseases 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
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 125000001118 alkylidene group Chemical group 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 150000007860 aryl ester derivatives Chemical class 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 208000015339 staphylococcus aureus infection Diseases 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 2
- 150000003952 β-lactams Chemical class 0.000 description 2
- QABMUYKBLKJHNP-MZLWKKIQSA-N (6r)-7-amino-8-oxo-3-(pyridin-1-ium-1-ylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;dihydrochloride Chemical compound Cl.Cl.S([C@@H]1C(C(N1C=1C([O-])=O)=O)N)CC=1C[N+]1=CC=CC=C1 QABMUYKBLKJHNP-MZLWKKIQSA-N 0.000 description 1
- FZENGILVLUJGJX-NSCUHMNNSA-N (E)-acetaldehyde oxime Chemical compound C\C=N\O FZENGILVLUJGJX-NSCUHMNNSA-N 0.000 description 1
- JHNRZXQVBKRYKN-VQHVLOKHSA-N (ne)-n-(1-phenylethylidene)hydroxylamine Chemical compound O\N=C(/C)C1=CC=CC=C1 JHNRZXQVBKRYKN-VQHVLOKHSA-N 0.000 description 1
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- ZYVYEJXMYBUCMN-UHFFFAOYSA-N 1-methoxy-2-methylpropane Chemical compound COCC(C)C ZYVYEJXMYBUCMN-UHFFFAOYSA-N 0.000 description 1
- JVLRBIADOALMLB-UHFFFAOYSA-N 2-ethoxy-1,2-dihydroquinoline Chemical compound C1=CC=C2C=CC(OCC)NC2=C1 JVLRBIADOALMLB-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- OMQHDIHZSDEIFH-UHFFFAOYSA-N 3-Acetyldihydro-2(3H)-furanone Chemical compound CC(=O)C1CCOC1=O OMQHDIHZSDEIFH-UHFFFAOYSA-N 0.000 description 1
- OPXYNEYEDHAXOM-UHFFFAOYSA-N 3-oxobutanenitrile Chemical compound CC(=O)CC#N OPXYNEYEDHAXOM-UHFFFAOYSA-N 0.000 description 1
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical class C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- MGIKUVYGKKXRTM-UHFFFAOYSA-N 5-oxo-5-phenylmethoxy-2-[2-(phenylmethoxycarbonylamino)-1,3-thiazol-4-yl]pent-2-enoic acid Chemical compound C=1SC(NC(=O)OCC=2C=CC=CC=2)=NC=1C(C(=O)O)=CCC(=O)OCC1=CC=CC=C1 MGIKUVYGKKXRTM-UHFFFAOYSA-N 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-N Acetoacetic acid Natural products CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
- 101100313763 Arabidopsis thaliana TIM22-2 gene Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- LKFVGXHZNBKJAE-XCWJXAQQSA-N NC1=NC(C(C(NC([C@H]2SCC(C[N+]3=CC=CC=C3)=C(C([O-])=O)N22)C2=O)=O)=CCC(O)=O)=CS1 Chemical compound NC1=NC(C(C(NC([C@H]2SCC(C[N+]3=CC=CC=C3)=C(C([O-])=O)N22)C2=O)=O)=CCC(O)=O)=CS1 LKFVGXHZNBKJAE-XCWJXAQQSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- 241000194017 Streptococcus Species 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- DYRDKSSFIWVSNM-UHFFFAOYSA-N acetoacetanilide Chemical compound CC(=O)CC(=O)NC1=CC=CC=C1 DYRDKSSFIWVSNM-UHFFFAOYSA-N 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 description 1
- PXAJQJMDEXJWFB-UHFFFAOYSA-N acetone oxime Chemical compound CC(C)=NO PXAJQJMDEXJWFB-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 241001148470 aerobic bacillus Species 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000008430 aromatic amides Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- WKMKIKIVJLGLCJ-RTOCNIJBSA-N benzhydryl (6R)-3-[(1-methyltetrazol-5-yl)sulfanylmethyl]-8-oxo-7-[[5-oxo-5-phenylmethoxy-2-[2-(phenylmethoxycarbonylamino)-1,3-thiazol-4-yl]pent-2-enoyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1(=CC=CC=C1)C(C1=CC=CC=C1)OC(=O)C1=C(CS[C@H]2N1C(C2NC(C(=CCC(=O)OCC1=CC=CC=C1)C=1N=C(SC=1)NC(=O)OCC1=CC=CC=C1)=O)=O)CSC1=NN=NN1C WKMKIKIVJLGLCJ-RTOCNIJBSA-N 0.000 description 1
- YDROWRWAIBYYQX-FBLFFUNLSA-N benzhydryl (6r)-7-amino-3-[(1-methyltetrazol-5-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound CN1N=NN=C1SCC1=C(C(=O)OC(C=2C=CC=CC=2)C=2C=CC=CC=2)N2C(=O)C(N)[C@H]2SC1 YDROWRWAIBYYQX-FBLFFUNLSA-N 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- XTHHUVLEDGJXCT-UHFFFAOYSA-N benzyl 2-(6-diphenylphosphanylcyclohexa-2,4-dien-1-ylidene)acetate Chemical compound C(C1=CC=CC=C1)OC(=O)C=C1C(C=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1 XTHHUVLEDGJXCT-UHFFFAOYSA-N 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
- 239000000872 buffer Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- CIISBNCSMVCNIP-UHFFFAOYSA-N cyclopentane-1,2-dione Chemical compound O=C1CCCC1=O CIISBNCSMVCNIP-UHFFFAOYSA-N 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical class [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000007257 deesterification reaction Methods 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940075933 dithionate Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000005059 halophenyl group Chemical group 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000004434 industrial solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- UHAAFJWANJYDIS-UHFFFAOYSA-N n,n'-diethylmethanediimine Chemical compound CCN=C=NCC UHAAFJWANJYDIS-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 125000003638 stannyl group Chemical group [H][Sn]([H])([H])* 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- NYBWUHOMYZZKOR-UHFFFAOYSA-N tes-adt Chemical class C1=C2C(C#C[Si](CC)(CC)CC)=C(C=C3C(SC=C3)=C3)C3=C(C#C[Si](CC)(CC)CC)C2=CC2=C1SC=C2 NYBWUHOMYZZKOR-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 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 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- 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
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
この発明は次式（）で表わされる7β−［２−
（２−アミノチアゾール−４−イル）−４−カルボ
キシ−２−ブテノイルアミノ］−３−セフエム−
４−カルボン酸およびそのアルカリ金属塩に関す
る。
（式中、
Ｒは水素原子、メチル基、ビニル基、１−メチ
ルテトラゾール−５−イルチオメチル基または１
−ピリジニオメチル基、
をそれぞれ示す）
前記アルカリ金属塩としてはリチウム塩、ナト
リウム塩、カリウム塩を例示できる。
化合物（）は、好気性、嫌気性の細菌に強い
抗菌性を示し、医薬として有用である。特に、グ
ラム陰極菌に対する抗菌力、吸収、***、分布な
どに特性を示す。感染症の予防、治療には、常法
により製剤化し、0.2〜６ｇ（注射）、0.2〜４ｇ
（内用）、0.01〜10mg（外用）等の日用量で投与す
る。製剤化には各種添加剤を用いうる。また、細
菌感受性試験用材料としても利用できる。
化合物（）に近縁の化合物は特公昭42−
10996号、特開昭57−93982号、ベルギー特許第
816408号、ベルギー特許第888389号などに記載さ
れているが、これらは医薬としての効果、吸収、
***などの特性が化合物（）には及ばない。
この発明の化合物は、例えば以下に記載の方法
などを用いて製造することができる。
(1) アミド化
次頁の反応式に従つてアミノセフエムカルボ
ン酸（）またはその反応性誘導体にアミノチ
アゾリルカルボキシブテン酸（）またはその
反応性誘導体を常法により作用させれば化合物
（）を製造できる。
反応式中、R1は水素またはアミノ保護基で、
後者は各種アルケニル（アセト酢酸エステルと
の
エナミンを形成するものなど）、アラルキル
（トリチルなど）、アシル（アルカノイル、第三
級ブトキシカルボニル、ベンジルカルボニルな
ど）、酸付加塩などのアミノ保護基である。
R2、R3は水素またはカルボキシ保護基で、
後者はペニシリン、セフアロスポリンの化学の
分野で、分子中の他の部分に不都合な変化を起
こすことなく着脱可能なものとして知られてい
る保護基、例えば、アラルキルエステル（ベン
ジルエステル、メチルベンジルエステル、ジメ
チルベンジルエステル、メトキシベンジルエス
テル、エトキシベンジルエステル、ニトロベン
ジルエステル、アミノベンジルエステル、ジフ
エニルメチルエステル、フタリジルエステル、
フエナシルエステルなど）、置換アルキルエス
テル（トリクロロエチルエステル、ｔ−ブチル
エステル、アリルエステルなど）、アリールエ
ステル（ペンタクロロフエニルエステル、イン
ダニルエステルなど）、Ｎ−ヒドロキシアミノ
化合物とのエステル（アセトンオキシム、アセ
トフエノンオキシム、アセトアルドキシム、Ｎ
−ヒドロキシこはく酸イミド、Ｎ−ヒドロキシ
フタルイミドなどとのエステル）、炭酸または
カルボン酸との酸無水物、反応性置換アミドな
どを構成する保護基である。
アミノセフエムカルボン酸（）の反応性誘
導体としては７位のアミノ基が、シリル基（ト
リメチルシリル、メトキシジメチルシリル、ｔ
−ブチルジメチルシリルなど）、スタニル基
（トリメチルスタニルなど）、アルキレン基（ア
ルデヒド、アセトン、アセチルアセトン、アセ
ト酢酸エステル、アセトアセトニトリル、アセ
トアセトアニリド、シクロペンタンジオン、ア
セチルブチロラクトンなどと結合した型のエナ
ミンを形成する基）、アルキリデン基（１−ハ
ロアルキリデン、１−ハロアラルキリデン、１
−アルコキシアルキリデン、１−アルコキシア
ラルキリデン、１−アルコキシ−１−フエノキ
シアルキリデン、アルキリデン、アラルキリデ
ンなど）、酸（鉱酸、カルボン酸、スルホン酸
などとの塩の形で）、外れ易いアシル基（アル
カノイルなど）、その他の基で活性化されたも
のと、分子中の他の官能基を前記のように保護
したものなどを例示できる。
アミノチアゾリルカルボキシブテン酸（）
は縮合剤［カーボジイミド類（Ｎ，N′−ジエ
チルカーボジイミド、Ｎ，N′−ジシクロヘキ
シルカーボジイミドなど）、カルボニル化合物
（カルボニルジイミダゾールなど）、イソキサゾ
リニウム塩、アシルアミノ化合物（２−エトキ
シ−１−エトキシカルボニル−１，２−ジヒド
ロキノリンなど）、その他］の存在下に反応さ
せる。
アミノチアゾリルカルボキシブテン酸（）
の反応性誘導体は酸無水物、対称酸無水物、混
合酸無水物［鉱酸（りん酸、硫酸、炭酸半エス
テルなど）、有機酸（アルカン酸、アラルカン
酸、スルホン酸など）との混合酸無水物など］、
分子内無水物（ケテン、イソシアネートなど）、
酸ハロゲン化物（ハロゲン化水素との混合酸無
水物）など］、酸ハロゲン化物、活性エステル
［エノールエステル（ビニルエステル、イソプ
ロペニルエステルなど）、アリールエステル
（フエニルエステル、ハロフエニルエステル、
ニトロフエニルエステルなど）、異項環エステ
ル（ピリジルエステル、ベンゾトリアゾリルエ
ステルなど）、Ｎ−ヒドロキシ化合物とのエス
テル、ジアシルヒドロキシルアミンとのエステ
ル（Ｎ−ヒドロキシスクシンイミド、Ｎ−ヒド
ロキシフタルイミドなどとのエステル）、チオ
ールエステル（アラルキルチオールエステル、
テトラゾリルチオールエステルなど）、その
他］、活性アミド［芳香族アミド（イミダゾー
ル、トリアゾール、２−エトキシ−１，２−ジ
ヒドロキノリンなどとのアミド）、ジアシルア
ニリンなど］、その他であつて、酸捕捉剤［無
機塩基（アルカリ金属、アルカリ土類金属など
の酸化物、水酸化物、炭酸塩、重炭酸塩など）、
有基塩基（第三級アミン、芳香族塩基など）、
オキシラン（アルキレンオキシド、アラルキレ
ンオキシドなど）、ピリジニウム塩（三塩化ト
リピリジオトリアジンなど）、吸着剤（セライ
トなど）、その他］の存在下に作用させる。
(2) 保護基の脱離
この様にして製造したアミノ基、カルボキシ
基が保護された化合物（）は、当技術分野で
常用の脱保護反応に付せば化合物（）を製造
できる。この脱保護反応には、たとえば下記の
ような、この分野で常用の操作法を適用するこ
とができる。
(a) 反応性の高いエステル、アミド、無水物な
どの保護基は酸、塩基、緩衝液、イオン交換
樹脂などと水性溶液中で接触させれば脱保護
できる。反応性が低い場合に公知方法によつ
て反応性を高めてから脱保護する場合もあ
る。トリクロルエチルエステルに金属と酸、
ｐ−ニトロベンジルエステルに接触還元やジ
チオン酸塩、フエナシルエステルに光照射な
どの活性化は好例である。
(b) アラルキルエステルは白金、パラジウム、
ニツケルなど触媒の存在下に水素を常法によ
り作用させて接触環元すれば脱保護できる。
(c) アラルキルエステル、シクロプロピルメチ
ルエステル、スルホニルエチルエステルなど
は、要すればカチオン捕捉剤の存在下に、鉱
酸、ルイス酸（塩化アルミニウム、塩化ス
ズ、四塩化チタンなど）、スルホン酸（メタ
ンスルホン酸、トリフルオロメタンスルホン
酸など）、強酸性カルボン酸（トリフルオロ
酢酸など）などを作用させれば脱保護でき
る。
(d) その他の均等な保護基脱離法も用い得る。
(3) 塩の製造
化合物（）にアルカリ金属塩基を作用させ
るか交換分解法により他種のカルボン酸のアル
カリ金属塩を作用させると化合物（）のアル
カリ金属塩を製造できる。操作法はこの分野の
常法を適用できる。例えば、遊離酸を炭酸水素
アルカリ金属塩で中和する方法、アルコール、
ケトン、エステルなどの極性有機溶媒中、低級
カルボン酸アルカリ金属塩を作用させたのち、
難溶性溶媒を加えて目的とする塩を析出させる
方法などが好ましい。
(4) 反応条件
前記合成方法(1)〜(3)は通常−30℃〜10℃、と
くに−20℃〜50℃の温度で10分間〜10時間かけ
て反応させることが多い。これらは溶媒中、要
すれば無水条件下に実施する。その他の常法
は、いずれも適用できる。
反応用溶媒としては、炭化水素（ペンタン、
ヘキサン、オクタン、ベンゼン、トルエン、キ
シレンなど）、ハロゲン化炭化水素（ジクロロ
メタン、クロロホルム、四塩化炭素、ジクロロ
エタン、トリクロロエタン、クロロベンゼンな
ど）、エーテル（ジエチルエーテル、メチルイ
ソブチルエーテル、ジオキサン、テトラヒドロ
フランなど）、ケトン（アセトン、メチルエチ
ルケトン、シクロヘキサノンなど）、エステル
（酢酸エチル、酢酸イソブチル、安息香酸メチ
ルなど）、ニトロ炭化水素（ニトロメタン、ニ
トロベンゼンなど）、ニトリル（アセトニトリ
ル、ベンゾニトリルなど）、アミド（ホルムア
ミド、アセトアミド、ジメチルホルムアミド、
ジメチルアセトアミド、ヘキサメチルホスホロ
トリアミドなど）、スルホキシド（ジメチルス
ルホキシドなど）、カルボン酸（ギ酸、酢酸、
プロピオン酸など）、有機塩基（ジエチルアミ
ン、トリエチルアミン、ピリジン、ピコリン、
コリジン、キノリンなど）、アルコール（メタ
ノール、エタノール、プロパノール、ヘキサノ
ール、オクタノール、ベンジルアルコールな
ど）、水、その他の系列に属する工業用溶媒ま
たはその混合物を例示できる。
(5) 後処理
目的とする生成物は反応液から未反応原料、
副生成物、溶媒などの夾雑物を抽出、蒸発、洗
浄、濃縮、沈殿、濾過、乾燥などの常法により
除去したのち、吸着、溶離、蒸留、沈殿、析
出、クロマトグラフイーなど、常用の後処理法
を組合せて処理すれば単離することができる。
(6) 実施例
以下に実施例を示して本発明の態様を説明す
る。
生成物の物理定数は、表にまとめて記載し
た。表中、IRはcm-1値を、NMRはδ値を、Ｊ
値は結合定数をHz値で示す。シン異性体は側鎖
ビニルプロトンのNMRスペクトルが高磁場、
アンチ異性体は低磁場に現れる幾何異性体を示
す。二種結合の水素とカルボニルがトランス位
にあるシン体は抗菌力が強い。
実施例中、量を表わす部は原料β−ラクタム
１重量に対する重量を、モル当量数は原料β−
ラクタム１モルに対するモル数を示す。
実施例中の後処理には、通常は反応液に、必
要に応じて水、酸、ジクロロメタンなどの溶媒
を加え、分液したのち、有機層を水洗、乾燥、
減圧濃縮して得られる残留物を、必要ならシリ
カゲル・クロマトグラフイーで精製したのち、
結晶化、沈殿、濾過などで採取する方法などを
組合わせて用いる。
実施例 １
（ナトリウム塩）
第２表のカルボン酸（）１ｇを0.5％炭酸水
素ナトリウム水６mlにとかし、塩酸でPH７とし、
酢酸エチルで洗い、脱塩したのち、10mlバイアル
に入れ、常法により凍結乾燥すれば、対応するナ
トリウム塩の粉末を得る。無菌条件下に製造した
上記ナトリウム塩１ｇを注射用蒸留水４ｇにとか
し、黄色ブドー球菌感染症の患者に一日二回づつ
静脈注射または経口投与すれば、この感染症を治
療することができる。
このナトリウム塩をとり、日本化学療法学会所
定の方法に準じて最小発育阻止濃度を測定すれ
ば、溶血性連鎖球菌C203株に対して3.1〜0.2μ
ｇ／ml、大腸菌Ｈ株に対して0.8〜0.025μｇ／ml
の範囲の価を示す。
実施例 ２
（アミド化）
(1) ７−アミノ−３−（１−メチル−５−テトラ
ゾリル）チオメチル−３−セフエム−４−カル
ボン酸ジフエニルメチルエステルと２−（２−
ベンジルオキシカルボニルアミノチアゾール−
４−イル）−４−ベンジルオキシカルボニル−
２−ブテン酸１モル当量をジクロロメタン50部
にとかし、Ｎ，N′−ジシクロヘキシルカーボ
ジイミド１モル当量を加え、室温で２時間かき
まぜたのち、反応液を減圧濃縮する。残留物を
酢酸エチル中かきまぜ、不溶物を濾去する。濾
液をカラムクロマトグラフイーにより精製すれ
ば、７−［２−（２−ベンジルオキシカルボニル
アミノチアゾール−４−イル）−４−ベンジル
オキシカルボニル−２−ブテノイルアミノ］−
３−（１−メチル−５−テトラゾリル）チオメ
チル−３−セフエム−４−カルボン酸ジフエニ
ルメチルエステルを得る。収率：90％。
(2) ７−アミノ−３−ピリジニオメチル−３−セ
フエム−４−カルボン酸塩酸塩塩化物を水10部
とジオキサン15部の混液にとかし、氷冷下にか
きまぜながら炭酸水素ナトリウム２モル当量、
２−（２−ベンジルオキシカルボニルアミノチ
アゾール−４−イル）−４−ベンジルオキシカ
ルボニル−２−ブテル酸1.2モル当量、１−ヒ
ドロキシベンゾトリアゾール1.2モル当量およ
びＮ，N′−ジシクロヘキシルカーボジイミド
1.2モル当量のジオキサン５部溶液を加え、同
温で3.5時間かきまぜる。反応液に1N−塩酸５
部を加えて濾過し、残渣をアセトン50部で洗
う。濾、洗液を合し、シリカゲルクロマトグラ
フイーにより精製、凍結乾燥すれば、７−［２
−（２−ベンジルオキシカルボニルアミノチア
ゾール−４−イル）−４−ベンジルオキシカル
ボニル−２−ブテノイルアミノ］−３−ピリジ
ニオメチル−３−セフエム−４−カルボキシレ
ートを得る。収率：50.8％。
(3) 前記(1)または(2)と同様の反応条件下、第一表
の化合物を合成できる。
実施例 ３
（脱エステル化）
(1) 第一表のジフエニルメチルエステル１部をジ
クロロメタン0.3〜３部、トリフルオロ酢酸0.3
〜３部およびアニソール0.5〜５部の混液にと
かし、−10〜40℃で10分〜３時間かきまぜる。
反応液を減圧下に濃縮して溶媒と試薬を留去
し、残留物をベンゼンで洗えば、対応する遊離
酸を70〜90％の収率で製造できる。
(2) 第一表の前記エステル１部をジクロロメタン
５〜９部とアニソール２〜８部の混液にとか
し、−10〜10℃で塩化アルミニウム、四塩化ス
ズまたは四塩化チタニウム３〜12モル当量を加
えたのち、１〜３時間かきまぜる。反応液を希
塩酸と水で洗い、乾燥したのち濃縮すれば、対
応する遊離酸を80〜95％の収率で製造できる。
アミノ保護基であるベンジルオキシカルボニル
も脱保護される。
(3) ７−［２−（２−ベンジルオキシカルボニルア
ミノチアゾール−４−イル）−４−ベンジルオ
キシカルボニル−２−ブテノイルアミノ］−３
−（１−メチル−５−テトラゾリル）チオメチ
ル−３−セフエム−４−カルボン酸ジフエニル
メチルエステルにアニソール12部と塩化アルミ
ニウム９モル当量を加え、０℃で４時間かきま
ぜる。反応液を５％炭素水素ナトリウム水で中
和し、不溶物を濾去し、濾液を酢酸エチルで洗
う。水層を塩酸酸性とし、酢酸エチルで洗い、
水層をダイヤイオンHP20（三菱化成(株)製合成
吸着剤）のカラムに吸着する。これを80％メタ
ノールで溶出すれば、７−［２−（２−アミノチ
アゾール−４−イル）−４−カルボキシ−２−
ブテノイルアミノ］−３−（１−メチル−５−テ
トラゾリル）チオメチル−３−セフエム−４−
カルボン酸を得る。収率：65％。
(4) ７−［２−（２−ベンジルオキシカルボニルア
ミノチアゾール−４−イル）−４−ベンジルオ
キシカルボニル−２−ブテノイルアミノ］−３
−ピリジニオメチル−３−セフエム−４−カル
ボン酸をアニソール２部に懸濁し、氷冷下に塩
化アルミニウム９モル当量を含むアニソール２
部を加えて3.5時間かきまぜる。反応液に10％
塩酸を加え、酢酸エチルで洗う。水層をダイヤ
イオンHP−20のカラムに通す。吸着物を５％
アセトン水で溶出し、凍結乾燥すれば、７−
［２−（２−アミノチアゾール−４−イル）−４
−カルボキシ−２−ブテノイルアミノ］−３−
ピリジニオメチル−３−セフエム−４−カルボ
キシレートを得る。収率：55％。
(5) 前記(1)〜(4)と同様の反応条件下、第二表の化
合物を合成できる。
製造例 １
(1) ２−（２−ベンジルオキシカルボニルアミノ
チアゾール−４−イル）−２−ホルミル酢酸ジ
フエニルメチルエステルとベンジルオキシカル
ボニルメチレントリフエニルホスフイン1.3モ
ル当量をジオキサン８部にとかし、100℃で６
時間かきまぜる。反応液を濃縮し、残渣をシリ
カゲルクロマトグラフイーにより精製すれば、
２−（２−ベンジルオキシカルボニルアミノチ
アゾール−４−イル）−４−ベンジルオキシカ
ルボニル−２−ブテン酸ジフエニルメチルエス
テル87％を得る。このうち、34％がシン、53％
がアンチ異性体で、精製を繰返せば相互に単離
できる。
（シン異性体）IR（CHCl3）：3400、1730cm-1。
（アンチ異性体）IR（CHCl3）：3410、1730cm
-1。
この生成物をジクロロメタン10部にとかし、
アニソール部とトリフルオロ酢酸２部を加え、
室温で２時間かきまぜる。反応液を濃縮し、残
渣をエーテル・ヘキサン混液で洗浄すれば、２
−（２−ベンジルオキシカルボニルアミノチア
ゾール−４−イル）−４−ベンジルオキシカル
ボニル−２−ブテン酸を得る。収率：89％。
（アンチ異性体）NMR（CDCl3−CD3OD）：
3.51（ｄ、Ｊ＝７Hz、2H）、5.13（ｓ、2H）、
5.26（ｓ、2H）、7.06（ｓ、1H）、7.0〜7.5（ｍ、
11H）．
（シン異性体）NMR（CDCl3−CD3OD）：3.73
（ｄ、Ｊ＝７Hz、2H）、5.13（ｓ、2H）、5.26
（ｓ、2H）、7.10（ｓ、1H）、7.0〜7.5（ｍ、
11H）．
両異性体はクラマトグラフイーで分離でき
る。
前記実施例により製造される下式セフエム化合
物の赤外線吸収スペクトルと核磁気共鳴スペクト
ルを次頁以下の第一表（R1＝ベンジルオキシカ
ルボニル、R2＝ベンジル、R3＝ジフエニルメチ
ル）および第二表（R1＝R2＝R3＝水素）に示す。
（略号） Mt＝１−メチルテトラゾール−５−
イル、Py+＝ピリジニオ。
Ｒ欄のシン：アンチ*は７位側鎖二重結合に
おける幾何異性体またはその比率を示す。
This invention is expressed by the following formula () 7β-[2-
(2-aminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-cephem-
4-Carboxylic acid and its alkali metal salt. (In the formula, R is a hydrogen atom, a methyl group, a vinyl group, a 1-methyltetrazol-5-ylthiomethyl group, or a 1-methyltetrazol-5-ylthiomethyl group.
-pyridiniomethyl group, respectively) Examples of the alkali metal salts include lithium salts, sodium salts, and potassium salts. Compound () exhibits strong antibacterial properties against aerobic and anaerobic bacteria and is useful as a medicine. In particular, it exhibits characteristics such as antibacterial activity against Gram-cathodobacteria, absorption, excretion, and distribution. For the prevention and treatment of infectious diseases, prepare by conventional methods, 0.2-6g (injection), 0.2-4g
Administer at a daily dose of 0.01 to 10 mg (for internal use) or 0.01 to 10 mg (for external use). Various additives can be used in formulation. It can also be used as a material for bacterial susceptibility testing. Compounds closely related to compound () are
No. 10996, JP-A-57-93982, Belgian Patent No.
No. 816408, Belgian Patent No. 888389, etc., but these are known for their medicinal effects, absorption,
Properties such as excretion are not comparable to compounds (). The compound of this invention can be produced using, for example, the method described below. (1) Amidation If aminocefemcarboxylic acid () or its reactive derivative is reacted with aminothiazolylcarboxybutenoic acid () or its reactive derivative in a conventional manner according to the reaction formula on the next page, the compound ( ) can be manufactured. In the reaction formula, R 1 is hydrogen or an amino protecting group,
The latter are various alkenyls (with acetoacetic acid ester) amino protecting groups such as aralkyl (such as trityl), acyl (such as alkanoyl, tertiary butoxycarbonyl, benzylcarbonyl), and acid addition salts. R 2 and R 3 are hydrogen or carboxy protecting groups,
The latter is a protective group known in the field of penicillin and cephalosporin chemistry as one that can be attached and removed without causing any unfavorable changes in other parts of the molecule, such as aralkyl esters (benzyl ester, methylbenzyl ester, dimethyl Benzyl ester, methoxybenzyl ester, ethoxybenzyl ester, nitrobenzyl ester, aminobenzyl ester, diphenylmethyl ester, phthalidyl ester,
phenacyl ester, etc.), substituted alkyl esters (trichloroethyl ester, t-butyl ester, allyl ester, etc.), aryl esters (pentachlorophenyl ester, indanyl ester, etc.), esters with N-hydroxyamino compounds (acetone oxime, Acetophenone oxime, acetaldoxime, N
It is a protecting group constituting esters with -hydroxysuccinimide, N-hydroxyphthalimide, etc.), acid anhydrides with carbonic acid or carboxylic acids, reactive substituted amides, etc. As a reactive derivative of aminocefem carboxylic acid (), the amino group at position 7 is a silyl group (trimethylsilyl, methoxydimethylsilyl, t
-butyldimethylsilyl, etc.), stannyl groups (trimethylstannyl, etc.), alkylene groups (aldehydes, acetone, acetylacetone, acetoacetate, acetoacetonitrile, acetoacetanilide, cyclopentanedione, acetylbutyrolactone, etc.) to form enamines. group), alkylidene group (1-haloalkylidene, 1-haloaralkylidene, 1
- alkoxyalkylidene, 1-alkoxyaralkylidene, 1-alkoxy-1-phenoxyalkylidene, alkylidene, aralkylidene, etc.), acids (in the form of salts with mineral acids, carboxylic acids, sulfonic acids, etc.), easily removed acyls Examples include those activated with groups (alkanoyl, etc.), other groups, and those activated with other functional groups in the molecule as described above. Aminothiazolylcarboxybutenoic acid ()
is a condensing agent [carbodiimides (N,N'-diethylcarbodiimide, N,N'-dicyclohexylcarbodiimide, etc.), carbonyl compounds (carbonyldiimidazole, etc.), isoxazolinium salts, acylamino compounds (2-ethoxy-1 -ethoxycarbonyl-1,2-dihydroquinoline, etc.), etc.]. Aminothiazolylcarboxybutenoic acid ()
The reactive derivatives of are acid anhydrides, symmetrical acid anhydrides, mixed acid anhydrides [mixed acids with mineral acids (phosphoric acid, sulfuric acid, carbonic acid half esters, etc.), organic acids (alkanoic acids, aralkanoic acids, sulfonic acids, etc.) anhydrous, etc.],
Intramolecular anhydrides (ketene, isocyanate, etc.),
acid halides (mixed acid anhydrides with hydrogen halides), etc.], acid halides, active esters [enol esters (vinyl esters, isopropenyl esters, etc.), aryl esters (phenyl esters, halophenyl esters,
nitrophenyl esters, etc.), heterocyclic esters (pyridyl esters, benzotriazolyl esters, etc.), esters with N-hydroxy compounds, esters with diacylhydroxylamines (esters with N-hydroxysuccinimide, N-hydroxyphthalimide, etc.) ), thiol esters (aralkyl thiol esters,
active amides [aromatic amides (amides with imidazole, triazole, 2-ethoxy-1,2-dihydroquinoline, etc.), diacylaniline, etc.], others, which are acid scavengers. agents [inorganic bases (oxides, hydroxides, carbonates, bicarbonates, etc. of alkali metals and alkaline earth metals),
Basic bases (tertiary amines, aromatic bases, etc.),
Oxirane (alkylene oxide, aralkylene oxide, etc.), pyridinium salt (tripyridiotriazine trichloride, etc.), adsorbent (Celite, etc.), etc.). (2) Removal of protecting group Compound () whose amino group or carboxy group is protected thus produced can be subjected to a deprotection reaction commonly used in the art to produce compound (). For this deprotection reaction, procedures commonly used in this field, such as those described below, can be applied. (a) Highly reactive protecting groups such as esters, amides, and anhydrides can be deprotected by contacting them with acids, bases, buffers, ion exchange resins, etc. in an aqueous solution. When the reactivity is low, deprotection may be carried out after increasing the reactivity by a known method. Trichloroethyl ester with metal and acid,
Activation such as catalytic reduction and dithionate of p-nitrobenzyl ester and light irradiation of phenacyl ester are good examples. (b) Aralkyl esters include platinum, palladium,
Deprotection can be achieved by catalytic ring formation in the presence of a catalyst such as nickel using hydrogen in a conventional manner. (c) Aralkyl esters, cyclopropyl methyl esters, sulfonyl ethyl esters, etc. can be prepared using mineral acids, Lewis acids (aluminum chloride, tin chloride, titanium tetrachloride, etc.), sulfonic acids (methane, etc.), optionally in the presence of cation scavengers. Sulfonic acid, trifluoromethanesulfonic acid, etc.) or strong acidic carboxylic acid (trifluoroacetic acid, etc.) can be used to deprotect the compound. (d) Other equivalent deprotection methods may also be used. (3) Production of salt An alkali metal salt of compound () can be produced by reacting compound () with an alkali metal base or with an alkali metal salt of another type of carboxylic acid by exchange decomposition. As for the operation method, conventional methods in this field can be applied. For example, methods for neutralizing free acids with alkali metal bicarbonate salts, alcohols,
After reacting with an alkali metal salt of a lower carboxylic acid in a polar organic solvent such as a ketone or ester,
Preferred is a method in which a poorly soluble solvent is added to precipitate the desired salt. (4) Reaction conditions In the synthesis methods (1) to (3), the reaction is usually carried out at a temperature of -30°C to 10°C, particularly -20°C to 50°C, for 10 minutes to 10 hours. These are carried out in a solvent, optionally under anhydrous conditions. Any other conventional law may be applied. Hydrocarbons (pentane,
Hexane, octane, benzene, toluene, xylene, etc.), halogenated hydrocarbons (dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, chlorobenzene, etc.), ethers (diethyl ether, methyl isobutyl ether, dioxane, tetrahydrofuran, etc.), ketones ( acetone, methyl ethyl ketone, cyclohexanone, etc.), esters (ethyl acetate, isobutyl acetate, methyl benzoate, etc.), nitrohydrocarbons (nitromethane, nitrobenzene, etc.), nitriles (acetonitrile, benzonitrile, etc.), amides (formamide, acetamide, dimethylformamide,
dimethylacetamide, hexamethylphosphorotriamide, etc.), sulfoxides (dimethylsulfoxide, etc.), carboxylic acids (formic acid, acetic acid,
propionic acid), organic bases (diethylamine, triethylamine, pyridine, picoline,
Examples include industrial solvents belonging to other series such as collidine, quinoline, etc.), alcohols (methanol, ethanol, propanol, hexanol, octanol, benzyl alcohol, etc.), water, and mixtures thereof. (5) Post-treatment The desired product is extracted from the reaction solution by removing unreacted raw materials,
After removing impurities such as by-products and solvents by conventional methods such as extraction, evaporation, washing, concentration, precipitation, filtration, and drying, and after regular use such as adsorption, elution, distillation, precipitation, precipitation, and chromatography. It can be isolated by combining treatment methods. (6) Examples Aspects of the present invention will be described below with reference to Examples. The physical constants of the products are summarized in a table. In the table, IR is the cm -1 value, NMR is the δ value, J
Values indicate coupling constants in Hz. The syn isomer has a side chain vinyl proton NMR spectrum in high magnetic field,
The anti-isomer refers to the geometric isomer that appears in the low magnetic field. Syn-isomers, in which the two-bond hydrogen and carbonyl are in the trans position, have strong antibacterial activity. In the examples, the part representing the amount is the weight per 1 weight of the raw material β-lactam, and the number of molar equivalents is the weight of the raw material β-lactam.
The number of moles per mole of lactam is shown. For post-treatment in the examples, usually a solvent such as water, acid, dichloromethane, etc. is added to the reaction solution as necessary, and the organic layer is separated, and then the organic layer is washed with water, dried,
The residue obtained by concentration under reduced pressure is purified by silica gel chromatography if necessary.
A combination of collection methods such as crystallization, precipitation, and filtration is used. Example 1 (Sodium salt) 1 g of the carboxylic acid () shown in Table 2 was dissolved in 6 ml of 0.5% sodium bicarbonate water, and the pH was adjusted to 7 with hydrochloric acid.
After washing with ethyl acetate and desalting, the solution is placed in a 10 ml vial and lyophilized using a conventional method to obtain a powder of the corresponding sodium salt. Staphylococcus aureus infection can be treated by dissolving 1 g of the above sodium salt prepared under sterile conditions in 4 g of distilled water for injection and administering the solution intravenously or orally twice a day to a patient suffering from Staphylococcus aureus infection. If you take this sodium salt and measure the minimum inhibitory concentration according to the method specified by the Japanese Society of Chemotherapy, it will be 3.1 to 0.2μ against hemolytic streptococcus C203 strain.
g/ml, 0.8-0.025 μg/ml for E. coli H strain
indicates a range of values. Example 2 (Amidation) (1) 7-amino-3-(1-methyl-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester and 2-(2-
Benzyloxycarbonylaminothiazole-
4-yl)-4-benzyloxycarbonyl-
1 molar equivalent of 2-butenoic acid is dissolved in 50 parts of dichloromethane, 1 molar equivalent of N,N'-dicyclohexylcarbodiimide is added, and after stirring at room temperature for 2 hours, the reaction solution is concentrated under reduced pressure. The residue was stirred in ethyl acetate and insoluble matter was filtered off. If the filtrate is purified by column chromatography, 7-[2-(2-benzyloxycarbonylaminothiazol-4-yl)-4-benzyloxycarbonyl-2-butenoylamino]-
3-(1-Methyl-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained. Yield: 90%. (2) Dissolve 7-amino-3-pyridiniomethyl-3-cephem-4-carboxylic acid hydrochloride chloride in a mixture of 10 parts of water and 15 parts of dioxane, and add 2 molar equivalents of sodium hydrogen carbonate while stirring under ice-cooling.
1.2 molar equivalents of 2-(2-benzyloxycarbonylaminothiazol-4-yl)-4-benzyloxycarbonyl-2-buteric acid, 1.2 molar equivalents of 1-hydroxybenzotriazole and N,N'-dicyclohexylcarbodiimide
Add 5 parts of 1.2 molar equivalent of dioxane solution and stir at the same temperature for 3.5 hours. 1N hydrochloric acid 5 to the reaction solution
1 part, filter, and wash the residue with 50 parts of acetone. The filtration and washing solutions are combined, purified by silica gel chromatography, and freeze-dried to obtain 7-[2
-(2-benzyloxycarbonylaminothiazol-4-yl)-4-benzyloxycarbonyl-2-butenoylamino]-3-pyridiniomethyl-3-cephem-4-carboxylate is obtained. Yield: 50.8%. (3) The compounds in Table 1 can be synthesized under the same reaction conditions as in (1) or (2) above. Example 3 (Deesterification) (1) 1 part of diphenyl methyl ester in Table 1 was mixed with 0.3 to 3 parts of dichloromethane and 0.3 parts of trifluoroacetic acid.
Dissolve in a mixture of ~3 parts and 0.5 to 5 parts of anisole and stir at -10 to 40°C for 10 minutes to 3 hours.
By concentrating the reaction solution under reduced pressure to remove the solvent and reagents, and washing the residue with benzene, the corresponding free acid can be produced with a yield of 70-90%. (2) Dissolve 1 part of the ester listed in Table 1 in a mixture of 5 to 9 parts of dichloromethane and 2 to 8 parts of anisole, and add 3 to 12 molar equivalents of aluminum chloride, tin tetrachloride, or titanium tetrachloride at -10 to 10°C. After adding, stir for 1 to 3 hours. By washing the reaction solution with dilute hydrochloric acid and water, drying, and concentrating, the corresponding free acid can be produced with a yield of 80-95%.
The amino protecting group benzyloxycarbonyl is also deprotected. (3) 7-[2-(2-benzyloxycarbonylaminothiazol-4-yl)-4-benzyloxycarbonyl-2-butenoylamino]-3
12 parts of anisole and 9 molar equivalents of aluminum chloride are added to -(1-methyl-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester, and the mixture is stirred at 0°C for 4 hours. The reaction solution is neutralized with 5% aqueous sodium bicarbonate, insoluble matter is filtered off, and the filtrate is washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid, washed with ethyl acetate,
The aqueous layer is adsorbed on a column of Diaion HP20 (synthetic adsorbent manufactured by Mitsubishi Kasei Corporation). If this is eluted with 80% methanol, 7-[2-(2-aminothiazol-4-yl)-4-carboxy-2-
butenoylamino]-3-(1-methyl-5-tetrazolyl)thiomethyl-3-cephem-4-
Obtain carboxylic acid. Yield: 65%. (4) 7-[2-(2-benzyloxycarbonylaminothiazol-4-yl)-4-benzyloxycarbonyl-2-butenoylamino]-3
- Pyridiniomethyl-3-cephem-4-carboxylic acid is suspended in 2 parts of anisole, and then anisole containing 9 molar equivalents of aluminum chloride is added under ice cooling.
and stir for 3.5 hours. 10% in reaction solution
Add hydrochloric acid and wash with ethyl acetate. Pass the aqueous layer through a Diaion HP-20 column. 5% adsorbent
If eluted with acetone water and freeze-dried, 7-
[2-(2-aminothiazol-4-yl)-4
-carboxy-2-butenoylamino]-3-
Pyridiniomethyl-3-cephem-4-carboxylate is obtained. Yield: 55%. (5) The compounds in Table 2 can be synthesized under the same reaction conditions as in (1) to (4) above. Production Example 1 (1) 1.3 molar equivalents of 2-(2-benzyloxycarbonylaminothiazol-4-yl)-2-formylacetic acid diphenylmethyl ester and benzyloxycarbonylmethylenetriphenylphosphine were dissolved in 8 parts of dioxane, and 100 ℃6
Stir the time. If the reaction solution is concentrated and the residue is purified by silica gel chromatography,
87% of 2-(2-benzyloxycarbonylaminothiazol-4-yl)-4-benzyloxycarbonyl-2-butenoic acid diphenylmethyl ester is obtained. Of these, 34% are thin, 53%
are anti-isomers and can be isolated from each other by repeated purification. (Syn isomer) IR (CHCl 3 ): 3400, 1730 cm -1 . (Anti-isomer) IR (CHCl 3 ): 3410, 1730cm
-1 . Dissolve this product in 10 parts of dichloromethane,
Add anisole part and 2 parts of trifluoroacetic acid,
Stir at room temperature for 2 hours. If the reaction solution is concentrated and the residue is washed with a mixture of ether and hexane, 2
-(2-benzyloxycarbonylaminothiazol-4-yl)-4-benzyloxycarbonyl-2-butenoic acid is obtained. Yield: 89%. (Anti-isomer) NMR ( CDCl3 - CD3OD ):
3.51 (d, J=7Hz, 2H), 5.13 (s, 2H),
5.26 (s, 2H), 7.06 (s, 1H), 7.0~7.5 (m,
11H). (Syn isomer) NMR ( CDCl3 - CD3OD ): 3.73
(d, J=7Hz, 2H), 5.13 (s, 2H), 5.26
(s, 2H), 7.10 (s, 1H), 7.0~7.5 (m,
11H). Both isomers can be separated by chromatography. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the cefem compound of the following formula produced according to the above example are shown in Table 1 (R 1 = benzyloxycarbonyl, R 2 = benzyl, R 3 = diphenylmethyl) and Table 2 below on the next page. (R 1 = R 2 = R 3 = hydrogen). (abbreviation) Mt=1-methyltetrazole-5-
Il, Py + = pyridinio. Syn:anti * in the R column indicates the geometric isomer or the ratio thereof at the 7-position side chain double bond.
【表】【table】
【表】【table】
【表】 実験例 化合物(A)の経口吸収と抗菌力 実験例 １ 経口吸収[Table] Experimental example: Oral absorption and antibacterial activity of compound (A) Experimental example 1 Oral absorption
【表】 実験例 ２ 抗菌力【table】 Experimental example 2 Antibacterial power
Claims (1)
アゾール−４−イル）−４−カルボキシ−２−ブ
テノイルアミノ］−３−セフエム−４−カルボン
酸およびそのアルカリ金属塩。 （式中、 Ｒは水素原子、メチル基、ビニル基、１−メチ
ルテトラゾール−５−イルチオメチル基または１
−ピリジニオメチル基、 をそれぞれ示す） ２ Ｒが水素原子またはビニル基である特許請求
の範囲１の化合物。[Scope of Claims] 7β-[2-(2-aminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-cephem-4-carboxylic acid represented by the following formula and an alkali metal salt thereof . (In the formula, R is a hydrogen atom, a methyl group, a vinyl group, a 1-methyltetrazol-5-ylthiomethyl group, or a 1-methyltetrazol-5-ylthiomethyl group.
-pyridiniomethyl group, respectively) 2 The compound according to claim 1, wherein R is a hydrogen atom or a vinyl group.
Priority Applications (49)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58186601A JPS6078987A (en) | 1983-10-04 | 1983-10-04 | Acrylamidocephalosporins |
| AU33300/84A AU575854B2 (en) | 1983-10-04 | 1984-09-19 | 7beta-(carboxyalkenamido) cephalosporins |
| NZ209634A NZ209634A (en) | 1983-10-04 | 1984-09-21 | 7#b#-(carboxyalkenoylamino)-3-cephem-4-carboxylic acid derivatives and pharmaceutical compositions |
| NZ218741A NZ218741A (en) | 1983-10-04 | 1984-09-21 | Carboxyalkenoic acid intermediates |
| PH31265A PH20223A (en) | 1983-10-04 | 1984-09-25 | Catboxyalkenamidocephalosporins |
| CA000464215A CA1238910A (en) | 1983-10-04 | 1984-09-27 | Carboxyalkenoic acids |
| PT79287A PT79287A (en) | 1983-10-04 | 1984-10-01 | Process for preparing carboxyalkenamidocephalosporins |
| NO843956A NO173238C (en) | 1983-10-04 | 1984-10-02 | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 7-BETA- (CARBOXYLKENOYLAMINO) -3-CEFEM-4-CARBOXYLIC ACID COMPOUNDS |
| FI843871A FI82057C (en) | 1983-10-04 | 1984-10-02 | PROCEDURE FOR FRAMSTAELLNING AV EN 7BETA- (CARBOXYKENOYLAMINO) -3-CEFEM-4-CARBOXYLSYRAFOERENING OCH DESS DERIVAT. |
| IE2524/84A IE57744B1 (en) | 1983-10-04 | 1984-10-03 | Carboxybutenamidocephalosporins |
| HU843743A HU193298B (en) | 1983-10-04 | 1984-10-03 | Process for production of derivatives of //carboxialkenoil/-amino//-cefem carbonic acid |
| ZA847767A ZA847767B (en) | 1983-10-04 | 1984-10-03 | Carboxyalkenamidocephalosporins |
| GB08424923A GB2154580B (en) | 1983-10-04 | 1984-10-03 | Carboxybutenamidocephalosporins |
| SU843805283A SU1500163A3 (en) | 1983-10-04 | 1984-10-03 | Method of producing carboxyalenamidocephalosporins or their esters or their salts with alkaline metals |
| HU871310A HU198003B (en) | 1983-10-04 | 1984-10-03 | Process for producing carboxy-alkenic acid derivatives substituted with heterocyclic or phenyl groups |
| DK474584A DK171043B1 (en) | 1983-10-04 | 1984-10-03 | 7-beta- (carboxyalkenoylamino) -3-cephem-4-carboxylic acid derivatives |
| MX013280A MX174328B (en) | 1983-10-04 | 1984-10-03 | PROCEDURE FOR THE PREPARATION OF CARBOXIALQUENOIC ACIDS |
| GR80544A GR80544B (en) | 1983-10-04 | 1984-10-03 | Carboxyalkenamidocephalosporins |
| DD84268008A DD232049A5 (en) | 1983-10-04 | 1984-10-04 | PROCESS FOR THE PREPARATION OF CARBOXYALKENAMIDOCEPHALOSPORINES |
| EP84111916A EP0136721B1 (en) | 1983-10-04 | 1984-10-04 | Carboxyalkenamidocephalosporins |
| KR1019840006134A KR880002376B1 (en) | 1983-10-04 | 1984-10-04 | Process for preparing carboxyalkenamido-cephalosporins |
| IL84653A IL84653A (en) | 1983-10-04 | 1984-10-04 | Amino-alpha-carboxyethylidenethiazoleacetic acid derivatives and processes for the preparation thereof |
| AT84111916T ATE99311T1 (en) | 1983-10-04 | 1984-10-04 | CARBOXYALKENAMIDOCEPHALOSPORINS. |
| DE3486259T DE3486259T2 (en) | 1983-10-04 | 1984-10-04 | Carboxyalkenamidocephalosporins. |
| DD84287318A DD243283A5 (en) | 1983-10-04 | 1984-10-04 | PROCESS FOR THE PREPARATION OF CARBOXYALKENSAEURES |
| CS847528A CS268513B2 (en) | 1983-10-04 | 1984-10-04 | Method of 7 beta-(carboxyalkanolamino)-3-cefem-carboxyl acids production |
| IL73159A IL73159A (en) | 1983-10-04 | 1984-10-04 | Carboxyalkenamido-cephalosporins,processes for the preparation thereof and methods for the use thereof |
| ES536502A ES8604602A1 (en) | 1983-10-04 | 1984-10-04 | Carboxyalkenamidocephalosporins. |
| AR84298181A AR242392A1 (en) | 1983-10-04 | 1984-10-04 | Carboxyalkenamidocephalosporins |
| DE198484111916T DE136721T1 (en) | 1983-10-04 | 1984-10-04 | CARBOXYALKENAMIDOCEPHALOSPORINE. |
| US06/711,017 US4634697A (en) | 1983-10-04 | 1985-03-12 | Carboxyalkenamidocephalosporins |
| ES547301A ES8605278A1 (en) | 1983-10-04 | 1985-08-29 | Carboxyalkenamidocephalosporins. |
| ES547300A ES8700222A1 (en) | 1983-10-04 | 1985-08-29 | Carboxyalkenamidocephalosporins. |
| NO853806A NO176567C (en) | 1983-10-04 | 1985-09-27 | Karboksyalkensyrer |
| CS859630A CS268528B2 (en) | 1983-10-04 | 1985-12-20 | Method of carboxy-alkene acid's derivatives production |
| CS859629A CS268527B2 (en) | 1983-10-04 | 1985-12-20 | Method of 7 beta-(carboxyalkenolamino)-3-cefem-4-carboxyl acids production |
| CS859628A CS268526B2 (en) | 1983-10-04 | 1985-12-20 | Method of 7 beta(carboxyakenoyl)-3-cefem-4-carboxyl acids production |
| US06/831,435 US4748170A (en) | 1983-10-04 | 1986-02-20 | Carboxyalkenamidocephalosporins |
| PH33818A PH21766A (en) | 1983-10-04 | 1986-05-27 | Carboxyalkenamido derivatives |
| SU864028353A SU1720487A3 (en) | 1983-10-04 | 1986-10-24 | Method of producing carboxyalkenic acids |
| GB08700123A GB2190914B (en) | 1983-10-04 | 1987-01-06 | Intermediates for carboxybutenamidocephalosporins |
| CS87445A CS268531B2 (en) | 1983-10-04 | 1987-01-21 | Method of carboxy-alkene acid's derivatives production |
| CA000531176A CA1272713A (en) | 1983-10-04 | 1987-03-04 | Carboxyalkenamidocephalosporins |
| GB08726623A GB2198727B (en) | 1983-10-04 | 1987-11-13 | Carboxyalkenamidocephalosporins |
| IL84653A IL84653A0 (en) | 1983-10-04 | 1987-11-27 | Carboxybutenoic acids and processes for the preparation thereof |
| US07/132,882 US4912224A (en) | 1983-10-04 | 1987-12-09 | Carboxyalkenamidocephalosporins |
| AU16194/88A AU601842B2 (en) | 1983-10-04 | 1988-05-16 | Carboxyalkenoic acid derivatives |
| KR1019880012223A KR880002684B1 (en) | 1983-10-04 | 1988-09-21 | Process for preparing carboxy alkenic acid and it's derivatives |
| NL940013C NL940013I2 (en) | 1983-10-04 | 1994-07-04 | Carboxyalkenamidocephalosporins. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58186601A JPS6078987A (en) | 1983-10-04 | 1983-10-04 | Acrylamidocephalosporins |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6078987A JPS6078987A (en) | 1985-05-04 |
| JPH0251555B2 true JPH0251555B2 (en) | 1990-11-07 |
Family
ID=16191412
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58186601A Granted JPS6078987A (en) | 1983-10-04 | 1983-10-04 | Acrylamidocephalosporins |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JPS6078987A (en) |
| DD (2) | DD243283A5 (en) |
| ZA (1) | ZA847767B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2501785B2 (en) * | 1984-07-09 | 1996-05-29 | 明治製菓株式会社 | New cephalosporin compounds |
| JP2544113B2 (en) * | 1986-07-02 | 1996-10-16 | 塩野義製薬株式会社 | Stable capsule formulation |
| JP3115455B2 (en) | 1992-12-18 | 2000-12-04 | 明治製菓株式会社 | New cephalosporin derivatives |
-
1983
- 1983-10-04 JP JP58186601A patent/JPS6078987A/en active Granted
-
1984
- 1984-10-03 ZA ZA847767A patent/ZA847767B/en unknown
- 1984-10-04 DD DD84287318A patent/DD243283A5/en unknown
- 1984-10-04 DD DD84268008A patent/DD232049A5/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DD243283A5 (en) | 1987-02-25 |
| ZA847767B (en) | 1985-06-26 |
| DD232049A5 (en) | 1986-01-15 |
| JPS6078987A (en) | 1985-05-04 |
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