JPH026357B2 - - Google Patents
Info
- Publication number
- JPH026357B2 JPH026357B2 JP9902382A JP9902382A JPH026357B2 JP H026357 B2 JPH026357 B2 JP H026357B2 JP 9902382 A JP9902382 A JP 9902382A JP 9902382 A JP9902382 A JP 9902382A JP H026357 B2 JPH026357 B2 JP H026357B2
- Authority
- JP
- Japan
- Prior art keywords
- ester
- groups
- group
- carboxylic acid
- salts
- 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
- 125000003277 amino group Chemical group 0.000 claims description 15
- 150000002148 esters Chemical class 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- DXDYAKVFATZEHE-ZIYOKLDJSA-N (6r)-3-hydroxy-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylic acid Chemical compound OC(=O)C1C(O)CS[C@@H]2CC(=O)N21 DXDYAKVFATZEHE-ZIYOKLDJSA-N 0.000 claims description 2
- -1 heptyloxycarbonyl Chemical group 0.000 description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 125000002252 acyl group Chemical group 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000000354 decomposition reaction Methods 0.000 description 7
- 238000002329 infrared spectrum Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 7
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- 125000004434 sulfur atom Chemical group 0.000 description 6
- 125000005907 alkyl ester group Chemical group 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 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 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000004442 acylamino group Chemical group 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000000676 alkoxyimino group Chemical group 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical compound NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 150000002169 ethanolamines Chemical class 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 2
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 125000001148 pentyloxycarbonyl group Chemical group 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
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 description 2
- YTCUEIOOUOMPAT-RXMQYKEDSA-N (6r)-3-hydroxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound OC(=O)C1=C(O)CS[C@@H]2CC(=O)N12 YTCUEIOOUOMPAT-RXMQYKEDSA-N 0.000 description 1
- FZEVMBJWXHDLDB-ZCFIWIBFSA-N (6r)-5-thia-1-azabicyclo[4.2.0]oct-2-en-8-one Chemical compound S1CC=CN2C(=O)C[C@H]21 FZEVMBJWXHDLDB-ZCFIWIBFSA-N 0.000 description 1
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 description 1
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 1
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 1
- AMOYMEBHYUTMKJ-UHFFFAOYSA-N 2-(2-phenylethoxy)ethylbenzene Chemical compound C=1C=CC=CC=1CCOCCC1=CC=CC=C1 AMOYMEBHYUTMKJ-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- DOZZSWAOPDYVLH-UHFFFAOYSA-N 2-phenylpropanamide Chemical compound NC(=O)C(C)C1=CC=CC=C1 DOZZSWAOPDYVLH-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-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
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 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
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 150000007860 aryl ester derivatives Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-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
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 125000002592 cumenyl group Chemical group C1(=C(C=CC=C1)*)C(C)C 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000268 heptanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005935 hexyloxycarbonyl group Chemical group 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 159000000003 magnesium salts Chemical class 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
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- JDEJGVSZUIJWBM-UHFFFAOYSA-N n,n,2-trimethylaniline Chemical compound CN(C)C1=CC=CC=C1C JDEJGVSZUIJWBM-UHFFFAOYSA-N 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229940127249 oral antibiotic Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[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
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 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
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Description
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ããDETAILED DESCRIPTION OF THE INVENTION This invention provides 3-cephem-4 by a novel reaction.
- It relates to a method for producing a carboxylic acid ester.
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ããå·¥æ¥çã«ã¯é©ããŠããªãã€ãã Conventionally, the method for producing 3-cephem-4-carboxylic acid ester is as follows: (1) 3-hydroxycephem-4-carboxylic acid is dehydrated, and then the obtained 3-cephem-4-carboxylic acid is treated by a conventional method. (2) 3-hydroxycepham-4-carboxylic acid is esterified by a conventional method, and then the obtained 3-
A method of dehydrating hydroxycefam-4-carboxylic acid ester is known. However, all of these methods require two steps and are not suitable for industrial use.
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ãã®çºæãå®äºããã The inventors have discovered that 3-hydroxycepham-4
-While investigating the reactivity of carboxylic acids, when a haloformic acid ester is reacted with it in the presence of a base,
We discovered a new reaction in which dehydration unsaturation and esterification to 3-cephem occur simultaneously, and 3-cepheme-4-carboxylic acid ester is obtained in one step.
This invention has been completed.
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ããã The method of this invention is expressed by the following general formula.
ïŒåŒäžãR1ã¯ã¢ããåºãŸãã¯ä¿è·ãããã¢ãã
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æãããšæ¬¡ã®ãšããã§ããã (In the formula, R 1 means an amino group or a protected amino group, and R 2 means an esterified carboxy group.) Suitable examples included in each definition in the above formula are explained in detail as follows. It is.
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å¥ã¯ïŒå以äžã®ççŽ ååãæããåºãæå³ããã Unless otherwise specified, the term "lower"
It has 1-6 carbon atoms, and the term "higher" refers to groups having 7 or more carbon atoms.
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ãæããããã Protected amino groups include amino groups substituted with groups commonly used as protecting groups for their 7- or 6-position amino groups in cephalosporin and penicillin chemistry, and more specifically, acylamino groups, and groups other than acyl,
Examples include amino groups substituted with groups such as alkyl (lower) alkyl such as benzyl, phenethyl, and trityl.
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ã«éšåã®é©åœãªäŸã¯æ¬¡ã®éãã§ããã Among these, the acyl moiety in the acylamino group includes aliphatic acyl, aromatic acyl and heterocyclic acyl. Here, aromatic acyl and heterocyclic acyl mean acyl containing an aromatic ring or a heterocyclic ring, respectively. Suitable examples of such acyl moieties are as follows.
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ãã«åºçãæããããã Examples of aliphatic acyl include lower or higher alkanoyl groups such as formyl, acetyl, succinyl, hexanoyl, heptanoyl, and stearoyl, methoxycarbonyl, ethoxycarbonyl, tertiary butoxycarbonyl, tertiary pentyloxycarbonyl, heptyloxycarbonyl, and the like. Examples include lower or higher alkoxycarbonyl groups, and lower or higher alkanesulfonyl groups such as methanesulfonyl, ethanesulfonyl, and heptanesulfonyl.
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ã«çã®ã¢ã¬ãŒã³ã¹ã«ããã«åºçãæããããã Examples of aromatic acyl include aroyl groups such as benzoyl, toluoyl, and naphthoyl; alkanoyl groups such as phenyl acetyl and phenylpropionyl; aryloxycarbonyl groups such as phenoxycarbonyl and naphthoxycarbonyl; Aryloxy (lower) alkanoyl groups such as cyacetyl and phenoxypropionyl, arylglyoxyloyl groups such as phenylglyoxyloyl and naphthylglyoxyloyl, and alkoxy (lower) alkoxy groups such as benzyloxycarbonyl and diphenylmethoxycarbonyl. Examples include carbonyl groups, arenesulfonyl groups such as benzenesulfonyl and para-toluenesulfonyl.
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ïŒå¡äžé£œååç°è€çŽ ç°åŒåºçãæããããã Examples of the heterocyclic acyl include a heterocyclic carbonyl group and a heterocyclic lower alkanoyl group. The heterocyclic moiety in the above heterocyclic carbonyl and heterocyclic lower alkanoyl group is a saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one heteroatom selected from nitrogen atom, sulfur atom, and oxygen atom. groups, among which preferable ones include, for example, thiazolyl group,
Isothiazolyl group, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-
a 3- to 8-membered unsaturated monocyclic heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as a thiadiazolyl group such as thiadiazolyl, 1,2,5-thiadiazolyl, and a dihydrothiadiazinyl group; 3-3 containing 1 to 2 sulfur atoms, such as a thienyl group, a dihydrodithinyl group, a dihydrodithiolyl group, etc.
Examples include 8-membered unsaturated monocyclic heterocyclic groups.
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åŠãé©åœãªçœ®æåºãæããŠããŠãããã The above acyl moieties include, for example, lower alkyl groups such as methyl and ethyl, lower alkoxy groups such as methoxy, ethoxy, and propoxy, lower alkylthio groups such as methylthio and ethylthio, halogens such as chlorine and bromine, amino groups, and the like mentioned above. Protected amino group, cyano group, nitro group, imino group, oxo group,
Formula = N-OR 3 [In the formula, R 3 is a hydrogen atom, a lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, a lower alkenyl group such as vinyl, allyl, 2-butenyl, ethynyl, Protected groups such as lower alkynyl groups such as 2-propynyl, lower alkoxycarbonyl (lower) alkyl groups such as methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, tert-butoxycarbonylmethyl, and 1-tert-butoxycarbonylethyl; It may have a suitable substituent such as a group represented by [meaning a carboxy-substituted lower alkyl group, etc.].
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ãããã More preferred examples of protected amino groups as defined above include al(lower)alkanamide groups such as phenyl(lower)alkanamides such as phenyl acetamide, phenylpropionamide; Lower alkoxycarbonyl (lower) such as butoxycarbonylmethoxyimino-2-(thiazol-4-yl)acetamide
5 or 6 membered containing 1 sulfur atom and 1 to 2 nitrogen atoms substituted with an esterified carboxy(lower)alkoxyimino such as an alkoxyimino-substituted thiazole(lower)alkanamide Unsaturated monocyclic heterocyclic (lower) alkanamide group; 2-methoxyimino-2
- one sulfur atom substituted with lower alkoxyimino and acylamino such as thiazole (lower) alkanamide and one sulfur atom substituted with lower alkoxyimino such as (2-formamidothiazol-4-yl)acetamide;
Mention may be made of 5- or 6-membered unsaturated monocyclic heterocyclic (lower) alkanamide groups containing ~2 nitrogen atoms.
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ãšã¹ãã«çãæããããã Examples of esters in esterified carboxy groups and haloformates include methyl ester, ethyl ester, propyl ester,
Lower alkyl esters such as isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, tertiary pentyl ester, hexyl ester, 1-cyclopropylethyl ester, lower alkenyl esters such as vinyl ester, allyl ester, Lower alkynyl esters such as ethynyl ester and propynyl ester, acetoxymethyl ester, 1-acetoxyethyl ester, propionyloxymethyl ester, 1-propionyloxyethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, lower alkanoyloxy (lower) alkyl ester such as hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, methoxycarbonyloxymethyl ester, 1-(ethoxycarbonyloxy)ethyl ester, 1-( Lower alkoxycarbonyloxy (lower) alkyl esters such as isopropoxycarbonyloxy)ethyl ester, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenylmethyl ester, bis(methoxyf) Substituted or unsubstituted phenyl (lower) alkyl esters such as phenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-ditertiary butylbenzyl ester, etc. Examples include aryl esters such as (lower) alkyl esters, phenyl esters, tolyl esters, tertiary butyl phenyl esters, xylyl esters, mesityl esters, and cumenyl esters.
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ã«ïŒäœçŽïŒã¢ã«ã³ãã·ã«ã«ããã«ãæããããã More preferred examples of such esterified carboxy groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, tertiary pentyl. oxycarbonyl, hexyloxycarbonyl,
Lower alkoxycarbonyl groups such as 1-cyclopropoxycarbonyl, benzyloxycarbonyl,
Al(lower) alkoxycarbonyl such as phenyl(lower)alkoxycarbonyl such as phenethyloxycarbonyl, trityloxycarbonyl, diphenylmethoxycarbonyl and the like can be mentioned.
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ãã Salts include commonly used non-toxic salts;
Salts with inorganic or organic bases, such as alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts, triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, Ethanolamine salt, dicyclohexylamine salt,
N,N'-dibenzylethylenediamine salts, etc., and inorganic or organic acid addition salts, such as hydrochlorides, hydrobromides, sulfates, phosphates, formates, acetates,
trifluoroacetate, maleate, tartrate,
Included are methanesulfonate, benzenesulfonate, paratoluenesulfonate, etc., as well as salts with basic or acidic amino acids, such as salts with arginine, aspartic acid, glutamic acid, etc.
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ãããšã«ããè¡ãªãããã The reaction of this invention is carried out by reacting the compound () or a salt thereof with a haloformic acid ester in the presence of a base.
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žãšã¹ãã«ãç¹çšãããã As the haloformic acid ester, chloroformic acid ester or bromoformic acid ester is frequently used.
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ãŠã ååç©ãé°ã€ãªã³äº€ææš¹èçãçšããããã As the base, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium carbonate,
Alkali metal carbonates such as potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, tertiary amines such as triethylamine and trimethylaniline, pyridine compounds such as pyridine, picoline, and lutidine, 1,5-diazabicyclo[4 , 3,0]-5-nonene, diazabicyclo compounds such as 1,5-diazabicyclo[5,4,0]-5-undecene, quaternary ammonium compounds such as Triton B, anion exchange resins, and the like.
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察ããŠéå°ã«çšããŠãããã Haloformates and bases are compounds ()
It is appropriate to use 2 times the mole or more for 3
It is preferable to use twice to four times the mole. Note that the molar numbers of the haloformic acid ester and the base may be the same or different. For example, the base may be used in excess relative to the haloformate.
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æž©äžã«è¡ãªãããã This reaction usually involves acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran,
It is carried out in a solvent which does not adversely affect the reaction, such as conventional solvents such as ethyl acetate, N,N-dimethylformamide, or mixtures thereof. Although the reaction temperature is not particularly limited, it is usually carried out at room temperature or with heating.
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åããã®çºæã«å«ãŸãããã®ãšããã In this reaction, R 1 in compound ()
is an amino group or the protected amino group of R 1 further contains an amino group or a protected amino group, a compound in which these groups are substituted with a substituted oxycarbonyl group derived from a haloformic acid ester () may be obtained, and the protecting group may be removed at that time, but these cases are also included in the present invention.
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ç©è³ªãšããŠæçšã§ããã The compound () obtained by this invention has antibacterial activity and is useful as an antibiotic, especially an oral antibiotic.
次ã«ããã®çºæãå®æœäŸã«ããããã«è©³çŽ°ã«èª¬
æããã Next, the present invention will be explained in more detail using examples.
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ïŒãåŸããExample 1 1.0 g (2.97 mmol) of 7-(2-phenylacetamido)-3-hydroxycephame-4-carboxylic acid was suspended in 10 ml of dry tetrahydrofuran and 10 ml of dry acetone, and 1.20 g (11.88 mmol, 4 times equivalent) of dry triethylamine was dissolved. ) to 20â25
Add at °C. Followed by 0.97g of ethyl chloroformate
(8.91 mmol, 3 times equivalent) at an internal temperature of 20-30â for 10
-Drop in 15 minutes. After continuing stirring at the same temperature for 30 minutes, the reaction solution was concentrated under reduced pressure. Dissolve the residue in 30 ml of methylene chloride and wash sequentially with 10 ml each of saturated aqueous sodium hydrogen carbonate solution, 1N hydrochloric acid, and saturated aqueous sodium chloride solution. The methylene chloride layer is dried over anhydrous magnesium sulfate and concentrated to obtain 1.2 g of yellowish white crystals. This was suspended in 50 ml of isopropyl ether, washed, collected, and dried. The result was mp193-203â (decomposition), pale yellowish white crystals.
(2-phenylacetamide)-3-cephem-4
-Carboxylic acid ethyl ester 0.92g (yield 89.3
%).
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ãåŸããIR spectrum (nujiol) 1770, 1720, 1660, 1630 cm -1 NMR spectrum (DMSO-d 6 ) 1.25 (3H, t, J = 8Hz), 3.55 (2H, s),
3.65 (2H, m), 4.25 (2H, q, J=Hz), 5.07
(1H, d, J=5Hz), 5.77 (1H, dd, J=5
Hz, 9Hz), 6.55 (1H, t, J=, 4Hz), 7.32
(5H, s), 9.09 (1H, d, J = 9Hz) ppm Elemental analysis (C 17 H 18 O 4 N 2 S) Calculated value C58.9, H5.2, N8.1 Experimental value C58.67, H5 .22, N8.02 Example 2 7-phenylacetamido-3-hydroxycepham-4-carboxylic acid 1.0 g (2.97 mmol)
in 10 ml of dry tetrahydrofuran and 10 ml of dry acetone and 1.20 ml of dry triethylamine.
g (11.88 mmol, 4 equivalents) at 20-25°C. Next, benzyl chloroformate 2.03g (11.88
(mmol, 4 times equivalent) was added dropwise over 10-15 minutes at an internal temperature of 20-30°C. After continuing stirring at the same temperature for 30 minutes,
Concentrate the reaction solution under reduced pressure. Dissolve the residue in 30 ml of methylene chloride, add 10 each of saturated aqueous sodium bicarbonate solution, 1N hydrochloric acid, and saturated aqueous sodium chloride solution.
Wash sequentially with ml. The methylene chloride layer is dried over anhydrous magnesium sulfate and concentrated to obtain 1.2 g of brown crystals. Add this to isopropyl ether 50
ml, wash, remove, and dry.
mp157-161â (decomposition), pale brown crystal 7-(2-
(phenylacetamide)-3-cephem-4-carboxylic acid benzyl ester 0.87g (yield 68.5%)
get.
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ããIR spectrum (nujiol) 1770, 1720, 1655, 1630 cm -1 NMR spectrum (DMSO-d 6 ) 3.60 (2H, s), 3.65 (2H, m), 5.08 (1H, d,
J = 5Hz), 5.28 (2H, s), 5.79 (1H, dd, J
=5Hz, 8.8Hz), 6.61 (1H, t, J = 4Hz),
7.30 (5H, s), 7.41 (5H, s), 9.10 (1H, d,
J=8.5Hz) ppm Elemental analysis (C 22 H 20 O 4 N 2 S) Calculated values C64.7, H4.9, N6.9 Experimental values C63.98, H5.02, N6.79 Example 3 Using 1 g of 7-(thiophenamide)-3-hydroxycepham-4-carboxylic acid, the same procedure as in Example 1 was carried out to obtain 7-(thiophenamide)-3-cephaem-4- at mp73-92°C (decomposition). 0.88 g (yield 85.4%) of crystals of carboxylic acid ethyl ester is obtained.
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4.5HzïŒã5.90ïŒ1HãddãïŒ4.5HzïŒã8.5HzïŒã
6.52ïŒ1HãïœãïŒïŒHzïŒïŒã7.17ïŒ1Hãddã
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8.00ïŒ1HãïœãïŒ3.5HzïŒã9.40ïŒ1Hãïœã
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ïŒãåŸããIR spectrum (nujiol) 1765, 1725, 1655 cm -1 NMR spectrum (DMSO-d 6 ) 1.23 (3H, t, J = 7Hz), 3.62 (2H, m),
4.27 (2H, q, J = 7Hz), 5.15 (1H, d, J =
4.5Hz), 5.90 (1H, dd, J=4.5Hz), 8.5Hz),
6.52 (1H, t, J = 5Hz)), 7.17 (1H, dd, J
=3.5Hz, 5Hz), 7.81 (1H, d, J = 5Hz),
8.00 (1H, d, J = 3.5Hz), 9.40 (1H, d, J
=8.5Hz)ppm Example 4 The same procedure as in Example 1 was carried out using 1 g of 7-[2-tert-butoxycarbonylmethoxyimino-2-(thiazol-4-yl)acetamide]-3-hydroxycepham-4-carboxylic acid (syn isomer). 7-[2-3] of mp75-90â (decomposition)
0.65 g (63.7%) of butoxycarbonylmethoxyimino-2-(thiazol-4-yl)acetamide]-3-cephem-4-carboxylic acid ethyl ester (syn isomer) is obtained.
IRã¹ãã¯ãã«ïŒããžãšãŒã«ïŒ
1785ã1725ã1685ã1635cm-1
NMRã¹ãã¯ãã«ïŒDMSOâd6ïŒ
1.27ïŒ3HãïœãïŒïŒHzïŒã1.47ïŒ9HãïœïŒã
3.62ïŒ2HãïœïŒ4.25ïŒ2HãïœãïŒïŒHzïŒã4.65
ïŒ2HãïœïŒã5.17ïŒ1HãïœãïŒïŒHzïŒã5.91ïŒ1Hã
ddãïŒïŒHzãïŒHzïŒã6.53ïŒ1HãïœãïŒïŒ
HzïŒã7.95ïŒ1HãïœãïŒïŒHzã9.17ïŒ1Hãïœã
ïŒïŒHzïŒã9.55ïŒïŒãïœãïŒïŒHzïŒppm
å®æœäŸ ïŒ
ïŒâãïŒâ第ïŒçŽãããã·ã«ã«ããã«ã¡ããã·
ã€ããâïŒâïŒãã¢ãŸãŒã«âïŒâã€ã«ïŒã¢ã»ãã¢
ãããâïŒâããããã·ã»ãã¢ã âïŒâã«ã«ãã³
é
žïŒã·ã³ç°æ§äœïŒïŒïœãçšããå®æœäŸïŒãšåæ§ã«
æäœããŠãmp75â88âïŒå解ïŒã®ïŒâãïŒâ第ïŒ
çŽãããã·ã«ã«ããã«ã¡ããã·ã€ããâïŒâïŒã
ã¢ãŸãŒã«âïŒâã€ã«ïŒã¢ã»ãã¢ãããâïŒâã»ã
ãšã âïŒâã«ã«ãã³é
žãã³ãžã«ãšã¹ãã«ïŒã·ã³ç°
æ§äœïŒ0.78ïœïŒ67.9ïŒ
ïŒãåŸããIR spectrum (nujiol) 1785, 1725, 1685, 1635cm -1 NMR spectrum (DMSO-d 6 ) 1.27 (3H, t, J = 7Hz), 1.47 (9H, s),
3.62 (2H, m) 4.25 (2H, q, J=7Hz), 4.65
(2H, s), 5.17 (1H, d, J=5Hz), 5.91 (1H,
dd, J = 5Hz, 9Hz), 6.53 (1H, t, J = 4
Hz), 7.95 (1H, d, J = 2Hz, 9.17 (1H, d, J
= 2Hz), 9.55 (1, d, J = 9Hz) ppm Example 5 The same procedure as in Example 2 was carried out using 1 g of 7-[2-tert-butoxycarbonylmethoxyimino-2-(thiazol-4-yl)acetamide]-3-hydroxycepham-4-carboxylic acid (syn isomer). 7-[2-3] of mp75-88â (decomposition)
0.78 g (67.9%) of butoxycarbonylmethoxyimino-2-(thiazol-4-yl)acetamide]-3-cephem-4-carboxylic acid benzyl ester (syn isomer) is obtained.
IRã¹ãã¯ãã«ïŒããžãšãŒã«ïŒ
1795ã1735ã1695ã1640cm-1
NMRã¹ãã¯ãã«ïŒDMSOâd6ïŒ
1.45ïŒ9HãïœïŒãïŒïŒ62ïŒ2HãïœïŒã4.65ïŒ2Hã
ïœïŒã5.18ïŒ1HãïœãïŒ5.5HzïŒã5.28ïŒ2Hã
ïœïŒã5.97ïŒ1HãddãïŒ5.5HzãïŒHzïŒã6.61
ïŒ1HãïœïŒã7.43ïŒ5HãïœïŒã7.95ïŒ1Hãïœã
ïŒïŒHzïŒã9.18ïŒ1HãïœãïŒïŒHzïŒã9.60ïŒ1Hã
ïœãïŒïŒHzïŒãppm
å®æœäŸ ïŒ
ïŒâãïŒâã¡ããã·ã€ããâïŒâïŒïŒâãã«ã ã¢
ãããã¢ãŸãŒã«âïŒâã€ã«ïŒã¢ã»ãã¢ãããâïŒ
âããããã·ã»ãã¢ã âïŒâã«ã«ãã³é
žïŒã·ã³ç°
æ§äœïŒïŒïœãçšããå®æœäŸïŒãšåæ§ã«æäœããŠåŸ
ãããæ²¹ç¶ç©çŽïŒïœãã20åééã®ã·ãªã«ã²ã«ã
çšããŠã«ã©ã ã¯ãããã°ã©ãã€ãŒïŒå±é溶åªã¯ã
ããã«ã ïŒã«ä»ããæåã®ãã©ã¯ã·ãšã³ãšããŠã
mp108â120âïŒå解ïŒã®ïŒâãïŒâã¡ããã·ã€ã
ãâïŒâïŒïŒâãšããã·ã«ã«ããã«ã¢ãããã¢ãŸ
ãŒã«âïŒâã€ã«ïŒã¢ã»ãã¢ãããâïŒâã»ããšã
âïŒâã«ã«ãã³é
žãšãã«ãšã¹ãã«ïŒã·ã³ç°æ§äœïŒ
ã®ç²æ«0.2ïœïŒåç16ïŒ
ïŒãåŸããIR spectrum (nujiol) 1795, 1735, 1695, 1640 cm -1 NMR spectrum (DMSO-d 6 ) 1.45 (9H, s), 3,62 (2H, m), 4.65 (2H,
s), 5.18 (1H, d, J=5.5Hz), 5.28 (2H,
s), 5.97 (1H, dd, J=5.5Hz, 9Hz), 6.61
(1H, m), 7.43 (5H, s), 7.95 (1H, d, J
= 2Hz), 9.18 (1H, d, J = 2Hz), 9.60 (1H,
d, J=9Hz), ppm Example 6 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamide]-3
Approximately 1 g of an oil obtained by the same procedure as in Example 1 using 1 g of -hydroxycefam-4-carboxylic acid (syn isomer) was subjected to column chromatography (development) using 20 times the weight of silica gel. as the first fraction (solvent chloroform),
7-[2-methoxyimino-2-(2-ethoxycarbonylaminothiazol-4-yl)acetamide]-3-cephem-4-carboxylic acid ethyl ester (syn isomer) at mp108-120â (decomposition)
0.2 g of powder (yield 16%) was obtained.
IRã¹ãã¯ãã«ïŒããžãšãŒã«ïŒ
1780ã1730ã1680ã1640cm-1
NMRã¹ãã¯ãã«ïŒDMSOâd6ïŒ
1.26ïŒ6HãïœãïŒïŒHzïŒã3.65ïŒ2HãïœïŒã
3.90ïŒ3HãïœïŒã4.27ïŒ4HãïœãïŒïŒHzïŒã
5.17ïŒ1HãïœãïŒ5.5HzïŒã5.90ïŒ1Hãddã
ïŒ5.5HzãïŒHzïŒã6.55ïŒ1HãïœïŒã7.33ïŒ1Hã
ïœïŒã9.68ïŒ1HãïœãïŒïŒHzïŒã12.00ïŒ1Hã
brãïœïŒppm
å
çŽ åæïŒC18H21O7N5S2ïŒ
èšç®å€C44.7ãH4.4ãN14.5
å®éšå€C43.84ãH4.45ãN13.73
次ã®ãã©ã¯ã·ãšã³ãšããŠãmp232â235âïŒå
解ïŒã®ïŒâãïŒâã¡ããã·ã€ããâïŒâïŒïŒâãã«
ã ã¢ãããã¢ãŸãŒã«âïŒâã€ã«ïŒã¢ã»ãã¢ããã
âïŒâã»ããšã âïŒâã«ã«ãã³é
žãšãã«ãšã¹ãã«
ïŒã·ã³ç°æ§äœïŒã®çµæ¶0.33ïœïŒåç32.2ïŒ
ïŒãåŸ
ããIR spectrum (nujiol) 1780, 1730, 1680, 1640 cm -1 NMR spectrum (DMSO-d 6 ) 1.26 (6H, t, J = 7Hz), 3.65 (2H, m),
3.90 (3H, s), 4.27 (4H, q, J=7Hz),
5.17 (1H, d, J = 5.5Hz), 5.90 (1H, dd, J
=5.5Hz, 9Hz), 6.55 (1H, m), 7.33 (1H,
s), 9.68 (1H, d, J=9Hz), 12.00 (1H,
br, s) ppm Elemental analysis (C 18 H 21 O 7 N 5 S 2 ) Calculated values C44.7, H4.4, N14.5 Experimental values C43.84, H4.45, N13.73 As the following fractions, 7-[2-Methoxyimino-2-(2-formamidothiazol-4-yl)acetamide] at mp232-235â (decomposition)
0.33 g (yield 32.2%) of crystals of -3-cephem-4-carboxylic acid ethyl ester (syn isomer) is obtained.
IRã¹ãã¯ãã«ïŒããžãšãŒã«ïŒ
1770ã1720ã1685ã1655cm-1
NMRã¹ãã¯ãã«ïŒDMSOâd6ïŒ
1.25ïŒ3HãïœãïŒïŒHzïŒã3.62ïŒ2HãïœïŒã
3.93ïŒ3HãïœïŒã4.28ïŒ2HãïœãïŒïŒHzïŒã
5.19ïŒ1Hãïœ
ãïŒïŒHzïŒã5.93ïŒ1HãddãïŒ
ïŒHzã8.5HzïŒã6.57ïŒ1HãïœãïŒïŒHzïŒã7.45
ïŒ1HãïœïŒã8.53ïŒ1HãïœïŒã9.70ïŒ1Hãïœã
ïŒ8.5HzïŒã12.57ïŒ1Hãbr ïœïŒppm
å
çŽ åæïŒC16H17O6N5S2ïŒ
èšç®å€C43.7ãH3.9ãN15.9
å®éšå€C43.53ãH3.84ãN15.89IR spectrum (nujiol) 1770, 1720, 1685, 1655 cm -1 NMR spectrum (DMSO-d 6 ) 1.25 (3H, t, J = 7Hz), 3.62 (2H, m),
3.93 (3H, s), 4.28 (2H, q, J=7Hz),
5.19 (1H, e, J = 5Hz), 5.93 (1H, dd, J =
5Hz, 8.5Hz), 6.57 (1H, t, J = 3Hz), 7.45
(1H, s), 8.53 (1H, s), 9.70 (1H, d, J
= 8.5Hz), 12.57 (1H, br s) ppm Elemental analysis (C 16 H 17 O 6 N 5 S 2 ) Calculated value C43.7, H3.9, N15.9 Experimental value C43.53, H3.84, N15.89
Claims (1)
åºãæå³ããïŒ ã§ç€ºãããïŒâããããã·ã»ãã¢ã âïŒâã«ã«ã
ã³é žãŸãã¯ãã®å¡©é¡ã«ããããé žãšã¹ãã«ãå¡©åº
ã®ååšäžã«åå¿ãããŠãäžè¬åŒ ïŒåŒäžãR2ã¯ãšã¹ãã«åãããã«ã«ããã·åºã
æå³ããR1ã¯åãšåãæå³ïŒ ã§ç€ºãããïŒâã»ããšã âïŒâã«ã«ãã³é žãšã¹ã
ã«ãŸãã¯ãã®å¡©é¡ãåŸãããšãç¹åŸŽãšãããïŒâ
ã»ããšã âïŒâã«ã«ãã³é žãšã¹ãã«ã®è£œé æ³ã[Claims] 1. General formula (In the formula, R 1 means an amino group or a protected amino group) 3-Hydroxycepham-4-carboxylic acid or a salt thereof is reacted with a haloformic acid ester in the presence of a base. , general formula (In the formula, R 2 means an esterified carboxy group, and R 1 has the same meaning as above.)
Method for producing cefem-4-carboxylic acid ester.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9902382A JPS58213785A (en) | 1982-06-08 | 1982-06-08 | Preparation of 3-cephem-4-carboxylic acid ester |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9902382A JPS58213785A (en) | 1982-06-08 | 1982-06-08 | Preparation of 3-cephem-4-carboxylic acid ester |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS58213785A JPS58213785A (en) | 1983-12-12 |
JPH026357B2 true JPH026357B2 (en) | 1990-02-08 |
Family
ID=14235627
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP9902382A Granted JPS58213785A (en) | 1982-06-08 | 1982-06-08 | Preparation of 3-cephem-4-carboxylic acid ester |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS58213785A (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH101482A (en) * | 1996-06-13 | 1998-01-06 | Otsuka Chem Co Ltd | Production of 3-norcephem compound |
-
1982
- 1982-06-08 JP JP9902382A patent/JPS58213785A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS58213785A (en) | 1983-12-12 |
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