EP0000645A1 - Isopenicilline, Verfahren zu ihrer Herstellung und pharmazeutische Bereitungen - Google Patents
Isopenicilline, Verfahren zu ihrer Herstellung und pharmazeutische Bereitungen Download PDFInfo
- Publication number
- EP0000645A1 EP0000645A1 EP78300169A EP78300169A EP0000645A1 EP 0000645 A1 EP0000645 A1 EP 0000645A1 EP 78300169 A EP78300169 A EP 78300169A EP 78300169 A EP78300169 A EP 78300169A EP 0000645 A1 EP0000645 A1 EP 0000645A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- oxo
- mmol
- heptane
- thia
- 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.)
- Granted
Links
- 229930191709 Isopenicillin Natural products 0.000 title abstract description 11
- 238000002360 preparation method Methods 0.000 title description 37
- 239000000203 mixture Substances 0.000 title description 19
- 238000000034 method Methods 0.000 title description 17
- 230000008569 process Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- 125000002252 acyl group Chemical group 0.000 claims abstract description 16
- 125000004442 acylamino group Chemical group 0.000 claims abstract description 15
- 150000002148 esters Chemical class 0.000 claims abstract description 12
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims abstract description 10
- 150000001768 cations Chemical class 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 3
- -1 hydroxy, hydroxymethyl Chemical group 0.000 claims description 62
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 16
- 239000002585 base Substances 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- NKBWMBRPILTCRD-UHFFFAOYSA-N 2-Methylheptanoic acid Chemical compound CCCCCC(C)C(O)=O NKBWMBRPILTCRD-UHFFFAOYSA-N 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical group 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 claims description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000005646 oximino group Chemical group 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
- 125000006244 carboxylic acid protecting group Chemical group 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 144
- 239000000243 solution Substances 0.000 description 59
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- 239000000047 product Substances 0.000 description 51
- 238000006243 chemical reaction Methods 0.000 description 40
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 32
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 22
- 239000000741 silica gel Substances 0.000 description 21
- 229910002027 silica gel Inorganic materials 0.000 description 21
- 239000002253 acid Substances 0.000 description 18
- 229910052786 argon Inorganic materials 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
- 239000012267 brine Substances 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 239000012300 argon atmosphere Substances 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 8
- 229930182555 Penicillin Natural products 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- 125000004185 ester group Chemical group 0.000 description 7
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 7
- 150000002960 penicillins Chemical class 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 238000005917 acylation reaction Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 5
- 230000010933 acylation Effects 0.000 description 5
- 239000006286 aqueous extract Substances 0.000 description 5
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 5
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- VYQLXFDWYFQLHL-UHFFFAOYSA-M potassium;2-thiophen-2-ylacetate Chemical compound [K+].[O-]C(=O)CC1=CC=CS1 VYQLXFDWYFQLHL-UHFFFAOYSA-M 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 3
- 125000002843 carboxylic acid group Chemical group 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- BTNMPGBKDVTSJY-UHFFFAOYSA-M keto-phenylpyruvate Chemical compound [O-]C(=O)C(=O)CC1=CC=CC=C1 BTNMPGBKDVTSJY-UHFFFAOYSA-M 0.000 description 3
- 239000002808 molecular sieve Substances 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- KRRIOYCIQFSWJR-UHFFFAOYSA-N [SH-].CN(C(N(C)C)=[NH2+])C Chemical compound [SH-].CN(C(N(C)C)=[NH2+])C KRRIOYCIQFSWJR-UHFFFAOYSA-N 0.000 description 2
- 239000000538 analytical sample Substances 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003637 basic solution Substances 0.000 description 2
- XXVPPEDUQUDVBG-UHFFFAOYSA-N benzhydryl 2-oxoacetate Chemical compound C=1C=CC=CC=1C(OC(=O)C=O)C1=CC=CC=C1 XXVPPEDUQUDVBG-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 150000003946 cyclohexylamines Chemical class 0.000 description 2
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- BRMYZIKAHFEUFJ-UHFFFAOYSA-L mercury diacetate Chemical compound CC(=O)O[Hg]OC(C)=O BRMYZIKAHFEUFJ-UHFFFAOYSA-L 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- SMJRBWINMFUUDS-UHFFFAOYSA-M thien-2-ylacetate Chemical group [O-]C(=O)CC1=CC=CS1 SMJRBWINMFUUDS-UHFFFAOYSA-M 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- PTDVPWWJRCOIIO-UHFFFAOYSA-N (4-methoxyphenyl)methanethiol Chemical compound COC1=CC=C(CS)C=C1 PTDVPWWJRCOIIO-UHFFFAOYSA-N 0.000 description 1
- ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- JDRYZFKJLZHIMX-YQGMFIQUSA-N 2-[(2r,3r)-3-amino-2-(bromomethyl)-4-oxoazetidin-1-yl]-2-ethanethioyloxyacetic acid Chemical compound CC(=S)OC(C(O)=O)N1[C@@H](CBr)[C@@H](N)C1=O JDRYZFKJLZHIMX-YQGMFIQUSA-N 0.000 description 1
- MFYSUUPKMDJYPF-UHFFFAOYSA-N 2-[(4-methyl-2-nitrophenyl)diazenyl]-3-oxo-n-phenylbutanamide Chemical compound C=1C=CC=CC=1NC(=O)C(C(=O)C)N=NC1=CC=C(C)C=C1[N+]([O-])=O MFYSUUPKMDJYPF-UHFFFAOYSA-N 0.000 description 1
- LJRNEONAETVESI-IINYFYTJSA-N 2-[2-[(2R,3R)-2-(bromomethyl)-3-[(2-hydroxyimino-2-phenylacetyl)amino]-4-oxoazetidin-1-yl]ethanethioyl]oxyacetic acid Chemical compound N(O)=C(C(=O)N[C@@H]1[C@@H](N(C1=O)CC(=S)OCC(=O)O)CBr)C1=CC=CC=C1 LJRNEONAETVESI-IINYFYTJSA-N 0.000 description 1
- GVCYNVXRKARCIK-WRWORJQWSA-N 2-[2-[(2R,3R)-2-(bromomethyl)-3-[[2-(cyanomethylsulfanyl)acetyl]amino]-4-oxoazetidin-1-yl]ethanethioyl]oxyacetic acid Chemical compound C(#N)CSCC(=O)N[C@@H]1[C@@H](N(C1=O)CC(=S)OCC(=O)O)CBr GVCYNVXRKARCIK-WRWORJQWSA-N 0.000 description 1
- XBUGDRKLKORHBA-SSDLBLMSSA-N 2-[2-[(2R,3R)-2-(bromomethyl)-4-oxo-3-[[2-(trifluoromethylsulfanyl)acetyl]amino]azetidin-1-yl]ethanethioyl]oxyacetic acid Chemical compound FC(F)(F)SCC(=O)N[C@@H]1[C@@H](N(C1=O)CC(=S)OCC(=O)O)CBr XBUGDRKLKORHBA-SSDLBLMSSA-N 0.000 description 1
- PPXUUPXQWDQNGO-UHFFFAOYSA-N 2-azidoacetic acid Chemical compound OC(=O)CN=[N+]=[N-] PPXUUPXQWDQNGO-UHFFFAOYSA-N 0.000 description 1
- MOFURJJIOPOBAM-UHFFFAOYSA-N 2-bromoethanethioic s-acid Chemical class SC(=O)CBr MOFURJJIOPOBAM-UHFFFAOYSA-N 0.000 description 1
- YZYIRDDUDUQDIV-NOORDXFBSA-N 2-hydroxy-2-[(2R,3R)-2-(iodomethyl)-4-oxo-3-[(2-phenoxyacetyl)amino]azetidin-1-yl]-3-phenylpropanoic acid Chemical compound O=C([C@H](NC(=O)COC=1C=CC=CC=1)[C@@H]1CI)N1C(O)(C(=O)O)CC1=CC=CC=C1 YZYIRDDUDUQDIV-NOORDXFBSA-N 0.000 description 1
- BHRPXMMXNNRIQB-UHFFFAOYSA-N 2-iodoethanethioic s-acid Chemical class SC(=O)CI BHRPXMMXNNRIQB-UHFFFAOYSA-N 0.000 description 1
- PKUPAJQAJXVUEK-UHFFFAOYSA-N 2-phenoxyacetyl chloride Chemical class ClC(=O)COC1=CC=CC=C1 PKUPAJQAJXVUEK-UHFFFAOYSA-N 0.000 description 1
- SMJRBWINMFUUDS-UHFFFAOYSA-N 2-thienylacetic acid Chemical compound OC(=O)CC1=CC=CS1 SMJRBWINMFUUDS-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- RORTVSDCNRHEFZ-UHFFFAOYSA-N 4-cycloheptyl-1,4-thiazepane Chemical class C1CCCCCC1N1CCSCCC1 RORTVSDCNRHEFZ-UHFFFAOYSA-N 0.000 description 1
- WSHJJCPTKWSMRR-UHFFFAOYSA-N 4-thia-1-azabicyclo[3.2.0]heptan-7-one Chemical class S1CCN2C(=O)CC21 WSHJJCPTKWSMRR-UHFFFAOYSA-N 0.000 description 1
- XOUSEUUZKHUUKU-UHFFFAOYSA-N 7-oxo-3-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound OC(=O)C1SCC2CC(=O)N12 XOUSEUUZKHUUKU-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- LOQRYAKJFBANJU-QUBYGPBYSA-N CS(=O)(=O)CC(=O)N[C@@H]1[C@H](CBr)N(CC(=S)OCC(O)=O)C1=O Chemical compound CS(=O)(=O)CC(=O)N[C@@H]1[C@H](CBr)N(CC(=S)OCC(O)=O)C1=O LOQRYAKJFBANJU-QUBYGPBYSA-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
- AAKRSFKHNBJTMZ-LSORHIGESA-N Cl.N[C@@H]1[C@@H](N(C1=O)CC(=S)OCC(=O)O)CBr Chemical compound Cl.N[C@@H]1[C@@H](N(C1=O)CC(=S)OCC(=O)O)CBr AAKRSFKHNBJTMZ-LSORHIGESA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 1
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- AMLIEBKYMIEINI-XHDPSFHLSA-N O=C1N(CC(=S)OCC(=O)O)[C@@H](CBr)[C@H]1NC(=O)CC1=CC=CC=C1 Chemical compound O=C1N(CC(=S)OCC(=O)O)[C@@H](CBr)[C@H]1NC(=O)CC1=CC=CC=C1 AMLIEBKYMIEINI-XHDPSFHLSA-N 0.000 description 1
- VTCXBBZHYKAZCI-QUBYGPBYSA-N OC(=O)COC(=S)CN1[C@@H](CBr)[C@@H](NC(=O)CC#N)C1=O Chemical compound OC(=O)COC(=S)CN1[C@@H](CBr)[C@@H](NC(=O)CC#N)C1=O VTCXBBZHYKAZCI-QUBYGPBYSA-N 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
- 229930195708 Penicillin V Natural products 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N alpha-methyl toluene Natural products CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- GXYZVBZLVIFFIN-UHFFFAOYSA-N benzhydryl 2-oxoacetate;hydrate Chemical compound O.C=1C=CC=CC=1C(OC(=O)C=O)C1=CC=CC=C1 GXYZVBZLVIFFIN-UHFFFAOYSA-N 0.000 description 1
- 229910052796 boron Inorganic materials 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
- 239000000872 buffer Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 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
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical group 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940089960 chloroacetate Drugs 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000007859 condensation product Substances 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
- 239000013058 crude material Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- WACQKHWOTAEEFS-UHFFFAOYSA-N cyclohexane;ethyl acetate Chemical compound CCOC(C)=O.C1CCCCC1 WACQKHWOTAEEFS-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- OIGOZSHDXQNVTK-UHFFFAOYSA-N disodium N,N-dimethylformamide sulfide Chemical compound [Na+].[Na+].[S-2].CN(C)C=O OIGOZSHDXQNVTK-UHFFFAOYSA-N 0.000 description 1
- DUYAAUVXQSMXQP-UHFFFAOYSA-N ethanethioic S-acid Chemical compound CC(S)=O DUYAAUVXQSMXQP-UHFFFAOYSA-N 0.000 description 1
- ZUKSLMGYYPZZJD-UHFFFAOYSA-N ethenimine Chemical compound C=C=N ZUKSLMGYYPZZJD-UHFFFAOYSA-N 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- HWIPKUZJQXCDEP-UHFFFAOYSA-N methyl 2-[(2,4-dimethoxyphenyl)methylimino]acetate Chemical compound COC(=O)C=NCC1=CC=C(OC)C=C1OC HWIPKUZJQXCDEP-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000004533 oil dispersion Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940056367 penicillin v Drugs 0.000 description 1
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 description 1
- 125000006207 phenyl benzoyl methyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(=O)C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229940079101 sodium sulfide Drugs 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- ZGHLCBJZQLNUAZ-UHFFFAOYSA-N sodium sulfide nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Na+].[Na+].[S-2] ZGHLCBJZQLNUAZ-UHFFFAOYSA-N 0.000 description 1
- 229940048181 sodium sulfide nonahydrate Drugs 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- RSASPWMZKNIURZ-UHFFFAOYSA-M sodium;2-thiophen-2-ylacetate Chemical compound [Na+].[O-]C(=O)CC1=CC=CS1 RSASPWMZKNIURZ-UHFFFAOYSA-M 0.000 description 1
- WMDLZMCDBSJMTM-UHFFFAOYSA-M sodium;sulfanide;nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Na+].[SH-] WMDLZMCDBSJMTM-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- QXKXDIKCIPXUPL-UHFFFAOYSA-N sulfanylidenemercury Chemical compound [Hg]=S QXKXDIKCIPXUPL-UHFFFAOYSA-N 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
Definitions
- This invention relates to isopenicillins showing antibacterial-activity, to processes for their preparation, and to pharmaceutical compositions containing them.
- the acyl group is preferably an acyl group known to impart antibacterial activity as a substituent in the 7-or 6- positions of cephalosporins or penicillins.
- acyl refers to acyl groups represented by the general formulae where
- the 5- or 6-membered heterocyclic rings referred to above include thienyl, furyl, thiazoyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl and the like.
- Each heterocyclic group may be unsubstituted or substituted with one or two substituents selected from lower alkyl, halo, hydroxy, nitro, lower alkoxy, aryl such as phenyl, lower aralkyl and the like.
- the terms lower alkyl or lower alkoxy refer to groups containing one to six carbon atoms.
- acyl groups include the following examples:
- the isopenicillin compounds of this invention decompose rapidly when the 2-carboxylic acid group is present in the free acid form. However, the compounds are stable when the acid is present as a salt or is protected with a protective ester. Therefore, it is apparent to the skilled chemist that all chemical reactions performed on these compounds must be done under conditions which take this fact into account.
- a carboxylic acid protective ester residue refers to those ester groups which are commonly employed to block or protect the carboxylic acid functionality while reactions are carried out on other functional groups within the molecule.
- the term has acquired a definite meaning within the 6 -lactam and organic chemical arts and many useful groups within this term are known in the art. These protective groups are known for the ease with which they may be cleaved to regenerate the carboxylic acid group.
- the term refers to those groups known in the art which can be cleaved by mild basic hydrolysis and/or hydrogenation in basic solution.
- ester protecting groups include lower alkyl such as methyl, 2,2,2-trichloroethyl, 8-iodoethyl, C 1 -C 6 -alkanoylmethyl, N-phthalimidomethyl, benzoylmethyl, halobenzoylmethyl, methylbenzoylmethyl, methane- sulfonylbenzoylmethyl, phenylbenzoylmethyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl and the like.
- the choice of which ester group to use is well within the ability of one skilled in the art.
- Factors which are considered include what subsequent reaction conditions the group must withstand and what conditions for removing the protecting ester is desirable.
- Particularly preferred esters are methyl, benzyl and benzhydryl.
- the selection of the proper protecting group is not critical to our invention since the point of novelty of our invention lies within the new isopenicillin nucleus and not within the ester groups substituted thereon.
- carboxyl protecting groups are not intended to be exhaustive. A person skilled in the art knows the purpose of these groups and is able to properly choose from the groups known and described in the art. Many articles and books have described the subject of protecting reactive groups, for example J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, 1973.
- salts of carboxylic acids for pharmaceutical formulations. These salts have improved properties, such as solubility, over the free acids.
- useful cations include alkali metals such as sodium and potassium, alkali earth metals and ammonium cations from inorganic or organic amine bases. These salts are prepared when the protective ester groups are hydrolyzed by base or when the isopenicillin nucleus is formed by base treatment as described below.
- salts of other acid moieties present within the acyl group of the compounds are prepared in the same manner as described above.
- the compounds of this invention may exist in hydrate or solvate form.
- the amount of water or solvent may vary.
- the compounds of this invention where R is acylamino and M is hydrogen or a pharmaceutically acceptable cation have antibacterial activity against Gram-positive and Gram-negative organisms.
- Minimum inhibitory concentrations (MIC's) against a variety of bacteria are shown in Table 1 for representative compounds. Data for standard antibacterial agents, penicillin V and 2-thienyl- methylpenicillin are included.
- the active compounds or their salts can be dissolved in water and used to sterilize laboratory equipment or for the treatment or prevention of bacterial infections in warm-blooded mammals such as man.
- R is acylamino and M is a carboxylic acid protecting ester group also exhibit antibacterial activity, for example against B. subtilis. These compounds may be used in the same manner as described for the compounds where M is not an ester.
- R is amino or azido and/or M is a carboxylic acid protecting ester group are useful as intermediates for the preparation of the therapeutically active compounds.
- R is azido
- reduction by chemical or catalytic methods also gives the useful free amino derivative.
- halogen or halo shall mean fluroine, chlorine, bromine or iodine.
- the compounds of this invention are novel bicyclic s-lactams which are prepared by a totally synthetic route.
- the key starting materials are cis-3-azido-4-oxo-2-azetidinylmethyl iodide (la) and cis-3-t-butoxycarbonylamino-2-hydroxymethyl-4-oxoazetidine (1b).
- These compounds can be prepared in good yield via a ketene-imine cyclization reaction of azidoacetic acid and methyl N-(2,4-dimethoxybenzyl)iminoacetate and subsequent chemical modification, all as set forth in Belgian Patent No. 841,234.
- the reaction sequence set forth in Scheme 1 involves first, a condensation of the 8-lactam 1 with an ester of glyoxylic acid to give the a-hydroxy-a-azetidinyl acetic acid derivative (2).
- the hydroxy group of this compound is converted to a halo derivative, such as chloro by the reaction with thionyl chloride, and the halo derivative is reacted with a salt of thiolacetic acid to give the sulfur-containing compound (3).
- Cyclization of compound (3) to the desired isopenicillin derivative can be effected by treatement with a base such as cyclohexylamine. If R is azido, reduction to the amino derivative followed by acylation with the desired acyl group gives the compounds of this invention. If M is a protecting ester group, it may be removed by base hydrolysis to give the compounds where M is a cation.
- a preferred route to the antibacterial compounds of this invention involves treating compound 3 where R is acylamino and M is a cation such as sodium with a base such as cyclohexylamine.
- R is t-butoxycarbonylamino
- M is benzhydryl
- thionyl chloride followed by potassium thiolacetate gives compound 3 (R and M are as above).
- any organic primary and secondary amine which preferentially hydrolyzes the thiolacetate moiety over attacking the B-lactam moiety gives the desired product.
- the selectivity of action is a result of choosing a base with the proper balance between basicity and nucleophilicity. The selection of the proper base is within the ability of a person skilled in the art.
- the preferred route is run in an organic solvent, preferably an aprotic solvent.
- the reaction is run at a temperature and a period of time which maximizes the formation of product and minimizes product decomposition. Temperatures may range from -30 to 30° with about 0° being a preferred temperature.
- Scheme 2 sets forth a different reaction sequence for converting the a-hydroxy compound 2,into the isopenicillins.
- the hydroxy group is converted into a chloro group as outlined above in Scheme 1.
- the resulting chloro .derivative is treated with sodium triphenylmethylmercaptide to give derivative 4.
- Cyclization of derivative 4 can be effected by treatment with metal ions such as silver or mercury or by treatment with a strong acid such as trifluoroacetic acid.
- the a-chloro compound (5) may also be converted directly into the desired isopenicillin as outlined in Scheme 3.
- Reagents useful for this conversion include hydrogen sulfide, sodium hydrosulfide, sodium sulfide and tetramethylguanidinium hydrosulfide.
- Acylations of the compounds of this invention are effected by standard methods.
- the carboxylic acid group which will be the carbonyl group in the acyl moiety is activated by known methods including mixed anhydride, activated esters, and acid halides.
- use of coupling reagents such as dicyclohexylcarbodiimide and carbonyldiimidazole is a possible method of acylation.
- any sensitive group in the acyl moiety for example, hydroxyl or carboxyl, can be protected by a standard protecting group such as those described previously and/or known in the art.
- acyl groups which are particularly useful in this invention contain an assymetric carbon atom. It is understood that each optical isomer separately and as mixtures of the isomers are within the scope of this invention. It has been found that the D-isomer is particularly useful and therefore is a preferred isomer as with the mandelamido containing compounds.
- the cis-fused isopenicillin ring system may exist as d and 1 isomers.
- the carboxylic acid group at position 2 can be in the a or 6 configuration and results in an additional center of asymmetry. All possible stereoisomers are within the scope of this invention.
- Benzyl glyoxylate (1.97 g, 12 mmol) was dissolved in toluene (25 ml) and a small amount was distilled out to dry the solution. The solution was cooled to 90° and the product of Preparation 1 (1 g, 3.97 mmol) was added. The reaction was heated for 5.5 hours under argon at 90°. The solution was evaporated in vacuo and the residue was chromatographed on silica gel (100 g). The product was eluted with 10% ethyl acetate in benzene, 1.28 g (78%).
- the combined extracts are washed copiously with water and brine.
- the dried extracts are distilled in vacuo to give 4.5 g of clear orange gum which was rapidly chromatographed on a column of 90 g of silica gel with methylene chloride and 20% ethyl acetate in methylene chloride as eluants to give the condensation products, 1.66 g (64%).
- Example 2 The compound from Example 2 (65 mg, 0.171 mmol) was hydrogenated at atmospheric pressure in ethyl acetate (2 ml) in the presence of Pto 2 (130 mg) for three hours. The mixture was filtered and evaporated to give the title product, 60 mg.
- Example 1 The compound of Example 1 (35 mg, 0.115 mmol) was hydrogenated in ethyl acetate with Pt0 2 as catalyst (70 mg) in the same manner as in Example 3 to give the title product, 32 mg.
- the compound of Preparation 12 (731 mg, 0.935 mmol) was dissolved in dichloromethane (30 ml) and anisole (4 ml), cooled to 0° under argon and treated with trifluoroacetic acid (36 ml). The mixture was stirred at 0° for 20 minutes and then was added rapidly to a cold mixture of aqueous N A HCO 3 layered with ethyl acetate. The layers were separated and the aqueous layer was reextracted with ethyl acetate. The combined organic phases were washed with brine, dried and evaporated to give the product which was chromatographed on silica gel (100 g).
- the title compound was also prepared by dissolving the intermediate chloro compound prepared above in anhydrous dimethylformamide (1.5 ml) and cooling to -20°. The cold solution was treated with a sodium sulfide- dimethylformamide solution (0.7 ml) which was prepared as follows:
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US819197 | 1977-07-26 | ||
US05/819,197 US4122086A (en) | 1977-07-26 | 1977-07-26 | Isopenicillins |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0000645A1 true EP0000645A1 (de) | 1979-02-07 |
EP0000645B1 EP0000645B1 (de) | 1981-01-28 |
Family
ID=25227463
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP78300169A Expired EP0000645B1 (de) | 1977-07-26 | 1978-07-20 | Isopenicilline, Verfahren zu ihrer Herstellung und pharmazeutische Bereitungen |
Country Status (7)
Country | Link |
---|---|
US (1) | US4122086A (de) |
EP (1) | EP0000645B1 (de) |
JP (1) | JPS5424891A (de) |
DE (1) | DE2860370D1 (de) |
DK (1) | DK328578A (de) |
IE (1) | IE47037B1 (de) |
IT (1) | IT1097306B (de) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4257947A (en) * | 1977-08-03 | 1981-03-24 | Smithkline Corporation | 3-Amino-2-hydroxy, halo or mercaptomethyl-4-oxoazetidines |
DE2967572D1 (en) * | 1978-08-14 | 1986-03-06 | Merck & Co Inc | Intermediates for the preparation of thienamycin and process for preparing the same |
US4174316A (en) * | 1978-08-14 | 1979-11-13 | Merck & Co., Inc. | 4-Iodomethylazetidin-2-one |
US4290947A (en) * | 1979-04-27 | 1981-09-22 | Merck & Co., Inc. | Process for the preparation of thienamycin and intermediates |
JPS62248766A (ja) * | 1986-04-21 | 1987-10-29 | タキゲン製造株式会社 | 扉用ハンドル装置 |
JPS63140464U (de) * | 1987-03-09 | 1988-09-16 | ||
US5563264A (en) * | 1993-02-10 | 1996-10-08 | Shionogi & Co., Ltd. | Preparation of βlactam compounds |
EP0611115B1 (de) * | 1993-02-10 | 2001-04-18 | Shionogi & Co., Ltd. | Herstellung von Beta-lactamverbindungen und Zwischenprodukte |
US5496816A (en) * | 1994-03-14 | 1996-03-05 | Merck & Co., Inc. | Carbapenem antibacterial compounds, compositions containing such compounds and methods of treatment |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2324639A1 (fr) * | 1975-05-05 | 1977-04-15 | Smithkline Corp | Composes analogues aux cephalosporines, leurs intermediaires et procedes pour les preparer |
-
1977
- 1977-07-26 US US05/819,197 patent/US4122086A/en not_active Expired - Lifetime
-
1978
- 1978-07-20 DE DE7878300169T patent/DE2860370D1/de not_active Expired
- 1978-07-20 EP EP78300169A patent/EP0000645B1/de not_active Expired
- 1978-07-24 IT IT26043/78A patent/IT1097306B/it active
- 1978-07-24 DK DK328578A patent/DK328578A/da not_active Application Discontinuation
- 1978-07-25 JP JP9140678A patent/JPS5424891A/ja active Granted
- 1978-07-25 IE IE1493/78A patent/IE47037B1/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2324639A1 (fr) * | 1975-05-05 | 1977-04-15 | Smithkline Corp | Composes analogues aux cephalosporines, leurs intermediaires et procedes pour les preparer |
Non-Patent Citations (2)
Title |
---|
J. AM. CHEM. SOC., vol. 99, no. 7, March 1977, pages 2352-3 * |
J. CHEM. SOC., (C) 1971, pages 188-190 * |
Also Published As
Publication number | Publication date |
---|---|
JPS5424891A (en) | 1979-02-24 |
US4122086A (en) | 1978-10-24 |
IE47037B1 (en) | 1983-11-30 |
DK328578A (da) | 1979-01-27 |
DE2860370D1 (en) | 1981-03-19 |
IE781493L (en) | 1979-01-26 |
IT7826043A0 (it) | 1978-07-24 |
IT1097306B (it) | 1985-08-31 |
EP0000645B1 (de) | 1981-01-28 |
JPS6143357B2 (de) | 1986-09-26 |
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