EP0000645A1 - Isopenicillins, processes for their preparation, and compositions containing them - Google Patents
Isopenicillins, processes for their preparation, and compositions containing them 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:
Abstract
- R is acylamino, azido, or amino; and
- M is hydrogen a pharmaceutically acceptable cation, or a removable carboxylic acid protecting ester, can be prepared by ring-closing an appropriately 3-substituted-4- halomethyl β-lactam of the formula
- R' is acylamino or azido;
- and when a compound (1) is required, in which R is amino, a protecting acyl group of an acylamino group R' is removed. Compound I show antibacterial activity against gram positive and gram negative organisms.
Description
- This invention relates to isopenicillins showing antibacterial-activity, to processes for their preparation, and to pharmaceutical compositions containing them.
- Since the 1940's penicillins have played an important role in the chemotherapy of infectious disease. Much research has been done and many derivatives of penicillins have been prepared. A number of penicillins have shown sufficient antibacterial activity to be commercialised. This large amount of research in all commercial products has been directed to penicillins which contain the 7-oxo- l-aza-4-thiabicyclo[3.2.0]heptane nucleus. Work on the total synthesis of penicillins has also been studied by various investigators but this work also has been directed to preparing compounds with the same 1-aza-4-thiabicyclo- heptane nucleus.
- A small amount of research has been conducted in an attempt to prepare penicillins with an unnatural nucleus. Examples of these include systems without the methyl groups 'or in which the sulfur atom is at a different position in the ring system. One unsuccessful attempt at preparing the 7-oxo-3-thia-l-azabicyclo[3.2.0]heptane-2-carboxylic acid system has been reported in the literature; J.Chem. Soc.(C), 188 (1971). The trivial name for this bicyclic nucleus has been recently proposed as isopenicillin, Can. J. Chem., 55, (1977).
-
- R is acylamino, azido or amino: and
- M is hydrogen, a pharmaceutically acceptable cation, or a carboxylic acid protecting ester residue.
- Compounds of the formula I have shown antibacterial activity.
- 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.
-
- X is thienyl, furyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl or phenyl substituted with one or two substituents selected from the group consisting of lower alkyl, lower alkoxyl, hydroxy, hydroxymethyl, halo, nitro, mercapto, lower alkylthio, trifluoromethyl, ureido, formamido, and carboxymethylamino;
- A is hydroxy, formyloxy, carboxyl, sulfo or (when the a-hydrogen is absent) methoxyimino or oximino: Y is cyano, azido, phenyl, phenoxy or a 5- or 6- membered heterocyclic ring containing carbon and 1-4 heteroatoms selected from the group conslsting of nitrogen, oxygen and sulfur;
- Z is phenyl, pyridyl, lower alkyl, trifluaro- methyl, trifluoroethyl, or cyanomethyl; and
- n is 0, 1 or 2.
- 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.
- Particularly preferred acyl groups include the following examples:
- phenylacetyl
- a-hydroxyphenylacetyl
- a-formyloxyphenylacetyl
- trifluoromethylmercaptoacetyl
- methylmercaptoacetyl
- methylsulfonylacetyl
- 2,2,2-trifluoroethylsulfinylacetyl cyanoacetyl
- cyanomethylmercaptoacetyl
- a-carboxy-2-thienylacetyl
- a-carboxy-3-thienylacetyl
- a-carboxyphenylacetyl
- a-sulphophenylacetyl
- 2-thienylacetyl
- 1-tetrazolylacetyl
- phenoxyacetyl
- 4-pyridylmercaptoacetyl
- syn-methoxyimino(2-furyl)acetyl
- a-oximinophenylacetyl
- 2,6-dimethoxybenzoyl
- 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.
- The term "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. As used within this disclosure, the term refers to those groups known in the art which can be cleaved by mild basic hydrolysis and/or hydrogenation in basic solution.
- Known ester protecting groups include lower alkyl such as methyl, 2,2,2-trichloroethyl, 8-iodoethyl, C1-C6-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.
- The above definition of carboxyl protecting groups is 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.
- The term "pharmaceutically acceptable cation" is also a well known term in the art. Many bases are known and used to prepare salts of carboxylic acids for pharmaceutical formulations. These salts have improved properties, such as solubility, over the free acids. Examples of 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.
- Also included within the scope of this invention is the salts of other acid moieties present within the acyl group of the compounds. These salts 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. These various forms of the compounds of this invention are also part of the invention disclosed and claimed herein.
- 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
- The compounds where 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.
- The compounds of this invention where 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. When R is azido, reduction by chemical or catalytic methods also gives the useful free amino derivative.
- Within this disclosure the terms 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
- The conversion of compound la or 1b into the compounds of this invention involve modifications of the various substituents by a series of chemical reactions. Schemes 1, 2 and 3 set forth different reactions which may be used to prepare compounds of this invention. It is readily apparent to one skilled in the art that the reactions set forth in these Schemes may be carried out by various methods in various sequences. In particular, at various points along the reaction pathway set forth in each of the Schemes, the R substituent may be converted from azido to amino and the amino group subsequently acylated with a desired acyl group. The most advantageous times to perform these conversions would be readily apparent to a person skilled in the art.
- 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.
- Within Scheme 1 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. Starting with compound 1 where R is t-butoxycarbonylamino (which is prepared by reacting compound 1b with tosyl chloride followed by sodium iodide), condensation with benzhydryl glyoxylate gives compound 2 (R is t-butoxycarbonylamino and M is benzhydryl). Treatment with thionyl chloride followed by potassium thiolacetate gives compound 3 (R and M are as above). Treatment with a strong acid such as trifluoroacetic acid hydrolyzes both the t-butoxycarbonyl and benzhydryl groups to give the salt of compound 3 where R is amino. Acylation of this amino compound by standard methods gives the compounds where R is acylamino. Any protecting groups within the acyl moiety are removed and the compound is converted to the acid salt which is treated with base as described above to give the desired products.
- Within the preferred route set out above, various bases may be used. In particular, 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.
-
- 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. In addition, use of coupling reagents such as dicyclohexylcarbodiimide and carbonyldiimidazole is a possible method of acylation. During the acylation reaction, 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. At the appropriate time, which was suggested in the above discussion of preparation of these compounds or at such other time which would be apparent to one skilled in the art the protecting group can be removed.
- Various 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.
- In addition, 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.
- The starting materials necessary to prepare the compounds of this invention are commercially available, described herein or prepared by methods known in the art and readily apparent to a person skilled in the art.
- The following examples are presented to illustrate general methods of preparing the compounds of this invention to one skilled in the art and are not to be construed as limitative of the scope thereof. All temperatures are given in degrees Centigrade.
- A degassed solution of cis-3-azido-4-oxo-2- azetidinylmethyl tosylate (2.36 g) in acetone (80 ml) was refluxed with NaI (5.85 g) overnight. Reaction was cooled and the acetone was removed in vacuo. The reaction mixture was partitioned between ethyl acetate and aqueous sodium thiosulfate solution. Phases were separated and the organic layer was extracted with thiosulfate solution. The combined aqueous extracts were extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried and evaporated to give an off- white solid. The product was recrystallized from ethyl acetate-hexane, melting point 130-2° (dec.), 1.5 g (75%).
- A degassed solution of cis-3-azido-4-oxo-2- azetidinylmethyl tosylate (0.41 g, 1.4 mmol) in dimethylformamide (5 ml) was heated to 90° with LiBr (0.43 g, 5 mmol) for 4 hours. The reaction was poured into ethyl acetate and washed copiously with water. The dried solution was evaporated to give the title compound.
- 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%).
- A solution of compound from Preparation 3 (130 mg, 0.31 mmol) in methylene chloride (3 ml) was stirred under an argon atmosphere at -10° and treated with pyridine (28.2 µl, 0.35 mmol) and thionyl chloride (24.9 µl, 0..35 mmol). The reaction was stirred for 20 minutes and the solvents were removed in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with water and brine, dried and evaporated. The residue was chromatographed on silica gel (10 g) and the product was eluted with 2% ethyl acetate in benzene to give the title product, 102 mg (72%).
- A solution of benzhydryl glyoxylate (3.9 g, 16 mmol) in toluene (40 ml) was heated to reflux under an argon atmosphere and 2 ml of toluene was removed by distillation. The toluene solution was allowed to cool to ca. 80°C and the 3-azido-4-oxo-2-azetidinemethyl iodide (1.5 g, 5.95 mmol) was added. The reaction mixture was heated at 85-90° for 5 hours and then was cooled and the solvents were removed in vacuo. Chromatography of the residue on silica gel using ethyl acetate-dichloromethane as eluant afforded the product as a clear colorless gum. Upon standing at room temperature for several hours, one diastereoisomer crystallized and was isolated and recrystallized from ether-hexane to give a white solid, m.p. 125-1270 (dec.).
- A solution of the compound of Preparation 3 (520 mg, 1.25 mmol) in tetrahydrofuran (10 ml) was cooled to -100 under argon and treated with pyridine (113 µl, 1.4 mmol) followed by thionyl chloride (100 µl, 1.4 mmol). After stirring 20 minutes, a suspension of sodium thiolacetate (137 mg, 1.5 mmol) in dimethylformamide (8 ml) was added. The reaction was stirred for 45 minutes at -10° and then for 2 hours at room temperature. The solvents were removed and the residue dissolved in ethyl acetate. The organic solution was washed with water and brine, dried and evaporated. The residue was chromatographed on silica gel (75 g) and the title product was eluted with 3% ethyl acetate in benzene, 400 mg (67%).
- To a stirred solution of product from Preparation 5 (0.514 g, 1.19 mmol) in anhydrous tetrahydrofuran (17 ml) at -20° under argon was added anhydrous pyridine (99 µl, 1.21 mmol) followed by thionyl chloride (87 µl, 1.21 mmol). The reaction mixture was stirred at -20° for 0.5 hour. A solution of potassium thiolacetate (0.209 g, 1.8 mmol) in anhydrous N,N-dimethylformamide (16 ml) was added. The reaction was allowed to come to ambient temperature over a period of 1 hour and then was poured into ethyl acetate and extracted five times with water. The combined aqueous extracts were extracted once with ethyl acetate and the combined ethyl acetate extracts were dried. Evaporation of the solvents in vacuo afforded a yellow gum which was purified by silica gel chromatography. Elution with ethyl acetate-dichloromethane gave the desired product as a semi-crystalline, light-yellow gum. Recrystallization from ethyl acetate-hexane afforded a white solid, m.p. 133-135° (dec.) which was a single diastereoisomer.
- A solution of cis-3-t-butoxycarbonylamino-2-hydroxymethyl-4-oxoazetidine (36 g, 0.166 mol) in pyridine (200 ml) was cooled in an ice-salt bath to -7° and treated with methanesulfonyl chloride (20.2 ml, 29.9 g, 0.261 mol) dropwise over a period of 23 minutes. When the addition was completed the reaction was stirred with continued cooling for 2.5 hours and then poured into ice water (700 ml). The precipitated solid was collected, washed with water and dried; 36.1 g, mp 151° (dec.). Concentration of the mother liquors yielded a second crop of product; 3.6 g, mp 148.5-149° (dec.).
- To a mixture of LiBr (49.0 g, 0.565 mol), Na2co3 (22 g) and dry dimethylformamide (450 ml) was added under a nitrogen atmosphere the above mesylate (33.3 g, 0.113 mol). The reaction was heated at 80° for 4.5 hours. The solution was filtered and the filtrate was concentrated in vacuo. The residue was triturated with ice water and the resulting solid was collected, washed generously with water and dried to give the title compound as a white solid; 24.1 g (76%).
- A solution of benzhydryl glyoxalate monohydrate (56.8 g, 0.22 mol) in dry dioxane (550 ml) was stirred over 40 grams of molecular sieves (4A) for 0.5 hours and then the product from Preparation 8 (55.8 g, 0.2 mol) was added followed by additional dry dioxane (50 ml) and dry triethylamine (27.6 ml, 0.2 mol). The reaction was stirred at room temperature for 3 hours and then filtered. The filtrate was evaporated in vacuo and the residue dissolved in ethyl acetate (300 ml). The solution was washed with dilute HC1 (100 ml), 5% NaHC03 (100 ml), water (100 ml), saturated NaHCO3 (2 x 100 ml) and water (100 ml). The dried organic layer was evaporated and the residue was dissolved in ether (300 ml). Upon cooling, the product crystallized and was collected; 81.8 g, mp 133-137°.
- A solution of the product from Preparation 9 (8.5 g, 0.016 mol) in dry tetrahydrofuran (140 ml) was dried over molecular sieves (4A) under nitrogen for 30 minutes at 0°. To this solution was added dry pyridine (3.2 g, 0.04 mol) followed by the dropwise addition of distilled thionyl chloride (3.8 g, 0.032 mol). After stirring at 0° for 45 minutes, the solution was cooled to -15° and treated dropwise with a solution of potassium thiolacetate (5.5 g, 0.048 mol) and dry dimethylformamide (140 ml) which had been dried over molecular sieves (4A) for one hour. The reaction was stirred at -150 for one hour and then at 0° for two hours. The solvents were removed in vacuo and the residue dissolved in ethyl acetate. The organic solution was washed with dilute HC1, 5% NaHC03, water and saturated brine. The dried organic phase was concentrated in vacuo and the residue was dissolved in ether. The dropwise addition of petroleum ether and cooling resulted in the formation of white solid product which was collected and washed with ether; 6.35 g (69%).
- For 20 minutes gaseous HC1 was passed through a H2S04 trap and then was bubbled into dry nitromethane (10 ml) which was cooled in an ice bath. To this solution was added the above product (0.57 g, 1 mmol) and the reaction was stirred for 30 minutes during which time a white precipitate formed. Ether was added and the resulting solid was collected, washed with ether and dried to give the title product as its hydrochloride salt; 0.3 g (86%).
- To a cold (0°C) solution of the product of Preparation 10 (0.35 g, 1 mmol) in dry chloroform (25 ml) was added diisopropylethylamine (0.43 g, 33 mmol) followed by a dropwise addition of freshly distilled thienylacetic acid chloride (0.176 g, 11 mmol). Reaction solution was stirred at 0°C for 3 hours and then was extracted with 3N HCl followed by 5% NaHC03. The basic aqueous extract was acidified to pH 1.5 with dilute HC1 and extracted several times with ethyl acetate. The organic phases were combined, dried, concentrated to one-third of the volume which was added to stirring petroleum ether and the precipitated product was collected (300 mg). An analytical sample was obtained by trituration with ether.
- To a stirred solution of compound from Preparation 13 (3.71 g, 7.08 mmol) in tetrahydrofuran (50 ml) at -15° under an argon atmosphere was added pyridine (0.642 ml, 7.95 mmol) and thionyl chloride (0.568 ml, 7.95 mmol). The reaction was stirred for 15 minutes and then a suspension of sodium triphenylmethylmercaptide (17.5 mmol) in tetrahydrofuran (24 ml) was added. The mixture was stirred for 15 minutes at -18° and then allowed to warm to room temperature over a one-hour period. The solvent was removed and the residue partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine, dried, and evaporated. The resulting residue was chromatographed on silica gel (300 g) to give 2.5 g of crude title product. Recrystallization from ethyl acetate-hexane gave a white crystalline product, 2.01 g (36%), mp 155-7° (dec.).
- To a suspension of cis-3-phenoxyacetamido-4-oxo-2-azetidinemethyl iodide (5.00 g, 0.014 mol) and freshly distilled benzyl glyoxylate (11.4 g, 0.0695 mol) in anhydrous tetrahydrofuran (100 ml) at 23°C under an atmosphere of argon was added freshly distilled boron trifluoride etherate (3.42 ml, 0.0278 mol). After 45 minutes at 23°C the reaction mixture was poured into a solution of sodium bicarbonate (2.5 g) in water (25 ml). The reaction was extracted with ethyl acetate and the product isolated in the usual way to give crude material (16 g) whicn was dissolved in dichloromethane and allowed to crystallize overnight at -23°C. The solution was filtered and the crystals dried to give a white crystalline solid; 2.6 g, mp 159-160.5°. The mother liquors were combined and chromatographed on silica gel to afford additional semi-crystalline product (3.71 g). The crystalline material was a single diastereoisomer while the material isolated by chromatography was a mixture of diastereoisomers.
- To a suspension of 1.78 g (5.08 mmol) of cis-3-(2'-thienylacetamido)-4-oxo-2-azetidinylmethyl iodide (Belgian Patent No. 841,234) and 2.66 g (16.2 mmol) of freshly distilled benzyl glyoxylate in 44 ml of anhydrous tetrahydrofuran under an argon atmosphere is added 1.31 ml (10.6 mmol) of freshly distilled boron. trifluoride etherate. The reaction mixture is stirred at ambient temperature for 1.25 hours, poured into aqueous NaHC03 and extracted with ethyl acetate. 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%).
- The above product is reacted with pyridine and thionyl chloride at -20° for 45 minutes and then with potassium thiolacetate, all according to the procedure given in Preparation 10 to give the thioacetoxy product. Recrystallization from ethyl acetate-hexane gave the benzyl ester of the thioacetoxy derivative as a white crystalline solid, mp 159-62°.
- A solution of 1.05 g (7.6 mmol) of anhydrous potassium carbonate in 50 ml of water is deoxygenated and cooled to 0° under argon. To this mixture is added a solution of 0.796 g (1.39 mmol) of above benzyl ester in 36 ml of tetrahydrofuran. The reaction is deoxygenated again and stirred at 0° for ca. 5 minutes and then without cooling for a total of 1 hour. The mixture is poured into 200 ml of ethyl acetate and extracted with 5% aq. NaHC03, water and brine. The aqueous extracts are combined, acidified to pH 2 with conc. H3P04, and then saturated with NaCl. The aqueous solution is extracted with ethyl acetate. The dried extracts are evaporated to give 0.493 g (73%) of crude acid which is chromatographed on silica gel with an eluant of 70:23:5:2 ethyl acetate: acetone:methanol:water. The acid is converted to its sodium salt by treating 0.525 g of the acid with 80 mg NaHCO3 in water and then lyophilizing the solution to obtain the sodium salt.
- To a stirred solution of the product from Preparation 6 (88 mg, 0.186 mmol) dissolved in dichloromethane (3 ml) at 0° under argon was added cyclohexylamine (52 ul, 0.45 mmol). The reaction was stirred at 0° for 90 minutes and then at room temperature for 30 minutes. The reaction solution was partitioned between ethyl acetate and 1N sulfuric acid. The organic phase was separated and washed with pH 7 buffer and brine. The dried solution was evaporated to give a crude product which was chromatographed on silica gel (10 g) with 2% ethyl acetate in benzene as eluant to give the title product, 37 mg (66%), mp 68-69°.
- A solution of the compound from Preparation 4 (96 mg, 0.226 mmol) and pyridine (100 µl, 1.24 mmol) in tetrahydrofuran (5 ml) under an argon atmosphere at 0° was treated with hydrogen sulfide for 20 minutes. The reaction mixture was stirred for 90 minutes at 0° and then purged with nitrogen. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with water and brine, dried, and evaporated. The residue was chromatographed on silica gel (10 g) with 2% ethyl acetate in benzene as eluant to give the title product, 21 mg (33%).
- A cold solution (0°) of thiolacetate from Preparation 7 (32 mg, 0.058 mmol) and anhydrous dichloromethane (1 ml) under an argon atmosphere was treated with cyclohexylamine (16 ul, 0.132 mmol). The reaction was stirred at 0° for 1 hour and then at 22° for 2 hours. The mixture was poured into ethyl acetate and extracted with dilute aqueous sulfuric acid and then with brine. The ethyl acetate phase was dried and evaporated to give a semi-crystalline residue. The product was chromatographed on silica gel with 1% ethyl acetate in benzene as eluant to give the pure title compound, 20 mg (91%).
- The compound from Example 2 (65 mg, 0.171 mmol) was hydrogenated at atmospheric pressure in ethyl acetate (2 ml) in the presence of Pto2 (130 mg) for three hours. The mixture was filtered and evaporated to give the title product, 60 mg.
- The compound of Example 1 (35 mg, 0.115 mmol) was hydrogenated in ethyl acetate with Pt02 as catalyst (70 mg) in the same manner as in Example 3 to give the title product, 32 mg.
- To a cold solution (0°) of the 6-amino derivative of Example 4 (56 mg, 0.2 mmol) in methylene chloride (2 ml) under argon was added triethylamine (27.7 µl, 0.2 mmol) and then phenylacetyl chloride (26.4 µl, 0.2 mmol). The reaction was stirred for 30 minutes and then the solvents were evaporated. The residue was chromatographed on silica gel (5 g) with 30% ethyl acetate in cyclohexane as eluant to give the title product, 26.1 mg (33%).
- Substitution of phenoxyacetyl chloride for phenylacetyl chloride in Example 5 gives the title compound. The product was purified by chromatography on silica gel with 10% ethyl acetate in benzene as eluant, 11 mg (24%).
- The 6-amino benzhydryl ester of Example 3 (60 mg, 0.17 mmol) was acylated in dichloromethane with 2'-thienylacetyl chloride (14.2 ul, 0.12 mmol) in the presence of triethylamine (16.5 µl, 0.12 mmol) all according to the procedure of Example 5. Crude product was chromatographed on silica gel and eluted with 10% ethyl acetate-benzene to give the title product, 20.3 mg (36%).
- A solution of benzyl ester in Example 6 (102 mg, 0.248 mmol) in 50% aqueous tetrahydrofuran (1 ml) was cooled to 0° under argon and treated dropwise with 0.1N NaOH (1 ml). Additional NaOH was added after 5 minutes (1 ml) and after 10 minutes (0.48 ml). The reaction was stirred for 30 minutes at 0° and then was washed with ether (3 x 1 ml). Unreacted starting material was removed by extraction with ethyl acetate. The resulting aqueous solution was lyophilized to give the title product, 27.2 mg (32%).
- A solution of the bromothioacetate derivative of Preparation 11 (100 mg, 0.22 mmol) and dichloromethane (20 ml) was.treated with cyclohexylamine (0.5 ml, 4.36 mmol) at 0° for 2.5 hours under argon. The solvent was evaporated and hexane was added to the residue. The resulting precipitate was triturated with hexane and ether to give 96 mg of product which contained some starting material. The crude product was suspended in dichloromethane (20 ml) and stirred at 0° under argon with cyclohexylamine (0.5 ml) for 5 hours. The solution was worked up again as described above to give the cyclohexylamine salt of the title compound as a white powder, 85 mg. The product assayed for 0.96 mol of NaBr.
- In a similar manner the iodothioacetate derivative of Preparation 14 was converted to the title compound by the procedure set forth above.
- To a solution of a compound from the Preparation 13 (0.233 g, 0.445 mmol) in anhydrous tetrahydrofuran (10 ml) at -20° under an argon atmosphere was added anhydrous pyridine (71 µl, 0.88 mmol) and thionyl chloride (63 ul, 0.88 mmol). The reaction was stirred for 20 minutes with continued cooling and the excess reagents were removed in vacuo. The residue was dissolved in anhydrous dichloromethane (8 ml) and treated with a solution of tetramethylguanidinium hydrosulfide (0.396 g, 2.66 mmol) and anhydrous pyridine (35 µl, 0.43 mmol) in anhydrous dichloromethane (25 ml) which had been cooled to -78° under an argon atmosphere. The reaction mixture was allowed to warm to -10° over a period of one hour and then was stirred at room temperature for 0.5 hour. The reaction mixture was extracted with water, dilute HCl, dilute NaHCO3, and brine. The dried organic phase was evaporated and the residue chromatographed on silica gel with ethyl acetate-benzene as eluant to give the title compound as a mixture of diastereoisomers.
- A solution of the tritylmercapto derivative of Preparation 12 (78.2 mg, 0.1 mmol) and dichloromethane (2 ml) was treated at room temperature under argon with pyridine (16 µl, 0.2 mmol) and a solution of silver fluoroborate (75 mg, 0.4 mmol) in benzene (2 ml). The reaction was stirred for 30 minutes and then hydrogen sulfide was passed over the solution for 10 minutes. After stirring an additional twenty minutes, the mixture was flushed with argon and the solids were removed. The filtrate was evaporated to give a residue which was chromatographed on silica gel with 20% ethyl acetate in benzene as eluant to give the title product (18 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 NAHCO3 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). Elution with an ethyl acetate-cyclohexane gradient gave the title product, 273 mg. Repeated chromatography on silica gel with 20% ethyl acetate in benzene as eluant gave pure compound, '102 mg (26%).
- A stirred solution of tritylmercapto-derivative of Preparation 12 (23 mg, 0.03 mmol), methanol (2 ml) and dichloromethane (2 ml) was treated at room temperature under argon with mercuric acetate (13.4 mg, 0.042 mmol). The reaction was stirred for 30 minutes and then hydrogen sulfide was passed over the solution. A rapid chromatography on silica gel (1 g) with 10% ethyl acetate and benzene as eluant gave 8 mg of a product which tlc analysis showed to be a mixture of 3 components, one of which was the title compound.
- A stirred solution of hydroxy derivative of Preparation 13 (100 mg, 0.19 mmol) and dry tetrahydrofuran (2.0 ml) was cooled to -10° and treated with pyridine (43.2 ul, 0.55 mmol) and thionyl chloride (38.9 ul, 0.55 mmol). The reaction was stirred for 20 minutes and the solvents were evaporated. The residue was added to a mixture of pyridine (43.2 µl, 0.55 mmol), sodium hydrosulfide (11.2 mg, 0.2 mmol) and dimethylformamide (1 ml) which was cooled to -10°. The reaction mixture was warmed to room temperature and the solvents were removed. The residue was dissolved in ethyl acetate and the resulting solution was washed with water and brine and then evaporated. The residue was dissolved in ethyl acetate and hexane was added to precipitate a solid, 36 mg. The filtrate was evaporated and the residue chromatographed on silica gel (0.5 g) with 2% ethyl acetate in dichloromethane as eluant to give the title product, 12.3 mg (16%).
- 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:
- A mixture of sodium sulfide nonahydrate (0.546 g) and sulfur (0.073 g, 2.28 mmol) and 95% ethanol (6.7 ml) was refluxed for 30 minutes, cooled slightly and dimethyl formamide (6 ml) was added. The mixture was again heated to reflux and 5.5 ml of distillate was removed to give the desired solution.
- The reaction was stirred at -23° overnight and then poured into ethyl acetate and extracted with water. The aqueous extracts were washed with ethyl acetate which was combined with the previous ethyl acetate solution. Evaporation of the organic phase in vacuo gave a solid product (56 mg) which was purified by preparative thin layer of chromatography (silica gel, 20 x 20 cm, 0.5 mm, 20% ethyl acetate-benzene) to give solid product, 32 mg (71%). Recrystallization from ethyl acetate-hexane gave an analytical sample, mp 118-120.5°.
- To a solution of benzyl a-(cis-3-phenoxy- acetamido-2-iodomethyl-4-oxoazetidinyl)-a-hydroxyacetate (0.1 g, 0.19 mmol) in anhydrous tetrahydrofuran (4.0 ml) at -0°C under an argon atmosphere was added anhydrous pyridine (15.4 ul, 0.19 mmol) followed by thionyl chloride (13.7 µl, 0.191 mmol). The reaction was stirred for 40 minutes and then the reagents were removed by distillation at reduced pressure. The residue was dissolved in dimethylformamide (3 ml) and cooled to 0° under argon and treated with a solution of the sodium salt of p-methoxy- benzylmercaptan which was prepared by suspending sodium hydride (19 mg, 0.45 mmol, 57% oil dispersion) in anhydrous tetrahydrofuran, adding the mercaptan (55 µl, 0.39 mmol), removing the tetrahydrofuran by distillation once hydrogen evolution had ceased, and dissolving the residue in dimethylformamide (1 ml). The reaction mixture was stirred at 0° for four hours and then poured into ethyl acetate and extracted several times with water. The organic phase was dried and evaporated to give the p-methoxybenzylmercapto derivative which was purified by preparative thin layer of chromatography (silica gel G, 20% ethyl acetate-benzene), 80 mg (72%).
- A mixture of the above product (52 mg, 0.089 mmol), mercuric acetate (124 mg, 0.389 mmol), dichloromethane (0.4 ml) and methanol (1.3 ml) was stirred at room temperature under an argon atmosphere for 18 hours. Ether was added and the reaction mixture was filtered. The resulting solid was suspended in dichloromethane (5 ml) and cooled to 0°. Hydrogen sulfide was bubbled through the mixture for 40 minutes at 0° and then the solution was flushed with nitrogen. The suspension was filtered to remove the mercury sulfide and the filtrate was concentrated to give a residue which was chromatographed on preparative thin layer plates (silica gel G, 20% ethyl acetate-benzene) to give the title product.
- When (cis-3-amino-2-bromomethyl-4-oxo-l-azetidinyl)thioacetoxyacetic acid hydrochloride is acylated by standard acylation methods known in the art with the appropriate carboxylic acid or an activated derivative thereof in which any sensitive group(s) are appropriately protected, the following products are obtained after removal by standard methods of any protecting group(s):
- [cis-3-phenylacetamido-2-bromomethyl-4-oxo-l-azetidinyl]thioacetoxyacetic acid
- [cis-3-(a-hydroxyphenylacetamido)-2-bromomethyl-4-oxo-1-azetidinyl]thioacetoxyacetic acid
- [cis-3-trifluoromethylmercaptoacetamido-2-bromomethyl-4-oxo-l-azetidinyl]thioacetoxyacetic acid
- [cis-3-methylmercaptoacetamido-2-bromomethyl-4-oxo-l-azetidinyllthioacetoxyacetic acid
- [cis-3-methylsulfonylacetamido-2-bromomethyl-4-oxo-l-azetidinyl]thioacetoxyacetic acid
- [cis-3-(2',2',2'-trifluoroethylsulfinylacetamido)-2-bromomethyl-4-oxo-l-azetidinyl]thioacetoxy- acetic acid
- [cis-3-cyanoacetamido-2-bromomethyl-4-oxo-l-azetidinyl]thioacetoxyacetic acid
- [cis-3-cyanomethylmercaptoacetamido-2-bromomethyl-4-oxo-l-azetidinyl]thioacetoxyacetic acid
- [cis-3-(a-carboxy-3'-thienylacetamido)-2-bromomethyl-4-oxo-l-azetidinyl]thioacetoxyacetic acid
- [cis-3-(a-carboxyphenylacetamido)-2-bromomethyl-4-oxo-l-azetidinyl]thioacetoxyacetic acid
- [cis-3-(l'-tetrazolylacetamido)-2-bromomethyl-4-oxo-l-azetidinyl]thioacetoxyacetic acid
- [cis-3-(4'-pyridylmercaptoacetamido-2-bromomethyl-4-oxoazetidinyl]thioacetoxyacetic acid
- [cis-3-(syn-α-methoxyimino-2'-furylacetamido)-2-bromomethyl-4-oxo-l-azetidinyl]thioacetoxy- acetic acid
- [cis-3-(α-oximinophenylacetamido)-2-bromomethyl-4-oxo-l-azetidinyl]thioacetoxyacetic acid.
- When each product of Example 14, preferably as its sodium or potassium salt, is treated with cyclohexylamine by the procedure set forth in Example 9 the following products are obtained as their cyclohexylamine salts:
- 6a-phenylacetamido-7-oxo-3-thia-l-azabicyclo-[3.2.0]heptane-2-carboxylic acid
- 6β-(α-hydroxyphenylacetamido)-7-oxo-3-thia-1-aza- bicyclo[3.2.0]heptane-2-carboxylic acid
- 6β-trifluoromethylmercaptoacetamido-7-oxo-3-thia- l-azabicyclo[3.2.0]heptane-2-carboxylic acid
- 6β-methylmercaptoacetamido-7-oxo-3-thia-1-aza- bicyclo[3.2.0]heptane-2-carboxylic acid
- 6β-methylsulfonylacetamido-7-oxo-3-thia-1-aza- bicyclo[3.2.0]heptane-2-carboxylic acid
- 6a-(2',2',2'-trifluoroethylsulfinylacetamido)-7-oxo-3-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
- 6a-cyanoacetamido-7-oxo-3-thia-l-azabicyclo-[3.2.0]heptane-2-carboxylic acid
- 6β-cyanomethylmercaptoacetamido-7-oxo-3-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
- 6β-(α-carboxy-3'-thienylacetamido)-7-oxo-3-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
- 6β-(α-carboxyphenylacetamido)-7-oxo-3-thia-1-aza- bicyclo[3.2.0]heptane-2-carboxylic acid
- 6β-(1'-tetrazolylacetamido)-7-oxo-3-thia-1-aza- bicyclo[3.2.0]heptane-2-carboxylic acid
- 6β-(4'-pyridylmercaptoacetamido)-7-oxo-3-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
- 68-(syn-methoxyimino-2'-furylacetamido)-7-oxo-3-thia-l-azabicyclo[3.2.0]heptane-2-carboxylic acid
- 66-(a-oximinophenylacetamido)-7-oxo-3-thia-l-azabicyclo[3.2.0]heptane-2-carboxylic acid
- The ester from Example 1 (20 mg, 0.066 mmol) was dissolved in tetrahydrofuran (5 ml) and water (5 ml). The solution under argon was treated with 1 ml of a basic solution of pH 9.2 (3.3 g K2CO3 and 2 g of NaHCO3 in 40 ml water). The reaction mixture was stirred for 55 minutes at room temperature and the organic solvent was removed. The basic aqueous phase was washed with ethyl acetate, adjusted to pH 2 with phosphoric acid and extracted with ethyl acetate. The extracts were washed with brine, dried and evaporated to give the title product, 11.7 mg (83%).
Claims (13)
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US819197 | 1977-07-26 | ||
US05/819,197 US4122086A (en) | 1977-07-26 | 1977-07-26 | Isopenicillins |
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EP78300169A Expired EP0000645B1 (en) | 1977-07-26 | 1978-07-20 | Isopenicillins, processes for their preparation, and compositions containing them |
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US (1) | US4122086A (en) |
EP (1) | EP0000645B1 (en) |
JP (1) | JPS5424891A (en) |
DE (1) | DE2860370D1 (en) |
DK (1) | DK328578A (en) |
IE (1) | IE47037B1 (en) |
IT (1) | IT1097306B (en) |
Families Citing this family (9)
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US4257947A (en) * | 1977-08-03 | 1981-03-24 | Smithkline Corporation | 3-Amino-2-hydroxy, halo or mercaptomethyl-4-oxoazetidines |
US4174316A (en) * | 1978-08-14 | 1979-11-13 | Merck & Co., Inc. | 4-Iodomethylazetidin-2-one |
DE2967572D1 (en) * | 1978-08-14 | 1986-03-06 | Merck & Co Inc | Intermediates for the preparation of thienamycin and process for preparing the same |
US4290947A (en) * | 1979-04-27 | 1981-09-22 | Merck & Co., Inc. | Process for the preparation of thienamycin and intermediates |
JPS62248766A (en) * | 1986-04-21 | 1987-10-29 | タキゲン製造株式会社 | Handle apparatus for door |
JPS63140464U (en) * | 1987-03-09 | 1988-09-16 | ||
US5563264A (en) * | 1993-02-10 | 1996-10-08 | Shionogi & Co., Ltd. | Preparation of βlactam compounds |
ES2157952T3 (en) * | 1993-02-10 | 2001-09-01 | Shionogi & Co | PREPARATION OF BETA-LACTAMA DERIVATIVES AND INTERMEDIARIES. |
US5496816A (en) * | 1994-03-14 | 1996-03-05 | Merck & Co., Inc. | Carbapenem antibacterial compounds, compositions containing such compounds and methods of treatment |
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FR2324639A1 (en) * | 1975-05-05 | 1977-04-15 | Smithkline Corp | COMPOUNDS ANALOGUE TO CEPHALOSPORINS, THEIR INTERMEDIARIES AND METHODS FOR PREPARING THEM |
-
1977
- 1977-07-26 US US05/819,197 patent/US4122086A/en not_active Expired - Lifetime
-
1978
- 1978-07-20 EP EP78300169A patent/EP0000645B1/en not_active Expired
- 1978-07-20 DE DE7878300169T patent/DE2860370D1/en not_active Expired
- 1978-07-24 IT IT26043/78A patent/IT1097306B/en active
- 1978-07-24 DK DK328578A patent/DK328578A/en not_active Application Discontinuation
- 1978-07-25 IE IE1493/78A patent/IE47037B1/en unknown
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Non-Patent Citations (2)
Title |
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J. AM. CHEM. SOC., vol. 99, no. 7, March 1977, pages 2352-3 * |
J. CHEM. SOC., (C) 1971, pages 188-190 * |
Also Published As
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IE47037B1 (en) | 1983-11-30 |
JPS6143357B2 (en) | 1986-09-26 |
IE781493L (en) | 1979-01-26 |
DE2860370D1 (en) | 1981-03-19 |
IT1097306B (en) | 1985-08-31 |
IT7826043A0 (en) | 1978-07-24 |
US4122086A (en) | 1978-10-24 |
EP0000645B1 (en) | 1981-01-28 |
DK328578A (en) | 1979-01-27 |
JPS5424891A (en) | 1979-02-24 |
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