HRP960131A2 - 4-thia-1-azabicyclo(3.2.0)heptane-3-imino-2-isopropylidene-7-oxo analogons of beta-lactams, processes for their preparation and use thereof - Google Patents
4-thia-1-azabicyclo(3.2.0)heptane-3-imino-2-isopropylidene-7-oxo analogons of beta-lactams, processes for their preparation and use thereof Download PDFInfo
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- HRP960131A2 HRP960131A2 HR960131A HRP960131A HRP960131A2 HR P960131 A2 HRP960131 A2 HR P960131A2 HR 960131 A HR960131 A HR 960131A HR P960131 A HRP960131 A HR P960131A HR P960131 A2 HRP960131 A2 HR P960131A2
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- hydrogen
- compound according
- bromine
- thia
- azabicyclo
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- 238000002360 preparation method Methods 0.000 title claims description 11
- 150000003952 β-lactams Chemical class 0.000 title claims description 10
- 238000000034 method Methods 0.000 title claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- 239000001257 hydrogen Substances 0.000 claims description 31
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 20
- 229910052736 halogen Chemical group 0.000 claims description 14
- 150000002367 halogens Chemical group 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 239000011541 reaction mixture Substances 0.000 claims description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 10
- -1 5-methyl-isoxazol-3-yl Chemical group 0.000 claims description 7
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 7
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 7
- 239000000543 intermediate Substances 0.000 claims description 4
- 150000003018 phosphorus compounds Chemical class 0.000 claims description 4
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical group C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 2
- 230000002195 synergetic effect Effects 0.000 claims description 2
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 2
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 8
- 229910052794 bromium Inorganic materials 0.000 claims 8
- 125000001246 bromo group Chemical group Br* 0.000 claims 8
- 150000002431 hydrogen Chemical group 0.000 claims 6
- 229910052801 chlorine Inorganic materials 0.000 claims 3
- 239000000460 chlorine Substances 0.000 claims 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 230000000845 anti-microbial effect Effects 0.000 claims 1
- 239000000010 aprotic solvent Substances 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 125000005543 phthalimide group Chemical group 0.000 claims 1
- 230000000717 retained effect Effects 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 229930182555 Penicillin Natural products 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 230000008707 rearrangement Effects 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 150000002960 penicillins Chemical class 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- MXIKYXJYNPMBMM-XTAIUZINSA-N (2s,4r,5r)-2-benzyl-6,6-dibromo-3,3-dimethyl-4,7-dioxo-4$l^{4}-thia-1-azabicyclo[3.2.0]heptane-2-carboxamide Chemical compound C([C@]1(N2[C@@H](C(C2=O)(Br)Br)[S@](=O)C1(C)C)C(N)=O)C1=CC=CC=C1 MXIKYXJYNPMBMM-XTAIUZINSA-N 0.000 description 3
- BYDOGQKHDYKYAS-UMDUXBMUSA-N (2s,4r,5r,6s)-2-benzyl-6-bromo-3,3-dimethyl-4,7-dioxo-4$l^{4}-thia-1-azabicyclo[3.2.0]heptane-2-carboxamide Chemical compound C([C@]1(N2C(=O)[C@H](Br)[C@H]2[S@](=O)C1(C)C)C(N)=O)C1=CC=CC=C1 BYDOGQKHDYKYAS-UMDUXBMUSA-N 0.000 description 3
- QVPZWLBJIFOUQS-CYBMUJFWSA-N (5r)-3-benzylimino-2-propan-2-ylidene-4-thia-1-azabicyclo[3.2.0]heptan-7-one Chemical compound S([C@H]1N(C(C1)=O)C1=C(C)C)C1=NCC1=CC=CC=C1 QVPZWLBJIFOUQS-CYBMUJFWSA-N 0.000 description 3
- VJWKKIXBFNJUTJ-XHDPSFHLSA-N (5r,6s)-3-benzylimino-6-bromo-2-propan-2-ylidene-4-thia-1-azabicyclo[3.2.0]heptan-7-one Chemical compound S([C@H]1N(C([C@@H]1Br)=O)C1=C(C)C)C1=NCC1=CC=CC=C1 VJWKKIXBFNJUTJ-XHDPSFHLSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- RBKMMJSQKNKNEV-RITPCOANSA-N penicillanic acid Chemical compound OC(=O)[C@H]1C(C)(C)S[C@@H]2CC(=O)N21 RBKMMJSQKNKNEV-RITPCOANSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000002132 β-lactam antibiotic Substances 0.000 description 3
- 229940124586 β-lactam antibiotics Drugs 0.000 description 3
- BYDOGQKHDYKYAS-GTXICJSNSA-N (2s,4s,5r,6s)-2-benzyl-6-bromo-3,3-dimethyl-4,7-dioxo-4$l^{4}-thia-1-azabicyclo[3.2.0]heptane-2-carboxamide Chemical compound C([C@]1(N2C(=O)[C@H](Br)[C@H]2[S@@](=O)C1(C)C)C(N)=O)C1=CC=CC=C1 BYDOGQKHDYKYAS-GTXICJSNSA-N 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical group O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins 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
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 102220079670 rs759826252 Human genes 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- RXSDPSQQCKMNRT-XLXLTHPISA-N (2S,4R,5R,6S)-N-benzyl-6-bromo-3,3-dimethyl-4,7-dioxo-4lambda4-thia-1-azabicyclo[3.2.0]heptane-2-carboxamide Chemical compound O=C([C@H]1C([S@]([C@H]2N1C([C@@H]2Br)=O)=O)(C)C)NCC1=CC=CC=C1 RXSDPSQQCKMNRT-XLXLTHPISA-N 0.000 description 1
- YTPQQILLXVWTQL-RKFVTTHHSA-N (2s,4r,5r)-2-benzyl-3,3-dimethyl-4,7-dioxo-4$l^{4}-thia-1-azabicyclo[3.2.0]heptane-2-carboxamide Chemical compound C([C@]1(N2C(=O)C[C@H]2[S@](=O)C1(C)C)C(N)=O)C1=CC=CC=C1 YTPQQILLXVWTQL-RKFVTTHHSA-N 0.000 description 1
- FCZNNHHXCFARDY-WQRUCBPWSA-N (2s,5r,6r)-3,3-dimethyl-4,7-dioxo-6-[(2-phenylacetyl)amino]-4$l^{4}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@H]1[C@@H]2N(C1=O)[C@H](C(S2=O)(C)C)C(O)=O)C(=O)CC1=CC=CC=C1 FCZNNHHXCFARDY-WQRUCBPWSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- WSHJJCPTKWSMRR-RXMQYKEDSA-N penam group Chemical group S1CCN2[C@H]1CC2=O WSHJJCPTKWSMRR-RXMQYKEDSA-N 0.000 description 1
- 150000002961 penems Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
Područje tehnike kojoj izum pripada
Int. klas. C07D 513/04
Izum se odnosi na nove derivate 4-tia-1-azabiciklo[3.2.0]heptan-3-imino-2-izopropiliden-7-okso spojeve, postupke za njihovu pripravu kao i njihovu upotrebu. Ovi spojevi su novi beta-laktamski analogoni bicikličke strukture sačinjene od beta-laktamskog i tiazolidinskog prstena s izopropilidenskim supstituentom u položaju 2 i imino supstituentom u položaju 3, te kao takvi predstavljaju stabilne intermedijere za daljnje kemijske transformacije.
Prema našim saznanjima i dostupnim literaturnim podacima o stanju tehnike 4-tia-1-azabiciklo[3.2.0] heptan-3- imino- 2-izopropiliden-7-okso analogoni beta-laktama nisu poznati kao ni postupci za njihovu pripravu.
Najsličniji poznati spojevi su 4-tia-1-azabiciklo[3.2.0]hept-2-en-3-amino-7-okso analogoni beta-laktama, koji su priređeni složenim kemijskim transformacijama preko azetidinon strukture. Kod priprave takvih spojeva nastaju i manje stabilni imino-penami, tautomerni nusprodukti 4-tia-1-azabiciklo[3.2.0]heptan-3-imino-7-okso derivati u prinosu do 15 % [Tetrahedron Lett, 28 (1987) 2283-2286].
Također su poznati i brojni 4-tia-1-azabiciklo[3.2.0]heptan-2-izopropiliden-3,7-diokso derivati poznati kao anhidro penicilini [Tetrahedron 52 (1996) 331-375], priređeni iz trietilaminske soli penicilina preko mješovitog anhidrida s trifluoroctenom kiselinom i naknadnom obradom piridinom.
Predmet ovog izuma su novi 4-tia-1-azabiciklo[3.2.0]heptan-3-imino-2-izopropiliden-7-okso analogoni beta-laktamske strukture prikazane općom formulom 1,
[image]
gdje radikali imaju značenje:
R1 je vodik ili halogen,
R2 je vodik, halogen, ftalimid,
R3 je vodik, alkil, benzil, heterocikl npr. izoksazol, pirazol i dr.
Daljnji predmet ovog izuma je postupak za pripravu 4-tia-1-azabiciklo[3.2.0]heptan-3-imino-2-izopropiliden-7-okso analogona beta-laktamske strukture prikazane općom formulom 1, gdje radikali imaju značenje kako je već navedeno, a koji se mogu pripraviti pregradnjom sulfoksida amida penicilanske kiseline opće formule II,
[image]
gdje radikali imaju značenje:
R1 je vodik ili halogen,
R2 je vodik, halogen, ftalimid,
R3 je vodik, alkil, benzil, heterocikl npr. izoksazol, pirazol i dr.
Postupak pregradnje amidopenicilina opće formule II se provodi u bezvodnim inertnim organskim otapalima uz prisutnost fosfornih spojeva kod temperature od 50 do 150 °C.
Pogodna inertna otapala su npr. bezvodni ugljikovodici kao benzen, toluen ili ksilen, eteri kao dietil-eter, dioksan ili tetrahidrofuran, klorirani ugljikovodici kao metilen-klorid ili kloroform ili nitrili karbonskih kiselina.
Pogodni fosforni spojevi su trimetil-fosfit , trietil-fosfit , trifenil-fosfin i drugi fosforni spojevi nižeg oksidativnog stupnja.
Priprava pogodnih polaznih spojeva prikazanih općom formulom II je predmet našeg prethodnog izuma opisanog u hrvatskoj patentnoj prijavi P 940 345A od 10.06.1994, pod naslovom: "Novi derivati 2-oksoazetidina, metode priprave, intermedijeri, soli i upotreba" ili je opisana u časopisu [J. Chem Research (S), 176; (M) 1501 (1988)].
Njihova sklonost pregradnji u nove bicikličke beta-laktamske analogone opće formule 1 je pronađena prilikom ispitivanja Cooper-ove pregradnje sulfoksida penicilanske kiseline koji ne posjeduju amidni postrani lanac u položaju 6. Originalna Cooper-ova pregradnja [J. Am. Chem. Soc., 92, 2575 (1972); Rearrangements of Cephalosporins and Penicillins, in Cephalosporins and Penicillins:, eds. E.H. Flynn, Academic Press, New York, 1972, p 201] je dobro poznati postupak za pripravu tiazolin-azetidinon bicikličke strukture reduktivnom pregradnjom polazeći od sulfoksida penicilina G. Takva vrsta pregradnje zahtjeva upotrebu zaštićene karboksilne kiseline, kao što su esteri i slobodni karboksamidni lanac u položaju 6, što ga posjeduju penicilini G i V.
Sada je nađeno da polazeći od sulfoksida penicilanske kiseline opće formule II, dakle takvih spojeva penam strukture, koji imaju amidnu skupinu u položaju 2 a ne posjeduju amidni postrani lanac u položaju 6, u sličnim uvjetima kao što su oni Cooper-ove pregradnje dolazi do stvaranja spojeva penicilanske strukture l s izopropilidenskim supstituentom u položaju 2 i imino supstituentom u položaju 3.
Poseban slučaj predstavlja pregradnja sulfoksida amida penicilanske kiseline opće formule II gdje radikali imaju značenje:
R1 je halogen,
R2 je halogen,
R3 je vodik, alkil, benzil, heterocikl npr. izoksazol, pirazol i dr.
gdje prije ili za vrijeme pregradnje može doći do hidrodehalogenacije i formiranja amida penicilanske kiseline opće formule II gdje radikali imaju značenje:
R1 je vodik, halogen,
R2 je vodik, halogen
R3 je vodik, alkil, benzil, heterocikl npr. izoksazol, pirazol i dr.
kod čega ti spojevi mogu biti izolirani ili bez izolacije dalje pregrađeni u beta-laktamsku strukturu prikazanu općom formulom l, gdje radikali imaju značenje:
R1 je vodik, halogen,
R2 je vodik, halogen
R3 je vodik, alkil, benzil, heterocikl npr. izoksazol, pirazol i dr.
Sve reakcije se odvijaju uz uobičajene reakcijske uvjete, a nastali produkti se izoliraju nakon obrade reakcijske smjese kristalizacijom ili kromatografijom na stupcu silikagela.
Daljnji predmet ovog izuma se odnosi na uporabu ovih spojeva kao korisnih reaktanata u procesu priprave novih monocikličkih beta-laktama, potencijalnih intermedijera za pripravu beta-laktamskih antibiotika ili sinergista beta-laktamskih antibiotika iz reda penema, oksipenema i carbapenema kao i na druge mogućnosti koje pružaju ovi supstrati.
Daljnji predmet ovog izuma se odnosi na uporabu ovih spojeva kao aktivnih komponenata u gotovim lijekovima s sinergističkim djelovanjem u kombinaciji s drugim beta-laktamskim antibioticima kao na pr s ampicilinom.
Ovaj izum je ilustriran slijedećim primjerima, koji ga ne limitiraju ni u kom pogledu.
(2S,4R,5R,6S)-2-Benzil-karbamoil-6-bromo-3,3-dimetil-7-okso-4-tia-1-azabiciklo[3.2.0]heptan-4-oksid
Primjer 1
Suspenzija (2S,4H,5fl)-2-benzil-karbamoil-6,6-dibromo-3,3-dimetil-7-okso-4-tia-1-azabiciklo[3.2.0]heptan-4-oksid (1160 mg, 2.5 mmol)) i trietil-fosfita (837 mg, 5 mmol) u suhom benzenu (30 ml) se miješa na sobnoj temperaturi kroz tri sata, kod čega nastane bistra otopina. Reakcijska smjesa se obradi vodom i slojevi odijele. Organski sloj se opere vodom, zatim zasićenom otopinom sode bikarbone i ponovo vodom. Uparavanjem osušenog (Na2SO4) organskog sloja pod sniženim pritiskom dobije se uljni ostatak, koji nakon kromatografije na silika-gelu daje (2S,4R,5R,6S)-2-benzil- karbamoil-6-bromo-3,3-dimetil-7-okso-4-tia-1-azabiciklo[3.2.0]heptan-4-oksid (810 mg, 84.2 %). Kristalizacijom iz dietil-etera dobije se produkt u obliku bijele krutine: t.t. 134-135 °C; Rf 0.40 [metilen-klorid etil-acetat (2:1 v/v)];
[α]D20= + 179°(c1,CH2Cl2);
IR (KBr)vmax/cm-1 3295s, 2980m, 1790vs, 1655s, 1530ms 1280m, 1240m, 1050s;
1H NMR (300 MHz, CDCl3) δ 1.39 i 1.67 svaki (3 H, s, CMe2), 4.34(1 H, s, 2-H), 4.40 i 4.50 svaki (1 H, dd, J 5.5, 6.4 i 14.6, CH2), 4.64(1 H, d, J 1.5, 6-H), 5.14(1 H, d, J 1.5, 5-H), 6.90(1 H, br, NH), 7.27-7.40(5 H, m, C6H5);
Anal. C15H17BrN2O3S
nađeno: C, 46.45; H, 4.50; N, 7.15; S, 8.10%;
izračunato: C, 46.76; H, 4.45; N, 7.27; S, 8.32%.
Primjer 2
(2S,4R,5R,6S)-2-Benzil-karbamoil-6-bromo-3,3-dimetil-7-okso-4-tia-1-azabiciklo[3.2.0]heptan-4-oksid nastaje miješanjem (2S,4R,5R)-2-benzil-karbamoil-6,6-dibromo-3,3-dimetil-7-okso-4-tia-1-azabiciklo[3.2.0]heptan-4-oksida i trietil-fosfita u hladnom (0°C) metilen-kloridu kroz 30 minuta. Nakon dovršene reakcije reakcijska smjesa se obradi kao u Primjeru 1 i prekristalizara iz dietil-etera.
(2S,4S,5R,6S)-2-Benzil-karbamoil-6-bromo-3,3-dimetil-7-okso-4-tia-1-azabiciklo[3.2.0]heptan-4-oksid
Primjer 3
U ohlađenu otopinu (0°C) (2S,4R5R)-2-benzil-karbamoil-6,6- dibromo-3,3-dimetil-7- okso-4-tia-1- azabiciklo[3.2.0] heptan-4-oksida (1160 mg, 2.5 mmol) u suhom metilen-kloridu (30 ml) se doda trifenil-fosfin (1310 mg, 5 mmol) i miješa 15 minuta. Reakcijska smjesa se obradi vodom i slojevi odijele. Organski sloj se opere vodom, zatim zasićenom otopinom sode bikarbone i ponovo vodom. Uparavanjem suhog (Na2SO4) organskog sloja pod sniženim pritiskom dobije se pjenasti ostatak, koji nakon kromatografije na silika-gelu daje (2S,4S,5R)6S)-2-benzil- karbamoil-6- bromo-3)3- dimetil-7- okso- 4-tia-1-azabiciklo[3.2.0]heptan-4-oksid (780 mg, 81.0%) Kristalizacijom iz dietil-etera dobije se produkt kao bijeli kristalinični prah: t.t. 141-143 °C; Rf 0.45 [metilen-klorid etil-acetat (2:1 v/v)];
[α]D20 = + 213 ° (c1, CH2Cl2); IR (KBr)vmax/cm-1 3335m, 2980m, 1795vs, 1660 s, 1525m, 1275m, 1040m;
1H NMR (300 MHz, CDCl3) δ 1.24 i 1.78 svaki (3H, s, CMe2), 4.47(1H, s, 2-H), 4.37 i 4.57 svaki (1H, dd, J 6.0, 6.3 i 14.7, CH2), 4.97(1H, d, J1.5, 6-H), 5.12(1 H, d, J 1.5, 5-H), 6.90(1 H, br, NH), 7.23-7.38(5 H, m, C6H5);
Anal. C15H17BrN2O3S;
nađeno: C, 46.55; H, 4.32; N, 7.50; S, 8.15%;
izračunato C, 46.76; H, 4.45; N, 7.27; S, 8.32%.
Primjer 4
(2S,4S,5/R,6S)-2-Benzil-karbamoil-6-bromo-3,3-dimetil-7-okso-4-tia-1-azabiciklo[3.2.0]heptan-4-oksid nastaje zagrijavanjem (2S,4R,5R)-2-benzil-karbamoil-6,6-dibromo-3,3-dimetil7-okso-4-tia-1-azabiciklo[3.2.0]heptan-4-oksida i trifenil-fosfina u toluenu na 50°C kroz 15 minuta. Nakon dovršene reakcije reakcijska smjesa se obradi kao u Primjeru 3 i prekristalizara iz dietil-etera.
(5R,6S)-3-Benzilimino-G-bromo-2-izopropiliden-7-okso-4-tia-1-azabiciklo[3.2.0]heptan
Primjer 5
Suspenzija (2S,4R,5R,6S)-2-benzil-karbamoil-6-bromo-3,3-dimetil-7-okso-4-tia-1-azabiciklo[3.2.0]heptan-4-oksida (200 mg, 0.52 mmol) trietil-fosfita (863 mg, 5.2 mmol) u suhom benzenu (30 ml) se miješa uz refluks 13 sati. Ohlađena reakcijska smjesa se opere vodom (20 ml), 1N solnom kiselinom i ponovo vodom. Organski ekstrakt se osuši nad natrijevim sulfatom, filtrira i upari u vakuumu do suha, a uljni ostatak nakon kromatografije na silika-gelu daje (5R,6S)-3-benzilimino-6-bromo-2-izopropiliden-7-okso-4-tia-1-azabiciklo[3.2.0]heptan (129 mg, 70.7 %) Prekristalizacijom iz smjese dietil-etera i n-heksana se dobije bijela krutina: t.t. 64-66 °C; Rf 0.55 (toluen);
[α]D20= + 84.6 ° (c1, CH2Cl2); MS m/z M+ 351;
IR (film)vmax/cm-1 2990w, 2910w, 1790vs, 1630vs, 1450w, 1350m, 1300s, 1160m, 1090m, 1030m;
1H NMR (300 MHz, CDCl3) δ 2.12 i 2.30 svaki (3H, s, CMe2), 4.50 i 4.57 svaki (1H, d, J 16.4, =NCH2),
4.92(1H, d, J 0.9, 6-H), 5.29(1H, d, J 0.9, 5-H), 7.25-7.36(5H, m, C6H5);
Anal. C15H15BrN2OS;
izračunato: C, 51.29; H, 4.35; N, 7.58%.
nađeno: C, 49.67; H, 4.22; N, 7.25%
Primjer 6
(5R6S)-3-Benzilimino-6-bromo-2-izopropiliden-7-okso-4-tia-1-azabiciklo[3.2.0]heptan nastaje zagrijavanjem (2S,4S,5R,6S)-2-benzil-karbamoil-6-bromo-3,3-dimetil-7-okso-4-tia-1-azabiciklo[3.2.0]heptan-4-oksida i trifenil- fosfina u vrijućem toluenu kroz 10 sati. Nakon dovršene reakcije reakcijska smjesa se obradi kao u Primjeru 5 i prekristalizara iz smjese dietil-etera i n-heksana.
Primjer 7
(5R,6S)-3-Benzilimino-6-bromo-2-izopropiliden-7-okso-4-tia-1-azabiciklo[3.2.0]heptan nastaje zagrijavanjem (2S,4R, 5R)-2-benzil-karbamoil-6,6-dibromo-3,3-dimetil-7-okso-4-tia-1-azabiciklo[3.2.0]heptan-4-oksida i trietil-fosfita u vrijućem toluenu kroz 10 sati. Nakon dovršene reakcije reakcijska smjesa se obradi kao u Primjeru 5 i prekristalizara iz smjese dietil-etera i n-heksana.
(5R)-3-Benzilimino-2-izopropiliden-7-okso-4-tia-1-azabiciklo[3.2.0]heptan
Primjer 8
Suspenzija (2S,4R,5R)-2-benzil-karbamoil-3,3-dimetil-7-okso-4-tia-1-azabiciklo[3.2.0]heptane-4-oksida (306 mg, 1.0 mmol) trietil-fosfita (863 mg, 5.2 mmol) u suhom benzenu (30 ml) se miješa uz refluks 30 sati. Ohlađena reakcijska smjesa se opere vodom (20 ml), 1N solnom kiselinom i ponovo vodom. Organski ekstrakt se osuši nad natrijevim sulfatom, filtrira i upari u vakuumu vodene sisaljke do suhog ostatka, koji nakon kromatografije na stupcu silika-gelu daje (5R)-3-benzilimino-2-izopropiliden-7-okso-4-tia-1 -azabiciklo[3.2.0]heptan kao bijeli kristalinični prah:
t.t. 73-74 °C (dietil-eter); Rf 0.28 (toluen);
[α]D20 = + 233.2 ° (c1, CH2Cl2); MS m/z M+ 272;
IR (film)vmax/cm-1 2960w, 2910w, 1780vs, 1630vs, 1450w, 1410m, 1350s, 1300vs, 1250m, 1220m, 1200m, 1150w, 1100m, 1010m;
1H NMR (300 MHz, CDCl3) δ 2.09 i 2.30 svaki (3H, s, CMe2), 3.27(1H, d, J1.7, 6P-H), 3.73(1H, d, J 4.1, 6a-H)
4.51 and 4.57 svaki (1H, d, J 16.8, =NCH2), 5.19(1H, dd, J 1.7 and 4.1, 5-H), 7.23-7.38(5 H, m, C6H5);
Anal. C15H16N2OS;
izračunato: C, 66.07; H, 5.92; N, 10.26%.
nađeno: C, 66.14; H, 6.05; N, 10.29%;
Primjer 9
(5R)-3-Benzilimino-2-izopropiliden-7-okso-4-tia-1-azabiciklo[3.2.0]heptan se također dobije ako se suspenzija (5R,6S)-3-benzilimino-6-bromo-2-izopropiliden-7-okso-4-tia-1-azabiciklo[3.2.0]heptana (200 mg, 0.57 mmol), NaHCO3 (5% vodena otopina, 15 ml) i 10% Pd-C katalizatora (200 mg) u etil-acetatu (20 ml) miješa na sobnoj temperaturi kroz 2 sata uz tlak od 2 ATM. Suspenzija se profiltrira preko Celita i slojevi odvoje. Organski sloj se pere sa slanom vodom osuši (Na2SO4) i upari pod sniženim pritiskom vodene pumpe a ostatak obradi kako je to opisano u Primjeru 8.
Claims (14)
1. 4-Tia-1-azabiciklo[3.2.0]heptan-3-imino-2-izopropiliden-7-okso analogoni beta-laktama opće formule 1,
[image]
gdje radikali imaju značenje:
R1 je vodik ili halogen,
R2 je vodik, halogen, ftalimid,
R3 je vodik, alkil, benzil, heterocikl npr. izoksazol, pirazol i dr.
2. Spoj prema zahtjevu 1, naznačen time da je R1 vodik, R2 vodik i R3 PhCH2;
3. Spoj prema zahtjevu 1, naznačen time da je R1 brom, R2 vodik i R3 PhCH2 ;
4. Spoj prema zahtjevu 1, naznačen time da je R1 brom, R2 vodik i R3 metil;
5. Spoj prema zahtjevu 1, naznačen time da je R1 brom, R2 vodik i R3 5-metil-izoksazol-3-il;
6. Spoj prema zahtjevu 1, naznačen time da je R1 brom, R2 vodik i R3 3,4-dimetil-izoksazol-5-il;
7. Spoj prema zahtjevu 1, naznačen time da je R1 brom, R2 vodik i R3 2-fenil-pirazol-3-il;
8. Spoj prema zahtjevu 1, naznačen time da je R1 brom, R2 vodik i R3 vodik;
9. Spoj prema zahtjevu 1, naznačen time da je R1 brom, R2 brom i R3 PhCH2;
10. Spoj prema zahtjevu 1, naznačen time da je R1 klor, R2 vodik i R3 PhCH2;
11. Spoj prema zahtjevu 1, naznačen time da je R1 klor, R2 klor i R3 PhCH2;
12. Spoj prema zahtjevu 1, naznačen time da je R1 vodik, R2 ftalimid i R3 PhCH2;
13. Postupak za pripravu 4-tia-1-azabiciklo[3.2.0]heptan-3-imino-2-izopropiliden-7-okso analogona beta-laktama opće formule 1, gdje radikali imaju značenje kako je navedeno u zahtjevu 1, naznačen time da se sulfoksidi amida penicilanske kiseline opće formule II,
[image]
gdje radikali imaju značenje:
R1 je vodik ili halogen;
R2 je vodik, halogen, ftalimid,
R3 je vodik, alkil, benzil, heterocikl npr. izoksazol, pirazol i dr.
podvrgnu reakciji s fosfornim spojevima kao što su trimetil-fosfit, trietil-fosfit, trifenil-fosfin i drugi kod čega dolazi do otvaranja tiazolidinskog prstena spoja II a zatim do ponovne intramolekularne ciklizacije u suhom organskom aprotičnom otapalu uz uobičajene reakcijske uvjete i obradu reakcijske smjese te izolaciju produkata opće poznatim metodama, kod čega jedan ili oba halogen atoma na položaju 6 mogu biti zadržani ili zamjenjeni vodikom.
14. Upotreba spojeva navedenih u zahtjevu 1, kao intermedijera u pripravama novih beta-laktamskih analogona s potencijalnim antimikrobnim ili sinergističkim djelovanjem.
Priority Applications (13)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HR960131A HRP960131A2 (en) | 1996-03-21 | 1996-03-21 | 4-thia-1-azabicyclo(3.2.0)heptane-3-imino-2-isopropylidene-7-oxo analogons of beta-lactams, processes for their preparation and use thereof |
| CA002199859A CA2199859A1 (en) | 1996-03-21 | 1997-03-12 | 4-thia-1-azabicyclo/3.2.0/heptane-3-imino-2-isopropylidene-7-oxo analogons of beta-lactams, processes for their preparation and the use thereof |
| JP9061299A JPH107678A (ja) | 1996-03-21 | 1997-03-14 | ３−イミノ−２−イソプロピリデン−７−オキソ−４−チア−１−アザビシクロ［３．２．０］ヘプタン化合物及びその製造方法 |
| SK333-97A SK33397A3 (en) | 1996-03-21 | 1997-03-14 | 4-thia-1-azabicyclo £3,2,0| heptane-3-imino-2-isopropylidene-7- -oxo-analogues of beta-lactames, preparation method thereof and their use |
| EP97104391A EP0796857A1 (en) | 1996-03-21 | 1997-03-14 | 4-thia-1-azabicyclo(3.2.0)heptane-3-imino-2-isopropylidene-7-oxo analogons of beta-lactams, processes for their preparation and the use thereof |
| PL97319024A PL319024A1 (en) | 1996-03-21 | 1997-03-18 | 4-thia-1-azabicyclo(3.2.0) heptane-3-imino-2-isopropylideno-7-ketoanalgones of beta-lactames, method of obtaining them and their application |
| CZ97835A CZ83597A3 (en) | 1996-03-21 | 1997-03-19 | 4-thia-1-azabicyclo(3,2,0(heptane-3-imino-2-isopropyliden-7-oxo derivatives of beta lactams, process of their preparation and use |
| CN97109644A CN1171403A (zh) | 1996-03-21 | 1997-03-20 | β－内酰胺的4－硫杂－1－氮杂双环[3.3.0]庚烷－3－亚氨基－2－异亚丙基－7－氧代类似物、它们的制备方法及应用 |
| BG101346A BG62654B1 (bg) | 1996-03-21 | 1997-03-21 | 4-тиа-1-азабицикло[3.2.0]хептан-3-имино-2-изопропилиден-7-оксо, аналозина бета-лактами, методи за тяхното получаване и използването им |
| SI9700067A SI9700067A (en) | 1996-03-21 | 1997-03-21 | 4-thia-1-azabicyclo /3.2.0./heptane-3-imino-2-isopropylidene-7-oxo analogons of beta-lactams, processes for their preparation and the use thereof |
| US08/828,267 US5856475A (en) | 1996-03-21 | 1997-03-21 | 4-thia-1-azabicyclo/3.2.0/Heptane-3-Imino-2-isopropylidene-7-oxo-analogons of beta-lactams, processes for their preparation and the use thereof |
| HU9700628A HUP9700628A3 (en) | 1996-03-21 | 1997-03-21 | 4-thia-1-aza-bicyclo[3.2.0]heptan-3-imino-2-izopropiliden-7-oxo-beta-lactame derivatives, process for producing them and use of them |
| BA960175A BA96175A (bs) | 1996-03-21 | 1997-05-03 | 4-Tia-1-azabiciklo¬3.2.0.¾heptan-3- imino-2-izopropiliden-7-okso analogoni beta-laktama postupci priprave i upotreba |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HR960131A HRP960131A2 (en) | 1996-03-21 | 1996-03-21 | 4-thia-1-azabicyclo(3.2.0)heptane-3-imino-2-isopropylidene-7-oxo analogons of beta-lactams, processes for their preparation and use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP960131A2 true HRP960131A2 (en) | 1998-04-30 |
Family
ID=10946374
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR960131A HRP960131A2 (en) | 1996-03-21 | 1996-03-21 | 4-thia-1-azabicyclo(3.2.0)heptane-3-imino-2-isopropylidene-7-oxo analogons of beta-lactams, processes for their preparation and use thereof |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US5856475A (hr) |
| EP (1) | EP0796857A1 (hr) |
| JP (1) | JPH107678A (hr) |
| CN (1) | CN1171403A (hr) |
| BA (1) | BA96175A (hr) |
| BG (1) | BG62654B1 (hr) |
| CA (1) | CA2199859A1 (hr) |
| CZ (1) | CZ83597A3 (hr) |
| HR (1) | HRP960131A2 (hr) |
| HU (1) | HUP9700628A3 (hr) |
| PL (1) | PL319024A1 (hr) |
| SI (1) | SI9700067A (hr) |
| SK (1) | SK33397A3 (hr) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HRP980026A2 (en) * | 1998-01-20 | 1999-10-31 | Pliva Pharm & Chem Works | 1-izothiazolydinone derivatives of azetidine-2-ones, processes for the preparation and use thereof |
| JP7344846B2 (ja) | 2020-06-23 | 2023-09-14 | 株式会社アマダ | レーザ加工システム及び加工パレットへの液体塗布方法 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3879408A (en) * | 1972-09-08 | 1975-04-22 | American Home Prod | Process for preparing anhydropenicillins |
-
1996
- 1996-03-21 HR HR960131A patent/HRP960131A2/hr not_active Application Discontinuation
-
1997
- 1997-03-12 CA CA002199859A patent/CA2199859A1/en not_active Abandoned
- 1997-03-14 JP JP9061299A patent/JPH107678A/ja active Pending
- 1997-03-14 EP EP97104391A patent/EP0796857A1/en not_active Withdrawn
- 1997-03-14 SK SK333-97A patent/SK33397A3/sk unknown
- 1997-03-18 PL PL97319024A patent/PL319024A1/xx unknown
- 1997-03-19 CZ CZ97835A patent/CZ83597A3/cs unknown
- 1997-03-20 CN CN97109644A patent/CN1171403A/zh active Pending
- 1997-03-21 US US08/828,267 patent/US5856475A/en not_active Expired - Fee Related
- 1997-03-21 BG BG101346A patent/BG62654B1/bg unknown
- 1997-03-21 SI SI9700067A patent/SI9700067A/sl unknown
- 1997-03-21 HU HU9700628A patent/HUP9700628A3/hu unknown
- 1997-05-03 BA BA960175A patent/BA96175A/bs unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BG62654B1 (bg) | 2000-04-28 |
| CZ83597A3 (en) | 1997-10-15 |
| PL319024A1 (en) | 1997-09-29 |
| HU9700628D0 (en) | 1997-05-28 |
| US5856475A (en) | 1999-01-05 |
| SI9700067A (en) | 1997-10-31 |
| BA96175A (bs) | 2000-11-06 |
| BG101346A (en) | 1998-03-31 |
| CN1171403A (zh) | 1998-01-28 |
| JPH107678A (ja) | 1998-01-13 |
| HUP9700628A3 (en) | 1998-01-28 |
| CA2199859A1 (en) | 1997-09-21 |
| HUP9700628A2 (en) | 1997-11-28 |
| EP0796857A1 (en) | 1997-09-24 |
| SK33397A3 (en) | 1997-10-08 |
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