WO1999018078A1 - Process for the synthesis of carbapenem intermediates, and compounds produced - Google Patents
Process for the synthesis of carbapenem intermediates, and compounds produced Download PDFInfo
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- WO1999018078A1 WO1999018078A1 PCT/US1998/020830 US9820830W WO9918078A1 WO 1999018078 A1 WO1999018078 A1 WO 1999018078A1 US 9820830 W US9820830 W US 9820830W WO 9918078 A1 WO9918078 A1 WO 9918078A1
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 63
- 238000000034 method Methods 0.000 title claims abstract description 40
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 title claims description 9
- 238000003786 synthesis reaction Methods 0.000 title description 11
- 230000015572 biosynthetic process Effects 0.000 title description 10
- 239000000543 intermediate Substances 0.000 title description 7
- -1 carbapenem compound Chemical class 0.000 claims abstract description 47
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 110
- 239000010948 rhodium Substances 0.000 claims description 74
- 229910052760 oxygen Inorganic materials 0.000 claims description 69
- 229910052717 sulfur Inorganic materials 0.000 claims description 62
- 229910052739 hydrogen Inorganic materials 0.000 claims description 59
- 239000001257 hydrogen Substances 0.000 claims description 59
- 125000005843 halogen group Chemical group 0.000 claims description 49
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 49
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 44
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 44
- 229910052757 nitrogen Inorganic materials 0.000 claims description 42
- 125000006239 protecting group Chemical group 0.000 claims description 37
- 229920006395 saturated elastomer Polymers 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 29
- 125000004429 atom Chemical group 0.000 claims description 28
- 229910052698 phosphorus Inorganic materials 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 16
- 229910052740 iodine Inorganic materials 0.000 claims description 16
- 125000004122 cyclic group Chemical group 0.000 claims description 14
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- 229910020008 S(O) Inorganic materials 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical group Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 10
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 7
- 229910052702 rhenium Inorganic materials 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical group CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 6
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical group FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- 229910052727 yttrium Inorganic materials 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 5
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 5
- 150000001768 cations Chemical class 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 239000003446 ligand Substances 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- DLQYXUGCCKQSRJ-UHFFFAOYSA-N tris(furan-2-yl)phosphane Chemical compound C1=COC(P(C=2OC=CC=2)C=2OC=CC=2)=C1 DLQYXUGCCKQSRJ-UHFFFAOYSA-N 0.000 claims description 5
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 229910001507 metal halide Inorganic materials 0.000 claims description 3
- 150000005309 metal halides Chemical class 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- BPLUKJNHPBNVQL-UHFFFAOYSA-N triphenylarsine Chemical compound C1=CC=CC=C1[As](C=1C=CC=CC=1)C1=CC=CC=C1 BPLUKJNHPBNVQL-UHFFFAOYSA-N 0.000 claims description 3
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 claims description 2
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 2
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 claims description 2
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 claims description 2
- DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 claims description 2
- RBYGDVHOECIAFC-UHFFFAOYSA-L acetonitrile;palladium(2+);dichloride Chemical compound [Cl-].[Cl-].[Pd+2].CC#N.CC#N RBYGDVHOECIAFC-UHFFFAOYSA-L 0.000 claims description 2
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- LNAMMBFJMYMQTO-FNEBRGMMSA-N chloroform;(1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].ClC(Cl)Cl.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 LNAMMBFJMYMQTO-FNEBRGMMSA-N 0.000 claims description 2
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- VJOFNWDVXXUHAG-UHFFFAOYSA-N n,n-dimethyl-1-pyridin-4-ylmethanamine Chemical compound CN(C)CC1=CC=NC=C1 VJOFNWDVXXUHAG-UHFFFAOYSA-N 0.000 claims description 2
- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 claims description 2
- HDKCVDHYIIKWFM-UHFFFAOYSA-K octanoate;rhodium(3+) Chemical group [Rh+3].CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.CCCCCCCC([O-])=O HDKCVDHYIIKWFM-UHFFFAOYSA-K 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- SVOOVMQUISJERI-UHFFFAOYSA-K rhodium(3+);triacetate Chemical compound [Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O SVOOVMQUISJERI-UHFFFAOYSA-K 0.000 claims description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 2
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 claims description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 2
- 229940102001 zinc bromide Drugs 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- JOCBASBOOFNAJA-UHFFFAOYSA-N N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid Chemical compound OCC(CO)(CO)NCCS(O)(=O)=O JOCBASBOOFNAJA-UHFFFAOYSA-N 0.000 claims 1
- 240000008042 Zea mays Species 0.000 claims 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 claims 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 claims 1
- 235000005822 corn Nutrition 0.000 claims 1
- 229910052703 rhodium Inorganic materials 0.000 claims 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims 1
- 229910052721 tungsten Inorganic materials 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 31
- 239000000243 solution Substances 0.000 description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 23
- 239000007787 solid Substances 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 14
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
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- 239000000460 chlorine Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 0 CC=CN(C)CCC[Sn]C** Chemical compound CC=CN(C)CCC[Sn]C** 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229940041011 carbapenems Drugs 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 241000894007 species Species 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- HOBYPSNNFBRLIX-UHFFFAOYSA-N 1,8-naphthosultam Chemical compound C1=CC(S(=O)(=O)N2)=C3C2=CC=CC3=C1 HOBYPSNNFBRLIX-UHFFFAOYSA-N 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- YKZIPKYZIGNUQW-UHFFFAOYSA-N C=S1(CN(c2cccc3cccc4c23)S4(=O)=O)(CCC2)CCCN2CCC1 Chemical compound C=S1(CN(c2cccc3cccc4c23)S4(=O)=O)(CCC2)CCCN2CCC1 YKZIPKYZIGNUQW-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 108010065152 Coagulase Proteins 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- PQBAWAQIRZIWIV-UHFFFAOYSA-N N-methylpyridinium Chemical compound C[N+]1=CC=CC=C1 PQBAWAQIRZIWIV-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical group [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 150000001562 benzopyrans Chemical class 0.000 description 1
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 230000007073 chemical hydrolysis Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 150000001907 coumarones Chemical class 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 239000007819 coupling partner Substances 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- XXTZHYXQVWRADW-UHFFFAOYSA-N diazomethanone Chemical compound [N]N=C=O XXTZHYXQVWRADW-UHFFFAOYSA-N 0.000 description 1
- 150000004826 dibenzofurans Chemical class 0.000 description 1
- IYYZUPMFVPLQIF-UHFFFAOYSA-N dibenzothiophene Chemical class C1=CC=C2C3=CC=CC=C3SC2=C1 IYYZUPMFVPLQIF-UHFFFAOYSA-N 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 1
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000004970 halomethyl group Chemical group 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- YGGXZTQSGNFKPJ-UHFFFAOYSA-N methyl 2-naphthalen-1-ylacetate Chemical compound C1=CC=C2C(CC(=O)OC)=CC=CC2=C1 YGGXZTQSGNFKPJ-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- LULXBAGMGMJJRW-UHFFFAOYSA-N n,2-bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)CC(=O)N[Si](C)(C)C LULXBAGMGMJJRW-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000005499 phosphonyl group Chemical group 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000003367 polycyclic group Polymers 0.000 description 1
- 229920005990 polystyrene resin Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical class N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DVFXLNFDWATPMW-IWOKLKJTSA-N tert-butyldiphenylsilyl Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO[Si](C=2C=CC=CC=2)(C=2C=CC=CC=2)C(C)(C)C)[C@@H](OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](CC(O2)N2C3=NC=NC(N)=C3N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)C1 DVFXLNFDWATPMW-IWOKLKJTSA-N 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/14—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 3
-
- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/22—Tin compounds
- C07F7/2208—Compounds having tin linked only to carbon, hydrogen and/or halogen
Definitions
- the present invention relates to a process for synthesizing carbapenem intermediates. Generally the carbapenems are substituted at the 2-position. The intermediate compounds are included as well.
- MRSA methicillin resistant Staphylococcus aureus
- MRSE methicillin resistant Staphylococcus epider idis
- MRCNS methicillin resistant coagulase negative Staphylococci
- R represents H or methyl
- P and P* represent protecting groups and each R 1 represents H, halo, OH, OP wherein P is a protecting group, -Ci- ⁇ straight- or branched-chain alkyl, unsubstituted or substituted with one to four R d groups; and -C3-7 cycloalkyl, unsubstituted or substituted with one to four R d groups; each R d independently represents halo; OP, wherein P is a protecting group, -CN; -N0 2 ; -NR e R f ; -ORg; -SRg; -CONR e R f ; -COORg; - SORg; -SO 2 Rg; -SO 2 NReRf; -NReS0 2 R f ; -CORe ; -NRe COR f ; -OCORe; - OCONReRf; -NReCONRfRg; -
- R e , R f and Rg represent hydrogen; -R*; -Ci-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four Ri groups; or R e and R 1 taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, -C(O)- or NR g with RS as defined above, said ring being unsubstituted or substituted with one to four Ri groups;
- each Ri independently represents halo; -CN; -NO2; phenyl; -NHS02R h ; -OR h , -SR h ; -N(R h )2; -N+(Rh) 3; -C(O)N(R h )2; - SO2N(R h )2; heteroaryl; heteroarylium; -C ⁇ 2R h ; -C(O)R h ; -OCOR h ; - NHCOR* 1 ; guanidinyl; carbamimidoyl or ureido;
- each Rh independently represents hydrogen, a -Ci-6 straight or branched-chain alkyl group, a -C3-C6 cycloalkyl group or phenyl, or when two R* 1 groups are present, said BP- groups may be taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, -C(O)-, NH and NCH3;
- Q is selected from the group consisting of:
- a and b are 1, 2 or 3;
- L " is a pharmaceutically acceptable counterion; ⁇ represents O, S or NR S ; ⁇ , ⁇ , ⁇ , ⁇ and ⁇ represent CRt, N or N + R s , provided that no more than one of ⁇ , ⁇ , ⁇ , ⁇ and ⁇ is N + R s ;
- R* is selected from the group consisting of:
- d represents O, S or NRk
- e, g, x, y and z represent CR m , N or N + R k , provided that no more than one of e, g, x, y and z in any given structure represents N + Rk;
- each R independently represents a member selected from the group consisting of: hydrogen; halo; -CN; -NO 2 ; -NR n R°; -OR n ; - SR n ; -CONRnR ; -COOR h ; -SOR n ; -S0 2 R n ; -S0 NR n R°; -NR n SO 2 R°; - COR*; -NRnCORo; -OCOR*; -OCONR n R°; -NRnCO 2 R h ; -NR n CONR°Rh; .
- R n and R° represent hydrogen, phenyl; -Ci-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four Ri groups; each R s independently represents hydrogen; phenyl or -Ci- straight- or branched-chain alkyl, unsubstituted or substituted with one to four R 1 groups;
- each R* independently represents hydrogen; halo; phenyl; - CN; -NO 2 ; -NR"R V ; -OR u ; -SR U ; -CONR u R v ; -COOR h ; -SOR u ; -SO 2 Ru ; - SO 2 NRuRv ; -NR u SO 2 R v ; -COR u ; -NR"COR v ; -OCOR u ; -OCONR ⁇ Rv; .
- R u and R v represent hydrogen or -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; or R u and R v together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR W or -C(O)-, said ring being unsubstituted or substituted with one to four Ri groups;
- each R w independently represents hydrogen; -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; C3-6 cycloalkyl optionally substituted with one to four R 1 groups; phenyl optionally substituted with one to four R 1 groups, or heteroaryl optionally substituted with 1-4 R 1 groups; or BP and R w taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, NH or NCH3;
- R x represents hydrogen or a Ci-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, SO2, NR W , N + R"R W , or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, NO2, OR w , SR W , SOR w , SO2R w , NR h R w , N+(R h )2R w , -C(O)-R w , C(O)NRhRw ?
- R and R z represent hydrogen; phenyl; -Ci_6 straight or branched chain alkyl, unsubstituted or substituted with one to four R 1 groups, and optionally interrupted by O, S, NR W , N+R h R w or -C(O)-;
- R x and R together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, SO2, NR W
- R, P and P* are as previously defined and L represents a leaving group, to produce a compound of formula 6.
- alkyl refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopentyl and cyclohexyl. When substituted, alkyl groups may be substituted with up to four substituent groups, selected from R" and R 1 , as defined, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with "branched alkyl group”.
- Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings which are fused.
- alkenyl refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond.
- Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
- alkynyl refers to a hydrocarbon radical straight or branched, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond.
- Preferred alkynyl groups include ethynyl, propynyl and butynyl.
- Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like.
- An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms.
- the preferred aryl groups are phenyl, naphthyl and phenanthrenyl.
- Aryl groups may likewise be substituted as defined.
- Preferred substituted aryls include phenyl and naphthyl.
- Heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a poly cyclic aromatic group having 8 to 16 atoms, containing at least one heteroatom, O, S, S(O), SO2 or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Examples of this type are pyrrole, pyridine, oxazole, thiazole and oxazine. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole and the like.
- polycyclic heteroaromatics examples include benzopyrans, benzofurans, benzopyrroles, benzimidazoles, benzothiazoles, quinolines, purines, isoquinolines, benzopyrimidines, dibenzofurans, dibenzothiophenes, 1,8-naphthosultams,
- heterocycle refers to a 5-16 membered cycloalkyl group (nonaromatic) with 1-4 rings, in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by heteroatoms.
- heteroatom means O, S, S(O), S(O) 2 or N, selected on an independent basis.
- Heteroarylium refers to heteroaryl groups bearing a quaternary nitrogen atom and thus a positive charge. Examples include the following:
- heterocycloalkyl refers to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by hetero atoms.
- quaternary nitrogen and “positive charge” refer to tetravalent, positively charged nitrogen atoms including, e.g., the positively charged nitrogen in a tetraalkylammonium group (e. g. tetramethylammonium), heteroarylium, (e.g., N-methyl- pyridinium), basic nitrogens which are protonated at physiological pH, and the like.
- Cationic groups thus encompass positively charged nitrogen-containing groups, as well as basic nitrogens which are protonated at physiologic pH.
- heteroatom means O, S or N, selected on an independent basis.
- Alkoxy refers to alkyl-O-, with the alkyl group optionally substituted as described herein.
- L refers to a leaving group. Examples of suitable L groups are methanesulfonyl (mesyl or OMs), toluenesulfonyl (OTs), trifluoromethanesulfonyl (triflate or OTf), halo, and phosphonyl based groups like diphenylphosphonyl.
- Halogen and "halo" refer to bromine, chlorine, fluorine and iodine. When the leaving group L is halo, this refers to Br, Cl and I.
- M is H or a metal cation. Metal cation as used herein refers to Na, K, Mg, Zn and Li. Preferably, M is H or a metal cation selected from Na and K.
- protecting groups for the compounds of the present invention will be recognized from the present application taking into account the level of skill in the art, and with reference to standard textbooks, such as Greene, T. W. et al. Protective Groups in Organic Synthesis Wiley, New York (1991). Examples of suitable protecting groups are contained throughout the specification.
- P, P ⁇ . and P* represent hydroxyl and carboxyl protecting groups, respectively.
- Y may represent a protecting group for X, which in turn represents O or N (see compound 4 below).
- These groups are generally removable, i.e., they can be removed, if desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule. Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with a transition metal catalyst and catalytic hydrogenation.
- carboxyl protecting groups P* include allyl, benzhydryl, 2-naphthylmethyl, benzyl, silyl groups such as t-butyldimethylsilyl (TBDMS), trimethylsilyl, (TMS), triethylsilyl (TES), phenacyl, p-methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl, p- nitrobenzyl, 4-pyridylmethyl and t-butyl.
- TDMS t-butyldimethylsilyl
- TMS trimethylsilyl
- TES triethylsilyl
- phenacyl p-methoxybenzyl
- o-nitrobenzyl p-methoxyphenyl
- p-methoxyphenyl p-methoxyphenyl
- 4-pyridylmethyl and t-butyl 4-pyridylmethyl and t-buty
- Suitable hydroxy protecting groups P and P ⁇ include TMS, TES, TBDMS, o-nitrobenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, t- butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and the like.
- suitable protecting groups Y for X equal to N include,for example, groups where the N is protected by or incorporated into a ring, such as by forming a piperidinyl group. Similarly, the N can be disubstituted to provide a nitrogen in protected form. In this instance, Y would represent disubstitution on the nitrogen atom.
- Y represents H or a protecting group as noted above.
- X and Y can be considered in combination to represent a ring system, containing from 1-4 rings comprised of from 5 to 16 atoms, 0 to 3 of which are N atoms, and 0 to 2 of which are selected from O, S, S(O) and S(0) 2 .
- the ring system is aromatic, non-aromatic or partially aromatic and is unsubstituted or substituted with 1-3 groups selected from the group consisting of halo, OH, OP, Ci-6 alkyl, Ci-6 alkyl substituted with 1-3 of OH, OP, halo, NH2, NHCi-4 alkyl or N(Cl-4 alkyl)2-
- X and Y are taken in combination to represent a ring system as defined above.
- the preferred ring system is a 1,8-naphthosultam, unsubstituted or substituted with 1- 3 groups selected from Ci-6 alkyl unsubstituted or substituted with 1-3 of halo, OH or OP.
- a preferred aspect of the invention relates to compounds of formulas 6, 4' and 5 wherein one R 1 represents a group which contains a positively charged moiety, and the remaining R 1 groups are selected from hydrogen and C ⁇ .Q straight or branched chain alkyl, unsubstituted or substituted with one to four R°- groups. More particularly, this subset of interest includes compounds of formulas 6, 4' and 5 wherein one R 1 represents a group containing a positively charged moiety and the remaining R 1 groups are hydrogen.
- the positively charged moiety or moieties that are contained in one or more R 1 groups it is preferred that from 1-3 positive charges be present, and most preferably two positive charges be present, balanced by a carboxylate anion and a negatively charged counterion.
- R 1 group represents a -Ci-6 straight or branched chain alkyl group, substituted with one to four Rd groups, wherein one R" group represents -R* or Q.
- R 1 group represents a -Ci-6 straight or branched chain alkyl group, substituted with one to four Rd groups, wherein one R" group represents -R* or Q.
- R3 is Cl, Br or I, which is comprised of reacting a compound of formula 2:
- R 2 is Cl, Br or I
- X represents O or NH and Y represents H or a protecting group, or in the alternative, X and Y taken in combination represent a ring system containing from 0-3 nitrogen atoms and 0-2 heteroatoms selected from O, S, S(O) and S(O)2, said ring system having
- R3 is Cl, Br or I, with a compound of the formula M-X-Y wherein M is H or a metal cation, and X and Y are as previously defined, to produce a compound of formula 4.
- each R 1 is as described above, comprising reacting a compound of formula 1:
- R3 is Cl, Br or I, with a naphthosultam of formula 5:
- R represents H or methyl
- P and P* represent protecting groups and each R 1 is as described above, comprising reacting a compound of formula 4':
- R, P and P* are as previously defined and L represents a leaving group, to produce a compound of formula 6.
- each R 1 is as described above, comprising reacting a compound of formula 1:
- R3 is Cl, Br or I, with a naphthosultam of formula 5:
- P represents a member selected from the group consisting of: TES, TMS, TBDMS, PNB, p-nitrobenzyloxycarbonyl, allyl and allyloxycarbonyl.
- P* represents a member selected from the group consisting of: TES, TMS, TBDMS, PNB, and allyl.
- L represents a leaving group selected from the group consisting of: diphenylphosphoryl, halo, mesyl and triflate.
- Compounds which are of interest herein include those represented by one of the following formulas:
- R3 is Cl, Br or I
- X represents O or NH and Y represents H or a protecting group, or X and Y taken in combination represent a ring system containing from 0-3 nitrogen atoms and 0-2 heteroatoms selected from O, S, S(O) and S(O)2, said ring system having 1-4 rings, with from 5-16 atoms, said system being non-aromatic, partially aromatic or aromatic, and being unsubstituted or substituted with from 1-3 groups selected from halo, OH, OP, wherein P is a protecting group, Ci_ alkyl and Cl-6 alkyl substituted with from 1-3 of halo, OH, OP, NH2, NHC W alkyl and N(C W alkyl) 2
- each R 1 represents H, halo, OH, OP wherein P is a protecting group, C j.g alkyl or C ⁇ alkyl substituted with 1-3 of halo, OH, OP, NH2,
- the stannatrane 2 having a halo group attached directly to the tin atom can be obtained in accordance with Vedejs, E. et al. J. Am. Chem. Soc. 114: 6556-6558 (1992), the teachings of which are incorporated herein by reference.
- the carbapenem 7 having a leaving group at position 2 can likewise be obtained in accordance with Schmitt, S. M. et al., J. Antibiotics 41(6): 780-787 (1988), the teachings of which are incorporated herein by reference.
- the carboxylic acid group at C-3 of the carbapenem is generally protected as a carboxyl protecting group such as p-nitrobenzyl (PNB), allyl, p-methoxybenzyl, trichloroethyl, 2- trimethylsilyl ethyl, and the like.
- PNB p-nitrobenzyl
- allyl allyl
- p-methoxybenzyl trichloroethyl
- 2- trimethylsilyl ethyl 2- trimethylsilyl ethyl
- the hydroxyl group of the ⁇ -(hydroxyethyl) side-chain is optionally protected with a hydroxyl protecting group such as trimethylsilyl (TMS), triethylsilyl (TES), tert- butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl, allyl oxycarbonyl, 2-trimethylsilylethoxy carbonyl, 2- trichloroethoxycarbonyl and the like.
- TMS trimethylsilyl
- TES triethylsilyl
- TDMS tert- butyldimethylsilyl
- TDPS tert-butyldiphenylsilyl
- acetyl acetyl, allyl oxycarbonyl, 2-trimethylsilylethoxy carbonyl, 2- trichloroethoxycarbonyl and the like.
- the compounds of the present invention are prepared as illustrated in flow sheet A.
- a suitable solvent such as tetrahydrofuran (THF)
- Addition of the CH 2 XY moiety to the carbapenem is accomplished by cross-coupling suitably protected 7 with stannatrane 4 in a suitable solvent such as dimethylpropylene urea (DMPU), hexamethylphosphoramide (HMPA), THF, toluene, DMF, NMP, NEP, and the like using an appropriate transition metal catalyst such as Pd(dba)2 and a ligand such as triphenyl phosphine, tris-2-furyl phosphine, triphenyl arsine and the like.
- DMPU dimethylpropylene urea
- HMPA hexamethylphosphoramide
- THF toluene
- DMF dimethylpropylene urea
- NMP hexamethylphosphoramide
- NEP hexamethylphosphoramide
- a ligand such as triphenyl phosphine, tris-2-furyl phosphine, triphenyl ar
- the final product may be characterized structurally by techniques such as NMR, IR, MS, and UV.
- the final product if not crystalline, may be lyophilized from water to afford an amorphous, easily handled solid.
- Still another aspect of the process that is of interest is the synthesis of a carbapenem compound of formula 6:
- R represents H or methyl
- P and P* represent protecting groups and each R 1 is as described above, comprising reacting a compound of formula 4':
- R, P and P* are as previously defined, P ⁇ represents a protecting group or hydrogen and L represents a leaving group, in the presence of a catalyst (such as rhodium octanoate, rhodium acetate and the like), and metal halide (such as zinc bromide, zinc chloride, and the like) contacting the mixture with a base (such as alkylamines such as diisopropyl amine, t-butyl amine, 2,2,6,6,tetramethylpiperidine, methylamine, hexylamine, ethylamine, triethylamine, diisopropylethylamine, trimethylamine, ethyldimethylamine, tri-n- propylamine and the like, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, imidazole, lutidine, collidine, 4-dimethylaminomethyl- pyridine, N,
- MRSA/MRCNS In vitro antibacterial activity is predictive of in vivo activity when the compounds are administered to a mammal infected with a susceptible bacterial organism.
- the compounds of the invention are determined to be active against MRSA.
- the compounds of the invention can be formulated in pharmaceutical compositions by combining the compound with a pharmaceutically acceptable carrier. Examples of such carriers are set forth below. The invention is further described in connection with the following non-limiting examples.
- Step 1 potassium l-(methoxycarbonylmethyl)-4-naphthalene sulfonate
- Step 2 l-(methoxycarbonylmethyl)-5-nitro-4-naphthalene sulfonic acid Potassium l-(methoxycarbonylmethyl)-4-naphthalene sulfonate (10 g, 31.4 mmol) was added portionwise over 30 minutes to 90% nitric acid, which was cooled in a methanol / ice bath to approximately -15 ° C. After 2 hours, the bath temperature had reached -10°C and diethyl ether (200 mL) was added to the mixture.
- Step 3 sodium l-(methoxycarbonylmethyl)-5-amino-4-naphthalene sulfonate l-(methoxycarbonylmethyl)-5-nitro-4-naphthalene sulfonic acid (2 g, 6.15 mmol) was dissolved in water (20 mL), containing 0.5 mL concentrated sulfuric acid, and was added dropwise over 5 minutes to a refluxing suspension of iron (4 g, 71.6 mmol) in water (100 mL). After refluxing for one hour, the dark mixture was cooled to room temperature, made basic with sodium carbonate, and concentrated to approximately 30mL. The residual mixture was placed on a CG-161 amberchrom resin column (2.5 x 30 cm).
- N,O-Bistrimethylsilylacetamide (0.31 mL, 1.25 mmol) was added to a solution of 4-(2-(hydroxy)-ethyl)- 1,8-naphthosultam (0.125 g,
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Abstract
A process of synthesizing a carbapenem compound of formula (6), is disclosed using a compound of formula (4'). The intermediate compounds that are described herein are also included in the present invention.
Description
TITLE OF THE INVENTION
PROCESS FOR THE SYNTHESIS OF CARBAPENEM
INTERMEDIATES, AND COMPOUNDS PRODUCED
BACKGROUND OF THE INVENTION
The present invention relates to a process for synthesizing carbapenem intermediates. Generally the carbapenems are substituted at the 2-position. The intermediate compounds are included as well.
Many of the carbapenems are useful against gram positive microorganisms, especially methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epider idis (MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS). These antibacterials thus comprise an important contribution to therapy for treating infections caused by these difficult to control pathogens. There is an increasing need for agents effective against such pathogens (MRSA/MRCNS) which are at the same time relatively free from undesirable side effects.
SUMMARY OF THE INVENTION In one aspect of the invention, a process of synthesizing a carbapenem compound of formula 6:
is disclosed wherein R represents H or methyl, P and P* represent protecting groups and each R1 represents H, halo, OH, OP wherein P is
a protecting group, -Ci-β straight- or branched-chain alkyl, unsubstituted or substituted with one to four Rd groups; and -C3-7 cycloalkyl, unsubstituted or substituted with one to four Rd groups; each Rd independently represents halo; OP, wherein P is a protecting group, -CN; -N02; -NReRf; -ORg; -SRg; -CONReRf; -COORg; - SORg; -SO2Rg; -SO2NReRf; -NReS02Rf; -CORe; -NRe CORf; -OCORe; - OCONReRf; -NReCONRfRg; -NReCO2Rh; -OCO2Rh; -C(NRe)NRfRg; - NReC(NH)NRfRg; -NReC(NRf)Rg; -R* or -Q;
Re, Rf and Rg represent hydrogen; -R*; -Ci-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four Ri groups; or Re and R1 taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, -C(O)- or NRg with RS as defined above, said ring being unsubstituted or substituted with one to four Ri groups;
each Ri independently represents halo; -CN; -NO2; phenyl; -NHS02Rh; -ORh, -SRh; -N(Rh)2; -N+(Rh)3; -C(O)N(Rh)2; - SO2N(Rh)2; heteroaryl; heteroarylium; -Cθ2Rh; -C(O)Rh; -OCORh; - NHCOR*1; guanidinyl; carbamimidoyl or ureido;
each Rh independently represents hydrogen, a -Ci-6 straight or branched-chain alkyl group, a -C3-C6 cycloalkyl group or phenyl, or when two R*1 groups are present, said BP- groups may be taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, -C(O)-, NH and NCH3;
Q is selected from the group consisting of:
C ® ® © a _ndΛ - © NRxRyRz
L" is a pharmaceutically acceptable counterion; α represents O, S or NRS; β, δ, λ, μ and σ represent CRt, N or N+Rs, provided that no more than one of β, δ, λ, μ and σ is N+Rs;
R* is selected from the group consisting of:
Rk represents hydrogen; -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; or - (CH )nQ where n = 1, 2 or 3 and Q is as previously defined;
each R independently represents a member selected from the group consisting of: hydrogen; halo; -CN; -NO2; -NRnR°; -ORn; - SRn; -CONRnR ; -COORh; -SORn; -S02Rn; -S0 NRnR°; -NRnSO2R°; - COR*; -NRnCORo; -OCOR*; -OCONRnR°; -NRnCO2Rh; -NRnCONR°Rh; . OCO2Rh; -CNRnNR°Rh; -NRnCNHNR°Rh; -NR"C(NR°)Rh; -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; -C3-7 cycloalkyl, unsubstituted or substituted with one to four Ri groups; and -(CH2)nQ where n and Q are as defined above;
Rn and R° represent hydrogen, phenyl; -Ci-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four Ri groups;
each Rs independently represents hydrogen; phenyl or -Ci- straight- or branched-chain alkyl, unsubstituted or substituted with one to four R1 groups;
each R* independently represents hydrogen; halo; phenyl; - CN; -NO2; -NR"RV; -ORu; -SRU; -CONRuRv; -COORh; -SORu; -SO2Ru; - SO2NRuRv; -NRuSO2Rv; -CORu; -NR"CORv; -OCORu; -OCONR^Rv; . NRuCO2Rv; -NRuCONRvR ; -OC02Rv; -Ci-6 straight- or branched- chain alkyl, unsubstituted or substituted with one to four Ri groups;
Ru and Rv represent hydrogen or -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; or Ru and Rv together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NRW or -C(O)-, said ring being unsubstituted or substituted with one to four Ri groups;
each Rw independently represents hydrogen; -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; C3-6 cycloalkyl optionally substituted with one to four R1 groups; phenyl optionally substituted with one to four R1 groups, or heteroaryl optionally substituted with 1-4 R1 groups; or BP and Rw taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, NH or NCH3;
Rx represents hydrogen or a Ci-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, SO2, NRW, N+R"RW, or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, NO2, ORw, SRW, SORw, SO2Rw, NRhRw, N+(Rh)2Rw, -C(O)-Rw, C(O)NRhRw? SO2NRhRw, CO2Rw, OC(O)Rw, OC(O)NRhRW} NRhC(O)Rw, NRhC(O)NRhRw, or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R1
groups or with one to two Ci-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R1 groups;
R and Rz represent hydrogen; phenyl; -Ci_6 straight or branched chain alkyl, unsubstituted or substituted with one to four R1 groups, and optionally interrupted by O, S, NRW, N+RhRw or -C(O)-;
or Rx and R together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, SO2, NRW
, N+R^Rw or -C(O)-, unsubstituted or substituted with 1 - 4 Ri groups, and when Rx and RJ together represent a 4-6 membered ring as defined above, Rz is as defined above or Rz represents an additional saturated 4-6 membered ring fused to the ring represented by Rx and RY taken together, optionally interrupted by O, S, NRW or -C(O)-, said rings being unsubstituted or substituted with one to four Ri groups
comprising reacting a compound of formula 4':
4'
with a carbapenem of formula 7:
wherein R, P and P* are as previously defined and L represents a leaving group, to produce a compound of formula 6.
DETAILED DESCRIPTION OF THE INVENTION
The invention is described herein in detail using the terms defined below unless otherwise specified.
The term "alkyl" refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopentyl and cyclohexyl. When substituted, alkyl groups may be substituted with up to four substituent groups, selected from R" and R1, as defined, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with "branched alkyl group".
Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings which are fused.
The term "alkenyl" refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
The term "alkynyl" refers to a hydrocarbon radical straight or branched, containing from 2 to 10 carbon atoms and at
least one carbon to carbon triple bond. Preferred alkynyl groups include ethynyl, propynyl and butynyl.
Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms. The preferred aryl groups are phenyl, naphthyl and phenanthrenyl. Aryl groups may likewise be substituted as defined. Preferred substituted aryls include phenyl and naphthyl.
Heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a poly cyclic aromatic group having 8 to 16 atoms, containing at least one heteroatom, O, S, S(O), SO2 or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Examples of this type are pyrrole, pyridine, oxazole, thiazole and oxazine. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole and the like.
Examples of polycyclic heteroaromatics include benzopyrans, benzofurans, benzopyrroles, benzimidazoles, benzothiazoles, quinolines, purines, isoquinolines, benzopyrimidines, dibenzofurans, dibenzothiophenes, 1,8-naphthosultams,
The term "heterocycle" (heterocyclyl) refers to a 5-16 membered cycloalkyl group (nonaromatic) with 1-4 rings, in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by heteroatoms.
The term "heteroatom" means O, S, S(O), S(O)2 or N, selected on an independent basis.
Heteroarylium refers to heteroaryl groups bearing a quaternary nitrogen atom and thus a positive charge. Examples include the following:
CH,
When a charge is shown on a particular nitrogen atom in a ring which contains one or more additional nitrogen atoms, it is understood that the charge may reside on a different nitrogen atom in the ring by virtue of charge resonance that occurs.
The term "heterocycloalkyl" refers to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by hetero atoms.
The terms "quaternary nitrogen" and "positive charge" refer to tetravalent, positively charged nitrogen atoms including, e.g., the positively charged nitrogen in a tetraalkylammonium group (e. g. tetramethylammonium), heteroarylium, (e.g., N-methyl- pyridinium), basic nitrogens which are protonated at physiological pH, and the like. Cationic groups thus encompass positively charged nitrogen-containing groups, as well as basic nitrogens which are protonated at physiologic pH.
The term "heteroatom" means O, S or N, selected on an independent basis.
Alkoxy refers to
alkyl-O-, with the alkyl group optionally substituted as described herein. L refers to a leaving group. Examples of suitable L groups are methanesulfonyl (mesyl or OMs), toluenesulfonyl (OTs), trifluoromethanesulfonyl (triflate or OTf), halo, and phosphonyl based groups like diphenylphosphonyl.
Halogen and "halo" refer to bromine, chlorine, fluorine and iodine. When the leaving group L is halo, this refers to Br, Cl and I. M is H or a metal cation. Metal cation as used herein refers to Na, K, Mg, Zn and Li. Preferably, M is H or a metal cation selected from Na and K.
When a group is termed "protected", such as by P, P*, PΛ, Y and the like, this means that the group is in modified form to preclude undesired side reactions at the protected site. Suitable protecting groups for the compounds of the present invention will be recognized from the present application taking into account the level of skill in the art, and
with reference to standard textbooks, such as Greene, T. W. et al. Protective Groups in Organic Synthesis Wiley, New York (1991). Examples of suitable protecting groups are contained throughout the specification. In some of the compounds of the present invention, P, PΛ. and P* represent hydroxyl and carboxyl protecting groups, respectively. Likewise, Y may represent a protecting group for X, which in turn represents O or N (see compound 4 below). These groups are generally removable, i.e., they can be removed, if desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule. Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with a transition metal catalyst and catalytic hydrogenation. Examples of carboxyl protecting groups P* include allyl, benzhydryl, 2-naphthylmethyl, benzyl, silyl groups such as t-butyldimethylsilyl (TBDMS), trimethylsilyl, (TMS), triethylsilyl (TES), phenacyl, p-methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl, p- nitrobenzyl, 4-pyridylmethyl and t-butyl. Examples of suitable hydroxy protecting groups P and PΛ include TMS, TES, TBDMS, o-nitrobenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, t- butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and the like.
Examples of suitable protecting groups Y for X equal to N include,for example, groups where the N is protected by or incorporated into a ring, such as by forming a piperidinyl group. Similarly, the N can be disubstituted to provide a nitrogen in protected form. In this instance, Y would represent disubstitution on the nitrogen atom.
When X represents O or NH, Y represents H or a protecting group as noted above. In the alternative, X and Y can be considered in combination to represent a ring system, containing from 1-4 rings comprised of from 5 to 16 atoms, 0 to 3 of which are N atoms, and 0 to 2 of which are selected from O, S, S(O) and S(0)2. The ring system is aromatic, non-aromatic or partially aromatic and is unsubstituted or substituted with 1-3 groups selected from the group consisting of halo,
OH, OP, Ci-6 alkyl, Ci-6 alkyl substituted with 1-3 of OH, OP, halo, NH2, NHCi-4 alkyl or N(Cl-4 alkyl)2- Preferably X and Y are taken in combination to represent a ring system as defined above. The preferred ring system is a 1,8-naphthosultam, unsubstituted or substituted with 1- 3 groups selected from Ci-6 alkyl unsubstituted or substituted with 1-3 of halo, OH or OP.
A preferred aspect of the invention relates to compounds of formulas 6, 4' and 5 wherein one R1 represents a group which contains a positively charged moiety, and the remaining R1 groups are selected from hydrogen and C\.Q straight or branched chain alkyl, unsubstituted or substituted with one to four R°- groups. More particularly, this subset of interest includes compounds of formulas 6, 4' and 5 wherein one R1 represents a group containing a positively charged moiety and the remaining R1 groups are hydrogen.
With respect to the positively charged moiety or moieties that are contained in one or more R1 groups, it is preferred that from 1-3 positive charges be present, and most preferably two positive charges be present, balanced by a carboxylate anion and a negatively charged counterion.
Another preferred aspect is represented by formulas 6, 4' and 5 wherein one R1 group represents a -Ci-6 straight or branched chain alkyl group, substituted with one to four Rd groups, wherein one R" group represents -R* or Q. Hence, a positively charged moiety -R* or Q is attached to an alkyl group.
One aspect of the process that is of interest herein is the synthesis of a compound of formula 1:
wherein R3 is Cl, Br or I,
which is comprised of reacting a compound of formula 2:
wherein R2 is Cl, Br or I,
with a compound of formula 3:
to produce a compound of formula 1.
Another aspect of the process that is of interest is the synthesis of a compound of formula 4:
wherein X represents O or NH and Y represents H or a protecting group, or in the alternative, X and Y taken in combination represent a ring system containing from 0-3 nitrogen atoms and 0-2 heteroatoms selected from O, S, S(O) and S(O)2, said ring system having
1-4 rings, with from 5-16 atoms, said system being non-aromatic, partially aromatic or aromatic, and being unsubstituted or substituted with from 1-3 groups selected from halo, OH, OP, wherein P is a protecting group, Cl-6 alkyl and Cl-6 alkyl substituted with from 1-3 of halo, OH, OP, NH2, NHC1.4 alkyl and N(CW alkyl)2
comprising reacting compound 1:
1
wherein R3 is Cl, Br or I, with a compound of the formula M-X-Y wherein M is H or a metal cation, and X and Y are as previously defined, to produce a compound of formula 4.
Another aspect of the process that is of particular interest is the synthesis of a compound of formula 4':
wherein each R1 is as described above, comprising reacting a compound of formula 1:
wherein R3 is Cl, Br or I, with a naphthosultam of formula 5:
wherein R1 is as previously defined, to produce a compound of formula 4'.
Another aspect of the process that is of interest is the synthesis of a carbapenem compound of formula 6:
wherein R represents H or methyl, P and P* represent protecting groups and each R1 is as described above, comprising reacting a compound of formula 4':
7
wherein R, P and P* are as previously defined and L represents a leaving group, to produce a compound of formula 6.
Another aspect of the process that is of particular interest is the synthesis of a compound of formula 4':
wherein each R1 is as described above, comprising reacting a compound of formula 1:
wherein R3 is Cl, Br or I, with a naphthosultam of formula 5:
wherein R1 is as previously defined, to produce a compound of formula 4'.
In particular, processes of interest are those described above wherein P represents a member selected from the group consisting of: TES, TMS, TBDMS, PNB, p-nitrobenzyloxycarbonyl, allyl and allyloxycarbonyl.
Other processes that are of particular interest are those described above wherein P* represents a member selected from the group consisting of: TES, TMS, TBDMS, PNB, and allyl.
Still other processes that are of particular interest are those described above wherein R represents methyl.
Still other processes that are of particular interest are those described above wherein R3 represents I. Still other processes that are of particular interest are those described above wherein R represents Cl.
Still other processes that are of particular interest are those described above wherein L represents a leaving group selected from the group consisting of: diphenylphosphoryl, halo, mesyl and triflate. Compounds which are of interest herein include those represented by one of the following formulas:
wherein X represents O or NH and Y represents H or a protecting group, or X and Y taken in combination represent a ring system containing from 0-3 nitrogen atoms and 0-2 heteroatoms selected from O, S, S(O) and S(O)2, said ring system having 1-4 rings, with from 5-16 atoms, said system being non-aromatic, partially aromatic or aromatic, and being unsubstituted or substituted with from 1-3 groups selected from halo, OH, OP, wherein P is a protecting group, Ci_ alkyl and Cl-6 alkyl substituted with from 1-3 of halo, OH, OP, NH2, NHCW alkyl and N(CW alkyl)2
wherein each R1 represents H, halo, OH, OP wherein P is a protecting group, Cj.g alkyl or C^ alkyl substituted with 1-3 of halo, OH, OP, NH2,
NHC1-4 alkyl or N(Cι_4 alkyltø.
Species that are of particular interest are as follows:
The process of the present invention is illustrated by the following generic scheme:
FLOW SHEET A
7
The stannatrane 2 having a halo group attached directly to the tin atom can be obtained in accordance with Vedejs, E. et al. J. Am. Chem. Soc. 114: 6556-6558 (1992), the teachings of which are incorporated herein by reference. The carbapenem 7 having a leaving group at position 2 can likewise be obtained in accordance with Schmitt, S. M. et al., J. Antibiotics 41(6): 780-787 (1988), the teachings of which are incorporated herein by reference. The carboxylic acid group at C-3 of the carbapenem is generally protected as a carboxyl protecting group such as p-nitrobenzyl (PNB), allyl, p-methoxybenzyl, trichloroethyl, 2- trimethylsilyl ethyl, and the like. Furthermore, the hydroxyl group of the β-(hydroxyethyl) side-chain is optionally protected with a hydroxyl protecting group such as trimethylsilyl (TMS), triethylsilyl (TES), tert- butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl, allyl oxycarbonyl, 2-trimethylsilylethoxy carbonyl, 2- trichloroethoxycarbonyl and the like.
The compounds of the present invention are prepared as illustrated in flow sheet A. Treatment of stannatrane 2 with halomethyl zinc halide or bis halomethyl zinc reagents 3 in a suitable solvent such as tetrahydrofuran (THF) at about -78 °C to about 35 °C for about 1 to 20
hours followed by isolation techniques yields the halomethyl stannatrane 1.
Reaction of 1 in a suitable solvent such as THF, DMF, DMSO, and the like with organometallic reagent MXY yields 4 which can be isolated by chromatography or crystallization.
Alternatively 4 can be prepared by treatment of the halostannatrane 2 with MCHXY in a solvent such as THF, t-butyl methyl ether and the like at about -100 °C to about 35 °C followed by an appropriate workup and isolation, wherein X=O and Y=tertiary butyl. Addition of the CH2XY moiety to the carbapenem is accomplished by cross-coupling suitably protected 7 with stannatrane 4 in a suitable solvent such as dimethylpropylene urea (DMPU), hexamethylphosphoramide (HMPA), THF, toluene, DMF, NMP, NEP, and the like using an appropriate transition metal catalyst such as Pd(dba)2 and a ligand such as triphenyl phosphine, tris-2-furyl phosphine, triphenyl arsine and the like. The temperature for this reaction is typically between 20 °C and 100 °C and the products are isolated by common techniques such as chromatography or crystallization. Suitable solvents for the invention disclosed herein include tetrahydrofuran (THF), ethyl acetate (EtOAc), H2O, C^ alcohol, toluene,
DMF, NMP, NEP, dichloromethane, acetonitrile, acetone and the like The synthesis of the target intermediate is completed by removing any protecting groups which are present in the penultimate intermediate 6. The deprotected final product is then purified, as necessary, using techniques such as ion exchange chromatography,
HPLC on reverse phase silica gel, MPLC on reverse phase polystyrene resin and recrystallization.
The final product may be characterized structurally by techniques such as NMR, IR, MS, and UV. For ease of handling, the final product, if not crystalline, may be lyophilized from water to afford an amorphous, easily handled solid.
Still another aspect of the process that is of interest is the synthesis of a carbapenem compound of formula 6:
wherein R represents H or methyl, P and P* represent protecting groups and each R1 is as described above, comprising reacting a compound of formula 4':
with a compound of formula 9:
wherein R, P and P* are as previously defined, PΛ represents a protecting group or hydrogen and L represents a leaving group, in the presence of a catalyst (such as rhodium octanoate, rhodium acetate and the like), and metal halide (such as zinc bromide, zinc chloride, and the like) contacting the mixture with a base (such as
alkylamines such
as diisopropyl amine, t-butyl amine, 2,2,6,6,tetramethylpiperidine, methylamine, hexylamine, ethylamine, triethylamine, diisopropylethylamine, trimethylamine, ethyldimethylamine, tri-n- propylamine and the like, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, imidazole, lutidine, collidine, 4-dimethylaminomethyl- pyridine, N,N,N',N'-tetramethylethylenediamine (TMEDA), N- methylmorpholine (NMM) and the like) and triflating agent (such as trifluoromethanesulfonic anhydride and the like) and reacting the resulting solution with a palladium catalyst (such as Pd(OAc)2, Pd(PPh3)4 PdCl2, PdCl2(PPh3)2, PdCl2(CH3CN)2, Pd2(dba)3, Pd2(dba)3CHCl3, Pd(dba)2, and the like, wherein dba is dibenzylideneacetone) in the presence of a ligand (such as a ligand such as triphenyl phosphine, tris-2-furyl phosphine, triphenyl arsine and the like) to produce a compound of formula 6. The compounds of the present invention are valuable intermediates for antibacterial agents that are active against various Gram-positive and to a lesser extent Gram-negative bacteria, and accordingly find utility in human and veterinary medicine.
Many of the compounds that can be made in accordance with the present invention are biologically active against
MRSA/MRCNS. In vitro antibacterial activity is predictive of in vivo activity when the compounds are administered to a mammal infected with a susceptible bacterial organism.
Using standard susceptibility tests, the compounds of the invention are determined to be active against MRSA.
The compounds of the invention can be formulated in pharmaceutical compositions by combining the compound with a pharmaceutically acceptable carrier. Examples of such carriers are set forth below. The invention is further described in connection with the following non-limiting examples.
PREPARATIVE EXAMPLE 1 SYNTHESIS OF 4-(2-(TRIMETHYLSILYLOXY)-ETHYL)-l,8- NAPHTHOSULTAM
70:30 + minor isomers
Step 1: potassium l-(methoxycarbonylmethyl)-4-naphthalene sulfonate
A solution of methyl 1-naphthaleneacetate (1 mL, 5.77 mmol) in carbon tetrachloride (1 mL) was cooled under nitrogen in an ice bath. Chlorosulfonic acid (0.38 mL, 5.7 mmol) was added dropwise over 8 minutes. After an additional 30 minutes, the viscous mixture was removed from the bath and was stirred at room temperature for 17 hours to give a white solid. The solid was partitioned between methylene chloride (5 mL) and water (5 mL). After filtering through solka-floc, the methylene chloride layer was extracted with more water (2 x 5 mL), and the combined aqueous extracts were basified with potassium carbonate to give a precipitate. The suspension was concentrated to approximately 5 mL and was cooled in an ice bath.
The suspension was then filtered and the collected solid was washed with cold water (2 mL). The solid was dried under a stream of nitrogen to give the title compound as a white solid (0.84 g).
!H NMR (DMSO-d6, 500 MHz) δ 3.73 (s, OMe), 4.27 (s, CH2Ar), 7.53 (d, ArH), 7.71 (t, ArH), 7.76 (t, ArH), 8.06 (d, ArH), 8.10 (d, ArH) and 8.73 (d, ArH).
Step 2: l-(methoxycarbonylmethyl)-5-nitro-4-naphthalene sulfonic acid Potassium l-(methoxycarbonylmethyl)-4-naphthalene sulfonate (10 g, 31.4 mmol) was added portionwise over 30 minutes to 90% nitric acid, which was cooled in a methanol / ice bath to approximately -15°C. After 2 hours, the bath temperature had reached -10°C and diethyl ether (200 mL) was added to the mixture. The precipitated solid was filtered, washed with ether (100 mL) and isopropanol (20 mL), and dried under a stream of nitrogen to give the title compound as an approximately 70:30 mixture of the 5- and 8-nitro isomers (approximately 12 g). lH NMR (D2O, 500 MHz) δ 3.69 (s, OMe), 4.30 (s, CH2Ar),
7.67 (t, ArH), 7.71 (d, ArH), 8.18 (d, ArH), 8.29 (d, ArH) and 8.33 (d, ArH).
Step 3: sodium l-(methoxycarbonylmethyl)-5-amino-4-naphthalene sulfonate l-(methoxycarbonylmethyl)-5-nitro-4-naphthalene sulfonic acid (2 g, 6.15 mmol) was dissolved in water (20 mL), containing 0.5 mL concentrated sulfuric acid, and was added dropwise over 5 minutes to a refluxing suspension of iron (4 g, 71.6 mmol) in water (100 mL). After refluxing for one hour, the dark mixture was cooled to room temperature, made basic with sodium carbonate, and concentrated to approximately 30mL. The residual mixture was placed on a CG-161 amberchrom resin column (2.5 x 30 cm). The column was washed with water (200 mL), 10% MeCN/ H2θ(200 mL), and 25% MeCN/ H2O (400 mL), collecting 25 mL fractions. Fractions 21-28 were combined and evaporated to give the title compound as a dark solid (0.675 g). lH NMR (D2O, 500 MHz) δ 3.64 (s, OMe), 4.18 (s, CH2Ar),
7.04 (d, ArH), 7.38 (d, ArH), 7.41 (d, ArH), 7.45 (t, ArH) and 8.22 (d, ArH). Step 4: 4-(methoxycarbonylmethyl)-1.8-naphthosultam
Sodium l-(methoxycarbonylmethyl)-5-amino-4-
naphthalene sulfonate (0.675 g, 2.13 mmol) was suspended in phosphorous oxychloride (10 g, 65.2 mmol) and was refluxed for 1 hour to give a thin suspension. The mixture was cooled to room temperature and was partitioned between ethyl acetate (100 mL) and water (100 mL). The water layer was extracted with ethyl acetate (50 mL) and the combined ethyl acetate layers were washed with saturated aqueous sodium chloride (100 mL), dried over magnesium sulfate, filtered and evaporated to give the title compound as a solid (0.55 g). lH NMR (CDCI3, 500 MHz) δ 3.72 (s, OMe), 4.15 (s, CH2Ar), 6.86 (br s, NH), 6.97 (d, ArH), 7.60 (t, ArH), 7.67 (d, ArH), 7.71 (d, ArH) and 7.95 (d, ArH).
Step 5: 4-(2-(hydroxy)-ethyl)-1.8-naphthosultam
A solution of 4-(methoxycarbonylmethyl)-l,8- naphthosultam (0.2 g, 0.72 mmol) in tetrahydrofuran (2 mL) was cooled under nitrogen in an ice bath. Lithium aluminum hydride (1.44 mL of a 1.0 M solution in THF, 1.44 mmol) was added over 1 minute to give a light yellow suspension. After 30 minutes, water was carefully added and the mixture was partitioned between ethyl acetate (30 mL) and IN hydrochloric acid (10 mL). The aqueous layer was extracted with ethyl acetate (50 mL) and the combined ethyl acetate layers were washed with saturated aqueous sodium chloride (10 mL), dried over magnesium sulfate, filtered and evaporated. The residual solid (0.16g) was purified by preparative thin layer chromatography (2 x 1000 micron silica gel plates, developed/ eluted with 5% MeOH/CH2Cl2) to give the title compound as a solid (0.127 g). lH NMR (0.14 mL CDCI3 and 0.01 mL CD3OD, 500 MHz) δ
3.33 (t, CH2Ar), 3.91 (t, CH2OH), 6.84 (d, ArH), 7.49 (dd, ArH), 7.59 (d,
ArH), 7.59 (d, ArH) and 7.83 (d, ArH).
Step 6: 4-(2-(trimethylsilyloxy)-ethyl)-1.8-naphthosultam
N,O-Bistrimethylsilylacetamide (0.31 mL, 1.25 mmol) was added to a solution of 4-(2-(hydroxy)-ethyl)- 1,8-naphthosultam (0.125 g,
0.50 mmol) in tetrahydrofuran (1 mL). After one hour the mixture was evaporated and the residue was dissolved in methylene chloride (2 mL)
and filtered through silica gel (2.5 g). The silica gel was eluted with methylene chloride (50 mL), the solvent was evaporated and the residue was lyophilized from benzene (3 mL) to give the title compound as an oil (0.16 g, quant.). iH NMR (CDCI3, 500 MHz) δ 0.035 (s, TMS), 3.37 (t, CH2Ar), 3.94 (t, CH2θ(TMS)), 6.95 (d, ArH), 7.56 (dd, ArH), 7.64 (d, ArH), 7.71 (d, ArH) and 7.92 (d, ArH).
EXAMPLE 1
A stirred suspension of potassium £-butoxide (1.68 g, 15.0 mmol) and t-butylmethyl ether (54 mL) under an atmosphere of dry nitrogen was cooled to -78 °C. A solution of sec-BuLi (9.1 mL of a 1.65 M solution in cyclohexane, 15.0 mmol) was added to the suspension over 5 min. After 2 h at - 78 °C, a solution of l-aza-5-chloro-5- stannabicyclo[3.3.3]undecane (A, 2.93 g, 10.0 mmol) and THF (60 mL) was added and the mixture was allowed to warm to rt over 4 h. After an additional 16 h at rt the solution was poured onto water (100 mL) and hexane (300 mL). The layers were partitioned and the organic phase was washed with water (2 x 100 mL), brine (50 mL) and dried (MgSO4) then concentrated to provide B as a clear light yellow oil (2.82g).
Η NMR (CDC13, 250 MHz) δ 3.09 (t, J = 6.4 Hz, 2H), 2.34 (m, 6H), 1.62 (m, 6H), 1.06 (s, 9H), 0.68 (m, 6H), 13C NMR (CDC13, 63 MHz) δ 72.9, 56.2, 54.7, 26.8, 23.2, 5.7.
EXAMPLE 2
A solution of Pd(dba)2 (19 mg, 0.03 mmol), tris-2- furylphosphine (19 mg, 0.08 mmol) and HMPA (1 mL) was heated to 50 °C under a nitrogen atmosphere for 15 min. To the resulting yellow solution was added a solution of enol triflate (C, 201 mg, 0.33 mmol), of 1- aza-5-t-butoxymethyl-5-stannabicyclo[3.3.3]undecane (B, 173 mg, 0.50 mmol) and HMPA (1 mL) via cannula. The resulting solution was aged at 70 °C for 2 h. The mixture was diluted with t-butylmethyl ether (50 mL) and then washed with water (3 x 10 mL). The organic phase was dried (MgSO4) and concentrated to provide a brown oil (318 mg). Flash chromatography on silica gel with 95:5 hexane/EtOAc eluent provided D as a colorless crystalline solid (110 mg, 61 %).
Η NMR (CDCI3, 250 MHz) δ 8.19 (m, 2H), 7.64 (m, 2H), 5.43 (d, J = 13.9 Hz, IH), 5.21 (d, J = 13.9 Hz, IH), 4.80 (d, J = 14.1 Hz, IH), 4.23 (m, 2H), 4.03 (dd, J = 14.2, 1.0 Hz, IH), 3.40 (m, IH), 3.22 (dd, J = 5.7, 3.0 Hz, IH), 1.23 (d, J = 6.2 Hz, 3H), 1.20 (s, 9H), 1.15 (d, J = 7.5 Hz, 3H), 0.84 (s, 9H), 0.58 (s, 3H), 0.52 (s, 3H), 13C NMR (CDC1S, 63 MHz) δ 175.2, 160.8, 152.6, 147.5, 142.9, 127.9, 125.5, 123.6, 73.5, 65.8, 65.1, 60.1, 56.4, 55.6, 40.1, 27.3, 25.6, 22.3, 17.8, 15.3, -4.3, -5.1.
EXAMPLE 3
A
Diethyl zinc (0.4 mL, 3.9 mmol) was added to dry THF (5 mL) under nitrogen at - 70 °C. Diiodomethane (0.6 mL, 7.4 mmol) was added dropwise. The mixture was aged at 0 °C for 1 h and then 30 min at 23 °C. The solution was cooled to 0 °C and l-aza-5-chloro-5- stannabicyclo[3.3.3]undecane (A, 450 mg, 1.5 mmol) was added in one portion. The mixture was stirred at rt for 20 h. Diethyl ether (10 mL) and water (10 mL) were added and the layers were partitioned. The organic phase was concentrated and the residue was applied to a silica column. Elution with hexane/EtOAc provided l-aza-5-iodomethyl-5- stannabicyclo[3.3.3]undecane (E) as a white solid (500 mg).
Η NMR (CDC13, 250 MHz) δ 2.37 (m, 6H), 1.67 (m, 6H), 1.66 (s, 2H), 0.82, (m, 6H). 13C NMR (CDCL, 63 MHz) δ 54.6, 23.3, 7.2, -13.5.
EXAMPLE 4
A suspension of l-aza-5-iodomethyl-5- stannabicyclo[3.3.3]undecane (E, 100 mg, 0.25 mmol), hydroxyethylnaphthosultam (F, 81 mg, 0.33 mmol),
(45 mg, 0.33 mmol) and DMF (0.5 mL) was stirred at 23 °C for 10 h. The mixture was partitioned between ether (5 mL) and water (5 mL) and the organic phase was washed with water (5 mL), dried (MgS04) then concentrated. The compound G was isolated by chromatography on silica with 4:1 hexane/EtOAc eluent to provide a white solid (110 mg).
Η NMR (CDC13, 250 MHz) δ 7.81 (d, J = 7.4 Hz, IH), 7.44 (m, 3H), 6.52 (m, IH). 3.91 (br m, 2H), 3.29 (t, J = 6.6 Hz, 2H), 2.90 (m, 2H). 2.35 (m, 6H), 1.65 (m, 6H), 0.82 (m, 6H), 13C NMR (CDC13, 63 MHz) δ 140.7, 138.8, 129.6, 129.4, 129.2, 128.4, 119.6, 119.3, 113.7, 102.1, 62.8, 54.7, 35.8, 29.8, 23.2, 8.1.
EXAMPLE 5
A solution of Pd(dba)2 (19 mg, 0.03 mmol), tris-2- furylphosphine (19 mg, 0.08 mmol) and HMPA (0.7 mL) was heated to 50 °C under a nitrogen atmosphere for 30 min. The resulting yellow solution was added to a solution of enol triflate C (167 mg, 0.27 mmol), stannane G (110 mg, 0.21 mmol) and HMPA (0.7 mL) via cannula. The resulting solution was warmed to 75 °C for 3 h then cooled to room temperature. The mixture was diluted with ether (10 mL) and then washed with water (10 mL). The organic phase was dried (MgS04) and concentrated. The compound H was isolated by preparative TLC using hexane/EtOAc as eluent to provide a colorless solid (78 mg).
Η NMR (CDClj, 250 MHz) δ 8.24 (m, 2H), 7.93 (m, IH), 7.73 - 7.47 (m, 5H), 6.72 (d, J = 7.2 Hz, IH), 5.54 (d, J = 13.9 Hz, IH), 5.40 (d, J = 17.2 Hz, IH), 5.37 (d, J = 13.96 Hz, IH), 4.66 (d, J = 17.2 Hz, IH), 4.24 (m, 2H), 4.01 (t, J = 6.5 Hz, 2H), 3.38 (m, 3H), 3.30 (dd, J = 4.9, 3.0 Hz, IH), 1.29 (d, J = 7.3 Hz, 3H), 1.20 (d, J = 6.2 Hz, 3H), 0.83 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H), 13CNMR (CDClj, 63 MHz) δ 174.5, 161.1 , 147.7, 147.1, 142.5, 141.6, 137.2, 129.9, 129.3, 129.0, 128.9, 128.3, 128.2, 123.8, 120.0, 119.7, 1 15.9, 103.8, 65.7, 65.4, 62.9, 60.4, 55.4, 40.7, 38.0, 35.7, 25.7, 22.2, 17.9, 15.6, -4.3, -5.0
EXAMPLE 6
A solution of alcohol G (521 mg, 1.0 mmol) and methylene chloride (10 mL) was cooled to -78 °C under nitrogen and 2,6-lutidine (0.26 mL, 2.2 mmol) was added dropwise. After 10 min, trifluoromethanesulfonic anhydride (0.18 mL, 1.1 mmol) was added dropwise and the solution was warmed to —20 °C over 2 h. The reaction mixture was applied to a 1.2 cm pad of silica that was eluted with methylene chloride. The solvent was removed in vacuo to provide I as a yellow solid (571 mg, 87%).
Η NMR (CDCI3, 250 MHz) δ 7.82 (d, J = 7.4 Hz, IH), 7.55 (m, 2H), 7.34 (d, J = 8.6 Hz, IH), 6.56 (d, J = 7.3 Hz, IH), 4.78 (t, J = 7.1 Hz, 2H), 3.58 (t, J = 7.1 Hz, 2H), 2.91 (t, J = 5.5 Hz, 2H), 2.36 (t, J = 5.5 Hz, 6H), 1.65 (m, 6H), 0.82 (m, 6H). 13C NMR (CDC13, 62.9 MHz) 5138.9, 136.0, 130.2, 129.2, 128.8, 119.5, 119.1, 118.4 (q, J = 320 Hz), 112.5, 102.3, 75.6, 54.5, 32.3, 29.8, 23.0, 8.0.
EXAMPLE 7
(40 mL) was cooled under nitrogen to -10 °C and dabcoacetamide triflate J (1.49 g, 4.87 mmol) was added in one portion. The resulting mixture was stirred at rt for 18 h. The reaction mixture was added slowly to
rapidly stirred diethylether (200 mL) and compound K was collected on a frit to provide 4.17 g of a yellow solid that was 93 wt% pure (90.3% yield, corrected).
Η NMR (CD3CN, 250 MHz) δ 7.98 (d, J=7.5 Hz, IH), 7.73 (d, J=7.5 Hz, IH), 7.60 (m, IH), 7.50 (d, J=8.7 Hz, IH), 6.83 (b, IH), 6.69 (d, J=7.3 Hz, IH), 6.43 (b, IH), 4.22 (s, 2H), 4.15 (m, 6H), 3.97 (m, 6H), 3.80 (m, 2H), 3.60 (m, 2H), 2.92 (s, 2H), 2.37 (t, J=5.6 Hz, 6H), 1.63 (m, 6H), 0.74 (t, J=6.8 Hz, 6H).
EXAMPLE 8
Iodomethylstannatrane E (1.01 g, 2.53 mmol), naphthosultam L (1.78 g, 2.53 mmol), diisopropylethylamine (1.32 L, 7.29 mmol) and N-methylpyrolidinone (30 mL) were combined and stirred at rt for 18 h. HPLC assay shows 91% assay yield. The reaction mixture was added slowly to rapidly stirred diethyl ether (300 mL). The resulting yellow solid K was collected on a frit (3.17 g, 51 wt%, 65% isolated yield). A pure sample was obtained by chromatography on C18 silica eluting with 20% to 40% acetonitrile and water. X represents the counterions for K, which is a mixture of iodide and triflate.
EXAMPLE 9
A mixture of diazoketon M (2.00 g), Rh2(octa)4 (19.9 mg), ZnBr2 (11.8 mg) and CH2C12 (20 mL) was refluxed for 4 h. The mixture was cooled to -78 °C and triethylamine (0.65 mL) was added dropwise. After 30 min Tf2O (0.87 mL) was added dropwise. After an additional 30 min DMPU (20 mL) was added and the mixture was warmed to 24 °C .
A separate flask was charged with Pd2(dba)3-CHC13 (20.7 mg), 2-fur3P (23.2 mg) and DMPU (1 mL). The mixture was degassed then warmed to 70 °C for 30 min to provide a clear yellow solution.
A separate flask was charged with the stannane K coupling partner (200 mg), the enol triflate solution (2.69 mL of a 0.115 M solution) and the catalyst solution. The mixture was degassed then warmed to 70 °C. After 2 h the assay yield of N was 47%.
EXAMPLE 10
EXAMPLE 11
A mixture of diazoketone Q (2.02 g), Rh2(octa)4 (16 mg),
ZnBr2 (49 mg) and CH2C12 (10 mL) was refluxed for 3 h. The mixture was cooled to -72 ®C and triethylamine (0.72 mL) was added dropwise. After 30 min Tf2O (0.71 mL) was added dropwise. After an additional 30 min NMP (12 mL) was added and the mixture was warmed to 24 °C .
The methylene chloride was removed in vacuo.
A separate flask was charged with Pd2(dba)3-CHC13 (2.6 mg), 2-fur3P (2.9 mg) and NMP (0.25 mL). The mixture was degassed with N2 then warmed to 70 °C for 30 min to provide a clear yellow solution.
A separate flask was charged with the stannane K (97 mg), the enol triflate solution (0.42 mL of the 0.29 M solution),
diisopropylethyl-amine (3.9 mg), NMP (1.24 mL), and the catalyst solution. The mixture was degassed then warmed to 70 °C. After 6 h the assay yield of P was 70%.
Claims
WHAT IS CLAIMED IS:
1. A process of synthesizing a compound of formula 1:
1
wherein R3 is Cl, Br or I, comprising reacting a compound of formula 2:
wherein R2 is Cl, Br or I, with a compound of formula 3:
to produce a compound of formula 1.
2. A process of synthesizing a compound of formula 4:
1-4 rings, with from 5-16 atoms, said system being non-aromatic, partially aromatic or aromatic, and being unsubstituted or substituted with from 1-3 groups selected from halo, OH, OP, wherein P is a protecting group, Cl-6 alkyl and Cl- alkyl substituted with from 1-3 of halo, OH, OP, NH2, NHCW alkyl and N(C1.4 alkyl)2 comprising reacting compound 1:
1
wherein R3 is Cl, Br or I, with a compound of the formula M-X-Y wherein M represents H or a metal cation, and X and Y are as previously defined, to produce a compound of formula 4.
A process of synthesizing a compound of formula 4':
4'
wherein each R1 represents H, halo, OH, OP wherein P is a protecting group, -Cl-6 straight- or branched-chain alkyl, unsubstituted or
substituted with one to four Rd groups; and -C3-7 cycloalkyl, unsubstituted or substituted with one to four Rd groups; each Rd independently represents halo; OP, wherein P is a protecting group, -CN; -NO2; -NReRf; -ORg; -SRg; -CONReRf; -COORg; - SORg; -SO2Rg; -SO2NReRf; -NReS02Rf; -CORe; -NRe CORf; -OCORe; - OCONReRf; -NReCONRfRg; -NReCO2Rh; -OCO2Rh; -C(NRe)NRiRg; - NReC(NH)NRfRg; -NReC(NR*)Rg; -R* or -Q;
Re, Rf and Rg represent hydrogen; -R*; -Cl-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four Ri groups; or Re and R1 taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, -C(O)- or NRg with Rg as defined above, said ring being unsubstituted or substituted with one to four Ri groups;
each Ri independently represents halo; -CN; -NO2; phenyl; -NHSO2Rh; -ORh, -SRh; -N(Rh)2; -N+(Rh)3; -C(0)N(Rh)2; - SO2N(Rh)2; heteroaryl; heteroarylium; -CO2Rh; -C(O)Rh; -OCORh; - NHCOR*1; guanidinyl; carbamimidoyl or ureido;
each BP independently represents hydrogen, a -Cl-6 straight or branched-chain alkyl group, a -C3-C6 cycloalkyl group or phenyl, or when two Rn groups are present, said Rn groups may be taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, -C(O)-, NH and NCH3;
Q is selected from the group consisting of:
RxRyR2
R* is selected from the group consisting of:
Rk represents hydrogen; -Cl-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; or - (CH )nQ where n = 1, 2 or 3 and Q is as previously defined;
each Rm independently represents a member selected from the group consisting of: hydrogen; halo; -CN; -N02; -NRnR°; -ORn; - SRn; -CONRnRo; -COORh; -SORn; -SO2Rn; -SO2NRnR°; -NRnSO2R°; -
CORn; -NRnCORo; -OCORn; -OCONRnR°; -NRnCO2Rh; -NRnCONR°Rh; - OCO2Rh; -CNRnNR°Rh; -NRnCNHNR°Rh; -NRnC(NR°)R* ; -Cl-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; -C3-7 cycloalkyl, unsubstituted or substituted with one to four Ri groups; and -(CH )nQ where n and Q are as defined above;
Rn and R° represent hydrogen, phenyl; -Ci- straight- or branched-chain alkyl unsubstituted or substituted with one to four Ri groups;
each Rs independently represents hydrogen; phenyl or -Cl-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups;
each Rt independently represents hydrogen; halo; phenyl; - CN; -N02; -NRuRv; -OR"; -SRU; -CONR"Rv; -COORh; -SORu; -SO2Ru; - SO2NRuRv; -NRuSO2Rv; -CORu; -NRuCORv; -OCORu; -OCONRuRv; - NRuCO2Rv; -NRuCONRvRw; -OCO2Rv; -Cl-6 straight- or branched- chain alkyl, unsubstituted or substituted with one to four Ri groups;
Ru and Rv represent hydrogen or -Cl-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; or Ru and Rv together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NRW or -C(O)-, said ring being unsubstituted or substituted with one to four Ri groups;
each Rw independently represents hydrogen; -Cl-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; C3-6 cycloalkyl optionally substituted with one to four R1 groups; phenyl optionally substituted with one to four R1 groups, or heteroaryl optionally substituted with 1-4 R1 groups; or BP and Rw taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, NH or NCH3;
Rx represents hydrogen or a Ci-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, SO2, NRW,
N+RnRw, or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, NO2, ORw, SRW, SORw, Sθ2Rw, NR^RW, N+(Rh)2Rw, -C(O)-Rw, C(O)NRhRw, SO2NRhRw, C02RW, OC(O)Rw, OC(0)NRhRw, NRhC(O)Rw, NRhC(0)NRhRw, or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R1 groups or with one to two Cl-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R1 groups;
Ry and Rz represent hydrogen; phenyl; -Cl-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R1 groups, and optionally interrupted by O, S, NRW, N+RhRw or -C(O)-;
or Rx and RJ together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, SO2, NRW
, N+R^RW or -C(O)-, unsubstituted or substituted with 1 - 4 BΪ groups, and when Rx and Ry together represent a 4-6 membered ring as defined above, Rz is as defined above or Rz represents an additional saturated 4-6 membered ring fused to the ring represented by Rx and BJ taken together, optionally interrupted by O, S, NRW or -C(O)-, said rings being unsubstituted or substituted with one to four R1 groups,
comprising reacting a compound of formula 1:
wherein R3 is Cl, Br or I, with a naphthosultam of formula 5:
wherein R1 is as previously defined, to produce a compound of formula 4'.
4. A process of synthesizing a carbapenem compound of formula 6:
wherein R represents H or methyl, P and P* represent protecting groups and each R1 represents H, halo, OH, OP wherein P is a protecting group, -Cl-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Rd groups; and -C3-7 cycloalkyl, unsubstituted or substituted with one to four Rd groups; each Rd independently represents halo; OP, wherein P is a protecting group, -CN; -NO2; -NReRf; -ORg; -SRg; -CONReRf; -COORg; - SORg; -SO2Rg; -SO2NReRf; -NReSO2Rf; -CORe; -NRe CORf; -OCORe; - OCONReRf; -NReCONR^Rg; -NReCO2Rh; -OCO2Rh; -C(NRe)NRfRg; - NReC(NH)NRfRg; -NReC(NRf)Rg; -R* or -Q;
Re, Rf and Rg represent hydrogen; -R*; -Cl-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four Ri groups; or Re and Rf taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, -C(O)- or NRg with Rg as defined above, said ring being unsubstituted or substituted with one to four Ri groups;
each Ri independently represents halo; -CN; -NO2; phenyl; -NHSO2R11; -ORh, -SRh; -N(Rh)2; -N+(Rh)3; -C(O)N(Rh)2; - SO2N(Rh)2; heteroaryl; heteroaryliu ; -CO2Rh; -C(O)Rh; -OCORh; - NHCORn; guanidinyl; carbamimidoyl or ureido;
each Rh independently represents hydrogen, a -Cl-6 straight or branched-chain alkyl group, a -C3-C6 cycloalkyl group or phenyl, or when two Rn groups are present, said Rn groups may be taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, -C(O)-, NH and NCH3;
Q is selected from the group consisting of:
Rx and S Λ--NRxRyR2
L" is a pharmaceutically acceptable counterion; α represents O, S or NRS; β, δ, λ, μ and σ represent CRt, N or N+Rs, provided that no more than one of β, δ, λ, μ and σ is N+Rs;
R* is selected from the group consisting of:
each Rm independently represents a member selected from the group consisting of: hydrogen; halo; -CN; -N02; -NRnR°; -ORn; - SRn; -CONRnR ; -COORh; -SORn; -SO2Rn; -SO2NR*R°; -NRnSO2R°; - CORn; -NRnCOR°; -OCORn; -OCONRnR°; -NRnCO2Rh; -NRnCONR°Rh; - OCO2Rh; -CNRnNRoRh; -NRnCNHNR°Rh; -NRnC(NRo)Rh; . ^Q straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; -C3-7 cycloalkyl, unsubstituted or substituted with one to four Ri groups; and -(CH2)nQ where n and Q are as defined above;
Rn and R° represent hydrogen, phenyl; -Cl-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four R groups;
each Rs independently represents hydrogen; phenyl or -Cl-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups;
each BP independently represents hydrogen; halo; phenyl; - CN; -NO2; -NRURV; -ORu; -SRU; -CONRuRv; -COORh; -SORu; -SO2Ru; - SO2NRuRV; -NRuSO2Rv; -CORu; -NRuCORv; -OCORU; -OCONRuRV; - NRuCO2Rv; -NRuCONRvRw; -OCO2Rv; -Cl-6 straight- or branched- chain alkyl, unsubstituted or substituted with one to four Ri groups;
Ru and Rv represent hydrogen or -Cl-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; or Ru and Rv together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NRW or -C(O)-, said ring being unsubstituted or substituted with one to four Ri groups;
each Rw independently represents hydrogen; -Cl-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; C3-6 cycloalkyl optionally substituted with one to four R1 groups; phenyl optionally substituted with one to four R1 groups, or heteroaryl optionally substituted with 1-4 R1 groups; or Rn and Rw taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, NH or NCH3;
Rx represents hydrogen or a Ci-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, SO2, NRW, N+RhRW, or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, NO2, ORw, SRW, SORw, SO2 w, NRhR , N+(Rh)2R , -C(O)-Rw, C(0)NRhRw, SO2NRhRw, CO2Rw, OC(O)Rw,
OC(O)NRhRw, NRhC(O)Rw, NRhC(O)NRhRW, or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R1 groups or with one to two Cl-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R1 groups;
Ry and Rz represent hydrogen; phenyl; -Cl-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R1 groups, and optionally interrupted by O, S, NRW, N+RhRw or -C(O)-;
or Rx and J together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, SO2, NRW
, N+RnRw or -C(O)-, unsubstituted or substituted with 1 - 4 R groups, and when Rx and Ry together represent a 4-6 membered ring as defined above, Rz is as defined above or Rz represents an additional saturated 4-6 membered ring fused to the ring represented by Rx and Ry taken together, optionally interrupted by O, S, NRW or -C(O)-, said rings being unsubstituted or substituted with one to four Ri groups
comprising reacting a compound of formula 4':
4'
with a carbapenem of formula 7:
wherein R, P and P* are as previously defined and L represents a leaving group, to produce a compound of formula 6.
5. A process in accordance with claim 3 wherein P represents a member selected from the group consisting of: TMS, TES, TBDMS, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, all loxycarbonyl, t-butyloxycarbonyl and 2,2,2- trichloroethyloxycarbonyl.
6. A process in accordance with claim 3 wherein P* represents a member selected from the group consisting of: allyl, benzhydryl, 2-naphthylmethyl, benzyl, silyl groups such as t-butyldimethylsilyl (TBDMS), trimethylsilyl, (TMS), triethylsilyl (TES-), phenacyl, p-methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl, p- nitrobenzyl, 4-pyridylmethyl and t-butyl.
7. A process in accordance with claim 3 wherein R represents methyl.
8. A process in accordance with claim 3 wherein L represents a member selected from the group consisting of: OMs, OTs, OTf , halo and diphenylphosphonyl.
9. A process in accordance with claim 1 wherein R3 represents I and at least one R1 represents a -Cl-6 straight or branched chain alkyl group, substituted with one to four R^ groups, wherein one R°- group represents -R* or Q.
10. A process in accordance with claim 2 wherein R3 represents I and at least one R1 represents a -Cl-6 straight or branched chain alkyl group, substituted with one to four R" groups, wherein one R°- group represents -R* or Q.
11. A process in accordance with claim 3 wherein R represents I and at least one R1 represents a -Cl-6 straight or branched chain alkyl group, substituted with one to four R" groups, wherein one Rd group represents -R* or Q.
12. A process in accordance with claim 9 wherein R3 represents Cl and at least one R1 represents a -Cl-6 straight or branched chain alkyl group, substituted with one to four Ru groups, wherein one R" group represents -R* or Q.
13. A process in accordance with claim 10 wherein R3 represents Cl and at least one R1 represents a -Cl-6 straight or branched chain alkyl group, substituted with one to four B& groups, wherein one Rd group represents -R* or Q.
14. A process in accordance with claim 11 wherein R3 represents Cl and at least one R1 represents a -Cl-6 straight or branched chain alkyl group, substituted with one to four R°- groups, wherein one Rd group represents -R* or Q.
15. A process of synthesizing a carbapenem compound of formula 6:
wherein R represents H or methyl, P and P* represent protecting groups and each R1 represents H, halo, OH, OP wherein P is a protecting group,
-Cl-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Rd groups; and -C3-7 cycloalkyl, unsubstituted or substituted with one to four Rd groups; each Rd independently represents halo; OP, wherein P is a protecting group, -CN; -NO2; -NReRf; -ORg; -SRg; -CONReRf; -COORg; -
SORg; -SO2Rg; -SO2NReRf; -NReSO2Rf; -CORe; -NRe CORf; -OCORe; -
OCONReRf; -NReCONRfRg; -NReCO2Rh; -OCO2Rh; -C(NRe)NR*Rg; -
NReC(NH)NRfRg; -NReC(NRf)Rg; -R* or -Q;
Re, R and Rg represent hydrogen; -R*; -Cl-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four Ri groups; or Re and Rf taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to
three of O, S, -C(O)- or NRg with Rg as defined above, said ring being unsubstituted or substituted with one to four R1 groups;
each Ri independently represents halo; -CN; -NO2; phenyl; -NHSO2Rh; -ORh, -SRh; -N(Rh)2; -N+(Rh)3; -C(O)N(Rh)2; - SO2N(Rh)2; heteroaryl; heteroarylium; -CO2Rh; -C(O)Rh; -OCORh; - NHCOR"; guanidinyl; carbamimidoyl or ureido;
each Rn independently represents hydrogen, a -Cl-6 straight or branched-chain alkyl group, a -C3-C6 cycloalkyl group or phenyl, or when two BP groups are present, said BP groups may be taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, -C(O)-, NH and NCH3;
Q is selected from the group consisting of:
RWR
L" is a pharmaceutically acceptable counterion; α represents O, S or NRS; β, δ, λ, μ and σ represent CRt, N or N+Rs, provided that no more than one of β, δ, λ, μ and σ is N+Rs;
R* is selected from the group consisting of:
each R independently represents a member selected from the group consisting of: hydrogen; halo; -CN; -NO ; -NRnR°; -ORn; - SRn; -CONRnR°; -COORh; -SORn; -SO2Rn; -SO2NRnR°; -NRnSO2R°; - CORn; -NRnCORo; -OCORn; -OCONRnR°; -NRnC02Rh; -NRnCONR°Rh; - OCO2Rh; -CNRnNR°Rh; -NRnCNHNR°Rh; -NRnC(NR°)Rh; -Cι_6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; -C3-7 cycloalkyl, unsubstituted or substituted with one to four Ri groups; and -(CH2)nQ where n and Q are as defined above;
Rn and R° represent hydrogen, phenyl; -Cl-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four Ri groups;
each Rs independently represents hydrogen; phenyl or -Cl-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups;
each R* independently represents hydrogen; halo; phenyl; - CN; -NO2; -NRURV; -ORu; -SRU; -CONRuRv; -COORh; -SORU; -SO2Ru; - SO2NRuRv; -NRuSO2Rv; -CORu; -NRuCORv; -OCORu; -OCONRuRV; . NRuCO2Rv; -NRuCONRvRw; -OCO2Rv; -Cl-6 straight- or branched- chain alkyl, unsubstituted or substituted with one to four Ri groups;
Ru and Rv represent hydrogen or -Cl-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; or Ru and Rv together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NRW or -C(O)-, said ring being unsubstituted or substituted with one to four R groups;
each Rw independently represents hydrogen; -Cl-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; C3-6 cycloalkyl optionally substituted with one to four R1 groups; phenyl optionally substituted with one to four R1 groups, or heteroaryl optionally substituted with 1-4 R1 groups; or BP and Rw taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, NH or NCH3;
Rx represents hydrogen or a Cl-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, SO2, NRW, N+RhR , or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, NO2, ORw, SRW, SORw, SO2Rw, NR^R , N+(Rh)2R , -C(O)-Rw, C(O)NRhRw, SO2NRhRw, CO2Rw, OC(O)Rw,
OC(O)NRhRW, NRhC(O)RW, NRhC(O)NRhRw, or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R1 groups or with one to two Cl-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R1 groups;
R and Rz represent hydrogen; phenyl; -Cl-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R1 groups, and optionally interrupted by O, S, NRW, N+RhRw or -C(O)-;
or Rx and Ry together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, SO2, NRW
, N+RhRW or -C(O)-, unsubstituted or substituted with 1 - 4 R1 groups, and when Rx and RJ together represent a 4-6 membered ring as defined above, Rz is as defined above or Rz represents an additional saturated 4-6 membered ring fused to the ring represented by Rx and Ry taken together, optionally interrupted by O, S, NRW or -C(O)-, said rings being unsubstituted or substituted with one to four Ri groups
comprising reacting a compound of formula 4':
4'
with a compound of formula 9:
wherein R, P and P* are as previously defined, PΛ represents a protecting group or hydrogen and L represents a leaving group, in the presence of a catalyst and metal halide, contacting the mixture with a base and triflating agent and reacting the resulting solution with a palladium catalyst in the presence of a ligand to produce a compound of formula 6.
16. A process according to claim 15 wherein the rhodium catalyst is selected from rhodium octanoate and rhodium acetate, the metal halide is selected from zinc bromide, and zinc chloride, the base is selected from diisopropyl amine, t-butyl amine,
2,2,6,6,tetramethylpiperidine, methylamine, hexylamine, ethylamine, triethylamine, diisopropylethylamine, trimethylamine, ethyldimethylamine, tri-n-propylamine, l,8-diazabicyclo[5.4.0]undec-7- ene (DBU), pyridine, imidazole, lutidine, collidine, 4-
dimethylaminomethyl-pyridine, N,N,N',N'-tetramethylethylenediamine (TMEDA) and N-methylmorpholine (NMM), the triflating agent is trifluoromethanesulfonic anhydride, the palladium catalyst is selected from Pd(OAc)2, Pd(PPh3)4 PdCl2, PdCl2(PPh3)2, PdCl2(CH3CN)2, Pd2(dba)3, Pd2(dba)3CHCl3, and Pd(dba)2„ and the ligand is selected from triphenyl phosphine, tris-2-furyl phosphine, and triphenyl arsine.
17. A compound represented by one of the following formulas:
wherein R3 is Cl, Br or I;
wherein X represents O or NH and Y represents H or a protecting group, or X and Y taken in combination represent a ring system containing from 0-3 nitrogen atoms and 0-2 heteroatoms selected from O, S, S(O) and S(O)2, said ring system having 1-4 rings, with from 5-16 atoms, said system being non-aromatic, partially aromatic or aromatic, and being unsubstituted or substituted with from 1-3 groups selected from halo, OH, OP, wherein P is a protecting group, Cl-6 alkyl and Cl-6 alkyl substituted with from 1-3 of halo, OH, OP, NH2, NHC1 alkyl and N(CM alkyl)2
wherein each R1 represents H, halo, OH, OP wherein P is a protecting group, -Cl-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Rd groups; and -C3_7 cycloalkyl, unsubstituted or substituted with one to four Rd groups; each Rd independently represents halo; OP, wherein P is a protecting group, -CN; -N02; -NReRf; -ORg; -SRg; -CONReRf; -COORg; - SORg; -SO2Rg; -SO2NReRf; -NReSO2Rf; -CORe; -NRe CORf; -OCORe; - OCONReRf; -NReCONRfRg; -NReC02Rh; -OCO2Rh; -C(NRe)NRfRg; - NReC(NH)NRfRg; -NReC(NRf)Rg; -R* or -Q;
Re, Rf and Rg represent hydrogen; -R*; -Cl-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four Ri groups; or Re and Rf taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, -C(O)- or NRg with Rg as defined above, said ring being unsubstituted or substituted with one to four Ri groups;
each Ri independently represents halo; -CN; -Nθ2; phenyl; -NHSθ2Rh; -ORh, -SRh; -N(Rh)2; -N+(Rh)3; -C(0)N(Rh)2; - SO2N(Rh)2; heteroaryl; heteroarylium; -CO2Rh; -C(0)Rh; -OCORh; - NHCORh; guanidinyl; carbamimidoyl or ureido;
each BP independently represents hydrogen, a -Cl-6 straight or branched-chain alkyl group, a -C3-C6 cycloalkyl group or phenyl, or when two BP groups are present, said Rn groups may be
taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, -C(O)-, NH and NCH3;
Q is selected from the group consisting of:
L" is a pharmaceutically acceptable counterion; represents O, S or NRS; β, δ, λ, μ and σ represent CRt, N or N+Rs, provided that no more than one of β, δ, λ, μ and σ is N+Rs;
R* is selected from the group consisting of:
Rk represents hydrogen; -Cl-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; or - (CH )nQ where n = 1, 2 or 3 and Q is as previously defined;
each Rm independently represents a member selected from the group consisting of: hydrogen; halo; -CN; -N02; -NRnR°; -ORn; - SRn; -CONRnR°; -COORh; _S0Rn; -S02Rn; -S02NRnR»; -NRnS02R°; - CORn; -NRnCORo; -OCORn; -OCONRnR°; -NRnC02Rh; -NRnCONRoRh; - OCO2Rh; -CNRnNRoRh; -NRnCNHNRoRh; -NRnC(NRo)Rh; -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one
to four R groups; -C3-7 cycloalkyl, unsubstituted or substituted with one to four Ri groups; and -(CH2)nQ where n and Q are as defined above;
Rn and R° represent hydrogen, phenyl; -Cl-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four R groups;
each Rs independently represents hydrogen; phenyl or -Cl-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups;
each R independently represents hydrogen; halo; phenyl; - CN; -NO2; -NRURV; -OR"; -SRU; -CONRuRv; -COORh; -SORu; -SO2Ru; - SO2NRuRv; -NRuSO2Rv; -CORu; -NRuCORv; -OCORu; -OCONRuRv; - NRuCO2Rv; -NRuCONRvRw; -OCO2Rv; -Cl-6 straight- or branched- chain alkyl, unsubstituted or substituted with one to four Ri groups;
Ru and Rv represent hydrogen or -Cl-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; or Ru and Rv together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NRW or -C(O)~, said ring being unsubstituted or substituted with one to four Ri groups;
each Rw independently represents hydrogen; -Cl-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; C3-6 cycloalkyl optionally substituted with one to four R1 groups; phenyl optionally substituted with one to four R1 groups, or heteroaryl optionally substituted with 1-4 R1 groups; or BP and Rw taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, NH or NCH3;
Rx represents hydrogen or a Ci-8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, SO2, NRW,
N+R"RW, or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, NO2, ORw, SRW, SOR , SO2Rw, NRhRw, N+(Rh)2Rw, -C(O)-Rw, C(O)NRhR , Sθ2NRhRw, Cθ2Rw, OC(O)Rw, OC(O)NRhRW, NRhC(O)Rw, NRhC(O)NRhRw, or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R1 groups or with one to two Cl-3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R1 groups;
Ry and Rz represent hydrogen; phenyl; -Cl-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R1 groups, and optionally interrupted by O, S, NRW, N+R^Rw or -C(O)-;
or Rx and RJ together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, SO2, NRW
, N+R^RW or -C(O)-, unsubstituted or substituted with 1 - 4 R* groups, and when Rx and RJ together represent a 4-6 membered ring as defined above, Rz is as defined above or Rz represents an additional saturated 4-6 membered ring fused to the ring represented by Rx and RJ taken together, optionally interrupted by O, S, NRW or -C(O)-, said rings being unsubstituted or substituted with one to four Ri groups.
18. A compound having the following structure:
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU96813/98A AU737447B2 (en) | 1997-10-07 | 1998-10-02 | Process for the synthesis of carbapenem intermediates, and compounds produced |
| EP98950888A EP1023271A4 (en) | 1997-10-07 | 1998-10-02 | Process for the synthesis of carbapenem intermediates, and compounds produced |
| JP2000514889A JP2001519332A (en) | 1997-10-07 | 1998-10-02 | Method for synthesizing carbapenem intermediate and compound produced |
| CA002305404A CA2305404A1 (en) | 1997-10-07 | 1998-10-02 | Process for the synthesis of carbapenem intermediates, and compounds produced |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US6123397P | 1997-10-07 | 1997-10-07 | |
| US60/061,233 | 1997-10-07 | ||
| GB9806031.2 | 1998-03-20 | ||
| GBGB9806031.2A GB9806031D0 (en) | 1998-03-20 | 1998-03-20 | Process for the synthesis of carbapenem intermediates, and compounds produced |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1999018078A1 true WO1999018078A1 (en) | 1999-04-15 |
Family
ID=26313326
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1998/020830 WO1999018078A1 (en) | 1997-10-07 | 1998-10-02 | Process for the synthesis of carbapenem intermediates, and compounds produced |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1023271A4 (en) |
| JP (1) | JP2001519332A (en) |
| AU (1) | AU737447B2 (en) |
| CA (1) | CA2305404A1 (en) |
| WO (1) | WO1999018078A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000015644A1 (en) * | 1998-09-15 | 2000-03-23 | Merck & Co., Inc. | Process for the synthesis of tin carbapenem intermediates |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4108990A (en) * | 1975-06-14 | 1978-08-22 | Schering Aktiengesellschaft | Method of killing bacteria and fungi |
-
1998
- 1998-10-02 CA CA002305404A patent/CA2305404A1/en not_active Abandoned
- 1998-10-02 AU AU96813/98A patent/AU737447B2/en not_active Ceased
- 1998-10-02 JP JP2000514889A patent/JP2001519332A/en not_active Withdrawn
- 1998-10-02 EP EP98950888A patent/EP1023271A4/en not_active Withdrawn
- 1998-10-02 WO PCT/US1998/020830 patent/WO1999018078A1/en not_active Application Discontinuation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4108990A (en) * | 1975-06-14 | 1978-08-22 | Schering Aktiengesellschaft | Method of killing bacteria and fungi |
Non-Patent Citations (5)
| Title |
|---|
| JURKSCHAT K., TZSCHACH A.: "1-AZA-5-STANNA-5,5-DIMETHYLBICYCLOÚ3.3.01.5¾OCTAN UND 1-AZA-5-STANNA-5-METHYLTRICYCLOÚ3.3.3.01.5¾ UNDECAN, PENTAKOORDINIERTE TETRAORGANOZINNVERBINDUNGEN.", JOURNAL OF ORGANOMETALLIC CHEMISTRY., ELSEVIER-SEQUOIA S.A. LAUSANNE., CH, vol. 272., 1 January 1984 (1984-01-01), CH, pages C13 - C16., XP002915399, ISSN: 0022-328X, DOI: 10.1016/0022-328X(84)80450-7 * |
| JURKSCHAT K., TZSCHACH A.: "CRYSTAL AND MOLECULAR STRUCTURE OF 1-AZA-5-STANNA-5-STANNA-5- CHLOROTRICYCLOÚ3.3.3.01.5 JUNDECANE, A 2,8,9-TRICARBASTANNATRANE.", JOURNAL OF ORGANOMETALLIC CHEMISTRY., ELSEVIER-SEQUOIA S.A. LAUSANNE., CH, vol. 290., no. 03., 6 August 1985 (1985-08-06), CH, pages 285 - 289., XP002915400, ISSN: 0022-328X, DOI: 10.1016/0022-328X(85)87291-0 * |
| KOLB U., ET AL.: "UNUSUAL HEXACOORDINATION IN A TRIORGANOTIN FLUORIDE SUPPORTED BY INTERMOLECULAR HYDROGEN BONDS. CRYSTAL AND MOLECULAR STRUCTURES OF 1-AZA-5-STANNA-5-HALOGENOTRICYCLOÚ3.3.3.01.5¾UNDECANES N (CH2CH2CH2)3SNF.H2O AND ((CH2CH2CH2)3SNX (X=CL,BR,I)", ORGANOMETALLICS, AMERICAN CHEMICAL SOCIETY, US, vol. 14., no. 06., 1 June 1995 (1995-06-01), US, pages 2827 - 2834., XP002915402, ISSN: 0276-7333, DOI: 10.1021/om00006a031 * |
| See also references of EP1023271A4 * |
| VEDEJA E., HAIGHT A. R., MOSS W. O.: "INTERNAL COORDINATION AT TIN PROMOTES SELECTIVE ALKYL TRANSFER IN THE STILLE COUPLING REACTION.", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, US, vol. 114., no. 16., 29 July 1992 (1992-07-29), US, pages 6556 - 6558., XP002915401, ISSN: 0002-7863, DOI: 10.1021/ja00042a044 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000015644A1 (en) * | 1998-09-15 | 2000-03-23 | Merck & Co., Inc. | Process for the synthesis of tin carbapenem intermediates |
Also Published As
| Publication number | Publication date |
|---|---|
| AU9681398A (en) | 1999-04-27 |
| CA2305404A1 (en) | 1999-04-15 |
| EP1023271A4 (en) | 2001-09-12 |
| AU737447B2 (en) | 2001-08-23 |
| JP2001519332A (en) | 2001-10-23 |
| EP1023271A1 (en) | 2000-08-02 |
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