CN1066438C - β-甲基碳代青霉烯中间体的制备 - Google Patents
β-甲基碳代青霉烯中间体的制备 Download PDFInfo
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- CN1066438C CN1066438C CN93119208A CN93119208A CN1066438C CN 1066438 C CN1066438 C CN 1066438C CN 93119208 A CN93119208 A CN 93119208A CN 93119208 A CN93119208 A CN 93119208A CN 1066438 C CN1066438 C CN 1066438C
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- 238000002360 preparation method Methods 0.000 title claims description 12
- 239000000543 intermediate Substances 0.000 title abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 20
- -1 methylmalonic acid ester Chemical class 0.000 claims abstract description 20
- 230000000269 nucleophilic effect Effects 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims description 22
- 239000003513 alkali Substances 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 239000012434 nucleophilic reagent Substances 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 229910001508 alkali metal halide Inorganic materials 0.000 claims description 5
- 150000008045 alkali metal halides Chemical class 0.000 claims description 5
- 239000003759 ester based solvent Substances 0.000 claims description 5
- 239000004210 ether based solvent Substances 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000000203 mixture Substances 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 230000032683 aging Effects 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 230000000707 stereoselective effect Effects 0.000 description 4
- OEYMQQDJCUHKQS-UHFFFAOYSA-N (4-oxoazetidin-2-yl) acetate Chemical compound CC(=O)OC1CC(=O)N1 OEYMQQDJCUHKQS-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 3
- 125000005103 alkyl silyl group Chemical group 0.000 description 3
- 235000010290 biphenyl Nutrition 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229910000077 silane Inorganic materials 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- YKMONJZIUAOVEM-WDSKDSINSA-N 1beta-methylcarbapenem Chemical compound C[C@H]1C=CN2C(=O)C[C@@H]12 YKMONJZIUAOVEM-WDSKDSINSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-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
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 2
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical group CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- IEOPZUMPHCZMCS-UHFFFAOYSA-N 2-(methoxymethyl)oxolane Chemical compound COCC1CCCO1 IEOPZUMPHCZMCS-UHFFFAOYSA-N 0.000 description 1
- PNWSHHILERSSLF-UHFFFAOYSA-N 4-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=CC=C(C(O)=O)C=C1C(O)=O PNWSHHILERSSLF-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- XEUVUNROHNLQED-UHFFFAOYSA-N C(CCC)Cl[SiH](C)C Chemical compound C(CCC)Cl[SiH](C)C XEUVUNROHNLQED-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- AQZGPSLYZOOYQP-UHFFFAOYSA-N Diisoamyl ether Chemical compound CC(C)CCOCCC(C)C AQZGPSLYZOOYQP-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000005466 alkylenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229940035429 isobutyl alcohol Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- HVZWVEKIQMJYIK-UHFFFAOYSA-N nitryl chloride Chemical compound [O-][N+](Cl)=O HVZWVEKIQMJYIK-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
- 239000008259 solid foam Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000003527 tetrahydropyrans Chemical class 0.000 description 1
- 125000005323 thioketone group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明是关于从式Ⅰ化合物制备式Ⅵ的β-甲基碳代青霉烯中间体的方法
其中R和P′是保护基，R1是甲基丙二酸酯，而Nu是亲核基团。这里也公开了中间体的制备方法。
Description
此公开的发明涉及制备1-β-甲基碳代青霉烯的方法。我们已知1-β-甲基碳代青霉烯抗菌素可治疗广谱革兰氏阴性和革兰氏阳性菌的感染。参见如1990年10月9日授权的U.S.4962103；1990年6月12日授权的U.S.4933333；1990年7月24日授权的的U.S.4943569；1992年6月16日授权的U.S.5122604；1991年7月23日授权的U.S.5034384(256)和1991年4月30日授权的U.S.5011832。
文献中已经引述了许多合成式Ⅵ的β-甲基碳代青霉烯中间体的路线：
Tetrahedron Letters,Vol.26,No.39,pp4739-4742,1985；J,Am.Chem,Soc,1986,108,4673-4675；Tetrahedron Letters,Vol.27,No.19,pp2149-2152,1986；Tetrahedron Letters.Vol.27,No.51,pp 6241-6244,1986；Can.J.Chem 65,2140(1987)；J.Org.Chem.1987,52,3174-3176；J.Org.Chem.1987,52,2563-2567；J.Org.Chem.1987,52,5491-5492；Tetrahedron Letters,Vol.28,No.1,pp83-86,1987；Tetrahedron Letters,Vol.28,No.5,pp507-510,1987；Tetrahedron Letters,Vol.28,No.17,pp 1857-1860,1987；Tetrahedron Letters,Vol.28,No.52,pp 6625-6628,1987；Can.J.Chem.66,1400(1988)；Can.J.Chem,Vol.66,(1988)；J.Chem.Soc.,Chem.Commun.,1988；J.Org.Chem.1988,53,2131-2132；J,Org.Chem.1988,53,4154-4156；Tetrahedron Vol.44,No.8,pp 2149 to 2165,1988；Tetrahedron Letters,Vol.29,No.1,pp 61-64,1988；Tetrahedron Letters,Vol.29,No.49,pp 6461-6464,1988；Tetrahedron Letters,Vol.29,No.48,pp6345-6348,1988；Chemistry Letters,pp 445-448,1989；J.Chem.Soc.Perkin Trans.I 1989；J.Org.Chem.1989,54.2103-2112；Tetrahedron Letters,Vol.30,No.1 pp 113-116,1989；Tetrahedron Letters,Vol.31,No.2,pp 271-274,1990；Tetrahedron Letters,Vol.31,No.4,pp 549-552,1990；Chem.Pharm.Bull,39(9)2225-2232(1991)；Tetrahedron Vol.47,No.16/17,pp2801-2820,1991；Tetrahedron：Asymmetry Vol.2,No.4,pp 255-256,1991；Tetrahedron Letters,Vol.32,No.19,pp 2143-2144,1991；J.Org.Chem.1992,57,2411-2418；Tetrahedron Vol.48, No.1,pp 55-66,1992；
前面关于立体有择性制备β-甲基碳代青霉烯的方法包括：
(1)将4-(2-丙烯基)取代的氮杂环丁酮氢化。
(2)将烯醇盐离子进行立体有择质子化。
(3)将4-乙酰氧基氮杂环丁酮与手性烯醇盐进行反应。
这些方法需要中间体(1)和/或试剂(3)困难的多步制备，高反应活性中间体在低温下的繁琐操作(2)，或者使用昂贵的试剂(2,3)。
这里公开的本发明提供了从容易得到的起始物质用四个步骤合成具有很高立体选择性的β-甲基中间体(Ⅵ，反应路线1)的通用途径。其中R和P′是保护基，R1是甲基丙二酸酯，而Nu是亲核基团。这里也公开了一些过程中间体。
本发明提供了一种制备式Ⅵ碳代青霉烯中间体的方法：其中
R是(a)氢，
(b)甲基，或
(c)羟基保护基
P′是氮保护基
Nu是亲核基团；该方法包括：将式Ⅴ化合物
在酯或醚溶剂中与弱酸接触得到式Ⅵ化合物，
本发明还提供了一种制备式Ⅵ碳代青霉烯中间体的方法，进一步包括：(c)将式Ⅳ化合物
在非反应活性溶剂或C1-5链烷醇溶剂中与碱和亲核剂接触，酸化后得到式Ⅴ化合物
本发明进一步提供了一种制备式Ⅵ碳代青霉烯中间体的方法，进一步包括：
将式Ⅲ化合物在非质子传递溶剂中与清除碱，碱金属卤化物和三有机基卤硅烷接触，得到式Ⅳ化合物
在一个实施方案中，本发明涉及制备式Ⅵ的β-甲基碳代青霉烯中间体的方法其中
R是(a)氢，
(b)甲基，或者
(c)羟基保护基，如三有机基甲硅烷基，包括三-C1-4烷基甲硅烷基，苯基二-C1-4烷基甲硅烷基和二苯基单C1-4烷基甲硅烷氧基，包括叔丁基二甲基甲硅烷基；以及异丙基二甲基甲硅烷基，以及
P′是氮保护基，如三有机基甲硅烷基，包括三-C1-4烷基甲硅烷基；苯基二C1-4烷基甲硅烷基和二苯基单C1-4烷基甲硅烷基，包括叔丁基二甲基甲硅烷基：以及异丙基二甲基甲硅烷基；
该方法包括：
(a)将式Ⅰ化合物
R1是(a)-O-(CO)-R″，其中R″包括C1-6烷基、烯丙基和取代的苯基，其中的取代基是氢，C1-3烷基，卤素，硝基，氰基或C1-3烷氧基，
(b)-S(O)n-R2，其中n是1或2，而R2是芳基如苯基，联苯基，萘基，所说的芳基未被取代或被如卤素如氯或溴，或C1-4烷基所取代，
(c)卤素，包括Cl和Br在非反应活性溶剂中与2,2,5-三甲基-1,3-二噁烷-4,6-二酮和碱接触得到式Ⅲ化合物：
为了达到本说明书的目的，R和P′中的保护基包括但并不限于如上面定义的三有机基甲硅烷基；合适的替代物引述在ProtectingGroups In Organic Synthesis，Theodora W Green，John Wiley和Sohs 1981中，
为了达到本说明书的目的，非反应活性溶剂被定义为包括许多不反应的加溶剂，包括芳族溶剂如苯，甲苯和二甲苯；醚类溶剂，包括乙醚，二正丁基和二异戊基醚，茴香醚，环醚，如四氢吡喃，4-甲基-1,3-二噁烷，二氢吡喃，四氢化糠基甲基醚，乙基醚，呋喃，2-乙氧基四氢呋喃和四氢呋喃(THF)；酯溶剂包括乙酸乙酯和异丙酯；卤代碳溶剂，包括单或二卤代C1-4烷基；醇类，包括C1-5链烷醇；和C5-10直链，支链或环状烃溶剂，包括己烷和甲苯；以及含氮溶剂，包括N,N-二甲基乙酰胺，N,N-二甲基甲酰胺和乙腈。
为了达到本说明书的目的，碱包括碳酸盐，包括碱性碳酸盐如K2CO3和C1-4烷基叔胺，包括三乙胺。
式Ⅰ化合物与甲基Meldrum氏酸的摩尔比应为约1∶1或更大。式Ⅰ化合物与碱的摩尔比应为约0.8-1.2∶1。反应可以在约0至60℃，优选40至50℃下进行。允许反应在1分钟至20小时内，典型地为14小时内进行直至基本上完成。
(b)将式Ⅲ化合物在非质子传递溶剂中与清除碱，碱金属卤化物和三有机基卤硅烷接触得到式Ⅳ化合物
为了达到本说明书目的，非质子传递溶剂包括N,N-二C1-6烷基羰酰胺如N,N-二甲基甲酰胺(DMF)，甲苯，四氢呋喃和二氯甲烷。清除碱包括吡咯，吡啶，吡咯烷，N,N-二C1-3烷基氨基吡啶如N,N-二甲基氨基吡啶，三-C1-4烷基胺如三乙胺和咪唑。碱金属卤化物可包括钠，钾或锂作金属，碘，溴或氯作卤素。三-有机基卤硅烷包括三C1-4烷基卤硅烷，如丁基二甲基甲硅烷基氯；苯基二C1-4烷基卤硅烷和二苯基C1-4烷基卤硅烷，其中的卤包括氯，溴和碘。式Ⅲ化合物与硅烷的比应为约1∶1或更少。硅烷与清除碱的摩尔比应为约1∶1或更少。硅烷与卤化物的比应为约1∶1或更少。
反应在0至70℃下进行2-72小时直至基本完成。
(C)将式Ⅳ化合物在非反应活性溶剂或C1-5链烷醇中与碱和式NuX的亲核剂接触，酸化后得到式Ⅴ化合物
非反应活性溶剂如上定义。
为了达到本说明书的目的，C1-6链烷醇应包括甲基，乙基，丙基，异丙基，丁基和异丁基醇。碱应包括碱金属氢氧化物，如钾，锂或钠氢氧化物并应包括碱金属碳酸盐，如钠或钾的碳酸盐。酸化可以用任何合适的酸来完成，如无机酸包括HCl，H2SO4或有机酸如乙酸或甲酸。
式Ⅳ与碱的比应为约1∶1或更少，并可用约1至2份酸来酸化。
式Ⅳ与亲核剂的比应为约1∶1或更大。反应允许在-20至25℃下进行10至100分钟直至基本完成。
正如本领域技术人员所知道的，所选择的特殊亲核剂并不是此公开发明的一个必要方面。可以选择大量亲核剂中的任何一个。例如，NuX包括醇，硫醇和烯醇的碱金属盐。因此，X包括Na，K，Li和Cs。相应地，Nu包括R2O-，其中R2是氢，C1-6烷基和取代的C1-6烷基及苯基；
此外，特别考虑到R2S-，R2包括碳代青霉烯2位上的取代基，如在可以买到的或其它活性碳代青霉烯抗菌素中存在的。
因此，在一个芳面，申请入预期了其化合物的用途和制备方法，如在下面所示的反应路线1和2中所说明的。
如反应路线1所示，将化合物a进行立体有择的脱羧反应得到化合物b。然后，按本领域已知的方法将化合物b转化为活性抗菌素。参见Shih,D.H.等，Heterocycles 1984,21,79。相似地，如反应路线2所示，将化合物a进行立体有择脱羧反应得到硫酮b′，将其按本领域已知的方法转化为活性抗菌素。参见Greenlee等，Heterocycles 1989,28,195及其中的参考文献。
反应路线1
因此，为了达到本说明书的目的，Nu包括，但不限于CH2CO2t-Bu，含有硫或氧的基团-SR2和-OR2，其中R2选自氢；具有1至10个碳原子的直链和支链低级烷基；具有2至10个碳原子的链烯基，炔基；具有3至6个碳原子的环烷基；其中环烷基部分含3至6个碳原子并且烷基部分含1至10个碳原子的环烷基烷基；其中烷基部分含1至6个碳原子并且环烷基部分含3至6个碳原子的烷基环烷基；芳基如苯基和萘基；芳烷基如苄基、苯乙基等；含有单和双环结构，具有5到10个环原子并且其中一个或多个杂原子选自氧，氮或硫的杂环基(饱和和不饱和的)，如噻吩，咪唑基，四唑基，呋喃基等；含有上述杂环基部分且烷基部分含有1至10个碳原子的杂环基烷基；与上文定义的基团有关的一个或多个取代基选自氨基，羟基，氰基，羧基，硝基，氯，溴，氟，具有1至6个碳原子的低级烷氧基，巯基，全卤代低级烷基如三氟甲基，低级烷硫基，胍基，脒基，氨磺酰基和N-取代的氨磺酰基，脒基和胍基，其中N-取代基是具有1至6个碳原子的低级烷基或具有6至10个碳原子的芳基。
为了加以说明，芳基包括但不限于R2，如在1990年10月9日授权的U.S.4962103中的定义，其中的-SR2定义为
及在U.S.4933333,U.S.4943569和U.S.5122604中的定义，其中的-SR2定义为
在1989年9月12日授权的U.S.4866171中的定义，其中的-SR2定义为在1991年7月23日授权的U.S.5034384中的定义，其中R2是并且在1991年4月30日授权的U.S.5011832中的定义，其中的R2是上述所有文献在此作为参考文献被引用。这些芳基上特有的取代基可由上面参考文献中公开的下列种类基团来说明。(d)将式Ⅴ化合物在酯或醚溶剂中与弱酸接触得到式Ⅵ化合物
为了达到本说明的目的，酯溶剂包括乙酸乙酯和异丙酯，而醚溶剂如上文所定义，包括甲基叔丁基醚。弱酸包括乙酸和甲酸。式Ⅴ化合物与酸的摩尔比应为1∶1或更大。反应可以在10至150℃下进行10至120分钟基本完成。
在第二个实施方案中，本发明涉及式Ⅲ，Ⅳ和Ⅴ的中间体化合物。
本发明在路线3和后面的实施例中进一步加以说明。
将4-乙酰氧基氮杂环丁酮l(路线3)与甲基Meldrum氏酸，Ⅱ(2,2,5-三甲基-1,3-二噁烷-4,6-二酮)进行反应得到β-内酰胺Ⅲ。用叔丁基二甲基甲硅烷基氯化物/三乙胺/碘化钠将Ⅲ甲硅烷基化得到N-甲硅烷基化的加合物Ⅳ。将Ⅳ与亲核剂反应得到羧酸衍生物Ⅴ，将其进行立体有择的脱羧反应得到β-甲基氮杂环丁酮Ⅵ，它即为β-甲基碳代青霉烯抗菌素的前体。中间体Ⅵ的使用在上面反应路线1和2中有所说明。反应路线3
实施例1Meldrum氏酸加合物Ⅲ的制备
将2,2,5-三甲基-1,3-二噁烷-4,6-二酮Ⅱ(17.4g,110mmol)，4-乙酰氧基氮杂环丁酮Ⅰ(28.7g,100mmol)和K2CO3(15.2g,110mmol)在无水乙腈(150ml,KF=5.6mg/ml)中混合并将混合物在45-50℃下老化14小时。完成后，将反应混合物冷至室温并加入水(150ml)。分出有机层并将水层用乙腈(100ml)反萃取。将合并的有机萃取液用盐水(100ml)洗涤并浓缩到约50ml。然后将混合物用庚烷(200ml)稀释并浓缩到50ml。再加入庚烷(150ml)并将混合物在室温下老化结晶。将所得产物过滤收集，用庚烷(50ml)洗涤并在40-50℃及真空下干燥15小时得到灰白色结晶固体(30.9g,80.2mmol)，将合并的滤液浓缩并洗涤至约50ml，并在室温下老化又得到白色松散固体(2.07g,5.4mmol)。两次的总产率为85.6％。熔程(℃)78-83d。1H NMR(in CDCl3)6.19(1H,宽,NH),4.20(1H,dq,J=3.7＆6.4Hz),4.15(1H,d,J=2.1Hz),3.54(1H,dd,J=2.1＆3.7Hz),1.77(3H,s,CH3),1.73(3H,s,CH3),1.62(3H,s,CH3),1.17(3H,d,J=6.4Hz),0.85(9H,s,Si-t-Bu),0.06＆0.05(6H,2 s,2 Si-CH3)；13C NMR(CDCl3)168.91,168.51,167.72,105.47,64.70,61.22,55.63,50.99,30.04，28.28,25.78,22.82,18.60,17.95,-4.32,-4.94。
实施例2Ⅳ的制备
将氮杂环丁酮Ⅲ(7.7g,20mmol)溶解在二甲基甲酰胺(100ml,KF=10mg/ml)中，并依次加入NaI(6.6g,44mmol)，三乙胺(8.4ml,60mmol)和N,N-二甲基氨基吡啶(0.25g,2mmol)。将混合物搅拌5分钟并一次加入叔丁基二甲基甲硅烷基氯化物(6.6g,44mmol)。将混合物在室温下搅拌48小时并在50-60℃搅拌15小时。完成后，将反应混合物冷却至室温并加入水(100ml)。将混合物用己烷萃取(100ml×2)。将合并的萃取液用1N HCl水溶液(100ml)和水(100ml)洗涤并浓缩至干。将所得油状剩余物溶于2-丙醇(40ml)中并滴加水(40ml)。加入晶种并继续滴加水(40ml)，在室温下老化以结晶。将所得产物过滤收集并在真空及40-50℃下干燥15小时得到浅橙色结晶固体(8.4g,16.8mmol)。产率为84.1％。熔程(℃)73-73d。1H NMR(in CDCl3)4.32(1H,d,J=2.2Hz),3.96(1H,dq,J=5.9＆9.4Hz),3.66(1H,dd,J=2.2＆9.4Hz),1.79(6H,s,2CH3),1.71(3H,s,CH3),1.34(3H,d,J=5.9Hz),0.95＆0.91(18H,2 s,2Si-t-Bu),0.25,0.14,0.12＆0.11(12H,4 s,4 Si-CH3)；13C NMR(CDCl3)173.72,168.56,167.44,105.43,68.39,63.13,60.92,50.45,29.80,28.09,26.67,25.95,23.61,23.03,19.06,18.02,-4.09,-4.38,-4.76,-4.90.
实施例3甲硅烷基化加合物Ⅳ的水解
将加合物Ⅳ(2.5g,5mmol)溶解在THF(10ml)中并将溶液冷至0℃。滴加1N NaOH水溶液(10ml,10mmol)同时将内部温度保持在5℃以下。将混合物在0℃下老化1小时并再滴加NaOH溶液(2ml,2mmol)加完后，将混合物用甲酸(1.1ml,30mmol)酸化并用乙酸乙酯(40ml)萃取。该溶液用于下一步。通过浓缩溶剂可分离出二酸。然后将所得固体从甲醇/水混合物中结晶。熔程(℃)97-99d。1H NMR(in CDCl3)4.39(1H,s),4.07(1H,q,J=6.5Hz),3.29(1H,d,J=6.2Hz),1.28(3H,d,J=7.6Hz),0.95＆0.90(18H,2 s,2 Si-t-Bu),0.28,0.14＆0.11(12H,3 s,4 Si-CH3)；13C NMR(CD3OD)176.79,173.78,67.94,62.15,57.81,27.21,26.59,22.31,20.14,19.01,17.71,-3.77,-4.46.
实施例4甲硅烷基化的加合物Ⅳ的甲醇醇解
将加合物Ⅳ(1.50g,3mmol)溶解在甲醇(20ml)中并将该溶液冷至0℃。分3批加入K2CO3(0.86g,6.2mmol)并将混合物在室温下老化1小时。完成后，将混合物先后用水(10ml)和HCl水溶液(10ml,1N)淬熄并用乙酸乙酯(20ml)萃取。将有机层用水(20ml)洗涤并浓缩至干得到白色泡沫状物(1.18g,2.5mmol)，产率80％。将泡沫状物进一步通过从甲醇/水混合物中结晶来纯化得到白色结晶固体。熔程(℃)125-135d。1H NMR(in CDCl3)8.5(1H,宽,CO2H),4.34(1H,d,J=2.4Hz),4.09(1H,q,J=6.4Hz),3.76(3H,s,OCH3),3.11(1H,dd,J=2.4＆6.8Hz),1.50(3H,s,CH3),1.22(3H,d,J=6.2Hz),0.96＆0.89(18H,2 s,2 Si-t-Bu),0.29,0.12,0.09＆0.08(12H,3 s,4 Si-CH3)；13C NMR(CDCl3)174.57,174.20,171.26,67.37,61.33,56.88,56.54,53.05,26.54,26.02,22.52,19.32,18.34,18.12,-3.99,-4.43,-4.60,-4.74.
实施例5二酸Ⅴ的脱羧反应
将从碱水解步骤中得到的在乙酸乙酯中的二酸与续加的甲酸(1.10ml,30mmol)回流2小时。等分试样分析表明为95∶5的β∶α甲基产物Ⅳ的混合物。将混合物冷至室温并浓缩得到油状物。将所得油状物溶解在NaOH水溶液(1N,10ml,10mmol)中并在室温下老化2小时。将溶液用HCl水溶液(1N,15ml,15mmol)酸化并用乙酸乙酯(30ml)萃取。将萃取物用水洗涤并浓缩至体积约5ml。向其中加入己烷(60ml)并在室温下老化。将白色结晶固体过滤收集，然后用己烷(10ml)洗涤得到纯的β-甲基式Ⅶ(0.96g,3.18mmol)。从中间体Ⅳ得到的总产率为64％。熔程(℃)144-146d。
Claims (4)
1．一种制备式Ⅵ碳代青霉烯中间体的方法其中
R是(a)氢，
(b)甲基，或
(c)羟基保护基
P′是氮保护基
Nu是亲核基团；该方法包括：
将式Ⅴ化合物
其中R、P′和Nu定义同上在酯或醚溶剂中与弱酸接触得到式Ⅵ化合物，其中R、P′和Nu定义同上。
2．按照权利要求1的方法，进一步包括：
(c)将式Ⅳ化合物在非反应活性溶剂或C1-5链烷醇溶剂中与碱和亲核剂接触，酸化后得到式Ⅴ化合物
式Ⅳ和Ⅴ中R、P′和Nu定义同权利要求1
3．按照权利要求2的方法，进一步包括：将式Ⅲ化合物
在非质子传递溶剂中与清除碱，碱金属卤化物和三有机基卤硅烷接触，得到式Ⅳ化合物P′为三-有机基甲硅烷基，式Ⅲ和Ⅳ中R定义同权利要求1。
4．一种制备式Ⅵ的β-甲基碳代青霉烯中间体的方法其中
R是(a)氢，
(b)甲基，或
(c)羟基保护基；
P′是三-有机基甲硅烷基；
Nu是亲核基团；该方法包括：
(a)将式Ⅰ化合物
其中
R1是(a)-O-C(O)-R″，其中R″为C1-6烷基，烯丙基或取代的苯基，其中的取代基是氢，C1-3烷基，卤素，硝基，氰基或C1-3烷氧基，
(b)-S(O)n-R2，其中n是1或2，而R2是苯基，联苯基，萘基，它们未被取代或被卤素或C1-4烷基任意取代，
(c)卤素，
R的定义如上，在非反应活性溶剂中与2,2,5-三甲基-1,3-二噁烷-4,6-二酮和碱接触，得到式Ⅲ化合物：其中R的定义如上；
(b)将式Ⅲ化合物在非质子传递溶剂中与清除碱，碱金属卤化物和三有机基卤硅烷接触，得到式Ⅳ化合物：
其中R和P′的定义如上；
(c)将式Ⅳ化合物在非反应活性溶剂或C1-5链烷醇溶剂中与碱和亲核剂式NuX接触，酸化后得到式Ⅴ化合物：
其中Nu是亲核性基团，而X是离去基团，其中R、P′和Nu的定义如上，(d)将式Ⅴ化合物在酯或醚溶剂中与弱酸接触得到式Ⅵ化合物。
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| KR100335848B1 (ko) * | 2000-03-31 | 2002-05-08 | 윤재승 | 아제티디논 유도체, 그 제조방법 및 이를 이용한1-β-알킬아제티디논의 제조방법 |
| US6625203B2 (en) * | 2001-04-30 | 2003-09-23 | Interdigital Technology Corporation | Fast joint detection |
| EP1878829A1 (de) | 2006-07-12 | 2008-01-16 | Papierfabriken Cham-Tenero AG | Beschichtetes Trägerpapier |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4576747A (en) * | 1984-05-07 | 1986-03-18 | The Upjohn Company | Isocyanato-azetidinediones |
| US4801719A (en) * | 1984-10-04 | 1989-01-31 | Ciba-Geigy Corporation | Silanes, process for their preparation, and their use |
| US4960880A (en) * | 1987-09-22 | 1990-10-02 | Shionogi & Co., Ltd. | Alkenylsilylazetidinone intermediates for carbapenems |
| US4992545A (en) * | 1989-09-20 | 1991-02-12 | Eli Lilly And Company | Process for preparing 4-substituted azetidinones |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1982001705A1 (en) * | 1980-11-13 | 1982-05-27 | Takeda Chemical Industries Ltd | 4-substituted-2-oxoazetidine derivatives and process for their preparation |
| AU548727B2 (en) * | 1981-03-12 | 1986-01-02 | Gruppo Lepetit S.P.A. | Beta-lactam acetic acid derivatives |
| DE3879791T2 (de) | 1987-07-17 | 1993-10-14 | Merck & Co Inc | 4-Substituierte 3-Oxobutanoat-Esterderivate. |
| EP0546742B1 (en) * | 1991-12-09 | 2001-06-20 | Takasago International Corporation | 4-(1,1-Dialkoxycarbonyl-alkyl)azetidin-2-one derivatives and synthesis of 4-(1-carboxy-alkyl)azetidin-2-one derivatives therefrom |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4576747A (en) * | 1984-05-07 | 1986-03-18 | The Upjohn Company | Isocyanato-azetidinediones |
| US4801719A (en) * | 1984-10-04 | 1989-01-31 | Ciba-Geigy Corporation | Silanes, process for their preparation, and their use |
| US4960880A (en) * | 1987-09-22 | 1990-10-02 | Shionogi & Co., Ltd. | Alkenylsilylazetidinone intermediates for carbapenems |
| US4992545A (en) * | 1989-09-20 | 1991-02-12 | Eli Lilly And Company | Process for preparing 4-substituted azetidinones |
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