WO2005005446A1 - カルバペネム中間体の製造方法 - Google Patents
カルバペネム中間体の製造方法 Download PDFInfo
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- WO2005005446A1 WO2005005446A1 PCT/JP2004/010087 JP2004010087W WO2005005446A1 WO 2005005446 A1 WO2005005446 A1 WO 2005005446A1 JP 2004010087 W JP2004010087 W JP 2004010087W WO 2005005446 A1 WO2005005446 A1 WO 2005005446A1
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- 238000000034 method Methods 0.000 title claims abstract description 29
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 166
- -1 β-lactam compound Chemical class 0.000 claims abstract description 76
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 21
- 230000002140 halogenating effect Effects 0.000 claims abstract description 17
- 125000005843 halogen group Chemical group 0.000 claims abstract description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
- 229920000642 polymer Polymers 0.000 claims abstract description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 125000001424 substituent group Chemical group 0.000 claims description 60
- 238000004519 manufacturing process Methods 0.000 claims description 49
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 30
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 26
- 230000003115 biocidal effect Effects 0.000 claims description 22
- 239000002585 base Substances 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 229910052783 alkali metal Inorganic materials 0.000 claims description 12
- 229910052751 metal Inorganic materials 0.000 claims description 12
- 239000002184 metal Substances 0.000 claims description 12
- 229910052987 metal hydride Inorganic materials 0.000 claims description 12
- 150000004681 metal hydrides Chemical class 0.000 claims description 12
- 230000000844 anti-bacterial effect Effects 0.000 claims description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 10
- 150000007522 mineralic acids Chemical class 0.000 claims description 10
- 150000007524 organic acids Chemical class 0.000 claims description 10
- 230000003389 potentiating effect Effects 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 8
- 239000003377 acid catalyst Substances 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 150000001340 alkali metals Chemical class 0.000 claims description 7
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002841 Lewis acid Substances 0.000 claims description 6
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 6
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 150000007517 lewis acids Chemical class 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 5
- 229910021529 ammonia Inorganic materials 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- 150000001339 alkali metal compounds Chemical class 0.000 claims description 4
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 4
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 4
- 150000001341 alkaline earth metal compounds Chemical class 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 229910052802 copper Inorganic materials 0.000 claims description 4
- 239000010949 copper Substances 0.000 claims description 4
- 229910052742 iron Inorganic materials 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 229910052725 zinc Inorganic materials 0.000 claims description 4
- 239000011701 zinc Substances 0.000 claims description 4
- 150000004703 alkoxides Chemical class 0.000 claims description 3
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 claims description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 16
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 abstract description 11
- 239000003242 anti bacterial agent Substances 0.000 abstract description 3
- 229940088710 antibiotic agent Drugs 0.000 abstract description 3
- 125000000547 substituted alkyl group Chemical group 0.000 abstract description 2
- 125000003107 substituted aryl group Chemical group 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 70
- 239000002904 solvent Substances 0.000 description 49
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 24
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 17
- 239000012044 organic layer Substances 0.000 description 15
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- 125000001309 chloro group Chemical group Cl* 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 7
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 230000035484 reaction time Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000004104 aryloxy group Chemical group 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 6
- 125000006575 electron-withdrawing group Chemical group 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 6
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- JLTDJTHDQAWBAV-UHFFFAOYSA-N phenyldimethylamine Natural products CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- PMBXCGGQNSVESQ-UHFFFAOYSA-N 1-Hexanethiol Chemical compound CCCCCCS PMBXCGGQNSVESQ-UHFFFAOYSA-N 0.000 description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 4
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 4
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 239000004210 ether based solvent Substances 0.000 description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 4
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- 238000006228 Dieckmann condensation reaction Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 3
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 3
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 3
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 3
- 239000000538 analytical sample Substances 0.000 description 3
- 125000005129 aryl carbonyl group Chemical group 0.000 description 3
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 239000005453 ketone based solvent Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 3
- 150000003141 primary amines Chemical class 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 150000003335 secondary amines Chemical class 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- BDFAOUQQXJIZDG-UHFFFAOYSA-N 2-methylpropane-1-thiol Chemical compound CC(C)CS BDFAOUQQXJIZDG-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 2
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- 230000002378 acidificating effect Effects 0.000 description 2
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 2
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- 125000005110 aryl thio group Chemical group 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
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- 238000009835 boiling Methods 0.000 description 2
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- 239000012043 crude product Substances 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003759 ester based solvent Substances 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
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- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
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- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
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- 238000012790 confirmation Methods 0.000 description 1
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- 230000008025 crystallization Effects 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- CDHICTNQMQYRSM-UHFFFAOYSA-N di(propan-2-yl)alumane Chemical compound CC(C)[AlH]C(C)C CDHICTNQMQYRSM-UHFFFAOYSA-N 0.000 description 1
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- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- CATWEXRJGNBIJD-UHFFFAOYSA-N n-tert-butyl-2-methylpropan-2-amine Chemical compound CC(C)(C)NC(C)(C)C CATWEXRJGNBIJD-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- KPADFPAILITQBG-UHFFFAOYSA-N non-4-ene Chemical compound CCCCC=CCCC KPADFPAILITQBG-UHFFFAOYSA-N 0.000 description 1
- UZGLIIJVICEWHF-UHFFFAOYSA-N octogen Chemical group [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)CN([N+]([O-])=O)C1 UZGLIIJVICEWHF-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- JLXKKJMDDIHVAH-UHFFFAOYSA-N pentyl 2-oxoacetate Chemical compound CCCCCOC(=O)C=O JLXKKJMDDIHVAH-UHFFFAOYSA-N 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000003361 porogen Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229960003857 proglumide Drugs 0.000 description 1
- AHIHJODVQGBOND-UHFFFAOYSA-M propan-2-yl carbonate Chemical compound CC(C)OC([O-])=O AHIHJODVQGBOND-UHFFFAOYSA-M 0.000 description 1
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 1
- FFWJHVGUAKWTKW-UHFFFAOYSA-N pyridine-3-thiol Chemical compound SC1=CC=CN=C1 FFWJHVGUAKWTKW-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- WDPZTIFGRQKSEN-UHFFFAOYSA-N tert-butyl 2-oxoacetate Chemical compound CC(C)(C)OC(=O)C=O WDPZTIFGRQKSEN-UHFFFAOYSA-N 0.000 description 1
- XKXIQBVKMABYQJ-UHFFFAOYSA-M tert-butyl carbonate Chemical compound CC(C)(C)OC([O-])=O XKXIQBVKMABYQJ-UHFFFAOYSA-M 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- WMXCDAVJEZZYLT-UHFFFAOYSA-N tert-butylthiol Chemical compound CC(C)(C)S WMXCDAVJEZZYLT-UHFFFAOYSA-N 0.000 description 1
- 150000007970 thio esters Chemical group 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
-
- 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
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- 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
Definitions
- the present invention relates to a method for producing an intermediate for the production of a potent antibacterial antibiotic
- the compound represented by the following formula (4a) is useful as an intermediate in the production of antibacterial anti-lubadenem antibiotics.
- a compound represented by the following formula (1a) is prepared by dicyclohexylcarbodiimide, azidotriethylamine diphenylphosphate, N, N—
- a condensing agent such as carbonyldiimidazole
- R ′ represents a phenyl group which may have a substituent, an aralkyl group which may have a substituent, or a pyridyl group which may have a substituent.
- the ester moiety R 'of the compound represented by the formula (8a) be an easily removable electron-withdrawing group.
- Ra is a strong electron-withdrawing group
- the present invention has been made in view of the circumstances of the related art, and is intended to produce a 0-lactam compound represented by the following formula (4), which is an intermediate for producing a carpanem antibiotic, at low cost and in a high yield:
- the first task is to provide a method of manufacturing well.
- a second object of the present invention is to provide a method for producing a compound represented by the following formula (8) with high yield from a ⁇ -lactam compound represented by the following formula (4). Disclosure of the invention
- the present inventors have conducted intensive studies to solve the above problems, and as a result, reacted a compound represented by the following formula (1) with a halogenocarbonate in the presence of a base, and then reacted the thiol compound. As a result, the present inventors have found that a / 3-lactam compound represented by the following formula (4) can be produced at low cost and with good yield.
- R 4 represents an alkyl group which may have a substituent or an aryl group which may have a substituent.
- a method for producing a 3-lactam compound is provided.
- a base and a compound represented by the above formula (2) are added to a solution or a suspension of the compound represented by the above formula (1), and then a compound represented by the following formula (3) is added. It is preferable to add the compounds, but the order is not particularly limited.
- the R 1 is a compound represented by the formula (a): R a R b R c S i (where R a , R b, R c is preferably employed compounds wherein the group represented by each independently represent an alkyl group or Ariru group of carbon number 6-12 carbon number 1 ⁇ 20.), R 1 is, More preferably, a compound that is a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a t-butyldimethylsilyl group, or a t-butyldiphenylsilyl group is used.
- R 1 represents a protecting group for a hydroxyl group
- R 2 represents a hydrogen atom or a methyl group
- R 4 may have an alkyl group or a substituent which may have a substituent.
- R s represents.
- a good Ariru group optionally having an optionally substituted alkyl group or a substituted group is reacted with Dariokishiru acid esters or multimers thereof represented by , Equation (6)
- the j8-lactam compound represented by the formula (4) is converted to a dalioxylate represented by the formula (5) in the presence of an acid catalyst.
- the acid catalyst may be an inorganic acid, an organic acid, a salt of an organic acid, a salt of an inorganic acid, or a Lewis acid.
- R 5 may be an alkyl optionally substituted.
- the compound represented by the formula (6) is reacted with a halogenating agent in the presence of a base to form a compound represented by the formula (7).
- the step is to obtain a compound.
- the base may be ammonia, an organic base, an alkaline earth metal, an alkaline metal hydride, an alkaline earth metal hydride, an alkaline earth metal hydride, or an alkali metal.
- the step (3) includes:
- a step of reducing the compound represented by the above formula with a metal hydride a compound represented by the formula (1) is reacted with a compound represented by the formula (2) and a compound represented by the formula (3) in the presence of a base, A / 3-lactam compound represented by the above formula (4) is produced, and then reacted with a glyoxylate or a polymer thereof represented by the above formula (5) to give a compound represented by the above formula (6). And then reacting with a halogenating agent to obtain a compound represented by the formula (7), and then reducing the compound, thereby reducing the compound represented by the formula (8).
- a method for producing an intermediate for producing a substance is provided. BEST MODE FOR CARRYING OUT THE INVENTION
- the present invention is divided into 1) a method for producing a -3-lactam compound represented by the formula (4), and 2) a method for producing an intermediate for producing a potent rubanem antibiotic represented by the formula (8). Will be described in detail.
- a first aspect of the present invention is a method for producing a) 9-lactam compound represented by the formula (4), which comprises converting a compound represented by the formula (1) in the presence of a base, a compound represented by the formula (2), It is characterized by reacting a compound represented by the formula (3).
- compound (1) a compound represented by the above formula (1) (hereinafter abbreviated as “compound (1)”) is used as a starting material.
- R 1 represents a protecting group for a hydroxyl group.
- the hydroxyl-protecting group is not particularly limited as long as it is a group which is inactive in the reaction of the present invention. Since it is possible, a group represented by the formula (a): R a R b R c S i is preferable.
- R a , R b , and Rc each independently represent an alkyl group having 1 to 20 carbon atoms or an aryl group having 6 to 12 carbon atoms.
- Examples of the alkyl group having 1 to 20 carbon atoms of R a , R b , and R c include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, t-butyl, n-pentyl, neopentyl, n-hexyl, n
- R a R b R c S i include a trimethylsilyl group-.
- Examples include an enylsilyl group and a phenyldimethylsilyl group.
- a t-butyldimethylsilyl group which can be deprotected under mild conditions in a post-process for producing a carpanem antibiotic, is particularly preferred.
- R 2 represents a hydrogen atom or a methyl group.
- esters (2) Compound represented by formula (2)
- the compound represented by the formula (2) (hereinafter abbreviated as “esters (2)”) is a halogenocarbonate compound (or a halogenoformate compound).
- X represents an octogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Among them, a chlorine atom or a bromine atom is preferred, and a chlorine atom is particularly preferred.
- R 3 represents an alkyl group which may have a substituent or an aryl group which may have a substituent.
- Alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, n-hexyl And C3-C6 cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group.
- the substituent of the alkyl group is not particularly limited as long as it is a group inert to the reaction.
- a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom; a cyano group; a nitro group; an alkenyl group such as a pinyl group; an alkylcarbonyloxy group such as an acetate group; Carbonyl group; aryl group such as phenyl group; alkylsulfonyl group such as methylsulfonyl group; 7-reel sulfonyl group such as p-methylphenylsulfonyl group; alkylthio group such as methylthio group; And aryloxy groups such as methoxy and ethoxy groups; and aryloxy groups such as phenoxy groups.
- Reel group includes phenyl group. 1-Naphthyl group, 2-Naphthyl group, 2-Pyridyl group, 3-Pyridyl group, 4-Pyridyl group, 2-Vyrazyl group, 3-Vilazyl group, 2-Pyrimidyl group , 4-monopyrimidyl group, 2-furyl group, 3-furyl group and the like.
- the substituent on the aryl group is not particularly limited as long as it is an inert group for each reaction of the present invention.
- halogen atoms such as fluorine atom, chlorine atom, and bromine atom; cyano group; nitro group; methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isoptyl group, sec-butyl group, t Alkyl groups having 1 to 6 carbon atoms such as -butyl group, n-pentyl group and n-hexyl group; aryl groups such as phenyl group; alkenyl groups such as bier group; alkylthio groups such as methylthio group: phenylthio group Alkylcarbonyl groups such as acetoxy groups; arylcarbonyl groups such as benzoyloxy groups; alkoxy groups having 1 to 6 carbon atoms such as methoxy and ethoxy groups; phenoxy groups and the like Aryloxy group; and the like.
- the alkyl group and the aryl group may have a plurality of the same or different substituents at arbitrary positions.
- the compounds (2) include methyl chlorocarbonate, ethyl chlorocarbonate, and isopropyl chlorocarbonate because of their ease of availability and the ability to obtain the desired product in good yield.
- Preferred are alkyl ester carbonates such as t-butyl carbonate.
- the amount of the compound (2) used may be at least 1 mol of the compound (1), and from the viewpoint of productivity and economy, it is preferably 1.1 to 1.6 mol. .
- R 4 may be an alkyl group which may have a substituent or a substituent. Represents a good aryl group.
- alkyl group for R 4 examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, n-pentyl group, neopentyl group, Alkyl groups having 1 to 20 carbon atoms such as n-hexyl group and n-heptyl group; and 3 to 20 carbon atoms such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and cyclooctyl group.
- the substituent of the alkyl group is not particularly limited as long as it is an inert group for each reaction of the present invention.
- a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom
- a cyano group such as an acetoxy group and a propionyloxy group
- an arylcarbonyl group such as a benzoyloxy group
- Aryl groups such as phenyl, 1-naphthyl and 2-naphthyl
- alkylsulfonyl such as methylsulfonyl
- arylsulfonyl such as p-methylphenylsulfonyl
- alkenyl such as vinyl
- Alkylthio groups such as methylthio groups
- arylthio groups such as phenylthio groups
- Examples of the aryl group for R 4 include phenyl, 1-naphthyl, 21-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-virazyl, 3-pyrazyl, 2 —Pyrimidyl group, 4-pyrimidyl group, 2-furyl group, 3-furyl group and the like.
- the substituent of this aryl group is not particularly limited as long as it is a group inert to the reaction.
- a halogen atom such as a fluorine atom, a chlorine atom, and a bromine atom; a cyano group; a nitro group; a methyl group; an ethyl group; an n-propyl group; an isopropyl group; an n-butyl group; an isobutyl group; C1-C6 alkyl groups such as butyl group, n-pentyl group and n-hexyl group; aryl groups such as phenyl group, 1-naphthyl group and 2-naphthyl group; alkenyl groups such as vinyl group; methylthio group Alkylthio groups such as ethylthio group; arylthio groups such as phenylthio group; alkylcarbonyloxy groups such as acetyloxy group; arylcarbonyl groups such as benzoyloxy group; methoxy group, ethoxy group, is
- substituents may be substituted at any position of the alkyl group or aryl group, and a plurality of same or different groups may be bonded.
- Specific examples of compound (3) include methyl mercaptan, ethyl mercaptan, Compounds in which R 4 is an alkyl group, such as pill mercaptan, isopropyl mercaptan, butyl mercaptan, isobutyl mercaptan, t-butyl mercaptan, cyclopentyl mercaptan, and hexyl mercaptan; Mercaptan, benzyl mercaptan, 4-chlorobenzyl mercaptan, 2,4-dimethylbenzyl mercaptan, methoxymethyl mercaptan, 21-chloroethyl mercaptan, 2-cyanoethyl mercaptan, 4-chlorocyclo Compounds in which R 4 is an alkyl group
- the compound (3) in which R 4 is an aryl group which may have a substituent is preferred because it is easily available, inexpensive, and the desired product can be obtained in high yield.
- R 4 is more preferably a compound (3) in which R 4 is an aryl group substituted with an electron-withdrawing group such as an octylogen atom, a nitro group, or a cyano group, and R 4 is an aryl group substituted with a halogen atom.
- Certain compounds (3) are particularly preferred.
- the amount of the compound (3) to be used may be usually 1 mol or more with respect to the compound (1), and from the viewpoint of productivity and economy, it is 1.1 to 1.6 mol. Is preferred.
- alkali metal hydrides alkali metal hydrides, alkaline earth metal hydrides, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates At least one selected from the group consisting of an alkaline earth metal carbonate, an alkali metal alkoxide, an alkaline earth metal alkoxide, an organic alkali metal compound, an organic alkaline earth metal compound, an alkali metal and an alkaline earth metal.
- it is a seed.
- Examples of the organic base include amines, ananilines, and nitrogen-containing heterocyclic compounds.
- Examples of the amines include methylamine, ethylamine, ⁇ -propylamine, isopropyl pyramine, ⁇ -butylamine-.t-butylamine, and cyclopentylamine.
- primary amines such as cyclohexylamine, arylamine and benzylamine; dimethylamine, dimethylamine, di-n-propylamine, diisopropylamine, di-n-butylamine, di-t-butylamine, dicyclopentylamine, dicyclohexylamine.
- Secondary amines such as cyclohexylmethylamine, diarylamine and dibenzylamine; trimethylamine, triethylamine, diisopropylethylamine, tri-n-butylamine, phenyldimethylamine, benzyldimethamine.
- Tertiary Amin such as Amin; and the like.
- anilines include aniline, 2-methylaniline, N-methylaniline, N, N-dimethylaniline and the like.
- nitrogen-containing heterocyclic compounds examples include pyridine, 4-dimethylaminopyridine, corridin, ⁇ -picoline, j3-picoline, apicolin, imidazole, pyrazole, pyrimidine, morpholine, quinoline, 1,5-diazavisic mouth [ 4. 3. 03 1 5—Nonene (DBN), 1,4-Diazabicyclo [2.2.2] Octane (DAB CO), 1, 8—Diazapiciclo [5.4.0] — 7-Dendene (DBU) Diaza bicycloundecene and the like.
- Examples of the alkali metal hydride include sodium hydride
- examples of the alkaline earth metal hydride include calcium hydride.
- alkali metal hydroxide examples include sodium hydroxide and potassium hydroxide
- examples of the alkaline earth metal hydroxide include magnesium hydroxide and calcium hydroxide.
- alkali metal carbonate examples include sodium carbonate and potassium carbonate
- examples of the alkaline earth metal carbonate include magnesium carbonate and calcium carbonate.
- Alkali metal alkoxides include sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium t-butoxide, and the like.
- Alkali earth metal alkoxides include magnesium methoxide, Magnesium ethoxide and the like. Examples of the organic alkali metal compound, N a N (CH (CH 3) 2) 2, N a N (S), N a N (CH (CH 3) 2) 2, N a N (S)
- Examples of the organic alkaline earth metal compound include (n-Bu) 2 Mg.
- Examples of the alkali metal include Li, Na, and K, and examples of the alkaline earth metal include Mg and Ca.
- the amount of the base to be used may be generally 1 mol or more with respect to the compound (1), and from the viewpoint of productivity and economy, it is preferably 1.1 to 1.6 mol. .
- the reaction of the compound (1) with the compound (2) and the compound (3) is not limited to the order of addition.
- the compound (2) and the base are added to a solution or suspension of the compound (1).
- a solution of the compound (3) is added, and the content is stirred at a predetermined temperature for a predetermined time.
- the solvent used for preparing the solution of the compound (1) is not particularly limited as long as it is inert to the reaction, for example, aromatic solvents such as benzene, toluene, and xylene; Ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate and n-butyl acetate; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone; n-pentane, n-hexane, Saturated hydrocarbon solvents such as chlorohexane and n-heptane; nitrile solvents such as acetonitrile and benzonitrile; ether solvents such as getyl ether, diisopropyl ether, dioxane, tetrahydrofuran and 1,2-dimethoxyethane
- a sulfoxide solvent such as dimethyl
- solvents can be used alone or in combination of two or more.
- Examples of the solvent used for preparing the solution of the compound (3) include the same solvents as those listed as the solvent for the compound (1), but they are the same as the solvents for the compound (1). Or different.
- the amount of the solvent for the compound (1) to be used is generally 10 to 1000 m, preferably 50 to 200 m1, for 10 g of the compound (1), from the viewpoint of economy and yield.
- the amount of the solvent for the compound (3) to be used is generally 10 to 1000 ml, preferably 20 to 10 Oml, for 10 g of the compound (3).
- the reaction is carried out by adding a base and a compound (2) to a solution of the compound (1), stirring the solution for several seconds to several hours in a temperature range from 1 l O Ot to the boiling point of the solvent to be used, and then reacting the solution of the compound (3). And stirring at a temperature from 100 to the boiling point of the solvent used for a few minutes to several hours.
- the completion of the reaction can be confirmed by the disappearance of the raw materials from the reaction solution and the formation of the desired product. Confirmation of the completion of the reaction can be performed, for example, by analyzing the reaction solution by a known analysis means such as liquid chromatography.
- the target compound After completion of the reaction, after performing ordinary post-treatment operations, the desired i3-lactam compound represented by the above formula (4) (hereinafter referred to as “the target compound”) is subjected to separation and purification means such as distillation, column chromatography and crystallization.
- Compound (4) is an intermediate for producing a carpanem antibiotic having excellent antibacterial activity.
- the compound (4) obtained is not isolated from the reaction solution obtained by the reaction of the present invention, but is used in the form of a solution in the case of production of the final target product, a carpanem antibiotic. It can also be subjected to the reaction of the step.
- a second aspect of the present invention is a step (1) of reacting a compound (4) with a dalioxylate ester represented by the formula (5) or a multimer thereof to obtain a compound represented by the formula (6). Reacting the compound represented by the formula (6) with a halogenating agent to obtain a compound represented by the formula (7) (2), and reducing the compound represented by the formula (7) (3) ).
- a method for producing an intermediate for the production of a potent antibacterial antibiotic represented by the above formula (8) As the compound (4) as a starting material, it is preferable to use a compound produced by the method for producing the compound (4) of the present invention, from which the compound (4) can be obtained inexpensively and with good yield.
- step (1) the compound (4) is reacted with a daroxylate ester represented by the formula (5) (hereinafter abbreviated as “compound (5)”) or a multimer thereof to obtain a compound of the formula (6) (Hereinafter abbreviated as “compound (6)”).
- compound (5) a daroxylate ester represented by the formula (5)
- compound (6) a compound of the formula (6)
- R 5 is an alkyl which may have a substituent. Represents an aryl group which may have a group or a substituent.
- alkyl group for R 5 examples include: methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, n-pentyl group, and n- Examples thereof include an alkyl group having 1 to 10 carbon atoms such as a xyl group, an n-octyl group, and an n-decyl group.
- Examples of the aryl group of R 5 include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 2-chenyl group, and a 2-furyl group. No.
- These substituents may be substituted at any position of the alkyl group and aryl group, and two or more of them may be the same or different.
- R 5 is preferably a group having a different reactivity from the thioester moiety of R 4 in consideration of the substituent conversion in the subsequent step, and leaving only R 5 while leaving R 4 More preferably, it is a group that can be used. Further, as described above, the R 4 is preferably an electron-withdrawing group, since the electron-withdrawing group, in the general acidic conditions is stable relatively, R 5 is under acidic conditions Are preferred.
- R 5 is an alkyl group which may have a substituent, and the substituent is a porogen atom, a cyano group, a nitro group, a substituent
- substituent is a porogen atom, a cyano group, a nitro group, a substituent
- Examples include at least one selected from the group consisting of a phenoxy group which may have a group and a substituent.
- the compound (5) include methyldaloxalate, ethyldiolioxalate, n-propyldalioxalate, isopropylglyoxalate, n-butyldarioxalate, isobutyldarioxalate, sec-butyldarioxalate Dali-xyl acrylates in which R s is an alkyl group having 1 to 6 carbon atoms, such as tert-butyl glyoxalate, n-pentyl glyoxalate, and n-hexyl dali oxalate; Oxalate, cyanomethyldalioxalate, nitromethyldalioxalate, benzylglyoxalate, p-methylbenzylglyoxalate, methylthiomethyldalioxalate, phenylthiomethyldalioxalate, methylsulfonylmethyldalioxa
- n represents a natural number of 2 or more, and R 5 has the same meaning as described above.
- an acid catalyst can be added to the reaction system to accelerate the reaction.
- Examples of the acid catalyst to be used include: inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid and salts thereof; organic acids such as benzenesulfonic acid which may have an alkyl substituent having 1 to 20 carbon atoms and salts thereof; Ride, Lewis acids such as titanium tetrachloride and aluminum chloride; and the like.
- Examples of salts of inorganic and organic acids include salts of alkali metals such as sodium and potassium, salts of alkaline earth metals such as magnesium and calcium, salts of transition metals such as copper, iron and manganese, and ammonium salts. can do.
- the amount of the acid catalyst to be added is not particularly limited, but is usually 0.0001 to 0 mol per 1 mol of compound (5) or a multimer thereof.
- the reaction in step (1) can be carried out without a solvent, but is preferably carried out in a solvent.
- the solvent used is not particularly limited as long as it does not inhibit the reaction.
- aliphatic hydrocarbon solvents such as n-pentane, n-hexane, n-heptane and n-octane; alicyclic hydrocarbon solvents such as cyclopentane and cyclohexane; benzene, toluene, xylene, Aromatic hydrocarbon solvents such as benzene, etc .; halogenated hydrocarbon solvents such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane; methyl formate, ethyl formate, n-propyl formate, n-formate —Ethyl solvents such as butyl, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, methyl propionate, and ethyl propionate; acetone, methyl ethyl
- the amount of these solvents to be used is not particularly limited, but is usually 0.01 to L: 0 g to the compound (4) lg.
- the compound (5) or a polymer thereof or a solvent solution thereof is added to the compound (4) or a solvent solution thereof, if necessary, together with an acid catalyst. It is performed by stirring for a time.
- the reaction temperature and reaction time of this reaction can be appropriately set depending on the reaction rate or the reaction completion time, but as a general range, the reaction temperature is 120 to +150.
- the reaction time is usually 1 minute to 1 minute. One week. After completion of the reaction, the desired compound (6) can be obtained by performing ordinary post-treatment operations.
- This product can be used to isolate the target product by known separation and purification means such as distillation and column chromatography. However, it can be used in the next step (2) without purification as crude product. Can also be provided. Further, the obtained compound (6) is obtained as a diastereomer mixture. These can be separated into their diastereomers by ordinary optical resolution means, but can also be subjected to the reaction in the next step (2) as a mixture of diastereomers as they are.
- step (2) the compound (6) obtained in the step (1) is reacted with a halogenating agent to give a compound represented by the formula ⁇ 7) (hereinafter abbreviated as “compound (7)”).
- compound (7) a compound represented by the formula ⁇ 7)
- the halogenating agent to be used is not particularly limited as long as it can replace the hydroxyl group of hemiacetal or ⁇ -acylamino alcohol with halogen.
- Specific examples of the halogenating agent to be used include chlorinating agents such as thionyl chloride, phosphorus oxychloride, phosgene, oxalyl chloride, phosphorus pentachloride, and hydrogen chloride; thionyl promide, phosphorus oxybromide, and oxalyl bromide. And brominating agents such as hydrogen bromide.
- the amount of the halogenating agent to be used is generally 1 to 10 mol, preferably 1.05 to 5 mol, per 1 mol of compound (6).
- the reaction between compound (6) and the halogenating agent is preferably performed in the presence of a base.
- Examples of the base used include ammonia; primary amines such as methylamine, ethylamine, propylamine and benzylamine; secondary amines such as dimethylamine, getylamine, dibutylamine and dibenzylamine; tertiary amines such as triethylamine and diisopropylethylamine; aniline Anilines, such as N, N-dimethylaniline; imidazole, 1,5-diazabicyclo [4.3.0]-5-nonene (DBN), 1,4-diazabicyclo mouth [2.2.2] octane (DAB CO), 1,8-diazabicyclo [5.4.0] N-containing heterocyclic compounds such as 171-decene (DBU), pyridine, and -dimethylaminopyridine; alkalis such as sodium hydroxide and potassium hydroxide Metal hydroxides; alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium methoxide,
- the amount of the base to be used is generally 0.1 to 10 mol, preferably 0.5 to 5 mol, per 1 mol of the halogenating agent.
- the reaction between compound (6) and the halogenating agent is usually performed in a solvent.
- the solvent used is not particularly limited as long as it is inert to the reaction. Specifically, the same solvents as those listed as the solvent that can be used in the reaction of step (1) can be mentioned. Although the amount of the solvent used is not particularly limited, the compound (6) is usually used in an amount of 0.01 to 100 g.
- the reaction temperature and reaction time of the reaction between compound (6) and the octalogizing agent can be appropriately set depending on the reaction rate or the reaction completion time, but as a general range, the reaction temperature is 150 to + 15 V, reaction time is 1 minute to 1 week.
- the desired compound (7) can be obtained by performing ordinary post-treatment operations.
- the target product can be isolated by separation and purification means such as distillation and column chromatography, but it can also be used in the next step (3) without purification as a crude product. it can.
- the obtained compound (7) may be obtained as a diastereomer mixture. These can be separated into respective diastereomers by a known optical resolution means, but can be subjected to the reaction in the next step (3) as a mixture of diastereomers as they are.
- step (3) the compound (7) obtained in the step (2) is reduced to obtain a compound represented by the formula (8) (hereinafter abbreviated as “compound (8)”).
- the method for reducing the compound (7) is not particularly limited as long as the compound (8) can be obtained by reductively removing the octagonal atom X of the compound (7).
- a method for reducing compound (7) (A) a method in which an inorganic acid or an organic acid is added to compound (7) and reduction is performed using a metal, and (B) compound (7) is hydrogenated It is preferable to employ either a method of reducing with hydrogen in the presence of a hydrogenation catalyst or a method of reducing the compound (7) with a metal hydride. According to these methods, the desired compound (8) can be obtained easily in good yield.
- the method (A) uses a metal in combination with an acid and utilizes the reducing power of the metal.
- the metal used is not particularly limited as long as it has a reducing power.
- zinc, iron, copper and the like can be used.
- the acid used include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid;
- Organic acids such as acid, acetic acid, propionic acid, benzoic acid, benzenesulfonic acid and p-toluenesulfonic acid.
- the amount of the metal to be used is generally 1 to 10 equivalents, preferably 1.2 to 5 equivalents, per 1 equivalent of compound (7).
- the amount of the acid used in combination with the metal is not particularly limited, and can be appropriately set depending on the metal used and the like.
- This reaction is usually performed in a solvent.
- the solvent used is not particularly limited as long as it is inert to the reaction.
- water alcohols such as methanol, ethanol, and isopropanol
- aliphatic hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, and n-octane
- cyclopentane, cyclohexane, and the like Alicyclic carbonization Hydrogen solvents; halogenated hydrocarbon solvents such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc .
- Ester solvents such as prop
- the compound (7) is catalytically reduced with hydrogen in the presence of a hydrogenation catalyst.
- the hydrogenation catalyst to be used is not particularly limited, and a known hydrogenation catalyst can be used. Examples include palladium carbon, Raney nickel, Raney cobalt, platinum oxide and the like.
- the amount of the hydrogenation catalyst is not particularly limited, but is usually 0.001 to 10 mol per 1 mol of compound (7).
- This reaction is performed in an inert solvent.
- the solvent to be used the same solvents as those listed as the solvent that can be used in the method (A) can be used.
- a solvent solution of compound (7) is placed in a sealable reaction vessel, a predetermined amount of a hydrogenation catalyst is added thereto, and the vessel is closed. It is performed by stirring for a time.
- the hydrogen gas pressure is not particularly limited, but is usually 1 ⁇ 10 5 Pa ⁇ : LX 10 6 Pa.
- the reaction temperature is usually 120 to 150 ° C, and the reaction time is usually several minutes to several tens of hours.
- the method (C) is a method in which the compound (7) is hydrogenated with a metal hydride.
- the metal hydride to be used include aluminum hydrides such as aluminum trihydride, lithium aluminum dimethyltetrahydride, sodium aluminum tetrahydride, diisopropyl aluminum hydride, and diisobutyl aluminum hydride; boron such as sodium boron tetrahydride; Hydrides can be mentioned.
- the amount of the metal hydride to be used is generally about 0.5 to 5 mol per 1 mol of compound (7).
- these metal hydrides can be used in combination with a Lewis acid or a base. Examples of the Lewis acid used include boron trifluoride, titanium tetrachloride, aluminum chloride and the like.
- tertiary amines such as triethylamine, diisopropylethylamine, etc .; 1,5-diazabisic mouth [4.3.0] 15-none (DBN), 1,4-diazabicyclo [2.2.2] octane (DAB CO), 1,8-diazabicyclo [5.4.0] —7-indene (DBU), pyridine, 4-dimethyla Nitrogen-containing heterocyclic compounds such as minopyridine; and the like.
- DBN 1,4-diazabicyclo [2.2.2] octane
- DBU 1,8-diazabicyclo [5.4.0] —7-indene
- pyridine 4-dimethyla Nitrogen-containing heterocyclic compounds such as minopyridine; and the like.
- the used amount of these Lewis acids and bases is usually 0.01 to 5 equivalents to 1 equivalent of the metal hydride.
- the reaction using the metal hydride can be performed in an organic solvent.
- the solvent used is not particularly limited as long as it is inert to the reaction.
- aliphatic hydrocarbon solvents such as n-pentane, n-hexane, n-heptane and n-octane
- alicyclic hydrocarbon solvents such as cyclopentane and cyclohexane
- getyl ether, tetrahi Ether solvents such as drofuran, dioxane, and 1,2-dimethyloxetane; and the like.
- the reaction temperature of the reaction using a metal hydride is usually 1 to 100 to +150.
- the reaction time depends on the scale of the reaction, but is usually 1 minute to 1 week.
- the usual post-treatment operation is performed, and the desired compound (8) is isolated by a known purification method such as distillation, column chromatography, or recrystallization. Can be.
- the compound (8) may be obtained as a mixture of diastereomers, but these can be separated into respective diastereomers by a known optical resolution means.
- the compound (8) obtained by the present invention is an intermediate for producing a carpanem antibiotic having excellent antibacterial activity.
- a solution of the present invention can be prepared without isolation from the reaction solution obtained by the reaction of the present invention.
- the reaction in the next step can be used as it is.
- Example 2 The same operation as in Example 1 was carried out except that ethyl acetate was used instead of dichloromethane as the reaction solvent.
- the (3S, 4S) -3-([1R) -t-butyldimethylsilyloxyethyl] 1- 4 was added to the organic layer.
- Example 2 A part of the organic layer obtained under the same conditions as in Example 1 was purified by silica gel column chromatography and further recrystallized with a hexane solvent to obtain a high-purity (3S, 4S )-3-[(1 R)-t-butyldimethylsilyloxhexyl] 1-4-[(1 R)-11-(4-chlorophenylthiocarbonyl) ethyl] 1-2-azetidinone . This was used as an analytical sample.
- the ⁇ -lactam compound represented by the above formula (4) can be produced at low cost and with high yield.
- an intermediate for producing a potent antibacterial antibiotic represented by the above formula (8) can be produced from the J3-lactam compound represented by the above formula (4) in good yield.
- an intermediate for producing a carpanem antibiotic represented by the above formula (8) can be produced at low cost and with high yield.
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CN100494204C (zh) * | 2006-01-12 | 2009-06-03 | 上海交通大学 | (1’r,3r,4r)-4-乙酸基-3-(1-叔丁基二甲基硅氧基乙基)氮杂环丁烷-2-酮的氧化合成方法 |
Citations (4)
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JPS5951286A (ja) * | 1982-09-10 | 1984-03-24 | Sankyo Co Ltd | カルバペネム誘導体の製造法 |
JPS62103084A (ja) * | 1984-12-27 | 1987-05-13 | Sumitomo Pharmaceut Co Ltd | β−ラクタム化合物の製造方法 |
JPH09278748A (ja) * | 1996-04-12 | 1997-10-28 | Sumitomo Chem Co Ltd | N−置換−β−ラクタム化合物の製造法 |
JP2002326985A (ja) * | 2001-04-27 | 2002-11-15 | Sumitomo Pharmaceut Co Ltd | アゼチジノン誘導体およびその製造方法 |
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JP2569455B2 (ja) * | 1992-03-06 | 1997-01-08 | 田辺製薬株式会社 | β−ラクタム誘導体の製法 |
JP2643753B2 (ja) * | 1992-03-06 | 1997-08-20 | 田辺製薬株式会社 | 2−オキシカルバペネム誘導体の製法 |
JPH0625243A (ja) * | 1992-07-08 | 1994-02-01 | Sankyo Co Ltd | 1−メチルカルバペネム誘導体の製造法 |
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JPS5951286A (ja) * | 1982-09-10 | 1984-03-24 | Sankyo Co Ltd | カルバペネム誘導体の製造法 |
JPS62103084A (ja) * | 1984-12-27 | 1987-05-13 | Sumitomo Pharmaceut Co Ltd | β−ラクタム化合物の製造方法 |
JPH09278748A (ja) * | 1996-04-12 | 1997-10-28 | Sumitomo Chem Co Ltd | N−置換−β−ラクタム化合物の製造法 |
JP2002326985A (ja) * | 2001-04-27 | 2002-11-15 | Sumitomo Pharmaceut Co Ltd | アゼチジノン誘導体およびその製造方法 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN100494204C (zh) * | 2006-01-12 | 2009-06-03 | 上海交通大学 | (1’r,3r,4r)-4-乙酸基-3-(1-叔丁基二甲基硅氧基乙基)氮杂环丁烷-2-酮的氧化合成方法 |
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