WO2003089432A1 - Process for producing carbapenem derivative - Google Patents
Process for producing carbapenem derivative Download PDFInfo
- Publication number
- WO2003089432A1 WO2003089432A1 PCT/JP2003/005061 JP0305061W WO03089432A1 WO 2003089432 A1 WO2003089432 A1 WO 2003089432A1 JP 0305061 W JP0305061 W JP 0305061W WO 03089432 A1 WO03089432 A1 WO 03089432A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- same
- ester residue
- group
- atom
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 12
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical class C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 29
- 239000002841 Lewis acid Substances 0.000 claims abstract description 19
- 150000002148 esters Chemical group 0.000 claims abstract description 19
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 19
- 239000002879 Lewis base Substances 0.000 claims abstract description 15
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical class SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims abstract description 15
- 150000007527 lewis bases Chemical class 0.000 claims abstract description 15
- 125000000962 organic group Chemical group 0.000 claims abstract description 11
- -1 amine compound Chemical class 0.000 claims description 45
- 125000006239 protecting group Chemical group 0.000 claims description 20
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 239000002994 raw material Substances 0.000 claims description 10
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 7
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000004434 sulfur atom Chemical group 0.000 claims description 7
- 229910052718 tin Inorganic materials 0.000 claims description 7
- 229910052719 titanium Inorganic materials 0.000 claims description 7
- 239000010936 titanium Substances 0.000 claims description 7
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052710 silicon Inorganic materials 0.000 claims description 5
- 239000010703 silicon Substances 0.000 claims description 5
- 229910052725 zinc Inorganic materials 0.000 claims description 5
- 239000011701 zinc Substances 0.000 claims description 5
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 claims description 4
- 229910052782 aluminium Inorganic materials 0.000 claims description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052796 boron Inorganic materials 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 239000011135 tin Substances 0.000 claims description 4
- 229910052726 zirconium Inorganic materials 0.000 claims description 4
- 229910052684 Cerium Inorganic materials 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- GYHNNYVSQQEPJS-UHFFFAOYSA-N Gallium Chemical compound [Ga] GYHNNYVSQQEPJS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052772 Samarium Inorganic materials 0.000 claims description 2
- 229910052787 antimony Inorganic materials 0.000 claims description 2
- WATWJIUSRGPENY-UHFFFAOYSA-N antimony atom Chemical compound [Sb] WATWJIUSRGPENY-UHFFFAOYSA-N 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 229910052797 bismuth Inorganic materials 0.000 claims description 2
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 claims description 2
- ZMIGMASIKSOYAM-UHFFFAOYSA-N cerium Chemical compound [Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce] ZMIGMASIKSOYAM-UHFFFAOYSA-N 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 229910052733 gallium Inorganic materials 0.000 claims description 2
- 229910052732 germanium Inorganic materials 0.000 claims description 2
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 claims description 2
- 229910052735 hafnium Inorganic materials 0.000 claims description 2
- VBJZVLUMGGDVMO-UHFFFAOYSA-N hafnium atom Chemical compound [Hf] VBJZVLUMGGDVMO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 claims description 2
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 claims description 2
- 229910052706 scandium Inorganic materials 0.000 claims description 2
- SIXSYDAISGFNSX-UHFFFAOYSA-N scandium atom Chemical compound [Sc] SIXSYDAISGFNSX-UHFFFAOYSA-N 0.000 claims description 2
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052721 tungsten Inorganic materials 0.000 claims description 2
- 239000010937 tungsten Substances 0.000 claims description 2
- 229910052720 vanadium Inorganic materials 0.000 claims description 2
- GPPXJZIENCGNKB-UHFFFAOYSA-N vanadium Chemical compound [V]#[V] GPPXJZIENCGNKB-UHFFFAOYSA-N 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 claims description 2
- VNWKTOKETHGBQD-NJFSPNSNSA-N carbane Chemical class [14CH4] VNWKTOKETHGBQD-NJFSPNSNSA-N 0.000 claims 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 4
- 239000004480 active ingredient Substances 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- 239000001301 oxygen Substances 0.000 abstract 1
- 229910052717 sulfur Inorganic materials 0.000 abstract 1
- 239000011593 sulfur Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 20
- 239000000203 mixture Substances 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- 239000003242 anti bacterial agent Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000012043 crude product Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 5
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 4
- 150000003973 alkyl amines Chemical class 0.000 description 4
- 125000003282 alkyl amino group Chemical group 0.000 description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
- 150000003842 bromide salts Chemical class 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 150000004694 iodide salts Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- OBYVIBDTOCAXSN-UHFFFAOYSA-N n-butan-2-ylbutan-2-amine Chemical compound CCC(C)NC(C)CC OBYVIBDTOCAXSN-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- UENWRTRMUIOCKN-UHFFFAOYSA-N benzyl thiol Chemical compound SCC1=CC=CC=C1 UENWRTRMUIOCKN-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 229940117389 dichlorobenzene Drugs 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000003396 thiol group Chemical class [H]S* 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- GPDKREBNFFEDHW-UHFFFAOYSA-N 1-(4-nitrophenyl)-2-phenylethane-1,2-dione Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(=O)C(=O)C1=CC=CC=C1 GPDKREBNFFEDHW-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- NKBWMBRPILTCRD-UHFFFAOYSA-N 2-Methylheptanoic acid Chemical compound CCCCCC(C)C(O)=O NKBWMBRPILTCRD-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 description 1
- 125000005083 alkoxyalkoxy group Chemical group 0.000 description 1
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 150000001782 cephems Chemical class 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- CMKBCTPCXZNQKX-UHFFFAOYSA-N cyclohexanethiol Chemical compound SC1CCCCC1 CMKBCTPCXZNQKX-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical class [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- KZCOBXFFBQJQHH-UHFFFAOYSA-N octane-1-thiol Chemical compound CCCCCCCCS KZCOBXFFBQJQHH-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000005633 phthalidyl group Chemical group 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003752 zinc compounds Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/02—Preparation
- C07D477/04—Preparation by forming the ring or condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/18—Oxygen atoms
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- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
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- 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
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- 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 novel method for producing a levulinem derivative useful as a synthetic intermediate for a levavenem antibacterial agent.
- the anti-bacterial agents of Lubadenem have excellent antibacterial activity against a wide range of pathogenic bacteria including gram-positive bacteria and gram-negative bacteria, and have a strong antibacterial activity, especially against cephem-resistant bacteria, and It is widely used as an antibacterial agent because of its excellent stability.
- various methods for synthesizing the antibacterial agent and intermediates thereof have been known. For example, 4- (phenylthiocarboylethyl) -12-azetidinone derivatives are produced by treating with a strong base such as hydrogenated sodium.
- a method of capturing a thiol with an alkyl group or an acylating agent and then treating the thiol with an active esterifying agent for a hydroxyl group to produce a carbapenem compound Japanese Patent Application Laid-Open No. Sho 62-110384; Is subjected to a ring-closing reaction in the presence of Louis acid or an oxidizing agent to give a 2-hydroxylvanem derivative, and then to react with mercaptan to produce a helvanene derivative (Japanese Patent Laid-Open No. 6-10G56). No. 4 gazette). Disclosure of the invention
- a main object of the present invention is to provide a novel production method for easily producing a potarubenem derivative useful as a synthetic intermediate of a potarubenem-based antibacterial agent under mild conditions with good yield.
- the present invention has the following formula
- R 1 represents a protecting group for a hydroxyl group
- R 2 and R 3 are the same or different and each represents a hydrogen atom or a lower alkyl group
- R 4 represents an ester residue
- R 5 represents an ester residue
- Y means O atom or S atom.
- R G represents an organic group.
- R 4 a refers to R 4 or R.
- RR ⁇ R 3 and R 5 are the same.
- the present invention also provides the following formula (1)
- R G represents an organic group.
- the present invention also relates to a method for producing a carbene derivative represented by the formula:
- the compound (1) is subjected to ring closure in the presence of a Lewis acid and a Lewis base to form a five-membered ring, and then, if necessary, to a substitution reaction with a mercaptan derivative (4).
- a substitution reaction with a mercaptan derivative (4) can be.
- the method of the present invention is represented by the following reaction formula.
- M represents a metal atom portion of a Lewis acid
- n 2-5
- 1 , RR 3 R 4 , R 5 and Y are the same as described above.
- ester residue represented by R 5 or ester residues are hydrolyzed metabolized in vivo, or an ester residue can be mentioned only * which can be a protecting group of the force Rupokishiru group.
- Examples of the former ester residue include any group that can be hydrolyzed in a living body to regenerate a lipoxyl group, and include groups used for deriving a group of compounds generally referred to as prodrugs.
- Preferred groups include lower alkanoyloxy lower alkyl, cycloalkyl lower alkyl, lower alkenyloxy lower alkyl, lower alkoxy lower alkyl lower alkyl, lower alkoxy lower alkyl, lower alkoxy lower alkoxy lower alkyl, lower alkyl.
- lower alkoxyalkoxy lower alkyl lower alkoxy lower alkoxy carbonyloxy lower alkyl, (5-lower alkyl-1,3-dioxolen-12-one-1-yl) methyl and the like.
- various commonly used protecting groups can be used.1
- a linear or branched chain having 1 to 5 carbon atoms such as methyl, ethyl, isopropyl, tert-butyl, etc.
- Lower alkyls having 1 to 5 carbon atoms such as halogenated lower alkyls such as 2-hydroxyethyl and 2,2,2-trichloroethyl, such as methyloxymethyl, ethyloxymethyl and isoptyloxymethyl.
- Lower alkyloxymethyl having 1 to 5 carbon atoms for example, lower aliphatic asiloxymethyl having 1 to 5 carbon atoms such as acetyloxymethylinole, propionyloxymethylinole, ptyryloxymethyl, and bivaloyloxymethyl
- 1-lower alkyl (1-5 carbon atoms) oxycarbonyloxyshethyl such as 1-ethyloxycarbonyloxyethyl
- benzoinole, aralkyl groups such as ⁇ -methinoleoxybenzinole, o-n-pentopenzinole, and 12-to-n-benzyl
- lower alkenyl having 3 to 7 carbon atoms such as aryl and 3-methylaryl, benzhydryl, and phthalidyl; .
- protective group for hydroxyl represented by R 1 is susceptible to various protective groups generally used, preferably, for example, tert- butyl O carboxymethyl lower alkyl O alkoxycarbonyl carbon number 1-5 such as carbonyl,
- tert- butyl O carboxymethyl lower alkyl O alkoxycarbonyl carbon number 1-5 such as carbonyl
- substituted or unsubstituted halogenoalkyloxycarbonyl having 1 to 5 carbon atoms such as 2-hydroxyethyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl, and aryloxycarbonyl.
- Lower alkenyloxycarbonyl having 3 to 7 carbon atoms such as benzyloxycarbonyl bonole, —methinoleoxybenzinoleoxycanolepo-nore, o—two-opening penzinoreoxy shikanoreponinore, —two-opening benzylinolexano Fara / lequinoleoxycanolebonyl such as repo-nore, for example, trimethylsilyl, triethylsilyl, tert-butyldimethyl Trialkylsilyl such Lil and the like.
- ester residue represented by R 4 examples include lower alkyl, cycloalkyl, 6-: L0-membered lower alkyl, 6-; L0-membered lower alkyl, 4-: L0 membered fat And a 4- to 10-membered aromatic heterocyclic group. Further, these groups may have one or more substituents. Examples of such a substituent include lower alkyl, hydroxyl, lower alkoxy, amino, lower alkylamino, di-lower alkylamino, mercapto, and lower alkylthio.
- the functional groups contained in these substituents can be protected by a protecting group, if necessary.
- the protecting group used is not particularly limited as long as it can be easily removed by a conventional method.
- TW Green, PGM Wuts Protective Group in Organic Synthesis; 3rd.ed., Wiley, New York, 1999. Ray is referred to by P. Kocienski, Protecting Groups, Thieme, Stuttgart, 1994.
- Preferred R 4 when Y is an S atom is an organic group used in known antibacterial agents.
- Organic groups used in rubanem antibacterial agents can be used.
- organic groups used in the known antibacterial agents of the present invention can be used.
- examples of such groups include lower alkyl, cycloalkyl, 6-10 membered aryl, and 6-10 membered aryl lower alkyl.
- these groups may have one or more substituents, such substituents as lower alkyl, hydroxyl, lower alkoxy, amino, lower alkylamino, di-lower alkylamino, mercapto, lower alkylthio. , Amidino, guanidino, canolebamoyl, thiocarbamoyl, sulfamoyl, cyano, carboxyl, lower alkoxycarbonyl, aralkilok shikanoreponinore, oxo, halogeno, cycloanolequinole, 6-10 membered arinole, 4-10 membered aliphatic And a 4- to 10-membered aromatic heterocyclic group.
- substituents as lower alkyl, hydroxyl, lower alkoxy, amino, lower alkylamino, di-lower alkylamino, mercapto, lower alkylthio.
- substituents such substituents as lower alkyl,
- the functional groups contained in these substituents can be protected by a protecting group, if necessary.
- the protecting group used is not particularly limited as long as it can be easily removed by a conventional method.
- TW Green, PGM Wuts Protective Groups in Organic Synthesis; 3rd. Ed., Wiley, New York, 1999, or P. Kocienski, Protecting Groups, Thieme, Stuttgart, 1994.
- Examples of the Lewis acid used in the present invention include aluminum, tin, zirconium, magnesium, boron, titanium, zinc, silicon, iron, germanium, antimony, hafnium, bismuth, scandium, yttrium, manganese, covanolate, nickel, copper, and gallium.
- salts / bromides, bromides, iodides, lower alkylated compounds and complexes having a central element such as zinc / silicon or tin, magnesium / boron / titanium, zinc / silicon / tin, and tin / zinc compound are preferred.
- a central element such as zinc / silicon or tin, magnesium / boron / titanium, zinc / silicon / tin, and tin / zinc compound.
- chlorides, bromides, iodides, lower alkylated compounds and complexes having titanium, dinoreconium or anorenium as a central element are particularly preferred.
- the amount of use can be 0.1 to 5.0 mol per 1 mol of the starting compound (1), preferably 0.5 to 4.0 mol, particularly 1.0 to 3.0 mol. It is preferably 0 mol.
- the Lewis base used in the present invention include organic amine compounds.
- tri-lower alkylamines such as triethylamine, triptylamine and diisopropylethylamine
- di-lower alkylamines such as getylamine, diisopropyl pyramine and di-sec-butylamine.
- the amount of use can be 0.1 to 6.0 mol per mol of the starting compound (1), preferably 0.5 to 5.0 mol, particularly 1.0 to 4.0 mol. It is preferably 0 mol.
- Ring closure of compound (1) in the presence of a Lewis acid and a Lewis base to form a five-membered ring This reaction can be carried out in a solvent, and the solvent is not particularly limited as long as it does not adversely affect the reaction. None, but preferred are, for example, aliphatic hydrocarbons such as hexane, heptane, octane, etc .; halogenated aliphatic hydrocarbons such as carbon tetrachloride, 1,2-dichloroethane; benzene, toluene; Examples thereof include aromatic hydrocarbons such as xylene, halogenated aromatic hydrocarbons such as monochlorobenzene and dichlorobenzene, and mixed solvents thereof.
- aliphatic hydrocarbons such as hexane, heptane, octane, etc .
- halogenated aliphatic hydrocarbons such as carbon tetrachloride, 1,2-dichloroethane
- This reaction can be suitably carried out under cooling to room temperature, for example, at a temperature of from 75 ° C to 40 ° C, especially from -40 ° C to 30 ° C.
- R 4 is benzyl, n-octyl, cyclohexyl,
- R 6 represents a protecting group for an amino group.
- the reaction for reacting the mercaptan derivative (4) is performed according to a conventional method.
- the reaction can be carried out in a suitable solvent in the presence or absence of a base.
- the base include organic amine compounds.
- tri-lower alkylamines such as triethylamine, triptylamine and diisopropylethylamine
- di-lower alkylamines such as getylamine, diisopropylamine and di-sec-butylamine are exemplified.
- the solvent is not particularly limited as long as it does not adversely affect the reaction, but preferred examples thereof include aliphatic hydrocarbons such as hexane, heptane, and octane, methylene chloride, chloroform, and carbon tetrachloride. , 1, 2-dichloroethane Examples thereof include aromatic hydrocarbons such as halogenated aliphatic hydrocarbons, benzene, tosoleene, and xylene; halogenated aromatic hydrocarbons such as benzene, dichlorobenzene, and the like; and mixed solvents thereof.
- aliphatic hydrocarbons such as hexane, heptane, and octane, methylene chloride, chloroform, and carbon tetrachloride.
- 1, 2-dichloroethane examples thereof include aromatic hydrocarbons such as halogenated aliphatic hydrocarbons, benzene, tosoleene, and xylene; halogen
- the reaction can be suitably carried out under cooling to room temperature, for example, at a temperature of from 75 ° C to 40 ° C, especially from 140 ° C to 30 ° C.
- the substituent R 4 in the compound (2) is an organic group used in a known antibacterial agent of ruvanem series, if necessary, RR 5 and / or R 4
- RR 5 and / or R 4 By removing the protecting group in the above, it is possible to directly lead to a ruvanem-based antibacterial agent, and such an intermediate (2) is particularly important.
- a part of the starting compound (1) is a novel compound, but it can be produced by the method described in Examples or a method analogous thereto.
- the starting compound (1) may have optical isomers based on its asymmetric carbon. However, when the optically active compound (1) is used as a starting material, the reaction proceeds while maintaining the steric structure, and Compound (2) and / or compound (3) can be converted to compound (5) without conversion.
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Abstract
A process for easily producing the carbapenem derivative shown below. The process, which is for producing a carbapenem derivative represented by the following formula (5): (5) (wherein R4a means R4 or an organic group), is characterized by reacting a compound represented by the formula (1) (wherein R1 means a hydroxy-protecting group; R2 and R3 each means hydrogen or lower alkyl; R4 and R5 each means an ester residue; and Y means oxygen or sulfur) in the presence of a Lewis acid and a Lewis base and optionally causing a mercaptan derivative to act on the resultant reaction product.
Description
明細書 Specification
力ルバぺネム誘導体の製造法 Method for producing carbenem derivatives
技術分野 Technical field
本発明は、 力ルバぺネム系抗菌剤の合成中間体として有用な力ルバぺネム誘導 体の新規製法に関する。 従来の技術 TECHNICAL FIELD The present invention relates to a novel method for producing a levulinem derivative useful as a synthetic intermediate for a levavenem antibacterial agent. Conventional technology
力ルバぺネム系抗菌剤は、 グラム陽性菌、 グラム陰性菌を含む広範囲の病原菌 に対して優れた抗菌作用を示し、 特にセフェム耐性菌に対しても強い抗菌力を示 し、 かつ生体内での安定性等にも優れていることから抗菌剤として汎用されてい る。 従来より該抗菌剤およびその中間体の種々の合成法が知られており、 例えば 、 4— (フエ二ルチオカルボ二ルェチル) 一 2ーァゼチジノン誘導体を水素化ナ トリゥムなどの強塩基で処理し、 産生するチオールをアルキルィヒ剤またはァシル 化剤で捕捉し、 次いで水酸基の活性エステル化剤で処理し、 カルバぺネム化合物 を製造する方法 （特開昭 6 2 - 1 0 3 0 8 4号公報） 、 ァゼチノン化合物をルイ ス酸または酸化剤の存在下閉環反応に付し、 2—ォキシ力ルバぺネム誘導体とし 、 ついでメルカブタンを作用させ力ルバぺネム誘導体を製造する方法 （特開平 6 - 1 0 G 5 6 4号公報） などが知られている。 発明の開示 The anti-bacterial agents of Lubadenem have excellent antibacterial activity against a wide range of pathogenic bacteria including gram-positive bacteria and gram-negative bacteria, and have a strong antibacterial activity, especially against cephem-resistant bacteria, and It is widely used as an antibacterial agent because of its excellent stability. Conventionally, various methods for synthesizing the antibacterial agent and intermediates thereof have been known. For example, 4- (phenylthiocarboylethyl) -12-azetidinone derivatives are produced by treating with a strong base such as hydrogenated sodium. A method of capturing a thiol with an alkyl group or an acylating agent and then treating the thiol with an active esterifying agent for a hydroxyl group to produce a carbapenem compound (Japanese Patent Application Laid-Open No. Sho 62-110384); Is subjected to a ring-closing reaction in the presence of Louis acid or an oxidizing agent to give a 2-hydroxylvanem derivative, and then to react with mercaptan to produce a helvanene derivative (Japanese Patent Laid-Open No. 6-10G56). No. 4 gazette). Disclosure of the invention
本発明の主な目的は、 力ルバぺネム系抗菌剤の合成中間体として有用な力ルバ ぺネム誘導体を、 緩和な条件下、 収率よく簡便に製造する新規製法を提供するこ とにある。 本発明は下記式 A main object of the present invention is to provide a novel production method for easily producing a potarubenem derivative useful as a synthetic intermediate of a potarubenem-based antibacterial agent under mild conditions with good yield. . The present invention has the following formula
で表わされる化合物をルイス酸とルイス塩基の存在下反応させ、 五員環を形成さ せることを特徴とし、 ついで必要に応じ式 Re S H ( 4 ) Reacting a compound represented by the formula with a Lewis acid in the presence of a Lewis base to form a five-membered ring, and then, if necessary, formula R e SH (4)
(式中の RGは有機基を意味する。 ） (In the formula, R G represents an organic group.)
で表わされるメルカプタン誘導体を作用させることからなる下記式
The following formula comprising reacting a mercaptan derivative represented by
(式中、 R R2、 R3および R5は前掲と同じ。 ） (Where RR 2 , R 3 and R 5 are the same as above.)
で表わされる化合物および Zまたは下記式 And Z or the following formula
( R4 aは、 R4または R。を意味し、 R R\ R3および R5は前掲と同じ。 ） で表わされる力ルバぺネム誘導体の製造法に関する。 本発明は、 また下記式 (1 )(R 4 a refers to R 4 or R., RR \ R 3 and R 5 are the same. As cited above) relates to a process for preparing represented by force Rubape Nemu derivatives. The present invention also provides the following formula (1)
(式中、 R R2、 R3、 R4、 R5および Yは前掲と同じ。 ） (Where RR 2 , R 3 , R 4 , R 5 and Y are the same as above.)
で表わされる化合物をルイス酸とルイス塩基の存在下反応させ、 下記式
Is reacted with a Lewis acid and a Lewis base in the presence of the following formula:
(式中、 R R2、 R3、 R4および R5は、 前掲と同じ）
で表わされる力ルバぺネム誘導体および下記式 (Where RR 2 , R 3 , R 4 and R 5 are the same as above) And a compound represented by the following formula:
(式中、 R R2、 R3および R5は、 前掲と同じ。 ） (Where RR 2 , R 3 and R 5 are the same as above.)
で表わされる化合物、 または上記式 （3) の化合物を製造し、 ついで必要に応じ 式 R° SH (4) Or a compound of the above formula (3), and if necessary, a compound of the formula R ° SH (4)
(式中の RGは有機基を意味する。 ） (In the formula, R G represents an organic group.)
で表わされるメルカブタン誘導体を作用させることによる上記式 （2) 、 (3) で表わされる化合物並びに下記式 Compounds represented by the above formulas (2) and (3) by reacting a mercaptan derivative represented by the following formula:
(式中、 R R2、 R3および R5は前掲と同じであり、 R "は、 R4または R0を 意味する。 ） (Wherein, RR 2 , R 3 and R 5 are the same as described above, and R ″ means R 4 or R 0. )
で表わされる力ルバぺネム誘導体の製法にも関する。 The present invention also relates to a method for producing a carbene derivative represented by the formula:
本発明方法によれば、 化合物 （1) を、 ルイス酸とルイス塩基存在下に閉環さ せ五員環を形成させ、 ついで必要に応じメルカブタン誘導体 （4) で置換反応す ることにより実施することができる。 本発明方法を反応式で示すと以下の通りである。
According to the method of the present invention, the compound (1) is subjected to ring closure in the presence of a Lewis acid and a Lewis base to form a five-membered ring, and then, if necessary, to a substitution reaction with a mercaptan derivative (4). Can be. The method of the present invention is represented by the following reaction formula.
(1) (2) (3) (one two Three)
またはOr
(3) (5) (3) (5)
(上記式中、 R。、 R\ R2、 R3、 R4、 R4 aおよび R5は前掲と同じ。 ） 化合物 （1 ) にルイス酸およびルイス塩基を作用させると、 例えば、 以下のよ うな中間体が生成し、 これを経由して本反応が進行するものと考えられる。 (In the above formula, R, R \ R 2 , R 3 , R 4 , R 4a and R 5 are the same as those described above.) When a Lewis acid and a Lewis base are allowed to act on compound (1), for example, It is considered that such an intermediate is generated and the reaction proceeds via this.
(式中、 Mはルイス酸の金属原子部分、 nは 2— 5を意味し、 1、 R R3 R 4、 R5および Yは前掲と同じ。 ） (In the formula, M represents a metal atom portion of a Lewis acid, n represents 2-5, and 1 , RR 3 R 4 , R 5 and Y are the same as described above.)
以下に原料として用いられる式 （1 ) で表わされる化合物の置換基について説 明する。 The substituent of the compound represented by the formula (1) used as a raw material will be described below.
R5で示されるエステル残基の例としては、 生体内で代謝を受け加水分解される エステル残基か、 あるいは力ルポキシル基の保護基となりうるエステル残基が挙 け*られる。 Examples of the ester residue represented by R 5, or ester residues are hydrolyzed metabolized in vivo, or an ester residue can be mentioned only * which can be a protecting group of the force Rupokishiru group.
前者のエステル残基としては、 生体内で加水分解されて力ルポキシル基を再生 する限りいかなるものも含み、 プロドラッグと総称される化合物群に誘導する際 に使用される基が挙げられる。 好ましい基としては、 低級アルカノィルォキシ低 級アルキル、 シクロアルキル力ルポエルォキシ低級アルキル、 低級アルケノィル ォキシ低級アルキル、 低級アルコキシ低級アル力ノィルォキシ低級アルキル、 低 級アルコキシ低級アルキル、 低級アルコキシ低級アルコキシ低級アルキル、 低級
アルコキシカルボニルォキシ低級アルキル、 低級アルコキシ低級アルコキシカル ボニルォキシ低級アルキル、 （5—低級アルキル一 1 , 3—ジォキソレン一 2— オン一 4一ィル) メチル等が挙げられる。 また後者のエステル残基としては、 通常用いられる各種の保護基が可能である 1 好ましくは例えばメチル、 ェチル、 イソプロピル、 tert—プチル等の直鎖状 または分枝鎖状で炭素数 1〜 5の低級アルキル、 例えば 2—ョゥ化工チル、 2 , 2 , 2—トリクロ口ェチル等の炭素数 1〜 5のハロゲノ低級アルキル、 例えばメ チルォキシメチル、 ェチルォキシメチル、 ィソプチルォキシメチル等の炭素数 1 〜 5の低級アルキルォキシメチル、 例えばァセチルォキシメチノレ、 プロピオニル ォキシメチノレ、 プチリルォキシメチル、 ビバロイルォキシメチル等の炭素数 1〜 5の低級脂肪族ァシルォキシメチル、 例えば 1 —ェチルォキシカルボニルォキシ ェチル等の 1一低級アルキル （炭素数 1〜 5 ) ォキシカルボニルォキシェチル、 例えばべンジノレ、 ρ—メチノレオキシベンジノレ、 o—二ト口べンジノレ、 一二ト口 ベンジル等のァラルキル基、 例えばァリル、 3—メチルァリル等の炭素数 3 ~ 7 の低級アルケニル、 ベンズヒドリル、 フタリジル等が挙げられる。 Examples of the former ester residue include any group that can be hydrolyzed in a living body to regenerate a lipoxyl group, and include groups used for deriving a group of compounds generally referred to as prodrugs. Preferred groups include lower alkanoyloxy lower alkyl, cycloalkyl lower alkyl, lower alkenyloxy lower alkyl, lower alkoxy lower alkyl lower alkyl, lower alkoxy lower alkyl, lower alkoxy lower alkoxy lower alkyl, lower alkyl. And lower alkoxyalkoxy lower alkyl, lower alkoxy lower alkoxy carbonyloxy lower alkyl, (5-lower alkyl-1,3-dioxolen-12-one-1-yl) methyl and the like. As the latter ester residue, various commonly used protecting groups can be used.1 Preferably, for example, a linear or branched chain having 1 to 5 carbon atoms such as methyl, ethyl, isopropyl, tert-butyl, etc. Lower alkyls having 1 to 5 carbon atoms, such as halogenated lower alkyls such as 2-hydroxyethyl and 2,2,2-trichloroethyl, such as methyloxymethyl, ethyloxymethyl and isoptyloxymethyl. Lower alkyloxymethyl having 1 to 5 carbon atoms, for example, lower aliphatic asiloxymethyl having 1 to 5 carbon atoms such as acetyloxymethylinole, propionyloxymethylinole, ptyryloxymethyl, and bivaloyloxymethyl For example, 1-lower alkyl (1-5 carbon atoms) oxycarbonyloxyshethyl such as 1-ethyloxycarbonyloxyethyl, for example, benzoinole, aralkyl groups such as ρ-methinoleoxybenzinole, o-n-pentopenzinole, and 12-to-n-benzyl; for example, lower alkenyl having 3 to 7 carbon atoms such as aryl and 3-methylaryl, benzhydryl, and phthalidyl; .
R1で示される水酸基の保護基としては、 通常用いられる各種の保護基が可能で あるが、 好ましくは、 例えば、 tert—ブチルォキシカルボニル等の炭素数 1〜 5 の低級アルキルォキシカルボニル、 例えば 2—ョゥ化工チルォキシカルボニル、 2 , 2 , 2—トリクロロェチルォキシカルボニル等の炭素数 1〜 5のハロゲノア ルキルォキシカルボニル、 例えばァリルォキシカルボニル等の置換または無置換 の炭素数 3〜 7の低級アルケニルォキシ力ルポニル、 例えばべンジルォキシカル ボニノレ、 —メチノレオキシベンジノレオキシカノレポ-ノレ、 o—二ト口ペンジノレオキ シカノレポ二ノレ、 —二ト口べンジノレォキシカノレポ-ノレ等のァラ /レキノレオキシカノレ ボニル、 例えばトリメチルシリル、 トリェチルシリル、 tert—ブチルジメチルシ リル等のトリアルキルシリル等が挙げられる。 As the protective group for hydroxyl represented by R 1, is susceptible to various protective groups generally used, preferably, for example, tert- butyl O carboxymethyl lower alkyl O alkoxycarbonyl carbon number 1-5 such as carbonyl, For example, substituted or unsubstituted halogenoalkyloxycarbonyl having 1 to 5 carbon atoms, such as 2-hydroxyethyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl, and aryloxycarbonyl. Lower alkenyloxycarbonyl having 3 to 7 carbon atoms, such as benzyloxycarbonyl bonole, —methinoleoxybenzinoleoxycanolepo-nore, o—two-opening penzinoreoxy shikanoreponinore, —two-opening benzylinolexano Fara / lequinoleoxycanolebonyl such as repo-nore, for example, trimethylsilyl, triethylsilyl, tert-butyldimethyl Trialkylsilyl such Lil and the like.
また、 R4で示されるエステル残基としては、 例えば低級アルキル、 シクロアル キル、 6〜： L 0員ァリール、 6〜； L 0員ァリール低級アルキル、 4〜： L 0員脂肪
族複素環式基、 4〜10員芳香族複素環式基等が挙げられる。 さらにこれらの基 は一つ以上の置換基を有していてもよく、 このような置換基としては、 低級アル キル、 水酸基、 低級アルコキシ、 ァミノ、 低級アルキルァミノ、 ジ低級アルキル ァミノ、 メルカプト、 低級アルキルチオ、 アミジノ、 グァニジノ、 力ルバモイル 、 チォカルバモイル、 スノレファモイノレ、 シァノ、 カルボキシル、 低級アルコキシ カルボニル、 ァラルキルォキシカルボニル、 ォキソ、 ハロゲノ、 シクロアノレキル 、 6〜 10員ァリール、 4〜 10員脂肪族複素環式基、 4〜 10員芳香族複素環 式基等が挙げられる。 これら置換基に含まれる官能基は必要に応じて保護基によ つて保護することができる。 用いられる保護基は常法により容易に除去し得るも のであれば特に制約が無く、 例えば T. W. Green, P. G. M. Wuts: Protective G roups in Organic Synthesis; 3rd. ed. , Wiley, New York, 1999、 めるレヽは P. Kocienski, Protecting Groups, Thieme, Stuttgart, 1994 を参照すること力 Sで さる。 Examples of the ester residue represented by R 4 include lower alkyl, cycloalkyl, 6-: L0-membered lower alkyl, 6-; L0-membered lower alkyl, 4-: L0 membered fat And a 4- to 10-membered aromatic heterocyclic group. Further, these groups may have one or more substituents. Examples of such a substituent include lower alkyl, hydroxyl, lower alkoxy, amino, lower alkylamino, di-lower alkylamino, mercapto, and lower alkylthio. , Amidino, guanidino, l'erbamoyl, thiocarbamoyl, snorefamoinole, cyano, carboxyl, lower alkoxycarbonyl, aralkyloxycarbonyl, oxo, halogeno, cycloanolequil, 6-10 membered aryl, 4-10 membered aliphatic complex And a cyclic group and a 4- to 10-membered aromatic heterocyclic group. The functional groups contained in these substituents can be protected by a protecting group, if necessary. The protecting group used is not particularly limited as long as it can be easily removed by a conventional method.For example, TW Green, PGM Wuts: Protective Group in Organic Synthesis; 3rd.ed., Wiley, New York, 1999. Ray is referred to by P. Kocienski, Protecting Groups, Thieme, Stuttgart, 1994.
Yが S原子である場合に好ましい R4としては、 既知力ルバぺネム系抗菌剤で使 用されている有機基が挙げられる。 例えば米国特許第 4194047号、 特開昭 60— 19787号、 特開昭 60— 104088号、 特開昭 60— 202886 号、 特開昭 61— 50 ·81号、 特開平 2— 49783号、 特開平 4 -27958 8号、 Journal of Organic Chemistry, 57, 4243-4249 (1992)、 Journal of Anti biotics, 46， 1866—1882 (1993)、 Heterocycles, 54, 497—528 (2001)等に記載の 既知力ルバぺネム系抗菌剤で使用されている有機基を用レ、ることができる。 次に、 メルカブタン誘導体である式 （4) の R° SHにおいて、 RQで示される 有機基について説明すると、 既知力ルバぺネム系抗菌剤で使用されている有機基 であれば、 特に制約が無く、 例えば上記に挙げた米国特許第 4194047号、 特開昭 60— 19787号、 特開昭 60— 104088号、 特開昭 60— 202Preferred R 4 when Y is an S atom is an organic group used in known antibacterial agents. For example, U.S. Pat. No. 4,940,047, JP-A-60-19787, JP-A-60-104088, JP-A-60-202886, JP-A-61-50 · 81, JP-A-2-49783, JP-A-2-49783 4 -27958 8, Journal of Organic Chemistry, 57, 4243-4249 (1992), Journal of Antibiotics, 46, 1866-1882 (1993), Heterocycles, 54, 497-528 (2001), etc. Organic groups used in rubanem antibacterial agents can be used. Next, the organic group represented by R Q in R ° SH of the formula (4), which is a mercaptan derivative, will be described. If it is an organic group used in a known antibacterial agent, it is particularly limited. No, for example, the above-mentioned U.S. Pat. No. 4,940,047, JP-A-60-19787, JP-A-60-104088, JP-A-60-202
886号、 特開昭 6 1— 5081号、 特開平 2— 49783号、 特開平 4一 27No. 886, JP-A-61-15081, JP-A-2-49783, JP-A-4-127
9588号、 Journal of Organic Chemistry, 57， 4243-4249 (1992)、 Journal o f Antibiotics, 46, 1866-1882 (1993)、 Heterocycles, 54, 497-528 (2001)等に
記載の既知力ルバぺネム系抗菌剤で使用されている有機基を用いることができる かかる基の例としては低級アルキル、 シク口アルキル、 6〜 1 0員ァリール、 6〜 1 0員ァリール低級アルキル、 ：〜 1 0員脂肪族複素環式基、 4〜 1 0員芳 香族複素環式基等が挙げられる。 さらにこれらの基は一つ以上の置換基を有して いても良く、 このような置換基としては、 低級アルキル、 水酸基、 低級アルコキ シ、 ァミノ、 低級アルキルァミノ、 ジ低級アルキルァミノ、 メルカプト、 低級ァ ルキルチオ、 アミジノ、 グァニジノ、 カノレバモイル、 チォカルバモイル、 スルフ ァモイル、 シァノ、 カルボキシル、 低級アルコキシカルボニル、 ァラルキルォキ シカノレポ二ノレ、 ォキソ、 ハロゲノ、 シクロアノレキノレ、 6 ~ 1 0員ァリーノレ、 4〜 1 0員脂肪族複素環式基、 4 ~ 1 0員芳香族複素環式基等が挙げられる。 これら 置換基に含まれる官能基は必要に応じて保護基によって保護することができる。 用いられる保護基は常法により容易に除去し得るものであれば特に制約が無く、 例えは T. W. Green, P. G. M. Wuts : Protective Groups in Organic Synthesis ； 3rd. ed. , Wiley, New York, 1999、 あるいは P. Kocienski, Protecting Gro ups, Thieme, Stuttgart, 1994 を参照することができる。 本発明で用いられるルイス酸としては、 アルミニウム、 スズ、 ジルコニウム、 マグネシウム、 ホウ素、 チタン、 亜鉛、 ケィ素、 鉄， ゲルマニウム、 アンチモン 、 ハフニウム、 ビスマス、 スカンジウム、 イットリビゥム、 マンガン、 コバノレト 、 ニッケル、 銅、 ガリウム、 サマリウム、 セリウム、 バナジウムあるいはタンダ ステン等を中心元素とする塩化物、 臭化物、 ヨウ化物、 低級アルキル化物おょぴ 錯体を挙げることができる。 No. 9588, Journal of Organic Chemistry, 57, 4243-4249 (1992), Journal of Antibiotics, 46, 1866-1882 (1993), Heterocycles, 54, 497-528 (2001), etc. The organic groups used in the known antibacterial agents of the present invention can be used. Examples of such groups include lower alkyl, cycloalkyl, 6-10 membered aryl, and 6-10 membered aryl lower alkyl. ,: To a 10-membered aliphatic heterocyclic group, a 4- to 10-membered aromatic heterocyclic group and the like. Further, these groups may have one or more substituents, such substituents as lower alkyl, hydroxyl, lower alkoxy, amino, lower alkylamino, di-lower alkylamino, mercapto, lower alkylthio. , Amidino, guanidino, canolebamoyl, thiocarbamoyl, sulfamoyl, cyano, carboxyl, lower alkoxycarbonyl, aralkilok shikanoreponinore, oxo, halogeno, cycloanolequinole, 6-10 membered arinole, 4-10 membered aliphatic And a 4- to 10-membered aromatic heterocyclic group. The functional groups contained in these substituents can be protected by a protecting group, if necessary. The protecting group used is not particularly limited as long as it can be easily removed by a conventional method. For example, TW Green, PGM Wuts: Protective Groups in Organic Synthesis; 3rd. Ed., Wiley, New York, 1999, or P. Kocienski, Protecting Groups, Thieme, Stuttgart, 1994. Examples of the Lewis acid used in the present invention include aluminum, tin, zirconium, magnesium, boron, titanium, zinc, silicon, iron, germanium, antimony, hafnium, bismuth, scandium, yttrium, manganese, covanolate, nickel, copper, and gallium. And chlorides, bromides, iodides, and lower alkylated complexes having samarium, cerium, vanadium, or tungsten as a central element.
好ましくは、 ァ /レミ-ゥム、 スズ、 ジノレコェゥム、 マグネシウム、 ホウ素、 チ タン、 亜鉛、 ケィ素あるいはスズを中心元素とする塩ィヒ物、 臭化物、 ヨウ化物、 低級アルキル化物およぴ錯体を挙げることができる。 Preferably, salts / bromides, bromides, iodides, lower alkylated compounds and complexes having a central element such as zinc / silicon or tin, magnesium / boron / titanium, zinc / silicon / tin, and tin / zinc compound are preferred. Can be mentioned.
特に好ましくはチタン、 ジノレコニゥムあるいはァノレミニゥムを中心元素とする 塩化物、 臭化物、 ヨウ化物、 低級アルキル化物および錯体を挙げることができる
また、 その使用量は、 原料化合物 （1) 1モルに対して 0. 1〜5. 0モル用い ることができるが、 好ましくは 0. 5〜4. 0 モ^ とりわけ 1. 0〜3. 0 モルであるのが好ましい。 本発明で用いられるルイス塩基としては、 有機アミン化合物を挙げることがで きる。 好ましくは、 例えばトリェチルァミン、 トリプチルァミン、 ジイソプロピ ルェチルァミン等のトリ低級アルキルァミンあるいはジェチルァミン、 ジィソプ 口ピルァミン、 ジ一sec—プチルァミン等のジ低級アルキルァミンを挙げることが できる。 Particularly preferred are chlorides, bromides, iodides, lower alkylated compounds and complexes having titanium, dinoreconium or anorenium as a central element. In addition, the amount of use can be 0.1 to 5.0 mol per 1 mol of the starting compound (1), preferably 0.5 to 4.0 mol, particularly 1.0 to 3.0 mol. It is preferably 0 mol. Examples of the Lewis base used in the present invention include organic amine compounds. Preferably, there may be mentioned, for example, tri-lower alkylamines such as triethylamine, triptylamine and diisopropylethylamine, and di-lower alkylamines such as getylamine, diisopropyl pyramine and di-sec-butylamine.
また、 その使用量は、 原料化合物 （1) 1モルに対して 0. 1〜6. 0モル用い ることができるが、 好ましくは 0. 5〜5. 0 モル、 とりわけ 1. 0〜4. 0 モルであるのが好ましい。 The amount of use can be 0.1 to 6.0 mol per mol of the starting compound (1), preferably 0.5 to 5.0 mol, particularly 1.0 to 4.0 mol. It is preferably 0 mol.
化合物 （1) を、 ルイス酸とルイス塩基存在下に閉環させ五員環を形成させる この反応は溶媒中で実施することができ、 溶媒としては反応に悪影響を及ぼさな いものであれば特に制約が無いが、 好ましいものとして例えばへキサン、 ヘプタ ン、 オクタン等の脂肪族炭化水素、 塩ィヒメチレン、 クロ口ホルム、 四塩化炭素、 1， 2—ジクロロェタン等のハロゲン化脂肪族炭化水素、 ベンゼン、 トルエン、 キシレン等の芳香族炭化水素、 モノクロ口ベンゼン、 ジクロロベンゼン等のハロ ゲン化芳香族炭化水素、 またはそれらの混合溶媒を挙げることができる。 Ring closure of compound (1) in the presence of a Lewis acid and a Lewis base to form a five-membered ring This reaction can be carried out in a solvent, and the solvent is not particularly limited as long as it does not adversely affect the reaction. None, but preferred are, for example, aliphatic hydrocarbons such as hexane, heptane, octane, etc .; halogenated aliphatic hydrocarbons such as carbon tetrachloride, 1,2-dichloroethane; benzene, toluene; Examples thereof include aromatic hydrocarbons such as xylene, halogenated aromatic hydrocarbons such as monochlorobenzene and dichlorobenzene, and mixed solvents thereof.
この反応は、 冷却〜室温下、 例えば一 75°C〜40°C、 とりわけ— 40°C〜3 0°Cで好適に実施できる。 式 （1) において、 Yが S原子である化合物を原料に用い、 ルイス酸とルイス 塩基存在下反応させると、 式 （2) の化合物と式 （3) の化合物の混合物が生成 する。 しかし R4がべンジル基、 n—ォクチル基、 シクロへキシル基、 This reaction can be suitably carried out under cooling to room temperature, for example, at a temperature of from 75 ° C to 40 ° C, especially from -40 ° C to 30 ° C. In the formula (1), when a compound in which Y is an S atom is used as a raw material and reacted with a Lewis acid in the presence of a Lewis base, a mixture of the compound of the formula (2) and the compound of the formula (3) is formed. But R 4 is benzyl, n-octyl, cyclohexyl,
あるいは下記式
Or the following formula
(式中、 R6はァミノ基の保護基を意味する。 ) (Wherein, R 6 represents a protecting group for an amino group.)
で表される基である化合物 （1) を用いると、 式 （2) の化合物が優先的に得ら れる。 一方、 R4がフエニル基の場合には、 式 （3) の化合物が優先的に得られる 0 When the compound (1) which is a group represented by is used, the compound of the formula (2) is preferentially obtained. On the other hand, when R 4 is a phenyl group, the compound of formula (3) is obtained preferentially 0
また、 式 （1) において、 Yが O原子である化合物を原料に用い、 ルイス酸と ルイス塩基存在下反応させると、 式 （3) の化合物 （力/レバぺナム誘導体） が生 成する。 また生成物 (2) および （3) の混合物、 あるいは生成物 （3) にメルカプタ ン誘導体、 R°SH (4) を作用させると、 下記式 （5 a) で表わされるカルバぺ ナム誘導体が得られる。 Further, when a compound in which Y is an O atom in the formula (1) is used as a raw material and reacted with a Lewis acid in the presence of a Lewis base, a compound of the formula (3) (force / levandam derivative) is generated. When a mercaptan derivative or R ° SH (4) is allowed to act on a mixture of the products (2) and (3) or the product (3), a carbanamide derivative represented by the following formula (5a) is obtained. Can be
(式中、 R°、 R1, R2、 R3および R5は前掲と同じ。 ） (In the formula, R °, R 1 , R 2 , R 3 and R 5 are the same as described above.)
このメルカブタン誘導体 （4) を作用させる反応は、 常法に従って行われる。 例えば、 塩基の存在または非存在下、 適当な溶媒中で実施することができる。 塩基としては有機アミン化合物を挙げることができる。 好ましくは、 例えばト リェチルァミン、 トリプチルァミン、 ジイソプロピルェチルァミン等のトリ低級 アルキルアミンあるいはジェチルァミン、 ジイソプロピルァミン、 ジ一 sec—ブチ ルァミン等のジ低級アルキルァミンを挙げることができる。 溶媒としては、 この反応に悪影響を及ぼさないものであれば特に制約が無いが 、 好ましいものとして、 例えばへキサン、 ヘプタン、 オクタン等の脂肪族炭化水 素、 塩化メチレン、 クロ口ホルム、 四塩化炭素、 1， 2—ジクロロェタン等のハ
ロゲン化脂肪族炭化水素、 ベンゼン、 トゾレエン、 キシレン等の芳香族炭化水素、 モノクロ口ベンゼン、 ジクロロベンゼン等のハロゲン化芳香族炭化水素、 あるい はそれらの混合溶媒を挙げることができる。 The reaction for reacting the mercaptan derivative (4) is performed according to a conventional method. For example, the reaction can be carried out in a suitable solvent in the presence or absence of a base. Examples of the base include organic amine compounds. Preferably, for example, tri-lower alkylamines such as triethylamine, triptylamine and diisopropylethylamine, and di-lower alkylamines such as getylamine, diisopropylamine and di-sec-butylamine are exemplified. The solvent is not particularly limited as long as it does not adversely affect the reaction, but preferred examples thereof include aliphatic hydrocarbons such as hexane, heptane, and octane, methylene chloride, chloroform, and carbon tetrachloride. , 1, 2-dichloroethane Examples thereof include aromatic hydrocarbons such as halogenated aliphatic hydrocarbons, benzene, tosoleene, and xylene; halogenated aromatic hydrocarbons such as benzene, dichlorobenzene, and the like; and mixed solvents thereof.
反応は、 冷却〜室温下、 例えば一 75 °C〜 40 °C、 とりわけ一 40 °C〜 30 °C で好適に実施できる。 The reaction can be suitably carried out under cooling to room temperature, for example, at a temperature of from 75 ° C to 40 ° C, especially from 140 ° C to 30 ° C.
本発明方法によれば、 緩和な反応条件で化合物 （2) 、 (3) 並びに （5) が 得られる。 According to the method of the present invention, compounds (2), (3) and (5) can be obtained under mild reaction conditions.
また、 化合物 （2) において、 置換基 R4が既知力ルバぺネム系抗菌剤で使用さ れている有機基である場合、 必要に応じて公知の方法に従い R R5および/ま たは R4における保護基を脱離せしめることによって、 直接力ルバぺネム系抗菌剤 に導くことができ、 この様な中間体 （2) は殊に重要である。 原料化合物 (1) の一部は新規化合物であるが、 実施例に示した方法あるいは これに準じた方法で製造できる。 In the case where the substituent R 4 in the compound (2) is an organic group used in a known antibacterial agent of ruvanem series, if necessary, RR 5 and / or R 4 By removing the protecting group in the above, it is possible to directly lead to a ruvanem-based antibacterial agent, and such an intermediate (2) is particularly important. A part of the starting compound (1) is a novel compound, but it can be produced by the method described in Examples or a method analogous thereto.
また原料化合物 （1) には、 その不斉炭素に基づく光学異性体が存在しうるが 、 原料として光学活性化合物 （1) を用いた場合、 反応は立体構造を保持したま ま進行し、 ェピマー化することなく化合物 （2) および/または化合物 （3) 、 さらには （5) へと変換することもできる。 The starting compound (1) may have optical isomers based on its asymmetric carbon. However, when the optically active compound (1) is used as a starting material, the reaction proceeds while maintaining the steric structure, and Compound (2) and / or compound (3) can be converted to compound (5) without conversion.
また力ルバぺネム系抗菌剤に導くてんから、 式 （1) において R3が水素原子で 、 R2が R配位のメチル基である化合物を原料として用いることは好ましい。 発明を実施するための最良の形態 Further, from the viewpoint of leading to the antibacterial agent, it is preferable to use, as a raw material, a compound in which R 3 is a hydrogen atom and R 2 is an R-coordinated methyl group in the formula (1). BEST MODE FOR CARRYING OUT THE INVENTION
以下実施例を挙げて、 本発明を具体的に説明する。 実施例 Hereinafter, the present invention will be described specifically with reference to examples. Example
実施例 1 Example 1
ァリル （4R,5S,6S)- 3_ベンジルチオ - 6 - [ (1R)-1- (t-プチルジメチルシリルォキ シ）ェチル] - 4-メチル -7 -ォキソ - 1 -ァザビシク口 [3.2.0]ヘプト- 2-ェン -2 -力
ノレボキシレート ： Aryl (4R, 5S, 6S) -3_benzylthio-6-[(1R) -1- (t-butyldimethylsilyloxy) ethyl] -4-methyl-7-oxo-1-azazabic [3.2. 0] Hept-2-en-2 power Noreboxylate:
アルゴン気流下、 S-ベンジル （2R)- 2_{(2S, 3S)- 1-ァリルォキシカルポニルメチ ル -3 - [(1R) - -ブチルジメチルシリルォキシ）ェチル] - 4 -ォキソァゼチジン - 2-イノレ}チォプロピオネート（101 rag, 0.20 mraol) およびプチルァミン（122 mg, 0 .66 mmol)の塩化メチレン溶液 （0.5 ml)に、 四塩化チタン（1M-塩化メチレン溶液 , 0.60 ml, 0.60 mmol)を- 50°C〜- 40 °Cで撹袢しながら 15〜20分かけて滴下し、 そのまま 1時間撹拌した。 反応混合物に水を加えて、 エーテル抽出を行い、有機層 を水洗、 飽和食塩水洗し、 無水硫酸ナトリウムで乾燥した。 溶媒を減圧留去し、 得られた粗生成物をシリカゲル力ラムクロマトグラフィー（へキサン：酢酸ェチル = 5 ： 1)で精製し、 無色非晶祈の目的物（71 rag, 収率 72%)を得た。 Under an argon stream, S-benzyl (2R) -2 _ {(2S, 3S) -1-aryloxycarbonylmethyl-3--[(1R)--butyldimethylsilyloxy) ethyl] -4-oxoazetidine- 2-Inole} thiopropionate (101 rag, 0.20 mraol) and butylamine (122 mg, 0.66 mmol) in methylene chloride (0.5 ml) were added to titanium tetrachloride (1M-methylene chloride solution, 0.60 ml, 0.60 ml). mmol) was added dropwise over 15-20 minutes while stirring at -50 ° C to -40 ° C, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ether. The organic layer was washed with water, saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give a colorless amorphous target (71 rag, yield 72%). I got
XH NMR (400 MHz, CDC13): δ = 0.061 (3Η, . s) , 0.068 (3Η, s)， 0,872 (9Η, s) ， 1.23 (3H, d, J = 7.2), 1.25 (3H, d， J = 6.4) , 3.17 (1H， dd， J = 6.4 and 2.8)， 3.26-3.34 (1H， m)， 4.04-4.08 (3H, ra), 4.17-4.23 (1H, m)， 4.66— 4.81 (2H, m), 5.21-5.25 (1H, m), 5.41— 5.46 (1H， m), 5.90-5.99 (1H， m), 7.23-7.37 (5H, ra) 実施例 2 X H NMR (400 MHz, CDC1 3): δ = 0.061 (. 3Η, s), 0.068 (3Η, s), 0,872 (9Η, s), 1.23 (3H, d, J = 7.2), 1.25 (3H, d, J = 6.4), 3.17 (1H, dd, J = 6.4 and 2.8), 3.26-3.34 (1H, m), 4.04-4.08 (3H, ra), 4.17-4.23 (1H, m), 4.66—4.81 (2H, m), 5.21-5.25 (1H, m), 5.41-5.46 (1H, m), 5.90-5.99 (1H, m), 7.23-7.37 (5H, ra)
ァリル （4R，5S，6S)- 3-ォクチルチオ -6-[(lR)-l-(t-ブチルジメチルシリルォキ シ）ェチル] - 4 -メチル - 7-ォキソ - 1 -ァザビシク口 [3.2.0]ヘプト -2 -ェン -2-力 ルボキシレート ： Aryl (4R, 5S, 6S) -3-octylthio-6-[(lR) -l- (t-butyldimethylsilyloxy) ethyl] -4-methyl-7-oxo-1-azazavic [3.2. 0] Hept-2-en-2-force ruboxylate:
アルゴン気流下、 S-ォクチル （2R)- 2- {(2S，3S)- 1-ァリルォキシカルボ二ルメチ ル- 3 - [(1R) - l-(t-ブチルジメチルシリルォキシ）ェチル ]-4-ォキソァゼチジン - 2 - ィル }チォプロピオネー 1、 (105 mg, 0.20 mraol)およびトリブチルァミン（122 rag, 0.66 mmol)の塩ィ匕メチレン溶液（0.5 ml)に、 四塩化チタン（1M -塩ィ匕メチレン溶 液， 0.60 ml, 0.60 mmol)を- 50°C〜- 40°Cで撹拌しながら 15〜20分かけて滴下し、 そのまま 1時間撹拌した。 反応混合物に水を加えて、 エーテル抽出を行い、有機層 を水洗、 飽和食塩水洗し、 無水硫酸ナトリウムで乾燥した。 溶媒を減圧留去し、 得られた粗生成物をシリカゲル力ラムクロマトグラフィー（へキサン：酢酸ェチル
= 5 ： 1)で精製し、 淡黄色非晶析の目的物 （66 mg, 収率 65%) を得た。 S-Octyl (2R) -2- 2-((2S, 3S) -1-aryloxycarbonylmethyl-3-([1R) -l- (t-butyldimethylsilyloxy) ethyl) ] -4-oxozetidine-2-yl} thiopropione 1 (105 mg, 0.20 mraol) and tributylamine (122 rag, 0.66 mmol) in methylene chloride solution (0.5 ml) were added to titanium tetrachloride (1M- A methylene salt solution (0.60 ml, 0.60 mmol) was added dropwise at −50 ° C. to −40 ° C. over 15 to 20 minutes, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ether. The organic layer was washed with water, saturated brine, and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the obtained crude product is subjected to silica gel column chromatography (hexane: ethyl acetate). = 5: 1) to give the target compound as pale yellow non-crystallized substance (66 mg, yield 65%).
NMR (400 MHz, CDC13): δ = 0.079 (6Η， s)， 0.883 (9Η， s), 1.22— 1.46 (1 9Η， m), 1.61— 1.68 (2Η， ra), 2.75-2.88 (2Η, ra), 3.18 (1H, dd, J = 6.6 and 2.4)， 3.25-3.33 (1H， m), 4.12-4.14 (1H, dd, J = 9.2 and 2.6), 4.19-4. 26 (1H, m), 4.66-4.81 (2H, m)， 5.21-5.25 (1H， ra), 5.42-5. 7 (1H， m), 5 .90— 6.00 (1H, ra) 実施例 3 NMR (400 MHz, CDC1 3) : δ = 0.079 (6Η, s), 0.883 (9Η, s), 1.22- 1.46 (1 9Η, m), 1.61- 1.68 (2Η, ra), 2.75-2.88 (2Η, ra), 3.18 (1H, dd, J = 6.6 and 2.4), 3.25-3.33 (1H, m), 4.12-4.14 (1H, dd, J = 9.2 and 2.6), 4.19-4.26 (1H, m) , 4.66-4.81 (2H, m), 5.21-5.25 (1H, ra), 5.42-5.7 (1H, m), 5.90—6.00 (1H, ra)
ァリル （4R，5S,6S)-3-シクロへキシルチオ - 6- [(1R)- 1- (t-ブチルジメチルシリ ルォキシ）ェチル ]- 4 -メチル -7-ォキソ -1-ァザビシクロ [3.2.0]ヘプト -2-ェン -2-力ノレボキシレート ： Aryl (4R, 5S, 6S) -3-cyclohexylthio-6-[(1R) -1- (t-butyldimethylsilyloxy) ethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0 ] Hept-2-ene-2-force norevoxylate:
アルゴン気流下、 S-シクロへキシル （2R)- 2- {(2S，3S) - 1 -ァリルォキシカルボ二 ルメチノレ- 3- [ (1R) -1- (t-プチルジメチルシリルォキシ）ェチル] - 4 -ォキソァゼチジ ン - 2-イノレ}チォプロピオネート （100 mg, 0.20 mmol)およびトリプチルァミン（1 22 mg, 0.66 ramol)の塩化メチレン溶液（0.5 ml)に、 四塩化チタン（1M-塩化メチレ ン溶液， 0.60 ml, 0.60 ramol)を- 20°C〜- 15°Cで撹拌しながら 15〜20分かけて滴 下し、 そのまま 1時間撹拌した。 反応混合物に水を加えて、 エーテル抽出を行い、 有機層を水洗、 飽和食塩水洗し、 無水硫酸ナトリウムで乾燥した。 溶媒を減圧留 去し、 得られた粗生成物をシリカゲル力ラムクロマトグラフィー（へキサン：酢酸 ェチル = 5 ： 1)で精製し、 淡黄色非晶析の目的物 （78 rag, 収率 81%) を得た。 LH NMR (400 MHz, CDC13)： δ = 0.082 (3Η, s), 0.087 (3Η, s)， 0, 889 (9H， s) ， 1.19一 1.52 (11H, m), 1.59— 1.71 (1H, m)， 1.76— 1.86 (2H， ra), 1.91一 2.02 (2H, m), 3.03-3.11 (1H， m)， 3.19 (1H， dd, J = 5.6 and 2.8), 3.24—3.32 (1H, m), 4.15 (1H, dd, J = 9.6 and 2.4)， 4.21-4.27 (1H， ra), 4.65-4.82 ( 2H, ra), 5.21-5.25 (1H, m), 5.42—5.47 (1H， m), 5.91-6.00 (1H， m) Under an argon stream, S-cyclohexyl (2R) -2- 2-((2S, 3S)-1-aryloxycarbonylmethinole-3- [(1R) -1- (t-butyldimethylsilyloxy) Ethyl] -4-oxoxethidin-2-inole} thiopropionate (100 mg, 0.20 mmol) and triptylamine (122 mg, 0.66 ramol) in methylene chloride (0.5 ml) were added to titanium tetrachloride (1M-chloride). (Methylene solution, 0.60 ml, 0.60 ramol) was added dropwise over 15-20 minutes while stirring at -20 ° C to -15 ° C, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ether. The organic layer was washed with water, brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give a pale yellow amorphous product (78 rag, yield 81%). ). L H NMR (400 MHz, CDC1 3): δ = 0.082 (3Η, s), 0.087 (3Η, s), 0, 889 (9H, s), 1.19 one 1.52 (11H, m), 1.59- 1.71 (1H , m), 1.76-1.86 (2H, ra), 1.91-2.02 (2H, m), 3.03-3.11 (1H, m), 3.19 (1H, dd, J = 5.6 and 2.8), 3.24-3.32 (1H, m), 4.15 (1H, dd, J = 9.6 and 2.4), 4.21-4.27 (1H, ra), 4.65-4.82 (2H, ra), 5.21-5.25 (1H, m), 5.42-5.47 (1H, m ), 5.91-6.00 (1H, m)
同様の手法で、 溶媒としてトルエンを用いたところ、 目的物 （69 mg, 収率 72% ) を得た。
実施例 4 In the same manner, when toluene was used as a solvent, the desired product (69 mg, yield 72%) was obtained. Example 4
ァリル （4R, 5S, 6S)- 6_[ (1R)_1- (t -プチルジメチルシリルォキシ）ェチル ]- 3-[ (3 S, 5S)- 5-ジメチルァミノカルボニル _l_(p-二ト口ベンジルォキシカルポニル）ピ 口リジン- 3 -ィルチオ] - 4 -メチル -7 -ォキソ -1-ァザビシク口 [3.2.0]ヘプト- 2- ェン -2-力ノレボキシレート ： Aryl (4R, 5S, 6S) -6 _ [(1R) _1- (t-butyldimethylsilyloxy) ethyl] -3--3-[(3S, 5S) -5-dimethylaminocarbonyl _l_ (p-dito Benzyloxycarponyl) pi-lysine-3-ylthio] -4--4-methyl-7-oxo-1-azavicic [3.2.0] hept-2-ene-2-hexanoloxylate:
アルゴン気流下、 S- [(3S， 5S)- 5-ジメチルァミノカルボニル- 1 -（p-二トロべンジ ノレォキシカルボニル） ピロリジン - 3-ィル] (2R)-2-{(2S, 3S)- 1-ァリルォキシカル ポニルメチル- 3 - [ (1R) - 1- (t_プチルジメチルシリルォキシ）ェチル ]-4 -ォキソァゼ チジン 2-ィル }チォプロピオネート （100 mg, 0.139 mmol)およびジ- sec-ブチル ァミン（81 mg, 0.63 瞧 ol)の塩化メチレン溶液（0.5 ral)に、 四塩化チタン（1M-塩 化メチレン溶液， 0.56 ml, 0.56 mmol)を- 20〜- 15 °Cで撹拌しながら 15〜20分か けて滴下し、 同温度で 2時間撹拌した。 反応混合物に水を加えて、 酢酸ェチル抽出 を行い、有機層を水洗、 飽和食塩水洗し、 無水硫酸ナトリウムで乾燥した。 溶媒を 減圧留去し、 得られた粗生成物をシリカゲル力ラムクロマトグラフィー（へキサン ：酢酸ェチノレ： = 1 : 4 - 0 : 1)で精製し、 淡黄色非晶析の目的物 (41 mg, 収率 42 %)を得た。 Under an argon stream, S-[(3S, 5S) -5-dimethylaminocarbonyl-1- (p-ditrobenzinoleoxycarbonyl) pyrrolidine-3-yl] (2R) -2-{(2S , 3S) -1-Aryloxycarponylmethyl-3--[(1R)-1-(t_butyldimethylsilyloxy) ethyl] -4 -oxoazetidine 2-yl} thiopropionate (100 mg, 0.139 mmol) And di-sec-butylamine (81 mg, 0.63 mol) in methylene chloride (0.5 ral), titanium tetrachloride (1M-methylene chloride solution, 0.56 ml, 0.56 mmol) at -20 to -15 ° C The mixture was added dropwise over 15 to 20 minutes while stirring at, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with water, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate: = 1: 4-0: 1) to give a pale yellow amorphous product (41 mg) , Yield 42%).
XH NMR (400 MHz, CDC13): δ = 0.07-0.09 (6Η, m), 0,86— 0.89 (9H， ra)， 1.2 3—1.28 (6H， m), 1.90— 1.98 (1H， m), 2.68-2.78 (1H, ra), 2.94—3.11 (6H, m), 3.20-3.31 (2H， m), 3.46-3.53 (1H, m), 3.61-3.75 (1H, ra), 4.02—4.2 8 (3H， ra), 4.66-4.80 (3H, m), 5.05—5.46 (4H, m), 5.90— 5.99 (1H， ra), 7. 43-7.54 (2H, ra), 8.18-8.24 (2H, m) 実施例 5 X H NMR (400 MHz, CDC1 3): δ = 0.07-0.09 (6Η, m), 0,86- 0.89 (9H, ra), 1.2 3-1.28 (6H, m), 1.90- 1.98 (1H, m ), 2.68-2.78 (1H, ra), 2.94—3.11 (6H, m), 3.20-3.31 (2H, m), 3.46-3.53 (1H, m), 3.61-3.75 (1H, ra), 4.02—4.2 8 (3H, ra), 4.66-4.80 (3H, m), 5.05-5.46 (4H, m), 5.90- 5.99 (1H, ra), 7.43-7.54 (2H, ra), 8.18-8.24 (2H , m) Example 5
p -二ト口べンジル (4R, 5S， 6S) -6- [ (1R) -1- (t-プチルジメチルシリノレオキシ）ェ チル] -4-メチル -3-フエ二ルチオ- 7-ォキソ -1-ァザビシクロ [3.2.0]ヘプト- 2 -ェ ン -2-カルボキシレートおよび p-Nitoventil (4R, 5S, 6S) -6-[(1R) -1- (t-butyldimethylsilinoleoxy) ethyl] -4-methyl-3-phenylthio-7-oxo -1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate and
p-二トロべンジル (4RS, 5S, 6S) - 6 - [ (1R) -1- (t-ブチルジメチルシリルォキシ）ェ チノレ]- 4-メチル- 3, 7 -ジォキソ -1-ァザビシク口 [3.2.0]ヘプタン- 2-カルボキシレ
ート p-Nitrobenzil (4RS, 5S, 6S) -6-[(1R) -1- (t-butyldimethylsilyloxy) ethynole] -4--4-methyl-3,7-dioxo-1-azabisik [3.2.0] Heptane-2-carboxyle To
窒素気流下に S- phenyl (2R)- 2- {(2S, 3S)- 1- [p-二トロべンジルォキシカルボ二 ルメチル] - 3- [ (lR)-l-(t -プチルジメチルシリルォキシ）ェチル] - 4 -ォキソァゼチ ジン - 2-ィル }チォプロピオネート （117 mg, 0.2 mmol)およびトリブチルアミン（ 122 mg, 0.66瞧 ol)の塩化メチレン溶液（0.5 ml)に、 四塩化チタン （1M-トルェ ン溶液， 0.6 ml， 0.6 mmol)を氷冷下で撹拌しながら 30分かけて滴下し、 室温まで 昇温して 30分間撹拌した。 反応混合物に水を加えて、 ジェチルエーテル抽出を行 い、有機層を水洗、 飽和食塩水洗し、 無水硫酸マグネシウムで乾燥した。 溶媒を減 圧留去し、 得られた粗生成物をシリカゲル薄層クロマトグラフィー (へキサン:酢 酸ェチル 二 2 ： 1)で精製し、 p-ュトロべンジル （4R，5S,6S)- 6 - [(1R)- 1- (t-プチ ルジメチルシリノレォキシ)ェチノレ ] -4-メチル- 3 -フエ二ルチオ- 7-ォキソ - 1 -ァザビ シクロ [3.2.0]ヘプト- 2-ェン -2-カルボキシレート（11 rag, 収率 10%)および p_ 二トロべンジル （4RS，5S，6S)-6- [(1R)-1- (t -プチルジメチルシリルォキシ）ェチ ル]- 4 -メチル -3, 7-ジォキソ -1-ァザビシク口 [3.2.0]ヘプタン- 2 -カルボキシレー ト （39mg, 収率 39%)を得た。 S-phenyl (2R) -2- 2-((2S, 3S) -1- [p-nitrobenzoyloxycarbonylmethyl]-3- [(lR) -l- (t-butyldimethyl (Silyloxy) ethyl] -4-oxoxetidine--2-yl} thiopropionate (117 mg, 0.2 mmol) and tributylamine (122 mg, 0.66 mol) in methylene chloride (0.5 ml) were added to Titanium chloride (1M-toluene solution, 0.6 ml, 0.6 mmol) was added dropwise over 30 minutes while stirring under ice cooling, and the mixture was heated to room temperature and stirred for 30 minutes. Water was added to the reaction mixture, extracted with getyl ether, and the organic layer was washed with water, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel thin-layer chromatography (hexane: ethyl acetate 2-2: 1) to give p-utrobenzil (4R, 5S, 6S) -6 -[(1R)-1- (t-butyldimethylsilinoleoxy) ethynole] -4-methyl-3- phenylthio-7-oxo-1- 1-azabicyclo [3.2.0] hept-2-e 2-Carboxylate (11 rag, 10% yield) and p_Nitrobenzyl (4RS, 5S, 6S) -6-[(1R) -1- (t-butyldimethylsilyloxy) ethyl ] -4-Methyl-3,7-dioxo-1-azabisic [3.2.0] heptane-2-carboxylate (39 mg, yield 39%) was obtained.
これらの物性データは文献 (M. Sunagawa, A. Sasaki, H. Matsumura, K. Goda and K. Tamoto, Chem. Pharm. Bull. , 42, 1381 (1994).) 記載のものに一致し These physical data correspond to those described in the literature (M. Sunagawa, A. Sasaki, H. Matsumura, K. Goda and K. Tamoto, Chem. Pharm. Bull., 42, 1381 (1994)).
実施例 6 Example 6
ァリル （4R， 5S， 6S)_6- [ (1R)- 1- (t-プチルジメチルシリルォキシ）ェチル ]-3- [ (3 S, 5S) - 5-ジメチルァミノ力ルポニル- 1- (ァリルォキシカルボニル） ピロリジン - 3- ィルチオ ] -4-メチル -7-ォキソ -1 -ァザビシクロ [3.2.0]ヘプト- 2 -ェン - 2 -カル ポキシレート ： Aryl (4R, 5S, 6S) _6-[(1R) -1- (t-butyldimethylsilyloxy) ethyl] -3-[(3S, 5S) -5-Dimethylaminoaminol-ponyl-1- (aryl Oxycarbonyl) pyrrolidine-3-ylthio] -4-methyl-7-oxo-1 -azabicyclo [3.2.0] hept-2-ene-2-carboxylate:
原料化合物として、 S-[(3S，5S) - 5-ジメチルァミノ力ルポ-ル- 1 -（ァリルォキシ カノレボニル） ピロリジン— 3—ィノレ] (2R)-2-{(2S, 3S)- 1-ァリルォキシカルポ-ノレメ チル- 3- [ (1R) -1- (t -プチルジメチルシリルォキシ）ェチル ]-4-ォキソァゼチジン - 2 -ィル }チォプロピオネート （100 mg, 0.156 mmol) およびジ- sec-ブチルァミン（
67 mg, 0.52 ramol)を用い実施例 4と同様にして （反応温度は最初- 45〜- 40 °C、 後に- 20〜- 15 °Cへ昇温） 、 目的物 （70 rag, 収率 72%) を得た。 このものの物性 ァータは文献 (Sakurai, Osamu； Ogiku, Tsuyoshi； Takanasi, Masarai； Hayashi, Masahito; Yamanaka, Takeshi； Horika a, Hirosni； I asaki, Tameo. J. Org. Chem. (1996), 61(22), 7889-7894.) 記載のものに一致した。 実施例 7 (原料の製法） As a raw material compound, S-[(3S, 5S) -5-dimethylaminophenol-1-(aryloxycanolebonyl) pyrrolidine- 3 -inole] (2R) -2-{(2S, 3S) -1-aryl Oxycarpo-noremetyl-3-[(1R) -1- (t-butyldimethylsilyloxy) ethyl] -4-oxoazetidine-2-yl} thiopropionate (100 mg, 0.156 mmol) -sec-Butylamine ( 67 mg, 0.52 ramol) in the same manner as in Example 4 (reaction temperature was first raised to -45 to -40 ° C, and then raised to -20 to -15 ° C), and the target compound (70 rag, yield 72 %). The physical properties of this product are described in the literature (Sakurai, Osamu; Ogiku, Tsuyoshi; Takanasi, Masarai; Hayashi, Masahito; Yamanaka, Takeshi; Horika a, Hirosni; Iasaki, Tameo. J. Org. Chem. (1996), 61 (22) ), 7889-7894.) Example 7 (Production method of raw materials)
S -べンジノレ (2R)-2-{(2S, 3S)- 1-ァリルォキシカルボニルメチル - 3- [(1R)- 1- ( t -ブチルジメチルシリルォキシ）ェチル] -4-ォキソァゼチジン -2 -ィル}チォプロ. ピオネート ： S-Venzinole (2R) -2-{(2S, 3S) -1-aryloxycarbonylmethyl-3-[(1R) -1- (t-butyldimethylsilyloxy) ethyl] -4-oxoazetidine -2 -Ill} Chopro. Pionate:
アルゴン気流下、 (2R)-2- {(2S, 3S)- 1-ァリルォキシ力ルポエルメチル -3-[(lR ) -1- (t -ブチルジメチルシリルォキシ）ェチル] - 4 -ォキソァゼチジン -2-ィル}プロ ピオン酸（600 mg, 1.50 mmol)のベンゼン溶液（12 ml)に、 0〜5 °Cで撹拌しながら Ν,Ν'-ジシクロへキシルカルポジイミド (340 rag, 1.65 mmol)、 次いで 4-ジメチル アミノビリジン（18 rag, 0.15 mraol)を加え、 20〜25 °Cで 30分撹拌した。 反応混合 物に 20〜25 °Cでフエニルメタンチオール（205 rag, 1.65 mmol)のベンゼン溶液（0. 5 ml) を滴下し、 さらに 16時間撹拌した。 反応混合物をセライトろ過し、 溶媒を 減圧留去して、 得られた粗生成物をシリ力ゲル力ラムクロマトグラフィー (へキサ ン:酢酸ェチル = 10 ： 1)で精製し、 無色液体の目的物 （533 mg, 収率 70%)を得 た。 Under a stream of argon, (2R) -2-{(2S, 3S) -1-aryloxy-propylmethyl-3-[(lR) -1- (t-butyldimethylsilyloxy) ethyl] -4-oxoxetidine-2-ル, Ν'-Dicyclohexylcarposimide (340 rag, 1.65 mmol) was added to a solution of benzyl} propionic acid (600 mg, 1.50 mmol) in benzene (12 ml) at 0-5 ° C with stirring. 4-Dimethylaminoviridine (18 rag, 0.15 mraol) was added, and the mixture was stirred at 20 to 25 ° C for 30 minutes. To the reaction mixture was added dropwise a benzene solution (0.5 ml) of phenylmethanethiol (205 rag, 1.65 mmol) at 20 to 25 ° C, and the mixture was further stirred for 16 hours. The reaction mixture was filtered through celite, the solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel gel column chromatography (hexane: ethyl acetate = 10: 1) to give the target compound as a colorless liquid. (533 mg, 70% yield).
NMR (400 MHz, CDC13): δ = 0.063 (3Η, s), 0.077 (3Η， s)， 0.866 (9Η， s) ， 1.22 (3H, d， J = 6.1 Hz), 1.25 (3H, d, J = 7.1 Hz), 3.01-3.07 (2H, m)， 3.87 (1H, d, J = 18.0 Hz), 4.07—4.17 (4H, m), 4.21 (1H， d, J = 18.0 Hz) , 4.60-4.63 (2H, m)， 5.24-5.36 (2H, m), 5.85— 5.95 (1H， tn), 7.22 - 7.32 (5H， in). 実施例 8 (原料の製法） NMR (400 MHz, CDC1 3) : δ = 0.063 (3Η, s), 0.077 (3Η, s), 0.866 (9Η, s), 1.22 (3H, d, J = 6.1 Hz), 1.25 (3H, d, J = 7.1 Hz), 3.01-3.07 (2H, m), 3.87 (1H, d, J = 18.0 Hz), 4.07-4.17 (4H, m), 4.21 (1H, d, J = 18.0 Hz), 4.60- 4.63 (2H, m), 5.24-5.36 (2H, m), 5.85—5.95 (1H, tn), 7.22-7.32 (5H, in). Example 8 (Production of raw materials)
S -ォクチル (2R) -2- { (2S, 3S) - 1 -ァリルォキシカルポニルメチル -3- [ (1R) -1- (t-
ブチノレジメチノレシリノレォキシ）ェチル] - 4-ォキソァゼチジン -2 -ィル }チォプロピ ォネート ： S-Octyl (2R) -2- {(2S, 3S)-1-aryloxycarbonylmethyl-3- [(1R) -1- (t- Butinoresimetinolecinoleoxy) ethyl]-4-oxoazetidine-2-yl} thiopropionate:
アルゴン気流下、 (2R)-2-{(2S, 3S) - 1-ァリルォキシカルボニルメチル- 3- [(1R) - l-(t -プチルジメチルシリルォキシ）ェチル ]-4-ォキソァゼチジン - 2_イノレ}プロピ オン酸（100 mg, 0.25 mmol)のァセトエトリル溶液（2 ml)に、 20〜25 °Cで撹拌し ながら Ν,Ν，-カルボエルジイミダゾール（49 mg, 0.30 mmol) を加え、 そのまま 1時 間撹拌した。 反応混合物に オクタンチオール (44 mg, 0.30 mmol)のァセトニトリ ノレ溶液 （0.2 ml)、 次いでトリェチルァミン（30 mg, 0.30隱 ol)のァセトニトリノレ 溶液 （0.2 ml) を順次滴下し、 同温度でさらに 1時間撹拌した。 反応混合物に IN— 塩酸水を加えて、 酢酸ェチル抽出を行い、有機層を水洗、 飽和食塩水洗し、 無水硫 酸ナトリウムで乾燥した。 溶媒を減圧留去し、 得られた粗生成物をシリカゲル力 ラムクロマトグラフィー (へキサン:酢酸ェチル = 5 ： 1)で精製し、 無色液体の目 的物（130 rag, 収率 98%)を得た。 Under a stream of argon, (2R) -2-{(2S, 3S) -1-aryloxycarbonylmethyl-3-[(1R) -l- (t-butyldimethylsilyloxy) ethyl] -4-oxoazetidine 2, Ν, -Carboerdiimidazole (49 mg, 0.30 mmol) was added to a solution of 2_inole} propionic acid (100 mg, 0.25 mmol) in acetone (2 ml) while stirring at 20 to 25 ° C. The mixture was further stirred for 1 hour. To the reaction mixture were successively added dropwise a solution of octanethiol (44 mg, 0.30 mmol) in acetone (0.2 ml) and then a solution of triethylamine (30 mg, 0.30 mmol) in acetone (0.2 ml), and the mixture was stirred at the same temperature for another hour. did. IN-hydrochloric acid solution was added to the reaction mixture, ethyl acetate extraction was performed, and the organic layer was washed with water, saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the target compound as a colorless liquid (130 rag, yield 98%). Obtained.
1 H應 R (400 MHz, CDC13 )： δ = 0.079 (3H， s)， 0.084 (3H， s)， 0.879 (9H, s) , 1.20-1.37 (18H, m)， 1.51— 1.59 (3H, m), 2.85 (2H， t, J = 7.4 Hz) , 2.99 -3.05 (2H， ra), 3.90 (1H， d, J = 18.0 Hz), 4.07 (1H， dd， J = 2.8 and 2.8 Hz), 4.13-4.19 (1H, m), 4.25 (1H, d, J = 18.0 Hz), 4.62— 4.64 (2H, m), 5 .24-5.37 (2H， m), 5.86— 5.96 (1H, m). 実施例 9 (原料の製法） 1 H Keio R (400 MHz, CDC1 3) : δ = 0.079 (3H, s), 0.084 (3H, s), 0.879 (9H, s), 1.20-1.37 (18H, m), 1.51- 1.59 (3H, m), 2.85 (2H, t, J = 7.4 Hz), 2.99 -3.05 (2H, ra), 3.90 (1H, d, J = 18.0 Hz), 4.07 (1H, dd, J = 2.8 and 2.8 Hz), 4.13-4.19 (1H, m), 4.25 (1H, d, J = 18.0 Hz), 4.62-4.64 (2H, m), 5.24-5.37 (2H, m), 5.86-5.96 (1H, m). Example 9 (Raw material production method)
S-シク口へキシル (2R) -2-{(2S, 3S) - 1-ァリルォキシカルボエルメチル- 3- [ (1R )- 1- (t -プチルジメチルシ Vルォキシ）ェチル ]-4-ォキソァゼチジン - 2-ィル }チォ プロピオネート ： S-cyclohexyl (2R) -2-{(2S, 3S)-1-aryloxycarbermethyl-3- [(1R)-1- (t-butyldimethylsyloxy) ethyl]- 4-oxoazetidine-2-yl} thiopropionate:
アルゴン気流下、 (2 )-2-{(2S, 3S) - 1-ァリルォキシカルボニルメチル- 3- [(1R)- 1 -（t -プチルジメチルシリルォキシ）ェチル ]-4-ォキソァゼチジン -2-ィル }チォプ ロピオン酸（1.20 g， 3.00 mmol)のァセトニトリル溶液（25 ml)に、 20〜25 °Cで撹 拌しながら N，N，-力ルポニルジイミダゾール（584 mg, 3.60 mmol)を加え、 そのま ま 1時間撹拌した。 反応混合物にシクロへキサンチオール (418 rag, 3.60 瞧 ol)の
ァセトニトリル溶液 （5 ml)、 次いでトリェチルァミン（364 mg, 3.60 ramol)のァ セトニトリル溶液 （5 ml) を順次滴下し、 同温度でさらに 11時間撹拌した。 反応 混合物に 1N—塩酸水を加えて、 酢酸ェチル抽出を行い、有機層を水洗、 飽和食塩水 洗し、 無水硫酸ナトリウムで乾燥した。 溶媒を減圧留去し、 得られた粗生成物を シリカゲル力ラムクロマトグラフィー（へキサン：酢酸ェチル = 7 ： 1)で精製し、 無色液体の目的物 （1.23 g, 収率 82%)を得た。 Under an argon stream, (2) -2-{(2S, 3S) -1-aryloxycarbonylmethyl-3-[(1R) -1- (t-butyldimethylsilyloxy) ethyl] -4-oxozetidine 2-Nyl} thiopropionic acid (1.20 g, 3.00 mmol) in acetonitrile solution (25 ml) was stirred at 20 to 25 ° C while stirring N, N, -force ruponyldiimidazole (584 mg, 3.60 mg). mmol), and the mixture was stirred for 1 hour. Add cyclohexanethiol (418 rag, 3.60 瞧 ol) to the reaction mixture. An acetonitrile solution (5 ml) and then a solution of triethylamine (364 mg, 3.60 ramol) in acetonitrile (5 ml) were sequentially added dropwise, and the mixture was further stirred at the same temperature for 11 hours. To the reaction mixture was added 1N aqueous hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with water, saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1) to obtain the target compound as a colorless liquid (1.23 g, yield 82%). Was.
XH NMR (400 MHz, CDC13)： δ = 0.082 (3H， s), 0.085 (3Η, s), 0.881 (9H， s) ， 1.20-1.48 (11H, m)， 1.53— 1.76 (3H， m)， 1.81— 1.94 (2H， m)， 2.95— 3.02 (2H， m), 3.42-3.54 (1H, ra), 3.90 (1H, d, J = 18.0 Hz)， 4.07 (1H, dd, J = 2.8 and 2.8 Hz), 4.12-4.19 (1H, m), 4.26 (1H， d, J = 18.0 Hz), 4.62—4 .64 (2H, m)， 5.24— 5.37 (2H, m), 5.86— 5.96 (1H， m). 実施例 10 (原料の製法） X H NMR (400 MHz, CDC1 3): δ = 0.082 (3H, s), 0.085 (3Η, s), 0.881 (9H, s), 1.20-1.48 (11H, m), 1.53- 1.76 (3H, m ), 1.81-1.94 (2H, m), 2.95-3.02 (2H, m), 3.42-3.54 (1H, ra), 3.90 (1H, d, J = 18.0 Hz), 4.07 (1H, dd, J = 2.8 and 2.8 Hz), 4.12-4.19 (1H, m), 4.26 (1H, d, J = 18.0 Hz), 4.62—4.64 (2H, m), 5.24—5.37 (2H, m), 5.86—5.96 ( 1H, m). Example 10 (Raw material production method)
S-[(3S, 5S) -5-ジメチルァミノ力ルポニル- 1 -（p-二ト口ベンジルォキシカルボニ ノレ） ピロリジン- 3-ィル] (2R) - 2 - {(2S，3S)- 1 -ァリルォキシカルボニルメチル- 3 - [ (1R)-1- (t-ブチルジメチルシリルォキシ）ェチル] -4-ォキソァゼチジン -2-ィル} チォプロピオネート ： S-[(3S, 5S) -5-Dimethylaminopropyl- 1- (p-nitrobenzyloxycarbonyl) pyrrolidine-3-yl] (2R) -2-{(2S, 3S)- 1-aryloxycarbonylmethyl-3-[[(1R) -1- (t-butyldimethylsilyloxy) ethyl] -4-oxoazetidine-2-yl} thiopropionate:
アルゴン気流下， (2R)-2-{(2S, 3S)- 1-ァリルォキシカルボニルメチル- 3- [(1R)- 1 - (t -ブチノレジメチルシ Vルォキシ）ェチル ] -4-ォキソァゼチジン - 2-ィノレ }チォプ ロピオン酸 (500 mg, 1.25 mmol) のァセトニトリル溶液（10 ml)に、 20〜25。Cで 撹拌しながら ， N' -カルポジィミダゾール（243 rag, 1.50 mmol)を加え、 1時間撹拌 した。 反応混合液に（3S， 5S)-5 -ジメチルァミノカルボニル- 3 -スルファニル _1 -（ p -ュト口ベンジスレオキシカルボニル)ピロリジン（439 rag, 1.30 mmol)のァセトニ トリル溶液（2.0 ml)、 次いでトリェチルァミン（152 mg， 1.50 mmol)のァセトニト リル溶液 （2.0 ml)を順次滴下し、 同温度でさらに 14時間撹拌した。 反応混合物に 1N—塩酸水を加えて、 酢酸ェチル抽出を行った。 有機層を水洗、 飽和食塩水洗し 、 無水硫酸ナトリウムで乾燥した。 溶媒を減圧留去し、 得られた粗生成物をシリ 力ゲルカラムクロマトグラフィー (へキサン：酢酸ェチル = 1 : 2— 1 : 1)で精製
し、 淡黄色非晶析の目的物 (679 mg, 収率 76%)を得た。 Under a stream of argon, (2R) -2-{(2S, 3S) -1-aryloxycarbonylmethyl-3-[(1R) -1- (t-butynoledimethylsyloxy) ethyl] -4- To a solution of oxazetidine-2-inole} thiopropionic acid (500 mg, 1.25 mmol) in acetonitrile (10 ml) was added 20-25. While stirring with C, N'-carposimidazole (243 rag, 1.50 mmol) was added, and the mixture was stirred for 1 hour. To the reaction mixture was added a solution of (3S, 5S) -5-dimethylaminocarbonyl-3-sulfanyl_1- (p-butopenisbenzoyloxycarbonyl) pyrrolidine (439 rag, 1.30 mmol) in acetonitrile (2.0 ml), Then, an acetonitrile solution (2.0 ml) of triethylamine (152 mg, 1.50 mmol) was sequentially added dropwise, and the mixture was further stirred at the same temperature for 14 hours. To the reaction mixture was added 1N-hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2-1: 1). Then, a light yellow non-crystallized target product (679 mg, yield 76%) was obtained.
X H N R (400 MHz, CDC13): δ = 0.063 (3Η， s), 0.082 (3Η， s)， 0.87 (9Η， s), 1.22-1.28 (6Η， m), 1.85—1.92 (1Η， ra), 2.67—2.81 (IH, ra)， 2.93—3.10 ( 8H, m), 3.45-3.51 (IH, m)， 3.85 (1H， d, J = 18.0 Hz), 3.93-4.19 (4H, m) , 4.25 (1H， d, J = 18.0 Hz), 4.62—4.77 (3H, m), 5.04—5.37 (4H, ra), 5.85 —5.96 (IH, m)， 7.44 (IH, d, J = 8.4 Hz), 7.51 (1H， d， J = 8.4 Hz), 8.19 -8.23 (2H, ra).
X HNR (400 MHz, CDC1 3 ): δ = 0.063 (3Η, s), 0.082 (3Η, s), 0.87 (9Η, s), 1.22-1.28 (6Η, m), 1.85-1.92 (1Η, ra) , 2.67—2.81 (IH, ra), 2.93—3.10 (8H, m), 3.45-3.51 (IH, m), 3.85 (1H, d, J = 18.0 Hz), 3.93-4.19 (4H, m), 4.25 (1H, d, J = 18.0 Hz), 4.62—4.77 (3H, m), 5.04—5.37 (4H, ra), 5.85—5.96 (IH, m), 7.44 (IH, d, J = 8.4 Hz), 7.51 (1H, d, J = 8.4 Hz), 8.19 -8.23 (2H, ra).
Claims
請求の範囲 The scope of the claims
下記式 The following formula
(式中、 R1は水酸基の保護基、 R2および R3は同一または異なって、 水素原子ま たは低級アルキル基、 R4はエステル残基、 R5はエステル残基をそれぞれ意味し 、 そして Υは Ο原子または S原子を意味する。 ) (Wherein, R 1 represents a protecting group for a hydroxyl group, R 2 and R 3 are the same or different and each represents a hydrogen atom or a lower alkyl group, R 4 represents an ester residue, and R 5 represents an ester residue, And Υ means Ο atom or S atom.)
で表わされる化合物をルイス酸とルイス塩基の存在下反応させ、 五員環を形成さ せることを特徴とし、 ついで必要に応じ式、 R° S H ( 4 ) Reacting the compound represented by with a Lewis acid in the presence of a Lewis base to form a five-membered ring.
(式中の R°は有機基を意味する。 ） (R ° in the formula means an organic group.)
で表わされるメルカプタン誘導体を作用させることからなる下記式
The following formula comprising reacting a mercaptan derivative represented by
(式中、 R R2、 R3および R5は前掲と同じ。 ） (Where RR 2 , R 3 and R 5 are the same as above.)
で表わされる化合物および/または下記式 And / or the following formula
(式中、 R "は、 R4または R。を意味し、 R R2、 R3および R5は前掲と同じ 0 ) (Wherein, R "means R 4 or R. RR 2 , R 3 and R 5 are the same as those described above for 0 )
で表わされる力ルバぺネム誘導体の製造法。 A method for producing a carbane derivative represented by the formula:
2 , 下記式 2, the following formula
(式中、 R1は水酸基の保護基、 R2および R3は同一または異なって、 水素原子ま
たは低級アルキル基、 R4はエステル残基、 R5はエステル残基をそれぞれ意味し 、 そして Yは O原子または S原子を意味する。 ） (Wherein, R 1 is a protecting group for a hydroxyl group, R 2 and R 3 are the same or different, and Or lower alkyl group, R 4 represents an ester residue, R 5 represents an ester residue, and Y represents an O atom or an S atom. )
で表わされる化合物をルイス酸とルイス塩基の存在下反応させ、 ついで必要に応 じ式、 R° S H ( 4 ) Is reacted with a Lewis acid in the presence of a Lewis base, and then, if necessary, the formula: R ° S H (4)
(式中の RGは有機基を意味する。 ） (In the formula, R G represents an organic group.)
で表わされるメルカプタン誘導体を作用させることを特徴とする下記式
Wherein a mercaptan derivative represented by the following formula is allowed to act:
(式中、 R"は、 R4または R。を意味し、 I 1、 R2、 R3および R5は前掲と同じ で表わされる力ルバぺネム誘導体の製造法。 (In the formula, R "means R 4 or R. I 1 , R 2 , R 3 and R 5 are the same as those described above, and are the same as those described above.
3 . 下記式 3. The following formula
(式中、 R1は水酸基の保護基、 R2および R3は同一または異なって、 水素原子ま たは低級アルキル基、 R4はエステル残基、 R5はエステル残基をそれぞれ意味し 、 そして Yは S原子を意味する。 ) (Wherein, R 1 represents a protecting group for a hydroxyl group, R 2 and R 3 are the same or different and each represents a hydrogen atom or a lower alkyl group, R 4 represents an ester residue, and R 5 represents an ester residue, And Y means S atom.)
で表わされる化合物をルイス酸とルイス塩基の存在下反応させることを特徴とす る下目 G式
Wherein the compound represented by the formula is reacted in the presence of a Lewis acid and a Lewis base.
(式中、 I 1、 R2、 R3、 R4および R5は前掲と同じ。 ） (In the formula, I 1 , R 2 , R 3 , R 4 and R 5 are the same as described above.)
で表わされる化合物およひ 'Zまたは下記式
And a compound represented by the formula 'Z or the following formula
(式中、 R R2、 R3および R5は前掲と同じ。 ） (Where RR 2 , R 3 and R 5 are the same as above.)
で表わされる力ルバぺネム誘導体の製造法。 A method for producing a carbane derivative represented by the formula:
4 . 下記式 4. The following equation
(式中、 R1は水酸基の保護基、 R2および R3は同一または異なって、 水素原子ま たは低級アルキル基、 R4はエステル残基、 R5はエステル残基をそれぞれ意味し 、 そして Yは O原子を意味する。 ） (Wherein, R 1 represents a protecting group for a hydroxyl group, R 2 and R 3 are the same or different and each represents a hydrogen atom or a lower alkyl group, R 4 represents an ester residue, and R 5 represents an ester residue, And Y means O atom.)
で表わされる化合物をルイス酸とルイス塩基の存在下反応させることを特徴とす る下記式
Wherein the compound represented by the following formula is reacted in the presence of a Lewis acid and a Lewis base.
(式中、 R1 R2、 R3および R5は前掲と同じ。 ） (In the formula, R 1 R 2 , R 3 and R 5 are the same as described above.)
で表わされる力ルバぺネム誘導体の製造法。 A method for producing a carbane derivative represented by the formula:
5 . 下 式 5.
(式中、 R1は水酸基の保護基、 R2および R3は同一または異なって、 水素原子ま たは低級アルキル基、 R4はエステル残基、 R5はエステル残基をそれぞれ意味し 、 そして Yは S原子を意味する。 ) (Wherein, R 1 represents a protecting group for a hydroxyl group, R 2 and R 3 are the same or different and each represents a hydrogen atom or a lower alkyl group, R 4 represents an ester residue, and R 5 represents an ester residue, And Y means S atom.)
で表わされる化合物をルイス酸とルイス塩基の存在下反応することを特徴とする
下記式 Reacting a compound represented by the formula with a Lewis acid and a Lewis base. The following formula
(式中、 R R2、 R\ R4および R5は前掲と同じ。 ） (Where RR 2 , R \ R 4 and R 5 are the same as above.)
で表わされる力ルバぺネム誘導体の製造法。 A method for producing a carbane derivative represented by the formula:
6 . 式 （1 ) において R3が水素原子で、 R2が R配位のメチル基である化 合物を原料として用いる請求項 1〜 5に記載のいずれかの力ルバぺネム誘導体の 6. The compound according to any one of claims 1 to 5, wherein a compound in which R 3 is a hydrogen atom and R 2 is an R-coordinated methyl group in the formula (1) is used as a raw material.
7 . ルイス酸がアルミニウム、 スズ、 ジルコニウム、 マグネシウム、 ホウ 素、 チタン、 亜鉛、 ケィ素、 鉄、 ゲルマニウム、 アンチモン、 ハフニウム、 ビス マス、 スカンジウム、 イットリビゥム、 マンガン、 コバノレト、 -ッケノレ、 銅、 ガ リウム、 サマリウム、 セリウム、 バナジウムまたはタングステンを中心元素とす る塩化物、 臭化物、 ヨウ化物、 低級アルキル化物または錯体である請求項 1〜 6 に記載のいずれかの力ルバぺネム誘導体の製造法。 7. Lewis acids are aluminum, tin, zirconium, magnesium, boron, titanium, zinc, silicon, iron, germanium, antimony, hafnium, bismuth, scandium, yttrium, manganese, covanolate, -ckenole, copper, gallium, The method for producing a carbane derivative according to any one of claims 1 to 6, which is a chloride, bromide, iodide, lower alkylate or complex having samarium, cerium, vanadium or tungsten as a central element.
8 . ルイス酸がアルミニウム、 スズ、 ジルコニウム、 マグネシウム、 ホウ 素、 チタン、 亜鉛、 ケィ素またはスズを中心元素とする塩化物、 臭化物、 ヨウ化 物、 低級アルキル化物または錯体である請求項 1 〜 6に記載のいずれかの力ルバ ぺネム誘導体の製造法。 8. The Lewis acid is a chloride, bromide, iodide, lower alkylated compound or complex mainly composed of aluminum, tin, zirconium, magnesium, boron, titanium, zinc, silicon or tin. The method for producing any of the active ingredient derivatives according to any one of the above.
9 . ルイス酸がチタン、 ジルコニウムまたはアルミニウムを中心元素とす る塩化物、 臭化物、 ヨウ化物、 低級アルキル化物または錯体である請求項 1〜 6 に記載のいずれかの力ルバぺネム誘導体の製造法。 9. The method for producing any of the carbane derivatives according to any one of claims 1 to 6, wherein the Lewis acid is a chloride, bromide, iodide, lower alkylate or complex having titanium, zirconium or aluminum as a central element. .
1 0 . ルイス酸がチタンを中心元素とする塩化物、 臭化物、 ヨウ化物、 低 級アルキル化物または錯体である請求項 1〜 6に記載のいずれかの力ルバぺネム 誘導体の製造法。 10. The process according to any one of claims 1 to 6, wherein the Lewis acid is a chloride, bromide, iodide, lower alkylate or complex having titanium as a central element.
1 1 . ルイス塩基が有機アミン化合物である請求項 1〜 1 0に記載のいず れかの力ルバぺネム誘導体の製造法。
11. The method according to any one of claims 1 to 10, wherein the Lewis base is an organic amine compound.
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|---|---|---|---|
| JP2003586153A JPWO2003089432A1 (en) | 2002-04-22 | 2003-04-21 | Method for producing carbapenem derivatives |
| AU2003227444A AU2003227444A1 (en) | 2002-04-22 | 2003-04-21 | Process for producing carbapenem derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2006049113A1 (en) * | 2004-11-01 | 2006-05-11 | Shionogi & Co., Ltd. | Intermediate for synthesizing carbapenem and method for preparation thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3641872A1 (en) * | 1986-12-08 | 1988-06-09 | Bayer Ag | Pyrazinylthiocarbapenems, processes for their preparation, and their use |
| JPH06100564A (en) * | 1992-03-06 | 1994-04-12 | Tanabe Seiyaku Co Ltd | Production of 2-oxycarbapenem derivative |
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| JP2696807B2 (en) * | 1992-08-06 | 1998-01-14 | 田辺製薬株式会社 | Preparation of carbapenem derivatives |
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2003
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- 2003-04-21 JP JP2003586153A patent/JPWO2003089432A1/en active Pending
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3641872A1 (en) * | 1986-12-08 | 1988-06-09 | Bayer Ag | Pyrazinylthiocarbapenems, processes for their preparation, and their use |
| JPH06100564A (en) * | 1992-03-06 | 1994-04-12 | Tanabe Seiyaku Co Ltd | Production of 2-oxycarbapenem derivative |
Non-Patent Citations (2)
| Title |
|---|
| MEYERS A.I. ET AL.: "An efficient enantioselective synthesis of the carbapenem-2-one system. An approach to (+)-thienamycin and related carbapenems", TETRAHEDRON LETTERS, vol. 28, no. 43, 1987, pages 5103 - 5106, XP002970010 * |
| SOWIN THOMAS J. ET AL.: "Enantioselective synthesis of the 1beta-methylcarbapenems via cycloadditiuon of 3-siloxypentadiene and 4-acetoxyazetidinone", J. ORG. CHEM., vol. 53, no. 17, 1988, pages 4154 - 4156, XP002970009 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006049113A1 (en) * | 2004-11-01 | 2006-05-11 | Shionogi & Co., Ltd. | Intermediate for synthesizing carbapenem and method for preparation thereof |
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| AU2003227444A1 (en) | 2003-11-03 |
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