CN1610663A - Process for producing azetidinone compounds - Google Patents
Process for producing azetidinone compounds Download PDFInfo
- Publication number
- CN1610663A CN1610663A CNA03801808XA CN03801808A CN1610663A CN 1610663 A CN1610663 A CN 1610663A CN A03801808X A CNA03801808X A CN A03801808XA CN 03801808 A CN03801808 A CN 03801808A CN 1610663 A CN1610663 A CN 1610663A
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- Prior art date
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- 238000000034 method Methods 0.000 title abstract description 21
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 title description 14
- -1 azetidinone compound Chemical class 0.000 claims abstract description 97
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 26
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract 2
- 239000002585 base Substances 0.000 claims description 57
- 229910052799 carbon Inorganic materials 0.000 claims description 52
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 50
- 238000002360 preparation method Methods 0.000 claims description 37
- 150000001875 compounds Chemical class 0.000 claims description 34
- 229910052751 metal Inorganic materials 0.000 claims description 28
- 239000002184 metal Substances 0.000 claims description 28
- 125000004429 atom Chemical group 0.000 claims description 22
- 239000003513 alkali Substances 0.000 claims description 17
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 7
- 241000790917 Dioxys <bee> Species 0.000 claims description 6
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000010936 titanium Substances 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000002097 pentamethylcyclopentadienyl group Chemical group 0.000 claims description 3
- 230000000737 periodic effect Effects 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- 150000003141 primary amines Chemical class 0.000 claims description 3
- 150000003222 pyridines Chemical class 0.000 claims description 3
- 150000003335 secondary amines Chemical class 0.000 claims description 3
- 150000003512 tertiary amines Chemical class 0.000 claims description 3
- 229910052727 yttrium Inorganic materials 0.000 claims description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical group [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 claims description 2
- 239000004411 aluminium Substances 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 2
- 229910052796 boron Inorganic materials 0.000 claims description 2
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 claims description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- 229910052707 ruthenium Inorganic materials 0.000 claims description 2
- 229910052706 scandium Inorganic materials 0.000 claims description 2
- SIXSYDAISGFNSX-UHFFFAOYSA-N scandium atom Chemical group [Sc] SIXSYDAISGFNSX-UHFFFAOYSA-N 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- 229910052719 titanium Inorganic materials 0.000 claims description 2
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 229910052726 zirconium Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 abstract description 45
- 229910052760 oxygen Inorganic materials 0.000 abstract description 45
- 238000006243 chemical reaction Methods 0.000 abstract description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 13
- 239000003242 anti bacterial agent Substances 0.000 abstract description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract 2
- 239000001257 hydrogen Substances 0.000 abstract 2
- 150000002736 metal compounds Chemical class 0.000 abstract 1
- 229910052717 sulfur Chemical group 0.000 abstract 1
- 239000011593 sulfur Chemical group 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 33
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 15
- 239000002904 solvent Substances 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
- 229910000765 intermetallic Inorganic materials 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 150000001989 diazonium salts Chemical class 0.000 description 9
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 229910052740 iodine Inorganic materials 0.000 description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 7
- 229910007930 ZrCl3 Inorganic materials 0.000 description 7
- 125000004423 acyloxy group Chemical group 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 239000011630 iodine Substances 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 229910010062 TiCl3 Inorganic materials 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 5
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 4
- KSUUDXKPIJEMBT-UHFFFAOYSA-N 2-diazo-3-oxopentanoic acid Chemical compound [N+](=[N-])=C(C(=O)O)C(CC)=O KSUUDXKPIJEMBT-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 125000006502 nitrobenzyl group Chemical group 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- YKMONJZIUAOVEM-WDSKDSINSA-N 1beta-methylcarbapenem Chemical compound C[C@H]1C=CN2C(=O)C[C@@H]12 YKMONJZIUAOVEM-WDSKDSINSA-N 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- AWXVZQXIMPKRGJ-UHFFFAOYSA-N 2-diazo-3-oxobutanoic acid Chemical compound [N+](=[N-])=C(C(=O)O)C(=O)C AWXVZQXIMPKRGJ-UHFFFAOYSA-N 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 3
- 229910007926 ZrCl Inorganic materials 0.000 description 3
- 229940041011 carbapenems Drugs 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 3
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 3
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 3
- UZYFEILHAHKSAB-UHFFFAOYSA-N (e)-2-diazonio-1-oxo-1-phenylmethoxypent-2-en-3-olate Chemical compound CCC(=O)C(=[N+]=[N-])C(=O)OCC1=CC=CC=C1 UZYFEILHAHKSAB-UHFFFAOYSA-N 0.000 description 2
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 2
- MFEIKQPHQINPRI-UHFFFAOYSA-N 3-Ethylpyridine Chemical compound CCC1=CC=CN=C1 MFEIKQPHQINPRI-UHFFFAOYSA-N 0.000 description 2
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 2
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KEWMVWGVLNGVDT-UHFFFAOYSA-N ClCCl.[N+](=[N-])=C(C(=O)O)C(C)=O Chemical compound ClCCl.[N+](=[N-])=C(C(=O)O)C(C)=O KEWMVWGVLNGVDT-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- OJGMBLNIHDZDGS-UHFFFAOYSA-N N-Ethylaniline Chemical compound CCNC1=CC=CC=C1 OJGMBLNIHDZDGS-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 2
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000005110 aryl thio group Chemical group 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000011097 chromatography purification Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000005828 desilylation reaction Methods 0.000 description 2
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000002084 enol ethers Chemical class 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- BHRZNVHARXXAHW-UHFFFAOYSA-N sec-butylamine Chemical compound CCC(C)N BHRZNVHARXXAHW-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 description 2
- JSLZUBLGGPEVQN-DIPNUNPCSA-N (2r)-4-methyl-2-propan-2-yl-2-[2-[4-[4-[2-(3,4,5-trimethoxyphenyl)ethyl]piperazin-1-yl]butoxy]phenyl]-1,4-benzothiazin-3-one Chemical compound COC1=C(OC)C(OC)=CC(CCN2CCN(CCCCOC=3C(=CC=CC=3)[C@@]3(C(N(C)C4=CC=CC=C4S3)=O)C(C)C)CC2)=C1 JSLZUBLGGPEVQN-DIPNUNPCSA-N 0.000 description 1
- SOVAZWBKYILMFE-AKGZTFGVSA-N (5s)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound CC1C=C(C(O)=O)N2C(=O)C[C@@H]12 SOVAZWBKYILMFE-AKGZTFGVSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
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- 125000006017 1-propenyl group Chemical group 0.000 description 1
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- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003748 yttrium compounds Chemical class 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 150000003752 zinc compounds Chemical class 0.000 description 1
- 150000003755 zirconium compounds Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
It is intended to provide a process for selectively obtaining an intermediate in synthesizing a desired carbapenem-type antibacterial agent having a methyl group at the 1'-beta-position in a short period and at a high yield under mild conditions while overcoming problems occurring in the existing method. Namely, a process for producing an azetidinone compound having a 1'-beta configuration characterized in that a reaction represented by the following formula is carried out in the presence of a specific metal compound and a base: wherein R<1> represents hydrogen or a hydroxy-protective group; L represents a leaving group; R<2> represents hydrogen or lower alkyl; R<3> represents alkyl, aralkyl, etc.; and X represents oxygen or sulfur.
Description
Technical field
The present invention relates to azetidinone compounds as the important synthetic intermediate of carbapenem compound.
Background technology
1 ' of 4 side chains that use when preparing important antimicrobial substance 1 Beta-methyl carbapenem (カ Le バ ペ ネ system) derivative have the azetidinone compounds of Beta-methyl important synthetic intermediate (3S, 4R)-3-[(R)-the 1-hydroxyethyl]-4-[(R)-oxygen carbonyl-2-oxo-propyl group that 1-methyl-3-diazo-3-replaces]-azetidine-2-ketone [A]:
[in the formula, R represents alkyl, can have substituent benzyl, can have substituent aryl.]
The preparation method, the known following reaction scheme 1 that for example has the spy to open the record of clear 57-123182 communique:
Represented preparation method; The spy opens the following reaction scheme 2 of clear 64-25779 communique record:
The preparation method of expression; The following reaction scheme 3 of Te Kaiping 6-321946 communique record:
The preparation method of expression; And special open that clear 58-103358 communique, spy are opened flat 6-199780 communique, the spy opens the following reaction scheme 4 of clear 61-275284 communique record:
The preparation method of expression etc.
But these preparation methods all have the problem of the following stated, not talkatively fully carry out.
That is, in the method for reaction scheme 1～3, use the starting raw material of high price, and, no matter be that yield or price are all undesirable more because of process number makes troublesome poeration.
In addition, in the method for reaction scheme 4, by relatively shorter operation preparation, but, therefore be difficult to the method for industry of saying so, and also be difficult to the economic method of saying so owing to must use unsettled silicomethane enol ether.
Disclosure of an invention
The objective of the invention is to solve the problem that above-mentioned existing method exists, be provided under the gentle condition, operation is short, yield good and optionally obtain the method for the synthetic intermediate of the required carbapenems antiseptic-germicide that has methyl in 1 '-β position.
The present invention relates to the compound of general formula [1] expression:
(in the formula, R
1, R
2, R
3With X and together following.)
The preparation method, it is characterized in that,
Make the compound of following general formula [2] expression:
(in the formula, R
1Expression hydrogen atom or hydroxyl protecting group, L represents leavings group)
Compound with following general formula [3] expression:
(in the formula, R
2Expression hydrogen atom or carbon number are 1～4 low alkyl group, R
3The expression carbon number is 1～12 alkyl, can to have substituent phenyl, can have substituent carbon number be 7～15 aralkyl or the alicyclic radical that can have substituent 5～8 Yuans rings, and X represents Sauerstoffatom or sulphur atom)
General formula [4] below:
MY
n(R
4)
m????????(4)
(in the formula, M represents atoms metal, and Y represents halogen atom, R
4The expression carbon number is that 1～4 low alkyl group, carbon number are 1～4 lower alkoxy, can have substituent phenoxy group, alkyl sulfonyl dioxy base, fragrant sulphonyl dioxy base, alkylsulfonyloxy, arylsulfonyloxy, cyclopentadienyl or pentamethyl-cyclopentadienyl, n and m are 0～4 integer, and n+m is the valence of M)
React under the metallic compound of expression and the existence of alkali.
Promptly, the inventor has carried out making great efforts research for achieving the above object, found that, only the diazonium compound represented of the compound by making top general formula [2] expression and top general formula [3] reacts in the presence of specific metallic compound and alkali, just can be optionally and yield prepare the required azetidinone compounds with 1 '-beta comfiguration [1] well, thereby finished the present invention.
Not the invention provides and will be transformed to the silicomethane enol ether by diazonium compound, only the diazonium compound represented of the compound by making top general formula [2] expression and top general formula [3] reacts in the presence of specific metallic compound and alkali, just can optionally prepare the method for the required azetidinone compounds with 1 '-beta comfiguration [1] under the condition of gentleness, this method operation is short, yield good.
The best mode that carries out an invention
In the compound of the aforementioned formula of in preparation method of the present invention, using [2] expression, as R
1The hydroxyl protecting group of expression is for example enumerated normally used all hydroxyl protecting groups in the field of chemistry of peptides and 'beta '-lactam compounds.
Promptly, for example, trimethyl silyl, triethylsilyl, the triisopropyl silyl, dimethyl sec.-propyl silyl, diethyl sec.-propyl silyl, dimethyl (2,3-dimethyl-2-butyl) silyl, t-butyldimethylsilyl, three (carbon number is 1～6 alkyl) silyl of dimethyl hexyl silyl etc., for example two (carbon number is 1～6 the alkyl)-carbon numbers of dimethyl cumyl silyl etc. are aryl-silyl of 6～18, t-butyldiphenylsilyl for example, two (carbon number is 6～18 aryl)-carbon numbers of diphenyl methyl silyl etc. are alkyl-silyl of 1～6, for example three (carbon number is 6～18 aryl) silyl of triphenyl silyl etc., for example tribenzyl silyl, the trisubstituted silyl of three (carbon number is 7～19 aralkyl) silyl of three (p-Xylol base) silyl etc. etc.; For example benzyl, 4-methoxy-benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl methyl, trityl group etc. can be that the carbon number of its 1～3 hydrogen atoms of replacement such as 1～4 alkoxyl group (for example methoxyl group, oxyethyl group) or nitro is 7～19 aralkyl by carbon number; For example, methoxycarbonyl, ethoxycarbonyl, tertbutyloxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl, 2-trimethylsilylethoxy) carbonyl etc. can be that the carbon number of 1～4 alkoxyl group (for example methoxyl group, oxyethyl group) or halogen atom (for example fluorine, chlorine, bromine, iodine etc.) or three (carbon number is 1～4 alkyl) silyl its 1～3 hydrogen atoms of replacement such as (for example trimethyl silyls) is 1～6 carbalkoxy by carbon number; For example, carbobenzoxy-(Cbz), 2-nitro carbobenzoxy-(Cbz), 4-nitro carbobenzoxy-(Cbz), 4-methoxyl group benzyloxy carbonyl, 3,4-dimethoxy-benzyl oxygen carbonyl etc. can be that carbon number that 1～4 alkoxyl group (for example methoxyl group, oxyethyl group etc.) or nitro replace its 1～3 hydrogen atom is 7～10 aryl alkyl carbonyl oxygen by carbon number; For example, the carbon number of vinyl oxygen carbonyl, allyloxycarbonyl etc. is 2～6 alkenyl oxygen carbonyl; For example, the acyl group that can replace its 1～3 hydrogen atom of formyl radical, ethanoyl, chloracetyl, dichloro-acetyl, tribromo-acetyl base, trifluoroacetyl group, propionyl, butyryl radicals, benzoyl, 4-toluyl, 4-anisoyl, 4-nitro benzoyl etc. by halogen atom (for example fluorine, chlorine, bromine, iodine etc.) or nitro etc.; Ring protection base of THP trtrahydropyranyl, tetrahydrofuran base etc. etc. for example.
Preference such as carbon number are that 7～19 aryl alkyl carbonyl oxygen (for example carbobenzoxy-(Cbz), 4-nitro carbobenzoxy-(Cbz) etc.), carbon number are 2～6 alkenyl oxygen carbonyl (for example allyloxycarbonyl), three (carbon number is 1～6 alkyl) silyl etc. in these protecting groups, more preferably t-butyldimethylsilyl etc.
In addition; the leavings group that L represents for example has acyloxy (for example, alkanoyloxy, aryl acyloxy, aryl alkanoyloxy, alkylsulfonyloxy, aryl-sulfonyl oxygen, alkoxycarbonyloxy, aralkoxycarbonyl oxygen base, alkoxyl group alkanoyloxy, formamyl oxygen base etc.), alkane acyl sulfenyl, fragrant acyl sulfenyl, alkylthio, arylthio, alkyl sulphinyl, aryl sulfonyl kia, alkyl sulphonyl, aryl sulfonyl, halogen atom etc.
Object lesson when being alkanoyloxy as L, can enumerate acetoxyl group, propionyloxy, butyryl acyloxy, α-acetyl fluoride oxygen base, α-chloroethene acyloxy, α-acetobrom oxygen base, alpha-iodine acetoxyl group, α, α-difluoro acetoxyl group, α, the side chain of the straight chain alkanoyloxy that can replace by substituting groups such as 1～3 halogen, cyano group of α-dichloro-acetoxy, alpha-cyano acetoxyl group etc., isobutyl acyloxy, cyclohexyl carbonyl oxygen base etc. or ring-type alkanoyloxy etc.
Object lesson when being aryl acyloxy as L, that can enumerate benzoyloxy, 1-naphthoyl oxygen base, 2-naphthoyl oxygen base, nicotinylsalicylic oxygen, different nicotinylsalicylic oxygen, chaff acyloxy (Off Le Off ロ イ Le オ キ シ) etc. can have heteroatomic monocycle or many cyclophanes acyloxy.
Object lesson when being the aryl alkanoyloxy as L can be enumerated phenyl acetoxyl group etc.
Object lesson when being alkylsulfonyloxy as L can be enumerated mesyloxy, ethanesulfonyloxy group, third sulfonyloxy, trifluoro-methanesulfonyl oxy etc.
Object lesson when being aryl sulfonyl as L can be enumerated phenylsulfonyloxy, tolysulfonyl oxygen base etc.
Object lesson when being alkoxycarbonyloxy as L can be enumerated methoxycarbonyl oxygen base, ethoxycarbonyl-oxygen base etc.
Object lesson when being aralkoxycarbonyl oxygen base as L can be enumerated carbobenzoxy-(Cbz) oxygen base etc.
Object lesson when being the alkoxyl group alkanoyloxy as L can be enumerated methoxyl group acetoxyl group, oxyethyl group acetoxyl group etc.
Object lesson when being carbamoyloxy as L can be enumerated N-methylamino methanoyl, N-ethylamino methanoyl, N-phenyl amino methanoyl etc.
Object lesson when being alkane acyl sulfenyl as L can be enumerated acetylthio, propionyl sulfenyl etc.
Object lesson when being fragrant acyl sulfenyl as L can be enumerated benzoyl sulfenyl, naphthoyl sulfenyl etc.
Object lesson when being alkylthio as L can be enumerated methylthio group, ethylmercapto group, positive rosickyite base, iprotiazem base, positive butylthio, isobutyl sulfenyl, uncle's butylthio etc.
Object lesson when being arylthio as L can be enumerated thiophenyl, naphthalene sulfenyl etc.
Object lesson when being alkyl sulphinyl as L can be enumerated methanesulfinyl, second sulfinyl, positive third sulfinyl, positive fourth sulfinyl etc.
Object lesson when being aryl sulfonyl kia as L can be enumerated benzenesulfinyl, p-tolysulfinyl etc.
Object lesson when being alkyl sulphonyl as L can be enumerated methylsulfonyl, ethylsulfonyl, positive third alkylsulfonyl, positive fourth alkylsulfonyl etc.
Object lesson when being aryl sulfonyl as L can be enumerated benzenesulfonyl, p-toluenesulfonyl etc.
Object lesson when being halogen atom as L can be enumerated fluorine, chlorine, bromine, iodine etc.
In these leavings groups, preferred especially acetoxyl group etc.
In the compound of the aforementioned formula of using among the preparation method of the present invention [3] expression, as R
2The carbon number of expression is the object lesson of 1～4 low alkyl group, can enumerate methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl etc.
In addition, as preferred R
2, can enumerate hydrogen atom or methyl.
In general formula [3], as R
3The carbon number of expression is the object lesson of 1～12 alkyl, can enumerate methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl etc.
As R
3The carbon number of expression is the object lesson of 2～5 alkenyl, can enumerate vinyl, allyl group, 1-propenyl, pseudoallyl, 1-butylene base, crotyl, 2-methacrylic etc.
As R
3The substituting group that substituent phenyl can be arranged of expression can be enumerated carbon number and be 1～4 low alkyl group, carbon number and be 1～4 lower alkoxy, nitro, halogen atom etc.
At this moment, as substituent carbon number the object lesson of 1～4 low alkyl group, can enumerate methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl etc.In addition, as carbon number the object lesson of 1～4 lower alkoxy, can enumerate methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy etc.As the object lesson of halogen atom, can enumerate fluorine, chlorine, bromine, iodine etc.
As R
3The substituent carbon number that can have of expression is the substituting group of 7～15 aralkyl, can enumerate carbon number and be 1～4 low alkyl group, carbon number and be 1～4 lower alkoxy, nitro, halogen atom etc.
At this moment, as substituent carbon number the object lesson of 1～4 low alkyl group, can enumerate methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl etc.In addition, as carbon number the object lesson of 1～4 lower alkoxy, can enumerate methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy etc.In addition, as the object lesson of halogen atom, can enumerate fluorine, chlorine, bromine, iodine etc.
In addition, be the object lesson of 7～15 aralkyl as substituent carbon number can be arranged, can enumerate benzyl, α-styroyl, β-styroyl, α-hydrocinnamyl, β-hydrocinnamyl, γ-hydrocinnamyl, menaphthyl etc.
As R
3The object lesson of the alicyclic radical that substituent 5～8 Yuans rings can be arranged of expression can be enumerated cyclopentyl, cyclohexyl, suberyl, ring octyl group etc.In addition, as substituting group, can enumerate carbon numbers such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl and be 1～4 low alkyl group.
Wherein, as particularly preferred R
3, can exemplified by methyl, carbon number such as ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl is 1～4 low alkyl group; Benzyl, the carbon number that can have a substituting group (nitro, methoxyl group etc.) to nitrobenzyl, to methoxy-benzyl etc. are 7～15 aralkyl; Carbon number such as vinyl, allyl group is 2～5 a alkenyl etc.
In the metallic compound of the aforementioned formula of using among the preparation method of the present invention [4] expression, the atoms metal of representing as M, can enumerate the general atoms metal that uses in Synthetic Organic Chemistry, the C-C formation reaction etc., more specifically, for example, the metal of periodictable the 4th family of IUPAC such as titanium, zirconium; The metal of IUPAC such as silicon, tin periodictable the 14th family; The metal of boron, aluminium IUPAC belonging to group 13 of periodic table such as (ア Le ニ ウ system); The metal of scandium, yttrium, lanthanon periodictable the 3rd families such as (lanthanum, cerium, praseodymium, neodymium, samarium, gadolinium, dysprosium, erbium, ytterbiums); The metal of periodictable such as iron, ruthenium the 8th family; The metal of periodictables such as zinc the 12nd family etc.
In the general formula [4], the halogen atom that Y represents can be enumerated fluorine atom, chlorine atom, bromine atoms, iodine atom etc.
In the general formula [4], as R
4The carbon number of expression is the object lesson of 1～4 low alkyl group, can enumerate methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl etc., in addition, be the object lesson of 1～4 lower alkoxy as carbon number, can enumerate methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy etc.
In addition, as R
4The substituting group that can have substituent phenoxy group of expression can be enumerated carbon number and be 1～4 low alkyl group, carbon number and be 1～4 lower alkoxy, halogen atom etc.
Here, it as substituent carbon number the object lesson of 1～4 low alkyl group, can enumerate methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl etc., in addition, be the object lesson of 1～4 lower alkoxy as carbon number, can enumerate methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy etc., in addition, as the object lesson of halogen atom, can enumerate fluorine, chlorine, bromine, iodine etc.
As R
4The object lesson of the alkyl sulfonyl dioxy base of expression can be enumerated methylsulfonyl dioxy base, second sulphonyl dioxy base, fluoroform sulphonyl dioxy base etc.
As R
4The object lesson of the arylsulfonyl dioxy base of expression can be enumerated benzene sulfonyl dioxy base, tolysulfonyl dioxy base etc.
As R
4The object lesson of the alkylsulfonyloxy of expression can be enumerated mesyloxy, ethanesulfonyloxy group, trifluoro-methanesulfonyl oxy etc.
As R
4The object lesson of the aryl-sulfonyl oxygen of expression can be enumerated phenylsulfonyloxy, tolysulfonyl oxygen base etc.
Preparation method as the compound of general formula [2] expression, there is no particular limitation, for example can pass through J.Am.Chem.Soc., 112 volumes, 7820～7822 pages (1990), TetrahedronLetters, 32 volumes, 2145～2148 pages (1991), Tetrahedron Letters, 32 volumes, the method for putting down in writing during wait 5991～5994 pages (1991) or synthesized according to the method for these methods.
As the object lesson of the compound of general formula [2] expression, can enumerate
4-acetoxy-3-[1-t-butyldimethylsilyl oxygen base ethyl]-azetidine-2-ketone,
4-acetoxy-3-[1-t-butyldiphenylsilyl oxygen base ethyl]-azetidine-2-ketone,
4-acetoxy-3-[1-triethylsilyl oxygen base ethyl]-azetidine-2-ketone,
4-acetoxy-3-[1-trimethyl silyl oxygen base ethyl]-azetidine-2-ketone,
4-acetoxy-3-[1-dimethyl decyl (テ キ シ Le) silyl oxygen ethyl]-azetidine-2-ketone,
4-acetoxy-3-[1-hydroxyethyl ethyl]-azetidine-2-ketone,
4-α-chloroethene acyloxy-3-[1-t-butyldimethylsilyl oxygen base ethyl]-azetidine-2-ketone,
4-isobutyl acyloxy-3-[1-t-butyldimethylsilyl oxygen base ethyl]-azetidine-2-ketone,
4-propionyloxy-3-[1-t-butyldimethylsilyl oxygen base ethyl]-azetidine-2-ketone,
4-benzoyloxy-3-[1-t-butyldimethylsilyl oxygen base ethyl]-azetidine-2-ketone,
4-is to toluene sulfenyl-3-[1-t-butyldimethylsilyl oxygen base ethyl]-azetidine-2-ketone,
4-thiophenyl-3-[1-t-butyldimethylsilyl oxygen base ethyl]-azetidine-2-ketone,
4-is to toluene sulfinyl oxygen base-3-[1-t-butyldimethylsilyl oxygen base ethyl]-azetidine-2-ketone,
4-phenylsulfinyl oxygen base-3-[1-t-butyldimethylsilyl oxygen base ethyl]-azetidine-2-ketone,
4-tolysulfonyl oxygen base-3-[1-t-butyldimethylsilyl oxygen base ethyl]-azetidine-2-ketone,
4-phenylsulfonyloxy-3-[1-t-butyldimethylsilyl oxygen base ethyl]-azetidine-2-ketone,
4-chloro-3-[1-t-butyldimethylsilyl oxygen base ethyl]-azetidine-2-ketone,
4-bromo-3-[1-t-butyldimethylsilyl oxygen base ethyl]-azetidine-2-ketone,
4-iodo-3-[1-t-butyldimethylsilyl oxygen base ethyl]-azetidine-2-ketone,
4-cyano group-3-[1-t-butyldimethylsilyl oxygen base ethyl]-azetidine-2-ketone etc.
As the preferred compound in these compounds, for example can enumerate 4-acetoxy-3-[1-t-butyldimethylsilyl oxygen base ethyl]-azetidine-2-ketone and 4-α-chloroethene acyloxy-3-[1-t-butyldimethylsilyl oxygen base ethyl]-azetidine-2-ketone etc.
As the preparation method of the diazonium compound of general formula [3] expression, there is no particular limitation, opens method that clear 61-275284 communique put down in writing or synthesize according to the method for these methods but for example can open clear 58-103385 communique, spy by the spy.
As the object lesson of the diazonium compound of general formula [3] expression, for example can enumerate,
2-diazo-3-ketobutyric acid methyl esters
2-diazo-3-oxopentanoic acid methyl esters
2-diazo-3-oxo methyl caproate
2-diazo-ethyl 3-oxobutanoate
2-diazo-3-oxopentanoic acid ethyl ester
2-diazo-3-oxo ethyl hexanoate
2-diazo-3-ketobutyric acid n-propyl
2-diazo-3-oxopentanoic acid n-propyl
2-diazo-3-oxo n-propyl hexylate
2-diazo-3-ketobutyric acid isopropyl ester
2-diazo-3-oxopentanoic acid isopropyl ester
2-diazo-3-oxo isopropyl hexylate
2-diazo-positive the butyl ester of 3-ketobutyric acid
2-diazo-positive the butyl ester of 3-oxopentanoic acid
2-diazo-positive the butyl ester of 3-oxo caproic acid
2-diazo-3-ketobutyric acid the tert-butyl ester
2-diazo-3-oxopentanoic acid the tert-butyl ester
2-diazo-3-oxo hecanoic acid t-butyl ester
2-diazo-3-ketobutyric acid benzyl ester
2-diazo-3-oxopentanoic acid benzyl ester
2-diazo-3-oxo benzyl hexanoate
2-diazo-3-ketobutyric acid is to the nitrobenzyl ester
2-diazo-3-oxopentanoic acid is to the nitrobenzyl ester
2-diazo-3-oxo caproic acid is to the nitrobenzyl ester
2-diazo-3-ketobutyric acid is to methoxy benzyl ester
2-diazo-3-oxopentanoic acid is to methoxy benzyl ester
2-diazo-3-oxo caproic acid is to methoxy benzyl ester
2-diazo-3-ketobutyric acid vinyl acetate
2-diazo-3-oxopentanoic acid vinyl acetate
2-diazo-3-oxo vinyl caproate
2-diazo-3-ketobutyric acid allyl ester
2-diazo-3-oxopentanoic acid allyl ester
2-diazo-3-oxo pineapple aldehyde
Deng.
As the preferred compound in these compounds, for example can enumerate 2-diazo-3-oxopentanoic acid tert-butyl ester, 2-diazo-3-oxopentanoic acid benzyl ester, 2-diazo-3-oxopentanoic acid to nitrobenzyl ester, 2-diazo-3-oxopentanoic acid allyl ester etc.
The metallic compound of the general formula that uses among the present invention [4] expression can directly use with commercially available product, can purify to it as required.
, as the object lesson of the metallic compound of general formula [4] expression, for example, can enumerate TiCl4、TiCl
3(OCH
3)、TiCl
3(OC
2H
5)、TiCl
3(O-n-pro-pyl), TiCl3(O-isopropyl), TiCl3(O-butyl), TiCl3(O-isobutyl group), TiCl3(O-sec-butyl), TiCl3(the O-tert-butyl group), TiCl2(O-methyl)2、TiCl
2(O-ethyl)2、TiCl
2(O-n-pro-pyl)2、TiCl
2(O-isopropyl)2、
TiCl
2(O-butyl)2、TiCl
2(O-isobutyl group)2、TiCl
2(O-sec-butyl)2、TiCl
2(the O-tert-butyl group)2、
Ti(Cp)
2Cl
2、Ti(Cp
*)
2Cl
2、TiBr
4、TiI
4Deng titanium compound; ZnCl2、ZnBr
2、
ZnI
2Deng zinc compound; ZrCl4、ZrCl
3(O-methyl), ZrCl3(O-ethyl), ZrCl3(O-n-pro-pyl), ZrCl3(O-isopropyl), ZrCl3(O-normal-butyl), ZrCl3(O-isobutyl group), ZrCl3(O-sec-butyl), ZrCl3(the O-tert-butyl group), Zr (Cp)2Cl
2、Zr(Cp
*)
2Cl
2、ZrBr
4、ZrI
4Deng zirconium compounds; AlCl3, Al (O-methyl)3, Al (O-ethyl)3, Al (O-n-pro-pyl)3, Al (O-isopropyl)3、AlCl
2Me、AlClMe
2、AlMe
3、AlCl
2Et、AlClEt
2、AlEt
3、AlBr
3、
AlI
3Deng aluminium compound; SnCl4、SnBr
4、SnI
4、Sn(OSO
2CF
3)
2Deng tin compound; FeCl3、FeBr
3、FeI
3Deng iron compound; (C2H
5)
2O·BF
3、(CH
3)
2BOSO
2CF
3、
(C
2H
5)
2BOSO
2CF
3、(Pr)
2BOSO
2CF
3、(Bu)
2BOSO
2CF
3Deng boron compound; (CH3)
3SiOSO
2CF
3、(CH
3)
3The silicon compound of SiCl etc.; ScF3、ScCl
3、ScBr
3、ScI
3, Sc (O-isopropyl)3、Sc(OSO
2CH
3)
3Deng scadium compound; YF3、YCl
3、YBr
3、YI
3, Y (O-isopropyl)3、Y(OSO
2CH
3)
3Deng yttrium compound; LaF3、LaCl
3、LaBr
3、LaI
3, La (O-isopropyl)3、La(OSO
2CH
3)
3Deng lanthanum compound; CeF3、CeCl
3、CeBr
3、
CeI
3, Ce (O-isopropyl)3、Ce(OSO
2CH
3)
3Deng cerium compound; PrF3、PrCl
3、PrBr
3、
PrI
3, Pr (O-isopropyl)3、Pr(OSO
2CH
3)
3Deng praseodymium compound; NdF3、NdCl
3、NdBr
3、
NdI
3, Nd (O-isopropyl)3、Nd(OSO
2CH
3)
3Deng neodymium compound; SmF3、SmCl
3、
SmBr
3、SmI
3, Sm (O-isopropyl)3、Sm(OSO
2CH
3)
3Deng samarium compound; GdF3、
GdCl
3、GdBr
3、GdI
3, Gd (O-isopropyl)3、Gd(OSO
2CH
3)
3Deng gadolinium compound; DyF3、DyCl
3、DyBr
3、DyI
3, Dy (O-isopropyl)3、Dy(OSO
2CH
3)
3Deng dysprosium compound; ErF3、ErCl
3、ErBr
3、ErI
3, Er (O-isopropyl)3、Er(OSO
2CH
3)
3Deng erbium compound; YbF3、YbCl
3、YbBr
3、YbI
3, Yb (O-isopropyl)3、Yb(OSO
2CH
3)
3Deng ytterbium compound etc.
In addition, above-mentioned Cp representative ring pentadienyl, Cp
*Expression pentamethyl-cyclopentadienyl.
More preferably TiCl in these metallic compounds
4(titanium tetrachloride), ZnCl
2(zinc dichloride), ZrCl
4(zirconium tetrachloride), AlCl
3(aluminum chloride), SnCl
4(tin tetrachloride), (C
2H
5)
2OBF
3(boron trifluoride ethyl ether complex), (CH
3)
3SiOSO
2CF
3(trimethylsilyl triflate), (CH
3)
3SiCl (trimethylsilyl chloride) etc.
These metallic compounds can use separately, and perhaps two or more appropriate combination are used.
As the alkali that uses among the preparation method of the present invention, can enumerate as primary amine, secondary amine, tertiary amine, pyridines etc.
Object lesson when alkali is primary amine has ethamine, propylamine, butylamine, aniline, benzylamine etc.
Object lesson when alkali is secondary amine has diethylamine, di-n-propyl amine, diisopropylamine, isopropyl methyl amine, ethyl isopropylamine, di-n-butyl amine, diisobutyl amine, two sec-butylamine, di-t-butyl amine, methylphenylamine, N-ethylaniline, tetramethyleneimine, piperidines, morpholine, piperazine, imidazoles, dibenzyl amine etc.
Object lesson when alkali is tertiary amine has Trimethylamine 99, triethylamine, tripropyl amine, triisopropylamine, diisopropyl methylamine, diisopropylethylamine, tri-n-butylamine, tribenzyl amine, N-methyl piperidine, N-ethylpiperidine, N-methylmorpholine, N-ethylmorpholine, 1,5-diazabicyclo [4.3.0]-5-nonene, 1,8-diazabicyclo [5.4.0]-7-undecylene, 1,4-diazabicyclo [2.2.2] octane, N, N, N, N-Tetramethyl Ethylene Diamine, N, N, N, N-tetramethyl--1,3-propylene diamine, xylidine, Diethyl Aniline etc.
Object lesson when alkali is pyridines has pyridine, α-Jia Jibiding, beta-picoline, γ-picoline, 2,6-lutidine, 2-ethylpyridine, 3-ethylpyridine, 4-ethylpyridine, N, N-dimethyl aminopyridine, quinoline, isoquinoline 99.9 etc.
In these alkali, for example, triethylamine, tri-n-butyl amine, diisopropylethylamine, N-methyl piperidine, N-ethylpiperidine, N-methylmorpholine, N-ethylmorpholine, 1,5-diazabicyclo [4.3.0]-5-nonene, 1,8-diazabicyclo [5.4.0]-7-undecylene, 1,4-diazabicyclo [2.2.2] octane, N, N-dimethyl aminopyridine etc., because of its selectivity and yield with versatility, reaction is also high, so be more preferably.
These alkali can use separately, also can two or more appropriate combination use.The alkali that the present invention uses can directly use commercially available product, also can carry out purifying as required.
For implementing preparation method of the present invention, wish under inert atmospheres such as argon gas or nitrogen, in organic solvent, to carry out.Under such condition, the diazonium compound by at first making general formula [3] expression and the metallic compound and the alkali reaction of general formula [4] expression make compound and its reaction of general formula [2] expression then, can prepare the azetidinone compounds that general formula [1] is represented.
As the organic solvent that uses in the reaction, do not get final product so long as do not influence the inert solvent of reaction, can enumerate as pentane, hexane, varsols such as heptane, hexanaphthene, alicyclic hydrocarbon type solvents such as methylcyclohexane, methylene dichloride, ethylene dichloride, chloroform, halogenated hydrocarbon solvents such as ethylene dibromide, benzene, chlorobenzene, toluene, aromatic hydrocarbon solvents such as dimethylbenzene, diethyl ether, diisopropyl ether, tetrahydrofuran (THF), glycol dimethyl ether, 1, the 3-dioxolane, 1, ether solvents such as 4-dioxane, acetonitrile, nitrile solvents such as propionitrile, dimethyl formamide, amide solvents such as N,N-DIMETHYLACETAMIDE etc.
These solvents can use separately, and perhaps two or more appropriate combination are used.
Preferred solvent in these solvents has halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ether solvent etc., wherein more preferably methylene dichloride, toluene, dimethylbenzene, tetrahydrofuran (THF) etc. from the selectivity of versatility, reaction and the high aspect of yield.
The usage quantity of these solvents has no particular limits, but with respect to the compound of general formula [2] expression, usually in the scope of about 1～50 times of volume, preferred about 5～20 times of volumes.
Temperature of reaction adopts about-70～100 ℃ usually, preferred about-70～0 ℃ scope approximately, by carry out about about 5 minutes～5 hours, preferred about about 10 minutes～3 hours reaction when keeping aforementioned temperature, reacting balance is carried out.
In the present invention, with respect to the compound of 1 mole of general formula [2] expression, the usage quantity of the diazonium compound of general formula [3] expression adopts about about 0.5～5 times of mole, the scope about preferred about 0.7～4 times of mole.
In the present invention, with respect to the compound of 1 mole of general formula [2] expression, the usage quantity of the metallic compound of general formula [4] expression adopts about about 0.5～2.5 times of mole, the scope about preferred about 0.7～2 times of mole.
Among the present invention, with respect to the compound of 1 mole of general formula [2] expression, the usage quantity of alkali adopts about about 1～8 times of mole, about preferred about 1.4～4 times of moles.
R in the above-mentioned reaction
2During for the alkyl of methyl etc., the kind and the various reaction conditions of the metallic compound of representing according to the diazonium compound of general formula [3] expression and general formula [4], α-the body that generates and the ratio of β-body to a certain extent can be different, but the content of target beta-body is generally and is not less than about 85%.
By known post-treating method, i.e. for example solvent extraction, change molten, crystallization, recrystallization, various chromatographys etc., can obtain required azetidinone compounds by the reaction solution that obtains by above-mentioned reaction.
Azetidinone compounds by the general formula that obtains by preparation method of the present invention [1] expression by known preparation method, can easily obtain general formula [B]
(in the formula, R
1The expression alkyl, R
3With preceding with) expression carbapenems.
Embodiment
Illustrate in greater detail the present invention by the following examples, but the present invention is not subjected to the restriction of these embodiment.
In addition, the abbreviation among each embodiment is as described below:
TBDMSO: t-butyldimethylsilyl oxygen base
OAc: acetoxyl group, PNB: to nitrobenzyl
Embodiment 1 (3S, 4R)-3-[(R)-1-t-butyldimethylsilyl oxygen base ethyl]-4-[(R)-1-methyl-3-diazo-3-is to nitrobenzyl oxygen carbonyl-2-oxo-propyl group]-preparation of azetidine-2-ketone
Under nitrogen atmosphere, with the 2-diazo-3-ketobutyric acid-dichloromethane solution (15mL) of nitrobenzyl ester 2.22g (8.0mmol) is cooled to-40 ℃, add titanium tetrachloride 0.39mL (3.55mmol),-40 ℃ stir 30 minutes after, add Tributylamine 1.81mL (7.57mmol), stirred 30 minutes at-40 ℃ again.Then, in this reaction solution, drip (3R, 4R)-the 4-acetoxy-3-[(R)-1-t-butyldimethylsilyl oxygen base ethyl]-dichloromethane solution (5mL) of azetidine-2-ketone 574mg (2.0mmol), stirred 1 hour at-40 ℃ again.Reaction mixture is injected 10% sodium bicarbonate aqueous solution stopped reaction, from organic layer sampling and washing.Result with efficient liquid phase chromatographic analysis is β: α=95: 5.Behind the organic layer with the anhydrous magnesium sulfate drying gained, heat up in a steamer and desolvate, use the chromatography purification residue, obtain Beta-methyl derivative (title compound) 757mg (yield 75%).
The physics value of this compound is consistent with the physics value that the spy opens clear 61-275284 number record.
Embodiment 2 (3S, 4R)-3-[(R)-1-t-butyldimethylsilyl oxygen base ethyl]-4-[(R)-1-methyl-3-diazo-3-is to nitrobenzyl oxygen carbonyl-2-oxo-propyl group]-preparation of azetidine-2-ketone
Under nitrogen atmosphere, with the 2-diazo-3-ketobutyric acid-dichloromethane solution (20mL) of nitrobenzyl ester 1.66g (6.0mmol) is cooled to-40 ℃, add titanium tetrachloride 0.66mL (6.0mmol),-40 ℃ stir 30 minutes after, add N-ethylpiperidine 1.65mL (12.0mmol), stirred 30 minutes at-40 ℃ again.Then, in this reaction solution, drip (3R, 4R)-the 4-acetoxy-3-[(R)-1-t-butyldimethylsilyl oxygen base ethyl]-dichloromethane solution (5mL) of azetidine-2-ketone 1.72g (6.0mmol), stirred 1 hour at-40 ℃ again.Add 1M hydrochloric acid 10mL in reaction mixture, stopped reaction is from organic layer sampling and washing.Result with efficient liquid phase chromatographic analysis is β: α=98: 2.Behind the organic layer with the anhydrous magnesium sulfate drying gained, heat up in a steamer and desolvate, use the chromatography purification residue, obtain Beta-methyl derivative (title compound) 2.09mg (yield 69%).
Embodiment 3,4
The titanium tetrachloride in using the various metallic compounds replacement embodiment 1 shown in the following table 1, react and aftertreatment according to method similarly to Example 1, separately with following yield with generate than having obtained azetidinone compounds similarly to Example 1.The result is as shown in table 1.
Table 1
| Embodiment | Metallic compound | Beta-methyl isomer: Alpha-Methyl isomer | Yield (%) |
| ????3 | ????ZrCl 4 | ????80∶20 | ????25 |
| ????4 | ????AlCl 3 | ????95∶5 | ????26 |
Embodiment 5
Except that using titanium tetrachloride and trimethylsilyl chloride as the metallic compound among the embodiment 1, react and aftertreatment according to mode similarly to Example 1, obtained azetidinone compounds similarly to Example 1, yield 68%, β-body: α-body (generating ratio)=95: 5.
Embodiment 6
Remove the temperature of reaction among the embodiment 1-40 ℃ is set at 5 ℃, use triethylamine to replace Tributylamine as beyond the alkali, react and aftertreatment according to mode similarly to Example 1, obtained azetidinone compounds similarly to Example 1, yield 69%, β-body: α-body (generating ratio)=95: 5.
Comparative example 1
The alkali in not using embodiment 1, when reacting, do not obtain target product fully according to mode similarly to Example 1.
Embodiment 7～9
The methylene dichloride in using the various reaction solvents replacement embodiment 1 shown in the following table 2, react and aftertreatment according to mode similarly to Example 1, separately with following yield with generate than having obtained azetidinone compounds similarly to Example 1.The result is as shown in table 2.
Table 2
| Embodiment | Solvent | β-isomer: α-isomer | Yield (%) |
| ????7 | Toluene | ????95∶5 | ????45 |
| ????8 | Acetonitrile | ????95∶5 | ????48 |
| ????9 | ??THF | ????92∶8 | ????45 |
Embodiment 10～13
Except that in embodiment 1, use with 2-diazo-3-ketobutyric acid-to nitrobenzyl ester (R=is to the compound of nitrobenzyl in the above-mentioned chemical formula) to nitrobenzyl with the various substituting group metathetical compounds shown in the following table 3 as diazonium compound, react and aftertreatment according to mode similarly to Example 1, in the various azetidinone compounds that obtain, obtained the Beta-methyl body with highly selective.The result is as shown in table 3.
Table 3
| Embodiment | ????R | Beta-methyl isomer: Alpha-Methyl isomer | Yield (%) |
| ????10 | Benzyl | ????96∶4 | ????38 |
| ????11 | Methyl | ????96∶4 | ????36 |
| ????12 | The tertiary butyl | ????86∶14 | ????40 |
| ????13 | Allyl group | ????94∶6 | ????34 |
Reference example 1 (1R, 5R, 6S)-to nitrobenzyl-2-diphenylphosphine acyloxy-6-[(R)-1-hydroxyethyl]-preparation of 1-methyl-carbapenem-3-carboxylic acid ester
Under stream of nitrogen gas, with (3S, 4R)-3-[(R)-1-t-butyldimethylsilyl oxygen base ethyl]-4-[(R)-1-methyl-3-diazo-3-is to nitrobenzyl oxygen carbonyl-2-oxo-propyl group]-after azetidine-2-ketone 149.7g (314mmol) is dissolved among the methyl alcohol 750mL, add 2M aqueous hydrochloric acid 44.5mL, stirring at room 22.5 hours.After adding ethyl acetate 1.1L stirs, to the organic layer sampling, and washing.Behind the organic layer that obtains with anhydrous magnesium sulfate drying, heat up in a steamer and desolvate, obtain desilylation product 107.6g.Resulting desilylation product 107.6g is dissolved among the ethyl acetate 1.1L, adds sad rhodium (Rh
2(Oct)
4) 0.65g, stirred 2.5 hours at 50 ℃.Heat up in a steamer and desolvate, the residue that obtains is dissolved among the acetonitrile 550mL, be cooled to-10 ℃ after, order adds diphenyl phosphate chloride 77.8g, diisopropylethylamine 39.2g, and stirs 3 hours at-10 ℃.Heat up in a steamer and desolvate, the residue that obtains is dissolved among the ethyl acetate 2.2L.After the organic layer washing that obtains, heat up in a steamer and desolvate, add heptane and make crystallization.Filtering for crystallizing is also dry, obtains title compound 137.9g.
The physics value of this compound and Heterocycles, 21 volumes, 29-40 page or leaf (1984) is consistent with the physics value that the spy opens this compound of putting down in writing for flat 6-321946 number.
Industrial applicibility
The invention provides under gentle condition, operation is few, yield good and optionally prepare the preparation method of azacyclo-butanone compound, wherein, azacyclo-butanone compound is the important synthetic intermediate for industrial preparation 1 β-methyl carbapenem derivative, and 1 β-methyl carbapenem derivative is suitable for preparing the Carbapenems antibiotics as antibacterial material. The present invention is obtaining significant effect aspect this.
Claims (14)
1. the preparation method of the compound of following formula [1] expression,
In the formula, R
1, R
2, R
3With identical in X and the following formula,
It is characterized in that,
The compound that makes following formula [2] expression and the compound of following formula [3] expression react under the existence of the compound represented of general formula [4] and alkali below,
R in the formula
1Expression hydrogen atom or hydroxyl protecting group, L represents leavings group,
In the formula, R
2Expression hydrogen atom or carbon number are 1～4 low alkyl group, R
3The expression carbon number is that 1～12 alkyl, carbon number are 2～5 alkenyl, can to have substituent phenyl, can have substituent carbon number be 7～15 aralkyl or the alicyclic radical that can have substituent 5～8 Yuans rings, and X represents Sauerstoffatom or sulphur atom,
MY
n(R
4)
m????????????(4)
In the formula, M represents atoms metal, and Y represents halogen atom, R
4The expression carbon number is that 1～4 low alkyl group, carbon number are 1～4 lower alkoxy, can have substituent phenoxy group, alkyl sulfonyl dioxy base, fragrant sulphonyl dioxy base, alkylsulfonyloxy, arylsulfonyloxy, cyclopentadienyl or pentamethyl-cyclopentadienyl, n and m are 0～4 integer, and n+m is the valence of M.
2. the described preparation method of claim 1, wherein, the atoms metal that M represents in the general formula [4] is the atoms metal of periodictable the 4th family.
3. the described preparation method of claim 2, wherein, the atoms metal of periodictable the 4th family is titanium or zirconium.
4. the described preparation method of claim 1, wherein, in the general formula [4], the atoms metal that M represents is the atoms metal of periodictable the 14th family.
5. the described preparation method of claim 4, wherein the atoms metal of periodictable the 14th family is silicon or tin.
6. the described preparation method of claim 1, wherein, in the general formula [4], the atoms metal that M represents is the atoms metal of belonging to group 13 of periodic table.
7. the described preparation method of claim 6, wherein, the atoms metal of belonging to group 13 of periodic table is boron or aluminium.
8. the described preparation method of claim 1, wherein, in the general formula [4], the atoms metal that M represents is the atoms metal of periodictable the 3rd family.
9. the described preparation method of claim 8, wherein, the atoms metal of periodictable the 3rd family is scandium, yttrium or lanthanon.
10. the described preparation method of claim 1, wherein, in the general formula [4], the atoms metal that M represents is the atoms metal of periodictable the 8th family.
11. the described preparation method of claim 10, wherein, the atoms metal of periodictable the 8th family is iron or ruthenium.
12. the described preparation method of claim 1, wherein, in the general formula [4], the atoms metal that M represents is the atoms metal of periodictable the 12nd family.
13. the described preparation method of claim 12, wherein the atoms metal of periodictable the 12nd family is a zinc.
14. each described preparation method of claim 1～13, wherein alkali is primary amine, secondary amine, tertiary amine and/or pyridines.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002082560A JP2003277390A (en) | 2002-03-25 | 2002-03-25 | Method for producing azetidinone compound |
| JP82560/2002 | 2002-03-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1610663A true CN1610663A (en) | 2005-04-27 |
| CN1277819C CN1277819C (en) | 2006-10-04 |
Family
ID=28449147
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB03801808XA Expired - Fee Related CN1277819C (en) | 2002-03-25 | 2003-02-17 | Process for producing azetidinone compounds |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JP2003277390A (en) |
| KR (1) | KR20040095198A (en) |
| CN (1) | CN1277819C (en) |
| AU (1) | AU2003211227A1 (en) |
| WO (1) | WO2003080571A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101891665B (en) * | 2009-05-22 | 2013-02-06 | 上海医药工业研究院 | (3S,4S)-4-acetyl-3-((R)-1-hydroxyethyl)-2-azetidinone and preparation method of same |
| CN102936217A (en) * | 2012-11-08 | 2013-02-20 | 浙江新东港药业股份有限公司 | Preparation method of intermediate for penem |
| CN103553995A (en) * | 2013-11-13 | 2014-02-05 | 凯莱英医药集团（天津）股份有限公司 | Method for preparing penem antibiotic midbody |
| WO2015070394A1 (en) * | 2013-11-13 | 2015-05-21 | 凯莱英医药集团（天津）股份有限公司 | Method for preparing penem antibiotic intermediate |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2732619A1 (en) | 2008-07-30 | 2010-02-04 | Ranbaxy Laboratories Limited | Process for the preparation of carbapenem compounds |
| WO2011048583A1 (en) | 2009-10-23 | 2011-04-28 | Ranbaxy Laboratories Limited | Process for the preparation of carbapenem compounds |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3509769A1 (en) * | 1985-03-19 | 1986-09-25 | Bayer Ag, 5090 Leverkusen | METHOD FOR PRODUCING CARBAPENE INTERMEDIATE PRODUCTS |
| DE3617626A1 (en) * | 1986-05-26 | 1987-12-03 | Bayer Ag | SUBSTITUTED 6-HYDROXYMETHYL CARBAPENEM ANTIBIOTICS, METHOD FOR THEIR PRODUCTION AND THEIR USE |
| NZ234411A (en) * | 1989-07-18 | 1991-05-28 | Merck & Co Inc | Preparation of 2-diazo-3-silyloxy-3-butenoate esters |
| GB9124850D0 (en) * | 1991-11-22 | 1992-01-15 | Harding Paul F | Assembly comprising clip device |
| JP3787819B2 (en) * | 1994-07-14 | 2006-06-21 | 日本曹達株式会社 | Azetidinone compound and method for producing the same |
| WO1999052908A1 (en) * | 1998-04-16 | 1999-10-21 | Merck & Co., Inc. | Titanium catalyzed preparation of carbapenem intermediates |
| JP4294124B2 (en) * | 1998-06-23 | 2009-07-08 | 日本曹達株式会社 | Method for producing azetidinone derivative |
-
2002
- 2002-03-25 JP JP2002082560A patent/JP2003277390A/en active Pending
-
2003
- 2003-02-17 KR KR10-2004-7008611A patent/KR20040095198A/en not_active Application Discontinuation
- 2003-02-17 WO PCT/JP2003/001615 patent/WO2003080571A1/en active Application Filing
- 2003-02-17 AU AU2003211227A patent/AU2003211227A1/en not_active Abandoned
- 2003-02-17 CN CNB03801808XA patent/CN1277819C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101891665B (en) * | 2009-05-22 | 2013-02-06 | 上海医药工业研究院 | (3S,4S)-4-acetyl-3-((R)-1-hydroxyethyl)-2-azetidinone and preparation method of same |
| CN102936217A (en) * | 2012-11-08 | 2013-02-20 | 浙江新东港药业股份有限公司 | Preparation method of intermediate for penem |
| CN103553995A (en) * | 2013-11-13 | 2014-02-05 | 凯莱英医药集团（天津）股份有限公司 | Method for preparing penem antibiotic midbody |
| WO2015070394A1 (en) * | 2013-11-13 | 2015-05-21 | 凯莱英医药集团（天津）股份有限公司 | Method for preparing penem antibiotic intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2003211227A1 (en) | 2003-10-08 |
| JP2003277390A (en) | 2003-10-02 |
| KR20040095198A (en) | 2004-11-12 |
| CN1277819C (en) | 2006-10-04 |
| WO2003080571A1 (en) | 2003-10-02 |
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