KR20040095198A - Process for producing azetidinone compounds - Google Patents
Process for producing azetidinone compounds Download PDFInfo
- Publication number
- KR20040095198A KR20040095198A KR10-2004-7008611A KR20047008611A KR20040095198A KR 20040095198 A KR20040095198 A KR 20040095198A KR 20047008611 A KR20047008611 A KR 20047008611A KR 20040095198 A KR20040095198 A KR 20040095198A
- Authority
- KR
- South Korea
- Prior art keywords
- group
- metal atom
- periodic table
- general formula
- represented
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 27
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 title description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 238000004519 manufacturing process Methods 0.000 claims abstract description 29
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 21
- 150000002736 metal compounds Chemical class 0.000 claims abstract description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 11
- 125000006239 protecting group Chemical group 0.000 claims abstract description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 3
- 229910052717 sulfur Chemical group 0.000 claims abstract description 3
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 28
- 229910052751 metal Inorganic materials 0.000 claims description 28
- 239000002184 metal Substances 0.000 claims description 28
- 125000001424 substituent group Chemical group 0.000 claims description 26
- 125000004429 atom Chemical group 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- 230000000737 periodic effect Effects 0.000 claims description 18
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 5
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- 239000010936 titanium Substances 0.000 claims description 4
- 125000002723 alicyclic group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 claims description 3
- 125000002097 pentamethylcyclopentadienyl group Chemical group 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
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 150000003141 primary amines 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
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-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 group [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 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
- 229910052796 boron Inorganic materials 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- 229910052747 lanthanoid Inorganic materials 0.000 claims description 2
- 150000002602 lanthanoids Chemical class 0.000 claims description 2
- 150000003222 pyridines Chemical class 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 compound [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
- 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
- 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
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- -1 azetidinone compound Chemical class 0.000 abstract description 111
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 13
- 239000004599 antimicrobial Substances 0.000 abstract description 4
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 abstract description 3
- 238000007796 conventional method Methods 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 229910007926 ZrCl Inorganic materials 0.000 description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- 150000008049 diazo compounds Chemical class 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000004423 acyloxy 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
- 229910052740 iodine Inorganic materials 0.000 description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 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 5
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- HEKGSEIAAGMGPL-UHFFFAOYSA-N (z)-3-diazonio-4-[(4-nitrophenyl)methoxy]-4-oxobut-2-en-2-olate Chemical compound CC(=O)C(\[N+]#N)=C(\[O-])OCC1=CC=C([N+]([O-])=O)C=C1 HEKGSEIAAGMGPL-UHFFFAOYSA-N 0.000 description 4
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 125000005103 alkyl silyl group Chemical group 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 4
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 4
- 150000002739 metals Chemical class 0.000 description 4
- 125000006606 n-butoxy group Chemical group 0.000 description 4
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 125000005920 sec-butoxy group Chemical group 0.000 description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 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
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 3
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 3
- 125000005333 aroyloxy group Chemical group 0.000 description 3
- 125000004391 aryl sulfonyl 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
- 238000001035 drying Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 description 2
- 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
- YKMONJZIUAOVEM-WDSKDSINSA-N 1beta-methylcarbapenem Chemical class C[C@H]1C=CN2C(=O)C[C@@H]12 YKMONJZIUAOVEM-WDSKDSINSA-N 0.000 description 2
- GKIDQSUMJNOXSY-UHFFFAOYSA-N 2-diazonio-1-[(2-methylpropan-2-yl)oxy]-1-oxopent-2-en-3-olate Chemical compound CCC([O-])=C([N+]#N)C(=O)OC(C)(C)C GKIDQSUMJNOXSY-UHFFFAOYSA-N 0.000 description 2
- GKQAKYGLWAEFQD-UHFFFAOYSA-N 2-diazonio-1-[(4-nitrophenyl)methoxy]-3-oxopent-1-en-1-olate Chemical compound CCC(=O)C([N+]#N)=C([O-])OCC1=CC=C([N+]([O-])=O)C=C1 GKQAKYGLWAEFQD-UHFFFAOYSA-N 0.000 description 2
- NJBCRXCAPCODGX-UHFFFAOYSA-N 2-methyl-n-(2-methylpropyl)propan-1-amine Chemical compound CC(C)CNCC(C)C NJBCRXCAPCODGX-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-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
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000790917 Dioxys <bee> Species 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-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
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-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
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-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
- INUVZQOIZPWVTG-UHFFFAOYSA-N [3-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxoazetidin-2-yl] 2-chloroacetate Chemical compound CC(C)(C)[Si](C)(C)OC(C)C1C(OC(=O)CCl)NC1=O INUVZQOIZPWVTG-UHFFFAOYSA-N 0.000 description 2
- GWHDKFODLYVMQG-UHFFFAOYSA-N [3-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxoazetidin-2-yl] acetate Chemical compound CC(C)(C)[Si](C)(C)OC(C)C1C(OC(C)=O)NC1=O GWHDKFODLYVMQG-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000005104 aryl silyl group Chemical group 0.000 description 2
- 125000005135 aryl sulfinyl 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
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 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
- 238000004440 column chromatography Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000005949 ethanesulfonyloxy group Chemical group 0.000 description 2
- 239000004210 ether based solvent Substances 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 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
- XHFGWHUWQXTGAT-UHFFFAOYSA-N n-methylpropan-2-amine Chemical compound CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000000704 physical effect Effects 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
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 2
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- 239000012442 inert solvent Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002506 iron compounds Chemical class 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 229910052746 lanthanum Inorganic materials 0.000 description 1
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum atom Chemical compound [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 description 1
- 150000002604 lanthanum compounds Chemical class 0.000 description 1
- 125000005394 methallyl group Chemical group 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- DMQSHEKGGUOYJS-UHFFFAOYSA-N n,n,n',n'-tetramethylpropane-1,3-diamine Chemical compound CN(C)CCCN(C)C DMQSHEKGGUOYJS-UHFFFAOYSA-N 0.000 description 1
- MXHTZQSKTCCMFG-UHFFFAOYSA-N n,n-dibenzyl-1-phenylmethanamine Chemical compound C=1C=CC=CC=1CN(CC=1C=CC=CC=1)CC1=CC=CC=C1 MXHTZQSKTCCMFG-UHFFFAOYSA-N 0.000 description 1
- 125000004708 n-butylthio group Chemical group C(CCC)S* 0.000 description 1
- RIVIDPPYRINTTH-UHFFFAOYSA-N n-ethylpropan-2-amine Chemical compound CCNC(C)C RIVIDPPYRINTTH-UHFFFAOYSA-N 0.000 description 1
- ISRXMEYARGEVIU-UHFFFAOYSA-N n-methyl-n-propan-2-ylpropan-2-amine Chemical compound CC(C)N(C)C(C)C ISRXMEYARGEVIU-UHFFFAOYSA-N 0.000 description 1
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 1
- 125000004706 n-propylthio group Chemical group C(CC)S* 0.000 description 1
- CATWEXRJGNBIJD-UHFFFAOYSA-N n-tert-butyl-2-methylpropan-2-amine Chemical compound CC(C)(C)NC(C)(C)C CATWEXRJGNBIJD-UHFFFAOYSA-N 0.000 description 1
- 125000005029 naphthylthio group Chemical group C1(=CC=CC2=CC=CC=C12)S* 0.000 description 1
- QEFYFXOXNSNQGX-UHFFFAOYSA-N neodymium atom Chemical class [Nd] QEFYFXOXNSNQGX-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000001400 nonyl 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])[H] 0.000 description 1
- HDKCVDHYIIKWFM-UHFFFAOYSA-K octanoate;rhodium(3+) Chemical compound [Rh+3].CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.CCCCCCCC([O-])=O HDKCVDHYIIKWFM-UHFFFAOYSA-K 0.000 description 1
- 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 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- PUDIUYLPXJFUGB-UHFFFAOYSA-N praseodymium atom Chemical compound [Pr] PUDIUYLPXJFUGB-UHFFFAOYSA-N 0.000 description 1
- 150000003114 praseodymium compounds Chemical class 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- KZLPVZXRSPCKFH-UHFFFAOYSA-N propan-2-yl 2-diazo-3-oxobutanoate Chemical compound CC(C)OC(=O)C([N+]#N)=C(C)[O-] KZLPVZXRSPCKFH-UHFFFAOYSA-N 0.000 description 1
- KXIXJPFLVWLACV-UHFFFAOYSA-N propan-2-yl 2-diazo-3-oxohexanoate Chemical compound CCCC(=O)C(=[N+]=[N-])C(=O)OC(C)C KXIXJPFLVWLACV-UHFFFAOYSA-N 0.000 description 1
- JLEYMKFBNLFSEG-UHFFFAOYSA-N propan-2-yl 2-diazo-3-oxopentanoate Chemical compound C(C)(C)OC(C(C(CC)=O)=[N+]=[N-])=O JLEYMKFBNLFSEG-UHFFFAOYSA-N 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- NUSYXJVYJMLRKA-UHFFFAOYSA-N propyl 2-diazo-3-oxobutanoate Chemical compound [N+](=[N-])=C(C(=O)OCCC)C(C)=O NUSYXJVYJMLRKA-UHFFFAOYSA-N 0.000 description 1
- BHEGXGVRWYYIDE-UHFFFAOYSA-N propyl 2-diazo-3-oxohexanoate Chemical compound CCCC(=O)C(=[N+]=[N-])C(=O)OCCC BHEGXGVRWYYIDE-UHFFFAOYSA-N 0.000 description 1
- AHKKVOBBRZLUSG-UHFFFAOYSA-N propyl 2-diazo-3-oxopentanoate Chemical compound [N+](=[N-])=C(C(=O)OCCC)C(CC)=O AHKKVOBBRZLUSG-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 description 1
- 150000003317 samarium compounds Chemical class 0.000 description 1
- 150000003326 scandium compounds Chemical class 0.000 description 1
- 150000003377 silicon compounds Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- CCAODYKZPWTKSQ-UHFFFAOYSA-N tert-butyl 2-diazo-3-oxohexanoate Chemical compound CCC\C([O-])=C(/[N+]#N)C(=O)OC(C)(C)C CCAODYKZPWTKSQ-UHFFFAOYSA-N 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 150000003606 tin compounds Chemical class 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- NVLRFXKSQQPKAD-UHFFFAOYSA-N tricarbon Chemical group [C]=C=[C] NVLRFXKSQQPKAD-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 description 1
- 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
- NAWDYIZEMPQZHO-UHFFFAOYSA-N ytterbium Chemical compound [Yb] NAWDYIZEMPQZHO-UHFFFAOYSA-N 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 150000003752 zinc compounds Chemical class 0.000 description 1
- 150000003755 zirconium compounds Chemical class 0.000 description 1
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 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
본 발명의 목적은 종래 방법의 문제점을 해소하고 원하는 1'-β 위치에 메틸기를 갖는 카바페넴계 항균제의 합성 중간체를 온화한 조건 하에서 짧은 공정으로 수율 좋고 선택적으로 얻는 방법을 제공하는 것이다. 즉, 특정의 금속 화합물과 염기의 존재 하에서 다음 식으로 표시되는 반응을 행하는 것을 특징으로 하는, 1'-β 위치를 갖는 아제티디논 화합물의 제조방법이 제공된다.An object of the present invention is to solve the problems of the conventional method and to provide a method for obtaining a good and selective yield of a synthetic intermediate of a carbapenem antimicrobial agent having a methyl group at a desired 1'-β position in a short process under mild conditions. That is, the manufacturing method of the azetidinone compound which has a 1 '-(beta) position characterized by performing reaction shown by following formula in presence of a specific metal compound and a base is provided.
(식중, R1은 수소 원자 또는 히드록시기의 보호기, L은 이탈기, R2는 수소 원자 또는 저급 알킬기, R3는 알킬기, 아르알킬기 등, X는 산소 원자 또는 유황 원자이다)(Wherein R 1 is a protecting group of a hydrogen atom or a hydroxyl group, L is a leaving group, R 2 is a hydrogen atom or a lower alkyl group, R 3 is an alkyl group, an aralkyl group, and X is an oxygen atom or a sulfur atom)
Description
항균물질로서 중요한 1β-메틸카바페넴 유도체의 제조에 이용되는 4위치 측쇄의 1' 위치에 β-메틸기를 갖는 아제티디논 화합물의 중요한 합성중간체인 (3S,4R)-3-[(R)-1-히드록시에틸]-4-[(R)-1-메틸-3-디아조-3-치환옥시카보닐-2-옥소-프로필]-아제티딘-2-온 [A](3S, 4R) -3-[(R)-, which is an important synthetic intermediate of the azetidinone compound having β-methyl group at the 1 'position of the 4-position side chain used in the preparation of the 1β-methylcarbapenem derivative, which is important as an antimicrobial substance 1-hydroxyethyl] -4-[(R) -1-methyl-3-diazo-3-substitutedoxycarbonyl-2-oxo-propyl] -azetidin-2-one [A]
[식중, R은 알킬기, 치환기를 가질 수 있는 벤질기, 치환기를 가질 수 있는 아릴기를 나타낸다.][Wherein R represents an alkyl group, a benzyl group which may have a substituent and an aryl group which may have a substituent.]
의 제조법으로서는, 예를 들어 일본 특허공개 소57-123182호 공보에 기재된다음 반응식 1로 표시되는 제조법,As a manufacturing method of the manufacturing method, for example, the manufacturing method represented by the following reaction formula 1 described in JP-A-57-123182,
일본 특허공개 소64-25779호 공보에 기재된 다음 반응식 2로 표시되는 제조법,The manufacturing method represented by following Reaction Formula 2 of Unexamined-Japanese-Patent No. 64-25779,
일본 특허공개 평6-321946호 공보에 기재된 다음 반응식 3으로 표시되는 제조법,The manufacturing method represented by following Reaction Formula 3 of Unexamined-Japanese-Patent No. 6-321946,
그리고, 일본 특허공개 소58-103358호 공보, 일본 특허공개 평6-199780호 공보, 일본 특허공개 소61-275284호 공보 등에 기재된 다음 반응식 4로 표시되는 제조법 등이 알려져 있다.And the manufacturing method shown by following Reaction Scheme 4 etc. which are described in Unexamined-Japanese-Patent No. 58-103358, Unexamined-Japanese-Patent No. 6-199780, Unexamined-Japanese-Patent No. 61-275284, etc. are known.
그러나, 이들 제조방법은 어느 것이나 각각 다음과 같은 문제점을 갖고 있어 충분히 만족스러운 것이라고는 말할 수 없다.However, all of these manufacturing methods have the following problems, and cannot be said to be sufficiently satisfactory.
즉, 반응식 1∼반응식 3의 방법에서는 고가의 출발원료를 사용하고, 공정수가 많기 때문에 조작이 복잡하게 되고, 수율 면에서만이 아니라 가격 면에서도 결코 바람직한 것이 아니다.In other words, in the methods of Schemes 1 to 3, expensive starting materials are used, and since the number of processes is large, the operation is complicated, and it is not preferable not only in terms of yield but also in price.
또한, 반응식 4의 방법에서는 비교적 짧은 공정으로 제조하고 있지만, 불안정한 실릴에놀에테르를 사용하지 않으면 안되기 때문에 공업적인 방법이라고는 말하기 어렵고, 또 경제적인 방법이라고 하기도 힘들다.In addition, although the method of Reaction Scheme 4 is manufactured in a relatively short process, it is difficult to say that it is an industrial method because it is necessary to use unstable silylenol ether and it is difficult to say it is an economic method.
본 발명은 카바페넴(carbapenem)계 화합물의 중요한 합성 중간체인 아제티디논 화합물의 제조방법에 관한 것이다.The present invention relates to a method for preparing an azetidinone compound which is an important synthetic intermediate of a carbapenem compound.
본 발명의 목적은 상기와 같은 종래 방법의 문제점을 해소하여, 원하는 1'-β 위치에 메틸기를 갖는 카바페넴계 항균제의 합성 중간체를 온화한 조건 하에서 짧은 공정으로 수율 좋게 선택적으로 얻는 방법을 제공하는 것에 있다.SUMMARY OF THE INVENTION An object of the present invention is to provide a method for selectively and efficiently obtaining a synthetic intermediate of a carbapenem-based antimicrobial agent having a methyl group at a desired 1'-β position in a short process under mild conditions by solving the problems of the conventional method as described above. have.
본 발명은 다음 일반식 [2]The present invention is the following general formula [2]
(식중, R1은 수소 원자 또는 히드록시기의 보호기를 나타내고, L은 이탈기를 나타낸다.)(Wherein R 1 represents a protecting group of a hydrogen atom or a hydroxyl group, and L represents a leaving group).
로 표시되는 화합물과, 다음 일반식 [3]A compound represented by the following Formula [3]
(식중, R2는 수소 원자 또는 탄소수 1∼4의 저급 알킬기를 나타내고, R3는 탄소수 1∼12의 알킬기, 치환기를 가질 수 있는 페닐기, 치환기를 가질 수 있는 탄소수 7∼15의 아르알킬기, 또는 치환기를 가질 수 있는 5∼8원환의 지환식기 (alicyclic group)를 나타내고, X는 산소 원자 또는 유황 원자를 나타낸다.)(Wherein R 2 represents a hydrogen atom or a lower alkyl group of 1 to 4 carbon atoms, R 3 represents an alkyl group of 1 to 12 carbon atoms, a phenyl group which may have a substituent, an aralkyl group of 7 to 15 carbon atoms that may have a substituent, or Represents an alicyclic group of 5 to 8 membered rings which may have a substituent, and X represents an oxygen atom or a sulfur atom.)
으로 표시되는 화합물을, 다음 일반식 [4]The compound represented by following General formula [4]
(식중, M은 금속 원자를 나타내고, Y는 할로겐 원자를 나타내고, R4는 탄소수 1∼4의 저급 알킬기, 탄소수 1∼4의 저급 알콕시기, 치환기를 가질 수 있는 페녹시기, 알킬설포닐디옥시기, 아릴설포닐디옥시기, 알킬설포닐옥시기, 아릴설포닐옥시기, 시클로펜타디에닐기, 또는 펜타메틸시클로펜타디에닐기를 나타내고, n 및 m은 0∼4의 정수이고, 또한 n+m은 M의 원자가이다.)(Wherein M represents a metal atom, Y represents a halogen atom, R 4 represents a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a phenoxy group which may have a substituent, and an alkylsulfonyldioxy group) , An arylsulfonyldioxy group, an alkylsulfonyloxy group, an arylsulfonyloxy group, a cyclopentadienyl group, or a pentamethylcyclopentadienyl group, n and m are integers of 0 to 4, and n + m is an M It is the valence.)
로 표시되는 금속 화합물, 및 염기의 존재 하에서 반응시키는 것을 특징으로 하는, 다음 일반식 [1]The reaction is carried out in the presence of a metal compound and a base represented by the following general formula [1]
(식중, R1, R2, R3및 X는 상기와 같다.)(Wherein R 1 , R 2 , R 3 and X are the same as above).
로 표시되는 화합물의 제조방법에 관한 것이다.It relates to a method for producing a compound represented by.
즉, 본 발명자들은 상기 목적을 달성하기 위하여 열심히 연구를 계속한 결과, 상기 일반식 [2]로 표시되는 화합물과 상기 일반식 [3]으로 표시되는 디아조 화합물을 특정 금속 화합물과 염기의 존재 하에서 반응시키는 것만으로 원하는 1'-β 배치를 갖는 아제티디논 화합물 [1]을 선택적이면서도 수율 좋게 제조하는 것이 가능하다는 것을 발견하여 본 발명을 완성하게 되었다.That is, the present inventors have studied diligently to achieve the above object, and as a result, the compound represented by the general formula [2] and the diazo compound represented by the general formula [3] in the presence of a specific metal compound and a base The present invention was completed by discovering that it is possible to produce an azetidinone compound [1] having a desired 1'-β configuration only in a selective and yieldable manner by only reacting it.
본 발명은 디아조 화합물이 실릴에놀에테르로 변환하는 것을 필요로 하지 않고, 일반식 [2]로 표시되는 화합물과 일반식 [3]으로 표시되는 디아조 화합물을 특정 금속 화합물과 염기의 존재 하에서 반응시키는 것만으로 원하는 1'-β 배치를 갖는 아제티디논 화합물을 온화한 조건 하에서 짧은 공정으로 수율 좋고 선택적으로 제조하는 방법을 제공하는 것이다.The present invention does not require the diazo compound to be converted to silylenol ether, and the compound represented by the general formula [2] and the diazo compound represented by the general formula [3] in the presence of a specific metal compound and a base It is to provide a method of producing a good and selective production of an azetidinone compound having a desired 1'-β configuration in a short process under mild conditions only by reacting.
본 발명의 제조방법에서 이용될 수 있는 상기 일반식 [2]로 표시되는 화합물에 있어서, R1으로 표시되는 히드록시기의 보호기로서는, 예를 들어 펩티드 화학이나 β-락탐 화합물의 분야에서 통상 이용되는 히드록시기의 보호기를 일반적으로 들 수 있다.In the compound represented by the general formula [2] which can be used in the production method of the present invention, as a protecting group of the hydroxy group represented by R 1 , for example, a hydroxyl group usually used in the field of peptide chemistry or β-lactam compound The protecting group of is mentioned generally.
즉, 히드록시기의 보호기로는, 예를 들어 트리메틸실릴기, 트리에틸실릴기, 트리이소프로필실릴기, 디메틸이소프로필실릴기, 디에틸이소프로필실릴기, 디메틸(2,3-디메틸-2-부틸)실릴기, tert-부틸디메틸실릴기 및 디메틸헥실실릴기 등의 트리-탄소수 1∼6 알킬실릴기, 예를 들어 디메틸쿠밀실릴기 등의 디-탄소수 1∼6 알킬-탄소수 6∼18 아릴실릴기, 예를 들어 tert-부틸디페닐실릴기 및 디페닐메틸실릴기 등의 디-탄소수 6∼18 아릴-탄소수 1∼6 알킬실릴기, 예를 들어 트리페닐실릴기 등의 트리-탄소수 6∼18 아릴실릴기, 예를 들어 트리벤질실릴기 및 트리-p-크실릴실릴기 등의 트리-탄소수 7∼19 아르알킬실릴기 등의 트리 치환 실릴기; 예를 들어 벤질기, 4-메톡시벤질기, 2-니트로벤질기, 4-니트로벤질기, 디페닐메틸기 및 트리페닐메틸기 등의 탄소수 1∼4 알콕시기(예를 들어, 메톡시기, 에톡시기 등)나 니트로기 등으로 그 수소 원자의 1∼3 개가 치환될 수 있는 탄소수 7∼19의 아르알킬기; 예를 들어 메톡시카보닐기, 에톡시카보닐기, tert-부톡시카보닐기, 2,2,2-트리클로로에톡시카보닐기 및 2-트리메틸실릴에톡시카보닐기 등의 탄소수 1∼4의 알콕시기(예를 들어, 메톡시기, 에톡시기 등), 할로겐 원자(예를 들어 불소, 염소, 브롬, 요오드 등) 또는 트리-탄소수 1∼4 알킬실릴기(예를 들어 트리메틸실릴기 등) 등으로 그 수소 원자의 1∼3 개가 치환될 수 있는 탄소수 1∼6의 알킬옥시카보닐기; 예를 들어 벤질옥시카보닐기, 2-니트로벤질옥시카보닐기, 4-니트로벤질옥시카보닐기, 4-메톡시벤질옥시카보닐기 및 3,4-디메톡시벤질옥시카보닐기 등의 탄소수 1∼4의 알콕시기(예를 들어 메톡시기, 에톡시기 등) 또는 니트로기로 그 수소 원자의 1∼3개가 치환될 수 있는 탄소수 7∼10의 아르알킬옥시카보닐기; 예를 들어 비닐옥시카보닐기 및 알릴옥시카보닐기 등의 탄소수 2∼6의 알케닐옥시카보닐기; 예를 들어 포르밀기, 아세틸기, 클로로아세틸기, 디클로로아세틸기, 트리클로로아세틸기, 트리플루오로아세틸기, 프로피오닐기, 부티릴기, 벤조일기, 4-톨루오일기, 4-아니소일기 및 4-니트로벤조일기 등의 할로겐 원자(예를 들어, 불소, 염소, 브롬, 요오드 등)나 니트로기 등으로 그 수소 원자의 1∼3 개가 치환될 수 있는 아실기; 예를 들어 테트라히드로피라닐기 및 테트라히드로푸라닐기 등의 환상의 보호기 등을 들 수 있다.That is, as a protecting group of a hydroxy group, for example, trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, dimethylisopropylsilyl group, diethylisopropylsilyl group, dimethyl (2,3-dimethyl-2-butyl Tri-carbon 1-6 alkylsilyl groups such as silyl group, tert-butyldimethylsilyl group and dimethylhexylsilyl group, for example, di-carbon 1-6 alkyl- 6-18 arylsilyl such as dimethylcumylsilyl group Groups, for example, 6- to 18-aryl aryl-C1-6 alkylsilyl groups such as tert-butyldiphenylsilyl group and diphenylmethylsilyl group, such as triphenylsilyl groups such as tri-C6-6 Tri-substituted silyl groups such as tri-carbon 7-19 aralkylsilyl groups such as 18 arylsilyl group, for example tribenzylsilyl group and tri-p-xylylsilyl group; For example, C1-4 alkoxy groups (for example, methoxy group, ethoxy group, such as benzyl group, 4-methoxybenzyl group, 2-nitrobenzyl group, 4-nitrobenzyl group, diphenylmethyl group, and triphenylmethyl group) And an aralkyl group having 7 to 19 carbon atoms in which 1 to 3 of the hydrogen atoms may be substituted with a nitro group or the like; For example, alkoxy groups having 1 to 4 carbon atoms such as methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group and 2-trimethylsilylethoxycarbonyl group (E.g., methoxy group, ethoxy group, etc.), halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.) or tri-C 1-4 alkylsilyl groups (e.g., trimethylsilyl group, etc.) C1-C6 alkyloxycarbonyl group which 1-3 of a hydrogen atom may substitute; For example, C1-4 carbon atoms, such as a benzyloxycarbonyl group, 2-nitrobenzyloxycarbonyl group, 4-nitrobenzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, and 3, 4- dimethoxybenzyloxycarbonyl group, etc. An alkoxy group (for example, a methoxy group, an ethoxy group, etc.) or a nitro group having 7 to 10 carbon atoms aralkyloxycarbonyl group in which 1 to 3 of the hydrogen atoms may be substituted; Alkenyloxycarbonyl groups having 2 to 6 carbon atoms such as vinyloxycarbonyl group and allyloxycarbonyl group; For example, formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl, butyryl, benzoyl, 4-toluoyl, 4-anisoyl and An acyl group in which 1 to 3 hydrogen atoms may be substituted with a halogen atom such as a 4-nitrobenzoyl group (for example, fluorine, chlorine, bromine or iodine) or a nitro group; For example, cyclic protecting groups, such as a tetrahydropyranyl group and a tetrahydrofuranyl group, etc. are mentioned.
이들 보호기 중에 바람직한 것으로는, 예를 들어 탄소수 7∼19의 아르알킬옥시카보닐기(예를 들어 벤질옥시카보닐기 및 4-니트로벤질옥시카보닐기 등), 탄소수 2∼6의 알케닐옥시카보닐기(예를 들어 알릴옥시카보닐기 등), 트리-탄소수 1∼6 알킬실릴기 등을 들 수 있고, 더욱 바람직한 것으로는 tert-부틸디메틸실릴기 등을 들 수 있다.Among these protecting groups, preferred are, for example, an aralkyloxycarbonyl group having 7 to 19 carbon atoms (eg, benzyloxycarbonyl group and 4-nitrobenzyloxycarbonyl group), and an alkenyloxycarbonyl group having 2 to 6 carbon atoms ( For example, an allyloxycarbonyl group etc.), a tri-C1-C6 alkylsilyl group, etc. are mentioned, More preferably, a tert- butyldimethyl silyl group etc. are mentioned.
또한, L로 나타낸 이탈기로서는, 예를 들어 아실옥시기(예를 들어, 알카노일옥시기, 아로일옥시기, 아릴알카노일옥시기, 알킬설포닐옥시기, 아릴설포닐옥시기, 알콕시카보닐옥시기, 아르알콕시카보닐옥시기, 알콕시알카노일옥시기, 카바모일옥시기 등을 들 수 있다.), 알카노일티오기, 아로일티오기, 알킬티오기, 아릴티오기, 알킬설피닐기, 아릴설피닐기, 알킬설포닐기, 아릴설포닐기, 할로겐 원자 등을 들 수 있다.As the leaving group represented by L, for example, an acyloxy group (for example, an alkanoyloxy group, an aroyloxy group, an arylalkanoyloxy group, an alkylsulfonyloxy group, an arylsulfonyloxy group, an alkoxycarbonyloxy group, Aralkoxycarbonyloxy group, alkoxyalkanoyloxy group, carbamoyloxy group, etc.), alkanoylthio group, aroylthio group, alkylthio group, arylthio group, alkylsulfinyl group, arylsulfinyl group, alkylsulfo And a halogen group, an arylsulfonyl group, and a halogen atom.
L이 알카노일옥시기인 경우의 구체적인 예로서는 아세톡시기, 프로피오닐옥시기, 부티릴옥시기, α-플루오로아세톡시기, α-클로로아세톡시기, α-브로모아세톡시기, α-요오도아세톡시기, α,α-디플루오로아세톡시기, α,α-디클로로아세톡시기 및 α-시아노아세톡시기 등의, 할로겐 원자, 시아노기 등의 치환기가 1∼3 개 치환될 수 있는 직쇄의 알카노일옥시기; 이소부티릴옥시기 및 시클로헥실카보닐옥시기 등의 분지 또는 환상의 알카노일옥시기 등을 들 수 있다.Specific examples of the case where L is an alkanoyloxy group are acetoxy, propionyloxy, butyryloxy, α-fluoroacetoxy, α-chloroacetoxy, α-bromoacetoxy and α-iodo 1 to 3 substituents such as a halogen atom and a cyano group, such as an acetoxy group, an α, α-difluoroacetoxy group, an α, α-dichloroacetoxy group and an α-cyanoacetoxy group, may be substituted Linear alkanoyloxy groups; Branched or cyclic alkanoyloxy groups, such as an isobutyryloxy group and a cyclohexyl carbonyloxy group, etc. are mentioned.
L이 아로일옥시기인 경우의 구체적인 예로서는 벤조일옥시기, 1-나프토일옥시기, 2-나프토일옥시기, 니코티노일옥시기, 이소니코티노일옥시기 및 푸르푸로일옥시기 등의 단환 또는 다환의 헤테로 원자를 가질 수 있는 아로일옥시기를 들 수 있다.Specific examples of the case where L is an aroyloxy group include monocyclic or polycyclic hetero, such as a benzoyloxy group, 1-naphthoyloxy group, 2-naphthoyloxy group, nicotinoyloxy group, isoninicotinoyloxy group, and furfuroyloxy group. Aroyloxy group which may have an atom is mentioned.
L이 아릴알카노일옥시기인 경우의 구체적인 예로서는 페닐아세톡시기 등을 들 수 있다.A phenylacetoxy group etc. are mentioned as a specific example in the case where L is an aryl alkanoyloxy group.
L이 알킬설포닐옥시기인 경우의 구체적인 예로서는 메탄설포닐옥시기, 에탄설포닐옥시기, 프로판설포닐옥시기, 트리플루오로메탄설포닐옥시기 등을 들 수 있다.Specific examples when L is an alkylsulfonyloxy group include a methanesulfonyloxy group, an ethanesulfonyloxy group, a propanesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like.
L이 아릴설포닐옥시기인 경우의 구체적인 예로서는 벤젠설포닐옥시기, p-톨루엔설포닐옥시기 등을 들 수 있다.As a specific example when L is an arylsulfonyloxy group, a benzenesulfonyloxy group, p-toluenesulfonyloxy group, etc. are mentioned.
L이 알콕시카보닐옥시기인 경우의 구체적인 예로서는 메톡시카보닐옥시기, 에톡시카보닐옥시기 등을 들 수 있다.As a specific example when L is an alkoxycarbonyloxy group, a methoxycarbonyloxy group, an ethoxycarbonyloxy group, etc. are mentioned.
L이 아르알콕시카보닐옥시기인 경우의 구체적인 예로서는 벤질옥시카보닐옥시기 등을 들 수 있다.Specific examples of the case where L is an alkoxycarbonyloxy group include benzyloxycarbonyloxy group and the like.
L이 알콕시알카노일옥시기인 경우의 구체적인 예로서는 메톡시아세톡시기, 에톡시아세톡시기 등을 들 수 있다.As a specific example in the case where L is an alkoxyalkanoyloxy group, a methoxyacetoxy group, an ethoxyacetoxy group, etc. are mentioned.
L이 카바모일옥시기인 경우의 구체적인 예로서는 N-메틸카바모일옥시기, N-에틸카바모일옥시기, N-페닐카바모일옥시기 등을 들 수 있다.As a specific example when L is a carbamoyloxy group, N-methyl carbamoyloxy group, N-ethyl carbamoyloxy group, N-phenyl carbamoyloxy group, etc. are mentioned.
L이 알카노일티오기인 경우의 구체적인 예로서는 아세틸티오기, 프로피오닐티오기 등을 들 수 있다.As a specific example when L is an alkanoylthio group, an acetylthio group, a propionylthio group, etc. are mentioned.
L이 아로일티오기인 경우의 구체적인 예로서는 벤조일티오기, 나프토일티오기 등을 들 수 있다.As a specific example when L is an aroylthio group, a benzoylthio group, a naphthoylthio group, etc. are mentioned.
L이 알킬티오기인 경우의 구체적인 예로서는 메틸티오기, 에틸티오기, n-프로필티오기, 이소프로필티오기, n-부틸티오기, 이소부틸티오기, tert-부틸티오기 등을 들 수 있다.Specific examples in the case where L is an alkylthio group include methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group, tert-butylthio group and the like.
L이 아릴티오기인 경우의 구체적인 예로서는 페닐티오기, 나프틸티오기 등을 들 수 있다.As a specific example when L is an arylthio group, a phenylthio group, a naphthylthio group, etc. are mentioned.
L이 알킬설피닐기인 경우의 구체적인 예로서는 메탄설피닐기, 에탄설피닐기, n-프로판설피닐기, n-부탄설피닐기 등을 들 수 있다.Specific examples in the case where L is an alkylsulfinyl group include methanesulfinyl group, ethanesulfinyl group, n-propanesulfinyl group, n-butanesulfinyl group and the like.
L이 아릴설피닐기인 경우의 구체적인 예로서는 벤젠설피닐기, p-톨루엔설피닐기 등을 들 수 있다.As a specific example in the case of L being an aryl sulfinyl group, a benzene sulfinyl group, p-toluene sulfinyl group, etc. are mentioned.
L이 알킬설포닐기인 경우의 구체적인 예로서는 메탄설포닐기, 에탄설포닐기, n-프로판설포닐기, n-부탄설포닐기 등을 들 수 있다.As a specific example when L is an alkylsulfonyl group, a methanesulfonyl group, an ethanesulfonyl group, n-propanesulfonyl group, n-butanesulfonyl group, etc. are mentioned.
L이 아릴설포닐기인 경우의 구체적인 예로서는 벤젠설포닐기, p-톨루엔설포닐기 등을 들 수 있다.As a specific example when L is an arylsulfonyl group, a benzenesulfonyl group, p-toluenesulfonyl group, etc. are mentioned.
L이 할로겐 원자인 경우의 구체적인 예로서는 불소, 염소, 브롬, 요오드 등을 들 수 있다.Specific examples of the case where L is a halogen atom include fluorine, chlorine, bromine and iodine.
이들 이탈기 중에서, 특히 바람직한 것으로는 아세톡시기 등을 들 수 있다.Especially among these leaving groups, an acetoxy group etc. are mentioned.
본 발명의 제조방법에서 사용되는 상기 일반식 [3]으로 표시되는 화합물에 있어서 R2로 표시되는 탄소수 1∼4의 저급 알킬기의 구체적인 예로서는 예를 들어 메틸기, 에틸기, n-프로필기, 이소프로필기, n-부틸기, 이소부틸기, sec-부틸기, tert-부틸기 등을 들 수 있다.As a specific example of the C1-C4 lower alkyl group represented by R <2> in the compound represented by the said General formula [3] used by the manufacturing method of this invention, it is a methyl group, an ethyl group, n-propyl group, isopropyl group, for example. , n-butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like.
또한, 바람직한 R2로서는 수소 원자 또는 메틸기를 들 수 있다.Moreover, as a preferable R <2>, a hydrogen atom or a methyl group is mentioned.
일반식 [3]에서 R3로 표시되는 탄소수 1∼12의 알킬기의 구체적인 예로서는, 예를 들어 메틸기, 에틸기, n-프로필기, 이소프로필기, n-부틸기, 이소부틸기, sec-부틸기, tert-부틸기, 펜틸기, 헥실기, 헵틸기, 옥틸기, 노닐기, 데실기, 운데실기, 도데실기 등을 들 수 있다.General formula [3] R 3 are specific examples of the alkyl group having 1 to 12 carbon atoms shown as in, for example, methyl group, ethyl group, n- propyl group, isopropyl group, n- butyl group, isobutyl group, sec- butyl group and tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, and dodecyl group.
R3로 표시되는 탄소수 2∼5의 알케닐기의 구체적인 예로서는, 예를 들어 비닐기, 알릴기, 1-프로페닐기, 이소프로페닐기, 1-부테닐기, 2-부테닐기, 2-메틸알릴기 등을 들 수 있다.As a specific example of the C2-C5 alkenyl group represented by R <3> , For example, a vinyl group, an allyl group, 1-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 2-methylallyl group, etc. Can be mentioned.
R3로 표시되는 치환기를 가질 수 있는 페닐기의 치환기로서는, 예를 들어 탄소수 1∼4의 저급 알킬기, 탄소수 1∼4의 저급 알콕시기, 니트로기, 할로겐 원자 등을 들 수 있다.As a substituent of the phenyl group which may have a substituent represented by R < 3 >, a C1-C4 lower alkyl group, a C1-C4 lower alkoxy group, a nitro group, a halogen atom, etc. are mentioned, for example.
여기에서 치환기인 탄소수 1∼4의 저급 알킬기의 구체적인 예로서는, 예를 들어 메틸기, 에틸기, n-프로필기, 이소프로필기, n-부틸기, 이소부틸기, sec-부틸기, tert-부틸기 등을 들 수 있다. 또한, 탄소수 1∼4의 저급 알콕시기의 구체적인예로서는, 예를 들어 메톡시기, 에톡시기, n-프로폭시기, 이소프로폭시기, n-부톡시기, 이소부톡시기, sec-부톡시기, tert-부톡시기 등을 들 수 있다. 그리고, 할로겐 원자의 구체적인 예로서는, 예를 들어 불소, 염소, 브롬, 요오드를 들 수 있다.As a specific example of a C1-C4 lower alkyl group which is a substituent here, a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert- butyl group etc. are mentioned, for example. Can be mentioned. Moreover, as a specific example of a C1-C4 lower alkoxy group, For example, a methoxy group, an ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert- Butoxy group etc. are mentioned. And as a specific example of a halogen atom, fluorine, chlorine, bromine, iodine is mentioned, for example.
R3로 표시되는 치환기를 가질 수 있는 탄소수 7∼15의 아르알킬기의 치환기로서는, 예를 들어 탄소수 1∼4의 저급 알킬기, 탄소수 1∼4의 저급 알콕시기, 니트로기, 할로겐 원자 등을 들 수 있다.As a substituent of a C7-15 aralkyl group which may have a substituent represented by R <3> , a C1-C4 lower alkyl group, a C1-C4 lower alkoxy group, a nitro group, a halogen atom, etc. are mentioned, for example. have.
여기에서 치환기인 탄소수 1∼4의 저급 알킬기의 구체적인 예로서는, 예를 들어 메틸기, 에틸기, n-프로필기, 이소프로필기, n-부틸기, 이소부틸기, sec-부틸기, tert-부틸기 등을 들 수 있다. 또한, 탄소수 1∼4의 저급 알콕시기의 구체적인 예로서는 예를 들어 메톡시기, 에톡시기, n-프로폭시기, 이소프로폭시기, n-부톡시기, 이소부톡시기, sec-부톡시기, tert-부톡시기 등을 들 수 있다. 그리고, 할로겐 원자의 구체적인 예로서는, 예를 들어 불소, 염소, 브롬, 요오드를 들 수 있다.As a specific example of a C1-C4 lower alkyl group which is a substituent here, a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert- butyl group etc. are mentioned, for example. Can be mentioned. Moreover, as a specific example of a C1-C4 lower alkoxy group, for example, a methoxy group, an ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butok Season, etc. can be mentioned. And as a specific example of a halogen atom, fluorine, chlorine, bromine, iodine is mentioned, for example.
또한, 치환기를 가질 수 있는 탄소수 7∼15의 아르알킬기의 치환기로서는, 벤질기, α-페네틸기, β-페네틸기, α-페닐프로필기, β-페닐프로필기, γ-페닐프로필기, 나프틸메틸기 등을 들 수 있다.Moreover, as a substituent of the C7-C15 aralkyl group which may have a substituent, a benzyl group, the (alpha)-phenethyl group, the (beta)-phenethyl group, the (alpha)-phenylpropyl group, (beta)-phenylpropyl group, (gamma)-phenylpropyl group, nap A methylmethyl group etc. are mentioned.
R3로 표시되는 치환기를 가질 수 있는 5∼8원환의 지환식기의 구체적인 예로서는, 시클로펜틸기, 시클로헥실기, 시클로헵틸기, 시클로옥틸기 등을 들 수 있다. 또한, 치환기로서는, 예를 들어 메틸기, 에틸기, 프로필기, 이소프로필기, 부틸기, 이소부틸기, sec-부틸기 및 tert-부틸기 등의 탄소수 1∼4의 저급 알킬기 등을 들수 있다.Specific examples of the 5- to 8-membered ring alicyclic group which may have a substituent represented by R 3 include a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like. Moreover, as a substituent, C1-C4 lower alkyl groups, such as a methyl group, an ethyl group, a propyl group, isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert- butyl group, etc. are mentioned, for example.
이들 중에서 특히 바람직한 R3로서는 메틸기, 에틸기, 프로필기, 이소프로필기, 부틸기, tert-부틸기 등의 탄소수 1∼4의 저급 알킬기; 벤질기, p-니트로벤질기, p-메톡시벤질기 등의 치환기(니트로기, 메톡시기 등)를 가질 수 있는 탄소수 7∼15의 아르알킬기; 비닐기 및 알릴기 등의 탄소수 2∼5의 알케닐기 등을 예시할 수 있다.Especially preferable R <3> among these is C1-C4 lower alkyl groups, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and a tert- butyl group; C7-C15 aralkyl group which may have substituents (nitro group, a methoxy group, etc.), such as a benzyl group, p-nitrobenzyl group, and p-methoxybenzyl group; C2-C5 alkenyl groups, such as a vinyl group and an allyl group, etc. can be illustrated.
본 발명의 제조방법에서 사용되는 상기 일반식 [4]로 표시되는 금속 화합물에 있어서, M으로 표시되는 금속 원자로서는, 예를 들어 유기합성화학, 탄소-탄소 결합 생성반응 등에서 일반적으로 사용되고 있는 금속 원자 등을 들 수 있고, 더욱 구체적으로는, 예를 들어 티탄, 지르코늄 등의 IUPAC에 의한 주기율표 제4족의 금속; 규소, 주석 등의 IUPAC에 의한 주기율표 제14족의 금속; 붕소, 알루미늄 등의 IUPAC에 의한 주기율표 제13족의 금속; 스칸듐, 이트륨, 란타노이드(란탄, 세륨, 프라세오딤, 네오딤, 사마륨, 가돌리늄, 디스프로슘, 에르븀, 이테르븀 등) 등의 주기율표 제3족의 금속; 철, 루테늄 등의 주기율표 제8족의 금속; 아연 등의 주기율표 제12족의 금속 등을 들 수 있다.In the metal compound represented by the general formula [4] used in the production method of the present invention, the metal atom represented by M is, for example, a metal atom generally used in organic synthesis chemistry, carbon-carbon bond formation reaction, or the like. These may be mentioned. More specifically, For example, metal of group 4 of the periodic table by IUPAC, such as titanium and zirconium; Metals of Group 14 of the Periodic Table according to IUPAC such as silicon and tin; Metal of Group 13 of the periodic table according to IUPAC such as boron and aluminum; Metals of Group 3 of the periodic table such as scandium, yttrium and lanthanoids (lanthanum, cerium, praseodymium, neodim, samarium, gadolinium, dysprosium, erbium, ytterbium and the like); Metals of Group 8 of the periodic table such as iron and ruthenium; And metals of Group 12 of the periodic table such as zinc.
일반식 [4]에서 Y로 표시되는 할로겐 원자로서는, 예를 들어 불소 원자, 염소 원자, 브롬 원자, 요오드 원자 등을 들 수 있다.As a halogen atom represented by Y in General formula [4], a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc. are mentioned, for example.
일반식 [4]에서 R4로 표시되는 탄소수 1∼4의 저급 알킬기의 구체적인 예로서는, 예를 들어 메틸기, 에틸기, n-프로필기, 이소프로필기, n-부틸기, 이소부틸기, sec-부틸기, tert-부틸기 등을 들 수 있고, 또한, 탄소수 1∼4의 저급 알콕시기의 구체적인 예로서는, 예를 들어 메톡시기, 에톡시기, n-프로폭시기, 이소프로폭시기, n-부톡시기, 이소부톡시기, sec-부톡시기, tert-부톡시기 등을 들 수 있다.General formula Specific examples of a carbon number of 1 to 4 lower alkyl group represented in [4] with R 4, for example, methyl, ethyl, n- propyl, isopropyl, n- butyl, isobutyl, sec- butyl A group, a tert- butyl group, etc. are mentioned, Moreover, as a specific example of a C1-C4 lower alkoxy group, For example, a methoxy group, an ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group , Isobutoxy group, sec-butoxy group, tert-butoxy group and the like.
또한, R4로 표시되는 치환기를 가질 수 있는 페녹시기의 치환기로서는, 예를 들어 탄소수 1∼4의 저급 알킬기, 탄소수 1∼4의 저급 알콕시기, 할로겐 원자 등을 들 수 있다.Moreover, as a substituent of the phenoxy group which may have a substituent represented by R < 4 >, a C1-C4 lower alkyl group, a C1-C4 lower alkoxy group, a halogen atom, etc. are mentioned, for example.
여기에서, 치환기인 탄소수 1∼4의 저급 알킬기의 구체적인 예로서는, 예를 들어 메틸기, 에틸기, n-프로필기, 이소프로필기, n-부틸기, 이소부틸기, sec-부틸기, tert-부틸기 등을 들 수 있고, 또한, 탄소수 1∼4의 저급 알콕시기의 구체적인 예로서는, 예를 들어 메톡시기, 에톡시기, n-프로폭시기, 이소프로폭시기, n-부톡시기, 이소부톡시기, sec-부톡시기, tert-부톡시기 등을 들 수 있다. 그리고, 할로겐 원자의 구체적인 예로서는, 예를 들어 불소, 염소, 브롬, 요오드를 들 수 있다.Here, as a specific example of the C1-C4 lower alkyl group which is a substituent, for example, a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert- butyl group Etc. Moreover, as a specific example of a C1-C4 lower alkoxy group, For example, a methoxy group, an ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec -Butoxy group, tert-butoxy group, etc. are mentioned. And as a specific example of a halogen atom, fluorine, chlorine, bromine, iodine is mentioned, for example.
R4로 표시되는 알킬설포닐디옥시기의 구체적인 예로서는, 예를 들어 메탄설포닐디옥시기, 에탄설포닐디옥시기, 트리플루오로메탄설포닐디옥시기 등을 들 수 있다.As a specific example of the alkylsulfonyl dioxy group represented by R <4> , methanesulfonyl dioxy group, an ethanesulfonyl dioxy group, a trifluoro methanesulfonyl dioxy group, etc. are mentioned, for example.
R4로 표시되는 아릴설포닐디옥시기의 구체적인 예로서는, 예를 들어 벤젠설포닐디옥시기, p-톨루엔설포닐디옥시기 등을 들 수 있다.As a specific example of the arylsulfonyl dioxy group represented by R <4> , a benzenesulfonyl dioxy group, p-toluenesulfonyl dioxy group, etc. are mentioned, for example.
R4로 표시되는 알킬설포닐옥시기의 구체적인 예로서는, 예를 들어 메탄설포닐옥시기, 에탄설포닐옥시기, 트리플루오로메탄설포닐옥시기 등을 들 수 있다.As a specific example of the alkylsulfonyloxy group represented by R <4> , a methanesulfonyloxy group, an ethanesulfonyloxy group, a trifluoromethanesulfonyloxy group, etc. are mentioned, for example.
R4로 표시되는 아릴설포닐옥시기의 구체적인 예로서는, 예를 들어 벤젠설포닐옥시기, p-톨루엔설포닐옥시기 등을 들 수 있다.As a specific example of the arylsulfonyloxy group represented by R <4> , a benzenesulfonyloxy group, p-toluenesulfonyloxy group, etc. are mentioned, for example.
일반식 [2]로 표시되는 화합물의 제조방법으로서는, 특히 이에 한정되는 것은 아니지만, 예를 들어J. Am. Chem. Soc., Vol. 112, pp.7820∼7822(1990),Tetrahedron Letters, Vol. 32, pp.2145∼2148(1991),Tetrahedron Letters, Vol. 32, pp.5991∼5994(1991) 등에 기재된 방법 또는 이에 준하는 방법 등에 의해 합성하는 것이 가능하다.As a manufacturing method of the compound represented by General formula [2], although it is not limited to this in particular, For example, J. Am. Chem. Soc. , Vol. 112, pp. 7820-7822 (1990), Tetrahedron Letters , Vol. 32, pp. 2145-2148 (1991), Tetrahedron Letters , Vol. 32, pp. 5991 to 5994 (1991), or the like, or a method similar thereto.
일반식 [2]에 나타낸 화합물의 구체적인 예로서는,As a specific example of the compound shown by General formula [2],
4-아세톡시-3-[1-tert-부틸디메틸실릴옥시에틸]-아제티딘-2-온,4-acetoxy-3- [1-tert-butyldimethylsilyloxyethyl] -azetidin-2-one,
4-아세톡시-3-[1-tert-부틸디페닐실릴옥시에틸]-아제티딘-2-온,4-acetoxy-3- [1-tert-butyldiphenylsilyloxyethyl] -azetidin-2-one,
4-아세톡시-3-[1-트리에틸실릴옥시에틸]-아제티딘-2-온,4-acetoxy-3- [1-triethylsilyloxyethyl] -azetidin-2-one,
4-아세톡시-3-[1-트리메틸실릴옥시에틸]-아제티딘-2-온,4-acetoxy-3- [1-trimethylsilyloxyethyl] -azetidin-2-one,
4-아세톡시-3-[1-디메틸덱실실릴옥시에틸]-아제티딘-2-온,4-acetoxy-3- [1-dimethyldecylsilyloxyethyl] -azetidin-2-one,
4-아세톡시-3-[1-히드록시에틸에틸]-아제티딘-2-온,4-acetoxy-3- [1-hydroxyethylethyl] -azetidin-2-one,
4-α-클로로아세톡시-3-[1-tert-부틸디메틸실릴옥시에틸]-아제티딘-2-온,4-α-chloroacetoxy-3- [1-tert-butyldimethylsilyloxyethyl] -azetidin-2-one,
4-이소부티릴옥시-3-[1-tert-부틸디메틸실릴옥시에틸]-아제티딘-2-온,4-isobutyryloxy-3- [1-tert-butyldimethylsilyloxyethyl] -azetidin-2-one,
4-프로피오닐옥시-3-[1-tert-부틸디메틸실릴옥시에틸]-아제티딘-2-온,4-propionyloxy-3- [1-tert-butyldimethylsilyloxyethyl] -azetidin-2-one,
4-벤조일옥시-3-[1-tert-부틸디메틸실릴옥시에틸]-아제티딘-2-온,4-benzoyloxy-3- [1-tert-butyldimethylsilyloxyethyl] -azetidin-2-one,
4-p-톨릴티오-3-[1-tert-부틸디메틸실릴옥시에틸]-아제티딘-2-온,4-p-tolylthio-3- [1-tert-butyldimethylsilyloxyethyl] -azetidin-2-one,
4-페닐티오-3-[1-tert-부틸디메틸실릴옥시에틸]-아제티딘-2-온,4-phenylthio-3- [1-tert-butyldimethylsilyloxyethyl] -azetidin-2-one,
4-p-톨루엔설피닐옥시-3-[1-tert-부틸디메틸실릴옥시에틸]-아제티딘-2-온,4-p-toluenesulfinyloxy-3- [1-tert-butyldimethylsilyloxyethyl] -azetidin-2-one,
4-벤젠설피닐옥시-3-[1-tert-부틸디메틸실릴옥시에틸]-아제티딘-2-온,4-benzenesulfinyloxy-3- [1-tert-butyldimethylsilyloxyethyl] -azetidin-2-one,
4-p-톨루엔설포닐옥시-3-[1-tert-부틸디메틸실릴옥시에틸]-아제티딘-2-온,4-p-toluenesulfonyloxy-3- [1-tert-butyldimethylsilyloxyethyl] -azetidin-2-one,
4-벤젠설포닐옥시-3-[1-tert-부틸디메틸실릴옥시에틸]-아제티딘-2-온,4-benzenesulfonyloxy-3- [1-tert-butyldimethylsilyloxyethyl] -azetidin-2-one,
4-클로로-3-[1-tert-부틸디메틸실릴옥시에틸]-아제티딘-2-온,4-chloro-3- [1-tert-butyldimethylsilyloxyethyl] -azetidin-2-one,
4-브로모-3-[1-tert-부틸디메틸실릴옥시에틸]-아제티딘-2-온,4-bromo-3- [1-tert-butyldimethylsilyloxyethyl] -azetidin-2-one,
4-요오도-3-[1-tert-부틸디메틸실릴옥시에틸]-아제티딘-2-온,4-iodo-3- [1-tert-butyldimethylsilyloxyethyl] -azetidin-2-one,
4-시아노-3-[1-tert-부틸디메틸실릴옥시에틸]-아제티딘-2-온 등을 들 수 있다.4-cyano-3- [1-tert-butyldimethylsilyloxyethyl] -azetidin-2-one, etc. are mentioned.
이들 화합물 중에서 보다 바람직한 것으로는, 예를 들어 4-아세톡시-3-[1-tert-부틸디메틸실릴옥시에틸]-아제티딘-2-온이나 4-α-클로로아세톡시-3-[1-tert-부틸디메틸실릴옥시에틸]-아제티딘-2-온 등을 들 수 있다.Among these compounds, more preferred is, for example, 4-acetoxy-3- [1-tert-butyldimethylsilyloxyethyl] -azetidin-2-one or 4-α-chloroacetoxy-3- [1- tert-butyldimethylsilyloxyethyl] -azetidin-2-one, etc. are mentioned.
일반식 [3]으로 표시되는 디아조 화합물의 제조방법으로서는, 특히 이들로 한정되는 것은 아니지만, 예를 들어 일본 특허공개 소58-103358호 공보, 일본 특허공개 소61-275284호 공보에 기재된 방법 또는 이들에 준하는 방법 등에 의해 합성하는 것이 가능하다.As a manufacturing method of the diazo compound represented by General formula [3], although it is not limited to these in particular, For example, the method of Unexamined-Japanese-Patent No. 58-103358, Unexamined-Japanese-Patent No. 61-275284, or It can synthesize | combine by the method etc. which correspond to these.
일반식 [3]으로 표시되는 디아조 화합물의 구체적인 예로서는,As a specific example of the diazo compound represented by General formula [3],
메틸 2-디아조-3-옥소부타노에이트,Methyl 2-diazo-3-oxobutanoate,
메틸 2-디아조-3-옥소펜타노에이트,Methyl 2-diazo-3-oxopentanoate,
메틸 2-디아조-3-옥소헥사노에이트,Methyl 2-diazo-3-oxohexanoate,
에틸 2-디아조-3-옥소부타노에이트,Ethyl 2-diazo-3-oxobutanoate,
에틸 2-디아조-3-옥소펜타노에이트,Ethyl 2-diazo-3-oxopentanoate,
에틸 2-디아조-3-옥소헥사노에이트,Ethyl 2-diazo-3-oxohexanoate,
n-프로필 2-디아조-3-옥소부타노에이트,n-propyl 2-diazo-3-oxobutanoate,
n-프로필 2-디아조-3-옥소펜타노에이트,n-propyl 2-diazo-3-oxopentanoate,
n-프로필 2-디아조-3-옥소헥사노에이트,n-propyl 2-diazo-3-oxohexanoate,
이소프로필 2-디아조-3-옥소부타노에이트,Isopropyl 2-diazo-3-oxobutanoate,
이소프로필 2-디아조-3-옥소펜타노에이트,Isopropyl 2-diazo-3-oxopentanoate,
이소프로필 2-디아조-3-옥소헥사노에이트,Isopropyl 2-diazo-3-oxohexanoate,
n-부틸 2-디아조-3-옥소부타노에이트,n-butyl 2-diazo-3-oxobutanoate,
n-부틸 2-디아조-3-옥소펜타노에이트,n-butyl 2-diazo-3-oxopentanoate,
n-부틸 2-디아조-3-옥소헥사노에이트,n-butyl 2-diazo-3-oxohexanoate,
tert-부틸 2-디아조-3-옥소부타노에이트,tert-butyl 2-diazo-3-oxobutanoate,
tert-부틸 2-디아조-3-옥소펜타노에이트,tert-butyl 2-diazo-3-oxopentanoate,
tert-부틸 2-디아조-3-옥소헥사노에이트,tert-butyl 2-diazo-3-oxohexanoate,
벤질 2-디아조-3-옥소부타노에이트,Benzyl 2-diazo-3-oxobutanoate,
벤질 2-디아조-3-옥소펜타노에이트,Benzyl 2-diazo-3-oxopentanoate,
벤질 2-디아조-3-옥소헥사노에이트,Benzyl 2-diazo-3-oxohexanoate,
p-니트로벤질 2-디아조-3-옥소부타노에이트,p-nitrobenzyl 2-diazo-3-oxobutanoate,
p-니트로벤질 2-디아조-3-옥소펜타노에이트,p-nitrobenzyl 2-diazo-3-oxopentanoate,
p-니트로벤질 2-디아조-3-옥소헥사노에이트,p-nitrobenzyl 2-diazo-3-oxohexanoate,
p-메톡시벤질 2-디아조-3-옥소부타노에이트,p-methoxybenzyl 2-diazo-3-oxobutanoate,
p-메톡시벤질 2-디아조-3-옥소펜타노에이트,p-methoxybenzyl 2-diazo-3-oxopentanoate,
p-메톡시벤질 2-디아조-3-옥소헥사노에이트,p-methoxybenzyl 2-diazo-3-oxohexanoate,
비닐 2-디아조-3-옥소부타노에이트,Vinyl 2-diazo-3-oxobutanoate,
비닐 2-디아조-3-옥소펜타노에이트,Vinyl 2-diazo-3-oxopentanoate,
비닐 2-디아조-3-옥소헥사노에이트,Vinyl 2-diazo-3-oxohexanoate,
알릴 2-디아조-3-옥소부타노에이트,Allyl 2-diazo-3-oxobutanoate,
알릴 2-디아조-3-옥소펜타노에이트,Allyl 2-diazo-3-oxopentanoate,
알릴 2-디아조-3-옥소헥사노에이트 등을 들 수 있다.And allyl 2-diazo-3-oxohexanoate.
이들 아조 화합물 중에서 보다 바람직한 것은, 예를 들어,More preferable one among these azo compounds is, for example,
tert-부틸 2-디아조-3-옥소펜타노에이트,tert-butyl 2-diazo-3-oxopentanoate,
벤질 2-디아조-3-옥소펜타노에이트,Benzyl 2-diazo-3-oxopentanoate,
p-니트로벤질 2-디아조-3-옥소펜타노에이트,p-nitrobenzyl 2-diazo-3-oxopentanoate,
알릴 2-디아조-3-옥소펜타노에이트 등을 들 수 있다.And allyl 2-diazo-3-oxopentanoate.
본 발명에서 이용되는 일반식 [4]로 표시되는 금속 화합물은 시판품을 그대로 이용하는 것도 좋고, 필요에 따라 이것을 정제하여 사용하여도 좋다.The metal compound represented by general formula [4] used by this invention may use a commercial item as it is, and may refine | purify this and use it as needed.
일반식 [4]로 표시되는 금속 화합물의 구체적인 예로서는, 예를 들어 TiCl4, TiCl3(OCH3), TiCl3(OC2H5), TiCl3(O-n-Pr), TiCl3(O-i-Pr), TiCl3(OBu), TiCl3(O-i-Bu), TiCl3(O-sec-Bu), TiCl3(O-tert-Bu), TiCl2(OMe)2, TiCl2(OEt)2, TiCl2(O-n-Pr)2, TiCl2(O-i-Pr)2, TiCl2(OBu)2, TiCl2(O-i-Bu)2, TiCl2(O-sec-Bu)2, TiCl2(O-tert-Bu)2, Ti(Cp)2Cl2, Ti(Cp*)2Cl2, TiBr4, TiI4등의 티탄 화합물; ZnCl2, ZnBr2, ZnI2등의 아연 화합물; ZrCl4, ZrCl3(OMe), ZrCl3(OEt), ZrCl3(O-n-Pr), ZrCl3(O-i-Pr), ZrCl3(O-n-Bu), ZrCl3(O-i-Bu), ZrCl3(O-sec-Bu), ZrCl3(O-tert-Bu), Zr(Cp)2Cl2, Zr(Cp*)2Cl2, ZrBr4, ZrI4등의 지르코늄 화합물; AlCl3, Al(OMe)3, Al(OEt)3, Al(O-n-Pr)3, Al(O-i-Pr)3, AlCl2Me, AlClMe2, AlMe3, AlCl2Et, AlClEt2, AlEt3, AlBr3, AlI3등의 알루미늄 화합물; SnCl4, SnBr4, SnI4, Sn(OSO2CF3)2등의 주석 화합물; FeCl3, FeBr3, FeI3등의 철 화합물; (C2H5)2O·BF3, (CH3)2BOSO2CF3, (C2H5)2BOSO2CF3, (Pr)2BOSO2CF3, (Bu)2BOSO2CF3등의 붕소 화합물; (CH3)3SiOSO2CF3, (CH3)3SiCl 등의 규소 화합물; ScF3, ScCl3, ScBr3, ScI3, Sc(O-i-Pr)3, Sc(OSO2CH3)3등의 스칸듐 화합물; YF3, YCl3, YBr3, YI3, Y(O-i-Pr)3, Y(OSO2CH3)3등의 이트륨 화합물; LaF3, LaCl3, LaBr3, LaI3, La(O-i-Pr)3, La(OSO2CH3)3등의 란탄 화합물; CeF3,CeCl3, CeBr3, CeI3, Ce(O-i-Pr)3, Ce(OSO2CH3)3등의 세륨 화합물; PrF3, PrCl3, PrBr3, PrI3, Pr(O-i-Pr)3, Pr(OSO2CH3)3등의 프라세오딤 화합물; NdF3, NdCl3, NdBr3, NdI3, Nd(O-i-Pr)3, Nd(OSO2CH3)3등의 네오딤 화합물; SmF3, SmCl3, SmBr3, SmI3, Sm(O-i-Pr)3, Sm(OSO2CH3)3등의 사마륨 화합물; GdF3, GdCl3, GdBr3, GdI3, Gd(O-i-Pr)3, Gd(OSO2CH3)3등의 가돌리늄 화합물; DyF3, DyCl3, DyBr3, DyI3, Dy(O-i-Pr)3, Dy(OSO2CH3)3등의 디스프로슘 화합물; ErF3, ErCl3, ErBr3, ErI3, Er(O-i-Pr)3, Er(OSO2CH3)3등의 에르븀 화합물; YbF3, YbCl3, YbBr3, YbI3, Yb(O-i-Pr)3, Yb(OSO2CH3)3등의 이테르븀 화합물을 들 수 있다.Specific examples of the metal compound represented by the general formula [4] include, for example, TiCl 4 , TiCl 3 (OCH 3 ), TiCl 3 (OC 2 H 5 ), TiCl 3 (On-Pr), and TiCl 3 (Oi-Pr ), TiCl 3 (OBu), TiCl 3 (Oi-Bu), TiCl 3 (O-sec-Bu), TiCl 3 (O-tert-Bu), TiCl 2 (OMe) 2 , TiCl 2 (OEt) 2 , TiCl 2 (On-Pr) 2 , TiCl 2 (Oi-Pr) 2 , TiCl 2 (OBu) 2 , TiCl 2 (Oi-Bu) 2 , TiCl 2 (O-sec-Bu) 2 , TiCl 2 (O- titanium compounds such as tert-Bu) 2 , Ti (Cp) 2 Cl 2 , Ti (Cp * ) 2 Cl 2 , TiBr 4 , TiI 4 and the like; Zinc compounds such as ZnCl 2 , ZnBr 2 , ZnI 2 ; ZrCl 4 , ZrCl 3 (OMe), ZrCl 3 (OEt), ZrCl 3 (On-Pr), ZrCl 3 (Oi-Pr), ZrCl 3 (On-Bu), ZrCl 3 (Oi-Bu), ZrCl 3 ( Zirconium compounds such as O-sec-Bu), ZrCl 3 (O-tert-Bu), Zr (Cp) 2 Cl 2 , Zr (Cp * ) 2 Cl 2 , ZrBr 4 , ZrI 4 ; AlCl 3 , Al (OMe) 3 , Al (OEt) 3 , Al (On-Pr) 3 , Al (Oi-Pr) 3 , AlCl 2 Me, AlClMe 2 , AlMe 3 , AlCl 2 Et, AlClEt 2 , AlEt 3 Aluminum compounds such as AlBr 3 and AlI 3 ; Tin compounds such as SnCl 4 , SnBr 4 , SnI 4 , Sn (OSO 2 CF 3 ) 2 and the like; Iron compounds such as FeCl 3 , FeBr 3 and FeI 3 ; (C 2 H 5 ) 2 OBF 3 , (CH 3 ) 2 BOSO 2 CF 3 , (C 2 H 5 ) 2 BOSO 2 CF 3 , (Pr) 2 BOSO 2 CF 3 , (Bu) 2 BOSO 2 CF Boron compounds such as 3 ; Silicon compounds such as (CH 3 ) 3 SiOSO 2 CF 3 and (CH 3 ) 3 SiCl; Scandium compounds such as ScF 3 , ScCl 3 , ScBr 3 , ScI 3 , Sc (Oi-Pr) 3 , Sc (OSO 2 CH 3 ) 3, and the like; Yttrium compounds such as YF 3 , YCl 3 , YBr 3 , YI 3 , Y (Oi-Pr) 3 and Y (OSO 2 CH 3 ) 3 ; Lanthanum compounds such as LaF 3 , LaCl 3 , LaBr 3 , LaI 3 , La (Oi-Pr) 3 and La (OSO 2 CH 3 ) 3 ; Cerium compounds such as CeF 3 , CeCl 3 , CeBr 3 , CeI 3 , Ce (Oi-Pr) 3 , Ce (OSO 2 CH 3 ) 3, and the like; Praseodymium compounds, such as PrF 3 , PrCl 3 , PrBr 3 , PrI 3 , Pr (Oi-Pr) 3 , Pr (OSO 2 CH 3 ) 3 ; Neodym compounds such as NdF 3 , NdCl 3 , NdBr 3 , NdI 3 , Nd (Oi-Pr) 3 , Nd (OSO 2 CH 3 ) 3 ; Samarium compounds such as SmF 3 , SmCl 3 , SmBr 3 , SmI 3 , Sm (Oi-Pr) 3 , Sm (OSO 2 CH 3 ) 3 ; Gadolinium compounds such as GdF 3 , GdCl 3 , GdBr 3 , GdI 3 , Gd (Oi-Pr) 3 , and Gd (OSO 2 CH 3 ) 3 ; Dysprosium compounds such as DyF 3 , DyCl 3 , DyBr 3 , DyI 3 , Dy (Oi-Pr) 3 , Dy (OSO 2 CH 3 ) 3 ; Erbium compounds such as ErF 3, ErCl 3, ErBr 3 , ErI 3, Er (Oi-Pr) 3, Er (OSO 2 CH 3) 3; YbF 3, YbCl 3, YbBr 3 , YbI 3, Yb (Oi-Pr) 3, Yb (OSO 2 CH 3) may be mentioned ytterbium compound such as 3.
상기 예에서 Cp는 시클로펜타디에닐기를, Cp*는 펜타메틸시클로펜타디에닐기를 나타낸다.In the above example, Cp represents a cyclopentadienyl group and Cp * represents a pentamethylcyclopentadienyl group.
이들 금속 화합물 중에서 보다 바람직한 것으로서는 TiCl4(사염화티탄), ZnCl2(이염화아연), ZrCl4(사염화지르코늄), AlCl3(삼염화알루미늄), SnCl4(사염화주석), (C2H5)2O·BF3(삼불화붕소에테레이트), (CH3)3SiOSO2CF3(트리메틸실릴트리플레이트), (CH3)3SiCl(트리메틸실릴클로라이드) 등을 들 수 있다.Among these metal compounds, TiCl 4 (titanium tetrachloride), ZnCl 2 (zinc dichloride), ZrCl 4 (zirconium tetrachloride), AlCl 3 (aluminum trichloride), SnCl 4 (tin tetrachloride), (C 2 H 5 ) 2 O · BF 3 (boron trifluoride etherate in fluoride), (CH 3) 3 SiOSO 2 CF 3 ( trimethylsilyl triflate), (CH 3) 3 SiCl and the like (trimethylsilyl chloride).
이들 금속 화합물은 단독으로 사용하여도, 또는 2 종 이상을 적의 조합하여 사용하여도 좋다.These metal compounds may be used alone or in combination of two or more thereof.
본 발명의 제조방법에서 사용되는 염기로서는, 예를 들어 제1급 아민, 제2급 아민, 제3급 아민, 피리딘류 등을 들 수 있다.As a base used by the manufacturing method of this invention, primary amine, secondary amine, tertiary amine, pyridine, etc. are mentioned, for example.
염기가 제1급 아민인 경우의 구체적인 예로서는, 예를 들어 에틸아민, 프로필아민, 부틸아민, 아닐린, 벤질아민 등을 들 수 있다.As a specific example in the case where a base is a primary amine, ethylamine, propylamine, butylamine, aniline, benzylamine, etc. are mentioned, for example.
염기가 제2급 아민인 경우의 구체적인 예로서는, 예를 들어 디에틸아민, 디n-프로필아민, 디이소프로필아민, 메틸이소프로필아민, 에틸이소프로필아민, 디n-부틸아민, 디이소부틸아민, 디sec-부틸아민, 디tert-부틸아민, N-메틸아닐린, N-에틸아닐린, 피롤리딘, 피페리딘, 모르폴린, 피페라진, 이미다졸, 디벤질아민 등을 들 수 있다.As a specific example when the base is a secondary amine, for example, diethylamine, din-propylamine, diisopropylamine, methylisopropylamine, ethylisopropylamine, din-butylamine, diisobutylamine And disec-butylamine, ditert-butylamine, N-methylaniline, N-ethylaniline, pyrrolidine, piperidine, morpholine, piperazine, imidazole, dibenzylamine and the like.
염기가 제3급 아민인 경우의 구체적인 예로서는, 트리메틸아민, 트리에틸아민, 트리프로필아민, 트리이소프로필아민, 디이소프로필메틸아민, 디이소프로필에틸아민, 트리n-부틸아민, 트리벤질아민, N-메틸피페리딘, N-에틸피페리딘, N-메틸모르폴린, N-에틸모르폴린, 1,5-디아자비시클로[4,3,0]-5-노넨, 1,8-디아자비시클로[5,4,0]-7-운데센, 1,4-디아자비시클로[2,2,2]옥탄, N,N,N,N-테트라메틸에틸렌디아민, N,N,N,N-테트라메틸-1,3-프로판디아민, 디메틸아닐린, 디에틸아닐린 등을 들 수 있다.Specific examples of the case where the base is a tertiary amine include trimethylamine, triethylamine, tripropylamine, triisopropylamine, diisopropylmethylamine, diisopropylethylamine, trin-butylamine, tribenzylamine, N-methylpiperidine, N-ethylpiperidine, N-methylmorpholine, N-ethylmorpholine, 1,5-diazabicyclo [4,3,0] -5-nonene, 1,8-dia Xavicyclo [5,4,0] -7-undecene, 1,4-diazabicyclo [2,2,2] octane, N, N, N, N-tetramethylethylenediamine, N, N, N, N-tetramethyl-1,3-propanediamine, dimethylaniline, diethylaniline, etc. are mentioned.
염기가 피리딘류의 경우의 구체적인 예로서는, 피리딘, α-피콜린, β-피콜린, γ-피콜린, 2,6-루티딘, 2-에틸피리딘, 3-에틸피리딘, 4-에틸피리딘, N,N-디메틸아미노피리딘, 퀴놀린, 이소퀴놀린 등을 들 수 있다.Specific examples of the base in the case of pyridines include pyridine, α-picoline, β-picoline, γ-picoline, 2,6-lutidine, 2-ethylpyridine, 3-ethylpyridine, 4-ethylpyridine, N , N-dimethylaminopyridine, quinoline, isoquinoline and the like.
이들 염기 중에서도, 예를 들어 트리에틸아민, 트리n-부틸아민, 디이소프로필에틸아민, N-메틸피페리딘, N-에틸피페리딘, N-메틸모르폴린, N-에틸모르폴린, 1,5-디아자비시클로[4,3,0]-5-노넨, 1,8-디아자비시클로[5,4,0]-7-운데센, 1,4-디아자비시클로[2,2,2]옥탄, N,N-디메틸아미노피리딘 등은 범용성이 있고, 반응의 선택성 및 수율도 높아서 더욱 바람직하다.Among these bases, for example, triethylamine, trin-butylamine, diisopropylethylamine, N-methylpiperidine, N-ethylpiperidine, N-methylmorpholine, N-ethylmorpholine, 1 , 5-diazabicyclo [4,3,0] -5-nonene, 1,8-diazabicyclo [5,4,0] -7-undecene, 1,4-diazabicyclo [2,2, 2] Octane, N, N-dimethylaminopyridine and the like are more preferable because they have general versatility, and the selectivity and yield of the reaction are also high.
이들 염기는 단독으로 사용하여도, 또는 2 종 이상 적의 조합하여 사용하여도 좋다. 본 발명에 사용할 수 있는 염기는 시판품을 그대로 사용하여도 좋고, 필요에 따라 이를 정제하여 사용하여도 좋다.These bases may be used alone or in combination of two or more thereof. The base which can be used for this invention may use a commercial item as it is, and may refine | purify it as needed.
본 발명의 제조방법을 실시하는 데에는, 아르곤이나 질소와 같은 불활성 기체 분위기 하에 유기용매 중에서 실시할 것이 요망된다. 이와 같은 조건 하에서 우선, 일반식 [3]으로 나타낸 디아조 화합물과 일반식 [4]로 나타낸 금속 화합물 및 염기를 반응시키고, 다음에 이것에 일반식 [2]로 나타낸 화합물을 반응시키는 것에 의해, 일반식 [1]로 나타낸 아제티디논 화합물을 제조할 수 있다.In carrying out the production method of the present invention, it is desired to carry out in an organic solvent under an inert gas atmosphere such as argon or nitrogen. Under such conditions, first, by reacting a diazo compound represented by the general formula [3], a metal compound represented by the general formula [4] and a base, and then reacting the compound represented by the general formula [2], The azetidinone compound shown by General formula [1] can be manufactured.
반응에 사용되는 유기용매로는 반응에 관여하지 않는 불활성인 용매라면 어느 것이어도 좋은데, 예를 들어 펜탄, 헥산, 헵탄 등의 탄화수소계 용매; 시클로헥산, 메틸시클로헥산 등의 지환식 탄화수소계 용매; 디클로로메탄, 디클로로에탄, 클로로포름, 디브로모에탄 등의 할로겐화 탄화수소계 용매; 벤젠, 클로로벤젠, 톨루엔, 크실렌 등의 방향족 탄화수소계 용매; 디에틸에테르, 디이소프로필에테르, 테트라히드로푸란, 디메톡시에탄, 1,3-디옥솔란, 1,4-디옥산 등의 에테르계 용매; 아세토니트릴, 프로피오니트릴 등의 니트릴계 용매; 디메틸포름아미드, 디메틸아세트아미드 등의 아미드계 용매 등을 들 수 있다.The organic solvent used for the reaction may be any inert solvent that does not participate in the reaction, for example, hydrocarbon solvents such as pentane, hexane, heptane; Alicyclic hydrocarbon solvents such as cyclohexane and methylcyclohexane; Halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, chloroform and dibromoethane; Aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene and xylene; Ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, 1,3-dioxolane and 1,4-dioxane; Nitrile solvents such as acetonitrile and propionitrile; Amide solvents, such as dimethylformamide and dimethylacetamide, etc. are mentioned.
이들 용매는 단독으로 사용하여도, 또는 2 종 이상의 혼합용매로서 사용하여도 좋다.These solvents may be used alone, or may be used as two or more kinds of mixed solvents.
이들 용매 중에서 더욱 바람직한 것으로는 할로겐화 탄화수소계 용매, 방향족 탄화수소계 용매, 에테르계 용매 등을 들 수 있고, 그 중에서도 디클로로메탄, 톨루엔, 크실렌, 테트라히드로푸란 등이 범용성이 있고 반응의 선택성 및 수율이 높아 더욱 바람직하다.Among these solvents, halogenated hydrocarbon solvents, aromatic hydrocarbon solvents, ether solvents, and the like are more preferable. Among them, dichloromethane, toluene, xylene, tetrahydrofuran, etc. are versatile, and the reaction selectivity and yield are high. More preferred.
이들 용매의 사용량은 특히 제한되는 것은 아니고, 일반식 [2]로 표시되는 화합물에 대하여 통상 약 1∼50 배 용량, 바람직하게는 약 5∼20 배 용량의 범위이다.The amount of these solvents to be used is not particularly limited and is usually in the range of about 1 to 50 times the dose, preferably about 5 to 20 times the volume of the compound represented by the general formula [2].
반응 온도는 통상 약 -70∼100 ℃ 정도, 바람직하게는 약 -70∼0 ℃ 정도의 범위가 채용되고, 상기 온도를 유지하면서 약 5 분∼5 시간 정도, 바람직하게는 약 10 분∼3 시간 정도 반응시키는 것에 의해 반응을 원활히 수행할 수 있다.The reaction temperature is usually in the range of about -70 to 100 ° C, preferably about -70 to 0 ° C, and about 5 minutes to 5 hours, preferably about 10 minutes to 3 hours, while maintaining the temperature. The reaction can be performed smoothly by reacting to a degree.
본 발명에 있어서, 일반식 [2]로 표시되는 화합물에 대한 일반식 [3]으로 표시되는 디아조 화합물의 사용량은, 전자 1 몰에 대해 후자는 약 0.5∼5 배 몰 정도, 바람직하게는 약 0.7∼4 배 몰 정도의 범위가 채용된다.In the present invention, the amount of the diazo compound represented by the general formula [3] relative to the compound represented by the general formula [2] is about 0.5 to 5 times the molar amount, and preferably about The range of about 0.7-4 times mole is employ | adopted.
본 발명에 있어서, 일반식 [2]로 표시되는 화합물에 대한 일반식 [4]로 표시되는 금속 화합물의 사용량은, 전자 1 몰에 대해 후자는 약 0.5∼2.5 배 몰 정도, 바람직하게는 약 0.7∼2 배 몰 정도의 범위가 채용된다.In the present invention, the amount of the metal compound represented by the general formula [4] relative to the compound represented by the general formula [2] is about 0.5 to 2.5 times the molar amount, preferably about 0.7 to 1 mole of the former. The range of about 2 times mole is employ | adopted.
본 발명에 있어서, 일반식 [2]로 표시되는 화합물에 대한 염기의 사용량은, 전자 1 몰에 대해 후자는 약 1∼8 배 몰 정도, 바람직하게는 약 1.4∼4 배 몰 정도의 범위가 채용된다.In the present invention, the amount of the base used for the compound represented by the general formula [2] is about 1 to 8 times mole, preferably about 1.4 to 4 times mole, based on 1 mole of the former. do.
상기 반응에 있어서 R2가 메틸기 등의 알킬기인 경우, 일반식 [3]으로 표시되는 디아조 화합물과 일반식 [4]로 표시되는 금속 화합물의 종류나 각종 반응 조건에 따라 생성되는 α-체와 β-체의 비율은 많거나 적을 수 있지만, 목적하는 β-체의 함유율은 통상 약 85 % 이상이다.In the above reaction, when R 2 is an alkyl group such as a methyl group, α-form formed according to the type of diazo compound represented by the general formula [3] and the metal compound represented by the general formula [4] or the reaction conditions; The ratio of β-forms may be large or small, but the desired content of β-forms is usually about 85% or more.
상기 반응에 따라 얻어진 반응액으로부터, 자체 공지인 후처리 방법, 즉 예를 들어 용매추출, 전용(轉溶; redissolution), 결정석출(晶出; crystallization), 재결정(recrystallization), 각종 크로마토그래피 등에 의해 원하는 아제티디논 화합물을 얻을 수 있다.From the reaction solution obtained in accordance with the above reaction, a known post-treatment method such as solvent extraction, redissolution, crystallization, recrystallization, various chromatography, or the like is employed. Desired azetidinone compounds can be obtained.
본 발명의 제조방법에 따라 얻어진 일반식 [1]로 표시되는 아제티디논 화합물로부터 공지의 제조방법을 이용하여 일반식 [B]From the azetidinone compound represented by the general formula [1] obtained according to the production method of the present invention using a known production method, the general formula [B]
(식중 R1는 아실기를 나타내고, R3는 상기와 동일하다.)로 표시되는 카바페넴류로 용이하게 전환될 수 있다.It can be easily converted to carbapenems represented by (wherein R 1 represents an acyl group and R 3 is the same as above).
이하에 실시예를 들어 본 발명을 보다 상세하게 설명하지만, 본 발명은 이들실시예에 의해 전혀 한정되지 않는다.Although an Example is given to the following and this invention is demonstrated in detail, this invention is not limited at all by these Examples.
각 실시예 중의 약호는 다음과 같다.The symbol in each Example is as follows.
TBDMSO: tert-부틸디메틸실릴옥시기TBDMSO: tert-butyldimethylsilyloxy group
OAc: 아세톡시기, PNB: p-니트로벤질기OAc: acetoxy group, PNB: p-nitrobenzyl group
실시예 1 (3S,4R)-3-[(R)-1-tert-부틸디메틸실릴옥시에틸]-4-[(R)-1-메틸-3-디아조-3-p-니트로벤질옥시카르보닐-2-옥소-프로필]-아제티딘-2-온의 제조Example 1 (3S, 4R) -3-[(R) -1-tert-butyldimethylsilyloxyethyl] -4-[(R) -1-methyl-3-diazo-3-p-nitrobenzyloxy Preparation of Carbonyl-2-oxo-propyl] -azetidin-2-one
질소 분위기 하에서 p-니트로벤질 2-디아조-3-옥소부타노에이트 2.22 g(8.0 mmol)의 염화메틸렌 용액(15 ㎖)을 -40 ℃로 냉각하고 사염화티탄 0.39 ㎖(3.55 mmol)을 가하여 -40 ℃에서 30 분간 교반한 후, 트리부틸아민 1.81 ㎖(7.57 mmol)을 가하여 다시 -40 ℃에서 30 분간 교반하였다. 다음에, 이 반응액에 (3S,4R)-4-아세톡시-3-[(R)-1-tert-부틸디메틸실릴옥시에틸]-아제티딘-2-온 574 ㎎(2.0 mmol)의 염화메틸렌 용액(5 ㎖)을 적하하고, 다시 -40 ℃에서 1 시간 교반하였다. 반응 혼합물을 10 % 탄산수소나트륨 수용액에 주입하여 반응을 정지시키고, 유기층을 분취하여 이것을 물로 세척하였다. 고속액체크로마토그래피로 분석한 결과, β:α=95:5였다. 얻어진 유기층을 무수 황산마그네슘으로 건조한 후, 용매를 증류 제거하고 잔사를 컬럼크로마토그래피로 정제하여, β-메틸 유도체(표기 화합물)757 ㎎을 얻었다(수율 75 %).Under nitrogen atmosphere, 2.22 g (8.0 mmol) of methylene chloride solution (15 mL) of p-nitrobenzyl 2-diazo-3-oxobutanoate was cooled to -40 DEG C, and 0.39 mL (3.55 mmol) of titanium tetrachloride were added to- After stirring at 40 ° C for 30 minutes, 1.81 mL (7.57 mmol) of tributylamine was added thereto, followed by stirring at -40 ° C for 30 minutes. Then, 574 mg (2.0 mmol) of (3S, 4R) -4-acetoxy-3-[(R) -1-tert-butyldimethylsilyloxyethyl] -azetidin-2-one was added to the reaction solution. Methylene solution (5 ml) was added dropwise and stirred at -40 ° C for 1 hour. The reaction mixture was poured into 10% aqueous sodium hydrogen carbonate solution to stop the reaction, and the organic layer was separated and washed with water. As a result of analysis by high performance liquid chromatography, β: α = 95: 5. After drying the obtained organic layer with anhydrous magnesium sulfate, the solvent was distilled off and the residue was purified by column chromatography to obtain 757 mg of β-methyl derivative (representative compound) (yield 75%).
이 화합물의 물성치는 일본 특허공개 소61-275284호에 기재된 물성치와 일치하였다.The physical properties of this compound were consistent with those in Japanese Patent Laid-Open No. 61-275284.
실시예 2 (3S,4R)-3-[(R)-1-tert-부틸디메틸실릴옥시에틸]-4-[(R)-1-메틸-3-디아조-3-p-니트로벤질옥시카르보닐-2-옥소-프로필]-아제티딘-2-온의 제조Example 2 (3S, 4R) -3-[(R) -1-tert-butyldimethylsilyloxyethyl] -4-[(R) -1-methyl-3-diazo-3-p-nitrobenzyloxy Preparation of Carbonyl-2-oxo-propyl] -azetidin-2-one
질소 분위기 하에서 p-니트로벤질 2-디아조-3-옥소부타노에이트 1.66 g(6.0 mmol)의 염화메틸렌 용액(20 ㎖)을 -40 ℃로 냉각하고 사염화티탄 0.66 ㎖(6.0 mmol)을 가하여 -40 ℃에서 30 분간 교반한 후, n-에틸피페리딘 1.65 ㎖(12.0 mmol)을 가하여 다시 -40 ℃에서 30 분간 교반하였다. 다음에, 이 반응액에 (3R,4R)-4-아세톡시-3-[(R)-1-tert-부틸디메틸실릴옥시에틸]-아제티딘-2-온 1.72 g(6.0 mmol)의 염화메틸렌 용액(5 ㎖)을 적하하고, 다시 -40 ℃에서 1 시간 교반하였다. 반응 혼합물에 1 몰 염산 10 ㎖를 가하여 반응을 정지시키고, 유기층을 분취하여 이것을 물로 세척하였다. 고속액체크로마토그래피로 분석한 결과, β:α=98:2였다. 얻어진 유기층을 무수 황산마그네슘으로 건조한 후, 용매를 증류 제거하고 잔사를 컬럼크로마토그래피로 정제하여, β-메틸 유도체(표기 화합물) 2.09 g을 얻었다(수율 69 %).1.66 g (6.0 mmol) of methylene chloride solution (20 mL) of p-nitrobenzyl 2-diazo-3-oxobutanoate under nitrogen atmosphere was cooled to -40 ° C, and 0.66 mL (6.0 mmol) of titanium tetrachloride was added to- After stirring at 40 ° C for 30 minutes, 1.65 mL (12.0 mmol) of n-ethylpiperidine was added thereto, followed by further stirring at -40 ° C for 30 minutes. Subsequently, 1.72 g (6.0 mmol) of (3R, 4R) -4-acetoxy-3-[(R) -1-tert-butyldimethylsilyloxyethyl] -azetidin-2-one was added to the reaction solution. Methylene solution (5 ml) was added dropwise and stirred at -40 ° C for 1 hour. 10 ml of 1 mol hydrochloric acid was added to the reaction mixture to stop the reaction, and the organic layer was separated and washed with water. As a result of analysis by high performance liquid chromatography, β: α = 98: 2. After drying the obtained organic layer with anhydrous magnesium sulfate, the solvent was distilled off and the residue was refine | purified by column chromatography to obtain 2.09 g of (beta) -methyl derivative (reference compound) (yield 69%).
실시예 3, 4Examples 3 and 4
실시예 1에서 사염화티탄 대신 하기 표 1에 나타낸 각종 금속 화합물을 사용하고, 그 외에는 실시예 1과 동일하게 반응 및 후처리를 행하여, 실시예 1과 같은 아제티디논 화합물을 각각 하기의 수율 및 생성비로 얻었다. 결과를 표 1에 정리해서 나타낸다.In Example 1, instead of titanium tetrachloride, various metal compounds shown in Table 1 below were used, and other reactions and post-treatments were carried out in the same manner as in Example 1 to give the same azetidinone compounds as in Example 1 in the following yields and yields. Got into the rain. The results are summarized in Table 1.
실시예 5Example 5
실시예 1에서 금속 화합물로서 사염화티탄과 트리메틸실릴클로라이드를 사용하고, 그 외에는 실시예 1과 동일하게 반응 및 후처리를 행하여, 실시예 1과 같은 아제티디논 화합물을 수율 68 %, β-체:α-체(생성비)=95:5로 얻었다.In Example 1, titanium tetrachloride and trimethylsilyl chloride were used as metal compounds, and the reaction and post-treatment were carried out in the same manner as in Example 1, yielding the same azetidinone compound as in Example 1 with a yield of 68% and β-form: α-body (production ratio) was obtained at 95: 5.
실시예 6Example 6
실시예 1에서 반응온도 -40 ℃를 5 ℃로 하고, 염기로서 트리부틸아민 대신에 트리에틸아민을 사용하고, 그 외에는 실시예 1과 동일하게 반응 및 후처리를 행하여, 실시예 1과 같은 아제티디논 화합물을 수율 69 %, β-체:α-체(생성비)=95:5로 얻었다.In Example 1, the reaction temperature of −40 ° C. was 5 ° C., triethylamine was used instead of tributylamine as the base, and the reaction and post-treatment were carried out in the same manner as in Example 1, except that the same agent as in Example 1 was used. A thidinone compound was obtained with a yield of 69% and a β-form: α-form (production ratio) = 95: 5.
비교예 1Comparative Example 1
실시예 1에서 염기를 전혀 사용하지 않고, 그 외에는 실시예 1과 동일하게 반응을 행하면, 목적물은 전혀 얻을 수 없었다.In Example 1, when no base was used at all and the reaction was carried out in the same manner as in Example 1, the target product was not obtained at all.
실시예 7∼9Examples 7-9
실시예 1에서 염화메틸렌 대신 다음 표 2에 나타낸 각종 반응용매를 사용하고, 그 외에는 실시예 1과 동일하게 반응 및 후처리를 행하여, 실시예 1과 같은 아제티디논 화합물을 각각 하기의 수율 및 생성비로 얻었다.In Example 1, various reaction solvents shown in Table 2 were used instead of methylene chloride, and the reaction and post-treatment were carried out in the same manner as in Example 1 to give the same azetidinone compounds as in Example 1 in the following yields and yields. Got into the rain.
실시예 10∼13Examples 10-13
실시예 1에서 아조 화합물로서 p-니트로벤질 2-디아조-3-옥소부타노에이트(상기 화학식에서 R이 p-니트로벤질기인 화합물)의 p-니트로벤질기를 다음 표 3에 나타낸 각종 치환기로 치환된 화합물을 사용하고, 그 외에는 실시예 1과 동일하게 반응 및 후처리를 행하여, 여러 가지 아제티디논 화합물에서 β-메틸체를 고선택적으로 얻었다. 결과를 표 3에 정리하여 나타낸다.Substituting the p-nitrobenzyl group of p-nitrobenzyl 2-diazo-3-oxobutanoate (the compound of which R is a p-nitrobenzyl group in the above formula) as the azo compound in Example 1 with various substituents shown in the following Table 3 The reaction was carried out in the same manner as in Example 1 except for using the obtained compound, and β-methyl was obtained highly selectively from various azetidinone compounds. The results are summarized in Table 3.
참고예 1 (1R,5R,6S)-p-니트로벤질-2-디페닐포스포릴옥시-6-[(R)-1-히드록시에틸]-1-메틸-카바페넴-3-카르복실레이트의 제조Reference Example 1 (1R, 5R, 6S) -p-nitrobenzyl-2-diphenylphosphoryloxy-6-[(R) -1-hydroxyethyl] -1-methyl-carbapenem-3-carboxylate Manufacture
질소 기류 하에서, (3S,4R)-3-[(R)-1-tert-부틸디메틸실릴옥시에틸]-4-[(R)-1-메틸-3-디아조-3-p-니트로벤질옥시카르보닐-2-옥소-프로필]-아제티딘-2-온 149.7 g(314 mmol)을 메탄올 750 ㎖에 용해시킨 후, 2 몰 염산수 44.5 ㎖를 가하여 실온에서 22.5 시간 교반하였다. 초산에틸 1.1 ℓ를 가하여 교반한 후, 유기층을 분취하고 이것을 물로 세척하였다. 얻어진 유기층을 무수 황산마그네슘으로 건조한 후, 용매를 증류 제거하여 탈실릴체 107.6 g을 얻었다. 얻어진 탈실릴체 107.6 g을 초산에틸 1.1 ℓ에 용해하고 로듐옥타노에이트(Rh2(Oct)4) 0.65 g을 가하여 50 ℃에서 2.5 시간 반응시켰다. 용매를 증류 제거하고 얻어진 잔사를 아세토니트릴 550 ㎖에 용해하고, -10 ℃까지 냉각한 후, 디페닐클로로포스페이트 77.8 g, 디이소프로필에틸아민 39.2 g을 차례로 가하여 -10 ℃에서 3 시간 교반하였다. 용매를 증류 제거하고 얻어진 잔사를 초산에틸 2.2 ℓ에 용해하였다. 얻어진 유기층을 물로 세척한 후 용매를 증류 제거하고, 헵탄을 가하여 결정석출시켰다. 결정을 여취하고 건조하여 표기 화합물 137.9 g을 얻었다.Under nitrogen stream, (3S, 4R) -3-[(R) -1-tert-butyldimethylsilyloxyethyl] -4-[(R) -1-methyl-3-diazo-3-p-nitrobenzyl After 149.7 g (314 mmol) of oxycarbonyl-2-oxo-propyl] -azetidin-2-one was dissolved in 750 ml of methanol, 44.5 ml of 2 molar hydrochloric acid was added, followed by stirring at room temperature for 22.5 hours. 1.1 L of ethyl acetate was added and stirred, and then the organic layer was aliquoted and washed with water. After drying the obtained organic layer with anhydrous magnesium sulfate, the solvent was distilled off and 107.6 g of desilyl bodies were obtained. 107.6 g of the obtained desilyl product was dissolved in 1.1 L of ethyl acetate, 0.65 g of rhodium octanoate (Rh 2 (Oct) 4 ) was added, and the mixture was reacted at 50 ° C. for 2.5 hours. The solvent was distilled off, and the obtained residue was dissolved in 550 ml of acetonitrile. After cooling to -10 ° C, 77.8 g of diphenylchlorophosphate and 39.2 g of diisopropylethylamine were added sequentially, followed by stirring at -10 ° C for 3 hours. The solvent was distilled off and the obtained residue was dissolved in 2.2 L of ethyl acetate. The organic layer obtained was washed with water, the solvent was distilled off, and heptane was added to crystallize. The crystals were filtered off and dried to give 137.9 g of the title compound.
이 화합물의 물성치는Heterocycles, Vol. 21, pp. 29-40(1984) 및 일본 특허공개 평6-321946호에 기재된 당해 화합물의 물성치와 일치하였다.Physical properties of this compound were reported in Heterocycles , Vol. 21, pp. The properties of the compounds described in 29-40 (1984) and Japanese Patent Laid-Open No. 6-321946 are consistent with those of the compound.
본 발명은 항균물질로서 유용한 카바페넴계 항생물질의 제조에 바람직하게 이용되는 1β-메틸카바페넴 유도체를 공업적으로 제조하기 위한 중요한 합성 중간체인 아제티디논 화합물을 온화한 조건 하에서 짧은 공정으로 수율 좋게 선택적으로 제조하는 방법을 제공하는 데 있어서 현저한 효과를 발휘한다.The present invention provides good yields of azetidinone compounds, which are important synthetic intermediates for the industrial production of 1β-methylcarbapenem derivatives, which are preferably used for the preparation of carbapenem antibiotics useful as antimicrobials in a short process under mild conditions. It has a remarkable effect in providing a method for producing the same.
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| 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 |
| WO2011048583A1 (en) | 2009-10-23 | 2011-04-28 | Ranbaxy Laboratories Limited | Process for the preparation of carbapenem compounds |
| 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 |
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| 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 |
| EP1071685A4 (en) * | 1998-04-16 | 2001-07-18 | 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 |
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