KR100385364B1 - Intermediate of Carbapenem Antibiotics and Process for the Preparation thereof - Google Patents
Intermediate of Carbapenem Antibiotics and Process for the Preparation thereof Download PDFInfo
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- KR100385364B1 KR100385364B1 KR10-2002-0052421A KR20020052421A KR100385364B1 KR 100385364 B1 KR100385364 B1 KR 100385364B1 KR 20020052421 A KR20020052421 A KR 20020052421A KR 100385364 B1 KR100385364 B1 KR 100385364B1
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- 238000000034 method Methods 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title abstract description 38
- 239000003242 anti bacterial agent Substances 0.000 title abstract description 8
- 229940088710 antibiotic agent Drugs 0.000 title abstract description 8
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 136
- -1 azetidinone compound Chemical class 0.000 claims abstract description 56
- 238000004519 manufacturing process Methods 0.000 claims abstract description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 239000012190 activator Substances 0.000 claims abstract description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 6
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 5
- 229910052736 halogen Chemical group 0.000 claims abstract description 4
- 150000002367 halogens Chemical group 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- 239000001301 oxygen Substances 0.000 claims abstract description 4
- 125000005907 alkyl ester group Chemical group 0.000 claims abstract description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 150000001923 cyclic compounds Chemical class 0.000 claims abstract description 3
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 3
- HMXSFYWGRLXKIZ-UHFFFAOYSA-N 5-methyl-4-oxo-3-phenyl-1-oxa-5-azaspiro[5.5]undec-2-ene-2-carboxylic acid Chemical compound CN1C(C(=C(OC11CCCCC1)C(=O)O)C1=CC=CC=C1)=O HMXSFYWGRLXKIZ-UHFFFAOYSA-N 0.000 claims description 4
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 claims description 3
- 150000001555 benzenes Chemical group 0.000 claims description 2
- LDCMOCGAIMMZPI-UHFFFAOYSA-N 2-methylundec-2-enoic acid Chemical compound CCCCCCCCC=C(C)C(O)=O LDCMOCGAIMMZPI-UHFFFAOYSA-N 0.000 claims 1
- 230000000707 stereoselective effect Effects 0.000 abstract description 16
- 239000002671 adjuvant Substances 0.000 abstract description 12
- 230000003115 biocidal effect Effects 0.000 abstract description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 10
- 239000002253 acid Substances 0.000 abstract description 10
- 238000005886 esterification reaction Methods 0.000 abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 8
- 238000007363 ring formation reaction Methods 0.000 abstract description 6
- 125000003342 alkenyl group Chemical group 0.000 abstract description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 4
- 238000011065 in-situ storage Methods 0.000 abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 abstract description 3
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- 125000006307 alkoxy benzyl group Chemical group 0.000 abstract description 2
- 125000003118 aryl group Chemical group 0.000 abstract description 2
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 abstract description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 abstract description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 2
- 125000001188 haloalkyl group Chemical group 0.000 abstract description 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 2
- 239000001257 hydrogen Substances 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 abstract description 2
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- 238000006243 chemical reaction Methods 0.000 description 43
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- 239000000243 solution Substances 0.000 description 18
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
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- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 8
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- 150000003839 salts Chemical class 0.000 description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 229910052725 zinc Inorganic materials 0.000 description 5
- 239000011701 zinc Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
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- 229960000583 acetic acid Drugs 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 229910052749 magnesium Inorganic materials 0.000 description 4
- 239000012454 non-polar solvent Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 4
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 3
- AVFXXXDFQOABLS-UHFFFAOYSA-N 4-oxo-3-phenyl-1-oxa-5-azaspiro[5.5]undec-2-ene-2-carboxylic acid Chemical compound O=C1C(=C(OC2(N1)CCCCC2)C(=O)O)C1=CC=CC=C1 AVFXXXDFQOABLS-UHFFFAOYSA-N 0.000 description 3
- YITZRQNREWCPNN-UHFFFAOYSA-N 5-(2-bromopropanoyl)-11-methyl-4-oxo-3-phenyl-1-oxa-5-azaspiro[5.5]undec-2-ene-2-carboxylic acid Chemical compound CC(Br)C(=O)N1C(=O)C(C=2C=CC=CC=2)=C(C(O)=O)OC11CCCCC1C YITZRQNREWCPNN-UHFFFAOYSA-N 0.000 description 3
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- 229910052783 alkali metal Inorganic materials 0.000 description 3
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- 239000003153 chemical reaction reagent Substances 0.000 description 3
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- 150000004692 metal hydroxides Chemical class 0.000 description 3
- MUWVIMJPXKIXJK-UHFFFAOYSA-N prop-2-enyl 2-bromoacetate Chemical compound BrCC(=O)OCC=C MUWVIMJPXKIXJK-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
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- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
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- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
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- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
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- 230000035484 reaction time Effects 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
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- ADHFTAKIDKDGBV-UHFFFAOYSA-N (4-nitrophenyl)methyl 2-bromoacetate Chemical compound [O-][N+](=O)C1=CC=C(COC(=O)CBr)C=C1 ADHFTAKIDKDGBV-UHFFFAOYSA-N 0.000 description 1
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 description 1
- IRSPCJLMPFDMGD-UHFFFAOYSA-N 1-hydroxybenzimidazole Chemical compound C1=CC=C2N(O)C=NC2=C1 IRSPCJLMPFDMGD-UHFFFAOYSA-N 0.000 description 1
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- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000011968 lewis acid catalyst Substances 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 1
- 229960002260 meropenem Drugs 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000004492 methyl ester group Chemical group 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical class CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910021332 silicide Inorganic materials 0.000 description 1
- FDNAPBUWERUEDA-UHFFFAOYSA-N silicon tetrachloride Chemical compound Cl[Si](Cl)(Cl)Cl FDNAPBUWERUEDA-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- HIAIVILTZQDDNY-UHFFFAOYSA-J tin(4+);trifluoromethanesulfonate Chemical compound [Sn+4].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HIAIVILTZQDDNY-UHFFFAOYSA-J 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical compound CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65611—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system (X = CH2, O, S, NH) optionally with an additional double bond and/or substituents, e.g. penicillins and analogs
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- Chemical & Material Sciences (AREA)
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- Biochemistry (AREA)
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- Molecular Biology (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
본 발명은 β-메틸카바페넴계 항생제의 제조를 위한 중간체로 유용한 다음 일반식(Ⅰ)로 표시되는 새로운 아제티디논 화합물과 그의 제조방법에 관한 것이다.The present invention relates to a novel azetidinone compound represented by the following general formula (I), which is useful as an intermediate for the preparation of β-methylcarbapenem antibiotics, and a method for preparing the same.
위 식에서 R은 수소, 또는 하이드록시 보호기를 나타내며, R1과 R2는 각각 C1-C15개의 동일한 알킬기, 벤질기 또는 R1과 R2가 연결된 5-6환의 고리화합물이며, 모두 탄소원자로 연결되었거나, 산소, 황 원자가 1개 이상 포함된 헤테로고리기를 나타낸다. R3는 저급 알킬기 또는 저급 알킬에스테르기를 나타내며, R4는 벤젠 또는 할로겐, 저급 알콕시기, 나이트로기가 치환된 벤젠고리를 나타낸다. 또한 상기 구조식에서 1' 위치의 메틸기가 R-배향을 하고 있음을 뜻하며, 이를 β-메틸로 나타내었고, 이하의 모든 구조식에서도 β-메틸로 표시한다.In the above formula, R represents hydrogen or a hydroxy protecting group, and R 1 and R 2 each represent a C 1 -C 15 identical alkyl group, a benzyl group, or a 5-6 ring cyclic compound in which R 1 and R 2 are linked, all of which are carbon atoms. Or a heterocyclic group having one or more oxygen or sulfur atoms connected thereto. R 3 represents a lower alkyl group or a lower alkyl ester group, and R 4 represents a benzene ring substituted with benzene or a halogen, a lower alkoxy group, and a nitro group. In addition, it means that the methyl group of the 1 'position in the structural formula R-oriented, which is represented by β-methyl, also represented by β-methyl in all the following structural formula.
또, 본 발명은 일반식(Ⅱ)의 4-아세톡시-아제티디논 화합물과 일반식(Ⅲ)의 α-할로프로피온아마이드 화합물을 반응시켜 일반식(Ⅰ)의 화합물인 새로운 아제티디논 화합물을 제조하는 방법에 관한 것이다.The present invention also reacts a 4-acetoxy-azetidinone compound of formula (II) with an α-halopropionamide compound of formula (III) to form a new azetidinone compound which is a compound of formula (I). It relates to a manufacturing method.
위 식에서 R, R1, R2, R3, R4는 위에서 정의한 바와 같고 X는 할로겐 원자를 나타낸다.Wherein R, R 1 , R 2 , R 3 and R 4 are as defined above and X represents a halogen atom.
또, 본 발명은 새로운 입체 선택 보조제인 일반식(Ⅲ)의 화합물인 α-할로프로피온산아마이드 화합물에 관한 것이다.Moreover, this invention relates to the alpha-halopropionic acid amide compound which is a compound of general formula (III) which is a new stereoselective adjuvant.
일반식(Ⅲ)의 화합물을 사용하여 입체 선택성이 우수하게 일반식(Ⅰ)의 화합물을 제조할 수 있다.The compound of general formula (I) can be manufactured excellent in stereoselectivity using the compound of general formula (III).
또, 본 발명은 일반식(Ⅷ)의 모노사이클릭 화합물과 일반식(Ⅸ)의 2-할로프로피온산 또는 그의 활성화물을 반응시켜 새로운 일반식(Ⅲ)의 α-할로프로피온산아마이드 화합물을 제조하는 방법에 관한 것이다.In addition, the present invention is a method for producing a new α-halopropionamide compound of the general formula (III) by reacting a monocyclic compound of the general formula (III) with 2-halopropionic acid or a activator thereof. It is about.
위 식에서 R1, R2, R3, R4, X는 앞에서 정의한 바와 같다.In the above formula, R 1 , R 2 , R 3 , R 4 , X are as defined above.
또, 본 발명은 일반식(Ⅴ)로 표시되는 β-메틸카바페넴 에스테르 화합물의 새로운 제조방법에 관한 것이다.Moreover, this invention relates to the new manufacturing method of the (beta) -methyl carbapenem ester compound represented by General formula (V).
즉, 일반식(Ⅰ)의 화합물과 일반식(Ⅹ)의 아세트산 화합물을 반응시켜 일반식(ⅩⅠ)의 N-치환 아제티디논 화합물을 얻고 이를 고리화 반응 및 에스테르화 반응을 in situ로 진행시켜 일반식(Ⅴ)의 화합물을 제조하는 새로운 방법에 관한 것이다.That is, the compound of general formula (I) is reacted with an acetic acid compound of general formula (VII) to obtain an N-substituted azetidinone compound of general formula (XI), which is subjected to a cyclization reaction and an esterification reaction in situ. It relates to a new process for the preparation of compounds of general formula (V).
위 식에서 R, R1, R2, R3, R4및 X는 위에서 정의한 바와 같고 R5는 카복실기의 보호기로 통상적인 방법으로 쉽게 제거될 수 있는 기로서 저급 알킬기, 저급 알케닐기, 할로 저급 알킬기, 나이트로벤질기, 저급 알콕시-벤질기, 벤즈히드릴기 등을 나타내고 OA는 에스테르화된 하이드록시기로서 -S-R6(여기서 R6은 항생작용을 하는 해당 헤테로고리기)가 쉽게 치환될 수 있는 구조로서 -OP(O)(OR7)2(여기서 R7은 아릴 또는 저급 알킬), 치환 또는 비치환 저급 알킬설포닐기(예로서 메탄설포닐기, 에탄설포닐기, 트리풀루오로메탄설포닐기), 아릴옥시카보닐기(예로서 벤질옥시카보닐기) 등이며, 이들 중에서 디아릴포스포릴옥시기, 디 저급 알킬포스포릴옥시기, 치환 또는 비치환 저급 알킬설포닐기, 치환 또는 비치환 아릴설포닐기 등의 하이드록시기의 에스테르화기가 바람직하다.In the above formula, R, R 1 , R 2 , R 3 , R 4 and X are as defined above and R 5 is a group of carboxyl group which can be easily removed in a conventional manner as lower alkyl group, lower alkenyl group, lower halo Alkyl group, nitrobenzyl group, lower alkoxy-benzyl group, benzhydryl group and the like, OA is an esterified hydroxy group, where -SR 6 (where R 6 is the corresponding heterocyclic group which is antibiotic) can be easily substituted. -OP (O) (OR 7 ) 2 (where R 7 is aryl or lower alkyl), substituted or unsubstituted lower alkylsulfonyl group (for example methanesulfonyl group, ethanesulfonyl group, tripulolomethanesulfonyl group) ), An aryloxycarbonyl group (e.g., benzyloxycarbonyl group), and among these, a diarylphosphoryloxy group, a di lower alkylphosphoryloxy group, a substituted or unsubstituted lower alkylsulfonyl group, a substituted or unsubstituted arylsulfonyl group S of hydroxyl groups such as Terminated groups are preferred.
또, 본 발명은 일반식(Ⅳ)로 표시되는 1'β-메틸아제티디논 화합물의 새로운제조방법에 관한 것이다.Moreover, this invention relates to the new manufacturing method of the 1 '(beta) -methylazetidinone compound represented by general formula (IV).
즉, 일반식(Ⅰ)의 화합물을 가수분해 반응을 통하여 일반식(Ⅳ)의 화합물을 제조하는 새로운 방법에 관한 것이다.That is, the present invention relates to a new method for preparing a compound of formula (IV) through a hydrolysis reaction of a compound of formula (I).
위 식에서 R은 앞에서 정의한 바와 같다.Where R is as defined above.
본 발명에서는 입체 선택 보조제인 일반식(Ⅲ)의 화합물을 사용하여 일반식(Ⅰ)의 화합물을 제조함으로써 일반식(Ⅰ) 화합물의 1' 위치가 β-메틸기인 입체 이성체질을 종래기술에서보다 월등히 높은 비율로 제조할 수 있게 되었다.In the present invention, by preparing a compound of general formula (I) using a compound of general formula (III) as a stereoselective adjuvant, stereoisomers having a 1-position of the compound of general formula (I) are β-methyl groups than those of the prior art It was possible to manufacture at an extremely high rate.
또 본 발명에서는 일반식(Ⅰ)의 화합물로부터 카바페넴 항생제의 최종 중간체인 일반식(Ⅴ)의 화합물을 제조하는 공정 중에서 입체 선택 보조제인 일반식(Ⅲ)의 화합물을 부산물로 회수하여 재사용할 수 있는 장점이 있다.In the present invention, the compound of formula (III), which is a stereoselective adjuvant, can be recovered and reused as a by-product during the process for preparing the compound of formula (V), which is the final intermediate of the carbapenem antibiotic, from the compound of formula (I). There is an advantage.
Description
본 발명은 β-메틸카바페넴계 항생제의 제조를 위한 중간체로 유용한 다음 일반식(Ⅰ)로 표시되는 새로운 아제티디논 화합물과 그의 제조방법에 관한 것이다.The present invention relates to a novel azetidinone compound represented by the following general formula (I), which is useful as an intermediate for the preparation of β-methylcarbapenem antibiotics, and a method for preparing the same.
위 식에서 R은 수소 또는 하이드록시 보호기를 나타내며, R1과 R2는 각각 C1-C15개의 동일한 알킬기, 벤질기 또는 R1과 R2가 연결된 5-6환의 고리화합물이며, 모두 탄소원자로 연결되었거나, 산소, 황 원자가 1개 이상 포함된 헤테로고리기를 나타낸다. R3는 저급 알킬기 또는 저급 알킬에스테르기를 나타내며, R4는 벤젠 또는 할로겐, 저급 알콕시기, 나이트로기가 치환된 벤젠고리를 나타낸다. 또한 상기 구조식에서 1' 위치의 메틸기가 R-배향을 하고 있음을 뜻하며, 이를 β-메틸로 나타내었고, 이하의 모든 구조식에서도 β-메틸로 표시한다.In the above formula, R represents hydrogen or a hydroxy protecting group, R 1 and R 2 are each C 1 -C 15 identical alkyl group, benzyl group or 5-6 ring cyclic compound in which R 1 and R 2 are linked, all linked with carbon atoms Or a heterocyclic group containing at least one oxygen or sulfur atom. R 3 represents a lower alkyl group or a lower alkyl ester group, and R 4 represents a benzene ring substituted with benzene or a halogen, a lower alkoxy group, and a nitro group. In addition, it means that the methyl group of the 1 'position in the structural formula R-oriented, which is represented by β-methyl, also represented by β-methyl in all the following structural formula.
또, 본 발명은 일반식(Ⅱ)의 4-아세톡시-아제티디논 화합물과 일반식(Ⅲ)의 α-할로프로피온아마이드 화합물을 반응시켜 일반식(Ⅰ)의 화합물인 새로운 아제티디논 화합물을 제조하는 방법에 관한 것이다.The present invention also reacts a 4-acetoxy-azetidinone compound of formula (II) with an α-halopropionamide compound of formula (III) to form a new azetidinone compound which is a compound of formula (I). It relates to a manufacturing method.
위 식에서 R, R1, R2, R3, R4는 위에서 정의한 바와 같고 X는 할로겐 원자를 나타낸다.Wherein R, R 1 , R 2 , R 3 and R 4 are as defined above and X represents a halogen atom.
또, 본 발명은 새로운 입체 선택 보조제인 일반식(Ⅲ)의 화합물인 α-할로프로피온산아마이드 화합물에 관한 것이다.Moreover, this invention relates to the alpha-halopropionic acid amide compound which is a compound of general formula (III) which is a new stereoselective adjuvant.
일반식(Ⅲ)의 화합물을 사용하여 입체 선택성이 우수하게 일반식(Ⅰ)의 화합물을 제조할 수 있다.The compound of general formula (I) can be manufactured excellent in stereoselectivity using the compound of general formula (III).
또, 본 발명은 일반식(Ⅷ)의 모노사이클릭 화합물과 일반식(Ⅸ)의 2-할로프로피온산 또는 그의 활성화물을 반응시켜 새로운 일반식(Ⅲ)의 α-할로프로피온산아마이드 화합물을 제조하는 방법에 관한 것이다.In addition, the present invention is a method for producing a new α-halopropionamide compound of the general formula (III) by reacting a monocyclic compound of the general formula (III) with 2-halopropionic acid or a activator thereof. It is about.
위 식에서 R1, R2, R3, R4, X는 앞에서 정의한 바와 같다.In the above formula, R 1 , R 2 , R 3 , R 4 , X are as defined above.
또, 본 발명은 일반식(Ⅴ)로 표시되는 β-메틸카바페넴에스테르 화합물의 새로운 제조방법에 관한 것이다.Moreover, this invention relates to the new manufacturing method of the (beta) -methyl carbapenem ester compound represented by General formula (V).
즉, 일반식(Ⅰ)의 화합물과 일반식(Ⅹ)의 아세트산 화합물을 반응시켜 일반식(ⅩⅠ)의 N-치환 아제티디논 화합물을 얻고 이를 고리화 반응 및 에스테르화 반응을 in situ로 진행시켜 일반식(Ⅴ)의 화합물을 제조하는 새로운 방법에 관한 것이다.That is, the compound of general formula (I) is reacted with an acetic acid compound of general formula (VII) to obtain an N-substituted azetidinone compound of general formula (XI), which is subjected to a cyclization reaction and an esterification reaction in situ. It relates to a new process for the preparation of compounds of general formula (V).
위 식에서 R, R1, R2, R3, R4및 X는 위에서 정의한 바와 같고 R5는 카복실기의 보호기로 통상적인 방법으로 쉽게 제거될 수 있는 기로서 저급 알킬기, 저급 알케닐기, 할로 저급 알킬기, 나이트로벤질기, 저급 알콕시-벤질기, 벤즈히드릴기 등을 나타내고 OA는 에스테르화된 하이드록시기로서 -S-R6(여기서 R6은 항생작용을 하는 해당 헤테로고리기)가 쉽게 치환될 수 있는 구조로서 -OP(O)(OR7)2(여기서 R7은 아릴 또는 저급 알킬), 치환 또는 비치환 저급 알킬설포닐기(예로서 메탄설포닐기, 에탄설포닐기, 트리풀루오로메탄설포닐기), 아릴옥시카보닐기(예로서 벤질옥시카보닐기) 등이며, 이들 중에서 디아릴포스포릴옥시기, 디 저급 알킬포스포릴옥시기, 치환 또는 비치환 저급 알킬설포닐기, 치환 또는 비치환 아릴설포닐기 등의 하이드록시기의 에스테르화기가 바람직하다.In the above formula, R, R 1 , R 2 , R 3 , R 4 and X are as defined above and R 5 is a group of carboxyl group which can be easily removed in a conventional manner as lower alkyl group, lower alkenyl group, lower halo Alkyl group, nitrobenzyl group, lower alkoxy-benzyl group, benzhydryl group and the like, OA is an esterified hydroxy group, where -SR 6 (where R 6 is the corresponding heterocyclic group which is antibiotic) can be easily substituted. -OP (O) (OR 7 ) 2 (where R 7 is aryl or lower alkyl), substituted or unsubstituted lower alkylsulfonyl group (for example methanesulfonyl group, ethanesulfonyl group, tripulolomethanesulfonyl group) ), An aryloxycarbonyl group (e.g., benzyloxycarbonyl group), and among these, a diarylphosphoryloxy group, a di lower alkylphosphoryloxy group, a substituted or unsubstituted lower alkylsulfonyl group, a substituted or unsubstituted arylsulfonyl group S of hydroxyl groups such as Terminated groups are preferred.
또, 본 발명은 일반식(Ⅳ)로 표시되는 1'β-메틸아제티디논 화합물의 새로운 제조방법에 관한 것이다.Moreover, this invention relates to the new manufacturing method of the 1 '(beta) -methylazetidinone compound represented by general formula (IV).
즉, 일반식(Ⅰ)의 화합물을 가수분해 반응을 통하여 일반식(Ⅳ)의 화합물을 제조하는 새로운 방법에 관한 것이다.That is, the present invention relates to a new method for preparing a compound of formula (IV) through a hydrolysis reaction of a compound of formula (I).
위 식에서 R은 앞에서 정의한 바와 같다.Where R is as defined above.
다음 일반식(ⅩⅡ)로 표시되는 β-메틸카바페넴계 항생제는 녹농균을 포함한 그람음성균과 그람양성균에 광범위하게 탁월한 항균작용을 나타내는 우수한 항생제이며 또한 페니실린계 또는 세팔로스포린계 항생제의 내성균에도 우수한 약효를 가지고 있다.The β-methylcarbapenem antibiotic represented by the following general formula (XII) is an excellent antibiotic that exhibits excellent antimicrobial activity against Gram-negative bacteria and Gram-positive bacteria, including Pseudomonas aeruginosa, and is also excellent for resistant bacteria of penicillin or cephalosporin antibiotics. Have
이 중에서 대표적인 것으로는 메로페넴(유럽공개특허 제 126587 호)과 바이아페넴(일본공개특허 평 1-25779 호) 등이 있으며, 이외에도 다수의 카바페넴계 항생제들이 개발되고 있다.Among them, typical examples include meropenem (European Patent No. 126587) and Baiapenem (Japanese Patent Laid-Open No. Hei 1-25779), and many other carbapenem antibiotics have been developed.
현재까지 알려진 합성방법은 대부분 다음과 같은 두 가지 경로를 통하고 있다.Most of the synthesis methods known to date are through two routes:
위 식에서 R, R5는 위에서 정의한 바와 같고 R6는 항생작용을 갖게하는 해당 헤테로고리기를 나타낸다.In the above formula, R and R 5 are as defined above and R 6 represents a corresponding heterocyclic group having antibiotic action.
첫째 경로로는 일반식(Ⅱ)로 표시되는 4-아세톡시-아제티디논 화합물을 출발물질로 하여 여러가지 입체 선택 보조제를 사용하여 일반식(Ⅳ)로 표시되는 β-메틸아제티디논 화합물을 만들고 이 일반식(Ⅳ)의 화합물로부터 5-6 단계의 반응을 거쳐 카바페넴 항생제의 전단계 최종 중간체인 일반식(Ⅴ)의 화합물을 만들며 이로부터 일반식(ⅩⅡ)의 β-메틸카바페넴계 항생제를 만든다.As a first route, the 4-acetoxy-azetidinone compound represented by the general formula (II) was used as a starting material, and various β-methylazetidinone compounds represented by the general formula (IV) were prepared using various stereoselective auxiliaries. From the compound of formula (IV), a compound of general formula (V), which is the final intermediate of the carbapenem antibiotic, is prepared by a reaction of 5-6 steps. From this, β-methylcarbapenem antibiotic of general formula (XII) is prepared. Make.
중간체인 일반식(Ⅳ)의 화합물로부터 카바페넴 최종 중간체인 일반식(Ⅴ)의 화합물의 제조방법은 일본공개특허 소 63-188662 호에 보고된 방법에 따라 제조할 수 있으므로 본 발명에서는 자세히 설명하지 않는다.The method for preparing the compound of formula (V), which is the final intermediate of carbapenem, from the compound of formula (IV), which is an intermediate, may be prepared according to the method reported in Japanese Patent Application Laid-Open No. 63-188662, and thus, the present invention will not be described in detail. Do not.
위 반응들은 알돌 형태의 반응으로 1'β-메틸기를 도입하는데 있어서 입체선택성은 우수하게 보고되어 있지만, 이때 사용되는 시약들은 예를 들어 틴 트리플레이트, 티타늄 클로라이드, 디부틸보론트리플레이트 등 다루기가 어렵고 고가이어서 대량생산에 어려움이 있었다.The above reactions have been reported to have good stereoselectivity in introducing 1'β-methyl groups into aldol-type reactions, but the reagents used are difficult to handle, for example, tin triflate, titanium chloride, dibutylboron triplate, etc. It was expensive and there was difficulty in mass production.
이와 유사한 제조방법들은 다음을 비롯하여 다수의 문헌에 보고되어 있다(일본공개특허 제 87-252786 호) :J.A.C.S.108권, 4675-4676면 1986년 : 동 잡지 108권, 4673-4675면, 1986년 :J. Antibiotics, 374면, 1989년,Tetrahedron Letters, 9657면, 1995년 : 동 잡지 27권, 5687면, 1986년).Similar manufacturing methods have been reported in a number of documents, including the following (Japanese Patent Publication No. 87-252786): JACS 108, pages 4675-4676 1986: 108, 4673-4675, 1986: J. Antibiotics , p. 374, 1989, Tetrahedron Letters , p. 9657, 1995: 27, pp. 5687, 1986).
그러나 이 방법은 이렇게 제조한 중간체인 일반식(Ⅳ)의 화합물로부터 5-6 단계를 거쳐 카바페넴계 항생제의 전단계 최종 중간체인 일반식(Ⅴ)의 화합물을 합성하는 방법으로 각 단계마다 수율은 좋으나, 전체 제조과정이 길다는 단점이 있다.However, this method is a method of synthesizing the compound of formula (V), which is the final intermediate of the previous step of the carbapenem antibiotic, through 5-6 steps from the compound of formula (IV), the intermediate thus prepared. The disadvantage is that the entire manufacturing process is long.
둘째 경로로는 첫째 경로의 단점을 개선한 것으로서 일본국의 타나베사에서 개발한 방법이 있다.The second route is the improvement of the shortcomings of the first route, which was developed by Tanabesa in Japan.
즉, 일반식(Ⅱ)로 표시되는 4-아세톡시-아제티디논 화합물을 출발물질로하여 일반식(Ⅵ)의 입체 선택 보조제를 사용하여 다루기 쉬운 아연, 마그네슘 금속을 작용시켜 레포마츠키(Reformatsky)형 반응으로 다음 일반식(Ⅶ)로 표시되는 1'β-메틸중간체를 얻고 이 일반식(Ⅶ)의 화합물을 가수분해시켜 첫째 경로의 일반식(Ⅳ)의 화합물을 얻거나, 일반식(Ⅶ)의 화합물로부터 N-알킬화 반응, 고리화 반응 및 에스테르화 반응을 거쳐 일반식(Ⅴ)의 화합물을 만들고 (한국특허등록 제 10-231223 호) 이로부터 일반식(ⅩⅡ)의 1β-메틸카바페넴계 항생제를 만든다.In other words, using a 4-acetoxy-azetidinone compound represented by the general formula (II) as a starting material, an easy-to-manage zinc and magnesium metal is reacted using a stereoselective adjuvant of the general formula (VI) (Reformatsky In a) -type reaction, a 1'β-methyl intermediate represented by the following general formula (VII) is obtained, and the compound of the general formula (VII) is hydrolyzed to obtain a compound of the general formula (IV) of the first route, or N-alkylation reaction, cyclization reaction, and esterification reaction from compound (iii) to form a compound of formula (V) (Korean Patent Registration No. 10-231223) from 1β-methylcarba of formula (XII) Make penem antibiotics.
위 식에서 R은 앞에서 정의한 바와 같으며, Z는 C3-C7알케닐기, C1-20알킬기, 아르알킬기로부터 선택된 1개에서 2개의 기로 치환된 메틸렌기이며, Y는 산소, 황, 메틸렌 또는 이민기를 나타내며, 환 B는 할로겐, 저급 알킬기, 저급 알콕시기가 치환된 벤젠환을 나타낸다.In the above formula, R is as defined above, Z is a methylene group substituted with one to two groups selected from C 3 -C 7 alkenyl group, C 1-20 alkyl group, aralkyl group, Y is oxygen, sulfur, methylene or An imine group is shown, and ring B represents the benzene ring which the halogen, the lower alkyl group, and the lower alkoxy group substituted.
이 둘째 경로의 방법이 위 첫째 경로의 방법보다 반응단계가 간편하며, 까다로운 반응조건이 없어서 산업적 측면에서 유리한 것으로 알려져 있다.This second route method is simpler than the first route method, and there are no demanding reaction conditions.
이와 유사한 제조방법들이 각종문헌에 보고되어 있다(예를 들어,Tetrahedron Letters, 2801면, 1991년 : 동 잡지 6625면, 1987년 : 일본공개특허공보 평7-82248 호 : 동 특허 평7-82249 호).Similar manufacturing methods are reported in various documents (for example, Tetrahedron Letters , p. 2801, 1991: 6625 p., 1987: Japanese Patent Laid-Open No. 7-82248: Japanese Patent No. 7-82249). ).
일반식(ⅩⅡ)의 β-메틸카바페넴계 항생제의 제조방법은 공지된 방법(예로서 일본국공개특허 평4-279588 호)에 따라 제조할 수 있다.The manufacturing method of the (beta) -methylcarbapenem type antibiotic of general formula (XII) can be manufactured according to a well-known method (for example, Unexamined-Japanese-Patent No. 4-279588).
즉 일반식(Ⅴ)의 화합물을 해당 헤테로사이클릭싸이올 화합물과 반응시켜 제조할 수 있다.That is, the compound of Formula (V) can be prepared by reacting with the heterocyclic thiol compound.
그러나 이 둘째 경로의 방법도 입체 선택성에 있어서는 바람직하지 못한 단점이 있다.However, this second route method also has disadvantages in terms of stereoselectivity.
본 발명에서는 β-메틸카바페넴 중간체를 입체 선택적으로 제조함에 있어서, 새로운 입체 선택 보조제인 일반식(Ⅲ)으로 표시되는 α-할로프로피온산아마이드로 레포마츠키형의 반응을 통하여 1'β-메틸카바페넴 중간체를 제조함으로써 1'α-메틸기에 대한 1'β-메틸기의 비율을 공지된 기술의 비율보다 높도록 하고자 한 것이다.In the present invention, in the stereoselective preparation of β-methylcarbapenem intermediate, 1'β-methylcarbapenem through the reaction of the repomatsuki type with α-halopropionic acid amide represented by the general formula (III), a new stereoselective adjuvant By preparing the intermediate, the ratio of 1'β-methyl group to 1'α-methyl group is intended to be higher than that of the known art.
본 발명은 β-메틸카바페넴계 항생제의 제조를 위한 중간체로 유용한 다음 일반식(Ⅰ)로 표시되는 새로운 아제티디논 화합물과 그 제조방법에 관한 것이다.The present invention relates to a novel azetidinone compound represented by the following general formula (I), which is useful as an intermediate for the preparation of β-methylcarbapenem antibiotics, and a method for preparing the same.
위 식에서 R, R1, R2, R3, R4는 위에서 정의한 바와 같다.In the above formula, R, R 1 , R 2 , R 3 , R 4 are as defined above.
R의 하이드록시 보호기의 예로서는 저급 알콕시카보닐기, 트리저급 알킬실릴기, 4급-부틸-디메틸실릴기, 벤질옥시카보닐기, 4-나이트로벤질옥시카보닐기 등이 포함된다.Examples of the hydroxy protecting group for R include lower alkoxycarbonyl groups, trilower alkylsilyl groups, quaternary-butyl-dimethylsilyl groups, benzyloxycarbonyl groups, 4-nitrobenzyloxycarbonyl groups and the like.
위 일반식(Ⅰ)의 화합물 중에서 가장 바람직한 화합물은 R이 4급-부틸-디메틸실릴기이고 R1및 R2는 같이 연결되어 사이클로헥실기를 나타내고, R3는 메틸에스테르기, R4는 벤젠고리인 일반식(Ⅰ)의 화합물이다.Among the compounds of the general formula (I), the most preferable compound is R is a quaternary-butyl-dimethylsilyl group, R 1 and R 2 are linked together to represent a cyclohexyl group, R 3 is a methyl ester group, and R 4 is benzene It is a compound of general formula (I) which is a ring.
일반식(Ⅰ)의 아제티디논 화합물의 염의 예는 무기산 부가염 및 유기산 부가염을 포함한다. 무기산 부가염의 예로는 하이드로클로라이드, 하이드로브로마이드 또는 설페이트 등을 사용할 수 있으며, 유기산 부가염의 예로는 아세테이트, 옥살레이트, 타르트레이트, 푸마레이트, 말리에이트 또는 벤젠설포네이트 등을 사용할 수 있다.Examples of the salt of the azetidinone compound of general formula (I) include inorganic acid addition salts and organic acid addition salts. Examples of the inorganic acid addition salt may include hydrochloride, hydrobromide or sulfate, and examples of the organic acid addition salt may include acetate, oxalate, tartrate, fumarate, maleate or benzenesulfonate.
또한 아제티디논 화합물(Ⅰ)은 1' 위치에 β-메틸기(R 배향)와 α-메틸기(S 방향)의 입체 이성질체가 포함될 수 있다.In addition, the azetidinone compound (I) may include stereoisomers of β-methyl group (R orientation) and α-methyl group (S direction) at the 1 'position.
일반식(Ⅰ)의 화합물의 제조방법은 다음과 같다.The manufacturing method of the compound of general formula (I) is as follows.
일반식(Ⅰ)의 화합물은 다음 일반식(Ⅱ)의 4-아세톡시-아제티디논 화합물과 다음 일반식(Ⅲ)의 α-할로프로피온산아마이드 화합물을 반응시켜 제조한다.The compound of the general formula (I) is prepared by reacting the 4-acetoxy-azetidinone compound of the following general formula (II) with the α-halopropionic acid amide compound of the following general formula (III).
위 식에서 R, R1, R2, R3, R4, X는 위에서 정의한 바와 같다.In the above formula, R, R 1 , R 2 , R 3 , R 4 , X are as defined above.
α-할로프로피온산아마이드(Ⅲ)와 아제티디논 화합물(Ⅱ)과의 반응은 비극성 용매 중에서 그리냐드(Grignard) 형태의 반응에 사용하는 금속이나, 입체 선택 보조제로 사용한 일반식(Ⅲ)의 화합물과 금속착화물을 잘 만들 수 있는 금속 등을 사용할 수 있으며, 그 예로서 아연, 마그네슘 등을 들 수 있다. 반응 용매로는 테트라하이드로퓨란, 톨루엔, 크실렌, 디메틸포름아마이드, 디메틸설폭사이드 중에서 선택하여 사용할 수 있다.The reaction of α-halopropionic acid amide (III) with an azetidinone compound (II) is a metal used for the reaction of Grignard type in a nonpolar solvent, or a compound of the general formula (III) used as a steric selection aid. Metals and the like, which can make metal complexes well, can be used, and examples thereof include zinc and magnesium. The reaction solvent may be selected from tetrahydrofuran, toluene, xylene, dimethylformamide and dimethyl sulfoxide.
일반식(Ⅲ)의 α-할로프로피온산아마이드 화합물은 일반식(Ⅱ)의 화합물에 대하여 1∼3 몰을 사용하며, 바람직하게는 1.2∼1.7 몰을 사용한다. 금속은 아연을 사용할 경우 2∼4 몰을 사용할 수 있다. 마그네슘을 사용할 경우에는 일반식(Ⅲ)의 화합물에 요오드화메틸 또는 1,2-디브로모에탄을 가하여 미리 그리냐드 형태의 화합물을 제조한 후 위의 반응을 수행한다. 이 반응은 -10∼100℃에서 수행하며, 특히 아연금속을 사용할 때에는 50∼80℃가 적당하며, 마그네슘을 사용할 때에는 0∼30℃에서 수행한다. 이 반응에서 루이스산 촉매(예로서 브롬화아연, 트리에틸보란, 트리메틸실릴클로라이드, 마그네슘브로마이드)를 0.01∼1 몰을 사용하면 반응이 촉진되어 반응시간을 단축시킬 수 있다.As for the (alpha) -halopropionic acid amide compound of general formula (III), 1-3 mol is used with respect to the compound of general formula (II), Preferably 1.2-1.7 mol is used. The metal may be 2 to 4 moles when using zinc. When magnesium is used, methyl iodide or 1,2-dibromoethane is added to the compound of general formula (III) to prepare a Grignard compound in advance, and the above reaction is performed. The reaction is carried out at -10 to 100 DEG C, in particular 50 to 80 DEG C when using zinc metal, and at 0 to 30 DEG C when using magnesium. In this reaction, when 0.01-1 mol of a Lewis acid catalyst (for example, zinc bromide, triethyl borane, trimethylsilyl chloride, magnesium bromide) is used, reaction can be accelerated | stimulated and a reaction time can be shortened.
또, 본 발명은 새로운 입체 선택 보조제인 일반식(Ⅲ)의 화합물인 α-할로프로피온산아마이드에 관한 것이다.Moreover, this invention relates to the alpha-halopropionic acid amide which is a compound of general formula (III) which is a new stereoselective adjuvant.
일반식(Ⅲ)의 화합물을 사용하여 입체 선택성이 우수하게 일반식(Ⅰ)의 화합물을 제조할 수 있다.The compound of general formula (I) can be manufactured excellent in stereoselectivity using the compound of general formula (III).
위 식에서 R1, R2, R3, R4, X는 위에서 정의한 바와 같다.In the above formula, R 1 , R 2 , R 3 , R 4 , X are as defined above.
또, 본 발명은 일반식(Ⅷ)의 모노사이클릭 화합물과 일반식(Ⅸ)의 2-할로프로피온산 또는 그 활성화물을 반응시켜 새로운 일반식(Ⅲ)의 α-할로프로피온산아마이드 화합물을 제조하는 방법에 관한 것이다.The present invention also provides a method for preparing a new α-halopropionamide compound of general formula (III) by reacting a monocyclic compound of general formula (III) with 2-halopropionic acid of general formula or an activator thereof. It is about.
위 식에서 R1, R2, R3, R4, X는 위에서 정의한 바와 같다.In the above formula, R 1 , R 2 , R 3 , R 4 , X are as defined above.
일반식(Ⅷ)의 모노사이클릭 화합물과 일반식(Ⅸ)의 2-할로프로피온산의 반응은 비극성 용매 중에서 탈수제의 존재하에서 수행하며, 용매로는 에틸에테르, 디클로로메탄, 클로로포름, 벤젠, 톨루엔, 테트라하이드로퓨란, 아세토니트릴 등에서 선택하여 사용할 수 있으며, 탈수제로는 카보닐디이미다졸, 디사이클로로카보디아마이드, 1-하이드록시벤즈이미다졸 등에서 선택 사용할 수 있다. 이 반응은 -10℃에서 50℃에서 수행하며 0℃ 내지 -25℃가 바람직하다.The reaction of the monocyclic compound of general formula and 2-halopropionic acid of general formula is carried out in the presence of a dehydrating agent in a nonpolar solvent. As a solvent, ethyl ether, dichloromethane, chloroform, benzene, toluene, tetra Hydrofuran, acetonitrile and the like can be selected and used, and as a dehydrating agent can be selected from carbonyldiimidazole, dicyclochlorocarbamide, 1-hydroxybenzimidazole and the like. This reaction is carried out at -10 ° C to 50 ° C, preferably 0 ° C to -25 ° C.
또한 이 반응에서 2-할로프로피온산의 해당 활성화물로 산 할라이드, 혼합산무수물을 사용하고 염기의 존재하에서 일반식(Ⅷ)의 모노사이클릭 화합물과 반응시켜서 제조할 수도 있다. 용매는 위의 반응에서 사용한 용매를 선택하여 사용할 수 있으며, 염기로는 알카리 금속, 저급 알킬리티움, 피리딘, 디-저급 알킬아닐린에서 선택 사용할 수 있다. 반응은 -20∼30℃에서 수행하는 것이 좋다.In this reaction, an acid halide or mixed acid anhydride may be used as the corresponding activator of 2-halopropionic acid, and the reaction may be prepared by reacting with a monocyclic compound of the general formula in the presence of a base. The solvent may be used by selecting a solvent used in the above reaction, and may be selected from alkali metal, lower alkylityium, pyridine, di-lower alkylaniline as the base. The reaction is preferably carried out at -20 to 30 ℃.
또, 본 발명은 일반식(Ⅴ)로 표시되는 β-메틸카바페넴 에스테르 화합물의새로운 제조방법에 관한 것이다.Moreover, this invention relates to the new manufacturing method of the (beta) -methyl carbapenem ester compound represented by General formula (V).
즉, 일반식(Ⅰ)의 화합물과 일반식(Ⅹ)의 아세트산 화합물을 반응시켜 일반식(ⅩⅠ)의 N-치환 아제티디논 화합물을 얻고 이를 고리화 반응 및 에스테르화 반응을 in situ로 진행시켜 일반식(Ⅴ)의 화합물을 제조하는 새로운 방법에 관한 것이다.That is, the compound of general formula (I) is reacted with an acetic acid compound of general formula (VII) to obtain an N-substituted azetidinone compound of general formula (XI), which is subjected to a cyclization reaction and an esterification reaction in situ. It relates to a new process for the preparation of compounds of general formula (V).
위 식에서 R, R1, R2, R3, R4, R5, X, OA는 위에서 정의한 바와 같다.In the above formula, R, R 1 , R 2 , R 3 , R 4 , R 5 , X, OA are as defined above.
일반식(Ⅰ)의 화합물과 일반식(Ⅹ)의 화합물과의 반응은 염기의 존재 하에서 비극성 용매를 사용하여 진행시킨다.The reaction between the compound of formula (I) and the compound of formula (VII) is carried out using a nonpolar solvent in the presence of a base.
염기로는 유기염기로 1,8-디아자바이사이클로[5,4,0]운데크-7-엔, 알칼리 금속 염기로 알칼리 금속하이드라이드, 알칼리 금속 하이드록사이드 또는 알칼리 금속 카보네이트, 아민의 금속 염으로 소디움아마이드, 리티움 디아이소프로필아마이드, 소디움 비스(트리메틸실릴)아마이드 등을 사용하고 용매로는 테트라하이드로퓨란, 벤젠, 톨루엔, 디클로로메탄 등을 사용하며, 반응은 -50℃에서 -20℃에서 수행한다.The base is an organic base with 1,8-diazabicyclo [5,4,0] undec-7-ene, an alkali metal base with alkali metal hydride, alkali metal hydroxide or alkali metal carbonate, amine metal salt Sodium amide, lithium diisopropylamide, sodium bis (trimethylsilyl) amide, and the like are used as a solvent, and tetrahydrofuran, benzene, toluene, dichloromethane and the like are used, and the reaction is performed at -20 ° C to -20 ° C. To perform.
일반식(Ⅰ)의 화합물과 일반식(Ⅹ)의 화합물과의 반응으로 얻어진 일반식(ⅩⅠ)의 화합물을 고리화 반응 및 에스테르화 반응을 in situ로 진행시켜 일반식(Ⅴ)의 화합물을 제조한다.The compound of general formula (VII) was subjected to a cyclization reaction and an esterification reaction in situ by the reaction of the compound of general formula (I) with the compound of general formula (VII) to prepare a compound of general formula (V). do.
일반식(ⅩⅠ)의 N-치환 아제티디논 화합물의 고리화 반응은 염기의 존재 하에서 수행할 수 있다. 염기로는 디크만형(Dieckmann-type) 반응에 사용되는 염기를 사용할 수 있으며, 그 예로서 소디움 비스(트리메틸실릴)아마이드, 리티움 비스(트리메틸실릴)아마이드 등의 알칼리 금속염을 들 수 있다. 염기의 사용량은 일반식(ⅩⅠ)의 화합물에 대하여 1.0에서 3.0 당량을 사용할 수 있으며, 바람직하게는 2.0에서 2.5 당량이 적당하다.The cyclization reaction of the N-substituted azetidinone compound of formula (XI) can be carried out in the presence of a base. As a base, the base used for a Dieckmann-type reaction can be used, As an example, Alkali metal salts, such as sodium bis (trimethylsilyl) amide and a lithium bis (trimethylsilyl) amide, are mentioned. The base may be used in an amount of 1.0 to 3.0 equivalents, preferably 2.0 to 2.5 equivalents, based on the compound of formula (XI).
사용되는 용매로는 테트라하이드로퓨란, 에틸에테르, 디옥산, 톨루엔, 벤젠 등이다. 반응은 -78℃에서 50℃에서 수행할 수 있으며, 바람직하게는 -60℃에서 10℃가 적당하다. 이때 생성되는 화합물은 일반식(ⅩⅢ)로 표시되는 엔올레이트염이 생성되고, 이를 따로 분리하지 않고 에스테르화 반응을 진행시킨다.The solvent used is tetrahydrofuran, ethyl ether, dioxane, toluene, benzene and the like. The reaction can be carried out at -78 ° C to 50 ° C, preferably -60 ° C to 10 ° C. At this time, the compound produced is an oleate salt represented by the general formula (XIII), and the esterification reaction proceeds without being separated.
위 식에서 R, R5는 위에서 정의한 바와 같고 M+는 알칼리 금속이온을 의미한다.In the above formula, R and R 5 are as defined above, and M + means an alkali metal ion.
분자내 고리화 반응에 의하여 생성된 일반식(ⅩⅢ)의 화합물의 하이드록시염에 에스테르화 반응을 해당 활성화물을 작용시켜 연속하여 진행시킬 수 있다. 해당활성화물로는 디-아릴포스페이트(예로서 디페닐포스페이트), 디 저급 일킬포스페이트(예로서 디에틸포스페이트) 등의 활성화물(즉 해당 산염화물, 해당 산 무수물)을 사용할 수 있다. 또한 이 반응에서 에스테르화제의 활성화물은 일반식(ⅩⅠ)의 화합물에 대하여 1.0에서 4.0 당량을 사용할 수 있으며, 바람직하게는 2.0에서 3.0 당량을 사용할 수 있다. 반응온도는 -78℃에서 30℃가 적당하며, 특히 -60℃에서 10℃가 바람직하다.The esterification reaction can be carried out continuously by reacting the corresponding activator with the hydroxy salt of the compound of the general formula (XIII) produced by the intramolecular cyclization reaction. As the corresponding activator, an activator such as di-aryl phosphate (for example diphenyl phosphate) and di lower yl phosphate (for example diethyl phosphate) can be used (ie, corresponding acid chloride, corresponding acid anhydride). In this reaction, the activator of the esterification agent may be used in the amount of 1.0 to 4.0 equivalents, preferably 2.0 to 3.0 equivalents, based on the compound of formula (XI). The reaction temperature is preferably -78 ° C to 30 ° C, particularly preferably -60 ° C to 10 ° C.
이 반응에서 분자내 고리화 반응 후 단리시키지 않고 이어서 에스테르화 반응을 진행시킬 때 염기를 가한 후 여기에 실릴화물을 가하여 진행시킬 수 있다. 실릴화물로는 트리메틸실릴 클로라이드,t-부틸디메틸실릴 클로라이드, 테트라클로로실란 등을 사용할 수 있다.In this reaction, after the intramolecular cyclization reaction is isolated, the base can be added to proceed with the esterification reaction, and then silylide can be added thereto. Examples of the silicides include trimethylsilyl chloride, t -butyldimethylsilyl chloride, tetrachlorosilane, and the like.
또한 에스테르화 반응에서 반응 촉매로 4-디메틸아미노피리딘을 사용하는 것이 반응시간을 단축시킬 수 있다. 이 촉매의 사용량은 일반식(ⅩⅠ)의 화합물에 대하여 0.01에서 0.5 당량을 사용할 수 있으며, 좋게는 0.05에서 0.1 당량을 사용한다. 분자내 고리화 반응을 시킬때 부산물로 일반식(Ⅷ)의 화합물이 얻어지며 이 화합물은 회수하여 입체 선택 보조제인 일반식(Ⅲ)의 화합물로 만들어 재사용이 가능하다.In addition, the use of 4-dimethylaminopyridine as a reaction catalyst in the esterification reaction can shorten the reaction time. The amount of the catalyst used may be 0.01 to 0.5 equivalents based on the compound of formula (XI), preferably 0.05 to 0.1 equivalents. When the intramolecular cyclization reaction is carried out, a compound of the general formula (Ⅷ) is obtained as a by-product, and the compound is recovered and reused as a compound of the general formula (III) as a stereoselective aid.
또, 본 발명은 일반식(Ⅳ)로 표시되는 1'β-메틸아제티디논 화합물의 새로운 제조방법에 관한 것이다.Moreover, this invention relates to the new manufacturing method of the 1 '(beta) -methylazetidinone compound represented by general formula (IV).
즉, 일반식(Ⅰ)의 화합물을 가수분해 반응을 통하여 일반식(Ⅳ)의 화합물을 제조하는 새로운 방법에 관한 것이다.That is, the present invention relates to a new method for preparing a compound of formula (IV) through a hydrolysis reaction of a compound of formula (I).
위 식에서 R은 위에서 정의한 바와 같다.Where R is as defined above.
일반식(Ⅰ)의 화합물의 가수분해 반응은 과산화수소와 수산화 금속염의 존재 하에서 비극성 용매 중에서 수행할 수 있다. 사용되는 용매로는 물과 디옥산, 테트라하이드로퓨란, 디메틸포름아마이드, 메틸알코올 등이며, 바람직하게는 물과 테트라히드로퓨란을 사용하는 것이 유리하다. 수산화 금속염으로는 수산화리튬, 수산화나트륨, 수산화칼륨 등이며, 좋게는 수산화리튬을 사용하는 것이 바람직하다. 과산화수소의 사용량은 일반식(Ⅰ)의 화합물에 대하여 1에서 10 당량을 사용하며, 바람직하게는 6에서 8 당량을 사용한다. 수산화 금속염의 사용량은 일반식(Ⅰ)의 화합물에 대하여 1에서 5 당량을 사용할 수 있으며, 바람직하게는 2에서 3 당량이 적합하다. 반응온도는 -5℃에서 5℃가 적합하다.The hydrolysis reaction of the compound of formula (I) can be carried out in a nonpolar solvent in the presence of hydrogen peroxide and a metal hydroxide. The solvent used is water, dioxane, tetrahydrofuran, dimethylformamide, methyl alcohol and the like, and it is advantageous to use water and tetrahydrofuran. Examples of the metal hydroxide include lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like, and lithium hydroxide is preferably used. The amount of hydrogen peroxide used is 1 to 10 equivalents, preferably 6 to 8 equivalents, based on the compound of formula (I). The amount of the metal hydroxide used may be 1 to 5 equivalents based on the compound of the general formula (I), preferably 2 to 3 equivalents. The reaction temperature is suitable from -5 ℃ to 5 ℃.
본 발명의 상세한 설명이나 특허청구범위에서 표현한 약자 중에서 "저급 알킬기"와 "저급 알콕시기" 및 "저급 알킬렌기"는 탄소원자가 1에서 4개를 갖는 직쇄 또는 분지쇄를 의미하여, "저급 알케닐기"는 2에서 6개의 탄소원자를 갖는 직쇄를 나타낸다.In the abbreviations expressed in the detailed description or claims of the present invention, "lower alkyl group", "lower alkoxy group", and "lower alkylene group" mean a straight or branched chain having 1 to 4 carbon atoms, and thus "lower alkenyl group." "Represents a straight chain having 2 to 6 carbon atoms.
이와 같은 본 발명은 다음의 실시예에 의거하여 더욱 상세히 설명하겠는바 본 발명이 이에 한정되는 것은 아니다.Such the present invention will be described in more detail based on the following examples, but the present invention is not limited thereto.
제조예 1 : 메틸 3-시아노-3-페닐파이루빅산 에스테르의 제조Preparation Example 1 Preparation of Methyl 3-cyano-3-phenylpyruvic Acid Ester
페닐아세토나이트릴 46.8g을 건조된 메틸알코올 200㎖에 용해시키고 금속 나트륨 12g(또는 같은 당량의 소디움메톡사이드)을 천천히 나누어 가하였다. 이때 발열로 50℃까지 온도가 상승한다. 이 온도에서 디메틸옥살레이트 47.2g을 가하고 서서히 상온으로 냉각시켜 상온에서 18시간 동안 교반하여 주었다. 반응물을 얼음물로 냉각시키고, 2N-황산수용액 200㎖를 가한 다음 용매를 감압하에서 메탄올 용매만 농축하였다. 잔여물을 초산에틸로 2회 추출하여 망초로 건조한 후 용매를 감압하에서 농축하였다. 얻어진 노란색 결정에 노르말 헥산을 가하여 여과한 후 진공하에서 건조하여 목적화합물 66.6g(82%)을 얻었다. mp 112∼114℃ ;1H-NMR(CDCl3, 200MHz)δ1.25-1.78(s, 8H), 2.04-2.27(m, 5H), 3.58(s, 3H), 6.99(bs, 1H), 7.25-7.37(m, 5H) ; IR(CHCl3) 1242, 1402, 1736, 2939, 3070, 3200cm-1.46.8 g of phenylacetonitrile was dissolved in 200 ml of dried methyl alcohol and 12 g (or equivalent of sodium methoxide) of metal sodium were added slowly in portions. At this time, the temperature rises to 50 ° C by exothermic heat. 47.2 g of dimethyl oxalate was added at this temperature, and the mixture was slowly cooled to room temperature and stirred at room temperature for 18 hours. The reaction was cooled with ice water, 200 mL of 2N-sulfuric acid solution was added, and then the solvent was concentrated only under methanol solvent. The residue was extracted twice with ethyl acetate, dried over forget-me-not and the solvent was concentrated under reduced pressure. Normal hexane was added to the obtained yellow crystals, and the filtrate was dried under vacuum to obtain 66.6 g (82%) of the title compound. mp 112-114 degreeC; 1 H-NMR (CDCl 3 , 200 MHz) δ 1.25-1.78 (s, 8H), 2.04-2.27 (m, 5H), 3.58 (s, 3H), 6.99 (bs, 1H), 7.25-7.37 (m, 5H); IR (CHCl 3 ) 1242, 1402, 1736, 2939, 3070, 3200 cm -1 .
제조예 2 : 에틸 3-시아노-3-페닐파이루빅산 에스테르의 제조Preparation Example 2 Preparation of Ethyl 3-cyano-3-phenylpyruvic Acid Ester
제조예 1에서 디메틸옥살레이트 대신에 디에틸옥살레이트를 사용하고 반응용매를 에탄올을 사용하는 이외에 같은 방법으로 제조하여 노란색 결정의 목적화합물을 75%의 수율로 얻었다. mp 95∼97℃ ;1H-NMR(CDCl3, 200MHz)δ1.51(t, J=7.2Hz, 3H), 4.53(AB-q, J=7.2Hz, 2H), 7.26-7.48(m, 3H), 7.66-7.92(m, 2H) ; MS(70ev, m/e) 217(M+), 193, 111.Diethyl oxalate was used instead of dimethyl oxalate in Preparation Example 1, and the reaction solvent was prepared in the same manner except using ethanol to obtain the target compound of yellow crystals in a yield of 75%. mp 95-97 ° C; 1 H-NMR (CDCl 3 , 200 MHz) δ 1.51 (t, J = 7.2 Hz, 3H), 4.53 (AB-q, J = 7.2 Hz, 2H), 7.26-7.48 (m, 3H), 7.66-7.92 (m, 2H); MS (70ev, m / e) 217 (M < + & gt ; ), 193, 111.
제조예 3 : 메틸 3-시아노 -3-(4-클로로페닐)파이루빅산 에스테르의 제조Preparation Example 3 Preparation of Methyl 3-cyano-3- (4-chlorophenyl) pyruvic Acid Ester
제조예 2에서 페닐아세토나이트릴 대신에 4-클로로페닐아세토나이트릴을 사용하여 노란색 결정상의 목적화합물을 82%의 수율로 얻었다. mp 105∼107℃ ;1H-NMR(CDCl3, 200MHz)δ4.20(s, 3H), 7.49(d, J=7.6Hz, 2H), 7.91(d, J=7.8Hz, 2H) ; MS(70ev, m/e) 237(M+), 183, 135.In Example 2, 4-chlorophenylacetonitrile was used instead of phenylacetonitrile to obtain the target compound as a yellow crystal in a yield of 82%. mp 105 to 107 ° C; 1 H-NMR (CDCl 3 , 200 MHz) δ 4.20 (s, 3H), 7.49 (d, J = 7.6 Hz, 2H), 7.91 (d, J = 7.8 Hz, 2H); MS (70ev, m / e) 237 (M + ), 183, 135.
제조예 4 : 메틸 3-시아노-3-(4-메톡시페닐)파이루빅산 에스테르의 제조Preparation Example 4 Preparation of Methyl 3-cyano-3- (4-methoxyphenyl) pyruvic Acid Ester
제조예 2에서 페닐아세토나이트릴 대신에 4-메톡시페닐아세토나이트릴을 사용하여 노란색 결정상의 목적화합물을 87%의 수율로 얻었다. mp 125∼127℃ ;1H-NMR(CDCl3, 200MHz)δ3.77(s, 3H), 4.00(s, 3H), 6.85(d, J=9.2Hz, 2H), 7.76(d, J=9.2Hz, 2H) ; MS(70ev, m/e) 233(M+), 173, 145.In Example 2, instead of phenylacetonitrile, 4-methoxyphenylacetonitrile was used to obtain the target compound as a yellow crystal in a yield of 87%. mp 125-127 degreeC; 1 H-NMR (CDCl 3 , 200 MHz) δ 3.77 (s, 3H), 4.00 (s, 3H), 6.85 (d, J = 9.2 Hz, 2H), 7.76 (d, J = 9.2 Hz, 2H); MS (70ev, m / e) 233 (M + ), 173, 145.
제조예 5 : 메틸 3-시아노-3-(4-나이트로페닐)파이루빅산 에스테르의 제조Preparation Example 5 Preparation of Methyl 3-cyano-3- (4-nitrophenyl) pyruvic acid ester
제조예 2에서 페닐아세토나이트릴 대신에 4-나이트로페닐아세토나이트릴을 사용하여 진한 갈색 결정상의 목적화합물을 35%의 수율로 얻었다. mp 135∼137℃ ;1H-NMR(CDCl3, 200MHz)δ3.82(s, 3H), 7.48(d, J=8.62Hz, 2H), 8.18(d, J=8.8Hz, 2H) ; MS(70ev, m/e) 248(M+).In the preparation example 2, 4-nitrophenylacetonitrile was used instead of phenylacetonitrile to obtain the target compound in dark brown crystals in a yield of 35%. mp 135-137 ° C; 1 H-NMR (CDCl 3 , 200 MHz) δ 3.82 (s, 3H), 7.48 (d, J = 8.62 Hz, 2H), 8.18 (d, J = 8.8 Hz, 2H); MS (70ev, m / e) 248 (M + ).
제조예 6 : 메틸 4-옥소-3-페닐-1-옥사-5-아자스피로[5.5]운데크-2엔-2-카복실산 에스테르(일반식(Ⅷ)의 화합물)의 제조Preparation Example 6 Preparation of Methyl 4-oxo-3-phenyl-1-oxa-5-azaspiro [5.5] undec-2ene-2-carboxylic acid ester (compound of general formula)
메틸 3-시아노-3-페닐파이루빅산 에스테르 52.5g을 빙초산 97㎖에 가하고 이어서 10℃에서 사이클로헥사논 29.4g 및 무수아세트산 32.7㎖를 차례로 가하였다. 동 온도에서 빙초산 97㎖에 농황산 48㎖를 녹인 용액을 천천히 가하고 서서히 상온으로 올려서 2시간 동안 교반하였다. 반응액을 빙냉한 후 물 100㎖를 가하고 10분간 교반하였다. 생성된 침전을 여과하여 노르말헥산 : 초산에틸 = 1:1 혼합용액으로 세척하고 헥산으로 각각 세척하여 진공하에서 건조하여 미색 고체상의 순수한 목적화합물 67g(82%)을 얻었다. mp 170∼172℃ ;1H-NMR(CDCl3, 200MHz)δ3.89(s,3H), 7.22-7.26(m, 5H), 7.77(d, 1H) ; IR(CHCl3) 1438, 1719, 2224, 3191cm-1.52.5 g of methyl 3-cyano-3-phenylpyruvic acid ester was added to 97 ml of glacial acetic acid, followed by 29.4 g of cyclohexanone and 32.7 ml of acetic anhydride at 10 ° C in turn. At the same temperature, a solution of 48 ml of concentrated sulfuric acid dissolved in 97 ml of glacial acetic acid was slowly added thereto, and slowly raised to room temperature, followed by stirring for 2 hours. After the reaction solution was ice-cooled, 100 ml of water was added thereto, followed by stirring for 10 minutes. The resulting precipitate was filtered, washed with a mixture of normal hexane: ethyl acetate = 1: 1, washed with hexane, and dried under vacuum to obtain 67 g (82%) of the pure target compound as an off-white solid. mp 170-172 degreeC; 1 H-NMR (CDCl 3 , 200 MHz) δ 3.89 (s, 3H), 7.22-7.26 (m, 5H), 7.77 (d, 1H); IR (CHCl 3 ) 1438, 1719, 2224, 3191 cm −1 .
제조예 7-14 : 일반식(Ⅷ)의 화합물의 제조Preparation Example 7-14: Preparation of a Compound of Formula (VII)
해당되는 제조예 화합물을 출발물질로 사용하고 해당되는 케톤화합물을 제조예 6의 방법으로 반응시켜 다음 표 1의 화합물들을 제조하였다.The compound of Preparation Example 1 was used as a starting material and the corresponding ketone compound was reacted by the method of Preparation Example 6 to prepare the compounds of Table 1 below.
실시예 1 : 메틸 5-(2-브로모프로피오닐)-4-옥소-3-페닐-1-옥사-5-아자스피로[5.5]운데크-2-엔-2-카복실산 에스테르(일반식(Ⅲ)의 화합물)의 제조Example 1 Methyl 5- (2-bromopropionyl) -4-oxo-3-phenyl-1-oxa-5-azaspiro [5.5] undec-2-ene-2-carboxylic acid ester Preparation of the compound of III)
메틸 4-옥소-3-페닐-1-옥사-5-아자스피로[5.5]운데크-2-엔-2-카복실산 에스테르 12.2g을 무수 테트라하이드로퓨란 60㎖에 용해시키고 -10℃로 냉각시킨 후 피리딘 4.26㎖를 가하고 이어서 2-브로모아세틸브로마이드 5.52㎖를 서서히 가하였다. 반응액을 상온으로 올려서 6시간 동안 교반하여 반응을 완결하였다. 반응액에 물을 가하여 희석하고 초산에틸 100㎖씩 2회 추출하고 유기층을 합하여 10% 중조 수용액으로 세척하여 준 후 망초로 건조하여 용매를 감압하에서 농축하였다. 잔여물에 아이소프로필알코올 50㎖를 가하여 잠시 교반하여 주면 결정화된다. 생성된 결정을 여과한 다음 아이소프로필알코올 10㎖씩 2회 세척하고 노르말헥산으로 세척하여 준 후 진공하에서 건조하여 미색의 고체상의 목적화합물 16.1g(92%)을 얻었다. mp 104∼105℃ ;1H-NMR(CDCl3, 200MHz)δ1.11-12.66(m, 10H), 1.84(d, J=6.6Hz, 3H), 3.64(s, 3H), 5.06(q, J=6.8Hz, 1H), 3H), 7.21-7.41(m, 5H) ; IR(CHCl3) 1384, 1445, 1675, 1631, 1735, 2866, 2940cm-1.12.2 g of methyl 4-oxo-3-phenyl-1-oxa-5-azaspiro [5.5] undec-2-ene-2-carboxylic acid ester was dissolved in 60 ml of anhydrous tetrahydrofuran and cooled to -10 deg. 4.26 mL of pyridine was added followed by the slow addition of 5.52 mL of 2-bromoacetylbromide. The reaction solution was raised to room temperature and stirred for 6 hours to complete the reaction. Water was added to the reaction mixture to dilute it, and 100 ml of ethyl acetate was extracted twice. The organic layers were combined, washed with 10% aqueous sodium bicarbonate solution, dried over forget-me-not, and the solvent was concentrated under reduced pressure. 50 ml of isopropyl alcohol is added to the residue, followed by stirring for a while to crystallize. The resulting crystals were filtered, washed twice with 10 ml of isopropyl alcohol, washed with normal hexane, and dried under vacuum to obtain 16.1 g (92%) of the target compound as an off-white solid. mp 104-105 ° C; 1 H-NMR (CDCl 3 , 200 MHz) δ1.11-12.66 (m, 10H), 1.84 (d, J = 6.6 Hz, 3H), 3.64 (s, 3H), 5.06 (q, J = 6.8 Hz, 1H ), 3H), 7.21-7.41 (m, 5H); IR (CHCl 3 ) 1384, 1445, 1675, 1631, 1735, 2866, 2940 cm -1 .
실시예 2-9 : 일반식(Ⅲ)의 화합물의 제조Example 2-9: Preparation of a Compound of Formula (III)
해당 출발물질과 2-브로모아세틸브로마이드를 실시예 1의 방법에 따라 각각 반응시켜 표 2의 화합물들을 제조하였다.The compounds of Table 2 were prepared by reacting the starting materials with 2-bromoacetylbromide according to the method of Example 1, respectively.
실시예 10 : 메틸 5-{(2R)-2-[(3S, 4R)-3-[(1R)-1-t-부틸디메틸실릴옥시에틸]-2-옥소-아제티딘-4-일]프로피오닐}-4-옥소-3-페닐-1-옥사-5-아자스피로[5.5]운데크-2-엔-2-카복실산 에스테르(일반식(Ⅰ)의 화합물)의 제조Example 10 Methyl 5-{(2R) -2-[(3S, 4R) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -2-oxo-azetidin-4-yl] Preparation of propionyl} -4-oxo-3-phenyl-1-oxa-5-azaspiro [5.5] undec-2-ene-2-carboxylic acid ester (compound of formula (I))
(3R, 4R)-4-아세톡시-3-[(1R)-1-t-부틸디메틸실릴옥시에틸]-2-아제티디논 5g을 무수 테트라하이드로퓨란 60㎖에 용해시키고, 아연분말 3.41g을 가하여 20분간 환류시켰다. 반응액을 상온으로 냉각시키고 메틸 5-(2-브로모프로피오닐)-4-옥소-3-페닐-1-옥사-5-아자스피로[5.5]운데크-2-엔-2-카복실산 에스테르 8.33g을 무수 테트라하이드로퓨란 20㎖에 용해시킨 용액을 천천히 가하였다. 다시 가열하여 2시간 동안 환류시켰다. 반응액을 상온으로 냉각시키고 포스페이트 완충용액(pH=7.0)을 가한 후 생성된 불용물을 여과하여 제거하고 여액을 초산에틸로 2회 추출하였다. 유기층을 망초로 건조하여 잔류물을 실리카겔 칼럼 크로마토그라피(용리제; 초산에틸:헥산=1:4)로 정제하여 목적화합물 9.92g(97%)을 얻었다.5 g of (3R, 4R) -4-acetoxy-3-[(1R) -1-t-butyldimethylsilyloxyethyl] -2-azetidinone is dissolved in 60 ml of anhydrous tetrahydrofuran and 3.41 g of zinc powder It was added to reflux for 20 minutes. The reaction solution was cooled to room temperature and methyl 5- (2-bromopropionyl) -4-oxo-3-phenyl-1-oxa-5-azaspiro [5.5] undec-2-ene-2-carboxylic acid ester 8.33 A solution of g dissolved in 20 ml of anhydrous tetrahydrofuran was slowly added. Heated again to reflux for 2 hours. The reaction solution was cooled to room temperature, phosphate buffer solution (pH = 7.0) was added, the produced insolubles were filtered off, and the filtrate was extracted twice with ethyl acetate. The organic layer was dried over forget-me-not and the residue was purified by silica gel column chromatography (eluent; ethyl acetate: hexane = 1: 4) to obtain 9.92 g (97%) of the title compound.
얻어진 목적화합물 중에는 상기 반응식에서 표시된 1' 위치의 입체 이성질체 1'R과 1'S의 혼합물이 존재하며, HPLC(Capcll park C-18컬럼, 용리제; 아세토니트릴:물=7:3)로 분석한 결과 1'R 이성체 : 1'S 이성체 = 95 : 5의 비율로 나타났다. mp 68∼70℃ ;1H-NMR(CDCl3, 200MHz)δ0.00(s, 6H), 0.80(s, 9H), 1.11(d, J=6.4Hz, 3H), 1.16(d, J=7.0Hz, 3H), 1.52-1.81(m, 6H), 2.02-2.41(m, 4H), 2.79-2.82(m, 1H, 1'S-H), 3.12-3.16(m, 1H, 1'R-H), 3.12-3.16(m, 1H), 3.37-3.44(m, 1H), 3.57(s, 3H), 3.85-3.89(m, 1H), 5.09(s, 1H), 3H), 7.13-7.21(m, 2H), 7.25-7.35(m, 3H) ; IR(CHCl3) 1377, 1447, 1633, 1678, 1758, 2857, 2949cm-1.Among the target compounds obtained, a mixture of stereoisomers 1'R and 1'S in the 1 'position shown in the above scheme was present, and analyzed by HPLC (Capcll park C-18 column, eluent; acetonitrile: water = 7: 3). 1'R isomer: 1'S isomer = 95: 5 ratio was shown. mp 68-70 ° C .; 1 H-NMR (CDCl 3 , 200 MHz) δ 0.00 (s, 6H), 0.80 (s, 9H), 1.11 (d, J = 6.4 Hz, 3H), 1.16 (d, J = 7.0 Hz, 3H), 1.52-1.81 (m, 6H), 2.02-2.41 (m, 4H), 2.79-2.82 (m, 1H, 1'S-H), 3.12-3.16 (m, 1H, 1'RH), 3.12-3.16 (m, 1H), 3.37-3.44 (m, 1H), 3.57 (s, 3H), 3.85-3.89 (m, 1H), 5.09 (s, 1H), 3H), 7.13-7.21 (m, 2H), 7.25-7.35 (m, 3H); IR (CHCl 3 ) 1377, 1447, 1633, 1678, 1758, 2857, 2949 cm −1 .
실시예 11-16 : 일반식(Ⅰ)의 화합물 제조Example 11-16: Preparation of Compound of Formula (I)
해당 출발물질과 (3R, 4R)-4-아세톡시-3-[(1R)-1-t-부틸디메틸실릴옥시에틸] -2-아제티디논을 실시예 10의 방법과 동일한 방법으로 각각 반응시켜 표 3의 화합물들을 제조하였다.Reaction of this starting material with (3R, 4R) -4-acetoxy-3-[(1R) -1-t-butyldimethylsilyloxyethyl] -2-azetidinone in the same manner as in Example 10 To prepare the compounds of Table 3.
실시예 17 : 메틸 5-{(2R)-2-[(3S, 4R)-3-[(1R)-1-t-부틸디메틸실릴옥시에틸]-2-옥소-아제티딘-4-일]프로피오닐}-4-옥소-3-페닐-1-옥사-5-아자스피로[5.5]운데크-2-엔-2-카복실산 에스테르(일반식(Ⅰ)의 화합물)의 제조Example 17 Methyl 5-{(2R) -2-[(3S, 4R) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -2-oxo-azetidin-4-yl] Preparation of propionyl} -4-oxo-3-phenyl-1-oxa-5-azaspiro [5.5] undec-2-ene-2-carboxylic acid ester (compound of formula (I))
실시예 10의 화합물의 다른 제조방법으로서 무수 테트라하이드로퓨란 15㎖에소량의 요오드를 가하고 655mg의 마그네슘 조각을 넣은 후 1,2-디브로모에탄 1.13g을 천천히 첨가하였다. 반응액이 발열반응으로 환류온도까지 올라갔다. 이때 1,2-디브로모에탄 2.26g을 테트라하이드로퓨란 4.5㎖에 녹인 용액을 천천히 가하고 30분간 환류시켰다. 이 혼합물을 5℃로 냉각시키고 (3R, 4R)-4-아세톡시-3-[(1R)-1-t-부틸디메틸실릴옥시에틸]-2-아제티디논 1.72g과 메틸 5-(2-브로모프로피오닐)-4-옥소-3-페닐-1-옥사-5-아자스피로[5.5]운데크-2-엔-2-카복실산 에스테르 2.88g을 테트라하이드로퓨란 8㎖에 용해시킨 것을 천천히 가하였다. 반응액을 10℃에서 1시간 동안 교반하여 준 후 포화 염화암모늄 수용액 90㎖를 가하여 반응을 중지시키고, 초산에틸로 추출하였다. 추출물을 소금물로 세척하여 망초로 건조하고 감압하에서 농축하였다. 잔여물을 실리카겔 칼럼 크로마토그라피로(용리제; 초산에틸:헥산=1:4)로 정제하여 목적화합물 3.07g(88%)을 얻었다. 이 화합물은 실시예 2의 화합물과 동일한 물질이고, HPLC(실시예 10에서와 같은 조건)로 분석한 결과 1'R-이성질체 : 1'S-이성질체 = 98 : 2의 혼합물이었다.As another method for preparing the compound of Example 10, a small amount of iodine was added to 15 ml of anhydrous tetrahydrofuran, 655 mg of magnesium flakes were added, and 1.13 g of 1,2-dibromoethane was added slowly. The reaction solution rose to the reflux temperature due to exothermic reaction. At this time, a solution obtained by dissolving 2.26 g of 1,2-dibromoethane in 4.5 ml of tetrahydrofuran was slowly added and refluxed for 30 minutes. The mixture was cooled to 5 ° C., 1.72 g of (3R, 4R) -4-acetoxy-3-[(1R) -1-t-butyldimethylsilyloxyethyl] -2-azetidinone and methyl 5- (2 Bromopropionyl) -4-oxo-3-phenyl-1-oxa-5-azaspiro [5.5] undec-2-ene-2-carboxylic acid ester was dissolved in 8 ml of tetrahydrofuran slowly Was added. The reaction solution was stirred at 10 ° C. for 1 hour, and then 90 ml of saturated aqueous ammonium chloride solution was added to stop the reaction, followed by extraction with ethyl acetate. The extract was washed with brine, dried over forget-me-not and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate: hexane = 1: 4) to obtain 3.07 g (88%) of the title compound. This compound was the same material as the compound of Example 2, and analyzed by HPLC (same conditions as in Example 10), and found to be a mixture of 1'R-isomer: 1'S-isomer = 98: 2.
실시예 18 : 메틸 5-{(2R)-2-[(3S, 4R)-1-알릴옥시카보닐메틸-3-[(1R)-1-t-부틸디메틸실릴옥시에틸]-2-옥소-아제티딘-4-일]프로피오닐}-4-옥소-3-페닐-1-옥사-5-아자스피로[5.5]운데크-2-엔-2-카복실산 에스테르(일반식(ⅩⅠ)의 화합물)의 제조Example 18 Methyl 5-{(2R) -2-[(3S, 4R) -1-allyloxycarbonylmethyl-3-[(1R) -1-t-butyldimethylsilyloxyethyl] -2-oxo -Azetidin-4-yl] propionyl} -4-oxo-3-phenyl-1-oxa-5-azaspiro [5.5] undec-2-ene-2-carboxylic acid ester (compound of formula (XI)) Manufacturing
메틸 5-{(2R)-2-[(3S, 4R)-3-[(1R)-1-t-부틸디메틸실릴옥시에틸]-2-옥소아제티딘-4-일]프로피오닐}-4-옥소-3-페닐-1-옥사-5-아자스피로[5.5]운데크-2-엔-2-카복실산 에스테르 5.0g을 무수 테트라하이드로퓨란 50㎖에 용해시키고 -60℃로 냉각시킨 후 질소기류하에서 알릴브로모아세테이트 1.53g을 가하고 이어서 소디움 비스(트리메틸실릴)아마이드(1몰의 테트라하이드로퓨란 용액) 9.76㎖를 천천히 가하였다. 동 온도에서 15분간 교반하여 준 후 서서히 온도를 올려서 -30℃에서 40분간 더 교반하여 주었다. 반응액에 물을 가하고 초산에틸로 추출하여 망초로 건조하여 감압하에서 농축하였다. 잔여물을 실리카겔 칼럼 크로마토그라피(용리제; 초산에틸:헥산=1:4)로 정제하여 유상의 목적화합물 4.89g(88%)을 얻었다.1H-NMR(CDCl3, 200MHz)δ0.08(s, 6H), 0.86(s, 9H), 1.24(d, J=4.0Hz, 3H), 1.27(d, J=3.0Hz, 3H), 1.62-2.24(m, 10H), 3.01(dd, J=7.6, 2.0Hz, 1H), 3.43-3.58(m, 1H), 3.63(s, 3H), 3.88-4.01(m, 2H), 5.21-5.39(m, 2H), 5.80-6.01(m, 1H), 7.19-7.39(m, 5H) ; IR(CHCl3) 1377, 1447, 1680, 1678, 1745, 2252, 2948cm-1.Methyl 5-{(2R) -2-[(3S, 4R) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionyl}- 5.0 g of 4-oxo-3-phenyl-1-oxa-5-azaspiro [5.5] undec-2-ene-2-carboxylic acid ester was dissolved in 50 ml of anhydrous tetrahydrofuran and cooled to -60 DEG C, followed by nitrogen 1.53 g of allylbromoacetate was added under airflow, followed by slowly adding 9.76 mL of sodium bis (trimethylsilyl) amide (1 mol of tetrahydrofuran solution). After stirring at the same temperature for 15 minutes, the temperature was gradually raised and further stirred at -30 ° C for 40 minutes. Water was added to the reaction solution, extraction was performed with ethyl acetate, dried over forget-me-not and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate: hexane = 1: 4) to obtain 4.89 g (88%) of the target compound in the oil phase. 1 H-NMR (CDCl 3 , 200 MHz) δ 0.08 (s, 6H), 0.86 (s, 9H), 1.24 (d, J = 4.0 Hz, 3H), 1.27 (d, J = 3.0 Hz, 3H), 1.62-2.24 (m, 10H), 3.01 (dd, J = 7.6, 2.0 Hz, 1H), 3.43-3.58 (m, 1H), 3.63 (s, 3H), 3.88-4.01 (m, 2H), 5.21- 5.39 (m, 2 H), 5.80-6.01 (m, 1 H), 7.19-7.39 (m, 5 H); IR (CHCl 3 ) 1377, 1447, 1680, 1678, 1745, 2252, 2948 cm -1 .
실시예 19 : 메틸 5-{(2R)-2-[(3S, 4R)-1-(4-메톡시벤질옥시카보닐메틸)-3-[(1R)-1-t-부틸디메틸실릴옥시에틸]-2-옥소-아제티딘-4-일]프로피오닐}-4-옥소-3-페닐-1-옥사-5-아자스피로[5.5]운데크-2-엔-2-카복실산 에스테르(일반식(ⅩⅠ)의 화합물)의 제조Example 19 Methyl 5-{(2R) -2-[(3S, 4R) -1- (4-methoxybenzyloxycarbonylmethyl) -3-[(1R) -1-t-butyldimethylsilyloxy Ethyl] -2-oxo-azetidin-4-yl] propionyl} -4-oxo-3-phenyl-1-oxa-5-azaspiro [5.5] undec-2-ene-2-carboxylic acid ester (general Preparation of the compound of formula (XI)
메틸 5-{(2R)-2-[(3S, 4R)-3-[(1R)-1-t-부틸디메틸실릴옥시에틸]-2-옥소-아제티딘-4-일]프로피오닐}-4-옥소-3-페닐-1-옥사-5-아자스피로[5.5]운데크-2-엔-2-카복실산 에스테르 3.0g과 알릴브로모아세테이트 대신에 4-메톡시벤질브로모아세테이트를 사용하여 실시예 18과 동일하게 처리하여 유상의 목적화합물 3.23g(83%)을 얻었다.1H-NMR(CDCl3, 200MHz)δ0.06(s, 6H), 0.86(s, 9H), 1.23(d, J=5.2Hz, 3H), 1.27(d, J=6.2Hz, 3H), 1.48-1.68(m, 5H), 2.04-2.21(m, 5H), 3.02(dd, J=7.4, 2.1Hz, 1H), 3.52-3.59(m, 1H), 3.63(s, 3H), 3.81(s, 3H), 4.17(dd, J=62.4, 18Hz, 2H), 4.05-4.17(m, 2H), 5.07(s, 2H), 6.91(m, 2H), 7.20-7.41(m, 7H).Methyl 5-{(2R) -2-[(3S, 4R) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -2-oxo-azetidin-4-yl] propionyl}- 3.0 g of 4-oxo-3-phenyl-1-oxa-5-azaspiro [5.5] undec-2-ene-2-carboxylic acid ester and 4-methoxybenzylbromoacetate instead of allylbromoacetate 3.23 g (83%) of the target compound in the oily state was obtained in the same manner as in Example 18. 1 H-NMR (CDCl 3 , 200 MHz) δ 0.06 (s, 6H), 0.86 (s, 9H), 1.23 (d, J = 5.2 Hz, 3H), 1.27 (d, J = 6.2 Hz, 3H), 1.48-1.68 (m, 5H), 2.04-2.21 (m, 5H), 3.02 (dd, J = 7.4, 2.1 Hz, 1H), 3.52-3.59 (m, 1H), 3.63 (s, 3H), 3.81 ( s, 3H), 4.17 (dd, J = 62.4, 18 Hz, 2H), 4.05-4.17 (m, 2H), 5.07 (s, 2H), 6.91 (m, 2H), 7.20-7.41 (m, 7H).
실시예 20 : 메틸 5-{(2R)-2-[(3S, 4R)-1-(4-나이트로벤질옥시카보닐메틸)-3-[(1R)-1-t-부틸디메틸실릴옥시에틸]-2-옥소-아제티딘-4-일]프로피오닐}-4-옥소-3-페닐-1-옥사-5-아자스피로[5.5]운데크-2-엔-2-카복실산 에스테르(일반식(ⅩⅠ)의 화합물)의 제조Example 20 Methyl 5-{(2R) -2-[(3S, 4R) -1- (4-nitrobenzyloxycarbonylmethyl) -3-[(1R) -1-t-butyldimethylsilyloxy Ethyl] -2-oxo-azetidin-4-yl] propionyl} -4-oxo-3-phenyl-1-oxa-5-azaspiro [5.5] undec-2-ene-2-carboxylic acid ester (general Preparation of the compound of formula (XI)
메틸 5-{(2R)-2-[(3S, 4R)-3-[(1R)-1-t-부틸디메틸실릴옥시에틸]-2-옥소-아제티딘-4-일]프로피오닐}-4-옥소-3-페닐-1-옥사-5-아자스피로[5.5]운데크-2-엔-2-카복실산 에스테르 600mg과 알릴브로모아세테이트 대신에 4-나이트로벤질브로모아세테이트를 사용하여 실시예 18과 동일하게 처리하여 유상의 목적화합물 646mg(84%)을 얻었다.1H-NMR(CDCl3, 200MHz)δ0.02(s, 6H), 0.82(s, 9H), 1.23(d, J=6.8Hz, 3H), 1.25(d, J=6.8Hz, 3H), 1.56-1.78(m, 6H), 2.01-2.36(m, 4H), 3.03(dd, J=7.3, 2.2, 1H), 2.04-2.21(m, 5H), 3.02(dd, J=7.4, 2.1Hz, 1H), 3.52-3.59(m, 1H), 3.60(s, 3H), 4.17(dd, J=62.4, 18Hz, 2H), 5.20(s, 2H), 6.91(m, 2H), 7.18-7.37(m, 5H), 7.45(d, J=8.6Hz, 2H), 8.21(d, J=8.6Hz, 2H).Methyl 5-{(2R) -2-[(3S, 4R) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -2-oxo-azetidin-4-yl] propionyl}- 600 mg of 4-oxo-3-phenyl-1-oxa-5-azaspiro [5.5] undec-2-ene-2-carboxylic acid ester and 4-nitrobenzylbromoacetate in place of allylbromoacetate The same procedure as in Example 18 was carried out to obtain 646 mg (84%) of the target compound in the oily state. 1 H-NMR (CDCl 3 , 200 MHz) δ 0.02 (s, 6H), 0.82 (s, 9H), 1.23 (d, J = 6.8 Hz, 3H), 1.25 (d, J = 6.8 Hz, 3H), 1.56-1.78 (m, 6H), 2.01-2.36 (m, 4H), 3.03 (dd, J = 7.3, 2.2, 1H), 2.04-2.21 (m, 5H), 3.02 (dd, J = 7.4, 2.1 Hz , 1H), 3.52-3.59 (m, 1H), 3.60 (s, 3H), 4.17 (dd, J = 62.4, 18 Hz, 2H), 5.20 (s, 2H), 6.91 (m, 2H), 7.18-7.37 (m, 5H), 7.45 (d, J = 8.6 Hz, 2H), 8.21 (d, J = 8.6 Hz, 2H).
실시예 21 : 알릴 (1R, 5R, 6S)-6-[(1R)-1-t-부틸디메틸실릴옥시에틸]-1-메틸-2-디페닐포스포릴옥시-2-카바펜-2-엠-3-카복실산 에스테르(일반식(Ⅴ)의 화합물)의 제조Example 21 Allyl (1R, 5R, 6S) -6-[(1R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-2-diphenylphosphoryloxy-2-carbafen-2- Preparation of M-3-carboxylic Acid Ester (Compound of Formula (V))
메틸 5-{(2R)-2-[(3S, 4R)-1-알릴옥시카보닐메틸-3-[(1R)-1-t-부틸디메틸실릴옥시에틸]-2-옥소-아제티딘-4-일]프로피오닐}-4-옥소-3-페닐-1-옥사-5-아자스피로[5.5]운데크-2-엔-2-카복실산 에스테르 4.89g을 무수 테트라하이드로퓨란 60㎖에 용해시키고 -45℃로 냉각시킨 후 질소기류하에서 소디움비스(트리메틸실릴)아마이드(1몰의 테트라하이드로퓨란 용액) 16.9㎖를 천천히 가하였다. 온도를 -30℃로 조절하고 클로로트리메틸실란 1.2㎖를 가하여 준후 동 온도에서 5분간 교반하였다. 이 반응액에 디페닐클로로포스페이트 2.23㎖를 천천히 가하여 준 후 4-디메틸아미노피리딘 44mg을 가하고 -30℃에서 -10℃를 유지하면서 2시간 동안 교반하여 주었다. 여기에 포스페이트 완충용액(pH=7.0)을 가하여 주고 초산에틸로 2회 추출하여 망초로 건조 후 감압하에서 농축하였다. 잔여물에 50㎖의 초산에틸:헥산=1:4 혼합용액을 가하여 결정화되는 것을 여과하면 노란색의 메틸 4-옥소-3-페닐-1-옥사-5-아자스피로[5.5]운데크-2-엔-2-카복실산 에스테르가 얻어지며 이 화합물은 제조예 2에 따라 입체 선택 보조제로 제조하여 재사용이 가능하다. 여액을 농축하여 실리카겔 칼럼 크로마토그라피(용리제; 초산에틸:헥산=1:4)로 정제하여 순수한 유상의 목적화합물 4.01g(91%)을 얻었다.1H-NMR(CDCl3, 200MHz)δ0.06(s, 6H), 0.87(s, 9H), 1.16(d, J=7.4Hz, 3H), 1.21(d, J=6.0Hz, 3H), 3.22(dd, J=6.4, 2.8Hz, 1H), 3.31-3.52(m, 1H), 4.07-4.21(m, 2H), 4.64(d, J=5.8Hz, 2H), 5.16(dd, J=10.6, 1.6Hz, 1H), 5.32(dd, J=17.4, 1.6Hz, 1H), 5.75-5.94(m, 1H), 7.17-7.44(m, 10H).Methyl 5-{(2R) -2-[(3S, 4R) -1-allyloxycarbonylmethyl-3-[(1R) -1-t-butyldimethylsilyloxyethyl] -2-oxo-azetidine- 4.89 g of 4-yl] propionyl} -4-oxo-3-phenyl-1-oxa-5-azaspiro [5.5] undec-2-ene-2-carboxylic acid ester was dissolved in 60 ml of anhydrous tetrahydrofuran and After cooling to −45 ° C., 16.9 mL of sodium bis (trimethylsilyl) amide (1 mol of tetrahydrofuran solution) was slowly added under a nitrogen stream. The temperature was adjusted to -30 ° C, 1.2 ml of chlorotrimethylsilane was added, followed by stirring at the same temperature for 5 minutes. 2.23 mL of diphenylchlorophosphate was slowly added to the reaction solution, and 44 mg of 4-dimethylaminopyridine was added thereto, followed by stirring for 2 hours while maintaining the temperature at -30 ° C to -10 ° C. Phosphate buffer solution (pH = 7.0) was added thereto, extracted twice with ethyl acetate, dried over forget-me-not and concentrated under reduced pressure. 50 ml of ethyl acetate: hexane = 1: 4 mixed solution was added to the residue, followed by crystallization. Yellow methyl 4-oxo-3-phenyl-1-oxa-5-azaspiro [5.5] undec-2- An en-2-carboxylic acid ester is obtained which can be reused by preparing a stereoselective adjuvant according to Preparation Example 2. The filtrate was concentrated and purified by silica gel column chromatography (eluent; ethyl acetate: hexane = 1: 4) to obtain 4.01 g (91%) of the target compound as a pure oil. 1 H-NMR (CDCl 3 , 200 MHz) δ 0.06 (s, 6H), 0.87 (s, 9H), 1.16 (d, J = 7.4 Hz, 3H), 1.21 (d, J = 6.0 Hz, 3H), 3.22 (dd, J = 6.4, 2.8 Hz, 1H), 3.31-3.52 (m, 1H), 4.07-4.21 (m, 2H), 4.64 (d, J = 5.8 Hz, 2H), 5.16 (dd, J = 10.6, 1.6 Hz, 1H), 5.32 (dd, J = 17.4, 1.6 Hz, 1H), 5.75-5.94 (m, 1H), 7.17-7.44 (m, 10H).
실시예 22 : 4-나이트로벤질 (1R, 5R, 6S)-6-[(1R)-1-t-부틸디메틸실릴옥시에틸]-1-메틸-2-디페닐포스포릴옥시-2-카바펜-2-엠-3-카복실산 에스테르(일반식(Ⅴ)의 화합물)의 제조Example 22 4-nitrobenzyl (1R, 5R, 6S) -6-[(1R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-2-diphenylphosphoryloxy-2-carba Preparation of phen-2-m-3-carboxylic acid ester (compound of formula (V))
메틸 5-{(2R)-2-[(3S, 4R)-1-(4-나이트로벤질옥시카보닐메틸)-3-[(1R)-1-t-부틸디메틸실릴옥시에틸]-2-옥소-아제티딘-4-일]프로피오닐}-4-옥소-3-페닐-1-옥사-5-아자스피로[5.5]운데크-2-엔-2-카복실산 에스테르 300mg을 출발물질로 하여 실시예 21과 동일한 방법으로 유상의 목적화합물 87mg(32%)을 얻었다.1H-NMR(CDCl3, 200MHz)δ0.06(s, 6H), 0.85(s, 9H), 1.22(d, J=5.2Hz, 3H), 1.28(d, J=6.2Hz, 3H), 3.23-3.33(m, 1H), 3.36-3.48(m, 2H), 5.21-5.39(q, J=10Hz, 2H), 7.12-7.42(m, 10H), 7.53(d, J=8.6Hz, 2H), 8.11(d, J=8.4Hz, 2H).Methyl 5-{(2R) -2-[(3S, 4R) -1- (4-nitrobenzyloxycarbonylmethyl) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -2 -Oxo-azetidin-4-yl] propionyl} -4-oxo-3-phenyl-1-oxa-5-azaspiro [5.5] undec-2-ene-2-carboxylic acid ester as starting material In the same manner as in Example 21, 87 mg (32%) of the target compound in the oily state was obtained. 1 H-NMR (CDCl 3 , 200 MHz) δ 0.06 (s, 6H), 0.85 (s, 9H), 1.22 (d, J = 5.2 Hz, 3H), 1.28 (d, J = 6.2 Hz, 3H), 3.23-3.33 (m, 1H), 3.36-3.48 (m, 2H), 5.21-5.39 (q, J = 10 Hz, 2H), 7.12-7.42 (m, 10H), 7.53 (d, J = 8.6 Hz, 2H ), 8.11 (d, J = 8.4 Hz, 2H).
실시예 23 : 4-메톡시벤질 (1R, 5R, 6S)-6-[(1R)-1-t-부틸디메틸실릴옥시에틸]-1-메틸-2-디페닐포스포릴옥시-2-카바펜-2-엠-3-카복실산 에스테르(일 반식(Ⅴ)의 화합물)의 제조Example 23 4-methoxybenzyl (1R, 5R, 6S) -6-[(1R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-2-diphenylphosphoryloxy-2-carba Preparation of phen-2-em-3-carboxylic acid ester (compound of general formula (V))
메틸 5-{(2R)-2-[(3S, 4R)-1-(4-메톡시벤질옥시카보닐메틸)-3-[(1R)-1-t-부틸디메틸실릴옥시에틸]-2-옥소-아제티딘-4-일]프로피오닐}-4-옥소-3-페닐-1-옥사-5-아자스피로[5.5]운데크-2-엔-2-카복실산 에스테르 323mg을 출발물질로 하여 실시예 21과 동일한 방법으로 유상의 목적화합물 222mg(85%)을 얻었다.1H-NMR(CDCl3, 200MHz)δ0.01(s, 6H), 0.82(s, 9H), 1.12(d, J=7.4Hz, 3H), 1.17(d, J=6.0Hz, 3H), 3.24-3.49(m, 1H), 3.72(s, 3H), 4.01-4.22(m, 2H), 7.08-7.41(m, 12H).Methyl 5-{(2R) -2-[(3S, 4R) -1- (4-methoxybenzyloxycarbonylmethyl) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -2 -Oxo-azetidin-4-yl] propionyl} -4-oxo-3-phenyl-1-oxa-5-azaspiro [5.5] undec-2-ene-2-carboxylic acid ester as starting material 222 mg (85%) of the target compound in the oily state was obtained in the same manner as in Example 21. 1 H-NMR (CDCl 3 , 200 MHz) δ 0.01 (s, 6H), 0.82 (s, 9H), 1.12 (d, J = 7.4 Hz, 3H), 1.17 (d, J = 6.0 Hz, 3H), 3.24-3.49 (m, 1H), 3.72 (s, 3H), 4.01-4.22 (m, 2H), 7.08-7.41 (m, 12H).
실시예 24 : (2R)-2-[(3S, 4R)-3-[(1R)-t-부틸디메틸실릴옥시에틸]-2-옥소 -아제티딘-4일]프로피온산(일반식(Ⅳ)의 화합물)의 제조Example 24: (2R) -2-[(3S, 4R) -3-[(1R) -t-butyldimethylsilyloxyethyl] -2-oxo-azetidin-4yl] propionic acid (General formula (IV)) Preparation of the compound
실시예 10에서 제조한 메틸 5-{(2R)-2-[(3S, 4R)-3-[(1R)-1-t-부틸디메틸실릴옥시에틸]-2-옥소-아제티딘-4-일]프로피오닐}-4-옥소-3-페닐-1-옥사-5-아자스피로[5.5]운데크-2-엔-2-카복실산 에스테르 388mg을 무수 테트라하이드로퓨란 10㎖와 물 0.34㎖에 용해시키고 0℃로 냉각한 후 30% 과산화수소 0.6㎖와 수산화리티움 56mg을 가하였다. 동 온도에서 1시간 동안 교반하여 준 후 반응액에 1.5 노르말 소디움설파이트 수용액 4㎖를 가하였다 . 테트라하이드로퓨란을 감압하에서 농축하고 남은 수용액에서 생성된 결정을 여과하면 메틸 4-옥소-3-페닐-1-옥사-5-아자스피로 [5.5]운데크-2-엔-2-카복실산 에스테르가 얻어진다. 여액을 클로로포름으로 세척하여 주고 10% 염산으로 pH를 약 1로 조절한 후 초산에틸로 추출하여 망초로 건조한 다음 감압하에서 농축하였다. 잔여물을 초산에틸과 헥산용매로 결정화하여 흰색 고체상의 목적화합물 144mg(73%)을 얻었다. mp 143-146℃.Methyl 5-{(2R) -2-[(3S, 4R) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -2-oxo-azetidine-4- prepared in Example 10 3] 3 mg of propionyl} -4-oxo-3-phenyl-1-oxa-5-azaspiro [5.5] undec-2-ene-2-carboxylic acid ester was dissolved in 10 ml of anhydrous tetrahydrofuran and 0.34 ml of water. After cooling to 0 ° C., 0.6 ml of 30% hydrogen peroxide and 56 mg of lithium hydroxide were added. After stirring for 1 hour at the same temperature, 4 ml of an aqueous 1.5 normal sodium sulfite solution was added to the reaction solution. The tetrahydrofuran was concentrated under reduced pressure and the resulting crystals were filtered to afford the methyl 4-oxo-3-phenyl-1-oxa-5-azaspiro [5.5] undec-2-ene-2-carboxylic acid ester. Lose. The filtrate was washed with chloroform and the pH was adjusted to about 1 with 10% hydrochloric acid, extracted with ethyl acetate, dried over forget-me-not and concentrated under reduced pressure. The residue was crystallized with ethyl acetate and hexane solvent to give 144 mg (73%) of the title compound as a white solid. mp 143-146 ° C.
본 발명의 입체 선택 보조제인 일반식(Ⅲ)의 화합물을 사용하여 일반식(Ⅰ)의 화합물을 제조함으로써 일반식(Ⅰ) 화합물의 1'-위치가 β-메틸기인 입체 이성체질만 효과적으로 제조할 수 있게 되었다.By preparing the compound of general formula (I) using the compound of general formula (III) which is the stereoselective adjuvant of the present invention, only stereoisomers in which the 1'-position of the compound of general formula (I) is β-methyl group can be effectively prepared. It became possible.
1996년도판 테트라헤드론 52권 3호 331-375면(Tetrahedron, Vol. 52, No. 2 pp. 331-375. 1996)을 보면 β-메틸카바페넴 항생제의 중간체에 관한 보고가 있는데, 살펴보면, 입체 선택 보조제를 사용하여 본 발명의 일반식(Ⅰ)의 화합물에 대응하는 화합물을 제조함에 있어서, 본 발명에서와 같이 반응 시약으로서 취급하기 쉬운 아연분말을 사용한 것만 추려, 정리하면 다음과 같다(표 4). Tetrahedron , Vol. 52, No. 2 pp. 331-375. 1996 published the 1996 edition of Tetraheadon Vol. 3, pp. 331-375. In preparing the compound corresponding to the compound of the general formula (I) of the present invention using the stereoselective adjuvant, only zinc powders which are easy to handle as reaction reagents are used as in the present invention. 4).
본 발명 실시예에서의 β-이성체의 비율이 가장 높게 나타난 것은 실시예 11의 98:2 이고 가장 낮게 나타난 것이 실시예 13의 92:8 이다. 이를 평균하여 보면 β-이성체의 비율은 96:4가 된다.The highest ratio of β-isomers in Examples of the present invention was 98: 2 in Example 11 and the lowest was 92: 8 in Example 13. On average, the ratio of β-isomers is 96: 4.
위 표 4를 살펴보면, 일본국의 타나베사의 β-이성체 비율이 92:8, 일본국의 사가미사의 β-이성체 비율이 각각 79:21, 91:9 로 기재되어 있다.Referring to Table 4 above, the β-isomer ratio of Tanabesa in Japan is 92: 8, and the β-isomer ratio of Sagamisa in Japan is 79:21 and 91: 9, respectively.
대비하여 보면, 본 발명에서의 β-이성체 비율이 훨씬 높게 나타남을 알 수 있다.In contrast, it can be seen that the β-isomer ratio in the present invention is much higher.
또 본 발명에서는 일반식(Ⅰ)의 화합물로부터 카바페넴 항생제의 최종 중간체인 일반식(Ⅴ)의 화합물을 제조하는 공정 중에서 입체 선택 보조제인 일반식(Ⅲ)의 화합물을 부산물로 회수하여 재사용할 수 있는 장점이 있다.In the present invention, the compound of formula (III), which is a stereoselective adjuvant, can be recovered and reused as a by-product during the process for preparing the compound of formula (V), which is the final intermediate of the carbapenem antibiotic, from the compound of formula (I). There is an advantage.
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