WO2001072704A1 - AZETIDINONE DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND A METHOD FOR PRODUCING 1-β-ALKYL AZETIDINONE USING THE SAME - Google Patents
AZETIDINONE DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND A METHOD FOR PRODUCING 1-β-ALKYL AZETIDINONE USING THE SAME Download PDFInfo
- Publication number
- WO2001072704A1 WO2001072704A1 PCT/KR2001/000507 KR0100507W WO0172704A1 WO 2001072704 A1 WO2001072704 A1 WO 2001072704A1 KR 0100507 W KR0100507 W KR 0100507W WO 0172704 A1 WO0172704 A1 WO 0172704A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- azetidinone
- formula
- alkyl
- tert
- represented formula
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 68
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 238000004519 manufacturing process Methods 0.000 title description 2
- 238000002360 preparation method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 239000002585 base Substances 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- 239000000460 chlorine Substances 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 15
- -1 oxalic bromidie Chemical compound 0.000 claims description 15
- 230000026030 halogenation Effects 0.000 claims description 12
- 238000005658 halogenation reaction Methods 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 150000002690 malonic acid derivatives Chemical class 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 235000019441 ethanol Nutrition 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 6
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- UPQZOUHVTJNGFK-UHFFFAOYSA-N diethyl 2-methylpropanedioate Chemical compound CCOC(=O)C(C)C(=O)OCC UPQZOUHVTJNGFK-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000002950 monocyclic group Chemical group 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000000758 substrate Substances 0.000 claims description 3
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims description 2
- HHBCEKAWSILOOP-UHFFFAOYSA-N 1,3-dibromo-1,3,5-triazinane-2,4,6-trione Chemical compound BrN1C(=O)NC(=O)N(Br)C1=O HHBCEKAWSILOOP-UHFFFAOYSA-N 0.000 claims description 2
- YMNNXLJCXALYDF-UHFFFAOYSA-N 1-bromopyrrolidine-2,5-dione;methylsulfanylmethane Chemical compound CSC.BrN1C(=O)CCC1=O YMNNXLJCXALYDF-UHFFFAOYSA-N 0.000 claims description 2
- MHZBKGCHHRDTGK-UHFFFAOYSA-N 1-bromopyrrolidine-2,5-dione;n,n-dimethylformamide Chemical compound CN(C)C=O.BrN1C(=O)CCC1=O MHZBKGCHHRDTGK-UHFFFAOYSA-N 0.000 claims description 2
- AORHLVDUGUXRKN-UHFFFAOYSA-N 1-bromopyrrolidine-2,5-dione;triphenylphosphane Chemical compound BrN1C(=O)CCC1=O.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 AORHLVDUGUXRKN-UHFFFAOYSA-N 0.000 claims description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 2
- ALHHNDQKFRHCOJ-UHFFFAOYSA-N 3-o-tert-butyl 1-o-ethyl 2-methylpropanedioate Chemical compound CCOC(=O)C(C)C(=O)OC(C)(C)C ALHHNDQKFRHCOJ-UHFFFAOYSA-N 0.000 claims description 2
- OIVUHPTVQVCONM-UHFFFAOYSA-N 6-bromo-4-methyl-1h-indazole Chemical compound CC1=CC(Br)=CC2=C1C=NN2 OIVUHPTVQVCONM-UHFFFAOYSA-N 0.000 claims description 2
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- QAWYDGFYZFJDCA-UHFFFAOYSA-K [Al+3].[Cl-].[Cl-].[Cl-].ClC(=O)C(Cl)=O Chemical compound [Al+3].[Cl-].[Cl-].[Cl-].ClC(=O)C(Cl)=O QAWYDGFYZFJDCA-UHFFFAOYSA-K 0.000 claims description 2
- ZJQALQKVUGRLFF-UHFFFAOYSA-N [Cl].CSC Chemical compound [Cl].CSC ZJQALQKVUGRLFF-UHFFFAOYSA-N 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 230000031709 bromination Effects 0.000 claims description 2
- 238000005893 bromination reaction Methods 0.000 claims description 2
- ZOAIGCHJWKDIPJ-UHFFFAOYSA-M caesium acetate Chemical compound [Cs+].CC([O-])=O ZOAIGCHJWKDIPJ-UHFFFAOYSA-M 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- QMMFVYPAHWMCMS-UHFFFAOYSA-N dimethylsulfide Substances CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 2
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 230000026045 iodination Effects 0.000 claims description 2
- 238000006192 iodination reaction Methods 0.000 claims description 2
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 claims description 2
- AZVCGYPLLBEUNV-UHFFFAOYSA-N lithium;ethanolate Chemical compound [Li+].CC[O-] AZVCGYPLLBEUNV-UHFFFAOYSA-N 0.000 claims description 2
- TVPHQZDWASGWFD-UHFFFAOYSA-N n,n-dimethylformamide;oxalyl dichloride Chemical compound CN(C)C=O.ClC(=O)C(Cl)=O TVPHQZDWASGWFD-UHFFFAOYSA-N 0.000 claims description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 150000003222 pyridines Chemical class 0.000 claims description 2
- WPFGFHJALYCVMO-UHFFFAOYSA-L rubidium carbonate Chemical compound [Rb+].[Rb+].[O-]C([O-])=O WPFGFHJALYCVMO-UHFFFAOYSA-L 0.000 claims description 2
- 229910000026 rubidium carbonate Inorganic materials 0.000 claims description 2
- FOGKDYADEBOSPL-UHFFFAOYSA-M rubidium(1+);acetate Chemical compound [Rb+].CC([O-])=O FOGKDYADEBOSPL-UHFFFAOYSA-M 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 229950009390 symclosene Drugs 0.000 claims description 2
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 claims description 2
- 125000005270 trialkylamine group Chemical group 0.000 claims description 2
- 229940086542 triethylamine Drugs 0.000 claims description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 3
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 2
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims 1
- INOGLHRUEYDAHX-UHFFFAOYSA-N 1-chlorobenzotriazole Chemical compound C1=CC=C2N(Cl)N=NC2=C1 INOGLHRUEYDAHX-UHFFFAOYSA-N 0.000 claims 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 239000000376 reactant Substances 0.000 abstract description 4
- 125000006239 protecting group Chemical group 0.000 abstract description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 238000010189 synthetic method Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229910052707 ruthenium Inorganic materials 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 125000003367 polycyclic group Polymers 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- IDKXMGZRWKCTGA-UHFFFAOYSA-N chloroimino(oxo)methane Chemical compound ClN=C=O IDKXMGZRWKCTGA-UHFFFAOYSA-N 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 229940093499 ethyl acetate Drugs 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical group C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- OEYMQQDJCUHKQS-UHFFFAOYSA-N (4-oxoazetidin-2-yl) acetate Chemical compound CC(=O)OC1CC(=O)N1 OEYMQQDJCUHKQS-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- BJLRVFDWAOVFCI-UHFFFAOYSA-N 1h-imidazole;quinoline Chemical compound C1=CNC=N1.N1=CC=CC2=CC=CC=C21 BJLRVFDWAOVFCI-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 0 C[C@]([*+]C([C@@]([C@@](*)C(O)=O)N1)C1=O)O* Chemical compound C[C@]([*+]C([C@@]([C@@](*)C(O)=O)N1)C1=O)O* 0.000 description 1
- 239000005046 Chlorosilane Substances 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003460 beta-lactamyl group Chemical group 0.000 description 1
- UORVGPXVDQYIDP-BJUDXGSMSA-N borane Chemical class [10BH3] UORVGPXVDQYIDP-BJUDXGSMSA-N 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- RCOSUMRTSQULBK-UHFFFAOYSA-N sodium;propan-1-olate Chemical compound [Na+].CCC[O-] RCOSUMRTSQULBK-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 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
- 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
-
- 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 System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to azetidinone derivatives, synthetic process of that, and synthetic process of 1- ⁇ -alkyl azetidinone using that, in more detail the present invention relates to new azetidinone derivatives, new synthetic process of that, and new synthetic process of 1- ⁇ -alkyl azetidinone using that.
- each R] is independently hydrogen or tert-butyl dimethyl silyl and R ⁇ represents a hydrogen or Cl ⁇ C4 alkyl.
- 4-acetoxy azetidinone(written 4-AA) is essential as a key intermediate to synthesize the l- ⁇ -methyl azetidinone (written 1-BMA) or 1-H-azetidinone (written 1-HA).
- JP 238066 it is a method that uses clisen-type's reaction. Although this method had advantage, which is obtained product in high yield, this method was pointed out disadvantages, which is difficult for industrial application because this method is required auto-clave in the case of butenyl chloro silane's synthesis.
- the method using 4-AA for intermediate need to be improved increasingly because of not only suffering from treatment of reagents and reactants but also having problem of industrial application in traditional synthetic method of 1 -BMA.
- the inventors get to the present invention as a result of a lot of researches and experiments in order to synthesize new compounds for the substitute of 4-AA, which is used as an intermediate in traditional synthetic method of 1-BMA.
- the first technical subject to accomplish in the present invention is to provide new compounds for the substitute of 4-AA, which is used as an intermediate in traditional synthetic method of 1-BMA.
- the second technical subject to accomplish in the present invention is to provide a synthetic process of above new compounds.
- the third technical subject to accomplish in the present invention is to provide a synthetic process of 1-BAA using above new compounds.
- the first technical subject in the present invention has accomplished by means of azetidinone derivatives represented Formula 2.
- X is independently halogen atom and K ⁇ is independently hydrogen or tert-butyl dimethyl silyl.
- each X is used independently chlorine, bromine, or iodine in the present invention.
- the second technical subject in the present invention has accomplished by means of synthetic process of azetidinone derivatives represented Formula 2, to which to include the reaction step that compound represented Formula 1 is reacted with a halogenation reagent and base is peculiar.
- each X is used independently chlorine, bromine, or iodine in the present invention. Also it is desirable that the temperature of above reaction is proceeded at -30 ⁇ 100°C . If the temperature is lower than -30 °C then the reaction does not proceed and if the reaction temperature is higher than 100°C then the ⁇ -lactam ring cleaves probably.
- the halogenation reagents used above synthetic process are, for example N-chloro succmimide, chlorine, l,3-dichloro-5,5-dimethyl hydantoin, l-chlorobenzotriazole, N-chloromorphorine, N-chloro succinimde-dimethyl sulfide, dimethylsulfide-chlorine, trichloro isocyanuric acid, trichloro methyl chloro formate, oxalic chloride, phosphorus(III) chloride, oxalic chloride-aluminum chloride complex, phosphorus(V) chloride, thionyl chloride, oxalic chloride-dimethyl formamide, phosphorus oxy chloride, and etc. It is desirable that N-chloro succmimide, chlorine, and l,3-dichloro-5,5-dimethyl hydantoin are used in the present invention.
- the halogenation reagents used above synthetic process are, for example N-iodo succinimide, iodine, l,3-diiodo-5,5-dimethyl hydantoin, iodine monobromide, iodine monochloride, and methyl triphenoxy phosphonuim iodide, and etc. It is desirable that N-iodo succinimide, iodine, and l,3-diiodo-5,5-dimethyl hydantoin are used in the present invention.
- the halogenation reagents used above synthetic process are, for example N-bromo succinimide, bromine, l,3-dibromo-5,5-dimethyl hydantoin, triphenyl phosphine-N-bromo succinimide, oxalic bromidie, 1,3-dibromo isocyanuric acid, 5,5-dibromo-2,2-dimethyl-l,3-dioxane-4,6-dione, thionyl bromide, phosphorus(III) bromide, N-bromo succinimide-dimethyl formamide, N-bromo succinimide-dimethyl sulfide, and etc.
- N-bromo succinimide, bromine, and l,3-dibromo-5,5-dimethyl hydantoin are used in the present invention.
- the reaction temperature's range, which is proceeded halogenation most actively is from -30 ° C to 100°C, thus it is desirable for chlorination and iodination that the temperature of above reaction is proceeded at -10 ⁇ 40 °C, for bromination that the temperature of above reaction is proceeded at -30 ⁇ 20 °C .
- the base is used in the presented invention, it is desirable that the base, for example:
- Alkali metal acetates lithium acetate, sodium acetate, potassium acetate, rubidium acetate, cesium acetate, and etc.
- Alkali metal carbonates lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, and etc.
- Alkali metal bicarbonates sodium bicarbonate, potassium bicarbonate, and etc.
- Trialkyl amines triethyl amine, and etc.
- Pyridine compounds pyridine, rutidine, picoline, and etc.
- each Ri is independently hydrogen or tert-butyl dimethyl silyl and R 4 represents a hydrogen or Cl ⁇ C4 alkyl.
- each alkyl group is used independently methyl, ethyl, n-propyl, or n-butyl in the present invention.
- the presented invention offers synthetic process of 1- ⁇ -alkyl azetidinone represented Formula 5, to which to include the reaction step that azetidinone derivatives represented Formula 2 are reacted with a base and malonic acid derivative represented Formula 6 is peculiar.
- R 2 and R 3 are identical or different and each represents a Cl ⁇ C4 alkyl, monocyclic or poly cyclic alkyl, C2 ⁇ C4 alkenyl, or aralkyl and R 4 represents a hydrogen or Cl ⁇ C4 alkyl.
- each alkyl group includes straight-chain or branched alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, and tert-butyl; and monocyclic or polycyclic alkyl groups such as cyclopentyl, cyclohexyl, menthyl, fencyl, and bornyl in the present invention.
- each alkenyl group includes straight-chain or branched alkyl groups such as vinyl, allyl, 2-butenyl, and 2-methyl-2-propenyl in the present invention.
- the base is used such as lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, sodium n-propoxide, potassium methoxide, potassium ethoxide, and potassium «-propoxide in the above synthetic process.
- a malonic acid derivative is added as a reactant together with a base in the course of synthesizing azetidinone derivative represented Formula 3 from azetidinone derivatives represented Formula 2.
- the malonic acid derivatives represented Formula 6 includes diethylmalonate, diethyl methyl malonate, dibenzyl methyl malonate, tert-butyl ethyl methyl malonate, and diallyl methyl malonate.
- the solvent is used as occasion demands and it is desirable that the solvent includes ethyl alcohol and THF; the most desirable solvent is a THF. It is desirable that 1 ⁇ 12 eq. of malonic acid derivatives represented
- Formula 6 and 3 ⁇ 12 eq. of base are used per 1 eq. of azetidinone derivatives represented Formula 2 in the presented invention. It is the most desirable that 10 eq. of malonic acid derivatives represented Formula 6 and 5 eq. of base are used per 1 eq. of azetidinone derivatives represented Formula 2 in the presented invention.
- the reaction temperature's range is from -78 ⁇ to 50 °C, thus it is desirable that the temperature of above reaction is proceeded at 0 ⁇ 30 °C .
- azetidinone derivatives represented Formula 3 which is synthesized by above process is converted to azetidinone derivatives represented Formula 4 by hydrolysis and then azetidinone derivatives represented Formula 4 is converted to 1-BAA by decarboxylation.
- R 2 and R 3 are identical or different and each represents a Cl ⁇ C4 alkyl, monocyclic or poly cyclic alkyl, C2 ⁇ C4 alkenyl, or aralkyl and R 4 represents a hydrogen or Cl ⁇ C4 alkyl.
- the intermediate is proceeded next reaction easily without using the strong base because the acidity of the proton of carbon is increased, the proton of carbon, due to the adjacent nitrogen atom which is activated by means of introduction of halogen atoms and stronger leaving ability and more electro-negative than acetate.
- Mass spectroscopy (M.W.: 263.83): 206.1(M-C(CH 3 ) 3 ), 171.1(M-C(CH 3 ) 3 -C1), 143.0(M-TBDMS-C1), 99.0, 92.9,
- aqueous layer was washed with lOmL of diethyl ether and then adjusted to pH 2 with 2N hydrochloric acid, and extraction was conducted using 30mL of diethyl ether.
- the diethyl ether layer obtained was washed with lOmL of saturated aqueous sodium chloride, subsequently dehydrated with anhydrous magnesium sulfate, and then filtered and concentrated, thereby obtaining 0.7 g(percent yield 80%) of a (3S,4S)-3-[(R)-l '-tert-butyl dimethyl silyloxy ethyl]-4-( 1 , 1 -dicarboxy ethyl)-2-azetidinone.
- 1-BAA especially 1-BMA, or 1-HA, which is an essential key intermediates of carbapenem antibiotics by taking advantage of new azetidinone derivatives.
- 1-BAA is synthesized only with a general base and reactant in high yield using new azetidinone derivatives without any additional protecting group.
Abstract
The present invention relates to new azetidinone derivatives represented formula 2, synthetic process of that, and synthetic process of 1-β-alkyl azetidinone using that. According to the present invention, 1-β-alkyl azetidinone is synthesized only with a general base and reactant in high yield using new azetidinone derivatives without any additional protecting group.
Description
AZETIDINONE DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND A METHOD FOR PRODUCING 1-B-ALKYL AZETIDINONE USING THE SAME
TECHNICAL FIELD
The present invention relates to azetidinone derivatives, synthetic process of that, and synthetic process of 1-β-alkyl azetidinone using that, in more detail the present invention relates to new azetidinone derivatives, new synthetic process of that, and new synthetic process of 1-β-alkyl azetidinone using that.
BACKGROUND ART
The 1-β-alkyl azetidinone represented Formula 5 below (written
1-BAA) is known to be valuable key intermediate when we synthesize the carbapenem antibiotics.
[Formula 5]
According to synthetic methods reported previously 4-acetoxy azetidinone(written 4-AA) is essential as a key intermediate to synthesize the l-β-methyl azetidinone (written 1-BMA) or 1-H-azetidinone (written 1-HA).
The synthetic methods generally known for the synthesis of 4-AA were divided into 3 parts.
Firstly, according to EP 371875, EP 369691, and EP 509821, it is a
method that uses ruthenium catalyst. But this method was pointed out disadvantages in, which ruthenium as an expensive catalyst, needs complicated regeneration process for reuse of ruthenium used, and needs to use highly toxic and explosive acetaldehyde or peroxide. Second, according to EP 167154, EP 280962, and EP 372699, it is a method that uses chloro isocyanate. This method was pointed out disadvantages in, which a highly toxic and unstable chloro isocyanate expensively for substrate, underwent at very low temperature in order to obtain maximum ratio of yield for purposed product from mixture of isomers, obtained product in low yield, and need complicated isolation process additionally.
Third, according to EP 259268 and EP 290385, it is a method for 4-AA that synthesizes chiral intermediate using enzyme, chiral borane compounds, metal borohydrides, chiral aluminum hydrides, Raney Nickel, or platinum then after cyclization reaction followed to isomerization reaction. This method was pointed out disadvantages, which used a expensive, moisture sensitive, air sensitive, and unstable enzyme and coenzyme, need not only many reaction step but also low yield because the cyclized intermediate was isomerized using special base for synthesis of 4-AA. Also synthetic methods for 1-BMA and 1-HA especially were reported widely using 4-AA. The synthetic methods were divided into 3 parts.
Firstly, according to EP 546742, EP 573667, EP 78026, USP 5654424, USP 5340927, USP 5493018, USP 5442055, USP 5075437, USP 5104984, JP 9316071, JP 63284176, JP 2292269, JP 63170377, JP 62158277, and WO 52908, it is a method that uses direct alkylation's reaction. But this method was pointed out disadvantages, which protection group additionally, influenced selectivity (β/α ratio) of product, which is depend on Lewis acids used, is used an additional chiral auxiliary, which is synthesized previously, and is not clear correlation between chiral auxiliaries and Lewis acids. Also this method was pointed out disadvantages, which is not only difficult for
industrial application because metal hydrides, Lewis acids, and chiral auxiliaries are difficult for treatment and expensive, but also is not competitive in the aspect of economic profit because of low yield.
Second, according to EP 516486, USP 5081238, USP 5075436, USP 4595750, USP 4873324, USP 6287197, JP 4368365, and WO 10323, it is a method that uses asymmetric reduction using catalyst. Although this method had advantage, which is obtained product high yield, this method was pointed out disadvantages, which is low selectivity (β/α ratio) of product, is difficult for industrial application because this method is required not only ruthenium or rhodium catalysts expensively, but also severe reaction conditions including high temperature and high pressure.
Third, according to JP 238066, it is a method that uses clisen-type's reaction. Although this method had advantage, which is obtained product in high yield, this method was pointed out disadvantages, which is difficult for industrial application because this method is required auto-clave in the case of butenyl chloro silane's synthesis.
Thus, the method using 4-AA for intermediate need to be improved increasingly because of not only suffering from treatment of reagents and reactants but also having problem of industrial application in traditional synthetic method of 1 -BMA.
DISCLOSURE OF INVENTION
The inventors get to the present invention as a result of a lot of researches and experiments in order to synthesize new compounds for the substitute of 4-AA, which is used as an intermediate in traditional synthetic method of 1-BMA.
The first technical subject to accomplish in the present invention is to provide new compounds for the substitute of 4-AA, which is used as an intermediate in traditional synthetic method of 1-BMA.
The second technical subject to accomplish in the present invention is to provide a synthetic process of above new compounds.
The third technical subject to accomplish in the present invention is to provide a synthetic process of 1-BAA using above new compounds. The first technical subject in the present invention has accomplished by means of azetidinone derivatives represented Formula 2.
[Formula 2]
It is desirable that above each X is used independently chlorine, bromine, or iodine in the present invention.
The second technical subject in the present invention has accomplished by means of synthetic process of azetidinone derivatives represented Formula 2, to which to include the reaction step that compound represented Formula 1 is reacted with a halogenation reagent and base is peculiar.
[Formula 1 ]
[Scheme 1]
(1) <2)
wherein, X is independently halogen atom and Rj is independently hydrogen or tert-butyl dimethyl silyl.
It is desirable that above each X is used independently chlorine, bromine, or iodine in the present invention. Also it is desirable that the temperature of above reaction is proceeded at -30 ~ 100°C . If the temperature is lower than -30 °C then the reaction does not proceed and if the reaction temperature is higher than 100°C then the β-lactam ring cleaves probably.
The halogenation reagents used above synthetic process are, for example N-chloro succmimide, chlorine, l,3-dichloro-5,5-dimethyl hydantoin, l-chlorobenzotriazole, N-chloromorphorine, N-chloro succinimde-dimethyl sulfide, dimethylsulfide-chlorine, trichloro isocyanuric acid, trichloro methyl chloro formate, oxalic chloride, phosphorus(III) chloride, oxalic chloride-aluminum chloride complex, phosphorus(V) chloride, thionyl chloride, oxalic chloride-dimethyl formamide, phosphorus oxy chloride, and etc. It is desirable that N-chloro succmimide, chlorine, and l,3-dichloro-5,5-dimethyl hydantoin are used in the present invention.
The halogenation reagents used above synthetic process are, for example N-iodo succinimide, iodine, l,3-diiodo-5,5-dimethyl hydantoin, iodine monobromide, iodine monochloride, and methyl triphenoxy phosphonuim iodide, and etc. It is desirable that N-iodo succinimide, iodine, and l,3-diiodo-5,5-dimethyl hydantoin are used in the present invention.
The halogenation reagents used above synthetic process are, for example N-bromo succinimide, bromine, l,3-dibromo-5,5-dimethyl hydantoin, triphenyl phosphine-N-bromo succinimide, oxalic bromidie, 1,3-dibromo isocyanuric acid, 5,5-dibromo-2,2-dimethyl-l,3-dioxane-4,6-dione, thionyl bromide, phosphorus(III) bromide, N-bromo succinimide-dimethyl formamide, N-bromo succinimide-dimethyl sulfide, and etc. It is desirable that N-bromo succinimide, bromine, and l,3-dibromo-5,5-dimethyl hydantoin are used in the present invention.
In the synthetic process of azetidinone derivatives represented Formula 2, the reaction temperature's range, which is proceeded halogenation most actively is from -30 °C to 100°C, thus it is desirable for chlorination and iodination that the temperature of above reaction is proceeded at -10 ~ 40 °C, for bromination that the temperature of above reaction is proceeded at -30 ~ 20 °C .
Also it is characteristic that the base is used in the presented invention, it is desirable that the base, for example:
In the inorganic bases, Alkali metal acetates : lithium acetate, sodium acetate, potassium acetate, rubidium acetate, cesium acetate, and etc.
Alkali metal carbonates : lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, and etc.
Alkali metal bicarbonates : sodium bicarbonate, potassium bicarbonate, and etc.
In the organic bases,
Trialkyl amines : triethyl amine, and etc.
Pyridine compounds : pyridine, rutidine, picoline, and etc.
Quinoline Imidazole, and etc.
Is used in the presented invention.
It is desirable that 1 eq. of halogenation reagent and 1~5 eq. of base are used per 1 eq. of substrate in the presented invention.
As above-stated, to react a common base and halogenation reagent with azetidinone derivatives represented Formula 1 leads to new azetidinone derivatives instead of 4-AA.
In addition to, as above-stated the azetidinone derivatives represented Formula 2 is used synthesis of 1-β-alkyl azetidinone represented Formula 5.
[Formula 5]
It is desirable that above each alkyl group is used independently methyl, ethyl, n-propyl, or n-butyl in the present invention.
In order to accomplish the third technical subject in the present invention, the presented invention offers synthetic process of 1-β-alkyl azetidinone represented Formula 5, to which to include the reaction step that azetidinone derivatives represented Formula 2 are reacted with a base and malonic acid derivative represented Formula 6 is peculiar.
[Formula 3]
[Formula 6]
[Scheme 2]
(2) (3)
wherein, X is independently halogen atom and each R] is independently hydrogen or tert-butyl dimethyl silyl. R2 and R3 are identical or different and each represents a Cl ~C4 alkyl, monocyclic or poly cyclic alkyl, C2 ~ C4 alkenyl, or aralkyl and R4 represents a hydrogen or Cl ~ C4 alkyl. It is desirable that above each alkyl group includes straight-chain or branched alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, and tert-butyl; and monocyclic or polycyclic alkyl groups such as cyclopentyl, cyclohexyl, menthyl, fencyl, and bornyl in the present invention.
It is desirable that above each alkenyl group includes straight-chain or branched alkyl groups such as vinyl, allyl, 2-butenyl, and 2-methyl-2-propenyl in the present invention.
It is desirable that the base is used such as lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, sodium n-propoxide, potassium methoxide, potassium ethoxide, and potassium «-propoxide in the above synthetic process.
Also it is desirable that a malonic acid derivative is added as a reactant together with a base in the course of synthesizing azetidinone derivative represented Formula 3 from azetidinone derivatives represented Formula 2. The malonic acid derivatives represented Formula 6 includes diethylmalonate, diethyl methyl malonate, dibenzyl methyl malonate, tert-butyl ethyl methyl malonate, and diallyl methyl malonate.
Also, the solvent is used as occasion demands and it is desirable that the solvent includes ethyl alcohol and THF; the most desirable solvent is a THF. It is desirable that 1 ~ 12 eq. of malonic acid derivatives represented
Formula 6 and 3~12 eq. of base are used per 1 eq. of azetidinone derivatives represented Formula 2 in the presented invention. It is the most desirable that 10 eq. of malonic acid derivatives represented Formula 6 and 5 eq. of base are used per 1 eq. of azetidinone derivatives represented Formula 2 in the presented invention.
In the synthetic process of azetidinone derivatives represented Formula 3 from azetidinone derivatives represented Formula 2, the reaction temperature's range is from -78^ to 50 °C, thus it is desirable that the temperature of above reaction is proceeded at 0 ~ 30 °C .
The azetidinone derivatives represented Formula 3, which is synthesized by above process is converted to azetidinone derivatives represented Formula 4 by hydrolysis and then azetidinone derivatives represented Formula 4 is converted to 1-BAA by decarboxylation.
[Formula 4]
[Formula 5]
[Scheme 3]
(3) (4) (5) wherein, X is independently halogen atom and each R! is independently hydrogen or tert-butyl dimethyl silyl. R2 and R3 are identical or different and each represents a Cl ~C4 alkyl, monocyclic or poly cyclic alkyl, C2 ~ C4 alkenyl, or aralkyl and R4 represents a hydrogen or Cl ~ C4 alkyl.
As mentioned above, the intermediate is proceeded next reaction easily without using the strong base because the acidity of the proton of carbon is increased, the proton of carbon, due to the adjacent nitrogen atom which is activated by means of introduction of halogen atoms and stronger leaving ability and more electro-negative than acetate.
If the reaction is proceeded without protection of β-lactam nitrogen atom many by-products and side-products are produced. So the reaction is proceeded by protection of group when the reaction starts and deprotection when the reaction is over. That is a major problem in traditional process. But because the halogen atom, which is attached nitrogen atom will act as both leaving group and protection group, our process in the presented invention doesn't need two processes including introduction of protection group and deprotection.
The presented invention is explained in detail using experimental examples and the presented invention is not limited to below experimental examples.
EXAMPLES
Example 1
3(S)-N-Cloro-3-fTRH '-tert-butyl dimethyl silyloxy ethyll-2- azetidinone
In lOOmL of ethanol was dissolved 60g(0.26 mol) of 3(S)-3-[(R)-l '-tert-butyl dimethyl silyloxy ethyl]-2-azetidinone and 23g(0.28 mol) of sodium acetate. The 38g(0.28 mol) of N-chloro succimide was added thereto dropwise at room temperature and a reaction was allowed to proceed at room temperature for 6 hours. To the reaction mixture was added lOOmL of water, and then extracted with 300mL n-hexane third times. Subsequently, the organic layer was evaporated in reduced pressure to obtain oilic substance. This oilic substance was purified by silica gel column chromatography using
developing solvent (n-hexane : ethylacetate = 1 : 1), thereby obtaining 68g(percent yield 98%) of a 3(S)-N-Cloro3-[(R)-l '-tert-butyl dimethyl silyloxy ethyl]-2-azetidinone as colorless liquid.
1H NMR(CDCl3,300MHz): δ 0.08(s,6H), 0.86(s,9H), 1.20(d,3H,J=6.2Hz), 3.36(q,lH,J=3.0Hz), 3.56(m,lH),
3.66(m,lH), 4.26(m,lH) ,3C NMR(CDCl3,300MHz): δ -5.18, -4.31, 17.76, 22.55, 25.59, 49.11, 59.31,
64.54, 168.02 Mass spectroscopy(M.W.: 263.83): 206.1(M-C(CH3)3), 171.1(M-C(CH3)3-C1), 143.0(M-TBDMS-C1), 99.0, 92.9,
75.0 Elementary analysis of CπH22N02ClSi Calcul.: C;50.07, H;8.40, N;5.31 Cl;13.43, Si;10.64 Founded: C;49.80, H;8.43, N;5.45, Cl;12.90, Si;9.69 UV- Visible: λmax= 230.0, ε= 537(n-hexane)
IR(neat, cπf1): 2950, 2872, 1807 [α]25 d = -63.2(c = 1.0, CHCl3)
Example 2 3(S)-N-Bromo-3-r(R)-r-tert-butyl dimethyl silyloxy ethyl1-2- azetidinone
In lOOmL of ethanol was dissolved 22.9g(0.1 mol) of 3(S)-3-[(R)-l '-tert-butyl dimethyl silyloxy ethyl]-2-azetidinone and 10.4g(0.2 mol) of sodium acetate at 0°C . The 16g(0.1 mol) of bromine was added thereto dropwise at OU and a reaction was allowed to proceed at 0°C for 30 minutes. To the reaction mixture was added lOOmL of water, and then extracted with 300mL n-hexane third times. Subsequently, the organic layer was evaporated in reduced pressure to obtain 30g(percent yield 97%) of an 3(S)-N-bromo-3-[(R)-l '-tert-butyl dimethyl silyloxy ethyl]-2-azetidinone as
colorless liquid.
1H NMR(CDCl3,300MHz): δ 0.15(s,6H), 0.95(s,9H), 1.26(d,3H,J=6.2Hz),
3.53(q,lH,J=3.0Hz), 3.59(m,lH),
3.69(m,lH), 4.33(m,lH) 13C NMR(CDCl3,300MHz): δ -5.08, -4.30, 17.79, 22.51, 25.65, 49.10, 60.98,
64.69, 169.45 UV- Visible: λmax= 295.0, ε= 323(n-hexane) λmax = 235.0, ε= 2007(n-hexane) IR(neat, cm"1): 2955, 2892, 2857,1775 [α]25 d = -68.8(c = 0.2, CHC13)
Example 3
3(S)-N-Cloro-3-r(R)-l '-hydroxy ethyll-2-azetidinone With the exception of substituting (3S)-3-[(R)-l'hydroxy ethyl]-2-azetidinone for (3 S)-3-[(R)-l '-tert-butyl dimethyl silyloxy ethyl]-2- azetidinone, the 3(S)-N-Cloro-3-[(R)-l '-hydroxy ethyl]-2-Azetidinone was obtained by same procedure of Example 1.
JH NMR(CDCl3,300MHz): δ 1.32(dd,3H,J=3.6, 6.2Hz), 1.96(d,lH,J=4.0Hz),
3.45(q,lH,J=4.2Hz), 3.67(d,2H,J=3.8Hz), 4.28(m,lH)
Example 4
(3 S)-N-Bromo-3-IYR 1 '-hydroxyethyn-2-azetidinone With the exception of substituting (3 S)-3-[(R)-l 'hydroxy ethyl]-2-azetidinone for (3 S)-3-[(R)-l '-tert-butyl dimethyl silyloxy ethyl]-2- azetidinone, the 3(S)-N-Cloro-3-[(R)-l '-hydroxy ethyl]-2-azetidinone was obtained by same procedure of Example 2
1H NMR(CDCl3,300MHz): 6 1.35(dd,3H,J=3.6, 6.2Hz), 1.98(d,lH,J=4.0Hz),
3.49(q,lH,J=4.2Hz), 3.72(d,2H,J=3.8Hz),
4.34(m,lH)
Example 5
(3 S,4S)-3-f(RVl '-tert-butyl dimethyl silyloxy ethyl -fU-diethoxy carbonyl ethyl)-2-azetidinone
In 50mL of ethanol was dissolved 10g(37.7 mmol) of
3(S)-N-Cloro-3-[(R)-l '-tert-butyl dimethyl silyloxy ethyl]-2-azetidinone and then the reaction solution was cooled at OT. The 71mL(188.5 mmol) of 41% sodium ethoxide was added and then the 105mL(377 mmol) of diethyl malonate was added. A reaction was vigorously stirred to proceed at 0°C for
1.5 hours. To the reaction mixture was added 50mL of saturated aqueous ammonium chloride and 50mL of water and then extracted with 200mL methylene chloride twice times. Subsequently, the organic layer was dried by anhydrous magnesium sulfate, evaporated in reduced pressure to obtain crude product. This oilic substance was purified by silica gel column chromatography using developing solvent(n-hexane : ethylacetate = 2 : 1), thereby obtaining 12.8g(percent yield 85%) of an (3S,4S)-3-[(R)-l '-tert-butyl dimethyl silyloxy ethyl]-4-(l,l-diethoxy carbonyl ethyl)-2-azetidinone as white crystals. 1H NMR(CDCl3,300MHz): δ 0.08(s,6H), 0.86(s,9H), 1.15(d,3H,J=6.2Hz),
1.25, 1.27(t,6H,J=7.1Hz), 1.47(s,3H), 3.0(m,lH), 4.14(d,lH,J=2.2Hz), 4.20(m,5H), 5.95(brs, 1H) Melting Point : 100 ~ 101 °C
Example 6
(3S,4SV3-r(R)-r-tert-butyl dimethyl silyloxy ethvH-4-(U-diethoxy carbonyl ethyl)-2-azetidinone
With the exception of substituting THF for ethanol as a solvent, 12.8g(percent yield 88%) of an (3S,4S)-3-[(R)-l '-tert-butyl dimethyl silyloxy
ethyl]-4-(l,l-diethoxy carbonyl ethyl)-2-azetidinone as white crystals.was obtained by same procedure of Example 5.
Example 7 (3S,4S)-3-r(RVr-tert-butyl dimethyl silyloxy emy 11-4-0,1 -dibenzyl carbonyl ethyl)-2-azetidinone
With the exception of substituting 112.3g(377 mmol) of a dibenzyl methyl malonate for 105mL(377 mmol) of a diethylmethyl malonate
16.4g(percent yield 80%) of an (3 S,4S)-3-[(R)-l '-tert-butyl dimethyl silyloxy ethyl]-4-( 1,1 -dibenzyl carbonyl ethyl)-2-azetidinone as white crystals.was obtained by same procedure of Example 6.
1H NMR(CDCl3,300MHz): δ 0.08(s,6H), 0.86(s,9H), 1.15(d,3H,J=6.2Hz),
1.47(s,3H), 3.0(m,lH), 4.14(d,lH,J=2.2Hz), 4.20(m,lH), 4.21(d,lH,J=2.1Hz), 5.12(m,lH), 5.95(br s, 1H), 7.20(m,4H), 7.35(m,6H)
Melting Point : 93 - 94 U
Example 8
(3 S,4S)-3-r(R -r -tert-butyl dimethyl silyloxy ethyll-4-r(l-(tert- butyloxy)-2-(ethoxy carbonyl ethyl)-2-azetidinone
With the exception of substituting 76.1g(377 mmol) of a tert-bytyl ethyl methyl malonate for 105mL(377 mmol) of a diethylmethyl malonate
13.1g(percent yield 83%) of an (3 S,4S)-3-[(R)-l ' -tert-butyl dimethyl silyloxy ethyl]-4-[(l-(tert- butyloxy) -2-(ethoxy) carbonyl ethyl)-2-azetidinone as white crystals.was obtained by same procedure of Example 6.
1H NMR(CDCl3,300MHz): δ 0.07(s,6H), 0.86(s,9H), 1.15,
1.20(dd,3H,J=6.2Hz), 1.27, 1.29(dd, 3H,J=7.1 MHz), 1.45, 1.47(s,9H), 3.0(m,lH), 4.04, 4.09(d, lH,J=2.1Hz), 4.21(m,5H), 5.95(br s, 1H) Melting Point : 73 ~ 74 °C
Example 9
(3S.4S)-3-r(R -l '-tert-butyl dimethyl silyloxy ethyn-4-(l-l-diaryloxy carbonyl ethyl)-2-azetidinone With the exception of substituting 74.6g(377 mmol) of a diaryl methyl malonate for 105mL(377 mmol) of a diethylmethyl malonate 12.5g(percent yield 80%) of an (3S,4S)-3-[(R)-l '-tert-butyl dimethyl silyloxy ethyl]-4- (1,1 -diary loxy carbonyl ethyl)-2-azetidinone as white crystals.was obtained by same procedure of Example 6. lH NMR(CDCl3,300MHz): δ 0.07(s,6H), 0.11(s,3H), 0.29(s,3H), 0.90,
0.95(s,9H), 1.22(d,3H,J=6.2Hz), 1.50(s,3H), 3.07(m,lH), 4.09(m,lH), 4.35(d,lH,J=2.6Hz), 4.64(m,4H), 5.30(m,4H), 5.90(m,2H)
Example 10 πS.4S)-3-r(R)-r-tert-butyl dimethyl silyloxy ethyn-4-(l.l-dicarboχy ethyl)-2-azetidinone
In a mixture of 20mL of ethanol and 5mL of water was dissolved 1.0g(2.49mmol) of the (3S,4S)-3-[(R)-l'-tert-butyl dimethyl silyloxy ethyl]-4-(l,l-diethoxy carbonyl ethyl)-2-azetidinone. Thereto was added a solution prepared by dissolving lg(7.36 mmol) of potassium hydroxide in 3mL of water. This mixture was kept being stirred for 5 hours with heating at 50 U . The reaction mixture was cooled to room temperature and then poured into 30mL of water. The resulting mixture was acidified with 2N hydrochloric acid and then the white solid thus formed was filtered off, washed with water, and then dried under a reduced pressure, thereby obtaining 0.55g(percent yield 65%) of a (3S,4S)-3-[(R)-l '-tert-butyl dimethyl silyloxy ethyl]-4-(l,l- dicarboxy ethyl)-2-azetidinone 1H NMR(CDCl3,300MHz): δ 0.02(s,3H), 0.04(s,3H), 0.87(s,9H), 1.14(d,3H,J=6.4Hz), 1.34(s,3H), 3.03(dd,lH,
J=2.7,2.1Hz), 4.19(d,lH,J=2.1Hz), 4.22(m,lH) Melting Point : 110 ~ 111 °C
Example 11 (3S.4SV3-r(R)- -fert-butyldimethylsilyloxy ethyl -ITRyi-carboxy ethyl]-2- azetidinone
In 15mL of diethylene glycol dimethyl ether was dissolved 1.0g(2.9 mmol) of a (3S,4S)-3-[(R)-l '-tert-butyl dimethyl silyloxy ethyl]-4-(l,l- dicarboxy ethyl)-2-azetidinone obtained in Example 10. This solution was heated at 120 °C for 3 hours. The reaction mixture was cooled to room temperature and extraction was then conducted using 20mL of diethyl ether and 15mL of a 5% aqueous solution of sodium hydroxide. Thereafter, aqueous layer was washed with lOmL of diethyl ether and then adjusted to pH 2 with 2N hydrochloric acid, and extraction was conducted using 30mL of diethyl ether. The diethyl ether layer obtained was washed with lOmL of saturated aqueous sodium chloride, subsequently dehydrated with anhydrous magnesium sulfate, and then filtered and concentrated, thereby obtaining 0.7 g(percent yield 80%) of a (3S,4S)-3-[(R)-l '-tert-butyl dimethyl silyloxy ethyl]-4-( 1 , 1 -dicarboxy ethyl)-2-azetidinone. The proportions of isomers were such that α : β = 5 : 95 and a
1H-NMR data is written down below.
1H NMR(CDCl3,300MHz): δ 0.08(s,6H), 0.87(s,9H), 1.21(d,3H,J=6.21Hz),
1.27(d,3H,J=7.03Hz), 2.75(m,lH), 3.04(m, 1H), 3.95(m,lH), 4.21(m,lH), 6.49(brs,lH) Melting Point : 143 ~ 1441
We can suggest economically and commercially valuable a new process, which is used synthesis of 1-BAA, especially 1-BMA, or 1-HA, which is an essential key intermediates of carbapenem antibiotics by taking
advantage of new azetidinone derivatives. 1-BAA is synthesized only with a general base and reactant in high yield using new azetidinone derivatives without any additional protecting group.
Claims
1. A azetidinone derivative represented by Formula 2:
[Formula 2]
2. Synthetic process of azetidinone derivatives represented Formula 2 as claimed in Claim 1, to which the reaction step that compound represented Formula 1 is reacted with a halogenation reagent and base is included.
[Formula 1 ]
3. A process as claimed in Claim 2, which is proceeded at -30 ~ 100°C .
4. A process as claimed in Claim 2, wherein said halogenation reagent is the chlorination reagent selected from the group consisting of N-chloro succinimide, chlorine, l,3-dichloro-5,5-dimethyl hydantoin, 1 -chloro benzotriazole, N-chloromorphorine, N-chloro succinimde-dimethyl sulfide, dimethylsulfide-chlorine, trichloro isocyanuric acid, trichloro methyl chloro formate, oxalic chloride, phosphorus(III) chloride, oxalic chloride-aluminum
chloride complex, phosphorus(V) chloride, thionyl chloride, oxalic chloride-dimethyl formamide, and phosphorus oxychloride.
5. A process as claimed in Claim 2, wherein said halogenation reagent is the iodination reagent selected from the group consisting of N-iodo succinimide, iodine, l,3-diiodo-5,5-dimethyl hydantoin, iodine monobromide, iodine monochloride, and methyl triphenoxy phosphonuim iodide.
6. A process as claimed in Claim 4 or Claim 5, which is proceeded at -10 ~ 40 °C.
7. A process as claimed in Claim 2, wherein said halogenation reagent is the bromination reagent selected from the group consisting of N-bromo succinimide, bromine, l,3-dibromo-5,5-dimethyl hydantoin, triphenyl phosphine-N-bromo succinimide, oxalic bromidie, 1,3-dibromo isocyanuric acid, 5,5-dibromo-2,2-dimethyl-l,3-dioxane-4,6-dione, thionyl bromide, phosphorus(III) bromide, N-bromo succinimide-dimethyl formamide, and N-bromo succinimide-dimethyl sulfide.
8. A process as claimed in Claim 7, which is proceeded at -30 ~ 20 °C .
9. A process as claimed in Claim 2, wherein said base is selected from the group consisting of;
Alkali metal acetates : lithium acetate, sodium acetate, potassium acetate, rubidium acetate, cesium acetate, and etc.
Alkali metal carbonates : lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, and etc. and Alkali metal bicarbonates : sodium bicarbonate, potassium bicarbonate, and etc.
10. A process as claimed in Claim 2, wherein said base is selected from the group consisting of;
Trialkyl amines : triethyl amine, and etc. Pyridine compounds : pyridine, rutidine, picoline, and etc. Quinoline and imidazole
11. A process as claimed in Claim 2, which is used 1 eq. of halogenation reagent and 1~5 eq. of base are used per 1 eq. of substrate.
12. A process for producing 1-β-alkyl azetidinone derivatives represented formula 5, which is used azetidinone derivatives represented Formula 2 as claimed in Claim 1.
[Formula 5]
13. A process of 1-β-alkyl azetidinone represented Formula 5, to which is included the reaction step that azetidinone derivatives represented Formula 2 as claimed in Claim 1 are reacted with a base and malonic acid derivative represented Formula 6. [Formula 3 J
14. A process as claimed in Claim 13, which is proceeded at -78 - 50 °C .
15. A process as claimed in Claim 13, wherein said base is selected from the group consisting of lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, sodium w-propoxide, potassium methoxide, potassium ethoxide, and potassium w-propoxide.
16. A process as claimed in Claim 13, wherein said malonic acid derivative represented Formula 6 is selected from the group consisting of diethylmalonate, diethyl methyl malonate, dibenzyl methyl malonate, tert-butyl ethyl methyl malonate, and diallyl methyl malonate.
17. A process as claimed in Claim 13, which is used ethyl alcohol or THF as a solvent.
18. A process as claimed in Claim 17, which is used THF as a solvent.
19. A process as claimed in any one of claims 13 to 18, which is used 1 - 12 eq. of malonic acid derivatives represented Formula 6 and 3-12 eq. of base are used per 1 eq. of azetidinone derivatives represented Formula 2.
20. A process as claimed in Claim 19, which is used 10 eq. of malonic acid derivatives represented Formula 6 and 5 eq. of base are used per 1 eq. of azetidinone derivatives represented Formula 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU44802/01A AU4480201A (en) | 2000-03-31 | 2001-03-29 | Azetidinone derivatives, a process for their preparation and a method for producing 1-beta-alkyl azetidinone using the same |
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|---|---|---|---|
| KR2000/17011 | 2000-03-31 | ||
| KR1020000017011A KR100335848B1 (en) | 2000-03-31 | 2000-03-31 | Azetidinone derivatives, a process for their preparation and a method for producing 1-β-alkylazetidinone using the same |
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| KR (1) | KR100335848B1 (en) |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20010107078A (en) * | 2000-05-25 | 2001-12-07 | 윤재승 | Method of preparing 4-alkoxy-2-azetidinone derivative and its optical isomer |
| WO2004103966A1 (en) * | 2003-05-21 | 2004-12-02 | Ckd Bio Corporation | Chiral 2-azetidinone compounds, process and use thereof |
| EP2030977A1 (en) * | 2006-06-16 | 2009-03-04 | Kaneka Corporation | Improved method for crystallization of azetidinonecarboxylic acid |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5081238A (en) * | 1985-10-29 | 1992-01-14 | Sagami Chemical Research Center | βmethyl azetidinone derivatives and stereoselective process for preparing the same |
| JPH05148260A (en) * | 1991-05-31 | 1993-06-15 | Sankyo Co Ltd | Azetidinone derivative and its production |
| JPH05155850A (en) * | 1991-12-09 | 1993-06-22 | Takasago Internatl Corp | Azetidine-2-one derivative |
| EP0573667A1 (en) * | 1991-12-26 | 1993-12-15 | Nippon Soda Co., Ltd. | Process for producing 4-substituted azetidinone derivative |
| US5654424A (en) * | 1992-09-18 | 1997-08-05 | Merck & Co., Inc. | Preparation of beta-methyl carbapenem intermediates |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0725848A (en) * | 1993-07-13 | 1995-01-27 | Nippon Soda Co Ltd | Production of 4-substituted azetidinone derivative |
| JP3748933B2 (en) * | 1996-01-19 | 2006-02-22 | 株式会社カネカ | Process for producing 1-substituted azetidinone derivatives |
| KR20000074884A (en) * | 1999-05-27 | 2000-12-15 | 김선진 | Process for the preparation of azetidinone derivatives |
| JP3191802B2 (en) * | 1999-06-17 | 2001-07-23 | 三菱電機株式会社 | Communication device and communication method |
-
2000
- 2000-03-31 KR KR1020000017011A patent/KR100335848B1/en not_active IP Right Cessation
-
2001
- 2001-03-29 WO PCT/KR2001/000507 patent/WO2001072704A1/en active Application Filing
- 2001-03-29 AU AU44802/01A patent/AU4480201A/en not_active Abandoned
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5081238A (en) * | 1985-10-29 | 1992-01-14 | Sagami Chemical Research Center | βmethyl azetidinone derivatives and stereoselective process for preparing the same |
| JPH05148260A (en) * | 1991-05-31 | 1993-06-15 | Sankyo Co Ltd | Azetidinone derivative and its production |
| JPH05155850A (en) * | 1991-12-09 | 1993-06-22 | Takasago Internatl Corp | Azetidine-2-one derivative |
| EP0573667A1 (en) * | 1991-12-26 | 1993-12-15 | Nippon Soda Co., Ltd. | Process for producing 4-substituted azetidinone derivative |
| US5654424A (en) * | 1992-09-18 | 1997-08-05 | Merck & Co., Inc. | Preparation of beta-methyl carbapenem intermediates |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20010107078A (en) * | 2000-05-25 | 2001-12-07 | 윤재승 | Method of preparing 4-alkoxy-2-azetidinone derivative and its optical isomer |
| WO2004103966A1 (en) * | 2003-05-21 | 2004-12-02 | Ckd Bio Corporation | Chiral 2-azetidinone compounds, process and use thereof |
| EP2030977A1 (en) * | 2006-06-16 | 2009-03-04 | Kaneka Corporation | Improved method for crystallization of azetidinonecarboxylic acid |
| EP2030977A4 (en) * | 2006-06-16 | 2011-06-01 | Kaneka Corp | Improved method for crystallization of azetidinonecarboxylic acid |
| US8232389B2 (en) | 2006-06-16 | 2012-07-31 | Kaneka Corporation | Method for crystallization of azetidinonecarboxylic acid |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20010094618A (en) | 2001-11-01 |
| KR100335848B1 (en) | 2002-05-08 |
| AU4480201A (en) | 2001-10-08 |
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