WO2006028037A1 - Process for production of intermediates for the synthesis of carbapenems - Google Patents
Process for production of intermediates for the synthesis of carbapenems Download PDFInfo
- Publication number
- WO2006028037A1 WO2006028037A1 PCT/JP2005/016230 JP2005016230W WO2006028037A1 WO 2006028037 A1 WO2006028037 A1 WO 2006028037A1 JP 2005016230 W JP2005016230 W JP 2005016230W WO 2006028037 A1 WO2006028037 A1 WO 2006028037A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- acid
- salt
- hydrogen
- ozone
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title claims abstract description 34
- 229940041011 carbapenems Drugs 0.000 title abstract 2
- 239000000543 intermediate Substances 0.000 title description 10
- 230000015572 biosynthetic process Effects 0.000 title 1
- 238000003786 synthesis reaction Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 88
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims abstract description 72
- 239000002253 acid Substances 0.000 claims abstract description 71
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 46
- 239000001257 hydrogen Substances 0.000 claims abstract description 46
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 43
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 23
- 230000003647 oxidation Effects 0.000 claims abstract description 19
- 230000001590 oxidative effect Effects 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims description 65
- 239000000126 substance Substances 0.000 claims description 45
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 39
- 125000006239 protecting group Chemical group 0.000 claims description 30
- 230000002411 adverse Effects 0.000 claims description 28
- 125000001424 substituent group Chemical group 0.000 claims description 22
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 19
- -1 alkyl silyl compound Chemical class 0.000 claims description 18
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 230000002829 reductive effect Effects 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 7
- 150000007513 acids Chemical class 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 125000003460 beta-lactamyl group Chemical group 0.000 abstract description 2
- 231100000989 no adverse effect Toxicity 0.000 abstract 2
- 235000002639 sodium chloride Nutrition 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 25
- 238000011282 treatment Methods 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 235000011054 acetic acid Nutrition 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000013067 intermediate product Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000005103 alkyl silyl group Chemical group 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- WURFKUQACINBSI-UHFFFAOYSA-M ozonide Chemical compound [O]O[O-] WURFKUQACINBSI-UHFFFAOYSA-M 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 230000020477 pH reduction Effects 0.000 description 3
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- 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 3
- 239000011541 reaction mixture Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 241000709400 Ruba Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- RBBOWEDMXHTEPA-UHFFFAOYSA-N hexane;toluene Chemical compound CCCCCC.CC1=CC=CC=C1 RBBOWEDMXHTEPA-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical class ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 description 1
- HYPHAZNETCAFJU-UHFFFAOYSA-N 2-propan-2-yloxypropane;toluene Chemical compound CC(C)OC(C)C.CC1=CC=CC=C1 HYPHAZNETCAFJU-UHFFFAOYSA-N 0.000 description 1
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical compound NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- ZKQDCIXGCQPQNV-UHFFFAOYSA-N Calcium hypochlorite Chemical compound [Ca+2].Cl[O-].Cl[O-] ZKQDCIXGCQPQNV-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 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 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- XNCRUNXWPDJHGV-UHFFFAOYSA-N alpha-Methyl-cinnamic acid Chemical compound OC(=O)C(C)=CC1=CC=CC=C1 XNCRUNXWPDJHGV-UHFFFAOYSA-N 0.000 description 1
- OJYGBLRPYBAHRT-UHFFFAOYSA-N alphachloralose Chemical compound O1C(C(Cl)(Cl)Cl)OC2C(O)C(C(O)CO)OC21 OJYGBLRPYBAHRT-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 125000000637 arginyl group Chemical class N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- VBQDSLGFSUGBBE-UHFFFAOYSA-N benzyl(triethyl)azanium Chemical class CC[N+](CC)(CC)CC1=CC=CC=C1 VBQDSLGFSUGBBE-UHFFFAOYSA-N 0.000 description 1
- YOUGRGFIHBUKRS-UHFFFAOYSA-N benzyl(trimethyl)azanium Chemical class C[N+](C)(C)CC1=CC=CC=C1 YOUGRGFIHBUKRS-UHFFFAOYSA-N 0.000 description 1
- 239000007844 bleaching agent Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 229910000358 iron sulfate Inorganic materials 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 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
- 150000002537 isoquinolines Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- ZUZLIXGTXQBUDC-UHFFFAOYSA-N methyltrioctylammonium Chemical class CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC ZUZLIXGTXQBUDC-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000008301 phosphite esters Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 150000003018 phosphorus compounds Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
- 239000004071 soot Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical class CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
Definitions
- the present invention relates to a method for producing a synthetic intermediate of force ruba penem, an intermediate for use in the method, and a method for producing force ruba penem using the same.
- Patent Document 2 Reference Example 13
- Patent Document 1 JP-A-5-105660
- Patent Document 2 JP-A-63-112558
- Non-Patent Document l Berks, A. H. Tetrahedron 1996, 52, 331-375
- Non-Patent Document 2 Itani, H .; Uyeo, S. Synlett 1995, 213
- Patent Document 3 Aratani, M .; Hirai, H .; Sawada, K .; Yamada, A .; Hashimoto, M. Tetra hedron Lett. 1987, 26, 223.
- Non-Patent Document 4 Ona, H .; Uyeo, S .; Motokawa, K .; Yoshida, T. Chem. Pharm. Bull, 1 985, 33, 4346.
- Non-Patent Document 5 Ponsford, RJ; Roberts, PM; Southgate, RJCS Chem. Comm., 1979, 847. or Bateson, JH; Quinn, AM; Southgate, R. Tetrahedron Lett. 19 87, 28, 1561.
- Non-Patent Document 6 Rakhit, S .; Gut, M. J. Org. Chem., 1964, 29, 229.
- R is an optionally substituted j8-lactam ring group that does not adversely affect ozone acid; and is substituted with hydrogen or a substituent that does not adversely affect ozone acid
- step of converting the compound (I) represented by V or lower alkyl) or a salt thereof into an ozone acid
- the production method according to the above (1) which comprises a step of subjecting the compound (I) or a salt thereof obtained by acidification with ozone to an acid treatment or a base treatment.
- R is an optionally substituted j8-lactam ring group that does not adversely affect ozone acid; and is substituted with hydrogen or a substituent that does not adversely affect ozone acid
- the compound (I) represented by V or lower alkyl) or a salt thereof is acidified with ozone and then reduced to give a compound represented by the formula:
- Equation (7)
- R is an optionally substituted j8-lactam ring group that does not adversely affect ozone acid; and is substituted with hydrogen or a substituent that does not adversely affect ozone acid
- V which may be lower alkyl
- R ′ is a carboxy-protecting group
- R is an optionally substituted j8-lactam ring group that does not adversely affect ozone acid; and is substituted with hydrogen or a substituent that does not adversely affect ozone acid
- R is the formula:
- R 1 is a substituent that does not adversely affect hydrogen or ozone acid
- R 2 is a hydrogen or an imino protecting group Described manufacturing Method.
- R is the formula:
- R 1 is hydrogen or protected, may be substituted with hydroxy, may be alkyl; R 2 is hydrogen or an imino protecting group) and is a j8-ratata ring group,
- the manufacturing method according to any one of 1 to 9 above.
- R is the formula:
- R is the formula:
- R 1 is hydrogen or protected, may be substituted with hydroxy, may be alkyl;
- R 2 is hydrogen or an imino protecting group) and is a j8-ratata ring group, 1-9 above
- R is lower alkyl, and R is a formula:
- R is hydrogen or lower alkyl; R 1 is optionally substituted with hydroxy, and alkyl; R 2 is hydrogen or imino protecting group) (1-1) ) Or a salt thereof, optionally in the presence of an acid, with an acid solution with ozone.
- R is an optionally substituted j8-lactam ring group that does not adversely affect ozone acid; and is substituted with hydrogen or a substituent that does not adversely affect ozone acid
- R is lower alkyl; R 1 is alkyl optionally substituted with protected hydroxy; R 2 is hydrogen or imino protecting group) (II-1) or a salt thereof, 19.
- II-1 imino protecting group
- the present invention relates to 1-alkylcarboxylic acids from acrylic acid derivatives using ozone acid.
- a method for efficiently producing the above is provided.
- the target product can be obtained with high yield by ozone oxidation in the presence of acid. It is also possible to control the isomerism of 1 ⁇ alkyl to a form by selecting post-treatment means after the oxidation reaction.
- the present invention also provides novel intermediates.
- each term has the following meanings singly or in combination unless otherwise specified. May be substituted with a substituent that does not adversely affect hydrogen or ozone acid! / ⁇ is lower alkyl, preferably hydrogen or lower alkyl (eg, C1-C6 alkyl). More preferred is lower alkyl, particularly methyl, and even more preferred is a j8 configuration as the configuration with respect to the ⁇ -lactam ring. Therefore, particularly preferred is 1 j8-methyl.
- R is a j8-ratata ring group which may be substituted with a substituent that does not adversely affect the ozone acid group.
- the substituents may be the same or different, and 1 to 3, preferably 1 to 2 substituents may be substituted at substitutable positions on the ⁇ -ratata ring.
- the substituent is more preferably one substituted at the 3-position carbon atom of the j8-ratata ring, and particularly preferably the above-mentioned alkyl (preferably C1-C10 alkyl, more preferably C1). -C6 alkyl), and more preferably alkyl substituted with protected hydroxy.
- “Substituents that do not adversely affect the ozone acid” means a group that does not adversely affect the ozone acid in terms of steric environment or electronic environment in performing the ozone acid of the compound (I). means.
- the group itself is not easily oxidized by ozone acid, and more preferably a structure or functional group that is highly reactive to ozone (eg, carbon-carbon unsaturated bond, aldehyde, acetal).
- Aldehyde group, amide-containing primary amine, sulfide, phosphine) are not included in the structure.
- a functional group protected by a protecting group eg, protected amino, protected hydroxy may be present.
- the “substituent that does not adversely affect the ozone acid” is more preferably 1) optionally substituted alkyl, preferably lower alkyl (e.g., 1 to 6 carbon atoms), more preferably carbon. Lower alkyl having 1 to 4 (eg, methyl, ethyl, n-propyl, isopropyl, n butyl, etc.), 2) optionally substituted cycloalkyl, preferably cycloalkyl having 3 to 6 carbons (eg, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3) substituted, cycloalkyl lower alkyl and the like. “It ’s replaced.
- substituent of “I” examples include hydroxy which may be protected, protected amino, carboxy which may be protected, lower alkyl, halogen, lower alkoxy, halogenated lower alkyl, halogenated lower alkoxy and the like. More preferably, it may be protected hydroxy.
- R is more specifically
- R 1 is a substituent that does not adversely affect hydrogen or ozone acid;
- R 2 is a hydrogen or an imino protecting group) and is a ⁇ -ratata ring group.
- R 1 is preferably hydrogen or optionally substituted alkyl as described above, and more preferably protected and optionally substituted with hydroxy! Well! /, Alkyl.
- R 2 is hydrogen or an imino protecting group, preferably hydrogen.
- R is particularly preferably the formula:
- hydroxy protecting groups include alkylsilyl (eg, trimethylsilyl, t-butyl dimethylsilyl), asil (eg, acetyl, bivaloyl), lower alkyl (eg, methyl, ethyl), alkoxyalkyl (eg, methoxymethyl, methoxyethyl), Examples of lower alkylsulfol (eg, methanesulfur) and alkoxycarbol (eg, methoxycarbol) are preferred. Alkylsilyl is preferable.
- Examples of the imino protecting group include the above alkylsilyl and optionally substituted lower alkyl ( Examples of substituents include optionally protected carboxy) and the like.
- a lower alkoxycarboxyl eg, aryloxycarbol
- substituted e.g, aryloxycarbol
- aralkyloxycarbole e.g, p-trobenzyloxycarbol
- the imino protecting group for R 2 is preferably CH CO R 4 (R 4 is
- a protective group eg, aryl, p-trobenzyl.
- the present invention provides a process for producing compound (III) or a salt thereof, which comprises the step of oxidizing compound (I) or a salt thereof.
- the “ozone oxidation” in the present invention means a reaction that leads to a target product by cleaving the bulge part of compound (I) with acidified with ozone. More specifically, various post-treatments (eg, oxidation, reduction, base treatment, hydrolysis, etc.) usually performed as desired in order to convert various intermediates (eg, molysonide, ozonide) generated by the oxidation reaction into stable products. ) Means the process including
- Ozone acid may be basically produced according to the reaction conditions of ozone acid well known to those skilled in the art.
- the oxidation requires only electric power and oxygen to generate ozone as an oxidation source, and does not generate waste such as heavy metals, so it is a very excellent oxidation method in terms of environment.
- ozone generation is usually performed by passing oxygen containing about 1-10% ozone into the reaction solution.
- Solvents used include hydrocarbons (eg pentane, hexane, heptane, cyclohexane, petroleum ether), halogenated hydrocarbons (eg dichloromethane, chloroform, carbon tetrachloride), alcohols (eg: (Methanol, ethanol), formic acid, acetic acid, propionic acid, ethyl acetate, acetone, formamide, nitromethane, acetonitrile, ether (eg, tetrahydrofuran, jetyl ether), water and mixed solvents thereof are exemplified, but preferably Is acetic acid, ethyl acetate or methanol.
- hydrocarbons eg pentane, hexane, heptane, cyclohexane, petroleum ether
- halogenated hydrocarbons eg dichloromethane, chloroform, carbon tetrachloride
- alcohols e
- the reaction temperature is usually 78 ° C to room temperature, preferably 78 ° C to 0 ° C.
- the time for the oxidation reaction itself is usually several minutes to several hours, more preferably several minutes to 30 minutes.
- the progress of the acid-oxidation reaction can be judged by the change in the color of the solution. Usually, when it is colored blue, the introduction of ozone is stopped, and preferably nitrogen substitution is performed. Next, the solution containing the produced intermediate product can be converted into the target oxide by post-treatment.
- the oxide is a force that is compound (III), or compound (II) that is an intermediate thereof.
- the present invention includes at least a two-route production method that varies in form depending on the use of an acid during ozone oxidation and the post-treatment method.
- each route will be described.
- This route is a method for directly obtaining the compound (III) or a salt thereof by ozone-oxidizing the compound (I) or a salt thereof.
- compound (III) or a salt thereof can be obtained by post-treatment of an intermediate product obtained by acidifying compound (I) or a salt thereof with ozone.
- the reaction temperature is more preferably ⁇ 50 to 0 ° C., further preferably ⁇ 45 to ⁇ 35 ° C.
- the oxidation is carried out in the presence or absence of a reaction accelerator.
- An example of the reaction accelerator is an acid, and the oxidation is preferably performed in the presence of an acid. This reaction proceeds without the addition of an acid, but this is thought to be because both the raw material compound (I) and the product (III) have a carboxylic acid structure.
- Examples of the acid used in combination include organic acids and inorganic acids.
- Organic acids include formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, propionic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, malic acid, citrate, ascorbic acid, oxalic acid, succinic acid, etc. Is exemplified.
- Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
- acetic acid or an acid having the same degree of acidity (eg, propionic acid, succinic acid).
- acetic acid which also serves as a solvent.
- the amount of the acid to be used is generally 0.1-50 equivalents, preferably 1-30 equivalents, relative to compound (I). More preferably, it is 3-20 equivalents, Most preferably, it is 5-15 equivalents.
- the structure of the intermediate product (ozone product) obtained by the above acid is not clear, and there may be a mixture of a plurality of intermediates other than the generally generated ozonide.
- the post-treatment method includes various methods capable of converting the intermediate product (ozone product) to the compound (III), and is preferably an oxidation treatment or a base treatment.
- oxidizing agents for the oxidation treatment include peracetic acid, performic acid, hydrogen peroxide, alkaline silver oxide, chromic acid, peroxytrifluoroacetic acid, m-chloroperbenzoic acid, bleached powder, and sodium peroxofolate.
- the exemplified power is preferably hydrogen peroxide, more preferably about 10-30% aqueous hydrogen peroxide.
- Examples of the base for base treatment include inorganic bases and organic bases.
- Inorganic bases include hydroxides and alkali metals (eg LiOH, NaOH, KOH), alkaline carbonates (eg Li CO, Na CO, K CO), alkali metal hydrogen carbonates (eg LiHCO, Na
- Examples are reusable metals (MgCO, CaCO 3).
- Organic bases include aliphatic amines (eg, trimethylamine, triethylamine, dicyclohexamine, ethanolamine, diethanolamine, triethanolamine, brocaine), aromatic amines (eg, pyridine, picoline, quinoline, amide). -Phosphorus) is exemplified.
- the post-treatment is preferably carried out by acid soot treatment. Also, if the post-treatment is too long, the intermediate product or final product may be decomposed.
- the time required for the post-treatment is usually several hours to several tens of hours, preferably 1 to L0 hours, more preferably 2 to 8 hours, and particularly preferably 3 to 6 hours.
- reaction mechanism of this route is not clear at the present time, and one example is shown below for reference, as it may be possible to follow multiple reaction paths. However, this is only an estimation and does not limit the present invention.
- This route is a method for obtaining compound (III) by obtaining compound (II) from compound (I), and specifically includes the following steps.
- An intermediate product is obtained by acidifying the compound (I) or a salt thereof with ozone.
- the conditions of the acid conditions are as described above. This process proceeds smoothly even without adding a reaction accelerator such as an acid.
- the reaction temperature is preferably lower than the A / rate, more preferably 78 ° C to -50 ° C.
- the intermediate product obtained is post-treated by a reduction reaction to obtain compound (II). Although the intermediate product has not been isolated, it is presumed that it passes through the ozonide represented by the above ( ⁇ ) in light of the general reaction mechanism of ozone oxidation.
- various methods can be used as long as they are generally used in the reductive decomposition reaction of ozonide.
- zinc powder catalytic hydrogenation method (hydrogen Z metal catalyst (Example: platinum, rhodium, nickel, rhodium)), phosphorus compounds (example: phosphite esters, triphenylphosphine), dimethylsulfide, sodium iodide, sodium hydrogen sulfite, sodium chloride
- catalytic hydrogenation method hydrogen Z metal catalyst (Example: platinum, rhodium, nickel, rhodium)
- phosphorus compounds example: phosphite esters, triphenylphosphine
- dimethylsulfide sodium iodide
- sodium hydrogen sulfite sodium chloride
- Reduction with iron sulfate is exemplified, but reduction with dimethylsulfide is preferable.
- the temperature of the reduction reaction is usually 78 ° C to 50 ° C, preferably 0 ° C to room temperature.
- the reaction time is several tens of minutes to several hours.
- oxidation method various methods can be used as long as they are generally methods capable of converting ketocarboxylic acid to carboxylic acid.
- the oxidizing agent include hydrogen peroxide, perchloric acid, hypochlorous acid, bleaching powder, m-chloroperbenzoic acid, sodium peroxoborate, periodic acid or a salt thereof, odosobenzene, ozone, and potassium peracid. Etc. are exemplified. Alternatively, it may be converted into carboxylic acid by hydrofluoric acid or hydrolysis using light.
- Solvents include hydrocarbons (eg, pentane, hexane, heptane, cyclohexane, petroleum ether), halogenated hydrocarbons (eg: dichloromethane, chloroform, carbon tetrachloride), alcohols (eg, methanol, ethanol). ), Ether (eg, tetrahydrofuran, jetyl ether), ethyl acetate, acetone, formamide, nitromethane, acetonitrile, water, or a mixed solvent thereof.
- hydrocarbons eg, pentane, hexane, heptane, cyclohexane, petroleum ether
- halogenated hydrocarbons eg: dichloromethane, chloroform, carbon tetrachloride
- alcohols eg, methanol, ethanol.
- Ether eg, tetrahydrofuran, jetyl ether
- the reaction temperature is usually _78 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
- the reaction time is several tens of minutes to several hours.
- the production method further includes the following aspects.
- compound (III) is obtained by the method of route A or B as described above.
- Compound (I) or a salt thereof may be isolated, but the reaction may be performed without complete isolation.
- the reaction liquid after deprotecting the compound ( ⁇ ) is post-treated (eg, washed with water, extracted and dried), concentrated, and then the solvent is added to the residue obtained to introduce ozone. . More preferably, the reaction proceeds from the compound (I ′) to the route A via the compound (I).
- various carboxy protecting groups can be used, and examples thereof include lower alkyl (eg, ethyl), aralkyl (eg, benzyl), and substituted silyl (eg, trimethylsilyl).
- Deprotection may be performed in accordance with the conditions of a normal carboxy deprotection reaction. For example, hydrolysis may be performed with an alkali (eg, NaOH). The reaction temperature is usually ⁇ 20 ° C. to 50 ° C., preferably under ice cooling to room temperature.
- the compound (II) is preferably the compound (II 1), more preferably the compound (II 2), particularly preferably the compound (II 3), and both are useful as a synthetic intermediate of the compound (III).
- Examples of the salt in the present specification include basic salts such as alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt; Triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, brocaine, medalamine, diethanolamine, ethylenediamine, and other aliphatic amines such as ⁇ , ⁇ -dibenzyl ethylenediamine, venetamine, etc.
- basic salts such as alkali metal salts such as sodium salt and potassium salt
- alkaline earth metal salts such as calcium salt and magnesium salt
- ammonium salt such as sodium salt and magnesium salt
- trimethylamine salt Triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, brocaine, medalamine, diethanolamine, ethylenediamine, and other aliphatic amines such as ⁇ , ⁇ -dibenzyl
- pyridine salt pyridine salt, picoline salt, quinori Heterocyclic aromatic amine salts such as chloroquine salts and isoquinoline salts; tetramethyl ammonium salt, tetraethyl ammonium salt, benzyltrimethyl ammonium salt, benzyltriethyl ammonium salt, benzyltributyl ammonium salt Quaternary ammonium salts such as -um salt, methyltrioctyl ammonium salt, tetrabutylammonium salt; and basic amino acid salts such as arginine salt and lysine salt.
- the acid salt examples include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; acetate, propionate, lactate, maleate , Organic acid salts such as fumarate, tartrate, malate, citrate, and ascorbate; sulfonic acids such as methanesulfonate, isethionate, benzenesulfonate, and P-toluenesulfonate Salt; acidic amino acids such as aspartate, glutamate and the like.
- inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; acetate, propionate, lactate, maleate , Organic acid salts such as fumarate, tartrate, malate, citrate, and ascorbate
- sulfonic acids such as methanesulfonate, isethionat
- Compounds (1) and (II) are used in the above reaction as they are or as salts.
- Compounds (II) and (III) can be obtained as free forms or as salts.
- the free form can be easily converted into various salts by subjecting it to a known salt formation reaction.
- Examples are shown below. Examples 1 to 4 are examples of the B route, and Examples 5 to 8 are examples of the A / rate. a l represents the isomer ratio of 1 j8-methyl.
- TBS t-Butino Resi Mechinoresirinore
- ⁇ ⁇ 9 ⁇ "'p ⁇ ) oz'i' ( s ⁇ 6) 8 '( s ⁇ ) 80' ( s ⁇ ) 90 ' ⁇ ) Awakening-H T in
- ketocarboxylic acid 2 200 mg
- dichloromethane / acetonitrile 1.OmL—2.0 mL
- a solution of bleached powder 289 mg
- acetic acid 0.3 mL
- the reaction solution was poured into a mixture of dichloromethane and aqueous Na 2 SO 4 solution.
- the organic layer was separated by adjusting the pH of the solution to 2 and washed with saturated brine. Dry with MgSO
- Acetic acid (1.74 mL) was added to an ethyl acetate solution (8.0 mL) of acrylic acid l (l.OOg), and the mixture was stirred at -40 ° C. Ozone was introduced for 15 minutes, and after confirming that the solution was colored pale blue, the atmosphere was replaced with nitrogen. After adding 30% hydrogen peroxide-hydrogen water (1.56 mL) and stirring under ice-cooling for 1 hour and further stirring at room temperature for 2 hours, the reaction mixture was mixed with ethyl acetate and Na S 0 aqueous solution (10 equivalents). Added to.
- Acetic acid (l.OmL) was added to an ethyl acetate solution (4.0 mL) of acrylic acid l (500 mg) and stirred at -10 ° C. Ozone was introduced for 15 minutes, and after confirming that the solution was colored pale blue, the atmosphere was replaced with nitrogen. The reaction solution was added dropwise to a saturated aqueous NaHCO solution (40 mL) under ice-cooling, and the mixture was stirred at room temperature. Reaction liquid
- Acetic acid (2.60 mL) was added to an ethyl acetate solution (7.0 mL) of acrylic acid l (l.OOg), stirred at -10 ° C, ozone was introduced for 15 minutes, and the solution turned pale blue. After confirmation, nitrogen substitution was performed. After adding 30% hydrogen peroxide aqueous solution (1.56 mL) and stirring at room temperature for 2.5 hours, the reaction solution was poured into a mixture of ethyl acetate and aqueous Na 2 S 0 solution (10 equivalents). The separated organic layer was washed with saturated brine.
- the present invention is useful as an industrial production method for powerful rubapenem antibacterial agents.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
[PROBLEMS] There is a need for a process enabling industrially efficient production of 1-alkylcarboxylic acids, preferably 1β-alkylcarboxylic acids, which are useful as the raw material in the production of carbapenems or the like. [MEANS FOR SOLVING PROBLEMS] A process for the production of compounds (III) which comprises the step of oxidizing a compound (I) with ozone: (X) wherein R is a β-lactam ring group optionally substituted with a group which has no adverse effect on the oxidation with ozone; and R0 is hydrogen or lower alkyl optionally substituted with a group which has no adverse effect on the oxidation with ozone.
Description
力ルバぺネムの合成中間体の製造方法 Method for producing synthetic intermediate of rubabapenem
技術分野 Technical field
[0001] 本発明は、力ルバぺネムの合成中間体の製造方法、該製造方法に使用するため の中間体、およびそれを利用した力ルバぺネムの製法に関する。 The present invention relates to a method for producing a synthetic intermediate of force ruba penem, an intermediate for use in the method, and a method for producing force ruba penem using the same.
背景技術 Background art
[0002] 1 βーメチルカルボン酸、詳しくは下記の 4 β ~(1 βーメチルー 1 カルボキシ ) 2 ーァゼチジノン（3)は、力ルバぺネム系抗菌剤の重要な合成中間体であり、これまで に多くの合成法が知られている（参考:非特許文献 1)。その中で、市販化合物 4から 安価かつ容易に製造できる公知の 4 18— (1 βーメチルー 2 カルボキシー 2 プロべ 二ル)一 2—ァゼチジノン (1)を出発原料に用いる合成法としては、過マンガン酸塩を 用いる酸ィ匕反応が知られているだけである (参考:特許文献 1、非特許文献 2)。当該 方法は、重金属である過マンガン酸塩を多量に用いるため環境負荷が高ぐまた 1か らの単離収率も 60%以下と低く、工業的製法としては満足の 、く方法ではな!/、。 [0002] 1 β-methyl carboxylic acid, specifically 4 β ~ (1 β-methyl-1 carboxy) 2 -azetidinone (3) below, is an important synthetic intermediate of power rubapenem antibacterial agent, A synthesis method is known (reference: Non-patent document 1). Among them, as a synthesis method using known 4 18- (1 β-methyl-2 carboxy-2 probe) 1-2-azetidinone (1) as a starting material, which can be produced inexpensively and easily from commercially available compound 4, permanganese is used. Only acid-acid reactions using acid salts are known (Reference: Patent Document 1, Non-Patent Document 2). This method uses a large amount of heavy metal permanganate, which has a high environmental impact, and the isolation yield from 1 is as low as 60% or less, which is not a satisfactory method for industrial production. /.
[化 1] [Chemical 1]
化 7→8 :非特許文献 3 7 → 8: Non-patent document 3
化 7→8→8'：非特許文献 4 7 → 8 → 8 ': Non-patent document 4
化 7→8 '：非特許文献 5 7 → 8 ': Non-patent literature 5
化 7→9：特許文献 2、参考例 13 7 → 9: Patent Document 2, Reference Example 13
また一般に酸存在下での脱カルボ-ルまたは脱炭酸を伴うオゾン酸ィ匕は、異常分 解反応の一つであると認識されており、以下のような反応が公知であるがあまり例は 多くな!/ヽ (参照：非特許文献 6等） In general, decarboxylation or decarboxylation in the presence of acid is recognized as one of the abnormal decomposition reactions, and the following reactions are known, but there are few examples. Many! / ヽ (Ref: Non-Patent Document 6 etc.)
[化 3] [Chemical 3]
特許文献 2：特開昭 63 - 112558 Patent Document 2: JP-A-63-112558
非特許文献 l : Berks, A. H. Tetrahedron 1996, 52, 331-375 Non-Patent Document l: Berks, A. H. Tetrahedron 1996, 52, 331-375
非特許文献 2 : Itani, H.; Uyeo, S. Synlett 1995, 213 Non-Patent Document 2: Itani, H .; Uyeo, S. Synlett 1995, 213
^^特許文献 3 :Aratani, M.; Hirai, H.; Sawada, K.; Yamada, A.; Hashimoto, M. Tetra hedron Lett. 1987, 26, 223. ^^ Patent Document 3: Aratani, M .; Hirai, H .; Sawada, K .; Yamada, A .; Hashimoto, M. Tetra hedron Lett. 1987, 26, 223.
非特許文献 4 : Ona, H.; Uyeo, S.; Motokawa, K.; Yoshida, T. Chem. Pharm. Bull, 1 985, 33, 4346. Non-Patent Document 4: Ona, H .; Uyeo, S .; Motokawa, K .; Yoshida, T. Chem. Pharm. Bull, 1 985, 33, 4346.
非特許文献 5 : Ponsford, R. J.; Roberts, P. M.; Southgate, R. J. C. S. Chem. Comm., 1979, 847.または Bateson, J. H.; Quinn, A. M.; Southgate, R. Tetrahedron Lett. 19
87, 28, 1561. Non-Patent Document 5: Ponsford, RJ; Roberts, PM; Southgate, RJCS Chem. Comm., 1979, 847. or Bateson, JH; Quinn, AM; Southgate, R. Tetrahedron Lett. 19 87, 28, 1561.
非特許文献 6 : Rakhit, S.; Gut, M. J. Org. Chem., 1964, 29, 229. Non-Patent Document 6: Rakhit, S .; Gut, M. J. Org. Chem., 1964, 29, 229.
発明の開示 Disclosure of the invention
発明が解決しょうとする課題 Problems to be solved by the invention
[0003] 力ルバぺネム類の製造原料等として有用な前記化合物 3に例示される 1 アルキ ルカルボン酸、好ましくは 1 β アルキルカルボン酸を工業的に効率よく製造する方 法が求められている。 [0003] There is a need for a method for industrially and efficiently producing 1 alkyl carboxylic acid, preferably 1 β alkyl carboxylic acid exemplified in Compound 3 useful as a raw material for producing strong rubapenems.
課題を解決するための手段 Means for solving the problem
[0004] 本発明者らは鋭意検討した結果、前記化合物 1に例示されるアクリル酸誘導体をォ ゾン酸ィ匕することにより、 1—アルキルカルボン酸を効率よく製造できることを見出し、 以下に示す本発明を完成した。 As a result of intensive studies, the present inventors have found that a 1-alkylcarboxylic acid can be efficiently produced by converting an acrylic acid derivative exemplified by the compound 1 into an oxalic acid. Completed the invention.
(1)式： (1 set:
[化 4]
[Chemical 4]
(式中、 Rは、オゾン酸ィ匕に悪影響を与えない置換基で置換されていてもよい j8—ラ クタム環基; は、水素、またはオゾン酸ィ匕に悪影響を与えない置換基で置換されて V、てもよ 、低級アルキル)で示される化合物（I)またはその塩をオゾン酸ィ匕する工程 を包含する、式： (Wherein R is an optionally substituted j8-lactam ring group that does not adversely affect ozone acid; and is substituted with hydrogen or a substituent that does not adversely affect ozone acid) And the step of converting the compound (I) represented by V or lower alkyl) or a salt thereof into an ozone acid,
(式中、 Rおよび Rは前記と同意義)で示される化合物 (III)またはその塩の製造方法 (Wherein R and R are as defined above), and a method for producing the compound (III) or a salt thereof
(2)化合物 (I)またはその塩をオゾンで酸ィ匕することにより得られたィ匕合物を、酸ィ匕処 理または塩基処理する工程を包含する、上記 1記載の製造方法。
(3)化合物 (I)またはその塩をオゾンで酸ィ匕することにより得られたィ匕合物を、過酸ィ匕 水素で酸化処理する工程を包含する、上記 1記載の製造方法。 (2) The production method according to the above (1), which comprises a step of subjecting the compound (I) or a salt thereof obtained by acidification with ozone to an acid treatment or a base treatment. (3) The production method according to the above (1), comprising a step of oxidizing a compound obtained by acidifying the compound (I) or a salt thereof with ozone with hydrogen peroxide.
(4)オゾンによる酸ィ匕を酸存在下で行う、上記 1〜 3のいずれかに記載の製造方法。 (4) The production method according to any one of (1) to (3) above, wherein the acidification with ozone is performed in the presence of an acid.
(5)オゾンによる酸ィ匕を酢酸存在下で行う、上記 1〜3のいずれかに記載の製造方法 (5) The production method according to any one of 1 to 3 above, wherein the acidification with ozone is performed in the presence of acetic acid.
(6)以下の工程: (6) The following steps:
(第 1工程） (First step)
式： Formula:
[化 6]
[Chemical 6]
(式中、 Rは、オゾン酸ィ匕に悪影響を与えない置換基で置換されていてもよい j8—ラ クタム環基; は、水素、またはオゾン酸ィ匕に悪影響を与えない置換基で置換されて V、てもよ 、低級アルキル)で示される化合物（I)またはその塩をオゾンで酸ィ匕した後、 還元処理することにより、式： (Wherein R is an optionally substituted j8-lactam ring group that does not adversely affect ozone acid; and is substituted with hydrogen or a substituent that does not adversely affect ozone acid) The compound (I) represented by V or lower alkyl) or a salt thereof is acidified with ozone and then reduced to give a compound represented by the formula:
[化 7] [Chemical 7]
(式中、 Rおよび は前記と同意義)で示される化合物 (Π)またはその塩を得る工程、 および (Wherein R and are as defined above), or a salt thereof, and
(第 2工程） (Second process)
化合物（II)またはその塩を酸ィ匕する工程を包含する、上記 1記載の化合物（III)また はその塩の製造方法。 2. A process for producing compound (III) or a salt thereof according to the above 1, comprising a step of acidifying compound (II) or a salt thereof.
(7)式: Equation (7):
[化 8]
[Chemical 8]
(式中、 Rは、オゾン酸ィ匕に悪影響を与えない置換基で置換されていてもよい j8—ラ クタム環基; は、水素、またはオゾン酸ィ匕に悪影響を与えない置換基で置換されて V、てもよ 、低級アルキル; R'はカルボキシ保護基)で示される化合物（I， )またはその 塩の R'部分を脱保護して化合物 (I)またはその塩を得る工程を包含する、上記 1〜6 の！、ずれかに記載の製造方法。 (Wherein R is an optionally substituted j8-lactam ring group that does not adversely affect ozone acid; and is substituted with hydrogen or a substituent that does not adversely affect ozone acid) And V, which may be lower alkyl; R ′ is a carboxy-protecting group), and includes the step of deprotecting the R ′ part of compound (I,) or a salt thereof to obtain compound (I) or a salt thereof The above 1-6! The manufacturing method according to any of the above.
(8)化合物 (I)またはその塩を単離せずに行う、上記 7記載の製造方法。 (8) The production method according to the above 7, wherein the compound (I) or a salt thereof is carried out without isolation.
(9)式: Equation (9):
(式中、 Rは、オゾン酸ィ匕に悪影響を与えない置換基で置換されていてもよい j8—ラ クタム環基; は、水素、またはオゾン酸ィ匕に悪影響を与えない置換基で置換されて V、てもよ 、低級アルキル)で示される化合物（II)またはその塩を酸ィ匕する工程を包含 する、上記 1記載の化合物（III)の製造方法。 (Wherein R is an optionally substituted j8-lactam ring group that does not adversely affect ozone acid; and is substituted with hydrogen or a substituent that does not adversely affect ozone acid) 2. A process for producing compound (III) according to the above 1, which comprises a step of acidifying the compound (II) represented by V or lower alkyl) or a salt thereof.
(10) は低級アルキルである、上記 1〜9のいずれかに記載の製造方法。 (10) The production method according to any one of 1 to 9 above, which is lower alkyl.
(11) Rはメチルである、上記 1〜9のいずれかに記載の製造方法。 (11) The production method according to any one of 1 to 9 above, wherein R is methyl.
(12) Rは 1 /3—メチルである、上記 1〜9のいずれかに記載の製造方法。 (12) The production method according to any one of 1 to 9 above, wherein R is 1 / 3-methyl.
(13) Rが式: (13) R is the formula:
[化 10]
[Chemical 10]
(式中、 R1は水素またはオゾン酸ィ匕に悪影響を与えない置換基; R2は水素またはイミ ノ保護基)で示される ι8—ラタタム環基である、上記 1〜9のいずれかに記載の製造
方法。 Any one of 1 to 9 above, wherein R 1 is a substituent that does not adversely affect hydrogen or ozone acid; R 2 is a hydrogen or an imino protecting group Described manufacturing Method.
( 14) Rが式: (14) R is the formula:
[化 11]
[Chemical 11]
(式中、 R1は水素または保護されて 、てもよ 、ヒドロキシで置換されて 、てもよ 、アル キル; R2は水素またはィミノ保護基)で示される j8—ラタタム環基である、上記 1〜9の Vヽずれかに記載の製造方法。 (Wherein R 1 is hydrogen or protected, may be substituted with hydroxy, may be alkyl; R 2 is hydrogen or an imino protecting group) and is a j8-ratata ring group, The manufacturing method according to any one of 1 to 9 above.
( 15) Rが式: (15) R is the formula:
[化 12] [Chemical 12]
(式中、 R2は水素またはィミノ保護基; R3はヒドロキシ保護基)で示される β—ラタタム 環基である、上記 1〜9のいずれかに記載の製造方法。 10. The production method according to any one of 1 to 9 above, which is a β-ratata ring group represented by the formula (wherein R 2 is hydrogen or an imino protecting group; R 3 is a hydroxy protecting group).
( 16) は低級アルキルであり、 Rが式： (16) is lower alkyl, R is the formula:
[化 13]
[Chemical 13]
(式中、 R1は水素または保護されて 、てもよ 、ヒドロキシで置換されて 、てもよ 、アル キル; R2は水素またはィミノ保護基)で示される j8—ラタタム環基である、上記 1〜9の(Wherein R 1 is hydrogen or protected, may be substituted with hydroxy, may be alkyl; R 2 is hydrogen or an imino protecting group) and is a j8-ratata ring group, 1-9 above
Vヽずれかに記載の製造方法。 V manufacturing method according to any one of the above.
( 17) Rは低級アルキルであり、 Rが式： (17) R is lower alkyl, and R is a formula:
[化 14]
(R七）[Chemical 14] (R7)
(式中、 R2は水素またはィミノ保護基; R3はヒドロキシ保護基)で示される β—ラタタム 環基である、上記 1 9のいずれかに記載の製造方法。 20. The production method according to any one of the above 19, which is a β-ratata ring group represented by the formula (wherein R 2 is hydrogen or an imino protecting group; R 3 is a hydroxy protecting group).
(18)式: Equation (18):
[化 15] [Chemical 15]
(式中、 Rは水素または低級アルキル; R1は保護されていてもよいヒドロキシで置換さ れて 、てもよ 、アルキル; R2は水素またはィミノ保護基)で示される化合物（1—1)また はその塩を、所望により酸存在下、オゾンで酸ィ匕することにより得られた化合物を、酸 化処理または還元処理する工程を包含する、式： (Wherein R is hydrogen or lower alkyl; R 1 is optionally substituted with hydroxy, and alkyl; R 2 is hydrogen or imino protecting group) (1-1) ) Or a salt thereof, optionally in the presence of an acid, with an acid solution with ozone.
[化 16] [Chemical 16]
(式中、 R° R1および R2は前記と同意義)で示される化合物（III— 1)またはその塩の 製造方法である、上記 1記載の製造方法。 2. The production method according to 1 above, which is a production method of the compound (III-1) represented by the formula (wherein R ° R 1 and R 2 are as defined above) or a salt thereof.
(19)式： Equation (19):
[化 17]
[Chemical 17]
(式中、 Rは、オゾン酸ィ匕に悪影響を与えない置換基で置換されていてもよい j8—ラ クタム環基; は、水素、またはオゾン酸ィ匕に悪影響を与えない置換基で置換されて
V、てもよ 、低級アルキル)で示される化合物（II)またはその塩。 (Wherein R is an optionally substituted j8-lactam ring group that does not adversely affect ozone acid; and is substituted with hydrogen or a substituent that does not adversely affect ozone acid) Been Compound (II) represented by V or lower alkyl) or a salt thereof.
(20)式: Equation (20):
[化 18] [Chemical 18]
(式中、 Rは低級アルキル; R1は保護されたヒドロキシで置換されていてもよいアルキ ル; R2は水素またはィミノ保護基)で示される化合物（II— 1)またはその塩である、上 記 19記載の化合物。 (Wherein R is lower alkyl; R 1 is alkyl optionally substituted with protected hydroxy; R 2 is hydrogen or imino protecting group) (II-1) or a salt thereof, 19. The compound according to 19 above.
(21)式: Equation (21):
[化 19] [Chemical 19]
(式中、 R2は水素; R3はヒドロキシ保護基)で示される化合物（II— 2)またはその塩で ある、上記 19記載の化合物。 20. The compound according to the above 19, which is a compound (II-2) represented by the formula (wherein R 2 is hydrogen; R 3 is a hydroxy protecting group) or a salt thereof.
(22)式: Equation (22):
[化 20] [Chemical 20]
(式中、 R3はヒドロキシ保護基)で示される化合物 (I卜 3)またはその塩である、上記 19記載の化合物。 20. The compound according to 19 above, which is a compound represented by (wherein R 3 is a hydroxy protecting group) (I 卜 3) or a salt thereof.
(23) R3はアルキルシリルである、上記 22記載の化合物またはその塩。 (23) The compound or a salt thereof as described in 22 above, wherein R 3 is alkylsilyl.
発明の効果 The invention's effect
本発明は、オゾン酸ィ匕を利用してアクリル酸誘導体から 1—アルキルカルボン酸類
を効率よく製造する方法を提供する。特に酸存在下でオゾン酸化することにより高収 率で目的物が得られる。また、酸化反応後の後処理手段を選択することにより、 1 β アルキルの a体への異性ィ匕を制御することも可能である。また本発明は新規中間 体も提供する。 The present invention relates to 1-alkylcarboxylic acids from acrylic acid derivatives using ozone acid. A method for efficiently producing the above is provided. In particular, the target product can be obtained with high yield by ozone oxidation in the presence of acid. It is also possible to control the isomerism of 1 β alkyl to a form by selecting post-treatment means after the oxidation reaction. The present invention also provides novel intermediates.
発明を実施するための最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION
本発明中、各用語は特に断らない限り、単独または併用で、以下の意味を示す。 は、水素またはオゾン酸ィ匕に悪影響を与えな 、置換基で置換されて 、てもよ!/ヽ 低級アルキルであり、好ましくは水素または低級アルキル（例： C1〜C6アルキル）で ある。より好ましくは、低級アルキル、特にメチルであり、さらに好ましくは、 β—ラクタ ム環に対する立体配置が j8配位である。よって特に好ましくは 1 j8—メチルである。 In the present invention, each term has the following meanings singly or in combination unless otherwise specified. May be substituted with a substituent that does not adversely affect hydrogen or ozone acid! / ヽ is lower alkyl, preferably hydrogen or lower alkyl (eg, C1-C6 alkyl). More preferred is lower alkyl, particularly methyl, and even more preferred is a j8 configuration as the configuration with respect to the β-lactam ring. Therefore, particularly preferred is 1 j8-methyl.
Rは、オゾン酸ィ匕に悪影響を与えない置換基で置換されていてもよい j8—ラタタム 環基である。該置換基は同一または異なり、 β ラタタム環上の置換可能な位置に 1 〜3個、好ましくは 1〜2個置換し得る。該置換基は、より好ましくは j8—ラタタム環の 3位の炭素原子に 1個置換し、特に好ましくは、前記の置換されていてもよいアルキ ル（好ましくは C1〜C10アルキル、より好ましくは C1〜C6アルキル）であり、さらに好 ましくは、保護されたヒドロキシで置換されて 、てもよ 、アルキルである。 R is a j8-ratata ring group which may be substituted with a substituent that does not adversely affect the ozone acid group. The substituents may be the same or different, and 1 to 3, preferably 1 to 2 substituents may be substituted at substitutable positions on the β-ratata ring. The substituent is more preferably one substituted at the 3-position carbon atom of the j8-ratata ring, and particularly preferably the above-mentioned alkyl (preferably C1-C10 alkyl, more preferably C1). -C6 alkyl), and more preferably alkyl substituted with protected hydroxy.
「オゾン酸ィ匕に悪影響を与えな 、置換基」とは、化合物 (I)のオゾン酸ィ匕を行う上で 、立体環境的または電子環境的にオゾン酸ィ匕に悪影響を与えない基を意味する。好 ましくは、自身もオゾン酸ィ匕によって酸ィ匕されにくい基であり、より好ましくは、オゾン に対して反応性の高い構造や官能基 (例:炭素間不飽和結合、アルデヒド、ァセター ル化アルデヒド、アミ入 1級ァミン、スルフイド、ホスフィン）をその構造中に含まない 基である。但し、保護基で保護された官能基 (例:保護アミノ、保護ヒドロキシ)は存在 していてもよい。「オゾン酸ィ匕に悪影響を与えない置換基」は、より好ましくは、 1)置 換されていてもよいアルキル、好ましくは低級アルキル (例:炭素数 1〜6)、より好まし くは炭素数 1〜4の低級アルキル（例：メチル、ェチル、 n—プロピル、イソプロピル、 n ブチル等）、 2)置換されていてもよいシクロアルキル、好ましくは炭素数 3〜6のシ クロアルキル（例：シクロプロピル、シクロブチル、シクロペンチル、シクロへキシル）、 3 )置換されて!、てもよ 、シクロアルキル低級アルキル等である。「置換されて 、てもよ
い」の置換基としては、保護されていてもよいヒドロキシ、保護されたァミノ、保護され ていてもよいカルボキシ、低級アルキル、ハロゲン、低級アルコキシ、ハロゲン化低級 アルキル、ハロゲンィ匕低級アルコキシなどが例示され、より好ましくは、保護されてい てもよぃヒドロキシである。 “Substituents that do not adversely affect the ozone acid” means a group that does not adversely affect the ozone acid in terms of steric environment or electronic environment in performing the ozone acid of the compound (I). means. Preferably, the group itself is not easily oxidized by ozone acid, and more preferably a structure or functional group that is highly reactive to ozone (eg, carbon-carbon unsaturated bond, aldehyde, acetal). Aldehyde group, amide-containing primary amine, sulfide, phosphine) are not included in the structure. However, a functional group protected by a protecting group (eg, protected amino, protected hydroxy) may be present. The “substituent that does not adversely affect the ozone acid” is more preferably 1) optionally substituted alkyl, preferably lower alkyl (e.g., 1 to 6 carbon atoms), more preferably carbon. Lower alkyl having 1 to 4 (eg, methyl, ethyl, n-propyl, isopropyl, n butyl, etc.), 2) optionally substituted cycloalkyl, preferably cycloalkyl having 3 to 6 carbons (eg, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3) substituted, cycloalkyl lower alkyl and the like. “It ’s replaced. Examples of the substituent of “I” include hydroxy which may be protected, protected amino, carboxy which may be protected, lower alkyl, halogen, lower alkoxy, halogenated lower alkyl, halogenated lower alkoxy and the like. More preferably, it may be protected hydroxy.
Rは、より具体的には、 R is more specifically
式： Formula:
[化 21]
[Chemical 21]
(式中、 R1は水素またはオゾン酸ィ匕に悪影響を与えない置換基; R2は水素またはイミ ノ保護基)で示される β—ラタタム環基である。 (Wherein R 1 is a substituent that does not adversely affect hydrogen or ozone acid; R 2 is a hydrogen or an imino protecting group) and is a β-ratata ring group.
R1は好ましくは、水素または前記の置換されていてもよいアルキルであり、さらに好 ましくは、保護されて 、てもよ 、ヒドロキシで置換されて！、てもよ！/、アルキルである。R 1 is preferably hydrogen or optionally substituted alkyl as described above, and more preferably protected and optionally substituted with hydroxy! Well! /, Alkyl.
R2は水素またはィミノ保護基である力 好ましくは水素である。 R 2 is hydrogen or an imino protecting group, preferably hydrogen.
Rは特に好ましくは式： R is particularly preferably the formula:
[化 22] [Chemical 22]
(式中、 R2は水素またはィミノ保護基; R3はヒドロキシ保護基)で示される β—ラタタム 環基である。 (Wherein R 2 is hydrogen or an imino protecting group; R 3 is a hydroxy protecting group) and is a β-ratata ring group.
ヒドロキシの保護基としては、アルキルシリル (例：トリメチルシリル、 t—ブシルジメチ ルシリル）、ァシル（例：ァセチル、ビバロイル）、低級アルキル（例：メチル、ェチル）、 アルコキシアルキル（例：メトキシメチル、メトキシェチル）、低級アルキルスルホ-ル（ 例：メタンスルホ -ル）、アルコキシカルボ-ル（例：メトキシカルボ-ル）、が例示され る力 好ましくは、アルキルシリルである。 Examples of hydroxy protecting groups include alkylsilyl (eg, trimethylsilyl, t-butyl dimethylsilyl), asil (eg, acetyl, bivaloyl), lower alkyl (eg, methyl, ethyl), alkoxyalkyl (eg, methoxymethyl, methoxyethyl), Examples of lower alkylsulfol (eg, methanesulfur) and alkoxycarbol (eg, methoxycarbol) are preferred. Alkylsilyl is preferable.
ィミノの保護基としては、前記アルキルシリル、置換されていてもよい低級アルキル (
置換基の例:保護されていてもよいカルボキシ)等が含まれる。好ましくは、低級アル ケ-ルォキシカルボ-ル（例：ァリルォキシカルボ-ル）、置換されて 、てもよ 、ァラル キルォキシカルボ-ル（例： p -トロベンジルォキシカルボ-ル）が例示される。 R2の ィミノ保護基は、好ましくは CH CO R4 (R4は、力ルバぺネムの 4位カルボキシの保 Examples of the imino protecting group include the above alkylsilyl and optionally substituted lower alkyl ( Examples of substituents include optionally protected carboxy) and the like. Preferably, a lower alkoxycarboxyl (eg, aryloxycarbol), substituted, or aralkyloxycarbole (eg, p-trobenzyloxycarbol) is exemplified. The The imino protecting group for R 2 is preferably CH CO R 4 (R 4 is
2 2 twenty two
護基 (例：ァリル、 p—-トロベンジル)である。 A protective group (eg, aryl, p-trobenzyl).
本発明は、化合物 (I)またはその塩をオゾン酸ィ匕する工程を包含する、化合物 (III) またはその塩の製法を提供する。 The present invention provides a process for producing compound (III) or a salt thereof, which comprises the step of oxidizing compound (I) or a salt thereof.
本発明の「オゾン酸化」とは、化合物 (I)のビュル部分をオゾンで酸ィ匕して開裂する ことにより目的物に導く反応を意味する。より詳しくは、該酸化反応により生ずる各種 中間体 (例:モルォゾニド、ォゾニド）を安定な生成物に変換するために通常、所望 により行われる後処理 (例:酸化、還元、塩基処理、加水分解等)も含めた工程を意 味する。 The “ozone oxidation” in the present invention means a reaction that leads to a target product by cleaving the bulge part of compound (I) with acidified with ozone. More specifically, various post-treatments (eg, oxidation, reduction, base treatment, hydrolysis, etc.) usually performed as desired in order to convert various intermediates (eg, molysonide, ozonide) generated by the oxidation reaction into stable products. ) Means the process including
オゾン酸ィ匕は、基本的には、当業者に周知のオゾン酸ィ匕の反応条件に従って行え ばよい。当該酸化は、酸化源としてはオゾンを発生させるための電力と酸素のみを必 要とし、重金属などの廃棄物を発生することがないので、環境面で非常に優れた酸 化方法である。具体的には、通常、オゾン発生機力も約 1〜10%のオゾンを含んだ 酸素を反応液中に通じて行う。 Ozone acid may be basically produced according to the reaction conditions of ozone acid well known to those skilled in the art. The oxidation requires only electric power and oxygen to generate ozone as an oxidation source, and does not generate waste such as heavy metals, so it is a very excellent oxidation method in terms of environment. Specifically, ozone generation is usually performed by passing oxygen containing about 1-10% ozone into the reaction solution.
使用される溶媒としては、炭化水素（例：ペンタン、へキサン、ヘプタン、シクロへキ サン、石油エーテル）、ハロゲン化炭化水素（例：ジクロロメタン、クロ口ホルム、四塩化 炭素）、アルコール（例：メタノール、エタノール）、ギ酸、酢酸、プロピオン酸、酢酸ェ チル、アセトン、ホルムアミド、ニトロメタン、ァセトニトリル、エーテル（例：テトラヒドロフ ラン、ジェチルエーテル）、水それらの混合溶媒等が例示されるが、好ましくは、酢酸 、酢酸ェチルまたはメタノールである。 Solvents used include hydrocarbons (eg pentane, hexane, heptane, cyclohexane, petroleum ether), halogenated hydrocarbons (eg dichloromethane, chloroform, carbon tetrachloride), alcohols (eg: (Methanol, ethanol), formic acid, acetic acid, propionic acid, ethyl acetate, acetone, formamide, nitromethane, acetonitrile, ether (eg, tetrahydrofuran, jetyl ether), water and mixed solvents thereof are exemplified, but preferably Is acetic acid, ethyl acetate or methanol.
反応温度は、通常、 78°C〜室温、好ましくは 78°C〜0°Cである。 The reaction temperature is usually 78 ° C to room temperature, preferably 78 ° C to 0 ° C.
酸化反応自体の時間は、通常、数分〜数時間であり、より好ましくは数分〜 30分で ある。 The time for the oxidation reaction itself is usually several minutes to several hours, more preferably several minutes to 30 minutes.
酸ィ匕反応の進行は溶液の色の変化により判断でき、通常、青に着色すればオゾン の導入を停止し、好ましくは窒素置換を行う。
次に、生成した中間生成物を含む溶液を後処理することにより、目的の酸化物へ変 換できる。該酸化物は、化合物（III)である力、またはその中間体である化合物（II)で ある。 The progress of the acid-oxidation reaction can be judged by the change in the color of the solution. Usually, when it is colored blue, the introduction of ozone is stopped, and preferably nitrogen substitution is performed. Next, the solution containing the produced intermediate product can be converted into the target oxide by post-treatment. The oxide is a force that is compound (III), or compound (II) that is an intermediate thereof.
本発明は詳しくは、オゾン酸ィ匕時の酸の併用や後処理の方法等によってその態様 が異なる、少なくとも 2ルートの製法を包含する。以下、各ルートについて説明する。 More specifically, the present invention includes at least a two-route production method that varies in form depending on the use of an acid during ozone oxidation and the post-treatment method. Hereinafter, each route will be described.
[化 23] [Chemical 23]
Route A Route A
(ルート A) (Route A)
本ルートは、化合物（I)またはその塩をオゾン酸ィ匕することにより直接、化合物（III) またはその塩を得る方法である。 This route is a method for directly obtaining the compound (III) or a salt thereof by ozone-oxidizing the compound (I) or a salt thereof.
具体的には、化合物 (I)またはその塩をオゾンで酸ィ匕することにより得られた中間生 成物を後処理することにより、化合物 (III)またはその塩が得られる。反応温度はより 好ましくは— 50〜0°C、さらに好ましくは— 45〜― 35°Cである。酸化は、反応促進剤 の存在下または非存在下に行われる。反応促進剤としては酸が例示され、好ましくは 酸存在下で酸化が行われる。本反応は酸の添加なしでも進行するが、これは原料化 合物（I)および生成物（III)ともにカルボン酸の構造を持っているためと考えられる。 併用する酸としては、有機酸または無機酸が例示される。 Specifically, compound (III) or a salt thereof can be obtained by post-treatment of an intermediate product obtained by acidifying compound (I) or a salt thereof with ozone. The reaction temperature is more preferably −50 to 0 ° C., further preferably −45 to −35 ° C. The oxidation is carried out in the presence or absence of a reaction accelerator. An example of the reaction accelerator is an acid, and the oxidation is preferably performed in the presence of an acid. This reaction proceeds without the addition of an acid, but this is thought to be because both the raw material compound (I) and the product (III) have a carboxylic acid structure. Examples of the acid used in combination include organic acids and inorganic acids.
有機酸としては、ギ酸、酢酸、トリフルォロ酢酸、メタンスルホン酸、 p—トルエンスル ホン酸、プロピオン酸、乳酸、マレイン酸、フマール酸、酒石酸、リンゴ酸、クェン酸、 ァスコルビン酸、蓚酸、コハク酸などが例示される。 Organic acids include formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, propionic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, malic acid, citrate, ascorbic acid, oxalic acid, succinic acid, etc. Is exemplified.
無機酸としては、塩酸、臭化水素酸、硫酸、硝酸、リン酸などが例示される。 Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
好ましくは酢酸またはそれと同程度の酸性度を有する酸 (例：プロピオン酸、コハク 酸)である。特に好ましくは酢酸であり、溶媒の役目も兼ねる。 Preferably, it is acetic acid or an acid having the same degree of acidity (eg, propionic acid, succinic acid). Particularly preferred is acetic acid, which also serves as a solvent.
酸の使用量は、化合物（I)に対して、通常 0. 1〜50当量、好ましくは 1〜30当量、
より好ましくは 3〜20当量、特に好ましくは 5〜15当量である。 The amount of the acid to be used is generally 0.1-50 equivalents, preferably 1-30 equivalents, relative to compound (I). More preferably, it is 3-20 equivalents, Most preferably, it is 5-15 equivalents.
上記酸ィ匕により得られた中間生成物 (オゾンィ匕物）の構造は定かではなぐまた一 般に生成するォゾニド以外の中間体が複数が混在している可能性がある。 The structure of the intermediate product (ozone product) obtained by the above acid is not clear, and there may be a mixture of a plurality of intermediates other than the generally generated ozonide.
後処理方法は、中間生成物 (オゾンィ匕物）を化合物 (III)に変換できる種々の方法を 包含するが、好ましくは酸化処理または塩基処理である。 The post-treatment method includes various methods capable of converting the intermediate product (ozone product) to the compound (III), and is preferably an oxidation treatment or a base treatment.
酸化処理の酸化剤としては、過酢酸、過ギ酸、過酸化水素、アルカリ性酸化銀、ク ロム酸、ペルォキシトリフルォロ酢酸、 m-クロ口過安息香酸、さらし粉、ペルォキソホ ゥ酸ナトリウムなどが例示される力 好ましくは過酸化水素、より好ましくは約 10〜30 %の過酸化水素水である。 Examples of oxidizing agents for the oxidation treatment include peracetic acid, performic acid, hydrogen peroxide, alkaline silver oxide, chromic acid, peroxytrifluoroacetic acid, m-chloroperbenzoic acid, bleached powder, and sodium peroxofolate. The exemplified power is preferably hydrogen peroxide, more preferably about 10-30% aqueous hydrogen peroxide.
塩基処理する場合の塩基としては、無機塩基または有機塩基が例示される。 Examples of the base for base treatment include inorganic bases and organic bases.
無機塩基としては、水酸ィ匕アルカリ金属（例： LiOH、 NaOH、 KOH)、炭酸アル力 リ金属（例： Li CO、 Na CO、 K CO )、炭酸水素アルカリ金属（例： LiHCO、 Na Inorganic bases include hydroxides and alkali metals (eg LiOH, NaOH, KOH), alkaline carbonates (eg Li CO, Na CO, K CO), alkali metal hydrogen carbonates (eg LiHCO, Na
2 3 2 3 2 3 3 2 3 2 3 2 3 3
HCO、KHCO )、水酸化アルカリ土類金属（Mg (OH) 、Ca (OH) 炭酸アル力HCO, KHCO), alkaline earth metal hydroxide (Mg (OH), Ca (OH) Al carbonate
3 3 2 2 3 3 2 2
リ土類金属（MgCO、 CaCO )が例示される。 Examples are reusable metals (MgCO, CaCO 3).
3 3 3 3
有機塩基としては、脂肪族ァミン (例：トリメチルァミン、トリェチルァミン、ジシクロへ キシルァミン、エタノールァミン、ジエタノールァミン、トリエタノールァミン、ブロカイン） 、芳香族ァミン (例：ピリジン、ピコリン、キノリン、ァ-リン）が例示される。 Organic bases include aliphatic amines (eg, trimethylamine, triethylamine, dicyclohexamine, ethanolamine, diethanolamine, triethanolamine, brocaine), aromatic amines (eg, pyridine, picoline, quinoline, amide). -Phosphorus) is exemplified.
後処理方法によっては、化合物 (I)の 1 j8—メチルの a体への異性化が起きる場合 もあるが、化合物 (III)の単離時の精製 (例:結晶ィ匕）によって分離可能である。該異 性ィ匕をできるだけ防ぐためには、後処理は好ましくは酸ィ匕処理によって行われる。ま た後処理が長すぎると中間生成物または最終物が分解する恐れもある。後処理に要 する時間は通常、数時間〜数十時間、好ましくは 1〜： L0時間、より好ましくは 2〜8時 間、特に好ましくは 3〜6時間である。 Depending on the post-treatment method, isomerization of 1 j8-methyl of compound (I) to a-form may occur, but it can be separated by purification during the isolation of compound (III) (eg crystal 匕). is there. In order to prevent this heterogeneity as much as possible, the post-treatment is preferably carried out by acid soot treatment. Also, if the post-treatment is too long, the intermediate product or final product may be decomposed. The time required for the post-treatment is usually several hours to several tens of hours, preferably 1 to L0 hours, more preferably 2 to 8 hours, and particularly preferably 3 to 6 hours.
本ルートの反応機構は現時点で明らかではなぐまた複数の反応経路をたどってい る可能性も考えられる力 参考までにその 1例を以下に示す。但し、これはあくまで推 測であり本発明を何ら制限するものではない。 The reaction mechanism of this route is not clear at the present time, and one example is shown below for reference, as it may be possible to follow multiple reaction paths. However, this is only an estimation and does not limit the present invention.
[化 24]
[Chemical 24]
(注： AcOH :酢酸（酸の 1例）、 Base :塩基、 Oxidation：酸化） (Note: AcOH: acetic acid (an example of acid), Base: base, Oxidation: oxidation)
(ルート B) (Route B)
本ルートは、化合物 (I)から化合物 (II)を得て、化合物 (III)を得る方法であり、詳しく は以下の工程を包含する。 This route is a method for obtaining compound (III) by obtaining compound (II) from compound (I), and specifically includes the following steps.
(第 1工程） (First step)
化合物（I)またはその塩をオゾンで酸ィヒ後、発生した中間生成物を還元処理するこ とによりィ匕合物（II)またはその塩を得る工程、および A step of obtaining compound (II) or a salt thereof by oxidizing compound (I) or a salt thereof with ozone and then reducing the generated intermediate product; and
(第 2工程） (Second process)
化合物 (II)またはその塩を酸ィ匕または加水分解する工程を経て、化合物 (III)また はその塩を得る工程。 A step of obtaining compound (III) or a salt thereof through a step of acidifying or hydrolyzing compound (II) or a salt thereof.
以下、ルート Bの各工程について説明する。 Hereinafter, each process of the route B will be described.
(第 1工程） (First step)
[化 25] [Chemical 25]
化合物 (I)またはその塩をオゾンで酸ィ匕することにより、中間生成物を得る。酸ィ匕条 件は前記の通りである力 本工程は、特に酸などの反応促進剤を添加しなくてもスム ーズに進行する。また反応温度は A/レートに比べて低温が好ましぐより好ましくは 78°C〜― 50°Cである。次に得られた中間生成物を還元反応で後処理することにより 化合物（II)が得られる。該中間生成物は単離していないが、一般のオゾン酸化の反 応機構に照らして、上記 (Γ )で示されるォゾニドを経由していると推測される。 An intermediate product is obtained by acidifying the compound (I) or a salt thereof with ozone. The conditions of the acid conditions are as described above. This process proceeds smoothly even without adding a reaction accelerator such as an acid. The reaction temperature is preferably lower than the A / rate, more preferably 78 ° C to -50 ° C. Next, the intermediate product obtained is post-treated by a reduction reaction to obtain compound (II). Although the intermediate product has not been isolated, it is presumed that it passes through the ozonide represented by the above (Γ) in light of the general reaction mechanism of ozone oxidation.
還元処理の方法としては、一般にォゾニドの還元分解反応に使用されるものであれ ば種々のものが使用可能である。例えば、亜鉛末、接触水素化法 (水素 Z金属触媒
(例：白金、ノ《ラジウム、ニッケル、ロジウム)）、リンィ匕合物（例：亜リン酸エステル、トリ フエ-ルホスフイン）、ジメチルスルフイド、ヨウ化ナトリウム、亜硫酸水素ナトリウム、塩 ィ匕スズ、硫酸鉄等による還元が例示されるが、好ましくはジメチルスルフイドによる還 元である。 As the reduction treatment method, various methods can be used as long as they are generally used in the reductive decomposition reaction of ozonide. For example, zinc powder, catalytic hydrogenation method (hydrogen Z metal catalyst (Example: platinum, rhodium, nickel, rhodium)), phosphorus compounds (example: phosphite esters, triphenylphosphine), dimethylsulfide, sodium iodide, sodium hydrogen sulfite, sodium chloride Reduction with iron sulfate is exemplified, but reduction with dimethylsulfide is preferable.
還元反応の温度は、通常、 78°C〜50°C、好ましくは 0°C〜室温である。 The temperature of the reduction reaction is usually 78 ° C to 50 ° C, preferably 0 ° C to room temperature.
反応時間は、数十分〜数時間である。 The reaction time is several tens of minutes to several hours.
還元処理は、オゾンィ匕に引き続いて、中間生成物を単離することなく速やかに行う のが望ましい。 It is desirable that the reduction treatment is carried out promptly without isolating the intermediate product following ozone.
(第 2工程） (Second process)
化合物 (II)またはその塩を酸ィ匕または加水分解して、化合物 (III)またはその塩を得 る。 Compound (II) or a salt thereof is acidified or hydrolyzed to obtain compound (III) or a salt thereof.
酸化法としては、一般にケトカルボン酸を酸ィ匕してカルボン酸に変換できる方法で あれば、種々の方法が使用できる。酸化剤としては、例えば、過酸化水素、過塩素酸 、次亜塩素酸、さらし粉、 m-クロ口過安息香酸、ペルォキソホウ酸ナトリウム、過ヨウ素 酸またはその塩、ョードソベンゼン、オゾン、過酸ィ匕カリウムなどが例示される。また臭 化水素酸や光を用いた加水分解などによりカルボン酸に変換してもよい。 As the oxidation method, various methods can be used as long as they are generally methods capable of converting ketocarboxylic acid to carboxylic acid. Examples of the oxidizing agent include hydrogen peroxide, perchloric acid, hypochlorous acid, bleaching powder, m-chloroperbenzoic acid, sodium peroxoborate, periodic acid or a salt thereof, odosobenzene, ozone, and potassium peracid. Etc. are exemplified. Alternatively, it may be converted into carboxylic acid by hydrofluoric acid or hydrolysis using light.
溶媒としては、炭化水素（例：ペンタン、へキサン、ヘプタン、シクロへキサン、石油 エーテル）、ハロゲンィ匕炭化水素（例：ジクロロメタン、クロ口ホルム、四塩化炭素）、ァ ルコール（例：メタノール、エタノール）、エーテル（例：テトラヒドロフラン、ジェチルェ 一テル）、酢酸ェチル、アセトン、ホルムアミド、ニトロメタン、ァセトニトリル、水、または それらの混合溶媒等が使用される。 Solvents include hydrocarbons (eg, pentane, hexane, heptane, cyclohexane, petroleum ether), halogenated hydrocarbons (eg: dichloromethane, chloroform, carbon tetrachloride), alcohols (eg, methanol, ethanol). ), Ether (eg, tetrahydrofuran, jetyl ether), ethyl acetate, acetone, formamide, nitromethane, acetonitrile, water, or a mixed solvent thereof.
反応温度は、通常、 _78°C〜100°C、好ましくは 0°C〜50°Cである。 The reaction temperature is usually _78 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
反応時間は、数十分〜数時間である。 The reaction time is several tens of minutes to several hours.
また、酸化剤に Ca(ClO)等を使用すると、 |8ラタタム環の NHがクロル化 (N-C1)され Also, when Ca (ClO) or the like is used as the oxidizing agent, NH of the 8 ratata ring is chlorinated (N-C1).
2 2
た化合物が生成する場合もある力 このものを引き続き NaHSO等で還元することによ The force that may produce a new compound. By continuing to reduce this with NaHSO, etc.
3 Three
り、容易に化合物 (III)に誘導できる。このような態様も本発明に包含される。 Thus, it can be easily derived into compound (III). Such an embodiment is also encompassed by the present invention.
本製法は、さらに以下の態様を包含する。 The production method further includes the following aspects.
[化 26]
化合物 (Γ )またはその塩の R'部分を脱保護して化合物 (I)またはその塩を生成さ せた後、前記の通りルート Aまたは Bの方法によりィ匕合物（III)を得る。化合物（I)また はその塩は、ー且、単離してもよいが、完全に単離せずに反応を行うこともできる。好 ましくは、化合物 (Γ )を脱保護した後の反応液を後処理 (例:水洗、抽出、乾燥)し、 濃縮して得られる残渣に、溶媒を添加し、オゾンを導入すればよい。より好ましくは、 化合物（I ' )から化合物（I)を経由してルート Aに進む反応である。 [Chemical 26] After deprotecting the R ′ moiety of compound (Γ) or a salt thereof to produce compound (I) or a salt thereof, compound (III) is obtained by the method of route A or B as described above. Compound (I) or a salt thereof may be isolated, but the reaction may be performed without complete isolation. Preferably, the reaction liquid after deprotecting the compound (Γ) is post-treated (eg, washed with water, extracted and dried), concentrated, and then the solvent is added to the residue obtained to introduce ozone. . More preferably, the reaction proceeds from the compound (I ′) to the route A via the compound (I).
R'としては、種々のカルボキシ保護基が使用可能であり、例えば低級アルキル (例 ：ェチル）、ァラルキル (例：ベンジル）、置換シリル (例：トリメチルシリル）が例示される 。脱保護は、通常のカルボキシの脱保護反応の条件に従って行えばよい。例えば、 アルカリ（例: NaOH)で加水分解すればよい。反応温度は、通常- 20°C〜50°C、好ま しくは氷冷下〜室温である。 As R ′, various carboxy protecting groups can be used, and examples thereof include lower alkyl (eg, ethyl), aralkyl (eg, benzyl), and substituted silyl (eg, trimethylsilyl). Deprotection may be performed in accordance with the conditions of a normal carboxy deprotection reaction. For example, hydrolysis may be performed with an alkali (eg, NaOH). The reaction temperature is usually −20 ° C. to 50 ° C., preferably under ice cooling to room temperature.
化合物（II)は、好ましくは前記化合物（II 1)、より好ましくは化合物（II 2)、特に 好ましくは化合物（II 3)であり、 、ずれも化合物（III)の合成中間体として有用であ る。 The compound (II) is preferably the compound (II 1), more preferably the compound (II 2), particularly preferably the compound (II 3), and both are useful as a synthetic intermediate of the compound (III). The
本明細書における塩としては、塩基性塩として、例えば、ナトリウム塩、カリウム塩等 のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩；アンモ- ゥム塩；トリメチルァミン塩、トリェチルァミン塩、ジシクロへキシルァミン塩、エタノール アミン塩、ジエタノールアミン塩、トリエタノールアミン塩、ブロカイン塩、メダルミン塩、 ジエタノールアミン塩またはエチレンジァミン塩等の脂肪族ァミン塩; Ν,Ν-ジベンジル エチレンジァミン、ベネタミン塩等のァラルキルアミン塩；ピリジン塩、ピコリン塩、キノリ
ン塩、イソキノリン塩等のへテロ環芳香族ァミン塩;テトラメチルアンモ -ゥム塩、テトラ ェチルァモ -ゥム塩、ベンジルトリメチルアンモ -ゥム塩、ベンジルトリェチルアンモ- ゥム塩、ベンジルトリブチルアンモ -ゥム塩、メチルトリオクチルアンモ -ゥム塩、テトラ ブチルアンモ-ゥム塩等の第 4級アンモ-ゥム塩；アルギニン塩、リジン塩等の塩基 性アミノ酸塩等が挙げられる。酸性塩としては、例えば、塩酸塩、硫酸塩、硝酸塩、リ ン酸塩、炭酸塩、炭酸水素塩、過塩素酸塩等の無機酸塩;酢酸塩、プロピオン酸塩 、乳酸塩、マレイン酸塩、フマール酸塩、酒石酸塩、リンゴ酸塩、クェン酸塩、ァスコ ルビン酸塩等の有機酸塩;メタンスルホン酸塩、イセチオン酸塩、ベンゼンスルホン 酸塩、 P-トルエンスルホン酸塩等のスルホン酸塩；ァスパラギン酸塩、グルタミン酸塩 等の酸性アミノ酸等が挙げられる。 Examples of the salt in the present specification include basic salts such as alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt; Triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, brocaine, medalamine, diethanolamine, ethylenediamine, and other aliphatic amines such as Ν, Ν-dibenzyl ethylenediamine, venetamine, etc. Salt; pyridine salt, picoline salt, quinori Heterocyclic aromatic amine salts such as chloroquine salts and isoquinoline salts; tetramethyl ammonium salt, tetraethyl ammonium salt, benzyltrimethyl ammonium salt, benzyltriethyl ammonium salt, benzyltributyl ammonium salt Quaternary ammonium salts such as -um salt, methyltrioctyl ammonium salt, tetrabutylammonium salt; and basic amino acid salts such as arginine salt and lysine salt. Examples of the acid salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; acetate, propionate, lactate, maleate , Organic acid salts such as fumarate, tartrate, malate, citrate, and ascorbate; sulfonic acids such as methanesulfonate, isethionate, benzenesulfonate, and P-toluenesulfonate Salt; acidic amino acids such as aspartate, glutamate and the like.
化合物（1)、 （II)はそのままで、または塩として、前記反応に使用される。また化合物 (II)や (III)はフリー体としてまたは塩として得られる。またフリー体は、公知の塩形成 反応に付すことにより容易に各種塩に変換できる。 Compounds (1) and (II) are used in the above reaction as they are or as salts. Compounds (II) and (III) can be obtained as free forms or as salts. The free form can be easily converted into various salts by subjecting it to a known salt formation reaction.
以下に実施例を示す。実施例 1〜4は Bルート、実施例 5〜8は A/レートの例である 。 a l は、 1 j8—メチルの異性体比を示す。 Examples are shown below. Examples 1 to 4 are examples of the B route, and Examples 5 to 8 are examples of the A / rate. a l represents the isomer ratio of 1 j8-methyl.
(略号） (Abbreviation)
TBS： t -ブチノレジメチノレシリノレ TBS: t-Butino Resi Mechinoresirinore
実施例 1 Example 1
アクリル酸 l(lO.Og)のジクロロメタン メタノール溶液 (60mL— 15mL)を- 78°Cに冷却 した後、オゾンを 15分間導入し、溶液が青く着色したのを確認した後に窒素置換した 。ジメチルスルフイド (8. lmL)をカ卩えて昇温し、室温下 3時間攪拌した。反応液を水、 N aHSO水溶液、飽和食塩水で洗浄し、 MgSOで乾燥した後濃縮した。へキサン—ジ A solution of acrylic acid l (lO.Og) in dichloromethane / methanol (60 mL-15 mL) was cooled to −78 ° C., ozone was introduced for 15 minutes, and after confirming that the solution was colored blue, the atmosphere was replaced with nitrogen. Dimethylsulfide (8. 1 mL) was added, the temperature was raised, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was washed with water, NaHSO aqueous solution and saturated brine, dried over MgSO and concentrated. Hexane
3 4 3 4
イソプロピルエーテル、次にトルエンージイソプロピルエーテルより結晶化することで ケトカルボン酸 2が得られた (2.7g, 27%)。 Crystallization from isopropyl ether and then toluene-diisopropyl ether gave ketocarboxylic acid 2 (2.7 g, 27%).
Anal. Calcd for C H NO Si: C, 54.68; H, 8.26; N 4.25. Found: C, 54.50; H, 8.23 Anal. Calcd for C H NO Si: C, 54.68; H, 8.26; N 4.25. Found: C, 54.50; H, 8.23
15 27 5 15 27 5
； N4.51. N4.51.
JH-NMR (CDC1 ); 0.05 ( 3H, s ), 0.07 ( 3H, s ), 0.86 ( 9H, s ), 1.07—1.24 ( 6H, m ), J H-NMR (CDC1); 0.05 (3H, s), 0.07 (3H, s), 0.86 (9H, s), 1.07—1.24 (6H, m),
3 Three
2.96-2.98 ( 1H, m ), 3.91—4.01 ( 2H, m ), 4.17-4.23 ( 1H, m ), 7.00 ( 1H, s ) ppm
2.96-2.98 (1H, m), 3.91—4.01 (2H, m), 4.17-4.23 (1H, m), 7.00 (1H, s) ppm
uidd ( s Ήΐ ) uidd (s Ήΐ)
SS"9 '( ZHS'9 'ZH8' =f 'Pb Ήΐ ) IZ'f '( Z'Z
SS "9 '(ZHS'9' ZH8 '= f' P b Ήΐ) IZ'f '(Z'Z
ε·9=ί" 'p Ήε ) oz'i '( s Ή6 ) 8 '( s Ήε ) 80 '( s Ήε ) 90 'θοαο) 醒- HT i n ε · 9 = ί "'p Ήε) oz'i' ( s Ή6) 8 '( s Ήε) 80' ( s Ήε) 90 'θοαο) Awakening-H T in
98·8 Ή ¾S'SS 'D： P画 d 'S9' N -S0"6 Ή '8Z"SS 'D： !S ON H D ^ P^PD "P 98 · 8 ¾ S'SS 'D: P picture d' S9 'N -S0 "6 Ή' 8Z" SS 'D:! S ON H D ^ P ^ PD "P
°([ 88/21： l ]%68
° ([88/21: l]% 68
— ϋ w^^ m -^ ^o ^n^ ^'m^m n — Ϋ w ^^ m-^ ^ o ^ n ^ ^ 'm ^ m n
¾ »斜萆 ^^mm^mm ^n ^^ ^ ° つ ¾ »Blank ^^ mm ^ mm ^ n ^^ ^ °
コ) Ψ 《继缀氺 s〇SHBN— ε〇つ HBN? ェ邈 4S¾继缀 ^翻 8止K) Ψ 《继 缀 氺s 〇SHBN— ε 〇HBN?
zrnm^ [ ΪΟΟ] zrnm ^ [ΪΟΟ]
0CZ9T0/S00Zdf/X3d 0簡 900Z OAV
Anal. Calcd for C H NO Si(H O) ： C, 55.12; H, 9.05; N 4.59. Found: C, 55.10; H 0CZ9T0 / S00Zdf / X3d 0 simple 900Z OAV Anal. Calcd for CH NO Si (HO): C, 55.12; H, 9.05; N 4.59. Found: C, 55.10; H
14 27 4 2 0.2 14 27 4 2 0.2
, 8.74; N4.79. , 8.74; N4.79.
[化 29] [Chemical 29]
[0019] 実施例 4 [0019] Example 4
ケトカルボン酸 2(200mg)のジクロロメタン一ァセトニトリル溶液 (1.OmL— 2.0mL)を室 温下攪拌し、さらし粉 (289mg)と酢酸 (0.3mL)を水 3mLに溶解させたものを滴下した。 2. 5時間攪拌した後、反応溶液をジクロロメタンと Na SO水溶液の混液中に注加した。 A solution of ketocarboxylic acid 2 (200 mg) in dichloromethane / acetonitrile (1.OmL—2.0 mL) was stirred at room temperature, and a solution of bleached powder (289 mg) and acetic acid (0.3 mL) dissolved in 3 mL of water was added dropwise. 2. After stirring for 5 hours, the reaction solution was poured into a mixture of dichloromethane and aqueous Na 2 SO 4 solution.
2 3 twenty three
溶液の pHを 2に調整して力も有機層を分取し、飽和食塩水で洗浄した。 MgSOで乾 The organic layer was separated by adjusting the pH of the solution to 2 and washed with saturated brine. Dry with MgSO
4 燥した後濃縮することで N-クロ口 1 βーメチルカルボン酸 10が無色油状液体として得 られた (167mg, 79%)。 4 Drying and concentration yielded N-black 1 β-methylcarboxylic acid 10 as a colorless oily liquid (167 mg, 79%).
HRMS(FAB+): Calcd for C H NO ClSi: 335.1398; Found: 336.1393 HRMS (FAB +): Calcd for C H NO ClSi: 335.1398; Found: 336.1393
14 26 4 14 26 4
'H-NMR (CDCl ); 0.07 ( 3H, s ), 0.08 ( 3H, s ), 0.88 ( 9H, s ), 1.19 ( 3H, d, J=6.3H 'H-NMR (CDCl); 0.07 (3H, s), 0.08 (3H, s), 0.88 (9H, s), 1.19 (3H, d, J = 6.3H
3 Three
z ), 1.36 ( 3H, d, J=6.9Hz ), 2.95 ( IH, qd, J=5.4Hz, 7.2Hz ), 3.25 ( IH, dd, J=2.7H z, 5.7Hz ), 4.16 ( IH, dd, J=5.1Hz, 2.1Hz ), 4.25 ( IH, qd, J=4.8Hz, 6.3Hz ) ppm こ ：のの I1I0を NaHSOにより還元することで 1 βーメチルカルボン酸 3を得た c z), 1.36 (3H, d, J = 6.9Hz), 2.95 (IH, qd, J = 5.4Hz, 7.2Hz), 3.25 (IH, dd, J = 2.7H z, 5.7Hz), 4.16 (IH, dd, J = 5.1Hz, 2.1Hz) , 4.25 (IH, qd, J = 4.8Hz, 6.3Hz) ppm this: c the I1I0 obtain a 1 beta-methylstyrene carboxylic acid 3 by reducing the NaHSO of the
[化 30] [Chemical 30]
[0020] 実施例 5 [0020] Example 5
アクリル酸 l(l.OOg)の酢酸ェチル溶液 (8.0mL)に酢酸 (1.74mL)をカ卩えて- 40°Cで攪 拌した。オゾンを 15分間導入し、溶液が薄青く着色したのを確認した後に窒素置換し た。 30%過酸ィ匕水素水 (1.56mL)をカ卩えて氷冷下 1時間攪拌し、室温下でさらに 2時間 攪拌した後、反応液を酢酸ェチルと Na S 0水溶液 (10当量)の混液に注加した。分取 Acetic acid (1.74 mL) was added to an ethyl acetate solution (8.0 mL) of acrylic acid l (l.OOg), and the mixture was stirred at -40 ° C. Ozone was introduced for 15 minutes, and after confirming that the solution was colored pale blue, the atmosphere was replaced with nitrogen. After adding 30% hydrogen peroxide-hydrogen water (1.56 mL) and stirring under ice-cooling for 1 hour and further stirring at room temperature for 2 hours, the reaction mixture was mixed with ethyl acetate and Na S 0 aqueous solution (10 equivalents). Added to. Preparative
2 2 3
した有機層を水、飽和食塩水で順次洗浄し、 MgSOで乾燥した後濃縮した。残渣をト 2 2 3 The organic layer was washed successively with water and saturated brine, dried over MgSO and concentrated. Residue
4 Four
ルェン一へキサンより結晶化することで 1 βーメチルカルボン酸 3が白色結晶として得 られた (710mg, 71%[ α体検出せず])。 Anal. Calcd for C H NO Si(H 0) ： C, 55.45; 1 β-methylcarboxylic acid 3 was obtained as a white crystal by crystallization from Luene monohexane (710 mg, 71% [α form not detected]). Anal. Calcd for C H NO Si (H 0): C, 55.45;
14 27 ' " 14 27 '"
H, 9.04; N 4.62. Found: C, 55.34; H, 8.90; N4.69. H, 9.04; N 4.62. Found: C, 55.34; H, 8.90; N4.69.
[化 31] [Chemical 31]
[0021] 実施例 6 [0021] Example 6
アクリル酸 l(500mg)の酢酸ェチル溶液 (4.0mL)に酢酸 (l.OmL)をカ卩えて- 10°Cで攪拌 した。オゾンを 15分間導入し、溶液が薄青く着色したのを確認した後に窒素置換した 。飽和 NaHCO水溶液 (40mL)に反応溶液を氷冷下滴下し、室温で攪拌した。反応液 Acetic acid (l.OmL) was added to an ethyl acetate solution (4.0 mL) of acrylic acid l (500 mg) and stirred at -10 ° C. Ozone was introduced for 15 minutes, and after confirming that the solution was colored pale blue, the atmosphere was replaced with nitrogen. The reaction solution was added dropwise to a saturated aqueous NaHCO solution (40 mL) under ice-cooling, and the mixture was stirred at room temperature. Reaction liquid
3 Three
に 1N塩酸をカ卩えて酸性にし、酢酸ェチルにより抽出した。飽和食塩水で洗浄し、 MgS 0で乾燥した後濃縮した。残渣をへキサンより結晶化することで 1 13ーメチルカルボン The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over MgS 0 and concentrated. By crystallizing the residue from hexane
4 Four
酸 3が白色結晶として得られた (356mg, 76.9%[ α / β = 7/93])。 Acid 3 was obtained as white crystals (356 mg, 76.9% [α / β = 7/93]).
[化 32] [Chemical 32]
[0022] 実施例 7 [0022] Example 7
アクリル酸 l(l.OOg)の酢酸ェチル溶液 (7.0mL)に酢酸 (2.60mL)をカ卩えて- 10°Cで攪 拌し、オゾンを 15分間導入し、溶液が薄青く着色したのを確認した後に窒素置換した 。 30%過酸ィ匕水素水 (1.56mL)を加えて室温で 2.5時間攪拌した後、反応液を酢酸ェチ ルと Na S 0水溶液 (10当量)の混液に注加した。分取した有機層を飽和食塩水で洗 Acetic acid (2.60 mL) was added to an ethyl acetate solution (7.0 mL) of acrylic acid l (l.OOg), stirred at -10 ° C, ozone was introduced for 15 minutes, and the solution turned pale blue. After confirmation, nitrogen substitution was performed. After adding 30% hydrogen peroxide aqueous solution (1.56 mL) and stirring at room temperature for 2.5 hours, the reaction solution was poured into a mixture of ethyl acetate and aqueous Na 2 S 0 solution (10 equivalents). The separated organic layer was washed with saturated brine.
2 2 3 2 2 3
浄し、 MgSOで乾燥した後濃縮した。残渣をトルエン一へキサンより結晶化することで
l j8—メチルカルボン酸 3が白色結晶として得られた (677mg, 76%[ α体検出せず])。 Anal. Calcd for C H NO Si: C, 55.78; H, 9.03; N 4.65. Found: C, 55.49; H, 8.90; N4.63. Clean, dry over MgSO and concentrate. By crystallizing the residue from toluene monohexane l j8-methylcarboxylic acid 3 was obtained as white crystals (677 mg, 76% [α form not detected]). Anal. Calcd for CH NO Si: C, 55.78; H, 9.03; N 4.65. Found: C, 55.49; H, 8.90; N4.63.
[化 33] [Chemical 33]
実施例 8 Example 8
アクリル酸エステル 6(2.00g)のアセトン溶液に氷冷下で IN水酸ィ匕ナトリウム水溶液 (8 .4mL)を加えた後、室温で終夜攪拌した。反応液中のアセトンを濃縮した後塩酸をカロ えて pH 10に調整し、酢酸ェチルにより 2度洗浄した。さらに塩酸をカ卩えて pH4とし、酢 酸ェチルにより抽出した。分離した有機層は水洗し、 MgSOで乾燥した後濃縮した。 To an acetone solution of acrylic ester 6 (2.00 g) was added IN aqueous sodium hydroxide solution (8.4 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. After concentrating the acetone in the reaction solution, the hydrochloric acid was removed and adjusted to pH 10 and washed twice with ethyl acetate. Further, hydrochloric acid was added to pH 4, and extracted with ethyl acetate. The separated organic layer was washed with water, dried over MgSO and concentrated.
4 Four
化合物 1を含む濃縮残渣に、酢酸ェチル (14.4mL)と酢酸 (3.22mL)をカ卩えて- 10°Cで 攪拌し、オゾンを 15分間導入し、溶液が薄青く着色したのを確認した後に窒素置換し た。 30%過酸ィ匕水素水 (3.0mL)をカ卩えて室温で 3.5時間攪拌した後、 5°Cで終夜放置し た。反応液を Na S 0水溶液 (10当量)の混液に注加した。分取した有機層を飽和食 After adding ethyl acetate (14.4 mL) and acetic acid (3.22 mL) to the concentrated residue containing Compound 1, stirring at -10 ° C, introducing ozone for 15 minutes, and confirming that the solution was colored pale blue Nitrogen replacement was performed. After adding 30% hydrogen peroxide aqueous solution (3.0 mL), the mixture was stirred at room temperature for 3.5 hours, and then allowed to stand at 5 ° C. overnight. The reaction mixture was poured into a mixture of aqueous Na S 0 solution (10 equivalents). Saturated food for the separated organic layer
2 2 3 2 2 3
塩水で 2度洗浄し、 MgSOで乾燥した後濃縮した。残渣をトルエン一へキサンより結 The extract was washed twice with brine, dried over MgSO and concentrated. Residue from toluene-hexane
4 Four
晶化することで l j8—メチルカルボン酸 3が白色結晶として得られた (1.33g, 78%[ α体 検出せず])。 Crystallization yielded l j8-methylcarboxylic acid 3 as white crystals (1.33 g, 78% [α form not detected]).
Anal. Calcd for C H NO Si(H O) ： C, 55.12; H, 9.05; N 4.59. Found: C, 55.21; H , 8.78; N4.67. Anal. Calcd for C H NO Si (H 2 O): C, 55.12; H, 9.05; N 4.59. Found: C, 55.21; H, 8.78; N4.67.
[化 34]
[Chemical 34]
産業上の利用可能性 Industrial applicability
本発明は、力ルバぺネム系抗菌剤の工業的製造方法として有用である
INDUSTRIAL APPLICABILITY The present invention is useful as an industrial production method for powerful rubapenem antibacterial agents.
Claims
請求の範囲 The scope of the claims
式： Formula:
[化 1]
[Chemical 1]
(式中、 Rは、オゾン酸ィ匕に悪影響を与えない置換基で置換されていてもよい j8—ラ クタム環基; は、水素、またはオゾン酸ィ匕に悪影響を与えない置換基で置換されて V、てもよ 、低級アルキル)で示される化合物（I)またはその塩をオゾン酸ィ匕する工程 を包含する、式： (Wherein R is an optionally substituted j8-lactam ring group that does not adversely affect ozone acid; and is substituted with hydrogen or a substituent that does not adversely affect ozone acid) And the step of converting the compound (I) represented by V or lower alkyl) or a salt thereof into an ozone acid,
[化 2]
[Chemical 2]
(式中、 Rおよび は前記と同意義)で示される化合物 (III)またはその塩の製造方法 (Wherein R and are as defined above) A method for producing compound (III) or a salt thereof
[2] 化合物（I)またはその塩をオゾンで酸ィ匕することにより得られたィ匕合物を、酸化処理ま たは塩基処理する工程を包含する、請求項 1記載の製造方法。 [2] The production method according to claim 1, comprising a step of oxidizing or base-treating the compound obtained by acidifying the compound (I) or a salt thereof with ozone.
[3] 化合物（I)またはその塩をオゾンで酸ィ匕することにより得られたィ匕合物を、過酸化水 素で酸化処理する工程を包含する、請求項 1記載の製造方法。 [3] The production method according to claim 1, comprising a step of oxidizing a compound obtained by acidifying the compound (I) or a salt thereof with ozone with hydrogen peroxide.
[4] オゾンによる酸化を酸存在下で行う、請求項 1〜3のいずれかに記載の製造方法。 [4] The production method according to any one of claims 1 to 3, wherein the oxidation with ozone is carried out in the presence of an acid.
[5] オゾンによる酸化を酢酸存在下で行う、請求項 1〜3のいずれかに記載の製造方法。 [5] The production method according to any one of claims 1 to 3, wherein the oxidation with ozone is carried out in the presence of acetic acid.
[6] 以下の工程： [6] The following steps:
(第 1工程） (First step)
式： Formula:
[化 3]
[Chemical 3]
(式中、 Rは、オゾン酸ィ匕に悪影響を与えない置換基で置換されていてもよい j8—ラ クタム環基; は、水素、またはオゾン酸ィ匕に悪影響を与えない置換基で置換されて V、てもよ 、低級アルキル)で示される化合物（I)またはその塩をオゾンで酸ィ匕した後、 還元処理することにより、式： (Wherein R is an optionally substituted j8-lactam ring group that does not adversely affect ozone acid; and is substituted with hydrogen or a substituent that does not adversely affect ozone acid) The compound (I) represented by V or lower alkyl) or a salt thereof is acidified with ozone and then reduced to give a compound represented by the formula:
[化 4] [Chemical 4]
(式中、 Rおよび は前記と同意義)で示される化合物 (Π)またはその塩を得る工程、 および (Wherein R and are as defined above), or a salt thereof, and
(第 2工程） (Second process)
化合物（II)またはその塩を酸ィ匕する工程を包含する、請求項 1記載の化合物（III)ま たはその塩の製造方法。 The method for producing compound (III) or a salt thereof according to claim 1, comprising a step of acidifying compound (II) or a salt thereof.
[7] 式： [7] Formula:
[化 5] [Chemical 5]
(式中、 Rは、オゾン酸ィ匕に悪影響を与えない置換基で置換されていてもよい j8—ラ クタム環基; は、水素、またはオゾン酸ィ匕に悪影響を与えない置換基で置換されて V、てもよ 、低級アルキル; R'はカルボキシ保護基)で示される化合物（I， )またはその 塩の R'部分を脱保護して化合物 (I)またはその塩を得る工程を包含する、請求項 1 〜6の 、ずれかに記載の製造方法。 (Wherein R is an optionally substituted j8-lactam ring group that does not adversely affect ozone acid; and is substituted with hydrogen or a substituent that does not adversely affect ozone acid) And V, which may be lower alkyl; R ′ is a carboxy-protecting group), and includes the step of deprotecting the R ′ part of compound (I,) or a salt thereof to obtain compound (I) or a salt thereof The manufacturing method according to any one of claims 1 to 6.
[8] 化合物 (I)またはその塩を単離せずに行う、請求項 7記載の製造方法。
[9] 式： [8] The production method according to claim 7, which is carried out without isolating compound (I) or a salt thereof. [9] Formula:
[化 6] [Chemical 6]
(式中、 Rは、オゾン酸ィ匕に悪影響を与えない置換基で置換されていてもよい j8—ラ クタム環基; は、水素、またはオゾン酸ィ匕に悪影響を与えない置換基で置換されて V、てもよ 、低級アルキル)で示される化合物（II)またはその塩を酸ィ匕する工程を包含 する、請求項 1記載の化合物 (III)の製造方法。 (Wherein R is an optionally substituted j8-lactam ring group that does not adversely affect ozone acid; and is substituted with hydrogen or a substituent that does not adversely affect ozone acid) The method for producing compound (III) according to claim 1, comprising a step of acidifying the compound (II) represented by V or lower alkyl) or a salt thereof.
[10] は低級アルキルである、請求項 1〜9の！、ずれかに記載の製造方法。 [10] is lower alkyl, according to claims 1-9! The manufacturing method according to any of the above.
[11] はメチルである、請求項 1〜9のいずれかに記載の製造方法。 [11] The production method according to any one of claims 1 to 9, wherein methyl is methyl.
[12] は 1 β—メチルである、請求項 1〜9のいずれかに記載の製造方法。 [12] The method according to any one of claims 1 to 9, wherein [12] is 1β-methyl.
[13] Rが式： [13] R is the formula:
[化 7] [Chemical 7]
(式中、 R1は水素またはオゾン酸ィ匕に悪影響を与えない置換基; R2は水素またはイミ ノ保護基)で示される β ラタタム環基である、請求項 1〜9のいずれかに記載の製 造方法。 10 or any one of claims 1-9, wherein R 1 is a substituent that does not adversely affect hydrogen or ozone acid; R 2 is hydrogen or an imino protecting group. The manufacturing method described.
[14] Rが式： [14] R is the formula:
[化 8] [Chemical 8]
(式中、 R1は水素または保護されて 、てもよ 、ヒドロキシで置換されて 、てもよ 、アル キル; R2は水素またはィミノ保護基)で示される j8—ラタタム環基である、請求項 1〜9
の！、ずれかに記載の製造方法。 (Wherein R 1 is hydrogen or protected, may be substituted with hydroxy, may be alkyl; R 2 is hydrogen or an imino protecting group) and is a j8-ratata ring group, Claims 1-9 of! The manufacturing method according to any of the above.
(式中、 R2は水素またはィミノ保護基; R3はヒドロキシ保護基)で示される β—ラタタム 環基である、請求項 1〜9のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 9, which is a β-ratata ring group represented by (wherein R 2 is hydrogen or an imino protecting group; R 3 is a hydroxy protecting group).
[16] Rは低級アルキルであり、 Rが式： [16] R is lower alkyl, and R is a formula:
[化 10] [Chemical 10]
(式中、 R1は水素または保護されて 、てもよ 、ヒドロキシで置換されて 、てもよ 、アル キル; R2は水素またはィミノ保護基)で示される j8—ラタタム環基である、請求項 1〜9 の！、ずれかに記載の製造方法。 (Wherein R 1 is hydrogen or protected, may be substituted with hydroxy, may be alkyl; R 2 is hydrogen or an imino protecting group) and is a j8-ratata ring group, Claims 1-9! The manufacturing method according to any of the above.
[17] Rは低級アルキルであり、 Rが式： [17] R is lower alkyl, and R is represented by the formula:
[化 11] [Chemical 11]
(式中、 R2は水素またはィミノ保護基; R3はヒドロキシ保護基)で示される β—ラタタム 環基である、請求項 1〜9のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 9, which is a β-ratata ring group represented by (wherein R 2 is hydrogen or an imino protecting group; R 3 is a hydroxy protecting group).
[18] 式： [18] Formula:
[化 12]
[Chemical 12]
(式中、 Rは水素または低級アルキル; R1は保護されていてもよいヒドロキシで置換さ れて 、てもよ 、アルキル; R2は水素またはィミノ保護基)で示される化合物（1—1)また はその塩を、所望により酸存在下、オゾンで酸ィ匕することにより得られた化合物を、酸 化処理または還元処理する工程を包含する、式： (Wherein R is hydrogen or lower alkyl; R 1 is optionally substituted with hydroxy, and alkyl; R 2 is hydrogen or imino protecting group) (1-1) ) Or a salt thereof, optionally in the presence of an acid, with an acid solution with ozone.
[化 13] [Chemical 13]
(式中、 R°、 R1および R2は前記と同意義)で示される化合物（III— 1)またはその塩の 製造方法である、請求項 1記載の製造方法。 The production method according to claim 1, which is a production method of the compound (III-1) or a salt thereof represented by the formula (wherein R °, R 1 and R 2 are as defined above).
[19] 式： [19] Formula:
[化 14] [Chemical 14]
(式中、 Rは、オゾン酸ィ匕に悪影響を与えない置換基で置換されていてもよい j8—ラ クタム環基; は、水素、またはオゾン酸ィ匕に悪影響を与えない置換基で置換されて V、てもよ 、低級アルキル)で示される化合物（II)またはその塩。 (Wherein R is an optionally substituted j8-lactam ring group that does not adversely affect ozone acid; and is substituted with hydrogen or a substituent that does not adversely affect ozone acid) And V (or lower alkyl)) (II) or a salt thereof.
[20] 式： [20] Formula:
[化 15] [Chemical 15]
式： Formula:
[化 16] [Chemical 16]
(式中、 R2は水素; R3はヒドロキシ保護基)で示される化合物（II— 2)またはその塩で ある、請求項 19記載の化合物。 20. The compound according to claim 19, which is a compound (II-2) represented by the formula (wherein R 2 is hydrogen; R 3 is a hydroxy protecting group) or a salt thereof.
[22] 式： [22] Formula:
[化 17] [Chemical 17]
(式中、 R3はヒドロキシ保護基)で示される化合物（II— 3)またはその塩である、 項 19記載の化合物。 (Wherein, R 3 is hydroxy protecting group) Compounds represented by (II- 3) or a salt thereof, compound of claim 19.
R3はアルキルシリルである、請求項 22記載の化合物またはその塩。
R 3 is an alkyl silyl compound or salt thereof according to claim 22, wherein.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004-258341 | 2004-09-06 | ||
| JP2004258341 | 2004-09-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2006028037A1 true WO2006028037A1 (en) | 2006-03-16 |
Family
ID=36036318
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP2005/016230 WO2006028037A1 (en) | 2004-09-06 | 2005-09-05 | Process for production of intermediates for the synthesis of carbapenems |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2006028037A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007145260A1 (en) * | 2006-06-16 | 2007-12-21 | Kaneka Corporation | Improved method for crystallization of azetidinonecarboxylic acid |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5726658A (en) * | 1980-07-24 | 1982-02-12 | Toyama Chem Co Ltd | 4r -4- 3-substituted carboxy-3-diazo-2-oxopropyl -2- azetidinone derivative and its preparation |
| JPH05105660A (en) * | 1991-10-15 | 1993-04-27 | Kanegafuchi Chem Ind Co Ltd | Production of intermediate for synthesizing carbapenem from 4-(1,2-substituted or non-substituted allyl)-2-azetidinone compound |
-
2005
- 2005-09-05 WO PCT/JP2005/016230 patent/WO2006028037A1/en not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5726658A (en) * | 1980-07-24 | 1982-02-12 | Toyama Chem Co Ltd | 4r -4- 3-substituted carboxy-3-diazo-2-oxopropyl -2- azetidinone derivative and its preparation |
| JPH05105660A (en) * | 1991-10-15 | 1993-04-27 | Kanegafuchi Chem Ind Co Ltd | Production of intermediate for synthesizing carbapenem from 4-(1,2-substituted or non-substituted allyl)-2-azetidinone compound |
Non-Patent Citations (2)
| Title |
|---|
| ITANI H. ET AL: "Two practical synthesis of a key intermediate of 1beta-methylcarbapenem antibiotics", SYNLETT., vol. 2, 1995, pages 213, XP002993798 * |
| MORI M. ET AL: "A simple and highly stereoselective route to a key intermediate carboxylic acid for the synthesis of 1beta-methylcarbapenems", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 3, no. 11, 1993, pages 2389 - 2392, XP002993797 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007145260A1 (en) * | 2006-06-16 | 2007-12-21 | Kaneka Corporation | Improved method for crystallization of azetidinonecarboxylic acid |
| 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 |
| JP5130208B2 (en) * | 2006-06-16 | 2013-01-30 | 株式会社カネカ | Improved crystallization method of azetidinone carboxylic acid |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| MX2015006458A (en) | Synthesis of spirocyclic isoxazoline derivatives. | |
| Ohtake et al. | Regioselective Synthesis of Nitrones by Decarboxylative Oxidation of N-Alkyl-. ALPHA.-amino Acids and Application to the Synthesis of 1-Azabicyclic Alkaloids. | |
| WO2006006290A1 (en) | PROCESS FOR PRODUCING 1-OXACEPHALOSPORIN-7α-METHOXY-3-CHLOROMETHYL DERIVATIVE | |
| WO2006028037A1 (en) | Process for production of intermediates for the synthesis of carbapenems | |
| Akiyama et al. | Stereoselective synthesis of cyclopentanols by Lewis acid-mediated [3+ 2] annulation of allyldiisopropylphenylsilane with α, β-unsaturated diesters | |
| JP2000219646A (en) | Production of adamantanols | |
| JP5688647B2 (en) | Iodoarene derivative, method for producing optically active spirolactone compound using the same, and method for producing optically active cycloaddition product | |
| WO2004043961A1 (en) | Process for producing carbapenem compound for oral administration | |
| JP2902178B2 (en) | Method for producing carbapenem synthesis intermediate from 4- (1,2-substituted or unsubstituted allyl) -2-azetidinone compound | |
| JP5183885B2 (en) | Process for producing optically active dihydrobenzofuran derivatives and chroman derivatives | |
| CN111556872A (en) | Synthesis of boronic ester derivatives and uses thereof | |
| PT93893A (en) | PROCESS FOR THE PREPARATION OF PNEMO COMPOUNDS | |
| JP7335849B2 (en) | Diester compound having a dimethylcyclobutane ring, method for producing the same, and method for producing a dimethylcyclobutane compound derived therefrom | |
| JP2007008921A (en) | Method for producing 4-methylthio-3-butenyl isothiocyanate and its intermediate of synthesis | |
| Banwell et al. | Improved synthetic route to enantiomerically pure samples of the tetrahydropyran-2-ylacetic acid core associated with the phytotoxic polyketide herboxidiene | |
| JP2787248B2 (en) | Method for producing 4-acetoxyazetidinones | |
| WO2007020960A1 (en) | Process for producing carbapenem derivatives through reactions without isolating intermediates | |
| JP3787809B2 (en) | Synthetic method of oxathiazepine ring | |
| JP2000136183A (en) | Production of n-benzyl-4-formylpiperidine | |
| JP2020029415A (en) | Process for preparing (e2)-cis-6,7-epoxy-2-nonenal | |
| US20040147756A1 (en) | Optically active fluorine-containing compounds and processes for their production | |
| JP2005145833A (en) | Method for producing syn-1,3-diol compound | |
| JP2008137898A (en) | Method for producing 4-methylthio-3-butenylisothiocyanate, its synthetic intermediate, and antimicrobial composition containing the same | |
| JP3917674B2 (en) | Method for synthesizing brefeldin compounds | |
| JP4483183B2 (en) | Process for producing 6,7-dihydroxycoumarin-3-carboxylic acid derivative and its intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase | ||
| NENP | Non-entry into the national phase |
Ref country code: JP |
|
| WWW | Wipo information: withdrawn in national office |
Country of ref document: JP |