JP2014504616A - (s,s)−2,8−ジアザビシクロ[4.3.0]ノナンの不斉合成方法、並びに、関係原料およびその調製方法 - Google Patents
(s,s)−2,8−ジアザビシクロ[4.3.0]ノナンの不斉合成方法、並びに、関係原料およびその調製方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 40
- KSCPLKVBWDOSAI-NKWVEPMBSA-N (4as,7as)-2,3,4,4a,5,6,7,7a-octahydro-1h-pyrrolo[3,4-b]pyridine Chemical compound N1CCC[C@H]2CNC[C@H]21 KSCPLKVBWDOSAI-NKWVEPMBSA-N 0.000 title claims abstract description 25
- 238000011914 asymmetric synthesis Methods 0.000 title claims abstract description 9
- 238000002360 preparation method Methods 0.000 title description 15
- 239000002994 raw material Substances 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 91
- -1 imide compound Chemical class 0.000 claims abstract description 56
- 125000006239 protecting group Chemical group 0.000 claims abstract description 53
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 40
- 230000002829 reductive effect Effects 0.000 claims abstract description 33
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 claims abstract description 17
- 150000001412 amines Chemical class 0.000 claims abstract description 14
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims abstract description 14
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims description 58
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 28
- 238000005984 hydrogenation reaction Methods 0.000 claims description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 238000004519 manufacturing process Methods 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 25
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 25
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 24
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 19
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 18
- 230000007062 hydrolysis Effects 0.000 claims description 18
- 238000006460 hydrolysis reaction Methods 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 229910052727 yttrium Inorganic materials 0.000 claims description 16
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 15
- 238000000926 separation method Methods 0.000 claims description 15
- 238000010992 reflux Methods 0.000 claims description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- MAPRDOKILZKGDP-UHFFFAOYSA-N bromo-chloro-iodomethanesulfonic acid Chemical group OS(=O)(=O)C(Cl)(Br)I MAPRDOKILZKGDP-UHFFFAOYSA-N 0.000 claims description 9
- 229910052763 palladium Inorganic materials 0.000 claims description 9
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 8
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 claims description 7
- 239000007868 Raney catalyst Substances 0.000 claims description 6
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 6
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 6
- 238000007259 addition reaction Methods 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- 150000003949 imides Chemical class 0.000 claims description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims 1
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 abstract description 6
- 229960003702 moxifloxacin Drugs 0.000 abstract description 6
- 239000000047 product Substances 0.000 description 71
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 229910001873 dinitrogen Inorganic materials 0.000 description 12
- 238000006268 reductive amination reaction Methods 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000003277 amino group Chemical group 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 238000006722 reduction reaction Methods 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 0 *C(CCC(CN(*)C1)C1=O)=* Chemical compound *C(CCC(CN(*)C1)C1=O)=* 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- XLKXIFXOWMGWNT-UHFFFAOYSA-N ethyl 1-benzyl-4-oxopyrrolidine-3-carboxylate Chemical compound C1C(=O)C(C(=O)OCC)CN1CC1=CC=CC=C1 XLKXIFXOWMGWNT-UHFFFAOYSA-N 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 238000007327 hydrogenolysis reaction Methods 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- 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 4
- BWOJQGUVAPALSH-UHFFFAOYSA-N 1-benzyl-4-(3-chloropropyl)pyrrolidin-3-one Chemical compound C1C(=O)C(CCCCl)CN1CC1=CC=CC=C1 BWOJQGUVAPALSH-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 238000006114 decarboxylation reaction Methods 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- RODWPRILKQTBPR-UHFFFAOYSA-N ethyl 4-(1-benzyl-4-oxopyrrolidin-3-yl)butanoate Chemical compound C1C(=O)C(CCCC(=O)OCC)CN1CC1=CC=CC=C1 RODWPRILKQTBPR-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 229910052987 metal hydride Inorganic materials 0.000 description 3
- 150000004681 metal hydrides Chemical class 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 125000000547 substituted alkyl group Chemical group 0.000 description 3
- VRJYCNOBQXHAIC-UHFFFAOYSA-N 1-benzyl-4-(3-chloropropyl)pyrrolidin-3-one;hydrochloride Chemical compound Cl.C1C(=O)C(CCCCl)CN1CC1=CC=CC=C1 VRJYCNOBQXHAIC-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
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 230000002152 alkylating effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 238000004517 catalytic hydrocracking Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002081 enamines Chemical class 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- VLADXSIKWDYABL-UHFFFAOYSA-N ethyl 3-(3-chloropropyl)-4-oxopyrrolidine-1-carboxylate Chemical compound CCOC(=O)N1CC(CCCCl)C(=O)C1 VLADXSIKWDYABL-UHFFFAOYSA-N 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 229940072132 quinolone antibacterials Drugs 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 description 1
- QWWKKLSUUVFQJO-UHFFFAOYSA-N 1-benzyl-4-(3-phenylmethoxypropyl)pyrrolidin-3-one Chemical compound C1C(CCCOCC=2C=CC=CC=2)C(=O)CN1CC1=CC=CC=C1 QWWKKLSUUVFQJO-UHFFFAOYSA-N 0.000 description 1
- SFOYQZYQTQDRIY-UHFFFAOYSA-N 1-chloro-3-iodopropane Chemical compound ClCCCI SFOYQZYQTQDRIY-UHFFFAOYSA-N 0.000 description 1
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- UWSVQQOHHLYPSZ-UHFFFAOYSA-N 3-(1-benzyl-4-oxopyrrolidin-3-yl)propyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCCCC(C(C1)=O)CN1CC1=CC=CC=C1 UWSVQQOHHLYPSZ-UHFFFAOYSA-N 0.000 description 1
- XYQPOKBAQDQMQP-UHFFFAOYSA-N 3-chloropropoxymethylbenzene Chemical compound ClCCCOCC1=CC=CC=C1 XYQPOKBAQDQMQP-UHFFFAOYSA-N 0.000 description 1
- 229910018072 Al 2 O 3 Inorganic materials 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 208000008745 Healthcare-Associated Pneumonia Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229910001514 alkali metal chloride Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005103 alkyl silyl group Chemical group 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 150000004718 beta keto acids Chemical class 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000000911 decarboxylating effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- ZCYXXKJEDCHMGH-UHFFFAOYSA-N nonane Chemical compound CCCC[CH]CCCC ZCYXXKJEDCHMGH-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000005870 sharpless asymmetric epoxidation reaction Methods 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyrrole Compounds (AREA)
Abstract
Description
Zは2つのHまたはOであり、Zが2つのHである場合には、Yはクロロ、ブロモ、ヨード、メタンスルホン酸エステル、p−トルエンスルホン酸エステル、ヒドロキシル基、または保護基を有するヒドロキシル基であり、ZがOである場合には、YはOR1である。R1はC1−4アルキル基である。
(1)ピロリジン−3−ケトン(II)とキラルアミン(R)−1−フェニルエチルアミンとの脱水反応によって、イミド化合物またはエナミン化合物を得る。
(2)イミド化合物またはエナミン化合物を還元して、式(I)のキラル構造を有する式(III)の化合物または式(IV)の化合物を得る。
(S,S)−2,8−ジアザビシクロ[4.3.0]ノナンの調製
1H NMR (500MHz,CDCl3) δ7.34-7.23(m,10H),4.16-4.12 (m,2H),3.76-3.75 (m,1H),3.54 (q,J=13.0Hz,2H),3.23-3.22 (m,1H),2.81-2.72 (m,2H),2.34 (t,J=7.75,2H),2.21-2.18 (m,3H),1.94 (m,1H),1.31-1.25 (m,7H)。MS-ESI: m/z: 381 (M++1)。
1H NMR (500MHz,CDCl3) δ7.35-7.24 (m,10H),6.03 (q,J=7.1Hz,1H),3.65-3.61 (m,2H),3.47 (d,J=12.9Hz,1H),3.07 (t,J=8.3Hz,1H),2.87 (t,J=8.3Hz,1H),2.54-2.19 (m,5H),1.67-1.66 (m,2H), 1.48 (d,J=7.2Hz,3H)。MS-ESI: m/z: 335 (M++1)。
1H NMR (500MHz,CDCl3) δ7.38-7.20 (m,10H),3.73 (q,J=13.5Hz,2H),3.63−3.58(m,2H),2.86-2.72 (m,3H),2.57 (t,J=4.5Hz,1H),2.29-2.26 (m,3H),1.61-1.60 (m,4H),1.30 (d,J=6.5Hz,3H)。MS-ESI: m/z:321 (M++1)。
1H NMR (500MHz,CDCl3) δ3.08-3.07 (m,1H),3.06-2.81 (m,4H),2.70−2.67 (m,1H),2.52-2.51 (m,1H),2.00-1.99 (m,1H),1.95-1.87 (br,2H),1.63-1.60 (m,2H),1.35-1.32 (m,2H)。
(S,S)−2,8−ジアザビシクロ[4.3.0]ノナンの調製
1H NMR (500MHz,CDCl3) δ7.34-7.24(m,10H),3.80-3.50 (m,1H),3.66-3.65 (m,2H),3.57-3.52 (m,2H),3.39-3.34 (m,1H),2.80-2.76 (m,2H),2.30-2.27 (m,1H),2.23-2.17 (m,2H),1.72-1.64 (m,2H), 1.52-1.45 (m,1H),1.36-1.34 (m,4H), MS-ESI: m/z: 339 (M++1)。
(S,S)−2,8−ジアザビシクロ[4.3.0]ノナンの調製
1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.3 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 7.20 (m, 10H), 4.36 (t, J = 6.0 Hz, 2H), 3.73 (d, J = 6.5 Hz, 1H), 3.55 (q, J = 12.9 Hz, 2H), 3.24 (d, J = 6.3 Hz, 1H), 2.84 (s, 1H), 2.79 - 2.68 (m, 1H), 2.22 (m, 3H), 1.85 - 1.69 (m, 3H), 1.44 (m, 1H), 1.28 (m, 4H)。
(S,S)−2,8−ジアザビシクロ[4.3.0]ノナンの調製
1H NMR (500MHz,CDCl3) δ7.33-7.23 (m,5H),4.17-4.12 (m,2H),3.68-3.57 (m,3H),3.35-3.32 (m,2H),3.27-3.22 (m,1H),2. 42-2.39 (m,1H),2.29-2.25 (m,2H), 1.62-1.22 (m,8H)。
1−ベンジル−4−(3−エトキシカルボニルプロピル)−3−ピロリドンの調製
1H NMR (500MHz,CDCl3) δ7.38-7.26 (m,5H),4.22-4.09 (m,4H),3.76-3.70 (m,2H),3.37 (d,J=9.65Hz,1H),3.10 (dd,J=77.5Hz 17.3Hz,2H),2.76 (d,J=9.65Hz,1H),2.51-2.10 (m,4H),1.30-1.22 (m,6H)。MS-ESI: m/z: 348 (M++1)。
1H NMR (500MHz,CDCl3) δ7.34-7.26 (m,5H),4.11 (q,J=7.15Hz,2H),3.71-3.65 (m,2H),3.29-3.23 (m,2H),2.74 (d,J=17.3,1H),2.47-2.36 (m,4H),2.07-2.04 (m,1H),1.72-1.70 (m,1H),1.32-1.22 (m,3H)。MS-ESI: m/z: 276 (M++1) 。
1−エトキシカルボニル−4−(3−クロロプロピル)−3−ピロリドンの調製
1H NMR (500 MHz, CDCl3) δ7.34-7.27 (m, 5H), 4,17 (q, J = 7.1Hz, 2H), 3.71 (s, 2H), 3.48-3.51 (m, 2H), 3.40 (d, J = 9.6Hz ,1H), 3.19 (d, J = 17.2Hz,1H), 2.99 (d, J = 17.2Hz,1H), 2.73 (d, J = 9.6Hz, 1H), 2.04-2.02 (m, 1H), 1.92-1.89 (m,2H), 1.71-1.69 (m, 1H), 1.24 (t, J = 7.1Hz, 3H)。MS-ESI: m/z:324(M++1)。
1H NMR (500 MHz, CDCl3) δ7.36-7.27 (m, 5H), 3.70 (s, 2H), 3.54-3.51(m, 2H), 3.30 (d, J = 8.0Hz ,1H), 3.25 (d, J = 17.0Hz ,1H), 2.74 (d, J = 17.0Hz,1H), 2.46-2.44 (m, 1H), 2.37 (dd, J = 8.8Hz,8.0Hz,1H), 1.91-1.86 (m,2H), 1.86-1.79 (m, 1H), 1.55-1.50 (m,1H)。MS-ESI: m/z:252 (M++1)。
1H NMR (500 MHz, CDCl3) δ4.21-4.16 (m, 3H), 4.05-3.90 (m, 1H), 3.74-3.70 (m, 1H), 3.56-3.53 (m ,2H), 3.34-3.30 (m ,1H), 2.58-2.42 (m,1H), 1.95-1.82 (m, 3H), 1.63-1.57 (m,1H), 1.28-1.25 (m,3H)。MS-ESI: m/z:234(M++1)。
1−ベンジル−4−(3−ベンジルオキシプロピル)−3−ピロリドンの調製
1H NMR (500 MHz, CDCl3) δ7.33-7.27 (m, 10H), 4.47 (s, 2H), 4.17 (q, 2H),3.67 (t 2H), 3.46-3.43 (m,3H), 3.19 (d, J = 17.1Hz ,1H), 2.94 (d, J = 17.1Hz ,1H), 2.72 (d,1H), 2.04-1.98 (m,1H), 1.85-1.82 (m,1H), 1.72-1.71 (m,1H), 1.56-1.53 (m,1H), 1.24 (t,3H)。
1−ベンジル−4−(3−ベンゾイルオキシプロピル)−3−ピロリドンの調製
1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.1 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.38 - 7.27 (m, 5H), 4.32 (t, J = 6.3 Hz, 2H), 3.70 (s, 2H), 3.37 - 3.21 (m, 2H), 2.76 (d, J = 17.2 Hz, 1H), 2.50 (dd, J = 13.4, 8.0 Hz, 1H), 2.41 (t, J = 8.9 Hz, 1H), 1.98 - 1.71 (m, 3H), 1.54 (m, 1H)。
(3S,4S)−1−ベンジル−3−[(1R)−フェニルエチルアミノ]−4−(3−クロロプロピル)−ピロリジンの調製
1H NMR (500MHz, CDCl3) δ7.34-7.23 (m,10H), 3.80-3.50 (m,5H), 3.23-3.22 (m,1H), 2.81-2.72 (m,2H), 2.21-2.18 (m,2H),1.93 (m,1H), 1.57-1.25 (m,7H)。MS-ESI: m/z: 357 (M++1)。
(S,S)−2,8−ジアザビシクロ[4.3.0]ノナンの調製
1H NMR (500MHz,CDCl3) δ7.38-7.20 (m,10H),3.73 (q,J=13.5Hz,2H), 3.63−3.58 (m,2H), 2.86-2.72 (m,3H), 2.57 (t,J=4.5Hz,1H), 2.29-2.26 (m,3H), 1.61-1.60 (m,4H), 1.30 (d,J=6.5Hz,3H)。MS-ESI: m/z: 321 (M++1)。
(S,S)−2,8−ジアザビシクロ[4.3.0]ノナンの調製(ワンポット合成)
LC-MS: m/z:319 (M++1)。
Claims (19)
- (S,S)−2,8−ジアザビシクロ[4.3.0]ノナン(I)の不斉合成方法であって、
ピロリジン−3−ケトン(II)とキラルアミンである(R)−1−フェニルエチルアミンとの脱水反応によってイミド化合物またはエナミン化合物を得るステップ(1)と、
前記イミド化合物または前記エナミン化合物を還元して、式(I)のキラル構造を有する式(III)の化合物または式(IV)の化合物を得るステップ(2)と、
を含む不斉反応ステップにより、式(I)のキラル構造を有する式(III)の化合物または式(IV)の化合物を得る段階を含む(S,S)−2,8−ジアザビシクロ[4.3.0]ノナン(I)の製造方法。
Rはアミノ保護基であり、特に加水分解または水素化によって除去可能なC1−4アルコキシカルボニル基、ベンジルオキシカルボニル基、またはベンジル基であり、
Zは2つのHまたはOであり、Zが2つのHである場合には、Yはクロロ、ブロモ、ヨード、メタンスルホン酸エステル、p−トルエンスルホン酸エステル、ヒドロキシル基、または保護基を有するヒドロキシル基であり、ZがOである場合には、YはOR1であり、当該R1はC1−4アルキル基である。] - 前記還元が、触媒水素化により行われる請求項1に記載の製造方法。
- 前記触媒水素化の触媒が、ラネーニッケルである請求項2に記載の製造方法。
- 前記触媒水素化の触媒が、パラジウム触媒である請求項2に記載の製造方法。
- 前記パラジウム触媒が、パラジウム炭素である請求項4に記載の製造方法。
- 前記脱水反応が、溶媒還流水分離法により行われ、
前記溶媒が、水と共沸混合物を形成可能な、メチルベンゼン、ベンゼン、およびn−ヘキサンからなる群から選択される請求項1に記載の製造方法。
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PCT/CN2012/081699 WO2013053281A1 (zh) | 2011-10-14 | 2012-09-20 | (s,s)-2,8-二氮杂双环[4,3,0]壬烷的不对称合成方法、相关原料及制备方法 |
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CN112920184B (zh) * | 2021-02-06 | 2022-03-01 | 台州市生物医化产业研究院有限公司 | 一种制备莫西沙星中间体(s,s)-2,8-二氮杂二环[4,3,0]壬烷的方法 |
CN112939847B (zh) * | 2021-02-06 | 2022-05-13 | 台州市生物医化产业研究院有限公司 | 一种制备莫西沙星中间体(s,s)-2,8-二氮杂二环[4,3,0]壬烷的方法 |
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EP2679588B1 (en) | 2015-07-08 |
WO2013053281A1 (zh) | 2013-04-18 |
CN103282361B (zh) | 2014-12-17 |
US20140066626A1 (en) | 2014-03-06 |
CN103044418B (zh) | 2015-02-04 |
US9238648B2 (en) | 2016-01-19 |
EP2679588A4 (en) | 2014-03-12 |
EP2679588A1 (en) | 2014-01-01 |
JP5963778B2 (ja) | 2016-08-03 |
ES2548078T3 (es) | 2015-10-13 |
CN103044418A (zh) | 2013-04-17 |
CN103282361A (zh) | 2013-09-04 |
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