JPWO2004007506A1 - Ruthenium compound, diamine ligand and method for producing optically active alcohol - Google Patents
Ruthenium compound, diamine ligand and method for producing optically active alcohol Download PDFInfo
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- JPWO2004007506A1 JPWO2004007506A1 JP2004521111A JP2004521111A JPWO2004007506A1 JP WO2004007506 A1 JPWO2004007506 A1 JP WO2004007506A1 JP 2004521111 A JP2004521111 A JP 2004521111A JP 2004521111 A JP2004521111 A JP 2004521111A JP WO2004007506 A1 JPWO2004007506 A1 JP WO2004007506A1
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- 150000003304 ruthenium compounds Chemical class 0.000 title claims abstract description 42
- 239000003446 ligand Substances 0.000 title claims abstract description 30
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 30
- 150000004985 diamines Chemical class 0.000 title claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title description 43
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine group Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 40
- 239000001257 hydrogen Substances 0.000 claims abstract description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 32
- 150000002576 ketones Chemical class 0.000 claims abstract description 29
- 230000003287 optical effect Effects 0.000 claims abstract description 27
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 22
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 20
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 4
- -1 diamine compound Chemical class 0.000 claims description 238
- 125000001424 substituent group Chemical group 0.000 claims description 142
- 125000000623 heterocyclic group Chemical group 0.000 claims description 43
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 15
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 125000003860 C1-C20 alkoxy group Chemical group 0.000 claims description 10
- 239000000852 hydrogen donor Substances 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- 125000004104 aryloxy group Chemical group 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 125000003627 8 membered carbocyclic group Chemical group 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- ZIHNPGWNXFQLIS-HZPDHXFCSA-N C1([C@H](N)CC[C@@H](N)C=2C=CC=CC=2)=CC=CC=C1 Chemical compound C1([C@H](N)CC[C@@H](N)C=2C=CC=CC=2)=CC=CC=C1 ZIHNPGWNXFQLIS-HZPDHXFCSA-N 0.000 claims description 4
- 125000000732 arylene group Chemical group 0.000 claims description 4
- 125000006165 cyclic alkyl group Chemical group 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 3
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 3
- JGQDLMSXMOGEMC-UHFFFAOYSA-N pentane-2,4-diamine Chemical compound CC(N)CC(C)N JGQDLMSXMOGEMC-UHFFFAOYSA-N 0.000 claims description 3
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 2
- BBPXVYVXKAYBSS-UHFFFAOYSA-N hexane-2,5-diamine Chemical compound CC(N)CCC(C)N BBPXVYVXKAYBSS-UHFFFAOYSA-N 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims 2
- 239000001273 butane Substances 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 26
- 150000001298 alcohols Chemical class 0.000 abstract description 18
- 229910052736 halogen Inorganic materials 0.000 abstract description 11
- 125000000217 alkyl group Chemical group 0.000 abstract description 10
- 150000002367 halogens Chemical class 0.000 abstract description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 91
- 238000006243 chemical reaction Methods 0.000 description 77
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 58
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 57
- 239000002904 solvent Substances 0.000 description 56
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 53
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 50
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- 238000006722 reduction reaction Methods 0.000 description 32
- 238000000034 method Methods 0.000 description 31
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 28
- 239000000243 solution Substances 0.000 description 28
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 26
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 26
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 24
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 18
- 239000002585 base Substances 0.000 description 18
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 18
- 229960001701 chloroform Drugs 0.000 description 17
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 16
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 15
- 239000003795 chemical substances by application Substances 0.000 description 15
- 125000005594 diketone group Chemical group 0.000 description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 15
- 239000008096 xylene Substances 0.000 description 15
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- DHCWLIOIJZJFJE-UHFFFAOYSA-L dichlororuthenium Chemical compound Cl[Ru]Cl DHCWLIOIJZJFJE-UHFFFAOYSA-L 0.000 description 14
- 150000002009 diols Chemical class 0.000 description 14
- 150000002170 ethers Chemical class 0.000 description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
- 238000010898 silica gel chromatography Methods 0.000 description 14
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 13
- 229910052717 sulfur Inorganic materials 0.000 description 13
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 12
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 12
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 12
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 12
- 238000009835 boiling Methods 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 11
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 11
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 11
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
- SMWUDAKKCDQTPV-UHFFFAOYSA-N 1,3-dimethylimidazolidine Chemical compound CN1CCN(C)C1 SMWUDAKKCDQTPV-UHFFFAOYSA-N 0.000 description 10
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 10
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 10
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 10
- 229910052794 bromium Inorganic materials 0.000 description 10
- 239000003638 chemical reducing agent Substances 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 10
- 229910052801 chlorine Inorganic materials 0.000 description 10
- FHIVAFMUCKRCQO-UHFFFAOYSA-N diazinon Chemical compound CCOP(=S)(OCC)OC1=CC(C)=NC(C(C)C)=N1 FHIVAFMUCKRCQO-UHFFFAOYSA-N 0.000 description 10
- 229930195733 hydrocarbon Natural products 0.000 description 10
- 125000001624 naphthyl group Chemical group 0.000 description 10
- 150000007530 organic bases Chemical class 0.000 description 10
- 239000003960 organic solvent Substances 0.000 description 10
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 10
- IOPQYDKQISFMJI-UHFFFAOYSA-N [1-[2-bis(4-methylphenyl)phosphanylnaphthalen-1-yl]naphthalen-2-yl]-bis(4-methylphenyl)phosphane Chemical group C1=CC(C)=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC(C)=CC=1)C=1C=CC(C)=CC=1)C1=CC=C(C)C=C1 IOPQYDKQISFMJI-UHFFFAOYSA-N 0.000 description 9
- 125000003277 amino group Chemical group 0.000 description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 9
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
- 235000019445 benzyl alcohol Nutrition 0.000 description 8
- 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 8
- 239000011737 fluorine Substances 0.000 description 8
- 229910052731 fluorine Inorganic materials 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 150000002430 hydrocarbons Chemical group 0.000 description 8
- 150000002825 nitriles Chemical class 0.000 description 8
- ADYYRXNLCZOUSU-UHFFFAOYSA-M potassium;propan-2-ol;hydroxide Chemical compound [OH-].[K+].CC(C)O ADYYRXNLCZOUSU-UHFFFAOYSA-M 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 7
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 7
- 229950005499 carbon tetrachloride Drugs 0.000 description 7
- 239000012973 diazabicyclooctane Substances 0.000 description 7
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 6
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 6
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 6
- 150000008064 anhydrides Chemical class 0.000 description 6
- 239000012300 argon atmosphere Substances 0.000 description 6
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 6
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 6
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 6
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 6
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- 229910052707 ruthenium Inorganic materials 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 229930192474 thiophene Natural products 0.000 description 6
- 150000003852 triazoles Chemical class 0.000 description 6
- 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 6
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 5
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- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- CHWRSCGUEQEHOH-UHFFFAOYSA-N potassium oxide Chemical compound [O-2].[K+].[K+] CHWRSCGUEQEHOH-UHFFFAOYSA-N 0.000 description 1
- 229910001950 potassium oxide Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229960005335 propanol Drugs 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical class [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 241000894007 species Species 0.000 description 1
- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical compound O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- SIMSUOWKMVWQAI-UHFFFAOYSA-N tert-butyl-[2-[tert-butyl(methyl)phosphanyl]ethyl]-methylphosphane Chemical compound CC(C)(C)P(C)CCP(C)C(C)(C)C SIMSUOWKMVWQAI-UHFFFAOYSA-N 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- VOITXYVAKOUIBA-UHFFFAOYSA-N triethylaluminium Chemical compound CC[Al](CC)CC VOITXYVAKOUIBA-UHFFFAOYSA-N 0.000 description 1
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- WXAZIUYTQHYBFW-UHFFFAOYSA-N tris(4-methylphenyl)phosphane Chemical compound C1=CC(C)=CC=C1P(C=1C=CC(C)=CC=1)C1=CC=C(C)C=C1 WXAZIUYTQHYBFW-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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- B01J31/2452—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring with more than one complexing phosphine-P atom
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Abstract
本発明は、式(1):[式中、X、Yは水素、ハロゲン等を、Pxはホスフィン配位子を、R1〜R8は水素、アルキル基等を、Aはアルキレン等を、n1は1又は2を表す。また、Aを構成する炭素原子、C#1、C#2のいずれか少なくとも1個が、光学活性を有する炭素である。]で表されるルテニウム化合物、及び該ルテニウム化合物を不斉還元触媒として用いて、縮合環ケトン類又はα−アミノケトン類を不斉還元する光学活性アルコール類の製造方法に関する。The present invention has the formula (1): [wherein, X and Y are hydrogen, halogen, etc., Px is a phosphine ligand, R1 to R8 are hydrogen, an alkyl group, etc., A is alkylene, etc., n1 is 1 or 2 is represented. Further, at least one of carbon atoms constituting C, C # 1, and C # 2 is carbon having optical activity. And a method for producing optically active alcohols in which condensed ring ketones or α-aminoketones are asymmetrically reduced using the ruthenium compound as an asymmetric reduction catalyst.
Description
技術分野:
本発明は、ルテニウム化合物、該ルテニウム化合物の配位子として好適に用いられるジアミン化合物、及び該ルテニウム化合物を不斉還元触媒として用いて、縮合環ケトン類又はα−アミノケトン類を不斉還元することを特徴とする光学活性アルコール類の製造方法に関する。
背景技術:
光学活性アルコール類は、医薬・農薬の合成中間体として有用である。
従来、縮合環ケトン類を触媒的不斉還元することによって、対応する光学活性アルコール類を得る方法としては、
▲1▼イリジウム錯体を触媒に用いる水素化による方法〔J.Am.Chem.Soc.,115,3318(1993)〕、
▲2▼ルテニウムを触媒に用いる水素移動による方法(特開平10−130289号公報)、
▲3▼ルテニウムを触媒に用いる水素化による方法(特開平11−189600号公報)等が知られている。
また、α−アミノケトン類を水素化反応することによって、対応する光学活性アミノアルコール類を得る方法としては、
▲4▼国際公開WO02/04401号公報および、J.Am.Chem.Soc.,122,510(2000)に報告例がある。
しかしながら、▲1▼の方法は、極めて高価なイリジウム錯体を用いるため、コスト面から実用化は困難であり、▲2▼の方法は、水素源として蟻酸等の有機化合物を用いなければならず、水素ガス等の安価な水素源を用いる場合に比べ、操作的・コスト的に不利であり、▲3▼の方法は、ケトン類の不斉還元方法として優れたものであるが、縮合環状ケトン類の不斉還元についての知見は得られておらず、また、▲4▼の方法は、α−アミノケトン類の不斉還元に関するものであるが、触媒としては複数の置換基を有する高価な2座ホスフィン配位子を用いなければ良好な結果が得られない等の問題があった。
従って、水素ガス等の安価な水素源を用いて、縮合環ケトン類やα−アミノケトン類から対応する光学活性アルコール類を高選択的、高収率に製造できる不斉還元触媒の開発が望まれている。
また、本発明に係わる配位性のアミノ基が置換した二つの炭素原子の間に一個あるいはそれ以上の炭素原子を含む光学活性ジアミン化合物としては、2,4−ペンタンジアミン、2,5−ヘキサンジアミン、3,4−O−イソプロピリデンジヒドロキシ−1,4−ブタンジアミンおよび(R,R)−1,4−ジフェニルブタンジアミン(Tetrahedron:Asymmetry,2000,11,3003−3015.)等が知られているが、該光学活性ジアミン化合物が縮合環ケトンやα−アミノケトンなどのケトン類の不斉還元触媒の配位子として極めて有用であることは知られていなかった。
発明の開示:
本発明は、製造容易なルテニウム化合物、該ルテニウム化合物の配位子として好適に用いることができるジアミン化合物、及び該ルテニウム化合物を不斉還元触媒として用いて、縮合環ケトン類又はα−アミノケトン類を不斉還元して、対応する光学活性アルコール類を高立体選択的、かつ高収率に製造する方法を提供することを課題とする。
本発明は、第1に、式(1):
(式中、X及びYは、それぞれ独立して、水素原子、ハロゲン原子、カルボキシル基、水酸基又はC1〜C20アルコキシ基を表し、Pxは、ホスフィン配位子を表し、R1乃至R8は、それぞれ独立して、水素原子、置換基を有してもよいC1〜C20アルキル基、置換基を有してもよいC2〜C20アルケニル基、置換基を有してもよいC3〜C8シクロアルキル基、置換基を有してもよいC7〜C20アラルキル基又は置換基を有してもよいアリール基を表す。
また、R1とR3、および/または、R5とR7が結合して環を形成してもよい。
Aは、置換基を有していてもよいC1〜C8アルキレン、置換基を有していてもよい1〜2個の酸素原子を含むC2〜C8アルキレン、置換基を有していてもよいC3〜C8シクロアルキレン、置換基を有していてもよいアリーレンまたは置換基を有していてもよい2価のヘテロ環基を表わす。Aがアルキレンの場合はR2とR6とが結合して環を形成してもよい。
また、Aを構成する炭素原子、C#1およびC#2のいずれか少なくとも一個が、光学活性を有する炭素である。
n1は1または2の整数を表す。)で表されるルテニウム化合物であり、
第2に、式(2−1): R1C*H(NH2)−A−R1C*H(NH2)
〔式中、R1およびAは前記と同じ意味を示し、*は光学活性を有する原子であることを示す。〕で表されるジアミン化合物を提供する。但し、2,4−ペンタンジアミン、2,5−ヘキサンジアミン、3,4−O−イソプロピリデンジヒドロキシ−1,4−ブタンジアミンおよび、(R,R)−1,4−ジフェニルブタン−1,4−ジアミンを除く。
本発明は第3に、式(3)又は(3’)
(式中、a環部は、置換基を有してもよい3〜8員炭素環または置換基を有してもよい4〜8員ヘテロ環を表し、b環部は、置換基を有してもよい4〜8員炭素環または置換基を有してもよい5〜8員ヘテロ環を表す。)で表される縮合環ケトン類を、本発明のルテニウム化合物のいずれか1種若しくは2種以上の存在下に、水素ガス又は水素供与体を水素源として用いて不斉水素還元する工程を有することを特徴とする式(4)又は(4’)
(式中、a環部、b環部及び*は前記と同じ意味を表す。)で表される光学活性アルコール類の製造方法を提供する。
本発明は第4に、式(5):Ra−CO−CH(Rb)−Rc
〔式中、Ra及びRcは、それぞれ独立して、水素原子、置換基を有してもよいC1〜C20アルキル基、置換基を有してもよいC2〜C20アルケニル基、置換基を有してもよいC3〜C8シクロアルキル基、置換基を有してもよいC7〜C20アラルキル基又は置換基を有してもよいアリール基を表す。
Rbは、
式(6):R9CO(R11)N−
式(7):R9CO(R10CO)N−
式(8):R9R11N−
で表される基から選ばれるいずれかの基を表す。
(ここで、R9、R10及びR11は、それぞれ独立して、水素原子、置換基を有してもよいC1〜C20アルキル基、置換基を有してもよいC2〜C20アルケニル基、置換基を有してもよいC1〜C20アルコキシ基、置換基を有してもよいC3〜C8シクロアルキル基、置換基を有してもよいC3〜C8シクロアルコキシ基、置換基を有してもよいC7〜C20アラルキル基、置換基を有してもよいC7〜C20アラルキルオキシ基、置換基を有してもよいアリール基又は置換基を有してもよいアリールオキシ基を表し、また、R9とR11若しくはR9とR10が結合して、5〜8員の含窒素ヘテロ環を形成してもよい。)〕で表されるα−アミノケトン類を、本発明の式(1)で表されるルテニウム化合物のいずれか1種若しくは2種以上の存在下に、水素ガス又は水素供与体を水素源として用いて不斉水素還元する工程を有する、
式(9):Ra−C*H(OH)−C(*)H(Rb)−Rc
〔式中、Ra、Rb、Rc及び*は前記と同じ意味を表し、C(*)はRcが水素以外の場合に不斉炭素であることを示す。〕で表される光学活性β−アミノアルコール類の製造方法を提供する。
本発明のルテニウム化合物は、入手容易なルテニウム誘導体を出発原料として用いるものであって、容易に製造をすることができる。また、本発明のジアミン化合物は、本発明のルテニウム化合物の配位子として好適に用いることができる。さらに、本発明の光学活性アルコール類の製造方法によれば、該ルテニウム化合物を不斉還元触媒として用い、縮合環ケトン類又はα−アミノケトン類を出発原料として、医薬・農薬の合成中間体として有用な前記式(4)、(4’)及び(9)で表される光学活性アルコール類を、水素ガス等の安価な水素源を用いて高立体選択的かつ高収率に製造することができる。
発明の実施の形態:
以下、本発明を詳細に説明する。
本発明は、▲1▼式(1)で表されるルテニウム化合物、▲2▼該ルテニウム化合物の配位子として好適に用いることができる式(2−1)で表される新規なジアミン化合物、▲3▼及び該ルテニウム化合物を不斉還元触媒として用いて、式(3)及び(3’)で表される縮合環ケトン類、又は式(5)で表されるα−アミノケトン類を、不斉還元して式(4),(4’)及び(9)で表される光学活性アルコール類を製造する方法である。
本発明の式(1)で表されるルテニウム化合物について説明する。
前記式(1)において、X及びYはそれぞれ独立して、水素原子;フッ素、塩素、臭素等のハロゲン原子、カルボキシル基、水酸基、又は、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、ペンチロキシ、ヘキシロキシ、シクロヘキシロキシ、ドデシロキシ等のC1〜C20アルコキシ基を表す。
Pxはホスフィン配位子を表す。Pxとしては、例えば、式:PRARBRCで表される単座ホスフィン配位子や、式:RDREP−W−PRFRGで表される2座ホスフィン配位子等が挙げられるが、光学活性であるのが好ましい。
前記式:PRARBRCで表される単座ホスフィン配位子において、RA、RB及びRCは、それぞれ独立して、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、sec−ブチル、t−ブチル、ペンチル及びその異性体,ヘキシル及びその異性体、ヘプチル及びその異性体、ノニル及びその異性体、ドデシルおよびその異性体等のC1〜C20アルキル基;置換基を有してもよいフェニル基;シクロプロピル、シクロペンチル、シクロヘキシル、シクロオクチル基等のC3〜C8シクロアルキル基;ベンジル、α−メチルベンジル、α,α−ジメチルベンジル基等のC7〜C20アラルキル基;等を表す。また、RA、RB及びRCのうちの2つが結合して、置換基を有してもよいPを含むヘテロ環を形成してもよい。
前記フェニル基及びPを含むヘテロ環の置換基としては、例えば、フッ素、塩素、臭素、ヨウ素等のハロゲン原子;水酸基;メチル、エチル、プロピル、ブチル、ペンチル,ヘキシル、ヘプチル、ノニル、ドデシル基等のC1〜C20アルキル基;エテニル、プロペニル、ブテニル、2−ヘキセニル基等のC2〜C20アルケニル基;シクロプロピル、シクロブチル、シクロペンチル基等のC3〜C8シクロアルキル基;ベンジル、α−メチルベンジル、α,α−ジメチルベンジル基等のC7〜C20アラルキル基;フェニル、1−ナフチル、2−ナフチル基等のアリール基;メトキシ、エトキシ、n−プロポキシ、イソプロポキシ、ブトキシ、ペンチロキシ、ヘキシロキシ、ドデシロキシ基等のC1〜C20アルコキシ基;アセトキシ、エチルカルボニルオキシ、ベンゾイルオキシ等のアシルオキシ基;ジオキソラン−2−イル、オキサゾリン−2−イル等のヘテロ環基;等が挙げられる。
単座ホスフィン配位子の具体例としては、トリメチルホスフィン、トリエチルホスフィン、トリブチルホスフィン、トリフェニルホスフィン、トリシクロヘキシルホスフィン、トリ(p−トリル)ホスフィン、ジフェニルメチルホスフィン、ジメチルフェニルホスフィン、ジイソプロピルメチルホスフィン、1−〔2−(ジフェニルホスフィノ)フェロセニル〕エチルメチルエーテル、2−(ジフェニルホスフィノ)−2’−メトキシ−1,1’−ビナフチル等の3級ホスフィンが好適なものとして挙げることができる。また、エチルメチルブチルホスフィン、エチルメチルフェニルホスフィン、イソプロピルエチルメチルホスフィン、シクロヘキシル(O−アニシル)メチルホスフィン等のRA、RB及びRCが3種とも異なる置換基からなるホスフィン配位子を用いることもできる。
前記式:RDREP−W−PRFRGで表される2座ホスフィン配位子において、RD、RE、RF及びRGは、それぞれ独立して、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、sec−ブチル、t−ブチル、ペンチル及びその異性体,ヘキシル及びその異性体、ヘプチル及びその異性体、ノニル及びその異性体、ドデシルおよびその異性体等のC1〜C20アルキル基;置換基を有してもよいフェニル基;又はシクロプロピル、シクロペンチル、シクロヘキシル基等のC3〜C8シクロアルキル基;等を表し、また、RDとRE及び/またはRFとRGが結合して置換基を有してもよいPを含む複素環を形成してもよい。
前記フェニル基及び複素環の置換基としては、例えば、フッ素、塩素、臭素、ヨウ素等のハロゲン原子;水酸基;メチル、エチル、プロピル、ブチル基等のC1〜C20アルキル基;エテニル、プロペニル、ブテニル基等のC2〜C20アルケニル基;シクロプロピル、シクロブチル、シクロペンチル基等のC3〜C8シクロアルキル基;ベンジル、α−メチルベンジル、α,α−ジメチルベンジル基等のC7〜C20アラルキル基;フェニル、1−ナフチル、2−ナフチル基等のアリール基;メトキシ、エトキシ、n−プロポキシ、イソプロポキシ、ブトキシ基等のC1〜C20アルコキシ基;アセトキシ、エチルカルボニルオキシ、ベンゾイルオキシ等のアシルオキシ基;ジオキソラン−2−イル、オキサゾリン−2−イル等のヘテロ環基;等が挙げられる。
Wは、置換基を有しても良い、メチレン、エチレン、プロピレン基等のC1〜C5アルキレン基;置換基を有しても良い、シクロプロピレン、シクロブチレン、シクロペンチレン、シクロヘキシレン基等のC3〜C6シクロアルキレン基;置換基を有しても良い、フェニレン、ナフチレン、1,1’−ビフェニル−2,2’−ジイル、1,1’−ビナフチル−2,2’−ジイル、1,1’−ビナフチル−7,7’−ジイル基等のアリーレン基;置換基を有しても良い、エテンジイル、プロペンジイル、イソプロペンジイル、ブテンジイル基等のC2〜C20アルケンジイル基;置換基を有しても良い、エチンジイル、プロピンジイル基等のC2〜C20アルキンジイル基;を表す。これらの2価基上の置換基としては、例えば、メチル、エチル、プロピル、ブチル基等のC1〜C20アルキル基;エテニル、プロペニル、ブテニル等のC2〜C20アルケニル基;メトキシ、エトキシ、n−プロポキシ、イソプロポキシ、ブトキシ基等のC1〜C20アルコキシ基;等が挙げられる。
2座ホスフィン配位子の具体例としては、ビスジフェニルホスフィノメタン、ビスジフェニルホスフィノエタン、ビスジフェニルホスフィノプロパン、ビスジフェニルホスフィノブタン、ビスジメチルホスフィノエタン、ビスジメチルホスフィノプロパン等が挙げられる。
さらに本発明においては、2,2’−ビス−(ジフェニルホスフィノ)−1,1’−ビナフチル(以下、BINAPと称す)、及びBINAPのナフチル環にアルキル基やアリール基等の置換基をもつBINAP誘導体、フッ素置換基を有するBINAP誘導体、リン原子上の2個のベンゼン環にそれぞれアルキル基やアルコキシ基等の置換基を1〜5個有するBINAPの誘導体等の不斉配位子も好適な2座ホスフィン配位子として例示できる。
これらの具体例としては、2,2’−ビス−(ジ−p−トリルホスフィノ)−1,1’−ビナフチル(Tol−BINAP)、2,2’−ビス〔ビス(3,5−ジメチルフェニル)ホスフィノ〕−1,1’−ビナフチル(Xylyl−BINAP)、1−〔1’,2−ビス(ジフェニルホスフィノ)フェロセニル〕エチルジアミン、2,2’−ビス−(ジシクロヘキシルホスフィノ)−6,6’−ジメチル−1,1’−ビフェニル、2,3−ビス−(ジフェニルホスフィノ)ブタン、1−シクロヘキシル−1,2−ビス−(ジフェニルホスフィノ)エタン、1−置換−3,4−ビス−(ジフェニルホスフィノ)ピロリジン、2,3−O−イソプロピリデン−2,3−ジヒドロキシ−1,4−ビス−(ジフェニルホスフィノ)ブタン、1,2−ビス〔(O−メトキシフェニル)フェニルホスフィノ〕エタン、置換−1,2−ビス(ホスホラノ)ベンゼン、5,6−ビス−(ジフェニルホスフィノ)−2−ノルボルネン、N,N’−ビス−(ジフェニルホスフィノ)−N,N’−ビス(1−フェニルエチル)エチレンジアミン、1,2−ビス−(ジフェニルホスフィノ)プロパン、2,4−ビス−(ジフェニルホスフィノ)ペンタン、[(5,6),(5’,6’)−ビス(メチレンジオキシ)ビフェニル−2,2’−ジイル]ビス(ジフェニルホスフィン)、1,2−ビス(t−ブチルメチルホスフィノ)エタン、2,4−ビス−(ジフェニルホスフィノ)ペンタン等が挙げられる。
なお、本発明に用いることのできるホスフィン配位子は、安定してルテニウム化合物を形成し得るものであれば、上記のものに限定されるものではない。
次に、式(1)で表されるルテニウム化合物における、式(2)で表されるジアミン配位子について説明する。
Aは、メチレン、エチレン、プロピレン等のC1〜C8のアルキレン;2−オキサプロパン−1,3−ジイル、3−オキサペンタン−1,5−ジイル、3,6−ジオキサオクタン−1,8−ジイル等の1〜2個の酸素原子を含むC2〜C8アルキレン基;シクロプロピレン、シクロブチレン、シクロペンチレン、シクロヘキシレン、シクロヘプチレン、シクロオクチレン等のC3〜C8のシクロアルキレン;フェニレン、ナフチレン等のアリーレン;または2価のヘテロ環基を表し、該ヘテロ環基としては、任意の位置に2価の結合手を有する、フラン、ピラン、ジオキソラン、チオフェン、チオピラン、ピロール、イミダゾール、ピラゾール、オキサゾール、トリアゾール、チアゾール、イソチアゾール、ピリジン、ピリダジン、ピラジン、ベンゾイミダゾール、ベンゾピラゾール、ベンゾチアゾール、キノリン、インドリン、フェナントロリン、ジオキソラン−2−オン、ジオキサン、ジオキサン−2,3−ジオン、オキサゾリジン、オキサゾリジノン、テトラヒドロフラン、テトラヒドロフラン−2,5−ジオン、テトラヒドロチオフェン、スルホラン等の飽和又は不飽和のヘテロ環が挙げられる。
これらの基は更に置換基を有していてよく、該置換基としては、メチル、エチル、プロピル等のC1〜C6アルキル基;メトキシ、エトキシ、プロポキシ等のC1〜C6アルコキシ基;フェニル、ナフチル等のアリール基;フェノキシ等のアリールオキシ基;ベンジルオキシ基等のC7〜C20アラルキルオキシ基が挙げられる。
Aがアルキレン基、1〜2個の酸素原子を含むアルキレン基のとき、R2とR6が結合して環を形成してもよい。
R1〜R8は、それぞれ独立して、水素原子;置換基を有してもよい、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、sec−ブチル、t−ブチル、ペンチル、ヘキシル基等のC1〜C20アルキル基(好ましくはC1〜C6のアルキル基);置換基を有してもよい、エテニル、n−プロペニル、イソプロペニル、n−ブテニル、sec−ブテニル、t−ブテニル、ペンテニル、ヘキセニル基等のC2〜C20アルケニル基(好ましくはC2〜C6のアルケニル基);置換基を有してもよい、シクロプロピル、シクロペンチル、シクロヘキシル基等のC3〜C8シクロアルキル基;ベンジル、α−メチルベンジル、α,α−ジメチルベンジル、α−エチルベンジル基等の置換基を有してもよいC7〜C20アラルキル基;又は、置換基を有してもよい、フェニル、1−ナフチル、2−ナフチル基等のアリール基;を表す。
前記C1〜C20アルキル基、C2〜C20アルケニル基、C3〜C8シクロアルキル基、C7〜C20アラルキル基及びアリール基の置換基としては、例えば、フッ素、塩素、臭素、ヨウ素等のハロゲン原子;置換アミノ基;メチル、エチル、n−プロピル、イソプロピル、n−ブチル、sec−ブチル、t−ブチル、n−ペンチル、イソペンチル、ネオペンチル、t−ペンチル、ヘキシル、ヘプチル、オクチル、ノニル、デシル、ドデシル基等のC1〜C20アルキル基;エテニル、n−プロペニル、イソプロペニル、n−ブテニル、sec−ブテニル、t−ブテニル、1,3−ブタジエニル、n−ペンテニル、2−ペンテニル、3−ペンテニル、ヘキセニル基等のC2〜C20アルケニル基;シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル基等のC3〜C8シクロアルキル基;ベンジル、α−メチルベンジル、α,α−ジメチルベンジル、α−エチルベンジル基等のC7〜C20アラルキル基;フェニル、1−ナフチル、2−ナフチル基等のアリール基;メトキシ、エトキシ、n−プロポキシ、イソプロポキシ、n−ブトキシ、sec−ブトキシ、t−ブトキシ基等のC1〜C20アルコキシ基;アシルオキシ基;又はヘテロ環基;等が挙げられる。
前記置換アミノ基としては、例えば、ジメチルアミノ、N−メチル−N−フェニルアミノ基等の炭化水素基が2個置換したアミノ基;アセチルアミノ、ベンゾイルアミノ基等のアシルアミノ基;メタンスルホニルアミノ、トルエンスルホニルアミノ基等のスルホニルアミノ基;N−メチル−N−アセチルアミノ、N−エチル−N−アセチルアミノ、N−メチル−N−ベンゾイルアミノ、N−エチル−N−アシルアミノ基等のN−アルキル−N−アシルアミノ基;N−メチル−N−スルホニルアミノ基、N−エチル−N−スルホニルアミノ基等のN−アルキル−N−スルホニルアミノ基;フタルイミド基等の環状イミド基;等が挙げられる。
前記アシルオキシ基としては、例えば、アセトキシ、エチルカルボニルオキシ、イソプロピルカルボニルオキシ基等のC1〜C12のアルキルカルボニルオキシ基;ベンゾイルオキシ基等のアリールカルボニルオキシ基;フェニルメチルカルボニルオキシ基等のアラルキルカルボニルオキシ基;等が挙げられ、前記アシル基としては、例えば、プロパノイル、イソプロピルカルボニル基等のC1〜C12のアルキルカルボニル基、メトキシカルボニル、エトキシカルボニル、イソプロポキシカルボニル、t−ブトキシカルボニル基等のアルコキシカルボニル基;ベンゾイル基等のアリールカルボニル基;フェニルメチルカルボニル基等のアラルキルカルボニル基;等が挙げられる。
前記ヘテロ環基としては、例えば、フラニル、ピラニル、ジオキソラニル基等の含酸素ヘテロ環基;チエニル基等の含イオウヘテロ環基;ピロリル、イミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、トリアゾリル、チアゾリル、イソチアゾリル、ピリジル、ピラダジル、ピラジニル、ベンゾイミダゾリル、ベンゾピラゾリル、ペンゾチアゾリル、キノリル、アントラニル、インドリル、フェナントロニリル基等の飽和若しくは不飽和の含窒素ヘテロ環基;等が挙げられる。
これらの置換基は、その置換位置、置換基の種類、置換基の数等に特に制限はない。また、本発明においては、R1がR3と、R5がR7と、および/またはR2がR6と結合して環を形成したジアミン化合物を用いることもできる。
また、Aを構成する炭素原子、C#1およびC#2のいずれか少なくとも一個が、光学活性を有する炭素である。
これらのジアミン化合物としては、合成及び入手容易性や経済性の観点から、式(2’)
R1R2C*(NR3R4)−A−R1R2C*(NR3R4)(2’)
で表される化合物をより好適に用いることができる。
ここで、R1がC1〜C8の直鎖、分岐、環状アルキル基、C2〜C8の直鎖、分岐、環状アルケニル基、置換基を有していても良いアリール基、置換基を有していても良いヘテロ環基であり、R2、R3及びR4が全て水素原子であり、Aがアルキレン基、1〜2個の酸素原子を含むアルキレン、フェニレン基または下記式(2−A),(2−B),(2−C)で表される2価基である化合物がより好ましい。
[式中、Ra’、Rb’は、それぞれ独立して、水素原子;置換基を有してもよいメチル、エチル、n−プロピル、イソプロピル、n−ブチル、sec−ブチル、t−ブチル、ペンチル、ヘキシル基等のC1〜C6アルキル基;ベンジル、α−メチルベンジル、α,α−ジメチルベンジル、α−エチルベンジル基等の置換基を有してもよいC7〜C20アラルキル基;置換基を有してもよいメトキシ、エトキシ、イソプロポキシ基等のC1〜C6アルコキシ基;置換基を有してもよいメトキシカルボニル、エトキシカルボニル、イソプロポキシカルボニル、t−ブトキシカルボニル基等のC1〜C6アルコキシカルボニル基;ヘテロ環基;又は、置換基を有してもよいフェニル、1−ナフチル、2−ナフチル基等のC6〜C14アリール基を示すか、あるいは、式(2−A)においては、Ra’とRb’が一緒になってカルボニル基を形成してもよく、式(2−B)においては、Ra’、Rb’同士がそれぞれ一緒になってカルボニル基を形成してもよい。]
これらのジアミン化合物の具体例としては、ビス(2−アミノプロピル)エーテルの(S,S)および(R,R)体、ビス(2−アミノ−2−フェニルエチル)エーテルの(S,S)および(R,R)体、(1S,4S)−1,4−ジアミノ−1,4−ジフェニルブタン、1,4−ジアミノ−1,4−ジシクロヘキシルブタンの(S,S)および(R,R)体、1,2−ビス(1−アミノエチル)ベンゼンの(S,S)および(R,R)体、光学活性1,2−ビス(1−アミノエチル)シクロヘキサン、光学活性1,1−ビス(1−アミノエチル)シクロペンタン、光学活性1,2−ビス(1−アミノエチル)シクロペンタン、(2R、3R、4R、5R)−3,4−O−イソプロピリデン−3,4−ジヒドロキシ−2,5−ヘキサンジアミン、(2S、3S、4S、5S)−3,4−O−イソプロピリデン−3,4−ジヒドロキシ−2,5−ヘキサンジアミン、(1R、2R、3R、4R)−2,3−O−イソプロピリデン−2,3−ジヒドロキシ−1,4−ジフェニル−1,4−ブタンジアミン、(1S、2S、3S、4S)−2,3−O−イソプロピリデン−2,3−ジヒドロキシ−1,4−ジフェニル−1,4−ブタンジアミン、(1R、2R、3R、4R)−2,3−O−(1−フェニルエチリデン)−2,3−ジヒドロキシ−1,4−ジフェニル−1,4−ブタンジアミン、(1S、2S、3S、4S)−2,3−O−(1−フェニルエチリデン)−2,3−ジヒドロキシ−1,4−ジフェニル−1,4−ブタンジアミン、(2R、3R、4R、5R)−3,4−O−イソプロピリデン−3,4−ジヒドロキシ−1,4−ジフェニル−2,5−ヘキサンジアミン、(2S、3S、4S、5S)−3,4−O−イソプロピリデン−3,4−ジヒドロキシ−1,4−ジフェニル−2,5−ヘキサンジアミン、(3R、4R、5R、6R)−4,5−O−イソプロピリデン−4,5−ジヒドロキシ−3,6−オクタンジアミン、(3S、4S、5S、6S)−4,5−O−イソプロピリデン−4,5−ジヒドロキシ−3,6−オクタンジアミン等が挙げられる。
次に、本発明のルテニウム化合物の製造方法について説明する。
ルテニウム化合物の製造方法に用いられる出発原料としては、0価、1価、2価、3価及び、さらに高原子価のルテニウム誘導体を用いることができる。これらの中でも、Angew.Chem.Int.Ed.,37,1703(1998)に記載の2価ルテニウム錯体を用いる方法が簡便である。すなわち、2価のルテニウム−ハライド錯体と2座ホスフィン配位子の溶媒溶液を加熱後、ジアミン化合物を加えることで式(1)で表されるルテニウム化合物を製造することができる。
以下、出発原料として2価のルテニウム−ハライド錯体を用いた場合のルテニウム化合物の製造方法についてより詳細に説明する。
まず、出発原料の2価のルテニウム−ハライド錯体とホスフィン配位子とを、溶媒中、加熱し反応させ、対応するホスフィン−ルテニウム−ハライド錯体を得る。
出発原料の2価のルテニウム−ハライド錯体としては、ホスフィン配位子及びアミン配位子と置換可能な配位子を有するルテニウム錯体であれば、特に制限されるものではない。その具体例としては、〔2塩化ルテニウム(ノルボルナジエン)〕多核体、〔2塩化ルテニウム(シクロオクタジエン)〕多核体、〔ビス(メチルアリル)ルテニウム(シクロオクタジエン)〕等のジエンが配位したハロゲン化ルテニウム化合物;〔2塩化ルテニウム(ベンゼン)〕二核体、〔2塩化ルテニウム(p−シメン)〕二核体、〔2塩化ルテニウム(トリメチルベンゼン)〕二核体、〔2塩化ルテニウム(ヘキサメチルベンゼン)〕二核体等の芳香族化合物が配位したハロゲン化ルテニウム;等が挙げられる。
ホスフィン配位子の使用量は、ルテニウム−ハライド錯体1モルに対して、単座の場合は、通常2〜3倍モル、好ましくは2倍モルであり、2座の場合は、通常1〜2倍モル、好ましくは等モルである。
この反応に用いられる溶媒としては、例えば、トルエン、キシレン等の芳香族炭化水素類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類;ペンタン、ヘキサン等の脂肪族炭化水素類;ジクロロメタン、クロロホルム、トリクロロメタン、四塩化炭素、1,2−ジクロロエタン等のハロゲン炭化水素類;ジエチルエーテル、テトラヒドロフラン(THF)、1,2−ジメトキシエタン、1,4−ジオキサン等のエーテル類;メタノール、エタノール、n−プロパノール、イソプロパノール、ブタノール、ベンジルアルコール等のアルコール類;N,N−ジメチルホルムアミド(DMF)、N,N−ジメチルアセタミド、1,3−ジメチルイミダゾリジン、1,3−ジメチル−2−イミダゾリジノン、N−メチルピロリドン、ヘキサメチルリン酸トリアミド(HMPT)等のアミド類;アセトニトリル、ベンゾニトリル等のニトリル類;ジメチルスルホキシド(DMSO)等が挙げられる。これらの溶媒は単独で、あるいは2種以上を混合して使用することもできる。
溶媒の使用量は、基質1gに対して1ml〜100ml、好ましくは、基質1gに対し、1ml〜10mlの範囲である。反応温度は、通常、0〜200℃、好ましくは、室温〜100℃の範囲である。
次に、得られたホスフィン−ルテニウム−ハライド錯体とジアミン化合物とを反応させて、対応するアミン−ホスフィン−ルテニウム−ハライド錯体を得ることができる。
この反応に用いられるジアミン化合物の使用量は、ホスフィン−ルテニウム−ハライド錯体に対して、通常1〜2倍モル、好ましくは等モルである。
反応温度は、通常、−100〜200℃、好ましくは−10〜50℃の範囲である。
また、あらかじめ単離したホスフィン−ルテニウム−ハライド錯体に、前記と同様の条件下にジアミン化合物を作用させることによっても、アミン−ホスフィン−ルテニウム−ハライド錯体を得ることができる。
次いで、得られたアミン−ホスフィン−ルテニウム−ハライド錯体を、溶媒中、塩基と反応させることによって式(1)で表される化合物のうち、X=Y=Hであるアミン−ホスフィン−ルテニウムヒドリド錯体を得ることができる。
用いられる塩基としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン、1,4−ジアザビシクロ〔2,2,2〕オクタン(DABCO)、1,4−ジアザビシクロ〔5,4,0〕ウンデ−7−エン(DBU)等の有機塩基;ナトリウムメトキシド、ナトリウムエトキシド、カリウムt−ブトキシド、マグネシウムエトキシド等の金属アルコキシド類;n−ブチルリチウム、リチウムジイソプロピルアミド(LDA)等の有機リチウム化合物;水酸化ナトリウム、水酸化カリウム等のアルカリ金属水酸化物;炭酸カリウム、炭酸ナトリウム等の炭酸塩;水素化ナトリウム等の金属水素化物;等が挙げられる。
塩基の使用量はアミン−ホスフィン−ルテニウム−ハライド錯体に対して、通常、2〜10,000倍モル、好ましくは、2〜40倍モルの範囲である。
この反応に用いる溶媒としては、例えば、トルエン、キシレン等の芳香族炭化水素類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類;ペンタン、ヘキサン等の脂肪族炭化水素類;ジクロロメタン、クロロホルム、トリクロロメタン、四塩化炭素、1,2−ジクロロエタン等のハロゲン炭化水素類;ジエチルエーテル、THF、1,2−ジメトキシエタン、1,4−ジオキサン等のエーテル類;メタノール、エタノール、n−プロパノール、イソプロパノール、ブタノール、ベンジルアルコール等のアルコール類;アセトニトリル、ベンゾニトリル等のニトリル類;DMF、N,N−ジメチルアセタミド、1,3−ジメチルイミダゾリジン、1,3−ジメチル−2−イミダゾリジノン、N−メチルピロリドン等のアミド類;DMSO等が挙げられる。これらの溶媒は単独で、あるいは2種以上を混合して使用することができる
溶媒の使用量は、アミン−ホスフィン−ルテニウム−ハライド錯体1gに対して、1ml〜101、好ましくは1ml〜11の範囲である。また、反応温度は、通常、−100〜200℃、好ましくは、−10〜50℃の範囲である。
式(1)中、Xおよび/又はYがカルボキシ基、水酸基、アルコキシ基であるルテニウム化合物は、上記の方法等で得られるアミン−ホスフィン−ルテニウム−ハライド錯体にRCOONaやRONa(Rはアルキル基を表す。)等を反応させて得ることができる。
次に本発明のジアミン化合物について説明する。
本発明のジアミン化合物は、前記式(2)で表されるジアミン化合物のうち、文献未記載の新規化合物であり、特に、式(2−1)で表される化合物である。
R1C*H(NH2)−A−R5C*H(NH2)(2−1)
ここで、R1は前記のC1〜C8の直鎖、分岐、環状アルキル基、C2〜C8の直鎖、分岐、環状アルケニル基、置換基を有していても良いアリール基、置換基を有していても良いヘテロ環基であり、R5はR1と同一の基であり、Aはアルキレン基、1〜2個の酸素原子を含むアルキレン基、フェニレン基または前記式(2−A),(2−B),(2−C)で表される2価基である。
Aがアルキレン基、1〜2個の酸素原子を含むアルキレン基、フェニレン基である化合物は、例えば、式(2a)で表されるジケトンを出発原料として、下記に示す反応スキームにしたがって製造することができる。
(式中、A,R1およびR5は前記と同じ意味を表し、R12は水素原子、C7〜C20の直鎖、分岐または環状アルキル基、C7〜C20の直鎖、分岐または環状アラルキル基を表す。)
すなわち、ジケトン(2a)を不斉還元して光学活性ジオール(2b)とし(工程I)、該光学活性ジオール(2b)を光学活性アジド(2c)に誘導し(工程II)、光学活性アジド(2c)を還元することにより(工程III)、容易にジアミン化合物(2−1)を製造するこができる。
また、ジケトン(2a)をジオキシム(2d)に変換し(工程IV)、このものを不斉還元してジアミン化合物(2−1)を製造することもできる(工程V)。
出発原料として用いられるジケトン(2a)としては、例えば、2,4−ペンタンジオン、2,5−ヘキサンジオン、1,3−ジフェニル−1,3−プロパンジオン、1,4−ジフェニル−1,4−ブタンジオン、1,2−ジ(アセチル)ベンゼン等が挙げられる。
工程Iのジケトン(2a)の不斉還元反応は、例えば、特開平11−189600号公報の記載と同様にして行うことができる。すなわち、ジケトン(2a)と不斉還元触媒とを有機溶媒中に混合し、さらに所望により塩基を添加して、所定圧力の水素ガス又は水素供与体の存在下に不斉還元する方法によって光学活性ジオール(2b)を得ることができる。
不斉還元触媒としては、例えば、本発明化合物である光学活性アミン−ホスフィン−ルテニウム−ハライド錯体を使用することができる。不斉還元触媒の使用量は、ジケトン(2a)に対して1/50〜1/2,000,000倍モル、好ましくは1/100〜1/1,000,000倍モルの範囲である。
添加する塩基としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン、DABCO、DBU等の有機塩基;ナトリウムメトキシド、ナトリウムエトキシド、カリウム t−ブトキシド、マグネシウムエトキシド等の金属アルコキシド類;水酸化ナトリウム、水酸化カリウム等のアルカリ金属水酸化物;水酸化マグネシウム等のアルカリ土類金属水酸化物;炭酸ナトリウム、炭酸カルシウム等の炭酸塩;水素化ナトリウム、水素化カルシウム等の金属水素化物;等が挙げられる。これら塩基の使用量は、不斉還元触媒の1モルに対し、2〜10,000倍モル、好ましくは、2〜40倍モルの範囲である。
有機溶媒としては、例えば、メタノール、エタノール、n−プロパノール、イソプロパノール、ブタノール、ベンジルアルコール等のアルコール類;ベンゼン、トルエン、キシレン等の芳香族炭化水素類;ペンタン、ヘキサン等の脂肪族炭化水素類;ジクロロメタン、クロロホルム、トリクロロメタン、四塩化炭素、1,2−ジクロロエタン等のハロゲン炭化水素類;ジエチルエーテル、THF、1,2−ジメトキシエタン、1,4−ジオキサン等のエーテル類;DMF、N,N−ジメチルアセタミド、1,3−ジメチルイミダゾリジン、1,3−ジメチル−2−イミダゾリジノン、N−メチルピロリドン、HMPT等のアミド類;アセトニトリル、ベンゾニトリル等のニトリル類;DMSO等を用いることができ、これらの溶媒は単独で、あるいは2種以上を混合して使用することもできる。これらの中でも、反応生成物がアルコール化合物であることからアルコール類の使用が好ましい。
水素の圧力は、通常、1〜200気圧、好ましくは3〜50気圧の範囲である。また、水素供与体としては、例えば、水素貯蔵合金やジイミド等を用いることができ、その使用量は、式(3)、(3’)又は(5)で表されるケトン類に対して、通常、1〜100倍モルの範囲である。
反応は−30〜100℃、好ましくは25〜40℃の温度範囲で円滑に進行する。反応時間は、ジケトン(2a)濃度、温度、圧力等の反応条件に依存するが、通常、数分〜1日である。
なお、本工程Iのジケトン(2a)の不斉還元反応は、オキサザボロジンを触媒として不斉ホウ素還元反応(Tetrahedron Lett.,31,601(1990))等の公知の方法に準じて行うこともできる。
工程IIの光学活性ジオール(2b)のアジド化反応としては、▲1▼溶媒中、アジド化剤及び塩基の存在下に室温あるいは加熱下に反応させる方法や、▲2▼ジオール(2b)とトシルクロリド、トリフルオロメチルスルホニルクロリド等とを塩基存在下に反応させることによりジスルホン酸エステルとした後、これとアジド化剤を反応させる方法、▲3▼ジオール(2b)と塩化チオニル等のハロゲン化剤と反応させることによりジハライドとした後、これとアジド化剤を反応させる方法等が挙げられる。
アジド化剤としては、ジフェニルホスホリルアジド等の有機アジド化剤、アジ化ナトリウム等無機アジド化剤等の一般的に購入できるものを使用することができる。アジド化剤の使用量は、光学活性ジオール(2b)に対して、通常2〜10倍モルの範囲である。
アジド化反応に添加する塩基としては、例えば、トリエチルアミン、ピリジン、DABCO、DBU等の有機塩基;ナトリウムメトキシド、ナトリウムエトキシド、カリウム t−ブトキシド、マグネシウムエトキシド等の金属アルコキシド類;水酸化ナトリウム、水酸化カリウム等のアルカリ金属水酸化物;水酸化マグネシウム等のアルカリ土類金属水酸化物;炭酸ナトリウム、炭酸カルシウム等の炭酸塩;水素化ナトリウム、水素化カルシウム等の金属水素化物;等が挙げられる。これらの中でも、DBU等の有機塩基が好ましい。
アジド化反応に用いられる溶媒としては、例えば、ベンゼン、トルエン、キシレン等の芳香族炭化水素類;ペンタン、ヘキサン等の脂肪族炭化水素類;ジクロロメタン、クロロホルム、トリクロロメタン、四塩化炭素、1,2−ジクロロエタン等のハロゲン炭化水素類;ジエチルエーテル、THF、1,2−ジメトキシエタン、1,4−ジオキサン等のエーテル類;DMF、N,N−ジメチルアセタミド、1,3−ジメチルイミダゾリジン、1,3−ジメチル−2−イミダゾリジノン、N−メチルピロリドン、HMPT等のアミド類;アセトニトリル、ベンゾニトリル等のニトリル類;等を用いることができる。これらの溶媒は単独で、あるいは2種以上を混合して使用することもできる
反応は、通常−78℃〜溶媒の沸点、好ましくは−30℃〜室温の範囲で円滑に進行する。反応時間は、通常、数分〜1日、好ましくは3〜18時間である。
また、光学活性ジアルコール(2b)を光学活性ジアジド(2c)に直接誘導することも可能である。すなわち、▲1▼溶媒中、2bとジフェニルホスホリルアジド等のホスホリルアジド系のアジド化剤を、例えば、トリエチルアミン、ピリジン、DABCO、DBU等の有機塩基の存在下に反応させる方法(J.Org.Chem.,1993,58,5886.)、▲2▼溶媒中で、2b、DEAD((NCOOEt)2)などのアゾジカルボキシレート類、トリフェニルホスフィンなどのホスフィン類、およびアジ化水素を反応させる方法(Helv.Chim.Acta.,1978,61,1832.)等である。
工程IIIの光学活性アジド(2c)の還元反応は、溶媒中、還元剤の存在下に室温又は加熱下に反応させて行う。
還元剤としては、一般的に使用される還元剤を用いることができるが、その具体例としては、水素化リチウムアルミニウム、水素化ホウ素ナトリウム、三水素化シアノホウ素ナトリウム、トリエチル水素化ホウ素リチウム、ジボラン等を挙げることができる。また、パラジウムや白金の炭素担持体を触媒として水添条件下で反応を行うこともできる。
還元反応に用いられる溶媒としては、例えば、メタノール、エタノール、n−プロパノール、イソプロパノール、ブタノール、ベンジルアルコール等のアルコール類;ベンゼン、トルエン、キシレン等の芳香族炭化水素類;ペンタン、ヘキサン等の脂肪族炭化水素類;ジエチルエーテル、THF、1,2−ジメトキシエタン、1,4−ジオキサン等のエーテル類;DMF、N,N−ジメチルアセタミド、1,3−ジメチルイミダゾリジン、1,3−ジメチル−2−イミダゾリジノン、N−メチルピロリドン、HMPT等のアミド類を用いることができる。これらの溶媒は単独で、あるいは2種以上を混合して使用することもできる。
反応は、通常−78℃〜溶媒の沸点、好ましくは−30℃〜室温の温度範囲で円滑に進行する。反応時間は、通常、数分〜1日、好ましくは、3〜18時間である。
工程IVのジケトン(2a)のオキシム化は、溶媒中、ジケトン(2a)と式:R12ONH2(R12は前記と同じ意味を示す。)で表されるアルコキシアミンとを室温又は加熱下に反応させて行う。なお、アルコキシアミンは塩の形で用い、塩基で中和させながら反応させることもできる。かかるアルコキシアミンの塩としては、例えば、メトキシアミン塩酸塩、エトキシアミン塩酸塩、ベンジルオキシアミン塩酸塩等が挙げられる。その使用量は、ジケトン(2a)に対して、1〜100倍モル、好ましくは2〜20倍モルの範囲である。
この反応に用いられる溶媒としては、不活性なものであればよく、工業的に使用できる一般的なものを用いることができる。その具体例としては、メタノール、エタノール、n−プロパノール、イソプロパノール、ブタノール、ベンジルアルコール等のアルコール類;ベンゼン、トルエン、キシレン等の芳香族炭化水素類;ペンタン、ヘキサン等の脂肪族炭化水素類;ジクロロメタン、クロロホルム、トリクロロメタン、四塩化炭素、1,2−ジクロロエタン等のハロゲン炭化水素類;ジエチルエーテル、THF、1,2−ジメトキシエタン、1,4−ジオキサン等のエーテル類;DMF、N,N−ジメチルアセタミド、1,3−ジメチルイミダゾリジン、1,3−ジメチル−2−イミダゾリジノン、N−メチルピロリドン、HMPT等のアミド類;アセトニトリル、ベンゾニトリル等のニトリル類;DMSO、水等が挙げられる。これらの溶媒は単独で、あるいは2種以上を混合して使用することもできる。
反応は、通常−50℃〜溶媒の沸点、好ましくは、室温〜溶媒の沸点の温度範囲で円滑に進行する。反応時間は、通常、数分〜1日、好ましくは、8〜18時間である。
工程Vのジオキシム(2d)の不斉還元反応は、例えば、オキサザボロリジンによる不斉ホウ素還元反応(J.Org.Chem.,65(18),5879(2000)参照。)等の公知の方法に準じて行うことができる。
本発明のジアミン化合物において、Aが前記(2−A),(2−B),(2−C)で表される2価基である化合物のうち(2−A)は、下記反応図に従って、式(a)で表される光学活性ジエステルを出発原料として製造することができる。
(図中、R1、Ra’、Rb’および*は前記と同じ意味を示し、raおよびrbは低級アルキル基を、rcはアルカンスルホニルやアレーンスルホニル基等を示す。)
すなわち、式(a)で表される光学活性酒石酸誘導体を出発原料として、これにアミンを作用させて光学活性ジアミド(b)に変換し(工程VI)、bをグリニャール反応で光学活性ジケトン(c)に誘導する(工程VII)。cを還元して得た光学活性ジアルコール(d)(工程VIII)を光学活性ジスルホネート(e)(工程IX)を経由して光学活性ジアジド(f)に誘導して(工程X)、fを還元すれば(工程XI)、一般式(2)のAの残基が2−Aであるものを製造するこができる。
出発原料として用いられるaとしては、例えば、ジメチル 2,3−O−イソプロピリデン−タルタレート、ジメチル 2,3−ベンジリデン−タルタレート、ジメチル 2,3−O−(1−フェニルエチリデン)−タルタレート等が挙げられる。
工程VIの、光学活性酒石酸誘導体(a)を光学活性ジアミド(b)に誘導する方法は、例えば、J.Med.Chem.,1996,39,2163.記載と同様に行うことができる。すなわち、N,O−置換ヒドロキシルアミンの塩酸または硫酸塩とトリアルキルアルミニウムを有機溶媒中、−70℃〜溶媒の沸点好ましくは−20℃〜室温で、1分〜16時間好ましくは15分〜3時間、混合し、この溶液にaを、−70℃〜溶媒の沸点好ましくは−40℃〜室温で、反応させることによってbを得ることができる。
N,O−置換ヒドロキシルアミンとしては、例えば、N,O−ジメチルヒドロキシルアミン、N−メチル−O−ベンジルヒドロキシルアミン、N−ベンジル−O−ベンジルヒドロキシルアミンを使用することができる。N,O−置換ヒドロキシルアミンの使用量はaの2倍モル〜10倍モル好ましくは3〜4倍モルである。
トリアルキルアルミニウムとしては、例えば、トリメチルアルミニウム、トリエチルアルミニウムなどのトリ低級アルキルアルミニウムが好適である。トリアルキルアルミニウムの使用量はN,O−置換ヒドロキシルアミンの0.1倍モル〜5倍モル好ましくは0.5倍〜2倍モルである。
有機溶媒としては、例えば、ベンゼン、トルエン、キシレン等の芳香族炭化水素類;ペンタン、ヘキサン等の脂肪族炭化水素類;ジクロロメタン、クロロホルム、トリクロロメタン、四塩化炭素、1,2−ジクロロエタン等のハロゲン系炭化水素類;ジエチルエーテル、THF、1,2−ジメトキシエタン、1,4−ジオキサン等のエーテル類等を用いることができ、これらの溶媒は単独で、あるいは2種以上を混合して使用することもできる。これらの中でも、ハロゲン系炭化水素類の使用が好ましい。
工程VIIの、光学活性ジアミド(b)の光学活性ジケトン(c)への誘導は、一般的に行われるグリニャール反応を適用することで、行うことができる。すなわち、(b)の有機溶媒溶液に一般式 R1Mgx
(R1は前記と同じ意味を、xは塩素、臭素等のハロゲン原子を示す。)で表されるグリニャール試薬を、−70℃〜溶媒の沸点好ましくは−20℃〜室温で、0.5時間〜16時間好ましくは1時間〜10時間、反応させることで(c)を得ることができる。
R1Mgxの使用量は(b)の等モル〜8倍モル好ましくは2倍モル〜4倍モルである。
有機溶媒としては、例えば、ベンゼン、トルエン、キシレン等の芳香族炭化水素類;ペンタン、ヘキサン等の脂肪族炭化水素類;ジエチルエーテル、THF、1,2−ジメトキシエタン、1,4−ジオキサン等のエーテル類等を用いることができ、これらの溶媒は単独で、あるいは2種以上を混合して使用することもできる。これらの中でも、エーテル類の使用が好ましい。
工程VIIIの、光学活性ジケトン(c)の光学活性ジアルコール(d)への誘導は、一般的に行われる還元剤による還元反応によって、行うことができる。すなわち、(c)の有機溶媒溶液に還元剤を、−100℃〜溶媒の沸点好ましくは−70℃〜室温で、数分〜数日間好ましくは1時間〜10時間、反応させることで主生成物として(d)を得ることができる。
還元剤は一般的に使用されるホウ素系、あるいはアルミニウム系のものを用いることができるが、その具体例としては、水素化リチウムアルミニウム、水素化ホウ素ナトリウム、三水素化シアノホウ素ナトリウム、トリエチル水素化ホウ素リチウム、ジボラン、L−セレクトライド、LS−セレクトライド等を挙げることができる。また、パラジウムや白金の炭素担持体を触媒として水添条件下で反応を行うこともできる。
還元剤の使用量はbの0.5倍モル当量〜3倍モル当量好ましくは等モル当量〜3倍モル当量である。
還元反応に用いられる溶媒としては、例えば、メタノール、エタノール、n−プロパノール、イソプロパノール、ブタノール、ベンジルアルコール等のアルコール類;ベンゼン、トルエン、キシレン等の芳香族炭化水素類;ペンタン、ヘキサン等の脂肪族炭化水素類;ジエチルエーテル、THF、1,2−ジメトキシエタン、1,4−ジオキサン等のエーテル類;DMF、N,N−ジメチルアセタミド、1,3−ジメチルイミダゾリジン、1,3−ジメチル−2−イミダゾリジノン、N−メチルピロリドン、HMPT等のアミド類等を用いることができる。これらの溶媒は単独で、あるいは2種以上を混合して使用することもできる。
工程IXの、光学活性ジアルコール(d)の光学活性ジスルホネート(e)への誘導は、塩基存在下にdにスルホン酸ハロゲン化物あるいは無水スルホン酸を反応させる、一般的に行われる方法によって行われる。すなわち、dと塩基の有機溶媒溶液にスルホン酸ハロゲン化物あるいは無水スルホン酸を、−40℃〜溶媒の沸点好ましくは−20℃〜60℃で、1時間〜24時間好ましくは6時間〜18時間、反応させることでeを得ることができる。
スルホン酸ハロゲン化物あるいは無水スルホン酸としては、置換基を有していても良いC1〜C20アルカンスルホニルハライド、置換基を有していても良いC6〜C14アレーンスルホニルハライド、置換基を有していても良いC1〜C20アルカンスルホン酸無水物、置換基を有していても良いC6〜C14アレーンスルホン酸無水物であり、置換基としては、塩素、臭素、C1〜C6の低級アルキル基、C1〜C6の低級アルコキシ基、フェニル基である。通常用いられるメシルクロライドや無水メタンスルホン酸、トシルクロリドや無水トシル酸、トリフロロメタンスルホン酸クロライドや無水トリフロロメタンスルホン酸、ベンゼンスルホン酸クロリドや無水ベンゼンスルホン酸が好適に使用できる。
塩基としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン、DABCO、DBU等の有機塩基;ナトリウムメトキシド、ナトリウムエトキシド、カリウム t−ブトキシド、マグネシウムメトキシド、マグネシウムエトキシド等の金属アルコキシド類;水酸化リチウム、水酸化ナトリウム、水酸化カリウム等のアルカリ金属水酸化物;水酸化マグネシウム、水酸化カルシウム等のアルカリ土類金属水酸化物;炭酸ナトリウム、炭酸カリウム等のアルカリ金属炭酸塩;炭酸水素ナトリウム、炭酸水素カリウム等のアルカリ金属炭酸水素塩;炭酸マグネシウム、炭酸カルシウム等のアルカリ土類金属炭酸塩;水素化ナトリウム、水素化カルシウム等の金属水素化物;が挙げられる。
使用するスルホン酸ハロゲン化物あるいは無水スルホン酸の量は、(d)の2倍モル〜10倍モル、好ましくは2.5倍モル〜5倍モルである。
添加する塩基の量は、使用するスルホン酸ハロゲン化物あるいは無水スルホン酸の量の等モル〜大過剰量、好ましくは1.2倍モル〜3倍モルであるが有機塩基を溶媒として使用する場合は大過剰量である。
有機溶媒としては、例えば、ベンゼン、トルエン、キシレン等の芳香族炭化水素類;ペンタン、ヘキサン等の脂肪族炭化水素類;ジクロロメタン、クロロホルム、トリクロロメタン、四塩化炭素、1,2−ジクロロエタン等のハロゲン系炭化水素類;ジエチルエーテル、THF、1,2−ジメトキシエタン、1,4−ジオキサン等のエーテル類;DMF、N,N−ジメチルアセタミド、1,3−ジメチルイミダゾリジン、1,3−ジメチル−2−イミダゾリジノン、N−メチルピロリドン、HMPT等のアミド類;アセトニトリル、ベンゾニトリル等のニトリル類;DMSO等を用いることができ、有機塩基を溶媒として用いることも可能であり、これらの溶媒は単独で、あるいは2種以上を混合して使用することもできる。
工程Xの、光学活性ジスルホネート(e)の光学活性ジアジド(f)への誘導は、(e)にアジド化剤を反応させる一般的に行われるアジド化反応によって行われる。すなわち、eの有機溶媒溶液にアジド化剤を、−40℃〜溶媒の沸点好ましくは0℃〜溶媒の沸点で、1時間〜48時間好ましくは6時間〜24時間、反応させることでfを得ることができる。
アジド化剤としては、アジ化ナトリウムやアジ化リチウム等の無機アジド化剤の一般的に購入できるものを使用することができる。アジド化剤の使用量は、(e)に対して、通常2倍〜100倍モル、好ましくは2.5倍〜50倍の範囲である。
本アジド化反応に用いられる溶媒としては、例えば、ベンゼン、トルエン、キシレン等の芳香族炭化水素類;ペンタン、ヘキサン等の脂肪族炭化水素類;ジクロロメタン、クロロホルム、トリクロロメタン、四塩化炭素、1,2−ジクロロエタン等のハロゲン炭化水素類;ジエチルエーテル、THF、1,2−ジメトキシエタン、1,4−ジオキサン等のエーテル類;DMF、N,N−ジメチルアセタミド、1,3−ジメチルイミダゾリジン、1,3−ジメチル−2−イミダゾリジノン、N−メチルピロリドン、HMPT等のアミド類;アセトニトリル、ベンゾニトリル等のニトリル類;DMSO;スルホラン等を用いることができる。これらの溶媒は単独で、あるいは2種以上を混合して使用することもできる。
工程XIIの、光学活性ジアジド(f)の一般式(2)の(2−A)への誘導は、(f)を還元することにより行われる。すなわち、溶媒中、(f)を還元剤の存在下に室温又は加熱下に反応させて行う。反応は、通常−78℃〜溶媒の沸点、好ましくは−30℃〜室温の範囲で円滑に進行する。反応時間は、通常、数分〜1日、好ましくは、3〜18時間である。
還元剤としては、一般的に使用される還元剤を用いることができるが、その具体例としては、水素化リチウムアルミニウム、水素化ホウ素ナトリウム、三水素化シアノホウ素ナトリウム、トリエチル水素化ホウ素リチウム、ジボラン等を挙げることができる。また、パラジウムや白金の炭素担持体を触媒として水添条件下で反応を行うこともできる。
還元反応に用いられる溶媒としては、例えば、メタノール、エタノール、n−プロパノール、イソプロパノール、ブタノール、ベンジルアルコール等のアルコール類;ベンゼン、トルエン、キシレン等の芳香族炭化水素類;ペンタン、ヘキサン等の脂肪族炭化水素類;ジエチルエーテル、THF、1,2−ジメトキシエタン、1,4−ジオキサン等のエーテル類;DMF、N,N−ジメチルアセタミド、1,3−ジメチルイミダゾリジン、1,3−ジメチル−2−イミダゾリジノン、N−メチルピロリドン、HMPT等のアミド類を用いることができる。これらの溶媒は単独で、あるいは2種以上を混合して使用することもできる。
また、工程XIのように、光学活性ジアルコール(d)を光学活性ジアジド(f)に直接誘導することも可能である。すなわち、▲1▼溶媒中、(d)とジフェニルホスホリルアジド等のホスホリルアジド系のアジド化剤を例えば、トリエチルアミン、ピリジン、DABCO、DBU等の有機塩基の存在下に反応させる方法(J.Org.Chem.,1993,58,5886.)、▲2▼溶媒中で、(d)、DEAD((NCOOEt)2)などのアゾジカルボキシレート類、トリフェニルホスフィンなどのホスフィン類、およびアジ化水素を反応させる方法(Helv.Chim.Acta.,1978,61,1832.)等である。
式(2−B)および(2−C)で表されるジアミン化合物は、上記方法に準じて製造することができる。
次に、本発明のルテニウム化合物を用いた光学活性アルコール類の製造方法について説明する。
縮合ケトン類(3)、(3’)又はα−アミノケトン類(5)を出発原料として、本発明のルテニウム化合物を触媒として不斉水素化還元反応により、それぞれに対応する光学活性アルコール(4)、(4’)又は(9)を製造することができる。
まず、基質となる縮合ケトン類(3)及び(3’)について説明する。
式(3)及び(3’)において、a環部は、置換基を有してもよい3〜8員炭素環または置換基を有してもよい4〜8員ヘテロ環を表し、b環部は、置換基を有してもよい4〜8員炭素環または置換基を有してもよい5〜8員ヘテロ環を表す。a環部における3〜8員炭素環としては、例えば、シクロプロペン、シクロブテン、シクロブタジエン、シクロペンテン、シクロペンタジエン、シクロヘキセン、シクロヘキサジエン、ベンゼン環等の不飽和炭化水素環が挙げられ、4〜8員ヘテロ環としては、例えば、フラン、ピラン、ジオキソラン等の含酸素ヘテロ環;チオフェン等の含イオウヘテロ環;ピロール、イミダゾール、ピラゾール、オキサゾール、イソオキサゾール、トリアゾール、チアゾール、イソチアゾール、ピリジン、ピリダジン、ピラジン、ベンゾイミダゾール、ベンゾピラゾール、ペンゾチアゾール、キノリン、インドリン、フェナントロリン等の飽和若しくは不飽和の含窒素ヘテロ環;等が挙げられる。
b環部における4〜8員炭素環としては、例えば、シクロブテン、シクロブタジエン、シクロペンテン、シクロペンタジエン、シクロヘキセン、シクロヘキサジエン、ベンゼン環等の不飽和炭化水素環が挙げられ、5〜8員ヘテロ環としては、例えば、フラン、ピラン等の含酸素ヘテロ環;チオフェン等の含イオウヘテロ環;ピロール、イミダゾール、ピラゾール、オキサゾール、イソオキサゾール、トリアゾール、チアゾール、イソチアゾール、ピリジン、ピリダジン、ピラジン、ベンゾイミダゾール、ベンゾピラゾール、ペンゾチアゾール、キノリン、インドリン、フェナントロリン等の飽和若しくは不飽和の含窒素ヘテロ環;等が挙げられる。
縮合環ケトン類の具体例としては、置換基を有してもよいα−テトラロン類、置換基を有してもよいβ−テトラロン類、置換基を有してもよいクロモン類、置換基を有してもよい4−クロマノン類、置換基を有してもよいチオクロマン−4−オン類、置換基を有してもよい2,3−ジヒドロ−1H−キノリン−4−オン類、置換基を有してもよい2−イソチオクロマン−4−オン類、置換基を有してもよい2,3−ジヒドロ−1H−イソキノリン−4−オン類、置換基を有してもよい1−インダノン類、置換基を有してもよい2H−ベンゾフラン−3−オン類、置換基を有してもよい2H−ベンゾチオピラン−3−オン類、置換基を有してもよいインドリン−3−オン類、置換基を有していてもよい4−ケト−4,5,6,7−テトラヒドロチアナフテン類等が挙げられる。
前記縮合環ケトン類の置換基としては、反応を阻害しないものであれば何でもよく、例えば、フッ素、塩素、臭素、ヨウ素等のハロゲン原子;水酸基;アミノ、メチルアミノ、ジメチルアミノ、アセチルアミノ等の置換されていてもよいアミノ基;メチル、エチル、n−プロピル、イソプロピル、n−ブチル、sec−ブチル、t−ブチル、n−ペンチル、イソペンチル、ネオペンチル、t−ペンチル、ヘキシル、ヘプチル、オクチル、ノニル、デシル、ドデシル基等のC1〜C20アルキル基;エテニル、n−プロペニル、イソプロペニル、n−ブテニル、sec−ブテニル、t−ブテニル、1,3−ブタジエニル、n−ペンテニル、2−ペンテニル、3−ペンテニル、ヘキセニル基等のC2〜C20アルケニル基;シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル基等のC3〜C8シクロアルキル基;ベンジル、α−メチルベンジル、α,α−ジメチルベンジル、α−エチルベンジル基等のC7〜C20アラルキル基;フェニル、1−ナフチル、2−ナフチル基等のアリール基;メトキシ、エトキシ、n−プロポキシ、イソプロポキシ、n−ブトキシ、sec−ブトキシ、t−ブトキシ基等のC1〜C20アルコキシ基;アシルオキシ基;アシル基;ヘテロ環基;等が挙げられる。
前記アシルオキシ基としては、例えば、アセトキシ、エチルカルボニルオキシ、イソプロピルカルボニルオキシ基等のC1〜C12のアルキルカルボニルオキシ基;ベンゾイルオキシ基等のアリールカルボニルオキシ基;フェニルメチルカルボニルオキシ基等のアラルキルカルボニルオキシ基;等が挙げられ、前記アシル基としては、例えば、プロパノイル、イソプロピルカルボニル基等のC1〜C12のアルキルカルボニル基、メトキシカルボニル、エトキシカルボニル、イソプロポキシカルボニル、t−ブトキシカルボニル基等のアルコキシカルボニル基;ベンゾイル基等のアリールカルボニル基;フェニルメチルカルボニル基等のアラルキルカルボニル基;等が挙げられる。
前記ヘテロ環基としては、例えば、フラニル、ピラニル、ジオキソラニル基等の含酸素ヘテロ環基;チエニル基等の含イオウヘテロ環基;ピロリル、イミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、トリアゾリル、チアゾリル、イソチアゾリル、ピリジル、ピラダジル、ピラジニル、ベンゾイミダゾリル、ベンゾピラゾリル、ペンゾチアゾリル、キノリル、アントラニル、インドリル、フェナントロニリル基等の飽和若しくは不飽和の含窒素ヘテロ環基;等が挙げられる。
これらの置換基は、その置換位置、置換基の種類、置換基の数等に特に制限はない。また、例示した縮合環ケトン類のベンゼン環がこれらの置換基を有してもよい他の縮合環に置き換わってもよい。
さらに、前記した置換基は反応を阻害しない範囲において置換基をさらに有してもよい。かかる置換基としては、例えば、フッ素、塩素、臭素等のハロゲン原子;水酸基;カルボキシル基;アミノ基;メチル、エチル、プロピル、イソプロピル、ブチル、sec−ブチル、t−ブチル、ペンチル、ヘキシル基等のC1〜C6アルキル基;メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、t−ブトキシ基等のC1〜C6アルコキシ基;メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニル、t−ブトキシカルボニル基等のC1〜C6アルコキシカルボニル基;ベンゼン環の任意の位置に置換基を有してもよいフェニル基;ナフタレン環の任意の位置に置換基を有してもよい、1−ナフチル、2−ナフチル基等のナフチル基;環の任意の位置に置換基を有してもよい、フラン、ピラン、ジオキソラン、ジオキサン、ピロール、チオフェン、イミダゾール、ピラゾール、オキサゾール、イソオキサゾール、トリアゾール、チアゾール、イソチアゾール、ピリジン、ピリダジン、ピラジン、ベンゾイミダゾール、ベンゾピラゾール、ベンゾチアゾール、キノリン等のヘテロ環基;等が挙げられる。
次に、α−アミノケトン類(5)について説明する。
式中、Ra及びRcは、それぞれ独立して、水素原子;置換基を有してもよい、メチル、エチル、プロピル、イソプロピル、ブチル、sec−ブチル、t−ブチル、ペンチル、イソペンチル、ネオペンチル、t−ペンチル、ヘキシル、ヘプチル、オクチル、ノニル、デシル、ドデシル基等のC1〜C20アルキル基;置換基を有してもよい、ビニル、1−プロペニル、2−プロペニル、1−イソプロペニル、1−ブテニル、1−イソプロペニル、2−ブテニル、3−ブテニル、1,3−ブタジエニル、1−ペンテニル、2−ペンテニル、3−ペンテニル基等のC2〜C20アルケニル基;置換基を有してもよい、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル基等のC3〜C8シクロアルキル基;置換基を有してもよい、ベンジル、α−メチルベンジル、α,α−ジメチルベンジル、α−エチルベンジル基等のC7〜C20アラルキル基;置換基を有してもよい、フェニル、1−ナフチル、2−ナフチル基等のアリール基;置換基を有してもよいヘテロ環基等を表す。
かかるヘテロ環基としては、例えば、フラニル、ピラニル、ジオキソラニル基等の含酸素ヘテロ環基;チエニル基等の含イオウヘテロ環基;ピロリル、イミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、トリアゾリル、チアゾリル、イソチアゾリル、ピリジル、ピラダジル、ピラジニル、ベンゾイミダゾリル、ベンゾピラゾリル、ペンゾチアゾリル、キノリル、アントラニル、インドリル、フェナントロニリル基等の飽和若しくは不飽和の含窒素ヘテロ環基;等が挙げられる。
前記アルキル基、アルケニル基、シクロアルキル基、アラルキル基、アリール基及びヘテロ環基の置換基としては、本反応を阻害することのない置換基であれば、その置換位置、置換基の種類、置換基の数等に特に制限はない。その具体例としては、フッ素、塩素、臭素等のハロゲン原子;水酸基;カルボキシル基;アミノ基;メチル、エチル、プロピル、イソプロピル、ブチル、sec−ブチル、t−ブチル、ペンチル、ヘキシル基等のC1〜C6アルキル基;メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、t−ブトキシ基等のC1〜C6アルコキシ基;メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニル、t−ブトキシカルボニル基等のC1〜C6アルコキシカルボニル基;ベンゼン環の任意の位置に置換基を有してもよいフェニル基;ナフタレン環の任意の位置に置換基を有してもよい(1−ナフチル、2−ナフチル基等の)ナフチル基;環の任意の位置に置換基を有してもよい(フラン、ピラン、ジオキソラン、ジオキサン、ピロール、チオフェン、イミダゾール、ピラゾール、オキサゾール、イソオキサゾール、トリアゾール、チアゾール、イソチアゾール、ピリジン、ピリダジン、ピラジン、ベンゾイミダゾール、ベンゾピラゾール、ベンゾチアゾール、キノリン等の)ヘテロ環基;等が挙げられる。
Rbは、式(6):R9CO(R11)N−、式(7):R9CO(R10CO)N−、式(8):R9R11N−、のいずれかの基を表す。
ここで、R9、R10及びR11はそれぞれ独立して、水素原子;メチル、エチル、プロピル、イソプロピル、ブチル、sec−ブチル、t−ブチル、ペンチル、イソペンチル、ネオペンチル、t−ペンチル、ヘキシル、ヘプチル基等のC1〜C20アルキル基;メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、t−ブトキシ、ペンチルオキシ、イソペンチルオキシ、ネオペンチルオキシ、t−ペンチルオキシ、ヘキシルオキシ基等の置換基を有してもよいC1〜C20アルコキシ基;シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル基等のC3〜C8シクロアルキル基;シクロペンチルオキシ、シクロヘキシルオキシ、ヘプチルオキシ基等のC3〜C8シクロアルコキシ基;置換基を有してもよいC1〜C20アルケニル基;ベンジル、4−クロロベンジル、α−メチルベンジル基等の置換基を有してもよいC7〜C20アラルキル基;ベンジルオキシ、4−クロロベンジルオキシ、4−メチルベンジルオキシ基等の置換基を有してもよいC7〜C20アラルキルオキシ基;フェニル、1−ナフチル、2−ナフチル基等の置換基を有してもよいアリール基;ベンゾイルオキシ、1−ナフチルオキシ、2−ナフチルオキシ基等の置換基を有してもよいアリールオキシ基;等を表す。
本発明において、Rcが水素原子以外の置換基の場合において、Rbが式(6)で表される基であって、R11が水素原子、かつ、R9がアルコキシ基、シクロアルコキシ基、アリールオキシ基及びアラルキルオキシ基の何れかであると、アンチ立体配置の光学活性アミノアルコールが優先的に得られる。このためシン立体配置の光学活性アミノアルコールを得る場合にはそれ以外の置換基の組み合わせを選択する必要がある。
ここで、シン立体配置とは炭素鎖を主鎖としてジグザグに左右方向に置いた場合に、その上下方向にそれぞれ置換するアミノ基とヒドロキシルが同じ面を向くような立体配置のことをいい、アンチ立体配置とはアミノ基とヒドロキシル基が逆の面を向くような立体配置のことをいう。
前記アルコキシ基、アルケニル基、アラルキル基、アラルキルオキシ基、アリール基及びアリールオキシ基の置換基としては、本反応を阻害することのない置換基であれば、その置換位置、置換基の種類、置換基の数等に特に制限はない。その具体例としては、フッ素、塩素、臭素等のハロゲン原子;水酸基;カルボキシル基;アミノ、メチルアミノ、アセチルアミノ等の置換基を有していてもよいアミノ基;メチル、エチル、プロピル、イソプロピル、ブチル、sec−ブチル、t−ブチル、ペンチル、ヘキシル基等のC1〜C20アルキル基;メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、t−ブトキシ基等のC1〜C20アルコキシ基;メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニル、t−ブトキシカルボニル基等のC1〜C20アルコキシカルボニル基;ベンゼン環の任意の位置に置換基を有してもよいフェニル基;ナフタレン環の任意の位置に置換基を有してもよい(1−ナフチル、2−ナフチル基等の)ナフチル基;環の任意の位置に置換基を有してもよい(フラン、ピラン、ジオキソラン、ジオキサン、ピロール、チオフェン、イミダゾール、ピラゾール、オキサゾール、イソオキサゾール、トリアゾール、チアゾール、イソチアゾール、ピリジン、ピリダジン、ピラジン、ベンゾイミダゾール、ベンゾピラゾール、ベンゾチアゾール、キノリン等の)ヘテロ環基;等が挙げられる
また、R9とR10とが又はR9とR11とが結合して、5〜8員の含窒素ヘテロ環を形成してもよい。かかるヘテロ環のとしては、例えば、スクシンイミド、マレイミド、フタルイミド、1,2−シクロヘキサンカルボキサミド、2,4,6−トリオキソピペリジン、α−ピリドン等のイミド類等が挙げられる。
Rbの具体例としては、アセチルアミノ、プロピオニルアミノ、プロピルカルボニルアミノ、ベンゾイルアミノ、4−メチルベンゾイルアミノ、2−クロロベンゾイルアミノ、3−メトキシベンゾイルアミノ、2−クロロ−4−メトキシベンゾイルアミノ基等のアシルアミノ基;ジアセチルアミノ、ジベンゾイルアミノ基等のジアシルアミノ基;N−アセチル−N−メチルアミノ、N−ベンゾイル−N−メチルアミノ、N−アセチル−N−エチルアミノ、N−ベンゾイル−N−エチルアミノ、N−アセチル−N−ベンジルアミノ、N−ベンゾイル−N−ベンジルアミノ、4−メチルベンゾイルメチルアミノ基等のN−アルキル−N−アシルアミノ基;N−アセチル−N−フェニルアミノ、N−アセチル−N−4−メチルファニルアミノ、N−アセチル−N−2−クロロフェニルアミノ、N−アセチル−N−2,4−ジクロロフェニルアミノ、N−ベンジル−N−フェニルアミノ、N−ベンジル−N−4−メチルフェニルアミノ、N−ベンジル−N−2−クロロフェニルアミノ、N−ベンジル−N−2,4−ジクロロフェニルアミノ基等のN−アリール−N−アシルアミノ基;N−メトキシカルボニル−N−メチルアミノ、N−エトキシカルボニル−N−メチルアミノ、N−メトキシカルボニル−N−エチルアミノ、N−エトキシカルボニル−N−エチルアミノ、N−プロポキシカルボニル−N−プロピルアミノ、N−イソプロポキシカルボニル−N−メチルアミノ、N−ブトキシカルボニル−N−エチルアミノ、N−t−ブトキシカルボニル−N−ブトキシアミノ基等のN−アルコキシカルボニル−N−アルキルアミノ基;
N−メトキシカルボニル−N−メチルアミノ、N−エトキシカルボニル−N−メチルアミノ、N−メトキシカルボニル−N−エチルアミノ、N−エトキシカルボニル−N−エチルアミノ、N−プロポキシカルボニル−N−プロピルアミノ、N−イソプロポキシカルボニル−N−メチルアミノ、N−ブトキシカルボニル−N−エチルアミノ、N−t−ブトキシカルボニル−N−メチルアミノ基、N−t−ブトキシカルボニル−N−ブトキシアミノ基等のN−アルコキシカルボニル−N−アルキルアミノ基;N−メトキシカルボニル−N−フェニルアミノ、N−エトキシカルボニル−N−フェニルアミノ、N−プロポキシカルボニル−N−フェニルアミノ、N−イソプロポキシカルボニル−N−フェニルアミノ、N−ブトキシカルボニル−N−フェニルアミノ、N−t−ブトキシカルボニル−N−フェニルアミノ基等のN−アルコキシカルボニル−N−アリールアミノ基;
N−メチル−メチルスルホニルアミノ、N−エチル−メチルスルホニルアミノ、N−プロピル−メチルスルホニルアミノ、N−イソプロピル−メチルスルホニルアミノ、N−ベンジル−メチルスルホニルアミノ、N−ブチル−メチルスルホニルアミノ、N−メチル−エチルスルホニルアミノ、N−エチル−エチルスルホニルアミノ、N−メチル−プロピルスルホニルアミノ、N−エチル−プロピルスルホニルアミノ、N−メチル−イソプロピルスルホニルアミノ、N−エチル−イソプロピルスルホニルアミノ、N−メチル−ブチルスルホニルアミノ、N−エチル−ブチルスルホニルアミノ、N−メチル−t−ブチルスルホニルアミノ、N−エチル−t−ブチルスルホニルアミノ等のN−アルキル−アルキルスルホニルアミノ基;N−メチル−フェニルスルホニルアミノ、N−エチル−フェニルスルホニルアミノ、N−ベンジル−フェニルスルホニルアミノ、N−メチル−4−メチルフェニルスルホニルアミノ、N−ベンジル−4−メチルフェニルスルホニルアミノ、N−エチル−2−クロロフェニルスルホニルアミノ、N−メチル−2,4−ジクロロフェニルスルホニルアミノ基等のN−アルキル−置換フェニルスルホニルアミノ基;
N−フェニル−メチルスルホニルアミノ、N−フェニル−エチルスルホニルアミノ、N−フェニル−プロピルスルホニルアミノ、N−フェニル−イソプロピルスルホニルアミノ、N−フェニル−ブチルスルホニルアミノ、N−フェニル−t−ブチルスルホニルアミノ等のN−アリール−アルキルスルホニルアミノ基;N−フェニル−フェニルスルホニルアミノ、N−フェニル−4−メチルフェニルスルホニルアミノ、N−フェニル−2−クロロフェニルスルホニルアミノ、N−フェニル−2,4−ジクロロフェニルスルホニルアミノ基等のN−アリール−置換フェニルスルホニルアミノ基;スクシンイミドイル基、マレイミドイル基、フタルイミドイル基、3−メチルフタルイミドイル基、4−メチルフタルイミドイル基、4−n−ブチルフタルイミドイル基、4−クロロフタルイミドイル基、テトラメチルフタルイミドイル基、1,2−シクロヘキサンカルボキサミドイル基、2,4,6−トリオキソピペリジン−1−イル基、α−ピリドン−1−イル基等のイミド基等を挙げることができる。
以上説明したような縮合ケトン類及びα−アミノケトン類は、公知の方法で製造し、入手することができる。
次に不斉水素化反応について説明する。
不斉水素化反応は、基質となる上記した縮合ケトン類(3)、(3’)又はα−アミノケトン類(5)を、式(1)で表されるルテニウム化合物の存在下に、所望により塩基を添加して、所定圧力の水素ガス又は水素供与体の存在下に不斉還元することにより行う。
また、本発明においては、ルテニウム化合物の原料となる▲1▼ルテニウム錯体(又はルテニウム塩)、リン化合物及びジアミン化合物とを別々に反応系に添加、又は▲2▼ホスフィン配位子を有するルテニウム錯体(又はルテニウム塩)及びジアミン化合物とを別々に反応系に添加して、必要に応じて塩基を添加してルテニウム化合物を生成させた後、該ルテニウム化合物を反応系から取り出すことなく、そこへ基質を添加することにより、in situで不斉水素化反応を行わせることもできる。
触媒として使用する式(1)で表されるルテニウム化合物の使用量は、反応容器の大きさや触媒活性によって異なるが、反応基質である縮合ケトン類又はα−ジアミノケトン類に対して、通常1/50〜1/2,000,000倍モル、好ましくは1/500〜1/500,000倍モルの範囲である。
用いられる塩基としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン、DABCO、DBU等の有機塩基;ナトリウムメトキシド、ナトリウムエトキシド、カリウム t−ブトキシド、マグネシウムメトキシド、マグネシウムエトキシド等の金属アルコキシド類;n−ブチルリチウム等の有機リチウム化合物;LDA、リチウムビストリメチルシリルアミド等のリチウムアミド類;水酸化リチウム、水酸化ナトリウム、水酸化カリウム等のアルカリ金属水酸化物;水酸化マグネシウム、水酸化カルシウム等のアルカリ土類金属水酸化物;炭酸ナトリウム、炭酸カリウム等のアルカリ金属炭酸塩;炭酸水素ナトリウム、炭酸水素カリウム等のアルカリ金属炭酸水素塩;炭酸マグネシウム、炭酸カルシウム等のアルカリ土類金属炭酸塩;水素化ナトリウム、水素化カルシウム等の金属水素化物;が挙げられる。
添加する塩基の量は、ルテニウム化合物に対し、通常2〜500,000倍モル、好ましくは、2〜5,000倍モルの範囲である。
溶媒としては、基質及び触媒を可溶化するものであれば特に制限ない。その具体例としては、メタノール、エタノール、n−プロパノール、イソプロパノール、ブタノール、ベンジルアルコール等のアルコール類;ベンゼン、トルエン、キシレン等の芳香族炭化水素類;ペンタン、ヘキサン等の脂肪族炭化水素類;ジクロロメタン、クロロホルム、トリクロロメタン、四塩化炭素、1,2−ジクロロエタン等のハロゲン炭化水素類;ジエチルエーテル、THF、1,2−ジメトキシエタン、1,4−ジオキサン等のエーテル類;DMF、N,N−ジメチルアセタミド、1,3−ジメチルイミダゾリジン、1,3−ジメチル−2−イミダゾリジノン、N−メチルピロリドン、HMPT等のアミド類;アセトニトリル、ベンゾニトリル等のニトリル類;DMSO等を用いることができる。これらの溶媒は単独で、あるいは2種以上を混合して使用することもできる。これらの溶媒の中でも、反応生成物がアルコール化合物であることから、アルコール類の使用が好ましい。
溶媒の使用量は、式(3)、(3’)又は(5)で表されるケトン類の溶解度及び経済性に依存し、場合によっては無溶媒又は高希釈条件に近い状態でも反応は進行するが、通常、該ケトン類100重量部に対して0.1〜10,000重量部、好ましくは20〜1,000重量部の範囲である。
水素の圧力は、通常、1〜200気圧、好ましくは3〜50気圧の範囲であり、水素供与体としては、例えば、水素貯蔵合金やジイミド等を用いることができ、その使用量は、式(3)、(3’)又は(5)で表されるケトン類に対して、通常、1〜100倍当量の範囲である。
反応温度は、通常−50〜100℃、好ましくは25〜40℃の温度範囲である。また、反応時間は、反応基質濃度や温度、圧力等の反応条件に依存するが、通常、数分〜数日である。反応形式としては特に制限はないが、例えば、バッチ式においても連続式においても実施することができる。
反応終了後は、通常の有機合成化学的手法により、単離・精製を行い目的物を得ることができる。目的物の構造は、1H−NMR、旋光度測定、液体クロマトグラフィー、ガスクロマトグラフィー等の公知の分析手段によって決定することができる。
発明の実施のための最良の形態:
次に、実施例で本発明を詳しく説明するが、本発明はこれらのみに限定されるものではない。尚、各実施例における物性の測定に用いた装置は次の通りである。
NMRスペクトル:Varian GEMINI−300(300MHz)、バリアン社製
旋光度:JASCO DIP−360、日本分光(株)製
高速液体クロマトグラフィー:LC−10Advp、SPD−10Avp、島津製作所(株)製
ガスクロマトグラフィー:GC−17A、C−R7A Plus、島津製作所(株)製
実施例1 (R,R)−1,4−ジアミノ−1,4−ジフェニルブタン塩酸塩
(工程1)(S,S)−1,4−ジヒドロキシ−1,4−ジフェニルブタンの製造
1,4−ジオキソ−1,4−ジフェニルブタン0.477g(2mmol)のイソプロパノール3ml溶液、トルエン5ml及び水酸化カリウムイソプロパノール溶液(1M)0.2mlを混合し脱気し、〔(R)−Xylyl−BINAP〕RuCl2〔(R)−1,1’−ジアニシル−2−イソプロピル−1,2−エチレンジアミン{(R)−DAIPENと略す:J.Am.Chem.Soc.,120、13529(1998)}〕12mg(0.01mmol)を加えた。その後、水素を8気圧まで圧入し、室温で18時間攪拌した。反応液をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=1/1)で精製して、目的の(S,S)−1,4−ジヒドロキシ−1,4−ジフェニルブタン0.43gを得た。収率90%
(工程2)(R,R)−1,4−ジアジド−1,4−ジフェニルブタンの製造
(S,S)−1,4−ジヒドロキシ−1,4−ジフェニルブタン0.55g(2.27mmol)とDBU0.7ml(2.72mmol)のトルエン6ml溶液にジフェニルホスホリルアジド1.78g(2.72mmol)を攪拌しながら0℃で添加した。室温で18時間攪拌した後、反応液を希塩酸にあけ酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、濃縮して得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=10/1)で精製することにより、目的の(R,R)−1,4−ジアジド−1,4−ジフェニルブタン0.21gを得た。収率32%
1H−NMR(CDCl3,δppm):7.5−7.3(m,10H)、4.4(t,2H)、1.9(m,2H)、1.7(m,2H)
(工程3)(1R,4R)−1,4−ジアミノ−1,4−ジフェニルブタン塩酸塩の製造
(R,R)−1,4−ジアジド−1,4−ジフェニルブタン0.21g(0.83mmol)のエタノール6ml溶液に、5%パラジウムカーボン0.1gを加え、反応系を水素置換して、常温、常圧下に48時間攪拌した。反応終了後、反応溶液から不溶物を濾別し、濾液に濃塩酸を加えて濃縮し、析出した結晶を濾取した。得られた結晶を酢酸エチルで洗浄し、乾燥することにより、目的とする(1R,4R)−1,4−ジアミノ−1,4−ジフェニルブタン塩酸塩0.1gを得た。収率37%
1H−NMR(DMSO−d6,δppm):8.6(s,6H)、7.4(s,10H)、4.2(m,2H)、2.0(m,2H)、1.5(m,2H)
[α]D 24=−10.1°(c=1.0,MeOH)
実施例2 (1R,4R)−1,4−ジアミノ−1,4−ジシクロヘキシルブタン
オートクレーブ中に(1R,4R)−1,4−ジアミノ−1,4−ジフェニルブタン0.2gをメタノール3mlに溶解し、ロジウム/アルミナ触媒を加えた後に10気圧の水素加圧下室温で5時間撹拌した。触媒を濾過し、濾液を濃縮することにより目的物を定量的に得た。第1表に1H−NMRデータを示した。
実施例3 (2R,3R,4R,5R)−3,4−O−イソプロピリデン−3,4−ジヒドロ キシ−2,5−ジアミノヘキサン
(工程1)(2R,3R,4R,5R)−3,4−O−イソプロピリデン−3,4−ジヒドロ キシ−2,5−ジアジドヘキサンの製造
(2S,3R,4R,5S)−3,4−O−イソプロピリデン−3,4−ジヒドロキシ−2,5−ヘキサンジオール ビスメタンスルホナート(1.52g、4.4mmol)をDMSO(15ml)に溶解し、アジ化ナトリウム(1.27g、17.5mmol)を加えて50度で24時間撹拌した。反応終了後、反応溶液に水を加え酢酸エチルで抽出した。有機相を無水硫酸マグネシウムで乾燥し、濃縮して得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=10/1)で精製することによりジアジド体0.71gを得た。収率67%。
(工程2)(2R,3R,4R,5R)−3,4−O−イソプロピリデン−3,4−ジヒドロキ シ−2,5−ジアミノヘキサンの製造
3,4−O−イソプロピリデン−(3R,4R)−ジヒドロキシ−(2R,5R)−ジアジドヘキサン0.71gをメタノール5mlに溶解し、5%パラジウムカーボン0.1gを加え反応系を水素置換して常温、常圧下24時間撹拌した。反応終了後反応溶液から不溶物を濾別し、濾液を濃縮して得られた残留物をクーゲルロールで蒸留(160度/5mmHg)して目的物0.49gを得た。収率88%
1H−NMR(CDCl3,δppm):3.68(m,2H)、3.0(m,2H)、1.46(bs,4H)、1.39(s,6H)、1.16(d,J=6.4Hz,6H)
〔α〕D 23=28.9°(c=1.4,MeOH)
上記実施例と同様にして得られた本発明のジアミン化合物を第1表に示した。
実施例4 RuCl 2 〔(S)−Tol−BINAP〕〔(2R,5R)−2,5−ジアミノヘ キサン〕
シュレンクチューブ中にイソプロパノール2ml、(2R,5R)−2,5−ジアミノヘキサン5mg(0.025mmol)を加え、脱気した後、RuCl2〔(S)−Tol−BINAP〕のDMF付加物25mg(0.025mmol)を加えて溶解させた。溶媒を減圧留去することにより目的物を得た。
この化合物の31P−NMR(CDCl3)を測定した結果、43.9ppmにシングレットピークが観測された。
実施例5 RuCl 2 〔(R)−Tol−BINAP〕〔(1R,4R)−1,4−ジアミノ− 1,4−ジフェニルブタン〕
シュレンクチューブ中にイソプロパノール2ml、(1R,4R)−1,4−ジアミノ−1,4−ジフェニルブタン8mg(0.025mmol)を加え、脱気した後、RuCl2〔(R)−Tol−BINAP〕のDMF付加物25mg(0.025mmol)を加えて溶解させた。溶媒を減圧留去することにより目的物を得た。
この化合物の31P−NMR(CDCl3)を測定した結果、44.6ppmにシングレットピークが観測された。
実施例6 RuCl 2 [(S)−binap][(2R,3R,4R,5R)−3,4−O−イ ソプロピリデン−3,4−ジヒドロキシ−2,5−ジアミノヘキサン]
シュレンクチューブ中に脱気したイソプロパノール5ml、(2R,3R,4R,5R)−3,4−O−イソプロピリデン−3,4−ジヒドロキシ−2,5−ジアミノヘキサン50mg(0.266mmol)、[RuCl2(シメン)]282mg(0.134mmol)を加え、還流下30分撹拌した。続いて(S)−BINAP166mg(0.266mmol)を加えて還流下45分撹拌した。冷却した後ヘキサンを加えて析出した結晶を濾別して目的物を得た。
この化合物の31P−NMR(CDCl3)を測定した結果、45.4ppmにシングレットピークが観測された。
実施例7 (R)−1,2,3,4−テトラヒドロ−1−ナフトールの製造
アルゴン雰囲気下、簡易型オートクレーブ(容量100ml)中に、(2R,5R)−2,5−ジアミノヘキサン塩酸塩1mg(0.005mmol)、テトラロン0.37g(2.5mmol)、水酸化カリウムイソプロパノール溶液(1M)75μl及びイソプロパノール1.5mlを室温で添加し、脱気した後、RuCl2[(S)−Tol−BINAP]のDMF付加物5mg(0.005mmol)を加えた。反応系内に水素を8気圧まで圧入し、室温にて1.5時間攪拌した。反応混合物をシリカゲルカラムクロマトグラフィー(溶離液:ジエチルエーテル)で精製して光学異性体混合物を得た。転化率64%
このものの光学純度をガスクロマトグラフィー(移動相:ヘリウム、カラム:CP−Chiralcel−Dex CB、クロムパック(株)製)で測定したところ、91%eeであった。
実施例7と同じ条件で、原料のテトラロンを変えた場合の反応生成物の光学純度(%ee)を第2表に示した。
実施例8 (S)−1,2,3,4−テトラヒドロ−1−ナフトールの製造
アルゴン雰囲気下、簡易型オートクレーブ(容量100ml)中に、(S,S)−2,4−ジアミノペンタン塩酸塩1.mg(0.005mmol)、テトラロン0.37g(2.5mmol)、水酸化カリウムイソプロパノール(1M)75μl及びイソプロパノール3mlを室温で添加し、脱気した後、RuCl2[(R)−Tol−BINAP]のDMF付加物5mg(0.005mmol)を加えた。反応系内に水素ガスを8気圧まで圧入し、室温にて1.5時間攪拌した後、反応混合物をシリカゲルカラムクロマトグラフィー(溶離液:ジエチルエーテル)で精製して光学異性体混合物を得た。転化率83%。
このものの光学純度を高速液体クロマトグラフィー(移動相:ヘキサン/イソプロパノール=9/1、カラム:Chiralcel OB、ダイセル化学工業(株)製)で測定したところ75%eeであった。
実施例8と同じ条件で、ジアミンを変えて反応を行い、得られた(S)−1,2,3,4−テトラヒドロ−1−ナフトールの転化率%、光学純度%eeを第3表に示した。
実施例9 光学活性7−メトキシ−1,2,3,4−テトラヒドロ−1−ナフトールの製造
簡易型オートクレーブ(容量100ml)中に、7−メトキシ−1−テトラロン0.19g(1mmol)、RuCl2[(R)−binap][(1R,4R)−1,4−ジフェニルブタン−1,4−ジアミン]5mg(0.005mmol)を加えアルゴン置換した後に、脱気したイソプロパノール2.5mlおよび水酸化カリウムイソプロパノール溶液(1M)100μlを加えた。反応系内に水素を8気圧まで圧入し、室温にて1.5時間撹拌した。反応混合物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=2/1)で精製し光学異性体混合物を定量的に得た。
このものの光学純度を高速液体クロマトグラフィー(移動相:ヘキサン/イソプロパノール=92/8、カラム:Chiralcel OD−H、ダイセル化学工業(株)製)で測定したところ、92%eeであった。
実施例10 光学活性5−メトキシ−1,2,3,4−テトラヒドロ−1−ナフトールの製 造
簡易型オートクレーブ(容量100ml)中に、5−メトキシ−1−テトラロン0.41g(2.5mmol)、RuCl2[(S)−binap][(2R,5R)−ジアミノヘキサン]5mg(0.005mmol)を加えアルゴン置換した後に、脱気したイソプロパノール2mlおよび水酸化カリウムイソプロパノール溶液(1M)100μlを加えた。反応系内に水素を8気圧まで圧入し、室温にて2時間撹拌した。反応混合物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=2/1)で精製し光学異性体混合物0.36gを得た。収率87%
このものの光学純度を高速液体クロマトグラフィー(移動相:ヘキサン/イソプロパノール=9/1、カラム:Chiralcel OB、ダイセル化学工業(株)製)で測定したところ、95%eeであった。
実施例11 光学活性シス−2−メチル−1,2,3,4−テトラヒドロ−1−ナフトールの 製造
簡易型オートクレーブ(容量100ml)中に、RuCl2[(S)−binap][3,4−O−イソプロピリデン−(3R,4R)−ジヒドロキシ−(2R,5R)−ジアミノヘキサン]5mg(0.005mmol)を加えアルゴン置換した後に、イソプロパノール2.5ml中に水酸化カリウムイソプロパノール溶液(1M)100μlおよび2−メチル−1−テトラロン0.16g(1mmol)を溶解したものを脱気した後に加えた。反応系内に水素を8気圧まで圧入し、室温にて2時間撹拌した。
このものをガスクロマトグラフィー(移動相:ヘリウム、カラム:βDEX325、スペルコ製)で測定したところ、転化率>99%、98%de、88%eeであった。
比較例1
ホスフィン配位子として(R)−Xylyl−BINAPを用い、ジアミンとして(1R,2R)−ジフェニルエチレンジアミンを用いた以外は実施例10と同じ条件で実験を行った。転化率26%、26%de、84%ee(cis体)、33%ee(trans体)であった。
実施例12 光学活性−1−フェニル−2−(N−メチル−N−ベンゾイルアミノ)−1−プ ロパノールの製造
アルゴン雰囲気下、簡易型オートクレーブ(容量100ml)中に、(2R,5R)−2,5−ジアミノヘキサン塩酸塩2.2mg(0.0125mmol)、1−フェニル−2−(N−メチル−N−ベンゾイル)アミノプロパン−1−オン0.67g(2.5mmol)、0.1Nのt−ブトキシカリウムのイソプロパノール1.5ml溶液及びイソプロパノール5mlを室温で添加し、脱気した後、RuCl2〔(S)−Tol−BINAP〕のDMF付加物12.5mg(0.0125mmol)を加えた。反応系内に水素を12気圧まで圧入し、25℃にて1時間攪拌した後、反応混合物をシリカゲルカラムクロマトグラフィー(溶離液:ジエチルエーテル)で精製して、光学活性−1−フェニル−2−(N−メチル−N−ベンゾイルアミノ)−1−プロパノール0.65gを得た。収率97%
このものの光学純度及びジアステレオマー純度を高速液体クロマトグラフィー(移動相:ヘキサン/エタノール=15/1、カラム:Chiralcel OJ、ダイセル化学工業(株)製)で測定したところ、光学純度は89%eeであり、ジアステレオマー純度は99%de以上であった。
実施例13 光学活性−1−フェニル−2−(N−メチル−N−ベンゾイルアミノ)−1−プ ロパノールの製造
アルゴン雰囲気下、簡易型オートクレーブ(容量100ml)中に、(1R,4R)−1,4−ジフェニルブタン−1,4−ジアミン3.6mg(0.01mmol)、1−フェニル−2−(N−メチル−N−ベンゾイル)アミノプロパン−1−オン0.53g(2mmol)、水酸化カリウムイソプロパノール(1M)100μl及びイソプロパノール5mlを室温で添加し、脱気した後、RuCl2[(R)−Tol−BINAP]のDMF付加物の10mg(0.01mmol)を加えた。反応系内に水素ガスを12気圧まで圧入し、25℃にて1時間攪拌した後、反応混合物をシリカゲルカラムクロマトグラフィー(溶離液:ジエチルエーテル)で精製して、光学活性−1−フェニル−2−(N−メチル−N−ベンゾイルアミノ)−1−プロパノール0.5gを得た。収率94%
このものの光学純度及びジアステレオマー純度を高速液体クロマトグラフィー(移動相:ヘキサン/エタノール=15/1、カラム:Chiralcel OJ、ダイセル化学工業(株)製)で測定したところ、光学純度94%eeであり、ジアステレオマー純度99%de以上であった。
実施例14 光学活性−1−フェニル−2−(N−メチル−N−ベンゾイル)アミノ−1−プ ロパノールの製造
簡易型オートクレーブ(容量100ml)中に1−フェニル−2−(N−メチル−N−ベンゾイル)アミノプロパン−1−オン13.4g(50mmol)およびイソプロパノール50mlを加え脱気した後アルゴン雰囲気に置換した。このものへ、脱気した1M水酸化カリウムのイソプロパノール0.5ml溶液及びイソプロパノール3mlにRuCl2[(S)−binap][3,4−O−イソプロピリデン−(3R,4R)−ジヒドロキシ−(2R,5R)−ジアミノヘキサン]2.5mg(0.0025mmol)を室温で添加ししばらく撹拌する事により調製した触媒溶液を加えた。反応系内に水素を100気圧まで圧入し、25℃にて18時間攪拌した後、転化率、光学純度及びジアステレオマー純度を高速液体クロマトグラフィー(移動相:ヘキサン/エタノール/イソプロパノール=80/10/10、カラム:Chiralcel OJ、ダイセル化学工業(株)製)で測定したところ、転化率90%、光学純度は95%eeであり、ジアステレオマー純度は99%de以上であった。
このものをヘキサン−イソプロパノール混合溶媒で再結晶することにより光学的に純粋な(1R,2R)−1−フェニル−2−(N−メチル−N−ベンゾイル)アミノ−1−プロパノールを9.86g得た。収率74%。
実施例15(1S,2S,3S,4S)−2,3−O−イソプロピリデン−(2,3)−ジヒ ドロキシ−(1,4)−ジアミノ−(1,4)−ジフェニルブタン
(工程1)(2R,3R)−2,3−O−イソプロピリデン−2,3−ジヒドロキシ−1,4− ジフェニル−1,4−ブタンジオンの製造
2R,3R−O−イソプロピリデン酒石酸 ビスN,O−ジメチルヒドロキシルアミド(2.0g、7.25mmol)をTHF(50ml)に溶解し、0℃でフェニルマグネシウムブロマイドの1M溶液30ml(30mmol)を加えて、2時間撹拌した。反応終了後、反応溶液に水を加え1規定の塩酸で中和した後に酢酸エチルで抽出した。有機相を無水硫酸マグネシウムで乾燥し、濃縮して得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=19/1−4/1)で精製することによりジケトン体1.87gを得た。収率82%。
(工程2)(1R,2S、3S,4R)−2,3−O−イソプロピリデン−2,3−ジヒドロキ シ−1,4−ジフェニル−1,4−ブタンジオールの製造
(2R,3R)−2,3−O−イソプロピリデン−(2,3)−ジヒドロキシ−(1,4)−ジフェニル−(1,4)−ブタンジオン80mg(0.25mmol)をTHF5mlに溶解し、水素化ホウ素ナトリウム10mgをメタノール5mlに溶かした溶液を−78度で加えて、1時間撹拌した。反応終了後、反応溶液に水を加え1規定の塩酸で中和した後に酢酸エチルで抽出した。有機相を無水硫酸マグネシウムで乾燥し、濃縮して得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=19/1−2/1)で精製することによりジオール体51mgを得た。収率64%。
(工程3)(1R,2S,3S,4R)−2,3−O−イソプロピリデン−2,3−ジヒドロキ シ−1,4−ジフェニル−1,4−ブタンジオール ビスメタンスルホナートの製造
(1R,2S,3S,4R)−2,3−O−イソプロピリデン−(2,3)−ジヒドロキシ−(1,4)−ジフェニル−(1,4)−ブタンジオール80mg(0.25mmol)をジクロロメタン1ml、ピリジン1mlに溶解し、無水メタンスルホン酸を0度で加えて、室温で18時間撹拌した。反応終了後、反応溶液に水を加え1規定の塩酸で中和した後に酢酸エチルで抽出した。有機相を無水硫酸マグネシウムで乾燥し、濃縮して得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=4/1−2/1)で精製することによりジオール体88mgを得た。収率75%。
(工程4)(1S,2S、3S,4S)−2,3−O−イソプロピリデン−2,3−ジヒドロキシ −1,4−ジアジド−1,4−ジフェニルブタンの製造
(1R,2S,3S,4R)−2,3−O−イソプロピリデン−(2,3)−ジヒドロキシ−(1,4)−ジフェニル−(1,4)−ブタンジオール ビスメタンスルホナート1.03g(2.19mmol)をDMSO20mlに溶解し、アジ化ナトリウム5.5g(84.6mmol)を加えて60度で18時間撹拌した。反応終了後、反応溶液に水を加え酢酸エチルで抽出した。有機相を無水硫酸マグネシウムで乾燥し、濃縮して得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=10/1−4/1)で精製することによりジアジド体0.61gを得た。収率77%。
(工程5)(1S,2S,3S,4S)−2,3−O−イソプロピリデン−2,3−ジヒドロキシ −1,4−ジアミノ−1,4−ジフェニルブタンの製造
(1S,2S,3S,4S)−2,3−O−イソプロピリデン−(2,3)−ジヒドロキシ−(1,4)−ジアジド−(1,4)−ジフェニルブタン0.61gをメタノール10mlに溶解し、5%パラジウムカーボン0.5gを加え1気圧の水素雰囲気下、室温で24時間撹拌した。反応終了後反応溶液から不溶物を濾別し、濾液を濃縮して得られた残留物をメタノール/ジエチルエーテルで再結晶することにより目的物0.122gを得た。収率23%。
1H−NMR(CDCl3,δppm):7.26(m,10H)、4.17(m,2H)、3.95(m,2H)、1.16(s,6H)
〔α〕D 28=−42.5°(c=0.2,MeOH)
前記の実施例3および15の合成方法によって合成した1,4−ジアミン
実施例16 RuCl 2 〔(R)−binap〕〔(1S,2S,3S,4S)−2,3−O−イソ プロピリデン−2,3−ジヒドロキシ−1,4−ジアミノ−1,4−ジフェニルブタン〕の製造
シュレンクチューブ中にイソプロパノール2ml、(1S,2S,3S,4S)−2,3−O−イソプロピリデン−(2,3)−ジヒドロキシ−(1,4)−ジアミノ−(1,4)−ジフェニルブタン7.8mg(0.025mmol)を加え、脱気した後、RuCl2〔(R)−BINAP〕のDMF付加物25mg(0.025mmol)を加えて溶解させた。溶媒を減圧留去することにより目的物を得た。
この化合物の31P−NMR(CDCl3)を測定した結果、45.0ppmにシングレットピークが観測された。
実施例17 (1S,2S)−1−フェニル−2−(N−メチル−N−ベンゾイルアミノ)−1− プロパノールの製造
アルゴン雰囲気下、簡易型オートクレーブ(容量100ml)中に、1−フェニル−2−(N−メチル−N−ベンゾイル)アミノプロパン−1−オン0.10g(0.38mmol)、水酸化カリウムイソプロパノール溶液(0.1M)1ml及びイソプロパノール2mlを室温で添加し、脱気した後、RuCl2〔(R)−binap〕〔(1S,2S,3S,4S)−2,3−O−イソプロピリデン−2,3−ジヒドロキシ−1,4−ジアミノ−1,4−ジフェニルブタン〕3mg(0.003mmol)を加えた。反応系内に水素を10気圧まで圧入し、25℃にて1時間攪拌した後、反応混合物をシリカゲルカラムクロマトグラフィー(溶離液:ジエチルエーテル)で精製して光学異性体混合物を得た。転化率99%以上。
このものの光学純度及びジアステレオマー純度を高速液体クロマトグラフィー(移動相:ヘキサン/エタノール/イソプロパノール=8/1/1、カラム:Chiralcel OJ、ダイセル化学工業(株)製)で測定したところ、光学純度は98%eeであり、ジアステレオマー純度は99%de以上であった。
産業上の利用可能性:
以上説明したように、本発明によれば、入手容易なルテニウム化合物、該ルテニウム化合物の配位子として好適に用いることができるジアミン化合物を提供できる。
また、該ルテニウム化合物を触媒として用いて、縮合環ケトン類やα−アミノケトン類を不斉還元することにより、対応する光学活性アルコール類を、高立体選択的かつ高収率で製造することができる。Technical field:
The present invention provides an asymmetric reduction of a condensed ring ketone or an α-aminoketone using a ruthenium compound, a diamine compound suitably used as a ligand of the ruthenium compound, and the ruthenium compound as an asymmetric reduction catalyst. The present invention relates to a method for producing optically active alcohols.
Background technology:
Optically active alcohols are useful as synthetic intermediates for pharmaceuticals and agricultural chemicals.
Conventionally, as a method of obtaining corresponding optically active alcohols by catalytic asymmetric reduction of condensed ring ketones,
(1) Hydrogenation method using iridium complex as catalyst [J. Am. Chem. Soc. ,1153318 (1993)],
(2) A method by hydrogen transfer using ruthenium as a catalyst (Japanese Patent Laid-Open No. 10-130289),
(3) A hydrogenation method using ruthenium as a catalyst (Japanese Patent Laid-Open No. 11-189600) is known.
In addition, as a method of obtaining a corresponding optically active amino alcohol by hydrogenating an α-aminoketone,
(4) International Publication No. WO02 / 04401 and J.A. Am. Chem. Soc. ,122, 510 (2000).
However, since the method (1) uses an extremely expensive iridium complex, it is difficult to put it to practical use in terms of cost, and the method (2) must use an organic compound such as formic acid as a hydrogen source. Compared with the case of using an inexpensive hydrogen source such as hydrogen gas, it is disadvantageous in terms of operation and cost, and the method (3) is an excellent method for asymmetric reduction of ketones. No knowledge has been obtained on the asymmetric reduction of benzene, and the method (4) relates to the asymmetric reduction of α-aminoketones, but the catalyst is an expensive bidentate having a plurality of substituents. There was a problem that good results could not be obtained unless a phosphine ligand was used.
Therefore, it is desired to develop an asymmetric reduction catalyst that can produce an optically active alcohol corresponding to condensed ring ketones and α-amino ketones with high selectivity and high yield using an inexpensive hydrogen source such as hydrogen gas. ing.
Examples of the optically active diamine compound containing one or more carbon atoms between two carbon atoms substituted with a coordinating amino group according to the present invention include 2,4-pentanediamine and 2,5-hexane. Diamine, 3,4-O-isopropylidenedihydroxy-1,4-butanediamine and (R, R) -1,4-diphenylbutanediamine (Tetrahedron: Asymmetry, 2000, 11, 3003-3015.) Are known. However, it has not been known that the optically active diamine compound is extremely useful as a ligand for asymmetric reduction catalysts of ketones such as condensed ring ketones and α-amino ketones.
Disclosure of the invention:
The present invention provides a ruthenium compound that can be easily produced, a diamine compound that can be suitably used as a ligand of the ruthenium compound, and a condensed ring ketone or α-aminoketone using the ruthenium compound as an asymmetric reduction catalyst. It is an object of the present invention to provide a method for producing a corresponding optically active alcohol with high stereoselectivity and high yield by asymmetric reduction.
The present invention, first, formula (1):
(In the formula, X and Y each independently represent a hydrogen atom, a halogen atom, a carboxyl group, a hydroxyl group, or a C1-C20 alkoxy group, Px represents a phosphine ligand, R1To R8Are each independently a hydrogen atom, a C1-C20 alkyl group which may have a substituent, a C2-C20 alkenyl group which may have a substituent, or a C3-C8 cyclo group which may have a substituent. An alkyl group, an optionally substituted C7-C20 aralkyl group or an optionally substituted aryl group is represented.
R1And R3And / or R5And R7May combine to form a ring.
A is C1-C8 alkylene which may have a substituent, C2-C8 alkylene containing 1 to 2 oxygen atoms which may have a substituent, and C3 which may have a substituent. -C8 cycloalkylene, the arylene which may have a substituent, or the bivalent heterocyclic group which may have a substituent is represented. R when A is alkylene2And R6May combine with each other to form a ring.
A carbon atom constituting A, C# 1And C# 2At least one of these is carbon having optical activity.
n1Represents an integer of 1 or 2. Is a ruthenium compound represented by
Second, the formula (2-1): R1C*H (NH2) -AR1C*H (NH2)
[In the formula, R1And A have the same meaning as described above, and * indicates an atom having optical activity. The diamine compound represented by this is provided. However, 2,4-pentanediamine, 2,5-hexanediamine, 3,4-O-isopropylidenedihydroxy-1,4-butanediamine, and (R, R) -1,4-diphenylbutane-1,4 -Excluding diamines.
Third, the present invention relates to the formula (3) or (3 ')
(In the formula, the a ring portion represents a 3- to 8-membered carbon ring which may have a substituent or a 4- to 8-membered heterocycle which may have a substituent, and the b-ring portion has a substituent. A condensed ring ketone represented by a 4- to 8-membered carbocyclic ring or an optionally substituted 5- to 8-membered heterocyclic ring, which is a ruthenium compound of the present invention, or Formula (4) or (4 ′) characterized by having a step of asymmetric hydrogen reduction using hydrogen gas or hydrogen donor as a hydrogen source in the presence of two or more species
(Wherein, a ring part, b ring part and * represent the same meaning as described above).
The present invention fourthly relates to the formula (5): Ra-CO-CH (Rb) -Rc.
[In the formula, Ra and Rc each independently have a hydrogen atom, a C1-C20 alkyl group that may have a substituent, a C2-C20 alkenyl group that may have a substituent, or a substituent. It represents an optionally substituted C3 to C8 cycloalkyl group, an optionally substituted C7 to C20 aralkyl group or an optionally substituted aryl group.
Rb is
Formula (6): R9CO (R11) N-
Formula (7): R9CO (R10CO) N-
Formula (8): R9R11N-
Represents any group selected from the group represented by:
(Where R9, R10And R11Are each independently a hydrogen atom, a C1-C20 alkyl group that may have a substituent, a C2-C20 alkenyl group that may have a substituent, or a C1-C20 alkoxy that may have a substituent. Group, a C3-C8 cycloalkyl group which may have a substituent, a C3-C8 cycloalkoxy group which may have a substituent, a C7-C20 aralkyl group which may have a substituent, and a substituent. Represents a C7 to C20 aralkyloxy group, an aryl group which may have a substituent or an aryloxy group which may have a substituent, and R9And R11Or R9And R10May combine to form a 5- to 8-membered nitrogen-containing heterocycle. )] In the presence of any one or more of the ruthenium compounds represented by formula (1) of the present invention, using hydrogen gas or a hydrogen donor as a hydrogen source. Asymmetric hydrogen reduction step,
Formula (9): Ra-C*H (OH) -C(*)H (Rb) -Rc
[In the formula, Ra, Rb, Rc and * represent the same meaning as described above;(*)Indicates an asymmetric carbon when Rc is other than hydrogen. ] The manufacturing method of optically active beta-amino alcohol represented by these is provided.
The ruthenium compound of the present invention uses a readily available ruthenium derivative as a starting material, and can be easily produced. Moreover, the diamine compound of this invention can be used suitably as a ligand of the ruthenium compound of this invention. Furthermore, according to the method for producing optically active alcohols of the present invention, the ruthenium compound is used as an asymmetric reduction catalyst, and a condensed ring ketone or α-aminoketone is used as a starting material, which is useful as a synthetic intermediate for pharmaceuticals and agricultural chemicals. The optically active alcohols represented by the above formulas (4), (4 ′) and (9) can be produced with high stereoselectivity and high yield using an inexpensive hydrogen source such as hydrogen gas. .
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in detail.
The present invention provides (1) a ruthenium compound represented by formula (1), (2) a novel diamine compound represented by formula (2-1) that can be suitably used as a ligand of the ruthenium compound, Using (3) and the ruthenium compound as an asymmetric reduction catalyst, condensed ring ketones represented by formulas (3) and (3 ′) or α-aminoketone represented by formula (5) This is a method for producing optically active alcohols represented by formulas (4), (4 ′) and (9) by simultaneous reduction.
The ruthenium compound represented by the formula (1) of the present invention will be described.
In the formula (1), X and Y are each independently a hydrogen atom; a halogen atom such as fluorine, chlorine or bromine, a carboxyl group, a hydroxyl group, or methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy , C1-C20 alkoxy groups such as cyclohexyloxy and dodecyloxy.
Px represents a phosphine ligand. As Px, for example, the formula: PRARBRCA monodentate phosphine ligand represented by the formula: RDREP-W-PRFRGAnd a bidentate phosphine ligand represented by the formula:
Formula: PRARBRCIn the monodentate phosphine ligand represented byA, RBAnd RCAre each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl and its isomer, hexyl and its isomer, heptyl and its isomer, nonyl and its Isomers, C1-C20 alkyl groups such as dodecyl and its isomers; phenyl groups optionally having substituents; C3-C8 cycloalkyl groups such as cyclopropyl, cyclopentyl, cyclohexyl, cyclooctyl groups; benzyl, α- C7-C20 aralkyl groups such as methylbenzyl and α, α-dimethylbenzyl groups; RA, RBAnd RCTwo of them may combine to form a heterocycle containing P which may have a substituent.
Examples of the substituent of the heterocyclic ring containing the phenyl group and P include, for example, halogen atoms such as fluorine, chlorine, bromine and iodine; hydroxyl groups; methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, nonyl, dodecyl groups and the like A C2-C20 alkenyl group such as ethenyl, propenyl, butenyl, 2-hexenyl group; a C3-C8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl group; benzyl, α-methylbenzyl, α, C7-C20 aralkyl groups such as α-dimethylbenzyl group; aryl groups such as phenyl, 1-naphthyl and 2-naphthyl groups; C1 such as methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy and dodecyloxy groups ~ C20 alkoxy group; acetoxy, ethyl Carbonyloxy, an acyloxy group benzoyloxy; dioxolan-2-yl, the heterocyclic group such as oxazolin-2-yl; and the like.
Specific examples of the monodentate phosphine ligand include trimethylphosphine, triethylphosphine, tributylphosphine, triphenylphosphine, tricyclohexylphosphine, tri (p-tolyl) phosphine, diphenylmethylphosphine, dimethylphenylphosphine, diisopropylmethylphosphine, 1- Preferred examples include tertiary phosphines such as [2- (diphenylphosphino) ferrocenyl] ethyl methyl ether and 2- (diphenylphosphino) -2′-methoxy-1,1′-binaphthyl. Also, R such as ethylmethylbutylphosphine, ethylmethylphenylphosphine, isopropylethylmethylphosphine, cyclohexyl (O-anisyl) methylphosphine, etc.A, RBAnd RCIt is also possible to use phosphine ligands comprising different substituents for all three types.
Formula: RDREP-W-PRFRGIn the bidentate phosphine ligand represented by RD, RE, RFAnd RGAre each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl and its isomer, hexyl and its isomer, heptyl and its isomer, nonyl and its An isomer, a C1-C20 alkyl group such as dodecyl and its isomer; a phenyl group which may have a substituent; or a C3-C8 cycloalkyl group such as cyclopropyl, cyclopentyl, cyclohexyl group, etc .; RDAnd REAnd / or RFAnd RGMay combine to form a heterocyclic ring containing P which may have a substituent.
Examples of the substituent for the phenyl group and heterocyclic ring include halogen atoms such as fluorine, chlorine, bromine and iodine; hydroxyl groups; C1-C20 alkyl groups such as methyl, ethyl, propyl and butyl groups; ethenyl, propenyl and butenyl groups. C2-C20 alkenyl group such as cyclopropyl, cyclobutyl, cyclopentyl group, etc .; C3-C8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl group; C7-C20 aralkyl group such as benzyl, α-methylbenzyl, α, α-dimethylbenzyl group; Aryl groups such as naphthyl and 2-naphthyl groups; C1-C20 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy and butoxy groups; acyloxy groups such as acetoxy, ethylcarbonyloxy and benzoyloxy; dioxolan-2-yl , Heterocyclic groups such as oxazolin-2-yl Etc. The.
W is a C1-C5 alkylene group such as methylene, ethylene or propylene group which may have a substituent; such as cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene group which may have a substituent; C3-C6 cycloalkylene group; optionally substituted, phenylene, naphthylene, 1,1′-biphenyl-2,2′-diyl, 1,1′-binaphthyl-2,2′-diyl, 1, An arylene group such as 1′-binaphthyl-7,7′-diyl group; an optionally substituted C2-C20 alkenediyl group such as ethenediyl, propenediyl, isopropenediyl, butenediyl group; Or C2-C20 alkynediyl groups such as ethynediyl and propynediyl groups. Examples of the substituent on these divalent groups include C1-C20 alkyl groups such as methyl, ethyl, propyl, and butyl groups; C2-C20 alkenyl groups such as ethenyl, propenyl, and butenyl; methoxy, ethoxy, and n-propoxy. , C1-C20 alkoxy groups such as isopropoxy and butoxy groups; and the like.
Specific examples of the bidentate phosphine ligand include bisdiphenylphosphinomethane, bisdiphenylphosphinoethane, bisdiphenylphosphinopropane, bisdiphenylphosphinobutane, bisdimethylphosphinoethane, bisdimethylphosphinopropane and the like. It is done.
Furthermore, in the present invention, 2,2′-bis- (diphenylphosphino) -1,1′-binaphthyl (hereinafter referred to as BINAP) and a naphthyl ring of BINAP have a substituent such as an alkyl group or an aryl group. Also suitable are asymmetric ligands such as BINAP derivatives, BINAP derivatives having a fluorine substituent, and BINAP derivatives each having 1 to 5 substituents such as alkyl groups and alkoxy groups on two benzene rings on the phosphorus atom. It can be illustrated as a bidentate phosphine ligand.
Specific examples thereof include 2,2′-bis- (di-p-tolylphosphino) -1,1′-binaphthyl (Tol-BINAP), 2,2′-bis [bis (3,5-dimethylphenyl) Phosphino] -1,1′-binaphthyl (Xylyl-BINAP), 1- [1 ′, 2-bis (diphenylphosphino) ferrocenyl] ethyldiamine, 2,2′-bis- (dicyclohexylphosphino) -6,6 '-Dimethyl-1,1'-biphenyl, 2,3-bis- (diphenylphosphino) butane, 1-cyclohexyl-1,2-bis- (diphenylphosphino) ethane, 1-substituted-3,4-bis -(Diphenylphosphino) pyrrolidine, 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis- (diphenylphosphino) butane, 1,2- Sus [(O-methoxyphenyl) phenylphosphino] ethane, substituted-1,2-bis (phosphorano) benzene, 5,6-bis- (diphenylphosphino) -2-norbornene, N, N′-bis- ( Diphenylphosphino) -N, N′-bis (1-phenylethyl) ethylenediamine, 1,2-bis- (diphenylphosphino) propane, 2,4-bis- (diphenylphosphino) pentane, [(5,6 ), (5 ′, 6 ′)-bis (methylenedioxy) biphenyl-2,2′-diyl] bis (diphenylphosphine), 1,2-bis (t-butylmethylphosphino) ethane, 2,4- And bis- (diphenylphosphino) pentane.
The phosphine ligand that can be used in the present invention is not limited to the above as long as it can stably form a ruthenium compound.
Next, the diamine ligand represented by the formula (2) in the ruthenium compound represented by the formula (1) will be described.
A is C1-C8 alkylene such as methylene, ethylene, propylene; 2-oxapropane-1,3-diyl, 3-oxapentane-1,5-diyl, 3,6-dioxaoctane-1,8- C2-C8 alkylene group containing 1 to 2 oxygen atoms such as diyl; C3-C8 cycloalkylene such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene; phenylene, naphthylene, etc. Arylene; or a divalent heterocyclic group, which has a divalent bond at any position, such as furan, pyran, dioxolane, thiophene, thiopyran, pyrrole, imidazole, pyrazole, oxazole, triazole , Thiazole, isothiazole, pyridine, pyridazine, pyrazine Benzimidazole, benzopyrazole, benzothiazole, quinoline, indoline, phenanthroline, dioxolan-2-one, dioxane, dioxane-2,3-dione, oxazolidine, oxazolidinone, tetrahydrofuran, tetrahydrofuran-2,5-dione, tetrahydrothiophene, sulfolane, etc. Or a saturated or unsaturated heterocycle.
These groups may further have a substituent, such as a C1-C6 alkyl group such as methyl, ethyl, propyl, etc .; a C1-C6 alkoxy group such as methoxy, ethoxy, propoxy, etc .; phenyl, naphthyl, etc. An aryloxy group such as phenoxy; a C7-C20 aralkyloxy group such as a benzyloxy group.
When A is an alkylene group, an alkylene group containing 1 to 2 oxygen atoms, R2And R6May combine to form a ring.
R1~ R8Are each independently a hydrogen atom; optionally substituted C1-C20 such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, hexyl group, etc. An alkyl group (preferably a C1-C6 alkyl group); an optionally substituted C2 such as ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, t-butenyl, pentenyl, hexenyl group, etc. -C20 alkenyl group (preferably C2-C6 alkenyl group); C3-C8 cycloalkyl group such as cyclopropyl, cyclopentyl, cyclohexyl group, etc. which may have a substituent; benzyl, α-methylbenzyl, α, α -C7-C20 aralkyl group which may have a substituent such as dimethylbenzyl and α-ethylbenzyl group; or May include phenyl, 1-naphthyl, aryl groups such as 2-naphthyl group; represents a.
Examples of the substituent for the C1-C20 alkyl group, C2-C20 alkenyl group, C3-C8 cycloalkyl group, C7-C20 aralkyl group and aryl group include halogen atoms such as fluorine, chlorine, bromine and iodine; Groups; methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl group, etc. C1-C20 alkyl group; C2 such as ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, t-butenyl, 1,3-butadienyl, n-pentenyl, 2-pentenyl, 3-pentenyl, hexenyl group, etc. ~ C20 alkenyl group; cyclopropyl, cyclobutyl, cyclope C3-C8 cycloalkyl groups such as til and cyclohexyl groups; C7-C20 aralkyl groups such as benzyl, α-methylbenzyl, α, α-dimethylbenzyl and α-ethylbenzyl groups; phenyl, 1-naphthyl and 2-naphthyl groups Aryl groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy groups and the like; acyloxy groups; or heterocyclic groups; and the like.
Examples of the substituted amino group include amino groups in which two hydrocarbon groups such as dimethylamino and N-methyl-N-phenylamino groups are substituted; acylamino groups such as acetylamino and benzoylamino groups; methanesulfonylamino and toluene Sulfonylamino groups such as sulfonylamino groups; N-alkyl- such as N-methyl-N-acetylamino, N-ethyl-N-acetylamino, N-methyl-N-benzoylamino, N-ethyl-N-acylamino groups N-acylamino group; N-alkyl-N-sulfonylamino group such as N-methyl-N-sulfonylamino group and N-ethyl-N-sulfonylamino group; cyclic imide group such as phthalimide group;
Examples of the acyloxy group include C1-C12 alkylcarbonyloxy groups such as acetoxy, ethylcarbonyloxy and isopropylcarbonyloxy groups; arylcarbonyloxy groups such as benzoyloxy groups; aralkylcarbonyloxy groups such as phenylmethylcarbonyloxy groups Examples of the acyl group include C1-C12 alkylcarbonyl groups such as propanoyl and isopropylcarbonyl groups, and alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, and t-butoxycarbonyl groups; Arylcarbonyl groups such as benzoyl group; aralkylcarbonyl groups such as phenylmethylcarbonyl group; and the like.
Examples of the heterocyclic group include oxygen-containing heterocyclic groups such as furanyl, pyranyl and dioxolanyl groups; sulfur-containing heterocyclic groups such as thienyl groups; pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl, isothiazolyl, pyridyl, And saturated or unsaturated nitrogen-containing heterocyclic groups such as pyradadyl, pyrazinyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, quinolyl, anthranyl, indolyl, and phenanthronylyl groups.
These substituents are not particularly limited in the position of substitution, the type of substituent, the number of substituents, and the like. In the present invention, R1Is R3And R5Is R7And / or R2Is R6It is also possible to use a diamine compound that forms a ring by bonding with the.
A carbon atom constituting A, C# 1And C# 2At least one of these is carbon having optical activity.
These diamine compounds are represented by the formula (2 ') from the viewpoints of synthesis, availability, and economy.
R1R2C*(NR3R4) -AR1R2C*(NR3R4) (2 ')
The compound represented by can be used more suitably.
Where R1Is a C1-C8 linear, branched, cyclic alkyl group, a C2-C8 linear, branched, cyclic alkenyl group, an aryl group that may have a substituent, or a heterocyclic ring that may have a substituent R and R2, R3And R4Are all hydrogen atoms, A is an alkylene group, alkylene containing 1 to 2 oxygen atoms, a phenylene group, or 2 represented by the following formulas (2-A), (2-B), (2-C) A compound that is a valent group is more preferred.
[Wherein Ra', RbEach independently represents a hydrogen atom; C1-C6 such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, hexyl group and the like which may have a substituent. Alkyl group; C7-C20 aralkyl group which may have a substituent such as benzyl, α-methylbenzyl, α, α-dimethylbenzyl, α-ethylbenzyl group; methoxy, ethoxy which may have a substituent; C1-C6 alkoxy group such as isopropoxy group; C1-C6 alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl group which may have a substituent; heterocyclic group; or substitution A C6-C14 aryl group such as phenyl, 1-naphthyl, 2-naphthyl group and the like, which may have a group, or a group represented by the formula ( In the -A), Ra'And Rb′ May be taken together to form a carbonyl group. In the formula (2-B), Ra', Rb'May be taken together to form a carbonyl group. ]
Specific examples of these diamine compounds include (S, S) and (R, R) forms of bis (2-aminopropyl) ether, and (S, S) of bis (2-amino-2-phenylethyl) ether. And (S, S) and (R, R) of (R, R) isomer, (1S, 4S) -1,4-diamino-1,4-diphenylbutane, 1,4-diamino-1,4-dicyclohexylbutane ) Form, (S, S) and (R, R) forms of 1,2-bis (1-aminoethyl) benzene, optically active 1,2-bis (1-aminoethyl) cyclohexane, optically active 1,1- Bis (1-aminoethyl) cyclopentane, optically active 1,2-bis (1-aminoethyl) cyclopentane, (2R, 3R, 4R, 5R) -3,4-O-isopropylidene-3,4-dihydroxy -2,5-hexanediamy , (2S, 3S, 4S, 5S) -3,4-O-isopropylidene-3,4-dihydroxy-2,5-hexanediamine, (1R, 2R, 3R, 4R) -2,3-O-isopropylidene Riden-2,3-dihydroxy-1,4-diphenyl-1,4-butanediamine, (1S, 2S, 3S, 4S) -2,3-O-isopropylidene-2,3-dihydroxy-1,4- Diphenyl-1,4-butanediamine, (1R, 2R, 3R, 4R) -2,3-O- (1-phenylethylidene) -2,3-dihydroxy-1,4-diphenyl-1,4-butanediamine (1S, 2S, 3S, 4S) -2,3-O- (1-phenylethylidene) -2,3-dihydroxy-1,4-diphenyl-1,4-butanediamine, (2R, 3R, 4R, 5R) -3,4-O- Sopropylidene-3,4-dihydroxy-1,4-diphenyl-2,5-hexanediamine, (2S, 3S, 4S, 5S) -3,4-O-isopropylidene-3,4-dihydroxy-1,4- Diphenyl-2,5-hexanediamine, (3R, 4R, 5R, 6R) -4,5-O-isopropylidene-4,5-dihydroxy-3,6-octanediamine, (3S, 4S, 5S, 6S) -4,5-O-isopropylidene-4,5-dihydroxy-3,6-octanediamine and the like.
Next, the manufacturing method of the ruthenium compound of this invention is demonstrated.
As a starting material used in the method for producing a ruthenium compound, zero-valent, monovalent, divalent, trivalent and even higher-valent ruthenium derivatives can be used. Among these, Angew. Chem. Int. Ed. ,37, 1703 (1998), a method using a divalent ruthenium complex is simple. That is, a ruthenium compound represented by the formula (1) can be produced by adding a diamine compound after heating a solvent solution of a divalent ruthenium-halide complex and a bidentate phosphine ligand.
Hereinafter, a method for producing a ruthenium compound when a divalent ruthenium-halide complex is used as a starting material will be described in more detail.
First, a divalent ruthenium-halide complex as a starting material and a phosphine ligand are reacted by heating in a solvent to obtain a corresponding phosphine-ruthenium-halide complex.
The divalent ruthenium-halide complex of the starting material is not particularly limited as long as it is a ruthenium complex having a phosphine ligand and an amine ligand that can be substituted. Specific examples thereof include [ruthenium dichloride (norbornadiene)] polynuclear, [ruthenium dichloride (cyclooctadiene)] polynuclear, halogens coordinated with dienes such as [bis (methylallyl) ruthenium (cyclooctadiene)]. Ruthenium chloride compounds; [ruthenium dichloride (benzene)] dinuclear, [ruthenium dichloride (p-cymene)] dinuclear, [ruthenium dichloride (trimethylbenzene)] dinuclear, [ruthenium dichloride (hexamethyl) Benzene)] ruthenium halides coordinated with aromatic compounds such as dinuclear compounds; and the like.
The amount of the phosphine ligand used is usually 2 to 3 times mol, preferably 2 times mol in the case of monodentate, and usually 1 to 2 times in the case of bidentate, relative to 1 mol of the ruthenium-halide complex. Mole, preferably equimolar.
Examples of the solvent used in this reaction include aromatic hydrocarbons such as toluene and xylene, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as pentane and hexane; dichloromethane, chloroform, Halogen hydrocarbons such as trichloromethane, carbon tetrachloride, 1,2-dichloroethane; ethers such as diethyl ether, tetrahydrofuran (THF), 1,2-dimethoxyethane, 1,4-dioxane; methanol, ethanol, n- Alcohols such as propanol, isopropanol, butanol, benzyl alcohol; N, N-dimethylformamide (DMF), N, N-dimethylacetamide, 1,3-dimethylimidazolidine, 1,3-dimethyl-2-imidazolide Non, N-methylpyrrolidone, hexamethy Amides such triamide phosphate (HMPT); acetonitrile, nitriles such as benzonitrile; dimethyl sulfoxide (DMSO) and the like. These solvents can be used alone or in admixture of two or more.
The amount of the solvent used is 1 ml to 100 ml with respect to 1 g of the substrate, and preferably 1 ml to 10 ml with respect to 1 g of the substrate. The reaction temperature is usually in the range of 0 to 200 ° C, preferably room temperature to 100 ° C.
Next, the obtained phosphine-ruthenium-halide complex can be reacted with a diamine compound to obtain a corresponding amine-phosphine-ruthenium-halide complex.
The usage-amount of the diamine compound used for this reaction is 1-2 times mole normally with respect to a phosphine-ruthenium-halide complex, Preferably it is equimolar.
The reaction temperature is usually in the range of −100 to 200 ° C., preferably −10 to 50 ° C.
An amine-phosphine-ruthenium-halide complex can also be obtained by allowing a diamine compound to act on a phosphine-ruthenium-halide complex isolated in advance under the same conditions as described above.
Subsequently, the amine-phosphine-ruthenium hydride complex in which X = Y = H among the compounds represented by the formula (1) by reacting the obtained amine-phosphine-ruthenium-halide complex with a base in a solvent. Can be obtained.
Examples of the base to be used include triethylamine, diisopropylethylamine, pyridine, 1,4-diazabicyclo [2,2,2] octane (DABCO), 1,4-diazabicyclo [5,4,0] unde-7-ene ( Organic bases such as DBU); metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, magnesium ethoxide; organolithium compounds such as n-butyllithium and lithium diisopropylamide (LDA); sodium hydroxide, Alkali metal hydroxides such as potassium hydroxide; carbonates such as potassium carbonate and sodium carbonate; metal hydrides such as sodium hydride;
The amount of base used is usually in the range of 2 to 10,000 times mol, preferably 2 to 40 times mol, of the amine-phosphine-ruthenium-halide complex.
Examples of the solvent used in this reaction include aromatic hydrocarbons such as toluene and xylene, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as pentane and hexane; dichloromethane, chloroform and trichloro Halogen hydrocarbons such as methane, carbon tetrachloride, 1,2-dichloroethane; ethers such as diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane; methanol, ethanol, n-propanol, isopropanol, Alcohols such as butanol and benzyl alcohol; Nitriles such as acetonitrile and benzonitrile; DMF, N, N-dimethylacetamide, 1,3-dimethylimidazolidine, 1,3-dimethyl-2-imidazolidinone, N -Amides such as methylpyrrolidone; DMSO, etc. And the like. These solvents can be used alone or in admixture of two or more.
The amount of the solvent used is in the range of 1 ml to 101, preferably 1 ml to 11, with respect to 1 g of the amine-phosphine-ruthenium-halide complex. Moreover, reaction temperature is -100-200 degreeC normally, Preferably, it is the range of -10-50 degreeC.
In the formula (1), a ruthenium compound in which X and / or Y is a carboxy group, a hydroxyl group, or an alkoxy group is converted into an amine-phosphine-ruthenium-halide complex obtained by the above-described method or the like with RCOONa or RONa (R represents an alkyl group) It can be obtained by reacting.
Next, the diamine compound of the present invention will be described.
The diamine compound of the present invention is a novel compound not described in any literature among the diamine compounds represented by the formula (2), and particularly a compound represented by the formula (2-1).
R1C*H (NH2) -AR5C*H (NH2(2-1)
Where R1May have the above-mentioned C1-C8 linear, branched, cyclic alkyl group, C2-C8 linear, branched, cyclic alkenyl group, an aryl group which may have a substituent, or a substituent. A heterocyclic group, R5Is R1And A is an alkylene group, an alkylene group containing 1 to 2 oxygen atoms, a phenylene group, or the above formula (2-A), (2-B), (2-C). It is a divalent group.
A compound in which A is an alkylene group, an alkylene group containing 1 to 2 oxygen atoms, or a phenylene group is produced according to the reaction scheme shown below using, for example, a diketone represented by formula (2a) as a starting material. Can do.
(Where A, R1And R5Represents the same meaning as above, R12Represents a hydrogen atom, a C7 to C20 linear, branched or cyclic alkyl group, and a C7 to C20 linear, branched or cyclic aralkyl group. )
That is, the diketone (2a) is asymmetrically reduced to an optically active diol (2b) (step I), the optically active diol (2b) is derived into an optically active azide (2c) (step II), By reducing 2c) (step III), the diamine compound (2-1) can be easily produced.
Alternatively, diketone (2a) can be converted to dioxime (2d) (step IV), and this can be asymmetrically reduced to produce diamine compound (2-1) (step V).
Examples of the diketone (2a) used as a starting material include 2,4-pentanedione, 2,5-hexanedione, 1,3-diphenyl-1,3-propanedione, 1,4-diphenyl-1,4. -Butanedione, 1,2-di (acetyl) benzene and the like.
The asymmetric reduction reaction of the diketone (2a) in Step I can be performed, for example, in the same manner as described in JP-A-11-189600. That is, optical activity is obtained by a method in which a diketone (2a) and an asymmetric reduction catalyst are mixed in an organic solvent, a base is added if desired, and asymmetric reduction is performed in the presence of hydrogen gas or a hydrogen donor at a predetermined pressure. Diol (2b) can be obtained.
As the asymmetric reduction catalyst, for example, an optically active amine-phosphine-ruthenium-halide complex which is the compound of the present invention can be used. The amount of the asymmetric reduction catalyst used is in the range of 1/50 to 1 / 2,000,000 times mol, preferably 1/100 to 1 / 1,000,000 times mol of the diketone (2a).
Examples of the base to be added include organic bases such as triethylamine, diisopropylethylamine, pyridine, DABCO and DBU; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide and magnesium ethoxide; sodium hydroxide, water Alkali metal hydroxides such as potassium oxide; alkaline earth metal hydroxides such as magnesium hydroxide; carbonates such as sodium carbonate and calcium carbonate; metal hydrides such as sodium hydride and calcium hydride; . The amount of these bases used is in the range of 2 to 10,000 times mol, preferably 2 to 40 times mol, per mol of the asymmetric reduction catalyst.
Examples of the organic solvent include alcohols such as methanol, ethanol, n-propanol, isopropanol, butanol, and benzyl alcohol; aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as pentane and hexane; Halogen hydrocarbons such as dichloromethane, chloroform, trichloromethane, carbon tetrachloride, 1,2-dichloroethane; ethers such as diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane; DMF, N, N -Amides such as dimethylacetamide, 1,3-dimethylimidazolidine, 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone and HMPT; Nitriles such as acetonitrile and benzonitrile; DMSO and the like are used These solvents can be used alone Rui can also be used by mixing two or more kinds. Among these, the use of alcohols is preferable because the reaction product is an alcohol compound.
The pressure of hydrogen is usually in the range of 1 to 200 atmospheres, preferably 3 to 50 atmospheres. Further, as the hydrogen donor, for example, a hydrogen storage alloy, diimide, or the like can be used, and the amount used thereof is based on the ketones represented by the formula (3), (3 ′), or (5). Usually, it is the range of 1-100 times mole.
The reaction proceeds smoothly in the temperature range of -30 to 100 ° C, preferably 25 to 40 ° C. The reaction time depends on the reaction conditions such as diketone (2a) concentration, temperature, pressure and the like, but is usually from several minutes to 1 day.
The asymmetric reduction reaction of the diketone (2a) in this step I is carried out using an oxazaborodine as a catalyst (Tetrahedron Lett.,31, 601 (1990)) or the like.
As the azidation reaction of the optically active diol (2b) in Step II, (1) a method of reacting in a solvent in the presence of an azidating agent and a base at room temperature or under heating, or (2) diol (2b) and tosyl A method of reacting chloride, trifluoromethylsulfonyl chloride and the like in the presence of a base to form a disulfonic acid ester and then reacting this with an azidating agent, and (3) a halogenating agent such as diol (2b) and thionyl chloride. And a method of reacting this with an azidating agent.
As the azidating agent, commercially available ones such as organic azidating agents such as diphenylphosphoryl azide and inorganic azidating agents such as sodium azide can be used. The amount of the azidating agent to be used is usually in the range of 2 to 10 times mol with respect to the optically active diol (2b).
Examples of the base to be added to the azidation reaction include organic bases such as triethylamine, pyridine, DABCO, and DBU; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and magnesium ethoxide; sodium hydroxide, Alkali metal hydroxides such as potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; carbonates such as sodium carbonate and calcium carbonate; metal hydrides such as sodium hydride and calcium hydride; It is done. Among these, organic bases such as DBU are preferable.
Examples of the solvent used in the azidation reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as pentane and hexane; dichloromethane, chloroform, trichloromethane, carbon tetrachloride, 1, 2 -Halogen hydrocarbons such as dichloroethane; Ethers such as diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane; DMF, N, N-dimethylacetamide, 1,3-dimethylimidazolidine, Amides such as 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone and HMPT; nitriles such as acetonitrile and benzonitrile; and the like can be used. These solvents can be used alone or in admixture of two or more.
The reaction proceeds smoothly in the range of usually −78 ° C. to the boiling point of the solvent, preferably −30 ° C. to room temperature. The reaction time is usually several minutes to 1 day, preferably 3 to 18 hours.
It is also possible to directly induce optically active dialcohol (2b) to optically active diazide (2c). That is, (1) a method in which 2b and a phosphoryl azide azidating agent such as diphenylphosphoryl azide are reacted in a solvent in the presence of an organic base such as triethylamine, pyridine, DABCO, DBU (J. Org. Chem). , 1993, 58, 5886.), 2) in solvent, 2b, DEAD ((NCOOEt)2Azodicarboxylates such as triphenylphosphine, and a method of reacting hydrogen azide (Helv. Chim. Acta., 1978, 61, 1832.).
The reduction reaction of the optically active azide (2c) in Step III is carried out in a solvent in the presence of a reducing agent at room temperature or under heating.
As the reducing agent, a commonly used reducing agent can be used. Specific examples thereof include lithium aluminum hydride, sodium borohydride, sodium tricyanoborohydride, lithium triethylborohydride, diborane. Etc. The reaction can also be carried out under hydrogenation conditions using a carbon support of palladium or platinum as a catalyst.
Examples of the solvent used in the reduction reaction include alcohols such as methanol, ethanol, n-propanol, isopropanol, butanol and benzyl alcohol; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatics such as pentane and hexane. Hydrocarbons; ethers such as diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane; DMF, N, N-dimethylacetamide, 1,3-dimethylimidazolidine, 1,3-dimethyl Amides such as -2-imidazolidinone, N-methylpyrrolidone, and HMPT can be used. These solvents can be used alone or in admixture of two or more.
The reaction proceeds smoothly in a temperature range of usually −78 ° C. to the boiling point of the solvent, preferably −30 ° C. to room temperature. The reaction time is usually several minutes to 1 day, preferably 3 to 18 hours.
The oximation of the diketone (2a) in step IV is carried out in a solvent with the diketone (2a) and the formula R12ONH2(R12Indicates the same meaning as described above. The reaction is performed at room temperature or under heating. The alkoxyamine can be used in the form of a salt and can be reacted while neutralizing with a base. Examples of such alkoxyamine salts include methoxyamine hydrochloride, ethoxyamine hydrochloride, benzyloxyamine hydrochloride, and the like. The usage-amount is 1-100 times mole with respect to diketone (2a), Preferably it is the range of 2-20 times mole.
The solvent used in this reaction may be an inert solvent, and a general solvent that can be used industrially can be used. Specific examples thereof include alcohols such as methanol, ethanol, n-propanol, isopropanol, butanol and benzyl alcohol; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as pentane and hexane; dichloromethane Halogen ethers such as chloroform, trichloromethane, carbon tetrachloride, 1,2-dichloroethane; ethers such as diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane; DMF, N, N— Amides such as dimethylacetamide, 1,3-dimethylimidazolidine, 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone and HMPT; nitriles such as acetonitrile and benzonitrile; DMSO, water and the like Can be mentioned. These solvents can be used alone or in admixture of two or more.
The reaction proceeds smoothly in a temperature range of usually −50 ° C. to the boiling point of the solvent, preferably room temperature to the boiling point of the solvent. The reaction time is usually several minutes to 1 day, preferably 8 to 18 hours.
The asymmetric reduction reaction of dioxime (2d) in Step V is, for example, an asymmetric boron reduction reaction with oxazaborolidine (J. Org. Chem.,65(18), 5879 (2000). ) And the like.
Of the compounds in which A is a divalent group represented by the above (2-A), (2-B), (2-C) in the diamine compound of the present invention, (2-A) is in accordance with the following reaction diagram. The optically active diester represented by the formula (a) can be produced as a starting material.
(In the figure, R1, Ra ', Rb' and * have the same meaning as described above, ra and rb each represent a lower alkyl group, and rc represents an alkanesulfonyl or arenesulfonyl group. )
That is, an optically active tartaric acid derivative represented by the formula (a) is used as a starting material, and an amine is allowed to act on this to convert it into an optically active diamide (b) (step VI). ) (Step VII). The optically active dialcohol (d) obtained by reducing c (step VIII) is converted to the optically active diazide (f) via the optically active disulfonate (e) (step IX) (step X), f (Step XI), a product in which the residue of A in the general formula (2) is 2-A can be produced.
Examples of a used as a starting material include dimethyl 2,3-O-isopropylidene-tartrate, dimethyl 2,3-benzylidene-tartrate, dimethyl 2,3-O- (1-phenylethylidene) -tartrate and the like. It is done.
The method of deriving the optically active tartaric acid derivative (a) to the optically active diamide (b) in Step VI is described, for example, in J. Am. Med. Chem. , 1996, 39, 2163. This can be done as described. That is, hydrochloric acid or sulfate of N, O-substituted hydroxylamine and trialkylaluminum in an organic solvent at −70 ° C. to the boiling point of the solvent, preferably −20 ° C. to room temperature, 1 minute to 16 hours, preferably 15 minutes to 3 Mixing for a period of time, b can be obtained by reacting a with this solution at −70 ° C. to the boiling point of the solvent, preferably −40 ° C. to room temperature.
As the N, O-substituted hydroxylamine, for example, N, O-dimethylhydroxylamine, N-methyl-O-benzylhydroxylamine, N-benzyl-O-benzylhydroxylamine can be used. The amount of N, O-substituted hydroxylamine to be used is 2 to 10 times mol, preferably 3 to 4 times mol of a.
As the trialkylaluminum, for example, tri-lower alkylaluminum such as trimethylaluminum and triethylaluminum is suitable. The amount of trialkylaluminum used is 0.1 to 5 times, preferably 0.5 to 2 times the mol of N, O-substituted hydroxylamine.
Examples of the organic solvent include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as pentane and hexane; halogens such as dichloromethane, chloroform, trichloromethane, carbon tetrachloride, and 1,2-dichloroethane. Hydrocarbons; ethers such as diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane, etc. can be used, and these solvents are used alone or in admixture of two or more. You can also Among these, the use of halogenated hydrocarbons is preferable.
In the step VII, the optically active diamide (b) can be introduced into the optically active diketone (c) by applying a Grignard reaction that is generally performed. That is, the organic solvent solution of (b) has the general formula R1Mgx
(R1Represents the same meaning as described above, and x represents a halogen atom such as chlorine or bromine. To obtain (c) by reacting the Grignard reagent represented by) at -70 ° C to the boiling point of the solvent, preferably -20 ° C to room temperature, for 0.5 to 16 hours, preferably for 1 to 10 hours. Can do.
R1The amount of Mgx used is from equimolar to 8-fold mole of (b), preferably 2-fold to 4-fold mole.
Examples of the organic solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as pentane and hexane; diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane, and the like. Ethers can be used, and these solvents can be used alone or in admixture of two or more. Of these, the use of ethers is preferred.
The induction of optically active diketone (c) to optically active dialcohol (d) in Step VIII can be performed by a reduction reaction with a reducing agent that is generally performed. That is, the main product is obtained by reacting the reducing agent with the organic solvent solution of (c) at −100 ° C. to the boiling point of the solvent, preferably −70 ° C. to room temperature, for several minutes to several days, preferably 1 hour to 10 hours. (D) can be obtained.
As the reducing agent, a commonly used boron-based or aluminum-based one can be used, and specific examples thereof include lithium aluminum hydride, sodium borohydride, sodium tricyanoborohydride, triethyl hydrogenated. Examples thereof include lithium lithium, diborane, L-selectride, and LS-selectride. The reaction can also be carried out under hydrogenation conditions using a carbon support of palladium or platinum as a catalyst.
The amount of the reducing agent used is 0.5 to 3 molar equivalents of b, preferably equimolar to 3 molar equivalents.
Examples of the solvent used in the reduction reaction include alcohols such as methanol, ethanol, n-propanol, isopropanol, butanol and benzyl alcohol; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatics such as pentane and hexane. Hydrocarbons; ethers such as diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane; DMF, N, N-dimethylacetamide, 1,3-dimethylimidazolidine, 1,3-dimethyl Amides such as -2-imidazolidinone, N-methylpyrrolidone, and HMPT can be used. These solvents can be used alone or in admixture of two or more.
Induction of optically active dialcohol (d) to optically active disulfonate (e) in step IX is carried out by a generally performed method in which d is reacted with sulfonic acid halide or sulfonic anhydride in the presence of a base. Is called. That is, sulfonic acid halide or sulfonic anhydride is added to an organic solvent solution of d and a base at −40 ° C. to the boiling point of the solvent, preferably −20 ° C. to 60 ° C. for 1 hour to 24 hours, preferably 6 hours to 18 hours, E can be obtained by reaction.
The sulfonic acid halide or sulfonic anhydride has a C1-C20 alkanesulfonyl halide which may have a substituent, a C6-C14 arenesulfonyl halide which may have a substituent, and a substituent. C1 to C20 alkanesulfonic acid anhydride, which may have a substituent, and C6 to C14 arenesulfonic acid anhydride. As the substituent, chlorine, bromine, C1 to C6 lower alkyl group, C1 A C6 lower alkoxy group and a phenyl group; Commonly used mesyl chloride, methanesulfonic anhydride, tosyl chloride, tosylic anhydride, trifluoromethanesulfonic acid chloride, trifluoromethanesulfonic anhydride, benzenesulfonic acid chloride, and anhydrous benzenesulfonic acid can be suitably used.
Examples of the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, DABCO, DBU; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, magnesium methoxide, magnesium ethoxide; lithium hydroxide Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium hydrogen carbonate and carbonic acid Alkali metal hydrogen carbonates such as potassium hydrogen; alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate; metal hydrides such as sodium hydride and calcium hydride;
The amount of the sulfonic acid halide or sulfonic anhydride to be used is 2 to 10 times mol, preferably 2.5 to 5 times mol of (d).
The amount of the base to be added is equimolar to large excess of the amount of the sulfonic acid halide or sulfonic anhydride to be used, preferably 1.2 times to 3 times the amount of the sulfonic acid halide, but when an organic base is used as the solvent. Large excess.
Examples of the organic solvent include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as pentane and hexane; halogens such as dichloromethane, chloroform, trichloromethane, carbon tetrachloride, and 1,2-dichloroethane. Hydrocarbons; ethers such as diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane; DMF, N, N-dimethylacetamide, 1,3-dimethylimidazolidine, 1,3- Amides such as dimethyl-2-imidazolidinone, N-methylpyrrolidone and HMPT; nitriles such as acetonitrile and benzonitrile; DMSO can be used, and an organic base can be used as a solvent. Solvents can be used alone or in admixture of two or more.
In the step X, the optically active disulfonate (e) is converted into the optically active diazide (f) by a general azidation reaction in which (e) is reacted with an azidating agent. That is, f is obtained by reacting the organic solvent solution of e with the azidating agent at −40 ° C. to the boiling point of the solvent, preferably 0 ° C. to the boiling point of the solvent for 1 hour to 48 hours, preferably 6 hours to 24 hours. be able to.
As the azidating agent, generally available inorganic azidating agents such as sodium azide and lithium azide can be used. The amount of the azidating agent used is usually 2 to 100 times mol, preferably 2.5 to 50 times the amount of (e).
Examples of the solvent used in the present azidation reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as pentane and hexane; dichloromethane, chloroform, trichloromethane, carbon tetrachloride, 1, Halogen hydrocarbons such as 2-dichloroethane; ethers such as diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane; DMF, N, N-dimethylacetamide, 1,3-dimethylimidazolidine Amides such as 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone and HMPT; nitriles such as acetonitrile and benzonitrile; DMSO; sulfolane and the like. These solvents can be used alone or in admixture of two or more.
In step XII, the optically active diazide (f) is induced to (2-A) of the general formula (2) by reducing (f). That is, the reaction is carried out in a solvent by reacting (f) in the presence of a reducing agent at room temperature or under heating. The reaction proceeds smoothly in the range of usually −78 ° C. to the boiling point of the solvent, preferably −30 ° C. to room temperature. The reaction time is usually several minutes to 1 day, preferably 3 to 18 hours.
As the reducing agent, a commonly used reducing agent can be used. Specific examples thereof include lithium aluminum hydride, sodium borohydride, sodium tricyanoborohydride, lithium triethylborohydride, diborane. Etc. The reaction can also be carried out under hydrogenation conditions using a carbon support of palladium or platinum as a catalyst.
Examples of the solvent used in the reduction reaction include alcohols such as methanol, ethanol, n-propanol, isopropanol, butanol and benzyl alcohol; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatics such as pentane and hexane. Hydrocarbons; ethers such as diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane; DMF, N, N-dimethylacetamide, 1,3-dimethylimidazolidine, 1,3-dimethyl Amides such as -2-imidazolidinone, N-methylpyrrolidone, and HMPT can be used. These solvents can be used alone or in admixture of two or more.
Further, as in Step XI, the optically active dialcohol (d) can be directly derived into the optically active diazide (f). (1) A method in which (d) is reacted with a phosphoryl azide-based azidating agent such as diphenylphosphoryl azide in a solvent in the presence of an organic base such as triethylamine, pyridine, DABCO, DBU (J. Org. Chem., 1993, 58, 5886.), (2) in a solvent, (d), DEAD ((NCOOEt)2Azodicarboxylates such as triphenylphosphine, and a method of reacting hydrogen azide (Helv. Chim. Acta., 1978, 61, 1832.).
The diamine compounds represented by the formulas (2-B) and (2-C) can be produced according to the above method.
Next, a method for producing optically active alcohols using the ruthenium compound of the present invention will be described.
An optically active alcohol (4) corresponding to each of the condensed ketones (3), (3 ′) or α-aminoketones (5) by an asymmetric hydrogenation reduction reaction using the ruthenium compound of the present invention as a catalyst. , (4 ′) or (9) can be produced.
First, the condensed ketones (3) and (3 ′) serving as substrates will be described.
In the formulas (3) and (3 ′), the a ring portion represents a 3- to 8-membered carbon ring which may have a substituent or a 4- to 8-membered heterocycle which may have a substituent, and ring b The part represents a 4- to 8-membered carbocycle which may have a substituent or a 5- to 8-membered heterocycle which may have a substituent. Examples of the 3- to 8-membered carbocyclic ring in the a-ring part include unsaturated hydrocarbon rings such as cyclopropene, cyclobutene, cyclobutadiene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, and benzene rings. Examples of the heterocycle include oxygen-containing heterocycles such as furan, pyran and dioxolane; sulfur-containing heterocycles such as thiophene; pyrrole, imidazole, pyrazole, oxazole, isoxazole, triazole, thiazole, isothiazole, pyridine, pyridazine, pyrazine, And saturated or unsaturated nitrogen-containing heterocycles such as benzimidazole, benzopyrazole, benzothiazole, quinoline, indoline, and phenanthroline.
Examples of the 4- to 8-membered carbocyclic ring in the b-ring part include unsaturated hydrocarbon rings such as cyclobutene, cyclobutadiene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, and benzene rings. For example, oxygen-containing heterocycles such as furan and pyran; sulfur-containing heterocycles such as thiophene; pyrrole, imidazole, pyrazole, oxazole, isoxazole, triazole, thiazole, isothiazole, pyridine, pyridazine, pyrazine, benzimidazole, benzopyrazole , Saturated or unsaturated nitrogen-containing heterocycles such as benzothiazole, quinoline, indoline and phenanthroline;
Specific examples of condensed ring ketones include α-tetralones which may have a substituent, β-tetralones which may have a substituent, chromones which may have a substituent, and substituents. 4-chromanones optionally having, thiochroman-4-ones optionally having substituents, 2,3-dihydro-1H-quinolin-4-ones optionally having substituents, substituents 2-isothiochroman-4-ones, which may have a substituent, 2,3-dihydro-1H-isoquinolin-4-ones which may have a substituent, 1- Indanones, 2H-benzofuran-3-ones optionally having substituents, 2H-benzothiopyran-3-ones optionally having substituents, indoline-3-ones optionally having substituents , 4-keto-4,5,6,7-tetrahydrothio which may have a substituent And naphthenes.
The condensed ring ketones may be any substituent as long as it does not inhibit the reaction, such as halogen atoms such as fluorine, chlorine, bromine and iodine; hydroxyl groups; amino, methylamino, dimethylamino, acetylamino and the like. Optionally substituted amino group; methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, hexyl, heptyl, octyl, nonyl C1-C20 alkyl groups such as decyl and dodecyl groups; ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, t-butenyl, 1,3-butadienyl, n-pentenyl, 2-pentenyl, 3- C2-C20 alkenyl groups such as pentenyl and hexenyl groups; cyclopropyl, cycl C3-C8 cycloalkyl groups such as butyl, cyclopentyl and cyclohexyl groups; C7-C20 aralkyl groups such as benzyl, α-methylbenzyl, α, α-dimethylbenzyl and α-ethylbenzyl groups; phenyl, 1-naphthyl, 2- Aryl groups such as naphthyl groups; C1-C20 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy groups; acyloxy groups; acyl groups; heterocyclic groups; Can be mentioned.
Examples of the acyloxy group include C1-C12 alkylcarbonyloxy groups such as acetoxy, ethylcarbonyloxy and isopropylcarbonyloxy groups; arylcarbonyloxy groups such as benzoyloxy groups; aralkylcarbonyloxy groups such as phenylmethylcarbonyloxy groups Examples of the acyl group include C1-C12 alkylcarbonyl groups such as propanoyl and isopropylcarbonyl groups, and alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, and t-butoxycarbonyl groups; Arylcarbonyl groups such as benzoyl group; aralkylcarbonyl groups such as phenylmethylcarbonyl group; and the like.
Examples of the heterocyclic group include oxygen-containing heterocyclic groups such as furanyl, pyranyl and dioxolanyl groups; sulfur-containing heterocyclic groups such as thienyl groups; pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl, isothiazolyl, pyridyl, And saturated or unsaturated nitrogen-containing heterocyclic groups such as pyradadyl, pyrazinyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, quinolyl, anthranyl, indolyl, and phenanthronylyl groups.
These substituents are not particularly limited in the position of substitution, the type of substituent, the number of substituents, and the like. In addition, the benzene rings of the exemplified condensed ring ketones may be replaced with other condensed rings which may have these substituents.
Furthermore, the above-described substituent may further have a substituent as long as the reaction is not inhibited. Examples of such substituents include halogen atoms such as fluorine, chlorine and bromine; hydroxyl groups; carboxyl groups; amino groups; methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl, hexyl groups and the like. C1-C6 alkyl group; C1-C6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy group; methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl group A C1-C6 alkoxycarbonyl group such as: a phenyl group which may have a substituent at any position of the benzene ring; a 1-naphthyl, 2-naphthyl which may have a substituent at any position of the naphthalene ring; A naphthyl group such as a group having a substituent at any position on the ring Furan, pyran, dioxolane, dioxane, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, triazole, thiazole, isothiazole, pyridine, pyridazine, pyrazine, benzimidazole, benzopyrazole, benzothiazole, quinoline, etc. A heterocyclic group; and the like.
Next, α-amino ketones (5) will be described.
In the formula, Ra and Rc are each independently a hydrogen atom; optionally substituted methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, t -C1-C20 alkyl group such as pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl group; vinyl, 1-propenyl, 2-propenyl, 1-isopropenyl, 1-butenyl which may have a substituent A C2-C20 alkenyl group such as 1-isopropenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl group; A C3-C8 cycloalkyl group such as propyl, cyclobutyl, cyclopentyl, cyclohexyl group; may have a substituent; C7-C20 aralkyl groups such as benzyl, α-methylbenzyl, α, α-dimethylbenzyl and α-ethylbenzyl groups; aryl groups such as phenyl, 1-naphthyl and 2-naphthyl groups which may have a substituent Represents a heterocyclic group which may have a substituent.
Examples of such heterocyclic groups include oxygen-containing heterocyclic groups such as furanyl, pyranyl and dioxolanyl groups; sulfur-containing heterocyclic groups such as thienyl groups; pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl, isothiazolyl, pyridyl, And saturated or unsaturated nitrogen-containing heterocyclic groups such as pyradadyl, pyrazinyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, quinolyl, anthranyl, indolyl, and phenanthronylyl groups.
As the substituent of the alkyl group, alkenyl group, cycloalkyl group, aralkyl group, aryl group and heterocyclic group, as long as the substituent does not inhibit this reaction, its substitution position, type of substituent, substitution There is no particular limitation on the number of groups. Specific examples thereof include halogen atoms such as fluorine, chlorine and bromine; hydroxyl groups; carboxyl groups; amino groups; C1-C1 such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl and hexyl groups. C6 alkyl group; C1-C6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy group; methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl group, etc. A C1-C6 alkoxycarbonyl group; a phenyl group which may have a substituent at any position on the benzene ring; a substituent at any position on the naphthalene ring (1-naphthyl, 2-naphthyl group, etc.) ) Naphthyl group; may have a substituent at any position of the ring Heterocycle (furan, pyran, dioxolane, dioxane, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, triazole, thiazole, isothiazole, pyridine, pyridazine, pyrazine, benzimidazole, benzopyrazole, benzothiazole, quinoline, etc.) Group; etc. are mentioned.
Rb is the formula (6): R9CO (R11) N-, formula (7): R9CO (R10CO) N-, formula (8): R9R11N- represents one of the groups.
Where R9, R10And R11Each independently represents a hydrogen atom; a C1-C20 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, heptyl group; methoxy; C1-C20 alkoxy group which may have a substituent such as ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy, hexyloxy group, etc. C3-C8 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups; C3-C8 cycloalkoxy groups such as cyclopentyloxy, cyclohexyloxy, and heptyloxy groups; C1-C20 alkenyl groups that may have a substituent; C7-C20 aralkyl group which may have a substituent such as benzyl, 4-chlorobenzyl and α-methylbenzyl group; a substituent such as benzyloxy, 4-chlorobenzyloxy and 4-methylbenzyloxy group C7-C20 aralkyloxy group which may be substituted; aryl group which may have a substituent such as phenyl, 1-naphthyl and 2-naphthyl group; substituent such as benzoyloxy, 1-naphthyloxy and 2-naphthyloxy group Represents an aryloxy group which may have
In the present invention, when Rc is a substituent other than a hydrogen atom, Rb is a group represented by the formula (6),11Is a hydrogen atom and R9When is an alkoxy group, a cycloalkoxy group, an aryloxy group or an aralkyloxy group, an optically active amino alcohol having an anti-configuration is preferentially obtained. Therefore, in order to obtain an optically active amino alcohol having a syn configuration, it is necessary to select a combination of other substituents.
Here, the syn configuration means a configuration in which when a carbon chain is placed as a main chain in a zigzag in the left-right direction, the amino group to be substituted in the vertical direction and the hydroxyl respectively face the same plane. The configuration means a configuration in which the amino group and the hydroxyl group are opposite to each other.
As the substituent of the alkoxy group, alkenyl group, aralkyl group, aralkyloxy group, aryl group and aryloxy group, the substitution position, the type of substituent, and the substitution, as long as the substituent does not inhibit this reaction There is no particular limitation on the number of groups. Specific examples thereof include halogen atoms such as fluorine, chlorine and bromine; hydroxyl groups; carboxyl groups; amino groups optionally having substituents such as amino, methylamino and acetylamino; methyl, ethyl, propyl, isopropyl, C1-C20 alkyl group such as butyl, sec-butyl, t-butyl, pentyl, hexyl group; C1-C20 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy group; methoxycarbonyl, ethoxycarbonyl , Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl group, etc., C1-C20 alkoxycarbonyl group; phenyl group which may have a substituent at any position of benzene ring; at any position of naphthalene ring May have a substituent (1-naphthyl A naphthyl group (such as 2-naphthyl group); may have a substituent at any position of the ring (furan, pyran, dioxolane, dioxane, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, triazole, thiazole , Heterocyclic groups such as isothiazole, pyridine, pyridazine, pyrazine, benzimidazole, benzopyrazole, benzothiazole, quinoline, etc.
R9And R10Toga or R9And R11And may form a 5- to 8-membered nitrogen-containing heterocycle. Examples of such a heterocyclic ring include imides such as succinimide, maleimide, phthalimide, 1,2-cyclohexanecarboxamide, 2,4,6-trioxopiperidine, α-pyridone, and the like.
Specific examples of Rb include acetylamino, propionylamino, propylcarbonylamino, benzoylamino, 4-methylbenzoylamino, 2-chlorobenzoylamino, 3-methoxybenzoylamino, 2-chloro-4-methoxybenzoylamino group and the like. Acylamino groups; diacylamino groups such as diacetylamino and dibenzoylamino groups; N-acetyl-N-methylamino, N-benzoyl-N-methylamino, N-acetyl-N-ethylamino, N-benzoyl-N-ethyl N-alkyl-N-acylamino groups such as amino, N-acetyl-N-benzylamino, N-benzoyl-N-benzylamino, 4-methylbenzoylmethylamino group; N-acetyl-N-phenylamino, N-acetyl -N-4-methylphanylamino, N- Cetyl-N-2-chlorophenylamino, N-acetyl-N-2,4-dichlorophenylamino, N-benzyl-N-phenylamino, N-benzyl-N-4-methylphenylamino, N-benzyl-N-2 N-aryl-N-acylamino groups such as chlorophenylamino and N-benzyl-N-2,4-dichlorophenylamino groups; N-methoxycarbonyl-N-methylamino, N-ethoxycarbonyl-N-methylamino, N- Methoxycarbonyl-N-ethylamino, N-ethoxycarbonyl-N-ethylamino, N-propoxycarbonyl-N-propylamino, N-isopropoxycarbonyl-N-methylamino, N-butoxycarbonyl-N-ethylamino, N N-alkoxy such as t-butoxycarbonyl-N-butoxyamino group Aryloxycarbonyl -N- alkylamino group;
N-methoxycarbonyl-N-methylamino, N-ethoxycarbonyl-N-methylamino, N-methoxycarbonyl-N-ethylamino, N-ethoxycarbonyl-N-ethylamino, N-propoxycarbonyl-N-propylamino, N- such as N-isopropoxycarbonyl-N-methylamino, N-butoxycarbonyl-N-ethylamino, Nt-butoxycarbonyl-N-methylamino group, Nt-butoxycarbonyl-N-butoxyamino group, etc. Alkoxycarbonyl-N-alkylamino group; N-methoxycarbonyl-N-phenylamino, N-ethoxycarbonyl-N-phenylamino, N-propoxycarbonyl-N-phenylamino, N-isopropoxycarbonyl-N-phenylamino, N-butoxycarbonyl-N-fu Niruamino, N- alkoxycarbonyl -N- arylamino groups such as N-t-butoxycarbonyl -N- phenylamino group;
N-methyl-methylsulfonylamino, N-ethyl-methylsulfonylamino, N-propyl-methylsulfonylamino, N-isopropyl-methylsulfonylamino, N-benzyl-methylsulfonylamino, N-butyl-methylsulfonylamino, N- Methyl-ethylsulfonylamino, N-ethyl-ethylsulfonylamino, N-methyl-propylsulfonylamino, N-ethyl-propylsulfonylamino, N-methyl-isopropylsulfonylamino, N-ethyl-isopropylsulfonylamino, N-methyl- N-alkyl-alkylsulfonylamino groups such as butylsulfonylamino, N-ethyl-butylsulfonylamino, N-methyl-t-butylsulfonylamino, N-ethyl-t-butylsulfonylamino; N-methyl- Phenylsulfonylamino, N-ethyl-phenylsulfonylamino, N-benzyl-phenylsulfonylamino, N-methyl-4-methylphenylsulfonylamino, N-benzyl-4-methylphenylsulfonylamino, N-ethyl-2-chlorophenylsulfonyl N-alkyl-substituted phenylsulfonylamino groups such as amino and N-methyl-2,4-dichlorophenylsulfonylamino groups;
N-phenyl-methylsulfonylamino, N-phenyl-ethylsulfonylamino, N-phenyl-propylsulfonylamino, N-phenyl-isopropylsulfonylamino, N-phenyl-butylsulfonylamino, N-phenyl-t-butylsulfonylamino, etc. N-aryl-alkylsulfonylamino group of N-phenyl-phenylsulfonylamino, N-phenyl-4-methylphenylsulfonylamino, N-phenyl-2-chlorophenylsulfonylamino, N-phenyl-2,4-dichlorophenylsulfonylamino N-aryl-substituted phenylsulfonylamino groups such as succinimidyl group, maleimidoyl group, phthalimidoyl group, 3-methylphthalimidoyl group, 4-methylphthalimidoyl group, 4-n-butyl group Such as ruimidoyl group, 4-chlorophthalimidoyl group, tetramethylphthalimidoyl group, 1,2-cyclohexanecarboxamidoyl group, 2,4,6-trioxopiperidin-1-yl group, α-pyridone-1-yl group, etc. An imide group etc. can be mentioned.
The condensed ketones and α-amino ketones as described above can be produced and obtained by known methods.
Next, the asymmetric hydrogenation reaction will be described.
In the asymmetric hydrogenation reaction, the above-mentioned condensed ketones (3), (3 ′) or α-amino ketones (5) serving as a substrate are optionally formed in the presence of a ruthenium compound represented by the formula (1). This is carried out by adding a base and performing asymmetric reduction in the presence of hydrogen gas or a hydrogen donor at a predetermined pressure.
In the present invention, (1) a ruthenium complex (or ruthenium salt), a phosphorus compound and a diamine compound as raw materials for the ruthenium compound are separately added to the reaction system, or (2) a ruthenium complex having a phosphine ligand. (Or a ruthenium salt) and a diamine compound are separately added to the reaction system, and a base is added as necessary to form a ruthenium compound. Then, the ruthenium compound is removed from the reaction system without taking out the substrate. Can be added to carry out the asymmetric hydrogenation reaction in situ.
The amount of the ruthenium compound represented by the formula (1) used as a catalyst varies depending on the size of the reaction vessel and the catalytic activity, but is usually 1 / (relative to the condensed ketones or α-diaminoketones which are reaction substrates). The range is 50 to 1 / 2,000,000 times mole, preferably 1/500 to 1 / 500,000 times mole.
Examples of the base used include organic bases such as triethylamine, diisopropylethylamine, pyridine, DABCO and DBU; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, magnesium methoxide and magnesium ethoxide; n Organic lithium compounds such as butyl lithium; lithium amides such as LDA and lithium bistrimethylsilylamide; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkalis such as magnesium hydroxide and calcium hydroxide Earth metal hydroxides; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkalis such as magnesium carbonate and calcium carbonate S metal carbonate; sodium hydride, metal hydrides such as calcium hydride; and the like.
The amount of the base to be added is usually in the range of 2 to 500,000 times mol, preferably 2 to 5,000 times mol, of the ruthenium compound.
The solvent is not particularly limited as long as it can solubilize the substrate and the catalyst. Specific examples thereof include alcohols such as methanol, ethanol, n-propanol, isopropanol, butanol and benzyl alcohol; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as pentane and hexane; dichloromethane Halogen ethers such as chloroform, trichloromethane, carbon tetrachloride, 1,2-dichloroethane; ethers such as diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane; DMF, N, N— Use amides such as dimethylacetamide, 1,3-dimethylimidazolidine, 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone and HMPT; nitriles such as acetonitrile and benzonitrile; use DMSO and the like Can do. These solvents can be used alone or in admixture of two or more. Among these solvents, the use of alcohols is preferred because the reaction product is an alcohol compound.
The amount of solvent used depends on the solubility and economics of the ketones represented by formula (3), (3 ′) or (5), and in some cases, the reaction proceeds even without solvent or near high dilution conditions. However, it is usually in the range of 0.1 to 10,000 parts by weight, preferably 20 to 1,000 parts by weight with respect to 100 parts by weight of the ketones.
The pressure of hydrogen is usually in the range of 1 to 200 atm, preferably 3 to 50 atm. As the hydrogen donor, for example, a hydrogen storage alloy or diimide can be used. It is usually in the range of 1 to 100 times equivalent to the ketones represented by 3), (3 ′) or (5).
The reaction temperature is usually in the temperature range of −50 to 100 ° C., preferably 25 to 40 ° C. Moreover, although reaction time is dependent on reaction conditions, such as a reaction substrate density | concentration, temperature, and pressure, it is normally several minutes-several days. Although there is no restriction | limiting in particular as a reaction format, For example, it can implement also in a batch type and a continuous type.
After completion of the reaction, the desired product can be obtained by isolation and purification by ordinary organic synthetic chemical techniques. The structure of the object is1It can be determined by known analytical means such as H-NMR, optical rotation measurement, liquid chromatography, gas chromatography and the like.
Best Mode for Carrying Out the Invention:
EXAMPLES Next, although an Example demonstrates this invention in detail, this invention is not limited only to these. In addition, the apparatus used for the measurement of the physical property in each Example is as follows.
NMR spectrum: Varian GEMINI-300 (300 MHz), manufactured by Varian
Optical rotation: JASCO DIP-360, manufactured by JASCO Corporation
High performance liquid chromatography: LC-10Advp, SPD-10Avp, manufactured by Shimadzu Corporation
Gas chromatography: GC-17A, C-R7A Plus, manufactured by Shimadzu Corporation
Example 1 (R, R) -1,4-diamino-1,4-diphenylbutane hydrochloride
(Process 1)Production of (S, S) -1,4-dihydroxy-1,4-diphenylbutane
A solution of 0.477 g (2 mmol) of 1,4-dioxo-1,4-diphenylbutane in 3 ml of isopropanol, 5 ml of toluene and 0.2 ml of potassium hydroxide isopropanol solution (1M) was mixed and degassed, [(R) -Xylyl -BINAP] RuCl2[(R) -1,1'-dianisyl-2-isopropyl-1,2-ethylenediamine {abbreviated as (R) -DAIPEN: Am. Chem. Soc. , 120, 13529 (1998)}] 12 mg (0.01 mmol) was added. Thereafter, hydrogen was injected to 8 atm and stirred at room temperature for 18 hours. The reaction solution was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to obtain 0.43 g of the desired (S, S) -1,4-dihydroxy-1,4-diphenylbutane. Yield 90%
(Process 2)Production of (R, R) -1,4-diazide-1,4-diphenylbutane
(S, S) -1,4-dihydroxy-1,4-diphenylbutane 0.55 g (2.27 mmol) and DBU 0.7 ml (2.72 mmol) in toluene 6 ml solution 1.78 g (2.72 mmol) of diphenylphosphoryl azide ) Was added at 0 ° C. with stirring. After stirring at room temperature for 18 hours, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated, and the residue obtained is purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to obtain the desired (R, R) -1,4. -0.21 g of diazide-1,4-diphenylbutane was obtained. Yield 32%
1H-NMR (CDCl3, Δ ppm): 7.5-7.3 (m, 10H), 4.4 (t, 2H), 1.9 (m, 2H), 1.7 (m, 2H)
(Process 3)Production of (1R, 4R) -1,4-diamino-1,4-diphenylbutane hydrochloride
To a 6 ml ethanol solution of 0.21 g (0.83 mmol) of (R, R) -1,4-diazide-1,4-diphenylbutane, 0.1 g of 5% palladium carbon was added, and the reaction system was replaced with hydrogen. The mixture was stirred at room temperature and normal pressure for 48 hours. After completion of the reaction, insolubles were filtered off from the reaction solution, concentrated hydrochloric acid was added to the filtrate, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethyl acetate and dried to obtain 0.1 g of the desired (1R, 4R) -1,4-diamino-1,4-diphenylbutane hydrochloride. Yield 37%
1H-NMR (DMSO-d6, Δ ppm): 8.6 (s, 6H), 7.4 (s, 10H), 4.2 (m, 2H), 2.0 (m, 2H), 1.5 (m, 2H)
[Α]D 24= -10.1 [deg.] (C = 1.0, MeOH)
Example 2 (1R, 4R) -1,4-diamino-1,4-dicyclohexylbutane
Dissolve 0.2 g of (1R, 4R) -1,4-diamino-1,4-diphenylbutane in 3 ml of methanol in an autoclave, add rhodium / alumina catalyst, and stir for 5 hours at room temperature under hydrogen pressure of 10 atm. did. The desired product was quantitatively obtained by filtering the catalyst and concentrating the filtrate. In Table 111 H-NMR data is shown.
Example 3 (2R, 3R, 4R, 5R) -3,4-O-isopropylidene-3,4-dihydro Xi-2,5-diaminohexane
(Process 1)(2R, 3R, 4R, 5R) -3,4-O-isopropylidene-3,4-dihydro Production of xyl-2,5-diazidehexane
(2S, 3R, 4R, 5S) -3,4-O-isopropylidene-3,4-dihydroxy-2,5-hexanediol bismethanesulfonate (1.52 g, 4.4 mmol) in DMSO (15 ml) After dissolution, sodium azide (1.27 g, 17.5 mmol) was added and stirred at 50 degrees for 24 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated, and the residue obtained was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to obtain 0.71 g of a diazide. Yield 67%.
(Process 2)(2R, 3R, 4R, 5R) -3,4-O-isopropylidene-3,4-dihydroxy Production of cis-2,5-diaminohexane
0.71 g of 3,4-O-isopropylidene- (3R, 4R) -dihydroxy- (2R, 5R) -diazidehexane is dissolved in 5 ml of methanol, 0.1 g of 5% palladium carbon is added, and the reaction system is replaced with hydrogen. The mixture was stirred at room temperature and normal pressure for 24 hours. After completion of the reaction, insoluble matters were filtered off from the reaction solution, and the residue obtained by concentrating the filtrate was distilled with a Kugelrohr (160 ° / 5 mmHg) to obtain 0.49 g of the desired product. Yield 88%
1H-NMR (CDCl3, Δ ppm): 3.68 (m, 2H), 3.0 (m, 2H), 1.46 (bs, 4H), 1.39 (s, 6H), 1.16 (d, J = 6. 4Hz, 6H)
[Α]D 23= 28.9 ° (c = 1.4, MeOH)
The diamine compounds of the present invention obtained in the same manner as in the above examples are shown in Table 1.
Example 4 RuCl 2 [(S) -Tol-BINAP] [(2R, 5R) -2,5-diaminohe Xan)
After adding 2 ml of isopropanol and 5 mg (0.025 mmol) of (2R, 5R) -2,5-diaminohexane in a Schlenk tube and degassing, RuCl2[(S) -Tol-BINAP] DMF adduct 25 mg (0.025 mmol) was added and dissolved. The target product was obtained by distilling off the solvent under reduced pressure.
Of this compound31P-NMR (CDCl3), A singlet peak was observed at 43.9 ppm.
Example 5 RuCl 2 [(R) -Tol-BINAP] [(1R, 4R) -1,4-diamino- 1,4-diphenylbutane]
After adding 2 ml of isopropanol and 8 mg (0.025 mmol) of (1R, 4R) -1,4-diamino-1,4-diphenylbutane in a Schlenk tube and degassing, RuCl2[(R) -Tol-BINAP] DMF adduct 25 mg (0.025 mmol) was added and dissolved. The solvent was distilled off under reduced pressure to obtain the desired product.
Of this compound31P-NMR (CDCl3), A singlet peak was observed at 44.6 ppm.
Example 6 RuCl 2 [(S) -binap] [(2R, 3R, 4R, 5R) -3,4-O-i Sopropylidene-3,4-dihydroxy-2,5-diaminohexane]
5 ml of isopropanol degassed in a Schlenk tube, 50 mg (0.266 mmol) of (2R, 3R, 4R, 5R) -3,4-O-isopropylidene-3,4-dihydroxy-2,5-diaminohexane, [RuCl 2 (Cymene)] 282 mg (0.134 mmol) was added, and the mixture was stirred under reflux for 30 minutes. Subsequently, 166 mg (0.266 mmol) of (S) -BINAP was added and stirred for 45 minutes under reflux. After cooling, hexane was added and the precipitated crystals were separated by filtration to obtain the desired product.
Of this compound31As a result of measuring P-NMR (CDCl3), a singlet peak was observed at 45.4 ppm.
Example 7 Production of (R) -1,2,3,4-tetrahydro-1-naphthol
(2R, 5R) -2,5-diaminohexane hydrochloride 1 mg (0.005 mmol), tetralone 0.37 g (2.5 mmol), potassium hydroxide isopropanol solution in a simple autoclave (capacity 100 ml) under argon atmosphere (1M) 75 μl and isopropanol 1.5 ml were added at room temperature, degassed and then RuCl25 mg (0.005 mmol) of a DMF adduct of [(S) -Tol-BINAP] was added. Hydrogen was injected into the reaction system to 8 atm and stirred at room temperature for 1.5 hours. The reaction mixture was purified by silica gel column chromatography (eluent: diethyl ether) to obtain an optical isomer mixture. Conversion rate 64%
The optical purity of this product was measured by gas chromatography (mobile phase: helium, column: CP-Chiralcel-Dex CB, manufactured by Chrome Pack Co., Ltd.) and found to be 91% ee.
Table 2 shows the optical purity (% ee) of the reaction product when the raw material tetralone was changed under the same conditions as in Example 7.
Example 8 Production of (S) -1,2,3,4-tetrahydro-1-naphthol
(S, S) -2,4-diaminopentane hydrochloride in a simple autoclave (capacity 100 ml) under an argon atmosphere. After adding mg (0.005 mmol), tetralone 0.37 g (2.5 mmol), potassium hydroxide isopropanol (1M) 75 μl and isopropanol 3 ml at room temperature and degassing, RuCl25 mg (0.005 mmol) of a DMF adduct of [(R) -Tol-BINAP] was added. Hydrogen gas was injected into the reaction system to 8 atm and stirred at room temperature for 1.5 hours, and then the reaction mixture was purified by silica gel column chromatography (eluent: diethyl ether) to obtain an optical isomer mixture. Conversion 83%.
The optical purity of this product was measured by high performance liquid chromatography (mobile phase: hexane / isopropanol = 9/1, column: Chiralcel OB, manufactured by Daicel Chemical Industries, Ltd.) and found to be 75% ee.
Table 3 shows the conversion rate (%) and optical purity% ee of (S) -1,2,3,4-tetrahydro-1-naphthol obtained by changing the diamine under the same conditions as in Example 8. Indicated.
Example 9 Production of optically active 7-methoxy-1,2,3,4-tetrahydro-1-naphthol
In a simple autoclave (capacity 100 ml), 0.19 g (1 mmol) of 7-methoxy-1-tetralone, RuCl2 [(R) -binap] [(1R, 4R) -1,4-diphenylbutane-1,4- After adding 5 mg (0.005 mmol) of diamine] and purging with argon, 2.5 ml of deaerated isopropanol and 100 μl of potassium hydroxide isopropanol solution (1M) were added. Hydrogen was injected into the reaction system to 8 atm and stirred at room temperature for 1.5 hours. The reaction mixture was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to quantitatively obtain an optical isomer mixture.
When the optical purity of this product was measured by high performance liquid chromatography (mobile phase: hexane / isopropanol = 92/8, column: Chiralcel OD-H, manufactured by Daicel Chemical Industries, Ltd.), it was 92% ee.
Example 10 Preparation of optically active 5-methoxy-1,2,3,4-tetrahydro-1-naphthol Construction
In a simple autoclave (capacity 100 ml), 0.41 g (2.5 mmol) of 5-methoxy-1-tetralone, 5 mg (0.005 mmol) of RuCl2 [(S) -binap] [(2R, 5R) -diaminohexane] Then, 2 ml of degassed isopropanol and 100 μl of potassium hydroxide isopropanol solution (1M) were added. Hydrogen was injected into the reaction system to 8 atm and stirred at room temperature for 2 hours. The reaction mixture was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to obtain 0.36 g of an optical isomer mixture. Yield 87%
The optical purity of this product was measured by high performance liquid chromatography (mobile phase: hexane / isopropanol = 9/1, column: Chiralcel OB, manufactured by Daicel Chemical Industries, Ltd.) and found to be 95% ee.
Example 11 optically active cis-2-methyl-1,2,3,4-tetrahydro-1-naphthol Manufacturing
RuCl in a simple autoclave (capacity 100 ml)2After adding 5 mg (0.005 mmol) of [(S) -binap] [3,4-O-isopropylidene- (3R, 4R) -dihydroxy- (2R, 5R) -diaminohexane] and purging with argon, A solution prepared by dissolving 100 μl of potassium hydroxide isopropanol solution (1M) and 0.16 g (1 mmol) of 2-methyl-1-tetralone in 5 ml was added after deaeration. Hydrogen was injected into the reaction system to 8 atm and stirred at room temperature for 2 hours.
When this product was measured by gas chromatography (mobile phase: helium, column: βDEX325, manufactured by Spelco), the conversion was> 99%, 98% de, 88% ee.
Comparative Example 1
The experiment was performed under the same conditions as in Example 10 except that (R) -Xylyl-BINAP was used as the phosphine ligand and (1R, 2R) -diphenylethylenediamine was used as the diamine. The conversion rates were 26%, 26% de, 84% ee (cis isomer), and 33% ee (trans isomer).
Example 12 Optically Active-1-Phenyl-2- (N-methyl-N-benzoylamino) -1-propyl Production of lopanol
In a simple autoclave (capacity 100 ml) under an argon atmosphere, 2.2 mg (0.0125 mmol) of (2R, 5R) -2,5-diaminohexane hydrochloride, 1-phenyl-2- (N-methyl-N— Benzoyl) aminopropan-1-one (0.67 g, 2.5 mmol), 0.1 N of t-butoxypotassium in 1.5 ml of isopropanol and 5 ml of isopropanol were added at room temperature, deaerated, and then RuCl.212.5 mg (0.0125 mmol) of a DMF adduct of [(S) -Tol-BINAP] was added. Hydrogen was injected into the reaction system up to 12 atm and stirred at 25 ° C. for 1 hour, and then the reaction mixture was purified by silica gel column chromatography (eluent: diethyl ether) to give optically active-1-phenyl-2- 0.65 g of (N-methyl-N-benzoylamino) -1-propanol was obtained. Yield 97%
The optical purity and diastereomeric purity of this product were measured by high performance liquid chromatography (mobile phase: hexane / ethanol = 15/1, column: Chiralcel OJ, manufactured by Daicel Chemical Industries, Ltd.). The optical purity was 89% ee. The diastereomeric purity was 99% de or higher.
Example 13 Optically Active-1-Phenyl-2- (N-methyl-N-benzoylamino) -1-propyl Production of lopanol
Under an argon atmosphere, 3.6 mg (0.01 mmol) of (1R, 4R) -1,4-diphenylbutane-1,4-diamine, 1-phenyl-2- (N— After adding 0.53 g (2 mmol) of methyl-N-benzoyl) aminopropan-1-one, 100 μl of potassium hydroxide isopropanol (1M) and 5 ml of isopropanol at room temperature and degassing, RuCl210 mg (0.01 mmol) of the DMF adduct of [(R) -Tol-BINAP] was added. Hydrogen gas was injected into the reaction system to 12 atm and stirred at 25 ° C. for 1 hour, and then the reaction mixture was purified by silica gel column chromatography (eluent: diethyl ether) to obtain optically active-1-phenyl-2. 0.5 g of-(N-methyl-N-benzoylamino) -1-propanol was obtained. Yield 94%
When the optical purity and diastereomeric purity of this product were measured by high performance liquid chromatography (mobile phase: hexane / ethanol = 15/1, column: Chiralcel OJ, manufactured by Daicel Chemical Industries, Ltd.), the optical purity was 94% ee. Yes, the diastereomeric purity was 99% de or higher.
Example 14 Optically Active-1-Phenyl-2- (N-methyl-N-benzoyl) amino-1-propyl Production of lopanol
13.4 g (50 mmol) of 1-phenyl-2- (N-methyl-N-benzoyl) aminopropan-1-one and 50 ml of isopropanol were added to a simple autoclave (capacity 100 ml) and deaerated, and the atmosphere was replaced with an argon atmosphere. . To this was added RuCl2 [(S) -binap] [3,4-O-isopropylidene- (3R, 4R) -dihydroxy- (2R, 3 ml of degassed 1M potassium hydroxide in 0.5 ml of isopropanol and 3 ml of isopropanol. 5R) -Diaminohexane] 2.5 mg (0.0025 mmol) was added at room temperature, and a catalyst solution prepared by stirring for a while was added. Hydrogen was injected into the reaction system to 100 atm and stirred at 25 ° C. for 18 hours, and then the conversion rate, optical purity and diastereomeric purity were measured by high performance liquid chromatography (mobile phase: hexane / ethanol / isopropanol = 80/10). / 10, column: Chiralcel OJ, manufactured by Daicel Chemical Industries, Ltd.), conversion was 90%, optical purity was 95% ee, and diastereomeric purity was 99% de or higher.
9.86 g of optically pure (1R, 2R) -1-phenyl-2- (N-methyl-N-benzoyl) amino-1-propanol was obtained by recrystallizing this from a hexane-isopropanol mixed solvent. It was. Yield 74%.
Example 15 (1S, 2S, 3S, 4S) -2,3-O-isopropylidene- (2,3) -dihi Droxy- (1,4) -diamino- (1,4) -diphenylbutane
(Process 1)(2R, 3R) -2,3-O-isopropylidene-2,3-dihydroxy-1,4- Production of diphenyl-1,4-butanedione
2R, 3R-O-isopropylidene tartaric acid bis N, O-dimethylhydroxylamide (2.0 g, 7.25 mmol) was dissolved in THF (50 ml), and 30 ml (30 mmol) of a 1M solution of phenylmagnesium bromide was added at 0 ° C. And stirred for 2 hours. After completion of the reaction, water was added to the reaction solution, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated, and the residue obtained was purified by silica gel column chromatography (hexane / ethyl acetate = 19 / 1-4 / 1) to obtain 1.87 g of diketone body. . Yield 82%.
(Process 2)(1R, 2S, 3S, 4R) -2,3-O-isopropylidene-2,3-dihydroxy Production of cis-1,4-diphenyl-1,4-butanediol
80 mg (0.25 mmol) of (2R, 3R) -2,3-O-isopropylidene- (2,3) -dihydroxy- (1,4) -diphenyl- (1,4) -butanedione was dissolved in 5 ml of THF, A solution prepared by dissolving 10 mg of sodium borohydride in 5 ml of methanol was added at −78 ° C. and stirred for 1 hour. After completion of the reaction, water was added to the reaction solution, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 19 / 1-2 / 1) to obtain 51 mg of a diol. Yield 64%.
(Process 3)(1R, 2S, 3S, 4R) -2,3-O-isopropylidene-2,3-dihydroxy Production of bis-1,4-diphenyl-1,4-butanediol bismethanesulfonate
80 mg (0.25 mmol) of (1R, 2S, 3S, 4R) -2,3-O-isopropylidene- (2,3) -dihydroxy- (1,4) -diphenyl- (1,4) -butanediol Dissolved in 1 ml of dichloromethane and 1 ml of pyridine, methanesulfonic anhydride was added at 0 degree and stirred at room temperature for 18 hours. After completion of the reaction, water was added to the reaction solution, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4 / 1-2 / 1) to obtain 88 mg of a diol. Yield 75%.
(Process 4)(1S, 2S, 3S, 4S) -2,3-O-isopropylidene-2,3-dihydroxy Production of -1,4-diazide-1,4-diphenylbutane
(1R, 2S, 3S, 4R) -2,3-O-isopropylidene- (2,3) -dihydroxy- (1,4) -diphenyl- (1,4) -butanediol bismethanesulfonate 1.03 g (2.19 mmol) was dissolved in 20 ml of DMSO, 5.5 g (84.6 mmol) of sodium azide was added, and the mixture was stirred at 60 ° C. for 18 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated, and the residue obtained was purified by silica gel column chromatography (hexane / ethyl acetate = 10 / 1-4 / 1) to obtain 0.61 g of diazide. . Yield 77%.
(Process 5)(1S, 2S, 3S, 4S) -2,3-O-isopropylidene-2,3-dihydroxy Production of -1,4-diamino-1,4-diphenylbutane
0.61 g of (1S, 2S, 3S, 4S) -2,3-O-isopropylidene- (2,3) -dihydroxy- (1,4) -diazido- (1,4) -diphenylbutane in 10 ml of methanol After dissolution, 0.5 g of 5% palladium carbon was added and stirred at room temperature for 24 hours under a hydrogen atmosphere of 1 atm. After completion of the reaction, insoluble matters were filtered off from the reaction solution, and the filtrate was concentrated. The residue obtained was recrystallized from methanol / diethyl ether to obtain 0.122 g of the desired product. Yield 23%.
1H-NMR (CDCl3, Δ ppm): 7.26 (m, 10H), 4.17 (m, 2H), 3.95 (m, 2H), 1.16 (s, 6H)
[Α]D 28= -42.5 [deg.] (C = 0.2, MeOH)
1,4-diamine synthesized by the synthesis method of Examples 3 and 15 above
Example 16 RuCl 2 [(R) -binap] [(1S, 2S, 3S, 4S) -2,3-O-iso Propyridene-2,3-dihydroxy-1,4-diamino-1,4-diphenylbutane]
2 ml of isopropanol in a Schlenk tube, (1S, 2S, 3S, 4S) -2,3-O-isopropylidene- (2,3) -dihydroxy- (1,4) -diamino- (1,4) -diphenylbutane After adding 7.8 mg (0.025 mmol) and degassing, RuCl2[(R) -BINAP] DMF adduct 25 mg (0.025 mmol) was added and dissolved. The solvent was distilled off under reduced pressure to obtain the desired product.
Of this compound31P-NMR (CDCl3) Was measured, and a singlet peak was observed at 45.0 ppm.
Example 17 (1S, 2S) -1-phenyl-2- (N-methyl-N-benzoylamino) -1- Propanol production
Under an argon atmosphere, in a simple autoclave (capacity 100 ml), 0.10 g (0.38 mmol) of 1-phenyl-2- (N-methyl-N-benzoyl) aminopropan-1-one, potassium hydroxide isopropanol solution ( 0.1M) 1 ml and isopropanol 2 ml at room temperature, degassed and then RuCl2[(R) -binap] [(1S, 2S, 3S, 4S) -2,3-O-isopropylidene-2,3-dihydroxy-1,4-diamino-1,4-diphenylbutane] 3 mg (0. 003 mmol) was added. Hydrogen was injected into the reaction system to 10 atm and stirred at 25 ° C. for 1 hour, and then the reaction mixture was purified by silica gel column chromatography (eluent: diethyl ether) to obtain an optical isomer mixture. Conversion rate is 99% or more.
The optical purity and diastereomeric purity of this product were measured by high performance liquid chromatography (mobile phase: hexane / ethanol / isopropanol = 8/1/1, column: Chiralcel OJ, manufactured by Daicel Chemical Industries, Ltd.). Was 98% ee, and the diastereomeric purity was 99% de or higher.
Industrial applicability:
As described above, according to the present invention, an easily available ruthenium compound and a diamine compound that can be suitably used as a ligand of the ruthenium compound can be provided.
In addition, by using the ruthenium compound as a catalyst, asymmetric reduction of condensed ring ketones and α-amino ketones can produce corresponding optically active alcohols with high stereoselectivity and high yield. .
Claims (9)
Ru(X)(Y)(Px)n1〔R1R2C#1(NR3R4)−A−R5R6C#2(NR7R8)〕〔式中、X及びYは、それぞれ独立して、水素原子、ハロゲン原子、カルボキシル基、水酸基又はC1〜C20アルコキシ基を表し、Pxは、ホスフィン配位子を表し、R1〜R8はそれぞれ独立して、水素原子、置換基を有してもよいC1〜C20アルキル基、置換基を有してもよいC2〜C20アルケニル基、置換基を有してもよいC3〜C8シクロアルキル基、置換基を有してもよいC7〜C20アラルキル基又は置換基を有してもよいアリール基を示し、
また、R1とR3、および/または、R5とR7が結合して環を形成してもよく、
Aは、置換基を有していてもよいC1〜C8アルキレン、置換基を有していてもよい1〜2個の酸素原子を含むC2〜C8アルキレン、置換基を有していてもよいC3〜C8シクロアルキレン、置換基を有していてもよいアリーレンまたは置換基を有していてもよい2価のヘテロ環基を表す。Aがアルキレンの場合はR2とR6が結合して環を形成してもよい。
また、Aを構成する炭素原子、C#1およびC#2のいずれか少なくとも一個が、光学活性を有する炭素である。
n1は1または2の整数を示す。〕で表されるルテニウム化合物。Formula (1):
Ru (X) (Y) ( Px) n 1 [R 1 R 2 C # 1 ( NR 3 R 4) -A-R 5 R 6 C # 2 (NR 7 R 8) ) (wherein, X and Y Each independently represents a hydrogen atom, a halogen atom, a carboxyl group, a hydroxyl group or a C1-C20 alkoxy group, Px represents a phosphine ligand, R 1 to R 8 each independently represent a hydrogen atom, A C1-C20 alkyl group that may have a substituent, a C2-C20 alkenyl group that may have a substituent, a C3-C8 cycloalkyl group that may have a substituent, or a substituent. A C7-C20 aralkyl group or an aryl group which may have a substituent,
R 1 and R 3 and / or R 5 and R 7 may combine to form a ring,
A is a C1-C8 alkylene which may have a substituent, a C2-C8 alkylene containing 1 to 2 oxygen atoms which may have a substituent, and C3 which may have a substituent. -C8 cycloalkylene, the arylene which may have a substituent, or the bivalent heterocyclic group which may have a substituent is represented. When A is alkylene, R 2 and R 6 may be bonded to form a ring.
Further, at least one of carbon atoms, C # 1 and C # 2 constituting A is carbon having optical activity.
n 1 represents an integer of 1 or 2. ] The ruthenium compound represented by this.
[R1R2C*(NR3R4)−A−R5R6C*(NR3R4)]
〔式中、A、R1、R2、R3、R4、R5、R6は請求項1と同じ意味を示し、
*は光学活性を有する原子であることを示す。〕で表される化合物である、請求項1記載のルテニウム化合物。The diamine in formula (1) is formula (2):
[R 1 R 2 C * ( NR 3 R 4) -A-R 5 R 6 C * (NR 3 R 4)]
[Wherein, A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 have the same meaning as in claim 1,
* Indicates an atom having optical activity. The ruthenium compound of Claim 1 which is a compound represented by this.
〔R1R2C*(NR3R4)−A−R1R2C*(NR3R4)〕
(式中、A、R1、R2、R3、R4、*は請求項2と同じ意味を示す。)で表される化合物である請求項1および2記載のルテニウム化合物。The diamine in formula (1) is represented by formula (2 ′):
[R 1 R 2 C * (NR 3 R 4) -A-R 1 R 2 C * (NR 3 R 4) ]
The ruthenium compound according to claim 1 or 2, which is a compound represented by the formula: wherein A, R 1 , R 2 , R 3 , R 4 and * have the same meaning as in claim 2.
〔式中、R1およびAは前記と同じ意味を示し、*は光学活性を有する原子であることを示す。〕で表される ジアミン化合物。但し、2,4−ペンタンジアミン、2,5−ヘキサンジアミン、(R,R)−1,4−ジフェニルブタン−1,4−ジアミンおよび3,4−O−イソプロピリデンジヒドロキシ−1,4−ブタンジアミンを除く。Formula (2-1): R 1 C * H (NH 2) -A-R 1 C * H (NH 2)
[Wherein, R 1 and A represent the same meaning as described above, and * represents an atom having optical activity. ] The diamine compound represented by this. However, 2,4-pentanediamine, 2,5-hexanediamine, (R, R) -1,4-diphenylbutane-1,4-diamine and 3,4-O-isopropylidenedihydroxy-1,4-butane Excludes diamines.
(式中、a環部は置換基を有してもよい3〜8員炭素環または置換基を有してもよい4〜8員ヘテロ環を表し、b環部は、置換基を有してもよい4〜8員炭素環または置換基を有してもよい5〜8員ヘテロ環を表す。)で表される縮合環ケトン類を、本発明のルテニウム化合物のいずれか1種若しくは2種以上の存在下に、水素ガス又は水素供与体を水素源として用いて不斉水素還元する工程を有することを特徴とする式(4)又は(4’)
(式中、a環部、b環部及び*は前記と同じ意味を表す。)で表される光学活性アルコール類の製造方法。Formula (3) or (3 ′)
(In the formula, the a ring portion represents a 3- to 8-membered carbocyclic ring which may have a substituent or a 4- to 8-membered heterocyclic ring which may have a substituent, and the b-ring portion has a substituent. 4-8-membered carbon ring which may be substituted or a 5- to 8-membered heterocycle which may have a substituent.) The condensed ring ketone represented by any one of ruthenium compounds of the present invention or 2 Formula (4) or (4 ′), which comprises a step of asymmetric hydrogen reduction using hydrogen gas or a hydrogen donor as a hydrogen source in the presence of a species or more
(Wherein a ring part, b ring part and * represent the same meanings as described above).
〔式中、Ra及びRcは、それぞれ独立して、水素原子、置換基を有してもよいC1〜C20アルキル基、置換基を有してもよいC2〜C20アルケニル基、置換基を有してもよいC3〜C8シクロアルキル基、置換基を有してもよいC7〜C20アラルキル基又は置換基を有してもよいアリール基を表す。
Rbは、
式(6):R9CO(R11)N−
式(7):R9CO(R10CO)N−
式(8):R9R11N−
で表されるいずれかの基を表す。
(ここで、R9、R10及びR11は、それぞれ独立して、水素原子、置換基を有してもよいC1〜C20アルキル基、置換基を有してもよいC2〜C20アルケニル基、置換基を有してもよいC1〜C20アルコキシ基、置換基を有してもよいC3〜C8シクロアルキル基、置換基を有してもよいC3〜C8シクロアルコキシ基、置換基を有してもよいC7〜C20アラルキル基、置換基を有してもよいC7〜C20アラルキルオキシ基、置換基を有してもよいアリール基又は置換基を有してもよいアリールオキシ基を表す。
また、R9とR11又はR9とR10は結合して、5〜8員の含窒素ヘテロ環を形成してもよい。)〕
で表されるα−アミノケトン類を、請求項1〜4記載のいずれかのルテニウム化合物の存在下に、水素ガス又は水素供与体を水素源として不斉水素還元する工程を有する、
式(9):Ra−C*H(OH)−CH(Rb)−Rc
〔式中、Ra、Rb、Rc及び*は前記と同じ意味を表す。〕で表される光学活性β−アミノアルコール類の製造方法。Formula (5): Ra-CO-CH (Rb) -Rc
[In the formula, Ra and Rc each independently have a hydrogen atom, a C1-C20 alkyl group that may have a substituent, a C2-C20 alkenyl group that may have a substituent, or a substituent. The C3-C8 cycloalkyl group which may be substituted, the C7-C20 aralkyl group which may have a substituent, or the aryl group which may have a substituent is represented.
Rb is
Equation (6): R 9 CO ( R 11) N-
Equation (7): R 9 CO ( R 10 CO) N-
Formula (8): R < 9 > R < 11 > N-
Represents any group represented by
(Wherein R 9 , R 10 and R 11 are each independently a hydrogen atom, a C1-C20 alkyl group which may have a substituent, a C2-C20 alkenyl group which may have a substituent, A C1-C20 alkoxy group which may have a substituent, a C3-C8 cycloalkyl group which may have a substituent, a C3-C8 cycloalkoxy group which may have a substituent, and a substituent. The C7-C20 aralkyl group which may have a C7-C20 aralkyloxy group which may have a substituent, the aryl group which may have a substituent, or the aryloxy group which may have a substituent is represented.
R 9 and R 11 or R 9 and R 10 may combine to form a 5- to 8-membered nitrogen-containing heterocycle. )]
A step of asymmetric hydrogen reduction using the hydrogen gas or hydrogen donor as a hydrogen source in the presence of any of the ruthenium compounds according to claim 1,
Formula (9): Ra-C * H (OH) -CH (Rb) -Rc
[Wherein, Ra, Rb, Rc and * represent the same meaning as described above. ] The manufacturing method of optically active (beta) -amino alcohol represented by these.
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