CN1550482A - 生产反式-(r,r)-放线菌醇的方法 - Google Patents
生产反式-(r,r)-放线菌醇的方法 Download PDFInfo
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- CN1550482A CN1550482A CNA2004100032687A CN200410003268A CN1550482A CN 1550482 A CN1550482 A CN 1550482A CN A2004100032687 A CNA2004100032687 A CN A2004100032687A CN 200410003268 A CN200410003268 A CN 200410003268A CN 1550482 A CN1550482 A CN 1550482A
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- amide
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- 238000000034 method Methods 0.000 title claims abstract description 38
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- YZNTYLFPPDPWDD-UHFFFAOYSA-N aminoazanide ruthenium(3+) Chemical compound [Ru+3].[NH-]N.[NH-]N.[NH-]N YZNTYLFPPDPWDD-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000003446 ligand Substances 0.000 claims abstract description 30
- 239000012327 Ruthenium complex Substances 0.000 claims abstract description 18
- 150000004985 diamines Chemical class 0.000 claims abstract description 16
- 239000000852 hydrogen donor Substances 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 230000007935 neutral effect Effects 0.000 claims abstract description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 239000003054 catalyst Substances 0.000 claims description 21
- 125000000217 alkyl group Polymers 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 238000009901 transfer hydrogenation reaction Methods 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- -1 aliphatic halogenated hydrocarbon Chemical class 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 11
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000003107 substituted aryl group Chemical group 0.000 claims description 8
- 230000003287 optical effect Effects 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000002837 carbocyclic group Chemical group 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- HVHHZSFNAYSPSA-ZCFIWIBFSA-N levodione Chemical compound C[C@@H]1CC(=O)CC(C)(C)C1=O HVHHZSFNAYSPSA-ZCFIWIBFSA-N 0.000 claims description 6
- JATMCAQQSXISOR-UHFFFAOYSA-N n-(2-aminoethyl)-4-methylbenzenesulfonamide Chemical compound CC1=CC=C(S(=O)(=O)NCCN)C=C1 JATMCAQQSXISOR-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 238000011065 in-situ storage Methods 0.000 claims description 4
- CYKXMJPJALYMBC-UHFFFAOYSA-N n-(3-aminopropyl)-4-methylbenzenesulfonamide Chemical compound CC1=CC=C(S(=O)(=O)NCCCN)C=C1 CYKXMJPJALYMBC-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
- UOPFIWYXBIHPIP-UHFFFAOYSA-N n-(2-amino-1,2-diphenylethyl)-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(C=1C=CC=CC=1)C(N)C1=CC=CC=C1 UOPFIWYXBIHPIP-UHFFFAOYSA-N 0.000 claims description 3
- VVOFSHARRCJLLA-UHFFFAOYSA-N n-(2-aminocyclohexyl)-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1C(N)CCCC1 VVOFSHARRCJLLA-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- YUWFEBAXEOLKSG-UHFFFAOYSA-N hexamethylbenzene Chemical compound CC1=C(C)C(C)=C(C)C(C)=C1C YUWFEBAXEOLKSG-UHFFFAOYSA-N 0.000 claims description 2
- UOPFIWYXBIHPIP-NHCUHLMSSA-N n-[(1r,2r)-2-amino-1,2-diphenylethyl]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N[C@H](C=1C=CC=CC=1)[C@H](N)C1=CC=CC=C1 UOPFIWYXBIHPIP-NHCUHLMSSA-N 0.000 claims description 2
- VVOFSHARRCJLLA-CHWSQXEVSA-N n-[(1r,2r)-2-aminocyclohexyl]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N[C@H]1[C@H](N)CCCC1 VVOFSHARRCJLLA-CHWSQXEVSA-N 0.000 claims description 2
- PKJIJTOTTMMAHF-SFTDATJTSA-N n-[(1s,2s)-2-amino-1,2-diphenylethyl]-4-methoxybenzenesulfonamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N[C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 PKJIJTOTTMMAHF-SFTDATJTSA-N 0.000 claims description 2
- UOPFIWYXBIHPIP-SFTDATJTSA-N n-[(1s,2s)-2-amino-1,2-diphenylethyl]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N[C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 UOPFIWYXBIHPIP-SFTDATJTSA-N 0.000 claims description 2
- CBIJQSFBJHOXDH-ZEQRLZLVSA-N n-[(1s,2s)-2-amino-1,2-diphenylethyl]naphthalene-1-sulfonamide Chemical compound C1([C@H](NS(=O)(=O)C=2C3=CC=CC=C3C=CC=2)[C@@H](N)C=2C=CC=CC=2)=CC=CC=C1 CBIJQSFBJHOXDH-ZEQRLZLVSA-N 0.000 claims description 2
- 150000003333 secondary alcohols Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- JKQXZKUSFCKOGQ-JLGXGRJMSA-N (3R,3'R)-beta,beta-carotene-3,3'-diol Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)C[C@@H](O)CC1(C)C JKQXZKUSFCKOGQ-JLGXGRJMSA-N 0.000 abstract description 2
- JKQXZKUSFCKOGQ-LQFQNGICSA-N Z-zeaxanthin Natural products C([C@H](O)CC=1C)C(C)(C)C=1C=CC(C)=CC=CC(C)=CC=CC=C(C)C=CC=C(C)C=CC1=C(C)C[C@@H](O)CC1(C)C JKQXZKUSFCKOGQ-LQFQNGICSA-N 0.000 abstract description 2
- QOPRSMDTRDMBNK-RNUUUQFGSA-N Zeaxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCC(O)C1(C)C)C=CC=C(/C)C=CC2=C(C)CC(O)CC2(C)C QOPRSMDTRDMBNK-RNUUUQFGSA-N 0.000 abstract description 2
- JKQXZKUSFCKOGQ-LOFNIBRQSA-N all-trans-Zeaxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2=C(C)CC(O)CC2(C)C JKQXZKUSFCKOGQ-LOFNIBRQSA-N 0.000 abstract description 2
- 235000021466 carotenoid Nutrition 0.000 abstract description 2
- 150000001747 carotenoids Chemical class 0.000 abstract description 2
- 150000002367 halogens Chemical class 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 abstract description 2
- 239000001775 zeaxanthin Substances 0.000 abstract description 2
- 229940043269 zeaxanthin Drugs 0.000 abstract description 2
- 235000010930 zeaxanthin Nutrition 0.000 abstract description 2
- 239000002243 precursor Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 12
- 235000019254 sodium formate Nutrition 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000004280 Sodium formate Substances 0.000 description 9
- 229910052717 sulfur Inorganic materials 0.000 description 9
- 229910052786 argon Inorganic materials 0.000 description 8
- 238000005984 hydrogenation reaction Methods 0.000 description 7
- 239000012442 inert solvent Substances 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000012455 biphasic mixture Substances 0.000 description 4
- YMWUJEATGCHHMB-DICFDUPASA-N deuterated dichloromethane Substances [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000006277 sulfonation reaction Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- CSPVUHYZUZZRGF-RNFRBKRXSA-N (4R,6R)-hydroxy-2,2,6-trimethylcyclohexanone Chemical compound C[C@@H]1C[C@@H](O)CC(C)(C)C1=O CSPVUHYZUZZRGF-RNFRBKRXSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229930185327 Actinol Natural products 0.000 description 3
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 238000005191 phase separation Methods 0.000 description 3
- 229910052707 ruthenium Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-trimethylbenzene Chemical compound CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 239000000386 donor Substances 0.000 description 2
- DZFYOYRNBGNPJW-UHFFFAOYSA-N ethoxythallium Chemical compound [Tl+].CC[O-] DZFYOYRNBGNPJW-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 238000004452 microanalysis Methods 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- QQFSIGWYINAJOB-UHFFFAOYSA-N 1,4-dicyclohexylbenzene Chemical compound C1CCCCC1C1=CC=C(C2CCCCC2)C=C1 QQFSIGWYINAJOB-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- QZVDAYMOAMNSBO-UHFFFAOYSA-N 3,3,4-trimethylcyclohexane-1,2-dione Chemical compound CC1CCC(=O)C(=O)C1(C)C QZVDAYMOAMNSBO-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000008331 benzenesulfonamides Chemical class 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 125000004799 bromophenyl group Chemical group 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 238000003965 capillary gas chromatography Methods 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004987 dibenzofuryl group Chemical group C1(=CC=CC=2OC3=C(C21)C=CC=C3)* 0.000 description 1
- DHCWLIOIJZJFJE-UHFFFAOYSA-L dichlororuthenium Chemical compound Cl[Ru]Cl DHCWLIOIJZJFJE-UHFFFAOYSA-L 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000009904 heterogeneous catalytic hydrogenation reaction Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229910052740 iodine Chemical group 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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Abstract
一种在同时用做溶剂的氢给体和一种氨基-酰胺-钌络合物,特别是式RuH(L{-H})(Y),其中Y代表一中性配位体,L代表一有或没有旋光活性的单磺酰化二胺配位体的存在下,左旋二酮非对映选择性转移加氢生产反式-(R,R)-放线菌醇的方法。该方法已在说明书中详细说明。另外,本发明涉及一些氨基-酰胺-钌络合物以及这些络合物相应的有卤素代替氢的前体。本发明方法的产品反式-(R,R)-放线菌醇是已知合成类胡萝卜素,如玉米黄质的重要结构单元。本方法可以生产对映体和非对映的纯度特别高的反式-(R,R)-放线菌醇。
Description
本申请为申请号为98123951.X、申请日为1998年11月6日专利申请的分案申请。
本发明涉及在一种氨基-酰胺-钌络合物催化剂存在下,由非对映选择性转移加氢生产反式-(R,R)-放线菌醇的方法。
旋光性的放线菌醇是合成类胡萝卜素,如玉米黄质的重要结构单元[纯化学和应用化学,51,535-564(1979)]。在已知的方法中,放线菌醇是用三甲基环己二酮左旋二酮生产的。一种方法的基础是在低碱含量的阮内镍存在下,左旋二酮的催化加氢[Helv.Chim.Acta 59,1832(1976)]。多相加氢的非对映选择性差,使生成的反式-和顺式-放线菌醇为3-4∶1的混合物,而结果是复杂的精制降低了收率;此外在多相催化的反应条件下左旋二酮有外消旋的危险。另一种精制方法是用一合适的精馏塔,在欧洲专利EP-A 0775685曾叙述过,但收率为中等。现在和过去一样,对能得到高对映体和非对映体纯度的放线菌醇的生产方法的兴趣仍然很大。
令人惊奇地,已经发现(R)-左旋二酮可以在一种氨基-酰胺-钌络合物的存在下,转移加氢而转化成(R,R)-放线菌醇,化学收率和光学收率都很高。
因而本发明涉及一种生产反式-(R,R)-放线菌醇(1)的方法:
这是用左旋二酮的非对映选择性转移加氢方法,该方法包括在一种同时用做溶剂的氢给体和一种氨基-酰胺-钌络合物的存在下将(R)-左旋二酮(2)加氢。
酮通过转移加氢生产醇的方法是已知的。如,R.Noyori等人[Acc.Chem.Res.
30,97-102(1997)]研究了芳基烷基酮的不对称转移加氢,如苯乙酮可以在一种氢给体,如异丙醇/氢氧化钾或醋酸/三乙胺,和一种钌的络合物的存在下,加氢而得到高光学和化学收率。但是,当二烷基酮用做作用物时,不仅化学收率而且光学收率都显著降低了。
本发明的方法优选采用一种如下通式的氨基-酰胺-钌络合物。
RuH(L{-H})(Y) I
其中
Y代表中性配位体,
L代表有或没有旋光活性的单磺酰化二胺,通式如下
R1代表未氟化或单一或多-氟化的烷基,烯基,炔基,环烷基,未取代或单一或多-取代的芳基,杂芳基或樟脑-10-基,
R2和R3每一个独立地代表氢,烷基,环烷基或未取代或单一或多-取代的芳基,或R2和R3与缔合基团-CH-(CH2)n-CH一起生成一个含4至8个碳原子的碳环,
R4代表氢或烷基,和
n代表0,1,2或3。
单磺酰化二胺在络合物中以一种单阴离子存在,在式I中用“L{-H}”表示。
本发明还涉及通式为I′的氨基-酰胺-钌络合物
RuH(L′{-H})(Y) I′
其中
Y,R1,R4,n的定义和以上相同;
L′代表通式II′的单磺酰化二胺
R1SO2-HN-CH2-(CH2)n-CH2-NHR4 II′
该氨基-酰胺-钌络合物,优选为RuH(Ts-en{-H}(对-异丙基苯甲烷)。
本发明还涉及通式为I″的氨基-酰胺-钌络合物
RuX(L′{-H})(Y) I″
其中
Y,L′,R1,R4,n的定义和以上相同;
该氨基-酰胺-钌络合物,优选为RuCl(Ts-en{-H})(p-Cym),和RuCl(Ts-en{-H})(六甲基苯)。
在本发明的范围内,“烷基”包括直链或枝链含1至8个碳原子,优选1至5个碳原子的任意的手性烷基。甲基,乙基,丙基,正-丁基,异丁基,叔丁基,正戊基,异戊基是这些烷基的例子。三氟甲基,2,2,2-三氟乙基和五氟乙基是单一或多-氟化烷基的例子。
“烯基”包括含3至8个碳原子的直链或枝链的烯基,如,烯丙基,2-丁烯基和3-丁烯基。
“炔基”代表直链或枝链含一个三键和3至8个碳原子的炔基,如丙炔基和丁炔基。
“环烷基”代表3-至7-元的脂环基,即环丙基,环丁基,环戊基,环己基或环庚基,优选环戊基和环己基。
“未取代或单一或多-取代芳基”包括苯基或萘基,它们可以是未被取代的,单一取代或多取代的。可以考虑的取代基有苯基,卤素,直链和枝链带1至5个碳原子的烷基和烷氧基,而多-取代苯基或萘基可以有相同或不同的取代基。在烷基和烷氧基中,分别优选甲基和和甲氧基。取代或未取代的芳基有苯基,氯-,溴-和氟苯基,甲苯基,甲氧苯基,2-4-二甲基苯基以及萘基。
“杂芳基”包括含O,S或N的5-或6-元杂环基,如呋喃基,噻吩基,苯并呋喃基,二苯并呋喃基,吨基,吡咯基和吡啶基。特别优选含氧的杂环基。
“中性配位体”在本发明的范围内有芳烃,特别是苯、萘或四氢化萘,其中苯可以是被直链或枝链含1至5个碳原子的烷基和/或烷氧基,优选甲基或甲氧基和/或环烷基的单一或多-取代的。这类配位体有苯,对-甲基异丙基苯,甲苯,苯甲醚,二甲苯,1,3,5-三甲基苯,对-二环己基苯,萘,四氢化萘。
用于本发明方法中的初始原料的(R)-左旋二酮可以用发酵的方法制得或购得。
用于本发明方法的一类特殊的氨基-酰胺-钌络合物由包括式II的配位体的式I的化合物组成,其中R2和R3每个独立地代表氢,烷基,环烷基或未取代或单一或多-取代的芳基,或R2和R3与缔合基团-CH-(CH2)n-CH-一起代表4-6个碳原子的碳环,n代表0或1,R1和R4的含意和以上的相同。
优选的单磺酰化二胺配位体L是具有式II的结构,其中R2和R3的含意相同,代表氢或苯基。优选的配位体L是R2和R3与缔合基团-CH-(CH2)n-CH-基一起代表含4-8碳原子的碳环。在两种情况下R4均优选地代表氢。在这些优选的配位体L中特别优选的是其中n代表零的那些。
特别优选的配位体L是具有式II结构的有旋光活性的,其中R2和R3不代表氢的单磺酰化二胺配位体。
不论单磺酰二胺配位体L是否具有旋光活性,优选的式II的配位体L中R1代表甲苯基,苯甲醚基或萘基。
特别优选的单磺酰二胺配位体L的例子是:
(1S,2S)-N-(2-氨基-1,2-二苯基-乙基)-4-甲基-苯磺酰胺,
(1R,2R)-N-(2-氨基-1,2-二苯基-乙基)-4-甲基-苯磺酰胺,
(1RS,2RS)-N-(2-氨基-1,2-二苯基-乙基)-4-甲基-苯磺酰胺(外消旋),
(1S,2S)-N-(2-氨基-1,2-二苯基-乙基)-4-甲氧基-苯磺酰胺,
萘-1-磺酸[(1S,2S)-(2-氨基-1,2-二苯基-乙基)-酰胺],
(1R,2R)-N-(2-氨基-环己基)-4-甲基-苯磺酰胺,
(1RS,2RS)-N-(2-氨基-环己基)-4-甲基-苯磺酰胺(外消旋),
N-(2-氨基-乙基)-4-甲基-苯磺酰胺和
N-(3-氨基-丙基)-4-甲基-苯磺酰胺。
前七个化合物是手性的,第八和第九个化合物是非手性的。
本发明的方法(转移加氢)可以方便地在同时做为氢给体的溶剂中进行,也可以在一种氢给体及一种合适的惰性溶剂的混合物中进行。同时是氢给体又是溶剂的有醇,特别是仲醇,如异丙醇。做为氢给体和惰性溶剂混合物可以使用醇和一种惰性溶剂的混合物,优选醇与低级脂族卤化烃,如二氯甲烷和氯化乙烯的混合物。其它适用的氢给体/溶剂混合物有甲酸或其盐与惰性溶剂如三乙胺的混合物。异丙醇是特别优选的氢给体/溶剂。在这种情况下就生成了丙酮,如果需要,可以将其连续地自反应系统中取出。当甲酸或其盐在惰性溶剂中用做还原剂时,通常采用相当于(R)-左旋二酮化学计量的甲酸或其盐。
当用氢给体和惰性溶剂混合物时,原则上所有的混合比例都适用。
催化剂(氨基-酰胺-钌络合物)对(R)-左旋二酮的比例通常约1∶20至约1∶10000mol∶mol,优选约1∶200至约1∶2000。
本发明的非对映选择性转移加氢可以在约0℃至约100℃,优选约20℃至约50℃,如果需要,在保护气体,优选氩下进行。另外,一般在常压或轻度减压下(为了易于将异丙醇生成的丙酮除去)进行。
有机化学中的常用技术,如精馏和结晶,可用于分离和提纯所生成的反式-(R,R)-放线菌醇。
本发明非对映选择性转移加氢的式I的催化剂氨基-酰胺-钌络合物不必这样使用。已发现可以在以下所述的生产过程的反应系统中当场生成这种催化剂。
本发明所用的式I的催化剂氨基-酰基-钌络合物可按方案I生产
方案I
在方案I中,X以外的其它符号具有以上叙述过的含意;X代表氯、溴或碘,特别是氯。
按方案I中的路线A,式I的钌催化剂是使4型的钌-卤素络合物和一种氢化物给体,例如甲醇钠或甲酸钠在溶剂(如低级醇)或特别是在两相系统二氯甲烷/水中反应生成的。该反应可以方便地在室温下进行。络合物的生成一般在30分钟内完成。这是一种把Ru(II)-卤素络合物转化成为Ru(II)-氢化物络合物的方法[见有机过渡金属化学的原理和应用,J.P.Collman等人.,University Science Books(1987)和Organometallics 4,1202及以下(1985)]。当场制备式I的氨基-酰胺-钌络合物是特别方便的。
式I的钌催化剂也可以把4型的钌-卤素-络合物和一种碱,如氢氧化钠或乙醇铊转化成5型的钌-二酰胺-络合物,然后再把该络合物和同时起溶剂作用的醇(如异丙醇)反应而得到。可以使用醇和/或水与一种惰性溶剂(如二氯甲烷)的混合物做溶剂。在这种情况下,反应可以方便地在室温下进行,通常络合物的生成在30分钟内完成。
有关这些已知方法的更多的参考资料有R.Noyori等人,J.Am.Them.Soc.
118,2521(1996)和R.Noyori等人,Angew Chencie
109(3),297(1997)。在这些和其它的参考资料,如PCT专利公开WO 97/20789中描述了式I的一些氨基-酰胺-钌络合物,其中R2和R3代表除氢以外的其它基团(因而它们有手性中心),以及按以上方法制备它们。这种类型的新络合物可用类似的方法制备。
以下方案II给出另一种制备本发明所用的式I催化剂氨基-酰胺-钌络合物的方法:
方案II:路线C
在此方案中X代表氯、溴或碘。Y的含意与以前相同,II代表上述式II有或没有旋光活性的单磺酰二胺(配位体L)。该反应条件(溶剂,反应温度和反应时间)和路线A和B相应。
在上述络合物中的配位体L(式II)部分是已知的化合物[见J.A.C.S.
62,2811-2812(1940)],它们中的一些可自市场购得。非市售的旋光活性的二胺可用拆分相应的外消旋二胺而制得。其余(新的)配位体L可按和已知配位体L相似的方法制备。
特别优选的式I氨基-酰胺-钌络合物是其中配位体L是N-(2-氨基-乙基)-4-甲基-苯磺酰胺,N-(3-氨基-丙基)-4-甲基-苯磺酰胺,N-(2-氨基-1,2-二苯基-乙基)-4-甲基-苯磺酰胺或N-(2-氨基-环己基)-4-甲基-苯磺酰胺。
式I的氨基-酰胺-钌络合物其中L代表通式II′的单磺酰二胺
R1-SO2-HN-CH2-(CH2)n-CH2-NHR4 II′
(即式II中R2和R3都是氢),其中的R1,R4和n的含意和以上相同,是新的化合物,也是本发明的一个目的。因为分别连接NH-SO2R1基和NHR4基的两个碳原子是非手性的,式II′的二胺配位体和在这些位置上有取代基(R2和R3)每一个都是氢以外的基团)的式II的二胺配位体是不同的。
式RuX(L′{H})(Y)(其中X代表氯、溴或碘,L′代表式II′的单磺酰二胺而Y代表一中性配位体)的相应的氨基-酰胺-钌络合物也是新的,因而也是本发明的一个方面。
以下的实例是对本发明的说明而不是对本发明的任何限制。在这些实例中的缩略语的含意为:
Ts-DPEN N-(2-氨基-1,2-二苯基-乙基)
-4-甲基-苯磺酰胺
(1-萘基S)DPEN 萘-1-磺酸(2-氨基-1,2-二苯
基-乙基)-酰胺
(p-AnS)-DPEN N-(2-氨基-1,2-二苯基-乙基)
-4-甲氧基苯磺酰胺
Ts-1,2-DACA N-(2-氨基-环己基)-4-甲基-
苯磺酰胺
Ts-en N-(2-氨基-乙基)-4-甲基-苯磺酰胺
Ts-pn N-(3-氨基-丙基)-4-甲基-苯磺酰胺
p-Cym 对异丙基苯甲烷
Me 甲基
Et 乙基
TLC 薄层色谱
GC 毛细管气体色谱
ee 对映体的过量
de 非对映体的过量
RT 室温
实施例1
5.0g(32.4mmol)(R)-左旋二酮,57ml异丙醇和19.5mg(0.0304mmol)[Ru((S,S)-Ts-DPEN{-2H})(p-Cym)]加入在手套箱内(O2含量<1ppm)的185ml钢容器中。关闭容器,在搅拌和20℃下进行转移加氢反应。加氢反应在24小时内结束(>99%转化率)。加氢溶液在40℃/50mbar(5kPa)下蒸发残余物,在110℃/0.2mbar(20Pa)下在一球管炉内蒸馏。得到了4.9g 94%/5%(R,R)-放线菌醇(1)/(S,R)-放线菌醇(3)的混合物。(R,R)-放线菌醇的ee值为99.4%。转化率,ee值和de值的测定是在气体色谱手相(BGB-176:2,3-二甲基-6-叔丁基-二甲基-甲硅烷基化的-β-环糊精)上进行。
实施例2
100.0g(0.648mol)(R)-左旋二酮,1.151异丙醇和0.389g(0.648mmol)[Ru(1S,S)-Ts-DPEN{-2H})(p-Cym)]加至2升的四颈圆烧瓶中,在搅拌和35℃下开始转移加氢反应。向反应溶液通入氩气,连续分离出加氢反应生成的丙酮。8小时后转化率为>99%。按实施例1中相似的方法进行后处理,得到98g 94%/6%(R,R)-反式-放线菌醇/(S,R)-顺式-放线菌醇的混合物。(R,R)-反式-放线菌醇的ee值是99.3%。
实施例3-14
按实施例1的相似方法进行实施例3-14的加氢反应,条件在表1中给出:
表1
实施例 | 芳烃(Y) | 二胺配位体(L) | T[℃] | t[h] | S/C[m/m] | 转化率[%] | 1/3 | ee1[%] |
3 | p-Cym | (s,s)-Ts-DPEN | 20 | 4 | 200 | >99 | 95/4 | 99.7 |
4 | p-Cym | (s,s)-Ts-DPEN | 30 | 3 | 200 | >99 | 94/5 | 99.8 |
5 | p-Cym | (s,s)-Ts-DPEN | 40 | 2 | 200 | >99 | 94/5 | 99.8 |
6 | p-Cym | (s,s)-Ts-DPEN | 50 | 2 | 200 | >99 | 93/6 | 99.8 |
7 | p-Cym | (s,s)-Ts-DPEN | 20 | 3 | 200 | >99 | 94/4 | 99.6 |
8 | p-Cym | (s,s)-Ts-DPEN | 20 | 3 | 200 | >99 | 94/5 | 99.4 |
9 | p-Cym | (s,s)-Ts-DPEN | 20 | 3 | 200 | 98 | 91/6 | 99.1 |
10 | p-Cym | (s,s)-Ts-DPEN | 20 | 3 | 200 | 97 | 89/7 | 98.8 |
11 | p-Cym | (s,s)-Ts-DPEN | 20 | 24 | 500 | 99 | 93/6 | 99.4 |
12 | p-Cym | (s,s)-Ts-DPEN | 20 | 24 | 1000 | 99 | 94/5 | 99.4 |
13 | p-Cym | (S,S)-(1-萘基)-DPEN | 40 | 23 | 1000 | 79 | 75/4 | 99.4 |
14 | p-Cym | (S,S)-(p-AnS)-DPEN | 20 | 23 | 1000 | 96 | 91/6 | 99.3 |
S/C 作用物/催化剂(mol/mol)
Conv.转化率
实施例15
用[RuH(Ts-en{H}(p-Cym))]做
实例当场制备催化剂的方法
所有的操作都是在无氧的条件下进行的。
方法A(路线A)
17.73mg(0.26mmol)甲酸钠,63.10mg(0.13mmol)[RuCl(Ts-en{-H})(p-Cym)],10ml二氯甲烷和1ml水在室温下剧烈搅拌约15分钟。分相后,有机相三次每次用10ml水洗涤然后在无水硫酸钠上干燥。
方法B(路线A)
5.7mg(0.08mmol)甲酸钠,20.2mg(0.04mmol)[RuCl(Ts-en{-H})(p-Cym)],3ml二氯甲烷和3ml水在室温下剧烈搅拌30分钟。分相后,有机相在无水硫酸钠上干燥。然后加入0.03ml(0.4mmol)丙酮,混合物搅拌15分钟。
方法C(路线B)
140.70mg(0.29mmol)[RuCl(Ts-en{-H})(p-Cym)],72.5mg(0.29mmol)乙醇铊和7ml异丙醇在室温下搅拌30分钟。滤掉生成的沉淀。
方法D(路线A)
3.88mg(0.06mmol)甲酸钠,27.6mg(0.06mmol)[RuCl(Ts-en{-H})(p-Cym)]和5ml甲醇在室温下搅拌30分钟。
方法E(路线A)
1.12mg甲醇钠,11mg[RuCl(Ts-en{-H})(p-Cym)]和5ml甲醇在室温下搅拌30分钟。
实施例16
11.3g(73.5mmol)(R)-左旋二酮在通氩保护的二颈圆底烧瓶内悬浮在130ml异丙醇中。按照实例15,方法A,由71.2mg(0.147mmol)[RuCl(Ts-en{-H})(p-Cym)]和20.0mg(0.294mmol)甲酸钠制成的催化剂在不接触空气的条件下加至二酮的悬浮液中。反应在3小时内完成,在转移加氢中生成的丙酮在搅拌和25℃下连续地蒸出。转化率为99.8气体色谱面积%。按实施例1的方法进行后处理后,得到10.9g 96%/4%(R,R)-放线菌醇/(S,R)-放线菌醇混合物。(R,R)-放线菌醇的ee值为98.1%。
实施例17-29
催化剂溶液是按照实施例15中的方法制备的。转移加氢17-29是按实施例1相同的方法在表3给出的条件下进行的:
表3
实施例 | [RuH(L{-H})(Y)]L= Y= | 方法 | t[h] | S/C[m/m] | 转化率[%] | 1/3 | ee1[%] | |
17 | (1RS,2RS)-Ts-DPEN | p-Cym | $ | 4 | 200 | 99 | 93/6 | 99.5 |
18 | (R,R)-Ts-DPEN | p-Cym | $ | 6 | 200 | 98 | 89/9 | 99.7 |
19 | (S,S)-Ts-DPEN | 1,3,5-Me3-C6H3 | $ | 4 | 200 | >99 | 92/7 | 99.4 |
20 | (S,S)-Ts-DPEN | C6H6 | $ | 4.5 | 200 | >99 | 93/6 | 98.7 |
21 | (S,S)-Ts-DPEN | p-Cy2-C6H4 | $ | 24 | 200 | 98 | 92/5 | 94.5 |
22 | (1RS,2RS)-Ts-1,2-DACH | p-Cym | C | 7 | 200 | >99 | 91/7 | 97.6 |
23 | (1RS,2RS)-Ts-1,2-DACH | p-Cym | A | 6 | 200 | 91 | 85/6 | 99.1 |
24 | (1RS,2SR)-Ts-1,2-DACH | p-Cym | A | 16 | 200 | 27 | 25/2 | 99.1 |
25 | Ts-en | p-Cym | C | 3 | 200 | >99 | 94/4 | 95.8 |
26 | Ts-en | p-Cym | A | 4 | 200 | >99 | 94/4 | 98.8 |
27 | Ts-en | p-Cym | D | 5 | 200 | 97 | 91/4 | 85.3 |
28 | Ts-en | p-Cym | B | 16 | 200 | >99 | 94/4 | 99.6 |
29 | Ts-en | p-Cym | A | 22 | 20 | 76 | 68/8 | 96 |
所有的实例都是在室温下进行的。作用物的浓度是2%(重量百分率)。
$催化剂的制备,分离和表征是按照和R.Noyori等人.,Angew.Chem.
109,297-300(1997),相似的方法进行的。
实施例30
101mg(0.21mmol)[RuCl(Ts-en{-H})(p-Cym)],1.42g(21.0mmol)甲酸钠和0.65g(4.2mmol)(R)-左旋二酮在50ml Schlenk管中,在无氧条件下悬浮在21ml二甲基亚砜(DMSO)中,在室温下搅拌2小时。反应时向悬浮液中不断通入少量氩气。然后,关闭Sclenk管,悬浮液再继续搅拌14小时。加入10ml水和50ml二氯甲烷,把两相分开。水相每次用50ml二氯甲烷萃取两次。有机相合在一起在无水硫酸钠上干燥,在一转动蒸发器上蒸发。残余物用气体色谱分析,转化率为99.3%,(R,R)-放线菌醇的含量为91.2%(76.1%ee)。
实施例31-34
加氢31-34是按实施例30类似的方法进行的,反应条件列于表4中:
表4
实施例 | [RuH(L{-H})(Y)]L= | 溶剂 | 氢化物给体 | C[M] | t[h] | 转化率[%] | 1/3 | ee1[%] |
31 | (R,R)-Ts-DPEN | 甲醇 | HCOONa | 0.2 | 2 | >99 | 94/6 | 90.5 |
32 | (R,R)-Ts-DPEN | DMSO | HCOONa | 0.2 | 6 | 85 | 81/4 | 96.2 |
33 | Ts-en | 甲醇 | HCOONa | 0.2 | 3 | >99 | 85/8 | 39.0 |
34 | (R,R)-Ts-DPEN | HCOOH/Et3N(5∶2) | HCOOH | 1 | 24 | 98 | 85/12 | 81.1 |
实施例35
由[RuCl(Ts-en{-H})(p-Cym)]制备
催化剂溶液
0.662g(9.73mmol)甲酸钠在120ml水的溶液和0.942g(1.95mmol)[RuCl(Ts-en{-H})(p-Cym)]在102ml二氯甲烷的溶液在氩气保护下加至一磺化瓶中。两相混合物在20-23℃下剧烈搅拌1小时。二氯甲烷相含[RuH(Ts-en{-H})(p-Cym)],活性催化剂。
转移加氢
300.0g(1.95mol)(R)-左旋二酮在一磺化烧瓶内悬浮在3440ml异丙醇中,同时在20-25℃下搅拌,通入氩气使系统呈惰性,把悬浮物加热至40℃。含催化剂的二氯甲烷相在无氧条件下加至左旋二酮中。反应溶液在40℃和150mbar(1.5kPa)部分真空下搅拌,首先把二氯甲烷,然后把转移加氢时生成的丙酮连续地蒸出。加入新的异丙醇取代蒸出的丙酮/异丙醇混合。6小时后,加氢反应完成。转化率为99.6气体色谱面积%。
为了分离催化剂,蒸发加氢溶液,剩余物溶解在二异丙醚中,溶液用活性炭处理。过滤和蒸发后,得到303.2g油状95%/5%(R,R)-1(S,R)-放线菌醇。(R,R)-放线醇的ee值为98.9%。100g这种混合物在二异丙醚/正-己烷结晶出来。得到75g纯(R,R)-放线菌醇,ee值>99.5%。
实施例36
由[RuCl2(p-Cym)]2(路线C)制备催化剂溶液
0.199g(0.324mmol)[RuCl2(p-Cym)]2和0.139g(0.648mmol)N-(P-甲苯磺酰基)-乙二胺溶解在20ml二氯甲烷内,在氩气保护下加至一磺化烧瓶中。再加入0.221g(3.25mmol)甲酸钠和0.036g(0.64mmol)溶于20ml水的溶液。两相混合物在20-23℃下剧烈搅拌1小时。二氯甲烷相含RuH(Ts-en{-H})(p-Cym)],活性催化剂。
转移加氢
100.0g(648.5mmol)(R)-左旋二酮和实施例35相似地进行了加氢反应。8小时后加氢完毕。得到了>99%收率的95%/5%(R,R)-放线菌醇/(S,R)-放线菌醇。(R,R)-放线菌醇的ee值为98.9%。
实施例37
[RuCl(Ts-en{-H})(p-Cym)]的制备
50.0g(0.233mol)N-对-(甲苯磺酰基)-乙二胺和71.5g(0.117mmol)[RuCl2(p-Cym)]2溶解在650ml二氯甲烷中,330ml水和230ml 1M氢氧化钾水溶液在氩气保护下加至121的磺化烧瓶中。两相混合物在室温下激烈搅拌30分钟。分相后,水相用300ml二氯甲烷反萃取,有机相合在一起在无水硫酸钠上干燥。过滤,蒸发后,橙-红色残余物溶解在400ml己烷中,在高真空下干燥。分离出橙色固体[RuCl(Ts-en{-H})(p-Cym)],收率97%(114.3g)。10g样品在甲醇中结晶,得到8.5g[RuCl(Ts-en{-H})(p-Cym)]的红色晶体。
1H-NMR(250MHz,CDCl3):7.75(d,2H),7.17(d,2H),5.7-5.3(m,5H),3.2-2.1(mbr,6H),2.34(s,3H),2.12(s,3H),1.22(d,6H)。
微量分析:C19H27N2O2RuSCl(484.02)计算:C 47.15;H 5.62;N 5.79;S 6.62;Cl 7.32;测得:C 47.21;H 5.64;N 5.80;S 6.4;Cl 7.23。
实施例38
[RuCl(Ts-en{-H})(Me6C6)]的制备
和实施例37相似,97.2mg(0.4mmol)N-(对-甲苯磺酰基)-乙二胺,152.4mg(0.2mmol)[RuCl2(Me6C6)]2和4.6ml 0.1M氢氧化钾水溶液在水/二氯甲烷中反应结束后,粗产品在甲醇中结晶,分离出106.0mg(46%)[RuCl(Ts-en{-H})(Me6C6)]的橙色晶体。
1H-NMR(250MHz,CDCl3):7.80(d,2H),7.11(d,2H),3.5-3.2(br,2H)2.5-2.5(br,4H),2.31(S,3H),2.17(s,18H)。
微量分析:C21H31N2O2RuSCl(512.07)计算:C 49.26;H 6.10;N 5.47;S 6.26;Cl 6.92;测得:C 49.03;H 5.96;N 5.51;S 6.02;Cl 6.86。
实施例39
[RuH(Ts-en{-H})(p-Cym)]的制备
19.0mg(0.04mmol)[RuCl[Ts-en{-H})(p-Cym)]和26.7mg(0.4mmol)和甲酸钠溶解在2ml D2O和2ml CD2Cl2中,在氩气保护下加入5ml Schlenk管内,此两相混合物在室温下搅拌30分钟。根据1H-NMR分析,黄色CD2Cl2相含[RuH(Ts-en{-H})(p-Cym)]和少量未反应的[RuCl(Ts-en{-H})(p-Cym)]。
1H-NMR(250MHz,CD2Cl2):7.46(d,2H),7.09(d,2H),5.0-4.5(m,4H),3.0-1.5(m,7H),2.21(s,3H),2.11(s,3H),1.10(d,6H),-6.85(s,1H)。
Claims (17)
3.权利要求2的一种方法,其中所采用的氨基-酰胺-钌络合物的式I的L代表式II的有或没有旋光活性的单磺酰化二胺,其中R1和R4的含意在权利要求2中已给出,R2和R3每一个独立地代表氢,烷基,环烷基或未取代或单一或多-取代的芳基,或R2和R3与缔合基-CH-(CH2)n-CH-一起生成一个含4至8个碳原子的碳环,n代表0或1。
4.权利要求2或3的一种方法,其中L代表式II有或没有旋光活性的单磺酰化二胺,其中R2和R3有相同含意并代表氢或苯基,或与缔合基-CH-(CH2)n-CH-一起生成一个含4至8个碳原子的碳环,R4代表氢。
5.权利要求4的一种方法,其中在一CH-(CH2)n-CH-基中的n代表零。
6.权利要求2至5中任一项的一种方法,其中所采用的氨基-酰胺-钌络合物的式I的L代表式II旋光活性的单磺酰化二胺,其中R2和R3二者都不代表氢。
7.权利要求2的一种方法,其中式I中所采用的氨基-酰胺-钌络合物L是一个选自以下的配位体
(1S,2S)-N-(2-氨基-1,2-二苯基-乙基)-4-甲基-苯磺酰胺,
(1R,2R)-N-(2-氨基-1,2-二苯基-乙基)-4-甲基-苯磺酰胺,
(1RS,2RS)-N-(2-氨基-1,2-二苯基-乙基)-4-甲基-苯磺酰胺(外消旋),
(1S,2S)-N-(2-氨基-1,2-二苯基-乙基)-4-甲氧基-苯磺酰胺,
萘-1-磺酸[(1S,2S)-(2-氨基-1,2-二苯基-乙基)-酰胺],
(1R,2R)-N-(2-氨基-环己基)-4-甲基-苯磺酰胺,
(1RS,2RS)-N-(2-氨基-环己基)-4-甲基-苯磺酰胺(外消旋),
N-(2-氨基-乙基)-4-甲基-苯磺酰胺和
N-(3-氨基-丙基)-4-甲基-苯磺酰胺。
8.权利要求1至7中任一项的一种方法,其中一种醇,优选的是一种仲醇,特别是异丙醇,用做氢给体的同时用做溶剂。
9.权利要求1至8中任一项的一种方法,其中一种低级脂族卤化烃,如二氯甲烷或氯化乙烯,或甲酸及其盐和三乙胺的混合物,用做(附加的)溶剂。
10.权利要求1至9中任一项的一种方法,其中的催化剂,特别是式I的氨基-酰胺-钌络合物与(R)-左旋二酮的比例约为1∶20至1∶10000mol:mol,优选地约为1∶200至约1∶2000mol:mol。
11.权利要求1至10中任一项的一种方法,其中非对映选择性转移加氢是在温度约0℃至约100℃,优选约20℃至约50℃下进行的。
12.权利要求1至11中任一项的一种方法,其中用做催化剂的式I的氨基-酰胺-钌络合物是在反应系统当场生成的。
13.通式为I′的氨基-酰胺-钌络合物
RuH(L′{-H})(Y) I′
其中
Y代表一个中性配位体,
L′代表通式II′的单磺酰化二胺
R1SO2-HN-CH2-(CH2)n-CH2-NHR4 II′
R1代表未氟化或单一或多-氟化的烷基,烯基,炔基,环己基,未取代或单一或多-取代的芳基,杂芳基或樟脑-10-基,
R4代表氢或烷基,和
n代表0,1,2或3。
14.权利要求13的氨基-酰胺-钌络合物,
RuH(Ts-en{-H}(对-异丙基苯甲烷)。
15.通式为I″的氨基-酰胺-钌络合物
RuX(L′{-H})(Y) I″
其中
X代表氯、溴或碘,
Y代表一个中性配位体,
L′代表一个通式II′的单磺酰化二胺
R1SO2-HN-CH2-(CH2)n-CH2-NHR4 II′
R1代表未氟化或单一或多-氟化烷基,烯基,炔基,环烷基,未取代或单一或多-取代的芳基,杂芳基或樟脑-10-基,
R4代表氢或烷基,和
n代表0,1,2或3。
16.权利要求15的氨基-酰胺-钌络合物,
RuCl(Ts-en{-H})(p-Cym)。
17.权利要求15的氨基-酰胺-钌络合物,
RuCl(Ts-en{-H})(六甲基苯)。
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CNB98123951XA Expired - Fee Related CN1142130C (zh) | 1997-11-06 | 1998-11-06 | 生产反式-(r,r)-放线菌醇的方法 |
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US (2) | US6187961B1 (zh) |
EP (1) | EP0915076B1 (zh) |
JP (1) | JP4422808B2 (zh) |
KR (1) | KR100678794B1 (zh) |
CN (2) | CN1142130C (zh) |
BR (1) | BR9804565A (zh) |
CA (1) | CA2253888C (zh) |
DE (1) | DE59802620D1 (zh) |
DK (1) | DK0915076T3 (zh) |
ES (1) | ES2170443T3 (zh) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
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AU2001276690A1 (en) * | 2000-08-01 | 2002-02-13 | Shionogi And Co., Ltd. | Process for producing alcohol with transition metal complex having amide compound as ligand |
GB0204129D0 (en) * | 2002-02-21 | 2002-04-10 | Novartis Ag | Process for the manufacture of organic compounds |
PT1375477E (pt) * | 2002-06-17 | 2009-11-20 | Saltigo Gmbh | Processo para a preparação de diaminas mono-nsulfoniladas |
GB0425320D0 (en) | 2004-11-17 | 2004-12-22 | Johnson Matthey Plc | Diamines |
WO2010106364A2 (en) * | 2009-03-17 | 2010-09-23 | Johnson Matthey Public Limited Company | Process |
CN103415524B (zh) * | 2011-03-10 | 2015-11-25 | Zach系统股份公司 | 不对称还原方法 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4072715A (en) | 1974-08-21 | 1978-02-07 | Hoffmann-La Roche Inc. | Optically active cyclohexane derivatives |
US5011995A (en) * | 1987-07-28 | 1991-04-30 | Ciba-Geigy Corporation | Process for the preparation of optically active secondary amines |
US5543559A (en) * | 1994-07-07 | 1996-08-06 | Hoffman-La Roche Inc. | Process for the enantioselective hydrogenation of ketosiophorone derivatives |
DE19543619A1 (de) | 1995-11-23 | 1997-05-28 | Basf Ag | Verfahren zur Reindarstellung von trans- und cis-4-Hydroxy-2,2,6-trimethyl-cyclohexan-l-on aus Isomerengemischen |
EP1300381B1 (en) | 1995-12-06 | 2006-03-08 | Japan Science and Technology Agency | Process for preparing optically active alcohols |
GB9706321D0 (en) | 1997-03-26 | 1997-05-14 | Zeneca Ltd | Catalytic hydrogenation |
-
1998
- 1998-10-20 US US09/175,784 patent/US6187961B1/en not_active Expired - Lifetime
- 1998-10-30 EP EP98120544A patent/EP0915076B1/de not_active Expired - Lifetime
- 1998-10-30 ES ES98120544T patent/ES2170443T3/es not_active Expired - Lifetime
- 1998-10-30 DK DK98120544T patent/DK0915076T3/da active
- 1998-10-30 DE DE59802620T patent/DE59802620D1/de not_active Expired - Lifetime
- 1998-11-04 CA CA002253888A patent/CA2253888C/en not_active Expired - Fee Related
- 1998-11-05 KR KR1019980047339A patent/KR100678794B1/ko not_active IP Right Cessation
- 1998-11-05 BR BR9804565-2A patent/BR9804565A/pt not_active Application Discontinuation
- 1998-11-06 CN CNB98123951XA patent/CN1142130C/zh not_active Expired - Fee Related
- 1998-11-06 CN CNB2004100032687A patent/CN1269828C/zh not_active Expired - Fee Related
- 1998-11-06 JP JP31551598A patent/JP4422808B2/ja not_active Expired - Fee Related
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2000
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Also Published As
Publication number | Publication date |
---|---|
EP0915076B1 (de) | 2002-01-16 |
CN1142130C (zh) | 2004-03-17 |
KR100678794B1 (ko) | 2007-06-04 |
KR19990045041A (ko) | 1999-06-25 |
JPH11236345A (ja) | 1999-08-31 |
CA2253888A1 (en) | 1999-05-06 |
BR9804565A (pt) | 2000-04-11 |
ES2170443T3 (es) | 2002-08-01 |
CA2253888C (en) | 2008-09-09 |
US6187961B1 (en) | 2001-02-13 |
DK0915076T3 (da) | 2002-04-22 |
EP0915076A1 (de) | 1999-05-12 |
DE59802620D1 (de) | 2002-02-21 |
CN1223998A (zh) | 1999-07-28 |
CN1269828C (zh) | 2006-08-16 |
US6300509B1 (en) | 2001-10-09 |
JP4422808B2 (ja) | 2010-02-24 |
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