CN107722068B - 三齿氮膦配体与其配合物、及其在酮的不对称催化氢化中的应用 - Google Patents
三齿氮膦配体与其配合物、及其在酮的不对称催化氢化中的应用 Download PDFInfo
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- CN107722068B CN107722068B CN201711099663.3A CN201711099663A CN107722068B CN 107722068 B CN107722068 B CN 107722068B CN 201711099663 A CN201711099663 A CN 201711099663A CN 107722068 B CN107722068 B CN 107722068B
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- ligand
- tridentate
- complex
- isopropanol
- phosphine ligand
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- 239000003446 ligand Substances 0.000 title claims abstract description 68
- KUXDQQMEFBFTGX-UHFFFAOYSA-N [N].P Chemical compound [N].P KUXDQQMEFBFTGX-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 150000002576 ketones Chemical class 0.000 title claims abstract description 13
- 238000009903 catalytic hydrogenation reaction Methods 0.000 title claims abstract description 7
- -1 p-toluenesulfonyl Chemical group 0.000 claims abstract description 41
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 7
- 150000003624 transition metals Chemical class 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 claims description 19
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 150000001298 alcohols Chemical class 0.000 claims description 8
- XQJHRCVXRAJIDY-UHFFFAOYSA-N aminophosphine Chemical compound PN XQJHRCVXRAJIDY-UHFFFAOYSA-N 0.000 claims description 7
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- YQMDBOZKFVFKPJ-UHFFFAOYSA-N azaphosphinine Chemical compound C1=CC=PN=C1 YQMDBOZKFVFKPJ-UHFFFAOYSA-N 0.000 claims description 3
- 229940125904 compound 1 Drugs 0.000 claims description 3
- 239000000852 hydrogen donor Substances 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 42
- 239000003054 catalyst Substances 0.000 abstract description 13
- 125000003118 aryl group Chemical group 0.000 abstract description 9
- 239000000758 substrate Substances 0.000 abstract description 8
- 230000003197 catalytic effect Effects 0.000 abstract description 5
- 125000003107 substituted aryl group Chemical group 0.000 abstract description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 abstract description 3
- 239000001301 oxygen Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 66
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 36
- 238000004128 high performance liquid chromatography Methods 0.000 description 34
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical group [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- 239000002904 solvent Substances 0.000 description 22
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- 229910052786 argon Inorganic materials 0.000 description 18
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 18
- 239000000741 silica gel Substances 0.000 description 18
- 229910002027 silica gel Inorganic materials 0.000 description 18
- 238000004440 column chromatography Methods 0.000 description 16
- 239000003480 eluent Substances 0.000 description 16
- 238000000825 ultraviolet detection Methods 0.000 description 15
- 125000001072 heteroaryl group Chemical group 0.000 description 11
- 125000000217 alkyl group Chemical group 0.000 description 8
- 238000004896 high resolution mass spectrometry Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-Phenylethanol Natural products OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 7
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000004679 31P NMR spectroscopy Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- WYECURVXVYPVAT-UHFFFAOYSA-N 1-(4-bromophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Br)C=C1 WYECURVXVYPVAT-UHFFFAOYSA-N 0.000 description 4
- GNKZMNRKLCTJAY-UHFFFAOYSA-N 4'-Methylacetophenone Chemical compound CC(=O)C1=CC=C(C)C=C1 GNKZMNRKLCTJAY-UHFFFAOYSA-N 0.000 description 4
- NTPLXRHDUXRPNE-UHFFFAOYSA-N 4-methoxyacetophenone Chemical compound COC1=CC=C(C(C)=O)C=C1 NTPLXRHDUXRPNE-UHFFFAOYSA-N 0.000 description 4
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 description 3
- 229960001372 aprepitant Drugs 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 150000007942 carboxylates Chemical class 0.000 description 3
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 3
- 229960005061 crizotinib Drugs 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 125000000000 cycloalkoxy group Chemical group 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 125000005366 cycloalkylthio group Chemical group 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229960002866 duloxetine Drugs 0.000 description 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 125000003226 pyrazolyl group Chemical group 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- PIMNFNXBTGPCIL-UHFFFAOYSA-N 1-(2-bromophenyl)ethanone Chemical compound CC(=O)C1=CC=CC=C1Br PIMNFNXBTGPCIL-UHFFFAOYSA-N 0.000 description 2
- DDUBOVLGCYUYFX-UHFFFAOYSA-N 1-(2-chlorophenyl)ethanol Chemical compound CC(O)C1=CC=CC=C1Cl DDUBOVLGCYUYFX-UHFFFAOYSA-N 0.000 description 2
- ZDOYHCIRUPHUHN-UHFFFAOYSA-N 1-(2-chlorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC=C1Cl ZDOYHCIRUPHUHN-UHFFFAOYSA-N 0.000 description 2
- UUWJBXKHMMQDED-UHFFFAOYSA-N 1-(3-chlorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC(Cl)=C1 UUWJBXKHMMQDED-UHFFFAOYSA-N 0.000 description 2
- BAYUSCHCCGXLAY-UHFFFAOYSA-N 1-(3-methoxyphenyl)ethanone Chemical compound COC1=CC=CC(C(C)=O)=C1 BAYUSCHCCGXLAY-UHFFFAOYSA-N 0.000 description 2
- XTDTYSBVMBQIBT-UHFFFAOYSA-N 1-(4-bromophenyl)ethanol Chemical compound CC(O)C1=CC=C(Br)C=C1 XTDTYSBVMBQIBT-UHFFFAOYSA-N 0.000 description 2
- BUZYGTVTZYSBCU-UHFFFAOYSA-N 1-(4-chlorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Cl)C=C1 BUZYGTVTZYSBCU-UHFFFAOYSA-N 0.000 description 2
- PJEUJVLFQCESRL-UHFFFAOYSA-N 1-phenyl-2-thiophen-2-ylethanone Chemical compound C=1C=CC=CC=1C(=O)CC1=CC=CS1 PJEUJVLFQCESRL-UHFFFAOYSA-N 0.000 description 2
- WAPNOHKVXSQRPX-UHFFFAOYSA-N 1-phenylethanol Chemical compound CC(O)C1=CC=CC=C1 WAPNOHKVXSQRPX-UHFFFAOYSA-N 0.000 description 2
- GZXPAZDRDZAMAT-UHFFFAOYSA-N 2-(furan-2-yl)-1-phenylethanone Chemical compound C=1C=CC=CC=1C(=O)CC1=CC=CO1 GZXPAZDRDZAMAT-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropanol Chemical compound CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical group [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 150000002503 iridium Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- SXFYVXSOEBCFLV-UHFFFAOYSA-N 1-(2-fluorophenyl)ethanol Chemical compound CC(O)C1=CC=CC=C1F SXFYVXSOEBCFLV-UHFFFAOYSA-N 0.000 description 1
- QMATYTFXDIWACW-UHFFFAOYSA-N 1-(2-fluorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC=C1F QMATYTFXDIWACW-UHFFFAOYSA-N 0.000 description 1
- QYUQVBHGBPRDKN-UHFFFAOYSA-N 1-(3-chlorophenyl)ethanol Chemical compound CC(O)C1=CC=CC(Cl)=C1 QYUQVBHGBPRDKN-UHFFFAOYSA-N 0.000 description 1
- YESOPGLEIJQAEF-UHFFFAOYSA-N 1-(3-fluorophenyl)ethanol Chemical compound CC(O)C1=CC=CC(F)=C1 YESOPGLEIJQAEF-UHFFFAOYSA-N 0.000 description 1
- HCEKGPAHZCYRBZ-UHFFFAOYSA-N 1-(3-fluorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC(F)=C1 HCEKGPAHZCYRBZ-UHFFFAOYSA-N 0.000 description 1
- JESIHYIJKKUWIS-UHFFFAOYSA-N 1-(4-Methylphenyl)ethanol Chemical compound CC(O)C1=CC=C(C)C=C1 JESIHYIJKKUWIS-UHFFFAOYSA-N 0.000 description 1
- MVOSNPUNXINWAD-UHFFFAOYSA-N 1-(4-chlorophenyl)ethanol Chemical compound CC(O)C1=CC=C(Cl)C=C1 MVOSNPUNXINWAD-UHFFFAOYSA-N 0.000 description 1
- HHAISVSEJFEWBZ-UHFFFAOYSA-N 1-[4-(trifluoromethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC=C(C(F)(F)F)C=C1 HHAISVSEJFEWBZ-UHFFFAOYSA-N 0.000 description 1
- VQENQLFGWQHXKF-UHFFFAOYSA-N 2-naphthalen-2-yl-1-phenylethanone Chemical compound C=1C=C2C=CC=CC2=CC=1CC(=O)C1=CC=CC=C1 VQENQLFGWQHXKF-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- GQENPXQJRUSMDY-UHFFFAOYSA-N [Ir+].ClC1=CCCC=CCC1 Chemical class [Ir+].ClC1=CCCC=CCC1 GQENPXQJRUSMDY-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- ORBBTCHHNMWMCP-UHFFFAOYSA-K cycloocta-1,5-diene trichloroiridium Chemical class [Ir](Cl)(Cl)Cl.C1=CCCC=CCC1 ORBBTCHHNMWMCP-UHFFFAOYSA-K 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N deuterated acetone Substances [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 238000012544 monitoring process 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 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
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F17/00—Metallocenes
- C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic Table
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
- C07C29/145—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones with hydrogen or hydrogen-containing gases
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
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Abstract
本发明属于有机及药物合成化学领域,公开了三齿氮膦配体,具有通式Ⅰ的结构:其中,R1为对甲苯磺酰基或2,4,6‑三异丙基苯磺酰基,R2为芳基或取代芳基。本发明还公开了三齿氮膦配体的配合物,由三齿氮膦配体和过渡金属络合物混合反应制备得到。配合物可以用于酮的不对称催化氢化。本发明的优势主要体现在以下几点:1、合成容易,手性配体只需要2~3步反应即可制得;2、配体稳定,该系列配体对水和氧气均不敏感,方便保存和使用;3、催化效果好,该体系催化剂对绝大多数适用底物均实现100%的转化和99%的立体选择性;4、原子经济性高,该催化体系活性极高,对绝大多数适用底物均能取得10000以上的转化数,最高转化数可达200000。
Description
技术领域
本发明属于有机及药物合成化学领域,具体涉及三齿氮膦配体与其配合物、及其在酮的不对称催化氢化中的应用。
背景技术
手性醇是一种广泛存在于药物分子和天然产物之中的重要片段,如Ezetimine、Duloxetine、Aprepitant、Crizotinib等。
由于手性醇在制药等领域具有巨大的工业价值,人们对合成手性醇的方法学进行了深入的研究。最终,不对称氢化反应被证明是最为直接有效合成手性醇的方法。在过去的数十年,利用钯、铑、钌等金属与手性膦配体络合所得的催化剂对酮进行不对称氢化反应,从而得到手性醇的技术得到了巨大的发展,多种手性膦配体被研发出来。但是,高效不对称氢化酮类化合物得到手性醇仍然有待改进。
发明内容
本发明的目的是发展一类新型的三齿氮膦配体,并将三齿氮膦配体制备成催化剂,用于酮的不对称催化氢化反应。
为达到上述目的,本发明采用以下技术方案:
三齿氮膦配体,具有通式Ⅰ的结构:
其中,R1为对甲苯磺酰基或2,4,6-三异丙基苯磺酰基,R2为芳基或取代芳基。
进一步地,三齿氮膦配体具有通式Ⅱ的结构:
其中,R1为对甲苯磺酰基或2,4,6-三异丙基苯磺酰基,R2为苯基或取代苯基;当n为1、2或3时,R3、R4各自独立地选自氢和烷基;当n为0时,R3、R4各自独立地选自氢、苯基、取代苯基,或者R3、R4=-(CH2)4-。
进一步地,三齿氮膦配体具有以下结构之一:
其中,R1为对甲苯磺酰基或2,4,6-三异丙基苯磺酰基,m为2、3、4或5,R2为苯基或3,5-二叔丁基苯基。
进一步地,三齿氮膦配体具有以下结构之一:
三齿氮膦配体的制备方法按照以下合成路线:
S1、化合物1与tBuLi、PCl3、R2MgBr反应得到化合物2;
S2、化合物2与醋酸酐反应得到化合物3;
将三齿氮膦配体和过渡金属络合物混合反应制备得到配合物(催化剂),在优选方案中,过渡金属络合物为[Ir(COD)Cl]2,中文全称为1,5-环辛二烯氯化铱二聚体,英文全称为Chloro(1,5-cyclooctadiene)iridium(I)dimer;在另一个优选方案中,三齿氮膦配体和过渡金属络合物的摩尔比为0.5:1~2,更优选0.5:1.05;在另一个优选方案中,反应以iPrOH为溶剂;在另一个优选方案中,反应温度为室温;在另一个优选方案中,反应时间为0.5~3h。
三齿氮膦配体的配合物应用于酮的不对称催化氢化:
在氢气氛围下,在iPrOH中,由手性三齿氮膦配体f-amphamide与金属铱盐[Ir(COD)Cl]2络合得到配合物(催化剂),加入酮化合物,进行不对称氢化反应,其反应通式如下
Ar可以为芳基、取代芳基、杂芳基、取代杂芳基,芳基优选苯基、萘基,杂芳基优选噻吩、呋喃,R可以为烷基,优选甲基、乙基;其中具有代表性的潜手性底物包括Ezetimine、Duloxetine、Aprepitant、Crizotinib。
一种手性醇的制备方法,在上述的三齿氮膦配体的配合物的存在下,用氢供体在碱性条件下对酮类进行加氢还原。反应包括第一步骤和第二步骤:第一步骤中,由手性配体与金属铱盐[Ir(COD)Cl]2在iPrOH溶剂中进行反应而得到配合物(催化剂);第二步骤中,在氢气氛围下,在铱/f-amphamide催化剂的存在下,加入酮类化合物和碱,酮类化合物发生不对称氢化反应,反应温度为20~30℃,碱与酮类化合物的摩尔比例为1:100,氢气压力为20~40大气压,反应时间12~48小时,酮类化合物与催化剂的摩尔比为5000~200000∶1。在第一步骤中得到的催化剂不需要单独分离,第一步骤和第二步骤连续地进行。
除非有相反陈述,在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团,其为包含1至20个碳原子的直链或支链基团,优选含有1至12个碳原子的烷基,更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,优选为6至10元,例如苯基和萘基。
取代芳基指至少有一个取代基的芳基,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
取代苯基指至少有一个取代基的苯基,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系,其中杂原子选自氧、硫和氮。杂芳基优选为5至10元,含1至3个杂原子;更优选为5元或6元,含1至2个杂原子;优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等,优选为咪唑基、吡唑基或嘧啶基、噻唑基;更有选吡唑基。
取代杂芳基指至少有一个取代基的杂芳基,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
本发明设计了新型三齿氮膦配体f-amphamide,其为C1对称的面手性二茂铁骨架配体,可以通过高效简单的方法合成,并通过使用这种新型三齿氮膦配体f-amphamide对具有潜手性的酮进行不对称氢化反应,制备一系列的手性醇,反应具有高对映选择性、高收率、高转化数(TON)的特点,绝大多数底物在催化剂用量0.01mol%(S/C=10000)的情况下可取得99%以上的转化率和99%以上的ee值,催化剂最低用量为为0.005mol%(S/C=200000),最高转化数达到200000,可以用于如Ezetimine、Duloxetine、Aprepitant、Crizotinib等一系列重要药物的合成,在医药工业生产具有重要的应用价值。
本发明通过以二茂铁为骨架的C1对称面手性配体f-amphamide系列实现了酮类化合物的不对称氢化。本发明的优势主要体现在以下几点:1、合成容易,手性配体f-amphamide只需要2~3步反应即可制得;2、配体稳定,该系列配体对水和氧气均不敏感,方便保存和使用;3、催化效果好,该体系催化剂对绝大多数适用底物均实现100%的转化和99%的立体选择性;4、原子经济性高,该催化体系活性极高,对绝大多数适用底物均能取得10000以上的转化数,最高转化数可达200000。
本发明操作简单、成本低廉、转化率和立体选择性都极高,具有原子经济性高,环境友好等特点,本发明所采用的催化体系具有广阔的工业化前景。
具体实施方式
下面结合具体实施例对本发明做进一步的说明。
除非另有说明,化学品均购自商业化产品并且不用经进一步纯化。薄层色谱分析(TLC)使用60F254硅胶板。硅胶柱层析使用青岛海洋硅胶(粒径0.040-0.063mm)。TLC显色采用UV光(254nm)。1H NMR和13C NMR使用Bruker 400MHz或者500MHz核磁共振仪表征,溶剂为氘代氯仿、氘代丙酮或氘代DMSO,以四甲基硅烷(TMS)为内标。化学位移的单位是ppm,耦合常数的单位是Hz。在1H NMR中,δ表示化学位移,s表示单峰,d表示双峰,t表示三重峰,q表示四重峰,p表示五重峰,m表示多重峰,br表示宽峰。在13C NMR中,δ表示化学位移。高分辨质谱(HRMS)使用Q-Exactive(Thermo Scientific)Inc质谱设备。在以下实施例中,mol%表示的是该物质相对于酮类化合物的摩尔百分比。
实施例1
三齿氮膦配体的合成
0℃、N2下,搅拌下将7mL tBuLi的正己烷溶液(1.6mol/L,11.2mmol)滴加入化合物1(2.57,g,10mmol)的无水乙醚(20mL)溶液中,滴加完毕后自然升至室温搅拌2h。随后降温到-78℃,慢慢滴加入重蒸的PCl3(11.46mmol,1mL),混合物升温到室温,反应过夜。随后再次降温到-78℃,用恒压漏斗慢慢滴加R2MgBr溶液(由30mmol R2Br和0.8g、33.3mmol镁屑在四氢呋喃中制备得到)。滴加完之后,慢慢升温反应过夜,随后加入20mL饱和NH4Cl溶液。油相有乙醚萃取三次,每次20mL乙醚。油相用无水硫酸钠干燥后,旋干,硅胶住层析,得到目标产物化合物2。
接着,氩气保护下,将化合物2(1mmol)和醋酸酐(1.5mL)的混合物在100℃加热约1~2h。TLC监测,待反应完毕后减压旋干醋酐得桔红色固体化合物3,用少量的iPrOH或者EtOH重结晶纯化,用于下一步反应。
黄色固体,72%产率。1H NMR(400MHz,Chloroform-d)δ7.65(d,J=8.3Hz,2H),7.57–7.51(m,2H),7.41–7.37(m,3H),7.29(d,J=7.8Hz,2H),7.26–7.14(m,5H),4.42(d,J=2.3Hz,1H),4.30(t,J=2.6Hz,1H),4.02(s,5H),4.02–4.00(m,1H),3.85–3.72(m,1H),2.45(s,3H),2.45–2.42(m,2H),2.29(t,J=5.4Hz,2H),1.34(d,J=6.6Hz,3H)。13C NMR(101MHz,CDCl3)δ143.07,139.95(d,J=9.9Hz),137.27,136.80(d,J=8.4Hz),134.97,134.77,132.90,132.71,129.87,129.60,129.23,128.56,128.45,128.39,128.28,128.21,127.20,97.04(d,J=23.1Hz),75.34(d,J=6.6Hz),71.53(d,J=4.4Hz),69.80,69.27,69.23,69.04,50.91(d,J=8.8Hz),44.55,42.83,21.61,19.18。31P NMR(162MHz,CDCl3)δ-24.97(s)。HRMS(ESI)calcd for C33H36FeN2O2PS[M+H]+:611.1579;Found:611.1577。
黄色固体,41%产率。1H NMR(400MHz,Chloroform-d)δ7.72(d,J=8.3Hz,2H),7.52–7.48(m,2H),7.44–7.36(m,3H),7.28(d,J=3.2Hz,2H),7.22–7.15(m,1H),7.12–7.02(m,4H),4.52(s,1H),4.37(t,J=2.6Hz,1H),4.08(s,5H),4.04–4.01(m,1H),3.71(d,J=1.3Hz,1H),2.45(s,3H),2.14–2.09(m,2H),1.97–1.89(m,1H),1.85–1.84(m,1H),1.53–1.43(m,2H),1.36(d,J=6.2Hz,3H),1.08–1.03(m,2H),0.94–0.76(m,2H)。13C NMR(101MHz,CDCl3)δ142.88,140.03(d,J=10.6Hz),137.45,136.80(d,J=9.5Hz),135.20,134.99,132.98,132.79,129.50,129.28,128.48,128.45,128.41,128.34,128.26,127.63,98.16,74.48,71.26(d,J=4.0Hz),70.55,69.82,69.67,69.35,57.92,57.07,46.56,32.25,29.98,24.93,24.10,21.68,20.19。31P NMR(162MHz,CDCl3)δ-24.61(s)。HRMS(ESI)calcdfor C37H42FeN2O2PS[M+H]+:665.2049;Found:665.2037。
黄色固体,60%产率。1H NMR(400MHz,Chloroform-d)δ7.43–7.41(m,2H),7.35–7.24(m,8H),7.22–7.16(m,2H),7.05–6.95(m,3H),6.91–6.90(m,3H),6.84(t,J=7.4Hz,2H),6.73–6.66(m,2H),6.62–6.55(m,2H),4.30–4.25(m,1H),4.21(t,J=2.6Hz,1H),3.93(d,J=7.5Hz,1H),3.86(s,5H),3.65–3.57(m,2H),3.55–3.51(m,1H),2.25(s,3H),1.07(d,J=6.4Hz,3H)。13C NMR(101MHz,CDCl3)δ142.45,140.73(d,J=11.0Hz),138.76,137.78(d,J=9.2Hz),135.52,135.31,132.85,132.67,129.18,129.01,128.65,128.58,128.55,128.34,128.21,128.13,127.79,127.76,127.74,127.68,127.45,127.33,127.10,98.77,74.35(d,J=9.5Hz),71.57(d,J=4.0Hz),69.90,69.64,69.53,64.87,63.39,47.75,29.83,21.55,19.83,1.16。31P NMR(162MHz,CDCl3)δ-23.52(s)。HRMS(ESI)calcd forC45H44FeN2O2PS[M+H]+:763.2205;Found:763.2188。
黄色固体,64%产率。1H NMR(400MHz,Chloroform-d)δ7.70(d,J=8.2Hz,2H),7.59–7.51(m,2H),7.44–7.36(m,3H),7.31–7.27(m,7H),4.45(s,1H),4.33–4.31(m,1H),4.06(s,5H),3.99–3.93(m,1H),3.79(s,1H),2.80–2.74(m,1H),2.71–2.65(m,1H),2.45(s,3H),2.26–2.16(m,2H),1.40(d,J=6.6Hz,3H),0.97–0.83(m,2H)。13C NMR(101MHz,CDCl3)δ143.00,139.75,137.40,134.95,134.75,133.09,132.89,129.63,129.25,128.77,128.65,128.59,128.34,128.26,127.18,97.07,75.37,71.42,69.84,69.50,69.15,51.68,51.58,45.34,43.24,28.21,21.63,19.41。31P NMR(162MHz,CDCl3)δ-25.40(s)。HRMS(ESI)calcdfor C34H38FeN2O2PS[M+H]+:625.1736;Found:625.1734。
黄色固体,47%产率。1H NMR(400MHz,Chloroform-d)δ7.56–7.49(m,2H),7.42–7.36(m,3H),7.26–7.22(m,2H),7.17(s,2H),7.14–7.06(m,3H),4.87(s,1H),4.41(s,1H),4.29(t,J=2.5Hz,1H),4.10–4.01(m,2H),4.06(s,5H),3.77–3.76(m,1H),2.99–2.89(m,1H),2.42(d,J=5.6Hz,1H),2.31(t,J=5.4Hz,2H),2.24(t,J=7.6Hz,1H),1.39(d,J=6.5Hz,3H),1.30(d,J=7.0Hz,6H),1.23(t,J=6.8Hz,12H)。13C NMR(101MHz,CDCl3)δ152.44,150.39,134.85,134.65,133.07,132.88,129.21,128.75,128.50,128.44,128.32,128.25,123.77,100.12,75.49(d,J=6.5Hz),71.36(d,J=4.2Hz),69.85,69.33(d,J=3.7Hz),68.97,50.89,50.80,44.43,42.45,34.30,29.62,25.06(d,J=2.6Hz),23.78(d,J=2.9Hz),19.22。31P NMR(162MHz,CDCl3)δ-25.33(s)。HRMS(ESI)calcd for C41H52FeN2O2PS[M+H]+:723.2831;Found:723.2816。
黄色固体,54%产率。1H NMR(400MHz,Chloroform-d)δ7.64(d,J=8.3Hz,2H),7.47–7.38(m,3H),7.28–7.26(m,3H),7.24–7.18(m,2H),4.36(s,1H),4.26(t,J=2.7Hz,1H),4.06(s,5H),3.99–3.92(m,1H),3.70(s,1H),2.43(s,3H),2.41–2.35(m,1H),2.12–2.05(m,3H),1.31(s,18H),1.29(d,J=6.5Hz,3H),1.18(s,18H)。13C NMR(101MHz,CDCl3)δ150.77(d,J=7.3Hz),150.38(d,J=7.3Hz),143.08,138.21,137.57,134.98(d,J=7.0Hz),129.67,129.11,128.90,127.99,127.78,127.15,123.12,122.77,96.16(d,J=23.0Hz),77.37,71.19(d,J=4.1Hz),69.77,69.12(d,J=3.4Hz),68.63,51.10,51.01,44.89,42.80,35.07,34.93,31.62,31.49,21.63,19.26。31P NMR(162MHz,CDCl3)δ-24.42(s)。HRMS(ESI)calcd for C49H68FeN2O2PS[M+H]+:835.4083;Found:835.4067。
实施例2
从苯乙酮制备1-苯乙醇(S/C=10 000)
在高纯氩气氛围下,将[Ir(COD)Cl]2(3.4mg,0.005mmol)和手性配体L6(9.2mg,0.011mmol)溶于异丙醇(1mL)中,在室温条件下搅拌3小时,得到橙色澄清溶液。以微量注射器取该橙色溶液20μL(0.001mol%),加入到苯乙酮(2mmol)、异丙醇(2mL)和叔丁醇锂(1mol%)的混合体系中。将反应体系置于高压釜中,在室温和H2(20atm)条件下搅拌12小时。减压除去溶剂,柱层析分离(采取硅胶柱,洗脱剂:乙酸乙酯),得纯品1-苯乙醇,产物经HPLC分析,测得ee值为98%。通过HPLC、Chiralcel OD-H柱测定对映体过量,正己烷:异丙醇=95:5;流速=1.0mL/min;UV检测在210nm;tR(R)=7.53min(minor),tR(S)=8.56min(major)。
实施例3
从苯丙酮制备1-苯丙醇(S/C=10 000)
在高纯氩气氛围下,将[Ir(COD)Cl]2(3.4mg,0.005mmol)和手性配体L6(9.2mg,0.011mmol)溶于异丙醇(1mL)中,在室温条件下搅拌3小时,得到橙色澄清溶液。以微量注射器取该橙色溶液20μL(0.001mol%),加入到苯丙酮(2mmol)、异丙醇(2mL)和叔丁醇锂(1mol%)的混合体系中。将反应体系置于高压釜中,在室温和H2(20atm)条件下搅拌12小时。减压除去溶剂,柱层析分离(采取硅胶柱,洗脱剂:乙酸乙酯),得纯品1-苯丙醇,产物经HPLC分析,测得ee值为99%。通过HPLC、Chiralcel OJ-H柱测定对映体过量,正己烷:异丙醇=95:5;流速=1.0mL/min;UV检测在210nm;tR(S)=8.68min(major),tR(R)=9.30min(minor)。
实施例4
从对甲基苯乙酮制备1-对甲基苯乙醇(S/C=10000)
在高纯氩气氛围下,将[Ir(COD)Cl]2(3.4mg,0.005mmol)和手性配体L6(9.2mg,0.011mmol)溶于异丙醇(1mL)中,在室温条件下搅拌3小时,得到橙色澄清溶液。以微量注射器取该橙色溶液20μL(0.001mol%),加入到对甲基苯乙酮(2mmol)、异丙醇(2mL)和叔丁醇锂(1mol%)的混合体系中。将反应体系置于高压釜中,在室温和H2(20atm)条件下搅拌12小时。减压除去溶剂,柱层析分离(采取硅胶柱,洗脱剂:乙酸乙酯),得纯品1-对甲基苯乙醇,产物经HPLC分析,测得ee值为99%。通过HPLC、Chiralcel OJ-H柱测定对映体过量,正己烷:异丙醇=95:5;流速=1.0mL/min;UV检测在210nm;tR(S)=10.61min(major),tR(R)=11.94min(minor)。
实施例5
从对甲氧基苯乙酮制备1-对甲氧基苯乙醇(S/C=10000)
在高纯氩气氛围下,将[Ir(COD)Cl]2(3.4mg,0.005mmol)和手性配体L6(9.2mg,0.011mmol)溶于异丙醇(1mL)中,在室温条件下搅拌3小时,得到橙色澄清溶液。以微量注射器取该橙色溶液20μL(0.001mol%),加入到对甲氧基苯乙酮(2mmol)、异丙醇(2mL)和叔丁醇锂(1mol%)的混合体系中。将反应体系置于高压釜中,在室温和H2(20atm)条件下搅拌12小时。减压除去溶剂,柱层析分离(采取硅胶柱,洗脱剂:乙酸乙酯),得纯品1-对甲氧基苯乙醇,产物经HPLC分析,测得ee值为97%。通过HPLC、Chiralcel OJ-H柱测定对映体过量,正己烷:异丙醇=95:5;流速=1.0mL/min;UV检测在230nm;tR(S)=18.06min(major),tR(R)=19.27min(minor)。
实施例6
从间甲氧基苯乙酮制备1-间甲氧基苯乙醇(S/C=10 000)
在高纯氩气氛围下,将[Ir(COD)Cl]2(3.4mg,0.005mmol)和手性配体L6(9.2mg,0.011mmol)溶于异丙醇(1mL)中,在室温条件下搅拌3小时,得到橙色澄清溶液。以微量注射器取该橙色溶液20μL(0.001mol%),加入到间甲氧基苯乙酮(2mmol)、异丙醇(2mL)和叔丁醇锂(1mol%)的混合体系中。将反应体系置于高压釜中,在室温和H2(20atm)条件下搅拌12小时。减压除去溶剂,柱层析分离(采取硅胶柱,洗脱剂:乙酸乙酯),得纯品1-间甲氧基苯乙醇,产物经HPLC分析,测得ee值为99%。通过HPLC、Chiralcel OJ-H柱测定对映体过量,正己烷:异丙醇=95:5;流速=1.0mL/min;UV检测在210nm;tR(S)=14.13min(major),tR(R)=15.86min(minor)。
实施例7
从邻氟苯乙酮制备1-邻氟苯乙醇(S/C=10000)
在高纯氩气氛围下,将[Ir(COD)Cl]2(3.4mg,0.005mmol)和手性配体L6(9.2mg,0.011mmol)溶于异丙醇(1mL)中,在室温条件下搅拌3小时,得到橙色澄清溶液。以微量注射器取该橙色溶液20μL(0.001mol%),加入到邻氟苯乙酮(2mmol)、异丙醇(2mL)和叔丁醇锂(1mol%)的混合体系中。将反应体系置于高压釜中,在室温和H2(20atm)条件下搅拌12小时。减压除去溶剂,柱层析分离(采取硅胶柱,洗脱剂:乙酸乙酯),得纯品1-邻氟苯乙醇,产物经HPLC分析,测得ee值为99%。通过HPLC、Chiralcel OJ-H柱测定对映体过量,正己烷:异丙醇=95:5;流速=1.0mL/min;UV检测在210nm;tR(S)=6.97min(major),tR(R)=7.72min(minor)。
实施例8
从间氟苯乙酮制备1-间氟苯乙醇(S/C=10000)
在高纯氩气氛围下,将[Ir(COD)Cl]2(3.4mg,0.005mmol)和手性配体L6(9.2mg,0.011mmol)溶于异丙醇(1mL)中,在室温条件下搅拌3小时,得到橙色澄清溶液。以微量注射器取该橙色溶液20μL(0.001mol%),加入到间氟苯乙酮(2mmol)、异丙醇(2mL)和叔丁醇锂(1mol%)的混合体系中。将反应体系置于高压釜中,在室温和H2(20atm)条件下搅拌12小时。减压除去溶剂,柱层析分离(采取硅胶柱,洗脱剂:乙酸乙酯),得纯品1-间氟苯乙醇,产物经HPLC分析,测得ee值为99%。通过HPLC、Chiralcel OD-H柱测定对映体过量,正己烷:异丙醇=95:5;流速=1.0mL/min;UV检测在210nm;tR(S)=6.94min(major),tR(R)=14.2min(minor)。
实施例9
从邻氯苯乙酮制备1-邻氯苯乙醇(S/C=10000)
在高纯氩气氛围下,将[Ir(COD)Cl]2(3.4mg,0.005mmol)和手性配体L6(9.2mg,0.011mmol)溶于异丙醇(1mL)中,在室温条件下搅拌3小时,得到橙色澄清溶液。以微量注射器取该橙色溶液20μL(0.001mol%),加入到邻氯苯乙酮(2mmol)、异丙醇(2mL)和叔丁醇锂(1mol%)的混合体系中。将反应体系置于高压釜中,在室温和H2(20atm)条件下搅拌12小时。减压除去溶剂,柱层析分离(采取硅胶柱,洗脱剂:乙酸乙酯),得纯品1-邻氯苯乙醇,产物经HPLC分析,测得ee值为99%。通过HPLC、Chiralcel OJ-H柱测定对映体过量,正己烷:异丙醇=95:5;流速=1.0mL/min;UV检测在210nm;tR(S)=7.59min(major),tR(R)=8.05min(minor)。
实施例10
从间氯苯乙酮制备1-间氯苯乙醇(S/C=10000)
在高纯氩气氛围下,将[Ir(COD)Cl]2(3.4mg,0.005mmol)和手性配体L6(9.2mg,0.011mmol)溶于异丙醇(1mL)中,在室温条件下搅拌3小时,得到橙色澄清溶液。以微量注射器取该橙色溶液20μL(0.001mol%),加入到间氯苯乙酮(2mmol)、异丙醇(2mL)和叔丁醇锂(1mol%)的混合体系中。将反应体系置于高压釜中,在室温和H2(20atm)条件下搅拌12小时。减压除去溶剂,柱层析分离(采取硅胶柱,洗脱剂:乙酸乙酯),得纯品1-间氯苯乙醇,产物经HPLC分析,测得ee值为96%。通过HPLC、Chiralcel OJ-H柱测定对映体过量,正己烷:异丙醇=95:5;流速=1.0mL/min;UV检测在210nm;tR(S)=8.99min(major),tR(R)=10.17min(minor)。
实施例11
从对氯苯乙酮制备1-对氯苯乙醇(S/C=10000)
在高纯氩气氛围下,将[Ir(COD)Cl]2(3.4mg,0.005mmol)和手性配体L6(9.2mg,0.011mmol)溶于异丙醇(1mL)中,在室温条件下搅拌3小时,得到橙色澄清溶液。以微量注射器取该橙色溶液20μL(0.001mol%),加入到对氯苯乙酮(2mmol)、异丙醇(2mL)和叔丁醇锂(1mol%)的混合体系中。将反应体系置于高压釜中,在室温和H2(20atm)条件下搅拌12小时。减压除去溶剂,柱层析分离(采取硅胶柱,洗脱剂:乙酸乙酯),得纯品1-对氯苯乙醇,产物经HPLC分析,测得ee值为97%。通过HPLC、Chiralcel OJ-H柱测定对映体过量,正己烷:异丙醇=95:5;流速=1.0mL/min;UV检测在210nm;tR(S)=8.99min(major),tR(R)=9.50min(minor)。
实施例12
从邻溴苯乙酮制备1-邻溴苯乙醇(S/C=10000)
在高纯氩气氛围下,将[Ir(COD)Cl]2(3.4mg,0.005mmol)和手性配体L6(9.2mg,0.011mmol)溶于异丙醇(1mL)中,在室温条件下搅拌3小时,得到橙色澄清溶液。以微量注射器取该橙色溶液20μL(0.001mol%),加入到邻溴苯乙酮(2mmol)、异丙醇(2mL)和叔丁醇锂(1mol%)的混合体系中。将反应体系置于高压釜中,在室温和H2(20atm)条件下搅拌12小时。减压除去溶剂,柱层析分离(采取硅胶柱,洗脱剂:乙酸乙酯),得纯品1-邻溴苯乙醇,产物经HPLC分析,测得ee值为96%。通过HPLC、Chiralcel OJ-H柱测定对映体过量,正己烷:异丙醇=95:5;流速=1.0mL/min;UV检测在210nm;tR(S)=7.72min(major),tR(R)=8.19min(minor)。
实施例13
从对溴苯乙酮制备1-对溴苯乙醇(S/C=10000)
在高纯氩气氛围下,将[Ir(COD)Cl]2(3.4mg,0.005mmol)和手性配体L6(9.2mg,0.011mmol)溶于异丙醇(1mL)中,在室温条件下搅拌3小时,得到橙色澄清溶液。以微量注射器取该橙色溶液20μL(0.001mol%),加入到对溴苯乙酮(2mmol)、异丙醇(2mL)和叔丁醇锂(1mol%)的混合体系中。将反应体系置于高压釜中,在室温和H2(20atm)条件下搅拌12小时。减压除去溶剂,柱层析分离(采取硅胶柱,洗脱剂:乙酸乙酯),得纯品1-对溴苯乙醇,产物经HPLC分析,测得ee值为96%。通过HPLC、Chiralcel OD-H柱测定对映体过量,正己烷:异丙醇=95:5;流速=1.0mL/min;UV检测在230nm;tR(S)=7.45min(major),tR(R)=8.04min(minor)。
实施例14
从对三氟甲基苯乙酮制备1-对三氟甲基苯乙醇(S/C=10000)
在高纯氩气氛围下,将[Ir(COD)Cl]2(3.4mg,0.005mmol)和手性配体L6(9.2mg,0.011mmol)溶于异丙醇(1mL)中,在室温条件下搅拌3小时,得到橙色澄清溶液。以微量注射器取该橙色溶液20μL(0.001mol%),加入到对溴苯乙酮(2mmol)、异丙醇(2mL)和叔丁醇锂(1mol%)的混合体系中。将反应体系置于高压釜中,在室温和H2(20atm)条件下搅拌12小时。减压除去溶剂,柱层析分离(采取硅胶柱,洗脱剂:乙酸乙酯),得纯品1-对三氟甲基苯乙醇,产物经HPLC分析,测得ee值为97%。通过HPLC、Chiralcel OJ-H柱测定对映体过量,正己烷:异丙醇=95:5;流速=1.0mL/min;UV检测在230nm;tR(S)=6.65min(major),tR(R)=7.14min(minor)。
实施例15
从2-萘基苯乙酮制备1-(2-萘基)苯乙醇(S/C=10 000)
在高纯氩气氛围下,将[Ir(COD)Cl]2(3.4mg,0.005mmol)和手性配体L6(9.2mg,0.011mmol)溶于异丙醇(1mL)中,在室温条件下搅拌3小时,得到橙色澄清溶液。以微量注射器取该橙色溶液20μL(0.001mol%),加入到对溴苯乙酮(2mmol)、异丙醇(2mL)和叔丁醇锂(1mol%)的混合体系中。将反应体系置于高压釜中,在室温和H2(20atm)条件下搅拌12小时。减压除去溶剂,柱层析分离(采取硅胶柱,洗脱剂:乙酸乙酯),得纯品1-(2-萘基)苯乙醇,产物经HPLC分析,测得ee值>99%。通过HPLC、Chiralcel OJ-H柱测定对映体过量,正己烷:异丙醇=95:5;流速=1.0mL/min;UV检测在210nm;tR(S)=27.72min(major),tR(R)=36.55min(minor)。
实施例16
从2-噻吩基苯乙酮制备1-(2-噻吩基)苯乙醇(S/C=10000)
在高纯氩气氛围下,将[Ir(COD)Cl]2(3.4mg,0.005mmol)和手性配体L6(9.2mg,0.011mmol)溶于异丙醇(1mL)中,在室温条件下搅拌3小时,得到橙色澄清溶液。以微量注射器取该橙色溶液20μL(0.001mol%),加入到2-噻吩基苯乙酮(2mmol)、异丙醇(2mL)和叔丁醇锂(1mol%)的混合体系中。将反应体系置于高压釜中,在室温和H2(20atm)条件下搅拌12小时。减压除去溶剂,柱层析分离(采取硅胶柱,洗脱剂:乙酸乙酯),得纯品1-(2-噻吩基)苯乙醇,产物经HPLC分析,测得ee值为96%。通过HPLC、Chiralcel OJ-H柱测定对映体过量,正己烷:异丙醇=95:5;流速=1.0mL/min;UV检测在250nm;tR(S)=9.99min(major),tR(R)=12.21min(minor)。
实施例17
从2-呋喃基苯乙酮制备1-(2-呋喃基)苯乙醇(S/C=10000)
在高纯氩气氛围下,将[Ir(COD)Cl]2(3.4mg,0.005mmol)和手性配体L6(9.2mg,0.011mmol)溶于异丙醇(1mL)中,在室温条件下搅拌3小时,得到橙色澄清溶液。以微量注射器取该橙色溶液20μL(0.001mol%),加入到2-呋喃基苯乙酮(2mmol)、异丙醇(2mL)和叔丁醇锂(1mol%)的混合体系中。将反应体系置于高压釜中,在室温和H2(20atm)条件下搅拌12小时。减压除去溶剂,柱层析分离(采取硅胶柱,洗脱剂:乙酸乙酯),得纯品1-(2-呋喃基)苯乙醇,产物经HPLC分析,测得ee值为92%。通过HPLC、Chiralcel OJ-H柱测定对映体过量,正己烷:异丙醇=95:5;流速=1.0mL/min;UV检测在210nm;tR(S)=8.62min(major),tR(R)=9.51min(minor)。
实施例18
溶剂的适应性
反应条件:2.0mmol底物,S/C=5000,0.010mol%[Ir(COD)Cl]2,0.021mol%配体,1mol%tBuOLi,2.0mL溶剂,室温(25-30℃);b:通过1H NMR光谱测定;c:由HPLC分析确定。
还原反应可以再多种溶剂中进行。
实施例19
三齿氮膦配体的适应性
反应条件:2.0mmol底物,S/C=5000,0.010mol%[Ir(COD)Cl]2,0.021mol%配体,1mol%tBuOLi,2.0mL iPrOH,室温(25-30℃);b:通过1H NMR光谱测定;c:由HPLC分析确定;d:S/C=10000。
实施例1的配体L1~L6均能高效催化酮的氢化还原反应。
以上所述,仅为本发明的具体实施方式,但本发明的保护范围并不局限于此,任何属于本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到的变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应该以权利要求的保护范围为准。
Claims (8)
4.三齿氮膦配体的配合物,其特征在于,所述的配合物由权利要求1或2所述的三齿氮膦配体和过渡金属络合物混合反应制备得到。
5.根据权利要求4所述的三齿氮膦配体的配合物,其特征在于,所述过渡金属络合物为[Ir(COD)Cl]2。
6.根据权利要求4或5所述的三齿氮膦配体的配合物,其特征在于,所述三齿氮膦配体和过渡金属络合物的摩尔比为0.5:1~2。
7.权利要求4或5所述的三齿氮膦配体的配合物在酮的不对称催化氢化中的应用。
8.一种手性醇的制备方法,其特征在于,在权利要求4或5所述的三齿氮膦配体的配合物的存在下,用氢供体在碱性条件下对酮类化合物进行加氢还原。
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